11 - PART 4 Oncology and Hematology

01 - SECTION 1 Neoplastic Disorders
SECTION 1 Neoplastic Disorders
Section 1	 Neoplastic Disorders
Dan L. Longo
Approach to the Patient
with Cancer
The application of current treatment techniques (surgery, radiation
therapy, chemotherapy, and biologic therapy) results in the cure of
nearly two of three patients diagnosed with cancer. Nevertheless,
patients experience the diagnosis of cancer as one of the most trau­
matic and revolutionary events that has ever happened to them. Inde­
pendent of prognosis, the diagnosis brings with it a change in a person’s
self-image and in their role in the home and workplace. The prognosis
of a person who has just been found to have pancreatic cancer is the
same as the prognosis of the person with aortic stenosis who develops
the first symptoms of congestive heart failure (median survival,
~8 months). However, the patient with heart disease may remain
functional and maintain a self-image as a fully intact person with just
a malfunctioning part, a diseased organ (“a bum ticker”). By contrast,
the patient with pancreatic cancer has a completely altered self-image
and is viewed differently by family and anyone who knows the
diagnosis. The patient is being attacked and invaded by a disease
that could be anywhere in the body. Every ache or pain takes on
TABLE 73-1  Distribution of Cancer Incidence and Deaths for 2021
MALE
FEMALE
SITES
%
NUMBER
SITES
%
NUMBER
Cancer Incidence
Prostate
299,010
Breast
310,720
Lung
116,310
Lung
118,270
Colorectal
81,540
Colorectal
71,270
Bladder
63,070
Endometrial
67,880
Melanoma
59,170
Melanoma
41,470
Kidney
52,380
Lymphoma
36,030
Lymphoma
44,590
Pancreas
31,910
Oral cavity
41,510
Thyroid
31,520
Leukemia
36,450
Kidney
29,230
Pancreas
34,530
Leukemia
26,320
All others
200,520
All others
207,440
All sites
1,029,080
All sites
972,060
Cancer Deaths
Lung
65,790
Lung
59,280
Prostate
35,250
Breast
42,250
Colorectal
28,700
Pancreas
24,480
Pancreas
25,270
Colorectal
24,310
Liver
19,120
Endometrial
13.250
Leukemia
13,640
Ovary
12,740
Esophagus
12,880
Liver
10,720
Bladder
12,290
Leukemia
10,030
Lymphoma
11,780
Lymphoma
8,360
CNS
10,690
CNS
8,070
All others
87,390
All others
75,4330
All sites
322,800
All sites
288,920
Source: From RL Siegel et al: Cancer statistics, 2024. CA Cancer J Clin 74:12, 2024. Reproduced John Wiley & Sons Ltd.
Oncology and Hematology
PART 4
desperate significance. Cancer is an exception to the coordinated
interaction among cells and organs. In general, the cells of a multicel­
lular organism are programmed for collaboration. Many diseases occur
because the specialized cells fail to perform their assigned task. Cancer
takes this malfunction one step further. Not only is there a failure of the
cancer cell to maintain its specialized function, but it also strikes out
on its own; the cancer cell competes to survive using natural mutability
and natural selection to seek advantage over normal cells in a reca­
pitulation of evolution. One consequence of the traitorous behavior of
cancer cells is that the patient feels betrayed by their body. The cancer
patient feels that they, and not just a body part, are diseased.
THE MAGNITUDE OF THE PROBLEM
No nationwide cancer registry exists; therefore, the incidence of cancer
is estimated on the basis of the National Cancer Institute’s Surveillance,
Epidemiology, and End Results (SEER) database, which tabulates
cancer incidence and death figures from 13 sites, accounting for about
10% of the U.S. population, and from population data from the U.S.
Census Bureau. In 2024, 2.001 million new cases of invasive cancer
(1,029,080 men and 927,060 women) were diagnosed, and 611,720 per­
sons (322,800 men and 288,920 women) died from cancer. The percent
distribution of new cancer cases and cancer deaths by site for men and
women is shown in Table 73-1. Cancer mortality continues to decline;
however, 6 of the 10 most common cancers have increased in incidence
by 1–3% in recent years, and troubling disparities among different
racial/ethnic groups persist. Mortality is twice as high in black people
than white people for cancers of the prostate, stomach, and uterine
corpus. Cancer is the cause of one in four deaths in the United States.

02 - 73 Approach to the Patient with Cancer
73 Approach to the Patient with Cancer
Section 1	 Neoplastic Disorders
Dan L. Longo
Approach to the Patient
with Cancer
The application of current treatment techniques (surgery, radiation
therapy, chemotherapy, and biologic therapy) results in the cure of
nearly two of three patients diagnosed with cancer. Nevertheless,
patients experience the diagnosis of cancer as one of the most trau­
matic and revolutionary events that has ever happened to them. Inde­
pendent of prognosis, the diagnosis brings with it a change in a person’s
self-image and in their role in the home and workplace. The prognosis
of a person who has just been found to have pancreatic cancer is the
same as the prognosis of the person with aortic stenosis who develops
the first symptoms of congestive heart failure (median survival,
~8 months). However, the patient with heart disease may remain
functional and maintain a self-image as a fully intact person with just
a malfunctioning part, a diseased organ (“a bum ticker”). By contrast,
the patient with pancreatic cancer has a completely altered self-image
and is viewed differently by family and anyone who knows the
diagnosis. The patient is being attacked and invaded by a disease
that could be anywhere in the body. Every ache or pain takes on
TABLE 73-1  Distribution of Cancer Incidence and Deaths for 2021
MALE
FEMALE
SITES
%
NUMBER
SITES
%
NUMBER
Cancer Incidence
Prostate
299,010
Breast
310,720
Lung
116,310
Lung
118,270
Colorectal
81,540
Colorectal
71,270
Bladder
63,070
Endometrial
67,880
Melanoma
59,170
Melanoma
41,470
Kidney
52,380
Lymphoma
36,030
Lymphoma
44,590
Pancreas
31,910
Oral cavity
41,510
Thyroid
31,520
Leukemia
36,450
Kidney
29,230
Pancreas
34,530
Leukemia
26,320
All others
200,520
All others
207,440
All sites
1,029,080
All sites
972,060
Cancer Deaths
Lung
65,790
Lung
59,280
Prostate
35,250
Breast
42,250
Colorectal
28,700
Pancreas
24,480
Pancreas
25,270
Colorectal
24,310
Liver
19,120
Endometrial
13.250
Leukemia
13,640
Ovary
12,740
Esophagus
12,880
Liver
10,720
Bladder
12,290
Leukemia
10,030
Lymphoma
11,780
Lymphoma
8,360
CNS
10,690
CNS
8,070
All others
87,390
All others
75,4330
All sites
322,800
All sites
288,920
Source: From RL Siegel et al: Cancer statistics, 2024. CA Cancer J Clin 74:12, 2024. Reproduced John Wiley & Sons Ltd.
Oncology and Hematology
PART 4
desperate significance. Cancer is an exception to the coordinated
interaction among cells and organs. In general, the cells of a multicel­
lular organism are programmed for collaboration. Many diseases occur
because the specialized cells fail to perform their assigned task. Cancer
takes this malfunction one step further. Not only is there a failure of the
cancer cell to maintain its specialized function, but it also strikes out
on its own; the cancer cell competes to survive using natural mutability
and natural selection to seek advantage over normal cells in a reca­
pitulation of evolution. One consequence of the traitorous behavior of
cancer cells is that the patient feels betrayed by their body. The cancer
patient feels that they, and not just a body part, are diseased.
THE MAGNITUDE OF THE PROBLEM
No nationwide cancer registry exists; therefore, the incidence of cancer
is estimated on the basis of the National Cancer Institute’s Surveillance,
Epidemiology, and End Results (SEER) database, which tabulates
cancer incidence and death figures from 13 sites, accounting for about
10% of the U.S. population, and from population data from the U.S.
Census Bureau. In 2024, 2.001 million new cases of invasive cancer
(1,029,080 men and 927,060 women) were diagnosed, and 611,720 per­
sons (322,800 men and 288,920 women) died from cancer. The percent
distribution of new cancer cases and cancer deaths by site for men and
women is shown in Table 73-1. Cancer mortality continues to decline;
however, 6 of the 10 most common cancers have increased in incidence
by 1–3% in recent years, and troubling disparities among different
racial/ethnic groups persist. Mortality is twice as high in black people
than white people for cancers of the prostate, stomach, and uterine
corpus. Cancer is the cause of one in four deaths in the United States.
Male
Prostate
Rate per 100,000 population
Lung & bronchus
Colorectum
Urinary bladder
PART 4
Oncology and Hematology
Thyroid
Livera
Melanoma of the skin
1975 1980 1985 1990 1995 2000
Year of diagnosis
2005 2010 2015 2020
FIGURE 73-1  Trends in cancer incidence for men and women, 1975–2020. Incidence data for 2020 are indicated by color dots separate from the trend lines. (Reproduced
with permission from RL Siegel et al: Cancer statistics, 2024. CA Cancer J Clin 74:1, 2024.)
The most significant risk factor for cancer overall is age; 58% of all
cases were in those aged >65 years, down from 61% in 1995, despite an
increase in this age group from 13% to 17% of the population. Cancer
incidence increases as the third, fourth, or fifth power of age in differ­
ent sites. For the interval between birth and age 49 years, 1 in 29 men
and 1 in 19 women will develop cancer; for the interval between ages
50 and 59 years, 1 in 15 men and 1 in 17 women will develop cancer;
for the interval between ages 60 and 69 years, 1 in 6 men and 1 in
10 women will develop cancer; and for people aged ≥70, 1 in 3 men
and 1 in 4 women will develop cancer. Overall, men have a 40.5% risk
of developing cancer at some time during their lives; women have a
38.9% lifetime risk.
Cancer is the second leading cause of death behind heart disease.
Deaths from heart disease have declined 45% in the United States since
1950 and continue to decline. Cancer has overtaken heart disease as the
number one cause of death in persons aged <85 years. Incidence trends
over time are shown in Fig. 73-1. After a 70-year period of increase,
cancer deaths began to decline in 1990–1991 (Fig. 73-2). Between
1990 and 2010, cancer deaths decreased by 21% among men and 12.3%
among women. The incidence has been steady since 2013. The magni­
tude of the decline is illustrated in Fig. 73-3. The five leading causes
of cancer deaths are shown for various populations in Table 73-2.
The 5-year survival for white patients was 39% in 1960–1963 and 68%
in 2010–2016. Cancers are more often deadly in blacks; the 5-year
survival was 63% for the 2010–2016 interval; however, the racial dif­
ferences are narrowing over time. Incidence and mortality vary among
racial and ethnic groups (Table 73-3). The basis for these differences
is unclear.
Advances in cancer prevention, diagnosis, and treatment since the
early 1990s have averted millions of cancer deaths based on projec­
tions from the slopes of the mortality curves leading up to the 1990s
(Fig. 73-4).
■
■CANCER AROUND THE WORLD
In 2022, nearly 20 million new cancer cases and 9.7 million can­
cer deaths were estimated worldwide, according to estimates of
GLOBOCAN 2022, developed by the International Agency for
Research on Cancer (IARC). Rates are increasing worldwide. When
Female
Breast
Lung & bronchus
Colorectum
Uterine corpus
Thyroid
Livera
Melanoma of the skin
1975 1980 1985 1990 1995 2000
Year of diagnosis
2005 2010 2015 2020
broken down by region of the world, almost half of cases were in Asia
(which has 59.2% of the world’s population), 26% in Europe (9.6% of
the world’s population), 13.1% in North America, 7.1% in Central/
South America (the Americas, North and South, account for 13.3% of
the world’s population), 6% in Africa (16.6% of the world’s population),
and 1% in Australia/New Zealand (0.5% of the world’s population)
(Fig. 73-5). Lung cancer is the most common cancer and the most
common cause of cancer death in the world. Its incidence is highly
variable, affecting only 2 per 100,000 African women but as many
as 61 per 100,000 North American men. Breast cancer is the second
most common cancer worldwide; however, it ranks fourth as a cause
of death behind lung, stomach, and liver cancer. Among the eight
most common forms of cancer, lung (2-fold), breast (3-fold), prostate
(2.5-fold), and colorectal (3-fold) cancers are more common in more
developed countries than in less developed countries. By contrast, liver
(2-fold), cervical (2-fold), and esophageal (2- to 3-fold) cancers are more
common in less developed countries. Stomach cancer incidence is simi­
lar in more and less developed countries but is much more common in
Asia than North America or Africa. The most common cancers in Africa
are cervical, breast, and liver cancers. It has been estimated that nine
modifiable risk factors are responsible for more than one-third of cancers
worldwide. These include smoking, alcohol consumption, obesity, physical
inactivity, low fruit and vegetable consumption, unsafe sex, air pollution,
indoor smoke from household fuels, and contaminated injections.
PATIENT MANAGEMENT
Important information is obtained from every portion of the routine
history and physical examination. The duration of symptoms may
reveal the chronicity of disease. The past medical history may alert the
physician to the presence of underlying diseases that may affect the
choice of therapy or the side effects of treatment. The social history
may reveal occupational exposure to carcinogens or habits, such as
smoking or alcohol consumption, that may influence the course of dis­
ease and its treatment. The family history may suggest an underlying
familial cancer predisposition and point out the need to begin surveil­
lance or other preventive therapy for unaffected siblings of the patient.
The review of systems may suggest early symptoms of metastatic dis­
ease or a paraneoplastic syndrome.
All sites combined
Deaths per 100,000 population
Males, by site
Stomach
Colorectum
Liver & intrahepatic bile duct
Pancreas
Lung & bronchus
Prostate
Leukemia
Deaths per 100,000 males
Females, by site
Stomach
Colorectum
Liver & intrahepatic bile duct
Pancreas
Lung & bronchus
Breast
Uterus (corpus and cervix combined)
Deaths per 100,000 females
Year of death
FIGURE 73-2  Trends in cancer mortality rates in men and women, 1930–2021. (Reproduced with permission
from RL Siegel et al: Cancer statistics, 2024. CA Cancer J Clin 74:1, 2024.)
■
■DIAGNOSIS
The diagnosis of cancer relies most heavily on invasive tissue biopsy
and should never be made without obtaining tissue; no noninvasive
diagnostic test is sufficient to define a disease process such as cancer
(one exception to this rule may be hepatocellular carcinoma, which
may be reliably diagnosed based on computed tomography [CT]
or magnetic resonance imaging [MRI] showing the characteristic
dynamic perfusion pattern of arterial hyperenhancement and venous
or delayed phase washout). Although in rare clinical settings (e.g., thy­
roid nodules), fine-needle aspiration is an acceptable diagnostic proce­
dure, the diagnosis generally depends on obtaining adequate tissue to
permit careful evaluation of the histology of the tumor, its grade, and
its invasiveness and to yield further molecular diagnostic information,
such as the expression of cell-surface markers or intracellular proteins
that typify a particular cancer, or the presence of a molecular marker,
such as the t(8;14) translocation of Burkitt’s lymphoma. Increasing
evidence links the expression of certain genes with the prognosis and
response to therapy (Chaps. 76 and 77).
Occasionally, a patient will present with a metastatic disease process
that is defined as cancer on biopsy but has no apparent primary site of
disease. Efforts should be made to define the pri­
mary site based on age, sex, sites of involvement,
histology and tumor markers, and personal and
family history. Particular attention should be
focused on ruling out the most treatable causes
(Chap. 97).
Male
Once the diagnosis of cancer is made, the
management of the patient is best undertaken
as a multidisciplinary collaboration among the
primary care physician, medical oncologists, sur­
gical oncologists, radiation oncologists, oncology
nurse specialists, pharmacists, social workers,
rehabilitation medicine specialists, and a number
of other consulting professionals working closely
with each other and with the patient and family.
Female
■
■DEFINING THE EXTENT OF
DISEASE AND THE PROGNOSIS
The first priority in patient management after the
diagnosis of cancer is established and shared with
the patient is to determine the extent of disease.
The curability of a tumor usually is inversely pro­
portional to the tumor burden. Ideally, the tumor
will be diagnosed before symptoms develop or as
a consequence of screening efforts (Chap. 75).
A very high proportion of such patients can be
cured. However, most patients with cancer pres­
ent with symptoms related to the cancer, caused
either by mass effects of the tumor or by altera­
tions associated with the production of cytokines
or hormones by the tumor.
CHAPTER 73
Approach to the Patient with Cancer
For most cancers, the extent of disease is
evaluated by a variety of noninvasive and inva­
sive diagnostic tests and procedures. This process
is called staging. There are two types. Clinical
staging is based on physical examination, radio­
graphs, isotopic scans, CT scans, and other
imaging procedures; pathologic staging takes into
account information obtained during a surgical
procedure, which might include intraoperative
palpation, resection of regional lymph nodes
and/or tissue adjacent to the tumor, and inspec­
tion and biopsy of organs commonly involved
in disease spread. Pathologic staging includes
histologic examination of all tissues removed
during the surgical procedure. Surgical proce­
dures performed may include a simple lymph
node biopsy or more extensive procedures such
as thoracotomy, mediastinoscopy, or laparotomy.
Surgical staging may occur in a separate procedure or may be done at
the time of definitive surgical resection of the primary tumor. A subset
of pathologic staging is the examination of tissue obtained at initial
surgery that occurs after the delivery of some treatment, which is called
neoadjuvant therapy. Stage of disease determined after neoadjuvant
therapy is designated with the prefix y.
Knowledge of the predilection of particular tumors for spreading to
adjacent or distant organs helps direct the staging evaluation.
Information obtained from staging is used to define the extent of
disease as localized, as exhibiting spread outside of the organ of origin
to regional but not distant sites, or as metastatic to distant sites. The
most widely used system of staging is the tumor, node, metastasis
(TNM) system codified by the International Union Against Cancer and
the American Joint Committee on Cancer. The TNM classification is
an anatomically based system that categorizes the tumor on the basis
of the size of the primary tumor lesion (T1–4, where a higher number
indicates a tumor of larger size), the presence of nodal involvement
(usually N0 and N1 for the absence and presence, respectively, of
involved nodes, although some tumors have more elaborate systems
of nodal grading), and the presence of metastatic disease (M0 and M1
Male
Rate per 100,000
Lung & bronchus
Colorectum
Leukemia
Brain & other nervous system
1975 1980 1985 1990 1995 2000 2005 2010 2015 2020
7,000
PART 4
Oncology and Hematology
6,000
5,000
Lung & bronchus
Number of deaths
4,000
3,000
Colorectum
Leukemia
2,000
1,000
Brain & other nervous system
1975 1980 1985 1990 1995 2000
Year of death
2005 2010 2015 2020
FIGURE 73-3  Trends in cancer incidence and death rates. (Reproduced with permission from RL Siegel et al: Cancer statistics, 2024. CA Cancer J Clin 74:1, 2024.)
TABLE 73-2  The Five Leading Primary Tumor Sites for Patients Dying of Cancer Based on Age and Sex in 2018
RANK
SEX
ALL AGES
UNDER 20
20–39
40–49
50-64
65–79
80
M
Lung
CNS
Colorectal
Colorectal
Lung
Lung
Lung
F
Lung
CNS
Breast
Breast
Lung
Lung
Lung
M
Prostate
Leukemia
CNS
Lung
Colorectal
Prostate
Prostate
F
Breast
Leukemia
Cervix
Colorectal
Breast
Breast
Breast
M
Colorectal
Bone sarcoma
Leukemia
CNS
Pancreas
Liver
Colorectal
F
Colorectal
Soft tissue sarcoma
Colorectal
Lung
Colorectal
Pancreas
Colorectal
M
Pancreas
Soft tissue sarcoma
Testis
Pancreas
Liver
Colorectal
Bladder
F
Pancreas
Bone sarcoma
CNS
Cervix
Pancreas
Colorectal
Pancreas
M
Liver
Lymphoma
Lymphoma
Esophagus
Esophagus
Liver
Pancreas
F
Ovary
Kidney
Leukemia
Ovary
Ovary
Ovary
Leukemia
Abbreviations: CNS, central nervous system; F, female; M, male.
Source: From RL Siegel et al: Cancer statistics, 2024. CA Cancer J Clin 74:12, 2024.
Female
Breast
Lung & bronchus
Colorectum
Uterine cervix
1975 1980 1985 1990 1995 2000 2005 2010 2015 2020
Breast
Lung & bronchus
Colorectum
Uterine cervix
1975 1980 1985 1990 1995 2000
Year of death
2005 2010 2015 2020
AGE, YEARS
TABLE 73-3  Cancer Incidence and Mortality in Racial and Ethnic Groups, United States, 2016–2020
SITE
SEX
WHITE
BLACK
Incidence per 100,000 Population
All
M
511.2
533.9
299.0
504.1
377.2
F
499.3
409.9
307.3
465.5
351.3
Breast
134.9
129.6
104.6
115.5
100.7
Colorectal
M
40.4
48.8
33.4
57.8
38.2
F
30.5
35.0
23.7
43.7
27.2
Kidney
M
24.3
26.4
11.6
43.9
23.5
F
12.1
13.7
5.5
23.9
13.3
Liver
M
11.2
17.0
18.4
27.3
20.4
F
4.2
5.5
6.7
12.3
8.4
Lung
M
765.7
72,4
40.8
67.2
34.3
F
54.8
45.8
28.1
58.6
24.0
Prostate
110.7
186.1
60.9
91.9
90.9
Stomach
M
7.1
13.0
11.8
13.1
11.4
F
3.4
7.4
6.9
7.8
7.7
Cervix
7.2
8.6
6.0
11.4
9.7
Endometrial
27.9
28.9
21.7
30.4
25.8
Deaths per 100,000 Population
All
M
183.3
217.4
111.6
221.6
130.2
F
133.6
150.2
83.7
157.9
93.5
Breast
19.7
27.8
11.8
21.1
13.7
Colorectal
M
15.5
22.4
11.0
23.1
13.6
F
11.1
14.4
7.8
16.0
8.5
Kidney
M
5.3
5.2
2.4
9.9
4.8
F
2.3
2.2
1.0
4.2
2.1
Liver
M
8.5
13.0
12.6
19.9
13.1
F
3.7
4.8
5.2
8.8
6.0
Lung
M
44.9
51.3
25.9
52.3
21.-
F
32.9
28.0
15.6
37.0
11.4
Prostate
17.9
37.9
8.7
22.5
15.4
Stomach
M
2.9
7.2
6.0
7.7
5.9
F
1.5
3.5
3.7
4.1
3.9
Cervix
2.0
3.3
1.7
2.3
2.5
Endometrial
4.6
9.1
3.5
4.9
4.3
aBased on Indian Health Service delivery areas.
Abbreviations: F, female; M, male.
Source:  From RL Siegel et al: Cancer statistics, 2024. CA Cancer J Clin 74:12, 2024. Reproduced  of John Wiley & Sons Ltd.
for the absence and presence, respectively, of metastases). The various
permutations of T, N, and M scores (sometimes including tumor histo­
logic grade [G]) are then broken into stages, usually designated by the
roman numerals I through IV. Tumor burden increases and curability
decreases with increasing stage. Other anatomic staging systems are
used for some tumors, e.g., the Dukes classification for colorectal can­
cers, the International Federation of Gynecologists and Obstetricians
classification for gynecologic cancers, and the Ann Arbor classification
for Hodgkin’s lymphoma.
Certain tumors cannot be grouped on the basis of anatomic con­
siderations. For example, hematopoietic tumors such as leukemia,
myeloma, and lymphoma are often disseminated at presentation and
do not spread like solid tumors. For these tumors, other prognostic
factors have been identified (Chaps. 109–116).
In addition to tumor burden, a second major determinant of
treatment outcome is the physiologic reserve of the patient. Patients
who are bedridden before developing cancer are likely to fare worse,
stage for stage, than fully active patients. Physiologic reserve is a
determinant of how a patient is likely to cope with the physiologic
stresses imposed by the cancer and its treatment. This factor is dif­
ficult to assess directly. Instead, surrogate markers for physiologic
ASIAN/PACIFIC
ISLANDER
AMERICAN INDIANa
HISPANIC
CHAPTER 73
Approach to the Patient with Cancer
reserve are used, such as the patient’s age or Karnofsky performance
status (Table 73-4) or Eastern Cooperative Oncology Group (ECOG)
performance status (Table 73-5). Older patients and those with a
Karnofsky performance status <70 or ECOG performance status ≥3
have a poor prognosis unless the poor performance is a reversible
consequence of the tumor. Some have advocated for using one of the
geriatric assessment tools to gauge physiologic reserve. See ASCO’s
video for an example of a geriatric assessment tool (https://www.
youtube.com/watch?v=jnaQIjOz2Dw).
Increasingly, biologic features of the tumor are being related to
prognosis. The expression of particular oncogenes, drug-resistance
genes, apoptosis-related genes, and genes involved in metastasis is
being found to influence response to therapy and prognosis. The
presence of selected cytogenetic abnormalities may influence sur­
vival. Tumors with higher growth fractions, as assessed by expression
of proliferation-related markers such as proliferating cell nuclear
antigen (detectable by staining with Ki67 antibody), behave more
aggressively than tumors with lower growth fractions. Information
obtained from studying the tumor itself will increasingly be used to
influence treatment decisions. Host genes involved in drug metabo­
lism can influence the safety and efficacy of particular treatments.
Male
Female
550,000
500,000
450,000
400,000
350,000
Number of deaths
300,000
2,794,900
cancer deaths averted
250,000
200,000
150,000
PART 4
Oncology and Hematology
100,000
50,000
Year of death
FIGURE 73-4  Cancer deaths averted in men and women since the early 1990s. Projections based on death continuing on the established trajectory. (Reproduced with
permission from RL Siegel et al: Cancer statistics, 2024. CA Cancer J Clin 74:1, 2024.)
Enormous heterogeneity has been noted by studying tumors; we
have learned that morphology is not capable of discerning certain
distinct subsets of patients whose tumors have different sets of abnor­
malities. Tumors that look the same by light microscopy can be very
different. Similarly, tumors that look quite different from one another
histologically can share genetic lesions that predict responses to treat­
ments. Furthermore, tumor cells vary enormously within a single
patient even though the cells share a common origin.
■
■MAKING A TREATMENT PLAN
From information on the extent of disease and the prognosis and in
conjunction with the patient’s wishes, it is determined whether the
treatment approach should be curative or palliative in intent. Coop­
eration among the various professionals involved in cancer treatment
is of the utmost importance in treatment planning. For some cancers,
chemotherapy or chemotherapy plus radiation therapy delivered
before the use of definitive surgical treatment (so-called neoadju­
vant therapy) may improve the outcome, as seems to be the case for
locally advanced breast cancer, head and neck cancers, and lung can­
cers, among others. In certain settings in which combined-modality
therapy is intended, coordination among the medical oncologist,
radiation oncologist, and surgeon is crucial to achieving optimal
results. Sometimes the chemotherapy and radiation therapy need to
be delivered sequentially and other times concurrently. Surgical pro­
cedures may precede or follow other treatment approaches. It is best
for the treatment plan either to follow a standard protocol precisely or
else to be part of an ongoing clinical research protocol evaluating new
treatments. Ad hoc modifications of standard protocols are likely to
compromise treatment results.
The choice of treatment approaches was formerly dominated by the
local culture in both the university and the practice settings. However,
it is now possible to gain access electronically to standard treatment
550,000
500,000
450,000
400,000
350,000
300,000
250,000
1,344,600
cancer deaths averted
200,000
150,000
100,000
50,000
Year of death
protocols and to every approved clinical research study in North
America through a personal computer interface with the Internet.1
The skilled physician also has much to offer the patient for whom
curative therapy is no longer an option. Often a combination of guilt and
frustration over the inability to cure the patient and the pressure of a busy
schedule greatly limit the time a physician spends with a patient who is
receiving only palliative care. Resist these forces. In addition to the medi­
cines administered to alleviate symptoms (see below), it is important to
remember the comfort that is provided by holding the patient’s hand,
continuing regular examinations, and taking time to talk.
■
■MANAGEMENT OF DISEASE AND
TREATMENT COMPLICATIONS
Although medicine has been guided through centuries by the aphorism
“primum non nocere,” first do no harm, it fits modern medicine poorly.
As a practical matter, nearly everything we do in patient care has risk
of doing harm; diagnostic tests, therapeutic interventions, and even
physical diagnosis can lead to patient harm. A more relevant guide to
modern medicine is “primum succerrere”; first hasten to help. Because
cancer therapies are toxic (Chap. 78), patient management involves
addressing complications of both the disease and its treatment as well
as the complex psychosocial problems associated with cancer. In the
short term during a course of curative therapy, the patient’s functional
1The National Cancer Institute maintains a database called PDQ (Physician
Data Query) that is accessible on the Internet under the name CancerNet at
https://www.cancer.gov/publications/pdq. Information can be obtained through
a facsimile machine using CancerFax by dialing 301-402-5874. Patient information is also provided by the National Cancer Institute in at least three formats: on the Internet via CancerNet at www.cancer.gov, through the CancerFax
number listed above, or by calling 1-800-4-CANCER. The quality control for
the information provided through these services is rigorous.
Mortality, males
Colorectum (5)
Esophagus (3)
Kaposi sarcoma (2)
Lip, oral cavity (2)
Lung (89)
Prostate (52)
Liver (24)
Stomach (8)
A
Mortality, females
Colorectum (4)
Stomach (2)
Esophagus (1)
Breast (112)
Cervix uteri (37)
Lung (23)
Liver (6)
B
FIGURE 73-5  Global maps showing most common cause of cancer mortality by country in 2022 among (A) men and (B) women. (Reproduced with permission from F Bray
et al: Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 74:229, 2024.)
TABLE 73-4  Karnofsky Performance Index
PERFORMANCE
STATUS
FUNCTIONAL CAPABILITY OF THE PATIENT
Normal; no complaints; no evidence of disease
Able to carry on normal activity; minor signs or symptoms of
disease
Normal activity with effort; some signs or symptoms of
disease
Cares for self; unable to carry on normal activity or do active
work
Requires occasional assistance but is able to care for most
needs
Requires considerable assistance and frequent medical
care
Disabled; requires special care and assistance
Severely disabled; hospitalization is indicated, although death
is not imminent
Very sick; hospitalization is necessary; active supportive
treatment is necessary
Moribund, fatal processes progressing rapidly
Dead
CHAPTER 73
Approach to the Patient with Cancer
status may decline. Treatment-induced toxicity is less acceptable if
the goal of therapy is palliation. The most common side effects of
treatment are nausea and vomiting (see below), febrile neutropenia
(Chap. 79), and myelosuppression (Chap. 78). Tools are now available
to minimize the acute toxicity of cancer treatment.
TABLE 73-5  The Eastern Cooperative Oncology Group (ECOG)
Performance Scale
ECOG grade 0: Fully active, able to carry on all predisease performance without
restriction
ECOG grade 1: Restricted in physically strenuous activity but ambulatory and
able to carry out work of a light or sedentary nature, e.g., light housework,
office work
ECOG grade 2: Ambulatory and capable of all self-care but unable to carry out
any work activities. Up and about >50% of waking hours
ECOG grade 3: Capable of only limited self-care, confined to bed or chair >50% of
waking hours
ECOG grade 4: Completely disabled. Cannot carry on any self-care. Totally
confined to bed or chair
ECOG grade 5: Dead
Source: Reproduced with permission from MM Oken et al: Toxicity and response
criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 5:649, 1982.
New symptoms developing in the course of cancer treatment should
always be assumed to be reversible until proven otherwise. The fatal­
istic attribution of anorexia, weight loss, and jaundice to recurrent or
progressive tumor could result in a patient dying from a reversible
intercurrent cholecystitis. Intestinal obstruction may be due to revers­
ible adhesions rather than progressive tumor. Systemic infections,
sometimes with unusual pathogens, may be a consequence of the
immunosuppression associated with cancer therapy. Some drugs used
to treat cancer or its complications (e.g., nausea) may produce central
nervous system symptoms that look like metastatic disease or may
mimic paraneoplastic syndromes such as the syndrome of inappropri­
ate antidiuretic hormone. A definitive diagnosis should be pursued and
may even require a repeat biopsy.
A critical component of cancer management is assessing the
response to treatment. In addition to a careful physical examination
in which all sites of disease are physically measured and recorded in
a flow chart by date, response assessment usually requires periodic
repeating of imaging tests that were abnormal at the time of staging.
If imaging tests have become normal, repeat biopsy of previously
involved tissue is performed to document complete response by patho­
logic criteria. Biopsies are not usually required if there is macroscopic
residual disease. A complete response is defined as disappearance of all
evidence of disease, and a partial response as >50% reduction in the
sum of the products of the perpendicular diameters of all measurable
lesions. The determination of partial response may also be based on a
30% decrease in the sums of the longest diameters of lesions (Response
Evaluation Criteria in Solid Tumors [RECIST]). Progressive disease is
defined as the appearance of any new lesion or an increase of >25% in
the sum of the products of the perpendicular diameters of all measur­
able lesions (or an increase of 20% in the sums of the longest diameters
by RECIST). Tumor shrinkage or growth that does not meet any of
these criteria is considered stable disease. Some sites of involvement
(e.g., bone) or patterns of involvement (e.g., lymphangitic lung or dif­
fuse pulmonary infiltrates) are considered unmeasurable. No response
is complete without biopsy documentation of their resolution, but
partial responses may exclude their assessment unless clear objective
progression has occurred.
PART 4
Oncology and Hematology
For some hematologic neoplasms, flow cytometric and genetic assays
may determine the presence of residual tumor cells that escape micro­
scopic detection. In general, these techniques can reliably detect as few
as 1 tumor cell among 10,000 cells. If such tests do not detect tumor cells,
the patient is said to have minimal residual disease negativity, a finding
generally associated with more durable remissions. Accumulating data
are defining interventions in patients with minimal residual disease
positivity that can extend remission duration and survival.
Tumor markers may be useful in patient management in certain
tumors. Response to therapy may be difficult to gauge with certainty.
However, some tumors produce or elicit the production of markers
that can be measured in the serum or urine, and in a particular patient,
rising and falling levels of the marker are usually associated with
increasing or decreasing tumor burden, respectively. Some clinically
useful tumor markers are shown in Table 73-6. Tumor markers are not
in themselves specific enough to permit a diagnosis of malignancy to
be made, but once a malignancy has been diagnosed and shown to be
associated with elevated levels of a tumor marker, the marker can be
used to assess response to treatment.
The recognition and treatment of depression are important compo­
nents of management. The incidence of depression in cancer patients
is ~25% overall and may be greater in patients with greater debility.
This diagnosis is likely in a patient with a depressed mood (dysphoria)
and/or a loss of interest in pleasure (anhedonia) for at least 2 weeks. In
addition, three or more of the following symptoms are usually present:
appetite change, sleep problems, psychomotor retardation or agitation,
fatigue, feelings of guilt or worthlessness, inability to concentrate, and
suicidal ideation. Patients with these symptoms should receive therapy.
Medical therapy with a serotonin reuptake inhibitor such as fluoxetine
(10–20 mg/d), sertraline (50–150 mg/d), or paroxetine (10–20 mg/d)
or a tricyclic antidepressant such as amitriptyline (50–100 mg/d) or
desipramine (75–150 mg/d) should be tried, allowing 4–6 weeks
TABLE 73-6  Tumor Markers
TUMOR
MARKERS
CANCER
NONNEOPLASTIC
CONDITIONS
Hormones
Human chorionic
gonadotropin
Gestational trophoblastic disease,
gonadal germ cell tumor
Pregnancy
Calcitonin
Medullary cancer of the thyroid
Catecholamines
Pheochromocytoma
Oncofetal Antigens
α Fetoprotein
Hepatocellular carcinoma,
gonadal germ cell tumor
Cirrhosis, hepatitis
Carcinoembryonic
antigen
Adenocarcinomas of the colon,
pancreas, lung, breast, ovary
Pancreatitis, hepatitis,
inflammatory bowel
disease, smoking
Enzymes
Prostatic acid
phosphatase
Prostate cancer
Prostatitis, prostatic
hypertrophy
Neuron-specific
enolase
Small-cell cancer of the lung,
neuroblastoma
Lactate
dehydrogenase
Lymphoma, Ewing’s sarcoma
Hepatitis, hemolytic
anemia, many others
Tumor-Associated Proteins
Prostate-specific
antigen
Prostate cancer
Prostatitis, prostatic
hypertrophy
Monoclonal
immunoglobulin
Myeloma
Infection, MGUS
CA-125
Ovarian cancer, some lymphomas
Menstruation,
peritonitis, pregnancy
CA 19-9
Colon, pancreatic, breast cancer
Pancreatitis, ulcerative
colitis
CD30
Hodgkin’s disease, anaplastic
large-cell lymphoma
—
CD25
Hairy cell leukemia, adult T-cell
leukemia/lymphoma
Hemophagocytic
lymphohistiocytosis
Abbreviation: MGUS, monoclonal gammopathy of uncertain significance.
for response. Effective therapy should be continued at least 6 months
after resolution of symptoms. If therapy is unsuccessful, other classes
of antidepressants may be used. In addition to medication, psychoso­
cial interventions such as support groups, psychotherapy, and guided
imagery may be of benefit.
Many patients opt for unproven or unsound approaches to treat­
ment when it appears that conventional medicine is unlikely to be
curative. Those seeking such alternatives are often well educated and
may be early in the course of their disease. Unsound approaches are
usually hawked on the basis of unsubstantiated anecdotes and not only
cannot help the patient but may be harmful. Physicians should strive to
keep communications open and nonjudgmental, so that patients are
more likely to discuss with the physician what they are actually doing.
The appearance of unexpected toxicity may be an indication that a
supplemental therapy is being taken.2
LONG-TERM FOLLOW-UP/LATE
COMPLICATIONS
At the completion of treatment, sites originally involved with tumor
are reassessed, usually by radiography or imaging techniques, and any
persistent abnormality is biopsied. If disease persists, the multidis­
ciplinary team discusses a new salvage treatment plan. If the patient
has been rendered disease-free by the original treatment, the patient
2Information about unsound methods may be obtained from the National
Council Against Health Fraud, Box 1276, Loma Linda, CA 92354, or from the
Center for Medical Consumers and Health Care Information, 237 Thompson
Street, New York, NY 10012.
is followed regularly for disease recurrence. The optimal guidelines
for follow-up care are not known. For many years, a routine practice
has been to follow the patient monthly for 6–12 months, then every
other month for a year, every 3 months for a year, every 4 months for
a year, every 6 months for a year, and then annually. At each visit, a
battery of laboratory and radiographic and imaging tests was obtained
on the assumption that it is best to detect recurrent disease before it
becomes symptomatic. However, where follow-up procedures have
been examined, this assumption has been found to be untrue. Studies
of breast cancer, melanoma, lung cancer, colon cancer, and lymphoma
have all failed to support the notion that asymptomatic relapses are
more readily cured by salvage therapy than symptomatic relapses. In
view of the enormous cost of a full battery of diagnostic tests and their
manifest lack of impact on survival, new guidelines are emerging for
less frequent follow-up visits, during which the history and physical
examination are the major investigations performed.
As time passes, the likelihood of recurrence of the primary cancer
diminishes. For many types of cancer, survival for 5 years without
recurrence is tantamount to cure. However, important medical prob­
lems can occur in patients treated for cancer and must be examined
(Chap. 100). Some problems emerge as a consequence of the disease
and some as a consequence of the treatment. An understanding of
these disease- and treatment-related problems may help in their detec­
tion and management.
Despite these concerns, most patients who are cured of cancer
return to normal lives.
■
■SUPPORTIVE CARE
In many ways, the success of cancer therapy depends on the success
of the supportive care. Failure to control the symptoms of cancer and
its treatment may lead patients to abandon curative therapy. Of equal
importance, supportive care is a major determinant of quality of life.
Even when life cannot be prolonged, the physician must strive to pre­
serve its quality. Quality-of-life measurements have become common
endpoints of clinical research studies. Furthermore, palliative care has
been shown to be cost-effective when approached in an organized
fashion. A credo for oncology could be to cure sometimes, to extend
life often, and to comfort always.
Management strategies for cancer pain, nausea, and other common
side effects of cancer and its treatment are outlined in Chap. 74. An
approach to end-of-life care is provided in Chap. 13.
Psychosocial Support 
The psychosocial needs of patients vary
with their situation. Patients undergoing treatment experience fear,
anxiety, and depression. Self-image is often seriously compromised
by deforming surgery and loss of hair. Women who receive cosmetic
advice that enables them to look better also feel better. Loss of control
over how one spends time can contribute to the sense of vulnerability.
Juggling the demands of work and family with the demands of treat­
ment may create enormous stresses. Sexual dysfunction is highly
prevalent and needs to be discussed openly with the patient. An empa­
thetic health care team is sensitive to the individual patient’s needs and
permits negotiation where such flexibility will not adversely affect the
course of treatment.
Cancer survivors have other sets of difficulties. Patients may have
fears associated with the termination of a treatment they associate with
their continued survival. Adjustments are required to physical losses
and handicaps, real and perceived. Patients may be preoccupied with
minor physical problems. They perceive a decline in their job mobility
and view themselves as less desirable workers. They may be victims
of job and/or insurance discrimination. Patients may experience dif­
ficulty reentering their normal past life. They may feel guilty for hav­
ing survived and may carry a sense of vulnerability to colds and other
illnesses. Perhaps the most pervasive and threatening concern is the
ever-present fear of relapse (the Damocles syndrome).
Patients in whom therapy has been unsuccessful have other prob­
lems related to the end of life.
Death and Dying 
The most common causes of death in patients
with cancer are infection (leading to circulatory failure), respiratory
failure, hepatic failure, and renal failure. Intestinal blockage may lead
to inanition and starvation. Central nervous system disease may lead
to seizures, coma, and central hypoventilation. About 70% of patients
develop dyspnea preterminally. However, many months usually pass
between the diagnosis of cancer and the occurrence of these compli­
cations, and during this period, the patient is severely affected by the
possibility of death. The path of unsuccessful cancer treatment usually
occurs in three phases. First, there is optimism at the hope of cure;
when the tumor recurs, there is the acknowledgment of an incurable
disease, and the goal of palliative therapy is embraced in the hope of
being able to live with disease; finally, at the disclosure of imminent
death, another adjustment in outlook takes place. The patient imagines
the worst in preparation for the end of life and may go through stages
of adjustment to the diagnosis. These stages include denial, isola­
tion, anger, bargaining, depression, acceptance, and hope. Of course,
patients do not all progress through all the stages or proceed through
them in the same order or at the same rate. Nevertheless, developing
an understanding of how the patient has been affected by the diagnosis
and is coping with it is an important goal of patient management.
It is best to speak frankly with the patient and the family regarding
the likely course of disease. These discussions can be difficult for the
physician as well as for the patient and family. The critical features of
the interaction are to reassure the patient and family that everything
that can be done to provide comfort will be done. They will not be
abandoned. Many patients prefer to be cared for in their homes or in a
hospice setting rather than a hospital. The American College of Physi­
cians has published a book called Home Care Guide for Cancer: How
to Care for Family and Friends at Home that teaches an approach to
successful problem-solving in home care. With appropriate planning,
it should be possible to provide the patient with the necessary medical
care as well as the psychological and spiritual support that will prevent
the isolation and depersonalization that can attend in-hospital death.
CHAPTER 73
Approach to the Patient with Cancer
The care of dying patients may take a toll on the physician. A “burn­
out” syndrome has been described that is characterized by fatigue, dis­
engagement from patients and colleagues, and a loss of self-fulfillment.
Efforts at stress reduction, maintenance of a balanced life, and setting
realistic goals may combat this disorder.
End-of-Life Decisions 
Unfortunately, a smooth transition in
treatment goals from curative to palliative may not be possible in all
cases because of the occurrence of serious treatment-related compli­
cations or rapid disease progression. Vigorous and invasive medical
support for a reversible disease or treatment complication is assumed
to be justified. However, if the reversibility of the condition is in doubt,
the patient’s wishes determine the level of medical care. These wishes
should be elicited before the terminal phase of illness and reviewed
periodically. Information about advance directives can be obtained
from the American Association of Retired Persons, 601 E Street, NW,
Washington, DC 20049, 202-434-2277, or Choice in Dying, 250 West
57th Street, New York, NY 10107, 212-366-5540. Some states allow
physicians to assist patients who choose to end their lives. This subject
is challenging from an ethical and a medical point of view. Discussions
of end-of-life decisions should be candid and involve clear informed
consent, waiting periods, second opinions, and documentation. A full
discussion of end-of-life management is provided in Chap. 13.
■
■FURTHER READING
Bray F et al: Global cancer statistics 2022: GLOBOCAN estimates of
incidence and mortality worldwide for 36 cancers in 185 countries.
CA Cancer J Clin 74:229, 2024.
Hesketh PJ et al: Antiemetics: ASCO guideline update. J Clin Oncol
38:2782, 2020.
Kelley AS, Morrison RS: Palliative care for the seriously ill. N Engl J
Med 373:747, 2015.
Martini RS et al: Integrative approaches for cancer pain management.
Curr Oncol Rep 26:691, 2024.
Samala RV et al: Frequently asked questions about managing cancer
pain: An update. Cleve Clin Med J 88:183, 2021.
Siegel RL et al: Cancer statistics, 2024. CA Cancer J Clin 74:12, 2024.

03 - 74 Symptom Control in Patients with Cancer
74 Symptom Control in Patients with Cancer
Charles L. Loprinzi, Thomas J. Smith
Symptom Control in
Patients with Cancer
THE FIRST STEP: IMPORTANCE OF PROPER
SYMPTOM ASSESSMENT AND RESOLUTION
Several randomized trials have now shown that for metastatic cancer
patients, prompt symptom assessment and resolution lead to substan­
tially increased survival. Basch and colleagues at Memorial Sloan Ket­
tering Cancer Center randomized 766 metastatic solid tumor patients to
usual care or once-a-week monitoring of 12 common symptoms (the
patient-reported outcomes [PRO] group); these patients checked in once
a week by computer or smartphone. Nurses monitored the symptom for
“spikes” such as in pain and contacted the patient or brought them in
for evaluation. Quality of life was significantly better in the PRO group.
Surprisingly, median overall survival (OS) was 31.2 months in the PRO
group and 26 months in the usual care group (p = .03). There was an
absolute difference in OS of 6 per 100 patients at 5 years in the PRO
group compared to the control group. In a similar trial of 121 stage III
and IV lung cancer patients randomized to usual care or once-weekly
PRO reporting, the median OS was 22.5 months versus 13.5 months.
The absolute OS difference at 2 years was 10–12 of every 100 patients.
In a cluster randomized trial of 52 oncology practices and 1191 patients,
PROs completed each week led to statistically significant improvements
in quality of life outcomes at 3 months; the primary outcome, OS, has not
been reported. This extra attention to symptom assessment and manage­
ment may be part of the reason that patients randomized to concurrent
palliative care in addition to their cancer care live longer.
PART 4
Oncology and Hematology
A general principle from the above trials is that the health care pro­
vider should use some form of PRO-related scale to assess symptoms.
Homsi et al. evaluated 200 patients referred to the Cleveland Clinic
using a 48-item symptom checklist versus what the patients volun­
teered. The median number of volunteered symptoms was one; the
median number using a checklist was 10. Fifty-two percent of these
symptoms were rated moderate or severe, 48% mild, and 53% distress­
ing. Fatigue and pain were the most common symptoms reported in
both groups.
Not everyone has access to an electronic computer-based PRO
system or the ability to integrate this into the electronic medical
record (EMR). Readily available and free scales such as the Edmonton
Symptom Assessment System–Revised can be done on paper or elec­
tronic tablets and pasted into the EMR. The most recent scale includes
questions on spirituality and financial distress and is available in many
languages (Fig. 74-1). Even with a nurse assisting the patient, the aver­
age completion time was only 117 s, so time should not be a barrier.
Using pain as the most common example of cancer symptoms, many
clinicians have been conditioned to use pain as the fifth vital sign and
almost immediately ask for a number from 0–10. First, try to establish
the generators of the symptom and classify it into a treatable subtype
(Table 74-1). It may be helpful to categorize how much each symptom
actually bothers the patient; for instance, anorexia may bother the
family but not the patient. Next, clinicians can attempt to manage the
cancer symptom. We have listed the most common cancer symptoms
in Table 74-1 and will review each in turn, including some uncommon
ones, and provide current therapeutic modalities.
INDIVIDUAL SYMPTOMS
■
■FATIGUE
Frequency 
Fatigue is the most commonly reported symptom by
patients, with often an 80% or higher prevalence.
Etiology 
Fatigue can be due to the cancer, electrolyte abnormalities
especially hypercalcemia, anemia, hypothyroidism, chemotherapy, and
immunotherapy such as pembrolizumab, nivolumab, and ipilimumab.
Besides general fatigue due to checkpoint inhibitors, 5–22% (average 6%)
of patients will develop hypothyroidism and another 1–2% de novo
hypophysitis.
Assessment 
Check for hypothyroidism, anemia, hypercalcemia
and other electrolyte abnormalities, and renal failure, also screen for
depression and/or demoralization. It is important to remember that
while most cases of hypothyroidism manifest in 6–8 weeks, it can
appear months after the patient has stopped the immunotherapy.
Treatment 
The simplest treatments consist of correcting anemia,
hypothyroidism, and/or electrolyte abnormalities (hypercalcemia).
There are few other modalities that work quickly or reliably. Paradoxi­
cally, structured exercise (e.g., 45 min of walking daily) has been shown
to be preventative and therapeutic. Rather than prescribe a new exer­
cise regimen, ask the patient what they have done before and urge them
to resume it. One can consider a trial of methylphenidate 5 mg at 7 and
11 a.m. for 48 h, with continuation if some benefit, or modafinil or
congeners. Bupropion helps; in a systematic review, six of seven studies
reported significant reductions in fatigue with minimal side effects. In
a recent randomized trial, 40 patients were randomized to bupropion
sustained release or placebo. The bupropion group had significant
improvements in fatigue and quality of life but no improvements in
depression. Steroids (e.g., dexamethasone 8 mg in the morning) can
benefit some patients, usually toward the end of life. Long-term use has
not been studied, and patients should be observed for hyperglycemia.
■
■PAIN
Frequency 
At least 80% of cancer patients will experience pain
during their lifetime. While secondary to fatigue in prevalence, it is the
most feared symptom.
Etiology 
Try to characterize the type of pain (Table 74-2).
Assessment 
Ask for a 0–10 rating for best, worst, and average pain
and what an acceptable pain score would be. List what the person
has tried before, including acupuncture, massage, other alternative/
complementary treatments, and medications. Ascertain if the patient
is on anticoagulants given the widespread use of novel oral anticoagu­
lants (NOACs).
Treatment 
• 
NOCICEPTIVE PAIN  For nociceptive pain, start
with acetaminophen, then nonsteroidal anti-inflammatory agents,
and then opioids, which should always be used with constipationpreventing measures. Recent studies have shown that the addition of
acetaminophen to high doses of opioids has no additional effect. Ste­
roids did slightly improve pain compared to placebo in cancer patients
and improved fatigue, nausea, and well-being; a Cochrane systematic
review found a reduction in pain of 0.84 on a 0-10 point scale at 1 week.
VISCERAL PAIN  Visceral pain is among the hardest to treat of all pains.
Nonsteroidal anti-inflammatory agents or neuropathic pain medica­
tions such as gabapentin or pregabalin, combined with opioids, may
be required. Octreotide in combination with opioids reduces visceral
hyperalgesia and may be helpful if nothing else works for malignant
bowel obstruction.
NEUROPATHIC PAIN  Several different classes of drugs are useful,
but the number needed to treat ranges from 3 to 7 or even 10 for all
of them. This necessitates 3- to 4-week trials of alternate drugs alone
or in combination. Contrary to common teaching, randomized trials
show that opioids do help neuropathic pain with as much benefit as
gabapentin or nortriptyline; the combination is even more effective.
A variety of neuropathic pain drugs are used: gabapentin, pregabalin,
duloxetine, nortriptyline, amitriptyline, carbamazepine, lamotrigine,
and many others. One systematic review reported that a reduction in
cancer pain intensity of >1 point was unlikely with any of these drugs.
Pain relief occurred in 4–8 days, if it occurred, so trials do not need to
be >2–3 weeks.
Chemotherapy-induced peripheral neuropathy (CIPN) is a promi­
nent clinical problem that is applicable to the vast majority of patients
Edmonton Symptom Assessment Scale (ESAS–FS)
Please circle the number that best describes your symptoms:
No Pain
No Fatigue
Worst Fatigue
No Nausea
Worst Nausea
No Depression
Worst Depression
No Anxiety
Worst Anxiety
No Drowsiness
Worst Drowsiness
No Shortness
of Breath
Worst Shortness
of Breath
Best Appetite
Worst Appetite
Best Feeling
of Well-being
Worst Feeling
of Well-being
Best Sleep
Worst Sleep
No Financial
Distress
(Distress/suffering experienced secondary to financial issues)
No Spiritual
Pain
(Pain deep in your soul/being that is not physical)
FIGURE 74-1  Edmonton Symptom Assessment System–Revised.
TABLE 74-1  Common Cancer Symptoms and Their Association
SYMPTOM
PREVALENCE
COMMONLY FOUND CAUSES/EXAMPLES
Fatigue
70–80%
Chemotherapy
Immunotherapy
Pain, all
40–70% overall
  Nociceptive
Pancreatic cancer pain
  Visceral
Intestinal obstruction
  Neuropathic
Chemotherapy-induced neuropathy
  Incident (movement)
Bone metastases
Oral and gastrointestinal
toxicity
Dependent on agents used; estimates from 30 to 40%
Standard chemotherapy such as doxorubicin
Molecularly targeted agents such as palbociclib, infigratinib, everolimus, lenvatinib
Radiation therapy
Nausea due to
chemotherapy
Dependent on emetogenic potential of drugs
administered; 10–90%
Nausea not due to
chemotherapy
Limited information on incidence but common
Due to small-bowel obstruction, opioids
Anorexia/cachexia
20–80% due to cancer
Most common in lung and pancreas cancers
Dyspnea
10–80% during a lifetime, more common near end of life
Most common in lung cancer patients or those with effusions, multiple pulmonary
metastases
Hot flashes
Two-thirds of breast cancer and three-quarters of
prostate cancer patients with androgen deprivation
Nasal vestibulitis
Up to 75% of patients
Those receiving taxanes, bevacizumab, etc.
Worst Pain
CHAPTER 74
Symptom Control in Patients with Cancer
Worst Financial
Distress
Worst Spiritual
Pain
Particularly common with cisplatin and doxorubicin
Very common but often not reported by either men or women
TABLE 74-2  Types of Commonly Encountered Cancer Pain
TYPE OF PAIN
CAUSE
CHARACTERISTICS
EXAMPLES
Nociceptive
Pressure on nerves
Deep, dull, aching, constant and worsening
with time
Visceral
Distention of a hollow viscus
Cramping, bloating pain, intermittent
Intestinal obstruction, renal colic
Neuropathic
Direct damage to the nerves from cancer,
treatment, or both
Local pain, sharp shooting, burning, stabbing,
often with allodynia (painful sensation with
normal touch) or hyperalgesia
Chemotherapy-induced neuropathic pain;
direct damage to the longest nerves with
damaged receptors and even loss of nerve
fiber density
Numbness, tingling, pain, which may be
mixed together; longest nerves affected most,
giving a stocking-glove neuropathy
Incident or movement
pain
Pathologic fractures, bone damage from
cancer, residual damage left after cancer
Minimal pain at rest, but excruciating pain
with movement “bone on bone”
receiving chemotherapy. Some chemotherapeutic agents are much
more prone to cause neuropathy than are others. Among the biggest
offenders are taxanes, platinums, epothilones, eribulin, vinca alka­
loids, bortezomib, and lenalidomide. At the time that this chapter was
written, there were no clearly established means for preventing CIPN
from any agent, other than decreasing the dose or stopping the offend­
ing drug. The most promising approach at the time this chapter was
penned involved attempts to decrease the concentration of paclitaxel in
the peripheral extremities using cryotherapy, compression therapy, or
both. Multiple preliminary trials have suggested that these approaches
are helpful. In 2024, a randomized clinical trial is ongoing to com­
pare compression therapy versus cryo-compression therapy versus a
control arm (minimal compression that is not thought to be enough
to decrease paclitaxel delivery to the distal extremities). At present,
American Society of Clinical Oncology (ASCO) guidelines suggest that
in patients who develop substantial CIPN in the midst of a treatment
course, the attending clinicians should consider stopping the offending
chemotherapy drug(s) or attenuating their dose.
PART 4
Oncology and Hematology
In terms of treating established CIPN in patients who have com­
pleted all planned neurotoxic chemotherapy, there is evidence from
more than one clinical trial that supports that duloxetine can attenuate
established neuropathy symptoms to a small degree (0.6–1.0 on a 0–10
scale). Currently, there are no other proven treatments for treating
established CIPN.
INCIDENT (MOVEMENT) PAIN DUE TO BONE METASTASES  There is
minimal evidence for any one modality to treat this type of pain.
In one convenience trial, six of six patients with bone metastasis–
incident pain had complete or near-complete responses to low doses
of gabapentin (100–200 mg three times a day) added to opioids, but
this has not been repeated (trial in the works). There is one case report
of complete pain remission for weeks until death after four treatments
with Scrambler Therapy, a form of cutaneous nerve stimulation, and
one report of “burst” ketamine with morphine.
■
■GASTROINTESTINAL AND ORAL MUCOSITIS
RELATED TO TREATMENT
Frequency 
Oral mucositis varies by drug but is reported in 30–40%
of people receiving molecularly targeted agents such as regorafenib,
sorafenib, or erdafitinib, or the breast cancer drug palbociclib. The
worst offending chemotherapy drug for oral mucositis, fluorouracil, is
not used frequently anymore. The most common cause of oral mucosi­
tis among commonly used chemotherapy drugs is doxorubicin.
Gastrointestinal (GI) mucositis can involve the entire GI tract, and
estimates range from 50–80% of cancer patients experiencing some
level of chemotherapy-induced diarrhea.
Etiology 
The most common cause is interference by the tyrosine
kinase inhibitors with endothelial growth factor receptors (GFRs) or
vascular GFRs. Drugs used for both chemotherapy and immune sup­
pression, such as everolimus, cause both inflammation and the usual
disruption of endothelial cells. At its worst, the entire GI tract can be
Pancreatic cancer pain, deep boring, and
epigastric
Increasingly common and dose limiting;
40–70% of people getting modern treatments.
Duloxetine only proven medication, which is
only moderately effective.
Very difficult to control
denuded, and the intestine cannot reabsorb the 25 L of intestinal fluid
made daily, producing high-output diarrhea. Most mucositis happens
7–10 days after treatment.
Assessment 
If the time course is right and the patient has received
a drug known to cause mucositis, suspicion should be high. Other
considerations for oral mucositis include thrush, aphthous stomatitis,
herpes, or other infections. Exam may show denuded raw areas that
are very painful.
GI mucositis is usually manifest by diarrhea, often accompanied by
cramps and pain. The diarrhea can be copious, resulting in liters per
day. If the time course is not right (very soon or weeks after cancer
therapy initiation), other causes such as infections or too many laxa­
tives should be sought.
Treatment 
For patients receiving bolus fluorouracil, sucking on
ice chips during infusion (oral cryotherapy) reduces the incidence and
severity by ~50%. There is conflicting evidence on the use of oral dexa­
methasone or other steroid rinses to prevent oral mucositis from drugs
such as everolimus and palbociclib. Most studies show improvement
after treatment with glucocorticoid rinses, regardless of the steroid.
Viscous lidocaine 2% is commonly recommended for pain. For ulcer­
ations, topical high-potency steroids are indicated, and a short course
of high-dose steroids may be necessary.
For GI mucositis manifested as diarrhea, loperamide is the first
choice, up to 24 mg a day. Octreotide up to 300 mg a day is reserved for
refractory cases. Glucocorticoids are also commonly employed.
■
■NAUSEA AND VOMITING RELATED TO
CHEMOTHERAPY
Frequency and Etiology 
It is well established that chemotherapy
can cause substantial nausea and/or vomiting, noting that this problem
is strongly associated with individual chemotherapy agents. Some
agents, such as cisplatin and doxorubicin, cause substantial nausea and
vomiting, whereas other agents, such as fluorouracil, do not cause any
substantial nausea and vomiting.
Assessment 
Clinical determination of whether a patient developed
nausea or vomiting from chemotherapy is obtained by talking to the
patient and/or their family and asking questions regarding these symp­
toms. This is often done when the patient comes back for another cycle
of therapy. Clinical trials use established PRO data that could also be
used in clinical practice. In clinical trials, data are usually obtained
before chemotherapy and then daily for a few days after each chemo­
therapy dose.
Treatment 
With highly emetogenic chemotherapy regimens, anti­
emetic drugs are started with initiation of chemotherapy and com­
monly given for a few days thereafter. Dexamethasone was established
as a helpful agent in the 1970s. In the 1990s, 5-HT3 receptor antagonists
became established agents. In the 2000s, NK1 receptor antagonists
were established as helpful agents for decreasing nausea and vomiting
in the days following highly emetogenic chemotherapy. These agents
did not decrease nausea and vomiting in the first 24 h, as did the 5-HT3
receptor antagonists; thus, NK1 receptor antagonists were added to the
antiemetic cocktail as opposed to replacing 5-HT3 receptor antagonists.
In the 2010s, olanzapine was demonstrated to decrease nausea and
vomiting when added to the three drug classes discussed above. Olan­
zapine appears to be the most effective of all of the drugs mentioned
in this section, potentially paving the way for decreasing use of other
agents in the four-drug antiemetic cocktail described above. Decreas­
ing dexamethasone doses and/or durations might decrease long-term
dexamethasone-associated toxicity.
■
■NAUSEA AND VOMITING UNRELATED TO
CHEMOTHERAPY
Frequency 
No recent data are available, but it is estimated that this
problem affects up to 40–70% of patients.
Etiology 
Nausea and vomiting in patients with cancer, not associ­
ated with chemotherapy, can be associated with multiple other etiolo­
gies, such as radiation therapy, bowel obstruction, other medications,
electrolyte abnormalities, post-anesthesia, and cerebral metastases.
Assessment 
Clinical determination of whether a patient has nausea
or vomiting is obtained from talking to the patient and/or their family
and asking questions regarding these symptoms. In clinical trials, data
are generally obtained daily, including the day prior to the planned
intervention and then for a few days following a proposed intervention.
Treatment 
A variety of drugs have been studied for treating nausea
and vomiting in this situation, but none of them are very effective; these
include diphenhydramine, metoclopramide, prochlorperazine, haloperi­
dol, methotrimeprazine, dexamethasone, ondansetron, and dronabinol.
In 2020, a double-blind, placebo-controlled clinical trial demon­
strated that a relatively low dose of olanzapine (5 mg/d) was very
effective for decreasing nausea and vomiting in patients with advanced
cancer who had not received chemotherapy or radiation therapy for at
least 2 weeks prior to study entry. In this trial involving a total of 30
patients, nausea scores decreased from 9/10 to 2/10 on the day after
olanzapine was started, in comparison to the placebo group whose
nausea scores were 9/10 on both the day before and the day after the
first dose of the placebo (p <.001). Another trial, published in 2023,
demonstrated that 2.5 mg/d of olanzapine markedly reduced nausea
and vomiting in patients with advanced cancer who were not receiving
highly emetogenic chemotherapy.
■
■ANOREXIA AND CACHEXIA
Frequency 
Up to 20% of all cancer deaths are strongly associated
with cancer cachexia. Anorexia is even more common, affecting 5–25%
of community-dwelling adults and twice that number of patients with
cancer.
Etiology 
Although most anorexia is caused by release of hormones by
cancer, it can be aggravated by drug treatments, radiation, mechanical dif­
ficulties in eating, and food insecurity. Cachexia is multifactorial and char­
acterized by weight loss of skeletal muscle and adipose tissue, an imbalance
in metabolic regulation, and reduced food intake. In general, cancer
cachexia cannot be reversed by simply replacing calories and nutrients.
Assessment 
Anorexia is determined simply by asking the patient
and family about appetite. Cachexia has been variously defined as 5 or
10% loss of precancer weight. More precise definitions have included
the presence of fatigue, anorexia, increased inflammatory markers such
as C-reactive protein, body mass index <20, and even sarcopenia on a
computed tomography scan.
Treatment 
Treatment is often unsatisfactory for both patients
and their families. A systematic review done for an ASCO guideline
regarding this topic showed that dietary counseling was associated
with increased weight gain in some but not all trials and can be rea­
sonably offered. The magnitude of this approach, however, is not large.
Enteral feeding tubes and intravenous nutrition are not recommended
and should not be used routinely. For anorexia, olanzapine is recom­
mended as the first-line agent and the only agent with good evidence
of benefit without potentially serious harm. In the largest randomized
controlled trial, 124 solid tumor patients received olanzapine 2.5 mg
at bedtime versus placebo. Sixty percent of the olanzapine patients
increased their weight by at least 5% versus 9% of placebo patients
(p <.001). Mirtazapine, which is commonly prescribed, was ineffective
in a large randomized trial and should not be used. Megestrol acetate
and corticosteroids do increase appetite in afflicted patients and lead to
some weight gain but have untoward side effects and do not appear to
improve patient survival. A novel approach is to block the elevated lev­
els of growth differentiation factor 15 (GDF-15), a serum cytokine that
is elevated in cachexia with ponsegromab. This monoclonal antibody
was associated with improved appetite, weight, and physical activity in
a randomized phase 2 trial, but it has not been approved by the FDA.
■
■CONSTIPATION
Frequency 
Constipation occurs in 20–90% of all cancer patients at
some time in their trajectory and can be both painful and associated
with anorexia and nausea.
CHAPTER 74
Etiology 
Causes include commonly used drugs such as opioids,
acetaminophen, ondansetron, chemotherapy (vandetanib, thalido­
mide, lenalidomide), and noncancer drugs such as diuretics and
antidementia drugs. Inactivity, dehydration, a low-fiber diet, hypercal­
cemia, and hypothyroidism (including up to 20% of patients receiving
checkpoint inhibitors) can all be contributing factors.
Symptom Control in Patients with Cancer
Assessment 
Clinicians should ask what the personal bowel habits
have been and when the patient last had a bowel movement. If it was 3
or more days ago, constipation is highly likely. Using a specific scale or
grading the consistency of the stool is not recommended.
Treatment 
Good bowel hygiene starts with prevention and using
drugs that the patient can tolerate. Every opioid prescription should be
accompanied by a plan to prevent constipation. Senna is the first choice,
starting at 1–2 tablets a day and working up to 8, along with sufficient
hydration. Some patients may have cramps from the stimulant action
requiring multiple doses a day or switching drugs. Polyethylene glycol is
added next, if needed and/or if senna is not tolerated. Lactulose and sor­
bitol are less commonly used because they commonly are less palatable.
Magnesium oxide (1 oz of a 300-mL bottle hourly until movements start)
can be helpful. Patients on opioids who are refractory to these measures
usually have success with opioid antagonists that reverse the opioid in the
periphery but not the brain. Because of cost, these agents currently may
require insurance preauthorization, so they are likely not used very often.
■
■DYSPNEA
Frequency 
Dyspnea (or breathlessness or air hunger) is, like pain, a
subjective experience that can only be assessed by the patient. Dyspnea
is common, with 10–70% of patients reporting it, especially toward
the end of life. Dyspnea portends a poor prognosis in advanced cancer
with an average survival of only days, weeks, or months, and should
trigger serious illness conversations such as being fully truthful about
prognosis and creation of an advance directive. ASCO guidelines rec­
ommend a systematic assessment for dyspnea at every inpatient and
outpatient visit in patients with advanced cancer.
Etiology 
As with most cancer symptoms, dyspnea is multifactorial.
Lung dysfunction may be due to the cancer, radiation, chemotherapy,
and/or immunotherapy. With immunotherapy, the average time to onset
was 52 days in one trial, and the incidence in one large series was 9.5%.
Assessment 
The first attempt should be to find something that is
reversible (e.g., hypoxia, pneumonia, pulmonary embolism, pleural
effusion, chronic obstructive pulmonary disease, asthma, or bronchial
constriction due to cancer). Next should come a careful review of
medication history, especially for checkpoint inhibitors, remembering
that pneumonitis may develop months after the immunotherapy has
stopped. The impact of the dyspnea on the patient and the family
should be assessed. Management of immunotherapy-related lung dis­
ease may best be done by experts, as the therapies can be challenging
and have been rapidly changing.
Treatment 
Treatment of the cancer, if deemed to have a good
chance of success, should be a mainstay. Other contributing factors
such as anxiety or chronic obstructive pulmonary disease (COPD)
should be maximally treated. High-dose steroids are commonly used
in the setting of lymphangitic carcinomatosis, COPD, or asthma. Opi­
oids at low doses are generally safe and can be helpful in relieving air
hunger, and low-dose benzodiazepines can help relieve anxiety. A fan
blowing cold air across the face can give some comfort.
Supplemental oxygen should be available for patients with hypox­
emia (i.e., SpO2 ≤90% on room air). High-flow nasal oxygen (HFNO) is
often used as a bridge to a next therapy, if there is one; commitment to
HFNO complicates referral to hospice or home due to the cost. Refer­
ral to palliative care should always be considered, along with truthful
information about prognosis and a serious illness conversation includ­
ing advance directives.
■
■HOT FLASHES
PART 4
Oncology and Hematology
Frequency 
Hot flashes are common; they occur in about twothirds of postmenopausal women treated for breast cancer, and almost
half have night sweats. Of men treated with chemical or surgical
orchiectomy for prostate cancer, three-quarters will have hot flashes.
Common knowledge, in the not too distant past, was that hot flashes
usually only lasted a couple of years. However, it is now understood
that patients can have them for decades.
Etiology 
Lack of estrogen or testosterone is the proximate cause of
hot flashes, especially when the decrease is rapid.
Assessment 
Asking about hot flashes, including frequency, sever­
ity, and interference with life, should be part of the appropriate care of
prostate or breast cancer patients.
Treatment 
• 
FEMALES  In the 1990s, four separate individuals
clinically noted that patients receiving newer antidepressants, at least
new at that time, appeared to have reduced hot flashes; these antide­
pressants were venlafaxine, paroxetine, sertraline, and fluoxetine. Such
observations resulted in randomized, placebo-controlled clinical trials
that showed that these and other antidepressants substantially helped
women with hot flashes. The authors of this chapter, when it is decided
to utilize an antidepressant for treating hot flashes, recommend citalo­
pram, 20 mg/d, as it appears as effective as other antidepressants and
is well tolerated. Gabapentin also has efficacy against hot flashes and
reduces anxiety in breast cancer survivors. Oxybutynin, immediate
or sustained release, also showed efficacy in randomized trials. This
can be a relatively inexpensive treatment approach. Caution is recom­
mended in older women, as there are concerns regarding mental status
changes in the setting of long-term use. In refractory patients, 20–40 mg of
megestrol acetate a day can control hot flashes. For women who desire
a one-time intramuscular injection, 400–500 mg of medroxyprogester­
one acetate can nicely decrease hot flashes for many months.
Fezolinetant, an NK3 receptor antagonist, became clinically avail­
able in 2023 as a nonhormonal agent for treating hot flashes in women
in general. Although it works as well as some of the other treatments
noted above, cross-study comparisons of the efficacy of this drug to the
other options mentioned above suggest that hot flash reductions are
similar. In a series of studies that included >1300 patients, some with a
history of breast cancer (which amounted to ~75% of the subjects) and
some without a history of breast cancer (the other 25% of patients), hot
flash outcomes were similar. Additionally, this article revealed that hot
flash reductions were similar whether or not a patient was receiving
tamoxifen.
MALES  Pilot trials of venlafaxine and paroxetine supported that they
were useful for alleviating hot flashes in men with prostate cancer.
However, a randomized trial was not able to demonstrate significant
benefit from venlafaxine for controlling hot flashes in men. A prospec­
tive, randomized, placebo-controlled trial demonstrated that 900 mg/d
of gabapentin works well for treating hot flashes in men, similarly to
how it works in women.
Progesterone analogues also decrease hot flashes in men, similarly
to how they do so in women.
Case reports support that oxybutynin is helpful in men with hot
flashes; a recently completed randomized, double-blind, placebocontrolled clinical trial demonstrated that this drug nicely decreased
hot flashes in this population, too.
■
■NASAL VESTIBULITIS
Frequency 
Nasal vestibulitis refers to an unpleasant inflamma­
tion of the vestibule of the nose. An observational interview study of
patients who had received at least 6 weeks of chemotherapy noted that
70% of those receiving taxanes and >80% of those receiving bevaci­
zumab experienced untoward nasal symptoms, such as pain, bleeding,
and/or scabbing. A prospective study of patients receiving a variety of
different chemotherapy regimens illustrated that >75% of patients who
received paclitaxel, nab-paclitaxel, or bevacizumab developed bother­
some nasal symptoms in the following weeks to months.
Etiology 
Chemotherapy can damage the epithelial cells in the nose,
leading to dryness, cracking, and secondary infection. Like mucositis,
it generally heals in 7–10 days but is a potential source for infection.
Assessment 
Asking about symptoms of dryness, bleeding, crust­
ing, or pain and an exam should confirm local tissue irritation.
Treatment 
Nasal sprays of saline and of rose geranium in sesame
oil have been used to treat this clinical problem, with data supporting
that the latter is more beneficial. This will have to be compounded; the
recipe is available from the authors or the Mayo Clinic.
■
■FURTHER READING
Basch E et al: Overall survival results of a trial assessing patientreported outcomes for symptom monitoring during routine cancer
treatment. JAMA 318:197, 2017.
Correa-Morales JE et al: Cancer and non-cancer fatigue treated with
bupropion: A systematic review. J Pain Symptom Manage 65:e21, 2023.
Finnerup NB et al: Neuropathic pain: From mechanisms to treatment.
Physiol Rev 101:259, 2021.
Groarke JD et al: Ponsegromab for the Treatment of Cancer Cachexia.
N Engl J Med 391:2291, 2024.
Homsi J et al: Symptom evaluation in palliative medicine: Patient
report vs systematic assessment. Support Care Cancer 14:444, 2006.
Hui D, Bruera E: The Edmonton Symptom Assessment System 25 years
later: Past, present, and future developments. J Pain Symptom Man­
age 53:630, 2017.
Loprinzi CL et al: Prevention and management of chemotherapyinduced peripheral neuropathy in survivors of adult cancers: ASCO
guideline update. J Clin Oncol 38:3325, 2020.
Mannix KA: Palliation of nausea and vomiting, in Oxford Textbook of
Palliative Medicine, 2nd ed. Doyle D et al (eds). Oxford, UK, Oxford
University Press, 1998, p. 48.
Molinares D et al: Chemotherapy-induced peripheral neuropathy:
Diagnosis, agents, general clinical presentation, and treatments. Curr
Oncol Rep 25:1227, 2023.
Navari RM et al: Olanzapine for the treatment of advanced cancerrelated chronic nausea and/or vomiting: A randomized pilot trial.
JAMA Oncol 6:895, 2020.
Roeland EJ et al: Cancer Cachexia Expert Panel. Cancer cachexia: ASCO
guideline rapid recommendation update. J Clin Oncol 41:4178, 2023.
Smith TJ, Saiki CB: Cancer pain management. Mayo Clin Proc
90:1428, 2015.

04 - 75 Prevention and Early Detection of Cancer
75 Prevention and Early Detection of Cancer
Jennifer M. Croswell, Otis W. Brawley,
Barnett S. Kramer
Prevention and Early
Detection of Cancer
Improved understanding of carcinogenesis has allowed cancer preven­
tion and early detection to expand beyond identification and avoid­
ance of carcinogens. Specific interventions to reduce cancer mortality
by preventing cancer in those at risk and effective screening for early
detection of cancer are the goals.
Carcinogenesis is a process that usually extends over years, a con­
tinuum of discrete tissue and cellular changes over time resulting in
aberrant physiologic processes. Prevention concerns the identification
and manipulation of the biologic, environmental, social, and genetic
factors in the causal pathway of cancer. Examination of national epide­
miologic patterns can provide indicators of the relative contributions
of advances in prevention, screening, and therapy in progress against
cancer, but randomized trials provide the best evidence to guide prac­
tice, especially in the healthy general population.
EDUCATION AND HEALTHFUL HABITS
Public education on the avoidance of identified risk factors for cancer
and encouraging healthy habits contributes to cancer prevention. The
clinician is a powerful messenger in this process. The patient-provider
encounter provides an opportunity to teach patients about the hazards
of smoking, influence of a healthy lifestyle and other exposures, and
use of proven cancer screening methods.
■
■SMOKING CESSATION
Tobacco smoking is a strong, modifiable risk factor for cardiovascu­
lar disease, pulmonary disease, and cancer. Smokers have an ∼1 in 3
lifetime risk of dying prematurely from a tobacco-related cancer, car­
diovascular, or pulmonary disease, and cigarette smoking shortens life
expectancy, on average, by a decade. Tobacco use causes more deaths
from cardiovascular disease than from cancer. Lung cancer and cancers
of the larynx, oropharynx, esophagus, kidney, bladder, colon, pancreas,
stomach, and uterine cervix are all tobacco related.
The number of cigarettes smoked per day and the level of inhalation
of cigarette smoke are correlated with risk of lung cancer mortality.
Light- and low-tar cigarettes are not safer because smokers tend to
inhale them more frequently and deeply.
Those who stop smoking have a 30–50% lower 10-year lung cancer
mortality rate compared to those who continue smoking, despite the
fact that some carcinogen-induced gene mutations persist for years
after smoking cessation. Smoking cessation and avoidance would save
more lives from cancer than any other public health activity.
The risk of tobacco smoke is not limited to the smoker. Environ­
mental tobacco smoke, known as secondhand or passive smoke, is
carcinogenic and associated with a variety of respiratory illnesses in
exposed children.
Tobacco use prevention is a pediatric issue. More than 80% of adult
American smokers began smoking before the age of 18 years. Tradi­
tional cigarette smoking has declined substantially in recent years: for
example, for high school seniors between 2012 and 2019, prevalence of
past 30-day cigarette smoking dropped from 19% to 7% for boys and
7% to 2% for girls. Electronic cigarettes, on the other hand, are rapidly
increasing in use: in 2020, approximately 20% of high school students
reported being current electronic cigarette users. Counseling of ado­
lescents and young adults is critical to prevent all forms of tobacco use.
A clinician’s simple advice can be of benefit. Providers should query
patients on tobacco use and offer smokers assistance in quitting or
referrals to cessation programs.
Current approaches to smoking cessation recognize nicotine in
tobacco as addicting (Chap. 465). The smoker who is quitting goes
through identifiable stages, including contemplation of quitting, an
action phase in which the smoker quits, and a maintenance phase.
Smokers who quit completely are more likely to be successful than
those who gradually reduce the number of cigarettes smoked or
change to lower-tar or lower-nicotine cigarettes. Organized cessation
programs may help individual efforts. Heavy smokers may need an
intensive broad-based cessation program that includes counseling,
behavioral strategies, and pharmacologic adjuncts, such as nicotine
replacement (gum, patches, sprays, lozenges, and inhalers), bupropion,
and/or varenicline. Electronic cigarettes have been advocated as a tool
to achieve smoking cessation or as a harm reduction strategy in adults,
but the net effects of electronic cigarettes on health are poorly studied.
Absence of strict manufacturing controls of vaping material has pro­
duced serious injury.
The health risks of cigars are similar to those of cigarettes. Smok­
ing one or two cigars daily doubles the risk for oral and esophageal
cancers; smoking three or four cigars daily increases the risk of oral
cancers more than eightfold and esophageal cancer fourfold. The risks
of occasional use are unknown.
Smokeless tobacco also represents a substantial health risk. Chewing
tobacco is linked to dental caries, gingivitis, oral leukoplakia, and oral
cancer. The systemic effects of smokeless tobacco (including snuff)
may increase risks for other cancers. Esophageal cancer is linked to
carcinogens in tobacco dissolved in saliva and swallowed.
CHAPTER 75
■
■PHYSICAL ACTIVITY
Physical activity is associated with a decreased risk of colon and breast
cancer. A variety of mechanisms have been proposed. However, such
studies are prone to confounding factors such as recall bias, association
of exercise with other health-related practices, and effects of preclinical
cancers on exercise habits (reverse causality).
Prevention and Early Detection of Cancer
■
■DIET MODIFICATION
International ecologic studies suggest that diets high in fat are associ­
ated with increased risk for cancers of the breast, colon, prostate, and
endometrium. Despite correlations, dietary fat has not been proven
to cause cancer. Case-control and cohort epidemiologic studies give
conflicting results. Diet is a highly complex exposure to many nutrients
and chemicals. Low-fat diets are associated with many dietary changes
beyond simple subtraction of fat. Other lifestyle factors are also associ­
ated with adherence to a low-fat diet.
In some observational studies, dietary fiber has been associated
with a reduced risk of colonic polyps and invasive cancer of the colon.
Two large prospective cohort studies of >100,000 health professionals
showed no association between fruit and vegetable intake and risk
of cancer, however. Cancer-protective effects of increasing fiber and
lowering dietary fat have not been shown in the context of a prospec­
tive clinical trial. The Polyp Prevention Trial randomly assigned 2000
elderly persons, who had polyps removed, to a low-fat, high-fiber diet
versus routine diet for 4 years. No differences were noted in polyp
formation.
The U.S. National Institutes of Health Women’s Health Initiative,
launched in 1994, was a long-term clinical trial enrolling >100,000
women age 45–69 years. It placed women into 22 intervention groups.
Participants received calcium/vitamin D supplementation; hormone
replacement therapy; and counseling to increase exercise, eat a lowfat diet with increased consumption of fruits, vegetables, and fiber,
and cease smoking. The study showed that although dietary fat intake
was lower in the diet intervention group, invasive breast cancers were
not reduced over an 8-year follow-up period compared to the control
group. Additionally, no reduction was seen in the incidence of colorec­
tal cancer in the dietary intervention arm. In the aggregate, cohort
studies and randomized trials suggest that reduction of red meat or
processed meat consumption has a small (if any) effect on cancer
incidence and mortality, although the overall evidence base is weak.
Evidence does not currently establish the anticarcinogenic value of
vitamin, mineral, or nutritional supplements in amounts greater than
those provided by a balanced diet.
■
■ENERGY BALANCE
Risk of certain cancers appears to increase modestly (relative risks gen­
erally in the 1.0–2.0 range) as body mass index (BMI) increases beyond
25 kg/m2. A cohort study of >5 million adults included in the U.K.
Clinical Practice Research Datalink (a primary care database) found
that each 5 kg/m2 increase in BMI was linearly associated with cancers
of the uterus, gallbladder, kidney, cervix, thyroid, and leukemia. High
BMI appears to have an inverse association with prostate and premeno­
pausal breast cancer.
■
■SUN AVOIDANCE
Nonmelanoma skin cancers (basal cell and squamous cell) are induced
by cumulative exposure to ultraviolet (UV) radiation. Evidence for a
direct association between cumulative UV exposure and melanoma is
weaker. Reduction of sun exposure through use of protective clothing
and changing patterns of outdoor activities can reduce skin cancer
risk. Sunscreens decrease the risk of actinic keratoses, the precursor
to squamous cell skin cancer, but melanoma risk may not be reduced.
Sunscreens prevent burning, but they may encourage more prolonged
exposure to the sun and may not filter out wavelengths of energy that
cause melanoma.
Appearance-focused behavioral interventions in young women
can decrease indoor tanning use and other UV exposures and may be
more effective than messages about long-term cancer risks. Those who
recognize themselves as being at risk tend to be more compliant with
sun-avoidance recommendations. Risk factors for melanoma include
a propensity to sunburn, a large number of benign melanocytic nevi,
and atypical nevi. However, about 70–80% of melanomas arise de novo,
rather than from existing benign nevi.
PART 4
Oncology and Hematology
CANCER CHEMOPREVENTION
Chemoprevention involves the use of specific natural or synthetic
chemical agents to reverse, suppress, or prevent carcinogenesis before
the development of invasive malignancy.
Cancer develops through an accumulation of tissue abnormalities
associated with genetic and epigenetic changes, and growth regulatory
pathways that are potential points of intervention to prevent cancer.
The initial changes are termed initiation. The alteration can be inher­
ited or acquired through the action of physical, infectious, or chemical
carcinogens. Like most human diseases, cancer arises from an interaction
between genetics and environmental exposures (Table 75-1). Influences
that cause the initiated cell and its surrounding tissue microenviron­
ment to progress through the carcinogenic process and change phe­
notypically are termed promoters. Promoters include hormones such
as androgens, linked to prostate cancer, and estrogen, linked to breast
and endometrial cancer. The difference between an initiator and pro­
moter is indistinct; some components of cigarette smoke are “complete
carcinogens,” acting as both initiators and promoters. Cancer can be
prevented or controlled through avoidance of the factors that cause
cancer initiation, promotion, or progression. Compounds of interest
in chemoprevention may have antimutagenic, hormone modulation,
anti-inflammatory, antiproliferative, or proapoptotic activity (or a
combination).
■
■CHEMOPREVENTION OF CANCERS OF THE
UPPER AERODIGESTIVE TRACT
Smoking causes diffuse epithelial injury in the oral cavity, esophagus,
and lung. Patients cured of squamous cell cancers of the lung, esopha­
gus, and oral cavity are at risk (as high as 5% per year) of developing
second cancers of the upper aerodigestive tract. Cessation of cigarette
smoking does not markedly decrease the cured cancer patient’s risk of
second malignancy, even though it does lower the cancer risk in those
who have never developed a malignancy.
Persistent oral human papillomavirus (HPV) infection, particularly
HPV-16, increases the risk for cancers of the oropharynx. This associa­
tion exists even in the absence of other risk factors such as smoking or
alcohol use (although the magnitude of increased risk appears greater
than additive when HPV infection and smoking are both present). Oral
HPV infection is believed to be largely sexually acquired. The use of
TABLE 75-1  Suspected Carcinogens
CARCINOGENSa
ASSOCIATED CANCER OR NEOPLASM
Alkylating agents
Acute myeloid leukemia, bladder cancer
Androgens
Prostate cancer
Aromatic amines (dyes)
Bladder cancer
Arsenic
Cancer of the lung, skin
Asbestos
Cancer of the lung, pleura, peritoneum
Benzene
Acute myelocytic leukemia
Chromium
Lung cancer
Diethylstilbestrol (prenatal)
Vaginal cancer (clear cell)
Epstein-Barr virus
Burkitt’s lymphoma, nasal T-cell lymphoma
Estrogens
Cancer of the endometrium, liver, breast
Ethyl alcohol
Cancer of the breast, liver, esophagus, head
and neck
Helicobacter pylori
Gastric cancer, gastric mucosa-associate
lymphoid tissue (MALT) lymphoma
Hepatitis B or C virus
Liver cancer
Human immunodeficiency virus
Non-Hodgkin’s lymphoma, Kaposi’s sarcoma,
squamous cell carcinomas (especially of the
urogenital tract)
Human papillomavirus
Cancers of the cervix, anus, oropharynx
Human T-cell lymphotropic virus
type 1 (HTLV-1)
Adult T-cell leukemia/lymphoma
Immunosuppressive agents
(azathioprine, cyclosporine,
glucocorticoids)
Non-Hodgkin’s lymphoma
Ionizing radiation (therapeutic
or diagnostic)
Breast, bladder, thyroid, soft tissue, bone,
hematopoietic, and many more
Nitrogen mustard gas
Cancer of the lung, head and neck, nasal
sinuses
Nickel dust
Cancer of the lung, nasal sinuses
Diesel exhaust
Lung cancer (miners)
Phenacetin
Cancer of the renal pelvis and bladder
Polycyclic hydrocarbons
Cancer of the lung, skin (especially squamous
cell carcinoma of scrotal skin)
Radon gas
Lung cancer
Schistosomiasis
Bladder cancer (squamous cell)
Sunlight (ultraviolet)
Skin cancer (squamous cell and likely
melanoma)
Tobacco (including smokeless)
Cancer of the upper aerodigestive tract,
bladder, kidney
Vinyl chloride
Liver cancer (angiosarcoma)
aAgents that are thought to act as cancer initiators and/or promoters.
the HPV vaccine is associated with a reduction in prevalence of oro­
pharyngeal infection rates and may eventually reduce oropharyngeal
cancer rates.
Oral leukoplakia, a premalignant lesion commonly found in smok­
ers, has been used as an intermediate marker of chemopreventive
activity in smaller shorter-duration, randomized, placebo-controlled
trials. Although therapy with high, relatively toxic doses of isotretinoin
(13-cis-retinoic acid) causes regression of oral leukoplakia, more toler­
able doses of isotretinoin have not shown benefit in the prevention of
head and neck cancer.
Several large-scale trials have assessed agents in the chemopreven­
tion of lung cancer in patients at high risk. In the α-tocopherol/βcarotene (ATBC) Lung Cancer Prevention Trial, participants were male
smokers with an average 30-plus pack-year history, age 50–69 years at
entry. After median follow-up of 6 years, lung cancer incidence and
mortality were statistically significantly increased in those receiving
β-carotene. α-Tocopherol had no effect on lung cancer mortality, but
patients receiving it had a higher incidence of hemorrhagic stroke.
The β-Carotene and Retinol Efficacy Trial (CARET) involved 17,000
American smokers and workers with asbestos exposure. This trial also
demonstrated harm from β-carotene: a lung cancer rate of 5 per 1000
subjects per year for those taking placebo versus 6 per 1000 subjects per
year for those taking β-carotene.
The ATBC and CARET results demonstrate the importance of
testing chemoprevention hypotheses in randomized trials before
widespread implementation because the results contradict a number of
observational studies.
■
■CHEMOPREVENTION OF COLON CANCER
No agent with sufficient evidence exists at present for the prevention of
colon cancer in the general population.
A meta-analysis of four randomized controlled trials primarily
designed to examine aspirin’s effects on cardiovascular events found
no association between low-dose aspirin use and colorectal cancer inci­
dence at up to 10 years of follow-up. The same review reported highly
variable results for colorectal cancer mortality and aspirin use and
noted that, overall, studies have not been adequately powered to assess
aspirin’s effects on colorectal cancer deaths. As such, the evidence
is insufficient that nonsteroidal anti-inflammatory drugs (NSAIDs)
reduce colorectal cancer incidence or mortality. However, there is clear
evidence that regular NSAID use is associated with important bleeding
harms, such as major gastrointestinal and intra- and extracranial bleed­
ing, particularly with increasing dosage and age.
Cyclooxygenase-2 (COX-2) inhibitors have been considered for
colorectal cancer and polyp prevention. Trials with COX-2 inhibitors
were initiated, but an increased risk of cardiovascular events in those
taking the COX-2 inhibitors was noted, so these agents are not suitable
for chemoprevention in the general population.
The Women’s Health Initiative demonstrated that postmenopausal
women taking estrogen plus progestin have a 44% lower relative risk
of colorectal cancer compared to women taking placebo. Of >16,600
women randomized and followed for a median of 5.6 years, 43 inva­
sive colorectal cancers occurred in the hormone group and 72 in the
placebo group. The positive effect on colon cancer is mitigated by the
modest increase in cardiovascular and breast cancer risks associated
with combined estrogen plus progestin therapy, and guidelines do
not recommend hormonal therapy as a standard preventive agent for
colorectal cancer incidence or mortality.
Most case-control and cohort studies have not confirmed early
reports of an association between regular statin use and a reduced risk
of colorectal cancer. No randomized controlled trials have addressed
this hypothesis. A meta-analysis of statin use showed no protective
effect of statins on overall cancer incidence or death.
■
■CHEMOPREVENTION OF BREAST CANCER
Tamoxifen is an antiestrogen with partial estrogen agonistic activity
in some tissues, such as endometrium and bone. One of its actions is
to upregulate transforming growth factor β, which decreases breast
cell proliferation. In a randomized placebo-controlled prevention
trial involving >13,000 pre- and postmenopausal women at high risk,
tamoxifen decreased the risk of developing breast cancer by 49% (from
43.4 to 22 per 1000 women) after a median follow-up of nearly 6 years.
Tamoxifen also reduced bone fractures; a small increase in risk of endo­
metrial cancer, stroke, pulmonary emboli, and deep vein thrombosis
was noted. The International Breast Cancer Intervention Study (IBIS-I)
and the Italian Randomized Tamoxifen Prevention Trial also demon­
strated reductions in breast cancer incidence with tamoxifen use. A
trial comparing tamoxifen with another selective estrogen receptor
modulator, raloxifene, performed in postmenopausal women showed
that raloxifene is comparable to tamoxifen in cancer prevention but
without the risk of endometrial cancer. Raloxifene was associated with
a smaller reduction in invasive breast cancers and a trend toward more
noninvasive breast cancers, but fewer thromboembolic events than
tamoxifen; the drugs are similar in risks of other cancers, fractures,
ischemic heart disease, and stroke. Both tamoxifen and raloxifene (the
latter for postmenopausal women only) have been approved by the U.S.
Food and Drug Administration (FDA) for reduction of breast cancer in
women at high risk for the disease (1.66% risk at 5 years based on the
Gail risk model: http://www.cancer.gov/bcrisktool/).
Because the aromatase inhibitors (anastrozole, exemestane, and
letrozole) are even more effective than tamoxifen in adjuvant breast
cancer treatment, it has been hypothesized that they would be
more effective in breast cancer prevention. A randomized, placebocontrolled trial of exemestane reported a 65% relative reduction
(from 5.5 to 1.9 per 1000 women) in the incidence of invasive breast
cancer in women at elevated risk after a median follow-up of about
3 years. Common adverse effects included arthralgias, hot flashes,
fatigue, and insomnia. No trial has directly compared aromatase
inhibitors with selective estrogen receptor modulators for breast cancer
chemoprevention.
■
■CHEMOPREVENTION OF PROSTATE CANCER
Finasteride and dutasteride are 5-α-reductase inhibitors. They inhibit
conversion of testosterone to dihydrotestosterone (DHT), a potent
stimulator of prostate cell proliferation. The Prostate Cancer Preven­
tion Trial (PCPT) randomly assigned men age 55 years or older at
average risk of prostate cancer to finasteride or placebo. All men in
the trial were being regularly screened with prostate-specific antigen
(PSA) levels and digital rectal examination. After 7 years of therapy,
the overall incidence of prostate cancer was 18.4% in the finasteride
arm, compared with 24.4% in the placebo arm, a statistically signifi­
cant reduction. However, the finasteride group had more patients with
tumors of Gleason score 7 and higher compared with the placebo arm
(6.4 vs 5.1%). Long-term (10–15 years) follow-up did not reveal any
statistically significant differences in overall or prostate cancer–specific
mortality between all men in the finasteride and placebo arms or in
men diagnosed with prostate cancer, but the power to detect a differ­
ence was limited.
CHAPTER 75
Prevention and Early Detection of Cancer
Dutasteride has also been evaluated as a preventive agent for pros­
tate cancer. The Reduction by Dutasteride of Prostate Cancer Events
(REDUCE) trial was a randomized double-blind trial in which ∼8200
men with an elevated PSA (2.5–10 ng/mL for men age 50–60 years
and 3–10 ng/mL for men age 60 years or older) and negative prostate
biopsy on enrollment received daily 0.5 mg of dutasteride or placebo.
The trial found a statistically significant 23% relative risk reduction in
the incidence of biopsy-detected prostate cancer in the dutasteride arm
at 4 years of treatment (659 cases vs 858 cases, respectively). Overall,
across years 1 through 4, no difference was seen between the arms in
the number of tumors with a Gleason score of 7 to 10; however, during
years 3 and 4, there was a statistically significant difference in tumors
with Gleason score of 8 to 10 in the dutasteride arm (12 tumors vs 1
tumor, respectively).
The finding of an apparent increased incidence of higher-grade
tumors likely represents an increased sensitivity of PSA and digital
rectal exam for high-grade tumors in men receiving 5-α-reductase
inhibitors due to a decrease in prostatic volume. Although detection
bias may have accounted for the finding, a causative role cannot be
conclusively dismissed. These agents are therefore not FDA-approved
for prostate cancer prevention.
Because all men in both the PCPT and REDUCE trials were being
screened and because screening approximately doubles the rate of
prostate cancer, it is not known if finasteride or dutasteride decreases
the risk of prostate cancer in men who are not being screened or
simply reduces the risk of non-life-threatening cancers detectable by
screening.
Several favorable laboratory and observational studies led to the
formal evaluation of selenium and α-tocopherol (vitamin E) as poten­
tial prostate cancer preventives. The Selenium and Vitamin E Cancer
Prevention Trial (SELECT), after a median follow-up of 7 years, found
a trend toward an increased risk of developing prostate cancer for men
taking vitamin E alone as compared to placebo (hazard ratio 1.17; 95%
confidence interval, 1.004–1.36).
■
■VACCINES AND CANCER PREVENTION
A number of infectious agents cause cancer. Hepatitis B and C viruses
are linked to liver cancer; some HPV strains are linked to cervical, anal,
and oropharyngeal cancer; and Helicobacter pylori is associated with
gastric adenocarcinoma and gastric lymphoma. Vaccines to protect
against these agents may therefore reduce the risk of their associated
cancers.
The hepatitis B vaccine is effective in preventing hepatitis and hepa­
tomas due to chronic hepatitis B infection.
A nonavalent HPV vaccine (covering strains 6, 11, 16, 18, 31, 33, 45,
52, and 58) is available for use in the United States. HPV types 6 and 11
cause genital papillomas. The remaining HPV types cause cervical and
anal cancer; reduction in HPV types 16 and 18 alone could theoreti­
cally prevent >70% of cervical cancers worldwide. For individuals not
previously infected with these HPV strains, the vaccine demonstrates
high efficacy in preventing persistent strain-specific HPV infections.
Studies also confirm the vaccine’s ability to prevent preneoplastic
lesions (cervical or anal intraepithelial neoplasia [CIN/AIN] I, II, and
III). The vaccine does not appear to impact preexisting infections. A
two-dose schedule is currently recommended in the United States for
females and males age 9–14 years; teens and young adults who start the
series between 15 and 26 years are recommended to receive three doses
of the vaccine. However, observational studies suggest similar efficacy
with a single dose in young girls, and a large randomized trial is cur­
rently comparing one to two doses.
SURGICAL PREVENTION OF CANCER
Some organs in some individuals are at such high risk of developing
cancer that surgical removal of the organ at risk may be considered.
Women with severe cervical dysplasia are treated with laser or loop
electrosurgical excision or conization. Colectomy may be used to
prevent colon cancer in patients with familial polyposis or ulcerative
colitis.
PART 4
Oncology and Hematology
Prophylactic bilateral mastectomy may be chosen for breast can­
cer prevention among women with high-risk genetic predisposition
to breast cancer. In a prospective series of 139 women with BRCA1
and BRCA2 mutations, at 3 years, no cases of breast cancer had been
diagnosed in those opting for surgery (n = 76), but eight of 63 patients
in the surveillance group had developed breast cancer. A larger retro­
spective cohort study reported three patients developed breast cancer
after prophylactic mastectomy compared with an expected incidence
of 30–53 cases. Postmastectomy breast cancer–related deaths were
81–94% lower in high-risk women compared with sister controls and
100% lower in moderate-risk women when compared with expected
rates.
Prophylactic salpingo-oophorectomy may also be employed for the
prevention of ovarian and breast cancers among high-risk women. A
prospective cohort study evaluating the outcomes of BRCA mutation
carriers demonstrated a statistically significant association between
prophylactic salpingo-oophorectomy and a reduced incidence of ovar­
ian or primary peritoneal cancer (36% relative risk reduction, or a 4.5%
absolute difference).
Studies of prophylactic oophorectomy for prevention of breast
cancer in women with genetic mutations have shown relative risks of
approximately 0.50; the risk reduction may be greatest for women hav­
ing the procedure at younger (i.e., <45–50) ages. The observation that
most high-grade serous “ovarian cancers” actually arise in the fallopian
tube fimbria raises the possibility that this lethal subtype may be pre­
vented by ovary-sparing salpingectomy. Formal testing of this hypoth­
esis is important because an emulated target trial (i.e., study design
principles of an randomized controlled trial applied to observational
data to estimate causal effects) demonstrated associations between
bilateral salpingo-oophorectomy during benign hysterectomy and an
increased risk for cardiovascular disease when done in premenopausal
women and a trend toward increased 10-year mortality in all ages (with
statistical significance in perimenopausal women).
All of the evidence concerning the use of prophylactic mastectomy
and salpingo-oophorectomy for prevention of breast and ovarian can­
cer in high-risk women has been observational; such studies are prone
to a variety of biases, including case selection bias, family relationships
between patients and controls, and inadequate information about
hormone use. Thus, they may give an overestimate of the magnitude
of benefit.
■
■CANCER SCREENING
Screening is a means of early detection in asymptomatic individuals,
with the goal of decreasing morbidity and mortality. While screening
can potentially reduce disease-specific deaths and has been shown to
do so in cervical, colon, lung, and breast cancer, it is also subject to
several biases that can suggest a benefit when there is none. Biases can
even mask net harm. Early detection does not in itself confer benefit.
Cause-specific mortality, rather than survival after diagnosis, is the
preferred endpoint (see below).
Because screening is done on asymptomatic, healthy persons, it
should offer substantial likelihood of benefit that outweighs harm.
Screening tests and their appropriate use should be carefully evaluated
before their use is widely encouraged in screening programs.
The Accuracy of Screening 
A screening test’s accuracy or ability
to discriminate disease is described by four indices: sensitivity, specificity,
positive predictive value, and negative predictive value (Table 75-2).
Sensitivity, also called the true-positive rate, is the proportion of per­
sons with the disease who test positive in the screen (i.e., the ability of
the test to detect disease when it is present). Specificity, or 1 minus the
false-positive rate, is the proportion of persons who do not have the
disease who test negative in the screening test (i.e., the ability of a test to
correctly indicate that the disease is not present). The positive predictive
value is the proportion of persons who test positive and who actually
have the disease. Similarly, negative predictive value is the proportion
testing negative who do not have the disease. The sensitivity and speci­
ficity of a test are relatively independent of the underlying prevalence
(or risk) of the disease in the population screened, but the predictive
values depend strongly on the prevalence of the disease.
Screening is most beneficial, efficient, and economical when the
target disease is common in the population being screened. Specific­
ity is at least as important to the ultimate feasibility and success of a
screening test as sensitivity.
Potential Biases of Screening Tests 
Common biases of screen­
ing are lead time, length-biased sampling (and related overdiagnosis),
and selection. These biases can make a screening test seem beneficial
when it is not (or even causes net harm). Whether beneficial or not,
screening can create the false impression of an epidemic by increasing
the number of cancers diagnosed. It can also produce a shift in the pro­
portion of patients diagnosed at an early stage (even without a reduc­
tion in absolute incidence of late-stage disease) and inflate survival
statistics without reducing mortality (i.e., the number of deaths from
a given cancer relative to the number of those at risk for the cancer in
TABLE 75-2  Assessment of the Value of a Diagnostic Testa
 
CONDITION PRESENT
CONDITION ABSENT
Positive test
a
b
Negative test
c
d
a = true positive
 
 
b = false positive
 
 
c = false negative
 
 
d = true negative
 
 
Sensitivity
The proportion of persons with the condition
who test positive: a/(a + c)
Specificity
The proportion of persons without the condition
who test negative: d/(b + d)
Positive predictive value (PPV)
The proportion of persons with a positive test
who have the condition: a/(a + b)
Negative predictive value
The proportion of persons with a negative test
who do not have the condition: d/(c + d)
Prevalence, sensitivity, and specificity determine PPV
PPV
prevalence sensitivity
(prevalence sensitivity) (1 prevalence)(1 specificity)
×
×
−
−
aFor diseases of low prevalence, such as cancer, poor specificity has a dramatic
adverse effect on PPV such that only a small fraction of positive tests are true
positives.
the total population). In such a case, the apparent duration of survival
(measured from date of diagnosis) increases without lives being saved
or life expectancy changed.
Lead-time bias occurs whether or not a test influences the natural
history of the disease; the patient is merely diagnosed at an earlier date.
Survival appears increased even if life is not prolonged. The screen­
ing test only prolongs the time the subject is aware of the disease and
spends as a cancer patient.
Length-biased sampling occurs because screening tests generally
can more easily detect slow-growing, less aggressive cancers than
fast-growing cancers. Cancers diagnosed due to the onset of symp­
toms between scheduled screenings are on average more aggressive,
and treatment outcomes are not as favorable. An extreme form of
length bias sampling is termed overdiagnosis, the detection of “pseudo
disease.” The reservoir of some slow-growing tumors is large. Many
of these tumors fulfill the histologic criteria of cancer but will never
become clinically significant or cause death during the patient’s
remaining life span. This problem is compounded by the fact that the
most common cancers appear most frequently at ages when competing
causes of death are more frequent.
Selection bias occurs because the population most likely to seek
screening often differs from the general population to which the
screening test might be applied. In general, volunteers for studies are
more health conscious and likely to have a better prognosis or lower
mortality rate irrespective of the screening result. This is termed the
healthy volunteer effect.
Potential Drawbacks of Screening 
Risks associated with screen­
ing include harm caused by the screening intervention itself, harm due
to the further investigation of persons with positive tests (both true and
false positives), and harm from the treatment of persons with a truepositive result, whether or not life is extended by treatment (e.g., even
if a screening test reduces relative cause-specific mortality by 15–30%,
70–85% of those diagnosed still go on to die of the target cancer). The
diagnosis and treatment of cancers that would never have caused medi­
cal problems (i.e., overdiagnosis) can lead to the harm of unnecessary
treatment (i.e., overtreatment) and give patients the anxiety of a cancer
diagnosis. The psychosocial impact of cancer screening can be substan­
tial when applied to the entire population.
Assessment of Screening Tests 
Good clinical trial design can
offset some biases of screening and directly identify the balance of risks
and benefits of a screening test. A randomized controlled screening
trial with cause-specific mortality as the endpoint provides the stron­
gest support for a screening intervention. Overall mortality should
also be reported to detect an adverse effect of screening and treatment
on other disease outcomes (e.g., cardiovascular disease, treatmentinduced cancers). In a randomized trial, two like populations are ran­
domly established. One is given the usual standard of care (which may
be no screening at all) and the other receives the screening intervention
being assessed. Efficacy for the population studied is established when
the group receiving the screening test has a lower cause-specific mor­
tality rate than the control group. Studies showing a reduction in the
incidence of advanced-stage disease, improved survival, or a stage shift
are weaker (and possibly misleading) evidence of benefit. These latter
criteria are early indicators but not sufficient to definitively establish
the value of a screening test.
Although a randomized, controlled screening trial provides the
strongest evidence to support a screening test, it is not perfect. Unless
the trial is population-based, it does not remove the question of gen­
eralizability to the target population. Screening trials generally involve
thousands of persons and last for years. Less definitive study designs
are therefore used to assess the effectiveness of a screening test of
proven efficacy in actual practice. However, every nonrandomized
study design is subject to strong confounders. In descending order of
strength, evidence may also be derived from the findings of internally
controlled trials using intervention allocation methods other than
randomization (e.g., allocation by birth date, date of clinic visit); the
findings of analytic observational studies; or the results of multiple
time series studies with or without the intervention.
Screening for Specific Cancers 
Screening for cervical, colon,
and breast cancer has the potential to be beneficial for certain age
groups. Although these tests can reduce deaths from the cancer being
screened for, meta-analyses of randomized trials have not shown that
they affect all-cause mortality. Lung cancer screening can also reduce
deaths in specific settings, depending on age and smoking history. Spe­
cial surveillance of those at high risk for a specific cancer because of a
family history or a genetic risk factor may be prudent, but few studies
have assessed the effect on mortality. A number of organizations have
considered whether or not to endorse routine use of certain screening
tests. Because their perspectives have varied, they have arrived at dif­
ferent recommendations. The American Cancer Society (ACS) and the
U.S. Preventive Services Task Force (USPSTF) publish screening guide­
lines (Table 75-3); the American Academy of Family Practitioners
(AAFP) often follows/endorses the USPSTF recommendations; and
the American College of Physicians (ACP) develops recommendations
based on structured reviews of other organizations’ guidelines.
BREAST CANCER  Breast self-examination, clinical breast examination
by a caregiver, mammography, and magnetic resonance imaging (MRI)
have all been variably advocated as useful screening tools.
A number of trials suggest that annual or biennial screening
with mammography in normal-risk women older than age 50 years
decreases breast cancer mortality. In most, breast cancer–related mor­
tality rates were decreased by 15–30%. Experts disagree on whether
average-risk women age 40–49 years should receive regular screening.
The U.K. Age Trial, the only randomized trial of breast cancer screen­
ing to specifically evaluate the impact of mammography in women age
40–49 years, found no statistically significant difference in breast can­
cer mortality for screened women versus controls after about 22 years
of follow-up (relative risk 0.88; 95% confidence interval, 0.74–1.03);
however, <70% of women received screening in the intervention arm,
potentially diluting the observed effect. A meta-analysis of nine large
randomized trials showed an 8% relative reduction in breast cancer
mortality (relative risk 0.92; 95% confidence interval, 0.75–1.02) from
mammography screening for women age 39–49 years after 11–20 years
of follow-up. This is equivalent to 3 breast cancer deaths prevented
per 10,000 women over 10 years (although the result is not statistically
significant). At the same time, nearly half of women age 40–49 years
screened annually will have false-positive mammograms necessitating
further evaluation, often including biopsy. Estimates of overdiagnosis
range from 10 to 50% of diagnosed invasive cancers.
CHAPTER 75
Prevention and Early Detection of Cancer
In the United States, widespread screening over the past several
decades has not been accompanied by a reduction in incidence of
metastatic breast cancer despite a large increase in early-stage disease,
suggesting a substantial amount of overdiagnosis at the population
level. In addition, the substantial improvements in systemic therapy
have likely decreased the impact of mammography and early detection
on falling breast cancer mortality rates.
Digital breast tomosynthesis is a newer method of breast cancer
screening that reconstructs multiple x-ray images of the breast into
superimposed “three-dimensional” slices. Although some evidence
is available concerning the test characteristics of this modality, there
are currently no data on its effects on health outcomes such as breast
cancer–related morbidity, mortality, or overdiagnosis rates. A large
randomized trial comparing standard digital mammography to tomo­
synthesis is in progress.
No study of breast self-examination has shown it to decrease mortal­
ity. A randomized controlled trial of approximately 266,000 women in
China demonstrated no difference in breast cancer mortality between
a group that received intensive breast self-exam instruction and rein­
forcement/reminders and controls at 10 years of follow-up. However,
more benign breast lesions were discovered and more breast biopsies
were performed in the self-examination arm.
Genetic screening for BRCA1 and BRCA2 mutations and other
markers of breast cancer risk has identified a group of women at high
risk for breast cancer. Unfortunately, when to begin and the optimal
frequency of screening have not been defined. Mammography is less
sensitive at detecting breast cancers in women carrying BRCA1 and
TABLE 75-3  Screening Recommendations for Asymptomatic Subjects Not Known to Be at Increased Risk for the Target Conditiona
CANCER TYPE
TEST OR PROCEDURE
USPSTF
ACS
Breast
Self-examination
“D”b (Not in current recommendations; from 2009)
Women, all ages: No specific recommendation
 
Clinical examination
Women ≥40 years: “I” (as a stand-alone without
mammography) (Not in current recommendations;
from 2009)
 
Mammography
Women aged 40-74 years: Biennial screening
mammography (“B”)
 
 
Women ≥75 years: “I”
 
 
Magnetic resonance
imaging (MRI)
“I”
Women with >20% lifetime risk of breast cancer: Screen
with MRI plus mammography annually
 
 
 
Women with 15–20% lifetime risk of breast cancer: Discuss
option of MRI plus mammography annually
 
 
 
Women with <15% lifetime risk of breast cancer: Do not
screen annually with MRI
Cervical
Pap test (cytology)
Women <21 years: “D”
Women 21–29 years: Screen with cytology alone every
3 years (“A”)
Women 30–65 years: Screen with cytology alone every
3 years, or with co-testing (HPV testing + cytology) every
5 years (two of three options, see HPV test below) (“A”)
Women >65 years, with adequate, normal prior Pap
screenings: “D”
Women after total hysterectomy for noncancerous
causes: “D”
PART 4
Oncology and Hematology
 
HPV test
Women <30 years: Do not use HPV testing for cervical
cancer screening
Women 30–65 years: Screen with HPV testing alone or
in combination with cytology every 5 years (two of three
options, see Pap test above) (“A”)
Women >65 years, with adequate, normal prior Pap
screenings: “D”
Women after total hysterectomy for noncancerous causes:
“D”
Colorectal
Overall
Adults 50–75 years: “A” Screen for colorectal cancer
Adults 45–50 years: “B” Screen for colorectal cancer
Adults 76–85 years: “C” Selectively offer screening for
colorectal cancer; consider the patient’s overall health, prior
screening history, and preferences
 
Sigmoidoscopy
Every 5 years; modeling suggests improved benefit if
performed every 10 years in combination with annual FIT
 
Fecal occult blood testing
(FOBT)
Every year
Adults ≥45 years: Every year
 
Colonoscopy
Every 10 years
Adults ≥45 years: Every 10 years
 
Fecal DNA testing
At least every 3 years
Adults ≥45 years: Every 3 years
 
Fecal immunochemical
testing (FIT)
Every year
Adults ≥45 years: Every year
 
Computed tomography
(CT) colonography
Every 5 years
Adults ≥45 years: Every 5 years
Lung
Low-dose CT scan
Adults 50–80 years, with a ≥20 pack-year smoking history,
still smoking or have quit within past 15 years, annually: “B”
Discontinue once a person has not smoked for 15 years
or develops a health problem that substantially limits life
expectancy or the ability to have curative lung surgery
Women, all ages: Do not recommend
Women 40–44 years: Provide the opportunity to begin
annual screening
Women 45–54 years: Screen annually
Women ≥55 years: Transition to biennial screening or have
the opportunity to continue annual screening
Women ≥40 should continue screening mammography as
long as their overall health is good and they have a life
expectancy of 10 years or longer
Women <21 years: No screening
Women 21–29 years: Screen every 3 years
Women 30–65 years: Screen with co-testing (HPV testing +
cytology) every 5 years or cytology alone every 3 years
(see HPV test below)
Women >65 years: No screening following adequate
negative prior screening
Women after total hysterectomy for noncancerous causes:
Do not screen
Women <30 years: Do not use HPV testing for cervical
cancer screening
Women 30–65 years: Preferred approach to screen with
HPV and cytology co-testing every 5 years (see Pap test
above)
Women >65 years: No screening following adequate
negative prior screening
Women after total hysterectomy for noncancerous causes:
Do not screen
Adults ≥45–75 years: Screen for colorectal cancer with
either a high-sensitivity stool-based test or a structural
(visual) examination (≥45 years, qualified recommendation;
≥50 years, strong recommendation).
Adults 76–85 years: Individualize screening based on
patient preferences, life expectancy, health status, and
prior screening history (qualified recommendation).
Adults >85 years: Discourage screening (qualified
recommendation).
Every 5 years
Adults ≥45 years: Every 5 years
Men and women, 50–80 years, with ≥20 pack-year smoking
history, current or former smoker, annually: Discuss
benefits, limitations, and harms of screening; offer smoking
cessation counseling and connection to resources where
relevant.
Individuals with comorbid conditions that substantially limit
life expectancy should not be screened.
(Continued)
TABLE 75-3  Screening Recommendations for Asymptomatic Subjects Not Known to Be at Increased Risk for the Target Conditiona
CANCER TYPE
TEST OR PROCEDURE
USPSTF
ACS
Ovarian
CA-125
Transvaginal ultrasound
Women, all ages: “D”
Women with a high-risk hereditary cancer syndrome:
No recommendation
Prostate
Prostate-specific antigen
(PSA)
Men 55–69 years: The decision to undergo periodic PSAbased screening should be an individual one. Men should
have an opportunity to discuss the potential benefits and
harms of screening with their clinician.
Clinicians should not screen men who do not express a
preference for screening (“C”)
Men ≥70 years: “D”
 
Digital rectal examination
(DRE)
No individual recommendation
As for PSA; if men decide to be tested, they should have the
PSA blood test with or without a rectal exam.
Skin
Complete skin
examination by clinician
or patient
Adults, all ages: “I”
No guidelines
aSummary of the screening procedures recommended for the general population by the USPSTF and the ACS. These recommendations refer to asymptomatic persons
who are not known to have risk factors, other than age or gender, for the targeted condition. bUSPSTF lettered recommendations are defined as follows: “A”: The USPSTF
recommends the service because there is high certainty that the net benefit is substantial; “B”: The USPSTF recommends the service because there is high certainty
that the net benefit is moderate or moderate certainty that the net benefit is moderate to substantial; “C”: The USPSTF recommends selectively offering or providing this
service to individual patients based on professional judgment and patient preferences; there is at least moderate certainty that the net benefit is small; “D”: The USPSTF
recommends against the service because there is moderate or high certainty that the service has no net benefit or that the harms outweigh the benefits; “I”: The USPSTF
concludes that the current evidence is insufficient to assess the balance of benefits and harms of the service. Table only includes final, not draft, recommendations, from
the USPSTF.
Abbreviations: ACS, American Cancer Society; USPSTF, U.S. Preventive Services Task Force.
BRCA2 mutations, possibly because such cancers occur in younger
women, in whom mammography is known to be less sensitive. MRI
screening may be more sensitive than mammography in women at
high risk due to genetic predisposition or in women with very dense
breast tissue, but specificity may be lower. An increase in overdiagnosis
may accompany the higher sensitivity. The impact of MRI on breast
cancer mortality with or without concomitant use of mammography
has not been evaluated in a randomized controlled trial.
CERVICAL CANCER  The cervical cancer mortality rate has fallen
substantially since the widespread use of the Pap smear. Screening
guidelines recommend regular Pap testing for all women who have
reached the age of 21 (before this age, even in individuals that have
begun sexual activity, screening may cause more harm than benefit).
The recommended interval for Pap screening is 3 years. In all cases,
screening more frequently adds little benefit but leads to important
harms, including unnecessary procedures and overtreatment of tran­
sient lesions. With the onset of sexual activity comes the risk of sexual
transmission of HPV, the fundamental etiologic factor for cervical can­
cer. Beginning at age 30, guidelines also include HPV testing with or
without Pap smear. The screening interval for women who test normal
using this approach may be lengthened to 5 years.
An upper age limit at which screening ceases to be effective is not
known, but women age 65 years with no abnormal results in the previ­
ous 10 years may choose to stop screening. Screening should be dis­
continued in women who have undergone a hysterectomy with cervical
excision for noncancerous reasons.
Although the efficacy of the Pap smear in reducing cervical cancer
mortality has never been directly confirmed in a randomized, con­
trolled setting, a clustered randomized trial in India evaluated the
impact of one-time cervical visual inspection and immediate colpos­
copy, biopsy, and/or cryotherapy (where indicated) versus counseling
on cervical cancer deaths in women age 30–59 years. After 7 years of
follow-up, the age-standardized rate of death due to cervical cancer was
39.6 per 100,000 person-years in the intervention group versus 56.7 per
100,000 person-years in controls.
COLORECTAL CANCER  Digital rectal examination (DRE), stool-based
testing (fecal occult blood testing [FOBT], fecal immunochemical tests
[FITs], multitargeted stool DNA tests), blood-based testing (SEPT9),
and optical testing (rigid and flexible sigmoidoscopy, colonoscopy,
(Continued)
Currently, there are no reliable screening tests for the
early detection of ovarian cancer. For women at high
risk of ovarian cancer, it has not been proven that using
transvaginal ultrasound or serum CA-125 lowers their
chances of dying from ovarian cancer.
Starting at age 50, men at average risk and with a life
expectancy of ≥10 years should talk to a doctor about the
uncertainties, risks, and potential benefits of screening.
If African American or have a father or brother who had
prostate cancer before age 65, men should have this
talk starting at age 45. For men with more than one firstdegree relative with prostate cancer diagnosed before
age 65, have this talk starting at age 40. How often they are
screened will depend on their PSA level.
CHAPTER 75
Prevention and Early Detection of Cancer
computed tomography [CT] colonography) have been considered for
colorectal cancer screening.
DRE is not an effective colorectal cancer screening test and is not
recommended by any medical organization.
Stool-Based Testing  A meta-analysis of five randomized controlled
trials demonstrated a 22% relative reduction in colorectal cancer
mortality after two to nine rounds of biennial FOBT at 30 years of
follow-up; annual screening was shown to result in a greater mortality
reduction in a single trial (a 32% relative reduction). However, only
2–10% of those with occult blood in the stool actually have cancer.
The high false-positive rate of FOBT therefore leads to a large number
of diagnostic follow-up colonoscopies. FITs have higher sensitivity for
colorectal cancer than FOBT tests and have largely replaced FOBT
in clinical practice. Limited evidence suggests FITs may not detect
proximal colonic tumors at the same rate as distal ones. Multitargeted
stool DNA testing (e.g., Cologuard) combines FIT with testing for
altered DNA biomarkers that are shed into the stool. Although limited
evidence demonstrates that it can have a higher single-test sensitivity
for colorectal cancer than FIT alone, its specificity is lower, resulting
in a higher number of false-positive tests and follow-up colonoscopies.
No studies have yet evaluated its effects on colorectal cancer incidence,
morbidity, or mortality.
Blood-Based Testing  A blood test for the methylated SEPT9 gene associ­
ated with colorectal cancer is available. Case-control studies suggest
that it has a lower sensitivity and specificity than the FIT stool test. It
also is more costly, and it is not recommended as a first-line screening
test.
Optical Testing  Two meta-analyses of five randomized controlled trials
of sigmoidoscopy found an 18% relative reduction in colorectal cancer
incidence and a 28% relative reduction in colorectal cancer mortality.
Participant ages ranged from 50 to 74 years, with follow-up ranging
from 6 to 13 years. Diagnosis of adenomatous polyps by sigmoidoscopy
should lead to evaluation of the entire colon with colonoscopy. The
most efficient interval for screening sigmoidoscopy is unknown, but an
interval of 5 years is often recommended. Case-control studies suggest
that intervals of up to 15 years may confer benefit; a randomized trial
in the U.K. demonstrated colorectal cancer mortality reduction with
one-time screening.
One-time colonoscopy detects ∼25% more advanced lesions (pol­
yps >10 mm, villous adenomas, adenomatous polyps with high-grade
dysplasia, invasive cancer) than one-time FOBT with sigmoidoscopy;
comparative programmatic performance of the two modalities over
time is not known. Perforation rates are about 4/10,000 for colonos­
copy and 1/10,000 for sigmoidoscopy. Debate continues on whether
colonoscopy is too expensive and invasive and whether sufficient
provider capacity exists to be recommended as the preferred screening
tool in standard-risk populations. Some observational studies suggest
that efficacy of colonoscopy to decrease colorectal cancer mortality is
higher on the left side of the colon than the right.
CT colonography, if done at expert centers, appears to have a sen­
sitivity for polyps ≥6 mm, comparable to colonoscopy. However, the
rate of extracolonic findings of abnormalities of uncertain significance
that must nevertheless be worked up is high (∼5–37%); the long-term
cumulative radiation risk of repeated colonography screenings is also
a concern.
LUNG CANCER  Chest x-ray and sputum cytology have been evaluated
in several randomized lung cancer screening trials. The most recent
and largest (n = 154,901) of these, a component of the Prostate, Lung,
Colorectal, and Ovarian (PLCO) cancer screening trial, found that,
compared with usual care, annual chest x-ray did not reduce the risk
of dying from lung cancer (relative risk 0.99; 95% confidence interval,
0.87–1.22) after 13 years. However, it showed evidence of overdiagno­
sis associated with chest x-ray. Low-dose CT has also been evaluated
in several randomized trials. The largest and longest of these, the
National Lung Screening Trial (NLST), was a randomized controlled
trial of screening for lung cancer in ∼53,000 persons age 55–74 years
with a 30+ pack-year smoking history. It demonstrated a statistically
significant reduction of about 3 fewer deaths per 1000 people screened
with CT compared to chest x-ray after 12 years. Harms include the
potential radiation risks associated with multiple scans, the discovery
of incidental findings of unclear significance, and a high rate of falsepositive test results. Both incidental findings and false-positive tests
can lead to invasive diagnostic procedures associated with anxiety,
complications, and expense. The NLST was performed at experienced
screening centers, and the balance of benefits and harms may differ in
the community setting at less experienced centers.
PART 4
Oncology and Hematology
OVARIAN CANCER  Adnexal palpation, transvaginal ultrasound
(TVUS), and serum CA-125 assay have been considered for ovarian
cancer screening. A large randomized, controlled trial has shown that
an annual screening program of TVUS and CA-125 in average-risk
women does not reduce deaths from ovarian cancer (relative risk 1.21;
95% confidence interval, 0.99–1.48). Adnexal palpation was dropped
early in the study because it did not detect any ovarian cancers that
were not detected by either TVUS or CA-125. A second large, random­
ized trial used a two-stage screening approach incorporating a risk of
ovarian cancer algorithm that determined whether additional testing
with CA-125 or TVUS was required. At 14 years of follow-up, there
was no statistically significant reduction in ovarian cancer deaths. The
risks and costs associated with the high number of false-positive results
are impediments to routine use of these modalities for screening. In the
PLCO trial, 10% of participants had a false-positive result from TVUS
or CA-125, and one-third of these women underwent a major surgical
procedure; the ratio of surgeries to screen-detected ovarian cancer was
approximately 20:1. In September 2016, the FDA issued a safety com­
munication recommending against using any ovarian cancer screening
test, including the algorithm for risk of the cancer.
PROSTATE CANCER  The most common prostate cancer screening
modalities are digital rectal exam (DRE) and serum PSA assay. An
emphasis on PSA screening has made prostate cancer the most com­
mon nonskin cancer diagnosed in American males. This disease is
prone to lead-time bias, length bias, and overdiagnosis, and substantial
debate continues among experts as to whether screening should be
offered unless the patient specifically asks to be screened. Virtually all
organizations stress the importance of informing men about the uncer­
tainty regarding screening efficacy and the associated harms. Prostate
cancer screening clearly detects many asymptomatic cancers, but men
older than age 50 years have a high prevalence of clinically insignificant
prostate cancers (about 30–50% of men, increasing further as men age).
The ability to distinguish tumors that are lethal but still curable from
those that pose little or no threat to health is limited, although evidence
suggests multiparametric MRI may aid decision-making.
Randomized trials indicate that the effect of PSA screening on pros­
tate cancer mortality across a population is, at best, small. Two major
trials have been published. The PLCO Cancer Screening Trial was a
multicenter U.S. trial that randomized almost 77,000 men age 55–74
years to receive either annual PSA testing for 6 years or usual care. At
13 years of follow-up, no statistically significant difference in the num­
ber of prostate cancer deaths was noted between the arms (rate ratio
1.09; 95% confidence interval, 0.87–1.36). More than half of men in the
control arm received at least one PSA test during the trial, which may
have diluted a small effect.
The European Randomized Study of Screening for Prostate Cancer
(ERSPC) was a multinational study that randomized ∼182,000 men
between age 50 and 74 years (with a predefined “core” screening
group of men age 55–69 years) to receive PSA testing or no screen­
ing. Recruitment and randomization procedures, as well as actual
frequency of PSA testing, varied by country. After a median follow-up
of 15.5 years, a 20% relative reduction in the risk of prostate cancer
death in the screened arm was noted in the “core” screening group.
The trial found that 570 men (95% confidence interval, 380–1137
men) would need to be invited to screening, and 18 cases of prostate
cancer detected, to avert 1 death from prostate cancer. There was an
unexplained imbalance in treatment between the two study arms, with
a higher proportion of men with clinically localized cancer receiving
radical prostatectomy in the screening arm and receiving it at experi­
enced referral centers.
Screening must be linked to effective therapy to have any benefit.
Two trials conducted after the initiation of widespread PSA testing
did not find a substantial decrease in prostate cancer deaths in control
arms of “watchful waiting” or monitoring (i.e., no curative treatment)
compared to radical prostatectomy or radiation therapy. Prostate
cancer–specific survival was very good (about 99%) and nearly identi­
cal at a median follow-up of 10 years. Treatments for low-stage prostate
cancer, such as surgery and radiation therapy, can cause substantial
morbidity, including impotence and urinary incontinence.
SKIN CANCER  Visual examination of all skin surfaces by the patient or
by a health care provider is used in screening for basal and squamous
cell cancers and melanoma. No prospective randomized study has been
performed to look for a mortality decrease. Unfortunately, screening is
associated with a substantial rate of overdiagnosis.
MULTICANCER EARLY DETECTION TESTS  Multicancer early detection
(MCED) tests look for multiple biomarkers in blood that are either
directly released or induced by cancer cells. One potential purpose of
these tests could be to screen for multiple cancers at the same time in
asymptomatic people. However, most of the evidence at present for
these tests comes from people who have already been diagnosed with
cancer (a fundamentally different population); additionally, no data
are available on health outcomes associated with using MCED tests for
cancer screening.
■
■FURTHER READING
Fenton JJ et al: Prostate-specific antigen-based screening for prostate
cancer: Evidence report and systematic review for the U.S. Preventive
Services Task Force. JAMA 319:1914, 2018.
Jonas DE et al: Screening for lung cancer with low-dose computed
tomography: Updated Evidence report and systematic review for the
US Preventive Services Task Force. JAMA 325:971, 2021.
Kramer BS, Croswell JM: Cancer screening: The clash of science
and intuition. Annu Rev Med 60:125, 2009.
Lin JS et al: Screening for colorectal cancer: Updated evidence report
and systematic review for the US Preventive Services Task Force.
JAMA 325:1978, 2021.

05 - 76 Cancer Genetics
76 Cancer Genetics
Manson JE et al: Vitamin D supplements and prevention of cancer and
cardiovascular disease. N Engl J Med 380:33, 2019.
Mcneil JJ et al: Effect of aspirin on all-cause mortality in the healthy
elderly. N Engl J Med 379:1519, 2018.
Melnikow J et al: Screening for cervical cancer with high-risk human
papillomavirus testing: Updated evidence report and systematic
review for the US Preventive Services Task Force. JAMA 320:687,
2018.
Welch HG et al: Epidemiologic signatures in cancer. N Engl J Med
384:14, 2019.
Woloshin S et al: Breast-cancer mortality trends in four countries
with varied screening practices. N Engl J Med 389:1061, 2023.
Zeraatkar D et al: Effect of lower versus high red meat intake on
cardiometabolic and cancer outcomes: A systematic review of ran­
domized trials. Ann Intern Med 171:721, 2019.
Fred Bunz, Bert Vogelstein
Cancer Genetics
CANCER IS A GENETIC DISEASE
Cancer arises through a series of somatic alterations in DNA that result
in unrestrained cellular proliferation. Most of these alterations involve
subtle sequence changes in DNA (i.e., mutations). The somatic mutations
may originate as a consequence of random replication errors or exposure
to carcinogens (e.g., radiation) and can be exacerbated by faulty DNA
repair processes. While most cancers arise sporadically, clustering of can­
cers occurs in families that carry a germline mutation in a cancer gene.
HISTORICAL PERSPECTIVE
The idea that cancer progression is driven by sequential somatic muta­
tions in specific genes has only gained general acceptance in the past
30 years. Before the advent of the microscope, cancer was believed to
be composed of aggregates of mucus or other noncellular matter. By
the middle of the nineteenth century, it became clear that tumors were
masses of cells and that these cells arose from the normal cells of the
tissue from which the cancer originated. The molecular basis for the
uncontrolled proliferation of cancer cells was to remain a mystery for
another century. During that time, a number of theories for the origin of
cancer were postulated. The great biochemist Otto Warburg proposed
the combustion theory of cancer, which stipulated that cancer was due
to abnormal oxygen metabolism. Others believed that all cancers were
caused by viruses and that cancer was in fact a contagious disease.
In the end, observations of cancer occurring in chimney sweeps,
studies of x-rays, and the overwhelming data demonstrating cigarette
smoke as a causative agent in lung cancer, together with Ames’s work
on chemical mutagenesis, were consistent with the idea that cancer
originated through changes in DNA. However, it was not until the
somatic mutations responsible for cancer were identified at the molec­
ular level that the genetic basis of cancer was definitively established.
Although the viral theory of cancer did not prove to be generally
accurate (with exceptions such as human papillomaviruses, which can
cause cervical and other cancers), the study of retroviruses led to the
discovery of the first human oncogenes in the late 1970s. Oncogenes
are one of the two major classes of cancer driver genes. The study of
families with genetic predisposition to cancer was instrumental to the
discovery of the other major class of cancer driver genes, called tumorsuppressor genes. Current technologies permit the sequence analysis of
entire cancer genomes and provide a comprehensive view of the genetic
changes that cause tumors to arise and become malignant. The field
that studies the various types of mutations, as well as the consequences
of these mutations in tumor cells, is now known as cancer genetics.
THE CLONAL ORIGIN AND MULTISTEP
NATURE OF CANCER
Nearly all cancers originate from a single cell; this clonal origin is a
critical discriminating feature between neoplasia and hyperplasia.
Multiple cumulative mutational events are invariably required for the
progression of a tumor from normal to fully malignant phenotype. The
process can be seen as Darwinian microevolution in which, at each
successive step, the mutated cells gain a growth advantage resulting
in the expansion of a neoplastic clone (Fig. 76-1). Based on observa­
tions of cancer frequency increases during aging, the epidemiologists
Armitage and Doll and Nordling independently proposed that cancer
is a result of three discrete cellular changes. Remarkably, this early
model has been validated by extensive sequencing of cancer genomes.
These studies revealed that just three causal mutations are required for
the development of several of the most common cancers. Overall, it is
currently believed that most common solid tumors require a minimum
of three mutated cancer driver genes (either oncogenes or tumorsuppressor genes) for their development. One or two mutations are
sufficient for benign tumorigenesis, but not for the invasive capacity
that distinguishes cancers from benign tumors. Less common tumors,
such as liquid tumors (leukemias or lymphomas), sarcomas, and
childhood tumors, appear to require only two driver gene alterations
for malignancy. Note that a cancer driver gene is best defined as one
containing a mutation that increases the selective growth advantage of
the cell containing it. Normally, cell birth and cell death are in perfect
equilibrium; every time a cell is born, another in the same lineage dies.
Cancer driver gene mutations alter this equilibrium, so that more cells
are born than die. The imbalance is often slight, so that the difference
between cell birth and cell death can be less than 1%. This explains, in
combination with the low rate of mutation, why tumorigenesis—the
journey from a normal cell to a typical malignant, solid tumor—often
takes decades.
CHAPTER 76
Cancer Genetics
We now know the precise nature of the genetic alterations respon­
sible for nearly all malignancies and are beginning to understand how
these alterations promote the distinct stages of tumor growth. The
prototypical example is colon cancer, in which analyses of genomes
from the entire spectrum of neoplastic growths—from normal colon
Initiation
Expansion
Invasion
FIGURE 76-1  Multistep clonal development of malignancy. In this diagram, a series
of three cumulative mutations, each with a modest growth advantage acting alone,
eventually results in a malignant tumor. Note that not all such alterations result in
progression. The actual number of cumulative mutations necessary to transform
from the normal to the malignant state has been estimated to be three for several of
the most common types of cancer. (Adapted and modified from PC Nowell: The clonal
evolution of tumor cell populations. Science 194:23, 1976.)
Microsatellite Instability (MIN) or
Chromosomal Instability (CIN)
SMAD4 or TGFb II
inactivation
TP53 inactivation
APC inactivation
or b-catenin
activation
KRAS or
BRAF
activation
Early
adenoma
Late
adenoma
Carcinoma
Metastasis
Normal
epithelium
Initiation
Expansion
Invasion
FIGURE 76-2  Progressive somatic mutational steps in the development of colon carcinoma. The
accumulation of alterations in a number of different genes results in the progression from normal epithelium
through adenoma to full-blown carcinoma. Genetic instability (microsatellite or chromosomal) accelerates
the progression by increasing the likelihood of mutation at each step. Patients with familial polyposis
are already one step into this pathway because they inherit a germline alteration of the APC gene. TGF,
transforming growth factor.
epithelium through adenoma to carcinoma—have identified mutations
that are highly characteristic of each type of lesion (Fig. 76-2).
PART 4
Oncology and Hematology
TWO TYPES OF CANCER GENES:
ONCOGENES AND TUMOR-SUPPRESSOR
GENES
Oncogenes and tumor-suppressor genes exert their effects on tumor
growth through their ability to determine cell fates, influence cell sur­
vival, and contribute to genome maintenance. The underlying molecu­
lar mechanisms can be extremely complex. While tightly regulated in
normal cells, oncogenes acquire mutations that typically relieve this
control and lead to increased activity of the gene products. This activat­
ing mutational event occurs in a single allele. In contrast, the normal
function of tumor-suppressor genes is usually to restrain cell growth,
and this function is lost in cancer. Because of the diploid nature of
mammalian cells, both alleles must be inactivated for a cell to com­
pletely lose the function of a tumor-suppressor gene. Thus, two genetic
events are required to inactivate a tumor-suppressor gene, while only
one genetic event is required to activate an oncogene.
A subset of tumor-suppressor genes controls the ability of the cell
to maintain the integrity of its genome. Cells with a deficiency in
these genes acquire an increased number of mutations throughout
their genomes, including those in oncogenes and tumor-suppressor
genes. This “mutator” phenotype was first
hypothesized by Loeb to explain how the
multiple rare mutational events required for
tumorigenesis can occur in the lifetime of
an individual. A mutator phenotype under­
lies several forms of cancer, such as those
associated with deficiencies in DNA mis­
match repair. The great majority of cancers
do not harbor repair deficiencies, and their
rate of mutation is similar to that observed
in normal cells. Many of these cancers,
however, appear to harbor a different kind
of genetic instability, affecting the loss or
gains of whole chromosomes or large parts
thereof (as explained in more detail below).
TABLE 76-1  Oncogenes Commonly Altered in Human Cancers
ONCOGENE
FUNCTION
ALTERATION IN CANCER
NEOPLASM
AKT1
Serine/threonine kinase
Point mutation
Skin
BRAF
Serine/threonine kinase
Point mutation
Melanoma, thyroid, colorectal
CCND1
Cell cycle progression
Amplification
Esophageal, head and neck
CTNNB1
Signal transduction
Point mutation
Colon, liver, uterine, melanoma
EGFR
Signal transduction
Point mutation
Lung
FLT3
Signal transduction
Point mutation
AML
IDH1
Chromatin modification
Point mutation
Glioma
MDM2
Inhibitor of p53
Amplification
Sarcoma, glioma
MDM4
Inhibitor of p53
Amplification
Breast
MYC
Transcription factor
Amplification
Prostate, ovarian, breast, liver,
pancreatic
ONCOGENES IN HUMAN
CANCER
Work by Peyton Rous in the early 1900s
revealed that a chicken sarcoma could be
transmitted from animal to animal in cellfree extracts, suggesting that cancer could
be induced by an agent acting positively to
MYCL1
Transcription factor
Amplification
Ovarian, bladder
MYCN
Transcription factor
Amplification
Neuroblastoma
PIK3CA
Phosphoinositol-3-kinase
Point mutation
Multiple cancers
KRAS
GTPase
Point mutation
Pancreatic, colorectal, lung
NRAS
GTPase
Point mutation
Melanoma
Abbreviation: AML, acute myeloid leukemia.
promote tumor formation. The agent responsible
for the transmission of the cancer was a retrovirus
(Rous sarcoma virus [RSV]), and the oncogene
responsible was identified 75 years later as V-SRC.
Other oncogenes were also discovered through
their presence in the genomes of retroviruses that
are capable of causing cancers in chickens, mice,
and rats. The nonmutated cellular homologues of
these viral genes are called proto-oncogenes and
are often targets of mutation or aberrant regula­
tion in human cancer. Whereas many oncogenes
were discovered on the basis of their presence in
retroviruses, other oncogenes, particularly those
involved in translocations characteristic of par­
ticular leukemias and lymphomas, were identi­
fied through genomic approaches. Investigators
cloned the sequences surrounding the chromo­
somal translocations observed cytogenetically and
identified the genes activated at the breakpoints
(see below). Some of these were oncogenes previ­
ously found in retroviruses (like ABL, involved in
chronic myeloid leukemia [CML]), whereas others
were new (like BCL2, involved in B-cell lymphoma). In the normal cel­
lular environment, proto-oncogenes have crucial roles in cell prolifera­
tion and differentiation. Table 76-1 is a partial list of oncogenes known
to be involved in human cancer.
The normal growth and differentiation of cells is controlled by
growth factors that bind to receptors on the surface of the cell. The
signals generated by the membrane receptors are transmitted inside
the cells through signaling cascades involving kinases, G proteins, and
other regulatory proteins. Ultimately, these signals affect the activity of
transcription factors in the nucleus, which regulate the expression of
genes crucial in cell proliferation, cell differentiation, and cell death.
Oncogene products function at critical steps in these signaling path­
ways (Chap. 77). Inappropriate activation of these pathways can lead
to tumorigenesis.
MECHANISMS OF ONCOGENE ACTIVATION
■
■POINT MUTATION
Point mutation (alternatively known as single nucleotide substitution)
is a common mechanism of oncogene activation. For example, point
mutations in KRAS are present in >95% of pancreatic cancers and
40% of colon cancers. Activating KRAS mutations are less common in
other cancer types, although they can occur at significant frequencies
in leukemia, lung, and thyroid cancers. Remarkably—and in contrast
to the diversity of mutations found in tumor-suppressor genes—most
of the activated KRAS alleles contain point mutations in codons 12, 13,
or 61. These mutations lead to constitutive activation of the mutant
RAS protein. The restricted pattern of mutations observed in onco­
genes compared to that of tumor-suppressor genes reflects the fact that
gain-of-function mutations must occur at specific sites, while a broad
variety of mutations can lead to loss of activity. Indeed, inactivation of a
gene can in theory be accomplished through the introduction of a stop
codon anywhere in the coding sequence, whereas activations require
precise substitutions at residues that can somehow lead to an increase
in the activity of the encoded protein under particular circumstances
within the cell.
■
■DNA AMPLIFICATION
The second mechanism for activation of oncogenes is DNA sequence
amplification, leading to overexpression of the gene product. This
increase in DNA copy number may cause cytologically recognizable
chromosome alterations referred to as homogeneous staining regions
(HSRs) if integrated within chromosomes, or double minutes (dmins)
if extrachromosomal.
Numerous genes have been reported to be amplified in cancer.
Several of these genes, including NMYC and LMYC, were identified
through their presence within the amplified DNA sequences of a tumor
and their homology to known oncogenes. Because amplified regions
often include hundreds of thousands of base pairs, multiple oncogenes
may be amplified in a single amplicon in some cancers. For example,
MDM2, GLI1, CDK4, and TPSPAN31 at chromosomal location 12q1315 have been shown to be co-amplified in several types of sarcomas and
other tumors; which of these genes play the causal role in the neoplastic
process is still an active area of research. Amplification of a cellular
gene is often a predictor of poor prognosis; for example, ERBB2/HER2
and NMYC are often amplified in aggressive breast cancers and neuro­
blastoma, respectively.
■
■CHROMOSOMAL REARRANGEMENT
Chromosomal alterations provide important clues to the genetic
changes in cancer. The chromosomal alterations in human solid
tumors such as carcinomas are heterogeneous and complex and occur
as a result of the frequent chromosomal instability observed in these
tumors (see below). In contrast, the chromosome alterations in myeloid
and lymphoid tumors are often simple translocations, that is, reciprocal
transfers of chromosome arms from one chromosome to another. The
breakpoints of recurring chromosome abnormalities usually occur at
the site of cellular oncogenes. Table 76-2 lists representative examples
of recurring chromosome alterations in malignancy and the associated
gene(s) rearranged or deregulated by the chromosomal rearrangement.
Translocations are often observed in liquid tumors in general and are
particularly common in lymphoid tumors, probably because these cell
TABLE 76-2  Representative Oncogenes at Chromosomal
Translocations
GENE (CHROMOSOME)
TRANSLOCATION
MALIGNANCY
BCR-ABL
(9;22)(q34;q11)
Chronic myeloid leukemia
BCL1 (11q13.3)–IgH
(14q32)
(11;14)(q13;q32)
Mantle cell lymphoma
BCL2 (18q21.3)–IgH
(14q32)
(14;18)(q32;q21)
Follicular lymphoma
FLI-EWSR1
(11;22)(q24;q12)
Ewing’s sarcoma
LCK-TCRB
(1;7)(p34;q35)
T-cell acute lymphocytic
leukemia
PAX3-FOXO1
(2;13)(q35;q14)
Rhabdomyosarcoma
PAX8-PPARG
(2;3)(q13;p25)
Thyroid
IL21R-BCL6
(3;16)(q27;p11)
Non-Hodgkin’s lymphoma
TAL1-TCTA
(1;3)(p34;p21)
Acute T-cell leukemia
TMPRSS2-ERG
Rearrangement on
Chr21q22
Prostate
types have the capability to rearrange their DNA to generate antigen
receptors. Indeed, antigen receptor genes are commonly involved in the
translocations, implying that an imperfect regulation of receptor gene
rearrangement may be involved in their pathogenesis. In addition to
transcription factors and signal transduction molecules, translocation
may result in the overexpression of cell cycle regulatory proteins or
proteins such as cyclins and of proteins that regulate cell death. Recur­
rent translocations have more recently been identified in solid tumors
such as prostate cancers. For example, fusions between TMPRSS2 and
ERG, which are normally located in tandem on chromosome 21, con­
tribute to more than one-third of all prostate cancers.
The first reproducible chromosome abnormality detected in human
malignancy was the Philadelphia chromosome detected in CML.
This cytogenetic abnormality is generated by reciprocal translocation
involving the ABL oncogene on chromosome 9, encoding a tyrosine
kinase, being placed in proximity to the breakpoint cluster region
(BCR) gene on chromosome 22. Figure 76-3 illustrates the genera­
tion of the translocation and its protein product. The consequence of
expression of the BCR-ABL gene product is the activation of signal
transduction pathways leading to cell growth independent of normal
external signals. Imatinib, a drug that specifically blocks the activity
of Abl tyrosine kinase, has shown remarkable efficacy with little tox­
icity in patients with CML. The successful targeting of BCR-ABL by
imatinib is the paradigm for molecularly targeted anticancer therapies.
CHAPTER 76
CHROMOSOMAL INSTABILITY IN SOLID
TUMORS
Solid tumors generally contain an abnormal number of chromosomes,
a state known as aneuploidy. Chromosomes from aneuploid tumors
also exhibit structural alterations such as translocations, deletions,
and amplifications. These abnormalities reflect an underlying defect
in cancer cells known as chromosomal instability. While aneuploidy
is a striking cellular phenotype, chromosomal instability is manifest as
only a small increase in the tendency of cells to gain, lose, or rearrange
chromosomes during any given cell cycle. This intrinsically low rate
of chromosome aberration implies that cancer cells become aneuploid
only after many generations of clonal expansion. The molecular basis
of aneuploidy remains incompletely understood. It is widely believed
that defects in checkpoints, the quality-control mechanisms that halt
the cell cycle if chromosomes are damaged or misaligned, contribute to
chromosomal instability. This hypothesis emerged from experimental
observations that the tumor suppressor p53 controls checkpoints that
regulate the initiation of DNA replication and the onset of mitosis.
These processes are therefore defective in many cancer cells. The
mitotic spindle checkpoint, which ensures proper chromosome attach­
ment to the mitotic spindle before allowing the sister chromatids to
separate, is also altered in some cancers, irrespective of p53 status.
The precise relationship between checkpoint deficiency, p53, and
chromosomal instability remains unclear, but it is believed that even
a subtle perturbation of the highly orchestrated process of cell divi­
sion can impact the ability of a cell to faithfully replicate and segregate
its complement of chromosomes. From a therapeutic standpoint, the
checkpoint defects that are prevalent in cancers have been proposed as
vulnerabilities that may be exploited by novel agents and combinatorial
strategies.
Cancer Genetics
In contrast to the genome-wide cytogenetic changes that are typical
indications of an underlying chromosomal instability, more focal pat­
terns of chromosomal rearrangement have been recurrently detected
in many cancer types. A curious phenomenon known as chromothripsis
causes dozens of distinct breakpoints that are localized on one or sev­
eral chromosomes. These striking structural alterations are thought
to reflect a single event in which a chromosome is fragmented and
then imprecisely reassembled. In some cancer types, chromothripsis
contributes to oncogene amplification and tumor suppressor gene
inactivation in a substantial proportion of tumors. While the exact pro­
cess that underlies chromothripsis remains obscure, a transient period
of extreme instability stands in contrast to the gradual loss, gain, and
rearrangement of chromosomes that are typically observed in serially
cultured cancer cells.
Chr 9
Changed Chr 9
Chr 22
BCR
BCR
Chromosome
translocation
9q34
ABL
22q11
FIGURE 76-3  Specific translocation seen in chronic myeloid leukemia (CML). The Philadelphia chromosome (Ph) is derived from a reciprocal translocation between
chromosomes 9 and 22 with the breakpoint joining the sequences of the ABL oncogene with the BCR gene. The fusion of these DNA sequences allows the generation of an
entirely novel fusion protein with modified function.
PART 4
Oncology and Hematology
TUMOR-SUPPRESSOR GENE INACTIVATION
IN CANCER
The normal role of tumor-suppressor genes is to restrain cell growth,
and the function of these genes is inactivated in cancer. The three
major types of somatic lesions observed in tumor-suppressor genes
during tumor development are point mutations, small insertions and/or
deletions known as indels, and large deletions. Point mutations or indels
in the coding region of tumor-suppressor genes will frequently lead to
truncated protein products or allele-specific loss of RNA expression by
the process of nonsense-mediated decay. Unlike the highly recurrent
point mutations that are found in critical positions of activated onco­
genes, known as mutational hotspots, the point mutations that cause
tumor-suppressor gene inactivation tend to be distributed throughout
the open reading frame. Large deletions lead to the loss of a functional
product and sometimes encompass the entire gene or even the entire
chromosome arm, leading to loss of heterozygosity (LOH) in the tumor
DNA compared to the corresponding normal tissue DNA (Fig. 76-4).
Mapping regions of LOH was a useful approach in the positional clon­
ing of many tumor-suppressor genes. The rate of LOH is increased
in the presence of chromosomal instability, a relationship that would
explain the selective forces leading to the high prevalence of aneuploidy
in late-stage cancers.
Gene silencing, an epigenetic change that leads to the loss of gene
expression, occurs in conjunction with hypermethylation of the
promoter and histone deacetylation, and is another mechanism of
tumor-suppressor gene inactivation. An epigenetic modification refers
to a covalent modification of chromatin, heritable by cell progeny that
may involve DNA but does not involve a change in the DNA sequence.
FAMILIAL CANCER SYNDROMES
A small fraction of cancers occurs in patients with a genetic predispo­
sition. Based on studies of inherited and sporadic forms of retinoblas­
toma, Knudson and others formulated a hypothesis that explains the
differences between sporadic and inherited forms of the same tumor
type. In inherited forms of cancer, called cancer predisposition syn­
dromes, one allele of a particular tumor-suppressor gene is inherited
in mutant form. This germline mutation is not sufficient to initiate a
tumor, however; the other allele, inherited from the unaffected parent,
must become somatically inactivated in a normal stem cell for tumori­
genesis to be initiated. In sporadic (noninherited) forms of the same
disease, all cells in the body start out with two normal copies of the
tumor-suppressor gene. A single cell must then sequentially acquire
Ph Chr
Chimeric gene
ABL
BCR
ABL
BCR-ABL fusion protein
mutations in both alleles of the tumor-suppressor gene to initiate a
tumor. Thus, biallelic mutations of the same tumor-suppressor gene are
required for both inherited and noninherited forms of the disease; the
only difference is that individuals with the inherited form have a “head
start”: they already have one allele mutated, from conception, and only
need one additional mutation to initiate the process (Fig. 76-4).
This distinction explains why those with inherited forms of the dis­
ease develop more cancers, at an earlier age, than the general popula­
tion. It also explains why, even though every cell in an individual with
a cancer predisposition syndrome has a mutant gene, only a relatively
small number of tumors arise during their lifetime. The reason is
that the vast majority of cells within such individuals are functionally
normal because one of the two alleles of the tumor-suppressor gene
is normal. Mutations are uncommon events, and only the rare cells
that develop a mutation in the remaining normal allele will exhibit
uncontrolled proliferation. The same principle applies to virtually all
types of cancer predisposition syndromes, though the particular genes
differ. For example, inherited mutations in RB1, WT1, VHL, APC, and
BRCA1 lead to predispositions to retinoblastomas, Wilms’ tumors,
renal cell carcinomas, colorectal carcinomas, and breast carcinomas,
respectively (Table 76-3). Also note that the biallelic inactivation of
any of these genes is not sufficient to develop cancer; it requires other,
additional somatic alterations in other genes for the initiating cells to
evolve to malignancy, as noted above.
Roughly 100 familial cancer syndromes have been reported; the great
majority are very rare. Most of these syndromes exhibit an autosomal
dominant pattern of inheritance, although some of those associated with
DNA repair abnormalities (xeroderma pigmentosum, Fanconi’s anemia,
ataxia telangiectasia) are inherited in an autosomal recessive fashion.
Table 76-3 shows a number of cancer predisposition syndromes and the
responsible genes.
Familial adenomatous polyposis (FAP) is a dominantly inherited
colon cancer syndrome caused by germline mutations in the adeno­
matous polyposis coli (APC) tumor-suppressor gene on chromosome
5. Affected individuals develop hundreds to thousands of adenomas
in the colon. In each of these adenomas, the APC allele inherited from
the nonaffected parent has been inactivated by virtue of a somatic
mutation (Fig. 76-2). This inactivation usually occurs through a gross
chromosomal event resulting in loss of all or a large part of the long
arm of chromosome 5, where APC resides. In other cases, the remain­
ing allele is inactivated by a subtle intragenic mutation of APC, which
is typically a single base substitution resulting in a nonsense codon.
A1
+
+
B1
A2
A1
+
Rb
B2
Markers
A and B
B2
Tumor formation
A1
+
Rb
B1
A3
B3
A1
Rb
Rb
B1
FIGURE 76-4  Diagram of possible mechanisms for tumor formation in an individual with hereditary (familial) retinoblastoma. On the left is shown the pedigree of an
affected individual who has inherited the abnormal (Rb) allele from her affected mother. The normal allele is shown as a (+). The four chromosomes of her two parents are
drawn to indicate their origin. Flanking the retinoblastoma locus are genetic markers (A and B) also analyzed in this family. Markers A3 and B3 are on the chromosome
carrying the retinoblastoma disease gene. Tumor formation results when the normal allele, which this patient inherited from her father, is inactivated. On the right are shown
four possible ways in which this could occur. In each case, the resulting chromosome 13 arrangement is shown. Note that in the first three situations, the normal allele (B1)
has been lost in the tumor tissue, which is referred to as loss of heterozygosity (LOH) at this locus.
Gross chromosomal losses occur more commonly than point muta­
tions in normal cells, explaining why chromosomal loss rather than
point mutation is the predominant mechanism underlying the inacti­
vation of the normal allele of APC. The same is true for other cancer
predisposition syndromes caused by other inherited tumor suppressor
gene mutations; gross chromosomal events are generally responsible
for inactivation of the tumor-suppressor gene allele inherited from
the nonaffected parent. Several thousand adenomas form in FAP
patients, and a small subset of the millions of cells within an adenoma
will acquire a second mutation, leading to tumor progression, that is,
a larger adenoma. A third mutation in such a larger adenoma may
convert it to a carcinoma. If untreated (by colectomy), at least one of
the adenomas will progress to cancer by the time patients are in their
mid-40s. APC is a gatekeeper for colon tumorigenesis in the sense that
in the absence of mutation in APC (or a gene acting within the same
pathway), a colorectal tumor simply cannot be initiated. Figure 76-5
shows the germline and somatic mutations found in the APC gene.
A negative regulator of a signaling pathway that determines cell fate
during development, the APC protein provides differentiation and
apoptotic cues to colonic epithelial cells as they migrate up the crypt.
Defects in this process can lead to abnormal accumulation of cells that
would otherwise differentiate and eventually undergo apoptosis.
In contrast to patients with FAP, patients with hereditary nonpol­
yposis colon cancer (HNPCC, or Lynch syndrome) do not develop
polyposis, but instead develop only one or a small number of adenomas
that rapidly progress to cancer. HNPCC is due to inherited mutations
in one of four DNA mismatch repair genes (Table 76-3) that are com­
ponents of a repair system responsible for correcting errors in newly
replicated DNA. Germline mutations in MSH2 and MLH1 together
account for more than 90% of HNPCC cases, and mutations in MSH6
and PMS2 account for the remainder. When a somatic mutation inac­
tivates the remaining wild-type allele of a mismatch repair gene, the
Chromosome
arrangement
in the tumor
Loss of normal chr 13
Rb
A3
B3
Loss and reduplication
A3
A3
Rb
Rb
B3
A3
B3
B3
Mitotic crossing over
A1
Rb
Rb
B3
A3
B3
CHAPTER 76
Independent mutation
or small deletion
A3
Cancer Genetics
B3
cell develops a hypermutable phenotype characterized by profound
genomic instability that is most readily apparent in short repeated
sequences called microsatellites and is sometimes called microsatellite
instability (MSI). The high rate of mutation in such cells impacts all
genes, including oncogenes and tumor-suppressor genes, and thereby
accelerates the activation of the former and the inactivation of the latter
(Fig. 76-2). HNPCC can be considered a disease of tumor progression;
once tumors are initiated (by an inactivating mutation of APC or by
some other gene in the APC pathway), tumors rapidly progress because
of the accelerated mutation rate. Progression from a tiny adenoma to
carcinoma takes only a few years in HNPCC patients instead of the
two or three decades this progression takes in patients with FAP (or
in patients with sporadic colorectal tumors). Approximately half of
HNPCC patients develop colorectal cancers by the time they are in
their mid-40s—similar to that of FAP patients. This coincidence in
age of onset emphasizes that both tumor initiation (abnormal in FAP
patients) and tumor progression (abnormal in HNPCC patients) are
the two pillars of cancer development and are equally important for
cancer development.
Another general principle is apparent from the comparison between
FAP and HNPCC patients. The tumors in FAP patients, like those in
patients without hereditary predisposition to cancers, exhibit chro­
mosomal instability rather than MSI. Indeed, MSI and chromosomal
instability tend to be mutually exclusive in colon cancers, suggest­
ing that they represent alternative mechanisms for the generation of
genomic instability (Fig. 76-2). Other cancer types rarely exhibit MSI.
Chromosomal instability is far more prevalent than MSI among all
cancer types, perhaps explaining why nearly all cancers are aneuploid.
Although most autosomal dominant inherited cancer syndromes
are due to mutations in tumor-suppressor genes (Table 76-3), there
are a few interesting exceptions. Multiple endocrine neoplasia type 2,
a dominant disorder characterized by pituitary adenomas, medullary
TABLE 76-3  Cancer Predisposition Syndromes and Associated Genes
SYNDROME
GENE
CHROMOSOME
INHERITANCE
TUMORS
Ataxia telangiectasia
ATM
11q22-q23
AR
Breast
Autoimmune lymphoproliferative syndrome
FAS
FASL
Birt-Hogg-Dubé syndrome
FLCN
17p11.2
AD
Kidney (hybrid oncocytic, chromophobe)
Bloom syndrome
BLM
15q26.1
AR
Various
Cowden syndrome
PTEN
10q23
AD
Breast, thyroid
Familial adenomatous polyposis
APC
MUTYH
Familial melanoma
CDKN2A
9p21
AD
Melanoma, pancreatic
Familial Wilms’ tumor
WT1
11p13
AD
Kidney (pediatric)
Hereditary breast/ovarian cancer
BRCA1
BRCA2
Hereditary diffuse gastric cancer
CDH1
16q22
AD
Stomach
Hereditary multiple exostoses
EXT1
EXT2
Hereditary retinoblastoma
RB1
13q14.2
AD
Retinoblastoma, osteosarcoma
Hereditary nonpolyposis colon cancer (HNPCC)
MSH2
MLH1
MSH6
PMS2
PART 4
Oncology and Hematology
Hereditary papillary renal carcinoma
MET
7q31
AD
Papillary kidney
Juvenile polyposis syndrome
SMAD4
BMPR1A
Li-Fraumeni syndrome
TP53
17p13.1
AD
Sarcoma, breast
Multiple endocrine neoplasia type 1
MEN1
11q13
AD
Parathyroid, endocrine, pancreas, and pituitary
Multiple endocrine neoplasia type 2a
RET
10q11.2
AD
Medullary thyroid carcinoma, pheochromocytoma
Neurofibromatosis type 1
NF1
17q11.2
AD
Neurofibroma, neurofibrosarcoma, brain
Neurofibromatosis type 2
NF2
22q12.2
AD
Vestibular schwannoma, meningioma, spine
Nevoid basal cell carcinoma syndrome (Gorlin’s syndrome)
PTCH1
9q22.3
AD
Basal cell carcinoma, medulloblastoma, jaw cysts
Peutz-Jeghers syndrome
STK11/LKB1
19p13.3
AD
Gastrointestinal, breast
Tuberous sclerosis
TSC1
TSC2
von Hippel–Lindau disease
VHL
3p25-26
AD
Kidney, cerebellum, pheochromocytoma
Abbreviations: AD, autosomal dominant; AR, autosomal recessive.
Number of mutations
Number of mutations
Somatic
O
ARM
15 aa
20 aa
Basic
E/D
APC
Germline
1000 1200 1400
FIGURE 76-5  Germline and somatic mutations in the tumor-suppressor gene adenomatous polyposis coli (APC). APC encodes a 2843-amino-acid protein with six major
domains: an oligomerization region (O), armadillo repeats (ARM), 15-amino-acid repeats (15 aa), 20-amino-acid repeats (20 aa), a basic region, and a domain involved in
binding EB1 and the Drosophila discs large homologue (E/D). Shown are 650 somatic and 826 germline mutations representative of the mutations that occur within the APC
gene (from the APC database at www.umd.be/APC). All known pathogenic mutations of APC result in the truncation of the APC protein. Germline mutations are found to
be relatively evenly distributed up to codon 1600 except for two mutation hotspots surrounding amino acids 1061 and 1309, which together account for one-third of the
mutations found in familial adenomatous polyposis (FAP) families.
10q24 1q23
AD
Lymphomas
5q21
1p34.1
AD
AR
Colorectal (early onset)
17q21
13q12.3
AD
Breast, ovarian, prostate
8q24
11p11-12
AD
Exostoses, chondrosarcoma
2p16
3p21.3
2p16
7p22
AD
Colon, endometrial, ovarian, stomach, small bowel,
ureter carcinoma
18q21
AD
Gastrointestinal, pancreatic
9q34
16p13.3
AD
Angiofibroma, renal angiomyolipoma
MCR
1600 1800 2000 2200 2400 2600 2800
Amino acid number
carcinoma of the thyroid, and (in some pedigrees) pheochromocy­
toma, is due to gain-of-function mutations in the proto-oncogene
RET on chromosome 10. Similarly, gain-of-function mutations in the
tyrosine kinase domain of the MET oncogene lead to hereditary papil­
lary renal carcinoma. Interestingly, loss-of-function mutations in the
RET gene cause a completely different disease, Hirschsprung’s disease
(aganglionic megacolon [Chaps. 339 and 400]).
Although the heritable forms of cancer have taught us much about
the mechanisms of growth control, most forms of cancer do not follow
simple Mendelian patterns of inheritance. The majority of human can­
cers arise in a sporadic fashion, solely as a result of somatic mutation,
and in the absence of any mutations in cancer-predisposing genes in
their germlines.
GENETIC TESTING FOR FAMILIAL CANCER
The discovery of cancer susceptibility genes raises the possibility of
DNA testing to predict the risk of cancer in individuals of affected
families. An algorithm for cancer risk assessment and decision making
in high-risk families using genetic testing is shown in Fig. 76-6. Once a
mutation is discovered in a family, subsequent testing of asymptomatic
family members is crucial. A negative gene test in these individuals
can prevent years of anxiety, providing comfort in the knowledge that
their cancer risk is no higher than that of the general population. On
the other hand, a positive test may lead to alteration of clinical man­
agement, such as increased frequency of cancer screening and, when
feasible and appropriate, prophylactic surgery. Potential negative con­
sequences of a positive test result include psychological distress (anxi­
ety, depression) and discrimination, although the Genetic Information
Patients (1) from family with a known cancer syndrome,
(2) from a family with a history of cancer, (3) with early onset cancer
Pretest counseling
Review of family history to confirm/identify
possible cancer syndromes and candidate genes
Informed consent
Testing of cancer patient
Negative test: no
disease-causing
mutations identified
Identification of disease-causing mutation
Screening of asymptomatic family members
Negative test: family member has
no increased risk of cancer
FIGURE 76-6  Algorithm for genetic testing in a family with cancer predisposition.
The key step is the identification of a disease mutation in a cancer patient, which
is an indication for the testing of asymptomatic family members. Asymptomatic
family members who test positive may require increased screening or surgery,
whereas those who test negative are at no greater risk for cancer than the general
population. It should be emphasized that no molecular assay used for this sort of
testing is 100% sensitive; negative results must be interpreted with this caveat in
mind.
Nondiscrimination Act (GINA) makes it illegal for predictive genetic
information to be used to discriminate in health insurance or employ­
ment. Testing should therefore not be conducted without counseling
before testing is administered and during and after disclosure of the
test result.
It is now feasible to obtain high-quality sequence of all of the proteincoding DNA sequences, and even of the entire genome, in any given
individual. In such studies, numerous variants in DNA sequences will
inevitably be identified in every subject, but the significance of the vast
majority of these DNA sequence findings will be unclear. Even muta­
tions in tumor-suppressor genes can be difficult to interpret unless
there is an obvious functional implication, such as the truncation of
the open reading frame, or that particular mutation has previously
been correlated with cancer in other individuals. Germline mutations
associated with cancer predisposition are uncommon in individuals
without a family history of cancer, though they do occur. Much more
common are variants of unknown significance (VUS). VUS that are
found during genetic testing cannot be used to evaluate the relative risk
of cancer but may nonetheless cause anxiety because they represent
a deviation from the reference allele that is established as “normal.”
Because of the low yield of informative mutations that modify cancer
risk and the frequent identification of VUS, it is generally not appropri­
ate to use DNA sequencing to assess cancer risk in individuals without
a family history of cancer. However, there are exceptions. Testing may
be appropriate in some subpopulations with a known increased risk,
even without a personal family history. For example, two mutations in
the breast cancer susceptibility gene BRCA1, 185delAG and 5382insC,
exhibit a sufficiently high frequency in the Ashkenazi Jewish popula­
tion that genetic testing based on ethnicity alone may be warranted.
CHAPTER 76
Cancer Genetics
It is important that genetic test results be communicated to families
by trained genetic counselors. To ensure that the families clearly under­
stand its advantages and disadvantages and the impact it may have on
disease management and psyche, genetic testing should never be done
before counseling. Significant expertise is needed to communicate the
results of genetic testing to families.
VIRUSES IN HUMAN CANCER
Several human malignancies are associated with viruses. Examples
include Burkitt’s lymphoma (Epstein-Barr virus; Chap. 199), hepato­
cellular carcinoma (hepatitis viruses), cervical cancer (human papil­
lomavirus [HPV]; Chap. 203), and T-cell leukemia (retroviruses;
Chap. 207). There are several types of HPV, including the high-risk
types 16 and 18 that are strongly associated with the development of
cervical, vulvar, vaginal, penile, anal, and oropharyngeal cancer. The
mechanisms of action of all these viruses involve inactivation of tumorsuppressor genes. For example, HPV proteins E6 and E7 bind to and
inactivate cellular tumor suppressors p53 and pRB, respectively. This is
the reason that HPV is such a potent initiator of cancer: infection with
a virus is tantamount to having two of the three mutant driver genes
required for cancer, that is, one viral oncogene inactivates p53 and the
other inactivates Rb. Once these two inactivated gene products initiate
tumorigenesis, only one additional mutant gene is required for these
tumors to progress to malignancy.
■
■CANCER GENOMES
The advent of relatively inexpensive technologies for rapid and
high-throughput DNA sequencing has facilitated the comprehensive
analysis of numerous genomes from many types of tumors. This
unprecedented view into the genetic nature of cancer has provided
remarkable insights. Most cancers do not arise in the context of a
mutator phenotype, and accordingly, the number of mutations in even
the most advanced cancers is relatively modest. Common solid tumors
harbor 30–70 subtle mutations that are nonsynonymous (i.e., result
in an amino acid change in the encoded protein). Liquid tumors such
as leukemias, as well as pediatric tumors, typically have fewer than 20
mutations. The vast majority of the mutations detected in tumors are
not functionally significant; they simply arose by chance in a single
cell that gave rise to an expanding clone. Such mutations, which pro­
vide no selective advantage to the cell in which they occur, are known
as passenger mutations. As noted above, only a small number of the
mutations confer a selective growth advantage and thereby promote
tumorigenesis. These functional mutations are known as driver muta­
tions, and the genes in which they occur are called driver genes.
The frequency and distribution of driver mutations within a single
tumor type can be represented as a topographical landscape. The
picture that emerges from cancer genome studies reveals that most
genes that are mutated in tumors are actually mutated at relatively low
frequencies, as would be expected of passenger genes, whereas a small
number of genes (the driver genes) are mutated in a large proportion
of tumors. Only ~200 driver genes contribute to the development of
solid tumors of all kinds. Driver genes that play a role in ever smaller
fractions of cancers are still being discovered. The majority of the muta­
tions in driver genes provide a direct selective growth advantage by
altering the signaling pathways that mediate cell survival or the deter­
mination of cell fate. The remaining driver gene mutations indirectly
provide a selective growth advantage by accelerating the mutation rate
of proto-oncogenes and tumor-suppressor genes. That the same driver
genes play a role in multiple cancer types was unexpected before their
discovery and has important implications for the development of new
“tumor-agnostic” therapeutic and diagnostic approaches. Moreover,
the functions of all these driver genes can be organized into a small
number of signaling pathways, as shown in Table 76-4.
As a consequence of the mutations they harbor, cancer cells invari­
ably express mutant proteins that are only rarely found in normal cells.
Some of these mutant proteins are processed and displayed on the
cell surface in the context of major histocompatibility complexes, a
process that would normally facilitate their recognition by the adaptive
immune system. Thus, all cancers have the theoretical potential to be
recognized as foreign, or “nonself,” via the display of these tumor-spe­
cific antigens, known as mutation-associated neoantigens (MANAs).
In fact, established tumors invariably prevent the activation of local T
cells by inducing an intercellular suppressive mechanism known as an
immune checkpoint. Therapeutic approaches to exploit this potential
vulnerability by blocking immune checkpoints have elicited striking
responses in patients with several types of cancer.
PART 4
Oncology and Hematology
It was hypothesized that the potential immunogenicity of a tumor
would be related to the total number of distinctive neoantigens it can
express, which in turn is directly determined by the total number
of mutations in the cancer genome. This does seem to be the case.
Colorectal cancers that develop as a result of mismatch repair defi­
ciency and smoking-related lung cancers, both of which characteristi­
cally harbor large numbers of mutations, exhibit more robust responses
to therapeutic immune checkpoint blockade than most other tumor
types. Notably, driver mutations as well as passenger mutations that
result in the expression of mutant proteins can both contribute to the
display of immunogenic neoantigens. Thus, the total number of coding
TABLE 76-4  Signaling Pathways Altered in Cancer
REPRESENTATIVE
DRIVER GENES
PROCESS
PATHWAY
Cell survival
Cell cycle regulation/
apoptosis
RB1, BCL2
 
RAS
KRAS, BRAF
 
PIK3CA
PTEN, PIK3CA
 
JAK/STAT
JAK2, FLT3
 
MAPK
MAP3K, ERK
 
TGF-β
BMPR1A, SMAD4
Cell fate
Notch
NOTCH1, FBWX7
 
Hedgehog
PTCH1, SMO
 
WNT/APC
APC, CTNNB1
 
Chromatin modification
DNMT1, IDH1
 
Transcriptional regulation
AR, KLF4
Genome maintenance
DNA damage signaling and
repair
ATM, BRCA1
mutations, a metric known as mutational load, is one of the determi­
nants of potential immunogenicity.
The ability of cancer cells to evade immune-mediated cell death is
an intrinsic property that is essential for their continued growth. While
tumor suppressor genes and oncogenes have been intensively studied
with respect to their effects on the intracellular signaling pathways
that regulate cell proliferation and cell death, little is known about how
these genetic alterations affect the interactions between cancer cells
and neighboring immune cells. In particular, neoplastic cells contain­
ing certain mutations may be culled by the immune system because the
mutations create neoantigens that can be recognized by T cells.
■
■TUMOR HETEROGENEITY
The mutant cells that compose a single tumor are not genetically
identical. Rather, cells obtained from different sites on a tumor will
harbor common mutations as well as mutations that are unique to each
sample. Genetic heterogeneity results from the ongoing acquisition of
mutations during tumor growth. Each time a genome is replicated,
there is a small but quantifiable probability that a mutation will spon­
taneously arise as a result of a replication error and be passed on to the
cellular progeny. This is true in normal cells or in tumor cells. Any ran­
domly chosen cell from the skin of one individual will harbor hundreds
of genetic alterations that distinguish it from a different randomly
chosen skin cell, and the same is true for all organs of self-renewing
tissues. Tumors are actually less genetically heterogeneous than normal
tissues; any two randomly chosen cells from a tumor of an individual
will have fewer differences than any two randomly chosen cells from
that individual’s normal tissues. The reason for this decrease in hetero­
geneity is clonal expansion, the fundamental feature of tumorigenesis.
Every time a clonal expansion occurs, a genetic bottleneck wipes out
heterogeneity among the cells that did not expand; these unexpanded
cells either die or form only a minute proportion of the total cells in
the expanding tumor.
The mutations that vary between cells of a given tumor are invari­
ably passenger mutations that arose since the last evolutionary bottle­
neck, that is, those mutations that arose during the expansion of the
founder cell that gave rise to the final clonal expansion. In contrast,
the passenger mutations that were present in the founder cell will be
uniformly present in every cell in the tumor. In that respect, these pas­
senger mutations are not heterogeneously distributed and are in fact
uniformly present in virtually all cancer cells. These “clonal” mutations,
i.e., present in all cells of the cancers, are the main source of MANAs
that can be exploited through immune checkpoint inhibitors. The total
number of mutations and their distribution within tumor cells repre­
sent a complex interplay between the age of the patient (the older the
patient, the more passenger mutations will have accumulated in the
founding cell of the first clonal expansion) and the evolutionary history
of the cancer (its age and number of clonal expansions it experienced).
Tumor heterogeneity has been recognized for decades at the cyto­
genetic, biochemical, and histopathologic levels. However, it is only
recently, with the advent of a deep understanding of cancer genetics,
that genetic heterogeneity can be interpreted in a medically relevant
fashion. The first important point to recognize about tumor hetero­
geneity is that it is only the variation in driver gene alterations that
is important; the cellular distribution of passenger gene mutations is
irrelevant except for immune-related phenomena. In this discussion of
heterogeneity, we can expand the definition of “driver genes” to include
those that provide a selective growth advantage in the face of therapy
in addition to those that provide a selective growth advantage during
tumor evolution, prior to treatment.
Type I heterogeneity refers to that among tumors of the same type
from different patients (Fig. 76-7). Though adenocarcinomas of the lung
generally harbor mutations in three or more driver genes, the genes dif­
fer among the patients, and the precise mutations within the same gene
can vary considerably. Type I heterogeneity is the basis for precision
medicine, where the goal is to treat patients with drugs that target the
proteins encoded by genetic alterations within their specific tumors.
Type II heterogeneity refers to the genetic heterogeneity among differ­
ent cells from the same primary tumor. Tumors continue to evolve as
Intratumoral heterogeneity
within a primary tumor
Intermetastatic heterogeneity
between two metastases
A
Clone 1
Clone 2
Liver
Founder
cells
Founder
cells
Clone 4
Clone 3
Intrametastatic heterogeneity
within metastatic lesions
Interpatient heterogeneity
D
C
FIGURE 76-7  Four types of tumor heterogeneity. Tumor heterogeneity is the inevitable result of cell proliferation, as new mutations are introduced during clonal expansion.
In a typical tumor (upper left), founder cells that harbor a large fraction of the total mutations give rise to subclones, which continue to evolve independently. The tumors of
the founding populations are shown in the middle of each circle; the distinct subclones are shown around the periphery. A. Heterogeneity among the cells of a primary tumor
is known as intratumoral heterogeneity. B. Heterogeneity among the founding cells of distinct metastatic lesions (marked as 1 and 2) that arise in the same patient is known
as intermetastatic heterogeneity. C. Heterogeneity among the cells of each metastatic tumor is known as intrametastatic heterogeneity. D. Interpatient heterogeneity.
The mutations in the tumors of two patients are almost completely distinct. (Reproduced with permission from  B Vogelstein et al: Cancer genome landscapes. Science
339(6127):1546, 2013.)
they grow, and different cells of the same cancer, in its original site (e.g.,
the pancreas), may acquire other driver gene mutations that are not
shared among the other cells of the tumor. Such a mutation can result
in a small clonal expansion that may or may not be important biologi­
cally. In cases in which the primary tumor can be surgically excised,
such mutations are unimportant unless they give rise to type III
heterogeneity (described below). The reason they are unimportant
is because all primary tumor cells, whether homogeneous or not, are
removed by the surgical procedure. In primary tumors that cannot be
completely excised (such as most advanced brain tumors and many
pancreatic ductal adenocarcinomas), heterogeneity is biomedically
important because it can give rise to drug resistance, analogously to
that described for type IV heterogeneity (see below). Type III hetero­
geneity refers to the genetic differences among the founder cells of the
metastatic lesions from the same patient. For example, a patient with
melanoma may have 100 different metastases distributed throughout
various organs. Only if a mutant BRAF is present in every founder
cell of every metastasis, then the patient has a chance at a complete
response to a BRAF inhibitor. There have been several recent detailed
studies of the metastases from various tumor types. Fortunately, these
studies suggest there is very little, if any, type III heterogeneity among
driver genes, a necessary prerequisite for the successful implementa­
tion of current and future targeted therapies. Finally, type IV hetero­
geneity refers to that among cells of individual metastatic lesions. As
the founder cell of each metastasis expands to become detectable, it
acquires mutations, a small number of which can act as “drivers” when
the patient is exposed to therapeutics. This type of heterogeneity is
of major clinical importance, as it has been shown to be responsible
for the development of resistance in virtually all targeted therapies.
The development of such resistance is a fait accompli based simply on
known mutation rates and genetic resistance mechanisms. The only
way to circumvent acquired resistance is to treat metastatic tumors
earlier (i.e., in adjuvant setting, before much tumor expansion has
occurred) or to treat with combinations of drugs for which crossresistance is genetically impossible.
B
Metastasis 1
Pancreas
Metastasis 2
Primary tumor
Patient 1
Patient 2
CHAPTER 76
Cancer Genetics
PERSONALIZED CANCER DETECTION AND
TREATMENT
High-throughput DNA sequencing has led to an unprecedented under­
standing of cancer at the molecular level. A comprehensive mutation
profile provides a molecular history of a given tumor and insights into
how it arose. Because tumor cells and tumor DNA are shed into the
blood and other bodily fluids, common driver mutations can be used as
highly specific biomarkers for early detection. For diagnosed tumors,
tumor-specific mutations can be used to estimate tumor burden, assess
treatment responses, and detect recurrence.
In some cases, information regarding specific genes and pathways
that are altered provides patients and physicians with options for
personalized therapy. This general approach is sometimes referred to
as precision medicine. Because tumor behavior is highly variable, even
within a tumor type, personalized information-based medicine can
supplement and perhaps eventually supplant histology-based tumor
assessment, especially in the case of tumors that are resistant to con­
ventional therapeutic approaches. Conversely, molecular nosology has
revealed similarities in tumors of diverse histotype. The success of the
precision medicine approach in any given patient depends on the pres­
ence of tumor-associated genetic alterations that are actionable (i.e.,
can be targeted with a specific drug). Examples of currently actionable
changes include mutations in BRAF (targeted by the drug vemu­
rafenib), RET (targeted by sunitinib and sorafenib), ALK rearrange­
ments (targeted by crizotinib), and mismatch repair genes (targetable
by immune checkpoint inhibitors).
The development of new targeted agents is at present hindered by
the fact that most such agents can only target activated oncogenes,
while the great majority of genetic alterations in common solid tumors
are those that inactivate tumor-suppressor genes. Because all drugs,
whether for use in oncology or any other purpose, can only inhibit
protein actions, drugs cannot be used to directly target the proteins
encoded by inactivated tumor-suppressor genes; these proteins are
already inactive. More information about the pathways through
which tumor-suppressor genes act may provide a way around this

06 - 77 Cancer Cell Biology
77 Cancer Cell Biology
obstacle. For example, when a tumor-suppressor gene is inactivated,
some downstream component of the pathway is likely to be activated,
thereby presenting a realistic target. Alternatively, the mutational inac­
tivation of a DNA repair pathway might create a unique dependence
on the repair pathways that remain intact. An example of this is pro­
vided by PARP-1 inhibitors, which have been successfully used to treat
patients whose tumors have inactivating mutations of genes involved in
DNA repair processes, such as BRCA1. Patterns of global gene expres­
sion can be used to help unravel such pathways and are already being
used to predict drug sensitivities and provide prognostic information
in addition to that provided by DNA sequence analysis. Evaluation of
proteomic and metabolomic patterns may also prove useful for this
purpose.
■
■THE FUTURE
A revolution in cancer genetics has occurred in the past 30 years. Most
types of cancer are now understood at the DNA sequence level, and
this accomplishment has led to an increasingly refined understanding
of tumorigenesis. Cancer gene mutations have proven to be reliable
biomarkers for cancer detection and monitoring as well as for inform­
ing therapeutics through precision medicine approaches. Gene-based
tests are already standard of care for patients with certain tumor types,
such as colorectal and lung cancers, and the utility of these tests will
undoubtedly be expanded in the coming years as new therapies and
ways of predicting responses to therapies are developed. While effec­
tive treatment of advanced cancers remains difficult, the early promise
shown by immune-based therapies notwithstanding, it is expected that
breakthroughs in these areas will continue to emerge and be applicable
to an ever-increasing number of cancers. Moreover, with the hoped-for
advances in diagnostics, particularly in the earlier detection of cancers,
the new and old therapies for cancer can be expected to have a much
greater impact on reducing cancer deaths.
PART 4
Oncology and Hematology
Acknowledgments
The authors gratefully acknowledge the past contributions of Pat J.
Morin, Jeff Trent, and Francis Collins to earlier versions of this chapter.
■
■FURTHER READING
Bunz F: Principles of Cancer Genetics, 3rd ed. Dordrecht, Springer,
2022.
Le DT et al: PD-1 Blockade in tumors with mismatch-repair deficiency.
N Engl J Med 372:2509, 2015.
Vogelstein B, Kinzler KW: The path to cancer—three strikes and
you’re out. N Engl J Med 373:1895, 2015.
Vogelstein B et al: Cancer genome landscapes. Science 339:1546,
2013.
Jeffrey W. Clark, Dan L. Longo
Cancer Cell Biology
■
■CANCER CELL BIOLOGY
Cancers are characterized by unregulated cell division, avoidance of
cell death, tissue invasion, and the ability to spread to other areas of the
body (metastasize). A neoplasm is benign when it grows in an unregu­
lated fashion without tissue invasion or metastasizing. The presence
of unregulated growth, tissue invasion, and the ability to metastasize
is characteristic of malignant neoplasms. Cancers are named based on
their tissue of origin: those derived from epithelial tissue are called car­
cinomas, those derived from mesenchymal tissues are sarcomas, and
those derived from hematopoietic tissue are leukemias, lymphomas,
and plasma cell dyscrasias (including multiple myeloma).
Cancers arise as a consequence of genetic alterations, the vast
majority of which begin in a single cell and therefore are monoclonal
in origin. However, because a wide variety of genetic and epigenetic
changes can occur in different cells within malignant tumors over
time, as well as varied responses with their microenvironments and the
biology of the patient, most cancers are characterized by plasticity and
marked heterogeneity in the populations of cells and their composite
behavior. In addition, extrinsic factors in the cancer environment (e.g.,
the stroma, infiltrating cells, various cell-to-cell interactions, spatial
orientation, secreted factors, and availability of oxygen and nutrients)
vary in different areas within the tumor or different metastases, com­
pounding this heterogeneity. This heterogeneity significantly compli­
cates the treatment of most cancers because it is likely that there are
subsets of cells that will be resistant to therapy for a variety of reasons
and will therefore survive and proliferate even if the majority of cells
are killed.
A few cancers appear to, at least initially, be primarily driven by an
alteration in a dominant gene that produces uncontrolled cell prolif­
eration. Examples include chronic myeloid leukemia (abl), about half
of melanomas (braf), Burkitt’s lymphoma (c-myc), and subsets of lung
adenocarcinomas (egfr, alk, ros1, met, ret, braf, and ntrk). Genes that
can promote cell growth when altered are often called oncogenes. They
were first identified as critical elements of viruses that cause animal
tumors; it was subsequently found that the viral genes had normal
counterparts with important functions in the cell and had been cap­
tured and mutated by viruses as they passed from host to host.
However, most human cancers are characterized by a multiple-step
process involving many genetic abnormalities, each of which contrib­
utes to the loss of control of cell proliferation and differentiation and
the acquisition of capabilities, such as tissue invasion, the ability to
metastasize, angiogenesis (development of new blood vessels required
for tumor growth), and alteration of the extracellular environment.
These properties are not found in the normal adult cell from which
the tumor is derived. Indeed, normal cells have a large number of
safeguards against DNA damage (including multiple DNA repair and
extensive DNA damage response mechanisms), uncontrolled prolif­
eration, and invasion. Many cancers go through recognizable steps of
progressively more abnormal phenotypes: hyperplasia, to adenoma, to
dysplasia, to carcinoma in situ, to invasive cancer with the ability to
metastasize (Table 77-1). For most cancers, these changes occur over a
prolonged period of time, usually many years.
In most organs, only primitive undifferentiated cells are capable of
proliferating and cells lose the capacity to proliferate as they differenti­
ate and acquire functional capabilities. The expansion of the primitive
cells (stem cells) is linked to some functional need in the host, such as
normal turnover of tissues or regeneration after acute injury, through
receptors that receive signals from cells and other factors in the local
tissue microenvironment or through hormonal and other influences
delivered by the vascular supply. In the absence of such signals, the
cells are at rest or quiescent (out of the cell cycle but capable of being
activated to reenter the cell cycle). The signals that induce quiescence
in primitive cells as well as those that keep the cells at rest are com­
plex, including the process for quiescent entry, maintenance, and exit.
Although much has been learned, including the importance of notch
signaling, the STING pathway, other quiescent factors, and transcrip­
tional, posttranscriptional, and epigenetic regulation in quiescent
entry and maintenance, overall control of the process within the body
remains incompletely understood. These signals must be, at least in
part, environmental, based on the observations that a regenerating liver
stops growing when it has replaced the portion that has been surgically
removed after partial hepatectomy and regenerating bone marrow
stops growing when the peripheral blood counts return to normal.
Cancer cells clearly have lost responsiveness to such controls and do
not recognize when they have overgrown the niche normally occupied
by the organ from which they are derived. A better understanding of
these mechanisms of growth regulation in the context of organ homeo­
stasis continues to evolve.
TABLE 77-1  Phenotypic Characteristics of Malignant Cells
Deregulated cell proliferation: Loss of function of negative growth regulators
(tumor suppressor genes, i.e., Rb, p53) and increased action of positive growth
regulators (oncogenes, i.e., Ras, Myc). Leads to aberrant cell cycle control and
includes loss of normal checkpoint responses.
Failure to differentiate: Arrest at a stage before terminal differentiation.
May retain stem cell properties. (Frequently observed in leukemias due to
transcriptional repression of developmental programs by the gene products of
chromosomal translocations.)
Loss of normal apoptosis pathways: Inactivation of p53, increases in Bcl-2
(antiapoptotic) family members. This defect enhances the survival of cells with
oncogenic mutations and genetic instability and allows clonal expansion and
diversification within the tumor without activation of physiologic cell death
pathways.
Genetic instability: Defects in DNA repair pathways leading to either single
nucleotide or oligonucleotide mutations (as in microsatellite instability, MIN) or,
more commonly, chromosomal instability (CIN) leading to aneuploidy (abnormal
number of chromosomes in a cell). Caused by loss of function of a number of
proteins including p53, BRCA1/2, mismatch repair genes, DNA repair enzymes,
and the spindle checkpoint. Leads to accumulation of a variety of mutations in
different cells within the tumor and heterogeneity.
Loss of replicative senescence: Normal cells stop dividing in vitro after 25–50
population doublings. Arrest is mediated by the Rb, p16INK4a, and p53 pathways.
While most cells remain arrested, genetic and epigenetic changes in a subset
of cells allow further replication, leading to telomere loss, with crisis leading
to death of many cells. Cells that survive often harbor gross chromosomal
abnormalities and the ability to continue to proliferate. These cells express
telomerase, which maintains telomeres and is important for ongoing growth of
these cells. Relevance to human in vivo cancer remains uncertain. Many human
cancers express telomerase.
Nonresponsiveness to external growth-inhibiting signals: Cancer cells have
lost responsiveness to signals normally present to stop proliferating when they
have overgrown the niche normally occupied by the organ from which they are
derived. Our understanding about this mechanism of growth regulation remains
limited.
Increased angiogenesis: Due to increased gene expression of proangiogenic
factors (VEGF, FGF, IL-8, angiopoietin) by tumor or stromal cells, or loss of
negative regulators (endostatin, tumstatin, thrombospondin).
Invasion: Cell mobility and ability to move through extracellular matrix and into
other tissues or organs. Loss of cell-cell contacts (gap junctions, cadherins) and
increased production of matrix metalloproteinases (MMPs). Can take the form
of epithelial-to-mesenchymal transition (EMT), with anchored epithelial cells
becoming more like motile fibroblasts.
Metastasis: Spread of tumor cells to lymph nodes or distant tissue sites. Limited
by the ability of tumor cells to migrate out of initial site and to survive in a foreign
environment, including evading the immune system (see below).
Evasion of the immune system: Downregulation of MHC class I and II molecules;
induction of T-cell tolerance; inhibition of normal dendritic cell and/or T-cell
function; antigenic loss variants and clonal heterogeneity; increase in regulatory
T cells.
Shift in cell metabolism: Complex changes including alterations due to
tumor stress such as hypoxia and energy generation shifts from oxidative
phosphorylation to aerobic glycolysis generate building blocks for malignant cell
production and proliferation.
Complex interactions with the extracellular environment around the
cancer cells: Induction of changes as well as complex interactions with the
extracellular environment around cancer cells, including modifications to the
extracellular matrix, vasculature, chemokines, mesenchymal stromal cells,
fibroblasts, immune cells, other hematopoietic cells, platelets, nerves, and
potentially infectious agents impacting many of the above processes.
Abbreviations: FGF, fibroblast growth factor; IL, interleukin; MHC, major
histocompatibility complex; VEGF, vascular endothelial growth factor.
■
■DIFFERENCES BETWEEN PEDIATRIC AND ADULT
CANCERS
The underlying importance of genetic mutations and other molecular
changes is similar for pediatric and adult cancers. However, some
important differences exist. Childhood cancers have a different epi­
demiology (e.g., they do not have the same extent of environmental
or lifestyle risk factors), are much less frequent, and have a different
spectrum of frequency beginning primarily during embryogenesis
in mesodermal (e.g., sarcomas or hematologic malignancies such as
acute lymphocytic leukemia [ALL] or lymphomas) or ectodermal (e.g.,
neuronal including brain and spinal) tissues. They generally have fewer
genetic changes and lower mutational burdens than adult cancers.
Likely due to a number of factors including the nature of the cancers
(e.g., less genetic complexity than adult cancers) and the ability of
children to tolerate more intense chemotherapy regimens, childhood
cancers generally tend to be much more responsive to chemotherapy
than adult cancers with significantly higher rates of cure.
■
■CANCER AS AN ORGAN THAT IGNORES ITS NICHE
The fundamental cellular defects that create a malignant neoplasm act
at the cellular level, and some of these are cell autonomous. However,
that is not the entire story. Cancers consist of both malignant cells as
well as other cells, blood vessels, extracellular matrix, and signaling
and other molecules in the cancer microenvironment. They behave as
organs that have lost their specialized function and stopped respond­
ing to signals that would limit their growth in tightly regulated normal
tissue homeostasis. Most human cancers usually become clinically
detectable when a primary mass is approximately 1 cm in diameter—
such a mass consists of about 109 cells. Often, patients present with
tumors that are approximately 1010 cells. Although it varies by type
of cancer and where the primary tumor and metastases are located,
a lethal tumor burden is usually about 1012–1013 cells. If all malignant
cells were dividing without any cell death at the time of diagnosis, most
patients would reach a lethal tumor burden in a very short time. How­
ever, human tumors grow by Gompertzian kinetics—this means that
not every daughter cell produced by a cell division is actively dividing.
In addition, the overall growth rate of a tumor depends on differences
between growth rates of different cells within the tumor and rate of
cell loss. The growth fraction of a tumor declines with time, largely
due to factors in the microenvironment and accumulation of genetic
damage over time. The growth fraction of the first malignant cell is
100%, and by the time a patient presents for medical care, the growth
fraction is estimated to be <5%, although the fraction varies between
different types of cancers and even different cancers of the same type
in different individuals. This fraction is often similar to the growth
fraction of normal bone marrow and normal intestinal epithelium, the
most highly proliferative normal tissues in the human body, a fact that
may explain the dose-limiting toxicities to these tissues of agents that
target dividing cells.
CHAPTER 77
Cancer Cell Biology
The implication of these data is that the tumor is slowing its own
growth over time. How does it do this? The tumor cells have multiple
genetic lesions that tend to promote proliferation, yet by the time the
tumor is clinically detectable, its capacity for proliferation has declined.
Better understanding of how a tumor slows its own growth would
provide important clues for better cancer treatment. A number of fac­
tors, including those in the tumor microenvironment, are known to
contribute to the decreased proliferation of tumor cells over time in
the patient. For example, normal cells and other factors in the micro­
environment can contribute to slowing down the growth of cancer
cells. Some cancer cells are hypoxemic and have inadequate supply of
nutrients and energy. Some have sustained too much genetic damage to
complete the cell cycle but have lost the capacity to undergo apoptosis
and therefore survive but do not proliferate. However, an important
subset is not actively dividing but retains the capacity to divide and can
start dividing again under certain conditions such as when the tumor
mass is reduced by treatments leading to improved conditions in the
tumor microenvironment favorable for cell proliferation.
Just as the bone marrow increases its rate of proliferation in response
to bone marrow–damaging agents, the tumor also seems to sense when
tumor cell numbers have been reduced and can respond by increasing
growth rate. However, the critical difference is that the marrow stops
growing when it has reached its production goals, whereas tumors do
not.
The ultimate structure and organization of an organ are based on
a number of factors including growth, migration, elimination, and
death of various cells; communication between cells to establish the
correct architecture; competition between cells; and the composition
of the extracellular matrix that is produced. In addition to normal cells
stopping proliferation in an organ when that is appropriate, normal
tissues have various mechanisms for eliminating cells in both the pro­
cess of development as well as ongoing homeostasis of an organ. These
include mechanical processes based on a number of factors including
cell size, cell shape, and topology between cells that can determine cell
fate as well as an active process of cell extrusion, which plays a major
role in the elimination of both cells that are no longer needed by the
organ and cells that are damaged and potentially dangerous (such as
those with mutations that might be precursors for malignancy). The
process of cell extrusion may depend on cell cycle arrest in the S phase;
aberrations in this process may contribute to the metastatic process. A
variety of processes, including major alterations in cell cycle control,
apoptosis and other mechanisms of cell death, and uncontrolled cell
signaling, all contribute to defects in appropriate cell extrusion contrib­
uting to the development of cancer.
Additional tumor cell vulnerabilities are likely to be detected when
we learn more about how normal cells respond to “stop” signals from
their environment, and why and how tumor cells and tissues fail to
heed such signals.
■
■CELL CYCLE CHECKPOINTS
The cell division cycle consists of four phases—G1 (growth and
preparation for DNA synthesis), S (DNA synthesis), G2 (preparation
to divide), and M (mitosis, cell division). Cells can also exit the cell
cycle and be quiescent (G0). Progression of a cell through the cell cycle
is tightly regulated at a number of checkpoints (especially at the G1/S
boundary, the G2/M boundary, and during M [spindle checkpoint])
by an array of genes that are targeted by specific genetic alterations in
cancer. These checkpoints are quality-control features; at G1, the check­
point does not allow cells to proceed that are not ready for genome
replication; at G2/M, the cell assesses whether the genome has been
appropriately duplicated and is ready to divide. Critical proteins in
these control processes that are frequently mutated or otherwise inacti­
vated in cancers are called tumor-suppressor genes because when they
function normally, they inhibit the development or growth of cancer
cells. Examples include p53 and Rb (discussed below).
PART 4
Oncology and Hematology
In the first phase, G1, preparations are made to replicate the genetic
material. The cell stops before entering the DNA synthesis phase, or
S phase, to take inventory. Are we ready to replicate our DNA? Is the
DNA repair machinery in place to fix any mutations that are detected?
Are the DNA replicating enzymes available? Is there an adequate
supply of nucleotides? Is there sufficient energy to proceed? The reti­
noblastoma protein, Rb, plays a central role in placing a brake on the
process until the cell is ready. When the cell determines that it is pre­
pared to move ahead, sequential activation of cyclin-dependent kinases
(CDKs) results in the inactivation of the brake, Rb, by phosphorylation.
Phosphorylated Rb releases the S phase–regulating transcription factor,
E2F/DP1, and genes required for S-phase progression are expressed. If
the cell determines that it is unready to move ahead with DNA replica­
tion, a number of inhibitors are capable of blocking the action of the
CDKs, including p21Cip2/Waf1, p16Ink4a, and p27Kip1. Nearly every
cancer has one or more defects in the G1 checkpoint that permit pro­
gression to S phase despite abnormalities in DNA repair machinery or
other deficiencies that would affect normal DNA synthesis.
At the end of the G2 phase and before the M phase, after the cell has
exactly duplicated its DNA content, a second inventory is taken at the
G2 checkpoint. Have all of the chromosomes been fully duplicated?
Were all segments of DNA copied only once? Has all damaged DNA
been repaired? Do we have the right number of chromosomes and the
right amount of DNA? If so, the cell proceeds to G2, in which the cell
prepares for division by synthesizing mitotic spindle and other proteins
needed to produce two daughter cells. If DNA damage is detected, the
p53 pathway is normally activated. Called the guardian of the genome,
p53 is a transcription factor that is normally present in the cell in very
low levels. This level is generally regulated through its rapid turnover.
Normally, p53 is bound to mdm2, a ubiquitin ligase that both inhibits
p53 transcriptional activation and also targets p53 for degradation in
the proteasome. When DNA damage is sensed, the ATM (ataxiatelangiectasia mutated) pathway is activated; ATM phosphorylates
DNA DAMAGE CHECKPOINT
ONCOGENE CHECKPOINT
myc, E2F, EIA
ATM/ATR
p53
mdm2
chk1/chk2
Induction of P14ARF
P
mdm2
P14ARF
mdm2
P
P
Transcriptional
activation of p53responsive genes
P
P
p53 Tetramer
FIGURE 77-1  Induction of p53 by the DNA damage and oncogene checkpoints.
In response to noxious stimuli, p53 and mdm2 are phosphorylated by the ataxiatelangiectasia mutated (ATM) and related ATR serine/threonine kinases, as well
as the immediate downstream checkpoint kinases, Chk1 and Chk2. This causes
dissociation of p53 from mdm2, leading to increased p53 protein levels and
transcription of genes leading to cell cycle arrest (p21Cip1/Waf1) or apoptosis (e.g.,
the proapoptotic Bcl-2 family members Noxa and Puma). Inducers of p53 include
hypoxemia, DNA damage (caused by ultraviolet radiation, gamma irradiation, or
chemotherapy), ribonucleotide depletion, and telomere shortening. A second
mechanism of p53 induction is activated by oncogenes such as Myc, which promote
aberrant G1/S transition. This pathway is regulated by a second product of the Ink4a
locus, p14ARF (p19 in mice), which is encoded by an alternative reading frame (ARF)
of the same stretch of DNA that codes for p16Ink4a. Levels of ARF are upregulated by
Myc and E2F, and ARF binds to mdm2 and rescues p53 from its inhibitory effect. This
oncogene checkpoint leads to the death or senescence (an irreversible arrest in G1
of the cell cycle) of renegade cells that attempt to enter S phase without appropriate
physiologic signals. Senescent cells have been identified in patients whose
premalignant lesions harbor activated oncogenes, for instance, dysplastic nevi
that encode an activated form of BRAF (see below), demonstrating that induction
of senescence is a protective mechanism that operates in humans to prevent the
outgrowth of neoplastic cells.
mdm2, releasing it from its inhibitory bond to p53. p53 then stops
cell cycle progression, directs the synthesis of repair enzymes, or if the
damage is too great, initiates apoptosis (programmed cell death) of the
cell to prevent the propagation of a damaged cell (Fig. 77-1).
A second method of activating p53 involves the induction of
p14ARF by hyperproliferative signals from oncogenes. p14ARF com­
petes with p53 for binding to mdm2, allowing p53 to escape the effects
of mdm2 and accumulate in the cell. p53 then stops cell cycle progres­
sion by activating CDK inhibitors such as p21 and/or initiating the
apoptosis pathway. Not surprisingly given its critical role in control­
ling cell cycle progression, mutations in the gene for p53 on chromo­
some 17p are among the most frequent mutations in human cancers,
although percentages vary between different cancers. Most commonly
these mutations are acquired in the malignant tissue in one allele
and the second allele is inactivated (such as by deletion or epigenetic
silencing), leaving the cell unprotected from DNA-damaging agents or
activated oncogenes.
Some environmental exposures produce signature mutations in p53;
for example, aflatoxin exposure leads to mutation of arginine to serine
at codon 249 and leads to hepatocellular carcinoma. In rare instances,
p53 mutations are in the germline (Li-Fraumeni syndrome) and pro­
duce a familial cancer syndrome. Another mechanism for inactivation
of p53 in malignant cells is due to alterations in regulators such as
overexpression of the inhibitory mdm2 protein. Whether inactivated
by mutation or inhibited by regulatory factors, absence of normal p53
function leads to chromosomal instability and accumulation of DNA
damage including acquisition of properties that give the abnormal cell
a proliferative and survival advantage. Like Rb dysfunction, most can­
cers have mechanisms that disable the p53 pathway. Indeed, the impor­
tance of p53 and Rb in the development of cancer is underscored by the
neoplastic transformation mechanism of human papillomavirus. This
virus has two main oncogenes, E6 and E7. E6 acts to increase the rapid
turnover of p53, and E7 acts to inhibit Rb function; inhibition of these
two targets is required for transformation of epithelial cells by the virus.
Another cell cycle checkpoint exists when the cell is undergoing
division (M phase); this is the spindle checkpoint, which acts to ensure
that there is proper attachment of chromosomes to the mitotic spindle
before progression through the cell cycle can occur. If the spindle
apparatus does not properly align the chromosomes for division, if the
chromosome number is abnormal (i.e., greater or less than 4n), or if
the centromeres are not properly paired with their duplicated partners,
then the cell initiates a cell death pathway to prevent the production
of aneuploid progeny (having an altered number of chromosomes).
Abnormalities in the spindle checkpoint facilitate the development
of aneuploidy, which is frequently found in cancers. In some tumors,
aneuploidy is a predominant genetic feature.
In other tumors, a defect in the cells’ ability to repair errors in the
DNA, such as due to mutations in genes coding for the proteins critical
for mismatched DNA repair, is the primary genetic lesion. Cancer cells
can have defects in any of several DNA repair pathways in addition to
mismatch repair, including deficient interstrand cross-link, doublestrand breaks (homologous recombination or nonhomologous end
joining repair), single-strand breaks, base excision, nucleotide excision,
and translesional synthesis.
In general, tumors have either defects in chromosome number or
defective DNA repair pathways but not both. Defects that lead to can­
cer include abnormal cell cycle checkpoints, inadequate DNA repair,
and failure to preserve genome integrity leading to DNA damage.
These defects and the stress of the resultant increased DNA damage
make cancer cells more vulnerable to additional DNA damage, which
can be exploited by chemotherapy, radiation therapy, targeted therapy,
and immunotherapy—the major systemic therapeutic approaches
effective against cancer.
Alternatively, research is ongoing in an attempt to therapeutically
restore the defects in cell cycle regulation and DNA repair that charac­
terize cancer, although this remains a challenging problem because it is
much more difficult to restore normal biologic function than to inhibit
abnormal function of proteins driving cell proliferation, such as occurs
with activated oncogenes. Newer approaches to gene editing (e.g.,
clustered regularly interspaced short palindromic repeats [CRISPR])
and subsequent modifications to this approach should eventually make
gene editing more clinically feasible.
■
■CELLULAR SENESCENCE
The irreversible cessation of growth of normal cells while the cells
remain viable has been termed cellular senescence. Senescence is
important for several processes involved in normal development and
homeostasis including embryogenesis and wound healing. It is also an
important component of host mechanisms to prevent tumorigenesis by
preventing replication of abnormal cells as well as other mechanisms
including secreted substances that can stimulate an immune response
against the abnormal senescent cell. However, paradoxically, senescent
cells in tumors can also stimulate tumorigenesis and malignant pro­
gression, in part by other secreted substances that stimulate a harmful
inflammatory response. It was initially identified by the fact that when
normal cells are placed in culture in vitro, most are not capable of sus­
tained growth. They quickly reach a point where they either undergo
cell death due to excessive DNA damage or other factors or they
become senescent. Fibroblasts are an exception to this rule. When they
are cultured, fibroblasts may divide 30–50 times and then they undergo
what has been termed a “crisis” during which the majority of cells stop
dividing (usually due to an increase in p21 expression, a CDK inhibi­
tor). This form of senescence is termed replicative senescence. Many
other cells die, and a small fraction emerge that have acquired genetic
and epigenetic changes that permit their uncontrolled growth. Among
the cellular changes during in vitro propagation is telomere shorten­
ing. DNA polymerase is unable to replicate the tips of chromosomes,
resulting in the loss of DNA at the specialized ends of chromosomes
(called telomeres) with each replication cycle. At birth, human telo­
meres are 15- to 20-kb pairs long and are composed of tandem repeats
of a six-nucleotide sequence (TTAGGG) that associate with specialized
telomere-binding proteins to form a T-loop structure that protects the
ends of chromosomes from being mistakenly recognized as damaged.
The loss of telomeric repeats with each cell division cycle causes grad­
ual telomere shortening, leading to growth arrest when one or more
critically short telomeres trigger a p53-regulated DNA-damage check­
point response. Cell death usually ensues when the unprotected ends of
chromosomes lead to chromosome fusions or other catastrophic DNA
rearrangements. Cells with certain abnormalities, such as those with
nonfunctional pRb and p53, can bypass this growth arrest. The ability
to bypass telomere-based growth limitations is thought to be a critical
step in the evolution of most malignancies. This occurs by reactivation
of telomerase expression in cancer cells. Telomerase is an enzyme that
adds TTAGGG repeats onto the 3′ ends of chromosomes. It contains
a catalytic subunit with reverse transcriptase activity (hTERT) and an
RNA component that provides the template for telomere extension.
Most normal somatic cells do not express sufficient telomerase to
prevent telomere attrition with each cell division. Exceptions include
stem cells (such as those found in hematopoietic tissues, gut and
skin epithelium, and germ cells) that require extensive cell division
to maintain tissue homeostasis. More than 90% of human cancers
express high levels of telomerase that prevent telomere shortening to
critical levels and allow indefinite cell proliferation. In vitro experi­
ments indicate that inhibition of telomerase activity leads to tumor cell
apoptosis. Major efforts are underway to develop methods to inhibit
telomerase activity in cancer cells. For example, the protein component
of telomerase (hTERT) may act as one of the most widely expressed
tumor-associated antigens and can be targeted by vaccine approaches.
However, a caveat to targeting telomerase for anticancer treatment is
the potential for inhibiting its activity in certain normal cells (such as
stem cells) required for maintaining the normal physiologic state.
CHAPTER 77
Cancer Cell Biology
Although most of the functions of telomerase relate to cell division,
it also has several other effects including interfering with the differenti­
ated functions of at least certain stem cells. However, the impact on dif­
ferentiated function of normal nonstem cells is less clear. The picture is
further complicated by the fact that rare genetic defects in the telom­
erase enzyme seem to cause dyskeratosis congenita (characterized by
abnormalities in various rapidly dividing cells in the body including
skin, nails, oral mucosa, hair, and bone marrow with increased risk
for leukemia and certain other cancers). This can be associated with
a number of other abnormalities including pulmonary fibrosis, bone
marrow failure (aplastic anemia), or liver fibrosis. However, paradoxi­
cally, defects in nutrient absorption in the gastrointestinal tract, a site
that should be highly sensitive to defective cell proliferation, are not
seen. Much remains to be learned about how telomere shortening
and telomere maintenance are related to human illness in general and
cancer in particular.
A variety of other stresses on cells (both environmental and intrin­
sic including radiation, chemotherapy, reactive oxygen species, and
oncogenic mutations) can also lead to senescence, primarily those that
induce DNA damage similar to that seen in cells with shortened telo­
meres. This is termed replicative senescence.
■
■SIGNAL TRANSDUCTION PATHWAYS IN CANCER
CELLS
Signals that affect cell behavior come from adjacent cells, the stroma in
which the cells are located, hormonal signals that originate remotely,
and the cells themselves (autocrine signaling). These signals generally
exert their influence on the receiving cell through activation of signal
transduction pathways that have as their end result the induction of
activated transcription factors that mediate a change in cell behavior
or function or the acquisition of effector machinery to accomplish a
new task. Although signal transduction pathways can lead to a wide
variety of outcomes, many such pathways rely on cascades of signals
that sequentially activate different proteins or glycoproteins and lipids
or glycolipids, and the activation steps often involve the addition or
removal of one or more phosphate groups on a downstream target.
Other chemical changes can result from signal transduction path­
ways, but reversible phosphorylation and dephosphorylation play a
major role. Proteins that add phosphate groups to other molecules
(proteins, lipids, or nucleic acids) are called kinases. Two major classes
of kinases involved in signal transduction pathways important for can­
cer cells are tyrosine kinases that phosphorylate tyrosine and serine/
threonine kinases that phosphorylate serine/threonine either directly
or indirectly. However, some kinases can phosphorylate both, such
as the MEK kinases that can phosphorylate both threonine and tyro­
sine. Phosphatases (protein tyrosine phosphatases and protein serine/
threonine phosphatases) remove the phosphate groups to reverse the
kinase activity.
Various kinases play critical roles in signal transduction pathways
important for malignant cells. These include a number of recep­
tor tyrosine kinases (RTKs) as well as various protein kinases (both
tyrosine and serine/threonine kinases) downstream of receptors that
transmit the signals within the cell (Fig. 77-2). Two important signal­
ing pathways are the RAS-RAF-MEK-ERK pathway and the phospha­
tidylinositol-3-kinase (PI3K) pathway (Fig. 77-2). Although pathways
are depicted as distinct, complex interactions between pathways occur
within cells.
Normally, kinase activity is short-lived and reversed by protein
phosphatases. However, in many human cancers, RTKs or compo­
nents of their downstream pathways are activated by mutation, gene
PART 4
Oncology and Hematology
PI3K
inhibitors
PIP2
RAS
Grb2/mSOS
PI3K
PIP3
PDK1
AKT
Multiple
targets
Everolimus
mTOR
Protein
synthesis
p70S6k
ERK1/2
Activated
transcription
factors
ECM
Integrin
receptor
Cytoskeleton
FAK
c-Src
Activated
kinases
STAT
Midostaurin
JAK inhibitors
JAK
PKC
Multiple
targets
PLC-γ
Ca2+
Tamoxifen
SERMS
PIP2
DAG
FIGURE 77-2  Therapeutic targeting of signal transduction pathways in cancer cells. Three major signal transduction pathways are activated by receptor tyrosine kinases
(RTKs). 1. The protooncogene Ras is activated by the Grb2/mSOS guanine nucleotide exchange factor, which induces an association with Raf and activation of downstream
kinases (MEK and ERK1/2). 2. Activated PI3K phosphorylates the membrane lipid PIP2 to generate PIP3, which acts as a membrane-docking site for a number of cellular
proteins including the serine/threonine kinases PDK1 and Akt. PDK1 has numerous cellular targets, including Akt and mTOR. Akt phosphorylates target proteins that promote
resistance to apoptosis and enhance cell cycle progression, while mTOR and its target p70S6K upregulate protein synthesis to potentiate cell growth. 3. Activation of PLC-γ
leads the formation of diacylglycerol (DAG) and increased intracellular calcium, with activation of multiple isoforms of PKC and other enzymes regulated by the calcium/
calmodulin system. Other important signaling pathways involve non-RTKs that are activated by cytokine or integrin receptors. Janus kinases (JAK) phosphorylate STAT
(signal transducer and activator of transcription) transcription factors, which translocate to the nucleus and activate target genes. Integrin receptors mediate cellular
interactions with the extracellular matrix (ECM), inducing activation of FAK (focal adhesion kinase) and c-Src, which activate multiple downstream pathways, including
modulation of the cell cytoskeleton. Many activated kinases and transcription factors migrate into the nucleus, where they regulate gene transcription, thus completing the
path from extracellular signals, such as growth factors, to a change in cell phenotype, such as induction of differentiation or cell proliferation. The nuclear targets of these
processes include transcription factors (e.g., Myc, AP-1, and serum response factor) and the cell cycle machinery (cyclin-dependent kinases [CDKs] and cyclins). Inhibitors
of many of these pathways have been developed for the treatment of human cancers. Examples of inhibitors that are either approved or are currently being evaluated in
clinical trials are shown in purple type.
amplification, or chromosomal translocations to have enhanced and/
or prolonged activity. Because these pathways are important in regulat­
ing proliferation, survival, migration, and angiogenesis, they have been
identified as important targets for cancer therapeutics.
Inhibition of kinase activity is effective in the treatment of a number
of neoplasms. Lung cancers with mutations in the epidermal growth
factor receptor are highly responsive to osimertinib as well as other
inhibitors (Table 77-2). Inhibitors have been developed to treat lung
cancers with other tyrosine kinase–activating mutations (including
anaplastic lymphoma kinase [ALK], ROS1, NTRK, MET, HER2, and
RET). BRAF (a serine/threonine kinase) inhibitors are highly effective
in melanomas and thyroid cancers and are also used in combination
with other agents for lung and colon cancers as well as other solid
tumors with BRAF V600E mutations. Targeting the MEK protein
(which phosphorylates both threonine and tyrosine residues) down­
stream of BRAF also has activity against BRAF mutant melanomas,
and combined inhibition of BRAF and MEK is more effective than
either alone with activity that extends to BRAF-mutant lung cancer.
Janus kinase (JAK) inhibitors are active in myeloproliferative syn­
dromes in which JAK2 activation is a pathogenetic event. Imatinib
(which targets a number of tyrosine kinases) is an effective agent in
Ligand
RTK
Monoclonal antibody
Under
investigation
Tyrosine kinase
inhibitors
Raf
kinase
inhibitors
RASC
inhibitors
Raf
GAP
MEK
inhibitors
MEK
ERK
inhibitors
Multiple
cytoplasmic
targets
AP-1 (Jun/Fos)
Serum response factor
MYC
Cyclin D1
CDK/cyclin
complexes
CDK H/b
inhibitors
Cell cycle
regulation
Nucleus
Estrogen
receptor
TABLE 77-2  Some FDA-Approved Molecularly Targeted Agents for the Treatment of Cancer
DRUG
MOLECULAR TARGET
DISEASE
MECHANISM OF ACTION
All-trans retinoic acid
PML-RARα oncogene
Acute promyelocytic leukemia M3 AML,
t(15;17)
Imatinib, dasatinib, nilotinib,
ponatinib, bosutinib
Bcr-Abl, c-Abl, c-Kit,
PDGFR-α/β
Chronic myeloid leukemia, GIST
Blocks ATP binding to tyrosine kinase active site
Ripretinib
c-Kit, PDGFR-α
GIST
Inhibits tyrosine kinase activity
Asciminib
Bcr-Abl
Chronic myeloid leukemia
Allosteric inhibitor of BCR-ABL
Sunitinib
c-Kit, VEGFR-2, PDGFR-β,
Flt-3
GIST, RCC, PNET
Inhibits activated c-Kit and PDGFR in GIST; inhibits VEGFR in
RCC and probably in PNET
Sorafenib
RAF, VEGFR-2, PDGFR-α/β,
Flt-3, c-Kit
RCC, hepatocellular carcinoma (HCC),
differentiated thyroid cancer, desmoid
Regorafenib
VEGFR1–3, TIE-2, FGFR1, KIT,
RET, PDGFR
Colorectal cancer, GIST, HCC
Competitive inhibitor ATP binding site of tyrosine kinase domain
multiple kinases including VEGFR
Larotrectinib, entrectinib
NTRK
Cancers with NTRK mutation
Competitive inhibitor of ATP binding site of the tyrosine kinase
domain of NTRK
Axitinib
VEGFR1–3
RCC
Competitive inhibitor ATP binding site of tyrosine kinase domain
VEGF receptors
Erlotinib
EGFR
NSCLC, pancreatic cancer
Competitive inhibitor of the ATP-binding site of the EGFR
Afitinib
EGFR (and other HER family)
NSCLC
Irreversible inhibitor of ATP-binding site of HER family members
Osimertinib
EGFR (T790M)
NSCLC
Inhibits EGFR mutations including T790M mutant NSCLC
Dacomitinib
EGFR
NSCLC (exon19 deletion/exon 21 L858R)
Inhibits EGFR mutant lung cancer
Mobocertinib/EGFR/NSCLC/Tumors with Exon20 insertion
mutations
Erdafitinib, pemigatinib,
futibatinib, infigratinib
FGFR2, FGFR3
Urothelial (erdafitinib), myeloid/
lymphoid neoplasms (pemigatinib)
cholangiocarcinoma (pemigatinib,
futibatinib)
Lapatinib, tucatinib, niratinib
HER2/neu
Breast cancer, CRC (tucatinib +
trastuzumab)
Crizotinib, ceritinib, alectinib,
brigatinib, lorlatinib
ALK
NSCLC ALK+ large cell lymphoma,
inflammatory myofibroblastic tumors
(crizotinib)
Crizotinib, entrectinib
repotrectinib
ROS1
NSCLC
Inhibitor of ROS1 tyrosine kinase
Palbociclib, ribociclib,
abemaciclib
CDK4/6
Breast
Inhibitor of CDK4/6
Bortezomib, carfilzomib,
ixazomib
Proteasome
Multiple myeloma
Inhibits proteolytic degradation of multiple cellular proteins
Vemurafenib, dabrafenib
Encorafenib
BRAF V600E
Melanoma lung cancer, CRC (combined
with Cetuximab)
Trametinib, Cobimetinib,
binimetinib
MEK
Melanoma
Inhibitor of serine-threonine kinase domain of MEK
Cabozantinib
RET, MET, VEGFR
MTC, RCC
Competitive inhibitor of ATP-binding site of tyrosine kinase
domain of multiple kinases, including VEGFR2 and RET
Capmatinib, tepotinib
MET
NSCLC with MET exon14 deletions
 
Selpercatinib, vandetinib,
pralsetinib
RET
NSCLC, MTC, RET fusion thyroid cancer,
RET fusion positive solid tumors
Temsirolimus
mTOR
RCC
Competitive inhibitor of mTOR serine-threonine kinase
Everolimus
mTOR
RCC, PNET
Binds to immunophilin FK binding protein-12, which forms a
complex that inhibits mTOR kinase
Vorinostat, romidepsin,
belinostat
HDAC
CTCL/PTL
HDAC inhibitor, epigenetic modulation
Panobinostat
HDAC
MM
HDAC inhibitor, epigenetic modulation
Ruxolitinib
JAK-1, 2
Myelofibrosis
Competitive inhibitor of tyrosine kinase
Vismodegib
Hedgehog pathway
Basel cell cancer (skin)
Inhibits smoothened in hedgehog pathway
Lenvatinib
Multikinase inhibitor
(VEGFR, FGFR, PGFR-α,
others)
RCC, thyroid cancer, HCC
Competitive inhibitor of ATP-binding site of tyrosine kinase
domain of multiple kinases
Olaparib, rucaparib,
niraparib, talazoparib
PARP
BRCA mutant ovarian, breast, prostate,
pancreas cancers; not all agents
approved for all cancers
Venetoclax
BCL-2
CLL (with 17p deletion)
Inhibits BCL-2 and enhances apoptosis
Ibrutinib, acalabrutinib
pirtobrutinib, zanubrutinib
Bruton tyrosine kinase (BTK) CLL, MCL, MZL, SLL, WM
Inhibitor of BTK
Inhibits transcriptional repression by PML-RARα
Adagrasib, Solorasib/KRAS12C/NSCLC/Inhibits KRAS12C
Targets VEGFR pathways in RCC and HCC. Possible activity
against BRAF in thyroid cancer
CHAPTER 77
Inhibits tyrosine kinase of FGFR
Cancer Cell Biology
Competitive inhibitor of the ATP-binding site of HER2
Inhibitor of ALK tyrosine kinase
Inhibitor of serine-threonine kinase domain of V600E mutant
of BRAF
Inhibitor of RET, VEGFR1, VEGFR2 tyrosine kinases
Inhibits PARP and DNA repair
(Continued)
TABLE 77-2  Some FDA-Approved Molecularly Targeted Agents for the Treatment of Cancer
DRUG
MOLECULAR TARGET
DISEASE
MECHANISM OF ACTION
Ivosidenib, olutasidenib
IDH1
AML, MDS, cholangiocarcinoma
IDH1 inhibitor
Gilteritinib, quizartinib
FLT3
AML
FLT3 inhibitor
Idelalisib
PI3K-delta
CLL
Inhibits PI3k-delta, preventing proliferation and inducing
apoptosis
Alpelisib
PIK3CA
Breast cancer with a PIK3CA mutation
Inhibits PIK3CA
Belzutifan
Hif-2α
HIF-1α-associated RCC, pancreatic
neuroendocrine, CNS hemangioblastoma
Capivasertib
AKT
Breast cancer
Inhibits AKT
Umbralisib
PI3K-delta, CK1-epsilon
MZL, FL
Inhibits PI3K-delta and CK1-epsilon
Selinexor
Exportin-1
MM, DLBCL
Induces apoptosis of cells
Tazemetostat
EZH2
FL, epithelioid sarcoma
Inhibits EZH2
Monoclonal Antibodies
Trastuzumab, margetuximab
HER2/neu (ERBB2)
Breast cancer, gastric or GEJ cancer
Binds HER2 on tumor cell surface and induces receptor
internalization
Pertuzumab
HER2/neu (ERBB2)
Breast cancer
Binds HER2 on tumor cell surface at distinct site from
trastuzumab and prevents binding to other receptors
Cetuximab
EGFR
Colon cancer, squamous cell carcinoma of the
head and neck
PART 4
Oncology and Hematology
Panitumumab
EGFR
Colon cancer
Similar to cetuximab but fully humanized rather than
chimeric
Necitumumab
EGFR
Squamous NSCLC
Binds EGFR
Rituximab
CD20
B-cell lymphomas and leukemias that express
CD20
Alemtuzumab
CD52
Chronic lymphocytic leukemia and CD52expressing lymphoid tumors
Bevacizumab
VEGF
Colorectal, lung cancers, RCC, glioblastoma
Inhibits angiogenesis by high-affinity binding to VEGF
Ziv-aflibercept
VEGFA, VEGFB, PLGF
Colorectal cancers
Inhibits angiogenesis by high-affinity binding to VEGFA,
VEGFB, and PLGF
Ramucirumab
VEGFR
Gastric, colorectal, lung cancers
Inhibits angiogenesis by binding to VEGFR
Ipilimumab
CTLA-4
Melanoma, HCC, MSI-high colorectal cancer
Blocks CTLA-4, preventing interaction with CD80/86 and
T-cell inhibition
Nivolumab, pembrolizumab,
dostarlimab-gxly, toripalimab,
retifanlimab-dlwr,
cemiplimab-rwlc
PD-1
Melanoma, head and neck cancer, NSCLC,
SCLC, Hodgkin’s disease, urothelial cancer,
RCC, HCC, gastric cancer, esophageal
cancer, cholangiocarcinoma, MSI-high
cancers, endometrial cancer, cervical
cancer, cutaneous squamous cell carcinoma,
basal cell carcinoma, breast cancer,
nasopharyngeal cancer, Merkel cell tumor
Atezolizumab, durvalumab,
avelumab
PD-L1
NSCLC, urothelial cancer, SCLC (durvalumab),
HCC (atezolizumab), Merkel cell cancer
(avelumab)
Relatlimab
LAG3
Melanoma (combined with nivolumab)
Blocks LAG3 interaction with MHCII and other ligands
inhibiting immune activation
Denosumab
Rank ligand
Breast, prostate
Inhibits Rank ligand, primary signal for bone removal
Dinutuximab
Glycolipid GD2
Neuroblastoma (pediatric)
Immune-mediated attack on GD2-expressing cells
Daratumumab, Isatuximab
CD38
MM
Binds to CD38 on MM cells causing apoptosis by
antibody-dependent or compliment-mediated cytotoxicity
Elotuzumab
SLAMF7
MM
Activating NK cells to kill MM cells
Olaratumab
PDGFRα
Soft tissue sarcomas
Blocks PDGFRα activity
Naxitamab
GD2
Neuroblastoma
Immune-mediated antitumor effect
Bispecific Antibodies
Blinatumomab
CD19 and CD3
Ph-relapsed precursor B-cell ALL
Binds CD19 on ALL cells and CD3 on T cells; immune
attack on CD19-expressing cells
Glofitamab-gxbm, epcoritamabbysp, mosunetuzumab-axgb
CD20 and CD3
DLBCL, FL
Binds CD20 on DLBCL or FL and CD3 on T cells, immune
attack on CD20-expressing cells
Teclistamab-cqyv,
elranatamab-bcmm
B-cell maturation
antigen (BCMA) and
CD3
MM
Binds BCMA on MM cells and CD3 on T cells
Talquetamab
CD3 and GPRC5D
MM
Binds CD3 T cells and GPRC5D-expressing MM cells
(Continued)
Inhibits Hif-2α
Binds extracellular domain of EGFR and blocks binding
of EGF and TGF-α; induces receptor internalization.
Potentiates the efficacy of chemotherapy and
radiotherapy
Multiple potential mechanisms, including direct induction
of tumor cell apoptosis and immune mechanisms
Immune mechanisms
Blocks PD-1, preventing interaction with PD-L1 and T-cell
inhibition
Blocks PD-L1, preventing interaction with PD-1 and T-cell
inhibition
(Continued)
TABLE 77-2  Some FDA-Approved Molecularly Targeted Agents for the Treatment of Cancer
DRUG
MOLECULAR TARGET
DISEASE
MECHANISM OF ACTION
Amivantamab-vmjw
EGFR and MET
NSCLC
Targets EGFR exon 20 insertion mutations by also inhibiting
MET
Tebentafusp-tebn
GP100 and CD3
Uveal melanoma
Binds GP100 on melanoma cells and CD3 on T cells
Antibody-Chemotherapy Conjugates
Brentuximab vedotin
CD30
Hodgkin’s disease, anaplastic lymphoma Delivers chemotherapeutic agent MMAE to CD30-expressing
Ado-trastuzumab emtansine
HER2
Breast cancer
Delivers chemotherapeutic agent emtansine to
HER2-expressing breast cancer cells
Fam-trastuzumab
HER2
Breast, NSCLC, and gastric cancers
Delivers chemotherapeutic agent deruxtecan to
HER2-expressing breast cancer cells
Sacituzumab govitecan
Trop2
Breast, urothelial cancers
Delivers chemotherapy to Trop2-expressing cells
Enfortumab-vedotin
Nectin-4
Urothelial cancers
Delivers chemotherapeutic agent MMAE to
Nectin-4-expressing cells
Polatuzumab-vedotin
CD79b
DLBCL or high-grade BCL
Delivers MMAE chemotherapy to B-cell lymphomas
Loncastuximab tesirine-lpyl
CD19
DLBCL
Delivers chemotherapy to CD19 expressing cells
Mirvetuximab
soravtansine-gynx
Folate receptor alpha
Ovarian, fallopian, peritoneal cancers
Delivers chemotherapy to folate receptor alpha tumors
Tisotumab vedotin-tftv
Tissue factor (TF)
Cervical cancer
Delivers chemotherapy to TF-positive cells
Gemtuzumab ozogamicin
CD33
Pediatric CD33+ AML
Delivery of chemotherapy to CD33+ cells
CAR-T Cells and Tumor-Infiltrating Lymphocyte (TIL)
Tisagenlecleucel,
axicabtagene ciloleucel,
brexucabtagene autoleucel,
lisocabtagene maraleucel
CD19
ALL (tisagenlecleucel), DLBCL/highgrade BCL (axicabtagene ciloleucel),
B-cell precursor ALL (brexucabtagene),
large BCL (lisocabtagene maraleucel)
Ciltacabtagene autoleucel
Idecabtagene vicleucel
BCMA
MM
Targets T cells to protein on surface of MM cells
Lifileucel
Melanoma antigens
Melanoma
Tumor-infiltrating lymphocyte therapy
Abbreviations: ALL, acute lymphocytic leukemia; AML, acute myeloid leukemia; BCL, B-cell lymphoma; CAR-T, chimeric antigen receptor T cells; CLL, chronic lymphocytic
leukemia; CRC, colorectal cancer; CTCL, cutaneous T cell lymphoma; DLBCL, diffuse large B-cell lymphoma; EGFR, epidermal growth factor receptor; FDA, U.S. Food and Drug
Administration; FGFR, fibroblast growth factor receptor; FL, follicular lymphoma; Flt-3, fms-like tyrosine kinase-3; GEJ, gastroesophageal junction; GIST, gastrointestinal stromal
tumor; HDAC, histone deacetylases; MCL, mantle cell lymphoma; MM, multiple myeloma; MSI, microsatellite instability; MMAE, monomethyl auristatin E; MTC, medullary thyroid
cancer; mTOR, mammalian target of rapamycin; MZL, mantle zone lymphoma; NK, natural killer; NSCLC, non-small-cell lung cancer; PARP, poly-ADP ribose polymerase; PDGFR,
platelet-derived growth factor receptor; PLGF, placenta growth factor; PML-RARα, promyelocytic leukemia–retinoic acid receptor-alpha; PNET, pancreatic neuroendocrine
tumors; PTL, peripheral T-cell lymphoma; RCC, renal cell cancer; t(15;17), translocation between chromosomes 15 and 17; SCLC, small-cell lung cancer; SLL, small lymphocytic
lymphoma; TGF-α, transforming growth factor-alpha; VEGFR, vascular endothelial growth factor receptor; WM, Waldenström’s macroglobulinemia.
Note: The pace of drug discovery is rapid and this list is not comprehensive.
tumors that have translocations of the c-Abl and BCR gene (such as
chronic myeloid leukemia), mutant c-Kit (gastrointestinal stromal cell
tumors), or mutant platelet-derived growth factor receptor (PDGFRα;
gastrointestinal stromal tumors). Second-generation inhibitors of
BCR-Abl, dasatinib and nilotinib, are even more effective, and the
third-generation agent bosutinib has activity in some patients who
have progressed on other inhibitors, while the third-generation agent
ponatinib has activity against the T315I mutation, which is resistant
to the other agents. Although almost all tyrosine kinase inhibitors are
not entirely selective for one protein, certain inhibitors have significant
activity against a broad number of proteins. These include sorafenib,
regorafenib, cabozantinib, sunitinib, and lenvatinib. These have shown
antitumor activity in various malignancies, including renal cell cancer
(RCC) (sorafenib, sunitinib, cabozantinib, lenvatinib), hepatocellular
carcinoma (sorafenib, regorafenib, lenvatinib), gastrointestinal stromal
tumor (GIST) (sunitinib, regorafenib), thyroid cancer (sorafenib, cabo­
zantinib, lenvatinib), colorectal cancer (regorafenib), and pancreatic
neuroendocrine tumors (sunitinib).
Inhibitors of the PI3K pathway also have been approved for cancer
therapy. The PI3K family includes three classes and several isoforms
within each class. Inhibitors against different isoforms have proved
effective against different types of malignancies, with inhibitors of the
delta isoform (either specifically or also with inhibition of other iso­
forms; e.g., idelalisib) having activity against lymphoid malignancies
(CLL), whereas the specific inhibitor of a mutation in the alpha isoform
(alpelisib) has activity against breast cancers with this mutation. Inhibi­
tors of mammalian target of rapamycin (mTOR; which is downstream
of PI3K; e.g., everolimus, temsirolimus) are active in RCC; welldifferentiated nonfunctional neuroendocrine tumors of pancreatic,
(Continued)
tumor cells
CHAPTER 77
Targeted T cells to protein on surface of malignant cells
Cancer Cell Biology
gastrointestinal, or lung origin; and breast cancer. Additional inhibitors
of the PI3K pathway and other phospholipid signaling pathways such
as the phospholipase C-gamma pathway, which are involved in a large
number of cellular processes important in cancer development and
progression, are being evaluated.
The list of active agents and treatment indications is growing rapidly
(Table 77-2). These agents have ushered in a new era of personalized
therapy. For many cancers, it is now standard for tumor biopsies to
be assessed for specific molecular changes that predict response and
to have clinical decision-making guided by those results. This is now
an important component of choosing therapy for metastatic lung, gas­
troesophageal, melanoma, breast, and colorectal cancers as well as in
adjuvant therapy for breast cancer. This list will continue to evolve as
both new agents against existing targets are developed and new targets
are discovered.
An alternative approach to testing samples directly from tumors is to
test blood for the presence of mutations or amplification in circulating
tumor DNA, which has the significant advantage of being noninvasive.
As cancers grow, some of the cells die, break apart, and release cellular
contents, including DNA, into the circulation. Sensitive methods have
been developed to detect this DNA and to identify mutations and other
DNA changes in the malignant cells. This has the potential advantage
over tumor biopsies of sampling all of the tumor and not being lim­
ited to one site that may not be representative of the overall tumor
heterogeneity. Distinct metastatic lesions may have different genetic
abnormalities that will not be detected in a biopsy of a single site.
In addition to identifying potential changes that can be targeted for
therapy, there is also the potential for monitoring a patient’s response to
therapy, identifying resistance mechanisms to therapy earlier, detecting
disease recurrence before it can be detected by tumor markers or scans,
monitoring bodily fluids in addition to blood, and possibly providing a
means of earlier initial detection of cancer if sufficiently sensitive and
specific detection methods can be developed. Optimizing the sensitiv­
ity and specificity of these tests is essential for their potential utility in
patient care. Research is ongoing to determine if other cellular compo­
nents specific to cancer cells (e.g., mRNA, proteins from mutant genes,
or other protein modifications found in cancer cells) might also be
useful for diagnosis or monitoring therapeutic response.
However, none of these targeted therapies has yet been curative by
themselves for any malignancy, although prolonged periods of disease
control lasting many years frequently occur in chronic myeloid leuke­
mia (CML), including a >80% survival rate at 10 years, and antibodies
to HER2 have increased survival for breast cancer patients in combina­
tion with chemotherapy. The reasons for the failure of targeted agents
to cure are not completely defined, although resistance to the treat­
ment ultimately develops in most patients. In some tumors, resistance
to kinase inhibitors is related to proliferation of cells with a mutation
in the target kinase that inhibits drug binding. Many of these kinase
inhibitors act as competitive inhibitors of the ATP-binding pocket.
ATP is the phosphate donor in these phosphorylation reactions. For
example, mutation in the critical BCR-ABL kinase in the ATP-binding
pocket (such as the threonine to isoleucine change at codon 315
[T315I]) can prevent imatinib binding. Other resistance mechanisms
include alterations in other signal transduction pathways to bypass
the inhibited pathway. As resistance mechanisms continue to be bet­
ter defined, rational strategies to overcome resistance are emerging.
In addition, many kinase inhibitors are less specific for an oncogenic
target than was hoped, and toxicities related to off-target inhibition of
kinases limit the use of the agent at a dose that would optimally inhibit
the cancer-relevant kinase.
PART 4
Oncology and Hematology
Antibodies against protein targets more highly expressed on malig­
nant than normal cells can also be used to deliver highly toxic com­
pounds relatively specifically to cancer cells. Examples of protein targets
for currently approved antibody-drug conjugates include CD30 for
Hodgkin’s and anaplastic lymphomas; HER2 on breast cancer; CD33 on
acute myeloid leukemias; CD22 on B-cell acute lymphocytic and hairy
cell leukemias; and CD79b on diffuse large B-cell lymphomas.
Another strategy to enhance the antitumor effects of targeted agents
is to use them in rational combinations with each other as well as with
chemotherapy or immunotherapy agents that kill cells in ways dis­
tinct from agents targeting specific mutant or overexpressed proteins.
Combinations of trastuzumab (a monoclonal antibody that targets the
HER2 receptor [member of the EGFR family]) with chemotherapy
have significant activity against breast, gastric, and esophageal cancers
that have high levels of expression of the HER2 protein. The activity of
trastuzumab and chemotherapy can be enhanced further by combina­
tions with another targeted monoclonal antibody (pertuzumab), which
prevents dimerization of the HER2 receptor with other HER family
members including HER3, or in some cases with immunotherapy,
such as combinations of chemotherapy, trastuzumab, and the immu­
notherapeutic agent pembrolizumab against HER2-positive gastric and
esophageal cancers.
Although targeted therapies have not yet resulted in cures when
used alone, their use in the adjuvant setting and when combined with
other effective treatments has substantially increased the fraction of
patients cured. For example, the addition of rituximab, an anti-CD20
antibody, to combination chemotherapy in patients with diffuse
large B-cell lymphoma improves cure rates by ~15%. The addition of
trastuzumab, an antibody to HER2, to combination chemotherapy in
the adjuvant treatment of HER2-positive breast cancer significantly
improves overall survival.
A major effort continues to develop targeted therapies for mutations
in the ras family of genes, which play a critical role in transmitting
signals through a number of downstream signaling pathways includ­
ing the MAP (mitogen-activated protein) kinase and PI3K pathways.
Mutations in ras are the most common mutations in oncogenes in
cancers (especially kras) but have proved to be very difficult targets for
a number of reasons related to the structure of RAS proteins as well
as mechanisms of activation and inactivation (active when bound to
guanosine triphosphate [GTP] and inactive when bound to guanosine
diphosphate [GDP]). RAS proteins are not kinases but bind directly
to the BRAF serine/threonine kinase with preferential binding when
RAS is in the active GTP bound state. Agents that target one of the
mutant forms of KRAS (12C), which is the most common RAS muta­
tion in lung cancer and is also found in a subset of other cancers, have
sufficient antitumor activity to now be approved for the treatment of
these lung cancers. They are under active study (often in combina­
tion with other agents) for the treatment of other cancers that have
the KRAS12C mutation. Agents targeting other mutations in the RAS
genes (especially other KRAS-mutant proteins) are also being evalu­
ated in clinical trials.
One strategy for new drug development is to take advantage of socalled oncogene addiction. This situation (Fig. 77-3) is created when
a tumor cell develops an activating mutation in an oncogene that
becomes a dominant pathway for survival and growth with reduced
contributions from other pathways, even when there may be abnor­
malities in those pathways. This dependency on a single pathway
creates a cell that is vulnerable to inhibitors of that oncogene pathway.
For example, cells harboring mutations in BRAF are sensitive to MEK
inhibitors that inhibit signaling via the BRAF pathway.
Proteins critical for transcription of other proteins essential for
malignant cell survival or proliferation provide another potential target
for treating cancers. The transcription factor nuclear factor (NF)-κB is
a heterodimer composed of p65 and p50 subunits that associate with
an inhibitor, IκB, in the cell cytoplasm. In response to growth factor
or cytokine signaling, a multisubunit kinase called IKK (IκB-kinase)
phosphorylates IκB and directs its degradation by the ubiquitin/
proteasome system. NF-κB, free of its inhibitor, translocates to the
nucleus and activates target genes, many of which promote the survival
of tumor cells. One of the mechanisms by which novel drugs called
proteasome inhibitors are thought to produce an anticancer effect is by
blocking the proteolysis of IκB, thereby preventing NF-κB activation.
For reasons that have not been fully elucidated, this has a differential
toxicity effect on tumor, as compared to normal cells. Although this
mechanism appears to be an important aspect of the antitumor effects
of proteasome inhibitors, other effects involving the inhibition of the
degradation of multiple cellular proteins important in malignant cell
survival or proliferation also play a role.
Proteasome inhibitors (e.g., bortezomib, carfilzomib, ixazomib)
have activity in patients with multiple myeloma, including partial
and complete remissions. Inhibitors of IKK are also in development,
with the hope of more selectively blocking the degradation of IκB,
thus “locking” NF-κB in an inhibitory complex and rendering the
cancer cell more susceptible to apoptosis-inducing agents. Many other
transcription factors are activated by phosphorylation, which can be
prevented by tyrosine or serine/threonine kinase inhibitors, a number
of which are currently in clinical trials.
Estrogen receptors (ERs) and androgen receptors (ARs), members
of the steroid hormone family of nuclear receptors, are targets of inhi­
bition by drugs used to treat breast and prostate cancers, respectively.
Selective estrogen receptor modulators (SERMs) have been developed
as a treatment approach for ER-positive breast cancer. Tamoxifen, a
partial agonist and antagonist of ER function, is frequently used in
breast cancer, can mediate tumor regression in metastatic breast cancer,
and can prevent disease recurrence in the adjuvant setting. Tamoxifen
binds to the ER and modulates its transcriptional activity, inhibiting
activity in the breast but promoting activity in bone but unfortunately
also in uterine epithelium, leading to a small increased risk of uterine
cancer. Attempts have been made to develop SERMs that would have
antiestrogenic effects in both breast and uterus while maintaining
protective effects on bone. However, none of these to date has been an
improvement over tamoxifen. Aromatase inhibitors, which block the
conversion of androgens to estrogens in breast and subcutaneous fat
tissues, have demonstrated improved clinical efficacy compared with
tamoxifen in postmenopausal women and are often used as first-line
therapy in postmenopausal patients with ER-positive disease. They are
occasionally used in premenopausal patients with ER-positive disease
Normal cell
Base
excision
repair
Tumor cell
BRCA1, 2
nonmutated
Normal cell
Base
excision
repair
Tumor cell
BRCA1, 2
mutated
FIGURE 77-3  Synthetic lethality. Genes are said to have a synthetic lethal relationship when mutation of either gene alone is tolerated by the cell, but mutation of both genes
leads to lethality, as originally noted by Bridges and later named by Dobzhansky. Thus, mutant gene a and gene b have a synthetic lethal relationship, implying that the loss of
one gene makes the cell dependent on the function of the other gene. In cancer cells, loss of function of a DNA repair gene like BRCA1, which repairs double-strand breaks,
makes the cell dependent on base excision repair mediated in part by PARP. If the PARP gene product is inhibited, the cell attempts to repair the break using the error-prone
nonhomologous end-joining method, which results in tumor cell death. High-throughput screens can now be performed using isogenic cell line pairs in which one cell line
has a defined defect in a DNA repair pathway. Compounds can be identified that selectively kill the mutant cell line; targets of these compounds have a synthetic lethal
relationship to the repair pathway and are potentially important targets for future therapeutics.
in combination with ovarian suppression approaches such as lutein­
izing hormone–releasing hormone (LHRH) agonists.
A number of approaches have been developed for blocking andro­
gen stimulation of prostate cancer, including decreasing production by
the testicles (e.g., orchiectomy, LHRH agonists or antagonists), directly
blocking actions of androgen (a number of agents have been developed
to do this), or blocking production by inhibiting the enzyme CYP17,
which is central in production of androgens from cholesterol.
■
■CANCER-SPECIFIC GENETIC CHANGES AND
SYNTHETIC LETHALITY
The concepts of oncogene addiction and synthetic lethality have
spurred new drug development targeting oncogene- and tumorsuppressor pathways. As discussed earlier in this chapter and outlined
in Fig. 77-3, cancer cells can become dependent upon signaling
pathways containing activated oncogenes; this can effect proliferation
(i.e., mutated KRAS, BRAF, overexpressed MYC, or activated tyrosine
kinases). Additional genetic changes in malignant cells or unique
features of tumors including defects in DNA repair (e.g., loss of
BRCA1 or BRCA2 gene function), modifications in cell cycle control
(e.g., changes in protein levels or mutations in cyclins and CDKs),
enhanced survival mechanisms (overexpression of Bcl-2 or NF-κB),
altered cell metabolism (such as occurs when mutant KRAS enhances
glucose uptake and aerobic glycolysis), tumor-stromal interactions,
and angiogenesis (e.g., production of vascular endothelial growth fac­
tor [VEGF] in response to HIF-2α in RCC) can also be successfully
exploited to relatively specifically target cancers. However, resistance
to inhibition of specific oncogenic pathways almost always eventually
develops. In addition, targeting defects in tumor-suppressor genes
has been much more difficult, both because the target of mutation is
PARP inhibition
PARP
PARP
PARP
PARP
PARP
PARP
PARP
PARP
Homologous
double strand
break repair
No cell
killing
CHAPTER 77
Homologous
double strand
break repair
Selective
tumor
cell killing
–
Cancer Cell Biology
often deleted and because it is much more difficult to restore normal
function than to inhibit abnormal function of a protein. Synthetic
lethality occurs when loss of function in either of two or more genes
individually has limited effects on cell survival but loss of function
in both (or more) genes leads to cell death. In the case of oncogeneaddicted pathways, identifying genes that have a synthetic lethal rela­
tionship with the activated pathway may allow enhanced cell killing
and decreased resistance by targeting those genes or their proteins.
In the case of mutant tumor-suppressor genes, identifying genes that
have a synthetic lethal relationship to those mutated pathways may
allow targeting by inhibiting proteins required uniquely by those cells
for survival or proliferation (Fig. 77-3). This is a much more tractable
approach than attempting to repair normal function of the mutant
suppressor gene itself. Examples of synthetic lethality with clinical
impact have been identified. For instance, cells with mutations in the
BRCA1 or BRCA2 tumor-suppressor genes (e.g., a subset of breast and
ovarian cancers) are unable to repair DNA damage by homologous
recombination. Poly-ADP ribose polymerase (PARP) is a family of
proteins important for single-strand break (SSB) DNA repair. PARP
inhibition results in selective killing of cancer cells that have lost
BRCA1 or BRCA2 function. A number of PARP inhibitors have been
approved for treatment of ovarian, breast, and pancreatic cancers with
BRCA mutations and are likely to have activity in other tumors with
defective DNA repair mechanisms. The concept of synthetic lethality
provides a framework for genetic screens to identify other synthetic
lethal combinations involving known tumor-suppressor genes and
development of novel therapeutic agents to target dependent path­
ways. Other unique aspects of malignant tumors, including those
outlined elsewhere in the chapter, may also be vulnerable to synthetic
lethal interactions.
■
■EPIGENETIC INFLUENCES ON CANCER GENE
TRANSCRIPTION
Chromatin structure regulates the hierarchical order of sequential
gene transcription that governs differentiation and tissue homeostasis.
Disruption of chromatin remodeling (the process of modifying chro­
matin structure to control exposure of specific genes to transcriptional
proteins, thereby controlling the expression of those genes) leads to
aberrant gene expression that can significantly alter the biology of
cells including inducing proliferation or migration of cells. Epigenetic
changes are those that alter the pattern of gene expression that persist
across at least one cell division but are not caused by changes in the
DNA code. These include alterations of chromatin structure mediated
by methylation of cytosine residues of DNA (primarily in context of
CpG dinucleotides in somatic cells), modification of histones by alter­
ing acetylation or methylation, or changes in higher-order chromo­
some structure (Fig. 77-4). Appropriate control of DNA methylation
is essential for normal cell function and development, and both altered
methylation and hypomethylation of histones occur in cancers. Hyper­
methylation of DNA promoter regions is a common mechanism by
which tumor-suppressor loci are epigenetically silenced in cancer cells.
Thus, one allele of a tumor-suppressor gene may be inactivated by
mutation or deletion, while expression of the other allele is epigeneti­
cally silenced, usually by methylation, leading to loss of gene function.
Aberrant hypomethylation is also frequently found in a number of
cancers consistent with the dysregulated pattern of gene transcription
that is a hallmark of cancer cells, with some genes being inappropri­
ately turned off while others are inappropriately turned on. Specific
changes in DNA methylation in cancer cells provide a potentially more
sensitive and specific approach to utilizing circulating tumor DNA to
identify the presence of cancer than utilizing only DNA mutational
analysis.
PART 4
Oncology and Hematology
Acetylation of the amino terminus of the core histones H3 and H4
induces an open chromatin conformation that promotes transcription
HDAC
MeCP
Nucleosomes
CpG Island in
promoter region
HAT: histone acetyl transferase
HDAC: histone deacetylase
:unmethylated CpG
:methylated CpG
DNMT: DNA methyltransferase
MeCP: methylcytosine binding protein
Co-activator
complex
HAT
HAT
Tc
factor
Tc
factor
Tc
factor
“Open” chromatin configuration
permits binding of multiple
sequence-specific transcription
factors that cooperatively promote
gene expression.
Nucleosomes
Nucleosomes
FIGURE 77-4  Epigenetic regulation of gene expression in cancer cells. Tumor-suppressor genes are often epigenetically silenced in cancer cells. In the upper portion, a CpG
island within the promoter and enhancer regions of the gene has been methylated, resulting in the recruitment of methyl-cytosine binding proteins (MeCP) and complexes
with histone deacetylase (HDAC) activity. Chromatin is in a condensed, nonpermissive conformation that inhibits transcription. Clinical trials are under way utilizing the
combination of demethylating agents such as 5-aza-2′-deoxycytidine plus HDAC inhibitors, which together confer an open, permissive chromatin structure (lower portion).
Transcription factors bind to specific DNA sequences in promoter regions and, through protein-protein interactions, recruit coactivator complexes containing histone acetyl
transferase (HAT) activity. This enhances transcription initiation by RNA polymerase II and associated general transcription factors. The expression of the tumor-suppressor
gene commences, with phenotypic changes that may include growth arrest, differentiation, or apoptosis.
initiation. Histone acetylases are components of coactivator complexes
recruited to promoter/enhancer regions by sequence-specific transcrip­
tion factors during the activation of genes (Fig. 77-4). Histone deacety­
lases (HDACs; multiple HDACs are encoded in the human genome) are
recruited to genes by transcriptional repressors and prevent the initia­
tion of gene transcription. Methylated cytosine residues in promoter
regions become associated with methyl cytosine–binding proteins that
recruit protein complexes with HDAC activity. The balance between
permissive and inhibitory chromatin structure is therefore largely
determined by the activity of transcription factors in modulating the
“histone code” and the methylation status of the genetic regulatory
elements of genes. The pattern of gene transcription is aberrant in all
human cancers, and in many cases, epigenetic events are responsible.
Epigenetic events play a critical role in carcinogenesis (e.g., long-lasting
changes in methylation induced by smoking) and are found in prema­
lignant lesions. Unlike genetic events that alter DNA primary structure
(e.g., deletions), epigenetic changes are potentially reversible and
appear amenable to therapeutic intervention. In certain human can­
cers, including a subset of pancreatic cancers and multiple myeloma,
the p16Ink4a promoter is inactivated by methylation, thus permitting
the unchecked activity of CDK4/cyclin D and rendering pRb nonfunc­
tional. In sporadic forms of renal, breast, and colon cancer, the von
Hippel–Lindau (VHL), breast cancer 1 (BRCA1), and serine/threonine
kinase 11 (STK11) genes, respectively, can be epigenetically silenced.
Other targeted genes include the p15Ink4b CDK inhibitor, glutathioneS-transferase (which detoxifies reactive oxygen species [ROS]), and
the E-cadherin molecule (important for junction formation between
epithelial cells). Epigenetic silencing can affect genes involved in DNA
repair, thus predisposing to further genetic damage. Examples include
MLH1 (mutL homologue in sporadic colon cancers that have micro­
satellite instability) and MSH2 in a subset of hereditary nonpolyposis
colon cancer patients who have a mutation in the 3′ end of epithelial
cell adhesion molecule (EPCAM). These are critical genes involved in
No transcription
Differentiation arrested
Deregulated proliferation
DNMT
HDAC
MeCP
Nucleosomes
Treatment:
5-aza-2'-deoxycytidine
HDAC inhibitors
Active transcription
of tumor
suppressor genes
RNA
polymerase II
and general
transcription
machinery
repair of mismatched bases that occur during DNA synthesis, and their
silencing can lead to mutations in the DNA.
Human leukemias often have chromosomal translocations that code
for novel fusion proteins with activities that alter chromatin structure
by interacting with HDACs or histone acetyl transferases (HATs).
For example, the promyelocytic leukemia–retinoic acid receptor α
(PML-RARα) fusion protein, generated by the t(15;17) translocation
observed in most cases of acute promyelocytic leukemia (APL), binds
to promoters containing retinoic acid response elements and recruits
HDACs to these promoters, effectively inhibiting gene expression.
This arrests differentiation at the promyelocyte stage and promotes
tumor cell proliferation and survival. Treatment with pharmacologic
doses of all-trans retinoic acid (ATRA), the ligand for RARα, results
in the release of HDAC activity and the recruitment of coactivators,
which overcome the differentiation block. This induced differentiation
of APL cells has improved treatment of these patients but also has led
to a novel treatment toxicity when newly differentiated tumor cells
infiltrate the lungs. ATRA represents a treatment paradigm for the
reversal of epigenetic changes in cancer. Other leukemia-associated
fusion proteins, such as Tel-acute myeloid leukemia (AML1), AML1eight-twenty-one (ETO), and the MLL fusion proteins seen in acute
myeloid leukemia (AML) and acute lymphocytic leukemia, also lead to
repression through the HDAC complex. Therefore, efforts are ongoing
to determine the structural basis for interactions between transloca­
tion fusion proteins and chromatin-remodeling proteins and to use
this information to rationally design small molecules that will disrupt
specific protein-protein associations, although this has proven to be
technically difficult. Several drugs that block the enzymatic activity
of HDACs (HDAC inhibitors [HDACis]) are approved for cancer
treatment, and others are being tested. HDACis have demonstrated
sufficient antitumor activity against cutaneous T-cell lymphoma (vori­
nostat, romidepsin), peripheral T-cell lymphoma (romidepsin, belino­
stat), and multiple myeloma (panobinostat) to be approved by the U.S.
Food and Drug Administration (FDA).
HDACis have also demonstrated antitumor activity in clinical stud­
ies against some solid tumors, and additional studies are ongoing.
HDACis may target cancer cells via a number of mechanisms including
both epigenetic modulation via histone acetylation and effects on other
proteins that are acetylated. The pleiotropic effects of some HDACis
include enhancement of apoptosis by upregulation of a number of pro­
teins that enhance apoptosis including death receptors (DR4/5, FAS,
and their ligands) and downregulation of proteins that inhibit apopto­
sis (e.g., X-linked inhibitor of apoptosis [XIAP]); upregulation of pro­
teins that inhibit cell cycle progression (e.g., p21Cip1/Waf1); inhibition
of DNA repair and generation of ROS leading to increased DNA dam­
age; and disruption of the chaperone protein HSP90. Efforts are also
under way to modulate other epigenetic processes such as reversing the
hypermethylation of CpG islands that characterizes many malignan­
cies. Drugs that induce DNA demethylation, such as 5-aza-2-deoxy­
cytidine, can lead to reexpression of silenced genes in cancer cells with
restoration of function, and 5-aza-2-deoxycytidine is approved for
use in myelodysplastic syndrome. However, 5-aza-2-deoxycytidine
has limited aqueous solubility and is myelosuppressive, limiting its
usefulness. Other inhibitors of DNA methyltransferases are in devel­
opment. In ongoing clinical trials, inhibitors of DNA methylation are
being combined with HDACis, with the idea that reversing coexisting
epigenetic changes will reverse the deregulated patterns of gene tran­
scription in cancer cells.
Epigenetic gene regulation can also occur via microRNAs or long
noncoding RNAs (lncRNA). MicroRNAs (miRNA) are short (average
22 nucleotides in length) single strand RNA molecules that regulate
gene expression after transcription by specifically binding to and
inhibiting the translation or promoting the degradation of mRNA
transcripts. It is estimated that >1000 miRNAs are encoded in the
human genome. Each tissue has a distinctive repertoire of miRNA
expression, and this pattern is altered in specific ways in cancers.
miRNA’s are involved in controlling multiple aspects of cell biology
through modulating protein expression (primarily by down regula­
tion) and thus are also  involved in multiple aspects of cancer biology.
Specific correlations between expression of different miRNA molecules
and tumor biology and clinical behavior are continuing to emerge.
Therapies targeting miRNAs are not currently at hand but represent an
ongoing area of treatment development. LncRNAs are longer than 200
nucleotides and comprise the largest group of noncoding RNAs. Some
of them have been shown to play important roles in gene regulation.
The potential for altering these RNAs for therapeutic benefit is an area
of active investigation. In addition to epigenetic changes, mutations in
genes (such as enhancer and promoter regions) involved in controlling
expression of other genes important in cancer cell biology can also
lead to enhanced or decreased expression of the protein products of
these genes.
APOPTOSIS AND OTHER MECHANISMS OF
CELL DEATH
Tissue homeostasis requires a balance between the death of aged,
terminally differentiated cells or severely damaged cells and their
renewal by proliferation of committed progenitors. Genetic damage to
growth-regulating genes of stem cells could lead to catastrophic results
for the host as a whole. Thus, in normal cells, the genetic events caus­
ing activation of oncogenes or loss of tumor suppressors, which would
be predicted to lead to unregulated cell proliferation unless corrected,
also usually activate signal transduction pathways that block aberrant
cell proliferation. These pathways can lead to forms of programmed
cell death including apoptosis or autophagy (degradation of proteins
and organelles by lysosomal proteases) or irreversible growth arrest
(senescence). A number of other regulated cell death processes have
been identified, including: pyroptosis, a caspase-1-dependent process
leading to cleavage of gasdermins with subsequent formation of pores
in the plasma membrane; ferroptosis (iron and reactive oxygen species
dependent); and necroptosis (caspase-independent regulated cell death
involving breakdown of cellular components and cell rupture, leading
to inflammation and damage to surrounding tissues), which also play
roles in tissue homeostasis and cell death. However, the exact roles
they play in the fate of cancer cells and tissues are still being elucidated.
Much as a panoply of intra- and extracellular signals impinge upon
the core cell cycle machinery to regulate cell division, so too these
signals are transmitted to a core enzymatic machinery that regulates
cell death and survival. Cancer cells have developed mechanisms that
either inhibit these processes to prevent cell death or utilize them to
enhance survival.
CHAPTER 77
Cancer Cell Biology
Apoptosis is a tightly regulated process induced by two main path­
ways (Fig. 77-5). The extrinsic pathway of apoptosis is activated by
cross-linking members of the tumor necrosis factor (TNF) receptor
superfamily, such as CD95 (Fas) and death receptors DR4 and DR5,
by their ligands, Fas ligand or TRAIL (TNF-related apoptosis-inducing
ligand), respectively. This induces the association of FADD (Fas-
associated death domain) and procaspase-8 to death domain motifs
of the receptors. Caspase-8 is activated and then cleaves and activates
effector caspases-3 and -7, which then target cellular constituents
(including caspase-activated DNase, cytoskeletal proteins, and a num­
ber of regulatory proteins), inducing the morphologic appearance
characteristic of apoptosis, which pathologists term karyorrhexis (liter­
ally “nucleus bursting”).
The intrinsic pathway of apoptosis is initiated by the release of
cytochrome c and SMAC (second mitochondrial activator of cas­
pases) from the mitochondrial intermembrane space in response to a
variety of noxious stimuli, including DNA damage, loss of adherence
to the extracellular matrix (ECM), oncogene-induced proliferation,
and growth factor deprivation. Upon release into the cytoplasm,
cytochrome c associates with dATP, procaspase-9, and the adaptor
protein APAF-1, leading to the sequential activation of caspase-9 and
effector caspases. SMAC binds to and blocks the function of inhibitor
of apoptosis proteins (IAP), negative regulators of caspase activation.
The release of apoptosis-inducing proteins from the mitochondria
is regulated by pro- and antiapoptotic members of the Bcl-2 family.
Antiapoptotic members (e.g., Bcl-2, Bcl-XL, and Mcl-1) associate with
the mitochondrial outer membrane via their carboxyl termini, expos­
ing to the cytoplasm a hydrophobic binding pocket composed of Bcl-2
Trail
DR4 or
DR5
FADD
Caspase 8
Pro-caspase 9
Cyt c
APAF-1
dATP
SMAC
IAP
BH3-only
proteins
Intermembrane
space
Bak
BcI2
Matrix
Bax
PART 4
Oncology and Hematology
Outer
membrane
Mitochondrion
FIGURE 77-5  Therapeutic strategies to overcome aberrant survival pathways in cancer cells. 1. The extrinsic pathway of apoptosis can be selectively induced in
cancer cells by TRAIL (the ligand for death receptors 4 and 5) or by agonistic monoclonal antibodies. 2. Inhibition of antiapoptotic Bcl-2 family members with antisense
oligonucleotides or inhibitors of the BH3-binding pocket will promote formation of Bak- or Bax-induced pores in the mitochondrial outer membrane. 3. Epigenetic silencing
of APAF-1, caspase-8, and other proteins can be overcome using demethylating agents and inhibitors of histone deacetylases. 4. Inhibitor of apoptosis proteins (IAP)
blocks activation of caspases; small-molecule inhibitors of IAP function (mimicking SMAC action) should lower the threshold for apoptosis. 5. Signal transduction pathways
originating with activation of receptor tyrosine kinase receptors (RTKs) or cytokine receptors promote survival of cancer cells by a number of mechanisms. Inhibiting
receptor function with monoclonal antibodies, such as trastuzumab or cetuximab, or inhibiting kinase activity with small-molecule inhibitors can block the pathway. 6. The
Akt kinase phosphorylates many regulators of apoptosis to promote cell survival; inhibitors of Akt may render tumor cells more sensitive to apoptosis-inducing signals;
however, the possibility of toxicity to normal cells may limit the therapeutic value of these agents. 7 and 8. Activation of the transcription factor NF-κB (composed of p65
and p50 subunits) occurs when its inhibitor, IκB, is phosphorylated by IκB-kinase (IKK), with subsequent degradation of IκB by the proteasome. Inhibition of IKK activity
should selectively block the activation of NF-κB target genes, many of which promote cell survival. Inhibitors of proteasome function are U.S. Food and Drug Administration
approved and may work in part by preventing destruction of IκB, thus blocking NF-κB nuclear localization. NF-κB is unlikely to be the only target for proteasome inhibitors.
homology (BH) domains 1, 2, and 3 that is crucial for their activity.
Perturbations of normal physiologic processes in specific cellular
compartments lead to the activation of BH3-only proapoptotic family
members (e.g., Bad, Bim, Bid, Puma, Noxa, and others) that can alter
the conformation of the outer-membrane proteins Bax and Bak, which
then oligomerize to form pores in the mitochondrial outer membrane
resulting in cytochrome c release. If proteins composed only by BH3
domains are sequestered by Bcl-2, Bcl-XL, or Mcl-1, pores do not
form and apoptosis-inducing proteins are not released from the mito­
chondria. The ratio of levels of antiapoptotic Bcl-2 family members
and the levels of proapoptotic BH3-only proteins at the mitochondrial
membrane determines the activation state of the intrinsic pathway. The
mitochondrion must therefore be recognized not only as an organelle
with vital roles in intermediary metabolism and oxidative phosphory­
lation but also as a central regulatory structure of the apoptotic process.
The evolution of tumor cells to a more malignant phenotype requires
the acquisition of genetic changes that subvert apoptosis pathways and
promote cancer cell survival and resistance to anticancer therapies.
GF
RTK
PI3K
Mdm2
AKT
Cytokine
receptor
Effector
caspases
BAD
Caspase
FKHR
Substrate
cleavage
IKK
IκB
p65
p50
Cytoskeletal
disruption
Proteasome
NF-κB
genes activated
DNA degradation
Chromatin condensation
Lamin cleavage
Nucleus
Death-inducing signals
• DNA damage
• Oncogene-induced proliferation
• Loss of attachment to ECM
• Chemotherapy, radiation therapy
However, this means that cancer cells may be more vulnerable than
normal cells to therapeutic interventions that target the apoptosis
pathways that cancer cells depend upon. For instance, overexpression
of Bcl-2 as a result of the t(14;18) translocation contributes to follicular
lymphoma, and it is highly expressed in many lymphoid malignancies
including chronic lymphocytic leukemia (CLL). Upregulation of Bcl-2
expression is also observed in other cancers including prostate, breast
and lung cancers, and melanoma. Targeting of antiapoptotic Bcl-2
family members has been accomplished by the identification of several
low-molecular-weight compounds that bind to the hydrophobic pock­
ets of either Bcl-2 or Bcl-XL and block their ability to associate with
death-inducing BH3-only proteins. An oral BH3 mimetic inhibitor of
BCL-2, venetoclax, is approved for use in patients with refractory CLL
with 17p deletion, and is active in AML. Preclinical studies targeting
death receptors DR4 and -5 have demonstrated that recombinant,
soluble, human TRAIL or humanized monoclonal antibodies with
agonist activity against DR4 or -5 can induce apoptosis of tumor cells
while sparing normal cells. The mechanisms for this selectivity may
include expression of decoy receptors or elevated levels of intracellular
inhibitors (such as FLIP, which competes with caspase-8 for FADD)
by normal cells but not tumor cells. Synergy has been shown between
TRAIL-induced apoptosis and chemotherapeutic agents in some pre­
clinical studies. However, studies have not yet shown significant clini­
cal activity of approaches targeting the TRAIL pathway.
Many of the signal transduction pathways perturbed in cancer pro­
mote tumor cell survival (Fig. 77-5). These include activation of the
PI3K/Akt pathway, increased levels of the NF-κB transcription factor,
and epigenetic silencing of genes such as APAF-1 (apoptosis protease
activating factor-1 involved in activating caspase-9 and essential for
apoptosis) and caspase-8. Each of these pathways is a target for thera­
peutic agents that, in addition to affecting cancer cell proliferation or
gene expression, may render cancer cells more susceptible to apoptosis,
thus promoting synergy when combined with other chemotherapeutic
agents.
Some tumor cells resist drug-induced apoptosis indirectly by elimi­
nating the noxious stimulus-inducing apoptosis through expression
of one or more members of the ABC (ATP-binding cassette proteins)
family of ATP-dependent efflux pumps that mediate the multidrug
resistance (MDR) phenotype. The prototype member of this family,
P-glycoprotein (PGP), spans the plasma membrane 12 times and has
two ATP-binding sites. Hydrophobic drugs (e.g., anthracyclines and
vinca alkaloids) are recognized by PGP as they enter the cell and are
pumped out. Numerous clinical studies have failed to demonstrate that
drug resistance can be overcome using inhibitors of PGP. However,
ABC transporters have different substrate specificities, and inhibition
of a single family member may not be sufficient to overcome the MDR
phenotype. Efforts to reverse PGP-mediated drug resistance continue.
In addition to its role in cell death, autophagy can also serve as a
homeostatic mechanism to promote cell survival by recycling cellular
components to provide necessary energy. The mechanisms that control
the balance between enhancing survival versus leading to cell death are
still not fully understood. Autophagy appears to play conflicting roles
in the development and survival of cancer. Early in the carcinogenic
process, it can act as a tumor suppressor by preventing the cell from
accumulating abnormal proteins and organelles. However, in estab­
lished tumors, it may serve as a mechanism of survival for cancer cells
when they are stressed by damage such as from chemotherapy. Preclin­
ical studies have indicated that inhibition of this process can enhance
the sensitivity of cancer cells to chemotherapy or radiation therapy, and
ongoing trials are evaluating inhibitors of autophagy in combination
with chemotherapy and/or radiation therapy. Better understanding of
the factors that control the survival-promoting versus death-inducing
aspects of autophagy is required in order to know how to best manipu­
late it for therapeutic benefit.
■
■METASTASIS
The metastatic process accounts for the vast majority of deaths from
solid tumors, and therefore, an understanding of this process is critical
for improvements in survival from cancer. The biology of metastasis
is complex and requires multiple steps. The initial step involves cell
migration and invasion through the ECM. The three major features
of tissue invasion are cell adhesion to the basement membrane, local
proteolysis of the membrane, and movement of the cell through the
rent in the membrane and the ECM. Cells that lose contact with the
ECM normally undergo programmed cell death (anoikis-apoptosis
induced by the loss of contact), and this process has to be suppressed
in cells that metastasize. Another process important for many, but not
necessarily all, metastasizing epithelial cancer cells is epithelial mes­
enchymal transition (EMT). This is a process by which cells lose their
epithelial properties and gain mesenchymal properties. This normally
occurs during the developmental process in embryos, allowing cells to
migrate to their appropriate destinations in the embryo. It also occurs
in wound healing, tissue regeneration, and fibrotic reactions, but in all
of these processes, cells stop proliferating when the process is complete.
Malignant cells that metastasize often undergo EMT as an important
step in that process but retain the capacity for unregulated prolifera­
tion. However, there is evidence that not all metastasizing cancer cells
require EMT, and the exact role of EMT in different metastasizing
cancer cells continues to be elucidated. Malignant cells that gain access
to the circulation must then repeat those steps at a remote site, find a
hospitable niche in a foreign tissue, avoid detection and elimination by
host defenses including the immune system, and induce the growth of
new blood vessels. Some metastatic cells occur as oligoclonal clusters,
which appear to be more potent in establishing metastasis than single
cells, perhaps, in part, through differential and cooperative effects
in evading host defenses. The rate-limiting step for metastasis is the
ability for tumor cells to survive and expand in the novel microenvi­
ronment of the metastatic site, and multiple host-tumor interactions
determine the ultimate outcome (Fig. 77-6).
As is true for cells in primary cancers, there is significant hetero­
geneity as well as plasticity in metastatic cancer cells. In addition to
actively dividing cells, a population of quiescent cells are present that
can evade the immune system as well as chemotherapy targeting divid­
ing cells. The processes that keep metastatic cancer cells quiescent as
well as lead them to divide are complex, as discussed in the introduc­
tory section. Efforts to inhibit growth of metastatic cells by modulating
these pathways are being explored. Few drugs have been developed to
attempt to directly target the process of metastasis, in part because the
specifics of the critical steps in the process that would be potentially
good targets for drugs are still being identified. However, a number
of potential targets are known. HER2 can enhance the metastatic
potential of breast cancer cells, and as discussed above, the monoclonal
antibody trastuzumab, which targets HER2, improves survival in the
adjuvant setting for HER2-positive breast cancer patients. A number
of other potential targets that increase metastatic potential of cells in
preclinical studies include HIF-1 and -2, transcription factors induced
by hypoxia within tumors, growth factors (e.g., cMET and VEGFR),
oncogenes (e.g., SRC), adhesion molecules (e.g., focal adhesion kinase
[FAK]), ECM proteins (e.g., matrix metalloproteinases 1 and 2), and
inflammatory molecules (e.g., COX-2).
CHAPTER 77
Cancer Cell Biology
The metastatic phenotype is likely restricted to a fraction of tumor
cells (Fig. 77-6). A number of genetic and epigenetic changes are
required for tumor cells to be able to metastasize, including activation
of metastatic-promoting genes and inhibition of genes that suppress
the metastatic ability. Given the role of microRNAs in controlling gene
expression (see epigenetic section) including those critical to the meta­
static process, efforts are under way to modulate these to try to inhibit
metastasis. Cells with metastatic capability frequently express chemo­
kine receptors that are likely important in the metastatic process. A
number of candidate metastasis-suppressor genes have been identified,
including genes coding for proteins that enhance apoptosis, suppress
cell division, are involved in the interactions of cells with each other
or the ECM, or suppress cell migration. The loss of function of these
genes enhances metastasis. Gene expression profiling is being used to
study the metastatic process and other properties of tumor cells that
may predict susceptibilities.
An example of the ability of malignant cells to survive and grow in
a novel microenvironment is bone metastases. Bone metastases can be
extremely painful, cause fractures of weight-bearing bones, can lead to
hypercalcemia, and are a major cause of morbidity for cancer patients.
Osteoclasts and their monocyte-derived precursors express the sur­
face receptor RANK (receptor activator of NF-κB), which is required
for terminal differentiation and activation of osteoclasts. Osteoblasts
and other stromal cells express RANK ligand (RANKL), as both a
membrane-bound and soluble cytokine. Osteoprotegerin (OPG), a
soluble receptor for RANKL produced by stromal cells, acts as a decoy
receptor to inhibit RANK activation. The relative balance of RANKL
and OPG determines the activation state of RANK on osteoclasts. Bone
modulation and resorption by osteoclasts is an important component
of the establishment and progression of metastases in bone. Many
tumors increase osteoclast activity by secretion of substances such as
parathyroid hormone (PTH), PTH-related peptide, interleukin (IL) 1,
or Mip1 that perturb the homeostatic balance of bone remodeling by
increasing RANK signaling. One example is multiple myeloma, where
tumor cell–stromal cell interactions activate osteoclasts and inhibit
osteoblasts, leading to the development of multiple lytic bone lesions.
Basement
membrane
Normal epithelial
cells
Cytokeratin
Adherens
junction
E-cadherin
Tumor cell
TGF-β
receptor
TGF-β
N-Cadherin
Snail
Twist
HGF
New integrin
expression
N-Cadherin
C-Met
PART 4
Oncology and Hematology
FIGURE 77-6  Oncogene signaling pathways are activated during tumor progression and promote metastatic potential. This figure shows a cancer cell that has undergone
epithelial to mesenchymal transition (EMT) under the influence of several environmental signals. Critical components include activated transforming growth factor beta
(TGF-β) and the hepatocyte growth factor (HGF)/c-Met pathways, as well as changes in the expression of adhesion molecules that mediate cell-cell and cell–extracellular
matrix interactions. Important changes in gene expression are mediated by the Snail and Twist family of transcriptional repressors (whose expression is induced by the
oncogenic pathways), leading to reduced expression of E-cadherin, a key component of adherens junctions between epithelial cells. This, in conjunction with upregulation
of N-cadherin, a change in the pattern of expression of integrins (which mediate cell–extracellular matrix associations that are important for cell motility), and a switch in
intermediate filament expression from cytokeratin to vimentin, results in the phenotypic change from adherent highly organized epithelial cells to motile and invasive cells
with a fibroblast or mesenchymal morphology. EMT is thought to be an important step leading to metastasis in some human cancers. Host stromal cells, including tumorassociated fibroblasts and macrophages, play an important role in modulating tumor cell behavior through secretion of growth factors and proangiogenic cytokines, and
matrix metalloproteinases that degrade the basement membrane. VEGF-A, -C, and -D are produced by tumor cells and stromal cells in response to hypoxemia or oncogenic
signals and induce production of new blood vessels and lymphatic channels through which tumor cells metastasize to lymph nodes or tissues.
Inhibition of RANKL by an antibody (denosumab) can prevent fur­
ther bone destruction. Bisphosphonates are also effective inhibitors
of osteoclast function that are used in the treatment of cancer patients
with bone metastases.
■
■CANCER STEM CELLS
Normal tissues have stem cells capable of self-renewal and repairing
damaged tissue, whereas the majority of cells in normal tissues do not
have this capacity. Similarly, only a small proportion of the cells within
a tumor are capable of initiating colonies in vitro or forming tumors
at high efficiency when injected into immunocompromised NOD/
SCID mice. For example, AML and CML have a small population of
cells (estimated to be <1%) that have properties of stem cells, such
as unlimited self-renewal and the capacity to cause leukemia when
serially transplanted in mice. These cells have an undifferentiated
phenotype (Thy1–CD34+CD38– and do not express other differentia­
tion markers) and resemble normal stem cells in many ways but are
no longer under homeostatic control (Fig. 77-7). Solid tumors may
also contain a population of stem cells. It is not yet known how often
cancers may originate within a stem cell population, although a body
of evidence argues that stem cells are likely involved in the develop­
ment of the majority of cancers. Cancer stem cells, like their normal
counterparts, have unlimited proliferative capacity and paradoxically
traverse the cell cycle at a slow rate; cancer growth occurs largely due
to expansion of the stem cell pool, the unregulated proliferation of an
Lamina propria
Tumor-associated
fibroblast
New lymph vessel
MMP
Cytokines
growth
factors
Tumor-associated
macrophage
Invasion
New blood vessel
VEGF-A
HOST STROMAL CELLS
amplifying population, and failure of apoptosis pathways (Fig. 77-7).
Slow cell cycle progression and high levels of expression of antiapop­
totic Bcl-2 family members and drug efflux pumps of the MDR family
render cancer stem cells less vulnerable to cancer chemotherapy or
radiation therapy.
Implicit in the cancer stem cell hypothesis is the idea that failure to
cure most human cancers is due to the fact that current therapeutic
agents are not very effective in killing stem cells. Efforts are ongoing
to identify and isolate cancer stem cells from different types of malig­
nancies, which should allow determination of the aberrant signaling
pathways that distinguish these cells from normal tissue stem cells.
These would serve as potential therapeutic targets. Evidence that cells
with stem cell properties can arise from other epithelial cells within
the cancer by processes such as epithelial mesenchymal transition also
implies that it is essential to treat all of the cancer cells, and not just
those with current stem cell–like properties, in order to eliminate the
self-renewing cancer cell population. The exact nature of cancer stem
cells remains an area of investigation. One of the unanswered questions
is the exact origin of cancer stem cells for the different cancers.
PLASTICITY AND RESISTANCE
Cancer cells, and especially stem cells, have the capacity for significant
plasticity, allowing them to alter multiple aspects of cell biology in
response to external factors (e.g., chemotherapy, radiation therapy,
inflammation, immune response). In addition, heterogeneity between
NORMAL TISSUE
CANCER
Stem Cells
Stem cell niche
Paracrine signals
Polarized division
Daughter
cell
Stem
cell
Transit-amplifying cells
Exponential growth
Regulated activation of
differentiation program
Loss of self-renewal
capacity
Multilineage differentiation
Growth arrest
Maintenance of tissue
architecture and homeostasis
FIGURE 77-7  Cancer stem cells play a critical role in the initiation, progression, and resistance to therapy of malignant neoplasms. In normal tissues (left), homeostasis is
maintained by asymmetric division of stem cells, leading to one progeny cell that will differentiate and one cell that will maintain the stem cell pool. This occurs within highly
specific niches unique to each tissue, such as in close apposition to osteoblasts in bone marrow, or at the base of crypts in the colon. Here, paracrine signals from stromal
cells, such as sonic hedgehog or Notch ligands, as well as upregulation of β-catenin and telomerase, help to maintain stem cell features of unlimited self-renewal while
preventing differentiation or cell death. This occurs in part through upregulation of the transcriptional repressor Bmi-1 and inhibition of the p16Ink4a/Arf and p53 pathways.
Daughter cells leave the stem cell niche and enter a proliferative phase (referred to as transit-amplifying) for a specified number of cell divisions, during which time a
developmental program is activated, eventually giving rise to fully differentiated cells that have lost proliferative potential. Cell renewal equals cell death, and homeostasis
is maintained. In this hierarchical system, only stem cells are long-lived. The hypothesis is that cancers harbor stem cells that make up a small fraction (i.e., 0.001–1%) of
all cancer cells. These cells share several features with normal stem cells, including an undifferentiated phenotype, unlimited self-renewal potential, and a capacity for
some degree of differentiation; however, due to initiating mutations (mutations are indicated by lightning bolts), they are no longer regulated by environmental cues. The
cancer stem cell pool is expanded, and rapidly proliferating progeny, through additional mutations, may attain stem cell properties, although most of this population is
thought to have a limited proliferative capacity. Differentiation programs are dysfunctional due to reprogramming of the pattern of gene transcription by oncogenic signaling
pathways. Within the cancer transit-amplifying population, genomic instability generates aneuploidy and clonal heterogeneity as cells attain a fully malignant phenotype
with metastatic potential. The cancer stem cell hypothesis has led to the idea that current cancer therapies may be effective at killing the bulk of tumor cells but do not
kill tumor stem cells, leading to a regrowth of tumors that is manifested as tumor recurrence or disease progression. Research is in progress to identify unique molecular
features of cancer stem cells that can lead to their direct targeting by novel therapeutic agents.
the different clones of cells within the tumor population and their
interactions with each other and the tumor microenvironment pro­
vides the tumor with the capacity for significant plasticity in dealing
with both internal and external stresses. Thus, a major problem in can­
cer therapy is that malignancies have a wide spectrum of mechanisms
for both initial and adaptive resistance to treatments. These include
inhibiting drug delivery to the cancer cells, blocking drug uptake
and retention, increasing drug metabolism, altering levels of target
proteins making them less sensitive to drugs, acquiring mutations in
target proteins making them no longer sensitive to the drug, modify­
ing metabolism and cell signaling pathways, using alternate signaling
pathways, adjusting the cell replication process including mechanisms
by which the cell deals with DNA damage, inhibiting apoptosis, and
evading the immune system. Thus, most metastatic cancers (except
those curable with chemotherapy such as germ cell tumors) eventually
become resistant to the therapy being utilized. Overcoming resistance
is a major area of research.
■
■CANCER METABOLISM
One of the distinguishing characteristics of cancer cells is that they have
altered metabolism as compared with normal cells in supporting sur­
vival, their high rates of proliferation, and ability to metastasize. Com­
plicating studies evaluating metabolic differences between normal and
malignant cells is that there is heterogeneity in metabolism between
different cells within a cancer. Malignant cells must focus a significant
fraction of their energy resources into synthesis of proteins and other
molecules (building blocks required for the production of new cells)
while still maintaining sufficient ATP production to survive and grow.
Differentiation
Cancer Stem Cells
Altered or expanded
stem cell niche
Initiating mutations
Transit-amplifying cells
Exponential growth
Altered transcription
program
Differentiation arrest
Genetic instability
Secondary mutations
Limited self-renewal capacity
Partial differentiation
No growth arrest
CHAPTER 77
Loss of tissue architecture
and homeostasis control
Cancer Cell Biology
Although normal proliferating cells also have similar needs, there are
differences in how cancer cells metabolize glucose and a number of
other compounds including the amino acid glutamine as compared to
normal cells in part because of genetic and epigenetic changes within
cancer cells but also likely due to differences in the environments of
cancer and normal cells. Many cancer cells utilize aerobic glycolysis
(the Warburg effect) (Fig. 77-8) to metabolize glucose, leading to
increased lactic acid production, whereas normal cells utilize oxidative
phosphorylation in mitochondria under aerobic conditions, a much
more efficient process for generating ATP for energy utilization but
one that does not produce the same level of building blocks needed for
new cells. One consequence is increased glucose uptake and utilization
by cancer cells, a fact utilized in fluorodeoxyglucose (FDG)-positron
emission tomography (PET) scanning to detect tumors. A number of
proteins in cancer cells, including cMYC, HIF1, RAS, p53, pRB, and
AKT, are involved in modulating glycolytic processes and controlling
the Warburg effect. Although these pathways overall remain difficult to
target therapeutically, some progress has been made in targeting HIF1
and the RAS pathways with inhibitors approved to treat cancers with
mutations in HIF1α or KRAS12C. In addition, both the PI3K pathway
with signaling through mTOR and the AMP-activated kinase (AMPK)
pathway that inhibits mTORC1 (a protein complex that includes
mTOR) are important in controlling the glycolytic process and thus
provide potential targets for inhibiting this process. An inhibitor of
mTOR is approved for use against RCC (temsirolimus), and another
inhibitor (everolimus) has activity against breast and neuroendocrine
cancer and RCC. Other mTOR inhibitors are in trials, and modulators
of AMPK are being investigated. The inefficient utilization of glucose
Differentiated tissue
Tumor
Proliferative
tissue
or
+O2
–O2
+/–O2
Glucose
Glucose
Glucose
Pyruvate
Pyruvate
Pyruvate
O2
O2
Lactate
Lactate
Lactate
CO2
Anaerobic
glycolysis
2 mol ATP/
mol glucose
Oxidative
phosphorylation
–36 mol ATP/
mol glucose
FIGURE 77-8  Warburg versus oxidative phosphorylation. In most normal tissues, the vast majority of cells are differentiated and dedicated to a particular function within
the organ in which they reside. The metabolic needs are mainly for energy and not for building blocks for new cells. In these tissues, ATP is generated by oxidative
phosphorylation that efficiently generates about 36 molecules of ATP for each molecule of glucose metabolized. By contrast, proliferative tumor tissues, especially in the
setting of hypoxia, a typical condition within tumors, use aerobic glycolysis to generate energy for cell survival and generation of building blocks for new cells.
PART 4
Oncology and Hematology
by malignant cells also leads to a need for alternative metabolic path­
ways for other compounds as well, one of which is glutamine. Similar
to glucose, this provides both a source for structural molecules as well
as energy production. Similarly to glucose, glutamine is also ineffi­
ciently utilized by cancer cells. Cancer cells can also take up nutrients
released by surrounding cells and tissues, increasing the complexity of
successfully therapeutically inhibiting metabolism in cancer.
Mutations in genes involved in the metabolic process occur in a
number of cancers. Among the most frequently found to date are muta­
tions in isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2). These
have been most commonly seen in gliomas, AMLs, and intrahepatic
cholangiocarcinomas. These mutations lead to the production of an
oncometabolite (2-hydroxyglutarate [2HG]) instead of the normal
product α-ketoglutarate. Although the exact mechanisms of oncogen­
esis by 2HG are still being elucidated, α-ketoglutarate is a key cofactor
for a number of dioxygenases involved in controlling DNA methyla­
tion. 2HG can act as a competitive inhibitor for α-ketoglutarate, lead­
ing to alterations in methylation status (primarily hypermethylation) of
genes (leading to epigenetic changes) that can have profound effects on
a number of cellular processes including differentiation. Inhibitors of
mutant IDH1 and/or IDH2 are approved for treating IDH mutant AML
and cholangiocarcinoma; and a dual IDH1/2 inhibitor is approved for
treatment of low-grade gliomas and astrocytomas with IDH mutations.
Much needs to be learned about the specific differences in metabo­
lism between cancer cells and normal cells in order to develop more
effective approaches to using these differences therapeutically; how­
ever, even with the currently limited state of knowledge, modulators of
metabolism are being tested clinically. One of these is the antidiabetic
agent metformin, both alone and in combination with chemotherapeu­
tic agents. Metformin inhibits gluconeogenesis and may have direct
effects on tumor cells by activating AMPK, a serine/threonine protein
kinase that is downstream of the LKB1 tumor suppressor, and thus
inhibiting mTOR complex 1 (mTORC1). This leads to decreased pro­
tein synthesis and proliferation. Studies to date have not yet established
metformin to have a clear role as an anticancer agent.
■
■TUMOR MICROENVIRONMENT, ANGIOGENESIS,
AND IMMUNE EVASION
Tumors consist not only of malignant cells but also of a complex
microenvironment including many other types of cells (including
lymphocytes, macrophages, myeloid cells; other inflammatory cells;
5%
85%
CO2
Aerobic
glycolysis
(Warburg effect)
–4 mol ATP/mol glucose
vascular cells, lymphatic endothelial cells, nerve cells, fibroblasts, and
fat cells), ECM, stroma, secreted factors (including growth factors and
hormones), reactive oxygen and nitrogen species, mechanical factors,
blood vessels, and lymphatics. There is extensive cross-talk between the
cells with each other, the ECM, and the various secreted factors within
the tumor microenvironment. This microenvironment is not static but
rather is dynamic and continually evolving. Both the complexity and
dynamic nature of the microenvironment enhance the difficulty of
treating tumors. The microenvironment is involved in altered tumor
metabolism, tumor maintenance, growth, phenotypic plasticity, metas­
tasis, and immune escape, and can contribute to resistance to antican­
cer therapies through a number of mechanisms. These include immune
evasion by a variety of mechanisms including suppression of effector
T cells, increase in regulatory T cells, induction of an inflammatory
environment, and altered vasculature that inhibits effector T-cell access
to malignant cells. Similarly, it contributes to drug resistance through
multiple mechanisms, alteration in metabolic pathways including
creating a hypoxic and acidic environment, vascular and mechanical
factors that limit drug access to malignant cells, various secreted factors
that inhibit apoptosis or stimulate survival pathways, and generation of
ROS that enhance drug resistance. Multiple additional mechanisms are
also involved in enhancing resistance to immune-mediated anticancer
effects and anticancer drug therapy.
■
■OBESITY AND CANCER
Significant evidence links obesity and the increased risk of devel­
oping certain cancers including postmenopausal breast, colorectal,
ovarian, endometrial, esophageal, gallbladder, thyroid, and kidney
cancers, among others. Less certain are the mechanisms responsible
for this risk. As outlined above, cancers arise in an environment with
multiple factors, many of which can stimulate cell proliferation. Obe­
sity impacts a variety of factors including hormonal factors, altered
metabolism (especially adipose metabolism), and mediators of inflam­
matory response that all can impact the development of malignancy.
Obesity is associated with a number of hormonal changes including
high insulin, glucagon, and leptin levels that can stimulate growth of
cells. It also leads to insulin resistance, which may contribute to cancer
cell development, in part by increasing insulin-like growth factor-1
(IGF-1) levels. Obesity also leads to alterations in adipose, including
fatty acid, metabolism with production of compounds important for
energy metabolism as well as for membrane function within cells that
may contribute to carcinogenic process. Obesity
contributes to an inflammatory environment in
a variety of ways including increased levels of
inflammatory proteins such as IL-6 and TNF-α.
In terms of impact on survival with cancer, data
primarily from breast cancer suggest that obesity
is associated with decreased survival likely due, at
least in part, to the impact of obesity on hormonal
factors in development of certain breast cancers,
although this may be limited to subsets of breast
cancer patients. Some studies have suggested, para­
doxically, that obesity may be associated with
improved survival in some patients such as those
with advanced-stage colorectal cancer. Further­
more, immune checkpoint inhibitor therapy has
appeared to be more effect in obese patients.
Clearly, the biology of the association between obe­
sity and cancer and its impact on disease outcome
is complex, and additional studies are necessary to
better define the mechanisms involved.
Vascular mimicry—
tumor cells as
part of vessel wall
Tumor
■
■MECHANISMS OF TUMOR VESSEL
FORMATION
One of the critical elements of tumor cell pro­
liferation is delivery of oxygen, nutrients, and
circulating factors important for growth and sur­
vival. Thus, a critical element in growth of pri­
mary tumors and formation of metastatic sites
is the angiogenic switch: the ability of the tumor
to promote the formation of new blood vessels,
including the recruitment of vascular endothelial
cells (ECs). The angiogenic switch is a phase in
tumor development when the dynamic balance of
pro- and antiangiogenic factors is tipped in favor of
vessel formation by the effects of the tumor on its
immediate environment. Stimuli for tumor angio­
genesis include hypoxemia, inflammation, and
genetic lesions in oncogenes or tumor suppressors
that alter tumor cell gene expression. Angiogenesis
consists of several steps, including the stimula­
tion of ECs by growth factors, degradation of the
ECM by proteases, proliferation and migration of
ECs into the tumor, and the eventual formation
of new capillary tubes. Tumors use a number of
mechanisms to promote vascularization, subvert­
ing normal angiogenic processes for this purpose
(Fig. 77-9). Primary or metastatic tumor cells
sometimes arise in proximity to host blood vessels
and grow around these vessels, parasitizing nutri­
ents by co-opting the local blood supply. However,
most tumor blood vessels arise by the process of
sprouting, in which tumors secrete trophic angio­
genic molecules, the most potent being vascular
endothelial growth factors (VEGFs), that induce the proliferation and
migration of host ECs into the tumor. Sprouting in normal and patho­
genic angiogenesis is regulated by three families of transmembrane
RTKs expressed on ECs and their ligands (VEGFs, angiopoietins, and
ephrins; Fig. 77-10), which are produced by tumor cells, inflammatory
cells, or stromal cells in the tumor microenvironment.
FIGURE 77-9  Tumor angiogenesis is a complex process involving many different cell types that must
proliferate, migrate, invade, and differentiate in response to signals from the tumor microenvironment.
Endothelial cells (ECs) sprout from host vessels in response to VEGF, bFGF, Ang2, and other proangiogenic
stimuli. Sprouting is stimulated by VEGF/VEGFR2, Ang2/Tie-2, and integrin/extracellular matrix (ECM)
interactions. Bone marrow–derived circulating endothelial precursors (CEPs) migrate to the tumor in
response to VEGF and differentiate into ECs, while hematopoietic stem cells differentiate into leukocytes,
including tumor-associated macrophages that secrete angiogenic growth factors and produce matrix
metalloproteinases (MMPs) that remodel the ECM and release bound growth factors. Tumor cells
themselves may directly form parts of vascular channels within tumors. The pattern of vessel formation is
haphazard: vessels are tortuous, dilated, leaky, and branch in random ways. This leads to uneven blood flow
within the tumor, with areas of acidosis and hypoxemia (which stimulate release of angiogenic factors) and
high intratumoral pressures that inhibit delivery of therapeutic agents.
Central to the angiogenic response are hypoxia-inducible factors
(HIFs; especially 1 and 2), which are transcription factors that normally,
in response to hypoxia, stimulate the transcription of a large number of
genes responsive to hypoxia, including genes involved in metabolism as
well as angiogenesis. HIF1 has a bigger role in stimulating metabolism
(glycogenesis), whereas HIF2 plays a bigger role in angiogenesis. HIF
protein function can also be enhanced in a number of ways in cancer
not involving hypoxia, including mutations in the von Hippel–Lindau
tumor suppressor gene (an E3 ubiquitin ligase that controls HIF levels
by targeting it for degradation), such as occurs in some RCCs. Among
CEP contributes newly
differentiated EC
HSC-derived
macrophage
Tumor
Leaky
vessels
Tumor
Region of
hypoxemia
100 µm
High
intratumoral
pressure
Dilated
leaky
tumor
vessel
VEGF
VEGF
VEGFR2
VEGFR2
Destabilization
Tie 2
Tie 2
Ang2
ανβ 2
ανβ 3
ανβ 5
α5β 1
α5β 1
ECM
Tie 2
New
sprout
Follows VEGF gradient to tumor
CHAPTER 77
Migrate to tumor
Host blood vessel
VEGFR2
CEP
CD133
Cancer Cell Biology
Bone marrow–derived cells
(from hemangioblast)
VEGFR1
HSC
c-kit
Tumor cells
Host EC
Tumor EC
Circulating endothelial
precursors (CEP)
Hematopoietic cell–derived
leukocytes (HSC)
the genes stimulated by HIF are VEGF and VEGF receptors. VEGFs
and their receptors are required for embryonic vasculogenesis (devel­
opment of new blood vessels when none preexist) and normal (wound
healing, corpus luteum formation) and pathologic angiogenesis (tumor
angiogenesis, inflammatory conditions such as rheumatoid arthritis).
VEGF-A is a heparin-binding glycoprotein with at least four isoforms
(splice variants) that regulates blood vessel formation by binding to
the RTKs VEGFR1 and VEGFR2, which are expressed on all ECs in
addition to a subset of hematopoietic cells (Fig. 77-9). VEGFR2 plays a
more direct role in regulating EC proliferation, migration, and survival,
whereas VEGFR1 appears to have more nuanced functions with a less
direct role in stimulating EC processes in the normal adult (even act­
ing as a decoy protein for VEGFA to decrease binding to VEGFR2) but
with important effects during embryogenesis and on tumor angiogen­
esis. Tumor vessels may be more dependent on VEGFR signaling for
growth and survival than normal ECs.
Endothelial cell–“specific” ligand/receptor complexes
PIGF
VEGF-A
VEGF-B
VEGF-C
Ang-1 Ang-2
Ephrins
Extracellular
matrix
bFGF
PDGF
Kinase
domain
αvβ3
Matrix
(attachment)
EPHB4
(Arteryvein
differentiation,
vessel
remodeling)
VEGFR1
VEGFR2
VEGFR3
(Endothelial cells)
(Lymphatics)
Tie-2
(Blood vessel
stabilization
and
remodeling)
Downstream pathways
Ras/MAPK
Pl3K/AKT
Rho/Rac/cdc42
NFκB
PART 4
Oncology and Hematology
Endothelial cell proliferation, migration, survival
FIGURE 77-10  Critical molecular determinants of endothelial cell biology. Angiogenic endothelium expresses
a number of receptors not found on resting endothelium. These include receptor tyrosine kinases (RTKs) and
integrins that bind to the extracellular matrix and mediate endothelial cell (EC) adhesion, migration, and invasion.
ECs also express RTKs (i.e., the fibroblast growth factor [FGF] and platelet-derived growth factor [PDGF] receptors)
that are found on many other cell types. Critical functions mediated by activated RTK include proliferation,
migration, and enhanced survival of endothelial cells, as well as regulation of the recruitment of perivascular
cells and bloodborne circulating endothelial precursors and hematopoietic stem cells to the tumor. Intracellular
signaling via EC-specific RTK utilizes molecular pathways that may be targets for future antiangiogenic therapies.
While VEGF signaling is a critical initiator of angiogenesis, this is
a complex process regulated by additional signaling pathways (Fig.
77-10). The angiopoietin, Ang1, produced by stromal cells, binds to
the EC RTK Tie-2 and promotes the interaction of ECs with the ECM
and perivascular cells, such as pericytes and smooth-muscle cells, to
form tight, nonleaky vessels. PDGF and basic fibroblast growth fac­
tor (bFGF) help to recruit these perivascular cells. Ang1 is required
for maintaining the quiescence and stability of mature blood vessels
and prevents the vascular permeability normally induced by VEGF
and inflammatory cytokines. For tumor cell–derived VEGF to initiate
sprouting from host vessels, the stability conferred by the Ang1/Tie2
pathway must be perturbed; this occurs by the secretion of Ang2 by
ECs that are undergoing active remodeling. Ang2 binds to Tie2 and is
a competitive inhibitor of Ang1 action: under the influence of Ang2,
preexisting blood vessels become more responsive to remodeling sig­
nals, with less adherence of ECs to stroma and associated perivascular
cells and more responsiveness to VEGF. Therefore, Ang2 is required at
early stages of tumor angiogenesis for destabilizing the vasculature by
making host ECs more sensitive to angiogenic signals. In the presence
of Ang2, there is no stabilization by the Ang1/Tie2 interaction, and
tumor blood vessels are leaky, hemorrhagic, and have poor association
of ECs with underlying stroma. Sprouting tumor ECs express high
levels of the transmembrane protein ephrin-B2 and its receptor, the
RTK EPH, whose signaling appears to work with the angiopoietins
during vessel remodeling. During embryogenesis, EPH receptors are
expressed on the endothelium of primordial venous vessels while the
transmembrane ligand ephrin-B2 is expressed by cells of primordial
arteries; the reciprocal expression may regulate differentiation and pat­
terning of the vasculature.
A number of additional ubiquitously expressed host molecules play
critical roles in normal and pathologic angiogenesis. Proangiogenic
cytokines, chemokines, and growth factors
secreted by stromal cells or inflammatory
cells make important contributions to neo­
vascularization, including bFGF, transform­
ing growth factor-β (TGF-β), TNF-α, and
IL-8. In contrast to normal endothelium,
angiogenic endothelium overexpresses spe­
cific members of the integrin family of ECMbinding proteins that mediate EC adhesion,
migration, and survival. Specifically, expres­
sion of integrins αvβ3, αvβ5, and α5β1
mediates spreading and migration of ECs and
is required for angiogenesis induced by VEGF
and bFGF, which in turn can upregulate EC
integrin expression. The αvβ3 integrin physi­
cally associates with VEGFR2 in the plasma
membrane and promotes signal transduction
from each receptor to promote EC prolifera­
tion (via focal adhesion kinase, src, PI3K, and
other pathways) and survival (by inhibition of
p53 and increasing the Bcl-2/Bax expression
ratio). In addition, αvβ3 forms cell-surface
complexes with matrix metalloproteinases
(MMPs), zinc-requiring proteases that cleave
ECM proteins, leading to enhanced EC
migration and the release of heparin-binding
growth factors, including VEGF and bFGF.
EC adhesion molecules can be upregulated
(i.e., by VEGF, TNF-α) or downregulated
(by TGF-β); this, together with chaotic blood
flow, explains poor leukocyte-endothelial
interactions in tumor blood vessels and may
help tumor cells avoid immune surveillance.
Generalized
growth factor
receptors
FGF
receptor
PDGF
receptor
(Recruitment
of smoothmuscle cells
and pericytes)
Tumor blood vessels are not normal; they
have chaotic architecture and blood flow.
Due to an imbalance of angiogenic regulators
such as VEGFs and angiopoietins (see below),
tumor vessels are tortuous and dilated with
an uneven diameter, excessive branching, and shunting. Tumor blood
flow is variable, with areas of hypoxemia and acidosis leading to the
selection of cancer cell variants that are resistant to hypoxemia-induced
apoptosis (often involving the loss of p53 expression). Tumor vessel
walls have numerous openings, widened interendothelial junctions,
and discontinuous or absent basement membrane. This contributes to
the high permeability of these vessels and, together with lack of func­
tional intratumoral lymphatics, causes increased interstitial pressure
within the tumor (which also interferes with the delivery of therapeutics
to the tumor; Figs. 77-9, 77-10, and 77-11). Tumor blood vessels have a
deficit of perivascular cells such as pericytes and smooth-muscle cells
that normally regulate flow in response to tissue metabolic needs.
Unlike normal blood vessels, the vascular lining of tumor vessels is not
a homogeneous layer of ECs but often consists of a mosaic of ECs and
tumor cells, which, because of their plasticity, can upregulate expres­
sion of genes normally only seen in ECs under hypoxic conditions.
These cancer cell–derived vascular channels, which may be lined by
ECM secreted by the tumor cells, are referred to as vascular mimicry.
During tumor angiogenesis, ECs are highly proliferative and express a
number of plasma membrane proteins that are characteristic of acti­
vated endothelium, including growth factor receptors and adhesion
molecules such as integrins. These abnormalities in tumor vascula­
ture provide potential differential sensitivities from normal vessels to
approaches inhibiting the process, allowing for the use of antiangio­
genic agents in cancer treatment.
Lymphatic vessels also exist within tumors. Development of tumor
lymphatics is associated with expression of VEGFR3 and its ligands
VEGF-C and VEGF-D. The role of these vessels in tumor cell metas­
tasis to regional lymph nodes remains to be determined. However,
VEGF-C levels correlate significantly with metastasis to regional lymph
nodes in lung, prostate, and colorectal cancers.
A. Normal blood vessel
Low IP
Normoxic
Physiologic pH
Hierarchical
branching
Even blood
distribution
Lumen
EC
BM
BM
Pericytes
Tight junctions between EC
Well-formed BM
Pericyte coverage
Normal permeability
C. Treatment with bevacizumab (Early)
D. Treatment with bevacizumab (Late)
Low IP
Less hypoxemia
Less acidosis
Normalization
of vessels
Improved
blood flow
Lumen
EC
BM
Pericytes
More efficient delivery of
chemotherapy and oxygen
Reduced permeability
Death of EC due to loss of VEGF
survival signals (plus chemotherapy
or radiotherapy)
Apoptosis of tumor due to starvation
and/or effects of chemotherapy
FIGURE 77-11  Normalization of tumor blood vessels due to inhibition of VEGF signaling. A. Blood vessels in normal tissues exhibit a regular hierarchical branching
pattern that delivers blood to tissues in a spatially and temporally efficient manner to meet the metabolic needs of the tissue (top). At the microscopic level, tight junctions
are maintained between endothelial cells (ECs), which are adherent to a thick and evenly distributed basement membrane (BM). Pericytes form a surrounding layer that
provides trophic signals to the EC and helps maintain proper vessel tone. Vascular permeability is regulated, interstitial fluid pressure (IP) is low, and oxygen tension and
pH are physiologic. B. Tumors have abnormal vessels with tortuous branching and dilated, irregular interconnecting branches, causing uneven blood flow with areas of
hypoxemia and acidosis. This harsh environment selects genetic events that result in resistant tumor variants, such as the loss of p53. High levels of VEGF (secreted by
tumor cells) disrupt gap junction communication, tight junctions, and adherens junctions between EC via src-mediated phosphorylation of proteins such as connexin 43,
zonula occludens-1, VE-cadherin, and α/β-catenins. Tumor vessels have thin, irregular BM, and pericytes are sparse or absent. Together, these molecular abnormalities
result in a vasculature that is permeable to serum macromolecules, leading to high tumor interstitial pressure, which can prevent the delivery of drugs to the tumor cells.
This is made worse by the binding and activation of platelets at sites of exposed BM, with release of stored VEGF and microvessel clot formation, creating more abnormal
blood flow and regions of hypoxemia. C. In experimental systems, treatment with bevacizumab or blocking antibodies to VEGFR2 leads to changes in the tumor vasculature
that have been termed vessel normalization. During the first week of treatment, abnormal vessels are eliminated or pruned (dotted lines), leaving a more normal branching
pattern. ECs partially regain features such as cell-cell junctions, adherence to a more normal BM, and pericyte coverage. These changes lead to a decrease in vascular
permeability, reduced interstitial pressure, and a transient increase in blood flow within the tumor. Note that in murine models, this normalization period lasts only for ~5–6
days. D. After continued anti-VEGF/VEGFR therapy (which is often combined with chemo- or radiotherapy), ECs die, leading to tumor cell death (either due to direct effects
of the chemotherapy or lack of blood flow).
■
■ANTIANGIOGENIC THERAPY
Angiogenesis inhibitors function by targeting the critical molecular
pathways involved in EC proliferation, migration, and/or survival,
many of which are highly expressed in the activated endothelium in
tumors. Inhibition of growth factor and adhesion-dependent signaling
B. Tumor blood vessel
High IP
High VEGF
Hypoxemia
Acidosis
Tortuous
vessels
Haphazard blood
flow
Lumen
EC
Tumor cells
Loss of EC junction complexes
Irregular or no BM
Absent (or few) pericyte
Increased permeability
CHAPTER 77
Collapse
of tumor
vasculature
Cancer Cell Biology
Lumen
EC
BM
Tumor cells
pathways can induce EC apoptosis with concomitant inhibition of
tumor growth. Different types of tumors can use distinct combinations
of molecular mechanisms to activate the angiogenic switch. Therefore,
it is doubtful that a single antiangiogenic strategy will suffice for all
human cancers; rather, a number of agents or combinations of agents
Ang 1
Ang 2
Novel
inhibitors
Anti-VEGF
MoAb
VEGF
VEGFR2
Kinase
domain
Tie2
receptor
Enhanced
binding to ECM,
vessel stabilization
Specific
kinase
inhibitors
Proliferation
survival
migration
Anti-integrin
MoAb,
RGD peptides
αvβ3
αvβ5
α5β1
Nucleus
Microtubules
Extracellular
matrix (ECM)
2-Methoxy estradiol
MMPs
(invasion,
growth factor
release)
MMP inhibitors
PART 4
Oncology and Hematology
FIGURE 77-12  Knowledge of the molecular events governing tumor angiogenesis has led to a number of therapeutic strategies to block tumor blood vessel formation.
The successful therapeutic targeting of VEGF and its receptors VEGFR is described in the text. Other endothelial cell (EC)–specific receptor tyrosine kinase pathways (e.g.,
angiopoietin/Tie2 and ephrin/EPH) are likely targets for the future. Ligation of the αvβ3 integrin is required for EC survival. Integrins are also required for EC migration and
are important regulators of matrix metalloproteinase (MMP) activity, which modulates EC movement through the ECM as well as release of bound growth factors. Targeting
of integrins includes development of blocking antibodies, small peptide inhibitors of integrin signaling, and arg-gly-asp–containing peptides that prevent integrin:ECM
binding. Peptides derived from normal proteins by proteolytic cleavage, including endostatin and tumstatin, inhibit angiogenesis by mechanisms that include interfering
with integrin function. Signal transduction pathways that are dysregulated in tumor cells indirectly regulate EC function. Inhibition of EGF-family receptors, whose signaling
activity is upregulated in a number of human cancers (e.g., breast, colon, and lung cancers), results in downregulation of VEGF and IL-8, while increasing expression of the
antiangiogenic protein thrombospondin-1. The Ras/MAPK, PI3K/Akt, and Src kinase pathways constitute important antitumor targets that also regulate the proliferation
and survival of tumor-derived EC. The discovery that ECs from normal tissues express tissue-specific “vascular addressins” on their cell surface suggests that targeting
specific EC subsets may be possible.
will be needed, depending on distinct programs of angiogenesis used
by different human cancers. Despite this, experimental data indicate
that for some tumor types, blockade of a single growth factor (e.g.,
VEGF) may inhibit tumor-induced vascular growth.
Bevacizumab, an antibody that binds circulating VEGF, modestly
potentiates the effects of a number of different types of active chemo­
therapeutic regimens used to treat a variety of different tumor types
including colon, lung, ovarian, and cervical cancers. It also has some
activity in combination with immunotherapy against RCCs and alone
for glioblastomas. Other protein inhibitors of the VEGF signaling path­
way approved for anticancer therapy include ramucirumab (a mono­
clonal antibody directed against VEGFR2, approved for use against
gastric/gastroesophageal, colon, and lung cancers) and ziv-aflibercept
(a recombinant protein inhibitor of VEGF, approved for colorectal
cancer). Hypertension is the most common side effect of inhibitors of
VEGF (or its receptors) but can be treated with antihypertensive agents
and uncommonly requires discontinuation of therapy. Rare but seri­
ous potential risks include arterial thromboembolic events, including
stroke and myocardial infarction, hemorrhage, bowel perforation, and
inhibition of wound healing.
Several small-molecule inhibitors (SMIs) that target VEGF RTK
activity but are also inhibitory to other kinases have also been approved
to treat certain cancers. Sunitinib (see above and Table 77-2) has activ­
ity directed against mutant c-Kit receptors (approved for GIST), but
also targets VEGFR and PDGFR, and has antitumor activity against
pancreatic neuroendocrine and metastatic RCCs, presumably on
the basis of its antiangiogenic activity. Similarly, sorafenib, originally
developed as a Raf kinase inhibitor but with potent activity against
VEGFR and PDGFR, has activity against RCC, differentiated thyroid
and hepatocellular cancers, and desmoid tumors. A closely related mol­
ecule to sorafenib, regorafenib, has activity against colorectal cancer,
Stromal cell
Novel
inhibitors
EPH receptor
Ephrin-B2
Endothelial cell
GIST, gastric, and hepatocellular cancers. Other inhibitors of the VEGF
pathway approved for the treatment of various cancers include axitinib,
pazopanib, lenvatinib, and cabozantinib.
Antiangiogenic agents have been particularly effective against RCC
for which angiogenic factors are important for its development and
growth. The modest success in targeting tumor angiogenesis against
most other cancers has led to enhanced enthusiasm for the develop­
ment of drugs that target other aspects of the angiogenic process;
some of these therapeutic approaches are outlined in Fig. 77-12. An
inhibitor of HIF2-α has sufficient antitumor activity against RCC,
pancreatic neuroendocrine tumors, and hemangioblastomas develop­
ing in patients with germline VHL mutations to be approved for these
indications.
Evidence of enhanced activity has been seen when anti-VEGF
agents are used in combination with immunomodulators including
immune checkpoint inhibitors. Examples of approved combinations
include durvalumab plus bevacizumab for HCC and lenvatinib plus
pembrolizumab for endometrial cancer and RCC.
■
■EVASION OF THE IMMUNE SYSTEM BY CANCERS
The immune system plays a critical role in maintaining organismal
integrity including by defending against pathogens as well as prevent­
ing and limiting the growth of cancers. There is a complex interaction
between cancer and the host from the development of the first malig­
nant cell to the establishment of a clinical cancer and its subsequent
growth, invasion, and metastasis. The immune system plays a critical
role in the prevention of cancer development. This is exemplified by the
increased risk for cancer development in individuals who are signifi­
cantly immunosuppressed, such as by inherited defects in mechanisms
important for immune function, the immunosuppression necessary to
maintain allogeneic organ transplants, and immunosuppression seen
from certain infections such as human immunodeficiency virus. It also
plays a critical role in inhibiting the process of cells metastasizing as
well as growth of metastatic cells at the sites of metastasis.
There are two components of the immune system. The first is
innate immunity (present in the organism and not dependent on prior
exposure to a specific antigen, such as those present in a pathogen or
malignant cell), which tends to be general and not specific and a stimu­
lus is not remembered if encountered again. The second is the adaptive
immune component, which depends on the innate immune process for
activation and provides the specificity to the response with significant
expansion of cells to target the specific antigens present on the patho­
gen or malignant cell and memory of the encounter such that exposure
to the same stimulus elicits an even more rapid and vigorous response.
Thus, while the innate process provides the first line of defense, the
adaptive process is necessary for the specificity of response and provid­
ing memory to more rapidly attack cells should the pathogen infection
recur or the malignant cells grow. The immune system has to be tightly
regulated to allow for clearance of unwanted antigens while preventing
an immune-mediated attack on the self. (See Chap. 360 for details on
the function of the immune system.)
Not surprisingly, since cancers arise from normal cells within the
body that have a variety of processes to prevent harm or destruction
by the immune system, they have a variety of mechanisms that allow
them to evade detection and elimination by the immune system. These
include downregulation of cell surface proteins involved in immune
recognition (including MHC proteins and tumor-specific antigens),
expression of other cell surface proteins that inhibit immune func­
tion (including members of the B7 family of proteins such as PD-L1),
secretion of proteins and other molecules that are immunosuppressive
such as TGF-β, recruitment and expansion of immunosuppressive
cells such as regulatory T cells (which are important for maintaining
tolerance against self-antigens), induction of T-cell tolerance, and
downregulation of death receptors. Due to the marked heterogeneity
of cells within a cancer, as well as the complexity and dynamic changes
in the tumor microenvironment, a variety of immune-suppressive
mechanisms are continuously occurring and changing. In addition,
the inflammatory effects of some of the immune mediator cells in the
tumor microenvironment (including tissue-associated macrophages
and myeloid-derived suppressor cells) can suppress effector T-cell
responses against the tumor as well as stimulate inflammation that can
enhance tumor growth.
There are marked differences in the way different malignancies
respond to current immunotherapeutic approaches. For example, mel­
anomas, RCC, Merkel cell carcinomas, cancers with defects in DNA
repair associated with microsatellite instability with accumulation of
gene mutations, and lymphomas (including Hodgkin’s) respond well to
current immunotherapeutic approaches, whereas microsatellite-stable
pancreatic and colon cancers do not. While there is not a complete
understanding of why these differences exist and many factors both
within the cancer cells and in the microenvironment may play a
role, several factors have been identified that appear to be important.
These include the number of mutations present in the tumor (tumor
mutational burden), presence of increased neoantigens, expression of
immune checkpoint proteins (e.g., PD-L1 for anti-PD-1 or anti-PD-L1
therapy), density of tumor-infiltrating lymphocytes, and host genetic
factors. One of these (PD-L1 expression by the tumor) has sufficient
predictive value for certain tumors (e.g., non-small-cell lung cancer or
gastroesophageal cancers) to be used in making treatment decisions
regarding the use of antibodies targeting PD-1 or PD-L1. However, nei­
ther PD-L1 expression nor any other marker can predict responsive­
ness of most tumors to immunotherapy. Better biomarkers that define
potential responsiveness of specific cancers to immunotherapy are
badly needed. A major area of research is to try to identify approaches
that would convert cancers that are not responsive to immunotherapy
to being responsive.
Immunotherapy approaches to treat cancer can be divided into
those aimed at activating the immune response and those designed to
release the brakes that prevent an effective immune response against
tumors. Releasing the brakes is also important for maintaining the
effectiveness of approaches that activate the immune response since,
given the normally tight regulation of immune function, activation
induces changes in the braking system to prevent the immune system
from damaging normal tissues. Approaches at activating the immune
response against cancer including using immunostimulatory mol­
ecules such as interferons, IL-2, and especially monoclonal antibod­
ies have had success in treating a number of different cancers. For
example, antibodies that target molecules highly expressed on certain
cancers, such as CD20 on malignant B cells or HER2 on a variety of
cancers including breast and gastroesophageal cancers, which acti­
vate the immune response locally against those malignancies, have
proven highly effective.
A more direct approach to enhance the activity of T cells directed
against specific tumors involves isolating T cells from patients and
reengineering the cells to express chimeric antigen receptors (CAR-T)
that recognize antigens present on the cells of that individual’s tumor.
The most commonly used approach to date has been to engineer the
cells to express receptors targeting the CD19 antigen on ALL, dif­
fuse large B-cell lymphoma (DLBCL) cells, follicular lymphoma, and
mantle cell lymphoma. These have been shown to have significant
antitumor activity in the treatment of patients with ALL and DLBCL,
including durable remissions in patients refractory to standard thera­
pies, and are approved for these malignancies. In addition, anti-B-cell
maturation antigen (BCMA) CAR-T therapies have been approved for
the treatment of multiple myeloma.
CHAPTER 77
However, there have also been significant issues with toxicity
including cytokine release syndrome, organ toxicity felt to be due to
inadvertent targeting of antigens present in the organ, neurotoxicity,
and potentially an increased risk for subsequent development of T-cell
malignancies. These patients often require aggressive supportive care
by individuals experienced in the delivery of CAR-T therapy. In addi­
tion, as is true for most anticancer therapies, mechanisms of resistance
have developed, most commonly the outgrowth of tumor cells no
longer expressing the antigen. Mechanisms for preventing the devel­
opment of resistant cells are being explored, including combinations
targeting different antigens. In addition to potentially preventing or
overcoming resistance to the targeting of a single antigen, this could
potentially increase efficacy and better reflects the normal immune
response to pathogens or cancers in targeting multiple different anti­
gens. CAR-T therapies are undergoing clinical investigation against
other hematologic malignancies and solid tumors. Approaches to
develop allogeneic CAR-T therapies are also being explored with the
aim of having an off-the-shelf product that could be used in a number
of patients rather than generating each treatment specifically for one
recipient.
Cancer Cell Biology
Another approach utilizing lymphocytes to treat cancer involves
utilization of autologous tumor-derived T cells. Tumor-infiltrating
lymphocyte therapy in combination with IL-2 is now approved for
the treatment of melanoma. Given previously demonstrated efficacy
against other cancers, such as RCC, tumor-infiltrating lymphocyte
therapy may eventually be approved for other cancers as well. However,
technical issues of getting adequate expansion of the cells may limit
this approach.
The immune response against cancers may also be able to be
enhanced through targeting of proteins or cells (e.g., regulatory T cells)
involved in normal homeostatic control to prevent autoimmune
damage to the host but that malignant cells and their stroma can
also utilize to inhibit the immune response directed against them. A
component of this process includes a number of immune checkpoints
that involve interaction of proteins on the surface of effector T cells
with proteins on self-cells (or cancer cells that arise from normal cells)
that inhibit activation of the T cells. By inhibiting the binding of the
proteins involved in this process, the brake on the effector T cells are
released and they can be activated. The presence of neoantigens (e.g.,
mutant proteins) enhances the activation of the T cells against cancer
cells as compared to normal cells. Sufficient clinical antitumor activity
has been seen for monoclonal antibodies targeting various proteins
involved in this process, including CTLA-4, PD-1, PD-L1, and LAG3
(others continue to be explored), for them to be approved. These are
Tumor cells
Elaboration of
immunosuppressive
cytokines
TGF-β
Interleukin-4
Interleukin-6
Interleukin-10
Immunosuppressive
immune cells
PART 4
Oncology and Hematology
T regulatory cells
CD11+ granulocytes
Macrophages
FIGURE 77-13  Tumor-host interactions that suppress the immune response to the tumor.
co-inhibitory molecules that are expressed on the surface of cancer
cells, and/or cells of the immune system, and/or stromal cells and are
involved in inhibiting the immune response against both normal cells
(their normal protective mechanism for the host) and also cancer cells
that use this inhibitory process to evade immune-mediated cell death
(Figs. 77-13 and 77-14). This approach has had clinical activity against
a wide variety of cancers. A monoclonal antibody directed against
CTLA-4 is approved for the treatment of melanoma and several other
malignancies, and antibodies targeting PD-1 or PD-L1 are approved
for use against melanoma, RCC, lung cancer (both non-small-cell lung
and small-cell lung), head and neck cancer, nasopharyngeal cancer,
urothelial cancer, cervical cancer, endometrial cancer, hepatocellular
carcinoma, gastric cancer, esophageal cancer, cutaneous squamous cell
carcinoma, basal cell carcinoma, Merkel cell cancer, primary B-cell
mediastinal lymphoma, Hodgkin’s lymphoma, and in a cancer-agnostic
PD-L1
PD-L1
Cancer cells
CD28
CD80/86
MHC
CD80/86
CTLA-4
Tumor
antigens (TA)
Antigen-presenting
cell/dendritic cell
FIGURE 77-14  Inhibition of T-cell activation against cancer cells by engagement of co-inhibitory molecules including PD-1, PD-L1, and CTLA-4 and reversal of this
inhibition by antibodies against these proteins. The red ovals in the T cell indicate inhibitory signals, and the green oval indicates stimulatory signals.
T-cell inactivation
Induction of CTLA-4
Induction of PD-1
Cell signaling disruption
Class I MHC loss
in tumor cells
STAT-3 signaling
loss in T cells
Generation of
indoleamine 2,
3-dioxygenase
Degradation of
T-cell receptor
ζ chain
approach, cancers with high microsatellite instability (MSI) or high
tumor mutational burden (TMB).
They continue to be evaluated against other malignancies as well.
The combination of anti-CTLA-4 and anti-PD-1 antibodies has been
approved for treatment of a number of malignancies, including mela­
noma, RCC, HCC, NSCLC, mesothelioma, and MSI-high metastatic
colorectal cancers. Specific determinants of response to immune
checkpoint inhibitors are still being defined, but in addition to high
PD-L1 expression, the presence of increased neoantigens in the tumor,
such as seen in patients with MSI-high and TMB-high cancers, may be
one important determinant of better responses.
A number of other proteins are involved in controlling the immune
response (both ones that enhance activity [e.g., CD27 and CD40] as
well as ones involved in inhibiting response [e.g., TIM-3, TIGIT]).
Antibodies have been developed to modulate function of these
Anti-PD-L1
antibodies
Anti-PD-1
antibodies
PD-1
+
–
PD-1
+
+
MHC
T-cell
receptor
T cell
receptor
–
+
Cancer cell
T cell
Anti-CTLA-4
antibodies

07 - 78 Principles of Cancer Treatment
78 Principles of Cancer Treatment
proteins, and many are in clinical development for cancer therapy.
In addition, various combinations targeting more than one protein
involved in modulating the immune response against cancers or with
other anticancer approaches (targeted agents, chemotherapy, radia­
tion therapy) that may lead to enhanced antitumor activity are also
being explored. An important aspect of these approaches is balancing
sufficient release of the negative control of the immune response to
allow immune-mediated attack on the tumors while not allowing too
much of an immune response against normal tissues and thus induc­
ing severe autoimmune effects (e.g., against lung, liver, skin, thyroid,
pituitary gland, gastrointestinal tract, or other organs). As is true for
other immunotherapeutic approaches against cancer, major efforts are
ongoing to better understand the mechanism of immune toxicity from
these approaches and, therefore, ways of controlling this while not
abrogating the antitumor effects. Improved knowledge of the biology
of the interactions between the immune system and cancers continues
to be rapid with the promise for additional significant improvements
in use of immunotherapy to treat cancer.
Given the success of vaccines against multiple viruses, many efforts
have been made over decades to develop anticancer vaccines that would
induce a sufficient immune response to lead to killing of cancer cells or
even potentially prevention. This has been largely unsuccessful for the
treatment of established cancers, although three vaccines are approved
for use in cancer care: bacillus Calmette-Guérin (BCG) for intravesical
treatment of superficial bladder cancer, sipuleucel-T for prostate can­
cer, and talimogene laherparepvec for direct injection into melanoma.
Except for BCG, and then only for superficial bladder cancer, these
have had relatively limited effectiveness. Perhaps more promising
are vaccines combined with other forms of immunotherapy. Benefit
may be enhanced by using a vaccine in combination with immune
checkpoint inhibition therapy to delay recurrence of resected high-risk
melanoma and provides hope that this approach may be effective in the
future. However, further studies are needed to confirm this.
IMPACT OF UNDERSTANDING CANCER
BIOLOGY ON PREVENTION AND EARLY
DETECTION
The biggest impacts on decreasing cancer mortality come from pre­
vention followed by early detection. In addition to the critical role
that new knowledge about cancer biology has in developing improved
treatment approaches, it is also critical in enhancing preventative and
early detection approaches. Examples in prevention include using
knowledge about the roles of certain viruses in the development of
some cancers to create vaccines for viruses (e.g., hepatitis B virus and
human papillomavirus) to decrease the risk of developing cancer from
these infections and using knowledge about how certain carcinogens
cause cancer to work on controlling or eliminating carcinogenic agents
(e.g., cigarette smoking and asbestos). The development of sensitive
methods for detecting circulating tumor DNA holds promise for earlier
detection of cancer, although this has not yet been firmly established.
Imaging agents for specific tissues (such as the use of proteins highly
expressed on specific cancer tissues including prostate-specific mem­
brane antigen PET imaging to detect prostate cancer or HER2 to detect
a subset of breast, gastric, and other cancers) or potentially against
mutant proteins found in cancers (e.g., KRAS or p53 mutations) hold
promise for earlier and more specific detection of cancer. As more is
learned about cancer biology, this knowledge will also continue to be
applied in preventative and early detection strategies.
SUMMARY
Just as human biology is complex, cancer biology is complex. Although
each of the biological aspects of cancers and examples of targeting
them has been addressed individually, clearly there is complicated
cross-talk between these that occurs in all cancers that needs to be
better understood to optimally treat different cancers. The explosion
of information on tumor cell biology, metastasis, and tumor-host
interactions (including angiogenesis, other tumor-stromal interactions,
and immune evasion by tumors) has ushered in a new era of rational
targeted therapy for cancers as well as the potential for individualized
therapy. Furthermore, it has become clear that specific molecular fac­
tors detected in individual tumors (gene mutations, gene expression
profiles, miRNA expression, overexpression of specific proteins) can be
used to tailor therapy and maximize antitumor effects.
Potentially of even greater impact on decreasing deaths from can­
cer, better understanding of the biology of early cancer development
should ultimately lead to better approaches for prevention. And tech­
nologic development to improve sensitivity and specificity in detect­
ing cancer-specific molecules (e.g., mutated genes) provide hope that
approaches for earlier detection of cancer can be developed.
■
■FURTHER READING
Agudo J et al: Targeting cancer cell dormancy. Nat Rev Cancer 24:97,
2024.
Bhullar KS et al: Kinase-targeted cancer therapies: Progress, chal­
lenges and future directions. Mol Cancer 17:48, 2018.
de Visser KE, Joyce JA: The evolving tumor microenvironment: From
cancer initiation to metastatic outgrowth. Cancer Cell 41:374, 2023.
Finley LWS: What is cancer metabolism? Cell 186:1670, 2023.
Fujii M et al: Decoding the basis of histological variation in human
cancer. Nat Rev Cancer 24:141, 2024.
Gacche RN: Changing landscape of anti-angiogenic therapy: Novel
approaches and clinical perspectives. Biochim Biophys Acta Rev
Cancer 1878:189020, 2023.
Gerstberger S et al: Metastasis. Cell 186:1564, 2023.
Hanahan D: Hallmarks of cancer: New dimensions. Cancer Discov
CHAPTER 78
12:31, 2022.
Matthews HK et al: Cell cycle control in cancer. Nat Rev Mol Cell
Principles of Cancer Treatment
Biol 23:74, 2022.
Pottier C et al: Tyrosine kinase inhibitors in cancer: Breakthrough
and challenges of targeted therapy. Cancers (Basel) 12:731, 2020.
Prager BC et al: Cancer stem cells: The architects of the tumor ecosystem.
Cell Stem Cell 24:41, 2019.
Reiter JG et al: An analysis of genetic heterogeneity in untreated cancers.
Nat Rev Cancer 19:639, 2019.
Romesser PB, Lowe SW: The potent and paradoxical biology of cellular
senescence in cancer. Annu Rev Cancer Biol 7:207, 2023.
Sharma P, et al: Immune checkpoint therapy: Current perspectives
and future directions. Cell 186:1652, 2023.
Tomuleasa C et al: Therapeutic advances of targeting receptor tyro­
sine kinases in cancer. Sig Transduct Target Ther 9:201, 2024.
Yang K et al: Antigen presentation in cancer: Mechanisms and clinical
implications for immunotherapy. Nat Rev Clin Oncol 20:604, 2023.
Yuan J, Ofengeim D: A guide to cell death pathways. Nat Rev Mol Cell
Biol 25:379, 2024.
Edward A. Sausville, Dan L. Longo
Principles of Cancer
Treatment
CANCER PRESENTATION
Localized or systemic cancer is frequent in the differential diagnosis
of a variety of common complaints. Affording patients the greatest
opportunity for cure or meaningful prolongation of life is greatly aided
by diagnosis of cancer early in its natural history. The spectrum of
possible cancer-related interventions to make cure possible is shown
in Table 78-1.
■
■DETECTION OF A CANCER
The term cancer, as used here, is synonymous with the term tumor,
whose original derivation from Latin simply meant “swelling,” not
TABLE 78-1  Spectrum of Cancer-Related Interventions
Asymptomatic patient screening (breast, cervix, colon, some lung)
Consideration of cancer in a differential diagnosis
Physical examination, imaging, or endoscopy to define a possible tumor
Phlebotomy for molecular studies and circulating tumor cell characterization
Diagnosis of cancer by biopsy or removal:
  Routine histology
  Specialized histology: immunohistochemistry
  Molecular studies
  Cytogenetic studies
Staging the cancer: Where has it spread?
Imaging (computed tomography, magnetic resonance imaging, positron emission
tomography)
Treatment
  Localized (surgical removal with or without local radiation therapy and/or
topical therapy; may be curative)
  Local plus systemic, multimodality: cure advanced disease, reverse organ
compromise
  Systemic, adjuvant (cure micrometastases; all evident disease has been
locally treated)
  Systemic, neoadjuvant (before local therapy to improve local and systemic
results)
  Systemic, palliative (improve symptoms, quality of life, progression-free
PART 4
Oncology and Hematology
survival)
Supportive care
  During treatment: related to tumor effects on patient
  During treatment: to counteract side effects of treatment
After treatment: to ameliorate the adverse effects of treatment
Palliative and end of life
  When useful treatments are not feasible or desired
otherwise specified. Swelling reflects increased interstitial fluid pres­
sure and increased cellular and stromal mass, compared to normal
tissue. Leukemia, a cancer of the blood-forming tissues, presents in
a disseminated form frequently without tumor masses. Tumors can
also present by organ dysfunction, such as dyspnea on exertion from
anemia caused by leukemia replacing normal marrow, cough from
lung cancers, jaundice from tumors blocking bile ducts, or neurologic
signs from gliomas. Hemorrhage frequently results from involvement
of hollow viscera, but also may reflect altered platelet number or blood
coagulation. Tumors may also present with a “paraneoplastic syn­
drome” owing to the effects of substances the tumor secretes. Although
the fraction of patients with cancer as the basis for a presenting sign or
symptom may be low, the implications of missing an early-stage tumor
call for considering cancer as a basis for persistent signs or symptoms.
Evidence of a tumor’s existence can come from careful physical
examination, e.g., enlarged lymph nodes in lymphomas or palpable
mass in a breast or soft tissue site. A mass may also be detected or con­
firmed by an imaging modality (e.g., x-ray, magnetic resonance imag­
ing [MRI], or ultrasound). Endoscopy may directly visualize a tumor.
■
■ESTABLISHING A CANCER DIAGNOSIS
Once a potential tumor is defined, establishing the diagnosis is the
next step. This requires a biopsy procedure in most circumstances
and pathologic confirmation that cancer is present; very rarely, where
biopsy would be definitely injurious and imaging modalities are
unequivocal, such as with a likely brainstem glioma, treatment might
be reasonably considered based on clinical and imaging evidence with­
out biopsy. In addition to light microscopy, biopsied tissue also allows
definition of genetic abnormalities and protein expression patterns to
recommend best treatment (Table 78-2).
The extent of specialized testing needs to be tailored to an individual
patient’s case. Global DNA sequencing of genes expressed in tumors
has not been shown to convey conclusive advantage in terms of sur­
vival. But the aggregate “mutational burden” present in tumors and
the intactness of DNA repair genes (e.g., breast cancer susceptibility 1
TABLE 78-2  Diagnostic Biopsy: Standard-of-Care Molecular and
Special Studies to Be Considered
All solid tumors
  Tumor mutational burden
  Microsatellite instability DNA repair pathway intactness
  Homologous recombination DNA repair pathway intactness
Breast cancer: primary and suspected metastatic
  Breast cancer susceptibility 1 and 2 (BRCA1/2) gene mutations
  Hormone receptor expression: estrogen, progesterone
  HER2/neu oncoprotein
  PI3KA mutation status
Lung cancer: primary and suspected metastatic
  If nonsquamous non-small-cell:
    Epidermal growth factor receptor (EGFR) mutation
    ALK, ROS1, NRTK, NRG1 gene fusion
    BRAF V600E mutation
    Programmed cell death ligand 1 (PD-L1) expression
Colon cancer: suspected metastatic
  KRAS mutation
  BRAF V600E mutation
Gastrointestinal stromal tumor
  KIT mutation
Melanoma
  BRAF mutation
  c-kit expression and KIT mutation if present
Pancreatic cancer
  BRCA1/2 mutation
Prostate cancer
  BRCA1/2 mutation
Thyroid cancer
  RET gene alterations (mutations, translocations, amplification)
Gliomas
  1p/19q co-deletion
  Alkylguanine alkyltransferase promoter methylation
  Isocitrate dehydrogenase 1 and 2 mutation
Leukemia (peripheral blood mononuclear cells and/or bone marrow)
  Cytogenetics
  Flow cytometry
  Treatment-defining chromosomal translocations/mutations
    Bcr-Abl fusion protein
    t(15;17)
    Inversion 16
    t(8;21)
  FMS-associated tyrosine kinase (FLT3) mutation
  Nucleophosmin gene mutational status
  Isocitrate dehydrogenase 1 and 2 mutation
Lymphoma
  Immunohistochemistry for CD20, CD30, and B- and T-cell markers
  Treatment-defining chromosomal translocations:
    t(14;18)
    t(8;14)
  Translocations involving ALK gene
and 2 [BRCA1/2], microsatellite instability, homologous recombination
pathway–associated genes) may suggest valuable treatment courses in
tumors without curative potential.
Optimally, an excisional biopsy occurs, in which the entire tumor
mass is removed with a margin of normal tissue surrounding it. If an
excisional biopsy cannot be performed, incisional biopsy is the proce­
dure of second choice: a wedge of tissue is removed, trying to include
the majority of the cross-sectional diameter to minimize sampling
error. Biopsy techniques that involve cutting into tumor risk facilitating
the spread of the tumor. Consideration with a surgeon of whether the
biopsy approach is a potential prelude to a curative surgery may inform
the approach taken. Core-needle biopsy usually obtains considerably
less tissue but can provide information to plan a treatment. Fine-needle
aspiration generally yields a suspension of cells from a mass. If positive
for cancer, it may allow inception of systemic treatment, or it can pro­
vide a basis for planning a more extensive surgical procedure. A “negative”
fine-needle aspiration cannot be taken as definitive evidence that a
tumor is absent. In some instances, features of diagnostic imaging are
sufficient to make a reliable diagnosis without obtaining tissue, usually
with presence of a tumor-associated circulating diagnostic marker, e.g.,
α fetoprotein in hepatocellular carcinoma or prostate-specific antigen
(PSA) in prostate cancer with apparent typical metastatic disease.
■
■CANCER STAGING
Defining the extent of disease determines whether localized treat­
ments, “combined-modality” approaches, or systemic treatments
should initially be considered. Radiographic and other imaging tests
can be helpful in defining the clinical stage; pathologic staging docu­
ments the histologic presence of tumor in tissue biopsies. Lymph node
sampling in breast cancer, melanoma, lung, head and neck, colon, and
other intra-abdominal cancers may provide crucial information.
Staging systems define a “T” component related to the size of the
tumor or its invasion into local structures, an “N” component related
to the number and nature of lymph node groups with tumor involve­
ment, and an “M” component, based on the presence of local or distant
metastatic sites. The various TNM components are then aggregated to
stages, usually stage I to III or IV, depending on the anatomic site. The
numerical stages reflect similar long-term survival outcomes of the
respective TNM grouping stage after treatment tailored to the stage. In
general, stage I tumors are T1 (reflecting small size), N0 or N1 (reflect­
ing no or minimal node spread), and M0 (no metastases). Such earlystage tumors are usually amenable to curative approaches with local
treatments. On the other hand, stage IV tumors have metastasized to
distant sites or locally invaded viscera in a nonresectable way. They are
treated with palliative intent, except for those diseases with exceptional
sensitivity to systemic treatments such as chemotherapy or immuno­
therapy. Also, the TNM staging system is not useful in diseases such as
leukemia, where bone marrow infiltration is never localized, or central
nervous system (CNS) tumors, where tumor histology and the extent
of feasible resection are more important in driving prognosis.
CANCER TREATMENT
The goal of cancer treatment is first to eradicate the cancer. If this is
not possible, the goal shifts to palliation: amelioration of symptoms and
preservation of quality of life while striving to extend life. When cure
of cancer is possible, cancer treatments may be undertaken despite the
certainty of severe toxicities, but these may produce toxicity with no
benefit. Conversely, when the clinical goal is palliation, careful atten­
tion to minimizing the toxicity of treatments becomes a significant
goal.
The two main types of cancer treatment are local and systemic. Local
treatments include surgery, radiation therapy (including photody­
namic therapy), and ablative approaches, including radiofrequency and
thermal or cryosurgical approaches. Systemic treatments include che­
motherapy (including hormonal therapy and molecular targeted ther­
apy) and biologic therapy (including immunotherapy). The modalities
are often used in combination. Oncology, the study of tumors including
treatment approaches, is a multidisciplinary effort with surgical, radia­
tion, and internal medicine–related areas of oncologic expertise.
Normal organs and cancers share the property of having a popula­
tion of cells actively progressing through the cell cycle, with their divi­
sion providing a basis for organ or tumor growth, and a population of
cells not in cycle; these include stem cells, whose properties are being
elucidated. Cancer stem cells serve as a basis for tumor initiating or
repopulating cells. Tumors follow a Gompertzian growth curve
(Fig. 78-1), with the growth fraction of a neoplasm high with small
tumor burdens but declining until, at the usual time of diagnosis
(tumor burden of 1–5 × 109) the growth fraction is only 1–4% for many
Growth fraction
Growth rate
Percent of maximum
Lethal
Tumor size
Clinically detectable
Tumor burden
logs of cells
Time, days
FIGURE 78-1  Gompertzian tumor growth. The growth fraction of a tumor declines
exponentially over time (top), peaking before it is clinically detectable (middle).
Tumor size increases slowly, goes through an exponential phase, and slows again
as the tumor has limitation of nutrients or host regulatory influences occur. The
maximum growth rate occurs at 1/e, the point at which the tumor is about 37% of its
maximum size (marked with an X). Tumor becomes detectable at a burden of about
109 (1 cm3) cells and kills the patient at a tumor cell burden of about 1012 (1 kg).
CHAPTER 78
solid tumors. Thus the most rapid growth rate occurs before the tumor
is detectable. An alternative explanation for such growth properties
may also emerge from the ability of tumors at metastatic sites to recruit
circulating tumor cells from the primary tumor or other metastases.
Key features of tumor growth are the ability to stimulate new sup­
porting stroma through angiogenesis and ingrowth of fibroblasts and
immune cells (Chap. 77).
Principles of Cancer Treatment
LOCALIZED CANCER TREATMENTS
■
■SURGERY
Surgery is the most effective means of treating cancer. At least 40% of
cancer patients are cured by surgery. Unfortunately, many patients with
solid tumors have disease not practically removable. “Palliative” surger­
ies, however, may afford local control of tumor, preserve organ func­
tion, and achieve debulking that permits more effective subsequent
therapy, while allowing more detailed staging. Cancer surgery aiming
for cure is usually planned to excise the tumor completely with an
adequate margin of normal tissue (the margin varies with the tumor and
the anatomy). Such a resection is defined as an R0 resection. R1 and R2
resections, in contrast, are imprecisely defined pathologically as having
microscopic or macroscopic, respectively, tumor at resection margins.
Such outcomes may be the basis for reoperation to obtain optimal mar­
gins if feasible and of likely clinical utility. Extending the procedure to
resect draining lymph nodes obtains prognostic information and may,
in some anatomic locations, improve survival.
Laparoscopic approaches are being used for primary abdominal and
pelvic tumors, although with certain tumors (e.g., uterine and cervix),
controversy exists as to the desirability of laparoscopic tumor removal.
Lymph node spread may be assessed using the sentinel node approach,
in which the first draining lymph node is defined by injecting a dye
or radioisotope into the tumor site at operation and then resecting
the first node to turn blue or collect isotope. Sentinel node assess­
ment appears to provide information without the risks (lymphedema,
lymphangiosarcoma) associated with resection of all regional nodes.
Advances in adjuvant chemotherapy (given systemically after removal
of all local disease without evidence of metastatic disease) and radia­
tion therapy following surgery have permitted a decrease in the extent
of primary surgery. Thus, “lumpectomy” with radiation therapy is as
effective as modified radical mastectomy for breast cancer, and limbsparing surgery followed or preceded by adjuvant radiation therapy
and chemotherapy has replaced amputation for most childhood
rhabdomyosarcomas and osteosarcomas. More limited surgery spares
organ function, as in larynx and bladder cancer. In some settings (e.g.,
bulky testicular cancer or stage III breast cancer), surgery is not the
first treatment modality used. After diagnostic biopsy, chemotherapy
and/or radiation therapy is delivered, followed by a surgical procedure
to remove residual masses; this is called neoadjuvant therapy. Coordi­
nation among the surgical oncologist, radiation oncologist, and medi­
cal oncologist is crucial.
Surgery may be curative in a subset of patients with metastatic
disease. Patients with limited lung metastases from osteosarcoma may
be cured by resection of the lung lesions. In patients with colon cancer
who have fewer than five liver metastases restricted to one lobe and
no extrahepatic metastases, hepatic lobectomy may produce longterm disease-free survival in 25% of selected patients. In the setting of
hormonally responsive tumors, oophorectomy may eliminate estrogen
production, and orchiectomy may reduce androgen production, hor­
mones that drive many breast and all prostate cancers, respectively.
In selecting a surgeon or center for primary cancer treatment, consid­
eration must be given to the volume of cancer surgeries undertaken
by the site. Studies in a variety of cancers have shown that increased
annual procedure volume appears to correlate with outcome. Surgery
is used in a number of ways for palliative or supportive care of the
cancer patient. These include insertion and care of central venous
catheters, control of pleural and pericardial effusions and ascites, caval
interruption for recurrent pulmonary emboli, stabilization of cancerweakened weight-bearing bones, and control of hemorrhage, among
others. Surgical bypass of gastrointestinal, urinary tract, or biliary tree
obstruction or spinal cord decompression can alleviate symptoms and
may prolong survival. Splenectomy may relieve symptoms and reverse
hypersplenism. Intrathecal or intrahepatic therapy relies on surgical
placement of appropriate infusion portals. Surgery may correct other
treatment-related toxicities such as adhesions or strictures. Plastic and
reconstructive surgery can correct the effects of disfiguring primary
treatment. Surgery is also a tool valuable in the prevention of cancers
in high-risk populations. Prophylactic mastectomy, colectomy, oopho­
rectomy, and thyroidectomy are mainstays of cancer prevention in
inherited cancer susceptibility syndromes.
PART 4
Oncology and Hematology
■
■RADIATION
Radiation Biology and Medicine 
Therapeutic radiation is gen­
erally ionizing, causing breaks in DNA and generation of free radicals
from cell water that damage cancer cell membranes, proteins, and
organelles.
Ionizing radiation + H2O → H2O+ + e−
H2O+ + H2O → H3O+ + OH•
OH• → cell damage
Radiation damage is augmented by oxygen; hypoxic cells are more
resistant. X-ray and gamma-ray photons are the forms of ionizing
radiation most commonly used to treat cancer. Particulate ionizing
radiation using protons has also become available.
Radiation dose is quantitated based on the amount of energy
absorbed by the tumor, not on radiation generated by the machine. The
International System (SI) unit for radiation dose is the Gray (Gy): 1 Gy
refers to 1 J/kg of tissue; 1 Gy equals 100 centigrays (cGy) of absorbed
dose. A historically used unit appearing in the oncology literature,
the rad (radiation absorbed dose), is defined as 100 ergs of energy
absorbed per gram of tissue and is equivalent to 1 cGy. Radiation dose
is measured by placing detectors at the body surface or in radiated
phantoms that resemble human form and substance. The features that
make a particular cell more or less sensitive to radiation involve DNA
repair proteins that, in their physiologic role, protect against environ­
mentally related DNA damage.
Localized Radiation Therapy 
Radiation effect is influenced by
three determinants: total absorbed dose, number of fractions, and time
of treatment. A typical course of radiation therapy should be described
as 4500 cGy delivered to a particular target (e.g., mediastinum) over
5 weeks in 180-cGy fractions. Most curative radiation treatment
programs are delivered once a day, 5 days a week, in 150- to 200-cGy
fractions. Nondividing cells are more resistant than dividing cells;
delivering radiation in repeated fractions is done to expose a larger
number of tumor cells that have entered the division cycle. The energy
of the radiation determines its ability to penetrate tissue. Low-energy
x-rays (150–400 kV) scatter when they strike the body, resulting in
more damage to adjacent normal tissues and less radiation deliv­
ered to the tumor. Megavoltage radiation (>1 MeV) has very low
lateral scatter; this produces a skin-sparing effect, more homogeneous
distribution of the radiation energy, and greater deposit of the energy
in the tumor, or target volume. The transit volume includes the tissues
through which the beam passes to the target volume. Computational
approaches and delivery of many beams to converge on a target volume
are the basis for “gamma knife” and related approaches to deliver high
doses to tumor, sparing normal tissue.
Therapeutic radiation is delivered in three ways: (1) teletherapy, with
focused beams of radiation generated at a distance and aimed at the
tumor within the patient; (2) brachytherapy, with encapsulated sources
of radiation implanted directly into or adjacent to tumor tissues; and
(3) systemic therapy, with radionuclides administered, for example,
intravenously but perhaps targeted by some means to a tumor site. For
example, systemically administered isotopes of iodide have an impor­
tant role in the treatment of thyroid neoplasms, owing to the selective
upregulation of the iodide transporter in the tumor cell compartment.
Likewise, isotopes of samarium and radium have been found useful
in the palliation of bony metastases of prostate cancer owing to their
selective deposition at the tumor-bone matrix interface.
Teletherapy with x-ray or gamma-ray photons is the most commonly
used form of radiation therapy and also delivers particulate forms of
radiation such as proton beams. The difference between photons and
protons relates to volume with greatest delivery of energy: protons have
a narrow range of energy deposition. Electron beams are a particulate
form of radiation that, in contrast to photons and protons, have a very
low tissue penetrance and are used to treat cutaneous tumors. Certain
drugs used in cancer treatment may also act as radiation sensitizers.
For example, compounds that incorporate into DNA (e.g., halogenated
pyrimidines, cisplatin) augment radiation effects at local sites and are
important adjuncts to radiation of certain tumors (e.g., squamous head
and neck, uterine cervix, and rectal cancers).
Toxicity of Radiation Therapy 
Although radiation therapy is
most often administered to a local region, systemic effects, including
fatigue, anorexia, nausea, and vomiting, may develop that are related
in part to the volume of tissue irradiated, dose fractionation, radiation
fields, and individual susceptibility. Radiation-injured tissues release
cytokines that act systemically to produce these effects. Bone is among
the most radio-resistant organs, with radiation effects being manifested
mainly in children through premature fusion of the epiphyseal growth
plate. By contrast, the male testis, female ovary, and bone marrow are
the most sensitive organs. Any bone marrow in a radiation field will
be eradicated by therapeutic irradiation. Organs with less need for cell
renewal, such as heart, skeletal muscle, and nerves, are more resistant
to immediate radiation effects. In radiation-resistant organs, the vas­
cular endothelium is the most sensitive component. Acute toxicities
include mucositis, skin erythema (ulceration in severe cases), and bone
marrow toxicity. Often these can be alleviated by periodic interruption
of treatment.
Chronic toxicities are more serious. Radiation of the head and neck
region produces thyroid failure; cataracts and retinal damage can lead
to blindness; salivary glands stop making saliva, which leads to dental
caries and poor dentition. Mediastinal irradiation increases myocardial
vascular disease. Other late vascular effects include chronic constric­
tive pericarditis, lung fibrosis, viscus stricture, spinal cord transection,
and radiation cystitis or enteritis.
A serious late toxicity is the development of hematologic tumors or
second solid tumors in or adjacent to the radiation fields. Such tumors
can develop in any organ or tissue and occur at a rate of ~1% per year
beginning in the second decade after treatment.
■
■OTHER LOCALIZED CANCER TREATMENTS
Endoscopy allows placement of stents to unblock viscera, palliating,
for example, gastrointestinal or biliary obstructions. Radiofrequency
ablation (RFA) refers to microwave nonionizing radiation to induce
thermal injury within a volume of tissue. RFA can be useful in the con­
trol of metastatic lesions, particularly in liver, that may threaten biliary
drainage. Cryosurgery uses extreme cold to sterilize lesions in certain
sites, such as prostate and kidney, at a very early stage, eliminating the
need for modalities with more side effects such as surgery.
Some chemicals (porphyrins, phthalocyanines) are preferentially
taken up by cancer cells. When intense light, delivered by a laser, is
shone on cells containing these compounds, free radicals are gener­
ated and the cells die. Such phototherapy is used to treat skin cancer;
ovarian cancer; and cancers of the lung, colon, rectum, and esophagus.
Palliation of recurrent locally advanced disease can sometimes be dra­
matic and last many months.
Infusion of chemotherapeutic or biologic agents or radiationbearing delivery devices such as isotope-coated glass spheres into local
sites through catheters have been used to treat disease limited to that
site; in selected cases, prolonged control of truly localized disease has
been possible.
SYSTEMIC CANCER TREATMENTS
The concept that systemically administered chemicals might have a
useful effect on cancers was historically derived from three sets of
observations. Paul Ehrlich in the nineteenth century observed that
different dyes reacted with different cell and tissue components. He
hypothesized the existence of “magic bullets” that might bind to
tumors, owing to the affinity of the agent for the tumor. Observation
of the toxic effects of certain mustard gas derivatives on the bone mar­
row during World War I suggested that smaller doses of these agents
might be used to treat tumors of marrow-derived cells. Finally, the
fact that tumors from hormone-responsive tissues, e.g., breast tumors,
could shrink after oophorectomy led to the idea that endogenous or
exogenous substances might modulate tumor growth by altering its
regulatory biology. Chemicals achieving each of these goals are cur­
rently used as cancer chemotherapy agents.
Anecdotal reports of tumor regression following intratumoral
injection of bacterial extracts raised the possibility of immune system–
mediated tumor regression. Serotherapy of infectious disease in the
preantibiotic era encouraged analogous efforts to develop vaccine- and
antibody-based treatments for cancer. Administration of autologous
immune cells obtained by pheresis procedures from a patient or puri­
fied from a patient’s removed tumor, activated by cytokines ex vivo,
achieved durable disease control in a small fraction of patients with
certain tumors, particularly renal cell cancers or melanoma. These
observations provided the rationale for more modern efforts to treat
tumors using cell-mediated immunity.
Systemic cancer treatments are of three broad types. Cytotoxic
chemotherapy agents are “small molecules” (generally with molecular
mass <1500 Da) that cause major regression of experimental tumors
growing in animals. These agents mainly target DNA structure or
segregation of chromosomes in mitosis. Cancer molecular target
therapies refer to small molecules designed and developed to interact
with a defined macromolecule important in maintaining the malig­
nant state. As described in Chap. 77, successful tumors have activated
biochemical pathways that lead to uncontrolled proliferation through
the action of hormone receptor proteins, oncogene products, loss of
cell cycle inhibitors, or loss of cell death regulation, and have acquired
the capacity to replicate chromosomes indefinitely, invade, metasta­
size, and evade the immune system. Cancer biologic therapies are most
frequently macromolecules, cells, or cell extracts that have a particular
target (e.g., anti–growth factor receptor, cytokine, or immunomodula­
tory antibodies) or may have the capacity to induce a host immune
response to kill tumor cells. Most recent additions to cancer biologic
therapies include genetically modified cells that directly attack tumor
cells and tumor-infecting viruses that can kill tumor cells but also elicit
host antitumor immune responses.
■
■SYSTEMIC CANCER THERAPY OVERVIEW
General Principles 
The therapeutic index of any drug is the degree
of separation between toxic and therapeutic doses. Really useful drugs
have large therapeutic indices, and this usually occurs when the drug
target is expressed in the disease-causing compartment as opposed to
the normal compartment. Cytotoxic chemotherapeutic agents have the
unfortunate property that their main targets, DNA and microtubules,
are present in both normal and tumor tissues. Therefore, they have
relatively narrow therapeutic indices. Targeted agents can also cause
effects on their target in normal tissues, or “off-target” effects on unre­
lated targets in organs experiencing damage. Biologic therapies may
elicit misdirected immune responses on normal organ function. A key
activity in oncology drug development is striving to administer a dose
that can convey benefit with a minimal or tolerable side effect profile.
Figure 78-2 illustrates steps in cancer drug development. Follow­
ing demonstration of antitumor activity in animal models, potentially
useful anticancer agents are further evaluated to define an optimal
schedule of administration and suitable drug formulation. Safety test­
ing in two animal species on an analogous schedule of administration
defines the starting dose for a phase 1 trial in humans, usually but not
always in patients with cancer who have exhausted “standard” (already
approved) treatments. The initial dose is usually one-sixth to one-tenth
of the dose just causing easily reversible toxicity in the more sensitive
animal species. If the agent is not intrinsically toxic, doses of drug
achieving fractions of the useful plasma concentrations from model
systems are studied. Escalating doses of drug are then given during
the human phase 1 trial until reversible toxicity is observed or the
desired drug concentration is achieved. Dose-limiting toxicity (DLT)
defines a dose that conveys greater toxicity than would be acceptable
in routine practice, allowing definition of a lower maximum-tolerated
dose (MTD). The occurrence of toxicity is, if possible, correlated with
plasma drug concentrations. The MTD or a dose just lower than the
MTD is usually the dose suitable for phase 2 trials, where a fixed dose
and schedule is administered to a relatively homogeneous set of patients
with a particular tumor type. If no toxicity has emerged in phase 1 tri­
als, administration of the optimal biologic dose to achieve effective
drug concentrations is undertaken. A partial response historically was
defined as a decrease of at least 50% in a tumor’s bidimensional area
obtained by imaging; more recent response criteria (e.g., Response
Evaluation Criteria in Solid Tumors [RECIST]) may use a 30% decrease
in aggregate unidimensional areas of target lesions. Response criteria
for immunologically directed agents may allow a substantial transient
increase in tumor volume as long as a patient’s clinical status is stable,
as these agents may evoke inflammatory responses in tumors with
subsequent shrinkage or stabilization of lesions. A complete response
connotes disappearance of all tumor; progression of disease signifies
an increase in size of existing lesions by >25% from baseline or best
response or development of new lesions; stable disease fits into none of
the above categories.
CHAPTER 78
Principles of Cancer Treatment
In a phase 3 trial, evidence of improved overall survival or improve­
ment in the time to progression of disease on the part of the new drug
is sought in comparison to an appropriate control population. Data
from the entire process are the basis for application to a regulatory
agency to approve the new agent for commercial marketing.
Cancer drug clinical trials conventionally use a toxicity grading
scale where grade 1 toxicities do not require treatment, grade 2 toxici­
ties may require symptomatic treatment but are not life-threatening,
grade 3 toxicities are potentially life-threatening if untreated, grade
4 toxicities are actually life-threatening, and grade 5 toxicities result
in the patient’s death. Active efforts to quantitate effects of anticancer
agents on quality of life also frequently occur in early development of
oncology drugs.
Development of targeted agents may proceed differently. While
phase 1–3 trials are still conducted, focus on a particular tumor type
even in phase 1 may be enabled by molecular analysis to define target
expression in a patient’s tumor necessary for or relevant to the drug’s
action. Ideally, pharmacodynamic studies would also assess whether
the drug’s target has been affected. The failure of a targeted therapy can
Preclinical Model (e.g., mouse or rat)
Phase II
Untreated
Growth
delay
Tumor size
Rx
Cytostatic
Cytotoxic
Time
Unique patient number
Phase II
Unique patient number
PART 4
Oncology and Hematology
Time
Time on Rx
FIGURE 78-2  Steps in cancer drug discovery and development. Preclinical activity (top left) in animal models of cancers may be used as evidence to support the entry of the
drug candidate into phase 1 trials in humans to define a correct dose and observe any clinical antitumor effect. The drug may then be advanced to phase 2 trials directed
against specific cancer types, with rigorous quantitation of antitumor effects. Waterfall plots are a standard representation of how patients’ tumor sizes change in relation
to treatment, with predefined cutoffs defining progression of disease (20% increase in size) or partial response (30% decrease in size) serving as benchmarks of potential
valuable effect (top right). Swimmer plots (bottom left) allow the delineation of patients with especially long (or short) times on treatment even without response, another
basis in the former case for potential perceived clinical benefit of the treatment. Kaplan-Meier plots (bottom right) of survival indices in phase 3 comparative trials may allow
definition of superiority, inferiority, or no difference of treatment effect compared to standard or no treatment.
be either because the drug missed the target or it hit the target but the
target was not central to the tumor’s growth and survival. Within the
past decade, agents have been approved for clinical use not in relation
to an originating organ site of disease but across all organ types pos­
sessing certain molecular or biologic features.
Useful cancer drug treatment strategies using conventional chemo­
therapy agents, targeted agents, hormonal treatments, or biologicals
all have one of two valuable outcomes. They can induce cancer cell
death, resulting in tumor shrinkage with corresponding clinical ben­
efit evidenced by improvement in patient survival, or increase in time
until the disease progresses. Another potential outcome is induction of
cancer cell differentiation or dormancy with loss of tumor cell replica­
tive potential and reacquisition of phenotypic properties resembling
normal cells. Interaction of a chemotherapeutic drug with its target
induces a “cascade” of further signaling steps. These signals ultimately
lead to cell death by triggering proteases, nucleases, and endogenous
regulators of the cell death pathway (Fig. 78-3) or differentiation by
alteration of cancer genome function.
Targeted agents differ from chemotherapy agents in that they do
not indiscriminately cause macromolecular lesions but regulate the
action of specific driver molecules regulating processes considered
“hallmarks” of cancer, including unregulated proliferation, physiologic
cell death, gene expression, angiogenesis, and escape from immune
mechanisms retarding tumor development.
Strategies in Systemic Cancer Management 
The past 35 years
have witnessed a marked evolution in the systemic treatment of cancer
not amenable to cure by locally applied treatments. Nonspecific cyto­
toxic agents of limited efficacy for most patients but highly active and
curative in a minority disease types have been joined by targeted and
biologic therapies. Table 78-3, A lists those tumors considered curable
% change tumor
% alive (overall survival) or
% relapse free
Phase III
Treatment A
Treatment B or no Rx
by conventionally available chemotherapeutic agents even when dis­
seminated or metastatic. If a tumor is truly localized to a single site,
consideration of surgery or primary radiation therapy should be
given as well. Chemotherapy may be used as part of multimodality
approaches to offer primary treatment to a clinically localized tumor
(Table 78-3, B), interdigitated with radiation and surgery. Chemother­
apy can be administered as an adjuvant, i.e., in addition to surgery or
radiation (Table 78-3, C), even after all clinically apparent disease has
been removed. This use of chemotherapy has curative potential in, for
example, lung, breast, and colorectal neoplasms, as it eliminates micro­
metastatic clinically unapparent tumor. Neoadjuvant chemotherapy
refers to administration of chemotherapy before any surgery or radia­
tion to a local tumor in an effort to enhance the effect of subsequent
local treatment.
Chemotherapy is routinely used in doses that produce reversible
acute side effects, primarily consisting of transient myelosuppression
with or without gastrointestinal toxicity (usually nausea). “High-dose”
chemotherapy regimens can produce markedly increased therapeutic
effect, although at the cost of potentially life-threatening complica­
tions that require intensive support, usually in the form of hemato­
poietic stem cell support from the patient (autologous) or from donors
matched for histocompatibility loci (allogeneic), or pharmacologic “res­
cue” strategies to block the effect of the high-dose chemotherapy on
normal tissues. High-dose regimens have curative potential in defined
clinical settings (Table 78-3, D).
If cure is not possible, chemotherapy may be undertaken with the
goal of palliating the tumor’s effect on the host (Table 78-3, E). In this
usage, value is perceived by the demonstration of improved symptom
relief, progression-free survival, or overall survival. The best data to
support these different therapeutic approaches result from clinical
research protocols. In the case of a new drug, these trials might be the
Tumor cell growth pathways
Tumor cell death pathways
Receptor-linked
tyrosine kinase
inhibitor
GDP
RAS
P
P
+
GTP
RAS
P13K
RAF/MEK
inhibitors
P
RAF
Metabolism
modulators
AKT
+
MTOR
Non receptor
linked
tyrosine kinase
inhibitor
MEK
Multi
kinase
inhibitors
Cell
division
Protein
synthesis
MAP
Nuclear export
inhibitors
DNA digestion
Nutrients,
O2
Gene products
CDK
inhibitor
Nucleus
Autophagy
Chromatin
epigenetic
modulators
HR
HR
RNA
Hormone
anatgonists
Immune
cells
Transcription
factor inhibitors
Blood vessels in
tumor stroma
FIGURE 78-3  Tumor growth and death pathways affected by targeted and cytotoxic agents. After a growth factor binds to its receptor (left side of figure), in the most
commonly activated cell proliferation pathway, increased tyrosine kinase activity occurs, either by autophosphorylation of receptor-linked kinases or through recruitment
of non-receptor-linked tyrosine kinases, which may also be active constitutively, without requiring a growth factor. This leads to docking of “adaptor” proteins to the
phosphorylated tyrosines. One important pathway activated occurs after exchange of GDP for GTP in the RAS family of proto-oncogene products. GTP-RAS activates
the RAF kinase, leading to a phosphorylation cascade of MEK and MAP kinases. Mutated KRAS inhibitors have been defined, as well as RAF isoform and MEK inhibitors. The
RAF/MEK/MAP kinase pathway ultimately alters gene function to activate cell cycle progression through cyclin-dependent kinases (CDKs). Another route to gene activation
utilizes hormone receptors (HRs) interacting with tissue-specific growth regulators such as steroid hormones to alter gene function leading to cell cycle activation.
Transcription factors acting at the level of RNA polymerase function at ensembles of gene promoters have proved difficult to target directly, but direct and indirect
modulators of transcription factor activity have been defined. Receptor and non-receptor linked tyrosine phosphorylation can lead to activation of phosphatidylinositol3-kinase (PI3K) to produce the phosphorylated lipid phosphatidylinositol-3-phosphate, which activates the AKT kinase to act downstream on the mammalian target of
rapamycin kinase (mTOR), directly increasing translation of key mRNAs for gene products regulating cell growth and stimulating cell metabolism by, for example, increasing
glucose transporter function. Cytotoxic agents cause cell death (right side of figure) through apoptosis and/or induction of autophagy. Apoptosis is also stimulated by
interruption of growth factor (GF) cytokine death signals (e.g., tumor necrosis factor receptor [TNF-R]), which activate “upstream” cysteine aspartyl proteases (caspases)
to directly digest cytoplasmic and nuclear proteins, resulting in activation of “downstream” caspases; these activate nucleases to cause DNA fragmentation, a hallmark
of apoptosis. Chemotherapy agents that create lesions in DNA or alter mitotic spindle function activate gene function to alter mitochondrial integrity. The antiapoptotic
protein BCL2 attenuates mitochondrial toxicity, whereas proapoptotic gene products such as BAX, PUMA, etc., antagonize the action of BCL2. Damaged mitochondria
release cytochrome C and apoptosis-activating factor (APAF), which activate caspase 9 to cause DNA fragmentation. In addition, membrane damage with activation of
sphingomyelinases results in the production of ceramides that can cause direct damage to mitochondria. Protein translation is followed by a folding process in the Golgi
apparatus. Misfolded proteins are processed through the proteasome for protease digestion and recycling of amino acids. Disruption of this process can contribute to
autophagy, where the cell starves for critical nutrients, or itself induce apoptosis through a distinct pathway activated by misfolded protein accumulation. Antiangiogenic
agents and immune therapies work in the tumor stroma (lower left) on supporting elements including blood vessels and host inflammatory cells.
basis for U.S. Food and Drug Administration (FDA) approval for com­
mercial use of the agent.
Patients treated with palliative intent should be aware of their diag­
nosis and the limitations of the proposed treatments, have access to
supportive care, and have suitable “performance status,” according to
assessment algorithms such as the one developed by Karnofsky (see
Death signal
receptor
Apoptosis
modulators
Membrane
damage
TNF-R
SMase
BC12
Ceramide
Mitochondrial
damage
Caspase 8
p53
+
+
Effector
caspases
Proapoptotic
Gene
Expression
BAX
PUMA
NOXA
PIGs, etc.
+
DNA damage
or
Cytochrome C
Caspase 3
APAF
Cell targets
Caspase 9
Nuclease
activation
CHAPTER 78
+
+
Disordered
chromosome
structure
or
Cell targets
Principles of Cancer Treatment
Misfolded proteins
Folded
proteins
Golgi
Protein production
Proteasome
Proteosome
inhibitors
Peptides
Amino acids
Table 73-4) or by the Eastern Cooperative Oncology Group (ECOG)
(see Table 73-5). ECOG performance status (PS) 0 patients are without
symptoms; PS1 patients are ambulatory but restricted in strenuous
physical activity; PS2 patients are ambulatory and active 50% or more
of the time but unable to work; PS3 patients are capable of limited
self-care but are active <50% of the time; and PS4 patients are totally
TABLE 78-3  Clinical Impact on Cancers with Cytotoxic Chemotherapy
A.  Advanced Cancers with Possible
D.  Cancers Possibly Cured with
Cure
Acute lymphoid and acute myeloid
leukemia (pediatric/adult)
Hodgkin’s disease (pediatric/adult)
Lymphomas—certain types (pediatric/
adult)
Germ cell neoplasms
  Embryonal carcinoma
  Teratocarcinoma
  Seminoma or dysgerminoma
  Choriocarcinoma
Gestational trophoblastic neoplasia
Pediatric neoplasms
  Wilms’ tumor
  Embryonal rhabdomyosarcoma
  Ewing’s sarcoma
  Peripheral neuroepithelioma
  Neuroblastoma
Small-cell lung carcinoma
Ovarian carcinoma
B.  Advanced Cancers Possibly Cured by
High-Dose Chemotherapy with
Stem Cell Support
Relapsed leukemias, lymphoid and
myeloid
Relapsed lymphomas, Hodgkin’s and
non-Hodgkin’s
Chronic myeloid leukemia
Multiple myeloma
E.  Cancers Responsive with Useful
Palliation, But Not Cured, by
Chemotherapy
Bladder carcinoma
Chronic myeloid leukemia
Hairy cell leukemia
Chronic lymphocytic leukemia
Lymphoma—certain types
Multiple myeloma
Gastric carcinoma
Cervix carcinoma
Endometrial carcinoma
Soft tissue sarcoma
Head and neck cancer
Adrenocortical carcinoma
Islet cell neoplasms
Breast carcinoma
Colorectal carcinoma
Glioma
Lung cancer
  Small-cell
  Non-small-cell
F.  Tumors Poorly Responsive
PART 4
Oncology and Hematology
Chemotherapy, Radiation, ± Surgery
Squamous carcinoma (head and neck)
Squamous carcinoma (anus)
Bladder carcinoma
Breast carcinoma
Carcinoma of the uterine cervix
Esophageal carcinoma
Non-small-cell lung carcinoma (stage III)
Small-cell lung carcinoma
C.  Cancers Possibly Cured with
in Advanced Stages to
Chemotherapy
Pancreatic carcinoma
Biliary tract neoplasms
Thyroid carcinoma
Carcinoma of the vulva
Prostate carcinoma
Melanoma
Hepatocellular carcinoma
Salivary gland cancer
Chemotherapy as Adjuvant to Surgery
Breast carcinoma
Colorectal carcinomaa
Osteogenic sarcoma
Soft tissue sarcoma
aRectum also receives radiation therapy.
confined to bed or chair and incapable of self-care. Only PS0, PS1, and
PS2 patients are generally considered suitable for palliative (noncura­
tive) treatment. If there is curative potential, even poor-PS patients may
be treated (especially if their symptoms are directly related to a cancer
that may respond to treatment), but their prognosis is usually inferior
to that of good-PS patients treated with similar regimens. Assessment
of physiologic reserve through use of the geriatric assessment tool can
be helpful, but no measure of comorbidities or physiologic reserve is
considered standard.
The turn of the millennium marked the arrival of new strategies for
cancer treatment. Prominent among these are cancer biologic therapy,
which harnesses the use of immune system–derived reagents or
strategies, and cancer targeted therapies, which are directed at specific
molecular targets differentially expressed in malignant as opposed to
normal tissues.
■
■CANCER BIOLOGIC THERAPY
Figure 78-4 presents the landscape of cancer biologic therapy agents
and actions. The goal of biologic therapy is to manipulate the hosttumor interaction in favor of the host, potentially at an optimum
biologic dose that might be different than MTD. As a class, biologic
therapies may be distinguished from cytotoxic and molecularly tar­
geted agents in that biologic therapies require activity (e.g., antigen
expression or internalization) on the part of the tumor cell or on the
part of the host (e.g., T-cell engagement or cytokine elaboration) to
allow therapeutic effect.
Antibody-Mediated Therapeutic Approaches 
Figure 78-4
illustrates current antibody-based strategies in cancer treatment. The
ability to grow very large quantities of high-affinity monoclonal anti­
bodies directed at specific tumor antigens produced by animals allows
the grafting of animal-derived antigen-combining sequences into
human immunoglobulin genes (chimerized or humanized products) or
derived de novo from mice bearing human immunoglobulin gene loci.
Four general strategies have emerged using antibodies. Anti-tumor cell
antibodies target tumor cells directly to inhibit intracellular functions or
attract immune or stromal cells. Bispecific tumor engaging (BiTe) anti­
bodies directly bind to a tumor cell and to a host immune cell. Immu­
noregulatory antibodies target antigens expressed on host immune cells
to boost the host’s immune response to the tumor. Finally, antibody
conjugates link the antibody to drugs, toxins, or radioisotopes to target
these “warheads” for delivery to the tumor. Stroma-directed antibodies
are currently available against tumor-supporting vasculature.
ANTI-TUMOR CELL ANTIBODIES (FIG. 78-4)  Humanized antibodies
against the CD20 molecule expressed on B-cell lymphomas (rituximab
and ofatumumab) are exemplary of antibodies that affect both signal­
ing events driving lymphomagenesis as well as activating immune
responses against B-cell neoplasms. They are used as single agents and
in combination with chemotherapy and radiation in the treatment of
B-cell neoplasms. Obinutuzumab is an antibody with altered glycosyl­
ation that enhances its ability to activate killer cells; it is also directed
against CD20 and is of value in chronic lymphocytic leukemia.
Unintended side effects of any antibody include infusion-related
hypersensitivity reactions, which can be managed with glucocorticoid
and/or antihistamine prophylaxis, and prolonged infusion strategies.
Anti-B-cell-directed antibodies can have the unintended effect of
exacerbating immunosuppression with the emergence of increased
opportunistic infections. Reactivation of latent infections may also
occur; an assessment of a patient’s hepatitis B and C status is conven­
tionally done before treatment. Concomitant use of antivirals directed
against hepatitis may be indicated. Patients with HIV and lymphoma
need antivirals optimized to minimize interaction with anti-lymphoma
treatments; consultation with infectious disease specialists is war­
ranted. Anti-tumor cell antibodies also include approaches to activate
complement and are exemplified by alemtuzumab directed against
CD52; it is active in chronic lymphoid leukemia and T-cell malignan­
cies. Tumor lysis syndrome prophylaxis may be warranted.
Epidermal growth factor receptor (EGFR)-directed antibodies (e.g.,
cetuximab and panitumumab) have activity in colorectal cancer refrac­
tory to chemotherapy, particularly when used to augment the activity
of an additional chemotherapy program, and in the primary treatment
of head and neck cancers treated with radiation therapy. Direct effects
on the tumor may mediate an antiproliferative effect as well as stimu­
late the participation of host mechanisms involving immune cell or
complement-mediated response to tumor cell–bound antibody. AntiEGFR antibodies can cause an acneiform rash requiring topical antibi­
otic and glucocorticoid cream treatment; photosensitivity also occurs.
The HER2/neu receptor overexpressed on epithelial cancers, espe­
cially breast and certain gastrointestinal cancers, was initially targeted
by trastuzumab, with activity in potentiating the action of chemo­
therapy in breast cancer as well as evidence of single-agent activity.
Trastuzumab appears to interrupt intracellular signals derived from
HER2/neu and to stimulate anti-tumor cell immune mechanisms. The
anti-HER2 antibody pertuzumab, specifically targeting the domain
of HER2/neu responsible for dimerization with other HER2 family
members, is more specifically directed against HER2 signaling func­
tion and augments the action of trastuzumab. Both trastuzumab and
pertuzumab can damage cardiac function, particularly in patients with
prior exposure to anthracyclines, and left ventricular function should
be checked before treatment and monitored during treatment.
Anti-tumor cell antibody
CCRX-4: Mogamulizumab
CD19: Tafasitamab
CD20: Obinutuzumab,
Ofatumummab,
Rituximab
CD38: Daratumumab,
Isatuximab
CD52: Alemtuzumab
EGFR: Cetuximab,
Panitumumab
EGFR (exon20insert)/MET:
Amivantamab
GD2 Ganglioide: Dinutuximab
HER2: Pertuzumab,
Trastuzumab
SLAMF7: Elotuzumab
T
Effector
mechanisms
Cells
Complement
T-Ag
T cell
Bispecific tumorT cell antibody
T-Ag
CD3-CD19: Blinatumomab
CD3-CD20: Glofitamab,
Epcoritamab,
Mosunetuzumab
CD3-BCMA: Teclistumab
CD3-gp100Tcr: Tebentafusp
Antigens
Antigen
presenting
cell
s
AgMHC
TcR
–
CTLA4
PD-L1
–
Immune-regulating
antibody
–
Cytotoxic
T cell
Tumor stroma
T-regulatory cells
Stroma
+
CTLA4: Ipilimumab,
Tremelimumab
LAG-3: Relatimab
PD-1: Cemiplimab,
Dostarlimab,
Nivolumab,
Pembrolizumab,
Retifanlimab
PD-L1: Atezolizumab,
Avelumab,
Durvalumab
Blood vessel in
tumor stroma
Antistroma antibody
VEGF: Bevacizumab
VEGFR2: Ramucirumab
FIGURE 78-4  Immunologic treatments for cancer. Anti–tumor cell antibodies targeting the indicated antigens (T-Ag) expressed on tumor cells or antibody-derived constructs
(upper left) can either directly interfere with tumor cell function by, e.g., inhibiting growth-promoting pathways, or recruit host immune effector cells actively (especially
through bispecific tumor-engaging [BiTe] strategies; middle left), Fc receptors, or cytotoxic mechanisms such as complement. Endogenous T cells can be activated by
immunomodulatory cell targeting antibodies (lower left). Specifically, tumor cell–derived antigens are taken up by antigen-presenting cells (APCs), also in the stroma.
Antigens are processed by the APCs to peptides presented by the major histocompatibility complex (MHC) to T-cell antigen receptors (TcRs), thus providing a positive (+)
activation signal for the cytotoxic tumor cells to kill tumor cells bearing that antigen. Negative (–) signals inhibiting cytotoxic T-cell action include the CTLA4 receptor (on
T cells), interacting with the B7 family of negative regulatory signals from APCs, and the PD receptor (on T cells), interacting with the PD ligand-1 (PD-L1) (–) signal coming
from tumor cells expressing the PD-L1. Strategies that inhibit CTLA4 and PD-1 function are a means of stimulating cytotoxic T-cell activity to kill tumor cells. Lymphocyte
activating gene 3 (LAG3) has recently been shown to promote PD axis immunosuppression, and inhibition of that target has shown clinical value. Tumor stroma-directed
antibodies cause anti–vascular endothelial cell growth factor (VEGF)–mediated antiangiogenic and tumor interstitial pressure-modulating strategies. Proceeding clockwise
in the figure from the upper right, antibody-drug conjugates have recently been designed to deliver cytotoxic drugs, indicated by “T” (upper right). Relatively nonspecific
immunomodulators include vaccines instilled directly into the tumor stroma, agents such as the “imids” that alter tumor and stromal cell cytokine production, and cytokines
such as interferon or interleukin 2 (IL-2), which can affect tumor-infiltrating lymphocyte function or have direct antitumor effects. Vaccines targeting tumor cell antigens or
live attenuated oncolytic viruses injected into tumors can cause tumor cell lysis with induction of a prominent host antitumor immune response to virus antigens and target
antigens (T-Ags) (middle right). In the right lower portion of the figure, strategies to deliver activated immune cells include harvest of autologous T cells that are then infected
with a lentivirus or other construct that targets antigens (T-Ags) expressed on tumor cells (chimeric antigen receptor [CAR] T cells), with the targeted antigen indicated.
The BiTe antibody blinatumomab was constructed to have an antiCD19 antigen-combining site directed at a cancer cell as one valency
with an anti-CD3 binding site as the other. This antibody can bring T cells
(with their anti-CD3 activity) close to neoplastic B cells bearing the
CD19 determinant. Blinatumomab is active in B-cell neoplasms such
as acute lymphocytic leukemia. Unique toxicities include cytokine
release syndrome (fever, hypotension, tachycardia) and neurologic
deterioration manifest initially by deterioration in handwriting accu­
racy, which can proceed to more florid cortical dysfunction, suggesting
a need for dose pausing and/or glucocorticoid use.
Antibody-drug conjugate
See Table 78-6 for:
Antibody linked DNA disruptors
Antibody linked microtubule agents
Antibody linked topo I inhibitors
T-Ag
Nontargeted/indirect
immunomodulator
Host
cells
Tumor cell
Bacille Calmette-Guerin (BCG)
Glucocorticoids (high-dose)
Imids: Lenalidomide,
Pomalidomide,
Thalidomide
CHAPTER 78
T-Ag
T-Ag
V-ag
V-ag
Oncolytic or
immunomodulating
virus to V or T antigens
V-ag
V-ag
Principles of Cancer Treatment
V-ag
V-ag
CART
Virus
Talimogene laherparepvec
Nadofaragene firadenovec
CAR-T cellular therapy
CD19: Axicabtagene ciloleucel,
Brexucabtagene autoleucel,
Tisagenlecleucel
CD38: Ciltacabtagene autoleucel
STROMA-DIRECTED ANTIBODIES (FIG. 78-4)  The anti–vascular endo­
thelial growth factor (VEGF) antibody bevacizumab shows evidence of
value in renal cancers, where activation of VEGF signaling occurs as
part of disabled hypoxia-induced signaling in the tumor cells. When
combined with chemotherapeutic agents, it may increase responses
in colorectal and nonsquamous lung cancers. The mechanism for this
effect may relate to improved delivery and tumor uptake of the cyto­
toxic, or even immunoregulatory, antibodies used to treat hepatocel­
lular cancer, owing to decreased tumor interstitial pressure. VEGF was
originally isolated as a “tumor permeability factor” causing leakiness
of tumor blood vessels. When used in gliomas, it may, by decreasing
vascular permeability, allow replacement of steroids to decrease intra­
cranial pressure. Bevacizumab has a number of side effects including
hypertension, thrombosis, proteinuria, hemorrhage, and gastrointesti­
nal perforations with or without prior surgeries; these adverse events
also occur with small-molecule drugs modulating VEGF receptor
(VEGFR) function.
IMMUNOREGULATORY ANTIBODIES (FIG. 78-4)  Purely immunoregu­
latory antibodies stimulate immune responses to mediate tumordirected cytotoxicity. An understanding of the tumor-host interface has
revealed that cytotoxic tumor-directed T cells are frequently inhibited
by ligands upregulated in the tumor cells. The programmed death
ligand 1 (PD-L1; also known as B7-homolog 1) was initially recognized
as inducing T-cell death through a receptor present on T cells, termed
the programmed death (PD) receptor, which physiologically regulates
the intensity of the immune response to any antigen. The PD family
of ligands and receptors also regulates macrophage function, present
in tumor stroma. These actions raised the hypothesis that antibodies
directed against the PD signaling axis (both anti-PD-L1 and anti-PD)
might be useful in cancer treatment by allowing reactivation of the
immune response against tumors.
Ipilimumab, an antibody directed against the anti-CTLA4 (cytotoxic
T lymphocyte antigen 4), which is expressed on T cells (not tumor
cells), responds to signals from antigen-presenting cells (Fig. 78-4) and
also downregulates the intensity of the T-cell proliferative response to
antigens derived from tumor cells. Indeed, manipulation of the CTLA4
axis was the first demonstration that purely immunoregulatory anti­
body strategies directed at T-cell physiology could be safe and effec­
tive in the treatment of cancer. Ipilimumab, alone or in combination
with PD-1-directed antibodies, is approved for treatment of metastatic
melanoma and lung cancers.
PART 4
Oncology and Hematology
Nivolumab, directed against the PD-1 receptor, and atezolizumab
(anti-PD-L1) are exemplary of anti-PD-1-directed immunoregula­
tory antibodies, with clinical benefits in many cancers (Table 78-4).
Pembrolizumab is approved for first-line treatment of metastatic
non-small-cell lung cancer tumors that express the PD-L1 ligand.
This development was a milestone in cancer therapeutics, replacing
chemotherapy in this patient subset. Lymphocyte activation gene 3
(LAG3) binds to major histocompatibility complex (MHC) on
antigen-presenting cells to augment the effect of the PD-1 and CTLA4
pathways. Relatlimab is a first-in-class inhibitor of LAG3 action and
augments the effect of nivolumab in melanoma.
Importantly, the clinical observation that tumors most amenable to
treatment with immunoregulatory antibodies were in sites (lung, skin,
genitourinary) exposed to environmental carcinogens or occurred in
patients with known mutations in DNA repair pathways stimulated
specific research as to whether the “mutational burden” of tumors
could predict value from anti-PD strategies. Results to date in general
support this hypothesis and led to the first regulatory approvals for
immunomodulating antibodies in a “tissue agnostic” fashion. Specifi­
cally, detection of deficiencies in a tumor DNA mismatch repair system
or with evidence of increased tumor mutation burden is a specific
indication for use of certain immunoregulatory agents, irrespective of
the disease site of origin. The increased efficacy in the setting of higher
tumor mutational burden is thought to be due to the presence of more
proteins in the tumor structurally altered by mutation that can be rec­
ognized as foreign by the immune system.
Prominent autoimmune hepatic, cardiac, endocrine, cutaneous,
neurologic, and gastrointestinal adverse events can occur with the use
of ipilimumab as well as the PD-1-directed antibodies. Emergency
use of glucocorticoids may be required to attenuate severe toxicities.
Although theoretically such glucocorticoid use can attenuate the
antitumor effect, response rates do not appear to be compromised
by their use to abrogate serious organ toxicity attributable to use of
immunomodulatory antibodies. Importantly for the general internist,
immunologic toxicities can occur late after exposure to the modulators
of PD and CTLA4 action, even while the patient may have sustained
control of tumor growth.
TABLE 78-4  Clinical Impact of Host T Lymphocyte–Modified Cellsa or
Host T Lymphocyte–Directed Immunoregulatory Antibodiesc
A.  Advanced Cancers with Positive Effect (at least 25% of treated patients
have stable disease or progression-free survival of ≥27 weeks or better) or
Frequent or Unexpected Prolonged Responders (efficacy may be limited to
CD expression–dependent or PD-1 ligand–expressing subtypes)
Acute lymphoid leukemiab
Adrenocortical carcinomac
Breast cancer, hormone receptor negative, HER2 negative (with chemotherapy)c
Colorectal cancer (microsatellite instability-high [MSI-H] or mismatch repair
deficient, usually with fluoropyrimidine, oxaliplatin, or irinotecan)c
Cervix, squamous carcinomac
Cutaneous, squamous carcinomac
Diffuse large B-cell non-Hodgkin’s lymphoma, not otherwise specifieda
Diffuse large B-cell non-Hodgkin’s lymphoma, primary mediastinal subtypeb
Endometrial carcinoma (with lenvatinib, if microsatellite instability-stable
[MSI-S] or mismatch repair wild-type)c
Esophageal squamous carcinomac
Gastric/gastroesophageal adenocarcinomac
Head and neck squamous carcinomac
Hepatocellular cancer (after sorafenib)c
Hodgkin’s diseasec
Mantle cell lymphomaa
Melanomac
Merkel cell carcinomac
Mesotheliomac
MSI-H or mismatch repair–deficient solid tumors without satisfactory
alternativec
Mycosis fungoidesc
Multiple myelomaa
Non-small-cell lung carcinomac
Paraganglioma/pheochromocytomac
Renal cell carcinomac
Sarcoma, alveolar soft partc
Small-cell lung carcinomac
Solid tumors with high tumor mutational burden (TMB) (≥10 mutations/
megabase) that have progressed following prior therapy without satisfactory
alternative treatmentc
Urothelial carcinomac (including bladder, ureter)
B.  Advanced Cancers with Insufficient Data to Support Host-Derived
T Lymphocyte or Immunoregulatory Antibody Treatmentd
Acute myeloid leukemia
Anus, squamous carcinoma
Breast cancer, hormone receptor positive
Breast cancer, hormone receptor negative, HER2 positive
Biliary tract cancers (if MSI-S or mismatch repair wild-type)
Chronic lymphocytic leukemia
Chronic myeloid leukemia
Gastrointestinal neuroendocrine/islet cell carcinoma
Glioma, all grades including glioblastoma
Germ cell neoplasms
Ovarian cancer
Osteogenic sarcoma
Pancreas adenocarcinoma
Pediatric tumors (Wilms’, rhabdomyosarcoma, Ewing’s, neuroblastoma,
osteosarcoma)
Prostate adenocarcinoma
Salivary gland carcinoma
Soft tissue sarcoma (except alveolar soft part)
T-cell non-Hodgkin’s lymphoma (except mycosis fungoides)
Vulva, squamous carcinoma
aChimeric antigen receptor (CAR)-modified autologous T cells in relapsed or
refractory cases. bBoth CAR-modified autologous T cells or an immunoregulatory
antibody. cT-cell-directed immunoregulatory antibody strategies including anti-PD-1
and/or anti-PD-L1 antibodies or bispecific tumor engaging (BiTe) antibodies against
a particular tumor cell antigen. dUnless MSI-high, mismatch repair deficient, or TMB
≥10 mutations/megabase.
Nontargeted Immunomodulators (Fig. 78-4) 
Bacille
Calmette-Guérin, a killed mycobacterial product, invokes a useful
immune response when instilled locally into the bladder in the setting
of preinvasive bladder cancers. The “imids” thalidomide, lenalidomide,
and pomalidomide alter cytokine elaboration in the tumor microen­
vironment and have antiangiogenic actions. They are a cornerstone
in the management of multiple myeloma. Thromboses (warranting
consideration of prophylactic anticoagulation), gastrointestinal and
neuropathic adverse events, and prominent teratogenicity can occur
as a consequence of their use. “High-dose” glucocorticoids stimulate
apoptosis in normal and neoplastic lymphoid cells and are a mainstay
in the treatment of lymphoid leukemias, lymphomas, and plasma cell
neoplasms.
Cytokines 
Only interferon α (IFN-α) and interleukin 2 (IL-2) are
considered for current treatment indications. IFN is not curative for
any tumor but can induce partial responses in follicular lymphoma,
hairy cell leukemia, chronic myeloid leukemia, melanoma, and Kaposi’s
sarcoma. It produces fever, fatigue, a flulike syndrome, malaise,
myelosuppression, and depression and can induce clinically significant
autoimmune disease.
IL-2 exerts its antitumor effects indirectly through augmentation of
immune function. Its biologic activity is to promote the growth and
activity of T cells and natural killer (NK) cells. High doses of IL-2 can
produce tumor regression in certain patients with metastatic mela­
noma and renal cell cancer. About 2–5% of patients may experience
complete remissions that are durable. Patients may require blood pres­
sure support and intensive care to manage the toxicity. However, once
the agent is stopped, most of the toxicities reverse completely within
3–6 days. Use of “high-dose” IL-2 regimens has been superseded by
immunoregulatory antibodies. Efforts to develop new IL-2-based strat­
egies with less toxicity and improved efficacy are continuing.
T Cell–Mediated Therapies 
Three types of currently used cancer
treatments take advantage of the ability of T cells to kill tumor cells.
Transfer of allogeneic T cells. This occurs in three major settings: in
allogeneic bone marrow transplantation; as purified lymphocyte
transfusions following bone marrow recovery after allogeneic bone
marrow transplantation; and as pure lymphocyte transfusions fol­
lowing immunosuppressive (nonmyeloablative) therapy (also called
reduced-intensity or minitransplants). In each of these settings, the
effector cells are donor T cells that recognize the tumor as being
foreign, probably through minor histocompatibility differences.
The main risk of such therapy is the development of graft-versushost disease because of the minimal difference between the cancer
and the normal host cells. This approach has been useful in certain
hematologic cancers refractory to chemotherapeutic strategies.
Transfer of autologous T cells. In this approach, the patient’s own
T cells are removed from the tumor-bearing host, manipulated in
several ways in vitro, and given back to the patient. Tumor antigen–
specific T cells can be developed after retroviral transduction of the
desired T-cell antigen receptor and expanded to large numbers over
many weeks ex vivo before administration. These chimeric antigen
receptor (CAR) T cells (Fig. 78-4) have evidence of sustained value
in patients with refractory hematopoietic neoplasms such as diffuse
large B-cell lymphoma, multiple myeloma, and mantle cell lym­
phoma. Prominent adverse effects include cytokine release syndrome
(fever, tachycardia, hypotension) and neurologic manifestations.
Clinical investigations are seeking to develop solid-tumor antigendirected CAR strategies, as well as to utilize different immune cell
populations such as NK cells to cause useful antitumor activity in
ways that may allow “off-the-shelf” products not requiring manipu­
lation and purification of patients’ autologous cells.
Tumor vaccines aimed at boosting T-cell immunity. Two types of
vaccine approaches are currently approved. Purified autologous
antigen-presenting cells can be pulsed with tumor, its membranes,
or particular tumor antigens and delivered as a vaccine. Vaccine
adjuvants such as granulocyte-macrophage colony-stimulating factor
(GM-CSF) may be co-administered. One such vaccine, sipuleucel-T,
is approved for use in patients with asymptomatic or minimally
symptomatic metastatic hormone-independent prostate cancer. In
this approach, the patient undergoes leukapheresis, wherein mono­
nuclear cells (that include antigen-presenting cells) are removed
from the patient’s blood. The cells are pulsed in a laboratory with an
antigenic fusion protein comprising a protein frequently expressed
by prostate cancer cells, prostate acid phosphatase, fused to GMCSF, and matured to increase their capacity to present the antigen
to immune effector cells. The cells are then returned to the patient
in a well-tolerated treatment. Although no objective tumor response
was documented in clinical trials, median survival was increased by
about 4 months.
  Another important vaccine strategy is directed at infectious
agents whose action ultimately is tied to the development of human
cancer. Hepatitis B vaccine in an epidemiologic sense prevents
hepatocellular carcinoma, and a tetravalent human papillomavirus
vaccine prevents infection by virus types currently accounting for
70% of cervical cancer. Unfortunately, these vaccines are ineffective
at treating patients who have developed a virus-induced cancer.
Oncolytic or Immunomodulating Viruses (Fig. 78-4) 
Labo­
ratory studies in animals have utilized viruses to destroy tumors because
tumor cells lack endogenous host mechanisms, e.g., IFN elaboration or
recognition strategies of viral nucleic acids, that limit virus spread.
Viral infection of tumors also can stimulate a prominent host response
to viral and tumor cell antigens, leading to immune effects against
local tumor cells. Talimogene laherparepvec is a clinically approved
attenuated herpes virus that acts to stimulate immune responses when
instilled locally into melanoma deposits. Systemic effects are minimal
in this application. This general strategy is being considered particularly
in tumors not amenable to useful effects of currently approved immu­
noregulatory antibodies or in conjunction with immunoregulatory anti­
bodies. Nadofaragene firadenovec is an adenovirus construct instilled
into the bladder; it is nonreplicating but can infect urothelial cells to
deliver a gene resulting in consistently produced IFN-α2b, which has a
local antitumor effect. It is useful in the treatment of superficial bladder
cancers. It is not established whether infection of tumor cells, normal
urothelial cells, or both contribute to the antitumor effect.
CHAPTER 78
Principles of Cancer Treatment
■
■CANCER CYTOTOXIC THERAPY
Table 78-5 lists commonly used cytotoxic cancer chemotherapy agents
and pertinent clinical aspects of their use, with particular reference
to adverse effects that might be encountered by the generalist in the
care of patients. The drugs were initially discovered through screening
of chemicals and natural product extracts for evidence of antitumor
activity in animals or were designed with knowledge of biochemi­
cal pathways affecting nucleic acid synthesis. They may be usefully
grouped into two general categories: those affecting DNA and those
affecting microtubules.
As illustrated in Fig. 78-3, disruption of DNA or microtubule integ­
rity is a major trigger of cellular apoptosis pathways. An additional
factor in drug effect stems from recent observations that tumor cells
have increased tolerance of specific types of DNA damage owing to
defects in DNA repair pathways. This state is thought to facilitate the
survival of the neoplastic clone as it experiences DNA mutations dur­
ing the course of carcinogenesis. DNA-directed cytotoxic agents can
create lesions in DNA that are poorly tolerated by cells with neoplasmpromoting DNA repair pathway mutations. This results in a “synthetic
lethal” interaction of the drug with cells bearing the DNA repair path­
way mutation. Examples of a potential “synthetic lethal effect” will be
pointed out in relation to clinical applications below.
DNA-Interactive Agents 
DNA replication occurs during the syn­
thesis or S-phase of the cell cycle, with chromosome segregation of the
replicated DNA in the M, or mitosis, phase. The G1 and G2 “gap phases”
precede S and M, respectively. Chemotherapeutic agents have been
divided into “phase-nonspecific” agents, which can act in any phase of
the cell cycle, and “phase-specific” agents, which require the cell to be
at a particular cell cycle phase to cause greatest effect.
TABLE 78-5  Commonly Used Cytotoxic Chemotherapy Agents
DRUG
ADVERSE EVENTS
NOTES
Direct DNA-Interacting Agentsa  
Alkylator or platinating drug  
Bendamustine
Vehicle allergy, My, Der, ↑LFTs
TLS, Ves, IR, DA-R, DA-H
Carboplatin
My, N, V, R
Dose according to CrCl: to AUC of 5–7 mg/mL per min [AUC = dose/(CrCl + 25)]
Chlorambucil
Common alkylator
 
Cisplatin
N, V, Neu, My, R, Ototoxic, ↓K+, ↓Mg2+, ↓Ca2+
Osmotic diuresis, N, V prophylaxis, DA-R
Cyclophosphamide
Common alkylator, cystitis, cardiac (high dose)
Liver required to activate, DA-R, DA-H, hydration ± mesna protects bladder
Dacarbazine (DTIC)
Common alkylator, Ves
DA-R
Ifosfamide
My, common alkylator, bladder, CNS
DA-R, must use concomitant mesna
Lomustine (CCNU)
Common alkylator but My, has delayed nadir, ↑LFTs
Plm ± fibrosis: PFTs prior to treatment and repeat frequently; cease if fibrosis
occurs
Lurbinectedin
My, ↑LFTs, N, V
CYP3A4
Melphalan
Common alkylator but My, has delayed nadir
DA-R
Oxaliplatin
N, V, My, Neu
Reversible laryngopharyngeal spasm risk
Procarbazine
Common alkylator, CNS
Disulfiram-like effect with alcohol, MAOI, like HBP after tyramine-rich foods
Temozolomide
Common alkylator but My, has delayed nadir
Pneumocystis prophylaxis
Antitumor antibiotics and topoisomerase poisons  
Bleomycin
Plm (↑FIO2 worsen), Der, Raynaud’s, IR*
Monitor DLCO before/during treatment, DA-R
PART 4
Oncology and Hematology
Dactinomycin
My, N, V, mucositis, Ves, alopecia
Radiation recall
Doxorubicin,
daunorubicin, epirubicin,
idarubicin
TOPOII; My, mucositis, alopecia, ↓LVEF acute/chronic, Ves
Co-administration with heparin aggregate, secondary leukemia, DA-H,
radiation recall
Doxorubicin, liposomal
TOPOII; My, ↓LVEF, IR*, PPED
DA-H, radiation recall
Etoposide
TOPOII; My, alopecia, IR with rapid IV, N, V, mucositis
DA-H, DA-R
Irinotecan
TOPOI; My, D: “early onset” with cramping, flushing,
vomiting: treat with atropine; “late onset” after several
doses: use loperamide 4 mg with first stool then 2 mg q2h
until 12 h without stool up to 16 mg/24 h; My dependent on
UGT1A1 phenotype, R, ILD
Irinotecan, liposomal
TOPOI; My, D (administer loperamide for D of any severity),
IR*, ILD
Mitoxantrone
TOPOII; Ves, blue urine, nails, and sclerae
Interacts with heparin; DA-H, alopecia, N, V, radiation recall
Topotecan
TOPOI; My, mucositis, N, V, alopecia
DA-R, rare ILD
Indirectly DNA-Interacting Agents
Pyrimidine analogues  
Capecitabine
My, D, PPED, cardiac adverse events, R, Der
Oral prodrug of 5-FU
Cytarabine (cytosine
arabinoside [ara-C])
My, mucositis, CNS (high dose), conjunctivitis (high
dose; use steroid eyedrops until 72 h after last dose),
noncardiogenic pulmonary edema
5-Fluorouracil (5-FU)
My, D, mucositis, CNS, Der, cardiac adverse events, PPED
Toxicity enhanced by leucovorin by increasing “ternary complex” with
thymidylate synthase; metabolism in tissue; dihydropyrimidine dehydrogenase
deficiency increases toxicity; enhances warfarin effect
Gemcitabine
My, N, V, ↑LFT, fever/”flu syndrome”
Rare ARDS; rare HUS, rare PRES, radiosensitization with long infusion
Trifluridine/tipiracil
My, mucositis, N, V, unusual PPED
Trifluridine directly inhibits thymidylate synthase and is incorporated into DNA;
tipiracil inhibits thymidine phosphorylase, which degrades trifluridine
Purine analogues
 
 
Fludarabine phosphate
My, mucositis, CNS, Der
Converted to F-ara ATP in cells by deoxycytidine kinase; DA-R
6-Mercaptopurine (6-MP),
6-thioguanine (6-TG)
Mv, N, ↑LFT
6-MP metabolized by xanthine oxidase, decrease dose with allopurinol; 6-MP
and 6-TG increased toxicity with thiopurine methyltransferase deficiency
Antifolates  
Methotrexate
My, ↑LFT with fibrosis with chronic use, Plm, R, mucositis
Toxicity lessened by leucovorin, bypassing block of dihydrofolate reductase,
excreted in urine; DA-R or hold; NSAIDs increase renal toxicity; sequestered
in third space fluids
Pemetrexed
My
Supplement folate/B12, omit for CrCl <45 mL/min
Miscellaneous Antimetabolite-Like Agents  
Asparaginase
Thrombosis by decrease of antithrombin IIII, but
↓fibrinogen can cause hemorrhage; ↑glucose; ↓albumin,
hypersensitivity; CNS; pancreatitis; ↑LFTs
Hydroxyurea
My, N, mucositis, rare ↓CrCl
DA-R, augments antimetabolite effect
Prodrug requires metabolism to active drug SN-38, which is cleared by
UGT1A1 with degree of My dependent on patient UGT1A1 genotype, DA-H
Consider guide dosing by UGT1A1 genotype testing, CYP3A4;
NO recommended dose for T Bili >ULN
Metabolized in tissues by deamination but renal excretion prominent at doses
500 mg; therefore, DA-R in “high-dose” regimens
Decrease protein synthesis; indirect inhibition of DNA synthesis by decreased
histone synthesis; blocks methotrexate action
(Continued)
(Continued)
TABLE 78-5  Commonly Used Cytotoxic Chemotherapy Agents
DRUG
ADVERSE EVENTS
NOTES
Antimitotic agents  
Docetaxel
IR*, VLS, My, ↑LFTs, Der, Neu, stomatitis, alopecia, N, V, D
Premedicate with steroids, H1 and H2 blockers; DA-H; monitor for second
primary malignancies; alcohol in vehicle
Eribulin
My, Neu, ↑QT
DA-H, DA-R
Ixabepilone
My, Neu, IR*, N, V, D, alopecia
Premedicate with steroids, H1 and H2 blockers; CYP3A4, DA-H
Nab-paclitaxel
My, Neu, Ves
DA-H, CYP3A4, CYP2C8
Paclitaxel
IR*, My, alopecia, N, V, D, mucositis, Neu, Ves
Premedicate with steroids, H1 and H2 blockers; DA-H, CYP3A4, CYP2C8, alcohol
in vehicle
Vinblastine
My, Ves, Neu, HBP, Raynaud’s, Ves, ↑LFTs, ileus/
constipation (use prophylactic stool softeners)
Vincristine
Ves, Neu, SIADH, ileus/constipation (use prophylactic
stool softeners)
Vinorelbine
My, Ves, allergic bronchospasm (immediate), dyspnea/
cough (subacute)
Note: Data abstracted in part from publicly available U.S. Food and Drug Administration label. All agents in this class have the potential for prominent embryofetal toxicity;
use without contraception by female patients of childbearing potential is not recommended. Effective contraception for female partners who are of childbearing potential of
patients undergoing treatment should also be considered; use during lactation is also not recommended; all DNA interacting agents have theoretical risk of late secondary
neoplasms, particularly where noted. Indications and events of prominent general medical importance include the following: ARDS, acute respiratory distress syndrome;
AUC, area under concentration-time curve; Common alkylator toxicities: N, V, My, alopecia, mucositis, ↓fertility, cumulative lung toxicity; CNS, central nervous system
(can include altered sensorium, cortical and cerebellar signs, dysarthria, altered seizure threshold); Cor, corneal keratopathy, consider pretreatment ophthalmologic exam
with prophylactic lubricating eyedrops ± ocular steroids; CrCl, creatinine clearance; CYP___, interaction with drugs metabolized by the indicated cytochrome(s) P450;
DA-H, dose adjust for hepatic dysfunction; DA-R, dose adjust for renal dysfunction; Der, dermatologic toxicity; HBP, high blood pressure; HUS, hemolytic-uremic syndrome;
ILD, interstitial lung disease; IR, infusion reaction; IR*, infusion reaction prophylaxis specifically recommended; LFT, liver function tests; ↓LVEF, left ventricular ejection
fraction, monitor echocardiogram; My, anemia, decrease in white blood cells, platelets, with risk of neutropenic fever, hemorrhage, therefore dose reduce or hold dose for
decreased neutrophil or platelet counts unless marrow infiltrated by drug-responsive tumor; N, nausea; Neu, peripheral neuropathy; Plm, pulmonary; PPED, palmar-plantar
erythrodysesthesia (i.e., hand-foot syndrome); PRES, posterior reversible leukoencephalopathy syndrome; PT, prothrombin time; PTT, partial thromboplastin time; ↑QT, pre-
and intratreatment electrocardiogram monitoring, normalize K+, Mg2+, ionized Ca2+; R, renal injury possible; SIADH, syndrome of inappropriate antidiuretic hormone; TLS,
risk of tumor lysis syndrome if brisk response; TOPO___, agent targets the indicated topoisomerase; UGT___, metabolism by UDP-glucuronosyltransferase of the indicated
genotype; Ves, extravasation injury possible; V, vomiting; VLS, vascular leak syndrome; VOD, veno-occlusive liver disease.
Alkylating agents (Table 78-5) as a class are cell cycle phase–nonspecific
agents. They break down, either spontaneously or after normal organ
or tumor cell metabolism, to reactive intermediates that covalently
modify bases in DNA. This leads to cross-linkage of DNA strands or
the appearance of breaks in DNA as a result of repair efforts. Damaged
DNA cannot complete normal cell division; in addition, it activates
apoptosis. Alkylating agents share common toxicities: myelosuppres­
sion, alopecia, gonadal dysfunction, mucositis, and pulmonary fibrosis.
They also share the capacity to cause “second” neoplasms, particularly
leukemia, years after use, particularly when used in low doses for pro­
tracted periods.
Cyclophosphamide is inactive unless metabolized by the liver to
4-hydroxy-cyclophosphamide, which decomposes into an alkylating
species, as well as to chloroacetaldehyde and acrolein. The latter causes
chemical cystitis; therefore, excellent hydration must be maintained
while using cyclophosphamide. If severe, the cystitis may be attenu­
ated or prevented altogether (if expected from the dose of cyclophos­
phamide to be used) by mesna (2-mercaptoethanesulfonate). Liver
disease impairs cyclophosphamide activation. Sporadic interstitial
pneumonitis leading to pulmonary fibrosis can accompany the use of
cyclophosphamide, and high doses used in conditioning regimens for
bone marrow transplant can cause cardiac dysfunction. Ifosfamide is a
cyclophosphamide analogue also activated in the liver, but more slowly,
and it requires co-administration of mesna to prevent bladder injury.
CNS effects, including somnolence, confusion, and psychosis, can fol­
low ifosfamide use; the incidence appears related to low body surface
area or decreased creatinine clearance.
Several alkylating agents are less commonly used. Bendamustine has
activity in chronic lymphocytic leukemia and certain lymphomas. It
is used in transplant preparation regimens. Melphalan shows variable
oral bioavailability and undergoes extensive binding to albumin and
α1-acidic glycoprotein. Mucositis appears more prominently; however,
it has prominent activity in multiple myeloma. Nitrosoureas break
down to carbamylating species that not only cause a distinct pattern
of DNA base pair–directed reactivity but also can covalently modify
proteins. Lomustine is used to treat brain tumors but causes delayed
myelotoxicity and can cause lung injury. Procarbazine is metabolized
DA-H, unusual; Plm, CYP3A4
DA-H, CYP3A4; less My than with vinblastine; unusual Plm
DA-H; less neurotoxic than other vincas
CHAPTER 78
Principles of Cancer Treatment
in the liver and possibly in tumor cells to yield a variety of free radical
and alkylating species. In addition to myelosuppression, it causes hyp­
notic and other CNS effects, including vivid nightmares. It can cause a
disulfiram-like syndrome on ingestion of ethanol. Both procarbazine
and lomustine are used in the treatment of brain tumors. Dacarbazine
(DTIC) is activated in the liver to yield the highly reactive methyl diazo­
nium cation. It causes only modest myelosuppression 21–25 days after
a dose but causes prominent nausea on day 1. It is an important com­
ponent of treatment regimens for Hodgkin’s lymphoma and sarcomas.
Temozolomide is structurally related to DTIC but is activated by non­
enzymatic hydrolysis in tumors and is bioavailable orally. Brain tumors
with alkylguanine alkyl transferase deficiency are selectively susceptible
to temozolomide, which alkylates the O6 position of guanine.
Cisplatin was discovered fortuitously by observing that bacteria
present in electrolysis solutions with platinum electrodes could not
divide. Only the cis diamine configuration is active as an antitumor
agent. In tumor cells, a chloride is lost from each position. The result­
ing positively charged species is an efficient DNA interactor, forming
Pt-based cross-links. Therefore “platinating agents” are considered
with alkylating agents as forming related lesions in DNA. Cisplatin
is administered with abundant hydration, including forced diuresis
with mannitol to prevent kidney damage; even with the use of hydra­
tion, gradual decrease in kidney function is common, along with
noteworthy anemia. Hypomagnesemia frequently attends cisplatin use
and can lead to hypocalcemia and tetany. Other common toxicities
include neurotoxicity with stocking-and-glove sensorimotor neuropa­
thy. Hearing loss occurs in 50% of patients treated with conventional
doses. Cisplatin is intensely emetogenic, requiring prophylactic anti­
emetics. Myelosuppression is less evident than with other alkylating
agents. Chronic vascular toxicity (Raynaud’s phenomenon, coronary
artery disease) is a more unusual toxicity. Carboplatin displays less
nephro-, oto-, and neurotoxicity. However, myelosuppression is more
frequent, and because the drug is exclusively cleared through the kid­
ney, adjustment of dose for creatinine clearance must be accomplished
through use of various dosing nomograms. Oxaliplatin is a platinum
analogue with noteworthy activity in colon cancers refractory to other
treatments. It is prominently neurotoxic.
Lurbinectedin binds to DNA through the “DNA minor groove”
with covalent interaction with the N2 position of certain guanines.
Transient altered liver function can occur, as well as cytopenias. Lurbi­
nectedin has activity in small-cell lung cancer. The first example of this
agent class, trabectedin, requires a prolonged infusion schedule but is
active in certain sarcomas, in part due to its modulation of transcrip­
tion factor function.
Antitumor Antibiotics and Topoisomerase Poisons 
Anti­
tumor antibiotics are substances produced by bacteria that provide a
chemical defense against hostile microorganisms. They bind to DNA
directly and can frequently undergo electron transfer reactions to gen­
erate free radicals in close proximity to DNA, leading to DNA damage
in the form of single-strand breaks or cross-links. Topoisomerase poi­
sons include natural products or semisynthetic derivatives that modify
enzymes that allow DNA to unwind during replication or transcription.
These include topoisomerase I, which creates single-strand breaks that
then rejoin following the passage of the other DNA strand through the
break. Topoisomerase II creates double-strand breaks through which
another segment of DNA duplex passes before rejoining. Owing to the
role of topoisomerase I in the replication fork, topoisomerase I poisons
cause lethality if the topoisomerase I–induced lesions occur in S-phase.
Doxorubicin intercalates into DNA, thereby altering DNA structure,
replication, and topoisomerase II function. It can also undergo reduc­
tion of its quinone ring system, with reoxidation to form reactive oxy­
gen radicals. It causes predictable myelosuppression, alopecia, nausea,
and mucositis. In addition, it can cause acute cardiotoxicity in the form
of atrial and ventricular dysrhythmias, but these are rarely of clinical
significance. In contrast, cumulative doses >550 mg/m2 are associated
with a 10% incidence of chronic cardiomyopathy. The incidence of
cardiomyopathy appears to be related to peak serum concentration,
with low-dose, frequent treatment or continuous infusions better toler­
ated than intermittent higher-dose exposures. Cardiotoxicity has been
related to iron-catalyzed oxidation and reduction of doxorubicin in
the heart. Dexrazoxane is an intracellular chelating agent that can act
as a cardio-protectant. Doxorubicin’s cardiotoxicity is increased when
given together with trastuzumab, the anti-HER2/neu antibody. Radia­
tion recall or interaction with concomitantly administered radiation
to cause local site complications is frequent. The drug is a powerful
vesicant, with necrosis of tissue apparent 4–7 days after an extravasa­
tion; therefore, it should be administered into a rapidly flowing intra­
venous line. Dexrazoxane also can mitigate doxorubicin extravasation.
Doxorubicin is metabolized by the liver, so doses must be reduced by
50–75% in the presence of liver dysfunction. Daunorubicin is closely
related to doxorubicin and is preferable to doxorubicin owing to less
mucositis and colonic damage with frequent high doses used in the
curative treatment of leukemia. Idarubicin is also used in leukemia
treatment and may have somewhat less cardiotoxicity. Encapsulation
of daunorubicin into a liposomal formulation has attenuated cardiac
toxicity with antitumor activity in Kaposi’s sarcoma, other sarcomas,
multiple myeloma, and ovarian cancer.
PART 4
Oncology and Hematology
Mitoxantrone is a synthetic topoisomerase II–directed agent with
a mechanism similar to the anthracyclines, with less but not absent
cardiotoxicity, comparing the ratio of cardiotoxic to effective doses; it
is still associated with a 10% incidence of cardiotoxicity at cumulative
doses of >150 mg/m2. Etoposide binds directly to topoisomerase II and
DNA in a reversible ternary complex. It stabilizes the covalent inter­
mediate in the enzyme’s action where the enzyme is covalently linked
to DNA. Prominent clinical effects include myelosuppression, nausea,
and transient hypotension related to the speed of administration of
the agent. Etoposide is a mild vesicant but is relatively free from other
large-organ toxicities.
Camptothecins target topoisomerase I. Topotecan is a camptoth­
ecin derivative approved for use in gynecologic tumors and small-cell
lung cancer. Toxicity is limited to myelosuppression and mucositis.
Irinotecan is a camptothecin with evidence of activity in colorectal
carcinoma. Irinotecan is a prodrug, metabolized in the liver to SN-38,
its active metabolite. Levels of SN-38 are particularly high in the set­
ting of Gilbert’s disease, characterized by defective uridine diphosphate
glucuronosyl transferase (UGT) 1A1 and indirect hyperbilirubinemia,
a condition that affects ~10% of the white population in the United
States. In addition, irinotecan’s myelosuppression is clearly influenced
by the patient’s genotype for UGT1As. Irinotecan causes a delayed
(48–72 h) secretory diarrhea related to the toxicity of SN-38. The diar­
rhea can be treated effectively with loperamide or octreotide; immedi­
ate diarrhea when it occurs is responsive to atropine.
Bleomycin remains an important component of curative regimens
for Hodgkin’s lymphoma and germ cell neoplasms. It forms complexes
with Fe2+ while also bound to DNA. Oxidation of Fe2+ gives rise to
superoxide and hydroxyl radicals, causing DNA damage. The drug
causes little, if any, myelosuppression. Bleomycin is cleared rapidly, but
augmented skin and pulmonary toxicity in the presence of renal failure
necessitates dose reduction in renal failure. Bleomycin is not a vesicant
and can be administered intravenously, intramuscularly, or subcutane­
ously. Common side effects include fever and chills, facial flush, and
Raynaud’s phenomenon. The most feared complication of bleomycin
treatment is pulmonary fibrosis, which increases in incidence at >300
cumulative units administered and is minimally responsive to treat­
ment (e.g., glucocorticoids). The earliest indicator of an adverse effect
is usually a decline in the carbon monoxide diffusing capacity (DLCO)
or coughing, although cessation of drug immediately upon docu­
mentation of a decrease in DLCO may not prevent further decline in
pulmonary function. Bleomycin is inactivated by a bleomycin hydro­
lase, which is poorly expressed in skin and lung. Because bleomycindependent electron transport is dependent on O2, bleomycin toxicity
may become apparent after exposure to transient very high fraction of
inspired oxygen (FIO2) even late after treatment. Thus, during surgi­
cal procedures, patients with prior exposure to bleomycin should be
maintained on the lowest FIO2 consistent with maintaining adequate
tissue oxygenation.
Dactinomycin interacts directly with DNA to inhibit RNA tran­
scription. It is important in the curative treatment of pediatric
neoplasms, some of which also occur in young adults. Prominent
myelosuppression, mucositis, alopecia, radiation recall, and nausea
require management.
Antimetabolites 
A broad definition of antimetabolites would
include compounds that interfere with purine or pyrimidine synthesis.
Some antimetabolites also cause DNA damage indirectly, through
misincorporation into DNA. They tend to convey greatest toxicity to
cells in S-phase, and the degree of toxicity increases with duration of
exposure. Common toxic manifestations include stomatitis, diarrhea,
and myelosuppression.
Methotrexate inhibits dihydrofolate reductase, which regenerates
reduced folates from the oxidized folates produced when thymi­
dine monophosphate is formed from deoxyuridine monophosphate.
Without reduced folates, cells die a “thymine-less” death. N5-Tet­
rahydrofolate or N5-formyltetrahydrofolate (leucovorin) can bypass
this block and rescue cells from methotrexate, which is retained in
cells by polyglutamylation. Methotrexate is transported into cells by
a membrane carrier, and high concentrations of drug can bypass this
carrier and allow diffusion of drug directly into cells. These properties
have suggested the design of “high-dose” methotrexate regimens with
leucovorin rescue of normal marrow and mucosa as part of curative
approaches to osteosarcoma in the adjuvant setting and hematopoi­
etic neoplasms of children and adults. Methotrexate is cleared by the
kidney via both glomerular filtration and tubular secretion, and toxic­
ity is augmented by renal dysfunction and drugs such as salicylates,
probenecid, and nonsteroidal anti-inflammatory agents that undergo
tubular secretion. With normal renal function, 15 mg/m2 leucovorin
will rescue 10−8–10−6 M methotrexate in 3–4 doses. However, with
decreased creatinine clearance, doses of 50–100 mg/m2 are continued
until methotrexate levels are <5 × 10−8 M. In addition to bone mar­
row suppression and mucosal irritation, methotrexate can cause renal
failure itself at high doses owing to crystallization in renal tubules;
therefore, high-dose regimens require alkalinization of urine with
increased flow by hydration. Methotrexate can be sequestered in thirdspace collections and diffuse back into the general circulation, causing
prolonged myelosuppression. Less frequent adverse effects include
reversible increases in transaminases and hypersensitivity-like pul­
monary syndrome. Chronic low-dose methotrexate can cause hepatic
fibrosis. When administered to the intrathecal space, methotrexate can
cause chemical arachnoiditis and CNS dysfunction.
Pemetrexed is a folate-directed antimetabolite that inhibits the
activity of several enzymes, including thymidylate synthetase (TS),
dihydrofolate reductase, and glycinamide ribonucleotide formyltrans­
ferase. To avoid toxicity to normal tissues, pemetrexed is given with
low-dose folate and vitamin B12 supplementation. Pemetrexed has
notable activity against certain lung cancers and, in combination with
cisplatin, also against mesotheliomas.
5-Fluorouracil (5-FU) represents an early example of “rational”
drug design in that tumor cells incorporate radiolabeled uracil more
efficiently into DNA than normal cells. 5-FU is metabolized in cells to
5′FdUMP, which inhibits TS. In addition, misincorporation can lead
to single-strand breaks, and RNA can aberrantly incorporate FUMP.
5-FU is metabolized by dihydropyrimidine dehydrogenase, and defi­
ciency of this enzyme can lead to excessive toxicity from 5-FU. Oral
bioavailability varies unreliably, but prodrugs such as capecitabine
have been developed that allow at least equivalent activity to parenteral
5-FU-based approaches. Intravenous administration of 5-FU leads to
bone marrow suppression after short infusions but to stomatitis after
prolonged infusions. Leucovorin augments the activity of 5-FU by pro­
moting formation of the ternary covalent complex of 5-FU, the reduced
folate, and TS. Less frequent toxicities include CNS dysfunction, with
prominent cerebellar signs, and endothelial toxicity manifested by
thrombosis, including pulmonary embolus and myocardial infarc­
tion. Trifluridine is a fluorinated pyrimidine that as the triphosphate
is directly incorporated into DNA, evoking DNA damage, and as the
monophosphate can inhibit TS. It is administered as a fixed-dose
combination with tipiracil, an inhibitor of trifluridine degradation by
thymidine phosphorylase.
Cytosine arabinoside (ara-C) is incorporated into DNA after for­
mation of ara-CTP, resulting in S-phase–related toxicity. Continuous
infusion schedules allow maximal efficiency, with uptake maximal
at 5–7 μM. Ara-C can be administered intrathecally. Adverse effects
include nausea, diarrhea, stomatitis, chemical conjunctivitis, and
cerebellar ataxia. Gemcitabine is a cytosine derivative that is similar
to ara-C in that it is incorporated into DNA after anabolism to the
triphosphate, rendering DNA susceptible to breakage and repair syn­
thesis, which differs from that in ara-C in that gemcitabine-induced
lesions are very inefficiently removed. In contrast to ara-C, gem­
citabine appears to have useful activity in a variety of solid tumors, with
limited nonmyelosuppressive toxicities.
6-Thioguanine and 6-mercaptopurine (6-MP) are used in the treat­
ment of acute lymphoid leukemia. Although administered orally, they
display variable bioavailability. 6-MP is metabolized by xanthine oxi­
dase and therefore requires dose reduction when used with allopurinol.
6-MP is also metabolized by thiopurine methyltransferase; genetic
deficiency of thiopurine methyltransferase results in excessive toxicity.
Fludarabine phosphate is a prodrug of F-adenine arabinoside
(F-ara-A). F-ara-A is incorporated into DNA and can cause delayed
cytotoxicity even in cells with low growth fraction, including chronic
lymphocytic leukemia and follicular B-cell lymphoma. CNS and
peripheral nerve dysfunction and T-cell depletion leading to opportu­
nistic infections can occur in addition to myelosuppression.
Agents that indirectly affect purine and pyrimidine metabolism
with anti-metabolite-like effects include hydroxyurea, which reversibly
inhibits ribonucleotide reductase, resulting in S-phase block. It is orally
bioavailable and useful for the acute management of myeloprolifera­
tive states. Asparaginase is a bacterial enzyme that causes breakdown
of extracellular asparagine required for protein synthesis in certain
leukemic cells. This effectively stops tumor cell DNA synthesis, as
DNA synthesis requires concurrent protein synthesis. Because aspara­
ginase is a foreign protein, hypersensitivity reactions are common, as
are effects on organs such as pancreas and liver that normally support
continuing protein synthesis of secreted products. This may result
in decreased insulin secretion with hyperglycemia, with or without
hyperamylasemia and clotting function abnormalities. Close moni­
toring of clotting functions should accompany use of asparaginase.
Paradoxically, owing to depletion of rapidly turning over anticoagulant
factors, thromboses particularly affecting the CNS may also be seen
with asparaginase.
Mitotic Spindle Inhibitors 
Microtubules form the mitotic spin­
dle, and in interphase cells, they are responsible for the cellular “scaf­
folding” along which various motile and secretory processes occur.
Microtubules are composed of repeating heterodimers of α and β iso­
forms of the protein tubulin. Vincristine binds to the tubulin heterodi­
mer with the result that microtubules are disaggregated. This results in
the block of growing cells in M-phase, where a structurally disordered
mitotic spindle apparatus is a powerful proapoptotic signal (Fig. 78-3).
Vincristine is metabolized by the liver, and dose adjustment in the pres­
ence of hepatic dysfunction is required. It is a powerful vesicant, and
infiltration can be treated by local heat and infiltration of hyaluroni­
dase. At clinically used intravenous doses, neurotoxicity in the form of
glove-and-stocking neuropathy is frequent. Acute neuropathic effects
include jaw pain, paralytic ileus, urinary retention, and the syndrome
of inappropriate antidiuretic hormone secretion. Myelosuppression is
not seen at conventional doses. Vinblastine is similar to vincristine,
except that it tends to be more myelotoxic, with more frequent throm­
bocytopenia and also mucositis and stomatitis. Vinorelbine is a vinca
alkaloid that appears to have differences in resistance patterns in com­
parison to vincristine and vinblastine; it may be administered orally.
CHAPTER 78
The taxanes include paclitaxel and docetaxel. These agents differ
from the vinca alkaloids in that the taxanes stabilize microtubules
against depolymerization. The “stabilized” microtubules function
abnormally and are not able to undergo the normal dynamic changes
of microtubule structure and function necessary for cell cycle comple­
tion. Taxanes are among the most broadly active antineoplastic agents
for use in solid tumors, with evidence of activity in ovarian, breast,
prostate, and non-small cell lung cancers, and Kaposi’s sarcoma. They
are administered intravenously, and their vehicles cause hypersensi­
tivity reactions. Premedication with dexamethasone (8–16 mg orally
or intravenously 12 and 6 h before treatment) and diphenhydramine
(50 mg) and cimetidine (300 mg), both 30 min before treatment,
decreases but does not eliminate the risk of hypersensitivity reactions
to the paclitaxel vehicle. A protein-bound formulation of paclitaxel
(called nab-paclitaxel) has at least equivalent antineoplastic activity and
decreased risk of hypersensitivity reactions. Paclitaxel may also cause
myelosuppression, neurotoxicity in the form of glove-and-stocking
numbness, and paresthesia. Docetaxel causes comparable degrees of
myelosuppression and neuropathy. Docetaxel uses a different vehicle
that can cause fluid retention in addition to hypersensitivity reactions;
dexamethasone premedication with or without antihistamines is also
generally used. Cabazitaxel is a taxane with somewhat better activity
in prostate cancers than earlier generations of taxanes, perhaps due to
superior delivery to sites of disease.
Principles of Cancer Treatment
Epothilones represent a class of microtubule-stabilizing agents
optimized for activity in taxane-resistant tumors. Ixabepilone has clear
evidence of activity in breast cancers resistant to taxanes and anthra­
cyclines such as doxorubicin. Side effects include myelosuppression
and peripheral sensory neuropathy. Eribulin is a microtubule-directed
agent with activity in patients who have had progression of disease on
taxanes. It alters dynamics of microtubule remodeling in cells.
■
■ANTIBODY-DRUG CONJUGATES
In an effort to improve therapeutic index and enhance antitumor effect,
antibody-drug conjugates (ADCs; Fig. 78-4) have recently entered clin­
ical practice. In this approach, humanized monoclonal antibodies are
covalently linked to cytotoxic agents by “linkers.” When bound to tar­
get antigens on tumor cells, the nature of the linker determines whether
the cytotoxic agent is released only after the ADC is internalized by
degradation in a lysosomal compartment, or release of the cytotoxin
might occur extracellularly by proteases or physical properties of the
tumor microenvironment, in the latter case allowing “bystander” cell
killing. Of importance is selection of antibodies with sufficient tumor
TABLE 78-6  Antibody-Drug Conjugates
TOXIC MECHANISM
TARGET ANTIGEN
DISEASE ACTIVITY
NOTES
DNA Structure
Gemtuzumab ozogamicin
CD33
Acute myeloid leukemia, CD33+
IR*, My, ↑LFTs ± VOD
Inotuzumab ozogamicin
CD22
Pre-B acute lymphoid leukemia
IR*, My, ↑LFTs ± VOD, ↑QT
Loncastuximab tesirine-lpyl
CD19
Diffuse large B-cell lymphoma
VLS, My, Der
Microtubule Structure
Ado-trastuzumab emtansine
HER2
Breast cancer, HER2+
IR, ↑LFTs, ↓LVEF, My, Plm, Neu
Belantamab mafadotin-blm
CD38
Myeloma
IR, My, Cor
Brentuximab vedotin
CD30
Hodgkin’s disease; anaplastic large-cell
lymphoma; mycosis fungoides, CD30+
Enfortumab vedotin
Nectin-4
Urothelial cancer
↑Glucose ± DKA, Neu, Cor, Ves, Der
Mirvetuximab soravtansine-gynx
Folate receptor α (FRα+)
Ovary, peritoneal, fallopian tube cancer, FRα+
Cor, Neu, My
Polatuzumab vedotin
CD79b
High-grade B-cell lymphoma
Neu, IR*, My, PML, TLS, ↑LFTs
Tisotumab vedotin-tftv
Tissue factor
Uterine cervix cancer
Neu, ↑PT, ↑PTT, Cor, bleeding, Plm
Topoisomerase I
Fam-trastuzumab deruxtecan-nxki
HER2
HER2 1+/weak BC, HER2 activating mutation+
NSCLC, HER2+ gastric
Sacituzumab govitecan-bziy
Trop2
Triple-negative BC, HR+/HER2– BC, urothelial
cancer
PART 4
Oncology and Hematology
Note: Data abstracted in part from publicly available U.S. Food and Drug Administration label. All agents in this class have the potential for prominent embryofetal toxicity;
use without contraception by female patients of childbearing potential is not recommended. Effective contraception for female partners who are of childbearing potential of
patients undergoing treatment should also be considered; use during lactation is also not recommended; all DNA interacting agents have theoretical risk of late secondary
neoplasms, particularly where noted. Indications and events of prominent general medical importance include the following: BC, breast cancer; Cor, corneal keratopathy,
consider pretreatment ophthalmologic exam with prophylactic lubricating eyedrops ± ocular steroids; CYP___, interaction with drugs metabolized by the indicated
cytochrome(s) P450; DA-H, dose adjust for hepatic dysfunction; DA-R, dose adjust for renal dysfunction; Der, dermatologic toxicity; DKA, diabetic ketoacidosis; G-CSF,
granulocyte colony-stimulating factor; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; ILD, interstitial lung disease; IR, infusion reaction; IR*,
infusion reaction prophylaxis specifically recommended; LFT, liver function tests; ↓LVEF, left ventricular ejection fraction, monitor echocardiogram; My, anemia, decrease
in white blood cells, platelets, with risk of neutropenic fever, hemorrhage, therefore dose reduce or hold dose for decreased neutrophil or platelet counts unless marrow
infiltrated by drug-responsive tumor; N, nausea; Neu, peripheral neuropathy; Plm, pulmonary; PML, progressive multifocal leukoencephalopathy risk; PT, prothrombin time;
PTT, partial thromboplastin time; ↑QT, pre- and intratreatment electrocardiogram monitoring, normalize K+, Mg2+, ionized Ca2+; R, renal injury possible; TLS, risk of tumor lysis
syndrome if brisk response; UGT___, metabolism by UDP-glucuronosyltransferase of the indicated genotype; V, vomiting; Ves, extravasation injury possible; VLS, vascular
leak syndrome; VOD, veno-occlusive liver disease.
cell selectivity to avoid damage to normal tissue. In addition, the linker
strategy should have low spontaneous release of the cytotoxic agent
prior to reaching the tumor environment. Table 78-6 lists currently
approved ADCs and features of importance relevant to their use for
the general internist.
Three major groups of ADCs are currently available, based on the
nature of the cytotoxic payload. ADCs targeting DNA structure include
those based on calicheamicin, a DNA-interacting antitumor antibiotic
too toxic for clinical use but, when used as an ADC, can be useful
in the treatment of CD33+ acute myeloid leukemia (gemtuzumab
ozogamicin) and CD22+ acute lymphocytic leukemia (inotuzumab
ozogamicin). Patients must be monitored for hypersensitivity reactions
and for hepatotoxicity due to veno-occlusive disease of hepatic veins,
resulting from release of the calicheamicin or its metabolites in the
liver. Likewise, the minor groove binder and DNA alkylator pyrrolo­
benzodiazepine dimer is the basis for CD19-directed loncastuximab
tesirine-lpyl, whose use in refractory diffuse large B-cell lymphoma can
be complicated by vascular leak syndrome, cytopenias, and cutaneous
reactions.
ADCs targeting microtubules (in all cases with the potential for
cytopenias and neuropathic adverse events) are of two types. Maytan­
sine derivatives include ado-trastuzumab emtansine, which is an ADC
employing the HER2/neu-directed trastuzumab and a highly toxic
microtubule-targeted emtansine, which by itself is too toxic for human
use; the ADC shows valuable activity in patients with breast cancer
who have developed resistance to trastuzumab alone (still watch for
cardiac and pulmonary side effects). Mirvetuximab soravtansine-gynx
targets folate receptor α in refractory ovarian cancers (monitor for
corneal side effects). The second microtubule-directed class of ADCs
is derived from the microtubule poison monomethylauristatin E as
cytotoxic agent. Brentuximab vedotin is an anti-CD30 ADC with activ­
ity in neoplasms such as Hodgkin’s lymphoma where the tumor cells
frequently express CD30. Polatuzumab vedotin analogously targets
Neu, IR, My, Plm, R, TLS, CYP3A4, ↑LFTs, DA-H,
DA-R
N/V prophylaxis, ILD prompt evaluate cough,
dyspnea, My, ↓LVEF
IR*, N/V prophylaxis, diarrhea consider
loperamide, My esp UGT1A1*28, consider G-CSF
CD79a in B-cell lymphomas. Enfortumab vedotin uses an antibody
to NECTIN4 to target the vedotin “warhead” to urothelial neoplasms
expressing that target. Belantamab mafodotin targets BCMA (B-cell
maturation) expressed myeloma but using a distinct microtubule toxin
derived from auristatin F. Belantamab mafodotin can cause ocular
keratopathy, which requires prospective monitoring.
Topoisomerase I–directed ADCs, including fam-trastuzumab derux­
tecan-nxki and sacituzumab govitecan-bziy, are ADCs that allow
specific targeting of camptothecin and SN-38, respectively to HER2positive neoplasms (monitoring for interstitial pneumonitis and cardiac
dysfunction) and, in the latter case, triple-negative breast cancers, which
abundantly express the antibody target Trop2, a cell surface glycoprotein
first discovered in trophoblast cells (but diarrhea should be vigorously
addressed with loperamide, similar to what might be encountered with
irinotecan). Both agents can cause cytopenias, nausea, and vomiting.
■
■CANCER MOLECULAR TARGETED THERAPY
Agents in this class share the characteristic that they are directed at
specific cancer cell molecular targets important in the proliferation of
tumors. While these agents can ultimately lead to tumor cell death, this
occurs by altered regulation of a specific biochemical pathway affecting
tumor cell susceptibility to apoptosis or growth arrest (Fig. 78-3). Since
many approved agents of this type are directed at specific mutations
present at diagnosis or that arise during the course of a patient’s clinical
course, their use must be guided by refined diagnostic strategies. Initial
molecular testing of a diagnostic biopsy, with repeated biopsies as war­
ranted, should be considered. Alternatively liquid biopsies to examine
plasma DNA shed from tumors or present in circulating tumor cells
have entered into routine clinical use to assist in making decisions
about best strategies to consider.
Hormone Receptor–Directed Therapy 
Steroid hormone
receptor–related molecules were arguably the first “molecular target”
classes of anticancer drugs. When bound to their ligands, these recep­
tors can alter gene transcription in hormone-responsive tissues. While
in some cases, such as breast cancer, demonstration of the target hor­
mone receptor is necessary for their use, in other cases such prostate
cancer (androgen receptor) and lymphoid neoplasms (glucocorticoid
receptor), the relevant receptor is always present in the tumor.
Glucocorticoids are generally given in “pulsed” high doses in leu­
kemias and lymphomas, where they induce cell death in tumor cells.
Cushing’s syndrome and inadvertent adrenal suppression on with­
drawal from high-dose glucocorticoids can be significant complica­
tions, along with infections common in immunosuppressed patients,
in particular Pneumocystis pneumonia, which classically appears a few
days after completing a course of high-dose glucocorticoids.
Tamoxifen is a partial estrogen receptor (ER) antagonist; it antago­
nizes growth in wild-type (ER; also designated ESR1 to specify estro­
gen receptor α) breast tumors, mirroring its effect on breast tissue,
but owing to agonistic activities in vascular and uterine tissue, side
effects include increased risk of thromboembolic phenomena and a
small increased incidence of endometrial carcinoma, which appears
after chronic use (usually >5 years). Progestational agents—including
medroxyprogesterone acetate, androgens including fluoxymesterone
(Halotestin), and paradoxically, estrogens—have approximately the
same degree of activity in primary hormonal treatment of breast can­
cers that have elevated expression of ER protein. Estrogen itself is not
used often due to prominent cardiovascular and uterotropic activity.
Aromatase refers to a family of enzymes that catalyze the forma­
tion of estrogen in various tissues, including ovary, peripheral adipose
tissue, and some tumor cells. Aromatase inhibitors are of two types:
irreversible steroid analogues such as exemestane and the reversible
inhibitors such as anastrozole and letrozole. Anastrozole is superior
to tamoxifen in the adjuvant treatment of breast cancer in postmeno­
pausal patients with ER-positive tumors. Letrozole treatment affords
benefit following tamoxifen treatment. Adverse effects of aromatase
inhibitors may include an increased risk of osteoporosis, fatigue, and
altered serum lipids. ESR1 mutations of various types are detected at
increased frequency after resistance to aromatase inhibitors occurs.
Fulvestrant is the prototype of a selective ER degrader. As a result
of its binding, the ER is degraded and ER-dependent proliferation may
diminish.
Metastatic prostate cancer is treated primarily by androgen depriva­
tion. Orchiectomy causes responses in 80% of patients. If not accepted
by the patient, testicular androgen suppression can also be induced
by luteinizing hormone–releasing hormone (LHRH) agonists such as
leuprolide and goserelin. These agents cause tonic stimulation of the
LHRH receptor, with loss of normal pulsatile activation resulting in net
decreased output of luteinizing hormone (LH) by the anterior pituitary.
Therefore, as primary hormonal manipulation in prostate cancer, one
can choose orchiectomy or an LHRH agonist, but not both. This path­
way can also be blocked by relugolix, an oral gonadotropin-releasing
hormone antagonist.
The addition of androgen receptor blockers, including flutamide or
bicalutamide, is of uncertain additional benefit in extending overall
response duration, although pretreatment with these agents before
LHRH agonists is important to avoid a surge in testosterone after
initial LH release. Enzalutamide also binds to the androgen receptor
and antagonizes androgen action in a mechanistically distinct way.
Somewhat analogous to inhibitors of aromatase, agents have been
derived that inhibit testosterone and other androgen synthesis in
the testis, adrenal gland, and prostate tissue. Abiraterone inhibits 17
α-hydroxylase/C17,20 lyase (CYP17A1) and has been shown to be
active in prostate cancer patients experiencing disease progression
despite androgen blockade.
Tumors that respond to a primary hormonal manipulation may fre­
quently respond to second and third hormonal manipulations. Thus,
breast tumors that had previously responded to tamoxifen have, on
relapse, notable response rates to withdrawal of tamoxifen itself or to
subsequent addition of an aromatase inhibitor or progestin. Likewise,
initial treatment of prostate cancers with leuprolide plus flutamide
may be followed after disease progression by response to withdrawal of
flutamide. These responses may result from the removal of antagonists
from mutant steroid hormone receptors that have come to depend on
the presence of the antagonist as a growth-promoting influence.
Non-Receptor-Linked Tyrosine Kinase Antagonists 
Table 78-7
lists currently approved non–hormone receptor pathway-directed
molecularly targeted chemotherapy agents, with features of their use
of import to the generalist, particularly in recognizing potential druginduced morbidities and interactions with other classes of drugs. The
basis for discovery of drugs of this type was the prior knowledge of
oncogene-directed pathways driving tumor growth (Fig. 78-3). In
most cases, non-receptor tyrosine kinases ultimately activate signal­
ing through the RAF/MEK/MAP kinase cascade, in common with
the receptor-linked tyrosine kinases. Diagnostic demonstration of an
active non-receptor tyrosine kinase may guide selection of an agent. A
repeated preclinical and clinical observation in a variety of tumor types
is that mutational activation of the tyrosine kinase target induces a
state of “oncogene addiction” on the part of the tumor. This then is the
basis for a “synthetic lethal” effect of the kinase inhibitor with respect
to tumor viability.
In hematologic tumors, the prototypic agent of this type is imatinib,
which targets the ATP binding site of the p210bcr-abl protein tyrosine
kinase that is formed as the result of the chromosome 9;22 translo­
cation producing the Philadelphia chromosome in chronic myeloid
leukemia (CML). Subsequent studies have shown value of imatinib
in gastrointestinal stromal tumor (GIST) and certain myeloprolifera­
tive disorders, driven by certain mutants of cKIT and platelet-derived
growth factor receptor (PDGFR). Imatinib has lesser activity in the
blast phase of CML, where the cells may have acquired additional muta­
tions in p210bcr-abl itself or other genetic lesions. Imatinib’s side effects
are relatively limited in most patients and include hepatic dysfunction,
diarrhea, and fluid retention. Rarely, patients receiving imatinib have
decreased cardiac function, which may persist after discontinuation of
the drug. The quality of response to imatinib enters into the decision
about when to refer patients with CML for consideration of stem cell
transplant approaches. Nilotinib is a tyrosine protein kinase inhibitor
with activity against p210bcr-abl but with increased potency and perhaps
better tolerance by certain patients. Dasatinib, another inhibitor of the
p210bcr-abl oncoproteins, also has activity against certain mutant variants
of p210bcr-abl that are refractory to imatinib and arise during therapy
or are present de novo. Dasatinib also has inhibitory action against
kinases belonging to the src tyrosine protein kinase family; this activity
may contribute to its effects. The T315I mutant of p210bcr-abl is resistant
to imatinib, nilotinib, bosutinib, and dasatinib; ponatinib has activity
in patients with this T315Ip210bcr-abl, but ponatinib has noteworthy
associated thromboembolic toxicity. Use of this class of targeted agents
is thus critically guided not only by the presence of the p210bcr-abl tyro­
sine kinase, but also by the presence of specific mutations in the ATP
binding site. Asciminib is a first-in-class non-ATP site p210bcr-abl inhibi­
tor that also has activity in BRC/ABL T315I mutant CML.
CHAPTER 78
Principles of Cancer Treatment
Janus kinases (JAK) 1 and 2 are mutated in certain myeloprolifera­
tive states; cytopenias and infrequent arrhythmias infrequently com­
plicate the use of ruxolitinib, the prototypic JAK inhibitor. Bruton’s
tyrosine kinase (BTK) is an intrinsic component of B-cell antigen
receptor signaling activated in many types of proliferating B cells and
B-cell neoplasms. Irreversible inhibitors of BTK, including ibrutinib,
acalabrutinib, and zanubrutinib, have noteworthy activity in certain
lymphomas. Cytopenias and cardiac arrhythmias can occur, along with
propensity to infection (indeed, the BTK was discovered as deficient in
congenital hypogammaglobulinemia, presenting with repeated infec­
tions in childhood). Initial use of the BTK inhibitors requires consid­
eration of prophylaxis against tumor lysis syndrome in case of a robust
lympholytic effect of the agent. If and when resistance to irreversible
BTK inhibitors develops (often associated with a C481S mutation), the
noncovalent inhibitor pirtobrutinib may have activity.
Receptor-Linked Tyrosine Kinase Antagonists 
Mutated
EGFR drives a significant fraction of non-small-cell lung cancers
(NSCLCs). Erlotinib and gefitinib are the prototypic EGFR antagonists
that, in early clinical trials, showed evidence of responses in a small
TABLE 78-7  Molecularly Targeted Agents
DRUG
TARGET/INDICATION
ADVERSE EVENTS
NOTES
Non-Receptor Tyrosine Kinase Antagonists
Acalabrutinib
BTK/certain B-cell malignancies
My, atrial fibrillation/flutter, infection
CYP3A4; avoid PPIs and stagger doses with H2 blockers;
irreversible BTK inhibitor
Asciminib
BCR/ABL/CML chronic phase after 2
TKIs or with BCR/ABL T315I
My, ↑lipase, ↑amylase, HBP, hypersensitivity,
cardiac events
Bosutinib
BCR/ABL wild-type, some mutants/CML
My, ↑LFT, cardiac, R, fluid retention
CYP3A4, PPI (use short-acting antacids or H2 blocker
staggered with dose)
Dasatinib
BCR/ABL/Ph+ CML, Ph+ ALL
My, pulmonary hypertension, fluid retention,
↓LVEF, ↑LFT, Der
Ibrutinib
As with acalabrutinib
My, stomatitis, HBP, arrhythmia, TLS
CY3A4, second primary malignancy
Imatinib
ABL, BCR/ABL wild-type, cKIT PDGFR/
CML, some ALL, certain GISTs,
eosinophil, mast cell, myelodysplastic
syndromes
My, edema, fluid retention, ↓LVEF, ↑LFT rare
liver failure, GI perforation, Der, TLS, ↓CrCl
Nilotinib
BCR/ABL wild-type/CML
CHF, ↑LFT, ↑QT, fluid retention, ↑lipase, TLS
CYP3A4, CYP2C8, CYP2C9, CYP2D6, CYP2B6; no food 2 h
before, 1 h after dose; monitor electrolytes, TFTs
Pirtobrutinib
As with acalabrutinib
My, arrhythmia, infection, hemorrhage
DA-R, CYP3A4; CYP2C8, 2C19, Pgp, BCRP substrates;
reversible BTK inhibitor, second primary malignancy
Ponatinib
T315I mutant BCR/ABL CML
Clotting, ↑LFT, TLS, ↓LVEF, pancreatitis, Neu,
arrhythmia
PART 4
Oncology and Hematology
Ruxolitinib
JAK1,2/myeloproliferative disorders
My, dizziness, headache
DA-R, DA-H, CYP3A4 or with fluconazole >200 mg doses
except with GVHD
Zanubrutinib
As with acalabrutinib
My, hemorrhage, cardiac arrhythmias
CYP3A4
Receptor-Linked Tyrosine Kinase Antagonists
Afatinib
Nonresistant ATP site mutated EGFR/
NSCLC
D, Der, Cor, ILD; ↑LFT
DA-R, DA-Pgp inhibitors, no food 2 h before, 1 h after dose
Alectinib
ALK rearranged/NSCLC
↑LFT, ILD, R, bradycardia, ↑CPK
Administer with food; can have muscle pain, tenderness,
weakness
Avapritinib
PDGFR mutants/GIST, mastocytosis
N, edema, CNS, sleep, mood change,
hallucinations
Capmatinib
MET + exon 14 skip/NSCLC
ILD, ↑LFT, photosensitivity, pancreatitis,
hypersensitivity
Ceritinib
ALK rearranged/NSCLC
GI, ↑LFT, ↑glucose, ↑QT, bradycardia,
pancreatitis
Crizotinib
ALK rearranged/NSCLC; inflammatory
myofibroblastic tumor, anaplastic largecell lymphoma
ILD, ↑LFT, ↑QT, bradycardia, ↓vision
CY3A4
Dacomitinib
EGFR exon 19 deletion or exon 21 L858R/
NSCLC
D, Der: hold and/or dose reduce; ILD
(permanently discontinue)
Erdafitinib
FGFR2/3 altered/urothelial cancer after
Pt regimen
Der, D, stomatitis, retina (ophthalmologic
exam before/during)
Erlotinib
As with afatinib; also wild-type EGFR/
NSCLC 2nd line or pancreatic 1st line
with gemcitabine
Der, D, R, ILD, ↑LFT, rare microangiopathic
anemia
Fruquintinib
Target VEGFR1,2,3/CRC
HBP, hemorrhage, arterial thromboses,
infection, GI perforation, ↑LFT, proteinuria,
↓wound healing, allergic bronchospasm
Futibatinib
FGFR2 gene fusions/
cholangiocarcinoma
Retina (ophthalmologic exam before/during)
CYP3A4, Pgp substrates; ↑PO4 due to effect on FGFR2/3/
Klotho, tissue and vascular calcification
Gefitinib
As with afatinib
Der, D, ILD, ocular keratitis, GI perforation
CYP3A4; avoid with PPIs; monitor warfarin effect
Gilteritinib
FLT3 mutated/AML
↑LFT, ↑QT, myalgia/arthralgia, N, V, GI, Der,
edema, dyspnea
Infigratinib
FGFR2 variants/cholangiocarcinoma
Retina (ophthalmologic exam before/during)
CYP3A4, avoid gastric acid reduction or stagger with
H2 blockers or locally acting agents, ↑PO4 due to effect
on FGFR2/3/Klotho, soft tissue including myocardial
mineralization
Lapatinib
HER2/HER2+ breast cancer
↓LVEF, ↑LFT, N, V, D, PPED
CYP3A4, CYP2C8, Pgp substrate; interaction, ILD, ↑QT
Larotrectinib
NTRK gene fusion without a resistance
mutation/any solid tumor
CNS with potential cognitive impairment; ↑LFT CYP3A4
Lorlatinib
ALK rearranged/NSCLC
Hyperlipidemia, AV block, CNS including
seizures, mental status changes
Neratinib
As with lapatinib
N, V, D, abdominal pain, ↑LFT
CYP3A4, aggressive D prophylaxis with loperamide; avoid
PPIs and stagger H2 blocker doses
CYP3A4, CYP2C9, Pgp; not an ATP site inhibitor but inhibit
by allosteric mechanism binding to myristoyl pocket in
BCR/ABL
CYP3A4, avoid PPIs and stagger doses with H2 blockers;
caution with agents with ↑QT
DA-H, DA-R, CYP3A4, CYP2D6; hemorrhage at tumor site
in GIST, cardiogenic shock with high eosinophil levels;
monitor TFTs with thyroid replacement
CYP3A4, PRES possible
CYP3A4, monitor for intracranial hemorrhage
 
CYP3A4, CYP2C9; if ILD, permanently discontinue
CYP2D6; avoid PPIs, use local antacids or give 6 h before
or 10 h after H2 blockers
CYP2C9, CYP3A4, also organic cation transporter 2 and
Pgp substrates, give 6 h before/after Pgp substrates; ↑PO4
due to effect on FGFR2/3/Klotho
CYP3A4, give 1 h before/2 h after meals, avoid PPIs,
stagger with H2 blockers; alter warfarin effect
CYP3A4; unusual, PPED, PRES
Monitor for PRES, pancreatitis, ↑Cr, eye disorders
CYP3A4 with severe ↑LFT with CYP3A interactors; monitor
for ILD and discontinue if occur
(Continued)
TABLE 78-7  Molecularly Targeted Agents
(Continued)
DRUG
TARGET/INDICATION
ADVERSE EVENTS
NOTES
Osimertinib
EGFR exon 19 altered or exon 21L858R or
T790M mutations/NSCLC
ILD, ↑QT, ↓LVEF, Cor
CYP3A4
Pemigatinib
FGFR2 fusion or other rearrangement/
cholangiocarcinoma
FGFR1 rearranged myeloid/lymphoid
neoplasms
N, D, stomatitis, ↑PO4 due to effect on
FGFR2/3/Klotho
Pralsetinib
RET mutant or fusion/NSCLC, thyroid
carcinomas
ILD, HBP, hemorrhage, ↑LFT, TLS, ↓wound
healing
Quizartinib
FLT3 mutated/AML
↑QT with risk of cardiac arrest
CYP3A4
Repotrectinib
Target ROS1 rearranged/NSCLC
CNS, ILD, ↑LFT, myalgia, ↑CPK
CYP3A4, Pgp, OCs; also target TRKA,B,C
Selpercatinib
RET mutant or fusion/NSCLC, thyroid
carcinomas
↑LFT, ↑QT, HBP, bleeding, ↓wound healing;
hold 1 week prior and 2 weeks after surgery
Tepotinib
MET with exon 14 skipping mutations/
NSCLC
ILD, ↑LFT
CYP3A4, Pgp; DA-H
Tucatinib
As with lapatinib
↑LFT, D
CYP3A4, CYP2C8
KRAS-G12C/RAF/MEK Antagonists
Adagrasib
KRAS G12C mutation/NSCLC
N, V, D, ↑LFT, ↑QT, ILD
CYP3A4, CYP2C9, CYP2D6, agents that ↑QT
Binimetinib
Targets MEK/BRAF V600E or V600K
mutated melanoma combined with
encorafenib
↓LVEF, venous thrombosis; ocular, ILD, ↑LFT,
rhabdomyolysis
Cobimetinib
Targets MEK/BRAF V600E or V600K
melanoma combined with vemurafenib;
alone in BRAF V600E or V600K
histiocytic neoplasms
Hemorrhage, retinal ↓LVEF, Der,
photosensitivity, rhabdomyolysis, ↑LFT
Dabrafenib
Targets BRAF in BRAF V600E or V600K
mutated tumors (not CRC) with trametinib
Hemorrhage, uveitis ↓LVEF, Der, ↑glucose,
hemolysis if G6PD deficient, pyrexia
Encorafenib
Targets BRAF in BRAF V600E or
V600K mutated tumors combined with
binimetinib (melanoma) or CRC with
cetuximab
Hemorrhage, uveitis, ↑QT
CYP3A4, organic anion transporter 1B1, BCRP
interactions, new malignancies, cutaneous and
noncutaneous
Sotorasib
KRAS G12C mutation/NSCLC
↑LFT, ILD, N, V, D
Avoid with PPIs and H2 receptor antagonists; if
necessary, administer 4 h before or 10 h after a local
antacid, avoid CYP3A4, Pgp substrates
Trametinib
Targets MEK/BRAF V600E or V600K
mutated tumors (not colorectal)
combined with dabrafenib
Hemorrhage, venous thromboembolism,
↓LVEF, ILD, pyrexia, Der, ↑glucose
Vemurafenib
Targets BRAF in BRAF V600E or V600K
mutated melanoma and ErdheimChester disease
Der including Stevens-Johnson, anaphylaxis
and allergic hypersensitivity, ↑QT, ↑LFT,
photosensitivity, radiation recall
Multikinase Antagonists
Axitinib
VEGFR, PDGFR, KIT/RCC
HBP, hemorrhage, thrombotic events; D,
other GI including GI perforation, PPED,
hypothyroidism, PRES, proteinuria, ↑LFT
Brigatinib
ALK, EGFR/NSCLC
ILD, bradycardia, HBP, visual disturbances,
↑glucose, ↑CPK
Cabozantinib
VEGFR2, MET, AXL, RET/RCC, HCC,
certain thyroid carcinoma
HBP, hemorrhage, thrombotic events, D,
other GI including fistula, perforation, wound
healing, PRES, PPED, proteinuria, ONJ
Capivasertib
Target PIK3CA/AKT1/PTEN- axis;
BC-HR(+) with mutation in pathway
Hypersensitivity reactions, Der, ↑glucose,
pneumonitis, ILD, D
Entrectinib
NRTK gene fusion/any solid tumor; ROS1
gene alteration/NSCLC
ILD, ↑LFT, photosensitivity, ↓LVEF, CNS effect,
skeletal fractures; hyperuricemia, ↑QT,
Fedratinib
JAK2, FLT3, RET/myeloproliferative
diseases
My, N, V, D, ↑LFT pancreatitis,
encephalopathy: check thiamine levels prior,
replete if deficient
Lenvatinib
VEGFR1/2/3, FGFR1/2/3/4, PDGFRα,
KIT, RET/thyroid, RC, HCC, endometrial
cancer
HBP, ↓LVEF, bleeding, arterial/venous clots,
RF, ONJ, proteinuria, ↑LFT, GI including D,
fistula/perforation, ↓wound healing, ↑QT,
↓Ca2+, PRES, ↓TFT
Midostaurin
FLT3 mutated/AML newly diagnosed,
mast cell neoplasms
ILD; N, D
CYP3A4; many other protein kinase targets in addition to
FLT3
CYP3A4, retinal detachment: ophthalmologic exam with
ocular tomography before and every 2–3 months during
treatment
CYP3A4, Pgp
Avoid with antacids, but take if not avoidable with food if
PPI or stagger with other antacid, CYP3A, CYP2C8
DA-H
CHAPTER 78
CYP3A4, new malignancies, cutaneous and noncutaneous
Principles of Cancer Treatment
CYP3A4, CYP2C8, CYP2C9, CYP2C19, CYP2B6, new
malignancies, cutaneous and noncutaneous
Colitis with GI perforation, ocular including retinal
vein occlusion, new malignancies, cutaneous and
noncutaneous
Dupuytren’s contracture and plantar fascial fibromatosis
has occurred; usually combined with cobimetinib in
melanoma; CYP3A4, CYP1A2, CYP2D6, new primary
cutaneous and noncutaneous neoplasms
DA-H, CYP3A4/5
CYP3A4, decreased hormonal contraceptive effectiveness
CYP3A4
CYP3A4, CYP2C9, BCRP substrates
CYP3A4, ophthalmologic exam if vision change
CYP3A4, CYP2C19
DA-H, DA-R
(Continued)
TABLE 78-7  Molecularly Targeted Agents
(Continued)
DRUG
TARGET/INDICATION
ADVERSE EVENTS
NOTES
Pazopanib
VEGFR 1/2/3, KIT, PDGFR, and FGFR/
RCC soft tissue sarcoma (not GIST or
adipocytic)
D, HBP; arterial and venous thrombosis ±
embolism, ↑QT, hemorrhage, ↑LFT
potentially severe/fatal; GI perforation or
fistula; proteinuria, ↓TFT, ↓LVEF, PRES, ILD,
thrombotic microangiopathy
Regorafenib
VEGFR1/2/3, KIT, RET, PDGFR-α/β,
FGFR1/2, TIE2, DDR2, Trk2A, Eph2A,
RAF1, BRAF, BRAF V600E, SAPK2, PTK5,
and ABL/CRC, GIST
↑LFT potentially severe/fatal; hemorrhage,
thromboses, PPED, Der, HBP, ↓LVEF, ↑QT, GI
perforation
Sorafenib
VEGFR2, VEGFR3, PDGFRβ, Flt3, KIT,
RAF1, BRAF/RCC, HCC, differentiated
thyroid carcinoma
D, ↑LFT potentially severe/fatal; hemorrhage,
PPED, Der, HBP, ↓LVEF, ↑QT, GI perforation
Sunitinib
VEGFRs; PDGFR, RET, KIT; other
protein kinases/RCC, pancreatic
neuroendocrine, GIST
HBP, ↑LFT potentially severe/fatal;
hemorrhage, GI perforation, CHF, altered TFTs,
ONJ, ↓wound healing, proteinuria, R
Vandetanib
VEGFR, RET, EGFR/medullary thyroid
cancer
D, Der, HBP, ↑QT, thromboses, ↓LVEF, fistulas,
ILD, ONJ, proteinuria, PRES
Cyclin-Dependent Kinase (CDK) Inhibitors
Abemaciclib
CDK4/6/HR+ BC
D, My, ↑LFT, venous thromboembolism, ILD
CYP3A4, avoid concomitant use of ketoconazole
Palbociclib
CDK4/6/HR+ BC
D, My, stomatitis, ILD, D
CYP3A4
Ribociclib
CDK4/6/HR+ BC
Der, ILD, ↑QT, ↑LFT, My
CYP3A4, agents known to ↑QT
PART 4
Oncology and Hematology
Protein Homeostasis Modulators
Bortezomib
Proteasome inhibitor/multiple myeloma,
mantle cell lymphoma
Neu, N, V, D, C, ↓BP, My, ILD, ↑LFT worsening
cardiac disease
Carfilzomib
Proteasome inhibitor/multiple myeloma
↓LVEF, myocardial ischemia, R, TLS,
pulmonary including ARDS, ILD,
HBP, IR*, thrombosis, hemorrhage,
PRES, thrombocytopenia, thrombotic
microangiopathy, ↑LFT potentially severe
Ixazomib
Proteasome inhibitor/multiple myeloma
relapsed, not as maintenance
Thrombocytopenia, N, V, D, C, Neu, edema,
Der, thrombotic microangiopathy, ↑LFT
Nuclear Export Inhibitor
Selinexor
Targets exportin 1/multiple myeloma,
certain DLBCLs
My, N, V, D, anorexia, ↓Na+, CNS, cataract
development or progression
Chromatin-Modifying Epigenetic Modulators
DNA Hypomethylating Agents
Azacytidine
Target DNA methyltransferase/
myelodysplastic syndromes, AML
My, ↑LFT, TL, CNS
Monitor if renal impairment, more N, V, D if SC
administration
Decitabine
As with azacytidine
My
Combined with cedazuridine (a cytidine deaminase
inhibitor) in an oral regimen
Histone Deacetylase Inhibitors
Belinostat
Peripheral T-cell lymphoma, relapsed or
refractory
My, ↑LFT, TLS, N, V
 
Panobinostat
Multiple myeloma, relapsed or
refractory
My, hemorrhage, ↑LFT, ↓Na+, ↓K+, ↓PO4, ↑Cr
CYP3A4, CYP2D6, avoid agents that ↑QT
Romidepsin
CTCL after one systemic therapy
My, ↑QT
CYP3A4, alter warfarin effect, may ↓ effectiveness of oral
contraceptives
Vorinostat
CTCL after two systemic therapies
My, N, V, D, venous thrombosis, ↑glucose
Monitor with mild or moderate liver disease
Histone Methyltransferase Inhibitors
Tazemetostat
Target EZH2 mutant or nonmutant/
epithelioid sarcoma, certain follicular
lymphomas
N, V, C, abdominal pain
CYP3A4, increased risk of secondary malignancies (MDS,
AML, lymphomas)
Transcription Factor Modulation
Arsenic trioxide
Target PML-RARα and redox
homeostasis/t(15;17) acute
promyelocytic leukemia
↑QT, hypersensitivity
APL differentiation syndrome: with pulmonary
dysfunction/infiltrate, pleural/pericardial effusion, fever,
treat with dexamethasone ± hydroxyurea
Belzutifan
Target HIF2α/von Hippel-Lindau
(VHL) disease–associated RCC, CNS
hemangioblastomas, GI neuroendocrine
tumors, non-VHL RCC after PD-1, VEGFR
inhibitor
Anemia, hypoxia, N, ↑Cr, ↑glucose
CYP2C19, UGTB17
Glasdegib
Targets smoothened receptor in
hedgehog pathway/AML
↑QT
CYP3A4, transmission to potentially pregnant partner
through semen or to blood product recipient
CYP3A4, CYP22D6, CYP2C8 interaction; use with
simvastatin increases the risk of ALT elevations and
should be undertaken with caution; avoid with PPIs or H2
blocker, stagger with other antacid doses
CYP3A4, impaired TSH suppression in thyroid cancer
As with regorafenib
CYP3A4, rare ↑QT, rare TLS in RCC and GIST with high
tumor burden
CYP3A4
Rare TLS, PRES
Administer after a hemodialysis procedure
DA-R, DA-H, CYP3A4
Advise against driving or dangerous equipment operation
if CNS altered
(Continued)
TABLE 78-7  Molecularly Targeted Agents
(Continued)
DRUG
TARGET/INDICATION
ADVERSE EVENTS
NOTES
Nirogacestat
Targets γ-secretase to inhibit Notch
signaling/desmoid tumor
D (can be severe), ovarian dysfunction, ↑LFTs,
PO4 and K+ abnormalities
Sonidegib
Targets smoothened receptor
in hedgehog pathway/basal cell
carcinoma locally advanced or
metastatic
Musculoskeletal adverse events with ↑CPK,
potential R, N, V, D
Tretinoin
Target PML-RARα/t(15;17) acute
promyelocytic leukemia
Der including cheilitis, skin dryness; ↑
intracranial pressure; ↑lipids, ↑LFT, usually
resolve
Vismodegib
As with sonidegib
Musculoskeletal adverse events, N, V, D, C
Transmission to potentially pregnant partner through
semen or to blood product recipient
Apoptosis Modulation
Venetoclax
Targets BCL2/CLL, SLL; AML +
azacytidine, decitabine, or low-dose
cytarabine
My, D, TLS
CYP3A4, stagger with Pgp substrates, no live attenuated
vaccines prior to, during, or after venetoclax treatment
Metabolism Modulation: mTOR Inhibitors/PI Kinase/IDH Inhibitors
Alpelisib
PIK3CA mutated/HR+HER2– BC
Der, hypersensitivity, ↑glucose, ILD, D
CYP3A, CYP2C9, BCRP substrates
Copanlisib
PI3Kα,δ/FL
My, HBP, noninfectious pneumonitis,
↑glucose, Der
Duvelisib
PI3Kδ,γ/CLL, SLL, FL
My, infection, D, colitis, Der, pneumonitis,
↑LFTs
Enasidenib
IDH2 mutated/AML
N, V, D, ↑LFTs
AML differentiation syndrome with pulmonary
dysfunction/infiltrate, pleural/pericardial effusion, fever
treat with dexamethasone ± hydroxyurea
Everolimus
mTOR/RCC, tuberous sclerosis–
associated neoplasms, HR+ BC,
neuroendocrine, pancreatic, lung, GI
NOT functional carcinoid
My, noninfectious pneumonitis, infections,
hypersensitivity reactions, R, impaired wound
healing, ↑glucose, ↑lipids, stomatitis
Ivosidenib
IDH1 mutated/AML,
cholangiocarcinoma, MDS
↑QT, Guillain-Barré syndrome
CYP3A4, QT-prolonging agents; AML differentiation
syndrome requiring corticosteroid treatment
Idelalisib
PI3Kδ/non-first-line CLL, SLL, FL
Fatal or serious ↑LFTs, D, colitis with GI
perforation, pneumonitis, infection, Der,
hypersensitivity
Olutasidenib
IDH1/AML
↑LFTs
CYP3A4, differentiation syndrome requiring corticosteroid
± hydroxyurea treatment
Sirolimus protein
bound particles
mTOR/perivascular epithelioid cell
tumor (PEComa)
My, stomatitis, infection, ↓K+, IR, ↑glucose,
ILD, hemorrhage, male infertility
Temsirolimus
mTOR/RCC
Hypersensitivity, ↑LFTs, infection, ILD,
stomatitis, thrombocytopenia, N, ↑glucose,
↑lipids, ↓wound healing, GI perforation, R ±
proteinuria
Poly-ADP Ribose Polymerase (PARP) Inhibitors
Niraparib
Ovarian, fallopian tube, or primary
peritoneal cancer with good response
to Pt
My, N, V, D, HBP, PRES
MDS
Olaparib
Ovarian: as with niraparib also with
various BRCA or HRR mutations; BC
mutant BRCA, HER2–; pancreatic
mutant BRCA with good response to Pt;
prostate with BRCA or HRR mutations
My, N, stomatitis, DVT ± PE, rare ILD
MDS, CY3A4
Rucaparib
As with niraparib; prostate BRCA
mutated after hormone and after taxane
My, stomatitis, N, V, D, ↑LFTs
MDS
Talazoparib
BC BRCA mutated HER2–; prostate
cancer, castrate-resistant HRR
mutation(+), with enzalutamide
My, N, V, D, ↑LFTs
MDS
Miscellaneous
177Lu-dotatate
Target somatostatin receptor (SSR)/
gastroenterohepatic neuroendocrine
tumors (SSR)+
My, R, ↑LFTs, IR,
Neuroendocrine hormonal crisis including flushing,
diarrhea, hypotension, bronchoconstriction; secondary
MDS, risks from radiation exposure
177Lu-vipivotide
tetraxetan
Target prostate-specific membrane
antigen (PSMA)/refractory prostate
cancer
My, R
Temporary or permanent infertility, risks from radiation
exposure
CYP3A4; avoid PPIs and stagger doses with H2 blockers;
nonmelanoma skin cancers; Der: monitor before and
during treatment
As with glasdegib
As with arsenic trioxide; also headache, visual
changes may indicate ↑intracranial pressure; check for
papilledema
CYP3A4
CHAPTER 78
CYP3A4
Principles of Cancer Treatment
CYP3A4, Pgp substrates, angioedema with concomitant
ACE inhibitors, consider alcohol-free mouthwash when
starting treatment; risk of reduced efficacy of vaccination
CYP3A4, not with bendamustine or rituximab
CYP3A4, avoid live vaccines
DA-H, CYP3A4
(Continued)
TABLE 78-7  Molecularly Targeted Agents
(Continued)
DRUG
TARGET/INDICATION
ADVERSE EVENTS
NOTES
Tagraxofusp-erzs Targets CD123 (IL-3 receptor)/blastic
IR*, ↑LFTs, VLS
Delivers a fragment of diphtheria toxin
plasmacytoid dendritic cell neoplasm
Ziv-aflibercept
Targets VEGF by solubilized VEGFR/CRC
with chemotherapy after an oxaliplatin
regimen
↓Wound healing with fistula, GI
perforation, hemorrhage, HBP, DVT, arterial
thromboembolism, proteinuria, PRES
Note: Data abstracted in part from publicly available U.S. Food and Drug Administration label. All agents in this class have the potential for prominent embryofetal toxicity;
use without contraception by female patients of childbearing potential is not recommended. Effective contraception for female partners who are of childbearing potential
of patients undergoing treatment should also be considered; use during lactation is also not recommended. Gene products are in capital letters; genes are italicized in
capitals. Indications and events of prominent general medical importance include the following: ACE, angiotensin-converting enzyme; ALK, anaplastic lymphoma kinase;
ALL, acute lymphoblastic leukemia; AML, acute myeloid leukemia; APL, acute promyelocytic leukemia; ARDS, acute respiratory distress syndrome; AV, atrioventricular;
BC, breast cancer; BCRP, breast cancer resistance protein; BP, blood pressure; BRCA, breast cancer gene; BTK, Bruton’s tyrosine kinase; C, constipation; CHF, congestive
heart failure; CLL, chronic lymphocytic leukemia; CML, chronic myelogenous leukemia; CNS, can include altered sensorium, cortical and cerebellar signs, dysarthria,
altered seizure threshold; Cor, corneal keratopathy, consider pretreatment ophthalmologic exam with prophylactic lubricating eyedrops ± ocular steroids; CRC, colorectal
cancer; CrCl, creatinine clearance; CTCL, cutaneous T-cell lymphoma; CYP___, interaction with drugs metabolized by the indicated cytochrome(s) P450; D, diarrhea; DA-H,
dose adjust for hepatic dysfunction; DA-R, dose adjust for renal dysfunction; Der, dermatologic toxicity; DLBCL, diffuse large B-cell lymphoma; DVT, deep vein thrombosis;
EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor receptor; FL, follicular lymphoma; GIST, gastrointestinal stromal tumor; GVHD, graft-versus-host
disease; H2, histamine receptor antagonist; HBP, high blood pressure; HCC, hepatocellular carcinoma; HER2, human epidermal growth factor receptor 2; HRR, homologous
recombination repair; HR, hormone receptor; HUS, hemolytic-uremic syndrome; IDH, isocitrate dehydrogenase; ILD, interstitial lung disease; IR, infusion reaction; IR*,
infusion reaction prophylaxis specifically recommended; LFT, liver function tests; LVEF, left ventricular ejection fraction monitor echocardiogram; MDS, myelodysplastic
syndrome; MET, hepatocyte growth factor; My, anemia, decrease in white blood cells, platelets, with risk of neutropenic fever, hemorrhage, therefore dose reduce or
hold dose for decreased neutrophil or platelet counts unless marrow infiltrated by drug-responsive tumor; N, nausea; Neu, peripheral neuropathy; NSCLC, non-smallcell lung cancer; OC, oral contraceptive; ONJ, osteonecrosis of the jaw; PDGFR, platelet-derived growth factor receptor; PE, pulmonary embolism; Pgp, P-glycoprotein
drug resistance protein; Ph, Philadelphia chromosome; Plm, pulmonary; PML, progressive multifocal leukoencephalopathy risk; PPED, palmar-plantar erythrodysesthesia
(i.e., hand-foot syndrome); PPI, proton pump inhibitor; PRES, posterior reversible leukoencephalopathy syndrome; Pt, platinating agent; PT, prothrombin time; PTT, partial
thromboplastin time; ↑QT, increase of QT interval needs pre- and intratreatment electrocardiogram monitoring and normalizing K+, Mg2+, ionized Ca2+; R, renal injury
possible; RCC, renal cell carcinoma; ROS1, receptor tyrosine kinase 1; SLL, small lymphocytic lymphoma; TFT, thyroid function test; TKI, tyrosine kinase inhibitor; TLS, risk
of tumor lysis syndrome if brisk response; TOPO___, agent targets the indicated topoisomerase; TSH, thyroid-stimulating hormone; UGT___, drug metabolism by UDPglucuronosyltransferase of the indicated genotype; V, vomiting; VEGFR, vascular endothelial growth factor receptor; Ves, extravasation injury possible; VLS, vascular leak
syndrome; VOD, veno-occlusive liver disease.
PART 4
Oncology and Hematology
fraction of patients with NSCLC. Subsequent studies by clinical oncol­
ogists in an effort to understand the basis of these excellent responses
found that the probability of response to the agents was markedly
increased in patients with an activating EGFR mutation, and current
practice now routinely profiles patients with NSCLC for the presence
of sensitizing mutations of EGFR. Side effects were generally accept­
able, consisting mostly of acneiform rash (treated with glucocorticoid
creams and clindamycin gel) and diarrhea. Patients with activating
mutations who initially responded to gefitinib or erlotinib but who
then had progression of the disease then acquired additional mutations
in the enzyme, analogous to the mutational variants responsible for
imatinib resistance in CML. Subsequent generations of EGFR antago­
nists have activity against more uncommon mutants (osimertinib) or a
biochemically irreversible mechanism (dacomitinib).
Mutated anaplastic lymphoma kinase (ALK) and activated RET
oncogene likewise drive distinct fractions of NSCLCs. Alectinib, ceri­
tinib, crizotinib, and lorlatinib target ALK, but have prominent adverse
cardiac, metabolic, and, in the case of lorlatinib, pulmonary events.
Selpercatinib targets RET in NSCLCs (and thyroid cancers) but also
with the chance of cardiac and liver toxicity. Repotrectinib is active in
ROS1 mutant NSCLC.
HER2-driven breast cancers may be usefully treated with lapatinib;
diarrhea and cardiac dysfunction can occur. Neratinib or tucatinib may
also be useful in HER2-positive breast cancers after trastuzumab has
ceased to be of value; diarrhea and liver toxicity also require monitor­
ing and management.
Alteration of fibroblast growth factor (FGF) signaling can contrib­
ute to the growth of urothelial carcinomas and cholangiocarcinomas.
Erdafitinib and pemigatinib, respectively, may be of utility with care­
ful attention to ocular toxicity and hyperphosphatemia; the latter is
an “on-target” toxicity of disrupting FGF receptor signaling in the
kidney. Likewise, gilteritinib is active against the FMS-like tyrosine
kinase-3 (FLT3) mutated in a fraction of poor-prognosis (treated by
conventional chemotherapy) acute myeloid leukemias (AMLs). Car­
diac, hepatic, gastrointestinal, and neurologic adverse events can occur,
along with “differentiation” of the AML cells with cytokine elaboration
and pulmonary side effects, requiring management with steroids and
potentially hydroxyurea.
The neurotropic tyrosine kinase receptor (NRTK) undergoes trans­
location with fusion to a variety of different partner genes to produce
Administer over 1 h, not as push or bolus
a family of chimeric proteins in a small fraction of a variety of solid
tumors. Larotrectinib and entrectinib may be quite useful in manag­
ing these tumors; indeed, these agents are exemplary of “histology
agnostic” agents, where the utility of the drug is not tied to a particular
histologic diagnosis, but to the possession of a specific NRTK gene
alteration. Neurotoxicity, a long half-life of the agents, and hepatotoxic
adverse events are of concern. Neuroregulin 1 (produced by the NRG1
gene) undergoes gene fusions to produce activators of HER family
heterodimer signaling, including HER3 and HER4; afatinib covalently
binds to all HER family members and has activity in patients with
NRG1 gene fusions.
RAF/MEK Pathway Antagonists 
The RAS proto-oncogene
family members (including HRAS, KRAS, and NRAS) act as “switches”
to bind GTP in response to activation of receptor tyrosine kinases;
RAS-GTP activates the RAF proto-oncogene–derived serine-threonine
kinase. RAS mutations of various types result in persistent activation of
RAS isoforms, resulting in hyperactivation of RAF and “downstream”
kinases, including MEK and MAPK. Sotorasib is a first-in-class inhibi­
tor of KRAS G12C signaling that in early clinical reports has evidence
of effecting stable disease in patients with a variety of neoplasm his­
tologies bearing that mutation, with fewer actual responses. Adagrasib
also targets KRAS-G12C with a distinct pharmaceutical profile. Neither
sotorasib nor adagrasib has activity against wild-type or other RAS
mutants, but their discovery marked a milestone, encouraging continu­
ing efforts to produce RAS-directed therapeutics.
The BRAF V600E mutation drives a substantial fraction of mela­
nomas and certain NSCLCs and has been detected in certain thyroid
tumors, colorectal tumors, hairy cell leukemias, and unusual gliomas.
BRAF inhibitors such as dabrafenib, vemurafenib, and encorafenib
have activity as single agents in many such tumors but are usually most
active when co-administered as “doublets” with the MEK inhibitors
trametinib, cobimetinib, and binimetinib, respectively, to promote
“shutdown” of RAF/MEK signaling at more than pathway member.
Cutaneous adverse events including generally indolent cutaneous
second neoplasms, and thromboembolic, cardiac, and ocular toxicity
can occur.
Multikinase Inhibitors 
Agents in this class also target specific
macromolecules promoting the viability of tumor cells. They are
“small-molecule” ATP site-directed antagonists that inhibit more than
one protein kinase and may have value in the treatment of several solid
tumors. Drugs of this type with prominent activity against the VEGFR
tyrosine kinase have activity in renal cell carcinoma. Sorafenib is a
VEGFR antagonist also with activity against the RAF serine-threonine
protein kinase, and regorafenib is a closely related drug with value in
relapsed advanced colon cancer. Pazopanib also prominently targets
VEGFR and has activity in renal carcinoma and soft tissue sarcomas.
Sunitinib has anti-VEGFR, anti-PDGFR, and anti-KIT activity. It
causes prominent responses and stabilization of disease in renal cell
cancers and GISTs. Side effects for agents with anti-VEGFR activity,
similar to those of the anti-VEGF antibody bevacizumab, prominently
include hypertension, proteinuria, and, more rarely, bleeding and clot­
ting disorders, perforation of scarred gastrointestinal lesions, and pos­
terior leukoencephalopathy, probably reflecting CNS vascular damage.
Also encountered are fatigue, diarrhea, and hand-foot syndrome, with
erythema and desquamation of the distal extremities, in some cases
requiring dose modification, particularly with sorafenib.
Other agents in this class include agents such as brigatinib (clinical
activity in ALK-dependent NSCLC, but also with anti-EGFR action),
entrectinib (clinical activity in NTRK fusion protein diseases, but also
in ROS-mutated NSCLC), and fedratinib (clinical activity in myelo­
proliferative neoplasms, but with RET activity in addition to JAK2 and
FLT3 antagonism). Agents with anti-RET activity are useful in certain
differentiated thyroid cancers and RET-fusion NSCLC.
Cyclin-Dependent Kinase Inhibitors 
Cyclin-dependent
kinases (CDKs) are activated as the result of oncogene pathway activ­
ity, and CDK4 and CDK6 phosphorylate the retinoblastoma (RB)
tumor-suppressor gene to allow entry into S-phase. Palbociclib, abe­
maciclib, and ribociclib, selective inhibitors of CDK4 and CDK6, have
noteworthy activity in advanced breast cancers also expressing the ER,
usually in conjunction with continued efforts to suppress ER signaling,
and frequently in conjunction with mammalian target of rapamycin
(mTOR) inhibitors. Further clinical investigations in other RB intact
tumors may broaden their role.
Protein Homeostasis Modulators 
The proteasome is a mac­
romolecular complex that degrades misfolded proteins tagged for
removal by ubiquitin ligases. Proteasome inhibitors were originally
designed as potential anti-inflammatory agents owing to proteasome
activity to produce inflammatory cytokines but had unexpected anti­
proliferative activity in a variety of cell types. Proteasome inhibitors
have clinical utility in myeloma and lymphoma, where unbalanced
synthesis of immunoglobulin components can accumulate after pro­
teasome inhibitor treatment and induce apoptosis or starve cells for
amino acids, inducing autophagy. Boronic acid proteasome inhibi­
tors, including bortezomib and ixazomib, cause thrombocytopenia,
gastrointestinal dysfunction, and neuropathy. Carfilzomib is a distinct
chemotype with attenuated neuropathy but increased incidence of
infusion reactions and cytokine release, with attendant risk of cardio­
pulmonary adverse events.
Exportin 1 is a nuclear membrane transport protein that is responsi­
ble for normal exit and entry of a variety of nuclear proteins. Selinexor
is an inhibitor of exportin action, resulting in abnormal nuclear accu­
mulation of, for example, tumor-suppressor gene products or needed
export of other products, such as oncogene products. Useful clinical
activity has been seen in myeloma and diffuse large B-cell lymphomas
including those arising from previously treated indolent lymphomas.
Cytopenias, gastrointestinal distress, and hyponatremia are features of
its clinical use.
Chromatin-Modifying Agents 
Gene function is altered not only
by mutation of DNA structure but also by “epigenetic” mechanisms
that alter the capacity of DNA to be transcribed or interact with regu­
latory proteins in the nucleus including transcription factors. Initial
epigenetic approaches to modulate gene expression extended from
the observation that 5′azacytidine and decitabine are misincorporated
into DNA and then scavenge DNA methyl transferase to disable DNA
methylation of cytosine near gene promoter regions and thus alter their
transcription. This “hypomethylation” causes differentiation of AML
cells with notably less host toxicity than higher concentrations of these
agents or indeed cytosine arabinoside, which does not have prominent
hypomethylation activity.
Histone deacetylase inhibitors alter the histone protein “packing”
density of chromatin and induce global changes in expression of cell
cycle regulatory proteins. Vorinostat, belinostat, and romidepsin are
useful in cutaneous and peripheral T-cell lymphomas; panobinostat
has activity in multiple myeloma. The agents are generally well toler­
ated but with the potential for cytopenias. The histone methyltrans­
ferase inhibitor tazemetostat is a first-in-class inhibitor of histone
methyltransferase with unique activity in epithelioid sarcoma owing
to its modulation of transcriptional mechanisms unique to that tumor
and, recently, in certain follicular lymphomas.
Transcription Factor Modulation 
Distinct from hormone
receptor agonists and antagonists, which as previously described mod­
ulate transcription factor activity by affecting the binding of endog­
enously produced ligands, such as androgens and estrogens, tretinoin
(all-trans-retinoic acid) binds to the fusion protein PML-RARα pro­
duced as a result of the t(15,17) chromosomal translocation that under­
lies the pathogenesis of most cases of acute promyelocytic leukemia
(APL). PML-RARα functions as transcriptional co-repressor of normal
granulocyte maturation; inhibiting the repressor leads to clinical value
in the curative treatment of APL. Adverse events include typical symp­
toms of hypervitaminosis A, including skin dryness, cheilitis, increased
intracranial pressure, and the development of a “leukemia differentia­
tion syndrome” marked by fever and lung and other organ infiltration
by newly differentiated leukocytes, which usually responds to gluco­
corticoids and hydroxyurea but can be life-threatening. Significantly,
the coagulopathy of APL is attenuated. Arsenic trioxide nonspecifically
affects PML-RARα and other targets by a redox mechanism, contrib­
uting to APL treatment with tretinoin regimens, but with a narrow
therapeutic index particularly related to increase of the QT interval,
which must be monitored during treatment, while also being carefully
attentive to K+, Mg2+, ionized Ca2+, and other drugs that can alter QT.
CHAPTER 78
Principles of Cancer Treatment
Belzutifan is a novel agent that antagonizes directly the action of
hypoxia-inducible factor 2 (HIF2) α, activated in von Hippel-Lindau
(VHL) disease–related neoplasms and many sporadic clear cell renal
carcinomas through loss of the VHL ubiquitin ligase tumor-suppressor
gene. It is safe, but anemia and hypoxemia may occur.
The sonic hedgehog factor pathway is regulated by the WNT ligands
acting on smoothened receptors, named in reference to Drosophila
mutants in which the pathway was originally revealed. In humans, the
pathway acts during embryonic and fetal life and in certain neoplasms,
and mediates effects on transcription through Gli proteins. Hedgehog
pathway inhibitors sonidegib and vismodegib are useful in nonsurgi­
cally treatable cutaneous basal cell carcinomas, and glasdegib is active
in certain AMLs where the pathway is active (see Table 78-7). The notch
pathway was likewise first noted in Drosophila and acts in metazoans
to signal cell position and motion. Notch receptors respond to their
ligands by undergoing endocytosis and processing by a γ-secretase,
followed by translocation to the nucleus, and function as specific gene
transcription factors. The notch pathway has long been known to be
active in hematopoietic tumors, but observation has shown confirmed
activity in desmoid tumors, inflammatory mesenchymal tumors with
poor evidence of control by conventional cytotoxic agents, by nirogace­
stat, the first γ-secretase inhibitor to enter clinical practice.
Cancer Cell Metabolism Modulators 
Oncogenic transforma­
tion causes a “rewiring” of cellular metabolism away from oxidative
phosphorylation to glycolysis (historically defined as the “Warburg
effect” of aerobic glycolysis in animal and human tumors) with atten­
dant tolerance of hypoxia and production of metabolites important
for sustaining cell proliferation. Recent clinical studies have defined
clinical value from inhibitors of the cell lipid membrane localized phos­
phoinositide-3 (PI3) kinase, mTOR, and extra-mitochondrial isocitrate
dehydrogenase isoforms 1 and 2.
mTOR is a kinase whose inhibition was originally discovered as
the basis for activity by the immunosuppressant rapamycin, isolated
from a soil bacterium (originally obtained from Rapa Nui), which had
evidence of antitumor activity in animals as well as decreased T-cell
proliferation. Sirolimus as a protein-bound formulation is used for
certain soft tissue tumors. Temsirolimus and everolimus are mTOR
inhibitors with activity in renal cancers. They produce stomatitis and
fatigue; some hyperlipidemia (10%) and myelosuppression (10%); and
rare lung toxicity and immunosuppression in regimens used clinically.
Everolimus is also useful in patients with hormone receptor–positive
breast cancers displaying resistance to hormonal inhibition and in
certain neuroendocrine and brain tumors, the latter arising in patients
with sporadic or inherited mutations in the pathway activating mTOR.
PI3 kinase is activated by numerous oncogenic tyrosine kinases to
ultimately cause a cascade of metabolic alterations including increased
glucose uptake and activation of mTOR isoforms, which selectively
increase translation efficiency of key regulators of cell cycle progression
and protein synthetic capacity.
Isoform-specific PI3 kinase inhibitors are of increasing importance
in breast cancers with mutated PI3Kα (alpelisib; hyperglycemia and
cutaneous eruptions can occur) or owing to selective use of PI3Kδ by
lymphoid tissues in lymphomas (idelalisib, copanlisib, and duvelisib).
Isocitrate dehydrogenase (IDH) inhibitors (ivosidenib specific for
IDH1 and enasidenib specific for IDH2) have activity in tumors with
IDH mutants (AML, cholangiocarcinomas) that generate the “onco­
metabolite” 2-hydroxyglutarate, which alters DNA and histone meth­
yltransferase activity. The drugs thus function indirectly as epigenetic
chromatin modulating agents through effects on cellular metabolism.
Vorasidenib, an IDH1/2 inhibitor with very favorable distribution
across the blood-brain barrier, is in very advanced stages of develop­
ment for certain brain tumors with IDH mutations.
DNA Repair Pathway Modulators 
DNA repair systems act
physiologically to lessen the impact of environmental genomic damag­
ing agents and influence the susceptibility to certain chemotherapy
agents. DNA repair enzyme mutations underlie inherited cancer sus­
ceptibility syndromes such as mutated BRCA tumor-suppressor gene–
associated breast and ovarian cancers, among others.
PART 4
Oncology and Hematology
Laboratory investigations revealed that poly-ADP ribose poly­
merase (PARP) acts as a synthetic lethal gene with mutations in the
homologous recombination repair pathway, including the BRCA gene.
PARP responds to detection of DNA lesions by creating chains of
poly-ADP, which serve as scaffolds for the localization of DNA repair
proteins still active even with mutated BRCA isoforms. However, with­
out PARP activity, the scaffolds cannot form, and the DNA damage
becomes lethal. This observation immediately suggested the potential
utility of PARP inhibitors (e.g., olaparib) as treatments potentially
useful for BRCA-induced tumors. Recently, PARP inhibitor utility has
been extended to tumors that do not harbor BRCA mutations but have
given evidence of responding to platinum drugs, as a way of extending
the useful effect of the chemotherapy treatment. This finding under­
scores the likelihood that sensitivity to DNA-directed cytotoxic drugs
on the part of a tumor is at least in part related to the drugs’ ability to
take advantage of a sensitizing effect of a tumor’s endogenous DNA
repair capacity.
Miscellaneous Targeted Therapies 
High-affinity binding to
receptors on tumor cells can target toxic agents besides drugs to
tumor cells, exemplified by the IL-3–diphtheria toxin fusion protein
tagraxofusp-erzs, targeting the IL-3 receptor (CD123) and useful in
blastic plasmacytoid dendritic cell neoplasms (Table 78-7). Capillary
leak syndrome induced due to adventitious “off-target” delivery of
the toxin component requires careful monitoring of fluid balance to
avoid pulmonary dysfunction in particular. The somatostatin receptor
conjugated to a chelate of 177-lutetium can deliver targeted radiation
to gastroenterohepatic endocrine neoplasms expressing that receptor.
Acutely, release of vasoactive and locally acting hormonal components
from dying tumor cells and myelosuppression can occur. Renal dam­
age and the risk of second hematopoietic tumors can complicate con­
tinuing use of the agent. Likewise, 177-lutetium can be delivered via
conjugation to a ligand of prostate-specific membrane antigen (PSMA)
in the treatment of hormone-resistant prostate cancer. Ziv-aflibercept
is not an antibody, but a solubilized VEGF receptor VEGF binding
domain, and therefore may have a distinct mechanism of action from
bevacizumab but with similar side effects.
RESISTANCE TO CANCER TREATMENTS
Resistance mechanisms to the conventional cytotoxic agents were
initially characterized in the late twentieth century as defects in drug
uptake, metabolism, or export by tumor cells. The multidrug resistance
(MDR) gene, encoding P-glycoprotein (Pgp), is prototypic of trans­
port proteins that efficiently excrete many drugs from tumor cells;
no clinically useful modulator of this process has yet emerged. Drug-
metabolizing enzymes such as cytidine deaminase are upregulated
in resistant tumor cells, and this is the basis for so-called “high-dose
cytarabine” regimens in the treatment of leukemia. Another resistance
mechanism defined during this era involved increased expression of a
drug’s target, exemplified by amplification of the dihydrofolate reduc­
tase gene, in patients who had lost responsiveness to methotrexate, or
mutation of topoisomerase II in tumors that relapsed after topoisom­
erase II modulator treatment.
A second class of resistance mechanisms involves loss of the cellular
apoptotic mechanism activated after the engagement of a drug’s target
by the drug. This occurs in a way that is heavily influenced by the biol­
ogy of the particular tumor type. For example, decreased alkylguanine
alkyltransferase expression defines a subset of glioblastoma patients
with the prospect of enhanced benefit from treatment with temozolo­
mide but has no value in predicting benefit from temozolomide in
epithelial neoplasms. Likewise, ovarian cancers resistant to platinating
agents have decreased expression of the proapoptotic gene BAX.
A related class of resistance mechanisms emerged from sequencing
of the targets of agents directed at oncogenic kinases, revealing mutated
targets, as described previously (e.g., p210bcr-ablT315I). This reflects the
phenomenon of tumor heterogeneity with distinct populations of sub­
clones that arise in a tumor during the process of carcinogenesis. These
subclones share to variable degrees mutations that may promote the
growth of some subclones but that are absent or are no longer relevant
to the growth of other subclones. This general mechanism of resis­
tance is emerging as a basis for limited value of clinical responses to
sotorasib, where sequencing of tumor DNA after clinical resistance has
documented “treatment-emergent” mutations in KRAS itself as well as
alterations in other proto-oncogenes and their targets. Really useful
targeted therapies address a “driver mutation” present in all subclones.
Finally, other mechanisms of resistance to targeted agents include
the upregulation of alternate means of activating the pathway targeted
by the agent. Thus, melanomas initially responsive to BRAF V600E
antagonists such as vemurafenib may reactivate RAF signaling by
employing variant isoforms that can bypass the drug. Likewise, inhibi­
tion of HER2/neu signaling in breast cancer cells can lead to the emer­
gence of variants with distinct ways of activating downstream effectors
such as PI3 kinase.
Mechanisms of resistance to immune checkpoint inhibitors such
as nivolumab and ipilimumab have not been well defined, but initial
characterization of tumors resistant to these agents demonstrates
alterations in antigen presentation pathways, concordant with the basis
for checkpoint inhibitor action.
SUPPORTIVE CARE DURING CANCER
TREATMENT
■
■MYELOSUPPRESSION
Most cytotoxic chemotherapeutic agents affect bone marrow function.
Polymorphonuclear leukocytes (PMNs; t1/2 = 6–8 h), platelets (t1/2 =
5–7 days), and red blood cells (RBCs; t1/2 = 120 days) have most, less,
and least susceptibility, respectively, to usually administered cytotoxic
agents. Maximal neutropenia occurs 6–14 days after conventional
doses of anthracyclines, antifolates, and antimetabolites. Alkylating
agents differ from each other in the timing of cytopenias. Nitrosoureas,
DTIC, temozolomide, and procarbazine can display delayed marrow
toxicity, first appearing 6 weeks after dosing.
Complications of myelosuppression relate to the missing cells’ func­
tion. Febrile neutropenia refers to the clinical presentation of fever
TABLE 78-8  Indications for the Clinical Use of G-CSF or GM-CSF
Preventive Uses
With the first cycle of chemotherapy (so-called primary CSF administration)
  Not needed on a routine basis
  Use if the probability of febrile neutropenia is ≥20%
  Use if patient has preexisting neutropenia or active infection
  Age >65 years treated for lymphoma with curative intent or other tumors
treated by similar regimens
  Poor performance status
  Extensive prior chemotherapy
  Dose-dense regimens in a clinical trial or with strong evidence of benefit
With subsequent cycles if febrile neutropenia has previously occurred (so-called
secondary CSF administration)
  Not needed after short-duration neutropenia without fever
  Use if patient had febrile neutropenia in previous cycle
  Use if prolonged neutropenia (even without fever) delays therapy
Therapeutic Uses
Afebrile neutropenic patients
  No evidence of benefit
Febrile neutropenic patients
  No evidence of benefit
  May feel compelled to use in the face of clinical deterioration from sepsis,
pneumonia, or fungal infection, but benefit unclear
In bone marrow or peripheral blood stem cell transplantation
  Use to mobilize stem cells from marrow
  Use to hasten myeloid recovery
In acute myeloid leukemia
  G-CSF of minor or no benefit
  GM-CSF of no benefit and may be harmful
In myelodysplastic syndromes
  Not routinely beneficial
  Use intermittently in subset with neutropenia and recurrent infection
What Dose and Schedule Should Be Used?
G-CSF: 5 mg/kg per day subcutaneously
GM-CSF: 250 mg/m2 per day subcutaneously
Pegfilgrastim: one dose of 6 mg 24 h after chemotherapy
When Should Therapy Begin and End?
When indicated, start 24–72 h after chemotherapy
Continue until absolute neutrophil count is 10,000/μL
Do not use concurrently with chemotherapy or radiation therapy
Abbreviations: CSF, colony-stimulating factor; G-CSF, granulocyte colony-stimulating
factor; GM-CSF, granulocyte-macrophage colony-stimulating factor.
Source: From the American Society of Clinical Oncology: J Clin Oncol 24:3187, 2006.
and <1500 granulocytes/μL. Management of febrile neutropenia is
considered in Chap. 79. Colony-stimulating factors (CSFs) are used
to augment bone marrow production of PMNs. The American Society
of Clinical Oncology has developed practice guidelines for the use of
granulocyte CSF (G-CSF) and GM-CSF (Table 78-8).
Dangerous degrees of thrombocytopenia do not frequently compli­
cate the management of patients with solid tumors receiving cytotoxic
chemotherapy (with the possible exception of certain carboplatincontaining regimens), but they are frequent in patients with hemato­
logic neoplasms. Severe bleeding related to thrombocytopenia occurs
with increased frequency at platelet counts <20,000/μL in patients with
acute leukemia and <10,000/μL in patients with solid tumors and is
prevalent at counts <5000/μL.
The precise “trigger” point at which to transfuse patients has been
defined as a platelet count of 10,000/μL or less in patients without
medical comorbidities that may increase the risk of bleeding. This issue
is important not only because of the costs of frequent transfusion but
also because unnecessary platelet transfusions expose the patient to
the risks of allosensitization and loss of value from subsequent transfu­
sion, as well as the infectious and hypersensitivity risks inherent in any
transfusion. Careful review of medication lists to prevent exposure to
nonsteroidal anti-inflammatory agents and maintenance of clotting
factor levels adequate to support near-normal prothrombin and partial
thromboplastin time tests are important in minimizing the risk of
bleeding in the thrombocytopenic patient.
Anemia associated with chemotherapy can be managed by transfu­
sion of packed RBCs. Transfusion is not undertaken until the hemo­
globin falls to <80 g/L (8 g/dL), compromise of end-organ function
occurs, or an underlying condition (e.g., coronary artery disease) calls
for maintenance of hemoglobin >90 g/L (9 g/dL). Randomized trials
in certain tumors have raised the possibility that erythropoietin (EPO)
use may promote tumor cell survival.
■
■NAUSEA AND VOMITING
The most common side effect of chemotherapy administration is
nausea, with or without vomiting. Nausea may be acute (within 24 h
of chemotherapy), delayed (>24 h), or anticipatory of the receipt of
chemotherapy. Highly emetogenic drugs (risk of emesis >90%) include
DTIC, cyclophosphamide at >1500 mg/m2, and cisplatin; moderately
emetogenic drugs (30–90% risk) include carboplatin, cytosine arabi­
noside (>1 g/m2), ifosfamide, conventional-dose cyclophosphamide,
and anthracyclines; low-risk (10–30%) agents include 5-FU, taxanes,
etoposide, and bortezomib, with minimal risk (<10%) afforded by
treatment with antibodies, bleomycin, busulfan, fludarabine, and vinca
alkaloids.
CHAPTER 78
Principles of Cancer Treatment
Serotonin antagonists (5-HT3) and neurokinin 1 (NK1) receptor
antagonists are useful in “high-risk” chemotherapy regimens. The
combination acts at both peripheral gastrointestinal and CNS sites
that control nausea and vomiting. For example, the 5-HT3 blocker
dolasetron, 100 mg intravenously or orally; dexamethasone, 12 mg;
and the NK1 antagonist aprepitant, 125 mg orally, are combined on the
day of administration of severely emetogenic regimens, with repeti­
tion of dexamethasone (8 mg) and aprepitant (80 mg) on days 2 and 3
for delayed nausea. Alternate 5-HT3 antagonists include ondansetron,
given as 0.15 mg/kg intravenously for three doses just before and at
4 and 8 h after chemotherapy; palonosetron at 0.25 mg over 30 s,
30 min before chemotherapy; and granisetron, given as a single dose of
0.01 mg/kg just before chemotherapy. Emesis from moderately emetic
chemotherapy regimens may be prevented with a 5-HT3 antagonist
and dexamethasone alone for patients not receiving doxorubicin and
cyclophosphamide combinations; the latter combination requires the
5-HT3/dexamethasone/aprepitant on day 1, but aprepitant alone on
days 2 and 3. Emesis from low-emetic-risk regimens may be prevented
with 8 mg of dexamethasone alone or with non-5-HT3, non-NK1
antagonist approaches including the following.
Antidopaminergic phenothiazines act directly at the chemoreceptor
trigger zone (CTZ) in the brainstem medulla and include prochlor­
perazine (Compazine), 10 mg intramuscularly or intravenously,
10–25 mg orally, or 25 mg per rectum every 4–6 h for up to four
doses; and thiethylperazine, 10 mg by potentially all of the above
routes every 6 h. Haloperidol is a butyrophenone dopamine antagonist
given at 1 mg intramuscularly or orally every 8 h. Metoclopramide
acts on peripheral dopamine receptors to augment gastric emptying
and is used in high doses for highly emetogenic regimens (1–2 mg/kg
intravenously 30 min before chemotherapy and every 2 h for up to
three additional doses as needed); intravenous doses of 10–20 mg
every 4–6 h as needed or 50 mg orally 4 h before and 8 and 12 h after
chemotherapy are used for moderately emetogenic regimens. 5-9-Tet­
rahydrocannabinol (Marinol) is a rather weak antiemetic compared to
other available agents, but it may be useful for persisting nausea and is
used orally at 10 mg every 3–4 h as needed. Olanzapine, an “atypical
antipsychotic” acting at multiple neurotransmitter receptors, may be of
value, most clearly in cases refractory to the measures described above.
Some practice guidelines have endorsed its earlier use in adults receiv­
ing highly emetogenic chemotherapy regimens in combination with an
NK1 antagonist plus a 5-HT3 antagonist plus dexamethasone.

08 - 79 Infections in Patients with Cancer
79 Infections in Patients with Cancer
■
■DIARRHEA
Similar to the vomiting syndromes, chemotherapy-induced diarrhea
may be immediate or can occur in a delayed fashion up to 48–72 h
after the drugs. Careful attention to maintained hydration and elec­
trolyte repletion, intravenously if necessary, along with antimotility
treatments such as “high-dose” loperamide (4 mg at the first occur­
rence of diarrhea, with 2 mg repeated every 2 h until 12 h without
loose stools, not to exceed a total daily dose of 16 mg), are appropriate.
Octreotide (100–150 μg), a somatostatin analogue, or intralumenally
acting opiate-based preparations may be considered for patients not
responding to loperamide.
■
■MUCOSITIS
Irritation and inflammation of the mucous membranes (mucositis)
particularly afflicting the oral and anal mucosa, but potentially involv­
ing the entire gastrointestinal tract, may accompany cytotoxic chemo­
therapy. Topical therapies, including anesthetics and barrier-creating
preparations, may provide symptomatic relief in mild cases.
■
■ALOPECIA
Chemotherapeutic agents vary widely in causing alopecia, with anthra­
cyclines, alkylating agents, and topoisomerase inhibitors reliably
causing near-total alopecia when given at therapeutic doses. Antime­
tabolites are more variably associated with alopecia. Psychological sup­
port and the use of cosmetic resources are to be encouraged. “Chemo
caps” that reduce scalp temperature to decrease the degree of alopecia
are controversial during treatment with curative intent of neoplasms,
such as leukemia or lymphoma, or in adjuvant breast cancer therapy.
The richly vascularized scalp can certainly harbor micrometastatic or
disseminated disease.
PART 4
Oncology and Hematology
■
■GONADAL DYSFUNCTION AND PREGNANCY
All cancer treatments described in this chapter should be regarded
as potentially injurious to the developing fetus and to newborns via
lactation. However, there are gradations to the degree of reproductive
harm. All agents tend to have increased risk of adverse outcomes when
administered during the first trimester, and strategies to delay chemo­
therapy, if possible, until after this milestone should be considered if
the pregnancy is to continue to term. Patients in their second or third
trimester can be treated with most regimens for the common neo­
plasms afflicting women in their childbearing years, with the excep­
tion of antimetabolites, particularly antifolates, which have notable
teratogenic or fetotoxic effects throughout pregnancy. The need for
anticancer chemotherapy per se is infrequently a clear basis to recom­
mend termination of a concurrent pregnancy, although each treatment
strategy in this circumstance must be tailored to the individual needs
of the patient.
Cessation of ovulation and azoospermia reliably result from regi­
mens that contain alkylating agents and topoisomerase poison. The
duration of these effects varies with age and sex. Sperm banking before
treatment may be considered. Females experience amenorrhea with
anovulation after alkylating agent therapy; egg preservation may be
considered but may delay inception of urgent treatment. Recovery of
normal menses is frequent if treatment is completed before age 30, but
patients are unlikely to recover menses after age 35. Even those who
regain menses usually experience premature menopause. Because the
magnitude and extent of decreased fertility can be difficult to predict,
patients should be counseled to maintain effective contraception,
preferably by barrier means, during and after therapy. Resumption of
efforts to conceive should be considered in the context of the patient’s
likely prognosis. Hormone replacement therapy should be undertaken
in women who do not have a hormonally responsive tumor. For
patients who have had a hormone-sensitive tumor primarily treated by
a local modality, conventional practice would counsel against hormone
replacement, but this issue is under investigation.
■
■PALLIATIVE AND SUPPORTIVE CARE
An important perspective the primary care provider may bring to patients
and their families facing incurable cancer is that, given the limited value
of chemotherapeutic approaches at some point in the natural history of
most metastatic cancers, palliative care or hospice-based approaches, with
meticulous and ongoing attention to symptom relief and with family,
psychological, and spiritual support, should receive prominent attention
as a valuable therapeutic plan (Chaps. 13 and 73). Optimizing the quality
of life rather than attempting to extend it becomes a valued intervention.
Patients facing the impending progression of disease in a life-threatening
way frequently choose to undertake toxic treatments of little to no poten­
tial value, and support provided by the primary caregiver in accessing
palliative and hospice-based options in contrast to receiving toxic and
ineffective regimens can be critical in providing a basis for patients to
make sensible choices.
Late effects of cancer and its treatment are reviewed in Chap. 100.
■
■FURTHER READING
Ascione L et al: Predicting response to antibody drug conjugates: A
focus on antigens’ targetability. Oncologist 28:944, 2023.
Chabner BA, Longo DL: Cancer Chemotherapy, Immunotherapy,
and Biotherapy; Principles and Practice, 7th ed. Philadelphia, Wolters
Kluwer, 2025.
Emadi A, Karp JE: Cancer Pharmacology: An Illustrated Manual of
Anticancer Drugs, 2nd ed. New York, Springer Publishing Co., 2024.
Federman N: Molecular pathogenesis of desmoid tumor and the role
of γ-secretase inhibition. NPJ Precis Oncol 6:62, 2022.
Hesketh PJ et al: Antiemetics: American Society of Clinical Oncology
clinical practice update. J Clin Oncol 35:3240, 2017.
Kaelin WG Jr: Von Hippel-Lindau disease: Insights into oxygen sens­
ing, protein degradation, and cancer J Clin Invest 132:e162480, 2022.
Morad G et al: Hallmarks of response, resistance, and toxicity to
immune checkpoint blockade. Cell 184:5309, 2021.
Nikanjam M et al: Liquid biopsy: Current technology and clinical
applications. J Hematol Oncol 15:131, 2022.
Puzanov I et al: Managing toxicities associated with immune check­
point inhibitors: Consensus recommendations from the Society for
Immunotherapy of Cancer (SITC) Toxicity Management Working
Group. J Immunother Cancer 5:95, 2017.
Rosen N, Longo DL: Targeting oncogenic RAS protein. N Engl J Med
387:184, 2022.
Sartor O et al: Lutetium-177–PSMA-617 for metastatic castrationresistant prostate cancer. N Engl J Med 385:1091, 2021.
Brahm H. Segal, Juan C. Gea-Banacloche
Infections in Patients
with Cancer
GENERAL CONCEPTS
Infection is an important complication of cancer and cancer therapy
and drives excess hospitalization and mortality. Prevention, diagnosis,
and treatment of infection increases survival and improves quality
of life. In this regard, the infectious diseases consultant works col­
laboratively with multiple stakeholders to prevent infection and to
effectively diagnose and treat infections when they occur. Cornerstones
of infection prevention are compliance with standard infection control
guidelines, limiting exposure to pathogens, vaccination of patients and
caregivers, and targeted use of antimicrobial prophylaxis. Although
there have been substantial improvements in diagnostic modalities
for infection including molecular and antigen-based diagnostics, the
infectious diseases physician is frequently confronted with patients
with suspected infection (e.g., neutropenic fever, lung lesions observed
by imaging) without a definitive diagnosis. In addition, infectious and
noninfectious disorders may have overlapping manifestations, such as
pneumonia versus drug-related pneumonitis and fever from infection
versus cancer-associated fever. Given the broad differential diagnosis,
aggressive diagnostic evaluation including biopsies may be required.
Sometimes, empirical therapy must be administered based on the most
likely or dangerous infections; these situations are common in patients
with hematologic malignancies in whom an invasive tissue diagnosis
may be unsafe due to thrombocytopenia.
We provide recommendations for therapy of both documented and
suspected infections. Specific treatment plans should consider several
factors, such as evidence of clearance of infection, whether a persistent
nidus exists (e.g., abscess or infectious phlebitis), the specific pathogen,
and the immune status of the patient. A general principle of therapy is
that longer courses are required in patients with persistent and severe
immunocompromise (e.g., prolonged neutropenia in patients with acute
leukemia or myelodysplastic syndrome). An individualized approach to
the diagnosis and management of infections that is tailored to overall
goals of care is recommended. For example, in the setting of uncon­
trolled malignancy (e.g., recurrent cholangitis from obstructive pan­
creatic or biliary cancers or secondary infections of tumor from bowel
fistulization), source control by surgery or catheter drainage may not be
feasible, and antibiotics may be used palliatively for patient comfort and
to avoid unnecessary hospitalizations rather than to cure an infection.
We will address the risk factors for infections and the preventive
measures that may be adopted based on those risk factors. Most spe­
cific infections have dedicated chapters, and readers are advised to
access those for in-depth discussions. We will focus here on infections
associated with (or caused by) the treatment of cancer. Chemotherapyinduced neutropenia is the most important etiology, and the manage­
ment of neutropenic fever will be discussed in detail. We will also
discuss infections associated with new treatment modalities, including
biologics, immunotherapy, and cellular therapies. Infections related to
hematopoietic stem cell transplant (HCT) are discussed in Chap. 148.
RISK FACTORS FOR INFECTION IN
PATIENTS WITH CANCER
When evaluating patients with cancer and suspected infection, it is
important to consider the major factors—both intrinsic and treatmentassociated—that predispose to infection. This knowledge, in turn,
guides the differential diagnosis, diagnostic evaluation, and initial
therapy.
■
■RISK FACTORS INTRINSIC TO THE CANCER
These are the direct consequence of the cancer. In the case of solid
tumors, the most obvious risk factor for infection relates to obstruc­
tion. As examples, lung tumors that obstruct the airway predispose to
postobstructive pneumonia, obstructive pancreatic and biliary tumors
predispose to cholangitis, and tumors that result in obstructive uropa­
thy predispose to urinary tract infections. Tumors of the head and neck
increase the risk of local infection and aspiration pneumonia. Gastro­
intestinal tumors can present with obstruction and local abscess pro­
duction by enteric flora and bloodstream infection (e.g., bloodstream
infection by Streptococcus gallolyticus or Clostridium septicum in colon
cancer). Direct invasion through the colonic mucosa is associated with
local abscess formation and sepsis by enteric flora.
Some hematologic malignancies are associated with specific immune
deficits. Acute leukemia and myelodysplastic syndrome can manifest
with pancytopenia at diagnosis. Patients may have a high burden of
circulating leukemic cells and lack normal circulating neutrophils.
Some patients with myelodysplastic syndrome or acute myelogenous
leukemia (AML) have mutations that are associated marrow failure and
immunodeficiency. For example GATA2 deficiency is associated with
major viral, bacterial, and fungal infections as well as hematological
malignancies and solid tumors. Multiple myeloma and chronic lym­
phocytic leukemia are associated with impaired immunoglobulin pro­
duction that can manifest with recurrent sinopulmonary infections and
poor antibody responses to both prior infections and vaccination. Case
series suggest that patients with hairy cell leukemia are at increased risk
of nontuberculous mycobacterial infections. T cell–associated leuke­
mias and lymphomas can be associated with human T lymphotropic
virus 1 (HTLV1) and have T cell impairment and opportunistic infec­
tions by Pneumocystis jirovecii, Cryptococcus neoformans, tuberculosis,
or disseminated strongyloidiasis.
■
■RISK FACTORS ASSOCIATED WITH
CANCER THERAPY
There has been a dramatic expansion in cancer therapeutics, most of
which influence host defense against infections (Table 79-1). Broadly
speaking, cancer therapy can compromise either or both the physical
barriers and immune responses that protect from infection. Examples
of physical barrier disruption include central venous catheters, surgical
wounds that can be a portal of entry for skin microbes, and disruption
of the lymphatic drainage after mastectomy and lymphadenectomy for
breast cancer.
The mucosal lining of the gastrointestinal tract, respiratory tract,
and other luminal surfaces constitutes the first line of host defense,
both as a physical barrier and by secretion of a variety of antimicrobial
products, such as immunoglobulin A (IgA), lactoferrin, and anti­
microbial peptides. Standard nonselective cytotoxic agents have the
combined effect of both pancytopenia and mucosal disruption that
predispose to infection. Radiation is sometimes administered concur­
rently with chemotherapy and, depending on the location of the radia­
tion field, can cause significant mucosal injury. Antineoplastic agents
that inhibit specific pathway(s) that drive tumor cell progression are
considered targeted, but they also impair specific components of the
immune system whose function relies on these same pathways. For
example, the anti-tumor activity of Bruton tyrosine kinase inhibitors
against B-cell malignancies is by inhibiting the B-cell receptor signaling
cascade, but this property can have broad immune effects that increase
the risk of viral and fungal infections.
CHAPTER 79
Infections in Patients with Cancer
Chemotherapy-Induced Neutropenia 
It has been recognized
for more than 50 years that the duration and degree of neutropenia
drive susceptibility to infections in patients with cancer. Cytotoxic regi­
mens that result in prolonged neutropenia also deplete other immune
cells (e.g., circulating monocytes and lymphocytes) and commonly
cause mucosal injury. The risk of infection is proportional to the degree
of neutropenia once the absolute neutrophil count (ANC) becomes
<1000/µL. For example, standard induction chemotherapy with
anthracycline plus cytarabine for AML causes prolonged neutropenia
and severe mucositis. The combination of prolonged neutropenia and
mucositis predisposes these patients to gastrointestinal tract infections
that include ulcerations of the oral mucosa, neutropenic enterocolitis
(typhlitis), and perirectal infections, as well as bloodstream infec­
tions by gastrointestinal flora such as viridians group streptococci,
enterococci, and Enterobacterales. Reactivation of oral mucosal herpes
simplex virus (HSV) is another common complication of leukemia
therapy. Reflecting the fact that Candida species are endogenous
gastrointestinal flora, these patients are also at risk for candidemia
and chronic disseminated candidiasis. Patients with more prolonged
neutropenia (e.g., ANC <500/µL for ≥2 weeks) are at risk for invasive
aspergillosis and other molds. Refractory and relapsed acute leukemia
further increase the risk of invasive fungal disease (Table 79-1).
Antimicrobial prophylaxis tailored to the underlying immune
defects has been shown to be effective in several settings, and it
should be used with knowledge of the proven benefits and the direct
and indirect toxicities (prevention of fever differs from prevention of
infection and prolongation of survival), as well as the limitations of the
available evidence. As an example, prophylaxis with a fluoroquinolone
like levofloxacin should be considered in adults with prolonged neu­
tropenia (e.g., ANC <500/µL for ≥7 days). Multiple studies have shown
decreased frequency of neutropenic fever and fewer documented infec­
tions, and meta-analyses suggest a survival benefit. In patients with
AML receiving induction chemotherapy, prophylaxis with posacon­
azole was associated with less invasive fungal disease (IFD) and a
survival benefit, so posaconazole is frequently recommended as
prophylaxis in patients with profound, prolonged neutropenia. It is
plausible that isavuconazole may be equally effective, but its efficacy in
this setting has not been demonstrated.
TABLE 79-1  Immune Defects and Associated Infections in Cancer Patients
HOST DEFENSE
DEFECT
PREDOMINANT PATHOGENS
PATIENTS WITH CANCER AT GREATEST RISK
Neutropenia (ANC
<500/µL)
Gram-negative and gram-positive bacteria
Cytotoxic chemotherapy, underlying hematologic malignancy
(e.g., myelodysplasia, acute leukemia)
Prolonged (≥10 days),
profound neutropenia
(ANC <100/µL)
Increased risk of bacterial infections
Candidemia
Invasive aspergillosis and other molds
HSV reactivation
Respiratory viral infections
T cell
immunodeficiency
Common bacterial infections
Intracellular bacteria (e.g., Listeria monocytogenes, Salmonella
species)
Nocardia species
Tuberculosis and NTM
Respiratory viral infections
Reactivation of herpes viruses (HSV, VZV); with severe impairment:
CMV, EBV-associated lymphoproliferative disease; HHV-6-associated
marrow suppression or encephalopathy, and HHV-8-associated
malignancies)
Mucosal candidiasis
Pneumocystis jirovecii
Dimorphic fungal infections (e.g., histoplasmosis,
coccidioidomycosis)
Cryptococcus neoformans
Invasive aspergillosis and other molds
Toxoplasmosis
Strongyloides hyperinfection
PART 4
Oncology and Hematology
B cell
immunodeficiency
Encapsulated bacteria (Streptococcus pneumoniae, Haemophilus
influenzae, Neisseria meningitidis)
Respiratory viral infections
Reactivation of HSV and VZV
Reactivation of HBV
PML (reactivation of JC virus)
Splenectomy and
functional asplenia
Encapsulated bacteria (can result in life-threating sepsis)
Malaria, babesiosis
Mucosal injury
Localized infections by oral and GI flora (e.g., dental infections,
neutropenic enterocolitis, perianal infection)
Bacteremia (coliforms, oral streptococci, enterococci, anaerobes;
can be polymicrobial)
Systemic
corticosteroids
Broad suppressive effect on innate and adaptive immunity related to
dose and duration of treatment
Increased risk of common bacterial and viral infections
Prolonged high-dose corticosteroids (e.g., prednisone equivalent
to ≥20 mg/day for ≥28 days) increases risk of multiple opportunistic
pathogens associated with impaired T cell immunity (e.g.,
Pneumocystis jirovecii)
Abbreviations: AIDS, acquired immunodeficiency syndrome; ANC, absolute neutrophil count; BTK, Bruton tyrosine kinase; CAR, chimeric antigen receptor; CMV,
cytomegalovirus; EBV, Epstein-Barr virus; GVHD, graft-versus-host disease; HBV, hepatitis B virus; HHV, human herpes virus; HSV, herpes simplex virus; MDS,
myelodysplastic syndrome; NTM, nontuberculous mycobacteria; PML, progressive multifocal leukoencephalopathy; TNF, tumor necrosis factor; VZV, varicella-zoster virus.
Corticosteroids 
Corticosteroids are part of several chemotherapy
regimens used in hematologic malignancies, such as in acute lymphoid
leukemias, lymphomas, and multiple myeloma. Patients with brain
tumors, both primary and metastatic, are treated with corticoste­
roids to control edema. In addition, corticosteroids are a mainstay of
therapy to control inflammatory complications of cancer therapy. For
example, immune checkpoint inhibitors are associated with pneumo­
nitis, colitis, and autoimmune endocrinopathies that are treated with
corticosteroids, and additional agents such as tumor necrosis factor α
blockade when corticosteroids alone are insufficient. Corticosteroids
are also used as therapy for graft-versus-host disease (GVHD) fol­
lowing allogeneic stem cell transplantation and for cytokine release
syndrome (CRS) following bispecific antibody therapy and adoptive
cellular therapy.
Induction/reinduction therapy for acute leukemia; pancytopenia
from underlying hematologic malignancy; myeloablative conditioning
regimens for stem cell transplantation and lymphodepletion for adoptive
cellular therapy
Underlying hematologic malignancy including primary T cell
malignancies
AIDS-associated malignancies
Corticosteroids, TNF-α blockade
Janus kinase inhibitors
Purine analogues
Alemtuzumab
GVHD
Lymphodepletion for adoptive cellular therapy
Lymphoid malignancies (e.g., chronic lymphocytic leukemia, multiple
myeloma)
B cell–depleting agents (e.g., rituximab, BTK inhibitors)
Stem cell transplantation, particularly with chronic GVHD
Bispecific antibodies and adoptive cellular therapy targeted against B
cell antigens (e.g., CD19-directed CAR T cell regimens)
Functional asplenia in chronic GVHD
Cytotoxic chemotherapy that results in both neutropenia and mucosal
injury
Radiation (e.g., for head and neck tumors or rectal cancer) predisposes
to local tissue damage, impaired blood flow, and secondary bacterial
infection
Corticosteroids are common components of antineoplastic regimens
for hematologic cancers (e.g., for acute lymphoblastic leukemia,
lymphomas, and multiple myeloma) and are administered concurrently
with other immunosuppressive therapies
Other common indications for corticosteroids are to reduce
inflammation from central nervous system tumors and as therapy for
immune-related toxicities
High-dose corticosteroids have inhibitory effects on multiple com­
ponents of innate and adaptive immunity. The risk of infections is
related to their dose and duration, the underlying malignancy, and
other immunosuppressive agents that are used concurrently. For exam­
ple, induction therapy for acute lymphoblastic leukemia includes both
cytotoxic agents that result in pancytopenia and corticosteroids that
cumulatively increase infection risk. Corticosteroids can also decrease
signs of infection such as fever and abdominal tenderness. The inhibi­
tory effect of corticosteroids on T cell immunity increases the risk of
infections by viruses (e.g., HSV, varicella-zoster virus [VZV]), myco­
bacteria, Nocardia species, and fungal infections, including mucosal
candidiasis, dimorphic fungi, and Pneumocystis jirovecii pneumonia
(PJP) (Table 79-1). Prophylaxis against Pneumocystis jirovecii with
trimethoprim sulfamethoxazole (TMP-SMX) (or an alternative agent if
intolerant) is recommended in patients receiving the adult equivalent
of prednisone ≥20 mg per day for at least 4 weeks.
Radiation 
Radiation causes direct tissue damage (including dam­
age to the vasculature) and impairs wound healing. Infectious com­
plications of radiation include local infection and fistulization. As an
example, neoadjuvant radiation therapy for rectal tumors increases the
risk of surgical site infections. Radiation to the head and neck increases
the risk of infections related to the tumor and as a surgical complica­
tion. Osteoradionecrosis of the jaw predisposes to secondary infections
of the soft tissue and bone that may require combined prolonged anti­
biotics and surgical removal of dead bone and reconstruction.
Splenectomy 
Splenectomy may be performed for diagnosis or
treatment of cancer. The spleen has several key immune functions
including removing of bacteria from blood, antigen presentation to
T cells, and housing B cells that are activated and produce antibodies.
Functional asplenia is present after splenic irradiation and with chronic
GVHD. Asplenic patients are principally at risk for overwhelming sepsis
by encapsulated bacteria like Streptococcus pneumoniae, Haemophilus
influenzae, and Neisseria meningitidis. Patients should be vaccinated
against these pathogens prior to planned splenectomy. Antibiotic pro­
phylaxis (e.g., with penicillin) should be considered for the first 2 years after
splenectomy, especially in patients with active malignancy or receiv­
ing immunosuppressive therapy. Asplenic patients with fever should
be started promptly on antibiotics active against S. pneumoniae (e.g.,
ceftriaxone or levofloxacin or moxifloxacin). Vancomycin should be
added in areas where high-level penicillin or cephalosporin resistance
is common. Asplenic individuals also have increased risk of babesiosis,
malaria, and infection with Capnocytophaga canimorsus (associated
with animal bites or scratches) and Salmonella spp.
B Cell–Depleting Agents 
B cell–depleting agents are used as
therapy for patients with B cell malignancies, such as B cell lymphomas
and chronic lymphocytic leukemia. They are commonly used in com­
bination with other antineoplastic agents. Antibody-based drugs such
as rituximab result in prolonged B cell depletion, while Bruton tyrosine
kinase (BTK) inhibitors (e.g., ibrutinib) interrupt a key enzyme and
B cell activation but have shorter-acting effects. The effects of B cell
depletion include increased risk of encapsulated bacteria and respi­
ratory viral infections. Importantly, these patients are likely to have
reduced immune responses to vaccination against bacteria and viruses,
including influenza, SARS-CoV-2, and hepatitis B. The risk of severe
COVID-19 is substantially increased in patients with hematologic
malignancies compared with patients with solid tumors, and B cell–
depleting agents are associated with increased COVID-19 severity and
lack of serologic responses to SARS-CoV-2 infection and vaccination.
All patients who will receive B cell–depleting agents should be screened
for hepatitis B infection and receive therapy for hepatitis B (e.g., with
entecavir or tenofovir alafenamide) for active or prior hepatitis B
infection (see Chaps. 350 and 352 on hepatitis viruses and Chap. 208
on human immunodeficiency virus [HIV] infections). Rituximab and
other B cell–depleting agents have been associated with progressive
multifocal leukoencephalopathy (PML) and PJP, but the magnitude of
the effect is difficult to ascertain. In addition, BTK inhibitors can have
off-target effects on innate immune cells and increase the risk of other
infections, including invasive aspergillosis, particularly when com­
bined with other immunosuppressive agents, such as corticosteroids.
Bispecific Antibodies 
Bispecific antibodies are engineered to
have dual specificity for a T cell antigen (e.g., CD3, a component of
the T cell receptor complex) and a tumor antigen with the goal of
stimulating T cell killing of tumor cells. When bispecific antibody con­
structs directed against B cell antigens (e.g., blinatumomab, a bispecific
antibody against CD3 and the B cell antigen CD19) are used against B
cell malignancies, the overall effect is a nonselective depletion of both
tumor cells and normal B cells. Importantly, bispecific antibodies are
commonly used in patients with refractory hematologic malignancies
who already are at high risk for infection based on the underlying can­
cer and prior therapy. Bispecific antibody therapy can result in CRS,
characterized by fever and inflammatory organ damage. Treatment of
CRS involves high-dose corticosteroids and interleukin 6 (IL-6) block­
ade, which further increases the risk of infections.
Adoptive Cellular Therapy 
Adoptive cellular therapy (ACT)
involves administration of genetically engineered cells targeted to
tumor antigens. The most commonly used ACT is chimeric antigen
receptor (CAR) T cells, in which autologous T cells are genetically engi­
neered to express a receptor directed against a tumor antigen. Engage­
ment of cells expressing this antigen results in the CAR T cell activation
and tumor cell killing. In contrast to bispecific antibodies, current ACT
involves lymphodepletion chemotherapy (usually with fludarabine and
cyclophosphamide) to deplete immune cells and allow maximal expan­
sion of the engineered T cells. A major goal of immunotherapy is to
make ACT more effective for a broad range of solid tumors; however,
the current use of ACT largely involves refractory B cell malignancies:
lymphoblastic leukemia, lymphomas, and multiple myeloma. Lym­
phodepletion regimens result in pancytopenia, and both neutropenia
and lymphopenia can be prolonged (months to years). In the case of
standard CD19-directed CAR T cells, B cell depletion is by design; the
persistence of CAR T cells is required for antitumor immunity, but it
is nonselective, and the duration of global B cell depletion can be for
years. ACT can also be complicated by CRS and an immune effector
cell–associated neurotoxicity syndrome that can be life-threatening
and requires treatment with intensive high-dose corticosteroids often
combined with IL-6 blockade. Additional hematologic complications
can occur after ACT, such as hemophagocytic lymphohistiocytosis
(HLH), which extends pancytopenia and entails additional immuno­
suppressive therapy.
CHAPTER 79
Infections in Patients with Cancer
Recommendations regarding prophylaxis following ACT are based
mainly on extrapolation and expert opinion. These include levofloxa­
cin during neutropenia, TMP-SMX while on systemic corticosteroids
or while CD4 count is <200/µL, acyclovir, and perhaps mold-active
prophylaxis (e.g., posaconazole) during periods of prolonged neutro­
penia. Recipients of CAR T cells constitute a heterogeneous population
due to the effect of multiple previous courses of therapy, sometimes
including allogeneic HCT, and prophylaxis should be tailored to the
degree of immunosuppression.
Cancer and HIV Infection 
HIV-associated malignancies include
Epstein-Barr virus–associated non-Hodgkin and Hodgkin lymphomas,
HHV-8-associated Kaposi sarcoma and primary effusion lymphoma,
and human papilloma virus–associated cervical and anal cancer. HIVpositive patients have higher risks of chronic hepatitis B and hepatitis
C infections that increase the risk of hepatocellular carcinoma. Patients
with HIV infection can also have cancers that are not HIV-associated.
A mainstay of cancer management in patients who are HIV-positive is
that the antineoplastic regimen must be concurrent with antiretroviral
therapy and appropriate prophylactic antimicrobials. The goals of anti­
retroviral therapy are a nondetectable HIV viral load and tolerability
of the regimen, which includes monitoring and avoiding drug–drug
interactions with antineoplastic chemotherapy. In general, it is recom­
mended to test for HIV and hepatitis B and hepatitis C infection prior
to starting antineoplastic therapy.
DIAGNOSIS AND MANAGEMENT OF
INFECTIONS IN PATIENTS WITH
NEUTROPENIA
Chemotherapy-induced neutropenia remains the major risk factor for
infection in patients with cancer. However, patients with cancer fre­
quently have multiple risk factors for infection, both from the under­
lying malignancy and its treatment. When evaluating patients with
neutropenia and suspected infection, it is important to consider these
other risk factors in the diagnostic evaluation and therapy (Fig. 79-1).
■
■NEUTROPENIC FEVER
A high proportion of cancer patients who become neutropenic after
receiving chemotherapy develop fever. The standard definition of neu­
tropenic fever (NF) is a single oral temperature ≥38.3°C or a tempera­
ture of ≥38.0°C sustained over 1 h, with an absolute neutrophil count
A
B
FIGURE 79-1  Multiple pulmonary infections in a patient with acute myelogenous
leukemia (AML). A patient with AML in remission after reinduction therapy
with cytarabine, granulocyte colony-stimulating factor, and fludarabine (FLAG)
presented with fever and neutropenia. A chest CT demonstrated diffuse pulmonary
infiltrates (A). Bronchoalveolar lavage (BAL) was unrevealing except for positive
PCR for Pneumocystis jirovecii, and trimethoprim-sulfamethoxazole was instituted.
After 11 days of appropriate treatment (B), a repeat CT showed resolution of the
infiltrates but a conspicuous, dense, well-circumscribed pulmonary nodule that
had not been appreciated initially. Targeted BAL of the left lower lobe was positive
for galactomannan, providing the diagnosis of probable invasive aspergillosis. The
initial BAL had been of the right middle lobe only. Immunocompromised patients
may have several infections simultaneously, and cancer patients often accumulate
risk factors for infection during their treatment.
PART 4
Oncology and Hematology
(ANC) of <500 cells/µL, or an ANC that is expected to decrease to
<500 cells/µL over the next 48 h.
During neutropenia localizing signs and symptoms of infection
may be subtle or altogether lacking, and infections may progress very
quickly. These two basic features mandate early initiation of empiri­
cal antibacterial agents in neutropenic patients whenever infection is
suspected. Although fever is the most common sign of infection, it is
not the only one, and similar management should be used whenever
infection is suspected in a neutropenic patient, such as in the presence
of otherwise unexplained pain, tenderness, or erythema potentially
secondary to infection.
NF is considered infectious in origin, but an infection is identified
in only a minority of cases. An infection may be documented micro­
biologically (e.g., Pseudomonas aeruginosa bacteremia identified by
positive blood cultures) or only clinically (e.g., abdominal pain and
bloody diarrhea with negative blood cultures, presumed to represent
neutropenic enterocolitis). Using standard diagnostic methods (i.e.,
routine cultures, serologic tests, and imaging studies) an infection is
documented in approximately 40% of episodes of NF. However, newer
diagnostic modalities using plasma cell–free DNA polymerase chain
reaction (PCR) identify a potential bacterial etiology most of the time.
Most bacteria identified by these studies are part of the normal flora
of skin and bowel (as are the bacteria isolated by standard culture
methods when these are positive), since these physical barriers are
often disrupted by the cancer treatments that caused the neutropenia.
Infections during neutropenia are typically caused by microorganisms
carried by the patient as part of their microbiome.
■
■MANAGEMENT OF NEUTROPENIC FEVER
First Neutropenic Fever 
There is a wealth of good-quality evi­
dence to support standard-of-care guidelines for the management
of the initial episode of NF. After a swift history and physical exam
(focused on potential portals of entry like the vascular catheter exit site,
mouth, and perianal area), blood cultures are obtained and empirical
antibiotic therapy is initiated using a single agent (monotherapy) with
broad-spectrum activity, including coverage of P. aeruginosa. Ideally, anti­
biotics should be given within 1 h of the onset of NF. The diagnostic
utility of chest imaging in the absence of respiratory symptoms or signs
has not been established.
Ceftazidime, cefepime, imipenem, meropenem, and piperacillintazobactam are the best-studied antibiotics used as monotherapy for
NF. The specific choice will vary from institution to institution based
on the local frequency of resistant bacteria. This “backbone regimen”
may be complemented with a second agent against resistant gramnegative or gram-positive bacteria depending on clinical features,
prior history of resistant pathogens, or local trends of antimicrobial
resistance.
It should be emphasized that standard empirical monotherapy
regimens for NF apply to clinically stable patients with NF of unclear
etiology. Management of neutropenic patients with localized signs of
infection (e.g., respiratory, intra-abdominal, intravascular catheter–
associated) are discussed below. In patients who are clinically unstable,
such as those with hypotension or signs of organ injury raising con­
cern for sepsis (e.g., impaired mental status, pulmonary edema, acute
renal injury), a broader-spectrum antimicrobial regimen is warranted.
Although the specific regimen for presumed or documented septic
shock varies based on the patient’s prior history of resistant infection
and local susceptibility patterns, an example of an initial regimen is
vancomycin, meropenem, and possibly an aminoglycoside; in patients
at risk for candidiasis, an echinocandin may be added.
The standard monotherapy regimens lack activity against specific
gram-positive pathogens. Gram-positive coverage with a glycopeptide
antibiotic (vancomycin in the United States) is not routinely part of
the initial regimen. Instead, the addition of a glycopeptide is reserved
for clinical situations in which a gram-positive pathogen resistant to
the standard regimen (e.g., methicillin-resistant Staphylococcus aureus
[MRSA]) is more likely. The Infectious Diseases Society of America
(IDSA) guidelines recommend empirical gram-positive coverage with
sepsis, clinically evident soft tissue infection, clinically suspected cath­
eter exit site infection, pneumonia, severe mucositis (only if ceftazi­
dime is used as empirical regimen, because mucositis is a risk factor
for viridans group streptococci), and known carrier status of MRSA or
penicillin-resistant pneumococcus. Meta-analysis has shown that the
routine inclusion of vancomycin in the initial regimen is not associated
with better outcomes but does result in more nephrotoxicity.
After starting antibiotics, fever usually resolves in 24–72 h. If an
infection was diagnosed, antibiotics are continued for the appropriate
amount of time for that specific infection. When a specific microbe is
isolated (e.g., from blood cultures), experts disagree regarding the need
for continuing the broad-spectrum coverage versus narrowing based
on susceptibility results.
If no microorganism is isolated and no source is identified, the
optimal strategy for antibiotic management of NF that resolves with
antibiotics is debated. In the past, empirical antibiotics were continued
until resolution of neutropenia. However, recent studies have suggested
that de-escalation from empiric therapy to prophylaxis or discontinua­
tion are safe if specific criteria are met, including clinical stability. The
advantage of such de-escalation or early discontinuation strategies
relates to reduced antibiotic exposure and lower risk of selection of
resistant pathogens; these benefits must be balanced against the poten­
tial for inadequately treated infection. Large, randomized, multicenter
trials are required to evaluate the benefits and safety of antibiotic deescalation or discontinuation of empirical antibiotic therapy in patients
with persistent neutropenia.
Persistent Fever 
If the fever continues while receiving empirical
antibiotic therapy without a diagnosis, evidence supports and guide­
lines recommend continuing the same antibiotic without addition or
modification in the absence of clinical changes or new microbiologic
data. The antibacterial regimen should be modified only if new clinical
features arise (e.g., hypotension) of if new microbiologic data become
available (e.g., a positive culture), and not just because of persistent
fever. Although there is agreement on this issue between different
guidelines, persistent, stable fever is a common reason why the anti­
bacterial regimen is modified in clinical practice. The longer the neu­
tropenic fever persists during the administration of broad-spectrum
antibiotics, the higher the likelihood of IFD. Depending on prior his­
tory, use of antifungal prophylaxis, and local practices, one may choose
to initiate empirical antifungal treatment after 5 days of fever (this was
standard of care for decades and is called empirical antifungal therapy)
or to perform tests focused on diagnosing an occult fungal infec­
tion and initiate antifungals only if these additional tests support the
possibility of IFD. This more recent approach has been named preemp­
tive antifungal strategy and seems to result in similar patient outcomes
with less use of antifungals. The empirical antifungal of choice will vary
depending on the antifungal prophylaxis used (if any). Caspofungin
and liposomal amphotericin B are the best-studied empirical antifun­
gal treatment of NF, but expert recommendations vary. A frequently
used approach is to administer posaconazole as antifungal prophylaxis
in high-risk patients with neutropenia (e.g., those receiving induc­
tion or reinduction regimens for acute myeloid leukemia) and to not
modify the antifungal regimen based solely on persistent or recurrent
neutropenic fever.
Recrudescent Fever and Fever at the Time of Neutrophil
Recovery 
In addition to the initial episode of fever and persistent
fever, there are two other NF scenarios that have been less well stud­
ied: recrudescent fever and fever at the time of neutrophil recovery.
Recrudescent fever refers to the situation in which the initial episode
of fever resolves without a diagnosis, neutropenia persists, the antibi­
otic regimen is continued unmodified, and fever reappears after the
patient has been afebrile for 48–96 h. This is not uncommon during
prolonged neutropenia during induction or reinduction therapy in
acute leukemia. In this case (as opposed to the first episode of NF), an
infection is identified most of the time (bacterial, fungal, or viral), and
the recommended approach is to empirically modify the antimicrobial
regimen that had successfully controlled the fever up to this point,
aiming for coverage of resistant bacteria and fungi. Intensive diagnos­
tic procedures, including CT imaging, should be undertaken. Where
available, CT combined with positron emission tomography (CT-PET)
may be considered.
Finally, fever at the time of neutrophil recovery may be infectious
in origin: either a preexisting infection that was silent due to lack of
neutrophils (sometimes this is considered analogous to the immune
reconstitution inflammatory syndrome [IRIS] seen after initiation of
antiretroviral therapy in AIDS) or, less likely, a superinfection. How­
ever, fever is frequently noninfectious at this time and is related to
myeloid engraftment. In any case, the recommended response to fever
that occurs simultaneously with resolution of neutropenia is not any
specific empirical antimicrobial regimen, but to pursue a thorough
diagnostic evaluation.
■
■OUTPATIENT THERAPY FOR NEUTROPENIC
FEVER
Outpatient therapy for neutropenic fever should be considered in
patients at lower risk for infectious complications from neutropenia.
These patients typically have solid rather than hematologic tumors
with a short expected duration of neutropenia, usually 7 days or less.
Criteria for candidates for outpatient empirical therapy include clinical
stability, no localizing symptoms or signs of infection, ability to eat and
drink without difficulty, absence of significant comorbidities such as
chronic lung or cardiovascular disease, normal renal and liver function,
and easy access to a hospital and a caregiver at home. Outpatient oral
antibiotic therapy in adults typically involves a quinolone (e.g., levo­
floxacin or ciprofloxacin) plus amoxicillin-clavulanate; such regimens
are appropriate only for patients who have not received a quinolone as
prophylaxis.
DOCUMENTED INFECTIONS DURING
NEUTROPENIA
■
■BACTEREMIA
Bacteremia is the most common microbiologically documented infec­
tion in neutropenic patients with fever. NF is associated with bacte­
remia in only 10% of cases, but this subgroup of patients has much
higher mortality than the general group of neutropenic patients
with fever, particularly with gram-negative bacteremia. Most recent
series show similar proportions of gram-positive (coagulase-negative
Staphylococcus, Streptococcus species, Enterococcus species including
vancomycin-resistant Enterococcus [VRE]) and gram-negative bacteria
(Enterobacterales and P. aeruginosa).
Bacteremia in neutropenic patients may be secondary to another site
of infection (e.g., pneumonia, neutropenic enterocolitis, cellulitis) or,
most commonly, to mucosal barrier injury (MBI) caused by the anti­
neoplastic treatment. The chemotherapy and/or radiation frequently
damages the mucosa of the gastrointestinal tract, facilitating translo­
cation of commensal bacteria during neutropenia. Clinically, one may
question whether the bacteremia may be a central line–associated blood­
stream infection (CLABSI). If the isolate is an intestinal bacterium, it
is considered related to MBI in the absence of local signs of infection
involving the venous catheter. If the isolate is part of the skin flora, like
coagulase-negative Staphylococcus, it is more likely to be a CLABSI,
but it may also represent a contaminant or colonization of the catheter.
Colonization or contamination should be presumed when only one of
several blood culture bottles is positive for normal skin flora, especially
if the culture takes more than 24 h to turn positive. When a blood
culture becomes positive for a gram-positive organism, it is important
to repeat blood cultures, ideally from both central and peripheral
sites, to determine whether the blood culture isolate is recovered from
more than one bottle and at different time points. Skin flora growing
from blood drawn from the catheter with negative peripheral blood
cultures can reflect catheter colonization (i.e., not a true bloodstream
infection) or CLABSI with low levels of bacteria in blood resulting in
negative peripheral cultures. When both the peripheral and the central
blood cultures are positive for the same organism, bacteremia is con­
firmed, and the differential time to positivity may allow establishing
the diagnosis of catheter-related bacteremia if the central line culture
grows at least 2 h earlier than the peripheral. However, the practice of
always obtaining a peripheral blood culture may not be practical on an
oncology ward, where patients may be febrile daily and are frequently
thrombocytopenic.
CHAPTER 79
Infections in Patients with Cancer
More important than whether blood cultures are collected from the
central catheter alone or from central and peripheral venous sources
is ensuring that an adequate volume of blood (as determined by the
specific blood culture platform) is collected. The optimal frequency
of blood cultures in NF has not been established. Similarly, the use
of surveillance blood cultures in neutropenic patients has not been
adequately studied. The amplification by PCR of plasma cell–free
DNA, with its superior yield compared with blood cultures, is still
investigational, and its place in the routine management of NF remains
to be defined.
If CLABSI is diagnosed, the preferred treatment is to remove
the catheter. Again, this may not always be practical in the case of
thrombocytopenic patients with limited access, and an attempt to
salvage a permanent catheter (i.e., tunneled catheter or port) may be
appropriate as long as the patient remains hemodynamically stable and
the blood cultures become negative upon initiating appropriate anti­
biotics. Antibiotic lock therapy should be considered, if feasible. The
likelihood of success when a catheter is colonized with S. aureus,
mycobacteria, or Candida species is low, and these catheters should
be removed as soon as possible. It is customary to provide some time
without central access (e.g., a 48-h “line holiday”) before replacing the
central venous catheter, although the evidence supporting this practice
is scant. Patients may require continuous central IV access, and in this
case it is reasonable to use nonsurgically placed lines (e.g., a peripher­
ally inserted central catheter) and to place a new surgically implanted
port (e.g., mediport) only when there is clear evidence of blood culture
clearance.
Endocarditis is rare during neutropenia, but it should be suspected
with persistently positive blood cultures or with clinical findings like
a new murmur or embolic phenomena. Routine echocardiogram in
every case of bacteremia in neutropenic patients is not recommended,
but patients with S. aureus bacteremia do require one.
■
■RESPIRATORY INFECTIONS
Sinusitis 
Sinusitis may manifest by pressure, facial pain, rhinor­
rhea, and postnasal drip but occasionally has very mild symptoms
that will be elicited only by targeted questioning during the physical
exam. Symptomatic sinusitis in neutropenic patients may be caused by
pathogens relatively uncommon in immunocompetent people, includ­
ing S. aureus, P. aeruginosa, and other gram-negative bacilli. Evaluation
by CT and consultation by otolaryngology to examine the integrity of
the mucosa and obtain samples for culture is recommended. Invasive
fungal sinusitis may be caused by Aspergillus species, agents of mucor­
mycosis, Fusarium species, and relatively less virulent dematiaceous
molds like Alternaria, Bipolaris, or Curvularia. CT findings sugges­
tive of fungal etiology include marked asymmetry, heterogeneous
radiodensity of the contents of the sinuses, and, later in the disease,
bony erosions. The endoscopic exam may show pale, devitalized
mucosa and, sometimes, necrotic ulceration of a turbinate caused by
the angioinvasive process. Invasive fungal sinusitis during neutropenia
mandates surgical resection. Repeated visits to the operating room
in conjunction with optimal antifungal therapy are necessary to save
the patient’s life. The empirical antifungal agent may vary depending
on the preexisting antifungal prophylaxis, but, given the possibility of
mucormycosis and fusariosis, many experts would recommend a lipid
formulation of amphotericin B, often considered the antifungal of
choice for mucormycosis, together with posaconazole, which is nonin­
ferior to voriconazole for Aspergillus species and has superior activity
in vitro against dematiaceous molds.
Pneumonia 
Pulmonary infiltrates are a common diagnostic chal­
lenge in immunocompromised hosts. A systematic approach to the
differential, which includes infections and noninfectious etiologies, is
mandatory. Some important noninfectious conditions to be consid­
ered include heart failure, fluid overload, transfusion reactions like
transfusion-associated circulatory overload (TACO) and transfusionassociated lung injury (TRALI), chemotherapy-associated pneumoni­
tis, organizing pneumonia, and diffuse alveolar hemorrhage, as well as
dissemination of the cancer itself. The radiologic appearance is useful
to separate unilateral focal processes (suggestive of bacterial or mold
infection) from multifocal or diffuse infections, which may be caused
in addition by viruses, atypical bacteria, and PJP. Single or multiple
dense, well-circumscribed nodules suggest IFD in high-risk patients
(e.g., those with leukemia and allogeneic stem cell transplant recipi­
ents), but Nocardia species may have the same appearance and other
bacteria like P. aeruginosa and Stenotrophomonas maltophilia may
cause angioinvasive infection and result in similar radiology. Unfor­
tunately, characteristic radiologic differences may not hold true in an
individual case, and every attempt should be made to obtain a respira­
tory sample for microbiologic diagnosis.
PART 4
Oncology and Hematology
Early bronchoscopy with bronchoalveolar lavage (BAL) in neutro­
penic patients with pneumonia is recommended. The yield of BAL is
highest for diffuse and multifocal processes. In the case of pulmonary
nodules accessible to percutaneous or endobronchial biopsy, the choice
of diagnostic procedure will often depend on institutional expertise,
clinical status, and comorbidities. The empirical antimicrobial regi­
men may vary slightly depending on the radiology and the individual
risk factors but should always provide optimal antibacterial coverage
by combining one of the antipseudomonal β-lactams together with
vancomycin and an agent active against Legionella, like azithromycin,
a fluoroquinolone, or doxycycline. If the patient has risk factors for
S. maltophilia (high prevalence in the institution, previous exposure
to carbapenems), the addition of TMP-SMX or levofloxacin should be
considered.
The empirical addition of TMP-SMX for PJP depends on the clinical
scenario and risk factors. If the only immune defect of the patient is
neutropenia, the main concerns are bacteria and molds, the likelihood
of PJP is low, and empirical anti-Pneumocystis coverage seems unnec­
essary. However, patients with hematologic malignancies often have
received corticosteroids or other agents that decrease cellular immu­
nity and put them at risk for PJP. In this case, empirical coverage until
PJP has been ruled out is reasonable. The current gold standard for the
diagnosis of PJP is PCR of respiratory secretions, which occasionally
may detect patients who are merely colonized. Serum β-d-glucan is
typically elevated in patients with PJP, and a positive result increases
the likelihood of PJP in a patient with appropriate risk factors and
radiologic findings. However, false-positive and -negative β-d-glucan
results occur, and this test is not specific for PJP; therefore, a positive
serum β-d-glucan does not always obviate the need for BAL.
Invasive fungal disease (IFD) is suggested by single or multiple
dense, well-circumscribed nodules, particularly larger than 2 cm. The
halo sign (ground glass opacity surrounding a dense nodule) or the
reverse halo sign (ground glass opacity seen inside a nodule, some­
times said to be more common in mucormycosis) may be present,
but these are not diagnostic. Peripheral wedge-shaped infiltrates also
may be seen. In patients at high risk for IFD, initiation or escalation of
antifungal therapy is commonly begun prior to establishing a diagno­
sis. Such decisions must consider the antifungal prophylaxis that the
patient is receiving. If the patient is on fluconazole or no antifungal
prophylaxis, a mold-active azole (e.g., voriconazole, posaconazole,
isavuconazole) as empirical therapy is reasonable pending a diagnosis,
since Aspergillus is by far the most likely mold infection. If on the other
hand, a suspected fungal infection occurs while receiving a mold-active
azole, many experts would recommend switching the regimen to lipo­
somal amphotericin B, while aggressively pursuing a diagnosis.
Evaluation of suspected pneumonia involves sputum and blood
cultures, nasopharyngeal swab for PCR for respiratory viruses, urine
Legionella antigen, and in patients with neutropenia, evaluation for IFD
(e.g., serum galactomannan, beta-glucan) should be included. If these
studies are negative and the empirical antimicrobial regimen does not
lead to improvement, early BAL or image-guided percutaneous lung
biopsy should be considered. If non-invasive diagnostic studies identify
a pathogen, it is important to consider the potential for concurrent or
secondary infection by other pathogens. For example, respiratory viral
infections can be complicated by secondary bacterial pneumonias,
and cases of invasive pulmonary aspergillosis following COVID-19
have been documented. It is therefore important to consider a broad
differential diagnosis and to repeat imaging and diagnostic evaluation
in patients with worsening pneumonia even when an initial diagnosis
has been made.
■
■INTRA-ABDOMINAL INFECTIONS
Neutropenic Enterocolitis (Typhlitis) 
Sometimes bacteria
invade the wall of the intestine and proliferate there, causing inflamma­
tion and even necrosis of segments of the bowel. The clinical syndrome
includes fever, abdominal pain, and tenderness and diarrhea, which is
occasionally bloody. The term typhlitis (inflammation of the cecum)
is sometimes used, as the cecum is most commonly involved, but the
terminal ileum, ascending colon, and other segments of the intestine
also may be affected, so the more general term neutropenic enterocolitis
is preferred. Blood cultures are frequently positive (with bowel flora),
but not always. Plain films of the abdomen are not sensitive or specific,
but a right lower quadrant soft tissue density, distended bowel loops,
ileus, or “thumbprinting” suggesting mucosal edema may sometimes
be seen. A CT scan of the abdomen and pelvis usually demonstrates
a right lower quadrant inflammatory mass, with thickened bowel wall
and stranding of the surrounding fat. Conservative management with
broad-spectrum antibiotics, bowel rest, bowel decompression, and
nutritional support is usually preferred. Surgery may be required if the
patient deteriorates and intestinal perforation, peritonitis, and hemo­
dynamic instability ensue. Carbapenems and piperacillin-tazobactam are
appropriate given their broader spectrum. If ceftazidime or cefepime is
used, additional agents against anaerobic bacteria (e.g., metronidazole)
must be added. In selecting an empirical regimen, it is important to
note prior infections with antibiotic-resistant infections, such as VRE,
and extended-spectrum β-lactamase (ESBL) of carbapenem-resistant
(CRE) gram-negative infections.
Similar to intra-abdominal infections, perirectal and perianal infec­
tions are caused by gastrointestinal flora in the context of neutropenia
and mucosal injury. CT imaging is helpful to assess the extent of infec­
tion. These infections typically respond to broad-spectrum antibiotic
therapy without the need for surgery, but follow-up imaging after neu­
trophil recovery may be necessary if symptoms or fever persist.
Clostridioides difficile (C. difficile)–Associated Disease 
Cancer
patients are at increased risk of C. difficile–associated disease (CDAD)
because of their frequent exposure to healthcare facilities, antibiotics,
and chemotherapeutic drugs. Patients with a history of CDAD in the
previous year are often treated prophylactically with oral vancomycin
(125 mg daily) when empirical antibiotic therapy for neutropenic fever
is begun. Every hospitalized neutropenic patient with diarrhea should
be tested for C. difficile. It is unclear whether neutropenic patients
with CDAD have worse outcomes, higher risk of complications, or
increased frequency of neutropenic enterocolitis. First-line treatment is
fidaxomicin, with oral vancomycin as an alternative. In case of ileus or
overwhelming CDAD, combination of either oral fidaxomicin or van­
comycin with IV metronidazole (which is secreted into the intestinal
lumen) is recommended.
Cholecystitis 
Cholecystitis is a rare infection during neutropenia,
and most cases have been seen during treatment of acute leukemia. The
presentation is like that in nonneutropenic individuals, but bacteremia
is more common. At least half of the reported cases have been acal­
culous cholecystitis. Conservative management, frequently including
cholecystostomy, is used until resolution of neutropenia when chole­
cystectomy can be performed more safely.
■
■CENTRAL NERVOUS SYSTEM INFECTIONS
Bacterial central nervous system (CNS) infections are uncommon
during neutropenia and usually secondary to an episode of bacteremia
(which may or may not have been detected) or to extension from the
paranasal sinuses. Meningitis caused by gram-negative bacilli, includ­
ing P. aeruginosa, may occur in this setting. Two unexpected causes of
CNS infections are worth mentioning. Rothia mucilaginosa, a grampositive coccus that is part of the oral flora, may seed the meninges
during a transient bacteremia that seemed to be controlled easily with
appropriate antibiotic treatment. This is a rare infection, and most
cases treated successfully have received meropenem and vancomycin.
Similarly, Bacillus cereus, a gram-positive bacillus ubiquitous in the
environment, has been reported as a cause of difficult-to-treat men­
ingitis and brain abscess in neutropenic patients with acute leukemia.
The combination of meropenem and vancomycin also has been used
successfully. Listeria monocytogenes meningitis and bacteremia are
most common in patients with impaired cellular immunity, includ­
ing patients with cancer receiving immunosuppressive regimens.
Besides meningitis, L. monocytogenes can also cause rhombencephalitis
(inflammation of the brainstem and cerebellum) and brain abscess.
The combination of ampicillin and gentamicin is recommended. In
cases of penicillin allergy TMP-SMX may be used. Listeria monocyto­
genes is susceptible in vitro to meropenem and linezolid, but clinical
experience is limited.
In patients with hematologic cancers and prolonged neutropenia,
brain lesions should raise the concern for opportunistic pathogens,
usually fungi. Aspergillus and Candida brain abscesses are usually
hematogenous; mucormycosis more frequently follows extension from
the sinuses. Empirical treatment should be administered including
antibacterial (typically meropenem plus vancomycin) and antifungal
agents until the etiology is established. As mentioned for pulmonary
infections, the choice of antifungal may be conditioned by preexisting
antifungal prophylaxis. Voriconazole is the preferred agent for CNS
aspergillosis and liposomal amphotericin B for mucormycosis. Echino­
candins do not achieve therapeutic levels in the brain or cerebrospinal
fluid (CSF), and they should not be relied upon for the treatment of
CNS infections.
Nocardia species and Toxoplasma gondii are important causes of
brain abscess in immunocompromised patients. The major risk factor
for these infections is suppressed T cell immunity. In patients with
cancer, prolonged intensive corticosteroid therapy and use of purine
analogues are examples of risk factors. TMP-SMX used as prophylaxis
for PJP may also confer some protection against Listeria, Nocardia, and
Toxoplasma.
Patients with cancer are at increased risk of viral encephali­
tis. Herpes simplex virus (HSV) encephalitis is characterized by
fever and decreased level of consciousness. Imaging shows unilateral
involvement of the temporal lobe. Abnormalities in the CSF may be
altered by radiation therapy or corticosteroids. The diagnosis is by
PCR of the CSF, which may be falsely negative early in the course of the
disease. Herpes zoster encephalitis is a rare but devastating complica­
tion in patients with defective T cell immunity. Human herpesvirus 6
(HHV-6) encephalitis is rare outside of allogeneic stem cell transplan­
tation (allo-HCT) (see Chap. 148). Finding a high level of HHV-6 in
blood in any other setting brings up the possibility of HHV-6 chromo­
somal integration, which is present in around 1% of the population.
In patients who have had neurosurgery, including those with
neurosurgical devices (e.g., shunts or reservoirs), infections by grampositive bacteria are most common, although gram-negative infections
including coliforms and P. aeruginosa can occur. Risk factors include
multiple neurosurgeries (e.g., for recurrent tumor), cranial irradiation,
antiangiogenics (which disrupt blood supply), and use of immuno­
suppressives. Vancomycin plus an antipseudomonal cephalosporin
(e.g., ceftazidime) is an appropriate initial regimen for postneuro­
surgical CNS infections, pending culture data. Surgical drainage and
debridement of infected material and removal of hardware are usually
required.
CHAPTER 79
■
■SKIN AND SOFT TISSUE INFECTIONS
As a rule, focal skin lesions in neutropenic, febrile patients should
be biopsied, as the diagnostic possibilities are multiple, and some of
the causes may be life-threatening and require immediate treatment.
Cellulitis may be caused by streptococci or S. aureus, but also by
gram-negative bacilli, and broad-spectrum coverage with an antip­
seudomonal β-lactam and vancomycin should be administered until
an etiologic diagnosis is established. Multiple foci of erythematous
tender plaques with underlying fasciitis and myositis are associated
with bacteremia by Clostridium septicum, sometimes seen in patients
with colorectal cancer. Ecthyma gangrenosum appears as a tender,
erythematous papule that then becomes necrotic and ulcerated. It may
be caused by local inoculation or by hematogenous seeding, typically of
P. aeruginosa but sometimes other gram-negative bacteria or even
molds like Fusarium species. Single or multiple lesions may be seen.
Disseminated candidiasis with hematogenous cutaneous disease mani­
fests with fever and other signs of systemic infection and multiple
raised cutaneous papules. Hemorrhagic bullae are described in cel­
lulitis caused by gram-negative bacteria (including Vibrio vulnificus,
which may be suspected with a history of liver dysfunction and expo­
sure to shellfish).
Infections in Patients with Cancer
Many noninfectious processes can cause skin lesions, but the pres­
ence of fever is unusual except in Sweet syndrome, also known as acute
neutrophilic dermatosis (Fig. 79-2). This is characterized by fever and
a variety of skin lesions including papules, nodules, plaques, and some­
times blisters. Skin lesions are often tender and may ulcerate. Sweet
syndrome can have many causes, including underlying cancer, usually
hematologic. Pathergy is characteristic, and lesions may appear at the
insertion site of an intravascular catheter, mimicking infection
(Fig. 79-2). Leukemia cutis may manifest as a variety of nontender
papules, nodules, or plaques. Fever is unusual. Chemotherapeutic
agents can cause a variety of skin reactions, including hyperpigmenta­
tion, hand-foot syndrome (erythema, edema, and blistering of palms
and soles), and several rashes. Definitive diagnosis often requires
biopsy of skin lesions with appropriate cultures and histopathology.
■
■URINARY TRACT INFECTIONS
It is common to obtain urine cultures in patients with NF regardless
of urinary symptoms, and sometimes bacteriuria is detected. The
question of whether it is just asymptomatic bacteriuria (common and
increasing with age in both men and women), unrelated to the fever,
or reflects true urinary tract infection (UTI) necessitating specific
treatment may not be immediately answerable. It is appropriate to
treat bacteriuria in patients with NF, and standard empirical antibiotic
regimens used for NF will cover most urinary pathogens. If UTI is
believed to be the source of NF, CT imaging should be considered to
A
B
C
D
PART 4
Oncology and Hematology
FIGURE 79-2  Sweet syndrome. A 47-year-old man admitted for acute myelogenous
leukemia (AML) received a surgically implanted catheter and was started on
idarubicin and cytosine arabinoside (Ara-C). He developed erythema and tenderness
at the insertion site and the cuff site after 24 h, followed by fever. The catheter
was removed and cultured (negative) and broad-spectrum antibiotics started,
without effect. The catheter exit site worsened, with bullae formation (A). New
skin nodules developed on his left thigh, both cheeks, and scalp. Tender induration
of the sternocleidomastoid muscle was noticeable clinically and by CT (B). Skin
biopsy showed a dense infiltrate of mature neutrophils consistent with Sweet
syndrome (C, D). The lesions and the fever resolved promptly with oral prednisone.
evaluate for complicated UTI with potential etiologies including geni­
tourinary tract obstruction by tumor or kidney stones, pyelonephritis,
and prostatitis.
PREVENTION OF INFECTIONS
IN PATIENTS WITH CANCER
Prevention measures to avoid infections should be tailored to the
immune status of the patient and consequent risk of infections. The
most stringent measures apply to patients with hematologic malignan­
cies with prolonged neutropenia, to stem cell transplant and adop­
tive cellular therapy recipients, and to other patients who may have
prolonged neutropenia for other reasons (e.g., aplastic anemia) or are
receiving intensive systemic corticosteroid therapy. At the other end of
the spectrum are patients with solid tumors who are in remission and
not receiving active chemotherapy or only receiving hormonal agents,
such as antiestrogen therapy for breast cancer. These patients should
adhere to guidelines to prevent infection that apply to the general
population such as hand hygiene, food safety, and guideline-based vac­
cines. This section is focused on prevention measures for patients with
cancer at high risk for infections including opportunistic infection.
■
■ENVIRONMENTAL PRECAUTIONS
Inpatient leukemia and transplant wards are typically engineered with
HEPA filters and appropriate air exchanges, and individual patient
rooms are under positive pressure relative to the outside. The principal
rationale for these precautions is to reduce mold spore exposure; these
structural precautions were in part driven by outbreaks of aspergillosis.
For similar reasons, houseplants are restricted from these wards. Con­
struction, which can release mold spores, must be performed under
stringent infection control precautions to minimize patient exposure.
In addition to limiting mold exposure, these precautions may have
additional benefits to limit airborne transmission of other infections.
The vast majority of chemotherapy regimens are administered
to outpatients, including to patients with hematologic malignancies
receiving intensive immunosuppressive regimens. The stringent envi­
ronmental precautions used for inpatients are not feasible in the out­
patient setting or in the home. Patients should not have construction
done in their homes and should avoid exposure to construction sites
during periods of significant immune compromise. Patients should
also not be involved in gardening, mulching, or similar activities that
result in spore exposure.
■
■PROTECTION FROM FOOD-BORNE INFECTIONS
The old practice of implementing “low-microbial diets” for neutrope­
nic patients did not show convincing benefit in well-designed studies
and carries the disadvantages of limiting nutrition and affecting quality
of life. Patients should be educated about food and water safety precau­
tions issued by the Centers for Disease Control and Prevention (www.
cdc.gov/food-safety/foods/weakened-immune-systems.html) and other
authoritative bodies that are tailored to immunocompromised persons
but are less restrictive than low-microbial diets. These guidelines stress
hand hygiene, washing vegetables and fruits, not consuming raw or
undercooked meat, poultry, or fish or unpasteurized dairy products,
avoidance of waterborne infections, and awareness of food-borne
outbreaks. Travel to regions where food and water safety is not reliable
should be avoided.
Animals also are a potential source of infection, particularly via the
fecal–oral route. Patients with cancer should avoid exposure to farm
animals and wild animals (e.g., hunting and butchering). Acquiring
a new pet while immunocompromised is not advisable. Existing pets
can continue to live in the patient’s house, but the patient should avoid
direct exposure to animal waste, such as cleaning a cat litter box or
bird cage. Patients should avoid dogs recently vaccinated for kennel
cough, if possible. Contact with more exotic pets (e.g., reptiles) should
be avoided because they can harbor more unusual pathogens (e.g.,
Salmonella species).
■
■RESPIRATORY VIRAL INFECTIONS
Patients with cancer should avoid contact with persons with symp­
toms or signs of respiratory infection to the extent feasible. Risk of
viral infection is increased in congregate settings that are indoors and
involve large numbers of people in close proximity. Precautions to limit
infection spread, such as choosing outdoor over indoor events and
avoiding crowded settings, are advisable. For example, a dinner at a
restaurant in which the table is limited to a few persons carries less risk
of transmissible infections than a crowded buffet-style setting.
Patients with cancer should be aware of local patterns of viral
infection. This point was amply demonstrated during the COVID-19
pandemic and applies to other viral infections, such as influenza and
respiratory syncytial virus (RSV). If local viral outbreaks occur, patients
with cancer should use additional precautions to limit exposure. In
addition to avoiding crowds, masking may provide an additional layer
of protection, especially in settings of high levels of community spread
of respiratory viral infections.
■
■SEXUAL INTIMACY
To avoid risk of sexually transmitted infections, it is recommended that
sexual intercourse be in a monogamous relationship. During neutrope­
nia, sexual intercourse and oral–genital or rectal stimulation may cause
injury and predispose to infection. Once the ANC recovers, sexual
activity usually can be resumed.
■
■ANTIMICROBIAL PROPHYLAXIS
Antimicrobial prophylaxis should be tailored to infection risk. Most
patients with solid tumors require no antimicrobial prophylaxis. In
addition to side effects of antibiotics, increased risk of C. difficile, and
selection of antibiotic-resistant flora, there is precedent for antibiotics
diminishing the efficacy of immune checkpoint inhibitors by disrup­
tion of the microbiome.
As discussed above, prophylaxis with a quinolone should be con­
sidered in adults with prolonged neutropenia (e.g., ANC <500/µL
for at least 7 days). Acyclovir prophylaxis to prevent HSV and VZV

09 - 80 Oncologic Emergencies
80 Oncologic Emergencies
reactivation is advised in the majority of patients with hematologic
malignancies on active therapy. In patients with AML receiving induc­
tion or reinduction chemotherapy, prophylaxis with posaconazole
should be included. Mold-active prophylaxis is also recommended in
patients with significant GVHD. PJP prophylaxis is recommended for
patients with severe T cell impairment (TMP-SMX is preferred). Exam­
ples include standard induction chemotherapy for acute lymphoblastic
leukemia that involves systemic corticosteroids, prolonged corticoste­
roids (described above), use of purine analogues (e.g., cladribine-con­
taining regimens), and GVHD. Pneumococcal prophylaxis (e.g., with
penicillin) should be considered for persons with asplenia or chronic
GVHD (described above).
■
■VACCINATION
Patients with cancer should receive all recommended non-live vac­
cines based on their approved indications. Yearly recommendations
regarding COVID-19 and influenza vaccines should be followed.
Patients with solid tumors in general mount greater antibody titers
than patients with hematologic malignancies, especially if they have
received B cell–depleting agents (e.g., rituximab, BTK inhibitors).
However, vaccination is still recommended for such patients with the
rationale that they may derive some protective benefit even if subopti­
mal. We also stress vaccination of household members, caretakers, and
other close contacts to prevent them from viral infection and transmis­
sion to the patient.
Live vaccines should not be given to immunocompromised per­
sons. However, household members including children should receive
age-appropriate vaccines, including live vaccines such as MMR and
varicella. If the child develops a rash following MMR or varicella vac­
cination, contact with the cancer patient should be limited until the
rash resolves.
■
■FURTHER READING
Kamboj M et al: Vaccination of adults with cancer: ASCO guideline.
J Clin Oncol 42:1699, 2024.
Lehrnbecher T et al: Guideline for the management of fever and
neutropenia in pediatric patients with cancer and hematopoietic cell
transplantation recipients: 2023 update. J Clin Oncol 41:1774, 2023.
Maertens J et al: Empiric vs preemptive antifungal strategy in highrisk neutropenic patients on fluconazole prophylaxis: A randomized
trial of the European Organization for Research and Treatment of
Cancer. Clin Infect Dis 76:674, 2023.
Martinez-Nadal G et al: Inappropriate empirical antibiotic treat­
ment in high-risk neutropenic patients with bacteremia in the era of
multidrug resistance. Clin Infect Dis 70:1068, 2020.
Maschmeyer G et al: Infectious complications of targeted drugs and
biotherapies in acute leukemia. Clinical practice guidelines by the
European Conference on Infections in Leukemia (ECIL), a joint ven­
ture of the European Group for Blood and Marrow Transplantation
(EBMT), the European Organization for Research and Treatment
of Cancer (EORTC), the International Immunocompromised Host
Society (ICHS) and the European Leukemia Net (ELN). Leukemia
36: 1215, 2022.
Stern A et al: Early discontinuation of antibiotics for febrile neutrope­
nia versus continuation until neutropenia resolution in people with
cancer. Cochrane Database Syst Rev 1:CD012184, 2019.
Taplitz RA et al: Antimicrobial prophylaxis for adult patients with
cancer-related immunosuppression: ASCO and IDSA clinical prac­
tice guideline update. J Clin Oncol 36:3043, 2018.
Zimmer AJ et al: Bloodstream infections in hematologic malig­
nancy patients with fever and neutropenia: Are empirical antibiotic
therapies in the United States still effective? Open Forum Infect Dis
9:ofac240, 2022.
■
■WEBSITE
NCCN Guidelines. Prevention and Treatment of Cancer-Related Infec­
tions. Version 2.2023. https://www.nccn.org/guidelines/guidelines-
detail?category=3&id=1457
Rasim Gucalp, Janice P. Dutcher
Oncologic Emergencies
Emergencies in patients with cancer may be classified into three groups:
pressure or obstruction caused by a space-occupying lesion, metabolic
or hormonal problems (paraneoplastic syndromes, Chap. 98), and
treatment-related complications.
STRUCTURAL-OBSTRUCTIVE ONCOLOGIC
EMERGENCIES
■
■SUPERIOR VENA CAVA SYNDROME
Superior vena cava syndrome (SVCS) is the clinical manifestation of
superior vena cava (SVC) obstruction, with severe reduction in venous
return from the head, neck, and upper extremities. Malignant tumors,
such as lung cancer, lymphoma, and metastatic tumors, are responsible
for the majority of SVCS cases. With the expanding use of intravascular
devices (e.g., permanent central venous access catheters, pacemaker/
defibrillator leads), the prevalence of benign causes of SVCS is now
increasing, accounting for at least 40% of cases. Lung cancer, particu­
larly of small-cell and squamous cell histologies, accounts for ~85% of
all cases of malignant origin. In young adults, malignant lymphoma is a
leading cause of SVCS. Hodgkin’s lymphoma involves the mediastinum
more commonly than other lymphomas but rarely causes SVCS. When
SVCS is noted in a young man with a mediastinal mass, the differential
diagnosis is lymphoma versus primary mediastinal germ cell tumor.
Metastatic cancers to the mediastinal lymph nodes, such as testicular and
breast carcinomas, account for a small proportion of cases. Other causes
include benign tumors, aortic aneurysm, thyromegaly, thrombosis, and
fibrosing mediastinitis from prior irradiation, histoplasmosis, or Behçet’s
syndrome. SVCS as the initial manifestation of Behçet’s syndrome may
be due to inflammation of the SVC associated with thrombosis.
CHAPTER 80
Oncologic Emergencies
Patients with SVCS usually present with neck and facial swelling
(especially around the eyes), dyspnea, and cough. Other symptoms
include hoarseness, tongue swelling, headaches, nasal congestion, epi­
staxis, hemoptysis, dysphagia, pain, dizziness, syncope, and lethargy.
Bending forward or lying down may aggravate the symptoms. The
characteristic physical findings are dilated neck veins; an increased
number of collateral veins covering the anterior chest wall; cyanosis;
and edema of the face, arms, and chest. Facial swelling and plethora
are typically exacerbated when the patient is supine. More severe cases
include proptosis, glossal and laryngeal edema, and obtundation. The
clinical picture is milder if the obstruction is located above the azygos
vein. Symptoms are usually progressive, but in some cases, they may
improve as collateral circulation develops.
Signs and symptoms of cerebral and/or laryngeal edema, though
rare, are associated with a poorer prognosis and require urgent evalu­
ation. Seizures are more likely related to brain metastases than to cere­
bral edema from venous occlusion. Patients with small-cell lung cancer
and SVCS have a higher incidence of brain metastases than those
without SVCS.
Cardiorespiratory symptoms at rest, particularly with positional
changes, suggest significant airway and vascular obstruction and
limited physiologic reserve. Cardiac arrest or respiratory failure can
occur, particularly in patients receiving sedatives or undergoing gen­
eral anesthesia.
Rarely, esophageal varices may develop, particularly in the setting
of SVC syndrome due to hemodialysis catheter. These are “downhill”
varices based on the direction of blood flow from cephalad to caudad
(in contrast to “uphill” varices associated with caudad to cephalad flow
from portal hypertension). Variceal bleeding may be a late complica­
tion of chronic SVCS.
SVC obstruction may lead to bilateral breast edema with bilateral
enlarged breasts. Unilateral breast dilation may be seen as a conse­
quence of axillary or subclavian vein blockage.
The diagnosis of SVCS is a clinical one. The most significant chest
radiographic finding is widening of the superior mediastinum, most
commonly on the right side. Pleural effusion occurs in only 25% of
patients, often on the right side. The majority of these effusions are exu­
dative and occasionally chylous. However, a normal chest radiograph
is still compatible with the diagnosis if other characteristic findings
are present. Computed tomography (CT) provides the most reliable
view of the mediastinal anatomy. The diagnosis of SVCS requires
diminished or absent opacification of central venous structures with
prominent collateral venous circulation. The focal hepatic hotspot
on CT scan (“hot quadrate”) sign suggests SVC obstruction, and it is
caused by portosystemic venous shunting between the SVC and portal
vein within liver. Magnetic resonance imaging (MRI) is increasingly
being used to diagnose SVC obstruction with a 100% sensitivity and
specificity, but dyspneic SVCS patients may have difficulty remaining
supine for the entire imaging process. Invasive procedures, includ­
ing bronchoscopy, percutaneous needle biopsy, mediastinoscopy, and
even thoracotomy, can be performed by a skilled clinician without
any major risk of bleeding. Endobronchial or esophageal ultrasoundguided needle aspiration may establish the diagnosis safely. For patients
with a known cancer, a detailed workup usually is not necessary, and
appropriate treatment may be started after obtaining a CT scan of the
thorax. For those with no history of malignancy, a detailed evaluation
is essential to rule out benign causes and determine a specific diagnosis
to direct the appropriate therapy.
PART 4
Oncology and Hematology
TREATMENT
Superior Vena Cava Syndrome
The one potentially life-threatening complication of a superior
mediastinal mass is tracheal obstruction. Upper airway obstruction
demands emergent therapy. Diuretics with a low-salt diet, head
elevation, and oxygen may produce temporary symptomatic relief.
Glucocorticoids have a limited role except in the setting of medias­
tinal lymphoma masses.
Radiation therapy is the primary treatment for SVCS caused by
non-small-cell lung cancer and other metastatic solid tumors. Che­
motherapy is effective when the underlying cancer is small-cell car­
cinoma of the lung, lymphoma, or germ cell tumor. SVCS recurs in
10–30% of patients; it may be palliated with the use of intravascular
self-expanding stents (Fig. 80-1). Endovascular therapy is more fre­
quently used first, to provide rapid relief of clinical symptoms with
reduced complications. Early stenting may be necessary in patients
with severe symptoms, particularly cerebral or laryngeal edema
or postural hypotension; however, the prompt increase in venous
return after stenting may precipitate heart failure and pulmonary
edema. Other complications of stent placement include hematoma
at the insertion site, SVC perforation, stent migration in the right
ventricle, stent fracture, and pulmonary embolism. Surgery may
play role in treatment of SVCS secondary to nonmalignant medi­
astinal fibrosis.
Clinical improvement occurs in most patients, although this
improvement may be due to the development of adequate collateral
circulation. The mortality associated with SVCS does not relate to
caval obstruction but rather to the underlying cause.
SVCS AND CENTRAL VENOUS CATHETERS IN ADULTS
The use of long-term central venous catheters has become common
practice in patients with cancer. Major vessel thrombosis may occur.
In these cases, catheter removal should be combined with antico­
agulation to prevent embolization. SVCS in this setting, if detected
early, can be treated by fibrinolytic therapy without sacrificing the
catheter. When managing patients with transvenous lead-related
SVC syndrome, anticoagulation, local and systemic thrombolytic
therapy, and surgical intervention can be effective therapy in select
patients. Endovascular stenting has also been shown to be safe and
promising, with minimal procedural or clinical complications. The
role of anticoagulation after SVC stent placement is controversial.
A
B
C
FIGURE 80-1  Superior vena cava syndrome (SVCS). A. Chest radiographs of a
59-year-old man with recurrent SVCS caused by non-small-cell lung cancer showing
right paratracheal mass with right pleural effusion. B. Computed tomography of
same patient demonstrating obstruction of the superior vena cava with thrombosis
(arrow) by the lung cancer (square) and collaterals (arrowheads). C. Balloon
angioplasty (arrowhead) with Wallstent (arrow) in same patient.
■
■PERICARDIAL EFFUSION/TAMPONADE
Malignant pericardial disease is found at autopsy in 5–10% of patients
with cancer, most frequently with lung cancer, breast cancer, leukemias,
and lymphomas. Cardiac tamponade as the initial presentation of
extrathoracic malignancy is rare. The origin is not malignancy in ~50%
of cancer patients with symptomatic pericardial disease, but it can be
related to irradiation; drug-induced pericarditis, including chemother­
apeutic agents such as all-trans retinoic acid, arsenic trioxide, imatinib,
and other abl kinase inhibitors; hypothyroidism; idiopathic pericarditis;
infection; or autoimmune diseases. Pericardial disease has been associ­
ated with immune checkpoint inhibitors specifically in patients with
advanced non-small-cell lung cancer. Two types of radiation pericardi­
tis occur: an acute inflammatory, effusive pericarditis occurring within
months of irradiation, which usually resolves spontaneously, and a
chronic effusive pericarditis that may appear up to 20 years after radia­
tion therapy and is accompanied by a thickened pericardium.
Most patients with pericardial metastasis are asymptomatic. How­
ever, the common symptoms are dyspnea, cough, chest pain, orthop­
nea, and weakness. Pleural effusion, sinus tachycardia, jugular venous
distention, hepatomegaly, peripheral edema, and cyanosis are the most
frequent physical findings. Relatively specific diagnostic findings, such
as paradoxical pulse, diminished heart sounds, pulsus alternans (pulse
waves alternating between those of greater and lesser amplitude with
successive beats), and friction rub are less common than with non­
malignant pericardial disease. Chest radiographs and electrocardio­
gram (ECG) reveal abnormalities in 90% of patients, but half of these
abnormalities are nonspecific. Echocardiography is the most helpful
diagnostic test. Pericardial fluid may be serous, serosanguineous, or
hemorrhagic, and cytologic examination of pericardial fluid is diagnos­
tic in most patients. Measurements of tumor markers in the pericardial
fluid are not helpful in the diagnosis of malignant pericardial fluid.
Pericardioscopy with targeted pericardial and epicardial biopsy may
differentiate neoplastic and benign pericardial disease. A combination
of cytology, pericardial and epicardial biopsy, and guided pericardios­
copy gives the best diagnostic yield. CT scan of chest may also reveal
the presence of a concomitant thoracic neoplasm. Cancer patients with
pericardial effusion containing malignant cells on cytology have a very
poor survival.
TREATMENT
Pericardial Effusion/Tamponade
Pericardiocentesis with or without the introduction of sclerosing
agents, the creation of a pericardial window, complete pericardial
stripping, cardiac irradiation, and systemic chemotherapy are effec­
tive treatments. Acute pericardial tamponade with life-threatening
hemodynamic instability requires immediate drainage of fluid. This
can be quickly achieved by pericardiocentesis. The recurrence rate
after percutaneous catheter drainage is ~20%. Sclerotherapy (peri­
cardial instillation of bleomycin, mitomycin C, or tetracycline) may
decrease recurrences. Alternatively, subxiphoid pericardiotomy can
be performed in 45 min under local anesthesia. Thoracoscopic
pericardial fenestration can be employed for benign causes; how­
ever, 60% of malignant pericardial effusions recur after this proce­
dure. In a subset of patients, drainage of the pericardial effusion is
paradoxically followed by worsening hemodynamic instability. This
so-called “postoperative low cardiac output syndrome” occurs in up
to 10% of patients undergoing surgical drainage and carries poor
short-term survival.
■
■INTESTINAL OBSTRUCTION
Intestinal obstruction and reobstruction are common problems in
patients with advanced cancer, particularly colorectal or ovarian car­
cinoma. However, other cancers, such as lung or breast cancer and
melanoma, can metastasize within the abdomen, leading to intestinal
obstruction. Metastatic disease from colorectal, ovarian, pancre­
atic, gastric, and occasionally breast cancer can lead to peritoneal
carcinomatosis, with infiltration of the omentum and peritoneal sur­
face, thus limiting bowel motility. Typically, obstruction occurs at mul­
tiple sites in peritoneal carcinomatosis. Melanoma has a predilection
to involve the small bowel; this involvement may be isolated, and
resection may result in prolonged survival. Intestinal pseudoobstruc­
tion is caused by infiltration of the mesentery or bowel muscle by
tumor, involvement of the celiac plexus, or paraneoplastic neuropathy
in patients with small-cell lung cancer. Paraneoplastic neuropathy is
associated with IgG antibodies reactive to neurons of the myenteric
and submucosal plexuses of the jejunum and stomach. Ovarian cancer
can lead to authentic luminal obstruction or to pseudoobstruction that
results when circumferential invasion of a bowel segment arrests the
forward progression of peristaltic contractions.
The onset of obstruction is usually insidious. Pain is the most com­
mon symptom and is usually colicky in nature. Pain can also be due
to abdominal distention, tumor masses, or hepatomegaly. Vomiting
can be intermittent or continuous. Patients with complete obstruction
usually have constipation. Physical examination may reveal abdomi­
nal distention with tympany, ascites, visible peristalsis, high-pitched
bowel sounds, and tumor masses. Erect plain abdominal films may
reveal multiple air-fluid levels and dilation of the small or large bowel.
Acute cecal dilation to >12–14 cm is considered a surgical emergency
because of the high likelihood of rupture. CT scan is useful in defining
the extent of disease and the exact nature of the obstruction and dif­
ferentiating benign from malignant causes of obstruction in patients
who have undergone surgery for malignancy. Malignant obstruction is
suggested by a mass at the site of obstruction or prior surgery, adenopa­
thy, or an abrupt transition zone and irregular bowel thickening at the
obstruction site. Benign obstruction is more likely when CT shows
mesenteric vascular changes, a large volume of ascites, or a smooth
transition zone and smooth bowel thickening at the obstruction site.
In challenging patients with obstructive symptoms, particularly lowgrade small-bowel obstruction (SBO), CT enteroclysis often can help
establish the diagnosis by providing distention of small-bowel loops.
In this technique, water-soluble contrast is infused through a naso­
enteric tube into the duodenum or proximal small bowel followed by
CT images. The prognosis for the patient with cancer who develops
intestinal obstruction is poor; median survival is 3–4 months. About
25–30% of patients are found to have intestinal obstruction due to
causes other than cancer. Adhesions from previous operations are a
common benign cause. Ileus induced by vinca alkaloids, narcotics, or
other drugs is another reversible cause.
CHAPTER 80
Oncologic Emergencies
TREATMENT
Intestinal Obstruction
The management of intestinal obstruction in patients with
advanced malignancy depends on the extent of the underlying
malignancy, options for further antineoplastic therapy, estimated
life expectancy, the functional status of the major organs, and the
extent of the obstruction. The initial management should include
surgical evaluation. Operation is not always successful and may
lead to further complications with a substantial mortality rate
(10–20%). Laparoscopy can diagnose and treat malignant bowel
obstruction in some cases. Self-expanding metal stents placed in
the gastric outlet, duodenum, proximal jejunum, colon, or rectum
may palliate obstructive symptoms at those sites without major sur­
gery. Patients known to have advanced intraabdominal malignancy
should receive a prolonged course of conservative management,
including nasogastric decompression. Percutaneous endoscopic or
surgical gastrostomy tube placement is an option for palliation of
nausea and vomiting, the so-called “venting gastrostomy.” Treat­
ment with antiemetics, antispasmodics, and analgesics may allow
patients to remain outside the hospital. Octreotide may relieve
obstructive symptoms through its inhibitory effect on gastrointes­
tinal secretion. Glucocorticoids have anti-inflammatory effects and
may help the resolution of bowel obstruction.
■
■URINARY OBSTRUCTION
Urinary obstruction may occur in patients with prostatic or gyneco­
logic malignancies, particularly cervical carcinoma; metastatic disease
from other primary sites such as carcinomas of the breast, stomach,
lung, colon, and pancreas; or lymphomas. Radiation therapy to pelvic
tumors may cause fibrosis and subsequent ureteral obstruction. Blad­
der outlet obstruction is usually due to prostate and cervical cancers
and may lead to bilateral hydronephrosis and renal failure.
Flank pain is the most common symptom. Persistent urinary tract
infection, persistent proteinuria, or hematuria in patients with cancer
should raise suspicion of ureteral obstruction. Total anuria and/or
anuria alternating with polyuria may occur. A slow, continuous rise
in the serum creatinine level necessitates immediate evaluation. Renal
ultrasound is the safest and cheapest way to identify hydronephrosis.
The function of an obstructed kidney can be evaluated by a nuclear
scan. CT scan can reveal the point of obstruction and identify a retro­
peritoneal mass or adenopathy.
TREATMENT
Urinary Obstruction
Obstruction associated with flank pain, sepsis, or fistula formation
is an indication for immediate palliative urinary diversion. Internal
ureteral stents can be placed under local anesthesia. Percutane­
ous nephrostomy offers an alternative approach for drainage. The
placement of a nephrostomy is associated with a significant rate
of pyelonephritis. In the case of bladder outlet obstruction due
to malignancy, a suprapubic cystostomy can be used for urinary
drainage. An aggressive intervention with invasive approaches to
improve the obstruction should be weighed against the likelihood
of antitumor response, and the ability to reverse renal insufficiency
should be evaluated.
PART 4
Oncology and Hematology
■
■MALIGNANT BILIARY OBSTRUCTION
This common clinical problem can be caused by a primary carcinoma
arising in the pancreas, ampulla of Vater, bile duct, or liver or by
metastatic disease to the periductal lymph nodes or liver parenchyma.
The most common metastatic tumors causing biliary obstruction are
gastric, colon, breast, and lung cancers. Jaundice, light-colored stools,
dark urine, pruritus, and weight loss due to malabsorption are usual
symptoms. Pain and secondary infection are uncommon in malig­
nant biliary obstruction. Ultrasound, CT scan, magnetic resonance
cholangiopancreatography (MRCP), or percutaneous transhepatic or
endoscopic retrograde cholangiopancreatography (ERCP) will identify
the site and nature of the biliary obstruction.
TREATMENT
Malignant Biliary Obstruction
Palliative intervention is indicated only in patients with disabling
pruritus resistant to medical treatment, severe malabsorption, or
infection. Stenting under radiographic control, surgical bypass,
or radiation therapy with or without chemotherapy may alleviate
the obstruction. The choice of therapy should be based on the site
of obstruction (proximal vs distal), the type of tumor (sensitive to
radiotherapy, chemotherapy, or neither), and the general condition
of the patient. Stenting under radiographic or endoscopic control,
surgical bypass, or radiation therapy with or without chemotherapy
may alleviate the obstruction. Photodynamic therapy and radiofre­
quency ablation are promising endoscopic therapies for malignant
biliary obstruction.
Endoscopic ultrasonography-guided biliary drainage is a safe
and effective method of biliary drainage in patients with malignant
biliary obstruction, particularly in patients whom standard ERCP
failed.
■
■SPINAL CORD COMPRESSION
Malignant spinal cord compression (MSCC) is defined as compression
of the spinal cord and/or cauda equina by an extradural tumor mass.
The minimum radiologic evidence for cord compression is indentation
of the theca at the level of clinical features. Spinal cord compression
(SCC) occurs in 5–10% of patients with cancer. Epidural tumor is the
first manifestation of malignancy in ~10% of patients. The underlying
cancer is usually identified during the initial evaluation; lung cancer is
the most common cause of MSCC.
Metastatic tumor involves the vertebral column more often than
any other part of the bony skeleton. Lung, breast, and prostate can­
cers are the most frequent offenders. Multiple myeloma also has a
high incidence of spine involvement. Lymphomas, melanoma, renal
cell cancer, and genitourinary cancers also cause cord compression.
The thoracic spine is the most common site (70%), followed by the
lumbosacral spine (20%) and the cervical spine (10%). Involvement of
multiple sites is most frequent in patients with breast and prostate car­
cinoma. Cord injury develops when metastases to the vertebral body
or pedicle enlarge and compress the underlying dura. Another cause of
cord compression is direct extension of a paravertebral lesion through
the intervertebral foramen. These cases usually involve a lymphoma,
myeloma, or pediatric neoplasm. Parenchymal spinal cord metastasis
due to hematogenous spread is rare. Intramedullary metastases can
be seen in lung cancer, breast cancer, renal cancer, melanoma, and
lymphoma, and are frequently associated with brain metastases and
leptomeningeal disease.
Expanding extradural tumors induce injury through several mecha­
nisms. Expanding extradural tumors induce mechanical injury to
axons and myelin. Compression compromises blood flow, leading to
ischemia and/or infarction.
The most common initial symptom in patients with SCC is localized
back pain and tenderness due to involvement of vertebrae by tumor.
Pain is usually present for days or months before other neurologic find­
ings appear. It is exacerbated by movement and by coughing or sneez­
ing. It can be differentiated from the pain of disk disease by the fact that
it worsens when the patient is supine. Radicular pain is less common
than localized back pain and usually develops later. Radicular pain in
the cervical or lumbosacral areas may be unilateral or bilateral. Radicu­
lar pain from the thoracic roots is often bilateral and is described by
patients as a feeling of tight, band-like constriction around the thorax
and abdomen. Typical cervical radicular pain radiates down the arm;
in the lumbar region, the radiation is down the legs. Lhermitte’s sign,
a tingling or electric sensation down the back and upper and lower
limbs upon flexing or extending the neck, may be an early sign of cord
compression. Loss of bowel or bladder control may be the presenting
symptom but usually occurs late in the course. Occasionally, patients
present with ataxia of gait without motor and sensory involvement due
to involvement of the spinocerebellar tract.
On physical examination, pain induced by straight leg raising,
neck flexion, or vertebral percussion may help to determine the level
of cord compression. Patients develop numbness and paresthesias in
the extremities or trunk. Loss of sensibility to pinprick is as common
as loss of sensibility to vibration or position. The upper limit of the
zone of sensory loss is often one or two vertebrae below the site of
compression. Motor findings include weakness, spasticity, and abnor­
mal muscle stretching. An extensor plantar reflex reflects significant
compression. Deep tendon reflexes may be brisk. Motor and sensory
loss usually precedes sphincter disturbance. Patients with autonomic
dysfunction may present with decreased anal tonus, decreased perineal
sensibility, and a distended bladder. The absence of the anal wink reflex
or the bulbocavernosus reflex confirms cord involvement. Autonomic
dysfunction is an unfavorable prognostic factor. Patients with progres­
sive neurologic symptoms should have frequent neurologic examina­
tions and rapid therapeutic intervention. Other illnesses that may
mimic cord compression include osteoporotic vertebral collapse, disk
disease, pyogenic abscess or vertebral tuberculosis, radiation myelopa­
thy, neoplastic leptomeningitis, benign tumors, epidural hematoma,
and spinal lipomatosis.
Neurologic exam
Normal
Suspicious for
myelopathy
Plain spine x-ray
Pain crescendo pattern
Lhermitte’s sign
Pain aggravated with cough,
Valsalva, and recumbency
Normal
Symptomatic therapy
Abnormal
If symptoms persists or progress
FIGURE 80-2  Management of cancer patients with back pain.  
Cauda equina syndrome is characterized by low back pain; dimin­
ished sensation over the buttocks, posterior-superior thighs, and
perineal area in a saddle distribution; rectal and bladder dysfunc­
tion; sexual impotence; absent bulbocavernous, patellar, and Achil­
les’ reflexes; and variable amount of lower-extremity weakness. This
reflects compression of nerve roots as they form the cauda equina
after leaving the spinal cord. The majority of cauda equina tumors
are primary tumors of glial or nerve sheath origin; metastases are
very rare.
Patients with cancer who develop back pain should be evaluated
for SCC as quickly as possible (Fig. 80-2). Treatment is more often
successful in patients who are ambulatory and still have sphincter
control at the time treatment is initiated. Patients should have a neuro­
logic examination and plain films of the spine. Those whose physical
examination suggests cord compression should receive dexamethasone
starting immediately and undergo MRI imaging.
Erosion of the pedicles (the “winking owl” sign) is the earliest
radiologic finding of vertebral tumor in plain films; however, plain
films are insensitive. Other radiographic changes include increased
intrapedicular distance, vertebral destruction, lytic or sclerotic lesions,
scalloped vertebral bodies, and vertebral body collapse. Vertebral
collapse is not a reliable indicator of the presence of tumor; ~20%
of cases of vertebral collapse, particularly those in older patients and
postmenopausal women, are due not to cancer but to osteoporosis.
Also, a normal appearance on plain films of the spine does not exclude
the diagnosis of cancer. The role of bone scans in the detection of cord
compression is not clear; this method is sensitive but less specific than
spinal radiography.
The full-length image of the cord provided by MRI is the imaging
procedure of choice. Multiple epidural metastases are noted in 25% of
Back pain
High-dose
dexamethasone
MRI of spine
Epidural metastases
No metastases
CHAPTER 80
Surgery followed by
radiation therapy or
radiation therapy alone
Symptomatic therapy
Oncologic Emergencies
Bone metastases but
no epidural metastases
Symptomatic therapy ±
radiation therapy
patients with cord compression, and their presence influences treat­
ment plans. On T1-weighted images, good contrast is noted between
the cord, cerebrospinal fluid (CSF), and extradural lesions. Owing to its
sensitivity in demonstrating the replacement of bone marrow by tumor,
MRI can show which parts of a vertebra are involved by tumor. MRI
also visualizes intraspinal extradural masses compressing the cord.
T2-weighted images are most useful for the demonstration of intra­
medullary pathology. Gadolinium-enhanced MRI can help to delineate
intramedullary disease. MRI is as good as or better than myelography
plus postmyelogram CT scan in detecting metastatic epidural disease
with cord compression. Myelography should be reserved for patients
who have poor MRIs or who cannot undergo MRI promptly. CT scan
in conjunction with myelography enhances the detection of small areas
of spinal destruction.
In patients with cord compression and an unknown primary
tumor, a simple workup including chest radiography, mammography,
measurement of prostate-specific antigen, and abdominal CT usually
reveals the underlying malignancy.
TREATMENT
Spinal Cord Compression
The treatment of patients with SCC is aimed at relief of pain and
restoration/preservation of neurologic function (Fig. 80-2). Man­
agement of MSCC requires a multidisciplinary approach.
Radiation therapy plus glucocorticoids is generally the initial
treatment of choice for most patients with SCC. The management
decision of SCC involves assessment of neurologic (N), onco­
logic (O), mechanical (M), and systemic factors (S). NOMS was
developed by Memorial Sloan Kettering Cancer Center (MSKCC)
researchers to provide an algorithm for management of SCC. The
neurologic assessment is based on the degree of epidural SCC,
myelopathy, and/or functional radiculopathy. Oncologic assess­
ment involves the radiosensitivity of the tumor type. In patients
with radioresistant tumors, stereotactic body radiotherapy (SBRT)
is the preferred approach if radiation is appropriate. Safe delivery
of SBRT requires a 2- to 3-mm margin away from the spinal cord.
Separation surgery followed by SBRT is necessary in patients with
high-grade SCC due to radioresistant tumors. Separation surgery is
the circumferential excision of epidural tumor to reconstitute the
thecal sac and provide a 2-mm margin for safe delivery of an abla­
tive radiation dose. In patients with mechanical instability or retro­
pulsion of bone fragments into the spinal canal or cord, a surgical
approach is the treatment of choice. Systemic factors that need to
be considered are the extent of disease and medical comorbidities
that determine the patient’s ability to tolerate planned therapy. Che­
motherapy may have a role in patients with chemosensitive tumors
who have had prior radiotherapy to the same region and who are
not candidates for surgery. Patients who previously received radio­
therapy for MSCC with an in-field tumor progression can be treated
with reirradiation with spine stereotactic radiosurgery (SRS) if they
are not surgical candidates.
Patients with painful pathologic compression fractures without
spinal instability may benefit from percutaneous vertebroplasty
or kyphoplasty, the injection of acrylic cement into a collapsed
vertebra to stabilize the fracture. Pain palliation is common, and
local antitumor effects have been noted. Cement leakage may cause
symptoms in ~10% of patients. Bisphosphonates and/or deno­
sumab may be helpful in prevention of SCC in patients with bony
involvement.
PART 4
Oncology and Hematology
The histology of the tumor is an important determinant of both
recovery and survival. Rapid onset and progression of signs and
symptoms are poor prognostic features.
■
■INCREASED INTRACRANIAL PRESSURE
About 25% of patients with cancer die with intracranial metastases.
The cancers that most often metastasize to the brain are lung and breast
cancers and melanoma. Brain metastases often occur in the presence of
systemic disease, and they frequently cause major symptoms, disability,
and early death. The initial presentation of brain metastases from a
previously unknown primary cancer is common. Lung cancer is most
commonly the primary malignancy. CT scans of the chest/abdomen
and MRI of the brain as the initial diagnostic studies can identify a
biopsy site in most patients.
The signs and symptoms of a metastatic brain tumor are similar to
those of other intracranial expanding lesions: headache, nausea, vom­
iting, behavioral changes, seizures, and focal, progressive neurologic
changes. Occasionally the onset is abrupt, resembling a stroke, with
the sudden appearance of headache, nausea, vomiting, and neurologic
deficits. This picture is usually due to hemorrhage into the metastasis.
Melanoma, germ cell tumors, and renal cell cancers have a particularly
high incidence of intracranial bleeding. The tumor mass and surround­
ing edema may cause obstruction of the circulation of CSF, with result­
ing hydrocephalus. Patients with increased intracranial pressure may
have papilledema with visual disturbances and neck stiffness. As the
mass enlarges, brain tissue may be displaced through the fixed cranial
openings, producing various herniation syndromes.
MRI is superior to CT scan. Gadolinium-enhanced MRI is more
sensitive than CT at revealing meningeal involvement and small
lesions, particularly in the brainstem or cerebellum. The MRI of the
brain shows brain metastases as multiple enhancing lesions of various
sizes with surrounding areas of low-density edema.
Intracranial hypertension (“pseudotumor cerebri”) secondary
to tretinoin therapy for acute promyelocytic leukemia has been
reported as another cause of intracranial pressure in the setting of a
malignancy.
TREATMENT
Increased Intracranial Pressure
Dexamethasone is the best initial treatment for all symptomatic
patients with brain metastases. The current success of immuno­
therapy approaches for primary and metastatic brain tumors may
preclude or limit glucocorticoid use since it may decrease antitumor
response. Bevacizumab should be considered in patients who are
unable to wean completely off of steroids as well as those who have
symptomatic brain edema and are on immunotherapy. Patients with
a single brain metastasis and with controlled extracranial disease
may be treated with surgical excision followed by SRS to the resec­
tion cavity. SRS is recommended in patients with a limited number
of brain metastases (one to four) who have stable, systemic disease
or reasonable systemic treatment options and in patients who have
a small number of metastatic lesions in whom whole-brain radia­
tion therapy has failed. The treatment of a larger number of intra­
cranial metastases remains controversial. More patients now receive
SRS because of cognitive dysfunction associated with whole-brain
radiation. Some patients with increased intracranial pressure asso­
ciated with hydrocephalus may benefit from shunt placement.
If neurologic deterioration is not reversed with medical therapy,
ventriculotomy to remove CSF or craniotomy to remove tumors or
hematomas may be necessary.
Targeted agents and checkpoint inhibitors have significant activ­
ity in brain metastases from non-small-cell lung cancer, breast
cancer, renal cancer, and melanoma.
■
■NEOPLASTIC MENINGITIS
Tumor involving the leptomeninges is a complication of both primary
central nervous system (CNS) tumors and tumors that metastasize to
the CNS. The incidence is estimated at 3–8% of patients with cancer.
Melanoma, breast and lung cancer, lymphoma (including AIDS-asso­
ciated), and acute leukemia are the most common causes. The lobular
or triple-negative subtypes of breast cancer, as well as tumors with
expression of the mutant epidermal growth factor receptor (EGFR) or
the anaplastic lymphoma kinase (ALK) rearrangement in non-smallcell lung cancer, are more likely to have CNS involvement including
neoplastic meningitis and brain metastases. Synchronous intrapa­
renchymal brain metastases are frequent in patients with neoplastic
meningitis. Leptomeningeal seeding is frequent in patients undergoing
resection of brain metastases or receiving stereotactic radiotherapy for
brain metastases.
Patients typically present with multifocal neurologic signs and
symptoms, including headache, gait abnormality, mental changes,
nausea, vomiting, seizures, back or radicular pain, and limb weakness.
Signs include cranial nerve palsies, extremity weakness, paresthesia,
and decreased deep tendon reflexes.
Diagnosis is made by demonstrating malignant cells in the CSF;
however, up to 40% of patients may have false-negative CSF cytology.
An elevated CSF protein level is nearly always present. Patients with
neurologic signs and symptoms consistent with neoplastic meningitis
who have a negative CSF cytology should have the spinal tap repeated at
least one more time for cytologic examination. MRI findings suggestive
of neoplastic meningitis include leptomeningeal, subependymal, dural,
or cranial nerve enhancement; superficial cerebral lesions; intradural
nodules; and communicating hydrocephalus. Spinal cord imaging by
MRI is a necessary component of the evaluation of nonleukemia neo­
plastic meningitis because ~20% of patients have cord abnormalities,
including intradural enhancing nodules that are diagnostic for lepto­
meningeal involvement. Cauda equina lesions are common, but lesions
may be seen anywhere in the spinal canal. Radiolabeled CSF flow stud­
ies are abnormal in up to 70% of patients with neoplastic meningitis;
ventricular outlet obstruction, abnormal flow in the spinal canal, or
impaired flow over the cerebral convexities may affect distribution of
intrathecal chemotherapy, resulting in decreased efficacy or increased
toxicity. Radiation therapy may correct CSF flow abnormalities before
use of intrathecal chemotherapy. Neoplastic meningitis can also lead to
intracranial hypertension and hydrocephalus. Placement of a ventricu­
loperitoneal shunt may effectively palliate symptoms in these patients.
The development of neoplastic meningitis usually occurs in the set­
ting of uncontrolled cancer outside the CNS; thus, prognosis is poor
(median survival 10–12 weeks). However, treatment of the neoplastic
meningitis may successfully alleviate symptoms and control the CNS
spread.
TREATMENT
Neoplastic Meningitis
Chemotherapy provided by either intrathecal injection or systemic
routes is used to control leptomeningeal disease throughout the
entire neuroaxis. Intrathecal chemotherapy, usually methotrexate,
cytarabine, or thiotepa, is delivered by lumbar puncture or by an
intraventricular reservoir (Ommaya). Among solid tumors, breast
cancer responds best to therapy. Focal radiotherapy may have a
role in bulky disease and in symptomatic or obstructive lesions.
Targeted therapy such as systemically administered EGFR tyrosine
kinase inhibitors (TKIs) in non-small-cell lung cancer may lead to
improvement in some patients with leptomeningeal spread. Patients
with neoplastic meningitis from either acute leukemia or lym­
phoma may be cured of their CNS disease if the systemic disease
can be eliminated.
■
■SEIZURES
Seizures occurring in a patient with cancer can be caused by the
tumor itself, by metabolic disturbances, by radiation injury, by cerebral
infarctions, by chemotherapy-related encephalopathies, or by CNS
infections. Metastatic disease to the CNS is the most common cause
of seizures in patients with cancer. However, seizures occur more
frequently in primary brain tumors than in metastatic brain lesions.
Seizures are a presenting symptom of CNS metastasis in 6–29% of
cases. Approximately 10% of patients with CNS metastasis eventually
develop seizures. Tumors that affect the frontal, temporal, and parietal
lobes are more commonly associated with seizures than are occipital
lesions. Both early and late seizures are uncommon in patients with
posterior fossa and sellar lesions. Seizures are common in patients with
CNS metastases from melanoma and low-grade primary brain tumors.
Very rarely, cytotoxic drugs such as etoposide, busulfan, ifosfamide,
and chlorambucil cause seizures. Treatment with bispecific antibodies
and chimeric antigen receptor (CAR) T cells may also cause CNS tox­
icity including seizures and encephalopathy. Another cause of seizures
related to drug therapy is reversible posterior leukoencephalopathy
syndrome (RPLS). Chemotherapy, targeted therapy, and immuno­
therapies have been associated with the development of RPLS. RPLS
occurs in patients undergoing allogeneic bone marrow or solid-organ
transplantation. RPLS is characterized by headache, altered conscious­
ness, generalized seizures, visual disturbances, hypertension, and sym­
metric posterior cerebral white matter vasogenic edema on CT/MRI.
Seizures may begin focally but are typically generalized.
TREATMENT
Seizures
Patients in whom seizures due to CNS metastases have been demon­
strated should receive anticonvulsive treatment with levetiracetam,
lacosamide, or lamotrigine. Prophylactic anticonvulsant therapy is
not recommended. In postcraniotomy patients, prophylactic anti­
epileptic drugs should be withdrawn during the first 2 weeks after
surgery. Most antiseizure medications including phenytoin induce
cytochrome P450 (CYP450), which alters the metabolism of many
antitumor agents, including irinotecan, taxanes, and etoposide,
as well as molecular targeted agents, including imatinib, gefitinib,
erlotinib, tipifarnib, sorafenib, sunitinib, temsirolimus, everolimus,
and vemurafenib. Levetiracetam, lacosamide, and lamotrigine are
anticonvulsant agents not metabolized by the hepatic CYP450
system and do not alter the metabolism of antitumor agents. Leve­
tiracetam has become the preferred drug. Surgical resection and
other antitumor treatments such as radiotherapy and chemotherapy
may improve seizure control.
■
■PULMONARY AND INTRACEREBRAL
LEUKOSTASIS
Hyperleukocytosis and the leukostasis syndrome associated with it
are potentially fatal complications of acute leukemia (particularly
myeloid leukemia) that can occur when the peripheral blast cell count
is >100,000/mL. The frequency of hyperleukocytosis is 5–13% in acute
myeloid leukemia (AML) and 10–30% in acute lymphoid leukemia;
however, leukostasis is rare in lymphoid leukemia. In AML, hyperleu­
kocytosis is more commonly seen in myelomonocytic AML (Fab-M4
and M5), those with 11q13 abnormalities involving the MLL gene,
and those with FLT3 mutations. At such high blast cell counts, blood
viscosity is increased, blood flow is slowed by aggregates of tumor
cells, and the primitive myeloid leukemic cells are capable of invading
through the endothelium and causing hemorrhage. Brain and lung are
most commonly affected. Patients with brain leukostasis may experi­
ence stupor, headache, dizziness, tinnitus, visual disturbances, ataxia,
confusion, coma, or sudden death. On examination, papilledema,
retinal vein distension, retinal hemorrhages, and focal deficit may be
present. Pulmonary leukostasis may present as respiratory distress and
hypoxemia and progress to respiratory failure. Chest radiographs may
be normal but usually show interstitial or alveolar infiltrates. Hyperleu­
kocytosis rarely may cause acute leg ischemia, renal vein thrombosis,
myocardial ischemia, bowel infraction, and priapism. Arterial blood
gas results should be interpreted cautiously. Rapid consumption of
plasma oxygen by the markedly increased number of white blood cells
can cause spuriously low arterial oxygen tension. Pulse oximetry is the
most accurate way of assessing oxygenation in patients with hyperleu­
kocytosis. Hydroxyurea can rapidly reduce a high blast cell count while
the diagnostic workup is in progress. After the diagnosis is established,
the patient should start quickly with effective induction chemotherapy.
Leukapheresis should be used in patients with symptoms of hyper­
leukocytosis. Patients with hyperleukocytosis are also at risk for dis­
seminated intravascular coagulation and tumor lysis syndrome. The
clinician should monitor the patient for these complications and take
preventive and therapeutic actions during induction therapy. Intra­
vascular volume depletion and unnecessary blood transfusions may
increase blood viscosity and worsen the leukostasis syndrome. Leu­
kostasis is very rarely a feature of the high white cell counts associated
with chronic lymphoid or chronic myeloid leukemia.
CHAPTER 80
Oncologic Emergencies
When acute promyelocytic leukemia is treated with differentiating
agents like tretinoin and arsenic trioxide, cerebral or pulmonary leu­
kostasis may occur as tumor cells differentiate into mature neutrophils.
This complication can be largely avoided by using cytotoxic chemo­
therapy together with the differentiating agents.
■
■HEMOPTYSIS
Hemoptysis may be caused by nonmalignant conditions, but lung can­
cer accounts for a large proportion of cases. Up to 20% of patients with
lung cancer have hemoptysis some time in their course. Endobronchial
metastases from carcinoid tumors, breast cancer, colon cancer, kidney
cancer, and melanoma may also cause hemoptysis. The volume of
bleeding is often difficult to gauge. Massive hemoptysis is defined as
200–600 mL of blood produced in 24 h. However, any hemoptysis
should be considered massive if it threatens life. When respiratory
difficulty occurs, hemoptysis should be treated emergently. The first
priorities are to maintain the airway, optimize oxygenation, and stabi­
lize the hemodynamic status. If the bleeding side is known, the patient
should be placed in a lateral decubitus position, with the bleeding side
down to prevent aspiration into the unaffected lung and given supple­
mental oxygen. If large-volume bleeding continues or the airway is
compromised, the patient should be intubated and undergo emergency
bronchoscopy. If the site of bleeding is detected, either the patient
undergoes a definitive surgical procedure or the lesion is treated with a
neodymium:yttrium-aluminum-garnet (Nd:YAG) laser, argon plasma
coagulation, or electrocautery. In stable patients, multidetector CT
angiography delineates bronchial and nonbronchial systemic arter­
ies and identifies the source of bleeding and underlying pathology
with high sensitivity. Massive hemoptysis usually originates from the
high-pressure bronchial circulation. Bronchial artery embolization is
considered a first-line definitive procedure for managing hemoptysis.
Bronchial artery embolization may control brisk bleeding in 75–90% of
patients, permitting the definitive surgical procedure to be done more
safely if it is appropriate.
Embolization without definitive surgery is associated with rebleed­
ing in 20–50% of patients. Recurrent hemoptysis usually responds to a
second embolization procedure. A postembolization syndrome charac­
terized by pleuritic pain, fever, dysphagia, and leukocytosis may occur;
it lasts 5–7 days and resolves with symptomatic treatment. Bronchial or
esophageal wall necrosis, myocardial infarction, and spinal cord infarc­
tion are rare complications. Surgery, as a salvage strategy, is indicated
after failure of embolization and is associated with better survival when
performed in a nonurgent setting.
Pulmonary hemorrhage with or without hemoptysis in hematologic
malignancies is often associated with fungal infections, particularly
Aspergillus spp. After granulocytopenia resolves, the lung infiltrates
in aspergillosis may cavitate and cause massive hemoptysis. Throm­
bocytopenia and coagulation defects should be corrected, if possible.
Surgical evaluation is recommended in patients with aspergillosisrelated cavitary lesions. Antibodies to vascular endothelial growth
factor (VEGF) including bevacizumab and ramucirumab that inhibit
angiogenesis, have been associated with life-threatening hemoptysis in
patients with non-small-cell lung cancer, particularly of squamous cell
histology. Non-small-cell lung cancer patients with cavitary lesions or
previous hemoptysis (≥2.5 mL) within the past 3 months have higher
risk for pulmonary hemorrhage.
PART 4
Oncology and Hematology
■
■AIRWAY OBSTRUCTION
Airway obstruction refers to a blockage at the level of the mainstem
bronchi or above. It may result either from intraluminal tumor growth
or from extrinsic compression of the airway. The most common cause
of malignant upper airway obstruction is invasion from an adjacent
primary tumor, most commonly lung cancer, followed by esophageal,
thyroid, and mediastinal malignancies including lymphomas. Extra­
thoracic primary tumors such as renal, colon, or breast cancer can
cause airway obstruction through endobronchial and/or mediastinal
lymph node metastases. Patients may present with dyspnea, hemoptysis,
stridor, wheezing, intractable cough, postobstructive pneumonia, or
hoarseness. Chest radiographs usually demonstrate obstructing lesions.
CT scans reveal the extent of tumor. Cool, humidified oxygen, glucocor­
ticoids, and ventilation with a mixture of helium and oxygen (Heliox)
may provide temporary relief. If the obstruction is proximal to the
larynx, a tracheostomy may be lifesaving. For more distal obstructions,
particularly intrinsic lesions incompletely obstructing the airway, bron­
choscopy with mechanical debulking and dilation or ablational treat­
ments including laser treatment, photodynamic therapy, argon plasma
coagulation, electrocautery, or stenting can produce immediate relief in
most patients (Fig. 80-3). However, radiation therapy (either externalbeam irradiation or brachytherapy) given together with glucocorticoids
may also open the airway. Symptomatic extrinsic compression may
be palliated by stenting. Patients with primary airway tumors such as
squamous cell carcinoma, carcinoid tumor, adenocystic carcinoma, or
non-small-cell lung cancer, if resectable, should have surgery.
METABOLIC EMERGENCIES
■
■HYPERCALCEMIA
Hypercalcemia is the most common paraneoplastic syndrome. Its
pathogenesis and management are discussed fully in Chaps. 98 and 422.
■
■SYNDROME OF INAPPROPRIATE SECRETION OF
ANTIDIURETIC HORMONE
Hyponatremia is a common electrolyte abnormality in cancer patients,
and syndrome of inappropriate secretion of antidiuretic hormone
A
B
FIGURE 80-3  Airway obstruction. A. Computed tomography scan of a 62-year-old
man with tracheal obstruction caused by renal carcinoma showing paratracheal
mass with tracheal invasion/obstruction (arrow). B. Chest x-ray of same patient
after stent (arrows) placement.
(SIADH) is the most common cause among patients with cancer.
SIADH is discussed fully in Chaps. 98 and 393.
■
■LACTIC ACIDOSIS
Lactic acidosis is a rare and potentially fatal metabolic complication of
cancer. Lactic acidosis associated with sepsis and circulatory failure is
a common preterminal event in many malignancies. Lactic acidosis in
the absence of hypoxemia may occur in patients with leukemia, lym­
phoma, or solid tumors. In some cases, hypoglycemia also is present.
Extensive involvement of the liver by tumor is often present. In most
cases, decreased metabolism and increased production by the tumor
both contribute to lactate accumulation. Tumor cell overexpression of
certain glycolytic enzymes and mitochondrial dysfunction can con­
tribute to its increased lactate production. HIV-infected patients have
an increased risk of aggressive lymphoma; lactic acidosis that occurs in
such patients may be related either to the rapid growth of the tumor or
from toxicity of nucleoside reverse transcriptase inhibitors. Symptoms
of lactic acidosis include tachypnea, tachycardia, change of mental
status, and hepatomegaly. The serum level of lactic acid may reach
10–20 mmol/L (90–180 mg/dL). Treatment is aimed at the underlying
disease. Sodium bicarbonate should be added if acidosis is very severe
or if hydrogen ion production is very rapid and uncontrolled. Other
treatment options include renal replacement therapy, such as hemodi­
alysis, and thiamine replacement. The prognosis is poor regardless of
the treatment offered.
■
■HYPOGLYCEMIA
Persistent hypoglycemia is occasionally associated with tumors other
than pancreatic islet cell tumors. Usually these tumors are large;
tumors of mesenchymal origin, hepatomas, or adrenocortical tumors
may cause hypoglycemia. Mesenchymal tumors are usually located in
the retroperitoneum or thorax. Obtundation, confusion, and behav­
ioral aberrations occur in the postabsorptive period and may precede
the diagnosis of the tumor. These tumors often secrete incompletely
processed insulin-like growth factor II (IGF-II), a hormone capable
of activating insulin receptors and causing hypoglycemia. Tumors
secreting incompletely processed big IGF-II are characterized by an
increased IGF-II to IGF-I ratio, suppressed insulin and C-peptide
level, and inappropriately low growth hormone and β-hydroxybutyrate
concentrations. Rarely, hypoglycemia is due to insulin secretion by
a non–islet cell carcinoma. The development of hepatic dysfunction
from liver metastases and increased glucose consumption by the tumor
can contribute to hypoglycemia. If the tumor cannot be resected, hypo­
glycemia symptoms may be relieved by the administration of glucose,
glucocorticoids, recombinant growth hormone, or glucagon.
Hypoglycemia can be artifactual; hyperleukocytosis from leukemia,
myeloproliferative diseases, leukemoid reactions, or colony-stimulating
factor treatment can increase glucose consumption in the test tube after
blood is drawn, leading to pseudohypoglycemia.
■
■ADRENAL INSUFFICIENCY
In patients with cancer, adrenal insufficiency may go unrecognized
because the symptoms, such as nausea, vomiting, anorexia, and ortho­
static hypotension, are nonspecific and may be mistakenly attributed
to progressive cancer or to therapy. Primary adrenal insufficiency
may develop owing to replacement of both glands by metastases
(lung, breast, colon, or kidney cancer; lymphoma), to removal of both
glands, or to hemorrhagic necrosis in association with sepsis or anti­
coagulation. Impaired adrenal steroid synthesis occurs in patients
being treated for cancer with mitotane, ketoconazole, or aminoglu­
tethimide or undergoing rapid reduction in glucocorticoid therapy.
Megestrol acetate, used to manage cancer and HIV-related cachexia,
may suppress plasma levels of cortisol and adrenocorticotropic hor­
mone (ACTH). Patients taking megestrol may develop adrenal insuf­
ficiency, and even those whose adrenal dysfunction is not symptomatic
may have inadequate adrenal reserve if they become seriously ill.
Paradoxically, some patients may develop Cushing’s syndrome and/or
hyperglycemia because of the glucocorticoid-like activity of megestrol
acetate. Ipilimumab, an anti-CTLA-4 antibody used for treatment of
malignant melanoma and other cancers, may cause autoimmunity
including autoimmune-like enterocolitis, hypophysitis (leading to sec­
ondary adrenal insufficiency), hepatitis, and, rarely, primary adrenal
insufficiency. Autoimmune hypophysitis may present with headache,
visual field defects, and pituitary hormone deficiencies manifesting
as hypopituitarism, adrenal insufficiency (including adrenal crisis), or
hypothyroidism. Ipilimumab-associated hypophysitis symptoms occur
at an average of 6–12 weeks after initiation of therapy. An MRI usually
shows homogenous enhancement of pituitary gland. Early glucocor­
ticoid treatment and hormone replacement are the initial treatment.
The role of high-dose glucocorticoids in the treatment of hypophysitis
is not clear. High-dose glucocorticoids may not improve the frequency
of pituitary function recovery. Autoimmune adrenalitis can also be
observed with anti-CTLA-4 antibody. Pituitary dysfunction is usually
permanent, requiring long-term hormone replacement therapy. Other
checkpoint inhibitors, such as monoclonal antibodies targeting pro­
grammed cell death 1 (PD-1), an inhibitory receptor expressed by T
cells or one of its ligands (PD-L1), may cause hypophysitis infrequently
(~1%). Autoimmune adrenalitis is more frequent with use of PD-1/
PD-L1 than with CTLA-4 inhibitors, but incidence is low. Cranial
irradiation for childhood brain tumors may affect the hypothalamuspituitary-adrenal axis, resulting in secondary adrenal insufficiency.
Rarely, metastatic replacement causes primary adrenal insufficiency as
the first manifestation of an occult malignancy. Metastasis to the pitu­
itary or hypothalamus is found at autopsy in up to 5% of patients with
cancer, but associated secondary adrenal insufficiency is rare.
Acute adrenal insufficiency is potentially lethal. Treatment of sus­
pected adrenal crisis is initiated after the sampling of serum cortisol
and ACTH levels (Chap. 398).
TREATMENT-RELATED EMERGENCIES
■
■TUMOR LYSIS SYNDROME
Tumor lysis syndrome (TLS) is characterized by hyperuricemia, hyper­
kalemia, hyperphosphatemia, and hypocalcemia and is caused by the
destruction of a large number of rapidly proliferating neoplastic cells.
Acidosis may also develop. Acute renal failure occurs frequently.
TLS is most often associated with the treatment of Burkitt’s lym­
phoma, acute lymphoblastic leukemia, AML, and other rapidly pro­
liferating lymphomas, but it also may be seen with chronic leukemias
and, rarely, with solid tumors. This syndrome is increased in frequency
in lymphoid neoplasms treated with venetoclax, a bcl-2 antagonist. TLS
has been observed with administration of glucocorticoids, hormonal
agents such as letrozole and tamoxifen, and monoclonal antibodies
such as rituximab, obinutuzumab, ofatumumab, and gemtuzumab. TLS
usually occurs during or shortly (1–5 days) after chemotherapy. Rarely,
spontaneous necrosis of malignancies causes TLS.
Hyperuricemia may be present at the time of chemotherapy. Effec­
tive treatment kills malignant cells and leads to increased serum uric
acid levels from the turnover of nucleic acids. Owing to the acidic local
environment, uric acid can precipitate in the tubules, medulla, and col­
lecting ducts of the kidney, leading to renal failure. Lactic acidosis and
dehydration may contribute to the precipitation of uric acid in the renal
tubules. The finding of uric acid crystals in the urine is strong evidence
for uric acid nephropathy. The ratio of urinary uric acid to urinary cre­
atinine is >1 in patients with acute hyperuricemic nephropathy and <1
in patients with renal failure due to other causes. Other events may lead
to renal failure in TLS. Calcium phosphate also precipitates in the inter­
stitium and renal microvasculature, leading to nephrocalcinosis. Both
types of crystals are toxic to the tubular epithelium, inducing local active
inflammatory and pro-oxidative responses. Soluble uric acid may induce
hemodynamic changes, with decreased renal blood flow due to vasocon­
striction and impaired autoregulation (crystal-independent pathway).
CHAPTER 80
Oncologic Emergencies
Hyperphosphatemia, which can be caused by the release of intracel­
lular phosphate pools by tumor lysis, produces a reciprocal depression
in serum calcium, which causes severe neuromuscular irritability and
tetany. Deposition of calcium phosphate in the kidney and hyperphos­
phatemia may cause renal failure. Potassium is the principal intracellular
cation, and massive destruction of malignant cells may lead to hyperka­
lemia. Hyperkalemia in patients with renal failure may rapidly become
life threatening by causing ventricular arrhythmias and sudden death.
The likelihood that TLS will occur in patients with Burkitt’s lym­
phoma is related to the tumor burden and renal function. Hyperurice­
mia and high serum levels of lactate dehydrogenase (LDH >1500 U/L),
both of which correlate with total tumor burden, also correlate with the
risk of TLS. In patients at risk for TLS, pretreatment evaluations should
include a complete blood count, serum chemistry evaluation, and
urinalysis. High leukocyte and platelet counts may artificially elevate
potassium levels (“pseudohyperkalemia”) due to lysis of these cells
after the blood is drawn. In these cases, plasma potassium instead of
serum potassium should be followed. In pseudohyperkalemia, no elec­
trocardiographic abnormalities are present. In patients with abnormal
baseline renal function, the kidneys and retroperitoneal area should be
evaluated by sonography and/or CT to rule out obstructive uropathy.
Urine output should be watched closely.
TREATMENT
Tumor Lysis Syndrome
Recognition of risk and prevention are the most important steps in
the management of this syndrome (Fig. 80-4). The standard pre­
ventive approach consists of allopurinol and aggressive hydration.
Urinary alkalization with sodium bicarbonate is no longer recom­
mended. It increases uric acid solubility, but a high pH decreases
the solubility of xanthine, hypoxanthine, and calcium phosphate,
potentially increasing the likelihood of intratubular crystallization.
Intravenous allopurinol may be given in patients who cannot toler­
ate oral therapy. Febuxostat, a potent nonpurine selective xanthine
Maintain hydration by administration of normal or 1/2 normal saline at 3000 mL/m2 per day
Administer allopurinol at 300 mg/m2 per day*
Monitor serum chemistry**
If, after 24–48 h
Serum uric acid >8.0 mg/dL
Serum creatinine >1.6 mg/dL
Correct treatable renal failure
(obstruction)
Start recombinant urate
oxidase, 0.2 mg/kg IV daily
No improvement
Delay chemotherapy or start
dialysis
PART 4
Oncology and Hematology
Serum K+ >6.0 meq/L
Serum uric acid >10 mg/dL
Serum creatinine >10 mg/dL
Serum phosphate >10 mg/dL or increasing
Symptomatic hypocalcemia present
Begin hemodialysis
*Use febuxostat in allopurinol allergy and/or renal failure.
**Specifically serum electrolytes, creatinine, calcium, phosphate, and uric acid.
FIGURE 80-4  Management of patients at high risk for the tumor lysis syndrome.  
oxidase inhibitor, is indicated for treatment of hyperuricemia. It
results in fewer hypersensitivity reactions than allopurinol. Febuxo­
stat does not require dosage adjustment in patients with mild
to moderate renal impairment. Febuxostat achieved significantly
superior serum uric acid control in comparison to allopurinol in
patients with hematologic malignancies at intermediate to high TLS
risk. In some cases, uric acid levels cannot be lowered sufficiently
with the standard preventive approach. Rasburicase (recombinant
urate oxidase) can be effective in these instances, particularly
when renal failure is present. Urate oxidase is missing from pri­
mates and catalyzes the conversion of poorly soluble uric acid to
readily soluble allantoin. Rasburicase acts rapidly, decreasing uric
acid levels within hours; however, it may cause hypersensitivity
reactions such as bronchospasm, hypoxemia, and hypotension.
Rasburicase should also be administered to high-risk patients for
TLS prophylaxis. Rasburicase is contraindicated in patients with
glucose-6-phosphate dehydrogenase deficiency who are unable to
break down hydrogen peroxide, an end product of the urate oxidase
reaction. Rasburicase is known to cause ex vivo enzymatic degra­
dation of uric acid in test tube at room temperature. This leads to
spuriously low uric acid levels during laboratory monitoring of the
patient with TLS. Samples must be cooled immediately to deacti­
vate the urate oxidase. Despite aggressive prophylaxis, TLS and/
or oliguric or anuric renal failure may occur. Renal replacement
therapy is often necessary and should be considered early in the
course. Hemodialysis is preferred. Hemofiltration offers a gradual,
continuous method of removing cellular by-products and fluid.
Serum uric acid <8.0 mg/dL
Serum creatinine <1.6 mg/dL
Start chemotherapy
a monitor serum chemistry
every 6–12 h
If
■
■HUMAN ANTIBODY INFUSION REACTIONS
The initial infusion of human or humanized antibodies (e.g., rituximab,
gemtuzumab, trastuzumab, alemtuzumab, panitumumab, brentuximab
vedotin, blinatumomab) is associated with fever, chills, nausea, asthe­
nia, and headache in up to half of treated patients. Bronchospasm and
hypotension occur in 1% of patients. Severe manifestations including
pulmonary infiltrates, acute respiratory distress syndrome (ARDS),
and cardiogenic shock occur rarely. Laboratory manifestations include
elevated hepatic aminotransferase levels, thrombocytopenia, and pro­
longation of prothrombin time. The pathogenesis is thought to be
activation of immune effector processes (cells and complement) and
release of inflammatory cytokines, such as tumor necrosis factor α,
interferon γ, interleukin (IL) 6, and IL-10 (cytokine release syndrome
[CRS]). Although its origins are not completely understood, CRS is
believed to be due to activation of a variety of cell types including
neutrophils, monocytes/macrophages, natural killer cells, and T and
B lymphocytes. Hemophagocytic lymphohistiocytosis (HLH)/mac­
rophage activation syndrome (MAS) can develop as part of CRS and
usually is a manifestation of severe CRS.
Severe CRS may require intensive support for ARDS and resistant
hypotension. Emerging clinical experience at several institutions has
concluded that tocilizumab is an effective treatment for severe or
life-threatening CRS. Tocilizumab prevents IL-6 binding to both cellassociated and soluble IL-6 receptors and therefore inhibits both clas­
sical and trans-IL-6 signaling. Other cytokine-directed therapies, such
as siltuximab, a chimeric anti-IL-6 monoclonal antibody, and anakinra,
an IL-1 receptor antagonist, have been used.
Adoptive transfer of CAR-engineered T cells is a promising therapy
for cancers. The most common acute toxicity of CAR T cells is CRS.
CAR T cell–associated CRS may be associated with cardiac dysfunc­
tion and neurotoxicity. In all cases, MAS could happen with CRS. The
management includes supportive care and tocilizumab.
■
■HEMOLYTIC-UREMIC SYNDROME
Malignancy can induce hemolytic-uremic syndrome (HUS) through
a wide variety of mechanisms, including systemic microvascular
metastases, extensive bone marrow invasion, or secondary necrosis.
HUS syndromes have been reported with metastatic gastric and ovar­
ian cancers, leukemias, and lymphomas. HUS and, less commonly,
thrombotic thrombocytopenic purpura (TTP) (Chap. 329) may rarely
occur after treatment with antineoplastic drugs, including mitomycin,
gemcitabine, cisplatin, bleomycin, and proteasome inhibitors, and with
VEGF inhibitors. Mitomycin and gemcitabine are the most common
offenders. Unlike mitomycin, there is no clear-cut relationship between
the cumulative dose of gemcitabine and risk of HUS. It occurs most
often in patients with gastric, lung, colorectal, pancreatic, and breast
carcinoma. In one series, 35% of patients were without evident cancer
at the time this syndrome appeared. Secondary HUS/TTP has also
been reported as a rare but sometimes fatal complication of bone mar­
row transplantation.
HUS usually has its onset 4–8 weeks after the last dose of chemo­
therapy, but it is not rare to detect it several months later. HUS is
characterized by microangiopathic hemolytic anemia, thrombocy­
topenia, and renal failure. Dyspnea, weakness, fatigue, oliguria, and
purpura are also common initial symptoms and findings. Systemic
hypertension and pulmonary edema frequently occur. Severe hyper­
tension, pulmonary edema, and rapid worsening of hemolysis and
renal function may occur after a blood or blood product transfusion.
Cardiac findings include atrial arrhythmias, pericardial friction rub,
and pericardial effusion. Raynaud’s phenomenon is part of the syn­
drome in patients treated with bleomycin.
Laboratory findings include severe to moderate anemia associ­
ated with red blood cell fragmentation and numerous schistocytes on
peripheral smear. Reticulocytosis, decreased plasma haptoglobin, and
an LDH level document hemolysis. The serum bilirubin level is usually
normal or slightly elevated. The Coombs test is negative. The white
cell count is usually normal, and thrombocytopenia (<100,000/μL) is
almost always present. Most patients have a normal coagulation profile,
although some have mild elevations in thrombin time and in levels of
fibrin degradation products. The serum creatinine level is elevated at
presentation and shows a pattern of subacute worsening within weeks
of the initial azotemia. The urinalysis reveals hematuria, proteinuria,
and granular or hyaline casts, and circulating immune complexes may
be present.
The basic pathologic lesion appears to be deposition of fibrin in
the walls of capillaries and arterioles, and these deposits are similar to
those seen in HUS due to other causes. These microvascular abnor­
malities involve mainly the kidneys and rarely occur in other organs.
The pathogenesis of cancer treatment–related HUS is not completely
understood, but probably the most important factor is endothelial
damage. Primary forms of HUS/TTP are related to a decrease in pro­
cessing of von Willebrand factor by a protease called ADAMTS13.
The case-fatality rate is high; most patients die within a few months.
Optimal treatment for chemotherapy-induced HUS is debated. Immu­
nocomplex removal through plasmapheresis, plasma exchange, immu­
noadsorption, or exchange transfusion, antiplatelet and anticoagulant
therapies, and immunosuppression have all been employed with vary­
ing degrees of success.
The outcome with plasma exchange is generally poor, as in many
other cases of secondary TTP. Rituximab is successfully used in
patients with chemotherapy-induced HUS as well as in ADAMTS13deficient TTP. Eculizumab, a complement inhibitor, is now considered
first-line treatment of atypical HUS. Ravulizumab, a humanized
monoclonal antibody that blocks terminal complement activation at
C5 and is engineered from eculizumab, has an extended half-life and
is approved by the U.S. Food and Drug Administration (FDA) for
atypical HUS. Vaccination against Neisseria meningitis is mandatory
before eculizumab and ravulizumab are administered.
■
■NEUTROPENIA AND INFECTION
These remain the most common serious complications of cancer
therapy. They are covered in detail in Chap. 79.
■
■PULMONARY INFILTRATES
Patients with cancer may present with dyspnea associated with diffuse
interstitial infiltrates on chest radiographs. Such infiltrates may be
due to progression of the underlying malignancy, treatment-related
toxicities, infection, and/or unrelated diseases. The cause may be mul­
tifactorial; however, most commonly, they occur as a consequence of
treatment. Infiltration of the lung by malignancy has been described in
patients with leukemia, lymphoma, and breast and other solid cancers.
Pulmonary lymphatics may be involved diffusely by neoplasm (pul­
monary lymphangitic carcinomatosis), resulting in a diffuse increase
in interstitial markings on chest radiographs. The patient is often
mildly dyspneic at the onset, but pulmonary failure develops over a
period of weeks. In some patients, dyspnea precedes changes on the
chest radiographs and is accompanied by a nonproductive cough. This
syndrome is characteristic of solid tumors. In patients with leukemia,
diffuse microscopic neoplastic peribronchial and peribronchiolar infil­
tration is frequent but may be asymptomatic. However, some patients
present with diffuse interstitial infiltrates, an alveolar capillary block
syndrome, and respiratory distress. Thickening of bronchovascular
bundles and prominence of peripheral arteries are CT findings sug­
gestive of leukemic infiltration. In these situations, glucocorticoids can
provide symptomatic relief, but specific chemotherapy should always
be started promptly.
CHAPTER 80
Oncologic Emergencies
Several cytotoxic agents, such as bleomycin, methotrexate, busulfan,
nitrosoureas, gemcitabine, mitomycin, vinorelbine, docetaxel, pacli­
taxel, fludarabine, pentostatin, and ifosfamide, may cause pulmonary
damage. The most frequent presentations are interstitial pneumonitis,
alveolitis, and pulmonary fibrosis. Some cytotoxic agents, including
methotrexate and procarbazine, may cause an acute hypersensitivity
reaction. Cytosine arabinoside has been associated with noncardio­
genic pulmonary edema. Administration of multiple cytotoxic drugs,
as well as radiotherapy and preexisting lung disease, may potentiate the
pulmonary toxicity. Supplemental oxygen may potentiate the effects of
drugs and radiation injury. Patients should always be managed with the
lowest Fio2 that is sufficient to maintain hemoglobin saturation.
The onset of symptoms may be insidious, with symptoms including
dyspnea, nonproductive cough, and tachycardia. Patients may have
bibasilar crepitant rales, end-inspiratory crackles, fever, and cyanosis.
The chest radiograph generally shows an interstitial and sometimes an
intraalveolar pattern that is strongest at the lung bases and may be sym­
metric. A small effusion may occur. Hypoxemia with decreased carbon
monoxide diffusing capacity is always present. Glucocorticoids may be
helpful in patients in whom pulmonary toxicity is related to radiation
therapy or to chemotherapy. Treatment is otherwise supportive.
Molecular targeted agents, imatinib, erlotinib, and gefitinib are
potent inhibitors of tyrosine kinases. These drugs may cause interstitial
lung disease (ILD). In the case of gefitinib, preexisting fibrosis, poor
performance status, and prior thoracic irradiation are independent
risk factors; this complication has a high fatality rate. In Japan, inci­
dence of ILD associated with gefitinib was ~4.5% compared to 0.5%
in the United States. Osimertinib may cause transient pulmonary
opacities (TPOs). TPOs are characterized asymptomatic and localized
ground-glass opacities (GGO) with or without nodular consolidation
on CT. TPOs typically resolve during continued osimertinib therapy.
Temsirolimus and everolimus, both esters of rapamycin (sirolimus),
are agents that block the effects of mammalian target of rapamycin
(mTOR), an enzyme that has an important role in regulating the
synthesis of proteins that control cell division. These agents may
cause GGO in the lung with or without diffuse interstitial disease and
lung parenchymal consolidation. Patients may be asymptomatic with
only radiologic findings or may be symptomatic. Symptoms include
cough, dyspnea, and/or hypoxemia, and sometimes patients present
with systemic symptoms such as fever and fatigue. The incidence of
everolimus-induced ILD also appears to be higher in Japanese patients.
HER2-targeting ADC trastuzumab-deruxtecan carries a known risk
of ILD with fatality. Treatment includes dose reduction or withdrawal
and, in some cases, the addition of glucocorticoids.
The FDA-approved immune checkpoint inhibitors (ICIs) of the
PD-1 and PD-L1 pathway, including nivolumab, pembrolizumab, dur­
valumab, avelumab, atezolizumab, and cemiplimab, enhance antitumor
activity by blocking negative regulators of T-cell function. Immunemediated pneumonitis is rare (10%) but may be a life-threatening
complication of these drugs. Pneumonitis symptoms include cough,
shortness of breath, dyspnea, and fever, and often involve only asymp­
tomatic radiographic changes. Pneumonitis shows ground-glass patchy
lesions and/or disseminated nodular infiltrates, predominantly in the
lower lobes. Identifying the exact cause of a pneumonitis in a patient
treated with ICIs could be challenging during the current COVID-19
outbreak (Fig. 80-5A). Chest CT manifestations of COVID-19 include
an imaging pattern of pure GGO, consolidation, nodules, fibrous
stripes, and mixed patterns, with the distribution slightly predomi­
nant in the lower lobe and peripheral areas of the lung. Treatment of
immune-mediated pneumonitis includes temporary or permanent
withdrawal of drug and the addition of high-dose glucocorticoids
(Fig. 80-5B).
Radiation pneumonitis and/or fibrosis are relatively frequent side
effects of thoracic radiation therapy. It may be acute or chronic.
Radiation-induced lung toxicity is a function of the irradiated lung
volume, dose per fraction, and radiation dose. The larger the irradi­
ated lung field, the higher is the risk for radiation pneumonitis. The
use of concurrent chemoradiation, particularly regimens including
PART 4
Oncology and Hematology
A
FIGURE 80-5  A. Computed tomography scan of a 63-year-old female with metastatic adenocarcinoma on nivolumab with immune check point inhibitor pneumonia showing
interlobular septal thickening and diffuse ground-glass opacity to nivolumab. B. Computed tomography scan of a 68-year-old female with resected adenocarcinoma of
lung and COVID-19 pneumonia showing peripheral and basilar predominant patchy ground-glass and consolidative opacity consistent with multifocal COVID pneumonia.
paclitaxel, increases pulmonary toxicity. Radiation pneumonitis usu­
ally develops 2–6 months after completion of radiotherapy. The
clinical syndrome, which varies in severity, consists of dyspnea, cough
with scanty sputum, low-grade fever, and an initial hazy infiltrate on
chest radiographs. The infiltrate and tissue damage usually are con­
fined to the radiation field. The CT scan may show GGOs, consolida­
tion, fibrosis, atelectatic cicatrization, pleural volume loss, or pleural
thickening. The patients subsequently may develop a patchy alveolar
infiltrate and air bronchograms, which may progress to acute respira­
tory failure that is sometimes fatal. A lung biopsy may be necessary
to make the diagnosis. Asymptomatic infiltrates found incidentally
after radiation therapy need not be treated. However, prednisone
should be administered to patients with fever or other symptoms.
The dosage should be tapered slowly after the resolution of radiation
pneumonitis, because abrupt withdrawal of glucocorticoids may cause
an exacerbation of pneumonia. Delayed radiation fibrosis may occur
years after radiation therapy and is signaled by dyspnea on exertion.
Often it is mild, but it can progress to chronic respiratory failure.
Therapy is supportive.
Classic radiation pneumonitis that leads to pulmonary fibrosis is
due to radiation-induced production of local cytokines such as plateletderived growth factor β, tumor necrosis factor, interleukins, and trans­
forming growth factor β in the radiation field.
SBRT is a radiotherapy treatment method that has been applied to
the treatment of stage I lung cancers in medically inoperable patients.
SBRT accurately delivers a high dose of irradiation in one or few
treatment fractions to an image-defined lung mass. Most of the acute
changes after SBRT occur later than 3 months after treatment, and the
shape of the SBRT-induced injury conforms more tightly to the tumor.
B
Pneumonia is a common problem in patients undergoing treatment
for cancer (Chap 79). In patients with pulmonary infiltrates who are
afebrile, heart failure and multiple pulmonary emboli are in the dif­
ferential diagnosis.
■
■NEUTROPENIC ENTEROCOLITIS
Neutropenic enterocolitis (typhlitis) is the inflammation and necrosis of
the cecum and surrounding tissues that may complicate the treatment
of acute leukemia. Nevertheless, it may involve any segment of the gas­
trointestinal tract including small intestine, appendix, and colon. This
complication has also been seen in patients with other forms of cancer
treated with taxanes, 5-fluorouracil, irinotecan, vinorelbine, cisplatin,
carboplatin, sacituzumab govitecan, and high-dose chemotherapy
(Fig. 80-6). It also has been reported in patients with AIDS, aplastic
anemia, cyclic neutropenia, idiosyncratic drug reactions involving
antibiotics, and immunosuppressive therapies. The patient develops
right lower quadrant abdominal pain, often with rebound tenderness
and a tense, distended abdomen, in a setting of fever and neutropenia.
Watery diarrhea (often containing sloughed mucosa) and bacteremia
are common, and bleeding may occur. Plain abdominal films are
generally of little value in the diagnosis; CT scan may show marked
bowel wall thickening, particularly in the cecum, with bowel wall
edema, mesenteric stranding, and ascites, and may help to differentiate
A
B
FIGURE 80-6  Abdominal computed tomography (CT) scans of a 72-year-old woman
with neutropenic enterocolitis secondary to chemotherapy. A. Air in inferior
mesenteric vein (arrow) and bowel wall with pneumatosis intestinalis. B. CT scan
of upper abdomen demonstrating air in portal vein (arrows).
neutropenic colitis from other abdominal disorders such as appendi­
citis, diverticulitis, and Clostridium difficile–associated colitis in this
high-risk population. Patients with bowel wall thickness >10 mm on
ultrasonogram have higher mortality rates. However, bowel wall thick­
ening is significantly more prominent in patients with C. difficile colitis.
Pneumatosis intestinalis is a more specific finding, seen only in those
with neutropenic enterocolitis and ischemia. The combined involve­
ment of the small and large bowel suggests a diagnosis of neutropenic
enterocolitis. Rapid institution of broad-spectrum antibiotics, bowel
rest, and nasogastric suction may reverse the process. Use of myeloid
growth factors improved outcome significantly. Surgical intervention is
reserved for severe cases of neutropenic enterocolitis with evidence of
perforation, peritonitis, gangrenous bowel, or gastrointestinal hemor­
rhage despite correction of any coagulopathy.
C. difficile colitis is increasing in incidence. Newer strains of C. diffi­
cile produce ~20 times more of toxins A and B compared to previously
studied strains. C. difficile risk is also increased with chemotherapy.
Antibiotic coverage for C. difficile should be added if pseudomembra­
nous colitis cannot be excluded.
■
■HEMORRHAGIC CYSTITIS
Hemorrhagic cystitis is characterized by diffuse bladder mucosal
bleeding that develops secondary to chemotherapy (mostly cyclophos­
phamide or ifosfamide), radiation therapy, bone marrow transplanta­
tion (BMT), and/or opportunistic infections. Both cyclophosphamide
and ifosfamide are metabolized to acrolein, which is a strong chemical
irritant that is excreted in the urine. Prolonged contact or high con­
centrations may lead to bladder irritation and hemorrhage. Symptoms
include gross hematuria, frequency, dysuria, burning, urgency, inconti­
nence, and nocturia. The best management is prevention. Maintaining
a high rate of urine flow minimizes exposure. In addition, 2-mer­
captoethanesulfonate (mesna) detoxifies the metabolites and can be
coadministered with the instigating drugs. Mesna usually is given three
times on the day of ifosfamide administration in doses that are each
20% of the total ifosfamide dose. If hemorrhagic cystitis develops, the
maintenance of a high urine flow may be sufficient supportive care. If
conservative management is not effective, irrigation of the bladder with
alum or formalin solution may stop the bleeding in most cases. N-Acet­
ylcysteine may also be an effective irrigant. Prostaglandin (carboprost)
can inhibit the process. In extreme cases, ligation of the hypogastric
arteries, urinary diversion, or cystectomy may be necessary.
CHAPTER 80
Oncologic Emergencies
In the BMT setting, early-onset hemorrhagic cystitis is related to
drugs in the treatment regimen (e.g., cyclophosphamide), and lateonset hemorrhagic cystitis is usually due to the polyoma virus BKV or
adenovirus type 11. BKV load in urine alone or in combination with
acute graft-versus-host disease correlates with development of hemor­
rhagic cystitis. Viral causes are usually detected by polymerase chain
reaction (PCR)–based diagnostic tests. Treatment of viral hemorrhagic
cystitis is largely supportive, with reduction in doses of immunosup­
pressive agents, if possible. No antiviral therapy is approved, although
cidofovir was reported to be effective in a small series. Hyperbaric oxy­
gen therapy has been used successfully in patients with BKV-associated
and cyclophosphamide-induced hemorrhagic cystitis during hemato­
poietic stem cell transplantation, as well as in hemorrhagic radiation
cystitis that occurs in up to 5% of patients after pelvic radiation.
■
■HYPERSENSITIVITY REACTIONS TO
ANTINEOPLASTIC DRUGS
Many antineoplastic drugs may cause hypersensitivity reaction. These
reactions are unpredictable and potentially life threatening. Most reac­
tions occur during or within hours of parenteral drug administration.
Taxanes, platinum compounds, asparaginase, etoposide, procarbazine,
and biologic agents, including rituximab, bevacizumab, trastuzumab,
gemtuzumab, cetuximab, and alemtuzumab, are more commonly
associated with acute hypersensitivity reactions than are other agents.
Hypersensitivity reactions to some drugs, such as taxanes, occur dur­
ing the first or second dose administered. Hypersensitivity to platinum
compounds occurs after prolonged exposure. Skin testing may identify
patients with high risk for hypersensitivity after carboplatin exposure.

10 - 81 Cancer of the Skin
81 Cancer of the Skin
Premedication with histamine H1 and H2 receptor antagonists and
glucocorticoids reduces the incidence of hypersensitivity reaction to
taxanes, particularly paclitaxel. Despite premedication, hypersensitiv­
ity reactions may still occur. In these cases, rapid desensitization in the
intensive care unit setting or re-treatment may be attempted with care,
but the use of alternative agents may be required. Skin testing is used to
assess the involvement of IgE in the reaction. Tryptase levels measured
at the time of the reaction help to explain the mechanism of the reac­
tion and its severity. Increased tryptase levels indicate underlying mast
cell activation. Candidate patients for desensitization include those
who have mild to severe hypersensitivity type I, with mast cell–medi­
ated and IgE-dependent reactions occurring during a chemotherapy
infusion or shortly thereafter.
■
■FURTHER READING
Azizi AH et al: Superior vena cava syndrome. JACC Cardiovasc Interv
13:2896, 2020.
Castells M et al: Hypersensitivity to antineoplastic agents: Mechanisms
and treatment with rapid desensitization. Cancer Immunol Immunother
61:1575, 2012.
Castinetti F et al: Endocrine side-effects of new anticancer therapies:
Overall monitoring and conclusions. Ann Endocrinol (Paris) 79:591,
2018.
Conte P et al: Drug-induced interstitial lung disease during cancer
PART 4
Oncology and Hematology
therapies: Expert opinion on diagnosis and treatment. ESMO Open
7:1, 2022.
Durani U, Hogan WJ: Emergencies in haematology: Tumour lysis
syndrome. Br J Haematol 188:494, 2020.
Fajgenbaum DC, June CH: Cytokine storm. N Engl J Med 383:2255,
2020.
Gonzalez Castro LN, Milligan TA: Seizures in patients with can­
cer. Cancer 126:1379, 2020.
Lawton AJ et al: Assessment and management of patients with metastatic
spinal cord compression: A multidisciplinary review. J Clin Oncol
37:61, 2019.
Paik WH, Park DH: Endoscopic management of malignant biliary
obstruction. Gastrointest Endosc Clin N Am 34:127, 2024
Schusler R, Meyerson SL: Pericardial disease associated with
malignancy. Curr Cardiol Rep 20:92, 2018.
Thomas MR, Scully M: How I treat microangiopathic hemolytic
anemia in patients with cancer. Blood 137:1310, 2021.
Vogelbaum MA et al: Treatment for brain metastases: ASCO-SNOASTRO Guideline. J Clin Oncol 4:492, 2022.
Brendan D. Curti, John T. Vetto,
Sancy A. Leachman
Cancer of the Skin
MELANOMA
Pigmented lesions are among the most common findings on skin exam­
ination. The challenge for the physician is to distinguish benign lesions
from cutaneous melanomas and nonmelanoma skin cancers (NMSCs),
both of which are increasing in frequency. Melanoma accounts for over
half of the deaths resulting from skin cancer, although recent advances
in immunotherapy and targeted therapy used in the neoadjuvant, adju­
vant, and advanced disease settings have significantly improved sur­
vival. Genomic analysis of melanoma has improved our understanding
of prognosis, and informed treatment and surveillance strategies
beyond traditional surgical staging. Melanoma is an aggressive malig­
nancy of melanocytes, pigment-producing cells that originate from the
neural crest and migrate to the skin, meninges, mucous membranes,
upper esophagus, and eyes. Melanocytes in each of these locations
have the potential for malignant transformation, but most melanomas
arise in the skin, facilitating detection when complete surgical excision
can lead to cure. Cutaneous melanoma occurs in people of all ages and
all colors. Noncutaneous melanomas have a different biology and a
lower probability of response to the immunotherapy agents that have
transformed the care of cutaneous melanoma. Examples of malignant
melanoma of the skin, mucosa, eye, and nail are shown in Fig. 81-1.
■
■RISK FACTORS AND EPIDEMIOLOGY
The epidemiologic patterns seen in melanoma reflect the genetic and
biologic features of melanocytes and their response to environmental
ultraviolet radiation (UVR). Clinical features that confer an increased
risk for melanoma include: (1) vulnerability to sun damage (light/red
coloration of skin, hair, or eyes; photodamaged skin; history of expo­
sure to natural or artificial UVR; prior history of skin cancers of any
type); (2) abnormal growth of melanocytes (increased absolute number
of nevi, increased size of nevi, or atypical features of moles such as mul­
tiple colors, speckles, or shapes); and (3) immunosuppression (innate,
functional, or drug-induced). Table 81-1 summarizes melanoma risk
factors and the relative risk associated with these factors.
The incidence and mortality rates are strongly influenced by ethnic,
geographic, and environmental factors. For instance, the incidence of
melanoma is 1/100,000 per year in populations with high skin eumelanin
(a brown-black pigment that absorbs ultraviolet [UV] photons efficiently
as they enter the epidermis) and up to 27/100,000 per year in populations
with low skin eumelanin. Men are affected slightly more than women
(1.4:1), and the median age at diagnosis is 66. Melanoma is one several
cancer types with increasing incidence in the United States and is now
the fifth leading cancer in men (59,170 new cases in 2024; probability
1:28) and the sixth leading cancer in women (41,460 new cases in 2024;
probability 1:41). Although these rankings are based on the total number
of new invasive melanoma cases in 2024, estimated at 100,640, an addi­
tional 99,700 cases of melanoma in situ (MIS) occurred in 2024.
Mortality rates begin to rise at age 55, with the greatest mortality in
men age >65 years. In contrast to the increasing incidence, the mortal­
ity rates for melanoma are decreasing, though this trend appears less
dramatic outside of the United States. The most likely reason for the
decreased mortality is the influence of immunotherapy and targeted
therapy on melanoma-specific survival. After U.S. Food and Drug
Administration (FDA) approval of ipilimumab and vemurafenib in
2011, the 1-year relative survival rate increased from 42% (2008–2010)
to 55% (2013–2015). The mortality rate from 2013 to 2017 dropped
annually by 7% in those aged 20–64 years old and dropped 5–6% per
year for individuals aged ≥65 years.
■
■GLOBAL CONSIDERATIONS
The incidence of both nonmelanoma and melanoma skin cancers
around the world has been increasing. Every year, between 2 and
3 million people develop NMSC, and in 2020, there were 324,635 cases
of melanoma. A disproportionate number of cases and deaths occur
in North America, Europe, Australia, and New Zealand. The highly
variable melanoma incidence rates in different populations are due
to the interplay between risk factors, including host genetics and
environmental factors, which distribute risk unevenly across these
populations and account for the absolute risk in different ethnic
groups and geographic areas.
Dark-skinned populations (such as those of India and Puerto Rico),
blacks, and East Asians also develop melanoma but at rates 10–20 times
lower than those in whites. Cutaneous melanomas in dark-skinned
populations are more often diagnosed at a higher stage, and patients
tend to have worse outcomes. Surveillance, Epidemiology, and End
Results (SEER) data (2016–2020) reveal that whites have the highest
incidence of melanoma at 37.9 (men) and 25.2 (women) per 100,000
and that the incidence drops substantially in Hispanics (4.5 [men]
and 4.3 [women] per 100,000), Native Americans (8.7 [men] and 7.8
[women] per 100,000), Asians/Pacific Islanders (1.3 [men] and 1.1
[women] per 100,000), and blacks (1 [men] and 0.9 [women] per
100,000). In nonwhite (Asian and dark-skinned) populations, the
A
B
C
D
E
F
G
H
I
FIGURE 81-1  Types of melanoma. A. Hypomelanotic melanoma. B. Superficial spreading melanoma. C. Melanoma arising in a nevus. D. Seborrheic keratoses-like melanoma
arising on the scalp. E. Nodular melanoma. F. Cutaneous melanoma metastases at a surgical margin (also known as melanoma satellites when <2 cm from the primary
tumor and in-transit melanoma when >2 cm). G. Mucosal melanoma arising in the vulva. H. Ciliary body melanoma, note visible tumor in the pupil and areas of involvement
in the iris and sclera. I. Acral melanoma with Hutchinson’s sign on the proximal nail fold. (Parts A-G and I photos courtesy of Dr. Leonard Swinyer Collection, © Copyright
2020 University of Utah and Oregon Health & Science University. Part H photo courtesy of Dr. Alison Skalet, © Copyright 2022 Oregon Health & Science University [OHSU].)
frequency of non–sun-exposed melanomas, such as acral (subungual,
plantar, palmar) and mucosal melanomas, is much higher; the inci­
dence of melanoma in black and Hispanic populations is not associated
with UV exposure. In China, ~20,000 new melanomas are reported
each year, and in contrast to the United States, mortality is increasing.
Non–sun-exposed melanomas have a different biology, have a lower
probability of response to immunotherapy, and carry a poorer prog­
nosis than cutaneous melanomas, thus accounting for the increase in
mortality of this melanoma subgroup. Little is known about the effects
of mixed ethnicity on melanoma risk.
■
■GENETIC SUSCEPTIBILITY TO MELANOMA
Approximately 20–40% of hereditary melanomas (0.2–2% of all
melanomas) are due to germline mutations in the cell cycle regulatory
gene cyclin-dependent kinase inhibitor 2A (CDKN2A). In fact, 70%
of all cutaneous melanomas have mutations or deletions affecting the
CDKN2A locus on chromosome 9p21. This locus encodes two distinct
tumor-suppressor proteins from alternate reading frames: p16 and
ARF (p14ARF). The p16 protein inhibits CDK4/6-mediated phosphory­
lation and inactivation of the retinoblastoma (RB) protein, whereas
ARF inhibits MDM2 ubiquitin-mediated degradation of p53. The loss
of CDKN2A results in inactivation of two critical tumor-suppressor
CHAPTER 81
Cancer of the Skin
pathways, RB and p53, which control entry of cells into the cell cycle.
Several studies have shown an increased risk of pancreatic cancer
among melanoma-prone families with CDKN2A mutations. A second
high-risk locus for melanoma susceptibility, CDK4, is located on chro­
mosome 12q13 and encodes the cyclin-dependent kinase inhibited by
p16. CDK4 mutations, which also inactivate the RB pathway, are much
rarer than CDKN2A mutations. Germline mutations in the melanoma
lineage-specific oncogene microphthalmia-associated transcription
factor (MITF), BRCA1-associated protein 1 (BAP-1), protection of
telomeres 1 (POT-1), and telomerase reverse transcriptase (TERT) also
predispose to familial melanoma with a not yet quantified high pen­
etrance, based on families that have been tested.
The melanocortin-1 receptor (MC1R) gene is a moderate-risk
inherited melanoma susceptibility factor. UVR stimulates the produc­
tion of melanocortin (α-melanocyte-stimulating hormone [α-MSH]),
the ligand for MC1R, which is a G-protein-coupled receptor that
signals via cyclic AMP and regulates the amount and type of pigment
produced by melanocytes. MC1R is highly polymorphic, and many
among its ~80 variants result in partial or full loss of signaling and lead
to the production of non-photoprotective red/yellow pheomelanins,
rather than photoprotective brown/black eumelanins. The red hair
color (RHC) phenotype produced by MC1R mutations includes lightly
TABLE 81-1  Melanoma Risk Factors and Relative Risk
RISK LEVEL
RISK FACTOR
RELATIVE RISK
1 atypical nevus versus 0
1.5
Total common nevi, 16+ versus <15
1.5
Blue eye color versus dark
1.5
Hazel eye color versus dark
1.5
Green eye color versus dark
1.6
Light brown hair versus dark
1.6
Indoor tanning in any gender versus never
1.7
Elevated
Fitzpatrick skin type II versus IV
1.8
Fitzpatrick skin type III versus IV
1.8
History of sunburn versus no sunburn
2.0
Blond hair versus dark
2.0
2 atypical nevi versus 0
2.1
Fitzpatrick skin type I versus IV
2.1
High density of freckles versus none
2.1
Total common nevi 41–60 versus <15
2.2
Family history of melanoma in 1 or more
first-degree relatives
1.7–3.0
3 atypical nevi versus 0
3.0
Moderately elevated
PART 4
Oncology and Hematology
Total common nevi 61–80 versus <15
3.3
Red hair versus dark
3.6
Chronic lymphocytic leukemia
3.9
History of actinic keratoses and/or
keratinocyte carcinoma versus not
4.3
Indoor tanning in women aged 30–39
versus never
4.3
4 atypical nevi versus 0
4.4
Transplant recipient versus not
2.2–4.6
Indoor tanning in women aged <30 versus
never
6.0
5 atypical nevi versus 0
6.4
High
Total common nevi 81–120 versus <15
6.9
Personal history of melanoma
8.2–13.4
CDK2NA mutation carrier
14–28
colored skin, red hair, freckles, increased sun sensitivity, and increased
risk of melanoma. In addition to its weak UV-shielding capacity rela­
tive to eumelanin, increased pheomelanin production in patients with
inactivating polymorphisms of MC1R also provides a UV-independent
carcinogenic contribution to melanomagenesis via oxidative damage
and reduced DNA damage repair.
Other more common, low-penetrance polymorphisms in genes
related to pigmentation, nevus count, immune responses, DNA repair,
metabolism, and the vitamin D receptor have small effects on melanoma
susceptibility. In sum, ~50–60% of the genetic risk for hereditary mela­
noma can be attributed to known melanoma predisposition genes, with
~40% of the known genetic risk attributable to CDKN2A. The other com­
ponents of inherited risk are most likely due to the presence of additional
modifier genes and/or shared environmental exposures of the host.
■
■PREVENTION AND EARLY DETECTION
Primary prevention of melanoma and NMSC is based on protection
from the sun. Public health initiatives, such as the SunSmart program
that started in Australia and is now operative in Europe and the United
States, have demonstrated that behavioral change can decrease the
incidence of NMSC and melanoma. Preventive measures should start
early in life because damage from UV light begins early even though
cancers develop years later. Early episodes of sunburns may be a greater
risk than chronic tanning. Some individuals tan compulsively. There is
now greater understanding of tanning addiction and the cutaneousneural connections that may give rise to this behavior. Compulsive
tanners exhibit differences in dopamine binding and reactivity in
reward pathways in the brain, such as the basal striatum, resulting in
cutaneous secretion of β-endorphins after UV exposure. Identifying
individuals with tanning addiction may be another prevention method.
Regular use of broad-spectrum sunscreens that block UV-A and UV-B
with a sun protection factor (SPF) of at least 30 and protective clothing
should be encouraged. Physical blockers such as zinc oxide and tita­
nium dioxide have less likelihood of being absorbed or of generating
an allergic reaction than chemical sunscreens. Avoidance of sunburns,
tanning beds, and midday sun exposure is recommended.
Secondary prevention comprises education and screening with the
goal of early detection and can be individualized based on risk factors.
A full-body skin exam is warranted in populations at higher risk for
melanoma such as patients with clinically atypical moles (dysplastic
nevi) and those with a personal history of melanoma. Surveillance
in high-risk patients should be performed by a dermatologist and
include total-body photography and dermoscopy where appropriate.
Individuals with three or more primary melanomas and families with
at least one invasive melanoma and two or more cases of melanoma
and/or pancreatic cancer, ocular melanoma, mesothelioma, or renal
cell carcinoma among first- or second-degree relatives on the same
side of the family may benefit from genetic testing. Atypical nevi and
MIS should be completely removed with at least a 5-mm margin. Early
detection of small lesions allows the use of simpler treatment modali­
ties with higher cure rates and lower morbidity. Monthly self-screening
augments provider-based screening. Patients should be taught to
recognize the clinical features of melanoma and advised to report any
change in a pigmented lesion. There is evidence supporting the ability
of media campaigns to reduce cancer mortality in lung cancer, and
results from Australia’s skin cancer campaigns demonstrate improve­
ment in attitude and behavior and a reduction in melanoma incidence.
A benefit/cost analysis in Australia showed a return of $3.85 for every
$1 invested. Although the U.S. Preventive Services Task Force states
that there is insufficient evidence to recommend skin screening for
the general population, additional research is anticipated to find best
practices for skin cancer detection and prevention.
■
■DIAGNOSIS
Early detection of melanoma before it becomes invasive and lifethreatening metastases have occurred is essential and may be facili­
tated by applying the ABCDEs: asymmetry (benign lesions are usually
symmetric); border irregularity (most nevi have clear-cut borders);
color variegation (benign lesions usually have uniform light or dark
pigment); diameter >6 mm (the size of a pencil eraser); and evolving
(any change in size, shape, color, or elevation or new symptoms such
as bleeding, itching, and crusting). In addition, any nevus that appears
atypical and different from the rest of the nevi on that individual (an
“ugly duckling”) should be considered suspicious.
The entire skin surface, including the scalp and mucous membranes,
as well as the nails should be examined in each patient. Bright room
illumination is important, and a hand lens or dermatoscope is helpful
for evaluating variation in pigment pattern. Any suspicious lesions
should be biopsied, evaluated by a specialist, or recorded by chart and/
or photography for follow-up. Dermoscopy employs low-level magni­
fication of the epidermis with polarized light or water interface and
permits a more precise visualization of patterns of pigmentation than
is possible with the naked eye.
Biopsy 
Any pigmented cutaneous lesion that has changed on exami­
nation or has the other features previously discussed is a candidate for
biopsy. An excisional biopsy with 1- to 3-mm margins (narrow-margin
excision) is suggested. This facilitates histologic assessment of the
lesion, permits accurate measurement of thickness if the lesion is mela­
noma, and constitutes definitive treatment if the lesion is benign. For
lesions that are large or involving anatomic sites where excisional biopsy
may not be feasible (such as the face, hands, and feet) or when suspicion
of malignancy is low, an incisional biopsy (e.g. shave, saucerization,
or punch) to include the most nodular or darkest area of the lesion is
acceptable. Incisional biopsy does not appear to facilitate the spread
of melanoma. For suspicious lesions, every attempt should be made to
preserve the ability to assess the deep and peripheral margins and to
perform immunohistochemistry. All biopsies should be deep enough to
include the deepest component of the entire lesion, and any pigment at
the base of the lesion should be removed and included with the biopsy
specimen. Punch biopsies are more likely to clear the deep margin but
more likely to be positive at the radial margins; the opposite is true for
shave biopsies. The choice of biopsy type should be guided by which is
most likely to remove the entire lesion for histologic evaluation.
The biopsy should be interpreted by a pathologist experienced in
pigmented lesions, and the report should include Breslow thickness,
mitotic rate, presence or absence of ulceration, lymphatic/vascular/
neural invasion, regression, microsatellitosis, and the status of the
peripheral and deep margins. Breslow thickness is the greatest thickness
of a primary cutaneous melanoma measured on the slide from the top
of the epidermal granular layer, or from the ulcer base, to the bottom of
the tumor. To distinguish melanomas from benign nevi in challenging
cases, genetic expression profiles (GEPs), fluorescence in situ hybridiza­
tion with multiple probes, or comparative genomic hybridization can be
helpful. GEPs have also been developed to determine prognosis.
■
■CLASSIFICATION AND PATHOGENESIS
Clinical 
More recent classifications of melanoma are based on
association with cumulative solar damage and nine different pathways
related to genomic attributes summarized in Table 81-2. This revised
classification incorporates traditional histopathologic designations
such as superficial spreading, lentigo maligna, acral lentiginous, and
desmoplastic, among others, but more precisely incorporates the
pathophysiology and genetic drivers of melanoma subtypes.
At present, genomic alteration pathways for melanomas are not
incorporated into American Joint Committee on Cancer (AJCC) stag­
ing or prognostic considerations, yet characterizing the genomic and
mutational profiles of melanoma has become increasingly common in
clinical practice. It is anticipated that genomic pathway characteriza­
tion will become increasingly important in determination of mela­
noma prognosis and may influence surveillance strategies, surgical
decisions, and medical therapy.
Genomic 
The advent of next-generation sequencing has led to
whole exome sequencing of thousands of cutaneous melanomas derived
from nonglabrous (hair-bearing) skin. This has revealed very complex
genomic changes resulting from both germline (see “Genetic Suscepti­
bility to Melanoma” above) and somatic mutations. Cutaneous melano­
mas have one of the highest somatic mutation rates (>10 mutations/Mb)
among all cancers; the majority (76% of primary tumors and 84% of
TABLE 81-2  Major Histologic Subtypes of Malignant Melanoma
TYPE
SITE
APPEARANCE
ASSOCIATED MUTATIONS
Lentigo maligna
Sun-exposed surfaces, particularly
malar region and temple
In flat portions, brown and tan predominate, but whitish gray
sometimes present; in nodules, reddish brown, bluish gray, bluish
black.
Superficial spreading
Any (more common on upper back
and, in women, lower legs)
Brown mixed with bluish red, bluish black, reddish brown, and often
whitish pink. The lesion border is often visibly and/or palpably raised.
Nodular
Any
Reddish blue, purple, or bluish black; can be uniform or mixed with
brown and black.
Acral lentiginous
Palm, sole, nail bed, mucous
membrane
In flat portions, dark brown; in raised lesions (plaques), brown-black
or blue-black.
Desmoplastic
Any (more common on head and
neck)
Highly variable; pigmentation is frequently absent. Can mimic nodular
basal cell carcinoma.
Uveal
Choroid, ciliary body, iris
Dome or mushroom shaped. Display low internal reflectivity on ocular
ultrasound.
Mucosal
Oral cavity, conjunctiva, sinuses,
alimentary tract including rectum
and anus, vulva
Can display radial growth pattern with ABCDE features associated
with cutaneous melanomas. Often present with advanced tumors
infiltrating local tissues
Abbreviation: ABCDE, asymmetry (benign lesions are usually symmetric); border irregularity (most nevi have clear-cut borders); color variegation (benign lesions usually
have uniform light or dark pigment); diameter >6 mm (the size of a pencil eraser); and evolving (any change in size, shape, color, or elevation or new symptoms such as
bleeding, itching, and crusting).
metastatic melanomas) exhibit mutations indicative of UVR expo­
sure. The mutation rate varies based on body site; melanomas arising in
chronic sun-damaged skin harbor substantially more mutations than
melanomas from non–sun-damaged skin.
Melanomas can harbor thousands of mutations, but only a few are
“driver” mutations that promote cell proliferation or inhibit normal
pathways of apoptosis or DNA repair and confer a growth advantage
to the neoplastic cell. Some of the driver mutations for cutaneous
melanoma are depicted in Fig. 81-2 along with the clinical evolution
of melanoma lesions. Driver mutations are often found in combination
with mutations to germline susceptibility genes such as p16, which
affect cell cycle arrest, and ARF, which result in defective apoptotic
responses to genotoxic damage. As melanocytes accumulate DNA
damage, they can undergo malignant transformation characterized by
invasion, metastasis, and angiogenesis.
A genomic classification of cutaneous melanoma has been proposed
based on the pattern of the most prevalent mutated genes, BRAF, RAS,
and NF1, along with a triple wild type (WT), lacking mutations in these
three genes. The pattern of DNA mutations can vary with the site of
origin and should be determined along with the histologic subtype of
the tumor. The proliferative pathways affected by the mutations include
the mitogen-activated protein (MAP) kinase and phosphatidylinositol
3′ kinase/AKT pathways. RAS and BRAF, members of the MAP kinase
pathway, which mediates the transcription of genes involved in cell
proliferation and survival, undergo somatic mutation in melanoma
and thereby represent potential therapeutic targets. NRAS is mutated in
∼20% of melanomas, and somatic activating BRAF mutations are found
in most benign nevi and 40–50% of cutaneous melanomas. Neither
mutation by itself appears to be sufficient to cause melanoma; thus,
they often are accompanied by other mutations, such as in TERT. The
BRAF mutation is most commonly a T→A point mutation that results
in a valine-to-glutamate amino acid substitution (V600E). V600E
BRAF mutations are more common in younger patients and are present
in most melanomas that arise on skin with intermittent sun exposure
and are less common in melanomas from chronically sun-damaged
skin (i.e., those of older patients).
CHAPTER 81
Cancer of the Skin
Melanomas may harbor mutations in AKT (primarily in AKT3) and
PTEN (phosphatase and tensin homolog). AKT can be amplified, and
PTEN may be deleted or undergo epigenetic silencing that leads to
constitutive activation of the PI3K/AKT pathway and enhanced cell
survival by antagonizing the intrinsic pathway of apoptosis. A loss-offunction mutation in NF1, which can affect both the MAP kinase and
PI3K/AKT pathways, has been described in 10–15% of melanomas.
BRAF 28%
NRAS 15%
PTEN
BRAF 57%
NRAS 18%
BRAF 47%
NRAS 33%
NRAS 25%
c-KIT 5-10%
BRAF 10%
MAPK and PI3K 73%
High tumor mutational burden,
BRAF and NRAS uncommon
BAP1, GNAQ, GNA11
KIT, NRAS, KRAS or BRAF
NF1
Driver Mutations
BRAF: 10%
NRAS: 10%
C-KIT: 5–10%
NF1: 48% of BRAF
and NRAS WT melanoma
in older patients
BRAF: 50%
NRAS: 20%
C-KIT: 0%
Nonchronic Sun Damage
Chronic Sun Damage
A
B
C
Photodamage
De Novo
Nevus
Dysplastic Nevus
F
D
PART 4
Oncology and Hematology
G
E
FIGURE 81-2  Cutaneous melanoma development and associated driver mutations. Chronic sun damage (with prominent solar elastosis) (A) predisposes to a lentigo
maligna (in situ) (B), which can evolve into lentigo maligna melanoma (invasive) (C). Similarly, nonchronic sun damage can initiate melanoma de novo or in nevomelanocytes,
where clinical and histologic changes of atypia may be seen prior to complete transformation. Nevi (D, E) can evolve into atypical lesions (F, G), in situ melanoma (H, I), and
eventually invasive nodular (J) or superficial spreading melanomas (K). Images E, G, and I are dermascopic photos of images D, F, and H, respectively. (Part A photo courtesy
of Dr. Sancy Leachman, © Copyright 2022 Oregon Health & Science University [OHSU]. Parts B, C, J, and K photos courtesy of Dr. Leonard Swinyer Collection, © Copyright
2020 University of Utah and OHSU. Parts D–I photos courtesy of Dr. Elizabeth Berry, © Copyright 2022 OHSU.)
In melanoma, these two signaling pathways (MAP kinase and PI3K/
AKT) enhance tumorigenesis, chemoresistance, migration, and cell
cycle dysregulation.
■
■PROGNOSTIC FACTORS
The most important clinical prognostic factors for a newly diagnosed
patient are incorporated in the AJCC staging classification. The best pre­
dictor of recurrence is Breslow thickness, followed by ulceration, which
together make up the T stage for melanoma. The anatomic site of the
primary tumor also influences prognosis; favorable sites are the forearm
and leg, and unfavorable sites include the scalp, hands, feet, and mucous
membranes. Women with stage I or II disease have better survival than
men, perhaps in part because of earlier diagnosis; women frequently
have melanomas on the lower leg, where self-recognition is more likely
compared to the back, where melanoma is more likely in men.
Older individuals, especially men >60, have a tendency toward
delayed diagnosis (and thus thicker tumors), have more head and
neck and acral melanomas (which tend to have earlier vertical growth
and distant metastases), and are more likely to develop melanomas in
chronically UVR-damaged skin (which are more often BRAF wild type,
with fewer options for therapy). All these factors help explain the worse
prognosis in older males. Other important adverse factors include high
mitotic rate and lymphatic/vascular invasion. Clinical features such as
microsatellite lesions and/or in-transit metastases, evidence of nodal
involvement, elevated serum lactate dehydrogenase (LDH), and certain
sites of distant metastases (e.g., brain, liver, and bone) all portend a
higher stage and worse prognosis.
GEPs and machine-learning algorithms that associate genomic
changes with clinical outcomes have been used to estimate the prog­
nosis of melanoma. A commercially available 31-gene GEP is available
that predicts for all-site (particularly distant) relapse and incorporates
the increased and decreased expression, as well as the dysregulation, of
Lentigo Maligna
Lentigo Maligna Melanoma
Nodular
Melanoma In Situ
J
H
Superficial Spreading
K
I
genes involved in many of the cellular processes leading to melanoma
progression described earlier. Although this 31-gene GEP can estimate
the probability of distant relapse, it has not supplanted the prognostic
estimates derived from surgical staging. GEPs have been incorporated
into management guidelines for breast, thyroid, and other cancers, but
their use in cutaneous melanoma care is still under investigation.
■
■STAGING
The purpose of staging is to estimate melanoma prognosis and deter­
mine treatment selection. The current melanoma staging criteria and
estimated 10-year survival by stage are depicted in Table 81-3.
The clinical stage is determined after the microscopic evaluation of
the melanoma skin lesion and clinical and radiologic assessment. The
pathologic stage incorporates the results from microscopic examina­
tion of clinically negative regional lymph nodes obtained at sentinel
lymph node biopsy (SLNB), any enlarged nodes found on exam or
imaging, and any suspected metastases amenable to open or imageguided biopsy.
All patients should have a complete history, with attention to symp­
toms that suggest metastatic disease, such as new palpable masses,
malaise, weight loss, headaches, vision changes, alterations in bowel
habits, hemoptysis, and pain. The provider should look for persistent
melanoma at the biopsy site, dermal or subcutaneous nodules that
could represent satellite or in-transit metastases, and lymphadenopa­
thy. A complete blood count, complete metabolic panel, and LDH
should be performed. Although these tests rarely lead to detection of
occult metastatic disease, a microcytic anemia would raise the possibil­
ity of bowel metastases, elevated liver function tests can suggest liver
metastases, and LDH is part of the AJCC system for stage IV disease.
Abnormal test results should prompt a more extensive evaluation,
including computed tomography (CT) scan or a positron emission
tomography (PET) scan (or CT/PET combined). Magnetic resonance
TABLE 81-3  Staging and Survival
10-YEAR MELANOMASPECIFIC SURVIVAL
ESTIMATE
STAGE
TNM
TisN0M0
99%
IA
T1aN0M0, T1bN0M0
98%
IB
T2aN0M0
94%
IIA
T2b-T3aN0M0
88%
IIB
T3b-T4aN0M0
81–83%
IIC
T4bN0M0
75%
IIIA
T1a-T2aN1a-2aM0
71–88%
IIIB
T2b-T3aN1a-N2bM0
60–77%
IIIC
T3b-4bN1a-N3cM0
44–60%
IIID
T4bN3a-N3cM0
24–30%
IV M1a
Any T, any N, skin, soft tissue, or
distant nodal sites
50% at 5 years
IV M1b
Any T, any N, lung + any M1a sites
35–50% at 5 years
IV M1c
Any T, any N, skin, non-CNS visceral
disease, any M1a or M1b sites
~25% at 5 years
IV M1d
Any T, any N, CNS metastasis + any
M1a,b,c sites
<5% at 5 years
Abbreviations: CNS, central nervous system; TNM, tumor-node-metastasis.
imaging (MRI) of the brain with contrast is recommended for the
initial evaluation of patients who present with neurologic symptoms or
have advanced disease on imaging or examination.
Despite all the above considerations, >80% of patients at presenta­
tion will have disease confined to the skin and a negative history and
physical examination, in which case imaging is not indicated. One
study suggests that imaging should be considered for node-negative
low-stage melanoma with a high-risk GEP, but this is not yet standard.
Imaging is sometimes done for very-high-risk primaries (e.g., >4 mm
with ulceration, clinical stages IIB and IIC) in which the chance for
occult distant metastases is higher than that for a positive SLNB, and
the prognosis is worse compared to stage IIIA disease. Medical oncolo­
gists now routinely provide consultation for stage IIB and IIC patients
to assess the potential value of adjuvant therapy (see “Treatment”).
TREATMENT
Melanoma
MANAGEMENT OF CLINICALLY LOCALIZED MELANOMA
(STAGE I, II)
For a newly diagnosed cutaneous melanoma, surgical wide exci­
sion (WE) of the lesion with a margin of normal skin is necessary
to remove all malignant cells and minimize the probability of
local recurrence. The National Comprehensive Cancer Network
(NCCN), based on data from six randomized trials, recommends
the following radial margins for a primary MIS, 0.5–1.0 cm; inva­
sive up to 1 mm thick, 1 cm; >1.01–2 mm, 1–2 cm; and >2 mm,
2 cm. Smaller margins may be used for “anatomically constrained”
locations such as the face, hands, feet, and genitalia due to the
higher likelihood of surgical morbidity in these regions, and in
some instances, Mohs with immunostaining is advantageous. In
all instances, inclusion of subcutaneous fat in the surgical speci­
men facilitates adequate thickness measurement and assessment of
surgical margins by the pathologist. When feasible, excision should
go down to fascia, with fascial resection for thick (T4) lesions.
Topical imiquimod, a toll-like receptor agonist, can stimulate skin
macrophages to induce an immune response useful to treat lentigo
maligna in cosmetically sensitive locations with narrow resec­
tion margins by promoting local immune response resulting in
decreased local recurrence.
SLNB provides prognostic information to identify patients at
high risk for relapse who may be candidates for adjuvant therapy.
The first (sentinel) draining node(s) from the primary site is (are)
located by injecting a blue dye and a gamma-emitting radioisotope
around the primary site. The sentinel node(s) then is (are) identified
using a handheld gamma detector brought sterilely into the opera­
tive field. The surgeon makes an incision of the area of uptake and
looks for the blue-stained, “hot” node(s), which is (are) removed
and subjected to histopathologic analysis with serial sectioning
using hematoxylin and eosin and immunohistochemical stains (e.g.,
S100, HMB45, MART-1, and MelanA) to identify melanocytes.
NCCN guidelines recommend SLNB for patients with a 10% or
greater chance of having tumor in the node. This includes patients
with tumors >1 mm thick (T2) or T1 tumors that have ulceration
(T1b). Patients with a 5–10% risk of node positivity (NCCN “Dis­
cuss and Consider” category), such as those with tumors measuring
between 0.75 and 1.0 mm, transected tumors, regressed tumors,
or lymphovascular invasion, should also be considered for SLNB.
The NCCN does not recommend SLNB for patients with a risk of a
positive SLNB ≤5% such as those with melanomas ≤0.75 mm thick
and no high-risk features. In these patients, WE alone is the usual
definitive therapy. There are computer nomograms that estimate
the risk of sentinel lymph node involvement based on melanoma
depth, clinical features (age, site), and histology (ulceration, mitotic
rate, lymphovascular invasion). GEPs in combination with these
other factors are being investigated as a sentinel lymph node risk
assessment tool in ongoing prospective trials.
CHAPTER 81
Patients with negative SLNB can either be followed or considered
for adjuvant therapy if the primary lesion is considered high risk.
Patients with thick and/or ulcerated stage IIB or IIC melanomas
have a significant risk of recurrence after wide local excision and
(negative) SLNB, estimated at 13–18% probability of death at
5 years using the AJCC melanoma database. Adjuvant anti-PD-1
immunotherapy using pembrolizumab or nivolumab for 1 year sig­
nificantly reduces the risk of melanoma recurrence or death in stage
IIB or IIC melanoma and has become a standard of care.
Cancer of the Skin
Patients with a positive sentinel lymph node should undergo
CT or PET/CT imaging to rule out distant metastatic disease, and
if none is found (i.e., stage III), adjuvant therapy should be offered
(see next section). Complete lymphadenectomy following identifi­
cation of a positive sentinel lymph node improves relapse-free but
not overall survival, and therefore, it is no longer offered routinely,
but should be considered in patients who cannot comply with
follow-up and/or forgo adjuvant therapy. This avoids the morbidity
of regional node dissection in most patients. However, patients not
undergoing immediate completion node dissection should have
nodal bed surveillance with physical examination and nodal bed
imaging (ultrasound or CT) at 4- to 6-month intervals for approxi­
mately 3 years to rule out isolated nodal bed progression.
Mohs micrographic surgery (MMS) is an alternative to WE and
is particularly useful in areas where tissue preservation is important
(e.g., face, genitalia, hands) and for lesions with extensive MIS.
MMS improves the probability of achieving negative margins,
decreases local recurrence, and enhances cosmesis compared to WE
in selected patients. It does not preclude SLNB, which can be done
before the MMS procedure.
MANAGEMENT OF REGIONALLY METASTATIC MELANOMA
(STAGE III)
Stage III melanoma comprises patients with a positive sentinel
lymph node, resected regional nodal macrometastases, or resected
locoregional disease (e.g., recurrences in the wide excision site,
within 2 cm of the site [“satellite metastases”], or >2 cm from the site
[“in-transit metastases”]). Even after complete resection of stage III
disease, the risk of developing distant metastases (stage IV) may be
high, and adjuvant systemic therapy should be offered. Melanomas
may recur at the edge of the incision or graft, as satellite metasta­
ses, in-transit metastases, or most commonly, regional spread to a
draining lymph node basin. Each of these presentations is managed
surgically followed by postsurgical adjuvant systemic immuno­
therapy or targeted therapy (for BRAF-mutant tumors), after which
there is the possibility of long-term disease-free survival. Topical
therapy with imiquimod has been useful for patients with lowvolume dermal lesions, but survival benefit has not been confirmed
with this approach. Talimogene laherparepvec is an engineered,
oncolytic herpes simplex virus type 1 that is FDA approved for
injection of primary or recurrent melanomas including cutaneous
and subcutaneous lesions or lymph node deposits that cannot be
completely removed by surgery.
Radiotherapy can reduce the risk of local recurrence after lymph­
adenectomy but does not improve overall survival. Patients with
large nodes (>3–4 cm), four or more involved lymph nodes, or
extranodal spread on microscopic examination should be consid­
ered for radiation as local recurrence in these high-risk patients
has significant morbidity. Systemic adjuvant therapy can also be
considered for patients with completely resected stage IV disease.
Current options for adjuvant systemic therapy include anti-PD-1
(nivolumab or pembrolizumab) or targeted therapy with BRAF/
MEK inhibitors in melanomas that harbor a BRAF V600 mutation.
Both anti-PD-1 and targeted therapy have been shown to confer
disease-free and overall survival benefits in patients with stage III
and stage IV melanoma (see below for further discussion).
A subset of patients with stage III melanoma has bulky disease
(usually palpable nodal involvement) at presentation (stages IIIC
and IIID) that may be difficult to resect with negative margins. Even
if surgery is feasible and postsurgical adjuvant immunotherapy
or targeted therapy is offered, the prognosis of these patients is
poor. A recent randomized phase II study comparing neoadjuvant
therapy followed by resection and adjuvant pembrolizumab versus
resection followed by adjuvant pembrolizumab showed significant
improvements in event-free and overall survival for the neoadjuvant
approach. Other randomized phase II clinical trials investigating
neoadjuvant plus adjuvant ipilimumab and nivolumab or relatlimab
plus nivolumab in patients with palpable nodal disease at diagnosis
have demonstrated a >50% probability of achieving a pathologic
complete response with neoadjuvant treatment and a low probability
of recurrence at 1 and 2 years. Neoadjuvant plus adjuvant targeted
therapy in patients with stage IIIC or IIID BRAF-mutated melanoma
has demonstrated a similar high probability of achieving pathologic
complete response and improved event-free survival in single-arm
phase II studies. Long-term follow-up data from randomized con­
trolled studies of neoadjuvant immunotherapy are not yet mature,
and comparisons of immunotherapy to targeted therapy in the
neoadjuvant setting have not yet been performed. GEP may help to
identify patients with stages II or III melanoma who are at lower risk
of recurrence and could avoid the toxicity and expense of adjuvant
therapy, although prospective data on this approach are needed.
PART 4
Oncology and Hematology
TREATMENT
Metastatic Disease
At diagnosis, 84% of patients with melanoma will have stage I or
II disease and 4% will present with metastases. Many others will
develop metastases after initial therapy for locoregional disease;
60% of deaths from melanoma occur in patients who were initially
diagnosed as stage I or II. The probability of recurrence is related
to initial stage, ranging from <5% with stage IA to >90% for subsets
of patients with stage IIID disease at presentation. Patients with a
history of melanoma who develop signs or symptoms suggesting
recurrent disease should undergo restaging imaging as described
earlier. Distant metastases (stage IV) commonly involve skin and
lymph nodes as well as viscera, bone, or the brain. The prognosis
is better for patients with skin and subcutaneous metastases (M1a)
than for lung (M1b) and worst for those with metastases to bone
or other visceral organs (M1c) or brain (M1d). An elevated serum
LDH is a poor prognostic factor and places the patient in stage M1c
regardless of the metastatic sites. The 15-year survival of patients
with stage IV melanoma was <10% before 2010; however, the
development of targeted therapy and immunotherapy has improved
TABLE 81-4  Treatment Options for Metastatic Melanoma
Immunotherapy
  Immune checkpoint blockade
    Anti-PD-1: pembrolizumab or nivolumab
    Anti-CTLA-4: ipilimumab
    Combined ipilimumab and nivolumab
    Combined relatlimab (anti-LAG-3) and nivolumab
  T-cell engager
    Tebentafusp (selected patients with uveal melanoma)
  Cytokine-based immunotherapy
    High-dose interleukin 2
Clinical trials investigating adoptive cellular therapy with tumor-infiltrating
lymphocytes for advanced disease and personalized vaccine targeting
neoantigens in high-risk resected melanoma
  Oncolytic virus
    Talimogene laherparepvec
  Targeted therapies
    BRAF inhibitors: vemurafenib, dabrafenib, encorafenib
    MEK inhibitors: trametinib, cobimetinib, binimetinib
  Local modalities
    Surgery
    Stereotactic radiation
disease-free and overall survival, especially for patients with M1a
and M1b disease, in whom the 15-year survival is nearly 50%. Even
patients with M1c disease may have prolonged survival, and those
who are progression-free for >2 years after immunotherapy or
targeted therapy have a high probability of living >5 years from the
onset of metastasis; some of these individuals may be cured.
FDA-approved agents since 2011 include three immune T-cell
checkpoint inhibitors (ipilimumab, nivolumab, and pembroli­
zumab), combination immunotherapy (ipilimumab plus nivolumab
or relatlimab plus nivolumab), six oral agents that target the MAP
kinase pathway (the BRAF inhibitors vemurafenib, dabrafenib, and
encorafenib, and the MEK inhibitors trametinib, cobimetinib, and
binimetinib), and the oncolytic virus talimogene laherparepvec.
Adoptive cellular therapy using tumor-infiltrating lymphocytes
(TILs) administered with interleukin 2 is undergoing FDA review
and may become a new standard of care for patients with progres­
sion on checkpoint immunotherapy (Table 81-4).
Local modalities, such as surgery and stereotactic radiosurgery,
should be considered for patients with a limited number of meta­
static sites (oligometastatic disease) because they may experience
long-term disease-free survival after metastasectomy or ablative
high-dose-per-fraction radiation. Patients with solitary metastases
are the best candidates, but local modalities can also be offered to
patients with metastases at more than one site if a complete resec­
tion or treatment of all sites can be achieved with reasonable side
effects. Patients rendered free of disease can be considered for
adjuvant therapy or a clinical trial because their risk of developing
additional metastases remains high. Surgery can also be used as an
adjunct to systemic therapy if only one or a few oligometastases
remain after systemic therapy. Surgery can be used to obtain tumor
for mutational profile analysis or to harvest tumor for TIL therapy.
IMMUNOTHERAPY
Immune Checkpoint Blockade  Immunotherapies are based on an
understanding of the control mechanisms of the normal immune
response. Inhibitory receptors or checkpoints, including CTLA-4,
PD-1, and lymphocyte activation gene 3 (LAG-3), are upregulated
on T cells after engagement of the T-cell receptor by cognate tumor
antigen in the context of the appropriate class I or II human leu­
kocyte antigen (HLA) molecules during the interaction between a
T cell and antigen-presenting cell. Immune checkpoints are needed
to ensure proper regulation of a normal immune response; however,
the continued expression of inhibitory receptors during chronic
infection (hepatitis, HIV) and in cancer patients leads to exhausted
T cells with limited potential for proliferation, cytokine production,
or cytotoxicity. Ipilimumab, a fully human IgG1 antibody that binds
CTLA-4 and blocks inhibitory signals, was the first drug shown in
a randomized trial to improve survival in patients with metastatic
melanoma. Anti-CTLA-4 monotherapy has been supplanted by
anti-PD-1 monotherapy or checkpoint combinations due to higher
objective response rates and longer durations of response.
The PD-1 blockers, nivolumab and pembrolizumab, have been
approved to treat patients with advanced melanoma. Combination
T-cell checkpoint therapy, blocking both inhibitory pathways with
ipilimumab and nivolumab, leads to superior antitumor activity
compared to treatment with either agent alone. Combined therapy
with IV ipilimumab and nivolumab is administered in the out­
patient setting every 3 weeks for four doses (induction), followed
by nivolumab given every 2–4 weeks (maintenance) for up to
1 year, and is associated with an objective response rate of 56% and
enhanced survival compared to ipilimumab monotherapy. Patients
who have >5% expression of PD-1 on T cells in a melanoma biopsy
sample derive a similar level of clinical benefit from nivolumab mono­
therapy, although using PD-1 expression to select therapy remains
problematic as some patients whose melanoma has no detectable
PD-1 expression can still respond to immunotherapy. Other elements
of genomic analysis, including an estimate of tumor mutational bur­
den (TMB), can be clinically useful as TMB is correlated with a higher
probability of objective response and longer progression-free survival
in patients treated with checkpoint antibody therapy in melanoma
and other solid tumors. TMB appears to be a more robust predictor
of response compared to PD-L1 expression in melanoma.
LAG-3 is another checkpoint present on CD4+ and CD8+ T cells
and is upregulated after chronic antigen exposure. The combination
of anti-LAG-3 using relatlimab and anti-PD-1 with nivolumab results
in objective responses comparable to ipilimumab plus nivolumab
with fewer side effects. Relatlimab plus nivolumab has been approved
by the FDA for the first-line treatment of advanced melanoma, has
activity after progression on other checkpoint inhibitors, and is being
investigated in the neoadjuvant setting as detailed above.
T-cell checkpoint antibodies can also interfere with normal immune
regulatory mechanisms, producing a novel spectrum of side effects.
The most common immune-related adverse events were skin rash
(discussed in depth in the Dermatology Drug Eruption section in
Chap. 63) and diarrhea (sometimes severe, life-threatening colitis), but
toxicity can involve almost any organ resulting in thyroiditis, hypophy­
sitis, hepatitis, nephritis, pneumonitis, myocarditis, and neuritis. The
severity and frequency of toxicity are greatest when anti-CTLA-4 and
anti-PD-1 are combined, followed by anti-CTLA-4, anti-LAG-3 plus
anti-PD-1, and then anti-PD-1 monotherapies. Vigilance, interruption
of therapy, and early intervention with steroids or other immuno­
suppressive agents, such as anti–tumor necrosis factor antibodies or
mycophenolate mofetil, can mitigate toxicity and prevent permanent
organ damage. Using immunosuppressive agents to mitigate toxicity
does not diminish antitumor activity, and benefit is manifest even in
patients who must discontinue immunotherapy due to immune-medi­
ated toxicity. Checkpoint immunotherapy can be administered safely
to selected patients with preexisting autoimmune conditions using a
multidisciplinary approach with input from endocrinology, rheuma­
tology, and other specialty services as clinically necessary. The use of
T-cell checkpoint antibodies for metastatic melanoma has become
commonplace, but there is controversy about whether all patients need
combined anti-CTLA-4 and anti-PD-1 and whether biomarkers can be
used to select patients who may benefit from anti-PD-1 alone. There is
also a significant economic impact with any anticancer therapy, which
must be placed in the context of the survival benefit.
TARGETED THERAPY
The RAS-RAF-MEK-ERK pathway delivers proliferation and sur­
vival signals from the cell surface to the cytoplasm and nucleus
and is mutated in approximately 50% of melanomas. Inhibitors of
BRAF and MEK can induce regression of melanomas that harbor a
BRAF mutation. Three BRAF inhibitors, vemurafenib, dabrafenib,
and encorafenib, have been approved for the treatment of patients
whose melanomas harbor a mutation at position 600 in BRAF.
Monotherapy with BRAF inhibitors has been supplanted with com­
bined BRAF and MEK inhibition to address the rapid adaptation of
melanomas that use MAP kinase pathway reactivation to facilitate
growth when BRAF is inhibited. Combined therapy with BRAF
and MEK inhibitors (dabrafenib and trametinib, vemurafenib with
cobimetinib, or encorafenib and binimetinib) improved progres­
sion-free and overall survival compared to monotherapy with a
BRAF inhibitor. Long-term results of inhibition of the MAP kinase
pathway confirm that some patients achieve long intervals of dis­
ease control, yet the major limitation of both monotherapy and
combined therapy appears to be the acquisition of resistance. The
mechanisms of resistance are diverse and reflect the genomic het­
erogeneity of melanoma; however, most instances involve reactiva­
tion of the MAPK pathway, often through RAS mutations or mutant
BRAF amplification. Patients who develop resistance to BRAF and
MEK inhibition are candidates for immunotherapy or clinical trials.
Targeted therapy is accompanied by manageable side effects that
differ from those experienced during immunotherapy. Headache,
pyrexia, and arthralgias are common. A class-specific side effect of
BRAF inhibitor monotherapy is the development of hyperprolifera­
tive skin lesions, including well-differentiated squamous cell skin
cancers (SCCs) in up to 25% of patients. Paradoxical activation of
the MAP kinase pathway occurs from BRAF inhibitor–mediated
changes in BRAF wild-type cells, and the activation is blocked by
MEK inhibitor, which explains why these lesions are infrequent
during combined therapy. Metastases from treatment-induced
SCCs have not been reported, and BRAF and MEK inhibitors can
be continued safely following simple excision of the SCCs. Cardiac
and ocular toxicities, although infrequent, can occur with BRAF and
MEK inhibitors and require medical evaluation, management, and
usually discontinuation of targeted therapy.
CHAPTER 81
Cancer of the Skin
Activating mutations in the c-kit receptor tyrosine kinase are
found in a minority of cutaneous melanomas with chronic sun dam­
age but are more common in mucosal and acral lentiginous subtypes.
When activating mutations of c-kit are present, imatinib therapy can
achieve clinically meaningful responses, similar to gastrointestinal
stromal tumors. The probability of objective response in patients
whose melanomas harbor a c-kit mutation is 29%, although most
responses are transient. N-RAS mutations occur in 15–20% of mela­
nomas. At present, there are no effective targeted agents for these
patients, but N-RAS inhibitors are being investigated in clinical trials.
Targeting proteins that are differentially expressed on melanoma
has been the basis for many clinical trials investigating vaccines
and engineered biologics. An engineered bispecific fusion protein
targeting gp100 on melanoma and CD3 on T cells, called teben­
tafusp, has garnered FDA approval for the treatment of metastatic
uveal melanoma in patients who have the HLA-A*02.01 tissue
type. Uveal melanoma is an aggressive melanoma subtype with a
propensity for metastasis to the liver and a much lower probability
of response to checkpoint immunotherapy than cutaneous melano­
mas. Objective response to tebentafusp is <10%, but overall survival
and progression-free survival are significantly improved compared
to checkpoint immunotherapy.
Other systemic therapies used to treat stage IV melanoma patients
include high-dose interleukin 2, which is also associated with dura­
ble remissions in some patients. Chemotherapy using dacarbazine
or taxanes is infrequently used and confers no survival benefit.
INITIAL APPROACH TO PATIENT WITH METASTATIC
DISEASE
Upon diagnosis of stage IV disease, a sample of the patient’s tumor
should be submitted for molecular testing to determine whether a
BRAF or c-kit mutation is present. Analysis of a metastatic lesion
biopsy is preferred, but any sample will suffice because there is little
discordance between primary and metastatic lesions. Treatment
algorithms start with determining the melanoma’s BRAF status.
For BRAF wild-type tumors, immunotherapy is recommended.
The best sequence of targeted therapy and immunotherapy in
patients with BRAF-mutated melanomas has been controversial.
A randomized study that compared anti-CTLA-4 plus anti-PD-1
followed by BRAF/MEK targeted therapy at progression to the
opposite sequence in patients with advanced melanoma showed
that immunotherapy followed by targeted therapy conferred sta­
tistically significant better overall survival at 2 years and a trend
toward better progression-free survival. Toxicities were similar
comparing the treatment sequences. The patient’s history, includ­
ing sites of disease, symptom burden, and history of autoimmune
conditions, influences the final recommendation for immuno­
therapy or targeted therapy, but survival data favor the initial use
of combined checkpoint immunotherapy in the advanced disease
setting. Despite improvements in therapy, most patients with meta­
static melanoma will not be cured, so enrollment in a clinical trial
is always an important consideration. Many will be poor candidates
for therapy because of extensive disease burden, poor performance
status, or concomitant illness; thus, the timely integration of pallia­
tive care and hospice remains an important element of care.
FOLLOW-UP AND SURVIVORSHIP
Skin examination and surveillance at least once a year are recom­
mended for all patients with melanoma. Routine blood work and
imaging for patients with stages IA–IIA (NCCN low risk) disease is
not recommended unless symptoms are present. Surveillance diag­
nostic imaging can be considered in patients with stages IIB–III
(NCCN high risk) disease but is mainly reserved for patients with
signs or symptoms of recurrent disease or to follow response to ther­
apy. The NCCN does not recommend surveillance imaging in asymp­
tomatic patients who had advanced melanoma and are free of disease
5 or more years out from treatment. For stage-specific recommenda­
tions, please consult the NCCN guidelines (see “Further Reading”).
PART 4
Oncology and Hematology
The increasing incidence of melanoma has been met with more
interest in advocacy and survivorship. Several national and inter­
national advocacy groups have called attention to issues such as
genetic screening, sun awareness, and the care of chronic treat­
ment-related side effects. These include, but are not limited to,
skin changes (such as vitiligo), lymphedema, neuropathies, and
gastrointestinal and endocrine disorders. Lymphedema can now be
managed in specialty clinics that offer support, nonsurgical treat­
ments, and newer surgical therapies such as lymphovenous bypass
and vascularized lymph node transplants.
NONMELANOMA SKIN CANCERS
NMSCs (mostly SCCs and basal cell cancer [BCC]) are the most com­
mon cancers in the United States. Although tumor registries do not
routinely gather data on the incidence of NMSCs, it is estimated that the
annual incidence is more than 5.3 million cases in the United States;
SCCs and BCCs account for 80 and 18%, respectively. While less com­
mon, the incidence of Merkel cell carcinoma (MCC) has tripled over
the past 20 years. There are now an estimated 2600 cases per year with
an annual increase in incidence of 8%. NMSCs can metastasize, but
MCCs do this most commonly, with sentinel lymph node positivity
rates of 25% (compared to 12–19% for melanoma) and mortality rates
approaching 33% at 3 years. SCCs, particularly those with high-risk
features, can also metastasize and account for 2400 deaths annually.
Recent advances in systemic therapy using checkpoint antibodies have
improved survival in patients with advanced NMSCs.
■
■PATHOPHYSIOLOGY AND ETIOLOGY
Like melanoma, the most significant cause of NMSCs is UVR, with a
dose-response relationship between tanning bed use and the incidence
of NMSC. As few as four tanning bed visits per year confers a 15%
increase in BCC and an 11% increase in SCC. The risk of lip or oral SCC
is increased with cigarette smoking and, like SCC of the ear, has a worse
prognosis than SCC found on other body sites. Human papillomavi­
ruses and UVR may act as co-carcinogens. Inherited disorders of DNA
repair, such as xeroderma pigmentosum, are associated with a greatly
increased incidence of skin cancer and help to establish the link between
UV-induced DNA damage, inadequate DNA repair, and skin cancer.
The genes associated with UV damage in SCC include p53 and
N-RAS, whereas BCC is primarily associated with damage to hedgehog
signaling pathway (Hh) genes, which lead to basal cell proliferation.
This is usually the result of loss of function of the tumor-suppressor
patched homolog 1 (PTCH1), which normally inhibits the signaling of
smoothened homolog (SMO).
Immunosuppression has also been associated with the development
of NMSCs; chronically immunosuppressed solid organ transplant
recipients have a 65-fold increase in SCC and a 10-fold increase in BCC.
The frequency of skin cancer is proportional to the level and duration
of immunosuppression and the extent of sun exposure before and after
transplantation. SCCs in this population are particularly aggressive,
demonstrating higher rates of local recurrence, metastasis, and mortal­
ity. Tumor necrosis factor (TNF) antagonist therapy of inflammatory
bowel disease and autoimmune disorders, such as rheumatoid and
psoriatic arthritis, may also confer an increased risk of NMSC.
Other risk factors for NMSCs include HIV infection, ionizing
radiation, thermal burn scars, BRAF inhibitor monotherapy, and
chronic ulcerations. Albinism, xeroderma pigmentosum, Muir-Torre
syndrome, Rombo’s syndrome, Bazex-Dupré-Christol syndrome, dys­
keratosis congenita, and basal cell nevus syndrome (Gorlin syndrome)
also increase the incidence of NMSC.
Although MCC is also clearly related to UV exposure, age, and
immunosuppression, this neural crest–derived cancer also appears to
have a viral etiology; an oncogenic Merkel cell polyomavirus (MCPyV)
is present in 80% of tumors. In patients with MCPyV-positive tumors,
there is inactivation of tumor-suppressor genes, specifically the p53
transcription factor and retinoblastoma protein (Rb). In addition, the
viral large T antigen is expressed on tumor cells, and many patients
have detectable cellular or humoral immune responses to polyoma
viral proteins, although this immune response is insufficient to eradi­
cate the malignancy.
■
■CLINICAL PRESENTATION
Basal Cell Carcinoma 
BCC arises from epidermal basal cells or
the follicular bulge. The least invasive of BCC subtypes, superficial BCC,
consists of often subtle, erythematous scaling plaques that slowly enlarge
and are most commonly seen on the trunk and proximal extremities
(Fig. 81-3). This subtype may be confused with benign inflammatory
dermatoses, especially nummular eczema and psoriasis or premalignant
actinic keratoses. BCC also can present as a small, slowly growing,
pearly nodule, often with tortuous telangiectatic vessels on its surface,
rolled borders, and a central crust (nodular BCC). The occasional pres­
ence of melanin in this variant of nodular BCC (pigmented BCC) may
lead to confusion with melanoma. Morpheaform (fibrosing), infiltrative,
and micronodular BCC, the most invasive and potentially aggressive
subtypes, manifest as solitary, flat or slightly depressed, indurated whit­
ish, yellowish, or pink scar-like plaques. Borders are typically indistinct,
and lesions can be subtle; thus, delay in treatment is common, and
tumors can be more extensive than expected clinically.
Squamous Cell Carcinoma 
Primary cutaneous SCC is a malig­
nant neoplasm of keratinizing epidermal cells that has a variable clini­
cal course, ranging from indolent to rapid growth, with the potential to
metastasize to regional and distant sites. Commonly, SCC appears as an
ulcerated erythematous nodule or superficial erosion on sun-exposed
skin of the head, neck, trunk, and extremities (Fig. 81-4). It may also
appear as a banal, firm, dome-shaped papule or rough textured plaque.
It is commonly mistaken for a wart or callous when the inflamma­
tory response to the lesion is minimal. Dotted or coiled vessels are a
hallmark of SCC when viewed through a dermatoscope. The margins
of this tumor may be ill defined, and fixation to underlying structures
may occur (“tethering”).
A very rapidly growing low-grade form of SCC, called keratoacan­
thoma (KA), typically appears as a large dome-shaped papule with a
central keratotic crater. Some KAs regress spontaneously without ther­
apy, but because progression to metastatic SCC has been documented,
A
B
C
FIGURE 81-3  Clinical, dermascopic, and confocal diagnostic findings of basal cell carcinoma. A. Typical basal cell carcinoma with skin-colored, slightly translucent
rolled borders and a small central erosion on chronically sun-damaged skin of the lateral posterior shoulder. B. Dermoscopic image of the same lesion as in panel A clearly
revealing the central erosion and classic gray, nonreticular globular structures of melanophages that characterize BCC. C. In vivo reflectance confocal microscopy of the
same lesion as in panel A showing typical nests of dermal basaloid cells (*) with classic cleft formation around the nests. (Photos courtesy of Dr. Alexander Witkowski and
Dr. Joanna Ludzik, © Copyright 2022 Oregon Health & Science University [OHSU].)
KAs should be treated in the same manner as other types of cutaneous
SCC. KAs occur in 15–25% of patients receiving monotherapy with a
BRAF inhibitor.
Actinic keratoses and cheilitis (actinic keratoses on the lip), both
premalignant forms of SCC, present as hyperkeratotic papules on
sun-exposed areas. Malignant transformation occurs in 0.25–20%
of untreated lesions. SCC in situ, also called Bowen’s disease, is the
intraepidermal form of SCC and usually presents as a scaling, ery­
thematous plaque. SCC in situ most commonly arises on sun-damaged
skin but can occur anywhere on the body. Bowen’s disease occurring
secondary to infection with human papillomavirus can arise on skin
with minimal or no prior sun exposure, such as the buttock or poste­
rior thigh. Treatment of premalignant and in situ lesions reduces the
subsequent risk of invasive disease.
Merkel Cell Carcinoma 
MCC, also known as cutaneous apu­
doma, primary neuroendocrine carcinoma of the skin, primary
small-cell carcinoma of the skin, and trabecular carcinoma of the skin,
arises from Merkel cells, which are neuroendocrine skin cells that act
as pressure receptors. Like other skin cancers, MCCs most commonly
arise as visible skin lesions, usually as raised, flesh-colored nodules or
masses; they can also be red or blue in color and vary in size from 0.5
to >5 cm in diameter and may enlarge rapidly. Although MCCs may
arise almost anywhere on the body, they are most often found in sunexposed areas such as the head, neck, or extremities. They can also be
found around the anus and on eyelids. The common clinical features
of MCC can be summarized by the acronym AEIOU: asymptomatic/
nontender, expand rapidly, immune suppression, older than 50 years,
and ultraviolet-exposed site.
■
■NATURAL HISTORY
Basal Cell Carcinoma 
The natural history of BCC is that of
a slowly enlarging, locally invasive neoplasm. The degree of local
destruction and risk of recurrence vary with the size, duration, loca­
tion, and histologic subtype of the tumor. Location on the central face,
ears, or scalp may portend a higher risk. Small nodular, pigmented,
cystic, or superficial BCCs respond well to most treatments. Large
lesions and micronodular, infiltrative, and morpheaform subtypes may
be more aggressive. The metastatic potential of BCC is low (0.1%) in
immunocompetent patients, but the risk of recurrence or a new pri­
mary NMSC is about 40% over 5 years.
CHAPTER 81
Cancer of the Skin
Squamous Cell Carcinoma 
The natural history of SCC depends
on tumor and host characteristics. Tumors arising on sun-damaged skin
have a lower metastatic potential than do those on non-sun-exposed
areas. Cutaneous SCC metastasizes in 0.3–5.2% of individuals, most
frequently to regional lymph nodes. Tumors occurring on the lower lip
and ear develop regional metastases in 13 and 11% of patients, respec­
tively, whereas the metastatic potential of SCC arising in scars, chronic
ulcerations, and genital or mucosal surfaces is higher. Recurrent SCC
has a 30% probability for metastatic spread. Large, poorly differenti­
ated, deep tumors with perineural or lymphatic invasion, multifocal
tumors, and those arising in immunosuppressed patients often behave
aggressively.
Merkel Cell Carcinoma 
MCCs usually present locally yet have
a high probability of spread to regional lymph nodes and distant sites.
Molecular markers of neuroendocrine origin such as synaptophysin or
chromogranin A are useful to diagnose MCC. Unlike other neuroen­
docrine tumors, such as small-cell lung cancer (SCLC), MCCs are not
associated with measurable hormone secretion or endocrine syndromes.
Survival with MCC depends on extent of disease: 90% of patients
with local disease are cured, whereas 52% with nodal involvement and
10% with distant disease survive. MCC has its own tumor-node-metastasis
(TNM) staging system, which incorporates tumor size (<2 cm vs >2 cm),
nodal status (which can be determined by SLNB for clinically negative
nodes), and the presence of distant metastases.
Independent of stage, the prognosis of MCC is improved if the tumor
cells contain virus, express RB protein, and exhibit intratumoral CD8+
T lymphocyte infiltration. p63 expression, lymphovascular infiltrative
pattern, and concomitant immunosuppression (e.g., organ transplant,
HIV infection, and certain cancers) portend a worse prognosis.
TREATMENT
Basal Cell, Squamous Cell, and Merkel Cell
Carcinoma
BASAL CELL CARCINOMA
Treatment for BCC includes electrodesiccation and curettage
(ED&C), excision, cryosurgery, radiation therapy (RT), laser ther­
apy, MMS, topical 5-fluorouracil, photodynamic therapy (PDT),
and topical immunomodulators, such as imiquimod. The choice
PART 4
Oncology and Hematology
A
B
C
D
E
F
G
H
I
A
B
C
D
E
F
G
H
I
FIGURE 81-4  Progression of basal cell (BCC) and squamous cell carcinoma (SCC). A. Superficial BCC; note salmon pink color, rolled boarder, erosions, and a gray central
globule. B. Nodular BCC; note shiny, slightly pearly character with prominent arborizing vessels. C. Eroded BCC with serous and sanguinous crusting. D. Multiple actinic
keratoses; note flat lesions are early, and thicker lesions may require biopsy to discriminate between advanced actinic keratosis versus early SCC. E. Superficial SCC. F.
Keratoacanthoma (well-differentiated SCC). G. Mucocutaneous SCC in a high-risk area on the lower lip. H. Cutaneous SCC. I. Large exophytic SCC on the wrist. (Photos
courtesy of the Dr. Leonard Swinyer Collection, © Copyright 2020 University of Utah and Oregon Health & Science University.)
of therapy depends on tumor characteristics including depth and
location, patient age, medical status, and patient preference. ED&C
remains the most frequent treatment for superficial, minimally
invasive nodular BCCs and low-risk tumors (e.g., a small tumor of
a less aggressive subtype in a favorable location without terminal
hairs). Wide local excision with standard margins is usually selected
for invasive, ill-defined, and more aggressive subtypes of tumors or
for cosmetic reasons. MMS, a specialized type of surgical excision
that provides the best method for tumor removal while preserv­
ing uninvolved tissue, is associated with cure rates of >98%. It is
the preferred modality for lesions that are recurrent, in high-risk
or cosmetically sensitive locations (including recurrent tumors
in these locations), and for which maximal tissue conservation is
critical (e.g., the eyelids, lips, ears, nose, and digits). RT can cure
patients not considered surgical candidates and can be used as a
surgical adjunct in high-risk tumors. Imiquimod can be used to
treat superficial and smaller nodular BCCs, although it is not FDA
approved for nodular BCC. Topical 5-fluorouracil therapy should
be limited to superficial BCC. PDT, which uses selective activation
of a photoactive drug by visible light, has been used in patients
with numerous tumors. Intralesional therapy (5-fluorouracil or
interferon) can also be employed. Like RT, it remains an option for
selected patients who cannot or will not undergo surgery. Systemic
therapy with a targeted hedgehog pathway inhibitor, such as vis­
modegib or sonidegib, is indicated for patients with metastatic or
advanced BCC that has recurred after local therapy and who are
not candidates for surgery or RT. Targeted therapy does not cure
patients with BCC but induces regression in approximately 50%
of patients with a median duration of response of 9–12 months in
patients with metastatic disease and ~2 years in patients with locally
advanced disease. Checkpoint immunotherapy using cemiplimab
can be offered to BCC patients who progress after targeted therapy.
SQUAMOUS CELL CARCINOMA
The principles for surgical management of SCC are the same as
for BCC. Cemiplimab, a monoclonal antibody targeting PD-1, has
become the systemic therapy of choice, inducing tumor regression
in 47% of patients with advanced disease. Neoadjuvant cemiplimab
has been given in stage II, III and IV SCC and is associated with a
50% probability of pathologic complete response and is becoming
a standard of care in patients with very-high-risk presentations and/
or who have disease that may be technically difficult to resect. SCC
and KAs that develop in patients receiving BRAF-targeted therapy
should be excised, after which BRAF therapy can be continued.
MERKEL CELL CARCINOMA
The epidemiology, clinical features, and treatments for MCC over­
lap those for melanoma and NMSC. Early-stage MCCs may be
cured with wide local excision of the primary tumor and nodal
staging with SLNB. Like SCLCs, MCC is sensitive to radiation, PD1-directed immunotherapy, and platinum-based chemotherapy. RT
is often used as postoperative adjuvant therapy at both the primary
excision and SLNB sites, although its use may be withheld around
sensitive areas such as the eyelids and hands and after a negative
SLNB. For nonsensitive areas, RT may allow for primary excision
margins smaller than the traditionally recommended 2-cm radial
margins. When a positive sentinel node is found, adjuvant RT, close
observation, and clinical trials investigating immunotherapy are
favored over completion nodal dissection.
For patients with metastatic disease, immunotherapy has sup­
planted chemotherapy. Avelumab (anti-PD-L1) therapy led to
objective responses in 33% of patients with advanced MCC; 82%
of the responses were durable. Pembrolizumab has an objective
response >50% in patients with MCPyV-associated and nonvirus-associated advanced MCC resulting in a median duration of
response approaching 2 years. Clinical trials should be offered to
MCC patients who progress after checkpoint therapy and whose
functional status can support additional treatment.
Follow-up of patients with MCC is based on stage and risk. Rou­
tine skin exams by a dermatologist familiar with MCC and regular
examinations of the nodal basins are recommended. Antibody
serum titers to MCPyV should be obtained in newly diagnosed
MCC patients. The test can be used to follow patients for relapse
if the titer is elevated at baseline and returns to normal after
A
C
F
D
B
E
G
FIGURE 81-5  Other malignant cutaneous tumors. A. Patch stage mycosis fungoides (variant of cutaneous T-cell lymphoma). B. Tumor stage mycosis fungoides. C.
Extramammary Paget’s disease. D. Merkel cell carcinoma. E. Dermatofibrosarcoma protuberans. F. and G. Kaposi’s sarcoma. (Parts A, B, and D-G photos courtesy of the Dr.
Leonard Swinyer Collection, © Copyright 2020 University of Utah and Oregon Health & Science University. Part C photo courtesy Dr. Justin Leitenberger, © Copyright 2022
Oregon Health & Science University [OHSU].)
treatment. Conversely, if the titer is elevated but does not return
to normal after treatment, imaging should be obtained to look for
occult metastases.
■
■PREVENTION
The principles for prevention are those described for melanoma earlier.
Unique strategies for NMSC include active surveillance for patients on
immunosuppressive medications or BRAF-targeted therapy. Chemopro­
phylaxis using synthetic retinoids and immunosuppression reduction
when possible may be useful in controlling new lesions and managing
patients with multiple tumors. Nicotinamide 500 mg BID may be used
in patients with large numbers of actinic keratoses and SCCs to reduce
the development and/or progression of disease. Field therapy with topi­
cal 5-fluorouracil (with or without calcipotriol), ingenol mebutate, or
imiquimod can reduce transformation to SCC in patients with severely
sun-damaged skin and numerous premalignant actinic keratoses. Older,
immunosuppressed patients should be managed with the lowest doses
of immunosuppression possible and encouraged to be particularly care­
ful to minimize UV exposure. Earlier biopsy of unusual-appearing skin
lesions may lead to better control of aggressive lesions.
■
■OTHER NONMELANOMA CUTANEOUS
MALIGNANCIES
Neoplasms of cutaneous adnexae and sarcomas of fibrous, mesenchy­
mal, fatty, and vascular tissues make up the remaining 1–2% of NMSCs
(Fig. 81-5). Lymphomas of B- or T-cell origin can also manifest in the
skin and can mimic benign conditions such as psoriasis and eczema.
CHAPTER 81
Extramammary Paget’s disease is an uncommon apocrine malig­
nancy arising from stem cells of the epidermis that is characterized
Cancer of the Skin

11 - 82 Head and Neck Cancer
82 Head and Neck Cancer
histologically by the presence of Paget cells. These tumors present
as moist erythematous patches on anogenital or axillary skin of the
elderly.
Outcomes are generally good with surgery, and 5-year diseasespecific survival is 95% with localized disease. Advanced age and
extensive disease at presentation confer poorer prognosis. RT or
topical imiquimod can be considered for more extensive disease. Local
management may be challenging because these tumors often extend
far beyond clinical margins; surgical excision with MMS has the high­
est cure rates. Similarly, MMS is the treatment of choice in other rare
cutaneous tumors with extensive subclinical extension such as derma­
tofibrosarcoma protuberans.
Kaposi’s sarcoma (KS) is a soft tissue sarcoma of vascular origin that
is induced by the human herpesvirus 8. The incidence of KS increased
dramatically during the AIDS epidemic but has now decreased tenfold
with the institution of highly active antiretroviral therapy.
Acknowledgment
Walter Urba, MD, PhD, provided valued feedback and suggested
improvements to this chapter. Clinical photos were generously provided
from the OHSU Swinyer Collection (Leonard Swinyer, MD) and by Drs.
Elizabeth Berry, Alexander Witkowski, Joanna Ludzik, Debbie Miller,
Alison Skalet, and Justin Leitenberger. Dermoscopic images were pro­
vided by Elizabeth Berry, Alexander Witkowski, Joanna Ludzik, and
Debbie Miller. Reflectance confocal microscopy images were provided by
Drs. Alexander Witkowski and Joanna Ludzik.
PART 4
Oncology and Hematology
■
■FURTHER READING
Atkins ME et al: Combination dabrafenib and trametinib versus
combination nivolumab and ipilimumab for patients with advanced
BRAF-mutant melanoma: The DREAMseq trial—ECOG-ACRIN
EA6134. J Clin Oncol 41:186, 2022.
Elder DE et al: The 2018 World Health Organization classification
of cutaneous, mucosal, and uveal melanoma. Arch Pathol Lab Med
44:500, 2020.
Faries MD et al: Completion dissection or observation for sentinel-node
metastasis in melanoma. N Engl J Med 376:2211, 2017.
Harms PW et al: The biology and treatment of Merkel cell carcinoma:
Current understanding and research priorities. Nat Rev Clin Oncol
15:763, 2018.
National Comprehensive Cancer Network: NCCN clinical practice
guidelines in oncology (NCCN guidelines): Melanoma. Available
from https://www.nccn.org/professionals/physician_gls/pdf/melanoma.
pdf.
Tawbi HA et al: Relatlimab and nivolumab versus nivolumab in
untreated advanced melanoma. N Engl J Med 386:24, 2022.
Wu YP et al: A systematic review of interventions to improve adher­
ence to melanoma preventive behaviors for individuals at elevated
risk. Prev Med 88:153, 2016.
Everett E. Vokes
Head and Neck Cancer
Epithelial carcinomas of the head and neck arise from the mucosal
surfaces in the head and neck and typically are squamous cell in origin.
This category includes tumors of the paranasal sinuses, the oral cavity,
and the nasopharynx, oropharynx, hypopharynx, and larynx. Tumors
of the salivary glands differ from the more common carcinomas of the
head and neck in etiology, histopathology, clinical presentation, and
therapy. They are rare and histologically highly heterogeneous. Thyroid
malignancies are described in Chap. 397.
■
■INCIDENCE AND EPIDEMIOLOGY
The number of new cases of head and neck cancers (oral cavity, phar­
ynx, and larynx) in the United States was estimated at 66,920 in 2023,
accounting for about 6% of adult malignancies; estimated deaths were
15,400. The worldwide incidence exceeds half a million cases annually.
In North America and Europe, the tumors usually arise from the oral
cavity, oropharynx, or larynx. The incidence of oropharyngeal cancers
has been increasing in Western countries. Nasopharyngeal cancer is
endemic in East Asia and some Mediterranean countries.
■
■ETIOLOGY AND GENETICS
Alcohol and tobacco use are the most significant environmental risk
factors for head and neck cancer, and when used together, they act
synergistically. Smokeless tobacco is an etiologic agent for oral can­
cers. Other potential carcinogens include marijuana and occupational
exposures such as nickel refining, exposure to textile fibers, and
woodworking.
Some head and neck cancers have a viral etiology. Epstein-Barr virus
(EBV) infection is frequently associated with nasopharyngeal cancer,
especially in endemic areas. EBV antibody titers can be measured to
screen high-risk populations and are under investigation to monitor
treatment response. Nasopharyngeal cancer has also been associated
with consumption of salted fish and indoor pollution.
In Western countries, the human papillomavirus (HPV) is associ­
ated with a rising incidence of tumors arising from the oropharynx,
that is, the tonsillar bed and base of tongue. Over 50% of oropha­
ryngeal tumors are caused by HPV in the United States, and in many
urban centers, this proportion is higher. HPV-16 is the dominant viral
subtype, although HPV-18 and other oncogenic subtypes are seen as
well. Alcohol- and tobacco-related cancers, on the other hand, have
decreased in incidence. HPV-related oropharyngeal cancer occurs in
a younger patient population and is associated with increased num­
bers of sexual partners and oral sexual practices. It is associated with
a better prognosis, especially for nonsmokers. Vaccination with the
nine-valent HPV vaccine may prevent the disease but is not likely to
result in a lower incidence for several decades due to long latency of
the carcinogenic process.
Dietary factors may contribute. The incidence of head and neck
cancer is higher in people with the lowest consumption of fruits and
vegetables. Certain vitamins, including carotenoids, may be protective
if included in a balanced diet. Supplements of retinoids, such as cisretinoic acid, have not been shown to prevent head and neck cancers
(or lung cancer) and may increase the risk in active smokers. No spe­
cific risk factors or environmental carcinogens have been identified for
salivary gland tumors.
■
■HISTOPATHOLOGY, CARCINOGENESIS, AND
MOLECULAR BIOLOGY
Squamous cell head and neck cancers are divided into well-differentiated,
moderately well-differentiated, and poorly differentiated categories.
Poorly differentiated tumors have a worse prognosis than well-differen­
tiated tumors. For nasopharyngeal cancers, the less common differenti­
ated squamous cell carcinoma is distinguished from nonkeratinizing
and undifferentiated carcinoma (lymphoepithelioma) that contains
infiltrating lymphocytes and is commonly associated with EBV.
Salivary gland tumors can arise from the major (parotid, subman­
dibular, sublingual) or minor salivary glands (located in the submucosa
of the upper aerodigestive tract). Most parotid tumors are benign, but
half of submandibular and sublingual gland tumors and most minor
salivary gland tumors are malignant. Malignant tumors include muco­
epidermoid and adenoid cystic carcinomas and adenocarcinomas.
The mucosal surface of the entire pharynx is exposed to alcohol-
and tobacco-related carcinogens and is at risk for the development
of a premalignant or malignant lesion. Erythroplakia (a red patch)
or leukoplakia (a white patch) can be histopathologically classified
as hyperplasia, dysplasia, carcinoma in situ, or carcinoma. However,
most head and neck cancer patients do not present with a known his­
tory of premalignant lesions. Multiple synchronous or metachronous
cancers can also be observed. In fact, over time, patients with treated
early-stage tobacco- and alcohol-related head and neck cancer are at
greater risk of dying from a second malignancy than from a recurrence
of the primary disease.
Second head and neck malignancies are usually not therapy induced;
they reflect the exposure of the upper aerodigestive mucosa to the
same carcinogens that caused the first cancer. These second prima­
ries develop in the head and neck area, the lung, or the esophagus.
Thus, computed tomography (CT) screening for lung cancer in heavy
smokers who have already developed a head and neck cancer is rec­
ommended. Rarely, patients can develop a radiation therapy–induced
sarcoma after having undergone prior radiotherapy for a head and
neck cancer.
Much progress has been made in describing the molecular features
of head and neck cancer. These features have allowed investigators
to describe the genetic and epigenetic alterations and the mutational
spectrum of these tumors. Early reports demonstrated frequent overex­
pression of the epidermal growth factor receptor (EGFR). Overexpres­
sion was shown to correlate with poor prognosis. However, it has not
proved to be a good predictor of tumor response to EGFR inhibitors,
which are active in only about 10–15% of patients as single agents.
Complex genetic analyses, including those by The Cancer Genome
Atlas project, have been performed. p53 mutations are found fre­
quently with other major affected oncogenic driver pathways including
the mitotic signaling and Notch pathways and cell cycle regulation in
HPV-negative tumors. HPV oncogenes act through direct inhibition of
the p53 and RB tumor-suppressor genes, thereby initiating the carcino­
genic process. HRAS mutations are detected in 4–8% of patients with
recurrent head and neck cancer and may be therapeutically targetable
in a small patient subset. While overall mutation rates are similar in
HPV-positive and carcinogen-induced tumors, the specific mutational
signature of HPV-positive tumors differs, with frequent alteration of
the PI3K pathway and occasional mutations in KRAS. Overall, these
alterations affect mitogenic signaling, genetic stability, cellular prolif­
eration, and differentiation.
■
■CLINICAL PRESENTATION AND DIFFERENTIAL
DIAGNOSIS
Most tobacco-related head and neck cancers occur in patients older
than age 60 years. HPV-related malignancies are frequently diagnosed
in younger patients, usually in their forties or fifties, whereas EBVrelated nasopharyngeal cancer can occur at all ages, including in teen­
agers. The manifestations vary according to the stage and primary site
of the tumor. Patients with nonspecific signs and symptoms in the head
and neck area should be evaluated with a thorough otolaryngologic
examination, particularly if symptoms persist longer than 2–4 weeks.
Males are more frequently affected than women by head and neck can­
cers, including HPV-positive tumors.
Cancer of the nasopharynx typically does not cause early symptoms.
However, it may cause unilateral serous otitis media due to obstruc­
tion of the eustachian tube, unilateral or bilateral nasal obstruction, or
epistaxis. Advanced nasopharyngeal carcinoma causes neuropathies of
the cranial nerves due to skull base involvement.
Carcinomas of the oral cavity present as nonhealing ulcers, changes
in the fit of dentures, or painful lesions and masses. Tumors of the
tongue base or oropharynx can cause decreased tongue mobility and
alterations in speech. Cancers of the oropharynx or hypopharynx
rarely cause early symptoms, but they may cause sore throat and/or
otalgia. HPV-related tumors frequently present with neck lymphade­
nopathy as the first sign.
Hoarseness may be an early symptom of laryngeal cancer, and
persistent hoarseness requires referral to a specialist for indirect laryn­
goscopy and/or radiographic studies. If a head and neck lesion treated
initially with antibiotics does not resolve in a short period, further
workup is indicated; to simply continue the antibiotic treatment may
be to lose the chance of early diagnosis of a malignancy.
Advanced head and neck cancers in any location can cause severe
pain, otalgia, airway obstruction, cranial neuropathies, trismus, ody­
nophagia, dysphagia, decreased tongue mobility, fistulas, skin involve­
ment, and massive cervical lymphadenopathy, which may be unilateral
Physical Examination in Office
FNA or excision of lymph node
If lymphoma, sarcoma,
or salivary gland tumor
If squamous cell carcinoma
Panendoscopy and directed biopsies.
Search for occult primary with biopsies
of tonsils, nasopharynx, base of tongue,
and pyriform sinus.
Specific workup
Stage-specific
multimodality therapy
Consider curative
neck dissection
Postoperative radiotherapy or chemoradiotherapy
CHAPTER 82
FIGURE 82-1  Evaluation of a patient with cervical adenopathy without a primary
mucosal lesion; a diagnostic workup. FNA, fine-needle aspiration.
or bilateral. Some patients have enlarged lymph nodes even though no
primary lesion can be detected by endoscopy or biopsy; these patients
are considered to have carcinoma of unknown primary (Fig. 82-1).
Tonsillectomy and directed biopsies of the base of tongue can iden­
tify a small primary tumor that frequently will be HPV related. If the
enlarged nodes are located in the upper neck and the tumor cells are of
squamous cell histology, the malignancy probably arose from a muco­
sal surface in the head or neck. Tumor cells in supraclavicular lymph
nodes may also arise from a primary site in the chest or abdomen.
Head and Neck Cancer
The physical examination should include inspection of all visible
mucosal surfaces and palpation of the floor of the mouth and of the
tongue and neck. In addition to a tumor, leukoplakia (a white muco­
sal patch) or erythroplakia (a red mucosal patch) may be observed;
these “premalignant” lesions can represent hyperplasia, dysplasia, or
carcinoma in situ and require biopsy. Further examination should
be performed by a specialist. Additional staging procedures include
CT or MRI of the head and neck to identify the extent of the disease.
Patients with lymph node involvement should have CT scan of the
chest and upper abdomen to screen for distant metastases. In heavy
smokers, the CT scan of the chest can also serve as a screening tool to
rule out a second lung primary tumor. A positron emission tomogra­
phy (PET) scan can help to identify or exclude distant metastases. CT
and PET scans may also be useful in evaluating response to therapy.
The definitive staging procedure is an endoscopic examination under
anesthesia, which may include laryngoscopy, esophagoscopy, and
bronchoscopy; during this procedure, multiple biopsy samples are
obtained to establish a primary diagnosis, define the extent of primary
disease, and identify any additional premalignant lesions or second
primaries.
Head and neck tumors are classified according to the tumor-nodemetastasis (TNM) system of the American Joint Committee on Cancer
(AJCC) (Fig. 82-2). This classification varies according to the specific
anatomic subsite. In general, primary tumors are classified as T1 to T3
by increasing size, whereas T4 usually represents invasion of another
structure such as bone, muscle, or root of tongue. Lymph nodes are
staged by size, number, and location (ipsilateral vs contralateral to
the primary). Overt distant metastases are found in <10% of patients
at initial diagnosis and are more common in patients with advanced
lymph node stage; microscopic involvement of the lungs, bones, or
liver is more common, particularly in patients with advanced neck
lymph node disease. HPV-related oropharyngeal malignancies have
consistently been shown to have a better prognosis, and in the eighth
Definition of TNM
Stage I
T1
N0-
Tumor ≤2 cm
in greatest
dimension ≤5 mm
depth of invasion (DOI)
Stage II
T2
Tumor ≥2 cm
but not more than
4 cm in greatest
dimension
OR DOI >5 mm
and ≤10 mm
PART 4
Oncology and Hematology
Stage III
T3
Tumor ≥4 cm
OR DOI
10 mm
Stage IVA
T4a
N2a-
Tumor invades skin,
mandible, ear canal,
fascial nerve, and/or
floor of mouth
Stage IVB
T4b
T4b
Tumor invades skull
base and/or pterygoid
plates and/or encases
carotid artery
Stage IVC
M1
M1
Any T
Any N
FIGURE 82-2  Tumor-node-metastasis (TNM) staging system. (Figure based on the AJCC Cancer Staging Manual, 8th edition.)
edition of the AJCC staging manual, a separate staging system that
takes into account the more favorable outlook of these patients has
been included. According to this system, patients with advanced nodal
stage can still be considered to have the equivalent of an overall early
stage (and associated good prognosis).
In patients with lymph node involvement and no visible primary,
the diagnosis should be made by fine-needle aspiration or by
DOI = depth of invasion
Stage groupings
T1
N0
N0
M0
No regional lymph
node metastasis
T2
N0
N0
M0
No regional lymph
node metastasis
N0-
N1
T3
N0
M0
Metastasis in a single
ipsilateral lymph node,
≤3 cm in greateast
dimension
N1-
N1
T1
M0
N1
T2
M0
T3
N1
M0
≤3 cm
N2
T4a
N0
M0
Metastasis in a single
ipsilateral lymph node,
3 cm but ≤6 cm
T4a
N1
M0
T1
N2
M0
Metastasis in multiple
ipsilateral lymph nodes,
none >6 cm
N2b-
T2
N2
M0
Metastasis in bilateral or
contralateral lymph
nodes, none >6 cm
N2c-
T3
N2
M0
T4a
N2
M0
≤6 cm
N3
M0
Any N
Metastasis in a lymph
node >6 cm in greatest
dimension or clinically
overt extranodal extension
N3-
N3
M0
Any T
6 cm
lymph node excision (especially if only a single node appears involved)
(Fig. 82-1). If the results indicate squamous cell carcinoma, a panen­
doscopy should be performed, with biopsy of all suspicious-appearing
areas and directed biopsies of common primary sites, such as the
nasopharynx, tonsil, tongue base, and pyriform sinus. HPV-positive
tumors especially can have small primary tumors that spread early to
locoregional lymph nodes.
TREATMENT
Head and Neck Cancer
Patients with head and neck cancer can be grossly categorized
into three clinical groups: those with localized disease, those with
locally or regionally advanced disease (lymph node positive), and
those with recurrent and/or metastatic disease below the neck.
Comorbidities associated with tobacco and alcohol abuse can affect
treatment outcome and define long-term risks for patients who are
cured of their disease.
LOCALIZED DISEASE
Nearly one-third of patients have localized disease, that is, T1 or T2
(stage I or stage II) lesions without detectable lymph node involve­
ment or distant metastases. These patients are treated with curative
intent by either surgery or radiation therapy. The choice of modality
differs according to anatomic location and institutional expertise.
Radiation therapy is often preferred for laryngeal cancer to preserve
voice function, and surgery is preferred for small lesions in the oral
cavity to avoid the long-term complications of radiation, such as
xerostomia and osteoradionecrosis and dental decay. Randomized
data have shown that a prophylactic staging neck dissection should
be part of the surgical procedure to eliminate occult nodal meta­
static disease. Overall 5-year survival is 60–90%. Most recurrences
occur within the first 2 years following diagnosis and are usually
local.
LOCALLY OR REGIONALLY ADVANCED DISEASE
Locally or regionally advanced disease—disease with a large pri­
mary tumor and/or cervical lymph node metastases—is the stage of
presentation for >50% of patients. Such patients can also be treated
with curative intent, but not usually with surgery or radiation
therapy alone. Combined-modality therapy, including surgery and/
or radiation therapy and chemotherapy, is most successful. Che­
motherapy can be administered as induction chemotherapy (che­
motherapy before surgery and/or radiotherapy) or as concomitant
(simultaneous) chemotherapy and radiation therapy. The latter is
most commonly used and supported by the best evidence. Five-year
survival rates exceed 50% in many trials, but part of this increased
survival may be due to an increasing fraction of study populations
with HPV-related tumors who carry a better prognosis. HPV test­
ing of newly diagnosed tumors should be performed for patients
with oropharyngeal tumors at the time of diagnosis. Clinical trials
for HPV-related tumors are focused on exploring reductions in
treatment intensity, especially radiation dose, in order to ameliorate
long-term toxicities (fibrosis, swallowing dysfunction).
In patients with intermediate-stage tumors (stage III and early
stage IV), concomitant chemoradiotherapy can be administered
as a primary treatment for patients with unresectable disease, to
pursue an organ-preserving approach especially for patients with
laryngeal cancer (omission of surgery), or in the postoperative set­
ting for smaller resectable tumors with adverse prognostic features.
Induction Chemotherapy  In this strategy, patients receive che­
motherapy (current standard is a three-drug regimen of docetaxel,
cisplatin, and fluorouracil [5-FU]) before surgery and radiation
therapy. Most patients who receive three cycles show tumor reduc­
tion, and the response is clinically “complete” in up to half of
patients. This “sequential” multimodality therapy allows for organ
preservation in patients with laryngeal and hypopharyngeal cancer
and results in higher cure rates compared with radiotherapy alone.
Concomitant Chemoradiotherapy  With the concomitant strategy,
chemotherapy and radiation therapy are given simultaneously
rather than in sequence. Tumor recurrences from head and neck
cancer develop most commonly locoregionally (in the head and
neck area of the primary and draining lymph nodes). The concomi­
tant approach is aimed at enhancing tumor cell killing by radiation
therapy in the presence of chemotherapy (radiation enhancement)
and is a conceptually attractive approach for bulky tumors. Toxicity
(especially mucositis, grade 3 or 4, in 70–80%) is increased with
concomitant chemoradiotherapy. However, meta-analyses of ran­
domized trials document an improvement in 5-year survival of 8%
with concomitant chemotherapy and radiation therapy. Cisplatin
is preferentially given weekly during a course of daily radiotherapy
over a 6- to 7-week course. In addition, concomitant chemoradio­
therapy produces better laryngectomy-free survival (organ pres­
ervation) than radiation therapy alone in patients with advanced
larynx cancer. For patients with advanced nasopharyngeal cancer,
the addition of neoadjuvant chemotherapy before concomitant
chemoradiotherapy has been adopted as standard of care leading
to 5-year survival rates exceeding 80% in a Southeast Asian study.
The outcome of HPV-related cancers also seems to be favorable
following cisplatin-based chemoradiotherapy. However, trials sub­
stituting cisplatin with the EGFR inhibitor cetuximab in that patient
population have shown inferior survival. Similarly, the investigation
of immune checkpoint inhibitors in this setting has not yet led to
improved outcomes.
The success of concomitant chemoradiotherapy in patients with
unresectable disease has led to the testing of a similar approach in
patients with resected intermediate-stage disease as a postopera­
tive therapy. Concomitant chemoradiotherapy produces a signifi­
cant improvement over postoperative radiation therapy alone for
patients whose tumors demonstrate higher risk features, such as
extracapsular spread beyond involved lymph nodes, involvement
of multiple lymph nodes, or positive margins at the primary site
following surgery.
CHAPTER 82
A monoclonal antibody to EGFR (cetuximab) increases sur­
vival rates when administered during radiotherapy compared with
radiotherapy alone and has been considered for patients unable to
tolerate concurrent chemoradiotherapy. The addition of cetuximab
to standard chemoradiotherapy regimens has failed to show further
improvement in survival and is not recommended.
Head and Neck Cancer
TREATMENT APPROACHES FOR HPV-RELATED HEAD AND
NECK CANCERS
Given consistent observations of high survival rates for patients
with advanced HPV-related oropharyngeal tumors using combinedmodality treatment strategies, de-escalation protocols have attracted
widespread interest. The goal here is to decrease the long-term
morbidity resulting from high-dose radiation therapy, including
extensive neck fibrosis, swallowing problems, and osteoradione­
crosis of the jaw. Current studies are investigating the use of lower
radiation doses, the use of induction chemotherapy and subse­
quent omission of chemotherapy or administration of significantly
reduced chemoradiation doses in very good responders, and other
strategies. In addition, interest has increased in surgical approaches
using robotic surgery, which allows better visualization of the base
of tongue and tonsil. While technically feasible, a large number
of patients with disease involving multiple lymph nodes will still
require postoperative chemoradiotherapy, thus negating the goal
of treatment de-escalation. At present, treatment guidelines for
HPV-related tumors are identical to carcinogen-induced tumors. It
is hoped that de-escalation approaches will be validated by ongoing
controlled clinical trials.
RECURRENT AND/OR METASTATIC DISEASE
Five to 10% of patients present with metastatic disease, and 30–50% of
patients with locoregionally advanced disease experience recurrence,
frequently outside the head and neck region. Patients with recurrent
and/or metastatic disease are, with few exceptions, treated with pal­
liative intent. Some patients may require local or regional radiation
therapy for pain control, but most are given systemic therapy.
Combination chemotherapy formerly was the first-line systemic
therapeutic approach to patients with recurrent disease after prior
curative intent surgery and/or chemoradiotherapy or those present­
ing initially with metastatic disease. In particular, a combination of
cisplatin with 5-FU and cetuximab (the EXTREME regimen) was
frequently used.

12 - 83 Neoplasms of the Lung
83 Neoplasms of the Lung
However, immunotherapies have proven to be of value in this
setting. In particular, inhibitors of the immunosuppressive lym­
phocyte surface receptor (PD-1) pathway have shown activity in
squamous cell cancers of the head and neck. A randomized trial
evaluating the PD-1 inhibitor nivolumab versus traditional chemo­
therapy in the second-line treatment of patients with recurrent or
metastatic disease showed a significant increase in 1-year survival
rates with fewer severe treatment-related toxicities. In addition,
some responses were of long duration, allowing a cohort of patients
to live far beyond the historical median of <1 year. The PD-1
inhibitor pembrolizumab also demonstrated activity in a similarly
designed randomized trial.
Pembrolizumab was also compared as single-agent therapy and
in combination with cisplatin and 5-FU with prior standard chemo­
therapy alone (cisplatin, 5-FU, and cetuximab). In this trial, overall
survival was improved with pembrolizumab versus chemotherapy
as well as with the combination of chemotherapy plus pembroli­
zumab with the relative benefit correlating with the expression of
PD-L1 in the tumor tissue. Patients with tumors high in expres­
sion (PD-L1 score >20%; i.e., expression of PD-L1 on 20% of
tumor cells) had a marked survival benefit with pembrolizumab
as single agent, whereas patients with lower PD-L1 expression had
a less impressive but still statistically significant survival benefit.
For the group expressing lower levels of PD-L1, the combination
of pembrolizumab with chemotherapy showed more substantial
benefit. Current standard treatment therefore frequently consists
of combination chemoimmunotherapy for patients with low PD-L1
expression, whereas those with higher expression can be treated
with immunotherapy alone, especially if overall tumor burden is
limited. Patients with no PD-L1 expression may still be treated
with the prior EXTREME chemotherapy standard. Patients who
experience progression after first-line chemoimmunotherapy or
immunotherapy can then be treated with additional single-agent or
combination chemotherapy.
PART 4
Oncology and Hematology
EGFR-directed therapies, including monoclonal antibodies (e.g.,
cetuximab) and tyrosine kinase inhibitors (TKIs) of the EGFR sig­
naling pathway (e.g., erlotinib or gefitinib), have single-agent activity
of ∼10%. Side effects are usually limited to an acneiform rash and
diarrhea (for the TKIs). Drugs targeting specific mutations are under
investigation, and patients with HRAS-driven tumors can experience
shrinkage with the farnesyltransferase inhibitor tipifarnib.
COMPLICATIONS
Complications from treatment of head and neck cancer are usually
correlated to the extent of surgery and exposure of normal tissue
structures to radiation. The extent of surgery can be limited or
surgery can be completely replaced by use of chemotherapy and
radiation therapy as the primary approach. Acute complications of
radiation include mucositis and dysphagia. Long-term complica­
tions include xerostomia, loss of taste, decreased tongue mobility,
second malignancies, dysphagia, and neck fibrosis. The compli­
cations of chemotherapy vary with the regimen used but usually
include myelosuppression, mucositis, nausea and vomiting, and
nephrotoxicity (with cisplatin).
The mucosal side effects of therapy can lead to malnutrition
and dehydration. Many centers address issues of dentition before
starting treatment, and some place feeding tubes to ensure control
of hydration and nutrition intake. About 50% of patients develop
hypothyroidism from the treatment; thus, thyroid function should
be monitored.
■
■SALIVARY GLAND TUMORS
Most benign salivary gland tumors are treated with surgical excision,
and patients with invasive salivary gland tumors are treated with
surgery and radiation therapy. These tumors may recur regionally;
adenoid cystic carcinoma has a tendency to recur along the nerve
tracks. Distant metastases may occur as late as 10–20 years after the
initial diagnosis. For metastatic disease, therapy is given with pallia­
tive intent, usually chemotherapy with doxorubicin and/or a platinum
agent by itself or in combination with a taxane. Identification of novel
agents with activity in these tumors is a high priority. It is hoped that
comprehensive genomic characterization of these rare tumors will
facilitate these efforts.
■
■FURTHER READING
Agrawal N et al: Exome sequencing of head and neck squamous
cell carcinoma reveals inactivating mutations in NOTCH1. Science
333:1154, 2011.
Burtness B et al: Pembrolizumab alone or with chemotherapy for
recurrent/metastatic head and neck squamous cell carcinoma in
KEYNOTE-048: Subgroup analysis by programmed death ligand-1
combined positive score. J Clin Oncol 40:2321, 2022.
Chan KCA et al: Analysis of plasma Epstein-Barr virus DNA to screen
for nasopharyngeal cancer. N Engl J Med 377:513, 2017.
D’Cruz AK et al: Elective versus therapeutic neck dissection in nodenegative oral cancer. N Engl J Med 373:521, 2015.
Ho AL et al: Tipifarnib in head and neck squamous cell carcinoma with
HRAS mutations. J Clin Oncol 39:1856, 2021.
Kang H et al: Whole-exome sequencing of salivary gland mucoepider­
moid carcinoma. Clin Cancer Res 23:283, 2017.
Lechner M et al: HPV-associated oropharyngeal cancer: Epidemiology,
molecular biology and clinical management. Nat Rev Clin Oncol
19:306, 2022.
Mehanna H et al: De-escalation after DE-ESCALATE and RTOG
1016: A Head and Neck Cancer Intergroup framework for future deescalation studies. J Clin Oncol 38:2552, 2020.
Mody MD et al: Head and neck cancer. Lancet 398:2289, 2021.
Zhang Y et al: Final overall survival analysis of gemcitabine and cisplatin
induction chemotherapy in nasopharyngeal carcinoma: A multicenter,
randomized phase III trial. J Clin Oncol 40:2420, 2022.
Eric K. Singhi, Christine M. Lovly
Neoplasms of the Lung
Over 2.2 million people globally were diagnosed with lung cancer
in 2020, ranking it as the second most frequently diagnosed cancer.
Although maintaining its status as the leading cause of cancer-related
deaths worldwide, claiming 1.8 million lives in the same year, a note­
worthy decline in lung cancer fatalities has emerged. This shift is
credited to advancements in screening and early detection methods,
improved therapeutic strategies, and a reduction in tobacco usage.
Tobacco consumption, established as the primary cause of lung
cancer in the mid-twentieth century, was solidified with the U.S. Sur­
geon General’s 1964 report on the health effects of tobacco smoking.
After the report, cigarette use declined in North America and parts
of Europe, and with it, so did the incidence of lung cancer. Although
tobacco smoking remains the leading global cause of lung cancer,
accounting for about two-thirds of lung cancer deaths worldwide,
~65% of new lung cancer diagnoses in the United States are in indi­
viduals with a former smoking history (smoked ≥100 cigarettes per
lifetime, quit ≥1 year) or individuals with no smoking history (smoked
<100 cigarettes per lifetime), with one in five women and one in 12 men
diagnosed having never smoked.
EPIDEMIOLOGY
Lung cancer is the most common cause of cancer death among
American men and women. Approximately 235,000 individuals will be
diagnosed with lung cancer in the United States in 2024, and >125,000
individuals will die from the disease. Lung cancer is less common
below age 40, with rates increasing until age 80, after which the rate
tapers off. The projected lifetime probability of developing lung cancer
is estimated at 1 in 16 for males and 1 in 17 for females as of 2023. Since
2006, there has been a steady decline in the incidence of lung cancer,
with an annual decrease of 2.5% in men and 1% in women. Despite this
positive trend, disparities persist. The incidence of lung cancer varies
among racial and ethnic groups, with African Americans exhibiting the
highest age-adjusted rates.
While the excess in age-adjusted rates among African Americans
occurs only among men, examination of age-specific rates shows
that below age 50, mortality from lung cancer is >25% higher among
African-American women compared to their Caucasian counterparts.
Additionally, African Americans face a 19% lower likelihood of receiv­
ing definitive surgical treatment, 11% higher likelihood of not receiv­
ing any treatment, and a 16% lower likelihood of surviving 5 years
compared to their Caucasian counterparts. Incidence and mortality
rates among Hispanics and Native and Asian Americans are ∼40–50%
of those among Caucasians. Consideration of these disparities prompts
reflection on potential equitable improvements in lung cancer care.
■
■RISK FACTORS
Persons who smoke have a 10-fold or greater increased risk of develop­
ing lung cancer compared to those who have never smoked. A largescale genomic study suggested that one genetic mutation is induced for
every 15 cigarettes smoked. The risk of lung cancer is lower among per­
sons who quit smoking than among those who continue smoking. The
size of the lung cancer risk reduction increases with the length of time
the person has quit smoking, although even long-term former smok­
ers have higher risks of lung cancer than those who never smoked.
Cigarette smoking has been shown to increase the risk of all major
types of lung cancer. Environmental tobacco smoke (ETS) or secondhand smoke is also an established cause of lung cancer. The risk from
ETS is less than from active smoking, with about a 20–30% increase in
lung cancer observed among never smokers married for many years
to smokers, in comparison to the 2000% increase among continuing
active smokers. The impact on the development of lung cancer among
users of alternate nicotine delivery devices (e-cigarettes or vaping) is
undefined. While one large, randomized study demonstrated the supe­
riority of e-cigarettes compared to traditional nicotine replacement
therapy in aiding smoking cessation, e-cigarette– or vaping-associated
lung injury (EVALI) is an emerging phenomenon that poses risks that
may counterbalance the potential benefit in helping patients reduce
traditional cigarette consumption and lung cancer risk.
Although cigarette smoking is the cause of the majority of lung
cancers, several other risk factors have been identified, including
occupational exposure to asbestos, arsenic, bischloromethyl ether,
hexavalent chromium, mustard gas, nickel (as in certain nickel-refining
processes), and polycyclic aromatic hydrocarbons.
Ionizing radiation is also an established lung carcinogen, most con­
vincingly demonstrated from studies showing increased rates of lung
cancer among survivors of the atom bombs dropped on Hiroshima
and Nagasaki and large excesses among workers exposed to alpha
irradiation from radon in underground uranium mining. Prolonged
exposure to low-level radon in homes might impart a risk of lung
cancer equal to or greater than that of ETS. Prior lung diseases such as
chronic bronchitis, emphysema, and tuberculosis have been linked to
increased risks of lung cancer as well. The risk of lung cancer appears to
be higher among individuals with low fruit and vegetable intake during
adulthood. This observation led to hypotheses that specific nutrients,
in particular retinoids and carotenoids, might have chemopreventative
effects for lung cancer. However, randomized trials failed to validate
this hypothesis.
Smoking Cessation 
Given the undeniable link between cigarette
smoking and lung cancer, physicians must promote complete tobacco
avoidance. Stopping tobacco use before middle age avoids >90% of the
lung cancer risk attributable to tobacco. Importantly, smoking cessa­
tion can even be beneficial in individuals with an established diagnosis
of lung cancer, as it is associated with improved overall survival, fewer
side effects from therapy, and an overall improvement in quality of life.
Consequently, it is important to promote smoking cessation even after
the diagnosis of lung cancer is established. This remains a challenge as
~30% of patients continue to smoke even after receiving a diagnosis of
lung cancer.
Physicians need to understand the essential elements of smoking
cessation therapy. Self-help strategies alone only marginally affect quit
rates, whereas individual and combined pharmacotherapies in com­
bination with counseling can significantly increase rates of cessation.
Therapy with an antidepressant (e.g., bupropion) and nicotine replace­
ment therapy (varenicline, a α4β2 nicotinic acetylcholine receptor par­
tial agonist) are approved by the U.S. Food and Drug Administration
(FDA) as first-line treatments for nicotine dependence. In a random­
ized trial, varenicline was shown to be more efficacious than bupropion
or placebo. Prolonged use of varenicline beyond the initial induction
phase proved useful in maintaining smoking abstinence. Clonidine and
nortriptyline are recommended as second-line treatments. A role for
e-cigarettes has not been definitively established (Chap. 465).
Inherited Predisposition to Lung Cancer 
Exposure to envi­
ronmental carcinogens, such as those found in tobacco smoke,
induces or facilitates the transformation from bronchoepithelial cells
to a malignant phenotype. The contribution of carcinogens to trans­
formation is modulated by polymorphic variations in genes that affect
aspects of carcinogen metabolism. Certain genetic polymorphisms of
the P450 enzyme system, specifically CYP1A1, and chromosome fra­
gility are associated with the development of lung cancer. These genetic
variations occur at relatively high frequency in the population, but
their contribution to an individual’s lung cancer risk is generally low.
However, because of their population frequency, the overall impact on
lung cancer risk could be high.
CHAPTER 83
Neoplasms of the Lung
First-degree relatives of lung cancer probands have a two- to three­
fold excess risk of lung cancer and other cancers, many of which are not
smoking-related. These data suggest that specific genes and/or genetic
variants may contribute to susceptibility to lung cancer. However, very
few such genes have yet been identified. Individuals with inherited
mutations in RB (patients with retinoblastoma living to adulthood)
and TP53 (patients with Li-Fraumeni syndrome) genes may develop
lung cancer. Common gene variants involved in lung cancer have
identified three separate loci that are associated with lung cancer
(5p15, 6p21, and 15q25) and include genes that regulate acetylcholine
nicotinic receptors and telomerase production. A rare germline muta­
tion (T790M) involving the epidermal growth factor receptor (EGFR)
maybe be linked to lung cancer susceptibility in never smokers. Like­
wise, a susceptibility locus on chromosome 6q greatly increases lung
cancer risk among light and never smokers. A study involving 7700
patients diagnosed with primary lung cancer who underwent germ­
line DNA sequencing and exon-level copy number analysis revealed
that 14.9% of them had one or more clinically significant pathogenic
germline variants; these variants were mainly found in DNA damage
repair genes, suggesting a higher prevalence of pathogenic germline
mutations in patients with primary lung cancer than previously sus­
pected. Additionally, the Taiwan National Lung Cancer Early Detection
Program, launched in July 2022, provided screening for nonsmoker
patients with a positive family history of lung cancer in their firstdegree relatives; this program demonstrated a 1.4% cancer detection
rate among individuals with a family history of lung cancer. Despite
this progress in identifying heritable risk factors for lung cancer, there
is still significant work to be done. Currently, no molecular criteria are
suitable for selecting patients for more intense screening programs or
specific chemopreventive strategies.
■
■PATHOLOGY
The World Health Organization (WHO) defines lung cancer as tumors
arising from the respiratory epithelium (bronchi, bronchioles, and
alveoli). The WHO classification system divides epithelial lung cancers
into four major cell types: small-cell lung cancer (SCLC), adenocar­
cinoma, squamous cell carcinoma, and large-cell carcinoma; the lat­
ter three types are collectively known as non-small-cell carcinomas
(NSCLCs) (Fig. 83-1). Small-cell carcinomas consist of small cells
with scant cytoplasm, ill-defined cell borders, finely granular nuclear
Non-Small-Cell Lung Cancer
Squamous cell
Adenocarcinoma
Large-cell carcinoma
Adenocarcinoma
Squamous
Large
Small
Small-Cell Lung Cancer
FIGURE 83-1  Histologic subsets of lung cancer.
chromatin, absent or inconspicuous nucleoli, and a high mitotic count.
SCLC may be distinguished from NSCLC by the presence of neuro­
endocrine markers including CD56, neural cell adhesion molecule
(NCAM), synaptophysin, chromogranin, and insulinoma-associated
protein 1 (INSM1). Adenocarcinomas possess glandular differentiation
or mucin production and may show acinar, papillary, lepidic, or solid
features or a mixture of these patterns. Squamous cell carcinomas of
the lung are morphologically identical to extrapulmonary squamous
cell carcinomas and cannot be distinguished by immunohistochemis­
try alone. Squamous cell tumors show keratinization and/or intercel­
lular bridges that arise from bronchial epithelium. The tumor consists
of sheets of cells rather than the three-dimensional groups of cells
characteristic of adenocarcinomas. Large-cell carcinomas compose
<10% of lung carcinomas. These tumors lack the cytologic and archi­
tectural features of small-cell carcinoma and glandular or squamous
differentiation. Together, these four histologic types account for ∼90%
of all epithelial lung cancers.
PART 4
Oncology and Hematology
All histologic types of lung cancer can develop in current and former
smokers, although squamous and small-cell carcinomas are more com­
monly associated with tobacco use. With the decline in cigarette con­
sumption, adenocarcinoma has become the most frequent histologic
subtype of lung cancer in the United States. In lifetime, never smokers
or former light smokers (<10 pack-year history), women, and younger
adults (<60 years), adenocarcinoma tends to be the most common
form of lung cancer.
In addition to distinguishing between SCLC and NSCLC, because
these tumors have quite different natural histories and therapeutic
approaches (see below), it is necessary to classify whether NSCLC
is squamous or nonsquamous. The classification system, developed
jointly by the International Association for the Study of Lung Cancer,
the American Thoracic Society, and the European Respiratory Society,
provides an integrated approach to the classification of lung adenocar­
cinoma that includes clinical, molecular, radiographic, and pathologic
information.
Even with advances in lung cancer screening and early detection,
many lung cancers are still detected in an advanced stage and may be
diagnosed based on small biopsies or cytologic specimens, rendering
clear histologic distinctions difficult. In such cases, particularly in
patients with advanced-stage disease, a repeat biopsy is recommended
to obtain additional tissue for further clarification. The distinction
between squamous and nonsquamous lung cancer is viewed as criti­
cal to optimal therapeutic decision-making, and a diagnosis of nonsmall-cell carcinoma, not otherwise specified is no longer considered
acceptable. This distinction can be achieved using a single marker for
adenocarcinoma (thyroid transcription factor-1 or napsin-A) plus a
squamous marker (p40 or p63) and/or mucin stains. If tissue is limited
and a clear morphologic pattern is evident, a diagnosis can be made
without immunohistochemistry staining. In addition to determining
histologic subtype, preservation of sufficient specimen material for
appropriate molecular testing and programmed death ligand 1 (PD-L1)
testing necessary to help guide therapeutic decision-making is recom­
mended (see below).
The terms adenocarcinoma in situ and minimally invasive adeno­
carcinoma are now recommended for small solitary adenocarcinomas
(≤3 cm) with either pure lepidic growth (term used to describe singlelayered growth of atypical cuboidal cells coating the alveolar walls)
or predominant lepidic growth with ≤5 mm invasion. Individuals
with these entities experience 100% or near 100% 5-year disease-free
survival with complete tumor resection. Invasive adenocarcinomas,
representing >70–90% of surgically resected lung adenocarcinomas,
are now classified by their predominant pattern: lepidic, acinar, papil­
lary, and solid patterns. In general, lepidic-predominant subtype has a
favorable prognosis, acinar and papillary have an intermediate progno­
sis, and solid-predominant has a poor prognosis. The terms signet ring
and clear cell adenocarcinoma have been eliminated from the variants
of invasive lung adenocarcinoma, whereas the term micropapillary, a
subtype with a particularly poor prognosis, has been added. Because of
prognostic implications, squamous cell carcinoma has also been modi­
fied to consist of keratinizing, nonkeratinizing, and basaloid, analogous
to head and neck cancers.
■
■IMMUNOHISTOCHEMISTRY
The diagnosis of lung cancer most often rests on the morphologic or
cytologic features correlated with clinical and radiographic findings.
Immunohistochemistry may be used to verify neuroendocrine differ­
entiation within a tumor, with markers such as neuron-specific enolase
(NSE), CD56 or NCAM, synaptophysin, chromogranin, and Leu7.
Immunohistochemistry is also helpful in differentiating primary from
metastatic adenocarcinomas; thyroid transcription factor-1 (TTF-1),
identified in tumors of thyroid and pulmonary origin, is positive in
70% of pulmonary adenocarcinomas and is a reliable indicator of pri­
mary lung cancer, provided a thyroid primary has been excluded. A nega­
tive TTF-1, however, does not exclude the possibility of a lung primary.
TTF-1 is also positive in neuroendocrine tumors of pulmonary and
extrapulmonary origin. Napsin-A (Nap-A) is an aspartic protease that
plays an important role in maturation of surfactant B7 and is expressed
in cytoplasm of type II pneumocytes. In several studies, Nap-A has
been reported in >90% of primary lung adenocarcinomas. Notably, a
combination of Nap-A and TTF-1 is useful in distinguishing primary
lung adenocarcinoma (Nap-A positive, TTF-1 positive) from primary
lung squamous cell carcinoma (Nap-A negative, TTF-1 negative) and
primary SCLC (Nap-A negative, TTF-1 positive). Cytokeratins (CK) 7
and 20 used in combination can help narrow the differential diagnosis;
nonsquamous NSCLC, SCLC, and mesothelioma may stain positive
for CK7 and negative for CK20, whereas squamous cell lung cancer
often will be both CK7 and CK20 negative. p63 is a useful marker for
the detection of NSCLCs with squamous differentiation when used in
cytologic pulmonary samples. Mesothelioma can be easily identified
ultrastructurally, but it has historically been difficult to differentiate
from adenocarcinoma through morphology and immunohistochemi­
cal staining. Several markers in the past few years have proven to be
more helpful including CK5/6, calretinin, and Wilms tumor gene-1
(WT-1), all of which show positivity in mesothelioma.
■
■MOLECULAR PATHOGENESIS
As proposed by Hanahan and Weinberg, virtually all cancer cells
acquire six hallmark capabilities: self-sufficiency in growth signals,
insensitivity to antigrowth signals, evading apoptosis, limitless replica­
tive potential, sustained angiogenesis, and tissue invasion and metas­
tasis. The order in which these hallmark capabilities are acquired is
variable. Events leading to acquisition of these hallmarks vary widely,
although broadly, cancers arise as a result of accumulations of gain-offunction mutations in oncogenes and loss-of-function mutations in
tumor-suppressor genes. Further complicating the study of lung cancer,
the sequence of events that leads to disease is clearly different for the
various histopathologic entities.
For cancers in general, one theory holds that a
small subset of the cells within a tumor (i.e., “stem
cells”) are responsible for the full malignant behavior
of the tumor. As part of this concept, the large bulk
of the cells in a cancer are “offspring” of these cancer
stem cells. While clonally related to the cancer stem
cell subpopulation, most cells by themselves cannot
regenerate the full malignant phenotype. The stem
cell concept may explain the failure of standard medi­
cal therapies to eradicate lung cancers, even when
there is a clinical complete response. Disease recurs
because therapies do not eliminate the stem cell
component, which may be more resistant to therapy.
Precise human lung cancer stem cells have yet to be
identified.
Among lung cancer histologies, adenocarcinomas
have been the most extensively catalogued for recur­
rent genomic gains and losses as well as for somatic
mutations (Fig. 83-2, Table 83-1). While multiple dif­
ferent kinds of aberrations have been found, a major
class involves “driver mutations,” which are mutations
that occur in genes encoding signaling proteins that,
when aberrant, drive initiation and maintenance of
tumor cells. Importantly, driver mutations can serve
as a potential Achilles’ heels for tumors, if their gene
products can be targeted appropriately. Several driver
oncogenes have been described in NSCLC. These
include activating mutations in receptor tyrosine
kinases, including EGFR, ERBB2/HER2, and MET,
and activating mutations in intracellular signaling
proteins, such as KRAS and BRAF. Additionally,
chromosomal rearrangements may also produce
driver oncogenes in lung tumors, such as those chromosomal rear­
rangements leading to activation of the ALK, ROS1, RET, and NTRK
tyrosine kinases. Each of these so-called “driver oncogenes” represents
a distinct molecular cohort of lung cancer, with differing prevalence
and varying levels of evidence regarding clinical actionability. So-called
“targeted therapies” directed against these aberrantly activated onco­
genes are discussed below. It is worth noting that most of these driver
oncogenes are enriched in nonsquamous tumors.
ROS1
RET
MEK1
NRAS
NTRK1
PIK3CA
FIGURE 83-2  Driver mutations in lung adenocarcinomas.
Three potential molecular targets have been identified in squamous
cell lung carcinomas: FGFR1 amplification, DDR2 mutations, and
PIK3CA mutations/PTEN loss, as well as BRAF and MET (Table 83-1).
A large number of tumor-suppressor genes have also been identi­
fied that are inactivated during the pathogenesis of lung cancer. These
include TP53, RB1, RASSF1A, CDKN2A/B, LKB1 (STK11), and FHIT.
Nearly 90% of SCLCs harbor mutations in TP53 and RB1. Several
tumor-suppressor genes on chromosome 3p appear to be involved in
nearly all lung cancers. Allelic loss of this region occurs very early in
lung cancer pathogenesis, including in histologically normal smokingdamaged lung epithelium.
EARLY DETECTION AND SCREENING
In lung cancer, clinical outcome is related to the stage at diagnosis, and
hence, it is generally assumed that early detection of occult tumors will
lead to improved survival. Early detection is a process that involves
screening tests, surveillance, diagnosis, and early treatment. Screening
refers to the use of tests across a healthy population in order to identify
individuals who harbor asymptomatic disease. For a screening pro­
gram to be successful, the target population must be a high-risk popu­
lation; the test must be sensitive, specific, accessible, and cost effective;
and effective treatment must be available that can reduce mortality.
With any screening procedure, it is important to consider the pos­
sible influence of lead-time bias (detecting the cancer earlier without
an effect on survival), length-time bias (indolent cancers are detected
on screening and may not affect survival, whereas aggressive cancers
are likely to cause symptoms earlier in patients and are less likely to be
detected), and overdiagnosis (diagnosing cancers so slow growing that
they are unlikely to cause the death of the patient).
AKT1
BRAF
ALK
AKT1
ALK
BRAF
EGFR
EGFR
HER2
Unknown
KRAS
MEK1
HER2
MET
NRAS
NTRK1
PIK3CA
KRAS
RET
CHAPTER 83
ROS1
Unknown
MET
Neoplasms of the Lung
Because a majority of lung cancer patients present with advanced
disease beyond the scope of surgical resection, the value of screening
for this condition is debated. Indeed, randomized controlled trials
conducted in the 1960s to 1980s using screening chest x-rays (CXR),
with or without sputum cytology, reported no impact on lung can­
cer–specific mortality in patients characterized as high risk (males age
≥45 years with a smoking history). These studies have been criticized
for their design, statistical analyses, and outdated imaging modalities.
In contrast to CXR, low-dose, noncontrast, thin-slice spiral chest com­
puted tomography (LDCT) has emerged as an effective tool to screen
for lung cancer. In nonrandomized studies conducted in the 1990s,
LDCT scans were shown to detect more lung nodules and cancers than
standard CXR in selected high-risk populations (e.g., age ≥60 years and
a smoking history of ≥10 pack-years). Notably, up to 85% of the lung
cancers discovered in these trials were classified as stage I disease and
therefore considered potentially curable with surgical resection.
These data prompted the National Cancer Institute (NCI) to initi­
ate the National Lung Screening Trial (NLST), a randomized study
designed to determine if LDCT screening could reduce mortality
TABLE 83-1  Genetic Alterations with Existing Therapies in Non-SmallCell Lung Cancer (NSCLC)
FREQUENCY IN
NSCLC
TYPICAL HISTOLOGY
GENE
ALTERATION
ALK
Rearrangement
3–7%
Adenocarcinoma
BRAF
Mutation
1–3%
Adenocarcinoma
EGFR
Mutation
10–35%
Adenocarcinoma
HER2
Mutation
2–4%
Adenocarcinoma
KRAS
Mutation
15–25%
Adenocarcinoma
MET
Amplification
2–4%
Adenocarcinoma
NRAS
Mutation
1%
Adenocarcinoma
NTRK
Rearrangement
1–2%
Adenocarcinoma
RET
Rearrangement
1–2%
Adenocarcinoma
ROS1
Rearrangement
1–2%
Adenocarcinoma
from lung cancer in high-risk populations as compared with standard
posterior anterior CXR. High-risk patients were defined as individuals
between 55 and 74 years of age with a ≥30 pack-year history of cigarette
smoking; former smokers must have quit within the previous 15 years.
Excluded from the trial were individuals with a previous lung cancer
diagnosis, a history of hemoptysis, an unexplained weight loss of >15 lb
in the preceding year, or a chest computed tomography (CT) within
18 months of enrollment. A total of 53,454 persons were enrolled and
randomized to annual screening yearly for 3 years (LDCT screening,
n = 26,722; CXR screening, n = 26,732). Any noncalcified nodule
measuring ≥4 mm in any diameter found on LDCT and CXR images
with any noncalcified nodule or mass was classified as “positive.”
Participating radiologists had the option of not calling a final screen
positive if a noncalcified nodule had been stable on the three screening
examinations. Overall, 39.1% of participants in the LDCT group and
16% in the CXR group had at least one positive screening result. Of
those who screened positive, the false-positive rate was 96.4% in the
LDCT group and 94.5% in the CXR group. This was consistent across
all three rounds. In the LDCT group, 1060 cancers were identified
compared with 941 cancers in the CXR group (645 vs 572 per 100,000
person-years; relative risk [RR], 1.13; 95% confidence interval [CI],
1.03–1.23). Nearly twice as many stage IA cancers were detected in
the LDCT group compared with the CXR group (40% vs 21%). The
overall rates of lung cancer death were 247 and 309 deaths per 100,000
participants in the LDCT and CXR groups, respectively, representing a
20% reduction in lung cancer mortality in the LDCT-screened popula­
tion (95% CI, 6.8–26.7%; p = .004). Compared with the CXR group, the
rate of death in the LDCT group from any cause was reduced by 6.7%
(95% CI, 1.2–13.6%; p = .02). The number needed to screen (NNTS) to
prevent one lung cancer death was calculated to be 320.
PART 4
Oncology and Hematology
The Nelson study was a second randomized trial comparing no
screening to CT scans at baseline and in years 1, 3, and 5.5 in 13,195
men and 2594 women. Participants were 50–75 years of age and were
current and former smokers with 10 years or less of cessation who
smoked >15 cigarettes a day for >25 years or >10 cigarettes daily for
30 years. Participants were selected from four regions in the Nether­
lands or Belgium and were excluded if they were in moderate or bad
self-reported health, were unable to climb two flights of stairs, had a
body weight >140 kg, had a CT of the chest within the past year or a
history of lung cancer <5 years ago or were still under treatment, or
had current or past renal cell carcinoma, melanoma, or breast cancer.
The hazard ratio for lung cancer mortality at 10 years was 0.74 (95% CI,
0.60–0.91; p = .003) and 0.61 (95% CI, 0.35–1.04; p = .0543) in men and
women, respectively. These two trials have validated the use of annual
CT scans for early detection of lung cancer in high-risk populations.
LDCT screening for lung cancer comes with known risks includ­
ing a high rate of false-positive results, false-negative results, potential
for unnecessary follow-up testing, radiation exposure, overdiagnosis,
changes in anxiety level and quality of life, and substantial financial
costs. One of the greatest challenges confronting the use of CT screen­
ing, in addition to its implementation, is the high false-positive rate.
False positives can have a substantial impact on patients through the
expense and risk of unneeded further evaluation and emotional stress.
The management of these patients usually consists of serial CT scans
over time to see if the nodules grow, attempted fine-needle aspirates,
or surgical resection. At approximately $300 per scan (NCI estimated
cost), the outlay for initial LDCT alone could run into the billions of
dollars annually, an expense that only further escalates when factoring
in various downstream expenditures an individual might incur in the
assessment of positive findings. A formal cost-effectiveness analysis
of the NLST demonstrated differences between sex, age, and current
smoking status and the method of follow-up. Despite some questions,
annual LDCT screening has been recommended for all patients meet­
ing the following updated criteria from the U.S. Preventive Services
Task Force as of 2021: individuals aged 50–80 years old with a 20-packyear or greater smoking history who currently smoke or formerly
smoked within the past 15 years. When discussing the option of LDCT
screening, use of absolute risks rather than relative risks is helpful
because studies indicate the public can process absolute terminology
TABLE 83-2  The Benefits and Harms of LDCT Screening for Lung
Cancer Based on NLST Data
 
LDCT
CXR
Benefits: How did CT scans help compared to CXR?
4 in 1000 fewer died from lung cancer
13 in 1000
17 in 1000
5 in 1000 fewer died from all causes
70 in 1000
75 in 1000
Harms: What problems did CT scans cause compared to CXR?
223 in 1000 had at least 1 false alarm
365 in 1000
142 in 1000
18 in 1000 had a false alarm leading to an
invasive procedure
25 in 1000
7 in 1000
2 in 1000 had a major complication from
an invasive procedure
3 in 1000
1 in 1000
Abbreviations: CT, computed tomography; CXR, chest x-ray; LDCT, low-dose
computed tomography; NLST, National Lung Screening Trial.
Source: From S Woloshin: Cancer screening campaigns getting past uninformative
persuasion. N Engl J Med 367:1167, 2012. Copyright © (2012) Massachusetts
Medical Society. Reprinted with permission from Massachusetts Medical Society.
more effectively than relative risk projections. A useful guide has been
developed by the NCI to help patients and physicians assess the ben­
efits and harms of LDCT screening for lung cancer (Table 83-2).
CLINICAL MANIFESTATIONS
Over half of all patients diagnosed with lung cancer present with locally
advanced or metastatic disease at the time of diagnosis. The majority
of patients present with signs, symptoms, or laboratory abnormalities
that can be attributed to the primary lesion, local tumor growth, inva­
sion or obstruction of adjacent structures, growth at distant metastatic
sites, or a paraneoplastic syndrome (Tables 83-3 and 83-4). A history
of chronic cough with or without hemoptysis in a current or former
smoker with chronic obstructive pulmonary disease (COPD) age 40 years
or older should prompt a thorough investigation for lung cancer even
in the face of a normal CXR. A persistent pneumonia without consti­
tutional symptoms and unresponsive to repeated courses of antibiotics
also should prompt an evaluation for the underlying cause. Lung can­
cer occurring in individuals who have never smoked is more prevalent
in, though not limited to, women and East Asians. These patients also
typically present at a younger age than their smoking counterparts at
the time of diagnosis. The clinical presentation of lung cancer in never
smokers tends to mirror that of current and former smokers.
Patients with central or endobronchial growth of the primary tumor
may present with cough, hemoptysis, wheeze, stridor, dyspnea, or
postobstructive pneumonia. Peripheral growth of the primary tumor
may cause pain from pleural or chest wall involvement, dyspnea on a
restrictive basis, and symptoms of a lung abscess resulting from tumor
TABLE 83-3  Presenting Signs and Symptoms of Lung Cancer
SYMPTOM AND SIGNS
RANGE OF FREQUENCY
Cough
8–75%
Weight loss
0–68%
Dyspnea
3–60%
Chest pain
20–49%
Hemoptysis
6–35%
Bone pain
6–25%
Clubbing
0–20%
Fever
0–20%
Weakness
0–10%
Superior vena cava obstruction
0–4%
Dysphagia
0–2%
Wheezing and stridor
0–2%
Source: Reproduced with permission from MA Beckles: Initial evaluation of the
patient with lung cancer. Symptoms, signs, laboratory tests, and paraneoplastic
syndromes. Chest 123:97, 2003.
TABLE 83-4  Clinical Findings Suggestive of Metastatic Disease
Symptoms elicited in
history
• Constitutional: weight loss >10 lb
• Musculoskeletal: pain
• Neurologic: headaches, syncope, seizures, extremity
weakness, recent change in mental status
Signs found on
physical examination
• Lymphadenopathy (>1 cm)
• Hoarseness, superior vena cava syndrome
• Bone tenderness
• Hepatomegaly (>13 cm span)
• Focal neurologic signs, papilledema
• Soft-tissue mass
Routine laboratory
tests
• Hematocrit, <40% in men; <35% in women
• Elevated alkaline phosphatase, GGT, SGOT, and
calcium levels
Abbreviations: GGT, gamma-glutamyltransferase; SGOT, serum glutamic-oxaloacetic
transaminase.
Source: Reproduced with permission from GA Silvestri et al: The noninvasive
staging of non-small cell lung cancer. Chest 123:147S, 2003.
cavitation. Regional spread of tumor in the thorax (by contiguous
growth or by metastasis to regional lymph nodes) may cause tra­
cheal obstruction, esophageal compression with dysphagia, recurrent
laryngeal nerve paralysis with hoarseness, phrenic nerve palsy with
elevation of the hemidiaphragm and dyspnea, and sympathetic nerve
paralysis with Horner’s syndrome (i.e., enophthalmos, ptosis, miosis,
and anhidrosis). Malignant pleural effusions can cause pain, dyspnea,
or cough. Pancoast (or superior sulcus tumor) syndromes result from
local extension of a tumor growing in the apex of the lung with involve­
ment of the eighth cervical and first and second thoracic nerves, and
present with shoulder pain that characteristically radiates in the ulnar
distribution of the arm, often with radiologic destruction of the first
and second ribs. Often Horner’s syndrome and Pancoast syndrome
coexist. Other problems of regional spread include superior vena cava
syndrome from vascular obstruction; pericardial and cardiac extension
with resultant tamponade, arrhythmia, or cardiac failure; lymphatic
obstruction with resultant pleural effusion; and lymphangitic spread
through the lungs with hypoxemia and dyspnea. In addition, lung
cancer can spread transbronchially, producing tumor growth along
multiple alveolar surfaces with impairment of gas exchange, respiratory
insufficiency, dyspnea, hypoxemia, and sputum production. Constitu­
tional symptoms may include anorexia, weight loss, weakness, fever,
and night sweats. These parameters cannot clearly distinguish SCLC
from NSCLC or even from neoplasms metastatic to lungs.
Extrathoracic metastatic disease is found at autopsy in >50% of
patients with squamous carcinoma, 80% of patients with adenocar­
cinoma and large-cell carcinoma, and >95% of patients with SCLC.
Approximately one-third of patients present with symptoms as a result
of distant metastases. Lung cancer metastases may occur in virtually
every organ system, and the site of metastatic involvement largely
determines other symptoms. Patients with brain metastases may pres­
ent with headache, nausea and vomiting, seizures, or neurologic defi­
cits. Patients with bone metastases may present with pain, pathologic
fractures, or spinal cord compression. The latter may also occur with
epidural metastases. Individuals with bone marrow invasion may pres­
ent with cytopenias or leukoerythroblastosis. Those with liver metas­
tases may present with hepatomegaly, right upper quadrant pain, fever,
anorexia, and weight loss. Liver dysfunction and biliary obstruction are
rare. Adrenal metastases are common but rarely cause pain or adrenal
insufficiency unless they are large.
Paraneoplastic syndromes are common in patients with lung cancer,
especially those with SCLC, and may be the presenting finding or the
first sign of recurrence. In addition, paraneoplastic syndromes may
mimic metastatic disease and, unless detected, lead to inappropriate
palliative rather than curative treatment. Often the paraneoplastic
syndrome may be relieved with successful treatment of the tumor. In
some cases, the pathophysiology of the paraneoplastic syndrome is
known, particularly when a hormone with biologic activity is secreted
by a tumor. However, in many cases, the pathophysiology is unknown.
Systemic symptoms of anorexia, cachexia, weight loss (seen in 30% of
patients), fever, and suppressed immunity are paraneoplastic syndromes
of unknown etiology or at least not well defined. Weight loss >10%
of total body weight is considered a bad prognostic sign. Endocrine
syndromes are seen in 12% of patients; hypercalcemia resulting from
ectopic production of parathyroid hormone (PTH) or, more commonly,
PTH-related peptide is the most common life-threatening metabolic
complication of malignancy, primarily occurring with squamous cell
carcinomas of the lung. Clinical symptoms include nausea, vomiting,
abdominal pain, constipation, polyuria, thirst, and altered mental status.
Hyponatremia may be caused by the syndrome of inappropriate
secretion of antidiuretic hormone (SIADH) or possibly atrial natri­
uretic peptide (ANP) (Chap. 98). SIADH resolves within 1–4 weeks
of initiating chemotherapy in the vast majority of cases. During this
period, serum sodium can usually be managed and maintained above
128 mEq/L via fluid restriction. Demeclocycline can be a useful
adjunctive measure when fluid restriction alone is insufficient. Vaso­
pressin receptor antagonists like tolvaptan also have been used in the
management of SIADH. However, the use of tolvaptan has significant
limitations including liver injury and overly rapid correction of the
hyponatremia, which can lead to irreversible neurologic injury. Like­
wise, the cost of tolvaptan may be prohibitive. Of note, patients with
ectopic ANP may have worsening hyponatremia if sodium intake is not
concomitantly increased. Accordingly, if hyponatremia fails to improve
or worsens after 3–4 days of adequate fluid restriction, plasma levels of
ANP should be measured to determine the causative syndrome.
CHAPTER 83
Ectopic secretion of ACTH by SCLC and pulmonary carcinoids
usually results in additional electrolyte disturbances, especially hypo­
kalemia, rather than the changes in body habitus that occur in Cush­
ing’s syndrome from a pituitary adenoma (Chap. 98). Treatment with
standard medications, such as metyrapone and ketoconazole, is largely
ineffective due to extremely high cortisol levels. The most effective
strategy for management of the Cushing’s syndrome is effective treat­
ment of the underlying SCLC. Bilateral adrenalectomy may be consid­
ered in extreme cases.
Neoplasms of the Lung
Skeletal–connective tissue syndromes include clubbing in 30% of
cases (usually NSCLCs) and hypertrophic primary osteoarthropathy
in 1–10% of cases (usually adenocarcinomas). Patients may develop
periostitis, causing pain, tenderness, and swelling over the affected
bones and a positive bone scan. Neurologic–myopathic syndromes
are seen in only 1% of patients but are dramatic and include the myas­
thenic Eaton-Lambert syndrome and retinal blindness with SCLC,
whereas peripheral neuropathies, subacute cerebellar degeneration,
cortical degeneration, and polymyositis are seen with all lung cancer
types. Many of these are caused by autoimmune responses such as
the development of anti-voltage-gated calcium channel antibodies in
Eaton-Lambert syndrome. Patients with this disorder present with
proximal muscle weakness, usually in the lower extremities, occa­
sional autonomic dysfunction, and rarely, cranial nerve symptoms
or involvement of the bulbar or respiratory muscles. Depressed deep
tendon reflexes are frequently present. In contrast to patients with
myasthenia gravis, strength improves with serial effort. Some patients
who respond to chemotherapy will have resolution of the neurologic
abnormalities. Thus, chemotherapy is the initial treatment of choice.
Paraneoplastic encephalomyelitis and sensory neuropathies, cerebellar
degeneration, limbic encephalitis, and brainstem encephalitis occur in
SCLC in association with a variety of antineuronal antibodies such as
anti-Hu, anti-CRMP5, and ANNA-3. Paraneoplastic cerebellar degen­
eration may be associated with anti-Hu, anti-Yo, or P/Q calcium chan­
nel autoantibodies. Coagulation or thrombotic or other hematologic
manifestations occur in 1–8% of patients and include migratory venous
thrombophlebitis (Trousseau’s syndrome), nonbacterial thrombotic
(marantic) endocarditis with arterial emboli, and disseminated intra­
vascular coagulation with hemorrhage, anemia, granulocytosis, and
leukoerythroblastosis. Thrombotic disease complicating cancer is usu­
ally a poor prognostic sign. Cutaneous manifestations such as dermato­
myositis and acanthosis nigricans are uncommon (1%), as are the renal
manifestations of nephrotic syndrome and glomerulonephritis (≤1%).
DIAGNOSING LUNG CANCER
Tissue sampling is required to confirm a diagnosis in all patients with
suspected lung cancer. In patients with suspected metastatic disease, a
biopsy of a distant site of disease is preferred for concurrent tissue and
staging confirmation. Given the greater emphasis placed on molecular
and PD-L1 testing for NSCLC patients, a core biopsy is preferred to
ensure adequate tissue for analysis. Tumor tissue may be obtained via
minimally invasive techniques such as bronchial or transbronchial
biopsy during fiberoptic bronchoscopy, by fine-needle aspiration (FNA)
or percutaneous biopsy using image guidance, or via endobronchial
ultrasound (EBUS)-guided biopsy. Depending on the location, lymph
node sampling may occur via transesophageal endoscopic ultrasound
(EUS)-guided biopsy, EBUS-guided biopsy, or blind biopsy. In patients
with suspected metastatic disease, a diagnosis may be confirmed by
bronchoscopy, percutaneous biopsy of a soft tissue mass, lytic bone
lesion, bone marrow, pleural or liver lesion, or an adequate cell block
obtained from a malignant pleural effusion. In patients with a suspected
malignant pleural effusion, if the initial thoracentesis is negative, repeat
thoracentesis is essential. Although the majority of pleural effusions are
due to malignant disease, particularly if they are exudative or bloody,
some may be parapneumonic. In the absence of distant disease, such
patients should be considered for possible curative treatment.
The diagnostic yield of any biopsy depends on several factors
including location (accessibility) of the tumor, tumor size, tumor type,
and technical aspects of the diagnostic procedure including the experi­
ence level of the bronchoscopist and pathologist. In general, central
lesions such as squamous cell carcinomas, small-cell carcinomas, or
endobronchial lesions such as carcinoid tumors are more readily diag­
nosed by bronchoscopic examination, whereas peripheral lesions such
as adenocarcinomas and large-cell carcinomas are more amenable to
transthoracic biopsy.
PART 4
Oncology and Hematology
Biomarker testing in lung cancer plays an essential role in guiding a
precision-based medicine approach for patient care. Ideally performed
at the time of initial diagnosis, biomarker testing is recommended for
all patients with advanced stage NSCLC by most current guidelines,
with consideration for those with squamous histology. Biomarker test­
ing aims to identify specific genetic alterations, or molecular markers,
within the tumor cells. Traditionally, the gold standard process involves
obtaining a tissue sample from the patient, which is then subjected to
advanced techniques such as next-generation sequencing (NGS) to
complete multigene sequencing. By completing this testing, clinicians
can discern the presence of driver oncogenes to allow for tailored treat­
ment approaches specific to the underlying molecular profile of the
tumor such as with targeted therapies. Of note, immunohistochemical
staining on tumor tissue should be employed for PD-L1 testing, quanti­
fied as tumor proportion score (TPS), as the level of PD-L1 expression
serves as an additional crucial biomarker in lung cancer management.
Advancements in the detection of circulating tumor DNA (ctDNA)
have emerged as a noninvasive strategy to perform a “liquid biopsy”
with a blood sample to assist in diagnosis and treatment monitoring.
This strategy may be particularly useful to overcome tissue limitations,
such as in cases where obtaining a tissue biopsy may be challenging
or not feasible due to a tumor’s location. The role of a liquid biopsy
continues to evolve, especially as the sensitivity and specificity of this
biopsy strategy continue to improve.
STAGING LUNG CANCER
Lung cancer staging consists of two parts: first, a determination of the
location of the tumor and possible metastatic sites (anatomic staging),
and second, an assessment of a patient’s ability to withstand various
antitumor treatments (physiologic staging). All patients with lung
cancer should have a complete history and physical examination, with
evaluation of all other medical problems, determination of perfor­
mance status (i.e., standardized measure assessing a patient’s physical
functioning and ability to perform activities of daily living to deter­
mine their overall health and suitability for treatment), and history
of weight loss. Staging with regard to a patient’s potential for surgical
resection is principally applicable to NSCLC.
■
■ANATOMIC STAGING OF PATIENTS WITH LUNG
CANCER
The accurate staging of patients with NSCLC is essential for deter­
mining the appropriate treatment in patients with resectable disease
and for avoiding unnecessary surgical procedures in patients with
advanced disease. All patients with NSCLC should undergo initial
radiographic imaging with CT scan, positron emission tomography
(PET), or preferably PET-CT. PET scanning attempts to identify sites
of malignancy based on glucose metabolism by measuring the uptake
of 18F-fluorodeoxyglucose (FDG). Rapidly dividing cells, presumably
in the lung tumors, will preferentially take up 18F-FDG and appear as a
“hot spot.” To date, PET has been mostly used for staging and detection
of metastases in lung cancer and in the detection of nodules >15 mm
in diameter. Combined 18F-FDG PET-CT imaging has been shown to
improve the accuracy of staging in NSCLC compared to visual correla­
tion of PET and CT or either study alone. PET-CT has been found to
be superior in identifying pathologically enlarged mediastinal lymph
nodes and extrathoracic metastases. A standardized uptake value
(SUV) of >2.5 on PET is highly suspicious for malignancy. False nega­
tives can be seen in diabetes, in lesions <8 mm, and in slow-growing
tumors (e.g., carcinoid tumors or well-differentiated adenocarcinoma).
False positives can be seen in certain infections and granulomatous
disease (e.g., tuberculosis). Thus, PET should never be used alone to
diagnose lung cancer, mediastinal involvement, or metastases. Confir­
mation with tissue biopsy is required. For brain metastases, magnetic
resonance imaging (MRI) is the most effective method. MRI can also
be useful in selected circumstances, such as superior sulcus tumors to
rule out brachial plexus involvement, but in general, MRI does not play
a major role in NSCLC staging.
If imaging is concerning for metastatic disease, biopsy of a distant
site of disease is preferred for concurrent tissue diagnosis and con­
firmation of staging. In patients in whom distant metastatic disease
has been ruled out, lymph node status needs to be assessed via mini­
mally invasive techniques such as those mentioned above, including
EBUS-guided mediastinal staging, and/or invasive techniques such
as mediastinoscopy, mediastinotomy, thoracoscopy, or thoracotomy.
Approximately one-quarter to one-half of patients diagnosed with
NSCLC will have mediastinal lymph node metastases at the time
of diagnosis. A standard nomenclature for referring to the location
of lymph nodes involved with lung cancer has evolved (Fig. 83-3).
Lymph node sampling is recommended in all patients with enlarged
nodes detected by CT or PET scan and in patients with large tumors or
tumors occupying the inner third of the lung. The extent of mediastinal
lymph node involvement is important in determining the appropriate
definitive intent treatment strategy: neoadjuvant/perioperative therapy
followed by surgical resection versus surgical resection followed by
adjuvant therapy versus combined chemoradiation followed by immu­
notherapy consolidation (durvalumab).
In SCLC patients, current staging recommendations include a
PET-CT scan and MRI of the brain (positive in 10% of asymptomatic
patients). Bone marrow biopsies and aspirations are rarely performed
now given the low incidence of isolated bone marrow metastases.
Confirmation of metastatic disease, ipsilateral or contralateral lung
nodules, or metastases beyond the mediastinum may be achieved by
the same modalities recommended earlier for patients with NSCLC.
If a patient has signs or symptoms of spinal cord compression (pain,
weakness, paralysis, urinary retention), a spinal CT or MRI scan should
be performed. If metastases are evident on imaging, a neurosurgeon
should be consulted for possible palliative surgical resection and/or a
radiation oncologist should be consulted for palliative radiotherapy to
the site of compression. If signs or symptoms of leptomeningeal disease
develop at any time in a patient with lung cancer, an MRI of the brain
and spinal cord should be performed, as well as a lumbar puncture,
for evaluation and detection of malignant cells in the cerebrospinal
fluid. If the lumbar puncture is negative, a repeat procedure should
be considered. Leptomeningeal disease remains a clinical challenge,
as there is currently no approved therapy for the specific treatment of
leptomeningeal disease.
Superior mediastinal nodes
Brachiocephalic
(innominate) a.
2R
Ao
4R
Azygos v.
4L
10R
PA
N2 = single digit, ipsilateral
N3 = single digit, contralateral or supraclavicular
11R
11L
Aortic nodes
10L
12, 13, 14R
12, 13, 14L
Inf.pulm. ligt.
Inferior mediastinal nodes
Ligamentum
arteriosum
L. pulmonary a.
Phrenic n.
N1 nodes
Ao
PA
FIGURE 83-3  Lymph node stations in staging non-small-cell lung cancer. The International Association for the Study
of Lung Cancer (IASLC) lymph node map, including the proposed grouping of lymph node stations into “zones” for
the purposes of prognostic analyses. a., artery; Ao, aorta; Inf. pulm. ligt., inferior pulmonary ligament; n., nerve; PA,
pulmonary artery; v., vein.
■
■STAGING SYSTEM FOR NON-SMALL-CELL LUNG
CANCER
The tumor-node-metastasis (TNM) international staging system pro­
vides useful prognostic information and is used to stage all patients
with NSCLC. The various T (tumor size), N (regional node involve­
ment), and M (presence or absence of distant metastasis) stages are
combined to form different stage groups (Tables 83-5 and 83-6). The
eighth edition of the TNM staging system went into effect in 2018. T1
tumors are divided into tumors ≤1 cm (T1a), >1 cm and ≤2 cm (T1b),
and >2 cm and ≤3 cm (T1c). T2 tumors are those that are >3 cm but
≤5 cm, involve the visceral pleura or main bronchus, or are associ­
ated with atelectasis; T2a tumors are >3 cm and ≤4 cm, and T2b are
4 cm and ≤5 cm. T3 tumors are >5 cm and ≤7 cm. T3 tumors also
include tumors with invasion into local structures such as the chest
wall and diaphragm and with additional nodules in the same lobe. T4
tumors include tumors >7 cm or tumors of any size with invasion into
mediastinum, heart, great vessels, trachea, esophagus, or spine or with
multiple nodules in the ipsilateral lung. Lymph node staging depends
on metastasis to ipsilateral pulmonary or hilar nodes (N1), mediastinal
or subcarinal nodes (N2), or contralat­
eral mediastinal, hilar, or supraclavicular
nodes (N3). Patients with metastasis may
be classified as M1a (malignant pleural
or pericardial effusion, pleural nodules,
or nodules in the contralateral lung),
M1b (single distant metastasis to a single
organ; e.g., bone, liver, adrenal, or brain
metastasis), or M1c (multiple metastases
to a single organ or metastases to mul­
tiple organs). The ninth edition of the
TNM classification is scheduled to be
introduced sometime in 2024.
1  Highest mediastinal
2  Upper paratracheal
3  Prevascular and retrotracheal
4  Lower paratracheal
(including azygos nodes)
The effect of stage on survival is illus­
trated in Fig. 83-4. Approximately 15%
of patients have localized disease that can
be treated with curative attempt (surgery
or radiotherapy), about a quarter have
local or regional disease that may or may
not be amenable to a curative attempt,
and half have metastatic disease at the
time of diagnosis. In 10%, the extent of
disease is undefined.
5  Subaortic (A-P window)
6  Para-aortic (ascending
aorta or phrenic)
CHAPTER 83
7  Subcarinal
■
■STAGING SYSTEM FOR
SMALL-CELL LUNG CANCER
In patients with SCLC, it is now recom­
mended that both the Veterans Admin­
istration system and the American Joint
Committee on Cancer/International
Union Against Cancer eighth edition
system (TNM) be used to classify the
tumor stage. The Veterans Administra­
tion system is a distinct two-stage system
dividing patients into those with limited-
or extensive-stage disease. Patients with
limited-stage disease (LD) have cancer
that is confined to the ipsilateral hemi­
thorax and can be encompassed within
a tolerable radiation port. Thus, contra­
lateral supraclavicular nodes, recurrent
laryngeal nerve involvement, and supe­
rior vena caval obstruction can all be
part of LD. Patients with extensive-stage
disease (ED) have overt metastatic dis­
ease by imaging or physical examination.
Cardiac tamponade, malignant pleural
effusion, and bilateral pulmonary paren­
chymal involvement generally qualify
disease as ED, because the involved organs cannot be encompassed
safely or effectively within a single radiation therapy port. Sixty to 70%
of patients are diagnosed with ED at presentation. The TNM staging
system is preferred in the rare SCLC patient presenting with what
appears to be clinical stage I disease (see above).
8  Paraesophageal
(below carina)
Neoplasms of the Lung
9  Pulmonary ligament
10  Hilar
11  Interlobar
12  Lobar
13  Segmental
14  Subsegmental
■
■PHYSIOLOGIC STAGING
Patients with lung cancer often have other comorbid conditions related
to smoking including cardiovascular disease and COPD. To improve
their preoperative condition, correctable problems (e.g., anemia,
electrolyte and fluid disorders, infections, cardiac disease, and arrhyth­
mias) should be addressed, appropriate chest physical therapy should
be instituted, and patients should be encouraged to stop smoking.
Patients with a forced expiratory volume in 1 s (FEV1) of >2 L or >80%
of predicted may tolerate a pneumonectomy, and those with an FEV1
1.5 L may have adequate reserve for a lobectomy. In patients with bor­
derline lung function but a resectable tumor, cardiopulmonary exercise
testing could be performed as part of the physiologic evaluation. This
test allows an estimate of the maximal oxygen consumption (VO2max).
TABLE 83-5  TNM Staging System for Lung Cancer (Eighth Edition)
Primary Tumor (T)
T1
Tumor ≤3 cm diameter, surrounded by lung or visceral pleura,
without invasion more proximal than lobar bronchus
  T1mi
Minimally invasive adenocarcinoma (pure lepidic pattern, <3 cm
in greatest dimension and <5 mm invasion)—T1a (size ≤1 cm)—
T1b (1 cm < size ≤ 2 cm)—T1c (2 cm < size ≤ 3 cm)
T2
Tumor >3 cm but ≤5 cm, or tumor with any of the following
features:
 
  Involves main bronchus without carina, regardless of
distance from carina
 
  Invades visceral pleura
 
  Associated with atelectasis or obstructive pneumonitis
that extends to the hilar region but does not involve the
entire lung
  T2a
Tumor >3 cm but ≤4 cm
  T2b
Tumor >4 cm but ≤5 cm
T3
Tumor >5 cm but ≤7 cm or any of the following:
 
Directly invades any of the following: chest wall,
pericardium, phrenic nerve
 
Separate (satellite) tumor nodules in the same lobe
T4
Tumor >7 cm or any tumor with invasion of mediastinum,
diaphragm, heart, great vessels, trachea, recurrent laryngeal
nerve, esophagus, vertebral body, or carina, or with separate
(satellite) tumor nodules in a different ipsilateral lobe
PART 4
Oncology and Hematology
Nodal Stage (N)
N0
No regional lymph node metastases
N1
Metastasis in ipsilateral peribronchial and/or ipsilateral
hilar lymph nodes and intrapulmonary nodes, including
involvement by direct extension
N2
Metastasis in ipsilateral mediastinal and/or subcarinal lymph
node(s)
N3
Metastasis in contralateral mediastinal or hilar lymph
node(s); ipsilateral/contralateral scalene/supraclavicular
lymph node(s)
Metastases (M)
M0
No distant metastasis
M1
Distant metastasis
  M1a
Separate tumor nodule(s) in a contralateral lobe; pleural/
pericardial nodule/malignant effusion
  M1b
Single extrathoracic metastasis, including single nonregional
lymph node
  M1c
Multiple extrathoracic metastases in one or more organs
Abbreviation: TNM, tumor-node-metastasis.
A VO2max <15 mL/(kg.min) predicts for a higher risk of postoperative
complications. Patients deemed unable to tolerate lobectomy or pneu­
monectomy from a pulmonary functional standpoint may be candi­
dates for more limited resections, such as wedge or anatomic segmental
resection, although such procedures are associated with significantly
TABLE 83-6  TNM Stage Groupings, Eighth Edition
T/M
Subcategory
N0
N1
N2
N3
T1
T1a
IA1
IIB
IIIA
IIIB
 
T1b
IA2
IIB
IIIA
IIIB
 
T1c
IA3
IIB
IIIA
IIIB
T2
T2a
IB
IIB
IIIA
IIIB
 
T2b
IIA
IIB
IIIA
IIIB
T3
T3
IIB
IIIA
IIIB
IIIC
T4
T4
IIIA
IIIA
IIIB
IIIC
M1
M1a
IVA
IVA
IVA
IVA
 
M1b
IVA
IVA
IVA
IVA
 
M1c
IVB
IVB
IVB
IVB
higher rates of local recurrence and a trend toward decreased overall
survival. All patients should be assessed for cardiovascular risk using
American College of Cardiology and American Heart Association
guidelines. A myocardial infarction within the past 3 months is a con­
traindication to thoracic surgery because 20% of patients will die of
reinfarction. An infarction in the past 6 months is a relative contrain­
dication. Other major contraindications include uncontrolled arrhyth­
mias, an FEV1 of <1 L, CO2 retention (resting PCO2 >45 mmHg), DLCO
<40%, and severe pulmonary hypertension.
TREATMENT
Non-Small-Cell Lung Cancer
OCCULT AND STAGE 0 CARCINOMAS
Patients with severe atypia on sputum cytology have an increased
risk of developing lung cancer compared to those without atypia. In
the uncommon circumstance where malignant cells are identified
in a sputum or bronchial washing specimen but the chest imaging
appears normal (TX tumor stage), the lesion must be localized.
More than 90% of tumors can be localized by meticulous examina­
tion of the bronchial tree with a fiberoptic bronchoscope under
general anesthesia and collection of a series of differential brushings
and biopsies. Surgical resection following bronchoscopic localiza­
tion has been shown to improve survival compared to no treatment.
Close follow-up of these patients is indicated because of the high
incidence of second primary lung cancers (5% per patient per year).
SOLITARY PULMONARY NODULE AND “GROUND-GLASS”
OPACITIES
A solitary pulmonary nodule is defined as an x-ray density com­
pletely surrounded by normal aerated lung with circumscribed
margins, of any shape, usually 1–6 cm in greatest diameter. The
approach to a patient with a solitary pulmonary nodule is based
on an estimate of the probability of cancer, determined according
to the patient’s smoking history, age, and characteristics on imag­
ing (Table 83-7). Prior CXRs and CT scans should be obtained if
available for comparison. A PET scan may be useful if the lesion is
7–8 mm in diameter. If no diagnosis is apparent, Mayo investiga­
tors reported that clinical characteristics (age, cigarette smoking
status, and prior cancer diagnosis) and three radiologic charac­
teristics (nodule diameter, spiculation, and upper lobe location)
were independent predictors of malignancy. At present, only two
radiographic criteria are thought to predict the benign nature of a
solitary pulmonary nodule: lack of growth over a period >2 years
and certain characteristic patterns of calcification. Calcification
alone, however, does not exclude malignancy; a dense central nidus,
multiple punctuate foci, and “bull’s eye” (granuloma) and “popcorn
ball” (hamartoma) calcifications are highly suggestive of a benign
lesion. In contrast, a relatively large lesion, lack of or asymmetric
calcification, chest symptoms, associated atelectasis, pneumonitis,
or growth of the lesion revealed by comparison with an old x-ray
or CT scan or a positive PET scan may be suggestive of a malig­
nant process and warrant further attempts to establish a histologic
diagnosis. An algorithm for assessing these lesions is shown in
Fig. 83-5.
Since the advent of screening CTs, small “ground-glass” opacities
(GGOs) have often been observed, particularly as the increased
sensitivity of CTs enables detection of smaller lesions. Many of these
GGOs, when biopsied, are found to be atypical adenomatous hyper­
plasia (AAH), adenocarcinoma in situ (AIS), or minimally invasive
adenocarcinoma (MIA). AAH is usually a nodule of <5 mm and is
minimally hazy, also called nonsolid or ground glass (i.e., hazy
slightly increased attenuation, no solid component, and preserva­
tion of bronchial and vascular margins). On thin-section CT, AIS
is usually a nonsolid nodule and tends to be slightly more opaque
than AAH. MIA is mainly solid, usually with a small (<5 mm)
central solid component. However, overlap exists among the imag­
ing features of the preinvasive and minimally invasive lesions in
100%
80%
60%
40%
20%
0%
Months
FIGURE 83-4  Influence of non-small-cell lung cancer stage on survival. Overall survival by non-small-cell lung cancer stage, according to eighth edition groupings using
entire database available for the eighth edition as of 2016.
the lung adenocarcinoma spectrum. Lepidic adenocarcinomas are
usually solid but may be nonsolid. Likewise, the small invasive
adenocarcinomas also are usually solid but may exhibit a small
nonsolid component.
PREFACE TO MANAGEMENT OF LUNG CANCER
The landscape of lung cancer management, spanning from screen­
ing and early detection to addressing early-stage, locally advanced,
and distant disease, is undergoing continuous evolution. The
dynamic nature of this evolution is best exemplified by the approval
of 12 drugs in the United States only between 2022 and 2023.
Within the confines of this single chapter, presenting the most
current and comprehensive management recommendations proves
challenging, if not impossible, due to the accelerated pace of the
evolving treatment armamentarium. Therefore, it is recommended
to consult the latest professional guidelines for the most up-to-date
best practices (Table 83-8).
MANAGEMENT OF STAGES I AND II NSCLC
Surgical Resection of Stage I and II NSCLC  Surgical resection,
ideally by an experienced thoracic surgeon, is the treatment of
choice for patients with clinical stage I and II NSCLC who are able
to tolerate the procedure. Operative mortality rates for patients
resected by thoracic or cardiothoracic surgeons are lower compared
to general surgeons. Moreover, survival rates are higher in patients
who undergo resection in facilities with a high surgical volume
compared to those performing fewer than 70 procedures per year,
even though the higher-volume facilities often serve older and less
socioeconomically advantaged populations. The improvement in
survival is most evident in the immediate postoperative period. In
TABLE 83-7  Assessment of Risk of Cancer in Patients with Solitary
Pulmonary Nodules
RISK
VARIABLE
LOW
INTERMEDIATE
HIGH
Diameter (cm)
<1.5
1.5–2.2
≥2.3
Age (years)
<45
45–60
60
Smoking status
Never smoker
Current smoker
(<20 cigarettes/d)
Current smoker
(>20 cigarettes/d)
Smoking cessation
status
Quit ≥7 years
ago or quit
Quit <7 years ago
Never quit
Characteristics of
nodule margins
Smooth
Scalloped
Corona radiata or
spiculated
Source: From The New England Journal of Medicine. The Solitary Pulmonary
Nodule. D Ost et al: 348:2535-2542. Copyright @ 2003 Massachusetts Medical
Society. Reprinted with permission from Massachusetts Medical Society.
Stage
24 months
60 months
77%
83%
92%
90%
94%
97%
IA3
IA2
IA1
IA3
IA2
IA1
68%
87%
IB
IB
IIA
IIB
IIIA
IIIB
60%
79%
IIA
53%
72%
IIB
36%
55%
IIIA
IIIC
IVA
IVB
26%
44%
IIIB
13%
24%
IIIC
10%
23%
IVA
0%
10%
IVB
CHAPTER 83
patients with stage I NSCLC, lobectomy is superior to wedge resec­
tion with respect to rates of local recurrence. There is also a trend
toward improvement in overall survival. In patients with comor­
bidities, compromised pulmonary reserve, and small peripheral
lesions, a limited resection, wedge resection, or segmentectomy
(potentially by video-assisted thoracoscopic surgery) may be rea­
sonable surgical options. Pneumonectomy is reserved for patients
with central tumors and should be performed only in patients with
excellent pulmonary reserve. According to the Surveillance, Epi­
demiology, and End Results (SEER) data from 2022, patients with
localized disease have a 5-year survival rate of 63%.
Neoplasms of the Lung
Accurate pathologic staging requires adequate segmental, hilar,
and mediastinal lymph node sampling. Ideally, this includes a medi­
astinal lymph node dissection. Although there are no evidence-based
guidelines mandating the number of lymph nodes to be removed
at surgery for adequate staging, the International Association for
the Study of Lung Cancer staging manual states that suitable nodal
staging generally includes sampling/dissection of lymph nodes
from stations 2R, 4R, 7, 10R and 11R on the right side, and from
stations 5, 6, 7, 10L, and 11L on the left side. Hilar lymph nodes
are typically resected and sent for pathologic review, although it is
helpful to specifically dissect and label level 10 lymph nodes when
possible. On the left side, level 2 and sometimes level 4 lymph
nodes are generally obscured by the aorta. Although the therapeutic
benefit of nodal dissection versus nodal sampling is controversial,
a pooled analysis of three trials involving patients with stages I to
IIIA NSCLC demonstrated a superior 4-year survival in patients
undergoing resection and a complete mediastinal lymph node dis­
section compared with lymph node sampling. Moreover, complete
mediastinal lymphadenectomy added little morbidity to a pulmo­
nary resection for lung cancer when carried out by an experienced
thoracic surgeon.
Radiation Therapy in Stages I and II NSCLC  There is currently
no role for postoperative radiation therapy in patients following
resection of stage I or II NSCLC with negative margins. However,
patients with stage I and II disease who either decline or are not
suitable candidates for surgery should be considered for radiation
therapy with curative intent. Stereotactic body radiation therapy
(SBRT) is a technique used to treat patients with isolated pulmo­
nary nodules (≤5 cm) who are not candidates for or refuse surgical
resection. Treatment is typically administered in three to five frac­
tions delivered over 1–2 weeks. In uncontrolled studies, disease
control rates are >90%, and 5-year survival rates of up to 60% have
been reported with SBRT. By comparison, survival rates typically
range from 13 to 39% in patients with stage I or II NSCLC treated
with standard external-beam radiotherapy. Cryoablation is another
New nodule identified on
standard CT scanning
Benign calcification pattern
on CT or stability for 2 yr on
archival films
Risk factors for surgery
• Predicted postoperative
FEV1 <0.8 L
• VO2 max <10–15 mL/kg/min
.
Does probability of cancer
warrant surgery, given the
surgical risk?
PART 4
Oncology and Hematology
Moderate probability of
cancer (10–60%)
Low probability of
cancer (<10%)
Additional testing
• PET if nodule ≥1 cm in diameter
• Contrast-enhanced CT, depending
on institutional experties
• Transthoracic fine-needle aspiration
biopsy if nodule is peripherally
located
• Bronchoscopy if air-bronchus sign
present
Negative
tests
Positive
tests
Video-assisted thoracoscopic
surgery; examination of a
frozen section, followed by
lobectomy if nodule is malignant
Serial high-resolution CT at
3, 6, 9, 12, 18, and 24 mo
FIGURE 83-5  Approach to the solitary pulmonary nodule. FEV1, forced expiratory volume in 1 s; PET, positron emission tomography.
technique occasionally used to treat small, isolated tumors (i.e.,
≤3 cm). However, very little data exist on long-term outcomes with
this technique.
Systemic Therapy in Stages I and II NSCLC  For nearly two
decades, chemotherapy has historically served as the cornerstone
of adjuvant systemic therapy for patients with early-stage resected
disease. The landmark meta-analysis of cisplatin-based adjuvant
chemotherapy trials in patients with resected stages I to IIIA NSCLC
(the Lung Adjuvant Cisplatin Evaluation [LACE] Study) published
in 2008 demonstrated a 5.4% improvement in 5-year survival for
cisplatin-based chemotherapy compared to surgery alone, thus
becoming the standard-of-care adjuvant therapy recommenda­
tion. The survival benefit was seemingly confined to patients with
stage II or III disease (Table 83-9). By contrast, survival was actually
TABLE 83-8  Select References to Professional Guidelines, in
Alphabetical Order
American Society of Clinical Oncology (ASCO), Thoracic Cancer
2.
European Society for Medical Oncology (ESMO) Clinical Practice
Guidelines: Lung and Chest Tumors
3.
International Association for the Study of Lung Cancer (IASLC),
Guidelines
4.
National Comprehensive Cancer Network (NCCN), Non-Small-Cell
Lung Cancer Guidelines
Yes
No further testing
No
Yes
No
worsened in stage IA patients with the application of adjuvant therapy.
In stage IB, there was a modest improvement in survival of question­
able clinical significance, particularly for patients with a resected
lesion ≥4 cm. Adjuvant chemotherapy was also detrimental in patients
with poor performance status (Eastern Cooperative Oncology Group
[ECOG] performance status = 2). These data suggest that adjuvant
chemotherapy is best applied in patients with resected stage II or III
NSCLC, with potential benefit for a select group of stage IB patients.
As with any treatment recommendation, the risks and benefits
of adjuvant chemotherapy should be considered on an individual
patient basis. If a decision is made to proceed with adjuvant che­
motherapy, in general, treatment should be initiated 6–12 weeks
after surgery, assuming the patient has fully recovered, and should
be administered for no more than four cycles. Although cisplatinbased chemotherapy is the preferred treatment regimen, carbo­
platin can be substituted for cisplatin in patients who are unlikely
to tolerate cisplatin for reasons such as reduced renal function,
presence of neuropathy, or hearing impairment. A large coop­
erative group trial compared cisplatin-based chemotherapy with
vinorelbine, pemetrexed, gemcitabine, or docetaxel with or without
antiangiogenic therapy. The study found similar efficacy across all
treatments. Therefore, no specific chemotherapy regimen is consid­
ered superior in this setting, and treatment selection may be based
on cost and patient comorbidities.
From 2020 onward, systemic therapies, initially employed
in the metastatic setting—such as targeted therapy and
TABLE 83-9  Adjuvant Chemotherapy Trials in Non-Small-Cell Lung
Cancer
5-YEAR
SURVIVAL
(%)
P
NO. OF
PATIENTS
TRIAL
STAGE
TREATMENT
IALT
I–III
Cisplatin-based
Control
44.5
40.4
BR10
IB–II
Cisplatin +
vinorelbine
Control
ANITA
IB–IIIA
Cisplatin +
vinorelbine
Control
ALPI
I–III
MVP
Control
BLT
I–III
Cisplatin-based
Control
CALGB
IB
Carboplatin +
paclitaxel
ECOG1505
IB > 4c
– IIIA
Cisplatin-based
Cisplatin-based +
bevacizumab
NR
NR
Abbreviations: ALPI, Adjuvant Lung Cancer Project Italy; ANITA, Adjuvant Navelbine
International Trialist Association; BLT, Big Lung Trial; CALGB, Cancer and Lung Cancer
Group B; ECOG, Eastern Cooperative Oncology Group; IALT, International Adjuvant
Lung Cancer Trial; MVP, mitomycin, vindesine, and cisplatin; NR, not reported.
immunotherapy—have been incorporated into the curative
approach for patients with NSCLC (Table 83-10).
Osimertinib, an EGFR tyrosine kinase inhibitor (TKI), dem­
onstrated improved disease-free survival in the adjuvant setting
TABLE 83-10  Select Therapeutic Strategies Incorporating
Immunotherapy or Targeted Therapy In Early-Stage, Resectable
Non-Small-Cell Lung Cancer (NSCLC)
STAGE AND
DISEASE
CHARACTERISTICS
REGIMEN
APPROVAL
ENDPOINT
TRIAL
Neoadjuvant
CheckMate
IB–IIIA
Irrespective of
PD-L1
Nivolumab +
chemotherapy × 3
cycles
EFS
HR 0.63, p = .005
Perioperative
KEYNOTE-671
II–IIIB (N2)
Irrespective of
PD-L1
Pembrolizumab +
chemotherapy × 4
cycles → surgery →
pembrolizumab × ~9
months
EFS
HR 0.58, p < .00001
OS
HR 0.72, p = .00517
Adjuvant
IMPower010
II–IIIA
PD-L1 positive
(≥1%)
Adjuvant
chemotherapy →
atezolizumab × 1 year
DFS
HR 0.66, p = .004
KEYNOTE 091/
PEARLS
IB–IIIA
Irrespective of
PD-L1
Adjuvant
chemotherapy →
pembrolizumab × 1
year
DFS
HR 0.73
ADAURA
IB–IIIA
EGFR exon 19
deletions or exon
21 L858R
Osimertinib × 3
years (irrespective
of adjuvant
chemotherapy)
DFS
HR 0.20, p < .0001
OS
HR 0.49, p < .001
ALINA
IB-IIIA ALK fusion
positive
Alectinib × 2 years
DFS HR 0.24;
P<0.001, 95% CI,
0.13 to 0.43
Abbreviations: DFS, disease-free survival; EFS, event-free survival; EGFR, epidermal
growth factor receptor; HR, hazard ratio; OS, overall survival; PD-L1, programmed
death ligand 1.
for patients with EGFR mutation (exon 19 deletion or L858R)–
positive NSCLC treated for 3 years with or without chemotherapy;
improved overall survival benefit with adjuvant osimertinib was
also reported. Regulatory authorities including the U.S. FDA, the
European Commission, and China’s National Medical Products
Administration have granted approval for adjuvant osimertinib in
resected, stages IB–IIIA EGFR-mutant NSCLC. Furthermore, the
exploration of additional targeted therapies in the adjuvant setting
is ongoing, as seen for example in the phase 3 ALINA trial investi­
gating oral alectinib for patients with ALK fusion oncogene–posi­
tive NSCLC. This highlights a dynamic landscape in the pursuit of
enhanced treatment outcomes for patients with early-stage NSCLC.
< .03
.03
.017
Approved adjuvant immunotherapy regimens, using either atezoli­
zumab or pembrolizumab, involve approximately 1 year of treat­
ment following adjuvant chemotherapy. This treatment approach
is supported by the disease-free survival benefit observed in the
IMpower010 and KEYNOTE-091 trials. Notably, the association
between treatment benefit and the level of PD-L1 expression varied.
.49
.90
Neoadjuvant chemotherapy, which is the application of chemo­
therapy administered before an attempted surgical resection, has
been advocated by some experts on the assumption that such an
approach will more effectively extinguish occult micrometastases
compared to postoperative chemotherapy. In addition, there is
thought that preoperative chemotherapy might render an inoper­
able lesion resectable. A meta-analysis of 15 randomized controlled
trials involving >2300 patients with stage I–III NSCLC suggested
there may be a modest 5-year survival benefit (i.e., ∼5%) that is
virtually identical to the survival benefit achieved with postop­
erative chemotherapy. Accordingly, neoadjuvant therapy may prove
useful in selected cases (see below). A decision to use neoadjuvant
chemotherapy should always be made in consultation with an
experienced surgeon. Neoadjuvant immunotherapy combined with
chemotherapy has gained approval for patients with stage IB–IIIA,
resectable NSCLC, with neoadjuvant nivolumab plus chemotherapy
for three cycles resulting in a pathologic complete response rate of
24% and statistically significant event-free survival benefit over
chemotherapy alone (hazard ratio [HR] 0.63; p = .005) in the
CheckMate 816 trial.
.10
.90
CHAPTER 83
Neoplasms of the Lung
Various perioperative (i.e., before and after surgical resection)
treatment strategies have been explored for patients with resect­
able NSCLC. This involves a neoadjuvant chemoimmunotherapy
approach followed by adjuvant immunotherapy. A perioperative
treatment approach with pembrolizumab in combination with
chemotherapy has been approved for patients with stages II–IIIB,
resectable NSCLC. This approval is based on the results of the
KEYNOTE-671 phase 3 trial that demonstrated a significant overall
survival and event-free survival benefit over preoperative chemo­
therapy alone.
All patients with resected NSCLC are at high risk of developing
a second primary lung cancer or recurrence, most of which occur
within 18–24 months of surgery. Thus, these patients should be
followed with regular physical examinations and periodic imaging
studies. Given the results of the NLST, periodic CT scans appear
to be the most appropriate screening modality. Professional guide­
lines, such as those from the National Comprehensive Cancer Net­
work (NCCN), recommend a chest CT scan every 3–6 months for
the first 3 years after surgery, then every 6 months for 2 years, and
then annually to monitor for recurrence.
MANAGEMENT OF STAGE III NSCLC
Management of patients with stage III NSCLC usually requires a
combined-modality approach. Patients with stage IIIA disease com­
monly are stratified into those with “nonbulky” or “bulky” medias­
tinal lymph node (N2) disease. Although the definition of “bulky”
N2 disease varies somewhat in the literature, the usual criteria
include the size of a dominant lymph node (i.e., >2–3 cm in shortaxis diameter as measured by CT), groupings of multiple smaller
lymph nodes, evidence of extracapsular nodal involvement, or
involvement of more than two lymph node stations. The distinction
between nonbulky and bulky stage IIIA disease is mainly used
to select potential candidates for upfront surgical resection or for
resection after neoadjuvant therapy. Many aspects of therapy of
patients with stage III NSCLC remain controversial, and the opti­
mal treatment strategy has not been clearly defined. Furthermore,
because stage III disease is highly heterogeneous, no single treat­
ment approach can be recommended for all patients. Key factors
guiding treatment choices include the particular combination of
tumor (T) and nodal (N) disease, the ability to achieve a complete
surgical resection if indicated, and the patient’s overall physi­
cal condition and preferences. For example, in carefully selected
patients with limited stage IIIA disease where involved mediastinal
lymph nodes can be completed resected, initial surgery followed by
postoperative chemotherapy (with or without radiation therapy)
may be indicated. By contrast, for patients with clinically evident
bulky mediastinal lymph node involvement, the standard approach
to treatment is concurrent chemoradiotherapy followed by a year of
consolidation immunotherapy with durvalumab.
Absent and Nonbulky Mediastinal (N2, N3) Lymph Node Disease  For
the subset of stage IIIA patients initially thought to have clinical
stage I or II disease (i.e., pathologic involvement of mediastinal
[N2] lymph nodes is not detected preoperatively), surgical resection
is often the treatment of choice. This is followed by adjuvant che­
motherapy in patients with microscopic lymph node involvement
in a resection specimen. Postoperative radiation therapy (PORT)
may also have a select role for those with close or positive surgical
margins. Patients with tumors exceeding 7 cm in size or involving
the chest wall or proximal airways within 2 cm of the carina with
hilar lymph node involvement (but not N2 disease) are classified
as having T3N1 stage IIIA disease. They too are best managed
with surgical resection, if technically feasible, followed by adjuvant
chemotherapy if completely resected. Patients with T3N0 or T3N1
disease due to the presence of satellite nodules within the same lobe
as the primary tumor are also candidates for surgery, as are patients
with ipsilateral nodules in another lobe and negative mediastinal
nodes (IIIA, T4N0 or T4N1). Although data regarding adjuvant
chemotherapy in the latter subsets of patients are limited, it is often
recommended.
PART 4
Oncology and Hematology
Patients with T4N0-1 may have involvement of the carina, supe­
rior vena cava, or a vertebral body and yet still be candidates for sur­
gical resection in selected circumstances. The decision to proceed
with an attempted resection must be made in consultation with an
experienced thoracic surgeon often in association with a vascular
or cardiac surgeon and an orthopedic surgeon depending on tumor
location. However, if an incomplete resection is inevitable or if there
is evidence of N2 involvement (stage IIIB), surgery for T4 disease
is contraindicated. Most T4 lesions are best treated with concurrent
chemoradiotherapy followed by durvalumab.
The role of PORT in patients with completely resected stage III
NSCLC is controversial. To a large extent, the use of PORT has
historically been dictated by the presence or absence of N2 involve­
ment and, to a lesser degree, by the biases of the treating physician.
Using the SEER database, a meta-analysis of PORT identified a
significant increase in survival in patients with N2 disease but not
in patients with N0 or N1 disease. An earlier analysis by the PORT
Meta-analysis Trialist Group using an older database produced
similar results. However, two large, randomized phase 3 trials
(PORT-C and Lung ART) have shown that PORT should not be
routinely recommended as standard of care for patients given no
improvement in disease-free survival and increased risk for cardio­
pulmonary toxicity.
Known Mediastinal (N2, N3) Lymph Node Disease  When patho­
logic involvement of mediastinal lymph nodes is documented
preoperatively, a combined-modality approach is recommended
assuming the patient is a candidate for treatment with curative
intent. These patients are at high risk for both local and distant
recurrence if managed with resection alone. For patients with stage
III disease who are not candidates for surgical resection, concurrent
chemoradiotherapy is most commonly used as the initial treatment
followed by durvalumab. Concurrent chemoradiotherapy has been
shown to produce superior survival compared to sequential chemo­
radiotherapy; however, it also is associated with greater host toxici­
ties (including fatigue, esophagitis, and neutropenia). Therefore, for
patients with a good performance status, concurrent chemoradio­
therapy is the preferred treatment approach, whereas sequential
chemoradiotherapy may be more appropriate for patients with a
performance status that is not as good. For patients who are not
candidates for a combined-modality treatment approach, typically
due to a poor performance status or a comorbidity that makes
chemotherapy untenable, radiotherapy alone may provide a modest
survival benefit in addition to symptom palliation.
For patients with potentially resectable N2 disease, it remains
uncertain whether surgery after neoadjuvant chemoradiotherapy
improves survival. In an NCI-sponsored Intergroup randomized
trial comparing concurrent chemoradiotherapy alone to concur­
rent chemoradiotherapy followed by attempted surgical resection,
no survival benefit was observed in the trimodality arm compared
to the bimodality therapy. In fact, patients subjected to a pneumo­
nectomy had a worse survival outcome. By contrast, those treated
with a lobectomy appeared to have a survival advantage based on a
retrospective subset analysis. Thus, in carefully selected, otherwise
healthy patients with nonbulky mediastinal lymph node involve­
ment, surgery may be a reasonable option if the primary tumor can
be fully resected with a lobectomy. This is not the case if a pneumo­
nectomy is required to achieve complete resection.
Advancements in neoadjuvant therapy, particularly in the realm
of combination chemoimmunotherapy, have led to interest in
exploring the benefits of such therapy for patients with N2 disease.
The NADIM II phase 2 trial is an illustrative example that exclu­
sively enrolled patients with stage IIIA–IIIB disease per American
Joint Committee on Cancer eighth edition criteria; notably, twothirds of these patients had N2 disease, including cases of multi­
station N2 disease. The trial demonstrated a pathologic complete
response rate (pCR) of 36–42% with chemoimmunotherapy for
patients with N2 disease, compared to 0–10% pCR rate for those
who received neoadjuvant chemotherapy alone. Additionally, the
study demonstrated the safety of a neoadjuvant chemoimmuno­
therapy approach in patients with N2 disease, without compromis­
ing the feasibility of surgical outcomes. Further investigation is
warranted to better define the role of novel neoadjuvant therapeutic
strategies for patients with N2 disease.
Superior Sulcus Tumors (Pancoast Tumors)  Superior sulcus
tumors represent a distinctive subset of stage III disease. These
tumors arise in the apex of the lung and may invade the second
and third ribs, the brachial plexus, the subclavian vessels, the stel­
late ganglion, and adjacent vertebral bodies. They also may be
associated with Pancoast syndrome, characterized by pain that
may arise in the shoulder or chest wall or radiate to the neck. Pain
characteristically radiates to the ulnar surface of the hand. Horner’s
syndrome (enophthalmos, ptosis, miosis, and anhidrosis) due to
invasion of the paravertebral sympathetic chain may be present as
well. Patients with these tumors should undergo the same staging
procedures as all patients with stage II and III NSCLC. Neoadjuvant
chemotherapy or combined chemoradiotherapy followed by sur­
gery is reserved for those without N2 involvement. This approach
yields excellent survival outcomes (>50% 5-year survival in patients
with an R0 resection). Patients with N2 disease are less likely to
benefit from surgery and can be managed with chemoradiotherapy
followed by durvalumab. Patients presenting with metastatic dis­
ease can be treated with radiation therapy (with or without chemo­
therapy) for symptom palliation.
SURGICAL MANAGEMENT OF NSCLC
Traditionally, in patients with NSCLC, the following have been
relative contraindications to potential curative resection: extratho­
racic metastases, superior vena cava syndrome, vocal cord and, in
most cases, phrenic nerve paralysis, malignant pleural effusion,
cardiac tamponade, tumor within 2 cm of the carina (poten­
tially curable with combined chemoradiotherapy), metastasis to
the contralateral lung, metastases to supraclavicular lymph nodes,
contralateral mediastinal node metastases (potentially curable with
combined chemoradiotherapy), and involvement of the main pul­
monary artery. In situations where it will make a difference in
treatment, abnormal scan findings should be further investigated
and require tissue confirmation of malignancy so that patients are
not precluded from having potentially curative therapy. The role of
surgical management of NSCLC continues to evolve, given emerg­
ing neoadjuvant/perioperative treatment strategies, and warrants
multidisciplinary discussion.
MANAGEMENT OF METASTATIC NSCLC
Approximately 40% of NSCLC patients present with advanced,
stage IV disease at the time of diagnosis. In addition, a significant
number of patients who first presented with early-stage NSCLC will
eventually relapse with distant disease. Patients who have recurrent
disease have a better prognosis than those presenting with meta­
static disease at the time of diagnosis. Standard medical manage­
ment, the appropriate use of pain medications, and the pertinent
use of radiotherapy and systemic therapy—which may consist of
targeted therapy, immunotherapy, and/or traditional cytotoxic che­
motherapy depending on the specific diagnosis as well as PD-L1
TPS and molecular subtype—form the cornerstone of management.
Systemic therapy palliates symptoms, improves quality of life, and
improves survival in patients with metastatic NSCLC, particularly
in patients with good performance status. Of note, the early applica­
tion of palliative care in conjunction with chemotherapy in patients
with advanced NSCLC is associated with both improved survival
and quality of life.
Targeted Therapies for Select Molecular Cohorts of NSCLC  For
a cohort of NSCLC patients, the presence of an oncogenic driver
mutation allows the use of oral therapies with significant antitumor
activity and improved survival compared to cytotoxic chemo­
therapy. These driver mutations occur in genes encoding signaling
proteins that, when aberrant, promote the uncontrolled growth and
metastasis of tumor cells. Importantly, driver mutations can serve
as Achilles’ heels for tumors, if their gene products can be targeted
therapeutically with small-molecule inhibitors. All patients with
advanced NSCLC should ideally undergo comprehensive molecular
testing (i.e., multigene testing encompassing at least all biomarkers
for which there are approved biomarker-matched therapies, includ­
ing less common driver mutations) with broad panel-based testing
techniques such as NGS as opposed to conventional, single-gene
targeted testing strategies. Point mutations, insertions/deletions,
chromosomal rearrangements (sometimes called “fusions”), and
copy number variants have been reported in a number of genes
including ALK, BRAF, EGFR, ERRB2, KRAS, MET, NRAS, NRG1,
NTRK, PIK3ca, RET, and ROS1, with varying levels of clinical
evidence. As our treatment armamentarium expands, knowledge
of these mutations is critical for selection of appropriate therapy.
EGFR mutations have been detected in 10–15% of North American
patients diagnosed with NSCLC. EGFR mutations are typically (but
not exclusively) associated with younger age, light (<10 pack-year)
and nonsmokers, and adenocarcinoma histology. Approximately
90% of these mutations are exon 19 deletions or exon 21 L858R
point mutations within the EGFR tyrosine kinase domain, resulting
in hyperactivation of both EGFR kinase activity and downstream
signaling. Lung tumors that harbor activating mutations within
the EGFR kinase domain display high sensitivity to small-molecule
EGFR TKIs. Osimertinib, erlotinib, gefitinib, afatinib, and dacomi­
tinib are FDA-approved oral small-molecule TKIs that inhibit
EGFR. Several large, international, phase 3 studies have demon­
strated improved response rates and progression-free survival in
patients with EGFR mutation–positive NSCLC treated with an
EGFR TKI as compared with standard first-line chemotherapy regi­
mens (Table 83-11). Osimertinib was shown in a randomized phase
3 trial to have superior progression-free and overall survival in
TABLE 83-11  Phase 3 Trials of EGFR TKIs in EGFR-Positive
Non-Small-Cell Lung Cancer
NO. OF
PATIENTS
ORR (%)
PFS (MONTHS)
TRIAL
THERAPY
IPASS
CbP
6.3
 
Gefitinib
9.3
EURTAC
CG
5.2
 
Erlotinib
9.7
OPTIMAL
CG
4.6
 
Erlotinib
13.1
NEJOO2
CG
5.4
 
Gefitinib
10.8
WJTOG3405
CD
6.3
 
Gefitinib
9.2
LUX LUNG 3
CP
6.9
 
Afatinib
11.1
LUX LUNG 6
CG
5.6
 
Afatinib
11.0
LUX LUNG 7
Erlotinib
10.9
CHAPTER 83
 
Afatinib
11.0
ARCHER 1050
Gefitinib
9.2
 
Dacomitinib
14.7
FLAURA
Erlotinib or
gefitinib
8.5
 
Osimertinib
17.2
Neoplasms of the Lung
FLAURA2
Osimertinib/
chemotherapy
25.5
 
Osimertinib
16.7
MARIPOSA
Amivantamab/
lazertinib
23.7
 
Osimertinib
16.6
Abbreviations: CbP, carboplatin and paclitaxel; CD, cisplatin and docetaxel; CG,
cisplatin and gemcitabine; CP, cisplatin and paclitaxel; EGFR, epidermal growth
factor receptor; ORR, overall response rate; PFS, progression-free survival; TKI,
tyrosine kinase inhibitor.
patients with EGFR-mutant NSCLC compared to earlier-generation
EGFR TKIs (erlotinib or gefitinib) and to chemotherapy. Emerging
combination strategies in the first-line setting, such as combining
osimertinib with platinum-based chemotherapy, are also gaining
traction. EGFR exon 20 insertion mutations are the third most com­
mon EGFR mutation. The anti-EGFR therapies described above are
not approved for use in the context of tumors that harbor EGFR
exon 20 insertion mutations. The current standard of care for EGFR
exon 20–mutated lung cancer is a combination of platinum-based
chemotherapy with amivantamab, which is an EGFR-MET bispe­
cific antibody.
HER2/ERBB2 mutations have also been detected in ~3% of
nonsquamous NSCLC. HER2, like EGFR, is a member of the ERBB
family of receptor tyrosine kinases. The most common HER2 muta­
tions in lung cancer encompass insertion variants within exon 20,
which is part of the tyrosine kinase domain (so-called “exon 20
insertions”). The anti-HER2 monoclonal antibody-drug conjugate,
trastuzumab deruxtecan, is approved for patients with previously
treated, metastatic NSCLC harboring a mutation in HER2/ERRB2,
with an objective response rate of ~50% and median progressionfree survival of ~8 months.
Chromosomal Rearrangements in NSCLC  Chromosomal rear­
rangements are found in ~10% of patients with NSCLC. Typically,
although not exclusively, chromosomal rearrangements are associ­
ated with younger age, no smoking history, and adenocarcinoma
histology. However, given the potential therapeutic impact, it is
strongly recommended that all patients are tested. Given that the
resultant fusion proteins include the entire tyrosine kinase domain,
the most effective therapeutic strategy at this time is with TKIs.
TABLE 83-12  Results of Phase 3 Trials Comparing First-Line ALK
Inhibitors in ALK-Positive NSCLC
NO. OF
PATIENTS
ORR (%)
MEDIAN PFS
TRIAL
THERAPY
Profile 1014
Crizotinib
10.9
Platinumchemotherapy
7.0
ALEX
Alectinib
82.9
34.8
Crizotinib
75.5
10.9
ALTA1L
Brigatinib
67% at 24 months
Crizotinib
43% at 11 months
eXalt3
Ensartinib
Crizotinib
25.8
12.7
CROWN
Lorlatinib
Crizotinib
64% at 60 months
9.1
Abbreviations: NSCLC, non-small-cell lung cancer; ORR, overall response rate; PFS,
progression-free survival.
In NSCLC, chromosomal rearrangements involving the ana­
plastic lymphoma kinase (ALK) gene on chromosome 2 have been
found in ∼3–7% of patients with NSCLC. ALK rearrangements lead
to hyperactivation of the ALK tyrosine kinase domain. Crizotinib
is a first-generation ALK TKI, whereas alectinib, brigatinib, and
ceritinib are second-generation ALK TKIs approved as first-line
treatment options for patients with lung tumors harboring ALK
rearrangements. Both alectinib and brigatinib have been found to
have superior progression-free survival to crizotinib. Lorlatinib, a
third-generation ALK TKI, is also approved for patients in the firstline setting and for patients who progress on a second-generation
ALK TKIs (Table 83-12). Unique adverse events of lorlatinib may
include hyperlipidemia, weight gain, and cognitive effects. ALK
testing may be performed via fluorescence in situ hybridization
(FISH), immunohistochemistry (IHC), or NGS.
PART 4
Oncology and Hematology
ROS1 fusions, detected by FISH or NGS, have been identified
in ∼1–2% of patients with NSCLC. Crizotinib, which inhibits both
ROS1 and MET kinases, and the ROS1/TRK inhibitors entrectinib
and repotrectinib have been FDA approved for patients whose
tumors harbor a ROS1 fusion. Entrectinib and repotrectinib offer
improved blood-brain barrier penetration.
RET alterations typically occur as chromosomal rearrange­
ments resulting in constitutive TKI activation. RET rearrange­
ments may be detected by either FISH or NGS in ~1% of NSCLC
patients. Analogous to capmatinib, pralsetinib and selperca­
tinib have demonstrated an excellent response rate; as many as
Obtain tissue
EGFR Exon 19
deletion and
EGFR L858R
Determine driver
EGFR Exon
20 Insertion
ERBB2 (HER2)
mutation
RET fusion
ALK fusion
ROS1 fusion
KRAS G12C
Alectinib
Brigatinib
Ceritinib
Crizotinib
Lorlatinib
Famtrastuzumab
deruxtecan-nxki,
Ado-trastuzumab
emtansine
Afatinib,
Dacomitinib,
Erlotinib,
Erlotinib +
ramucirumab,
Erlotinib +
bevacizumab,
Gefitinib,
Osimertinib,
Osimertinib +
chemotherapy
Amivantamab +
Carboplatin/
Pemetrexed
(nonsquamous)
Adagrasib*,
Sotorasib*
Targeted therapy
Treatment
Options
Approved as second-line therapy only.
FIGURE 83-6  United States-centric approach to targeted therapy in non-small-cell lung cancer (NSCLC) based on drug approvals. Acknowledging regional variances in
approvals. Drugs are listed alphabetically, not by author preference. Current as of June 2024.
78–85% of treatment-naïve NSCLC patients with RET alterations
responded.
NTRK fusions occur in members of the NTRK gene family
(NTRK1, NTRK2, NTRK3) and result in constitutive protein kinase
activation. NTRK fusions are rare, occurring in <1% of patients with
NSCLC. Entrectinib and larotrectinib have demonstrated durable
antitumor efficacy and are currently approved for NTRK-positive
NSCLC.
Targeting the Mitogen-Activated Protein Kinase (MAPK) Pathway
in NSCLC  The MAPK pathway may be dysregulated in a subset
of patients with NSCLC. For example, mutations within the KRAS
GTPase are found in ∼25% of lung adenocarcinomas, with muta­
tions in KRAS G12C occurring in ~14% of adenocarcinomas.
Agents targeting KRAS G12C such as adagrasib and sotorasib are
now approved, with objective response rates of ~42 and ~37%,
respectively. Defining mechanisms of acquired resistance to smallmolecule inhibitors is a high research priority.
Oncogenic mutations in BRAF have been observed in ~2% of
patients with NSCLC and, similar to KRAS, may serve as a key
oncogene in the MAP kinase pathway. BRAF mutations may occur
in both squamous and nonsquamous NSCLC and with an equal
prevalence in patients with a history of smoking. This mutation is
typically most targetable when it occurs at the 600th amino acid
valine (V600). Combined inhibition with a BRAF and MEK inhibi­
tor, dabrafenib plus trametinib or encorafenib with binimetinib,
is a first-line or later therapeutic option in patients with BRAF
V600–mutant NSCLC and appears to be superior to BRAF or MEK
inhibition alone.
MET exon 14 skipping mutations have also been identified in
~3–5% of patients with NSCLC. Notably, MET exon 14 skipping
mutations may occur in both squamous and nonsquamous NSCLC
patients and those with a history of smoking. Pharmacologic
inhibition of the overactive MET pathway with FDA-approved
capmatinib or tepotinib resulted in response rates >70%, particu­
larly in treatment-naïve NSCLC patients. A unique and challenging
potential adverse event of oral MET inhibition with capmatinib
and tepotinib is peripheral edema. All NCCN-supported targetable
oncogenic driver mutations and potential therapeutic options are
summarized in Fig. 83-6.
Immunotherapy  Immune checkpoint inhibitors have significantly
improved survival for a group of patients with locally advanced
and metastatic NSCLC. These agents are used primarily in patients
whose tumors do not express a targetable genetic lesion (Fig. 83-7).
Immune checkpoint inhibitors work by blocking interactions
between T cells and antigen-presenting cells (APCs) or tumor
cells that lead to T-cell inactivation. By inhibiting this interaction,
the immune system is effectively upregulated and T cells become
Core biopsy to prove
metastatic disease
Atypical EGFR
mutations:
G719X, L861Q,
and S768I
BRAF
V600E
mutation
MET exon 14
skipping
mutation
NTRK
1/2/3 Fusion
Crizotinib,
Entrectinib,
Repotrectinib,
(Ceritinib),
(Lorlatinib)
Dabrafenib/
Trametinib,
Encorafenib/
Binimetinib,
Vemurafenib
Capmatinib,
Crizotinib,
Tepotinib
Entrectinib
Larotrectinib
Pralsetinib,
Selpercatinib
Afatinib
Obtain tissue
Determine histology
Squamous
Determine PD-L1 status
PD-L1 ≥50%
PD-L1 ≥1%
Anti-PD-1/PD-L1
monotherapy
plus histologyspecific
chemotherapy
Anti-PD-1/PD-L1
monotherapy
Treatment options
Anti-PD-1/PD-L1
monotherapy plus
histology-specific
chemotherapy
Anti-PD-1 plus
Anti-CTLA-4
therapy
Anti-PD-1 plus
Anti-CTLA-4
therapy plus
histologyspecific
chemotherapy
FIGURE 83-7  Approach to first-line therapy in a patient with stage IV, driver mutation–negative non-small-cell lung cancer (NSCLC).
activated against tumor cells. Several randomized studies have
demonstrated superior overall survival in patients treated with
pembrolizumab or atezolizumab monotherapy or nivolumab plus
ipilimumab combination immunotherapy compared to chemo­
therapy in patients with metastatic NSCLC with PD-L1 expression
in ≥50% of tumor cells (KEYNOTE-024, IMPOWER 110) and ≥1%
of tumor cells (KEYNOTE-042, CheckMate 227) (Table 83-13).
The evidence supporting the use of single-agent immunotherapy in
patients with tumor PD-L1 <50% remains unclear; current recom­
mendations suggest the use of chemotherapy plus immunotherapy
or immunotherapy combinations as the first-line treatment strategy
in patients with metastatic NSCLC with tumor PD-L1 <50%. As
discussed below, specific regimens vary by tumor histology (adeno­
carcinoma vs squamous cell carcinoma). Although PD-L1 has been
identified as a biomarker that can predict response to immune
checkpoint inhibitors, responses are observed in patients who do
not appear to express the biomarker, and not all PD-L1-positive
patients respond to checkpoint inhibition. Importantly patients
with driver mutations such as EGFR and ALK appear to derive
greater benefit from targeted therapy than immunotherapy and
should be treated with a TKI, even in the presence of high PD-L1
expression. Further evaluation of these agents in the neoadjuvant
and perioperative settings and combined with chemoradiotherapy
is ongoing.
Cytotoxic Chemotherapy for Metastatic or Recurrent NSCLC 
Cytotoxic chemotherapy is typically used in combination with
immunotherapy as the initial treatment in patients with metastatic
or recurrent NSCLC only when there is no contraindication to
immunotherapy. Selected chemotherapy agents perform quite dif­
ferently in squamous carcinomas versus adenocarcinomas. Patients
with nonsquamous NSCLC have an improved survival when
Core biospy of most
distant site of disease
to prove metastatic
disease
Nonsquamous and no
actionable mutations
PD-L1 ≥1%
PD-L1 <50% and
EGFR, ALK, and
ROS1 negative
PD-L1 <1%
PD-L1 ≥50%
Anti-PD-1/PD-L1
monotherapy
plus histologyspecific
chemotherapy
Anti-PD-1/PD-L1
monotherapy
plus histologyspecific
chemotherapy
Anti-PD-1/PD-L1
monotherapy
plus histologyspecific
chemotherapy
Anti-PD-1/PD-L1
monotherapy
Anti-PD-1/PD-L1
monotherapy plus
histology-specific
chemotherapy
CHAPTER 83
Anti-PD-1 plus
Anti-CTLA-4
therapy plus
histologyspecific
chemotherapy
Anti-PD-1 plus
Anti-CTLA-4
therapy plus
histologyspecific
chemotherapy
Anti-PD-1 plus
Anti-CTLA-4
therapy
Anti-PD-1 plus
Anti-CTLA-4
therapy plus
histologyspecific
chemotherapy
Neoplasms of the Lung
treated with cisplatin and pemetrexed compared to cisplatin and
gemcitabine. By contrast, patients with squamous carcinoma have
an improved survival when treated with cisplatin and gemcitabine.
This survival difference is thought to be related to the differential
expression between tumor types of thymidylate synthase (TS).
Squamous cancers have a much higher expression of TS compared
to adenocarcinomas, accounting for their lower responsiveness to
pemetrexed. By contrast, the activity of gemcitabine is not impacted
by the levels of TS.
Second-Line Therapy and Beyond  Second-line therapy for
advanced NSCLC relies on docetaxel; it improves survival com­
pared to supportive care alone. Ramucirumab is a recombinant
human IgG1 monoclonal antibody that targets VEGFR-2 and
blocks the interaction of VEGF ligands and VEGFR-2. A phase 3
trial demonstrated a significant improvement in progression-free
survival and overall survival when ramucirumab was combined
with docetaxel as second-line therapy in patients who had pro­
gressed on platinum-based chemotherapy. Contrary to bevaci­
zumab, ramucirumab was safe in patients with both squamous
and nonsquamous NSCLC and is approved regardless of histology.
Many new agents are being developed and tested in clinical trials for
second-line and beyond therapy in the metastatic setting, including
novel immune checkpoint agents, antibody-drug conjugates, and
even cellular therapies. Improved therapies in this setting remain
an area of great need for patients with lung cancer.
Supportive Care  No discussion of the treatment strategies for
patients with advanced lung cancer would be complete without a
mention of supportive care. Coincident with advances in chemo­
therapy and targeted therapy was a pivotal study that demonstrated
that the early integration of palliative care with standard treatment
TABLE 83-13  Results of Phase 3 Trials Comparing First-Line Immunotherapy with or without Chemotherapy Versus Chemotherapy Alone in Patients
with NSCLC
STUDY
THERAPY
NO. OF PATIENTS
OS (MONTHS)
PFS (MONTHS)
KEYNOTE-024
Pembrolizumab
30.0
7.9
PD-L1 ≥50%
Platinum-chemotherapy
14.2
3.5
KEYNOTE-042
Pembrolizumab
16.7
5.4
PD-L1 ≥1%
Platinum-chemotherapy
12.1
6.5
IMPOWER 110
Atezolizumab
20.2
8.1
PD-L1 ≥50% TC or ≥15% IC
Platinum-chemotherapy
13.1
5.0
KEYNOTE-189
Pembrolizumab + platinum-chemotherapy
NR
8.8
Nonsquamous
Platinum-chemotherapy
11.3
4.9
KEYNOTE-407
Pembrolizumab + platinum-chemotherapy
15.9
6.4
Squamous
Platinum-chemotherapy
11.3
4.8
IMPOWER 150
Atezolizumab + platinum-chemotherapy
19.2
8.3
Nonsquamous
Platinum-chemotherapy
14.7
6.8
IMPOWER 130
Atezolizumab + platinum-chemotherapy
18.6
7.0
Nonsquamous
Platinum-chemotherapy
13.9
5.5
EMPOWER-Lung 3
Cemiplimab + platinum-chemotherapy
Platinum-chemotherapy
CheckMate 227
Nivolumab + ipilimumab
17.1
5.1
PART 4
Oncology and Hematology
Platinum-chemotherapy
13.9
5.6
CheckMate-9LA
Nivolumab + ipilimumab plus two cycles of
platinum-chemotherapy
Platinum-chemotherapy
10.7
POSEIDON
Tremelimumab + durvalumab and platinum-chemotherapy
Platinum-chemotherapy
Abbreviations: IC, immune cells; NR, not reported; NSCLC, non-small-cell lung cancer; OS, overall survival; PFS, progression-free survival; TC, tumor cells.
Note: Platinum-chemotherapy refers to first-line platinum doublet or triplet chemotherapy.
strategies improves both quality of life and overall survival for
patients with stage IV NSCLC (Chaps. 13 and 74). Aggressive pain
and symptom control are important components of optimal treat­
ment of these patients.
TREATMENT
Small-Cell Lung Cancer
The overall treatment approach to patients with SCLC is shown in
Fig. 83-8.
SURGERY FOR LIMITED-DISEASE SCLC
SCLC is a highly aggressive disease characterized by its rapid
doubling time, high growth fraction, early development of dis­
seminated disease, and dramatic response to first-line chemo­
therapy and radiation. In general, surgical resection is not routinely
recommended for patients because even patients with LD-SCLC
still have occult micrometastases. However, the American College
of Chest Physicians Evidence-Based Clinical Practice Guidelines
recommend surgical resection over nonsurgical treatment in SCLC
patients with clinical stage I disease after a thorough evaluation for
distant metastases and invasive mediastinal stage evaluation (grade
2C). After resection, these patients should receive platinum-based
adjuvant chemotherapy (grade 1C). If the histologic diagnosis of
SCLC is made in patients on review of a resected surgical specimen,
such patients should receive standard SCLC chemotherapy as well.
CHEMOTHERAPY
In patients with limited-stage SCLC, concurrent chemoradiother­
apy with cisplatin-etoposide for four cycles has remained standard
of care for over 4 decades. Two randomized phase 3 trials have
demonstrated that chemotherapy with either cisplatin or carbo­
platin plus either etoposide and a PD-L1 inhibitor, atezolizumab
(IMPOWER 133) or durvalumab (CASPIAN), provides superior
progression-free and overall survival compared to chemotherapy
21.9
13.0
8.2
5.0
14.1
6.8
11.7
6.2
4.8
alone, making combination therapy the preferred choice in appro­
priate patients. Despite response rates to first-line therapy as high as
80%, the median survival ranges from 12 to 20 months for patients
with LD and ~12 months for patients with ED. Regardless of disease
extent, the majority of patients relapse and develop chemotherapyresistant disease. The prognosis is especially poor for patients who
relapse within the first 3 months of therapy; these patients are said
to have chemotherapy-resistant disease. Patients are said to have
sensitive disease if they relapse >3 months after their initial therapy
and are thought to have a somewhat better overall survival. These
patients also are thought to have the greatest potential benefit from
second-line chemotherapy. Topotecan and lurbinectedin are FDAapproved agents for second-line therapy in patients with SCLC.
Topotecan has only modest activity and can be given either intra­
venously or orally; it appears to have more efficacy in patients with
chemotherapy-sensitive disease. Lurbinectedin has a 35% response
rate and progression-free survival of 3.5 months, with a greater ben­
efit in patients with chemotherapy-sensitive disease. Other agents
with similar low levels of activity in the second-line setting include
irinotecan, paclitaxel, docetaxel, vinorelbine, oral etoposide, and
gemcitabine. The treatment of refractory SCLC is a pressing con­
cern, prompting the investigation of various new targets and drugs.
For example, at the time this chapter is being written, one of the
most exciting advancements in SCLC is the development of deltalike ligand 3 (DLL3)-targeting agents. For example, in the phase 2
DeLLphi-301 study, tarlatamab, a bispecific T-cell engager immu­
notherapy targeting DLL3 and CD3, demonstrated a 40% objective
response rate and a median progression-free survival of 4.9 months
in the 10-mg group for patients with previously treated SCLC. Con­
firmatory evidence from the phase 3 study remains pending.
THORACIC RADIATION THERAPY
Thoracic radiation therapy (TRT) and concurrent chemotherapy
with curative intent are standard for patients with limited-stage
SCLC with suitable performance status. Without TRT, virtually
Complete history and physical examination
Determination of performance status and weight loss
Complete blood count with platelet determination
Measurement of serum electrolytes, glucose, and calcium; renal and liver function tests
CT scan of chest, abdomen, and pelvis or CT-PET to evaluate for metastatic disease
MRI of brain
Bone scan if not able to do PET scan
No signs, symptoms,
or imaging to suggest
metastatic disease
Patient has no contraindication
to combined chemotherapy
and radiation therapy
Patient has contraindication
to combined chemoradiation
therapy
Combined-modality treatment
with platinum-based therapy
and etoposide and radiation
therapy
Sequential treatment with
chemotherapy and radiation
therapy
FIGURE 83-8  Algorithm for management of small-cell lung cancer. MRI, magnetic resonance imaging; PET, positron emission tomography.
all patients with limited-stage SCLC will progress on systemic
therapy alone within 1 year. Meta-analyses indicate that chemo­
therapy combined with TRT improves 3-year survival by ~5% com­
pared with chemotherapy alone. The 5-year survival rate, however,
remains low at ~29–34%. Most commonly, TRT is combined with
concurrent platinum and etoposide because of a better toxicity pro­
file compared to anthracycline-based regimens. For limited-stage
SCLC, concurrent chemoradiation is more effective than sequential
chemoradiation but is associated with significantly more esophagi­
tis and hematologic toxicity. Ideally, TRT should be administered by
the second cycle of chemotherapy because later application appears
slightly less effective. If for reasons of fitness or availability con­
current chemoradiation cannot be administered, TRT should fol­
low induction chemotherapy in alignment with an extensive-stage
SCLC paradigm. With respect to fractionation of TRT, twice-daily
1.5-Gy fractioned radiation therapy has been shown to improve
survival in limited-stage SCLC patients but is associated with higher
rates of grade 3 esophagitis and pulmonary toxicity. Patients should
be carefully selected for concurrent chemoradiation therapy based
on good performance status and adequate pulmonary reserve. The
role of radiotherapy in ED-SCLC is mainly limited to palliation of
tumor-related symptoms such as bone pain and bronchial obstruc­
tion. Notably, consolidation TRT has demonstrated a survival
benefit in extensive-stage SCLC in prospective studies; however,
translating these study findings into current clinical practice is
challenging due to their completion before the introduction of
immunotherapy in the first-line setting.
PROPHYLACTIC CRANIAL IRRADIATION
Prophylactic cranial irradiation (PCI) has historically been offered
to all patients with SCLC without progression on initial treat­
ment for limited-stage and extensive-stage disease. A meta-analysis
including seven trials and 987 patients with limited-stage SCLC
who had achieved a complete remission after upfront chemotherapy
yielded a 5.4% improvement in overall survival for patients treated
Single lesion detected
on imaging
Multiple lesions
detected on imaging
Biopsy lesion
Negative for
metastatic disease
Positive for
metastatic disease
CHAPTER 83
Chemotherapy with
immunotherapy and/or
radiation therapy for
palliation of symptoms
Neoplasms of the Lung
with PCI. However, the role of PCI has become controversial as
these studies were conducted before brain MRIs for staging. In
patients with ED-SCLC who have responded to first-line chemo­
therapy and had no CNS disease, patients randomized to observa­
tion had a higher incidence of brain metastases; however, use of PCI
did not improve overall survival.
THYMIC TUMORS
Thymic tumors are rare malignancies, accounting for 0.5–1.5% of all
malignancies in the United States with a higher incidence among Asian
populations. They are particularly rare among children and young
adults with incidence peaking in the fifth decade of life. There is no
difference between sexes, and no clear risk factors have been identified.
■
■CLINICAL MANIFESTATIONS
The majority of thymic tumors occur in the anterior mediastinum.
Approximately 40% of patients with mediastinal masses will be
asymptomatic with an incidental finding on chest imaging. In patients
presenting with an anterior mediastinal mass, if appropriate, serum
β-human chorionic gonadotropin (HCG) and α-fetoprotein (AFP)
should be sent to rule out a germ cell tumor. A patient with a sign or
symptom of thymoma or thymic carcinoma may present with chest
pain, dyspnea, cough, or superior vena cava syndrome secondary
to effects on adjacent organs or a paraneoplastic syndrome, most
commonly myasthenia gravis, pure red cell aplasia, or hypogam­
maglobulinemia. More rare paraneoplastic syndromes include limbic
encephalitis, aplastic anemia, hemolytic anemia, and autoimmune
disease such as Sjögren’s syndrome, polymyositis, rheumatoid arthritis,
and ulcerative colitis, among others.
■
■STAGING
Given the rarity of the tumor, patients with suspected thymoma should
be evaluated by a multidisciplinary team including a surgeon, medical
and radiation oncologist, and pathologist with experience in treating
the disease. A CT scan of the chest with contrast is recommended to

13 - 84 Breast Cancer
84 Breast Cancer
TABLE 83-14  Staging Thymic Tumors
MASAOKA STAGE
DEFINITION
I
Grossly and microscopically encapsulated
IIA
Microscopic transcapsular invasion
IIB
Macroscopic invasion into surrounding tissue excluding
pericardium, lung, and great vessels
III
Macroscopic invasion into neighboring organs of the lower
neck or upper chest
IVA
Pleural or pericardial dissemination
IVB
Hematogenous or lymphatic dissemination to distal organs
WHO
A
Tumor with few lymphocytes
AB
Tumor with features of type A and foci rich in lymphocytes
B1
Tumor with features of normal epithelial cells with
vesicular nuclei and distinct nucleoli and an abundant
population of lymphocytes. Also known as cortical
thymoma, lymphocyte-rich thymoma
B2
Thymoma with no or mild atypia with round or polygonalshaped cells with small component of lymphocytes
B3
Well-differentiated thymic carcinoma with mild atypia
C
Thymic carcinoma with high atypia
PART 4
Oncology and Hematology
determine if the mass is resectable based on relationship to surround­
ing structures. An MRI with contrast may be performed if clinically
indicated. A PET scan may be useful in the evaluation of a patient
with thymic tumors, although it may be less useful in the staging of
thymoma compared to thymic carcinoma. A core needle biopsy is
considered standard of care for obtaining a histologic diagnosis of an
anterior mediastinal tumor. This may be obtained via CT or ultrasound
imaging. However, in some circumstances, a mediastinoscopy or open
biopsy may be required.
Thymomas are commonly staged using the Masaoka system or the
WHO staging system, as described in Table 83-14. WHO types A, AB,
and B1 tend to be more well-differentiated, types B2 and B3 are mod­
erately differentiated, and type C is poorly differentiated.
■
■TREATMENT
Surgical resection is the mainstay of treatment for patients with Masa­
oka type I and II thymic tumors. In patients with type III and IV who
have potentially resectable thymic tumors, neoadjuvant chemotherapy
may be given to decrease the tumor size and allow for a resection with
negative margins. Surgery remains controversial and provides a limited
role in the treatment of stage III and IV disease. No additional therapy
may be required in patients with type I who have a resection with nega­
tive margins. Postoperative radiation therapy may be recommended
based on extracapsular extension and the presence of positive margins
in patients with type II or III thymic tumors or histologic evaluation
WHO B3 and C. Radiation therapy may be beneficial in patients with
locally advanced disease (type III or IV) or in patients with symptoms
secondary to compression of surrounding structures. Chemotherapy
with cisplatin, doxorubicin, and cyclophosphamide (CAP) remains
the mainstay of therapy in the neoadjuvant and adjuvant setting as
well as first-line therapy in patients with metastatic thymoma, whereas
carboplatin and paclitaxel are often employed in patients with thymic
carcinoma. Limited additional agents are recommended based on
small phase 2 trials as second-line therapy and beyond.
SUMMARY
The management of SCLC and NSCLC has undergone major change in
the past decade, resulting in a reduction in lung cancer mortality. For
patients with early-stage disease, advances in radiotherapy and surgical
procedures as well as new systemic therapies in the neoadjuvant and
perioperative settings have greatly improved prognosis in all diseases.
For patients with advanced lung cancer, major progress in understand­
ing tumor genetics and tumor immunology has led to the development
of rational targets and specific inhibitors, which have documented
efficacy in specific subsets of NSCLC. Furthermore, increased under­
standing of how to activate the immune system to drive antitumor
immunity has proven to be a successful therapeutic strategy for a
subset of patients with advanced lung cancer. However, only a small
subset of patients responds to immune checkpoint inhibitors, and the
majority of patients treated with targeted therapies or chemotherapy
eventually develop resistance, which provides strong motivation for
further research and enrollment of patients onto clinical trials in this
rapidly evolving area.
Acknowledgment
David Johnson, Leora Horn, and Wade Iams contributed to this chapter
in the prior edition and material from that chapter has been retained here.
■
■FURTHER READING
Cascone T et al: Perioperative nivolumab in resectable lung cancer. N
Engl J Med 390:1756, 2024.
Ettinger D et al: NCCN Guidelines® Insights: Non-Small Cell Lung
Cancer, Version 2.2023. J Natl Compr Canc Netw 21:340, 2023.
Hsu M et al: Lung cancer survivorship: Physical, social, emotional,
and medical needs of NSCLC survivors. J Natl Compr Canc Netw
22:e237072, 2024.
Owen D et al: Therapy for stage IV non-small-cell lung cancer with
driver alterations: ASCO Living Guideline, Version 2023.2. J Clin
Oncol 41:e63, 2023.
Rudin C et al: Small-cell lung cancer. Nature Rev Dis Primers 7:3, 2021.
Wakelee H: Chemotherapy and immunotherapy in early-stage
NSCLC: Neoadjuvant vs adjuvant therapy. Clin Adv Hematol Oncol
21:648, 2023.
Nancy E. Davidson
Breast Cancer
Breast cancer is the most common nonskin cancer diagnosed in
women in the world. In 2024, it is estimated that in the United States
310,000 women will be diagnosed with invasive breast cancer, >56,000
women will receive a diagnosis of ductal carcinoma in situ (DCIS),
and about 42,250 women will die from breast cancer. Although largely
a disease of women, about 2800 men will be diagnosed with and 530
men will die from breast cancer in 2024 in the United States. Thanks
to advances in understanding of breast cancer biology, screening, diag­
nosis, treatment, and decreased use of hormone replacement therapy,
5-year relative survival in the United States is currently 91%. These
advances have also made it possible to conceptualize the evolution of
breast cancer and how available interventions can be applied across the
continuum of changes to improve outcomes (Fig. 84-1).
EPIDEMIOLOGY AND RISK FACTORS
■
■NONGENETIC RISK FACTORS
Female gender and increasing age are the most common risk factors for
breast cancer. About 70% of breast cancer in the United States is diag­
nosed in women 55 years and older, and median age of diagnosis is 63.
Incidence is highest in non-Hispanic whites followed by non-Hispanic
blacks and is lower in Hispanic, Asian/Pacific Islander, and American
Indian/Alaska Native women; in contrast, mortality is highest in nonHispanic blacks followed by non-Hispanic whites and individuals of
other race/ethnicity. Both incidence and mortality vary considerable
around the globe, but studies of immigrant populations show that pop­
ulations who migrate from low-incidence regions to high-incidence
regions will attain the breast cancer risk of the higher incidence region
within one or two generations.
Breast cancer continuum
High risk
In situ
Invasive
Micro-metastases
Detectable
metastases
Mortality
Normal
Ductal
carcinoma
in situ
Normal
duct
Intraductal
hyperplasia
Atypical
ductal
hyperplasia
Risk assessment
Risk reduction/chemoprevention
Screening
Primary Rx (surgery/radiation)
FIGURE 84-1  Breast cancer continuum conceptual model. Most breast cancers begin in epithelial cells within the lobules or ducts. They proceed through a continuum of
atypia and hyperplasia to in situ malignancy to invasion into surrounding normal tissues followed by intravasation into lymph and blood channels to local lymph nodes and
distant organs, culminating in distant metastases. This is a conceptual model. Not all metastatic breast cancers have progressed through these stages, and many lesions
do not progress to the next.
Breast cancer is predominantly a disease resulting from prolonged
exposure of the breast to estrogen. Thus, early menarche, late meno­
pause, and late first pregnancy are known risk factors. Likewise, pro­
longed exposure to hormone replacement therapy (but paradoxically
not estrogen replacement therapy) is associated with increased risk as
is current use of oral contraceptives. Postmenopausal obesity (but not
premenopausal obesity) is also a risk factor, likely because of increased
estrogen exposure. Studies of diet and breast cancer risk have not been
conclusive, but alcohol consumption is a risk factor.
The best documented exogenous risk factor for breast cancer is
exposure to ionizing radiation during adolescence. Studies of other
environmental factors such as pesticide or other chemical exposures
have not been convincing.
Women diagnosed with some types of benign breast pathology
also have a higher risk of subsequent invasive breast cancer diagnosis.
In particular, the diagnosis of atypical ductal or lobular hyperplasia
increases risk about four- to fivefold, whereas a diagnosis of lobular
carcinoma in situ (LCIS) increases risk 7- to 12-fold. Recent studies
also suggest that women with high breast density on mammography
may be at increased risk of breast cancer.
■
■GENETIC RISK FACTORS
Family history is a critical risk factor, although only 20% of
women diagnosed with breast cancer have a family history. Diag­
nosis of breast cancer in a first-degree relative (parent, sibling, or
daughter) doubles breast cancer risk. A personal diagnosis of previous
invasive breast cancer also increases the risk of developing a new breast
cancer in the ipsilateral or contralateral breast.
Prevention, diagnosis, and management of breast cancer have been
revolutionized by the identification of a family of hereditary breast
cancer susceptibility genes that account for 5–10% of breast cancers.
These genes play a role in DNA damage repair, and inherited muta­
tions, which are transmitted in an autosomal dominant fashion,
Regional
lymph node
Lymph
or blood
vessels
Invasive
ductal
cancer
Distant organs
Distant organs
CHAPTER 84
Adjuvant Systemic Rx
Breast Cancer
Survivorship
Palliative treatment
generally lead to protein truncation and loss of function of DNA repair
proteins. The most common mutations are in the BRCA1 (located on
chromosome 17q21) or BRCA2 (located on chromosome 13q12) genes,
and they impart a 50–80% risk of developing invasive breast cancer
by age 80 years as well as a 30% risk of developing ovarian cancer.
Germline mutations in other genes also lead to a higher risk of breast
cancer including TP53 (Li-Fraumeni syndrome), PALB2, ATM, STK11
(Peutz-Jeghers syndrome), and PTEN (Cowden syndrome). Certain
populations have a higher incidence of BRCA mutations, especially
Ashkenazi Jews. Commercially available assays for germline, breast
cancer susceptibility mutations have expanded from just the two
originally discovered genes (BRCA1/2) to panels including these
and the genes listed above to panels that include these and 20 or more
additional genes. Two major concerns have arisen over time regarding
the relative lack of clinical correlations inherent in these panels and
the unknown association with risk, which have led to some confusion
and discomfort among patients: (1) variants of unknown significance
(VUS) in the genes known to be associated with increased risk; and
(2) genes included in the panels about which little is known regarding
clinical risk. Efforts to develop polygenic risk scores that evaluate single
nucleotide polymorphisms (SNPs) in other genes are under study but
are not yet ready for clinical application.
Testing for germline mutations is readily done using panel testing on
DNA obtained from peripheral blood or saliva after appropriate coun­
seling. It is not recommended for the general population. Evidencebased guidelines from the American Society of Clinical Oncology and
Society of Surgical Oncology recommend consideration of testing for
high-penetrance breast cancer susceptibility genes in individuals with
a personal history of breast cancer with specific features including
diagnosis ≤65 years. Older patients should be offered testing for clini­
cal features such as Ashkenazi Jewish ancestry; multiple breast cancers;
certain types of breast cancer, including breast cancer lacking expres­
sion of the estrogen and progesterone receptors and HER2 proteins
(triple-negative breast cancer [TNBC]) and lobular breast cancer with
personal or family history of diffuse gastric cancer; or close blood rela­
tive with early-onset or male breast cancer, ovarian cancer, pancreatic
cancer, or metastatic prostate cancer. Testing for individuals without a
cancer diagnosis should be considered for those with a family member
who tests positive or those with a family history as outlined above or
those with higher risk based on existing risk assessment tools such as
Tyrer-Cuzick score, BRCAPro, or CanRisk.
PREVENTION
Current strategies to prevent breast cancer include surgery, chemo­
prevention, and lifestyle modification; their use and impact will vary
depending on the underlying risk of developing breast cancer.
■
■PROPHYLACTIC SURGERY
Prophylactic mastectomy reduces risk of developing breast cancer
by about 90% including in individuals who carry a germline breast
cancer susceptibility gene mutation. Women who opt for prophylactic
mastectomy in this setting should be counseled that breast cancer may
develop in residual breast tissue. However, preventive mastectomy is
not likely to improve outcomes in women with low or only modest risk
and should be discouraged. Though the primary role for prophylactic
oophorectomy is for ovarian cancer prevention in germline mutation
carriers, it can also reduce breast cancer incidence in premenopausal
women by about 50% because of reduction in estrogen exposure.
PART 4
Oncology and Hematology
■
■CHEMOPREVENTION
Ample evidence exists for the use of chemoprevention approaches that
target estrogen signaling pathways in high-risk women. Tamoxifen
reduces risk of invasive breast cancer in women at higher risk (≥60 years,
diagnosis of LCIS, or younger women with risk of developing invasive
breast cancer ≥1.67% over 5 years based on current risk assessment
tools). Newer data suggest that low-dose tamoxifen for 3 years may be
effective and well tolerated. Side effects include postmenopausal symp­
toms and increased risk for endometrial cancer and thromboembolic
events, especially in women over 50. Raloxifene may be an alternative
for postmenopausal women. Though less effective in reducing breast
cancer risk than tamoxifen, it is associated with fewer uterine cancers.
The aromatase inhibitors, exemestane or anastrozole, also reduce
breast cancer incidence by about 50% in postmenopausal women
who are at moderate-high risk for breast cancer. The U.S. Preventive
Services Task Force recommends that clinicians offer risk-reducing
medications like tamoxifen, raloxifene, or aromatase inhibitors to
women who are at increased risk for breast cancer and at low risk for
medication side effects. Uptake is low despite the substantial evidence
that demonstrates a huge benefit.
■
■LIFESTYLE MODIFICATION
Potential lifestyle modifications to reduce breast cancer risk include
maintenance of a normal body mass index, avoidance of alcohol, and
minimizing use of hormone replacement therapy. Regular exercise,
especially during adolescence, may be associated with reduced risk.
Long-term follow-up from the dietary substudy of the Women’s Health
Initiative showed that a low-fat diet in postmenopausal women who
were cancer-free at the time of study enrollment resulted in a nonsig­
nificant reduction in breast cancer incidence but appeared to reduce
risk of death from breast cancer. The role of newer GLP-1 agents has
not been studied.
SCREENING
Breast cancer screening has been an area of active investigation and
controversy for decades. Issues include lack of consensus around the
goal of screening, the target population (e.g., age, risk), and the type
and frequency of screening. Multiple guidelines exist and continue to
evolve. Initial trials focused on three modalities: breast self-exam, clini­
cal breast exam (CBE), and mammography. Though widely promoted
in the past, emphasis on breast self-exam has waned, in part because
of two randomized clinical trials in China and Russia that showed no
benefit. In contrast, a randomized trial in India of CBE every 2 years in
women aged 35–64 years with no history of breast cancer indicated that
CBE led to a significant reduction in the proportion of women diag­
nosed with stage III or IV disease and a nonsignificant 15% reduction
in breast cancer mortality, largely in women ≥50 years.
Nine randomized trials have studied screening mammography. In
aggregate, they demonstrated that screening mammography reduced
breast cancer mortality by about 20–25% in women ≥50 years without
an impact on overall mortality. The UK Age trial suggested a simi­
lar benefit for women who began screening at 40 years. Screening
frequency has varied from 1–2 years across trials. Mammography
techniques have evolved over the years, and a current U.S. trial is
evaluating the role of tomosynthesis as a means of improving ben­
efit from mammography. Multiple guidelines exist and continue to
evolve. Most recommend that women aged 50–70 years have mam­
mography every 1–3 years, and many recommend screening for
women aged 40–50 years as well. When to stop is not known, but
it is generally accepted that benefits are limited to women with a
predicted life expectancy of at least 10 years.
The role of magnetic resonance imaging (MRI) as a screening
modality is less well studied. MRI is more sensitive, less specific, and
more complex to perform. Some guidelines suggest that it be used for
women who have a lifetime predicted risk of ≥20%, which includes
those with germline pathogenic mutations in the BRCA genes. Its use
has also been suggested for those with very dense breasts on mam­
mography, but clear evidence of benefit is lacking. Screening ultra­
sound has also been studied, but evidence supporting its routine use
is lacking.
There is considerable interest in the use of multicancer early detec­
tion (MCED) tests using circulating DNA as a screening test for dis­
eases like breast cancer. Initial studies have not shown that these tests
can substitute for or augment conventional mammographic screening,
and women who do have MCED assays performed should still undergo
mammographic screening, even if the MCED test is negative.
DIAGNOSIS AND STAGING
Clinical signs and symptoms suggestive of breast cancer may include
a breast lump or skin or nipple changes or palpable regional nodes.
Thanks to mammographic screening, many patients present with
abnormal mammographic findings including a mass, distortion, and/
or suspicious microcalcifications without any symptoms or physi­
cal exam findings. Figure 84-2 shows an algorithm for diagnostic
evaluation of breast abnormalities noted on physical exam or imaging.
Final diagnosis rests on pathologic confirmation, which is generally
carried out by image-guided core biopsy to confirm diagnosis, assess
tumor grade and morphology, and carry out biomarker evaluation for
expression of estrogen receptor (ER) and progesterone receptor (PR)
and HER2 proteins and potentially HER2 gene amplification. Suspi­
cious axillary lymph nodes should also be biopsied via image-guided
techniques. It is important to image both breasts because up to 3% of
women with newly diagnosed breast cancer have unsuspected con­
tralateral disease. Evaluation of the breasts with MRI after a biopsyproven diagnosis is controversial. On the one hand, MRI is more
sensitive than radiologic mammography and will commonly detect
previously unidentified disease. On the other hand, this observation
may lead to additional surgery, including mastectomy, without obvious
improvements in outcomes.
Staging is a cornerstone for breast cancer management because
it provides information about natural history and informs decisions
about therapy. The traditional TNM (tumor-node-metastasis) staging
system has evolved to consider molecular testing including biomarkers
as above and certain genomic tests such as the Oncotype 21 gene assay.
Staging may take place at time of diagnosis (c or clinical staging) or
after surgery (p or pathologic staging) or after preoperative systemic
therapy followed by surgery (designated with a “y” prefix). For most
asymptomatic individuals presenting with early breast cancer, a careful
history and physical exam will be sufficient, and testing can be limited
to breast imaging and any testing needed to ensure a safe surgical
procedure. Individuals who present with symptoms suggestive of meta­
static disease or physical findings of more advanced disease (e.g., large
Diagnostic Evaluation of the Breast
Suspicious clinical breast finding
Suspicious breast finding
Diagnostic breast imaging
mammography
ultrasonography
MRI (if indicated)
Negative/benign
Ductal carcinoma in situ
with microcalcifications
Follow-up exam
Uncertain or clinical
suspicion persists
Resolved
Refer to experienced
breast diagnostician
Routine follow-up
screening
mammogram as
indicated
FIGURE 84-2  Evaluation and workup of breast lesions. For more extensive details, see https://www.nccn.org/professionals/physician_gls/pdf/breast-screening.pdf.
(Mammographic images courtesy of Drs. Mark Helvie and Colleen Neal, Department of Radiology, Michigan Medicine. Photomicrographs courtesy of Dr. Celina Kleer,
Department of Pathology, Michigan Medicine.)
tumor, skin changes, extensive regional adenopathy) should undergo
radiologic imaging with computed tomography and radionuclide
scanning to look for overt metastatic disease. Suspicious lesions should
be biopsied whenever possible to confirm a diagnosis of metastatic
breast cancer because of the implications for prognosis and selection
of therapy. Less than 10% of patients present with de novo metastatic
breast cancer.
Breast cancer staging is currently carried out according to the guide­
lines of the American Joint Committee on Cancer (AJCC) eighth edi­
tion. Conceptually, stages I and II represent early-stage disease, which
is confined to breast and ipsilateral nodes, whereas stage III comprises
locally advanced breast cancer and stage IV denotes de novo meta­
static breast cancer, designated as M1 in the current staging system.
Common sites for breast cancer metastasis include soft tissues, lung,
bone, liver, and brain. One study suggested that M1 disease can be
further divided into at least four subgroups with substantially different
prognoses, based on sites and burden of disease as well as biological
features. However, these findings have not yet been incorporated into
the formal AJCC staging system. Outcomes are directly related to stage
at presentation and vary by race and ethnicity in the United States, as
shown in Table 84-1.
Screening breast imaging
No suspicious breast finding
Suspicious
mass
Suspicious
microcalcifications
Routine follow-up
screening mammogram
as indicated
CHAPTER 84
Confirmed suspicious finding
Invasive ductal carcinoma
Biopsy
Breast Cancer
Progesterone
receptor (PR)
positive
HER2 negative
Estrogen receptor
(ER) positive
CURRENT UNDERSTANDING OF BREAST
CANCER BIOLOGY AND CLINICAL
IMPLICATIONS
It is now accepted that invasive breast cancer is in fact a disease with
diverse subtypes, both histologic and molecular. Two decades of
molecular analyses have documented multiple transcriptional, epi­
genetic, and genetic changes that characterize invasive breast cancer.
TABLE 84-1  Five-Year Breast Cancer Relative Survival Rate (%) by
Stage at Diagnosis and Race/Ethnicity in United States from 2012–2018a
STAGE
ALL
WHITE
BLACK
AIAN
HISPANIC
API
I
99
99
99
99
99
99
II
III
IV
aRace is exclusive of Hispanic origin.
Abbreviations: AIAN American Indian/Alaska Native; API Asian/Pacific Islander.
Source: Adapted from AN Giaquinto et al: Breast cancer statistics, 2022. CA Cancer
J Clin 72:524, 2022.
This has led to the division of invasive breast cancer into at least four
major molecular subtypes. Luminal A and B subtypes both express
ER and are viewed as generally likely to be responsive to antiestrogen
strategies (also called hormonal or endocrine therapies). However,
luminal B tumors are characterized by other findings such as reduced
PR expression or increased proliferation, usually measured by expres­
sion of Ki67, and are associated with a poorer outcome than luminal
A tumors. The HER2 subtype expresses HER2 protein at high levels
and is more likely to benefit from the use of HER2-targeted therapies.
Basal tumors tend to lack expression of ER, PR, and HER2 proteins
(TNBC). TNBCs carry a poorer prognosis and are generally managed
with chemotherapy and immunotherapy. TNBC can be further divided
into at least six subtypes, which may also have therapeutic implications,
especially in the metastatic setting.
Pathologic evaluation of a breast cancer specimen begins with an
assessment of morphology. Most invasive breast cancers are ductal,
but about 10–15% are lobular histologies. Lobular cancers are usually
ER positive and HER2 negative. They are distinguished by absence of
E-cadherin staining or function, and they have a different natural his­
tory, with a propensity to spread to serosal surfaces, including omen­
tum, pleura, and meninges or to various parenchyma, such as ovaries
and upper and lower gastrointestinal tracts. This curious site for meta­
static recurrence may result in unusual clinical presentations that may
delay diagnosis if metastatic disease is not considered. Other special
subtypes are also recognized such as mucinous, medullary, papillary,
and metaplastic histologies. Mucinous and pure medullary cancers
(distinguished by high levels of lymphocytic invasion surrounding the
tumor) are associated with very favorable prognoses with local therapy
only. Metaplastic cancers may present as very poorly differentiated
tumors or even as squamous or sarcomatoid differentiations. They
are generally approached as ductal cancers but may be treated in a
manner consistent with their relative subtypes, such as squamous or
sarcoma-like differentiation. Tumor grade is also assessed using stan­
dard approaches such as Nottingham grade, ranging from grade 1 to 3;
higher grade is generally associated with poorer prognosis.
PART 4
Oncology and Hematology
Further profiling of the primary tumor specimens may follow
depending on the clinical circumstances. Early-stage ER-positive
breast cancers are often evaluated by genomic transcriptional profiling
assays to identify patients with such a favorable prognosis that adjuvant
chemotherapy in addition to endocrine therapy is not needed; five of
these are recommended by the American Society of Clinical Oncol­
ogy: Oncotype Dx (21 genes), MammaPrint (70 genes), ProSigna (50
genes), EndoPredict (12 genes), and Breast Cancer Index (two genes
plus a proliferation signature). Although any one of these appears to
be relatively accurate in terms of prognosis, they do not measure the
same thing and they have not been compared head-to-head. Therefore,
ordering more than one assay for a single case is discouraged. At pres­
ent, more detailed molecular analysis is usually restricted to metastatic
tumor specimens to identify molecular alterations that are associated
with response to specific targeted therapies, as discussed in the section
on treatment of metastatic breast cancer.
TREATMENT
Breast Cancer
MANAGEMENT OF IN SITU BREAST CANCER
Ductal Carcinoma In Situ (DCIS)  Routine use of screening mam­
mography has led to a marked increase in the diagnosis of DCIS
and LCIS. Untreated DCIS (which is confined to the duct without
evidence of invasion through the basement membrane into sur­
rounding interstitial tissue) is associated with a 30% risk of devel­
oping a subsequent invasive cancer in the same breast. Therapy is
generally focused on excision of the lesion to negative margins and
to confirm absence of invasion; evaluation of axillary lymph nodes
is not generally undertaken. Excision may be followed by radiother­
apy to the ipsilateral breast and consideration of endocrine therapy
if the DCIS expresses ER protein to reduce risk of breast recurrence
or contralateral primary. Patients with extensive DCIS may require
mastectomy, whereas those with a small disease burden may opt for
excision alone with regular mammographic surveillance. Molecular
assays that can predict lack of benefit from radiotherapy after exci­
sion are sometimes used.
Lobular Carcinoma In Situ (LCIS)  LCIS is often an incidental find­
ing on a breast biopsy done for abnormalities on physical exam or
mammography. It is viewed as a marker for increased risk of devel­
oping invasive breast cancer as about 25–30% of women with LCIS
subsequently develop invasive disease in either breast. The primary
management is continued breast cancer screening and consider­
ation of chemoprevention with tamoxifen or aromatase inhibitor to
decrease risk of invasive disease. Bilateral prophylactic mastectomy
is sometimes considered but should be generally limited to those
who have other risk factors or concerns.
TREATMENT OF EARLY-STAGE BREAST CANCER
Multidisciplinary care is a cornerstone for optimal treatment of
early breast cancer. The current approach to treatment of earlystage breast cancer reflects evolution from the initial concept of
breast cancer as an orderly disease that spreads from breast to
axillary nodes to systemic disease to our current understanding of
breast cancer as a potentially systemic disease almost from onset.
Therefore, treatment approaches incorporate surgery and radiation
to treat local disease and systemic therapy to eliminate or suppress
any microscopic distant disease. The goal of these treatments in
early-stage disease is reduction of subsequent distant recurrence
and mortality. They are given in a manner to optimize efficacy
while minimizing toxicity and avoiding overtreatment.
Surgery  Six randomized trials have demonstrated equivalent sur­
vival with the use of breast-conservation therapy (lumpectomy and,
usually, radiotherapy to the remaining breast) or modified radical
mastectomy for individuals with early-stage breast cancer. Contra­
indications to breast conservation include patient preference, poor
cosmesis, multifocal disease, previous chest radiation, and ongoing
pregnancy that prevents timely administration of radiotherapy.
Though not an absolute contraindication, germline mutation in a
member of the BRCA gene family can drive a decision for bilat­
eral mastectomy because of the high risk of subsequent disease in
either breast. Patients who require or choose mastectomy should be
informed about availability of immediate or delayed reconstruction
options using autologous tissue or implants as clinically appropri­
ate. It is clear, though, that most women with early breast cancer
are well served by a lumpectomy to negative margins with axillary
management, followed by radiation as appropriate.
Management of the ipsilateral axilla continues to evolve as well.
For patients with small tumors and clinically negative axillary
nodes, sentinel node localization is used to identify clinically rel­
evant nodes for removal and pathologic assessment to finalize stag­
ing and inform decisions about extent of radiotherapy and selection
of adjuvant systemic therapy. Use of axillary dissection (removal of
level 1 and 2 lymph nodes) is restricted to individuals with palpable
lymph nodes or those with substantial pathologic involvement of
sentinel lymph nodes. Randomized trials have shown excellent
outcomes with omission of any sentinel node evaluation for older
women with small biologically favorable tumors and clinically
negative axilla who will take adjuvant endocrine therapy as well as
omission of axillary dissection for women with low tumor burden
in sentinel nodes who will receive radiation.
Radiation  As with surgery, the use of postoperative radiotherapy
to minimize breast recurrence and nodal recurrence has also
changed as a result of data accumulated from serial clinical trials.
Current treatment strategies are tailored to the individual based
on age, tumor size, and nodal status. Options for external-beam
radiotherapy include a standard scheme of daily whole breast
radiotherapy (WBR) for 4–6 weeks, hypofractionated schedules
lasting 5 days to 3 weeks, or partial breast radiation, usually given in
a hypofractionated regimen. Clinical trials of the latter have failed
to demonstrate its benefit over WBR. Extension of the radiotherapy
port to include regional and axillary nodes is also considered based
on pathology and type of surgery. The safety of omitting radio­
therapy for women older than 65 with low-risk ER-positive tumors
who will take endocrine therapy has been demonstrated. Brachy­
therapy to apply a radiation source directly to the tumor bed is also
employed in some cases as a way of shortening duration of therapy.
Patients who undergo mastectomy may also benefit from chest
wall radiotherapy to reduce risk of both local and distant recur­
rence, thus improving survival. Potential candidates include those
with large tumors or positive axillary lymph nodes, especially
those with four or more involved nodes, while those with one to
three positive nodes or close/minimally involved margins are also
considered.
Systemic Therapy  It has been recognized that breast cancer is
often a systemic disease at time of diagnosis. Enhanced understand­
ing of breast cancer biology, including the concept that resistant
clones evolve as a function of random mutations over time, and
the identification of multiple targets of therapy have greatly refined
our understanding of the role of systemic therapy in early breast
cancer. Such therapy may be given preoperatively (neoadjuvant)
or postoperatively (adjuvant) and may take the form of cytotoxic
chemotherapy, endocrine therapy directed toward ER, and other
targeted therapies such anti-HER2, poly (ADP-ribose) polymerase
(PARP) inhibitors in cancers with BRCA1/2 mutations, and/or
immunotherapy directed toward immune checkpoints. Treatment
algorithms are constantly evolving based on results from clinical
trials, and current evidence-based guidelines are available through
groups like the National Comprehensive Cancer Network,
American Society of Clinical Oncology, or European Society of
Medical Oncology.
SELECTION OF NEOADJUVANT VERSUS ADJUVANT
SYSTEMIC THERAPY
The primary goal of neoadjuvant therapy (also designated “pre­
operative” adjuvant therapy) compared to classic postoperative
adjuvant therapy is to downsize tumor to make it more amenable
to surgery. A second goal is to provide an in vivo assessment of
tumor response to the selected systemic therapy and perhaps direct
subsequent adjuvant therapy. Data suggest that individual patients
who attain a complete pathologic response (pCR) to neoadjuvant
therapy have a better outcome than those who do not, although
randomized trials of adjuvant versus neoadjuvant therapy have not
shown a difference in survival. At least one trial has demonstrated
that patients who fail to experience a pCR to standard combination
chemotherapy containing an anthracycline, an alkylating agent,
and a taxane, especially those with TNBC, appear to benefit from
subsequent capecitabine. Currently, neoadjuvant therapy with che­
motherapy and anti-HER2 agents is considered for individuals
with HER2-positive tumors that are ≥2 cm or node-positive dis­
ease, while neoadjuvant therapy with chemotherapy and possibly
the checkpoint inhibitor pembrolizumab are considered for indi­
viduals with TNBC ≥2 cm or node-positive disease. Neoadjuvant
endocrine therapy can be used for postmenopausal women with
ER- or PR-positive breast cancer to reduce extent of surgery or per­
haps avoid surgery for older women with multiple comorbidities.
Women with small tumors of any subtype are often better served
by initial surgery to establish pathologic stage followed by tailored
selection of systemic therapy.
Types of Systemic Therapy for Early Breast Cancer  Endocrine
therapy is a mainstay for management of ER- and/or PR-positive
invasive breast cancer; positive tumors are commonly defined as
those with ≥1% staining by immunohistochemistry. Because of their
mechanisms of action as blockers of interaction between estrogen
ligand and ER, the selective ER modulators tamoxifen and toremi­
fene can be used in women with any menopausal status. In contrast,
estrogen deprivation approaches depend on menopausal status.
The use of aromatase inhibitors, such as anastrozole, letrozole,
and exemestane, as monotherapy is restricted to postmenopausal
women. Ovarian suppression by gonadotropin hormone–releasing
hormone (GnRH), such as the luteinizing hormone–releasing
hormone (LHRH) agonists goserelin or leuprolide, or alternatively
surgical oophorectomy, can be used to reduce circulating estradiol
levels in premenopausal women to postmenopausal levels. These
women can then also be treated either with tamoxifen or an AI.
The CDK4/6 inhibitors abemaciclib and ribociclib may be used in
combination with endocrine therapy for high-risk, early-stage, ERpositive breast cancer.
Multiple cytotoxic agents have shown efficacy for treatment of
metastatic breast cancer and are now used in treatment of early-stage
disease. The most common regimens include cyclophosphamide,
doxorubicin, paclitaxel, docetaxel, 5-fluorouracil, methotrexate, and/
or one of the platin salt compounds (cisplatin or carboplatin).
Several anti-HER2 therapies are also available. Two monoclonal
antibodies, trastuzumab and pertuzumab, and two tyrosine kinase
inhibitors, neratinib and lapatinib, are approved for use in earlystage breast cancer; multiple other agents are available for meta­
static disease, as discussed below, and are undergoing testing for use
in earlier stages of disease.
CHAPTER 84
The role of immunotherapy with the checkpoint inhibitors is
also under evaluation. At present, pembrolizumab for patients with
TNBC is the only U.S. Food and Drug Administration (FDA)-
approved agent for early-stage breast cancer, but others are under
investigation.
A targeted agent, olaparib, an oral PARP inhibitor, is also used
as an adjunct to chemotherapy for women with high-risk, germline
BRCA-mutated, HER2-negative breast cancer who have completed
(neo)adjuvant chemotherapy. It is particularly active in cancers with
DNA repair pathway defects.
Breast Cancer
GENERAL GUIDELINES FOR (NEO)ADJUVANT SYSTEMIC
THERAPY FOR EARLY BREAST CANCER
Approach to ER- and/or PR-Positive Breast Cancer  Endocrine
therapy is the foundation for adjuvant therapy for women with ER-
and/or PR-positive breast cancer. Selection is based on menopausal
status and consideration of side effect profiles. For premenopausal
women with low-risk breast cancer, tamoxifen for 5–10 years is
the standard. Premenopausal women with higher risk tumors are
candidates for combined endocrine therapy with an LHRH agonist
plus tamoxifen or aromatase inhibitor for 5 years. Multiple random­
ized trials have shown that aromatase inhibitors for 5 years provide
modest but statistically significant superior outcome compared
with tamoxifen for postmenopausal women. Women with ERpositive breast cancers are at risk for distant recurrence long after
their original diagnosis, from 10–20 or more years. Some trials
suggest that up to 10 years of endocrine therapy may be indicated
for healthy postmenopausal women with higher risk tumors and
good tolerance.
Given the chronic nature of adjuvant endocrine therapy, careful
attention to side effects is warranted. Tamoxifen is associated with
postmenopausal symptoms and a small chance of thromboembolic
events or uterine cancer, especially in women over 50 years. Aro­
matase inhibitors are associated with postmenopausal symptoms,
arthralgias, and bone loss, while LHRH agonists are associated
with postmenopausal symptoms and bone loss. Although the three
aromatase inhibitors appear to be equally effective, tolerance may
vary; patients who are intolerant of one aromatase inhibitor may
benefit from change to another member of the family or tamoxifen.
A critical decision in this setting is the value of chemotherapy in
addition to endocrine therapy. Its absolute (as opposed to relative or
proportional) benefit varies by menopausal status and nodal status.
Genomic multigene expression testing of the tumor with assays
like Oncotype, MammaPrint, ProSigna, EndoPredict, or Breast
Cancer Index will identify a substantial portion of patients with
zero to three positive nodes who would not benefit from adjuvant
chemotherapy.
Neoadjuvant chemotherapy should be administered to healthy
individuals with a large tumor burden or more than three positive
nodes, especially premenopausal patients with a primary goal of
reducing tumor size. However, in ER-positive disease, the likeli­
hood of a pCR is low. Regardless, adjuvant chemotherapy (neoad­
juvant or standard) is considered for healthy individuals with four
or more positive lymph nodes as well as for those with lesser nodal
burden who have high genomic signature score. Established chemo­
therapy regimens are outpatient based and use multiple agents for
3–6 months with appropriate supportive care including antiemet­
ics and colony-stimulating factors as appropriate to reduce risk of
febrile neutropenia. Long-term side effects can include premature
menopause in premenopausal women and a small risk of doxorubicinrelated cardiomyopathy, taxane-related peripheral neuropathy, or
secondary leukemia, and possible cognitive dysfunction.
Women with node-positive or high-risk node-negative, ER- and/
or PR-positive, HER2-negative breast cancer who have completed
adjuvant chemotherapy should consider use of a CDK4/6 inhibi­
tor in conjunction with endocrine therapy. Current information
supports the use of abemaciclib for 2 years or ribociclib for 3 years;
addition of palbociclib for 2 years did not improve outcomes. Those
with HER2-negative germline BRCA-mutated breast cancer who
have received (neo)adjuvant chemotherapy should consider a year
of oral olaparib. When used in conjunction with chemotherapy or
anti-HER2 therapy, endocrine therapy is generally delayed until
completion of adjuvant chemotherapy to minimize toxicity.
PART 4
Oncology and Hematology
Approach to HER2-Positive Breast Cancer  Healthy individuals
with tumor ≥3 cm or positive lymph nodes are candidates for neo­
adjuvant therapy with multiagent chemotherapy and trastuzumab
with or without pertuzumab for 4–5 months. Those who achieve
a pCR should receive further trastuzumab with or without pertu­
zumab therapy to complete a year. By contrast, those with residual
invasive disease at surgery should switch to complete a year of the
antibody-drug conjugate (ADC) trastuzumab emtansine (TDM-1).
High-risk individuals who have completed a year of anti-HER2
therapy can also consider addition of oral neratinib for another
year, although the benefits are incremental.
Toxicity of trastuzumab is relatively uncommon. Few patients
have any side effects during treatment. However, the greatest risk
is reduction of cardiac ejection fraction. Therefore, baseline cardiac
evaluation with an echocardiogram should be obtained, and trastu­
zumab should not be given to those with low ejection fraction, or
they should be evaluated by an experienced cardiologist if therapy is
felt to be critical. Serial echocardiograms should be obtained during
adjuvant trastuzumab therapy but are not indicated once therapy
is discontinued if the patient has not had any evidence of cardiac
dysfunction.
Pertuzumab is commonly associated with loose stools or diar­
rhea. This can be managed with conservative loperamide treatment.
However, the added benefit of adjuvant pertuzumab to trastuzumab
is modest, and if diarrhea is not easily controlled, trastuzumab
should be continued alone.
Individuals who present with smaller tumors with clinically neg­
ative nodes should be considered for upfront surgery to establish
pathologic stage. This is because women with pathologically nodenegative tumors <3 cm have excellent outcomes with a regimen of
single-agent weekly paclitaxel for 12 weeks in conjunction with a
year of trastuzumab with or without pertuzumab.
Patients with HER2-positive tumors that are ER and/or PR posi­
tive should receive endocrine therapy as described above. Endocrine
therapy is generally initiated after completion of any chemotherapy
and can be given concurrent with anti-HER2 therapy. Neither
CDK4/6 inhibitors nor PARP inhibitors have been tested as an adju­
vant therapy in early-stage HER2-positive breast cancer.
Triple-Negative Breast Cancer (TNBC)  Healthy patients with
early-stage TNBC are frequently candidates for (neo)adjuvant che­
motherapy. Those with tumors >2 cm or tumors >1 cm and positive
axillary nodes should be considered for neoadjuvant multiagent
chemotherapy, perhaps in conjunction with the checkpoint inhibi­
tor pembrolizumab. If chemoimmunotherapy is utilized, then pem­
brolizumab is continued postoperatively to complete a year. Those
who achieve a pCR receive pembrolizumab alone. Those patients
who do not have a pCR may also consider further chemotherapy
with capecitabine. In contrast, those with smaller tumors that are
clinically node negative are best served by initial surgery to estab­
lish pathologic stage, which might permit a refinement of choice of
chemotherapy regimen.
Follow-Up of Survivors of Early-Stage Breast Cancer  Asymp­
tomatic survivors of early-stage breast cancer should be followed
regularly with history and physical examination to look for any
evidence of recurrent disease and to assess for toxicities of prior or
ongoing treatments. These exams are conducted every 3–6 months
for the first 3 years and diminish in frequency over time. As noted,
serial echocardiograms beyond 12 months of trastuzumab therapy
are not needed. Annual breast imaging to look for ipsilateral or
contralateral disease is the only routine testing needed. In the
absence of symptoms or physical exam findings, routine imaging of
other types or blood studies have not been shown to enhance wellbeing or outcome from breast cancer. Current research is focused
on use of blood-based assays for circulating tumor cells (CTCs) or
circulating free tumor DNA (ctDNA) as markers for early detection
of recurrent disease, but these are investigational approaches at
present. As many patients have long survival, routine follow-up by
a primary care provider and adherence to age-appropriate general
health guidelines are key.
Symptom management is a key aspect of follow-up, especially
for those on adjuvant endocrine therapy as adherence is a crucial
determinant of outcome. Hot flashes may be ameliorated by use of
antidepressants like venlafaxine or gabapentin, while vaginal dry­
ness should be addressed through topical agents or, if unsuccessful,
vaginal estrogen. Avoidance of hormone replacement therapy is
preferred. Aromatase inhibitor–associated musculoskeletal symp­
toms may be treated by switching from one aromatase inhibitor
to another after a 4- to 6-week washout period, or they can be
addressed by exercise, nonsteroidal anti-inflammatory agents, acu­
puncture, or the antidepressant duloxetine. Persistent taxane-related
peripheral neuropathy is sometimes responsive to gabapentin.
Special Considerations in Management of Individuals with Early
Breast Cancer 
Use of Bisphosphonates 
Bone health can be compromised by
breast cancer therapy, especially the estrogen-deprivation agents,
aromatase inhibitors and LHRH agonists. Patients who receive
these therapies may benefit from use of a bisphosphonate, zoledro­
nate every 6 months for 3 years, or oral clodronate or ibandronate
as a bone-strengthening agent. In addition, a meta-analysis suggests
that this therapy is associated with decreased breast cancer recur­
rence, especially in bone. Data on denosumab are less compelling
at present.
Pregnancy, Fertility, and Childbearing in Premenopausal
Women 
The diagnosis of breast cancer during pregnancy can
be difficult because of the evolving changes in the pregnant breast.
Suspicious lumps or skin or nipple changes should be evaluated as
above though imaging modalities of choice including ultrasound or
MRI. If breast cancer is diagnosed and pregnancy is continued, the
goal is to administer appropriate multimodality therapy to optimize
maternal outcome from breast cancer and minimize toxicity to the
fetus. Breast surgery can be safely undertaken during the second
and third trimesters, but any therapeutic radiation must be delayed
until after delivery. If indicated, certain chemotherapy agents such
as doxorubicin and cyclophosphamide can be administered during
the second and third trimesters, whereas others such as methotrex­
ate and 5-fluorouracil should be avoided. In general, endocrine
and targeted therapies should not be used until after delivery. Comanagement by experienced multidisciplinary breast cancer and
high-risk obstetrical teams is preferred.
Diagnosis of breast cancer in all premenopausal women neces­
sitates discussion about fertility preservation and pregnancy with
those women who desire later pregnancy. Premature menopause
is a known consequence of adjuvant chemotherapy, and likeli­
hood is related to type and duration of chemotherapy and age of
patient. It is seen in <50% of women <40 years old but is common
in those who are over 40. Patients are asked to avoid pregnancy
while on adjuvant endocrine therapy. Thus, counseling about and
implementation of fertility-preservation techniques are a priority in
newly diagnosed premenopausal women if further childbearing is
planned. A meta-analysis suggests that concurrent administration
of an LHRH agonist to suppress ovarian function during adjuvant
chemotherapy may help to preserve subsequent ovarian func­
tion without adverse breast cancer outcomes. Avoidance of oral
contraceptives or hormone-based intrauterine devices is recom­
mended for premenopausal breast cancer survivors who require
contraception.
Though data are not extensive, pregnancy after early stage
breast cancer diagnosis appears to be safe. There is no evidence of
increased rate of recurrence compared to matched patients who did
not become pregnant, nor is there evidence of increased fetal anom­
alies. A recent study has documented the safety and pregnancy
success rate for women with treated early ER-positive breast cancer
who stop adjuvant tamoxifen after 18–24 months of therapy and
then resume after pregnancy to complete their prescribed course.
Male Breast Cancer 
Men with breast cancer usually present
with a breast lump or other physical abnormality. Principles about
diagnosis, staging, and local therapy are like those for women,
although most men undergo mastectomy for primary management
for anatomic reasons. Men with breast cancer should undergo
genetic testing as germline BRCA mutation is seen in up to 14% of
men with breast cancer. About 90% of male breast cancers express
ER, and adjuvant endocrine therapy is standard. Tamoxifen is the
drug of choice; if an aromatase inhibitor is indicated (as for example
in an individual who has a history of thromboembolic disease),
concomitant administration of an LHRH agonist is required.
Guidelines for use of adjuvant chemotherapy are like those for
postmenopausal women.
LOCALLY ADVANCED BREAST CANCER
In the United States, about 10% of patients present with locally
advanced or stage III breast cancers, although this presentation
is more common in less-resourced countries. These tumors are
characterized by a large primary tumor, involvement of skin or
chest wall, or fixed tumors or axillary lymph nodes, findings that
make primary surgical resection difficult or impossible. Inflam­
matory tumors that present with rapid onset of erythema, swelling,
and tenderness of the breast are a subset of locally advanced breast
cancer and are sometimes confused with mastitis or other infection.
Breast or skin biopsy is critical in the setting of breast inflammation
that fails to resolve after antibiotics. Skin biopsy showing dermal
lymphatic invasion with tumor cells is often associated with the
diagnosis of inflammatory breast cancer. Because up to one-third
of these patients have detectable metastasis at time of diagnosis, an
evaluation for metastatic disease is recommended even in asymp­
tomatic patients.
Combined-modality therapy begins with neoadjuvant systemic
therapy, whose selection is guided by biomarker status as outlined
above, to downstage tumor to permit resection. Mastectomy with
axillary dissection is often required in the case of inflammatory or
other T4 lesions because breast-conserving therapy has been associ­
ated with an unacceptably high incidence of locoregional recurrence.
Postoperative radiotherapy is the norm in conjunction with systemic
therapy with chemotherapy and/or anti-HER2 therapy and/or endo­
crine therapy tailored to the biological qualities of the tumor.
METASTATIC BREAST CANCER
Presentation and Evaluation  About 20–25% of patients who are
treated for early breast cancer subsequently develop metastatic
disease, presumably because of micrometastatic disease at time
of diagnosis that was or becomes resistant to adjuvant systemic
therapy. Metastatic disease can be detected years to decades after
primary diagnosis, especially in the setting of ER-positive disease,
whereas it is most likely to be diagnosed within 3–7 years after
treatment for TNBC or ER-negative/HER2-positive breast cancer.
Only about 5% of patients present with de novo metastatic or stage
IV breast cancer in the United States.
Patients may present with abnormal physical exam or symptoms
suggestive of metastases. As shown in Fig. 84-3, careful evaluation
of extent of disease with computed tomography and radionuclide
imaging, routine blood studies, and measurement of tumor mark­
ers such as carcinoembryonic antigen (CEA) and either CA27/29
or CA15-3 should be undertaken. Wherever possible, it is critical
to biopsy a suspicious lesion to confirm the diagnosis of metastatic
breast cancer and assay tumor markers including ER, PR, and
HER2 because they may have changed from the initial biopsy under
the pressure of time or therapy. In addition, PD-L1 staining and
tumor mutational burden should be assessed in tumor, and assays
for PIKC3A and ESR1 mutations should be performed in blood or
tumor to delineate options for treatment. Next-generation sequenc­
ing of tumor may also be considered to simultaneously survey for
any other targetable changes to guide selection of therapy or eligi­
bility for a clinical trial.
CHAPTER 84
Goals of Care and General Management  Metastatic breast cancer
is rarely curable, and the goals of therapy, which is chronic—to
palliate or prevent symptoms without undue toxicity—should be
explicitly discussed with the patient at the time of diagnosis of
metastatic disease. Median survival is <3 years, although the range
is wide. Some patients with favorable characteristics such as ERpositive disease, nonvisceral disease, long disease-free interval,
and good performance status may survive using serial therapies for
many years, whereas those with TNBC are more likely to progress
sooner and succumb to their disease. Advances in our understand­
ing of biology of ER- and HER2-positive and genetically mutated
(e.g., BRCA1/2, PIK3CA) breast cancer and development of a
myriad of targeted treatments have led to improved outcome for
these subtypes in recent years.
Breast Cancer
Unlike in early breast cancer, the primary intervention in meta­
static breast cancer is systemic therapy. Surgery is generally limited
to excision of isolated local recurrence or a solitary brain metastasis
or stabilization of a bone metastasis. Randomized trials suggest that
patients who present with de novo metastatic breast cancer do not
have improved outcomes with surgical treatment for the primary
breast cancer in addition to systemic therapy and the focus should be
on systemic therapy. Radiotherapy may be used at any time to palli­
ate symptomatic localized disease such as bony or brain metastases.
All patients with metastatic breast cancer should have access to
palliative therapy approaches in addition to antineoplastic therapy
to maximize symptom control and quality of life. In addition, those
with metastatic bone disease should be considered for regular
administration of bisphosphonate or denosumab in addition to
antineoplastic therapy to reduce the chance of skeletal morbidity
including pain, fracture, and need for radiotherapy.
Patients with metastatic breast cancer require regular followup with history and physical exam to gauge response to therapy.
Patient well-being and relief of symptoms are paramount, and use
of imaging and blood studies should be personalized to the patient
and therapy to adjust dose or schedule and to assist in decisions
about efficacy and toxicity of therapy. Current algorithms suggest
changes in therapy only if the patient has clear signs of disease
progression or unacceptable toxicity. Studies to evaluate the role
of serial liquid biopsies to track CTC or ctDNA as an indicator to
switch therapy, and even to switch to a targeted therapy suggested
by the mutational profile of the ctDNA, in the absence of clinical or
radiologic evidence of disease progression are in progress.
Management of ER-Positive Metastatic Breast Cancer  Whenever
possible, serial use of endocrine therapy is the preferred approach
Clinical symptom
History, physical exam
Suspicious history or
clinical finding
Diagnostic workup
Imaging as indicated
(direct image of suspicious site;
anatomic imaging: CT or MRI; scintigraphic imaging:
bone or PET scan)
blood tests as indicated
(CBC, liver function tests,
circulating tumor biomarkers: CA15-3 or 27.29; CEA)
Confirmed suspicious finding
Nondiagnostic
Follow-up
evaluation
Biospy if possible
PART 4
Oncology and Hematology
Resolved
Uncertain
or persists
Routine
follow-up
Routine
follow-up
Continue follow-up rule out noncancer
etiology repeat diagnostic workup if indicated
FIGURE 84-3  Evaluation of new signs or symptoms in a patient with prior history of early-stage breast cancer. See text for details. CBC, complete blood count; CEA,
carcinoembryonic antigen; ER, estrogen receptor; NGS, next-generation sequencing; PET, positron emission tomography; PgR, progesterone receptor.
to patients whose recurrent tumor is ER and/or PR positive and
whose clinical presentation is not dire. Use of chemotherapy can
be reserved for those with life-threatening visceral disease like
lymphangitic lung metastases or impending liver failure. However,
a prospective trial has suggested that overall survival was the same
in patients with apparent rapidly growing visceral disease ran­
domly assigned to either chemotherapy or endocrine therapy and
a CDK4/6 inhibitor. There is no value for concurrent endocrine
therapy and chemotherapy for management of metastatic breast
cancer. Selection of type of endocrine therapy will depend on
menopausal status and previous adjuvant endocrine therapy. It may
be paired with targeted therapy depending on the molecular profile
of the cancer and clinical scenario.
For the uncommon patient who presents with untreated ER-posi­
tive metastatic breast cancer, therapy generally begins with aromatase
inhibitor plus CDK4/6 inhibitor for postmenopausal women and
LHRH agonist plus aromatase inhibitor plus CDK4/6 inhibitor for
premenopausal women; median progression-free survival is about
2 years, and median overall survival is >3 years with this approach.
More commonly, patients present with recurrent disease diag­
nosed while on or after completing adjuvant endocrine therapy. For
those who have received aromatase inhibitor, up to one-half will have
evidence of ESR1 mutation and may be candidates for the oral selec­
tive estrogen receptor degrading (SERD) agent elacestrant if they
have also received a CDK4/6 inhibitor. Those without evidence of
ESR1 mutation are often treated with an alternate SERD, fulvestrant,
which is administered monthly by intramuscular injection; this may
be coupled with a CDK4/6 inhibitor if the patient has not previously
received such an agent. The value of continuing or switching to
another CDK4/6 inhibitor for those who have previously received
adjuvant CDK4/6 inhibitor is not clearly defined in this setting.
For postmenopausal patients previously treated with endocrine
therapy who are found to have a PIKC3A mutation by liquid or
tissue biopsy, the use of alpelisib (a selective inhibitor of PI3Kα)
with fulvestrant can be considered. Postmenopausal patients with
Other cancer
or condition
Positive for
metastases
Benign
Further
evaluation
and
treatment as
indicated
Re-evaluate tumor
biomarker status ER,
PgR, HER2, PIK3CA
mutation, PD-L1, NGS
(tissue or circulating)
PIK3CA/AKT1/PTEN alterations who have received one endocrine
therapy for metastatic disease or recur within 12 months of complet­
ing adjuvant therapy can receive capivasertib (a pan-AKT inhibitor)
with fulvestrant. The use of aromatase inhibitor plus everolimus, an
mTOR inhibitor, can be considered for patients without targetable
mutations as it, too, has been shown to increase progression-free
survival over endocrine therapy alone. Each of these targeted agents
carries a unique set of toxicities, and careful monitoring of clinical
status and blood studies is needed for safe administration.
Other approaches, especially for patients who have demonstrated
repeated and lengthy responses to serial hormone therapies, can
include switch to another aromatase inhibitor or tamoxifen or
administration of additive hormone therapies such as progestins,
androgens, and estrogens. The latter category of agents is seldom
used at present because of concerns about toxicity and the advent
of newer more targeted therapies.
At some point, it will become apparent that a patient has tumor
that is unresponsive to endocrine therapy, which necessitates a
transition to other types of systemic therapy. The timing of this
decision may be informed in part by the observation that likelihood
of disease control and the duration of benefit are decreased by about
one-half with each successive switch in endocrine therapy.
Management of Endocrine-Unresponsive ER-Positive, HER2-Negative
Breast Cancer or TNBC  Chemotherapy is the backbone of sys­
temic therapy for individuals with metastatic HER2-negative breast
cancer that is not responsive to endocrine therapy. Unlike in the
setting of early breast cancer where multiagent chemotherapy is the
norm, use of combination chemotherapy in metastatic breast cancer
should be reserved for the uncommon situation of visceral crisis
where a rapid reduction in tumor burden is desirable. For most
patients, serial use of single-agent chemotherapy is associated with
an acceptable likelihood of disease palliation without excess toxic­
ity; combination chemotherapy does not improve overall survival
over sequential monotherapy.

14 - 85 Upper Gastrointestinal Tract Cancers
85 Upper Gastrointestinal Tract Cancers
Many chemotherapeutic agents are active in metastatic breast
cancer, and selection is based on previous adjuvant chemotherapy
and patient preference about route and schedule of administration
and side effects. The oral agent capecitabine is often used initially
because of ease of administration and acceptable side effect profile.
However, several studies have demonstrated that a small percent­
age of the population harbors deleterious mutations in the DPYD
gene, which is responsible for converting capecitabine to its inac­
tive metabolites for excretion. Such patients are prone to suffering
extreme and, in some cases, lethal toxicities, and some guidelines
call for routine testing for this gene before initiating capecitabine
or other fluoropyrimidines, such as 5-fluorouracil. Other options
include taxanes, anthracycline (depending on previous adjuvant
exposure), vinorelbine, gemcitabine, cyclophosphamide, metho­
trexate, eribulin, ixabepilone, and platinum-based agents; the last
is often considered in TNBC because of evidence of activity of
platinums in that subtype. For patients with TNBC that expresses
PD-L1, administration of paclitaxel with the checkpoint inhibitor
pembrolizumab can be considered because the combination results
in better outcomes than taxane alone; activity of other checkpoint
inhibitors is under investigation.
ADCs are increasingly finding a role in treatment of metastatic
breast cancer. Sacituzumab govitecan, an antibody targeted against
TROP-2SN-38 coupled to an irinotecan metabolite, has shown
activity against TNBC and endocrine-unresponsive ER-positive,
HER2-negative breast cancer. A second ADC, trastuzumab derux­
tecan, which couples trastuzumab with the cytotoxic deruxtecan
(discussed in greater detail below in the HER2 section) is also active
against tumors that express low levels of HER2 (1+ or 2+/fluorescence
in situ hybridization [FISH] negative) and were initially labeled
HER2 negative and thus ineligible for adjuvant anti-HER2 therapy
using other anti-HER2 agents. Development and testing of novel
ADCs are very vibrant areas in treatment of metastatic breast can­
cer, and findings are beginning to challenge some of our concepts
about targeted therapy.
For patients whose tumors have evidence of germline or somatic
BRCA mutation, use of single-agent PARP inhibitor with olaparib
or taloparib should also be considered, perhaps before the transi­
tion to infusional therapies because of convenience.
Management of HER2-Positive Breast Cancer  The landscape of
treatment for metastatic breast cancer has changed substantially in
the 25 years since the importance of HER2 protein expression as
a predictor for response to anti-HER2 therapy was demonstrated.
FDA-approved HER2-directed therapies now include monoclo­
nal antibodies (trastuzumab, pertuzumab, margetuximab), smallmolecule tyrosine kinase inhibitors (lapatinib, neratinib, tucatinib),
and ADCs (ado-trastuzumab emtansine or TDM-1, trastuzumabderuxtecan), and others are under development. Apart from
trastuzumab-deruxtecan, their clinical benefit is seen only in indi­
viduals whose tumors express 3+ HER2 staining by immunohisto­
chemistry or are gene-amplified by FISH.
The preferred first-line treatment for metastatic HER2-positive
breast cancer is a combination of taxane, pertuzumab, and trastu­
zumab for several months; taxane chemotherapy may be stopped
when disease stability is reached, and the anti-HER2 agents are
continued as maintenance therapy. In some cases, this approach
can lead to long-term remission, and an active area of research is
how long to continue anti-HER2 therapy for those with complete
response. A randomized clinical trial has established the superior­
ity of trastuzumab-deruxtecan for second-line therapy. Thereafter,
serial administration of anti-HER2 agents, in some cases in com­
bination with single-agent chemotherapy, is pursued. Patients who
have HER2-positive, ER- and/or PR-positive breast cancer may
benefit from concomitant endocrine therapy as well.
HER2-positive breast cancers have a propensity for involvement
of the central nervous system. Because control of systemic disease
with anti-HER2 therapies can be excellent and penetration of
the antibody-based agents across the blood-brain barrier is poor,
patients with this disease subtype are often found to have brain
metastasis and may require radiotherapy for local disease control.
The small-molecule inhibitors may also offer disease control as they
cross into the central nervous system.
■
■FURTHER READING
Andre F et al: Biomarkers for adjuvant endocrine and chemotherapy
in early-stage breast cancer: ASCO Guideline Update. J Clin Oncol
40:1816, 2022.
Bedrosian I et al: Germline testing in patients with breast cancer:
ASCO-Society of Surgical Oncology guideline. J Clin Oncol 42:584,
2024.
Benitez Fuentes JD et al: Global stage distribution of breast cancer at
diagnosis: A systemic review and meta-analysis. JAMA Oncol 10:71,
2024.
Burstein HJ: Systemic therapy for estrogen receptor-positive, HER-2
negative breast cancer. N Engl J Med 383:2557, 2020.
Curigliano G et al: Understanding breast cancer complexity to
improve patient outcomes: The St Gallen International Consensus
Conference for the Primary Therapy of Individuals with Early Breast
Cancer 2023. Ann Oncol 34:970, 2023.
Giordano S et al: Systemic therapy for advanced human epidermal
CHAPTER 85
growth factor receptor 2-positive breast cancer: ASCO guideline
update. J Clin Oncol 40:2636, 2022.
Henry NL et al: Biomarkers for systemic therapy in metastatic breast
cancer: ASCO guideline update. J Clin Oncol 40:3205, 2022.
Jackson EB, Chia SKL: Sequencing of endocrine therapy targeted ther­
apies in hormone-sensitive, human epidermal growth factor receptor
2-negative advanced breast cancer. J Clin Oncol 41:3976, 2023.
Loibl S et al: Breast cancer. Lancet 397:1750, 2021.
Nielsen S, Narayan AK: Breast cancer screening modalities, recom­
Upper Gastrointestinal Tract Cancers
mendations, and novel imaging techniques. Surg Clin North Am
103:63, 2023.
PDQ Screening and Prevention Editorial Board: Breast
Cancer Prevention (PDQR). https://www.ncbi.nlm.nih.gov/books/
NBK65884/.  Accessed January 7, 2024.
David Kelsen
Upper Gastrointestinal
Tract Cancers
Cancers of the upper gastrointestinal tract include malignancies of the
esophagus, stomach, and small bowel. Esophageal, gastroesophageal
junction (GEJ), and gastric cancers are among the most common of
human malignancies, with 1.693 million global new cases diagnosed
in 2020; as a measure of the gravity of such a diagnosis, there were an
estimated 1.312 million deaths. In the United States, a lower-risk area,
it is estimated that in 2023, esophageal cancer will be diagnosed in
21,560 people and cause 16,120 deaths; for gastric cancer, 26,500 new
cases will be diagnosed and 11,130 deaths will occur. Small intestine
cancers are rare.
ESOPHAGEAL CANCER
■
■GLOBAL DIFFERENCES IN INCIDENCE AND
CAUSATIVE FACTORS
Two distinct forms of cancer with different epidemiologies, causative
factors, and genomic profiles arise within the esophagus: squamous
cell cancers (SCCs), which occur more frequent in the upper and mid
esophagus; and adenocarcinomas, which are almost always located
in the lower esophagus and at the GEJ. The incidence of esophageal
cancer varies up to 20-fold in global geographic distribution: it is
relatively uncommon in North America but has a high incidence in
Asia (especially China), the Normandy coast of France, and Middle
Eastern countries such as Iran. This marked global variation is likely
due to different causative factors in the development of the malignancy,
leading to two different cancer types within the same organ: glob­
ally, SCCs make up the majority of cases, as they are more common
in high-incidence areas, usually with lower of the four-tier Human
Development Index (HDI) scores (a measure of economic develop­
ment that includes standard of living, health, and education). Overall,
approximately 604,100 new cases of esophageal cancer were diagnosed
globally in 2020; esophageal cancer was the tenth most common cause
of malignancy and the sixth most common cause of cancer-related
mortality, with an estimated 544,076 deaths.
The most established high-risk factors for the SCC subtype in
Western countries are alcohol or tobacco abuse; concurrent alcohol and
tobacco abuse further increases the risk. Ingestion of extremely hot sub­
stances (such as tea in Iran and mate [maté] in South America) has been
proposed as a risk factor; in India, chewing the areca (betel) nut increases
the risk of esophageal SCC. Less common risk factors include chronic
achalasia, radiation therapy (such as is delivered for treatment of Hodg­
kin’s lymphoma or breast cancer), lye ingestion, and Plummer-Vinson
(Patterson-Kelly) syndrome (iron deficiency anemia, glossitis, cheilosis,
and the development of esophageal webs). Adenocarcinoma of the lower
esophagus and GEJ has been the predominant histologic subtype in the
United States and Western Europe for several decades, now making up
75% of all incident cases. Risk factors for adenocarcinoma include
chronic reflux esophagitis leading to inflammation and the development
of Barrett’s esophagus (the finding of glandular gastric type mucosa
extending into the esophagus). Although obesity increases the risk of
reflux esophagitis, a substantial number of patients with newly diag­
nosed adenocarcinoma of the esophagus and GEJ are younger and fit;
Barrett’s esophagus may still be found in these patients. In patients with
adenocarcinoma of the lower esophagus in which Barrett’s esophagus is
not present, the disease may arise without Barrett’s esophagus, or an exten­
sive tumor found at diagnosis may obliterate previous areas of Barrett’s.
Genomic alterations may be identified even before the development of
frank adenocarcinoma in patients with dysplasia associated with Barrett’s
esophagus. These include mutations of TP53, a gene critical in regulating
uncontrolled cell division, and aneuploidy in dysplastic regions. Risk of
progression of Barrett’s esophagus to cancer is about 0.4–0.5% per year.
Management of Barrett’s esophagus is discussed in Chap. 334.
PART 4
Oncology and Hematology
As opposed to other gastrointestinal malignancies, such as colorec­
tal cancer, inherited cancer susceptibility genes are rarely associated
with esophagus and GEJ cancers. An exception is the rare inherited
cancer susceptibility gene driving tylosis palmaris and plantaris; a
mutation in the RHBDF2 gene is associated with an increased risk
for SCC of the esophagus. Both Lynch syndrome and germline BRCA
mutation carriers have a modestly increased risk of gastric and poten­
tially GEJ adenocarcinomas. Identification of these germline mutations
is important because it guides choices of systemic therapy, as well as
counseling of family relatives (see below).
■
■SCREENING AND SURVEILLANCE OF HIGHER
RISK GROUPS
Because of its low incidence in North America and the absence of
proven blood-based biomarkers for esophageal cancer assays, screen­
ing of the asymptomatic general population using, e.g., upper endos­
copy is not currently recommended in the United States. Periodic
endoscopy is used for surveillance of higher risk patients, such as those
with Barrett’s esophagus, especially with dysplasia, based on expert
opinion guidelines.
Early-Onset GEJ and Gastric Cancers 
A marked increase in
the incidence of early-onset gastrointestinal malignancies (EOGI;
cancer occurring in people <50 years of age) has been noted over the
past several decades. First noted were early-onset colorectal cancers,
occurring particularly in the left-sided colon or rectum; the start of
the steep increase was traced back to the mid-1990s. A similar trend
has been noted in upper gastrointestinal tract cancers, particularly in
women. The large majority of EOGI patients do not have inherited
germline cancer susceptibility gene mutations or a family history of
malignancy for colon cancer or small-bowel cancer or inflammatory
bowel disease. Driving factors suggested for the steep increase include
lifestyle changes such as being more sedentary (less exercise), dietary
changes leading to obesity, use of alcohol and tobacco, changes in the
microbiome, and exposure to an as not yet identified environmental
agent, not previously used, which was introduced to the general popu­
lation in the 1980s or 1990s. Because the absolute number of young
people developing GEJ or gastric cancers is still small, surveillance
upper endoscopy or imaging is not recommended (for colon cancer
screening, current U.S. recommendations are to start at age 45 years).
Efforts are underway to develop sensitive and specific early detection
biomarkers such as blood-based assays. Because these cancers are
uncommon in young patients, symptoms may be attributed to benign
illnesses so that advanced stages are common at the time of diagnosis.
Physicians should be aware that symptoms in a young person found
more typically in older patients, such as dysphagia, odynophagia, or
upper abdominal discomfort, may be related to malignancy, leading to
the same diagnostic studies as performed in older patients.
■
■GENOMIC ALTERATIONS
Genomic alteration analyses have revealed substantial genomic dif­
ferences between adenocarcinomas and SCCs of the esophagus. The
well-known integrated analysis involving several different genomic
platforms, performed by The Cancer Genome Atlas (TCGA) Research
Network investigators, demonstrated that esophageal SCC more
closely resembled SCCs of other primary sites, such as the head and
neck, than adenocarcinomas arising in the esophagus. Three molecu­
lar subclasses of SCC were identified (of note, as opposed to SCC of
the head and neck, human papillomavirus was not identified in any of
the three subgroups). Similarly, a study of 528 Chinese SCC patients,
using whole genome sequencing, evaluated structural variations
resulting in rearrangements; five types of structural variations were
identified, and some of these may be of clinical significance. In adeno­
carcinomas, HER2/ERBB2 is frequently amplified, and microsatellite
instability can be found in both esophageal and GEJ adenocarcinomas.
Epstein-Barr virus (EBV) infection is a driver in adenocarcinoma. The
similar genomic profile for adenocarcinomas of the distal esophagus,
GEJ, and cardia of the stomach suggests that proximal gastric and
GEJ tumors may have a similar driving factor (see below). A genomewide association study identified 27 risk loci for the development of
adenocarcinomas of the esophagus or GEJ, with a difference between
adenocarcinoma arising in Barrett’s esophagus versus not. Other stud­
ies comparing transcriptomes of adenocarcinomas and SCC across
organs (i.e., the same tumor histology arising in different organs, such
as SCCs and adenocarcinomas from the esophagus, lung, and uterine
cervix) found that the same histologies among the different organs
showed more similarity than between the different histologies within
the same organ. In addition to implications regarding driving factors in
the initiation and progression of cancer, these genomic alterations are
important for therapeutic decisions involving systemic agents given
in the neoadjuvant or postoperative adjuvant setting or for advanced
metastatic disease. For esophageal adenocarcinoma, genomic abnor­
malities that should be considered in prescribing drug-based therapy
include analysis for HER2/ERBB2 amplification, programed death
ligand 1 (PD-L1) expression, and hypermutated tumors/microsatellite
instability (see Table 85-1, and below). For SCC of the esophagus, the
degree of PD-L1 expression may be of importance.
CLINICAL FEATURES
■
■PRESENTING SYMPTOMS
The most common symptoms leading to suspicion of esophageal can­
cer are dysphagia or odynophagia and, less frequently, hematemesis or
melena. More subtle symptoms include anorexia and weight loss, and
TABLE 85-1  AJCC Prognostic Stage Groups for Esophageal Cancer Using cTNM (Pretreatment)a
TNM
CLINICAL STAGE
PRESENTING AT THIS STAGEb,c
SQUAMOUS
ADENOCARCINOMA
cTis, N0, M0
1.2%
75%
82%
cT1-2, N0, M0
I
17%
75%
78%
cT1-2, N1-3, M0
IIA
7%
53%
50%
cT3-4a, N0, M0
IIB
13%
40%
40%
cT3-4a, N1-3, M0c
III
31%
25%
25%
cT4b, any N, M0
IVA
17%
21%
cAny T, any N, M1
IVB
5%
10%
18%
Survival by ypTNM Staging After Neoadjuvant Chemotherapy
ESTIMATED 5-YEAR SURVIVAL RATE
TNM
yp STAGE
SQUAMOUS
ADENOCARCINOMA
T1-2, N0, M0
T1, N1, M0
I
46%
52%
T3, N0-1, M0
T2, N1-2 M0
T1, N2-3, M0
T4a, N0, M0
II
34%
38%
T4a, N1-3 M0
T4b, any N, M0
T3, N2-3, M0
T2, N3, M0
III
22%
27%
Any T, any N, M1
IV
10%
12%
aAJCC Cancer Staging Manual Version 9 expected in 2024. bSquamous cell and adenocarcinoma histologies combined. CSurgical series; underestimates incidence of M1
disease at presentation. dIncidence includes cT4b and cNanyMO.
Sources: Adapted from TW Rice et al: CA Cancer J Clin 67:304, 2017; TW Rice et al: Dis Esophagus 29:707, 2016; and TW Rice et al: personal communication.
fatigue and shortness of breath if anemia from gastrointestinal bleed­
ing is present. Because the symptoms of dysphagia or odynophagia are
usually not perceived by the patient until substantial obstruction of
the esophageal lumen has occurred, the large majority of patients with
esophageal cancer are found with locally advanced if not metastatic dis­
ease. Patients with symptoms of dysphagia and/or odynophagia should
undergo upper endoscopy to determine the presence or absence of
malignancy; biopsy should be performed at the same setting to deter­
mine histology. Depending on the tumor stage, molecular diagnostic
or next-generation sequencing (NGS) analysis to assist in determining
potential therapies should be performed. PD-LI, which may guide use
of immune modulation therapy, is assessed by immunohistochemistry
(IHC). NGS requires adequate tumor cellularity, which may be difficult
to achieve from endoscopic biopsy. NGS is currently probably the most
efficient methodology for genomic analysis (other than PD-L1), and
genomic analysis should be done on all patients with metastatic disease
because it will guide therapy. Some high-volume U.S. centers routinely
perform NGS on all specimens, including from all but the most earlystage primary tumors of patients without metastatic disease.
■
■STAGING
Therapeutic strategy is currently based on the stage of the disease using
a system such as the eighth version of the American Joint Committee
on Cancer (AJCC) Staging Manual (for esophageal and gastric cancers,
the ninth version is expected in 2024) tumor-node-metastasis (TNM)
staging system. The T stage is based on the size of the tumor and
depth of penetration through the esophageal wall (which for most of
its course is not covered by serosa so that invasion through the muscle
layer leads directly into periesophageal tissues) (Fig. 85-1). Patients
with regional lymph node metastases are still potentially curable. Meta­
static disease is generally treated with palliative intent with rare excep­
tions. Because neoadjuvant (preoperative) therapy is widely employed
for esophageal cancer to improve subsequent surgical outcomes, the
AJCC TNM staging system includes clinical, pathologic (for patients
5-YEAR SURVIVAL RATE
CHAPTER 85
Upper Gastrointestinal Tract Cancers
undergoing initial surgery as first treatment), and ypTNM staging
assessment for those treated with preoperative therapy. See Table 85-2
for the TNM staging classification for gastric cancer, which is similar
to esophageal cancer.
Determining tumor extent includes careful physical examination,
which may reveal palpable lymphadenopathy or hepatomegaly; imag­
ing studies including computed tomography (CT) and fluorodeoxyglu­
cose (FDG) positron emission tomography (PET)-CT scan are used
to assess for metastatic disease. If no metastatic disease is identified,
endoscopic ultrasonography (EUS) is commonly performed to more
definitively determine depth of penetration of the primary tumor (T)
and regional lymph node involvement. Deep learning artificial intel­
ligence methodology may assist the imaging analysis to improve the
diagnostic sensitivity and specificity of EUS for both esophageal and
gastric cancers. For tumors of the mid and upper esophagus (5% of
esophageal cancers are in the upper third of the esophagus, 20% in the
middle third, and 75% in the lower third), bronchoscopy may be per­
formed to rule out invasion of the tracheobronchial tree. The finding
of invasion of the trachea or bronchus rules out surgical intervention
with curative intent. Regional lymph nodes may be biopsied under
EUS guidance. For GEJ tumors, as for gastric cancers, laparoscopy is
performed at many centers to assess for peritoneal involvement if the
T stage is more advanced. If metastatic disease is suspected, biopsy to
confirm tumor staging and to obtain adequate tissue for molecular and
genomic alterations analysis should be performed. Assay of plasma
ctDNA (circulating tumor DNA) can be used to detect genomic altera­
tions before treatment if biopsy tissue is too limited to allow NGS or
molecular diagnostics; ctDNA is being studied as a measure of minimal
residual disease after definitive regional therapy (surgery or chemora­
diation therapy). If systemic therapy is indicated as a portion of the
treatment (for metastatic disease or for preoperative therapy for locally
advanced cancers), serial FDG-PET/CT scans, using decrease in FDG
avidity as a surrogate measure of effectiveness, are being used to guide
whether the initial therapy should be continued or changed.
Tis
(HGD)
T1a
T1b
T2
T3
T4a
T4b
NO
N1 1 or 2
N2 3 to 6
N3 7 or more
PART 4
Oncology and Hematology
M1
Pleura
FIGURE 85-1  Patterns of spread of esophageal cancer and the basis for anatomic staging. HGD, high-grade dysplasia. (Reproduced with permission from TW Rice et al:
Cancer of the esophagus and esophagogastric junction: An eighth edition staging primer. J Thorac Oncol 12:36, 2017.)
TREATMENT
Esophageal Cancer
Although the prognosis for patients with esophageal cancer (all
stages) is still poor, a slow but steady improvement in 5-year survival
has been noted. Because no cost-effective early detection methods
exist in low-incidence countries, the number of U.S. patients found
to have very-early-stage cancers at the time of diagnosis has not
markedly increased; the modest improvement in survival is prob­
ably a combination of somewhat improved systemic therapy as well
as decreased operative morbidity and mortality when surgery is
performed by high-volume surgeons at high-volume centers, as well
as improvements in the delivery of external-beam radiation therapy.
For patients without evidence of metastatic disease, the goal of
therapy is cure, usually by employing combined-modality therapies.
Except for patients with early-stage esophageal cancer, who might
be treated by surgery alone (or for very-early-stage lesions [Tis
or T1a], by endoscopic mucosal resection [EMR] or submucosal
dissection [ESD] for smaller [<2 cm] tumors); EMR and ESD are
also used as part of initial staging to determine more definitively
T stage), preoperative treatment including systemic drug therapy
is a standard of care option for patients with esophageal and GEJ
cancers. For locally advanced adenocarcinomas of the esophagus
and GEJ, systemic therapy alone may be indicated: in the ESO­
PEC trial, preoperative systemic FLOT chemotherapy resulted
in improved survival compared to preoperative chemoradiation
(using the CROSS regimen). For selected patients with adenocar­
cinomas (e.g., not able to tolerate regimens such as FLOT), and
for patients with SCC of the esophagus, chemoradiation remains a
standard of care option; for SCC, chemoradiation may be definitive
therapy. If surgery is planned after preoperative chemoradiation, a
prolonged delay before surgery has been associated with a poorer
outcome. For selected patients with GEJ adenocarcinomas, systemic
Lamina propria
Epithelium
Basement membrane
Submucosa
Muscularis mucosae
Muscularis
propria
Adventitia
Aorta
therapy alone may be given before definitive surgical resection.
For patients with SCC of the upper and mid esophagus, combined
chemotherapy plus concurrent radiation therapy is a standard
option, with surgery reserved for patients not achieving a complete
radiographic and endoscopic response. Radiation therapy alone is
rarely given with curative intent, as chemotherapy plus concurrent
radiation was superior to radiation therapy alone in several clinical
trials. Increasingly, all systemic therapy with curative intent is given
before operation, although if surgery is the initial therapy and the
patient is found to have more locally advanced cancer at pathol­
ogy (e.g., regional lymph node metastasis), postoperative systemic
therapy is used in the adjuvant setting. Adjuvant chemotherapy is
more frequently indicated in patients with adenocarcinoma than
SCCs. The CheckMate 577 trial demonstrated that for esophageal
or GEJ cancer patients who received preoperative chemoradiation
therapy and underwent a R0 (negative margins) resection but who
had residual tumor in the resection specimen (i.e., not ypT0N0M0),
postoperative adjuvant therapy with nivolumab, an immune-mod­
ulating agent targeting PD-1, significantly improved survival. For
patients with metastatic disease, the goal of therapy is symptom
palliation and life extension. No randomized trials of supportive
care only versus systemic therapy plus best supportive care have
been reported in patients with esophageal cancers. For gastric
cancer (an adenocarcinoma histology, as are most distal esophageal
and GEJ tumors), clinical trials performed in the 1980s and 1990s
indicated a modest improvement in 1- and 2-year survival when
systemic therapy plus best supportive care was used versus best
supportive care only. While the cytotoxic chemotherapy regimens
used for palliation have not changed dramatically over the past
10 years (currently including, for first-line treatment, a platinum
compound such as oxaliplatin and a fluorinated pyrimidine such
as fluorouracil or capecitabine; the FLOT [fluorouracil, leucovorin,
oxaliplatin, and docetaxel] regimen includes docetaxel and is used
TABLE 85-2  Staging System for Gastric Carcinomaa
DATA FROM ACS IN THE
UNITED STATES
NO. OF
CASES, %
5-YEAR
SURVIVAL, %
STAGE
TNM
FEATURES
TisN0M0
Node negative; limited to
mucosa
IA
T1N0M0
Node negative; invasion
of lamina propria or
submucosa
IB
T2N0M0
T1N1M0
Node negative; invasion of
muscularis propria
II
T1N2M0
T2N1M0
Node positive; invasion
beyond mucosa but within
wall
or
T3N0M0
Node negative; extension
through wall
IIIA
T2N2M0
T3N1-2M0
Node positive; invasion
of muscularis propria or
through wall
IIIB
T4N0-1M0
Node negative; adherence
to surrounding tissue
IIIC
T4N2-3M0
3 nodes positive; invasion
of serosa or adjacent
structures
T3N3M0
7 or more positive nodes;
penetrates wall without
invading serosa or
adjacent structures
IV
T4N2M0
Node positive; adherence
to surrounding tissue
or
T1-4N0-2M1
Distant metastases
aAJCC Cancer Staging Manual, Eighth Edition.
Abbreviation: TNM, tumor-node-metastasis.
in very fit patients), subgroups of patients have been identified
who benefit from therapies targeting specific genomic alterations
(Table 85-3). Approximately 20–25% of patients with adenocar­
cinoma of the esophagus or GEJ are found to have amplified or
overexpressed HER2/ERBB2; trastuzumab plus chemotherapy, or
trastuzumab, chemotherapy, plus immune therapy using pembro­
lizumab (for progression-free survival), results in higher response
rates and longer progression-free and overall survival compared
to chemotherapy alone. For patients whose tumors do not express
HER2/ERBB2, immune-modulating therapy using PD-1 inhibi­
tors is a standard option as part of first-line therapy (in combina­
tion with chemotherapy) and as second-line palliative therapy for
patients who have esophageal cancers expressing PD-L1. Patients
TABLE 85-3  Molecular Diagnostics and Genomic Alteration Analyses
Help Guide Systemic Therapy
SITE HISTOLOGY
FACTOR
ASSAY TYPE
THERAPY OPTIONS
Esophageal SCC
PD-L1
IHC
Immunomodulation
Esophageal Adeno/
GEJ
PD-L1
IHC
Immunomodulation
Esophageal Adeno
GEJ
ERRB2/HER2
IHC/FISH/NGS
Trastuzumab;
trastuzumab-deruxtecan
Esophageal Adeno
GEJ/gastric
dMMRP/MSI
IHC/NGS
Immunomodulation
Gastric Adeno
Claudin 18.2
IHC
Zolbetuximaba
aZolbetuximab is currently investigational.
Abbreviations: Adeno, adenocarcinoma; dMMRP, deficient mismatch repair
protein; FISH, fluorescent in situ hybridization; IHC, immunohistochemistry; MSI,
microsatellite instability; NGS, next-generation sequencing; PD-LI, programmed
death ligand 1; SCC, squamous cell carcinoma.
whose tumors have high PD-L1 combined positive score (CPS) may
have greater benefit. For patients with hypermutated or microsat­
ellite-unstable tumors, immune therapy alone is considered, using
agents such as pembrolizumab, or nivolumab plus ipilimumab.
As noted above, molecular diagnostic or NGS genomic alteration
analysis assays to identify these biomarkers should be performed
routinely in patients with metastatic esophageal, GEJ, and gastric
cancer to help guide therapy.
Supportive measures to improve nutrition and quality of life
include placement of an endoluminal stent in the setting of highgrade obstruction; use of enteral nutrition can also be performed
using a percutaneous gastrostomy. Photodynamic therapy and
endoscopic laser therapy have been used to treat symptoms of
endoluminal obstruction.
TUMORS OF THE STOMACH
■
■ADENOCARCINOMA OF THE STOMACH
Incidence and Causative Factors 
Since the 1920s, the incidence
of gastric cancer has steadily decreased; while the reason for this has
not been definitively identified, it coincided with widespread use of
refrigeration and a decreased need for food preservatives. In 2023,
it is estimated that there will be 27,500 new cases of gastric cancer
diagnosed in the United States; while now seen much less frequently, it
remains a lethal disease, with 11,130 deaths. As noted above, globally,
gastric cancer is the third most common cause of cancer mortality.
High-incidence areas, as is the case for esophageal cancers, include
large Asian countries such as China, Korea, and Japan; South American
countries such as Chile; and Eastern European countries.
CHAPTER 85
Upper Gastrointestinal Tract Cancers
While the number of new cases of body and distal gastric cancers
has decreased in Western, high-tier HDI countries, the incidence of
adenocarcinomas of the GEJ has markedly increased in the same areas
over the past several decades, including as described earlier in younger
patients. For gastric cancer overall, a higher incidence in some coun­
tries may be due to the ingestion of high concentrations of nitrates
found in dried, smoked, and salted foods. Chronic inflammation,
caused by an infection, is a major cause of gastric cancer. Helicobacter
pylori infection is a known driver in many cases of gastric cancer. While
H. pylori is extremely common, occurring in approximately half of all
humans, gastric cancer occurs in only a small subset of those infected.
Higher cancer risk has been associated with certain strains of H. pylori;
while analyses of H. pylori are identifying high-risk genomic factors, a
specific human genomic profile increasing risk of gastric cancer in the
setting of H. pylori has not yet been identified. H. pylori and ingestion
of partially decayed bacterially contaminated food may lead to the gen­
eration of carcinogenic nitrites from nitrates. Supportive evidence that
H. pylori infection is a causative factor in the development of gastric
cancer includes prospective studies demonstrating that treatment of
H. pylori infection decreases the overall risk of gastric cancer. For exam­
ple, patients with H. pylori infection who had at least one first-degree
relative with a history of gastric cancer (increasing their own risk of
stomach cancer) were randomly assigned to placebo or treatment for
H. pylori. The group receiving H. pylori eradication showed a signifi­
cant decrease in the incidence of gastric cancer (especially for those in
whom H. pylori was successfully eradicated) compared to the control
group. Earlier studies had demonstrated that treatment of H. pylori in
Korean patients who had a prior very-early-stage gastric cancer decreased
the incidence of a second gastric cancer. These data suggest that treat­
ment of asymptomatic H. pylori gastric infection should be considered
for patients who have a first-degree relative who has had gastric cancer
or who themselves have a prior history of an early-stage gastric cancer.
The spectrum of the gastric microbiome beyond H. pylori may also be
contributory to an increased risk of gastric cancer, with gastric cancer
patients having a higher bacterial load than controls.
EBV has also been associated with an increased risk for gastric cancer,
and gastric cancer EBV phenotype and genotype have been well described.
Another inflammation-driven cause is suspected to be reflux of gastric
contents into the esophagus, particularly in obese people, increasing the
risk of GEJ and esophageal adenocarcinomas. Obesity alone is not the
cause, as a substantial number of GEJ patients are fit and not overweight.
In addition to chronic inflammatory conditions, inherited cancer
susceptibility genes increase the risk of gastric cancer. These include
mutations of CDH1, which encodes for the cell cohesion gene e-cadherin;
germline CDH1 mutations markedly increase the risk for the diffuse
cell (signet cell) gastric cancer subtype (see below for discussion of
histologic subtypes). Prophylactic gastrectomy as a risk-reducing sur­
gical procedure is an option for patients with an inherited deleterious
CDH1 mutation. CDH1 mutations also increase the risk for lobular
breast cancer. Germline mutations in the mismatch repair pathway
(Lynch syndrome) and in the homologous repair pathway (BRCA
mutations) slightly increase the risk for gastric cancer. Other inherited
cancer susceptibility genetic syndromes that increase the risk of gastric
cancer include familial adenomatous polyposis, juvenile polyposis, and
Peutz-Jeghers syndrome. Surveillance programs for the early detec­
tion of gastric cancer for the higher risk germline cancer susceptibility
genes (e.g., CDH1) should be employed. In addition, systemic therapy
options for patients with certain germline mutations may be different
from those with sporadic gastric cancer (e.g., for Lynch syndrome,
immune modulation therapy; and for BRCA, use of DNA-damaging
agents such as platinum compounds).
Gastric cancer stem cells, mostly located in the isthmus of individual
gastric glands and possibly originating in the bone marrow, may play
an important role in the development of gastric cancer. H. pylori may
be an inciting factor for recruitment of such bone marrow gastric stem
cells. If this hypothesis is confirmed, it may have important implica­
tions for therapy of gastric cancers.
PART 4
Oncology and Hematology
Clinical Features 
• 
SURVEILLANCE STRATEGIES  As is the case
for esophageal cancer, the incidence of gastric cancer in Western patients
is relatively low, and early detection methodologies such as endoscopy
are not routinely employed. The development of a “pan-cancer” bloodbased biomarker or a biomarker specific for gastric cancer would allow
broader screening. At this time, the overwhelming majority of Western
patients with gastric cancer are symptomatic at the time of diagnosis.
Early detection programs in Japan and Korea, where gastric cancer has
been among the most common of malignancies (although its incidence
has been decreasing), include upper endoscopy; these programs have
increased the number of patients found with early gastric cancer and
Cardia
GE
junction
CIN
• Intestinal histology
• TP53 mutation
• RTK-RAS activation
Pylorus
Antrum
GS
• Diffuse histology
• CDH1, RHOA mutations
• CLDN18–ARHGAP fusion
• Cell adhesion
FIGURE 85-2  Molecular/genomic characterization of subtypes of gastric carcinomas. CIMP, CpG-island methylator phenotype; CIN, chromosomally unstable; EBV, EpsteinBarr virus-associated; GE, gastroesophageal; GS, genomically stable; MSI, microsatellite instability-associated.
decreased mortality rates. This strategy has not been cost effective in
populations in which the incidence of gastric cancer is much lower,
such as in the United States. As noted above, in high-incidence areas,
treatment of symptomatic H. pylori is a preventive measure.
PRESENTING SYMPTOMS  Presenting symptoms include vague upper
abdominal discomfort, hematemesis or melena, anorexia and early
satiety, and unexplained weight loss. For patients with esophagogastric
junction cancers, dysphagia or odynophagia may be the presenting
symptom. Anemia may be found due to occult bleeding. These symp­
toms and signs lead to upper (and if site of bleeding is uncertain, lower)
endoscopy and biopsy. Occasionally, imaging using CT performed to
evaluate abdominal symptoms may identify gastric thickening or a gas­
tric mass leading to upper endoscopy. Physical examination can reveal
left supraclavicular adenopathy (Virchow’s node), a periumbilical mass
(Sister Mary Joseph nodule), a pelvic mass on rectal exam (Blumer’s
shelf), ascites, or an ovarian mass (Krukenberg tumor). More com­
monly, physical examination is unrevealing.
Upper endoscopy may reveal an ulcer or ulcerated mass, biopsy of
which shows adenocarcinoma. For the diffuse subtype of gastric can­
cer, a mass or ulceration may not be seen, but rather, thickened gastric
rugae may be noted. Initial biopsy may not reveal diffuse gastric cancer,
which may track below the mucosal surface. In these patients, EUS may
guide biopsy.
Histopathology Classification of Primary Gastric Adeno­
carcinomas 
The large majority (~85%) of gastric malignancies are
adenocarcinomas or subtypes of adenocarcinoma. Other malignancies,
discussed below, include neuroendocrine tumors (carcinoid tumors),
primary gastric lymphomas, gastrointestinal stromal tumors (GISTs),
and other rare malignancies. Using the Lauren classification, patholo­
gists classify adenocarcinomas on the basis of histopathology as intestinal
(more common) or diffuse subtype (~20%). As noted above, the diffuse
subtype is associated with inherited CDH1 mutations; in addition, in the
TCGA genomic analysis of gastric cancer and in other genomic analysis
studies, approximately a third of diffuse subtype cases had somatic CDH1
mutations. The intestinal subtype is associated with H. pylori infection
and atopic gastritis. Histologic grade also influences the clinical course.
Genomic analysis performed by several groups has resulted in
molecular classifications of gastric cancer that may, in the future,
Fundus
EBV
• PIK3CA mutation
• PD-L1/2 overexpression
• EBV-CIMP
• CDKN2A silencing
• Immune cell signaling
Body
MSI
• Hypermutation
• Gastric-CIMP
• MLH1 silencing
• Mitotic pathways
inform staging systems; they already provide a better understanding of
the driving factors in the development of gastric cancer and important
information on treatment options as outlined above (Fig. 85-2). For
example, the TCGA group reported the results of a multiplatform
analysis of 295 patients with previously untreated gastric cancer; both
Western and Asian patients were included in the analysis. Four sub­
types of gastric cancer were identified: high EBV burden, microsatel­
lite unstable with hypermutation, genomically stable (associated with
the diffuse subtype), and chromosomal unstable. The Asian Cancer
Research Group (ACRG), studying primary tumors from 300 Korean
patients, analyzed gene expression profiles and found four subtypes:
mesenchymal, microsatellite unstable, microsatellite stable with TP53
expressed, and microsatellite unstable with TP53 mutated. Clinical out­
come was correlated with genomic subtype in both studies, with micro­
satellite unstable tumors having the best outcome (in an era before use
of immune modulation therapy) and genomically stable (TCGA) and
mesenchymal (ACRG) types having the worst outcome.
In addition to histopathology, as is the case for esophageal cancer,
molecular diagnostics and genomic alteration analysis using NGS are
an important part of the pathology workup. The molecular subtypes
have therapeutic implications; for example, as discussed above, ~20%
of gastric cancer or GEJ cancer patients’ tumors have overexpression
or amplification of HER2/ERBB2, which would lead to the addition of
agents such as trastuzumab-based therapy as part of systemic treatment
for metastatic disease. Immune modulation therapy would be used in
patients with hypermutated tumors, found by NGS (tumor mutation
burden) or by polymerase chain reaction (PCR) for microsatellite
instability (MSI). An evaluation for overexpression or amplification of
HER2/ERBB2, quantification of PD-L1 by IHC, and assessment of MSI
by PCR or deficient mismatch repair protein (dMMRP) expression
should be a routine part of the pathology workup of patients with meta­
static gastric cancer. Claudin 18.2 has recently been identified as a tar­
get for therapy; if agents targeting Claudin 18.2 are approved by the U.S.
Food and Drug Administration (FDA), an assay for this factor should
be included in the pathologic evaluation of metastatic gastric cancer.
More controversial is whether these assays should also be routinely
performed in patients with potentially operable gastric cancer because,
for example, the addition of trastuzumab to neoadjuvant chemotherapy
has not yet been shown to change outcome. In large-volume centers,
NGS is routinely performed on pretreatment biopsies. Currently, the
finding on pathologic assays of positive tumor EBV (identified in
8–10% of gastric cancer patients) does not change therapeutic options.
Staging 
Once a diagnosis of a primary gastric adenocarcinoma is
made, algorithms for clinical evaluation of stage include physical exam­
ination and imaging studies (Fig. 85-3; Table 85-2). Tumor-related
biomarkers such as carcinoembryonic antigen (CEA) or CA19-9 may
be elevated but are nonspecific (may be elevated in a number of other
gastrointestinal and other site cancers). Diagnostic CT scan of the
chest, abdomen, and pelvis should be performed. If metastatic disease
is suspected on imaging, a biopsy of a metastatic site should be strongly
considered to confirm stage IV disease, which changes the goals of
care from potentially curative to palliative treatment and provides tis­
sue for molecular and genomic analyses. As is the case for esophageal
cancer, FDG-PET/CT, which is more sensitive than diagnostic CT scan
in identifying sites of metastatic disease, should be performed if the
anatomic CT is negative for metastatic disease. Note, however, that
FDG-PET may be noninformative (the primary tumor may not be
FDG-avid, particularly in diffuse-type gastric cancer). If imaging does
not reveal metastatic disease, EUS should be considered to determine
depth of penetration of the primary tumor and the presence or absence
of regional lymphadenopathy suspicious for metastasis. Lymph node
biopsy and, on occasion, biopsy of left hepatic parenchymal lesions
found on EUS can be performed at the same setting. Endoscopic
biopsies usually provide enough tumor tissue for molecular diagnostic
pathology testing for HER2/ERBB2, MSI/MMRP, and PD-L1 assess­
ment; it may not provide enough tissue for NGS genomic alteration
analysis. If neoadjuvant therapy is planned, laparoscopy should be
considered to allow evaluation of the peritoneal cavity, with peritoneal
washing for cytology if no peritoneal metastases are visible. The perito­
neal cavity is a common site of metastases, especially from diffuse-type
gastric cancer. The finding of peritoneal involvement either visibly or
by positive cytology is staged as metastatic disease and generally rules
out the chance for curative resection.
The AJCC staging classification for gastric cancer is summarized in
Table 85-2. Three staging classifications are provided: cTNM clinical
staging (before any therapy has been given), pTNM pathologic staging
(for patients not undergoing preoperative therapy), and a post–neoad­
juvant therapy classification staging (ypTNM). The three components
take into account current standard-of-care options for therapy in
which the AJCC prognostic stage groups from clinical staging guide
therapeutic decisions. For example, after clinical evaluation, a large
percentage of newly diagnosed patients will be found to have higherstage primary cancers (penetrating through the gastric wall [T3 or T4]
or lymph node–positive tumors), in which case perioperative (neoad­
juvant) systemic therapy may be chosen. Pathologic examination of
the resected specimen for prognostic stage classification must take into
account exposure to preoperative therapies that may lead to down­
staging (thus, ypTNM staging). Nomograms have been developed for
predicting outcome in patients undergoing surgery as initial treatment.
CHAPTER 85
TREATMENT
Gastric Cancer
POTENTIALLY CURABLE GASTRIC CANCER: SURGERY
Surgical removal of the primary tumor with negative microscopic
margins (an R0 resection) and with resection of regional lymph
nodes is currently the only curative therapy; with surgery alone,
overall 5-year survival rates are approximately 25% (higher for
very-early-stage tumors). If tumor cells are found at the margin
of resection (R1) or if visible cancer is left at the time of surgical
removal of the primary tumor (R2), surgery is palliative rather
than curative. For patients with early-stage tumors (mostly clinical
stage I), surgery without perioperative systemic therapy may be
performed. For patients with more locally advanced tumors (clini­
cal stages IIA, IIB, III), who compose approximately 70% of newly
diagnosed operable patients, multimodality therapy (surgery and
systemic chemotherapy) improves overall survival. Both neoadju­
vant (preoperative) and postoperative systemic therapy are accepted
approaches. If staging studies demonstrate a locally advanced can­
cer (or node positive), preoperative treatment is recommended in
a medically fit patient. If surgery is performed first and a locally
advanced cancer is found, postoperative chemotherapy or che­
motherapy plus chemoradiation is recommended. For selected
very-early-stage gastric cancers (primary tumors that are ≤2 cm in
diameter, are well to moderately differentiated, do not invade the
deep submucosa [T1], and do not show lymphovascular invasion
or lymph node metastasis), which are not commonly found in the
United States, EMR or ESD may be performed by experienced gas­
troenterologists in place of surgical resection, with favorable results
in studies in high-incidence areas such as Japan.
Upper Gastrointestinal Tract Cancers
For patients in whom the primary tumor is in the distal stom­
ach, a subtotal gastrectomy is the preferred surgical procedure. For
tumors of the proximal stomach, the options for resection include
total gastrectomy or, alternatively, proximal gastrectomy. Esophago­
gastrectomy is performed for tumors involving the GEJ. In selected
patients, a jejunostomy feeding tube may be placed if postoperative
radiation therapy is part of the treatment plan.
As noted above, laparoscopy is commonly performed at highvolume centers before a final decision regarding the role of surgery.
If staging has already demonstrated clinically suspicious lymph
nodes or an advanced T stage tumor, but laparoscopy does not
demonstrate peritoneal metastasis, perioperative chemotherapy is
given before surgical resection.
Palliative resection of the primary tumor is usually performed
only if symptoms such as uncontrollable bleeding or obstruction are
present that cannot be relieved by other means.
No evidence of
metastatic disease
MI disease suspect
FDG-PET/CT
No MI disease
MI disease
PART 4
Oncology and Hematology
EUS
Stage 1
Consider laparoscopy
Consider laparoscopy
No peritoneal metastasis
No MI peritoneum
MI peritoneum
Resection
Neoadjuvant therapy
pT1–2 N0 M0
pT3 Nany M0
Resection
Active
surveillance
Adjuvant
therapy
FIGURE 85-3  Staging for gastric adenocarcinoma. CT, computed tomography; EUS, endoscopic ultrasound; FDG-PET, fluorodeoxyglucose positron emission tomography.
As is the case for colorectal cancer, a correlation exists between
the number of lymph nodes removed and sampled and outcome.
Sentinel lymph node biopsy is not performed in gastric cancer
outside of a research study setting. The goal is to examine at least
15 lymph nodes from the resected specimen; it is more contro­
versial whether more extensive lymph node resection itself affects
outcome; the extent of lymphadenopathy can be classified using
a D0–D3 system with a higher number meaning more extensive
lymphadenopathy. In the United States, a modified D2 (D1+)
resection preserving the spleen and avoiding pancreatectomy is
recommended but should be performed by experienced surgeons
at high-volume centers. Japanese investigators and others have
used very extensive lymph node dissections, but studies have not
demonstrated an advantage for a D3 resection. Both resection of
the primary tumor and its regional lymph nodes can be performed
laparoscopically in appropriate patients.
Endoscopy and biopsy positive
Diagnostic CT
Biopsy if technically
feasible
Systemic therapy
Stage 2/3
Systemic therapy
In the hands of experienced surgeons, operative mortality would
be anticipated to be ≤2%.
NEOADJUVANT AND POSTOPERATIVE ADJUVANT
THERAPY FOR RESECTABLE GASTRIC CANCER
The large majority of potentially resectable Western gastric cancer
patients have locally advanced tumors (cTNM stage IIA/B or III).
Multimodality therapy using systemic chemotherapy plus surgery
improves 5-year survival rates by 10–15% compared to surgery
alone. An older but widely cited study, the MAGIC clinical trial,
randomly assigned patients with potentially resectable disease to
receive perioperative chemotherapy or to proceed directly to surgery.
Five-year overall survival for patients undergoing surgery alone was
23%; for those receiving pre- and postoperative chemotherapy, it was
36%. On the basis of this and other clinical trials, for most medically
fit patients with stage cTNM II and III resectable gastric cancers,
preoperative systemic chemotherapy followed by resection and, if tol­
erable, postoperative chemotherapy is a standard approach. Because
it is challenging to give postgastrectomy systemic therapy using
currently employed regimens (<50% of patients receive or complete
postoperative treatment), total neoadjuvant therapy is favored at
some centers. For patients with MSI/hypermutated tumors, immune
modulation therapy (PD-1/PD-L1 or PD-1 plus CTLA-4 agents)
can be considered in place of chemotherapy, although substantial
pathologic response rates were seen in a small number of patients
in the DANTE trial using FLOT alone. Preoperative chemoradiation
as given for esophageal cancers is usually used for GEJ tumors. If an
R1 or R2 resection is performed, postoperative chemoradiation can
be considered. Use of postoperative chemoradiation therapy, with
exceptions outlined above, did not improve outcome when com­
pared to systemic chemotherapy alone. Preoperative chemotherapy
followed by chemoradiation is under study. For patients being
treated with multimodality therapy, close interactions among the
surgeon, medical oncologist, and radiation oncologist are essential.
Clinical trials have compared different preoperative cytotoxic
chemotherapy regimens, most of which include a platinum com­
pound—either cisplatin or oxaliplatin. Currently, a platinum
compound plus a fluorinated pyrimidine, such as fluorouracil
or capecitabine, given for three to four cycles before surgery is a
standard-of-care option. Drug combinations are favored; for very
fit patients, a combination of FLOT may be chosen. An alternative
is, for example, the FOLFOX regimen, which includes fluorouracil,
leucovorin, and oxaliplatin. Addition of trastuzumab to preop­
erative chemotherapy has not improved outcomes for patients
with HER2-positive cancers. Careful monitoring of chemotherapyrelated toxicities with appropriate dose modifications is important.
For patients receiving preoperative systemic chemotherapy and
undergoing an R0 D2/D1+ dissection, postoperative chemoradia­
tion therapy has not improved outcome.
For patients in whom the primary tumor has been resected and
who did not receive preoperative chemotherapy, who are found to
have stage II or III cancers, or who have <15 lymph nodes found in
the resected specimen (less than D2 resection), postoperative che­
motherapy or chemoradiation is a treatment option. Chemotherapy
and chemoradiation therapy may also be given for unresectable
cancers in selected patients. As noted above, plasma ctDNA as a
measure of minimal residual disease (regional or metastatic cancer
not identifiable by current imaging modalities) is being studied.
Data from other gastrointestinal tumors suggest that conversion
of a positive ctDNA assay to negative after systemic postoperative
therapy is associated with a better outcome.
PALLIATIVE THERAPY FOR INCURABLE GASTRIC CANCER
Patients with clinical stage IV gastric cancers with an adequate per­
formance status should be offered systemic drug therapies. Small
clinical trials performed in the 1980s and 1990s showed a survival
benefit for systemic therapy compared to best supportive care only.
As discussed above, genomic and molecular diagnostic analysis has
identified several distinct cohorts of gastric cancer patients. These
analyses guide therapy. While the cytotoxic chemotherapy regimens
most commonly employed are still based on a platinum compound
and a fluorinated pyrimidine (e.g., FOLFOX, as is used in the peri­
operative setting), a major advance has been the demonstration that
immune modulation therapy plus chemotherapy improves outcome
(including overall survival) compared to chemotherapy alone. In
the CheckMate 649 trial, 1581 patients with HER2/ERBB2-negative
advanced gastric or GEJ cancers were randomly assigned to receive
nivolumab plus chemotherapy (oxaliplatin plus capecitabine or
FOLFOX) versus chemotherapy alone. Overall survival, progres­
sion-free survival, and response rates were significantly better for
patients receiving nivolumab plus chemotherapy; this effect was
most marked for patients with PD-L1 CPS of >5. CheckMate 649
and other data have led to guidelines recommending use of immune
modulation therapy plus chemotherapy as an option for first-line
treatment for patients with HER2/EBB2-nonexpressing, PD-L1 CPS
5 metastatic gastric and gastroesophageal cancers; chemotherapy
plus immune modulation therapy may also have benefit for patients
with lower PD-L1 CPS scores. Those whose tumors have overex­
pressed or amplified HER2 should receive HER2-targeted agents
such as trastuzumab or trastuzumab, pembrolizumab, plus cyto­
toxic chemotherapy. Beyond first-line therapy, additional HER2targeted therapy using agents such as trastuzumab-deruxtecan, a
monoclonal antibody-drug conjugate, is recommended for patients
whose tumors have amplification of HER2/ERBB2. For patients
with metastatic MSI/dMMRP gastric cancers, immune modulation
therapy using either PD-1 inhibitors such as pembrolizumab or
combinations such as nivolumab plus ipilimumab may be employed
as first-line therapy; guidelines include the option of immune
therapy plus chemotherapy.
When disease progresses after first-line treatment, other therapies
include the combination of a VEGF receptor–targeted agent, ramu­
cirumab, either alone or in combination with paclitaxel. Immune
modulation inhibitors are an option for second-line therapy for
patients whose tumors are microsatellite unstable (e.g., nivolumab
plus ipilimumab if single-agent pembrolizumab was used as firstline therapy). For patients with microsatellite stable gastric cancers
(the large majority), immune modulators are an option if not used
in the first-line setting, if PD-L1 is positive. As above, for patients
with HER2/ERBB2-amplified tumors, trastuzumab-deruxtecan can
be used. Several other cytotoxic agents have activity in the thirdline setting including trifluridine-tipiracil and irinotecan. Even with
improvements in therapy including immune modulation therapy,
the best results from clinical trials indicate overall survival for treated
patients with stage IV disease is still only 12–15 months. Investiga­
tional studies include targeting Claudin 18.2, a cell surface type junc­
tion molecule that is overexpressed in ~50% of gastric cancers. In
the SPOTLIGHT trial, previously untreated, HER2/ERBB2-negative
patients assigned to zolbetuximab (targeting Claudin 18.2) plus
FOLFOX chemotherapy had an improvement in survival compared
to those receiving FOLFOX chemotherapy alone. Zolbetuximab plus
chemotherapy may become another first-line option for advanced
gastric cancer. Additional studies targeting Claudin 18.2 including
those using chimeric antigen receptor (CAR) T cells are underway.
CHAPTER 85
Upper Gastrointestinal Tract Cancers
Radiation therapy using shorter regimens may be employed to
palliate bleeding. For patients with advanced incurable disease,
other supportive measures include placement of a duodenal stent to
relieve gastric outlet obstruction; in selected patients, surgical pro­
cedures for gastric outlet obstruction may be performed. Radiation
therapy might be used if not previously given. Enteral feeding using
a jejunostomy tube may support nutritional needs.
GASTRIC LYMPHOMAS
Lymphomas of the stomach are an uncommon (~3%) but important
subgroup of gastric malignancies. They are extranodal non-Hodgkin’s
lymphomas (NHL). The gastrointestinal tract is the most common site
for extranodal NHL, and the stomach is the most common site within
the gastrointestinal tract. The presenting symptoms can be similar to
those of the much more common adenocarcinoma of the stomach
described above, including pain, anorexia, and bleeding. Symptoms of
fever and night sweats occur in 10–15% of patients with gastric NHL.
Because the treatment options are so different, obtaining adequate tis­
sue for definitive pathologic examination is crucial in diagnosing both
gastric lymphomas (as opposed to adenocarcinoma) as well as defin­
ing the subtype of lymphoma. On occasion, this may be challenging
because, similar to diffuse subtype adenocarcinoma, lymphomas may
track below the mucosal surface. A fine-needle aspirate may not be suf­
ficient; multiple deep biopsies or mucosal resection may be needed to
provide enough tissue for definitive pathologic assessment.
Potential driving forces in the development of gastric lymphomas
include active or prior H. pylori infection, which is associated with
mucosa-associated lymphoid tissue (MALT) subtype gastric lympho­
mas and has been described as a potential driver in some patients with
diffuse large B-cell lymphomas (DLBCLs). MALT lymphomas may
develop in nearly any organ, but the stomach is the most frequent pri­
mary site, accounting for ~35% of all MALT lymphomas. Identifying a
MALT lymphoma is important because antibacterial therapy directed
against H. pylori alone can be a highly effective treatment. Other infec­
tions should be considered either as driving factors or as risks from
treatment, such as reactivation of hepatitis B virus (HBV); testing for
HBV is recommended before initiation of lymphoma therapy. Hepatitis
C infection has been associated with DLBCL and with marginal zone
lymphomas. Other forms of NHL may involve the stomach either as
primary gastric lymphoma or as a secondary site of disease, including
both B-cell (e.g., mantle cell lymphoma, Burkitt’s lymphoma, and fol­
licular lymphoma) and T-cell lymphomas (e.g., enteropathy-associated
T-cell lymphoma, anaplastic large-cell lymphoma, and peripheral
T-cell lymphoma).
Staging is performed using similar imaging modalities as for gastric
adenocarcinoma, but the staging systems are different (see below, and
presented in more detail in the chapter on lymphomas [see Chap. 113]).
As a staging study, FDG-PET/CT is performed, as well as a contrastenhanced, diagnostic-quality CT. FDG-PET/CT is used both as an
initial staging study and to assess response. EUS may be used to deter­
mine depth of invasion in patients in whom no evidence of metastatic
disease is noted. Examination of the peripheral blood and bone mar­
row aspirate should be considered as part of the workup. In all patients
with gastric lymphoma, H. pylori infection status should be evaluated.
If H. pylori testing is negative by histopathology, noninvasive testing by
either stool antigen test or urea breath test should be used.
PART 4
Oncology and Hematology
■
■STAGING
The TNM staging system is not employed for gastric lymphomas.
Several classification systems are used for lymphomas, including the
Lugano staging system (a modification of Ann Arbor staging), the
revised World Health Organization (WHO) Fifth Edition of the WHO
Classification of Haematolymphoid Tumours (WHOHAEM5), and the
International Consensus Classification (ICC). These are discussed in
Chap. 113 on lymphomas. The Lugano staging system for gastroin­
testinal lymphomas is still widely used; it divides patient groups into
stages I, II, III, and IV. Stage I tumors are limited to the gastric wall;
stage II tumors have regional lymph node involvement or invasion of
local structures; stage III tumors have lymph node involvement above
and below the diaphragm. Stage IV tumors have either more extensive
lymph node involvement or have distant metastasis, including to the
bone marrow or other extranodal sites.
■
■PATHOLOGIC CLASSIFICATION
The two most common histologic subtypes of gastric lymphoma are
marginal zone B-cell lymphomas (gastric marginal zone B-cell lympho­
mas or MALT; ~40% of newly diagnosed patients) and DLBCLs (~55%).
The distinction is critical because therapeutic options are different. The
large majority of MALT cases are associated with H. pylori infection.
The finding of a t(11;18) translocation identifies a subgroup less likely
to respond to H. pylori eradication (or in non-H. pylori–associated
MALT). This translocation may be detected using PCR or fluorescent in
situ hybridization (FISH); it creates a chimeric protein composed of the
amino terminal of API1 (apoptosis inhibitor) and the carboxy terminus
of MALT1, leading to activation of nuclear factor-κB signaling. Note that
even H. pylori–negative MALT tumors may respond to anti–H. pylori
therapy. Other, rarer subtypes of primary gastric lymphomas include
those of T-cell lineage.
TREATMENT
Gastric Lymphoma
Unlike adenocarcinoma of the stomach, surgical resection has no
role in the treatment of primary gastric lymphoma in the absence
of complications of therapy such as perforation or uncontrollable
bleeding. Resection of gastric lymphoma does not improve clinical
outcomes.
For patients with MALT lymphoma, eradication of H. pylori
with antibiotics is highly effective therapy. If tests for H. pylori are
positive and t(11;18) translocation assay is negative, one of the cur­
rently accepted antibiotic regimens for treating H. pylori should
be the initial therapy. H. pylori eradication is associated with high
response rates including complete remissions in the majority of
patients. Treatment with an anti–H. pylori regimen may induce
remission even in patients in whom standard testing for H. pylori,
described above, is negative. The time to remission may be pro­
longed (in some studies averaging 15–16 months); therefore, careful
monitoring is important before determining that a MALT tumor is
not responding to anti–H. pylori therapy. For patients in whom the
t(11;18) translocation assay is positive, options for therapy include
anti–H. pylori antibiotic therapy plus involved-field radiation ther­
apy or, if radiation is contraindicated, the use of single-agent ritux­
imab, a monoclonal antibody targeting CD20. For patients who are
H. pylori negative, in whom anti–H. pylori therapy may have been
used without response, moderate-dose (24–30 Gy) involved-site
radiation therapy or single-agent rituximab is a treatment option.
For selected, more advanced, stage IV MALT patients who
have not responded to or who have progressed after receiving
anti–H. pylori antibiotic therapy and/or rituximab, cytotoxic che­
motherapy regimens such as R-CHOP (rituximab, cyclophospha­
mide, doxorubicin, vincristine, and prednisolone), dose-adjusted
R-EPOCH (an infusional regimen of rituximab, etoposide, prednis­
olone, vincristine, cyclophosphamide, and doxorubicin), or ritux­
imab and lenalidomide may be considered.
DLBCL may be a result of transformation from more indolent
MALT lymphoma or may arise de novo. De novo tumors are more
likely to be BCL2 and CD10 positive. MALT lymphomas that have
transformed to DLBCLs are more frequently BCL2 and CD10
negative.
For patients with DLBCL, earlier-stage tumors may be treated by
combination chemotherapy alone or chemotherapy plus involvedfield radiation therapy. For more advanced gastric DLBCL tumors,
chemotherapy using the R-CHOP or R-EPOCH regimen is stan­
dard therapy. Some reports have suggested that eradication
of H. pylori is effective treatment for early-stage DLBCL when the
patient also has H. pylori.
UNCOMMON TUMORS OF THE ESOPHAGUS
AND STOMACH
■
■GASTROINTESTINAL STROMAL TUMORS
GISTs are rare tumors of the gastrointestinal tract associated with
activating somatic mutations in the cKIT (the majority) or PDGFRA
genes; in a minority of cases, neither gene is mutated. GISTs arise
from Cajal cells, which bridge between the autonomic nerves to the
muscle layer of the bowel. The stomach is the most frequent primary
site (~60%), followed by the small bowel in about 25%. As endoscopy
for other indications has become more widely used, otherwise asymp­
tomatic and probably clinically insignificant small GISTs have been
identified more frequently; it is not clear that the actual incidence
has substantially increased. Symptoms associated with GISTs include
acute gastrointestinal bleeding leading to melena and/or hemateme­
sis. Anemia may be reflected in generalized weakness. With larger
tumors, abdominal distention and pain may be presenting symptoms.
At endoscopy, a nonspecific smooth bulging mass covered by normal
mucosa is the most frequent finding. Initial biopsy may not reveal a
mesenchymal neoplasm. The radiologic features found on diagnostic
CT scan (which may identify an asymptomatic tumor) may raise the
question of a GIST tumor. EUS can be performed, but if biopsy is
done, it may not provide an adequately cellular specimen to allow
genomic sequencing, which is required to help guide systemic therapy
(if needed).
Histologically, a spindle cell neoplasm is the most common subtype
(~70%), with epithelioid cells making up 20%; 10% of cases are mixed
histology. KIT expression is found in ~95% and PDGFRA in ~80% of
cases. NGS is usually used to assess for gain-of-function KIT, PDGFRA,
or other, rarer mutations.
For nonmetastatic GIST tumors, risk of recurrence assessment
(guiding use of postoperative therapy) is based on the size of the pri­
mary tumor, mitotic index, and location in the gastrointestinal tract.
For gastric GISTs, resected tumors ≤2 cm with a mitotic index of ≤5%
have a near 0 risk of progression. For larger tumors, especially those
≥10 cm, with a mitotic index >5%, the risk is moderate to high. Post­
operative adjuvant imatinib for 3 years is a standard-of-care option.
Avapritinib is used for tumors with certain PDGFRA mutations. For
patients with metastatic disease, imatinib (for KIT mutation–bearing
tumors) or avapritinib (targeting PDGFRA) is used; the location of the
KIT mutation (exon 11 vs 9) is associated with degree of effectiveness.
However, resistance almost invariably develops, and the development
of newer agents effective in tumors with secondary mutations is a high
priority; ripretinib, which targets both KIT and PDGFRA, is now also
FDA approved.
■
■SMALL-BOWEL NEOPLASMS
Small-bowel neoplasms make up ~3% of gastrointestinal tumors; in
2023, 12,000 new cases are expected in the United States. The spectrum
of malignant small-bowel neoplasms includes neuroendocrine tumors
(NETs; carcinoid), adenocarcinomas, lymphomas, and GISTs. In the
United States, NETs, which have increased in incidence, are slightly
more frequent (40–45%) than adenocarcinomas (30–40%), with the
remainder mostly lymphomas and ~8% GISTs. The duodenum is
the most common portion of the small bowel in which malignancies
develop (~50%), with ~30% occurring in the jejunum and 20% in the
ileum. NETs are the most common benign and malignant tumors of
the ileum. Risk factors for the development of small-bowel adeno­
carcinoma include inflammatory bowel disease (Crohn’s disease);
inherited germline mutation syndromes such as Lynch syndrome,
familial adenomatous polyposis (FAP), and Peutz-Jeghers syndrome;
and celiac disease (which is also associated with an increased risk for
lymphomas).
While an asymptomatic small-bowel primary adenocarcinoma
might be found during surveillance in patients at high risk (e.g., FAP),
for many small-bowel tumors, the finding of positive stool occult
blood, unexplained anemia, or small-bowel obstruction leads to the
diagnosis. Both adenocarcinoma and lymphomas might present with
perforation. Evaluation by diagnostic CT imaging may reveal a smallbowel lesion. CT and/or magnetic resonance enterography (CTE or
MRE) have a high positive predictive value (for adenocarcinoma, MRE
appears to be more accurate). A variety of endoscopic techniques are
used for diagnostic evaluation of the small bowel, including deviceassisted enteroscopy (DAE), e.g., double-balloon enteroscopy; smallbowel capsule endoscopy (SBCE) may also be employed. DAE allows
tissue diagnosis; a tattoo helps localize the small bowel neoplasm
(SBN) for resection; DAE may also allow stent placement for palliation
of obstruction. SBCE is contraindicated in the setting of obstruction.
As is the case for gastric imaging studies, deep learning artificial intelli­
gence is being studied to improve the analysis of small-bowel imaging.
For NETs, a gallium-68 or copper-64 DOTATATE scan may identify
both the primary site as well as metastatic disease. Blood tumor bio­
markers are nonspecific for the primary site (e.g., CEA or CA19-9 for
adenocarcinoma); these assays are better used to monitor response or
progression of disease rather than for diagnosis.
The median age at diagnosis for sporadic small-bowel adeno­
carcinoma is in the seventh or eighth decade of life, but genetically
predisposed patients and those with inflammatory bowel disease may
be diagnosed at a much earlier age. African Americans have a higher
incidence of small-bowel cancer than whites. While systemic therapies
are usually modeled on agents used to treat colorectal cancer, genomic
analyses have indicated that small-bowel adenocarcinoma has distinct
genomic alterations compared to either colorectal or gastric cancers.
Genomic alterations less frequent in small-bowel than in colorectal
cancers include TP53, BRAF V600E, and APC mutations, whereas
the rate of KRAS mutations is similar to colorectal cancer (a genomic
analysis of Chinese small-bowel cancer patients, mostly duodenal
cancers, noted a somewhat different profile than U.S. patients). Within
small-bowel sites, the most striking difference is the higher rate of
ERBB2 alterations (of which a minority are amplifications) in duodenal
cancers. Not surprisingly, because Lynch syndrome increases the risk
of small-bowel adenocarcinoma, 15–20% of these tumors are MSI high
or mismatch repair deficient; small-bowel adenocarcinoma associated
with celiac disease also may have an increased rate of MSI-high tumors.
MSI/MMRP status should be assessed in all patients with small-bowel
adenocarcinoma. Somatic tumor genomic analysis may suggest a
germline mutation, but appropriate genetic testing for a germline
driver mutation should be performed in all patients with small-bowel
adenocarcinoma.
Small-bowel adenocarcinoma has its own staging classification in
the eighth edition of the AJCC Cancer Staging Manual.
TREATMENT
Small-Bowel Adenocarcinomas
Surgical resection with negative microscopic margins (R0), as is
the case for other gastrointestinal tumors, is the best chance for
cure. For duodenal adenocarcinomas, a Whipple procedure may
be needed; for more distal duodenal cancers and jejunal adenocar­
cinomas, a segmental resection with adequate margins should be
performed. Distal ileal tumors may require right hemicolectomy.
CHAPTER 85
Small-bowel cancers are frequently found with locally advanced
disease at the time of diagnosis. If the tumor is resectable, post­
operative adjuvant systemic therapy is currently recommended
for lymph node–positive patients, using regimens such as those
employed for colorectal cancer (capecitabine and oxaliplatin or
FOLFOX). Benefit from adjuvant therapy has not yet been proven.
Small-bowel cancers developing in patients with Lynch syndrome
probably have a better prognosis; if colorectal cancer is a model,
postoperative adjuvant therapy for patients with Lynch syndrome
may include consideration of immune modulation therapy. For
duodenal cancers, chemoradiation is considered if the resection
margins are still positive.
Upper Gastrointestinal Tract Cancers
For patients with advanced metastatic disease, in the absence of
Lynch syndrome or a hypermutated tumor, similar cytotoxic regi­
mens as deployed for gastric (duodenal) or colon cancers (jejunum
or ileum) have been widely used. For tumors that are MSI high or
dMMRP positive, immunotherapy is indicated; for tumors that are
HER2 amplified or BRAF mutated, targeted therapy may be useful.
■
■SMALL-BOWEL GASTROINTESTINAL STROMAL
TUMORS
Like small-bowel adenocarcinomas, small-bowel GISTs may pres­
ent with obstruction or bleeding. Diagnostic techniques are those
employed for other small-bowel neoplasms. While the pathological
criteria for malignant potential are somewhat different than those used
for gastric GISTs, postoperative management and treatment of meta­
static disease are the same as those described above for gastric GIST.
■
■BENIGN NEOPLASMS OF THE SMALL BOWEL
As is the case for malignant small-bowel tumors, benign neoplasms of
the small bowel are rare. In addition to cancers, the precursor lesion
adenomas or hamartomas (from which cancers develop) may be driven
by inherited cancer susceptibility genes (e.g., FAP, Lynch syndrome,
Peutz-Jeghers syndrome). Other benign neoplasms include lipomas,
leiomyomas, neurofibromas, and benign lymphoid nodular hyperplasia.
Patients with benign small-bowel neoplasms not associated with
an inherited cancer susceptibility gene (in which case, a benign tumor
may be found during surveillance) are usually asymptomatic. A mass
may be noted on an imaging study (usually a CT) ordered for another
reason. Workup for occult or overt bleeding or intussusception of the
bowel may lead to the discovery of a benign small-bowel neoplasm.
Diagnostic evaluation is similar to that described above for malig­
nant tumors. In general, benign neoplasms, if found during surveil­
lance, are removed endoscopically, if technically feasible, to decrease
the risk of intussusception in Peutz-Jeghers syndrome. Mucosectomy
may be used to treat bleeding hemangiomas.
NEUROENDOCRINE TUMORS OF THE
ESOPHAGUS, STOMACH, AND SMALL
BOWEL
Neuroendocrine neoplasms include NETs (more well differentiated,
classified as grades 1–3) and neuroendocrine carcinomas (NECs).
Neuroendocrine neoplasms including pancreas NETs are described
in detail in Chap. 89. The following describes NET and NEC of the
esophagus, stomach, and small bowel.
■
■ESOPHAGEAL AND GASTRIC NEUROENDOCRINE
TUMORS
NETs of the esophagus are rare, accounting for <1% of gastrointestinal
NETs. Presenting symptoms are similar to those of SCC or adenocarci­
noma of the esophagus, with dysphagia or odynophagia or with more
nonspecific symptoms such as substernal discomfort or burning consis­
tent with reflux esophagitis. A potential driving factor of NEC is smok­
ing. The initial diagnostic evaluation includes upper endoscopy and
biopsy. Pathology may reveal a well-differentiated NET (grades 1–3;
grade guided by percent Ki-67 positivity) with a low to relatively low
metastatic potential; at the other end of the spectrum are small-cell or
large-cell NECs, which are fully malignant and frequently metastasize.
In the absence of metastatic disease, EUS to assess depth of penetra­
tion and presence or absence of regional lymph node metastasis is fre­
quently performed. Imaging studies include CT; for high-grade NEC,
an FDG-PET/CT scan to assess for metastatic disease is done. For NET,
somatostatin receptor imaging studies such as gallium-68 or copper-64
DOTATATE scans may be performed if metastatic disease is suspected.
PART 4
Oncology and Hematology
Gastric NETs (also called gastric carcinoid tumors) represent
7–9% of gastrointestinal NETs but <1% of gastric neoplasms; several
types have been described, based in part on whether there is associ­
ated achlorhydria and hypergastrinemia. For all gastric NETs, initial
evaluation includes upper endoscopy and biopsy. EUS may be help­
ful in assessing depth of invasion for larger tumors and for assessing
regional lymph node metastases in higher grade tumors. Somatostatin
analogue imaging using DOTATATE scanning may be performed
if metastatic disease is suspected. As is the case for other NETs, the
finding of unresectable metastatic disease that is DOTATATE avid not
only provides staging information but also guides potential therapy
using somatostatin receptor–targeted therapy. See Chap. 89 for a more
detailed discussion.
TREATMENT
Esophageal Neuroendocrine Tumors
For early-stage, lower-grade NETs, endoscopic resection including
EMR or ESD may be performed. Surgery may be employed for
more advanced-stage locoregional but not metastatic NET. Smallcell or large-cell NECs that are not metastatic are usually treated
with chemotherapy plus external-beam radiation therapy using
chemotherapy regimens similar to those employed for small- and
large-cell neuroendocrine cancers of the lung (Chap. 83). For
metastatic NETs, somatostatin receptor DOTATATE scans guide
therapy. See below discussion for small-bowel NETs for discus­
sion of use of somatostatin receptor blockade with agents such as
octreotide or lanreotide and the use of peptide-related radiation
therapy (PRRT). Systemic therapy for metastatic small- and largecell esophagogastric NECs is also modeled on therapy for small-
and large-cell thoracic NECs.
TREATMENT
Gastric Neuroendocrine Tumors
Type 1 tumors can be treated endoscopically with polypectomy or
endomucosal resection. For larger tumors (>2 cm) or tumors invad­
ing through the muscularis or to regional lymph nodes, surgical
resection is recommended. Type 2 tumors have a higher risk for
regional lymph node metastasis and are usually treated surgically,
although selected patients may have a combination of endoscopic
resection and limited surgical resection. Type 3 tumors are not asso­
ciated with elevated gastrin levels and have a higher propensity for
regional lymph node metastasis and distant metastasis. Surgery is
the treatment of choice for localized type 3 tumors, although EMR
has been used in selected patients. Adenocarcinoma of the stomach
may be found in 5–10% of type 3 tumors. The role of surgery in
mixed NEC-adenocarcinoma neoplasms is not well established.
■
■NEUROENDOCRINE TUMORS (CARCINOID)
OF THE SMALL BOWEL
In the United States, NET are the most common small-bowel neo­
plasms. For not yet identified reasons, the incidence of small-bowel
carcinoid tumors has markedly increased over the past several decades.
A recent study found a 9% incidence of inherited germline cancer
susceptibility genes in patients with small-bowel NET; however, it is
unlikely that this is the cause of the increased incidence (Chap. 89).
Even with an increase in incidence, small-bowel NETs are still uncom­
mon (~12 cases per million in the United States); the disease is more
common in African Americans than whites.
Anatomically, the ileum is the most common part of the small
bowel affected (~49%), followed by the duodenum and the jejunum.
The same grading system, based on histology and the Ki-67 prolifera­
tive index or mitotic count, as for other gastrointestinal NETs is used.
In the absence of metastatic disease to the liver in the subgroup of
patients whose tumors are functional (i.e., produce a hormone, usually
serotonin; a duodenal NET may produce gastrin), presenting symp­
toms may be vague abdominal discomfort until or unless small-bowel
obstruction occurs. Carcinoid syndrome (including diarrhea and/
or flushing) may occur in patients whose tumors are diagnosed with
already established hepatic metastasis. Because the liver is very efficient
at clearing serotonin on first pass, carcinoid syndrome as a result of
small-bowel carcinoid tumors usually does not occur in the absence of
hepatic metastasis.
Clinical evaluation includes a diagnostic-quality CT or MRI of the
abdomen and pelvis. For duodenal NET, upper endoscopy with EUS
is also performed. For ileal NET, colonoscopy with evaluation of the
terminal ileum is performed. Imaging studies are similar to those
used for diagnosis and localization of small-bowel adenocarcinomas.
Somatostatin analogue imaging using gallium-68 or copper-64 DOT­
ATATE PET/CT is helpful in assessing extent of disease in patients
whose tumors are somatostatin analogue avid, as well as in identify­
ing patients who may benefit from therapy targeting the somatosta­
tin receptor. Plasma or urine assay for 5-hydroxyindoleacetic acid
(5-HIAA) is performed to assess for a functional small-bowel NET. The
AJCC Ninth Edition Cancer Staging Manual has a specific small-bowel
NET TNM stage classification (for the duodenum and ampulla and for
the jejunum and ilium).
The majority of patients present with locoregional disease, with
approximately 40% having identified lymph node metastasis. Ten to
15% of patients have metastatic disease (usually to the liver) at the time
of initial diagnosis.
Initial management should be surgical resection with curative intent;
for patients with extensive adenopathy involving the root of the mesen­
tery, vascular reconstruction may be required. Since small-bowel NETs
may involve multiple tumors (15–30% of patients), the entire small
bowel should be carefully examined at surgery. For patients with func­
tional carcinoid tumors, somatostatin analogue therapy using agents
such as octreotide should be given before the induction of anesthesia
to avoid a carcinoid crisis. For patients with hepatic metastasis, resec­
tion or regional therapy including ablation or hepatic artery emboliza­
tion for functional tumors may provide effective palliation. Carcinoid
syndrome may also be palliated by somatostatin receptor–targeted
therapy in the patients in whom DOTATATE scanning is positive (the
majority of patients with carcinoid syndrome), including agents such as
octreotide or lanreotide, or by peptide-directed radiation therapy using
agents such as lutetium-177. Everolimus, an mTOR kinase inhibitor,
has modest activity in metastatic small-bowel carcinoid tumors.

15 - 86 Colorectal Cancer
86 Colorectal Cancer
■
■FURTHER READING
Ben-Aharon I et al: Early-onset cancer in the gastrointestinal tract is
on the rise-evidence and implications. Cancer Discov 13:538, 2023.
Cancer Genome Atlas Research Network: Comprehensive molec­
ular characterization of gastric adenocarcinoma. Nature 513:202,
2014.
Cancer Genome Atlas Research Network et al: Integrated
genomic characterization of oesophageal carcinoma. Nature 541:169,
2017.
Choi IJ et al: Helicobacter pylori and prevention of gastric cancer. N
Engl J Med 378:2244, 2018.
Choi IJ et al: Family history of gastric cancer and Helicobacter pylori
treatment. N Engl J Med 382:427, 2020.
Dermawan JK et al: Novel genomic risk stratification model for pri­
mary gastrointestinal stromal tumors (GIST) in the adjuvant therapy
era. Clin Cancer Res. 29:3974, 2023.
Hoeppner J et al: Perioperative chemotherapy or preoperative chemo­
radiotherapy in esophageal cancer. N Engl J Med 392:323, 2025.
Janjigian YY et al: Pembrolizumab plus trastuzumab and chemo­
therapy for HER2-positive gastric or gastro-oesophageal junction
adenocarcinoma: Interim analyses from the phase 3 KEYNOTE-811
randomised placebo-controlled trial. Lancet 402:2197, 2023.
Pourmand K, Itzkowitz SH: Small bowel neoplasms and polyps.
Curr Gastroenterol Rep 18:23, 2016.
Watanabe M et al: Recent progress in multidisciplinary treatment for
patients with esophageal cancer. Surg Today 50:12, 2020.
David P. Ryan
Colorectal Cancer
■
■INCIDENCE
Colorectal cancer is the most common cancer of the gastrointestinal
system in the United States. In 2024, 153,000 cases are expected, with
~106,000 cases in the colon and 46,000 cases in the rectum. It is the
second most common cause of death from cancer (lung cancer is first)
with 53,000 expected deaths. There is a slight male predominance in
the incidence of colorectal cancer, and it is more common in black
Americans than white Americans. Since 1985, there has been a steady
decline in the incidence of colorectal cancer in both men and women
likely due to the adoption of widespread screening guidelines for
colonoscopy. This decline is seen in adults older than 50. However, a
steady increase in the incidence of colorectal cancer has been seen in
patients under the age of 50. While in older adults a gradual shift into
predominantly right-sided cancer has been noted, a gradual increase
in left-sided colon and rectal cancers has been seen in patients under
the age of 50. This increase in incidence has resulted in an increase
in mortality rates from colorectal cancer among young adults. Colon
cancer is now the leading cause of cancer death for young men age
20–49 and the second leading cause of cancer death after breast cancer
for women age 40–49.
■
■ADENOMATOUS POLYPS
Most colorectal cancers arise from adenomatous polyps as opposed
to a hyperplastic polyp, hamartomatous polyp, or a serrated polyp.
While adenomatous polyps are clearly premalignant, only a minority
of adenomatous polyps will ever develop into an adenocarcinoma.
Adenomatous polyps are common in the United States and western
societies, with approximately 25% of people having adenomatous
polyps by age 50. The rate steadily rises as people age, and as many as
50% of 70-year-old people will have adenomatous polyps. Less than 5%
of adenomatous polyps are expected to progress to an adenocarcinoma.
The vast majority of adenomatous polyps are asymptomatic and do not
bleed. The risk of progression to cancer is associated with size of the
polyp and the histology. Villous adenomas develop into cancer three­
fold more often than tubular adenomas.
■
■MOLECULAR PATHOGENESIS
The majority of colon cancers arise from a series of genetic and epi­
genetic events involving tumor suppressor genes and oncogenes. Three
major types of molecular pathways are involved in sporadic colorectal
cancer: the chromosomal instability (CIN) pathway, the mismatch
repair (MMR) pathway, and the CpG island methylation pathway
(CIMP). The CIN pathway is the most common molecular pathway
associated with colon cancer and is characterized by early loss of the
adenomatous polyposis coli (APC) gene, which is a tumor suppressor
gene. Subsequent mutations in important oncogenes involving the
MAP kinase pathway, such as KRAS and BRAF, are acquired sequen­
tially. Finally, loss of p53 tumor suppressor gene is a common final step.
The defects in the MMR pathway in sporadic colon cancer are often
caused by hypermethylation of the promoters for mismatch repair
genes. This results in a phenotype known as microsatellite instability
high (MSI-high), which is characterized by altered sizes of various
mono- and di-nucleotide repeat sequences. A defect in the MMR
pathway is the etiology of Lynch syndrome, which involves a germline
mutation in one of the genes encoding for the proteins involved in the
MMR pathway. It is critical to test for MSI-high because these tumors
are dramatically sensitive to immune checkpoint inhibition and less
sensitive to chemotherapy. The third major molecular pathway is the
CIMP phenotype. These tumors are often right sided and associated
with methylation of MLH1. They can be either MSI-high or microsat­
ellite stable (MSS). The three major pathways are not mutually exclu­
sive, and often overlapping changes can be seen in individual cancers.
CHAPTER 86
Colorectal Cancer
■
■ETIOLOGY AND RISK FACTORS
Risk factors for the development of colorectal cancer are listed in
Table 86-1.
■
■HEREDITARY FACTORS AND SYNDROMES
Advances in germline genotyping have made this technology more
widely available to the population of patients getting colon cancer.
Approximately 10% of all patients with colorectal cancer will have an
inherited, germline predisposition to colorectal cancer, and this rises
to ~15% of young adults with colorectal cancer (Table 86-2). The
germline mutations can be divided into high penetrance and moderate
penetrance based on their risk of colon cancer development.
Familial Adenomatous Polyposis (FAP) 
FAP and its variants
are due to a mutation in the APC gene located on chromosome 5q2122. It is inherited in an autosomal dominant pattern, although a sig­
nificant minority of cases are due to de novo mutations. FAP accounts
for <1% of all colon cancer and is characterized by the development of
hundreds to thousands of colonic polyps. It is diagnosed in childhood
in the classical form of FAP, and colorectal cancer develops in virtually
100% of individuals if left untreated. An attenuated form of FAP is char­
acterized by tens of polyps and cancers developing at a later age. FAP
TABLE 86-1  Risk Factors for the Development of Colorectal Cancer
Diet: Animal fat, obesity
Hereditary syndromes
  Polyposis coli
  MYH-associated polyposis
  Nonpolyposis syndrome (Lynch’s syndrome)
Inflammatory bowel disease
Streptococcus bovis bacteremia
Tobacco use
TABLE 86-2  Heritable (Autosomal Dominant) Gastrointestinal Neoplasia Syndromes
DISTRIBUTION OF
POLYPS
HISTOLOGIC TYPE
SYNDROME
Familial adenomatous
polyposis
Large intestine
Adenoma
Common
—
Gardner’s syndrome
Large and small
intestines
Adenoma
Common
Osteomas, fibromas, lipomas, epidermoid cysts, ampullary cancers,
congenital hypertrophy of retinal pigment epithelium
Turcot’s syndrome
Large intestine
Adenoma
Common
Brain tumors
MYH-associated polyposis
Large intestine
Adenoma
Common
None
Lynch syndrome
(nonpolyposis syndrome)
Large intestine (often
proximal)
Adenoma
Common
Endometrial and ovarian tumors (most frequently), gastric,
genitourinary, pancreatic, biliary cancers (less frequently)
Peutz-Jeghers syndrome
Small and large
intestines, stomach
Hamartoma
Rare
Mucocutaneous pigmentation; tumors of the ovary, breast, pancreas,
endometrium
Juvenile polyposis
Large and small
intestines, stomach
Hamartoma, rarely
progressing to adenoma
can be associated with extracolonic manifestations such as desmoid
tumors (Gardner’s syndrome) or brain tumors (Turcot’s syndrome).
Patients with classic FAP should undergo colectomy, as well as those
patients with attenuated FAP that is too difficult to screen endoscopi­
cally. Colectomy patients with FAP should be followed for extracolonic
tumors and manifestations. Chemoprevention with nonsteroidal antiinflammatory drugs (NSAIDs) can be tried because it has been asso­
ciated with polyp regression and delayed progression, but its overall
effect on cancer prevention has not been established.
PART 4
Oncology and Hematology
MUTYH-Associated Polyposis (MAP) 
MAP is an autosomal
recessive polyposis syndrome caused by a biallelic mutation in the
MUTYH gene. The MUTYH gene is a base excision repair gene, and
failure of base excision repair leads to somatic CG-AT transversions in
multiple genes. MAP accounts for <1% of colorectal cancers. The clini­
cal presentation of MAP overlaps with attenuated FAP in that individu­
als may have tens of polyps that develop by the fifth or sixth decade of
life. Individuals with MAP are at increased risk of duodenal cancers and
thyroid cancer. Screening and colectomy guidelines for this syndrome
are less clear than for polyposis coli, but annual to biennial colonoscopic
surveillance is generally recommended starting at age 25–30 years.
Lynch Syndrome 
Lynch syndrome, previously known as heredi­
tary nonpolyposis colon cancer, is the most common inherited pre­
disposition to colorectal cancer, accounting for ~3% of all colorectal
cancers, and confers an up to 17-fold risk of colorectal cancer. Lynch
syndrome is due to a mutation in one of the MMR genes. The MMR
genes are MLH1 (Chr 3p22), MSH2 (2p21-16), MSH6 (2p16), and
PMS2 (7p22). Lynch syndrome can also occur due to deletion of the
EPCAM gene, which causes loss of expression of MSH2. These muta­
tions are inherited in an autosomal dominant fashion. The MMR
system maintains genomic integrity by correcting base substitution
mismatches, and failure of the MMR system results in the accumula­
tion of a thousand-fold more mutations in genes that drive carcino­
genesis compared with MMR-proficient tumors. Lynch syndrome
has multiple extracolonic manifestations including increased risk of
cancers of the ovary, endometrium, stomach, small bowel, pancreati­
cobiliary system, genitourinary system, brain, and skin.
Lynch syndrome may not be associated with multiple polyps and
therefore is often unrecognized. Universal testing of colorectal tumors
for defects in the MMR system is recommended and accomplished by
either immunohistochemistry for MMR proteins in the tumor sample
or evaluation for microsatellite instability on the tumor sample. For
patients without a Lynch syndrome–associated cancer, family history is
the most reliable way to recognize Lynch syndrome, and several family
history criteria (Amsterdam Criteria and Revised Bethesda Criteria)
have been developed. Germline testing is recommended for all patients
with defects in the MMR system noted on the tumor sample or for
those non-cancer-affected patients with an appropriate family history.
Germline testing should be done in the context of appropriate pre- and
posttest genetic counseling.
MALIGNANT
POTENTIAL
ASSOCIATED LESIONS
Rare
Various congenital abnormalities
BRCA1/2 Mutation 
The hereditary breast and ovarian cancer
syndromes due to mutations in the tumor suppressor genes BRCA1 and
BRCA2 may carry an increased risk of colorectal cancer. In particular,
BRCA1 mutation may confer a 1.5-fold increased risk of colorectal can­
cer. Currently, the evidence is inconsistent, and therefore, guidelines
do not recommend increased screening. Nevertheless, BRCA carriers
may have an increased risk of young adult–onset colorectal cancer, and
clinicians should be aware of these data.
Diet 
The etiology for most cases of large-bowel cancer appears to
be related to environmental factors. The disease occurs more often in
upper socioeconomic populations who live in urban areas. Mortality
from colorectal cancer is directly correlated with per capita con­
sumption of calories, meat protein, and dietary fat and oil as well as
elevations in the serum cholesterol concentration and mortality from
coronary artery disease. Geographic variations in incidence largely
are unrelated to genetic differences because migrant groups tend
to assume the large-bowel cancer incidence rates of their adopted
countries. Furthermore, population groups such as Mormons and
Seventh Day Adventists, whose lifestyle and dietary habits differ
somewhat from those of their neighbors, have significantly lowerthan-expected incidence and mortality rates for colorectal cancer.
The incidence of colorectal cancer has increased in Japan since that
nation has adopted a more “Western” diet. At least three hypotheses
have been proposed to explain the relationship to diet, none of which
is fully satisfactory.
ANIMAL FATS  One hypothesis is that the ingestion of animal fats
found in red meats and processed meat leads to an increased propor­
tion of anaerobes in the gut microflora (the “microbiome”), resulting
in the conversion of normal bile acids into carcinogens. This provoca­
tive hypothesis is supported by several reports of increased amounts of
fecal anaerobes (Fusobacterium nucleatum, Bacteroides fragilis) in the
stools of patients with colorectal cancer. Diets high in animal (but not
vegetable) fats are also associated with high serum cholesterol, which
is also associated with enhanced risk for the development of colorectal
adenomas and carcinomas.
INSULIN RESISTANCE  The large number of calories in Western diets
coupled with physical inactivity has been associated with a higher
prevalence of obesity. Obese persons develop insulin resistance with
increased circulating levels of insulin, leading to higher circulating
concentrations of insulin-like growth factor type I (IGF-I). This growth
factor appears to stimulate proliferation of the intestinal mucosa.
FIBER  Contrary to prior beliefs, the results of randomized trials and
case-controlled studies have failed to show any value for dietary fiber
or diets high in fruits and vegetables in preventing the recurrence of
colorectal adenomas or the development of colorectal cancer.
The weight of epidemiologic evidence, however, implicates diet as
being the major etiologic factor for colorectal cancer, particularly diets
high in animal fat and in calories.
■
■INFLAMMATORY BOWEL DISEASE (CHAP. 337)
Colon and rectal cancers (but not anal cancers) are more common
in patients with inflammatory bowel disease (IBD). Most of the data
supporting this come from patients with ulcerative colitis. The risk of
colorectal cancer in a patient with IBD is relatively small during the first
10 years of the disease but then appears to increase at a rate of ~0.5–1%
per year. Cancer may develop in 8–30% of patients. The risk is higher
in patients with more extensive, more severe, and longer-lasting colitis.
The data are less consistent with Crohn’s disease, but this may be due
to the difficulty in distinguishing the two entities and also the different
amount of pancolitis in the two diseases. The molecular pathogenesis
of colorectal cancer arising from IBD appears to be distinctly different
from sporadic cancers. For instance, K-ras and APC mutations appear
to be less common in colon cancers arising in IBD patients.
Cancer surveillance strategies in patients with IBD are unsatisfac­
tory due to the lack of the classic polyp-to-cancer sequence. Symptoms
such as bloody diarrhea, abdominal cramping, and obstruction, which
may signal the appearance of a tumor, are similar to the complaints
caused by a flare-up of the underlying inflammatory disease. Surveil­
lance for colorectal cancer in patients with IBD is highly technical and
requires management by physicians specializing in this area. In patients
with longstanding ulcerative colitis, surgical removal of the colon (sub­
total or total) eliminates or significantly reduces the risk of colorectal
cancer depending on the extent of the operation. In patients undergo­
ing subtotal colectomy with preservation of the rectum, continued
surveillance of the remaining rectum is required.
■
■OTHER HIGH-RISK CONDITIONS
Tobacco Use 
Cigarette smoking is linked to the development of
colorectal adenomas, particularly after >35 years of tobacco use. No
biologic explanation for this association has yet been proposed.
Alcohol Use 
Moderate to excessive alcohol consumption has been
associated with an increased risk of colorectal cancer. It is difficult to
tease out the effect compared with other lifestyle risk factors.
Obesity, Insulin Resistance, and Diabetes Mellitus 
Mul­
tiple studies demonstrate an increased risk of colorectal cancer in obese
individuals. Additionally, diabetes is associated with an increased risk of
colorectal cancer. This has led to a theory that metabolic syndrome and
hyperinsulinemia are risk factors for the development of colorectal cancer.
Vitamin D Deficiency 
Multiple studies have demonstrated an
association between low levels of vitamin D and colon cancer. Never­
theless, no evidence suggests that vitamin D supplementation results
in fewer colon cancers.
■
■PRIMARY PREVENTION
Several orally administered compounds have been assessed as possible
inhibitors of colon cancer. The most effective class of chemopreventive
agents is aspirin and other NSAIDs, which are thought to suppress cell
proliferation by inhibiting prostaglandin synthesis. Regular aspirin
use as demonstrated in randomized studies reduces the risk of colon
adenomas. Regular aspirin use in cohort studies has demonstrated
reduced incidence of colon cancer. However, prospective trials using
aspirin to prevent colon cancer have had conflicting results in part due
to the delayed effects of aspirin on colon carcinogenesis; prevention
may increase with the duration and dosage of aspirin, and the effects
may take years to manifest. Meta-analyses have suggested that regular
aspirin use prevents colon cancer. However, given the potential side
effects of aspirin, regular use of aspirin is an individualized decision.
Antioxidant vitamins such as ascorbic acid, tocopherols, and
β-carotene are ineffective at reducing the incidence of subsequent
adenomas in patients who have undergone the removal of a colon
adenoma. Estrogen replacement therapy has been associated with a
reduction in the incidence of colorectal cancer in women but not mor­
tality from colorectal cancer.
■
■SCREENING
The rationale for colorectal cancer screening programs is that the
removal of adenomatous polyps will prevent colorectal cancer and that
TABLE 86-3  Screening Strategies for Colorectal Cancer
Digital rectal examination
Stool testing
• Occult blood
• Fecal DNA
Imaging
• Contrast barium enema
• Virtual (i.e., computed tomography colonography)
Endoscopy
• Flexible sigmoidoscopy
• Colonoscopy
earlier detection of localized, superficial cancers in asymptomatic indi­
viduals will increase the surgical cure rate. It is important to note that
screening studies did not take into account the presence of inherited
predisposition and germline genetics. Due to the rise in incidence of
colorectal cancer in younger adults, the U.S. Preventative Services Task
Force updated their screening recommendations in 2021 and lowered
the age for recommended screening to 45.
Screening strategies for colorectal cancer that have been examined
during the past several decades are listed in Table 86-3.
CHAPTER 86
The rationale for screening asymptomatic individuals has under­
gone change over many decades, and it is important to understand how
that change influences our current approach. Initially, patients were
screened for the presence of occult blood in the stool, which would
then lead to colonoscopy. Unfortunately, even when performed opti­
mally, the fecal occult blood test has major limitations as a screening
technique. About 50% of patients with documented colorectal cancers
have a negative fecal occult blood test, consistent with the intermittent
bleeding pattern of these tumors. When random cohorts of asymptom­
atic persons have been tested, 2–4% have fecal occult blood–positive
stools. Colorectal cancers have been found in <10% of these “test-posi­
tive” cases, with benign polyps being detected in an additional 20–30%.
Thus, a colorectal neoplasm will not be found in most asymptomatic
individuals with occult blood in their stool. Nevertheless, prospec­
tively controlled trials have shown a statistically significant reduction
in mortality rate from colorectal cancer for individuals undergoing
annual stool guaiac screening. However, this benefit only emerged after
many years of follow-up and was due to colonoscopic intervention,
which likely provided the opportunity for cancer prevention through
the removal of potentially premalignant adenomatous polyps because
the eventual development of cancer was reduced by 20% in the cohort
undergoing annual screening.
Colorectal Cancer
Due to the importance of endoscopic screening in preventing death
from colon cancer, many societies shifted from testing stool for the
presence of occult blood to offering endoscopic screening for the
asymptomatic population. Colonoscopy evaluates the entire colon
but is associated with more complications, the need for cathartics
to remove stool from the colon, the need for sedation in most cases,
and more overall expense. Sigmoidoscopy does not require an enema,
is associated with less perforations and morbidity, does not require
sedation, and can identify patients at high risk of needing a full colo­
noscopy if polyps or cancer is found in the rectum or sigmoid colon.
The recommendation for the inclusion of flexible sigmoidoscopy is
strongly supported by randomized studies evaluating a one-time sig­
moidoscopy as opposed to usual standard of care. A reduction in both
colorectal cancer incidence and colorectal cancer mortality is obtained
for patients undergoing screening, and this effect persists for >15 years.
One of the downsides of using screening sigmoidoscopy alone is that
in the presence of a normal sigmoidoscopy, ~1.5% of individuals will
have either a high-risk polyp or adenocarcinoma in the proximal colon.
The issue of missing advanced neoplasms in the proximal colon when
using only sigmoidoscopy was addressed by increased frequency of sig­
moidoscopy (every 5 years instead of every 10 years for colonoscopy)
and the use of annual fecal immunohistochemical test (FIT) for occult
blood. While randomized studies evaluating the combination are
lacking, most professional societies offer this approach as an alternative
to colonoscopy screening.
With the appreciation that the carcinogenic process leading to the
progression of the normal bowel mucosa to an adenomatous polyp and
then to a cancer is the result of a series of molecular changes, investi­
gators have examined fecal DNA for evidence of mutations associated
with such molecular changes as evidence of the occult presence of
precancerous lesions or actual malignancies. A multitarget stool DNA
test evaluates stool that is collected at home for DNA changes including
methylation combined with a FIT test. This multitarget stool DNA test,
when done in patients undergoing colonoscopy, has a >90% specificity
and sensitivity for detecting a colorectal adenocarcinoma but a <50%
sensitivity for detecting an advanced precancerous lesion.
The use of imaging studies to screen for colorectal cancers has also
been explored. Air contrast barium enemas had been used to identify
sources of occult blood in the stool prior to the advent of fiberoptic
endoscopy; the cumbersome nature of the procedure and inconve­
nience to patients limited its widespread adoption. The introduction
of computed tomography (CT) scanning led to the development of
virtual (i.e., CT) colonography as an alternative to the growing use of
endoscopic screening techniques. Virtual colonography requires use
of colon cathartic bowel preparations and appears to have good accu­
racy at detecting large lesions (>10 mm) but has not been compared
in a randomized study with colonoscopy. Two other disadvantages of
virtual colonoscopy are that it may have interuser variability and any
findings need to be followed up with a colonoscopy requiring a second
bowel cathartic preparation.
PART 4
Oncology and Hematology
Most professional societies agree that screening for colon cancer
should begin at age 45 for patients at average risk. In the United States,
there is ~60% compliance with screening and the emphasis is on get­
ting patients screened initially with either direct observation using sig­
moidoscopy or colonoscopy or indirect tests such as FIT or multitarget
stool DNA. The best combination approach and frequency of screening
likely will involve risk stratification factors in the future.
■
■CLINICAL FEATURES
Presenting Symptoms 
Symptoms vary with the anatomic loca­
tion of the tumor. Because stool is relatively liquid as it passes through
the ileocecal valve into the right colon, cancers arising in the cecum
and ascending colon may become quite large without resulting in
any obstructive symptoms or noticeable alterations in bowel habits.
Lesions of the right colon commonly ulcerate, leading to chronic,
insidious blood loss without a change in the appearance of the stool.
Consequently, patients with tumors of the ascending colon often pres­
ent with symptoms associated with hypochromic, microcytic anemia,
indicative of iron deficiency. As a result, the unexplained presence of
iron-deficiency anemia in any adult (with the possible exception of a
premenopausal, multiparous woman) mandates a thorough endoscopic
and/or radiographic visualization of the entire large bowel (Fig. 86-1).
Because stool becomes more formed as it passes into the transverse
and descending colon, tumors arising there tend to impede the pas­
sage of stool, resulting in the development of abdominal cramping,
occasional obstruction, and even perforation. Radiographs and CTs of
the abdomen often reveal characteristic annular, constricting lesions
(“apple-core”) (Fig. 86-2).
Cancers arising in the rectosigmoid are often associated with
hematochezia, tenesmus, and narrowing of the caliber of stool. While
these symptoms may lead patients and their physicians to suspect the
presence of hemorrhoids, the development of rectal bleeding and/or
altered bowel habits demands a prompt digital rectal examination and
sigmoidoscopy.
Staging, Prognostic Factors, and Patterns of Spread 
The
prognosis for individuals having colorectal cancer is related to the
depth of tumor penetration into the bowel wall and the presence
of both regional lymph node involvement and distant metastases.
These variables are incorporated into a TNM classification method,
in which T represents the depth of tumor penetration, N the presence
of lymph node involvement, and M the presence or absence of distant
FIGURE 86-1  Double-contrast air-barium enema revealing a sessile tumor of the
cecum in a patient with iron-deficiency anemia and guaiac-positive stool. The lesion
at surgery was a stage II adenocarcinoma.
metastases (Fig. 86-3). Superficial lesions that do not involve regional
lymph nodes and do not penetrate through the submucosa (T1) or the
muscularis (T2) are designated as stage I (T1–2N0M0) disease; tumors
that penetrate through the muscularis but have not spread to lymph
nodes are stage II disease (T3–4N0M0); regional lymph node involve­
ment defines stage III (TXN1–2M0) disease; and metastatic spread to
sites such as liver, lung, or bone indicates stage IV (TXNXM1) disease.
Unless gross evidence of metastatic disease is present, disease stage
cannot be determined accurately before surgical resection and patho­
logic analysis of the operative specimens.
The majority of recurrences occur within the initial 5 years after
resection. Occasionally tumors can recur between 5 and 10 years after
resection, and this appears to be more common with rectal cancer
FIGURE 86-2  Annular, constricting adenocarcinoma of the descending colon. This
radiographic appearance is referred to as an “apple-core” lesion and is always
highly suggestive of malignancy.
Stage
I
II
T1
T2
No deeper
than
submucosa
Not through
muscularis
Extent of tumor
90%
5-year survival
95%
23%
Colon
Stage at
presentation
Rectal
34%
Mucosa
Muscularis
mucosa
Submucosa
Muscularis
propria
Serosa
Fat
Lymph nodes
FIGURE 86-3  Staging and prognosis for patients with colorectal cancer.
than colon cancer. The likelihood for 5-year survival in patients with
colorectal cancer is stage-related (Fig. 86-3), and the survival rates per
stage have been improving in the past several decades. The most plau­
sible explanation for improved survival is the more thorough evalua­
tion for metastatic disease and the positive effects of chemotherapy for
treatment of adjuvant and systemic disease. A minimum of 12 sampled
lymph nodes is thought necessary to accurately define tumor stage,
and the more nodes examined, the better reliability that a patient is
either node negative or node positive. Other predictors of a poor prog­
nosis after a total surgical resection include tumor penetration through
the bowel wall into pericolic fat, poorly differentiated histology, per­
foration and/or tumor adherence to adjacent organs (increasing the
risk for an anatomically adjacent recurrence), and venous invasion by
tumor (Table 86-4). Tumors with microsatellite instability or defects
in MMR have improved prognosis presumably due to an enhanced
immune response against the tumor. Tumors arising in the left colon
are associated with a better prognosis than those appearing in the right
colon, likely due to differences in molecular patterns. In contrast to
most other cancers, the prognosis in colorectal cancer is not influenced
by the size of the primary lesion when adjusted for nodal involvement
and histologic differentiation.
Colorectal cancer generally spreads to the liver, lungs, and peritoneal
cavity. The liver represents the most frequent visceral site of metastasis;
it is the initial site of distant spread in one-third of recurring colorectal
TABLE 86-4  Predictors of Poorer Outcomes Following Total Surgical
Resection of Colorectal Cancer
Tumor spread to regional lymph nodes
Number of regional lymph nodes involved
Tumor penetration through the bowel wall
Poorly differentiated histology
Perforation
Tumor adherence to adjacent organs
Venous invasion
Preoperative elevation of CEA titer (>5 ng/mL)
Specific chromosomal deletion (e.g., mutation in the b-raf gene)
Right-sided location of primary tumor
Abbreviation: CEA, carcinoembryonic antigen.
Staging of colorectal cancer
III
IV
N1
N2
M
T3
≥4 lymph node
metastases
1–3 lymph node
metastases
Distant
metastases
Through
muscularis
50–70%
25–60%
<5%
70–85%
26%
20%
31%
26%
15%
25%
CHAPTER 86
Colorectal Cancer
cancers and is involved in more than two-thirds of such patients at the
time of death. It can spread to the brain and bones but not typically
as an initial site of metastatic disease, but rather after years of having
systemic metastases. Nevertheless, prompt evaluation of signs and
symptoms of bone and brain involvement should be efficiently done
because lack of prompt treatment can have devastating consequences
(e.g., cord compression, brain hemorrhage).
TREATMENT
Colorectal Cancer
Staging should consist of a complete blood count, comprehensive
metabolic panel, serum carcinoembryonic antigen (CEA), and a
chest, abdomen, and pelvic CT scan. Additional imaging such as
magnetic resonance imaging (MRI) and positron emission tomog­
raphy (PET) scan can be dependent on the findings of the CT scan.
When possible, a colonoscopy of the entire large bowel should
be performed to identify synchronous neoplasms and/or polyps.
While surgical resection is the standard of care for cure in patients
with localized disease, initial treatment of colorectal cancer when
possible should be delayed until MMR status or microsatellite sta­
bility status is known. MSI-high rectal cancers can be treated for
cure with checkpoint inhibitors (PD-1 antibodies) without the need
for surgery, radiation, and chemotherapy. Studies are underway
involving management of MSI-high colon cancers with checkpoint
inhibition.
LOCALIZED COLON CANCER
For the vast majority of patients with MSS colon adenocarcinoma,
initial surgical resection is the standard of care. Surgery with
minimally invasive techniques such as laparoscopy and robotic
approaches has largely replaced open approaches. Following com­
plete surgical resection, patients with stage I disease are considered
cured. Patients with high-risk stage II and stage III colon cancer are
considered for the appropriateness of adjuvant chemotherapy. The
standard adjuvant approaches generally improve overall survival
and cure rates by ~30%. Adjuvant chemotherapy for 3–6 months either
with single-agent fluoropyrimidine (IV or oral) or in combination
with oxaliplatin is considered the standard adjuvant treatment for
MSS colon cancer.
Following recovery from a complete resection, patients should
be observed carefully for 5 years using physical examinations
and blood chemistry measurements at regular intervals. Some
authorities favor measuring plasma CEA levels at 3-month inter­
vals because of the sensitivity of this test as a marker for otherwise
undetectable tumor recurrence. The value of periodically assessing
plasma for the presence of circulating tumor DNA as a biomarker
for residual or recurrent disease is under study. Subsequent endo­
scopic surveillance of the large bowel 1 year after resection and then
usually every 3 years is indicated because patients who have been
cured of one colorectal cancer have a 3–5% probability of develop­
ing an additional bowel cancer during their lifetime and a >15% risk
for the development of adenomatous polyps. Anastomotic (“sutureline”) recurrences are infrequent in colorectal cancer patients,
provided the surgical resection margins were adequate and free
of tumor. The value of periodic CT scans of the abdomen, assess­
ing for an early, asymptomatic indication of tumor recurrence, is
uncertain; however, CT has been recommended semi-annually to
annually for the first 3 postoperative years.
LOCALIZED RECTAL CANCER
For the vast majority of patients with MSS rectal adenocarcinoma,
surgical resection is considered the standard curative therapy. In
addition to the staging above, pelvic MRI should be standard in
staging for all patents with rectal cancer to assess mesorectal mar­
gin and nodal status. Surgical resection can either be a low anterior
resection (LAR) or an abdominal-perineal resection (APR). An
APR requires a permanent colostomy due to resection of the anal
sphincter. Unlike colon cancer, rectal cancers (defined as tumor at
or below the peritoneal reflection) have an increased risk of local
recurrence after surgery. The risk of local recurrence increases with
stage and closeness to the mesorectal border and decreases with
distance from the anus. Thus, tumors requiring an APR have a high
risk of local recurrence. The risk of local recurrence can be reduced
with preoperative chemotherapy and radiation. Patients with stage
II and III rectal cancer are deemed to have a risk high enough to
warrant consideration of preoperative therapy.
PART 4
Oncology and Hematology
Two new treatment paradigms have emerged for patients with
rectal cancer in specific circumstances. The first situation involves
patients in whom the consequences of radiation therapy are deemed
unacceptable. Radiation is associated with the potential long-term
side effects of radiation proctitis (increased risk in patients with IBD),
small-bowel obstruction to adhesions, and malignancy (~1% risk
after 10 years). Notably, radiation therapy in women causes infertility
due to the effects of radiation on the uterus even when the ovaries are
not included in the radiation field. Preoperative therapy with a fluo­
ropyrimidine and oxaliplatin followed by surgical resection produces
similar rates of local control to preoperative chemoradiation and can
be considered for average-risk stage II and III rectal cancer patients.
The second circumstance involves patients with stage II and III
rectal cancer treated with total preoperative therapy who experience
a complete clinical response. Nonoperative management can be
considered in these patients because 60–70% will be cured without
an LAR or APR. It is important to note that 30–40% of patients will
experience a recurrence so patients need to be followed intensively
in the years following chemotherapy and radiation. The majority
of patients who experience a local recurrence during nonoperative
management can be cured with surgery.
METASTATIC COLORECTAL CANCER
The first principle to note is that complete resection of metastatic
disease is considered curative for patients with colorectal cancer,
particularly in the setting of metastases isolated to one site (liver,
lungs, peritoneum). Consultation with the appropriate surgical spe­
cialists is preferred before starting systemic chemotherapy.
The detection of metastases should not preclude surgery to
remove the primary tumor in patients with tumor-related symp­
toms such as gastrointestinal bleeding or obstruction but usually
prompts the initiation of chemotherapy unless those symptoms are
viewed to be life-threatening. Studies have demonstrated that resec­
tion of the primary tumor in the setting of unresectable metastatic
disease does not improve overall survival and should be done only
on an ad hoc basis.
Patients with MSI-high colon cancer should be treated with a
checkpoint inhibitor as initial treatment. Long-term survival is pos­
sible in these patients, and some will have a complete response and
may not ever have recurrence of their cancer. For the vast majority
of patients with MSS colorectal adenocarcinoma who are not can­
didates for complete resection of metastatic disease, treatment with
systemic chemotherapy is associated with marked improvement in
overall survival compared with palliative care alone. A patient with
metastatic disease lives on average for 2–3 years with systemic che­
motherapy, and as many as 25% of patients will live for at least 5 years
on and off chemotherapy.
The mainstays of therapy for patients with metastatic colon
cancer are the following medications: 5-fluorouracil (5-FU; or
capecitabine), irinotecan, oxaliplatin, and bevacizumab. These
medications are used in combination all together (e.g., FOLIR­
INOX-bevacizumab or FOLFOXIRI-bevacizumab) or in partial
combination (e.g., FOLFOX-bevacizumab, FOFIRI-bevacizumab).
5-FU is an inhibitor of thymidylate synthase and is used in con­
junction with folinic acid (leucovorin). It is metabolized by dihy­
dropyrimidine dehydrogenase (DPD), which is deficient in ~1% of
adults. Individuals with DPD deficiency can experience increased
side effects from 5-FU, especially myelosuppression and mucositis.
Testing for DPD gene mutations may identify patients at high risk
of DPD deficiency and toxicity from 5-FU. Irinotecan is a topoi­
somerase I inhibitor and is metabolized by glucuronidation in the
liver. Thus, patients with UGT mutations can experience decreased
clearance and enhanced toxicity, principally myelosuppression.
Oxaliplatin is a platinum analogue that is metabolized generally
and can cause permanent peripheral neuropathy. Bevacizumab is
a monoclonal antibody against vascular endothelial growth fac­
tor (VEGF). Side effects of bevacizumab include hypertension,
nephrotic syndrome, and impaired wound healing. Untreated
hypertension from bevacizumab has been associated with posterior
reversible leukoencephalopathy syndrome.
Other agents with proven disease-altering effects in the meta­
static setting include trifluridine-tipiracil, regorafenib, and fruquin­
tinib. Trifluridine is a nucleoside analogue that is used with tipiracil,
a thymidine phosphorylase inhibitor. Regorafenib is an oral multi­
targeted tyrosine kinase inhibitor, including VEGF. Fruquintinib is
an oral VEFG tyrosine kinase inhibitor.
Molecular genotyping of the primary tumor should be done in
all patients with metastatic colon cancer if possible. Patients without
mutations of the RAS/RAF pathway can have excellent responses
and prolonged survival with the addition of antibodies against epi­
dermal growth factor (EGF), such as cetuximab and panitumumab.
These agents are often given in combination with either FOLFOX
or FOLFIRI. The effect of cetuximab and panitumumab appears
to be limited to left-sided colon cancers because right-sided colon
cancers have upregulation of receptor tyrosine kinases that create
resistance to these antibodies. The main side effects of these two
antibodies are the class effects of diarrhea and acneiform rash.
Cetuximab, which is partially murine, is also associated with aller­
gic reactions.
Patients who harbor BRAF V600E mutations may have a particu­
larly virulent form of colon cancer that does not respond as well to
standard chemotherapy. These mutations tend to occur more com­
monly in right-sided tumors and women. They often involve meth­
ylation of MLH1 and can be MMR deficient. The BRAF inhibitor
encorafenib is approved for use with cetuximab in patients with
BRAF-mutant colorectal cancer.
HER2 overexpression can be seen in colorectal cancer, and con­
sideration of anti-HER2–targeted therapy is warranted. Tucatinib
(HER2 tyrosine kinase inhibitor) and trastuzumab (anti-HER2
monoclonal antibody) are approved in the United States for patients
with HER2-positive colorectal cancers that lack a RAS mutation.

16 - 87 Tumors of the Liver and Biliary Tree
87 Tumors of the Liver and Biliary Tree
Rarely, RET fusions and TRK fusions can be seen in patients with
metastatic colorectal cancer. These patients can have tremendous
responses to the appropriate RET and TRK inhibitors with marked
prolongation of survival.
CANCERS OF THE ANUS
Cancers of the anus account for 1–2% of the malignant tumors of the
large bowel. Anal cancer by convention refers to squamous cell carci­
nomas arising in the anorectal region. Other types of cancers including
melanoma, neuroendocrine cancer, lymphoma, and mesenchymal
tumors can arise in these regions but are referred to by their histologic
subtype and are not the subject of this chapter. True adenocarcinomas
arising from the glands in the anal canal that are distinct from rectal
adenocarcinoma can also arise but, for all intents and purposes, are
indistinguishable from rectal adenocarcinoma and treated accordingly.
Most anal cancers arise in the anal canal, the anatomic area extend­
ing from the anorectal ring to a zone approximately halfway between
the pectinate (or dentate) line and the anal verge. The dentate line can
be quite variable in adults but, on average, is 4 cm from the anal verge.
Squamous cell carcinomas are characterized as either nonkeratinizing
or keratinizing. Older terms such as cloacogenic and basaloid are not
used anymore, and these tumors are instead characterized as nonkera­
tinizing. Outcomes for keratinizing and nonkeratinizing squamous cell
carcinoma of the anus are not different.
The development of anal cancer is associated with infection by
human papillomavirus (HPV), the same virus etiologically linked to
cervical and oropharyngeal cancers. The same HPV subtypes associ­
ated with cervical cancer are seen in anal cancer. The infection may
lead to squamous intraepithelial lesions (SILs), which are classified as
either low grade (LSIL) or high grade (HSIL). LSILs are associated with
non–cancer-causing HPV subtypes, are not considered precancerous,
and can spontaneously regress. HSILs are associated with HPV16 and
are considered precancerous. Anal cancer risk is increased in both men
and women with immunocompromised states including solid organ
transplant patients, patients with chronic immunosuppression with
glucocorticoids, and patients living with HIV, particularly with low
CD4 counts. Anal cancers occur most commonly in middle-aged per­
sons and are more frequent in women than men. At diagnosis, patients
may experience bleeding, pain, sensation of a perianal mass, and pru­
ritus. Examination of and attention to the inguinal lymph nodes on
imaging is important because anal cancers often spread initially to the
inguinal region rather than the iliac nodes like rectal cancer.
The standard treatment for anal cancers consists of 5-FU, mitomy­
cin, and concurrent external beam radiation therapy. The majority of
patients will experience a complete response to therapy. Some patients
will have ongoing resolution of their cancer over the 6 months after
completion of therapy. Therefore, the decision about whether a patient
has had a complete response to therapy is not made until after 6 months
following chemoradiation.
Patients who are considered primarily refractory to chemoradiation
or those with locally recurrent disease can be cured with radical resec­
tion (i.e., APR). In addition to those experiencing a local recurrence,
~10% of patients may experience continued rectal incontinence due to
the effects of radiation therapy and undergo a subsequent colostomy.
Metastatic anal cancer is considered incurable. It may respond well
to carboplatin and paclitaxel. PD-1 antibodies have limited activity in
patients with metastatic disease.
Acknowledgment
Robert J. Mayer contributed to this chapter in the prior edition and material
from that chapter has been retained here.
■
■FURTHER READING
André T et al: Pembrolizumab in microsatellite-instability-high
advanced colorectal cancer. N Engl J Med 383:2207, 2020.
Cercek A et al: PD-1 blockade in mismatch repair-deficient locally
advanced rectal cancer. N Engl J Med 386:2363, 2022.
Colón-López V et al: Anal cancer risk among people with HIV infec­
tion in the United States. J Clin Oncol 36:68, 2018.
Dekker E et al: Colorectal cancer. Lancet 394:1467, 2019.
Eng C et al: Anal cancer: emerging standards in a rare disease. J Clin
Oncol 40:2022.
Grothey A et al: Duration of adjuvant chemotherapy for stage III
colon cancer. N Engl J Med 378:1177, 2019.
Inadomi JM: Screening for colorectal neoplasia. N Engl J Med 376:149,
2017.
Long H et al: Pathways of colorectal carcinogenesis. Gastroenterology
158:291, 2020.
Petrelli F et al: Prognostic survival associated with left-sided vs
right-sided colon cancer. A systemic review and meta-analysis. JAMA
Oncol 3:211, 2017.
Schrag D et al: Preoperative treatment of locally advanced rectal
cancer. N Engl J Med 389:1631, 2023.
Siegel RL et al: Colorectal cancer statistics 2024. CA Cancer J Clin
12:49, 2024.
Josep M. Llovet
Tumors of the Liver
and Biliary Tree
CHAPTER 87
Tumors of the Liver and Biliary Tree
Liver cancer is the sixth most common cancer worldwide, the third
leading cause of cancer-related deaths and the leading cause of death
among cirrhotic patients. Liver cancer comprises a heterogeneous
group of malignant tumors that range from hepatocellular carcinoma
(HCC; ~85 cases), intrahepatic cholangiocarcinoma (iCCA; ~10%),
and other malignancies, such as fibrolamellar HCC, mixed HCCiCCA, epithelioid hemangiothelioma, and the pediatric cancer hepato­
blastoma. The burden of liver cancer is increasing globally.
HEPATOCELLULAR CARCINOMA
■
■EPIDEMIOLOGY AND RISK FACTORS
Overall, liver cancer accounts for 7% of all cancers (~900,000 new cases
each year), and HCC represents 85% of primary liver cancers. The
highest incidence rates of HCC occur in Asia and sub-Saharan Africa
due to the high prevalence of hepatitis B virus (HBV) infection, with
20–35 cases per 100,000 inhabitants. Southern Europe and now North
America have intermediate incidence rates (10 cases per 100,000),
whereas Northern and Western Europe have low incidence rates of less
than 5 cases per 100,000 inhabitants. In the United States, the incidence
of liver cancer is 40,000 cases per year (Fig. 87-1). HCC has a strong
male preponderance, with a male-to-female ratio estimated to be 2.5:1.
The incidence increases with age, reaching a peak at 65–70 years old.
In Chinese and in black African populations (where vertical transmis­
sion of HBV occurs), the mean age is 40–50 years. By contrast, in Japan
mean age in men is now around 75 years.
The main risk factors for HCC development are cirrhosis—an asso­
ciated chronic liver damage caused by inflammation and fibrosis—of
any etiology, chronic infection by HBV or hepatitis C virus (HCV)
infection, alcohol abuse, metabolic syndrome, and hemochromatosis
(associated to HFE1 gene germline mutations) (Fig. 87-1). Cirrhotic
patients represent 1% of the human population, and one-third of them
will develop HCC during their lifetime. Long-term follow-up studies
have established an annual risk of HCC development of 3–8% in
HBV- or HCV-infected cirrhotic patients. HCC is less common (1–2%
per year) in cirrhosis associated with alcohol, metabolic dysfunction–
associated steatohepatitis (MASH, formerly known as nonalcoholic
steatohepatitis or NASH), α1-antitrypsin deficiency, autoimmune hepa­
titis, Wilson’s disease, and cholestatic liver disorders. Predictors of liver
cancer development among cirrhotic patients have been associated
Central
Europe
Western
Europe
North America
Western
Africa
Andean Latin
America
South Latin
America
ASR (World) per 100,000
≥8.4
5.8–8.4
4.7–5.8
3.3–4.7
PART 4
Oncology and Hematology
Not applicable
No data
<3.3
FIGURE 87-1  Distribution of hepatocellular carcinoma (HCC) incidence according to geographical area and etiology. HBV, hepatitis B virus; HCV, hepatitis C virus; NASH,
nonalcoholic steatohepatitis. (Reproduced with permission from JM Llovet et al: Hepatocellular carcinoma. Nat Rev Disease Primers 21:76, 2021.)
with liver disease severity (platelet count of <100,000/µL, presence
of portal hypertension), the degree of liver stiffness as measured by
transient elastography, and liver gene signatures capturing the cancer
field effect.
In terms of attributable risk fraction, HBV infection—a DNA virus
that can cause insertional mutagenesis and affects ~300 million people
globally—accounts for ~50% of HCC cases globally (60% in Asia and
Africa and 20% in the Western world). Among patients with HBV
infection, a family history of HCC, HBeAg seropositivity, high viral
load, and genotype C are independent predictors of HCC development.
HCV infection—an RNA virus that affects ~70 million people—is
responsible for ~30% of cases and is the main cause of HCC in Europe
and North America. Among patients with HCV infection, HCC occurs
almost exclusively when relevant advanced liver damage and fibrosis
are present, particularly if associated with HCV genotype 1b.
Alcohol consumption and metabolic syndrome due to diabetes and
obesity are responsible for ~30% of cases. MASH is the fastest grow­
ing cause of cirrhosis in developed countries and currently represents
~15–20% of HCC cases in the West. The annual incidence of HCC
in MASH-related cirrhosis (1–2%/year) justifies including cirrhotic
patients in surveillance programs. Nonetheless, it has to be taken into
account that 25–30% of MASH-associated HCCs occur in the absence
of cirrhosis. A PNPLA3 polymorphism is strongly associated with
fatty and alcoholic chronic liver diseases and HCC occurrence. Finally,
other cofactors contributing to HCC development in all etiologies are
tobacco, aflatoxin B1 (a fungal carcinogen present in food supplies that
induces TP53 mutations), and aristolochic acid contained in Chinese
medicine herbs.
■
■MOLECULAR PATHOGENESIS
HCC development is a complex multistep process that starts with
precancerous cirrhotic nodules, so-called low-grade dysplastic nodules
(LGDN) that evolve to high-grade dysplastic nodules (HGDN) that
can transform into early-stage HCC. Molecular studies support the
pivotal role of adult hepatocytes as the cell of origin, either by directly
transforming to HCC or by de-differentiating into hepatocyte precur­
sor cells. Alternatively, progenitor cells also give rise to HCC with
progenitor markers.
Genomic analysis has provided a clear picture of the main drivers
responsible for HCC initiation and progression. This tumor results
Eastern
Europe
Japan
East Asia
South-East Asia
North Africa,
Middle East
Oceania
Etiology
HCV
Alcohol
HBV
Southern Africa
NASH & other
from the accumulation of around 40–60 somatic genomic alterations
per tumor, among which 4–8 are considered driver cancer genes.
HCC is a prototypical inflammation-associated cancer, where immune
microenvironment and oxidative stress present in chronically damaged
livers play pivotal roles in inducing mutations. In preneoplastic HGDN,
mutations in telomere reverse transcriptase (TERT) gene (20% of cases)
and gains in 8q have been described. Oncogenic transformation occurs
upon additional genomic hits. The main molecular drivers of HCC
are in the telomerase reverse transcriptase (TERT) promoter (56%),
TP53 (27%), and CTNNB1 (26%), all of which are unactionable with
molecular therapies. Genes commonly mutated in other solid tumors
such as EGFR, HER2, PIK3CA, BRAF, or KRAS are rarely mutated in
HCC (<5%) (Table 87-1). Studies assessing copy-number alterations
in HCCs have consistently identified: (1) high-level amplifications at
5–10% prevalence containing oncogenes in 11q13 (CCND1 and FGF19)
and 6p21 (VEGFA), TERT focal amplification, and homozygous dele­
tion of CDKN2A; and (2) common amplifications containing MYC
(8q gain). Overall, only ~20–25% of HCCs have at least one actionable
mutation. Some risk factors have been associated with specific molecu­
lar aberrations. HBV integrates into the genome of driver genes, such as
the TERT promoter, MLL4, and cyclin E1 (CCNE1). Alcohol abuse and
HCV infection have been associated with CTNNB1 mutations. TP53
mutations are the most frequent alterations with a specific hotspot of
mutation (R249S) in patients with aflatoxin B1 exposure.
Molecular and Immune Classes 
Genomic studies have revealed
two molecular subclasses of HCC, each representing ~50% of patients.
The proliferative subclass associated with poor outcomes, HBV-related
etiologies, and overexpression of α-fetoprotein is enriched by activa­
tion of Ras, mammalian target of rapamycin (mTOR), and insulin-like
growth factor (IGF) signaling and FGF19 amplification. By contrast,
the so-called nonproliferative subclass contains a subtype character­
ized by CTNNB1 mutations and better outcome. Another classification
based upon immune status has been proposed. It defines an inflamed
HCC class in ~35% of cases (i.e., hot tumors), characterized by immune
infiltrate with expression of PD-1/PD-L1, enrichment of T-cell activa­
tion, and better response to immunotherapies, and a noninflamed class
(cold tumors), which includes the excluded subclass associated with
activation of pathways related with immune escape (i.e., Wnt signal­
ing) or absence of T-cell infiltrate. None of this molecular knowledge
TABLE 87-1  Molecular Aberrations Common in Hepatocellular
Carcinoma (HCC)a
PATHWAY
TARGET
PREVALENCE (%)
Mutations
Telomere stability
TERT promoter
p53/cell cycle control
TP53
ATM
RB1
Wnt/β-catenin signaling
CTNNB1
AXIN1
Chromatin remodeling
ARID1A
ARID2
KMT2A
KMT2C
Ras/PI3K/mTOR pathway
RPS6KA3
TSC1/TSC2
Oxidative stress
NFE2L2
KEAP1
High-level focal amplifications
VEGF signaling
VEGFA
FGF signaling
FGF19
Cell-cycle control
CCND1 protein
Target with homozygous deletion
TP53/cell-cycle control
CDKN2A
TP53
Retinoblastoma 1
Wnt/β-catenin signalling
AXIN1
aRecurrent mutations, focal amplifications, or homozygous deletions in HCC based
on next-generation sequencing analyses.
has yet been translated into actual clinical benefits for any specific
molecularly based subgroups, and thus, precision oncology is still an
unmet goal of therapy.
■
■PREVENTION AND EARLY DETECTION
Prevention 
Primary prevention of HCC can be achieved by vac­
cination against HBV and effective treatment of HBV and HCV infec­
tion. Universal vaccination against HBV infection is associated with a
significant decrease of the incidence of HCC. Nowadays, HBV vaccina­
tion is recommended to all newborns and high-risk groups, following
World Health Organization guidelines, and people with risk factors
for acquiring HBV infection, such as health workers, travelers to areas
where HBV infection is prevalent, injecting drug users, and people
with multiple sex partners.
Effective antiviral treatments for patients with chronic HBV infection—
achieving undetectable viral titers (circulating HBV-DNA)—result in
50–80% risk reduction of HCC development. Treatment of HCV with
direct-acting antiviral agents (DAAs) yields >90% sustained virological
response (SVR) rates after 12 weeks of treatment, thus significantly
reducing HCC occurrence. Once cirrhosis is established, the incidence
of HCC is lower for patients with SVR than for those with active viral
disease, although they continue to have persistent HCC risk. Clinical
practice guidelines recommend coffee consumption as a preventive
strategy in patients with chronic liver disease. Aspirin, statins, and
metformin have shown preventive effects but are not yet recommended
as formal chemopreventive strategies.
Surveillance 
Surveillance programs aim to reduce cancer-related
mortality. This is usually achieved through early detection that
enhances the applicability and cost-effectiveness of curative therapies.
U.S. and European guidelines recommend surveillance for patients at
high risk for HCC on the basis of cost-effectiveness analyses.
Surveillance is recommended for cirrhotic patients owing to
any cause, those with HCV-related advanced fibrosis, and patients
with chronic HBV infection if Asian aged >40 years, African aged
20 years, family history of HCC, or patients with sufficient risk by risk
scores such as PAGE-B. In terms of liver dysfunction, the presence of
advanced cirrhosis (Child-Pugh class C) prevents potentially curative
therapies from being employed, and thus surveillance is not recom­
mended. As an exception, patients on the waiting list for liver trans­
plantation, regardless of liver functional status, should be screened for
HCC in order to detect tumors exceeding conventional criteria and to
define priority policies for transplantation.
Ultrasonography every 6 months with serum α-fetoprotein (AFP)
levels is the recommended method of surveillance. It has a sensitivity
of ~65% and a specificity of >90% for early detection. A shorter followup interval (every 3–6 months) is recommended when a nodule of
<1 cm has been detected. Computed tomography (CT) and magnetic
resonance imaging (MRI) are not recommended as screening tools due
to lack of data on accuracy, high cost, and possible harm (i.e., radiation
with CT). Contrast-enhanced MRI can be considered in patients with
obesity and fatty liver, where visualization with ultrasound is subopti­
mal. The accuracy of other serum biomarkers proposed, such as des-γ
carboxyprothrombin (DCP) and the L3 fraction of AFP (AFP-L3), in
early detection is not known.
CHAPTER 87
Despite the fact that surveillance is cost-effective in HCC, the global
implementation of such programs is estimated to engage ~50% of the
target population in Europe and ~30% in the United States. Public
health policies encouraging the implementation of such programs
could lead to an increase in early tumor detection.
Tumors of the Liver and Biliary Tree
Diagnosis 
HCC is generally diagnosed at early or intermediate
stages in Western countries but at advanced stages in most Asian
(except Japan) and African countries. A surveillance program yields
detection of early HCC in 70–80% of cases. At these stages, the
tumor is asymptomatic, and diagnosis can be made by noninvasive
(radiological) or invasive (biopsy) approaches. Without surveillance,
HCC is discovered either as a radiological finding or due to cancerrelated symptoms. If symptoms are present, the disease is already at an
advanced stage, with a median life expectancy of <1 year. Symptoms
include malaise, weight loss, anorexia, abdominal discomfort, or signs
related to advanced liver dysfunction.
NONINVASIVE (RADIOLOGICAL) DIAGNOSIS  Patients enrolled in a
surveillance program are diagnosed by identification of a new liver
nodule on abdominal ultrasound. Noninvasive criteria can only be
applied to cirrhotic patients and are based on imaging techniques
obtained by four-phase multidetector CT scan (four phases are unen­
hanced, arterial, venous, and delayed) or dynamic contrast-enhanced
MRI. A flowchart of diagnosis and recall policy recommended by U.S.
and European guidelines is summarized in Fig. 87-2. In nodules >1 cm
or with AFP ≥20 ng/mL or rising AFP, multiphasic contrast-enhanced
CT or MRI is recommended. Using these techniques, the typical hall­
mark of HCC consists of vascular uptake of the nodule in the arterial
phase with washout in the portal venous or delayed phases. This radio­
logical pattern captures the hypervascular nature characteristic of HCC
and has a diagnostic specificity of ~95–100%, making a biopsy unnec­
essary. The Liver Imaging Reporting and Data System (LI-RADS) has
been proposed as a way of classifying radiological findings. Essentially,
nodules >10 mm visible on multiphase exams are assigned category
codes reflecting their relative probability of being benign, HCC, or
other hepatic malignant neoplasm. LI-RADS-1 lesions have a 0% prob­
ability of HCC, whereas lesions assigned to the LI-RADS-4 category
are likely to be an HCC in 60–70% of cases and repeated imaging
within 3–6 months or biopsy is recommended. Finally, LI-RADS-5
lesions have a ~95% probability of being HCCs. LI-RADS-M category
comprises lesions that have malignant radiological features but are only
HCC in ~35% of cases.
Nodules <1 cm in size are unlikely to be HCC and would be very
difficult to diagnose, and thus ultrasound follow-up at 3–4 months is
recommended. Contrast-enhanced ultrasound (CEUS) and angiography
Mass/Nodule on US
1 cm, AFP ≥20 ng/mL or rising AFP
<1 cm
Repeat US at 3–6 mos
Growing/changing pattern
1 positive technique
HCC radiological hallmark or LI-RADS 5*
Stable
LI-RADS 4
LI-RADS 3
Use alternative imaging
PART 4
Oncology and Hematology
Inconclusive
*Hallmark of HCC: Contrast uptake in arterial phase and washout in venous or delayed phase
**Consider a second biopsy in case of inconclusive
FIGURE 87-2  Recall diagnosis schedule for HCC (EASL). EASL, European Association for the Study of Liver Disease; HCC, hepatocellular carcinoma. (Modified with
permission from EASL. J Hepatology 69:182, 2018.)
are less accurate for HCC diagnosis. Positron emission tomography
(PET) scan performs poorly for early diagnosis. AFP levels ≥400 ng/dL
are highly suspicious but not diagnostic of HCC according to guidelines.
PATHOLOGICAL DIAGNOSIS  Pathological diagnosis is required: (1) in
patients without cirrhosis, (2) if radiology is not typical in at least one
of two imaging techniques (CT and MRI), and (3) for a LI-RADS-4
lesion. Biopsy has not been used as the gold standard in clinical prac­
tice, although with the advent of molecular therapies, some guidelines
advocate obtaining tissue samples in the setting of all research stud­
ies in HCC, even if radiological criteria are met. Sensitivity of liver
biopsies ranges between 70 and 90% for all tumor sizes but decreases
to <50% in tumors 1–2 cm in size. The risk of complications, such
as tumor seeding and bleeding, after liver biopsy is ~2–3%. Biopsies
should be assessed by an expert hepatopathologist. The use of special
stains may help to resolve diagnostic uncertainties. Positive staining in
two of four markers (glypican 3 [GPC3], glutamine synthetase, heat
shock protein 70 [HSP70], and clathrin heavy chain) is highly specific
for HCC. Additional staining can be considered to detect progenitor
cell features (K19 and epithelial cell adhesion molecule [EpCAM]) or
assess neovascularization (CD34). A negative biopsy does not elimi­
nate the diagnosis of HCC. A second biopsy is recommended in case
of inconclusive findings or growth or change in enhancement pattern
identified during follow-up (Fig. 87-2).
■
■TREATMENT
Overview 
The landscape of management of HCC has substan­
tially changed during the last decade. For early stages, resection, liver
transplantation, and local ablation have substantially improved life
expectancy, with median overall survival (OS) times beyond 5 years
(Fig. 87-3). Adjuvant therapy with atezolizumab plus bevacizumab
improves recurrence-free survival in patients at high risk of recurrence
undergoing resection or ablation. For intermediate stages, transarterial
chemoembolization (TACE) has improved the natural history of 16
Four-phase contrast-enhanced CT or
Multiphasic contrast-enhanced/or gadoxetic-enhanced MRI
Yes
HCC
Biopsy**
Benign or non-HCC
malignant
months to ~30 months, and when combined with durvalumab plus
bevacizumab, it improves progression-free survival. Systemic drugs
for advanced tumors (atezolizumab plus bevacizumab, durvalumab
plus tremelimumab, sorafenib, lenvatinib, regorafenib, cabozantinib,
and ramucirumab) have improved median survivals from 8 months to
even beyond 19 months in front-line and to 10 months in second-line
treatment (Fig. 87-3).
Staging Systems and Treatment Allocation 
Staging systems are
aimed at stratifying patients according to prognostic factors and out­
come and allocating the best available therapies according to evidence.
The most accepted staging system is the Barcelona Clinic Liver Cancer
(BCLC) Classification, which is endorsed by U.S. and European clinical
practice guidelines (Fig. 87-3). This staging system defines five prog­
nostic subclasses and allocates specific treatments for each stage. The
BCLC staging system has been externally validated by numerous stud­
ies. It is an evolving system that allows incorporation of new therapies
and treatment-dependent variables as new evidence emerges. Several
treatments improve survival in HCC, and thus have been incorporated
in the therapeutic algorithm: surgical resection, liver transplanta­
tion, radiofrequency (RF) ablation, microwave, chemoembolization,
and systemic therapies (atezolizumab-bevacizumab, durvalumab plus
tremelimumab, sorafenib, lenvatinib, regorafenib, cabozantinib, and
ramucirumab). The BCLC assigns each patient to a given treatment
allocation. Treatment stage migration is also applied by this scheme,
meaning that if patients are not candidates for the selected therapy, the
next effective therapy at more advanced stages can be given.
In HCC, three parameters are relevant for defining treatment strat­
egy: tumor status, cancer-related symptoms, and liver dysfunction.
The BCLC staging captures all three variables and allocates patients
to treatments according to evidence. Since >80% of patients have two
diseases, HCC and cirrhosis, a clear measurement of liver dysfunction
should be in place. The prognosis of chronic liver disease is com­
monly assessed using the Child-Pugh score, which uses five clinical
Hepatocellular carcinoma
Very early (BCLC 0)
Early (BCLC A)
Stages
Stratification
Treatment
Single nodule ≤2 cm
Child-Pugh A, ECOG 0
Single or ≤3 nodules ≤3 cm
Child-Pugh A-B, ECOG 0
2–3 nodules
≤3 cm
Solitary
Yes
Optimal
surgical
candidate
No
Yes
Transplant
candidate
No
Transplantation
(LT)
Ablation
First
choice#
Second
choice##
Ablation
Resection
Systemic therapy*
Best supportive
care
Downstaging LT
TACE (TARE, SBRT)
Extended criteria LT
(TARE)
Resection
Expected
outcomes
Median OS: 10 yr Transplantation;
6 yr for resection/ablation
FIGURE 87-3  Staging system and therapeutic strategy. BCLC classification comprises five stages that select the best candidates for therapies according to evidence-based
data. Patients with asymptomatic early tumors (stages 0 -A) are candidates for radical therapies (resection, transplantation, or local ablation). Asymptomatic patients with
multinodular HCC (stage B) are suitable for transcatheter arterial chemoembolization (TACE), whereas patients with advanced symptomatic tumors and/or an invasive
tumoral pattern (stage C) are candidates to receive systemic therapies. End-stage disease (stage D) includes patients with poor prognosis that should be treated by best
supportive care. BCLC, Barcelona Clinic Liver Cancer; DDLT, deceased donor liver transplantation; EASL, European Association for the Study of Liver Disease; ECOG,
Eastern Cooperative Oncology Group Performance Status; EORTC, European Organisation for Research and Treatment of Cancer; GRADE, grading of recommendations
assessment, development, and evaluation; HCC, hepatocellular carcinoma; LDLT, living donor liver transplantation; OS, overall survival; PEI, percutaneous ethanol injection;
RF, radiofrequency ablation; TACE, transcatheter arterial chemoembolization. (Modified with permission from JM Llovet et al: Molecular pathogenesis and systemic
therapies for hepatocellular carcinoma. Nature Cancer 3:386, 2022.)
*Around 70–80% of patients are expected to receive this regimen
#Based on high level evidence studies.
##Based on low or moderate level of evidence studies.
measures—total bilirubin, serum albumin, prothrombin time, ascites
severity, and hepatic encephalopathy grade—to classify patients into
one of three groups (A–C) of predicted survival rates. In brief, ChildPugh class A reflects well-preserved liver function, Child-Pugh class B
moderate liver dysfunction, and Child-Pugh class C severe liver dys­
function. Other measurements of liver dysfunction, such as the Model
for End-Stage Liver Disease (MELD) score or the albumin-bilirubin
score, are not integrated in this staging system. Performance status is
assessed by Eastern Cooperative Oncology Group (ECOG) scale (a
5-point scale where higher numbers indicate greater disability), and
presence of cancer-related symptoms (ECOG 1–2) is considered a sign
of advanced stage.
Considering all these prognostic/predictive variables and evidencebased treatment efficacy, five BCLC stages have been defined (Fig. 87-3).
Patients with liver-only neoplastic disease, no symptoms (ECOG 0),
and mild to moderate liver dysfunction (Child-Pugh A-B) can be clas­
sified as very early (stage 0), early (stage A), or intermediate (stage B)
stage depending on tumor size and number. Very early HCC (BCLC 0)
is defined by single tumors ≤2 cm (if pathology is available, the tumors
should be well-differentiated with absence of microvascular invasion
or satellites). Early HCC (BCLC A) includes either single tumors or a
Intermediate (BCLC B)
Advanced (BCLC C)
Terminal (BCLC D)
Portal invasion, N1, M1
Child Pugh A-B, ECOG 1–2
Multinodular
Child-Pugh A-B, ECOG 0
Child Pugh C
ECOG >2
TACE
candidate
No
Yes
CHAPTER 87
Chemoembolization
(+ systemic therapies)
Tumors of the Liver and Biliary Tree
Median OS
~26–30 mo
mPFS: 15 mo
1st line: ~16–19 mo
2nd line: 13–15 mo
3rd line: 8–12 mo
Median OS
3–6 months
maximum of three nodules of ≤3 cm in diameter. Intermediate stage
(BCLC B) is defined by all other liver-only tumors. Conversely, HCC
is considered at advanced stages (BCLC C) when patients present with
cancer-related symptoms (ECOG 1–2) or tumors with macrovascular
invasion (of any type, including branch, hepatic, or portal vein), lymph
node involvement, or extrahepatic spread. Finally, end-stage disease
(BCLC D) is considered in cases of severe impairment of quality of
life or severe cancer-related symptoms (ECOG 3–4) or severe liver
dysfunction (Child-Pugh C).
Around 40% of patients are diagnosed at stages 0 and A and hence
are eligible for potentially curative therapies, resection, transplantation,
or local ablation. These treatments provide median survival rates of
60 months and beyond, which are in sharp contrast with outcomes
of 36 months reported in historical controls (Fig. 87-3, Table 87-2).
Adjuvant therapy with atezolizumab plus bevacizumab is recom­
mended in patients after resection or local ablation who are at high risk
of recurrence. Patients at intermediate stage (stage B) with preserved
liver function have a documented natural history of around 16 months.
These patients benefit from TACE, as reported in two randomized
studies and one meta-analysis and achieve an estimated survival of
25–30 months. Combination of durvalumab plus bevacizumab with TACE
TABLE 87-2  Summary of Key Results of Randomized and Cohort Studies in the Management of Hepatocellular Carcinoma (HCC)
TREATMENT OF EARLY AND INTERMEDIATE STAGE HCC
TREATMENTS
HCC STAGE
TREATMENT ARMS
OUTCOMES (OS)
Treatments for early HCC
Resection
Early
Optimal (single nodule; no portal hypertension)
5-year: 50–70%
Suboptimal (multinodular or portal hypertension)
5-year: 35–55%
Resection + adjuvant
Early
Adjuvant atezolizumab + bevacizumab vs surveillance
12-month RFS: 78 vs 65%
Liver transplantation
Early
Milan (1 nodule <5 cm, 2–3 nodules ≤3 cm, no MVI, no EHS)
5-year: 70–80%
Early/intermediate
Downstaged (1 nodule ≤6.5 cm, ≤3 nodules ≤4.5 cm and total diameter ≤8 cm,
no MVI, no EHS)
Ablation
Early
RFA
Median: 50–60 months
Treatments for intermediate HCC
Transarterial therapies
Intermediate
TACE
Median: 20–32 months
Median PFS: 8 months
Locoregional + systemic
Intermediate
TACE + durvalumab + bevacizumab
Median PFS: 15.2 months
TREATMENT OF ADVANCED STAGE HCC
STUDY NAME
TREATMENT
MEDIAN OS, MONTHS (HR 95% CI)
MEDIAN PFS, MONTHS (HR 95% CI)
ORR mRECIST/RECIST
First-line therapies
IMbrave150
Atezolizumab + bevacizumab
19.2 vs 13.5 (HR 0.66, 0.452–0.85)
6.9 (HR 0.65, 0.53–0.81)
35.4%/29.8%
HIMALAYA
Durvalumab + tremelimumab
16.4 (HR 0.78, 0.65–0.93)
3.7 (HR 0.90, 0.77–1.05)
NA/20%
PART 4
Oncology and Hematology
SHARP
Sorafenib
10.7 (HR 0.69, 0.55–0.87)
10.7 (HR 0.69, 0.55–0.87)
NA/2%
REFLECT
Lenvatinib
13.6 (HR 0.92, 0.79–1.06)
7.4 (HR 0.66, 0.57–0.77)
24.1%/18.8%
Second-line therapies
RESORCE
Regorafenib
10.6 (HR 0.63, 0.5–0.79)
3.1 (HR 0.46, 0.37–0.56)
11%/7%
CELESTIAL
Cabozantinib
10.2 (HR 0.76, 0.63–0.92)
5.2 (HR 0.44, 0.36–0.52)
NA/4%
REACH-2
Ramucirumab
8.5 (HR 0.71, 0.53–0.95)
2.8 (HR 0.45, 0.34–0.6)
NA/5%
Abbreviations: CI, confidence interval; EHS, extrahepatic spread; HCC, hepatocellular carcinoma; HR, hazard ratio; mRECIST, modified Response Evaluation Criteria in Solid
Tumors; MVI, microvascular invasion; NA, not available; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; RFA, radiofrequency ablation; TACE,
transarterial chemoembolization.
has shown benefits in progression-free survival compared with TACE
alone. Patients progressing on TACE or at advanced stage (stage C)
benefit from systemic treatments. First-line therapy for advanced
HCC includes atezolizumab plus bevacizumab or durvalumab plus
tremelimumab. Both combinations were superior to sorafenib in phase
3 trials. In patients with contraindications for immunotherapies, both
sorafenib or lenvatinib are recommended Three additional targeted
therapies have shown to improve survival compared to placebo in
patients with HCC progressing on sorafenib: regorafenib, cabozantinib,
and ramucirumab (only in patients with AFP >400 ng/mL). Therefore,
these treatments have been adopted by guidelines and incorporated
into the treatment algorithm. Patients with end-stage disease (BCLC D)
should be considered for nutritional and psychological support and
proper management of pain.
Although the BCLC establishes validated stages and treatment
assignment according to evidence, clinical practice is not always
aligned with this classification. In large cohort studies and surveys, only
half of patients, or even less in Asia, are treated accordingly. Alterna­
tive staging or scoring systems have been proposed, such as the Hong
Kong classification or the Japan Integrated Staging score. These systems
capture extended indications for resection and TACE applied in clini­
cal practice in Asia. Finally, the tumor-node-metastasis (TNM) stag­
ing system is not used in HCC since it does not incorporate the main
prognostic variables related to liver function and performance status.
Due to the complexities of HCC diagnosis and management, it is
recommended to refer patients to centers with multidisciplinary liver
cancer programs that include a hepatologist, oncologist, hepatobiliary
and transplant surgeons, interventional and body imaging radiologist,
hepatopathologist, and specialized nurses.
■
■SURGICAL THERAPIES
Resection 
Surgical resection is the first-line option for noncirrhotic
patients with early-stage HCC (BCLC 0 or A) with solitary tumors
5-year: 60–70%
(Fig. 87-3). In cirrhotic patients, ablation competes with resection for
BCLC 0 tumors (<2 cm in diameter). Which is better is not defined.
Cost-effectiveness approaches report a benefit for local ablation with
RF. For single tumors >2 cm (BCLC A), resection remains the mainstay
of treatment in patients with Child-Pugh A with normal bilirubin and
absence of portal hypertension (no esophageal/gastric varices or platelet
count >100,000/µL associated with splenomegaly). Anatomic resections
following the functional segments of the liver are recommended to spare
uninvolved liver parenchyma and to remove satellite tumors. Applying
these criteria, resection is associated with perioperative decompensa­
tion rate of 5%, perioperative mortality of <1%, and 5-year survival
of 60–70%, as opposed to ~35–55% for suboptimal candidates (Table
87-2). Macrovascular invasion, extrahepatic involvement, and liver dys­
function (Child-Pugh B-C) are major contraindications for resection.
Adjuvant Treatments 
Tumor recurrence represents a major com­
plication of resection and local ablation (with 5-year rates of 50–70%).
Predictors of recurrence are tumor size, tumor number, presence of
microsatellites, or microvascular invasion at the specimen analysis.
Most recurrences are intrahepatic metastases, but at least one-third are
considered de novo tumors, new clones developing in the cirrhotic car­
cinogenic field. The type of recurrence can only be defined by molecu­
lar studies. An adjuvant regimen after resection or local ablation with
atezolizumab plus bevacizumab for 12 months significantly improved
recurrence-free survival in patients at high risk of recurrence and has
been incorporated into the guidelines of practice.
Liver Transplantation 
Liver transplantation is the first treatment
choice for cirrhotic patients with single tumors ≤5 cm and portal hyper­
tension (including Child-Pugh B and C) or with small multinodular
tumors (three or fewer nodules, each ≤3 cm) (Fig. 87-3). These so-called
Milan criteria have been validated over the years and lead to median sur­
vival times of 10 years. Perioperative mortality rates have been reduced
to <3%. Transplantation simultaneously cures the tumor and the
underlying cirrhosis, and it is associated with a low risk of recurrence,
around 10–15% at 5 years. No immunosuppressive regimens or antitu­
mor therapies after transplantation have demonstrated any preventive
effect on recurrence. Milan criteria are integrated in the treatment strat­
egy (BCLC 0 and A) and have also been adopted by the United Network
for Organ Sharing (UNOS) pretransplant staging for organ allocation in
the United States (stage T2). Aside from size and number, conventional
contraindications for organ transplantation procedures (e.g., ABO
incompatibility, comorbidities) are applied in this setting.
Liver transplantation has a couple of important limitations, such as
cost and donor availability, that limit this procedure to <5% of HCC
cases worldwide. The scarcity of donors represents a major drawback
of liver transplantation. Donor scarcity varies geographically, and
deceased liver donation is almost zero in some Asian countries. Due to
the shortage of donors, median waiting times in Western programs is
~6–12 months, leading to 20% of candidates dropping off the list due to
tumor progression before receiving the procedure. Neoadjuvant treat­
ments with locoregional therapies are recommended when the waiting
time exceeds 6 months.
Expansion of Milan criteria by using locoregional therapies to effec­
tively downstage the tumor (i.e., UNOS-downstaging criteria) have
reported good results. Since policies for enhancing organ donation
have reached a ceiling during the past several years, alternatives to
donation have emerged. Living donor liver transplantation represents
a plausible alternative that accounts for ~5% of total transplantations
performed globally. Outcomes reported are similar to those with
deceased liver donors, and it is recommended as an alternative option
in patients on a waiting list exceeding 6 months. The risks and ben­
efits of this procedure should take into account both donor (death is
estimated in 0.3%) and recipient, a concept known as double equipoise.
Due to the complexity of this treatment, it must be restricted to centers
of excellence in hepatobiliary surgery and transplantation.
■
■LOCOREGIONAL THERAPIES
Local Ablation 
Thermal ablation with RF or microwave (MWA)
is recommended as the primary ablative technique (Fig. 87-4). The
Advanced stage HCC (BCLC C, portal invasion and/or extrahepatic spread) or
Intermediate stage HCC (BCLC B, multinodular) progressing upon/not candidates for
loco-regional therapies. Child-Pugh A, ECOG 0–1
Candidate for immunotherapy?
Yes
No (Autoimmune disorder,
Prior liver transplantation)
High risk of gastrointestinal/
esophageal bleeding
Yes
No
First/second
line
Atezolizumab + bevacizumab*
Tremelimumab + durvalumab
Sorafenib or Lenvatinib
PD
Second/third
line
Regorafenib/cabozantinib/ramucirumab
Nivolumab + ipilimumab
Pembrolizumab
FIGURE 87-4  Treatment strategy for advanced hepatocellular carcinoma with systemic therapies. Drugs in bold have positive results from phase 3 trials with regulatory
approval (atezolizumab plus bevacizumab, durvalumab plus tremelimumab, sorafenib, lenvatinib, regorafenib, cabozantinib, and ramucirumab). Drugs in bold italic have
received accelerated approval from the Food and Drug Administration on the basis of promising efficacy results in phase 2 trials in second line (pembrolizumab and
nivolumab ipilimumab). Key details of the patient populations are provided. BCLC, Barcelona Clinic Liver Cancer (classification); ECOG, Eastern Cooperative Oncology Group;
PD, progressive disease. (Modified from JM Llovet et al: Nat Rev Clin Oncol 15:599, 2018.)
energy generated by RF ablation (heating of tissue at 80°–100°C)
induces coagulative necrosis of the tumor, producing a safety ring
in the peritumoral tissue, which might eliminate small undetected
satellites. Treatment consists of one or two sessions performed using
a percutaneous approach, although in some instances, ablation with
laparoscopy is needed. HCC patients treated by RF ablation have
5-year survival rates of ~60% (Table 87-2). In tumors <2 cm, both RF
and MWA ablation achieve complete responses in 90–100% of cases
with good long-term outcome and compete with resection in terms of
cost-effectiveness as a first-line option. For BCLC A cases, local abla­
tion techniques are considered in patients with three tumors <3 cm in
diameter unsuitable for surgical therapies.
For patients with unresectable HCC >3 cm in diameter who are
not candidates for liver transplantation, transarterial radioemboliza­
tion (TARE) with yttrium-90 and stereotactic body radiation (SBRT)
are considered alternative options based on propensity-matched score
studies and phase 2 investigations.
Chemoembolization 
TACE is the most widely used primary
treatment for unresectable HCC worldwide and the first-line indica­
tion for patients with intermediate BCLC B stage (Fig. 87-3). Conven­
tional chemoembolization (c-TACE) consists of local hepatic artery
administration of chemotherapy (either doxorubicin 50 mg/m2 or
cisplatin) mixed with an emulsion of lipiodol followed by obstruction
of the feeding artery with sponge particles. The best randomized phase
3 investigations have provided median survivals for TACE of 20–30
months in properly selected populations (compared to 16 months for
pooled control arms). Median objective response rates are 50–70%.
In randomized studies, the treatment is either performed at a regular
schedule of 0, 2, and 6 months (median number of sessions is three)
or on demand according to tumor response. TACE procedures should
be stopped upon tumor progression or any other contraindication.
Around 50% of patients present with a limited postembolization
syndrome of fever and abdominal pain related to ischemic injury
and release of cytokines. Less than 5% of patients have major com­
plications (liver abscess, ischemic cholecystitis, or liver failure), and
CHAPTER 87
Tumors of the Liver and Biliary Tree
in <2% of cases, treatment-related death occurs. Drug-eluting bead
chemoembolization (DEB-TACE) differs from c-TACE in the use of
more standardized embolic spheres of regular size embedded with
chemotherapy. This strategy achieves similar antitumor activity (objec­
tive responses of ~60%) as c-TACE and is associated with significantly
fewer systemic toxic effects and better patient tolerance, but there are
no clear differences in clinical outcomes.
Overall, TACE can only be applied to 50% of patients at intermediate
stage, mostly as a result of the presence of liver failure (Child B or asci­
tes or encephalopathy), technical contraindications to the procedure
(i.e., impaired portal vein blood flow), or infiltrative/massive tumor
burden (i.e., generally main tumor size >10 cm). Super-selective TACE
minimizes the ischemic insult to nontumor tissue. According to guide­
lines, treatment stage migration allows performing TACE on patients
at early stages not suitable for surgical or ablative therapies. TACE plus
durvalumab plus bevacizumab significantly increases progression-free
survival compared to TACE alone (median progression-free survival,
15.2 vs 8 months) with manageable treatment-related adverse events.
Radioembolization and Other Intra-arterial Therapies 
Trans­
arterial radioembolization (TARE) using beads coated with yttrium-90
(Y-90)—an isotope that emits short-range β radiation—is the most
promising alternative to TACE. Several phase II studies reported
objective responses and overall outcome with a safe profile similar to
TACE, and thus TARE has been endorsed by clinical practice guide­
lines. Radioembolization requires prevention of severe lung shunting
and intestinal radiation before the procedure. Around 20% of patients
experience liver-related toxicity, and <2% experience treatment-related
death. Due to the minimally embolic effect of Y-90 microspheres,
treatment can be safely used in patients with portal vein thrombosis,
a setting where survival results in phase II studies were encouraging.
PART 4
Oncology and Hematology
■
■SYSTEMIC THERAPIES
Approximately 50–60% of patients with HCC are currently exposed
to systemic therapies during their life span, either because they have
been diagnosed at advanced stages or because they have progressed
after locoregional therapies. In 2007, a phase III trial demonstrated
survival benefits for patients with advanced-stage disease treated
with sorafenib, thus becoming the first systemic therapy for HCC.
Subsequently atezolizumab plus bevacizumab and durvalumab plus
tremelimumab have demonstrated survival superiority compared to
sorafenib, whereas lenvatinib showed noninferior effects (Fig. 87-4).
In Asia, other combinations (i.e., carmelizumab plus rivoceranib)
also were superior versus sorafenib in terms of survival. Three addi­
tional therapies, regorafenib, cabozantinib, and ramucirumab (only in
patients with AFP >400 ng/mL), have been shown to benefit patients
progressing on sorafenib. Of note, classical chemotherapy and radio­
therapy have not resulted in benefits in survival. Similarly, due to the
low prevalence of actionable molecular aberrations, precision oncology
regimens are not yet available in HCC.
First-Line Therapies 
Atezolizumab (anti–PD-1 checkpoint
inhibitor) plus bevacizumab (monoclonal antibody against VEGF-A)
demonstrated survival differences compared to sorafenib (median OS,
19.2 vs 13.4 months) and has become the standard of care in first-line
treatment (Fig. 87-4, Table 87-2). This combination treatment resulted
in improved progression-free survival, patient-reported outcomes
reflecting quality of life, and objective response rates (30 vs 12% for
sorafenib). The combination had fewer adverse events compared to
sorafenib (grade 3-4 adverse events, 36 vs 50%, respectively). The most
common side effects associated with the combination are hyperten­
sion, proteinuria, and low-grade diarrhea, whereas autoimmune events
are infrequent and manageable. Treatment-related adverse event rate
leading to discontinuation of any drugs is 15%. Screening for varices
with upper gastrointestinal endoscopies has become standard before
first-line therapy in advanced HCC to mitigate the risk of bleeding
associated with bevacizumab. In cases with varices, the use of one ses­
sion of banding or carvedilol is recommended.
The combination of tremelimumab (a CTLA-4 inhibitor) and dur­
valumab (a PD-L1 inhibitor) (STRIDE regimen) has demonstrated a
survival advantage versus sorafenib (median OS, 16.4 vs 13.7 months
for sorafenib). No differences were identified regarding progressionfree survival, and the response rate was 20.1% with the combination
versus 5.1% with sorafenib. This regimen can be administered even
in patients with portal hypertension or varices. STRIDE was associ­
ated with more immune-related adverse events, and 20% of patients
required glucocorticoid treatments (Fig. 87-4).
Alternatively, sorafenib or lenvatinib is indicated for patients with
advanced HCC with contraindications for immunotherapies (i.e., due
to autoimmune disease or liver transplantation) (Fig. 87-4, Table 87-2).
A phase 3 study comparing sorafenib (a multikinase inhibitor) versus
placebo showed increased survival from 7.9 months to 10.7 months
(hazard ratio [HR], 0.69; 31% reduction in risk of death). Patients
with HCV-related HCC achieve significantly better outcomes with
sorafenib, with a median survival of 14 months. Median treatment
duration is about 6 months. Treatment is associated with manageable
adverse events, such as diarrhea, hand-foot skin reactions, fatigue, and
hypertension. These toxicities lead to treatment discontinuation in
15% of patients and dose reduction in up to half. It has been estimated
that this therapy cannot be administered to approximately one-third
of the targeted patients due to toxicity, advanced age, or liver failure
(ascites or encephalopathy). Active vascular disease, either coronary
or peripheral, is considered a formal contraindication. Median time to
progression on sorafenib is 4–5 months in phase 3 trials.
Another alternative to sorafenib is the multikinase inhibitor len­
vatinib, which was shown to be noninferior in a phase 3 investiga­
tion (Fig. 87-4). A phase 3 study comparing lenvatinib (an inhibitor
of vascular endothelial growth factor receptor [VEGFR], fibroblast
growth factor recepctor [FGFR], platelet-derived growth factor recep­
tor [PDGFR], RET, and c-Kit) with sorafenib showed noninferiority
of results in terms of OS (13.6 vs 12.3 months; HR, 0.92). Lenvatinib
induces objective responses in 24% of cases. The main side effects
are hypertension, proteinuria, asthenia, diarrhea, and weight loss.
This treatment is associated with a 55% rate of grade 3-4 drug-related
adverse events, resulting in a ~15% withdrawal rate.
Second-Line Therapies 
Three drugs (regorafenib, cabozantinib,
and ramucirumab) have shown survival benefits versus placebo in
patients progressing to sorafenib, and two additional treatments have
been approved by the U.S. Food and Drug Administration (FDA)
based on promising phase 2 data (pembrolizumab, and nivolumab
plus ipilimumab) (Fig. 87-4). It is estimated that only half of patients
progressing on sorafenib can be considered for second-line therapies,
and their median survival with no treatment is 7–8 months (obtained
from patients allocated to the placebo arm).
A phase 3 study comparing regorafenib (a more potent multikinase
inhibitor than sorafenib, but targeting similar kinases) versus placebo
in patients progressing to sorafenib reported an increase in survival
from 7.8 to 10.6 months (HR, 0.62; 38% reduction in risk of death)
(Fig. 87-5). Response rate was 10% based on modified Response
Evaluation Criteria in Solid Tumors. Median time on treatment was
3.5 months. Prevalence of toxicity (hand-foot reaction, fatigue, and
hypertension) was higher compared with reported toxicity from
sorafenib, but adverse events only led to treatment discontinuation
in 10% of cases. Cabozantinib, a multikinase VEGFR inhibitor with
activity against both AXL and cMET, improves survival compared to
placebo after progression to sorafenib (10.2 months for cabozantinib
vs 8.0 months in the placebo arm; HR, 0.76). Toxicity was manageable,
with the most common grade 3–4 events being palmar-plantar erythro­
dysesthesia, hypertension, increased aspartate aminotransferase level,
fatigue, and diarrhea. Ramucirumab, an anti–VEGFR-2 monoclonal
antibody, is the only biomarker-guided therapy in HCC based on AFP
levels. The randomized, placebo-controlled, phase 3 REACH-2 study
studied patients with advanced HCC in second-line treatment with
baseline AFP ≥400 ng/dL. This trial demonstrated positive survival
results, and a further meta-analysis established a median survival for
ramucirumab of 8.1 months compared to 5 months for patients receiv­
ing placebo. The most common grade 3–4 treatment-related adverse
events were hypertension, hyponatremia, and increased aspartate
Mass-forming
Periductalinfiltrating
Left, right, common
hepatic ducts
Intraductalgrowing
FIGURE 87-5  Anatomical classification of cholangiocarcinoma. Cholangiocarcinoma is classified as intrahepatic
(iCCA) and extrahepatic (eCCA). eCCA can be subclassified as perihilar (pCCA) and distal (dCCA). (Reproduced
from JM Banales et al: Cholangiocarcinoma 2020: The next horizon in mechanisms and management. Nat Rev
Gastroenterol Hepatol 17:557, 2020.)
aminotransferase. Patients progressing after second-line therapy might
be considered for third-line approaches. Patients with tumors at a
BCLC D stage should receive best supportive palliative care, including
management of pain, nutrition, and psychological support.
CHOLANGIOCARCINOMA
Cholangiocarcinoma (CCA) is classified according to its anatomic
location as intrahepatic (iCCA; ~20–30%), perihilar (pCCA; ~50–60%),
and distal (dCCA: ~20–30%). The latter two are also known as extra­
hepatic cholangiocarcinomas (eCCA), with the second-order bile ducts
acting as the separation point (Fig. 87-5). The three subtypes of CCA
differ in their anatomic location, epidemiology and risk factors, cell
of origin, pathogenesis, and treatment. iCCA originates from adult
cholangiocytes, transdifferentiation of adult hepatocytes, and hepatic
progenitor cell–cholangiocyte precursors (Fig. 87-6), as opposed to
HCC, which originates only from hepatic progenitor cells or adult
hepatocytes. Mixed HCC-iCCA originates from hepatic progenitor
cells, whereas eCCA arises from the biliary epithelium and peribiliary
glands. Moreover, their mutational profile also differs. FGFR2 fusions
and IDH1/2 mutations mostly occur in iCCA, whereas ERBB2/3 ampli­
fications and SMAD4 aberrations are characteristic of eCCA. iCCA
has been recognized as a distinct entity with specific clinical practice
guidelines, which should be tailored according to each biological/
anatomical subtype of CCA.
■
■EPIDEMIOLOGY, RISK FACTORS, AND
MOLECULAR TRAITS
CCA is the second most common liver cancer following HCC, with
a 5-year survival of 10%. iCCA has globally increasing incidence and
mortality rates. The incidence of iCCA varies according to exposure to
risk factors, ranging from 1–2 cases per 100,000 inhabitants in Europe
and North America to the highest incidence in some areas of Southeast
Asia, particularly in Thailand (>80 cases/100,000 inhabitants). The
male-to-female ratio is 1.2:1. Only 30% of patients with CCA have
a known risk factor. The classical risk factors for CCA development
include primary sclerosing cholangitis (PSC), biliary duct cysts, hepa­
tolithiasis, and Caroli’s disease. Parasitic biliary infestation with flukes
(most common are Opisthorchis viverrini and Clonorchis sinensis) is
a prevalent etiology in Asia that can be prevented with an antihel­
minth therapy, praziquantel. PSC is a clear risk factor for iCCA and
pCCA development, with a lifetime incidence ranging from 5 to 10%.
Surveillance in PSC patients is recommended with annual imaging
techniques and CA 19-9 serum determina­
tion. Common risk factors for HCC, such
as HBV and HCV infection and cirrhosis,
have been associated with iCCA develop­
ment. More recently, sweetened beverages
were reported to constitute a risk factor in
the development of eCCA and gallbladder
carcinoma (GBC) in a population cohort
study.
Bile
ductules
iCCA
(10–20%)
Segmental
ducts
Molecular Classification and Actionable
Drivers 
A morphological and molecular
classification subclassifies iCCA into the
large duct type, which is associated with
IDH (15–20%) and FGFR2 (15%) mutations
and better prognosis, and the small duct
type, which is associated with KRAS (15%)
and SMARD4 (<5%) mutations and poor
prognosis. Overall, up to 40% of iCCAs
have a targetable mutation. Similarly, a
molecular classification of eCCA has been
proposed, dividing tumors into four cat­
egories (metabolic, proliferation, mesen­
chymal, and immune) based on molecular
traits. It has been suggested that the prolif­
eration class with enrichment of ERBB2/3
mutations might respond to monoclonal
antibodies against this receptor, while the immune class might respond
to checkpoint inhibitors, a fact that needs clinical confirmation. The
most common mutations of pCCA/dCCA are P53 (~30%) and KRAS
(~25%), whereas ERBB2 amplifications (~20%) are common in gall­
bladder cancer.
pCCA
(50–60%)
Common
bile duct
dCCA
(20–30%)
CHAPTER 87
Tumors of the Liver and Biliary Tree
■
■INTRAHEPATIC CHOLANGIOCARCINOMA
Surveillance, Diagnosis, and Staging 
Guidelines currently
only recommend surveillance for early diagnosis in the following atrisk subpopulations: (1) patients with primary biliary sclerosis (PBS;
surveillance is recommended with CA 19-9 and magnetic resonance
cholangiopancreatography [MRCP] every 12 months) and (2) patients
with cirrhosis or those infected with liver flukes (surveillance is rec­
ommended with abdominal ultrasound every 6 months). Otherwise,
incidental diagnosis occurs due to cross-sectional imaging performed
for other reasons. In most cases, iCCA is diagnosed at advanced stages
when symptoms such as weight loss, malaise, abdominal discomfort,
or jaundice are present. Diagnosis of iCCA requires pathological con­
firmation. Differential diagnosis should be established with metastatic
adenocarcinoma (i.e., colorectal, breast, and lung cancer) and mixed
iCCA-HCC tumors. Immunohistochemistry using K7, K19, and K20
is useful to confirm iCCA and to distinguish it from metastatic liver
cancer. Hepatocytic markers such as Hep-Par-1, GPC3, and HSP70
may aid in pointing to a mixed HCC-iCCA tumor. Current guidelines
recommend the use of abdominal MRI, chest and abdomen CT scan,
and PET scan for establishing the disease extension once the pathologi­
cal diagnosis has been confirmed. Meta-analysis has defined a role for
PET scanning in identifying lymph node metastasis in patients with
no apparent lymph node invasion with MRI and/or CT scan. Lymph
node sampling by endoscopic ultrasound with fine-needle aspiration
would be considered before resection in selected unclear cases. Tumor
biomarker CA 19-9 at a cutoff level of 100 U/mL has prognostic sig­
nificance but lacks accuracy (sensitivity and specificity of ~60%) for
early diagnosis.
■
■TREATMENT
The European Association for the Study of Liver Disease–International
Liver Cancer Association (ILCA) guidelines for management of iCCA
proposed an updated treatment algorithm, which has been adapted to
the current accepted treatment modalities (Fig. 87-7). iCCA can be
classified as early, intermediate, or advanced cases according to size of
the nodules and invasion of lymph nodes (N1), metastasis, and ECOG
Hepatic progenitor cell
Progenitor-like
HCC
Progenitor-like
iCCA
Hepatocyte
precursor
Cholangiocyte
precursor
De-differentiation
Mixed
HCC-iCCA
Biliary-like cell
Mature
hepatocyte
Transdifferentiation
PART 4
Oncology and Hematology
HCC
iCCA
FIGURE 87-6  Cell of origin of liver cancer. Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) can develop from the neoplastic transformation
of mature hepatocytes and cholangiocytes, respectively. There is evidence showing that hepatic progenitor cells (HPCs), their intermediate states, or dedifferentiated
hepatocytes can originate liver cancers with progenitor-like features, including mixed HCC-CCA (e.g., cholangiolocellular carcinoma [CLC]). Mature hepatocytes can be
also reprogrammed into cells that closely resemble biliary epithelial cells and induce the onset of iCCA. (Printed with permission from © Mount Sinai Health System.)
performance status and liver dysfunction. Approximately 30–40% of
iCCA cases are deemed resectable, and the median reported survival
for single tumors is ~40–50 months, whereas survival decreases
to ~20 months in intermediate/multinodular resectable tumors. The
main predictors of recurrence (~50–60% at 3 years) and survival
are identified at the pathological examination, including presence of
vascular invasion, lymph node metastases, and poor differentiation
degree. In terms of adjuvant therapy, a phase 3 trial (BILCAP trial)
including all types of CCA in a prespecified per-protocol analysis
reported improved survival (53 vs 36 months; adjusted HR, 0.75).
Based on this trial, American Society of Clinical Oncology guidelines
recommend adjuvant capecitabine for a period of 6 months. A small
proportion of patients with early/intermediate tumors can have contra­
indications for resection, particularly in cirrhotic patients, and should
be first considered for local ablation or even liver transplantation if the
diameter of the main tumor is <2 cm.
Nonsurgical candidates have a dismal life expectancy. Overall,
patients with multinodular unresectable tumors might be considered
for locoregional therapies, such as chemoembolization or radioembo­
lization, but the level of evidence is low and mostly based on cohort
studies. A meta-analysis of 14 trials testing locoregional therapies
reported median survival times of 15 months. External-beam radiation
therapy is not recommended as standard therapy. At more advanced
stages in patients with ECOG of 0–1, systemic chemotherapy with
the combination of gemcitabine, cisplatin, and durvalumab showed
significantly better survival and progression-free survival compared
with gemcitabine plus cisplatin alone (12.8 vs 11.5 months) in the
setting of the TOPAZ1 phase 3 trial including 685 patients. Objective
response was 27%. Similar results were obtained with the combination
De-differentiation?
CLC
Mature
cholangiocyte
Tumor type
HCC
iCCA
Mixed HCC-iCCA
of chemotherapy with pembrolizumab versus chemotherapy alone in a
phase 3 trial including 1069 patients. The median OS was 12.7 months
in the pembrolizumab group and 10.9 months in the placebo group
(HR, 0.83; 95% CI, 0.72–0.95; one-sided p = .0034). Therefore, triplet
therapy is now considered the standard for the management of CCA.
In the second-line setting, a phase 3 study that randomized patients
who had progressed on cisplatin and gemcitabine to mFOLFOX
(leucovorin, fluorouracil, and oxaliplatin) versus best supportive care
showed improvement in median OS of 5.3 to 6.2 months (adjusted
HR, 0.69). In addition, three molecular and immune therapies have
been approved in the second-line setting in iCCA patients with IDH1/2
mutations, FGFR2 aberrations, or deficient mismatch repair (dMMR)
or microsatellite instability high (MSI-H). A phase 3 trial compared
ivosidenib, an IDH-1 inhibitor, versus placebo in the second-line set­
ting and demonstrated an improved primary end point of progressionfree survival (2.7 vs 1.4 months; HR, 0.37) and improved OS in an
adjusted analysis. A single-arm phase 2 study assessing pemigatinib
(FGFR2 inhibitor) in iCCA patients with FGFR2 fusions showed a
median survival of 21 months with an objective response of 35%, lead­
ing to FDA accelerated approval. Similar results have been observed in
phase 3 trials testing other FGFR2 inhibitors, such as infigratinib and
futibatinib. Finally, regulatory agencies granted approval of pembroli­
zumab for MSI-H or dMMR solid tumors that progressed following
prior treatment based on a basket tissue-agnostic trial. This recom­
mendation excludes patients receiving durvalumab in first line.
Mixed HCC-iCCA is a rare neoplasm accounting for <0.5% of all
primary liver cancers. Diagnosis is based on pathology. The 2010
World Health Organization classification defined two subtypes: the
classical type and the stem cell feature type. Molecular data have also
Intrahepatic cholangiocarcinoma (iCCA)
Advanced, metastatic disease
(Periductal invasion, N1, M1)
Early and intermediate stages
Resectable (30–40%)
Intrahepatic
Disease only
Single iCCA ≤2 cm
in cirrhotic patient
Extrahepatic Disease
Local-ablation
(or Liver
Transplantation)
Surgical resection
(curative intent)
Adjuvant chemotherapy
(capecitabine/6 mo)
Median survival: 43 mo
Median survival: 15 mo
*Treatments used as standard of practice. No enough evidence for standard of care.
**Patients with ECOG > 2 or liver dysfunction are only suitable for best supportive care.
FIGURE 87-7  Staging and treatment schedule for intrahepatic cholangiocarcinoma (iCCA). (Modified from EASL-ILCA Guidelines. J Hepatol 79:181, 2023.)
characterized a third unique entity, cholangiolocellular carcinoma,
with distinct molecular traits and better outcome. Due to their low
incidence, the demographic features and clinical behavior of these
tumors remain ill-defined. Survival and management are similar to
iCCA.
■
■EXTRAHEPATIC CHOLANGIOCARCINOMA
Perihilar and Distal Cholangiocarcinoma 
pCCA tumors arise
between the second-order bile ducts up to the insertion of the cystic
duct, whereas dCCAs arise from this point to the ampulla of Vater
(Fig. 87-5). Thus, dCCA can be difficult to distinguish from early pan­
creatic cancer. Both entities have a similar diagnostic approach. Acute
onset of painless jaundice occurs in 90% of patients with pCCA, and
10% of patients present with cholangitis. Primary biliary cholangitis
with a cutoff for CA 19-9 >129 U/mL is suspicious for CCA. Imag­
ing assessment starts with CT and MRI; they have a good sensitivity
and specificity (>85%) for detecting the degree of bile duct involve­
ment and hepatic and portal vein invasion. MRI cholangiography is
optimal for defining the extent of the bile duct lesion. Ruling out IgG4
cholangiopathy by assessing serum IgG4 is mandatory. As a second
step, endoscopic retrograde cholangiography with brushing to explore
cytology and fluorescence in situ hybridization (FISH)—for exploring
polysomy—are recommended. FISH enhances the sensitivity of cytol­
ogy from 20 to ~40%.
Diagnosis is based on pathology. The treatment algorithm for
pCCA indicates that in cases of a dominant stricture with positive
cytology/biopsy or polysomy, a lymph node biopsy through endo­
scopic ultrasound should be obtained. pCCA with negative lymph node
involvement is best treated by surgery, resection, or transplantation,
Unresectable (60–70%)
Local-regional
therapy*
Chemoemboliation (TACE)
Radioembolization (TARE)
1st line**:
Gemcitabine+ cisplatin+
(durvalumab or pembrolizumab)
CHAPTER 87
2nd line
FOLFOX
FGFR2 inhibitor (pemigatinib)
IDH inhibitor (ivosidenib)
Checkpoint inhibitor for MSI-H/dMMR
Tumors of the Liver and Biliary Tree
Median survival:
1st line : ~13 mo
2nd line : 6–12 mo
the sole curative options. Staging laparoscopy is recommended to
exclude metastatic disease prior to surgery, which occurs in 15% of
cases. Resection entails hepatic and bile duct removal and Roux-enY hepaticojejunostomy with regional lymphadenectomy. Bilobular
involvement is considered a surgical contraindication. Perioperative
mortality rate is up to 10%, mostly as a result of liver failure. In a few
referral centers, unresectable single pCCAs <3 cm without dissemi­
nation can be considered for liver transplantation with neoadjuvant
chemoradiation. This procedure is associated with 5-year survival rates
of ~70%. If lymph node involvement is present, systemic chemotherapy
can be considered along with biliary tract stenting. Surgical resection
(Whipple procedure) is the primary option for management of dCCA,
a procedure that achieves a median survival of 24 months and 5-year
survival rates of ~25%. Main contraindications for resection are pres­
ence of distant lymph node involvement, metastases, or major vascular
invasion. At the pathological examination, perineural invasion, lymph
node metastasis, R0 resection (absence of residual tumor at pathologi­
cal examination), and tumor differentiation are predictors of survival.
Adjuvant therapy with capecitabine for 6 months is accepted based on
the BILCAP study, which has been previously discussed. For advanced
cases, consensus statements endorse first-line (gemcitabine and cis­
platin plus durvalumab or pembrolizumab) and second-line therapies
(FOLFOX) similar to those for iCCA. No molecular targeted therapies
are available for these entities.
■
■GALLBLADDER CANCER
Gallbladder cancer is the most common cancer of the biliary tract
worldwide. The estimated number of cases of gallbladder cancer in the
United States in 2016 was 11,400, more than CCA. The female-to-male
ratio is 3:1. Cholelithiasis is the major risk factor, but <1% of patients
with cholelithiasis develop this cancer. Gallbladder polyps at risk of
transformation are those ≥10 mm in diameter. Early cases are discov­
ered incidentally at routine cholecystectomy. Clinical symptoms, such
as jaundice, pain, and weight loss, are associated with advanced stages.
Staging of gallbladder cancer involves local disease (tumor confined to
the gallbladder) and advanced disease (tumor outside gallbladder with
lymph node or distant metastases). The most accurate technique to
define staging and vascular and biliary tract invasion is the magnetic
resonance cholangiopancreatography. CT and PET scan can also be
useful for preoperative staging.
The mainstay of treatment is surgical resection, either simple or
radical cholecystectomy (partial hepatectomy and regional lymph node
dissection) for local disease. Only ~20% of patients are candidates for
surgery with curative intent, and 5-year survival rates range from 60
to 90% depending on prognostic factors such as lymph node or tumor
invasion beyond muscular layer. Adjuvant therapy with capecitabine is
recommended in R0 cases. Gallbladder cancers at advanced stage are
considered unresectable. For patients with ECOG of 0–1, chemother­
apy with gemcitabine, cisplatin, and durvalumab is the standard of care
based on the TOPAZ 1 phase 3 trial that included 171 patients with
gallbladder cancer (25%). Overall, median survival is 10–12 months in
advanced cases. Second-line therapy includes FOLFOX chemotherapy.
Percutaneous transhepatic drainage is indicated in case of biliary
obstruction. Radiotherapy is not effective.
PART 4
Oncology and Hematology
■
■OTHER MALIGNANT LIVER TUMORS
Fibrolamellar Hepatocellular Carcinoma 
Fibrolamellar hepa­
tocellular carcinoma (FLC) is a rare form of primary liver cancer that
typically affects children and young adults (10–30 years of age) with­
out background liver disease. FLC accounts for 0.85% of all primary
hepatic malignancies in the United States, and its incidence rate is 0.02
cases per 100,000 inhabitants. FLC is considered a unique entity with
a specific fusion oncogene PRKACA-DNAJB1 present in 80–100% of
cases. Few additional mutations have been described in <10% of cases.
FLC has a better prognosis than HCC, probably due to the absence
of cirrhosis and the earlier age of presentation. Surgical resection is
the mainstay of treatment, and indications are less restrictive than
for HCC. A retrospective series of 575 FLC cases reported a median
survival of 70 months after resection. At advanced stages, the expected
outcome is <20 months. There is no standard systemic therapy, and
clinical trials are focused on targeting the fusion protein with kinase
inhibitors or immunomodulatory agents.
Hepatoblastoma 
Hepatoblastoma (HB) is the most frequent pri­
mary liver tumor in children. The incidence of the disease is 1.5 cases
per 1,000,000, and onset of the disease occurs before the age of 3 years.
Background liver disease is rare in these patients. WNT signaling plays
a major role, with CTNNB1 mutations (70%) as the most frequently
reported molecular event. Overexpression of IGF2 and genes in the
14q32 DLK1/DIO3 locus is also very prevalent. At diagnosis, ~30%
of patients are amenable to surgery. Resection followed by chemo­
therapy with doxorubicin/cisplatin is the mainstay treatment strategy.
Among the remaining 70% of patients, neoadjuvant chemotherapy
achieved response in >90% of cases and enabled resection with good
clinical outcomes. A study including 1605 patients randomized in eight
clinical trials reported better outcome for patients with stage I–II of the
PRETEXT (Pretreatment Extent of Tumor) classification (out of four
stages), age <3 years, AFP >1000 ng/mL, and absence of metastases.
As opposed to HCC, low AFP <100 ng/mL indicates poor prognosis.
Overall, 5-year survival is 70% (ranging from 50 to 90% depending on
PRETEXT stage).
BENIGN LIVER TUMORS
The most common benign liver tumors are hemangiomas, focal nodu­
lar hyperplasia (FNH), and hepatocellular adenomas (HCA). Most
benign tumors are identified incidentally by abdominal ultrasound
or other imaging techniques. Hemangiomas are present in ~5% of the
general population and are diagnosed by ultrasound except in cirrhotic
patients or oncology patients, in whom contrast-enhanced imaging
(contrast-enhanced ultrasound, CT, or MRI) is required. Conserva­
tive management is appropriate, and follow-up is not recommended.
Exceptionally, growing lesions causing symptoms by compression can
be considered for resection. FNH is a benign tumor present in <2%
of the population and occurring mostly in females aged 40–50 years.
FNH is a polyclonal hepatocellular proliferation due to an arterial mal­
formation. MRI has the highest diagnostic accuracy with a specificity
of 100%, when typical imaging features are present (homogeneous
enhancement in the arterial phase with a central scar). Atypical FNH
requires biopsy for diagnosis. Treatment is not recommended because
these tumors do not degenerate or cause complications. In exceptional
cases of expanding symptomatic lesions, surgery is the treatment of
choice.
Hepatic adenomas are clonal benign proliferations resulting from
single-gene driver mutations. HCAs have a low prevalence of 0.001%
of the population and are frequently diagnosed in women aged 35–40
years. The female-to-male ratio is 10:1, and the main risk factors are
oral contraceptives in females and use of anabolic androgenic steroids
in male body builders. HCAs have the potential for hemorrhage and
HCC development, particularly when >5 cm. Nowadays, there is a
clear understanding of the molecular classification of HCA in subtypes
defined by CTNNB1 mutations (10–20%), HNF1A inactivation, and
activation of inflammatory pathways (50–60%) or Hedgehog signaling
pathway. Diagnosis is based on MRI, which is able to correlate with
molecular subtypes in 80% of cases (inflammatory and HNF-1A type).
For defining HCA with CTNNB1 mutations, biopsy is required. Upon
diagnosis, discontinuation of oral contraceptives and weight loss are
recommended. Resection is indicated in all cases >5 cm, in men, or
with CTNNB1 mutation. For HCA <5 cm, 1-year follow-up is recom­
mended. In case of active HCA bleeding, embolization followed by
resection is the treatment of choice. The presence of multiple HCAs
is common, and guidelines endorse treating them based on the size of
the main nodule.
■
■FURTHER READING
EASL-EORTC Clinical Practice Guidelines: Management of
hepatocellular carcinoma. J Hepatol 69:182, 2018.
EASL-ILCA Clinical Practice Guidelines on the management of intra­
hepatic cholangiocarcinoma. J Hepatol 79:181, 2023.
Finn RS et al: Atezolizumab plus bevacizumab in unresectable hepato­
cellular carcinoma. N Engl J Med 382:1894, 2020.
Haber PK et al: Evidence-based management of hepatocellular carci­
noma: Systematic review and meta-analysis of randomized controlled
trials (2002-2020). Gastroenterology 161:879, 2021.
Ilyas SI: Cholangiocarcinoma: novel biological insights and therapeu­
tic strategies. Nat Rev Clin Oncol 20:470, 2023.
Llovet JM et al: Hepatocellular carcinoma. Nat Rev Dis Primers
21;7:6, 2021.
Llovet JM et al: Locoregional therapies in the era of molecular and
immune treatments for hepatocellular carcinoma Nat Rev Gastroen­
terol Hepatol 18:293, 2021.
Llovet JM et al: Immunotherapies for hepatocellular carcinoma. Nat
Rev Clin Oncol 19:151, 2022.
Llovet JM et al: Molecular pathogenesis and systemic therapies for
hepatocellular carcinoma. Nat Cancer 3:386, 2022.
Oh DY et al: Durvalumab plus gemcitabine and cisplatin in advanced
biliary tract cancer. NEJM Evid 1:2022.
Singal AG et al: AASLD Practice Guidance on prevention, diagnosis,
and treatment of hepatocellular carcinoma. Hepatology 78:1922,
2023.
Villanueva A: Hepatocellular carcinoma. N Engl J Med 380:1450,
2019.

17 - 88 Pancreatic Cancer
88 Pancreatic Cancer
Eileen M. O’Reilly, Andrew M. Lowy,
Daniel D. Von Hoff
Pancreatic Cancer
Pancreatic cancer is the third leading cause of cancer-related mortality
in the United States, with >66,000 Americans diagnosed and >51,000
dying from the disease each year. Pancreatic cancer is projected to be
the second leading cause of death from cancer in the United States by
2030. Worldwide, pancreatic cancer is the eleventh most common can­
cer, with about half a million diagnoses per annum. Pancreatic cancer
is the most lethal human cancer, with an overall 5-year survival of 13%.
However, that situation is changing. In particular, (1) an enhanced
understanding of the pathobiology and genomic landscape of pancre­
atic cancer is steadily giving rise to new therapeutic opportunities, (2)
the integration of multimodality therapy for patients with localized
disease has improved outcomes, and (3) increasingly more molecularly
defined groups of patients are eligible for targeted therapy beyond
cytotoxic therapy.
■
■EPIDEMIOLOGY
Pancreatic cancer accounts for 3% of all new cancer cases in the
United States and ~8.3% of all deaths from cancer in the United States.
The lifetime risk of developing pancreatic cancer is ~1.7%; however,
the incidence has been increasing about 1.1% per year overall, but
notably in people <55 years of age, it has been increasing 2.36% per
year in women and 0.62% per year in men. Pancreatic cancer is more
common with increasing age and slightly more common in men than
in women. The 5-year survival rate for all stages has increased from 3%
in 1975 to 13% in 2024. The latest information from the U.S. Surveil­
lance, Epidemiology, and End Results (SEER) database predicts that
the 5-year survival is about 44% for patients with localized pancreatic
cancer, 16% for those with regional disease, and 3.2% for patients with
metastatic disease. Pancreatic cancer is more common in developed
countries (although it tracks with the prevalence of smoking). The inci­
dence is highest in Eastern (e.g., Hungary and Slovakia) and Western
(e.g., Germany) Europe and North America followed by other areas in
Europe, Australia, New Zealand, and Southcentral Asia.
■
■RISK FACTORS
Age is one of the strongest risk factors for pancreatic cancer with
median age at diagnosis of 71 years (the disease is most frequently
diagnosed in the 65–79 age group; for men, 65–69; for women, 75–79).
The number of new cases per 100,000 persons and the number of
deaths per 100,000 persons are higher for males and for black people
of both sexes. People who have a non-O blood type are at higher risk
of developing pancreatic cancer.
Environment 
The greatest risk factor for pancreatic cancer is
cigarette smoking. The risk correlates with the increased number of
cigarettes smoked and persists for at least 10 years following smoking
cessation. Twenty-five to 30% of pancreatic cancers are believed to be
caused by smoking. Exposure to cadmium as part of cigarette smoking
or via exposure to welding, soldering, or dietary exposure has been
weakly associated with an increased risk of pancreatic cancer.
Dietary factors may contribute to risk, acknowledging confound­
ing issues; however, high intake of fat or meat (particularly well-done
barbequed meat) are risk factors. High intake of citrus fruits and veg­
etables are associated with a decreased risk of pancreatic cancer. Coffee
and low-to-moderate alcohol consumption are not associated with an
increased risk for pancreatic cancer, although consumption of sugary
carbonated drinks has been associated with elevated risk.
Hereditary Factors, Genetics, and Screening 
Hereditary fac­
tors account for 10–16% of all pancreatic cancers. Family members of
patients with pancreatic cancer and selected individuals with certain
pathogenic germline variants should seek participation in an early
detection program with genetic counseling, definition of risk, and if
appropriate, periodic magnetic resonance imaging (MRI) screening
and endoscopic ultrasound of the pancreas, ideally enrolled on a pro­
spective registry. Table 88-1 summarizes the various germline variants
along with familial cancer syndromes where there is known to be an
increased risk for pancreatic cancer. For an average-risk individual
(without any known predisposing factors), there is currently no recom­
mended screening.
Knowing that an individual carries a BRCA1/2 or PALB2 germline
variant or any of the above mutations requires referral of that person
to an early detection or high-risk screening clinic. For patients with a
BRCA1/2 or PALB2 pathogenic germline variant, a poly(ADP-ribose)
polymerase (PARP) inhibitor should be considered (see below) as
part of treatment for metastatic pancreatic cancer. Other pathogenic
germline variants are under study to determine their increased risk of
pancreatic cancer, including CFTR, PRSS2, CDK4, FANCC, APC, ATM,
BRIP1, BRCA1, EPCAM, MEN1, MLH1, MSH2, MSH6, NF1, PMS2,
SMAD4, TP53, TSC1, TSC2, and VHL. Some of these variants are also
associated with pancreatic neuroendocrine tumors (Chap. 89).
In addition to recognized genetic syndromes from single gene vari­
ants, other individuals without any of these identifiable germline vari­
ants may be at higher risk for this cancer. For example, a family history
of pancreatic cancer is associated with increased risk based on the
number of affected relatives. Having one first-degree relative with pan­
creatic cancer, one’s risk for developing the disease is increased 4.6-fold,
having two first-degree relatives increases the risk 6.4-fold, and three or
more first-degree relatives confers a 32-fold increased risk. The risk is
also increased if a relative developed pancreatic cancer at <55 years old
and is further compounded by smoking.
CHAPTER 88
Pancreatic Cancer
Medical Conditions 
Chronic pancreatitis that is nonfamilial is
associated with an increased risk of pancreatic cancer (2.3–16.5-fold
increase). Risk is also increased in people with chronic pancreatitis
associated with cystic fibrosis or tropical pancreatitis.
A clear association exists between diabetes mellitus (both type 1 and
type 2) and pancreatic cancer. Whether this is a causal association or
whether the diabetes is the result of the cancer is not exactly clear. Newonset (particularly with concomitant weight loss) or unexpected wors­
ening of type 2 (or type 3c) diabetes may be associated with pancreatic
cancer, and research programs are evaluating screening in otherwise
healthy individuals in this setting.
High body mass index (BMI) is considered a risk factor for pancre­
atic cancer. A high BMI of ≥30 is associated with a doubling of pancre­
atic cancer risk. As obesity is a risk factor for diabetes, the contribution
of obesity alone is unclear. Interestingly, patients with severe obesity
TABLE 88-1  Germline Mutations, Familial Cancer Syndromes,
and Fold Risk of Pancreatic Cancer
ESTIMATED INCREASED
RISK (FOLD) OF
PANCREATIC CANCER
FAMILIAL CANCER
SYNDROME
GERMLINE MUTATION
BRCA2 a
Familial breast/ovarian
cancer and others
3.5–10
PALB2 (partner and
localizer of BRCA2)
Familial breast cancer
and others
~Sixfold
p16/CDKN2A
Familial atypical
multiple mole melanoma
(FAMMM)
15–22
STKII (LKB1)
Peutz-Jeghers syndrome
76–140
PRSS1 or SPIN11b
Hereditary (familial)
pancreatitis
ATM
Ataxia-telangiectasia
6c
MLH1, MSH2, MSH6,
PMS2
Heredity nonpolyposis
colorectal syndrome or
Lynch syndromed
9–36
aParticularly common in individuals with Ashkenazi Jewish heritage. bForty
percent chance of pancreatic cancer by the age of 70. cCalculated at age 70. dVery
important because this is associated with microsatellite instability, which is a
marker for response to immune checkpoint blockade.
who undergo a bariatric intervention experience a reduction in the
incidence of gastrointestinal cancers, including pancreatic cancer, by
30% in the first 3 years (along with a decrease in their hemoglobin A1c
and blood glucose level). Physical inactivity also has been associated
with an increased risk of pancreatic cancer.
Other Considerations 
Most patients with pancreatic cancer relate
that they have had developing symptoms over months to years before
diagnosis. Efforts at early detection of the disease have not yet been
fruitful, but this is an area of very active investigation.
■
■PATHOLOGY AND MOLECULAR CONSIDERATION
Location 
The posterior location of the pancreas in the abdomen is
one of the issues that makes diagnosis more challenging (Fig. 88-1A).
Pathology 
Cancers of the pancreas can be divided into neoplasms
of the endocrine pancreas (Chap. 89) and those of the exocrine pan­
creas. The most common neoplasm of the exocrine pancreas and most
lethal is ductal adenocarcinoma. These cancers arise in the head, body,
or tail of the pancreas and are characterized by infiltrating desmoplas­
tic stromal reactions (Fig. 88-1B).
Other subtypes of nonneuroendocrine pancreatic cancers include
acinar cell carcinoma (tumors of the exocrine enzyme producing cell),
colloid carcinoma, medullary carcinoma, adenosquamous carcinoma,
and other rare subtypes. Each of these is different in behavior and in
their molecular characteristics and often requires other specific types
of treatment. Occasionally, metastases to the pancreas occur second­
ary to renal, breast, lung, and urothelial carcinomas, melanoma, lym­
phoma, and other malignancies.
PART 4
Oncology and Hematology
Molecular Characteristics 
The mutational landscape of pan­
creatic ductal adenocarcinoma is characterized by alterations in four
genes that are commonly mutated or inactivated. The most common
of these is the KRAS oncogene (mutations primarily in codon 12). It
is increasingly important to identify the specific mutant KRAS allele
as novel drugs targeting specific alleles now exist and others are in
development. KRAS mutations are seen in 90–95% of pancreatic
adenocarcinomas. A subset of pancreatic cancers is termed “KRAS
Stomach
Splenic artery
Hepatic artery
Portal vein
Spleen
Common bile duct
Kidney
Jejunum
Pancreas
Duodenum
Superior mesenteric artery
Superior mesenteric vein
A
FIGURE 88-1  A. Note the relationship of the pancreas to the major vessels of the retroperitoneum. B. Ductal adenocarcinoma of the pancreas (black arrows), with intense
stromal component (white arrows). (Part A is courtesy of Mary Kay Washington, MD, PhD, Vanderbilt University. Part B is courtesy of Haiyong Han, PhD, Translational
Genomics Research Institute [TGen].)
wildtype,” where no alteration in KRAS is observed. This form of
pancreatic cancer is more frequently observed in patients <55 years
of age, and often other therapeutically actionable findings are identi­
fied in these cancers, including mutations in BRAF, rare oncogenic
targetable fusions (e.g., NRG-1, NTRK1-3), or microsatellite instability.
p16/CDKN2A mutation or epigenetic silencing is present in >90% of
invasive pancreatic adenocarcinomas. TP53 is mutated in ~75% and
DPC4/SMAD4 is mutated in about half of these tumors. As a reference
point, the BRCA2 gene noted in Table 88-1 is mutated in 3.5–10% of
pancreatic adenocarcinomas.
Precursor Lesions 
Most pancreatic cancers are believed to arise
from pancreatic intraepithelial neoplasia (PanINs), which have vary­
ing degrees of dysplasia designated as PanINs 1–3 (and constitute a
progression model for pancreatic cancer). Genetic alterations become
more frequent as the PanIN grade increases (e.g., grade 3). Most
PanIN lesions will never progress to invasive malignancy. An alternate
precursor lesion is an intraductal papillary neoplasm (IPMN), which
is usually noninvasive. Unfortunately, even high-grade PanIN lesions
are not detectable by currently available imaging modalities. In con­
trast, some pancreatic adenocarcinomas arise from noninvasive cystic
epithelial precursor lesions. These lesions can be seen on magnetic
resonance imaging (MRI) and computed tomography (CT) imaging,
and thus detection may permit early diagnosis of pancreatic cancer. As
compared to main pancreatic duct IPMN, a side branch duct IPMN
is more likely to be noninvasive. MRI and endoscopic ultrasound are
commonly used to assess malignant potential based on risk factors
such as size, growth rate, main pancreatic duct size, and the presence
of mural nodularity.
One other rare pancreatic tumor is the mucinous cystic neoplasm;
they may be seen as incidental findings on scans and are more com­
mon in the body and tail of the pancreas and tend to occur in women.
These lesions are less likely to progress to malignancy. Clinical signs of
concern include large size (>3 cm) and the presence of mural nodules
and/or thickening. Even after rare progression to mucinous adeno­
carcinoma, they typically have a more favorable prognosis relative to
typical ductal adenocarcinoma.
B
A
B
C
D
E
F
FIGURE 88-2  Selected images from contrast-enhanced computed tomography (CT) in patients with locally advanced adenocarcinoma of the pancreas. A high-quality
contrast-enhanced CT scan (arterial phase in panels A–C and portal venous phase in panels D–F) is required for optimal staging of pancreas cancer. Panel A demonstrates
the typical features of adenocarcinoma of the pancreas on arterial phase axial CT scans (dotted outline) with tumor encasement of the superior mesenteric artery (white
arrow). Note the dilatation of the common bile duct (red arrow). Panels B (magnified coronal) and C (sagittal) show reconstruction of CT images into additional orthogonal
planes with exquisite details to confirm the unresectable nature of the tumor due to vascular encasement. Panel D demonstrates the typical features of adenocarcinoma of
the pancreas on portal venous phase axial CT scans in a different subject. The dotted line outlines a pancreas cancer lesion in the pancreatic head, which is encasing the
portal splenic confluence (dotted outline). Panels E (white arrow) and F show the pinched appearance of the portal splenic confluence by tumor abutment and invasion of
the superior mesenteric vein (white arrow) on coronal and sagittal views. Note the presence of a stent in the common bile duct (red arrow) to help relieve biliary obstruction
caused by the tumor. CA, celiac axis; SMA, superior mesenteric artery.
■
■CLINICAL FEATURES
History and Physical 
A classic presentation for a patient with
pancreatic cancer arising in the head of the gland is “painless” jaundice.
Jaundice is visually detectable with a bilirubin of >2 mg/dL, and pruritus
may also occur due to bile salt deposition in the skin. However, pain is
also common in newly diagnosed patients and is typically mid epigas­
tric (sometimes described as a “boring-like” pain) with radiation to the
back (due to retroperitoneal invasion of the splanchnic nerve plexus).
The pain may be exacerbated by eating or lying flat. In the presence of
jaundice, light stool color from the absence of bile occurs (steatorrhea
also causes malodorous stools). Other signs include the onset of diabetes
(particularly with concomitant weight loss) or hyperglycemia/elevated
hemoglobin A1c in the preceding 1–2 years. The association of pancreatic
cancer with depression remains controversial.
In addition to jaundice, physical signs of pancreatic cancer include
evidence of weight loss, including loss of muscle mass, and a palpable
gallbladder in the setting of biliary obstruction (Courvoisier’s sign).
Migratory superficial thrombophlebitis and presentation with both deep
venous and arterial thromboses can occur (Trousseau’s syndrome). Signs
of late-stage disease include a lymph node palpable in the supraclavicu­
lar fossa (usually on the left where the thoracic duct enters the subcla­
vian vein). This is referred to as Virchow’s node. Occasionally, one can
palpate subcutaneous metastases in the periumbilical area referred to
as a Sister Mary Joseph’s node—named after one of the operating room
nurses from the Mayo Clinic who noted that when she prepped that
area and felt those nodules, the patient often had peritoneal metastases.
The history and symptoms noted above lead to imaging as the next
step, including ultrasonography (jaundice) and CT or MRI.
■
■DIAGNOSTIC WORKUP
Imaging 
A key diagnostic tool is the use of a dual-phase con­
trast-enhanced CT using a pancreas cancer protocol, which allows
CHAPTER 88
Pancreatic Cancer
arterial phase enhancement and portal venous phase enhancement and
detailed visualization of tumor–blood vessel relationships to inform
both resectability and staging. Figure 88-2 demonstrates such a CT
scan (with vascular involvement). Figure 88-3 demonstrates the use of
an 18F-glucose positron emission tomography (PET) scan that can aid
in the detection of otherwise occult metastatic disease.
FIGURE 88-3  Positron emission tomography scan demonstrating metastatic
disease—baseline and after 6 weeks of chemotherapy with partial resolution of
liver metastases.
Histologic Diagnosis 
A histologic (tissue) diagnosis is essential
and should be obtained with a Tru-Cut biopsy needle (fine-needle aspi­
ration cytology is an acceptable but less preferred alternative). Obtain­
ing adequate tissue not only secures a histologic/cytologic diagnosis
but also facilitates molecular testing (next-generation sequencing for
genomic alterations including KRAS) and microsatellite status. Increas­
ingly subsets of patients based on genomic characterization are being
identified and for whom therapies are available, making the need for
adequate tissue sampling increasingly relevant to patient management.
A core needle (18- to 22-gauge) biopsy can be obtained via endo­
scopic ultrasound-guided technique for a tumor localized to the pan­
creas. To biopsy the liver or a lymph node, a larger (16- to 18-gauge)
percutaneous needle biopsy by an interventional radiologist is typically
undertaken.
Serum Markers 
Before treatment and, ideally, once the bilirubin
level has normalized (biliary obstruction is associated with elevated
CA19-9), a serum sample should be obtained for level of CA19-9,
carcinoembryonic antigen (CEA), and CA125 (can be helpful for the
8–15% of patients with nondetectable CA19-9–Lewis antigen nonse­
cretors). Trends of these tumor markers over time can inform thera­
peutic decision-making.
■
■IMPORTANT IMMEDIATE CONSIDERATIONS
IN PATIENT CARE
During the life cycle of this cancer, biliary tract obstruction is a fre­
quent occurrence for tumors arising in the head of the gland (and the
attendant risk for sepsis from the biliary tree). A metallic biliary wall
stent is typically placed endoscopically to alleviate jaundice and pru­
ritus. If surgery is under consideration as the initial therapeutic step,
biliary stent placement is not necessarily warranted; however, if neo­
adjuvant (preoperative) systemic therapy is planned, both a histologic/
cytologic diagnosis and placement of a biliary wall stent are required
(where the latter is medically indicated). Of important note, all patients
with localized pancreatic cancer require multidisciplinary evaluation
by surgical, medical, and radiation oncology to optimize therapeutic
decision-making.
PART 4
Oncology and Hematology
Patients with metastatic pancreatic cancer may have a hyperco­
agulable state and frequently have thrombophlebitis (Trousseau’s sign)
and deep vein thrombosis with pulmonary emboli and/or more rarely
arterial thrombotic events. Anticoagulation using either a direct oral
anticoagulant or low-molecular-weight heparin is required in these
setting in the absence of a contraindication to anticoagulation.
Control of pain or of active cancer-related symptomatology includ­
ing anorexia, weight loss, and malabsorption should be proactively
treated. Pancreatic enzyme replacement therapy (PERT) is a critical
measure to address symptoms of malabsorption, including abdominal
cramping, bloating, steatorrhea, excess flatus, and weight loss. Early
involvement of a supportive care team can help maximize symptom
control, facilitate treatment readiness, and extend a better quality of
life.
■
■CLINICAL STAGING
The clinical staging of pancreatic cancer according to the American
Joint Commission on Cancer staging is presented in Table 88-2.
Table 88-3 presents another clinical way to express extent of disease
as well as therapeutic approaches (to be discussed later).
For optimal staging, a laparoscopy is selectively indicated either
before or at the time of definitive surgery. If metastatic disease is identi­
fied at laparoscopy, curative intent surgery is not undertaken.
TREATMENT
Pancreatic Cancer
RESECTABLE DISEASE (10–20%)
For all patients with localized pancreatic cancer, multidisciplinary
evaluation should be undertaken. A standard approach for resect­
able disease (10–15% of patients; as defined in Table 88-3) is
upfront surgery. Neoadjuvant therapy (systemic therapy prior to
surgery) is an option for patients with resectable disease. The ratio­
nales for preoperative chemotherapy include the following: (1) to
control micrometastatic disease; (2) to assess tumor biology and
response to the selected chemotherapy regimen (this allows patients
with progressive disease to avoid nontherapeutic, morbid surgery);
(3) to assure delivery of systemic therapy because therapy is better
tolerated in the preoperative setting and is not subject to omission
of drugs or altering doses due to delayed postoperative recovery;
and (4) to achieve tumor downstaging to enhance the potential for a
margin-negative surgical resection. The type of surgery for patients
with tumors in the pancreatic head, neck, or uncinate process
is typically a pancreaticoduodenectomy with or without pylorus
preservation. For tumors in the body or tail, a distal subtotal pan­
createctomy and splenectomy are performed. These operations may
be performed using a traditional “open” surgical technique or using
minimally invasive techniques. Clinical and pathologic findings of
the resection are defined as either an R0 resection (no macroscopic
or microscopic disease left after surgery) or an R1 resection, which
refers to microscopic residual disease at the surgical margin. An R2
resection refers to gross residual disease remaining after surgery
and is a highly undesirable oncologic outcome. The best outcomes
are achieved in patients with a small tumor (<2 cm), no lymph
node involvement (N0), and R0 (stage I), in whom 5-year survival
ranges from 50 to 90% depending on actual tumor size and grade.
Overall, only a small fraction of tumors are diagnosed when stage I;
however, a key goal of screening is to “stage migrate” and increase
the proportion of tumors that are diagnosed as early stage I lesions.
Several approaches are designed to maximize outcome for local­
ized pancreatic cancer.
Postoperative Adjuvant Therapy  A standard of care is 24 weeks
of adjuvant treatment with the modified FOLFIRINOX regimen
(folinic acid, 5-fluorouracil, irinotecan, oxaliplatin). The median
survival was 54 months for modified FOLFIRINOX compared to
35 months for gemcitabine alone (hazard ratio [HR] 0.64; 95%
confidence interval [CI] 0.48–0.86; p = .003) in the definitive trial
supporting this therapy. Main side effects included fatigue, gastro­
intestinal toxicity, myelosuppression, and neuropathy.
Neoadjuvant Therapy  A newer approach is the use of neoadjuvant
chemotherapy (systemic therapy given before surgery) to shrink
the tumor, eradicate micrometastatic disease, and normalize serum
CA19-9 level. Neoadjuvant therapy is the standard approach for
patients with borderline resectable or locally advanced disease. The
role of radiation in the treatment of localized pancreatic cancer is
controversial.
LOCALLY ADVANCED DISEASE (25–30% OF PATIENTS) 
For patients with locally advanced disease (defined by tumor
contact with arterial structures >180° and/or venous contact that
does not permit resection/reconstruction), the median survival is
poor (6–18 months). Complications from local disease progression
can be significant and include pain, biliary and duodenal obstruc­
tion, vascular thromboses, varices, bleeding, and infection/sepsis.
Typical treatment paradigms for locally advanced disease include
systemic chemotherapy with or without radiation therapy. A pro­
portion of patients with locally advanced disease (~20%) may be
rendered operable following neoadjuvant therapy.
METASTATIC DISEASE (50–60% OF PATIENTS) 
The mainstay of treatment for metastatic pancreatic cancer is
systemic chemotherapy. Several treatment regimens including
FOLFIRINOX, gemcitabine, albumin-bound paclitaxel, and, more
recently, NALIFIRINOX (nanoliposomal irinotecan, 5-fluorouracil,
leucovorin, oxaliplatin; NAPOLI-3) have all demonstrated a survival
advantage compared to prior standards in untreated metastatic pan­
creatic cancer. In a previously treated setting, liposomal irinotecan
and infusional 5-fluorouracil and leucovorin (NAPOLI-1) regimen
has been shown to improve survival. Predictors of outcome in the
TABLE 88-2  Definition of Primary Tumor (T)
T CATEGORY
T CRITERIA
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
Tis
Carcinoma in situ
This includes high-grade pancreatic intraepithelial neoplasia (PanIn-3), intraductal papillary mucinous neoplasm with
high-grade dysplasia, intraductal tubulopapillary neoplasm with high-grade dysplasia, and mucinous cystic neoplasm
with high-grade dysplasia
T1
  T1a
  T1b
  T1c
Tumor ≤2 cm in greatest dimension
Tumor ≤0.5 cm in greatest dimension
Tumor >0.5 cm and <1 cm in greatest dimension
Tumor 1–2 cm in greatest dimension
T2
Tumor >2 cm and ≤4 cm in greatest dimension
T3
Tumor >4 cm in greatest dimension
T4
Tumor involves celiac axis, superior mesenteric artery, and/or common hepatic artery, regardless of size
N CATEGORY
N CRITERIA
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastases
N1
Metastasis in one to three regional lymph nodes
N2
Metastasis in four or more regional lymph nodes
M CATEGORY
M CRITERIA
M0
No distant metastasis
M1
Distant metastasis
AJCC Prognostic Stage Groups
WHEN T IS…
AND N IS…
AND M IS…
THEN THE STAGE GROUP IS….
Tis
N0
M0
T1
N0
M0
IA
T1
N1
M0
IIB
T1
N2
M0
III
T2
N0
M0
IB
T2
N1
M0
IIB
T2
N2
M0
III
T3
N0
M0
IIA
T3
N1
M0
IIB
T3
N2
M0
III
T4
Any N
M0
III
Any T
Any N
M1
IV
Source: Used with permission of the American College of Surgeons, Chicago, Illinois. The original source for this information is the AJCC Cancer Staging System (2023).
TABLE 88-3  Extent of Disease and Therapeutic Approach
DESIGNATION (MEDIAN SURVIVAL)
THERAPEUTIC APPROACHES
Resectable (localized): (18–23 mo)
Surgery followed by adjuvant therapy
• mFOLFIRINOX or gemcitabine +/–
• No solid tumor contact with celiac
axis, hepatic artery, or superior
mesenteric artery (SMA), contact
with superior mesenteric–portal
veins of <180°
• Patent superior mesenteric–portal
capecitabine or nab-paclitaxel
Neoadjuvant chemotherapy followed
by surgery
veins
• No extrapancreatic disease
Locally advanced: (6–18 mo)
Chemotherapy
Chemotherapy +/– radiation
Evaluate for surgery following
systemic therapy
• Arterial involvement of >180°
(superior mesenteric artery, others)
• Venous occlusion (superior
mesenteric vein [SMV] or portal)
• No extrapancreatic disease
Metastatic: (6–12 mo)
Chemotherapy with special
consideration for tumors with
specific targets (e.g., mismatch
repair high, BRCA1/2, BRAF, etc.)
Abbreviation: mFOLFIRINOX, modified FOLFIRINOX (folinic acid, 5-fluorouracil,
irinotecan, and oxaliplatin (T Conroy et al: N Engl J Med 379:2395, 2018).
CHAPTER 88
Pancreatic Cancer
metastatic setting include good physical functioning (performance
status), favorable nutritional status, the absence of liver metastases,
lung-only metastases, and the presence of select pathogenic germ­
line variants. Table 88-4 details combination regimens that have
further improved survival modestly. Median overall survival ranges
from 6 to 12 months. However, 1-year survival is improving, with
subsets of patients whose survival with metastatic disease can reach
a couple of years or longer.
PATIENTS WITH A SPECIFIC MOLECULAR PROFILE IN
THEIR TUMOR/GERMLINE 
PARP inhibitors have activity in patients with pathogenic germline
or somatic (tumor-based) BRCA2, BRCA1, or PALB2 (i.e., defective
DNA repair proteins) variants. In addition, these tumors might
be more sensitive to specific combinations of chemotherapy that
include platinum agents (gemcitabine and cisplatin or FOLFIRI­
NOX). About 1% of pancreatic cancers have microsatellite insta­
bility, typically with high numbers of mutations in their tumors,
due to deficient mismatch repair, and these tumors are likely to
benefit from immune checkpoint blockade with anti-PD-1 (pem­
brolizumab, nivolumab) and anti-CTLA-4 inhibitors. KRAS muta­
tions occur ubiquitously in pancreatic cancer. Current treatment
guidelines include drugs targeting KRAS G12C (~1% of pancreatic

18 - 89 Gastrointestinal Neuroendocrine Tumors
89 Gastrointestinal Neuroendocrine Tumors
TABLE 88-4  Combination Chemotherapy Regimens That Have an
Impact on Survival in Stage IV Disease
NO. OF
PATIENTS
MEDIAN OVERALL
SURVIVAL (MONTHS)
STUDY DESIGN (AUTHOR/REF)
Gemcitabine + erlotinib vs gemcitabine
(Moore et al: J Clin Oncol 26:1960, 2007)
6.24 vs 5.91 (HR 0.82;
95% CI 0.69–0.99;
p = .038)
FOLFIRINOX (folinic acid + 5-fluorouracil +
irinotecan + oxaliplatin) vs gemcitabine
(Conroy et al: N Engl J Med 364:1817, 2011)
11.1 vs 6.8 (HR 0.57;
95% CI 0.45–0.70;
p <.001)
Nab-paclitaxel + gemcitabine vs
gemcitabine (Von Hoff et al: N Eng J Med
369:1691, 2013)
8.5 vs 6.7 (HR 0.72;
95% CI 0.62–0.83;
p <.001a
Nanoliposomal irinotecan, 5-fluorouracil +
folinic acid vs nanoliposomal irinotecan
monotherapy vs 5-fluorouracil + folinic acid
(Wang-Gillam et al: Lancet 387:545, 2015)
6.1 vs 4.2 (HR 0.67;
95% CI 0.49–0.92;
p = .012b)
NALIRIFOX (nanoliposomal irinotecan,
5-fluorouracil, folinic acid, oxaliplatin) vs
nab-paclitaxel and gemcitabine (Wainberg
et al: Lancet 402:1272, 2023)
11.1 vs 9.2 (HR 0.83;
95% CI 0.70–0.99;
p = .036)
aThe 2-year survival rate with this regimen is 9%, and the 3+ year rate is 4%. Other
studies have not reported on these parameters. bHR is for nanoliposomal irinotecan +
5-fluorouracil + folinic acid vs 5-fluorouracil + folinic acid.
Abbreviations: CI, confidence interval; HR, hazard ratio.
PART 4
Oncology and Hematology
cancers); however, agents that target more common KRAS muta­
tions (G12D, G12V, G12R) are being evaluated in clinical trials
and have high potential to become part of standard treatment
algorithms in the future. Other rare actionable alterations include
oncogenic fusions in RET, ALK, MET, NRG-1, ROS, and BRAF
V600E mutations, for which therapeutic agents are available and
are in clinical trials.
MAINTENANCE THERAPY FOR PATIENTS RESPONDING
TO TREATMENT 
For patients with a germline BRCA1 or BRCA2 mutation whose
metastatic pancreatic cancer has not grown during an initial plati­
num-based regimen, the PARP inhibitor olaparib has been shown
to improve progression-free survival (7.4 vs 3.8 months; HR 0.53;
95% CI 0.35–0.82; p = .004) and maintenance of quality of life, both
relative to placebo.
■
■FUTURE DIRECTIONS
Multiple novel therapies are under development in pancreatic cancer.
Immunotherapy using personalized neoantigen vaccines or using an
antigenic target such as a “public” or shared neoantigen such as KRAS
has demonstrated early promise following resection of pancreatic
cancer as an adjunct to standard chemotherapy. Mid-phase trials are
planned/underway to further explore these signals. KRAS has hereto­
fore been considered nondruggable; however, developments in organic
chemistry, biosynthesis, and other innovations have led to a series of
therapeutics directly targeting KRAS with promise that these agents
in the proximate future will be integrated as part of standard therapy
for pancreatic cancer. Multiple therapeutic approaches targeting the
tumor immune microenvironment are being explored, capitalizing on
an increased understanding of the pathobiology of this cancer. Other
important developments include innovation in clinical trial design,
novel approaches to screening and surveillance utilizing “liquid” bio­
markers (incorporating DNA fragments, methylation, and proteomic
profiles), and other technologic developments.
Acknowledgment
Thank you to the American Joint Committee on Cancer for providing
the tables.
■
■FURTHER READING
Conroy T et al: FOLFIRINOX versus gemcitabine for metastatic
pancreatic cancer. N Engl J Med 364:1817, 2011.
Conroy T et al: FOLFIRINOX or gemcitabine as adjuvant therapy for
pancreatic cancer. N Engl J Med 379:2395, 2018.
Golan T et al: Maintenance olaparib for germline BRCA-mutated
metastatic pancreatic cancer. N Engl J Med 381:317, 2019.
Hu ZI, O’Reilly EM: Therapeutic developments in pancreatic cancer.
Nat Rev Gastroenterol Hepatol 21:7, 2024.
Hruban RJ et al: Genetic progression in the pancreatic ducts. Am J
Pathol 156:1821, 2000.
Park W et al: Pancreatic cancer: A review. JAMA 326:851, 2021.
Rahib L et al: Evaluation of pancreatic cancer clinical trials and
benchmarks for clinically meaningful future trials: A systemic review.
JAMA Oncol 2:1209, 2016.
Rawla P et al: Epidemiology of pancreatic cancer: Global trends, etiology,
and risk factors. World J Oncol 10:10, 2019.
Solomon S et al: Inherited pancreatic cancer syndromes. Cancer J
18:485, 2012.
Von Hoff D et al: Increased survival in pancreatic cancer with nabpaclitaxel plus gemcitabine. N Engl J Med 369:1691, 2013.
Wainberg Z et al: NALIRIFOX versus nab-paclitaxel and gemcitabine
in treatment-naive patients with metastatic pancreatic ductal adeno­
carcinoma (NAPOLI 3): A randomised, open-label, phase 3 trial.
Lancet 402:1272, 2023.
Yuan C et al: Diabetes, weight change, and pancreatic cancer risk.
JAMA Oncol 6:e202948, 2020.
Matthew H. Kulke
Gastrointestinal
Neuroendocrine Tumors
Gastrointestinal (GI) neuroendocrine tumors (NETs) can be broadly
grouped according to their site of origin as either extrapancreatic
NETs, historically called carcinoid tumors, or pancreatic NETs. While
NETs can pursue a broad range of clinical behaviors, they classically
follow a course that is more indolent than many other malignancies.
NETs also have the ability to synthesize peptides, growth factors, and
bioactive amines that may be ectopically secreted, giving rise to a range
of unique clinical syndromes.
INCIDENCE AND PREVALENCE
The diagnosed incidence of NETs has been steadily increasing over the
past several decades. An analysis of data from the Surveillance, Epidemi­
ology, and End Results (SEER) program, comprising population-based
data in the United States from 1973 to 2012, showed that the overall inci­
dence had increased 6.4-fold over this time period and that the estimated
prevalence of patients who had been diagnosed with a NET was >170,000.
Gastroenteropancreatic neuroendocrine tumors comprise the majority
of neuroendocrine tumors, and recent analyses suggest the incidence in
this subgroup has risen proportionately and continues to rise (Fig. 89-1).
These same studies have also found that overall survival durations for
patients with NETs have improved significantly over time. The increasing
incidence and improved survival durations for patients with NETs likely
reflect, at least in part, advances in both diagnosis and treatment.
While environmental or other factors leading to an increased inci­
dence of NETs cannot be excluded, common cancer risk factors such as
tobacco or alcohol use and dietary patterns have not been clearly linked
to NET development.
A minority of NETs develop in the context of autosomal inherited
genetic syndromes associated with mutations in specific tumorsuppressor genes. The most common of these is multiple endocrine
neoplasia type 1 (MEN 1), due to mutation and loss of function of
the menin gene, located on chromosome 11q13 (Chap. 400). Patients
Age adjusted incidence of
neuroendocrine tumors in U.S.
(per 100,000)
Age adjusted incidence of all
malignancies in the U.S.
(per 100,000)
A
B
FIGURE 89-1  Incidence of gastroenteropancreatic neuroendocrine tumors (NETs). The incidence of
gastroenteropancreatic neuroendocrine tumors has been increasing over the past several decades,
an observation that has been attributed in part to improved diagnosis and classification. (Adapted
from Z Xu et al: Epidemiologic trends of and factors associated with overall survival for patients
with gastroenteropancreatic neuroendocrine tumors in the United States. JAMA Network Open
4:e2124750, 2021, Figure 1A.)
with MEN 1 are at risk for developing pancreatic NETs as well as
hyperparathyroidism and pituitary adenomas; less commonly, they
may develop bronchial and thymic NETs. Other inherited syndromes
associated with NETs include von Hippel–Lindau disease (VHL), von
Recklinghausen’s disease (neurofibromatosis type 1), and tuberous
sclerosis (Bourneville’s disease). Inherited mutations in the VHL gene,
located on chromosome 3p25, are associated with the development of
cerebellar hemangioblastomas, renal cancer, and pheochromocytomas
and, less commonly, pancreatic NETs. Mutations in neurofibromin
(NF1) are associated with neurofibromatosis (von Recklinghausen’s
disease); patients with neurofibromatosis are at risk of developing both
pancreatic and extrapancreatic NETs. Tuberous sclerosis is caused by
mutations that alter either hamartin (TSC1) or tuberin (TSC2). Both
hamartin and tuberin function as inhibitors of the phosphatidylinositol
3-kinase and the mechanistic target of rapamycin (mTOR) signaling
cascades, and pancreatic NETs have been reported in these patients.
Rare cases of familial small intestine NETs have also been reported;
in these cases, multiple synchronous tumors generally arise within the
small intestine. A characteristic inherited mutation has not been iden­
tified to date in the majority of these cases.
HISTOLOGIC CLASSIFICATION AND
MOLECULAR FEATURES
The histologic features of NETs vary widely and are one of the most
important determinants of both clinical behavior and treatment. NETs
are classified based on the degree tumor differentiation (well or poorly
TABLE 89-1  Histologic Classification of Neuroendocrine Tumors
CLASSIFICATION
DIFFERENTIATION
GRADE
MITOTIC COUNT
KI-67
Neuroendocrine tumor
Well differentiated
Low grade (grade 1)
<2 per 10 HPF
<3%
Neuroendocrine tumor
Well differentiated
Intermediate grade (grade 2)
2–20 per 10 HPF
3–20%
Neuroendocrine tumor
Well differentiated
High grade (grade 3)
20 per 10 HPF
20%
Neuroendocrine carcinoma
Poorly differentiated
High grade (grade 3)
20 per 10 HPF
20%
Abbreviation: HPF, high-power field.
differentiated), as assessed by a pathologist, and tumor
grade (grades 1–3) (Table 89-1). Tumor grade closely
correlates with mitotic count and Ki-67 proliferative
index. Classic, well-differentiated NETs are composed
of monotonous sheets of small round cells with uniform
nuclei and only rare mitoses. Immunocytochemical
staining for chromogranins and synaptophysin is typical.
Ultrastructurally, these tumors contain electron-dense
neurosecretory granules containing peptides and bio­
active amines that may be ectopically secreted, giving
rise to a range of clinical syndromes. These classic well-
differentiated NETs have low-grade features and gener­
ally have a mitotic index of <2 mitoses per 10 high-power
fields (HPFs) and a Ki-67 proliferative index of <3%. Less
commonly, well-differentiated NETs have an intermedi­
ate histologic grade and pursue a somewhat more aggres­
sive clinical course. Intermediate-grade tumors typically
have a mitotic count of 2–20 per 10 HPF and a mitotic
index of 3–20%. Well-differentiated high-grade tumors
are rare and have mitotic counts that exceed 20 per 10
HPF and a Ki-67 proliferative index of >20%. Poorly dif­
ferentiated high-grade tumors form the most clinically
aggressive category; prognosis and treatment for these
tumors differ markedly from their well-differentiated
counterparts.
CHAPTER 89
Whole exome sequencing of sporadic pancreatic NETs
has shown that the most frequently altered gene was
MEN1, occurring in 44% of tumors. In addition, 43%
of tumors had mutations in genes encoding two sub­
units of a transcription/chromatin remodeling complex
consisting of DAXX (death-domain-associated protein)
and ATRX (α-thalassemia/mental retardation syndrome
X-linked). Mutations in genes associated with the mTOR
pathway were identified in 15% of tumors. In contrast, recurrent
mutations in extrapancreatic NETs appear to be rare. In one study
that evaluated 180 small intestinal NETs using a combination of whole
exome and more targeted genome-sequencing analysis, recurrent
mutations were only observed in the CDKN1B gene (cyclin-dependent
kinase inhibitor 1B [p27Kip1]) in 8% of cases. Loss of chromosome 18 is
a common finding in small-bowel NETs. Small-intestinal GI carcinoids
commonly have epigenetic changes; however, the clinical significance
of these alterations remains uncertain.
Gastrointestinal Neuroendocrine Tumors
CLINICAL PRESENTATION AND
MANAGEMENT OF LOCALIZED
PANCREATIC NEUROENDOCRINE TUMORS
Pancreatic NETs have been subcategorized as either “functional,”
meaning associated with symptoms of hormone secretion, or non­
functional, in which case they may be clinically silent until they cause
anatomic symptoms. The clinical presentation of functional pancreatic
NETs depends on the type of hormone secreted and can sometimes
lead to dramatic clinical presentations (Table 89-2). The most com­
mon functional pancreatic NETs are insulinomas, followed in inci­
dence by glucagonomas and gastrinomas. Pancreatic NETs secreting
other hormones, including somatostatin, vasoactive intestinal pep­
tide (VIP), adrenocorticotropic hormone (ACTH), and parathyroid
hormone (PTH), have also been described but are uncommon. Only
~20% of pancreatic NETs are associated with symptoms of hormone
TABLE 89-2  Clinical Presentation and Management of Secretory
Syndromes Associated with Neuroendocrine Tumors
TREATMENT OPTIONS
TO CONTROL
SECRETORY SYMPTOMS
CLINICAL SYMPTOMS
AND MANIFESTATIONS
Pancreatic Neuroendocrine Tumors
Gastrinoma (generally
located in “gastrinoma
triangle”)
Zollinger-Ellison
syndrome:
gastroesophageal reflux,
peptic ulcer disease,
diarrhea
Proton pump inhibitors,
somatostatin analogues
Insulinoma
Hypoglycemia leading
to confusion, lethargy,
coma; weight gain
Diazoxide, everolimusa
Glucagonoma
Skin rash (necrolytic
migratory erythema),
glucose intolerance,
weight loss
Somatostatin analogues
VIPoma
Verner-Morrison
syndrome: watery
diarrhea, hypokalemia,
achlorhydria
Somatostatin analogues
ACTHoma
Cushing’s syndrome:
hyperglycemia, weight
gain, hypokalemia
Ketoconazole,
metyrapone, consider
adrenalectomy
PART 4
Oncology and Hematology
Extrapancreatic Gastrointestinal Neuroendocrine Tumors
Typically in setting
of advanced disease
from small intestine or
appendiceal primary
tumors
Carcinoid syndrome:
flushing, diarrhea, rightsided valvular heart
disease, mesenteric
fibrosis
Somatostatin analogues,
telotristat ethyl
aSuccessful use of monoclonal anti-insulin receptor antibodies to treat insulininduced hypoglycemia has been reported but remains investigational.
Abbreviations: ACTH, adrenocorticotropic hormone; VIP, vasoactive intestinal
peptide.
hypersecretion; the majority of pancreatic NETs are “nonfunctional”
and are diagnosed either incidentally or after patients present with
abdominal pain, weight loss, or other anatomic symptoms related to
tumor bulk.
■
■GASTRINOMA
Patients with gastrinoma typically present with Zollinger-Ellison syn­
drome (ZES) (Chap. 335). The most common symptoms associated
with this syndrome are abdominal pain, diarrhea, gastroesophageal
reflux disease (GERD), and peptic ulcer disease. Peptic ulcer disease
manifesting as multiple ulcers with associated diarrhea is a classic pre­
sentation. Up to 25% of patients with ZES have MEN 1, and a diagnosis
of gastrinoma should prompt a family history as well as an assessment
for concurrent hyperparathyroidism. Fasting hypergastrinemia is a
nearly universal finding in patients with gastrinoma. Importantly,
however, proton pump inhibitors (PPIs) can suppress acid secretion
sufficiently to cause hypergastrinemia and can confound the diagno­
sis. Achlorhydria, usually in the context of chronic atrophic gastritis,
will also elevate serum gastrin levels but can usually be easily distin­
guished from gastrinoma given the absence of other evidence of acid
hypersecretion.
While often classified as pancreatic NETs, the majority of gastri­
nomas in fact arise in the “gastrinoma triangle,” an anatomic region
bounded by the duodenum, pancreas, and confluence of the cystic
and common bile ducts. Most gastrinomas (50–90%) in sporadic ZES
arise in the duodenum. They are frequently small and may be dif­
ficult to localize. Imaging studies generally include either computed
tomography (CT) or magnetic resonance imaging (MRI); endoscopic
ultrasound or somatostatin scintigraphy may also be helpful.
PPIs are generally highly effective in the treatment of symptoms
related to gastrinoma and are considered the initial treatment of choice.
Rapid resolution of both abdominal pain and diarrhea related to acid
hypersecretion is common. Somatostatin analogues may also be helpful
in controlling symptoms in refractory cases. Once symptoms are con­
trolled, surgical resection is generally recommended for patients with
sporadic gastrinomas, both to eliminate the cause of gastrin secretion
and to decrease the risk of developing metastatic disease. The tech­
nique used for resection depends in large part on the precise location
of the tumor. In some cases where preoperative imaging is not success­
ful but a diagnosis is strongly suspected, exploratory laparotomy with
intraoperative ultrasound may be undertaken. In gastrinoma patients
who have underlying MEN 1, tumors are generally small and multiple;
the role of routine surgery in this setting remains more controversial
but generally is still recommended in patients with larger tumors mea­
suring ≥1.5–2 cm in diameter.
■
■INSULINOMA
Patients with insulinoma generally present with symptoms of hypogly­
cemia, which may include confusion, headache, disorientation, visual
difficulties, irrational behavior, and even coma. In some cases, the diag­
nosis of insulinoma may not be immediately evident, and patients with
insulinoma may initially be diagnosed with psychiatric illnesses that in
retrospect were hypoglycemic symptoms. The diagnosis of insulinoma
is generally confirmed with elevated fasting insulin levels in conjunc­
tion with elevated proinsulin and C-peptide. Fasting hypoglycemia can
also be caused by severe liver disease, alcoholism, and poor nutrition.
Postprandial hypoglycemia may also occur after gastric bypass surgery.
Surreptitious use of insulin or hypoglycemic agents may be difficult to
distinguish from an insulinoma. Evaluation of proinsulin and C-pep­
tide levels, both of which should be normal in patients using exogenous
insulin, and measurement of sulfonylurea levels in serum or plasma are
helpful in such cases.
The hypoglycemia associated with insulinomas can be severe and
challenging to manage. While somatostatin analogues are usually effec­
tive in treating symptoms of hormone hypersecretion associated with
other types of NETs, they should be used with caution in patients with
insulinoma. Somatostatin analogues may suppress counterregulatory
hormones, such as growth hormone (GH), glucagon, and catechol­
amines, and precipitously worsen hypoglycemia. Diazoxide has histori­
cally been used in the initial management of patients with insulinoma
and results in inhibition of insulin release, though it can also be associ­
ated with side effects including sodium retention and nausea. Evero­
limus, in addition to its antitumor effect (see below), is effective in
improving glycemic control in patients with insulinoma. The benefits
of everolimus in this setting may be related both to induction of insulin
resistance and a direct antitumor effect. The use of anti-insulin recep­
tor monoclonal antibodies may be highly effective in treating the hypo­
glycemia associated with insulinoma, although currently their use for
this indication remains investigational Insulinomas may be difficult to
localize, as they are less consistently avid on somatostatin scintigraphy
than other pancreatic NETs. Insulinomas are also generally small, with
the majority measuring <2 cm in diameter. Because of their generally
small size, insulinomas are best localized with endoscopic ultrasound
(EUS). In the absence of metastatic disease, surgical resection is usu­
ally recommended. The primary treatment for exophytic or peripheral
insulinomas is enucleation. If enucleation is not possible because of
invasion or the location of the tumor within the pancreas, then pan­
creatoduodenectomy for tumors in the head of the pancreas or distal
pancreatectomy with preservation of the spleen for smaller tumors not
involving splenic vessels may be considered.
■
■GLUCAGONOMA
Patients with glucagonoma most commonly present with a charac­
teristic dermatitis, called necrolytic migratory erythema (Fig. 89-2).
The rash usually involves intertriginous sites, especially in the groin or
buttock, and can wax and wane. Other common presenting symptoms
of glucagonoma include glucose intolerance and weight loss. The diag­
nosis of glucagonoma can be confirmed by demonstrating an increased
plasma glucagon level, generally in excess of 1000 pg/mL. Somatostatin
analogues are usually highly effective as an initial treatment to alleviate
the symptoms and rash associated with glucagon hypersecretion. The
majority of glucagonomas are large in size at presentation and arise in
FIGURE 89-2  Glucagonoma syndrome. Patients with glucagonoma may present
with a classic skin rash, necrolytic migratory erythema (shown). Other presenting
symptoms include glucose intolerance and weight loss.
the tail of the pancreas. For patients with localized disease, distal pan­
createctomy and splenectomy are recommended. A hypercoagulable
state has been reported in up to 33% of patients with glucagonoma, and
perioperative anticoagulation should generally be employed.
■
■SOMATOSTATINOMA
Patients with somatostatinoma typically present with diabetes mellitus,
gallbladder disease, diarrhea, and steatorrhea. Somatostatinomas occur
primarily in the pancreas or duodenum, are usually large, and are com­
monly metastatic at presentation. They are only rarely associated with
MEN 1. The diagnosis of somatostatinoma is based on the demonstra­
tion of elevated plasma somatostatin levels, and as such, the potential
benefits of using somatostatin analogues as a treatment for patients
with somatostatinoma are questionable. Surgery is recommended for
patients with localized disease.
■
■VIPOMA
VIPomas are associated with a distinct syndrome that has been
variously called Verner-Morrison syndrome, pancreatic cholera, and
WDHA syndrome (watery diarrhea, hypokalemia, and achlorhydria).
VIP is a 28-amino-acid peptide that mimics the effects of the cholera
toxin by stimulating chloride secretion in the small intestine and
increasing smooth-muscle contractility, resulting in profound diarrhea.
Treatment of dehydration, hypokalemia, and electrolyte losses with
fluid and electrolyte replacement is the most critical initial treatment
for patients with VIPoma. VIPomas are usually solitary and arise in the
pancreatic tail. Elevated plasma levels of VIP are typical but should not
be the only basis of the diagnosis of VIPomas because they can occur
with some diarrheal states including inflammatory bowel disease, in
the setting of small-bowel resection, and radiation enteritis. Chronic
surreptitious use of laxatives/diuretics can be particularly difficult to
detect clinically. Somatostatin analogues are usually highly effective
in controlling the diarrhea; surgical resection is recommended for
patients with localized disease.
■
■OTHER SECRETORY PANCREATIC NETS
Pancreatic NETs secreting GH-releasing factor (GRF), calcitonin,
ACTH, and PTH-related protein have also been described; it is also
possible for pancreatic NETs to secrete more than one hormone or for
the secretory profiles to evolve over time. Gastrinomas, in particular,
may evolve and may be associated with secretion of ACTH, resulting
in ectopic Cushing’s syndrome. Tumors secreting these hormones
may not be as responsive to treatment with somatostatin analogues
as the more common pancreatic NETs and the associated hormonal
symptoms may cause significant morbidity. As with other pancreatic
NETs, patients with localized disease are generally treated with surgi­
cal resection. In patients with ACTH-secreting tumors, the associated
symptoms of Cushing’s syndrome can be alleviated with the use of
metyrapone, an agent that directly inhibits cortisol synthesis. Adrenal­
ectomy may also be considered if resection of the primary tumor is not
possible or in the setting of metastatic disease.
■
■PANCREATIC NETS ARISING IN THE SETTING OF
MEN 1
Pancreatic NETs occurring in patients with MEN 1 are typically
multiple and often pursue a relatively indolent course. Because of the
high probability of multiple tumors, surgical resection of confirmed
pancreatic NETs in patients with MEN 1 is usually undertaken with
caution given the likelihood of tumors arising in the remaining pan­
creas if partial pancreatectomy is undertaken as well as the significant
morbidities associated with total pancreatectomy. However, for symp­
tomatic tumors or for growing tumors >2 cm in size, surgical resection
may still be considered.
CHAPTER 89
■
■NONFUNCTIONING PANCREATIC NETS
As noted above, the majority of pancreatic NETs are not associated
with symptoms of hormone hypersecretion and are considered “non­
functional.” As a result, they often remain clinically silent and either
are diagnosed incidentally or are not diagnosed until widespread,
metastatic disease is present resulting in anatomic symptoms. If they
are localized at diagnosis, the general treatment recommendation is
surgical resection; however, the management of small, asymptomatic
pancreatic NETs is debated. Assuming tumors are low grade, patients
with incidentally discovered, low-grade tumors measuring <1 cm in
size can generally be safely followed. However, some studies have sug­
gested that at least some tumors measuring <2 cm in size can pursue a
more aggressive course and that surgical resection may be warranted in
some cases. Management of small, incidentally discovered, asymptom­
atic, low-grade pancreatic NETs is therefore based on clinical judge­
ment, taking into account surgical risk and patient comorbidities. For
tumors measuring >2 cm in diameter, metastases pose a significant risk
and surgical resection is generally recommended in patients for whom
surgery is not contraindicated.
Gastrointestinal Neuroendocrine Tumors
CLINICAL PRESENTATION AND
MANAGEMENT OF LOCALIZED
EXTRAPANCREATIC GASTROINTESTINAL
NEUROENDOCRINE TUMORS
Extrapancreatic GI NETs, historically called carcinoid tumors, may
arise virtually anywhere in the GI tract and differ significantly in their
clinical characteristics depending on their location. The most common
locations for extrapancreatic NETs are the stomach, distal small intes­
tine, appendix, and rectum.
■
■GASTRIC NETS
Gastric NETs can be categorized into three groups: type 1 (associated
with chronic atrophic gastritis); type 2 (associated with gastrinomas
and ZES), and type 3 (sporadic, gastric NETs). Type 1 gastric NETs are
the most common of the three types. In type 1 gastric NETs, chronic
atrophic gastritis results in loss of acid secretion with consequent loss
of the negative feedback loop on gastrin-producing cells in the antrum
of the stomach. Pernicious anemia is also commonly associated with
this condition; classic laboratory findings are a markedly elevated
gastrin level and low levels of vitamin B12. Unchecked gastrin secretion
in these patients results in hyperplasia of the endocrine cells in the
gastric fundus. A typical finding on endoscopy is diffuse endocrine cell
hyperplasia with multiple gastric carcinoid tumors (Fig. 89-3). These
PART 4
Oncology and Hematology
FIGURE 89-3  Multifocal gastric neuroendocrine tumor. (Courtesy of Christopher
Huang, MD, Boston Medical Center.)
tumors generally pursue a benign course and can be monitored with
serial endoscopy. In cases where tumors continue to grow or become
symptomatic, antrectomy to remove the source of gastrin production
can result in tumor regression. Type 2 tumors are rare and usually
occur in the setting of gastrinoma; as with type 1 gastric NETs, elevated
gastrin levels result in diffuse gastric neuroendocrine hyperplasia and
multifocal gastric NETs. Resection of the gastrinoma, removing the
source of gastrin production, is the treatment of choice.
In contrast to type 1 and type 2 gastric NETs, type 3 gastric NETs are
generally solitary, arise in the setting of normal gastrin levels, and may
pursue a far more aggressive course. For early-stage, smaller tumors,
endoscopic or wedge resection may be performed. For larger tumors,
partial gastrectomy with lymphadenectomy is recommended.
■
■NETS OF THE SMALL INTESTINE
Small-bowel NETs occur most commonly in the terminal ileum and are
notoriously difficult to diagnose at an early stage. One reason for this
is that they arise within the muscularis, and their submucosal location
makes them difficult to see during routine colonoscopy (Fig. 89-4A).
Small-bowel NETs are also often multifocal; multifocal tumors appear
to arise independently throughout the small intestine, although the
mechanisms underlying this phenomenon remain uncertain.
A
B
FIGURE 89-4  Small intestine neuroendocrine tumor. A. Small intestine neuroendocrine tumors arising in submucosal location. The submucosal location of small intestine
neuroendocrine tumors, together with their location beyond the ileocecal valve in the terminal ileum, can make endoscopic detection challenging. B. Classic “spoke
and wheel” appearance of calcified mesenteric mass associated with small intestine primary neuroendocrine tumor. Mesenteric fibrosis commonly leads to intermittent
obstructive symptoms and can also lead to ischemia when the mesenteric vasculature is involved. (Fig. B: Courtesy of Christina LeBedis, MD, Boston Medical Center.)
Small-bowel NETs are often associated with desmoplasia and mes­
enteric fibrosis, likely as a result of fibroblast proliferation stimulated
by tumor serotonin secretion. Mesenteric fibrosis frequently results
in intermittent small-bowel obstruction and, in some cases, bowel
ischemia due to involvement of the mesenteric vessels. Patients may
experience symptoms of intermittent abdominal pain and associated
diarrhea, sometimes for months or years before diagnosis, that because
of the difficulty in diagnosis are often attributed to irritable bowel syn­
drome. One classic finding that can aid in diagnosis is that the lymph
node metastases associated with small intestine NETs are usually larger
than the primary tumor and may be calcified, which, together with the
tethering of the small intestine caused by the associated fibrosis, results
in a classic “spoke and wheel” appearance on CT (Fig. 89-4B).
Surgical resection of the primary tumor and associated metastases
is recommended when feasible and is performed with curative intent
when distant metastatic disease is not already present. Resection
should also be considered in patients with metastatic disease experi­
encing intermittent obstruction or abdominal discomfort thought to
be related to the primary tumor or associated mesenteric disease. Some
have also advocated the routine resection of asymptomatic small-bowel
primary tumors in patients with distant metastatic disease, with the
rationale that this may be a way to prevent the future development of
fibrosis and obstruction and preempt the development of unresectable
disease due to tumor involvement of the mesenteric vessels. However,
the available data on the benefits of resecting an asymptomatic primary
tumor in this context are conflicting. Some studies have suggested that
this practice results in an overall survival benefit, but the retrospective
nature of these studies makes the data difficult to interpret given the
high potential for selection bias in patients taken to surgery compared
with those who were not. Other studies have suggested that prophy­
lactic primary tumor resection confers no survival benefit and that
surgery can be safely delayed until it is indicated based on the develop­
ment of symptoms.
■
■NETS OF THE APPENDIX
NETs are one of the most common tumors arising in the appendix.
They are typically discovered incidentally in younger individuals
undergoing appendectomy for acute appendicitis and not uncom­
monly are identified only at the time of pathology review. While the
unexpected diagnosis of an appendiceal NET in such situations can
cause considerable anxiety, in the majority of cases, the prognosis is
excellent. Indeed, the clinical behavior of appendiceal NETs has been
inferred from multiple large retrospective surgical series that suggest
that the risk of lymph node or distant metastases from appendiceal
NETs with well-differentiated histology and a tumor diameter measur­
ing <2 cm is extremely low. In such cases, appendectomy alone is felt
to be a sufficient surgical procedure.
In contrast, the risk of metastases for tumors measuring 2–3 cm
is ~20–30% and is even greater for tumors measuring >3 cm. For
patients with larger tumors, more formal staging studies with either
cross-sectional imaging or somatostatin scintigraphy are generally
recommended to assess for distant metastases, and a subsequent right
colectomy to remove regional lymph nodes is performed if no distant
metastases are observed. Whether right colectomy should be per­
formed for tumors measuring <2 cm with features such as mesoappen­
diceal invasion or tumor origin at the appendiceal base, which in some
series have suggested a poorer prognosis, remains uncertain. Addi­
tionally, tumors may arise in which neuroendocrine cells are admixed
with mucin-producing cells or cells exhibiting features of frank adeno­
carcinoma. In such mixed neuroendocrine-adenocarcinoma tumors,
sometimes termed “adenocarcinoids,” treatment recommendations are
generally dictated by the more aggressive component of the tumor and
align with typical recommendations for colorectal adenocarcinoma.
■
■RECTAL NETS
With the increased use of screening colonoscopy, the diagnosis of
rectal NET has also become more common. For unclear reasons,
the incidence of rectal carcinoid tumors shows geographic variation.
In European studies, they compose up to 14% of all NETs, while in
some Asian series (Japan, China, Korea), they compose up to 90% of
all NETs. The majority of rectal NETs are small, measuring <1 cm in
diameter, and have well-differentiated histology. These tumors rarely
metastasize and can usually be safely removed endoscopically with
subsequent endoscopic monitoring. In contrast, up to one-third of
rectal NETs between 1 and 2 cm are associated with metastases, and
those >2 cm, though uncommon, metastasize in >70% of patients.
When identified early, these tumors generally require a surgical resec­
tion. In contrast to NETs of the appendix and small intestine, hormone
secretion from rectal NETs, even when metastatic, is exceedingly rare.
CLINICAL PRESENTATION, DIAGNOSIS,
AND EVALUATION OF PATIENTS WITH
METASTATIC NEUROENDOCRINE TUMORS
While patients who undergo resection of localized NETs may be at risk
of developing tumor recurrence or metastatic disease, postoperative
treatment has not yet been shown to alter the risk of recurrence, and
systemic adjuvant therapy is not recommended following resection of
well-differentiated NETs, as it is for some other cancers. Whether adju­
vant systemic therapy may be of benefit following resection of highgrade NETs is uncertain, and an approach utilizing platinum-based
chemotherapy with or without external-beam radiation, analogous to
that used in small-cell carcinoma, is sometimes considered.
The evaluation of patients with known or suspected metastatic
disease generally includes both standard cross-sectional imaging such
as CT or MRI and somatostatin scintigraphy. Somatostatin scintig­
raphy in this setting is based on the fact that >90% of NETs express
somatostatin receptors. Gallium-68 (68GA) dotatate, as well as 68GA
DOTATOC and copper-64 dotatate, are all radioligands bound to a
somatostatin analogue and can be used as a nuclear medicine tracer to
perform positron emission tomography (PET) scanning that is highly
sensitive in detecting both primary NETs and metastases (Fig. 89-5).
Because of the sensitivity of these approaches, false-positive results can
occur due to somatostatin receptor expression in other tissues. Physi­
ologic uptake in the pancreatic uncinated process is common; uptake
can also occur in the setting of sarcoidosis, in meningiomas, and in
thyroid goiter or thyroiditis. Standard fluorodeoxyglucose (FDG)
PET scans are often negative in well-differentiated NET due to their
low metabolic activity but can show uptake in higher-grade tumors;
conversely, rates of somatostatin expression tend to be lower in highergrade tumors, and 68GA dotatate scans may be negative in this setting.
The utility of blood-based tumor markers in NETs is controversial.
The circulating tumor marker chromogranin A is commonly used as
a screen for the presence of NETs and also to monitor for both recur­
rence and progression of disease in patients with known metastases.
While chromogranin A is elevated in patients with metastatic NETs, it
is neither particularly sensitive nor specific. A broad range of different
assays for chromogranin A have also posed challenges in interpreting
results in a standardized fashion. Chromogranin A is often elevated
in a number of nonmalignant conditions, including in patients with
CHAPTER 89
FIGURE 89-5  Gallium-68 dotatate positron emission tomography (PET) scan
demonstrating a small-bowel neuroendocrine tumor and associated mesenteric
mass. (Courtesy of Sara Meibom, MD, Boston Medical Center.)
Gastrointestinal Neuroendocrine Tumors
impaired renal function and in patients who are taking PPIs. Elevated
values of chromogranin A should be interpreted with caution in
patients in whom a NET is being considered but in whom a diagnosis
has not been established.
The overall survival durations for patients with metastatic NETs
vary significantly, depending on both the primary location of the
tumor and the histologic grade. Median survival durations for patients
with well-differentiated NETs have markedly increased in recent years,
likely reflecting both earlier diagnoses and improved treatments. For
example, in early analyses of the SEER database, the median survival
for patients with advanced pancreatic NETs was ~2 years; this had
increased to 4 years in a more recent analysis. Similar increases were
observed in patients with advanced small intestine NETs, where the
median survival for patients with well-differentiated small intestine
NETs exceeds 5 years. The sometimes prolonged survival of patients
with NETs can make it challenging to determine at what point to
initiate treatment. In patients with symptoms of hormone secretion,
decisions to initiate therapy are straightforward. In asymptomatic
patients, on the other hand, observation off treatment can sometimes
be appropriate. Nevertheless, the natural course of NETs is ultimately
to progress, and if treatment is not initiated, close monitoring is essen­
tial to ensure patients maximize access to available treatment options
over the course of their disease.
MANAGEMENT OF SYMPTOMS OF
HORMONE HYPERSECRETION AND THE
CARCINOID SYNDROME
Patients with advanced NETs may in some cases experience more
symptoms from hormone hypersecretion than from tumor bulk. The
management of hormonal symptoms associated with pancreatic NETs
depends on the hormone being secreted (see above). Patients with GI
NETs, particularly those with small intestine or appendiceal primaries,
may develop the carcinoid syndrome. Flushing and diarrhea are the
two most common symptoms associated with carcinoid syndrome. The
characteristic flush is of sudden onset; it is a deep red or violaceous
erythema of the upper body, especially the neck and face, often associ­
ated with a feeling of warmth. Flushes may be precipitated by stress,
alcohol, exercise, and certain foods such as cheese. Flushing episodes
initially are brief, lasting 2–5 min, though later in the disease course,
they may last hours. The diarrhea associated with carcinoid syndrome
Carcinoid tumor
Tryptophan
Telotristat ethyl
Tryptophan hydroxylase
Hydroxytryptophan
(5-HTP)
Aromatic L-amino acid
decarboxylase
Serotonin
(5-HT)
5-HT stored in
secretory granules
Secretion
5-HT in blood
Monoamine oxidase
Aldehyde dehydrogenase
5-Hydroxyindolacetic acid
(5-HIAA)
PART 4
Oncology and Hematology
5-HIAA filtered
by kidney
Excretion
5-HIAA in urine
FIGURE 89-6  Serotonin synthesis and secretion in neuroendocrine tumors.
Tryptophan is converted to hydroxytryptophan by tryptophan hydroxylase within
the tumor cell and, subsequently, to serotonin (5-HT). Serotonin is subsequently
converted to 5-hydroxyindole acetic acid (5-HIAA), which can be measured in a 24-h
urine collection and can facilitate the diagnosis of carcinoid syndrome. Telotristat
ethyl inhibits tryptophan hydroxylase and can be used as a treatment for carcinoid
syndrome.
may or may not be associated with flushing and is described as watery
in nature. Diarrhea can be profound, sometimes occurring in excess
of 10 times daily and is one of the symptoms that most significantly
interferes with activities of daily living. Less common manifestations
of the carcinoid syndrome include wheezing or asthma-like symptoms.
Impaired cognitive function has also been described in particularly
advanced cases.
The main secretory product implicated in the carcinoid syndrome
is serotonin (5-HT). Serotonin is synthesized from tryptophan by the
enzyme tryptophan hydroxylase (Fig. 89-6). Up to 50% of dietary tryp­
tophan can be used in this synthetic pathway by tumor cells, resulting
in inadequate supplies for conversion to niacin; hence, some patients
develop symptoms of niacin deficiency and pellagra-like lesions.
Serotonin has numerous biologic effects, including the stimulation of
intestinal secretion, increasing intestinal motility, and the stimulation
of fibroblast growth. Other secreted products contributing to carcinoid
syndrome symptoms are thought to include histamines and tachyki­
nins, including substance P.
■
■DIAGNOSIS AND TREATMENT OF THE
CARCINOID SYNDROME
While the carcinoid syndrome can develop in patients with NETs from
almost any site, it is most commonly associated with appendiceal or
small intestine NETs. In these patients, the syndrome usually develops
only after the development of hepatic metastases or retroperitoneal
lesions, allowing entry of serotonin and other vasoactive substances
into the systemic circulation. While serotonin levels can be measured
in plasma, such measurements are frequently highly variable. Evi­
dence of excess serotonin secretion can be more reliably confirmed by
measuring levels of the serotonin metabolite 5-hydroxyindole acetic
acid (5-HIAA), either in plasma or using a 24-h urine collection. Urine
collections can be challenging, and false-positive elevations may occur
if the patient is eating serotonin-rich foods (e.g., salmon, eggs). As
a result, elevated levels of 5-HIAA are suggestive but not diagnostic
of the carcinoid syndrome. Patients with NETs may also experience
symptoms of carcinoid syndrome related to other secreted products,
including histamine, absent evidence of serotonin secretion. Con­
versely, patients without NETs may also describe symptoms analogous
to carcinoid syndrome but due to other causes. The symptoms associ­
ated with systemic mastocytosis, in particular, can be easily confused
with carcinoid syndrome.
The symptoms of carcinoid syndrome, including diarrhea, are
generally refractory to standard antidiarrheals or other traditional
medications but can often be well controlled with somatostatin
analogues (Fig. 89-7). Somatostatin is a 14-amino-acid peptide that
inhibits the secretion of a broad range of hormones. Due to its short
half-life, administration of somatostatin itself is not therapeutically
practical. Longer-acting somatostatin analogues, including octreotide
and lanreotide, share an 8-amino-acid binding domain with naturally
occurring somatostatin and bind primarily to somatostatin receptor
subtypes 2 and 5. Both have been shown to be effective in the treatment
of carcinoid syndrome.
The presence of somatostatin receptors on NETs is predictive of
response to somatostatin analogues and can be easily confirmed with
uptake on somatostatin scintigraphy such as 68GA dotatate PET scan.
Somatostatin analogue side effects are generally mild. Mild nausea,
abdominal discomfort, bloating, and loose stools occur in up to onethird of patients during the first month or two of treatment but usually
subsequently subside. Patients with persistent symptoms of bloating
or loose stools may be experiencing pancreatic insufficiency associ­
ated with use of somatostatin analogues; use of pancreatic enzyme
supplements can ameliorate these symptoms. Mild glucose intoler­
ance may also occur due to inhibition of insulin secretion. One of the
more significant side effects associated with somatostatin analogues
is impaired gallbladder contractility, resulting in delayed gallbladder
emptying, and long-term administration of somatostatin analogues
has been associated with an increased risk of cholelithiasis. For this
reason, patients with advanced NETs in whom surgery is planned and
for whom somatostatin analogue therapy is being considered should
generally also undergo prophylactic cholecystectomy.
Over time, for reasons that remain uncertain, patients receiving
somatostatin analogues for symptoms of hormone secretion may
become refractory to treatment. Not uncommonly, such patients
experience symptom exacerbation toward the final week of each treat­
ment cycle. Such patients may benefit from an increased frequency of
administration (i.e., every 3 weeks) or use of additional short-acting
octreotide for breakthrough symptoms.
The association between high levels of circulating serotonin and
symptoms of the carcinoid syndrome has also led to efforts aiming to
directly inhibit serotonin synthesis (Fig. 89-6). This approach was first
undertaken in the late 1960s with the drug para-chlorophenylalanine,
which was reported to reduce symptoms of carcinoid syndrome but also
caused significant central nervous system (CNS) side effects. Telotristat
ethyl, a tryptophan hydroxylase inhibitor with minimal CNS penetra­
tion, was evaluated in a randomized trial that enrolled 135 patients
with persistent carcinoid syndrome–related diarrhea while receiving
somatostatin analogues. Treatment with telotristat ethyl was associated
with a reduction in bowel movement frequency as well as significant
decreases in urinary 5-HIAA compared to placebo, consistent with its
mechanism of directly inhibiting serotonin synthesis. Thus, telotristat
is a treatment option for patients with carcinoid syndrome who have
persistent diarrhea despite treatment with somatostatin analogues.
■
■CARCINOID CRISIS
Carcinoid crisis has been described in the setting of tumor manipula­
tion during surgery and, less commonly, after other interventions such
as hepatic artery embolization or radionuclide therapy. It may also
occur as a result of exogenous administration of epinephrine or during
Gly
Cys
Ala
s
s
Cys
Thr
Phe
Ser
Native somatostatin-14
D-Phe
Cys
Phe
D-BNAL
Cys
D-Trp
s
s
s
s
Lys
Cys
Thr
Thr
Cys
Thr
Octreotide
Lanreotide
FIGURE 89-7  Somatostatin analogues. Commonly used somatostatin analogues include octreotide and lanreotide, which mirror the molecular structure of human
somatostatin and bind to somatostatin receptors on neuroendocrine tumors. Somatostatin analogues inhibit tumoral hormone secretion and also have an antiproliferative
effect. Radiolabeled somatostatin analogues such as 177Lu-DOTA-octreotate, shown in the figure, share a similar molecular structure and are used therapeutically.
induction of anesthesia. It is most common in patients who already
have significant symptoms of carcinoid syndrome and is thought to
be caused by a sudden release of biologically active compounds from
the tumor. Carcinoid crisis can be life-threatening and can manifest as
either profound hypotension or hypertension. Prospective studies on
the prevention and management of carcinoid crisis are limited; how­
ever, somatostatin analogues should be readily available during surgical
procedures, and in some cases, continuous prophylactic intravenous
administration of somatostatin analogues has been utilized as a way
to mitigate risk.
■
■CARCINOID HEART DISEASE
Carcinoid heart disease occurs in approximately two-thirds of patients
with the carcinoid syndrome. Carcinoid heart lesions are characterized
by plaque-like, fibrous endocardial thickening that classically involves
the right side of the heart and often causes retraction and fixation of the
leaflets of the tricuspid and pulmonary valves (Fig. 89-8). The fibrosis
in carcinoid heart disease is thought to be directly related to exposure
of heart valve fibroblasts to high circulating levels of serotonin. Lesions
FIGURE 89-8  Carcinoid heart disease. Fibrosis secondary to elevated levels of
circulating serotonin classically involves the tricuspid valve, resulting in valve
retraction and tricuspid regurgitation.
Asn
Phe
Lys
Phe
Trp
Lys
Thr
D-Phe Cys
Tyr
HN
HOOC
Tyr
O
D-Trp
N
N
s
D-Trp
177Lu
s
Lys
N
N
Lys
Thr
Cys
Thr
Val
HOOC
COOH
177Lu-DOTA-Tyr3-Octreotate
CHAPTER 89
similar to those observed in carcinoid heart disease were observed
in patients receiving fenfluramine, a drug also known to increase
serotonin signaling, as well as in patients receiving ergot-containing
dopamine receptor agonists for Parkinson’s disease. Metabolites of
fenfluramine, as well as the dopamine receptor agonists, have high
affinity for serotonin receptor subtype 5-HT2B receptors, whose activa­
tion is known to cause fibroblast mitogenesis and which are normally
expressed in heart valve fibroblasts. These observations support the
hypothesis that serotonin overproduction in patients with carcinoid
syndrome mediates the valvular changes by activating 5-HT2B receptors
in the endocardium.
Gastrointestinal Neuroendocrine Tumors
Tricuspid regurgitation is a nearly universal feature of carcinoid
heart disease; tricuspid stenosis, pulmonary regurgitation, and pulmo­
nary stenosis may also occur. Left-sided heart disease occurs in <10%
of patients and has been associated with the presence of a patent fora­
men ovale. The preponderance of lesions in the right heart is related
directly to the fact that serotonin is secreted by liver metastases or
retroperitoneal tumor deposits into the venous circulation and subse­
quently into the right atrium and right ventricle. The lower incidence
of heart disease in the left heart is postulated to be due to the fact that
serotonin is metabolized in the pulmonary vasculature before entering
the left atrium and ventricle. Among patients with carcinoid syndrome,
patients with heart disease exhibit higher levels of serum serotonin and
urinary 5-HIAA excretion than patients without heart disease. Treat­
ment with somatostatin analogues resulting in decreased serotonin
secretion does not result in regression of cardiac lesions. Reduction of
serotonin levels as a result of treatment with somatostatin analogues or
with the tryptophan hydroxylase inhibitor telotristat ethyl seems likely
to slow progression of carcinoid heart disease but has not been formally
evaluated in clinical trials.
Right-sided heart failure in patients with carcinoid heart disease may
lead to significant morbidity and mortality. The development of mul­
tiple new treatments to improve overall disease control in patients with
advanced NETs has led to increased interest in valvular replacement, which
may result in significant clinical benefit in appropriately selected patients
with carcinoid heart disease. The appropriate timing of valve replace­
ment in such patients can be challenging given the competing desires to
perform surgery before the onset of severe right-sided heart failure, which
can increase surgical morbidity, and the need to achieve adequate overall
tumor control. However, advanced and less invasive techniques, includ­
ing catheter-based valve replacement, have made valve replacement an
increasingly attractive option for patients with this condition.
HEPATIC-DIRECTED THERAPY FOR
METASTATIC NETS
The liver is one of the most common sites for metastases in patients
with NETs and, in some cases, is the only site of metastatic disease.
Hepatic-directed therapies can often be effective as a means of control­
ling, if not eliminating, metastases, particularly in patients who have
more indolent tumors with well-differentiated histology. Common
approaches for such patients include surgical resection, ablation or
embolization, and orthotopic liver transplantation.
For patients with limited hepatic disease whose tumors have welldifferentiated histology, surgical resection is generally considered the
preferable option. While data are limited to retrospective series with
the consequent risk of selection bias, long-term survival durations and
symptomatic improvements reported in select populations of patients
undergoing hepatic resection of neuroendocrine liver metastases
compare favorably with outcomes associated with other management
approaches, and 5-year survival rates approach 90% in some series. In
patients in whom anatomy precludes resection or in whom a greater
number of lesions are present, radiofrequency ablation or cryoabla­
tion can also be used, either as a primary treatment modality or as an
adjunct to surgical resection. While ablation is considered to be less
morbid than hepatic resection, it is generally utilized only in smaller
tumors so that zones of ablation are limited.
PART 4
Oncology and Hematology
In most cases, however, liver metastases are large, multiple, and
involve both lobes of the liver. In such cases, the benefit of surgical
resection and ablation is limited. Hepatic arterial embolization can be
considered in these cases, assuming that extrahepatic disease remains
relatively limited and that clinical benefit can be achieved by reduc­
ing hepatic tumor bulk. Hepatic artery embolization is based on the
principle that tumors in the liver derive most of their blood supply
from the hepatic artery, whereas healthy hepatocytes derive most of
their blood supply from the portal vein. Multiple different emboliza­
tion techniques have been explored, ranging from the simple infusion
of gel foam powder into the hepatic artery (bland embolization) to the
administration of chemotherapy or chemotherapy-eluting beads into
the hepatic artery (chemoembolization) or the intra-arterial admin­
istration of radioisotope-tagged microspheres (radioembolization).
Limited data suggest an optimal approach to embolization, and few
studies have compared these approaches directly. Tumor response rates
with all of these approaches generally exceed 50%. Specific approaches
are therefore often tailored to the patient, taking into account tumor
location, overall tumor burden, and comorbidities. Bland emboliza­
tion, for example, may be associated with less morbidity, whereas che­
moembolization or radioembolization may result in longer durations
of response.
The role of orthotopic liver transplantation for the treatment of
NETs remains uncertain. Data from available institutional series sug­
gest that a small number of highly selected patients may achieve longterm survival. However, 5-year overall median survival durations in
most series are ~50%, and the majority of patients undergoing hepatic
transplantation develop tumor recurrence. Additionally, the wide­
spread utility of hepatic transplantation is limited by organ availability.
Decisions regarding proceeding with transplantation in patients with
advanced NETs are therefore highly individualized.
SYSTEMIC TREATMENT TO CONTROL
TUMOR GROWTH
While hepatic-directed therapies can be effective in the management
of patients with liver-predominant disease, a majority of patients will
either present with or ultimately develop more widespread metastases.
A number of systemic treatment options have been developed and can
be effective in treating such patients. These options include treatment
with traditional somatostatin analogues, peptide receptor radioligand
therapy, traditional cytotoxic chemotherapy, and an increasing array of
molecularly targeted therapies targeting the mTOR or vascular endo­
thelial growth factor (VEGF) pathways (Table 89-3). The choice and
sequence of therapy depend in part on the type of tumor, the extent of
disease, and patient symptoms and comorbidities.
TABLE 89-3  Selected Randomized Trials of Therapeutic Agents for the
Treatment of Advanced Neuroendocrine Tumors (NETs)
NUMBER OF
PATIENTS
PROGRESSION-FREE
SURVIVAL
TUMOR TYPE
Pancreatic and Extrapancreatic NETs
Lanreotide vs placebo
(CLARINET)
65% vs 33% at 2 years
(p <.001)
177-Lutetium dotatate vs
octreotide (NETTER 2)
226 (limited to
histologic grade 2
and 3 tumors)
22.8 vs 8.5 months (p <.0001)
Cabozantinib vs placebo
(CABINET)
298 (203
extrapancreatic
NETs [epNET] and
95 pancreatic NETs
[pNET])
8.5 vs 4 months (epNET);
13.8 vs 4.5 months (pNET)
(p <.0001 for both cohorts)
Pancreatic NET
Everolimus vs placebo
(RADIANT 3)
11 vs 4.6 months (p <.001)
Sunitinib vs placebo
11.4 vs 5.5 months (p <.001)
Surufatinib vs placebo
10.9 vs 3.7 months (p = .001)
Temozolomide/
capecitabine vs
temozolomide
22.7 vs 14.4 months (p = .021)
Extrapancreatic NET
Octreotide vs placebo
(PROMID)
14.3 vs 6 monthsa
Everolimus + octreotide vs
octreotide (RADIANT 2)
16.4 vs 11.3 months
Everolimus vs placebo
(RADIANT 4)
11 vs 3.9 months
Surufatinib vs placebo
9.2 vs 3.8 months (p <.0001)
Pazopanib vs placebo
11.6 vs 8.5 months (p <.0005)
177-Lutetium dotatate vs
octreotide (NETTER 1)
65.2 vs 10.8% at 20 months
(p <.001)
aTime to tumor progression.
■
■SOMATOSTATIN ANALOGUES
Somatostatin analogues were originally developed as a treatment to
reduce hormone secretion in NETs but are also effective in slowing
tumor growth. The biologic mechanisms underlying this effect remain
uncertain, but clinical studies have been definitive. The first of these
studies, the PROMID study, randomized patients with metastatic
small-intestinal NET to receive either octreotide LAR at a dose of
30 mg monthly or placebo. The median time to tumor progression
in patients receiving octreotide was 14 months compared to only 6
months for patients receiving placebo. Because the study was limited
to patients with small-intestinal NET, the generalizability of these
results to patients with NETs of other origins, including pancreatic
NET, was initially uncertain. This question was ultimately addressed
by the phase 3 CLARINET trial, which compared lanreotide, a soma­
tostatin analogue that is similar to octreotide in its somatostatin
receptor–binding affinities, to placebo in 204 patients with a range of
advanced well- or moderately differentiated gastroenteropancreatic
NETs. Progression-free survival duration at 2 years was 65% in patients
receiving lanreotide and 33% in patients receiving placebo, a difference
that was statistically significant. One unusual aspect of the PROMID
and CLARINET studies is the difference in progression-free survival
durations in the placebo arms of the studies, which has been attributed
to differences in patient selection. Either octreotide or lanreotide is
currently considered an acceptable option for control of tumor growth
in patients with advanced NETs.
The timing of initiation of somatostatin analogues in patients with
advanced NETs remains uncertain. The variable clinical course of
NETs means that tumors can remain indolent for years even without
treatment. For patients with asymptomatic, small-volume disease,
observation alone may be an appropriate initial option. However, for
patients with a larger disease burden, evidence of disease progression,
or symptomatic disease, somatostatin analogues are generally used as
an initial systemic treatment due to their ease of use and tolerability.
■
■PEPTIDE RECEPTOR RADIOLIGAND THERAPY
Peptide receptor radioligand therapy employs the systemic administra­
tion of radiolabeled somatostatin analogues and is a treatment option
for patients who require more aggressive treatment due to progression
on traditional somatostatin analogues or other therapies (Fig. 89-7).
Peptide receptor radioligand therapy may also be considered as an
initial treatment in patients with significant symptoms or tumor bur­
den. With this approach, a radioligand is coupled to a somatostatin
analogue, using the somatostatin analogue to target the tumor. When
bound to the tumor cell, the radioligand is then internalized, resulting
in cell death. Due to its mechanism of action, peptide receptor radioli­
gand therapy is only considered in patients whose tumors demonstrate
uptake on somatostatin scintigraphy.
Several different radioligands have been evaluated, the most suc­
cessful of which have been yttrium (90Y) and lutetium (177Lu). These
two ligands differ from one another in terms of their particle energy
and tissue penetration; of the two, 90Y-DOTA-TOC emits higherenergy β particles and has deeper tissue penetration. 90Y-DOTA-TOC
has been evaluated in numerous series with overall tumor responses
reported in approximately one-third of patients. Enthusiasm for this
approach, however, has been tempered due to concerns about side
effects including both renal and hematologic toxicity.
177Lu-DOTA-octreotate emits both β particles and lower-energy γ
particles and, in most studies, has been associated with less toxicity
than 90Y-DOTA-TOC. Initial single-center studies with 177Lu-DOTAoctreotate showed promising antitumor activity, and based on these
studies, a randomized trial of 177Lu-dotatate in midgut GI NETs was
undertaken. In this study (NETTER-1), 229 patients with inoper­
able, somatostatin receptor–positive midgut NETs were randomly
assigned to receive either four doses of 177Lu-dotatate administered
intravenously every 8 weeks or treatment with high-dose octreotide
LAR (60 mg) every 4 weeks. Treatment with 177Lu-dotatate was associ­
ated with objective tumor responses in 18% of patients and also was
associated with a significant improvement in progression-free survival:
progression-free survival at month 20 was 10.8% for octreotide LAR
alone and 65.2% in the 177Lu-dotatate group. Subsequent analyses have
also suggested improved overall survival associated with 177Lu-dotatate
treatment, as well as improvements in quality of life across a number of
parameters, including global health status, overall physical functioning,
fatigue, pain, and diarrhea.
One limitation of the NETTER-1 study was its restriction to patients
with advanced small intestine NETs with low-grade histology. A subse­
quent study, NETTER-2, randomized 226 patients with a broader range
of gastroenteropancreatic neuroendocrine tumors that were higher
grade (grade 2 or 3) to receive treatment with 177Lu-dotatate or octreo­
tide alone. This study confirmed the activity of 177Lu-dotatate in this
patient population; median progression-free survival was 22.8 months
for patients receiving 177Lu-dotatate and 8.5 months for patients receiv­
ing octreotide alone.
The renal clearance of radiopeptides, including 177Lu-DOTA-octreo­
tate, poses a risk of renal toxicity; this risk can be mitigated with the
coadministration of intravenous amino acids during treatment. Longerterm safety data are available from large institutional series that include
1000 patients. Reported toxicities from these series have included rare
cases of acute leukemia and myelodysplastic syndrome, presumably
associated with radiation exposure. Nevertheless, these studies generally
support both the efficacy and safety of 177Lu-dotatate as a treatment for
patients with a range of somatostatin receptor–positive NETs.
■
■ALKYLATING AGENTS
While the efficacy of traditional cytotoxic chemotherapy appears to
be minimal in most extrapancreatic GI NETs, alkylating agents have a
clear role in the treatment of advanced pancreatic NETs. Streptozocinbased combination therapy was historically used as treatment standard
in such patients but has largely fallen out of favor due to both toxicity
concerns and a cumbersome administration schedule. Temozolomide
is an orally administered alkylating agent that has largely replaced
streptozocin as a backbone in combination regimens used for the treat­
ment of pancreatic NETs.
Initial studies evaluating temozolomide in combination with a range
of different agents showed that temozolomide-based combination ther­
apy was associated with tumor responses in 24–70% of patients. One
of the most active combination regimens appeared to be temozolomide
and capecitabine. This combination was subsequently compared to
temozolomide alone in a prospective randomized study undertaken by
the Eastern Cooperative Oncology Group (ECOG) that enrolled 144
patients with advanced pancreatic NETs. The overall response rates
in the two arms were relatively similar; 33% of patients who received
the combination of temozolomide and capecitabine experienced
objective tumor responses as compared to 28% of the patients who
received temozolomide as a single agent. However, progression-free
survival was significantly longer in the combination arm (22.7 vs 14.4
months). Based on these results, the combination of temozolomide
and capecitabine is now the preferred chemotherapy combination for
advanced pancreatic NETs.
The reason that some pancreatic NETs respond to alkylating agents
while others do not is uncertain. In patients with glioblastoma, methyl­
ation of the promoter region for methylguanine DNA methyltransfer­
ase (MGMT) is associated with decreased MGMT protein expression
and is highly associated with temozolomide responsiveness. MGMT
is an enzyme that is responsible for repairing DNA damage induced
by alkylating agents. Reduced levels of MGMT presumably impair the
ability of tumor cells to repair their DNA in response to treatment and
enhance the cytotoxicity of temozolomide. Several retrospective stud­
ies, as well as data from the prospective ECOG study, have suggested
that lack of MGMT expression in pancreatic NET may be associated
with responsiveness to temozolomide-based therapy, although findings
have not been definitive.
CHAPTER 89
Gastrointestinal Neuroendocrine Tumors
SMALL-MOLECULE TYROSINE KINASE
INHIBITORS
The highly vascular nature of NETs combined with observations in
preclinical models that disruption of signaling pathways associated
with VEGF inhibits neuroendocrine cell growth prompted a number
of clinical trials evaluating therapeutic agents that inhibit the VEGF
pathway in both pancreatic and extrapancreatic NETs. The VEGF
pathway is activated through the binding of VEGF to its cell surface
receptor, which initiates an intracellular signaling cascade that pro­
motes angiogenesis as well as cell growth, proliferation, and survival.
Clinical trials of VEGF pathway inhibitors in NETs have included a
number of small-molecule tyrosine kinase inhibitors that, while they
differ to some extent in specificity, all have in common the property
targeting VEGFR2, the receptor isoform most strongly implicated in
promoting angiogenesis.
Sunitinib, a multitargeted tyrosine kinase inhibitor that inhibits a
range of growth factor receptors including VEGFR2, was one of the
first agents in this class found to have activity in pancreatic NETs. In
an initial phase 2 trial, sunitinib was administered to 109 patients with
either pancreatic or extrapancreatic NET. Of 61 patients with pancre­
atic NET enrolled in the study, 11 had evidence of an objective tumor
response. Based on these observations, sunitinib was evaluated in an
international, randomized trial in which continuous administration of
sunitinib (37.5 mg daily) was compared with placebo in 171 patients
with advanced, progressive pancreatic NET. The median progressionfree survival was significantly longer in patients treated with sunitinib
compared with patients treated with placebo (11.4 vs 5.5 months).
Common side effects associated with sunitinib included hypertension,
proteinuria, and fatigue.
A second VEGFR-targeted tyrosine kinase inhibitor, surufatinib,
was evaluated in a randomized trial in which 264 patients with
advanced pancreatic NETs from 21 centers in China were randomized
to receive either surufatinib, administered at a dose of 300 mg daily, or
placebo. Patients receiving surufatinib experienced a median progressionfree survival duration of 10.9 months, as compared to 3.7 months in
patients receiving placebo, closely mirroring the results of the earlier
sunitinib study. Cabozantinib, a tyrosine kinase inhibitor with activ­
ity against not only VEGFR but also c-MET and related growth factor
receptors, was evaluated against placebo in a randomized trial led by
the ALLIANCE cooperative group that included both pancreatic and
extrapancreatic NETs. Among the 95 pancreatic NET patients in the
study, median progression-free survival was 13.8 months for those
receiving cabozantinib and 4.5 months for those receiving placebo.
Other small-molecule tyrosine kinase inhibitors that have been evalu­
ated in smaller, single-arm studies and have shown activity in pancre­
atic NETs, include sorafenib, pazopanib, and axitinib.
Small-molecule tyrosine kinase inhibitors targeting the VEGF path­
way have also been evaluated in patients with advanced nonpancreatic
GI NET. In most of these studies, objective tumor response rates are
lower than those seen in pancreatic NET, though many of these initial
studies also revealed low rates of tumor progression and encouraging
progression-free survival durations, suggesting that these agents had
antitumor activity. Pazopanib was compared to placebo in a random­
ized study undertaken by the ALLIANCE cooperative group, which
enrolled 171 patients with nonpancreatic NETs. Patients treated with
pazopanib in this study had a superior progression-free survival com­
pared to those who received placebo (11.6 vs 8.5 months), a difference
that was statistically significant. Surufatinib was used in a randomized
study of 198 patients with extrapancreatic NETs; the median progres­
sion-free survival was 9.2 months in patients receiving surufatinib
and 3.8 months in those receiving placebo. The strongest results to
date have come from a randomized study of cabozantinib (see above)
that included 205 patients with extrapancreatic GI NET. In this study,
median progression-free survival was 8.5 months in the cabozantinib
arm as compared with 4 months in the placebo arm. Taken together
with the results in the pancreatic NET cohort (above), these results
provide a strong rationale for considering cabozantinib as a treatment
option for patients with both advanced pancreatic and nonpancreatic
GI NET.
PART 4
Oncology and Hematology
■
■mTOR INHIBITORS
mTOR is an intracellular protein kinase that has been implicated in
the regulation of a number of processes regulating cell growth in both
normal and malignant cells. It functions as a downstream component
of the PI3-AKT-mTOR pathway. This pathway is negatively regulated
by the tuberous sclerosis complex, comprising TSC1 and TSC2. An
association between the development of pancreatic NETs and inherited
mutations in TSC2 in patients with tuberous sclerosis complex was a
contributing factor to initial interest in exploring mTOR inhibition as
a therapeutic approach in this setting.
Following initial evidence of antitumor activity associated with
everolimus (10 mg daily) in an international, multicenter, phase 2 trial
of 160 patients, everolimus monotherapy (10 mg daily) was compared
with best supportive care alone in the RADIANT-3 trial that enrolled
410 patients with advanced progressing pancreatic NET. While overall
objective responses were uncommon, treatment with everolimus was
associated with a significant prolongation in median progression-free
survival (11.0 vs 4.6 months) compared to placebo, supporting its
use as a standard treatment to control tumor growth in patients with
advanced pancreatic NET. Common toxicities associated with evero­
limus are generally mild and can include stomatitis and rash; a more
severe but less common side effect is pneumonitis.
Everolimus was also associated with promising activity in early
phase 2 studies enrolling patients with extrapancreatic NET. The first
large, randomized study evaluating everolimus was the RADIANT-2
trial; 429 patients with advanced GI NETs were randomly assigned to
receive octreotide LAR (30 mg intramuscularly every 28 days) with or
without everolimus (10 mg daily). Treatment with everolimus in this
study was associated with an improvement in median progressionfree survival (16.4 vs 11.3 months), but the difference in this study
was of only borderline statistical significance. A second study, the
RADIANT-4 study, enrolled 302 patients with advanced NETs of
either GI (excluding pancreatic) or lung origin, randomizing them
to receive either everolimus or placebo. In this study, treatment with
octreotide was not required. As in the RADIANT-3 study, objective
tumor responses were uncommon; however, median progression-free
survival in patients who received everolimus was significantly longer
than in those who received placebo (11 vs 3.9 months). Based on the
results of this study, everolimus is considered a standard treatment for
control of tumor growth in extrapancreatic NETs.
■
■OTHER SYSTEMIC TREATMENTS FOR CONTROL
OF TUMOR GROWTH
Interferon α has been used as a treatment for advanced NETs for sev­
eral decades. With the development of newer approaches, its routine
use has diminished. The use of interferon α was based primarily on
observations in large, retrospective series where low-dose interferon
α was reported to both reduce symptoms of hormonal hypersecre­
tion and slow tumor progression. Interferon can be myelosuppres­
sive, requiring dose titration, and in some patients can induce both
fatigue and depression. Antitumor activity has also been reported with
oxaliplatin-based chemotherapy regimens. A combined analysis of two
phase 2 trials examining oxaliplatin-fluoropyrimidine chemotherapy
plus bevacizumab in advanced NET suggested antitumor activity for
these regimens; the benefit appeared to be greatest in patients with
intermediate-grade rather than low-grade tumors.
Treatment with immune checkpoint inhibitors has been found to
be effective across multiple cancer types. The role of immune check­
point inhibitors for the treatment of neuroendocrine tumors has not
yet been clearly established and appears to depend at least in part on
tumor grade. Immunohistochemical and transcriptomic profiling in
well-differentiated neuroendocrine tumors has revealed only low levels
of PD-1 and PD-L1 expression together with high levels of immuno­
suppressive gene expression in tumor-associated myeloid cells. The
KEYNOTE-158 study investigated the efficacy of pembrolizumab, a
monoclonal antibody targeting the checkpoint marker PD-1, in mul­
tiple cancers, including 107 patients with neuroendocrine tumors of
various sites. The overall tumor response rate in the neuroendocrine
tumor cohort was only 3.7%. Other immunotherapeutic approaches,
including use of chimeric antigen receptor T cells for the treatment of
neuroendocrine tumors, remain investigational.
■
■SYSTEMIC THERAPY FOR HIGH-GRADE
NEUROENDOCRINE CARCINOMA
High-grade NETs are relatively uncommon and tend to pursue an
aggressive clinical course. In contrast to well-differentiated neuroen­
docrine tumors, high-grade neuroendocrine carcinomas may, at least
in some cases, be quite responsive to immunotherapeutic approaches.
A basket trial evaluating a combination of the anti-CTLA-4 mono­
clonal antibody ipilimumab together with the anti-PD-1 monoclonal
antibody nivolumab enrolled 32 patients with poorly differentiated
nonpancreatic neuroendocrine tumors; the overall tumor response rate
was 44% in this cohort. Apart from these more recent immune-based
approaches, chemotherapy for advanced high-grade neuroendocrine
carcinoma has historically followed a paradigm analogous to that used
for small-cell carcinoma of the lung, with combinations of either cis­
platin or carboplatin administered together with etoposide generally
considered the preferred first-line approach. One of the most impor­
tant elements in determining the optimal chemotherapeutic approach
is assessing the Ki-67 proliferative index. A large retrospective series
that evaluated 252 patients with high-grade neuroendocrine carci­
noma found that the activity of platinum-based therapy was greatest
in patients who had a Ki-67 proliferative index of 55% or higher; in
these patients, the overall tumor response rate was 42%. In contrast, the
overall response rate in patients in whom the Ki-67 proliferative index
was <55% was only 15%.
Acknowledgment
Dr. Robert Jensen contributed this chapter in previous editions and some
material from his chapter is retained here.
■
■FURTHER READING
Caplin ME et al: Lanreotide in metastatic enteropancreatic neuroen­
docrine tumors. N Engl J Med 371:224, 2014.

19 - 90 Renal Cell Carcinoma
90 Renal Cell Carcinoma
Dasari A et al: Trends in the incidence, prevalence, and survival out­
comes for patients with neuroendocrine tumors in the United States.
JAMA Oncol 3:1336, 2017.
Kulke MH et al: Telotristat ethyl, a tryptophan hydroxylase inhibitor
for the treatment of carcinoid syndrome. J Clin Oncol 35:14, 2017.
Kunz PL et al: Randomized study of temozolomide or temozolomide
and capecitabine in patients with advanced pancreatic neuroendo­
crine tumors (ECOG-ACRIN E2211). J Clin Oncol 41:1359, 2023.
Patel SP et al: A phase II basket trial of dual anti-CTLA-4 and antiPD-1 blockade in rare tumors (DART SWOG 1609) in patients with
nonpancreatic neuroendocrine tumors. Clin Cancer Res 26:2290,
2020.
Raymond E et al: Sunitinib malate for the treatment of pancreatic neu­
roendocrine tumors. N Engl J Med 364:501, 2011.
Rindi G et al: A common classification framework for neuroendocrine
neoplasms: An International Agency for Research on Cancer (IARC)
and World Health Organization (WHO) expert consensus proposal.
Mod Pathol 31:1770, 2018.
Scarpa A et al: Whole genome landscape of pancreatic neuroendo­
crine tumors. Nature 543:65, 2017.
Strosberg J et al: Phase 3 trial of 177 Lu-dotatate for midgut neuroen­
docrine tumors. N Engl J Med 376:125, 2017.
Xu Z et al: Epidemiologic trends of and factors associated with overall
survival for patients with gastroenteropancreatic neuroendocrine
tumors in the United States. JAMA Network Open 4:e2124750, 2021.
Yao JC et al: Everolimus for advanced pancreatic neuroendocrine
tumors. N Engl J Med 364:514, 2011.
Robert J. Motzer, Martin H. Voss
Renal Cell Carcinoma
Renal cell carcinomas account for 90–95% of malignant neoplasms
arising from the kidney. Notable features include frequent diagnosis
without symptoms, resistance to cytotoxic agents, robust activity of
angiogenesis-targeted agents, immune infiltration commonly render­
ing tumors susceptible to checkpoint-directed immunotherapy, and a
variable clinical course for patients with metastatic disease, including
anecdotal reports of spontaneous regression. Most of the remaining
TABLE 90-1  Hereditary Renal Cell Tumors
SYNDROME
CHROMOSOME(S)
GENE
PROTEIN
KIDNEY TUMOR TYPE
ADDITIONAL CLINICAL FINDINGS
von Hippel-Lindau
syndrome
3p25
VHL
von Hippel-Lindau protein
Clear cell
Hemangioblastoma of the retina
and central nervous system;
pheochromocytoma; pancreatic and
renal cysts; neuroendocrine tumors
Hereditary papillary RCC
7p31
MET
MET
Papillary
Bilateral and multifocal kidney tumors
Hereditary
leiomyomatosis and RCC
(HLRCC syndrome)
1q42
FH
Fumarate hydratase
FH-deficient/HLRCC syndrome–
associated RCC
Birt-Hogg-Dubé syndrome 17p11
FLCN
Folliculin
Chromophobe; clear cell;
oncocytoma
Tuberous sclerosis
9q34
16p13
TSC1
TSC2
Hamartin
Tuberin
BAP1 tumor
predisposition syndrome
3p21
BAP1
BAP1
Mostly clear cell, but chromophobe
and papillary have also been
reported
Abbreviations: ESC, eosinophilic solid and cystic; FH, fumarate hydratase; HLRCC; hereditary leiomyomatosis and RCC; RCC, renal cell carcinoma; TSC, tuberous sclerosis.
5–10% of malignant neoplasms arising from the kidney are transitional
cell carcinomas (urothelial carcinomas) originating in the lining of the
renal pelvis. See Chap. 91 for transitional cell carcinomas.
■
■EPIDEMIOLOGY
The incidence of cancers of the kidney and renal pelvis rose for three
decades, reached a plateau of approximately 64,000 cases annually in
the United States between 2012 and 2018, but has since increased to
approximately 81,000 cases annually, resulting in close to 15,000 deaths
per year. It is the seventh most common cancer overall in the United
States, the sixth most common in males, and the ninth most common
in females; the male-to-female ratio is 2:1. Although this malignancy
may be diagnosed at any age, it is uncommon in those under 45 years,
and incidence peaks between the ages of 55 and 75 years. Many factors
have been investigated as possible contributing causes; associations
include cigarette smoking, obesity, and hypertension. Risk is also
increased for patients with polycystic kidney disease that has been
complicated by chronic renal failure.
Most cases of renal cell carcinoma (RCC) are sporadic, although
familial forms have been reported (Table 90-1). One well-established
example includes clear cell RCC arising in the context of von HippelLindau (VHL) syndrome, an autosomal dominant disorder. Genetic
studies identified the VHL gene on the short arm of chromosome 3.
Individuals with VHL syndrome have a 70% estimated lifetime risk of
developing clear cell RCC. Other VHL-associated neoplasms include
retinal hemangioma, hemangioblastoma of the spinal cord and cerebel­
lum, pheochromocytoma, and neuroendocrine tumors. Belzutifan, an
oral inhibitor of hypoxia-inducible factor (HIF-2α), is approved for
treatment of VHL-associated cancers. Birt-Hogg-Dubé syndrome is
a rare human autosomal dominant genetic disorder characterized by
fibrofolliculomas (benign tumors arising in hair follicles), pulmonary
cysts, and RCCs of varying histologies, most commonly the chromo­
phobe type, occurring in about a third of patients. This disorder is
associated with mutations in the FLCN gene, which codes for folliculin.
Other hereditary syndromes are summarized in Table 90-1.
CHAPTER 90
Renal Cell Carcinoma
■
■PATHOLOGY AND GENETICS
Renal cell malignancies represent a heterogeneous group of tumors
with distinct histopathologic, genetic, and clinical features (Table 90-2).
Categories include clear cell carcinoma (70% of cases), papillary RCC
(10–15%), chromophobe RCC (≤5%), molecularly defined entities
such as TFE3-rearranged RCC (<5%), and other less common vari­
ants. Papillary tumors can be bilateral and multifocal. Chromophobe
tumors tend to have a more indolent clinical course. TFE3-rearranged
RCC, rare in adult patients, is the predominant histology in chil­
dren. SMARCB1-deficient RCC, previously called renal medullary
Leiomyoma; uterine leiomyoma/
leiomyosarcoma
Facial fibrofolliculoma; pulmonary
cysts
Angiomyolipomas; TSC-associated
lymphangioleiomyomatosis; rare
RCC with variety of histologic
appearances including eosinophilic
solid and cystic (ESC) RCC
Angiofibroma, subungual fibroma;
cardiac rhabdomyoma; adenomatous
small intestine polyps; pulmonary
and renal cysts; cortical tuber;
subependymal giant cell astrocytomas
Atypical Spitz tumors; uveal melanoma;
cutaneous melanoma; basal cell
carcinoma; malignant mesothelioma
TABLE 90-2  Classification of Malignant Epithelial Neoplasms Arising from the Kidney
CARCINOMA TYPE
CHARACTERISTIC GROWTH PATTERN
CHROMOSOMAL EVENTS
Clear cell
Varying growth patterns, including acinar, solid
and sarcomatoid
Papillary
Papillary or sarcomatoid
+7, +17, 9p–
MET, CDKN2A (focal deletions)
Chromophobe
Solid, tubular, or sarcomatoid
Whole arm losses (1, 2, 6, 10, 13, 17,
and 21)
TFE3-rarranged and
TFEB-altered renal cell
carcinomas
Mimicking clear cell and papillary variants
Xp11.2 translocations; t(6;11)
translocations
SMARCB1-deficient renal
medullary carcinoma
Varying growth patterns, including cribriform,
reticular, sarcomatoid, adenoid, and microcystic
carcinoma, is rare, very aggressive, and associated with sickle cell trait.
Tumors that do not meet criteria for defined variants are generally
referred to as “unclassified” with variable clinical courses.
Clear cell tumors, the predominant histology, are found in >80%
of patients who develop metastases and arise from the epithelial cells
of the proximal tubules. Loss of chromosome 3p is uniformly seen as
the earliest event in the development of these cancers. This leads to
loss of heterozygosity for a number of relevant 3p genes, including
VHL, PBRM1, BAP1, and SETD2, which can be functionally silenced
through secondary events in the remaining allele. VHL encodes a
tumor-suppressor protein that is involved in regulating the transcrip­
tion of vascular endothelial growth factor (VEGF) and a number of
other effectors through ubiquitination of hypoxia-inducible factors
(HIF). Inactivation of VHL, through upregulation of VEGF signaling,
promotes tumor angiogenesis and growth, ultimately rendering clear
cell RCC cells susceptible to antiangiogenesis therapy.
PART 4
Oncology and Hematology
Large-scale sequencing efforts have helped elucidate recurrent
patterns of genomic evolution that correlate with distinct clinical
phenotypes, e.g., varying levels of aggressiveness or specific patterns of
metastatic spread. For example, early loss of chromosome 9p appears
to confer a high risk for early metastatic dissemination and correlates
with poor cancer-specific survival.
A growing number of other RCC variants are well defined (see Table
90-2 for examples) yet can further vary by molecular features. For
instance, up to 15% of RCCs are of the papillary subtype, and variant
features can be distinguished by light microscopy but also molecular
assays. Activating mutations in the MET oncogene or gain of chromo­
some 7 (where MET is located) are hallmark events of certain papil­
lary variants and considered actionable via targeted MET inhibitors.
Tumors of the less common chromophobe subtype originate from the
distal nephron. They are typically characterized by aneuploidy with
common loss of an entire chromosome copy for chromosomes 1, 2, 6,
10, 13, and 17.
■
■CLINICAL PRESENTATION
Presenting signs and symptoms may include hematuria, flank or
abdominal pain, and a palpable mass. Other symptoms are fever,
weight loss, anemia, and a varicocele. Tumors are, however, commonly
detected as an incidental finding on a radiograph. Widespread use
of radiologic cross-sectional imaging (computed tomography [CT],
magnetic resonance imaging [MRI]) contributes to earlier detection
of renal masses during evaluation for other medical conditions. The
increasing number of incidentally discovered low-stage tumors has
contributed to an improved 5-year survival for patients with RCC and
increased use of nephron-sparing surgery (partial nephrectomy). A
spectrum of paraneoplastic syndromes has been associated with these
malignancies, including erythrocytosis, hypercalcemia, nonmetastatic
hepatic dysfunction (Stauffer’s syndrome), and acquired dysfibrino­
genemia. Erythrocytosis is noted at presentation in only about 3% of
patients. Anemia, commonly a sign of more advanced disease, is more
common. Kidney cancer was called the “internist’s tumor” since it
was often discovered from the initial presentation of a paraneoplastic
GENES WITH RECURRENT SOMATIC
ALTERATIONS
3p–, 5q+, 14q–, 9p–
VHL, PBRM1, BAP1, SETD2
TP53, PTEN, TERT promotor
TFE3 gene fusions, TFEB gene fusions
+8q, 22q–, 22q translocations
SMARCB1 (focal deletions, mutations,
gene fusions), SETD2
syndrome. This was more common before the era of modern imaging,
as was initial presentation by the classic triad of hematuria, flank pain,
and a palpable abdominal mass.
The standard evaluation of patients with suspected renal tumors
includes a CT scan of the abdomen and pelvis, chest radiograph, and
urine analysis. If metastatic disease is suspected from the chest radio­
graph, a CT of the chest is warranted. MRI is useful in evaluating the
inferior vena cava in cases of suspected tumor involvement or invasion
by thrombus, or when intravenous contrast administration given with
CT is prohibited by impaired renal function. In clinical practice, any
solid renal masses should be considered malignant until proven
otherwise; a definitive diagnosis is required. If no metastases are dem­
onstrated, surgery is indicated, even if the renal vein or inferior vena
cava is invaded. In small tumors (particularly those of clear cell variant),
the risk of impending metastatic spread is lower and surgery can poten­
tially be delayed. In that setting, a needle biopsy should be performed
to confirm the underlying histology, and radiographic surveillance is
indicated until the time of surgery. The differential diagnosis of a renal
mass includes cysts, benign neoplasms (adenoma, angiomyolipoma,
oncocytoma), inflammatory lesions (pyelonephritis or abscesses), and
other malignancies originating in the kidney such as transitional cell
carcinoma of the renal pelvis, sarcoma, lymphoma, and Wilms’ tumor
or metastases from cancers originating in other organs. All of these are
less common causes of renal masses than is RCC. The most common
sites of distant metastases are the lungs, lymph nodes, liver, bone, and
brain. These tumors may follow an unpredictable and protracted clini­
cal course.
■
■STAGING AND PROGNOSIS
Staging is based on the American Joint Committee on Cancer (AJCC)
staging system (Fig. 90-1). Stage I tumors are ≤7 cm in greatest diameter
and confined to the kidney; stage II tumors are >7 cm and confined to
the kidney; stage III tumors extend through the renal capsule but are
confined to Gerota’s fascia, grossly infiltrate the renal vein, or involve
regional lymph nodes (N1); and stage IV disease includes tumors that
have invaded adjacent organs or involve nonregional lymph nodes or
distant metastases. Sixty-five percent of patients present with stage I
or II disease, 15–20% with stage III, and 15–20% with stage IV. The
5-year survival rate is currently 77% across all RCCs but varies greatly
by stage.
Prognostic risk models are helpful for counseling patients diagnosed
with metastatic disease and for anticipating survival rates when design­
ing a clinical trial. A widely used prognostic model for advanced dis­
ease, the International Metastatic RCC Database Consortium (IMDC)
risk model, incorporates six factors shown to correlate with worse sur­
vival: poor performance status, low hemoglobin concentration, high
serum calcium, high neutrophil levels, high platelet levels, and <1-year
interval from diagnosis to systemic treatment. Patients with zero risk
factors achieve significantly longer median survival (≥5 years) than
patients with one or two risk factors (~4 years) and those with three
to six risk factors (~3 years) when treated with first-line checkpoint
inhibitor–containing combination regimens (see below).
T1
T2
Involvement
TNM
TX
Primary not involved
T1
T1a
T1b
≤7 cm
≤4 cm
4 cm
T2
T2a
T2b
7 cm to ≤10 cm
7 cm
10 cm
T3
into major veins or perinephric tissues
T3a
in renal vein, renal sinus fat, or
pelvicalyceal system
T3b
T3c
into vena cava
into vena cava
T3
T4
T4
invasion beyond Gerota’s fascia
Regional
NX
Regional lymph nodes not assessed
N0
No regional lymph node involvement
N1
Regional lymph node involvement
Distant Metastases
M0
M1
No distant metastases
Distant metastases, including nonregional lymph nodes
FIGURE 90-1  Renal cell carcinoma staging. TNM, tumor-node-metastasis.
TREATMENT
Renal Cell Carcinoma
LOCALIZED TUMOR
The standard management for stage I or II tumors and selected
cases of stage III disease is radical or partial nephrectomy. A radical
nephrectomy involves en bloc removal of Gerota’s fascia and its con­
tents, including the kidney, and commonly the ipsilateral adrenal
gland and regional lymph nodes that appear abnormal on imaging
or intraoperatively. Open, laparoscopic, or robotic surgical tech­
niques may be used. The role of a template lymphadenectomy in
patients without apparent lymphadenopathy is controversial. Exten­
sion into the renal vein or inferior vena cava (stage III disease) does
not preclude resection, which would then include thrombectomy.
Nephron-sparing approaches, i.e., open or laparoscopic partial
nephrectomy, may be appropriate depending on the size and loca­
tion of the tumor. This approach is particularly relevant for patients
with solitary kidneys, bilateral tumors, or chronic renal insuf­
ficiency but can also be applied electively to resect small masses
for patients with normal kidney function. Radical nephrectomy
carries a greater risk for chronic kidney disease and cardiovascular
morbidity and mortality.
Adjuvant systemic therapies, including cytokines and targeted
agents, have been studied in randomized clinical trials, largely
with negative results. The checkpoint inhibitor pembrolizumab is
approved in patients with increased risk of recurrence following
nephrectomy, where 12 months of therapy was shown to improve
disease-free survival compared to placebo. For those with low risk
of recurrence, the standard of care remains active surveillance after
nephrectomy.
METASTATIC DISEASE
Surgery has a limited role for patients with metastatic disease.
Long-term survival may occur in patients who relapse with a soli­
tary site that is removed (metastasectomy). Nephrectomy despite
presence of metastases (cytoreductive nephrectomy) is considered
for carefully selected patients with stage IV disease. One indica­
tion for this approach can be to alleviate pain or hemorrhage of a
primary tumor.
Radiation therapy is used for palliation of bone or brain metas­
tases. The type of radiotherapy most commonly used is externalbeam therapy, including stereotactic radiosurgery and other forms
of image-guided radiotherapy.
Extent of Disease
Anatomic Stage/Prognostic Groups
I
N0
M0
T1
II
N0
M0
T2
III
N0 or N1
N1
M0
M0
T3
T1 or T2,
limited to kidney
IV
Any N
Any N
M0
M1
T4
Any T
limited to kidney
not beyond Gerota’s fascia
not beyond Gerota’s fascia
below diaphragm
above diaphragm
including contiguous extensions
& into ipsilateral adrenal gland
CHAPTER 90
Systemic therapy is the mainstay of care for metastatic disease.
The timing of initiating such treatment should be carefully con­
sidered; some patients are asymptomatic at diagnosis, and with
indolent behavior, it may be best to document progression before
initiating treatment.
Renal Cell Carcinoma
Metastatic RCC is refractory to cytotoxic chemotherapy. Patients
are treated with molecularly targeted agents, including targeted
immunotherapies, i.e., checkpoint inhibitors. Treatments are con­
tinued with noncurative intent while tolerated and until disease
progression is evident on cross-sectional imaging. Outcomes for
patients with metastatic disease improved when increased under­
standing of underlying biology led to the successful development
of several tyrosine kinase inhibitors (TKIs) targeting proangio­
genic signaling through the VEGF receptors as well as allosteric
inhibitors of mammalian target of rapamycin (mTOR) signaling.
Serial large-scale randomized trials demonstrated that such agents,
typically orally available, could be administered sequentially and
in combination. Pivotal studies, by design, defined a dedicated
space for each regimen in treatment-naïve or pretreated patients
(Table 90-3).
Targeted immunotherapies were introduced after VEGF- and
mTOR-directed agents had established standards of care in the
first- and second-line setting. Nivolumab, a checkpoint inhibitor
targeting PD-1, demonstrated superior overall survival compared
to the mTOR inhibitor everolimus in a randomized trial in patients
who had progressed on prior TKI therapy, challenging the standard
approach in pretreated patients and positioning nivolumab as the
new second-line agent of choice. Subsequently, immunotherapy
combination regimens demonstrated efficacy in randomized trials
conducted in treatment-naïve patients. In separate studies, four
doublets demonstrated survival benefit over standard sunitinib
therapy and changed the standard of care for untreated metastatic
clear cell RCC toward two-drug, immunotherapy-containing regi­
mens: nivolumab in combination with the CTLA-4–directed check­
point inhibitor ipilimumab; the TKI axitinib together with the PD-1
inhibitor pembrolizumab; the TKI cabozantinib plus nivolumab;
and the TKI lenvatinib paired with pembrolizumab. These combi­
nations demonstrated objective radiographic responses in 40–70%
of patients, and complete radiographic disappearance of cancer is
achieved in about 10% of patients. The majority of such anticancer
effects were reported to be long-lasting.
With an ever-growing number of approved options directed
toward different molecular targets, biomarkers are urgently needed
to help individualize therapeutic choices and to gain insight as to

20 - 91 Cancer of the Bladder and Urinary Tract
91 Cancer of the Bladder and Urinary Tract
TABLE 90-3  Commonly Used Systemic Regimens for Metastatic Renal Cell Carcinoma
CLASS
DRUG
Antiangiogenic: TKIs
Sunitinib
Advanced RCC, first line
Pazopanib
Advanced RCC, first line
Axitinib
Advanced RCC, pretreated
Cabozantinib
Tivozanib
Advanced RCC, pretreated with two or more prior
systemic therapies
Immunotherapy: checkpoint inhibitor
Nivolumab
Advanced RCC, pretreated with antiangiogenic therapy
Combination therapies
  TKI + mTOR inhibitor
Lenvatinib + everolimus
Advanced RCC, pretreated with one antiangiogenic
therapy
  PD-1 inhibitor + CTLA-4 inhibitor
Nivolumab + ipilimumab
Advanced intermediate-risk or poor-risk RCC, first line
  PD-1 inhibitor + TKI
Pembrolizumab + axitinib
Advanced RCC, first line
Nivolumab + cabozantinib
Advanced RCC, first line
Pembrolizumab + lenvatinib
Advanced RCC, first line
Abbreviations: CTLA-4, cytotoxic T lymphocyte-associated protein; FDA, U.S. Food and Drug Administration; mTOR, mammalian target of rapamycin; PD-1, programmed cell
death-1; RCC, renal cell carcinoma; TKI, tyrosine kinase inhibitor.
PART 4
Oncology and Hematology
whether and why treatments are working. Although a multitude of
candidate biomarkers have been investigated for their predictive value
in metastatic RCC, none have been validated for clinical use to date.
Projected overall survival in patients starting systemic therapies
for newly diagnosed metastatic disease has tripled over the past
15–20 years; this can largely be attributed to the successful drug
developments discussed here.
■
■GLOBAL CONSIDERATIONS
Worldwide, >400,000 patients are diagnosed each year with malignant
tumors arising from the kidney, resulting in >175,000 deaths annu­
ally. Kidney cancer is the sixth most common cancer in men and the
10th most common cancer in women. Higher incidence is observed
in developed countries, including the United States, Canada, Europe,
Australia, New Zealand, and Uruguay. Lower rates are reported in
Southeast Asia and Africa, though it is speculated that these rates
may be underreported due to lack of disease-reporting structure and
reduced access to diagnostic facilities. The incidence of kidney cancer
has been steadily increasing over the past four decades. Mortality
trends have stabilized in Europe and the United States, but not in less
developed countries. This is likely related to differences in access to
optimal therapies. Treatment guidelines for both localized and meta­
static renal cancer are similar between U.S. and European documents
and contingent on the access to adequate health care and availability of
targeted drugs to treat metastases.
■
■FURTHER READING
Choueiri TK et al: Adjuvant pembrolizumab after nephrectomy in
renal-cell carcinoma. N Engl J Med 385:683, 2021.
Choueiri TK et al: Nivolumab plus cabozantinib versus sunitinib for
advanced renal-cell carcinoma. N Engl J Med 384:829, 2021.
Huang J et al: A global trend analysis of kidney cancer incidence and
mortality and their associations with smoking, alcohol consumption,
and metabolic syndrome. Eur Urol Focus 8:200, 2022.
Jonasch E et al: Belzutifan for renal cell carcinoma in von Hippel–
Lindau Disease. N Engl J Med 385:2036, 2021.
Moch H et al: The 2022 WHO classification of tumours of the urinary
system and male genital organs—Part A: renal, penile, and testicular
tumours. Eur Urol 82:458, 2022.
Motzer RJ et al: Molecular subsets in renal cancer determine outcome
to checkpoint and angiogenesis blockade. Cancer Cell 38:803, 2020.
Motzer RJ et al: Nivolumab plus ipilimumab versus sunitinib in
advanced renal-cell carcinoma. N Engl J Med 378:1277, 2018.
FIRST FDA APPROVAL
FOR RCC
CURRENTLY USED FOR
Advanced RCC, pretreated with antiangiogenic therapy
Advanced RCC, first line
Noah M. Hahn
Cancer of the Bladder
and Urinary Tract
GLOBAL CONSIDERATIONS
Within the United States, urothelial carcinomas of the bladder and
urinary tract are most closely related to tobacco smoking history.
However, within developing countries, water supplies contaminated
with arsenic or schistosomiasis parasites also are major carcinogenic
contributors.
INTRODUCTION
Cancers of the urinary tract including the bladder, renal pelvis, ureter,
and urethra occur frequently, and they represent the second most com­
mon class of genitourinary cancers. Bladder cancer alone represents
the sixth most common cancer diagnosis annually in the United States
with 82,290 new cases and 16,710 deaths every year. Because cancers
of the renal pelvis are often lumped in with all kidney cancers, the true
incidence and mortality from nonbladder urinary tract cancers are less
precise. While less frequent than bladder cancer, an additional 20,000
new cases and 5000 deaths are estimated every year. An accelerated
understanding of the molecular underpinnings of bladder and uri­
nary tract cancer biology has led to a significant increase in urothelial
cancer clinical trials resulting in U.S. Food and Drug Administration
(FDA) approval of multiple new therapeutic agents since 2016 with
more expected to follow. This chapter reviews the established, current,
and emerging evidence that serves as the basis for the rapidly evolving
standards of care for patients with bladder and urinary tract cancers.
■
■CLINICAL EPIDEMIOLOGY AND RISK FACTORS
Bladder cancer typically affects older patients with a median age at
diagnosis of 73 years. Males are four times more frequently affected
than females. Similarly, bladder cancer is more common in Caucasians
than in Asian patients. Inheritable germline genetic risk factors have
been observed in up to one-seventh of patients with bladder or urinary
tract cancers. However, a predominant, singular germline genetic alter­
ation has not been identified. Patients with defects in mismatch repair
genes leading to microsatellite instability (MLH1, MSH2, MSH6, etc.)
as part of the familial cancer Lynch syndrome are at particular risk of
upper urinary tract cancers of the renal pelvis and ureter. Additionally,
patients with Cowden disease (PTEN mutations) or retinoblastoma
(RB1 mutations) are at increased risk for developing bladder cancer.
Historically, associations have existed between environmental toxic
exposures and higher rates of developing bladder cancer. The aromatic
amines benzidine and β-naphthylamine that can be present in indus­
trial dyes as well as arsenic that can be found in drinking water supplies
in underdeveloped countries have been associated with increased blad­
der cancer risk. Other chemicals in the leather, paint, rubber, textiles,
and printing industries have been associated with bladder cancer.
Associations with exposures to hair dyes and hair sprays in workers
in the hairstyling field have been suggested. Additionally, concern has
been raised regarding use of the antidiabetic medication, pioglitazone,
and bladder cancer risk. Extensive reviews and meta-analyses have
produced differing conclusions. The data suggest a small risk of blad­
der cancer from long-term pioglitazone use, which has led to inclusion
of bladder cancer risk within the pioglitazone prescribing information.
An association between chronic inflammatory states and the develop­
ment of squamous bladder cancer clearly exists in underdeveloped
countries in patients chronically infected with the parasitic disease
schistosomiasis and in paraplegic patients with chronic indwelling
catheters. Above and beyond each of these associations, however,
smoking of tobacco products (cigarettes, cigars, pipes, etc.) remains the
overwhelming leading risk factor for development of bladder cancer.
Among new bladder cancer diagnoses, 90% of cases occur in current or
former smokers. Toxicologists have estimated that >70 confirmed car­
cinogenic toxins are present within tobacco smoke. It is estimated that
one-third of bladder cancer cases could be prevented through simple
modification of lifestyle choices, in particular cessation of smoking.
■
■CLINICAL PRESENTATION AND DIAGNOSTIC
WORKUP
Occasionally, patients will present with flank pain in association with
an upper tract renal pelvis or ureter cancer or due to hydronephrosis
in association with a bladder tumor obstructing the orifice of the ureter
within the bladder. Only in rare cases do patients present with sig­
nificant cachexia and widespread metastatic disease. For most patients,
painless hematuria (either gross or microscopic) represents the ini­
tial manifestation of an underlying urinary tract cancer. In females,
hematuria due to malignancy can often be mistaken for a urinary tract
infection or menstrual bleeding. While treatment with antibiotics is
warranted if a concurrent urinary tract infection is noted on initial
urinalysis, persistent hematuria requires further workup. Painless
hematuria in males is almost always abnormal and should be worked
up. Initial investigations in patients of either sex should include urine
cytology and visual examination of the bladder by cystoscopy. Cytology is
successful in identifying cancer in only 50% of individuals with highgrade bladder cancers. In addition to urine cytology, radiographic eval­
uation of the kidneys and upper urinary tract by CT urogram should be
performed. A magnetic resonance (MR) urogram may be substituted
in patients with poor renal function. Additional diagnostic testing
of the urine to assess for cancer-associated chromosomal changes by
fluorescent in situ hybridization, increased levels of nuclear mitotic
proteins, increased bladder tumor–associated antigens, or higher levels
of staining on cells shed by the bladder may identify some cancers
missed by traditional cytology testing. However, they may also produce
abnormal results in patients who do not have cancer. For now, these
adjunct molecular tests are primarily utilized in detecting recurrent
cancer in patients with a prior diagnosis of urinary tract cancer. Small
tumors, particularly flat noninvasive tumors of the bladder, may be
detected at higher rates with the use of blue light cystoscopy or narrowband imaging cystoscopy. Both blue light and narrow-band imaging
cystoscopies are now used routinely in the monitoring of patients with
bladder cancer. For patients with no bladder abnormalities in whom
upper tract tumors are suspected, visualization of the upper urinary
tracts and renal pelvises should be performed by ureteroscopy or ret­
rograde pyelography.
In all patients with abnormalities noted in the bladder or upper
urinary tracts, complete endoscopic resection for histologic diagnosis
and staging should be performed when possible via either transurethral
resection of bladder tumor (TURBT) or endoscopic resection of upper
tract tumors. All metastatic patients should have genomic sequencing
performed on their tumor tissue, circulating tumor DNA (ctDNA),
or both. The role of genomic sequencing in earlier stages of disease is
evolving.
■
■HISTOLOGY
Urothelial carcinoma, often called transitional cell carcinoma in
the past, is the most common urinary tract cancer histology and is
observed in ~90% of cases. Squamous, glandular, micropapillary, plas­
macytoid, sarcomatoid, and other variant features can often be found
in portions of urothelial carcinoma tumors; however, pure variant
histologies are rare. The presence of some variant histologies includ­
ing micropapillary and plasmacytoid has been associated with worse
surgical outcomes compared to urothelial carcinoma. Nonurothelial
variant histologies including squamous cell carcinoma, adenocarci­
noma, small-cell carcinoma, and carcinosarcoma collectively account
for ≤10% of urinary tract tumors. Examples of traditional urothelial
carcinoma and some of the variant histologies are shown in Fig. 91-1.
■
■MOLECULAR BIOLOGY
Clinically, urothelial carcinoma of the bladder displays a biphasic phe­
notype characterized by (1) low-grade papillary tumors that frequently
recur but rarely invade or metastasize and (2) high-grade sometimes
flat tumors that invade early leading to lethal metastatic disease. In
both of these phenotypes, loss of portions of chromosomes 9q and
9p by loss of heterozygosity is an early molecular event, whose exact
significance is not clear. Potential candidate regulatory genes in these
genomic regions include CDNK2A, a cyclin-dependent kinase inhibi­
tor, and TSC1, a gene encoding hamartin mutated in tuberous sclerosis.
Genomic investigations have demonstrated that low-grade tumors
are characterized by alterations in the RAS/RAF signaling pathway
with activating FGFR3 mutations or gene fusions present in 60–80%
of patients. In contrast, the high-grade invasive phenotype is notable
for early deleterious mutations in TP53 and RB1, alterations in CDH1
(E-cadherin), and increased expression of VEGFR2. In urothelial car­
cinoma of the renal pelvis and ureter, 10–20% of cases may be associ­
ated with Lynch syndrome hereditary defects in the MLH1, MSH2,
or MSH6 mismatch repair genes, leading to microsatellite instability
and frequent DNA mutations. Testing for germline mutations in these
genes is recommended in patients with upper urinary tract urothelial
carcinoma under the age of 60 at diagnosis, with a first-degree relative
with a Lynch syndrome–associated cancer diagnosed under the age of
50, or with two first-degree relatives with a Lynch syndrome–associated
cancer regardless of the age at diagnosis.
CHAPTER 91
Cancer of the Bladder and Urinary Tract
As genomic analysis technologies have improved, so has our under­
standing of the molecular biology unique to urothelial carcinoma.
In 2017, the full bladder cancer results of The Cancer Genome Atlas
(TCGA) project were published. This effort comprehensively analyzed
gene mutations, fusions, expression, copy number variations, meth­
ylation, and microRNA across the genome of patients with bladder
urothelial carcinoma treated with surgery. Key findings from this effort
include (1) genomic alterations in genes (e.g., FGFR3, EGFR, ERBB2,
ERBB3, PIK3CA, TSC1, etc.) targetable by currently approved drugs
or drugs in development in 71% of patients; (2) genomic alterations
in chromatin-modifying genes (KMT2D, KDM6A, KMT2C, EP300,
CREBBP, etc.) in the majority of patients; (3) hypermethylation with
epigenetic silencing of gene expression in one-fourth of patients; and
(4) the identification by RNA sequencing of five distinct intrinsic
molecular subtypes (luminal papillary, luminal infiltrated, luminal,
basal squamous, and neuronal) closely resembling luminal and basal
subclassifications of breast cancers. These bladder TCGA findings
have led to clinical trial designs enriching for patients with specific
gene mutation profiles as well as interrogation of candidate biomarkers
according to intrinsic molecular subtypes.
■
■STAGING AND OUTCOMES BY STAGE
The staging of bladder cancer is dependent on the depth of invasion
within the bladder wall, involvement of lymph nodes, and spread to
A
B
PART 4
Oncology and Hematology
C
D
FIGURE 91-1  Bladder and urinary tract cancer histologies. A. Urothelial carcinoma. B. Squamous cell carcinoma. C. Small-cell carcinoma. D. Plasmacytoid variant.
(Courtesy of Alex Baras, MD, PhD, Johns Hopkins University Department of Pathology.)
surrounding and distant organs as depicted in Fig. 91-2. Approxi­
mately 75% of bladder cancer presents with non–muscle-invasive
bladder cancer (NMIBC), 18% with disease invading into or through
the muscular wall of the bladder, and only 3% with metastatic spread
to distant organs. NMIBC is defined by tumors that involve only the
immediate epithelial layer of cells (carcinoma in situ [CIS] and Ta) or
that only penetrate into the connective tissue below the urothelium
(T1) but not into the muscular layer known as the muscularis propria.
Muscle-invasive bladder cancer (MIBC) is defined by tumors that
invade into the muscularis propria (T2), through the muscularis
propria to involve the surrounding serosa (T3), or into immediately
adjacent pelvic organs such as the rectum, prostate, vagina, or cervix
(T4). Lymph node staging is classified according to involvement of a
solitary node within the true pelvis (N1), two nodes involved in the
true pelvis (N2), or involvement of the common iliac nodes (N3). Any
disease that has spread beyond the common iliac nodes is considered
metastatic (M1). The staging of bladder cancer is driven primarily
by the T stage of the tumor, with stages 0a–II defined entirely by the
T stage in the absence of nodal or metastatic disease. Involvement of
regional lymph nodes in the true pelvis or along the common iliac
artery qualifies as stage III disease, whereas involvement of any distant
metastases qualifies as stage IV disease. Clinical outcomes of patients
with bladder cancer correlate closely with staging at diagnosis with
5-year overall survival rates of 70–90% for disease confined to the
bladder (stage I–II), 39–50% for disease that penetrates through the
bladder or has spread to regional lymph nodes (stage III), and only 8%
for disease extending to metastatic sites (stage IV).
■
■TREATMENT APPROACHES
Early-Stage Disease 
For NMIBC, removal of all visible tumors by
TURBT in the operating room is considered the mainstay of surgical
treatment. Risk of recurrence can be classified as low, intermediate, or
high depending on the presence of features summarized in Table 91-1.
For patients with low-risk disease, meta-analyses have demonstrated a
12% reduction in early relapses when a single chemotherapy treatment
of mitomycin C, epirubicin, or gemcitabine was instilled directly into
the bladder (intravesical therapy) within 24 hours of the TURBT. For
patients with intermediate- or high-risk tumors, weekly intravesical
instillations for 6 consecutive weeks of the attenuated mycobacte­
rium strain known as Bacille Calmette-Guérin (BCG) reduce the risk
of recurrence from 50 to 29%. In addition, BCG treatment has been
shown to decrease the rate of progression to MIBC by 27%. Intravesical
BCG is generally well tolerated. Side effects can include dysuria, uri­
nary frequency, bladder spasms, hematuria, and, in rare cases (<5%),
a systemic inflammatory response that can mimic disseminated BCG
infection. Following a 6-week induction BCG schedule, additional
maintenance BCG treatments given according to the Southwest
Bladder T-staging
Bladder lymph node staging
T2
T3
Muscularis
propria
Lamina
propria
T1
N3
N3
Ta
N3
T4
Urothelium
Tis
Internal
iliac artery
External
iliac artery
Prostate*
Obturator
artery
*Direct tumor extension
into other adjacent pelvic
organs (rectum, vagina,
cervix) or the pelvic or
abdominal walls also
qualifies as T4
True pelvis
border
Bladder cancer prognosis according to stage
N1 - Cancer spread to 1 lymph
node in the true pelvis
T
N
M
Stage
5-yr survival
0is/0a
M0
M0
M0
M0
M0
M1
N0
N0
N0
N0
N1-N3
Any N
96%
90%
70%
50%
36%
5%
Tis/Ta
T1
T2
T3
T1-T4
Any T
N2 - Cancer spread to 2 lymph
nodes in the true pelvis
N3 - Cancer spread to lymph
nodes along the common
iliac artery
FIGURE 91-2  Bladder cancer staging and prognosis. TNM, tumor-node-metastasis.
Oncology Group schedule further reduce the risk of recurrent NMIBC
compared to induction BCG alone. In patients with NMIBC that
recurs long after initial BCG treatment, a repeat course of BCG can
be considered. For patients with recurrence after a second adequate
course of BCG or with relapsed NMIBC within 6 months of initial
BCG exposure, surgical removal of the entire bladder by cystectomy is
recommended due to the high risk of progression to MIBC and poten­
tially metastatic disease. For patients who are not fit enough for or who
refuse cystectomy, non-BCG alternative intravesical agents (nadofara­
gene firadenovec, mitomycin C, gemcitabine, docetaxel, valrubicin) or
systemically administered agents that inhibit the PD-1/PD-L1 immune
checkpoint pathway (pembrolizumab) can achieve durable tumor
responses in a small fraction of patients.
Upper Tract Disease 
In patients with urothelial carcinoma of the
renal pelvis or ureter, endoscopic tissue acquisition and staging are
TABLE 91-1  Non–Muscle-Invasive Bladder Cancer Recurrence Risk
Groups
RISK GROUP
CHARACTERISTICS
Low risk
Initial tumor, solitary tumor, low grade, <3 cm, no CIS
Intermediate risk
All tumors not defined in the two adjacent categories
(between the category of low and high risk)
High risk
Any of the following:
• T1 tumor
• High-grade
• CIS
• Multiple and large (>3 cm) Ta low-grade tumors in
patients over age 70 (all conditions must be met for this
point on Ta low-grade tumors)
Abbreviation: CIS, carcinoma in situ.
more challenging than primary tumors
located in the bladder. Tumors possessing
all of the following are considered low risk:
solitary tumor, low grade, size <1 cm, and
no invasive component on imaging. Lowrisk tumors can successfully be treated
by laser ureteroscopic ablation or surgical
resection and reanastomosis of the remain­
ing ureter ends in tumors that cannot be
successfully eradicated endoscopically.
Aorta
Common
iliac artery
Muscle-Invasive Disease 
In patients
with urothelial carcinoma of the bladder
that invades into or through the muscularis
propria but with no evidence of metastatic
spread, more aggressive therapy options
summarized in Table 91-2 are required to
achieve cure. In carefully selected patients
with no evidence of CIS or hydronephro­
sis, bladder-sparing combined-modality
therapy with concurrent chemotherapy
and radiation can achieve cure in ~65% of
patients. Various chemotherapy regimens
have been utilized in combination with
radiation including cisplatin, carboplatin,
5-fluorouracil, mitomycin C, paclitaxel,
and gemcitabine. It is important to note
that a maximal debulking of all visible
tumor by TURBT is required prior to ini­
tiation of combined-modality therapy. In
patients who achieve a complete response
to combined-modality therapy, regu­
lar cystoscopic monitoring of the blad­
der is required with salvage cystectomy
offered to patients who develop MIBC in
follow-up.
N2
N2
N1
CHAPTER 91
Cancer of the Bladder and Urinary Tract
In a similar fashion, bladder-sparing
partial cystectomy can be performed in a very small subset of MIBC
patients. The ideal patient for partial cystectomy is the patient with a
solitary, clinical T2 urothelial carcinoma in the dome of the bladder. In
such patients, the tumor and immediate surrounding urothelium can
TABLE 91-2  Treatment Approaches to MIBC Patients
TREATMENT
PATIENT SELECTION
CLINICAL OUTCOMES
Bladder-sparing
chemoradiation
No CIS, no
hydronephrosis, maximal
TURBT required
65% cure, 55% bladder intact,
highly dependent on patient
selection
Bladder-sparing
partial cystectomy
Solitary tumors in dome
of bladder are ideal
Variable, highly dependent on
patient selection
Cystectomy
Any MIBC patient
50% cure with surgery
alone, highly dependent on
pathologic stage
Neoadjuvant
cisplatin-based
chemotherapy
Cisplatin-eligible MIBC
patients
5–10% improvement in
overall survival compared to
cystectomy alone
Adjuvant
cisplatin-based
chemotherapy
Cisplatin-eligible, highrisk, postcystectomy
MIBC patients (pT3-4,
N+)
Similar improvement as
neoadjuvant treatment, data
less robust, many patients not
suitable for adjuvant treatment
Adjuvant nivolumab
anti–PD-1
immunotherapy
Postsurgery, high-risk
MIBC and UTUC patients
(pT3-4, N+, cisplatineligible after neoadjuvant
therapy OR pT2-4, N+,
cisplatin-ineligible
who did not receive
neoadjuvant therapy)
30% improvement in diseasefree survival compared to
surgery alone
Abbreviations: CIS, carcinoma in situ; MIBC, muscle-invasive bladder cancer;
TURBT, transurethral resection of bladder tumor; UTUC, upper tract urothelial
carcinoma.
be resected with reconstruction of the remaining bladder to maintain
near physiologic urinary function.
In the majority of patients, however, resection of the entire bladder
is required. In males, a cystoprostatectomy with removal of the bladder,
prostate, and pelvic lymph nodes is performed, whereas in females, an
anterior exenteration with removal of the bladder, uterus, ovaries, cer­
vix, and pelvic lymph nodes is performed. With the bladder removed,
three options exist to reroute the urine outflow. In an ileostomy, the
bilateral ureters are connected to a portion of ileum that is brought
through an incision in the abdominal wall to create a stoma that drains
urine into an affixed bag outside of the body. In a continent urinary
reservoir or “Indiana pouch,” the ureters are connected to a portion of
ileum that has been separated on both ends from the rest of the smallbowel transit to form a urinary reservoir. The remaining small bowel
is reanastomosed, and the urinary reservoir is brought up just beneath
the abdominal wall muscles with patients catheterizing the urinary res­
ervoir several times per day via a small stoma tract. Last, in a neoblad­
der, the same urinary reservoir described previously is brought down
into the pelvis and is anastomosed to the remaining urethra to provide
the opportunity to the patient to void urine through the urethra. The
choice of which urinary reconstruction to perform is affected not only
by patient choice but also by anatomic tumor considerations and urolo­
gist experience with each procedure. Regardless of the type of surgery
performed, all patients undergo a significant catabolic change in their
metabolism following removal of the bladder. While many MIBC
patients are affected by weight loss preoperatively, it is not uncommon
for postcystectomy patients to lose an additional 10–15 pounds in the
first month postoperatively. In addition, patients can experience longterm nutritional changes such as low B12 levels due to alterations in
small-bowel physiology caused by all of the urinary diversion options.
PART 4
Oncology and Hematology
Despite aggressive surgery, only half of patients undergoing cystec­
tomy are cured by surgery alone. Therefore, many clinical trials have
investigated the role of systemic chemotherapy and immunotherapy
before (neoadjuvant) or after (adjuvant) surgery. Meta-analyses have
shown a 5–10% absolute overall survival advantage when combination
chemotherapy regimens utilizing cisplatin have been used before sur­
gery. Importantly, non–cisplatin-containing chemotherapy regimens
have proven inferior to cisplatin-containing regimens. Therefore, if
patients are not suitable candidates for cisplatin administration due
to poor functional status or comorbidities (e.g., poor renal function),
patients should proceed directly to surgery and forego neoadjuvant
therapy. A similar benefit exists with cisplatin-based combination che­
motherapy given after surgery. However, in the postoperative setting,
some patients may not recover sufficiently from their surgery within
a time frame optimal for chemotherapy administration. In bladder
and upper tract urothelial cancer patients with high-risk postsur­
gery pathology features, adjuvant treatment with the PD-1–targeting
immune checkpoint inhibitor, nivolumab, has demonstrated a 30%
improvement in disease-free survival compared to observation and is
considered a standard treatment option.
For patients with high-risk urothelial carcinoma of the upper urinary
tract, resection of the kidney and ureter (including the ureter bladder
cuff) by nephroureterectomy is preferred. Segmental ureterectomy
may be appropriate in patients with decreased renal function in which
nephron-sparing outcomes are critical to prevent the need for dialysis.
Similarly, in CIS patients, administration of BCG therapy via a nephros­
tomy tube can be considered to preserve intact renal function. The use
of cisplatin-based neoadjuvant chemotherapy has been associated with
a pathologic complete response at surgery of 14% in upper tract urothe­
lial carcinoma patients. Similarly, in the post-nephroureterectomy set­
ting, adjuvant platinum-based chemotherapy (carboplatin or cisplatin)
reduced recurrence rates by 55% compared to surgery alone. The use
of perioperative chemotherapy (before or after surgery) or PD-1–tar­
geting immunotherapy (after surgery) is now recommended for upper
tract urothelial carcinoma patients in national guidelines.
Metastatic Disease 
For patients with metastatic urothelial carci­
noma regardless of primary tumor origin, systemic platinum-based
chemotherapy remained the established initial treatment for decades.
However, the regimen of a nectin-4–targeting antibody-drug con­
jugate, enfortumab vedotin, carrying the monomethyl auristatin E
(MMAE) cytotoxic payload combined with the PD-1 immune check­
point inhibitor pembrolizumab (EV+P) supplanted platinum-based
chemotherapy in 2023 as the preferred first-line therapy for meta­
static urothelial carcinoma patients. In a randomized, phase 3 clini­
cal trial, EV+P treatment resulted in a highly significant improved
median overall survival of 31.5 months compared to 16.2 months with
platinum-based chemotherapy. These results led to the FDA approval
of the EV+P regimen in first-line metastatic urothelial carcinoma
patients. The optimal second-line therapy for patients who experience
disease progression on front-line EV+P is not defined. Second-line
options include platinum-based chemotherapy or fibroblast growth
factor receptor (FGFR) inhibitor therapy (erdafitinib) for patients
with activating FGFR genomic alterations. For patients with progres­
sion after receiving both platinum-based chemotherapy and a PD-1/
PD-L1 immune checkpoint inhibitor, the Trop-2–targeting antibodydrug conjugate sacituzumab govitecan, containing a topoisomerase-
inhibiting cytotoxic payload, SN-38, remains a third-line option.
Prior to the approval of EV+P in the metastatic front-line setting,
maintenance treatment with the PD-L1 immune checkpoint inhibitor
avelumab had demonstrated an improvement in overall survival com­
pared to platinum-based chemotherapy alone in patients demonstrat­
ing stable disease or objective response to their front-line treatment.
The role of maintenance PD-1/PD-L1 immune checkpoint inhibitor
therapy in the second-line and beyond settings is undefined and is
being evaluated in ongoing clinical trials. Additional novel urothelial
carcinoma therapeutics are under ongoing investigation.
With the increased number of therapeutic agents for metastatic
urothelial cancer patients now available, differing toxicity profiles
between treatment regimens commonly impact treatment decisions
for individual patients. With platinum-based chemotherapy, renal
insufficiency, myelosuppression, nausea, and neuropathy are common.
With enfortumab vedotin, myelosuppression can occur; however,
neuropathy is dose-limiting with rare but serious skin toxicity and
new-onset diabetes events. Myelosuppression and significant diarrhea
requiring intravenous fluid support are common with sacituzumab
govitecan. In contrast, myelosuppression is uncommon with PD-1/
PD-L1 immune checkpoint inhibitors. Rare immune-related toxicities
can be severe and may include colitis, pneumonitis, hepatitis, nephri­
tis, myocarditis, rash, hypothyroidism, Guillain-Barré syndrome,
idiopathic thrombocytopenia purpura, and adrenal insufficiency.
Lastly, erdafitinib side effects are notable for hyperphosphatemia,
dystrophic nail changes, and rare central serous retinopathy. Thus,
ophthalmologic evaluations are recommended for patients receiving
FGFR inhibitor therapies.
■
■FURTHER READING
American Cancer Society: Cancer Facts & Figures 2023. Atlanta,
GA: Available from https://www.cancer.org/cancer/bladder-cancer/
detection-diagnosis-staging/survival-rates.html.
Carlo MI et al: Cancer susceptibility mutations in patients with urothelial
malignancies. J Clin Oncol 38:5, 2020.
Chou R et al: Intravesical therapy for the treatment of nonmuscle
invasive bladder cancer: A systemic review and meta-analysis. J Urol
197:5, 2017.
Coleman JA et al: Diagnosis and management of non-metastatic
upper tract urothelial carcinoma: AUA/SUO guideline. J Urol 209:6,
2023.
Dyrskjøt L et al: Bladder cancer. Nat Rev Dis Primers 9:1, 2023.
Howlader N et al: SEER Cancer Statistics Review, 1975-2017. Avail­
able from https://seer.cancer.gov/csr/1975_2017/. Based on November
2019 SEER data submission, posted to the SEER website, April 2020.
Powles T et al: Enfortumab vedotin and pembrolizumab in untreated
advanced urothelial cancer.  N Engl J Med 390:10, 2024.
Robertson AG et al: Comprehensive molecular characterization of
muscle-invasive bladder cancer. Cell 171:3, 2017.

21 - 92 Benign and Malignant Diseases of the Prostate
92 Benign and Malignant Diseases of the Prostate
Siegel RL et al: Cancer statistics, 2023. CA Cancer J Clin 73:1, 2023.
Sylvester RJ et al: European Association of Urology (EAU) prognostic
factor risk groups for non–muscle-invasive bladder cancer (NMIBC)
incorporating the WHO 2004/2016 and WHO 1973 classification
systems for grade: An update from the EAU NMIBC guidelines
panel. Eur Urol 79:4, 2021.
US Food and Drug Administration: FDA approves enfortumab
vedotin-ejfv with pembrolizumab for locally advanced or metastatic
urothelial cancer. Available from: https://www.fda.gov/drugs/resourcesinformation-approved-drugs/fda-approves-enfortumab-vedotin-ejfvpembrolizumab-locally-advanced-or-metastatic-urothelial-cancer.
Oliver Sartor, James A. Eastham
Benign and Malignant
Diseases of the Prostate
Benign and malignant changes in the prostate increase with age.
Autopsies of men in the eighth decade of life show hyperplastic
changes in >90% and malignant changes in >70% of individuals. The
high prevalence of these diseases among the elderly, who often have
competing causes of morbidity and mortality, mandates a risk-adapted
approach to diagnosis and treatment. This can be achieved by consid­
ering these diseases as a series of states. Each state represents a distinct
clinical milestone for which therapy(ies) may be recommended based
on disease extent, current symptoms, risk of developing symptoms,
and/or the risk of death from prostate cancer in relation to death from
other causes. Given the complexities and, at times, the uncertainties of
optimal decision-making, patient preferences are an important consid­
eration. For benign proliferative disorders, symptoms of bladder outlet
obstruction and potential complications including urinary retention
and urinary tract infection are weighed against the side effects and
complications of medical or surgical intervention. For prostate malig­
nancies, the likelihood that a clinically significant cancer is present in
the gland and the concomitant risk of symptoms or death from cancer
are necessarily balanced against the risks and morbidities of the recom­
mended treatments.
ANATOMY AND PATHOLOGY
The prostate is in the pelvis and is adjacent to the rectum, the bladder,
the periprostatic and dorsal vein complexes, the neurovascular bundles
that are responsible for erectile function, and the urinary sphincter that
is responsible for passive urinary control. The prostate is composed
of branching tubuloalveolar glands arranged in lobules surrounded
by fibromuscular stroma. The acinar unit includes an epithelial
compartment made up of epithelial, basal, and neuroendocrine cells
separated by a basement membrane and a stromal compartment that
includes fibroblasts and smooth-muscle cells. Prostate-specific antigen
(PSA) is produced in the epithelial cells. Both prostate epithelial cells
and stromal cells express androgen receptors (ARs) and depend on
androgens for growth. Testosterone, the major circulating androgen,
is converted by prostatic 5α-reductase to dihydrotestosterone, a more
potent androgen.
The periurethral portion of the gland increases in size during
puberty and after the age of 55 years due to the growth of nonma­
lignant cells in the transition zone of the prostate that surrounds the
urethra. Most cancers develop in the peripheral zone, and cancers in
this location may or may not be palpated during a digital rectal exami­
nation (DRE).
PROSTATE CANCER
The American Cancer Society’s estimates for prostate cancer in the
United States for 2024 are 299,010 new prostate cancer cases and
35,250 deaths from prostate cancer. In the United States, prostate
cancer is the most common nonskin malignancy in men and the sec­
ond leading cause of cancer death. The absolute number of prostate
cancer deaths has decreased in the past 30 years, attributed by some to
the widespread use of PSA-based detection strategies. The incidence/
mortality ratio for prostate cancer is extremely high relative to most
other malignancies, and most men diagnosed with prostate cancer will
not die from their disease.
■
■EPIDEMIOLOGY
Epidemiologic studies show that the risk of being diagnosed with pros­
tate cancer increases 2.5-fold if one first-degree relative is affected and
even more if two or more are affected. Risk is greatest for those whose
relatives are diagnosed before the age of 65. Current estimates are that
40% of early-onset and 5–10% of all prostate cancers are hereditary.
Prostate cancer affects ethnic groups differently. Matched for age,
African-American patients have a higher incidence and present at
a more advanced stage with higher-grade, more aggressive cancers.
The causes for this disparity are debated, but genetic, environmental,
and societal factors are implicated. Genome-wide association studies
(GWAS) have identified >100 prostate cancer susceptibility loci that are
estimated to explain up to 25% of prostate cancer risk. Each prostatic
risk loci typically confers only a small incremental risk of cancer, but
combinations are more impactful. Some mutated genes such as BRCA2,
HOXB13, ATM, and PALB2 clearly confer an increased risk of prostate
cancer; however, that risk can be substantially modulated by presence
or absence of additional genomic prostatic risk loci. Polygenic risk
scores to better ascertain prostate cancer risk are under development
but not routinely available for clinical care today.
CHAPTER 92
Benign and Malignant Diseases of the Prostate
The prevalence of autopsy-detected cancers is relatively similar around
the world, while the incidence of clinical disease varies. In part, this is due
to the substantial variations in the use of PSA screening tests. Environ­
mental and dietary factors may play a role in prostate cancer growth and
progression. High consumption of dietary fats, such as α-linoleic acid or
polycyclic aromatic hydrocarbons that form when red meats are cooked,
is believed to increase risk. Like breast cancer in Asians, the risk of
prostate cancer in Asians increases when they move to Western environ­
ments. Reasons for this are poorly understood but in part likely reflect a
greater probability of PSA screening tests in the Western world. Protec­
tive factors may include consumption of lycopene found in tomatoes and
inhibitors of cholesterol biosynthesis (e.g., statin drugs). Not smoking
and avoiding obesity reduce the risk of disease progression.
■
■DIAGNOSIS AND TREATMENT BY CLINICAL STATE
The prostate cancer continuum—from the appearance of a preneo­
plastic and invasive lesion that is localized to the gland to a metastatic
lesion causing symptoms and, ultimately, mortality—can span years to
decades. To limit overdiagnosis of clinically insignificant cancers and
for disease management in general, competing risks are considered
in the context of a series of clinical states (Fig. 92-1). The states are
defined operationally based on whether or not a cancer diagnosis has
been established and, for those with a diagnosis, the state of the primary
tumor (treated vs untreated), the presence of absence of metastases on
imaging studies, and the measured level of testosterone in the blood.
With this approach, an individual resides in only one state and remains
in that state until progression. At each assessment, the decision to offer
treatment and the specific form of treatment are based on the presence
or absence of cancer-related symptoms and, if absent, the risk posed by
the cancer relative to competing causes of morbidity and mortality that
may be present in that individual. It follows that the more advanced the
disease, the greater is the need for treatment. Individual decision-making
and patient preferences are key for prostate cancer throughout the
continuum. Considerable heterogeneity can be encountered in patients
seeking treatment recommendations given widely varying perceptions
of risks and benefits, especially for those with early-stage disease.
Rising PSA:
no visible
metastases:
castrate
Rising PSA:
no visible
metastases:
non-castrate
Clinically
localized
disease
No
cancer
diagnosis
Clinical
metastases:
non-castrate
Death from cancer
exceeds death from
other causes
PART 4
Oncology and Hematology
FIGURE 92-1  Clinical states of prostate cancer. PSA, prostate-specific antigen.
For those without a cancer diagnosis, the decision to undergo
testing to detect a cancer is based on the individual’s estimated life
expectancy and, separately, the probability that a clinically significant
cancer may be present. For those with a prostate cancer diagnosis, the
clinical states model considers the probability of developing symptoms
or dying from the disease. Thus, a patient with a localized tumor that
has been surgically removed remains in the state of localized disease if
the PSA remains undetectable. The time within a state then becomes a
measure of the efficacy of an intervention. Because many patients with
active cancer are not at risk for developing metastases, symptoms, or
death, the clinical states model allows a distinction between cure—the
elimination of all cancer cells, the primary therapeutic objective of
treatment for most cancers—and cancer control, by which the tempo of
the illness is determined to be so slow or has been altered by treatment
to the point where it is unlikely to cause symptoms, to metastasize,
or to shorten a patient’s life expectancy. Importantly, from a patient
standpoint, both outcomes can be considered equivalent therapeuti­
cally assuming the patient has not experienced symptoms of the dis­
ease or the treatment needed to control it. Even when a recurrence is
documented, immediate therapy is not always necessary. Rather, as at
the time of diagnosis, the need for intervention is based on the tempo
of the illness as it unfolds in the individual, relative to the risk-tobenefit ratio of the intervention being considered. Assessment of the
future risk and tempo of the cancer, balanced with an understanding
of the patient’s morbidities and life expectancy, is key to management
of prostate cancer.
■
■NO CANCER DIAGNOSIS
Prevention 
No agent is currently approved for the prevention of
prostate cancer. The results from several large double-blind, random­
ized chemoprevention trials have established 5α-reductase inhibitors
(5ARIs) as the predominant therapy to reduce the future risk of a pros­
tate cancer diagnosis; however, most of the prevented cancers were low
risk, and those cancers typically require no treatment as their natural
history is indolent. No drug is approved for prostate cancer prevention.
Various vitamins and supplements have been studied in large-scale
prostate cancer prevention trials, but no intervention has been shown
to be effective.
Early Detection and Diagnosis 
The decision to pursue a diag­
nosis of prostate cancer must balance the benefit from detecting
Clinical
metastases:
castrate
first line
Clinical
metastases:
castrate
second line
Clinical
metastases:
castrate
third line
Detectable
metastases
and treating clinically significant cancers that, left untreated, would
adversely affect a patient’s quality and duration of life, against the
morbidity associated with the overtreatment of clinically insignifi­
cant cancers highly prevalent in the general population. The balance
is best approached through shared decision-making between the
patient and physician; however, the complexities of the subject and
the limited time available for most primary care physicians often
preclude truly informed decisions. Considerations regarding whether
to pursue a diagnosis include symptoms, an abnormal DRE, or more
typically, a change in or elevated serum PSA. Genetic risk and family
history are also relevant in the decision-making process, and those
with a family history of lethal cancer represent patients of particular
concern.
PHYSICAL EXAMINATION  The digital rectal exam (DRE) focuses on
prostate size, symmetry, consistency, and abnormalities within and/or
beyond the gland. Most cancers occur in the peripheral zone and may
be palpated on DRE. Carcinomas are characteristically hard, nodular,
irregular, and often result in an asymmetric DRE finding. Induration
may also be due to benign prostatic hyperplasia (BPH) or calculi. Over­
all, 20–25% of patients with an abnormal DRE have prostate cancer.
The DRE is a not accepted as a validated prostate cancer screening test
given the frequent false positives and false negatives associated with
this exam.
PROSTATE-SPECIFIC ANTIGEN  PSA (kallikrein-related peptidase 3;
KLK3) is a kallikrein-related serine protease that causes liquefaction of
seminal coagulum. It is produced by both nonmalignant and malignant
epithelial cells and, as such, is prostate specific, not prostate cancer
specific. Serum levels of PSA may increase from prostatitis, BPH, or
prostate cancer. PSA circulating in the blood is inactive and mainly
occurs as a complex with the protease inhibitor α1-antichymotrypsin
and as free (unbound) PSA forms. A lower free PSA is more likely to
be associated with cancer at the time of biopsy. PSA levels should be
undetectable after about 6 weeks if the prostate has been completely
removed (radical prostatectomy). If there is no prostate, there should
be no detectable PSA. Persistence of measurable serum PSA after pros­
tate removal is typical of recurrent cancer.
PSA testing was approved by the U.S. Food and Drug Administra­
tion (FDA) in 1994 for early detection of prostate cancer, and the
widespread use of the test has played a significant role in the propor­
tion of patients diagnosed with early-stage cancers: today, >70–80% of
newly diagnosed cancers are clinically organ confined. The level of PSA
in blood is strongly associated with the risk and outcome of prostate
cancer. A single PSA measured at age 60 is associated (area under the
curve [AUC] of 0.90) with lifetime risk of death from prostate cancer.
Most (90%) prostate cancer deaths occur among patients with PSA lev­
els in the top quartile (>2 ng/mL), although only a minority of patients
with PSA >2 ng/mL will develop lethal prostate cancer. Despite this
and mortality rate reductions reported from large, randomized prostate
cancer screening trials, routine use of the test remains controversial
given both false positives and false negatives and the fact that PSA test­
ing may lead to the diagnosis and treatment of indolent cancers that
pose little risk to the patient’s overall health.
The U.S. Preventive Services Task Force (USPSTF) current guideline
states, “For men aged 55 to 69 years, the decision to undergo periodic
PSA-based screening for prostate cancer should be an individual one.
Before deciding whether to be screened, men should have an oppor­
tunity to discuss the potential benefits and harms of screening with
their clinician and to incorporate their values and preferences in the
decision.” The USPSTF recommends against screening men aged 70 or
older. The USPSTF guideline can be accessed at https://www.uspreven­
tiveservicestaskforce.org/uspstf/draft-update-summary/prostate-cancerscreening-adults. The American Urologic Association (AUA) guidelines
indicate that “clinicians should engage in shared decision-making with
people for whom prostate cancer screening would be appropriate and
proceed based on a person’s values and preferences.” In contrast to the
USPSTF, the AUA guidelines state that “clinicians should offer prostate
cancer screening beginning at age 40 to 45 years for people at increased
risk of developing prostate cancer based on the following factors: Black
ancestry, germline mutations, strong family history of prostate cancer.”
Further, “clinicians should offer regular prostate cancer screening every
2 to 4 years to people aged 50 to 69 years.” The current AUA guide­
lines are available at https://www.auanet.org/guidelines-and-quality/
guidelines/early-detection-of-prostate-cancer-guidelines.
There is no rationale for recommending PSA screening in asymp­
tomatic patients with a short life expectancy. Hence, patients over the
age of 70 should only be tested in selected circumstances, such as a
higher than median PSA measured before age 70 or excellent overall
health. In addition, because a baseline PSA is a strong predictor of
the future risk of lethal prostate cancer, patients with low PSAs, for
example <1 ng/mL, can undergo testing less frequently, perhaps every
4 years, with screening possibly ending at age 60 if the PSA remains at
≤1 ng/mL
Though early detection of prostate cancer can potentially reduce the
risk of prostate cancer death, high proportions of patients with screendetected prostate cancer may not need immediate treatment and can be
managed by active surveillance. The goal of prostate cancer screening
should be to maximize the benefits of early cancer detection among
patients who can benefit from treatment and minimize its harms.
The PSA criteria used to recommend additional testing have evolved
over time. However, based on the commonly used cut point (a total
PSA ≥4 ng/mL), most patients with a PSA elevation do not have
histologic evidence of prostate cancer at biopsy. In addition, many
patients with PSA levels below this cut point harbor cancer cells in
their prostate. Information from the large Prostate Cancer Prevention
Trial demonstrates that there is no PSA below which the risk of prostate
cancer is zero. Thus, the PSA level helps establish the likelihood that a
person will harbor cancer if he undergoes a prostate biopsy. The goal
is to increase the sensitivity of the test for younger patients harboring
clinically significant cancers that may shorten survival and to reduce
the frequency of detecting cancers of low malignant potential in
patients more likely to die of other causes. Patients with symptomatic
bacterial prostatitis should have a course of antibiotics before biopsy.
However, the routine use of antibiotics in an asymptomatic person with
an elevated PSA level is discouraged.
SECOND-LINE SCREENING TESTS  Several tests have been developed to
better stratify patients with an elevated PSA test into those more or less
likely to have clinically significant prostate cancer. The 4K Score Test
(OPKO Lab, Nashville, TN) measures four prostate-specific kallikreins
(total PSA, free PSA, intact PSA, and human kallikrein 2). The results
are combined with clinical information in an algorithm that estimates
an individual’s percent risk of having an aggressive prostate cancer
should that individual opt for a prostate biopsy.
The Prostate Health Index (PHI; Innovative Diagnostic Laboratory,
Richmond, VA) is a blood test that estimates the risk of having prostate
cancer. The PHI test is a combination of free PSA, total PSA, and the
[–2]proPSA isoform of free PSA. These three tests are combined in a
formula that calculates the PHI score. The PHI score is a better predic­
tor of prostate cancer than the total PSA test alone or the free PSA test
alone. Urine-based testing measuring exosomes (ExoDx Prostate Test)
or mRNA levels of prostate cancer–related genes (Select-MDx) are also
available.
The most important current test to stratify risk after detection of an
elevated PSA is multiparametric prostate magnetic resonance imaging
(mpMRI). The mpMRI varies from a traditional magnetic resonance
imaging (MRI) by including not only the T1/T2-weighted images
but also measurement of diffusion-weighted imaging with or without
dynamic contrast enhancement. Using a structured reading system
termed the Prostate Imaging Reporting and Data System (PI-RADS),
patients can be risk stratified to determine the risk of clinically sig­
nificant cancer. Data indicate that men with a PI-RADS 1–2 lesion can
safely avoid biopsy, whereas patients with a PI-RADS 3–5 lesion can
have targeted biopsies that are more likely to yield a true sense of the
findings within the gland. The addition of an mpMRI in the prebiopsy
decision-making unequivocally reduces the number of patients under­
going biopsy and reduces the diagnosis of Gleason 6 (grade group 1)
cancers, without compromising the diagnosis of clinically relevant can­
cers. Today, an mpMRI of the prostate should be obtained in most cases
prior to performing a prostate biopsy. Doing so will reduce the number
of patients who are recommended to have a biopsy and improve the
accuracy of the biopsies that are performed.
CHAPTER 92
Benign and Malignant Diseases of the Prostate
PROSTATE BIOPSY  A diagnosis of cancer is established by an imageguided needle biopsy. Direct visualization of the gland by transrectal
ultrasound (TRUS), MRI, or fusion of the ultrasound and MRI images
ensures that all areas of the gland, including suspicious areas, are
sampled. Contemporary schemas advise an extended-pattern 12-core
biopsy that includes sampling from the peripheral zone as well as a
lesion-directed palpable nodule or suspicious image-guided sampling.
MRI-guided biopsy is superior to that of ultrasound-guided biopsy in
terms of ascertaining an accurate depiction of the prostate pathology.
Patients with an elevated PSA and a negative biopsy should continue
to be followed as a negative biopsy does not rule out a future diagnosis
of cancer.
PATHOLOGY  Each core of the biopsy is examined for the presence of
cancer, and the amount of cancer should be quantified based on the
length of the cancer within the core and the percentage of the core
involved. Of the cancers identified, >95% are adenocarcinomas; the
rest are squamous or transitional cell tumors or, rarely, carcinosarco­
mas or small-cell histologies. Metastases to the prostate are rare, but
colon cancers or transitional cell tumors of the bladder can invade the
gland by direct extension.
When prostate cancer is diagnosed, a measure of histologic aggres­
siveness is assigned using the Gleason grading system, in which the
dominant and secondary glandular histologic patterns are scored from
1 (well differentiated) to 5 (undifferentiated) and summed to give a
total score of 6–10 for each tumor. The most poorly differentiated
area of tumor (i.e., the area with the highest histologic grade) often
determines biologic behavior. The presence or absence of perineural
invasion and extracapsular spread should also be recorded.
Over the years, the Gleason grading system has undergone several
changes. Currently, Gleason total scores of 2–5 are no longer assigned,
and in practice, the lowest total score now assigned is 6. This leads to a
logical yet incorrect assumption on the part of patients that a Gleason
6 cancer is in the middle of the scale, triggering the fear that their can­
cer is serious and the assumption that treatment is necessary despite
TABLE 92-1  TNM Classification
TNM (tumor, node, metastasis) Staging System for Prostate Cancera
Tx
Primary tumor cannot be assessed
T0
No evidence of primary tumor
Localized Disease
T1
Clinically inapparent tumor, neither palpable nor visible by imaging
T1a
Tumor incidental histologic finding in ≤5% of resected tissue; not
palpable
T1b
Tumor incidental histologic finding in >5% of resected tissue
T1c
Tumor identified by needle biopsy (e.g., because of elevated PSA)
T2
Tumor confined within prostateb
T2a
Tumor involves half of one lobe or less
T2b
Tumor involves more than one half of one lobe, not both lobes
T2c
Tumor involves both lobes
Local Extension
T3
Tumor extends through the prostate capsulec
T3a
Extracapsular extension (unilateral or bilateral)
T3b
Tumor invades seminal vesicles
T4
Tumor is fixed or invades adjacent structures other than seminal
vesicles such as external sphincter, rectum, bladder, levator muscles,
and/or pelvic wall
PART 4
Oncology and Hematology
Metastatic Disease
N1
Positive regional lymph nodes
M1
Distant metastases
aRevised from SB Edge et al (eds): AJCC Cancer Staging Manual, 7th ed. New York,
Springer, 2010. bTumor found in one or both lobes by needle biopsy, but not palpable
or reliably visible by imaging, is classified as T1c. cInvasion into the prostatic apex
or into (but not beyond) the prostatic capsule is classified not as T3 but as T2.
Abbreviation: PSA, prostate-specific antigen.
Gleason score 6 being favorable risk. To address these issues, a new
five-grade group system has been developed:
Grade group 1 (Gleason score ≤6)
Grade group 2 (Gleason score 3 + 4 = 7)
Grade group 3 (Gleason score 4 + 3 = 7)
Grade group 4 (Gleason score 4 + 4 = 8)
Grade group 5 (Gleason scores 9 and 10)
The new system simplifies the grading of prostate cancer, appropri­
ately classifying the lowest risk as grade group 1 (rather than Gleason
score 6), and accurately predicts prognosis.
PROSTATE CANCER STAGING  The TNM (tumor, node, metastasis)
staging system includes categories for cancers that are identified solely
based on an abnormal PSA (T1c), those that are palpable but clinically
confined to the gland (T2), and those that have extended outside the
gland (T3 and T4) (Table 92-1 and Fig. 92-2). DRE alone is inaccurate
A
B
C
D
FIGURE 92-2  T stages of prostate cancer. A. T1—Clinically inapparent tumor, neither palpable nor visible by imaging. B. T2—Tumor confined within prostate. C. T3—Tumor
extends through prostate capsule and may invade the seminal vesicles. D. T4—Tumor is fixed or invades adjacent structures. Eighty percent of patients present with local
disease (T1 and T2), which is associated with a 5-year survival rate of 100%. An additional 12% of patients present with regional disease (T3 and T4 without metastases),
which is also associated with a 100% survival rate after 5 years. Four percent of patients present with distant disease (T4 with metastases), which is associated with a
30% 5-year survival rate. (Three percent of patients are ungraded.) (© 2010 Memorial Sloan-Kettering Cancer Center, New York, NY. All rights reserved. Republished with
permission.)
in determining the extent of disease within the gland, the presence
or absence of capsular invasion, involvement of seminal vesicles, and
extension of disease to lymph nodes. Unfortunately, no single test has
been proven to perfectly indicate the stage or the presence of organconfined disease, seminal vesicle involvement, or lymph node spread
in part due to fact that cancer cells can microscopically spread below
the limits of sensitivity for any imaging test. That said, mpMRI imag­
ing can often reveal evidence of extracapsular spread or seminal vesicle
invasion with a higher degree of accuracy than DRE, and taking MRI
findings into account is typically done in staging today.
Prognosis and classification for nonmetastatic prostate cancer are
typically done in three broad categories (low, intermediate, and high
risk). Low-risk tumors are confined to the prostate with a PSA of <10
ng/mL and grade group 1. Intermediate-risk tumors are confined to
the prostate, have a PSA between 10 and 20 ng/mL, or are grade group
2 or 3 (Gleason 7). This category is typically divided into a “favor­
able” and “unfavorable” intermediate risk depending on grade group 2
(favorable) or 3 (unfavorable) and number of positive biopsies (>50%
of cores positive for cancer is unfavorable). High-risk tumors extend
outside the prostate, have a PSA >20 ng/mL, or are grade group 4 or 5
(Gleason 8–10). There is also a subset of high-risk tumors termed “very
high risk” in which the cancer extends into the seminal vesicles (T3b)
or adjacent organs, i.e., rectum or bladder (T4), or there are multiple
biopsy samples with high-grade cancer.
Computed tomography (CT) lacks sensitivity and specificity to
detect extraprostatic extension and is inferior to MRI in visualization
of lymph nodes. In general, mpMRI is superior to CT to detect cancers
in the prostate, to assess local disease extent, and fused with ultrasound
imaging, to guide sites to biopsy within the gland. Thus, mpMRI can be
quite useful for the planning of surgery and radiation therapy.
The use of prostate-specific membrane antigen (PSMA) positron
emission tomography (PET) scans has radically altered the assessment
of prostate cancer spread beyond the prostate. This scan is now FDA
approved for patients with intermediate- and high-risk prostate cancer
and is substantially more sensitive and accurate in the detection of
metastases as compared to conventional imaging (including MRI).
Currently, state-of-the-art staging for Gleason grade group 3 and
higher patients involves PSMA PET imaging before treatment. PSMA
PET scans significantly improve specificity over conventional imaging
while maintaining comparable sensitivity. PSMA PET scans are not
capable of detecting low-volume microscopic disease. In studies where
surgically removed lymph nodes were assessed for metastatic prostate
cancer, sensitivity was consistently <50%. Simply stated, PET scans
cannot detect microscopic disease (<2 mm focus), and a negative scan
cannot rule out the possibility of cancer spread. We emphasize that no
test is capable of microscopic cancer detection and note that a “nega­
tive” scan is not equated with the definitive absence of cancer.
Radionuclide bone scans (bone scintigraphy) have been used in the
past to evaluate spread to osseous sites. This test is insensitive relative
to PSMA PET and nonspecific because it does not detect the cancer
itself, only reaction of the bone in the presence of the cancer. Staging
early-stage cancers with a bone scan is much less effective than using
PSMA PET, and most centers no longer routinely use bone scans for
initial staging in patients with suspected localized cancer given its
known insensitivity and propensity for false-positive findings.
TREATMENT
Prostate Cancer
CLINICALLY LOCALIZED PROSTATE CANCER
Patients with clinically localized disease are typically managed by
radical prostatectomy, radiation therapy, or active surveillance.
Choice of therapy requires the consideration of several factors: the
presence of symptoms, the probability that the untreated tumor
will adversely affect the quality or duration of survival, and the
probability that the tumor can be cured by single-modality therapy
directed to the prostate versus requiring combinations of both local
and systemic therapy.
There is no clear evidence for the superiority of any one form of
local therapy relative to another. This is due to the lack of prospec­
tive randomized trials, referral bias and physician bias, variation
in the experience of the treating teams, and differences in trial end
points and the definitions of cancer control. Often, PSA relapsefree survival is used because an effect on metastatic progression or
survival may not be apparent for years (if ever). A PSA recurrence
does not necessarily mean that the disease will cause symptoms or
shorten survival. The rate at which PSA doubles (PSA doubling
time [PSADT]) is an important predictor of future clinical impact.
Those with a PSADT of 14 months or greater are at low risk of
clinical consequences, while those with a more rapid PSADT, espe­
cially those with a doubling time of 3 months or less, are at much
higher risk for future clinically relevant events. Understanding the
PSADT and the age/comorbidities of the patient is essential for
decision-making.
After radical surgery to remove all prostate tissue, PSA should
become undetectable in the blood within 6 weeks. If PSA remains
or becomes detectable after radical prostatectomy, the patient is
considered to have persistent or recurrent disease. A patient with no
prostate should have no detectable PSA. After radiation therapy, in
contrast, PSA does not become undetectable because the remaining
nonmalignant elements of the gland continue to produce PSA even
if the cancer cells have been eliminated.
Similarly, cancer control is not well defined by PSA for a patient
managed by active surveillance. For patients with an intact prostate
and a PSA of <10 ng/mL, the fluctuations in PSA are more reflec­
tive of the benign rather than malignant cells in the prostate. Other
outcomes are time to objective progression (local or systemic),
cancer-specific survival, and overall survival; however, these out­
comes may take years to ascertain; thus, studies of localized disease
are necessarily large, long, and often quite expensive.
The more extensive the local disease, the higher the probability
of regional lymph node involvement (even when imaging studies
are normal), the lower the probability of local control, and the
higher the probability of relapse and the development of metastases.
More important is that within the categories of clinical stage T1,
T2, and T3 disease are cancers with a range of prognoses. Some T3
tumors are curable with therapy directed solely at the prostate, and
some T1 lesions have a high probability of systemic relapse that
requires the integration of local and systemic therapy to achieve
cure. For T1c cancers, stage alone is inadequate to predict outcome
and select treatment; other factors (especially Gleason score) must
be considered. Genomic stratification of risk is increasingly viewed
as important, and tools such as transcriptomic profiling may one
day be routinely used in addition to traditional pathology.
To better assess risk and guide treatment selection, many groups
have developed prognostic models or nomograms that use a com­
bination of the initial clinical T stage, biopsy Gleason score, number
of biopsy cores in which cancer is detected, and baseline PSA. Not
all variables are equally important, and Gleason score is required
to make accurate prognostication. Some prognostic models use
discrete cut points, as mentioned above (PSA <10 or ≥10 ng/mL;
Gleason score of ≤6, 7, or ≥8), while others employ nomograms that
use PSA and Gleason score as continuous variables. More than 100
nomograms have been reported to predict (1) the probability that
a clinically significant cancer is present, (2) disease extent (organconfined vs non–organ-confined, node-negative or -positive), or
(3) the relative probability of treatment success for specific local
therapies using pretreatment variables.
Exactly what probability of success or failure would lead a physi­
cian to recommend and a patient to seek alternative approaches is
controversial and highly dependent on the age and comorbidities
of the patient. As an example, it may be appropriate to recommend
radical surgery for a younger patient with intermediate-risk disease,
while recommending surveillance for an older patient with a tumor
having identical characteristics. Nomograms and various biomark­
ers are being refined continually to incorporate additional clinical
parameters and biologic determinants that can affect outcomes,
making treatment decisions a dynamic process. Patient prefer­
ences are also critically important in shared decision-making. Side
effects of therapy are not the same for various treatment options,
and patient preferences for one approach or another may require
careful discussions that extend beyond the simple calculations of
risk and benefit.
CHAPTER 92
Radical Prostatectomy  The goal of radical prostatectomy is to
excise the cancer completely with a clear margin, to maintain conti­
nence by preserving the external sphincter, and to preserve potency
by sparing the autonomic nerves in the neurovascular bundle. The
procedure is advised for patients with a life expectancy of 10 years or
more with a Gleason score 7 or higher disease. Radical prostatectomy
can be performed via a retropubic or perineal approach or via a min­
imally invasive robotic-assisted or handheld laparoscopic approach.
Outcomes can be predicted using postoperative nomograms that
consider pretreatment factors and the pathologic findings at surgery.
PSA failure is usually defined as a value >0.1 or 0.2 ng/mL, but as
stated above, the patient without a prostate should typically have no
detectable PSA. Specific criteria to guide the choice of one surgical
approach over another are lacking. Minimally invasive approaches
offer the advantage of a shorter hospital stay and reduced blood
loss. Rates of cancer control, recovery of continence, and recovery of
erectile function are comparable for robotic and open surgery. The
individual surgeon, rather than the surgical approach used, is most
important in determining outcomes after surgery.
Benign and Malignant Diseases of the Prostate
Neoadjuvant hormonal treatment with gonadotropin-releasing
hormone (GnRH) agonists/antagonists alone has also been explored
to improve the outcomes of surgery for high-risk patients using a
variety of definitions. The results of several large trials evaluating
3 or 8 months of androgen depletion before surgery have not been
shown to improve clinically relevant outcomes. Currently, neoadju­
vant hormonal therapies are not considered to be standard of care
for surgically treated patients.
Factors associated with incontinence following radical prosta­
tectomy include older age and membranous urethral length, which
impacts the ability to preserve the urethra beyond the apex and the
distal sphincter. The skill and experience of the surgeon are also
critical factors.
The likelihood of recovery of erectile function is associated with
younger age, quality of erections before surgery, and the absence
of damage to the neurovascular bundles. In general, erectile func­
tion begins to return ~6 months after surgery if neurovascular
tissue has been preserved. Potency is reduced by half if at least one
neurovascular bundle is sacrificed. Overall, with the availability
of drugs such as sildenafil, intraurethral inserts of alprostadil, and
intracavernosal injections of vasodilators, many patients recover
satisfactory sexual function.
Radiation Therapy  Radiation therapy is given by external beam,
by radioactive sources implanted into the gland, or by a combina­
tion of the two techniques.
Contemporary external beam intensity-modulated radiation
therapy (IMRT) permits shaping of the dose and allows the delivery
of higher doses to the prostate and a dramatic reduction in normal
tissue exposure compared to three-dimensional conformal treat­
ment alone. These advances have enabled the safe administration
of doses >78 Gy and resulted in higher local control rates and fewer
side effects. Proton beam radiation has not been demonstrated to
have superior outcomes as compared to conventional radiation with
IMRT. Lack of randomized studies prevents the use of routinely
adopting proton beam as a standard of care.
Cancer control after radiation therapy has been defined by vari­
ous criteria, including a decline in PSA to <0.5 or 1 ng/mL, “non­
rising” PSA values, and (rarely) a negative biopsy of the prostate
2 years after completion of treatment. The standard definition of
biochemical failure is a rise in PSA by ≥2 ng/mL higher than the
lowest PSA achieved; however, newer data question whether the cut­
off should be lower, particularly in those with higher grade cancers.
Radiation dose is critical to the eradication of prostate cancer.
In a representative study, a PSA nadir of <1.0 ng/mL was achieved
in 90% of patients receiving 81.0 Gy versus 76% and 56% of those
receiving 70.2 and 64.8 Gy, respectively. Positive biopsy rates at 2.5
years were 4% for those treated with 81 Gy versus 27% and 36%
for those receiving 75.6 and 70.2 Gy, respectively. Higher doses of
radiation, however, may be associated with a higher risk of adverse
events.
PART 4
Oncology and Hematology
Hypofractionation schedules, utilizing fewer treatments of
higher radiation doses, have been evaluated and shown to provide
good cancer control rates based on posttreatment biopsies showing
no evidence of cancer, with no apparent increase in treatmentrelated morbidity. Hypofractionated treatments can range from as
few as 5 treatments to upward of 26 treatments, with both regimens
representing substantial reductions in treatment length.
Multiple clinical trials have evaluated the use of androgen depri­
vation therapy (ADT) in combination with radiation. In patients
with unfavorable intermediate-risk prostate cancer, short-course
ADT (6 months), when combined with external beam radiotherapy,
has demonstrated significant improvements in overall survival.
Higher doses of radiation cannot substitute for ADT. In patients
with high-risk localized disease, longer courses of ADT (18–36
months) have proven superior to shorter courses and represent
the current standard of care when combined with radiotherapy.
Novel genomic and transcriptomic biomarkers are being explored
to assess the responsiveness of tumors to ADT, but as of yet, there
are no accepted biomarkers that determine who should or should
not receive ADT. Artificial intelligence assessments are promising,
and new assays suggest the possibility that prostate cancers treated
with radiation can be stratified into those that do and do not benefit
from androgen deprivation.
For patients with nonmetastatic cancer by conventional imaging
(bone scan, CT, or MRI) and two or more high risk factors (Gleason
8–10, stage T3/T4, or PSA ≥40 ng/mL) or positive pelvic lymph
nodes, a large randomized trial demonstrated that the addition of
abiraterone/prednisone to 2 years of ADT and radiotherapy is supe­
rior to 3 years of ADT and radiotherapy. This study defined a new
standard of care for these particularly high-risk patients.
The Prostate Testing for Cancer and Treatment (ProtecT) trial
investigated the effects of active monitoring, radical prostatectomy,
and radical radiotherapy with hormones on patient-reported out­
comes in patients diagnosed with predominantly low-risk prostate
cancer (~75% with Gleason score 6 or grade group 1 cancer). Cancer
outcomes were essentially the same for these three approaches.
Patient-reported outcomes among 1643 patients who completed
questionnaires before diagnosis, at 6 and 12 months, and annually
thereafter were compared. Of the three treatments, prostatectomy
had the greatest negative effect on sexual function and urinary
continence, and although there was some recovery, these outcomes
remained worse in the prostatectomy group than in the other
groups throughout the trial. The negative effect of radiotherapy
on sexual function was greatest at 6 months, but sexual function
then recovered somewhat and was stable thereafter; radiotherapy
had little effect on urinary continence. Sexual and urinary function
declined gradually in the active-monitoring group. Bowel function
was worse in the radiotherapy group at 6 months than in the other
groups but then recovered somewhat, except for the increasing fre­
quency of bloody stools; bowel function was unchanged in the other
groups. Urinary voiding and nocturia were worse in the radio­
therapy group at 6 months but then mostly recovered and were like
the other groups after 12 months. Effects on quality of life mirrored
the reported changes in function. No significant differences were
observed among the groups in measures of anxiety, depression,
or general health-related or cancer-related quality of life. Taken
together, both surgery and radiation had clear side effects, but these
side effects were distinct.
Brachytherapy  Brachytherapy is the direct implantation of radio­
active sources into the prostate. It is based on the principle that the
deposition of radiation energy in tissues decreases as a function of
the square of the distance from the source (Chap. 78). The goal
is to deliver intensive irradiation to the prostate, minimizing the
exposure of the surrounding tissues. The current standard tech­
nique achieves a more homogeneous dose distribution by delivering
radiation according to a customized template based on imaging
assessment of the cancer and computer-optimized dosimetry. The
implantation is typically performed transperineally as an outpatient
procedure with real-time imaging.
Improvements in brachytherapy techniques have resulted in
fewer complications and a marked reduction in local failure rates.
In a series of 197 patients followed for a median of 3 years, 5-year
actuarial PSA relapse–free survival for patients with pretherapy
PSA levels of 0–4, 4–10, and >10 ng/mL were 98, 90, and 89%,
respectively. In a separate report of 201 patients who underwent
posttreatment biopsies, 80% were negative, 17% were indetermi­
nate, and 3% were positive. The results did not change with longer
follow-up. Brachytherapy is well tolerated, although most patients
experience urinary frequency and urgency that can persist for
several months. Higher complication rates are observed in patients
who have undergone a prior transurethral resection of the prostate
(TURP), while those with obstructive symptoms at baseline are at a
higher risk for retention and persistent voiding symptoms. Proctitis
has been reported in <2% of patients. Like surgery, brachytherapy is
best performed by those well-practiced in the technique.
Active Surveillance  With the advent of PSA testing, many
patients are diagnosed with low-risk prostate cancers that may
not pose a threat to either the quantity or quality of a person’s life.
Active surveillance, described previously as watchful waiting or
deferred therapy, initially evolved from (1) studies that evaluated
predominantly elderly patients with well-differentiated tumors
(Gleason 6 or grade group 1) who remained untreated and demon­
strated no clinically significant progression for protracted periods,
(2) recognition of the contrast between incidence and disease-
specific mortality, (3) the high prevalence of autopsy cancers, and
(4) an effort to reduce overtreatment and treatment-related side
effects. In practice, active surveillance is the treatment recom­
mended to patients with cancers of low aggressiveness that can be
safely monitored at fixed intervals with DREs, PSA measurements,
imaging (best done with prostate mpMRI), and repeat prostate
biopsies as indicated until histopathologic or serologic changes
correlative of progression warrant treatment with curative intent.
It is important to recognize that no treatment has proven superior
to active surveillance for those with PSA-detected grade group 1
(Gleason score 6) disease. Surveillance remains underutilized today,
and needless morbidity can result from overtreatment of those who
have little chance to benefit from therapy given the indolent nature
of the vast majority of patients with Gleason 6 localized disease.
Case selection is critical, and determining the clinical parameters
predictive of cancer aggressiveness that can be used to reliably select
patients most likely to benefit from active surveillance is an area of
intense study. One set of criteria includes patients with clinical T1c
tumors that are biopsy Gleason grade 6. Nomograms to help predict
which patients can safely be managed by active surveillance con­
tinue to be refined, and as their predictive accuracy improves, it can
be anticipated that more patients will be candidates. Older patients
and those with substantial comorbidities can have more permissive
criteria for surveillance including those with Gleason 3 + 4 = 7
(grade group 2) localized disease. Treatment decision-making for
all localized prostate cancers depends on both the characteristics
of the cancer and the age and comorbidities of the patient. Anxiety
remains a problem for some patients with untreated cancers, and
management of that anxiety can at times be problematic.
RISING PSA AFTER DEFINITIVE LOCAL THERAPY
Patients in this state include those in whom the sole manifestation
of disease is a rising PSA after surgery and/or radiation therapy. For
most of these patients in the initial phases, there is no evidence of
disease on imaging studies. For these patients, the central issue is
whether the rise in PSA results from persistent disease in the pri­
mary site, systemic disease, or both. Disease in the primary site may
still be curable by additional local treatment.
The decision to recommend radiation therapy after prosta­
tectomy is guided by the age and comorbidities of the patient,
pathologic findings at surgery, the timing of PSA failure, the PSA
doubling time, and the PSA level at the time of failure. Traditional
imaging (MRI, CT, and radionucleotide bone scans), especially at
low levels of PSA, is typically uninformative, but newer imaging
methods may or may not be useful.
New PET tracers such as 18F-fluciclovine and 18F- or 68Ga-PSMA
that directly image the cancer are more sensitive and can detect
low-volume disease in the prostate bed or other sites to better
inform the decisions regarding treatment. Detection rates, both in
and outside the prostate bed, correlate with the absolute level of
PSA and the rate of PSA rise. Factors that predict for response to
salvage radiation therapy after radical prostatectomy are a positive
surgical margin, lower Gleason score in the surgical specimen, a
long interval from surgery to PSA failure, slower PSA doubling
time, a low (<0.5 ng/mL) PSA value at the time of radiation treat­
ment, and the absence of distant disease when using a PSMA or
fluciclovine PET scan.
For patients with a rising PSA after radiation therapy, salvage
local therapy can be considered if persistent disease has been docu­
mented by a biopsy of the prostate and if no disease is detectable
outside of the prostate bed or regional lymph nodes by imaging.
Unfortunately, case selection is poorly defined in most series.
Local treatment options for patients with recurrence after radiation
include salvage radical prostatectomy, salvage cryotherapy, salvage
radiation therapy, and salvage high-intensity focused ultrasound.
Unfortunately, morbidities can be significant in the postradiated
patient.
A rise in PSA after surgery or radiation therapy may indicate
subclinical or micrometastatic disease with or without local recur­
rence. The need for treatment depends, in part, on the estimated
probability that the patient will develop clinical symptoms and in
what time frame. That immediate therapy is not always required
was shown in a well-annotated series where patients who developed
a rising PSA after radical prostatectomy received no systemic ther­
apy until metastatic disease was documented. Overall, the median
time to metastatic progression was 8 years, and 63% of the patients
with rising PSA values remained free of metastases at 5 years. Fac­
tors associated with progression included the Gleason score of the
radical prostatectomy specimen, time to recurrence after surgery,
and PSADT. For those with Gleason score ≥8, the probability of
metastatic progression was 37, 51, and 71% at 3, 5, and 7 years,
respectively. If the time to recurrence was <2 years and PSADT was
long (>10 months), the proportions with metastatic disease at the
same time intervals were 23, 32, and 53%, versus 47, 69, and 79% if
the doubling time was short (<10 months).
PSADTs are also prognostic for survival. Most physicians advise
treatment when PSA doubling times are ≤10 months. A difficulty
with predicting the risk of metastatic spread, symptoms, or death
from disease in the rising PSA state is that many patients receive
some form of therapy before the development of metastases as
detected by conventional imaging. Nevertheless, predictive models
continue to be refined with a consensus that lower risk patients can
be watched, whereas higher risk patients may require some inter­
vention. Given that new molecular imaging techniques are now
FDA approved, the interplay between imaging and risk continues
to be refined.
METASTATIC DISEASE: NONCASTRATE
The state of noncastrate metastatic disease includes patients with
metastases visible on an imaging study at the time of diagnosis or
after local therapy(ies) who have noncastrate levels of testosterone
(>50 ng/dL). The prognosis is distinct for those with metastases
detected by conventional imaging versus those detected only with
molecular imaging. Symptoms of metastatic disease may include
pain from osseous spread, although many patients are asymptom­
atic despite extensive spread. Less common are symptoms related
to weight loss, fatigue, malaise, lymphedema, marrow infiltration
by tumor (myelophthisis), coagulopathy, blood clots, or spinal cord
compression. Standard treatment is to deplete or lower androgens
via ADT by medical or surgical means, the latter being the least
acceptable to patients. More than 90% of male hormones originate
in the testes; <10% are synthesized in the adrenal gland (Fig. 92-3).
CHAPTER 92
Testosterone-Lowering Agents  Medical therapies that lower tes­
tosterone levels include the GnRH agonists/antagonists, pure
GnRH antagonists, 17,20-lyase inhibitors, CYP17 inhibitors, and
estrogens such as oral diethylstilbestrol (DES) (Fig. 92-3). DES is
not utilized today due to the excessive risk of vascular complica­
tions that include fluid retention, phlebitis, emboli, and stroke.
GnRH agonists, such as leuprolide acetate and goserelin acetate, ini­
tially produce a very brief rise in luteinizing hormone and folliclestimulating hormone followed by a downregulation of receptors in
the pituitary gland, which causes a chemical castration. Regulatory
approval was based on randomized trials showing reduced cardio­
vascular toxicities relative to DES, with equivalent potency. The ini­
tial rise in testosterone may occasionally result in a clinical flare of
the disease, and as such, these agents are relatively contraindicated
in patients with significant urinary obstructive symptoms, cancerrelated pain, or spinal cord compromise. AR antagonists that block
testosterone binding to the receptor are commonly used to reduce
the risk of flare. Increases in testosterone do not occur with GnRH
antagonists such as degarelix, given by injection, or relugolix, given
orally, and these agents as well as abiraterone acetate rapidly achieve
castrate levels of testosterone.
Benign and Malignant Diseases of the Prostate
Agents that lower testosterone are associated with an androgendeprivation syndrome that includes hot flushes, weakness, fatigue,
loss of muscle mass, risk of osteoporosis and fracture, anemia,
changes in cognition and personality, and depression. Changes
in lipids, obesity, and insulin resistance and an increased risk
of diabetes and cardiovascular disease may also be seen, along
with a decrease in bone density that worsens over time and may
result in an increased risk of clinical fractures. This is a particular
concern in patients with preexisting osteopenia that results from
hypogonadism that may be worsened with steroid or alcohol use
and significantly underappreciated. Baseline fracture risk can be
assessed using the FRAX scale, and to minimize fracture risk,
patients can be advised to take a bisphosphonate or RANK-ligand
inhibitor (denosumab) in combination with calcium and vitamin D
supplementation. Hot flushes may be ameliorated by oxybutynin or
certain antidepressants such as venlafaxine.
Antiandrogens  Nonsteroidal first-generation antiandrogens such
bicalutamide and nilutamide have largely been replaced by the
more potent next-generation agents (enzalutamide, apalutamide,
and darolutamide) that do not lower serum androgen levels and
result in fewer hot flushes, less of an effect on libido, less muscle
wasting, fewer personality changes, and less bone loss relative to
Hypothalamus
GnRH
CRH
Pituitary
GnRH agonists
GnRH antagonists
Degarelix
Relugolix
Estrogens
Prednisone
ACTH
LH
Testis
Adrenal
glands
CYP17
inhibitors
abiraterone
PART 4
Oncology and Hematology
Testosterone
Androstenedione
DHEA DHEA-S
Dutasteride
Prostate
DHT
Prostate cell
Next generation
anti-androgens
AR
Enzalutamide
Apalutamide
Darolutamide
AR
AR
DHT
AR
Prostate
cell nucleus
AR
DHT
ARE
DNA
FIGURE 92-3  Sites of action of different hormone therapies.
testosterone-lowering therapies. However, over time, testosterone
levels increase and are converted to estrogen, which can result in
mastalgia and gynecomastia that limits long-term use. The side
effect of antiandrogens as monotherapy can be prevented in part by
tamoxifen, aromatase inhibitors, or prophylactic breast irradiation.
Most reported randomized trials in metastatic patients suggest
that the cancer-specific outcomes are inferior when antiandrogens
are used alone. Bicalutamide, even at a dose of 150 mg (three times
the approved dose for use in combination in GnRH agonists),
resulted in a shorter time to progression and inferior survival com­
pared to surgical castration for patients with established metastatic
disease. Newer studies for those without metastatic disease suggest
that enzalutamide is appropriate in selected patients with a PSADT
of 10 months or less.
Improving on the outcomes with ADT alone was a focus of the
field for decades. Older antiandrogens such as bicalutamide or flu­
tamide did not convincingly achieve these goals. Practice standards
changed when an improvement in time to progression and overall
survival was shown when ADT was combined with docetaxel rela­
tive to ADT alone. The greatest benefit was seen for patients with
“high-volume” disease defined as the presence of ≥4 lesions on
radionuclide bone scan or visceral disease. Longer progressionfree and overall survival times have been noted in separate phase
3 trials comparing ADT with abiraterone, a CYP17 inhibitor that
blocks androgen synthesis, and ADT with the AR antagonists such
as enzalutamide and apalutamide versus the ADT standard, further
changing the standard of care.
Intermittent Androgen Deprivation Therapy  One way to reduce
the side effects of androgen depletion is to administer hormonal
therapy on an intermittent basis; however, the use of this approach
in metastatic disease has yet to be proven useful for those being
treated with ADT plus a novel hormone such as abiraterone, apalu­
tamide, or enzalutamide. Additional studies in the metastatic set­
ting with intermittent therapy are under consideration.
Chemotherapy  Studies with ADT plus docetaxel indicate that
patients with high-volume metastatic disease benefit from the
addition of docetaxel. However, more recent studies indicate that
ADT and docetaxel are not appropriate choices today given that the
addition of abiraterone or darolutamide is superior to that of ADT
plus docetaxel. Consultation with a clinician practiced in the art of
advanced prostate cancer is appropriate given the rapidly changing
standards of care.
Outcomes of Androgen Deprivation  The anti–prostate cancer
effects of the various newer androgen depletion strategies (abi­
raterone, apalutamide, or enzalutamide in combination with medical
or surgical castration) are similar, and the clinical course is predict­
able: an initial response, a period of stability in which tumor cells
are dormant and nonproliferative, followed after a variable period
of time by a rise in PSA and regrowth that is visible on a scan as
a castration-resistant lesion. Androgen depletion is not curative
because cells that survive castration are present when the disease
is first diagnosed. Considered by disease manifestation, PSA levels
return to normal in 60–70% of patients, and measurable disease
regression occurs in >50%. Duration of survival is inversely pro­
portional to disease extent at the time androgen depletion is first
started and the nadir level of PSA at 6–8 months. Patients with
nadir PSA values >4 ng/mL have markedly inferior survival times
and should be considered for alternative approaches.
METASTATIC DISEASE: CASTRATE
Castration-resistant prostate cancer (CRPC), disease that pro­
gresses while the measured levels of testosterone in the blood are
50 ng/mL or lower, can produce some of the most feared complica­
tions of the disease and is lethal for most patients. The most com­
mon manifestation is a rising PSA, frequently co-occurring with
progression in bone. Nodal and/or visceral progression is less fre­
quent. Symptoms may or may not be present. Critical for manage­
ment is that therapeutic objectives be based on the manifestations
of the disease in the individual at the time a change in therapy is
being considered. As such, for the patient with symptomatic bone
disease, relief of pain can be more clinically relevant than lowering
the PSA. Naturally, for all patients, the central focus is delaying or
preventing disease progression, symptoms, and death from disease.
Through 2010, docetaxel was the only FDA-approved life-
prolonging therapy for CRPC. Since then, our understanding of the
biology of the disease has increased significantly, which in turn has
led to improved therapies. It is now recognized that the majority of
metastatic CRPCs continue to express the AR and remain AR sig­
naling dependent. For those with progression after ADT alone, the
next-generation antiandrogen enzalutamide and the CYP17 inhibi­
tor abiraterone acetate (given in combination with prednisone)
have been proven to prolong life and are FDA approved for use in
CRPC in both the pre- and postchemotherapy setting.
Large-scale molecular profiling efforts have led to a biologically
based disease taxonomy that continues to evolve and showed a mark­
edly higher than expected frequency of germline (~6% of patients)
and somatic BRCA (also ~6% of patients) alterations, along with other
genes in the DNA damage repair pathway that have been targeted
successfully with poly-ADP ribose polymerase (PARP) inhibitors of
which two, olaparib and rucaparib, are FDA approved as monothera­
pies. Combinations of abiraterone and olaparib are FDA approved for
BRCA1/BRCA2-mutated CRPC patients, and enzalutamide/talozapa­
rib combinations are approved for BRCA1/BRCA2-mutated patients
and other DNA repair pathway mutations. Also approved are the
checkpoint inhibitors pembrolizumab and dostarlimab for tumors
with high microsatellite instability (MSI) scores, mismatch repair
gene deficiency, or patients with a high tumor mutational burden.
These alterations are found in ~3% of prostate cancers.
Other classes of therapy approved for selected CRPC patients
based on demonstrated survival benefits include the biologic
agent sipuleucel-T, the second-generation taxane cabazitaxel, the
α-emitting bone-targeting radiopharmaceutical radium-223, and
the PSMA-directed radionuclide therapy 177-lutetium PSMA-617.
The use of 177-lutetium PSMA-617 has garnered intense interest
given that this targeted form of radiation was able to extend sur­
vival in patients who had exhausted most conventional forms of
therapy. Overall, an intense focus of current CRPC research is to
understand the optimal sequence in which to utilize these agents
to maximize benefit for the individual patient. Most of these agents
are also being tested earlier in the course of the disease when tumor
burdens are lower and the disease less heterogeneous. The result
has been an increase in the frequency of late-state tumors that have
undergone a lineage transformation from epithelial to alternative
phenotypes (neuroendocrine and more) and are highly resistant to
available therapies.
Pain Management  Pain secondary to osseous metastases is one of
the most feared complications of the disease and a major cause of
morbidity, worsened by the narcotics needed to control symptoms.
Management requires accurate diagnoses because noncancer eti­
ologies including degenerative disease, spinal stenosis, and vertebral
TABLE 92-2  AUA Symptom Index
QUESTIONS TO BE ANSWERED
NOT AT ALL
Over the past month, how often have you had a sensation of not
emptying your bladder completely after you finished urinating?
0+
Over the past month, how often have you had to urinate again
less than 2 h after you finished urinating?
Over the past month, how often have you found you stopped and
started again several times when you urinated?
Over the past month, how often have you found it difficult to
postpone urination?
Over the past month, how often have you had a weak urinary
stream?
Over the past month, how often have you had to push or strain to
begin urination?
Over the past month, how many times did you most typically get
up to urinate from the time you went to bed at night until the time
you got up in the morning?
(None)
(1 time)
(2 times)
(3 times)
(4 times)
(5 times)
Sum of 7 circled numbers (AUA Symptom Score): ____
Abbreviation: AUA, American Urological Association.
Source: Modified with permission from MJ Barry et al: The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee
of the American Urological Association. J Urol 148:1549, 1992.
collapse secondary to bone loss are common. Neurologic symptoms,
including those suggestive of base of skull disease or spinal cord
compromise, require emergency evaluation because loss of function
may be permanent if not addressed quickly. Neurologic symptoms
and loss of function are best treated with external beam radiation,
as are single sites of pain. Diffuse symptoms in the absence of neu­
rologic deficits can be treated with bone-seeking radioisotopes, such
as radium-223 or the β emitter 153Sm–ethylene-diamine-tetrameth­
ylene-phosphonic acid (EDTMP); mitoxantrone; or other systemic
therapies. Radium-223 is indicated for patients with symptoms and
has been shown to prolong survival, whereas 153Sm-EDTMP and
mitoxantrone are approved for the palliation of pain but have not
been shown to prolong life. Abiraterone, enzalutamide, docetaxel,
cabazitaxel, and Lu-177 PSMA-617 do not have a formal indication
for pain but were shown to palliate pain in the registration trials that
led to their approval by showing a survival benefit.
Other bone-targeting agents, including bisphosphonates such as
zoledronic acid and the RANK-ligand inhibitor denosumab, have
been shown to reduce the frequency and development of skeletal
complications including pain requiring analgesia, neurologic com­
promise from epidural extension of tumor, and/or the need for
surgery or radiation therapy to treat symptomatic osseous disease.
It is important to note that, for all of these agents, the direct effects
on the tumor are limited and benefits are seen without declines in
PSA or improvements on imaging.
CHAPTER 92
BENIGN DISEASE
Benign and Malignant Diseases of the Prostate
■
■BENIGN PROSTATIC HYPERPLASIA
BPH is a pathologic process that contributes to the development of
lower urinary tract symptoms (LUTS) in patients. LUTS, arising from
lower urinary tract dysfunction, are further subdivided into obstruc­
tive symptoms (urinary hesitancy, straining, weak stream, terminal
dribbling, prolonged voiding, incomplete emptying) and irritative
symptoms (urinary frequency, urgency, urge incontinence, small
voided volumes). LUTS and other sequelae of BPH are not just due to
a mass effect but are also likely due to a combination of the prostatic
enlargement and age-related detrusor dysfunction.
Diagnostic Procedures and Treatment 
LUTS are generally
measured using a validated, reproducible index that is designed to
determine disease severity and response to therapy—the AUA’s Symp­
tom Index (AUASI), also adopted as the International Prostate Symp­
tom Score (IPSS) (Table 92-2). Serial AUASI is particularly useful in
AUA SYMPTOM SCORE (CIRCLE 1 NUMBER ON EACH LINE)
LESS THAN 1
TIME IN 5
LESS THAN HALF
THE TIME
ABOUT HALF
THE TIME
MORE THAN HALF
THE TIME
ALMOST
ALWAYS

22 - 93 Testicular Cancer
93 Testicular Cancer
following patients as they are treated with various forms of therapy.
Asymptomatic patients do not require treatment regardless of the size
of the gland, while those with an inability to urinate, gross hematuria,
recurrent infection, or bladder stones require evaluation and treat­
ment. In patients with symptoms, uroflowmetry can identify those
with normal flow rates who are unlikely to benefit from treatment, and
bladder ultrasound can identify those with high postvoid residuals who
may need intervention. Pressure-flow (urodynamic) studies detect pri­
mary bladder dysfunction. Cystoscopy is recommended if hematuria
is documented and to assess the urinary outflow tract before surgery.
Imaging of the upper tracts is advised for patients with hematuria, a
history of calculi, or prior urinary tract problems.
Symptomatic relief is the most common reason patients seek treat­
ment for BPH, and therefore, symptomatic relief is usually the goal of
therapy for BPH. α-Adrenergic receptor antagonists are thought to treat
the dynamic aspect of BPH by reducing sympathetic tone of the blad­
der outlet, thereby decreasing resistance and improving urinary flow.
5ARIs are thought to treat the static aspect of BPH by reducing prostate
volume and having a similar, albeit delayed effect. 5ARIs have also
proven beneficial in the prevention of BPH progression, as measured
by prostate volume, the risk of developing acute urinary retention, and
the risk of having BPH-related surgery. The use of an alpha-adrenergic
receptor antagonist and a 5ARI as combination therapy seeks to provide
symptomatic relief while preventing progression of BPH.
PART 4
Oncology and Hematology
Another class of medications that has shown improvement in
LUTS secondary to BPH is phosphodiesterase-5 (PDE5) inhibitors,
used currently in the treatment of erectile dysfunction. All four of the
PDE5 inhibitors available in the United States—sildenafil, vardenafil,
tadalafil, and avanafil—appear to be effective in the treatment of LUTS
secondary to BPH. The use of PDE5 inhibitors is not without con­
troversy, however, given the fact that short-acting phosphodiesterase
inhibitors such as sildenafil need to be dosed separately from alpha
blockers such as tamsulosin because of potential hypotensive effects.
Symptoms due to BPH often coexist with symptoms due to overac­
tive bladder, and the most common pharmacologic agents for the treat­
ment of overactive bladder symptoms are anticholinergics. This has led
to multiple studies evaluating the efficacy of anticholinergics for the
treatment of LUTS secondary to BPH.
Surgical therapy is now considered second-line therapy and is usu­
ally reserved for patients after a trial of medical therapy. The goal of
surgical therapy is to reduce the size of the prostate, effectively reduc­
ing resistance to urine flow. Surgical approaches include TURP, trans­
urethral incision, or removal of the gland via a retropubic, suprapubic,
or perineal approach. Also used are transurethral ultrasound–guided
laser-induced prostatectomy (TULIP), stents, and hyperthermia.
■
■FURTHER READING
Bergengren O et al: 2022 Update on prostate cancer epidemiology
and risk factors: A systematic review. Eur Urol 84:191, 2023.
Deek MP et al: Multi-institutional analysis of metastasis-directed ther­
apy with or without androgen deprivation therapy in oligometastatic
castration-sensitive prostate cancer. Eur Urol Oncol 7:1403, 2024.
Donovan JL et al: Patient-reported outcomes 12 years after localized
prostate cancer treatment. NEJM Evid 2:EVIDoa2300018, 2023. Erra­
tum in: NEJM Evid 2:EVIDx2300122, 2023.
Eastham JA et al: Clinically localized prostate cancer: AUA/ASTRO
Guideline. J Urol 208:505, 2022.
Fendler WP et al: Assessment of 68Ga-PSMA-11 PET accuracy in
localizing recurrent prostate cancer: A prospective single-arm clinical
trial. JAMA Oncol 5:856, 2019.
Haile ES et al: Medical management of benign prostatic hyperplasia.
Cleve Clin J Med 91:163, 2024.
Hamdy FC et al: Fifteen-year outcomes after monitoring, surgery, or
radiotherapy for prostate cancer. N Engl J Med 388:1547, 2023.
Hugosson J et al: Prostate cancer screening with PSA and MRI fol­
lowed by targeted biopsy only. N Engl J Med 387:2126, 2022.
Hussain M et al: Survival with olaparib in metastatic castration-
resistant prostate cancer. N Engl J Med 383:2345, 2020.
Kasivisvanathan V et al: MRI-targeted or standard biopsy for
prostate-cancer diagnosis. N Engl J Med 378:1767, 2018.
Merseburger AS et al: Genomic testing in patients with metastatic
castration-resistant prostate vancer: A pragmatic guide for clinicians.
Eur Urol 79:519, 2021.
Morgan TM et al: Salvage therapy for prostate cancer: AUA/ASTRO/
SUO guideline part I: Introduction and treatment decision-making at
the time of suspected biochemical recurrence after radical prostatec­
tomy. J Urol 211:509, 2024.
Pinsky PF, Parnes H: Screening for prostate cancer. N Engl J Med
388:1405, 2023.
Roach M 3rd et al: Prostate cancer, race, and health disparity: What we
know. Cancer J 29:328, 2023.
Sartor O et al: Lutetium-177-PSMA-617 for metastatic castrationresistant prostate cancer. N Engl J Med 385:1091, 2021.
Virgo KS et al: Initial management of noncastrate advanced, recurrent,
or metastatic prostate cancer: ASCO guideline update. J Clin Oncol
39:1274, 2021.
David J. Vaughn
Testicular Cancer
Testicular germ cell tumors (GCTs) represent 95% of all testicular neo­
plasms. Non-GCTs of the testis are much less common. Approximately
5% of GCTs arise in extragonadal locations including the mediastinum,
retroperitoneum, and pineal gland. Treatment for testicular GCTs
is determined by pathology and stage. The development of effective
chemotherapy for this disease represents a landmark achievement in
oncology. About 95% of newly diagnosed patients with testicular GCTs
will be cured. For this reason, testicular cancer has been called “a model
for a curable neoplasm.”
INCIDENCE AND GLOBAL
CONSIDERATIONS
In 2023, ∼9200 cases of testicular GCTs will be diagnosed in the United
States, with 470 deaths. The incidence of testicular GCTs appears to
be increasing worldwide. The disease has the highest incidence in
Scandinavia, Western Europe, and Australia/New Zealand. Africa and
Asia have the lowest incidence. The incidence in the United States and
the United Kingdom is intermediate. While a distinct biology related to
geography is not apparent, several countries have reported a migration
to earlier stage disease in part related to public awareness and earlier
diagnosis.
■
■EPIDEMIOLOGY
Testicular GCT is the most common malignancy diagnosed in adoles­
cent and young adult males (defined as age 15–39 years). The incidence
in patients over 50 is increasing. Testicular GCT is most commonly
diagnosed in Caucasians. The disease is much less commonly seen in
African Americans. Testicular GCTs have an estimated heritability of
almost 50%. Interestingly, the risk of GCT is higher in male siblings
than in offspring of the patient. Although epidemiologic studies have
been performed attempting to identify a relationship with environmental
exposures, no conclusive causal links have been established.
Risk Factors 
The strongest risk factors for testicular GCT include a
prior history of the disease, cryptorchidism, and a history of testicular
germ cell neoplasia in situ. Patients with a prior history of testicular
GCT have a 1–2% risk of developing a contralateral GCT. These are
more commonly metachronous than synchronous. Men with crypt­
orchidism have approximately a four- to sixfold increased risk of
developing testicular GCT. Orchidopexy before puberty decreases but
does not eliminate this risk. Interestingly, the contralateral descended
testis is also at risk for this disease. Men undergoing infertility evalu­
ation in which a testicular biopsy demonstrates germ cell neoplasia
in situ have a significant risk of developing GCT. Although scrotal
ultrasound of patients with testicular GCT may demonstrate testicular
microcalcifications that may be related to germ cell neoplasia in situ,
the significance of testicular microcalcifications in the general popula­
tion is unclear.
■
■BIOLOGY
The primordial germ cell is the cell of origin for GCTs. Most malignant
GCTs arise from in situ neoplasia. The molecular events that result in
the development of germ cell neoplasia in situ and subsequent malig­
nant GCT have not been fully determined. However, genetic analysis
of GCTs has demonstrated an excess copy number of isochromosome
12p (i[12p]) in most cases. Several genome-wide association studies
have identified multiple independent loci associated with testicular
GCT risk. The strongest of these is the KITLG (KIT ligand) locus on
chromosome 12. These loci contribute significantly to the heritable risk
of this disease.
■
■PATHOLOGY
GCTs are either seminomas or nonseminomas. For a tumor to be
considered a seminoma, it must be 100% seminoma. Any mixed GCT
should be approached as a nonseminomatous GCT. Seminomas repre­
sent ∼50% of cases. Seminomas arise most commonly in patients in the
fourth decade of life. Seminomas may contain syncytiotrophoblastic
cells, which may secrete β-human chorionic gonadotropin (hCG).
Seminomas do not secrete α-fetoprotein (AFP). Seminomas are exqui­
sitely sensitive to both chemotherapy and radiation therapy. Nonsemi­
nomatous GCTs are most commonly diagnosed in the third decade of
life. The histologic subtypes include embryonal carcinoma, yolk sac
tumor, choriocarcinoma, and teratoma. Embryonal carcinoma is the
most undifferentiated nonseminomatous GCT subtype with the poten­
tial to differentiate into the other subtypes. Embryonal carcinoma may
secrete AFP, hCG, both, or neither. Yolk sac tumor often secretes AFP.
Choriocarcinoma is an aggressive subtype, often secreting hCG at very
high levels. These nonseminomatous GCT subtypes are all considered
chemotherapy sensitive. Teratoma is composed of somatic cell types
that are derived from two or more germinal layers (endoderm, meso­
derm, and ectoderm). Teratomas are classified as mature, in which
cell types resemble normal adult somatic tissue; immature, in which cell
types resemble fetal somatic tissue; and malignant, in which the cell
types have undergone malignant transformation into the malignant
counterpart of the somatic tissue. Teratomas are chemotherapy resis­
tant and must be treated surgically.
■
■INITIAL PRESENTATION
Signs and Symptoms 
Although a painless testicular mass is
pathognomonic of a GCT, most patients present with testicular swell­
ing, firmness, discomfort, or a combination of these. The differential
diagnosis may include epididymitis or orchitis, and a trial of antibacte­
rials may be considered. Patients with retroperitoneal metastases may
complain of back or flank pain. Patients may have cough, shortness
of breath, or hemoptysis because of lung metastases. In patients with
elevation of serum hCG, gynecomastia may be present. Diagnostic
delay is not uncommon and may be associated with a more advanced
stage at diagnosis.
Physical Examination 
Careful examination of the affected testis
and the contralateral normal testis should be performed. Many tumors
will have a hard consistency to palpation. Some patients may show
testicular atrophy. Evaluation for supraclavicular lymphadenopathy,
gynecomastia, and abdominal mass should be performed. Inguinal
lymphadenopathy is rare. Most patients with lung metastases will have
normal auscultation of the lungs.
Diagnostic Testing 
If a firm testicular mass is identified, a scrotal
ultrasound should be performed. Patients with suspected epididymitis
or orchitis who do not respond to antibiotics should also undergo
scrotal ultrasound. Scrotal ultrasound should include both testicles.
On ultrasound, a testicular GCT is hypoechoic and may be multifocal.
A solid mass identified on ultrasound should be considered malignant
until otherwise proven. Transscrotal aspiration or biopsy of a testicular
mass should never be performed. Such scrotal violation may result in
tumor seeding of the scrotum or inguinal lymph nodes.
Serum Tumor Markers 
Serum AFP, hCG, and lactate dehydro­
genase (LDH) should be measured in patients suspected of testicular
GCT. AFP is elevated in ∼60–70% of patients who present with non­
seminomatous GCTs. Seminomas never secrete AFP. A patient with
a seminoma with elevation of AFP should be approached as having
a nonseminomatous GCT. The half-life of AFP is 5–7 days. A falsely
elevated AFP may be seen in patients with hepatic disease or a condi­
tion called hereditary persistence of AFP, in which patients may have
baseline AFP levels that are mildly elevated. hCG may be elevated in
both nonseminomatous GCTs as well as seminomas. Patients with cho­
riocarcinoma may have markedly elevated levels of hCG. The half-life
for hCG is 24–36 h. False-positive elevation of hCG may be seen sec­
ondary to hypogonadism, marijuana use, or because of interfering sub­
stances measured by the assay. LDH is a nonspecific marker for GCT.
Its principal use is to help in the assessment of the risk classification of
a patient with metastatic disease. Although elevation of serum tumor
markers supports the diagnosis of a testicular GCT, most patients with
seminoma and up to a third of patients with nonseminomatous GCTs
do not have elevated levels. Serum microRNA (miR)-371a-3 has been
identified as a promising biomarker for GCT, and validation studies
are ongoing.
CHAPTER 93
Testicular Cancer
■
■INITIAL MANAGEMENT
Inguinal Orchiectomy 
Prompt referral to urology should be
performed if a testicular GCT is suspected. The initial treatment for
most patients suspected of having a testicular GCT is radical ingui­
nal orchiectomy with removal of the testicle and spermatic cord to
the level of the internal inguinal ring. In patients who present with
metastatic disease and the diagnosis of GCT is certain, orchiectomy
may be deferred until completion of chemotherapy. Although some
institutions perform testis-sparing surgery in select patients, the gold
standard remains radical inguinal orchiectomy. Pathologic examina­
tion of the entire testicle is important, since testicular GCTs may be
multifocal. Given the rarity of this cancer, review by an experienced
pathologist is essential for accurate tumor classification. Serum tumor
markers should be obtained before and after orchiectomy.
Staging 
The staging of testicular GCT is based on an understanding
of the pattern of spread. The initial spread is by the lymphatic route to the
retroperitoneal lymph nodes. A left-sided testicular GCT spreads first to
the primary landing zone of left paraaortic lymph nodes inferior to the
left renal vessels. A right-sided testicular GCT spreads first to the primary
landing zone of the aortocaval nodes inferior to the right renal vessels.
Nodal metastases may extend into the iliac regions. If scrotal violation
occurred, inguinal lymph node metastases may be seen. Subsequent
lymphatic spread is to the retrocrural, mediastinal, and supraclavicular
lymph nodes. Hematogenous spread to the lung is the next most com­
mon site of metastasis. Metastases to the liver, bone, and brain are less
common. Patients with newly diagnosed testicular GCTs should undergo
computed tomography (CT) scan of the abdomen and pelvis. Chest x-ray
should be performed. CT scan of the chest is performed if retroperitoneal
metastases are present or if lung nodules are identified on chest x-ray.
Bone scan and magnetic resonance imaging (MRI) of the brain are
not routinely performed unless clinically indicated. Positron emission
tomography (PET) has little role in the initial staging of testicular GCTs.
The American Joint Committee on Cancer tumor-node-metastasis
(TNM) staging classification is used. There are three main stages of
testicular GCT. Stage I is limited to the testis; stage II involves the ret­
roperitoneal lymph nodes; and stage III includes lymph node involve­
ment beyond the retroperitoneum and/or distant metastatic disease.
■
■STAGE-BASED MANAGEMENT
Treatment of testicular GCT is based on two factors: (1) whether the
tumor is seminoma or nonseminomatous GCT and (2) the stage of the
patient. This is summarized in Fig. 93-1.
Stage I 
• 
SEMINOMA  About 70% of newly diagnosed patients
with seminoma present with stage I disease. This is defined as no
evidence of metastatic disease on imaging of the chest, abdomen, and
pelvis. Approximately 15% of patients with stage I seminoma have
metastatic disease at the microscopic level, usually in the retroperito­
neum. Historically, patients with stage I seminoma were treated with
a course of adjuvant radiation therapy to the paraaortic lymph nodes.
While still an option, this is not usually performed because of concerns
for late radiation-induced secondary malignancies. Active surveillance
is the most common approach elected by these patients following
orchiectomy. With active surveillance, interval physical examination
and CT scan of the abdomen are performed. For the 15% of patients
who develop metastatic disease during active surveillance, treatment
is curative in nearly all. A third option for clinical stage I seminoma
is adjuvant chemotherapy with carboplatin monotherapy for one or
two cycles. While effective in decreasing the risk of recurrence, most
patients are cured by orchiectomy alone, and therefore, the additional
treatment is unnecessary. In addition, long-term data on toxicity are
not available.
PART 4
Oncology and Hematology
NONSEMINOMATOUS GCTS  About 40% of newly diagnosed patients
with nonseminomatous GCTs present with stage I disease. Because
nonseminomatous GCTs have an increased potential for invasion and
metastasis, spread to the retroperitoneum and beyond is more com­
mon than with seminoma. If pre-orchiectomy serum tumor markers
are elevated, these must normalize after orchiectomy to be considered
stage I. Patients with persistently elevated or rising serum tumor mark­
ers after orchiectomy have stage IS disease and should be treated with
cisplatin-based chemotherapy. If the tumor is limited to testis without
lymphovascular invasion, the risk of recurrence is approximately 20%.
However, if the tumor has high-risk features including lymphovascular
invasion, invasion of the spermatic cord, or invasion of the scrotum,
the risk of recurrence is ∼50% or higher. Historically, a prophylactic
retroperitoneal lymph node dissection (RPLND) was performed.
This surgery is not only diagnostic but also therapeutic. In fact, most
patients who undergo prophylactic RPLND will never require chemo­
therapy. While still an option, this approach subjects many patients
to unnecessary major abdominal surgery. RPLND is also associated
with a small risk of retrograde ejaculation due to nerve injury, and
nerve-sparing techniques have been developed. Active surveillance is
frequently performed especially for patients without lymphovascular
invasion. Most patients who relapse will be treated with cisplatin-based
chemotherapy and achieve cure rates approaching 100%. Active sur­
veillance can also be employed for patients with higher risk features,
although the risk of progression is significantly higher. For this rea­
son, some advocate adjuvant cisplatin-based chemotherapy with BEP
(bleomycin, etoposide, cisplatin) for one cycle for these patients. Other
centers favor a prophylactic RPLND. Almost all patients who present
with stage I nonseminomatous GCTs will achieve cure.
Stage II 
• 
SEMINOMA  Approximately 15–20% of newly diag­
nosed patients with seminoma present with stage II disease. Patients
are subgrouped into IIA, IIB, or IIC based on the size of the retroperi­
toneal nodes (≤2 cm, >2 to 5 cm, or >5 cm, respectively). Patients with
stage IIA disease are usually treated with “dogleg” radiation therapy
(referring to the shape of the radiation field), which includes the para­
aortic and ipsilateral iliac nodes. Cisplatin-based chemotherapy may
also be considered. Stage IIB disease is treated with cisplatin-based
chemotherapy or, in select patients, radiation therapy. Most patients
treated with radiation therapy who relapse will subsequently be cured
with cisplatin-based chemotherapy. RPLND has been considered in
select patients with stage IIA and nonbulky stage IIB seminoma in an
effort to avoid chemotherapy and radiation therapy. For patients with
stage IIC disease, cisplatin-based chemotherapy should be used.
NSGCTS  Approximately 15% of newly diagnosed patients with non­
seminomatous GCTs present with clinical stage II disease. Patients with
stage IIA disease may be treated with primary RPLND. Alternatively,
these patients may be treated with cisplatin-based chemotherapy.
Patients with stage IIB and IIC disease are best initially managed with
cisplatin-based chemotherapy.
Stage III 
Patients who present with stage III GCT (seminoma or
nonseminomatous GCT) are treated with cisplatin-based chemother­
apy. These patients are classified into good-, intermediate-, or poor-risk
categories using the International Germ Cell Consensus Classification
system, which is based on clinical factors including histology, site of
primary, the presence of nonpulmonary visceral metastatic disease,
and the level of postorchiectomy serum tumor markers (Table 93-1).
Most patients with stage III GCT present with good-risk disease and
90% will be cured. The remainder present with intermediate-risk or
poor-risk disease associated with 5-year survival rates of ∼80% and
50%, respectively. Select patients with rapidly progressive metastatic
disease and life-threatening symptoms such as hemoptysis in whom
there is a high clinical suspicion of GCT should emergently initiate
cisplatin-based chemotherapy, even without a tissue diagnosis.
Chemotherapy 
The development of cisplatin-based chemotherapy
represents an important advance in cancer medicine. Through a series
of carefully performed clinical trials with the aim of maximizing cure
while minimizing the extent of treatment, the chemotherapy approach
to the treatment of these patients has been standardized. Patients with
good-risk metastatic GCT are treated with either three cycles of BEP or
four cycles of etoposide and cisplatin (EP). Patients with intermediate- and
poor-risk metastatic disease are treated with either four cycles of BEP
or four cycles of etoposide, ifosfamide, and cisplatin (VIP). Maintain­
ing dose and schedule is important, as dose modifications and delays
have been associated with inferior outcomes. Serum tumor markers
should be monitored throughout treatment and should normalize
during or after treatment. Cisplatin-based chemotherapy is associated
with myelosuppression, nausea and vomiting, and alopecia. Cisplatin
may result in nephrotoxicity, ototoxicity, and peripheral neuropathy.
Bleomycin may result in pulmonary toxicity, and risk factors for this
include age >40, renal failure, tobacco use, and the cumulative dose
of bleomycin received. For patients at increased risk of bleomycininduced pneumonitis, non–bleomycin-containing regimens as noted
above may be given. Cisplatin-based chemotherapy is also associated
with sterility. Approximately 30% of newly diagnosed testicular GCT
patients have severe oligospermia or azoospermia. For the remainder
with normal baseline spermatogenesis who receive cisplatin-based
chemotherapy, all will be azoospermic at the completion of therapy.
Approximately 80% of these patients will recover spermatogenesis
over a period of several years. For this reason, prechemotherapy sperm
banking should be offered to all patients treated with chemotherapy.
Postchemotherapy Surgery 
Upon completion of cisplatin-based
chemotherapy, many patients with normalized serum tumor markers
will have radiographic evidence of residual masses. In approximately
half of patients with nonseminomatous GCT, the residual mass is
composed of necrosis and/or fibrosis. About 40% will have residual
teratoma, and only 10% will have residual viable nonteratomatous
GCT. Unfortunately, radiographic imaging cannot accurately differen­
tiate between these entities. For this reason, nonseminomatous GCT
patients with residual masses after chemotherapy undergo resection of
all sites of disease. This most commonly includes a postchemotherapy
RPLND. However, thoracotomy and neck dissection are required in
some patients. Given the complexity of this surgery, patients should
be referred to highly experienced centers. If the patients are found to
have residual necrosis or teratoma, no additional therapy is required.
Testis
Seminoma
NSGCT
Stage IA
Testis only, no lymphovascular
invasion
Active surveillance; or
Adjuvant carboplatin × 1 or 2
cycles; or Adjuvant para-aortic RT
Stage IB
Testis only, with
lymphovascular invasion or
invasion of spermatic cord or scrotum
Active surveillance; or
Adjuvant carboplatin × 1 or 2
cycles; or Adjuvant para-aortic RT
Stage IS
Elevated serum tumor markers postorchiectomy
BEP × 3 cycles; or
EP × 4 cycles
BEP × 3 cycles; or
EP × 4 cycles
A
Lymph
nodes
Seminoma
NSGCT
Stage IIA
N1: nodes ≤ 2 cm
Para-aortic and ipsilateral iliac RT; or
BEP × 3 cycles or EP × 4 cycles;
Nerve-sparing RPLND in select
patients
Stage IIB
N2: nodes > 2 to 5 cm
BEP × 3 cycles or EP × 4 cycles; or
Para-aortic and ipsilateral iliac RT
BEP × 3 cycles or EP × 4 cycles +/–
postchemotherapy RPLND
Stage IIC
N3: nodes > 5 cm
BEP × 3 cycles or EP × 4 cycles
BEP × 3 cycles or EP × 4 cycles +/–
postchemotherapy RPLND
B
FIGURE 93-1  Stage-based management of testicular germ cell tumor.
Stage 1
CHAPTER 93
Active surveillance; or
Nerve-sparing RPLND; or
Adjuvant BEP × 1 cycle
Active surveillance; or
Adjuvant BEP × 1 cycle; or
Nerve-sparing RPLND
Testicular Cancer
Stage 2
Testis
Nerve-sparing RPLND; or
BEP × 3 cycles or EP × 4 cycles
Stage 3
Lungs
Liver
Lymph
nodes
Testis
PART 4
Oncology and Hematology
Seminoma
NSGCT
Stage IIIA
(good-risk)
BEP × 3 cycles;
or EP × 4 cycles
BEP × 3 cycles;
or EP × 4 cycles;
+/– Postchemotherapy surgery
Stage IIIB
(intermediate-risk)
BEP × 4 cycles; or
VIP × 4 cycles
BEP × 4 cycles; or
VIP × 4 cycles
+/– Postchemotherapy surgery
Stage IIIC
(poor-risk)
N/A
BEP × 4 cycles; or
VIP × 4 cycles
+/– Postchemotherapy surgery
Abbreviations: BEP, bleomycin, etoposide, cisplatin; EP, etoposide, cisplatin; N/A,
not applicable; NSGCT, nonseminomatous germ cell tumor; RPLND, retroperitoneal
lymph node dissection; RT, radiation therapy; VIP, etoposide, ifosfamide, cisplatin.
C
FIGURE 93-1  (Continued)
TABLE 93-1  International Germ Cell Consensus Classification System
RISK GROUP
SEMINOMA
NSGCT
Good
Any primary site; and
normal AFP, any hCG, any
LDH; and nonpulmonary
visceral metastases
absent
Gonadal or retroperitoneal primary;
and nonpulmonary visceral
metastases absent; and
AFP <1000 ng/mL; and
hCG <5000 mIU/mL; and
LDH <1.5 × ULN
Intermediate
Any primary site; and
normal AFP, any hCG, any
LDH; and nonpulmonary
visceral metastases
present
Gonadal or retroperitoneal primary;
and nonpulmonary visceral
metastases absent; and one of the
following:
AFP 1000–10,000 ng/mL
HCG 5000–50,000 mIU/mL
LDH 1.5–10 × ULN
Poor
N/A
Mediastinal primary; or
nonpulmonary visceral metastases
present; or one of the following:
AFP >10,000 ng/mL
HCG >50,000 mIU/mL
LDH >10 × ULN
Abbreviations: AFP, α-fetoprotein; hCG, human chorionic gonadotropin; LDH, lactate
dehydrogenase; N/A, not applicable; NSGCT, nonseminomatous germ cell tumor;
ULN, upper limit normal. Nonpulmonary visceral metastases include liver, bone, and
brain.
Source: Reproduced with permission from International Germ Cell Cancer
Collaborative Group: International Germ-Cell Consensus Classification: A prognostic
factor based staging system for metastatic germ cell tumors. J Clin Oncol 15:594, 1997.
Brain
Bone
However, for patients with residual viable nonteratomatous GCT, two
additional cycles of chemotherapy may be considered. It should be
noted that in most centers, patients with minimal residual tumors
defined as retroperitoneal lymph nodes of ≤1 cm forego postchemo­
therapy RPLND. Patients who experience normalization of serum
tumor markers with first-line chemotherapy but have enlarging
tumors, most often cystic masses in the retroperitoneum, may have
“growing teratoma syndrome.” These patients are best approached with
surgery.
For patients with metastatic seminoma, most residual masses are
necrotic and do not harbor viable tumor. Patients with residual masses
of 3 cm or less may be observed without surgery. For patients with
residual masses >3 cm, fluorodeoxyglucose (FDG)-PET may be used to
distinguish necrosis from viable seminoma and identify patients who
should be considered for postchemotherapy surgery or short interval
imaging.
■
■RELAPSED DISEASE
Approximately 20–30% of patients with metastatic GCTs treated with
cisplatin-based chemotherapy will not achieve durable disease control.
Most of these patients will experience disease progression within 2 years
following completion of chemotherapy. The International Prognostic
Factors Study Group developed a risk stratification classification sys­
tem for patients in first relapse. Contributors to a worsened prognosis
include NSGCT histology, extragonadal primary, incomplete response
to first-line chemotherapy, time to relapse of 3 months or less, level of
serum tumor markers at relapse, and the presence of nonpulmonary
visceral metastatic disease.

23 - 94 Gynecologic Malignancies
94 Gynecologic Malignancies
Patients in first relapse may be treated with either conventionaldose salvage chemotherapy or high-dose salvage chemotherapy with
autologous stem cell rescue. There is controversy concerning which
approach is optimal. Some institutions advocate for risk stratification,
with more favorable prognosis patients receiving conventional-dose
chemotherapy and worse prognosis patients receiving high-dose che­
motherapy. The most commonly utilized conventional-dose regimen
includes paclitaxel, ifosfamide, and cisplatin (TIP). High-dose chemo­
therapy consists of initial salvage therapy followed by stem cell harvest
and then two or three cycles of high-dose carboplatin and etoposide
(CE) with stem cell rescue. A large retrospective analysis has com­
pared conventional-dose salvage chemotherapy to high-dose salvage
chemotherapy in patients in first relapse. This study reports a more
favorable outcome with high-dose salvage chemotherapy across nearly
all risk groups. However, given the retrospective nature of this study
and the controversy concerning optimal approaches, an international
randomized trial comparing conventional-dose chemotherapy (TIP) to
high-dose chemotherapy with autologous stem cell rescue (TI-CE) has
completed accrual and results are forthcoming.
Some patients who experience disease progression after conven­
tional-dose salvage chemotherapy may successfully be treated with
high-dose salvage chemotherapy with autologous stem cell rescue.
Patients with disease progression after high-dose salvage chemo­
therapy may be treated with subsequent chemotherapy regimens that
include gemcitabine/oxaliplatin, gemcitabine/paclitaxel, epirubicin/
cisplatin, and oral etoposide. While these patients may benefit from
third-line chemotherapy, few will achieve durable disease control.
Select patients with relapsed but resectable disease may be candidates
for salvage or so-called “desperation” surgery. Studies of molecularly
targeted agents and immune checkpoint inhibitors in this population
have to date been generally disappointing.
Patients who experience disease progression >2 years after chemo­
therapy are considered to have “late relapse.” Late relapse appears to
have a different biology than early relapse. These patients tend to have
more chemotherapy-resistant disease. Patients with late relapse usu­
ally have nonseminomatous GCT with elevation of serum AFP. Many
of these patients experience recurrence in the retroperitoneum many
years after first-line chemotherapy, and this likely represents residual
retroperitoneal disease that was not controlled after first-line therapy.
These patients are best approached with salvage surgery.
■
■EXTRAGONADAL GERM CELL TUMORS
Approximately 5% of patients who present with GCTs have extrago­
nadal primaries. These mainly originate in the mediastinum or retro­
peritoneum. Patients suspected of extragonadal GCT should undergo
scrotal ultrasound to exclude a gonadal primary. Extragonadal semi­
nomas have a similar excellent prognosis as their gonadal counterparts
and are approached the same. Mediastinal nonseminomatous GCTs are
classified as poor risk and are treated with either four cycles of BEP or
four cycles of VIP. These patients frequently require postchemotherapy
thoracic surgery for residual disease. For this reason, some advocate
avoiding bleomycin in this patient population. Klinefelter’s syndrome
is associated with an increased risk of mediastinal nonseminomatous
GCTs. Rarely, mediastinal nonseminomatous GCTs are associated with
hematologic disorders including acute myeloid leukemia. Nonsemi­
nomatous GCTs arising in the retroperitoneum do not have a worse
prognosis than their gonadal counterparts. Many patients who present
with extragonadal GCTs will undergo core needle biopsy for diagno­
sis. However, select patients with extragonadal tumors and definitive
elevation of serum tumor markers may initiate chemotherapy without
a tissue diagnosis.
Cancers of unknown primary are defined as histologically proven
metastatic malignancy in which the primary site is not obvious. A
subgroup of patients with cancer of unknown primary have occult
GCTs. Male gender, age <65 years, midline tumors, and nonsmok­
ing status increase the likelihood of this presentation. Pathology may
demonstrate a poorly differentiated malignant neoplasm. Immunohis­
tochemical staining is used to exclude lymphoma. Tumor may be ana­
lyzed by fluorescence in situ hybridization for i(12p), which confirms
the diagnosis. Even if the diagnosis is not certain, patients should be
treated with cisplatin-based chemotherapy, which will cure up to 20%
of this patient group.
■
■TESTICULAR NON–GERM CELL TUMORS
Rarely, patients may develop testicular non-GCTs. These include nonHodgkin’s lymphoma, most commonly occurring in men over the age
of 50; sex cord stromal tumors including Leydig cell tumors and Sertoli
cell tumors; mesothelioma of the tunica vaginalis; and paratesticular
sarcoma. Metastasis to the testis is rare, most commonly occurring in
patients with advanced prostate cancer and melanoma.
■
■SURVIVORSHIP AND LATE EFFECTS
Because most patients with testicular GCT will experience long-term
survival, survivorship care is important. Since primary care physicians
will follow many of these patients, an understanding of the physical,
psychological, and social late effects is important. Late effects are
defined as health problems that occur months or years after a disease
is diagnosed or after treatment has ended. Late effects may be related to
the underlying cancer or to the treatment the patient received. In longterm survivors of testicular GCT, increased cardiovascular risk and
increased secondary malignancies have been reported. Patients treated
with cisplatin-based chemotherapy have an increased risk of hyperten­
sion, hyperlipidemia, metabolic syndrome, and cardiovascular events.
Patients treated with high cumulative doses of etoposide (e.g., patients
who receive standard chemotherapy, relapse, and then receive salvage
high-dose chemotherapy) may experience up to a 1–2% risk of devel­
oping acute myeloid leukemia, typically 2–3 years after completing
therapy and associated with an 11q23 translocation. Patients treated
with radiation therapy, cisplatin-based chemotherapy, or both have an
increased risk of developing secondary solid malignancies.
CHAPTER 94
Gynecologic Malignancies
■
■FURTHER READING
King J et al: Testicular cancer: Biology to bedside. Cancer Res 81:5369,
2021.
Lobo J et al: Molecular biomarkers with potential clinical application
in testicular cancer. Mod Pathol 36:100307, 2023.
Pluta J et al: Identification of 22 novel susceptibility loci associated
with testicular germ cell tumors. Nat Commun 12:4487, 2021.
Travis LB et al: Adolescent and young adult germ cell tumors: Epi­
demiology, genomics, treatment, and survivorship. J Clin Oncol
42:696-706, 2024.
David Spriggs
Gynecologic
Malignancies
OVARIAN CANCER
■
■INCIDENCE AND PATHOLOGY
Ovarian cancer remains a leading cause of cancer deaths in American
women, ranking behind lung, breast, colon, and pancreatic cancers.
The ovary is responsible for hormone production and egg produc­
tion, including maturation and ovulation with the supporting cyclical
production of sex steroid hormones. These complex biologic func­
tions are linked to populations of stromal cells, ovarian germ cells,
and the enveloping epithelial cells. Malignancies arising from each
group include multiple histologic variants, each with unique neoplastic
behaviors. Epithelial tumors are, by far, the most common histologic
variant of ovarian neoplasms; they may be benign (50%), frankly
malignant (33%), or of borderline malignancy (low malignant poten­
tial) (16%). In adnexal masses detected by imaging or physical exam,
age influences risk of malignancy; tumors in younger women are more
likely benign. In the malignant group, the most common tumors are
epithelial. In the group of the ovarian epithelial malignancies are the
serous tumors (60–70%), mucinous tumors (10%), endometrioid
tumors (10–15%), and clear cell tumors (10–15%) tumors. The dis­
tribution of histologic types varies in different parts of the world. The
less common stromal tumors arise from the ancillary, supportive cells
such as steroid hormone–producing cells and likewise have different
phenotypes and clinical presentations. Most stromal tumors do not
produce estrogen, but ectopic hormone production can be seen in
certain subtypes. Tumors arising in the ovarian germ cell lineage are
generally similar in biology and behavior to testicular tumors in males,
although their intraperitoneal location alters some metastatic behaviors
(Chap. 93). Ovarian tissue may also host metastatic epithelial tumors
arising from breast, colon, gastric, and pancreatic primaries. Bilateral
ovarian masses from metastatic mucin-secreting gastrointestinal can­
cers are termed Krukenberg tumors. Consideration of other potential
malignancies is part of the diagnostic workup of ovarian masses.
■
■OVARIAN CANCER OF EPITHELIAL ORIGIN
Epidemiology 
An American woman has approximately a 1 in 72
lifetime risk (1.6%) of developing ovarian cancer, with the majority of
affected women developing epithelial tumors. In 2024 in the United
States, ~19,710 cases of ovarian cancer are expected to be diagnosed,
with >13,270 deaths. Sporadic (not familial) epithelial tumors of the
ovary have a peak incidence in women in their fifties and sixties,
although age at presentation ranges from the third decade to the eight­
ies and nineties. Ovarian cancer risk has been linked to an interactive
mixture of epidemiologic, environmental, and genetic factors. Nul­
liparity, obesity, diet, infertility treatments, talc exposure, and possibly
hormone replacement therapy have all been linked to an increase in
risk. Protective factors include the use of oral contraceptives, multipar­
ity, tubal ligation, aspirin use, and breast-feeding. Other epidemiologic
factors such as the historical use of perineal talc agents remain contro­
versial. The mechanisms underlying the various protective factors are
largely unknown, but it is increasingly clear that dysplasia and in situ
cancers are seen within the fallopian tube and probably are the original
site for a large percentage of cancers.
PART 4
Oncology and Hematology
Genetics and Pathogenesis 
Ovarian cancers are divided into
type 1 cancers and the more aggressive type 2 variant. The type 1 can­
cers are characterized by low-grade histology and generally indolent
behavior. These tumors include the low malignant potential tumors,
low-grade endometrial and mucinous histologies, and clear cell can­
cers (which are more aggressive). Genetic alterations in type 1 cancers
include mutations in KRAS, BRAF, PTEN, and PIK3CA. In contrast,
type 2, high-grade serous epithelial ovarian cancers show serial genetic
changes in the fallopian tube with loss of BRCA1/2 function and TP53
mutation leading to intraepithelial cancer in the luminal epithelium.
Following these early genetic events, additional mutations in these
transformed cells lead to tumor cell shedding, metastasis, and invasion.
These type 2, poorly differentiated, serous cancer cells can then spread
to the ovaries and the peritoneal cavity, aided by the ovarian cancer
cell’s expression of MUC16 and binding to mesothelin-expressing cells.
Genetically, type 2 serous ovarian cancer is classically a disease
characterized by loss of TP53 (95%) and BRCA1/2 function in nearly all
cases. Widespread amplifications and deletions rather than single-gene
point mutations or common gene fusions are also present. Low preva­
lence but statistically recurrent somatic mutations in seven other genes
including NF1, RB1, and CDK12 were also seen. The most common
heritable abnormality linked to ovarian cancer is a germline mutation
in either BRCA1 (chromosome 17q12–21) or BRCA2 (chromosome
13q12–13). These genes are essential parts of the homologous DNA
repair machinery for double-stranded DNA break repair. Individuals
inheriting a single copy of a mutant allele have an increased lifetime
risk of breast (46–87% for BRCA1; 38–84% for BRCA2) and ovarian
cancer (39–63% for BRCA1; 16.5–27% for BRCA2). Many of these
women have a family history that includes multiple cases of breast and/
or ovarian cancer at an early age. Male breast cancer, pancreatic cancer,
and prostate cancer are also linked to familial BRCA2 mutations. The
most common malignancy in women carrying germline BRCA1/2
mutations is breast carcinoma, although women harboring germline
BRCA1 mutations also have a marked increased risk of developing
ovarian malignancies in their forties and fifties. Women harboring a
mutation in BRCA2 have a lower penetrance of ovarian cancer with
onset typically in their fifties or sixties. Other uncommon germline
mutations of other genes encoding proteins linked to homologous
DNA repair (e.g., PALB2) can also contribute to cancer risk, although
the frequency of mutation and magnitude of risk increment are much
lower. Germline BRCA1/2 testing is recommended for all incident epi­
thelial ovarian cancers to detect probands to identify relatives for early
therapeutic intervention. Women with these high-risk germline muta­
tions are advised to undergo prophylactic removal of fallopian tubes
and ovaries after completing childbearing, ideally before age 40. Early
prophylactic salpingo-oophorectomy is highly protective. Salpingooophorectomy also appears to protect these women from subsequent
breast cancer (risk reduction 50%). Prophylactic salpingectomy is
almost certainly the key part of any surgical prophylaxis strategy for
ovarian cancer prevention. Although less common, women with type
II Lynch syndrome caused by mutations in one of the DNA mismatch
repair genes (MSH2, MLH1, MLH6, PMS1, PMS2) are at risk for
ovarian and endometrial cancer. Like BRCA1/2-related cancers, these
cancers develop earlier than sporadic ovarian cancer.
Neoplasms of the ovary tend to be painless unless they undergo
torsion. Nonspecific gastrointestinal symptoms like bloating and early
satiety are common at presentation, probably related to compression of
local organs or due to symptoms from metastatic disease. Women with
ovarian tumors also may have an increased incidence of symptoms
including pelvic discomfort, bloating, and perhaps changes in urinary
or bowel pattern. Unfortunately, these same symptoms are common in
primary care and are frequently dismissed by either the woman or her
health care team until later stages of disease. The pathogenic factors and
timing of spread beyond the ovary are still not well understood. The
most common symptoms at presentation of advanced disease include
a period of progressive complaints of nausea, early satiety, bloating,
indigestion, constipation, and abdominal pain. Signs include the rapid
increase in abdominal girth due to the accumulation of ascites that
typically alerts the patient and her physician that the concurrent gas­
trointestinal symptoms are likely associated with malignant pathology.
Radiologic evaluation typically demonstrates a complex adnexal mass
with ascites, carcinomatosis, and pelvic, para-aortic, and mesenteric
adenopathy in advanced disease. Positron emission tomography (PET)
scans are generally not required. Laboratory evaluation often demon­
strates a markedly elevated serum CA-125, the shed mucin component
(MUC16) associated with, but not specific for, ovarian cancer. Ovarian
cancers are divided into four stages, with stage I tumors confined to the
ovary, stage II malignancies confined to the pelvis, and stage III con­
fined to the peritoneal cavity and retroperitoneal nodes (Table 94-1).
These three stages are subdivided, with the most common presenta­
tion, stage IIIC, defined as tumors with bulky intraperitoneal disease or
positive lymph node involvement. About 70% of women present with
stage III disease. Stage IV disease includes women with parenchymal
metastases (liver, lung, spleen) or, alternatively, abdominal wall or pleu­
ral disease. The 30% of patients not presenting with stage III disease are
roughly evenly distributed among the other stages.
Screening 
Advanced ovarian cancer is a highly lethal condition.
It is curable in early stages but seldom curable in advanced stages;
hence, screening continues to be of considerable interest. Early-stage
tumors often secrete excessive amounts of normal proteins that can be
measured in the serum such as CA-125, mesothelin, and HE-4. Never­
theless, the incidence of ovarian cancer in the middle-aged female pop­
ulation is very low, with only ~1 in 2000 women between the ages of 50
and 60 carrying an asymptomatic and undetected tumor. Large, welldesigned screening studies, even in the mutated BRCA1/2 families,
have thus far failed to decrease ovarian cancer mortality in prospective
testing. Circulating DNA approaches have also been unsuccessful so
far. Screening for ovarian cancer is currently not recommended outside
TABLE 94-1  Staging and Survival in Gynecologic Malignancies
STAGE
OVARIAN
5-YEAR SURVIVAL, %
ENDOMETRIAL
5-YEAR SURVIVAL, %
CERVIX
5-YEAR SURVIVAL, %
—
—
Carcinoma in situ
I
Confined to ovary
88–95
Confined to corpus
90
Confined to uterus
II
Confined to pelvic organs
70–80
Involves corpus and
cervix
III
Intra-abdominal spread to
omentum, diaphragm, or
lymph nodes
20–40
Extends outside the
uterus but not outside
the true pelvis
IV
Spread outside abdominal
cavity, parenchymal spread,
and pleural effusion cytology
10–20
Extends outside the
true pelvis or involves
the bladder or rectum
of a clinical trial, but a careful history for familial cancers and directed
genetic testing for susceptibility genes are definitely appropriate.
TREATMENT
Ovarian Cancer
Epithelial ovarian cancer can be divided into distinct “disease
states” for the purpose of treatment selection, as shown in Fig. 94-1.
Detection by ultrasonography generally can identify a complex
ovarian mass as “suspicious,” but surgery by a skilled gynecologic
oncologist remains the preferred initial diagnostic and therapeutic
option for an isolated adnexal mass or a more involved picture of
peritoneal involvement. The amount of residual visible cancer at the
end of a primary operation is strongly predictive of outcome and is
paired with histology, grade, and stage to determine prognosis and
treatment. Metastatic disease to the ovary can be seen from primary
tumors of the colon, appendix, stomach (Krukenberg tumors),
and breast. Needle biopsy of adnexal masses is contraindicated
to avoid malignant contamination of the peritoneal cavity with
malignant cells. Typically, women undergo laparoscopic evaluation
Primary
Treatment
First Remission
Maintenance
Consolidation
Diagnostic surgery
Primary debulking
Interval debulking
HRD abnormal ->
Poly-(ADP-ribose)-
polymerase inhibitor
for 2 y
Platinum complex
taxane
Chemotherapy
HRD wild type
No treatment
Platinum-Resistant/Recurrent Disease
Persistent cancer following platinum treatment or recurrence within 6 months of last platinum dose
Single-agent treatment with or without bevacizumab: Liposomal doxorubicin, topotecan, docetaxel, weekly
paclitaxel, gemcitabine, vinorelbine, pemetrexed, etoposide, bevacizumab, mirvetuximab, soravtansine
Investigational therapy
Death From Disease
FIGURE 94-1  Disease states model of epithelial ovarian cancer and its treatment. Each box represents a relatively homogenous group of patients who share a palette of
potential treatment choices and have a similar prognosis. The arrows indicate that a single patient may move from one state to another during the course of her illness, and
the choice of treatments will become different in her new disease state. HRD, homologous recombination deficiency.
~75
Invades beyond uterus but
not to pelvic wall
45–60
Extends to pelvic wall and/
or lower third of vagina, or
hydronephrosis
~20
Invades mucosa of bladder
or rectum or extends beyond
the true pelvis
and unilateral salpingo-oophorectomy for diagnostic purposes. If
pathology reveals a primary ovarian malignancy or the laparoscopy
proves disseminated disease is present, then the procedure should
be followed by a total hysterectomy, removal of the remaining tube
and ovary, omentectomy, and pelvic node sampling along with
biopsies of the peritoneal cavity and diaphragms. This extensive
surgical procedure is performed because ~30% of tumors that, by
visual inspection, appear to be confined to the ovary have already
disseminated to the peritoneal cavity and/or surrounding lymph
nodes. As with axillary dissections in breast cancer, node sampling
is diagnostic, but full lymphadenectomy appears to provide little or
no additional therapeutic advantage over nodal sampling. The tar­
get outcome of an ovarian cancer surgery is always an R0 resection
(no visible residual cancer). The less favorable “optimal resection”
(no residual disease >1 cm in size) is still clinically useful, and the
prognosis of those patients is much better than that of patients
who are left with >1 cm of disease at the end of surgery. These
“suboptimally debulked” patients derive very little benefit from
their surgery. If large deposits of unresectable residual tumor are
anticipated, the surgery should be delayed until after several cycles
of neoadjuvant chemotherapy. Such “interval debulking” surgery
CHAPTER 94
Gynecologic Malignancies
Cure of Disease
Platinum-Sensitive
Relapse
Subsequent
Remission
• Interval surgery
• Maintenance therapy
with poly-(ADP-ribose)-
polymerase inhibitors
• Carboplatin with
either liposomal
doxorubicin, paclitaxel,
or gemcitabine
• Bevacizumab
achieves similar results to primary surgery with diminished surgical
morbidity and more timely chemotherapy. Patients without gross
residual disease (R0 resection) after resection have a median sur­
vival in excess of 60 months, compared to 28–42 months for those
left with macroscopic tumor or those undergoing interval debulk­
ing, regardless of treatment strategy.
After appropriate surgical treatment, primary chemotherapy
will consist of combination treatment with paclitaxel and carbo­
platin. Primary chemotherapy can be delivered intravenously, or
alternatively, some therapy can be directly administered into the
peritoneal cavity via an indwelling catheter. The intraperitoneal
approach is technically more difficult and is increasingly replaced
by carboplatin and paclitaxel, which appears to offer similar results.
Although interest in immunotherapy or chemoimmunotherapy has
been high, immunotherapeutics have not yet improved primary
chemotherapy.
With optimal debulking surgery and platinum-based chemo­
therapy, 70% of women who present with advanced-stage tumors
show tumor reduction, and 40–50% experience a complete remis­
sion with normalization of their CA-125, computed tomography
(CT) scans, and physical examination. For women with evidence of
functional homologous DNA repair defects, administration of oral
poly-ADP ribose polymerase inhibitors (PARPi) such as nirapa­
rib, olaparib, or rucaparib will improve survival outcomes when
administered at the completion of intravenous chemotherapy as
consolidation. These drugs substantially delay recurrence and pro­
vide survival advantages as well. In the majority of patients, disease
still recurs within 1–4 years from the completion of their primary
therapy. CA-125 levels often increase as a first sign of relapse, and
CT scan findings are eventually confirmatory. Recurrent disease
is often successfully managed for years but rarely cured, despite a
growing panel of chemotherapeutic agents and antibody-drug con­
jugates. Additional surgical therapy does not appear to extend sur­
vival in randomized trials. Patients with a treatment-free interval
are often best treated with additional platinum doublets, combining
carboplatin with liposomal doxorubicin, gemcitabine, or a taxane.
Eventually all women who experience relapse develop chemother­
apy-refractory disease. Refractory ascites, poor bowel motility, and
obstruction or tumor-infiltrated aperistaltic bowel are all common
premorbid events. Limited surgery to relieve intestinal obstruction,
localized radiation therapy to relieve pressure or pain from masses,
or palliative chemotherapy may be helpful. Agents with >15%
response rates include gemcitabine, topotecan, liposomal doxorubi­
cin, and bevacizumab. Five-year survival correlates with the stage of
disease: stage I, 90–95%; stage II, 70–80%; stage III, 25–40%; stage
IV, 10–15% (Table 94-1). Prognosis is improved by lower histologic
grade and presence of BRCA1 or BRCA2 germline mutation.
PART 4
Oncology and Hematology
■
■UNCOMMON OVARIAN TUMORS
Low Malignant Potential Tumors (Borderline Tumors) 
These type 1 tumors are found in younger women (age 30–50 years)
and are indolent in behavior, and few of these patients will succumb
to their tumors (10-year survival may approach 98%), although recur­
rence is not uncommon. Certain features, such as micropapillary
histology and microinvasion, are linked to more aggressive behavior.
Tumors of low malignant potential have different mutations includ­
ing mutations BRAF or KRAS and cyclin-dependent kinase inhibitor
(CDKN) 2A/2B deletion. Borderline tumor patients are managed pri­
marily by surgery, but targeted therapy for the RAS/RAF pathway and
hormonal treatments sometimes have benefit.
Stromal Tumors 
Approximately 7% of ovarian neoplasms are
stromal tumors, with ~1800 cases expected each year in the United
States. Ovarian stromal tumors or sex cord tumors are most common
in women in their fifties or sixties, but tumors can present at any age.
These tumors arise from the mesenchymal components of the ovary,
including both steroid-producing cells and fibroblasts. Most of these
tumors are indolent tumors with limited metastatic potential and pres­
ent as unilateral solid masses. These tumors primarily are discovered by
the detection of an abdominal mass, sometimes with abdominal pain
due to ovarian torsion, intratumoral hemorrhage, or rupture. Rarely,
stromal tumors can produce estrogen and present with breast tender­
ness as well as precocious puberty in children, menstrual disturbances
in reproductively active women, or postmenopausal bleeding. In some
women, estrogen-associated secondary malignancies, such as endo­
metrial or breast cancer, may present as synchronous malignancies.
Sertoli-Leydig tumors often present with hirsutism and virilization
due to increased production of androgens. Hormonally inert tumors
include fibromas, which present as solitary masses often in association
with ascites and occasionally hydrothorax, also known as Meigs’s syn­
drome. A subset of these tumors presents in individuals with a variety
of inherited disorders that predispose them to mesenchymal neoplasia
including Ollier’s disease (juvenile granulosa cell tumors) and PeutzJeghers syndrome (ovarian sex cord tumors). The treatment of these
tumors is primarily complete surgical resection, without adjuvant che­
motherapy. Chemotherapy with carboplatin and paclitaxel is generally
reserved for either unresectable or multiply recurrent tumors.
Germ Cell Tumors of the Ovary 
Germ cell tumors, like their
counterparts in the testis, are cancers of germ cells. These totipotent
cells contain the programming for differentiation to essentially all tis­
sue types, and hence, the germ cell tumors include a histologic menag­
erie of bizarre tumors, including benign teratomas (dermoid cysts)
and a variety of malignant tumors, such as dysgerminoma, immature
teratomas, yolk sac malignancies, and choriocarcinomas. Benign tera­
toma (or dermoid cyst) is the most common germ cell neoplasm of
the ovary and often presents in young women. These tumors include a
complex mixture of differentiated tissue including tissues from all three
germ layers. In older women, these differentiated tumors can develop
malignant transformation, most commonly squamous cell carcinomas.
Malignant germ cell tumors include dysgerminomas, yolk sac tumors,
immature teratomas, and embryonal and choriocarcinomas. Germ
cell tumors can present at all ages, but the peak age of presentation
tends to be in adolescents. Typically, these tumors will become large
ovarian masses, which eventually present as palpable low abdominal
or pelvic masses. Like sex cord tumors, torsion or hemorrhage may
present urgently or emergently as acute abdominal pain. Some germ
cell tumors produce elevated levels of human chorionic gonadotropin
(hCG) or α-fetoprotein (AFP). Unlike epithelial ovarian cancer, these
tumors have a higher proclivity for nodal or hematogenous metastases.
Germ cell tumors typically present in women who are of childbearing
age, and because bilateral tumors are uncommon (except in dysgermi­
noma, 10–15%), the typical treatment is unilateral oophorectomy or
salpingo-oophorectomy with lymph node sampling. Most commonly,
women with advanced malignant germ cell tumors typically receive
bleomycin, etoposide, and cisplatin (BEP) chemotherapy, in an analo­
gous fashion to the treatment of testicular cancers. In the majority of
these women, even those with advanced-stage disease, cure is expected.
Dysgerminoma is the ovarian counterpart of testicular seminoma and
is highly curable. Although the tumor is highly radiation-sensitive,
radiation produces infertility in many patients. BEP chemotherapy is
as effective or more so without causing infertility.
FALLOPIAN TUBE CANCER
Transport of the egg to the uterus occurs through the fallopian tube,
with the distal ends of these tubes composed of fimbriae that drape
about the ovarian surface and capture the egg as it erupts from the
ovarian cortex. As described above, the majority of type 2 ovarian
cancers are now thought to arise from the tubal epithelium. Fallopian
tube malignancies are typically of serous histology and share the same
biology and recommended treatment approaches as serous ovar­
ian cancer. These tumors often present as clinically isolated adnexal
masses, but like ovarian cancer, these tumors spread relatively early
throughout the peritoneal cavity. Fallopian tubal cancers have a
natural history and treatment that are essentially identical to ovarian
cancer (Table 94-1).
CERVICAL CANCER
■
■ETIOLOGY AND GENETICS
Cervical cancer is the second most common and the most lethal
malignancy in women worldwide. Infection with high-risk strains
of human papillomavirus (HPV) is the primary neoplastic-initiating
event in the vast majority of women with invasive cervical cancer. This
double-stranded DNA virus infects epithelium near the transformation
zone of the cervix where underlying columnar epithelium becomes
squamous epithelium. More than 60 types of HPV are known, with
~20 types having the ability to generate high-grade dysplasia and
malignancy. HPV16 and 18 are the types most frequently associated
with high-grade dysplasia, but types 31, 33, 35, 52, and 58 are also
considered to be high-risk variants. The large majority of sexually
active adults are exposed to HPV, and most women clear the infection
without specific intervention. The 8-kb HPV genome encodes seven
early genes, most notably E6 and E7, which can bind to RB and p53,
respectively. High-risk types of HPV encode E6 and E7 molecules that
are particularly effective at inhibiting the normal cell cycle checkpoint
functions of these regulatory proteins, leading to immortalization but
not full transformation of cervical epithelium. A minority of women
will fail to clear the infection, with subsequent HPV integration into
the host genome. Over as little as a few months to several years, some
of these persistently infected women develop worsening dysplasia, a
premalignant condition that, untreated, can progress to cervical carci­
noma. Complete transformation to cancer occurs over a period of years
and almost certainly requires the acquisition of other genetic mutations
within the infected and immortalized epithelium.
In 2024, more than half a million new cases of cervical cancer will
occur worldwide, with an estimated >300,000 deaths. Cancer incidence
is particularly high in women residing in Central and South America,
the Caribbean, and southern and eastern Africa. The mortality rate is
disproportionately high in Africa. In the United States, an estimated
13,960 women will be diagnosed with cervical cancer in 2024 and
~4300 women will die of the disease.
In the integrated genomic characterization of cervical cancer by
The Cancer Genome Atlas (TCGA), integration of HPV sequences
was found in all of the HPV18-linked cancers and over three-quarters
of the HPV16 cancers. The cervical tumors also showed a charac­
teristic APOBEC (apolipoprotein B mRNA editing enzyme, catalytic
polypeptide-like; a family of cytidine deaminases that edit DNA and
are endogenous mutagenic enzymes) pattern of mutagenesis, with
ERBB3, CASP8, and TGFRB2 identified as significantly mutated genes
presumably linked to progression from dysplasia to carcinoma. In the
much smaller number of HPV-negative cancers, which are more com­
mon in older women, mutations in oncogenes KRAS, ARID1A, and
PTEN were frequently seen. The clinical behavior of these cancers is
likely to be different.
■
■HPV INFECTION AND PREVENTION
The Pap smear is the primary detection method for asymptomatic
preinvasive cervical dysplasia of squamous epithelial lining during a
gynecologic exam. Because the progression from dysplasia to cervi­
cal cancer takes several years, annual (or longer interval) screening
and prevention strategies that detect precancerous dysplasia and
carcinoma in situ can be implemented successfully. Annual or bian­
nual cervical scraping for cytology (Pap smear) is highly effective
in reducing the incidence of cervical cancer by early detection and
subsequent surgical treatment of premalignant disease. The incorpo­
ration of HPV testing by polymerase chain reaction (PCR) or other
molecular techniques increases the sensitivity of detecting cervical
pathology but at the cost of lower sensitivity in that it identifies many
women with transient infections who require no specific medical
intervention. Unfortunately, both the collection of a Pap smear and its
cytologic evaluation require infrastructure beyond the means of many
middle- and low-income countries. High-throughput, low-technology
prevention strategies and point-of-care testing are needed to identify
and treat women bearing high-risk cervical dysplasia to prevent cancer
development.
A primary prevention strategy relies on HPV vaccines. In the United
States, the Gardasil-9 vaccine protects against HPV types 6, 11, 16,
18, 31, 33, 45, 52, and 58. Vaccination of girls and women between
ages 9 and 45 years is recommended with three injections (0, 2, and
6 months). Vaccination before the initiation of sexual activity dra­
matically reduces the rate of high-risk HPV infection and subsequent
dysplasia. Vaccination of both boys and girls is increasingly considered
to reduce the risk of HPV-induced cancers of the pharynx. Vaccinated
women are still at risk for HPV infection and still benefit from standard
Pap smear screening.
■
■CLINICAL PRESENTATIONS
Risk Factors 
Clinical risk factors include the prevalence of highrisk HPV subtypes in the population and HPV infection–linked
features such as a high number of sexual partners, early age of first
intercourse, and history of venereal disease. Smoking is a cofactor;
heavy smokers have a higher risk of dysplasia with HPV infection. HIV
infection, especially when associated with low CD4+ T-cell counts,
is associated with a higher rate of high-grade dysplasia and likely a
shorter latency period between infection and invasive disease. Histo­
logically, the majority (80%) of cervical malignancies are squamous
cell carcinomas associated with HPV, but adenocarcinomas are also
HPV related, and both arise in the transitional zone of the endocervi­
cal canal; the lesions in the canal or cervical glands may not be seen
by visual inspection of the cervix and can be missed by Pap smear
screening. Other malignancies, such as vulvar cancer, anal cancer, and,
increasingly, pharyngeal cancer, are also linked to HPV infection.
CHAPTER 94
Gynecologic Malignancies
Diagnosis of Cervical Cancer 
Early cancer of the cervix is
asymptomatic, and this biology underlies the recommendations for
routine gynecologic care. Larger, invasive carcinomas often have
symptoms or signs including postcoital spotting or intermenstrual
cycle bleeding or menometrorrhagia. Foul-smelling or persistent
yellow discharge may also be present. Symptoms such as pelvic or
sacral pain suggest lateral extension into the pelvic nerve plexus by
either the primary tumor or a pelvic node metastasis and indicate
advanced-stage disease. Likewise, flank pain from hydronephrosis
from ureteral compression or deep-venous thrombosis from iliac vessel
compression suggests either extensive nodal disease or direct extension
of the primary tumor to the pelvic sidewall. The most common finding
upon physical exam is a visible tumor on the cervix, but deeper tumors
in the cervical os and glands should be considered. Larger tumors may
be identified by inspection and biopsied directly. Staging of cervical
cancer is performed by expert clinical exam. Stage I cervical tumors
are confined to the cervix, whereas stage II tumors extend into the
upper vagina or paracervical soft tissue (Fig. 94-2). Stage III tumors
extend to the lower vagina or the pelvic sidewalls, whereas stage IV
tumors invade the bladder or rectum or have spread to distant sites.
While radiographic studies are not part of the formal clinical staging
of cervical cancer, treatment planning requires them for appropriate
therapy. CT can detect hydronephrosis indicative of pelvic sidewall
disease but is not accurate at evaluating other pelvic structures. Mag­
netic resonance imaging (MRI) is more accurate at estimating uterine
extension and paracervical extension of disease into soft tissues typi­
cally bordered by broad and cardinal ligaments that support the uterus
in the central pelvis. Very small stage I cervical tumors can be treated
with a variety of surgical procedures, but minimally invasive surgery
has inferior outcome compared to standard open hysterectomy. In
young women desiring to maintain fertility, radical trachelectomy
removes the cervix with subsequent anastomosis of the upper vagina
to the uterine corpus; however, subsequent pregnancies may be more
problematic. Patients with large stage I cervical tumors (4 cm) confined
to the cervix and all stage II to IV patients are treated with radiation
therapy in combination with cisplatin-based immunochemotherapy
with concurrent PD-1 blockers. This multimodality treatment can
offer the patient with advanced-stage disease a 40–80% chance of cure
depending on the clinical circumstances. Immunotherapy with PD-1
blockade, cisplatin, paclitaxel, bevacizumab, and tisotumab vedotin
are generally considered as appropriate palliative choices for metastatic
Staging of cervix cancer
Stage
I
II
III
IV
Disease
to pelvic
wall or
lower 1/3
vagina
Disease
beyond cervix
but not to pelvic
wall or lower
1/3 of vagina
Confined
to cervix
Extent of
tumor
Carcinoma
in situ
65%
85%
5-year
survival
100%
4%
Stage at
presentation
28%
47%
Uterine
cavity
Fundus
Fallopian
tube
Uterine
wall
Corpus
IIB
Internal os
IIIB
Cervix
IIA
IIIA
External os
Vagina
FIGURE 94-2  Anatomic display of the stages of cervix cancer defined by location, extent of tumor, frequency of
presentation, and 5-year survival.
PART 4
Oncology and Hematology
cervical cancer patients. Secondary chemotherapy confers minimal
improvement in most patients. Additional immunotherapies targeting
HPV antigens are potential avenues for improved outcomes in recur­
rent, unresectable cancers of the cervix.
UTERINE CANCER
■
■EPIDEMIOLOGY
Several different tumor types arise in the uterine corpus. Most tumors
arise in the glandular lining and are endometrial adenocarcinomas.
Benign (leiomyomas) and malignant smooth muscle tumors (leiomyo­
sarcomas) can also arise in the uterus and have very different clinical
features. The endometrioid histologic subtype is the most common
gynecologic malignancy in the United States. In 2024, the American
Cancer Society predicted that 66,200 new cancers of the uterine corpus
are expected in 2024 with 13,030 resulting deaths. Development of
these tumors is a multistep process, with estrogen playing an impor­
tant early role in driving endometrial gland proliferation. Relative
overexposure to this class of hormones is the principal risk factor for
the subsequent development of endometrioid tumors. In contrast, pro­
gestins drive glandular maturation and are protective. Hence, women
with high endogenous or pharmacologic exposure to estrogens, espe­
cially if unopposed by progesterone, are at higher risk for endometrial
cancer. Obese women, women treated with postmenopausal estrogens,
or women with estrogen-producing tumors are at higher risk for endo­
metrial cancer. In addition, long-term treatment with tamoxifen, which
has antiestrogenic effects in breast tissue but can show weak estrogenic
effects in uterine epithelium, is associated with an increased risk of
endometrial cancer.
Genetics 
Women with a germline mutation in one of a series of
DNA mismatch repair genes associated with the Lynch syndrome, also
known as hereditary nonpolyposis colon cancer (HNPCC) syndrome,
are at increased risk for endometrioid endometrial carcinoma. These
individuals have germline mutations in MSH2, MLH1, and, in rare
cases, PMS1 and PMS2. Individuals who carry these mutations typi­
cally have a family history of cancer and are at markedly increased risk
for colon cancer and modestly increased risk for ovarian cancer and a
variety of other tumors. Middle-aged women with HNPCC carry a 4%
annual risk of endometrial cancer and a relative overall risk of ~200fold as compared to age-matched women without HNPCC. In sporadic
cancers, secondary events such as mutation of the PI3K gene or the loss
of the PTEN tumor-suppressor gene likely serve as secondary genetic
“hits” in the carcinogenesis related to estrogenic excess. The molecular
events that underlie less common endo­
metrial cancers such as clear cell and
papillary serous tumors of the uterine
corpus are not well understood.
Invades bladder,
rectum or
metastasis
■
■PATHOLOGY
Approximately 75–80% of endometrial
cancers are adenocarcinomas and have
been characterized as type 1 (estrogenlinked) endometrial cancers and type 2
cancers that have less clear associations
with estrogens (clear cell cancers, serous
cancers, and mucinous cancers). Endo­
metrial serous cancers show TP53 loss of
function and behave clinically more like
ovarian cancers with high risk for sys­
temic recurrence. Prognosis for endome­
trial cancer depends on stage, histologic
grade, and depth of myometrial invasion.
7%
35%
21%
Pelvic
side wall
■
■CLINICAL PRESENTATION
The majority of women with tumors of
the uterine corpus present with post­
menopausal vaginal bleeding due to
shedding of the malignant endometrial
lining. Premenopausal women often will
present with atypical bleeding between typical menstrual cycles. These
signs typically bring a woman to the attention of health care providers,
and the majority of women have early-stage disease in which the tumor
is confined to the uterine corpus and, consequently, have a high cure
rate. Diagnosis is typically established by endometrial biopsy. Type 1
tumors may spread to pelvic or para-aortic lymph nodes and are gen­
erally subjected to sentinel lymph node biopsy at the time of primary
surgery. Serous tumors tend to have patterns of spread similar to highgrade serous ovarian cancer, and patients may present with omental/
peritoneal disease and sometimes ascites. Some women presenting
with uterine sarcomas will present with pelvic pain. Uterine sarcomas
(carcinosarcomas and leiomyosarcomas) commonly are found by
detection of symptomatic large pelvic masses that may not be associ­
ated with dysfunctional vaginal bleeding.
TREATMENT
Uterine Cancer
Most women with endometrial cancer have disease that is local­
ized to the uterus (75% are stage I, Table 94-1), and definitive
treatment typically involves a hysterectomy with removal of the
ovaries and fallopian tubes. The resection of lymph nodes does not
improve outcome, but sentinel node resection provides important
staging and prognostic information. Node involvement defines
stage IIIC disease, which is treated with immunochemotherapy.
Tumor grade and depth of invasion are two key prognostic vari­
ables in early-stage tumors, and women with low-grade and/or
minimally invasive tumors (<50% myometrial penetration) are
typically observed after definitive surgical therapy. Patients with
high-grade tumors or tumors that are deeply invasive (stage IB)
are at higher risk for pelvic recurrence or recurrence at the vaginal
cuff, which is typically prevented by intravaginal brachytherapy.
It is now routine to test all endometrial cancers for microsatellite
instability (MSI) with a larger number of mutations in the tumor.
MSI cancers, when recurrent or present at an advanced stage, are
likely to respond to immune checkpoint therapy and PD-1–targeted
therapy should be part of treatment for those patients. Women
with regional metastases or metastatic disease (3% of patients) with
low-grade tumors can be treated with progesterone or tamoxifen.
In contrast, poorly differentiated tumors lack hormone receptors
and are typically unresponsive to hormonal manipulation. The
role of adjuvant chemotherapy in stage I–II disease is generally
restricted to serous endometrial cancers. For more advanced-stage
cancers (stage III–IV), chemotherapy and/or immune checkpoint
blockade are administered because of the higher rates of recurrent
systemic disease. Carboplatin and paclitaxel combinations with
immune targeting agents are the current standard of care. Chemo­
therapy for metastatic disease is delivered with palliative intent.
Even patients with advanced cancer and known mismatch repair
deficits may respond well to immunotherapy with antagonists
of the PD-1/PD-L1 axis. Lenvatinib and pembrolizumab (even
for microsatellite-stable tumors) have become the most common
second-line treatments. Other potentially active treatments include
bevacizumab and mammalian target of rapamycin (mTOR) inhibi­
tors (e.g., temsirolimus). Newer antibody-drug conjugates may have
good responses in patients with expression of the target antigens.
Carcinosarcomas of the uterus (also called Müllerian tumors) con­
tain both mesenchymal and epithelial components but will often
respond to paclitaxel and platinum complex therapy. Other uterine
sarcomas require an entirely different approach and need histologyspecific consideration. The most common are the leiomyosarcomas
of the uterus, which are treated with docetaxel/gemcitabine at
recurrence but do not appear to benefit from adjuvant therapy.
Ifosfamide/doxorubicin and trabectedin can have some benefit in
refractory disease.
GESTATIONAL TROPHOBLASTIC TUMORS
Gestational trophoblastic diseases represent a spectrum of neoplasia
from benign hydatidiform mole to choriocarcinoma due to persistent
trophoblastic disease associated most commonly with molar preg­
nancy but occasionally seen after normal gestation. The most common
presentations of trophoblastic tumors are partial and complete molar
pregnancies. These represent approximately 1 in 1500 conceptions in
developed Western countries. The incidence widely varies globally,
with areas in Southeast Asia having a much higher incidence of molar
pregnancy. Regions with high molar pregnancy rates are often associ­
ated with diets low in carotene and animal fats.
■
■RISK FACTORS
Trophoblastic tumors result from the outgrowth or persistence of
placental tissue. They arise most commonly in the uterus but can also
arise in other sites such as the fallopian tubes due to ectopic pregnancy.
Risk factors include poorly defined dietary and environmental factors
as well as conceptions at the extremes of reproductive age, with the
incidence particularly high in females conceiving at younger than age
16 or older than age 50. In older women, the incidence of molar preg­
nancy might be as high as one in three, likely due to increased risk of
abnormal fertilization of the aged ova. Most trophoblastic neoplasms
are associated with complete moles, diploid tumors with all genetic
material from the paternal donor (known as uniparental disomy). This
is thought to occur when a single sperm fertilizes an enucleate egg that
subsequently duplicates the paternal DNA. Trophoblastic proliferation
occurs with exuberant villous stroma. If pseudopregnancy extends out
past the 12th week, fluid progressively accumulates within the stroma,
leading to “hydropic changes.” Fetal development does not occur in
complete moles.
Partial moles arise from the fertilization of an egg with two sperm
cells; hence, two-thirds of genetic material is paternal in these triploid
tumors. Hydropic changes are less dramatic, and fetal development
can often occur through late first trimester or early second trimester,
at which point spontaneous abortion is common. Laboratory findings
will include excessively high hCG and high AFP. The risk of persistent
gestational trophoblastic disease after partial mole is ~5%. Complete
and partial moles can be noninvasive or invasive. Myometrial invasion
occurs in no more than one in six complete moles and a lower portion
of partial moles.
■
■PRESENTATION OF INVASIVE TROPHOBLASTIC
DISEASE
The clinical presentation of molar pregnancy is changing in developed
countries due to the early detection of pregnancy with home pregnancy
kits and the very early use of Doppler and ultrasound to evaluate the
early fetus and uterine cavity for evidence of a viable fetus. Thus, in
these countries, the majority of women presenting with trophoblastic
disease have their moles detected early and have typical symptoms of
early pregnancy including nausea, amenorrhea, and breast tenderness.
With uterine evacuation of early complete and partial moles, most
women experience spontaneous remission of their disease as moni­
tored by serial serum β-hCG levels. These women require no chemo­
therapy. Patients with persistent elevation of β-hCG or rising β-hCG
after uterine evacuation have persistent or actively growing gestational
trophoblastic disease and require therapy. Most series suggest that
between 15 and 25% of women will have evidence of persistent gesta­
tional trophoblastic disease after molar evacuation.
In women who lack access to prenatal care, presenting symptoms
can be life-threatening, including the development of preeclampsia
or even eclampsia. Hyperthyroidism can also be seen with very high
β-hCG values. Evacuation of large moles can be associated with lifethreatening complications including uterine perforation, volume loss,
high-output cardiac failure, and adult respiratory distress syndrome
(ARDS).
For women with evidence of rising β-hCG or radiologic confir­
mation of metastatic or persistent regional disease, prognosis can be
estimated through a variety of scoring algorithms that identify women
at low, intermediate, and high risk for requiring multiagent chemother­
apy. In general, women with widely metastatic nonpulmonary disease,
very elevated β-hCG, and prior normal antecedent term pregnancy are
considered at high risk and typically require multiagent chemotherapy
at an expert center for cure. Even very advanced gestational tropho­
blastic disease is almost uniformly curable when managed by an expert
in this rare malignancy.
CHAPTER 94
Gynecologic Malignancies
TREATMENT
Invasive Trophoblastic Disease
Management of invasive trophoblastic disease should be 100%
curative, and complex patients should only be managed by clini­
cians experienced in this disease. The management for a persistent
and rising β-hCG after evacuation of a molar conception is typi­
cally chemotherapy, although surgery can play an important role
for chemotherapy-resistant disease that is isolated in the uterus
(especially if childbearing is complete) or to control hemorrhage.
For women wishing to maintain fertility or with metastatic disease,
the preferred treatment is chemotherapy or immunotherapy tar­
geting the PD-1 axis. Trophoblastic disease is exquisitely sensitive
to chemotherapy, and guided by serial serum β-hCG testing, suc­
cessful, curative treatment is the rule. Single-agent treatment with
dactinomycin or methotrexate cures 90% of women with low-risk
disease. Patients with high-risk disease (very high β-hCG levels,
presentation ≥4 months after pregnancy, brain or liver metastases,
failure of methotrexate therapy) are typically treated with mul­
tiagent chemotherapy (etoposide, methotrexate, and dactinomycin,
alternating with cyclophosphamide and vincristine [EMA-CO]),
which is typically curative even in women with extensive metastatic
disease. A regimen of cisplatin and etoposide alternating with
etoposide/methotrexate/dactinomycin is used for the highest-risk
patients. In the highest-risk patients with liver, lung, and brain
metastases, hemorrhage from the rich tumor vasculature is a major
risk during chemotherapy initiation. Cured women may become
pregnant again without evidence of increased fetal or maternal
complications.
■
■FURTHER READING
Longo DL: Personalized medicine for primary treatment of serous
ovarian cancer. N Engl J Med 381:2471, 2019.
Lu KH, Broaddus RR: Endometrial cancer. N Engl J Med 383:2053,
2020.
Moore KN et al: Mirvetuximab soravtansine in FRα-positive,
platinum-resistant ovarian cancer. N Engl J Med 389:2162, 2023.

24 - 95 Primary and Metastatic Tumors of the Nervous System
95 Primary and Metastatic Tumors of the Nervous System
Mary Jane Lim-Fat, Patrick Y. Wen
Primary and Metastatic
Tumors of the Nervous
System
An estimated 95,000 people will be diagnosed with a primary brain
tumor annually in the United States. At least 27,000 of these tumors
are malignant, and most of these are gliomas. Meningiomas account for
41% of all central nervous system (CNS) tumors, vestibular schwanno­
mas 10%, and CNS lymphomas ~2%. Brain metastases are three times
more common than all primary brain tumors combined and are diag­
nosed in ~150,000 people each year. Metastases to the leptomeninges
and epidural space of the spinal cord each occur in ~2–12% of patients
with systemic cancer and are also a major cause of neurologic disability.
APPROACH TO THE PATIENT
Primary and Metastatic Tumors of the Nervous
System
PART 4
Oncology and Hematology
CLINICAL FEATURES
Brain tumors of any type can present with a variety of symptoms
and signs that fall into two categories: general and focal; patients
often have a combination of the two (Table 95-1). General symp­
toms include headache, with or without nausea or vomiting, cog­
nitive difficulties, personality change, and gait disorder. These
symptoms arise when the enlarging tumor and its surrounding
edema cause an increase in intracranial pressure or compression
of cerebrospinal fluid (CSF) circulation, leading to hydrocephalus.
The classic brain tumor headache predominates in the morning and
improves during the day, but this pattern is seen in a minority of
patients. Headaches are often holocephalic but can be ipsilateral to
the side of a tumor. Occasionally, headaches have features of a typi­
cal migraine with unilateral throbbing pain associated with visual
scotoma. Personality changes may include apathy and withdrawal
from social situations, mimicking depression. Focal or lateralizing
findings include hemiparesis, aphasia, or visual field defect. Later­
alizing symptoms are typically subacute and progressive; language
difficulties may be mistaken for confusion. Seizures are common,
occurring in ~25% of patients with brain metastases or malignant
gliomas, and are the presenting symptom in up to 90% of patients
with a low-grade glioma. All seizures arising from a brain tumor
will have a focal onset whether or not it is apparent clinically.
NEUROIMAGING
Cranial magnetic resonance imaging (MRI) is the preferred diag­
nostic test for any patient suspected of having a brain tumor and
should be performed with gadolinium contrast administration.
TABLE 95-1  Symptoms and Signs at Presentation of Brain Tumors
HIGH-GRADE GLIOMA (%)
LOW-GRADE GLIOMA (%)
MENINGIOMA (%)
METASTASES (%)
Generalized
Impaired cognitive function
Hemiparesis
Headache
Lateralizing
Seizures
70+
Aphasia
<5
—
Visual field deficit
—
—
—
Computed tomography (CT) scan should be reserved for those
patients unable to undergo MRI. Malignant brain tumors—whether
primary or metastatic—typically enhance with gadolinium, have
central areas of necrosis, and are surrounded by edema of the neigh­
boring white matter. Low-grade gliomas usually do not enhance
with gadolinium and are best appreciated on fluid-attenuated inver­
sion recovery (FLAIR) MRI sequences. Meningiomas have a typical
appearance on MRI because they are dural-based enhancing tumors
with a dural tail and compress but do not invade the brain. Dural
metastases or a dural lymphoma can have a similar appearance.
Imaging is characteristic for many primary and metastatic tumors
and sometimes will suffice to establish a diagnosis when the
location precludes surgical intervention (e.g., brainstem glioma).
Functional MRI is useful in presurgical planning to define eloquent
sensory, motor, or language cortex. Positron emission tomography
(PET) is useful in determining the metabolic activity of the lesions
seen on MRI; MR perfusion and spectroscopy can provide infor­
mation on blood flow or tissue composition. These techniques
may help distinguish tumor progression from tissue necrosis due
to treatment with radiation and chemotherapy. Neuroimaging is
the only test necessary to diagnose a brain tumor. Laboratory tests
are rarely useful, although patients with metastatic disease may
have elevation of a serum tumor marker (e.g., β human chorionic
gonadotropin [β-hCG] from testicular cancer). Additional testing
such as cerebral angiogram, electroencephalogram (EEG), or lum­
bar puncture is rarely indicated or helpful.
TREATMENT
Brain Tumors
Therapy of any intracranial malignancy requires both symptomatic
and definitive treatments. Definitive treatment is based on the
specific tumor type and includes surgery, radiotherapy, and chemo­
therapy. However, symptomatic treatments apply to brain tumors of
any type. Most high-grade malignancies are accompanied by sub­
stantial surrounding edema, which contributes to neurologic dis­
ability and raised intracranial pressure. Glucocorticoids are highly
effective at reducing perilesional edema and improving neurologic
function, often within hours of administration. Dexamethasone
has been the glucocorticoid of choice because of its relatively low
mineralocorticoid activity; initial doses are 4–12 mg/d in one to
two daily doses. Glucocorticoids rapidly ameliorate symptoms and
signs, but their long-term use causes substantial toxicity including
insomnia, weight gain, diabetes mellitus, steroid myopathy, and
personality changes. Consequently, a taper is indicated as definitive
treatment is administered and the patient improves.
Patients with brain tumors who present with seizures require
antiepileptic drug therapy. Prophylactic antiepileptic drugs are
occasionally used in the perioperative setting, but there is no
role for extended use in patients who have not had a seizure. The
agents of choice are drugs that do not induce the hepatic micro­
somal enzyme system. These include levetiracetam, topiramate,
lamotrigine, valproic acid, and lacosamide (Chap. 447). Other
drugs, such as phenytoin and carbamazepine, are used less fre­
quently because they are potent enzyme inducers that can interfere
with both glucocorticoid and chemotherapy metabolism. Venous
thromboembolic disease occurs in 20–30% of patients with HGGs
or brain metastases. Prophylactic anticoagulants should be used
during hospitalization and in nonambulatory patients. Those who
have had either a deep vein thrombosis or a pulmonary embolus
can receive therapeutic doses of anticoagulation safely and without
increasing the risk of hemorrhage into the tumor. Inferior vena cava
filters are reserved for patients with absolute contraindications to
anticoagulation such as recent craniotomy.
PRIMARY BRAIN TUMORS
■
■EPIDEMIOLOGY
No etiology has been identified for most primary brain tumors. The
only established risk factors are exposure to ionizing radiation (menin­
giomas, gliomas, and schwannomas) and immunosuppression (pri­
mary CNS lymphoma). There is no proven evidence for any association
with exposure to electromagnetic fields including cellular telephones,
head injury, foods containing N-nitroso compounds, or occupational
risk factors. A small minority of patients have a family history of
brain tumors. Some of these familial cases are associated with genetic
syndromes (Table 95-2).
■
■MOLECULAR PATHOGENESIS
As with other neoplasms, brain tumors arise as a result of a multistep
process driven by the sequential acquisition of genetic alterations.
These include loss of tumor-suppressor genes (e.g., p53, cyclindependent kinase inhibitor 2A and 2B [CDKN2A/B], and phosphatase
TABLE 95-2  Genetic Syndromes Associated with Primary Brain Tumors
SYNDROME
INHERITANCE
GENE/PROTEIN
ASSOCIATED TUMORS
Cowden’s syndrome
AD
Mutations of PTEN (ch10p23)
Dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease),
meningioma, astrocytoma
Familial schwannomatosis
Sporadic
Hereditary
Mutations in INI1/SNF5 (ch22q11)
Schwannomas, gliomas
Gardner’s syndrome
AD
Mutations in APC (ch5q21)
Medulloblastoma, glioblastoma, craniopharyngioma
Gorlin syndrome (basal cell
nevus syndrome)
AD
Mutations in Patched 1 gene (ch9q22.3)
Medulloblastomas
Basal cell carcinoma
Li-Fraumeni syndrome
AD
Mutations in p53 (ch17p13.1)
Gliomas, medulloblastomas
Sarcomas, breast cancer, leukemias, others
Lynch syndrome
AD
Mutations in MSH2, MSH1, MSH6, PMS2
Glioblastoma and other gliomas
Gastrointestinal, endometrial, and other cancers
Multiple endocrine neoplasia 1
(Wermer’s syndrome)
AD
Mutations in Menin (ch11q13)
Pituitary adenoma, malignant schwannomas
Parathyroid and pancreatic islet cell tumors
NF1
AD
Mutations in NF1/neurofibromin
(ch17q12-22)
NF2
AD
Mutations in NF2/merlin (ch22q12)
Bilateral vestibular schwannomas, astrocytomas, multiple
meningiomas, ependymomas
TSC (Bourneville disease)
AD
Mutations in TSC1/TSC2 (ch9q34/16)
Subependymal giant cell astrocytoma, ependymomas, glioma,
ganglioneuroma, hamartoma
Turcot syndrome
AD
Mutations in APCa (ch5)
Gliomas, medulloblastomas
AR
hMLH1 (ch3p21)
Adenomatous colon polyps, adenocarcinoma
VHL
AD
Mutations in VHL gene (ch3p25)
Hemangioblastomas
aVarious DNA mismatch repair gene mutations may cause a similar clinical phenotype, also referred to as Turcot syndrome, in which there is a predisposition to
nonpolyposis colon cancer and brain tumors.
Abbreviations: AD, autosomal dominant; APC, adenomatous polyposis coli; AR, autosomal recessive; ch, chromosome; NF, neurofibromatosis; PTEN, phosphatase and tensin
homologue; TSC, tuberous sclerosis complex; VHL, von Hippel-Lindau.
and tensin homolog on chromosome 10 [PTEN]) and amplification
and overexpression of protooncogenes such as the epidermal growth
factor receptor (EGFR) and platelet-derived growth factor receptors
(PDGFR). The accumulation of these genetic abnormalities results in
uncontrolled cell growth and tumor formation. Many brain tumors,
including glioblastomas, are characterized by significant molecular
heterogeneity, which contributes to the difficulty in developing effec­
tive therapies.
Important progress has been made in understanding the molecular
pathogenesis of several types of brain tumors, including glioblastoma
and medulloblastoma, allowing them to be separated into different
subtypes with different prognoses. This has led the World Health
Organization (WHO) to issue an update on the classification of CNS
tumors in 2016 that for the first time incorporated molecular param­
eters in addition to traditional histology into the diagnosis of brain
tumors. The most recent 2021 WHO Classification of Tumors of the
CNS further stressed the use of integrated diagnoses based on both
molecular diagnostics and histology. This has improved the classifica­
tion of brain tumors, allowing for better understanding of the progno­
sis and optimal therapy for patients.
INTRINSIC “MALIGNANT” TUMORS
CHAPTER 95
■
■DIFFUSE GLIOMA
Gliomas are the most common type of malignant primary brain tumor.
The 2021 WHO Classification now differentiates gliomas as “adult
type” or “pediatric type” based on molecular genetic differences. Both
adult-type and pediatric-type diffuse gliomas can be subclassified into
high- or low-grade glioma based on histology and are further charac­
terized by key molecular alterations (Table 95-3). Although uncom­
mon, pediatric-type diffuse gliomas also occur in adults, hence their
inclusion here.
Primary and Metastatic Tumors of the Nervous System
Breast, endometrial, thyroid cancer, trichilemmomas
Familial polyposis, multiple osteomas, skin and soft tissue tumors
Schwannomas, astrocytomas, optic nerve gliomas, meningiomas
Neurofibromas, neurofibrosarcomas, others
Retinal angiomas, renal cell carcinoma, pheochromocytoma,
pancreatic tumors and cysts, endolymphatic sac tumors of the
middle ear
TABLE 95-3  Summary of Gliomas and Relevant Molecular Alterations
CHARACTERISTIC MOLECULAR
ALTERATIONS
TUMOR TYPE
Adult-Type Diffuse Gliomas
Astrocytoma, IDH-mutant
IDH1, IDH2
Oligodendroglioma, IDH-mutant,
1p/19q-codeleted
IDH1, IDH2, 1p/19q
Glioblastoma, IDH wild type
Chromosome 7 gain and 10 loss, TERT,
EGFR
Pediatric-Type Diffuse High-Grade Gliomas
Diffuse midline glioma, H3 K27-altered
H3 K27M, H3K27me3, EGFR, EZHIP
Diffuse hemispheric glioma, H3
G34-mutant
H3.3 G34R/V
Diffuse pediatric-type high-grade
glioma, H3 wild type and IDH wild type
EGFR, PDGFRA, MYCN
Pediatric-Type Diffuse Low-Grade Gliomas
Diffuse low-grade glioma, MAPK
pathway-altered
MAPK pathway genes (BRAF V600E
mutation, BRAF fusion, FGFR mutation)
Abbreviations: IDH, isocitrate dehydrogenase; TERT, telomerase reverse
transcriptase; EGFR, epidermal growth factor receptor; FGFR, fibroblast growth
factor receptor; MAPK, mitogen-activated protein kinase; EZHIP, EZH inhibitor
protein; PDGFRA, platelet-derived growth factor receptor alpha; MYCN, MYCN
proto-oncogene.
PART 4
Oncology and Hematology
■
■ADULT-TYPE DIFFUSE GLIOMA
Adult-type diffuse gliomas are classified based on the presence of a
mutation in a key driver, the isocitrate dehydrogenase (IDH) gene,
followed by the presence of 1p/19q co-deletion. Both of these molecu­
lar alterations have significant prognostic impact and lead to the
emergence of three distinct groups: IDH-mutant astrocytoma (1p/19q
intact), IDH-mutant oligodendroglioma (1p/19q co-deleted), and IDH
wild-type glioblastoma.
Diffuse gliomas can present rarely as widespread infiltration of the
brain tissue without a focal mass. Such tumors usually present with
cognitive problems, and the MRI demonstrates confluent, typically
nonenhancing areas of increased signal on FLAIR sequences without
significant mass effect. Formerly known as gliomatosis cerebri, these
lesions are now categorized by the pathology identified on biopsy, but
they can be diagnostically challenging when the nature of the imaging
abnormalities is unclear. Often diagnosis is delayed until the patient
develops worsening deficits or there is clear progression on imaging.
Treatment is then determined by the pathology.
Astrocytoma, IDH-Mutant 
IDH-mutant astrocytoma can be
further classified into grade 2, 3, or 4 based on histologic features, with
higher grade tumors incorporating additional features of malignancy.
CDKN2A/B homozygous deletion is associated with poor prognosis,
and its presence confers a grade 4 to IDH-mutant astrocytomas with
lower-grade histologic features. Low-grade (grade 2) IDH-mutant
astrocytomas are infiltrative tumors that usually present with sei­
zures in young adults or can be detected incidentally. They appear as
nonenhancing tumors with increased T2/FLAIR signal (Fig. 95-1). If
feasible, patients should undergo maximal surgical resection, although
complete resection is rarely possible because of the invasive nature of
the tumor. In patients at higher risk for recurrence (subtotal resection
or above the age of 40 years), there is evidence that radiation therapy
(RT) followed by PCV (procarbazine, lomustine, and vincristine) or
temozolomide chemotherapy may be of benefit. The tumor transforms
to a higher-grade astrocytoma in most patients, leading to variable
survival with a median of ~10 years. The IDH-inhibitor vorasidenib
has been showed to be effective in delaying the progression-free sur­
vival and time to next intervention, and IDH inhibitors may become
an integral part of the management for both IDH-mutant low-grade
glioma astrocytoma and oligodendroglioma. High-grade IDH-mutant
astrocytoma includes grade 3 astrocytoma (formerly termed anaplas­
tic astrocytoma) and grade 4 astrocytoma (previously IDH-mutant
glioblastoma) and generally presents in the fourth and fifth decades
FIGURE 95-1  Fluid-attenuated inversion recovery (FLAIR) MRI of a left frontal lowgrade astrocytoma. This lesion did not enhance.
of life as variably enhancing tumors. Treatment is the same as for glio­
blastoma, consisting of maximal safe surgical resection followed by RT
and adjuvant temozolomide alone or RT with concurrent and adjuvant
temozolomide. The median survival for high-grade anaplastic astrocy­
toma can range from 3 to 9 years.
Oligodendroglioma, IDH-Mutant and 1p/19q Co-deleted 
Oligodendrogliomas account for ~15–20% of gliomas. They are
characterized by co-deletion of 1p/19q and have IDH mutations. Oli­
godendrogliomas are classified by the WHO into grade 2 or grade 3
oligodendrogliomas (formerly anaplastic oligodendrogliomas). Oligo­
dendrogliomas have distinctive pathologic features such as perinuclear
clearing—giving rise to a “fried egg” appearance—and a reticular
pattern of blood vessel growth. Some tumors have both an oligoden­
droglial as well as an astrocytic component. With molecular testing, it
is now clear that almost all of these mixed tumors (oligoastrocytomas)
are genetically either astrocytomas or oligodendrogliomas. As a result,
the diagnosis of oligoastrocytoma is now rarely made unless molecular
testing is not available.
Grade 2 oligodendrogliomas are generally more responsive to
therapy and have a better prognosis than pure astrocytic tumors. These
tumors present similarly to grade 2 astrocytomas in young adults. The
tumors are nonenhancing and often partially calcified. They should be
treated with surgery and, in patients with residual disease or aged
40 years, RT and chemotherapy. Targeting mutant IDH with inhibi­
tors such as vorasidenib to delay progression and transformation to
higher grade may become an effective strategy in low-grade oligoden­
droglioma. Patients with oligodendrogliomas have a median survival
in excess of 10 years.
Grade 3 oligodendrogliomas present in the fourth and fifth decades
as variably enhancing tumors. They are more responsive to therapy
than grade 3 astrocytomas. Treatment involves maximal safe resection
followed by RT and PCV or temozolomide chemotherapy. Median
survival of patients is in excess of 10 years.
Glioblastoma 
Glioblastomas account for the majority of high-grade
astrocytomas and are now defined by the absence of IDH mutations.
With the new WHO classification, grade 2 and 3 astrocytomas without
the classic histologic features of glioblastoma (necrosis and endothe­
lial proliferation) but harboring molecular features of glioblastoma
FIGURE 95-2  Postgadolinium T1 MRI of a large cystic left frontal glioblastoma.
(epidermal growth factor amplification, combined with whole chromo­
some 7 gain and 10 loss, or telomerase reverse transcriptase [TERT]
promoter mutations) are considered molecular glioblastomas.
Glioblastomas are the most common malignant primary brain
tumor, with >12,000 cases diagnosed each year in the United States.
Patients usually present in the sixth and seventh decades of life with
headache, seizures, or focal neurologic deficits. The tumors appear
as ring-enhancing masses with central necrosis and surrounding
edema (Fig. 95-2). These are highly infiltrative tumors, and the areas
of increased T2/FLAIR signal surrounding the main tumor mass
contain invading tumor cells. Treatment involves maximal surgical
resection followed by involved-field external-beam RT (6000 cGy in
thirty 200-cGy fractions) with concomitant temozolomide, followed
by 6 months of adjuvant temozolomide. With this regimen, median
survival is increased to 15–18 months compared to only 12 months
with RT alone, and 5-year survival is ~10%. Efforts to increase the
dose of RT locally using brachytherapy or stereotactic radiosurgery
(SRS) have failed to improve the outcome, and these treatments are not
recommended. Patients whose tumor contains the DNA repair enzyme
O6-methylguanine-DNA methyltransferase (MGMT) are relatively
resistant to temozolomide and have a worse prognosis compared to
those whose tumors contain low levels of MGMT as a result of silenc­
ing of the MGMT gene by promoter hypermethylation. Implantation
of biodegradable polymers containing carmustine chemotherapy into
the tumor bed after resection of the tumor or addition of tumor treat­
ing fields (scalp electrodes delivering low-intensity electric currents)
produces a modest improvement in survival.
For elderly patients aged >65–70 years, a hypofractionated RT regi­
men of 40 Gy over 3 weeks with temozolomide is well tolerated and
likely leads to similar outcomes as the 6-week standard RT regimen.
Despite optimal therapy, glioblastomas invariably recur. Treatment
options for recurrent disease may include reoperation, reirradiation,
and treatment with bevacizumab and standard chemotherapeutic regi­
mens. Bevacizumab, a humanized vascular endothelial growth factor
(VEGF) monoclonal antibody, has activity in recurrent glioblastoma,
increasing progression-free survival but not overall survival and reduc­
ing peritumoral edema and glucocorticoid use (Fig. 95-3). Immune
checkpoint inhibitors have been successful in a variety of solid tumors
but have failed to demonstrate substantial activity in glioblastoma. A
recent phase 3 trial comparing bevacizumab with nivolumab in recur­
rent glioblastoma demonstrated an identical median overall survival
CHAPTER 95
A
Primary and Metastatic Tumors of the Nervous System
B
FIGURE 95-3  Postgadolinium T1 MRI of a recurrent glioblastoma before (A) and
after (B) administration of bevacizumab. Note the decreased enhancement and
mass effect.
of approximately 10 months in the two arms, with similar toxicities.
Treatment decisions for patients with recurrent glioblastoma must be
made on an individual basis, taking into consideration such factors as
previous therapy, time to relapse, performance status, and quality of
life. Whenever feasible, patients should be enrolled in clinical trials.
Novel therapies undergoing evaluation in patients with glioblastoma
include targeted molecular agents directed at receptor tyrosine kinases
and signal transduction pathways; immunotherapy using vaccines,
novel checkpoint inhibitors, or chimeric antigen receptor (CAR)
T cells; oncolytic viruses; antiangiogenic agents; chemotherapeutic
agents that cross the blood-brain barrier more effectively than cur­
rently available drugs; and infusion of radiolabeled drugs and targeted
toxins into the tumor and surrounding brain by means of convectionenhanced delivery.
The most important adverse prognostic factors in patients with
glioblastomas are older age, unmethylated MGMT promoter, poor
Karnofsky performance status, and unresectable tumor.
Gliosarcomas are a variant of glioblastoma containing both an astro­
cytic and a sarcomatous component and are treated in the same way as
glioblastomas.
■
■PEDIATRIC-TYPE DIFFUSE HIGH-GRADE GLIOMA
Pediatric-type diffuse high-grade gliomas (HGGs) are clinically and
biologically distinct and are further classified based on their location,
which also corresponds to specific molecular alterations. These tumors
are typical in younger patients, including young adults, and prior to the
recognition of these specific molecular drivers, many pediatric-type
HGGs, which do not harbor IDH mutations, were often diagnosed and
treated as glioblastoma.
Diffuse Midline Glioma, H3K27-Altered 
These tumors arise
from midline structures including the pons, thalamus, or spinal cord
and have an infiltrative appearance, often without contrast enhance­
ment on MRI. They harbor mutations in the H3F3A gene, resulting in
lysine-to-methionine substitution in amino acid residue 27 (K27M).
H3K27-altered glioma can occur both in children and adults and car­
ries a poor prognosis regardless of grade. As gross total resection is not
feasible in these tumors, treatment mostly consists of RT, while sys­
temic therapy options remain limited in efficacy. The median overall
survival is about 1 year.
Diffuse Hemispheric Glioma, H3 G34-Mutant 
Another HGG
that preferentially occurs in young adults is the diffuse hemispheric
glioma with the histone variant H3.3 glycine to arginine or valine
(H3.3-G34R/V) mutation. These tend to occur in a hemispheric loca­
tion, and the progression remains poor, with median overall survival of
18–22 months. No standard-of-care treatment exists for these tumors,
which are often treated similar to GBM with RT and chemotherapy.
PART 4
Oncology and Hematology
■
■PEDIATRIC-TYPE LOW-GRADE GLIOMA
While most common in pediatric patients, pediatric-type low-grade gli­
omas can also arise in young and older adults. They include avian myelo­
blastosis viral oncogene (MYB)-altered or MYB proto-oncogene like 1
(MYBL1)-altered diffuse gliomas and mitogen-activated protein kinase
(MAPK)-altered diffuse gliomas (commonly v-Raf murine sarcoma
viral oncogene homolog B [BRAF] or fibroblast growth factor receptor
[FGFR] alterations). Gross total resection can be curative in many cases,
and systemic therapy can provide durable response with oral BRAF or
MAPK inhibitors when a targetable mutation or fusion is found.
■
■CIRCUMSCRIBED ASTROCYTOMA AND OTHER
GLIONEURONAL TUMORS
These tumors regroup several histologies of more circumscribed
tumors, with a typically more indolent natural history. Pilocytic astro­
cytomas (WHO grade 1) are the most common tumor of childhood.
They occur typically in the cerebellum but may also be found elsewhere
in the neuraxis, including the optic nerves and brainstem. Frequently
they appear as cystic lesions with an enhancing mural nodule. Often,
they have BRAF fusions or mutations. These are well-demarcated
lesions that are potentially curable if they can be resected completely.
Subependymal giant cell astrocytomas (SEGAs) are usually found in
the ventricular wall of patients with tuberous sclerosis, discussed later.
Gangliogliomas and pleomorphic xanthoastrocytomas occur in
young adults. They behave as more indolent forms of grade 1 gliomas
and are usually treated with surgery. Frequently they will have BRAF
V600E mutations, which can be targeted with BRAF inhibitors.
■
■EPENDYMOMAS
Ependymomas are tumors derived from ependymal cells that line the
ventricular surface. They arise in three different compartments and
are classified according to location as supratentorial, posterior fossa,
or spinal ependymomas. Further molecular stratification within each
location (supratentorial ependymoma with ZFTA or YAP1 oncogenic
fusion; posterior fossa A or posterior fossa B; and spinal with or with­
out MYCN amplification) and grading can help guide management.
Children typically present with posterior fossa ependymoma followed
by supratentorial ependymoma. Although adults can have intracranial
ependymomas, they occur more commonly in the spine, especially in
the filum terminale of the spinal cord where they have a myxopapillary
histology. Ependymomas that can be completely resected are poten­
tially curable. Partially resected ependymomas will recur and require
irradiation. The less common anaplastic ependymoma is more aggres­
sive and is treated with resection and RT; chemotherapy has limited
efficacy. Subependymomas are slow-growing benign lesions arising in
the wall of ventricles that often do not require treatment.
■
■PRIMARY CENTRAL NERVOUS SYSTEM
LYMPHOMA
Primary central nervous system lymphoma (PCNSL) is a rare nonHodgkin’s lymphoma accounting for <3% of primary brain tumors.
For unclear reasons, its incidence is increasing, particularly in immu­
nocompetent, older individuals.
PCNSL in immunocompetent patients is usually a diffuse large
B-cell lymphoma. Immunocompromised patients, especially those
infected with the human immunodeficiency virus (HIV) or organ
transplant recipients, are at risk for PCNSL that is typically large cell
with immunoblastic and more aggressive features. Epstein-Barr virus
(EBV) plays an important role in the pathogenesis of PCNSL in this
population. These patients are usually severely immunocompromised,
with CD4 counts of <50/mL.
Immunocompetent patients with PCNSL are older (median age,
60 years) than those with HIV-related PCNSL (median age, 31 years).
PCNSL usually presents as a mass lesion, with neuropsychiatric
symptoms, lateralizing signs, or seizures. Ocular and leptomeningeal
involvement each occur in 15–20% of patients, and involvement of
these compartments may be asymptomatic. Rarely, it may present as
isolated ocular lymphoma or as primary leptomeningeal lymphoma.
When restricted to the leptomeninges, it may present as a subacute
or chronic meningitis that causes progressive cranial and spinal nerve
dysfunction. CSF cytologic examination or flow cytometry is required
to establish the diagnosis.
On contrast-enhanced MRI, PCNSL usually appears as a densely
enhancing tumor (Fig. 95-4). Immunocompetent patients have solitary
lesions more often than immunosuppressed patients. Frequently, there
is involvement of the basal ganglia, corpus callosum, or periventricular
region. Stereotactic biopsy is necessary to obtain a histologic diagno­
sis. Whenever possible, glucocorticoids should be withheld until after
the biopsy has been obtained because they have a cytolytic effect on
FIGURE 95-4  Postgadolinium T1 MRI demonstrating a large bifrontal primary
central nervous system lymphoma (PCNSL). The periventricular location and diffuse
enhancement pattern are characteristic of lymphoma.
lymphoma cells and may lead to nondiagnostic tissue. In addition,
patients should be tested for HIV, and the extent of disease should be
assessed by performing PET or CT of the body, MRI of the spine, CSF
analysis, and slit-lamp examination of the eye. Bone marrow biopsy
and testicular ultrasound are occasionally performed.
TREATMENT
Primary Central Nervous System Lymphoma
PCNSL is more sensitive to glucocorticoids, chemotherapy, and RT
than other primary brain tumors. Durable complete responses and
long-term survival are possible with these treatments. High-dose
methotrexate, a folate antagonist that interrupts DNA synthesis,
produces response rates ranging from 35 to 80% and median
survival of up to 50 months. The combination of methotrexate
with other chemotherapeutic agents such as cytarabine increases
the response rate to 70–100%. The addition of whole-brain RT
(WBRT) to methotrexate-based chemotherapy prolongs progres­
sion-free survival but not overall survival, but it is associated with
delayed neurotoxicity, especially in patients aged >60 years. As a
result, full-dose RT is frequently omitted, but there may be a role for
reduced-dose RT. The anti-CD20 monoclonal antibody rituximab
is often incorporated into the chemotherapy regimen, although
there are studies questioning its benefit. For some patients, highdose chemotherapy with autologous stem cell rescue may offer
the best chance of preventing relapse. At least 50% of patients will
eventually develop recurrent disease. Treatment options include RT
for patients who have not had prior irradiation, retreatment with
methotrexate, and other chemotherapeutic agents such as temo­
zolomide and pemetrexed. High-dose chemotherapy with autolo­
gous stem cell rescue may be appropriate in selected patients with
relapsed disease. Bruton’s tyrosine kinase (BTK) inhibitors such
as ibrutinib, immunomodulatory drugs such as pomalidomide
and lenalidomide, and immune checkpoint inhibitors have shown
promising preliminary activity and are being evaluated in clinical
trials, as are CAR-T cells.
PCNSL IN IMMUNOCOMPROMISED PATIENTS
PCNSL in immunocompromised patients often produces multiple
ring-enhancing lesions that can be difficult to differentiate from
metastases or infections such as toxoplasmosis. The diagnosis is
usually established by examination of the CSF for cytology and
EBV DNA; toxoplasmosis serologic testing; brain PET imaging
for hypermetabolism of the lesions, which, although nonspecific,
can be consistent with tumor; and, if necessary, brain biopsy. Since
the advent of highly active antiretroviral drugs, the incidence of
HIV-related PCNSL has declined. These patients are preferably
treated with high-dose methotrexate-based regimens and initiation
of highly active antiretroviral therapy; WBRT is reserved for those
who cannot tolerate systemic chemotherapy. In organ transplant
recipients, reduction of immunosuppression may improve outcome.
■
■MEDULLOBLASTOMA
Medulloblastomas are the most common malignant brain tumor of
childhood, accounting for ~20% of all primary CNS tumors among chil­
dren. They arise from granule cell progenitors or from multipotent pro­
genitors from the ventricular zone. Approximately 5% of children with
medulloblastoma have an inherited syndrome, such as Gorlin, Turcot,
or Li-Fraumeni, which predisposes to the development of medulloblas­
toma. Histologically, medulloblastomas are highly cellular tumors with
abundant dark staining, round nuclei, and rosette formation (HomerWright rosettes). In the 2016 WHO pathologic classification, they have
been divided into four molecular subgroups: (1) WNT-activated (pri­
marily affects children and has the best outcome); (2) SHH-activated
(affects adults, infants, and children, with the younger patients having
the better outcome and adults doing poorly); (3) non-WNT/non-SHH,
group 3 (frequently has disseminated CNS disease at diagnosis and has
the worst outcome); and (4) non-WNT/non-SHH, group 4 (30% have
metastases at diagnosis, but 5-year progression-free survival is 95%).
Regardless of subtype, patients present with headache, ataxia, and signs
of brainstem involvement. On MRI, they appear as densely enhanc­
ing tumors in the posterior fossa, sometimes associated with hydro­
cephalus. Treatment involves maximal surgical resection, craniospinal
irradiation, and chemotherapy with agents such as cisplatin, lomustine,
cyclophosphamide, and vincristine. Approximately 70% of patients
overall have long-term survival but usually at the cost of significant neu­
rocognitive impairment. A major goal of current research is to improve
survival while minimizing long-term complications, and clinical trials
are now being designed for specific molecular subgroups.
■
■PINEAL REGION TUMORS
A large variety of tumors can arise in the region of the pineal gland.
These typically present with headache, visual symptoms, and hydroceph­
alus. Patients may have Parinaud’s syndrome characterized by impaired
upgaze and accommodation. Some pineal tumors such as pineocytomas
and benign teratomas can be treated by surgical resection. Germinomas
respond to irradiation, whereas pineoblastomas and nongerminomatous
germ cell tumors require craniospinal RT and chemotherapy.
EXTRINSIC “BENIGN” TUMORS
CHAPTER 95
■
■MENINGIOMA
Meningiomas are diagnosed with increasing frequency as more people
undergo neuroimaging for various indications. They are now the most
common primary brain tumor, accounting for ~35% of the total. Their
incidence increases with age. They tend to be more common in women
and in patients with neurofibromatosis type 2 (NF2). They also occur
more commonly in patients with a history of cranial irradiation.
Primary and Metastatic Tumors of the Nervous System
Meningiomas arise from the dura mater and are composed of
neoplastic meningothelial (arachnoidal cap) cells. They are most com­
monly located over the cerebral convexities, especially adjacent to the
sagittal sinus, but they can also occur in the skull base and along the
dorsum of the spinal cord. Meningiomas are classified by the WHO
into three histologic grades of increasing aggressiveness: grade I
(benign), grade II (atypical), and grade III (malignant).
Many meningiomas are found incidentally following neuroimaging
for unrelated reasons. They can also present with headaches, seizures,
or focal neurologic deficits. On imaging studies, they have a charac­
teristic appearance usually of a densely enhancing extra-axial tumor
arising from the dura (Fig. 95-5). Typically they have a dural tail, con­
sisting of thickened, enhanced dura extending like a tail from the mass.
The main differential diagnosis of meningioma is a dural metastasis.
If the meningioma is small and asymptomatic, no intervention is
necessary and the lesion can be observed with serial MRI studies.
Larger, symptomatic lesions should be resected. If complete resection
is achieved, the patient is cured. Incompletely resected tumors tend
to recur, although the rate of recurrence can be very slow with grade
I tumors. Tumors that cannot be resected or can only be partially
removed may benefit from external-beam RT or SRS. These treatments
may also be helpful in patients whose tumor has recurred after surgery.
Hormonal therapy and chemotherapy are currently unproven.
Rarer tumors that resemble meningiomas include hemangiopericy­
tomas and solitary fibrous tumors. Since they share similar molecular
alterations (NAB2-STAT6 fusion), the 2016 WHO classification intro­
duced the combined term solitary fibrous tumor/hemangiopericytoma
for this entity. These tumors are treated with surgery and RT but have
a higher propensity to recur locally or metastasize systemically.
■
■SCHWANNOMA
These are generally benign tumors arising from the Schwann cells
of cranial and spinal nerve roots. The most common schwannomas,
termed vestibular schwannomas or acoustic neuromas, arise from the
vestibular portion of the eighth cranial nerve and account for ~9%
of primary brain tumors. Patients with NF2 have a high incidence of
vestibular schwannomas that are frequently bilateral. Schwannomas
arising from other cranial nerves, such as the trigeminal nerve (cranial
nerve V), occur with much lower frequency. Neurofibromatosis type 1
PART 4
Oncology and Hematology
FIGURE 95-5  Postgadolinium T1 MRI demonstrating multiple meningiomas along
the falx and left parietal cortex.
(NF1) is associated with an increased incidence of schwannomas of the
spinal nerve roots.
Vestibular schwannomas may be found incidentally on neuroim­
aging or present with progressive unilateral hearing loss, dizziness,
tinnitus, or, less commonly, symptoms resulting from compression
of the brainstem and cerebellum. On MRI, they appear as densely
enhancing lesions, enlarging the internal auditory canal and often
extending into the cerebellopontine angle (Fig. 95-6). The differential
diagnosis includes meningioma. Very small, asymptomatic lesions can
be observed with serial MRIs. Larger lesions should be treated with
surgery or SRS. The optimal treatment will depend on the size of the
tumor, symptoms, and the patient’s preference. In patients with small
vestibular schwannomas and relatively intact hearing, early surgical
intervention increases the chance of preserving hearing.
FIGURE 95-6  Postgadolinium MRI of a right vestibular schwannoma. The tumor
can be seen to involve the internal auditory canal.
■
■PITUITARY TUMORS
These are discussed in detail in Chap. 392.
■
■CRANIOPHARYNGIOMAS
Craniopharyngiomas are rare, usually suprasellar, partially calcified,
solid, or mixed solid-cystic benign tumors that arise from remnants
of Rathke’s pouch. They have a bimodal distribution, occurring pre­
dominantly in children but also between the ages of 55 and 65 years.
They present with headaches, visual impairment, and impaired growth
in children and hypopituitarism in adults. Treatment involves surgery,
RT, or a combination of the two. The papillary subtype of craniopha­
ryngiomas often has BRAF V600E mutations and can be treated with
RAF/MEK inhibitors.
■
■OTHER BENIGN TUMORS
Epidermoid Cysts 
These consist of squamous epithelium sur­
rounding a keratin-filled cyst. They are usually found in the cerebel­
lopontine angle and the intrasellar and suprasellar regions. They may
present with headaches, cranial nerve abnormalities, seizures, or
hydrocephalus. MRI demonstrates an extra-axial lesion with charac­
teristics that are similar to CSF but have restricted diffusion. Treatment
involves surgical resection.
Dermoid Cysts 
Like epidermoid cysts, dermoid cysts arise from
epithelial cells that are retained during closure of the neural tube. They
contain both epidermal and dermal structures such as hair follicles,
sweat glands, and sebaceous glands. Unlike epidermoid cysts, these
tumors usually have a midline location. They occur most frequently in
the posterior fossa, especially the vermis, fourth ventricle, and supra­
sellar cistern. On MRI, dermoid cysts resemble lipomas, demonstrating
T1 hyperintensity and variable signal on T2. Symptomatic dermoid
cysts can be treated with surgery.
Colloid Cysts 
These usually arise in the anterior third ventricle
and may present with headaches, hydrocephalus, and, very rarely, sud­
den death. Surgical resection is curative, or a third ventriculostomy
may relieve the obstructive hydrocephalus and be sufficient therapy.
NEUROCUTANEOUS SYNDROMES
(PHAKOMATOSES)
A number of genetic disorders are characterized by cutaneous lesions
and an increased risk of brain tumors. Most of these disorders have an
autosomal dominant inheritance with variable penetrance.
■
■NEUROFIBROMATOSIS TYPE 1
(von RECKLINGHAUSEN’S DISEASE)
NF1 is an autosomal dominant disorder with variable penetrance and
an incidence of ~1 in 2600–3000. Approximately one-half of cases
are familial; the remainder are caused by new mutations arising in
patients with unaffected parents. The NF1 gene is located on chromo­
some 17q11.2 and encodes neurofibromin, a guanosine triphosphatase
(GTPase) activating protein (GAP) that is a negative regulator of the
RAS–mitogen-activated protein (MAP) kinase signaling pathway,
which includes the downstream kinase MEK. It is a classic tumor
suppressor, and biallelic loss can result in a variety of nervous system
tumors including neurofibromas, plexiform neurofibromas, optic
nerve gliomas, astrocytomas, and meningiomas. In addition to neuro­
fibromas, which appear as multiple, soft, rubbery cutaneous tumors,
other cutaneous manifestations of NF1 include café-au-lait spots and
axillary freckling. NF1 is also associated with hamartomas of the iris
termed Lisch nodules, pheochromocytomas, pseudoarthrosis of the
tibia, scoliosis, epilepsy, and intellectual disability. The MEK inhibi­
tor selumetinib has activity against inoperable plexiform neurofibro­
mas and is the only treatment that targets the dysregulated signaling
pathway.
■
■NEUROFIBROMATOSIS TYPE 2
NF2 is less common than NF1, with an incidence of 1 in 25,000–
40,000. It is an autosomal dominant disorder with full penetrance. As
with NF1, approximately one-half of cases arise from new mutations.
The NF2 gene on 22q encodes a cytoskeletal protein, merlin (moesin,
ezrin, radixin-like protein), that functions as a tumor suppressor.
NF2 is characterized by bilateral vestibular schwannomas in >90% of
patients, multiple meningiomas, and spinal ependymomas and astro­
cytomas. Treatment of bilateral vestibular schwannomas can be chal­
lenging because the goal is to preserve hearing for as long as possible.
These patients may also have diffuse schwannomatosis that may affect
the cranial, spinal, or peripheral nerves; posterior subcapsular lens
opacities; and retinal hamartomas.
■
■TUBEROUS SCLEROSIS (BOURNEVILLE DISEASE)
This is an autosomal dominant disorder with an incidence of ~1 in
5000–10,000 live births. It is caused by mutations in either the TSC1
gene, which encodes a protein termed hamartin, or the TSC2 gene,
which encodes the protein tuberin. Hamartin forms a complex with
tuberin, which inhibits cellular signaling through the mammalian tar­
get of rapamycin (mTOR), and acts as a negative regulator of the cell
cycle. Patients with tuberous sclerosis may have seizures, intellectual
disability, adenoma sebaceum (facial angiofibromas), shagreen patch,
hypomelanotic macules, periungual fibromas, renal angiomyolipomas,
and cardiac rhabdomyomas. These patients have an increased inci­
dence of subependymal nodules, cortical tubers, and SEGAs. Patients
frequently require anticonvulsants for seizures. SEGAs do not always
require therapeutic intervention, but the most effective therapy is with
the mTOR inhibitors sirolimus or everolimus, which often decrease
seizures as well as SEGA size.
TUMORS METASTATIC TO THE BRAIN
Brain metastases arise from hematogenous spread and frequently origi­
nate from a lung primary or are associated with pulmonary metastases.
Most metastases develop at the gray matter–white matter junction in
the watershed distribution of the brain where intravascular tumor
cells lodge in terminal arterioles. The distribution of metastases in the
brain approximates the proportion of blood flow such that ~85% of all
metastases are supratentorial and 15% occur in the posterior fossa. The
most common sources of brain metastases are lung and breast carcino­
mas; melanoma has the greatest propensity to metastasize to the brain,
being found in 80% of patients at autopsy (Table 95-4). Other tumor
types such as ovarian and esophageal carcinoma rarely metastasize to
the brain. Prostate and breast cancers also have a propensity to metas­
tasize to the dura and can mimic meningioma. Leptomeningeal metas­
tases are common from hematologic malignancies and also breast and
lung cancers. Spinal cord compression primarily arises in patients with
prostate and breast cancer, tumors with a strong propensity to metas­
tasize to the axial skeleton.
■
■DIAGNOSIS OF METASTASES
Brain metastases are best visualized on MRI, where they usually appear
as well-circumscribed lesions (Fig. 95-7). The amount of perilesional
edema can be highly variable, with large lesions causing minimal edema
and sometimes very small lesions causing extensive edema. Enhance­
ment may be in a ring pattern or diffuse. Occasionally, intracranial
TABLE 95-4  Frequency of Nervous System Metastases for Common
Primary Tumors
BRAIN (%)
LM (%)
ESCC (%)
Lung
Breast
Melanoma
Prostate
GIT
—
Renal
Lymphoma
<1
Sarcoma
Other
—
Abbreviations: ESCC, epidural spinal cord compression; GIT, gastrointestinal tract;
LM, leptomeningeal metastases.
CHAPTER 95
A
Primary and Metastatic Tumors of the Nervous System
B
FIGURE 95-7  Postgadolinium T1 MRI of multiple brain metastases from non-smallcell lung cancer involving the right frontal (A) and right cerebellar (B) hemispheres.
Note the diffuse enhancement pattern and absence of central necrosis.
metastases will hemorrhage; melanoma, thyroid, and kidney cancer
have the greatest propensity to hemorrhage, but the most common
cause of a hemorrhagic metastasis is lung cancer because it accounts for
the majority of brain metastases. The radiographic appearance of brain
metastasis is nonspecific, and similar-appearing lesions can occur with
infection including brain abscesses, demyelinating lesions, sarcoidosis,
radiation necrosis in a previously treated patient, or a primary brain
tumor that may be a second malignancy in a patient with systemic
cancer. Biopsy is rarely necessary for diagnosis because imaging alone
in the appropriate clinical situation usually suffices. However, in ~10%
of patients, a systemic cancer may present with a brain metastasis, and
if there is not an easily accessible systemic site to biopsy, a brain lesion
must be removed for diagnostic purposes.
TREATMENT
Tumors Metastatic to the Brain
DEFINITIVE TREATMENT
The number and location of brain metastases often determine the
therapeutic options. The patient’s overall condition and current or
potential control of systemic disease are also major determinants.
Brain metastases are single in approximately one-half of patients
and multiple in the other half.
RADIATION THERAPY
The standard treatment for brain metastases has previously been
WBRT usually administered to a total dose of 3000 cGy in 10 frac­
tions. This affords rapid palliation, and ~80% of patients improve
with glucocorticoids and RT. However, it is not curative, is associated
with neurocognitive toxicity, and produces median survival of only
4–6 months. Hippocampal avoidance during WBRT can preserve
cognitive function without increasing the risk of an intracranial
relapse. The use of WBRT has declined with the development of
more effective systemic options and access to SRS. If feasible, SRS
has become the primary radiation oncology approach to brain
metastases. It can be delivered through a variety of equally effective
techniques including the gamma knife, linear accelerator, proton
beam, or CyberKnife, all of which can deliver highly focused doses of
RT, usually in a single fraction. SRS can effectively sterilize the visible
lesions and afford local disease control in 80–90% of patients. Some
patients have been cured of their brain metastases using SRS, whereas
this is distinctly rare with WBRT. Traditionally SRS was used only for
patients with 1–3 metastases, but recent data suggest that SRS can
effectively treat 10 or more lesions. It is, however, confined to lesions
of ≤3 cm and is most effective in metastases of ≤1 cm. The addition
of WBRT to SRS improves disease control in the nervous system but
does not prolong survival and thus is rarely employed.
PART 4
Oncology and Hematology
SURGERY
Randomized controlled trials have demonstrated that surgical extir­
pation of a single brain metastasis followed by WBRT is superior
to WBRT alone. Removal of two lesions or a single symptomatic
mass, particularly if compressing the ventricular system, can also
be useful. This is particularly important in patients who have highly
radioresistant lesions such as renal carcinoma. Surgical resection
can produce rapid amelioration of symptoms, improve control of
edema, and result in prolonged survival. WBRT administered after
complete resection of a brain metastasis improves disease control
but does not prolong survival. There is increasing use of focal RT
or even SRS to a resected cavity, especially if there is concern that
tumor has been left behind, but most avoid postoperative WBRT
because of its cognitive effects.
CHEMOTHERAPY
Chemotherapy and targeted therapy are becoming increasingly
useful for brain metastases. Metastases from tumor types that are
highly chemosensitive, such as germ cell tumors or small-cell lung
cancer, may respond to chemotherapeutic regimens chosen accord­
ing to the underlying malignancy. Increasingly, data demonstrate
responsiveness of brain metastases to targeted therapeutics, such
as for patients with lung cancer harboring EGFR mutations that
sensitize them to EGFR inhibitors. Immunotherapy is also effective
against those primary tumors that are sensitive to this approach,
such as melanoma. Antiangiogenic agents such as bevacizumab
are effective in the treatment of CNS metastases in those primary
tumors for which it is approved.
LEPTOMENINGEAL METASTASES
Leptomeningeal metastases are also described as carcinomatous men­
ingitis, meningeal carcinomatosis, or, in the case of specific tumors,
leukemic or lymphomatous meningitis. Among the hematologic
malignancies, acute leukemias most commonly metastasize to the
subarachnoid space, followed in frequency by aggressive diffuse lym­
phomas. Among solid tumors, breast and lung carcinomas and mela­
noma most frequently spread in this fashion. Tumor cells reach the
subarachnoid space via the arterial circulation or occasionally through
retrograde flow in venous systems that drain metastases along the bony
spine or cranium. In addition, leptomeningeal metastases may develop
as a direct consequence of prior brain metastases and occur in almost
40% of patients who have a metastasis resected from the cerebellum.
■
■CLINICAL FEATURES
Leptomeningeal metastases are characterized by multilevel symptoms
and signs along the neuraxis. Combinations of lumbar and cervi­
cal radiculopathies, cranial neuropathies, seizures, confusion, and
encephalopathy from hydrocephalus or raised intracranial pressure
can be present. Focal deficits such as hemiparesis or aphasia are rarely
due to leptomeningeal metastases unless there is direct brain infiltra­
tion. New-onset limb pain in patients with breast cancer, lung cancer,
or melanoma should prompt consideration of leptomeningeal spread.
■
■LABORATORY AND IMAGING DIAGNOSIS
Leptomeningeal metastases are particularly challenging to diagnose
because identification of tumor cells in the subarachnoid compart­
ment may be elusive. MRI can be definitive when there are clear tumor
nodules adherent to the cauda equina or spinal cord, enhancing cranial
nerves, or subarachnoid enhancement on brain imaging (Fig. 95-8).
Imaging is diagnostic in ~75% of patients and is more often positive
in patients with solid tumors. Demonstration of tumor cells in the
CSF is definitive and often considered the gold standard. However,
CSF cytologic examination is positive in only 50% of patients on the
first lumbar puncture and still misses 10% after three CSF samples.
New technologies, such as rare cell capture, enhance identification of
tumor cells in the CSF; molecular profiling of the CSF can also identify
tumor-specific mutations, indicating malignancy in the leptomeninges.
CSF cytologic examination is most useful in hematologic malignancies,
especially when combined with flow cytometry to identify a clonal
population. Accompanying CSF abnormalities include an elevated
protein concentration and an elevated white blood cell count; hypo­
glycorrhachia is noted in <25% of patients but is useful when present.
Identification of tumor markers may be helpful in some solid tumors.
TREATMENT
Leptomeningeal Metastases
The treatment of leptomeningeal metastasis is palliative because
there is no curative therapy. RT to the symptomatically involved
areas, such as skull base for cranial neuropathy, can relieve pain and
sometimes improve function. Craniospinal irradiation (CSI) was
previously avoided because it has significant toxicity with myelosup­
pression and gastrointestinal irritation as well as limited effectiveness.
However, recent data on proton beam CSI suggest better disease con­
trol with fewer systemic toxicities. Systemic chemotherapy, targeted
therapeutics, and immunotherapy have all demonstrated limited
efficacy in the appropriate setting. Alternatively, intrathecal chemo­
therapy can be effective, particularly in hematologic malignancies.
This is optimally delivered through an intraventricular cannula
(Ommaya reservoir) rather than by lumbar puncture. Few drugs
can be delivered safely into the subarachnoid space, and they have
a limited spectrum of antitumor activity, perhaps accounting for
the relatively poor response to this approach, particularly in solid
tumors. In addition, impaired CSF flow dynamics can compromise
intrathecal drug delivery. Surgery has a limited role in leptomen­
ingeal metastasis. A ventriculoperitoneal shunt can relieve raised
intracranial pressure but complicates the use of intrathecal drugs.
EPIDURAL METASTASIS
Epidural metastasis occurs in 3–5% of patients with a systemic malig­
nancy and causes neurologic compromise by compressing the spinal
cord or cauda equina. The most common cancers that metastasize to
FIGURE 95-9  Postgadolinium T1 MRI showing circumferential epidural tumor
around the thoracic spinal cord from esophageal cancer.
A
B
FIGURE 95-8  Postgadolinium MRI images of extensive leptomeningeal metastases
from breast cancer. Nodules along the dorsal surface of the spinal cord (A) and
cauda equina (B) are seen.
the epidural space are those malignancies that spread to bone, such as
breast and prostate. Lymphoma can cause bone involvement and com­
pression, but it can also invade an intervertebral foramen and cause
spinal cord compression without bone destruction. The thoracic spine
is affected most commonly, followed by the lumbar and then cervical
spine.
■
■CLINICAL FEATURES
Back pain is the presenting symptom of epidural metastasis in virtu­
ally all patients; the pain may precede neurologic findings by weeks or
months. The pain is usually exacerbated by lying down; by contrast,
arthritic pain is often relieved by recumbency. Leg weakness is seen
in ~50% of patients, as is sensory dysfunction. Sphincter problems are
present in ~25% of patients at diagnosis.
CHAPTER 95
■
■DIAGNOSIS
Diagnosis is established by imaging, preferably with an MRI of the
entire spine (Fig. 95-9). Any patient with cancer who has severe back
pain should undergo an MRI. Plain films, bone scans, or even CT
scans may show bone metastases, but only MRI can reliably delineate
epidural tumor. For patients unable to have an MRI, CT myelography
should be performed to outline the epidural space. The differen­
tial diagnosis of epidural tumor includes epidural abscess, acute or
chronic hematomas, epidural lipomatosis, and, rarely, extramedullary
hematopoiesis.
Primary and Metastatic Tumors of the Nervous System
TREATMENT
Epidural Metastasis
Epidural metastasis requires immediate treatment. A randomized
controlled trial demonstrated the superiority of surgical resection
followed by RT compared to RT alone. However, patients must be
able to tolerate surgery, and the surgical procedure of choice is a
complete removal of the mass, which is typically anterior to the
spinal canal, necessitating an extensive approach and resection.
Otherwise, RT is the mainstay of treatment and can be used for
patients with radiosensitive tumors, such as lymphoma, or for those
unable to undergo surgery. SRS or stereotactic body radiotherapy is
increasingly being used, especially for radioresistant tumor types or
for reirradiation. Chemotherapy is rarely used for epidural metas­
tasis unless the patient has minimal to no neurologic deficit and a
highly chemosensitive tumor such as lymphoma or germinoma.
Patients generally fare well if treated before there is a severe neu­
rologic deficit. Recovery from paraparesis is better after surgery
than with RT alone, but survival is often short due to widespread
metastatic tumor.
NEUROLOGIC TOXICITY OF THERAPY
■
■TOXICITY FROM RADIOTHERAPY
RT can cause a variety of toxicities in the CNS. These are usually
described based on their relationship in time to the administration of
RT: acute (occurring within days of RT), early delayed (months), or
late delayed (years). In general, the acute and early delayed syndromes
resolve and do not result in persistent deficits, whereas the late delayed
toxicities are usually permanent and sometimes progressive.
Acute Toxicity 
Acute cerebral toxicity may occur during RT to the
brain. RT can cause a transient disruption of the blood-brain barrier,
resulting in edema and elevated intracranial pressure. This is usually
manifest as headache, lethargy, nausea, and vomiting and can be both
prevented and treated with the administration of glucocorticoids.
Early Delayed Toxicity 
Early delayed toxicity is usually apparent
weeks to months after completion of cranial irradiation and is likely
due to focal demyelination. Clinically it may be asymptomatic or take
the form of worsening or reappearance of a preexisting neurologic
deficit. At times, a contrast-enhancing lesion can be seen on MRI/CT
that can mimic the tumor for which the patient received the RT. For
patients with a malignant glioma, this has been described as “pseu­
doprogression” because it mimics tumor recurrence on MRI, but it
represents inflammation and necrotic debris engendered by effective
therapy. This is seen with increased frequency when chemotherapy,
particularly temozolomide, is given concurrently with RT. Pseudopro­
gression can resolve on its own or, if very symptomatic, may require
glucocorticoids, resection, or bevacizumab.
In the spinal cord, early delayed RT toxicity is manifest as a Lher­
mitte symptom with paresthesias of the limbs or along the spine when
the patient flexes the neck. Although frightening, it is benign, resolves
on its own, and does not portend more serious problems.
PART 4
Oncology and Hematology
Late Delayed Toxicity 
Late delayed toxicities are the most serious
because they are often irreversible and cause severe neurologic deficits.
In the brain, late toxicities can take several forms, the most common of
which include radiation necrosis and leukoencephalopathy. Radiation
necrosis is a focal mass of necrotic tissue that is contrast enhancing
on CT/MRI and may be associated with significant edema. This may
appear identical to pseudoprogression but is seen months to years after
RT and is always symptomatic. Clinical symptoms and signs include
seizures and findings referable to the location of the necrotic mass.
The necrosis is caused by the effect of RT on cerebral vasculature with
fibrinoid necrosis and occlusion of blood vessels. It can mimic tumor
radiographically, but unlike tumor, it is typically hypometabolic on a
PET scan and has reduced cerebral blood volume on perfusion MR
sequences. It may require resection for diagnosis and treatment unless
it can be managed with glucocorticoids. There are reports of improve­
ment with bevacizumab and laser interstitial thermal therapy.
Leukoencephalopathy is seen most commonly after WBRT as
opposed to focal RT. On T2 or FLAIR MR sequences, there is dif­
fusely increased signal seen throughout the hemispheric white matter,
often bilaterally and symmetrically. There tends to be a periventricular
predominance that may be associated with atrophy and ventricular
enlargement. Clinically, patients develop cognitive impairment, a gait
disorder, and later urinary incontinence, all of which can progress over
time. These symptoms mimic those of normal pressure hydrocephalus,
and placement of a ventriculoperitoneal shunt can improve function in
some patients but does not reverse the deficits completely. Increased
age is a risk factor for leukoencephalopathy but not for radiation necro­
sis. Necrosis appears to depend on an unidentified predisposition.
Other late neurologic toxicities include endocrine dysfunction if the
pituitary or hypothalamus was included in the RT port. An RT-induced
neoplasm can occur many years after therapeutic RT for either a prior
CNS or a head and neck tumor; accurate diagnosis requires surgical
resection or biopsy. In addition, RT causes accelerated atherosclerosis,
which can cause stroke either from intracranial vascular disease or
carotid plaque from neck irradiation.
The peripheral nervous system is relatively resistant to RT toxici­
ties. Peripheral nerves are rarely affected by RT, but the plexus is more
vulnerable. Plexopathy develops more commonly in the brachial than
in the lumbosacral distribution. It must be differentiated from tumor
progression in the plexus, which is usually visualized by CT/MRI
or PET scan demonstrating tumor infiltrating the region. Clinically,
tumor progression is usually painful, whereas RT-induced plexopathy
is painless. Radiation plexopathy is also more commonly associated
with lymphedema and myokymia of the affected limb. Sensory loss and
weakness are seen in both.
TABLE 95-5  Neurologic Toxicities Caused by Agents Commonly Used
in Patients with Cancer
Acute encephalopathy (delirium)
  Methotrexate (high-dose IV, IT)
  Cisplatin
  Vincristine
  Asparaginase
  Procarbazine
  5-Fluorouracil (± levamisole)
  Cytarabine (high-dose)
  Nitrosoureas (high-dose or arterial)
  Ifosfamide
  Etoposide (high-dose)
  Bevacizumab (PRES)
  CAR-T cells
Chronic encephalopathy (dementia)
  Methotrexate
  Carmustine
  Cytarabine
  Fludarabine
Visual loss
  Tamoxifen
  Gallium nitrate
  Cisplatin
  Fludarabine
Cerebellar dysfunction/ataxia
  5-Fluorouracil (± levamisole)
  Cytarabine
  Procarbazine
Seizures
  Methotrexate
  Etoposide (high-dose)
  Cisplatin
  Vincristine
  Asparaginase
  Nitrogen mustard
  Carmustine
  Dacarbazine (intraarterial or
high-dose)
  Busulfan (high-dose)
Myelopathy (IT drugs)
  Methotrexate
  Cytarabine
  Thiotepa
Peripheral neuropathy
  Vinca alkaloids
  Cisplatin
  Procarbazine
  Etoposide
  Teniposide
  Cytarabine
  Taxanes
  Suramin
  Bortezomib
Abbreviations: CAR, chimeric antigen receptor; IT, intrathecal; IV, intravenous;
PRES, posterior reversible encephalopathy syndrome.
■
■TOXICITY FROM CHEMOTHERAPY
Neurotoxicity is second to myelosuppression as the dose-limiting tox­
icity of chemotherapeutic agents (Table 95-5). Chemotherapy causes
peripheral neuropathy from many commonly used agents, and the
type of neuropathy can vary depending on the drug. Vincristine causes
paresthesias but little sensory loss and is associated with motor dys­
function, autonomic impairment (frequently ileus), and, rarely, cranial
nerve compromise. Cisplatin causes large-fiber sensory loss resulting
in sensory ataxia but little cutaneous sensory loss and no weakness.
The taxanes also cause a predominately sensory neuropathy. Agents
such as bortezomib and thalidomide also cause neuropathy. Sometimes
a severe neuropathy emerges after multiple neurotoxic agents have
been used together or in sequence.
Encephalopathy and seizures are common toxicities from che­
motherapeutic drugs. Ifosfamide can cause a severe encephalopathy,
which is reversible with discontinuation of the drug. Fludarabine also
causes a severe global encephalopathy that may be permanent. Beva­
cizumab and other anti-VEGF agents can cause posterior reversible
encephalopathy syndrome. Cisplatin can cause hearing loss and less
frequently vestibular dysfunction. Immunotherapy with monoclonal
antibodies such as ipilimumab or nivolumab can cause an autoimmune
hypophysitis, Guillain-Barré syndrome, or an autoimmune encephali­
tis. CAR-T cells frequently cause a reversible encephalopathy due to an
immune effector cell–associated neurotoxicity syndrome (Chap. 318).
■
■FURTHER READING
Aizer AA et al: Brain metastases: A Society for Neuro-Oncology
(SNO) consensus review on current management and future direc­
tions. Neuro Oncol 24:1613, 2022.
Grommes C et al: Comprehensive approach to diagnosis and treatment
of newly diagnosed primary CNS lymphoma. Neuro Oncol 21:296,
2019.

25 - 96 Soft Tissue and Bone Sarcomas and Bone Metastases
96 Soft Tissue and Bone Sarcomas and Bone Metastases
Lamba N et al: Epidemiology of brain metastases and leptomeningeal
disease. Neuro Oncol 23:1447, 2021.
Louis DN et al: The 2021 WHO classification of tumors of the central
nervous system: A summary. Neuro-Oncology 23:1231, 2021.
Mellinghoff IK et al: Vorasidenib in IDH1- or IDH2-mutant lowgrade glioma. N Engl J Med 389:589, 2023.
Ostrom QT et al: CBTRUS statistical report: Primary brain and other
central nervous system tumors diagnosed in the United States in
2016-2020. Neuro Oncol 25:iv1-iv99, 2023.
Schiff D et al: Recent developments and future directions in adult
lower-grade gliomas: Society for Neuro-Oncology (SNO) and Euro­
pean Association of Neuro-Oncology (EANO) consensus. Neuro
Oncol 21:837, 2019.
Wen PY et al: Glioblastoma in adults: A Society for Neuro-Oncology
(SNO) and European Society of Neuro-Oncology (EANO) consensus
review on current management and future directions. Neuro Oncol
22:1073, 2020.
Shreyaskumar R. Patel
Soft Tissue and Bone
Sarcomas and Bone
Metastases
Sarcomas are rare (<1% of all malignancies) mesenchymal neoplasms
that arise in bone and soft tissues. These tumors are usually of meso­
dermal origin, although a few are derived from neuroectoderm, and
they are biologically distinct from the more common epithelial malig­
nancies. Sarcomas affect all age groups; 15% are found in children
<15 years of age, and 40% occur after age 55 years. Sarcomas are one
of the most common solid tumors of childhood and are the fifth most
common cause of cancer deaths in children. Sarcomas may be divided
into two groups, those derived from bone and those derived from soft
tissues.
SOFT TISSUE SARCOMAS
Soft tissues include muscles, tendons, fat, fibrous tissue, synovial tissue,
vessels, and nerves. Approximately 60% of soft tissue sarcomas arise in
the extremities, with the lower extremities involved three times as often
as the upper extremities. Thirty percent arise in the trunk, with the ret­
roperitoneum accounting for 40% of all trunk lesions. The remaining
10% arise in the head and neck.
■
■INCIDENCE
Approximately 13,400 new cases of soft tissue sarcomas occurred in
the United States in 2023. The annual age-adjusted incidence is 3 per
100,000 population, but the incidence varies with age. Soft tissue sarco­
mas constitute 0.7% of all cancers in the general population and 6.5%
of all cancers in children.
■
■EPIDEMIOLOGY
Malignant transformation of a benign soft tissue tumor is extremely
rare, with the exception that malignant peripheral nerve sheath tumors
(neurofibrosarcoma, malignant schwannoma) can arise from neuro­
fibromas in patients with neurofibromatosis. Several etiologic factors
have been implicated in soft tissue sarcomas.
Environmental Factors 
Trauma or previous injury is rarely
involved, but sarcomas can arise in scar tissue resulting from a prior
operation, burn, fracture, or foreign body implantation. Chemical car­
cinogens such as polycyclic hydrocarbons, asbestos, and dioxin may be
involved in the pathogenesis.
Iatrogenic Factors 
Sarcomas in bone or soft tissues occur in
patients who are treated with radiation therapy. The tumor nearly
always arises in the irradiated field. The risk increases with time.
Viruses 
Kaposi’s sarcoma (KS) in patients with HIV type 1, classic
KS, and KS in HIV-negative homosexual men is caused by human
herpesvirus (HHV) 8 (Chap. 200). No other sarcomas are associated
with viruses.
Immunologic Factors 
Congenital or acquired immunodefi­
ciency, including therapeutic immunosuppression, increases the risk
of sarcoma.
■
■GENETIC CONSIDERATIONS
Li-Fraumeni syndrome is a familial cancer syndrome in which
affected individuals have germline abnormalities of the tumorsuppressor gene p53 and an increased incidence of soft tissue
sarcomas and other malignancies, including breast cancer, osteosar­
coma, brain tumor, leukemia, and adrenal carcinoma (Chap. 76).
Neurofibromatosis 1 (NF-1; peripheral form, von Recklinghausen’s
disease) is characterized by multiple neurofibromas and café-au-lait
spots. Neurofibromas occasionally undergo malignant degeneration to
become malignant peripheral nerve sheath tumors. The gene for NF1
is located in the pericentromeric region of chromosome 17 and
encodes neurofibromin, a tumor-suppressor protein with guanosine
5′-triphosphate (GTP)ase-activating activity that inhibits ras function
(Chap. 95). Germline mutation of the RB1 locus (chromosome 13q14)
in patients with inherited retinoblastoma is associated with the devel­
opment of osteosarcoma in those who survive the retinoblastoma and
of soft tissue sarcomas unrelated to radiation therapy. Other soft tissue
tumors, including desmoid tumors, lipomas, leiomyomas, neuroblasto­
mas, and paragangliomas, occasionally show a familial predisposition.
CHAPTER 96
Soft Tissue and Bone Sarcomas and Bone Metastases
Insulin-like growth factor (IGF) type II is produced by some sarco­
mas and may act as an autocrine growth factor and as a motility factor
that promotes metastatic spread. IGF-II stimulates growth through
IGF-I receptors, but its effects on motility are through different recep­
tors. If secreted in large amounts, IGF-II may produce hypoglycemia
(Chaps. 98 and 418). A large international sarcoma kindred study
including 1162 patients and 6545 Caucasian controls revealed that
about half the patients with sarcoma have putatively pathogenic mono­
genic and polygenic variation in previously reported and new cancer
genes, some of them representing therapeutically actionable targets.
These patients were diagnosed with sarcoma at an earlier age compared
to controls.
■
■CLASSIFICATION
Approximately 20 different groups of sarcomas are recognized on
the basis of the pattern of differentiation toward normal tissue. For
example, rhabdomyosarcoma shows evidence of skeletal muscle fibers
with cross-striations; leiomyosarcomas contain interlacing fascicles
of spindle cells resembling smooth muscle; and liposarcomas contain
adipocytes. When precise characterization of the group is not possible,
the tumors are called unclassified sarcomas. All of the primary bone
sarcomas can also arise from soft tissues (e.g., extraskeletal osteosar­
coma). The entity malignant fibrous histiocytoma (MFH) includes
many tumors previously classified as fibrosarcomas or as pleomorphic
variants of other sarcomas and is characterized by a mixture of spindle
(fibrous) cells and round (histiocytic) cells arranged in a storiform
pattern with frequent giant cells and areas of pleomorphism. As immu­
nohistochemical suggestion of differentiation, particularly myogenic
differentiation, may be found in a significant fraction of these patients,
many are now characterized as poorly differentiated leiomyosarcomas,
and the terms undifferentiated pleomorphic sarcoma (UPS) and myxofi­
brosarcoma are replacing MFH and myxoid MFH.
For purposes of treatment, most soft tissue sarcomas can be consid­
ered together. However, some specific tumors have distinct features.
For example, liposarcoma can have a spectrum of behaviors. Pleomor­
phic liposarcomas and dedifferentiated liposarcomas behave like other
high-grade sarcomas; in contrast, well-differentiated liposarcomas
(better termed atypical lipomatous tumors) lack metastatic potential,
and myxoid liposarcomas metastasize infrequently, but, when they do,
they have a predilection for unusual metastatic sites containing fat,
such as the retroperitoneum, mediastinum, and subcutaneous tissue.
Rhabdomyosarcomas, Ewing’s sarcoma, and other small-cell sarcomas
tend to be more aggressive and are more responsive to chemotherapy
than other soft tissue sarcomas.
Approximately a third of all soft tissue sarcomas have a translocation
that may have diagnostic and prognostic relevance; for example, 90% of
synovial sarcomas contain a characteristic chromosomal translocation
t(X;18)(p11;q11) involving a nuclear transcription factor on chromo­
some 18 called SYT and two breakpoints on X. Patients with transloca­
tions to the second X breakpoint (SSX2) may have longer survival than
those with translocations involving SSX1. Targeting these transloca­
tions for therapy is an area of ongoing investigation.
Gastrointestinal stromal tumors (GISTs), previously classified as
gastrointestinal leiomyosarcomas, are now recognized as a distinct
entity within soft tissue sarcomas. Its cell of origin resembles the
interstitial cell of Cajal, which controls peristalsis. The majority of
malignant GISTs have activating mutations of the c-kit gene that result
in ligand-independent phosphorylation and activation of the KIT
receptor tyrosine kinase, leading to tumorigenesis. Approximately
5–10% of tumors will have a mutation in the platelet-derived growth
factor receptor α (PDGFRA). GISTs that are wild type for both KIT and
PDGFRA mutations may show mutations in SDH B, C, or D and may
be driven by the IGF-I pathway.
PART 4
Oncology and Hematology
■
■DIAGNOSIS
The most common presentation is an asymptomatic mass. Mechanical
symptoms referable to pressure, traction, or entrapment of nerves or
muscles may be present. All new and persistent or growing masses should
be biopsied, either by a small incision or by a cutting needle (core-needle
biopsy) placed so that it can be encompassed in the subsequent excision
without compromising a definitive resection. Lymph node metastases
occur in 5%, except in synovial and epithelioid sarcomas, clear cell
sarcoma (melanoma of the soft parts), angiosarcoma, and rhabdomyo­
sarcoma, where nodal spread may be seen in 17%. The pulmonary paren­
chyma is the most common site of metastases. Exceptions are GISTs,
which metastasize to the liver; myxoid liposarcomas, which seek fatty
tissue; and clear cell sarcomas, which may metastasize to bones. Central
nervous system metastases are rare, except in alveolar soft part sarcoma.
Radiographic Evaluation 
Imaging of the primary tumor is best
with plain radiographs and magnetic resonance imaging (MRI) for
tumors of the extremities or head and neck and by computed tomog­
raphy (CT) for tumors of the chest, abdomen, or retroperitoneal cavity.
A radiograph and CT scan of the chest are important for the detection
of lung metastases. Other imaging studies may be indicated, depending
on the symptoms, signs, or histology.
■
■STAGING AND PROGNOSIS
The histologic grade and size of the primary tumor are the most
important prognostic factors. The current American Joint Committee
on Cancer (AJCC) staging system is shown in Table 96-1. Prognosis
is related to the stage. Cure is common in the absence of metastatic
disease, but a small number of patients with metastases can also be
cured. Historically, most patients with stage IV disease used to die within
12 months, but with availability of multiple lines of treatments, median
survival in second-line and beyond ranges from 13 to 18 months, and
some patients may live with stable or slowly progressive disease for
many years.
TREATMENT
Soft Tissue Sarcomas
AJCC stage I patients are adequately treated with surgery alone.
Stage II patients are considered for adjuvant radiation therapy.
Stage III patients may benefit from neoadjuvant or adjuvant che­
motherapy. Stage IV patients are managed primarily with systemic
therapy, with or without other modalities.
TABLE 96-1  American Joint Commission on Cancer Staging System for
Sarcomas, Eighth Edition
T1
Tumor ≤5 cm in greatest dimension
T2
Tumor >5 cm and ≤10 cm in greatest dimension
T3
Tumor >10 cm and ≤15 cm in greatest dimension
T4
Tumor >15 cm in greatest dimension
N0
No regional lymph node metastasis or unknown lymph
node status
N1
Regional lymph node metastasis
M0
No distant metastasis
M1
Distant metastasis
Stage Groups
Stage IA
T1; N0; M0; G1
Stage IB
T2, T3, T4; N0; M0; G1
Stage II
T1; N0; M0; G2/3
Stage IIIA
T1A, T2; N0; M0; G2/3
Stage IIIB
T3, T4; N0; M0; G2/3
Stage IV
Any T; N1; M0; any G
Any T; any N; M1; any G
SURGERY
Soft tissue sarcomas tend to grow along fascial planes, with the
surrounding soft tissues compressed to form a pseudocapsule that
gives the sarcoma the appearance of a well-encapsulated lesion.
This is invariably deceptive because “shelling out,” or marginal exci­
sion, of such lesions results in a 50–90% probability of local recur­
rence. Wide excision with a negative margin, incorporating the
biopsy site, is the standard surgical procedure for local disease. The
adjuvant use of radiation therapy and/or chemotherapy improves
the local control rate and permits the use of limb-sparing surgery
with a local control rate (85–90%) comparable to that achieved by
radical excisions and amputations. Limb-sparing approaches are
indicated except when negative margins are not obtainable, when
the risks of radiation are prohibitive, or when neurovascular struc­
tures are involved so that resection will result in serious functional
consequences to the limb.
RADIATION THERAPY
External-beam radiation therapy is an adjuvant to limb-sparing
surgery for improved local control. Preoperative radiation therapy
allows the use of smaller fields and smaller doses but results in a
higher rate of wound complications. Postoperative radiation therapy
must be given to larger fields, because the entire surgical bed must
be encompassed, and in higher doses to compensate for hypoxia in
the operated field. This results in a higher rate of late complications.
Brachytherapy or interstitial therapy, in which the radiation source
is inserted into the tumor bed, is comparable in efficacy (except in
low-grade lesions), less time consuming, and less expensive.
With the advent of stereotactic body radiotherapy (SBRT), the
role of radiation therapy in oligometastatic disease in various vis­
ceral sites is evolving.
ADJUVANT CHEMOTHERAPY
Chemotherapy is the mainstay of treatment for Ewing’s sarcomas/
primitive neuroectodermal tumors (PNETs) and rhabdomyosar­
comas. Meta-analysis of 14 randomized trials in non-small-cell
sarcomas revealed a significant improvement in local control and
disease-free survival in favor of doxorubicin-based chemotherapy.
Overall survival improvement was 4% for all sites and 7% for the
extremity site. An updated meta-analysis including four additional
trials with doxorubicin and ifosfamide combination reported a
statistically significant 6% survival advantage in favor of chemo­
therapy. A chemotherapy regimen including an anthracycline and
ifosfamide with growth factor support improved overall survival by
19% for high-risk (high-grade, ≥5 cm primary, or locally recurrent)
extremity soft tissue sarcomas. Long-term follow-up of a trial
evaluating neoadjuvant use of the same combination confirms
survival advantage and reports a 10-year survival of 61%. A more
contemporary randomized trial compared the standard anthra­
cycline and ifosfamide combination to specific histology-tailored
chemotherapy as an active control and confirmed superiority of the
standard regimen.
ADVANCED DISEASE
Metastatic soft tissue sarcomas are largely incurable, but up to 20%
of patients who achieve a complete response become long-term sur­
vivors. The therapeutic intent, therefore, is to produce a complete
remission with chemotherapy (<10%) and/or surgery (30–40%).
Surgical resection of metastases, whenever possible, is an integral
part of the management. Some patients benefit from repeated surgi­
cal excision of metastases. The two most active chemotherapeutic
agents are doxorubicin and ifosfamide. These drugs show a steep
dose-response relationship in sarcomas. Gemcitabine with or with­
out docetaxel has become an established second-line regimen and
is particularly active in patients with UPS and leiomyosarcomas.
Dacarbazine also has some modest activity. Taxanes have selective
activity in angiosarcomas, and vincristine, etoposide, and irino­
tecan are effective in rhabdomyosarcomas and Ewing’s sarcomas.
Pazopanib, an inhibitor of the vascular endothelial growth factor,
platelet-derived growth factor (PDGF), and c-kit, is approved for
patients with advanced soft tissue sarcomas excluding liposarcomas
after failure of chemotherapy. Two additional chemotherapy drugs
have gained approval from the U.S. Food and Drug Administration
(FDA). Trabectedin was compared to dacarbazine in a large phase 3
randomized study in advanced leiomyosarcomas and liposarcomas
after failure of an anthracycline and resulted in significant improve­
ment in progression-free survival. Eribulin was also tested in a
similar trial and showed improvement in survival, predominantly
in the liposarcoma subgroup, and is therefore now approved for that
subset. Tazemetostat, an EZH2 inhibitor, is now approved for use
in metastatic epithelioid sarcomas characterized by loss of tumorsuppressor gene INI1, resulting in activation of the EZH2 pathway.
Nab-sirolimus, an inhibitor of the mammalian target of rapamycin
(mTOR) pathway, is now approved for treatment of metastatic
perivascular epithelioid cell tumors (PEComas). The FDA granted
approval for nirogacestat, a γ-secretase inhibitor, for the treatment
of desmoid tumors. Imatinib targets KIT and PDGF tyrosine kinase
activity and is standard therapy for advanced/metastatic GISTs and
dermatofibrosarcoma protuberans. Imatinib is also indicated as
adjuvant therapy for completely resected primary GISTs. Three
years of adjuvant imatinib appear to be superior to 1 year of
therapy for high-risk GISTs, although the optimal treatment dura­
tion remains unknown. Sunitinib and regorafenib are approved for
second- and third-line use, respectively, in metastatic GIST after
failure of or intolerance to imatinib. Ripretinib, an inhibitor of
c-kit and PDGFRA, was approved for fourth-line use in metastatic
GIST based on a placebo-controlled randomized trial reporting an
improved median progression-free and overall survival. Avapritinib
also received approval for use in the specific molecular subset of
PDGFRA D842V–mutant metastatic GIST.
Immune checkpoint inhibitors have generally been ineffective in
most forms of sarcoma, but atezolizumab, an anti-PD-L1 antibody,
has produced responses in about one-third of patients with alveolar
soft part sarcoma.
BONE SARCOMAS
■
■INCIDENCE AND EPIDEMIOLOGY
Bone sarcomas are rarer than soft tissue sarcomas; they accounted for
only 0.2% of all new malignancies and 3970 new cases in the United
States in 2023. Several benign bone lesions have the potential for
malignant transformation. Enchondromas and osteochondromas can
transform into chondrosarcoma; fibrous dysplasia, bone infarcts, and
Paget’s disease of bone can transform into either UPS or osteosarcoma.
■
■CLASSIFICATION
Benign Tumors 
The common benign bone tumors include
enchondroma, osteochondroma, chondroblastoma, and chondromyx­
oid fibroma, of cartilage origin; osteoid osteoma and osteoblastoma, of
bone origin; fibroma and desmoplastic fibroma, of fibrous tissue ori­
gin; hemangioma, of vascular origin; and giant cell tumor, of unknown
origin.
Malignant Tumors 
The most common malignant tumors of bone
are plasma cell tumors (Chap. 116). The four most common malignant
nonhematopoietic bone tumors are osteosarcoma, chondrosarcoma,
Ewing’s sarcoma, and UPS. Rare malignant tumors include chordoma
(of notochordal origin), malignant giant cell tumor, adamantinoma
(of unknown origin), and hemangioendothelioma (of vascular origin).
Musculoskeletal Tumor Society Staging System 
Sarcomas of
bone are staged according to the Musculoskeletal Tumor Society stag­
ing system based on grade and compartmental localization. A Roman
numeral reflects the tumor grade: stage I is low grade, stage II is high
grade, and stage III includes tumors of any grade that have lymph node
or distant metastases. In addition, the tumor is given a letter reflecting
its compartmental localization. Tumors designated A are intracom­
partmental (i.e., confined to the same soft tissue compartment as the
initial tumor), and tumors designated B are extracompartmental (i.e.,
extending into the adjacent soft tissue compartment or into bone). The
tumor-node-metastasis (TNM) staging system is shown in Table 96-2.
CHAPTER 96
■
■OSTEOSARCOMA
Osteosarcoma, accounting for almost 45% of all bone sarcomas, is a
spindle cell neoplasm that produces osteoid (unmineralized bone) or
bone. Approximately 60% of all osteosarcomas occur in children and
Soft Tissue and Bone Sarcomas and Bone Metastases
TABLE 96-2  Staging System for Bone Sarcomas
Primary tumor (T)
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
T1
Tumor ≤8 cm in greatest dimension
T2
Tumor >8 cm in greatest dimension
T3
Discontinuous tumors in the primary
bone site
Regional lymph nodes (N)
NX
Regional lymph nodes cannot be
assessed
N0
No regional lymph node metastasis
N1
Regional lymph node metastasis
Distant metastasis (M)
MX
Distant metastasis cannot be assessed
M0
No distant metastasis
M1
Distant metastasis
M1a
Lung
M1b
Other distant sites
Histologic grade (G)
GX
Grade cannot be assessed
G1
Well differentiated—low grade
G2
Moderately differentiated—low grade
G3
Poorly differentiated—high grade
G4
Undifferentiated—high grade (Ewing’s
is always classed G4)
Stage Grouping
Stage IA
T1
N0
M0
G1,2 low grade
Stage IB
T2
N0
M0
G1,2 low grade
Stage IIA
T1
N0
M0
G3,4 high grade
Stage IIB
T2
N0
M0
G3,4 high grade
Stage III
T3
N0
M0
Any G
Stage IVA
Any T
N0
M1a
Any G
Stage IVB
Any T
N1
Any M
Any G
Any T
Any N
M1b
Any G
adolescents in the second decade of life, and ∼10% occur in the third
decade of life. Osteosarcomas in the fifth and sixth decades of life are
frequently secondary to either radiation therapy or transformation in a
preexisting benign condition, such as Paget’s disease. Males are affected
1.5–2 times as often as females. Osteosarcoma has a predilection for
metaphyses of long bones; the most common sites of involvement are
the distal femur, proximal tibia, and proximal humerus. The classifica­
tion of osteosarcoma is complex, but 75% of osteosarcomas fall into
the “classic” category, which includes osteoblastic, chondroblastic,
and fibroblastic osteosarcomas. The remaining 25% are classified as
“variants” on the basis of (1) clinical characteristics, as in the case of
osteosarcoma of the jaw, postradiation osteosarcoma, or Paget’s osteo­
sarcoma; (2) morphologic characteristics, as in the case of telangiectatic
osteosarcoma, small-cell osteosarcoma, or epithelioid osteosarcoma; or
(3) location, as in parosteal or periosteal osteosarcoma. Diagnosis usu­
ally requires a synthesis of clinical, radiologic, and pathologic features.
Patients typically present with pain and swelling of the affected area. A
plain radiograph reveals a destructive lesion with a moth-eaten appear­
ance, a spiculated periosteal reaction (sunburst appearance), and a cuff
of periosteal new bone formation at the margin of the soft tissue mass
(Codman’s triangle). A CT scan of the primary tumor is best for defin­
ing bone destruction and the pattern of calcification, whereas MRI is
better for defining intramedullary and soft tissue extension. A chest
radiograph and CT scan are used to detect lung metastases. Metastases
to the bony skeleton should be imaged by a bone scan or by fluoro­
deoxyglucose positron emission tomography (FDG-PET). Almost all
osteosarcomas are hypervascular and PET-avid. Pathologic diagnosis is
established either with a core-needle biopsy, where feasible, or with an
open biopsy with an appropriately placed incision that does not com­
promise future limb-sparing resection. Most osteosarcomas are high
grade. The most important predictive factor for long-term survival
is response to chemotherapy. Preoperative chemotherapy followed by
limb-sparing surgery (which can be accomplished in >80% of patients)
followed by postoperative chemotherapy is standard management. The
effective drugs are doxorubicin, ifosfamide, cisplatin, and high-dose
methotrexate with leucovorin rescue. The various combinations of
these agents that have been used have all been about equally success­
ful. Long-term survival rates in extremity osteosarcoma range from 60
to 80%. Osteosarcoma is radioresistant; radiation therapy has no role
in the routine management. UPS is considered a part of the spectrum
of osteosarcoma and is managed similarly. A randomized trial has
shown improved progression-free survival with regorafenib compared
to placebo.
PART 4
Oncology and Hematology
■
■CHONDROSARCOMA
Chondrosarcoma, which constitutes ~20–25% of all bone sarcomas, is
a tumor of adulthood and old age, with a peak incidence in the fourth
to sixth decades of life. It has a predilection for the flat bones, especially
the shoulder and pelvic girdles, but can also affect the diaphyseal por­
tions of long bones. Chondrosarcomas can arise de novo or as a malig­
nant transformation of an enchondroma or, rarely, of the cartilaginous
cap of an osteochondroma. Chondrosarcomas have an indolent natural
history and typically present as pain and swelling. Radiographically,
the lesion may have a lobular appearance with mottled or punctate
or annular calcification of the cartilaginous matrix. It is difficult to
distinguish low-grade chondrosarcoma from benign lesions by x-ray
or histologic examination. The diagnosis is therefore influenced by
clinical history and physical examination. A new onset of pain, signs
of inflammation, and progressive increase in the size of the mass sug­
gest malignancy. The histologic classification is complex, but most
tumors fall within the classic category. Like other bone sarcomas, highgrade chondrosarcomas spread to the lungs. Most chondrosarcomas
are resistant to chemotherapy, and surgical resection of primary or
recurrent tumors, including pulmonary metastases, is the mainstay of
therapy with the exception of two histologic variants. Dedifferentiated
chondrosarcoma has a high-grade osteosarcoma or a UPS component
that responds to chemotherapy. Mesenchymal chondrosarcoma, a rare
variant composed of a small-cell element, also is responsive to systemic
chemotherapy and is treated like Ewing’s sarcoma.
■
■EWING’S SARCOMA
Ewing’s sarcoma, which constitutes ~10–15% of all bone sarcomas, is
common in adolescence and has a peak incidence in the second decade
of life. It typically involves the diaphyseal region of long bones and also
has an affinity for flat bones. The plain radiograph may show a charac­
teristic “onion peel” periosteal reaction with a generous soft tissue mass,
which is better demonstrated by CT or MRI. This mass is composed of
sheets of monotonous, small, round, blue cells and can be confused with
lymphoma, embryonal rhabdomyosarcoma, and small-cell carcinoma.
The presence of p30/32, the product of the mic-2 gene (which maps to
the pseudoautosomal region of the X and Y chromosomes), is a cell-sur­
face marker for Ewing’s sarcoma (and other members of the Ewing fam­
ily of tumors, previously also called PNETs). Most PNETs arise in soft
tissues; they include peripheral neuroepithelioma, Askin’s tumor (chest
wall), and esthesioneuroblastoma. The classic cytogenetic abnormality
associated with this disease is a reciprocal translocation of the long arms
of chromosomes 11 and 22, t(11;22), which creates a chimeric gene
product of unknown function with components from the fli-1 gene on
chromosome 11 and ews on chromosome 22. This disease is very aggres­
sive, and it is therefore considered a systemic disease. Common sites of
metastases are lung, bones, and bone marrow. Systemic chemotherapy
is the mainstay of therapy, often being used before surgery. Doxoru­
bicin, cyclophosphamide or ifosfamide, etoposide, and vincristine are
active drugs. Topotecan or irinotecan in combination with an alkylating
agent is often used in relapsed patients. Local treatment for the primary
tumor includes surgical resection, usually with limb salvage or radiation
therapy. Overall cure rates approach 60–70% for localized tumors.
TUMORS METASTATIC TO BONE
Bone is a common site of metastasis for carcinomas of the prostate,
breast, lung, kidney, bladder, and thyroid and for lymphomas and
sarcomas. Prostate, breast, and lung primaries account for 80% of all
bone metastases. Metastatic tumors of bone are more common than
primary bone tumors. Tumors usually spread to bone hematogenously,
but local invasion from soft tissue masses also occurs. In descending
order of frequency, the sites most often involved are the vertebrae,
proximal femur, pelvis, ribs, sternum, proximal humerus, and skull.
Bone metastases may be asymptomatic or may produce pain, swelling,
nerve root or spinal cord compression, pathologic fracture, or myelo­
phthisis (replacement of the marrow). Symptoms of hypercalcemia
may be noted in cases of bony destruction.
Pain is the most frequent symptom. It usually develops gradually
over weeks, is usually localized, and often is more severe at night.
When patients with back pain develop neurologic signs or symptoms,
emergency evaluation for spinal cord compression is indicated
(Chap. 80). Bone metastases exert a major adverse effect on quality of
life in cancer patients.
Cancer in the bone may produce osteolysis, osteogenesis, or both.
Osteolytic lesions result when the tumor produces substances that can
directly elicit bone resorption (vitamin D–like steroids, prostaglan­
dins, or parathyroid hormone–related peptide) or cytokines that can
induce the formation of osteoclasts (interleukin 1 and tumor necrosis
factor). Osteoblastic lesions result when the tumor produces cytokines
that activate osteoblasts. In general, purely osteolytic lesions are best
detected by plain radiography, but they may not be apparent until they
are >1 cm. These lesions are more commonly associated with hyper­
calcemia and with the excretion of hydroxyproline-containing peptides
indicative of matrix destruction. When osteoblastic activity is promi­
nent, the lesions may be readily detected using radionuclide bone scan­
ning (which is sensitive to new bone formation), and the radiographic
appearance may show increased bone density or sclerosis. Osteoblastic
lesions are associated with higher serum levels of alkaline phosphatase
and, if extensive, may produce hypocalcemia. Although some tumors
may produce mainly osteolytic lesions (e.g., kidney cancer) and oth­
ers mainly osteoblastic lesions (e.g., prostate cancer), most metastatic
lesions produce both types of lesion and may go through stages where
one or the other predominates.
In older patients, particularly women, it may be necessary to
distinguish metastatic disease of the spine from osteoporosis. In

26 - 97 Carcinoma of Unknown Primary
97 Carcinoma of Unknown Primary
osteoporosis, the cortical bone may be preserved, whereas cortical
bone destruction is usually noted with metastatic cancer.
TREATMENT
Metastatic Bone Disease
Treatment of metastatic bone disease depends on the underlying
malignancy and the symptoms. Some metastatic bone tumors are
curable (lymphoma, Hodgkin’s lymphoma), and others are treated
with palliative intent. Pain may be relieved by local radiation
therapy. Hormonally responsive tumors are responsive to hormone
inhibition (antiandrogens for prostate cancer, antiestrogens for
breast cancer). Strontium-89, samarium-153, and radium-223 are
bone-seeking radionuclides that can exert antitumor effects and
relieve symptoms. Denosumab, a monoclonal antibody that binds
to RANK ligand, inhibits osteoclastic activity and increases bone
mineral density. Bisphosphonates such as pamidronate may relieve
pain and inhibit bone resorption, thereby maintaining bone min­
eral density and reducing risk of fractures in patients with osteo­
lytic metastases from breast cancer and multiple myeloma. Careful
monitoring of serum electrolytes and creatinine is recommended.
Monthly administration prevents bone-related clinical events and
may reduce the incidence of bone metastases in women with breast
cancer. When the integrity of a weight-bearing bone is threatened
by an expanding metastatic lesion that is refractory to radiation
therapy, prophylactic internal fixation is indicated. Overall survival
is related to the prognosis of the underlying tumor. Bone pain at the
end of life is particularly common; an adequate pain relief regimen
including sufficient amounts of narcotic analgesics is required. The
management of hypercalcemia is discussed in Chap. 422.
■
■FURTHER READING
Alvarez RA et al: Optimization of the therapeutic approach to patients
with sarcoma: Delphi consensus. Sarcoma 2019:4351308, 2019.
Ballinger ML et al: Monogenic and polygenic determinants of sarcoma
risk: An international genetic study. Lancet Oncol 17:1261, 2016.
Beird HC et al: Osteosarcoma. Nat Rev Dis Primers 8:77, 2022.
Gounder M et al: Nirogacestat, a γ-secretase inhibitor for desmoid
tumors. N Engl J Med 388:898, 2023.
Meyer M, Seetharam M: First-line therapy for metastatic soft tissue
sarcoma. Curr Treat Options Oncol 20:6, 2019.
Pasquali S, Gronchi A: Neoadjuvant chemotherapy in soft tissue
sarcomas: Latest evidence and clinical implications. Ther Adv Med
Oncol 9:415, 2017.
Patel S, Reichardt P: An updated review of the treatment landscape
for advanced gastrointestinal stromal tumors. Cancer 127:2185, 2021.
Ratan R, Patel SR: Chemotherapy for soft tissue sarcoma. Cancer
122:2952, 2016.
Wagner MJ et al: Chemotherapy for bone sarcoma in adults. J Oncol
Pract 12:208, 2016.
Kanwal Raghav, James L. Abbruzzese
Carcinoma of Unknown
Primary
Carcinoma (or cancer) of unknown primary (CUP) is a biopsy-proven
malignancy for which the anatomic site of origin remains unidenti­
fied after a standardized detailed diagnostic evaluation. CUP is one
of the 10 most frequently diagnosed cancers globally, accounting for
3–5% of all malignancies. Most investigators limit CUP to epithelial
or undifferentiated cancers and do not include lymphomas, metastatic
melanomas, and metastatic sarcomas because these cancers have spe­
cific histology and stage-based management guidelines, even in the
absence of a primary site. CUP can occur in patients of all age groups
including adolescents and young adults.
The emergence of sophisticated imaging, robust immunohisto­
chemistry (IHC), and genomic and proteomic tools has challenged
the “unknown” designation. Additionally, effective targeted therapies
in several cancers and tissue-agnostic biomarker-driven therapies
have endorsed a change in paradigm from empiricism to a personal­
ized approach to CUP management. The reasons cancers present as
CUP remain unclear. One hypothesis is that the primary tumor either
regresses after seeding the metastasis or remains so small that it is
not detected. It is possible that CUP falls on the continuum of cancer
presentation where the primary has been contained or eliminated by
the natural body defenses, including the immune system. Alterna­
tively, CUP may represent a specific malignant event that results in
an increase in metastatic spread or survival relative to the primary.
Whether the CUP metastases truly define a clone that is genetically
and phenotypically unique to this diagnosis remains to be determined.
Since liver is a common site of CUP presentation, intrahepatic chol­
angiocarcinoma (ICC) can be often misdiagnosed as CUP. Of note, the
incidence of ICC is increasing, whereas at the same time, that of CUP
is declining. Improvements in diagnostic technologies including nextgeneration sequencing and other molecular techniques and awareness
among clinicians to differentiate the two are possibly contributing to an
increased recognition and incidence of ICC.
CHAPTER 97
Carcinoma of Unknown Primary
CUP BIOLOGY
Studies looking for unique signature abnormalities in CUP tumors
have not been positive. Abnormalities in chromosomes 1 and 12 and
other complex cytogenetic abnormalities have been reported. Aneu­
ploidy has been described in 70% of CUP patients with metastatic
adenocarcinoma or undifferentiated carcinoma. The overexpression
of various genes, including RAS, BCL2 (40%), HER2 (11%), and P53
(26–53%), has been identified in CUP samples, but they are found in
many other malignancies. The extent of angiogenesis in CUP relative to
that in metastases from known primaries has also been evaluated, but
no consistent findings have emerged. Although current comprehen­
sive genomic profiling efforts may help identify targeted therapeutic
approaches to improve outcomes for this disease as discussed below,
they have failed thus far to reveal a distinct molecular signature. More
comprehensive and integrated multiomic efforts are needed to provide
insights into CUP biology through recognition of molecular aberra­
tions that specifically drive metastatic growth.
APPROACH TO THE PATIENT
Carcinoma (or Cancer) of Unknown Primary
Initial CUP evaluation has two goals: search for the primary or
“putative primary” tumor based on clinicopathologic evaluation
of the metastases and determine the extent of disease. Focused
evaluation directed by clinicopathologic cues allows for judicious
and efficient use of diagnostic tests. Obtaining a thorough medical
history from CUP patients is essential, including paying particular
attention to risk factors, prior surgeries, and family medical history
to assess potential hereditary cancers. Adequate physical examina­
tion, including a digital rectal examination in men and breast and
pelvic examinations in women, should be performed based on clini­
cal presentation. Finally, all patients with CUP, in the absence of
contraindication, must undergo a computed tomography (CT) scan
of chest, abdomen, and pelvis as a part of their standard workup.
■
■ROLE OF SERUM TUMOR MARKERS AND
CYTOGENETICS
Most tumor markers, including carcinoembryonic antigen (CEA),
CA-125, CA 19-9, and CA 15-3, are nonspecific and not helpful in
determining the primary site. Men who present with adenocarcinoma
and predominant osteoblastic metastasis should undergo a prostatespecific antigen (PSA) test. In patients with undifferentiated or poorly
differentiated carcinoma (especially with a midline tumor), elevated
β-human chorionic gonadotropin (β-hCG) and α fetoprotein (AFP)
levels suggest the possibility of an extragonadal germ cell (testicular)
tumor. With the availability of advanced IHC, cytogenetic studies are
rarely needed.
■
■ROLE OF IMAGING STUDIES
In the absence of contraindications, a baseline intravenous (IV) con­
trast CT scan of the chest, abdomen, and pelvis is the standard of
care. This helps to search for the primary tumor, evaluate the extent of
disease, and select the most accessible biopsy site. With precise imag­
ing and reporting, latent primary cancers, defined as appearance of a
new primary cancer after a latent period of several months to years, is
uncommon and seen in ≤5% of CUP patients, usually in patients with
very indolent presentations and/or highly responsive metastatic cancers
that allows a latent primary to emerge (grow) over time.
Mammography should be performed in women who present with
metastatic adenocarcinoma, especially in those with isolated axillary
lymphadenopathy. Magnetic resonance imaging (MRI) of the breast
can be considered in patients with axillary adenopathy and suspected
occult primary breast carcinoma following a negative mammography
and ultrasound. The results of these imaging modalities can influence
surgical management; a negative MRI of the breast predicts a low
tumor yield at mastectomy.
PART 4
Oncology and Hematology
A conventional workup for a squamous cell carcinoma and cervical
CUP (neck lymphadenopathy with no known primary tumor) includes
a CT scan or MRI and invasive studies, including indirect and direct
laryngoscopy, bronchoscopy, and upper endoscopy. Ipsilateral (or bilat­
eral) staging tonsillectomy has been recommended for these patients.
18-Fluorodeoxyglucose positron emission tomography (18-FDG-PET)
scans are useful in this patient population and may help guide the
biopsy; determine the extent of disease; facilitate the appropriate treat­
ment, including planning radiation fields; and help with disease sur­
veillance. Several studies have evaluated the utility of PET in patients
with squamous cervical CUP, and head and neck primary tumors were
identified in ~21–30%.
The diagnostic contribution of PET to the evaluation of other CUP
presentations (outside of the neck adenopathy indication) remains
controversial and is not routinely recommended. PET-CT can be help­
ful for patients with bone metastases and those deemed candidates
for aggressive multimodality therapy (surgical intervention/radiation)
such as patients with solitary metastatic disease because the identifica­
tion of disease in addition to the solitary metastatic site may affect
treatment planning.
Invasive studies, including upper endoscopy, colonoscopy, and
bronchoscopy, should be limited to symptomatic patients or those with
laboratory, imaging, or pathologic abnormalities that suggest that these
techniques will result in a high yield in finding a primary cancer.
CK7     CK20
CK7+     CK20+
CK7+     CK20–
CK7–     CK20+
CK7–     CK20–
Lung adenocarcinoma
Breast carcinoma
Thyroid carcinoma
Endometrial carcinoma
Cervical carcinoma
Salivary gland carcinoma
Cholangiocarcinoma
Pancreatic carcinoma
Urothelial tumors
Ovarian mucinous
adenocarcinoma
Pancreatic
adenocarcinoma
Cholangiocarcinoma
FIGURE 97-1  Approach to cytokeratin (CK7 and CK20) markers used in adenocarcinoma of unknown primary.
TABLE 97-1  Major Histologies in Carcinoma (Cancer) of Unknown
Primary
HISTOLOGY
PROPORTION, %
Well to moderately differentiated adenocarcinoma
Squamous cell cancer
Poorly differentiated adenocarcinoma, poorly
differentiated carcinoma
Neuroendocrine
Undifferentiated malignancy
■
■ROLE OF PATHOLOGIC STUDIES
A detailed pathologic examination of the most accessible biopsied
tissue specimen is mandatory in CUP patients. Pathologic evaluation
typically consists of hematoxylin and eosin stains and IHC tests. The
importance of adequate tissue acquisition cannot be overemphasized
in CUP. In addition to pathologic evaluation, tissue is also needed for
molecular profiling, which can aid in identifying biomarkers suggest­
ing the primary site for effective therapeutics including targeted agents,
immunotherapy, and clinical trials.
Light Microscopy Evaluation 
Adequate tissue obtained prefer­
ably by excisional biopsy or core needle biopsy (instead of only a fineneedle aspiration) is stained with hematoxylin and eosin and subjected
to light microscopic examination. On light microscopy, 60–65% of
CUP is adenocarcinoma, and 5% is squamous cell carcinoma. The
remaining 30–35% is poorly differentiated adenocarcinoma, poorly
differentiated carcinoma, or poorly differentiated neoplasm. A small
percentage of lesions are diagnosed as neuroendocrine cancers (2%),
mixed tumors (adenosquamous or sarcomatoid carcinomas), or undif­
ferentiated neoplasms (Table 97-1).
Role of IHC Analysis 
IHC stains are peroxidase-labeled antibod­
ies against specific tumor antigens that are used to define tumor lin­
eage. The number of available IHC stains is ever-increasing. However,
a tiered and uniform approach to tissue evaluation in the CUP setting
is lacking. For CUP cases, more is not necessarily better, and IHC
stains should be used in conjunction with the patient’s clinical presen­
tation and imaging studies to select the best therapy. Communication
between the clinician and pathologist is essential. No stain is 100%
sensitive or specific, and under-/overinterpretation should be avoided.
Poor differentiation, even in known primary tumors, decreases sensi­
tivity of hallmark IHC markers. PSA and thyroglobulin tissue markers,
which are positive in prostate and thyroid cancer, respectively, are two
of the most specific markers. However, these cancers rarely present as
CUP, so the yield of these tests may be low. Figure 97-1 delineates a
simple algorithm for immunohistochemical staining in CUP cases.
Table 97-2 lists additional tests that may be useful to further define
the tumor lineage. A more comprehensive algorithm may improve the
diagnostic accuracy but can make the process complex and increase
Colorectal carcinoma
Merkel cell carcinoma
Hepatocellular carcinoma
Renal cell carcinoma
Prostate carcinoma
Squamous cell and small-
cell lung carcinoma
Head and neck carcinoma
TABLE 97-2  Select Immunohistochemical Stains Useful in the
Diagnosis of CUP
COMMONLY CONSIDERED IHC TO ASSIST IN
DIFFERENTIAL DIAGNOSIS OF CUPa
LIKELY PRIMARY PROFILE
Breast
ER, GCDFP-15, mammaglobin, HER2/neu, GATA3
Ovarian/müllerian
ER, WT1, CK7, PAX8, PAX2
Lung adenocarcinoma
TTF-1; nuclear staining, napsin A, SP-A1
Germ cell
β-hCG, AFP, OCT3/4, CKIT, CD30 (embryonal),
SALL4
Prostate
PSA, α-methylacyl CoA racemase/P504S (AMACR/
P504S), P501S (prostein), PSMA, NKX3-1
Intestinal
CK7, CK20, CDX-2, CEA
Neuroendocrine
Chromogranin, synaptophysin, CD56
Sarcoma
Desmin (desmoid tumors), factor VIII
(angiosarcomas), CD31, smooth muscle actin
(leiomyosarcoma), MyoD1 (rhabdomyosarcoma)
Renal
RCC, CD10, PAX8, CD10
Hepatocellular carcinoma
Hep Par-1, Arg-1, glypican-3
Melanoma
S100, SOX-10, vimentin, HMB-45, tyrosinase,
melan-A
Urothelial
CK7, CK20, thrombomodulin, uroplakin III
Mesothelioma
Calretinin, WT1, D2-40, mesothelin
Lymphoma
LCA, CD3, CD4, CD5, CD20, CD45
SCC
p63, p40 (lung SCC), CK5/6
aPatterns emerging from coexpression of stains are better than individual stains to
suggest putative primary site. Even with optimization, no IHC panel is 100% sensitive
or specific (e.g., ovarian mucinous carcinoma can exhibit positivity with intestinal
markers).
Abbreviations: AFP, α fetoprotein; Arg-1, arginase-1; β-hCG, β-human chorionic
gonadotropin; CEA, carcinoembryonic antigen; CUP, carcinoma of unknown
primary; ER, estrogen receptor; GCDFP-15, gross cystic disease fibrous protein-15;
IHC, immunohistochemistry; LCA, leukocyte common antigen; PSA, prostatespecific antigen; PSMA, prostate-specific membrane antigen; SCC, squamous cell
carcinoma; SP-A1, surfactant protein A precursor; TTF, thyroid transcription factor;
WT, Wilms’ tumor.
cost. With the use of IHC markers, electron microscopic analysis,
which is time-consuming and expensive, is rarely performed today.
There are >20 subtypes of cytokeratin (CK) intermediate filaments
with different molecular weights and differential expression in various
cell types and cancers. Monoclonal antibodies to specific CK subtypes
have been used to help classify tumors according to their site of origin;
commonly used CK stains in adenocarcinoma CUP are CK7 and
CK20. CK7 is found in tumors of the lung, ovary, endometrium, breast,
and upper gastrointestinal tract including pancreaticobiliary cancers,
whereas CK20 is normally expressed in the gastrointestinal epithelium,
urothelium, and Merkel cells. The nuclear CDX-2 transcription fac­
tor, which is the product of a homeobox gene necessary for intestinal
organogenesis, is often used to aid in the diagnosis of gastrointestinal
adenocarcinomas. However, CDX-2 positivity can be seen with enteric
or mucinous differentiation in tumors from diverse primary sites (e.g.,
mucinous ovarian cancers).
Thyroid transcription factor 1 (TTF-1) nuclear staining is frequently
positive in lung and thyroid cancers. Approximately 68% of adeno­
carcinomas and 25% of squamous cell lung cancers stain positive for
TTF-1, which helps differentiate a lung primary tumor from metastatic
adenocarcinoma in a pleural effusion, the mediastinum, or the lung
parenchyma.
Gross cystic disease fibrous protein-15 (GCDFP-15), a 15-kDa
monomer protein, is a marker of apocrine differentiation that is
detected in 62–72% of breast carcinomas. GATA3 is being increasingly
used in the CUP setting when there is concern for a breast primary and
can be particularly useful as a marker for metastatic breast carcinoma,
especially triple-negative and metaplastic carcinomas, which lack spe­
cific endocrine markers of mammary origin. UROIII, high-molecularweight cytokeratin, thrombomodulin, and CK20 are the markers used
to diagnose lesions of urothelial origin.
IHC performs the best when used in groups that give rise to patterns
that are strongly indicative of certain profiles. For example, the TTF-1/
CK7+ and CK20+/CDX-2+/CK7− phenotypes have been reported
as very suggestive of lung and lower gastrointestinal cancer profiles,
respectively. Despite their practical utility, these patterns have not
been validated prospectively in CUP patients. IHC is not without its
limitations; several factors affect tissue antigenicity (antigen retrieval,
specimen processing, and fixation), interpretation of stains in tumor
(nuclear, cytoplasmic, membrane) versus normal tissue, inter- and
intraobserver variability, variable performance of different antibodies
said to recognize the same antigen, and tissue heterogeneity and inad­
equacy (given small biopsy sizes). Communication with the patholo­
gist is critical to determine if acquisition of additional tissue will be
beneficial in the pathologic evaluation. Pathologic features should
not always supersede clinical or radiologic findings when considering
testing for biomarkers of therapeutic response (e.g., epidermal growth
factor receptor [EGFR], ALK mutations, human epidermal growth fac­
tor receptor 2 [HER2]).
Role of Cancer Classifier Molecular Profiling 
In the absence
of a known primary, developing therapeutic strategies for CUP is chal­
lenging. The current diagnostic yield with imaging and immunochem­
istry is ~20–30% for CUP patients. To reduce diagnostic uncertainty,
sophisticated molecular analytics have been applied to CUP samples.
These include gene expression profiling, messenger RNA (mRNA),
microRNA, and genetic and epigenetic profiling to classify CUP.
CHAPTER 97
Gene expression profiles are most commonly generated using quan­
titative reverse transcriptase polymerase chain reaction (RT-PCR) or
DNA microarray. Neural network programs are then used to develop
predictive algorithms from the gene expression profiles. Typically,
a training set of gene profiles from known cancers (preferably from
metastatic sites) is used to train the software. Comprehensive gene
expression databases that have become available for common malig­
nancies are then applied to CUP samples, and the program can then be
used to predict the putative origin of a CUP sample.
Carcinoma of Unknown Primary
mRNA- or microRNA-based tissue of origin cancer classifier assays
have also been studied in prospective and retrospective CUP trials. Other
assays such as DNA methylation profiling predicted a primary cancer in
87% of 216 CUP patients. Incorporation of machine learning and nextgeneration sequencing has furthered prediction of these classifiers.
Despite the sophistication of the cancer classifier molecular assays,
most of the CUP studies have evaluated assay performance, although
the challenge with validating the accuracy of an assay for CUP is
that, by definition, the primary cancer diagnosis cannot be verified.
Thus, current estimates of tissue of origin test accuracy have relied
on indirect metrics, including comparison with pathology/IHC, clini­
cal presentation, appearance of latent primaries, and autopsies. Using
these measures, the assays suggest a plausible primary in ~70–80% of
patients studied. Three outcomes-based studies have been performed.
First, a single-arm study reported a median survival of 12.5 months
for patients who received assay-directed site-specific therapy. Second,
a phase 2 trial of site-specific therapy, including molecularly targeted
therapy, based on predicted tumor site from an algorithm using gene
expression and alteration profile showed a 1-year survival of 53.1%.
However, two randomized clinical trials evaluating site-specific therapy
directed by gene expression profiling versus empirical chemotherapy
with either paclitaxel plus carboplatin or gemcitabine plus cisplatin
failed to show a significant improvement in survival with this approach.
Firm conclusions of therapeutic impact cannot be drawn from these
studies given the sample size, design, statistical biases, confounding
variables including use of subsequent lines of (empiric) therapy, and
heterogeneity of the CUP cancers. Additional studies are needed to bet­
ter understand the clinical impact of tissue of origin profiling tools and
how these assays complement IHC and help guide therapy.
Role of Next-Generation Sequencing 
A significant push is
being made toward personalized medicine across all cancer types
with the goal of identifying driver mutation(s) in a patient who can
be treated with targeted agents independent of the site of origin. A
retrospective study of 200 CUP tumor specimens reported on genomic
alterations using the hybrid capture–based FoundationOne assay. The
authors reported that a large number of CUP samples (85%) harbored
at least one clinically relevant genomic alteration with the potential to
influence and personalize therapy. The mean number of genomic alter­
ations was 4.2 per tumor, and the most common genetic alterations
included TP53 (55%), KRAS (20%), CDKN2A (19%), and ARID1A
(11%). The adenocarcinoma CUP tumors were more frequently driven
by genetic alterations in the receptor tyrosine kinase (RTK)/Ras/mitogenactivated protein kinase (MAPK) signaling pathway than nonadeno­
carcinoma CUP tumors. Although druggable genetic lesions seen in
CUP are comparable to those in known primary cancer databases,
whether molecularly stratified approaches for CUP will successfully
improve outcomes remains to be seen and clinical trials are needed.
In a single-arm phase 2 study of 97 patients with molecularly targeted
therapy, five patients were found to have targetable EGFR mutations.
Of these, four patients were treated with afatinib, an anti-EGFR drug,
and two patients achieved a progression-free survival of >6 months. It
is anticipated that second- and third-generation drugs targeting EGFR
mutations are likely to be even more effective. The emerging use of
assays looking for circulating tumor DNA (ctDNA), so-called liquid
biopsies, has been increasingly useful within known tumor types and
has stirred interest in their potential utility in CUP (Chap. 503).
Ongoing histology and cellular-context agnostic prospective clinical
trials are studying the presence of actionable mutations and matching
patients to the right targeted drug. As this strategy gains traction, CUP
would be a natural fit for genomic alteration–based targeted therapy
independent of tumor site. Established tumor-agnostic therapies such
as immune checkpoint inhibitors (pembrolizumab) for microsatellite
instability high (MSI-H) or deficient mismatch repair (dMMR) tumors
or tumors with high tumor mutation burden (TMB) and NTRK inhibi­
tors for NTRK fusion–positive tumors can help a small minority of
CUP patients.
PART 4
Oncology and Hematology
TREATMENT
Carcinoma (or Cancer) of Unknown Primary
GENERAL CONSIDERATIONS
The treatment of CUP continues to evolve, albeit slowly. The median
survival of most patients with disseminated CUP is ~6–10 months.
Adenocarcinoma
Poorly differentiated adenocarcinoma CUP
IHC to suggest “favored” primary
Isolated
axillary nodes
in women
Bone-only
metastases in
men (blastic)
Solitary site
of metastasis
Peritoneal
carcinoma
Disseminated
cancer, 2 or
more sites
involved
Check PSA (in
tumor and
serum). If
elevated, Rx as
prostate cancer.
If resectable, resect
with or without prior
C or CRT. If
unresectable, C, RT,
or CRT depending
on location of tumor
Breast MRI if
mammogram
and ultrasound
are negative
If PSA not
elevated, C or
RT as indicated
MRI (+). Breast surgery
or radiation. C and/or
hormonal therapy for
breast cancer.
MRI (–). No
surgery, consider
radiation. C for
breast cancer.
FIGURE 97-2  Treatment algorithm for adenocarcinoma and poorly differentiated adenocarcinoma of unknown primary (CUP). C, chemotherapy; CRT, chemoradiation;
GI, gastrointestinal; IHC, immunohistochemistry; MRI, magnetic resonance imaging; PSA, prostate-specific antigen; RT, radiation.
Squamous cell
CUP
Disseminated,
visceral
metastases
Metastatic inguinal
adenopathy
Metastatic cervical
adenopathy
Directed invasive
tests as needed
Perineal exam,
anoscopy if needed.
Pelvic examination
in women. PET is
optional.
Triple endoscopy,
consider tonsillectomy.
CT neck and chest.
PET is optional.
If no extra-cervical
disease—neck
dissection followed by
adjuvant RT vs RT
alone. C for bulky
disease.
If localized, lymph
node dissection,
followed by local RT
in select patients
C in good
performance
status patients.
RT as indicated.
FIGURE 97-3  Treatment algorithm for squamous cell carcinoma of unknown
primary (CUP). C, chemotherapy; CT, computed tomography; PET, positron emission
tomography; RT, radiation.
Systemic chemotherapy is the primary treatment modality in most
patients with disseminated disease, but the careful integration
of surgery, radiation therapy, and even periods of observation is
important in the overall management of this condition (Figs. 97-2
and 97-3). Prognostic factors include performance status, site and
number of metastases, response to chemotherapy, and serum lactate
dehydrogenase (LDH) levels. Culine and colleagues developed a
prognostic model using performance status and serum LDH levels,
which allowed the assignment of patients into two subgroups with
divergent outcomes. Raghav and colleagues developed a prognostic
nomogram to provide individualized survival estimates for patients
with CUP based on baseline gender, Eastern Cooperative Oncology
If not suggestive of
primary peritoneal,
GI workup for
primary. C, if good
performance status.
If suggestive of
primary
peritoneal
cancer, treat as
ovarian cancer
C, if good
performance
status
Group performance status, histology, number of metastatic sites,
and neutrophil-lymphocyte ratio. Future prospective trials using
this prognostic model are warranted. Clinically, some CUP diagno­
ses fall into a favorable prognostic subset. Others, including those
with disseminated CUP, have a more unfavorable prognosis.
TREATMENT OF FAVORABLE CUP SUBSETS
Women with Isolated Axillary Adenopathy  Women with isolated
axillary adenopathy with adenocarcinoma or carcinoma are usually
treated for stage II or III breast cancer based on pathologic findings.
These patients should undergo a breast MRI if mammogram and
ultrasound are negative. Radiation therapy to the ipsilateral breast
is indicated if the MRI of the breast is positive. Chemotherapy and/
or hormonal therapy are indicated based on patient’s age (pre­
menopausal or postmenopausal), nodal disease bulk, and hormone
receptor and HER2 status (Chap. 84). It is important to verify
that the pathology suggests a breast cancer profile (morphology,
IHC breast markers including estrogen receptor, mammaglobin,
GCDFP-15, GATA3, HER2 gene expression) before embarking on
a breast cancer therapeutic program.
Women with Peritoneal Carcinomatosis  The term primary peri­
toneal papillary serous carcinoma (PPSC) has been used to describe
CUP with carcinomatosis with the pathologic and laboratory
(elevated CA-125 antigen) characteristics of ovarian cancer but no
ovarian primary tumor identified on transvaginal sonography or
laparotomy. Studies suggest that ovarian cancer and PPSC, which
are both of müllerian origin, have similar gene expression profiles.
Like patients with ovarian cancer, patients with PPSC are candi­
dates for cytoreductive surgery, followed by adjuvant taxane- and
platinum-based chemotherapy. In one retrospective study of
258 women with peritoneal carcinomatosis who had undergone
cytoreductive surgery and chemotherapy, 22% of patients had a
complete response to chemotherapy; the median survival duration
was 18 months (range 11–24 months). However, not all peritoneal
carcinomatosis in women is PPSC. Careful pathologic evaluation can
help diagnose a colon cancer profile (CDX-2+, CK20+, CK7−) or a
pancreaticobiliary cancer or even a mislabeled peritoneal mesothe­
lioma (calretinin, D2-40 positive; BerEp4, MOC-31 negative).
Poorly Differentiated Carcinoma with Midline Adenopathy
(Chap. 93)  Men with poorly differentiated or undifferentiated
carcinoma who present with midline adenopathy should be evalu­
ated for extragonadal germ cell malignancy. If diagnosed and
treated as such, they often experience a good response to treatment
with platinum-based combination chemotherapy. Response rates
of >50% have been noted, and long-term survival rates of 10–15%
have been reported. Older patients, especially smokers, who present
with mediastinal adenopathy are more likely to have a lung or head
and neck cancer profile.
Neuroendocrine Cancer (Chap. 89)  Low-grade neuroendocrine
tumor (NET) often has an indolent course, and treatment decisions
are based on symptoms and tumor bulk. Urine 5-HIAA and serum
chromogranin may be elevated and can be followed as markers.
Often the patient is treated with somatostatin analogues alone for
hormone-related symptoms (diarrhea, flushing, nausea). Specific
local therapies or systemic therapy would only be indicated if the
patient is symptomatic with local pain secondary to significant
growth of the metastasis or the hormone-related symptoms are
not controlled with endocrine therapy. Novel therapy options have
demonstrated benefit in patients with low-grade NET, including
sunitinib (which targets the vascular endothelial growth factor
pathway), everolimus (which inhibits the mammalian target of
rapamycin), and lutetium-177 dotatate (a somatostatin peptide
receptor radioligand). Patients with high-grade NET are treated
with platinum-based doublet therapy; 20–25% show a complete
response, and up to 10% patients with limited/oligo presentations
survive for >5 years. Some degree of neuroendocrine differentiation
can be seen in diverse poorly differentiated carcinomas.
Squamous Cell Carcinoma Presenting as Neck Adenopathy  Patients
with early-stage squamous cell carcinoma involving the cervical
lymph nodes are candidates for node dissection and radiation
therapy, which can result in long-term survival. The role of che­
motherapy in these patients is undefined, although chemoradiation
therapy or induction chemotherapy is often used and is beneficial
in bulky N2/N3 lymph node disease.
Solitary Metastatic Sites  Patients with solitary metastases can
also experience good treatment outcomes. Some patients who pres­
ent with locoregional disease are candidates for aggressive trimo­
dality (chemotherapy, radiation, and surgery) management—both
prolonged disease-free survival and, occasionally, cure are possible.
Men with Blastic Skeletal Metastases and Elevated PSA
(Chap. 92)  Blastic bone-only metastasis is a rare presentation, and
elevated serum PSA or tumor staining with PSA may provide con­
firmatory evidence of prostate cancer in these patients. Those with
elevated levels are candidates for hormonal or other therapy for
prostate cancer, although it is important to rule out other primary
tumors (lung most common).
MANAGEMENT OF DISSEMINATED CUP
Patients who present with liver, brain, and adrenal metastatic
disease usually have a poor prognosis. Patients with peritoneal
carcinomatosis secondary to metastatic adenocarcinoma have a
broad differential diagnosis, which includes mainly gastrointestinal
cancers including gastric, appendiceal, colon, and pancreaticobili­
ary cancers.
CHAPTER 97
Traditionally, platinum-based combination chemotherapy regi­
mens have been used to treat CUP. Several broadly used regimens
have been studied in the past two decades; these include paclitaxelcarboplatin, gemcitabine-cisplatin, gemcitabine-oxaliplatin, and
irinotecan and fluoropyrimidine-based therapies. These chemo­
therapeutic agents used as empiric regimens have shown response
rates of 25–40%, and their use obtains median survival times of
6–13 months.
Carcinoma of Unknown Primary
Outside of favorable subsets, there is a small group of patients
with a “definitive” IHC profile. These patients usually have a single
diagnosis based on their clinicopathologic presentation and are
often treated for the putative primary tumor. This does not guar­
antee a response, although it increases the probability of response
when select drugs are chosen from a class of drugs known to be
effective in that cancer type. Efforts should be made to search for
biomarkers of response to tumor-agnostic effective therapies such
as immunotherapy for MSI-H/dMMR tumors. Patients who do
not fall into those categories are candidates for broad-spectrum
platinum-based regimens, clinical trials, and additional trial-based
genomic and proteomic tests. Today, we do not have many effective
drugs for several CUP cancer profiles, and treatments overlap for
some cancers. Immunotherapy has been an area of active interest
due to robust and durable responses in cancers with known prima­
ries and has shown some activity in CUP. However, biomarkers of
response and immune-sensitive subsets need to be defined within
CUP.
SUMMARY
Patients with CUP should undergo a directed diagnostic search for
the primary tumor based on clinical and pathologic data. Subsets of
patients have prognostically favorable disease, as defined by clinical
or histologic criteria, and may substantially benefit from aggressive
treatment; in these patients, prolonged survival can be expected. How­
ever, for most patients who present with advanced CUP, the prognosis
remains poor with early resistance to available cytotoxic therapy. The
current focus has shifted away from empirical chemotherapeutic trials
to understanding the metastatic phenotype, tissue of origin profiling in
select patients, and next-generation sequencing to identify actionable
mutations in CUP patients. As novel therapies evolve in cancers with
known primaries, investigations to assess their value in CUP will likely
have a positive impact on management of CUP patients.

27 - 98 Paraneoplastic Syndromes- Endocrinologic-Hematologic
98 Paraneoplastic Syndromes: Endocrinologic/Hematologic
■
■FURTHER READING
Gatalica Z et al: Comprehensive analysis of cancers of unknown pri­
mary for the biomarkers of response to immune checkpoint blockade
therapy. Eur J Cancer 94:179, 2018.
Hayashi H et al: Randomized phase II trial comparing site-specific
treatment based on gene expression profiling with carboplatin and
paclitaxel for patients with cancer of unknown primary site. J Clin
Oncol 37:570, 2019.
Hayashi H et al: Site-specific and targeted therapy based on molecu­
lar profiling by next-generation sequencing for cancer of unknown
primary site: A nonrandomized phase 2 clinical trial. JAMA Oncol
6:1, 2020.
Huey R et al: Feasibility and value of genomic profiling in cancer of
unknown primary: Real-world evidence from prospective profiling
study. J Natl Cancer Inst 115:994, 2023.
Kato S et al: Utility of genomic analysis in circulating tumor DNA
from patients with carcinoma of unknown primary. Cancer Res 77:
4238, 2017.
National Comprehensive Cancer Network: Occult Primary
(Cancer of Unknown Primary) version 2.2017, October 2016. https://
www.nccn.org/guidelines/guidelines-detail?category=1&id=1451.
Raghav K et al: Cancer of unknown primary in adolescents and young
adults: Clinicopathological features, prognostic factors and survival
outcomes. PLoS One 11:e0154985, 2016.
Raghav K et al: Development and validation of a novel nomogram for
PART 4
Oncology and Hematology
individualized prediction of survival in cancer of unknown primary.
Clin Cancer Res 27:3414, 2021.
Raghav K et al: Efficacy of pembrolizumab in patients with advanced
cancer of unknown primary (CUP): A phase 2 non-randomized clini­
cal trial. J Immunother Cancer 10:e004822, 2022.
Ross JS et al: Comprehensive genomic profiling of carcinoma of
unknown primary site: New routes to targeted therapies. JAMA
Oncol 1:40, 2015.
Varadhachary GR, Raber MN: Cancer of unknown primary site. N
Engl J Med 371:757, 2014.
J. Larry Jameson, Dan L. Longo
Paraneoplastic
Syndromes:
Endocrinologic/Hematologic
Neoplastic cells can produce a variety of substances that can alter the
physiology of hormonal, hematologic, dermatologic, rheumatologic,
renal, and neurologic systems. Paraneoplastic syndromes refer to the
disorders that accompany benign or malignant tumors but are not
directly related to mass effects or invasion. Tumors of neuroendo­
crine origin, such as small-cell lung carcinoma (SCLC) and carci­
noids, are common causes of paraneoplastic syndromes, but these
syndromes are associated with many types of tumors that produce
peptide hormones, cytokines, and growth factors and induce the
production of antibodies. Studies of the prevalence of paraneoplastic
syndromes indicate that they are more common than is generally
appreciated. The signs, symptoms, and metabolic alterations associ­
ated with paraneoplastic disorders are easily overlooked in the con­
text of a malignancy and its treatment. Consequently, atypical clinical
manifestations in a patient with cancer should prompt consideration
of a paraneoplastic syndrome. The most common hormonal and
hematologic syndromes associated with underlying neoplasia will be
discussed here.
ENDOCRINE PARANEOPLASTIC
SYNDROMES
Etiology 
Hormones can be produced from eutopic or ectopic
sources. Eutopic refers to the expression of a hormone from its normal
tissue of origin, whereas ectopic refers to hormone production from
an atypical tissue source. For example, adrenocorticotropic hormone
(ACTH) is expressed eutopically by the corticotrope cells of the
anterior pituitary, but it can be expressed ectopically in SCLC. Many
hormones are produced at low levels from tissues other than the clas­
sic endocrine source. Thus, ectopic expression is often a quantitative
change rather than an absolute change in tissue expression. Neverthe­
less, the term ectopic expression is firmly entrenched and conveys the
abnormal physiology associated with hormone production by neoplas­
tic cells. In addition to high levels of hormones, ectopic expression is
often characterized by abnormal regulation of hormone production
(e.g., defective feedback control in ectopic ACTH) and peptide pro­
cessing (resulting in large, unprocessed precursor peptide such as
proopiomelanocortin [POMC]).
Many different molecular mechanisms can cause ectopic hormone
production. In rare instances, genetic rearrangements account for
aberrant hormone expression. For example, translocation of the para­
thyroid hormone (PTH) gene can result in high levels of PTH expres­
sion in tissues other than the parathyroid gland because the genetic
rearrangement brings the PTH gene under the control of atypical
regulatory elements. A related phenomenon is well documented in
many forms of leukemia and lymphoma, in which somatic genetic rear­
rangements confer a growth advantage and alter cellular differentiation
and function. Although genetic rearrangements cause selected cases of
ectopic hormone production, this mechanism is rare, as many tumors
are associated with excessive production of numerous peptides. Cellu­
lar dedifferentiation probably underlies most cases of ectopic hormone
production. Many cancers are poorly differentiated, and certain tumor
products, such as human chorionic gonadotropin (hCG), PTH–related
protein (PTHrP), and α-fetoprotein, are characteristic of gene expres­
sion at earlier developmental stages. In contrast, the propensity of
certain cancers to produce particular hormones (e.g., squamous cell
carcinomas produce PTHrP) suggests that dedifferentiation is partial
or that selective pathways are derepressed. These expression profiles
probably reflect epigenetic modifications that alter transcriptional
repression, microRNA expression, and other pathways that govern cell
differentiation.
Ectopic hormone production might be considered merely epiphe­
nomenon associated with cancer if it did not cause clinical manifes­
tations. Excessive and unregulated production of hormones such as
ACTH, PTHrP, and vasopressin can lead to substantial morbidity and
complicate the cancer treatment plan. Moreover, the paraneoplastic
endocrinopathies may be a presenting clinical feature of underlying
malignancy and prompt the search for an unrecognized tumor.
General features that confirm cancer-associated ectopic hormone
syndromes include: (1) excess hormone production from an atypical
tissue source; (2) documentation of tumor hormone production based
on immunostaining, mRNA production, or hormone secretion in
vitro; (3) hormone gradient across the tumor vascular supply; and (4)
resolution or decline of hormone levels after reduction of tumor mass.
Imaging studies, including computed tomography (CT), magnetic
resonance imaging (MRI), positron emission tomography (PET), and
octreotide scintigraphy also play an important role in the detection and
characterization of tumors associated with paraneoplastic syndromes,
particularly when endocrine clinical manifestations precede a cancer
diagnosis (i.e., ectopic ACTH in lung cancer). Treatment of the under­
lying tumor is the mainstay of all paraneoplastic endocrine syndromes.
Depending on the hormone produced, specific therapies can be used
(see below) to ameliorate symptoms but rarely influence overall sur­
vival or cancer progression.
A large number of paraneoplastic endocrine syndromes have been
described, linking overproduction of particular hormones with specific
types of tumors. However, certain recurring syndromes emerge from
this group (Table 98-1). The most common paraneoplastic endocrine
TABLE 98-1  Paraneoplastic Syndromes Caused by Ectopic Hormone Production
PARANEOPLASTIC SYNDROME
ECTOPIC HORMONE
TYPICAL TUMOR TYPESa
Common
Hypercalcemia of malignancy
Parathyroid hormone–related protein (PTHrP)
Squamous cell (head and neck, lung, skin), breast, genitourinary,
gastrointestinal; osteolytic metastases
1,25-Dihydroxyvitamin D
Lymphomas
Parathyroid hormone (PTH) (rare)
Lung, ovary
Prostaglandin E2 (PGE2) (rare)
Renal, lung
Syndrome of inappropriate antidiuretic
hormone secretion (SIADH)
Vasopressin
Lung (squamous, small cell), gastrointestinal, genitourinary, breast,
ovary
Cushing’s syndrome
Adrenocorticotropic hormone (ACTH)
Lung (small cell, bronchial carcinoid, adenocarcinoma,
squamous), thymus, pancreatic islet, medullary thyroid carcinoma,
pheochromocytoma
Corticotropin-releasing hormone (CRH) (rare)
Pancreatic islet, carcinoid, lung, prostate
Ectopic expression of gastric inhibitory peptide (GIP),
luteinizing hormone (LH)/human chorionic gonadotropin
(hCG), other G protein–coupled receptors (rare)
Less Common
Non–islet cell hypoglycemia
Insulin-like growth factor type II (IGF-II)
Mesenchymal tumors, sarcomas, adrenal, hepatic,
gastrointestinal, kidney, prostate
Insulin (rare)
Cervix (small-cell carcinoma)
Male feminization
hCGb
Testis (embryonal, seminomas), germinomas, choriocarcinoma,
lung, hepatic, pancreatic islet
Diarrhea or intestinal hypermotility
Calcitoninc
Lung, colon, breast, medullary thyroid carcinoma
Vasoactive intestinal peptide (VIP)
Pancreas, pheochromocytoma, esophagus
Rare
Oncogenic osteomalacia
Fibroblast growth factor 23 (FGF23) or phosphatonin
Hemangiopericytomas, osteoblastomas, fibromas, sarcomas, giant
cell tumors, prostate, lung
Acromegaly
Growth hormone–releasing hormone (GHRH)
Pancreatic islet, bronchial, and other carcinoids
Growth hormone (GH)
Lung, pancreatic islet
Hyperthyroidism
Thyroid-stimulating hormone (TSH)
Hydatidiform mole, embryonal tumors, struma ovarii
Hypertension
Renin
Juxtaglomerular tumors, kidney, lung, pancreas, ovary
Consumptive hypothyroidism
Type 3 deiodinase
Hepatic and other hemangiomas
Cancer immunotherapy associated
autoimmune diseases
Autoimmune hormone deficiencies
Thyroiditis, Graves’ disease
aOnly the most common tumor types are listed. For most ectopic hormone syndromes, an extensive list of tumors has been reported to produce one or more hormones.
bhCG is produced eutopically by trophoblastic tumors. Certain tumors produce disproportionate amounts of the hCG α or hCG β subunit. High levels of hCG rarely cause
hyperthyroidism because of weak binding to the TSH receptor. cCalcitonin is produced eutopically by medullary thyroid carcinoma and is used as a tumor marker.
Abbreviations: CTLA-4, cytotoxic T lymphocyte-associated protein-4; PD-1, programmed cell death protein 1; PD-L1, programmed death ligand 1.
syndromes include hypercalcemia from overproduction of PTHrP and
other factors, hyponatremia from excess vasopressin, and Cushing’s
syndrome from ectopic ACTH.
■
■HYPERCALCEMIA CAUSED BY ECTOPIC
PRODUCTION OF PTHRP
(See also Chap. 422).
Etiology 
Humoral hypercalcemia of malignancy (HHM) occurs in
up to 20% of patients with cancer. HHM is most common in cancers
of the lung, head and neck, skin, esophagus, breast, and genitourinary
tract and in multiple myeloma and lymphomas, as well as metastases
associated with these, and other cancers. There are several distinct
humoral causes of HHM, but it is caused most commonly by overpro­
duction of PTHrP. In addition to acting as a circulating humoral factor,
bone metastases (e.g., breast, multiple myeloma) may produce PTHrP
and other chemokines, leading to local osteolysis and hypercalcemia.
PTHrP may also affect the initiation and progression of tumors by act­
ing through pro-survival and chemokine pathways.
PTHrP is structurally related to PTH and binds to the PTH receptor,
explaining the similar biochemical features of HHM and hyperpara­
thyroidism. PTHrP plays a key physiologic role in skeletal development
and regulates cellular proliferation and differentiation in other tissues,
including skin, bone marrow, breast, and hair follicles. The mecha­
nism of PTHrP induction in malignancy is incompletely understood;
Macronodular adrenal hyperplasia
CHAPTER 98
Paraneoplastic Syndromes: Endocrinologic/Hematologic
Cancers treated with immunotherapy, particularly anti–CTLA-4,
PD-1, PD-L1
however, tumor-bearing tissues commonly associated with HHM nor­
mally produce PTHrP during development or cell renewal. Hypometh­
ylation of the PTHLH locus, which encodes PTHrP, suggests a role for
epigenetic factors in upregulating PTHrP production. PTHrP expres­
sion is stimulated by hedgehog pathways and Gli transcription factors
that are active in many malignancies. Transforming growth factor β
(TGF-β), which is produced by many tumors, also stimulates PTHrP.
Mutations in certain oncogenes, such as Ras, also can activate PTHrP
expression, as does loss of the tumor suppressor, p53. In addition to its
role in HHM, the PTHrP pathway may also provide a potential target
for therapeutic intervention to impede cancer growth.
Another relatively common cause of HHM is excess production of
1,25-dihydroxyvitamin D. Like granulomatous disorders associated
with hypercalcemia, lymphomas can produce an enzyme that converts
25-hydroxyvitamin D to the more active 1,25-dihydroxyvitamin D,
leading to enhanced gastrointestinal calcium absorption. Other causes
of HHM include tumor-mediated production of osteolytic cytokines
and inflammatory mediators.
Clinical Manifestations 
The typical presentation of HHM is a
patient with a known malignancy who is found to be hypercalcemic on
routine laboratory tests. Less often, hypercalcemia is the initial present­
ing feature of malignancy. Particularly when calcium levels are mark­
edly increased (>3.5 mmol/L [>14 mg/dL]), patients may experience
fatigue, mental status changes, polyuria, dehydration, or symptoms of
nephrolithiasis. Hypercalcemia can shorten ST segments and QT inter­
vals, as well as bundle branch blocks and bradyarrhythmias.
Diagnosis 
Features that favor HHM, as opposed to primary hyper­
parathyroidism, include known malignancy, recent onset of hypercal­
cemia, and very high serum calcium levels. Like hyperparathyroidism,
hypercalcemia caused by PTHrP is accompanied by hypercalciuria
and hypophosphatemia. Patients with HHM typically have metabolic
alkalosis rather than hyperchloremic acidosis, as is seen in hyperpara­
thyroidism. In contrast to PTH, PTHrP does not appear to stimulate
1-α-hydroxylase and 1,25-dihydroxyvitamin D levels. Measurement of
PTH is useful to exclude primary hyperparathyroidism; the PTH level
should be suppressed in HHM. An elevated PTHrP level confirms the
diagnosis, and it is increased in ~80% of hypercalcemic patients with
cancer. 1,25-Dihydroxyvitamin D levels may be increased in patients
with lymphoma.
TREATMENT
Humoral Hypercalcemia of Malignancy
The management of HHM begins with removal of excess calcium
in the diet, medications, or intravenous (IV) solutions. Saline
rehydration (typically 200–500 mL/h) is used to dilute serum
calcium and promote calciuresis; exercise caution in patients with
cardiac, hepatic, or renal insufficiency. Forced diuresis with furo­
semide (20–80 mg IV in escalating doses) or other loop diuretics
can enhance calcium excretion but provides relatively little value
except in life-threatening hypercalcemia. When used, loop diuret­
ics should be administered only after complete rehydration and
with careful monitoring of fluid balance. Oral phosphorus (e.g.,
250 mg Neutra-Phos 3–4 times daily) should be given until serum
phosphorus is >1 mmol/L (>3 mg/dL). Bisphosphonates such as
zoledronate (4–8 mg IV), pamidronate (60–90 mg IV), and etidro­
nate (7.5 mg/kg per day orally [PO] for 3–7 consecutive days) can
reduce serum calcium within 1–2 days and suppress calcium release
for several weeks. Bisphosphonate infusions can be repeated, or oral
bisphosphonates can be used for chronic treatment. Denosumab
(120 mg subcutaneously [SC] weekly for 4 weeks and then monthly)
can be used in patients who do not respond adequately to bisphos­
phonates. It acts as a decoy receptor for RANK ligand to mitigate
stimulation of osteoclasts. Cinacalcet (30 mg PO bid to 90 mg PO
qid) stimulates calcium-sensing receptors to suppress PTH secre­
tion and is therefore applicable in parathyroid carcinoma and rare
cases of ectopic PTH-producing tumors. Hypercalcemia associated
with lymphomas, multiple myeloma, or leukemia may respond to
glucocorticoid treatment (e.g., prednisone 40–100 mg PO in four
divided doses). Dialysis should be considered in severe hypercal­
cemia when saline hydration and bisphosphonate treatments are
not possible or are too slow in onset. Previously used agents such as
calcitonin and mithramycin have little utility now that bisphospho­
nates and other agents are available.
PART 4
Oncology and Hematology
■
■ECTOPIC VASOPRESSIN: TUMOR-ASSOCIATED
SYNDROME OF INAPPROPRIATE ANTIDIURETIC
HORMONE
(See also Chap. 56).
Etiology 
Vasopressin is an antidiuretic hormone normally pro­
duced by the posterior pituitary gland. Ectopic vasopressin production
by tumors is a common cause of the syndrome of inappropriate antidi­
uretic hormone (SIADH), occurring in at least half of patients with
SCLC. SIADH also can be caused by a number of nonneoplastic condi­
tions, including central nervous system (CNS) trauma, infections, and
medications (Chap. 398). Compensatory responses to SIADH, such as
decreased thirst, may mitigate the development of hyponatremia. How­
ever, with prolonged production of excessive vasopressin, the osmostat
controlling thirst and hypothalamic vasopressin secretion may become
reset. In addition, intake of free water, orally or intravenously, can
quickly worsen hyponatremia because of reduced renal diuresis.
Tumors with neuroendocrine features, such as SCLC and carcinoids,
are the most common sources of ectopic vasopressin production, but
it also occurs in other forms of lung cancer and with CNS lesions,
head and neck cancer, and genitourinary, gastrointestinal, and ovarian
cancers. The mechanism of activation of the vasopressin gene in these
tumors is unknown, but the frequent concomitant expression of the
adjacent oxytocin gene suggests derepression of this locus.
Clinical Manifestations 
Most patients with ectopic vasopressin
secretion are asymptomatic and are identified because of the presence
of hyponatremia on routine chemistry testing. Symptoms may include
weakness, lethargy, nausea, confusion, depressed mental status, and
seizures. The severity of symptoms reflects the rapidity of onset as well
as the severity of hyponatremia. Hyponatremia usually develops slowly
but may be exacerbated by the administration of IV fluids or the insti­
tution of new medications.
Diagnosis 
The diagnostic features of ectopic vasopressin produc­
tion are the same as those of other causes of SIADH (Chaps. 56 and
398). Hyponatremia and reduced serum osmolality occur in the set­
ting of an inappropriately normal or increased urine osmolality. Urine
sodium excretion is normal or increased unless volume depletion is
present. Other causes of hyponatremia should be excluded, including
renal, adrenal, or thyroid insufficiency. Physiologic sources of vaso­
pressin stimulation (CNS lesions, pulmonary disease, nausea), adaptive
circulatory mechanisms (hypotension, heart failure, hepatic cirrho­
sis), and medications, including many chemotherapeutic agents, also
should be considered as possible causes of hyponatremia. Vasopressin
measurements are not usually necessary to make the diagnosis.
TREATMENT
Ectopic Vasopressin: Tumor-Associated SIADH
Most patients with ectopic vasopressin production develop hypo­
natremia over several weeks or months. The disorder should be
corrected gradually unless mental status is altered or there is risk of
seizures. Rapid correction can cause brain dehydration and central
pontine myelinolysis. Treatment of the underlying malignancy
may reduce ectopic vasopressin production, but this response is
slow if it occurs at all. Fluid restriction to less than urine output,
plus insensible losses, is often sufficient to correct hyponatremia
partially. However, strict monitoring of the amount and types of
liquids consumed or administered intravenously is required for
fluid restriction to be effective. Salt tablets and saline are not helpful
unless volume depletion is also present. Demeclocycline (150–300 mg
orally 3–4 times daily) can be used to inhibit vasopressin action
on the renal distal tubule, but its onset of action is relatively slow
(1–2 weeks), and it has largely been supplanted by newer vasopres­
sin receptor antagonists. The vaptan class of drugs acts by inhibiting
vasopressin receptors (V1A, V1B, V2) in the renal collecting ducts.
Nonpeptide V2-receptor antagonists, tolvaptan (15 mg PO daily)
or conivaptan (20–120 mg PO bid or 10–40 mg IV), are particu­
larly effective when used in combination with fluid restriction in
euvolemic hyponatremia. Severe hyponatremia (Na <115 meq/L) or
mental status changes may require treatment with hypertonic (3%)
or normal saline infusion together with furosemide to enhance
free water clearance. The rate of sodium correction should be slow
(0.5–1 meq/L per hour) to prevent rapid fluid shifts and the possible
development of central pontine myelinolysis.
■
■CUSHING’S SYNDROME CAUSED BY ECTOPIC
ACTH PRODUCTION
(See also Chap. 398).
Etiology 
Ectopic ACTH production accounts for 10–20% of cases
of Cushing’s syndrome. The syndrome is particularly common in
neuroendocrine tumors. SCLC is the most common cause of ectopic
ACTH, followed by bronchial and thymic carcinoids, islet cell tumors,
other carcinoids, and pheochromocytomas. Ectopic ACTH production
is caused by increased expression of the proopiomelanocortin (POMC)
gene, which encodes ACTH, along with melanocyte-stimulating
hormone (MSH), β-lipotropin, and several other peptides. In many
tumors, there is abundant but aberrant expression of the POMC gene
from an internal promoter, proximal to the third exon, which encodes
ACTH. However, because this product lacks the signal sequence nec­
essary for protein processing, it is not secreted. Increased production
of ACTH arises instead from less abundant, but unregulated, POMC
expression from the same promoter site used in the pituitary. Because
tumors lack many of the enzymes needed to process the POMC poly­
peptide, it is typically released as multiple large, biologically inactive
fragments along with relatively small amounts of fully processed, active
ACTH.
Rarely, corticotropin-releasing hormone (CRH) is produced by pan­
creatic islet cell tumors, SCLC, medullary thyroid cancer, carcinoids, or
prostate cancer. When levels are high enough, CRH can cause pituitary
corticotrope hyperplasia and Cushing’s syndrome. Tumors that pro­
duce CRH sometimes also produce ACTH, raising the possibility of a
paracrine mechanism for ACTH production.
A distinct mechanism for ACTH-independent Cushing’s syndrome
involves ectopic expression of various G protein–coupled receptors in
adrenal nodules. Ectopic expression of the gastric inhibitory peptide
(GIP) receptor is the best-characterized example of this mechanism. In
this case, meals induce GIP secretion, which inappropriately stimulates
adrenal growth and glucocorticoid production.
Clinical Manifestations 
The clinical features of hypercorti­
solemia are detected in only a fraction of patients with documented
ectopic ACTH production. Patients with ectopic ACTH syndrome gen­
erally exhibit less marked weight gain and centripetal fat redistribution,
probably because the exposure to excess glucocorticoids is relatively
brief and because cachexia reduces the propensity for weight gain
and fat deposition. The ectopic ACTH syndrome is associated with
several clinical features that distinguish it from other causes of Cush­
ing’s syndrome (e.g., pituitary adenomas, adrenal adenomas, iatrogenic
glucocorticoid excess). The metabolic manifestations of ectopic ACTH
syndrome are dominated by fluid retention and hypertension, hypo­
kalemia, metabolic alkalosis, glucose intolerance, and occasionally
steroid psychosis. The very high ACTH levels often cause increased
pigmentation, reflecting increased activity of MSH derived from the
POMC precursor peptide. The extraordinarily high glucocorticoid
levels in patients with ectopic sources of ACTH can lead to marked
skin fragility and easy bruising. In addition, the high cortisol levels
often overwhelm the renal 11β-hydroxysteroid dehydrogenase type
II enzyme, which normally inactivates cortisol and prevents it from
binding to renal mineralocorticoid receptors. Consequently, in addi­
tion to the excess mineralocorticoids produced by ACTH stimulation
of the adrenal gland, high levels of cortisol exert activity through the
mineralocorticoid receptor, leading to severe hypokalemia.
Diagnosis 
The diagnosis of ectopic ACTH syndrome is usually not
difficult in the setting of a known malignancy. Urine-free cortisol levels
fluctuate but are typically greater than two to four times normal, and
the plasma ACTH level is usually >22 pmol/L (>100 pg/mL). A sup­
pressed ACTH level excludes this diagnosis and indicates an ACTHindependent cause of Cushing’s syndrome (e.g., adrenal or exogenous
glucocorticoid). In contrast to pituitary sources of ACTH, most ectopic
sources of ACTH do not respond to glucocorticoid suppression. There­
fore, high-dose dexamethasone (8 mg PO) suppresses 8:00 a.m. serum
cortisol (50% decrease from baseline) in ~80% of pituitary ACTHproducing adenomas but fails to suppress ectopic ACTH in ~90% of
cases. Bronchial and other carcinoids are well-documented exceptions
to these general guidelines, as these ectopic sources of ACTH may
exhibit feedback regulation indistinguishable from pituitary adeno­
mas, including suppression by high-dose dexamethasone, and ACTH
responsiveness to adrenal blockade with metyrapone. If necessary,
petrosal sinus catheterization can be used to evaluate a patient with
ACTH-dependent Cushing’s syndrome when the source of ACTH is
unclear. After CRH stimulation, a 3:1 petrosal sinus:peripheral ACTH
ratio strongly suggests a pituitary ACTH source. Imaging studies (CT
or MRI) are also useful in the evaluation of suspected carcinoid lesions,
allowing biopsy and characterization of hormone production using
special stains. If available, PET scans or octreotide scintigraphy may
identify some sources of ACTH production.
TREATMENT
Cushing’s Syndrome Caused by Ectopic ACTH
Production
The morbidity associated with the ectopic ACTH syndrome can
be substantial. Patients may experience depression or personality
changes because of extreme cortisol excess. Metabolic derange­
ments, including diabetes mellitus and hypokalemia, can worsen
fatigue. Poor wound healing and predisposition to infections can
complicate the surgical management of tumors, and opportunis­
tic infections caused by organisms such as Pneumocystis carinii
and mycoses are often the cause of death in patients with ectopic
ACTH production. These patients have increased risk of venous
thromboembolism, reflecting the combination of malignancy and
altered coagulation factor profiles. Depending on prognosis and
treatment plans for the underlying malignancy, measures to reduce
cortisol levels are often indicated. Treatment of the underlying
malignancy may reduce ACTH levels but is rarely sufficient to
reduce cortisol levels to normal. Adrenalectomy is not practical for
most of these patients but should be considered during surgery for
the malignancy or if the underlying tumor is not resectable and the
prognosis is otherwise favorable (e.g., carcinoid). Medical therapy
with ketoconazole (300–600 mg PO bid), metyrapone (250–500
mg PO every 6 h), mitotane (3–6 g PO in four divided doses,
tapered to maintain low cortisol production), etomidate (0.1–0.3
mg/kg/h IV), or other agents that block steroid synthesis or action
is often the most practical strategy for managing the hypercorti­
solism associated with ectopic ACTH production. Glucocorticoid
replacement should be provided to prevent adrenal insufficiency
(Chap. 398). Unfortunately, many patients eventually progress despite
medical blockade. Mifepristone (200–1000 mg PO qd) inhibits
both glucocorticoid and progesterone receptors, has rapid onset
of action, and improves glucose intolerance and hypertension in a
subset of patients. ACTH-neutralizing antibodies and ACTH recep­
tor blockers are under investigation, as are selective inhibitors of the
glucocorticoid receptor.
CHAPTER 98
Paraneoplastic Syndromes: Endocrinologic/Hematologic
■
■TUMOR-INDUCED HYPOGLYCEMIA CAUSED BY
EXCESS PRODUCTION OF INSULIN-LIKE GROWTH
FACTOR TYPE II
(See also Chap. 418) Mesenchymal tumors, hemangiopericytomas,
hepatocellular tumors, adrenal carcinomas, and a variety of other large
tumors have been reported to produce excessive amounts of insulinlike growth factor type II (IGF-II) precursor, which binds weakly to
insulin receptors and more strongly to IGF-I receptors, leading to
insulin-like actions. The gene encoding IGF-II resides on chromosome
11p15, a locus that is normally imprinted (that is, expression is exclu­
sively from a single parental allele). Biallelic expression of the IGF-II
gene occurs in a subset of tumors, suggesting loss of methylation and
loss of imprinting as a mechanism for gene induction. In addition to
increased IGF-II production, IGF-II bioavailability is increased due to
complex alterations in circulating binding proteins. Increased IGF-II
suppresses growth hormone (GH) and insulin, resulting in reduced
IGF binding protein 3 (IGFBP-3), IGF-I, and acid-labile subunit (ALS).
The reduction in ALS and IGFBP-3, which normally sequester IGF-II,
causes it to be displaced to a small circulating complex that has greater
access to insulin target tissues. For this reason, circulating IGF-II levels
may not be markedly increased despite causing hypoglycemia. In addi­
tion to IGF-II–mediated hypoglycemia, tumors may occupy enough of
the liver to impair gluconeogenesis.
In most cases, a tumor causing hypoglycemia is clinically apparent
(usually >10 cm in size), and hypoglycemia develops in association
with fasting. As with other causes of hypoglycemia, patients may
present with sweating, tremors, palpitations, confusion, seizures, or
coma. The diagnosis is made by documenting low serum glucose and
suppressed insulin levels in association with symptoms of hypoglyce­
mia. Serum IGF-II levels may not be increased (IGF-II assays may not
detect IGF-II precursors), but an elevated IGF-II/IGF-I ratio greater
than 10:1 is suggestive. Increased IGF-II mRNA expression is found in
most of these tumors. Any medications associated with hypoglycemia
should be eliminated. Treatment of the underlying malignancy, if pos­
sible, may reduce the predisposition to hypoglycemia. Frequent meals
and IV glucose, especially during sleep or fasting, are often necessary
to prevent hypoglycemia. Glucagon, recombinant GH, and glucocorti­
coids have also been used to enhance glucose production. Antibodies
that inhibit IGF-II action are under development.
■
■HUMAN CHORIONIC GONADOTROPIN
hCG is composed of α and β subunits and can be produced as intact
hormone, which is biologically active, or as uncombined biologically
inert subunits. Ectopic production of intact hCG occurs most often
in association with testicular embryonal tumors, germ cell tumors,
extragonadal germinomas, lung cancer, hepatoma, and pancreatic
islet tumors. Eutopic production of hCG occurs with trophoblastic
malignancies. hCG α subunit production is particularly common
in lung cancer and pancreatic islet cancer. In men, high hCG levels
stimulate steroidogenesis and aromatase activity in testicular Leydig
cells, resulting in increased estrogen production and the development
of gynecomastia. Precocious puberty in boys or gynecomastia in men
should prompt measurement of hCG and consideration of a testicular
tumor or another source of ectopic hCG production. Most women are
asymptomatic. hCG is easily measured. Treatment should be directed
at the underlying malignancy.
PART 4
Oncology and Hematology
■
■ONCOGENIC OSTEOMALACIA
Hypophosphatemic oncogenic osteomalacia, also called tumor-induced
osteomalacia (TIO), is caused by excessive production of fibroblast growth
factor 23 (FGF23), previously referred to as phosphotonin. Oncogenic
osteomalacia is characterized by markedly reduced serum phosphorus
and renal phosphate wasting, leading to muscle weakness, bone pain, and
osteomalacia. Serum calcium and PTH levels are normal. FGF23 inhibits
the renal conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin
D, resulting in low levels of 1,25-dihydroxyvitamin D. Oncogenic osteo­
malacia is usually caused by benign mesenchymal tumors, such as
hemangiopericytomas, fibromas, and giant cell tumors, often of the
skeletal extremities or head. It has also been described in sarcomas
and in patients with prostate or lung cancer. Resection of the tumor
reverses the disorder, confirming its humoral basis. FGF23 levels are
increased in some, but not all, patients with osteogenic osteomalacia.
FGF23 forms a ternary complex with the klotho protein and renal FGF
receptors to reduce renal phosphate reabsorption. Treatment involves
removal of the tumor, if possible, and supplementation with phosphate
and vitamin D. Octreotide treatment reduces phosphate wasting in
some patients with tumors that express somatostatin receptor subtype 2.
Octreotide scans may also be useful in detecting these tumors. A human
monoclonal antibody against FGF23, burosumab (0.5 mg/kg every
4 weeks) has been approved for the treatment of osteogenic osteomala­
cia. If needed, it can be increased to 2 mg/kg every 2 weeks. Burosumab
improves metabolic features of the disease and may improve bone
structure and fracture risk, but these outcomes are still being evaluated.
The calcium-sensing receptor agonist cinacalcet has been effective in
some patients, apparently by reducing PTH-mediated phosphaturia.
FGF receptor inhibitors hold promise as future therapies targeted
either to pathways that stimulate FGR23 production (e.g., FGFR1) or
inhibit its action (e.g., FGF23 receptor).
■
■CONSUMPTIVE HYPOTHYROIDISM
Newborns with hepatic hemangiomas can develop a rare form of hypo­
thyroidism caused by overexpression of type 3 deiodinase (D3), an
enzyme that degrades and inactivates thyroxine (T4) and triiodothyro­
nine (T3). The very high expression of D3 and consumption of thyroid
hormones apparently outstrip the thyroid gland’s rate of hormone
production. The disorder is characterized by low T4, low T3, high TSH,
and markedly elevated reverse T3 (rT3), reflecting the degradation of
T4 to rT3. In addition to treating the underlying hemangioma (rarely
other tumor types), patients are treated with l-thyroxine replacement,
titrated to normalize TSH. Steroids and propranolol may provide ben­
efit, perhaps by inhibiting growth factor pathways thought to stimulate
D3 production.
■
■CANCER IMMUNOTHERAPY-ASSOCIATED
ENDOCRINOPATHIES (SEE ALSO CHAPS. 78, 401)
Although not strictly a paraneoplastic endocrine syndrome, the intro­
duction of cancer immunotherapies, particularly immune checkpoint
inhibitors (i.e., anti–CTLA-4, PD-1, PD-L1), is associated with a high
incidence (~10%) of autoimmune endocrine disease. Hypophysitis
and autoimmune thyroid diseases are most common, but autoimmune
diabetes mellitus, adrenal insufficiency, hypoparathyroidism, and dia­
betes insipidus also occur. The mechanism of these autoimmune side
effects remains unclear. CTLA-4 is expressed in the pituitary gland,
likely explaining predisposition to anti–CTLA-4–associated hypophy­
sitis. Genetic predisposition and underlying endocrine autoimmunity
likely play a role in thyroid and other endocrinopathies, becoming
exacerbated following checkpoint inhibitor–induced immune activa­
tion. Autoimmune endocrine disease can emerge in the early weeks of
immunotherapy but can also present after several months. At present,
screening and prophylactic treatment are not routinely recommended.
However, clinicians should be attuned to clinical or laboratory features
of these disorders as they can be challenging to identify during can­
cer management. Treatment is similar to that of individual hormone
deficiencies (Chaps. 391, 395, and 398). These endocrinopathies are
generally irreversible and require lifelong hormone replacement.
HEMATOLOGIC SYNDROMES
The elevation of granulocyte, platelet, and eosinophil counts in most
patients with myeloproliferative disorders is caused by the prolif­
eration of the myeloid elements due to the underlying disease rather
than to a paraneoplastic syndrome. The paraneoplastic hematologic
syndromes in patients with solid tumors are less well characterized
than are the endocrine syndromes because the ectopic hormone(s) or
cytokines responsible have not been identified in most of these tumors
(Table 98-2). The extent of the paraneoplastic syndromes parallels the
course of the cancer. With very rare exception, red cell, white cell, or
platelet numbers are self-limited and not associated with symptomatic
abnormalities. In some circumstances, elevations in platelet counts can
be a marker that influences prognosis. By far, the most consequential
hematologic abnormality in cancer patients is hypercoagulability.
■
■ERYTHROCYTOSIS
Ectopic production of erythropoietin by cancer cells causes most para­
neoplastic erythrocytosis. The ectopically produced erythropoietin
TABLE 98-2  Paraneoplastic Hematologic Syndromes
CANCERS TYPICALLY ASSOCIATED
WITH SYNDROME
SYNDROME
PROTEINS
Erythrocytosis
Erythropoietin
Renal cancers, hepatocarcinoma,
cerebellar hemangioblastomas
Granulocytosis
G-CSF, GM-CSF, IL-6
Lung cancer, gastrointestinal cancer,
ovarian cancer, genitourinary cancer,
Hodgkin’s disease
Thrombocytosis
IL-6
Lung cancer, gastrointestinal cancer,
breast cancer, ovarian cancer,
lymphoma
Eosinophilia
IL-5
Lymphoma, leukemia, lung cancer
Thrombophlebitis
Unknown
Lung cancer, pancreatic cancer,
gastrointestinal cancer, breast
cancer, genitourinary cancer, ovarian
cancer, prostate cancer, lymphoma
Abbreviations: G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocytemacrophage colony-stimulating factor; IL, interleukin.
stimulates the production of red blood cells (RBCs) in the bone mar­
row and raises the hematocrit. Other lymphokines and hormones
produced by cancer cells may stimulate erythropoietin release but have
not been proved to cause erythrocytosis.
Most patients with erythrocytosis have an elevated hematocrit
(>52% in men, >48% in women) that is detected on a routine blood
count. Approximately 3% of patients with renal cell cancer, 10% of
patients with hepatoma, and 15% of patients with cerebellar heman­
gioblastomas have erythrocytosis. In most cases, the erythrocytosis is
asymptomatic.
Patients with erythrocytosis due to a renal cell cancer, hepatoma, or
CNS cancer should have measurement of red cell mass. If the red cell
mass is elevated, the serum erythropoietin level should be measured.
Patients with a cancer that has been associated with erythrocytosis, ele­
vated erythropoietin levels, and no other explanation for erythrocytosis
(e.g., hemoglobinopathy that causes increased O2 affinity; Chaps. 66 and
103) have the paraneoplastic syndrome.
TREATMENT
Erythrocytosis
Successful resection of the cancer usually resolves the erythrocy­
tosis. If the tumor cannot be resected or treated effectively with
radiation therapy or chemotherapy, phlebotomy may control any
symptoms or risk related to erythrocytosis.
■
■GRANULOCYTOSIS
Approximately 30% of patients with solid tumors have granulocytosis
(granulocyte count >8000/μL). In about half of patients with granu­
locytosis and cancer, the granulocytosis has an identifiable nonpara­
neoplastic etiology (e.g., infection, tumor necrosis, glucocorticoid
administration). The other patients have proteins in urine and serum
that stimulate the growth of bone marrow cells. Tumors and tumor
cell lines from patients with lung, ovarian, and bladder cancers have
been documented to produce granulocyte colony-stimulating factor
(G-CSF), granulocyte-macrophage colony-stimulating factor (GMCSF), and/or interleukin 6 (IL-6). However, the etiology of granulocy­
tosis has not been characterized in most patients.
Patients with granulocytosis are nearly all asymptomatic, and the
differential white blood cell count does not have a shift to immature
forms of neutrophils. Granulocytosis occurs in 40% of patients with
lung and gastrointestinal cancers, 20% of patients with breast cancer,
30% of patients with brain tumors and ovarian cancers, 20% of patients
with Hodgkin’s disease, and 10% of patients with renal cell carcinoma.
Patients with advanced-stage disease are more likely to have granulo­
cytosis than are those with early-stage disease.
Paraneoplastic granulocytosis does not require treatment. The
granulocytosis resolves when the underlying cancer is treated.
■
■THROMBOCYTOSIS
Some 35% of patients with thrombocytosis (platelet count >400,000/μL)
have an underlying diagnosis of cancer. IL-6, a candidate molecule for
the etiology of paraneoplastic thrombocytosis, stimulates the produc­
tion of platelets in vitro and in vivo. Some patients with cancer and
thrombocytosis have elevated levels of IL-6 in plasma. Another can­
didate molecule is thrombopoietin, a peptide hormone that stimulates
megakaryocyte proliferation and platelet production. The etiology of
thrombocytosis has not been established in most cases.
Patients with thrombocytosis are nearly all asymptomatic. Throm­
bocytosis is not clearly linked to thrombosis in patients with cancer.
Thrombocytosis is present in 40% of patients with lung and gas­
trointestinal cancers; 20% of patients with breast, endometrial, and
ovarian cancers; and 10% of patients with lymphoma. Patients with
thrombocytosis are more likely to have advanced-stage disease and
have a poorer prognosis than do patients without thrombocytosis. In
ovarian cancer, IL-6 has been shown to directly promote tumor growth.
Paraneoplastic thrombocytosis does not require treatment other than
treatment of the underlying tumor.
■
■EOSINOPHILIA
Eosinophilia is present in ~1% of patients with cancer. Tumors and
tumor cell lines from patients with lymphomas or leukemia may
produce IL-5, which stimulates eosinophil growth. Activation of IL-5
transcription in lymphomas and leukemias may involve translocation
of the long arm of chromosome 5, to which the genes for IL-5 and other
cytokines map.
Patients with eosinophilia are typically asymptomatic. Eosinophilia
is present in 10% of patients with lymphoma, 3% of patients with lung
cancer, and occasional patients with cervical, gastrointestinal, renal,
and breast cancer. Patients with markedly elevated eosinophil counts
(>5000/μL) can develop shortness of breath and wheezing. A chest
radiograph may reveal diffuse pulmonary infiltrates from eosinophil
infiltration and activation in the lungs.
TREATMENT
Eosinophilia
Definitive treatment is directed at the underlying malignancy.
Tumors should be resected or treated with radiation or chemo­
therapy. In most patients who develop shortness of breath related
to eosinophilia, symptoms resolve with the use of oral or inhaled
glucocorticoids. IL-5 antagonists exist but have not been evaluated
in this clinical setting.
CHAPTER 98
■
■THROMBOPHLEBITIS AND DEEP VENOUS
THROMBOSIS
Deep venous thrombosis and pulmonary embolism are the most
common thrombotic conditions in patients with cancer. Migratory
or recurrent thrombophlebitis may be the initial manifestation of
cancer. Nearly 15% of patients who develop deep venous thrombosis
or pulmonary embolism have a diagnosis of cancer (Chap. 122). The
coexistence of peripheral venous thrombosis with visceral carcinoma,
particularly pancreatic cancer, is called Trousseau’s syndrome.
Paraneoplastic Syndromes: Endocrinologic/Hematologic
Pathogenesis 
Patients with cancer are predisposed to thromboem­
bolism because they are often at bed rest or immobilized, and tumors
may obstruct or slow blood flow. Postoperative deep venous throm­
bosis is twice as common in cancer patients who undergo surgery.
Chronic IV catheters also predispose to clotting. In addition, clotting
may be promoted by release of procoagulants or cytokines from tumor
cells or associated inflammatory cells or by platelet adhesion or aggre­
gation. The specific molecules that promote thromboembolism have
not been identified.
Chemotherapeutic agents, particularly those associated with endo­
thelial damage, can induce venous thrombosis. The annual risk of
venous thrombosis in patients with cancer receiving chemotherapy
is about 11%, sixfold higher than the risk in the general population.
Bleomycin, l-asparaginase, nitrogen mustard, thalidomide analogues,
cisplatin-based regimens, and high doses of busulfan and carmustine
are all associated with an increased risk.
In addition to cancer and its treatment causing secondary thrombo­
sis, primary thrombophilic diseases may be associated with cancer. For
example, the antiphospholipid antibody syndrome is associated with
a wide range of pathologic manifestations (Chap. 369). About 20% of
patients with this syndrome have cancers. Among patients with cancer
and antiphospholipid antibodies, 35–45% develop thrombosis.
Clinical Manifestations 
Patients with cancer who develop deep
venous thrombosis usually develop swelling or pain in the leg, and
physical examination reveals tenderness, warmth, and redness. Patients
who present with pulmonary embolism develop dyspnea, chest pain,
and syncope, and physical examination shows tachycardia, cyanosis,
and hypotension. Some 5% of patients with no history of cancer who
have a diagnosis of deep venous thrombosis or pulmonary embolism
will have a diagnosis of cancer within 1 year. The most common
cancers associated with thromboembolic episodes include lung, pan­
creatic, gastrointestinal, breast, ovarian, and genitourinary cancers;
lymphomas; and brain tumors. Patients with cancer who undergo
surgical procedures requiring general anesthesia have a 20–30% risk of
deep venous thrombosis.
Diagnosis 
The diagnosis of deep venous thrombosis in patients
with cancer is made by impedance plethysmography or bilateral
compression ultrasonography of the leg veins. Patients with a noncom­
pressible venous segment have deep venous thrombosis. If compres­
sion ultrasonography is normal and there is a high clinical suspicion
for deep venous thrombosis, venography should be done to look for a
luminal filling defect. Elevation of d-dimer is not as predictive of deep
venous thrombosis in patients with cancer as it is in patients without
cancer; elevations are seen in people over age 65 years without concom­
itant evidence of thrombosis, probably as a consequence of increased
thrombin deposition and turnover in aging.
Patients with symptoms and signs suggesting a pulmonary embo­
lism should be evaluated with a chest radiograph, electrocardiogram,
arterial blood gas analysis, and ventilation-perfusion scan. Patients
with mismatched segmental perfusion defects have a pulmonary
embolus. Patients with equivocal ventilation-perfusion findings should
be evaluated as described above for deep venous thrombosis in their
legs. If deep venous thrombosis is detected, they should be antico­
agulated. If deep venous thrombosis is not detected, they should be
considered for a pulmonary angiogram.
Patients without a diagnosis of cancer who present with an initial
episode of thrombophlebitis or pulmonary embolus need no additional
tests for cancer other than a careful history and physical examination.
In light of the many possible primary sites, diagnostic testing in asymp­
tomatic patients is wasteful. However, if the clot is refractory to standard
treatment or is in an unusual site, or if the thrombophlebitis is migra­
tory or recurrent, efforts to find an underlying cancer are indicated.
PART 4
Oncology and Hematology
TREATMENT
Thrombophlebitis and Deep Venous Thrombosis
Patients with cancer and a diagnosis of deep venous thrombosis or
pulmonary embolism should be treated initially with IV unfraction­
ated heparin or low-molecular-weight heparin for at least 5 days,
and warfarin should be started within 1 or 2 days. The warfarin
dose should be adjusted so that the international normalized ratio
(INR) is 2–3. Patients with proximal deep venous thrombosis and a
relative contraindication to heparin anticoagulation (hemorrhagic
brain metastases or pericardial effusion) should be considered for
placement of a filter in the inferior vena cava (Greenfield filter) to
prevent pulmonary embolism. Warfarin should be administered
for 3–6 months. An alternative approach is to use low-molecularweight heparin for 6 months. The new oral anticoagulants (factor
Xa and thrombin inhibitors) are attractive because they do not
require close monitoring of the prothrombin time and are not
affected by dietary factors. Oral apixaban (10 mg bid for 7 days fol­
lowed by 5 mg bid for 6 months) is noninferior to dalteparin in the
treatment of cancer patients who develop deep vein thrombosis or
pulmonary embolism. Patients with cancer who undergo a major
surgical procedure should be considered for heparin prophylaxis or
pneumatic boots. Breast cancer patients undergoing chemotherapy
and patients with implanted catheters should be considered for
prophylaxis. Guidelines recommend that hospitalized patients with
cancer and patients receiving a thalidomide analogue receive pro­
phylaxis with low-molecular-weight heparin or low-dose aspirin.
Use of prophylaxis routinely during chemotherapy is controversial.
Risk is affected by type of cancer, type of therapy, blood counts, and
body mass index (all taken into account in the Khorana risk score;
Table 98-3). Studies of Khorana high-risk patients with cancer
using rivaroxaban and apixaban as clot prophylaxis have resulted in
a 50% reduction in risk with a level of bleeding of about 5%. How­
ever, prophylaxis is not routinely recommended by the American
Society of Clinical Oncology.
TABLE 98-3  Khorana Risk Score for Venous Thromboembolism in
Cancer Patients
PATIENT CHARACTERISTICS
RISK SCORE POINTS
Site of cancer
  Very high risk (stomach, pancreas)
  High risk (lung, lymphoma, gynecologic,
genitourinary excluding prostate)
Prechemotherapy platelet count ≥350,000/μL
Hemoglobin level <10 g/dL or use of red cell
growth factors
Prechemotherapy leukocyte count >11,000/μL
BMI ≥35 kg/m2
RATES OF sVTE ACCORDING
TO SCORES (%)
RISK SCORE (POINTS)
RISK CATEGORY
Low
0.3–0.8
1–2
Intermediate
1.8–2.0
≥3
High
6.7–7.1
Abbreviations: BMI, body mass index; sVTE, symptomatic venous thromboembolism.
Source: Reproduced from AJM Muñoz et al: Clinical guide SEOM on venous
thromboembolism in cancer patients. Clin Transl Oncol 16:1079-1090, 2014.
MISCELLANEOUS REMOTE EFFECTS OF
CANCER
Patients with cancer can develop paraneoplastic autoimmune disor­
ders (e.g., thrombocytopenia) and dysfunction of organs not directly
invaded or involved with the cancer (rheumatologic and renal abnor­
malities are among the most frequent). The pathogenesis of these
disorders is undefined, but often, the conditions reverse if the tumor is
removed or successfully treated.
Cutaneous paraneoplastic syndromes are discussed in Chap. 61.
Neurologic paraneoplastic syndromes are discussed in Chap. 99.
■
■FURTHER READING
Agnelli G et al: Apixaban for the treatment of venous thromboembo­
lism associated with cancer. N Engl J Med 382:1599, 2020.
Asonitis N et al: Diagnosis, pathophysiology and management of
hypercalcemia in malignancy: A review of the literature. Horm Metab
Res 51:770, 2019.
Catani MV et al: The “Janus face” of platelets in cancer. Int J Mol Sci
21:788, 2020.
Dynkevich Y et al: Tumors, IGF-2, and hypoglycemia: Insights from
the clinic, the laboratory, and the historical archive. Endocr Rev
34:798, 2013.
Feelders RA et al: Advances in the medical treatment of Cushing’s
syndrome. Lancet Diabetes Endocrinol 7:300, 2019.
Farge D et al: 2022 international clinical practice guidelines for the
treatment and prophylaxis of thromboembolism in patients with
cancer, including COVID19. Lancet Oncol 23:e334, 2022.
Hattersley R et al: Endocrine complications of immunotherapies: A
review. Clin Med 21:e212, 2021.
Jan de Beur SM et al: Burosumab for the treatment of tumor-induced
osteomalacia. J Bone Miner Res 36:627, 2021.
Lin RJ et al: Paraneoplastic thrombocytosis: The secrets of tumor selfpromotion. Blood 124:184, 2014.
Onyema MC et al: Endocrine abnormality in paraneoplas­
tic syndrome. Best Pract Res Clin Endocrinol Metab 36:101621,
Pelosof LC, Gerber DE: Paraneoplastic syndromes: An approach to
diagnosis and treatment. Mayo Clin Proc 85:838, 2010.
Workeneh BT et al: Hyponatremia in the cancer patient. Kidney Int
98:870, 2020.

28 - 99 Paraneoplastic Neurologic Syndromes and Autoimmune Encephalitis
99 Paraneoplastic Neurologic Syndromes and Autoimmune Encephalitis
Josep Dalmau, Francesc Graus
Paraneoplastic Neurologic
Syndromes and
Autoimmune Encephalitis
Paraneoplastic neurologic disorders (PNDs) are cancer-related syn­
dromes that can affect any part of the nervous system (Table 99-1).
Initially defined as syndromes of unknown cause, currently most PNDs
are considered to have an autoimmune pathogenesis triggered by the
underlying cancer. In 60% of patients, the neurologic symptoms pre­
cede the cancer diagnosis. Clinically disabling PNDs occur in 0.5–1%
of all cancer patients, but they affect 2–3% of patients with neuroblas­
toma or small-cell lung cancer (SCLC) and 30–50% of patients with
thymoma.
PATHOGENESIS
Most PNDs are mediated by immune responses triggered by neuro­
nal proteins ectopically expressed by tumors (e.g., SCLC and other
cancers) or as a result of altered immunologic responses caused by
some types of tumors such as thymomas or lymphomas. In PNDs of
the central nervous system (CNS), many antibody-associated immune
responses have been identified. These antibodies react with neurons
and the patient’s tumor, and their detection in serum or cerebrospinal
fluid (CSF) variably predicts the presence of cancer. According to the
frequency of an underlying tumor, these antibodies are classified as
high risk (>70% probability of an underlying tumor; Table 99-2); inter­
mediate risk (30–70% probability of an underlying tumor; Table 99-3),
and low risk (<30% probability of an underlying tumor; Table 99-4).
All the target antigens of high-risk antibodies are intracellular proteins
except for Tr (DNER [delta/notch-like epidermal growth factor-related
receptor]), which is expressed on the cell surface. By contrast, all target
antigens of intermediate- and low-risk antibodies are cell-surface pro­
teins or receptors except for GAD65 and glial fibrillary acidic protein
(GFAP), which are intracellular. When the antigens are intracellular,
most neurologic syndromes are associated with extensive infiltrates
of CD4+ and CD8+ T cells, microglial activation, gliosis, and variable
neuronal loss. The infiltrating T cells are often in close contact with
neurons undergoing degeneration, suggesting a primary pathogenic
role. T-cell–mediated cytotoxicity may contribute directly to cell death
TABLE 99-1  Paraneoplastic Syndromes of the Nervous System
CLASSIC SYNDROMES: HIGH RISK
OF ASSOCIATED CANCERa
NONCLASSIC SYNDROMES: MODERATE
OR LOW RISK OF ASSOCIATED CANCER
Encephalomyelitis
Limbic encephalitis
Cerebellar degeneration (adults)
Opsoclonus-myoclonus
Sensory neuronopathy
Gastrointestinal pseudoobstruction (enteric neuropathy)
Dermatomyositis (adults)
Lambert-Eaton myasthenic
syndrome
Cancer- or melanoma-associated
retinopathy
Brainstem encephalitis
Stiff-person syndrome
Progressive encephalomyelitis with rigidity
and myoclonus
Necrotizing myelopathy
Motor neuron disease
Subacute axonal sensory-motor
neuropathies
Paraproteinemic neuropathies
Pure autonomic neuropathy
Acute necrotizing myopathy
Polymyositis
Optic neuropathy
BDUMP
Peripheral nerve hyperexcitability
(neuromyotonia)
Myasthenia gravis
aThese syndromes frequently associate with cancer.
Abbreviation: BDUMP, bilateral diffuse uveal melanocytic proliferation.
TABLE 99-2  High-Risk Antibodies (>70% Probability of an Underlying
Cancer), Syndromes, and Associated Tumors
ANTIBODYa
ASSOCIATED NEUROLOGIC
SYNDROME(S)
TUMORS
Anti-Hu (ANNA1)
Encephalomyelitis, sensory
neuronopathy
SCLC
Anti-Yo (PCA1)
Rapidly progressive cerebellar
syndrome
Ovary, breast
Anti-Ri (ANNA2)
Cerebellar degeneration,
opsoclonus, brainstem encephalitis
Breast, gynecologic,
SCLC
Anti-CRMP5 (CV2)
Encephalomyelitis, chorea,
optic neuritis, uveitis, peripheral
neuropathy
SCLC, thymoma,
other
Anti-Tr (DNER)
Rapidly progressive cerebellar
syndrome
Hodgkin’s lymphoma
Anti-Ma proteins
Limbic, hypothalamic, brainstem
encephalitis
Testicular (Ma2),
other (Ma)
Anti-PCA2 (MAP1B) Sensorimotor neuropathy, rapidly
SCLC, non-SCLC,
breast cancer
progressive cerebellar syndrome,
and encephalomyelitis
Anti-Kelch-like
protein 11
Brainstem encephalitis, ataxia,
sensorineural hearing loss
Seminoma, germ cell
tumor, teratoma,
CHAPTER 99
Anti-amphiphysinb
Stiff-person syndrome,
encephalomyelitis
Breast, SCLC
Anti-SOX1
LEMS, rapidly progressive
cerebellar syndrome with and
without LEMS
SCLC
Paraneoplastic Neurologic Syndromes and Autoimmune Encephalitis
aAll the antibodies of this table are against intracellular antigens, except for Tr
(DNER), which is a cell-surface protein. bAmphiphysin is likely exposed to the cell
surface during synaptic vesicle endocytosis.
Abbreviations: CRMP, collapsin response-mediator protein; DNER, delta/notch-like
epidermal growth factor-related receptor; LEMS, Lambert-Eaton myasthenic
syndrome; MAP1B, microtubule associated protein 1B; PCA, Purkinje cell antigen;
SCLC, small-cell lung cancer.
in these PNDs and probably underlies the resistance of many of these
conditions to therapy.
In contrast to the predominant role of cytotoxic T-cell mechanisms in
PNDs associated with antibodies against intracellular antigens, those asso­
ciated with antibodies to antigens expressed on the neuronal cell surface of
the CNS or at the neuromuscular junction are mediated by direct antibody
effects on the target antigens and are more responsive to immunotherapy
(Tables 99-3 and 99-4, Fig. 99-1). These disorders occur with and without
a cancer association and may affect children and young adults. Some
disorders are triggered by viral encephalitis such as herpes simplex virus
encephalitis or Japanese encephalitis leading to autoimmune encephalitis.
TABLE 99-3  Intermediate-Risk Antibodies (30–70% Probability of an
Underlying Cancer), Syndromes, and Associated Tumors
TUMOR TYPE WHEN
ASSOCIATED
ANTIBODYa
NEUROLOGIC SYNDROME
Anti-NMDARb
Anti-NMDAR encephalitis
Teratoma in young
women (children and
men rarely have tumors)
Anti-AMPARb
Limbic encephalitis with relapses
SCLC, thymoma, breast
Anti-GABABRc
Limbic encephalitis with early and
prominent seizures
SCLC
Anti-Caspr2b
Morvan syndrome
Thymoma
Anti-mGluR5b
Autoimmune encephalitis without
distinctive features
Hodgkin lymphoma
Anti-VGCCb
LEMS, cerebellar degeneration
SCLC
aAll the antibodies of this table are against neuronal cell-surface proteins. bA direct
pathogenic role of these antibodies has been demonstrated in cultured neurons or
animal models. cThese antibodies are strongly suspected to be pathogenic.
Abbreviations: AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
receptor; Caspr2, contactin-associated protein-like 2; GABABR, γ-aminobutyric
acid B receptor; LEMS, Lambert-Eaton myasthenic syndrome; mGluR, metabotropic
glutamate receptor; NMDAR, N-methyl-d-aspartate receptor; SCLC, small-cell lung
cancer; VGCC, voltage-gated calcium channel.
TABLE 99-4  Low-Risk Antibodies (<30% Probability of an Underlying
Cancer), Syndromes, and Associated Tumors
TUMOR TYPE WHEN
ASSOCIATED
ANTIBODYa
NEUROLOGIC SYNDROME
Anti-LGI1b
Limbic encephalitis,
hyponatremia, faciobrachial
dystonic seizures
Rarely thymoma
Anti-GABAARb
Encephalitis with prominent
seizures and status epilepticus
Thymoma in ~20% of the
patients
Anti-DPPXb
Agitation, myoclonus, tremor,
seizures, hyperekplexia,
encephalomyelitis with rigidity
No cancer, but
frequent diarrhea or
cachexia suggesting
paraneoplasia
Anti-glycine
receptorb
PERM, stiff-person syndrome
Rarely, thymoma, lung,
Hodgkin’s lymphoma
Anti-IgLON5b
NREM and REM sleep disorder,
brainstem dysfunction, movement
disorder, obstructive sleep apnea,
stridor
No tumor association
Anti-GAD65
Stiff-person, cerebellar
syndrome, encephalitis with
seizures, limbic encephalitis
Infrequent tumor
association (thymoma,
lung, and breast cancer)
Anti-mGluR1b
Cerebellar syndrome
Hodgkin’s lymphoma in
<10% of patients
PART 4
Oncology and Hematology
Anti-GFAP
Meningoencephalitis and myelitis
No cancer association
Anti-aquaporin 4b Neuromyelitis optica spectrum
Lung and breast
adenocarcinomas in a
few patients
disorders
Anti-MOG
ADEM, optic neuritis, myelitis,
cortical encephalitis
No cancer association
Anti-AChR
(muscle)b
Myasthenia gravis
Thymoma
Anti-AChR
(neuronal)b
Autonomic ganglionopathy
SCLC
aAll the antibodies of this table are against cell-surface proteins except for
GAD65 and GFAP which are intracellular proteins. Rare antibodies reported in
<30 patients are not included. bA direct pathogenic role of these antibodies has
been demonstrated in cultured neurons or animal models.
Abbreviations: AChR, acetylcholine receptor; ADEM, acute disseminated
encephalomyelitis; DPPX, dipeptidyl-peptidase-like protein-6; GABAAR,
γ-aminobutyric acid A receptor; GAD, glutamic acid decarboxylase; GFAP, glial
fibrillary acidic protein; LGI1, leucine-rich glioma-inactivated 1; mGluR, metabotropic
glutamate receptor; MOG, myelin oligodendrocyte glycoprotein; NREM, non–rapid
eye movement; PERM, progressive encephalomyelitis with rigidity and myoclonus;
REM, rapid eye movement; SCLC, small-cell lung cancer.
In patients with cancer, the use of immune checkpoint inhibitors
is associated in <3% of cases with neurologic immune-related adverse
events that may be accompanied by neuronal antibodies, in which case
the associated syndromes are indistinguishable from PNDs.
Other PNDs are likely immune-mediated, although their antigens
are unknown. The best example is opsoclonus-myoclonus syndrome
associated with neuroblastoma or SCLC. For still other PNDs, the
cause remains quite obscure. These include, among others, several
neuropathies that occur in the terminal stages of cancer and a number
of neuropathies associated with plasma cell dyscrasias or lymphoma
without evidence of tumor infiltration or deposits of immunoglobulin,
cryoglobulin, or amyloid.
APPROACH TO THE PATIENT
Paraneoplastic Neurologic Disorders
Three key concepts are important for the diagnosis and manage­
ment of PNDs. First, it is common for symptoms to appear before
the presence of a tumor is known; second, the neurologic syndrome
usually develops rapidly, producing severe deficits in a short period
of time; and third, there is evidence that prompt tumor control
improves the neurologic outcome. Therefore, the major concern of
the physician is to recognize a disorder as paraneoplastic as early as
possible and to identify and treat the tumor.
PND OF THE CENTRAL NERVOUS SYSTEM AND DORSAL ROOT
GANGLIA
When symptoms involve brain, spinal cord, or dorsal root ganglia,
the suspicion of PND is usually based on a combination of clinical,
radiologic, and CSF findings. Presence of antineuronal antibodies
(Tables 99-2, 99-3, and 99-4) may help in the diagnosis, but only
60–70% of PNDs of the CNS and <20% of those involving the
peripheral nervous system have neuronal or neuromuscular junc­
tion antibodies that can be used as diagnostic tests.
Magnetic resonance imaging (MRI) and CSF studies are impor­
tant to rule out neurologic complications due to the direct spread
of cancer, particularly metastatic and leptomeningeal disease. In
most PNDs, the MRI findings are nonspecific. Paraneoplastic
limbic encephalitis is usually associated with characteristic MRI
abnormalities in the mesial temporal lobes (see below), but similar
findings can occur with other disorders (e.g., nonparaneoplastic
autoimmune limbic encephalitis and human herpesvirus type 6
[HHV-6] encephalitis) (Fig. 99-2A). The CSF profile of patients
with PND of the CNS or dorsal root ganglia typically consists of
mild to moderate pleocytosis (<200 mononuclear cells, predomi­
nantly lymphocytes), an increase in the protein concentration, and
a variable presence of oligoclonal bands. There are no specific
electrophysiologic tests that are diagnostic of PND of the CNS.
Moreover, a biopsy of the affected tissue is often difficult to obtain,
and although useful to rule out other disorders (e.g., metastasis),
the pathologic findings are not specific for PND.
PND OF NERVE AND MUSCLE
If symptoms involve peripheral nerve, neuromuscular junction, or
muscle, the diagnosis of a specific PND is usually established on
clinical, electrophysiologic, and pathologic grounds. The clinical
history, accompanying symptoms (e.g., anorexia, weight loss), and
type of syndrome dictate the studies and degree of effort needed to
demonstrate a neoplasm. For example, the frequent association of
Lambert-Eaton myasthenic syndrome (LEMS) with SCLC should
lead to a chest and abdomen computed tomography (CT) or body
positron emission tomography (PET) scan and, if negative, periodic
tumor screening for at least 3 years after the neurologic diagnosis. In
contrast, the weak association of polymyositis with cancer calls into
question the need for repeated cancer screenings in this situation.
Serum and urine immunofixation studies should be considered in
patients with peripheral neuropathy of unknown cause; detection of
a monoclonal gammopathy suggests the need for additional studies
to uncover a B-cell or plasma-cell malignancy. In paraneoplastic
neuropathies, diagnostically useful neuronal antibodies are limited
to CRMP5 (CV2) and Hu (ANNA1).
For any type of PND, if neuronal antibodies are negative, the
diagnosis relies on the demonstration of cancer and the exclusion
of other cancer-related or independent neurologic disorders. Com­
bined CT and PET scans often uncover tumors undetected by other
tests. For germ cell tumors of the testis and teratomas of the ovary,
ultrasound (testicular, transvaginal, or pelvic) and MRI or CT of the
abdomen and pelvis may reveal tumors undetectable by PET.
SPECIFIC PARANEOPLASTIC NEUROLOGIC
SYNDROMES
■
■PARANEOPLASTIC ENCEPHALOMYELITIS
AND FOCAL ENCEPHALITIS WITH HIGH-RISK
ANTIBODIES FOR AN UNDERLYING CANCER
The term encephalomyelitis describes an inflammatory process with
multifocal involvement of the nervous system, including brain, brain­
stem, cerebellum, and spinal cord. It is often associated with dorsal root
ganglia and autonomic dysfunction. For any given patient, the clinical
A
B
C
D
E
F
G
H
I
J
FIGURE 99-1  Antibody reactivity and pathologic findings in patients with antibodies against intracellular antigens compared with those of patients with antibodies
against neuronal surface antigens. In encephalitis associated with antibodies against intracellular antigens, the antibodies cannot reach the intracellular epitopes and
cytotoxic T-cell mechanisms are predominantly involved (A), whereas in encephalitis with antibodies against surface antigens, the antibodies have access to the epitopes
and can potentially alter the structure and function of the antigen (B). The Hu antibodies (C, E) are shown here to exemplify the group of antibodies against intracellular
antigens, and the NMDAR antibodies (D, F) are shown to exemplify the group of antibodies against cell-surface antigens. In rodent brain immunofluorescence with tissue
permeabilized to allow entry of antibodies, the Hu antibodies produce a discrete pattern of cellular immunolabeling (C), whereas the NMDAR antibodies produce a pattern of
neuropil-like immunolabeling (D). In contrast, with live cultured neurons, only the NMDAR antibodies have access to the target antigen showing intense immunolabeling (F),
whereas the Hu antibodies cannot reach the intracellular antigen showing no immunolabeling (E). In autopsy studies, patients with encephalitis associated with antibodies
to intracellular antigens (Hu or other) have extensive neuronal loss and inflammatory infiltrates (not shown); the T cells show direct contact with neurons (arrows in G) likely
contributing to neuronal degeneration via perforin and granzyme mechanisms (arrow in H). In contrast, patients with antibodies against cell-surface antigens (NMDAR
shown here, and probably applicable to other antigens) have moderate brain inflammatory infiltrates along with plasma cells (brown cells in I), deposits of IgG (diffuse brown
staining in J), and microglial proliferation (inset in J), without evidence of predominant T-cell–mediated neuronal loss (not shown). All human tissue sections (G-J) were
obtained from hippocampus. (From J Dalmau: Antibody mediated encephalitis. N Engl J Med 378:840, 2018. Copyright © 2018 Massachusetts Medical Society. Reprinted
with permission.)
CHAPTER 99
Paraneoplastic Neurologic Syndromes and Autoimmune Encephalitis
A
B
PART 4
Oncology and Hematology
C
D
FIGURE 99-2  Brain MRI findings in paraneoplastic and autoimmune encephalitis.
Representative MRI studies of patients with several types of autoimmune
encephalitides. A. Limbic encephalitis (LE) may result from several different immune
responses (Hu, Ma2, AMPAR, GABABR, LGI1, Caspr2) and typically manifests
with unilateral or bilateral medial temporal lobe increased FLAIR signal. B. AntiNMDAR encephalitis often occurs with normal MRI findings or mild FLAIR signal
abnormalities. C. In contrast, anti-GABAAR encephalitis usually occurs with multiple
cortical-subcortical increased FLAIR signal changes. D. Cortical encephalitis can
occur in patients with myelin oligodendrocyte glycoprotein (MOG) antibodies,
as shown in this T2-weighted MRI image from a 3-year-old boy who presented
with extensive cortical abnormalities with mild enhancement (not shown here)
suggesting cortical necrosis. (Panels A-C from J Dalmau: Antibody mediated
encephalitis. N Engl J Med 378:840, 2018. Copyright © 2018 Massachusetts Medical
Society. Reprinted with permission. Panel D from T Armangue: Associations of
paediatric demyelinating and encephalitic syndromes with myelin oligodendrocyte
glycoprotein antibodies: A multicentre observational study. Lancet Neurol 19:234,
2020.)
manifestations are determined by the areas predominantly involved,
but pathologic studies almost always reveal abnormalities beyond the
symptomatic regions. Several clinicopathologic syndromes may occur
alone or in combination: (1) cortical encephalitis, which may present as
“epilepsia partialis continua”; (2) limbic encephalitis, characterized by
confusion, depression, agitation, anxiety, severe deficit forming new
memories (“short-term memory deficit”), and temporal lobe or gen­
eralized seizures (the MRI usually shows unilateral or bilateral medial
temporal lobe abnormalities, best seen with T2 and fluid-attenuated
inversion recovery [FLAIR] sequences); (3) brainstem encephalitis,
resulting in eye movement disorders (nystagmus, opsoclonus, supra­
nuclear or nuclear paresis), cranial nerve paresis, dysarthria, dysphagia,
unsteady gait, and central autonomic dysfunction; (4) cerebellar gait
and limb ataxia; (5) myelitis, which may cause lower or upper motor
neuron symptoms, myoclonus, muscle rigidity, spasms, fasciculations,
sensory deficits, and sphincter dysfunction; and (6) autonomic dys­
function as a result of involvement of the neuraxis at multiple levels,
including hypothalamus, brainstem, and autonomic nerves (see
“Paraneoplastic Peripheral Neuropathies,” below). Cardiac arrhythmias,
postural hypotension, and central hypoventilation can be the cause of
death in patients with encephalomyelitis.
Paraneoplastic encephalomyelitis and focal encephalitis are usually
associated with SCLC, but many other cancers have been implicated.
Patients with SCLC and these syndromes usually have Hu antibodies
in serum and CSF. CRMP5 antibodies occur less frequently; some of
these patients may develop chorea, uveitis, or optic neuritis. Antibodies
to Ma proteins are associated with limbic, hypothalamic, and brainstem
encephalitis and occasionally with cerebellar symptoms; some patients
develop hypersomnia, cataplexy, and severe hypokinesia. MRI abnor­
malities are frequent, including those described with limbic encepha­
litis and variable involvement of the hypothalamus, basal ganglia, or
upper brainstem. Kelch-like protein 11 antibodies are predominantly
associated with brainstem encephalitis, vertigo, sensorineural hearing
loss, and seminomas, germ cell tumors, and teratomas. Amphiphysin
antibodies usually are associated with paraneoplastic stiff-person
syndrome, but in some patients, they can occur with paraneoplastic
encephalomyelitis or isolated myelitis. The oncologic associations of
these antibodies are shown in Table 99-2.
Most types of paraneoplastic encephalitis and encephalomyelitis in
which the antigens are intracellular respond poorly to treatment. Sta­
bilization of symptoms or partial neurologic improvement may occur,
particularly if there is a satisfactory response of the tumor to treatment.
Controlled trials of therapy are lacking, but many reports and the opin­
ion of experts suggest that therapies aimed to remove the antibodies
against intracellular antigens, such as intravenous immunoglobulin
(IVIg) or plasma exchange, usually fail. The main concern should be
to treat the tumor and consider immunotherapies aimed at cytotoxic
T-cell responses. Approximately 30% of patients with anti-Ma2-associ­
ated encephalitis respond to treatment of the tumor (usually a germ cell
neoplasm of the testis) and immunotherapy.
Cortical encephalitis can occur with antibodies against myelin
oligodendrocyte glycoprotein (MOG) (Chap. 456), and encephalomy­
elitis can occur with antibodies against GFAP (Chap. 456). These two
disorders rarely associate with cancer and respond better to immu­
notherapy than the indicated paraneoplastic syndromes. Encephalitis
with seizures, limbic encephalitis, stiff-person syndrome, or cerebellar
ataxia can occur with GAD65 antibodies; this type of autoimmunity
rarely associates with cancer but responds less frequently to immu­
notherapy than similar syndromes associated with antibodies against
neuronal surface proteins.
■
■ENCEPHALITIDES WITH INTERMEDIATE- OR
LOW-RISK ANTIBODIES FOR AN UNDERLYING
CANCER
These disorders are important for four reasons: (1) they can occur with
and without tumor association; less frequently, they develop after a
viral encephalitis (herpes simplex or Japanese encephalitis); (2) some
syndromes predominate in young individuals and children; (3) despite
the severity of the symptoms, patients usually respond to treatment of
the tumor, if found, and immunotherapy (e.g., glucocorticoids, IVIg,
plasma exchange, rituximab, or cyclophosphamide); and (4) for many
of these disorders, the antibody pathogenicity has been demonstrated
in models using cultures of neurons or passive transfer of patients’
antibodies to animals (Fig. 99-3).
Encephalitis with N-methyl-d-aspartate receptor (NMDAR) antibod­
ies usually occurs in young women and children, but men and older
patients of both sexes can be affected. The disorder has a character­
istic pattern of symptom progression that often includes a prodrome
resembling a viral process, followed in a few days by the onset of severe
psychiatric symptoms, sleep dysfunction (usually insomnia), reduced
verbal output, memory loss, seizures, decreased level of consciousness,
abnormal movements (orofacial, limb, and trunk dyskinesias, dystonic
postures), autonomic instability, and frequent hypoventilation. Mono­
symptomatic episodes, such as pure psychosis, occur in about 5% of
patients. Clinical relapses occur in 12–24% of patients (12% during
the first 2 years after initial presentation). Most patients have intrathe­
cal synthesis of antibodies, likely by infiltrating plasma cells in brain
and meninges (Fig. 99-1I). In about 65% of patients, the brain MRI is
normal; in the other 35%, it shows FLAIR abnormalities that can affect
cortical and subcortical regions, usually mild and transient, and rarely
A
B
D
E
F
FIGURE 99-3  Proposed mechanisms of disease and functional interactions of autoantibodies with neuronal surface proteins. The graph shows a multistep process that
results in antibody-mediated neuronal dysfunction; some of the steps have been demonstrated in reported studies, whereas others are based on proposed hypotheses. Two
well-known triggers of autoimmune encephalitides are represented: herpes simplex encephalitis (A) and systemic tumors (B); the genetic susceptibility of some autoimmune
encephalitides and unknown immunologic triggers are not depicted. It is postulated that antigens released by viral-induced neuronal destruction or apoptotic tumor cells
are loaded into antigen-presenting cells (APCs; dendritic cells) and transported to regional lymph nodes. In the lymph nodes, naïve B cells exposed to the processed
antigens, with cooperation of CD4+ T cells, become antigen-experienced and differentiate into antibody-producing plasma cells. After entering the brain, memory B cells
undergo restimulation, antigen-driven affinity maturation, clonal expansion, and differentiation into antibody-producing plasma cells (C). The contribution of systemically
produced antibodies to the pool of antibodies present in the brain is unclear and may depend on systemic antibody titers and integrity of the blood-brain barrier. Based
on experimental models with cultured neurons, the presence of antibodies in the brain may lead to neuronal dysfunction by different mechanisms, including functional
blocking of the target antigen (GABABR antibodies; D), receptor crosslinking and internalization (NMDAR antibodies; E), and disruption of protein-protein interaction, leading
to downstream effects on receptors (LGI1 leading to a decrease of Kv1 potassium channels and AMPAR; F). These mechanisms are influenced by the type of antibodies; for
example, whereas IgG1 antibodies frequently crosslink and internalize the target antigen, IgG4 antibodies are less effective at crosslinking the target and more often alter
protein-protein interactions. (Panels D-F from J Dalmau: Antibody mediated encephalitis. N Engl J Med 378:840, 2018. Copyright © 2018 Massachusetts Medical Society.
Reprinted with permission.)
the presence of contrast enhancement (Fig. 99-2B). The syndrome
may be misdiagnosed as a viral or idiopathic encephalitis, neuroleptic
malignant syndrome, or encephalitis lethargica, and some patients are
initially evaluated by psychiatrists with the suspicion of acute psychosis
as the presentation of a primary psychiatric disease. The detection of
an associated teratoma is dependent on age and gender: 46% of female
patients 12 years or older have uni- or bilateral ovarian teratomas,
whereas <7% of girls younger than 12 have a teratoma (Fig. 99-4A).
In young male patients, the detection of a tumor is rare. Patients older
than 45 years are more frequently male; about 20% of these patients
have tumors (e.g., cancer of the breast, ovary, or lung). Prompt diag­
nosis and treatment with immunotherapy (and tumor removal when
it applies) improve outcome. Treatment usually includes first-line
immunotherapy (steroids, IVIg, or plasma exchange), and if there is no
response, second-line immunotherapy (rituximab and cyclophospha­
mide). Rituximab is highly effective and is increasingly used as part of
first-line treatments. The response to treatment can take several weeks,
and the improvement is usually slow. Overall, about 85–90% of patients
have substantial neurologic improvement or full recovery. Deficits of
C
CHAPTER 99
Paraneoplastic Neurologic Syndromes and Autoimmune Encephalitis
attention, memory, and executive functions may recover slowly over
many months. During the process of recovery, patients often develop
transient hypersomnia and, less frequently, hyperphagia, hypersexual­
ity, apathy, and irritability, resembling a Kleine-Levin syndrome.
Approximately 25% of patients with herpes simplex encephalitis
develop a form of autoimmune encephalitis that usually is associ­
ated with abnormal movements (choreoathetosis after herpes simplex
encephalitis) in children and with cognitive and psychiatric symptoms
in adults. This disorder develops a few weeks after the viral infection
has resolved, is associated with new synthesis of antibodies against the
NMDAR and other neuronal cell surface proteins, and is usually less
responsive to immunotherapy than anti-NMDAR encephalitis (idio­
pathic or teratoma-associated).
Encephalitis with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid (AMPA) receptor antibodies affects middle-aged women, who
develop acute limbic dysfunction or, less frequently, prominent psychi­
atric symptoms; 70% of patients have an underlying tumor in the lung,
breast, or thymus (Fig. 99-4B). In about 50% of cases, the brain MRI
shows typical features of limbic encephalitis (similar to Fig. 99-2A).
A
B
FIGURE 99-4  Immunopathological studies in tumors of patients with autoimmune encephalitis. A. Neurons and neuronal processes (brown cells; stained with MAP2) in
the teratoma of a patient with anti-NMDA receptor encephalitis; these neurons express NMDAR (not shown). B. Lung cancer from a patient with anti–α-amino-3-hydroxy5-methyl-4-isoxazolepropionic acid (AMPA) receptor encephalitis showing expression of AMPA receptors by the neoplastic cells (brown cells). (Panel B from M Lai et al:
AMPA receptor antibodies in limbic encephalitis alter synaptic receptor location. Ann Neurol 65:424, 2009.)
PART 4
Oncology and Hematology
Neurologic relapses may occur; these also respond to immunotherapy
and are not necessarily associated with tumor recurrence.
Encephalitis with GluK2 antibodies can affect children and adults
and is associated with rapidly progressive encephalopathy with cer­
ebellar ataxia or cerebellitis. Symptoms of encephalopathy may include
impairment of memory and level of consciousness and motor altera­
tions such as dyskinesias, choreoathetosis, bradykinesia, and spastic
paraparesis. Some patients develop intracranial hypertension. In one
patient, the symptoms were associated with teratoma.
Encephalitis with γ-aminobutyric acid type A (GABAA) receptor anti­
bodies may affect children and adults and is associated with prominent
seizures and status epilepticus often requiring a pharmacologically
induced coma. In approximately 80% of patients, the brain MRI shows
multifocal, asynchronous, cortical-subcortical T2/FLAIR abnormali­
ties predominantly involving temporal and frontal lobes, but also basal
ganglia and other regions (Fig. 99-2C). Most patients do not have an
underlying tumor, but some may have thymoma.
Encephalitis with GABAB receptor antibodies is usually associated
with limbic encephalitis and seizures. In >50% of cases, the MRI shows
increased medial temporal lobe FLAIR changes characteristic of limbic
encephalitis (similar to Fig. 99-2A). In rare instances, patients develop
cerebellar symptoms and opsoclonus. Fifty percent of patients have
SCLC or a neuroendocrine tumor of the lung. The outcome is substan­
tially better in patients without cancer.
Encephalitis with glycine receptor (GlyR) antibodies usually manifests
with a syndrome characterized by progressive encephalomyelitis with
rigidity and myoclonus (PERM) or stiff-person spectrum of symptoms.
The disease usually occurs in adults and rarely in children. About 20%
of adult patients have a concurrent underlying tumor (thymoma, B-cell
lymphoma, or breast or lung cancer) or past history of cancer (thymoma,
breast cancer, Hodgkin’s lymphoma, or melanoma).
Encephalitis with metabotropic glutamate receptor 5 (mGluR5) anti­
bodies is characterized by nonspecific clinical features of encephalitis
(confusion, agitation, memory loss, delusions, paranoid ideation,
hallucinations, psychosis, or seizures) without distinctive MRI
changes and frequent association with Hodgkin’s lymphoma. The
encephalitis is highly responsive to immunotherapy and treatment
of the tumor.
Encephalitis with antibodies against dopamine-2 receptor has been
reported in children with basal ganglia encephalitis manifesting with
abnormal movements (coarse tremor, parkinsonism, chorea, ocu­
logyric crises) along with psychiatric features, lethargy, drowsiness,
brainstem dysfunction, or ataxia. The disorder is extremely rare and is
not associated with cancer.
Encephalitis with leucine-rich glioma-inactivated 1 (LGI1) antibod­
ies predominates in patients older than 50 years (65% male) and
frequently presents with short-term memory loss and seizures (limbic
encephalopathy), along with hyponatremia and sleep dysfunction.
The MRI often shows increased FLAIR signal in one or both medial
temporal lobes. In about 40% of patients, these symptoms are preceded
by faciobrachial dystonic seizures, which consist of sudden, shortlasting, mainly distal muscle contractions involving the arm, face, or
leg. These are unilateral but can independently affect both sides and
occur multiple times during the day or night. About 15% of patients
present with rapidly progressive cognitive decline, resembling a rap­
idly progressive dementia. Less than 5% of patients have thymoma.
An association with the human leukocyte antigen (HLA) haplotypes
DRB1∗07:01, DQB1∗02:02, DQA1∗02:01, and DRB4 has been identi­
fied. All symptoms, including faciobrachial dystonic seizures, respond
to immunotherapy, although about two-thirds of patients are left with
memory or cognitive deficits. Despite the improvement with initial
immunotherapy, video-polysomnography or prolonged electroen­
cephalogram studies frequently uncover persistent alterations (facio­
brachial dystonic seizures, other seizures, rapid eye movement [REM]
sleep behavior disorder) only detectable during sleep. These altera­
tions, which might contribute to residual memory or cognitive deficits,
respond to additional or prolonged immunotherapy.
Encephalitis with contactin-associated protein-like 2 (Caspr2) anti­
bodies predominates in patients older than 50 years and is associated
with a form of encephalitis with three or more of the following core
symptoms: encephalopathy (which can be similar to limbic encephali­
tis), cerebellar symptoms, peripheral nervous system hyperexcitability,
dysautonomia, insomnia, neuropathic pain, and weight loss. Patients
with Morvan syndrome, which includes clinical features of encephalitis
(confusion, hallucinations, prominent sleep dysfunction, or “agrypnia
excitata”), autonomic alterations, and peripheral nerve hyperexcitabil­
ity or neuromyotonia, usually have Caspr2 antibodies. About 20% of
patients with Caspr2 antibody–associated syndromes have thymoma;
this percentage is higher (~50%) in patients with Morvan syndrome.
An association of Caspr2 antibody–associated syndromes with HLA
DRB1∗11.01 has been reported.
Encephalitis with dipeptidyl-peptidase-like protein-6 (DPPX) anti­
bodies is usually preceded or develops concurrently with diarrhea,
other gastrointestinal symptoms, and substantial loss of weight that
often suggest the presence of a gastrointestinal disease. Neurologic
symptoms include agitation, hallucinations, paranoid delusions, and
features of CNS hyperexcitability such as hyperekplexia, tremor, myoc­
lonus, nystagmus, or seizures. Some patients develop a clinical picture
similar to progressive encephalomyelitis with rigidity and myoclonus.
The few patients reported with an associated tumor usually had B-cell
neoplasms.
Encephalitis with antibodies against neurexin 3 alpha does not have
distinctive clinical features; the experience is limited, and the disorder
does not appear to be associated with cancer.
Anti-IgLON5 disease is a chronic or subacute encephalopathy that
characteristically is associated with REM and non-REM (NREM)
parasomnia along with obstructive sleep apnea that may be preceded
or accompanied by bulbar symptoms (mainly dysphagia and stridor
due to vocal cord palsy), unsteadiness, movement disorders (chorea,
craniofacial dyskinesias), oculomotor dysfunction, and, in less than
half of cases, cognitive decline. The median age of the patients is in the
early 60s, and men and women are equally affected. The sleep disorder
is characterized by abnormal sleep initiation with undifferentiated
NREM sleep associated with frequent vocalizations and quasi-purposeful
movements. Brain MRI is unrevealing or demonstrates minor changes
of unclear clinical relevance; the CSF is usually normal or may show
transient lymphocytic pleocytosis. It is not associated with cancer
but shows a strong association with the HLA-DRB1∗10:01 and HLADQB1∗05 haplotypes, which are present in 60% of patients. The
response to immunotherapy is poor. In some patients, neuropathologic
studies show a neuronal tauopathy predominantly involving the hypo­
thalamus and tegmentum of the brainstem; however, not all autopsy
studies show deposits of hyperphosphorylated tau, and in some
patients, mild inflammatory infiltrates have been identified.
With the exception of patients with anti-IgLON5 disease, who rarely
respond to treatment, most patients with autoimmune or paraneoplas­
tic encephalopathies associated with antibodies against cell-surface
or synaptic proteins respond to immunotherapy and treatment of the
tumor (if appropriate). Although there are no specific standardized
treatment protocols, the most frequent approach is similar to that indi­
cated for anti-NMDAR encephalitis and consists of progressive escala­
tion of immunotherapy using first a combination of glucocorticoids,
IVIg, and plasma exchange, and then, if there is no response, rituximab
or cyclophosphamide.
Encephalitis with MOG antibodies can present with a clinical picture
suggestive of autoimmune encephalitis related to neuronal antibodies.
Most patients with MOG antibody–associated syndromes are children
and young adults who present with optic neuritis, myelitis, brainstem
(mainly pons) and cerebellar symptoms, or acute disseminated enceph­
alomyelitis (ADEM). About 85% of patients with these syndromes
respond to immunotherapy, although relapses occur in about 30% of
cases. Besides these syndromes, there is a small group of adults and
children who present with unilateral or bilateral cortical encephalitis,
and their response to treatment is variable. In children, two pheno­
types of poor prognosis include ADEM-like relapses progressing to
leukodystrophy-like features and extensive cortical encephalitis evolv­
ing to atrophy (Fig. 99-2D). In general, MOG antibody syndromes are
not associated with tumors.
■
■PARANEOPLASTIC CEREBELLAR DEGENERATION
This disorder is often preceded by a prodrome that may include dizzi­
ness, oscillopsia, blurry or double vision, nausea, and vomiting. A few
days or weeks later, patients develop dysarthria, gait and limb ataxia,
and variable dysphagia. The examination usually shows downbeating
nystagmus and, rarely, opsoclonus. Brainstem dysfunction or upgoing
toes may occur. Early in the course, MRI studies are usually normal;
later, the MRI reveals cerebellar atrophy. The disorder results from
extensive degeneration of Purkinje cells, with variable involvement of
other cerebellar cortical neurons, deep cerebellar nuclei, and spinocer­
ebellar tracts. The tumors more frequently involved are SCLC, cancer
of the breast and ovary, and Hodgkin’s lymphoma.
Anti-Yo (PCA1) antibodies in patients with breast or gynecologic
cancers typically are associated with prominent or pure cerebellar
degeneration. A variable degree of cerebellar dysfunction can be asso­
ciated with virtually any of the antibodies and PND of the CNS shown
in Table 99-2. A number of single case reports have described neuro­
logic improvement after tumor removal, plasma exchange, IVIg, cyclo­
phosphamide, rituximab, or glucocorticoids. However, most patients
with paraneoplastic cerebellar degeneration and any of the antibodies
shown in Table 99-2 do not improve with treatment; an exception are
the cerebellar syndromes associated with antibodies against surface
antigens (e.g., Tr antibodies and Hodgkin’s lymphoma, VGCC antibod­
ies and SCLC), which are more responsive to immunotherapy.
Antibody-associated cerebellar symptoms can also occur without
cancer association. The most common is cerebellar ataxia with anti­
bodies against GAD65 (an intracellular synaptic protein). The median
age at diagnosis is 60 years and 75% of cases are women. Concurrent
organ-specific autoimmune diseases, mainly type 1 diabetes, are pres­
ent in 80% of patients. The clinical course is chronic, but in 40% of
patients, the presentation is subacute (<6 months). Response to immu­
notherapy is poor. Subacute onset of symptoms and prompt initiation
of immunotherapy are associated with a better chance for improve­
ment. By contrast, the cerebellar syndrome associated with mGluR1
antibodies is more responsive to immunotherapy, and a substantial
improvement occurs in almost half of the patients. Immunotherapy is
also effective in patients with GluK2 antibodies, who can present with
cerebellitis and posterior fossa edema with compression of the fourth
ventricle, and in those with septin-5 antibodies. Although septin-5 is
an intracellular antigen, it is likely exposed to the cell surface during
the process of endo- and exocytosis at synaptic terminals.
CHAPTER 99
Paraneoplastic Neurologic Syndromes and Autoimmune Encephalitis
■
■PARANEOPLASTIC OPSOCLONUS-MYOCLONUS
SYNDROME
Opsoclonus is a disorder of eye movement characterized by involuntary,
chaotic saccades that occur in all directions of gaze; it is frequently
associated with myoclonus and ataxia. Opsoclonus-myoclonus may
be cancer-related or idiopathic. When the cause is paraneoplastic, the
tumors involved are usually cancer of the lung and breast in adults and
neuroblastoma in children. The pathologic substrate of opsoclonusmyoclonus is unclear, but studies suggest that disinhibition of the fas­
tigial nucleus of the cerebellum is involved. Most patients do not have
neuronal antibodies. A small subset of patients with ataxia, opsoclonus,
and other eye-movement disorders have Ri antibodies; these patients
may also develop muscle rigidity, laryngeal spasms, and autonomic
dysfunction. The tumors most frequently involved in anti-Ri-associated
syndromes are breast, ovarian, and lung cancers. If the tumor is
not successfully treated, the syndrome in adults often progresses to
encephalopathy, coma, and death. In addition to treating the tumor,
symptoms may respond to immunotherapy (glucocorticoids, plasma
exchange, and/or IVIg).
At least 50% of children with opsoclonus-myoclonus have an
underlying neuroblastoma. Hypotonia, ataxia, behavioral changes, and
irritability are frequent accompanying symptoms. Neurologic symp­
toms often improve with treatment of the tumor and glucocorticoids,
adrenocorticotropic hormone (ACTH), plasma exchange, IVIg, ritux­
imab, or cyclophosphamide. Many patients are left with psychomotor
retardation and behavioral and sleep problems.
■
■PARANEOPLASTIC SYNDROMES OF THE SPINAL
CORD
The number of reports of paraneoplastic spinal cord syndromes, such
as subacute motor neuronopathy and acute necrotizing myelopathy,
has decreased over the years. This may represent a true decrease in
incidence, due to improved and prompt oncologic interventions, or
the identification of nonparaneoplastic etiologies. Some patients with
cancer or lymphoma develop upper or lower motor neuron dysfunction
or both, resembling amyotrophic lateral sclerosis. It is unclear whether
these disorders have a paraneoplastic etiology or simply coincide with
the presence of cancer.
Paraneoplastic myelitis may present with upper or lower motor neu­
ron symptoms, segmental myoclonus, sensory deficits, sphincter dys­
function, and neurogenic pruritus and can be the first manifestation of
encephalomyelitis. The spine MRI usually shows longitudinally exten­
sive, symmetric tract or gray matter abnormalities in the spinal cord. It
is mainly associated with breast and lung carcinomas and with CRMP5
or amphiphysin antibodies. The prognosis is poor. Neuromyelitis optica
(NMO) with aquaporin 4 antibodies may occur in rare instances as a
paraneoplastic manifestation of a cancer. NMO is discussed in detail
in Chap. 456.
■
■PARANEOPLASTIC STIFF-PERSON SYNDROME
This disorder is characterized by progressive muscle rigidity, stiff­
ness, and painful spasms triggered by auditory, sensory, or emotional
stimuli. Rigidity mainly involves the lower trunk and legs, but it can
affect the upper extremities and neck. Sometimes, only one extremity
is affected (stiff-limb syndrome). Symptoms improve with sleep and
general anesthetics. Electrophysiologic studies demonstrate continuous
motor unit activity. The associated antibodies target proteins (GAD65,
amphiphysin) involved in the function of inhibitory synapses that use
γ-aminobutyric acid (GABA) or glycine as neurotransmitters. The
presence of amphiphysin antibodies usually indicates a paraneoplastic
etiology related to SCLC and breast cancer. By contrast, GAD antibod­
ies may occur in some cancer patients but are much more frequently
present in the nonparaneoplastic disorder. GlyR antibodies may occur
in some patients with stiff-person syndrome; these antibodies are more
frequently detectable in patients with PERM (Fig. 99-5).
PART 4
Oncology and Hematology
Optimal treatment of stiff-person syndrome requires therapy of
the underlying tumor, glucocorticoids, and symptomatic use of drugs
that enhance GABA-ergic transmission (diazepam, baclofen, sodium
valproate, tiagabine, vigabatrin). IVIg and plasma exchange are tran­
siently effective in some patients, and there are reports of responses
FIGURE 99-5  Schematic representation of an inhibitory synapse showing the main autoimmune targets (GAD, amphiphysin, GABA receptor, and glycine receptor) and
the corresponding neurologic disorders. GAD antibodies predominantly occur in stiff-person syndrome (SPS), cerebellar ataxia, and epilepsy, sometimes in the setting
of encephalitis. Amphiphysin antibodies are markers of paraneoplastic SPS and breast cancer, GlyR antibodies often associate with progressive encephalomyelitis with
rigidity and myoclonus (PERM), and GABAA receptor antibodies occur in a form of autoimmune encephalitis that is frequently associated with refractory seizures and status
epilepticus. (Modified from F Graus et al: Nat Rev Neurol 16:353, 2020.)
to rituximab and CD19 CAR T-cell therapy in patients who did not
respond to other treatments.
■
■PARANEOPLASTIC SENSORY NEURONOPATHY OR
DORSAL ROOT GANGLIONOPATHY
This syndrome is characterized by sensory deficits that may be
symmetric or asymmetric, painful dysesthesias, radicular pain, and
decreased or absent reflexes. All modalities of sensation and any part
of the body including face and trunk can be involved. Special senses
such as taste and hearing can also be affected. Electrophysiologic stud­
ies show decreased or absent sensory nerve potentials with normal or
near-normal motor conduction velocities. Symptoms result from an
immune-mediated process that targets the dorsal root ganglia, causing
neuronal loss and secondary degeneration of the posterior columns
of the spinal cord. The dorsal and, less frequently, the anterior nerve
roots and peripheral nerves may also be involved. This disorder often
precedes or is associated with encephalomyelitis and autonomic dys­
function and has the same immunologic and oncologic associations
(Hu antibodies, SCLC).
As with anti-Hu-associated encephalomyelitis, the therapeutic
approach focuses on prompt treatment of the tumor and cytotoxic
T-cell–mediated mechanisms. Glucocorticoids occasionally produce
clinical stabilization or improvement. The benefit of IVIg and plasma
exchange is not proven.
■
■PARANEOPLASTIC PERIPHERAL NEUROPATHIES
These disorders may develop any time during the course of the neo­
plastic disease. Neuropathies occurring at late stages of cancer or
lymphoma usually cause mild to moderate sensorimotor deficits due
to axonal degeneration of unclear etiology. These neuropathies are
often masked by concurrent neurotoxicity from chemotherapy and
other cancer therapies. In contrast, the neuropathies that develop in the
early stages of cancer frequently show a rapid progression, sometimes
with a relapsing and remitting course, and evidence of inflammatory
infiltrates and axonal loss or demyelination. Besides the subacute onset,
an asymmetric distribution of symptoms, presence of neuropathic pain
and dysautonomia, clinical or neuroimaging evidence of involvement
of the spinal cord or nerve roots, and detection of an axonal pattern in
the electrophysiological studies are features that suggest the possibility
of a paraneoplastic etiology. The response to treatment is usually poor,
but if demyelinating features predominate (Chaps. 457 and 458), IVIg,
plasma exchange, or glucocorticoids may improve symptoms. Occa­
sionally, CRMP5 antibodies are present; detection of Hu antibodies
suggests concurrent dorsal root ganglionitis.
Guillain-Barré syndrome (Chap. 458) and brachial plexitis (Chap. 457)
have occasionally been reported in patients with Hodgkin’s lymphoma,
but there is no clear evidence of a paraneoplastic association.
Diseases associated with paraproteinemia such as multiple myeloma,
osteosclerotic myeloma, cryoglobulinemia, amyloidosis, Waldenström’s
macroglobulinemia, or POEMS (polyneuropathy, organomegaly, endo­
crinopathy, M-protein spike, and skin manifestations) syndrome,
among others, may cause neuropathy by a variety of mechanisms,
including compression of roots and plexuses by metastasis to verte­
bral bodies and pelvis, by deposits of amyloid in peripheral nerves, or
through a direct interaction of the abnormal immunoglobulin with
peripheral nerve antigens. In other patients, the mechanisms under­
lying the neuropathy remain unknown and paraneoplastic immunemediated mechanisms have not been ruled out. Neuropathies more
often occur with IgM paraproteinemia followed by IgG and IgA. The
phenotype of the neuropathy and likelihood of improvement with suc­
cessful treatment of the paraproteinemia are dependent on the under­
lying hematologic disorder (Chap. 458).
Vasculitis of the nerve and muscle causes a painful symmetric or
asymmetric distal axonal sensorimotor neuropathy with variable
proximal weakness. It predominantly affects elderly men and is associ­
ated with an elevated erythrocyte sedimentation rate and increased
CSF protein concentration. SCLC and lymphoma are the primary
tumors involved. Glucocorticoids and cyclophosphamide often result
in neurologic improvement.
Peripheral nerve hyperexcitability (neuromyotonia, or Isaacs’ syn­
drome) is characterized by spontaneous and continuous muscle fiber
activity of peripheral nerve origin. Clinical features include cramps,
muscle twitching (fasciculations or myokymia), stiffness, delayed
muscle relaxation (pseudomyotonia), and spontaneous or evoked
carpal or pedal spasms. The involved muscles may be hypertrophic,
and some patients develop paresthesias and hyperhidrosis. The elec­
tromyogram (EMG) shows fibrillations; fasciculations; and doublet,
triplet, or multiplet single-unit (myokymic) discharges that have a high
intraburst frequency. Some patients have Caspr2 antibodies usually in
the context of Morvan syndrome, but most patients with isolated neu­
romyotonia are antibody negative. The disorder often occurs without
cancer; if paraneoplastic, benign and malignant thymomas and SCLC
are the usual tumors. Phenytoin, carbamazepine, and plasma exchange
improve symptoms.
Paraneoplastic autonomic neuropathy usually develops as a compo­
nent of other disorders, such as LEMS and encephalomyelitis. It may
rarely occur as a pure or predominantly autonomic neuropathy with
cholinergic or adrenergic dysfunction at the pre- or postganglionic
levels. Patients can develop several life-threatening complications,
such as gastrointestinal paresis with pseudo-obstruction, cardiac dys­
rhythmias, and postural hypotension. Other clinical features include
abnormal pupillary responses, dry mouth, anhidrosis, erectile dys­
function, and problems with sphincter control. The disorder occurs
in association with several tumors, including SCLC, cancer of the
pancreas or testis, carcinoid tumors, and lymphoma. Because auto­
nomic symptoms can be the presenting feature of encephalomyelitis,
serum Hu and CRMP5 antibodies should be sought. Antibodies to
ganglionic (α3-type) neuronal acetylcholine receptors are the cause
of autoimmune autonomic ganglionopathy, a disorder that frequently
occurs without cancer association (Chap. 451).
■
■LAMBERT-EATON MYASTHENIC SYNDROME
LEMS is discussed in Chap. 459.
■
■MYASTHENIA GRAVIS
Myasthenia gravis is discussed in Chap. 459.
■
■POLYMYOSITIS-DERMATOMYOSITIS
Polymyositis and dermatomyositis are discussed in detail in Chap. 377.
■
■IMMUNE-MEDIATED NECROTIZING MYOPATHY
Patients with this syndrome develop myalgias and rapid progression
of weakness involving the extremities, neck, pharyngeal, respiratory,
and sometimes cardiac muscles. Serum muscle enzymes are elevated,
and muscle biopsy shows extensive necrosis with minimal or absent
inflammation and sometimes deposits of complement. The disorder
may occur without cancer association (sometimes as a result of statin
exposure, connective tissue disease, or HIV) or with cancer asso­
ciation. Patients with antibodies against 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMGCR) and seronegative patients are more
likely to have an underlying cancer than those with antibodies against
signal recognition particle. No specific type of cancer has been found
to be predominant. Successful treatment of the tumor and aggressive
immunotherapy (steroids, IVIg, and steroid-sparing immunosuppres­
sants) may lead to complete or substantial recovery. Immune-mediated
necrotizing myopathy is discussed in Chap. 377.
CHAPTER 99
Paraneoplastic Neurologic Syndromes and Autoimmune Encephalitis
■
■PARANEOPLASTIC VISUAL SYNDROMES
This group of disorders involves the retina and, less frequently, the
uvea and optic nerves. The term cancer-associated retinopathy is used
to describe paraneoplastic cone and rod dysfunction characterized by
photosensitivity, progressive loss of vision and color perception, central
or ring scotomas, night blindness, and attenuation of photopic and
scotopic responses in the electroretinogram (ERG). The most com­
monly associated tumor is SCLC. Melanoma-associated retinopathy
affects patients with metastatic cutaneous melanoma. Patients develop
acute onset of night blindness and shimmering, flickering, or pulsating
photopsias that often progress to visual loss. The ERG shows reduced
b-waves with normal dark adapted a-waves. Paraneoplastic optic neu­
ritis and uveitis can develop in association with encephalomyelitis.
Patients with paraneoplastic uveitis and optic neuritis may harbor
CRMP5 antibodies.
Some paraneoplastic retinopathies are associated with serum anti­
bodies that specifically react with the subset of retinal cells undergoing
degeneration, supporting an immune-mediated pathogenesis. The
best-characterized retinal antibodies are against recoverin and have
been described in patients with SCLC and cancer-associated retinopa­
thy. However, the specificity of this and other retinal antibodies is low
as they have also been reported in nonparaneoplastic autoimmune
and nonautoimmune retinopathies. Paraneoplastic retinopathies rarely
show substantial improvement after treatment of the tumor and immu­
notherapy; however, stabilization of symptoms and partial responses to
a variety of immunotherapies (glucocorticoids, plasma exchange, IVIg,
rituximab, or alemtuzumab) have been reported.
■
■FURTHER READING
Armangue T et al: Associations of paediatric demyelinating and
encephalitic syndromes with myelin oligodendrocyte glycoprotein
antibodies: A multicentre observational study. Lancet Neurol 19:234,
2020.
Armangue T et al: Neurological complications in herpes simplex
encephalitis: Clinical, immunological and genetic studies. Brain
146:4306, 2023.
Cellucci T et al: Clinical approach to the diagnosis of autoimmune
encephalitis in the pediatric patient. Neurol Neuroimmunol Neuro­
inflamm 7:e663, 2020.
Dalmau J, Graus F: Autoimmune Encephalitis and Related Disorders
of the Nervous System. Cambridge, Cambridge University Press, 2022.

30 - SECTION 2 Hematopoietic Disorders
SECTION 2 Hematopoietic Disorders
traditionally been performed by oncologists, but the magnitude of the
problem mandates that primary care providers and preventive medi­
cine specialists be trained in the follow-up of treated cancer patients
in remission or undergoing chronic therapy. All former cancer patients
should undergo surveillance for recurrence and second malignancies
and be monitored for long-term effects of treatment; however, nearly
all recurrences are detected because of symptoms. Health promotion
and disease prevention with age- and sex-specific routine screening
tests (e.g., colonoscopy, Pap smears, mammography, human papillo­
mavirus vaccination, dual-energy x-ray absorptiometry scans) should
be a focus of survivorship care along with psychosocial well-being.
Annual mammography should start no later than 10 years after breast
radiation. Patients receiving radiation fields encompassing thyroid tis­
sue should have regular thyroid examinations and TSH testing. Local­
ized pain or palpable abnormality in a previously radiated field should
prompt radiographic evaluation. Patients treated with alkylating agents
or topoisomerase inhibitors should have a complete blood count every
6–12 months, and cytopenias, abnormal cells on peripheral smear, or
macrocytosis should be evaluated with bone marrow biopsy and aspi­
rate and include cytogenetics, flow cytometry, or fluorescence in situ
hybridization (FISH) studies as appropriate.
As the population of cancer survivors increases and patients live
longer, cancer survivorship has become increasingly important, and
the Institute of Medicine and National Research Council have pub­
lished a monograph entitled From Cancer Patient to Cancer Survivor:
Lost in Transition. The monograph proposes a plan that would inform
clinicians caring for cancer survivors of the complete details of patients’
previous treatments, complications thereof, signs and symptoms of late
effects, and recommended screening and follow-up procedures.
PART 4
Oncology and Hematology
OUTLOOK
Survivorship care is a burgeoning problem facing oncologists today.
The challenge is to develop cancer treatments that maximize clini­
cal benefit including cure of disease while also mitigating the risks
of long-term toxicity. As cancer treatments continue to improve, the
prevalence of cancer survivors increases along with an increase in life
expectancy. Further, since emerging therapies often have improved
tolerability profiles, a greater number of patients with advanced age or
comorbid medical conditions will become cancer survivors with per­
sistent treatment-related toxicities. As treatment paradigms continue to
evolve, the nature and biologic basis for toxicities will change and phar­
macovigilance of new therapies is critical. Advances in genomic medi­
cine may allow for more risk-stratified personalized care. The choice of
therapy needs to be tailored to the type of cancer, expected outcomes,
and patient-related risk factors for both acute and long-term toxicities.
After therapy is complete, longitudinal monitoring of the health and
health-related quality of life of cancer survivors is critical since the inci­
dence of late effects of treatment does not appear to plateau over time.
Acknowledgment
We would like to acknowledge the contribution of Carl E. Freter who
coauthored a previous version of this chapter; material from his chapter
was retained in this version.
■
■FURTHER READING
Armenian SH et al: Cardiovascular disease in survivors of childhood
cancer: Insights into epidemiology, pathophysiology, and prevention.
J Clin Oncol 36:2135, 2018.
Brinkman TM et al: Psychological symptoms, social outcomes,
socioeconomic attainment, and health behaviors among survivors
of childhood cancer: Current state of the literature. J Clin Oncol
36:2190, 2018.
Chow EJ et al: New agents, emerging late effects, and the development
of precision survivorship. J Clin Oncol 36:2231, 2018.
Ehrhardt MJ et al: Health care transitions among adolescents and
young adults with cancer. J Clin Oncol 42:743, 2024.
Lustberg MB et al: Mitigating long-term and delayed adverse events
associated with cancer treatment: Implications for survivorship. Nat
Rev Clin Oncol 20:527, 2023.
Rowland JH et al: Survivorship science at the NIH: Lessons learned
from grants funded in fiscal year 2016. J Natl Cancer Inst 111:109,
2019.
Shapiro CL: Cancer survivorship. N Engl J Med 379:2438, 2018.
Shapiro CL et al: ReCAP: ASCO core curriculum for cancer survivor­
ship education. J Oncol Pract 12:e08, 2016.
Shree T et al: Impaired immune health in survivors of diffuse large
B-cell lymphoma. J Clin Oncol 38:1664, 2020.
Turcotte LM et al: Risk, risk factors, and surveillance of subsequent
malignant neoplasms in survivors of childhood cancer: A review. J Clin
Oncol 36:2145, 2018.
Section 2	 Hematopoietic Disorders
David T. Scadden, Dan L. Longo
Hematopoietic Stem
Cells
All of the cell types in the blood and some cells in every tissue of the
body are derived from hematopoietic (hemo: blood; poiesis: creation)
stem cells. If the hematopoietic stem cell is damaged and can no longer
function (e.g., due to a nuclear accident), a person would survive
2–4 weeks in the absence of extraordinary support measures. With the
clinical use of hematopoietic stem cells, tens of thousands of lives are
saved each year (Chap. 119). Stem cells produce hundreds of billions
of blood cells daily from a stem cell pool that is estimated to be only
20,000–200,000. How stem cells do this, how they persist for many
decades despite the production demands, and how they may be better
used in clinical care are important issues in medicine.
The study of blood cell production has become a paradigm for how
other tissues may be organized and regulated. Basic research in hema­
topoiesis includes defining stepwise molecular changes accompanying
functional changes in maturing cells, aggregating cells into functional
subgroups, and demonstrating hematopoietic stem cell regulation by
a specialized microenvironment; these concepts are worked out in
hematology and offer models for other tissues. Moreover, these con­
cepts may not be restricted to normal tissue function but extend to
malignancy.
CARDINAL FUNCTIONS OF
HEMATOPOIETIC STEM CELLS
All stem cell types have two cardinal functions: self-renewal and dif­
ferentiation (Fig. 101-1). Stem cells exist to generate, maintain, and
repair tissues. They function successfully if they can replace a wide
variety of shorter-lived mature cells over prolonged periods. The pro­
cess of self-renewal (see below) assures that a stem cell population can
be sustained over time. Without self-renewal, the stem cell pool would
become exhausted and tissue maintenance would not be possible. The
process of differentiation leads to production of the effectors of tissue
function: mature cells. Without proper differentiation, the integrity of
tissue function would be compromised and organ failure or neoplasia
would ensue.
In the blood, mature cells have variable average life spans, ranging
from hours for mature neutrophils to a few months for red blood cells
to many years for memory lymphocytes. However, the stem cell pool is
the central, durable source of all blood and immune cells, maintaining
a capacity to produce a broad range of cells from a single cell source,
yet keeping itself vigorous over decades of life. As an individual stem
cell divides, it has the capacity to accomplish one of three division
outcomes: two stem cells, two cells destined for differentiation, or one
stem cell and one differentiating cell. The former two outcomes are the

31 - 101 Hematopoietic Stem Cells
101 Hematopoietic Stem Cells
traditionally been performed by oncologists, but the magnitude of the
problem mandates that primary care providers and preventive medi­
cine specialists be trained in the follow-up of treated cancer patients
in remission or undergoing chronic therapy. All former cancer patients
should undergo surveillance for recurrence and second malignancies
and be monitored for long-term effects of treatment; however, nearly
all recurrences are detected because of symptoms. Health promotion
and disease prevention with age- and sex-specific routine screening
tests (e.g., colonoscopy, Pap smears, mammography, human papillo­
mavirus vaccination, dual-energy x-ray absorptiometry scans) should
be a focus of survivorship care along with psychosocial well-being.
Annual mammography should start no later than 10 years after breast
radiation. Patients receiving radiation fields encompassing thyroid tis­
sue should have regular thyroid examinations and TSH testing. Local­
ized pain or palpable abnormality in a previously radiated field should
prompt radiographic evaluation. Patients treated with alkylating agents
or topoisomerase inhibitors should have a complete blood count every
6–12 months, and cytopenias, abnormal cells on peripheral smear, or
macrocytosis should be evaluated with bone marrow biopsy and aspi­
rate and include cytogenetics, flow cytometry, or fluorescence in situ
hybridization (FISH) studies as appropriate.
As the population of cancer survivors increases and patients live
longer, cancer survivorship has become increasingly important, and
the Institute of Medicine and National Research Council have pub­
lished a monograph entitled From Cancer Patient to Cancer Survivor:
Lost in Transition. The monograph proposes a plan that would inform
clinicians caring for cancer survivors of the complete details of patients’
previous treatments, complications thereof, signs and symptoms of late
effects, and recommended screening and follow-up procedures.
PART 4
Oncology and Hematology
OUTLOOK
Survivorship care is a burgeoning problem facing oncologists today.
The challenge is to develop cancer treatments that maximize clini­
cal benefit including cure of disease while also mitigating the risks
of long-term toxicity. As cancer treatments continue to improve, the
prevalence of cancer survivors increases along with an increase in life
expectancy. Further, since emerging therapies often have improved
tolerability profiles, a greater number of patients with advanced age or
comorbid medical conditions will become cancer survivors with per­
sistent treatment-related toxicities. As treatment paradigms continue to
evolve, the nature and biologic basis for toxicities will change and phar­
macovigilance of new therapies is critical. Advances in genomic medi­
cine may allow for more risk-stratified personalized care. The choice of
therapy needs to be tailored to the type of cancer, expected outcomes,
and patient-related risk factors for both acute and long-term toxicities.
After therapy is complete, longitudinal monitoring of the health and
health-related quality of life of cancer survivors is critical since the inci­
dence of late effects of treatment does not appear to plateau over time.
Acknowledgment
We would like to acknowledge the contribution of Carl E. Freter who
coauthored a previous version of this chapter; material from his chapter
was retained in this version.
■
■FURTHER READING
Armenian SH et al: Cardiovascular disease in survivors of childhood
cancer: Insights into epidemiology, pathophysiology, and prevention.
J Clin Oncol 36:2135, 2018.
Brinkman TM et al: Psychological symptoms, social outcomes,
socioeconomic attainment, and health behaviors among survivors
of childhood cancer: Current state of the literature. J Clin Oncol
36:2190, 2018.
Chow EJ et al: New agents, emerging late effects, and the development
of precision survivorship. J Clin Oncol 36:2231, 2018.
Ehrhardt MJ et al: Health care transitions among adolescents and
young adults with cancer. J Clin Oncol 42:743, 2024.
Lustberg MB et al: Mitigating long-term and delayed adverse events
associated with cancer treatment: Implications for survivorship. Nat
Rev Clin Oncol 20:527, 2023.
Rowland JH et al: Survivorship science at the NIH: Lessons learned
from grants funded in fiscal year 2016. J Natl Cancer Inst 111:109,
2019.
Shapiro CL: Cancer survivorship. N Engl J Med 379:2438, 2018.
Shapiro CL et al: ReCAP: ASCO core curriculum for cancer survivor­
ship education. J Oncol Pract 12:e08, 2016.
Shree T et al: Impaired immune health in survivors of diffuse large
B-cell lymphoma. J Clin Oncol 38:1664, 2020.
Turcotte LM et al: Risk, risk factors, and surveillance of subsequent
malignant neoplasms in survivors of childhood cancer: A review. J Clin
Oncol 36:2145, 2018.
Section 2	 Hematopoietic Disorders
David T. Scadden, Dan L. Longo
Hematopoietic Stem
Cells
All of the cell types in the blood and some cells in every tissue of the
body are derived from hematopoietic (hemo: blood; poiesis: creation)
stem cells. If the hematopoietic stem cell is damaged and can no longer
function (e.g., due to a nuclear accident), a person would survive
2–4 weeks in the absence of extraordinary support measures. With the
clinical use of hematopoietic stem cells, tens of thousands of lives are
saved each year (Chap. 119). Stem cells produce hundreds of billions
of blood cells daily from a stem cell pool that is estimated to be only
20,000–200,000. How stem cells do this, how they persist for many
decades despite the production demands, and how they may be better
used in clinical care are important issues in medicine.
The study of blood cell production has become a paradigm for how
other tissues may be organized and regulated. Basic research in hema­
topoiesis includes defining stepwise molecular changes accompanying
functional changes in maturing cells, aggregating cells into functional
subgroups, and demonstrating hematopoietic stem cell regulation by
a specialized microenvironment; these concepts are worked out in
hematology and offer models for other tissues. Moreover, these con­
cepts may not be restricted to normal tissue function but extend to
malignancy.
CARDINAL FUNCTIONS OF
HEMATOPOIETIC STEM CELLS
All stem cell types have two cardinal functions: self-renewal and dif­
ferentiation (Fig. 101-1). Stem cells exist to generate, maintain, and
repair tissues. They function successfully if they can replace a wide
variety of shorter-lived mature cells over prolonged periods. The pro­
cess of self-renewal (see below) assures that a stem cell population can
be sustained over time. Without self-renewal, the stem cell pool would
become exhausted and tissue maintenance would not be possible. The
process of differentiation leads to production of the effectors of tissue
function: mature cells. Without proper differentiation, the integrity of
tissue function would be compromised and organ failure or neoplasia
would ensue.
In the blood, mature cells have variable average life spans, ranging
from hours for mature neutrophils to a few months for red blood cells
to many years for memory lymphocytes. However, the stem cell pool is
the central, durable source of all blood and immune cells, maintaining
a capacity to produce a broad range of cells from a single cell source,
yet keeping itself vigorous over decades of life. As an individual stem
cell divides, it has the capacity to accomplish one of three division
outcomes: two stem cells, two cells destined for differentiation, or one
stem cell and one differentiating cell. The former two outcomes are the
Stem cell
Self-renewal
Differentiation
Stem cell
Differentiated cells
FIGURE 101-1  Signature characteristics of the stem cell. Stem cells have two
essential features: the capacity to differentiate into a variety of mature cell types and
the capacity for self-renewal. Intrinsic factors associated with self-renewal include
expression of Bmi-1, Gfi-1, PTEN, STAT5, Tel/Atv6, p21, p18, MCL-1, Mel-18, RAE28,
and HoxB4. Extrinsic signals for self-renewal include Notch, Wnt, SHH, angiogenin,
and Tie2/Ang-1. Based mainly on murine studies, hematopoietic stem cells express
the following cell surface molecules: CD34, Thy-1 (CD90), c-Kit receptor (CD117),
CD133, CD164, and c-Mpl (CD110, also known as the thrombopoietin receptor).
result of symmetric cell division, whereas the latter indicates a different
outcome for the two daughter cells—an event termed asymmetric cell
division. The relative balance for these types of outcomes may change
during development and under particular kinds of demands on the
stem cell pool.
■
■DEVELOPMENTAL BIOLOGY OF HEMATOPOIETIC
STEM CELLS
During development, blood cells are produced at different sites.
Initially, the yolk sac provides oxygen-carrying red blood cells and
many of the macrophage-like cells that are resident in tissues: cells like
microglia in the brain. The placenta and several sites of intraembryonic
blood cell production then become involved in sequential order. These
move from the genital ridge at a site where the aorta, gonadal tissue,
and mesonephros are emerging to the fetal liver and then, in the sec­
ond trimester, to the bone marrow and spleen. As the location of stem
cells changes, the cells they produce also change. The yolk sac provides
red cells expressing embryonic hemoglobins and tissue-resident mac­
rophages. Intraembryonic sites of hematopoiesis generate stem cells,
red cells, platelets, and the circulating cells of innate immunity. The
production of the cells of adaptive immunity occurs then as well but
becomes robust as the thymus forms and the bone marrow is colonized
in the second trimester. Stem cell proliferation remains high, even in
the bone marrow, until shortly after birth, when it appears to dramati­
cally decline. The cells in the bone marrow are thought to arrive by the
bloodborne transit of cells from the fetal liver after calcification of the
long bones has begun. The presence of stem cells in the circulation is
not unique to a time window in development, however, as hemato­
poietic stem cells circulate throughout life. The time that stem cells
spend freely circulating appears to be brief (measured in minutes in the
mouse), but the stem cells that do circulate are functional and can be
used for transplantation. The number of stem cells that circulate can be
increased in a number of ways to facilitate their harvest and transfer to
the same or a different host.
■
■MOBILITY OF HEMATOPOIETIC STEM CELLS
Cells entering and exiting the bone marrow do so through a series of
molecular interactions. Circulating stem cells (through CD162 and
CD44) engage the lectins (carbohydrate binding proteins) P- and
E-selectin on the endothelial surface to slow the movement of the
cells to a rolling phenotype. Stem cell integrins are then activated
and accomplish firm adhesion between the stem cell and vessel wall,
with a particularly important role for stem cell VCAM-1 engaging
endothelial VLA-4. The chemokine CXCL12 (SDF1) interacting
with stem cell CXCR4 receptors and ionic calcium interacting with the
calcium-sensing receptor are important in the process of stem cells
getting from the circulation to where they engraft in the bone marrow.
This is particularly true in the developmental move from fetal liver to
bone marrow.
In the adult, the role for CXCR4 is in retention of stem cells in the
bone marrow as well as getting them there. Interrupting that retention
process through specific molecular blockers of the CXCR4/CXCL12
interaction, cleavage of CXCL12, or downregulation of the CXCR4
receptor can result in the release of stem cells into the circulation. This
process is an increasingly important aspect of recovering stem cells for
therapeutic use as it has permitted the harvesting process to be done
by leukapheresis rather than bone marrow punctures in the operating
room. Granulocyte colony-stimulating factor and plerixafor, a mac­
rocyclic compound that can block CXCR4, are both used clinically to
mobilize marrow hematopoietic stem cells for transplant.
■
■HEMATOPOIETIC STEM CELL
MICROENVIRONMENT
The concept of a specialized microenvironment, or stem cell niche, was
first proposed to explain why cells derived from the bone marrow of
one animal could be used in transplantation and again be found in the
bone marrow of the recipient. This niche is more than just a housing
site for stem cells, however. It is an anatomic location where regula­
tory signals are provided that allow the stem cells to thrive, to expand
if needed, and to provide varying amounts of descendant daughter
cells. In addition, unregulated growth of stem cells may be problematic
based on their undifferentiated state and self-renewal capacity. Thus,
the niche also regulates the number of stem cells produced. In this
manner, the niche has the dual function of serving as a site of nurture
but imposing limits for stem cells: in effect, acting as both a nutritive
and constraining home.
CHAPTER 101
Hematopoietic Stem Cells
The niche for blood stem cells changes with each of the sites of
blood production during development, but for most of human life, it is
located in the bone marrow. Within the bone marrow, the perivascular
space particularly in regions of trabecular bone serves as a niche. The
mesenchymal and endothelial cells of the marrow microvessels pro­
duce kit ligand and CXCL12, both known to be important for hema­
topoietic stem cells. Other cell types, such as sympathetic neurons,
nonmyelinating Schwann cells, macrophages, megakaryocytes, osteo­
clasts, and osteoblasts, have been shown to regulate stem cells, some by
direct and others by indirect effects. Extracellular matrix proteins like
osteopontin and heparan sulfates also affect stem cell function. The
endosteal region appears to be particularly important for transplanted
cells, in part because many of the mesenchymal cells and sinusoidal
blood vessels of the central marrow are disrupted by the conditioning
regimens used to prepare a patient for transplantation. The function­
ing of the niche as a supportive context for stem cells is of obvious
importance for maintaining hematopoiesis and in transplantation. An
active area of study involves determining whether the niche is altered
in disease as experimental models have shown that mutations in niche
cells can lead to myeloid malignancies.
■
■EXCESS CAPACITY OF HEMATOPOIETIC STEM
CELLS
In the absence of disease, one never runs out of hematopoietic stem
cells. Indeed, serial transplantation studies in mice suggest that suf­
ficient stem cells are present to reconstitute several animals in succes­
sion, with each animal having normal blood cell production. The fact
that allogeneic stem cell transplant recipients also never run out of
blood cells over decades argues that even the limiting numbers of stem
cells provided to them are sufficient. How stem cells respond to dif­
ferent conditions to increase or decrease their mature cell production
remains poorly understood. Clearly, negative feedback mechanisms
affect the level of production of most of the cells, leading to the normal
tightly regulated blood cell counts. However, many of the regulatory
mechanisms that govern production of more mature progenitor cells
do not apply or apply differently to stem cells. Similarly, most of the
molecules shown to be able to change the size of the stem cell pool
have little effect on more mature blood cells. For example, the growth
factor erythropoietin, which stimulates red blood cell production
from precursor cells, has no effect on stem cells. Similarly, granulocyte
colony-stimulating factor drives the rapid proliferation of granulocyte
precursors but has little or no effect on the cell cycling of stem cells.
Rather, it changes the location of stem cells by indirect means, altering
molecules such as CXCL12 that tether stem cells to their niche. Mole­
cules shown to be important for altering the proliferation, self-renewal,
or survival of stem cells, such as cyclin-dependent kinase inhibitors,
transcription factors like Bmi-1, microRNA-processing enzymes like
Dicer, or even metabolic regulators like pyruvate kinase isoforms,
have little or different effects on progenitor cells. Hematopoietic stem
cells have governing mechanisms that are distinct from the cells they
generate.
■
■HEMATOPOIETIC STEM CELL DIFFERENTIATION
Hematopoietic stem cells sit at the base of a branching hierarchy of
cells culminating in the many mature cell types that compose the
blood and immune system (Fig. 101-2). The maturation steps leading
to terminally differentiated and functional blood cells take place both
as a consequence of intrinsic changes in gene expression and external,
Stem Cells
Progenitor Cells
Lineage Committed
PART 4
Oncology and Hematology
LEF1, E2A,
EBF, PAX-5
Common
Lymphoid
Progenitor
B-Cell
Progenitor
IL7
NOTCH1
IL7
T/NK Cell
Progenitor
IKAROS
PU1
IL7
Lymphomyeloid
Potent
Progenitor
Hematopoietic
stem cell
cMyb
Multipotent
Progenitor
Hox, Pbx1,
SCL, GATA2,
NOTCH
Granulocyte
Monocyte
Progenitor
SCF
TPO
GM-CSF
GATA1, FOG
NF-E2, SCL
Rbtn2
Common
Myeloid
Progenitor
IL3, SCF
TPO
Megakaryocyte
Progenitor
Megakaryocyte
Erythroid
Progenitor
FIGURE 101-2  Hierarchy of hematopoietic differentiation. Stem cells are multipotent cells that are the source of all descendant cells and have the capacity to provide
either long-term (measured in years) or short-term (measured in months) cell production. Progenitor cells have a more limited spectrum of cells they can produce and are
generally a shorter-lived, highly proliferative population also known as transient amplifying cells. Precursor cells are cells committed to a single blood cell lineage but with
a continued ability to proliferate; they do not have all the features of a fully mature cell. Mature cells are the terminally differentiated product of the differentiation process
and are the effector cells of specific activities of the blood and immune system. Progress through the pathways is mediated by alterations in gene expression. The regulation
of the differentiation by soluble factors and cell-cell communications within the bone marrow niche are still being defined. The transcription factors that characterize
particular cell transitions are illustrated on the arrows; the soluble factors that contribute to the differentiation process are in blue. This picture is a simplification of the
process. Active research is revealing multiple discrete cell types in the maturation of B cells and T cells and has identified cells that are biased toward one lineage or
another (rather than uncommitted) in their differentiation. EPO, erythropoietin; RBC, red blood cell; SCF, stem cell factor; TPO, thrombopoietin.
niche-directed or cytokine-directed changes in the cells. Our knowl­
edge of the details remains incomplete. As stem cells mature to pro­
genitors, precursors, and, finally, mature effector cells, they undergo a
series of functional changes. These include the acquisition of functions
defining mature blood cells, such as phagocytic capacity or hemoglobin
synthesis. They also include the progressive loss of plasticity (i.e., the
ability to become other cell types). For example, some myeloid progeni­
tors can make all cells in the myeloid series but none in the lymphoid
series. As common myeloid progenitors mature, they become precur­
sors for either monocytes and granulocytes or erythrocytes and mega­
karyocytes, but not both. Some amount of reversibility of this process
may exist early in the differentiation cascade, but that is lost beyond a
distinct stage in normal physiologic conditions.
As cells differentiate, they may also lose proliferative capacity
(Fig. 101-3). Mature granulocytes are incapable of proliferation and
only increase in number by increased production from precursors. The
exceptions to the rule are some tissue-resident macrophages, which
appear capable of proliferation, and lymphoid cells. Lymphoid cells
retain the capacity to proliferate but have linked their proliferation to
the recognition of particular proteins or peptides by specific antigen
Mature Cells
Precursors
Aiolos,
PAX-5, AML-1
B Cell
IL4
T-Cell
Progenitor
IKAROS,
NOTCH,CBF1
E2A, NOTCH1,
GATA3
T Cell
IL2
IL7
NOTCH1
Id2, Ets-1
IL7
NK Cell
IL15
NK Cell
Progenitor
Plasmacytoid
Dendritic Cell
FLT-3 Ligand
Monocytoid
Dendritic Cell
RelB, ICSBP, ld2
FLT-3 Ligand
Egn1, Myb
Monocyte
M-CSF
Monocyte
Progenitor
Granulocyte
C/EBPα
G-CSF
Basophil
IL3, SCF
Granulocyte
Progenitor
Mast Cell
C/EBPε
IL5
Eosinophil
Erythrocyte
Progenitor
GATA1
RBCs
EPO
EPO
Fli-1
AML-1
TPO
Platelets
TPO
Stem
Precursor
Progenitor
Mature
Differentiation state
More
Less
Self-renewal ability
Proliferation activity
Lymphoid
exception
(memory B
and T cells)
FIGURE 101-3  Relative function of cells in the hematopoietic hierarchy. The boxes
represent distinct functional features of cells in the myeloid (upper box) versus
lymphoid (lower box) lineages.
receptors on their surface. Like many tissues with short-lived mature
cells such as the skin and intestine, blood cell proliferation is largely
accomplished by a more immature progenitor population. In general,
cells within the highly proliferative progenitor cell compartment are
also relatively short-lived, making their way through the differentia­
tion process in a defined molecular program involving the sequential
activation of particular sets of genes. For any particular cell type, the
differentiation program is difficult to speed up. The time it takes for
hematopoietic progenitors to become mature cells is ~10–14 days in
humans, evident clinically by the interval between cytotoxic chemo­
therapy and blood count recovery in patients.
Although hematopoietic stem cells are generally thought to have the
capacity to form all cells of the blood, individual stem cells are hetero­
geneous in their differentiation potential. That is, some stem cells are
“biased” to become mature cells of a particular type. In addition, indi­
vidual stem cells may respond differently to proliferation or cell death
signals. Therefore, the stem cell population is an aggregate of cells with
somewhat distinctive properties that have the collective characteristics
ascribed to hematopoietic stem cells.
■
■SELF-RENEWAL AND CLONAL DYNAMICS
Self-renewal is the ability to divide while preserving an undifferentiated
state. This stem cell characteristic is generally not seen in progenitor or
mature cells where proliferation is coupled with progressive differen­
tiation. Stem cells being able to asymmetrically divide, such that one
daughter cell is the product of self-renewal and the other enters into
the differentiating progenitor pool, enables the hematopoietic system
to have a modestly sized pool of stem cells yet produce seven orders of
magnitude greater numbers of mature blood cells each day.
Self-renewal has its risks, however. Genetic mutations that occur in
a stem cell will durably persist in stem cells because of self-renewal.
In contrast, mutations in progenitors will largely be lost as the cells
terminally differentiate and die. It is the stem cell then that has greater
potential to accumulate genetic mutations, a setting that can lead to
cancer. Countering this risk is the small number of stem cells, the
radioprotective environment of their bone localized niche, and the
relative quiescence of stem cells.
Stem cells have distinctive cell cycle regulation. Some are deeply qui­
escent, serving as a deep reserve, whereas others are more proliferative
and replenish the short-lived progenitor population. Hematopoietic
stem cells are generally cytokine-resistant, remaining dormant even
when cytokines drive bone marrow progenitors to proliferation rates
measured in hours. Stem cells, in contrast, are thought to divide at far
longer intervals, measured in months to years, for the most quiescent
cells. This quiescence is difficult to overcome in vitro, limiting the abil­
ity to effectively expand human hematopoietic stem cells. The process
may be controlled by particularly high levels of cyclin-dependent
kinase inhibitors like p57 or CDKN1c that restrict entry of stem cells
into the cell cycle by blocking the G1-S transition. Exogenous signals
from the niche also appear to enforce quiescence, including angio­
genin, interleukin 18, and perhaps angiopoietin 1.
Individual stem cells may vary in their proliferation and self-renewal
features. This can lead to distortions in the representation of any given
clone of stem cells, a feature commonly seen with aging and often
associated with acquired somatic mutations. Hematopoietic stem cells
are estimated to acquire 17 somatic mutations with each year of life
based on deep sequencing studies. Some of these appear to provide a
fitness advantage to the stem cell as the presence of mutated or “variant”
alleles contributing to >1% of blood cells is virtually uniform by age 70.
Furthermore, it is estimated that 10–20 such clones exist in individuals
by 70, and in aggregate, those clones provide between 30 and 60% of
the blood cells. Thus, the diversity of active stem cell clones declines
with age with a likely accompanying reduced diversity of functions that
each clone provides. Whether this contributes to immune alterations or
other aspects of aging is to be determined. However, some expanded
clones are associated with “driver” mutations observed in myelodys­
plasia and myeloid leukemias. These clones do have a low frequency
of progression to overt neoplastic disease, and at least one of them,
an inactivating mutation of TET2, can also increase adverse outcomes
from a number of chronic inflammatory conditions.
CHAPTER 101
The most common mutations associated with clonal hematopoiesis
are of epigenetic regulatory genes. For example, inactivating mutations
of the DNA methyl transferase DNMT3a or the dioxygenase involved
in DNA demethylation, TET2, are commonly found, as are mutations
in ASXL1, a member of the polycomb family of genes whose products
alter chromatin structure, a high-order DNA organization that affects
transcription. Therefore, epigenetic control appears to be critical for
homeostasis of the hematopoietic stem cell pool and constraining the
outgrowth of potentially pathogenic stem cell clones.
Hematopoietic Stem Cells
THE RELATIONSHIP OF STEM CELLS TO
CANCER
Some cancers have been shown to have a cellular hierarchy similar to
normal tissues, with stem-like cells having the capacity to self-renew
and differentiate. These stem-like cells can be experimentally trans­
planted into immunodeficient animals and initiate a new cancer. It
is hypothesized that these stem-like cells may be the basis for disease
relapse after therapy as they have distinctive molecular features from
other cells in the cancer that may render them less vulnerable to
therapies. Myeloid leukemias have been experimentally shown to be
consistent with this model. Focusing therapies on the stem-like cells
as opposed to the bulk population of the cancer cells as a means to
improve cure rates is an active area of investigation.
Given that hematopoietic stem cells can accumulate genetic muta­
tions by virtue of their self-renewal, it is logically appealing to regard
them as the likely cell source of leukemias. Experimental testing of
this hypothesis has shown that stem cells are more likely to result in
malignancy following an oncogenic mutation. However, some more
mature populations with less well-defined self-renewal capability can
also be transformed to malignancy. Therefore, self-renewal may also
be acquired by mutation, and cancer stem-like cells need not have
originated in normal stem cells.
STEM CELLS AS TARGETS OF GENE
THERAPY OR GENE EDITING
The hematopoietic stem cell is the ideal cell target for genetic therapies
intended to durably change the genome of blood cells. Because stem
cells can persist for the lifetime of an individual, genetically modify­
ing them can provide curative therapies for genetic disorders such as
hemoglobinopathies or congenital immunodeficiencies. The extensive
cell proliferation with limited or no self-renewal among progenitor
populations makes them less able to provide durable benefit if they
are genetically modified. Therefore, modification of stem cells is criti­
cal and requires integration of the genetic therapy into the host cell’s

33 - 103 Disorders of Hemoglobin
103 Disorders of Hemoglobin
■
■TREATMENT
Treatment of the underlying disorder controls anemia of inflammation,
as shown by the effect of anti-IL-6 agents in Castleman’s disease and
rheumatoid arthritis. Standard treatment of anemia in CKD is based on
ESAs (Chap. 322) with a target hemoglobin established at <11.5 g/dL to
avoid cardiovascular complications. Since iron deficiency leads to ESA
hyporesponsiveness, iron supplementation is usually required, mostly
parenterally, because in advanced CKD high hepcidin levels prevent
iron absorption. Intravenous iron is administered at high or refracted
doses, ideally to maintain transferrin saturation at 30–40% and ferritin
between 200 and 700 μg/L. Iron supplementation may lower the dose of
ESA required to maintain the hemoglobin target. An oral alternative to
intravenous iron is ferric citrate, which, binding intestinal phosphate,
provides iron while reducing phosphate levels. Prolyl hydroxylase
inhibitors that stabilize HIF-2α have been approved in some coun­
tries with the aim of replacing with a single oral drug both ESA and
iron, since HIF upregulates EPO production as well as duodenal iron
absorption. Although these novel antianemic drugs are efficacious,
safety concerns still exist for their long-term use.
Intravenous iron can be used in cancer-related anemia to reduce
the need of transfusions, especially with ferritin <100 μg/L and before
elective surgery. ESAs are used in low-risk myelodysplastic syndromes
and in patients receiving chemotherapy notably when cancer is deemed
uncurable. Intravenous iron supplementation is currently recommended
in CHF patients with either ferritin <100 μg/L or transferrin saturation
<20% with ferritin of 100–300 μg/L. Nonetheless, there is still some
uncertainty as to whether this represents the best definition of iron defi­
ciency in CHF. Novel drugs targeting the hepcidin-ferroportin axis to
counteract iron maldistribution are under investigation.
Blood transfusions remain the therapeutic option for severe ane­
mia in the ICU, with guidelines increasingly recommending restric­
tive hemoglobin thresholds (7–8 g/dL) for hemodynamically stable
patients. Intravenous iron is proposed to minimize the use of trans­
fusions, with some studies reporting improved clinical outcomes,
although the risk of infections and hypophosphatemia are of concern
in these fragile patients.
ANEMIA OF AGING
Prevalence of anemia in the elderly is ~10% at the age of 65 years, 25%
in people >85 years, and 50% in those affected by multimorbidity, hos­
pitalized, or institutionalized. Anemia is typically mild (hemoglobin
11–12 g/dL) and multifactorial, and its impact is frequently underesti­
mated. Mounting evidence strengthens its negative influence on quality
of life, muscle weakness, and the risk of falls and fractures, as well as its
independent association with mortality. The adverse effects of anemia
are seen in black patients at hemoglobin levels ~1 g/dL lower than in
white patients.
Approximately one-third of the cases are estimated to be due to
nutritional causes, especially iron deficiency; one-third are due to
inflammation, including CKD; and one-third remain without a detect­
able origin and are defined “unexplained anemia of aging.” Age-related
decline in testosterone levels in males, stem cell exhaustion, and EPO
reduction might contribute. Absolute iron deficiency is common, due
to poor dietary iron intake, impaired absorption by chronic gastritis, or
the use of proton pump inhibitors and blood losses. A gastrointestinal
malignancy should always be ruled out in anemic elderly patients, but
chronic bleeding may also result from nonmalignant intestinal lesions
such as angiodysplasias and the use of antithrombotic drugs for com­
mon disorders such as atrial fibrillation. A recent study has shown that
100 mg of daily aspirin given for primary cardiovascular prevention in
elderly subjects was associated with a 20% higher risk of anemia and
iron deficiency as compared to placebo. The proposed ferritin cutoff
for iron deficiency (45–70 μg/L) is higher than in younger patients.
Treatment of iron deficiency may mitigate the negative prognostic
implications of anemia.
Functional iron deficiency due to overt or subclinical inflam­
mation often contributes, complicating the laboratory diagnosis.
Traditionally “bone marrow senescence,” now known as clonal hema­
topoiesis of indeterminate potential (CHIP), is present in >10% of
otherwise-healthy individuals aged 70 years and increases sharply to
60% in the eighties. CHIP is associated with a chronic low-grade
inflammatory status that worsens anemia and cardiovascular risk.
Patients should be followed up for the risk of developing myelodys­
plastic syndromes (Chap. 107). The unexplained anemia of aging is
usually characterized by an EPO level that is lower than expected for
the degree of anemia. EPO can increase the hemoglobin level, but it is
unclear whether that change has an influence on the hospitalization,
frailty, and mortality risks associated with the anemia.
■
■FURTHER READING
Camaschella C: Iron deficiency. Blood 133:30, 2019.
Cleland JFG et al: Redefining both iron deficiency and anaemia in
cardiovascular disease. Eur Heart J 44:1992, 2023.
Galy B et al: Mechanisms controlling cellular and systemic iron
homeostasis. Nat Rev Mol Cell Biol 25:133, 2024.
Ganz T: Anemia of Inflammation. N Engl J Med 381:1148, 2019.
GBD 2021 Anaemia Collaborators: Prevalence, years lived with
disability, and trends in anaemia burden by severity and cause,
1990-2021: Findings from the Global Burden of Disease Study 2021.
Lancet Haematol 10:e713, 2023.
Macdougall I: Anaemia in CKD: Treatment standard. Nephrol Dial
CHAPTER 103
Transplant 26:770, 2024.
Oyedeji CI et al: How I treat anemia in older adults. Blood 143:205,
2024.
Pasricha SR et al: Iron deficiency. Lancet 397:233, 2021.
Patel KV et al: Haemoglobin concentration and the risk of death in
older adults: Differences by race/ethnicity in the NHANES III follow-up.
Br J Haematol 145:514, 2009.
Van Doren L, Auerbach M: IV iron formulations and use in adults.
Disorders of Hemoglobin
Hematol Am Soc Hematol Educ Program 1:622, 2023.
Weyand AC et al: Prevalence of iron deficiency and iron-deficiency
anemia in US females aged 12-21 years, 2003-2020. JAMA 329:2191,
2023.
Vijay G. Sankaran, Martin H. Steinberg
Disorders of Hemoglobin
Hemoglobinopathies result from changes in the amino acid sequence
of globin; in thalassemia, synthesis of normal globin is insufficient.
Together the disorders of hemoglobin compose the most common
Mendelian genetic diseases. In addition, they are responsible for most
instances of hemolytic anemia. Sickle cell disease and the hemoglobin
E (HbE)–associated syndromes are the most prevalent hemoglobin­
opathies; β and α thalassemia are the most prevalent thalassemias.
In addition to these common disorders of hemoglobin, rare globin
mutations cause hemoglobin instability, cause increased or decreased
affinity of hemoglobin for oxygen (O2), and allow spontaneous oxida­
tion of hemoglobin, reducing its O2 transport. O2 transport can also be
reduced by exposure to carbon monoxide (CO) and extrinsic oxidizing
agents (Table 103-1).
HEMOGLOBIN
Easy access to erythrocytes to study hemoglobin structure and func­
tion, reticulocytes to examine hemoglobin biosynthesis, and leukocyte
DNA to define the mutations of hemoglobin, with the availability of
hematopoietic stem and progenitor cells from blood and bone mar­
row, has placed hemoglobin disorders in the forefront of molecular
medicine. The biology of hemoglobin provides the background for
understanding the pathophysiology of its many genetic and acquired
disorders and approaches to their treatment.
TABLE 103-1  Disorders of Hemoglobin
I.	 Hemoglobinopathies—hemoglobin variants with amino acid sequence
variants that alter the physical, chemical, or functional properties of
hemoglobin
A.	 Common variants with unusual properties
HbS—polymerization
HbE—reduced biosynthesis
HbC—hemoglobin-membrane interaction
B.	 Altered oxygen affinity
High affinity—erythrocytosis
Low affinity—cyanosis, anemia
C.	 Hemoglobins that oxidize readily
Unstable hemoglobins—hemolytic anemia, jaundice
M hemoglobins—methemoglobinemia, cyanosis
II.	 Thalassemias—defective biosynthesis of globin chains
A.	 α Thalassemias
B.	 β Thalassemias
C.	 Complex thalassemias
III.	 Hereditary persistence of fetal hemoglobin—persistence of higher than
normal levels of HbF into adult life
A.	 Deletions within the HBB cluster—15–30% HbF in heterozygotes,
pancellular HbF
B.	 Point mutations in HBG2/1 promoters—5–30% HbF in heterozygotes;
PART 4
Oncology and Hematology
pancellular or heterocellular HbF
IV.	 Acquired hemoglobinopathies
A.	 Methemoglobin due to toxic exposures
B.	 Sulfhemoglobin due to toxic exposures
C.	 Carboxyhemoglobin
D.	 HbH in erythroleukemia
E.	 Elevated HbF in myelodysplasia
■
■DEVELOPMENTAL BIOLOGY
Successive waves of erythropoiesis direct the synthesis of different
hemoglobin molecules that result from sequential activation and
silencing of globin genes (Fig. 103-1). Hemoglobin is a tetramer of
two pairs of unlike globin polypeptide chains, each containing a tet­
rapyrrole heme group. O2 binds to heme as erythrocytes traverse the
lungs and is released in the tissues. Heme is nestled within a protective
pocket of each globin subunit.
HBB at
11p15.5
HS5 4 3 2 1
LCR
HBA at
16pter
HbA
HS R1-R4
MCS
B
A
FIGURE 103-1  Globin gene clusters and their hemoglobin products during gestation. A. The order of globin genes in the β- and α-globin gene clusters along with their
upstream enhancers, the β-globin locus control region (LCR) and α-globin multispecies conserved sequences (MCS), which contain critical regulatory elements. Normal
hemoglobin tetramers contain two α-globin chains and two non-α-globin chains. In the example shown, this is adult HbA. The β-globin gene cluster contains an embryonic
ε-globin gene (HBE), two nearly identical fetal γ-globin genes (HBG2, HBG1), a major adult β-globin gene (HBB), and a minor adult δ-globin gene (HBD). The α-globin gene
cluster contains an embryonic ζ-globin gene (HBZ) and duplicated α-globin genes (HBA2, HBA1) coding for identical proteins. Embryonic hemoglobins include Gower I
(ζ2ε2), Gower II (α2ε2), Portland I (ζ2γ2), and Portland II (ζ2β2). Fetal hemoglobin (HbF, α2γ2) production begins at 6–8 weeks’ gestation, peaks during mid-gestation, then falls to
<1% of total hemoglobin during the first 6 months of extrauterine life. B. Sites of erythropoiesis and globin synthesized from the yolk sac and the early embryo (months 1–3),
the fetus (months 3–9), after delivery (months 9–12), and afterward (adult).
■
■GLOBIN GENE CLUSTERS
Globin is encoded in two nonallelic gene clusters. The β-globin gene
cluster is on chromosome 11; the α-globin gene cluster is on chromo­
some 16 (Fig. 103-1). Tetramers of α-like and β-like globins form
embryonic, fetal, and adult hemoglobins. Fetal hemoglobin (HbF, α2γ2)
production begins at 6–8 weeks’ gestation, peaks during mid-gestation,
then falls to <1% of total hemoglobin during the first 6 months of
extrauterine life. Adult hemoglobin A (HbA, α2β2) production follows
a pattern reciprocal to that of HbF. The hemoglobin composition of
normal adults is >95% HbA, ~1% HbF, and 2–3% HbA2 (α2δ2). HbF
and HbA2 are not functionally important in normal adults because of
their low concentrations. Measuring their levels can provide helpful
diagnostic clues for thalassemia and some hemoglobinopathies. Hemo­
globin is subject to posttranslational modifications. Most important
clinically is the nonenzymatic glycosylation of HbA forming the adduct
HbA1c, which is useful in the management of diabetes mellitus.
■
■HEMOGLOBIN STRUCTURE
All globin polypeptides have similar but not identical primary struc­
tures. α-Globins contain 141 amino acids, and β-like globins have
146 amino acids. This primary structure dictates, according to the
constraints of protein folding, the secondary structure of globin into
α-helical sections joined by small nonhelical stretches. Each globin
chain folds into a tertiary conformation known as the globin fold,
whereby charged amino acid residues face the exterior of the molecules
while uncharged residues face the hydrophobic interior. The ironcontaining tetrapyrrole heme moiety is protected from oxidation and
located between two of the helical segments; O2 loading and unload­
ing occur when heme iron is in its reduced ferrous form. Globin gene
mutations affecting critical heme-binding amino acid residues allow
iron to be oxidized, forming methemoglobin, which has high O2 affin­
ity and does not release O2 in tissues. Dimers of α- and non-α-globin
chains reversibly assemble into the tetrameric quaternary structure.
■
■HEMOGLOBIN FUNCTION
Hemoglobin transports O2 from lungs to tissues and carbon dioxide
(CO2) from tissues to lungs. As a nitrate reductase, it releases nitric
oxide (NO) from nitrite to promote vasodilation. Oxygen binding is
defined by the hemoglobin-O2 dissociation curve. P50 is a point on this
sigmoidal curve that indicates the partial pressure of O2 where hemo­
globin is half saturated (Fig. 103-2). Normal P50 is ~26 mmHg; low P50
indicates that hemoglobin has high O2 affinity, decreasing O2 delivery
Yolk sac
Spleen
Bone marrow
Liver
Globin synthesis (%)
HBG1
HBG2
HBB
HBE1
HBD
Adult
pH
Less
O2
delivered
Oxyhemoglobin
2,3-BPG
T°
Percent saturation of hemoglobin
pH
More
O2
delivered
2,3-BPG
P50
T°
Deoxyhemoglobin
Tissue PO2 (mmHg)
FIGURE 103-2  Hemoglobin-oxygen dissociation curve. The P50 is influenced by the
binding of 2,3-bisphosphoglycerate (2,3-BPG), a product of glycolysis, in the central
cavity of hemoglobin, pH, and temperature. The hemoglobin tetramer can bind up
to four molecules of oxygen (O2) in the iron-containing sites of the heme molecules.
As O2 is bound, 2,3-BPG and carbon dioxide (CO2) are expelled. Salt bridges are
broken, and each of the globin molecules changes its conformation to facilitate O2
binding. O2 release to the tissues is the reverse process, with salt bridges being
formed and 2,3-BPG and CO2 bound. Deoxyhemoglobin does not bind O2 efficiently
until the cell returns to conditions of higher pH, the most important modulator of O2
affinity (Bohr effect). When acid is produced in the tissues, the dissociation curve
shifts to the right, facilitating O2 release and CO2 binding. Alkalosis has the opposite
effect, reducing O2 delivery.
to tissues; high P50 indicates that hemoglobin has low O2 affinity, releas­
ing more O2 to tissues. The conformation of hemoglobin fully saturated
with O2 is known as the R or relaxed state; desaturated hemoglobin is
in the T or tense state. The transition between T and R states occurs
when two or three O2 molecules are bound. Cooperativity describes
the progressively more rapid binding of O2 once the first molecule is
bound. Hemoglobin variants that decrease P50 are characterized by
isolated erythrocytosis as compensation for hypoxia; variants with
increased P50 sometimes are accompanied by cyanosis and anemia as
hemoglobin becomes unsaturated and O2 delivery is enhanced. Muta­
tions of residues critical for heme binding, R-T transitions, or tetramer
stability cause hemoglobinopathies characterized by hemolytic anemia,
methemoglobinemia, erythrocytosis and cyanosis.
■
■GLOBIN GENE SWITCHING
The sequential activation and inactivation of globin genes during
development is called “hemoglobin switching.” Transcription factors
along with epigenetic elements, such as DNA and histone methyltrans­
ferases and demethylases, interact with enhancers “upstream” of the
gene clusters that contact globin gene promoters, silencing the embry­
onic and fetal genes. Developmental factors such as RNA-binding fac­
tors and microRNAs also impact hemoglobin switching.
β-Globin Gene Switching 
HbF reactivation by drugs and gene
therapy is a prime therapeutic goal for treating sickle cell disease and β
thalassemia, meriting a discussion of the controls of HbF gene silenc­
ing. An upstream enhancer called the β-globin locus control region
(LCR) binds erythroid-specific and ubiquitous transcription factors.
The LCR interacts directly with globin gene promoters; transcription
factors that silence and activate genes also interact with elements of
the globin genes. Competition among the β-like genes for the LCR
and autonomous silencing of the embryonic and fetal globin genes
depends on transcription factors. Silencing, first of the embryonic
gene HBE and then of the two fetal genes, HBG2 and HBG1, favors the
interaction of the LCR with HBB allowing its expression (Fig. 103-1).
The transcription factors BCL11A (2p16) and ZBTB7A (19p13) are
the major repressors of HbF gene expression. BCL11A, a zinc finger
protein that represses HbF genes, binds TGACCA motifs, the most
important at position –115 in the promoter of each γ-globin gene.
ZBTB7A binds 85 nucleotides upstream of these BCL11A binding
sites. Mutations in these binding sites abolish the normal silencing
of the HbF genes, leading to one type of the benign condition called
hereditary persistence of fetal hemoglobin (HPFH). When binding of
either BCL11A or ZBTB7A is disrupted, HBG2 and HBG1 are dere­
pressed. BCL11A single nucleotide variants (SNVs) are common and
are thought to underlie a large portion of the interindividual variation
in HbF levels. Disruption of the BCL11A regulatory elements or the
promotor binding sites for BCL11A and other repressive factors by
gene editing in patient hematopoietic stem cells using CRISPR/Cas
leads to 30–50% HbF with possible “cure” of sickle cell disease and β
thalassemia, with the former strategy receiving U.S. Food and Drug
Administration (FDA) approval for both conditions.
`-Globin Gene Switching 
A less complex switch takes place in
the α-globin gene cluster. A regulatory locus of four elements termed
R1–R4 is present within introns of the gene NPRL3 that is upstream
of HBA2. R1–R4 are critical for α-globin gene expression, as dem­
onstrated by natural deletions causing thalassemia. A developmental
switch from embryonic ζ- to adult α-globin gene expression occurs at
about 6 weeks’ gestation.
Modulation of HbF Level and Haplotypes of the a-Globin
Gene Cluster 
Variations in three quantitative trait loci (QTL),
BCL11A, MYB (6q23), and a locus linked to the HBB cluster (11p15),
are associated with HbF variation among normal individuals and
patients with sickle cell anemia and β thalassemia. The MYB gene is
essential for hematopoiesis and erythroid differentiation. MYB inhibits
HbF expression directly by activation of KLF1 and other repressors
and indirectly through alteration of the kinetics of erythroid differ­
entiation. The third QTL is marked by a common variant 158 nucleo­
tides upstream of the transcription start site of HBG2. Five common
haplotypes associated with the HBB cluster have been defined by its
SNVs. Sickle cell anemia patients with the Senegal and Arab-Indian
HbS gene-associated haplotypes have the common –158 C-T variant
in the HBG2 promoter. They have higher HbF levels than patients with
Benin, Bantu, and Cameroon haplotypes. When young, they might
have a milder clinical course.
CHAPTER 103
Disorders of Hemoglobin
GENERAL ASPECTS OF HEMOGLOBIN
DIAGNOSIS
α-Globin gene mutations are expressed in the embryo and fetus and
persist throughout life; HbF mutations are expressed in the fetus and
in the first months of life, vanishing from notice afterward; δ-globin
gene mutations are innocuous and usually not detected; β-globin gene
mutations can become clinically apparent after the synthesis of HbF
dwindles to stable adult levels.
With rare exceptions, all disorders of hemoglobin are autosomal
recessive or co-dominant disorders; a family history, usually of ane­
mia, a common feature of most symptomatic hemoglobinopathies and
thalassemias, is often present. In addition to pallor and jaundice, sple­
nomegaly is often present. A small number of laboratory tests can con­
firm the diagnosis starting with a complete blood count that includes
a reticulocyte count with a careful review of a peripheral blood film.
A sustained increase in reticulocyte count indicates the presence of
hemolytic anemia. Hemoglobin fractionation by high-performance
liquid chromatography (HPLC) or capillary electrophoresis, especially
when, in addition to the index case, family members are available for
study, is often sufficient to confirm a diagnosis at the level of hemoglo­
bin phenotype. DNA sequencing of the globin genes allows definitive
diagnosis; available from excellent reference laboratories, it is a prereq­
uisite for genetic counseling.
Sickle cell disease and β thalassemia are chronic hemolytic ane­
mias sharing hemolysis-related complications like venous thrombosis,
leg ulcers, and pulmonary hypertension. Differences are that only
deoxyHbS polymerizes, while ineffective erythropoiesis is the key
pathophysiologic feature of β thalassemia. Both diseases are “cured” by
successful allogeneic hematopoietic stem cell transplantation and gene
therapy as discussed below.
SICKLE CELL DISEASE
Sickle cell disease is a clinical and hematologic phenotype caused by an
assortment of genotypes (Table 103-2). Sickle cell anemia, defined as
homozygosity for the sickle hemoglobin mutation (α2βS
2; glutamic acid
[E] 7 valine [V] GAG-GTG), is the most common of these genotypes,
followed by HbSC disease or compound heterozygosity for HbS and
HbC (α2βC
2; E 7 lysine [K] GAG-AAG) genes. Many different thalas­
semia mutations contribute to the HbS-β thalassemias. Compound
heterozygous genotypes are less common than HbS homozygotes. HbS
has been described in compound heterozygotes with many other vari­
ant hemoglobins. Few of these genotypes, other than HbSOArab, HbSE,
and HbSDPunjab are symptomatic.
■
■ORIGIN, SPREAD, AND EPIDEMIOLOGY
HbS originated in Africa between 7000 and 22,000 years ago, reaching
high frequencies because of the increased genetic fitness of heterozy­
gotes under selective pressure from Plasmodium falciparum. HbS gene
haplotypes have a loose association with the severity of disease because
each haplotype has a different average level of HbF. In some regions
of Africa, India, and the Middle East, nearly half the population have
sickle cell trait. Nigeria alone has ~150,000 newborns each year with
sickle cell anemia, about one-third of the world’s total newborns; most
die before age 5. Coerced and free population movement has spread
the HbS gene throughout the world. The HbS carrier, or sickle cell
trait, prevalence is 2–15% in emigrant populations; ~100,000 patients
in the United States have sickle cell disease. In the United States, death
in childhood is rare; the median age of death in patients with sickle cell
anemia is in the fifth or sixth decade.
PART 4
Oncology and Hematology
■
■PATHOPHYSIOLOGY
Pathophysiologic features of sickle cell disease are summarized in
Fig. 103-3. HbS is physiologically like HbA in most respects except
it polymerizes when deoxygenated. Contacts between one of the
TABLE 103-2  Common Sickle Hemoglobinopathies
GENOTYPE
CLINICAL ABNORMALITIES
Sickle cell trait
(HbAS)
8% of African Americans; hematuria, papillary necrosis, hyposthenuria,
increased incidence of chronic kidney disease; 2–4 times increased VTE risk;?
stroke; splenic infarction at altitude; rhabdomyolysis
Sickle cell anemia
(HbSS)
Vasoocclusion related: pain, acute chest syndrome, osteonecrosis,
splenic infarction
Hemolysis related: stroke, pulmonary and systemic vasculopathy, nephropathy,
leg ulceration gallstones, priapism
HbS-β0 thalassemia
Rate of complications similar to HbSS
80–100 (8–11)/60–85
HbS: >75
HbF: 2–15
HbA2: 5–6
HbS-β+ thalassemia
Rate of complications about half the rate of HbSS depending on percent HbA
100–140 (10–14)/70–80
HbS: 60–90
HbA: 5–40
HbF: 1–10
HbA2: 5–6
Hemoglobin SC
disease (HbSC)
Nearly asymptomatic to disease as severe as HbSS; about half the rate of
complications as HbSS. Increased risk of retinopathy
HbSE
Resembles clinically HbS-β+ thalassemia; symptoms delayed; often
Asian/Indian ancestry
HbSS-α thalassemia
Present in 30% of HbSS; phenocopies HbS-β0 thalassemia because of
microcytosis and high HbA2; like HbSS but with fewer strokes and leg ulcers
and less pulmonary vascular and renal disease
Note: Laboratory values are averages in untreated adults.
Abbreviation: VTE, venous thromboembolism.
β7 valine residues of deoxyHbS and specific amino acid residues of
β- and α-globin culminate in fascicles of hemoglobin that injure the
sickle erythrocyte. A delay occurs between the initiation of polym­
erization and the accumulation of sufficient polymer to damage the
cell. It is unclear how much polymer is needed for cell injury, but
polymer leads directly and indirectly to the multiple abnormalities of
the sickle erythrocyte that generate the pathophysiology of disease.
Prominent among these abnormalities are HbS polymer penetration
of the membrane causing vesiculation with membrane microparticle
release; increased activity of the Gardos, K/CL cotransport, and Psickle
channels that dehydrate the cell, increasing mean corpuscular sickle
hemoglobin concentration (MC[HbS]C), reducing cellular deform­
ability, and increasing the polymerization potential of HbS; transloca­
tion of amino phospholipids such as phosphatidylserine to the outer
leaflet of the membrane; and oxidation of erythrocyte contents. These
and other abnormalities lead to the formation of irreversibly sickled
cells (ISCs), which are sickle erythrocytes that are forever deformed
because of permanent membrane damage regardless of whether HbS
remains polymerized. Damaged sickle erythrocytes are responsible for
initiating the vasoocclusive, hemolytic, and inflammatory features of
the disease shown in Fig. 103-3.
■
■DIAGNOSIS
Although sickle cell disease can appear in any ethnic group, most often
it is present in people of African, Middle Eastern, Mediterranean, and
Indian descent. The chief presenting symptom is pain. This might be
an arthritis-like hand-foot syndrome in young children or the typical
acute painful episode in older children and adults. In HbSC disease and
HbS-β+ thalassemia, acute vasoocclusive episodes occur at about half
the rate as in sickle cell anemia while complications develop later; rarely,
patients with these genotypes are asymptomatic. The key elements
of laboratory diagnosis are outlined in Table 103-2 showing typical
hematologic findings and hemoglobin fractions. Figure 103-4 displays
HPLC profiles and blood films in typical patients with sickle cell trait,
sickle cell anemia, and HbSC disease. Clinical and basic laboratory
diagnosis is sufficient for general management and counseling; genetic
counseling and family planning usually require DNA-based diagnosis.
HEMOGLOBIN LEVEL,
g/L (g/dL)/MCV, fL
HEMOGLOBIN FRACTIONS (%)
Normal
HbA: 60–70
HbS: 30–40
Percent HbS dependent on presence
or absence of α thalassemia
70–100 (7–10)/80–100
HbS: >75
HbF: 2–25
HbA2: 3–4
100–140 (10–14)/70–100 HbS: 50
HbC: 50
90–130 (9–13)/65–75
HbS: 65
HbE: 35
HbF: 1–5
80–100 (8–11)/60–85
HbS: >75
HbF: 2–15
HbA2: 4–5
HbS polymer
Triplet
codon
T
7 Glu
Valine
residue
GAG
HbS
solution
HbS
polymer
N
Oxygenated
Deoxygenated
Hemolysis
HbS
cell
Cell heterogeneity
FIGURE 103-3  Pathophysiology of sickle cell disease. HbS is in solution when oxygenated but reversibly polymerizes when deoxygenated. Polymerization is dependent
on the 30th power of hemoglobin concentration. In the sickle cell, this means that small changes in hemoglobin concentration or cell hydration can have large effects on
polymerization. Polymerization begins seconds to minutes following deoxygenation. Erythrocyte deformation, or sickling, is initially reversible, but after an undetermined
number of cell sickling events, the cell becomes irreversibly deformed. These are known as irreversibly sickled cells (ISCs). Their membrane is permanently damaged,
although depending on their oxygen (O2) content, HbS could be in solution. Sickle erythrocytes lead to the clinical and laboratory phenotypes of disease. Sickle cells
interact with endothelial cells and other blood cells, occluding flow in small and sometimes large vessels and causing the many complications thought to be a result of
vasoocclusion. Sickle cells also live <20 days (normal ~120 days) hemolyzing intra- and extravascularly. Intravascular hemolysis depletes haptoglobin and hemopexin while
liberating heme, arginase, and other danger-associated molecular patterns (DAMPs) into the blood. This scavenges nitric oxide (NO), activates platelets and endothelium,
reduces antioxidant activity, causes vasoconstriction, and is proinflammatory.
■
■COMPLICATIONS
Complications of sickle cell disease can be grouped into those that
likely are a consequence of the related entities of sickle vasoocclusion
and those due to intravascular hemolysis (Fig. 103-3). Complications
associated with vasoocclusion seem to respond best to induction of
HbF. Some complications of disease are presented in Table 103-3.
Acute Painful Episodes 
Characterized by unprovoked severe
pain in extremities or the torso that is often symmetrical and stereo­
typical for each patient and that usually requires treatment with strong
opioids in the emergency department, acute painful episodes are the
most common acute events in sickle cell disease. They are the chief
cause of concern for patients, most of whom have them at some time
in their life. Their frequency varies; most patients have one to two
episodes a year; some rarely have them; others are hardly ever without
them. Acute painful episodes last days to weeks. Pain in sickle cell dis­
ease can also be chronic from osteonecrosis, osteoporosis, or leg ulcers.
Chronic and acute pain can overlap. Pain can also be induced by the
opioids. Most of the time, patients have some degree of pain that does
not reach the intensity of the acute episode. This can be treated with
oral opioids dispensed monthly.
No diagnostic test can confirm or refute the presence of an acute pain
episode whose cause is uncommonly identified. Physical examination is
not often useful diagnostically. Some patients will have pain on pressure
over an affected area, perhaps accompanied by swelling; mild fever is
common. Often a 1–2 g/dL decrease in hemoglobin level and a modest
increase in the leukocyte count are noted. The presence of ISCs and
Vasoocclusion
R
RBC
ISC
EC
NO
NO synthase
NO –
CHAPTER 103
Arginine
NO
Arginase
Ornithine
Citruline
Disorders of Hemoglobin
the reticulocyte count are of no diagnostic value. Drastic decreases in
hemoglobin and platelet levels with more extreme leukocytosis can por­
tend development of severe acute chest syndrome or multiorgan failure.
Some patients die suddenly shortly after admission for an acute
painful episode. The cause of this sudden unexpected death is usually
unknown; among the possibilities are arrhythmias and pulmonary
embolism. Admitting patients to monitored beds or using continuous
pulse oximetry for the first 48–72 h of hospitalization might prevent
some of these deaths and help identify early acute chest syndrome that
follows within 72 h in about a quarter of admissions for acute pain.
After searching for possible precipitants such as infection or dehydra­
tion and treating these appropriately, the foundation of treatment is
the proper dosing of opioid analgesics. By the time a patient presents
at the emergency department or clinic requesting treatment, they have
usually tried nonsteroidal anti-inflammatory drugs (NSAIDs) and oral
opioids. In most patients, relief of pain requires intravenous opioids.
Many patients are opioid tolerant, requiring higher than usual doses for
satisfactory relief. Dosing should not be on an “as-needed” schedule;
patient-controlled analgesia or frequent fixed doses of opioids with res­
cue doses for breakthrough pain are the preferred means of treatment,
with frequent assessments to ensure pain relief without excessive seda­
tion. Adjunctive treatment includes incentive spirometry to forestall
pulmonary complications, maintaining hydration with half-normal
saline with care not to overhydrate, prophylaxis for thromboembolism,
and antihistamines and laxatives to counter expected side effects of
opioids. Unless hypoxia is present, supplemental O2 is unnecessary.
NSAIDs have little value in patients receiving intravenous opioids.
45.0
45.0
37.5
37.5
30.0
30.0
15.0
%
22.5
22.5
E
2.14
A2
3.64
15.0
1.20 1.36
1.67
7.5
7.5
4.51
2.33
0.0
0.0
HbF
HbS
HbA
HbA2 HbS
PART 4
Oncology and Hematology
FIGURE 103-4  Diagnosis of sickle cell disease. A. From left to right, high-performance liquid chromatography separation in sickle cell trait, sickle cell anemia, and
HbSC disease. Beneath each chromatogram, the individual protein peaks are identified. B. Left: Dense, elongated, and pointed cells are the irreversibly sickled cells
characteristic of the sickle cell anemia and sickle cell-β0 thalassemia. Target cells and nucleated red cells are also present. Right: Target cells, cells with squared ends of
HbC crystals, cells folded like tacos, and contracted microspherocytes are typical of HbSC disease. (Source: B [right]: Reproduced with permission from American Society
of Hematology.)
TABLE 103-3  Complications of Sickle Cell Disease
COMPLICATION
INCIDENCE, DIAGNOSIS, AND FEATURES
TREATMENT
Priapism
~30% of males; can be episodic and short duration (stuttering); severe
episodes can cause impotence; associated with markers of hemolysis
Stroke and silent
infarction
10–15% of all cases; infarction in early childhood into adulthood;
hemorrhagic in adults; neurocognitive abnormalities in adults even
without apparent stroke; associated with markers of hemolysis
Gallstones/surgery
~40% of patients; bilirubin levels and stones related to polymorphisms
of UGT1A; in surgery requiring general anesthesia, simple preoperative
transfusion to a hemoglobin of 10 g/dL is recommended
Hepatic disease
80% of patients have hepatomegaly; intrahepatic cholestasis can have
bilirubin ~100 mg/dL; viral hepatitis, iron overload, RBC sequestration,
extrahepatic cholestasis also contribute
Nephropathy
~30% of adults age >30 years; hyperfiltration in children, renal failure in
adults; early albuminuria, later nephrotic-range proteinuria; associated
with markers of hemolysis
Lung/pulmonary
hypertension
Restrictive disease; asthma common; 5–10% have pulmonary hypertension
by right heart catheterization; 30% have increased TRV that portends poor
prognosis; associated with markers of hemolysis
Retinopathy
30% in HbSC disease, 3% in HbSSa; develops in peripheral retina; vitreous
hemorrhage and retinal detachment can cause blindness
Acute anemic episodes
B19 parvovirus infection, folic acid deficiency, splenic sequestration,
delayed hemolytic transfusion reaction with destruction of transfused and
sometimes autologous red cells
Multiorgan failure
Can accompany severe acute chest syndrome; often confused with sepsis
and can coexist with sepsis; CNS liver, muscle, lung, kidney affected
Pregnancy
Screening both partners for hemoglobin disorders with risk counseling is
critical component of family planning
aSickle cell anemia (HbSS).
Abbreviations: ACE, angiotensin-converting enzyme; CNS, central nervous system; ICU, intensive care unit; NSAIDs, nonsteroidal anti-inflammatory drugs; RBC, red blood
cell; TRV, tricuspid regurgitant jet velocity.
45.0
37.5
30.0
22.5
3.65
15.0
3.61
2.20
2.33
F
1.14
7.5
2.43
A2
4.51
4.67
A2
5.17
0.0
HbS
HbC
Many therapies including α-adrenergic agonists, stilbesterol;
consult urology for treatment, which is time-critical
Transcranial Doppler screening in children ages 2–16;
transfusion for at-risk patients; hydroxyurea
If asymptomatic, usually let be; otherwise, laparoscopic
cholecystectomy
Exchange transfusion for intrahepatic cholestasis; transplant
for end-stage liver failure
Screen for microalbuminuria by age 10 years; avoid NSAIDs;
use ACE inhibitors or receptor antagonists for albuminuria;
erythropoietin for symptomatic anemia; dialysis or transplant
for renal failure
Consult expert pulmonologist; screen yearly by
echocardiography measurement of TRV
Screen annually starting at age 10 tears with fluorescein
angiography; laser photocoagulation for proliferative disease
RBC transfusion if symptomatic; splenectomy if more than 1 or 2
episodes of sequestration; anti-parvovirus IgM positive in acute
infection, IgG in past infection
Exchange transfusion, ICU support
All pregnancies are “high risk”; transfuse if sickle cell events
increase, if previous miscarriage, multiple fetuses
Acute Chest Syndrome 
This pneumonia-like illness is the second
most frequent acute sickle cell–related event. It occurs in >50% of
patients, often more than once. Acute chest syndrome can be mild,
especially in children, in whom it can result from viral infection, or
devastating, where multiple lobes of the lung are affected with severe
hypoxia, multiorgan failure, and death. Chest pain, cough, fever, and
hypoxia and a pulmonary infiltrate on chest x-ray are the major diag­
nostic criteria. The etiology includes in situ thrombosis, emboli, any
type of infection, and postoperative hypoventilation. Management in
adults is dictated by the severity of the episode and the need for supple­
mental oxygen. Patients who are hypoxic and febrile can be admitted
directly to the intensive care unit. Antibiotics are almost always used in
these patients even though a causative bacterium is not often cultured.
Supplemental O2 is given for an O2 saturation <95%. Overhydration
and excessive opioids can compound dyspnea and hypoxia. Hypoxic
patients who are febrile with leukocytosis with more than a trivial
infiltrate on x-ray are transfused. In the severely ill patient, exchange
transfusion, if possible, is the preferred modality. However, if transfu­
sion of the severely ill patient is indicated and hours are needed to
arrange red cell exchange, simple or top-up transfusion should be
started first. Simple transfusions also suffice for less severely affected
patients. Most patients survive acute chest syndrome, but in the most
severe cases, often caused by embolization of necrotic bone marrow,
death can be rapid even with prompt and proper treatment. Thrombo­
cytopenia, leukocyte counts >20,000/dL, and rapidly developing acute
anemia often portend severe acute chest syndrome with its possibility
of acute respiratory distress syndrome and multiorgan failure. Asthma
is very common in patients with sickle cell disease. Some adults have
chronic lung disease with reduced diffusing capacity for CO that could
be a sequela of acute chest syndrome.
Osteonecrosis 
This painful and sometimes crippling complica­
tion that most often affects hips bilaterally occurs in about half of all
patients with sickle cell anemia and is also common in HbSC disease;
shoulders are less often affected. Beginning with chronic pain that
can become severe, loss of function, especially in the hips, is often the
final stage. Magnetic resonance imaging (MRI) can detect the earliest
stages, whereas x-ray is less sensitive. Physical therapy and NSAIDs
provide some initial relief; oral opioids are sometimes required. Joint
replacement can restore lost mobility while relieving pain. Life span of
prosthetic joints is finite, so surgery should be delayed as long as mobil­
ity is satisfactory and pain tolerable.
Leg Ulcers 
The incidence of leg ulcers is highly dependent on
geography and hemoglobin genotype. They are far less common in
HbSC disease and HbS-β+ thalassemia than in sickle cell anemia and
HbS-β0 thalassemia. In temperate climates, 10–20% of patients are
affected; tropical and subtropical areas have an incidence rate up to
75%; ulcers rarely occur in patients from the Middle East. Leg ulcers
can be small and superficial or deep and encompass most of the lower
leg. They can be extraordinarily painful. Long-standing, recurrent large
ulcers are difficult to treat. Wet-to-dry dressings and Unna boots are
reasonable choices for initial treatment.
■
■SICKLE CELL TRAIT (CARRIERS, OR SIMPLE
HETEROZYGOSITY FOR THE HBS GENE)
Carriers of sickle cell trait outnumber patients with the disease by 25
to 1. Although testing for sickle cell disease is part of most perinatal
cord blood screening programs, counseling and follow-up of detected
carriers are imperfect, so adolescents and adults can be unaware they
carry sickle cell trait. Counseling carriers about the complications of
sickle cell trait and their likelihood of having offspring with sickle cell
disease is essential. Carriers should be counseled prior to participation
in sports because of the risk, albeit small, of sudden death from heatrelated exertional rhabdomyolysis. Optimal hydration before and dur­
ing exercise can prevent most episodes of heat-related illness. Usually
a benign condition with a normal life expectancy, some complications
are shown in Table 103-2.
■
■TREATMENT, SCREENING, COUNSELING, AND
ANTENATAL DIAGNOSIS
Patients should, if possible, be referred to a sickle cell center for initial
consultation, institution of therapy, and follow-up. Cooperation among
primary care providers, hematologists, and other specialists provides
the best preventive care and management of complications. The fre­
quency at which a patient is seen depends on their therapeutic regimen
and complications.
Remarkable changes in the treatment landscape have occurred with
the promise of even greater benefits from new curative approaches. The
following discussion focuses on treatment to prevent the complications
of disease.
Hydroxyurea 
Hydroxyurea is the standard of care for all patients
with sickle cell anemia and HbS-β0 thalassemia regardless of symptoms.
Although in some symptomatic patients with HbSC disease, its benefits
in this genotype are understudied. The major mechanism of action of
hydroxyurea is to induce high levels of HbF. Hydroxyurea increases
HbF unevenly among red cells (heterocellularly), so some cells have
greater protection from HbS polymerization than others. When started
in adults, where the average baseline HbF is ~5%, HbF increases to
~10%. Nevertheless, pain and acute chest syndrome are reduced by
about half, hemoglobin concentration increases by ~1 g/dL, and after
17.5 years of follow-up, mortality was reduced by 49%. In contrast, all
young children respond robustly to hydroxyurea. When started at <1
year of age at a dose of ~27 mg/kg, HbF levels were 33.3 ± 9.1% and
hemoglobin concentration was 10.1 ± 1.3 g/dL. Acute events were
markedly reduced with little toxicity. Based on these and other studies
in high- and low-resource countries, unless there is a contraindication,
hydroxyurea should be given to all infants with sickle cell anemia and
HbS-β0 thalassemia starting at 9 months of age at a dose of ~20 mg/kg
and titrated to the maximal tolerated dose based on neutrophil and
platelet counts.
CHAPTER 103
Disorders of Hemoglobin
Voxelotor 
Voxelotor increases the affinity of the hemoglobin mol­
ecule for O2. At a dose of 1500 mg daily, hemoglobin concentration
increased ~1 g/dL in 59% of patients with a reduction in the biomark­
ers of hemolysis. Its effects on acute vasoocclusive events are unclear.
Many questions remain about the long-term effects of voxelotor. Less
hemolysis reduces the propensity for stroke, nephropathy, pulmonary
hypertension, leg ulcers, and priapism. Will voxelotor be accompanied
by these long-term benefits? Could the high O2 affinity of a modi­
fied hemoglobin be harmful for some patients? The answers to these
important questions require further study.
Crizanlizumab 
Downstream effects of HbS polymerization
include adhesive interactions among endothelial cells, leukocytes,
platelets, and erythrocytes. P-selectin is one molecule involved in these
interactions; blocking selectins prevents sickle cell–endothelial cell
adhesion. Crizanlizumab, a P-selectin-blocking monoclonal antibody
given intravenously every month, reduced acute painful episodes by
~45%. Hemolysis was unaffected. A follow-up trial failed to replicate
the results of the rigorous study that led to FDA approval.
l-Glutamine 
The mechanism of action of this agent, presumed to
be the reduction of oxidative stress in sickle erythrocytes, is unsettled.
A phase 3 placebo-controlled trial showed that l-glutamine was asso­
ciated with a 25% reduction in painful episodes and 33% reduction in
hospitalization.
There is little consensus regarding how these recently approved
drugs should be integrated into treatment with hydroxyurea. The
effects of voxelotor and crizanlizumab appear to be additive to those
of hydroxyurea. Voxelotor can be added to hydroxyurea if the benefits
of hydroxyurea alone are insufficient, as they are in most adults. If
both hydroxyurea and voxelotor are taken at effective doses and acute
vasoocclusive complications continue, crizanlizumab might then be
added. The dropout rates in the crizanlizumab and l-glutamine trials
were ~35%, so adherence to these therapeutics could be problematic.
Transfusion 
Transfusions are overutilized and underutilized.
Major indications for transfusion include severe symptomatic anemia;
treatment and prevention of stroke; increasing hemoglobin level to
~10 g/dL before surgery requiring general anesthesia; and severe acute
chest syndrome. Sometimes transfusions are given during pregnancy
when there is a history of complications or fetal loss. Transfusions
should usually be avoided in acute pain episodes and for repair of stable
chronic anemia. Automated red cell exchange transfusion is preferred
in acute stroke, severe acute chest syndrome, or multiorgan failure
or when chronic transfusions are planned. Expert guidelines recom­
mended extended red cell antigen profiling, if possible, before the first
transfusion and antigen matching for Rh (C, E or C/c, E/e) and K anti­
gens in addition to ABO/RhD. Complications of transfusion include
hyperviscosity, alloimmunization (which occurred in 18.6% of patients
transfused between 1979 and 1984 and 27.3% of patients transfused
between 2001 and 2011), iron overload, and delayed hemolytic transfu­
sion reactions with hyperhemolysis.
Stem Cell Transplantation 
Given the excellent results of human
leukocyte antigen (HLA)–identical related donor transplants, which
have an event-free survival of >95%, this option might be extended to
all patients with a suitable donor. Unfortunately, only 15% of patients
have a fully matched donor. New approaches to haploidentical trans­
plants are improving event-free survival in these patients.
PART 4
Oncology and Hematology
Gene Therapy 
Two forms of ex vivo gene therapy are approved for
sickle cell disease. Both use mobilized autologous CD34+ stem cells
and increase levels of a hemoglobin that inhibits HbS polymerization.
In one approach, an HbA gene containing the βT87Q mutation respon­
sible for the antipolymerization effects of HbF is introduced into stem
cells via a lentiviral vector. In the second, the major enhancer of the
HbF repressor, BCL11A, is disrupted using CRISPR/Cas9 gene editing.
In both approaches, following myeloablative conditioning, engineered
cells are reinfused and engraft. Both treatments have resulted in near
pancellular distribution of 30–50% HbF or HbAT87Q, reduced hemoly­
sis, and total hemoglobin concentrations of >12 g/dL, with nearly total
prevention of acute vasoocclusive events. Long-term safety and cure
rate will take many more years of follow-up to establish.
Preventive Measures and Screening 
Cord blood screening for
sickle cell disease is done in many countries and all 50 states. Affected
patients are then directed to clinics that can initiate early preventive
care. In childhood, transcranial Doppler screening beginning at age 2
years and repeated annually until age 16 years, prophylactic penicillin
(125 mg for children younger than 3 years; 250 mg for children 3 years
and older) twice daily until age 5 years, and vaccination with pneumo­
coccal vaccines are the main measures to prevent stroke and invasive
pneumococcal infection. Folic acid, 1 mg daily, is given to prevent
megaloblastic erythropoiesis; it is probably unnecessary in people with
nutritious diets.
All women planning pregnancy should be screened for disorders of
hemoglobin by blood counts, erythrocyte indices, and HPLC analysis
of hemoglobin. Individuals with HbS or β thalassemia trait should have
their partners tested. Only then is it possible to know the risks of a
fetus having sickle cell disease (Table 103-2). Antenatal diagnosis using
chorionic villus sampling or cell free DNA testing is widely available.
THALASSEMIA
Thalassemia is caused by reduced accumulation of either α- or β-globin
chains causing a relative excess of the unaffected chain. Unbalanced
globin synthesis is the hallmark of thalassemia and the proximate cause
of its pathophysiology; unpaired globin chains damage the developing
erythroblast. Like the HbS mutation and many other red cell traits,
thalassemia reached polymorphic levels in tropical and subtropical
populations because heterozygotes are protected from severe forms of
P. falciparum infection. Estimates are that 1–5% of the world’s popula­
tion carries a thalassemia mutation; in some locales, most people have
a thalassemia mutation. These mutations can affect any globin gene,
but clinically, β and α thalassemia are the most important. With nearly
500 unique thalassemia-causing mutations (www.globin.bx.psu.edu)
that can interact with each other and with hemoglobinopathies, thal­
assemia syndromes are remarkably diverse. Where resources permit
and the mutation is known, genetic counseling can be provided and
antenatal diagnosis is possible.
HbE (β27 glu-lys) is a common variant whose biosynthesis is reduced
because the site of the mutation alters its mRNA processing. Its reduced
biosynthesis leads to a deficit of βE-globin chains and features of β thal­
assemia. Hemoglobin Constant Spring is caused by a mutation of the
termination codon of HBA2 that leads to the synthesis of an elongated
α-globin chain that is unstable and suboptimally synthesized. This
variant therefore behaves as an α thalassemia variant.
a THALASSEMIA
■
■EPIDEMIOLOGY
Once known as Mediterranean anemia, because of the concentration
of cases in Italy, Greece, and other countries bordering the Mediter­
ranean Sea, or as Cooley’s anemia after the physician first describ­
ing cases, β thalassemia is common in most areas of the world where
malaria was endemic, including the Mediterranean region, Asia, and
the Middle East. Effective programs of screening, counseling, and
antenatal diagnosis have reduced the birth of new cases in a number
of regions. About 40,000 β thalassemia patients are born yearly. In the
United States, there are ~1000 cases of severe β thalassemia.
■
■CLASSIFICATION
β0 Thalassemia mutations totally prevent the accumulation of any
globin from the affected gene; β+ thalassemia mutations cause minor
or moderate reductions in β-globin synthesis. β Thalassemia major
and β thalassemia intermedia are now categorized as transfusiondependent and non-transfusion-dependent based on the number and
frequency of transfusions required to sustain a good quality of life.
Pathophysiology 
Single nucleotide changes are the most common
β thalassemia mutations, but gene deletions also occur. A partial listing
of the classes of mutations causing β thalassemia include mutations in
the promoter elements affecting gene transcription causing mild and
sometimes silent β+ thalassemia; mutations in the junctions between
exons and introns that affect mRNA processing causing β0 and β+ thal­
assemia; introduction of alternative splice sites into introns or exons
usually causing β+ thalassemia; 3′ end-processing sequence mutations
preventing RNA polyadenylation leading to mild or silent β+ thalas­
semia; mutations preventing initiation of translation causing β0 thal­
assemia; and introduction of stop codons that prematurely terminate
translation (nonsense mutations) producing reading frameshifts and
resulting in truncated globin mRNA and β0 thalassemia. In addition,
rare causes of β thalassemia have been identified that are unlinked
from the β globin locus and caused by mutations in general transcrip­
tion regulators, such as SUPT5H and TFIIH, or erythroid transcription
factors like GATA1.
In β thalassemia, the deficit in β-globin chain synthesis allows
α-globin chains to accumulate in excess. Without a non-α-globin
chain partner in dimer and tetramer formation, unpaired α-globin
chains are unstable, cannot form a tetramer, and precipitate within the
developing erythroblast, causing membrane lipid oxidation and dam­
age. The predominant cause of anemia is intramedullary destruction
of erythroid precursors, known as ineffective erythropoiesis. Reduced
deformability and phosphatidyl serine exposure also cause extra- and
intravascular hemolysis of those erythrocytes that gain entrance into
the circulation. In poorly treated β thalassemia, severe anemia leads
to bone marrow expansion; hepatosplenomegaly; iron accumulation
in liver, heart, and endocrine organs; pulmonary hypertension; and
thromboembolic disease.
Frightening pictures of children with severe β thalassemia permeate
the literature. These examples of near-terminal disease should be rel­
egated to history because treatment with transfusion and iron chelation
can prevent their occurrence, hematopoietic stem cell transplantation
can “cure” patients who have suitable donors, and efficacious gene
therapies are now approved.
■
■DIAGNOSIS
Heterozygous β thalassemia, also known as β thalassemia trait and β
thalassemia minor, has mild or no anemia but microcytic/hypochro­
mic erythrocytes with minimal or no increase in reticulocyte count.
After recognizing these hematologic abnormalities and excluding
iron deficiency, finding an elevated level of HbA2 and perhaps HbF by
HPLC is sufficient to establish this diagnosis. The hematologic char­
acteristics of this heterozygous carrier state are listed in Table 103-4.
Sometimes, the spleen is enlarged. Before genetic counseling and ante­
natal diagnosis are considered after carrier identification by red cell
indices and quantitation of HbA2, the thalassemia-causing mutation
should be identified. Sequencing is the key to preventing homozygotes
or compound heterozygotes with transfusion-dependent thalassemia.
The more severe forms of β thalassemia are hemolytic anemias with
hypochromia, microcytosis, reticulocytosis, marked anisocytosis, and
poikilocytosis with variable numbers of circulating nucleated red cells
(Fig. 103-5).
■
■COMPLICATIONS
Complications of severe β thalassemia are many. They are a consequence
of chronic hemolytic anemia, chronic transfusion, and iron loading.
Increased iron absorption is especially common in non-transfusiondependent thalassemia. Most complications, listed in Table 103-5,
develop because of either inadequate blood transfusion and/or poor
iron chelation and iron loading. Even when chelation is optimized,
some complications attributable to iron toxicity will develop. Many
complications have complex and multifactorial etiologies. Iron stores are
estimated by serum ferritin levels; MRI is the most widespread means of
noninvasively measuring iron accumulation in liver and heart.
■
■MANAGEMENT, SCREENING, COUNSELING, AND
ANTENATAL DIAGNOSIS
Heterozygote screening and counseling couples at risk for affected
fetuses, with antenatal diagnosis, if needed, is an effective preven­
tive approach. Severe thalassemia should be dealt with in specialized
centers where these and other services are available and managed by
a team led by a hematologist experienced with this disease with help
from endocrinologists, cardiologists, transfusion medicine specialists,
and social services.
Transfusion and Iron Chelation 
Transfusion every 2–4 weeks
with a goal pretransfusion hemoglobin concentration of 9–10.5 g/dL
TABLE 103-4  β Thalassemias
HEMOGLOBIN
(g/dL)/MCV (fL)
HEMOGLOBIN
FRACTIONS (%)
CLINICAL FEATURES
CLASSIFICATION
β-Thalassemia trait
100–140
(10–14)/60–80
HbA: 94
HbF:1–2
HbA2: 4–6
Non-transfusion-dependent
β thalassemia (thalassemia
intermedia)
70–120 (7–12)/65–80
HbA: 60–90
HbF: 10–40
HbA2: 4–6
20–40 (2–4)/50–80
HbA: 0–5
HbF: 90–100
HbA2: 2–5
Transfusion-dependent β
thalassemia (Thalassemia
major)
HbE-β thalassemia
50–80 (5–8)/60–70
HbE: 50–70
HbF: 30–50
110–120
(11–12)/65–75
HbA: 70
HbF: 7–13
HbA2: 2
δβ Thalassemia and Hb
Lepore
Gene deletion hereditary
persistence of fetal
hemoglobin (HPFH)
120–140
(12–14)/75–85
HbA: 70
HbF: 15–30
HbA2: 2
Note: Laboratory results are averages in adults.
FIGURE 103-5  α Thalassemia intermedia. Target cells and marked variation in cell
size and shape but with general hypochromia and microcytosis characterize the
blood film. A lymphocyte is shown for size comparison.
to suppress ineffective erythropoiesis, coupled with iron chelation to
prevent the accumulation of excess toxic iron that accompanies trans­
fusion, has prevented the development of cardiomyopathy and endo­
crinopathies while extending life to at least 50 years. When to begin
transfusions, whether partial exchange transfusion is preferable to
simple transfusion, and the choice of blood product require consulta­
tion with experts. To be effective, transfusions and iron chelation must
be started early, be uninterrupted, and continue lifelong. Older patients
who did not have the advantage of effective chelation are more likely
to develop multiple disease-related morbidities such as osteoporosis,
endocrinopathies, liver disease, and renal failure. Two orally effective
chelating agents, deferasirox and deferiprone, and one intravenous
chelator, deferoxamine, are available.
CHAPTER 103
Disorders of Hemoglobin
Improving Ineffective Erythropoiesis 
Luspatercept is a fusion
protein containing the extracellular domain of human activin type IIB
receptor and the Fc domain of human IgG. By binding transforming
growth factor β superfamily ligands and reducing Smad2/3 signaling,
luspatercept enhances late-stage erythropoiesis. Given subcutaneously,
1 mg/kg every 3 weeks, it was associated with a 33% reduction in trans­
fusion requirements.
Heterozygosity for β+ or β0 thalassemia mutations; “silent” carriers can have normal HbA2
and red cell indices.
Defined by infrequent or no transfusion requirement; caused by many different genotypes
including homozygosity for “mild” β+ mutations, combinations of β and α thalassemia,
homozygous β thalassemia with high HbF-producing capacity, and many others. Iron
loading, thromboembolic disease, and pulmonary hypertension are major clinical events.
Caused by many different genotypes including homozygosity and compound heterozygosity
for β0 and β+ mutations, combinations of β and α thalassemia; transplantation curative; iron
chelation required.
Common in Southeast Asian populations; in some parts of the world, the most prevalent
severe thalassemia; in HbE-β0 thalassemia, only HbE and HbF are found; in HbE-β+
thalassemia, HbA is present. Transfusion dependence depends in part on the thalassemia
mutation.
Rare; deletions removing the δ- and β-globin genes cause δβ thalassemia; Lepore
hemoglobins are fusion globin chains; values are for heterozygotes; homozygotes have
100% HbF with hemoglobin 10–11 g/dL.
Rare; large deletions removing the δ- and β-globin genes; values are for heterozygotes;
homozygotes, who are asymptomatic, have 100% HbF without anemia.
TABLE 103-5  Complications of a Thalassemia
COMPLICATION
INCIDENCE, DIAGNOSIS, AND FEATURES
Growth retardation
Most often a feature of delayed or inadequate
transfusions but can occur in well-transfused children.
Delayed puberty;
secondary
amenorrhea
50% and 25%, respectively.
Splenomegaly
Can trap 1–40% of red blood cell volume; increases
plasma volume, worsening heart failure. Splenectomy
indicated when transfusion requirement to maintain
ideal hemoglobin increases. Prophylactic penicillin after
splenectomy.
Heart
Due to chronic anemia, heightened sensitivity to iron
toxicity, thromboembolic pulmonary hypertension, other
causes. Progresses through stages to congestive failure
and arrhythmias. Assessed by T2* on magnetic resonance
imaging (MRI). The available chelating agents might
have differential effects on different measure of cardiac
function and can be used in combination.
Leg ulcers
Common in thalassemia intermedia.
Hepatic disease
Fibrosis progressing to cirrhosis is related to hepatic iron
concentration that can be monitored by MRI. Hepatitis
also plays a role.
Lung disease/
pulmonary
hypertension
Fibrosis, chronic thromboembolic disease, restrictive
pathophysiology, intravascular hemolysis, and reduced
nitric oxide bioavailability.
PART 4
Oncology and Hematology
Thromboembolism
Multifactorial etiology, including platelet activation, red
cell–endothelial interactions, thrombocytosis, endothelial
activation, splenectomy.
Endocrinopathies
Diabetes, hypothyroidism, hypoparathyroidism, adrenal
insufficiency; hypogonadism; hypothalamic-pituitary axis
might be especially sensitive to iron.
Bone disease
Caused by bone marrow expansion, severe iron loading,
hypogonadism; osteoporosis in ~50% of patients, even
those well treated. Extramedullary hematopoietic masses
are a feature of thalassemia intermedia.
Infections
Transfusion associated; linked to iron overload (Yersinia);
malaria.
Hematopoietic Stem Cell Transplantation 
There is consensus
that patients with available donors should be offered transplantation
because of the difficulty of lifelong transfusion and chelation and its
imperfect efficacy. Quality of life in successfully transplanted patients
TABLE 103-6  
Thalassemias-GLOBIN GENE
ARRANGEMENT
HEMOGLOBIN LEVEL,
g/L (g/dL)/MCV (fL)
CLINICAL FEATURES
CLASSIFICATION
120–150 (12–15)/65–80
The chromosome with one deleted α gene (—α/) is called α+ thalassemia
(α thalassemia-2); the chromosome with both deleted α genes is α0
thalassemia (α thalassemia-1); non–gene deletion α thalassemias (αT)
often have a more severe phenotype.
α-Thalassemia trait
−α/αα
−α/−α
− −/αα
αTα/αα
Hemoglobin H disease
− −/−α
αTα/− −
αTα/αTα
50–120 (5–12)/60–70
Mild to moderate anemia depending on genotype; non–gene deletion
forms of α thalassemia can produce severe HbH disease.
Hb Bart’s hydrops fetalis
−−/−−
Fatal in utero or at birth with rare survivors. Hydrops can also result from
combinations of gene deletion and non–gene deletion α thalassemia.
α Thalassemia/intellectual disability
syndromes
(ATR-16)
(ATR-X)
− −/αα or − −/−α in
ATR-16
αα/αα in ATR-X
αα/αα
Mutations in ATRX; striking male predominance. Hematologic findings of
HbH disease.
α Thalassemia with myelodysplasia
(ATMDS)
Note: Laboratory values are averages in adults. αα/denotes the chromosome with two intact α-globin genes; –α/chromosome with one α-globin gene deleted;
– –/chromosome with both α-globin genes deleted; αT represents non–gene deletion α thalassemia caused by point mutations. The –α/chromosome, referred to as α+ or
α thalassemia-2, most often has a deletion of 3.7 kb of DNA (–α3.7) or 4.2 kb of DNA (–α4.2) that leaves a single α-globin gene intact. The chromosome where both α-globin
genes are deleted (– –/) is called α0 thalassemia or α thalassemia-1. These chromosomes are caused by different-sized deletions that are usually named after their regions
of highest frequency such as -SEA, -MED, -FI, and -THAI.
exceeds that in patients treated with transfusion and chelation. Trans­
plantation from matched sibling donors is curative in >80% of all
cases. Unfortunately, only a third of patients have matched donors.
The best results are in the youngest patients who have been effectively
chelated and received fewer transfusions. Graft failure, graft rejection,
graft-versus-host disease, and a mortality of 5–20% depending on risk
factors are the major drawbacks of this procedure. Results of haploi­
dentical and unrelated donor transplants are improving but lag those
of matched sibling donors.
Gene Therapy 
The same gene therapy approaches approved for
sickle cell disease are approved for transfusion-dependent β thalas­
semia (see Sickle Cell Disease). CRISPR/Cas editing to downregulate
BCL11A has resulted in increases in total hemoglobin ≥12 g/dL and
HbF ≥10 g/dL, leading to transfusion independence in >90% of 52
patients aged between 12 and 35 years with transfusion-dependent
β thalassemia. Results of lentiviral-mediated HbAT87Q additive gene
therapy were best with non-β0/β0 genotypes, although some individuals
with β0/β0 genotypes could be effectively treated as higher viral titers
were used in subsequent gene therapy protocols.
` THALASSEMIA
In some respects, the obverse of β thalassemia, clinically consequential
α thalassemia is less common than severe β thalassemia. α Thalas­
semia is most often found in Asian populations and is usually caused
by deletion of α-globin genes rather than point mutations.
■
■EPIDEMIOLOGY
Carriers of the most common α thalassemia chromosomes (Table 103-6)
are found in 5–80% of people from tropical and subtropical regions of
Africa, the Middle East, Asia, and Melanesia. About 30% of African
Americans carry the common –α3.7 chromosome that contains a single
functional α-globin gene. HbH disease, the chief clinically important
α thalassemia, is most prevalent in southern China and Southeast Asia.
Estimates are that in Thailand ~3500 patients with severe α thalas­
semia are born yearly. Pregnancies affected by hemoglobin (Hb) Bart’s
hydrops fetalis occur mainly in southern China and southeastern Asia.
■
■CLASSIFICATION
Each normal chromosome 16 contains two α-globin genes; normal
diploid individuals have four α-globin genes. A classification of inher­
ited α thalassemia, as summarized in Table 103-6, is based on the
number of functional α-globin genes. If one or two α-globin genes
are missing or poorly expressed, these people have α thalassemia
ATR-16: Large deletions and rearrangements in chr16p.
ATR-X: No α-globin gene deletion or mutation, ATRX mutations, X-linked.
trait. Their hematologic abnormalities are almost always trivial. HbH
disease is usually caused by deletion or malfunction of three α-globin
genes. Hb Bart’s hydrops fetalis fetuses have no normally functioning
α-globin genes. Hundreds of different-sized deletions and rarer point
mutations affect the production of α-globin and the magnitude of
imbalanced globin synthesis. Because of this mutational complexity,
many different variations of the common α thalassemia syndromes
are found.
■
■PATHOPHYSIOLOGY
Reduced accumulation of α-globin leaves non-α-globins unpaired
and unable to participate in the formation of functional hemoglobin
tetramers. In the fetus, absent or reduced synthesis of α-globin allows
unpaired γ-globin chains, part of the HbF tetramer, to form γ4 or Hb
Bart’s; in adults, when γ-globin synthesis is mostly silenced, unpaired
β-globin chains, lacking a suitable partner to form HbA, tetramerize as
β4 or HbH. Both Hb Bart’s and HbH have very high O2 affinity and do
not unload O2 in tissues; HbH is also unstable. Severe anemia in Hb
Bart’s hydrops fetalis is a result of absent normal hemoglobin and inef­
fective erythropoiesis; in HbH disease, unstable HbH leads to oxidative
membrane damage with extravascular hemolysis in the spleen and
ineffective erythropoiesis.
■
■DIAGNOSIS
Microcytosis/hypochromia with nearly normal hemoglobin concen­
trations, in the absence of iron deficiency and the increased level of
HbA2 that is diagnostic of β thalassemia, is sufficient for a presumptive
diagnosis of α thalassemia trait. When genetic counseling is needed
and antenatal diagnosis contemplated, the molecular basis of the pre­
sumed α thalassemia is required. HbH disease, which is usually due
to compound heterozygosity for one chromosome with both α-globin
genes deleted and one chromosome with only a single α-globin gene,
is defined by the hematologic findings shown in Table 103-6 along
with varying levels of reticulocytosis. At birth, when hemoglobin is
separated by HPLC, 20–30% Hb Bart’s is present; in adults, traces to
40% HbH are present along with residual Hb Bart’s in some cases. HbH
inclusions can be induced in some red cells after incubation and stain­
ing with brilliant cresyl blue. Hemoglobin composition in Hb Bart’s
hydrops fetalis is predominantly Hb Bart’s with some Hb Portland if
the deletion removing α-globin genes preserves the ζ-globin gene.
■
■COMPLICATIONS
HbH disease is very heterogeneous because of the different combina­
tions of genotypes that can cause this phenotype. Generally, when
non–gene deletion mutants, such as Hb Constant Spring, contribute
TABLE 103-7  HbC, HbE, and Rare Hemoglobinopathies
CLASSIFICATION
CLINICAL ABNORMALITIES
HbC trait
2% of African Americans; target cells; no disease
Normal
HbC: 30–40
HbA2: 2–3
HbC disease
Target cells; HbC crystals; mild reticulocytosis;
splenomegaly
HbE trait
50% incidence in some Asian populations; a few
target cells; clinically normal
HbE disease
No hemolysis; 20–80% target cells;
no splenomegaly
High O2 affinity hemoglobins
Isolated erythrocytosis; often familial; no
splenomegaly; no JAK2V617F mutation
Low O2 affinity hemoglobins
Asymptomatic mild anemia; cyanosis
100–140 (10–14)
~50% variant
Unstable hemoglobins
Pigmenturia; hemolysis; reticulocytosis;
splenomegaly
M hemoglobins
Some have mild hemolysis; few symptoms
100–140 (10–14)/80–90
20–50% variant depending on gene affected
Note: Laboratory values are averages in adults. As noted for HbAS, the amount of HbC and HbE in heterozygotes depends on the number of α-globin genes.
to the genotype, the disease is more severe, and intermittent or regular
transfusions are necessary. In the most common − −/−α genotype,
mean hemoglobin in adults is ~11 g/dL. Hepatosplenomegaly, jaun­
dice, thalassemic bone changes in the face, and growth impairment
are seen in 20–50% of cases, depending on the underlying genotype.
Iron loading occurs but is not the severe problem it is in β thalassemia.
Pregnancy in these patients should be considered high risk and man­
aged accordingly. Mothers of infants with Hb Bart’s hydrops fetalis have
a history of stillbirth and develop preeclampsia, polyhydramnios, and
antepartum hemorrhage and have difficult labor and delivery. Intra­
uterine transfusion of the fetus is possible.
■
■MANAGEMENT, SCREENING, COUNSELING, AND
ANTENATAL DIAGNOSIS
When planning families, couples from regions where α thalassemia
is common who have red cell indices that suggest the possibility of
carrying an α thalassemia gene should have genetic counseling based
on DNA analysis of their globin genes. Iron should be avoided in noniron-deficient individuals with α thalassemia trait and microcytosis.
Transfusions are not usually needed in HbH disease. Nevertheless,
depending on the genotype of disease, transfusions might be necessary
especially when anemia becomes more severe, for example, with acute
anemic episodes or pregnancy. Iron stores should be checked periodi­
cally by measuring serum ferritin or MRI; chelation does not appear
to be needed.
CHAPTER 103
Hb Bart’s hydrops fetalis is best prevented by screening couples
at risk and antenatal diagnosis. Intrauterine therapy and perinatal
intensive care have permitted survival of some infants with Hb Bart’s
hydrops fetalis. As growth retardation affects ~40% and neurodevel­
opmental delay is present in 20% of survivors, prevention is the best
approach.
Disorders of Hemoglobin
OTHER HEMOGLOBINOPATHIES OF
CLINICAL IMPORTANCE (TABLE 103-7)
More than 1500 mutations affecting hemoglobin structure have been
described (www.globin.bx.psu.edu). Most are clinically silent. HbC and
HbE are common. HbC is found in people of African descent and HbE
in South China and Southeast Asia. Heterozygotes for HbC and HbE
are unaffected clinically. Even individuals homozygous for these muta­
tions, where the variant hemoglobin comprises >90% of the hemoly­
sate, are clinically well with very mild anemia and microcytosis. The
major importance of these variants is the interaction of HbC with HbS
and HbE with β thalassemia, as outlined in Tables 103-2 and 103-4.
A definitive diagnosis for all rare variants depends on DNA analysis.
HEMOGLOBIN LEVEL,
g/L (g/dL)/MCV, fL
HEMOGLOBIN FRACTIONS (%)
100–130 (10–13)/60–70
HbC: >95
HbF: 2–4
HbA2: 2–3
120–140 (12–14)/80–90
HbE: 27–31
HbF: 1
HbA2: 3
100–120 (10–12)/65–75
HbE: 85–95
HbF: 3–7
HbA2: 3
150–200 (15–20)
Variants in α- and β-globin genes; patients are
heterozygotes; ~25–50% variant
90–140 (9–14)/70–90
20–35% variant; rare hyperunstable variants can be
undetectable and have the phenotype of thalassemia

34 - 104 Megaloblastic Anemias
104 Megaloblastic Anemias
Unexpected low O2 saturation by pulse oximetry (SpO2) with nor­
mal O2 saturation of arterial blood is occasionally seen in rare hemo­
globin variants with clinical phenotypes. Asymptomatic patients with
unexpectedly low SpO2 should not be subjected to unneeded cardio­
pulmonary investigations in search of the cause of their “hypoxemia”
until the existence of a hemoglobin variant is excluded.
■
■M HEMOGLOBINS
M (met) hemoglobins are characterized by oxidation of the heme-iron
from its ferrous (Fe++) to ferric (Fe+++) form. The major clinical feature
of these disorders is asymptomatic cyanosis. Thirteen M hemoglobin
variants have been described. In nine, the mutation involves histidine
residues that interact with heme. Asymptomatic slate gray/brownish
pseudocyanosis is the main clinical finding. Spectrophotometric
recording of the visible spectrum of the hemolysate is diagnostic. To
distinguish M hemoglobins from methemoglobinemia due to drugs
or cytochrome b5 reductase (CYB5R3) deficiency, potassium cyanide
(KCN) can be added to the hemolysate; methemoglobin-containing
blood will turn red, but KCN has no effect on M hemoglobin. Treat­
ment is not needed.
■
■UNSTABLE HEMOGLOBINS
Sometimes referred to as congenital Heinz body hemolytic anemias,
some mutations result in a hemoglobin tetramer that is unstable and
precipitates intracellularly. One-hundred-fifty-six such variants have
been described and are often a result of a new mutation that affects
the tertiary or quaternary structure of the molecule. The most com­
mon class of mutations introduce a proline residue in the α helix or
a polar amino acid into the interion of the molecule. Heinz bodies
are intraerythrocytic precipitates that are detectable as dark globular
aggregates after staining with a dye such as brilliant cresyl blue. Three
unstable hemoglobins are the most common. Hemoglobin Köln (β99
val-met) has been found in multiple families, Hb Hasharon (α47 asphis) is found in Ashkenazi Jews, and Hb Zurich (β63 his-arg) is suscepti­
ble to oxidant drug-induced hemolysis. Unstable variants present with
nonspherocytic hemolytic anemia, but presentation is highly variable.
The associated disease is usually mild and does not require transfusion.
Heating blood to 50°C or incubation with isopropanol precipitates
unstable hemoglobins but must be done with careful controls. Some
variants can be detected by HPLC.
PART 4
Oncology and Hematology
■
■HEMOGLOBINS WITH HIGH OXYGEN AFFINITY
AND LOW OXYGEN AFFINITY
Rare mutations in areas involved in the R-T transition, at critical inter­
faces between globin chains of the tetramer that reduce the affinity for
2,3-bisphosphoglycerate, or present in the heme pocket account for
most of these variants. High O2 affinity hemoglobins (103) outnumber
low O2 affinity variants (48). Isolated erythrocytosis in the absence of
splenomegaly suggests the presence of a high O2 affinity hemoglobin.
High O2 affinity hemoglobin variants shift the hemoglobin-O2 disso­
ciation curve leftward, causing a low P50 and thereby stimulating eryth­
ropoiesis. Many of these variants are due to new mutations. The clinical
course is benign, and phlebotomy because of erythrocytosis is usually
not required. Early diagnosis is important to forestall unnecessary
diagnostic procedures and therapeutics such as cardiac catheteriza­
tion to exclude congenital heart disease or treatment for polycythe­
mia vera. Low O2 affinity variants often present with cyanosis. Their
hemoglobin-O2 dissociation curve is right-shifted with high P50. HPLC
might reveal the presence of a hemoglobin variant. Treatment is often
not necessary.
■
■ACQUIRED DISORDERS OF HEMOGLOBIN
CO binds hemoglobin with high affinity forming carboxyhemoglobin.
Carboxyhemoglobin levels can be accurately measured by co-oximetry
of arterial blood. Standard pulse oximeters cannot accurately make this
measurement. Some newly developed pulse oximeters can measure
both carboxyhemoglobin and methemoglobin. Bound CO inhibits
the transport of O2; the hemoglobin-O2 binding curve is left-shifted.
Acute and chronic CO intoxication, caused by occupational exposure
and other sources of incomplete combustion of hydrocarbons, presents
with headache, altered mental status, and other constitutional symp­
toms. High-flow O2 via facemask is the preferred treatment; criteria
have been developed to guide the use of hyperbaric O2.
Acquired methemoglobinemia and methemoglobinemia due to
deficiency of CYB5R3 are more common than the M hemoglobins.
CYB5R3 is required for the reduction of methemoglobin by NADH.
Affected individuals with “toxic” methemoglobinemia can be cyanotic
and symptomatic. As in carboxyhemoglobinemia, O2 transport is
reduced and reflected by the left shift in the hemoglobin-O2 binding
curve. CYB5R3 deficiency usually affects only erythrocytes (type I),
causing a mild disorder; when all cells are affected (type II), a severe
disease results. Intravenous methylene blue is the preferred treatment in
symptomatic patients with acquired methemoglobinemia and 40–60%
methemoglobin. The usual dose is 1–2 mg/kg. Alternative treatment
with ascorbic acid is preferable in people who are glucose-6-phosphate
dehydrogenase deficient. Methylene blue interferes with co-oximetry,
reducing the value of co-oximetry for monitoring treatment.
Many drugs and chemicals can induce methemoglobin in the
absence of CYB5R3 deficiency. Dapsone and topical anesthetics such
as benzocaine are the most common offending agents.
■
■FURTHER READING
Frangoul H et al: Exagamglogene autotemcel for severe sickle cell
disease. N Engl J Med 290:1649, 2024.
Hardouon G et al: Sickle cell disease: From genetics to curative
approaches. Ann Rev Genomics Hum Genet 24:255, 2023.
Leonard A et al: Gene therapy for hemoglobinopathies: Beta-thalassemia,
sickle cell disease. Hematol Oncol Clin North Am 36:769, 2022.
Locatelli F et al: Defining curative endpoints for sickle cell disease in
the era of gene therapy and gene editing. Am J Hematol 99:430, 2024.
Piel FB et al: Defining global strategies to improve outcomes in sickle
cell disease: A Lancet Haematology Commission. Lancet Haematol.
10:e633, 2023.
Pinto VM et al: Management of the aging beta-thalassemia transfusiondependent population: The Italian experience. Blood Rev 38:100594,
2019.
Pinto VM et al: Management of the sickle cell trait: An opinion by
expert panel members. J Clin Med 12:3441, 2023.
Ribeil J-A et al: An integrated therapeutic approach to sickle cell
disease management beyond infancy. Am J Hematol 98:1087, 2023.
Sheth S et al: Management of luspatercept therapy in patients with
transfusion-dependent β-thalassaemia. Br J Haematol 201:824, 2023.
Taher AT et al: Beta-thalassemia. N Engl J Med 384:727, 2021.
A. Victor Hoffbrand
Megaloblastic Anemias
The megaloblastic anemias are a group of disorders characterized by
the presence of distinctive morphologic appearances of the developing
red cells in the bone marrow. The marrow is usually hypercellular, and
the anemia is based on ineffective erythropoiesis. The cause is usually a
deficiency of either cobalamin (vitamin B12) or folate, but megaloblastic
anemia may occur because of genetic or acquired abnormalities that
affect the metabolism of these vitamins or because of defects in DNA
synthesis not related to cobalamin or folate (Table 104-1).
COBALAMIN
Cobalamin (vitamin B12) exists in a number of different chemical
forms. All have a cobalt atom at the center of a corrin ring. In nature,
the vitamin is mainly in the 2-deoxyadenosyl (ado) form, which is
located in mitochondria. It is the cofactor for the enzyme L-methylmalonyl
TABLE 104-1  Causes of Megaloblastic Anemia
Cobalamin deficiency or abnormalities of cobalamin metabolism
(see Tables 104-3, 104-4)
Folate deficiency or abnormalities of folate metabolism (see Table 104-5)
Therapy with antifolate drugs (e.g., methotrexate)
Independent of either cobalamin or folate deficiency and refractory to cobalamin
and folate therapy:
  Some cases of acute myeloid leukemia, myelodysplasia
  Therapy with drugs interfering with synthesis of DNA (e.g., cytosine
arabinoside, hydroxyurea, 6-mercaptopurine, azidothymidine [AZT])
  Orotic aciduria (responds to uridine)
  Thiamine-responsive
coenzyme A (CoA) mutase. The other major natural cobalamin is
methylcobalamin, the form in human plasma and in cell cytoplasm. It
is the cofactor for methionine synthase. Minor amounts of hydroxo­
cobalamin are also present to which methyl- and ado-cobalamin are
converted rapidly by exposure to light.
■
■DIETARY SOURCES AND REQUIREMENTS
Cobalamin is synthesized solely by microorganisms. Ruminants obtain
cobalamin from the foregut, but the only source for humans is food of
animal origin, for example, meat, fish, and dairy products. Vegetables,
fruits, and other foods of nonanimal origin are free from cobalamin
unless they are contaminated by bacteria. A normal Western diet con­
tains 5–30 μg of cobalamin daily. Adult daily losses (mainly in the urine
and feces) are 1–3 μg (∼0.1% of body stores), and because the body
does not have the ability to degrade cobalamin, daily requirements are
also about 1–3 μg. Body stores are of the order of 2–3 mg, sufficient for
3–4 years if supplies are completely cut off.
■
■ABSORPTION
Two mechanisms exist for cobalamin absorption. One is passive, occur­
ring equally through buccal, duodenal, and ileal mucosa; it is rapid but
extremely inefficient, with <1% of an oral dose being absorbed by
this process. The normal physiologic mechanism is active; it occurs
through the ileum and is efficient for small (a few micrograms) oral
doses of cobalamin, and it is mediated by gastric intrinsic factor (IF).
Dietary cobalamin is released from protein complexes by enzymes
in the stomach, duodenum, and jejunum; it combines rapidly with a
salivary glycoprotein that belongs to the family of cobalamin-binding
proteins known as haptocorrins (HCs). In the intestine, the HC is
digested by pancreatic trypsin and the cobalamin is transferred to IF.
IF (gene at chromosome 11q13) is produced in the gastric parietal
cells of the fundus and body of the stomach, and its secretion parallels
that of hydrochloric acid. Normally, a vast excess of IF is available.
The IF-cobalamin complex passes to the ileum, where IF attaches
to a specific receptor (cubilin) on the microvillus membrane of the
enterocytes. Cubilin also is present in yolk sac and renal proximal
tubular epithelium. Cubilin appears to traffic by means of amnionless
(AMN), an endocytic receptor protein that directs sublocalization
and endocytosis of cubilin with its ligand IF-cobalamin complex. The
cobalamin-IF complex enters the ileal cell, where IF is destroyed. After
a delay of about 6 h, the cobalamin appears in portal blood attached to
transcobalamin (TC) II.
Between 0.5 and 5 μg of cobalamin enter the bile each day. This
binds to IF, and a major portion of biliary cobalamin normally is reab­
sorbed together with cobalamin derived from sloughed intestinal cells.
Because of the appreciable amount of cobalamin undergoing entero­
hepatic circulation, cobalamin deficiency develops more rapidly in
individuals who malabsorb cobalamin than it does in vegans, in whom
reabsorption of biliary cobalamin is intact.
■
■TRANSPORT
Two main cobalamin transport proteins exist in human plasma;
they both bind cobalamin—one molecule for one molecule. One an
HC, also known as transcobalamin (TC) I, is closely related to other
cobalamin-binding HCs in milk, gastric juice, bile, saliva, and other
fluids. The gene TCNL is at chromosome 11q11-q12.3. These HCs differ
from each other only in the carbohydrate moiety of the molecule. TC I is
derived primarily from the specific granules in neutrophils. Normally, it
is about two-thirds saturated with cobalamin, which it binds tightly. TC
I does not enhance cobalamin entry into tissues. Glycoprotein receptors
on liver cells are involved in the removal of TC I from plasma, and TC I
may play a role in the transport of cobalamin analogues (which it binds
more effectively than does IF) to the liver for excretion in bile.
The other major cobalamin transport protein in plasma is transco­
balamin, also known as TC II. The gene is on chromosome 22q11-q13.1.
As for IF and HCs, there are nine exons. The three proteins are likely
to have a common ancestral origin. TC II is synthesized by liver and by
other tissues, including macrophages, ileum, and vascular endothelium.
It normally carries only 20–60 ng of cobalamin per liter of plasma and
readily gives up cobalamin to marrow, placenta, and other tissues, which
it enters by receptor-mediated endocytosis involving the TC II receptor
and megalin (encoded by the LRP-2 gene). The TC II cobalamin is inter­
nalized by endocytosis via clathrin-coated pits; the complex is degraded,
but the receptor probably is recycled to the cell membrane as is the case
for transferrin. Export of “free” cobalamin is via the ATP-binding cas­
sette drug transporter alias multidrug resistance protein 1.
CHAPTER 104
FOLATE
■
■DIETARY FOLATE
Folic (pteroylglutamic) acid is a yellow, crystalline, water-soluble substance.
It is the parent compound of a large family of natural folate compounds,
which differ from it in three respects: (1) they are partly or completely
reduced to dihydrofolate (DHF) or tetrahydrofolate (THF) derivatives, (2)
they usually contain a single carbon unit (Table 104-2), and (3) 70–90%
of natural folates are folate-polyglutamates. These usually have a chain of
four to six glutamate moieties rather than one, as in the monoglutamate
folic acid. The whole family is known as folate or vitamin B9.
Megaloblastic Anemias
Most foods contain some folate. The highest concentrations are
found in liver, yeast, spinach, other greens, and nuts (>100 μg/100 g).
The total folate content of an average Western diet is 400−500 μg daily,
but the amount varies widely according to the type of food eaten and
the method of cooking. Folate is easily destroyed by heating, particu­
larly in large volumes of water. Total-body folate in the adult is ∼10 mg,
with the liver containing the largest store. Daily adult requirements are
100–200 μg, and so stores are sufficient for only 3–4 months in normal
adults, and severe folate deficiency may develop rapidly.
■
■ABSORPTION
Folates are absorbed rapidly from the upper small intestine. The
absorption of folate polyglutamates is less efficient than that of mono­
glutamates; on average, ∼50% of food folate is absorbed. Polyglutamate
forms are hydrolyzed to the monoglutamate derivatives either in the
lumen of the intestine or within the mucosa. All dietary folates are
converted to 5-methyl-THF (5-MTHF) within the small intestinal
mucosa before entering portal plasma. Monoglutamates are actively
transported across the enterocyte by a proton-coupled folate trans­
porter (PCFT, SCL46A1). This is situated at the apical brush border
and is most active at pH 5.5, which is about the pH of the duodenal
and jejunal surface. Genetic mutations of this protein underlie heredi­
tary malabsorption of folate (see below). Pteroylglutamic acid at doses
400 μg is absorbed largely unchanged and converted to natural folates
in the liver. Lower doses are converted to 5-MTHF during absorption
through the intestine.
About 60–90 μg of folate enter the bile each day and are excreted
into the small intestine. Loss of this folate, together with the folate of
sloughed intestinal cells, accelerates the speed with which folate defi­
ciency develops in malabsorption conditions.
■
■TRANSPORT
Folate is transported in plasma; about one-third is loosely bound to
albumin, and two-thirds are unbound. In all body fluids (plasma,
cerebrospinal fluid, milk, bile), folate is largely, if not entirely, 5-MTHF
TABLE 104-2  Biochemical Reactions of Folate Coenzymes
COENZYME FORM OF FOLATE
INVOLVED
REACTION
Formate activation
THF
−CHO
Generation of 10-formyl-THF
Purine synthesis
 
 
 
  Formation of glycinamide
5,10-Methylene-THF
−CHO
Formation of purines needed for DNA, RNA synthesis, but
reactions probably not rate-limiting
ribonucleotide
  Formylation of aminoimidazole
10-Formyl (CHO)THF
 
 
carboxamide ribonucleotide (AICAR)
Pyrimidine synthesis
 
 
 
  Methylation of deoxyuridine
5,10-Methylene-THF
−CH3
Rate limiting in DNA synthesis
Oxidizes THF to DHF
Some breakdown of folate at the C-9–N-10 bond
monophosphate (dUMP) to thymidine
monophosphate (dTMP)
Amino acid interconversion
 
 
 
  Serine-glycine interconversion
THF
=CH2
Entry of single carbon units into active pool
  Homocysteine to methionine
5-Methyl(M)THF
−CH3
Demethylation of 5-MTHF to THF; also requires cobalamin, flavine
adenine dinucleotide, ATP, and adenosylmethionine
  Forminoglutamic acid to glutamic
THF
−HN−CH=
 
acid in histidine catabolism
Abbreviations: DHF, dihydrofolate; THF, tetrahydrofolate.
PART 4
Oncology and Hematology
(the monoglutamate form). Three types of folate-binding protein are
involved. A reduced folate transporter (RFC, SLC19A1) is the major
route of delivery of plasma folate (5-MTHF) to cells. Two folate recep­
tors, FR2 and FR3 embedded in the cell membrane by a glycosyl
phosphatidylinositol anchor, transport folate into the cell via receptormediated endocytosis. The third protein, proton-coupled folate trans­
porter (PCFT), transports folate at low pH from the vesicle to the cell
cytoplasm. The reduced folate transporter also mediates uptake of
methotrexate by cells.
■
■BIOCHEMICAL FUNCTIONS
Folates (as the intracellular polyglutamate derivatives) act as coenzymes in
the transfer of single-carbon units (Fig. 104-1 and Table 104-2). Two
of these reactions are involved in purine synthesis and one in pyrimi­
dine synthesis necessary for DNA and RNA replication. Folate is also
a coenzyme for methionine synthesis, in which methylcobalamin is
also involved and in which THF is regenerated. THF is the acceptor
of single carbon units newly entering the active pool via conversion
of serine to glycine. Methionine, the other product of the methionine
synthase reaction, is the precursor for S-adenosylmethionine (SAM),
the universal methyl donor involved in >100 methyltransferase reac­
tions (Fig. 104-1).
During thymidylate synthesis, 5,10-methylene-THF is oxidized to
DHF. The enzyme DHF reductase converts this to THF. The drugs
methotrexate, pyrimethamine, and (mainly in bacteria) trimethoprim
inhibit DHF reductase and so prevent formation of active THF coen­
zymes from DHF. A small fraction of the folate coenzyme is not recy­
cled during thymidylate synthesis but is degraded at the C9-N10 bond.
BIOCHEMICAL BASIS OF MEGALOBLASTIC
ANEMIA
The common feature of all megaloblastic anemias is a defect in DNA
synthesis that affects rapidly dividing cells in the bone marrow. Con­
ditions that give rise to megaloblastic changes have in common a
disparity in the availability of the four immediate precursors of DNA
or a block in their condensation to form DNA. The four precursors
are the deoxyribonucleoside triphosphates (dNTPs)—dA(adenine)
TP and dG(guanine)TP (purines), dT(thymine)TP, and dC(cytosine)
TP (pyrimidines). In deficiencies of either folate or cobalamin, con­
version of deoxyuridine monophosphate (dUMP) to deoxythymidine
monophosphate (dTMP), the precursor of deoxythymidine triphos­
phate (dTTP) (Fig. 104-1) fails. This occurs because folate is needed
as the coenzyme 5,10-methylene-THF polyglutamate for conversion
of dUMP to dTMP. The availability of 5,10-methylene-THF is reduced
in either cobalamin or folate deficiency. Because of the shortage of one
SINGLE CARBON UNIT
TRANSFERRED
IMPORTANCE
or more precursor, DNA replication from multiple origins along the
chromosome is slower than normal during mitosis, and the incomplete
replicons fail to join up with resulting single-stranded DNA breaks.
An alternative and less likely theory for megaloblastic anemia in
cobalamin or folate deficiency is misincorporation of uracil into DNA
because of the accumulation of deoxyuridine triphosphate (dUTP) at
the DNA replication fork as a consequence of the block in conversion
of dUMP to dTMP.
■
■COBALAMIN-FOLATE RELATIONS
Folate is required for many reactions in mammalian tissues (Table 104-2).
Only two reactions in the body are known to require cobalamin.
Methylmalonyl-CoA isomerization requires adocobalamin, and the
methylation of homocysteine to methionine requires both methylco­
balamin and 5-MTHF (Fig. 104-1). This reaction is the first step in
the pathway by which 5-MTHF, which enters bone marrow and other
cells from plasma, is converted into all the intracellular folate coen­
zymes. The coenzymes are all polyglutamated (the larger size aiding
retention in the cell), but the enzyme folate polyglutamate synthase
can use only THF, not 5-MTHF, as substrate. In cobalamin deficiency,
5-MTHF accumulates in plasma, and intracellular folate concentra­
tions fall due to failure of formation of THF, the substrate on which
folate polyglutamates are built. This has been termed THF starvation,
or the methylfolate trap. This trap also occurs at the polyglutamate
level with accumulation of the methyl form at the expense of the other
one-carbon forms.
This theory explains the abnormalities of folate metabolism that
occur in cobalamin deficiency (high serum folate, low cell folate,
positive purine precursor aminoimidazole carboxamide ribonucleotide
[AICAR] excretion) (Table 104-2) and also why the anemia of cobala­
min deficiency responds to folic acid in large doses, which overcome
the methylfolate trap (Fig 104-1).
CLINICAL FEATURES
Many symptomless patients are detected through the finding of a raised
mean corpuscular volume (MCV) on a routine blood count. The main
clinical features in more severe cases are those of anemia. Anorexia
is usually marked, and weight loss, diarrhea, or constipation may be
present. Glossitis, angular cheilosis, a mild fever in more severely
anemic patients, jaundice (unconjugated), and reversible melanin skin
hyperpigmentation also may occur with a deficiency of either folate or
cobalamin. Thrombocytopenia sometimes leads to bruising, and this
may be aggravated by vitamin C deficiency or alcohol in malnourished
patients. The anemia and low leukocyte count may predispose to infec­
tions, particularly of the respiratory and urinary tracts. Cobalamin
Methylated product
(e.g., methylated lipids, myelin
basic protein, DOPA, DNA)
GSH
Pyruvate
S-Adenosylhomocysteine
(SAH)
Cysteine
Cystathionine
Cystathionine
synthase
vitamin B6
Homocysteine
Methionine
Cell
Tetrahydrofolate
5-Methyl
tetrahydrofolate
5,10-Methylenetetrahydrofolate
reductase
5, 10-Methylene
tetrahydrofolate
5-Methyl
tetrahydrofolate
(monoglutamate)
Deoxyuridine
monophosphate
Folic acid
Folic acid
Plasma
FIGURE 104-1  The role of folates in DNA synthesis and in formation of S-adenosylmethionine (SAM), which is involved in numerous methylation reactions. DHF, dihydrofolate;
GSH, glutathione. (Reproduced with permission from AV Hoffbrand et al [eds]: Postgraduate Haematology, 5th ed. Oxford, UK, Blackwell Publishing, 2005.)
deficiency has also been associated in a few studies with impaired
bactericidal function of phagocytes and with osteoporosis.
Neurologic Manifestations 
Cobalamin is needed for the myelin­
ation of the central nervous system. Its deficiency may cause a bilateral
peripheral neuropathy or degeneration (demyelination) of the cervical
and thoracic posterior and lateral (pyramidal) tracts of the spinal cord
and, less frequently, of the cranial nerves and of the white matter of
the brain. Optic atrophy and cerebral symptoms including dementia,
depression, psychotic symptoms, and cognitive impairment may be
prominent. Anosmia and loss of taste may occur. Magnetic resonance
imaging (MRI) may show the “spongy” degeneration of the cord.
The patient, more frequently male, typically presents with pares­
thesias, muscle weakness, or difficulty in walking but sometimes may
present with dementia, psychotic disturbances, or visual impairment.
Loss of proprioception and vibration sensation is usually present with
positive Romberg and Lhermitte signs. Gait may be ataxic with spas­
ticity (hyperreflexia). Autonomic nervous dysfunction can result in
postural hypotension, impotence, and incontinence.
Long-term nutritional cobalamin deficiency in infancy leads to poor
brain development and impaired intellectual development. In infancy,
feeding difficulties, lethargy, and coma may be noted. Convulsions
Substrate
Methyltransferases
S-Adenosylmethionine
(SAM)
THE METHYLATION
CYCLE
ATP
Polyglutamate
synthase
glutamates
Methionine synthase
methylcobalamin
DHF
reductase
Serine
Glycine
CHAPTER 104
Purines
Formate
Dihydrofolate
10-Formyl
tetrahydrofolate
DNA CYCLE
(CELL REPLICATION)
Megaloblastic Anemias
Deoxythymidine
monophosphate
and myoclonus have been described. An important clinical problem
is the nonanemic patient with neurologic or psychiatric abnormalities
and a low or borderline serum cobalamin level. In such patients, it is
necessary to try to establish whether significant cobalamin deficiency
is present, for example, by careful examination of the blood film for
macrocytosis or hypersegmented neutrophils (see below), tests for
pernicious anemia (PA) by serum gastrin level and antibodies to IF or
parietal cells, and serum methylmalonic acid (MMA) measurement.
A trial of cobalamin therapy for at least 3 months will usually also be
needed to determine whether the symptoms improve.
The biochemical basis for cobalamin neuropathy remains obscure.
Its occurrence in the absence of methylmalonic aciduria in TC II
deficiency suggests that the neuropathy is related to the defect in
homocysteine-methionine conversion. Accumulation of S-adenosyl­
homocysteine in the brain, resulting in inhibition of transmethylation
reactions, has been suggested. Folate deficiency has been suggested
to cause organic neurologic disease, but this is uncertain, although
methotrexate injected into the cerebrospinal fluid may cause brain or
spinal cord damage.
Psychiatric disturbance, as discussed above, is common in both
folate and cobalamin deficiencies. This, like the neuropathy, has been
attributed to a failure of the synthesis of SAM, which is needed in
methylation of biogenic amines (e.g., dopamine) as well as that of pro­
teins, phospholipids, and neurotransmitters in the brain (Fig. 104-1).
■
■GENERAL TISSUE EFFECTS OF COBALAMIN AND
FOLATE DEFICIENCIES
Epithelial Surfaces 
After the marrow, the next most frequently
affected tissues are the epithelial cell surfaces of the mouth (with glos­
sitis), stomach, small intestine, and respiratory, urinary, and female
genital tracts. The cells show macrocytosis with increased numbers
of multinucleate and dying cells. The deficiencies may cause cervical
smear abnormalities.
Complications of Pregnancy 
The gonads are also affected, and
infertility is common in both men and women with severe deficiency
of either vitamin. Maternal folate deficiency has been implicated as a
cause of prematurity, and both folate and cobalamin deficiencies have
been implicated in recurrent fetal loss and neural tube defects.
Neural Tube Defects 
Folic acid supplements at the time of con­
ception and in the first 12 weeks of pregnancy can reduce by ∼80% the
incidence of neural tube defects (NTDs) (anencephaly, meningomyelo­
cele, encephalocele, and spina bifida) in the fetus. Most of this protec­
tive effect can be achieved by taking folic acid, 0.4 mg daily, before and
at the time of conception.
PART 4
Oncology and Hematology
The incidence of cleft palate and harelip also can be reduced by
prophylactic folic acid. No clear simple relationship exists between
maternal folate status and these fetal abnormalities, although for
NTDs, it has been established that the lower the maternal folate, the
greater is the risk to the fetus. NTDs also can be caused by antifolate
and antiepileptic drugs.
An underlying maternal folate metabolic abnormality has also been
postulated. One abnormality has been identified: reduced activity of
the enzyme 5,10-methylene-THF reductase (MTHFR) (Fig. 104-1)
caused by a common C677T polymorphism in the MTHFR gene. In
one study, the prevalence of this polymorphism was found to be higher
than in controls in the parents of NTD fetuses and in the fetuses them­
selves: homozygosity for the TT mutation was found in 13% of cases
compared with 5% of control subjects. The polymorphism codes for a
thermolabile form of MTHFR. The homozygous state results in a lower
mean serum and red cell folate level compared with control subjects, as
well as significantly higher serum homocysteine levels. Tests for muta­
tions in other enzymes possibly associated with NTDs, for example,
methionine synthase and serine–glycine hydroxymethylase, have been
negative. Serum cobalamin levels are also lower in the sera of mothers
of NTD infants than in controls. In addition, maternal TC II receptor
polymorphisms are associated with increased risk of NTD births. How­
ever, no studies have been undertaken that show that dietary fortifica­
tion with cobalamin reduces the incidence of NTDs.
Cardiovascular Disease 
Children with severe homocystinuria
(blood levels ≥100 μmol/L) due to deficiency of one of three enzymes
(methionine synthase, MTHFR, or cystathionine synthase; Fig. 104-1)
have vascular disease, for example, ischemic heart disease, cerebrovas­
cular disease, or pulmonary embolus, as teenagers or in young adult­
hood. Lesser degrees of raised serum homocysteine and low levels of
serum folate and homozygous inherited mutations of MTHFR have
been found to be associated with cerebrovascular, peripheral vascular,
and coronary heart disease and with deep vein thrombosis. Prospective
randomized trials of lowering homocysteine levels with supplements
of folic acid, vitamin B12, and vitamin B6 against placebo over a 5-year
period in patients with vascular disease or diabetes have not, however,
shown a reduction of first event fatal or nonfatal myocardial infarction,
nor have these supplements reduced the risk of recurrent cardiovascu­
lar disease after an acute myocardial infarct. Meta-analysis showed an
18% reduction in strokes. The benefit for stroke prevention has been
confirmed by a large (>20,000 subjects) randomized prospective study
in hypertensive subjects in China. This showed a significant reduction
in the first incidence of stroke in subjects receiving enalapril and folic
acid compared to enalapril alone. The effect was especially marked in
the subjects commencing the prospective trial with the lowest serum
folate levels. Venous thrombosis has been reported to be more frequent
in folate-deficient or cobalamin-deficient subjects than in controls and
to occur at unusual sites such as cerebral venous sinuses. This tendency
was ascribed to raised plasma homocysteine levels in folate or cobala­
min deficiency, but no evidence exists that folic acid or cobalamin
supplements reduce the prevalence of venous thrombosis.
Cognitive Decline 
Association between low serum folate or
cobalamin levels and higher homocysteine levels with the development
of decreased cognitive function and of dementia in Alzheimer’s disease
has been reported. A meta-analysis of randomized, placebo-controlled
trials of homocysteine-lowering B-vitamin supplementation of indi­
viduals with and without cognitive impairment, however, showed that
supplementation with vitamin B12, vitamin B6, and folic acid alone or
in combination did not improve cognitive function or slow cognitive
decline. It is unknown whether prolonged treatment with these B vitamins
can reduce the risk of dementia in later life.
Malignancy 
Prophylactic folic acid in pregnancy has been found
in some but not all studies to reduce the subsequent incidence of acute
lymphoblastic leukemia (ALL) in childhood. A significant negative
association has also been found with the MTHFR C677T polymor­
phism and leukemias with mixed lineage leukemia (MLL) transloca­
tions, but a positive association was found with hyperdiploidy in
infants with ALL or acute myeloid leukemia or with childhood ALL.
A second polymorphism in the MTHFR gene, A1298C, is also strongly
associated with hyperdiploid leukemia. Various positive and negative
associations are noted between polymorphisms in folate-dependent
enzymes and the incidence of adult ALL. The C677T polymorphism
is thought to lead to increased thymidine pools and “better quality” of
DNA synthesis by shunting one-carbon groups toward thymidine and
purine synthesis. This may explain its reported association with a lower
risk for colorectal cancer. Most but not all studies suggest that prophy­
lactic folic acid also protects against colon adenomas. Other tumors
that have been associated with folate polymorphisms or status include
follicular lymphoma, breast cancer, and gastric cancer.
A meta-analysis of 50,000 individuals given folic acid (0.5–40 mg
daily) or placebo in cardiovascular (n = 10) or colon adenoma pre­
vention (n = 3) trials found that folic acid supplementation did not
significantly increase or decrease the overall incidence of cancer or of
any site-specific cancer during a weighted average scheduled treatment
duration of 5.7 years. Because folic acid may “feed” tumors, it prob­
ably should be avoided in those with established tumors unless severe
megaloblastic anemia due to folate deficiency is present.
HEMATOLOGIC FINDINGS
■
■PERIPHERAL BLOOD
Oval macrocytes, usually with considerable anisocytosis and poikilo­
cytosis, are the main feature (Fig. 104-2A). The MCV is usually >100 fL
unless a cause of microcytosis (e.g., iron deficiency or thalassemia
trait) is present. Some of the neutrophils are hypersegmented (more
than five nuclear lobes). There may be leukopenia due to a reduction
in granulocytes and lymphocytes, but this is usually >1.5 × 109/L; the
platelet count may be moderately reduced, rarely to <40 × 109/L. The
severity of all these changes parallels the degree of anemia. In a non­
anemic patient, the presence of a few macrocytes and hypersegmented
neutrophils in the peripheral blood may be the only indication of the
underlying disorder.
■
■BONE MARROW
In a severely anemic patient, the marrow is hypercellular with an accu­
mulation of primitive cells due to selective death by apoptosis of more
mature forms. The erythroblast nucleus maintains a primitive, fine
chromatin appearance despite maturation and hemoglobinization of
the cytoplasm. The cells are larger than normoblasts, and an increased
number of cells with eccentric lobulated nuclei or nuclear fragments
may be present (Fig. 104-2B). Giant and abnormally shaped meta­
myelocytes and enlarged hyperpolyploid megakaryocytes are charac­
teristic. In severe cases, the accumulation of primitive cells (“blasts”)
B
A
FIGURE 104-2  A. The peripheral blood in severe megaloblastic anemia. B. The bone marrow in severe megaloblastic anemia. (Reprinted from AV Hoffbrand et al [eds]:
Postgraduate Haematology, 5th ed. Oxford, UK, Blackwell Publishing, 2005; with permission.)
may mimic acute myeloid leukemia, whereas in less anemic patients,
the changes in the marrow may be difficult to recognize. The terms
intermediate, mild, and early have been used. The term megaloblastoid
is best avoided. It has been used to describe cells with both immatureappearing nuclei and defective hemoglobinization refractory to folic
acid or cobalamin therapy, especially seen in myelodysplasia.
■
■CHROMOSOMES
Bone marrow cells, transformed lymphocytes, and other proliferating
cells in the body show a variety of chromosomal changes, including
random breaks, reduced contraction, spreading of the centromere,
and exaggeration of secondary chromosomal constrictions and over­
prominent satellites. Similar abnormalities may be produced by
antimetabolite drugs (e.g., cytarabine, hydroxyurea, thioguanine, and
methotrexate) that interfere with either DNA replication or folate
metabolism and that also cause megaloblastic appearances.
■
■INEFFECTIVE HEMATOPOIESIS
Unconjugated bilirubin accumulates in plasma due to the death of
nucleated red cells in the marrow (ineffective erythropoiesis). Other
evidence for this includes raised urine urobilinogen, reduced hapto­
globins, positive urine hemosiderin, and raised serum lactate dehydro­
genase. A weakly positive direct antiglobulin test due to complement
only can lead to a false diagnosis of autoimmune hemolytic anemia.
CAUSES OF COBALAMIN DEFICIENCY
Cobalamin deficiency is usually due to malabsorption. The only other
cause is inadequate dietary intake.
■
■INADEQUATE DIETARY INTAKE
Adults 
Dietary cobalamin deficiency arises in vegans who omit
meat, fish, eggs, cheese, and other animal products from their diet.
The largest group in the world consists of Hindus, and it is likely that
many millions of Indians are at risk of deficiency of cobalamin on a
nutritional basis. Subnormal serum cobalamin levels are found in up
to 50% of randomly selected, young, adult Indian vegans, but the defi­
ciency usually does not progress to megaloblastic anemia since the diet
of most vegans is not totally lacking in cobalamin and the enterohe­
patic circulation of cobalamin is intact. Dietary cobalamin deficiency
may also arise rarely in nonvegetarian individuals who exist on grossly
inadequate diets because of poverty or psychiatric disturbance.
CHAPTER 104
Megaloblastic Anemias
Infants 
Cobalamin deficiency has been described in infants born
to severely cobalamin-deficient mothers. These infants develop mega­
loblastic anemia at about 3–6 months of age, presumably because they
are born with low stores of cobalamin and because they are fed breast
milk with low cobalamin content. The babies have also shown growth
retardation, impaired psychomotor development, and other neurologic
sequelae. MRI shows delayed myelination and brain atrophy.
■
■GASTRIC CAUSES OF COBALAMIN
MALABSORPTION
See Tables 104-3 and 104-4.
Formerly, the pathogenesis of cobalamin malabsorption was distin­
guishable based on the results of a Schilling test in which a radioac­
tive form of cobalamin was administered orally and its appearance
in the urine was a sign of absorption. Radioactive cobalamin is no
longer available, and Schilling tests are no longer performed. Other
approaches to the differential diagnosis of cobalamin malabsorption
are now employed.
Pernicious Anemia 
PA, the dominant cause of severe cobalamin
deficiency in Western countries, may be defined as a severe lack of IF
due to gastric atrophy. It is a common disease in northern Europeans
but occurs in all countries and ethnic groups. It is more frequent in
people of African than Asian ancestry. The overall incidence is about
TABLE 104-3  Causes of Cobalamin Deficiency Sufficiently Severe to
Cause Megaloblastic Anemia
NUTRITIONAL
VEGANS
Malabsorption
Pernicious anemia
Gastric causes
Congenital absence of intrinsic factor or functional
abnormality
 
Total or partial gastrectomy
Intestinal causes
Intestinal stagnant loop syndrome: jejunal diverticulosis,
ileocolic fistula, anatomic blind loop, intestinal stricture, etc.
 
Ileal resection and Crohn’s disease
 
Selective malabsorption with proteinuria
 
Tropical sprue
 
Transcobalamin II deficiency
 
Fish tapeworm
TABLE 104-4  Malabsorption of Cobalamin May Occur in the Following
Conditions but Is Not Usually Sufficiently Severe and Prolonged to
Cause Megaloblastic Anemia
Gastric causes
  Simple atrophic gastritis (food cobalamin malabsorption)
  Zollinger-Ellison syndrome
  Gastric bypass or bariatric surgery
  Use of proton pump inhibitors
Intestinal causes
  Gluten-induced enteropathy
  Severe pancreatitis
  HIV infection
  Radiotherapy
  Graft-versus-host disease
Deficiencies of cobalamin, folate, protein,? riboflavin,? nicotinic acid
Therapy with colchicine, para-aminosalicylate, neomycin, slow-release
potassium chloride, anticonvulsant drugs, metformin,a cytotoxic drugs
Alcohol
aIt is now thought that metformin lowers serum vitamin B12 level by lowering the
level of transcobalamin I.
PART 4
Oncology and Hematology
120 per 100,000 population in the United Kingdom (UK). The ratio of
incidence in men and women among whites is ∼1:1.6, and the median
age of onset is 70–80 years, with only 10% of patients being <40 years
of age. However, in some ethnic groups, notably blacks and Latin
Americans, the age at onset of PA is generally lower. The disease occurs
more commonly than by chance in close relatives and in persons
with other organ-specific autoimmune diseases, for example, thyroid
diseases, vitiligo, hypoparathyroidism, type 1 diabetes, and Addison’s
disease. It is also associated with hypogammaglobulinemia, premature
graying or blue eyes, and persons of blood group A. An association with
human leukocyte antigen (HLA) 3 has been reported in some but not
all series and, in those with endocrine disease, with HLA-B8, -B12, and
-BW15. Life expectancy is normal in women once regular treatment has
begun. Men had in earlier decades a slightly subnormal life expectancy
as a result of a higher incidence of carcinoma of the stomach than in con­
trol subjects, but current data on their life expectancy are unavailable.
Gastric output of hydrochloric acid, pepsin, and IF is severely reduced.
The serum gastrin level is raised, and serum pepsinogen I levels are low.
Gastric Biopsy 
A single endoscopic examination is recommended
if PA is diagnosed. Gastric biopsy usually shows atrophy of all layers
of the body and fundus, with loss of glandular elements, an absence
of parietal and chief cells and replacement by mucous cells, a mixed
inflammatory cell infiltrate, and perhaps intestinal metaplasia. The
infiltrate of plasma cells and lymphocytes contains an excess of CD4
cells. These are directed against gastric H/K-ATPase. The antral
mucosa is usually well preserved. Helicobacter pylori infection occurs
infrequently in PA, but it has been suggested that H. pylori gastritis
occurs at an early phase of atrophic gastritis and presents in younger
patients as iron-deficiency anemia and in older patients as PA. H. pylori
is suggested to stimulate an autoimmune process directed against pari­
etal cells. It has been suggested that H. pylori infection is replaced, in
some individuals, by the autoimmune process.
Serum Antibodies 
Two types of IF immunoglobulin G antibody
may be found in the sera of patients with PA. The “blocking,” or type I,
antibody prevents the combination of IF and cobalamin, whereas the
“binding,” or type II, antibody prevents attachment of IF to ileal mucosa.
Type I occurs in the sera of ∼55% of patients, and type II in 35%. IF
antibodies cross the placenta and may cause temporary IF deficiency in
a newborn infant. Type I antibody has been detected rarely in the sera of
patients without PA but with thyrotoxicosis, myxedema, Hashimoto’s disease,
or diabetes mellitus and in relatives of PA patients. IF antibodies have also been
detected in gastric juice in ∼80% of PA patients. These gastric antibodies may
reduce absorption of dietary cobalamin by combining with small amounts of
remaining IF. Patients with PA also show cell-mediated immunity to IF.
Parietal cell antibody is present in the sera of almost 90% of adult
patients with PA but is frequently present in other subjects. Thus, it
occurs in as many as 16% of randomly selected female subjects age
60 years. The parietal cell antibody is directed against the α and β
subunits of the gastric proton pump (H+, K+-ATPase).
■
■JUVENILE PERNICIOUS ANEMIA
This usually occurs in older children and resembles PA of adults.
Gastric atrophy, achlorhydria, and serum IF antibodies are all present,
although parietal cell antibodies are usually absent. About one-half of
these patients show an associated endocrinopathy such as autoimmune
thyroiditis, Addison’s disease, or hypoparathyroidism; in some, muco­
cutaneous candidiasis occurs.
■
■CONGENITAL INTRINSIC FACTOR DEFICIENCY
OR FUNCTIONAL ABNORMALITY
An affected child usually presents with megaloblastic anemia in the
first to third year of life; a few have presented as late as the second
decade. The child usually has no demonstrable IF but has a normal
gastric mucosa and normal secretion of acid. The inheritance is auto­
somal recessive. Parietal cell and IF antibodies are absent. Variants have
been described in which the child is born with IF that can be detected
immunologically but is unstable or functionally inactive, unable to
bind cobalamin or to facilitate its uptake by ileal receptors.
■
■GASTRECTOMY
After total gastrectomy, cobalamin deficiency is inevitable, and pro­
phylactic cobalamin therapy should be commenced immediately
after the operation. After partial gastrectomy, 10–15% of patients also
develop this deficiency. The exact incidence and time of onset are
most influenced by the size of the resection and the preexisting size of
cobalamin body stores.
■
■FOOD COBALAMIN MALABSORPTION
Failure of release of cobalamin from binding proteins in food is
responsible for this condition, which is more common in the elderly. It
is associated with low serum cobalamin levels, with or without raised
serum levels of MMA and homocysteine. Typically, these patients have
normal cobalamin absorption, as measured with crystalline cobala­
min, but show malabsorption when a modified test using food-bound
cobalamin is used. It is usually due to mild forms of atrophic gastritis
or therapy with proton pump inhibitors. Bariatric surgery is likely to be
an increasing cause of this form of cobalamin malabsorption and defi­
ciency. The frequency of progression to severe cobalamin deficiency
and the reasons for this progression are not clear.
■
■INTESTINAL CAUSES OF COBALAMIN
MALABSORPTION
Intestinal Stagnant Loop Syndrome 
Malabsorption of cobala­
min occurs in a variety of intestinal lesions in which there is coloniza­
tion of the upper small intestine by fecal organisms. This may occur in
patients with jejunal diverticulosis, entero-anastomosis, or an intestinal
stricture or fistula or with an anatomic blind loop due to Crohn’s dis­
ease, tuberculosis, or an operative procedure.
Ileal Resection 
Removal of ≥1.2 m of terminal ileum causes
malabsorption of cobalamin. In some patients after ileal resection,
particularly if the ileocecal valve is incompetent, colonic bacteria may
contribute further to the onset of cobalamin deficiency.
Selective Malabsorption of Cobalamin with Proteinuria
(Imerslund’s Syndrome; Imerslund-Gräsbeck Syndrome;
Congenital Cobalamin Malabsorption; Autosomal Reces­
sive Megaloblastic Anemia; MGA1) 
This autosomal recessive
disease is the most common cause of megaloblastic anemia due to
cobalamin deficiency in infancy in Western countries. More than 200
cases have been reported with familial clusters in Finland, Norway, the
Middle East, and North Africa. The patients secrete normal amounts
of IF and gastric acid but are unable to absorb cobalamin. In Finland,
impaired synthesis, processing, or ligand binding of cubilin due to
inherited mutations is found. In Norway, mutation of the gene for
AMN has been reported. Other tests of intestinal absorption are nor­
mal. Over 90% of these patients show nonspecific proteinuria, but renal
function is otherwise normal, and renal biopsy has not shown any con­
sistent renal defect. A few have shown aminoaciduria and congenital
renal abnormalities, such as duplication of the renal pelvis.
Tropical Sprue 
Nearly all patients with acute and subacute tropi­
cal sprue show malabsorption of cobalamin. This may persist as the
principal abnormality in the chronic form of the disease, when the
patient may present with megaloblastic anemia or neuropathy due to
cobalamin deficiency. Absorption of cobalamin usually improves after
antibiotic and, in the early stages, folic acid therapy.
Fish Tapeworm Infestation 
The fish tapeworm (Diphylloboth­
rium latum) lives in the small intestine of humans and accumulates
cobalamin from food, rendering the cobalamin unavailable for absorp­
tion. Individuals acquire the worm by eating raw or partly cooked fish.
Infestation was common around the lakes of Scandinavia, Germany,
Japan, North America, and Russia. Megaloblastic anemia or cobalamin
neuropathy occurs only in those with a heavy infestation.
Gluten-Induced Enteropathy 
Malabsorption of cobalamin
occurs in ∼30% of untreated patients (presumably those in whom the
disease extends to the ileum). Cobalamin deficiency is not severe in
these patients and is corrected with a gluten-free diet.
Severe Chronic Pancreatitis 
In this condition, lack of trypsin is
thought to cause dietary cobalamin attached to gastric non-IF (HC)
binder to be unavailable for absorption. It also has been proposed that,
in pancreatitis, the concentration of calcium ions in the ileum falls
below the level needed to maintain normal cobalamin absorption.
HIV Infection 
Serum cobalamin levels tend to fall in patients with
HIV infection and are subnormal in 10–35% of those with AIDS. Mal­
absorption of cobalamin not corrected by IF has been shown in some,
but not all, patients with subnormal serum cobalamin levels. Cobala­
min deficiency sufficiently severe to cause megaloblastic anemia or
neuropathy is rare.
Zollinger-Ellison Syndrome 
Malabsorption of cobalamin has
been reported in the Zollinger-Ellison syndrome. It is thought that
there is a failure to release cobalamin from HC binding protein due to
inactivation of pancreatic trypsin by high acidity, as well as interference
with IF binding of cobalamin.
Radiotherapy 
Both total-body irradiation and local radiotherapy
to the ileum (e.g., as a complication of radiotherapy for carcinoma of
the cervix) may cause malabsorption of cobalamin.
Graft-Versus-Host Disease 
This commonly affects the small
intestine. Malabsorption of cobalamin due to abnormal gut flora, as
well as damage to ileal mucosa, is common.
Drugs 
The drugs that have been reported to cause malabsorption
of cobalamin are listed in Table 104-4. However, megaloblastic anemia
due to these drugs is rare. It has been suggested that metformin lowers
serum cobalamin by lowering TC I level rather than causing malab­
sorption of cobalamin.
■
■ABNORMALITIES OF COBALAMIN METABOLISM
Congenital Transcobalamin II Deficiency or Abnormality 
Infants with TC II deficiency usually present with megaloblastic anemia
within a few weeks of birth. Serum cobalamin and folate levels are normal,
but the anemia responds to massive (e.g., 1 mg three times weekly) injec­
tions of cobalamin. Some cases show neurologic complications. The pro­
tein may be present but functionally inert. Genetic abnormalities found
include mutations of an intraexonic cryptic splice site, extensive deletion,
single nucleotide deletion, nonsense mutation, and an RNA editing defect.
Malabsorption of cobalamin occurs in all cases, and serum immunoglob­
ulins are usually reduced. Failure to institute adequate cobalamin therapy
or treatment with folic acid may lead to irreversible neurologic damage.
Congenital Methylmalonic Acidemia and Aciduria 
Infants
with this abnormality are ill from birth with vomiting, failure to thrive,
severe metabolic acidosis, ketosis, and intellectual disability. Anemia,
if present, is normocytic and normoblastic. The condition may be due
to a functional defect in either mitochondrial methylmalonyl-CoA
mutase or its cofactor adocobalamin. Mutations in the methylmal­
onyl-CoA mutase are not responsive or are only poorly responsive
to treatment with cobalamin. A proportion of infants with failure of
adocobalamin synthesis respond to cobalamin in large doses. Some
children have combined methylmalonic aciduria and homocystinuria
due to defective formation of both cobalamin coenzymes. This usually
presents in the first year of life with feeding difficulties, developmental
delay, microcephaly, seizures, hypotonia, and megaloblastic anemia.
Acquired Abnormality of Cobalamin Metabolism: Nitrous
Oxide Inhalation 
Nitrous oxide (N2O) irreversibly oxidizes meth­
ylcobalamin to an inactive precursor; this inactivates methionine
synthase. Megaloblastic anemia has occurred in patients undergoing
prolonged N2O anesthesia (e.g., in intensive care units). A neuropathy
resembling cobalamin neuropathy has been described in dentists and
anesthetists who are exposed repeatedly to N2O. Methylmalonic acid­
uria does not occur as adocobalamin is not inactivated by N2O.
CHAPTER 104
CAUSES OF FOLATE DEFICIENCY
(Table 104-5)
■
■NUTRITIONAL
Dietary folate deficiency is common except in countries that fortify
their diet with folic acid. In most patients with folate deficiency, a
nutritional element is present. Certain individuals are particularly
prone to have diets containing inadequate amounts of folate (Table
104-5). In the United States and other countries where fortification
Megaloblastic Anemias
TABLE 104-5  Causes of Folate Deficiency
Dietarya
  Particularly in: old age, infancy, poverty, alcoholism, chronic invalids, and the
psychiatrically disturbed; may be associated with scurvy or kwashiorkor
Malabsorption
  Major causes of deficiency
    Tropical sprue, gluten-induced enteropathy in children and adults, and in
association with dermatitis herpetiformis, specific malabsorption of folate,
intestinal megaloblastosis caused by severe cobalamin or folate deficiency
  Minor causes of deficiency
    Extensive jejunal resection, Crohn’s disease, partial gastrectomy, congestive
heart failure, Whipple’s disease, scleroderma, amyloid, diabetic enteropathy,
systemic bacterial infection, lymphoma, sulfasalazine (Salazopyrin)
Excess utilization or loss
  Physiologic
    Pregnancy and lactation, prematurity
  Pathologic
    Hematologic diseases: chronic hemolytic anemias, sickle cell anemia,
thalassemia major, myelofibrosis
    Malignant diseases: carcinoma, lymphoma, leukemia, myeloma
    Inflammatory diseases: tuberculosis, Crohn’s disease, psoriasis, exfoliative
dermatitis, malaria
    Metabolic disease: homocystinuria
    Excess urinary loss: congestive heart failure, active liver disease
    Hemodialysis, peritoneal dialysis
Antifolate drugsb
  Anticonvulsant drugs (phenytoin, primidone, barbiturates), sulfasalazine
  Nitrofurantoin, tetracycline, antituberculosis (less well documented)
Mixed causes
  Liver diseases, alcoholism, intensive care units
aIn severely folate-deficient patients with causes other than those listed under
Dietary, poor dietary intake is often present. bDrugs inhibiting dihydrofolate
reductase are discussed in the text.
of the diet with folic acid has been adopted, the prevalence of folatedeficient megaloblastic anemia has dropped dramatically and is now
restricted to high-risk groups with increased folate needs. Nutritional
folate deficiency occurs in kwashiorkor and scurvy and in infants with
repeated infections or those who are fed solely on goats’ milk, which
has a low folate content.
■
■MALABSORPTION
Malabsorption of dietary folate occurs in tropical sprue and in gluteninduced enteropathy. In the rare congenital recessive syndrome of selec­
tive malabsorption of folate due to mutation of the PCFT, there is an
associated defect of folate transport into the cerebrospinal fluid, and these
patients show megaloblastic anemia, which responds to physiologic doses
of folic acid given parenterally but not orally. They also show intellectual
disability, convulsions, and other central nervous system abnormalities.
Minor degrees of malabsorption may also occur after jejunal resection or
partial gastrectomy, in Crohn’s disease, and in systemic infections, but in
these conditions, if severe deficiency occurs, it is usually largely due to
poor nutrition. Malabsorption of folate has been described in patients
receiving sulfasalazine (Salazopyrin), cholestyramine, and triamterene.
■
■EXCESS UTILIZATION OR LOSS
Pregnancy 
Folate requirements are increased by 50% daily in a
normal pregnancy, partly because of transfer of the vitamin to the fetus
but mainly because of increased folate catabolism due to cleavage of
folate coenzymes in rapidly proliferating tissues. A dietary folate intake
of 600 µg daily is recommended. Megaloblastic anemia due to folate
deficiency is prevented by prophylactic folic acid therapy. It occurred in
0.5% of pregnancies in the UK and other Western countries before pro­
phylaxis with folic acid, but the incidence is much higher in countries
where the general nutritional status is poor. During lactation, folate
requirements are increased about 25 and a dietary intake of 500 µg
of folate daily is advised.
PART 4
Oncology and Hematology
Prematurity 
A newborn infant, whether full term or premature,
has higher serum and red cell folate concentrations than an adult.
However, a newborn infant’s demand for folate has been estimated to
be up to 10 times that of adults on a weight basis, and the neonatal
folate level falls rapidly to the lowest values at about 6 weeks of age.
The falls are steepest and are liable to reach subnormal levels in
premature babies, a number of whom develop megaloblastic anemia
responsive to folic acid at about 4–6 weeks of age. This occurs particu­
larly in the smallest babies (<1500 g birth weight) and those who have
feeding difficulties or infections or have undergone multiple exchange
transfusions. In these babies, prophylactic folic acid should be given.
Hematologic Disorders 
Folate deficiency frequently occurs in
chronic hemolytic anemias, particularly in sickle cell disease, autoim­
mune hemolytic anemia, and congenital spherocytosis. In these and in
other conditions of increased cell turnover (e.g., myelofibrosis, malig­
nancies), folate deficiency arises because it is not completely reutilized
after performing coenzyme functions.
Inflammatory Conditions 
Chronic inflammatory diseases such
as tuberculosis, rheumatoid arthritis, Crohn’s disease, psoriasis, exfolia­
tive dermatitis, bacterial endocarditis, and chronic bacterial infections
cause deficiency by reducing the appetite and increasing the demand
for folate. Systemic infections also may cause malabsorption of folate.
Severe deficiency is virtually confined to the patients with the most
active disease and the poorest diet.
Homocystinuria 
This is a rare metabolic defect in the conversion
of homocysteine to cystathionine. Folate deficiency occurring in most
of these patients may be due to excessive utilization because of com­
pensatory increased conversion of homocysteine to methionine.
Long-Term Dialysis 
Because folate is only loosely bound to
plasma proteins, it is easily removed from plasma by dialysis. In
patients with anorexia, vomiting, infections, and hemolysis, folate
stores are particularly likely to become depleted. Routine folate pro­
phylaxis is now given.
Congestive Heart Failure and Liver Disease 
Excess urinary
folate losses of >100 μg per day may occur in some of these patients. It
appears to be due to release of folate from damaged liver cells.
■
■ANTIFOLATE DRUGS
A large number of people with epilepsy receiving long-term therapy
with phenytoin or primidone, with or without barbiturates, develop
low serum and red cell folate levels. The exact mechanism is unclear.
Alcohol may also be a folate antagonist, as patients who are drinking
spirits may develop megaloblastic anemia that will respond to normal
quantities of dietary folate or to physiologic doses of folic acid only
if alcohol is withdrawn. Macrocytosis of red cells is associated with
chronic alcohol intake even when folate levels are normal. Inadequate
folate intake is the major factor in the development of deficiency in
spirit-drinking alcoholics. Beer is relatively folate-rich in some coun­
tries, depending on the technique used for brewing.
The drugs that inhibit DHF reductase include methotrexate, pyri­
methamine, and trimethoprim. Methotrexate has the most powerful
action against the human enzyme, whereas trimethoprim is most active
against the bacterial enzyme and is likely to cause megaloblastic ane­
mia only when used in conjunction with sulfamethoxazole in patients
with preexisting folate or cobalamin deficiency. The activity of pyri­
methamine is intermediate. The antidote to these drugs is a reduced
form of folate, folinic acid (5-formyl-THF).
■
■CONGENITAL ABNORMALITIES OF FOLATE
METABOLISM
Some infants with congenital defects of folate enzymes (e.g., cyclohy­
drolase or methionine synthase) have had megaloblastic anemia.
DIAGNOSIS OF COBALAMIN AND FOLATE
DEFICIENCIES
The diagnosis of cobalamin or folate deficiency has traditionally
depended on the recognition of the relevant abnormalities in the
peripheral blood and analysis of the blood levels of the vitamins.
■
■COBALAMIN DEFICIENCY
Serum Cobalamin 
This is measured by an automated enzymelinked immunosorbent assay (ELISA) or competitive-binding lumi­
nescence assay (CBLA). Normal serum levels range from 118–148
pmol/L (160–200 ng/L) to ∼738 pmol/L (1000 ng/L). In patients with
megaloblastic anemia due to cobalamin deficiency, the level is usually
<74 pmol/L (100 ng/L). In general, the more severe the deficiency,
the lower is the serum cobalamin level. In patients with spinal cord
damage due to the deficiency, levels are very low even in the absence
of anemia. Values between 74 and 148 pmol/L (100 and 200 ng/L) are
regarded as borderline. They may occur, for instance, in pregnancy, in
patients with megaloblastic anemia due to folate deficiency. They may
also be due to heterozygous, homozygous, or compound heterozygous
mutations of the gene TCN1 that codes for HC (TC I). There is then no
clinical or hematologic abnormality. The serum cobalamin level is suf­
ficiently robust, cost-effective, and most convenient to rule out cobala­
min deficiency in the vast majority of patients suspected of having
this problem. However, problems have arisen with commercial CBLA
assays involving IF in PA patients with intrinsic antibodies in serum.
These antibodies may cause false normal serum cobalamin levels in up
to 50% of cases tested. Where clinical indications of PA are strong, a
normal serum cobalamin does not rule out the diagnosis. Serum MMA
levels will be elevated in untreated PA (see below).
Folate deficiency, TC I (HC) deficiency, oral contraceptives, and
multiple myeloma have all been associated with low serum cobalamin
levels that do not indicate cobalamin deficiency. On the other hand,
high serum cobalamin levels are usually due to raised serum TC I lev­
els and can be due to the presence of liver, renal, or myeloproliferative
diseases or to cancer of the breast, colon, or liver.
Serum Methylmalonate and Homocysteine 
In patients with
cobalamin deficiency sufficient to cause anemia or neuropathy, the
serum MMA level is raised. Sensitive methods for measuring MMA
and homocysteine in serum have been introduced and recommended
for the early diagnosis of cobalamin deficiency, even in the absence of
hematologic abnormalities or subnormal levels of serum cobalamin.
Serum MMA levels fluctuate, however, in patients with renal failure.
Mildly elevated serum MMA and/or homocysteine levels occur in up
to 30% of apparently healthy volunteers, with serum cobalamin levels
up to 258 pmol/L (350 ng/L) and normal serum folate levels; 15% of
elderly subjects, even with cobalamin levels >258 pmol/L (>350 ng/L),
have this pattern of raised metabolite levels. These findings bring into
question the exact cutoff points for normal MMA and homocysteine
levels. It is also unclear at present whether these mildly raised metabo­
lite levels have clinical consequences.
Serum homocysteine is raised in both early cobalamin and folate
deficiency but may be raised in other conditions, for example, chronic
renal disease, alcoholism, smoking, pyridoxine deficiency, hypothy­
roidism, and therapy with steroids, cyclosporin, and other drugs. Levels
are also higher in serum than in plasma, in men than in premenopausal
women, in women taking hormone replacement therapy or in oral con­
traceptive users, and in elderly persons and patients with several inborn
errors of metabolism affecting enzymes in trans-sulfuration pathways of
homocysteine metabolism. Thus, homocysteine levels must be care­
fully interpreted for diagnosis of cobalamin or folate deficiency.
Tests for the Cause of Cobalamin Deficiency 
Only vegans,
strict vegetarians, or people living on a totally inadequate diet will
become cobalamin deficient because of inadequate intake. Studies of
cobalamin absorption once were widely used, but difficulty in obtain­
ing radioactive cobalamin and ensuring that IF preparations are free
of viruses has made these tests obsolete. Tests to diagnose PA include
serum gastrin, which is raised; serum pepsinogen I, which is low in PA
(90–92%) but also in other conditions; and gastric endoscopy. Tests for
IF and parietal cell antibodies are also used, as well as tests for indi­
vidual intestinal diseases.
Patients with atrophic gastritis may also have sufficient occult gas­
trointestinal blood loss to have iron deficiency as well as cobalamin
deficiency. Iron deficiency may blunt the development of macrocytosis.
Iron deficiency is much more common than cobalamin deficiency. In
people older than age 60 years, cobalamin deficiency may accompany
iron deficiency in 15–20% of cases. Thus, older patients diagnosed
with iron-deficiency anemia should have cobalamin levels assessed,
and those diagnosed with cobalamin deficiency should have their iron
status assessed.
■
■FOLATE DEFICIENCY
Serum Folate 
This is also measured by a chemiluminescence immu­
noassay or ELISA technique. In most laboratories, the normal range is
from 11 nmol/L (2 μg/L) to ∼82 nmol/L (15 μg/L). The serum folate level
is low in all folate-deficient patients. It also reflects recent diet. Because
of this, serum folate may be low before there is hematologic or bio­
chemical evidence of deficiency. Serum folate rises in severe cobalamin
deficiency because of the block in conversion of 5-MTHF to THF inside
cells; raised levels have also been reported in the intestinal stagnant-loop
syndrome due to absorption of bacterially synthesized folate.
Red Cell Folate 
The red cell folate assay is a valuable test of body
folate stores. It is less affected than the serum assay by recent diet and
traces of hemolysis. In normal adults, concentrations range from 880
to 3520 μmol/L (160–640 μg/L) of packed red cells. Subnormal levels
occur in patients with megaloblastic anemia due to folate deficiency
but also in nearly two-thirds of patients with severe cobalamin defi­
ciency. False-normal results may occur if a folate-deficient patient has
received a recent blood transfusion or if a patient has a raised reticulo­
cyte count. Serum homocysteine assay is discussed earlier.
Tests for the Cause of Folate Deficiency 
The diet history is
important. Tests for transglutaminase antibodies are performed to
confirm or exclude gluten–induced enteropathy. If positive, duodenal
biopsy is needed. An underlying disease causing increased folate break­
down should also be excluded.
TREATMENT
Cobalamin and Folate Deficiency
It is usually possible to establish which of the two deficiencies, folate
or cobalamin, is the cause of the anemia and to treat only with the
appropriate vitamin. In patients who enter the hospital severely ill,
however, it may be necessary to treat with both vitamins in large
doses once blood samples have been taken for cobalamin and folate
assays and a bone marrow biopsy has been performed (if deemed
necessary). Transfusion is usually unnecessary and inadvisable. If it
is essential, packed red cells should be given slowly, one or two units
only, with the usual treatment for heart failure if present. Occasion­
ally, an excessive rise in platelets occurs after 1–2 weeks of therapy.
Antiplatelet therapy, for example, aspirin, should be considered if
the platelet count rises to >800 × 109/L.
COBALAMIN DEFICIENCY
It is usually necessary to treat patients who have developed
severe cobalamin deficiency, as from PA, with lifelong regular
cobalamin injections. In the UK, hydroxocobalamin is used; in
the United States, cyanocobalamin. In a few instances, the under­
lying cause of cobalamin deficiency can be permanently corrected,
for example, fish tapeworm, tropical sprue, or an intestinal stagnant
loop that is amenable to surgery. The indications for starting cobal­
amin therapy are a well-documented megaloblastic anemia or other
hematologic abnormalities and/or neuropathy due to the deficiency.
Cobalamin should be given routinely to all patients who have had
a total gastrectomy or ileal resection. Patients who have undergone
gastric reduction for control of obesity or who are receiving longterm treatment with proton pump inhibitors should be screened
and, if necessary, given cobalamin replacement.
CHAPTER 104
Megaloblastic Anemias
Replenishment of body stores should be complete with six 1000-μg
IM injections of hydroxocobalamin given at 3- to 7-day intervals.
More frequent doses are usually used in patients with cobalamin
neuropathy, but there is no evidence that they produce a better
response. Allergic reactions are rare and may require desensitiza­
tion or antihistamine or glucocorticoid cover. For maintenance
therapy, 1000 μg hydroxocobalamin IM once every 3 months is sat­
isfactory. Because of the poorer retention of cyanocobalamin, pro­
tocols generally use higher and more frequent doses, for example,
1000 μg cyanocobalamin IM, monthly, for maintenance treatment.
Because a small fraction of cobalamin can be absorbed passively
through mucous membranes even when there is complete failure of
physiologic IF-dependent absorption, large daily oral doses (1000–
2000 μg) of cyanocobalamin may be used in PA for replacement
(especially in Canada and Sweden) and maintenance of normal
cobalamin status. Sublingual therapy has also been proposed for
those in whom injections are difficult because of a bleeding ten­
dency and who may not tolerate parenteral therapy. If oral therapy
is used, it is important to monitor compliance, particularly with
elderly, forgetful patients. This author prefers parenteral therapy
for initial treatment for PA, particularly in severe anemia or if a
neuropathy is present, and for maintenance.
Treatment of patients with subnormal serum cobalamin levels
with a normal MCV and no hypersegmentation of neutrophils and
a negative IF antibody is, however, problematic. Some (perhaps
15%) cases may be due to TC I (HC) deficiency. Homocysteine and/
or MMA measurements may help, but in the absence of these tests
and with otherwise normal gastrointestinal function, repeat serum
cobalamin assay after 6–12 months may help one decide whether
to start cobalamin therapy. Oral cyanocobalamin therapy with low
doses (e.g., 50 μg daily) has a large role in treating patients thought
to have food malabsorption of cobalamin.
Cobalamin injections are used in a wide variety of diseases, often
neurologic, despite normal serum cobalamin and folate levels and a
normal blood count and in the absence of randomized, double-blind,
controlled trials. These conditions include multiple sclerosis and
chronic fatigue syndrome/myalgic encephalomyelitis (ME). It seems
probable that any benefit is due to the placebo effect of a usually
painless, pink injection. In ME, oral cobalamin therapy, despite pro­
viding equally large amounts of cobalamin, has not been beneficial,
supporting the view of the effect of the injections being placebo only.
FOLATE DEFICIENCY
Oral doses of 5–15 mg of folic acid daily are satisfactory, as suf­
ficient folate is absorbed from these extremely large doses even
in patients with severe malabsorption. The length of time therapy
must be continued depends on the underlying disease. It is cus­
tomary to continue therapy for about 4 months, when all folatedeficient red cells will have been eliminated and replaced by new
folate-replete populations.
Before large doses of folic acid are given, cobalamin deficiency
must be excluded and, if present, corrected; otherwise, cobalamin
neuropathy may develop as the deficiency progresses despite a
response of the anemia of cobalamin deficiency to folate therapy.
Long-term folic acid therapy is required when the underlying
cause of the deficiency cannot be corrected and the deficiency is
likely to recur, for example, in chronic dialysis or chronic hemolytic
anemias. It may also be necessary in gluten-induced enteropathy that
does not respond to a gluten-free diet. Where mild but chronic folate
deficiency occurs, it is preferable to encourage improvement in the
diet after correcting the deficiency with a short course of folic acid. In
any patient receiving long-term folic acid therapy, it is important to
measure the serum cobalamin level at regular (e.g., once-yearly) inter­
vals to exclude the coincidental development of cobalamin deficiency.
PART 4
Oncology and Hematology
Folinic Acid (5-Formyl-THF)  This is a stable form of fully reduced
folate. It is given orally or parenterally to overcome the toxic effects
of methotrexate or other DHF reductase inhibitors, for example,
trimethoprim or cotrimoxazole.
PROPHYLACTIC FOLIC ACID
Prophylactic folic acid is used in chronic dialysis patients and in par­
enteral feeds. Prophylactic folic acid has been used to reduce homo­
cysteine levels to prevent cardiovascular disease and for cognitive
function in the elderly, but there are no firm data to show any benefit.
Pregnancy  In over 80 countries (but none in Europe), food is for­
tified at a level of 120–250 µg/100 g with folic acid (in grain, flour,
or rice) to reduce the risk of NTDs. In all countries that have studied
this, fortification has led to a lower prevalence of NTD pregnancies
and births. Nevertheless, folic acid, 400 μg daily, should also be given
as a supplement before and throughout pregnancy to prevent mega­
loblastic anemia and reduce the incidence of NTDs, even in coun­
tries with fortification of the diet. Most if not all the folic acid used in
fortification and eaten over three meals a day will be converted dur­
ing absorption to 5-MTHF. This compound at the levels achieved
by fortification will not correct the anemia in cobalamin deficiency.
Studies in the United States suggest that there is no increase in the
proportion of individuals with low serum cobalamin levels and no
anemia since food fortification with folic acid. It is unknown if there
has been a change in incidence of cobalamin neuropathy, but no
country has reported this since mandating fortification.
Data in early pregnancy show significant lack of compliance
with taking folic acid supplements, emphasizing the need for food
fortification. In women who have had a previous fetus with an NTD
and others at high risk (e.g., diabetes, sickle cell anemia), a dose of
5 mg daily is recommended when pregnancy is contemplated and
throughout the subsequent pregnancy.
Infancy and Childhood  The incidence of folate deficiency is so
high in the smallest premature babies during the first 6 weeks of
life that folic acid (e.g., 1 mg daily) should be given routinely to
those weighing <1500 g at birth and to larger premature babies who
require exchange transfusions or develop feeding difficulties, infec­
tions, or vomiting and diarrhea.
The World Health Organization currently recommends routine
supplementation with iron and folic acid in children in countries
where iron deficiency is common and child mortality, largely due
to infectious diseases, is high. However, some studies suggest that in
areas where malaria rates are high, this approach may increase the
incidence of severe illness and death. Even where malaria is rare,
there appears to be no survival benefit.
MEGALOBLASTIC ANEMIA NOT DUE TO
COBALAMIN OR FOLATE DEFICIENCY OR
ALTERED METABOLISM
This may occur with many antimetabolite drugs (e.g., hydroxyurea,
cytarabine, mercaptopurine, thioguanine) that inhibit DNA replica­
tion. Antiviral nucleoside analogues used in treatment of HIV infec­
tion may also cause macrocytosis and megaloblastic marrow changes.
In the rare disease orotic aciduria, two consecutive enzymes in purine
synthesis are defective. The condition responds to therapy with uridine,
which bypasses the block. In thiamine-responsive megaloblastic ane­
mia, there is a genetic defect in the high-affinity thiamine transporter
(SLC19A2) gene. This causes defective RNA ribose synthesis through
impaired activity of transketolase, a thiamine-dependent enzyme in the
pentose cycle. This defect leads to reduced nucleic acid production. It
may be associated with diabetes mellitus and deafness and the presence
of many ringed sideroblasts in the marrow. The explanation is unclear
for megaloblastic changes in the marrow in some patients with acute
myeloid leukemia and myelodysplasia.
The most frequent causes of macrocytosis without megaloblastic
changes are alcohol, liver disease, hypothyroidism, and pregnancy.
Myelodysplasia, myeloma and other paraproteinemias, aplastic ane­
mia, and smoking are other causes.
■
■FURTHER READING
Berry RJ: Lack of historical evidence to support folic acid exacerbation
of the neuropathy caused by vitamin B12 deficiency. Am J Clin Nutr
110:554, 2019.
Bunn HF: Vitamin B12 and pernicious anemia: The dawn of molecular
medicine. N Engl J Med 370:773, 2014.
Del Bo C et al: Effect of two different sublingual dosages of vitamin
B12 on cobalamin nutritional status in vegans and vegetarians with a
marginal deficiency: A randomized controlled trial. Clin Nutr 38:575,
2019.
Green R: Vitamin B12 deficiency from the perspective of a practicing
hematologist. Blood 129:2603, 2017.
Green R et al: Vitamin B12 deficiency. Nat Rev Dis Primers 3:17040,
2017.
Hesdorffer CS, Longo DL: Drug-induced megaloblastic anemia.
N Engl J Med 373:1649, 2015.
Hoffbrand V: The Folate Story: A Vitamin Under the Microscope.
Leicestershire, UK, Troubador Publishing, 2023.
Kancherla V et al: Preventing birth defects, saving lives, and promot­
ing health equity: An urgent call to action for universal mandatory
food fortification with folic acid. Lancet Global Health 10:e1053, 2022.
Ma F et al: Effects of folic acid and vitamin B12 alone and in combina­
tion on cognitive function and inflammatory factors in the elderly
with mild cognitive impairment: A single blind experimental design.
Curr Alzheimer Res 16:622, 2019.
Miller JW: Proton pump inhibitors, H2-receptor antagonists, metfor­
min, and vitamin B-12 deficiency: Clinical implications. Adv Nutr
9:511S, 2018.
O’connor DMA et al: Low folate predicts cognitive decline: 8-year fol­
low–up of 3140 older adults in Ireland. Eur J Clin Nutr 76:950, 2022.
Rogers LM et al: Global folate status in women of reproductive age: A
systematic review with emphasis on methodological issues. Ann N Y
Acad Sci 1431:35, 2018.
Salinas M et al: High frequency of anti-parietal cell antibody (APCA)
and intrinsic factor blocking antibody (IFBA) in individuals with
severe vitamin B12 deficiency: An observational study in primary
care patients. Clin Chem Lab Med 58:424, 2020.
Wald NJ: Folic acid and neural tube defects: Discovery, debate and the
need for policy change. J Med Screening 29:138, 2022.
Zaric BL et al: Homocysteine and hyperhomocysteinaemia. Curr Med
Chem 26: 2948, 2019.

35 - 105 Hemolytic Anemias
105 Hemolytic Anemias
Lucio Luzzatto, Lucia De Franceschi
Hemolytic Anemias
■
■DEFINITIONS
Turnover is typical of all blood cells, including erythrocytes, that have a
finite life span. Hence, a logical, time-honored classification of anemias
is in three groups: (1) decreased production of red cells, (2) increased
destruction of red cells, and (3) acute blood loss. Decreased production
is covered in Chaps. 102, 103, and 107; acute blood loss in Chap. 106;
increased destruction is covered in this chapter.
All patients who are anemic as a result of either increased destruc­
tion of red cells or acute blood loss have one important element in
common: the anemia results from overconsumption of red cells from
the peripheral blood, whereas the supply of cells from the bone marrow is
normal (indeed, it is usually increased). However, with blood loss, as in
acute hemorrhage, the red cells are physically lost from the body itself;
this is fundamentally different from destruction of red cells within the
body, as in hemolytic anemias (HAs).
With respect to primary etiology, HAs may be inherited or acquired;
from a clinical point of view, they may be more acute or more chronic,
and they may vary from mild to very severe; the site of hemolysis may
be predominantly intravascular or extravascular. With respect to mech­
anisms, HAs may be due to intracorpuscular causes or to extracorpus­
cular causes (Table 105-1). But before reviewing the individual types
of HA, it is appropriate to consider what general features they have in
common, in terms of clinical aspects and pathophysiology.
■
■GENERAL CLINICAL AND LABORATORY
FEATURES
The clinical presentation of a patient with anemia is greatly influenced
in the first place by whether the onset is abrupt or gradual, and HAs are
no exception. A patient with autoimmune HA or with favism may be
a medical emergency, whereas a patient with mild hereditary sphero­
cytosis (HS) or with cold agglutinin disease (CAD) may be diagnosed
after years. This is due in large measure to the remarkable ability of
the body to adapt to anemia when it is slowly progressing (Chap. 66).
What differentiates HAs from other anemias is that the patient has
signs and symptoms arising directly from hemolysis (Table 105-2). At
the clinical level, the main sign is jaundice; in addition, the patient may
report discoloration of the urine. In many cases of HA, the spleen is
enlarged because it is a preferential site of hemolysis; in some cases, the
liver may be enlarged as well; and gallstones are common. In all severe
congenital forms of HA, there may also be skeletal changes due to over­
activity of the bone marrow: they are never as severe as in thalassemia
TABLE 105-1  Classification of Hemolytic Anemiasa
EXTRACORPUSCULAR
FACTORS
 
INTRACORPUSCULAR DEFECTS
Inherited
Hemoglobinopathies
Enzymopathies
Membrane-cytoskeletal defects
Familial (atypical) hemolyticuremic syndrome
Acquired
Paroxysmal nocturnal
hemoglobinuria (PNH)
Mechanical destruction
(microangiopathic)
Toxic agents
Drugs
Infectious
Autoimmune
aHereditary causes correlate with intracorpuscular defects because these defects
are due to inherited mutations; the one exception is PNH because the defect is
due to an acquired somatic mutation. Conversely, acquired causes correlate with
extracorpuscular factors because mostly these factors are exogenous; the one
exception is familial hemolytic-uremic syndrome (HUS; often referred to as atypical
HUS [aHUS]) because here an inherited abnormality permits complement activation
triggered by exogenous factors to become excessive, with bouts of production of
membrane attack complex capable of destroying normal red cells. Interestingly, in
both PNH and aHUS, hemolysis is complement-mediated.
TABLE 105-2  Features Common to Most Patients with a Hemolytic
Disorder
GENERAL EXAMINATION
JAUNDICE, PALLOR
Other physical findings
Spleen may be enlarged; bossing of skull in severe
congenital cases
Hemoglobin level
From normal to severely reduced
MCV, MCH
Usually increased
Reticulocytes
Usually increased
Bilirubin
Almost always increased (mostly unconjugated)
LDH
Increased (up to 10× normal with intravascular
hemolysis)
Haptoglobin
Reduced to absent if hemolysis is at least in part
intravascular
Abbreviations: LDH, lactate dehydrogenase; MCH, mean corpuscular hemoglobin;
MCV, mean corpuscular volume.
major because ineffective erythropoiesis is less, or even absent. Since
several forms of HA are inherited, it is important to include family his­
tory in the initial appraisal.
The laboratory features of HA are related to (1) hemolysis per se
and (2) the erythropoietic response of the bone marrow. In most
cases, hemolysis is largely extravascular, and it produces an increase
in unconjugated bilirubin and aspartate aminotransferase (AST) in
the serum; urobilinogen will be increased in both urine and stool. If
hemolysis is mainly intravascular, the telltale sign is hemoglobinuria
(often associated with hemosiderinuria); in the serum, there is free
hemoglobin, lactate dehydrogenase (LDH) is increased, and haptoglo­
bin is reduced. In contrast, the serum bilirubin level may be normal
or only mildly elevated. The main sign of the erythropoietic response
by the bone marrow is an increase in reticulocytes (a test all too often
neglected in the initial workup of a patient with anemia). Usually the
increase will be reflected in both the percentage of reticulocytes (the
more commonly quoted figure) and in the absolute reticulocyte count
(the more definitive parameter). The increased number of reticulocytes
is associated with an increased mean corpuscular volume (MCV) in
the blood count. On the blood smear, this is reflected in the presence
of macrocytes; polychromasia is also present, and sometimes one
sees nucleated red cells. In most cases, a bone marrow aspirate is not
necessary in the diagnostic workup; if it is done, it will show erythroid
hyperplasia. In practice, once an HA is suspected, specific tests will
usually be required for a definitive diagnosis of a specific type of HA.
CHAPTER 105
Hemolytic Anemias
■
■GENERAL PATHOPHYSIOLOGY
The mature red cell is the product of a developmental pathway that
brings the phenomenon of differentiation to an extreme. An orderly
sequence of events produces synchronous changes, whereby the
gradual accumulation of a huge amount of hemoglobin in the cyto­
plasm (to a final level of 340 g/L, i.e., about 5 mM) goes hand in hand
with the gradual loss of cellular organelles and of biosynthetic abilities.
In the end, the erythroid cell undergoes a process that has features of
apoptosis, including nuclear pyknosis and eventually extrusion of the
nucleus. However, the final result is more altruistic than suicidal; the
cytoplasmic body, instead of disintegrating, is now able to provide oxy­
gen to all cells in the human organism for some remaining 120 days of
the red cell life span.
As a result of this unique process of differentiation and maturation,
intermediary metabolism is drastically curtailed in mature red cells
(Fig. 105-1); for instance, cytochrome-mediated oxidative phosphory­
lation has been lost with the loss of mitochondria (through a process
of physiologic autophagy); therefore, there is no backup to anaerobic
glycolysis, which in the red cell is the only provider of adenosine tri­
phosphate (ATP). Also, the capacity of making protein has been lost
with the loss of ribosomes. This places the cell’s limited metabolic
apparatus at risk, because if any protein component deteriorates, it
cannot be replaced, as it would be in most other cells; and in fact,
the activity of most enzymes gradually decreases as red cells age. At
the same time, during their long time in circulation, various red cell
Embden-Meyerhof pathway
Hexose monophosphate shunt
Glutathione
reductase
GSH
GSSG
glucose
hexokinase
ATP
NADPH
NADP+
ADP
glucose-6-phosphate
6-phosphogluconate
G6PD
glucose phosphate
isomerase
fructose-6-phosphate
ATP
ADP
phosphofructokinase
fructose-1, 6-diphosphate
aldolase
glyceraldehyde-3-phosphate
NAD+
glyceraldehyde 3-phosphate
dehydrogenase
HbFe2+
NADH
HbFe3+
2,3-bisphosphoglycerate mutase
1,3-bisphosphoglycerate
ADP
phosphoglycerate
kinase
2,3-bisphosphoglycerate
ATP
2,3-bisphosphoglycerate phosphatase
3-phosphoglycerate
PART 4
Oncology and Hematology
3-phosphoglycerate
mutase
2-phosphoglycerate
enolase
phosphoenolpyruvate
pyruvate kinase
ADP
ATP
pyruvate
NADH
lactate
dehydrogenase
NAD+
lactate
FIGURE 105-1  Red blood cell (RBC) metabolism. The Embden-Meyerhof pathway
(glycolysis) generates ATP required for cation transport and for membrane
maintenance. The generation of NADH maintains hemoglobin iron in a reduced
state. The hexose monophosphate shunt generates NADPH that is used to
reduce glutathione, which protects the red cell against oxidant stress; the
6-phosphogluconate, after decarboxylation, can be recycled via pentose sugars to
glycolysis. Regulation of the 2,3-bisphosphoglycerate level is a critical determinant
of oxygen affinity of hemoglobin. Enzyme deficiency states in order of prevalence:
glucose-6-phosphate dehydrogenase (G6PD) > pyruvate kinase > glucose-6phosphate isomerase > rare deficiencies of other enzymes in the pathway. The
more common enzyme deficiencies are encircled.
components inevitably accumulate damage and become physically
denser. The anion exchanger known as band 3 is the most abundant pro­
tein in the red cell membrane (Fig. 105-2 and Table 105-3), with about
1.2 million molecules per red cell. As red cells age and become denser,
probability is increased that a region of the band 3 molecule becomes
exposed on the cell surface and contributes to creating an antigenic
site recognizable by low-avidity naturally occurring anti–band 3
IgG antibodies. This process might be enhanced by the clustering of
band 3 molecules favored by the antibody itself and by the binding
of hemichromes arising from hemoglobin degradation. Senescent red
cells thus become opsonized, and this is the signal for phagocytosis by
macrophages in the spleen, in the liver, and elsewhere. This process
may become accelerated in various ways in HA.
Another consequence of the relative simplicity of red cells is that
they have a limited range of ways to manifest distress under hardship;
in essence, any sort of metabolic failure will eventually lead either to
structural damage to the membrane or to failure of the cation pump. In
either case, the life span of the red cell is reduced, which is the defini­
tion of a hemolytic disorder. If the rate of red cell destruction exceeds
the capacity of the bone marrow to produce more red cells, the hemo­
lytic disorder will manifest as HA.
Thus, the essential pathophysiologic process common to all HAs is
an increased red cell turnover; in many HAs, this is due at least in part
to an acceleration of the senescence process described above. The gold
standard for proving that the life span of red cells is reduced (compared
to the normal value of ~120 days) is a red cell survival study, which can
be carried out by labeling the red cells with 51Cr and measuring the fall
in radioactivity over several days or weeks (this classic test can now be
replaced by a methodology using the nonradioactive isotope 15N). If the
hemolytic event is transient, it does not usually cause any long-term
consequences, except for an increased requirement for erythropoietic
factors, particularly folic acid. However, if hemolysis is recurrent or
persistent, the increased bilirubin production favors the formation of
gallstones. If a considerable proportion of hemolysis takes place in the
spleen, as is often the case, splenomegaly may become increasingly a
feature, and hypersplenism may develop, with consequent neutropenia
and/or thrombocytopenia.
The increased red cell turnover has important consequences. In nor­
mal subjects, the iron from effete red cells is very efficiently recycled by
the body; however, with chronic intravascular hemolysis, the persistent
hemoglobinuria will cause considerable iron loss, needing replace­
ment. With chronic extravascular hemolysis, the opposite problem,
iron overload, is more common, especially if the patient needs frequent
blood transfusions. Even without blood transfusion, when erythropoi­
esis is massively increased, the release of erythroferrone from erythroid
cells suppresses hepcidin, causing increased iron absorption. In the
long run, in the absence of iron-chelation therapy, iron overload will
cause secondary hemochromatosis; this will cause damage particularly
to the liver, eventually leading to cirrhosis, and to the heart muscle,
eventually causing heart failure.
Compensated Hemolysis versus Hemolytic Anemia 
Red cell
destruction is a potent stimulus for erythropoiesis, which is mediated
by erythropoietin (EPO) produced by the kidney. This mechanism is so
effective that in many cases the increased output of red cells from the
bone marrow can fully balance an increased destruction of red cells. In
such cases, we say that hemolysis is compensated. The pathophysiology of
compensated hemolysis is similar to what we have just described, except
there is no anemia. This notion is important from the diagnostic point
of view, because a patient with a hemolytic condition, even an inherited
one, may present without anemia; and it is also important from the point
of view of management because compensated hemolysis may become
“decompensated,” i.e., anemia may suddenly appear in certain circum­
stances, for instance in pregnancy, folate deficiency, or renal failure inter­
fering with adequate EPO production. Another general feature of chronic
HAs is seen when any intercurrent condition, such as an acute infection,
depresses erythropoiesis. When this happens, in view of the increased rate
of red cell turnover, the effect will be predictably much more marked than
in a person who does not have hemolysis. The most dramatic example is
infection by parvovirus B19, which may cause a rather precipitous fall in
hemoglobin—an occurrence sometimes referred to as aplastic crisis.
■
■INHERITED HEMOLYTIC ANEMIAS
The red cell has three essential components: (1) hemoglobin, (2) the
membrane-cytoskeleton complex, and (3) the metabolic machinery
necessary to keep hemoglobin and the membrane-cytoskeleton com­
plex in working order. Diseases caused by inherited abnormalities of
hemoglobin, or hemoglobinopathies, are covered in Chap. 103. Here
we will deal with diseases of the other two components.
Hemolytic Anemias due to Abnormalities of the MembraneCytoskeleton Complex 
The detailed architecture of the red cell
membrane is complex, but its basic design is relatively simple (Fig.
105-2). The lipid bilayer incorporates phospholipids and cholesterol,
and it is spanned by a number of proteins that have their hydrophobic
transmembrane domain(s) embedded in the membrane; most of these
proteins also extend to both the outside (extracellular domains) and
the inside of the cell (cytoplasmic domains). Other proteins are teth­
ered to the membrane through a glycosylphosphatidylinositol (GPI)
anchor; these have only an extracellular domain. Membrane proteins
include energy-dependent ion transporters, ion channels, receptors
Ankyrin complex
RhAG
AChE
CD59
Rh
KCNN4
ABCB6
Band 3
Band 3
CD47
PIEZO1
4.2
GPA
Adducin
-Spectrin
4.1R
Ankyrin
-Spectrin
Tropomyosin
Self-association site
PIEZO1
KCNN4
ABCB6
Glut1
Band 3
HCO3
–
Cl–
Na+
K+
Ca2+
Glucose
FIGURE 105-2  The red cell membrane and cytoskeleton schematic diagram. Within the membrane lipid bilayer, several
integral membrane proteins are shown (see inset). Other proteins, e.g., acetylcholinesterase (AChE) and the two
complement-regulatory proteins CD59 and CD55, are tethered to the membrane through the glycosylphosphatidylinositol
(GPI) anchor: in these cases, the entire polypeptide chain is extracellular. Many of the membrane proteins bear
polypeptide and/or carbohydrate red cell antigens. Underneath the membrane, the α-β spectrin dimers, which
associate head-to-head into tetramers, together with actin and other proteins, form most of the cytoskeleton. The
ankyrin complex, which also involves the band 4.2 protein, and the junctional complex, which involves the band 4.1
protein and dematin, connect the membrane to the cytoskeleton. The ankyrin complex provides mainly radial (also
called vertical) connections; the junctional complex provides mainly tangential (also called horizontal) connections.
Pathogenic changes in the former can cause spherocytosis, whereas pathogenic changes in the latter can cause
elliptocytosis; pathogenic changes in spectrin can cause either. Branched lines symbolize carbohydrate moiety of
proteins. The various molecules are obviously not drawn to the same scale. Inset. Schematic diagram of membrane
transporters, abnormalities of which underlie channelopathies. Band 3 (anion exchanger 1 [AE1]) is the most abundant.
Mutations of SLC4A1 (encoding band 3) can inactivate anion exchange, causing cation leak or negatively affecting
interactions with neighboring membrane proteins. PIEZO1 is a huge protein that is embedded in the membrane as a
homo-trimer with a three-bladed, propeller-shaped structure; it is a mechano-sensitive cation channel. KCNN4 encodes
a Ca2+ activated K+ channel, also known as the Gardos channel. PIEZO1 mutations can be associated with abnormal Ca2+
entry, resulting in overactivation of the Gardos channel; this promotes K+ efflux and red cell dehydration Mutations on
KCC4 induce alterations of channel properties (kinetic or ion trafficking), resulting again in abnormal K+ efflux and red
cell dehydration. ABCB6 encodes a mitochondrial porphyrin transporter, but some mutations can cause increased K+
efflux from red cells and stomatocytosis. Glut1 facilitates glucose transport; it is encoded by SLC2A1, and mutations can
block the glucose transport and induce Na+, K+ leakage. (Modified from N Young et al: Clinical Hematology. Philadelphia,
Elsevier, 2006; and from A Iolascon et al: Br J Haematol 187:13, 2019.)
for complement components, and receptors for other ligands. The
most abundant red cell membrane proteins are glycophorins and the
so-called band 3, an anion transporter that is an integral membrane
protein. The extracellular domains of many of these proteins are heav­
ily glycosylated, and they carry antigenic determinants that correspond
to blood groups. Underneath the membrane, and tangential to it, is a
network of other proteins that make up the cytoskeleton. The main
cytoskeletal protein is the spectrin tetramer, consisting of a headto-head association of two α-spectrin-β-spectrin heterodimers. The
cytoskeleton is linked to the membrane through the ankyrin complex
(that includes also band 4.2) and the junctional complex (that includes
adducin and band 4.1) (Fig. 105-2). These multiprotein complexes
make membrane and cytoskeleton intimately connected to each other,
thus supporting membrane stability and at the same time providing the
erythrocyte with the important property of deformability.
The membrane-cytoskeleton complex
has essentially three functions: it is an
envelope for the red cell cytoplasm; it
maintains the normal red cell shape;
and it provides cross-membrane trans­
port of electrolytes and of metabolites
such as glucose and amino acids. In
the membrane-cytoskeleton complex,
the individual components are so inti­
mately associated with each other that
an abnormality of almost any of them
will be disturbing or disruptive, causing
mechanical instability of the membrane
and/or reduced red cell deformability,
ultimately causing hemolysis. These
abnormalities are almost invariably
inherited mutations; thus, diseases of the
membrane-cytoskeleton complex belong
to the category of inherited HAs. Before
the red cells lyse, they often exhibit
more or less specific changes that alter
the normal biconcave disk shape. Thus,
the majority of the diseases in this group
have been known for over a century
as hereditary spherocytosis (HS) and
hereditary elliptocytosis (HE). More
recently, a third morphologic entity,
whereby on a blood smear the roundshaped central pallor of a red cell is
replaced by a linear-shaped central pale
area, has earned the name stomatocytosis;
because this abnormal shape is related to
abnormalities of channel molecules, the
underlying disorders are also referred
to as channelopathies. From an under­
standing of the molecular basis of these
disorders, it has emerged (Table 105-3)
that, although these disorders are pre­
dominantly monogenic, no one-to-one
correlation exists between a certain gene
and a certain disorder. Rather, what has
been regarded as a single disorder (e.g.,
HS) can arise through mutation of one of
several genes; conversely, what have been
regarded as different disorders can arise
through different mutations of the very
same gene (Fig. 105-3).
Junctional complex
CD55
GPC
Glut1
p55
Dematin
Actin protofilament
Tropomodulin
CHAPTER 105
Hemolytic Anemias
HEREDITARY
SPHEROCYTOSIS  This
is most common among this group of
HAs, with an estimated prevalence of
1:2000–1:5000 in populations of European
ancestry. Its identification is credited to
Minkowksy and Chauffard, who, at the
end of the nineteenth century, reported families who had spherocytes in
their peripheral blood (Fig. 105-4A). In vitro studies revealed that the red
cells were abnormally susceptible to lysis in hypotonic media; indeed, the
increase in osmotic fragility became the main diagnostic test for HS. Today
we know that HS, thus defined, is genetically heterogeneous; i.e., it can arise
from a variety of mutations in one of several genes (Table 105-3). It has been
also recognized that the inheritance of HS is not always autosomal domi­
nant (with the patient being heterozygous); indeed, some of the most severe
forms are instead autosomal recessive (with the patient being homozygous).
Clinical Presentation and Diagnosis  The spectrum of clinical severity of
HS is broad. Severe cases may present in infancy with severe anemia,
whereas mild cases may present in young adults or even later in life.
The main clinical findings are jaundice, an enlarged spleen, and often
gallstones; indeed, it may be the finding of gallstones in a young person
that triggers diagnostic investigations.
TABLE 105-3  Inherited Diseases of the Red Cell Membrane-Cytoskeleton Complex
CHROMOSOMAL
LOCATION
PROTEIN PRODUCED
DISEASE(S) WITH CERTAIN
MUTATIONS (INHERITANCE)
COMMENTS
GENE
SPTA1
1q22-q23
α-Spectrin
HS (recessive)
Rare
 
 
 
HE (dominant)
Mutations of this gene account for about 65% of HE. More severe
forms may be due to coexistence of an otherwise silent mutant allele.
SPTB
14q23-q24.1
β-Spectrin
HS (dominant)
Rare
 
 
 
HE (dominant)
Mutations of this gene account for about 30% of HE, including some
severe forms.
ANK1
8p11.2
Ankyrin
HS (dominant)
May account for majority of HS.
SLC4A1
17q21
Band 3; also known as AE (anion
exchanger) or AE1
HS (dominant)
Mutations of this gene may account for about 25% of HS.
Southeast Asia ovalocytosis
(dominant)
Stomatocytosis
(cryohydrocytosis)
EPB41
1p33-p34.2
Band 4.1
HE (dominant)
Mutations of this gene account for about 5% of HE, mostly with
prominent morphology but little/no hemolysis in heterozygotes; severe
hemolysis in homozygotes.
EPB42
15q15-q21
Band 4.2
HS (recessive)
Mutations of this gene account for about 3% of HS.
RHAG
6p21.1-p11
Rhesus-associated glycoprotein
Chronic nonspherocytic
hemolytic anemia (recessive)
PART 4
Oncology and Hematology
PIEZO1
16q23-q24
PIEZO1 (mechanosensitive ion
channel component 1 channel)
Dehydrated hereditary
stomatocytosis (dominant)
KCNN4
19q13.31
KCNN4
Intermediate conductance
calcium-activated potassium
channel protein 4 (Gardos
channel)
Dehydrated hereditary
stomatocytosis (dominant)
ABCB6
2q35-q36
ATP-binding cassette subfamily
B member 6
Familial pseudohyperkalemia
(dominant)
SLC2A1
1p34.2
GLUT1 glucose transporter
Overhydrated hereditary
stomatocytosis
Note: PIEZO1, KCNN4, ABCB6, and GLUT1 are channel molecules; conditions associated with mutations in the respective genes are appropriately named channelopathies.
Abbreviations: HE, hereditary elliptocytosis; HS, hereditary spherocytosis.
The variability in clinical manifestations that is observed among
patients with HS is largely due to the different underlying molecular
lesions (Table 105-3). Not only are mutations of several genes involved,
ANK1
EPB42
HS
SPTA1
SPTB
SLC4A1
EPB41
HE
SLC2A1
RHAG
PIEZ01
HSt
KCNN4
ABCB6
FIGURE 105-3  Hereditary spherocytosis (HS), hereditary elliptocytosis (HE),
and hereditary stomatocytosis (HSt) are three morphologically distinct forms of
congenital hemolytic anemia. It has emerged that each one can arise from mutation
of one of several genes and that different mutations of the same gene can give one
or another form. (See also Table 105-3.) Genes encoding membrane proteins are in
black; genes encoding cytoskeleton proteins are in green; genes encoding proteins
in the junctional and ankyrin complexes are in purple.
Polymorphic mutation (deletion of nine amino acids); in
heterozygotes, clinically asymptomatic and protective against
Plasmodium falciparum.
Certain specific missense mutations shift protein function from anion
exchanger to cation conductance.
Very rare; associated with total loss of all Rh antigens.
One specific mutation in this gene entails loss of stomatin from the
cell membrane, causing overhydrated stomatocytosis.
Also known as xerocytosis with pseudohyperkalemia. Patients may
present with perinatal edema.
Clinical presentation similar to that of PIEZO1 mutants.
Increased potassium leakage upon storage in blood bank condition:
this can cause hyperkalemia in the recipient. ABCB6 mutation is
present in 0.3% of blood donors.
Associated with serious neurologic manifestations.
but also different mutations of the same gene can give very different
clinical manifestations. In milder cases, hemolysis is often compen­
sated (see above), but changes in clinical expression may be seen even
in the same patient because intercurrent conditions (e.g., pregnancy,
infection) may cause decompensation. The anemia is usually nor­
mocytic with the characteristic morphology that gives the disease its
name. An increased mean corpuscular hemoglobin concentration
(MCHC >34 g/dL) and increased red cell distribution width (RDW
14%) associated with normal or slightly decreased MCV on an
ordinary blood count report should raise the suspicion of HS. The
spleen plays a key role in HS through a dual mechanism. On one hand,
because HS red cells are less deformable, transit through the splenic
circulation makes them more prone to vesiculate; on the other hand,
like in many other HAs, the spleen itself is a major site of destruction
through phagocytosis by macrophages.
When there is a family history, it is usually easy to make a diagnosis
based on features of HA and typical red cell morphology. However, fam­
ily history may be negative for at least two reasons. First, the patient may
have a de novo mutation, i.e., a mutation that has taken place in a germ
cell of one of the patient’s parents or early after zygote formation. Second,
the patient may have a recessive form of HS (Table 105-3). In such cases,
more extensive laboratory investigations are required, including osmotic
fragility, the acid glycerol lysis test, the eosin-5′-maleimide (EMA)–bind­
ing test, sodium dodecyl sulfate (SDS)-gel electrophoresis of membrane
proteins, and ektacytometry (testing red cell deformability as a function
of shear stress at different osmolality); these tests are usually carried out
in laboratories with special expertise in this area. Sometimes a definitive
diagnosis can be obtained only by molecular studies demonstrating a
mutation in one of the genes underlying HS (Table 105-3).
TREATMENT
Hereditary Spherocytosis
We do not have a causal treatment for HS; i.e., no way has yet been
found to correct the basic defect in the membrane-cytoskeleton
structure. Given the special role of the spleen in HS (see above), sple­
nectomy is often beneficial. Current recommendations are to proceed
with splenectomy at the age of 4–6 years in severe cases, to delay sple­
nectomy until puberty in moderate cases, and to avoid splenectomy
in mild cases. Partial splenectomy can be considered in certain cases,
and it is helpful to know about the outcome of splenectomy in the
patient’s affected relatives. Before splenectomy, vaccination against
encapsulated bacteria (Neisseria meningitidis and Streptococcus pneu­
moniae) is imperative; penicillin prophylaxis after splenectomy is
controversial. Along with splenectomy, cholecystectomy should not
be carried out automatically, but it should be carried out, usually by
the laparoscopic approach, whenever it is clinically indicated, mainly
when gallstones are symptomatic. The most severe cases of HS (esti­
mated at <10%) are transfusion dependent, and in infants with severe
HS, erythropoietin may prove to be transfusion sparing.
HEREDITARY ELLIPTOCYTOSIS  HE is at least as heterogeneous as HS,
both from the genetic point of view (Table 105-3, Fig. 105-3) and from
the clinical point of view. The global incidence of HE is 1:2000–4000
subjects. Again, it is the shape of the red cells (Fig. 105-4B) that gives
the name to the condition, but there is no direct correlation between
the elliptocytic morphology and clinical severity. In fact, some mild or
even asymptomatic cases may have nearly 100% elliptocytes (or ovalo­
cytes). Indeed, the diagnosis of HE is generally incidental, because
hemolysis may be compensated and there may be no anemia, although
this may become evident in the course of infection. One particular
in-frame deletion of nine amino acids in the SLC4A1 gene encoding
band 3 underlies the so-called Southeast Asia ovalocytosis (SAO): it
is not a disease, but rather a polymorphism with a frequency of up
to 5–7% in certain populations (e.g., Papua New Guinea, Indonesia,
Malaysia, Philippines), presumably as a result of malaria selection. It
is asymptomatic in heterozygotes and probably lethal in homozygotes.
The cases of HE with the most severe HA are those with biallelic muta­
tions of one of the genes involved (see Fig. 105-3), and these are said
to have hereditary pyropoikilocytosis (HPP): here the instability of the
cytoskeleton protein network may result from decreased tetrameriza­
tion of spectrin dimers. The red cell volume is decreased (MCV:
50–60 fL), and all kinds of bizarre poikilocytes are seen on the blood
smear (Fig. 105-4C). HPP patients have splenomegaly and often ben­
efit from splenectomy.
Channelopathies 
These rare conditions (see Fig. 105-3) are char­
acterized by abnormalities in red cell ion content and alteration of
erythrocyte volume. Cation leak can cause hyperkalemia; in some
cases, this leak is accelerated in the cold (the resulting spuriously high
serum K+ is then referred to as pseudo-hyperkalemia). The less rare
form, dehydrated stomatocytosis (DHS; also referred to as xerocyto­
sis), is a (usually compensated) macrocytic hemolytic disorder, with
increased MCHC (generally >36 g/dL) associated with mild jaundice.
Mutations in either PIEZO1, encoding an ion channel activated by
pressure (mechanoreceptor), or in KCCN4, encoding the Ca2+ activated
K+ channel (Gardos channel) have been recognized to cause DHS (see
Table 105-3).
Another form is overhydrated stomatocytosis (OHS). OHS is also
macrocytic (MCV >110 fL), but the MCHC is low (<30 g/dL). The
underlying mutation is in the Rhesus gene RHAG, which encodes an
ammonia channel. Yet other patients with stomatocytosis (Table 105-3)
have mutations in SLC4A1 (encoding band 3) and SLC2A1 (encoding
the glucose transporter GLUT1). Mutations of the latter are responsible
for cryohydrocytosis, a channelopathy in which the red cells swell and
burst when they are cooled. In vivo hemolysis can vary from relatively
mild to quite severe. Familial hyperkalemia has been recently linked
to mutations in ABCB6, resulting in abnormal cation leak with extra­
cellular release of a large amount of K+ (hyperkalemia). Mutations in
A
CHAPTER 105
Hemolytic Anemias
B
C
FIGURE 105-4  Peripheral blood smear from patients with membrane-cytoskeleton
abnormalities. A. Hereditary spherocytosis. B. Hereditary elliptocytosis,
heterozygote. C. Pyropoikilocytosis, with both alleles of the α-spectrin gene
mutated.
ABCB6 have been identified in almost 0.3% of blood donors. However,
splenectomy is contraindicated in stomatocytosis due to the significant
proportion of severe thromboembolic complications observed in sple­
nectomized DHS patients.
Laser diffraction analysis, or ektacytometry, can measure the
deformability of red blood cells subjected to either increasing shear
stress or to an osmotic stress. This technique has been used extensively
to investigate membrane-cytoskeleton abnormalities, and it can differ­
entiate stomatocytosis from spherocytosis.
Enzyme Abnormalities 
When an important defect in a compo­
nent of the membrane-cytoskeleton complex is present, hemolysis is
a direct consequence of the fact that the very structure of the red cell
is compromised. Instead, when one of the enzymes is defective, the
consequences will depend on the precise role of that enzyme in the
metabolic machinery of the red cell. This machinery has two main
functions: (1) to provide energy in the form of ATP, and (2) to prevent
oxidative damage to hemoglobin and to other proteins by providing
sufficient reductive potential; the key molecule for this is NADPH,
required for regeneration of glutathione (GSH) and for degradation
of H2O2.
ABNORMALITIES OF THE GLYCOLYTIC PATHWAY  Because red cells,
in the course of their differentiation, have sacrificed not only their
nucleus and their ribosomes but also their mitochondria, they rely
exclusively on the anaerobic portion of the glycolytic pathway for
producing ATP, most of which is required by the red cell for cation
transport against a concentration gradient across the membrane. If
this fails due to a defect of any of the enzymes of the glycolytic pathway
(Table 105-4), the result will be hemolytic disease.
PART 4
Oncology and Hematology
Pyruvate Kinase Deficiency  Abnormalities of the glycolytic pathway are
all inherited and all rare. Among them, deficiency of pyruvate kinase
(PK) is the least rare, with an estimated prevalence in most populations
of 1:10,000. However, recently, a polymorphic PK mutation (E277K)
was found in some African populations with heterozygote frequen­
cies of 1–7%, suggesting that this may be another malaria-related
TABLE 105-4  Red Cell Enzyme Abnormalities Causing Hemolysis
GENE SYMBOL;
CHROMOSOMAL
LOCATION
PREVALENCE OF ENZYME
DEFICIENCY (RANK)
ENZYME (ACRONYM)
Glycolytic Pathway
Hexokinase (HK)
HK1; 10q22
Very rare
 
May benefit from splenectomy; BMTc
Glucose-6-phosphate isomerase (G6PI)
GPI; 19q31.1
Rare (4); at least 60 cases
reporteda
NM, CNS
May benefit from splenectomy
Phosphofructokinase (PFK)b
PFKM; 12q13
Very rare
Myopathy;
myoglobinuria
Aldolase
ALDOA; 16q22-24
Very rare
Myopathy
 
Triose phosphate isomerase (TPI)
TPI1; 12p13.31
Very rare
CNS (severe), NM
 
Glyceraldehyde 3-phosphate
dehydrogenase (GAPD)
GAPDH; 12p13.31
Very rare
Myopathy
 
Bisphosphoglycerate mutase (BPGM)
BPGM; 7q33
Very rare
 
Erythrocytosis rather than hemolysis;
some of the rare mutations are in the
enzyme active site
Phosphoglycerate kinase (PGK)
PGK1; Xq21.1
Very rare
CNS, NM
May benefit from splenectomy; BMTc
Pyruvate kinase (PK)
PKLR; 1q22
Rare (2)a
 
May benefit from splenectomy; BMTc
Redox
Glucose-6-phosphate dehydrogenase
(G6PD)
G6PD; Xq28
Common (1)a
Very rarely granulocytes In almost all cases, only AHA from
Glutathione synthase
GSS; 20q11.22
Very rare
CNS
 
Glutathione reductase
GSR; 8p12
Very rare
Cataracts
AHA from exogenous trigger (favism)
γ-Glutamylcysteine synthase
GCLC; 6p12.1
Very rare
CNS
Mutations affect catalytic subunit
Cytochrome b5 reductase
CYB5R3; 22q13.2
Rare
CNS
Methemoglobinemia rather than
hemolysis
Nucleotide Metabolism
Adenylate kinase (AK)
AK1; 9q34.11
Very rare
CNS
May benefit from splenectomy
Pyrimidine 5’ nucleotidase (P5N)
NTSC3A; 7p14.3
Rare (3)a
 
May benefit from splenectomy
aThe numbers from (1) to (4) indicate the ranking order of these enzymopathies in terms of frequency. bPFK deficiency is associated with increased glycogen in muscle, and
it is also known as glycogen storage disease type VII or Tarui’s disease. cOccasional report of successful treatment of the hematologic manifestations by BMT.
Abbreviations: AHA, acquired hemolytic anemia; BMT, bone marrow transplantation; CNS, central nervous system; NM, neuromuscular.
polymorphism. HA secondary to PK deficiency is an autosomal reces­
sive disease (Fig. 105-5).
The clinical picture of homozygous (or biallelic) PK deficiency is
that of an HA that often presents in the newborn with severe neo­
natal jaundice, requiring nearly always phototherapy and frequently
exchange transfusion; the jaundice often persists, and it is often
associated with reticulocytosis. The anemia is of variable severity;
sometimes it is so severe as to require regular blood transfusion treat­
ment, whereas sometimes it is mild, bordering on a nearly compen­
sated hemolytic disorder. As a result, the diagnosis may be delayed: in
some cases, it is made, for instance, in a young woman during her first
pregnancy, when the anemia may get worse. The delay in diagnosis
may be caused in part by the fact that the anemia is often remarkably
well tolerated because the metabolic block at the last step in glycolysis
causes an increase in 2,3-bisphosphoglycerate (or DPG; Fig. 105-1),
a major effector of the hemoglobin-oxygen dissociation curve; thus,
for a certain level of hemoglobin, the oxygen delivery to the tissues is
enhanced, a remarkable compensatory feat.
TREATMENT
Pyruvate Kinase Deficiency
Until recently, the management of PK deficiency has been sup­
portive. Folic acid supplements should be given constantly. Blood
transfusion should be used as necessary, and iron chelation may
be required even in some patients who, though not receiving
blood transfusion, may be developing iron overload (see “General
Pathophysiology” above). About one-half of patients sooner or
later undergo splenectomy, which usually provides a modest but
significant increase in hemoglobin (paradoxically, reticulocytes
also often increase, because they were previously trapped in the
CLINICAL
MANIFESTATIONS
EXTRA-RED CELL
COMMENTS
 
exogenous trigger
PK deficiency
G6PD deficiency
(autosomal)
(X-linked)
Homozygous
normal
Heterozygous
Homozygous
deficient
FIGURE 105-5  Different phenotypes of heterozygotes for red cell enzymopathies.
In a heterozygote for deficiency of pyruvate kinase (PK), encoded by an autosomal
gene (see Table 105-4), the level of enzyme is about one-half of normal in all red cells.
Because this level of enzyme is sufficient, there are no clinical consequences, i.e.,
PK deficiency is recessive. In a heterozygote for deficiency of glucose-6-phosphate
dehydrogenase (G6PD), encoded by an X-linked gene, the situation is quite different:
X-chromosome inactivation generates red cell mosaicism, whereby some red cells
are entirely normal and others are G6PD deficient. Therefore, G6PD deficiency is
expressed in heterozygotes; it is not recessive.
spleen). Cholecystectomy may also be required. A major advance
has been the introduction of mitapivat, an allosteric activator of PK,
and the first drug for a red cell enzymopathy, approved on grounds
of a significant increase in hemoglobin in one-half of PK-deficient
patients—those in whom either one or both PKLR mutations are of
the missense type. Some patients with severe disease have received
bone marrow transplantation (BMT) from human leukocyte anti­
gen (HLA)-identical PK-normal sibling. Prenatal diagnosis has
been carried out in a mother who had already had an affected child.
Rescue of inherited PK deficiency through lentiviral-mediated
human PK gene transfer has been successful in mice and is cur­
rently undergoing a clinical trial in patients.
Other Glycolytic Enzyme Abnormalities  All of these defects are rare to very
rare (Table 105-4), and most of them cause HA with varying degrees
of severity. It is not unusual for the presentation to be in the guise of
severe neonatal jaundice, which may require exchange transfusion; if
the anemia is less severe, it may present later in life, or it may even
remain asymptomatic and be detected incidentally when a blood count
is done for unrelated reasons. The spleen is often enlarged. When other
systemic manifestations occur, they can involve the central nervous
system (sometimes entailing severe intellectual disability, particularly
in the case of triose phosphate isomerase deficiency), the neuromuscu­
lar system, or both (see Table 105-4). This is not altogether surprising
if we consider that these are housekeeping genes, i.e., expressed in all
tissues. The diagnosis of HA is usually not difficult, thanks to the triad
of normo-macrocytic anemia, reticulocytosis, and hyperbilirubinemia.
Enzymopathies should be considered in the differential diagnosis of
any chronic Coombs-negative HA. Unlike with membrane disorders,
in most cases of glycolytic enzymopathies, morphologic abnormali­
ties are conspicuous by their absence. A definitive diagnosis can be
made only by demonstrating the deficiency of an individual enzyme
by quantitative assays; these are carried out in only a few specialized
laboratories. If a particular molecular abnormality is already known in
the family, then one could test directly for that defect at the DNA level,
thus bypassing the need for enzyme assays. Of course, the time may
be getting nearer when a patient will present with their exome already
sequenced, and we will need to concentrate on which genes to look up
within the file. The principles for the management of these conditions
are similar as for PK deficiency. In isolated clinically severe cases of
glycolytic enzyme abnormalities, BMT has been carried out success­
fully, although unfortunately, nonhematologic manifestations, if any,
are not reversed.
ABNORMALITIES OF REDOX METABOLISM  • 
Glucose-6-Phosphate
Dehydrogenase (G6PD) Deficiency  G6PD is a housekeeping enzyme
critical in the redox metabolism of all aerobic cells (Fig. 105-1). In
red cells, its role is even more critical because it is the only source
of NADPH, which directly and via GSH defends these cells against
oxidative stress (Fig. 105-6). G6PD deficiency–related HA is a prime
example of an HA due to interaction between an intracorpuscular
cause and an extracorpuscular cause; indeed, in the vast majority of
cases, hemolysis is triggered by an exogenous agent. Although the
G6PD activity is decreased in most tissues of G6PD-deficient subjects,
in other cells, the decrease is much less pronounced than in red cells,
and it does not seem to impact on clinical expression.
■
■GENETIC CONSIDERATIONS
The G6PD gene is X-linked, and this has important implications.
First, because males have only one G6PD gene (i.e., they are
hemizygous for this gene), they must be either normal or G6PD
deficient. By contrast, females, who have two G6PD genes, can be
either normal or deficient (homozygous) or intermediate (heterozy­
gous). Second, as a result of the phenomenon of X chromosome inac­
tivation, heterozygous females are genetic mosaics (see Fig. 105-5),
with a highly variable ratio of G6PD-normal to G6PD-deficient cells
and an equally variable degree of clinical expression; some heterozy­
gotes can be just as affected as hemizygous males. The enzymatically
active form of G6PD is either a dimer or a tetramer of a single protein
subunit of 514 amino acids. G6PD-deficient subjects have been found
invariably to have mutations in the coding region of the G6PD gene.
Almost all of the over 230 different mutations known are single mis­
sense point mutations, entailing single amino acid replacements in the
G6PD protein. In most cases, these mutations cause G6PD deficiency
by decreasing the in vivo stability of the protein; thus, the physiologic
decrease in G6PD activity that takes place with red cell aging is greatly
accelerated. In some cases, an amino acid replacement can also affect
the catalytic function of the enzyme. The genetic heterogeneity of
G6PD deficiency is clinically important, and for the variants that are
widespread, it also has public health implications. Therefore, the
World Health Organization (WHO) has worked out a classification
(Table 105-5).
CHAPTER 105
Hemolytic Anemias
Among these mutations, those underlying chronic nonspherocytic
hemolytic anemia (CNSHA; see below) are a discrete subset. This
much more severe clinical phenotype can be ascribed in some cases to
adverse qualitative changes (e.g., a decreased affinity for the substrate
glucose-6-phosphate) or simply to the fact that the enzyme deficit is
more extreme because of a more severe instability of the enzyme. For
instance, a cluster of mutations map at or near the dimer interface, and
clearly, they compromise severely the formation of the dimer.
Epidemiology  G6PD deficiency is widely distributed in tropical and
subtropical parts of the world (Africa, southern Europe, the Middle
East, Southeast Asia, and Oceania) (Fig. 105-7) and wherever people
from those areas have migrated. A conservative estimate is that at
least 500 million people have a G6PD deficiency gene. In several of
these areas, the frequency of a G6PD deficiency gene may be as high
as 20% or more. It would be quite extraordinary for a trait that causes
significant pathology to spread widely and reach high frequencies
in many populations without conferring some biologic advantage.
Indeed, G6PD is one of the best-characterized examples of genetic
polymorphisms in the human species. Clinical field studies and in
vitro experiments strongly support the view that G6PD deficiency has
been selected by Plasmodium falciparum malaria because it confers a
relative resistance against this highly lethal infection. As in other cases
of balanced polymorphism, it is heterozygotes, therefore females, who
are protected. Different G6PD variants (class B) underlie most of the
prevalence of G6PD deficiency in different parts of the world. Exam­
ples of widespread variants are G6PD Mediterranean on the shores of
that sea, in the Middle East, and elsewhere; G6PD A– in Africa, in the
Middle East, and in southern Europe; G6PD Orissa in India; G6PD
Viangchan and G6PD Mahidol in Southeast Asia; G6PD Kaiping and
G6PD Canton in China; and G6PD Union worldwide. The heterogene­
ity of polymorphic G6PD variants is proof of their independent origin,
further supporting the notion of selection by a common environmental
Divicine
(fava beans)
Primaquine
ROS from
neutrophils
O2
–
Superoxide dismutase
Rasburicase
H2O2
Uric acid
GSH
Catalase
Glutathione
reductase
Prx2-SHGSSG
NADPH
H2O
Glutathione
peroxidase
Prx2-S-SA
Divicine
(fava beans)
Primaquine
OXIDATIVE
DAMAGE
ROS from
neutrophils
O2
–
PART 4
Oncology and Hematology
Superoxide dismutase
Rasburicase
H2O2
Uric acid
GSH
Catalase
Glutathione
reductase
Prx2-SHGSSG
NADPH
H2O
Glutathione
peroxidase
Prx2-S-SB
FIGURE 105-6  The role of glucose-6-phosphate dehydrogenase (G6PD) in protecting red cells from oxidative damage. A. In G6PD-normal red cells, G6PD and
6-phosphogluconate dehydrogenase—two of the enzymes of the pentose phosphate pathway—provide ample supply of NADPH, which in turn regenerates glutathione
(GSH) when this is oxidized by reactive oxygen species (e.g., O2
– and H2O2). Thus when O2
– (meant here to represent itself and other reactive oxygen species [ROS]) is
produced by pro-oxidant compounds such as primaquine, or the glucosides in fava beans (divicine), or the oxidative burst of neutrophils, these ROS are rapidly neutralized;
similarly, when rasburicase administered to degrade uric acid produces an equimolar amount of hydrogen peroxide, this is rapidly degraded by the combined action of
glutathione peroxidase, catalase, and Prx2 (peroxiredoxin-2; all three mechanisms are NADPH dependent). B. In G6PD-deficient red cells, where the enzyme activity is
reduced, NADPH production is limited, and it may not be sufficient to cope with the excess ROS generated by pro-oxidant compounds and the consequent excess hydrogen
peroxide. This diagram also explains why a defect in GSH reductase has very similar consequences to G6PD deficiency.
agent, namely malaria, in keeping with the concept of convergent evo­
lution (Fig. 105-7).
Clinical Manifestations  The vast majority of people with G6PD defi­
ciency remain clinically asymptomatic throughout their lifetime; how­
ever, all of them have an increased risk of developing neonatal jaundice
(NNJ) and a risk of developing acute HA (AHA) when challenged
by a number of oxidative agents. NNJ related to G6PD deficiency is
rarely present at birth; the peak incidence of clinical onset is between
day 2 and day 3, and in most cases, the anemia is not severe. However,
TABLE 105-5  Current World Health Organization Classification of
Glucose 6-Phosphate Dehydrogenase (G6PD) Variants
G6PD
VARIANT
CLASS
MEDIAN OF G6PD
ACTIVITY (% OF
NORMAL)
ASSOCIATED CLINICAL MANIFESTATIONS
Aa
<20%b
Chronic hemolytic anemia
Bc
<45%
Neonatal jaundice; acute hemolytic anemia
triggered by certain medicines, fava beans,
and infections
Ca
60%
None reported
Ud
Any
Uncertain clinical significance
aClass A corresponds to former class I; class C corresponds to former class IV.
bA variant with <20% activity will be in class A only if it is associated with chronic
hemolytic anemia. cIn view of the extensive overlap in enzyme activity and in
clinical expression of variants in former class II and class III, these have been
merged into class B. dA temporary assignment for variants for which there is
currently insufficient information regarding clinical manifestations.
Glucose 6-phosphate
NADP
Glucose 6-phosphate
dehydrogenase
6-Phosphoglucono-δ-lactone
6-Phosphoglucono
lactonase
6-Phosphogluconate
6-Phosphogluconate
dehydrogenase
Ribulose 5-phosphate
Glucose 6-phosphate
NADP
Glucose 6-phosphate
dehydrogenase
6-Phosphoglucono-δ-lactone
6-Phosphoglucono
lactonase
6-Phosphogluconate
6-Phosphogluconate
dehydrogenase
Ribulose 5-phosphate
NNJ can be very severe in some G6PD-deficient babies, especially in
association with prematurity, infection, and/or environmental factors
(e.g., naphthalene-camphor balls, which may be used in babies’ bed­
ding and clothing); and the risk of severe NNJ is also increased by the
coexistence of a monoallelic or biallelic mutation in the uridyl trans­
ferase gene (UGT1A1; the same mutations are associated with Gilbert’s
syndrome). It is imperative to manage promptly NNJ associated with
G6PD deficiency because it can produce kernicterus and permanent
neurologic damage.
AHA can develop as a result of three types of triggers: (1) fava beans,
(2) infections, and (3) drugs (Table 105-6). Typically, a hemolytic attack
starts with malaise, weakness, and abdominal or lumbar pain. Within a
time frame of several hours to 2–3 days, the patient develops jaundice
and often dark urine. The onset can be extremely abrupt, especially
with favism in children. The anemia is moderate to extremely severe,
usually normocytic and normochromic, and due partly to intravascular
hemolysis; hence, it is associated with hemoglobinemia, hemoglobin­
uria, high LDH, and low or absent plasma haptoglobin. The blood
film shows anisocytosis, polychromasia, and spherocytes; in addition,
the most typical feature of G6PD deficiency is the presence of bizarre
poikilocytes, with red cells that appear to have unevenly distributed
hemoglobin (“hemighosts”) and red cells that appear to have had parts
of them bitten away (“bite cells” or “blister cells”) (Fig. 105-8). A classi­
cal test, now rarely carried out, is supravital staining with methyl violet,
which, if done promptly, reveals the presence of Heinz bodies (consist­
ing of precipitates of denatured hemoglobin and hemichromes), which
are regarded as a signature of oxidative damage to red cells (they are
A–
Canton
Coimbra
Kaiping
Kalyan
Mahidol
Med
Orissa
Union
Viangchan
No data
<1%
1–4.9%
5–9.9%
10–14.9%
15–19.9%
20%
FIGURE 105-7  Epidemiology of glucose-6-phosphate dehydrogenase (G6PD) deficiency throughout the world. Each country on the map is shaded in a color based on the
best estimate of the mean frequency of G6PD deficiency allele(s) in that country (this is the same as the frequency of G6PD-deficient males). The small panel on the left gives
the key to color shadings corresponding to each country. The larger panel gives a color-coded list of 10 common G6PD variants associated with G6PD deficiency: asteriskshaped symbols in the corresponding colors are shown in the countries where these variants have been observed (for graphic reasons, symbols could not be inserted in all
countries). (Reproduced with permission from L Luzzatto, M Ally, R Notaro. Glucose-6-phosphate dehydrogenase deficiency. 136:1225, 2020.)
also seen with unstable hemoglobins). Since there is also a substantial
component of extravascular hemolysis, unconjugated bilirubin is high
and there is often clinical icterus. The most serious threat from AHA
in adults is the development of acute renal failure (this is exceedingly
rare in children). Once the threat of acute anemia is over and in the
TABLE 105-6  Drugs That Carry Risk of Clinical Hemolysis in Persons
with Glucose 6-Phosphate Dehydrogenase Deficiency
RISK OF ACUTE HEMOLYTIC ANEMIA
DRUG CLASS
HIGH
MEDIUM TO LOW
 
Antimalarials
Primaquine
Tafenoquine
Chloroquine
Hydroxychloroquine
Quinine
 
Sulphonamides/
sulphones
Dapsone
Sulfadimidine
Sulfamethoxazole
Sulfasalazine
 
Antibacterial/
antibiotics
 
Chloramphenicol
Ciprofloxacin
Cotrimoxazole
Nalidixic acid
Nitrofurantoin
Norfloxacin
p-Aminosalicylic acid
 
Anti-helmint
 
Niridazole
 
Antipyretic/
analgesics
Acetylsalicylic
acid high dose
(>3 g/d)
Acetaminophen
Acetanilide
Phenacetin
Phenazopyridine
 
Other
Rasburicase
Pegloticase
Methylene blue
Toluidine blue
Ascorbic acid (>1 g)
Doxorubicin
Probenecid
Vitamin K analogues
 
CHAPTER 105
Hemolytic Anemias
absence of comorbidity, full recovery from AHA associated with G6PD
deficiency is the rule.
It was primaquine (PQ)-induced AHA that led to the discovery of
G6PD deficiency, but this drug has not been very prominent subse­
quently because it is not necessary for the treatment of life-threatening
P. falciparum malaria. Today there is a revival in the use of PQ for two
reasons. First, it is the only effective agent for eliminating the gameto­
cytes of P. falciparum (thus preventing further transmission): a small
single dose (0.25 mg/kg) is required, and it is safe for G6PD-deficient
persons. Second, a 14-day course of PQ is the standard treatment for
eliminating the hypnozoites of Plasmodium vivax (thus preventing
endogenous relapse) (Chap. 231). In countries aiming to eliminate
malaria, there may be a call for mass administration of PQ; this ought
FIGURE 105-8  Peripheral blood smear from a glucose-6-phosphate dehydrogenase
(G6PD)-deficient boy experiencing hemolysis. Note the red cells that are misshapen
and called “bite” cells. (From MA Lichtman et al: Lichtman’s Atlas of Hematology:
http://www.accessmedicine.com. Copyright © The McGraw-Hill Companies, Inc. All
rights reserved.)
to be associated with G6PD testing. At the other end of the historic
spectrum, the latest additions to the list of potentially hemolytic
drugs (Table 105-6) are rasburicase and pegloticase; again, G6PD test­
ing ought to be made mandatory before giving either of these drugs
because fatal cases have been reported upon using one of these drugs,
which generate hydrogen peroxide, in newborns with kidney injury
and in children and adults with tumor lysis syndrome.
Although drug-induced AHA has been prominent in the study of
G6PD deficiency, the most common clinical manifestations are in fact
NNJ and favism, both of which are of public health importance in
many populations. Contrary to beliefs that are still widespread, fava
bean pollen inhalation does not cause favism, and other beans are safe.
A very small minority of subjects with G6PD deficiency, those who
have a class A variant, suffer from CNSHA of variable severity. The
patient is nearly always a male, usually with a history of NNJ, who may
present with anemia, unexplained jaundice, or gallstones later in life.
The spleen may be enlarged. The severity of anemia ranges in differ­
ent patients from borderline to transfusion dependent. The anemia is
usually normo-macrocytic, with reticulocytosis. Bilirubin and LDH
are increased. Although hemolysis is, by definition, chronic in these
patients, they are also vulnerable to acute oxidative damage, and there­
fore, the same agents that can cause AHA in people with the ordinary
type of G6PD deficiency will cause severe exacerbations in people with
CNSHA associated with G6PD deficiency. In some cases of CNSHA,
the deficiency of G6PD is so severe in granulocytes that it limits their
capacity to produce an oxidative burst, with consequent increased sus­
ceptibility to some bacterial infections.
PART 4
Oncology and Hematology
Laboratory Diagnosis  The suspicion of G6PD deficiency can be con­
firmed by semiquantitative methods often referred to as screening
tests, which are suitable for population studies and can correctly clas­
sify male subjects, in the steady state, as G6PD normal or G6PD defi­
cient. However, in clinical practice, a diagnostic test is usually needed
when the patient has had a hemolytic attack, whereby the oldest, most
G6PD-deficient red cells have been selectively destroyed, and young
red cells, having higher G6PD activity, are being released into the
circulation. Under these conditions, only a quantitative test can give
a definitive result. In males, this test will identify normal hemizygotes
and G6PD-deficient hemizygotes; among females, some heterozygotes
will be missed, but those who are at most risk of hemolysis will be iden­
tified. Of course, G6PD deficiency also can be diagnosed by DNA test­
ing. Currently easy-to-use point-of-care tests for G6PD deficiency are
becoming available, geared especially to the prospect of mass adminis­
tration of PQ or of the newly introduced derivative tafenoquine.
TREATMENT
G6PD Deficiency
The AHA of G6PD deficiency is largely preventable by avoiding
exposure to triggering factors of previously screened subjects. Of
course, the practicability and cost-effectiveness of screening depend
on the prevalence of G6PD deficiency in each individual commu­
nity. Favism is entirely preventable in G6PD-deficient subjects by
not eating fava beans. Drug-induced hemolysis can be prevented by
testing for G6PD deficiency before prescribing; in many cases, one
can use alternative drugs. When AHA develops and once its cause is
recognized, no specific treatment is needed in most cases. However,
if the anemia is severe, it may be a medical emergency, especially
in children, requiring immediate action, including blood transfu­
sion. This has been the case with an antimalarial drug combination
containing dapsone (called Lapdap, introduced in 2003) that has
caused severe acute hemolytic episodes in children with malaria
in several African countries; after a few years, the drug was taken
off the market. If there is acute renal failure, hemodialysis may be
necessary, but if there is no previous kidney disease, recovery is the
rule. The management of NNJ associated with G6PD deficiency is
no different from that of NNJ due to other causes.
In cases with CNSHA, if the anemia is not severe, regular folic
acid supplements and regular hematologic surveillance will suffice.
It will be important to avoid exposure to potentially hemolytic
drugs, and blood transfusion may be indicated when exacerbations
occur, mostly in concomitance with intercurrent infection. In rare
patients, regular blood transfusions may be required, in which case
appropriate iron chelation should be instituted. Unlike in HS, there
is no evidence of selective red cell destruction in the spleen; how­
ever, in practice, splenectomy has proven beneficial in severe cases.
Other Abnormalities of the Redox System  As mentioned previously, GSH is a
key player in the defense against oxidative stress. Inherited defects of GSH
metabolism are exceedingly rare, but each one can give rise to chronic
HA (Table 105-4). A rare, peculiar, and severe but usually self-limited
HA occurring in the first month of life, called infantile poikilocytosis, may
be associated with deficiency of glutathione peroxidase (GSHPX) due
not to an inherited abnormality, but to transient nutritional deficiency of
selenium, an element essential for the activity of GSHPX.
PYRIMIDINE 5′-NUCLEOTIDASE (P5N) DEFICIENCY  P5N is a key
enzyme in the catabolism of nucleotides arising from the degradation of
nucleic acids that takes place in the final stages of erythroid cell matura­
tion. How exactly its deficiency causes HA is not well understood, but a
highly distinctive feature of this condition is a morphologic abnormal­
ity of the red cells known as basophilic stippling. The condition is rare,
but it probably ranks third in frequency among red cell enzyme defects
(after G6PD deficiency and PK deficiency). The anemia is lifelong, is of
variable severity, and may benefit from splenectomy.
Familial (Atypical) Hemolytic-Uremic Syndrome (aHUS) 
This term is used to designate a group of rare disorders, mostly affect­
ing children, characterized by microangiopathic HA with presence of
fragmented erythrocytes in the peripheral blood smear, thrombocy­
topenia (usually mild), and acute renal failure. (The word atypical in
this phrase should be consigned to history; it was introduced originally
to distinguish this condition from the hemolytic-uremic syndrome
[HUS] caused by infection with Escherichia coli producing the Shiga
toxin, regarded as typical.) The disease is caused by dysregulation of
the complement alternative pathway: in some cases, this results from
anti–factor H autoantibodies, but in the majority of cases, it is a conse­
quence of mutations in genes encoding proteins that are components
or regulators of the complement system, i.e., C3 (encoding complement
component C3), CFB (encoding complement factor B), CFH (encod­
ing complement factor H), CD46 (encoding the membrane cofactor
protein), CFI (encoding complement factor I), THBD (encoding
thrombomodulin), and rarely others. Patients may have abnormalities
in one, two, or even three of the above genes. Pathogenic variants of
these genes predispose to HUS with autosomal dominant inheritance;
because clinical aHUS requires a triggering factor, most commonly
infection, the penetrance is incomplete. Thus, whereas all other inher­
ited HAs are due to intrinsic red cell abnormalities, this group is unique
in that hemolysis results from an inherited defect external to red cells
(Table 105-1). Because the regulation of the complement cascade has
considerable redundancy, in the steady state, any of the above abnor­
malities can be tolerated. However, when an intercurrent infection or
some other trigger briskly activates complement, the deficiency of one
of the complement regulators becomes critical. Endothelial cells get
damaged, especially in the kidney. At the same time, and partly as a
result of this, there will be brisk hemolysis; thus, the more common
Shiga toxin–related HUS (Chap. 172) can be regarded as a phenocopy
of aHUS. aHUS is a severe disease; before anticomplement therapy was
available, mortality was up to 15% in the acute phase, and up to 50% of
cases progressed to end-stage renal disease (ESRD). Not infrequently,
aHUS undergoes spontaneous remission. Because it is an inherited
abnormality, it is not surprising that, given renewed exposure to a
trigger, the syndrome will tend to recur; when it does, the prognosis
is always serious. The traditional treatment has been plasma exchange,
which will supply the deficient complement regulator and clear
complement activation products. This has changed since the introduc­
tion of the anti-C5 complement inhibitor eculizumab (see “Paroxysmal
Nocturnal Hemoglobinuria”), which was found to greatly ameliorate the
microangiopathic picture, with improvement in platelet counts and in
renal function, thus abrogating the need for plasma exchange, which is
not always effective and not free of complications. Once a full remis­
sion is obtained, with urine dipstick negative for hemoglobinuria,
within 3–6 months, eculizumab can be discontinued. Given the genetic
background of aHUS, relapses are possible. Fortunately, patients who
relapsed after discontinuing eculizumab have responded again. No
current evidence supports continuing eculizumab indefinitely.
For the diagnosis of inherited red cell abnormalities, including those
of the membrane-cytoskeleton, channelopathies, and enzymopathies,
DNA sequencing of a gene panel (e.g., next-generation sequencing
[NGS]) has become increasingly popular. This approach (which may
or may not be more expensive) has the advantage of being potentially
comprehensive and of providing definitive data. On the other hand, the
mutations identified may be of uncertain significance, in which case, the
diagnosis must be still confirmed by conventional methodology. Thus,
the use of NGS is specially useful with unsolved cases of hereditary HAs.
■
■ACQUIRED HEMOLYTIC ANEMIA
Mechanical Destruction of Red Cells 
Although red cells are
characterized by the remarkable deformability that enables them to
squeeze through capillaries narrower than themselves for thousands of
times in their lifetime, there are at least two situations in which they
succumb to shear, if not to wear and tear; the result is intravascular
hemolysis, resulting in hemoglobinuria (Table 105-7). One situation
is acute and self-inflicted, march hemoglobinuria. Why sometimes a
marathon runner may develop this complication, whereas on another
occasion, this does not happen, we do not know (perhaps their
footwear needs attention). A similar syndrome may develop after
prolonged barefoot ritual dancing or intense playing of bongo drums.
The other situation is chronic and iatrogenic (it has been called micro­
angiopathic hemolytic anemia). It takes place in patients with prosthetic
heart valves, especially when paraprosthetic regurgitation is present.
If the hemolysis consequent on mechanical trauma to the red cells is
mild, and if the supply of iron is adequate, the loss may be largely com­
pensated; if more than mild anemia develops, reintervention to correct
regurgitation may be required.
Infection 
By far, the most frequent infectious cause of HA in
endemic areas is malaria (Chap. 231). In other parts of the world, the
most frequent direct cause is probably Shiga toxin–producing E. coli
O157:H7, now recognized as the main etiologic agent of HUS, which is
more common in children than in adults (Chap. 166). Life-threatening
intravascular hemolysis, due to a toxin with lecithinase activity,
occurs with Clostridium perfringens sepsis, particularly following open
wounds, septic abortion, or as a disastrous accident due to a contami­
nated blood unit. Rarely, and if at all in children, HA is seen with sepsis
or endocarditis from a variety of organisms. In addition, bacterial and
viral infections can cause HA by indirect mechanisms (see Table 105-7).
TABLE 105-7  Diseases and Clinical Situations in Which Hemolysis Is Largely Intravascular
 
ONSET/TIME COURSE
MAIN MECHANISM
Mismatched blood
transfusion
Abrupt
Nearly always ABO
incompatibility
Paroxysmal nocturnal
hemoglobinuria (PNH)
Chronic with acute
exacerbations
Complement (C)-mediated
destruction of CD59(−) red cells
Paroxysmal cold
hemoglobinuria (PCH)
Acute
Immune lysis of normal red
cells
Septicemia
Very acute
Exotoxins produced by
Clostridium perfringens
Microangiopathic
Acute or chronic
Red cell fragmentation
Red cell morphology on
blood smear
March hemoglobinuria
Abrupt
Mechanical destruction
Targeted history taking
Has been reported after extreme ritual dancing
Favism
Acute
Destruction of older fraction of
G6PD-deficient red cells
aThe trigger of acute hemolytic anemia, often with hemoglobinuria, can be infection or a drug (see Table 105-5) rather than fava beans. Hemoglobinuria may or may not be
reported by patient, but it is often macroscopic, i.e., recognizable by simple inspection of urine.
Abbreviation: G6PD, glucose 6-phosphate dehydrogenase.
Immune Hemolytic Anemias 
These can arise through at least
two distinct mechanisms. First, when an antibody directed against a
certain molecule (e.g., a drug) reacts with that molecule, red cells may
get caught in the reaction (the so-called innocent bystander mechanism;
see later section “Hemolytic Anemia from Toxic Agents and Drugs”),
whereby they are damaged or destroyed. Second, and more frequently,
a true autoantibody is directed against a red cell antigen, i.e., a molecule
present on the surface of red cells. Autoimmune HAs have been origi­
nally classified into two types, depending on the thermal amplitude of
the autoantibodies involved; this classification is valid because the two
types have different pathophysiologic and clinical features.
AUTOIMMUNE HEMOLYTIC ANEMIA, WARM TYPE (WAIHA; FOR SIM­
PLICITY, WE WILL USE THE ACRONYM AIHA)  AIHA has an estimated
incidence in the United States of about 1–3:100,000 per year, and a
prevalence of 17:100,000. AIHA can be serious because even with
appropriate management the mortality is ~5–10%.
Clinical Features and Diagnosis  The onset is often abrupt and can be dra­
matic. The hemoglobin level may drop, within days, to as low as 4 g/dL;
the massive red cell removal will produce jaundice, and sometimes the
spleen is enlarged. When this triad is present, the suspicion of AIHA must
be high. The reticulocyte count is typically elevated, except when erythroid
precursors are also targeted by the autoantibody attack. LDH may also be
elevated. In some cases, AIHA can be associated, on first presentation or
subsequently, with autoimmune thrombocytopenia. This double autoim­
mune condition, referred to as Evans syndrome, may be a manifestation
of common variable immune deficiency, and in children, it may suggest
one of several primary immune deficiency syndromes. Evans syndrome
signals high-risk disease. Other predictors of the outcome and of the prob­
ability of relapse of AIHA are severe anemia (hemoglobin <6 g/dL), certain
characteristics of the antibody, acute renal failure, and infection.
CHAPTER 105
Hemolytic Anemias
There are few situations in hematology where one laboratory test
is as informative as the direct antiglobulin test developed in 1945 by
R. R. A. Coombs and known since then by this name. The currently
recommended version of this test uses in the first instance a “broadspectrum” reagent, i.e., one that will detect not only immunoglobulins
(Ig) but also complement (C) components (usually C3 fragments)
bound to the surface of the patient’s red cells. If the test is positive, it
is, almost on its own, diagnostic of AIHA. False positives may occur
as a result of previous blood transfusion or, much more rarely, fol­
lowing organ transplantation procedures or administration of antilymphocyte or immunoglobulin products. One can then determine,
by using specific reagents, whether Ig or C or both are implicated. The
sensitivity of the Coombs test varies depending on the techniques that
are used. In general, the test is positive if there is an average of at least
400 molecules of Ig and/or C on each red cell; but with more advanced
techniques involving flow cytometry analysis or enzyme-linked radio­
labeled tests, the sensitivity can be pushed to as low as 30–40 molecules
APPROPRIATE
DIAGNOSTIC PROCEDURE
COMMENTS
Repeat cross-match
 
Flow cytometry to display a
CD59(−) red cell population
Exacerbations due to C activation through any
pathway
Test for Donath-Landsteiner
antibody
Often triggered by viral infection
Blood cultures
Other organisms may be responsible
Different causes ranging from endothelial damage to
hemangioma to leaky prosthetic heart valve
G6PD assay
Triggered by ingestion of large dish of fava beansa
per red cell. Therefore, liaison with a specialized laboratory is desirable;
a dual direct antiglobulin test has also been developed. In the past, the
diagnosis of “Coombs-negative AIHA” was regarded as a last resort, but
it is important to know that a patient with this label may have severe
AIHA, because if the antibody is powerful (high affinity/avidity),
few molecules may be sufficient to opsonize red cells. Based on the
Coombs test findings as well as on the thermal characteristics and the
antigenic specificities of the autoantibodies (Table 105-8), AIHA has
been classified into subtypes.
In AIHA, the autoantibody reacts best at 37°C, and it is usually
Rhesus specific (sometimes specifically anti-e). The main mechanism
of hemolysis in AIHA is that the Fc portion of the IgG antibody bound
to red cells is recognized by the Fc receptor of macrophages. This will
trigger erythrophagocytosis wherever macrophages are abundant, i.e.,
in the liver, in the bone marrow, but especially in red pulp of the spleen
(Fig. 105-9), which, also because of its special anatomy, is often the
predominant site of red cell destruction.
AIHA may be seen in isolation (and it is then called idiopathic) or as
secondary to other disorders such as systemic autoimmune disorders
(systemic lupus erythematosus [SLE]; sometimes, AIHA may be the
first manifestation that leads to a diagnosis of SLE) or lymphoprolif­
erative disorders (Table 105-8). Like all autoimmune diseases, AIHA
must arise from a dysregulation of immunity. It is therefore not sur­
prising that it is increasingly being recognized in chronic lymphocytic
PART 4
Oncology and Hematology
TABLE 105-8  Classification of Acquired Immune Hemolytic Anemias
TYPE OF ANTIBODY
COLD, MOSTLY
IgM, OPTIMAL
TEMPERATURE
4°C–30°C
WARM, MOSTLY IgG, OPTIMAL
TEMPERATURE 37°C; OR MIXED
CLINICAL SETTING
Primary
CAD
AIHA (idiopathic)
Secondary to viral
infection
EBV
CMV
Other
Parvovirus B19
HIV
HCV
EBV
Viral vaccines
Secondary to other
infection
Mycoplasma
infection:
paroxysmal cold
hemoglobinuria
Babesia
Secondary to/
associated with
other disease
CAD in:
Waldenström’s
disease
Lymphoma
AIHA in:
SLE, scleroderma, RA
CLL
Lymphoproliferative disorders
Multiple myeloma
Other malignancy
Chronic inflammatory disorders
(e.g., IBD)
Thyroiditis (including Hashimoto)
After allogeneic HSCT
Common variable immunodeficiency
After immune checkpoint
modulating drugs
Secondary to
drugs: druginduced immune
hemolytic anemia
Small minority (e.g.,
with lenalidomide)
Majority: currently most common
culprit drugs are cefotetan,
ceftriaxone, piperacillin,
methyldopa, fludarabine
Drug-dependent: antibody destroys red cells only when
drug present (e.g., rarely penicillin)
Drug-independent: antibody can destroy red cells even
when drug no longer present (e.g., methyldopa)
Associated with
Pregnancy
Abbreviations: AIHA, autoimmune hemolytic anemia; CAD, cold agglutinin disease;
CLL, chronic lymphocytic leukemia; CMV, cytomegalovirus; EBV, Epstein-Barr virus;
HCV, hepatitis C virus; HIV, human immunodeficiency virus; HSCT, hematopoietic
stem cell transplantation; IBD, inflammatory bowel disease; SLE, systemic lupus
erythematosus; RA, rheumatoid arthritis.
leukemia (CLL), whether treated or untreated; after BMT; and after
solid organ transplantation entailing immunosuppressive treatment.
Recently, warm antibody AIHA has also occurred as a side effect of the
use of immune checkpoint inhibitors, such as nivolumab, in patients
with various types of cancer.
TREATMENT
Warm Antibody Autoimmune Hemolytic Anemia
Severe acute AIHA can be a medical emergency. The immediate
treatment almost invariably includes transfusion of red cells. This
may pose a special problem because many or all of the blood units
cross-matched may be incompatible. In these cases, it is often cor­
rect, if paradoxical, to transfuse ABO-matched but incompatible
blood, with the rationale being that the transfused red cells will be
destroyed no less—but no more—than the patient’s own red cells,
and in the meantime, the patient stays alive. A situation like this
requires close liaison and understanding between the clinical unit
treating the patient and the blood transfusion/serology lab. When­
ever the anemia is not immediately life-threatening, blood trans­
fusion should be withheld (because compatibility problems may
increase with each unit of blood transfused) and medical treatment
started immediately with prednisone (1 mg/kg per day), which
will produce a remission promptly in at least one-half of patients.
Rituximab (anti-CD20), previously regarded as second-line treat­
ment, is increasingly being used at a relatively low dose (100 mg/
week × 4), together with prednisone as part of first-line treatment.
It is especially encouraging that this approach seems to reduce the
rate of relapse, a common occurrence in AIHA.
For patients who do relapse or are refractory to medical treat­
ment, additional therapeutic strategies are now available. Sple­
nectomy does not cure the disease, but it can produce significant
benefit by removing a major site of hemolysis, thus improving the
anemia and/or reducing the need for other therapies (e.g., the dose
of prednisone); of course, splenectomy is not free of risk, as it entails
increased risk of sepsis and of thrombosis. The response rates to
splenectomy and rituximab are similar. Since the introduction of
rituximab, azathioprine, cyclophosphamide, cyclosporine, myco­
phenolate, and intravenous immunoglobulin have become sec­
ond- or third-line agents. In very rare severe refractory cases, one
may have to consider a high dose of cyclophosphamide (50 mg/kg
per day for 4 days), followed by a myelo-stimulating agent, or the
anti-CD52 agent alemtuzumab. Fostamatinib, an inhibitor of intra­
cellular cell signaling (Syk kinase) mediating erythrophagocytosis,
has shown beneficial effects in an open-label clinical study, becom­
ing an interesting third-line therapeutic option (Fig. 105-9). When
severe anemia is associated with inadequate reticulocyte output, the
use of EPO may help to reduce or avoid the requirement for trans­
fusion of red cells. Several new agents, including inhibitors of the
neonatal Fc receptor and others, are currently under investigation.
PAROXYSMAL COLD HEMOGLOBINURIA (PCH)  PCH is a rare form of
AIHA occurring mostly in children, usually triggered by a viral infec­
tion, usually self-limited, and characterized by the so-called DonathLandsteiner antibody. In vitro, this antibody has unique serologic
features; it has usually anti-P specificity, and it binds to red cells only
at a low temperature (optimally at 4°C), but when the temperature is
shifted to 37°C, lysis of red cells takes place in the presence of comple­
ment. Consequently, in vivo, there is intravascular hemolysis, resulting
in hemoglobinuria. Clinically the differential diagnosis must include
other causes of hemoglobinuria (Table 105-7), but the presence of
the Donath-Landsteiner antibody will prove PCH. Active supportive
treatment, including blood transfusion, may be needed to control the
anemia; subsequently, recovery is the rule.
COLD AGGLUTININ DISEASE  This designation indicates the other
main type of AIHA, which has quite different features when compared
with warm antibody AIHA. First, cold agglutinin disease (CAD) is a
IgG Warm Ab
Rituximab
Alemtuzumab
CD20
CD52
Spleen
Fc receptor
BTK
B cell
Venetoclax
Ibrutinib
Complement
blockers (C1S)
Plasma
cell
Complement
Bortezomib
IgM Cold Ab
FIGURE 105-9  Basic mechanisms involved in warm antibody– and cold antibody-mediated autoimmune hemolytic anemias. Top. With warm antibodies (usually IgG),
opsonized red cells are removed by Fc receptor–bearing macrophages, largely in the spleen (extravascular hemolysis); fragmentation and spherocyte formation also play a
role, with the spleen again being the main site. Bottom. In cold agglutinin disease (CAD), the antibody is IgM, which, once bound to red cells, causes complement activation
through the classic pathway, with consequent intravascular hemolysis. In addition, C3b-opsonized red cells will undergo erythrophagocytosis by Kupffer cells in the liver,
with consequent extravascular hemolysis. The inset on the left illustrates the B cells that make these autoantibodies: polyclonal in the case of warm antibody–mediated
autoimmune hemolytic anemia and monoclonal in the case of CAD. The new therapeutic approaches in addition to glucocorticoids for autoimmune hemolytic anemias are
shown in red. The inset highlights drugs targeting immune cells involved in generation of antibodies. Ab, antibody; BTK, Bruton’s tyrosine kinase; Syk, spleen tyrosine kinase.
chronic and more frequently indolent condition—in contrast to the
abrupt onset of warm antibody AIHA. Second, the term cold refers to
the fact that the autoantibody involved reacts with red cells poorly or
not at all at 37°C, whereas it reacts strongly at lower temperatures. As
a result, hemolysis is more prominent the more the body is exposed to
the cold. Third, the antibody is produced by a clone of autoreactive B
lymphocytes. Sometimes the antibody concentration in the serum is
high enough to show up as a spike in plasma protein electrophoresis,
thus qualifying CAD as an IgM monoclonal gammopathy; however,
it differs from Waldenström macroglobulinemia by not having the
characteristic MYD88 mutation (see Chap. 116); instead, a somatic
mutation in the KMT2D gene, encoding a lysine histone methylase, is
present in the B-cell clone of a majority of CAD patients: this seems to
favor proliferation. The antibody produced by the B-cell clone is IgM;
usually it has an anti-I specificity (the I antigen is present on the red
cells of almost everybody), and it may have a very high titer (1:100,000
or more has been observed). IgM, when bound to red cells, is a power­
ful activator of the complement cascade, with ultimate formation of
the membrane attack complex (see Fig. 105-9); this will directly cause
destruction of red cells (intravascular hemolysis; indeed, CAD patients
may present with hemoglobinuria). In addition, once complement
is activated, C3b will bind to red cells that, thus opsonized, will be
destroyed by macrophages (extravascular hemolysis); unlike in AIHA,
the spleen is not predominant in this process.
In mild forms of CAD, avoidance of exposure to cold may be all that
is needed to enable the patient to have a reasonably comfortable quality
of life; but in more severe forms, the management of CAD is not easy.
Plasma exchange will remove antibodies and is, therefore, in theory, a
rational approach in severe cases. However, the management of CAD
has changed significantly with the advent of the anti-CD20 antibody
rituximab; up to 60% of patients respond. If remission is followed by
relapse, a new course of rituximab may be again effective, and remis­
sions may be more durable with a combination of rituximab with either
Fostamatinib
Spherocytes
Syk
Erythroid
microparticles
Extravascular
hemolysis
Liver
Extravascular
hemolysis
Complement
activation with
formation of
membrane attack
complex
CHAPTER 105
Intravascular
hemolysis
Hemolytic Anemias
fludarabine or bendamustine, in particular in CAD associated with
a clinically manifested lymphoproliferative disorder. Therefore, even
in the absence of a formal trial, rituximab has become de facto firstline treatment, especially since previously used immunosuppressive/
cytotoxic agents, although they can reduce the antibody titer, have lim­
ited clinical efficacy and, in view of the chronic nature of CAD, their
side effects may prove unacceptable. Unlike in AIHA, prednisone and
splenectomy are ineffective. In the management of CAD in relapse,
the B-cell receptor inhibitors venetoclax and ibrutinib, as well as for
the proteasome inhibitor bortezomib, are emerging as effective agents.
A different approach targeting complement inhibitors has been also
explored by using sutimlimab (anti-C1s); a limitation of this approach
is that hemolysis will be curbed only for as long as this agent is admin­
istered (Fig. 105-9).
In terms of supportive treatment, blood transfusion may be help­
ful, despite the fact that red cells from the donor, being I positive, will
survive no longer than those of the patient. Both the blood bag and the
patient’s extremities must be kept warm during transfusion.
Hemolytic Anemia from Toxic Agents and Drugs 
A number
of chemicals with oxidative potential, whether medicinal or not, can
cause hemolysis even in people who are not G6PD deficient (for which,
see above). Examples are hyperbaric oxygen (or 100% oxygen), nitrates,
chlorates, methylene blue, dapsone, cisplatin, and numerous aromatic
(cyclic) compounds. Other chemicals may be hemolytic through
nonoxidative, largely unknown mechanisms; examples include arsine,
stibine, copper, and lead. The HA caused by lead poisoning is charac­
terized by basophilic stippling; it is in fact a phenocopy of that seen in
P5N deficiency (see above), suggesting it is mediated at least in part by
lead inhibiting this enzyme.
In these cases, hemolysis appears to be mediated by a direct chemi­
cal action on red cells. But drugs can cause hemolysis through at least
two other mechanisms. (1) A drug can behave as a hapten and induce
antibody production; in rare subjects, this happens, for instance, with
penicillin. Upon a subsequent exposure, red cells are caught, as inno­
cent bystanders, in the reaction between penicillin and antipenicillin
antibodies. Hemolysis will subside as soon as penicillin administra­
tion is stopped. (2) A drug can trigger, perhaps through mimicry, the
production of an antibody against a red cell antigen. The best-known
example is methyldopa, an antihypertensive agent no longer in use,
which in a small fraction of patients stimulated the production of the
Rhesus antibody anti-e. In patients who have this antigen, the anti-e is
a true autoantibody, which then causes true AIHA (see above). Usually
this will gradually subside once methyldopa is discontinued.
Severe intravascular hemolysis can be caused by the venom of cer­
tain snakes (cobras and vipers), and HA can also follow spider bites.
Paroxysmal Nocturnal Hemoglobinuria (PNH) 
PNH is an
acquired chronic HA characterized by persistent intravascular hemo­
lysis with occasional or frequent recurrent exacerbations. In addition
to (1) hemolysis, there may be (2) pancytopenia and (3) a distinct
tendency to venous thrombosis. This triad makes PNH a truly unique
clinical condition; however, when not all of these three features are
manifest on presentation, the diagnosis is often delayed, although it can
always be made by appropriate laboratory investigations (see below).
PNH is encountered in all populations throughout the world, but
it is a rare disease, with an estimated prevalence of 5–10 per million
(it may be somewhat less rare in Southeast Asia and in the Far East).
PNH has about the same frequency in men and women. PNH is not
inherited, and it has never been reported as a congenital disease, but
it can present in small children or as late as in the seventies, although
most patients are young adults.
PART 4
Oncology and Hematology
CLINICAL FEATURES  When seeking medical attention, the patient
may report that one morning, they “passed blood instead of urine.”
This distressing or frightening event may be regarded as the classic
presentation; however, more frequently, this symptom is not noticed
or not reported. Indeed, the patient often presents simply as a prob­
lem in the differential diagnosis of anemia, whether symptomatic or
discovered incidentally. Sometimes the anemia is associated from the
outset with neutropenia, thrombocytopenia, or both, thus signaling an
element of bone marrow failure (see below). Some patients may present
with recurrent attacks of severe abdominal pain eventually found to be
related to thrombosis in abdominal veins, or attributable to nitric oxide
depletion associated with intravascular hemolysis. When thrombosis
affects the hepatic vein, it may produce acute hepatomegaly and ascites,
i.e., a full-fledged Budd-Chiari syndrome, which, in the absence of liver
disease, ought to raise the suspicion of PNH.
The natural history of PNH can extend over decades. In the past,
with supportive treatment only, the median survival was estimated
to be about 10–20 years, with the most common cause of death being
venous thrombosis, followed by infection secondary to severe neutro­
penia and hemorrhage secondary to severe thrombocytopenia. Rarely
(estimated 1–2% of all cases), PNH may terminate in acute myeloid
leukemia. On the other hand, full spontaneous recovery from PNH has
been documented, albeit rarely.
LABORATORY INVESTIGATIONS AND DIAGNOSIS  The most consistent
blood finding is anemia, which may range from mild to moderate
to very severe. The anemia is usually normo-macrocytic, with unre­
markable red cell morphology. If the MCV is high, it is usually largely
accounted for by reticulocytosis, which may be quite marked (up to
20%, or up to 400,000/μL). The anemia may become microcytic if
the patient is allowed to become iron deficient as a result of chronic
iron loss through hemoglobinuria. Unconjugated bilirubin is mildly
or moderately elevated; LDH is typically markedly elevated (values in
the thousands are common); and haptoglobin is usually undetectable.
All of these findings make the diagnosis of HA compelling. Hemo­
globinuria may be overt in a random urine sample; if it is not, it may
be helpful to obtain serial urine samples because hemoglobinuria can
vary dramatically from day to day and even from hour to hour. The
bone marrow is usually cellular, with marked to massive erythroid
hyperplasia, often with mild to moderate dyserythropoietic features
(these overlap with those seen in myelodysplastic syndromes, but PNH
remains a separate entity). At some stage of the disease, the marrow
may become hypocellular or even frankly aplastic (see below).
The definitive diagnosis of PNH must be based on the demonstra­
tion that a substantial proportion of the patient’s red cells are deficient
in proteins (notably CD59 and CD55) that normally protect the red
cells from activated complement (C). The sucrose hemolysis test is
unreliable; in contrast, the acidified serum (Ham) test is highly reliable.
The gold standard today is flow cytometry, which can be carried out on
granulocytes as well as on red cells and has a very high sensitivity. In
PNH, characteristically, one sees a bimodal distribution of cells, with
a discrete population that is CD59 and CD55 negative. Although very
small populations of CD59(–) cells are of interest in terms of patho­
physiology (particularly of aplastic anemia [AA]), no patient should
be diagnosed with PNH unless the proportion is substantial: in first
approximation, at least 5% of the total red cells and at least 20% of the
total granulocytes.
PATHOPHYSIOLOGY  Hemolysis in PNH is mainly intravascular and
is due to an intrinsic abnormality of the red cell, which makes it
exquisitely sensitive to activated C, whether C is activated through
the alternative pathway or through an antigen-antibody reaction
(classic pathway). The former mechanism is mainly responsible for
chronic hemolysis in PNH; the latter explains why the hemolysis
can be dramatically exacerbated in the course of a viral or bacterial
infection. Hypersusceptibility to C is due to deficiency in the red cell
membrane of several protective proteins (Fig. 105-10), among which
CD59 is the most important because it is able to hinder the insertion
into the membrane of C9 polymers (the so-called membrane attack
complex [MAC]). The molecular basis for the deficiency of these
proteins has been pinpointed not to a defect in any of the respective
genes, but rather to the shortage of a unique glycolipid molecule, GPI
(Fig. 105-2), which, through a peptide bond, anchors these proteins
to the surface membrane of cells. The shortage of GPI is due in turn
to a somatic mutation in an X-linked gene, called PIGA, required for
an early step in GPI biosynthesis. As a result, the patient’s marrow is
a mosaic of mutant and nonmutant cells, and the peripheral blood
always contains both GPI-negative (PNH) cells and GPI-positive (nonPNH) cells; in most cases, the former prevail. Thrombosis is one of the
most immediately life-threatening complications of PNH and yet one
of the least understood in its pathogenesis. It could be that deficiency
of CD59 on the PNH platelet causes inappropriate platelet activation;
however, other mechanisms are possible. In very rare cases, PNH can
be caused by biallelic mutations of the autosomal PIGT gene, which
maps to chromosome 20q, in the absence of a PIGA mutation. In these
cases, because GPI is produced but cannot bind to proteins, the clinical
picture is further complicated by the coexistence of a chronic inflam­
matory state.
BONE MARROW FAILURE (BMF) AND RELATIONSHIP BETWEEN PNH
AND AA  It is not unusual that patients with firmly established PNH
have a previous history of AA, sometimes well documented; in many
cases, BMF preceding overt PNH may have passed unnoticed, but it is
probably the rule rather than the exception. On the other hand, some­
times a patient with PNH becomes less hemolytic and more pancyto­
penic and ultimately has the clinical picture of AA. The relationship
between PNH and AA manifested in the clinical course of patients
reflects a close link in pathogenesis. AA is thought to be an organspecific autoimmune disease, in which T cells cause damage to hemato­
poietic stem cells via an as yet unidentified molecular target. The same
may be true of PNH, and in this condition, the target might be the GPI
molecule itself. This would explain why GPI-negative (PNH) stem cells
are spared; PIGA mutations can be demonstrated in normal people.
Thus, PNH results from the combined action of two factors: failure of
normal hematopoiesis and massive expansion of a PNH clone. There
is evidence from mouse models that PNH stem cells do not expand on
their own, and there is evidence from human patients that expansion
is associated with negative selection against GPI-positive cells by GPIspecific T cells. Thus, PNH is a prime example of a clonal disease that
is not malignant.
Classic
pathway
Lectin
pathway
C5
C3
C4b2a
C4b2aC3b
C5 convertase
C3 convertase
fD
Amplification
loop
Amplification
loop
fB
C3(H2O)Bb,
C3bBb
C3 convertases
C3BbC3b
C5 convertase
C5b
C3b
Alternative
pathway
C6 C7
CD55
C8
C9
CD59
Normal blood
B
A
Classic
pathway
Lectin
pathway
C5
C3
C3
C4b2aC3b
C5 convertase
C4b2a
C3 convertase
C4b2a
C3 convertase
ECULIZUMAB
fD
Amplification
loop
Amplification
loop
fB
RAVULIZUMAB
C3(H2O)Bb,
C3bBb
C3 convertases
C3BbC3b
C5 convertase
C5b
C3b
Alternative
pathway
C6 C7
C8
Macrophages
C9
EXTRAVASCULAR
HEMOLYSIS
PNH patient,
C5 blockade
D
C
FIGURE 105-10  The complement cascade and the fate of red cells. A. In normal blood, when complement is activated, red cells are protected from lysis in several ways:
primarily by the two glycosylphosphatidylinositol (GPI)-linked surface proteins CD55 (prevents binding of C3 fragments) and CD59 (prevents the membrane attack complex
[MAC] from inserting into the membrane). B. Paroxysmal nocturnal hemoglobinuria (PNH) red cells are deficient in CD55 and CD59 because the glycosylphosphatidylinositol
(GPI) biosynthetic pathway is blocked as a result of a PIGA mutation; therefore, C3 fragments, particularly C3d, bind to their surface, and the red cells are rapidly lysed by the
action of the MAC. C. With drugs (monoclonal antibodies) that bind to C5 and prevent it from splitting into C5a and C5b, the entire distal pathway from C5 onward is blocked,
MAC is not formed, and intravascular hemolysis (IVH) is abrogated. However, red cells opsonized by C3d will be destroyed in the spleen and elsewhere; this drug-induced
extravascular hemolysis (EVH) varies in severity between patients. The Coombs test, which is characteristically negative in PNH, becomes positive (provided that a “broadspectrum” or an anticomplement reagent is used). D. With a drug that targets C3, C3b formation is inhibited, and the distal pathway is not triggered by C3b. Therefore, again,
no MAC is formed (abrogating IVH), and at the same time, opsonization of red cells by C3d is prevented, so that EVH is also curbed. The same is largely true for drugs that
target factor B or factor D, although C3b can still be formed through the classical pathway. (Reproduced with permission from L Luzzatto: Control of hemolysis in patients
with PNH. Blood 138:1908, 2021.)
TREATMENT
Paroxysmal Nocturnal Hemoglobinuria
Until around 20 years ago, there were essentially two treatment
options for PNH: either allogeneic BMT, providing a definitive cure
at the cost of nonnegligible risks; or continued supportive treatment
for what, unlike other acquired HAs, may be a lifelong condition. A
major advance has been the introduction in 2007 of a humanized
Classic
pathway
Lectin
pathway
C5
C3
C4b2aC3b
C5 convertase
C4b2a
C3 convertase
fD
fB
C3(H2O)Bb,
C3bBb
C3 convertases
C3BbC3b
C5 convertase
C5b
C3b
Alternative
pathway
C6 C7
C8
C9
MAC
MAC
INTRAVASCULAR
HEMOLYSIS
PNH patient
CHAPTER 105
Classic
pathway
Lectin
pathway
PEGCETACOPLAN
C5
Hemolytic Anemias
C4b2aC3b
C5 convertase
fD
DANICOPAN
fB
IPTACOPAN
C3(H2O)Bb,
C3bBb
C3 convertases
C3BbC3b
C5 convertase
C3b
C5b
Alternative
pathway
C6 C7
Macrophage
C8
C9
MAC
MAC
PNH patient,
C3 blockade
monoclonal antibody, eculizumab, which binds to the complement
component C5 near the site that, when cleaved, will trigger the
distal part of the complement cascade leading to formation of the
MAC. With C5 blocked by anti-C5, the patient is relieved of intra­
vascular hemolysis and of its attendant consequences, including
hemoglobinuria, with a reduced risk of thrombosis. In the majority
of patients who needed regular blood transfusion, the transfusion
requirement is either abolished or significantly reduced. For many
PNH patient,
untreated
PNH patient
on eculizumab
PNH patient
on pegcetacoplan
A
C5 blockade
C3
C5
C5
C5
MAC
MAC
MAC
C3
C5
C5
C5
MAC
MAC
MAC
Escape from C5 blockade
C5
C5
C5
MAC
MAC
MAC
C3
C5
C5
C5
MAC
MAC
MAC
B
PART 4
Oncology and Hematology
FIGURE 105-11  Impact and implications of anticomplement therapy in paroxysmal nocturnal hemoglobinuria (PNH). A. The three vertical bars symbolize red cell
composition in examples of PNH patients. In the untreated patient, severe anemia is present with ~30% PNH red cells. In the patient on eculizumab, PNH red cells are
protected from intravascular hemolysis, although at the expense of iatrogenic extravascular hemolysis (see text), and therefore, mild anemia is still present and can become
severe. In the patient on pegcetacoplan, both intravascular and extravascular hemolysis are prevented, and the anemia is completely corrected. Note that the increase in
red cells in the treated patients consists entirely of PNH red cells. B. Schematics of complement action and inhibition. In the untreated patient (left), the membrane attack
complex (MAC) produces intravascular hemolysis. On eculizumab (middle), C5 blockade prevents MAC formation; if blockade is incomplete, some MAC is formed, with
consequent breakthrough hemolysis. On pegcetacoplan (right), C5 convertase cannot be formed, and therefore, MAC formation is equally prevented; however, since there
is an enzymatic cascade upstream of C5 cleavage, if blockade is incomplete, MAC formation will be more abundant with consequently more severe breakthrough hemolysis,
potentially more massive as the PNH red cells are greatly increased in both relative and absolute terms. RBC, red blood cell.
PNH patients, eculizumab has meant a real transformation in the
quality of life, as well as a decrease in complications, particularly
thrombosis; thrombosis may still occur, but much more rarely. At
the same time, it is important to know that in patients on eculi­
zumab, the PNH red cells, now protected from being lysed through
the MAC, do still bind C3 fragments and thus become opsonized;
thus, the Coombs test becomes positive and hemolysis persists,
which is now iatrogenic and mainly extravascular. The extent to
which this happens depends in part on a genetic polymorphism of
the complement receptor CR1. Based on its half-life, eculizumab
must be administered intravenously every 14 days. Ravulizumab, a
derivative of eculizumab with longer life in circulation, is adminis­
tered at 8-week intervals, with obvious practical advantage. Patients
who, upon C5 blockade, are still receiving blood transfusions are at
risk of iron overload.
Persistent blood transfusion requirement and extravascular
hemolysis in PNH patients on C5 blockade therapy have been a
stimulus to developing agents that may inhibit complement activa­
tion more upstream, at the level of C3. This has been found not only
to prevent intravascular hemolysis but also to avoid C3 opsoniza­
tion of red cells, thus not causing extravascular hemolysis. Pegce­
tacoplan, an inhibitor of C3, and iptacopan, an inhibitor of factor
B (which, once activated, becomes part of the alternative pathway
C3 convertase) are already approved drugs; and danicopan, an
inhibitor of factor D (required for the activation of factor B), has
given promising results in clinical trials. Thus, several drug therapy
options are available for an ultra-rare disease (Fig. 105-11). Com­
pared to C5 blockade, C3 blockade has a greater chance to com­
pletely correct anemia. We must consider that correction of anemia
takes place by the buildup of a much larger population of PNH red
cells than would ever be possible in an untreated PNH patient, and
this population may undergo sudden lysis if complement blockade
is abrogated, whether by omission or otherwise.
Eculizumab and the other complement inhibitors are very expen­
sive and, for this reason, not accessible to patients in many parts
of the world. Therefore, the management of PNH by supportive
PNH RBC
Normal RBC
C3 blockade
C3
Escape from C3 blockade
C5
C5
C5
MAC
MAC
MAC
C3
treatment is still very important. Folic acid supplements (at least
3 mg/d) are mandatory; the serum iron should be checked periodi­
cally, and iron supplements should be administered as appropriate.
Transfusion of white cell-free red cells should be used whenever nec­
essary, which, for some patients, means quite frequently. Long-term
glucocorticoids are not indicated because there is no evidence that
they have any effect on chronic hemolysis; in fact, they are contra­
indicated because their side effects are considerable. A short course
of prednisone may be useful when an inflammatory process exacer­
bates hemolysis. Any PNH patient who has had venous thrombosis
or who has been found after a thrombophilia screen to have a genetic
risk factor should be on regular anticoagulant prophylaxis. With
thrombotic complications that do not resolve otherwise, thrombo­
lytic treatment with tissue plasminogen activator may be indicated.
Where anti-C5 therapy is available, the proportion of PNH patients
receiving BMT has decreased significantly. However, when an HLAidentical sibling is available, BMT should be taken into consideration
for any young patient with severe PNH, and for patients with the socalled PNH-AA syndrome, since C inhibitors have no effect on BMF.
For these patients, immunosuppressive treatment with antithymocyte
globulin and cyclosporine A may be an alternative, and it may be com­
patible with concurrent administration of eculizumab.
■
■FURTHER READING
Berentsen S, Barcellini W: Autoimmune hemolytic anemias. N
Engl J Med 385:1407, 2021.
Brodsky RA: Warm autoimmune hemolytic anemia. N Engl J Med
381:64, 2019.
Dacie J: The Haemolytic Anaemias. London, Churchill Livingstone,
volumes 1-5, 1985–1999.
De Franceschi L et al: Acute hemolysis by hydroxycloroquine was
observed in G6PD-deficient patient with severe COVD-19 related
lung injury. Eur J Intern Med 77:136, 2020.
Grace RF et al: Safety and efficacy of mitapivat in pyruvate kinase
deficiency. N Engl J Med 381:933, 2019.

36 - 106 Anemia Due to Acute Blood Loss
106 Anemia Due to Acute Blood Loss
Loirat C et al: An international consensus approach to the manage­
ment of atypical hemolytic uremic syndrome in children. Pediatr
Nephrol 31:15, 2016.
Luzzatto L et al: Glucose-6-phosphate dehydrogenase deficiency.
Blood 136:1225, 2020.
Notaro R, Luzzatto L: Breakthrough hemolysis in PNH with proxi­
mal or terminal complement inhibition. N Engl J Med 387:160, 2022.
Roy NBA et al: The use of next-generation sequencing in the diagnosis
of rare inherited anaemias: A joint BSH/EHA Good Practice Paper.
Br J Haematol 198:459, 2022.
Uyoga S et al: Glucose-6-phosphate dehydrogenase deficiency and
susceptibility to childhood diseases in Kilifi, Kenya. Blood Adv
4:5942, 2020.
Dan L. Longo
Anemia Due to Acute
Blood Loss
Blood loss causes anemia by two main mechanisms: (1) by the direct
loss of red cells; and (2) if the loss of blood is protracted, it will gradu­
ally deplete iron stores, eventually resulting in iron deficiency. The
latter type of anemia is covered in Chap. 102. Here, we are concerned
with the former type, that is, posthemorrhagic anemia, which follows
acute blood loss. This can be external (e.g., after trauma or obstetric
hemorrhage) or internal (e.g., from bleeding in the gastrointestinal
tract, rupture of the spleen, rupture of an ectopic pregnancy, sub­
arachnoid hemorrhage, leaking aneurysm). In any of these cases, after
the sudden loss of a large amount of blood, there are three clinical/
pathophysiologic stages. (1) At first, the dominant feature is hypovo­
lemia, which poses a threat particularly to organs that normally have
a high blood supply, like the brain and the kidneys; therefore, loss of
consciousness and acute renal failure are major threats. It is important
to note that at this stage an ordinary blood count will not show anemia
because the hemoglobin concentration is not affected. As hypovolemia
is corrected with intravenous fluids acutely, the hemoglobin will gradu­
ally fall over several hours. On physical exam, tachycardia, tachypnea,
decreased pulse pressure, cold skin that appears pale and mottled,
and decreased urine output may be noted reflecting the efforts of the
sympathetic nervous system to compensate. (2) Next, as an emergency
response, baroreceptors and stretch receptors will cause release of
vasopressin and other peptides, and the body will shift fluid from the
extravascular to the intravascular compartment, producing hemodilu­
tion; thus, the hypovolemia gradually converts to anemia. The degree
of anemia will reflect the amount of blood lost. If after 3 days the hemo­
globin is, for example, 7 g/dL, it means that about half of the entire
blood has been lost. (3) Provided bleeding does not continue, the bone
marrow response will gradually ameliorate the anemia. In this phase of
the process, the reticulocyte count and erythropoietin levels will be ele­
vated. The physiologic increase in marrow red cell production reflected
by the increase in reticulocytes is similar to the marrow response to
hemolysis. Hemolysis and compensatory marrow increase in red blood
cell (RBC) production are the two major mechanisms associated with
anemia that is accompanied by an increase in reticulocyte count.
The diagnosis of acute posthemorrhagic anemia (APHA) is usually
straightforward, although sometimes internal bleeding episodes (e.g.,
after a traumatic injury), even when large, may not be immediately
obvious. When the scene is bloody, often the estimate of the volume of
blood loss is overestimated. Always check the patient carefully. Look for
physical findings that may help localize the bleeding if the site of bleed­
ing is not obvious. Grey Turner sign (flank ecchymosis) may reflect
retroperitoneal bleeding. Cullen sign (umbilical ecchymosis) may
suggest intraperitoneal or retroperitoneal bleeding. Dullness to chest
percussion may suggest intrapleural bleeding. Whenever an abrupt fall
in hemoglobin has taken place, whatever history is given by the patient,
APHA should be suspected. Supplementary history may have to be
obtained by asking the appropriate questions, and appropriate investi­
gations (e.g., a sonogram or an endoscopy) may have to be carried out.
If blood loss is mild, enhanced O2 delivery is achieved through
changes in the O2–hemoglobin dissociation curve mediated by a
decreased pH or increased CO2 (Bohr effect). With acute blood loss,
hypovolemia dominates the clinical picture, and the hematocrit and
hemoglobin levels do not reflect the volume of blood lost. Signs of
vascular instability appear with acute losses of 25% or more of the
total blood volume. The donation of a unit of blood (~20% of the
blood volume) is often minimally symptomatic. In patients who lose
a larger percentage of the blood volume, the issue is not anemia but
hypotension and decreased organ perfusion. When >30% of the blood
volume is lost suddenly, patients are unable to compensate with the
usual mechanisms of sympathetic nervous system increases in heart
rate, vascular contraction, and changes in regional blood flow. The
patient prefers to remain supine and will show postural hypotension
and tachycardia. If the volume of blood lost is >40% (i.e., >2 L in the
average-sized adult), signs of hypovolemic shock including confu­
sion, dyspnea, diaphoresis, hypotension, and tachycardia appear. Such
patients have significant deficits in vital organ perfusion and require
immediate volume replacement.
CHAPTER 106
Symptoms associated with more chronic or progressive anemia
depend on the age of the patient and the adequacy of blood supply to
critical organs. Symptoms associated with moderate anemia include
fatigue, loss of stamina, breathlessness, and tachycardia (particularly
with physical exertion). However, because of the intrinsic compensa­
tory mechanisms that govern the O2–hemoglobin dissociation curve,
the gradual onset of anemia—particularly in young patients—may not
be associated with signs or symptoms until the anemia is severe (hemo­
globin <70–80 g/L [7–8 g/dL]). When anemia develops over a period of
days or weeks, the total blood volume is normal to slightly increased,
and changes in cardiac output and regional blood flow help compen­
sate for the overall loss in O2-carrying capacity. Changes in the posi­
tion of the O2–hemoglobin dissociation curve account for some of the
compensatory response to anemia. With chronic anemia, intracellular
levels of 2,3-bisphosphoglycerate rise, shifting the dissociation curve to
the right and facilitating O2 unloading. This compensatory mechanism
can only maintain normal tissue O2 delivery in the face of a 20–30 g/L
(2–3 g/dL) deficit in hemoglobin concentration. Finally, further protec­
tion of O2 delivery to vital organs is achieved by the shunting of blood
away from organs that are relatively rich in blood supply, particularly
the kidney, gut, and skin.
Anemia Due to Acute Blood Loss
TREATMENT
Anemia Due to Acute Blood Loss
In patients who are hemodynamically unstable, the usual airway,
breathing, and circulation assessments take priority. In the face of
bleeding associated with hypotension, pharmacologic support with
vasopressors is critical. With respect to anemia treatment, a twopronged approach is imperative. (1) In many cases, the blood lost
needs to be replaced promptly. Unlike with many chronic anemias,
when finding and correcting the cause of the anemia is the first pri­
ority and blood transfusion may not be even necessary because the
body is adapted to the anemia, with acute blood loss, the reverse is
true. Because the body is not adapted to the anemia, blood transfu­
sion takes priority. (2) While the emergency is being confronted, it
is imperative to stop the hemorrhage and to eliminate its source.
In an acute hemorrhage situation, plasma may be preferred to saline
for volume expansion since dilution of clotting factors with crystalloid
may interfere with hemostasis. Furthermore, trauma can lead to
vascular and platelet abnormalities that enhance the bleeding risk.
A special type of APHA is blood loss during and immediately
after surgery, which can be substantial (e.g., up to 2 L in the case of a

38 - 108 Polycythemia Vera and Other Myeloproliferative Neoplasms
108 Polycythemia Vera and Other Myeloproliferative Neoplasms
anti-CD52 monoclonal antibody alemtuzumab are especially effec­
tive in younger MDS patients (<60 years old) with more favorable
IPSS. In a consortium retrospective review, about 50% of patients
with mainly refractory anemia responded to ATG, usually com­
bined with cyclosporine, particularly patients with hypocellular
marrow.
HGFs can improve blood counts but, as in most other marrow
failure states, have been most beneficial to patients with the least
severe pancytopenia. EPO alone or in combination with G-CSF can
improve hemoglobin levels, particularly in those with low serum
EPO levels who have no or a modest need for transfusions. Sur­
vival is improved by EPO and its amelioration of anemia. G-CSF
treatment alone failed to improve survival in a controlled trial.
Thrombopoietin mimetics appear to improve platelet counts in
some patients, but TPO agonists may increase the rate of leukemic
progression in high-risk MDS. No clear evidence suggests that they
increase leukemic transformation in low-risk MDS.
Luspatercept, which affects transforming growth factor β–mediated
suppression of erythropoiesis, has been approved by the FDA for
anemia in low-risk MDS, particularly those with SF3B1 mutations.
The FDA has approved ivosidenib, an IDH1 inhibitor, for MDS.
Venetoclax, a BCL2 inhibitor, is FDA approved for patients with
AML and has been used in combination with HMA in high-risk
MDS; however, it remains investigational.
PART 4
Oncology and Hematology
Promising novel agents in trials include targeted therapies (i.e.,
TP53, splicing factor mutations), inflammation pathway inhibitors
(including inflammasome and interleukin 1 receptor–associated
kinase), and imetelstat, a telomerase inhibitor. Likely, HMA alone
will be replaced with HMA combination therapies.
The same principles of supportive care described for aplastic
anemia apply to MDS. Many patients will be anemic for years. RBC
transfusion support should be accompanied by iron chelation to
prevent secondary hemochromatosis.
MYELOPHTHISIC ANEMIAS
Fibrosis of the bone marrow (see Fig. 65-19), usually accompanied by
a characteristic blood smear picture called leukoerythroblastosis, can
occur as a primary hematologic disease, called myelofibrosis or myeloid
metaplasia (Chap. 108), and as a secondary process, called myelophthi­
sis. Myelophthisis, or secondary myelofibrosis, is reactive. Fibrosis can
be a response to invading tumor cells, usually an epithelial cancer of
breast, lung, or prostate origin or neuroblastoma. Marrow fibrosis may
occur with infection of mycobacteria (both Mycobacterium tuberculosis
and Mycobacterium avium), fungi, or HIV and in sarcoidosis. Intracel­
lular lipid deposition in Gaucher disease and obliteration of the mar­
row space related to absence of osteoclast remodeling in congenital
osteopetrosis also can produce fibrosis. Secondary myelofibrosis is a
late consequence of radiation therapy or treatment with radiomimetic
drugs. Usually the infectious or malignant underlying processes are
obvious. Marrow fibrosis can also be a feature of a variety of hema­
tologic syndromes, especially chronic myeloid leukemia, multiple
myeloma, lymphomas, myeloma, and hairy cell leukemia.
The pathophysiology has three distinct features: proliferation of
fibroblasts in the marrow space (myelofibrosis); the extension of hema­
topoiesis into the long bones and into extramedullary sites, usually the
spleen, liver, and lymph nodes (myeloid metaplasia); and ineffective
erythropoiesis. The etiology of the fibrosis is unknown but most likely
involves dysregulated production of growth factors: platelet-derived
growth factor and transforming growth factor β have been implicated.
Abnormal regulation of other hematopoietins would lead to localiza­
tion of blood-producing cells in nonhematopoietic tissues and uncou­
pling of the usually balanced processes of stem cell proliferation and
differentiation. Myelofibrosis is remarkable for pancytopenia despite
very large numbers of circulating hematopoietic progenitor cells.
Anemia is dominant in secondary myelofibrosis, usually normocytic
and normochromic. The diagnosis is suggested by the characteristic
leukoerythroblastic smear. Erythrocyte morphology is highly abnor­
mal, with circulating nucleated RBCs, teardrops, and shape distortions.
WBC numbers are often elevated, sometimes mimicking a leukemoid
reaction, with circulating myelocytes, promyelocytes, and myeloblasts.
Platelets may be abundant and are often of giant size. Inability to aspi­
rate the bone marrow, the characteristic “dry tap,” can allow a presump­
tive diagnosis in the appropriate setting before the biopsy is decalcified.
The course of secondary myelofibrosis is determined by its etiology,
usually a metastatic tumor or an advanced hematologic malignancy.
Treatable causes must be excluded, especially tuberculosis and fungus.
Transfusion support can relieve symptoms.
■
■FURTHER READING
Arber DA et al: International Consensus Classification of myeloid
neoplasms and acute leukemias: Integrating morphologic, clinical,
and genomic data. Blood 140:1200, 2022.
Bernard E et al: Molecular International Prognostic Scoring System
for myelodysplastic syndromes. NEJM Evid 1:EVIDoa2200008, 2022.
Cazzola M: Myelodysplastic syndromes. N Engl J Med 383:1358,
2020.
DeFilipp Z et al: Hematopoietic cell transplantation in the manage­
ment of myelodysplastic syndrome: An evidence-based review from
the American Society for Transplantation and Cellular Therapy
Committee on Practice Guidelines. Transplant Cell Ther 29:71, 2022.
Gurnari C, Maciejewski JP: How I manage acquired pure red cell
aplasia in adults. Blood 15;137:2001, 2021.
Hellstrom-Lindberg ES et al: Clinical decision-making and treat­
ment of myelodysplastic syndromes. Blood 142:2268, 2023.
Khoury JD et al: The 5th edition of the World Health Organization
classification of haematolymphoid tumours: Myeloid and histiocytic/
dendritic neoplasms. Leukemia 36:1703, 2022.
Mustjoki S, Young NS: Somatic mutations in “benign” disease. N
Engl J Med 384:2039, 2021.
Townsley DM et al: Eltrombopag added to standard immunosuppres­
sion for aplastic anemia. N Engl J Med 376:1540, 2017.
Young NS: Aplastic anemia. N Engl J Med 379:1643, 2018.
Jerry L. Spivak
Polycythemia Vera and
Other Myeloproliferative
Neoplasms
The World Health Organization (WHO) classification of the chronic
myeloproliferative neoplasms (MPNs) includes eight disorders, some
of which are rare or poorly characterized (Table 108-1) but all of which
share an origin in a hematopoietic stem cell; overproduction of one or
more of the formed elements of the blood without significant dysplasia;
and a predilection to extramedullary hematopoiesis, myelofibrosis, and
transformation at varying rates to acute leukemia. Within this broad
TABLE 108-1  World Health Organization Classification of Chronic
Myeloproliferative Neoplasms
Chronic myeloid leukemia, BCR-ABL–positive
Chronic neutrophilic leukemia
Chronic eosinophilic leukemia, not otherwise specified
Polycythemia vera
Primary myelofibrosis
Essential thrombocytosis
Mastocytosis
Myeloproliferative neoplasms, unclassifiable
classification, however, significant phenotypic heterogeneity exists.
Some diseases such as chronic myelogenous leukemia (CML), chronic
neutrophilic leukemia (CNL), and chronic eosinophilic leukemia
(CEL) express primarily a myeloid phenotype, whereas in other dis­
eases, such as polycythemia vera (PV), primary myelofibrosis (PMF),
and essential thrombocytosis (ET), erythroid or megakaryocytic
hyperplasia predominates. The latter three disorders, in contrast to
the former three, also appear capable of transforming into each other.
Such phenotypic heterogeneity has a genetic basis; CML is the con­
sequence of the balanced translocation between chromosomes 9 and 22
(t[9;22][q34;11]); CNL has been associated with a mutation of CSF3R
and a t(15;19) translocation; and CEL occurs with a deletion or bal­
anced translocations involving the PDGFRα usually with the FIP1L1,
PDGFRβ, FGFR1, and PCM1-JAK2 genes. By contrast, PV, PMF, and
ET are characterized by driver mutations that directly or indirectly
constitutively activate JAK2, a tyrosine kinase essential for the function
of the erythropoietin and thrombopoietin receptors and also utilized
by the granulocyte colony-stimulating factor receptor. This important
distinction is reflected in the natural histories of CML, CNL, and CEL,
which are usually measured in years, with a high rate of leukemic trans­
formation. The natural histories of PV, PMF, and ET, by contrast, are
usually measured in decades, and transformation to acute leukemia is
uncommon in the absence of chemotherapy. This chapter focuses only
on PV, PMF, and ET because their clinical features and driver mutation
overlap are substantial, although their disease duration and clinical
manifestations vary.
The other chronic MPNs will be discussed in Chaps. 110 and 115.
POLYCYTHEMIA VERA
PV is a clonal hematopoietic stem cell disorder in which phenotypically
normal red cells, granulocytes, and platelets accumulate in the absence
of a recognizable physiologic stimulus. The most common of the MPNs,
PV occurs in 2.5 per 100,000 persons, sparing no adult age group and
increasing with age to rates >10/100,000. Familial transmission is infre­
quent, and women under age 50 predominate among sporadic cases.
■
■ETIOLOGY
Nonrandom chromosome abnormalities such as deletion 20q and
deletion 13q or trisomy 9 occur in up to 30% of untreated PV patients,
but unlike CML, no consistent cytogenetic abnormality has been asso­
ciated with the disorder. However, a mutation in the autoinhibitory
pseudokinase domain of the tyrosine kinase JAK2 that replaces valine
with phenylalanine (V617F), causing constitutive kinase activation, has
a central role in PV pathogenesis.
JAK2 is a member of an evolutionarily well-conserved, nonreceptor
tyrosine kinase family and serves as the cognate tyrosine kinase for
the erythropoietin and thrombopoietin receptors. It also functions as
an obligate chaperone for these receptors in the Golgi apparatus and
is responsible for their cell-surface expression. The conformational
change induced in the erythropoietin and thrombopoietin receptors
following binding to their respective cognate ligands, erythropoi­
etin or thrombopoietin, leads to JAK2 autophosphorylation, receptor
phosphorylation, and phosphorylation of proteins involved in cell
proliferation, differentiation, and resistance to apoptosis. Transgenic
animals lacking JAK2 die as embryos from severe anemia. Constitu­
tive activation of JAK2, on the other hand, explains the erythropoietin
hypersensitivity, erythropoietin-independent erythroid colony forma­
tion, rapid terminal differentiation, increased Bcl-XL expression, and
apoptosis resistance in the absence of erythropoietin that characterize
the in vitro behavior of PV erythroid progenitor cells.
More than 95% of PV patients express this mutation, as do ∼50%
of PMF and ET patients. Importantly, the JAK2 gene is located on the
short arm of chromosome 9, and loss of heterozygosity on chromo­
some 9p involving the segment containing the JAK2 locus over time
due to mitotic recombination (uniparental disomy) is the most com­
mon cytogenetic abnormality in PV. Loss of heterozygosity in this
region leads to homozygosity for JAK2 V617F and occurs in ∼60% of
PV patients and to a lesser extent in PMF but is rare in ET. Most PV
patients who do not express JAK2 V617F express a mutation in exon 12
of the gene and are not clinically different from those who do, with the
exception of a higher frequency of isolated erythrocytosis, nor do JAK2
V617F heterozygotes differ clinically from homozygotes. Importantly,
the predisposition to acquire JAK2 mutations appears to be associated
with a specific JAK2 gene haplotype, GGCC. JAK2 V617F is the basis
for many of the phenotypic and biochemical characteristics of PV such
as increased blood cell production and increased inflammatory cyto­
kine production; however, it cannot solely account for the entire PV
phenotype and is probably not the initiating lesion in any of the MPNs.
First, PV patients with the same phenotype and documented clonal
disease can have mutations in LNK, a JAK2 inhibitor, or rarely, calre­
ticulin (CALR), an ER chaperone, since MPN driver mutations are not
mutually exclusive. Second, ET and PMF patients have the same muta­
tions but different clinical phenotypes. Third, familial PV can occur
without the mutation, even when other members of the same family
express it. Finally, in some JAK2 V617F–positive PV or ET patients,
acute leukemia can occur in a JAK2 V617F–negative progenitor cell,
suggesting the presence of an ancestral precursor cell.
■
■CLINICAL FEATURES
Although PV is a panmyelopathy, isolated thrombocytosis, leukocy­
tosis, or splenomegaly can be its presenting manifestation, but most
often, the disorder is first recognized by the incidental discovery of a
high hemoglobin, hematocrit, or red cell count. With the exception of
aquagenic pruritus or erythromelalgia, no symptoms distinguish PV
from other causes of erythrocytosis.
CHAPTER 108
Uncontrolled erythrocytosis causes hyperviscosity, leading to neu­
rologic symptoms such as vertigo, tinnitus, headache, visual distur­
bances, and transient ischemic attacks (TIAs). Systolic hypertension is
also a feature of the red cell mass elevation. In some patients, venous
or arterial thrombosis may be the presenting manifestation of PV. Any
vessel can be affected, but cerebral, cardiac, and mesenteric vessels
are most commonly involved. Hepatic venous thrombosis (BuddChiari syndrome) is particularly common in young women and may
be catastrophic if sudden and complete obstruction of the hepatic vein
occurs; portal vein thrombosis is more common in male PV patients.
Indeed, PV should be suspected in any woman who develops hepatic
vein thrombosis, since this is the only type of thrombosis associated
with JAK2 V617F expression. Digital ischemia, easy bruising, epistaxis,
acid-peptic disease, or gastrointestinal hemorrhage may occur due to
vascular stasis or extreme thrombocytosis (>900,000/mL). In the lat­
ter instance, absorption and proteolysis of high-molecular-weight von
Willebrand multimers by the large platelet mass cause acquired von
Willebrand’s disease. Erythema, burning, and pain in the extremities, a
symptom complex known as erythromelalgia, is another complication
of thrombocytosis in PV due to increased platelet stickiness. Given the
large turnover of hematopoietic cells, hyperuricemia with secondary
gout, uric acid stones, and symptoms due to hypermetabolism can also
complicate the disorder.
Polycythemia Vera and Other Myeloproliferative Neoplasms
■
■DIAGNOSIS
When PV presents with erythrocytosis in combination with leukocyto­
sis, thrombocytosis, or splenomegaly or any combination of these, the
diagnosis is apparent. However, when patients present with an elevated
hemoglobin, hematocrit, and red cell count alone, the diagnostic evalu­
ation is more complex because of the many diagnostic possibilities
(Table 108-2). Furthermore, unless the hemoglobin level is ≥20 g/dL
(hematocrit ≥60%), it is not possible to distinguish true erythrocytosis
from disorders causing plasma volume contraction. This is because
uniquely in PV, in contrast to other causes of true erythrocytosis,
there is expansion of the plasma volume, which can mask the elevated
red cell mass, particularly in women; thus, red cell mass and plasma
volume determinations are necessary to establish the presence of an
absolute erythrocytosis and distinguish this from relative erythrocyto­
sis due to a reduction in plasma volume alone (also known as stress or
spurious erythrocytosis or Gaisböck’s syndrome). Figure 66-18 illustrates
a diagnostic algorithm for the evaluation of suspected erythrocytosis.
While an assay for JAK2 or rarely LNK mutations in the presence of
a normal arterial oxygen saturation appears to provide an alternative
TABLE 108-2  Causes of Erythrocytosis
Relative Erythrocytosis
Hemoconcentration secondary to dehydration, diuretics, ethanol abuse,
androgens, or tobacco abuse
Absolute Erythrocytosis
Hypoxia
Tumors
Carbon monoxide intoxication
Hypernephroma
High-oxygen-affinity hemoglobin
Hepatoma
High altitude
Cerebellar hemangioblastoma
Pulmonary disease
Uterine myoma
Right-to-left cardiac or vascular shunts
Adrenal tumors
Sleep apnea syndrome
Meningioma
Hepatopulmonary syndrome
Pheochromocytoma
Renal Disease
Drugs
Renal artery stenosis
Androgens
SGLT2 inhibitors
Focal sclerosing or membranous
glomerulonephritis
Recombinant erythropoietin
Familial (with normal hemoglobin
function)
Postrenal transplantation
Renal cysts
Erythropoietin receptor mutations
PART 4
Oncology and Hematology
Bartter’s syndrome
VHL mutations (Chuvash polycythemia)
2,3-BPG mutation
PHD2 (EGLN1) and HIF2α (EPAS1)
mutations
LNK mutations
Polycythemia vera
Abbreviations: 2,3-BPG, 2,3-bisphosphoglycerate; VHL, von Hippel-Lindau.
diagnostic approach to isolated erythrocytosis since red cell mass and
plasma volume determinations are not usually available, isolated eryth­
rocytosis is uncommon as an initial manifestation of PV, and not every­
one expressing a low JAK2 V617F quantitative mutation allele burden
(variant allele frequency [VAF] ≤5%) actually has a blood disease. In
addition, a normal serum erythropoietin level does not exclude the
presence of PV, but an elevated erythropoietin level is most consistent
with a secondary cause for the erythrocytosis.
Other laboratory studies that may aid in diagnosis include the red
cell count, mean corpuscular volume, and red cell distribution width
(RDW), particularly when the hematocrit or hemoglobin levels are
<60% or 20 g/dL, respectively. Only three situations cause microcytic
erythrocytosis: β-thalassemia trait, hypoxic erythrocytosis, and PV.
With β-thalassemia trait, the RDW is usually normal, whereas with
hypoxic erythrocytosis or PV, the RDW may be elevated due to associ­
ated iron deficiency. Today, however, the quantitative assay for JAK2
V617F or JAK2 exon 12 mutations using next-generation sequencing
technology has superseded the other surrogate tests for establishing the
diagnosis of PV.
A bone marrow aspirate and biopsy provide no specific diagnostic
information because these may be normal or indistinguishable from
ET or PMF. Similarly, no specific cytogenetic abnormality is associated
with the disease, and the absence of a cytogenetic marker does not
exclude the diagnosis.
■
■COMPLICATIONS
Many of the clinical complications of PV relate directly to the increase
in blood viscosity associated with red cell mass elevation and indirectly
to the increased turnover of red cells, leukocytes, and platelets with the
attendant increase in uric acid and inflammatory cytokine production.
The latter also appears to be responsible for some of the constitutional
symptoms in PV. Peptic ulcer disease can also be due to Helicobacter
pylori infection, the incidence of which is increased in PV, while the
pruritus associated with this disorder may be a consequence of mast
cell activation by JAK2 V617F. A sudden increase in spleen size can
be associated with painful splenic infarction. Myelofibrosis appears to
be part of the natural history of the disease but is a reactive, reversible
process that does not itself impede hematopoiesis and by itself has no
prognostic significance in PV. In ∼15% of patients, however, myelofi­
brosis is associated with hematopoietic stem cell failure, manifested by
substantial extramedullary hematopoiesis in the liver and spleen and
transfusion-dependent anemia. Organomegaly can cause significant
mechanical discomfort, portal hypertension, and progressive cachexia.
Although the incidence of acute myeloid leukemia is increased in
PV, the incidence of acute leukemia in patients not exposed to chemo­
therapy or radiation therapy is very low. Interestingly, chemotherapy,
including hydroxyurea, has been associated with acute leukemia in
JAK2 V617F–negative hematopoietic stem cells (HSCs) in some PV
patients. Erythromelalgia is a curious syndrome of unknown etiology
associated with thrombocytosis, primarily involving the lower extremi­
ties and usually manifested by erythema, warmth, and pain of the
affected appendage and occasionally digital infarction. It occurs with a
variable frequency and is usually responsive to salicylates. Some of the
central nervous system symptoms observed in patients with PV, such
as ocular migraine, appear to represent a variant of erythromelalgia.
Left uncontrolled, erythrocytosis can lead to thrombosis involving
vital organs such as the liver, heart, brain, or lungs. Patients with mas­
sive splenomegaly are particularly prone to thrombotic events because
the associated increase in plasma volume masks the true extent of the
red cell mass elevation measured by the hematocrit or hemoglobin
level. A “normal” hematocrit or hemoglobin level in a PV patient with
massive splenomegaly should be considered indicative of an elevated
red cell mass until proven otherwise.
TREATMENT
Polycythemia Vera
PV is generally an indolent disorder, the clinical course of which
is measured in decades, and its management should reflect its
tempo. Thrombosis due to erythrocytosis is the most significant
complication and often the presenting manifestation; maintenance
of the hemoglobin level at ≤140 g/L (14 g/dL; hematocrit <45%)
in men and ≤120 g/L (12 g/dL; hematocrit <42%) in women is
mandatory to avoid thrombotic complications. Phlebotomy serves
initially to reduce hyperviscosity by reducing the red cell mass
to normal while further expanding the plasma volume. Periodic
phlebotomies thereafter serve to maintain the red cell mass within
the normal range and induce a state of iron deficiency that prevents
accelerated reexpansion of the red cell mass. In most PV patients,
once an iron-deficient state is achieved, phlebotomy is usually
only required at 3-month intervals. Neither phlebotomy nor iron
deficiency increases the platelet count relative to the effect of the
disease itself, and neither thrombocytosis nor leukocytosis is cor­
related with thrombosis in PV, in contrast to the strong correlation
between erythrocytosis and thrombosis. The use of salicylates to
prevent thrombosis in PV patients is potentially harmful not only if
the red cell mass is not controlled by phlebotomy, but also due to an
increased incidence of bleeding, particularly in patients over age 60.
Anticoagulation is indicated when a thrombosis has occurred,
and the newer oral anticoagulants may be preferable to a vitamin K
antagonist since they do not require monitoring. Asymptomatic
hyperuricemia (<10 mg/dL) requires no therapy, but allopurinol
should be administered to avoid further elevation of the uric acid
when chemotherapy is used to reduce splenomegaly or leukocytosis
or to treat pruritus. Generalized pruritus intractable to antihistamines
or antidepressants such as doxepin can be a major problem in PV;
the JAK1/2 inhibitor ruxolitinib, pegylated interferon α (IFN-α),
psoralens with ultraviolet light in the A range (PUVA) therapy, and
hydroxyurea are other methods of palliation. Asymptomatic throm­
bocytosis requires no therapy unless the platelet count is sufficiently
high to cause bleeding due to acquired von Willebrand’s disease,
but bleeding in this situation is not usually spontaneous and is
responsive to tranexamic acid or ε-aminocaproic acid. Symptomatic
splenomegaly can be treated with either ruxolitinib or pegylated
IFN-α. Both ruxolitinib and pegylated IFN-α target the involved
HSCs in PV and are not mutagenic; hydroxyurea does not target
the involved HSCs in PV and is mutagenic. Furthermore, pegylated
IFN-α allows only biweekly administration and produced complete
hematologic and molecular remissions in ∼20% of PV patients.
Anagrelide, a phosphodiesterase inhibitor, can reduce the platelet
count and, if tolerated, is preferable to hydroxyurea because it lacks
marrow toxicity and is also protective against venous thrombosis,
whereas hydroxyurea is not. However, chronic anagrelide therapy
is cardiotoxic and nephrotoxic, particularly in older PV patients.
A reduction in platelet number may be necessary for the treat­
ment of erythromelalgia or ocular migraine if salicylates are not
effective or if the platelet count is sufficiently high to increase the risk
of hemorrhage but only to the degree that symptoms are alleviated.
Alkylating agents and radioactive sodium phosphate (32P) are leuke­
mogenic in PV, and their use should be avoided. If a cytotoxic agent
must be used, hydroxyurea is preferred, but this drug does not pre­
vent either thrombosis or myelofibrosis in PV, is itself leukemogenic,
and should be considered as a short-duration therapy. Previously,
PV patients with massive splenomegaly unresponsive to reduction
by chemotherapy or IFN required splenectomy. However, with the
introduction of the nonspecific JAK1/2 inhibitor ruxolitinib, it has
been possible in the majority of patients with PV complicated by
myelofibrosis and myeloid metaplasia to reduce spleen size while
at the same time alleviating constitutional symptoms and pruritus
due to cytokine release while reducing the phlebotomy requirement.
However, in contrast to PMF, PV patients have a more chronic
course; in contrast to other malignancies, PV patients have a low
rate of mutation accumulation, and the acquisition of deleterious
mutations such as TP53 mutations as detected by next-generation
sequencing is usually associated with leukemic transformation. Since
hydroxyurea antagonizes TP53 and also causes del17p, leading to
TP53 haploinsufficiency, its chronic use should be constrained in PV.
Ruxolitinib has also been demonstrated in a phase 3 clinical
trial to be effective in PV patients without myelofibrosis who are
intolerant or refractory to hydroxyurea or best available supportive
therapy. Three other JAK2 inhibitors, fedratinib, pacritinib, and
momelotinib, have been approved for treatment of PV patients
with myelofibrosis in whom ruxolitinib treatment failed or who
were intolerant to the drug. In some PV patients with end-stage
disease, pulmonary hypertension may develop due to fibrosis or
extramedullary hematopoiesis. A role for bone marrow transplanta­
tion, either allogeneic or haploidentical, in PV has not been defined.
Most patients with PV can live long lives without functional
impairment when their red cell mass is effectively managed with
phlebotomy alone. Chemotherapy is never indicated to control the
red cell mass in PV, but when venous access is an issue, ruxolitinib
or pegylated IFN is the preferred therapy. Interestingly, hepcidin
production is suppressed, but not absent in PV, and a hepcidin
agonist has been shown to reduce phlebotomy requirements in PV.
■
■PRIMARY MYELOFIBROSIS
Chronic PMF (other designations include idiopathic myelofibrosis,
agnogenic myeloid metaplasia, or myelofibrosis with myeloid metaplasia)
is a clonal HSC disorder associated with mutations in JAK2, MPL, or
CALR, and characterized by marrow fibrosis, extramedullary hema­
topoiesis, variable suppression of hematopoiesis, and splenomegaly.
PMF is the least common MPN, and establishing its diagnosis in the
absence of a specific clonal marker is difficult because myelofibrosis
and splenomegaly are also features of both PV and CML. Furthermore,
myelofibrosis and splenomegaly also occur in a variety of benign and
malignant disorders (Table 108-3), many of which are amenable to
specific therapies not effective in PMF. In contrast to the other MPNs
and so-called acute or malignant myelofibrosis, which can occur at any
age, PMF primarily afflicts men in their sixth decade or later.
■
■ETIOLOGY
Nonrandom chromosome abnormalities such as 9p, 20q−, 13q−,
trisomy 8 or 9, or partial trisomy 1q are common in PMF, but no
TABLE 108-3  Disorders Causing Myelofibrosis
MALIGNANT
NONMALIGNANT
Acute leukemia (lymphocytic,
myelogenous, megakaryocytic)
HIV infection
Hyperparathyroidism
Renal osteodystrophy
Systemic lupus erythematosus
Tuberculosis
Vitamin D deficiency
Thorium dioxide exposure
Gray platelet syndrome
Chronic myeloid leukemia
Hairy cell leukemia
Hodgkin’s disease
Primary myelofibrosis
Lymphoma
Multiple myeloma
Myelodysplasia
Metastatic carcinoma
Polycythemia vera
Systemic mastocytosis
cytogenetic abnormality specific to the disease has been identified.
JAK2 V617F is present in ∼55% of PMF patients, and mutations in
the thrombopoietin receptor, MPL, occur in ~4%. Most of the rest
have mutations in the calreticulin gene (CALR) that alter the carboxyterminal portion of the protein, permitting it to bind and activate MPL
while presenting it at the cell surface. The degree of myelofibrosis and
the extent of extramedullary hematopoiesis are not related. Fibrosis in
this disorder is associated with overproduction of transforming growth
factor β and tissue inhibitors of metalloproteinases and thrombopoi­
etin, while osteosclerosis is associated with overproduction of osteo­
protegerin, an osteoclast inhibitor. Marrow angiogenesis occurs due
to increased production of vascular endothelial growth factor. Impor­
tantly, fibroblasts in PMF are polyclonal and not part of the neoplastic
clone but can be induced by it to produce inflammatory cytokines.
CHAPTER 108
Polycythemia Vera and Other Myeloproliferative Neoplasms
■
■CLINICAL FEATURES
No signs or symptoms are specific for PMF. Many patients are asymp­
tomatic at presentation, and the disease is often detected by the dis­
covery of splenic enlargement and/or abnormal blood counts during a
routine examination. In contrast to its companion MPN, night sweats,
fatigue, and weight loss are common presenting complaints. A blood
smear will show the characteristic features of extramedullary hemato­
poiesis: teardrop-shaped red cells, nucleated red cells, myelocytes, and
promyelocytes; myeloblasts may also be present (Fig. 108-1). Anemia,
usually mild initially, is common, whereas the leukocyte and platelet
counts are either normal or increased, but either can be depressed.
Mild hepatomegaly may accompany splenomegaly but is unusual in its
FIGURE 108-1  Teardrop-shaped red blood cells indicative of membrane damage
from passage through the spleen, a nucleated red blood cell, and immature myeloid
cells indicative of extramedullary hematopoiesis are noted. This peripheral blood
smear is related to any cause of extramedullary hematopoiesis.
FIGURE 108-2  This marrow section shows the marrow cavity replaced by fibrous
tissue composed of reticulin fibers and collagen. When this fibrosis is due to a
primary hematologic process, it is called myelofibrosis. When fibrosis is secondary
to a tumor or a granulomatous process, it is called myelophthisis.
PART 4
Oncology and Hematology
absence; isolated lymphadenopathy should suggest another diagnosis.
Both serum lactate dehydrogenase and alkaline phosphatase levels can
be elevated. Marrow is usually inaspirable due to the myelofibrosis
(Fig. 108-2), and bone x-rays may reveal osteosclerosis. Exuberant
extramedullary hematopoiesis can cause ascites; portal, pulmonary, or
intracranial hypertension; intestinal or ureteral obstruction; pericardial
tamponade; spinal cord compression; or skin nodules. Splenic enlarge­
ment can be sufficiently rapid to cause splenic infarction with fever and
pleuritic chest pain. Hyperuricemia and secondary gout may ensue.
■
■DIAGNOSIS
While the clinical picture described above is characteristic of PMF,
all of these clinical features can be observed in PV or CML. Massive
splenomegaly commonly masks erythrocytosis in PV, and reports of
intraabdominal thrombosis in PMF most likely represent instances of
unrecognized PV. In some PMF patients, erythrocytosis has developed
during the course of the disease. Importantly, because many other dis­
orders have features that overlap with PMF but respond to distinctly
different therapies, the diagnosis of PMF is one of exclusion, which
requires that the disorders listed in Table 108-3 be ruled out.
The presence of teardrop-shaped red cells, nucleated red cells,
myelocytes, and promyelocytes establishes the presence of extramedul­
lary hematopoiesis, while the presence of leukocytosis, thrombocytosis
with large and bizarre platelets, and circulating myelocytes suggests the
presence of an MPN as opposed to a secondary form of myelofibrosis
(Table 108-3). Marrow is usually inaspirable due to increased marrow
reticulin, but marrow biopsy will usually reveal a hypercellular mar­
row with trilineage hyperplasia and, in particular, increased numbers
of megakaryocytes in clusters and with large, dysplastic nuclei. A
small number of PMF patients with a low JAK2 V617F mutation allele
burden (≤25%) have a faster time to anemia and leukopenia and a
shortened survival. However, there are no specific bone marrow mor­
phologic abnormalities that distinguish PMF from the other MPNs.
Splenomegaly due to extramedullary hematopoiesis may be sufficiently
massive to cause portal hypertension and variceal formation. In some
patients, exuberant extramedullary hematopoiesis dominates the clini­
cal picture.
An intriguing feature of PMF is the occurrence of autoimmune
abnormalities such as immune complexes, antinuclear antibodies,
rheumatoid factor, or a positive Coombs’ test. Whether these represent
a host reaction to the disorder or are involved in its pathogenesis is
unknown. Cytogenetic analysis of the blood is useful both to exclude
CML and for prognostic purposes, because the development of com­
plex karyotype abnormalities portends a poor prognosis in PMF. It is
thought that impaired expression of the cytokine CXCL4 is responsible
for the markedly increased number of circulating CD34+ cells in PMF
TABLE 108-4  Three Current Scoring Systems for Estimating Prognosis
in PMF Patients
RISK FACTOR
IPSS (2009)a
DIPSS (2010)b
DIPSS PLUS (2011)c
Anemia (<10 g/dL)
X
X
X
Leukocytosis (>25,000/μL)
X
X
X
Peripheral blood blasts (≥1%) X
X
X
Constitutional symptoms
X
X
X
Age (>65 years)
X
X
X
Unfavorable karyotype
X
Platelet count (<100,000/μL)
X
Transfusion dependence
X
aBlood 113:2895, 2009. bBlood 115:1703, 2010. cJ Clin Oncol 29:392, 2011.
Note: The Dynamic International Prognostic Scoring System (DIPSS) was developed
to determine if the International Prognostic Scoring System (IPSS) risk factors
identified as important for survival at the time of primary myelofibrosis (PMF)
diagnosis could also be used for risk stratification following their acquisition
during the course of the disease. One point is assigned to each risk factor for
IPSS scoring. For DIPSS, the same is true, but anemia is assigned 2 points. The
DIPSS Plus scoring system represents recognition that the addition of unfavorable
karyotype, thrombocytopenia, and transfusion dependence improved the DIPSS
risk stratification system for which additional points are assigned (Table 108-5).
More recent studies suggest that mutational analysis of the ASXL1, EZH2, SRSF2,
and IDH1/2 genes further improves risk stratification for survival and leukemic
transformation (Leukemia 27:1861, 2013), as can cytogenetic abnormalities
(Leukemia 32:1631, 2018). These prognostic scoring systems are not accurate for
risk assessment in polycythemia vera or essential thrombocytosis patients who
have developed myelofibrosis (Haematologica 99:e55, 2014).
(>15,000/μL) compared to PV patients, unless they too develop extra­
medullary hematopoiesis.
Importantly, ∼55% of PMF patients, like patients with its companion
MPNs, express the JAK2 V617F mutation, often as homozygotes. Such
patients are usually older and have higher hematocrits than patients
with MPL (4%) or CALR (36%) mutations; PMF patients expressing
an MPL mutation tend to be more anemic and have lower leukocyte
counts than JAK2 V617F–positive patients. Somatic mutations (due to
deletions [type 1] or insertions [type 2]) in exon 9 of CALR have been
found in a majority of patients with PMF who lack mutations in either
JAK2 or MPL. In some studies, type 1 mutations, the most common
CALR mutation in PMF, had a survival advantage compared to JAK2 or
MPL mutations but not with respect to leukemic transformation. PMF
patients who lack a known MPN driver mutation (triple-negative)
appear to have the worst prognosis.
■
■COMPLICATIONS
Survival in PMF varies according to specific risk factors at diagnosis
(Tables 108-4 and 108-5) but is much shorter than in PV and ET
patients. The natural history of PMF is one of increasing marrow fail­
ure with transfusion-dependent anemia and increasing organomegaly
due to extramedullary hematopoiesis. As with CML, PMF can evolve
from a chronic to an accelerated phase with constitutional symptoms
and increasing marrow failure. About 10% of patients spontaneously
transform to an aggressive form of acute leukemia for which therapy is
usually ineffective. Additional important prognostic factors for disease
acceleration during the course of PMF include the presence of complex
TABLE 108-5  IPSS and DIPSS Risk Stratification Systems
NUMBER OF RISK FACTORS
RISK CATEGORIESa
IPSS
DIPSS
DIPSS PLUS
Low
Intermediate-1
1–2
Intermediate-2
3–4
2–3
High
≥3
4
4–6
aThe corresponding survival curves for each risk category can be found in the
references cited in the footnotes of Table 108-4.
Abbreviations: DIPSS, Dynamic International Prognostic Scoring System; IPSS,
International Prognostic Scoring System.
cytogenetic abnormalities, thrombocytopenia, and transfusion-dependent
anemia. Mutations in the ASXL1, EZH2, SRSF2, and IDH1/2 genes have
been identified as risk factors for early death or transformation to acute
leukemia, as have complex cytogenetic abnormalities, and have proved
to be more useful for PMF risk assessment than the clinical scoring
systems.
TREATMENT
Primary Myelofibrosis
No specific therapy exists for PMF. The causes for anemia are mul­
tifarious and include ineffective erythropoiesis uncompensated by
splenic extramedullary hematopoiesis, hemodilution due to sple­
nomegaly, splenic sequestration, blood loss secondary to throm­
bocytopenia or portal hypertension, folic acid deficiency, systemic
inflammation, and autoimmune hemolysis. Neither recombinant
erythropoietin nor androgens such as danazol have proven to be
consistently effective as therapy for anemia. Erythropoietin may
worsen splenomegaly and will be ineffective if the serum erythro­
poietin level is >125 mU/L. Given the inflammatory milieu that
characterizes PMF, glucocorticoids can ameliorate anemia as well as
constitutional symptoms such as fever, chills, night sweats, anorexia,
and weight loss, and combining these with low-dose thalidomide has
proved effective as well. Thrombocytopenia can be due to impaired
marrow function, splenic sequestration, or autoimmune destruction
and may also respond to low-dose thalidomide and prednisone.
Splenomegaly is by far the most distressing and intractable prob­
lem for PMF patients, causing abdominal pain, portal hypertension,
easy satiety, and cachexia, whereas surgical removal of a massive
spleen is associated with significant postoperative complications
including mesenteric venous thrombosis, hemorrhage, rebound
leukocytosis and thrombocytosis, and hepatic extramedullary
hematopoiesis with no amelioration of either anemia or thrombo­
cytopenia when present. For unexplained reasons, splenectomy also
increases the risk of blastic transformation.
Splenic irradiation is, at best, temporarily palliative and associ­
ated with a significant risk of neutropenia, infection, and subsequent
operative hemorrhage if splenectomy is attempted. Allopurinol can
control significant hyperuricemia, and bone pain can be alleviated
by local irradiation. Pegylated IFN-α can ameliorate fibrosis in
early PMF, but in advanced disease, it may exacerbate bone mar­
row failure. The JAK1/2 inhibitor ruxolitinib has proved effective
in reducing splenomegaly and alleviating constitutional symptoms
in a majority of advanced PMF patients while possibly prolonging
survival, but in some patients, ruxolitinib is associated with RAS
mutations. Although anemia and thrombocytopenia are its major
side effects, these are dose-dependent, and with time, anemia
stabilizes, and thrombocytopenia may improve. Fedratinib, a new
tyrosine kinase inhibitor with anti-FLT3 activity, has proved useful
in patients with disease refractory to ruxolitinib. Two other JAK2
inhibitors have been approved for PMF therapy, pacritinib, which is
useful when thrombocytopenia is present, and momelotinib, which
may be useful in improving red cell production.
In some patients, hypomethylating agents such as azacytidine
or decitabine in combination with high-dose ruxolitinib have been
used to control the disease or prepare patients for bone marrow
transplantation. Transformation to acute leukemia in PMF, like PV
or ET, is usually refractory to treatment.
Allogeneic bone marrow transplantation is the only curative
treatment for PMF and should be considered in younger patients
and older patients with high-risk disease; nonmyeloablative con­
ditioning regimens permit hematopoietic cell transplantation to be
extended to older individuals.
ESSENTIAL THROMBOCYTOSIS
ET (other designations include essential thrombocythemia, idiopathic
thrombocytosis, primary thrombocytosis, and hemorrhagic thrombocy­
themia) is a clonal hematopoietic stem cell disorder associated with
TABLE 108-6  Causes of Thrombocytosis
Tissue inflammation: collagen vascular
disease, inflammatory bowel disease
Hemorrhage
Malignancy
Iron-deficiency anemia
Infection
Surgery
Myeloproliferative disorders: polycythemia
vera, primary myelofibrosis, essential
thrombocytosis, chronic myelogenous
leukemia
Rebound: Correction of vitamin B12
or folate deficiency, post-ethanol
abuse, postsplenectomy
Myelodysplastic disorders: 5q– syndrome,
idiopathic refractory sideroblastic anemia
Hemolysis
Postsplenectomy or hyposplenism
Familial: Thrombopoietin
overproduction, JAK2, CALR, or
MPL mutations
mutations in JAK2 (V617F), MPL, or CALR and manifested clinically by
overproduction of platelets without a definable cause. ET has an incidence
of 1–2/100,000 and a distinct female predominance. Canonical MPN
driver mutations distinguish 90% of ET patients from the more common
nonclonal, reactive forms of thrombocytosis (Table 108-6); mutationnegative ET patients may have either uncommon MPL mutations, JAK2
V617F expression limited to the platelets, or a hereditary form of throm­
bocytosis. Once considered a disease of the elderly and responsible for
significant morbidity due to hemorrhage or thrombosis, it is now clear
that ET can occur at any age in adults and often without symptoms or dis­
turbances of hemostasis. There is an unexplained female predominance
in contrast to PMF or the reactive forms of thrombocytosis where no sex
difference exists. Because no specific clonal marker is available, clinical
and laboratory criteria have been proposed to distinguish ET from other
MPNs, which may also present initially with isolated thrombocytosis but
have differing prognoses and therapies (Table 108-6). These criteria are
useful in identifying disorders such as CML, PV, PMF, or myelodysplasia,
which can masquerade as ET. Furthermore, as with “idiopathic” erythro­
cytosis, nonclonal benign forms of thrombocytosis exist (e.g., hereditary
overproduction of thrombopoietin and those with noncanonical JAK2
driver mutations) that are not widely recognized because we currently
lack diagnostic assays. Approximately 50% of ET patients express JAK2
V617F, 30% CALR (both type 1 and type 2), and 8% MPL mutations. ET
patients lacking a canonical MPN driver mutation usually have a benign
prognosis.
CHAPTER 108
Polycythemia Vera and Other Myeloproliferative Neoplasms
■
■ETIOLOGY
Megakaryocytopoiesis and platelet production depend on thrombo­
poietin and its receptor MPL. As in the case of early erythroid and
myeloid progenitor cells, early megakaryocytic progenitors require
the presence of interleukin 3 (IL-3) and stem cell factor for optimal
proliferation in addition to thrombopoietin. Their subsequent terminal
development is also enhanced by the chemokine stromal cell-derived
factor 1 (SDF-1). Interestingly, terminal megakaryocyte maturation
and platelet production do not require thrombopoietin.
Megakaryocytes are unique among hematopoietic progenitor cells
because reduplication of their genome is endomitotic rather than
mitotic and promoted by thrombopoietin. Unlike erythropoietin,
thrombopoietin is produced only in the liver but has important func­
tions in the bone marrow where it functions to maintain hematopoi­
etic stem cells quiescent in their endosteal niches; once released from
their niches, thrombopoietin promotes the proliferation of these cells
in the sinusoidal niches. Like plasma erythropoietin and its target
erythroblasts, an inverse correlation exists between the platelet count
and plasma thrombopoietin. However, unlike erythropoietin, throm­
bopoietin is only constitutively produced and the plasma thrombopoi­
etin level is controlled by the size of the platelet and megakaryocyte
progenitor cell pools. Also, in contrast to erythropoietin, but like
its myeloid counterparts, granulocyte and granulocyte-macrophage
colony-stimulating factors, thrombopoietin not only enhances the
proliferation of its target cells but also enhances the reactivity of their
end-stage product, the platelet. Paradoxically, in the three MPNs,
expression of the thrombopoietin receptor, MPL, is impaired and
plasma thrombopoietin is increased despite the increased number of
megakaryocytes and platelets.
The clonal nature of ET was established by analysis of glucose-6-
phosphate dehydrogenase isoenzyme expression in patients hemizy­
gous for this gene. Although thrombocytosis is its principal manifesta­
tion, like the other MPNs, the hematopoietic stem cell is involved in
ET. Furthermore, a number of families have been described in which
ET was inherited, in one instance as an autosomal dominant trait. In
addition to ET, PMF and PV have also been observed in such kindreds.
■
■CLINICAL FEATURES
Clinically, ET is most often identified incidentally when a platelet
count is obtained during the course of a routine medical evaluation.
Occasionally, review of previous blood counts will reveal that an
elevated platelet count was present but overlooked for many years.
No symptoms or signs are specific for ET, but these patients can have
hemorrhagic and thrombotic tendencies expressed as easy bruising
for the former and microvascular occlusive events for the latter such
as erythromelalgia, ocular migraine, or a TIA. Physical examination is
generally unremarkable. Splenomegaly is indicative of another MPN,
in particular PV, PMF, or CML.
Anemia is unusual, but a mild neutrophilic leukocytosis is not.
The blood smear is most remarkable for the number of platelets pres­
ent, some of which may be very large. The large mass of circulating
platelets may prevent the accurate measurement of serum potassium
due to release of platelet potassium upon blood clotting. This type of
hyperkalemia is a test tube artifact and not associated with electrocar­
diographic abnormalities. Similarly, arterial oxygen measurements can
be inaccurate unless thrombocythemic blood is collected on ice. The
prothrombin and partial thromboplastin times are normal, whereas
abnormalities of platelet function such as a prolonged bleeding time
and impaired platelet aggregation can be present. However, despite
much study, no platelet function abnormality is characteristic of ET,
and no platelet function test predicts the risk of clinically significant
bleeding or thrombosis.
PART 4
Oncology and Hematology
The elevated platelet count may hinder marrow aspiration, but
marrow biopsy usually reveals megakaryocyte hypertrophy and hyper­
plasia, as well as an overall increase in marrow cellularity. If marrow
reticulin is increased, another diagnosis should be considered. The
absence of stainable iron demands an explanation because iron defi­
ciency alone can cause thrombocytosis, and absent marrow iron in the
presence of marrow hypercellularity is a feature of PV.
Nonrandom cytogenetic abnormalities occur in ET but are uncom­
mon, and no specific or consistent abnormality is notable, even those
involving chromosomes 3 and 1, where the genes for thrombopoietin
and its receptor, MPL, respectively, are located.
■
■DIAGNOSIS
Thrombocytosis is encountered in a broad variety of clinical disorders
(Table 108-6), in many of which inflammatory cytokine production
is increased. The absolute level of the platelet count is not a useful
diagnostic aid for distinguishing between benign and clonal causes of
thrombocytosis. About 50% of ET patients express the JAK2 V617F
mutation. When JAK2 V617F is absent, cytogenetic evaluation is man­
datory to determine if the thrombocytosis is due to CML or a myelo­
dysplastic disorder such as the 5q– syndrome or sideroblastic anemia.
Because the BCR-ABL translocation can be present in the absence of
the Ph chromosome, and because the BCR-ABL reverse transcriptase
polymerase chain reaction is associated with false-positive results,
fluorescence in situ hybridization (FISH) analysis for BCR-ABL is the
preferred assay in patients with thrombocytosis in whom a cytogenetic
study for the Ph chromosome is negative. CALR mutations (type 1 or
type 2) are present in 30% and MPL mutations are present in 8% of
ET patients who do not have a JAK2 mutation. Anemia and ringed
sideroblasts are not features of ET, but they are features of idiopathic
refractory sideroblastic anemia with the SF3B1 mutation, and in
some of these patients, thrombocytosis occurs in association with
expression of JAK2 V617F, CALR, or an MPL mutation. Significant
splenomegaly should suggest the presence of another MPN such as PV
or PMF, because splenomegaly can mask the presence of erythrocyto­
sis. Importantly, what appears to be ET can evolve into PV (usually in
women with JAK2 V617F) or PMF (usually in men with type 1 CALR
mutations) after a period of many years due to clonal evolution or
succession. There is sufficient overlap of the JAK2 V617F neutrophil
allele burden between ET and PV that this test cannot be used as a dis­
tinguishing diagnostic feature with the exception that, in ET, the quan­
titative JAK2 V617F neutrophil allele is never greater than 50%, and
importantly in this regard, 64% of JAK2 V617F–positive ET patients
in one study actually were found to have PV when red cell mass and
plasma volume determinations were performed. Claims that ET and
PV form a biological continuum are unfounded as these disorders have
different gene expression profiles and different natural histories.
■
■COMPLICATIONS
Perhaps no other condition in clinical medicine has caused otherwise
astute physicians to intervene inappropriately more often than throm­
bocytosis, particularly if the platelet count is >1 × 106/μL. It is com­
monly believed that a high platelet count causes thrombosis; however,
no controlled clinical study has ever established this association, and
in patients younger than age 60 years, the incidence of thrombosis
was not greater in patients with thrombocytosis than in age-matched
controls, and tobacco use appears to be the most important risk factor
for thrombosis in ET patients.
To the contrary, very high platelet counts are associated primarily
with hemorrhage due to acquired von Willebrand’s disease. This is not
meant to imply that an elevated platelet count cannot cause symptoms
in an ET patient, but rather that the focus should be on the patient, not
the platelet count. For example, some of the most dramatic neurologic
problems in ET are migraine-related and respond only to lowering of
the platelet count, whereas other symptoms such as erythromelalgia
respond simply to platelet cyclooxygenase-1 inhibitors such as aspirin
or ibuprofen, without a reduction in platelet number. Still others may
represent an interaction between an atherosclerotic vascular system
and a high platelet count, and others may have no relationship to
the platelet count whatsoever. Recognition that PV can present with
thrombocytosis alone as well as the discovery of previously unrecog­
nized causes of hypercoagulability (Chaps. 121 and 122) make the
older literature on the complications of thrombocytosis unreliable.
TREATMENT
Essential Thrombocytosis
Survival of ET patients is not different than the general population
regardless of their driver mutation. An elevated platelet count in
an asymptomatic patient without cardiovascular risk factors or
tobacco use requires no therapy. Indeed, before any therapy is initi­
ated in a patient with thrombocytosis, the cause of symptoms must
be clearly identified as due to the elevated platelet count. When
the platelet count rises above 1 × 106/μL, a substantial quantity of
high-molecular-weight von Willebrand multimers are removed
from the circulation and destroyed by the enlarged platelet mass,
resulting in an acquired form of von Willebrand’s disease. This can
be identified by a reduction in ristocetin cofactor activity. In this
situation, aspirin could promote hemorrhage. Bleeding in this situ­
ation is rarely spontaneous and usually responds to tranexamic acid
or ε-aminocaproic acid, which can be given prophylactically before
and after elective minor surgery.
Plateletpheresis is at best a temporary and inefficient remedy
that is rarely required. Importantly, ET patients treated with 32P or
alkylating agents are at risk of developing acute leukemia without
any proof of benefit; combining either therapy with hydroxyurea
increases this risk. If platelet reduction is deemed necessary on the
basis of symptoms refractory to salicylates alone, pegylated IFN-α,
the quinazoline derivative anagrelide, or hydroxyurea can be used
to reduce the platelet count, but none of these is uniformly effec­
tive or without significant side effects. Hydroxyurea and aspirin

39 - 109 Acute Myeloid Leukemia
109 Acute Myeloid Leukemia
were more effective than anagrelide and aspirin for prevention of
TIA because hydroxyurea is a nitric oxide donor, but they were not
more effective for the prevention of other types of arterial throm­
bosis and actually less effective for venous thrombosis. The risk of
gastrointestinal bleeding is also higher when aspirin is combined
with anagrelide. Normalizing the platelet count does not prevent
either arterial or venous thrombosis. Pegylated IFN can produce a
complete molecular remission in some ET patients, but a role for
it or ruxolitinib in ET management has not yet been established.
As more clinical experience is acquired, ET appears more benign
than previously thought. Evolution to acute leukemia is more likely
to be a consequence of therapy than of the disease itself. In manag­
ing patients with thrombocytosis, the physician’s first obligation is
to do no harm.
■
■FURTHER READING
Alvarez-Larran A et al: Antiplatelet therapy versus observation in
low-risk essential thrombocythemia with CALR mutation. Haema­
tologica 101:926, 2016.
Guglielmelli P et al: Clinical impact of mutated JAK2 allele burden
reduction in polycythemia vera and essential thrombocythemia. Am
J Hematol 99:1550, 2024.
Passamonti F et al: Myelofibrosis. Blood 141:1954, 2023.
Spivak JL: How I treat polycythemia vera. Blood 134:341, 2019.
Wouters HJCM et al: Erythrocytosis in the general population: Clinical
characteristics and association with clonal hematopoiesis. Blood Adv
4:6353, 2020.
William Blum
Acute Myeloid Leukemia
INCIDENCE
Acute myeloid leukemia (AML) is a neoplasm characterized by infil­
tration of the blood, bone marrow, and other tissues by proliferative,
clonal, poorly differentiated cells of the hematopoietic system. These
leukemias comprise a spectrum of malignancies that untreated are
uniformly fatal. In 2023, the estimated number of new AML cases in
the United States was 20,380. AML is the diagnosis in 1% of all cancer
cases and 31% of all new acute leukemias but causes 62% of leukemic
deaths. AML is the most common acute leukemia in older patients,
with a median age at diagnosis of 69 years. U.S. registry data report that
only 32% of patients survive 5 years.
■
■ETIOLOGY
Most cases of AML are idiopathic. Genetic predisposition, radiation,
chemical/other occupational exposures, and drugs have been impli­
cated in the development of AML, but AML with established etiology
is relatively uncommon. No direct evidence suggests a viral etiology.
Genome sequencing studies suggest that most cases of AML arise
from a limited number of mutations that accumulate with advancing
age. Indeed, genome sequencing provides paradigm-shifting advances
in our understanding of leukemogenesis. The Cancer Genome Atlas
(TCGA) and other databases demonstrate that blood cells from up to
5–6% of normal individuals aged >70 years contain potentially “prema­
lignant” mutations that are associated with clonal expansion.
Use of the term premalignant to describe these lesions is not pre­
cisely accurate; rather, these mutations represent clonal hematopoiesis
of indeterminate potential (CHIP; sometimes called age-related clonal
hematopoiesis). The genes most commonly mutated in CHIP are the
epigenetic regulators DNMT3A, TET2, and ASXL1. Study of CHIP is
important because it has relevance not just to blood cancer evolution
but also other medical conditions. Clonal expansion driven by the
acquisition of new mutations is associated with a 10-fold increase in
risk for developing a hematologic malignancy (compared to matched
patients without CHIP), but it is clear that additional “hits” must occur
to drive toward leukemia. We do not yet fully understand why or how
these secondary lesions occur.
Patients with CHIP also have increased risk of cardiovascular mor­
tality that is not fully explained. The link between these two seemingly
unrelated issues (cardiovascular and hematologic malignancy) may
lie in the interactions between circulating clonally expanded blood
cells and vascular endothelium. A “proinflammatory” state caused
by clonal, infiltrating monocytes leads to accelerated atherosclerotic
plaque development and altered cardiac remodeling. Similar phenom­
ena may occur in the marrow/blood. An altered relationship between
hematopoietic stem cells and the marrow microenvironment (along
with altered immune surveillance) contributes to clonal survival and
expansion. These perturbations increase the likelihood that a clone
with somatic mutations may survive, acquire additional mutations,
and then further expand eventually to leukemia. Whether early identi­
fication of CHIP in patients will provide therapeutic opportunities for
patients remains to be seen. Certainly, modifying cardiovascular risk
in patients with CHIP seems prudent, but development of mutationdirected therapy designed to eliminate a problematic clone and prevent
future leukemia is likely to be more elusive.
CHAPTER 109
Genetic Predisposition 
Myeloid neoplasms occur sporadically
in adults; inherited predisposition is uncommon. Yet, it is clear that
myeloid neoplasms with germline predisposition represent an impor­
tant and growing subset of disease. Germline mutations associated
with increased risk of developing a myeloid neoplasm include CEBPA,
DDX41, TP53, RUNX1, ANKRD26, ETV6, and GATA2, and others
(Table 109-1). Myeloid neoplasms with germline predisposition are
Acute Myeloid Leukemia
TABLE 109-1  World Health Organization 2022, Subtypes of Myeloid
Neoplasms Associated with Germline Predisposition
Myeloid neoplasms with germline predisposition without a preexisting platelet
disorder or organ dysfunction
• Germline CEBPA P/LP variant (CEBPA-associated familial AML)
• Germline DDX41 P/LP varianta
• Germline TP53 P/LP varianta (Li-Fraumeni syndrome)
Myeloid neoplasms with germline predisposition and preexisting platelet
disorder
• Germline RUNX1 P/LP varianta (familial platelet disorder with associated
myeloid malignancy [FPD-MM])
• Germline ANKRD26 P/LP varianta (thrombocytopenia 2)
• Germline ETV6 P/LP varianta (thrombocytopenia 5)
Myeloid neoplasms with germline predisposition and potential organ
dysfunction
• Germline GATA2 P/LP variant (GATA2 deficiency)
• Bone marrow failure syndromes
• Severe congenital neutropenia (SCN)
• Shwachman-Diamond syndrome (SDS)
• Fanconi anemia (FA)
• Telomere biology disorders
• RASopathies (neurofibromatosis type 1, CBL syndrome, Noonan syndrome or
Noonan syndrome-like disordersa)
• Down syndromea
• Germline SAMD9 P/LP variant (MIRAGE syndrome)
• Germline SAMD9L P/LP variant (SAMD9L-related ataxia pancytopenia
syndrome)b
• Biallelic germline BLM P/LP variant (Bloom syndrome)
aLymphoid neoplasms can also occur. bAtaxia is not always present.
Abbreviations: LP, likely pathogenic; P, pathogenic.
Source: Modified from JD Khoury et al: The 5th edition of the World Health
Organization Classification of Haematolymphoid Tumours: Myeloid and histiocytic/
dendritic neoplasms. Leukemia 36:1703, 2022.
a feature of several well-described clinical syndromes, including bone
marrow failure disorders (e.g., Fanconi anemia, Shwachman-Diamond
syndrome, Diamond-Blackfan anemia) and telomere biology disorders
(e.g., dyskeratosis congenita). As new mutations and associations are
added to a rapidly growing list, it is clear that genetic predisposition
plays a larger role than has been previously understood.
Several genetic syndromes with somatic cell chromosome aneu­
ploidy, such as Down syndrome with trisomy 21, are associated with
an increased incidence of AML. Down syndrome–associated AML in
young children (<4 years) is typically of megakaryocytic differentiation
and is associated with mutation in the GATA1 gene. Such patients have
excellent clinical outcomes but require dose modification of chemo­
therapy due to high treatment-related toxicities. Inherited diseases with
defective DNA repair (e.g., Fanconi anemia, Bloom syndrome, and
ataxia-telangiectasia) are also associated with AML. Each syndrome is
associated with unique clinical features and atypical toxicities with che­
motherapy, requiring expert care. Congenital neutropenia (Kostmann
syndrome), due to mutations in the genes encoding the granulocyte
colony-stimulating factor receptor and neutrophil elastase, is another
disorder that may evolve into AML.
Chemical, Radiation, and Other Exposures 
Anticancer drugs
are the leading cause of therapy-associated AML. AML post chemo­
therapy (AML-pCT) with alkylating agents occurs 4–6 years after
exposure; affected individuals often have multilineage dysplasia,
monosomy/aberrations in chromosomes 5 and 7, mutations of TP53,
and poor prognosis. AML-pCT with topoisomerase II inhibitors
occurs 1–3 years after exposure; affected individuals often have AML
with monocytic features and aberrations involving chromosome 11q23
(involved gene previously called MLL, now KMT2A). The risk of acute
leukemia is much higher after combined-modality therapy with alkyl­
ating agent–based chemotherapy plus external beam radiation therapy.
Exposure to ionizing radiation, benzene, chloramphenicol, phenylbu­
tazone, and other drugs can result in bone marrow failure that may
evolve into AML.
PART 4
Oncology and Hematology
■
■CLASSIFICATION
Historically, marrow (or blood) myeloid blast count of ≥20% estab­
lished the diagnosis of AML. However, biologically distinct groups
are now primarily classified based on genetic aberrations, in addition
to clinical features and light microscopy. It is increasingly understood
that genetic aberrations drive clinical presentation and clinical course,
and thus, in 2022, the World Health Organization (WHO) eliminated
the blast percent requirement among cases with specific, defined
genetic aberrations (Table 109-2). In the WHO system referenced
here, genetic aberrations are notated by the gene mutation or fusion
involved; learners may find clarity by also reviewing the European
LeukemiaNet (ELN) risk classification (Table 109-3), which lists asso­
ciated cytogenetic abnormalities alongside the gene fusions. Dueling
classification systems of the WHO and the International Consensus
Classification (ICC) assign AML diagnosis inconsistently with regard
to blast percent, but the differences are semantic. Cases with <20%
blasts that are still classified as AML have recurrent genetic abnor­
malities including t(15;17), t(8;21), inv(16), t(16;16), rearrangements
involving KMT2A (with many different fusion partners), mutations in
NPM1 (nucleophosmin), and other defined genetic aberrations. The
emergence of novel targeted treatment options for specific aberrations,
such as menin inhibitors for patients with KMT2A rearrangement,
NPM1 mutation, or (possibly) NUP98 rearrangement, suggests that a
practical approach to classification based on the presence of a specific
aberration regardless of blast count may indeed be most appropriate.
All AML cells contain genetic mutations, most of which are recurring;
in 2024, the majority of AML patients will have a genetic lesion that can
be specifically targeted with a novel drug.
Genetic Findings 
Subtypes of AML are recognized due to
the presence or absence of specific, recurrent cytogenetic, and/or
genetic abnormalities. For example, the diagnosis of acute promy­
elocytic leukemia (APL) is based on the presence of the t(15;17)
TABLE 109-2  World Health Organization 2022 Classification of Acute
Myeloid Leukemia
Acute myeloid leukemia with defining genetic abnormalities
  Acute promyelocytic leukemia with PML::RARA fusion
  Acute myeloid leukemia with RUNX1::RUNX1T1 fusion
  Acute myeloid leukemia with CBFB::MYH11 fusion
  Acute myeloid leukemia with DEK::NUP214 fusion
  Acute myeloid leukemia with RBM15::MRTFA fusion
  Acute myeloid leukemia with BCR::ABL1 fusiona
  Acute myeloid leukemia with KMT2A rearrangement
  Acute myeloid leukemia with MECOM rearrangement
  Acute myeloid leukemia with NUP98 rearrangementb
  Acute myeloid leukemia with NPM1 mutation
  Acute myeloid leukemia with CEBPA mutationa,c
  Acute myeloid leukemia, myelodysplasia-relateda,d
  Acute myeloid leukemia with other defined genetic alterationsa
Acute myeloid leukemia, defined by differentiation
  Acute myeloid leukemia with minimal differentiation
  Acute myeloid leukemia without maturation
  Acute myeloid leukemia with maturation
  Acute basophilic leukemia
  Acute myelomonocytic leukemia
  Acute monocytic leukemia
  Acute erythroid leukemia
  Acute megakaryoblastic leukemia
aRequires ≥20% blasts. bNUP98 rearrangements involve 11p15, with many fusion
partners, usually cryptic on cytogenetic analysis. cIncludes biallelic (biCEBPA) as
well as single mutations located in the basic leucine zipper (bZIP) region. dDefining
characteristics of Acute myeloid leukemia, myelodysplasia-related (AML-MR)
include history of myelodysplastic syndrome (MDS) or MDS/myeloproliferative
neoplasm (MPN) and/or one of the following: complex karyotype, several other
specific chromosome aberrations typical of MDS, or mutation of ASXL1, BCOR,
EZH2, SF3B1, SRSF2, STAG2, U2AF1, or ZRSR2.
Source: Modified from JD Khoury et al: The 5th edition of the World Health
Organization Classification of Haematolymphoid Tumours: Myeloid and histiocytic/
dendritic neoplasms. Leukemia 36:1703, 2022.
(q22;q12) cytogenetic rearrangement or the PML-RARA fusion. Simi­
larly, core binding factor (CBF) AML is designated based on the pres­
ence of t(8;21)(q22;q22), inv(16)(p13.1q22), or t(16;16)(p13.1;q22) or
the respective fusion products RUNX1-RUNX1T1 and CBFB-MYH11.
Each of these three groups identifies patients with favorable clinical
outcomes when appropriately treated.
Many genetic AML subtypes are associated with a specific mor­
phologic appearance such as a complex karyotype (and/or mutation
of TP53) and dysplastic morphology in AML, myelodysplasia-related
(AML-MR). One abnormality is invariably associated with a spe­
cific morphologic feature: t(15;17)(q22;q12) or the molecular fusion
PML-RARA with APL. Further examples include inv(16)(p13.1q22)
with AML and abnormal bone marrow eosinophils; t(8;21)(q22;q22)
and slender Auer rods, expression of CD19, and increased normal
eosinophils; and rearrangements involving KMT2A with monocytic
features. AML with mutation of NPM1, especially when co-occurring
with mutation of FLT3 (fms-related tyrosine kinase 3), often pres­
ents with blasts having “cup-shaped” nuclear morphology. Recurring
genetic aberrations in AML may also be loosely associated with spe­
cific clinical characteristics. More commonly associated with younger
age are t(8;21) and t(15;17), and with older age are del(5q), del(7q),
and mutated TP53. Myeloid sarcomas are associated with t(8;21); dis­
seminated intravascular coagulation (DIC) is associated with t(15;17).
KMT2A aberrations and monocytic leukemia are associated with
extramedullary sites of involvement at presentation, especially gingival
hypertrophy. High leukocyte count is commonly observed with NPM1
and/or FLT3 mutation. Many other cytogenetic and genetic findings
commonly, but not always, are associated with a morphologic descrip­
tion, highlighting the necessity of genetic and cytogenetic testing for
precise diagnosis.
TABLE 109-3  2022 European LeukemiaNet Risk Classification of Acute
Myeloid Leukemia (AML) by Genetics at Initial Diagnosisa
RISK CATEGORY
GENETIC ABNORMALITY
Favorable
• t(8;21)(q22;q22.1)/RUNX1::RUNX1T1b,c
• inv(16)(p13.1q22) or t(16;16)(p13.1;q22)/CBFB::MYH11b,c
• Mutated NPM1b,d without FLT3-ITD
• bZIP in-frame mutated CEBPAe
Intermediate
• Mutated NPM1b,d with FLT3-ITD
• Wild-type NPM1 with FLT3-ITD (without adverse-risk
genetic lesions)
• t(9;11)(p21.3;q23.3)/MLLT3::KMT2Ab,f
• Cytogenetic and/or molecular abnormalities not
classified as favorable or adverse
Adverse
• t(6;9)(p23.3;q34.1)/DEK::NUP214
• t(v;11q23.3)/KMT2A-rearrangedg
• t(9;22)(q34.1;q11.2)/BCR::ABL1
• t(8;16)(p11.2;p13.3)/KAT6A::CREBBP
• inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2)/GATA2,
MECOM(EVI1)
• t(3q26.2;v)/MECOM(EVI1)-rearranged
• −5 or del(5q); −7; −17/abn(17p)
• Complex karyotype,h monosomal karyotypei
• Mutated ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2,
STAG2, U2AF1, and/or ZRSR2j
• Mutated TP53k
aFrequencies, response rates, and outcome measures should be reported by
risk category and, if sufficient numbers are available, by specific genetic lesions
indicated. Acute promyelocytic leukemia is excluded from this table. bMainly
based on results observed in intensively treated patients. Initial risk assignment
may change during the treatment course based on the results from analyses of
measurable residual disease. cConcurrent KIT and/or FLT3 gene mutation does not
alter risk categorization. dAMLs with NPM1 mutation and adverse-risk cytogenetic
abnormalities are categorized as adverse risk. eOnly in-frame mutations affecting
the basic leucine zipper (bZIP) region of CEBPA, irrespective of whether they occur
as monoallelic or biallelic mutations, have been associated with favorable outcome.
fThe presence of t(9;11)(p21.3;q23.3) takes precedence over rare, concurrent
adverse-risk gene mutations. gExcluding KMT2A partial tandem duplication
(PTD). hComplex karyotype: three or more unrelated chromosome abnormalities
in the absence of other class-defining recurring genetic abnormalities; excludes
hyperdiploid karyotypes with three or more trisomies (or polysomies) without
structural abnormalities. iMonosomal karyotype: presence of two or more distinct
monosomies (excluding loss of X or Y), or one single autosomal monosomy in
combination with at least one structural chromosome abnormality (excluding corebinding factor AML). jFor the time being, these markers should not be used as an
adverse prognostic marker if they co-occur with favorable-risk AML subtypes.
kTP53 mutation at a variant allele fraction of at least 10%, irrespective of the
TP53 allelic status (mono- or biallelic mutation); TP53 mutations are significantly
associated with AML with complex and monosomal karyotype.
Source: Reproduced with permission from H Döhner et al: Diagnosis and
management of AML in adults: 2022 recommendations from an international expert
panel on behalf of the ELN. Blood 140:1345, 2022.
WHO classification incorporates molecular abnormalities by rec­
ognizing fusion genes or specific genetic mutations with a role in leu­
kemogenesis. As a classic example, t(15;17) results in the fusion gene
PML-RARA that encodes a chimeric protein, promyelocytic leukemia
(Pml)–retinoic acid receptor α (Rarα), which is formed by the fusion of
the retinoic acid receptor α (RARA) gene from chromosome 17 and the
promyelocytic leukemia (PML) gene from chromosome 15. Unique
clinical therapy with retinoic acid and arsenic trioxide has revolution­
ized the care of APL patients (see “Treatment of Acute Promyelocytic
Leukemia” section). Similar examples of molecular subtypes included
in the category of AML with recurrent genetic abnormalities are those
characterized by the leukemogenic fusion genes RUNX1-RUNX1T1
and CBFB-MYH11 and the so-called CBF AML subtypes noted
cytogenetically as t(8;21), inv(16), or t(16;16). Additional examples
of fusions are MLLT3-KMT2A and DEK-NUP214, resulting from
t(9;11) and t(6;9)(p23;q34). Mutated genes are also critical elements of
AML classification. The most common is AML with mutated NPM1,
a mutation seen in 30% of AML patients and in 60% of those with
cytogenetically normal AML (CN-AML). Another subtype is AML
with mutated CEBPA (specifically in-frame bZIP mutation). Both are
associated with more favorable clinical outcomes, though the presence
of coexisting mutation in FLT3 negatively affects NPM1 prognostic
impact. Activating mutations of FLT3 are present in ∼30% of adult
AML patients, primarily due to internal tandem duplications (ITDs)
in the juxtamembrane domain that have negative prognostic impact.
In contrast, point mutations of the activating loop of the kinase, called
tyrosine kinase domain (TKD) mutations, have uncertain prognostic
impact. Aberrant activation of the FLT3-encoded protein provides
increased proliferation and antiapoptotic signals to the myeloid pro­
genitor cell. FLT3-ITD, the most common of the FLT3 mutations,
also occurs preferentially in patients with CN-AML. The importance
of identifying FLT3-ITD at diagnosis relates to the fact that it is not
only useful as a negative prognosticator but also predicts response to
specific treatment such as a tyrosine kinase inhibitor (TKI). Several
TKIs targeting FLT3 are either approved for AML (e.g., midostaurin
or quizartinib, only in first-line therapy in combination with chemo­
therapy; gilteritinib, in relapse as monotherapy) or currently in clinical
investigation.
Immunophenotypic Findings 
The immunophenotype of
human leukemia cells can be studied by multiparameter flow cytom­
etry after the cells are labeled with monoclonal antibodies to cellsurface antigens. This can be important in quickly distinguishing AML
from acute lymphoblastic leukemia and for identifying some subtypes
of AML. For example, AML with minimal differentiation, character­
ized by immature morphology and no lineage-specific cytochemical
reactions, may be diagnosed by flow-cytometric demonstration of
the myeloid-specific antigens cluster designation (CD) 13 and/or 117.
Similarly, acute megakaryoblastic leukemia can often be diagnosed
only by expression of the platelet-specific antigens CD41 and/or CD61.
Although flow cytometry is widely used, and in some cases essential for
the diagnosis of AML, it has only a supportive role in establishing the
different subtypes of AML through the WHO classification given the
paramount importance of genetics. Increasingly, multiparameter flow
cytometry is used for the measurement of measurable residual disease
(MRD) after remission is achieved.
CHAPTER 109
Acute Myeloid Leukemia
■
■PROGNOSTIC FACTORS
Several factors predict outcome of AML patients treated with che­
motherapy; they should be used for risk stratification and treatment
guidance.
Chromosome and molecular investigations performed at diagnosis
provide the most important prognostic information. Patients with
t(15;17) have a very good prognosis (∼85% cured), and those with
t(8;21) and inv(16) have a good prognosis (∼55% cured), whereas
those with no cytogenetic abnormality have an intermediate outcome
risk (∼40% cured). Patients with NPM1 mutation without a FLT3-ITD
also have favorable risk and high cure rate; conversely, those with
TP53 mutation, complex karyotype, t(6;9), inv(3), or –7 have adverse
risk and very poor clinical outcomes with virtually no chance for cure
without transplantation.
For patients lacking prognostic cytogenetic abnormalities, i.e., those
with CN-AML, testing for several mutated genes can help to risk-stratify.
In addition to NPM1 mutation and FLT3-ITD as described above,
in-frame bZIP CEBPA mutation has favorable prognosis. Given the
proven prognostic importance of NPM1, FLT3, and CEBPA, molecular
assessment of these genes and others at diagnosis has been incorpo­
rated into AML management guidelines by the National Comprehen­
sive Cancer Network (NCCN) and the ELN. The same markers help to
define genetic groups in the ELN standardized reporting system, which
is based on both cytogenetic and molecular abnormalities and is used
for comparing clinical features/treatment response among subsets of
patients reported across different clinical studies (Table 109-3). These
genetic groups should be used for risk stratification and treatment
guidance (note that APL is excluded from the table).
In addition to NPM1, FLT3, CEBPA, and TP53 mutations, molecu­
lar aberrations in other genes are routinely used for prognostication.
Among these mutated genes are those encoding receptor tyrosine
kinases, transcription factors (RUNX1 and WT1), and epigenetic
modifiers (ASXL1, DNMT3A, isocitrate dehydrogenase 1 [IDH1], IDH2,
and TET2). Among an expanding panel of mutated genes associated
with adverse risk (at least when not coexisting with favorable aber­
rations) are ASXL1, BCOR, EZH2, RUNX1, SF3B1, SRSF2, STAG2,
U2AF1, ZRSR2, and TP53. Because prognostic molecular markers in
AML are not mutually exclusive and often occur concurrently (>80%
patients have at least two or more prognostic gene mutations), distinct
marker combinations will certainly be part of continued evolution of
AML classification, prognosis, and treatment.
Novel drugs that inhibit/modulate cellular pathways activated
by genetic aberrations (especially FLT3, IDH1, IDH2, and NPM1/
KMT2A/NUP98) have been remarkably effective in subsets of dis­
ease (see section on treatment of AML). Epigenetic changes (e.g.,
DNA methylation and/or posttranslational histone modification) and
microRNAs are often involved in deregulation of genes involved in
hematopoiesis, contribute to leukemogenesis, and may associate with
the previously discussed prognostic gene mutations. These changes
have been shown to provide biologic insights into leukemogenic
mechanisms and provide independent prognostic information. Thera­
peutic progress based on advances in understanding the role of epi­
genetic changes in AML over the last decade has been tremendous. For
example, in patients with mutations of IDH1 or IDH2, novel enzymes
produced from these respective mutations have aberrant activity and
“hijack” the citric acid cycle. These mutations lead to production of a
novel “oncometabolite,” 2-hydroxyglutarate, which disrupts a myriad
of epigenetic processes. Pharmacologic inhibition of these aberrant
enzymes can reverse these leukemogenic activities and restore normal
marrow function (though monotherapy is not typically curative).
PART 4
Oncology and Hematology
In addition to cytogenetic and molecular aberrations, several clini­
cal factors are associated with outcome in AML. Age at diagnosis is the
most important. Advancing age is associated with a poor prognosis for
two reasons: (1) its influence on the ability to survive induction therapy
due to coexisting medical comorbidities, and (2) with each successive
decade of age, a greater proportion of patients have intrinsically more
resistant disease/adverse genetic risk. Next, a prolonged symptomatic
interval with cytopenias preceding AML diagnosis, or a history of
antecedent hematologic disorders including myelodysplastic syndrome
(MDS) or myeloproliferative neoplasm, is often found in older patients.
Preexisting cytopenia is a clinical feature associated with a lower com­
plete remission (CR) rate and shorter survival time. The CR rate is
lower in patients who have had anemia, leukopenia, and/or thrombo­
cytopenia for >3 months before the diagnosis of AML when compared
to those without such a history. Responsiveness to chemotherapy
declines as the duration of the antecedent disorder increases. Likewise,
AML-pCT, typically developing after treatment with cytotoxic agents
for other malignancies, is often resistant to treatment given its associa­
tion with adverse genetic features. In general, older patients less fre­
quently harbor favorable genetic aberrations (e.g., t[8;21], inv[16], and
t[16;16], NPM1 mutation) and more frequently harbor adverse genetic
aberrations (e.g., complex karyotypes, mutations in ASXL1, TP53).
Other factors independently associated with worse outcome are
poor performance status, which influences ability to survive induction
therapy, and a high presenting leukocyte count that in some series is
an adverse prognostic factor for attaining a CR. Among patients with
hyperleukocytosis (>100,000/μL), early central nervous system bleed­
ing and pulmonary leukostasis contribute to poor outcomes.
Following administration of therapy, achievement of CR is associ­
ated with better outcome and longer survival, of course. CR is defined
after examination of both blood and bone marrow and essentially rep­
resents eradication of detectable leukemia and restoration of normal
hematopoiesis. The blood neutrophil count must be ≥1000/μL and
the platelet count ≥100,000/μL for formal criteria; CR with incomplete
recovery of counts is a lesser but still meaningful response. Hemoglo­
bin concentration is not considered in determining CR. Circulating
blasts should be absent. Although rare blasts may be detected in the
blood during marrow regeneration, they should disappear on succes­
sive studies. At CR, the bone marrow should contain <5% blasts, and
extramedullary leukemia should not be present.
■
■CLINICAL PRESENTATION
Symptoms 
Patients with AML usually present with nonspecific
symptoms that begin gradually, though sometimes abruptly, and are
the consequence of anemia, leukocytosis, leukopenia/leukocyte dys­
function, or thrombocytopenia. Nearly half have symptoms for ≤3 months
before the leukemia is diagnosed.
Fatigue is a frequent first symptom among AML patients. Anorexia
and weight loss are common. Fever with or without an identifiable
infection is the initial symptom in ∼10% of patients. Signs of abnor­
mal hemostasis (bleeding, easy bruising) are common. Bone pain,
lymphadenopathy, nonspecific cough, headache, or diaphoresis may
also occur.
Rarely, patients may present with symptoms from a myeloid sar­
coma (a tumor mass consisting of myeloid blasts occurring at anatomic
sites other than bone marrow). Sites involved are most commonly the
skin, lymph node, gastrointestinal tract, soft tissue, and testis. This may
precede or coincide with blood and/or marrow involvement by AML.
Patients who present with isolated myeloid sarcoma typically develop
blood and/or marrow involvement quickly thereafter and cannot be
cured with local therapy (radiation or surgery) alone.
Physical Findings 
Fever, infection, and hemorrhage are often
found at the time of diagnosis; splenomegaly, hepatomegaly, lymph­
adenopathy, and “bone pain” may also be present but less commonly.
Hemorrhagic complications are most commonly and, classically, found
in APL. APL patients often present with DIC-associated minor hem­
orrhage but may have significant gastrointestinal bleeding, intrapul­
monary hemorrhage, or intracranial hemorrhage. Counterintuitively,
thrombosis while less frequent is another well recognized clinical
feature of DIC in APL. Complications associated with coagulopathy
may also occur in monocytic AML and with extreme degrees of leuko­
cytosis or thrombocytopenia in other morphologic subtypes. Retinal
hemorrhages are detected in 15% of patients. Infiltration of the gin­
giva, skin, soft tissues, or meninges with leukemic blasts at diagnosis
is characteristic of the monocytic subtypes and those with KMT2A
chromosomal abnormalities.
Hematologic Findings 
Anemia is usually present at diagnosis,
although it is not typically severe. The anemia is usually normocytic
normochromic. Decreased erythropoiesis in the setting of AML often
results in a reduced reticulocyte count, and red blood cell (RBC) sur­
vival is decreased by accelerated destruction. Active blood loss may
rarely contribute to the anemia.
The median presenting leukocyte count for new AML cases is
∼15,000/μL. Lower presenting leukocyte counts are more typical
of older patients and those with antecedent hematologic disorders.
Between 25 and 40% of patients have counts <5000/μL, and 20% have
counts >100,000/μL. Fewer than 5% have no detectable leukemic cells
in the blood. In AML blasts, the cytoplasm often contains primary
(nonspecific) granules, and the nucleus shows fine, lacy chromatin
with one or more nucleoli characteristic of immature cells. Abnormal
rod-shaped granules called Auer rods are not uniformly present, but
when they are, AML (and not acute lymphocytic leukemia) is certain
(Fig. 109-1).
Platelet counts <100,000/μL are found at diagnosis in ∼75% of
patients, and ∼25% have counts <25,000/μL. Both morphologic and
functional platelet abnormalities can be observed, including large and
bizarre shapes with abnormal granulation and inability of platelets to
aggregate or adhere normally to one another.
Pretreatment Evaluation 
Once the diagnosis of AML is suspected,
thorough evaluation and initiation of appropriate therapy should follow.
In addition to clarifying the subtype of leukemia, initial studies should
evaluate the overall functional integrity of the major organ systems,
including the cardiovascular, pulmonary, hepatic, and renal systems
(Table 109-4). Factors that have prognostic significance, either for
achieving CR or for CR duration, should also be assessed before initiat­
ing treatment including cytogenetics and molecular markers. Leukemic
A
C
FIGURE 109-1  Morphology of acute myeloid leukemia (AML) cells. A. Uniform population of primitive myeloblasts with immature chromatin, nucleoli in some cells, and
primary cytoplasmic granules. B. Leukemic myeloblast containing an Auer rod. C. Promyelocytic leukemia cells with prominent cytoplasmic primary granules. D. Peroxidase
stain shows dark blue color characteristic of peroxidase in granules in AML.
cells should be obtained from all consenting patients and cryopreserved
for future investigational testing as well as potential use as new diagnos­
tics and therapeutics become available. All patients should be evaluated
for infection. Patients with respiratory symptoms should undergo test­
ing for the presence of the novel coronavirus, SARS-CoV-2, and other
viruses before initiation of chemotherapy.
Most patients are anemic and thrombocytopenic at presentation.
Replacement of the appropriate blood components, if necessary, should
begin promptly. Because qualitative platelet dysfunction or the pres­
ence of an infection may increase the likelihood of bleeding, evidence
of hemorrhage justifies the immediate use of platelet transfusion even
if the platelet count is only moderately decreased.
About 50% of patients have a mild to moderate elevation of serum
uric acid at presentation. Only 10% have marked elevations, but renal
precipitation of uric acid and the nephropathy that may result is a seri­
ous but uncommon complication. The initiation of chemotherapy may
aggravate hyperuricemia, and patients are usually started immediately
on allopurinol and hydration at diagnosis. Rasburicase (recombinant
uric oxidase) is also useful for treating uric acid nephropathy and
often can normalize the serum uric acid level within hours with a
single dose of treatment, although its expense suggests that limiting its
use to patients with severe hyperuricemia and/or kidney injury may
be prudent (and it should be avoided in setting of glucose-6-phosphate
dehydrogenase deficiency). The presence of high concentrations of
lysozyme, a marker for monocytic differentiation, may be etiologic in
renal tubular dysfunction for a minority of patients.
B
CHAPTER 109
Acute Myeloid Leukemia
D
TREATMENT
Acute Myeloid Leukemia
Treatment of the newly diagnosed patient with AML is usually
divided into two phases, induction and postremission management
(consolidation) (Fig. 109-2). The initial goal is to induce CR. Once
CR is obtained, further therapy must be given to prolong sur­
vival and achieve cure. The initial induction treatment and subse­
quent postremission therapy are chosen based on the patient’s age,
overall fitness, and cytogenetic/molecular risk. Intensive therapy
with cytarabine and anthracycline in younger patients (<60 years)
increases the cure rate of AML. In older patients, the benefit of
intensive therapy is controversial in all but favorable-risk patients;
novel approaches for selecting patients predicted to be responsive
to treatment and new therapies are being pursued. Importantly,
even infirm older patients should be considered for therapy; treat­
ment is better than supportive care for all candidates. Improved
options have emerged for older AML patients such as the addition
of the BCL2 antagonist venetoclax to one of several low-intensity
chemotherapies. Venetoclax is currently in testing in combination
with intensive chemotherapies as well. Likewise, novel oral drugs
targeting IDH1/IDH2, alone (IDH1) or in combination (IDH1
and IDH2) with low-intensity chemotherapy, may be considered as
initial therapy for unfit older patients who have mutations in those
respective pathways.
TABLE 109-4  Initial Diagnostic Evaluation and Management of Adult
Patients with AML
History
Increasing fatigue or decreased exercise tolerance (anemia)
Excess bleeding or bleeding from unusual sites (DIC, thrombocytopenia)
Fevers or recurrent infections (neutropenia)
Headache, vision changes, nonfocal neurologic abnormalities (CNS leukemia or
bleed)
Early satiety (splenomegaly)
Family history of AML (Fanconi, Bloom, or Kostmann syndromes or
ataxia-telangiectasia)
History of cancer (exposure to alkylating agents, radiation, topoisomerase II
inhibitors)
Occupational exposures (radiation, benzene, petroleum products, paint, smoking,
pesticides)
Physical Examination
Performance status (prognostic factor)
Ecchymosis and oozing from IV sites (DIC, possible acute promyelocytic
leukemia)
Fever and tachycardia (signs of infection)
Papilledema, retinal infiltrates, cranial nerve abnormalities (CNS leukemia)
PART 4
Oncology and Hematology
Poor dentition, dental abscesses
Gum hypertrophy (leukemic infiltration, most common in monocytic leukemia)
Skin infiltration or nodules (leukemia infiltration, most common in monocytic
leukemia)
Lymphadenopathy, splenomegaly, hepatomegaly
Back pain, lower extremity weakness (spinal granulocytic sarcoma, most likely
in t[8;21] patients)
Laboratory and Radiologic Studies
CBC with manual differential cell count
Chemistry tests (electrolytes, creatinine, BUN, calcium, phosphorus, uric acid,
hepatic enzymes, bilirubin, LDH, amylase, lipase)
Clotting studies (prothrombin time, partial thromboplastin time, fibrinogen,
d-dimer)
Viral serologies (CMV, HSV-1, varicella-zoster)
RBC type and screen
HLA typing for potential allogeneic HCT
Bone marrow aspirate and biopsy (morphology, cytogenetics, flow cytometry,
molecular studies)
Cryopreservation of viable leukemia cells
Myocardial function (echocardiogram or MUGA scan)
PA and lateral chest radiograph
Placement of central venous access device
Interventions for Specific Patients
Dental evaluation (for those with poor dentition)
Lumbar puncture (for those with symptoms of CNS involvement)
Screening spine MRI (for patients with back pain, lower extremity weakness,
paresthesias)
Social work referral for patient and family psychosocial support
Counseling for All Patients
Provide patients with information regarding their disease and genetic risks,
sperm banking or menstrual suppression, financial counseling, support group
contact, and consent for tissue banking of leukemic cells
Abbreviations: AML, acute myeloid leukemia; BUN, blood urea nitrogen; CBC,
complete blood count; CMV, cytomegalovirus; CNS, central nervous system; DIC,
disseminated intravascular coagulation; HLA, human leukocyte antigen; HCT,
hematopoietic stem cell transplantation; HSV, herpes simplex virus; IV, intravenous;
LDH, lactate dehydrogenase; MRI, magnetic resonance imaging; MUGA, multigated
acquisition; PA, posteroanterior; RBC, red blood (cell) count.
INDUCTION CHEMOTHERAPY
The most commonly used induction regimens (for patients other
than those with APL) consist of combination chemotherapy with
cytarabine and an anthracycline (e.g., daunorubicin, idarubicin).
Cytarabine is a cell cycle S-phase–specific antimetabolite that
becomes phosphorylated intracellularly to an active triphosphate
form that interferes with DNA synthesis. Anthracyclines are DNA
intercalators. Their primary mode of action is thought to be inhibi­
tion of topoisomerase II, leading to DNA breaks.
In adults, cytarabine used at standard dose (100–200 mg/m2)
is administered as a continuous intravenous infusion for 7 days.
With cytarabine, anthracycline therapy generally consists of dau­
norubicin (60–90 mg/m2) or idarubicin (12 mg/m2) intravenously
on days 1, 2, and 3 (the 7+3 regimen). Other agents can be added
(e.g., gemtuzumab ozogamicin) when 60 mg/m2 of daunorubicin
is used. Patients failing remission after one induction are offered
reinduction with the same (or slightly modified) therapy. The
CD33-targeting immunoconjugate gemtuzumab ozogamicin may
be added to induction therapy for subsets of patients, especially
those with CBF AML. Many alternative intensive approaches other
than 7+3 chemotherapy exist and are commonly used.
In older patients (age ≥60–65 years), the outcome with conventional
intensive therapy is generally poor due to a higher frequency of resistant
disease and increased rate of treatment-related morbidity and mortal­
ity. Patients still fare far better with treatment than with supportive
care only. Conventional therapy for fit older patients is similar to that
for younger patients: the 7+3 regimen with standard-dose cytarabine
and idarubicin (12 mg/m2) or daunorubicin (60 mg/m2). For patients
aged >65 years, high-dose daunorubicin (90 mg/m2) has increased
toxicity and is not recommended. A liposomal preparation of
cytarabine and daunorubicin in a fixed molar ratio may instead be
administered, especially to fit patients with AML-MR. Patients over
75 years and those unable to receive intensive therapy due to medi­
cal comorbidity may receive repetitive cycles of lower intensity ther­
apy with a hypomethylating agent (HMA; decitabine or azacitidine)
or low-dose cytarabine in combination with daily venetoclax (BCL2
antagonist). As noted, targeted IDH1- or IDH2-directed therapy is
another consideration for particularly infirm patients. All patients
should be considered for clinical trials.
With the 7+3 regimen (or other similar approaches), 60–80%
of younger and 33–60% of older patients (among those who are
candidates for intensive therapy) with primary AML achieve CR.
Response rates around 60% in first line have been similarly reported
with the combination of HMA plus venetoclax in older or infirm
patient groups. Induction death is more frequent with advancing
age and medical comorbidity, but the most common reason for
treatment failure is lack of remission. Patients with refractory dis­
ease after inductions should be considered for salvage treatments,
preferably on clinical trials. Planning for the possibility of alloge­
neic hematopoietic stem cell transplantation (HCT) for all eligible
patients under age 75 years is part of optimal initial AML care. Typi­
cally, allogeneic HCT is performed only for patients who are in CR
but at risk for relapse, but fit younger patients with primary refrac­
tory disease (not in remission after initial induction) have ∼15–20%
cure rates with allogeneic HCT after myeloablative conditioning.
For this reason, early planning for possible future allogeneic HCT
(including human leukocyte antigen [HLA] typing, donor search,
etc.) should be part of the initial approach for most AML patients.
POSTREMISSION THERAPY
Induction of a durable first CR (CR1) is critical to long-term
survival in AML. However, without further therapy, virtually all
CR patients will eventually relapse. Thus, postremission therapy
is designed to eradicate residual (typically undetectable) leukemic
cells to prevent relapse and prolong survival. As with induction,
the type of postremission therapy in AML is selected for each indi­
vidual patient based on age, fitness, and cytogenetic/molecular risk.
The choice between consolidation with chemotherapy or with
transplantation is complex and based on age, risk, and practi­
cal considerations. In younger patients receiving chemotherapy,
postremission therapy with intermediate- or high-dose cytarabine
for two to four cycles is standard practice. Higher doses of cyta­
rabine during postremission therapy appear more effective than
Refractory
or relapsed
Previously
untreateda
Favorable-risk
Intermediate-risk
Either option
acceptable
Either option
acceptable
Induction therapy:
Daunorubicin+
cytarabine-based
regimen
Induction therapy:
Daunorubicin+
cytarabine-based
regimenb,c
Investigational
therapyb
Investigational
therapyc
If CR,
consolidation therapy:
Allogeneic HCT (preferred),
or IDAC or autologous
HCT if age <60d
If CR:
Investigational
therapyd
If CR:
Investigational
therapyd
If CR, consolidation
therapy:
IDACd
Refractory (no CR)
or relapsed
FIGURE 109-2  Algorithm for the therapy of newly diagnosed acute myeloid leukemia (AML). aRisk stratification according to the European LeukemiaNet (see Table 109-3).
bYounger patients (<60–65 years) should routinely be offered investigational therapy on a backbone of standard intensive chemotherapy for induction and consolidation.
cOlder patients, especially those >65 years or with adverse risk disease, or those who are unfit for intensive anthracycline + cytarabine regimens, may be considered for
investigational therapy alone or in combination or lower intensity chemotherapy plus venetoclax. Whether venetoclax-containing regimens will be effective in younger,
fit patients when compared to intensive chemotherapy is an important question. dNovel allogeneic transplantation approaches are preferred for nonfavorable risk when
available; other investigational therapy or oral azacitidine (approved in nonfavorable risk) as maintenance should be considered following consolidation.
    Allogeneic hematopoietic cell transplantation (HCT) is a consideration for all eligible patients in first complete remission (CR) with non–favorable-risk disease and highly
recommended for all older patients (60–75 years) and those with adverse risk.
    For all forms of AML in fit patients, except acute promyelocytic leukemia (APL), standard induction therapy includes a regimen based on a 7-day continuous infusion
of cytarabine (100–200 mg/m2/d) and a 3-day course of daunorubicin (60–90 mg/m2/d) with or without additional drugs. Idarubicin (12 mg/m2/d) can be used in place of
daunorubicin (not shown). The value of postremission/consolidation therapy for older patients (>60 years) who do not have favorable-risk disease is uncertain. Patients who
achieve CR undergo postremission consolidation therapy, including sequential courses of intermediate-dose cytarabine, allogeneic HCT, autologous HCT, or novel therapies,
based on their predicted risk of relapse (i.e., risk-stratified therapy). Patients receiving induction of lower intensity chemotherapy with venetoclax (or investigational
therapy) typically receive repetitive cycles of same on an attenuated schedule, if necessary due to myelotoxicity, after achieving remission. Patients with APL (see text for
treatment) usually receive tretinoin and arsenic trioxide–based regimens with or without anthracycline-based chemotherapy and possibly maintenance with tretinoin. HLA,
human leukocyte antigen; IDAC, intermediate-dose cytarabine.
standard doses (such as are used in induction) for those who do
not have adverse-risk genetics. Studies have shown that the longstanding practice of high-dose cytarabine (3 g/m2, every 12 h on
days 1, 3, and 5) may not improve survival over intermediate-dose
cytarabine (IDAC; 1–1.5 g/m2) for such patients. Thus, the ELN has
recommended IDAC at 1–1.5 g/m2, every 12 h, on days 1–3, as the
optimal postremission chemotherapy approach for favorable- and
intermediate-risk younger patients, for two to four cycles. While
high-dose cytarabine may not be necessary, it is important to note
that younger, favorable-risk patients have worse outcomes when doses
<1 g/m2 are used. In contrast to favorable-risk patients, intermediate-
or adverse-risk patients should proceed with allogeneic HCT in
CR1 when feasible (see transplant discussion below). Because older
patients have increased toxicities with higher doses of cytarabine,
ELN recommends relatively attenuated cytarabine doses (0.5–1 g/m2,
every 12 h, on days 1–3) in favorable-risk older patients. There is no clear
value for intensive postremission therapy in non–favorable-risk
older patients; allogeneic HCT in CR1 (up to age 75 years) or
investigational postremission therapy is recommended. Indeed,
postremission therapy is an appropriate setting for introduction of
new agents in both older and younger patients. For older patients
(with nonfavorable cytogenetic risk) in CR after intensive therapy
who have no transplantation option, maintenance treatment with
prolonged low-dose oral azacitidine improves survival.
Diagnosis AML
Salvage
treatment
Adverse-risk
Patient with primary induction
failure and candidate for
myeloablative allogeneic HCT
or CR2 achieved  with salvage
treatment and has suitable
donor available
Either option
acceptable
Induction therapy:
Daunorubicin+
cytarabine-based
regimenb,c
Investigational
therapyc
Yes:
Allogeneic
HCT
If CR,
consolidation therapy:
Allogeneic HCT (alternative
donor transplant if no HLAmatched donor available)d
If CR:
Investigational
therapyd
No:
Investigational
therapy, autologous
HCT considered
for favorable-risk
patients in CR2 with
prolonged CR1
duration (>12
months)
CHAPTER 109
Acute Myeloid Leukemia
For patients treated initially with lower intensity regimens that
include venetoclax, the current practice is to continue repetitive
cycles of the same combination of agents after remission until
disease progression. Therapy often must be abbreviated over time
due to cumulative myelotoxicity. In the largest published trial with
azacitidine and venetoclax in older AML, patients had median
survival of <15 months; survival depended on genetic risk. The
median duration of remission (including those with incomplete
count recovery) was 17.5 months.
Allogeneic HCT is the best relapse-prevention strategy cur­
rently available for AML. Allogeneic HCT is best understood as an
opportunity for immunotherapy; residual leukemia cells potentially
elicit an immunologic response from donor immune cells, the socalled graft-versus-leukemia (GVL) effect. The benefit of GVL in
relapse risk reduction unfortunately is offset somewhat by increased
morbidity and mortality from complications of HCT including
graft-versus-host disease (GVHD). Given that relapsed AML is
typically resistant to chemotherapy, allogeneic HCT in CR1 (i.e.,
before relapse ever occurs) is a favored strategy. We have often
explained to patients that transplant can effectively “eliminate the
needle in a haystack, but not a stack of needles.” Transplant is recom­
mended for patients age <75 years who do not have favorable-risk
disease and who have an available HLA-compatible donor (related
or unrelated). We recommend allogeneic HCT in CR1 for patients
with intermediate-risk disease (Table 109-3). However, consider­
able debate exists regarding whether allogeneic HCT in CR1 is a
requirement for younger patients with intermediate-risk AML,
as one large series from the Medical Research Council reported
that such patients have similar outcomes if transplanted only after
relapse (and achievement of CR2), sparing some the long-term
morbidity of transplantation. That said, allogeneic HCT is generally
recommended as soon as possible after CR1 is achieved unless the
patient is in a favorable-risk group. Patients without HLA-matched
donors are considered for alternative donor transplants (e.g., HLAmismatched unrelated, haploidentical related, and umbilical cord
blood) even in CR1. More effective and safe methods of in vivo
T-cell depletion (e.g., posttransplant cyclophosphamide following
mismatched transplantation or use of abatacept) have broadened
the availability of potential allogeneic HCT donors. Now, virtually
any patient with a healthy parent or child has an available donor
suitable for allogeneic HCT if desired. Long-term outcomes with
conventional chemotherapy for older patients are dismal; trans­
plantation for such patients is expanding and improving outcomes.
Trials comparing allogeneic HCT with intensive chemotherapy
or autologous HCT have shown improved duration of remission
with allogeneic HCT. The relapse risk reduction observed with
allogeneic HCT, however, is partially offset by the increase in
fatal treatment-related toxicity (GVHD, organ toxicity). Despite
this, there is no debate that patients with adverse-risk AML have
improved long-term survival with early allogeneic HCT. For rare
patients with no allogeneic donor option, high-dose chemotherapy
with autologous HCT rescue is another postremission approach in
non–adverse-risk subsets. Autologous HCT patients receive their
own stem cells (collected during remission and cryopreserved), fol­
lowing administration of myeloablative chemotherapy. The toxicity
is relatively low with autologous HCT (5% mortality rate), but the
relapse rate is higher than with allogeneic HCT due to the absence
of the GVL effect. Favorable- and intermediate-risk patients may
benefit from autologous HCT; it is not recommended in adverserisk patients. Practically speaking, autologous HCT in AML patients
is less frequently employed currently due to enhanced relapse risk
reduction seen with allogeneic HCT and the growing availability of
HLA-mismatched donors (and novel transplantation approaches).
PART 4
Oncology and Hematology
Prognostic factors help to select the appropriate postremission
therapy in patients in CR1. Our approach includes allogeneic HCT
in CR1 for patients without favorable cytogenetics or genotype.
Patients with adverse-risk disease should proceed to allogeneic
HCT at CR1 if possible. The decision for allogeneic HCT for
younger intermediate-risk patients is complex and individualized
as described above; we recommend it. Subsets of patients may
benefit from targeted therapy given during remission; emerging
data demonstrate survival benefit from incorporation of the FLT3
inhibitors midostaurin or quizartinib, for example, into induction
and postremission therapies for patients with FLT3-mutated AML.
Allogeneic transplantation in CR1 is still recommended for most of
these patients.
For patients in morphologic CR, measurement of MRD remains
a very important and challenging research area. Cytogenetics are
a mainstay of disease assessment, and persistence of abnormal
karyotype (despite morphologic CR) is clearly associated with poor
clinical outcomes. Immunophenotyping (flow cytometry) to detect
minute populations of blasts and/or sensitive molecular assays such
as quantitative reverse transcriptase polymerase chain reaction
(RT-PCR) to detect AML-associated molecular abnormalities when
present (e.g., NPM1, RUNX1/RUNX1T1 and CBFB/MYH11 tran­
scripts, PML/RARA) can be performed to assess MRD at sequential
time points during or after treatment. We know that continued
detection of MRD after therapy is unfavorable. Whether emerg­
ing next-generation sequencing or serial quantitative assessment
using flow or PCR, performed during remission, can effectively
direct subsequent therapy and improve clinical outcome remains
to be determined for most subtypes. Currently, no consensus exists
for the optimal MRD measurement technique or its application,
although testing is increasingly employed in clinical practice. Data
suggest that MRD measurement can in some settings be a reliable
discriminator between patients who will continue in CR or relapse,
but whether subsequent therapy (i.e., allogeneic HCT or additional
therapy) can effectively eradicate disease in such patients is not yet
clear. For patients with NPM1 mutation, MRD-negative status by
NPM1 PCR after two courses of chemotherapy predicts favorable
outcome without transplantation (even for patients with coexisting
FLT3 mutation); emerging data demonstrate that transplantation of
MRD-positive patients does indeed improve outcome (rather than
just predict they will do poorly irrespective of subsequent therapy
given). In the subset of patients with APL, serial PCR (for the PML/
RARA transcript) is a very useful and reliable tool to detect early
relapse and to direct initiation of reinduction therapy prior to onset
of overt relapse. Critical in the general understanding of MRD in all
disease subsets is the recognition that even patients with undetect­
able levels of MRD remain at risk for leukemic relapse.
SUPPORTIVE CARE
Measures geared to supporting patients through several weeks of
neutropenia and thrombocytopenia are critical to successful AML
therapy. Patients with AML should be treated in centers expert in
providing supportive care. Multi-lumen central venous catheters
should be inserted as soon as newly diagnosed AML patients have
been stabilized. They should be used thereafter for administration
of intravenous medications/chemotherapy and transfusions, as well
as for blood drawing instead of venipuncture during prolonged
periods of myelosuppression.
Adequate and prompt blood bank support is critical to therapy of
AML. Platelet transfusions should be given as needed to maintain a
platelet count ≥10,000/μL. The platelet count should be kept at higher
levels in febrile patients and during episodes of active bleeding or DIC.
Patients with poor posttransfusion platelet count increments may
benefit from administration of ABO-matched platelets or platelets
from HLA-matched donors. RBC transfusions should be considered
to keep the hemoglobin level >70–80 g/L (7–8 g/dL) in the absence of
active bleeding, DIC, or congestive heart failure, which may require
higher hemoglobin levels. Blood products leukodepleted by filtra­
tion should be used to avert or delay alloimmunization as well as
febrile reactions. Blood products may also be irradiated to prevent
transfusion-associated GVHD.
Neutropenia (neutrophils <500/μL or <1000/μL and predicted
to decline to <500/μL over the next 48 h) can be part of the initial
presentation and/or a side effect of the chemotherapy treatment in
AML patients. Thus, infectious complications remain the major
cause of morbidity and death during induction and postremission
chemotherapy for AML. Antibacterial (e.g., quinolones) and anti­
fungal (e.g., posaconazole) prophylaxis, especially in conjunction
with regimens that cause mucositis, is beneficial. For patients who
are herpes simplex virus or varicella-zoster seropositive, antiviral
prophylaxis should be initiated (e.g., acyclovir, valacyclovir).
Fever develops in most patients with AML, but infections are
documented in only half of febrile patients. Empiric initiation of
empirical broad-spectrum antibacterial and antifungal antibiotics
has significantly reduced the number of patients dying of infectious
complications (Chap. 79). An antibiotic regimen adequate to treat
gram-negative organisms should be instituted at the onset of fever in
a neutropenic patient after clinical evaluation, including a detailed
physical examination with inspection of the indwelling catheter
exit site and a perirectal examination (for perirectal abscess), as
well as procurement of cultures and radiographs aimed at docu­
menting the source of fever. Specific antibiotic regimens should
be based on institutional antibiotic sensitivity data obtained from
where the patient is being treated. Acceptable regimens for empiric
antibiotic therapy include monotherapy with imipenem-cilastatin,
meropenem, piperacillin/tazobactam, or an extended-spectrum
antipseudomonal cephalosporin (cefepime or ceftazidime). The
combination of an aminoglycoside with an antipseudomonal peni­
cillin (e.g., piperacillin) or an aminoglycoside in combination with
an extended-spectrum antipseudomonal cephalosporin should
be considered in complicated or resistant cases. Aminoglycosides
should be avoided, if possible, in patients with renal insufficiency.
Empirical vancomycin should be added in neutropenic patients
with catheter-related infections, blood cultures positive for grampositive bacteria before final identification and susceptibility test­
ing, hypotension or shock, or known colonization with penicillin/
cephalosporin-resistant pneumococci or methicillin-resistant
Staphylococcus aureus. In special situations where decreased sus­
ceptibility to vancomycin, vancomycin-resistant organisms, or van­
comycin toxicity is documented, other options including linezolid
and daptomycin need to be considered.
Caspofungin (or a similar echinocandin), voriconazole, isavu­
conazonium, or liposomal amphotericin B should be considered
for antifungal treatment if fever persists for 4–7 days following
initiation of empiric antibiotic therapy. Although liposomal for­
mulations of amphotericin B have improved the toxicity profile of
this agent, use has been limited to situations with high risk of or
documented mold infections, especially in those in whom an azole
fails. Caspofungin has been approved for empiric antifungal treat­
ment. Voriconazole has also been shown to be equivalent in efficacy
and less toxic than amphotericin B; isavuconazonium may also be
effective with fewer drug-drug interactions. Unfortunately, use of
prophylactic or empiric antibiotics contributes to the development
of resistance and increased incidence of nosocomial infections such
as Clostridium difficile colitis, so hospital-wide antibiotic surveil­
lance and isolation strategies should be employed to reduce these
complications. Recombinant hematopoietic growth factors have a
limited role in AML; myeloid growth factors may be useful in the
postremission setting but are not recommended in induction or for
“palliative” care for patients not in remission.
TREATMENT FOR REFRACTORY OR RELAPSED AML
In patients who relapse after achieving CR, the length of first CR is
predictive of response to salvage chemotherapy treatment; patients
with longer first CR (>12 months) generally relapse with drugsensitive disease and have a higher chance of attaining a CR, even
with the same chemotherapeutic agents used for first remission
induction. Patients with short prior CR duration are at high risk
for treatment failure. Similar to patients with refractory disease,
patients with relapsed disease are rarely, if ever, cured by salvage
chemotherapy treatments alone. Therefore, patients who eventually
achieve a second CR and are eligible for allogeneic HCT should
be transplanted. For patients who relapse after allogeneic HCT, no
consensus for best therapy exists; outcomes in this setting are very
poor.
Because achievement of a second CR with routine salvage thera­
pies is relatively uncommon, especially in patients who relapse rapidly
after achievement of first CR (<12 months), these patients and those
lacking HLA-compatible donors or who are not candidates for alloge­
neic HCT should be considered for innovative approaches on clinical
trials. Many new agents are in current testing (Table 109-5). The dis­
covery of novel gene mutations and mechanisms of leukemogenesis
that might represent actionable therapeutic targets has prompted
the development of many new targeting agents. In addition to
kinase inhibitors for FLT3-mutated AML, other compounds target­
ing the aberrant activity of mutant proteins (e.g., IDH1/2 inhibi­
tors) and numerous other biologic mechanisms are either approved
by the Food and Drug Administration (FDA) or being tested in
clinical trials. Inhibitors of FLT3 (gilteritinib, quizartinib), IDH1
(ivosidenib, olutasidenib), or IDH2 (enasidenib) are approved in
AML. Exciting early clinical data with menin inhibitors in AML
with KMT2A rearrangement, NPM1 mutation, or other genetic
aberrations with shared biology of HOXA cluster gene upregulation
are likely to result in FDA approval of the first agent in this pathway
during 2024. Furthermore, approaches with antibodies targeting
markers commonly expressed on leukemia blasts (e.g., CD33) or
leukemia-initiating cells (e.g., CD123) are also under investiga­
tion. Next-generation immune compounds such as bispecific or
TABLE 109-5  Novel Therapies in Clinical Development in Acute
Myeloid Leukemia (AML)
APPROVED BY
FOOD AND DRUG
ADMINISTRATION
SINCE 2017
UNDER INVESTIGATION
Kinase inhibitors/
cell signaling
FLT3 inhibitors
IRAK-4 inhibitors
KIT inhibitors
PI3K/AKT/mTOR inhibitors
Aurora and polo-like kinase
inhibitors, CDK4/6 inhibitors, CDK9
inhibitors, CHK1, WEE1, CSFR1,
and MPS1 inhibitors
SRC and HCK inhibitors
Syk inhibitors
Midostaurin (FLT3)
Gilteritinib (FLT3)
Quizartinib (FLT3)
Pemigatinib (FGFR1)
Epigenetic
modulators
Menin inhibitors, other
spliceosome modulators
DNA methyltransferase inhibitors
Histone methylation or acetylation
modulators
Other spliceosome modulators
IDH1 and IDH2 inhibitors
DOT1L inhibitors
BET-bromodomain inhibitors
Revumenib (menin
inhibitor; FDA review
pending, 2024)
Enasidenib (IDH2)
Ivosidenib (IDH1)
Olutasidenib (IDH1)
CHAPTER 109
Chemotherapeutic
agents
Liposomal preparations
Nucleoside analogues
CPX-351 (liposomal
cytarabine and
daunorubicin)
Oral azacitidine
Acute Myeloid Leukemia
Mitochondrial
inhibitors
BH3 mimetics; Bcl-2, Bcl-xL, and
Mcl-1 inhibitors
Caseinolytic protease inhibitors
Venetoclax (BCL2)
Therapies targeting
oncogenic proteins
Fusion transcript targeting
EVI1 targeting
NPM1 targeting
Hedgehog inhibitors
Glasdegib (hedgehog)
Antibodies and
immunotherapies
Monoclonal antibodies against
CD33, CD44, CD47, CD123, CLEC12A
Immunoconjugates
Bispecific T-cell engagers (BiTEs)
and dual-affinity retargeting
molecules (DARTs) for CD33,
CD123, others
Trispecific T-cell or NK-cell
engagers
Chimeric antigen receptor (CAR) T
cells, genetically engineered T-cell
receptor (TCR) T cells, CAR-NK
cells
Immune checkpoint inhibitors
(PD-1/PD-L1, CTLA-4, LAG-3,
LILRB4)
Vaccines
Gemtuzumab
ozogamicin
(CD33-toxin)
Therapies targeting
AML environment
CXCR4 and CXCL12 antagonists
Antiangiogenic therapies
Source: Reproduced with permission from H Döhner et al: Diagnosis and management
of acute myeloid leukemia in adults: 2017 recommendations from an international
expert panel. Blood 129:424, 2017.
trispecific antibodies are promising and under study. Investigation
of these in combination with other molecular targeting compounds
and/or chemotherapy should be pursued.
TREATMENT OF ACUTE PROMYELOCYTIC LEUKEMIA
APL is a highly curable AML subtype, and ∼85% of these patients
achieve long-term survival with current approaches. APL has long
been shown to be responsive to cytarabine and daunorubicin.
However, in the past, patients who were treated with these drugs

40 - 110 Chronic Myeloid Leukemia
110 Chronic Myeloid Leukemia
alone frequently died from DIC induced by the release of gran­
ule components by the chemotherapy-treated leukemia cells. The
prognosis of APL patients changed dramatically first with the
introduction of tretinoin (all-trans-retinoic acid [ATRA]) and then
with combined ATRA and arsenic trioxide (ATO). ATRA is an oral
drug that induces the differentiation of leukemic cells bearing the
t(15;17), which disrupts the RARA gene encoding retinoid acid
receptor. ATRA decreases the frequency of DIC but often produces
another complication called the APL (differentiation) syndrome.
Occurring within the first 3 weeks of treatment, it is characterized
by fever, fluid retention, dyspnea, chest pain, pulmonary infiltrates,
pleural and pericardial effusions, and hypoxemia. The syndrome
is related to adhesion of differentiated neoplastic cells to the pul­
monary vasculature endothelium. Glucocorticoids, chemotherapy
for cytoreduction, and/or supportive measures can be effective for
management of the APL syndrome. Temporary discontinuation of
ATRA is necessary in cases of severe APL syndrome (i.e., patients
developing renal failure or requiring admission to the intensive
care unit due to respiratory distress). The mortality rate of this
syndrome is ∼10% if unrecognized. APL syndrome may also occur,
less commonly, with ATO.
In adults with low-risk APL (low leukocyte count at presenta­
tion), ATRA (45 mg/m2/d) plus ATO (0.15 mg/kg/d) was compared
to ATRA plus concurrent idarubicin chemotherapy. ATRA/ATO
was superior and is the new standard of care for such patients. CR
rates in low-risk disease approach 100%, with excellent long-term
survival. Notably, patients with high-risk APL (defined as leukocyte
count >10,000/μL) must be uniquely treated, as they require imme­
diate cytoreduction with chemotherapy due to life-threatening APL
syndrome and rapidly rising leukocyte count after initiation of
ATRA. High-risk patients are at increased risk for induction death
due to this syndrome as well as increased frequency of hemorrhagic
complications (related to DIC).
PART 4
Oncology and Hematology
Assessment of residual disease by PCR amplification of the
t(15;17) chimeric gene product PML-RARA following the final
cycle of treatment is important. Disappearance of the signal is
associated with long-term disease-free survival; its persistence or
reemergence invariably predicts relapse. Sequential monitoring by
PCR for PML-RARA is now considered standard for postremission
monitoring of APL, at least in high-risk patients.
■
■FURTHER READING
Dinardo CD et al: Venetoclax combined with decitabine or azacitidine
in treatment-naive, elderly patients with acute myeloid leukemia.
Blood 133:7, 2019.
Döhner H et al: Diagnosis and management of AML in adults: 2022
recommendations from an international expert panel on behalf of the
ELN. Blood 140:1345, 2020.
Issa GC et al: The menin inhibitor revumenib in KMT2A-rearranged
or NPM1-mutant leukaemia. Nature 615: 920, 2023.
Jaiswal S, Ebert BL: Clonal hematopoiesis in human aging and dis­
ease. Science 366:eaan4673, 2019.
Jongen-Lavrenic M et al: Molecular minimal residual disease in
acute myeloid leukemia. N Engl J Med 378:1189, 2018.
Khoury JD et al: The 5th edition of the World Health Organization Clas­
sification of Haematolymphoid Tumours: Myeloid and histiocytic/
dendritic neoplasms. Leukemia. 36:1703, 2022.
Perl AE et al: Gilteritinib or chemotherapy for relapsed or refractory
FLT3-mutated AML. N Engl J Med 381:1728, 2019.
Pollyea DA et al: Enasidenib, an inhibitor of mutant IDH2 proteins,
induces durable remissions in older patients with newly diagnosed
acute myeloid leukemia. Leukemia 33:2575, 2019.
Roboz GJ et al: Ivosidenib induces deep durable remissions in patients
with newly diagnosed IDH1-mutant acute myeloid leukemia. Blood
135:463, 2020.
Stone RM et al: Midostaurin plus chemotherapy for acute myeloid
leukemia with a FLT3 mutation. N Engl J Med 377:454, 2017.
Hagop Kantarjian, Elias Jabbour
Chronic Myeloid
Leukemia
Chronic myeloid leukemia (CML) is a clonal hematopoietic myelopro­
liferative stem cell neoplasm. The disease is driven by the BCR::ABL1
chimeric gene that codes for a constitutively active tyrosine kinase,
resulting from a reciprocal balanced translocation between the long
arms of chromosomes 9 and 22, t(9;22)(q34.1;q11.2), known as the
Philadelphia chromosome (Ph) (Fig. 110-1). Untreated, the course of
CML is typically biphasic or triphasic, with an early indolent or chronic
phase, followed often by an accelerated phase and a terminal blastic
phase. Before the era of BCR::ABL1 tyrosine kinase inhibitors (TKIs),
the median survival in CML was 3–7 years, and the 10-year survival
rate was 30% or less. Introduced into standard CML therapy in 2000,
TKIs have revolutionized the treatment, natural history, and progno­
sis of CML. Today, the estimated 10-year survival rate with imatinib
mesylate, the first BCR::ABL1 TKI approved, is >85% and approaches
that of a normal age-matched population. Allogeneic hematopoietic
stem cell transplantation (HSCT), a curative approach but one that
involves more risks, is now offered as later-line therapy after failure
of TKIs.
■
■INCIDENCE AND EPIDEMIOLOGY
CML accounts for ∼15% of all cases of leukemia. There is a slight male
predominance (male-to-female ratio 1.6:1). The median age at diag­
nosis is 55–65 years. It is uncommon in children; only 3% of patients
with CML are younger than 20 years, although in recent years, a higher
proportion of young patients have been diagnosed. The incidence of
CML increases gradually with age, with a steeper increase after the age
of 40–50 years. The annual incidence of CML is 2 cases per 100,000
individuals. In the United States, this translates into about 9000 new
cases per year. The incidence of CML has not changed over several
decades. By extrapolation, the worldwide annual incidence of CML is
about 250,000 cases. With a median survival of 3–6 years before 2000,
the disease prevalence in the United States was ~30,000 cases. With
TKI therapy, the annual mortality has been reduced from 10–20% to
about 1–2%. Therefore, the prevalence of CML is expected to continue
to increase. Based on these estimates (incidence of 9000 cases, annual
mortality of 2%), the plateau prevalence of CML is estimated to be
reached at ~450,000 in the United Stated (9000 × 100/2) by about
2040, with full TKI optimal treatment penetration. The worldwide
prevalence will depend on the treatment penetration of TKIs and their
effect on reduction of worldwide annual mortality. Ideally, with full
TKI treatment penetration, the worldwide prevalence should plateau at
35 times the incidence, or ~9–10 million patients. These estimates are
based on extrapolations from the incidence and prevalence of CML in
the United States, as well as an estimated annual mortality of 2% with
modern TKI therapy; they could vary considerably if the estimates
were to change.
■
■ETIOLOGY
There are no familial associations in CML. The risk of developing CML
is not increased in monozygotic twins or in relatives of patients with
CML. No etiologic agents are incriminated, and no associations exist
with exposures to benzene or other toxins, fertilizers, insecticides, or
viruses. CML is not a frequent secondary leukemia following therapy
of other cancers with alkylating agents and/or radiation. Exposure to
ionizing radiation (e.g., nuclear accidents, higher doses of radiation
treatment) has increased the risk of CML, which peaks at 5–10 years
after exposure and is dose-related. The median time to development
of CML among atomic bomb survivors was 6.3 years. Following the
Chernobyl accident, no increase in the incidence of CML was reported,
suggesting that larger dose exposures of radiation are required to
cause CML. Because of adequate protection, the risk of CML has not
q34
t(9;22)(q34.1;q11.2)
A
Chromosomes
Minor BCR
BCR
Major BCR
ABL1
Micro BCR
Normal
ABL1
Breakpoint
Translocation (9;22)
B
FIGURE 110-1  A. The Philadelphia (Ph) chromosome cytogenetic abnormality. B. Breakpoints in the long arms of chromosome 9 (ABL1 locus) and chromosome 22 (BCR
regions) result in at least three different BCR::ABL1 oncoprotein messages, p210BCR::ABL1 (most common message in chronic myeloid leukemia [CML]), p190BCR::ABL1 (present
in two-thirds of patients with Ph-positive acute lymphoblastic leukemia; rare in CML), and p230BCR::ABL1 (rare in CML and associated with an indolent course). Other
rearrangements (e.g., e14a3, e14a3) are less common. (© 2013 The University of Texas MD Anderson Cancer Center.)
increased among individuals working in the nuclear industry or among
radiologists.
■
■PATHOPHYSIOLOGY
The t(9;22)(q34.1;q11.2) is present in >90% of classical CML cases. It
results from a balanced reciprocal translocation between the long arms
of chromosomes 9 and 22. It is present in hematopoietic cells (myeloid,
erythroid, megakaryocytes, and monocytes; less often mature B lym­
phocytes; rarely mature T lymphocytes, but not stromal cells), but not
in other cells in the human body. As a result of the genetic transloca­
tion, DNA sequences from the cellular ABL proto-oncogene 1 (ABL1)
are juxtaposed to the major breakpoint cluster region (BCR) gene on
chromosome 22, generating a hybrid BCR::ABL1 oncogene. Depending
on the breakpoint site in the major BCR region on chromosome 22 (e13
or e14), two main messenger RNA transcripts occur, e13a2 (previously
b2a2) and e14a2 (previously b3a2). Both transcripts encode for a novel
oncoprotein of molecular weight 210 kDa, referred to as p210BCR::ABL1
(Fig. 110-1B). This oncoprotein exhibits constitutive kinase activity
that leads to increased proliferation and reduced apoptosis of CML
cells, endowing them with a growth advantage over their normal coun­
terparts. Over time, normal hematopoiesis is suppressed, but normal
stem cells can persist and reemerge following effective anti-CML ther­
apy, for example with TKIs. In two-thirds of patients with Ph-positive
q11.2
5'
e1
e1'
e2'
e12
e13
e14
e15
e16
CHAPTER 110
5'
e19
1b
Chronic Myeloid Leukemia
1a
a2
a3
3'
e1a2
e13a2
e14a2
e19a2
a11
p210BCR-ABL1 p230BCR-ABL1
p190BCR-ABL1
3'
acute lymphoblastic leukemia (ALL) and in rare cases of CML, the
breakpoint in BCR is more centromeric, in a region called the minor
BCR region (mBCR). As a result, a shorter sequence of BCR is fused
to ABL1, with a consequent e1a2 transcript and a smaller BCR::ABL1
oncoprotein, p190BCR::ABL1. When occurring in Ph-positive CML, this
translocation is associated with a worse outcome. A rarer breakpoint
in BCR occurs telomeric to the major BCR region in the micro-BCR
(μ-BCR) region. It juxtaposes a larger fragment of the BCR gene to
ABL1 and produces an e19a2 transcript and a larger p230BCR::ABL1 onco­
protein (associated with a more indolent CML course). Other rear­
rangements (based on different breakpoints in the ABL region), such
as e13a3 or e14a3 (also resulting in a p210BCR::ABL1 oncoprotein), occur
much less frequently. These are not readily identifiable nor quantifi­
able with the routine polymerase chain reaction (PCR) probes, thus
producing falsely negative PCR levels on follow-up studies if not tested
at diagnosis.
The constitutive activation of BCR::ABL1 results in autophosphory­
lation and activation of multiple downstream pathways that affect gene
transcription, apoptosis, stromal adherence, skeletal organization,
and degradation of inhibitory proteins. These transduction pathways
involve RAS, mitogen-activated protein (MAP) kinases, signal trans­
ducers and activators of transcription (STAT), phosphatidylinositol3-kinase (PI3k), MYC, and others. These interactions are mostly
mediated through tyrosine phosphorylation and require binding
of BCR::ABL1 to adapter proteins such as GRB-2, CRK, CRK-like
(CRK-L) protein, and Src homology containing proteins (SHC). Most
BCR::ABL1 TKIs (imatinib, dasatinib, bosutinib, nilotinib, ponatinib)
bind to the BCR::ABL1 ATP-binding domain, inhibiting its kinase
activity, preventing the activation of transformation pathways, and
inhibiting downstream signaling. As a result, proliferation of CML cells
is inhibited and apoptosis induced, allowing the reemergence of nor­
mal hematopoiesis. An additional layer of complexity in CML is related
to differences in signal transduction between CML-differentiated
cells and early progenitors. Beta-catenin, Wnt1, Foxo3a, transforming
growth factor β, interleukin 6, PP2A, SIRT1, and others have been
implicated in CML stem cell survival. ABL1 also has a myristoyl site
that functions as a negative regulator of its kinase activity. This site
and its negative regulatory activity are lost upon fusion with BCR.
Asciminib, a novel “third-generation” TKI (third generation refers to
novel TKIs that inhibit the ABL1-T315I-mutated CML disease, such as
ponatinib), is the first-in-class TKI that works through a novel mecha­
nism that specifically targets the ABL1 myristoyl pocket (STAMP is an
acronym for specifically targets the ABL1 myristoyl pocket). Asciminib
binds this myristoyl site and restores the lost inhibitory activity. Muta­
tions in other cancer-associated genes may also occur at diagnosis, most
frequently in ASXL1, IKZF1, and RUNX1. Their significance is being
clarified. Some reports suggest that their presence may be associated
with worse response to TKI therapy and a higher risk of transforma­
tion to blastic phase. An ASXL1 mutation is often associated with a
higher incidence of recurrent cytopenias on TKI therapy, resulting
in frequent treatment interruptions, TKI dose reductions, failure to
achieve optimal therapeutic milestones, and the need to proceed to
allogeneic HSCT.
PART 4
Oncology and Hematology
Experimental models have established the causal relationship
between the BCR::ABL1 rearrangement and the development of
CML. In animal models, expression of BCR::ABL1 in normal hema­
topoietic cells produced CML-like disorders or lymphoid leukemia,
demonstrating the leukemogenic potential of BCR::ABL1 as a single
oncogenic abnormality. Other models, however, suggest the need for a
“second hit.”
The cause of the BCR::ABL1 rearrangement is unknown. Molecular
techniques that detect BCR::ABL1 at a level of 1 in 108 cells identify
this molecular abnormality in the blood of up to 25% of normal adults
and 5% of infants, but 0% of cord blood samples. This suggests that
BCR::ABL1 is not sufficient to cause overt CML in the overwhelming
majority of individuals in whom it occurs. Because CML develops in
only 2 of 100,000 individuals annually, additional molecular events or
poor immune recognition of the rearranged cells may contribute to
overt CML.
CML is defined by the presence of the BCR::ABL1 fusion gene
in a patient with a myeloproliferative neoplasm. In some patients
with a typical morphologic picture of CML, the Ph chromosome is
not detectable by standard G-banding karyotype, but fluorescence
in situ hybridization (FISH) and/or molecular studies (PCR) detect
BCR::ABL1. These patients have a course similar to patients with Phpositive CML and respond to TKI therapy. Many of the remaining
patients have atypical morphologic or clinical features and have other
diseases, such as atypical CML, chronic myelomonocytic leukemia,
and myelodysplastic syndrome/myeloproliferative neoplasms (MDS/
MPN). These individuals do not respond to TKI therapy and usually
have a poor prognosis with a median survival of ~2–3 years. Detection
of mutations in the granulocyte colony-stimulating factor receptor
(CSF3R) in chronic neutrophilic leukemia (80% of cases) and in some
cases of atypical CML (5–10% of cases), mutations in SETBP1 in atypi­
cal CML (25% of cases), and mutations in SF3B1 in MDS/MPN with
ringed sideroblasts and marked thrombocytosis (MDS/MPN-RS-T;
50–70% of cases, associated with longer median survival of 7 years
vs 3.3 years with wild-type SF3B1) supports the notion that these are
distinct molecular and biologic entities. Patients with chronic neu­
trophilic leukemia or atypical CML whose disease is associated with
CSF3R mutation may respond to ruxolitinib (a JAK2 inhibitor) therapy
(complete response rate 50–60%).
The events associated with the transition of CML from a chronic
to the accelerated-blastic phase are poorly understood. Characteristic
chromosomal abnormalities such as a double Ph, trisomy 8, isochro­
mosome 17 or deletion of 17p (loss of TP53), 20q–, translocations
involving 3q26, and others may be noted with disease acceleration.
Molecular events associated with transformation include mutations
in TP53, retinoblastoma 1 (RB1), myeloid transcriptions factors like
RUNX1, and cell cycle regulators like p16. A plethora of other muta­
tions or functional abnormalities have been implicated in blastic trans­
formation, but no unifying theme has emerged other than the fact that
BCR::ABL1 itself induces genetic instability that favors the acquisition
of additional molecular defects and eventually results in blastic trans­
formation. One critical effect of TKIs is to stabilize the CML genome,
leading to a reduced transformation rate. In particular, the previously
observed sudden blastic transformations (i.e., abrupt transformation to
blastic phase in a patient who had been in cytogenetic response) have
become uncommon, occurring rarely in younger patients in the first
1–2 years of TKI therapy (usually sudden lymphoid blastic transfor­
mation). Sudden blastic transformations beyond the third year of TKI
therapy are rare in patients who continue on TKI therapy. The inci­
dence of any CML blastic transformation is now reduced to 5–6% at 10
years. Moreover, the course of CML is now frequently more indolent
in patients treated with TKI, even without cytogenetic response, com­
pared to previous experience with hydroxyurea/busulfan, suggesting a
definite clinical benefit of continued inhibition of the kinase activity.
Among patients developing resistance to TKIs, several resistance
mechanisms have been observed. The most clinically relevant one is the
development of ABL1 kinase domain mutations that may prevent the
binding of TKIs to the catalytic site (ATP-binding site) of the kinase or
maintain the kinase activity despite the presence of a TKI. More than 100
ABL1 kinase domain mutations have now been described, many of which
confer relative or absolute resistance to imatinib. Consequently, secondgeneration (i.e., dasatinib, nilotinib, bosutinib) and third-generation
TKIs (ponatinib, asciminib, olverembatinib [approved in China; ongoing
trials worldwide since 2023]) were developed. All three third-generation
TKIs demonstrate significant efficacy against T315I, a “gatekeeper”
mutation that prevents binding of, and causes resistance to, imatinib and
the second-generation TKIs (dasatinib, bosutinib, nilotinib).
■
■CLINICAL PRESENTATION
The presenting signs and symptoms in CML depend on the availabil­
ity of and access to health care, including physical examinations and
screening tests. In developed countries, because of the wider access to
health care screening and physical examinations, 50–60% of patients
are diagnosed on routine blood tests and have minimal symptoms
at presentation, such as fatigue. In geographic locations where access
to health care is more limited, patients often present with high CML
disease burden including splenomegaly, anemia, and related symptoms
(abdominal pain, weight loss, fatigue), associated with a higher fre­
quency of high-risk CML. Presenting findings in patients diagnosed in
the United States are shown in Table 110-1.
Symptoms 
Most patients with CML (90%) present in the indolent
or chronic phase. Depending on the timing of diagnosis, patients are
often asymptomatic (if the diagnosis is discovered during health care
screening tests). Common symptoms, when present, are manifestations
of anemia and splenomegaly. These include fatigue, malaise, weight
loss (if high leukemia burden), or early satiety and left upper quadrant
pain or masses (from splenomegaly). Less common presenting find­
ings include thrombotic or hyperviscosity-related events from severe
leukocytosis or thrombocytosis. These include priapism, cardiovas­
cular complications, myocardial infarction, venous thrombosis, visual
disturbances, dyspnea and pulmonary insufficiency, drowsiness, loss of
coordination, confusion, or cerebrovascular accidents. Manifestations
of bleeding diatheses include retinal hemorrhages, gastrointestinal
bleeding, and others. Patients who present with, or progress to, the
accelerated or blastic phases frequently have additional symptoms
including unexplained fever, significant weight loss, severe fatigue,
bone and joint pain, bleeding and thrombotic events, and infections.
TABLE 110-1  Presenting Signs and Symptoms of Newly Diagnosed
Philadelphia Chromosome–Positive Chronic Myeloid Leukemia in
Chronic Phase
PARAMETER
PERCENTAGE
Age ≥60 years (median)
40–50 (55–65)
Female gender
35–45
Splenomegaly
Hepatomegaly
5–10
Lymphadenopathy
Other extramedullary disease
Hemoglobin <10 g/dL
10–15
Platelets
 
   >450 × 109 cells/L
30–35
   <100 × 109 cells/L
3–5
White blood cells ≥50 × 109 cells/L
35–40
Marrow
 
   ≥5% blasts
   ≥5% basophils
10–15
Peripheral blood
 
   ≥3% blasts
8–10
   ≥7% basophils
Additional chromosomal abnormalities (other than the
Philadelphia chromosome)
4–5
Sokal risk
 
   Low
60–65
   Intermediate
25–30
   High
Physical Findings 
Splenomegaly is the most common physical
finding, occurring in 20–70% of patients depending on health care
screening frequency. Less common findings include hepatomegaly
(5–10%), lymphadenopathy (5%), and extramedullary disease (skin
or subcutaneous lesions). The latter indicates CML transformation
if a biopsy confirms predominance of blasts. Other physical findings
are manifestations of complications of high tumor burden described
earlier (e.g., cardiovascular, cerebrovascular, bleeding). High basophil
counts may be associated with histamine overproduction causing pru­
ritus, diarrhea, flushing, and even gastrointestinal ulcers.
Hematologic and Marrow Findings 
In untreated CML, leuko­
cytosis ranging from 10–500 × 109/L is common. The peripheral blood
differential shows left-shifted hematopoiesis with predominance of
neutrophils and the presence of bands, myelocytes, metamyelocytes,
promyelocytes, and blasts (usually ≤5%). Basophils and/or eosinophils
are frequently increased. Thrombocytosis is common, but thrombocy­
topenia is rare and, when present, suggests a worse prognosis, disease
acceleration, or an unrelated etiology. Anemia is present in one-third of
patients. Cyclic oscillations of counts are noted in 10–20% of patients
without treatment. Biochemical abnormalities include a low leukocyte
alkaline phosphatase score and high levels of vitamin B12, uric acid,
lactic dehydrogenase, and lysozyme. The presence of unexplained and
sustained leukocytosis, with or without splenomegaly, should lead to a
marrow examination and cytogenetic analysis.
The bone marrow is hypercellular with marked myeloid hyperpla­
sia and a high myeloid-to-erythroid ratio of 15–20:1. Marrow blasts
are typically 5% or less; when higher, they carry a worse prognosis
or represent transformation to accelerated phase (if they are ≥15%).
Increased reticulin fibrosis (detected with silver stain) is common, with
30–40% of patients demonstrating grade 3–4 reticulin fibrosis. This
was considered adverse in the pre-TKI era. With TKI therapy, reticulin
fibrosis resolves in most patients and is not an indicator of poor prog­
nosis. Collagen fibrosis (Wright-Giemsa stain) is rare at diagnosis. Dis­
ease progression with a “spent phase” of myelofibrosis (myelophthisis,
or burnt-out marrow) was a common end-stage CML condition with
busulfan therapy (20–30%); it is extremely rare now with TKI therapy.
Cytogenetic and Molecular Findings 
The diagnosis of CML is
straightforward and depends on documenting the translocation t(9;22)
(q34.1;q11.2), which is identified by G-banding in 90% of cases. This is
known as the Philadelphia chromosome (initially identified in Philadel­
phia as a minute chromosome; later identified to be chromosome 22)
(Fig. 110-1). Some patients (~10%) may have complex translocations
(complex variant Ph) involving three or more chromosomes including
chromosomes 9 and 22 and one or more additional chromosomes.
Others may have a “masked Ph,” involving translocations between
chromosome 9 and a chromosome other than 22 (but molecularly
showing the ABL1 rearrangement; known as simple variant Ph). The
prognosis of these patients and their response to TKI therapy are like
those in patients with Ph. Translocation (9;22)(q34;p13)/ETV6::ABL1
is now classified as a myeloproliferative neoplasm-eosinophilia and
may respond better to second-generation TKIs. About 5–10% of
patients may have additional chromosomal abnormalities (ACAs) in
the Ph-positive cells at diagnosis. These usually involve trisomy 8, a
double Ph, isochromosome 17 or 17p deletion, 20q–, or others. This
was historically a sign of adverse prognosis, particularly when trisomy
8, double Ph, or chromosome 17 abnormalities were noted. A less com­
mon abnormality involving chromosome 3q26.2 occurs with disease
progression and carries a poor prognosis.
CHAPTER 110
Techniques such as FISH and PCR are now used to aid in the diag­
nosis of CML. They are more sensitive to estimate the CML burden in
patients on TKI therapy. They can be done on peripheral blood and
thus are more convenient to patients. Patients with CML at diagnosis
should have a FISH analysis to quantify the percentage of Ph-positive
cells, if FISH is used to replace marrow cytogenetic analysis in moni­
toring response to therapy. FISH will not detect additional chromo­
somal abnormalities; thus, a cytogenetic analysis is recommended at
the time of diagnosis. In addition, 10–15% of patients may develop
chromosomal abnormalities in Ph-negative metaphases after respond­
ing to TKIs. These abnormalities may carry a worse prognosis but are
not detected by FISH unless already identified and FISH is used to
follow them. Molecular studies at diagnosis are important to docu­
ment the type and presence of BCR::ABL1 transcripts to avoid spurious
“undetectable” BCR::ABL1 transcripts on follow-up studies, with the
false impression of a complete molecular response. The presence of the
Philadelphia chromosome with “negative” PCR with standard method­
ology should prompt investigation of atypical transcripts (e13a3, e14a3,
e19a2, others).
Chronic Myeloid Leukemia
Both FISH and PCR studies can be falsely positive at low levels or
falsely negative because of technical issues. Therefore, a diagnosis of
CML must always rely on a marrow analysis with routine cytogenetics.
The diagnostic bone marrow confirms the presence of the Ph chromo­
some, detects additional chromosomal abnormalities, and quantifies
the percentage of marrow blasts and basophils. In 10% of patients, the
percentage of marrow blasts and basophils can be significantly higher
than in the peripheral blood, conferring poorer prognosis or even rep­
resenting disease transformation.
Monitoring patients on TKI therapy by cytogenetics, FISH, and
PCR has become an important standard practice to assess response to
therapy, emphasize compliance, evaluate possible treatment resistance,
identify the need to change TKI therapy, and determine the need to
assess for kinase domain mutations. Because of the decreasing reliance
of bone marrow aspirations to monitor response, equivalence has been
established to correlate cytogenetic results with PCR values. These
are not absolute correlations but provide adequate guidance. A partial
cytogenetic response is defined as the presence of 35% or less Ph-
positive metaphases by routine cytogenetic analysis. This is roughly
equivalent to BCR::ABL1 transcripts on the International Scale (IS) of
10% or less. A complete cytogenetic response refers to the absence of
Ph-positive metaphases (0% Ph positivity). This is approximately equiv­
alent to BCR::ABL1 transcripts (IS) ≤1% (MR2). A major molecular
response (MMR or MR3) refers to BCR::ABL1 transcripts (IS) ≤0.1%,
or roughly a 3-log or greater reduction of BCR::ABL1 transcripts from
a standardized baseline. MR4 (deep molecular response; DMR) refers
to BCR::ABL1 transcripts (IS) ≤0.01%, and MR4.5 refers to BCR::ABL1
transcripts (IS) ≤0.0032%, roughly equivalent to a 4.5-log reduction or
greater of transcripts.
Findings in CML Transformation 
Progression of CML is usu­
ally associated with leukocytosis resistant to therapy, increasing
anemia, fever and constitutional symptoms, and increased blasts and
basophils in the peripheral blood or marrow. Criteria of acceleratedphase CML, historically associated with median survival of <2 years,
include the presence of 15% or more peripheral blasts, 30% or more
peripheral blasts plus promyelocytes, 20% or more peripheral baso­
phils, cytogenetic clonal evolution (presence of additional chromo­
somal abnormalities other than Ph), and thrombocytopenia <100 ×
109/L (unrelated to therapy). About 5–10% of patients present with
de novo accelerated phase or blastic phase. The prognosis of de novo
accelerated phase with TKI therapy has improved, with an estimated
8-year survival rate of 60–70%. The median survival of accelerated
phase evolving from chronic phase has also improved from a histori­
cal median survival of 18 months to an estimated 3-year survival rate
of 50% on TKI therapy. Therefore, the criteria for accelerated-phase
CML should be revisited because most clinical criteria defining accel­
erated phase have lost much of their prognostic significance. The
newest World Health Organization (WHO) classification suggested
eliminating accelerated-phase CML as an entity and classifying such
patients as high-risk CML. However, the survival of patients with both
de novo and evolved accelerated-phase CML is significantly worse
than in high-risk CML. The accelerated-phase definition should be
maintained in order to recognize such patients and treat them differ­
ently than chronic-phase CML, either with existing standards of care
(combinations of TKIs with other agents, allogeneic HSCT) or on
investigational trials of novel TKIs or other modalities. Blastic-phase
CML is defined by the presence of 30% or more peripheral or mar­
row blasts or the presence of sheets of blasts in extramedullary disease
(usually skin, soft tissues, or lytic bone lesions). Blastic-phase CML is
commonly myeloid (60%) but can present uncommonly as erythroid,
promyelocytic, monocytic, or megakaryocytic. Lymphoid blastic phase
occurs in about 25% of patients. Lymphoblasts are terminal deoxy­
nucleotide transferase positive and peroxidase negative (although
occasionally with low positivity up to 3–5%) and express lymphoid
markers (CD10, CD19, CD20, CD22). They also often express myeloid
markers (50–80%), resulting in diagnostic challenges. Proper immu­
nophenotypic diagnosis is important because lymphoid blastic-phase
CML is responsive to anti-ALL-type chemotherapy (e.g., hyper-CVAD
[cyclophosphamide, vincristine, doxorubicin, and dexamethasone])
in combination with TKIs and immunotherapies (complete response
rate 70%; median survival 3 years; high rates of bridging to allogeneic
HSCT and possible cure).
PART 4
Oncology and Hematology
■
■PROGNOSIS AND CML COURSE
Before the TKI era, the annual mortality in CML was 10% in the
first 2 years and 15–20% thereafter. The median survival in CML
was 3–7 years (with hydroxyurea-busulfan and interferon α). With­
out a curative option of allogeneic HSCT, the course of CML was
toward transformation to, and death from, accelerated or blastic
phases for most patients. Even disease stability was unpredictable,
with some patients demonstrating sudden transformation to a blastic
phase. With imatinib therapy, the annual mortality rate in CML has
decreased to 1–2% in the first 20 years of observation. The 10-year
survival rate is about 85%, the 10-year CML-specific survival rate is
90%, and CML-specific mortality rate is 10%; the 10-year incidence
of blastic transformation is 5–6%. More than half of the deaths are
from conditions other than CML, such as old age, comorbidities,
accidents, suicides, other cancers, and other medical conditions (e.g.,
infections, surgical procedures) (Fig. 110-2). The course of CML has
also become quite predictable. In the first 2 years of TKI therapy, rare
sudden transformations are still reported (1–2%), usually lymphoid
blastic transformations that respond to combinations of chemother­
apy and TKIs followed by allogeneic HSCT. These may be explained
by the intrinsic mechanisms of sudden transformation already exist­
ing in the CML clones before the start of therapy that were not ame­
nable to TKI inhibition, in particular imatinib. Second-generation
TKIs (nilotinib, dasatinib, bosutinib) used as frontline therapy have
reduced the incidence of transformation in the first 2–3 years from
4–6% with imatinib to 1–2% with second-generation TKIs. Disease
transformation to accelerated or blastic phase is rare with continued
TKI therapy, estimated at <1% annually in years 4–10 of follow-up.
Patients usually develop resistance in the form of cytogenetic relapse,
followed by hematologic relapse and subsequent transformation,
rather than the previously feared sudden transformation without the
warning signals of cytogenetic-hematologic relapse.
Before the imatinib era, several pretreatment prognostic factors
predicted for worse outcome in CML and have been incorporated into
prognostic models and staging systems. These have included older age,
significant splenomegaly, anemia, thrombocytopenia or thrombocyto­
sis, high percentages of blasts and basophils (and/or eosinophils), mar­
row fibrosis, additional chromosomal abnormalities, and others. The
introduction of TKIs into CML therapy has decreased or eliminated
the prognostic impact of these prognostic factors and the significance
of the CML models (e.g., Sokal, Hasford, European Treatment and
Outcome Study [EUTOS]). Treatment-related prognostic factors have
emerged as the most important prognostic factors in the era of ima­
tinib therapy. Achievement of complete cytogenetic response (MR2)
has become the major therapeutic endpoint and is the only endpoint
associated with improvement in survival. Achievement of MMR
(MR3) is associated with decreased risk of events (relapse) and CML
transformation but not with survival prolongation among patients
with complete cytogenetic response. This may be due to the efficacy
of salvage TKI therapies, which are implemented at the first evidence
of cytogenetic relapse. Achievement of durable DMR (MR4/MR4.5)
may offer the possibility of treatment-free remission (TFR). A durable
DMR for 2+ years is associated with a TFR rate of 50%; a durable DMR
for 5+ years is associated with a TFR rate of 80%+. A TFR may allow
a temporary TKI therapy interruption in women pursuing pregnancy.
The lack of achievement of MMR or DMR should not be considered as
“failure” of a particular TKI therapy and/or an indication to change the
TKI or to consider allogeneic HSCT.
Long-term updates of randomized trials suggest that second-
generation TKIs and imatinib are similarly effective in lower-risk CML;
second-generation TKIs may offer a therapeutic advantage in high-risk
CML and when TFR is an important treatment endpoint (younger
patients).
TREATMENT
Chronic Phase Chronic Myeloid Leukemia
Since 2001, six oral BCR::ABL1 TKIs have been approved by
the U.S. Food and Drug Administration (FDA) for the treat­
ment of CML. These include imatinib (Gleevec, Glivec), nilotinib
(Tasigna), dasatinib (Sprycel), bosutinib (Bosulif), ponatinib (Iclu­
sig), and asciminib (Scemblix). Dasatinib, nilotinib, and bosutinib
are referred to as second-generation TKIs; ponatinib and asciminib
are referred to as third-generation TKIs, a term also used generally
for the more recently developed TKIs that are active against T315Imutated CML (asciminib is also referred to as a STAMP inhibitor
because of its different mechanism of action). Nilotinib is similar
in structure to imatinib but 30 times more potent. Dasatinib and
bosutinib inhibit the SRC family of kinases in addition to ABL1,
with dasatinib reported to be 300 times more potent and bosuti­
nib 30–50 times more potent than imatinib (Table 110-2). Pona­
tinib inhibits vascular endothelial growth factor receptor (VEGFR),
which may be partly responsible for the high incidence of hyperten­
sion observed with this agent (Table 110-2).
ESTABLISHED AND EVOLVING THERAPEUTIC CONCEPTS
IN CML
In the early days of TKI development, the primary aim in CML
therapy was to improve survival, as the therapeutic miracle of
1.0
0.8
Survival probability
0.6
0.4
Total Died
TKI 2001-present
Death-CML
TKI 2001-present
Death-CML or SCT
TKI 2001-present
1996-2000
1991-1995
1983-1990
<1982
0.2
0.0
Years
A
CML Phase Referral Year    Total    Died  Median (months)
Accelerated
Accelerated
Blastic
Blastic
1.0
0.8
Survival probability
0.6
0.4
0.2
0.0
B
FIGURE 110-2  A. Survival in newly diagnosed chronic-phase chronic myeloid leukemia (CML) by era of therapy (MD Anderson Cancer Center experience from 1965 to
present). Top blue curve is survival with tyrosine kinase inhibitors (TKIs), accounting for only CML-related deaths. The orange curve (second from top) accounts for deaths
related to CML or CML treatment complications (e.g., deaths following allogeneic hematopoietic stem cell transplant [HSCT]). The red curve (third from top) is survival
including all deaths regardless of causality (old age, car accidents, suicide, gun shots, second cancers, complications of unrelated surgeries, infections, others). The
difference in the denominators, 613 minus 597 cases, is because 16 deaths were from unknown/undocumented causes (outside MD Anderson and no good tracking for cause
of death). B. Survival in patients with accelerated- and blastic-phase CML referred to MD Anderson Cancer Center by era of therapy, demonstrating the significant survival
benefit in the TKI era in accelerated-phase CML but the modest benefit in blastic-phase CML. Referred cases included de novo and post-chronic-phase transformations.
TABLE 110-2  Medical Therapeutic Options in Chronic Myeloid Leukemia
AGENT (BRAND NAME)
APPROVED INDICATIONS
DOSE SCHEDULE
NOTABLE TOXICITIES
Imatinib mesylate (Gleevec)
All phases
400 mg daily
See text
Dasatinib (Sprycel)
All phases
First-line: 100 mg daily
Salvage: 100 mg daily in chronic phase; 140 mg daily in
transformation
Nilotinib (Tasigna)
All phases except blastic
phase
First-line: 300 mg twice daily
Salvage: 400 mg twice daily
Bosutinib (Bosulif)
All phases
First line: 400 mg daily
Salvage: 500 mg daily
Ponatinib (Iclusig)
T315I mutation; failure
of ≥2 tyrosine kinase
inhibitors
45 mg daily (may consider lower starting doses, e.g.,
30 mg daily; lower the dose to 15 mg daily once a complete
cytogenetic response is achieved)
Asciminib (Scemblix)
Third-line therapy; T315I
mutation
40 mg twice daily or 80 mg daily; T315I: 200 mg twice daily
Arterial occlusive events; hypertension;
(others?)
Omacetaxine
mepesuccinate (Synribo)
Failure ≥2 tyrosine kinase
inhibitors
1.25 mg/m2 subcutaneously twice daily for 14 days of
induction; 7 days of maintenance every month (consider
shorter dose schedules, 7 days of induction, 2–5 days of
maintenance)
95%
92%
86%
67%
44%
37%
8%
CHAPTER 110
1980–2000
2001–2013
1980–2000
2001–2013
p <0.001
Chronic Myeloid Leukemia
41%
p <0.001
19%
5%
2%
p = 0.015
Years
Myelosuppression; pleural and pericardial
effusions; pulmonary hypertension
Diabetes; arterio-occlusive events; pancreatitis
Diarrhea; liver toxicity; renal dysfunction
Skin rashes (10–20%); pancreatitis (5%);
arterio-occlusive events (10–20%); systemic
hypertension (10–15%)
Myelosuppression
near-normal survival with TKI therapy was never anticipated. It
was thought that CML cells would develop resistance mechanisms
after a period of TKI exposure. This happened, as CML was the first
tumor demonstrating the development of mutations in the ABL1
kinase domain that prevented the binding of the TKIs. However, the
true resistance rate was only 10% after 10 years of imatinib expo­
sure. The TKIs were developed at a dose level below the maximum
tolerated dose (MTD; traditional development of chemotherapy
agents in cancer), based on the toxicities noted in the first one to
two courses or few months of therapy. As the success of therapy
required treatment continuation for years, or even a patient’s life­
time, additional unanticipated toxicities were observed with longterm exposures. This shifted the concept to develop these targeted
therapies in CML (and in other cancers) at an “optimal biologic
dose” (OBD; a dose that presumably maintains the same efficacy
but reduces toxicities). Such OBDs were derived initially from clini­
cal experience in CML, although ongoing trials are basing them on
translational studies of the drug exposure and target modulation,
compared with preclinical research findings. This led, in CML, to
study dasatinib 50 mg daily as frontline therapy, which proved to
be as effective and less toxic than 100 mg daily. Similar results were
reported with other TKIs where dose adjustments after achiev­
ing a good molecular response maintained efficacy. Other early
concepts included the following: (1) changing a TKI if evidence of
toxicity (rather than lowering the TKI dose, with the concern being
that lowering the TKI dose will compromise efficacy and cause
resistance); (2) changing a TKI if the National Comprehensive
Cancer Network (NCCN)/European Leukemia Network (ELN)
landmark-defined milestones of “failure” or “warning” were noted;
and (3) changing TKI therapy in a responding patient (MMR or
even MR4), in order to achieve a complete molecular response and
aim for a TFR status. As experience matured, it was noted that such
strategies may be harmful, as they increased the cost of therapy and
increased the risk of potential additional side effects, without ben­
efiting patients. At present, therapy of CML may consider lowerdose schedules of TKIs as frontline or later-line therapy; reducing
the TKI dose once a good molecular response (≥MR2) is achieved;
not changing TKI therapy in patients in good molecular response;
and perhaps not changing TKI therapy based on the NCCN/ELN
milestones (as the long-term follow-up data showed survival to be
favorable even among patients who did not achieve these molecular
milestones). These concepts will be discussed further.
PART 4
Oncology and Hematology
At the beginning of the TKI experience, survival prolongation
was the primary goal of therapy, but once near-normal survival was
accomplished, investigators started addressing additional treatment
endpoints. Thus, a second treatment goal was whether CML is cur­
able (defined, as in other cancers, as the ability to stop TKI therapy
without disease recurrence after several years of observation).
This led to studies aimed at stopping TKI therapy after 2–5 years
of durable DMR and achieving a TFR status. The third treatment
goal is to make TKI therapies available and affordable to all patients
(rather than the few who can afford them), a problem addressed
with the availability of generic TKIs. The fourth treatment goal is
to minimize the early and long-term toxicities (currently addressed
with studies investigating the OBDs of TKIs).
Frontline Therapy of CML  Imatinib, dasatinib, bosutinib, and nilo­
tinib are all acceptable frontline therapies in CML. The long-term
results of imatinib are very favorable. The 10-year cumulative rate
of MMR is 90%, and of DMR 80%. The 10-year survival rate was
82%, and 10-year relative (compared with age-matched population)
survival rate 92%. About 25% had to change to second-generation
TKIs, 10% because of resistance to imatinib and 15% for other
reasons (adverse events). The 10-year incidence of blastic-phase
CML was 5.8%. In multiple randomized studies, (e.g., ENESTnd,
DASISION, BFORE), the second-generation TKIs resulted in bet­
ter outcomes in early surrogate endpoints (higher rates of MMR
and MR4.5; lower rates of blastic transformation). However, none
showed survival benefit. This may be because the rate of complete
cytogenetic response (MR2) was ultimately similarly high with ima­
tinib versus second-generation TKIs and because later-line salvage
TKI therapy (following close observation and treatment change
at progression) provided highly effective therapy; this ensured
adequate long-term outcome despite resistance or intolerance to
initial imatinib therapy.
The choice of TKI frontline CML therapy depends on several
factors: (1) the treatment aims (survival, TFR), which are tightly
linked to age; (2) the TKI cost and affordability (generic vs patented
TKIs); and (3) the patient comorbidities (e.g., avoid dasatinib if his­
tory of lung injury or chronic lung disease; avoid nilotinib if history
of pancreatitis, diabetes mellitus, or arterio-/veno-occlusive spastic
events; avoid bosutinib if history of liver or renal dysfunction
of gastrointestinal problems [colitis, diverticulitis]). In general, if
survival is the treatment aim in CML, all four TKIs achieve similar
outcomes. However, if TFR is the treatment aim, then secondgeneration TKIs may be preferred. Second-generation TKIs may
also be preferred in high-risk chronic-phase CML. Two additional
important aims include the comparative long-term toxicities and
the TKI treatment value.
The frontline TKI dose schedules are as follows: imatinib 400 mg
orally daily; dasatinib 100 mg orally daily; bosutinib 400 mg orally
daily (use dose escalation of 100–200 mg daily for 1–2 weeks, 300 mg
daily for 2 weeks, then 400 mg daily to avoid the early self-limited
gastrointestinal toxicity [diarrhea, nausea, and vomiting]); and
nilotinib 300 mg orally twice a day (on an empty stomach). Dasat­
inib 50 mg orally daily is as effective in frontline therapy as 100 mg
daily and significantly less toxic.
A recent randomized trial compared asciminib to investigator’s
TKI of choice in frontline CML therapy. The 12-month MMR was
significantly higher with asciminib versus other TKIs (68% vs 49%;
p<.001) and with asciminib versus imatinib (69% vs 40%); p<.001),
but not with asciminib versus second-generation TKIs (66% vs
58%). Whether the higher MMR rate will translate into better longterm survival or TFR rates, lower long-term side-effects, or better
treatment value is an open question.
Management of TKI Toxicities  In the first 10–15 years of the
TKI experience, it was common practice to change TKI therapy
when toxicities occurred because of the erroneous assumption that
reducing the TKI dose may reduce efficacy. This was not borne
out in the long-term experience, particularly in patients who are in
good molecular response. Among such patients, the TKI dose can
be reduced for mild-moderate or even severe reversible toxicities.
Imatinib can be reduced to 100–300 mg daily, dasatinib to 20–50
mg daily, nilotinib to 200 mg daily or 150 mg twice daily, bosutinib
to 100–300 mg daily, and ponatinib to 15–30 mg daily, depending
on the toxicities and molecular response.
Side effects of TKIs are generally mild to moderate, although
with long-term TKI therapy, they could affect the patient’s quality
of life. Serious side effects occur in <5–10% of patients. With ima­
tinib therapy, common mild to moderate side effects include fluid
retention, weight gain, nausea, diarrhea, skin rashes, periorbital
edema, bone or muscle aches, fatigue, and others (rates of 10–20%).
In general, second-generation TKIs are associated with lower rates
of these bothersome adverse events. However, dasatinib 100 mg
daily is associated with higher rates of myelosuppression (20–30%),
particularly thrombocytopenia; pleural (10–25%) or pericardial
effusions (≤5%); and pulmonary hypertension (<5%). A lower dose
of dasatinib (50 mg daily instead of 100 mg daily) used in frontline
CML therapy resulted in similar efficacy and a lower incidence
of serious side effects (pleural effusions <5%, myelosuppression
<10%). Nilotinib is associated with higher rates of hyperglycemia
(10–20%), pruritus and skin rashes, hyperbilirubinemia (typically
among patients with Gilbert’s syndrome and mostly of no clinical
consequences), and headaches. Nilotinib is also associated with
occasional instances of pancreatitis (<5%). Nilotinib 300–400 mg
twice daily is associated with a 10-year cumulative incidence of
cardiovascular complications of 25–35%. Bosutinib is associated
with higher rates of liver toxicity, renal dysfunction, and early
and self-limited gastrointestinal adverse events, particularly diar­
rhea. Occasionally, the gastrointestinal symptoms mimic chronic
severe enterocolitis, which reverses with treatment discontinuation.
Ponatinib 45 mg daily is associated with higher rates of serious
skin rashes (10–15%), pancreatitis (10%), elevations of amylase/
lipase (10%), and systemic hypertension (50–60%; severe in 20%).
Arterio-occlusive events (cardiovascular, cerebrovascular, and
peripheral arterial) have been reported with most TKIs. The inci­
dence appears to be highest with ponatinib, but both nilotinib
and dasatinib are associated with these events at an incidence
significantly higher than imatinib or bosutinib. Among the TKIs,
imatinib and bosutinib are associated with the lowest incidence of
cardiovascular events.
With long-term follow-up, rare but clinically relevant serious
toxicities are emerging. Renal dysfunction and occasionally renal
failure (creatinine elevations >2–3 mg/dL) are observed in 2–3% of
patients, more frequently with imatinib and bosutinib than other
TKIs, and usually reverse with TKI discontinuation and/or dose
reduction. Rarely, patients may develop TKI-related peripheral
neuropathy or even central neurotoxicities that are misdiagnosed
as dementia or Alzheimer’s disease; these may reverse slowly after
TKI discontinuation.
Some toxicities are prohibitive and require a change of TKI
therapy: recurrent pleural effusions (most commonly with dasat­
inib; least with imatinib and nilotinib; responsive to a short course
of steroids); vasospastic or vaso-occlusive events (cerebrovascular
accidents, myocardial infarction or unstable angina; more common
with ponatinib and nilotinib; least with imatinib and bosutinib);
pulmonary hypertension (1–2% with dasatinib, but can occur
with other TKIs; slowly reversible with a short course of steroids
and sildenafil citrate), pancreatitis (2% with nilotinib, 2–4% with
ponatinib); neurologic problems (dementia-like, parkinsonism;
rare and slowly reversible with TKI discontinuation); immunemediated events (pneumonitis, myocarditis, pericarditis, hepatitis,
nephritis; usually reversible with TKI discontinuation and a short
course of high-dose steroids [e.g., methylprednisolone 50 mg twice
daily for 3–5 days]); and severe colitis (bosutinib; reversible with
discontinuation).
When switching TKI therapy for prohibitive toxicity, the dose of
the new TKI does not have to be the dose recommended for “failure”
(a term that historically encompassed resistance and intolerance).
Many of these patients are already in good molecular response, and
the dose of the new TKI used for previous TKI intolerance can be
lower, particularly if the patient is already in ≥MR2: dasatinib
20–50 mg daily; bosutinib 100–300 mg daily; nilotinib 200 mg daily
or 150 mg twice a day; ponatinib 15–30 mg daily.
TKI cross-intolerance may be more common than previously
thought. Because the TKIs have different chemical structures,
cross-intolerance was thought to be uncommon. With experience,
it appears that patients who have intolerance to one TKI may more
often have intolerance to others, with the intolerance/side effect
manifesting as the same or as a different one.
Discontinuation of TKIs and TFR  Several studies have confirmed
that TKI discontinuation among patients who achieve DMR (MR4)
for longer than 2–3 years can result in TFR rates of 40–60%. Discon­
tinuation of TKI therapy after 5+ years of DMR is associated with
TFR rates of 80%+. Since the incidence of durable MR4 is 60–80%,
~30–60% of all patients with CML on TKI therapy may potentially
achieve TFR with optimization of the current TKI strategies. Sug­
gested conditions to attempt TFR include low or intermediate Sokal
risk CML in first chronic phase (no evidence or history of transfor­
mation); quantifiable BCR::ABL1 transcripts (e13a2, e14a2); longterm TKI therapy (5+ years); and documented DMR for >2–5 years.
Once TFR is attempted, patients should be monitored molecularly
every 1.5–2 months in the first 6–12 months, every 2–3 months in
the second year, and then every 3–6 months in subsequent years
(perhaps for up to 6–8 years of TFR status). TKIs should not be
restarted unless the BCR::ABL1 transcripts (IS) increase to >0.1%
(documented at least twice).
Management of TKI Resistance  Resistance to a TKI refers today
to BCR::ABL1 transcripts (IS) >10% after 6 months of TKI frontline
therapy or BCR::ABL1 transcripts (IS) >1% after 12+ months of
frontline TKI therapy. The NCCN and ELN updates of the criteria
for resistance and suboptimal response have evolved over time,
settling on more conservative criteria to change TKI therapy. The
long-term follow-up studies have shown that patients who previ­
ously met suboptimal or resistance criteria still had excellent longterm survival without changing TKI therapy. For example, older
patients with persistent BCR::ABL1 transcripts (IS) 1–10% at 2 years
of imatinib therapy still had 10-year survival rates similar to those
with transcripts <1%.
Before switching TKI therapy for resistance, it is important
to check for BCR::ABL1 kinase domain mutations. About 50%
of patients with TKI resistance have BCR::ABL1 mutations that
may selectively respond to particular TKIs. For example, muta­
tions involving Y253H, E255K/V, and F359V/C/I respond better
to dasatinib or bosutinib. Mutations involving V299L, T315A, and
F317L/F/I/C respond better to nilotinib. T315I mutations require
therapy with ponatinib or asciminib and serious consideration of
allogeneic HSCT.
CHAPTER 110
Dasatinib, bosutinib, nilotinib, ponatinib, and asciminib are
approved for CML salvage therapy. The second-generation TKIs are
excellent second-line therapies after imatinib frontline resistance.
In patients with resistance to one second-generation TKI, switch­
ing to another second-generation TKI yields poor results (MR2
rate 10–20%; unless specific guiding mutations), and switching to
ponatinib is indicated. Ponatinib is a very potent TKI with high
activity in T315I-mutated CML and in CML after two TKI expo­
sures (particularly if there is resistance to a second-generation TKI).
In third-line therapy, ponatinib produces high molecular response
rates and improves survival compared with second-generation
TKIs. Asciminib is approved as third-line therapy and for T315Imutated disease.
Chronic Myeloid Leukemia
The TKI dose schedule in later-line therapy for CML resistance
is as follows: dasatinib 100 mg daily; nilotinib 400 mg twice daily;
bosutinib 500 mg daily; ponatinib 45 mg daily; and asciminib 40 mg
twice daily or 80 mg once daily or 200 mg twice daily in T315Imutated CML. Because ponatinib 45 mg daily may be associated
with serious side effects, a response-directed dose-adjusted regi­
men (starting dose of 45 mg and reduction to 15 mg once MR2 is
achieved) was investigated and resulted in a lower incidence of
arterio-occlusive events.
TKI later-line therapy in chronic-phase CML with dasatinib,
nilotinib, bosutinib, ponatinib, or asciminib is associated with
MR2 rates of 30–80%, depending on the line of therapy (second vs
later), CML status (cytogenetic/molecular relapse vs hematologic
relapse), prior response to other TKIs, number of prior TKIs used,
and the mutations at the time of relapse. The estimated 6- to 8-year
survival rates with second-generation TKIs as second-line therapy
are 65–75% (compared with <30–40% before their availability).
Ponatinib third-line therapy resulted in an MR2 rate of 50–60%,
MMR rate of 40%, and a 5-year overall survival rate of 70–75%. Its
results appear even surprisingly better in real-word data: MR2 rate
80%, MMR rate 70–75%, and MR4 rate 40%.
ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANT
Allogeneic HSCT, a curative modality in CML, is associated with
long-term survival rates of 50–70% when implemented in chronic
phase. It carries the risk of complications related to myelosuppres­
sion, infections, and graft-versus-host disease (GVHD). Conse­
quently, the early (1-year) mortality rate is 5–30%, and 10–15% of
patients die in the subsequent 1–2 decades from long-term com­
plications of the transplant (rather than from CML relapse). These
are related to GVHD, organ dysfunction, development of second
cancers, occasional late relapses, and hazard ratios for mortality
higher than in the normal population. Other significant morbidi­
ties include infertility, chronic immune-mediated complications,
cataracts, hip necrosis, and other morbidities affecting quality of
life. The cure and early mortality rates in chronic-phase CML are
also associated with several factors: patient age, duration of chronic
phase, whether the donor is related or unrelated, degree of match­
ing, preparative regimen, and others. In accelerated-phase CML,
the cure rates with allogeneic HSCT are 30–50%, depending on
the definition of accelerated disease. Patients with clonal evolution
as the only criterion have cure rates of 40–50%. Patients undergo­
ing allogeneic HSCT in second chronic phase have cure rates of
40–50%. The cure rates with allogeneic HSCT in blastic-phase CML
are ≤20%. Post–allogeneic HSCT strategies in the setting of molecu­
lar or cytogenetic relapse include the use of TKIs for prevention
or treatment of relapse, donor lymphocyte infusions, and second
allogeneic HSCTs, among others. TKIs are successful at reinducing
cytogenetic/molecular remissions in the setting of cytogenetic or
molecular relapse after allogeneic HSCT.
Choice and Timing of Allogeneic HSCT  Allogeneic HSCT was
considered first-line CML therapy before 2000. The positive experi­
ence with TKIs has now relegated its use as a later-line approach.
It should be considered in any patient in chronic-phase CML
who develops resistance to a second-generation TKI or with a
T315I-mutated disease. Relying on third-generation TKIs in these
settings as long-term therapy can be very expensive ($250,000 to
$1.5 million per year) and may be associated with serious toxici­
ties. Among patients who present with or evolve to blastic phase,
combinations of chemotherapy and TKIs should be used to induce
remission, followed by allogeneic HSCT as soon as possible. The
same applies to patients who evolve from chronic to accelerated
phase. Patients with de novo accelerated-phase CML may do well
with long-term TKI therapy (estimated 8-year survival rate 75%).
Older patients with CML (age 65–70 years or older) have a reason­
able CML-specific 10-year overall survival rate even with persistent
molecular disease after 2 years of TKI therapy, with BCR::ABL1
transcripts (IS) 1–10%, or even > 10%. Such patients may opt to
continue on daily TKI therapy alone or with the addition of other
agents (hydroxyurea, decitabine, low-dose cytarabine). They can
then remain in chronic-phase CML disease without MR2 and
avoid the adverse events and poorer quality of life associated with
allogeneic HSCT.
MONITORING THERAPY IN CML
Achievement of complete cytogenetic response by 12 months of
imatinib therapy and its persistence later, the only consistent prog­
nostic factor associated with prolonged survival, is now the main
therapeutic endpoint in CML. Failure to achieve a complete cyto­
genetic response by 12 months or occurrence of later cytogenetic
or hematologic relapse is considered as treatment failure and
an indication to change therapy. Because later-line TKI therapy
may re-establish good outcome, it is important to ensure patient
compliance to continued TKI therapy and change therapy when
cytogenetic relapse is confirmed unless this is related to nonad­
herence. Patients on frontline imatinib therapy should be closely
monitored until documentation of complete cytogenetic response,
at which time they can be monitored every 6 months with periph­
eral blood PCR or more frequently (e.g., every 3 months) if there
are concerns about changes in BCR::ABL1 transcripts. Cytogenetic
relapse on imatinib is an indication of treatment failure and need
to change TKI therapy. Mutational analysis in this instance helps in
the selection of the next TKI and identifies mutations in 30–50% of
patients. Mutational studies by standard Sanger sequencing (which
is the technique currently available in most clinical laboratories) in
patients in complete cytogenetic response (in whom there may be
PART 4
Oncology and Hematology
concerns of increasing BCR::ABL1 transcripts) identify mutations
in ≤5% and are therefore not indicated.
Changes of TKI therapy for patients with “slow” molecular
response have not been proven to be of long-term benefit compared
to changes when more obvious signs of resistance appear.
TREATMENT OF ACCELERATED AND BLASTIC PHASES
Patients in accelerated or blastic phase may receive therapy with
TKIs, preferably second- or third-generation TKIs (dasatinib, nilo­
tinib, bosutinib, ponatinib), alone or in combination with chemo­
therapy, to reduce the CML burden, before undergoing allogeneic
HSCT. Response rates (major hematologic) with single-agent TKIs
range from 30 to 50% in accelerated phase and from 20 to 30% in
blastic phase. Cytogenetic responses, particularly complete cytoge­
netic responses, are uncommon (10–30%) and transient in blastic
phase. Studies of TKIs in combination with chemotherapy show
that combined TKI-chemotherapy strategies increase the response
rates and their durability and improve survival. This is particularly
true in CML lymphoid blastic phase, where the combination of
anti-ALL chemotherapy with TKIs results in complete response
rates of 70% and median survival times of 3 years (compared with
historical response rates of 40–50% and median survival times of
12–18 months). This allows many patients to undergo allogeneic
HSCT in a state of minimal CML burden or second chronic phase,
which are associated with higher probability of long-term survival.
In CML nonlymphoid blastic phase, anti–acute myeloid leukemia
chemotherapy combined with TKIs results in complete remission
rates of 30–50% and median survival times of 12 months (compared
with historical response rates of 20–30% and median survival times
of 3–5 months). In accelerated phase, response to single TKIs is
significant in conditions where “softer” accelerated phase criteria
are considered (e.g., clonal evolution alone, thrombocytosis alone,
significant splenomegaly or resistance to hydroxyurea, but without
evidence of high blast and basophil percentages). In accelerated
phase, combinations frequently include TKIs with low-intensity
chemotherapy such as low-dose cytarabine, decitabine, interferon
α, hydroxyurea, or others.
OTHER TREATMENTS AND SPECIAL THERAPEUTIC
CONSIDERATIONS
Interferon `  Interferon α is considered in combination with TKIs
(an investigational approach) and occasionally in patients during
pregnancy.
Chemotherapeutic Agents  Hydroxyurea remains a safe and effec­
tive agent (at daily doses of 0.5–10 g) to reduce initial CML burden,
as a temporary measure in between definitive therapies, or in com­
bination with TKIs to sustain complete hematologic or cytogenetic
responses. Busulfan is often used in allogeneic HSCT preparative
regimens. Because of its side effects (delayed myelosuppression,
Addison-like disease, pulmonary and cardiac fibrosis, myelofi­
brosis), it is now rarely used in the chronic management of CML.
Omacetaxine, low-dose cytarabine, decitabine, 6-mercaptopurine,
6-thioguanine, thiotepa, anagrelide, and other agents are sometimes
useful in different CML settings to control the disease burden, usu­
ally in combination with a daily TKI.
Others  Leukapheresis is occasionally used in patients presenting
with extreme leukocytosis and leukostatic complications. Single
doses of high-dose cytarabine or high doses of hydroxyurea, with
tumor lysis management, may be as effective and less cumbersome.
Pregnancy and CML  TKI therapy in the first trimester of preg­
nancy is associated with fetal malformations (2–10%). Women
with CML who become pregnant should discontinue TKI therapy
immediately. Among 125 babies delivered to women with CML
who discontinued imatinib therapy as soon as the pregnancy was
known, three babies were born with neurologic, skeletal, and renal
malformations, suggesting the teratogenicity of imatinib known
from animal studies. A similar experience has been reported with
dasatinib, where the incidence of malformations was reported to
be higher, 10–12%. Data are scant with other TKIs. Control of
CML during pregnancy can be managed with leukapheresis for
severe symptomatic leukocytosis in the first trimester and with
hydroxyurea subsequently until delivery. TKI therapy with ima­
tinib (but not dasatinib; scant data with nilotinib or bosutinib), if
indicated, may be safe after 20 weeks of gestation and in the third
trimester. There are reports of successful pregnancies and deliveries
of normal babies with interferon α therapy and registry studies in
essential thrombocytosis, but interferon α has side effects that may
be troublesome during pregnancy, can be antiangiogenic, and may
increase the risk of spontaneous abortions.
Cytogenetic Abnormalities in Ph-Negative Cells; Mutations and
CML  Approximately 5% of patients on TKI therapy and in
cytogenetic/molecular response may develop chromosomal
abnormalities in the Ph-negative cells. These may involve loss of
chromosome Y, trisomy 8, 20q–, chromosome 5 or 7 abnormalities,
and others. Most chromosomal abnormalities disappear spon­
taneously and may be indicative of the genetic instability of the
hematopoietic stem cells that predisposes the patient to develop
CML in the first place. Rarely (in <1% of instances), abnormalities
involving chromosomes 5 or 7 may be truly clonal and evolve into
myelodysplastic syndrome, acute myeloid leukemia, or myelo­
proliferative neoplasms. This is thought to be part of the natural
course of patients in whom CML was suppressed and who live long
enough to develop other hematologic malignancies. The presence
of mutations (ASXL1, DNMT3A, RUNX1, TET2, EZH2, IDH1/2) at
diagnosis or later during CML was discussed earlier.
■
■GLOBAL ASPECTS OF CML
Routine physical examinations and blood tests in the United States and
advanced countries result in early detection of CML in most patients.
About 50–70% of patients with CML are diagnosed incidentally,
and high-risk CML as defined by prognostic models (e.g., Sokal risk
groups) is found in only 10% of patients. This is different in emerging
nations where most patients are diagnosed following evaluation for
symptoms and many present with high tumor burden, such as massive
splenomegaly, and advanced phases of CML (high-risk CML docu­
mented in 20–30%). Therefore, the prognosis of such patients on TKI
therapy may be worse than the published experience.
The high cost of TKI therapies (annual costs of $120,000–270,000
in the United States; lower but variable in the rest of the world) makes
the general affordability of such treatments difficult. Fortunately, in
2024, some imatinib generic formulations cost about $500/year in the
United States and worldwide. Generic dasatinib is also available in
many geographies, and generic formulations of bosutinib, nilotinib,
and ponatinib may become available by 2027. Therefore, in frontline
CML therapy, if survival is the treatment endpoint, generic imatinib is
a good choice. If TFR is the endpoint, generic dasatinib (50 or 100 mg
daily) is a good choice. Although TKI treatment penetration is high in
nations with universal health care and where cost of therapy is not an
issue (e.g., Europe, Canada, Australia, United Kingdom), it may be less
so in other nations, even in advanced ones like the United States, where
out-of-pocket expenses may be prohibitive to a subset of patients. The
estimated 10-year survival rate in CML is >85% in single-institution or
national studies in countries with TKI affordability (Sweden) (Figs. 110-2
and 110-3), whereas the estimated 10-year survival rate worldwide is
likely to be <50%. The Surveillance, Epidemiology, and End Results
(SEER) data from the United States report an estimated 5-year survival
rate of 70% in the era of TKIs. It appears that the treatment penetra­
tion of imatinib and other TKIs into CML therapy worldwide is still
not optimal.
The current high cost of TKI therapies, particularly in later-line
therapy, encouraged considering allogeneic HSCT as third-line therapy
(one-time cost of $20,000–500,000) despite the associated mortality
and morbidities. Safe and effective generic TKIs should be preferred
frontline and second-line therapies in CML, precluding the necessity
1.0
0.8
0.6
Overall survival
0.4
0.2
Chronic phase
Accelerated phase
Blast crisis
0.0
Years after diagnosis
No. at risk
CP
AP
BC
CHAPTER 110
FIGURE 110-3  Survival in chronic (CP), accelerated (AP), and blastic phase (BP)
phases of chronic myeloid leukemia (CML) in the population-based Swedish
national registry study. The accelerated- and blastic-phase cases are de novo
presentations. The favorable outcome with de novo blastic phase may be due to use
of 20% blasts or more to define blastic phase. (From Dr. Martin Hoglund, Swedish
CML Registry, 2013.)
Chronic Myeloid Leukemia
of an allogeneic HSCT until evidence of resistance to generic secondgeneration TKIs.
■
■FURTHER READING
Cortes JE et al: Bosutinib versus imatinib for newly diagnosed chronic
myeloid leukemia: Results from the randomized BFORE Trial. J Clin
Oncol 36:231, 2018.
Cortes JE et al: Ponatinib efficacy and safety in Philadelphia
chromosome-positive leukemia: Final 5-year results of the phase 2
PACE trial. Blood 132:393, 2018.
Gener-Ricos G et al: Low-dose dasatinib (50 mg daily) frontline
therapy in newly diagnosed chronic phase chronic myeloid leukemia:
5-year follow-up results. Clin Lymphoma Myeloma Leuk 23:742,
2023.
Haddad FG, Kantarjian H: Navigating the management of chronic
phase CML in the era of generic BCR::ABL1 tyrosine kinase inhibi­
tors. J Natl Compr Canc Netw 22:e237116, 2024.
Hochhaus A et al: Asciminib in newly diagnosed chronic myeloid
leukemia. N Engl J Med 391:885, 2024.
Kantarjian H et al: Long-term outcomes with frontline nilotinib ver­
sus imatinib in newly diagnosed chronic myeloid leukemia in chronic
phase: ENESTnd 10-year analysis. Leukemia 35:440, 2021.
Kantarjian HM et al: Revising six established practices in the treat­
ment of chronic myeloid leukaemia. Lancet Haematol 10:e860, 2023.
Kantarjian HM: What is the impact of failing to achieve TKI therapy
milestones in chronic myeloid leukemia. Leukemia 37:2324, 2023.
Mahon FX et al: European Stop Tyrosine Kinase Inhibitor Trial
(EURO-SKI) in chronic myeloid leukemia: Final analysis and novel
prognostic factors for treatment-free remission. J Clin Oncol 42:1875,
2024.
Senapati J et al: Management of chronic myeloid leukemia in 2023:
Common ground and common sense. Blood Cancer J 13:58, 2023.
Shih YT et al: Treatment value of second-generation BCR-ABL1 tyro­
sine kinase inhibitors compared with imatinib to achieve treatment-free
remission in patients with chronic myeloid leukaemia: A modelling
study. Lancet Haematol 6:e398, 2019.

41 - 111 Acute Lymphoid Leukemia
111 Acute Lymphoid Leukemia
Dieter Hoelzer
Acute Lymphoid
Leukemia
In acute lymphoblastic leukemia (ALL), the malignant clone arises
from hematopoietic progenitors in the bone marrow or lymphatic
system resulting in an increase of immature nonfunctioning leukemic
cells. Infiltration of bone marrow leads to anemia, granulocytopenia,
and thrombocytopenia with the clinical manifestations of fatigue,
weakness, infection, and hemorrhage. These symptoms are more often
the reason a patient first seeks medical advice rather than consequences
of tumor bulk, such as lymph node enlargement, hepatosplenomegaly
caused by leukemic infiltration, or symptoms of the central nervous
system (meningeosis leukemica).
■
■INCIDENCE AND AGE
ALL is the most frequent neoplastic disease in children with an early
peak at the age of 3–4 years. The incidence in adults ranges from 0.7 to
1.8/100,000 per year, being somewhat higher in adolescents and young
adults (AYAs), decreasing in adults but increasing again in elderly peo­
ple. Thus, Philadelphia chromosome–positive ALL (Ph+ ALL; BCR/
ABL translocation) is observed in half of the elderly B-lineage patients.
The frequency of immunologic, cytogenetic, and genetic subtypes
changes substantially with age.
PART 4
Oncology and Hematology
■
■ETIOLOGY
The etiology of acute leukemias is unknown. Internal and external
factors influence the incidence of leukemia. Exposure to ionizing
radiation or to chemicals, including prior chemotherapy, is associated
with an increased risk of developing leukemia, more often observed
in acute myeloid leukemia (AML). However, increasingly, second­
ary ALLs have been observed, particularly after cytostatic treatment
with alkylating agents and topoisomerase inhibitors as treatment for
primary tumors, most often for AML, myelodysplastic syndromes, or
breast cancer.
■
■CONGENITAL DISORDERS
Patients with some rare congenital chromosomal abnormalities have a
higher risk of developing acute leukemia (e.g., Klinefelter’s syndrome,
Fanconi’s anemia, Bloom’s syndrome, ataxia-telangiectasia, and neuro­
fibromatosis). Those with Down’s syndrome have a 20-fold increased
incidence of leukemia; ALL is increased in childhood and AML at an
older age.
■
■INFECTIOUS AGENTS
No direct evidence implicates viruses as a major cause of human
acute leukemia. However, viruses are involved in the pathogenesis
of two lymphoid neoplasias. In the endemic African type of Burkitt’s
lymphoma, the Epstein-Barr virus, a DNA virus of the herpes family,
has been implicated as a potential causative agent (see Chap. 199).
Endemic infection with human T-cell leukemia virus I in Japan and
the Caribbean has been shown to be an etiologic agent for rare cases of
adult T-cell leukemia/lymphoma (see Chap. 207).
■
■DIAGNOSIS AND CLASSIFICATION
The diagnosis of acute leukemia is first made by examination of the
peripheral blood and bone marrow. For further classification of the
leukemic blast cells, cytochemical stains, immunologic markers, and
cytogenetic and molecular analysis are required. The immunologic
markers are still the major criteria to subdivide into B-cell lineage or
T-cell lineage ALL leukemias.
■
■PERIPHERAL BLOOD
Peripheral blood counts and a differential count from a WrightGiemsa–stained blood smear are essential at the time of presentation.
TABLE 111-1  Laboratory Values at Diagnosis of Acute Lymphoblastic
Leukemia (ALL)
ALL
NO.
Initial white blood cell count (× 109/L)
<10
10–50
50–100
100
41%
31%
28%
16%
Neutrophils (× 109/L)
<50–100
<100,000
12%
16%
Platelets (× 109/L)
<20
21–40
41–100
100
22%
22%
29%
27%
Hemoglobin (g/dL)
<7
7–9
9
20%
33%
47%
Leukemic blasts in peripheral blood
0%
25–75%
75%
8%
34%
36%
Leukemic blasts in bone marrow
<50%
51–90%
90%
4%
25%
71%
Source: Data from three consecutive German Multicenter Trials for Adult ALL
(GMALL).
The white blood cell (WBC) count in ~40% of ALL patients is reduced
or normal (Table 111-1). Only 16% of patients have a WBC above
100 × 105/L. It is noteworthy that in 8% of ALL patients, no circulating
leukemic blast cells were observed. Thus, in the frequently used auto­
matic blood cell counting, the diagnosis may not be detected.
Peripheral blood characteristically shows anemia, thrombocytope­
nia, and neutropenia. Nearly one-third of patients have hemoglobin
levels <7–8 g/dL. A platelet count below the critical number of 20 ×
109/L, associated with the risk of bleeding, and neutropenia (neutro­
phils <0.5 × 109/L), associated with a higher risk of infection, are each
noted in one-fifth of adults with ALL.
■
■BONE MARROW EXAMINATION
Bone marrow aspirates/biopsies are important to assess immunologic,
cytogenetic, and genetic markers. A biopsy of the bone marrow is
essential to confirm the diagnosis of acute leukemia and to distinguish
between AML and ALL. The bone marrow is usually heavily packed
with leukemic blast cells with >90% in ~70% of patients, and thus, the
normal hemopoietic elements are greatly reduced or absent.
■
■LUMBAR PUNCTURE
The examination of the cerebrospinal fluid is an essential routine
diagnostic measure for ALL. Central nervous system (CNS) leukemia
is diagnosed if ≥5 cells/μL or leukemic blast cells were observed by
morphology in cerebrospinal fluid. Opinions differ as to when the first
lumbar puncture should be done—i.e., either delay lumbar puncture
until remission is achieved to avoid seeding of the CNS with leukemic
blast cells from the peripheral blood during the spinal tap or perform
the lumbar puncture before treatment starts, since early recognition
of CNS disease will lead to immediate CNS-specific therapy. Lumbar
puncture is restricted to patients with an adequate platelet count (>20 ×
109/L) and without manifest clinical hemorrhages. To eliminate poten­
tially transferred blast cells, patients should receive intrathecal metho­
trexate at the first lumbar puncture.
■
■MORPHOLOGIC SUBTYPES IN ALL
The French-American-British (FAB) classification distinguished three
subgroups. L1 and L2 morphology has no clinical consequences. Only
the L3 morphology, observed in up to 5% of adult patients, is indicative
for mature B-cell lineage ALL (B-ALL) (see Chap. 65).
■
■IMMUNOLOGIC SUBTYPES
A series of monoclonal antibodies is employed to identify antigens
expressed on the surface of leukemic cells, corresponding to the path­
ways of normal B-cell differentiation (see Fig. 113-2). The immuno­
logic classification aims to subdivide ALLs according to the presence
or absence of B-cell or T-cell markers. A marker is considered positive
if >20% of the cells are stained with the monoclonal antibody.
There are different immunologic classifications, such as that of the
European Group for the Immunological Characterization of Leuke­
mias (EGIL), with clear therapeutic implications. Table 111-2 gives
a simplified correlation of immunologic subtypes, cytogenetics and
molecular aberrations, and clinical characteristics.
B-Cell Lineage ALL (B-ALL) 
More than 70% of adult ALLs are
of B-cell origin, and the most frequent immunologic subtype, common
ALL, is characterized by the presence of the ALL antigen CD10 with­
out markers of relatively mature B cells such as cytoplasmic or surface
membrane immunoglobulins. Pre-B-ALL (early B-ALL) is charac­
terized by the expression of cytoplasmic immunoglobulin, which is
negative in common ALL, but otherwise is identical with respect to all
other cell markers. Pro-B-ALL corresponds to early B-cell differentia­
tion and was formerly termed non-T-, non-B-ALL or null ALL because
neither T-cell nor B-cell features could be demonstrated. This subtype
is HLA-DR, terminal deoxynucleotidyl transferase, and CD19 positive
and composes ~12% of adults ALL.
Mature B-ALL is seen in 3–4% of adults and is also known as
Burkitt’s leukemia. In mature B-ALL, blast cells express surface anti­
gens of mature B cells, including the sIgM.
T-Cell Lineage ALL (T-ALL) 
Approximately 25% of adult ALLs
are of T-cell lineage. All cases express the T-cell antigen CD7 and cyto­
plasmatic CD3 (CyCD3) or surface CD3. According to their stage of
TABLE 111-2  Immunologic, Cytogenetic, Molecular, and Clinical Characteristics of Adult Acute Lymphoblastic Leukemia (ALL)
FREQUENT
CYTOGENETIC
ABERRATIONS
SUBTYPES
MARKER
INCIDENCE
B-lineage ALL
(B-ALL)
HLA-DR+, TdT+, CD19+,
and/or CD79a+, and/or
cyCD22+
76%
Pro B-ALL
No additional
differentiation markers
Frequent myeloid
coexpression (>50%)
CD10–
112%
t(4;11)
(q21;q23)
Common ALL
CD10+
49%
t(9;22)(q34;q11)
del(6q)
Pre-B-ALL
CD10±, cyIg+
12%
t(9;22)(q34;q11)
t(1;19)(q23;p13)
Mature B-ALL
TdT–, CD34–, sIg+
4%
t(8;14)(q24;q32)
t(2;8)(p12;q24)
t(8;22)(q24;q11)
TdT±, cyCD3, CD7+
24%
t(10;14)(q24;q11)
t(11;14)(p13;q11)
T-lineage ALL
(T-ALL)
Early Pro/Pre
T-ALL
Cortical T-ALL
No additional
differentiation markers,
mostly CD2–/(+), SCD3–,
CD1a–
CD1a+, sCD3±
sCD3+, CD1a–
6%
12%
Mature T-ALL
6%
Abbreviations: BM, bone marrow; CNS, central nervous system; WBC, white blood cells.
T-cell differentiation, they may express other T-cell antigens (e.g., the
E-rosette receptor CD2 and/or the cortical thymocyte antigen CD1a).
Early pro/pre-T-ALL (also termed early T precursor ALL [ETP-ALL]),
cortical or thymic T-ALL, and mature T-ALL can be distinguished with
these markers. ETP-ALL is characterized by lack of CD1a and CD8,
weak CD5 expression, and at least one myeloid/stem cell marker.
Biphenotypic or Mixed Leukemias 
Biphenotypic leukemias are
defined as those expressing markers of both lymphoid and myeloid
lineages on the same leukemic cells. Bilineage leukemias are those with
two populations of blast cells with either lymphoid or myeloid antigens.
It is not clear whether these patients should receive an ALL or AML
treatment protocol. In pediatric studies, starting with a pediatric ALL
protocol seemed preferable, which was then followed by AML consoli­
dation elements.
■
■CYTOGENETIC AND MOLECULAR ANALYSIS
Cytogenetic and molecular analyses should be performed in all cases.
They are important to define ALL subtypes, can identify independent
prognostic markers of disease-free survival, and may determine spe­
cific targeted therapies.
The diagnostic techniques for ALL are standard cytogenetics, fluo­
rescence in situ hybridization, and reverse transcriptase polymerase
chain reaction. These methods allow the detection of Ph+ ALL, with
the chromosomal translocation t(9;22)(q34;q11) and the detection
of the corresponding BCR-ABL1 gene rearrangement. Further ALL
entities that have been identified are t(4;11)(q21;q23)/MLL-AFA4,
abn11q23/MLL, and t(1;19)(q23;p13)/PBX-E2A.
CHAPTER 111
Gene expression profiling, single nucleotide polymorphism array
analysis, array-comparative genomic hybridization, and next-generation
sequencing recognize the newly defined ALL entities: ETP-ALL and
Ph-like ALL.
Acute Lymphoid Leukemia
GENETIC
ABERRATIONS
AND FUSION
TRANSCRIPTS
CLINICAL CHARACTERISTICS
RELAPSE KINETICS AND
LOCALIZATION
70% ALL1-AF4 (20%
Flt3 in MLL+)
High WBC (>100,000/μL) (26%)
Mainly BM (>90%)
33% BCR::ABL1 with
54% IKFZ1 del
25% CDKN2A/B
Higher age >50 years (24%)
Mainly BM (>90%)
Prolonged relapse
kinetics (up to 5–7 years)
4% t(1;19)/PBX-E2A
Higher age >55 years (27%)
Frequent organ involvement
(32%) and CNS involvement
(13%)
Frequent CNS (10%)
Short relapse kinetics
(up to 1–1.5 years)
50% NOTCH1B
33% HOX11b
5% HOX11L2b
4% NUP213-ABL1
Younger age (90% <50 years)
Frequent mediastinal tumors
(60%)
Frequent CNS involvement (8%)
High WBC (>50/μL) (46%)
Frequent CNS (up to
10%)
Extramedullary (6%)
Intermediate relapse
kinetics (up to 3–4 years)
When relapsed, fast
progression
TABLE 111-3  Response Parameters According to Minimal Residual
Disease (MRD)
TERMINOLOGY
DEFINITION
Complete hematologic
remission (CHR)
Leukemic cells not detectable by light
microscopy (<5% blast cells in bone marrow
[BM])
Complete molecular
remission/MRD negativity
Patient in complete remission, MRD not
detectable, ≤0.01% = ≤1 leukemia cell in 10,000
BM cells
Molecular failure/MRD
positivity
Patient in complete hematologic remission, but
not in molecular complete remission >0.01%
Molecular relapse/MRD
positivity
Patient still in complete remission, had prior
molecular complete remission, leukemic blast
cells in BM not detectable (<5%)
Hematologic relapse
5% blast cells in BM/blood
Ph-like ALL, also known as BCR-ABL1-like ALL, is characterized
by genetic lesions similar to Ph+ ALL, associated with IKZF1 (Ikaros)
gene deletion, CLRF2 (gene for cytokine-like receptor-2) overexpres­
sion, and tyrosine kinase activating rearrangements involving ABL1,
JAK2, PDGFRB, and several other genes; however, it is BCR-ABL1
negative. The frequency is 10% in children and 25–30% in young
adults but does not increase further with age like Ph+ ALL. Treatment
based on the underlying genetic lesion with BCR-ABL inhibitors (e.g.,
dasatinib) or JAK2 inhibitors (e.g., ruxolitinib) has so far had limited
success in adults.
PART 4
Oncology and Hematology
■
■MINIMAL RESIDUAL DISEASE
Minimal residual disease (MRD) is the detection of residual leuke­
mic cells that are not recognizable by light microscopy. Methods for
determining MRD are based on the detection of leukemia-specific
aberrant immunophenotypes by flow cytometry, the evaluation of
leukemia-specific rearranged immunoglobulin or T-cell receptor
sequences by real-time quantitative polymerase chain reaction, or the
Frequent Chemotherapy Regimens in Adult ALL
BFM-like Regimen
Pre     Induction
Consolidation
Re-Induction
Consolidation
Maintenance
HDMTX
Asp
Pred
Vind
Adria
Asp
HDMTX
HDAraC
Vind
VP16
Asp
Dexa/Pred
Vincristine
Dauno/Ida
Cyclo
AraC
VP16
6MP
Asp
Hyper-CVAD Regimen
POMP
± other
Dexa
Vincristine
Doxo
Cyclo
HDMTX
HD AraC
MRD evaluation
• Prophylactic CNS treatment; intrathecal monotherapy; MTX or intratecal triple MTX, AraC, Dexa/Pred, +/– cranial irradiation (24 Gy)
• MRD evaluation; material collection at diagnosis, evaluation after Induction I, Induction II, Consolidation I, then every 3 months.
• Rituximab in B-lineage, nelarabine in T-lineage
• Maintenance therapy, ~2 years in all subtypes (except Burkitt)
FIGURE 111-1  A schematic treatment algorithm in acute lymphoblastic leukemia (ALL). 6-MP, 6-mercaptopurine; Adria, Adriamycin (doxorubicin); AraC, cytarabine;
Asp, asparaginase; BFM, Berlin-Frankfurt-Münster; CNS, central nervous system; CR1, first complete remission; Cyclo, cyclophosphamide; Dauno, daunorubicin; Dexa,
dexamethasone; Doxo, doxorubicin; HD, high-dose; Hyper-CVAD, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone; Ida, idarubicin; MRD,
minimal residual disease; MTX, methotrexate; POMP, mercaptopurine, vincristine, methotrexate, and prednisolone; Pred, prednisolone; Vind, vindesine; VP16, etoposide.
detection of fusion genes associated with chromosomal abnormalities
(e.g., BCR-ABL, MLL-AF4). The detection limit with these methods is
10−3–10−5 (0.1–0.001%). With new techniques such as next-generation
sequencing (NGS) or digital droplet polymerase chain reaction
(ddPCR), the sensitivity may increase to 10−5–10−6. The phenotypic
aberrations are unique to each patient with ALL and can be detected
in up to 95% of individuals. Collection of bone marrow at diagno­
sis for identification of patients’ individual markers is essential for
follow-up of MRD.
■
■MOLECULAR RESPONSE AFTER INDUCTION
THERAPY AND IMPACT ON OUTCOME
Achievement of molecular complete response/molecular remission is
the most relevant independent prognostic factor for disease-free and
overall survival in pediatric and adult ALL (Table 111-3). Patients
with molecular complete remission after induction therapy have sig­
nificantly superior outcomes in several studies, with a disease-free
survival rate of ~70% compared to <40% for MRD-positive patients.
Patients with molecular failure after induction should proceed to a
targeted therapy to reduce the tumor load, followed by allogeneic stem
cell transplantation (SCT), if possible.
■
■PROGNOSTIC FACTORS, RISK STRATIFICATION,
AND MRD
The aim of identification of prognostic parameters at diagnosis, which
include age, WBC count, immunophenotype, and cytogenetic and
genetic aberrations, is to stratify patients into risk groups: standardrisk patients are patients without any risk factors, and high-risk
patients are those with one or more risk factors. High-risk patients are
most often candidates for SCT in first complete remission (CR). MRD
is thus the most important prognostic factor during therapy (Fig. 111-1);
20–30% of adult ALL patients who are MRD negative after induction
will relapse. Potential reasons include loss of sensitivity, evolution of
leukemic subclones, and extramedullary origin of disease. If the MRD
status of a patient is not available, risk stratification should rely on
clinical and laboratory risk factors evaluated at diagnosis.
6-MP
MTX
± other
Stem Cell Transplantation in CR1
according to risk factors/MRD
■
■TREATMENT PRINCIPLES
Treatment of ALL consists usually of pre-phase therapy, induction
therapy, consolidation cycles, and maintenance treatment. Treatment
should start immediately when the diagnosis of ALL is established and
can later be specified or adapted when ALL subtype is known (e.g.,
Ph+).
Pre-Phase Therapy 
Pre-phase therapy consisting of glucocorti­
coids (prednisone 20–60 mg/d or dexamethasone 6–16 mg/d, both
IV or PO) alone or in combination with another drug (e.g., vincris­
tine, cyclophosphamide) is usually given for ~5–7 days. It allows
safe tumor reduction to avoid tumor lysis syndrome, to initiate sup­
portive therapy, such as substitution of platelets/erythrocytes, or to
treat infections. The time required for pre-phase therapy will also allow
time to obtain results of the diagnostic workup (e.g., cytogenetics,
molecular genetics).
Induction Therapy 
The goal of induction therapy is the achieve­
ment of a CR or, even better, a molecular CR. With current regimens,
the CR rate has increased to 80–90% and is higher for standard-risk
patients (>90%) and lower for high-risk patients (~60%).
Induction regimens are centered around vincristine, glucocorti­
coids, and anthracyclines with or without cyclophosphamide or cyta­
rabine. L-Asparaginase is the only ALL-specific drug and is now more
intensively used in adults. Pegylated asparaginase has the advantage of
a significantly longer period of asparagine depletion. Dexamethasone
is often preferred to prednisone because it penetrates the blood-brain
barrier and also acts on resting leukemic blast cells.
Two chemotherapy regimens are widespread (Fig. 111-1). One is
patterned after the pediatric BFM (Berlin-Frankfurt-Münster) pro­
tocol, which is mostly used in European adult ALL trials. Another
approach is to repeat two different alternating intensive chemotherapy
cycles, identical for induction and consolidation, for eight cycles, such
as Hyper-CVAD (hyperfractionated cyclophosphamide, vincristine,
doxorubicin, and dexamethasone) protocol, which is preferentially
used in the United States but also in many other parts of the world.
Postremission Consolidation 
Usual protocols use six to eight
courses and often contain systemic high-dose (HD) therapy to reach
sufficient drug levels in sanctuary sites such as the CNS. Most often
HD methotrexate (1–1.5 g/m2 and up to 3–5 g/m2) and/or HD cytara­
bine (4–12 doses at 1–3 g/m2) are administered.
Maintenance Therapy 
Maintenance therapy, a strategy trans­
ferred from childhood ALL, is mandatory. It consists of 6-mercapto­
purine and methotrexate plus intrathecal therapy. The potential effect
of further intensification cycles during maintenance remains unclear.
The duration of maintenance therapy for T-ALL and B-ALL is 2–2.5
years, except for Burkitt’s leukemia, for which a half year to 1 year is
sufficient. In Ph+ ALL, patients also require maintenance therapy that
should include a tyrosine kinase inhibitor (TKI), most likely the TKI
that has been used during induction and consolidation therapy. It is
also standard to give a TKI after allogeneic SCT. The duration of main­
tenance therapy with a TKI is also 2–2.5 years and should be guided by
MRD evaluation. TKI use is often interrupted or switched to another
TKI if toxicity occurs.
■
■TREATMENT OF ALL PATIENTS ACCORDING TO
AGE
The outcome of ALL is strictly related to the age of a patient, with
cure rates of ~90% in children, decreasing to <10% in elderly or frail
patients. Thus, age-adapted protocols have emerged, where the age
limits are directed by the hematologic and nonhematologic toxicities.
Table 111-4 provides a summary of the best results obtained in adult
ALL according to ALL subtype, age, and treatment. The major risk of
relapse is in the first 2 years and is less likely after 5 years.
■
■PROPHYLAXIS AND TREATMENT OF CENTRAL
NERVOUS SYSTEM LEUKEMIA
Prophylactic CNS therapy in ALL is essential in order to prevent CNS
leukemia and to avoid spread of leukemic cells from the CNS back
TABLE 111-4  Best Results in Recent Studies for Adult Acute
Lymphoblastic Leukemia (ALL)
SUBTYPE
TREATMENT
OVERALL SURVIVAL
Burkitt’s leukemia
Short intensive chemotherapy
rituximab; no SCT; no
maintenance
80–90%
B-lineage ALL, Ph–
  AYA 15–35/45 years
Pediatric inspired, few/no SCT
≥70–80%
  Adults 45–55 years
Intensive chemotherapy +/– SCT
50–60%
  Elderly 55–70 years
Less intensive chemotherapy +
immunotherapy
~30%
  Frail >70/75 years
Various
≤10%
B-lineage ALL, Ph+
  Ph BCR-ABL
Intensive chemotherapy +
TKI +/– SCT
60–70%
  Ph-like ALL
Chemotherapy + dasatinib/JAK
inhibitors
≤50%
T-lineage ALL
  Early (ETP)
Intensive chemotherapy +
nelarabine + SCT
40–50%
  Cortical/thymic
Intensive chemotherapy +
nelarabine, no SCT
70–84%
CHAPTER 111
  Mature
Intensive chemotherapy +
nelarabine + SCT
30–50%
Abbreviations: AYA, adolescent and young adult; ETP, early T precursor; Ph,
Philadelphia chromosome; SCT, stem cell transplantation; TKI, tyrosine kinase
inhibitor.
Acute Lymphoid Leukemia
to the periphery. Treatment options include intrathecal therapy, sys­
temic HD chemotherapy, and cranial radiation therapy (CRT). Wide
variations exist in CNS prophylaxis regimens. Intrathecal therapy
mostly consists of methotrexate as a single drug or in combination
with cytosine arabinoside (AC) with or without glucocorticoids. The
route of intrathecal therapy application is generally lumbar puncture.
Systemic HD chemotherapy may comprise HDAC or HD methotrexate
since both drugs reach cytotoxic drug levels in the cerebrospinal fluid
and show effectiveness in overt CNS leukemia. CRT (18–24 Gy in 12
fractions over 16 days) is also effective as preventive treatment of CNS
leukemia. Using combined modalities for CNS prophylaxis, the CNS
relapse rate has decreased to 2–5%.
Particular attention to CNS prophylaxis is required for targeted
therapies. In Ph+ ALL, not all TKIs cross the blood-brain barrier
equally such as imatinib and nilotinib but dasatinib and probably
ponatinib do. In immunotherapies, intrathecal therapy is required
because most antibodies do not enter the CNS.
CNS involvement at diagnosis is observed in 5–10% of adult patients
and is higher in mature B-ALL (up to 10–15%) and T-ALL (up to 10%).
Treatment consists of the standard chemotherapy with additional
intrathecal applications 3–5 times per week until blast cells are cleared
in the spinal fluid. Patients with initial CNS involvement have a similar
overall survival as CNS-negative patients.
Relapse in CNS is usually accompanied by bone marrow involve­
ment, and if blast cells are not seen morphologically, MRD as a sign of
discrete infiltration is positive in nearly all cases. CNS relapse requires
local as well as systemic therapy. The outcome after CNS relapse is dis­
mal, and salvage chemotherapy followed by allogeneic SCT is the most
effective option. Chimeric antigen receptor (CAR) T cells (most often
targeting CD19) can cross the blood-brain barrier and achieve CRs in
patients with CNS relapse.
Extramedullary manifestation and relapses in ALL are often
observed. Patients should have the general treatment and, if required,
local intervention (e.g., local radiation if residual mediastinal mass).
■
■STEM CELL TRANSPLANTATION
SCT is an essential part of the treatment strategy for adult ALL. Peripheral
blood cells are more often being used as a stem cell source, instead
of bone marrow. If no matched sibling stem cell donors are available,
increasingly matched unrelated donors or haploidentical donors are
used. Indications for SCT in first CR are controversial. However, in
most studies, SCT is recommended for high-risk patients defined either
by conventional prognostic factors or by MRD positivity. High-risk
patients transplanted in first CR have a survival rate of 50% or greater.
Decreasing transplant-related mortality from 20–30% to 10–15% has
contributed substantially to better outcomes. For standard-risk patients
with sustained molecular remission, allogeneic SCT in first CR is not
recommended. Autologous SCT should be restricted to MRD-negative
patients, BCR-ABL–negative patients and older patients because it is
less toxic but associated with a substantially higher relapse rate. For
all relapsed adult ALL patients, an allogeneic SCT is thus far the only
curative option.
■
■PEDIATRIC-INSPIRED THERAPIES FOR
ADOLESCENTS AND YOUNG ADULTS
The principle of pediatric-inspired therapies is to have higher doses
and more applications of ALL-specific drugs such as glucocorticoids,
vincristine, and L-asparaginase and fewer myeloablative anthracyclines
or alkylating agents, with strict adherence to time-dose intensity, thereby
reducing the role of SCT. The overall survival rates for AYAs are 70–80%.
■
■ADULT ALL
The treatment results for adult ALL patients have greatly improved
with more intensive chemotherapy, optimized SCT, and better sup­
portive care. In several recent multicenter prospective trials, the overall
survival rate for standard-risk patients was >70% with chemotherapy
alone, and for high-risk patients, the overall survival rate has increased
from 20–30% to >50%.
PART 4
Oncology and Hematology
■
■ALL IN THE ELDERLY
Palliative treatment regimens for elderly patients have failed, with
CR rates of ~40%, a high early death rate of 24%, and a poor overall
survival of only a few months. Intensive chemotherapy has also failed,
with a higher CR rate of 56%, but still an early death rate of 23%, and
only moderate improvement of overall survival to 14 months. Specific
elderly ALL protocols with less intensive therapy based on glucocor­
ticoids, vincristine, and asparaginase, largely avoiding anthracyclines
and alkylating agents, have improved outcomes. The early treatmentrelated death rate decreased to <10%, CR rates improved to ~90%, and
overall survival of ~30 months was noted.
Frail patients above the age of 70–75 years have very poor survival
of <10%. Hopefully, this will improve with ongoing targeted therapies
with either TKIs in Ph+ ALL or immunotherapies.
■
■TARGETED THERAPIES
Substantial progress in adult ALL has been made in the past decade by
the introduction of new targeted therapies, including TKIs and immu­
notherapeutic approaches (Table 111-5).
■
■TYROSINE KINASE INHIBITORS IN
PHILADELPHIA-POSITIVE ALL
Patients with Ph+ ALL constitute ~25% of adult B-ALL patients, with
the frequency increasing to ~50% among elderly patients. In the preimatinib era, CR rates were 60–70%; survival with chemotherapy was
~10%, and after allogeneic SCT, it was ~30%. With the first-generation
TKI imatinib, CR rates increased to 80–90%, the rate of BCR-ABL
negativity increased from 5 to 50%, and the 5- to 10-year overall sur­
vival improved to 50–70%.
Faster and deeper molecular responses are achieved with secondgeneration TKIs (dasatinib, nilotinib), and these responses apparently
translate into a survival benefit. The third-generation TKI ponatinib
is also effective in tumors bearing mutations (particularly T315I) that
convey resistance to earlier-generation TKIs.
Treating adult Ph+ ALL with an allogeneic SCT in first CR is still
a good treatment option for adult patients, with a 5-year overall sur­
vival of 60–70%. In elderly patients, when low-intensity chemotherapy
was combined with dasatinib, the CR rate was >90%. In a next step,
by combining mini-chemotherapy with a TKI and adding immuno­
therapy with inotuzumab (an anti-CD22 antibody), the CR rate was
TABLE 111-5  Targeted Therapies in Adult Acute Lymphoblastic
Leukemia (ALL)
Tyrosine Kinase Inhibitors (TKIs)
Ph/BCR-ABL+ ALL
  TKIs
  Imatinib, dasatinib, nilotinib, bosutinib, ponatinib, asciminib
Ph/BCR-ABL-like ALL
  ABL1, ABL2: dasatinib, ponatinib; JAK2: ruxolitinib
Immunologic Approaches
Antibodies directed against leukemia surface antigens
  Monovalent antibodies
  Bivalent antibodies against the tumor and CD3 (e.g., blinatumomab)
Adoptive cellular therapy
  T cells engineered to kill leukemic cells
Checkpoint Inhibitors
  PD-1 inhibitors: pembrolizumab, nivolumab
  CTLA-4 inhibitors: ipilimumab
Targeted Agents
  Proteasome inhibitors: bortezomib, ixazomib
  BCL-2 inhibitors: venetoclax, navitoclax
90% and the overall survival improved further. A pilot experience
with a chemotherapy-free regimen composed of dexamethasone, the
TKI dasatinib, and the bispecific antibody blinatumomab (anti-CD19
and anti-CD3) demonstrated a CR rate of 98% and 2-year overall and
disease-free survival rates of 95% and 88%, respectively. Blinatumomab
eliminates Ph+ leukemic cells with resistant mutations.
■
■IMMUNOTHERAPEUTIC APPROACHES
Treatments involving monoclonal antibodies or activated T cells are
currently changing the treatment paradigm of ALL. The prerequisite is
that B-lineage blast cells express a variety of specific antigens, such as
CD19, CD20, and CD22 (Table 111-6) that are targetable with a wide
variety of monoclonal antibodies. A new treatment principle is the acti­
vation of the patient’s T cells to destroy their CD19+ leukemic blasts.
Anti-CD20 
The anti-CD20 monoclonal antibody rituximab has
improved the outcome of patients with de novo Burkitt’s leukemia/
lymphoma. With repeated short cycles of intensive chemotherapy
combined with rituximab, the overall survival increased to >80%.
Rituximab is now included in most B-ALL regimens and is given at
the usual dose of 375 mg/m2 on day –1 before chemotherapy for at
TABLE 111-6  Expression of Antigens in B-Cell Lineage Acute
Lymphoblastic Leukemia (ALL) for Potential Antibody Therapy
SURFACE
ANTIGEN
ALL SUBTYPES
EXPRESSION
ON LBCa
MONOCLONAL ANTIBODY
CD20
Burkitt’s lymphoma/
leukemia
B-precursor
86–100%
30–40%
Rituximab
Ofatumumab
CD22
B-precursor
Mature B-ALL
93–98%
~100%
Inotuzumab
Epratuzumab
Moxetumomab pasudotox
CD19
B-precursor
Mature B-ALL
95–<100%
94–<100%
T cell–activating therapies
Blinatumomab
Bispecific CD3/CD19
Chimeric antigen receptor
modified T cells (CAR T
cells)
aDefined as ≥20% positive blast cells.
Abbreviation: LBC, leukemic blast count.
Source: Reproduced with permission from D Hoelzer: Novel antibody-based therapies
for acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program
2011:243, 2011.

42 - 112 Chronic Lymphocytic Leukemia
112 Chronic Lymphocytic Leukemia
least eight or more cycles. This leads to a significant increase in MRD
negativity and improved survival.
Anti-CD22 
Monoclonal antibodies directed against CD22 are
linked to cytotoxic agents, such as calicheamicin (inotuzumab ozo­
gamicin), or to plant or bacterial toxins (epratuzumab). In a random­
ized trial of relapsed or refractory ALL patients, the CR rate was
66% and significantly superior to the CR rate with standard chemo­
therapy. Inotuzumab is now included in first-line therapy for Ph+ and
Ph– patients.
Anti-CD19 
Targeting CD19 is of great interest because this antigen
is highly expressed in all B-lineage cells, most likely including early
lymphoid precursor cells. A new promising approach is the bispecific
antibody blinatumomab, which combines single-chain antibodies to
CD19 and CD3, such that T cells lyse the CD19-bearing B cells.
Blinatumomab is particularly effective in MRD-positive patients,
with a 70–80% conversion to MRD negativity, translating into improved
overall survival; ~25% of MRD-negative patients survived without any
further treatment. Blinatumomab has also moved to frontline therapy.
CAR-T Cells 
The adoptive transfer of CAR-modified T cells
directed against CD19 is a promising approach for the treatment of
CD19+ childhood or adult ALL. In the first three larger studies in adults
with relapsed or refractory ALL, the CR rate ranged from 67 to 91% with
MRD negativity in 60–81% of the patients who achieved CR. Overall
survival is 50% or more at ≥2 years, which is remarkable for these heavily
pretreated patients. CAR-T cells are also effective in CNS leukemia and
in other extramedullary sites. CAR-T cell therapy in relapsed or refrac­
tory ALL was first considered as a bridge to allogeneic SCT, applied in
10–50% of patients, but the necessity for an allogeneic SCT after CAR-T
cells is unclear. CAR-T cell therapies are also moving to the frontline.
CD19-negative relapses after CAR-T cell therapy or blinatumomab due
to downregulation of CD19 expression are a relevant obstacle.
Toxicities of Immunotherapies 
The anti-CD22 agent inotu­
zumab ozogamicin is associated with hepatotoxicity, including venoocclusive disease, particularly after allogeneic SCT, but can be managed
by reduced dosing and limitation of cycles. For anti-CD19 therapies,
cytokine release syndrome and severe neurotoxicity are the most
prominent toxicities and often require intensive care unit care (more so
after CAR-T cells than blinatumomab). Management of these compli­
cations has improved with early recognition. Because toxic death after
immunotherapies is very low compared to intensive chemotherapy or
allogeneic SCT, immunotherapies are now increasingly included in
frontline therapy.
■
■TREATMENT OF T-ALL
Immunotherapy for T-ALL is still not available, and intensive chemo­
therapy is still the mainstay in combination with the T cell–specific
drug nelarabine. Currently, γ-secretase targeting NOTCH1, checkpoint
inhibitors such as bortezomib and venetoclax, and HDAC inhibitors
are being explored.
■
■CONCLUSION AND FUTURE DIRECTIONS
Cytogenetic and molecular analysis at diagnosis allows identification
of ALL subentities requiring different treatment options. Evaluation
of MRD is the most important parameter for treatment decisions.
The greatest progress has been achieved by targeted therapies, such
as TKIs for Ph+ ALL and new immunotherapeutic approaches. This
will lead to further improved outcome of adult ALL patients, 50% of
whom are already surviving 5–10 years and are most likely cured. New
options and advances, such as low-intensity chemotherapy, reduction
of SCT, incorporation of targeted therapies, and reduction of toxicities,
will improve the quality of life of patients and lead to individualized
approaches for each patient.
■
■FURTHER READING
Caracciolo D et al: The emerging scenario of immunotherapy for
T-cell acute lymphoblastic leukemia: Advances, challenges and future
perspectives. Exp Hematol Oncol 12:5, 2023.
Gökbuget N et al: Diagnosis, prognostic factors and assessment of
ALL in adults: 2023 ELN recommendations from a European expert
panel. Blood 143:1891, 2024.
Gökbuget N et al: Management of ALL in adults: 2023 ELN recom­
mendations from a European expert panel. Blood 143:1903, 2024.
Hoelzer D et al: ESMO Clinical Practice Guideline interim update on
the use of targeted therapy in acute lymphoblastic leukaemia. Ann
Oncol 35:15, 2024.
Prockop S, Wachter F: The current landscape: Allogeneic hemato­
poietic stem cell transplant for acute lymphoblastic leukemia. Best
Pract Res Clin Haematol 36:101485, 2023.
Ribera J-M, Chiaretti S: Modern management options for Ph+ ALL.
Cancers 14:4554, 2022.
Shimony S et al: Nelarabine: when and how to use in the treatment of
T-cell acute lymphoblastic leukemia. Blood Adv 8:23, 2024.
Short N et al: Using immunotherapy and novel trial designs to
optimise front-line therapy in adult acute lymphoblastic leukaemia:
Breaking with the traditions of the past. Lancet Haematol 10:e382,
2023.
CHAPTER 112
Jennifer A. Woyach, John C. Byrd
Chronic Lymphocytic
Leukemia
Chronic Lymphocytic Leukemia
Chronic lymphocytic leukemia (CLL) is a monoclonal proliferation of
mature B lymphocytes defined by an absolute number of malignant
cells in the blood (5 × 109/L). The presence of malignant B cells under
this count in the blood without nodal, spleen, or liver involvement and
absent cytopenias is a precursor of this disease called monoclonal B-cell
lymphocytosis (MBL) with ~1–2% chance per year of progressing to
overt CLL. CLL is a heterogeneous disease in terms of natural history,
with some patients presenting asymptomatically and never requiring
therapy, whereas most will need therapy and a small subset will pres­
ent with symptomatic disease, require multiple lines of therapy, and
eventually die of their disease. Over the past two decades, the under­
standing of CLL origin and biology has grown exponentially, leading
first to more refined disease definition, prognostic markers, and, subse­
quently, introduction of novel therapies that have significantly changed
the natural history of this disease to where only a small minority will
die from CLL. In this way, CLL has served as a prototype of a cancer
where understanding the biologic underpinnings in absence of unified
mutation drivers has informed therapy development. In this chapter,
we review the epidemiology, biology, and management of CLL, with
a focus on new knowledge that has changed and continues to change
standards of care.
EPIDEMIOLOGY
CLL is primarily a disease of older adults, with a median age at diag­
nosis of 71 and an age-adjusted incidence of 4.6/100,000 people in the
United States; 18,740 peoples were diagnosed and 4490 people died of
CLL in the United States in 2023. The prevalence of CLL has increased
over the past decades due to improvements in therapy for this disease
and also survival of older patients from other medical ailments. In
1980, the 5-year overall survival of patients was 70%, and this increased
to 92% in 2015 and is likely even higher today. The male-to-female
ratio is 2:1; however, as patients age, the ratio becomes more even, and
over the age of 80, the incidence is equal between men and women. The
disease is most common in Caucasians, less common in Hispanic and
African Americans, and is rare in the Asian population.
Unlike many other malignancies, there have been no definitive links
between CLL and exposures. Indeed, CLL is one of the only types of
leukemia not linked to radiation exposure. Agent Orange exposure has
been implicated, and CLL is thus a service-connected condition for
those who were exposed to Agent Orange in the Vietnam conflict, burn
pit exposure from the Middle East conflicts, and Camp Lejune water.
CLL is one of the most familial-associated malignancies, and the
first-degree relative of a CLL patient has an 8.5-fold elevated risk of
developing CLL than the general population. MBL is also more com­
mon in families with two first-degree relatives having CLL, further sup­
porting a genetic predisposition of this disease. Despite this, specific
genes conferring risk in the familial setting outside of specific families
have been difficult to identify. In genome-wide association studies
(GWAS), ~30 single nucleotide polymorphisms (SNPs) have been
identified, which is estimated to account for 19% of the familial risk of
CLL. Genes involved in apoptosis, telomere function, B-cell receptor
(BCR) activation, and B-cell differentiation have all been implicated
in GWAS. Variants in shelterin complex proteins involved in telomere
maintenance such as POT1 have been identified in a small number of
families.
BIOLOGY AND PATHOPHYSIOLOGY
■
■CELL OF ORIGIN
The cell of origin in CLL has not definitively been established. The
morphology, immunophenotype, and gene expression pattern of CLL
cells are that of a mature B cell (Fig. 112-1), and so it has long been
presumed that the initiating cell is a mature lymphocyte, perhaps
memory B cells. However, many facets of CLL biology do not support
this idea, including antigen-binding characteristics of CLL cells and the
presence of stereotyped BCRs. Other possibilities include a stepwise
process including a series of transforming events at various stages of
B-cell development, potentially including de-differentiation of more
mature cells. The self-renewing, multipotent hematopoietic stem cell
(HSC) might also be the originating cell of CLL, postulated based on
transplant studies in mice showing clonal leukemic cell development
with different characteristics from donor leukemia after transplanta­
tion of HSC from CLL patients. More work will be required to elucidate
the origins of CLL.
PART 4
Oncology and Hematology
■
■B-CELL RECEPTOR SIGNALING IN CLL
Perhaps the most important advancement in CLL biology is the under­
standing of the role of BCR signaling in the disease. CLL has distinct
BCR signaling as compared to normal B cells, which is characterized
by low-level IgM expression, variable response to antigen stimulation,
and tonic activation of antiapoptotic signaling pathways that promote
tumor survival. CLL cells by gene expression profiling share many
features with antigen-activated mature B cells, suggesting a role for
activation of BCR signaling in the disease pathogenesis. Tissue-based
microarrays have revealed upregulation of BCR pathway genes in the
lymph nodes and bone marrow compared to the peripheral blood,
FIGURE 112-1  Chronic lymphoid leukemia in the peripheral blood.  (From Williams
Hematology, 7th ed, in M Lichtman et al [eds]: New York, McGraw-Hill, 2005.)
suggesting a particular importance of this pathway in microenviron­
mental homing.
Fitting with the role of BCR signaling in CLL, one of the most influ­
ential prognostic factors identified in this disease is the mutational
status of the immunoglobulin heavy chain variable (IGHV) region.
During normal B-cell maturation, the variable regions of the immu­
noglobulin heavy chain undergo somatic hypermutation. In CLL,
~60% of patients have IGHV that is ≥2% mutated from germline. This
may indicate a more mature, postgerminal center progenitor, and is
typically associated with a more indolent disease course. Conversely,
~40% of patients will have IGHV <2% mutated from germline, which
is associated with more rapid progression of disease and short survival
before the era of therapeutics that target BCR. Unfavorable biologic
properties including enhanced telomerase activity, overexpression of
activation-induced cytidine deaminase, increased nuclear factor-κB
(NF-κB) activity, high-risk genomic mutations (e.g., NOTCH1, SF3B1,
TP53, ATM), and clonal evolution are also associated with IGHV
unmutated disease. In addition to the mutational status of IGHV, about
30% of CLL patients express “stereotyped” BCRs, where the stereotype
subset predicts clinical course, with subsets 1 and 2 predicting higherrisk disease.
■
■CYTOGENETIC ABNORMALITIES
Besides IGHV mutational status, recurrent cytogenetic abnormalities
are the most robust prognostic factor clinically available in CLL. These
abnormalities are typically identified by fluorescent in situ hybridiza­
tion (FISH) analysis; however, stimulated metaphase karyotype has a
role as well. The most well-characterized abnormalities include del(13)
(q14.3), trisomy 12, del(11)(q22.3), and del(17)(p13.1) (Fig. 112-2).
The presence of sole del(13)(q14.3) is associated with more indolent
disease, prolonged survival, and good response to traditional therapies.
Usually this abnormality is not seen on banded karyotype analysis, and
when present on karyotype, it indicates a larger deletion involving the
retinoblastoma gene, which negates the favorable prognosis associated
with this marker. Trisomy 12 has a more intermediate prognosis. The
del(11)(q23.3) results in deletion of the ATM gene and is associated
with bulky lymphadenopathy and aggressive disease in young patients,
with inferior prognosis, and more rapid progression to symptomatic
disease. The del(17)(p13.1) results in loss of one allele of the tumor
suppressor TP53 and is associated with the poorest prognosis in CLL
with rapid disease progression, poor response to traditional thera­
pies, and shorter survival. Other abnormalities have been shown to
be important in smaller studies but are not routinely performed at
all centers. Finally, complex karyotype (three or more abnormalities)
on stimulated metaphase karyotype analysis has significant adverse
impact on time to treatment and overall survival, with data indicating
that increasing complexity is even more deleterious to response and
survival.
Clonal evolution, or acquisition of cytogenetic or molecular abnor­
malities, is common in CLL, especially in patients with IGHV unmu­
tated CLL. Because the cytogenetics of patients can change even in
the absence of therapy, it is recommended that FISH, with or without
cytogenetics, is checked before every line of therapy, mostly to evaluate
acquisition of del(17)(p13.1).
■
■GENE MUTATIONS AND MIR ALTERATIONS
Compared with many other malignancies, the genome in CLL is rela­
tively simple, with an average CLL genome carrying ~20 nonsynony­
mous alterations and ~5 structural abnormalities. And, unlike many
other hematologic malignancies, there is no unifying genetic lesion,
and most recurrent genetic driving mutations exist at frequencies of
<5%. Whole genome and whole exome sequencing have identified the
most common mutations in CLL to be in SF3B1, NOTCH1, MYD88,
ATM, and TP53 (Table 112-1). Most of the identified mutations in
these genes are common among different malignancies, and with the
exception of MYD88, they are generally identified with much higher
frequency in IGHV unmutated disease.
NOTCH1 mutations are present in ~15% of CLL patients and are
commonly associated with trisomy 12. Although multiple different
Patients surviving (%)
108 120 132 144 156 168
Months
No. at Risk
17p deletion
11q deletion
12q trisomy
Normal
13q deletion as sole
abnormality
FIGURE 112-2  Outcomes among CLL patients with various cytogenetic abnormalities.  (From The New England Journal of Medicine, Genomic Aberrations and Survival in Chronic
Lymphocytic Leukemia, H Dohner et al: 343: 1910. Copyright @2000 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.)
mutations are seen, most are located within the PEST (proline, glu­
tamic acid, serine, and threonine) domain and result in constitutive
NOTCH signaling. NOTCH1 mutations have been associated with
lower sensitivity to CD20 antibody therapy and increased risk of
transformation to aggressive diffuse large B-cell lymphoma (DLBCL;
Richter’s transformation), although its relevance in the era of targeted
therapies is less clear. SF3B1 is a component of the RNA spliceosome
and is mutated in 10–15% of CLL cases. Mutations appear to be associ­
ated with intermediate-risk disease, and functionally, SF3B1 may be
important in the response to DNA damage.
Mutations of the tumor suppressor TP53 are found in ~5% of CLLs
in previously untreated early-stage disease and up to 40% in later stages.
TABLE 112-1  Recurrent Mutations in CLL
GENE
FREQUENCY OF MUTATIONS (%)
SF3B1
8–14
TP53
5–13
NOTCH1
10–13
MYD88
4–8
ATM
8–11
BIRC3
<5
XPO1
<5
FBXW7
<5
POT1
<5
BRAF
<5
EGR2
<5
IKZF3
<5
Abbreviation: CLL, chronic lymphocytic leukemia.
17p deletion
11q deletion
12q trisomy
Normal
13q deletion as
sole abnormality
CHAPTER 112
Chronic Lymphocytic Leukemia
Seventy percent of the time, these mutations coexist with del(17)(p13.1),
effectively eliminating TP53 function. As expected, and consistent with
other malignancies, TP53 mutations are associated with a poor prognosis
and expected lack of response to DNA-damaging therapies.
ATM mutations, which are heterogeneous and occur throughout the
gene, occur in 10–15% of CLL patients. ATM mutations often coexist
with del(11)(q22.3), eliminating ATM on the alternate allele. Similar to
TP53, mutations in ATM tend to result in impaired response to DNA
damage, which can reduce responsiveness to chemotherapy.
In contrast to the aforementioned mutations, those in MYD88 tend
to occur in IGHV-mutated CLL and be associated with a more indolent
prognosis. This gene is involved in Toll-like receptor signaling, and the
most common mutation, L265P, results in constitutive activation and
NF-κB activity.
Along with abnormalities in coding genes, it has become appar­
ent that noncoding genes such as microRNAs are recurrently altered
in CLL. The most common cytogenetic abnormality, del(13)(q14.3),
results in loss of the miR15/16 cluster, which is important in the patho­
genesis of CLL. In normal cells, miR15A/miR16A inhibits antiapop­
totic gene expression (including BCL2, CCND1, CCND3, and CDK6),
and this specific deletion allows for overexpression of these genes and
thus increased cell survival. Loss of other miR expression such as miR181a leads to overexpression of proteins such as the antiapoptotic genes
MCL1 and TCL1. Overexpression of miR-155, an onco-miR associated
with B-cell transformation, has also been documented in the majority
of CLL patients.
■
■IMMUNOLOGY
CLL is characterized by dysregulation of the normal immune system in
addition to the malignant immune cells. Besides numerical abnormali­
ties due to bone marrow dysfunction, even in the early stages of disease,
there are skewed ratios of immune cells and functional abnormalities.
Innate immune system defects associated with CLL include reduced
complement proteins and activity, qualitative neutrophil defects, and
functional defects of natural killer cells.
More focus has been placed on the impairments in the adaptive
immune system in this disease. Within the CD4+ T-cell compartment,
a qualitative defect is noted similar to chronic antigen stimulation
inducing a phenotype of T-cell exhaustion typical of what is seen in
chronic viral infections such as hepatitis. This has been demonstrated
to lead to impaired T-cell cytotoxic capacity and reduced proliferative
ability. Additionally, there are physical changes in the T-cell cytoskel­
eton that cause impaired immune synapse formation with antigen
presenting cells. In addition to a lack of capacity to respond to patho­
gens, the T-cell defect in CLL also likely leads to tumor cell tolerance.
During the course of the disease, the polarization of the CD4+ T cells
shifts from a Th1 (cytotoxic) phenotype to a Th2 phenotype, which
leads to expansion of immunosuppressive cytokines such as interleukin
(IL) 10. Additionally, in the later stage of disease, T regulatory cells are
expanded, which contributes to an immunosuppressive phenotype.
Other components of the immune microenvironment are altered as
well to form a more supportive environment for the malignant cells.
M2 monocytes have been shown to differentiate into a type of tumorassociated macrophage known as a nurse-like cell in CLL. These cells
promote survival by secreting chemokines and cytokines that increase
migration and activation.
PART 4
Oncology and Hematology
The humoral immune system in CLL is also dysregulated, as is
expected for a malignancy that results in very few normal B cells.
Hypogammaglobulinemia is very common and affects all subclasses of
immunoglobulins, occurring in ~85% of patients at some time in their
disease course, and is more common as disease progresses. A correla­
tion between low IgG and IgA and infection risk has been established,
but isolated IgM reduction does not seem to be associated with excess
infection risk. Also, CLL cells can secrete monoclonal IgM or IgG in a
small number of cases, and this can correlate with disease progression.
CLINICAL PRESENTATION AND DIAGNOSIS
OF CLL
■
■CLINICAL PRESENTATION AND DIAGNOSIS
The presentation of CLL most commonly occurs as an incidental
diagnosis made at the time of medical evaluation for another cause. In
this regard, CLL is most commonly diagnosed on routine blood work
demonstrating an elevated lymphocyte count in asymptomatic indi­
viduals, although some patients present with symptoms and require
early therapy. When noting either an elevated total white blood cell
(WBC) count with lymphocytic predominance or a normal WBC with
a differential showing a lymphocytosis, the next step is to perform
flow cytometry on the peripheral blood. In CLL, this will reveal the
typical immunophenotype that includes the typical B-cell markers
CD19, CD20, CD22, CD23, CD200, the T-cell marker CD5 (CD5 is
also expressed on the B1 subset of B cells that typically has unmutated
immunoglobulin and responds to antigens independent of cognate
T-cell help), and dim surface immunoglobulin of either kappa or
lambda type (Table 112-2). Atypical phenotypes can be seen as well
and usually can be differentiated on the basis of morphology, cytoge­
netics, or clinical presentation. In cases in which the clonal B-cell count
based on flow cytometry is ≥5 × 109/L, no further workup is needed to
confirm the diagnosis of CLL.
Some patients will present with a small clonal proliferation of CLL
cells in the peripheral blood but will also have lymphadenopathy or
TABLE 112-2  Typical Immunophenotype of CLL Compared with Other B-Cell Malignancies
DISEASE
CD5
CD10
CD19
CD20
CD23
CYCLIN D1
SURFACE IG
CLL
+
−
+
(dim)
−
(dim)
Mantle cell lymphoma
−
+
(mod/bright)
−
(mod/bright)
Marginal zone lymphoma
−/+
−
(mod/bright)
−/+
−
(mod/bright)
Follicular lymphoma
−
−
 
Abbreviation: CLL, chronic lymphocytic leukemia.
splenomegaly. In these cases, the likely diagnosis is small lymphocytic
lymphoma (SLL), a semantic designation from CLL that denotes a pri­
marily tissue-based disease rather than bone marrow/blood-based dis­
ease. The genetic and molecular features of SLL are identical to those of
CLL. The retention of the cells in tissues may be related to the expres­
sion of a particular adhesion molecule. Thus, SLL patients are managed
identically to CLL patients, and often in the later stages of disease, these
patients will have blood and bone marrow involvement as well.
MONOCLONAL B-CELL LYMPHOCYTOSIS
Patients who do not meet the diagnostic criteria for CLL based on
quantification of clonal B cells in the peripheral blood and who do
not have associated signs of CLL including lymphadenopathy, organo­
megaly, or cytopenias have a disorder known as monoclonal B-cell
lymphocytosis (MBL), which is now thought to precede every case of
CLL. Analogous to monoclonal gammopathy of uncertain significance
(MGUS) in myeloma, not all MBL progresses to CLL. MBL is initially
characterized by a CLL-like immunophenotype in ~75% of cases but
can also be atypical (CD23 negative or bright CD20) or CD5 negative.
More relevant for prognosis is characterization by count, with lowcount MBL defining patients with <0.5 × 109 clonal B cells/L and highcount MBL defining patients with >0.5 × 109 but <5 × 109/L. Patients
with low-count MBL have a negligible rate of progression to CLL,
whereas those with high count progress to overt CLL at a rate of 1–2%
per year, warranting continued monitoring. Population-based stud­
ies have estimated the prevalence of MBL up to ~12% in the general
population, where it is most common in elderly men. It is especially
common in first-degree relatives of CLL patients, where the frequency
is ~18%.
Although the risk of MBL progression is relatively low, it has
become apparent that patients still experience complications that sug­
gest an immune dysfunction in MBL that is similar to that seen with
CLL. Rates of serious infections requiring hospitalization appear to be
significantly increased in MBL, similar to the rates seen in CLL. In a
case-control study, patients with MBL had a 16% chance of hospitaliza­
tion over a 4-year time period, compared with 18.4% in patients with
newly diagnosed CLL. Secondary cancers also appear to be increased
in MBL. These data suggest that monitoring for patients with MBL
should focus on vaccinations and age-appropriate cancer screening, as
the probability of complications appears to be higher than the risk of
progression in most of these patients. Follow-up for patients with MBL
can occur with the primary care physician as this does not represent a
malignancy, whereas CLL is mostly co-managed with both a primary
care physician and a hematologist.
COMPLICATIONS OF CLL
A significant amount of morbidity and mortality related to CLL is due
to complications of the disease. In general, complications besides dis­
ease progression include infections, secondary cancers, autoimmune
complications, and transformation to a more aggressive clonally related
lymphoma.
■
■INFECTIONS
Infections are a leading cause of both disease-related morbidity and
death in patients with CLL, with ~30–50% of deaths in CLL patient
attributed to infection. Owing to the immune dysfunction associ­
ated with the disease, patients are at risk for both typical and atypical
infections. Besides this baseline risk of infections, most CLL therapies,
even targeted therapies, can increase infection risk. Viral prophylaxis
is also indicated for many patients when therapy is initiated (even with
targeted agents) and for patients with a history of varicella-zoster to
diminish reactivation and morbidity from this virus.
Because of the abnormalities in cellular and humoral immunity,
vaccine responses in CLL are limited in many patients, especially in
the later stages of disease. In one study, one dose of 13-valent pneu­
mococcal vaccine produced an adequate immune response in only
58% of patients compared with 100% in age-matched controls. Vaccine
efficacy can be improved in CLL patients by repeated booster vaccina­
tions, vaccine adjuvants, and protein conjugation. Despite the known
limitations, vaccination against influenza, COVID-19, varicella-zoster,
pneumococcal pneumonia (Prevnar 20), and respiratory syncytial
virus is recommended in CLL. The recombinant zoster vaccine has
approximately a 60% response in previously untreated CLL, is safe,
and should be considered for this patient group. Efficacy of the newer
20-valent pneumococcal vaccine in patients with CLL has not yet been
reported. In contrast, live vaccines should be avoided in the setting of
CLL because of the small risk of viral reactivation with an immuno­
compromised host.
Vaccine effectiveness in terms of humoral response is also decreased
by most CLL therapies, although this can be overcome in some cases by
booster vaccinations. When possible, receiving vaccinations before the
initiation of therapy is recommended.
As discussed earlier, hypogammaglobulinemia is common in CLL
and can be associated with significant risk for infections, primarily of
mucocutaneous etiology such as sinusitis and bronchitis. In addition,
women can have frequent urinary tract infections. While administra­
tion of prophylactic intravenous immunoglobulin (IVIg) has not been
shown to improve survival, it has been shown to reduce the number
of minor or moderate bacterial infections, and thus is indicated in
patients with hypogammaglobulinemia who suffer from recurrent
infections or have pulmonary bronchiectasis. It is also our practice
to administer at least one dose of immunoglobulin to CLL patients
who develop influenza with coexisting hypogammaglobulinemia to
diminish risk of postinfluenza pneumococcal pneumonia. IVIg is also
indicated in patients who have been hospitalized for a serious infection
and in those whose IgG level is <300–500 mg/dL.
■
■SECONDARY MALIGNANCIES
Multiple population-based studies have shown that patients with
CLL are at an elevated risk of developing other cancers, with a rate
up to three times that of the general population, even in the absence
of cytotoxic chemotherapy. The most common types of cancers seen
in CLL are skin, prostate, and breast cancers, although other cancers
are seen as well. Skin cancers are particularly common, with a rate
of 8- to 15-fold higher than the general population, and may behave
more aggressively. All CLL patients should be counseled on the use
of sunscreen while outdoors and should undergo preventative skin
examinations at least yearly.
In one single-center study, older age at CLL diagnosis, male sex,
high β2-microglobulin, high lactate dehydrogenase (LDH), and chronic
kidney disease were associated with excess risk of other cancers; other
CLL-specific risk factors have not shown association with other cancer
risk.
While cancer risk is higher, there are no specific recommendations
for increased cancer screening in CLL patients. Age- and sex-appro­
priate screenings should be recommended. In addition, we extend
screening beyond age 70–75 years for CLL patients based on the higher
frequency of cancers.
Conflicting data exist regarding the risk of cancers after CLL-specific
therapy. Chemoimmunotherapy, in particular alkylator-containing
regimens, seems to be associated with an increased risk for second­
ary cancers. Secondary cancers are also seen in the setting of targeted
therapies. Bruton tyrosine kinase (BTK) inhibitors appear to have a
secondary cancer risk similar to what is seen in the CLL population
in general, but potentially a higher rate of nonmelanoma skin cancers.
Compared with chemoimmunotherapy, venetoclax plus obinutuzumab
has been associated with a numerically but not statistically higher rate
of secondary cancers at follow-up of 6 years.
■
■AUTOIMMUNE COMPLICATIONS
Autoimmune complications are frequent in CLL. Most commonly,
these include autoimmune cytopenias, but autoimmune complications
of other organs including glomerulonephritis, vasculitis, and neu­
ropathies have also been reported. Of the autoimmune cytopenias, the
most common is autoimmune hemolytic anemia (AIHA), which is an
antibody-mediated destruction of autologous red blood cells (RBCs).
Second most common is immune thrombocytopenia (ITP), which
shares some features with AIHA and has a similar mechanism targeting
platelets. These two syndromes may occur in isolation, sequentially in
the same patient, or present in combination as Evan’s syndrome. Pure
red cell aplasia (PRCA) and autoimmune granulocytopenia (AIG) are
comparatively rare and can occur alone or in combination with other
autoimmune cytopenias. It is difficult to tease out whether autoim­
mune cytopenias lead to worse prognosis in CLL because of various
complicating factors. However, it is clear that these can lead to sig­
nificant morbidity, both due to the process itself and due to therapies
required for management.
AIHA usually presents as an isolated anemia with an elevated reticu­
locyte count and features of hemolysis including elevated bilirubin and
LDH and low haptoglobin. Detection of a warm IgG antibody on the
surface of RBCs with a Coombs test can help solidify the diagnosis,
although Coombs-negative cases can occur. Immediate therapy is
almost always necessary and consists of transfusion and immunosup­
pression. Glucocorticoids are often used for initial therapy, although in
most cases, additional treatment is needed due to either poor response
or recurrence with taper of steroid dosing. Rituximab can be success­
ful, and therapy directed toward the underlying CLL is often effective
in more resistant cases. Transfusion of blood in cases of robust AIHA
must be initiated with caution as transfusion reactions can be seen due
to poorly matched blood, but it should be pursued in those with severe,
symptomatic anemia. Death from uncontrolled AIHA can occur in the
absence of appropriate supportive care.
CHAPTER 112
Chronic Lymphocytic Leukemia
ITP can be more difficult to diagnose, as it may be difficult to dif­
ferentiate from progression of disease due to the lack of laboratory
tests that identify platelet destruction from this mechanism. Signs that
point toward ITP include isolated thrombocytopenia and rapid decline
in platelet levels in the absence of an alternative etiology. A bone mar­
row biopsy showing normal or increased megakaryocytes can be used
to confirm the diagnosis but is often not necessary. In CLL, treatment
for ITP is usually instituted when platelet levels drop to 20,000–30,000
or if there is evidence of bleeding complications or need for invasive
procedures. Like AIHA, initial therapy consists of glucocorticoids and
IVIg, with rituximab also being an effective method to induce longterm remissions. Also, the thrombopoietin receptor agonists romip­
lostim and eltrombopag are effective in secondary ITP. In many cases,
ITP can be successfully treated without treating the underlying CLL.
In cases in which anemia or thrombocytopenia appear, it is impor­
tant to investigate the mechanism because the approach to therapy of
autoimmune cytopenias in CLL differs from that for cytopenias due to
marrow replacement.
■
■RICHTER’S TRANSFORMATION
One of the most devastating complications of CLL is Richter’s trans­
formation, transformation of CLL to an aggressive lymphoma, most
commonly DLBCL. The World Health Organization also recognizes
Hodgkin’s lymphoma (HL) as a variant of Richter’s transforma­
tion; other aggressive lymphomas are rarely identified. Some older
series have included prolymphocytic transformation in this category,
although this has much less prognostic impact on long-term outcome.
The prevalence of Richter’s transformation is difficult to estimate based
on previous studies, but one prospective observational study estimated
a rate of 0.5% per year for DLBCL and 0.05% per year for HL. Risk
factors for development include bulky lymphadenopathy, NOTCH1
mutations, del(17)(p13.1), and a specific stereotyped IGVH usage.
Lymphomas arising in the setting of CLL can either be clonally related
or unrelated to the initial CLL, with prognosis significantly better for
clonally unrelated lymphomas. In addition, patients with Hodgkin’s
transformation have improved outcome when treated with standard
Hodgkin’s disease treatment. B-cell prolymphocytic leukemia (PLL)
arising from CLL is currently classified as Richter’s transformation as
well; however, clinical features and therapy are quite different, so these
two should be differentiated for therapeutic purposes.
Clinical signs of Richter’s transformation include rapid progression
in adenopathy, often in a specific area, and constitutional symptoms
including fatigue, night sweats, fever, and weight loss. LDH is usually
high. In suspected cases, the first step is 18FDG-PET/CT (fluorode­
oxyglucose–positron emission tomography combined with computed
tomography) scan to localize an area for biopsy. Standardized uptake
values (SUVs) <5 are consistent with CLL and can rule out Richter’s
transformation in many cases. SUVs >5 are suspicious for Richter’s
transformation, with SUVs ≥10 being very concerning. Excisional
biopsy is the preferred mode of diagnosis, and fine-needle aspiration
should be discouraged.
Therapy for DLBCL Richter’s transformation usually involves com­
bination chemoimmunotherapy. Outcomes are poor, with median
survivals of 6–16 months in most series for clonally related Richter’s
versus ~5 years for clonally unrelated. This highlights an area of unmet
need in CLL therapy and an area of active investigation. Intensive
chemotherapy is ineffective for most patients and results in significant
toxicity. For fit patients who achieve a response with therapy, stem
cell transplantation has the possibility to induce long-term remissions
and should be explored. In addition, chimeric antigen receptor (CAR)
T-cell (CAR-T) therapy has shown promising results in small groups
of patients and remains an area of active clinical investigation. Limited
data using bispecific antibodies are also encouraging. Patients with
Hodgkin’s disease can be treated according to the algorithm for this
disease, with many individuals being cured.
PART 4
Oncology and Hematology
WORKUP OF CLL AND APPROACH TO
THERAPY
■
■WORKUP AND STAGING
Workup of a patient with new diagnosis of CLL based on typical
immunophenotyping includes a detailed history of infectious disease;
family history of CLL; and careful physical examination with attention
to the lymph nodes, spleen, and liver. In patients desiring to know the
expected natural history of their CLL, prognostic testing using FISH
and stimulated karyotype and sequencing for TP53 and IGHV muta­
tion status can be performed. Imaging with CT scan is usually not
necessary unless there are symptoms and concern for intraabdominal
nodes out of proportion to peripheral nodes. Bone marrow biopsy is
not undertaken until therapy is initiated, except in cases of unexplained
cytopenias.
■
■STAGING
There are two widely used staging systems in CLL: The Rai staging
system is used more commonly in the United States, whereas the Binet
system is more commonly used in Europe. Both characterize CLL on
the basis of disease bulk and marrow failure (Table 112-3). Both rely
on physical examination and laboratory studies and do not require
TABLE 112-3  Staging of CLL
Rai Staging System
Low risk (stage 0)
Lymphocytosis only
Intermediate risk (stage I/II)
Lymphocytosis with lymphadenopathy, with or
without splenomegaly or hepatomegaly
High risk (stage III/IV)
Lymphocytosis with anemia or thrombocytopenia
due to bone marrow involvement
Binet Staging System
A
<3 areas of lymphadenopathy
B
≥3 areas of lymphadenopathy
C
Hemoglobin ≤10 g/dL and/or platelets <100,000/μL
Abbreviation: CLL, chronic lymphocytic leukemia.
TABLE 112-4  CLL International Prognostic Index
Risk Score
 
 
VARIABLE
ADVERSE FACTOR
RISK SCORE
TP53 status
Deleted or mutated
IGHV mutational status
Unmutated
3.5 mg/L
β2-Microglobulin
concentration
Clinical stage
Rai I–IV or Binet B–C
Age
65 years
Implications of Risk Score  
5-YEAR SURVIVAL
(TRAINING SET DATA)
RISK SCORE
RISK CLASSIFICATION
0-1
Low
93.2%
2-3
Intermediate
79.3%
4-6
High
63.3%
7-10
Very high
23.3%
imaging or bone marrow analysis. While the initial staging systems
could reliably predict survival in CLL, with the changes in therapy
since the original description of the stages, the impact of initial stage
on survival is not as clear. Cytogenetic and genomic testing can help
refine outcome of these staging tests. An international collaboration
integrated both clinical and genomic staging to better predict outcome
at diagnosis and time of initial treatment, which led to development of
the CLL International Prognostic Index (Table 112-4). This index has
been shown to be useful in prediction of both time to first treatment
and outcome with chemoimmunotherapy. Validation in the setting of
novel targeted therapies has not occurred.
■
■CRITERIA FOR THE INITIATION OF THERAPY
Currently, a watchful waiting strategy is used for most patients with
CLL, with therapy reserved for patients with symptomatic disease.
This recommendation is based on multiple trials showing no survival
advantage with earlier therapy, although this question continues to be
a focus of active investigation.
With the exception of patients participating in early intervention
studies in CLL, disease-related symptoms that require the initiation of
therapy are outlined in Table 112-5. Except for the rare patient who
presents with disease requiring urgent therapy, in most cases, these
symptoms can be monitored over short periods to determine related­
ness to CLL and need for therapy.
■
■INITIAL THERAPY FOR CLL
Over the past decade, the initial therapy of CLL has dramatically
changed. Whereas chemoimmunotherapy was once standard for all
patients, now most patients are treated with oral therapies targeted
TABLE 112-5  Criteria for the Initiation of Therapy
Symptoms Indicating Need for Therapy in CLL
Evidence of progressive marrow failure (worsening of anemia or
thrombocytopenia not due to autoimmune destruction)
Massive (≥6 cm below costal margin), progressive, or symptomatic splenomegaly
Massive (≥10 cm), progressive, or symptomatic lymphadenopathy
Progressive lymphocytosis with an increase of ≥50% over a 2-month period or
lymphocyte doubling time <6 months
Autoimmune anemia or thrombocytopenia not responsive to standard therapy
Symptomatic or functional extranodal involvement
Constitutional symptoms (one or more of the following: unintentional weight loss
≥10% over 6 months, significant fatigue, fevers ≥100.5°F for 2+ weeks without
infection, night sweats for >1 month without infection)
Abbreviation: CLL, chronic lymphocytic leukemia.
against BTK or BCL2 with an anti-CD20 monoclonal antibody. This
continues to be an area of active investigation, with standards of care
shifting rapidly. The major classes of these therapies will be outlined
here.
BTK Inhibitors 
BTK is an attractive target in CLL because,
unlike other kinases in the BCR pathway, BTK does not have natu­
ral redundancy and is relatively selective for B cells, so inhibition
leads to a predominant B-cell–specific phenotype. The first-in-class
covalent BTK inhibitor is ibrutinib, which is relatively selective for
BTK but also inhibits a number of structurally similar kinases. As
initial therapy, ibrutinib was initially compared with chlorambucil
(RESONATE study), and there was an 84% lower risk of progression
or death with ibrutinib, with 59% of ibrutinib-treated patients alive
and progression-free at 7 years. Subsequent studies have compared
ibrutinib alone or with the anti-CD20 antibody rituximab to standard
chemoimmunotherapy with fludarabine plus cyclophosphamide plus
rituximab (FCR) or bendamustine plus rituximab (BR) and shown
superiority of targeted therapy to chemoimmunotherapy. Ibrutinib
also has immune modulatory roles to expand and also enhance T-cell
function that may improve CAR-T efficacy. Side effects noted to occur
with this class of agents include arthralgias/myalgias, rash, diarrhea,
dyspepsia, bruising/bleeding (particularly when on antiplatelet/antico­
agulation therapy or with surgery), hypertension, atrial fibrillation, and
ventricular arrhythmias.
Two second-generation covalent BTK inhibitors, acalabrutinib and
zanubrutinib, were developed to be more specific for BTK than ibruti­
nib and consequentially show better tolerability. Two trials performed
in relapsed/refractory CLL have positioned acalabrutinib and zanubru­
tinib as preferred BTK inhibitors compared with ibrutinib. Acalabru­
tinib was compared head-to-head with ibrutinib in previously treated
patients with high-risk relapsed CLL in the ELEVATE-RR trial. Acala­
brutinib was shown to be noninferior to ibrutinib in terms of efficacy
and to have lower rates of atrial fibrillation, hypertension, myalgias/
arthralgias, bruising, and skin and nail changes than reported with
ibrutinib. Zanubrutinib was compared head-to-head with ibrutinib in
the ALPINE trial, which enrolled patients with relapsed CLL without
regard to risk status. In this study, zanubrutinib was shown to be supe­
rior to ibrutinib in terms of overall response rate and progression-free
survival (PFS). Zanubrutinib was also associated with lower rates of
atrial fibrillation but similar rates of other adverse events.
Because acalabrutinib and zanubrutinib are newer, follow-up is
shorter than with ibrutinib, but all three covalent BTK inhibitors
appear to be similarly active in the frontline setting. Acalabrutinib was
studied in the treatment-naïve setting in the ELEVATE-TN trial, where
acalabrutinib resulted in a 6-year PFS of 62% and acalabrutinib given
with obinutuzumab resulted in a 4-year PFS of 78%. Zanubrutinib was
studied in treatment-naïve CLL in the SEQUOIA study, where 2-year
PFS was 85.5% for patients treated with zanubrutinib.
Importantly, with the follow-up that is available from frontline
studies of covalent BTK inhibitors in CLL, traditional prognostic fac­
tors, including IGHV mutational status and FISH, have less impact on
outcome. Indeed, age and performance status were the only variables
that predicted survival in the ELEVATE-TN trial.
BCL2 Inhibitor 
Venetoclax is an orally bioavailable, selective
allosteric inhibitor of the antiapoptotic protein BCL2, which is upregu­
lated in CLL. Similar to the BTK inhibitors, phase 3 trials support the
frontline use of venetoclax in combination with obinutuzumab (VO)
compared with chemoimmunotherapy. The CLL14 study compared
VO versus chlorambucil plus obinutuzumab in previously untreated
patients with coexisting medical conditions. Unlike BTK inhibitors,
which are continuously administered until disease progression, VO
treatment is administered for a fixed duration of 1 year. Median PFS
for VO was 76.2 months, compared with 36.4 months for patients
treated with chlorambucil plus obinutuzumab. The CLL13/GAIA trial
also studied VO, as well as VO plus ibrutinib (IVO) and venetoclax
plus rituximab (VR), compared with effective chemoimmunotherapy
regimens (FCR for younger patients and BR for older patients) in fit
patients. At 4 years, VO and IVO showed superior PFS compared with
chemoimmunotherapy (81.8% and 85.5%, respectively, vs 77.2%), but
VR was not superior to chemoimmunotherapy. Side effects associated
with venetoclax include tumor lysis syndrome, neutropenia, and nau­
sea/vomiting/diarrhea. Importantly, genomic risk features including
IGHV mutational status and FISH/cytogenetics appear to be more
relevant to PFS with fixed-duration VO therapy as compared with
indefinite BTK inhibitor therapy.
Targeted Therapy Combinations 
Due to synergy between BTK
and BCL2 inhibition, there has been considerable interest in studies
combining agents with these two mechanisms to allow for fixedduration therapies. As described earlier, 1-year fixed-duration IVO was
shown to be superior to chemoimmunotherapy in previously untreated
fit patients in the CLL13/GAIA study. The GLOW study is a registra­
tion trial comparing ibrutinib plus venetoclax (IV) to chemoimmuno­
therapy in previously untreated older or unfit patients. In this trial with
1 year of IV, 42-month PFS was 74.6% for IV compared with 24.8% for
chlorambucil plus obinutuzumab. Although this study led to regulatory
approval of IV in Europe, it is not approved by the U.S. Food and Drug
Administration (FDA). It is not yet clear whether IV or IVO is a more
effective therapy than the other fixed-duration standard, VO. Current
studies are also using more selective inhibitors of BTK in an attempt to
improve efficacy and safety of these combinations.
CHAPTER 112
Chemoimmunotherapy 
For the most part, targeted therapy
has supplanted chemoimmunotherapy in CLL. However, long-term
follow-up of studies of FCR has demonstrated that a subset of patients
treated with this regimen can have durable responses over 20 years,
with a likely cure of CLL. This group is composed almost exclusively
of patients with mutated IGVH and favorable cytogenetics. However,
despite the efficacy of this regimen, short- and long-term toxicities
limit its adaptability to many patients with IGHV-mutated disease.
Short-term toxicities are mostly related to myelosuppression and
include neutropenia and infection. Long-term cytopenias are less com­
mon, but they do occur. Also, there is about a 3–5% risk of therapyrelated myeloid neoplasm with this regimen that is almost always fatal.
In the E1912 study of FCR versus ibrutinib plus rituximab (IR), at
follow-up, there was no difference in PFS or overall survival between
FCR and IR for patients with mutated IGHV, suggesting that a place for
this regimen may remain in clinical practice. In addition, current stud­
ies are focused on limiting chemotherapy and/or adding novel agents
in efforts to achieve cure but limit toxicity.
Chronic Lymphocytic Leukemia
■
■THERAPY OF RELAPSED CLL
Currently, the mainstays of treatment for relapsed CLL are the same
classes as initial therapy, and the choice of second-line therapy is heav­
ily dependent on the agent that was used in the frontline setting. The
optimal sequencing of targeted agents in CLL has not been established;
however, the available data suggest that the sequence of either BTK
inhibitor and then BCL2 inhibitor and the reverse are both accept­
able. In addition, some patients treated initially with venetoclax-based
regimens can likely be successfully retreated with venetoclax. In a trial
of venetoclax for patients who had relapsed after ibrutinib therapy,
overall response rate (ORR) was 65%, with a median PFS of ~2 years,
in a very heavily pretreated patient population. Retrospective data of a
BTK inhibitor given after venetoclax suggest that this sequence is also
effective, with an ORR of 84% and median PFS of 32 months. PI3K
inhibitors also have activity in relapsed CLL; however, activity follow­
ing both BTK and BCL2 inhibitors is likely minimal. In addition, many
new agents are in development in CLL, including novel oral targeted
therapies, antibodies, and immune-based treatments.
Noncovalent Inhibitors of BTK 
Despite the activity of covalent
BTK inhibitors in CLL, a subset of patients will eventually relapse, and
the primary mechanism of acquired resistance to ibrutinib, acalabru­
tinib, and zanubrutinib is acquisition of a mutation at the binding site
of the drug (predominantly BTK C481S). Noncovalent BTK inhibitors
TABLE 112-6  Response Criteria in CLL
LYMPHOCYTE
COUNT
LYMPH NODESa
SPLEEN/LIVER SIZEb
BONE MARROWc
PERIPHERAL BLOOD COUNTS
 
CR
<4000/μL
None >1.5 cm
Not palpable
Normocellular, <30%
lymphocytes, no B
lymphoid nodules
PR
Decrease ≥50%
from baseline
Decrease ≥50% from
baseline
Decrease ≥50% from
baseline
Stable disease
Not meeting CR/
PR/PD criteria
Not meeting CR/PR/
PD criteria
Not meeting CR/PR/PD
criteria
PD
Increase ≥50%
Increase ≥50%
Increase ≥50%
 
• Platelet count ≤50% of baseline due to CLL
• Hemoglobin decrease >2 g/dL due to CLL
aRefers to sum of the products of multiple lymph nodes evaluated by CT scan. bBased on physical examination. cBone marrow only required to confirm CR.
Abbreviations: CLL, chronic lymphocytic leukemia; CR, complete response; PD, progressive disease; PR, partial response.
have been developed to overcome this resistance mechanism by bind­
ing both reversibly and to alternative sites on BTK. Pirtobrutinib is
the first in class of these agents and is an extremely selective inhibitor
of BTK that has achieved accelerated approval by the U.S. FDA for
use in patients who have been previously treated with both BTK and
BCL2 inhibitors. This is based on the BRUIN study, where an overall
response rate of 82.2% and median PFS of 19.6 months were seen in a
heavily pretreated high-risk group of patients, with equivalent efficacy
noted for patients with C481S mutations in BTK.
PART 4
Oncology and Hematology
Immune Therapies 
Immune therapies in CLL are currently
focused in the relapsed setting and include allogenic stem cell trans­
plantation, CAR-T therapy, and bispecific antibodies.
Stem cell transplantation is a curative approach to CLL. Because
most CLL patients are older and many have significant comorbidities,
myeloablative transplants incur extensive morbidity and mortality,
making them prohibitive in many individuals. Reduced-intensity
conditioning (RIC) allogeneic transplants have been successfully incor­
porated into the treatment of patients up to ~75 years in age but still
have a ≥50% frequency of chronic graft-versus-host disease. This is still
considered a standard treatment in CLL but has fallen out of favor with
the introduction of well-tolerated novel agents, as well as clinical trials
of CAR-T therapy. CD19 CAR-T trials have not been as successful in
CLL as they have in other B-cell malignancies, due to the immunosup­
pression associated with the disease. The most robust data have come
with lisocabtagene maraleucel (liso-cel), where in the TRANSCEND
CLL 004 trial, the ORR was 43%, with a median PFS of 11.9 months
in patients previously treated with BTK inhibitors and venetoclax.
Many current trials are focused on optimizing CD19 CAR-T by add­
ing agents such as BTK inhibitors or PI3K inhibitors or modifying the
CAR-T structure, and other studies are testing different targets outside
of CD19. This area remains a focus of intense investigation in CLL.
■
■ASSESSING RESPONSE TO THERAPY AND
MINIMAL RESIDUAL DISEASE IN CLL
Following the completion of therapy or during therapy for indefinite
targeted agents, response is initially assessed using physical exami­
nation and laboratory studies (Table 112-6). If residual disease is
not detected using these methodologies, CT scans are used to assess
response. Bone marrow biopsies with flow cytometry are indicated if
no disease is detected to confirm CR.
It has been established in various malignancies that complete
tumor eradication is associated with longer survival. In CLL, if no
malignant cells can be detected in the bone marrow down to a level
of 1 CLL cell in 104 leukocytes (0.01%), the patient is said to be
negative for minimal residual disease (MRD). Following combination
• Platelet count >100,000/μL
• Hemoglobin >11 g/dL
• Neutrophils >1500/μL
Infiltrate ≤50% of baseline
One of the following:
• Platelet count >100,000/μL or ≥50% from baseline
• Hemoglobin >11 g/dL or ≥50% from baseline
• Neutrophils >1500/μL or ≥50% from baseline
Not meeting CR/PR/PD
criteria
Not meeting CR/PR/PD criteria
chemoimmunotherapy, eradication of MRD correlates with long-term
survival and potentially cure in a subset of patients receiving FCR
chemoimmunotherapy. Undetectable MRD in blood or bone mar­
row is also associated with improvement in PFS in venetoclax-based
regimens. However, eradication of MRD has not been shown to be
a meaningful endpoint with BTK inhibitors as monotherapy. Higher
sensitivity of 1 CLL in 106 leukocytes (0.0001%) can be obtained using
next-generation sequencing methods such as ClonoSeq. Treatment of
MRD-relapsing CLL is being explored as part of clinical trials.
■
■CONCLUSION
CLL is treated only when it becomes symptomatic. At the time of ther­
apy, FCR chemoimmunotherapy in a small subset of young patients
with very good risk CLL is potentially curative. In the majority of
patients with symptomatic CLL, targeted therapy directed at BTK and/
or BCL2 can produce durable remissions and allow patients many years
of disease-free survival.
■
■FURTHER READING
Brown JR et al: Zanubrutinib or ibrutinib in relapsed or refractory
chronic lymphocytic leukemia. N Engl J Med 388:319, 2023.
Byrd JC et al: Acalabrutinib versus ibrutinib in previously treated
chronic lymphocytic leukemia: Results of the first randomized phase
III trial. J Clin Oncol 39:3441, 2021.
Fischer K et al: Venetoclax and obinutuzumab in patients with CLL
and coexisting conditions. N Engl J Med 380:2225, 2019.
Hallek M et al: iwCLL guidelines for diagnosis, indications for treat­
ment, response assessment, and supportive management of CLL.
Blood 131:2745, 2018.
Landau DA et al: Evolution and impact of subclonal mutations in
chronic lymphocytic leukemia. Cell 152:714, 2013.
Mato AR et al: Pirtobrutinib after a covalent BTK inhibitor in chronic
lymphocytic leukemia. N Engl J Med 389:33, 2023.
Puente XS et al: Whole-genome sequencing identifies recurrent muta­
tions in chronic lymphocytic leukaemia. Nature 475:101, 2011.
Sharman JP et al: Acalabrutinib with or without obinutuzumab versus
chlorambucil and obinutuzumab for treatment-naïve chronic lym­
phocytic leukemia (ELEVATE TN): A randomized, controlled, phase
3 trial. Lancet 395:1278, 2020.
Siddiqi T et al: Lisocabtagene maraleucel in chronic lymphocytic
leukaemia and small lymphocytic lymphoma (TRANSCEND CLL
004): A multicentre, open-label, single-arm, phase 1–2 study. Lancet
402:641, 2023.
Thompson PA et al: Fludarabine, cyclophosphamide, and rituximab
treatment achieves long-term disease-free survival in IGHV-mutated
chronic lymphocytic leukemia. Blood 127:303, 2016.

43 - 113 Non-Hodgkin’s Lymphoma
113 Non-Hodgkin’s Lymphoma
Caron A. Jacobson, Dan L. Longo
Non-Hodgkin’s
Lymphoma
Non-Hodgkin’s lymphomas (NHLs) are cancers of mature B, T, and
natural killer (NK) cells. They were distinguished from Hodgkin’s lym­
phoma (HL) upon recognition of the Reed-Sternberg (RS) cell and dif­
fer from HL with respect to their biologic and clinical characteristics.
Whereas ∼80–85% of patients with HL will be cured of their lymphoma
by chemotherapy with or without radiotherapy, the prognosis and
natural history of NHL tend to be more variable. NHL can be classi­
fied as either a mature B-NHL or a mature T/NK-NHL depending on
whether the cancerous lymphocyte is a B, T, or NK cell, respectively.
Within each category are lymphomas that grow quickly and behave
aggressively, as well as lymphomas that are more indolent, or slow
growing, in nature. For a list of the World Health Organization (WHO)
classification of lymphoid neoplasms, see Table 113-1.
■
■EPIDEMIOLOGY AND ETIOLOGY
In 2023, it is estimated that there will be 80,550 new cases of NHL in
the United States, ∼4% of all new cancers in both males and females,
making it the seventh most common cause of cancer-related death in
both women and men. The incidence is nearly 10 times the incidence
TABLE 113-1  WHO-HAEM5 Classification of Lymphoid Malignancies
B CELL
T CELL
Mature (peripheral) B-cell neoplasms
Mature (peripheral) T-cell neoplasms
  Lymphoplasmacytic lymphoma
  T-cell granular lymphocytic leukemia
(Waldenström’s macroglobulinemia)
  Hairy cell leukemia
  Splenic marginal zone B-cell
  Adult T-cell leukemia/lymphoma
(HTLV-1+)
  Extranodal NK/T-cell lymphoma,
lymphoma
  Extranodal marginal zone B-cell
nasal type
  Enteropathy-associated T-cell
lymphoma of MALT type
  Nodal marginal zone B-cell
lymphoma
  Hepatosplenic T-cell lymphoma
lymphoma
  Follicular lymphoma
  Mantle cell lymphoma
  Diffuse large B-cell lymphoma
  Subcutaneous panniculitis-like T-cell
lymphoma
  Mycosis fungoides
  Sezary syndrome
(including subtypes)
  High-grade B-cell lymphoma with
  Peripheral T-cell lymphoma NOS
MYC and BCL2 rearrangements
  High-grade B-cell lymphoma NOS
  High-grade B-cell lymphoma with
  Angioimmunoblastic T-cell
lymphoma
  Anaplastic large-cell lymphoma,
ALK+
11q aberrations
  Burkitt’s lymphoma/Burkitt’s cell
  Anaplastic large-cell lymphoma,
ALK–
leukemia
  Primary mediastinal large B-cell
lymphoma
  Mediastinal grey zone lymphoma
  Primary large B-cell lymphoma of
immune-privileged sites
  Plasmablastic lymphoma
 
  Primary effusion lymphoma
 
  HHV8+ DLBCL NOS
 
  Intravascular large B-cell lymphoma
 
  ALK+ large B-cell lymphoma
 
Abbreviations: DLBCL, diffuse large B-cell lymphoma; HHV, human herpesvirus;
HTLV, human T-cell lymphotropic virus; MALT, mucosa-associated lymphoid tissue;
NK, natural killer; NOS, not otherwise specified; WHO, World Health Organization.
Source: Adapted from R Alaggio et al: The 5th edition of the World Health
Organization classification of haematolymphoid tumours: Lymphoid neoplasms.
Leukemia 36:1720, 2022.
of HL. There is a slight male-to-female predominance and a higher
incidence for Caucasians than for African Americans. The incidence
rises steadily with age, especially after age 40, but lymphomas are also
among the most common malignancies in adolescent and young adult
patients. The incidence of NHL has nearly doubled over the past 20–40
years and continues to rise by 1.5–2% each year. Patients with both
primary and secondary immunodeficiency states are predisposed to
developing NHL. These include patients with HIV infection, patients
who have undergone organ transplantation, and patients with inherited
immune deficiencies and autoimmune conditions. The 5-year survival
rate for NHL is 74% and is higher for Caucasians than it is for African
Americans.
The incidence of NHL and the patterns of expression of the various
subtypes differ geographically and across age groups. T-cell lympho­
mas are more common in Asia than in Western countries, whereas
certain subtypes of B-cell lymphomas such as follicular lymphoma (FL)
are more common in Western countries. A specific subtype of NHL
known as the angiocentric nasal T/NK-cell lymphoma has a striking
geographic occurrence, being most frequent in southern Asia and parts
of Latin America. Another subtype of NHL associated with infection
by human T-cell lymphotropic virus (HTLV) 1 is seen particularly in
southern Japan and the Caribbean (see Chap. 207). Likewise, there
are differences in the age-dependent incidence of NHL by histologic
subtype, with aggressive lymphomas like diffuse large B-cell lymphoma
(DLBCL) and Burkitt’s lymphoma (BL) being the most common enti­
ties in children, and DLBCL and indolent lymphomas including FL
being the most common forms in adults. The relative frequencies of
the various types of lymphoid malignancies, including HL, plasma cell
disorders, and lymphoid leukemias, are shown in Fig. 113-1.
CHAPTER 113
Non-Hodgkin’s Lymphoma
A number of environmental factors have been implicated in the
occurrence of NHL, including infectious agents, chemical exposures,
and medical treatments. Several studies have demonstrated an associa­
tion between exposure to agricultural chemicals and an increased inci­
dence of NHL. Patients treated for HL can develop NHL; it is unclear
whether this is a consequence of the HL or its treatment, especially
radiation.
Several NHLs are associated with infectious agents (Table 113-2).
Epstein-Barr virus (EBV) is associated with the development of BL
in Central Africa and the occurrence of aggressive NHL in immuno­
suppressed patients in Western countries. The majority of primary
central nervous system (CNS) lymphomas are associated with EBV.
EBV infection is strongly associated with the occurrence of extrano­
dal nasal NK/T-cell lymphomas in Asia and South America. HTLV-1
infects T cells and leads directly to the development of adult T-cell
lymphoma (ATL) in a small percentage of patients infected as babies
through ingestion of breast milk of infected mothers. The median age
of patients with ATL is ∼56 years; thus, HTLV-1 demonstrates a long
latency from infection to oncogenesis (Chap. 207). Infection with HIV
predisposes to the development of aggressive B-cell NHL. This may
be through overexpression of interleukin 6 by infected macrophages.
Infection of the stomach by the bacterium Helicobacter pylori induces
the development of gastric mucosa-associated lymphoid tissue (MALT)
lymphomas. This association is supported by evidence that patients
treated with antibiotics to eradicate H. pylori have regression of their
MALT lymphoma. The bacterium does not transform lymphocytes to
produce the lymphoma; instead, a vigorous immune response is made
to the bacterium, and the chronic antigenic stimulation leads to the
neoplasia. MALT lymphomas of the skin may be related to Borrelia
species infections in Europe, those of the eyes to Chlamydophila psit­
taci, and those of the small intestine to Campylobacter jejuni. Chronic
hepatitis C virus infection has been associated with the development of
lymphoplasmacytic lymphoma and splenic marginal zone lymphoma
(MZL). Human herpesvirus 8 is associated with primary effusion lym­
phoma in HIV-infected persons and multicentric Castleman’s disease, a
diffuse lymphadenopathy associated with systemic symptoms of fever,
malaise, and weight loss.
In addition to infectious agents, a number of other diseases or expo­
sures may predispose to developing lymphoma (Table 113-3). Diseases
of inherited and acquired immunodeficiency as well as autoimmune
Plasma cell
disorders
16%
CLL
9%
Non-Hodgkin’s
lymphoma
62.4%
Hodgkin’s
disease
8.2%
ALL
3.8%
PART 4
Oncology and Hematology
FIGURE 113-1  Relative frequency of lymphoid malignancies. ALL, acute lymphoid leukemia; CLL, chronic lymphocytic leukemia; MALT, mucosa-associated lymphoid tissue.
diseases are associated with an increased incidence of lymphoma.
The association between immunosuppression and induction of NHLs
is compelling because if the immunosuppression can be reversed, a
percentage of these lymphomas regress spontaneously. The incidence
of NHL is nearly a hundredfold increased for patients undergoing
organ transplantation necessitating chronic immunosuppression and
is greatest in the first year posttransplant. About 30% of these arise
as a polyclonal B-cell proliferation that evolves into a clonal B-cell
malignancy. The NHLs that occur in the context of immunosuppres­
sion or immunodeficiency, including HIV infection, are frequently
associated with EBV. Histologically, DLBCLs are most frequently asso­
ciated with immunosuppression and autoimmune diseases, although
almost all histologies can be seen, especially MALT lymphomas in
the context of autoimmune diseases such as Sjögren’s syndrome and
Hashimoto’s thyroiditis. The rare inherited immunodeficiency diseases
X-linked lymphoproliferative syndrome, Wiskott-Aldrich syndrome,
Chédiak-Higashi syndrome, ataxia-telangiectasia, and common vari­
able immunodeficiency syndrome are complicated by highly aggressive
TABLE 113-2  Infectious Agents Associated with the Development of
Lymphoid Malignancies
INFECTIOUS AGENT
LYMPHOID MALIGNANCY
Epstein-Barr virus
Burkitt’s lymphoma
 
Post–organ transplant lymphoma
 
Primary CNS diffuse large B-cell lymphoma
 
Hodgkin’s lymphoma
 
Extranodal NK/T-cell lymphoma, nasal type
HTLV-1
Adult T-cell leukemia/lymphoma
HIV
Diffuse large B-cell lymphoma
 
Burkitt’s lymphoma
Hepatitis C virus
Lymphoplasmacytic lymphoma
Helicobacter pylori
Gastric MALT lymphoma
Human herpesvirus 8
Primary effusion lymphoma
 
Multicentric Castleman’s disease
Abbreviations: CNS, central nervous system; HIV, human immunodeficiency virus;
HTLV, human T-cell lymphotropic virus; MALT, mucosa-associated lymphoid tissue;
NK, natural killer.
Non-Hodgkin’s
lymphoma
subtypes
31% Diffuse large B-cell lymphoma
22% Follicular lymphoma
7.6% MALT lymphoma
7.6% Mature T-cell lymphoma
6.7% Small lymphocytic lymphoma
6% Mantle cell lymphoma
2.4% Mediastinal large B-cell lymphoma
2.4% Anaplastic large-cell lymphoma
2.4% Burkitt’s lymphoma
1.8% Nodal marginal zone lymphoma
1.7% Precursor T-lymphoblastic lymphoma
1.2% Lymphoplasmacytic lymphoma
7.4% Others
lymphomas. The elevated incidence of lymphoma in iatrogenic immu­
nosuppression, AIDS, and autoimmune disease argues strongly for
immune dysregulation contributing to the pathogenesis of some lym­
phomas. An increased risk of NHL has been observed in first-degree
relatives with NHL, HL, or chronic lymphocytic leukemia (CLL). In
large database studies, ∼9% of patients with lymphoma or CLL have a
first-degree relative with a lymphoproliferative disorder.
■
■IMMUNOLOGY
All lymphoid cells are derived from a common hematopoietic pro­
genitor that gives rise to lymphoid, myeloid, erythroid, monocyte, and
megakaryocyte lineages. Through the ordered and sequential activa­
tion of a series of transcription factors, the cell first becomes commit­
ted to the lymphoid lineage and then gives rise to B and T cells.
About 90% of all lymphomas are of B-cell origin. A cell becomes
committed to B-cell development when it expresses the master B lin­
eage transcription factor PAX5, which ultimately results in a transcrip­
tional program that leads to the rearrangement of its immunoglobulin
genes, which involves chromosomal recombination as well as somatic
hypermutation to create an immunoglobulin gene that is unique to
that B cell. The sequence of cellular changes, including changes in
TABLE 113-3  Diseases or Exposures Associated with Increased Risk of
Development of Malignant Lymphoma
Inherited immunodeficiency disease
  Klinefelter’s syndrome
  Chédiak-Higashi syndrome
  Ataxia-telangiectasia syndrome
  Wiskott-Aldrich syndrome
  Common variable immunodeficiency
Autoimmune disease
  Sjögren’s syndrome
  Celiac sprue
  Rheumatoid arthritis and systemic
lupus erythematosus
Chemical or drug exposures
  Phenytoin
  Dioxin, phenoxy herbicides
  Radiation
  Prior chemotherapy and radiation
disease
Acquired immunodeficiency diseases
  Iatrogenic immunosuppression
  HIV-1 infection
  Acquired hypogammaglobulinemia
therapy
  Anti-TNF drugs
Abbreviations: HIV, human immunodeficiency virus; TNF, tumor necrosis factor.
Bone marrow
Pre–B ALL
Unclassified
ALL
TdT
HCR
κR or D
TdT
TdT
HCR
HCR
λR or D
H
H
HLA–DR+
CD19+
HLA–DR+
HLA–DR+
CD19+
CD19+
CD10+
CD10+
CD20+
CD22+
Lymphoid
stem cell
Early B cells
Intermediate B cells
Mature
B cells
Antigen-independent differentiation
Antigen-driven differentiation
FIGURE 113-2  Pathway of normal B-cell differentiation and relationship to B-cell lymphomas. HLA-DR, CD10, CD19, CD20, CD21, CD22, CD5, and CD38 are cell markers
used to distinguish stages of development. Terminal transferase (TdT) is a cellular enzyme. Immunoglobulin heavy chain gene rearrangement (HCR) and light chain gene
rearrangement or deletion (κR or D, λR or D) occur early in B-cell development. The approximate normal stage of differentiation associated with particular lymphomas is
shown. ALL, acute lymphoid leukemia; CLL, chronic lymphocytic leukemia; SL, small lymphocytic lymphoma.
cell-surface phenotype that characterizes normal B-cell development,
is shown in Fig. 113-2. Most B-cell lymphomas arise following the
process of immunoglobulin gene recombination and somatic hyper­
mutation, which leads to class switching and affinity maturation of the
mature immunoglobulin, respectively, suggesting that it is the errorprone nature of these genetic events that contributes to oncogenesis.
Certainly the frequency of chromosomal translocations that result in
the activation of an oncogene or the inactivation of a tumor-suppressor
gene in B-cell NHL may be the result of these normal cellular processes
gone awry (see below). In addition, the key roles of the transcription
factors MYC and BCL6 and the antiapoptotic protein BCL2 in the
process of B-cell development explain why the genes encoding these
proteins are commonly mutated in B-cell lymphomas.
A cell becomes committed to T-cell differentiation upon migration
to the thymus and rearrangement of T-cell receptor (TCR) genes. This
requires the expression of the T-cell master regulatory transcription
factor, NOTCH-1. As in B cells, the development of the mature TCR
involves the rearrangement and recombination of the TCR loci, which
is error-prone and potentially oncogenic. The sequence of the events
that characterize T-cell development is depicted in Fig. 113-3.
Although lymphoid malignancies often retain the cell-surface
phenotype of lymphoid cells at particular stages of differentiation,
this information is of little clinical or prognostic consequence. The
so-called stage of differentiation of a malignant lymphoma does not
predict its natural history. The antigen footprint, or immunopheno­
type, of the cell, however, is valuable diagnostically as it allows for the
distinguishing of specific NHL subtypes. It can be detected by flow
Follicular/diffuse
IgM±IgG
or
IgG
lymphomas
Burkitt’s
Lymphoid follicle
HLA–DR+
IgM
IgM
IgM
CD19+/−
CD20+
IgD
IgG
CD22+/−
CD21+/−
Follicular center B cells
Multiple
myeloma
HLA–DR+
HLA–DR+
HLA–DR+
Waldenström’s
CD19+
CD19+
CD19+
IgM
CD20+
CD20+
CD20+
CD22+
CD22+
CD22+
CD21+
CD21+
CD21+
Mantle cell
lymphoma
CLL
SL
CD19+/−
CD38+
CD20+
PCA–1+
IgM±IgD
IgM
IgD
CD38+
CHAPTER 113
Secretory B cells
HLA–DR+
HLA–DR+
CD19+
CD19+
Non-Hodgkin’s Lymphoma
CD10+/−
CD20+
CD20+
CD22+/−
CD22+
CD21+
CD21+
CD5+
CD5+
Mantle zone B cells
cytometry of single-cell suspension from blood, bone marrow, body
fluid, or disaggregated tissue using fluorescently labeled antibodies
against these antigens or by immunohistochemical staining of paraffinembedded tissue sections with enzyme-linked antibodies against these
antigens followed by a colorimetric reaction.
As already mentioned, malignancies of lymphoid cells are associated
with recurring genetic abnormalities including chromosomal translo­
cations and genetic mutations that may in part be the result of aberrant
immunoglobulin or TCR development. While specific genetic abnor­
malities have not been identified for all subtypes of lymphoid malig­
nancies, it is presumed that they exist. As previously discussed, B cells
are even more susceptible to acquiring mutations during their matura­
tion in germinal centers; the generation of antibody of higher affinity
requires the introduction of mutations into the variable region genes in
the germinal centers. Given this, other nonimmunoglobulin genes, e.g.,
bcl-6, may acquire mutations as well. Likewise, many lymphomas con­
tain balanced chromosomal translocations involving the antigen recep­
tor genes; immunoglobulin genes on chromosomes 2, 14, and 22 in B
cells; and T-cell antigen receptor genes on chromosomes 7 and 14 in T
cells. The rearrangement of chromosome segments to generate mature
antigen receptors must create a site of vulnerability to aberrant recom­
bination. Examples of this type of event include the (8;14)(q24;q32)
translocation in BL, involving the MYC proto-oncogene and the IgH
gene; the (14;18)(q32;q32) translocation in FL, involving the BCL2
proto-oncogene and the IgH gene; and the (11;14) (q13;q32) translo­
cation in mantle cell lymphoma (MCL), involving the gene encoding
cyclin D1 (CCDN1) and the IgH gene. Less commonly, chromosomal
T-CELL
DIFFERENTIATION
T-CELL
MALIGNANCIES
THYMUS
Stage I
Prothymocyte
Majority of
T-cell ALL
CD:  2, 7, 38, 71
Stage II
Thymocyte
Minority of T-ALL
Majority of T-LL
CD:  1, 2, 4, 7, 8, 38
Stage III
Thymocyte
Minority of T-LL
Rare T-ALL
CD:  2, 3, 4/8, 5, 6, 7;  TCR
PERIPHERAL BLOOD AND NODES
Majority of
T-CLL, CTCL,
Sezary Cell, NHL
Mature T Helper
Cell
CD:  2, 3, 4, 5, 6, 7;  TCR
PART 4
Oncology and Hematology
Mature T Cytotoxic/
Suppressor Cell
Minority of
T-CLL, NHL
CD:  2, 3, 5, 6, 7, 8;  TCR
FIGURE 113-3  Pathway of normal T-cell differentiation and relationship to T-cell
lymphomas. CD1, CD2, CD3, CD4, CD5, CD6, CD7, CD8, CD38, and CD71 are cell
markers used to distinguish stages of development. T-cell antigen receptors (TCR)
rearrange in the thymus, and mature T cells emigrate to nodes and peripheral
blood. ALL, acute lymphoid leukemia; CTCL, cutaneous T-cell lymphoma; NHL, nonHodgkin’s lymphoma; T-ALL, T-cell ALL; T-CLL, T-cell chronic lymphocytic leukemia;
T-LL, T-cell lymphoblastic lymphoma.
translocations produce fusion genes that encode chimeric oncogenic
proteins. Examples of this include the (2;5)(p23;q35) translocation
involving the ALK and NPM1 genes in anaplastic large-cell lymphoma
(ALCL) and the t(11;18)(q21;q21) translocation involving the API2
and MLT genes in MALT lymphoma. Table 113-4 presents the most
common translocations and associated oncogenes for various subtypes
of lymphoid malignancies.
Gene profiling using array technology allows the simultaneous
assessment of the expression of thousands of genes. This technology
provides the possibility to identify new genes with pathologic impor­
tance in lymphomas, the identification of patterns of gene expression
with diagnostic and/or prognostic significance, and the identification
of new therapeutic targets. Recognition of patterns of gene expression
is complicated and requires sophisticated mathematical techniques.
Early successes using this technology in lymphoma include the iden­
tification of previously unrecognized subtypes of DLBCL whose gene
expression patterns resemble either those of follicular or germinal cen­
ter B (GCB) cells or activated peripheral blood B cells (ABC). Patients
whose lymphomas have a GCB-like pattern of gene expression have
a considerably better prognosis than those whose lymphomas have a
pattern resembling ABCs. This improved prognosis is independent
of other known prognostic factors. These subcategories have been
more specifically refined into five subcategories, using more advanced
genetic sequencing techniques, that differ with respect to biology and
driver genes, as well as prognosis, and may have important treatment
implications in the future. Similar information is being generated in
FL and MCL. The challenge remains to provide information from such
techniques in a clinically useful time frame.
APPROACH TO THE PATIENT
Regardless of the type of lymphoid malignancy, the initial evalua­
tion of the patient should include performance of a careful history
and physical examination. These will help confirm the diagnosis,
TABLE 113-4  Genetic Features of B- and T-Cell Lymphomas
GENETIC FEATURE
GENES
LYMPHOMA
t(8;14)
t(2;8)
t(8;22)
MYC/IgH
MYC/Igκ
MYC/Ig λ
Burkitt’s lymphoma
t(11;14)
BCL1 (CCND1)/IgH
Mantle cell lymphoma; multiple
myeloma
t(14;18)
t(3;14)
BCL2/IgH
BCL6/IgH
Follicular lymphoma, diffuse
large B-cell lymphoma (DLBCL)
t(11;18)
t(1;14)
t(14;18)
t(3;14)
API2/MALT1
BCL10/IgH
MALT1/IgH
FOXP1/IgH
MALT lymphoma
Trisomy 3
7q21 deletion
Unknown
CDK6
Splenic marginal zone
lymphoma
t(9;14)
6q21 deletion
PAX5/IgH
Unknown
Lymphoplasmacytic lymphoma
inv(14)
t(14;14)
TCRα/TCL1
Peripheral T-cell lymphoma,
NOS; T-PLL
t(2;5)
t(1;2)
t(2;3)
t(2;17)
inv(2)
NPM1/ALK
TPM3/ALK
TFG/ALK
CTLC/ALK
ATIC/ALK
Anaplastic large-cell lymphoma
(ALCL)
Trisomy 3
Trisomy 5
Unknown
Unknown
Angioimmunoblastic T-cell
lymphoma
Isochromosome 7q
Unknown
Hepatosplenic T-cell lymphoma
Abbreviations: MALT, mucosa-associated lymphoid tissue; NOS, not otherwise
specified; T-PLL, T-cell prolymphocytic leukemia.
identify those manifestations of the disease that might require
prompt attention, and aid in the selection of further studies to
optimally characterize the patient’s status to allow the best choice
of therapy. It is difficult to overemphasize the importance of a care­
fully done history and physical examination. They might provide
observations that lead to reconsidering the diagnosis, provide hints
at etiology, clarify the stage, and allow the physician to establish rap­
port with the patient that will make it possible to develop and carry
out a therapeutic plan.
The duration of symptoms and pace of symptomatic progres­
sion are important in distinguishing aggressive from more indo­
lent lymphomas, as are the presence or absence of “B” symptoms,
such as fevers, night sweats, or unexplained weight loss. Patients
should be asked about localizing symptoms that may point toward
lymphomatous involvement of specific sites, such as the chest,
abdomen, or CNS. Comorbid diagnoses that may impact therapy
or monitoring on therapy should be reviewed and acknowledged,
including a history of diabetes or congestive heart failure. A physi­
cal examination should pay close attention to all the peripherally
accessible sites of lymph nodes; the liver and spleen size; Waldeyer’s
ring; whether there is a pleural or pericardial effusion or abdominal
ascites; whether there is an abdominal, testicular, or breast mass;
and whether there is cutaneous involvement because all of these
findings may influence further evaluation and disease management.
Laboratory studies should include a complete blood count,
routine chemistries, liver function tests, and serum protein elec­
trophoresis to document the presence of circulating monoclonal
paraproteins. The serum β2-microglobulin level and serum lactate
dehydrogenase (LDH) are important independent prognostic fac­
tors in NHL. Staging of certain diseases may involve a bone mar­
row biopsy; results of other laboratory and staging studies may also
warrant a marrow evaluation. A lumbar puncture for evaluation
of lymphomatous involvement may be indicated in the setting of
concerning neurologic signs or symptoms or diseases that are high
risk for CNS involvement. The latter may include disease involv­
ing the paranasal sinuses, testes, breast, kidneys, adrenal glands,
and epidural space, as well as highly aggressive histologies like BL.
Since HIV and hepatitis B and C infection can be risk factors for
developing NHL, and since treatment for some NHLs can result in
the potentially life-threatening reactivation of hepatitis B, patients
with a new diagnosis of NHL should be screened for these viruses
as well.
Lymphoma histology and clinical presentation dictate which
imaging studies should be ordered. Chest, abdominal, and pelvic
computed tomography (CT) scans are essential for accurate stag­
ing to assess lymphadenopathy for indolent lymphomas, whereas
positron emission tomography (PET) using 18F-fluorodeoxyglucose
(FDG-PET) is useful for aggressive lymphomas, including BL,
DLBCL, plasmablastic lymphoma, and the aggressive T-cell NHLs.
FDG-PET is highly sensitive for detecting both nodal and extra­
nodal sites involved by NHL. The intensity of FDG avidity, or
standardized uptake value (SUV), correlates with histologic aggres­
siveness, and may be useful in cases when disease transformation
of an indolent lymphoma to a diffuse aggressive lymphoma is sus­
pected. PET scanning can also differentiate between treated disease
and active disease at the end of therapy in patients with residual
masses on CT scans. Consensus recommendations regarding PET
scanning were published as a result of an International Harmoniza­
tion Project and state that PET should only be used for DLBCL
and HL, that scanning during therapy should only be done as part
of clinical trials, and that the end-of-treatment scan should not be
done before 3 weeks but preferably 6–8 weeks after chemotherapy
and 8–12 weeks after radiation or chemoradiotherapy. There is no
evidence that long-term follow-up should include PET scanning.
More recently, though, PET scan results at the end of therapy
for FL have been associated with prognosis, with patients with
residual PET-avid disease at the end of treatment having a poorer
prognosis than those who are PET negative, and so it may be used
for this prognostic purpose. Finally, magnetic resonance imaging
(MRI) is useful in detecting bone, bone marrow, and CNS disease
in the brain and spinal cord. The staging evaluation is outlined in
Table 113-5.
The Ann Arbor staging system developed in 1971 for HL was
adapted for staging NHLs (Table 113-6). This staging system focuses
on the number of tumor sites (nodal and extranodal), location, and
the presence or absence of systemic, or B, symptoms. Table 113-6
summarizes the essential features of the Ann Arbor system.
This anatomic based system is less useful in NHL, which dis­
seminates widely, not in an ordered stepwise fashion. A majority of
patients with NHL have advanced-stage disease at diagnosis. Apart
TABLE 113-5  Staging Evaluation for Non-Hodgkin’s Lymphoma
Physical examination
Documentation of B symptoms
Laboratory evaluation
  Complete blood counts
  Liver function tests
  Uric acid
  Calcium
  Serum protein electrophoresis
  Serum β2-microglobulin
Chest radiograph
CT scan of abdomen, pelvis, and usually chest
Bone marrow biopsy
Lumbar puncture in lymphoblastic, Burkitt’s, and diffuse large B-cell lymphoma
with positive marrow biopsy
Gallium scan (SPECT) or PET scan in large-cell lymphoma
Abbreviations: CT, computed tomography; PET, positron emission tomography;
SPECT, single-photon emission computed tomography.
TABLE 113-6  Ann Arbor Staging for Lymphomaa
STAGE
DESCRIPTION
I
Involvement of a single lymph node region (I) or single extranodal
site (IE)
II
Involvement of two or more lymph node regions or lymphatic
structures on the same side of the diaphragm alone (II) or with
involvement of limited, contiguous, extralymphatic organ or
tissue (IIE)
III
Involvement of lymph node regions on both sides of the
diaphragm (III), which may include the spleen (IIIS), or limited,
contiguous, extralymphatic organ or tissue (IIIE), or both (IIIES)
IV
Diffuse or disseminated foci of involvement of one or more
extralymphatic organs or tissues, with or without associated
lymphatic involvement
aAll stages are further subdivided according to the absence (A) or presence (B) of
systemic B symptoms including fevers, night sweats, and/or weight loss (>10% of
body weight over 6 months prior to diagnosis).
from early-stage disease limited to a radiation field where local
therapy with radiation is an option, all other disease is treated the
same regardless of stage. Histology and clinical parameters at pre­
sentation are more important than stage with respect to prognosis.
The International Prognostic Index (IPI) is perhaps the best predic­
tor of outcome (Table 113-7). The IPI was developed based on the
analysis of >2000 patients with aggressive NHLs treated with an
anthracycline-containing regimen. Age (≤60 vs >60), serum LDH
(≤ normal vs > normal), performance status (0 or 1 vs 2–4), stage
(I or II vs III or IV), and extranodal involvement (<1 site vs >1 site)
were identified as independently prognostic for overall survival
(OS). A point is awarded for each risk factor and then summed,
defining four risk groups: low (0 or 1); low-intermediate (2); highintermediate (3); and high (4–5). The 5-year OS rates for patients
with scores of 0–1, 2, 3, and 4–5 were 73, 51, 43, and 26%, respec­
tively. The age-adjusted IPI separates patients ≤60 from patients
For the age-adjusted IPI, only stage, LDH, and performance
status were important. Younger patients with 0, 1, 2, or 3 risk factors
had 5-year survival rates of 83, 69, 46, and 32%, compared to 56, 44,
37, and 21% for older patients. When factoring in the introduction
and clinical benefit of rituximab, the 4-year progression-free sur­
vival rates are 94, 80, and 53% for 0–1, 2, or 3 or more risk factors,
respectively.
CHAPTER 113
Non-Hodgkin’s Lymphoma
The Follicular Lymphoma International Prognostic Index
(FLIPI) is a similar predictive model for FL, derived from the
analysis of >4000 patients. Age >60, stage III/IV disease, the
TABLE 113-7  International Prognostic Index for NHL
Five Clinical Risk Factors
Age ≥60 years
Serum lactate dehydrogenase levels elevated
Performance status ≥2 (ECOG) or ≤70 (Karnofsky)
Ann Arbor stage III or IV
1 site of extranodal involvement
For Diffuse Large B-Cell Lymphoma
0, 1 factor = low risk
35% of cases; 5-year survival, 73%
2 factors = low-intermediate risk
27% of cases; 5-year survival, 51%
3 factors = high-intermediate risk
22% of cases; 5-year survival, 43%
4, 5 factors = high risk
16% of cases; 5-year survival, 26%
For Diffuse Large B-Cell Lymphoma Treated With R-CHOP
0 factor = good
10% of cases; 4-year survival, 94%
1, 2 factors = intermediate
45% of cases; 4-year survival, 80%
3, 4, 5 factors = poor
45% of cases; 4-year survival, 53%
Abbreviations: ECOG, Eastern Cooperative Oncology Group; NHL, non-Hodgkin’s
lymphoma; R-CHOP, rituximab, cyclophosphamide, doxorubicin, vincristine,
prednisone.
presence of >4 nodal sites, an elevated serum LDH concentration,
and a hemoglobin <12 were identified as independent prognostic
variables, and summation of each variable identified three risk
groups. The median 10-year survival rates for patients with zero to
one (low risk), two (intermediate risk), or three or more (high risk)
of these adverse factors were 71, 51, and 36%, respectively. Similar
disease-specific IPIs have been developed for MCL and periph­
eral T-cell lymphoma (PTCL) as well. These prognostic indices
take into account the proliferative index and cell-surface markers,
respectively.
Finally, as mentioned previously, gene expression profiling has
identified DLBCLs with differential prognoses: GCB and ABC,
where GCB-like DLBCL is associated with a significantly better
OS. A more readily accessible immunohistochemical algorithm has
been developed, based on the presence or absence of CD10, BCL6,
and MUM1, that correlates closely with gene expression profiles
and can differentiate the majority of GCB from non–GCB-like
DLBCL. These profiles have prognostic importance but, to date, do
not alter treatment recommendations for the primary treatment of
DLBCL. Current clinical trials do stratify by DLBCL subtype, and it
appears that agents like the Bruton tyrosine kinase (BTK) inhibitor
ibrutinib and lenalidomide are most active in non-GCB DLBCL in
the relapsed setting. Treatment may then be differentiated by these
subtypes in the future.
PART 4
Oncology and Hematology
CLINICAL FEATURES, TREATMENT, AND
PROGNOSIS OF SPECIFIC NHL
■
■MATURE B-CELL NEOPLASMS
B-cell NHLs can be characterized into two broad groups—those that
behave aggressively, require immediate or urgent treatment with
combination chemotherapy regimens, and are potentially curable; and
those that are more indolent in nature, can be observed and treated
only when they cause symptoms or signs of organ function impair­
ment, are very responsive to therapy, but are not ultimately curable
in the vast majority of cases. Among the aggressive diseases, the most
common is DLBCL, and the most rapidly growing is BL. FL is the sec­
ond most common NHL and the most common indolent NHL. Other
indolent NHLs include MZL, lymphoplasmacytic lymphoma (LPL),
and hairy cell leukemia (HCL). MCL is an intermediate-grade lym­
phoma that shares some characteristics with the aggressive lymphomas
(fairly urgent need for treatment and aggressive upfront combination
chemotherapy regimens), but like the indolent lymphomas, it is not
readily curable with conventional-dose therapies.
Burkitt’s Lymphoma 
Burkitt’s lymphoma/leukemia (BL) is a rare
disease in adults in the United States, making up <1% of NHL, but it
makes up ∼30% of childhood NHL. It is one of the fastest growing neo­
plasms, with a doubling time of <24 h. In general, it is a pediatric tumor
that has three major clinical presentations. The endemic (African) form
presents as a jaw or facial bone tumor that spreads to extranodal sites
including ovary, testis, kidney, breast, and especially the bone marrow
and meninges. The nonendemic form has an abdominal presentation
with massive disease, ascites, and renal, testis, and/or ovarian involve­
ment and, like the endemic form, also spreads to the bone marrow and
CNS. Immunodeficiency-related cases more often involve lymph nodes
and may present as acute leukemia. BL has a male predominance and is
typically seen in patients <35 years of age.
On biopsy, there is a monotonous infiltration of medium-sized cells
with round nuclei, multiple nucleoli, and basophilic cytoplasm with
vacuoles. The proliferation rate is ∼100%, and tingible body macro­
phages give rise to the classic “starry sky” appearance of this tumor
(Fig. 113-4). Tumor cells are positive for B-cell antigens CD19 and
CD20 and surface immunoglobulin. They are also uniformly positive
for CD10 and BCL6 but negative for BCL2. Endemic BLs are EBV posi­
tive, whereas the majority of nonendemic BLs are EBV negative. BL is
associated with a translocation involving MYC on chromosome 8q24
in >95% of the cases. The most common partners are chromosomes 14,
FIGURE 113-4  Burkitt’s lymphoma. The neoplastic cells are homogeneous, mediumsized B cells with frequent mitotic figures, a morphologic correlate of high growth
fraction. Reactive macrophages are scattered through the tumor, and their pale
cytoplasm in a background of blue-staining tumor cells gives the tumor a so-called
starry sky appearance.
2, or 22, rearrangements that produce fusions of MYC with either the
IgH (80%), kappa (15%), or lambda (5%) light chain genes, respectively.
While exquisitely chemosensitive, it is imperative that treatment
for BL be initiated quickly given the rapid doubling time and high
morbidity of this disease. There are several effective intensive combi­
nation chemotherapy regimens, all of which incorporate high doses
of cyclophosphamide. Prophylactic therapy to the CNS is mandatory.
Cure can be expected in 80–90% of patients when treated promptly
and correctly. Modified Magrath and dose-adjusted EPOCH-R (ritux­
imab, infusional etoposide/vincristine/doxorubicin, cyclophospha­
mide, prednisone) are highly effective regimens. Salvage therapy has
been generally ineffective in patients whose disease progresses after
upfront therapy, emphasizing the importance of the initial treatment
approach and referral to a tertiary cancer center with experience treat­
ing this disease.
Diffuse Large B-Cell Lymphoma 
DLBCL is the most common
histologic subtype of NHL diagnosed, representing about one-third of
all cases. Previously felt to be “one disease,” it is now recognized as a
heterogeneous collection of multiple entities. It is slightly more com­
mon in Caucasians and men, and the median age at diagnosis is 64.
The relative risk (RR) of DLBCL is higher among people with affected
first-degree relatives (RR 3.5-fold), and patients with congenital or
acquired immunodeficiency, patients on immunosuppression, and
patients with autoimmune disorders also have a higher risk of develop­
ing DLBCL, often EBV-related. The majority of patients present with
advanced-stage disease, with only 30–40% of patients having stage I
or II disease; ∼40% of patients will have “B” symptoms, and 50% of
patients will have an elevated LDH. Up to 40% of patients will have
involvement of non–lymph node sites including bone marrow, CNS,
gastrointestinal tract, thyroid, liver, and skin. Patients with extensive
bone marrow involvement or involvement of the testes, breast, kidney,
adrenal gland, paranasal sinus, or epidural space are at increased risk
of CNS dissemination.
The tumor consists of a diffuse proliferation of large, atypical lym­
phocytes with a high proliferative index (Fig. 113-5). These cells typi­
cally express the B-cell antigens CD19, CD20, and CD79a. Expression
of CD10 and BCL6 is consistent with the tumor cell being of germinal
center origin (GCB), while the expression of MUM1 corresponds with
the non–germinal center or ABC subtype. BCL2 is overexpressed in
anywhere from 25 to 80% of DLBCLs, whereas BCL6 is positive in
more than two-thirds of cases, as the result of translocations, gain of
copy number, or promoter mutations. MYC is rearranged in 10% of
DLBCLs, and ∼20% of MYC-rearranged cases have a concurrent BCL2
rearrangement, a combination referred to as “double-hit lymphoma.”
These double-hit lymphomas constitute one subtype of high-grade
B-cell lymphoma (HGBL) and are associated with an extremely poor
FIGURE 113-5  Diffuse large B-cell lymphoma. The neoplastic cells are
heterogeneous but predominantly large cells with vesicular chromatin and
prominent nucleoli.
prognosis with a median OS of only 12–18 months. The other subtype
of HGBL is called HGBL not otherwise specified (NOS) and is defined
based on blastoid or Burkitt-like morphologic features. Amplification
and/or overexpression of MYC independent of rearrangements or
amplification have also been described and are also associated with a
poor, albeit better, prognosis.
Combination chemotherapy offers potentially curative therapy
for DLBCL, regardless of the stage. The addition of the anti-CD20
antibody rituximab to cyclophosphamide, doxorubicin, vincristine,
and prednisone (R-CHOP) improved survival beyond CHOP alone
and has been the standard first-line chemotherapy for this disease for
decades. The combination of R-CHP (R-CHOP without vincristine)
and the antibody-drug conjugate (ADC) polatuzumab was compared
to R-CHOP in the randomized POLARIX study and demonstrated a
progression-free survival benefit with polatuzumab–R-CHP, leading to
the approval of this regimen as a new standard option for patients with
IPI 2 or higher disease. For patients with early-stage disease localized to
a radiation field, treatment options include full-course chemotherapy
with R-CHOP every 3 weeks for six cycles or abbreviated chemo­
therapy for three to four cycles followed by involved field radiotherapy.
The randomized FLYER studies compared four versus six cycles of
R-CHOP chemotherapy for early favorable-risk DLBCL and showed
no benefit to a more extended course of chemotherapy. For advancedstage DLBCL, therapy is with a full course of chemotherapy. On aver­
age, ∼65–70% of patients with DLBCL can be expected to be cured with
this approach, and the likelihood of cure is predicted by the IPI, gene
expression profile cell of origin, and/or MYC cytogenetics and expres­
sion. Several studies, other than the above mentioned POLARIX study,
have investigated alternative anthracycline-containing chemotherapy
regimens and/or consolidation autologous stem cell transplanta­
tion in first remission for higher-risk disease without improvement
over R-CHOP alone. Dose-adjusted R-EPOCH is one such regimen.
Although this regimen did not appear to be better than R-CHOP for
DLBCL in one multicenter clinical trial, it is often used to treat primary
mediastinal large B-cell lymphoma and double-hit DLBCL based on
results from phase 2 and retrospective studies, respectively. CNS pro­
phylaxis with either intrathecal chemotherapy or high-dose systemic
methotrexate and leucovorin rescue offers unclear benefit to patients
at high risk for CNS relapse and is increasingly not being used based
on results of retrospective and observational studies.
Over one-third of patients will either have primary refractory
disease or disease that relapses after first-line chemotherapy. These
patients may still be cured with either salvage chemotherapy regimens
followed by autologous stem cell transplantation (for patients relaps­
ing >12 months from the completion of therapy) or CD19 chimeric
antigen receptor (CAR) T cells (for patients with primary refractory
or early relapsing disease or those who are not felt to be autologous
stem cell transplantation candidates). However, patients with a poor
performance status or certain comorbid conditions who are not can­
didates for such approaches are often managed with palliative inten­
tions. Radiation to symptomatic areas of disease can be transiently
helpful. Less intensive chemotherapy with drugs such as gemcitabine,
cytarabine, or bendamustine can help control disease and symptoms
for a limited period of time. Newer drugs including the CD79b ADC
polatuzumab in combination with bendamustine and rituximab (BR),
the high-affinity CD19 monoclonal antibody (mAb) tafasitamab in
combination with lenalidomide, the CD19 ADC loncastuximab, and
the CD20-CD3 bispecific antibodies epcoritamab and glofitamab have
been approved for use in these palliative settings as well as for patients
who relapse after CAR-T therapy or autologous stem cell transplanta­
tion. Some of these agents can be used as a bridge to a definitive allo­
geneic stem cell transplantation
For patients in whom more aggressive therapy is an option, treatment
for late relapsing patients is with combination chemotherapy using vari­
ous combinations of drugs primarily in order to identify patients with
chemosensitive disease. Patients with chemosensitive disease have the
greatest likelihood of benefiting from high-dose chemotherapy and
autologous stem cell transplant, which improves response duration
and survival over salvage chemotherapy alone and leads to long-term
disease-free survival in ∼40–50% of patients. The randomized ZUMA-7
and TRANSFORM studies of the CD19 CAR-T therapies axicabtagene
ciloleucel (axi-cel) and lisocabtagene autoleucel (liso-cel) established
both of these CAR-T therapies as the most effective option for patients
with primary refractory or early (<12 months) relapsing disease over
salvage chemotherapy and autologous stem cell transplantation.
CHAPTER 113
For this therapy, T cells are collected from a patient and are then
genetically modified to express a receptor that will bind to a surface
antigen expressed on the patient’s own tumor cells. In the case of B-cell
malignancies, CD19 has been targeted most commonly. After infu­
sion, autologous CAR-T cells home to sites of disease and persist over
time. The CARs consist of an extracellular antigen recognition domain
(typically a single-chain Fv variable fragment from a monoclonal anti­
body) linked via a transmembrane domain to an intracellular signaling
domain (usually the CD3ζ endodomain), resulting in the redirection of
T-cell specificity toward target antigen-positive cells, and one or more
costimulatory domains including CD28, 4-1BB, or OX40 to enhance
cytokine secretion and effector cell expansion and prevent activationinduced apoptosis and immune suppression by tumor-related metabo­
lites. For late relapsing patients with chemorefractory disease, CAR-T
therapies such as axi-cel, liso-cel, and tisagenlecleucel (tisa-cel) offer a
potentially curative option in the third-line setting as well. In this set­
ting, the response rate of CAR-T cells is >80%, with >50% of patients
achieving a complete response. These responses appear to be durable,
with 40% of patients in remission at long-term follow-up.
Non-Hodgkin’s Lymphoma
Other large B-cell lymphomas include intravascular large B-cell
lymphoma, T-cell/histiocyte–rich large B-cell lymphoma, EBV-positive
DLBCL of the elderly, and ALK-positive large B-cell lymphoma.
Patients with the latter two diseases tend to have a poor progno­
sis, whereas the addition of rituximab to CHOP chemotherapy
has dramatically improved outcomes with intravascular large B-cell
lymphoma, and the outcomes in T-cell/histiocyte–rich large B-cell
lymphoma are similar to DLBCL. R-CHOP remains the treatment of
choice for each of these lymphomas.
Follicular Lymphoma 
FLs are the second leading NHL diagnosis
in the United States and Europe and make up 22% of NHLs worldwide
and at least 30% of NHLs diagnosed in the United States. This type of
lymphoma can be diagnosed accurately on morphologic findings alone
and has been the diagnosis in the majority of patients in therapeutic
trials for “low-grade” lymphoma in the past.
Evaluation of an adequate biopsy by an expert hematopathologist is
sufficient to make a diagnosis of FL. The tumor is composed of small
cleaved and large cells in varying proportions organized in a follicular
pattern of growth (Fig. 113-6). Confirmation of B-cell immunopheno­
type (monoclonal immunoglobulin light chain, CD19, CD20, CD10,
and BCL6 positive, and CD5 and CD23 negative) and the existence of
t(14;18) and abnormal expression of BCL2 protein are confirmatory.
FIGURE 113-6  Follicular lymphoma. The normal nodal architecture is effaced by
nodular expansions of tumor cells. Nodules vary in size and contain predominantly
small lymphocytes with cleaved nuclei along with variable numbers of larger cells
with vesicular chromatin and prominent nucleoli.
While >85% of FLs will harbor a t(14;18) and overexpress the anti­
apoptotic protein BCL2, this genetic event is necessary but not suffi­
cient for malignant transformation of the B lymphocytes, and multiple
genetic events are required for the development of FL. Studies have
identified the most common recurrent genetic events in FL, and they
included mutations in several epigenetic modifying genes, including
MLL2, EZH2, CREBBP, and EP300. The major differential diagnosis is
between lymphoma and reactive follicular hyperplasia. The coexistence
of DLBCL must be considered. Patients with FL are often subclassi­
fied, or graded, into those with predominantly small cells, those with
a mixture of small and large cells, and those with predominantly large
cells. The WHO classification adopted grading from I to III based on
the number of centroblasts, or large cells, counted per high-power
field (hpf): grade I, from 0 to 5 centroblasts/hpf; grade II, from 6 to
15 centroblasts/hpf; and grade III, >15 centroblasts/hpf. Grade III has
been subdivided into grade IIIa, in which centrocytes predominate,
and follicular large B-cell lymphoma (FLBCL), in which there are
sheets of centroblasts. While this distinction cannot be made simply or
very reproducibly, these subdivisions do have prognostic significance.
Patients with FL with predominantly large cells have a higher prolifera­
tive fraction, progress more rapidly, and have a shorter OS with simple
chemotherapy regimens. FLBCL is an aggressive disease and consid­
ered most similar to DLBCL and treated as such with curative intent.
PART 4
Oncology and Hematology
The most common presentation for FL is with new, painless lymph­
adenopathy. Multiple sites of lymphoid involvement are typical, and
unusual sites such as epitrochlear nodes are sometimes seen. However,
essentially any organ can be involved, and extranodal presentations
do occur. Most patients do not have an elevated LDH or fevers, night
sweats, or weight loss, although histologic transformation to DLBCL
does occur at a rate of ∼3% per year and can be associated with these
signs or symptoms. As discussed previously, prognosis is best predicted
by the FLIPI. Staging is typically done with CT scans of the chest,
abdomen, and pelvis, as well as the neck if neck disease is suspected,
although PET/CT scans can be helpful in cases where disease trans­
formation is suspected, as transformed disease will be more FDG avid
than indolent disease, or for confirmation of early-stage disease, where
definitive local therapy with radiation may be considered.
Although FL is highly sensitive to chemotherapy and radiotherapy,
these therapies are usually not ultimately curative, except in the setting
of early-stage disease. If the disease can be encompassed in a radiation
field, involved field radiotherapy at a dose of 24–30 Gy may be cura­
tive, with 5-, 10-, and 15-year freedom from treatment failure rates
of 72, 46, and 39%, and overall 5-, 10-, and 15-year survival rates of
93, 75, and 62%, respectively. If radiation therapy would not be toler­
ated or if a patient prefers not to receive radiation, observation is a
reasonable alternative with a median time to treatment not reached at
7 years of follow-up in one study. Many of these patients are diagnosed
incidentally or at a time when their lymphoma is not causing symp­
toms or signs of organ function impairment. Numerous studies have
shown that treating patients with asymptomatic disease does not
improve survival compared with a program of close observation, with
treatment reserved for symptomatic disease progression or organ dys­
function. Thus, asymptomatic patients should be observed.
When systemic treatment is indicated, a variety of treatment
options are available, including the use of the monoclonal antibody
against CD20, rituximab, alone or in combination with chemotherapy
or with the oral drug lenalidomide. Treatment decisions are often
determined by the indication for treatment and/or by the volume of
disease being treated. For patients requiring therapy for inflamma­
tory or autoimmune phenomenon thought to be driven by FL or for
patients with low-volume disease, single-agent rituximab is associ­
ated with a response rate of ∼70% and a median response duration of
2 years. This response duration is improved with the addition of main­
tenance rituximab following a favorable response to rituximab induc­
tion therapy. For patients with a larger volume of disease at the time
of treatment initiation, the addition of rituximab (R) to chemotherapy
regimens such as CHOP or cyclophosphamide, vincristine, and pred­
nisone (CVP) has improved survival in this disease. The combination
of bendamustine and rituximab (BR) has been compared to R-CHOP
and results in longer response duration and less toxicity. Thus, BR has
become the standard of care for the first-line therapy of medium- to
high-volume FL. Similarly, the addition of maintenance rituximab
following a good response to R-CHOP or R-CVP improves response
duration when used in newly treated FL patients. A newer anti-CD20
antibody, obinutuzumab, has been tested in combination with chemo­
therapy in a randomized trial against rituximab plus chemotherapy in
previously untreated FL. The obinutuzumab combinations resulted in
improvements in minimal residual disease (MRD) negativity as well as
progression-free survival at the expense of more infection and infusion
reactions. Based on these results, both rituximab plus chemotherapy
and obinutuzumab plus chemotherapy are options for untreated FL in
need of treatment. The superiority of one over the other has not been
established. Finally, a randomized study has compared rituximab plus
chemotherapy with either BR, R-CHOP, or R-CVP to rituximab plus
lenalidomide, and results were similar in both arms, thus making the
chemotherapy-free rituximab-lenalidomide regimen an option for the
frontline treatment of FL.
In patients with FL, the disease nearly always recurs following
therapy, after which retreatment is again reserved for symptomatic
disease or disease interfering with organ function. Single-agent ritux­
imab or alternative chemotherapy regimens, with both rituximab and
obinutuzumab, can again be employed. Both autologous and allogeneic
hematopoietic stem cell transplantations yield high complete response
rates in patients with relapsed FL, and long-term remissions can occur
in 40 and 60% of patients, respectively. The latter is associated with con­
siderable treatment-related morbidity and mortality and so is usually
reserved for patients with multiply relapsed FL that is no longer respon­
sive to chemotherapy. More targeted oral therapies like lenalidomide
and the EZH2 inhibitor tazemetostat are active in relapsed FL. The PI3
kinase inhibitors idelalisib, duvelisib, and copanlisib are active in FL
but are no longer available given the lack of randomized confirmatory
evidence to support their efficacy. The anti-CD19–directed CAR-T
therapies axi-cel and tisa-cel have been approved for relapsed FL in the
third-line setting and beyond, with complete responses seen in >80%
of patients with multiply relapsed disease, and with many of those
responses proving durable, albeit with limited follow-up. Longer followup is needed to determine if this may be a definitive treatment strategy
for a subset of relapsed FL patients. The CD20-CD3 bispecific antibody
mosunetuzumab has been approved for FL in the third-line setting and
beyond as well and offers a highly effective and potentially less toxic
option for patients compared with CAR-T therapy. On average, most
patients will live with FL for 15–20 years, a number that is increasing
given our improved understanding of the genetics and microenviron­
ment of FL and the increasing number of drugs and therapies being
tested in this disease. However, in addition to a high-risk FLIPI, patients
who do not have a complete metabolic response by PET/CT scanning
to their primary therapy and patients who relapse within 2 years of
the completion of their primary chemotherapy tend to do poorly
with chemotherapy and should be considered for some of these non­
chemotherapy options. Randomized trials comparing chemotherapy,
lenalidomide-based therapy, and CAR-T therapy in the second-line set­
ting for these refractory or early relapsing patients are underway.
Patients with FL have a high rate of histologic transformation to
DLBCL (∼3% per year). This is recognized ∼40% of the time during
the course of the illness by repeat biopsy and is present in almost all
patients at autopsy. This transformation is usually heralded by rapid
growth of lymph nodes—often localized—and the development of
systemic symptoms such as fevers, sweats, and weight loss. When this
happens in patients who have had previously untreated FL, treatment
with R-CHOP chemotherapy, as for DLBCL, can be curative for the
aggressive component while the FL may eventually recur. In patients
with previously treated FL that transforms to DLBCL, prognosis is
poor, and successful therapy with an aggressive combination chemo­
therapy regimen should be consolidated with an autologous stem cell
transplant. CAR-T therapy and other therapies for relapsed/refractory
DLBCL are options for chemorefractory transformations. Finally, as
discussed previously, grade IIIb FL is more similar to DLBCL than it is
to FL and should be treated as such.
Marginal Zone Lymphoma 
The second most common indolent
B-cell NHL is MZL. There are three main types: splenic MZL, extrano­
dal MZL of MALT, and nodal MZL.
Nodal MZL most closely resembles FL clinically, and much of the
way we manage and treat it is based on studies done in FL. Tumor
biopsies in this disease show parafollicular and perivascular infiltration
by monocytoid-appearing atypical lymphocytes with folded nuclear
contours that are positive for CD19, CD20, and CD79a but negative for
CD10 and largely negative for CD5. Some cases can have plasmacytoid
differentiation and can be associated with a monoclonal expression of
kappa or lambda light chains and with small monoclonal immunoglob­
ulin spikes. Treatment is often similar to that of FL, with the exception
that the BTK inhibitors ibrutinib and zanubrutinib are highly active in
this disease, while largely disappointing in FL, and are good treatment
options for relapsed nodal MZL as well as other MZL subtypes. CAR-T
therapy is not approved in MZL but has been tested in clinical trials
with similar efficacy to what has been shown in FL.
Splenic MZL is largely a disease of older Caucasian patients; infec­
tion with hepatitis C is a risk factor for this disease, and treatment of
hepatitis C can result in regression of the lymphoma. Patients present
with a lymphocytosis with or without cytopenias and splenomegaly.
Bone marrow involvement is common. Diagnosis can be made by
flow cytometry of the peripheral blood; malignant lymphocytes will
be positive for surface immunoglobulin, CD19, and CD20 and will
generally lack CD5 and CD10. On peripheral smear, they have small
nuclei and abundant cytoplasm with “shaggy” or villous projections. It
can be differentiated from HCL by the absence of CD25, CD103, and
annexin A1. Recurrent cytogenetic abnormalities include trisomy 3
and abnormalities of chromosome 7q. Therapy is indicated for symp­
tomatic disease or significant cytopenias. Splenectomy is reasonable
for selected patients with excellent relief of symptoms and cytopenias.
Splenectomy is associated with an overall response rate of 85% and
estimated progression-free survival and OS rates at 5 years of 58 and
77%, respectively. Single-agent rituximab can improve splenomegaly
and cytopenias in >90% of patients. In a study of induction with
weekly rituximab followed by maintenance, the response rate was 95%,
with OS and progression-free survival rates at 5 years of 92 and 73%,
respectively. Other options for therapy at relapse are similar to those
used for FL and include retreatment with rituximab, alkylating agents,
and purine analogues in combination with rituximab. The survival rate
of patients is in excess of 70% at 10 years.
MALT lymphoma is an MZL lymphoma of extranodal tissue, most
commonly the stomach, but other common sites include the skin, sali­
vary glands, lung, small bowel, ocular adnexa, breasts, bladder, thyroid,
dura, and synovium. It is associated with states of chronic inflamma­
tion due to either autoimmune diseases like Sjögren’s syndrome or
Hashimoto’s thyroiditis or chronic infections with organisms such as
H. pylori (gastric), Borrelia burgdorferi (skin), C. psittaci (conjunctiva),
C. jejuni (intestines), and hepatitis C virus. The essential pathologic
feature of MALT lymphoma is the presence of lymphoepithelial lesions,
which result from invasion of mucosal glands and crypts by the neo­
plastic lymphocytes. These cells are positive for CD19, CD20, and CD79a
and negative for CD5 and CD10. Recurrent cytogenetic abnormalities
include t(11;18), t(14;18), t(1;14), t(3;14), and trisomy 8. The t(11;18) is
most common, occurring in up to 50% of MALT lymphomas. It results
in the fusion of the apoptosis inhibitor 2 (API2) gene and the MALT1
gene, resulting in activation of nuclear factor-κB (NF-κB). Unlike
other indolent B-cell lymphomas, MALT lymphomas present most
commonly with stage I or II disease. In these cases, radiation therapy
may be curative. Alternatively, patients may respond to antibiotics
for the associated underlying infection. Treatment of symptomatic
or organ-impairing relapsed, refractory, or advanced-stage disease is
similar to approaches used in FL with chemotherapy, immunotherapy,
or chemoimmunotherapy.
Lymphoplasmacytic Lymphoma 
About 1% of all NHLs will
be LPLs, which are indolent B-cell NHLs with lymphoplasmacytic
differentiation, most commonly associated with a monoclonal IgM
paraprotein. Nearly all patients will have stage IV disease at diagnosis
with bone marrow involvement. Patients with high levels of circulating
IgM paraproteins constitute a specific entity known as Waldenström’s
macroglobulinemia and can have symptoms due to hyperviscosity as a
result of the circulating IgM. Activating mutations in MYD88, an adap­
tor protein that is involved in signaling downstream of the Ig receptor
leading to NF-κB activation, are present in >90% of cases. Tumor biop­
sies are notable for proliferation of small lymphocytes, lymphoplasma­
cytic cells, and plasma cells, and malignant lymphocytes are positive
for CD19, CD20, and surface IgM but generally negative for CD5 and
CD10. Like the other indolent NHLs, treatment is indicated for disease
that causes symptoms or interferes with organ function; hyperviscosity
related to elevated serum IgM and paraneoplastic neuropathy are addi­
tional indications for therapy. Single-agent rituximab may be useful
for low-volume disease but can be associated with a transient rise in
serum IgM concentrations that can cause or exacerbate hyperviscos­
ity. Chemoimmunotherapy with regimens such as BR and rituximab,
cyclophosphamide, and dexamethasone is active, as are myeloma
therapies such as bortezomib. Ibrutinib and zanubrutinib in combina­
tion with rituximab are highly active in this disease and are options for
both previously untreated and relapsed disease. Given that 85% of IgM
remains intravascular, acute relief of hyperviscosity symptoms can be
obtained by plasmapheresis. For recurrent disease, one can often use
agents that were previously used. For patients with more refractory
LPL, the mammalian target of rapamycin (mTOR) inhibitor everolimus
and the bcl-2 inhibitor venetoclax are active. Selected patients with
relapsed disease are considered for high-dose therapy with autologous
or allogeneic stem cell transplantation. The results seen are similar to
those of other indolent lymphomas.
CHAPTER 113
Non-Hodgkin’s Lymphoma
Mantle Cell Lymphoma 
MCL composes ∼6% of NHLs. It is an
intermediate-grade lymphoma that, like the indolent B-cell NHLs,
is not curable with conventional therapies but, like the aggressive
lymphomas, often requires more aggressive chemoimmunotherapy
regimens with or without an autologous stem cell transplant to achieve
a reasonable response duration. This therapy is not curative, however,
and median survival with this disease is on the order of 5–10 years. An
exception to this is a more indolent SOX11 variant that often presents
with circulating disease with splenomegaly but without significant
lymphadenopathy and with a low Ki67 (<10%). This subset behaves
more like the indolent B-cell NHLs and can be observed until treat­
ment is indicated by symptoms or organ function impairment. Simi­
larly, there is a blastic variant with a high Ki67 index that is associated
with a poor prognosis and a median OS of only 18 months. For other
patients, prognosis is best predicted by the biologic MCL International
Prognostic Index (MIPI), which factors in age, performance status,
LDH, white blood cell count, and Ki67 expression to determine a risk
group. This disease is more common in men, and the average age of
diagnosis is 63. MCLs with a mutation in TP53 or a complex karyo­
type are particularly high risk as well. Over two-thirds of patients will
have stage IV disease, mostly with bone marrow and peripheral blood
involvement, at the time of diagnosis. Another common extranodal site
of involvement is the gastrointestinal tract, where diffuse lymphoma­
tous polyposis may be seen.
The pathognomonic cytogenetic finding in MCL is t(11;14), which
brings the gene for the cell cycle control protein cyclin D1 under the
control of the immunoglobulin heavy chain gene promoter on chromo­
some 14. This translocation is present in >90% of cases. The remaining
cases usually overexpress cyclin D2, cyclin D3, or cyclin E. Tumor cells
also are positive for B-cell markers CD19 and CD20, as well as CD5.
They usually lack CD10 and CD23.
Therapies for MCL are evolving. Patients with localized dis­
ease might be treated with combination chemotherapy followed by
radiotherapy; however, these patients are exceedingly rare. Similarly,
patients with the indolent variant can be observed until disease pro­
gresses to cause symptoms or signs of organ function impairment. For
the usual presentation with disseminated disease, standard lymphoma
treatments like R-CHOP have been unsatisfactory, with the minority
of patients achieving complete remission. The addition of high-dose
cytarabine to an R-CHOP–like backbone with or without consolidation
autologous stem cell transplantation in first remission has improved
progression-free survival, but it has not elicited cures in this disease.
These include the Nordic regimens and R-HyperCVAD (rituximab,
cyclophosphamide, vincristine, doxorubicin, dexamethasone, cytara­
bine, and methotrexate). BR has activity in this disease and is more
effective and better tolerated than R-CHOP. Newer studies with short
follow-up suggest that strategies that combine BR with cytarabine
with or without autologous stem cell transplant may be effective and
well tolerated. The SHINE study randomized patients to BR alone
versus BR plus ibrutinib and showed a modest benefit with the addi­
tion of ibrutinib. It is not clear, however, if this benefit is greater than
the sequencing of upfront BR followed by BTK inhibition at relapse.
Maintenance rituximab, following a good response to induction che­
motherapy or after autologous stem cell transplant, also improves out­
comes over observation alone. Increasing evidence suggests that with
modern induction therapies, high-dose chemotherapy and autologous
stem cell rescue may no longer provide benefit in the frontline setting.
The randomized European TRIANGLE study showed no benefit of
autologous transplant when added to induction chemoimmunotherapy
with ibrutinib followed by rituximab and ibrutinib maintenance. An
ongoing randomized study in the United States is asking a similar
question for patients who are treated with chemoimmunotherapy
without upfront BTK inhibition. For relapsed disease, the BTK inhibi­
tors ibrutinib, acalabrutinib, and zanubrutinib have single-agent activ­
ity with a response rate of almost 70% but a response duration of only
18–24 months. These drugs are being explored in combination with
chemotherapy as well as with the BCL2 antagonist venetoclax. AntiCD19–directed CAR-T therapies are approved for the treatment of
relapsed/refractory MCL; two-thirds of patients who had progressed
after chemoimmunotherapy (with or without an autologous stem cell
transplant) and BTK inhibition have achieved complete responses,
many of which are durable through limited follow-up. As in FL, longer
follow-up is needed to determine if some of these patients may be
cured, which would make this the only curative therapy for this disease
outside of an allogeneic stem cell transplantation. The noncovalent
BTK inhibitor pirtobrutinib has activity in MCL that has progressed
on prior covalent BTK inhibitors and is now approved in this setting.
Drugs such as lenalidomide, venetoclax, bortezomib, and temsirolimus
can similarly induce transient partial responses. Appropriate patients
who respond to salvage therapy, with the exception of CAR-T therapy,
should be considered for allogeneic stem cell transplant, which can
lead to long-term disease-free survival in 30–50% of patients.
PART 4
Oncology and Hematology
■
■MATURE (PERIPHERAL) T-CELL DISORDERS
Mature T-cell disorders include cutaneous lymphomas, such as mycosis
fungoides, and the PTCLs, some of which are distinguished based on
specific clinical presentations or contexts or by molecular or biologic
features, but many of which fall into the category of PTCL not other­
wise specified (NOS). T-cell NHLs are significantly rarer than B-cell
NHLs, and as such, our understanding of their biology is less advanced
and our therapies are less well developed. While some T-cell lympho­
mas, like mycosis fungoides, can behave indolently and some, like
ALK-positive ALCL, can be cured with chemotherapy, the majority are
associated with a poor prognosis. The advent of genomic technologies
is enhancing our ability to understand the genetic and biologic basis of
these neoplasms.
Mycosis Fungoides 
Mycosis fungoides is also known as cutaneous
T-cell lymphoma. This lymphoma is more often seen by dermatologists
than internists. The median age of onset is in the mid-fifties, and the
disease is more common in males and in blacks.
Mycosis fungoides is an indolent lymphoma, with patients often
having several years of eczematous or dermatitic skin lesions before
the diagnosis is finally established. The skin lesions progress from
patch stage to plaque stage to cutaneous tumors. Early in the disease,
biopsies are often difficult to interpret, and the diagnosis may only
become apparent by observing the patient over time. Adenopathy may
reflect involvement with mycosis fungoides or be read as dermatopathic
change. In advanced stages, the lymphoma can spread to lymph nodes
and visceral organs. Patients with this lymphoma may develop general­
ized erythroderma and circulating tumor cells, called Sézary’s syndrome.
Rare patients with localized early-stage mycosis fungoides can be
cured with radiotherapy, often total-skin electron beam irradiation.
More advanced disease has been treated with topical glucocorticoids,
topical nitrogen mustard, phototherapy, psoralen with ultraviolet A
(PUVA), extracorporeal photopheresis, retinoids (bexarotene), electron
beam radiation, interferon, antibodies, fusion toxins, histone deacety­
lase inhibitors, brentuximab (for CD30+ disease), and systemic cyto­
toxic therapy. Mogamulizumab, an anti-CCR4 antibody, has activity in
this disease and has been approved by the U.S. Food and Drug Adminis­
tration for this indication. Unfortunately, these treatments are palliative.
Peripheral T-Cell Lymphoma, Not Otherwise Specified 
PTCLs include a number of entities, which constitute 15% of all NHLs
in adults. PTCL NOS, which composes 6% of all NHLs, is the term used
for cases that are not other entities defined in the WHO classification.
Named varieties include ALCL, angioimmunoblastic T-cell lymphoma
(AITL), hepatosplenic T-cell lymphoma, enteropathy-associated T-cell
lymphoma, and subcutaneous panniculitis T-cell lymphoma. PTCL
NOS is a disease of older individuals, with a median age at presentation
of 65, and the majority of patients will have advanced-stage disease at
diagnosis, with involvement of the bone marrow, liver, spleen, and skin
being common. Associated “B” symptoms and pruritis are also com­
mon. These lymphomas can be associated with a reactive eosinophilia
as well as hemophagocytic syndrome. The IPI has been applied to
PTCL NOS and provides some assessment of outcomes, but even the
low-risk group has a median OS of just >2 years.
This diagnostic category is a collection of heterogeneous lympho­
mas that vary widely and lack typical findings of other specific PTCL
subgroups. Because of this heterogeneity, histology, immunophe­
notype, and genetics are variable. Often lymph nodes are effaced by
atypical lymphoid cells of various sizes, sometimes associated with
vascular proliferation or an infiltrate of eosinophils and/or macro­
phages. As most of these lymphomas behave aggressively, note is often
made of mitotic and apoptotic figures as well as geographic necrosis.
The cells often are positive for CD3, and the majority of PTCL NOS
is positive for CD4 rather than CD8, but some are negative for both
markers. There can be loss of more mature T-cell markers like CD5
and CD7, and this is associated with a more aggressive course. There
are some recurrent translocations, including t(7;14), t(11;14), inv(14),
and t(14;14), all of which involve the TCR genes.
The most common primary therapy for PTCL NOS involves a
CHOP-like chemotherapy backbone—either CHOP alone or CHOP
in combination with etoposide (CHOEP). The latter may provide the
most benefit to younger patients and patients with more favorable dis­
ease risk factors. Brentuximab in combination with cyclophosphamide,
doxorubicin, and prednisone (CHP) has been tested in a randomized
clinical trial against CHOP in CD30+ T-cell lymphomas; progressionfree survival was improved with the brentuximab-containing arm, and
this was most pronounced for patients with ALCL (see below). Autolo­
gous stem cell transplant has been investigated for patients in their
first remission and does seem to improve progression-free survival in
certain contexts. Drugs such as gemcitabine, bendamustine, and prala­
trexate have activity in relapsed disease, as do the histone deacetylase
inhibitors romidepsin and belinostat. The PI3 kinase inhibitor duvelisib
is being investigated in these diseases with early signals of activity. All
of these agents are associated with transient responses in a minority of
patients. Patients should be considered for clinical trials. For patients
who do achieve remission, reduced-intensity allogeneic stem cell trans­
plantation can yield long-term nonrelapse survival rates of ∼40–50%.
Angioimmunoblastic T-Cell Lymphoma 
AITL constitutes
∼20% of T-cell NHLs and ∼4% of all NHLs diagnosed. Patients present
with a variety of signs and symptoms, most often including lymphade­
nopathy, hepatosplenomegaly, “B” symptoms, rash, polyarthritis, and
hemolytic anemia. Over 80% of patients have advanced-stage disease
at diagnosis, and bone marrow involvement is common. Polyclonal
hypergammaglobulinemia is common, as are elevated LDH, eosino­
philia, a positive Coombs test, and opportunistic infections.
On biopsy, lymph nodes are effaced by a polymorphous infiltrate
of lymphocytes, ranging in size and shape, and of immunoblasts. The
neoplastic lymphocytes are positive for CD3 as well as CXCL13, PD-1,
CD10, and BCL6, most closely resembling CD4-positive follicular
helper T cells. There is an expanded follicular dendritic cell network
surrounding tumor cells. Scattered immunoblasts are often EBV posi­
tive and may give rise to secondary EBV-positive B-cell lymphomas
at a later time. Genetic analysis of this disease has revealed recurrent
mutations in TET2 (76%), DNMT3 (33%), and IDH2 (20%).
A subset of AITL can remit with immunosuppression with agents
like glucocorticoids or methotrexate. Most patients, however, will need
combination chemotherapy with regimens like those used in PTCL NOS.
Median response duration is short, and median OS is only 15–36 months.
Treatment of relapsed disease is similar to that of relapsed PTCL NOS.
Anaplastic Large-Cell Lymphoma 
ALCL is the next most com­
mon T-cell lymphoma after AITL but is more common in children,
accounting for up to 10% of pediatric lymphomas. Approximately
40–60% of cases harbor t(2;5), which fuses a portion of the nucleolar
protein nucleophosmin-1 (NPMI) gene to a part of the anaplastic
lymphoma kinase (ALK) gene, the product of which has constitutive
tyrosine kinase activity. These patients have a much more favorable
prognosis compared to ALK-negative ALCL, akin to that of DLBCL.
There is an additional, more indolent and favorable subtype that occurs
in the breast tissue of patients with breast implants, and there is a cuta­
neous variant. In general, this is a disease that is more common in men.
ALK-positive disease is a disease of younger patients, with a median
age at diagnosis of 34 years, whereas the median age at diagnosis of
ALK-negative patients is 58. With the exception of the cutaneous vari­
ant and the variant associated with breast implants, most patients pres­
ent with rapidly growing lymphadenopathy with or without extranodal
involvement; “B” symptoms are common.
Most cases of ALCL involve large atypical lymphocytes with horse­
shoe-shaped nuclei with prominent nucleoli (“hallmark” cells). Tumor
cells tend to be localized within the lymph node sinuses, and almost
all are positive for CD30 but negative for CD15. A majority will also
express CD3, CD25, CD43, and CD4. ALK-rearranged ALCL can be
diagnosed by fluorescence in situ hybridization (FISH) cytogenetics for
t(2;5) or by immunohistochemical staining for ALK.
ALCL is generally treated with CHOP, although like PTCL NOS,
CHOEP may benefit younger patients, particularly with ALK-positive
disease. Overall, ALCL has a better prognosis than PTCL, and this is
particularly true for ALK-positive disease, which has an 8-year OS rate
of 82%, versus 49% for ALK-negative disease. Relapsed ALK-positive
ALCL is treated similarly to relapsed DLBCL, with salvage combination
chemotherapy to identify chemotherapy sensitivity followed by autolo­
gous stem cell transplant. For patients with chemotherapy-insensitive
disease or for ALK-negative disease, the conjugated anti-CD30 anti­
body to monomethyl auristatin E (MMAE)/brentuximab is highly
active, with a response rate of 86% and a complete response rate of
57%. As mentioned earlier, brentuximab in combination with CHP
chemotherapy is an approved frontline regimen for the treatment
of CD30+ T-cell lymphomas, including ALCL. The ALK inhibitors,
including crizotinib, are active in refractory ALK-positive ALCL with
excellent outcomes.
Other PTCL Subtypes 
Enteropathy-associated T-cell lymphoma,
hepatosplenic T-cell lymphoma, and subcutaneous panniculitis-like
T-cell lymphoma are other less common PTCL subtypes. Enteropathytype intestinal T-cell lymphoma is a rare disorder. Type I occurs in
patients with a history of gluten-sensitive enteropathy and is associ­
ated with HLADQA1∗0501, DQB1∗0201; a gluten-free diet can pre­
vent the development of this lymphoma. Type II is now referred to as
monomorphic epitheliotropic intestinal T-cell lymphoma and is not
associated with celiac disease. Patients are frequently cachectic and
sometimes present with intestinal perforation. The prognosis is poor,
with a median survival of 10 months. Therapy is often with combina­
tion chemotherapy, including high-dose methotrexate, and autologous
stem cell transplant in first remission.
Hepatosplenic γδ T-cell lymphoma is a systemic illness that presents
with sinusoidal infiltration of the liver, spleen, and bone marrow by
malignant T cells. Tumor masses generally do not occur. The disease is
associated with systemic symptoms and is often difficult to diagnose.
Recurrent genetic events include isochromosome 7q and trisomy 8.
Treatment outcome is poor, but regimens that include ifosfamide, such
as ifosfamide, carboplatin, and etoposide (ICE) or ifosfamide, etopo­
side, and cytarabine (IVAC), are associated with better outcomes in
small series of patients. Responding patients should be considered for
allogeneic stem cell transplantation.
CHAPTER 113
Non-Hodgkin’s Lymphoma
Subcutaneous panniculitis-like T-cell lymphoma is a rare disorder
that is often confused with panniculitis. Patients present with multiple
subcutaneous nodules, which progress and can ulcerate. There is a
more indolent form that tends to express α/β TCRs and can be man­
aged with immune suppression, whereas lymphomas that express γ/δ
TCRs are more aggressive and are associated with a worse prognosis
and coincident hemophagocytic syndrome. This is a disease of young
men in their fifth and sixth decades of life. Patients with aggressive
disease are managed with multiagent chemotherapy, and responding
patients should be considered for allogeneic stem cell transplantation.
Adult T-Cell Leukemia/Lymphoma 
Adult T-cell leukemia/
lymphoma (ATLL) is a disease that is most prevalent in Japan and the
Caribbean basin (Chap. 207). It is a neoplasm that is driven by HTLV-1,
often contracted through the breast milk of infected mothers. The
average age at diagnosis is 60, so there is a long latency between viral
infection and viral transformation, and only 4% of infected patients
will develop the disease. This suggests that HTLV-1 may not be suffi­
cient to cause the malignant phenotype. There are four disease variants:
acute (60% of patients), lymphomatous (20% of patients), chronic (15%
of patients), and smoldering (5% of patients); prognosis varies across
these groups, with median survival times of 6, 10, and 24 months, and
not yet reached, respectively. Presentation depends on the subtype, but
most commonly, patients present with circulating disease and bone
marrow involvement, hypercalcemia, lytic bone lesions, lymphadenop­
athy, hepatosplenomegaly, skin lesions, and opportunistic infections.
The pathognomonic finding is the malignant “flower cell” that is
positive for CD4 and CD25, as well as CD2, CD3, and CD5 but lack­
ing CD7 (Fig. 113-7). Combination chemotherapy is generally used,
but for patients fortunate enough to respond, response durations are
very short. Other active agents in this disease include the antiretro­
viral agent zidovudine, interferon α, arsenic and mogamulizumab, a
humanized monoclonal antibody that blocks the CCR4 chemokine
receptor. In any patients who do respond to therapy, allogeneic stem
cell transplant should be considered.
Extranodal NK/T-Cell Lymphoma, Nasal Type 
Extranodal
NK/T-cell lymphoma, nasal type, is a lymphoma that is associated with

44 - 114 Hodgkin’s Lymphoma
114 Hodgkin’s Lymphoma
FIGURE 113-7  Adult T-cell leukemia/lymphoma. Peripheral blood smear showing
leukemia cells with typical “flower-shaped” nucleus.
EBV infection in nearly all cases and more common in Asia and native
populations in Peru. It usually presents with a mass and obstructive
symptoms in the upper aerodigestive tract with occasional extranodal
sites, but over two-thirds of patients will have localized disease. It is
more common in men, and the median age at diagnosis is 60. This
disease has its own prognostic score, which takes into account the
presence or absence of “B” symptoms, disease stage, whether LDH is
elevated, and whether there is lymph node involvement. EBV viral load
at diagnosis and at the end of therapy is also predictive.
PART 4
Oncology and Hematology
Treatment for early-stage disease is usually with combined-modality
therapy of chemotherapy (commonly using etoposide, ifosfamide,
cisplatin, and dexamethasone) and intensity-modulated radiation
therapy (50–55 Gy), and patients with localized disease involving the
nasal passages do quite well, with 3-year OS of ∼85%. Patients with
more advanced-stage disease do poorly, with disseminated extranodal
relapse occurring frequently, and the median OS is only 4.3 months.
The most commonly used treatment regimen is the SMILE regi­
men (dexamethasone, methotrexate, ifosfamide, l-asparaginase, and
etoposide).
■
■FURTHER READING
Horwitz S et al: The ECHELON-2 Trial: 5-year results of a random­
ized, phase III study of brentuximab vedotin with chemotherapy for
CD30-positive peripheral T-cell lymphoma. Ann Oncol 33:288, 2022.
Morschhauser F et al: Rituximab plus lenalidomide in advanced
untreated follicular lymphoma. N Engl J Med 379:934, 2018.
Tille H et al: Polatuzumab vedotin in previously untreated diffuse
large B-cell lymphoma. N Engl J Med 386:351, 2022.
Westin JR et al: Survival with axi-cabtagene ciloleucel in large B-cell
lymphoma. N Engl J Med 389:148, 2023.
Caron A. Jacobson, Dan L. Longo
Hodgkin’s Lymphoma
Hodgkin’s lymphoma (HL) is a malignancy of mature B lymphocytes.
It represents ~10% of all lymphomas diagnosed each year. The majority
of HL diagnoses are classical HL (cHL), but there is a second subtype
of HL, nodular lymphocyte-predominant HL (NLPHL). While this
diagnosis does resemble cHL morphologically in certain respects,
there is some evidence that it is more related to the indolent B-cell
non-Hodgkin’s lymphomas (NHLs) biologically than it is to cHL. The
majority of this chapter will be specific to cHL, with a discussion of
NLPHL at the end.
cHL is one of the success stories of modern oncology. Until the
advent of extended-field radiotherapy in the mid-twentieth century,
it was a highly fatal disease of young people. Radiation therapy cured
some patients with early-stage disease, and the introduction of mul­
tiagent chemotherapy in the 1970s resulted in further improved cure
rates, for both patients with early- and advanced-stage disease. Cure
rates now are >85%. The new challenge in the treatment of HL is late
therapy-related toxicity, including a high rate of secondary malignan­
cies and cardiovascular disease. Current clinical trials are aimed at
minimizing this risk while preserving efficacy.
■
■EPIDEMIOLOGY AND ETIOLOGY
HL is of B-cell origin. The incidence of HL appears fairly stable, with an
estimated 8830 new cases diagnosed in the United States in 2023. HL
is more common in whites than in blacks and more common in males
than in females. A bimodal distribution of age at diagnosis has been
observed, with one peak incidence occurring in patients in their twen­
ties and the other in those in their eighties. Some of the late age peak
may be attributed to confusion among entities with similar appearance
such as anaplastic large-cell lymphoma and T-cell/histiocyte–rich B-cell
lymphoma. There are four distinct subtypes of cHL that are differentiated
based on their histopathologic features (Table 114-1): nodular scle­
rosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted.
Patients in the younger age groups diagnosed in the United States
largely have the nodular sclerosing subtype of HL. Elderly patients,
patients infected with HIV, and patients in developing countries more
commonly have mixed-cellularity HL or lymphocyte-depleted HL.
Together, nodular sclerosis and mixed-cellularity types account for
nearly 95% of cases. Infection by HIV is a risk factor for developing
HL. In addition, an association between infection by Epstein-Barr virus
(EBV) and HL has been suggested. A monoclonal or oligoclonal pro­
liferation of EBV-infected cells in 20–40% of the patients with HL has
led to proposals for this virus having an etiologic role in HL. However,
the matter is not settled definitively. Viral oncogenesis appears to play
a greater role in HIV-related cHL: EBV can be detected in nearly all
cases of HIV-associated cHL, compared to only one-third of cases of
non–HIV-associated cHL. Reed-Sternberg (HRS) cells are the malig­
nant cells in HL. HRS cells in HIV-associated cHL express the EBVtransforming protein latent membrane protein 1 (LMP-1), and the
EBV genomes from multiple disease sites in the same HIV-associated
cHL patient are episomal and clonal, suggesting that EBV is directly
involved in early lymphomagenesis.
Histologically, the HRS cell is diagnostic of cHL (Fig. 114-1).
These cells are large cells with abundant cytoplasm with bilobed and/
or multiple nuclei. By immunohistochemistry, they are often PAX-5
positive but have low to no expression of other B-cell antigens like
CD19 and CD20. They express CD15 and CD30 in 85 and 100% of
cases, respectively. These cells, though, comprise <1% of the tumor
cellularity, with the majority of the tumor made up of a surround­
ing inflammatory infiltrate of polyclonal lymphocytes, eosinophils,
neutrophils, macrophages, plasma cells, fibroblasts, and collagen. The
HRS cell interacts with its microenvironment via cell-cell contact and
elaboration of growth factors and cytokines, which results in a sur­
rounding cellular milieu that protects it from host immune attack.
The surrounding environmental cells likewise support the HRS cells
via cell-cell signaling and cytokine production, which provides signals
TABLE 114-1  World Health Organization Classification of Hodgkin’s
Lymphoma
Nodular lymphocyte-predominant Hodgkin’s lymphoma
Classical Hodgkin’s lymphoma
Nodular sclerosis
Lymphocyte-rich
Mixed cellularity
Lymphocyte-depleted
FIGURE 114-1  Hodgkin’s disease: A classic Reed-Sternberg (RS) cell is present
near the center of the field. RS cells are large cells with a bilobed nucleus and
prominent nucleoli surrounded by a pleiomorphic cellular infiltrate. (From DL Kasper:
Harrison’s Principles of Internal Medicine, 16th ed. New York, NY: McGraw-Hill; 2005,
Fig. 97-11, p. 654.)
that promote proliferation and survival of the HRS cell itself. Interest­
ingly, 97% of HRS cells in cHL harbor genetic aberrations in the PD-L1
locus on chromosome 9p24.1, resulting in overexpression of PD-L1,
the ligand for the inhibitory PD-1 receptor on immune cells. This is
one mechanism whereby the HRS cell may be able to avoid immune
destruction in its inflammatory microenvironment and may contribute
to the generalized immune suppression in HL patients.
APPROACH TO THE PATIENT
Classical Hodgkin’s Lymphoma
Most patients with cHL present with palpable lymphadenopathy
that is nontender; in most patients, these lymph nodes are in the
neck, supraclavicular area, and axilla. More than half of the patients
will have mediastinal adenopathy at diagnosis, and this is some­
times the initial manifestation. Subdiaphragmatic presentation of
cHL is unusual and more common in older males. One-third of
patients present with fevers, night sweats, and/or weight loss, or “B”
symptoms. Occasionally, HL can present as a fever of unknown ori­
gin. This is more common in older patients who are found to have
mixed-cellularity HL in an abdominal site. Rarely, the fevers persist
for days to weeks, followed by afebrile intervals and then recurrence
of the fever. This pattern is known as Pel-Ebstein fever. HL can occa­
sionally present with unusual manifestations. These include severe
and unexplained itching, cutaneous disorders such as erythema
nodosum and ichthyosiform atrophy, paraneoplastic cerebellar
degeneration and other distant effects on the CNS, nephrotic syn­
drome, immune hemolytic anemia and thrombocytopenia, hyper­
calcemia, and pain in lymph nodes on alcohol ingestion.
Evaluation of patients with HL will typically begin with a careful
history and physical examination. Patients should be asked about
the presence or absence of “B” symptoms. Comorbid diagnoses
that may impact therapy should be reviewed, including a history
of pulmonary disease and congestive heart failure given the use of
chemotherapy drugs that can cause both lung and heart toxicity.
A physical examination should pay attention to the peripherally
accessible sites of lymph nodes and to the liver and spleen size.
Laboratory evaluation should include a complete blood count with
differential; erythrocyte sedimentation rate (ESR); chemistry stud­
ies reflecting major organ function including serum albumin; and
HIV and hepatitis virus testing. A positron emission tomography
(PET)/computed tomography (CT) scan is used for staging and is
more accurate than a bone marrow biopsy for evaluation of bone
marrow involvement as the bone marrow involvement in cHL tends
to be patchy and therefore potentially missed on a unilateral bone
TABLE 114-2  The Ann Arbor Staging System for Hodgkin’s Lymphoma
STAGE
DEFINITION
I
Involvement of a single lymph node region or lymphoid structure
(e.g., spleen, thymus, Waldeyer’s ring)
II
Involvement of two or more lymph node regions on the same side of
the diaphragm (the mediastinum is a single site; hilar lymph nodes
should be considered “lateralized” and, when involved on both
sides, constitute stage II disease)
III
Involvement of lymph node regions or lymphoid structures on both
sides of the diaphragm
  III1
  Subdiaphragmatic involvement limited to spleen, splenic hilar
nodes, celiac nodes, or portal nodes
  III2
  Subdiaphragmatic involvement includes paraaortic, iliac, or
mesenteric nodes plus structures in III1
IV
Involvement of extranodal site(s) beyond that designated as “E”
 
  More than one extranodal deposit at any location
 
  Any involvement of liver or bone marrow
A
No symptoms
B
Unexplained weight loss of >10% of the body weight during the
6 months before staging investigation
 
Unexplained, persistent, or recurrent fever with temperatures >38°C
during the previous month
CHAPTER 114
 
Recurrent drenching night sweats during the previous month
E
Localized, solitary involvement of extralymphatic tissue, excluding
liver and bone marrow
Hodgkin’s Lymphoma
marrow biopsy. The initial evaluation of a patient with HL or NHL
is similar. In both situations, the determination of an accurate ana­
tomic stage is an important part of the evaluation. Staging is done
using the Ann Arbor staging system (Table 114-2).
The diagnosis of HL is established by review of an adequate
biopsy specimen by an expert hematopathologist. HL is a tumor
characterized by rare neoplastic cells of B-cell origin (immunoglob­
ulin genes are rearranged but not expressed) in a tumor mass that
is largely polyclonal inflammatory infiltrate, probably a reaction to
cytokines produced by the tumor cells. The differential diagnosis
of a lymph node biopsy suspicious for HL includes inflammatory
processes, mononucleosis, NHL, phenytoin-induced adenopathy,
and nonlymphomatous malignancies.
Staging for cHL is anatomically based given the propensity of the
disease to march from one lymph node group to the next group,
often contiguous to the first. Staging is important for selecting
therapy of appropriate duration and intensity, but the outcome of
optimal therapy for all the stages is excellent. Patients are stratified
based on whether they have early-stage disease (stage I or II) or
advanced-stage disease (stage III or IV). Patients with early-stage
disease have a better prognosis overall but are further classified as
favorable or unfavorable based on a variety of factors. These fac­
tors vary from study to study but include bulky disease, number of
lymph node areas involved, an elevated ESR (>30 if “B” symptoms
are present; >50 if “B” symptoms are absent), and age. Prognosis in
advanced-stage disease is best predicted by the International Prog­
nostic Score (IPS), which ascribes 1 point for male sex, older age
(>45 years), stage IV disease, serum albumin <4 g/dL, hemoglobin
<10.5 g/dL, white blood cell count ≥15,000/μL, and a lymphocyte
count <600/μL and/or <8% of white blood cell count. Five-year
progression-free survival ranges from 88% for patients with no risk
factors to 62% for patients with four or more factors, but very few
patients have multiple risk factors.
TREATMENT
Classical Hodgkin’s Lymphoma
The overwhelming majority of patients with HL will be cured with
either chemotherapy alone or a combination of chemotherapy
and radiation therapy. It has long been appreciated that patients
with advanced-stage disease do not benefit from the addition
of radiation therapy to chemotherapy and are thus treated with
chemotherapy alone. For early-stage disease, however, treatment
with combined-modality therapy has been associated with a small
decrease in risk of relapse but with an increased risk of late toxicity
including secondary malignancies, thyroid disease, and prema­
ture cardiovascular disease and stroke resulting in minimal or no
improvement in long-term survival. Much of this risk can be attrib­
uted to radiation therapy. Thus, investigation into the treatment of
early-stage HL at present is aimed at trying to maximize treatment
outcome without using radiotherapy. This is an area of controversy
in the treatment of HL.
EARLY-STAGE DISEASE
The most common chemotherapy regimen used to treat early-stage
HL in the United States is ABVD (doxorubicin, bleomycin, vin­
blastine, and dacarbazine). This regimen is given every other week,
with each cycle including two treatments. In patients with low-risk,
or favorable, disease, the use of four to six cycles of ABVD alone,
without radiation therapy, results in progression-free and overall
survival rates of 88–92% and 97–100%, respectively, at 5–7 years.
This may be associated with a slightly increased risk of relapse when
compared with abbreviated chemotherapy (ABVD for four cycles)
followed by involved field radiation therapy (30 Gy), but with no
difference in overall survival owing to the excellent salvage strate­
gies used for relapsed HL and to the late toxicities seen following
radiation therapy to the chest. German studies have examined a
very abbreviated chemotherapy regimen (ABVD for two cycles) and
low-dose radiation (20 Gy) for particularly good-risk disease with
two or fewer lymph node areas involved and found that this was
equally effective to standard combined-modality therapy of ABVD
for four cycles and 30 Gy of radiation. However, long-term followup is not yet available to assess the impact of the lower radiotherapy
dose on late toxicities. Finally, the use of an early interim PET/CT
scan can aid decisions regarding the duration and extent of therapy.
In one study, a negative PET/CT scan after three cycles of ABVD
predicted for excellent outcomes with no additional therapy; in
another, a negative PET/CT scan after two cycles of ABVD pre­
dicted for good outcomes with two additional cycles of ABVD
alone, without radiation therapy.
PART 4
Oncology and Hematology
For unfavorable-risk disease, the omission of radiation ther­
apy following chemotherapy is associated with a more significant
increased risk of relapse compared to favorable-risk disease, but
again with no change in overall survival. For these patients, treat­
ment options would include ABVD for four cycles followed by
involved field radiation therapy or ABVD alone for six cycles.
Treatment decisions are often based on the extent of the radiation
field and the unfavorable risk factor, with patients with nonbulky
disease being candidates for chemotherapy alone if radiation would
be contraindicated for another reason. Combined modality therapy
has typically been used for patients with bulky disease, although
patients with bulky disease who have a negative PET/CT scan after
chemotherapy may not benefit from additional radiation therapy.
Alternative chemotherapy regimens to ABVD have been devel­
oped and include the Stanford V regimen and escalated BEACOPP
(bleomycin, etoposide, doxorubicin, cyclophosphamide, vincris­
tine, procarbazine, and prednisone). Neither of these regimens has
resulted in improved outcomes in patients with early-stage disease.
ADVANCED-STAGE DISEASE
Patients with advanced-stage disease do not benefit from the addi­
tion of radiation therapy after a complete response to chemotherapy
alone and should be treated with chemotherapy alone. The most
common regimens used in the United States include ABVD or
brentuximab vedotin plus doxorubicin, vinblastine, and dacarba­
zine (AVD) for six cycles. Brentuximab is an antibody-drug con­
jugate (ADC) that targets CD30 on the HRS cell and is conjugated
to the microtubule inhibitor monomethyl auristatin E (MMAE). It
was approved in the relapsed setting as a single agent and then was
tested in phase 1 and 2 trials in combination with AVD chemo­
therapy for the upfront treatment of advanced-stage cHL. A phase
3 study, ESCHELON-1, randomized patients with advanced-stage
cHL to either ABVD or brentuximab-AVD and demonstrated
both a progression-free and overall survival benefit with brentux­
imab-AVD. Again, Stanford V and escalated BEACOPP have been
evaluated in advanced-stage disease and are not associated with an
improvement in overall survival but are associated with increased
toxicity. The small fraction of patients who do not achieve complete
remission with chemotherapy alone (partial responders with persis­
tent PET scan positivity account for <10% of patients) may benefit
from the addition of involved field radiotherapy.
Drugs that target the PD-1/PD-L1 axis have been developed
for the treatment of relapsed HL based on the known genomic
alterations leading to PD-L1 overexpression on the HRS cell (see
“Relapsed Disease,” below). In the setting of relapsed disease, these
drugs, which include pembrolizumab and nivolumab, have very
high response rates and are associated with durable responses.
Phase 2 studies combining these drugs with either brentuximab
(nivolumab) or ICE (nivolumab; ifosfamide, carboplatin, and etopo­
side) or GND (pembrolizumab; gemcitabine, vinorelbine, and doxo­
rubicin) chemotherapy have demonstrated high complete response
rates in order to get patients to autologous stem cell transplantation.
A multicenter randomized trial comparing brentuximab-AVD to
nivolumab-AVD in the upfront treatment of advanced-stage cHL
has been presented, and there was a progression-free survival ben­
efit with nivolumab-AVD and the regimen had an arguably more
favorable toxicity profile. We await longer follow-up and U.S. Food
and Drug Administration review of these results to determine if this
study establishes a new standard of care for the upfront treatment
of advanced-stage cHL.
RELAPSED DISEASE
Patients who relapse after primary therapy of HL can frequently
still be cured. Patients who relapse after an effective chemother­
apy regimen are usually not curable with subsequent chemotherapy
administered at standard doses. Alternative salvage chemotherapy
administered at standard doses, then, is given in order to document
sensitivity to chemotherapy and to achieve maximum reduction of
tumor mass. For patients who respond completely or nearly so,
autologous stem cell transplantation can cure over half of patients.
Standard salvage chemotherapy regimens have historically included
ICE and GND. Newer combinations, including brentuximab with
immune checkpoint inhibitors such as nivolumab, have also been
tested with promising results for patients who have not seen
brentuximab in the frontline setting. The combinations of ICE or
GND with nivolumab or pembrolizumab, respectively, are similarly
highly effective and lead to high complete remission rates and
success in getting patients to definitive autologous stem cell trans­
plantation. These novel combinations have largely replaced standard sal­
vage chemotherapy approaches, as the chemotherapy/immunotherapy
combinations appear to be more effective and are associated with
higher rates of durable response after autologous stem cell trans­
plantation, perhaps owing to the chemosensitizing effects that have
been observed following immune checkpoint inhibition. Studies are
ongoing to investigate whether autologous transplant is necessary
for patients who have a favorable response to chemotherapy/immu­
notherapy combinations based on this observed phenomenon. For
patients with early-stage disease who do not respond sufficiently
to salvage chemotherapy, radiation therapy can be very effective
to achieve a remission; whether to consolidate such a remission
with an autologous stem cell transplant is debated. Brentuximab is
also used as a maintenance therapy following successful autologous
stem cell transplantation based on results of the AETHERA study, a
randomized trial of brentuximab maintenance versus observation.
Finally, anti-CD30 chimeric antigen receptor (CAR) T-cell therapy
has been tested in multiply relapsed cHL with promising early
results; these products are now being tested in multicenter phase 2
clinical trials.

45 - 115 Less Common Lymphoid and Myeloid Malignancies
115 Less Common Lymphoid and Myeloid Malignancies
SURVIVORSHIP
Because of the very high cure rate in patients with HL, long-term
complications have become a major focus for clinical research.
In fact, in some series of patients with early-stage disease, more
patients died from late complications of therapy than from HL itself.
This is particularly true in patients with localized disease. The most
serious late side effects include second malignancies and cardiac
injury. Patients are at risk for the development of acute leukemia in
the first 10 years after treatment with combination chemotherapy
regimens that contain alkylating agents plus radiation therapy. The
risk for development of acute leukemia is greater after MOPP-like
(mechlorethamine, vincristine, procarbazine, and prednisone) and
BEACOPP-like regimens than with ABVD or brentuximab-AVD.
The risk of development of acute leukemia after treatment for HL is
also related to the number of exposures to potentially leukemogenic
agents (i.e., multiple treatments after relapse) and the age of the
patient being treated, with those aged >60 years at particularly high
risk. The development of carcinomas as a complication of treatment
for HL is a major problem. These tumors usually occur ≥10 years
after treatment and are associated with use of radiotherapy. For
this reason, young women treated with thoracic radiotherapy for
HL should institute screening mammograms or breast MRI exams
5–10 years after treatment, and all patients who receive thoracic
radiotherapy for HL should be discouraged from smoking. Medias­
tinal radiation also accelerates coronary artery disease, and patients
should be encouraged to minimize risk factors for coronary artery
disease such as smoking and elevated cholesterol levels. Cervical
radiation therapy increases the risk of carotid atherosclerosis and
stroke and thyroid disease, including cancer.
A number of other late side effects from the treatment of HL
are well known. Patients who receive thoracic radiotherapy are at
very high risk for the eventual development of hypothyroidism
and should be observed for this complication; intermittent mea­
surement of thyrotropin should be made to identify the condition
before it becomes symptomatic. Lhermitte’s syndrome occurs in
∼15% of patients who receive thoracic radiotherapy. This syn­
drome is manifested by an “electric shock” sensation into the lower
extremities on flexion of the neck. Because of the young age at
which HL is often diagnosed, infertility is a concern for patients
undergoing treatment for HL. Chemotherapy regimens containing
alkylating agents induce permanent infertility in nearly all men.
The risk of permanent infertility in women treated with alkylat­
ing agent–containing chemotherapy is age-related, with younger
women more likely to recover fertility. Infertility is very rare after
treatment with ABVD.
NODULAR LYMPHOCYTE-PREDOMINANT HODGKIN’S
LYMPHOMA
NLPHL is now recognized as an entity distinct from cHL. Previous
classification systems recognized that biopsies from a small subset
of patients diagnosed as having HL contained a predominance of
small lymphocytes and rare Reed-Sternberg–like cells; tumors had
a nodular growth pattern and a clinical course that varied from that
of patients with cHL. This is an unusual clinical entity and repre­
sents <5% of cases of HL and defines NLPHL.
NLPHL has a number of characteristics that suggest its relation­
ship to NHL, rather than cHL, however. The HRS-like cell, or L&H
(lymphocyte and histiocyte) or “popcorn” cell, is a clonal prolifera­
tion of B cells that are positive for B-cell markers CD45, CD79a,
CD20, CD19, and BCL2. They do not express two markers nor­
mally found on HRS cells, CD30 and CD15. This lymphoma tends
to have a chronic, relapsing course and sometimes transforms to
diffuse large B-cell lymphoma, including a specific subtype of dif­
fuse large B-cell lymphoma known as T-cell/histiocyte–rich B-cell
lymphoma, which shares an immunophenotype with the L&H cell.
This natural history most closely resembles that of the indolent
B-cell NHLs outlined in Chaps. 113 and 115.
Patients with NLPHL are more commonly male (75%). Like cHL,
the age distribution of patients with this disease has two peaks,
but unlike cHL, these peaks include children and adults age 30–40
years, respectively. The majority of patients diagnosed have stage I
or II disease (75%), with a minority having advanced-stage disease
at diagnosis. “B” symptoms are uncommon.
Patients with early-stage disease at diagnosis should be treated
with definitive radiotherapy. This is associated with a 15-year
nonrelapse survival rate of 82%. The treatment of patients with
advanced-stage NLPHL is controversial. Some clinicians favor no
treatment of asymptomatic disease and merely close follow-up,
akin to the indolent B-cell NHLs. For patients who need therapy
due to symptoms or signs of organ function impairment, both
cHL regimens and B-cell NHL regimens have been used, including
ABVD and R-CHOP (rituximab, cyclophosphamide, doxorubi­
cin, vincristine, and prednisone). A single-institution experience
with R-CHOP resulted in a 100% response rate in a small group
of patients without a single relapse with 42 months of follow-up.
Although this is short follow-up for an indolent disease, some
believe R-CHOP may be curative in this disease and advocate treat­
ing patients with advanced-stage disease at diagnosis, regardless of
symptoms or organ function.
CHAPTER 115
■
■FURTHER READING
Ansell SM et al: Overall survival with brentuximab vedotin in stage III
or IV Hodgkin’s lymphoma. N Engl J Med 387:310, 2022.
Chen R et al: Pembrolizumab in relapsed or refractory Hodgkin
lymphoma: 2-year follow-up of KEYNOTE-087. Blood 134:1144,
2019.
Gillessen S et al: Intensified treatment of patients with early stage,
Less Common Lymphoid and Myeloid Malignancies
unfavourable Hodgkin lymphoma: Long-term follow-up of a randomised,
international phase 3 trial of the German Hodgkin Study Group
(GHSG HD14). Lancet Haematol 8:e278, 2021.
Herrera AF et al: Nivolumab+AVD in advanced-stage classic Hodg­
kin’s lymphoma. N Engl J Med 391:1379, 2024.
Moskowitz CH et al: Five-year PFS from the AETHERA trial of
brentuximab vedotin for Hodgkin lymphoma at high risk of progression
or relapse. Blood 132:2639, 2018.
Rashidi A et al: Allogeneic hematopoietic stem cell transplantation
in Hodgkin lymphoma: A systemic review and meta-analysis. Bone
Marrow Transplant 51:521, 2016.
Straus DJ et al: CALGB 50604: Risk-adapted treatment of nonbulky
early-stage Hodgkin lymphoma based on interim PET. Blood 132:
1013, 2018.
Ayalew Tefferi, Dan L. Longo
Less Common Lymphoid
and Myeloid Malignancies
The most common lymphoid malignancies are discussed in Chaps.
111, 112, 113, 114, and 116, myeloid leukemias in Chaps. 109 and
110, myelodysplastic syndromes (MDS) in Chap. 107, and myelopro­
liferative syndromes in Chap. 108. This chapter will focus on the more
unusual forms of hematologic malignancy. The diseases discussed here
are listed in Table 115-1. Each of these entities accounts for <1% of
hematologic neoplasms.
RARE LYMPHOID MALIGNANCIES
All the lymphoid tumors discussed here are mature B-cell or T-cell
natural killer (NK) cell neoplasms.
TABLE 115-1  Unusual Lymphoid and Myeloid Malignanciesa
Lymphoid
Mature B-cell neoplasms
  B-cell prolymphocytic leukemia
  Splenic marginal zone lymphoma
  Hairy cell leukemia
  Nodal marginal zone B-cell lymphoma
  Mediastinal large B-cell lymphoma
  Intravascular large B-cell lymphoma
  Primary effusion lymphoma
  Lymphomatoid granulomatosis
Mature T-cell and natural killer (NK) cell neoplasms
  T-cell prolymphocytic leukemia
  T-cell large granular lymphocytic leukemia
  Aggressive NK cell leukemia
  Extranodal NK/T-cell lymphoma, nasal type
  Enteropathy-type T-cell lymphoma
  Hepatosplenic T-cell lymphoma
  Subcutaneous panniculitis-like T-cell lymphoma
  Blastic NK cell lymphoma
PART 4
Oncology and Hematology
  Primary cutaneous CD30+ T-cell lymphoma
  Angioimmunoblastic T-cell lymphoma
Myeloid
Chronic neutrophilic leukemia
Chronic eosinophilic leukemia/hypereosinophilic syndrome
Histiocytic and Dendritic Cell Neoplasms
Histiocytic sarcoma
Langerhans cell histiocytosis
Langerhans cell sarcoma
Interdigitating dendritic cell sarcoma
Follicular dendritic cell sarcoma
Mast cells
Mastocytosis
Cutaneous mastocytosis
Systemic mastocytosis
Mast cell sarcoma
Extracutaneous mastocytoma
aThis list is not exhaustive. Many named entities are very rare and not discussed
here. A complete listing is available in the online version of this chapter.
■
■MATURE B-CELL NEOPLASMS
B-Cell Prolymphocytic Leukemia (B-PLL) 
This is a malig­
nancy of medium-sized (about twice the size of a normal small lym­
phocyte), round lymphocytes with a prominent nucleolus and light
blue cytoplasm on Wright’s stain. It predominantly affects the blood,
bone marrow (BM), and spleen and usually does not cause adenopa­
thy. The median age of affected patients is 70 years, and men are more
often affected than women (male-to-female ratio is 1.6). This entity is
distinct from chronic lymphoid leukemia (CLL) and does not develop
as a consequence of that disease.
Clinical presentation is generally from symptoms of splenomegaly
or incidental detection of an elevated white blood cell (WBC) count.
The clinical course can be rapid. The cells express surface IgM (with or
without IgD) and typical B-cell markers (CD19, CD20, CD22). CD23
is absent, and about one-third of cases express CD5. The CD5 expres­
sion along with the presence of the t(11;14) translocation in 20% of
cases leads to confusion in distinguishing B-PLL from the leukemic
form of mantle cell lymphoma. No reliable criteria for the distinction
have emerged, and gene expression studies suggest a close relationship
between mantle cell lymphoma and B-PLL and significant differences
with CLL. About half of patients have mutation or loss of p53, and
deletions have been noted in 11q23 and 13q14. Nucleoside analogues
like fludarabine and cladribine and combination chemotherapy (cyclo­
phosphamide, doxorubicin, vincristine, and prednisone [CHOP]) have
produced responses. CHOP plus rituximab may be more effective than
CHOP alone, but the disease is sufficiently rare that large series have
not been reported. Splenectomy can produce palliation of symptoms
but appears to have little or no impact on the course of the disease. BM
transplantation may be curative. Imatinib may also have activity.
Splenic Marginal Zone Lymphoma (SMZL) 
This tumor of
mainly small lymphocytes originates in the marginal zone of the spleen
white pulp, grows to efface the germinal centers and mantle, and
invades the red pulp. Splenic hilar nodes, BM, and peripheral blood
(PB) may be involved. The circulating tumor cells have short surface
villi and are called villous lymphocytes. Table 115-2 shows differences
in tumor cells of a number of neoplasms of small lymphocytes that aid
in the differential diagnosis. SMZL cells express surface immunoglobu­
lin and CD20 but are negative for CD5, CD10, CD43, and CD103. Lack
of CD5 distinguishes SMZL from CLL, and lack of CD103 separates
SMZL from hairy cell leukemia.
The median age of patients with SMZL is mid-fifties, and men and
women are equally represented. Patients present with incidental or
symptomatic splenomegaly or incidental detection of lymphocytosis
in the PB with villous lymphocytes. Autoimmune anemia or throm­
bocytopenia may be present. The immunoglobulin produced by these
cells contains somatic mutations that reflect transit through a germinal
center, and ongoing mutations suggest that the mutation machinery
has remained active. About 40% of patients have either deletions or
translocations involving 7q21, the site of the FLNC gene (filamin Cγ,
involved in cross-linking actin filaments in the cytoplasm). NOTCH2
mutations are seen in 25% of patients. Chromosome 8p deletions may
also be noted. The genetic lesions typically found in extranodal mar­
ginal zone lymphomas (e.g., trisomy 3 and t[11;18]) are uncommon
in SMZL.
The clinical course of disease is generally indolent with median sur­
vivals exceeding 10 years. Patients with elevated lactate dehydrogenase
(LDH) levels, anemia, and hypoalbuminemia generally have a poorer
prognosis. Long remissions can be seen after splenectomy. Rituximab,
ibrutinib, and PI3 kinase inhibitors are also active. A small fraction
of patients undergo histologic progression to diffuse large B-cell lym­
phoma with a concomitant change to a more aggressive natural history.
Experience with combination chemotherapy in SMZL is limited.
Hairy Cell Leukemia 
Hairy cell leukemia is a tumor of small
lymphocytes with oval nuclei, abundant cytoplasm, and distinctive
membrane projections (hairy cells). Patients have splenomegaly and
diffuse BM involvement. While some circulating cells are noted, the
clinical picture is dominated by symptoms from the enlarged spleen
and pancytopenia. The mechanism of the pancytopenia is not com­
pletely clear and may be mediated by both inhibitory cytokines and
TABLE 115-2  Immunophenotype of Tumors of Small Lymphocytes
 
CD5
CD20
CD43
CD10
CD103
sIG
CYCLIN D1
Follicular
lymphoma
neg
pos
pos
pos
neg
pos
neg
Chronic lymphoid
leukemia
pos
pos
pos
neg
neg
pos
neg
B-cell
prolymphocytic
leukemia
pos
pos
pos
neg
neg
pos
pos
Mantle cell
lymphoma
pos
pos
pos
neg
neg
pos
pos
Splenic marginal
zone lymphoma
neg
pos
neg
neg
neg
pos
neg
Hairy cell
leukemia
neg
pos
?
neg
pos
pos
neg
Abbreviations: neg, negative; pos, positive.
TABLE 115-3  Differential Diagnosis of “Dry Tap”—Inability to Aspirate
Bone Marrow
Dry taps occur in about 4% of attempts and are associated with:
  Metastatic carcinoma infiltration
17%
  Chronic myeloid leukemia
15%
  Myelofibrosis
14%
  Hairy cell leukemia
10%
  Acute leukemia
10%
  Lymphomas, Hodgkin’s disease
9%
  Normal marrow
Rare
marrow replacement. The marrow has an increased level of reticulin
fibers; indeed, hairy cell leukemia is a common cause of inability to
aspirate BM or so-called “dry tap” (Table 115-3). Monocytopenia is
profound and may explain a predisposition to atypical mycobacte­
rial infection that is observed clinically. The tumor cells have strong
expression of CD22, CD25, and CD103; soluble CD25 level in serum
is an excellent tumor marker for disease activity. The cells also express
tartrate-resistant acid phosphatase. The immunoglobulin genes are
rearranged and mutated, indicating the influence of a germinal center.
No specific cytogenetic abnormality has been found, but most cases
contain the activating BRAF mutation V600E.
The median age of affected patients is mid-fifties, and the maleto-female ratio is 5:1. Treatment options are numerous. Splenectomy
is often associated with prolonged remission. Nucleosides including
cladribine and deoxycoformycin are highly active but are also associ­
ated with further immunosuppression and can increase the risk of
certain opportunistic infections. However, after brief courses of these
agents, patients usually obtain very durable remissions during which
immune function spontaneously recovers. Interferon α is also an
effective therapy but is not as effective as nucleosides. Chemotherapyrefractory patients have responded to vemurafenib, a BRAF inhibitor.
Vemurafenib does not appear to be curative, but responses can be
maintained with chronic treatment. More durable remissions occur
when rituximab is added to vemurafenib.
Nodal Marginal Zone B-Cell Lymphoma 
This rare nodebased disease bears an uncertain relationship with extranodal marginal
zone lymphomas, which are often mucosa-associated and are called
mucosa-associated lymphoid tissue (MALT) lymphomas, and SMZLs.
Patients may have localized or generalized adenopathy. The neoplastic
cell is a marginal zone B cell with monocytoid features and has been
called monocytoid B-cell lymphoma in the past. Up to one-third of
the patients may have extranodal involvement, and involvement of
the lymph nodes can be secondary to the spread of a mucosal primary
lesion. In authentic nodal primaries, the cytogenetic abnormalities
associated with MALT lymphomas (trisomy 3 and t[11;18]) are very
rare. The clinical course is indolent. Patients often respond to combi­
nation chemotherapy, although remissions have not been durable. Few
patients have received CHOP plus rituximab, which is likely to be an
effective approach to management.
Mediastinal (Thymic) Large B-Cell Lymphoma 
This entity
was originally considered a subset of diffuse large B-cell lymphoma;
however, additional study has identified it as a distinct entity with its
own characteristic clinical, genetic, and immunophenotypic features.
This is a disease that can be bulky in size but usually remains confined
to the mediastinum. It can be locally aggressive, including progressing
to produce a superior vena cava obstruction syndrome or pericardial
effusion. About one-third of patients develop pleural effusions, and
in 5–10% of cases, disease can disseminate widely to kidney, adrenal,
liver, skin, and even brain. The disease affects women more often than
men (male-to-female ratio is 1:2–3), and the median age is 35–40 years.
The tumor is composed of sheets of large cells with abundant
cytoplasm accompanied by variable, but often abundant, fibrosis. It
is distinguished from nodular sclerosing Hodgkin’s disease by the
paucity of normal lymphoid cells and the absence of lacunar variants
of Reed-Sternberg cells. However, more than one-third of the genes
that are expressed to a greater extent in primary mediastinal large
B-cell lymphoma than in usual diffuse large B-cell lymphoma are also
overexpressed in Hodgkin’s disease, suggesting a possible pathogenetic
relationship between the two entities that affect the same anatomic
site. Tumor cells may overexpress MAL. The genome of tumor cells is
characterized by frequent chromosomal gains and losses. The tumor
cells in mediastinal large B-cell lymphoma express CD20, but surface
immunoglobulin and human leukocyte antigen (HLA) class I and class
II molecules may be absent or incompletely expressed. Expression of
lower levels of class II HLA identifies a subset with poorer prognosis.
The cells are CD5 and CD10 negative but may show light staining
with anti-CD30. The cells are CD45 positive, unlike cells of classical
Hodgkin’s disease.
Methotrexate, leucovorin, doxorubicin, cyclophosphamide, vin­
cristine, prednisone, and bleomycin (MACOP-B) and rituximab plus
CHOP are effective treatments, achieving 5-year survival of 75–87%.
Dose-adjusted therapy with prednisone, etoposide, vincristine, cyclo­
phosphamide, and doxorubicin (EPOCH) plus rituximab has pro­
duced 5-year survival of 97%. A role for mediastinal radiation therapy
has not been definitively demonstrated, but it is frequently used, espe­
cially in patients whose mediastinal area remains positron emission
tomography–avid after 4–6 cycles of chemotherapy.
CHAPTER 115
Intravascular Large B-Cell Lymphoma 
This is an extremely
rare form of diffuse large B-cell lymphoma characterized by the pres­
ence of lymphoma in the lumen of small vessels, particularly capillaries.
It is also known as malignant angioendotheliomatosis or angiotropic
large-cell lymphoma. It is sufficiently rare that no consistent picture has
emerged to define a clinical syndrome or its epidemiologic and genetic
features. It is thought to remain inside vessels because of a defect in
adhesion molecules and homing mechanisms, an idea supported by
scant data suggesting absence of expression of β-1 integrin and ICAM-1.
Patients commonly present with symptoms of small-vessel occlusion,
skin lesions, or neurologic symptoms. The tumor cell clusters can
promote thrombus formation. A subset of patients have tumors with
MYD88 or CD79B mutations. In general, the clinical course is aggres­
sive and the disease is poorly responsive to therapy. Often a diagnosis
is not made until very late in the course of the disease or at autopsy.
Diagnosis may be revealed in random skin biopsies in settings where
localized findings are limited.
Less Common Lymphoid and Myeloid Malignancies
Primary Effusion Lymphoma 
This entity is another variant of
diffuse large B-cell lymphoma that presents with pleural effusions,
usually without apparent tumor mass lesions. It is most common in
the setting of immune deficiency disease, especially AIDS, and is
caused by human herpes virus 8 (HHV-8)/Kaposi’s sarcoma herpes
virus (KSHV). It is also known as body cavity–based lymphoma. Some
patients have been previously diagnosed with Kaposi’s sarcoma. It can
also occur in the absence of immunodeficiency in elderly men of Medi­
terranean heritage, similar to Kaposi’s sarcoma but even less common.
The malignant effusions contain cells positive for HHV-8/KSHV,
and many are also co-infected with Epstein-Barr virus. The cells
are large with large nuclei and prominent nucleoli that can be con­
fused with Reed-Sternberg cells. The cells express CD20 and CD79a
(immunoglobulin-signaling molecule), although they often do not
express immunoglobulin. Some cases aberrantly express T-cell mark­
ers such as CD3 or rearranged T-cell receptor genes. No characteristic
genetic lesions have been reported, but gains in chromosome 12 and X
material have been seen, similar to other HIV-associated lymphomas.
The clinical course is generally characterized by rapid progression and
death within 6 months. CHOP plus lenalidomide or bortezomib may
produce responses. Highly active antiretroviral therapy for HIV should
be maintained during treatment.
Lymphomatoid Granulomatosis 
This is an angiocentric,
angiodestructive lymphoproliferative disease comprised by neoplas­
tic Epstein-Barr virus–infected monoclonal B cells accompanied and
outnumbered by a polyclonal reactive T-cell infiltrate. The disease is
graded based on histologic features such as cell number and atypia in
the B cells. It is most often confused with extranodal NK/T-cell lym­
phoma, nasal type, which can also be angiodestructive and is EpsteinBarr virus–related. The disease usually presents in adults (males >
females) as a pulmonary infiltrate. Involvement is often entirely extra­
nodal and can include kidney (32%), liver (29%), skin (25%), and
brain (25%). The disease often but not always occurs in the setting of
immune deficiency.
The disease can be remitting and relapsing in nature or can be rap­
idly progressive. The course is usually predicted by the histologic grade.
The disease is highly responsive to combination chemotherapy and is
curable in most cases. Some investigators have claimed that low-grade
disease (grade I and II) can be treated with interferon α.
■
■MATURE T-CELL AND NK CELL NEOPLASMS
T-Cell Prolymphocytic Leukemia 
This is an aggressive leu­
kemia of medium-sized prolymphocytes involving the blood, mar­
row, nodes, liver, spleen, and skin. It accounts for 1–2% of all small
lymphocytic leukemias. Most patients present with elevated WBC
count (often >100,000/μL), hepatosplenomegaly, and adenopathy. Skin
involvement occurs in 20%. The diagnosis is made from PB smear,
which shows cells about 25% larger than those in small lymphocytes,
with cytoplasmic blebs and nuclei that may be indented. The cells
express T-cell markers like CD2, CD3, and CD7; two-thirds of patients
have cells that are CD4+ and CD8–, and 25% have cells that are CD4+
and CD8+. T-cell receptor β chains are clonally rearranged. In 80% of
patients, inversion of chromosome 14 occurs between q11 and q32.
Ten percent have t(14;14) translocations that bring the T-cell receptor
alpha/beta gene locus into juxtaposition with oncogenes TCL1 and
TCL1b at 14q32.1. Chromosome 8 abnormalities are also common.
Deletions in the ATM gene are also noted. Activating JAK3 mutations
have also been reported.
PART 4
Oncology and Hematology
The course of the disease is generally rapid, with median survival of
about 12 months. Responses have been seen with the anti-CD52 anti­
body alemtuzumab, nucleoside analogues, and CHOP chemotherapy.
Histone deacetylase inhibitors like vorinostat and romidepsin may also
have activity. Small numbers of patients with T-cell prolymphocytic
leukemia have also been treated with high-dose therapy, and allogeneic
BM transplantation after remission has been achieved with alemtu­
zumab or conventional-dose therapy.
T-Cell Large Granular Lymphocytic Leukemia 
T-cell large
granular lymphocytic (LGL) leukemia is characterized by increases in
the number of LGLs in the PB (2000–20,000/μL) often accompanied
by severe neutropenia, with or without concomitant anemia. Pure red
cell aplasia may occur in 15–20% of patients. Splenomegaly is seen
in 25% of patients; adenopathy is generally absent. B symptoms are
rare, but 20–30% of patients may have infections related to the severe
neutropenia. Patients may have splenomegaly and frequently have evi­
dence of systemic autoimmune disease, including rheumatoid arthritis,
hypergammaglobulinemia, autoantibodies, and circulating immune
complexes. BM involvement is mainly interstitial in pattern, with <50%
lymphocytes on differential count. Usually the cells express CD3, T-cell
receptors, usually TCRα/β, and CD8; NK-like variants may be CD3–.
Like other T-cell neoplasms, loss of expression of CD5 and/or CD7
is common. The leukemic cells often express Fas and Fas ligand. The
JAK/STAT pathway is often activated.
The course of the disease is generally indolent and dominated by the
neutropenia. Paradoxically, immunosuppressive therapy with cyclo­
sporine, methotrexate, or cyclophosphamide plus glucocorticoids can
produce an increase in granulocyte counts. Nucleosides have been used
anecdotally. Occasionally the disease can accelerate to a more aggres­
sive clinical course.
Aggressive NK Cell Leukemia 
NK neoplasms are very rare,
and they may follow a range of clinical courses from very indolent
to highly aggressive. They are more common in Asians than whites,
and the cells frequently harbor a clonal Epstein-Barr virus episome.
The PB white count is usually not greatly elevated, but abnormal large
lymphoid cells with granular cytoplasm are noted. The aggressive form
is characterized by symptoms of fever and laboratory abnormalities of
pancytopenia. Hepatosplenomegaly is common; node involvement is
less common. Patients may have hemophagocytosis, coagulopathy, or
multiorgan failure. Serum levels of Fas ligand are elevated.
The cells express CD2 and CD56 and do not have rearranged T-cell
receptor genes. Deletions involving chromosome 6 are common. The
disease can be rapidly progressive. Some forms of NK neoplasms are
more indolent. They tend to be discovered incidentally with LGL
lymphocytosis and do not manifest the fever and hepatosplenomegaly
characteristic of the aggressive leukemia. The cells are also CD2 and
CD56 positive, but they do not contain clonal forms of Epstein-Barr
virus and are not accompanied by pancytopenia or autoimmune
disease.
Extranodal NK/T-Cell Lymphoma, Nasal Type 
Like lym­
phomatoid granulomatosis, extranodal NK/T-cell lymphoma tends
to be an angiocentric and angiodestructive lesion, but the malignant
cells are not B cells. In most cases, they are CD56+ Epstein-Barr
virus–infected cells; occasionally, they are CD56–Epstein-Barr virus–
infected cytotoxic T cells. They are most commonly found in the nasal
cavity. Historically, this illness was called lethal midline granuloma,
polymorphic reticulosis, and angiocentric immunoproliferative lesion.
This form of lymphoma is prevalent in Asia, Mexico, and Central and
South America; it affects males more commonly than females. When
it spreads beyond the nasal cavity, it may affect soft tissue, the gastro­
intestinal tract, or the testis. In some cases, hemophagocytic syndrome
(HPS) may influence the clinical picture. Patients may have B symp­
toms. Many of the systemic manifestations of disease are related to the
production of cytokines by the tumor cells and the cells responding to
their signals. Deletions and inversions of chromosome 6 are common.
Many patients with extranodal NK/T-cell lymphoma, nasal type,
have excellent antitumor responses with combination chemotherapy
regimens, particularly those with localized disease. Radiation therapy
is often used after completion of chemotherapy. Four risk factors have
been defined, including B symptoms, advanced stage, elevated LDH,
and regional lymph node involvement. Patient survival is linked to the
number of risk factors: 5-year survival is 81% for zero risk factors, 64%
for one risk factor, 32% for two risk factors, and 7% for three or four
risk factors. Combination regimens without anthracyclines have been
touted as superior to CHOP, but data are sparse. High-dose therapy
with stem cell transplantation has been used, but its role is unclear.
Enteropathy-Type T-Cell Lymphoma 
Enteropathy-type T-cell
lymphoma is a rare complication of longstanding celiac disease. It most
commonly occurs in the jejunum or the ileum. In adults, the lymphoma
may be diagnosed at the same time as celiac disease, but the suspicion
is that the celiac disease was a longstanding precursor to the develop­
ment of lymphoma. The tumor usually presents as multiple ulcerating
mucosal masses but may also produce a dominant exophytic mass or
multiple ulcerations. The tumor expresses CD3 and CD7 nearly always
and may or may not express CD8. The tumor may express CD30,
but therapies directed at CD30 have not been adequately tested. The
normal-appearing lymphocytes in the adjacent mucosa often have a
similar phenotype to the tumor. Most patients have the HLA genotype
associated with celiac disease, HLA DQA1∗0501 or DQB1∗0201.
The prognosis of this form of lymphoma is typically poor (median
survival is 7–11 months), but some patients have a good response to
CHOP chemotherapy. Patients who respond can develop bowel per­
foration from responding tumor. If the tumor responds to treatment,
recurrence may develop elsewhere in the celiac disease–affected small
bowel.
An indolent form of T-cell or NK cell lymphoma occurs rarely that
affects mainly the small intestine and presents with dyspepsia, vomit­
ing, and diarrhea. The cells often contain genetic changes that result in
JAK-STAT activation. The disease is most often chronic with little or
no propensity to spread and develop aggressive growth. A variety of
approaches have been tested; none are reliably curative.
Hepatosplenic T-Cell Lymphoma 
Hepatosplenic T-cell lym­
phoma is a malignancy derived from T cells expressing the gamma/delta
T-cell antigen receptor that affects mainly the liver and fills the sinu­
soids with medium-size lymphoid cells. When the spleen is involved,
dominantly the red pulp is infiltrated. It is a disease of young people,
especially young people with an underlying immunodeficiency or with
an autoimmune disease that demands immunosuppressive therapy.
The use of thiopurine and infliximab is particularly common in the
history of patients with this disease. The cells are CD3+ and usually
CD4– and CD8–. The cells may contain isochromosome 7q, often
together with trisomy 8. The lymphoma has an aggressive natural
history. Combination chemotherapy may induce remissions, but
most patients relapse. Cytarabine/etoposide/platinum-based regimens
appear more effective than CHOP-based regimens. Median survival
is about 2 years. The tumor does not appear to respond to reversal of
immunosuppressive therapy.
Subcutaneous Panniculitis-Like T-Cell Lymphoma 
Subcutaneous panniculitis-like T-cell lymphoma involves multiple
subcutaneous collections of neoplastic T cells that are usually cytotoxic
cells in phenotype (i.e., contain perforin and granzyme B and express
CD3 and CD8). The rearranged T-cell receptor is usually alpha/betaderived, but occasionally, the gamma/delta receptors are involved, par­
ticularly in the setting of immunosuppression. The cells are negative
for Epstein-Barr virus. A history of autoimmune disease, particularly
lupus erythematosus, in the patient or the family is present in almost
one-third of patients. Patients may have an HPS in addition to the skin
infiltration; fever and hepatosplenomegaly may also be present. Nodes
are generally not involved. Patients frequently respond to combination
chemotherapy, including CHOP. When the disease is progressive, the
HPS can be a component of a fulminant downhill course. Effective
therapy can reverse the HPS.
Blastic NK Cell Lymphoma 
The neoplastic cells express NK cell
markers, especially CD56, and are CD3 negative. They are large blasticappearing cells and may produce a leukemia picture, but the dominant
site of involvement is the skin. Morphologically, the cells are similar
to the neoplastic cells in acute lymphoid and myeloid leukemia. No
characteristic chromosomal abnormalities have been described. The
clinical course is rapid, and the disease is largely unresponsive to typi­
cal lymphoma treatments.
Primary Cutaneous CD30+ T-Cell Lymphoma 
This tumor
involves the skin and is composed of cells that appear similar to the
cells of anaplastic T-cell lymphoma. Among cutaneous T-cell tumors,
~25% are CD30+ anaplastic lymphomas. If dissemination to lymph
nodes occurs, it is difficult to distinguish between the cutaneous and
systemic forms of the disease. The tumor cells are often CD4+, and the
cells contain granules that are positive for granzyme B and perforin
in 70% of cases. The typical t(2;5) of anaplastic T-cell lymphoma is
absent; indeed, its presence should prompt a closer look for systemic
involvement and a switch to a diagnosis of anaplastic T-cell lymphoma.
This form of lymphoma has sporadically been noted as a rare com­
plication of silicone or saline breast implants. The natural history of
breast implant–associated lymphoma is generally indolent. Cutaneous
CD30+ T-cell lymphoma often responds to therapy. The anti-CD30
immunotoxin conjugate brentuximab vedotin is active. Radiation
therapy can be effective, and surgery can also produce long-term dis­
ease control. Five-year survival exceeds 90%.
Angioimmunoblastic T-Cell Lymphoma 
Angioimmunoblastic
T-cell lymphoma is a systemic disease that accounts for ~15% of all
T-cell lymphomas. Patients frequently have fever, advanced stage, dif­
fuse adenopathy, hepatosplenomegaly, skin rash, polyclonal hypergam­
maglobulinemia, and a wide range of autoantibodies including cold
agglutinins, rheumatoid factor, and circulating immune complexes.
Patients may have edema, arthritis, pleural effusions, and ascites. The
nodes contain a polymorphous infiltrate of neoplastic T cells and non­
neoplastic inflammatory cells together with proliferation of high endo­
thelial venules and follicular dendritic cells (FDCs). The most common
chromosomal abnormalities are trisomy 3, trisomy 5, and an extra
X chromosome. Aggressive combination chemotherapy can induce
regressions. The underlying immune defects make conventional lym­
phoma treatments more likely to produce infectious complications.
RARE MYELOID MALIGNANCIES
The World Health Organization (WHO) and the International Consensus
Classification (ICC) systems use PB counts, PB smear analysis, BM mor­
phology, and cytogenetic and molecular genetic tests in order to classify
myeloid malignancies into several major categories (Table 115-4). Among
them, acute myeloid leukemia (AML) and AML-related disorders are
discussed in Chap. 109, MDS and MDS/AML in Chap. 107, chronic
myeloid leukemia (CML) in Chap. 110, and JAK2 mutation–prevalent
myeloproliferative neoplasms (MPN), including essential thrombocy­
themia, polycythemia vera, and primary myelofibrosis, in Chap. 108.
In this chapter, we focus on some of the remaining myeloid neoplasms
listed in Table 115-4, which are less frequent: (1) other MPNs includ­
ing chronic neutrophilic leukemia (CNL), chronic eosinophilic leu­
kemia, not otherwise specified (CEL-NOS), and MPN, unclassifiable
(MPN-U); (2) MDS/MPN overlap including chronic myelomonocytic
leukemia (CMML), atypical CML (aCML), MDS/MPN with mutated
SF3B1 and thrombocytosis, MDS/MPN with ring sideroblasts and
thrombocytosis, not otherwise specified (MDS/MPN-RS-T-NOS), and
MDS/MPN, not otherwise specified (MDS/MPN-NOS); (3) juvenile
myelomonocytic leukemia (JMML); (4) transient myeloproliferative
disorder (TMD); (5) hypereosinophilia including those associated
with tyrosine kinase gene fusions (TKGFs) and hypereosinophilic syn­
drome (HES); (6) mastocytosis; and (7) histiocytic and dendritic cell
neoplasms (hemophagocytic lymphohistiocytosis [HLH] is discussed
in Chap. 68).
CHAPTER 115
Less Common Lymphoid and Myeloid Malignancies
■
■CHRONIC NEUTROPHILIC LEUKEMIA
CNL is a clonal proliferation of mature neutrophils with few or no
circulating immature granulocytes. Other clinical features include
hepatosplenomegaly and constitutional symptoms. The disease is
molecularly characterized by activating mutations of the gene (CSF3R)
encoding for the receptor for granulocyte colony-stimulating factor
(G-CSF), also known as colony-stimulating factor 3 (CSF3). Patients
with CNL might be asymptomatic at presentation but can also display
constitutional symptoms, splenomegaly, anemia, and thrombocytope­
nia. A population-based study suggested an overall incidence of 0.1
cases/million individuals, using combined Surveillance, Epidemiology,
and End Results and National Cancer Database data. CNL typically
presents in elderly patients with a median age at diagnosis of 66.5 years
(range, 15–86 years) and slight male preponderance (56–58% of cases).
Median survival is ~2 years, and causes of death include transforma­
tion to acute leukemia, progressive disease associated with severe cyto­
penias, and marked treatment-refractory leukocytosis.
CSF3 is the main growth factor for granulocyte proliferation and
differentiation. Accordingly, recombinant CSF3 is used for the treat­
ment of severe neutropenia, including severe congenital neutropenia
(SCN). Some patients with SCN acquire CSF3R mutations, and the
frequency of such mutations is significantly higher (~80%) in patients
who experience leukemic transformation. SCN-associated CSF3R
mutations occur in the region of the gene coding for the cytoplasmic
domain of CSF3R and result in truncation of the C-terminal–negative
regulatory domain. In 2013, Maxson et al described a different class
of CSF3R mutations in ~90% of patients with CNL; these were mostly
membrane proximal, the most frequent being a C-to-T substitution at
nucleotide 1853 (T618I). In a subsequent confirmatory study, CSF3R
mutations were found to be specific to WHO-defined CNL. About
40% of the T618I-mutated cases also harbored SETBP1 mutations.
CSF3R T618I has been shown to induce lethal myeloproliferative
disorder in a mouse model and to have in vitro sensitivity to JAK
inhibition.
Diagnosis of CNL requires exclusion of the more common causes
of neutrophilia including infections and inflammatory processes
(Table 115-5). In addition, one should be mindful of the association
between some forms of metastatic cancer or plasma cell neoplasms
with secondary neutrophilia. Neoplastic neutrophilia also occurs in
other myeloid malignancies, which should be excluded during the
TABLE 115-4  International Consensus Classification of Myeloid
Neoplasms
6.	 Acute myeloid leukemia (AML)
a.	 AML diagnosis requiring ≥10% bone marrow (BM) or peripheral blood (PB)
blasts
i.	 Acute promyelocytic leukemia
ii.	 Core binding factor AML
iii.	 AML with KMT2A rearrangement
iv.	 AML with DEK::NUP214
v.	 AML with MECOM rearrangements
vi.	 AML with NPM1 mutation
vii.	 AML with in-frame bZIP CEBPA mutations
viii.	 AML with other rare recurring translocations
ix.	 Myelodysplastic syndrome (MDS)/AML with TP53 mutations
x.	 MDS/AML with myelodysplasia-related mutations
xi.	 MDS/AML with myelodysplasia-related karyotype
xii.	 MDS/AML not otherwise specified (NOS)
b.	 AML diagnosis requiring ≥20% BM or PB blasts
i.	 AML with t(9;22)-BCR::ABL1
ii.	 AML with TP53 mutations, other than pure erythroid leukemia
iii.	 AML with myelodysplasia-related gene mutations
iv.	 AML with myelodysplasia-related karyotype
v.	 AML NOS
7.	 AML-related disorders
PART 4
Oncology and Hematology
a.	 Pure erythroid leukemia (PEL; TP53 mutated)
b.	 Myeloid sarcoma
c.	 Blastic plasmacytoid dendritic cell neoplasm
d.	 Acute leukemia of ambiguous lineage
e.	 Acute undifferentiated leukemia
f.	 Mixed phenotype acute leukemia
8.	 Myelodysplastic syndromes (MDS)
a.	 MDS with mutated TP53
b.	 MDS with excess blasts (5–9% BM or 2–9% PB)
c.	 MDS without excess blasts (<5% BM and <2% PB)
i.	 MDS with del(5q) [isolated or accompanied by only one other
cytogenetic abnormality other than 7/del(7q); no multi-hit TP53]
ii.	 MDS with SF3B1 [variant allele frequency ≥10%/no RUNX1 or multi-hit
TP53; no del(5q), –7/del(7q), complex karyotype, or abnormal 3q26.2]
iii.	 MDS, NOS–single-lineage dysplasia
iv.	 MDS, NOS–multilineage dysplasia
v.	 MDS, NOS without dysplasia
9.	 MDS/AML
a.	 MDS/AML (BM/PB blasts 10–19%)
b.	 MDS/AML with mutated TP53
10.	Myeloproliferative neoplasms (MPN)
a.	 Chronic myeloid leukemia
b.	 Polycythemia vera
c.	 Essential thrombocythemia
d.	 Primary myelofibrosis (PMF)
i.	 Early/prefibrotic PMF
ii.	 Overt PMF
e.	 MPN, unclassifiable (MPN-U)
f.	 Chronic neutrophilic leukemia
g.	 Chronic eosinophilic leukemia, NOS
11.	MDS/MPN
a.	 Chronic myelomonocytic leukemia (CMML) (≥0.5 × 109/L absolute and ≥10%
PB monocytes)
i.	 CMML-1 (<10% BM and <5% PB blasts)
ii.	 CMML-2 (10–19% BM or 5–19% PB blasts)
b.	 Atypical chronic myeloid leukemia
c.	 MDS/MPN with mutated SF3B1 and thrombocytosis
d.	 MDS/MPN with ring sideroblasts and thrombocytosis, NOS
e.	 MDS/MPN, NOS
i.	 MDS/MPN with isolated isochromosome (17q)
12.	Eosinophilic disorders
13.	Mastocytosis
14.	Hematologic neoplasms with germline predisposition
15.	Pediatric myeloid malignancies
16.	Premalignant clonal hematopoiesis
diagnostic workup (Table 115-5). Accordingly, the ICC diagnostic crite­
ria for CNL are designed to exclude the possibilities of both secondary/
reactive neutrophilia and leukocytosis associated with myeloid malig­
nancies other than CNL (Table 115-5). The discovery of CSF3R
mutations (see above) and their almost invariable association with
ICC-defined CNL has allowed its incorporation in the ICC diagnostic
criteria (Table 115-5). In general, the presence of a membrane proxi­
mal CSF3R mutation in a patient with predominantly neutrophilic
granulocytosis should be sufficient for the diagnosis of CNL, regard­
less of the degree of leukocytosis. Unfortunately, several exclusionary
criteria still need to be met for diagnosing CNL in the absence of
CSF3R mutations (Table 115-5).
Current treatment in CNL is largely palliative and suboptimal in
its efficacy. Several drugs alone or in combination have been tried,
and none have shown remarkable efficacy. As such, allogeneic hema­
topoietic stem cell transplant (ASCT) is reasonable to consider in the
presence of symptomatic disease, especially in younger patients. Oth­
erwise, cytoreductive therapy with hydroxyurea is probably as good
as anything, and a more intensive combination chemotherapy may
not have additional value. However, response to hydroxyurea therapy
is often transient, and some have successfully used interferon α as an
alternative drug. JAK inhibitor therapy has emerged as an additional
therapeutic option but is not necessarily superior to hydroxyurea
(estimated response rate of 30%). It is thus recommended that CNL
patients first and foremost be evaluated for eligibility and disposition
for ASCT, with the remaining therapeutic agents being aimed at con­
trolling myeloproliferation (targeting leukocytes <25–30 × 109/L) and
alleviating symptoms.
■
■CHRONIC EOSINOPHILIC LEUKEMIA, NOT
OTHERWISE SPECIFIED
In a Mayo Clinic survey of 1416 patients with PB eosinophilia evalu­
ated between 2008 and 2019, 17 patients (1.2%) fulfilled the ICC crite­
ria for CEL-NOS (Table 115-5); median age was 63 years, with the vast
majority of patients (88%) presenting with systemic symptoms. Organ
involvement was a prominent feature including spleen, cardiac, pulmo­
nary, and distal esophagus. Laboratory abnormalities included anemia,
leukocytosis, and eosinophilia (median eosinophil count of 6.4 × 109/L;
range, 2.0–53.1 × 109/L). The most common bone marrow abnormali­
ties included abnormal eosinophils, abnormal and increased mega­
karyocytes, and fibrosis (18%). Cytogenetic abnormalities occurred
in 88% of patients and included trisomy 8, complex karyotype, 13q–,
20q–, and chromosome 1 abnormalities. All seven patients with
next-generation sequencing studies harbored one or more mutations
including ASXL1 (43%) and IDH1 (29%). Half of patients treated with
hydroxyurea-based regimens responded with a persistent decline in
eosinophil count for a median duration of 18 months. One-third of
patients treated with prednisone responded, with a median duration
of response at 13 months. Three patients were treated with imatinib,
of whom two had normalization of eosinophil count. At a median
follow-up of 13 months, nine patients had died, including three who
underwent leukemic transformation.
■
■MYELOPROLIFERATIVE NEOPLASM,
UNCLASSIFIABLE
The category of MPN-U includes MPN-like neoplasms that cannot
be clearly classified as one of the other subcategories of MPN listed
in Table 115-1. Examples include patients presenting with unusual
thrombosis or unexplained organomegaly with normal blood counts
but found to carry MPN-characteristic mutations such as JAK2 and
CALR or display bone marrow morphology that is consistent with
MPN. It is possible that some cases of MPN-U represent earlier disease
stages in polycythemia vera (PV) or essential thrombocythemia (ET),
which, however, fail to meet the threshold hemoglobin levels or platelet
counts that are required per WHO diagnostic criteria. Specific treat­
ment interventions might not be necessary in asymptomatic patients
with MPN-U, whereas patients with arterial thrombotic complications
might require cytoreductive and aspirin therapy and those with venous
thrombosis might require systemic anticoagulation.
TABLE 115-5  International Consensus Classification (ICC) Diagnostic Criteria for Chronic Neutrophilic Leukemia (CNL), Atypical Chronic Myeloid
Leukemia (aCML), and Chronic Myelomonocytic Leukemia (CMML)
VARIABLES
CNLa
aCML
CMML
PB leukocyte count
≥13 × 109/Ld
≥13 × 109/L
 
PB segmented neutrophils/bands
≥80%
 
 
PB neutrophil precursorsb
<10%
≥10%
 
PB blasts
Usually absente
<20%
<20%
PB monocyte count
<10% of leukocytes
No or minimal monocytosis
≥0.5 × 109/Lg
Cytopeniah
 
Yes
Yes
Dysgranulopoiesis
 
Yes
 
PB basophil/eosinophil percentage
 
<10%
 
PB monocyte percentage
 
<10%
≥10%
BM
Hypercellular
↑ Neutrophils, number and %
<5% blasts
Normal neutrophilic maturation
 
BCR-ABL1
No
No
No
Tyrosine kinase gene fusionsf
No
No
No
CSF3R T618I or other activating CSF3R mutation
or persistent neutrophilia, splenomegaly, no
identifiable cause of reactive neutrophilia,c
if plasma cell neoplasm is present, need
demonstration of clonality of myeloid cells by
cytogenetic or molecular studies
Yes
 
 
PB and BM blasts/promonocytes
 
<20%
<20%
Evidence for other MPN: CML, PV, ET, PMF
No
No
No
Evidence for reactive leukocytosis or monocytosis
No
No
No
aDiagnosis requires meeting all criteria. bNeutrophil precursors include myeloblasts, promyelocytes, myelocytes, and metamyelocytes. cCauses of reactive neutrophilia
include plasma cell neoplasms, solid tumor, infections, and inflammatory processes. d≥25 × 109/L in cases lacking CSF3R T618I or another activating CSF3R mutation.
e10–19% blasts constitute accelerated phase and ≥20% blast phase. fTyrosine kinase gene fusions involve PDGFRA, PDGFRB, FGFR1, ABL1, JAK2, and FLT3. gPB monocytes
≥1 × 109/L in cases without evidence of clonality; the latter is signified by abnormal karyotype or a myeloid neoplasm associated mutation with ≥10% variant allele frequency.
hHemoglobin <12 g/dL in females and <13 g/dL in males, absolute neutrophil count <1.8 × 109/L, and/or platelets <150 × 109/L, that is not explained by another condition.
Abbreviations: AML, acute myeloid leukemia; BM, bone marrow; CML, chronic myeloid leukemia; ET, essential thrombocythemia; MDS, myelodysplastic syndromes; MPN,
myeloproliferative neoplasms; PB, peripheral blood; PMF, primary myelofibrosis; PV, polycythemia vera.
■
■CHRONIC MYELOMONOCYTIC LEUKEMIA
CMML is classified under the ICC category of MDS/MPN neoplasms
and is defined by sustained (>3 months) PB monocytosis (≥0.5 × 109/L;
monocytes ≥10% of leukocyte count), consistent BM morphology,
<20% BM or PB blasts (including promonocytes), and cytogenetic or
molecular evidence of clonality. The median age at CMML diagno­
sis is ~73–75 years, with a male preponderance (1.5–3:1). The exact
incidence of CMML remains unknown but is estimated at 4 cases per
100,000 persons per year. Clinical presentation is variable and depends
on whether the disease presents with MDS-like (MDS-CMML) or
MPN-like (MP-CMML) phenotype, based on the presence or absence
of leukocyte count of ≥13 × 109/L; the former is associated with cyto­
penias and the latter with splenomegaly and features of myeloprolif­
eration such as fatigue, night sweats, weight loss, and cachexia. About
20% of patients with CMML experience unique symptoms including
systemic inflammatory syndromes (e.g., arthritis, pericardial effusion,
pleural effusion, ascites), autoimmune diseases, leukemia cutis, and
lysozyme-induced nephropathy.
During the diagnostic workup of CMML, it is important to first
exclude reactive causes of monocytosis, including tuberculosis, fungal
infections, subacute bacterial endocarditis, viral and protozoal infec­
tions, connective tissue diseases, sarcoidosis, lipid storage disorders,
postsplenectomy state, and the recovery phase of an acute infection or
BM regeneration after chemotherapy. Other myeloid neoplasms in the
differential diagnosis include CML (BCR::ABL1-defined) and other
fusion gene-associated entities including those with rearrangements
of PDGFRA, PDGFRB, FGFR1, JAK2, FLT3, and ABL1. Similarly, it
Persistent and lasting for at least 3 months
Hypercellular
↑ Granulocyte proliferation
Granulocytic dysplasia ±
erythroid/megakaryocyte
Dysplasia
<20% blasts 
Hypercellular due to myeloproliferation and
increased monocytes and lacking diagnostic
features of AML, MPN, or other conditions
associated with monocytosis 
CHAPTER 115
Less Common Lymphoid and Myeloid Malignancies
should be noted that monocytosis can be associated with MPN such
as primary myelofibrosis (PMF) and PV, where its presence adversely
impacts survival. BM examination often shows morphologic dysplasia
in at least one hematopoietic lineage and granulocytic and monocytic
proliferation. On immunophenotyping, the abnormal cells often
express myelomonocytic antigens such as CD13 and CD33, with
variable expression of CD14, CD64, CD68, and CD163. Monocyticderived cells are almost always positive for the cytochemical non­
specific esterases (e.g., butyrate esterase), while normal granulocytic
precursors are positive for lysozyme and chloroacetate esterase. In
CMML, it is common to have a hybrid cytochemical staining pattern
with cells expressing both chloroacetate and butyrate esterases simul­
taneously (dual esterase staining).
Based on flow cytometric expression of CD14/CD16, monocytes
can be classified into classical MO1 (CD14+/CD16–), intermediate
MO2 (CD14+/CD16+), and nonclassical MO3 (CD14−/CD16+) frac­
tions, with MO1 constituting the major monocyte population (85%)
in healthy conditions. CMML patients have a characteristic increase
in classical monocytes, distinguishing CMML from other causes of
reactive and clonal monocytosis. Almost all patients with CMML har­
bor somatic mutations that are neither specific nor disease-defining,
including (1) mutations in epigenetic control of transcription, such
as histone modification (EZH2, ASXL1, UTX), and DNA methylation
(TET2, DNMT3A, IDH1, IDH2); (2) mutations in the spliceosome
machinery (SF3B1, SRSF2, U2AF1, ZRSR2, PRPF8); (3) mutations in
genes that regulate cell signaling (JAK2, KRAS, NRAS, CBL, PTPN11,
NF1, FLT3); (4) mutations in transcription factors and nucleosome
assembly regulators (RUNX1, GATA2, SETBP1); and (5) mutations
in DNA damage response genes such as TP53 and PHF6. Of these,
those involving TET2 (~60%), SRSF2 (~50%), ASXL1 (~40%), and
the oncogenic RAS pathway (~30%) are the most frequent, with only
frameshift and nonsense ASXL1 mutations consistently and indepen­
dently adversely impacting survival. Clonal cytogenetic abnormalities
are seen in about a third of patients with CMML and include trisomy 8
and abnormalities of chromosome 7.
Several risk models serve similar purposes in identifying high-risk
patients who are considered for ASCT earlier than later. Risk factors
in the Mayo Molecular Model (MMM) include presence of truncating
ASXL1 mutations, absolute monocyte count >10 × 109/L, hemoglobin
<10 g/dL, platelet count <100 × 109/L, and the presence of circulating
immature myeloid cells. The resulting four-tiered risk categorization
includes high (three or more risk factors), intermediate-2 (two risk
factors), intermediate-1 (one risk factor), and low (no risk factors);
the corresponding median survivals are 16, 31, 59, and 97 months,
respectively. ASCT is the only treatment modality that secures cure or
long-term survival and is appropriate for MMM high/intermediate-2
risk disease. In one of the largest retrospective cohorts involving 513
CMML patients (median age, 53 years), the European Group for Blood
and Marrow Transplantation reported a 4-year relapse-free survival
rate of 27% and an overall survival rate of 33%. At present, for younger
patients with higher risk disease and an acceptable comorbidity index,
ASCT is the preferred treatment modality. Drug therapy is currently
not disease-modifying and includes hydroxyurea and hypomethylat­
ing agents; a phase 3 study (DAKOTA) comparing hydroxyurea and
decitabine in high-risk MP-CMML showed similar overall survival
at 23.1 versus 18.4 months, respectively, despite response rates being
higher for decitabine (56 vs 31%).
PART 4
Oncology and Hematology
■
■ATYPICAL CHRONIC MYELOID LEUKEMIA
aCML is formally classified under the MDS/MPN category of myeloid
malignancies and is characterized by left-shifted granulocytosis and
dysgranulopoiesis. Diagnostic criteria are listed in Table 115-2 and
include leukocyte count of ≥13 × 109/L, dysgranulopoiesis, cytopenia,
≥10% immature granulocytes, <20% PB or BM myeloblasts, <10%
PB monocytes, <10% PB eosinophilia, absence of otherwise specific
mutations such as BCR::ABL1 or TKGFs (involving PDGFRA, PDG­
FRB, FGFR1, JAK2, ABL1, or FLT3; Table 115-6), and not meeting
WHO criteria for CML, PMF, PV, or ET. The BM in aCML is hyper­
cellular with granulocyte proliferation and dysplasia with or without
erythroid or megakaryocytic dysplasia. The differential diagnosis
of aCML includes CML, which is distinguished by the presence of
BCR::ABL1; CNL, which is distinguished by the absence of dysgranu­
lopoiesis and presence of CSF3R mutations; and CMML, which is
distinguished by the presence of monocytosis (absolute monocyte
count ≥0.5 × 109/L).
TABLE 115-6  Primary Eosinophilia Classification
EOSINOPHILIA ASSOCIATED
WITH TKGF (M/LN-EO-TK)
VARIABLES
Absolute eosinophil count
≥1500 × 109/L
≥1500 × 109/L
≥1500 × 109/L
≥1500 × 109/L
PB eosinophil %
≥10%
≥10%
≥10%
≥10%
Documentation of chronicity of eosinophilia
Advised
Advised
Advised
Advised
Comorbidity associated with secondary
eosinophilia
Absent
Absent
Absent
Absent
PB blast ≥2% or BM blast ≥5%
Yes or no
Yes or no
No
No
Abnormal karyotype
Yes or no
Yes or no
No
No
TKGF
Yes
No
No
No
BCR-ABL1
No
No
No
No
Abnormal T lymphocyte phenotype or clonal
T-cell clones
No
No
Yes
No
Eosinophil-mediated tissue/organ damage
Yes or no
Yes or no
Yes or no
Yes
Abbreviations: ABL1 (e.g., ETV6::ABL1); BM, bone marrow; FGFR1 (e.g., ZMYM2::FGFR1); FLT3 (ETV6::FLT3); JAK2 (PCM1::JAK2); M/LN-eo-TK, myeloid/lymphoid neoplasms
with eosinophilia and TKGF; PB, peripheral blood; TKGF, tyrosine kinase gene fusions, often involving PDGFRA (e.g. FIP1L1::PDGFRA) or PDGFRB (e.g., ETV6::PDGFRB).
The molecular pathogenesis of aCML is incompletely understood;
about one-fourth of patients express SETBP1 mutations, which are,
however, also found in several other myeloid malignancies, including
CNL and CMML. SETBP1 mutations in aCML were prognostically
detrimental and mostly located between codons 858 and 871; similar
mutations are seen with Schinzel-Giedion syndrome (a congenital
disease with severe developmental delay and various physical stigmata
including midface retraction, large forehead, and macroglossia). A
somatic missense mutation in ethanolamine kinase 1 (ETNK1 N244S)
was described in 9% of patients with aCML but was also seen in 14%
of patients with CMML, 6% of patients with mastocytosis (especially in
association with eosinophilia), and rarely in other MPNs.
In a series of 55 patients with WHO-defined aCML, median age
at diagnosis was 62 years, with female preponderance (57%); sple­
nomegaly was reported in 54% of the patients, red cell transfusion
requirement in 65%, abnormal karyotype in 20% (20q– and trisomy
8 being the most frequent), and leukemic transformation in 40%.
Median survival was 25 months. Outcome was worse in patients with
marked leukocytosis, transfusion requirement, and increased imma­
ture cells in the PB. In a more recent Mayo Clinic study of 25 molecu­
larly annotated and strictly WHO-defined aCML patients, median age
was 70 years and 84% were male. Cytogenetic abnormalities were seen
in 36% and gene mutations in 100%. Mutational frequencies were as
follows: ASXL1 28%, TET2 16%, NRAS 16%, SETBP1 12%, RUNX1
12%, ETNK1 8%, and PTPN11 4%. Median survival was 10.8 months,
and at last follow-up (median, 11 months), 17 (68%) deaths and 2 (8%)
leukemic transformations were documented. In multivariable analysis,
advanced age, low hemoglobin, and TET2 mutations were shown to
carry independent prognostic significance; other mutations, includ­
ing ASXL1 and SETBP1 lacked prognostic significance. Conventional
chemotherapy is largely ineffective in the treatment of aCML. Similarly,
treatment response to the JAK1/2 inhibitor ruxolitinib has not been
impressive. However, a favorable experience with ASCT was reported
in nine patients; after a median follow-up of 55 months, the majority
of the patients remained in complete remission.
■
■MDS/MPN WITH MUTATED SF3B1 OR WITH
RING SIDEROBLASTS, BOTH ASSOCIATED WITH
THROMBOCYTOSIS OR NOT OTHERWISE SPECIFIED
The ICC classifies patients with morphologic and laboratory features
that resemble both MDS and MPN as “MDS/MPN overlap.” This cat­
egory is broad and is distinguished from MPN by the presence of “cyto­
penia.” Leukocytosis is also part of the definition for the subcategories
of MDS/MPN, including MDS/MPN with mutated SF3B1 (MDS/
MPN-T-SF3B1), MDS/MPN with ring sideroblasts and thrombocyto­
sis, NOS (MDS/MPN-RS-T-NOS), and MDS/MPN-NOS. Diagnostic
criteria for MDS/MPN-T-SF3B1 include thrombocytosis (≥450 ×
109/L), anemia, blasts <1% in PB and <5% in BM, presence of SF3B1
CHRONIC EOSINOPHILIC
LEUKEMIA, NOT OTHERWISE
SPECIFIED (CEL-NOS)
LYMPHOCYTIC VARIANT
HYPEREOSINOPHILIA
HYPEREOSINOPHILIC
SYNDROME
(variant allele frequency [VAF] >10%), and not otherwise classified as
another myeloid neoplasm; corresponding criteria for MDS/MPN-RST-NOS also include thrombocytosis and anemia and absence of excess
blasts but, in addition, require presence of ≥15% BM ring sideroblasts
and absence of SF3B1 mutation. The term MDS/MPN-NOS is reserved
for MDS/MPN that does not meet criteria for either of the aforemen­
tioned MDS/MPN entities despite displaying thrombocytosis (≥450 ×
109/L) or leukocytosis (≥13 × 109/L).
■
■JUVENILE MYELOMONOCYTIC LEUKEMIA
JMML is primarily a disease of early childhood and is now considered
a unique clonal disorder of childhood, separated from MDS/MPN.
Both CMML and JMML feature leukocytosis, monocytosis, and hepa­
tosplenomegaly. Additional characteristic features in JMML include
thrombocytopenia and elevated fetal hemoglobin. Myeloid progenitors
in JMML display granulocyte-macrophage colony-stimulating factor
(GM-CSF) hypersensitivity that has been attributed to dysregulated
RAS/MAPK signaling. The latter is believed to result from mutually
exclusive mutations involving RAS, PTPN11, and NF1. A third of
patients with JMML that is not associated with Noonan syndrome
carry PTPN11 mutations, while the incidence of NF1 in patients
without neurofibromatosis type 1 and RAS mutations is ~15% each. In
general, ~85% of JMML cases have one of the classical RAS pathway
mutations (PTPN11, NRAS, KRAS, NF1, or CBL); in addition, a myriad
of other mutations, such as ASXL1, RUNX1, SETBP1, JAK3, and CUX1,
among others, have recently been reported. Taken together, it is cur­
rently believed that almost all patients with JMML harbor mutations in
the RAS pathway; clonal disorders that mimic JMML but do not harbor
a RAS pathway mutation are classified as JMML-like neoplasms.
The 2022 ICC diagnostic criteria for JMML require the presence of
PB monocyte count ≥1 × 109/L, <20% blasts in PB or BM, splenomeg­
aly, and absence of BCR::ABL1. Diagnosis also requires the presence of
one of the following: (1) somatic mutations of PTPN11, KRAS, NRAS,
or RRAS; (2) germline NF1 mutation and loss of heterozygosity of NF1
or clinical diagnosis of neurofibromatosis type 1; and (3) germline
mutation and loss of heterozygosity of CBL. Drug therapy is relatively
ineffective in JMML, and the treatment of choice is ASCT, which
results in a 5-year survival of ~50%.
■
■TRANSIENT MYELOPROLIFERATIVE DISORDER
TMD, also referred to as transient abnormal myelopoiesis (TAM),
constitutes an often but not always transient phenomenon of abnor­
mal megakaryoblast proliferation, which occurs in ~10% of infants
with Down syndrome. TMD is usually recognized at birth and either
undergoes spontaneous regression (75% of cases) or progresses to acute
megakaryoblastic leukemia (AMKL; 25% of cases). Almost all patients
with TMD and TMD-derived AMKL display somatic GATA1 muta­
tions. TMD-associated GATA1 mutations constitute exon 2 insertions,
deletions, or missense mutations, affecting the N-terminal transactiva­
tion domain of GATA-1 and resulting in loss of full-length (50 kD)
GATA-1 and its replacement with a shorter isoform (40 kD) that retains
friend of GATA-1 (FOG-1) binding. In contrast, inherited forms of
exon 2 GATA1 mutations produce a phenotype with anemia, whereas
exon 4 mutations that affect the N-terminal, FOG-1-interactive domain
produce familial dyserythropoietic anemia with thrombocytopenia or
X-linked macrothrombocytopenia.
■
■HYPEREOSINOPHILIA
Eosinophilia refers to a PB absolute eosinophil count (AEC) that is
above the upper normal limit of the reference range. The term hype­
reosinophilia (HE) is used when the AEC is ≥1500 × 109/L. The ICC
recommends both BM and PB examination for diagnostic evaluation of
HE. The former should include cytogenetic and molecular analysis as
well as immunohistochemistry for mast cells (CD117, tryptase, CD25),
and the latter should include lymphocyte flow cytometry with T-cell
panel, TCR gene rearrangement studies, and serum tryptase. The most
frequent causes of HE include infections, especially those related to
tissue-invasive helminths, allergic/vasculitic diseases, drugs, and meta­
static cancer. Primary HE is the focus of this chapter and is considered
when a cause for secondary eosinophilia is not readily apparent.
In the presence of normal BM morphology and absence of genetic
abnormalities, the two major diagnostic possibilities are lymphocytic
variant HE and idiopathic HE (Table 115-3); the former is character­
ized by the presence of an abnormal T-cell phenotype or clone. Both
conditions might be associated with tissue/organ dysfunction due to
eosinophilic infiltrates, in which case their nomenclature is modified
into lymphocytic variant hypereosinophilic syndrome and idiopathic
hypereosinophilic syndrome (iHES), respectively. In the presence of a
TKGF, a diagnosis of myeloid/lymphoid neoplasm with eosinophilia
and TKGF is considered (Table 115-3). The genes involved in TKGFassociated HE are listed in Table 115-6: PDGFRA, PDGFRB, FGFR1,
ABL, JAK2, and FLT3. Once the latter possibility is excluded, other
ICC-defined myeloid or lymphoid neoplasms (e.g., systemic mastocy­
tosis, acute myeloid or lymphoblastic leukemia, CML, MPN or MDS/
MPN, Hodgkin’s and non-Hodgkin’s lymphoma) must be considered
and excluded. CEL-NOS is considered in the presence of cytogenetic
abnormalities, excess blasts, or morphologic evidence of dysplasia,
including that of megakaryocytes.
The diagnostic workup for HE that is not associated with morpho­
logically overt myeloid malignancy should start with PB mutation
screening for PDGFRA and PDGFRB mutations using fluorescence in
situ hybridization (FISH) or reverse transcriptase polymerase chain
reaction. If mutation screening is negative, a BM examination with
cytogenetic and molecular studies is indicated. In this regard, one
must first pay attention to the presence or absence of TKGF or associ­
ated cytogenetic abnormalities (Table 115-6). CEL-NOS is a subset of
clonal eosinophilia that is neither molecularly defined nor classified as
an alternative clinicopathologically assigned myeloid malignancy. We
prefer to use the term strictly in patients with an HES phenotype who
also display either a clonal cytogenetic/molecular abnormality, excess
blasts in the BM or PB, or abnormal BM morphology (Table 115-6).
CHAPTER 115
Less Common Lymphoid and Myeloid Malignancies
■
■HYPEREOSINOPHILIA ASSOCIATED WITH
TYROSINE KINASE GENE FUSIONS
Both platelet-derived growth factor receptors α (PDGFRA; located on
chromosome 4q12) and β (PDGFRB; located on chromosome 5q31q32) are involved in MPN-relevant activating mutations. Clinical phe­
notype in both instances includes prominent blood eosinophilia and
excellent response to imatinib therapy. In regard to PDGFRA muta­
tions, the most popular is FIP1L1-PDGFRA, a karyotypically occult
del(4)(q12), which was described in 2003 as an imatinib-sensitive acti­
vating mutation. Functional studies have demonstrated transforming
properties in cell lines and the induction of MPN in mice. Cloning of
the FIP1L1-PDGFRA fusion gene identified a novel molecular mecha­
nism for generating this constitutively active fusion tyrosine kinase,
wherein an ~800 kb interstitial deletion within 4q12 fuses the 5′ por­
tion of FIP1L1 to the 3′ portion of PDGFRA. FIP1L1-PDGFRA occurs
in a very small subset of patients who present with the phenotypic
features of either systemic mastocytosis (SM) or HES, but the presence
of the mutation reliably predicts complete hematologic and molecular
response to imatinib therapy.
In a retrospective survey of 151 patients with FIP1L1-PDGFRA–
associated eosinophilia (143 males; mean age at diagnosis, 49 years),
organopathy involved the spleen (44%), skin (32%), lungs (30%),
heart (19%), and CNS (9%); none of 31 patients initially treated with
corticosteroids achieved complete hematologic remission, whereas
all 148 patients treated with imatinib achieved complete hematologic
responses and also molecular responses, when evaluated. Treatment
discontinuation was documented in 46 patients followed by a 57%
relapse rate; the 1-, 5-, and 10-year overall survival rates in imatinibtreated patients were 99%, 95%, and 84%, respectively. Other studies
have confirmed the possibility of treatment-free remissions in some
patients after imatinib discontinuation. Infrequent occurrence of
FIP1L1-PDGFRA–mutated AML associated with eosinophilia has also
been shown to respond to low-dose imatinib therapy (100 mg/d).
The association between eosinophilic myeloid malignancies and
PDGFRB rearrangement was first characterized and published in
1994 when fusion of the tyrosine kinase encoding region of PDGFRB
to the ets-like gene, ETV6 (ETV6-PDGFRB, t(5;12)(q33;p13), was
demonstrated. The fusion protein was transforming to cell lines and
resulted in constitutive activation of PDGFRB signaling. Since then,
several other PDGFRB fusion transcripts with similar disease pheno­
types have been described, cell line transformation and MPD induction
in mice have been demonstrated, and imatinib therapy was effective
when employed.
The 8p11 myeloproliferative syndrome (EMS) (also known as
human stem cell leukemic/lymphoma syndrome) constitutes a clini­
cal phenotype with features of both lymphoma and eosinophilic MPN
and is characterized by a fusion mutation that involves the gene for
fibroblast growth factor receptor 1 (FGFR1), which is located on chro­
mosome 8p11 [e.g., ZMYM2::FGFR1, t(8;13)(p11.1;q12.1)]; disease
phenotypes include T-cell acute lymphoblastic leukemia, large B-cell
lymphoma, and MPN-like disease with HE. In EMS, both myeloid and
lymphoid lineage cells exhibit the 8p11 translocation, thus demon­
strating the stem cell origin of the disease. The disease features several
8p11-linked chromosome translocations, and some of the correspond­
ing fusion FGFR1 mutants have been shown to transform cell lines and
induce EMS- or CML-like disease in mice depending on the specific
FGFR1 partner gene (ZNF198 or BCR, respectively). Consistent with
this laboratory observation, some patients with BCR-FGFR1 mutation
manifest a more indolent CML-like disease. The mechanism of FGFR1
activation in EMS is similar to that seen with PDGFRB-associated
MPN; the tyrosine kinase domain of FGFR1 is juxtaposed to a dimer­
ization domain from the partner gene. EMS is an aggressive disease
often requiring combination chemotherapy followed by ASCT. Pemi­
gatinib, which targets FGFR1/2/3, has been introduced and shown to
induce hematologic and cytogenetic response in >70% of patients with
FGFR1-rearranged myeloid/lymphoid neoplasms.
PART 4
Oncology and Hematology
The 2022 ICC includes a number of other subcategories of myeloid/
lymphoid neoplasms with eosinophilia and TKGFs (M/LN-eo-TK):
(1) ETV6::ABL1, t(9;12)(q34.1;p13.2), phenotypically similar to CML
and treated the same way with imatinib or similar tyrosine kinase
inhibitors (TKIs) with good response; (2) PCM1::JAK2 or BCR::JAK2
or other JAK2 partners, t(8;9)(p22;p24.1), phenotypically similar to
MPN or MDS/MPN with >90% response rate to ruxolitinib but not
durable and requiring bridging to ASCT; and (3) ETV6::FLT3, t(12;13)
(p13.2;q12.2), phenotypically similar to lymphoblastic leukemia or
lymphoma, CEL, or MDS/MPN, with some responses seen with FLT3
inhibitor therapy.
■
■HYPEREOSINOPHILIC SYNDROME
Blood eosinophilia that is neither secondary nor clonal is operationally
labeled as being “idiopathic.” HES is a subcategory of idiopathic eosin­
ophilia with persistent increase of the AEC to ≥1.5 × 109/L and pres­
ence of eosinophil-mediated organ damage, including cardiomyopathy,
gastroenteritis, cutaneous lesions, sinusitis, pneumonitis, neuritis, and
vasculitis. In addition, some patients manifest thromboembolic com­
plications, hepatosplenomegaly, and either cytopenia or cytosis.
BM histologic and cytogenetic/molecular studies should be exam­
ined before a working diagnosis of HES is made. Additional blood
studies that are currently recommended during the evaluation of
HES include serum tryptase (an increased level suggests mastocytosis
and warrants molecular studies to detect FIP1L1-PDGFRA), T-cell
immunophenotyping, and T-cell receptor antigen gene rearrangement
analysis (a positive test suggests an underlying clonal or phenotypically
abnormal T-cell disorder). In addition, initial evaluation in HES should
include echocardiogram and measurement of serum troponin levels to
screen for myocardial involvement by the disease.
Initial evaluation of the patient with eosinophilia should include
tests that facilitate assessment of target organ damage, including com­
plete blood count, chest x-ray, echocardiogram, and serum troponin
level. Increased level of serum cardiac troponin has been shown to
correlate with the presence of cardiomyopathy in HES. Typical echo­
cardiographic findings in HES include ventricular apical thrombus,
posterior mitral leaflet or tricuspid valve abnormality, endocardial
thickening, dilated left ventricle, and pericardial effusion.
In a Mayo Clinic study of 98 consecutive patients with idiopathic
eosinophilia, including HES, median age was 53 years (55% male),
and overt organ involvement was seen in >80% of the cases, including
54% involving organs other than the skin. The frequencies of cardiac
involvement, hepatosplenomegaly, and increased serum tryptase and
interleukin (IL) 5 levels were 8%, 4%, 24%, and 31%, respectively. The
study also revealed that 11% of the affected patients harbored pathoge­
netic mutations including TET2, ASXL1, and KIT; the presence of such
mutations did not appear to influence phenotype, and the number of
informative cases was too small to assess prognostic relevance. Instead,
the study identified anemia and presence of cardiac involvement or
hepatosplenomegaly as risk factors for survival.
Glucocorticoids are the cornerstone of therapy in HES. Treatment
with oral prednisone is usually started at 1 mg/kg per day and contin­
ued for 1–2 weeks before the dose is tapered slowly over the ensuing
2–3 months. If symptoms recur at a prednisone dose level of >10 mg/d,
either hydroxyurea or interferon α is used as steroid-sparing agent. In
patients in whom usual therapy fails as outlined above, mepolizumab
or alemtuzumab might be considered. Mepolizumab is a monoclonal
antibody that targets IL-5, which is a well-recognized growth factor
for eosinophils. Alemtuzumab targets the CD52 antigen, which has
been shown to be expressed by eosinophils but not by neutrophils.
In a recently reported placebo-controlled phase 3 study, HES patients
received subcutaneous mepolizumab (300 mg) every 4 weeks, in addi­
tion to their preprotocol therapy, and experienced significantly fewer
disease flare-ups or treatment discontinuations (28 vs 56% for pla­
cebo), without excess adverse events. Mepolizumab was U.S. Food and
Drug Administration approved for use in HES on September 25, 2020.
In a smaller phase 2 study, benralizumab (monoclonal antibody target­
ing the receptor for IL-5; 30 mg given subcutaneously every 4 weeks)
was also shown to reduce eosinophil count more efficiently compared
to placebo (90 vs 30%).
■
■MASTOCYTOSIS
SM is characterized by proliferation of neoplastic mast cells (MCs)
in BM and/or other extracutaneous organs and is distinguished from
cutaneous mastocytosis (CM; skin involvement only) and mast cell
sarcoma (MCS; high-grade focal MC tumor). According to the ICC
and WHO-proposed fifth edition (WHO5) classification systems
(Table 115-4), SM is subclassified into indolent (ISM), smoldering
(SSM), aggressive (ASM), SM with associated myeloid (SM-AMN,
per ICC) or hematologic (SM-AHN, per WHO5) neoplasm, and mast
cell leukemia (MCL). WHO5 also includes an additional “low-grade”
SM subtype, namely BM mastocytosis (BMM); the latter is described
as consisting of (1) absence of skin lesions, (2) absence of B findings,
and (3) serum tryptase level <125 ng/mL. The ICC considers BMM
as a clinicopathologic variant and not an SM subtype. Both ICC and
WHO5 have also refined their diagnostic criteria for SM in general.
Diagnosis per ICC requires the presence of a major criterion (multifo­
cal aggregates of ≥15 MCs) or, in its absence, the presence of at least
three minor criteria, including (1) BM biopsy or extracutaneous organ
section with >25% MCs with atypical morphology; (2) MC expres­
sion of CD25, CD2, and/or CD30; (3) KIT D816V or other activating
KIT mutation; and (4) increased serum tryptase >20 ng/mL (needs
to be adjusted in the presence of hereditary α-tryptasemia); in addi­
tion, presence of myeloid/lymphoid neoplasm with eosinophilia with
TKGRs must be excluded. SM diagnosis per WHO5 requires the pres­
ence of the major criterion as well as one other minor criterion or at
least three minor criteria.
The term advanced SM (AdvSM) includes ASM, SM-AMN/AHN,
and MCL; AdvSM is distinguished from non-AdvSM by the presence
of either an associated myeloid/hematologic neoplasm (e.g., AML,
CMML, MDS, MPN) or organopathy resulting from MC infiltra­
tion. MC-associated organopathy is defined by the presence of one
or more C findings: (1) ≥1 cytopenia (hemoglobin <10 g/dL, absolute
neutrophil count <1 × 109/L, or platelet count <100 × 109/L); (2) pal­
pable hepatomegaly with abnormal liver function tests, ascites, or por­
tal hypertension; (3) palpable splenomegaly with thrombocytopenia
attributed to hypersplenism; (4) MC infiltration of the gastrointestinal
system with resultant malabsorption with weight loss; and (5) large
osteolytic lesions with or without pathologic fractures.
The ICC system requires the AHN component in SM-AHN to be of
myeloid lineage, resulting in a revised nomenclature (i.e., SM-AMN). By
contrast, WHO5-defined SM-AHN allows the AHN component to be
of either myeloid or lymphoid lineage. Additional divergence between
ICC and WHO5 concerns the definition of MCL; both systems require
the presence of ≥20% MCs in BM aspirate, but ICC criteria require, in
addition, immature cytomorphology (i.e., promastocytes, metachro­
matic blast-like cells, or multinucleated or highly pleomorphic MC)
of the excess MCs; furthermore, ICC no longer differentiates between
leukemic (≥10% circulating MC) versus aleukemic MCL variants. Both
the ICC and WHO5 use similar B findings to distinguish indolent from
smoldering SM, with the latter requiring the presence of two or more B
findings, including (1) MCs >30% of BM cellularity on BM biopsy and
serum tryptase >200 ng/mL; (2) cytopenia not meeting criteria for C
findings or cytosis; and (3) palpable hepatomegaly without liver func­
tion impairment or splenomegaly without thrombocytopenia or >1 cm
lymphadenopathy on palpation or imaging; in addition, KIT D816V
VAF ≥10% qualifies as a B finding, per WHO5.
In a study of 329 patients with AdvSM, including WHO5 subcat­
egories of SM-AHN (64%), ASM (30%), and MCL (6%) or ICC subcat­
egories of SM-AMN (64%), ASM (33%), and MCL (3%), multivariable
analysis that included the Mayo Alliance risk factors for survival in
SM (age >60 years, anemia, thrombocytopenia, increased alkaline
phosphatase) revealed more accurate survival prediction with the ICC
versus WHO5 classification order: (1) survival was significantly worse
with ICC-defined MCL versus WHO5-defined MCL with otherwise
mature MC cytomorphology; (2) prognostic distinction was con­
firmed for ICC-defined MCL versus ICC-defined SM-AMN but not
for WHO5-defined MCL versus WHO-defined SM-AHN; (3) survival
was similar between WHO5-defined MCL with mature cytomorphol­
ogy versus ICC-defined SM-AMN; and (4) ICC-defined SM-AMN but
not WHO-defined SM-AHN with lymphoid lineage was prognostically
distinct from ASM. Accordingly, our views on the classification of
AdvSM are in line with those of the ICC system. We believe that these
details are therapeutically relevant considering the emergent nature
of ICC-defined MCL and the fact that SM-AMN, as opposed to SMAHN, carries a prognostically worse designation that might require
therapeutic intervention with ASCT sooner than later.
Currently available drugs for treatment include KIT inhibitors
(KITi), which exhibit remarkable activity in reducing MC and mutant
KIT burden but have not been shown to extend survival. On the other
hand, we are impressed by the remarkable activity of currently available
KITi on the MC component of SM, with the caveat that such drugs are
expensive, have significant side effects, and need long-term use. The
first step in treatment decision-making is to identify whether the AMN
component takes priority over the SM component of the disease, for
treatment purposes. High-grade AMNs, including AML, high-/veryhigh-risk MDS or CMML, or those with >10% BM blasts, likely take
precedence in this regard. Accordingly, in a fit patient with SM-AML or
SM-high/very-high-risk MDS, intensive remission induction therapy
or hypomethylating agent (HMA) therapy can be considered. If the
SM is incidentally diagnosed or is associated with minimal symptoms,
we generally limit SM therapy to supportive/symptomatic care, includ­
ing with antihistamine and/or antileukotriene agents or cromolyn, as
well as taking precautions for anaphylaxis prevention/treatment. For
SM with significantly high MC or symptom burden, concurrent MC
cytoreduction can be considered, particularly for those with relapsed/
refractory disease, although there are no clear protocols in this regard.
ASCT has an important role in the treatment of SM-high-grade
AMN, although there is no consensus regarding optimal timing, deb­
ulking strategy, and so on; overall survival appears to be most favorable
for SM-AMN patients compared to other subgroups, and survival was
superior in those receiving myeloablative versus reduced-intensity
conditioning, thereby indicating the need for effective cytoreduction
prior to stem cell transplantation. For SM-AMN patients with a lowgrade AMN, such as PV or ET, or low-risk MDS, conventional therapy
for the AMN including therapeutic phlebotomies, low-dose aspirin,
hydroxyurea or interferon α, or erythropoiesis-stimulating agents is
pursued. If the SM disease component does not warrant cytoreduction
(e.g., no C findings), supportive/symptomatic care, as described earlier,
is pursued, along with intermittent monitoring of disease status. If MC
cytoreduction is warranted, monotherapy with a TKI or cladribine can
be pursued, depending on individual risk, benefit considerations, treat­
ment availability, cost considerations, and so on.
We find cladribine, midostaurin, and avapritinib to be reasonable
drug considerations for AdvSM as well as MCL. While avapritinib
has theoretical advantages over midostaurin, including a more potent
inhibitory effect on KIT D816V and proven efficacy in patients previ­
ously treated with midostaurin, we are agnostic regarding the choice
of TKI given the lack of head-to-head comparison; instead, we recom­
mend an individualized approach to TKI selection that weighs drug
accessibility/affordability, comorbid conditions, risk tolerance for
anticipated adverse events, and provider/center experience with the
particular TKI. We continue to utilize cladribine as a reasonable alter­
native to TKI therapy, based on decades-long experience, long-term
safety record, and qualitatively better toxicity profile that is mostly
limited to cytopenias, as opposed to cognitive impairment and other
side effects with avapritinib and intolerance due to diarrhea with
midostaurin. For ASM patients who exhibit disease progression and/
or leukemic transformation despite adequate TKI dosing or cladribine,
we recommend ASCT as salvage therapy. We consider “true” MCL an
oncologic emergency, and collaboration with an experienced hema­
topathologist to expeditiously confirm the diagnosis is critical, as is
expedited molecular testing for KIT D816V and other AMN-relevant
mutations.
CHAPTER 115
■
■DENDRITIC AND HISTIOCYTIC NEOPLASMS
Dendritic cell (DC) and histiocyte/macrophage neoplasms are
extremely rare. DCs are antigen-presenting cells, whereas histiocyte/
macrophages are antigen-processing cells. BM myeloid stem cells
(CD34+) give rise to monocyte (CD14+, CD68+, CD11c+, CD1a–) and
DC (CD14–, CD11c+/–, CD1a+/c) precursors. Monocyte precursors,
in turn, give rise to macrophages (CD14+, CD68+, CD11c+, CD163+,
lysozyme+) and interstitial DCs (CD68+, CD1a–). DC precursors
give rise to Langerhans cell DCs (Birbeck granules, CD1a+, S100+,
langerin+) and plasmacytoid DCs (CD68+, CD123+). Follicular DCs
(CD21+, CD23+, CD35+) originate from mesenchymal stem cells.
Dendritic and histiocytic neoplasms are operationally classified into
macrophage/histiocyte-related and DC-related. The former includes
histiocytic sarcoma/malignant histiocytosis and the latter Langerhans
cell histiocytosis, Langerhans cell sarcoma, interdigitating DC sarcoma,
and follicular DC sarcoma.
Less Common Lymphoid and Myeloid Malignancies
Histiocytic Sarcoma/Malignant Histiocytosis 
Histiocytic
sarcoma represents malignant proliferation of mature tissue histiocytes
and is often localized. Median age at diagnosis is estimated at 46 years
with slight male predilection. Some patients might have a history of
lymphoma, MDS, or germ cell tumors at time of disease presentation.
The three typical disease sites are lymph nodes, skin, and the gastro­
intestinal system. Patients may or may not have systemic symptoms
including fever and weight loss, and other symptoms include hepato­
splenomegaly, lytic bone lesions, and pancytopenia. Immunopheno­
type includes presence of histiocytic markers (CD68, lysozyme, CD11c,
CD14) and absence of myeloid or lymphoid markers. Prognosis is poor,
and treatment is often ineffective. The term malignant histiocytosis
refers to a disseminated disease and systemic symptoms. Lymphomalike treatment induces complete remissions in some patients, and
median survival is estimated at 2 years. In one of the largest series of
histiocytic sarcoma, 330 cases were included with median age of 61
years (59% male). In the latter study, the most common sites of pre­
sentation were skin, connective tissue, lymph nodes, gastrointestinal
tract, and hematopoietic system; median overall survival was 6 months,
and treatment included systemic chemotherapy, radiotherapy, and
surgery. Factors associated with poor outcome included older age,
high comorbidity index, and disease involving the hematopoietic and
reticuloendothelial system.
Langerhans Cell Histiocytosis 
Langerhans cells (LCs) are spe­
cialized DCs that reside in mucocutaneous tissue and upon activation
become specialized for antigen presentation to T cells. LC histiocytosis
(LCH; also known as histiocytosis X) represents neoplastic proliferation
of LCs (S100+, CD1a+, and Birbeck granules on electron microscopy).
LCH incidence is estimated at 5 per million, and the disease typically
affects children, with a male predilection. Presentation can be either
unifocal (eosinophilic granuloma) or multifocal. The former usually
affects bones and less frequently lymph nodes, skin, and lung, while the
latter is more disseminated. Unifocal disease often affects older chil­
dren and adults, while multisystem disease affects infants. LCH of the
lung in adults is characterized by bilateral nodules. Prognosis depends
on organs involved. Only 10% of patients progress from unifocal to
multiorgan disease. LCH of the lung might improve upon cessation
of smoking. Approximately 55% of patients with LCH harbor BRAF
V600E gain-of-function mutations, which indicates high-risk disease
and resistance to first-line therapy, while responses to targeted therapy
with vemurafenib have been reported. Other forms of treatment for
LCH include combination chemotherapy and MEK inhibitors in BRAF
wild-type but with other MAPK pathway mutations. Unfortunately, such
targeted therapy has not secured long-lasting treatment-free remissions.
In one retrospective study, 33 adult patients with LCH were studied
including 21 with single-system LCH, 10 with multisystem LCH, and
2 with pulmonary LCH. Patients with single-system unifocal involve­
ment were successfully treated with local therapies such as surgery
and radiotherapy. Most of the multisystem LCH patients and patients
with single-system multifocal involvement were treated with systemic
chemotherapy. Cladribine was the first choice in 10 of 11 patients who
received chemotherapy. Among all patients, the overall response rate
(ORR) was 97%. Among those who had cladribine in the first line, the
ORR was 81%. All these patients achieved a complete remission and
were alive at the last visit. The median follow-up was 38 months (range,
2–183 months). The median progression-free survival (PFS) has not yet
been reached. Ten-year PFS was 90.9%. Expert consensus recommenda­
tions for treatment include local therapies for unifocal disease, smoking
cessation as first-line therapy for pulmonary LCH, and systemic therapy
for multifocal and multisystem disease; the latter might include cladrib­
ine, cytarabine, and targeted therapy with BRAF and MEK inhibitors.
PART 4
Oncology and Hematology
In one study, 26 adult patients with non-LCH, including 17
with Erdheim-Chester disease (ECD), 3 with Rosai-Dorfman disease
(RDD), 5 with ECD/RDD, and 1 with ECD/LCH, were treated with
the MEK inhibitor trametinib; the most common treatment-related
toxicity was rash (27%), whereas the response rate of the 17 evaluable
patients was 71%, including 73% without a detectable BRAF V600E;
median time-to-treatment failure was 37 months; most patients har­
bored mutations in BRAF (either classic BRAF V600E or other BRAF
alterations) or alterations in other genes involved in the MAPK path­
way (e.g., MAP2K, NF1, GNAS, or RAS).
Langerhans Cell Sarcoma 
Langerhans cell sarcoma (LCS) also
represents neoplastic proliferation of LCs with overtly malignant mor­
phology. The disease can present de novo or progress from antecedent
LCH. There is a female predilection, and median age at diagnosis is
estimated at 41 years. Immunophenotype is similar to that seen in
LCH, and liver, spleen, lung, and bone are the usual sites of disease.
Prognosis is poor, and treatment is generally ineffective.
Interdigitating Dendritic Cell Sarcoma 
Interdigitating DC
sarcoma (IDCS), also known as reticulum cell sarcoma, represents
neoplastic proliferation of interdigitating DCs. The disease is extremely
rare and affects elderly adults with no sex predilection. Typical presen­
tation is asymptomatic solitary lymphadenopathy. Immunophenotype
includes S100+ and negative for vimentin and CD1a. Prognosis ranges
from benign local disease to widespread lethal disease.
Follicular Dendritic Cell Sarcoma 
Follicular dendritic cells
(FDCs) reside in B-cell follicles and present antigen to B cells. FDC
neoplasms (FDCNs) are usually localized and often affect adults. FDCN
might be associated with Castleman’s disease in 10–20% of cases, and
increased incidence in schizophrenia has been reported. Cervical
lymph nodes are the most frequent site of involvement in FDCNs, and
other sites include maxillary, mediastinal, and retroperitoneal lymph
nodes; oral cavity; the gastrointestinal system; skin; and breast. Sites of
metastasis include lung and liver. Immunophenotype includes CD21,
CD35, and CD23. Clinical course is typically indolent, and treatment
includes surgical excision followed by regional radiotherapy and some­
times systemic chemotherapy.
Hemophagocytic Lymphohistiocytosis (see Chap. 68) 
Hemo­
phagocytic lymphohistiocytosis (HLH) represents nonneoplastic pro­
liferation and activation of macrophages and cytotoxic lymphocytes
that induce cytokine-mediated bone marrow suppression, features
of intense phagocytosis in bone marrow and liver, and multiorgan
dysfunction including cytopenias, coagulopathy, and fever. HLH may
result from genetic (primary) or acquired (secondary) disorders of
macrophages. The former entail genetically determined inability to
regulate macrophage proliferation and activation and might include
alterations in familial HLH genes, including those of perforin (PRF1,
UNC13D, STXBP2, and STX11), granule/pigment abnormality genes
(RAB27A, LYST, and AP3B1), or X-linked lymphoproliferative disease
genes (SH2D1A and XIAP). Acquired HLH is often precipitated by
viral infections, including Epstein-Barr virus. HLH might also accom­
pany certain malignancies such as T-cell lymphoma and autoimmune
diseases, ASCT, and chimeric antigen receptor (CAR) T-cell therapy.
In a recent population-based study from Sweden, the annual incidence
of malignancy-associated HLH had increased 10-fold and was at least
0.71 per 100,000 adults from 2012 to 2018, and early survival improved
significantly, likely due to increased awareness and more HLH-directed
therapy. Regardless of the cause, the common tissue/organ-damaging
pathway involves excessive inflammatory cytokine release, including
IL-6, IL-2, IL-1, interferon γ, and tumor necrosis factor (TNF).
Clinical presentation of HLH includes fever, severe constitutional
symptoms, enlarged lymph nodes, hepatosplenomegaly, neurologic
dysfunction, and abnormalities in multiple organ function tests.
Diagnosis is accomplished by either detection of HLH-related muta­
tions or meeting five of the following eight conventional criteria: (1)
hemophagocytosis in the bone marrow/spleen/lymph nodes; (2) serum
ferritin ≥500 µg/L; (3) hypofibrinogenemia (fibrinogen ≤1.5 g/L) or
hypertriglyceridemia (triglycerides ≥3 mmol/L); (4) low NK cell activ­
ity; (5) elevated soluble IL-2 receptor (CD25) ≥2400 U/mL; (6) bi- or
tri-cytopenia (platelets <100 × 109/L, hemoglobin <9 g/dL, absolute
neutrophil count <1 × 109/L); (7) splenomegaly palpable >3 cm below
left costal margin; and (8) fever. Clinical course is often fulminant
and fatal with reported 1-year survival rates of <30% in patients with
hematologic malignancy. Current therapeutic approaches for primary
or secondary HLH include the so-called HLH-94 protocol, which con­
sists of weekly treatments with etoposide and dexamethasone, stem cell
transplant, emapalumab (a monoclonal antibody that binds and neu­
tralizes interferon γ and is approved in primary HLH), and the JAK1/2
inhibitor ruxolitinib. The latter has recently been shown to increase
survival rate in affected patients to >80%.
■
■FURTHER READING
Alaggio R et al: The 5th edition of the World Health Organization
Classification of Haematolymphoid Tumours: Lymphoid neoplasms.
Leukemia 36:1720, 2022.
Arber DA et al: International Consensus Classification of myeloid
neoplasms and acute leukemias: Integrating morphologic, clinical,
and genomic data. Blood 140:1200, 2022.
de Leval L et al: A practical approach to the modern diagnosis and
classification of T- and NK-cell lymphomas. Blood 144:1855, 2024.
Khoury JD et al: The 5th edition of the World Health Organization
Classification of Haematolymphoid Tumours: Myeloid and histio­
cytic/dendritic neoplasms. Leukemia 36:1703, 2022.
Miranda RN et al: The 5th edition of the World Health Organization
Classification of Hematopoietic and lymphoid tissues: Mature T-cell,
NK-cell, and stroma-derived neoplasms of lymphoid tissues. Mod
Pathol 37:100512, 2024.
Szuber N et al: Chronic neutrophilic leukemia: 2022 update on diagno­
sis, genomic landscape, prognosis, and management. Am J Hematol
97:491, 2022.

46 - 116 Plasma Cell Disorders
116 Plasma Cell Disorders
Nikhil C. Munshi, Dan L. Longo,
Kenneth C. Anderson
Plasma Cell Disorders
The plasma cell disorders are monoclonal neoplasms related to each
other by virtue of their development from common progenitors in the
late B-lymphocyte lineage. Multiple myeloma (MM), Waldenström’s
macroglobulinemia, primary amyloidosis (Chap. 117), and the heavy
chain diseases comprise this group and may be designated by a variety
of synonyms such as monoclonal gammopathies, paraproteinemias,
plasma cell dyscrasias, and dysproteinemias. Mature B lymphocytes des­
tined to produce IgG bear surface immunoglobulin molecules of both
μ and γ heavy chain isotypes with both isotypes having identical idio­
types (variable regions). Under normal circumstances, maturation to
antibody-secreting plasma cells and their proliferation is stimulated by
exposure to the antigen for which the surface immunoglobulin is spe­
cific; however, in the plasma cell disorders, the control over this process
is lost. The clinical manifestations of all the plasma cell disorders relate
to the expansion of the neoplastic cells, to the secretion of cell products
(immunoglobulin molecules or subunits, lymphokines), and to some
extent to the host’s response to the tumor. Normal development of
B lymphocytes is discussed in Chap. 360 and depicted in Fig. 113-2.
Three categories of structural variation are present among immu­
noglobulin molecules that form antigenic determinants, and these are
used to classify immunoglobulins. Isotypes are those determinants that
distinguish among the main classes of antibodies of a given species
and are the same in all normal individuals of that species. Therefore,
isotypic determinants are, by definition, recognized by antibodies from
a distinct species (heterologous sera) but not by antibodies from the
same species (homologous sera). There are five heavy chain isotypes
(M, G, A, D, E) and two light chain isotypes (κ, λ). Allotypes are distinct
determinants that reflect regular small differences between individuals
of the same species in the amino acid sequences of otherwise similar
immunoglobulins. These differences are determined by allelic genes;
by definition, they are detected by antibodies made in the same spe­
cies. Idiotypes are the third category of antigenic determinants. They
are unique to the molecules produced by a given clone of antibodyproducing cells. Idiotypes are formed by the unique structure of the
antigen-binding portion of the molecule.
Antibody molecules (Fig. 116-1) are composed of two heavy chains
(~50,000 molecular weight [mol wt]) and two light chains (~25,000 mol
wt). Each chain has a constant portion (limited amino acid sequence
variability) and a variable region (extensive sequence variability). The
light and heavy chains are linked by disulfide bonds and are aligned
so that their variable regions are adjacent to one another. This variable
region forms the antigen recognition site of the antibody molecule; its
unique structural features form idiotypes that are reliable markers for a
particular clone of cells because each antibody is formed and secreted
by a single clone. Because of the mechanics of the gene rearrangements
necessary to specify the immunoglobulin variable regions (VDJ joining
for the heavy chain, VJ joining for the light chain), a particular clone
rearranges only one of the two chromosomes to produce an immuno­
globulin molecule of only one light chain isotype and only one allotype
(allelic exclusion) (Fig. 116-1). After exposure to antigen, the variable
region may become associated with a new heavy chain isotype (class
switch). Each clone of cells performs these sequential gene arrange­
ments in a unique way. This results in each clone producing a unique
immunoglobulin molecule. In most plasma cells, light chains are syn­
thesized in slight excess, secreted as free light chains, and cleared by the
kidney, but <10 mg of such light chains are excreted per day.
Electrophoretic analysis permits separation of components of the
serum proteins (Fig. 116-2). The immunoglobulins move hetero­
geneously in an electric field and form a broad peak in the gamma
region. There is a sharp spike in this region called an M component
(M for monoclonal) in the sera of patients with plasma cell tumors.
Less commonly, the M component may appear in the β2 or α2 globulin
region. The monoclonal antibody must be present at a concentration
of at least 5 g/L (0.5 g/dL) to be accurately quantitated by this method.
This corresponds to ~109 antibody producing cells. Confirmation of
the type of immunoglobulin and that it is truly monoclonal is deter­
mined by immunoelectrophoresis that reveals a single heavy and/or
light chain type. Hence, immunoelectrophoresis and electrophoresis
provide qualitative and quantitative assessment of the M component,
respectively. The amount of M component in the serum is a reli­
able measure of the tumor burden and an excellent tumor marker
to manage therapy, yet it is not specific enough to be used to screen
asymptomatic patients. In addition to the plasma cell disorders, M
components may be detected in other lymphoid neoplasms such as
chronic lymphocytic leukemia (CLL) and lymphomas of B- or T-cell
origin; nonlymphoid neoplasms such as chronic myeloid leukemia,
breast cancer, and colon cancer; a variety of nonneoplastic conditions
such as cirrhosis, sarcoidosis, parasitic diseases, Gaucher’s disease, and
pyoderma gangrenosum; and a number of autoimmune conditions,
including rheumatoid arthritis, myasthenia gravis, and cold agglutinin
disease. Monoclonal proteins are also observed in immunosuppressed
patients after organ transplant and, rarely, allogeneic transplant. At
least two very rare skin diseases—lichen myxedematosus (also known
as papular mucinosis) and necrobiotic xanthogranuloma—are associ­
ated with a monoclonal gammopathy. In papular mucinosis, highly
cationic IgG is deposited in the dermis of patients. This organ specific­
ity may reflect the specificity of the antibody for some antigenic com­
ponent of the dermis. Necrobiotic xanthogranuloma is a histiocytic
infiltration of the skin, usually of the face, that produces red or yellow
nodules that can enlarge to plaques. Approximately 10% progress to
myeloma. Five percent of patients with sensory motor neuropathy also
have a monoclonal paraprotein.
CHAPTER 116
Plasma Cell Disorders
The nature of the M component is variable in plasma cell disorders.
It may be an intact antibody molecule of any heavy chain subclass, or it
may be an altered antibody or fragment. Isolated light or heavy chains
may be produced. In some plasma cell tumors such as extramedullary
or solitary bone plasmacytomas, less than one-third of patients will
have an M component. In ~20% of myelomas, only light chains are
produced and, in most cases, are secreted in the urine as Bence Jones
proteins. The frequency of myelomas of a particular heavy chain class
is roughly proportional to the serum concentration, and therefore, IgG
myelomas are more common than IgA and IgD myelomas. In ~1% of
patients with myeloma, biclonal or triclonal gammopathy is observed.
MULTIPLE MYELOMA
■
■DEFINITION
MM represents a malignant proliferation of plasma cells derived from a
single clone. The tumor, its products, and the host response to it result
in a number of organ dysfunctions and symptoms, including bone pain
or fracture, renal failure, susceptibility to infection, anemia, hypercal­
cemia, and occasionally clotting abnormalities, neurologic symptoms,
and manifestations of hyperviscosity.
■
■ETIOLOGY
The cause of myeloma is not known. Myeloma occurred with increased
frequency in those exposed to the radiation of nuclear warheads in
World War II after a 20-year latency. Myeloma has been seen more
commonly than expected among farmers, wood workers, leather work­
ers, and those exposed to petroleum products. A variety of recurrent
chromosomal alterations have been found in patients with myeloma:
hyperdiploidy (trisomies involving one or more of chromosomes 3, 5,
7, 9, 11, 15, 19, or 21) is observed in half of the patients, while the other
half have translocations involving the 14q32 chromosome with variable
partners including t(11;14)(q13;q32), t(4;14)(p16;q32), and t(14;16).
Other frequent abnormalities include 13q14 deletion, 1q amplification
or 1p deletion, and 17p13 deletions. Evidence is strong that errors in
switch recombination—the genetic mechanism to change antibody
heavy chain isotype—participate in the early transformation process.
However, no single common molecular pathogenetic pathway has yet
λ  Light-chain locus
L1 Vλ1
L2 Vλ2
Jλ1
Jλ2
Jλ4
L Vλ–30
Cλ1
Cλ2
Cλ4
κ  Light-chain locus
L1 Vκ1
L2 Vκ2
L3 Vκ3
Jκ1–5
L Vκ–36
Cκ
Heavy-chain locus
L1 VH1
L2 VH2
L3 VH3
JH 1–6
Cµ
LH VH–40
DH1–23
Light chain
Heavy chain
L
V
J
C
L
V
J
D
Germline DNA
PART 4
Oncology and Hematology
Somatic
recombination
DNA
RNA
Protein
D–J rearranged
DNA joined
Somatic
recombination
L
V
J
C
V–J or V–DJ joined
rearranged DNA
Transcription
L
V
J
C
Primary
transcript RNA
AAA
Splicing
L
V
J
C
mRNA
AAA
Translation
VL
CL
Polypeptide chain
FIGURE 116-1  Immunoglobulin genetics and the relationship of gene segments to the antibody protein. The top portion of the figure is a schematic of the organization of
the immunoglobulin genes, λ on chromosome 22, κ on chromosome 2, and the heavy chain locus on chromosome 14. The heavy chain locus is >2 megabases, and some
of the D region gene segments are only a few bases long, so the figure depicts the schematic relationship among the segments, not their actual size. The bottom portion of
the figure outlines the steps in going from the noncontiguous germline gene segments to an intact antibody molecule. Two recombination events juxtapose the V-D-J (or
V-J for light chains) segments. The rearranged gene is transcribed, and RNA splicing cuts out intervening sequences to produce an mRNA, which is then translated into
an antibody light or heavy chain. The sites on the antibody that bind to antigen (the so-called CDR3 regions) are encoded by D and J segments for heavy chains and the
J segments for light chains. (Adapted from Janeway’s Immunobiology, 8th ed by Kenneth Murphy. Copyright © 2012 by Garland Science, Taylor & Francis Group, LLC. Used
by permission of W. W. Norton & Company, Inc.)
emerged. Genome sequencing efforts have allowed for characterization
of critical genes, pathways, and clonal heterogeneity in myeloma. The
median number of mutations per transcribed genome in myeloma is
~58, and within the whole genome, it is >7000. A very heterogeneous
mutational landscape with no unifying mutation has been observed.
The most frequently mutated genes are KRAS and NRAS (~20% each),
followed by TP53, DIS3, FAM46C, and BRAF, all mutated in 5–10%
C
C
L
V
DJ
C
L
V
DJ
C
L
V
DJ
AAA
C
L
V
DJ
AAA
CH3
CH2
CH1
VH
of patients. All other mutations were observed in <5% of the patients.
These results are now being applied to develop new targeted personal­
ized therapies in myeloma. Evidence of complex clusters of subclonal
variants is present at diagnosis, and additional mutations are acquired
over time, indicative of genomic evolution that may drive disease
progression. Interleukin (IL) 6 may play a role in driving myeloma cell
proliferation. It remains difficult to distinguish benign from malignant
SP
G
A
M
Κ
λ
SP
G
A
M
Κ
λ
SP
G
A
M
Κ
λ
Normal
Polyclonal increase
Monoclonal IgG lambda
FIGURE 116-2  Representative patterns of serum electrophoresis and immunofixation. The upper panels represent agarose gel, middle panels are the densitometric tracing
of the gel, and lower panels are immunofixation patterns. The panel on the left illustrates the normal pattern of serum protein on electrophoresis. Because there are
many different immunoglobulins in the serum, their differing mobilities in an electric field produce a broad peak. In conditions associated with increases in polyclonal
immunoglobulin, the broad peak is more prominent (middle panel). In monoclonal gammopathies, the predominance of a product of a single cell produces a “church
spire” sharp peak, usually in the γ globulin region (right panel). The immunofixation (lower panel) identifies the type of immunoglobulin. For example, normal and polyclonal
increases in immunoglobulins produce no distinct bands; however, the right panel shows distinct bands in IgG and lambda protein lanes, confirming the presence of IgG
lambda monoclonal protein. (Courtesy of Dr. Neal I. Lindeman.)
plasma cells based on morphologic criteria in all but a few cases
(Fig. 116-3).
■
■INCIDENCE AND PREVALENCE
In 2024 in the United States, 35,780 new cases of myeloma were esti­
mated to be diagnosed, and 12,540 people were estimated to die from
the disease. Myeloma increases in incidence with age. The median
age at diagnosis is 69 years; it is uncommon under age 40. Males are
more commonly affected than females, and blacks have nearly twice
the incidence of whites. In 2021, myeloma accounted for 1.8% of all
malignancies, with incidence rates per 100,000 of 8.1 and 5.1 in white
and 17.1 and 13.0 in black men and women, respectively.
■
■GLOBAL CONSIDERATIONS
The incidence of myeloma is highest in blacks and Pacific Islanders;
intermediate in Europeans and North American whites; and lowest in
FIGURE 116-3  Multiple myeloma (marrow). The cells bear characteristic
morphologic features of plasma cells: round or oval cells with an eccentric nucleus
composed of coarsely clumped chromatin, a densely basophilic cytoplasm, and a
perinuclear clear zone containing the Golgi apparatus. Binucleate and multinucleate
malignant plasma cells can be seen.
CHAPTER 116
Plasma Cell Disorders
people from developing countries including Asia. The higher incidence
in more developed countries may result from the combination of a lon­
ger life expectancy and more frequent medical surveillance. Incidence
of MM in other ethnic groups including native Hawaiians, female
Hispanics, American Indians from New Mexico, and Alaskan natives is
higher relative to U.S. whites in the same geographic area. Chinese and
Japanese populations have a lower incidence than whites. Immunopro­
liferative small-intestinal disease (IPSID) with α heavy chain disease is
most prevalent in the Mediterranean area. Despite these differences in
prevalence, the characteristics, response to therapy, and prognosis of
myeloma are similar worldwide.
■
■PATHOGENESIS AND CLINICAL MANIFESTATIONS
MM cells bind via cell-surface adhesion molecules to bone marrow
stromal cells (BMSCs) and extracellular matrix (ECM), which trig­
gers MM cell growth, survival, drug resistance, and migration in the
bone marrow milieu (Fig. 116-4). These effects are due both to direct
MM cell–BMSC binding via adhesion molecules and to induction of
various cytokines, including IL-6, insulin-like growth factor type 1
(IGF-1), and vascular endothelial growth factor (VEGF). Growth, drug
resistance, and migration are mediated via Ras/Raf/mitogen-activated
protein kinase, PI3K/Akt, and protein kinase C signaling cascades,
respectively. Other cellular elements in the bone marrow microen­
vironment also significantly impact MM cell growth and survival,
especially interactions with endothelial cells and osteoclasts. Immune
cells such as plasmacytoid dendritic cells (pDC), myeloid-derived sup­
pressor cells (MDSC), and T helper 17 (TH17) cells are increased in
number and support myeloma growth, while antimyeloma immune
responses, especially T helper and cytotoxic cells, B cells, and natural
killer T cells, are suppressed.
Bone pain is the most common symptom in myeloma, affecting
nearly 70% of patients. The bone lesions of myeloma are caused by the
proliferation of tumor cells, activation of osteoclasts that destroy bone,
and suppression of osteoblasts that form new bone. The increased
osteoclast activity is mediated by osteoclast activating factors (OAFs)
produced by the myeloma cells (mediated by several cytokines, includ­
ing IL-1, lymphotoxin, VEGF, receptor activator of nuclear factor-κB
[RANK] ligand, macrophage inhibitory factor [MIP]-1α, and tumor
TH17
Osteoclast
↑Proliferation
↑Differentiation
↑Activity
IL-17
RANK
IL-6
MM cell
RANKL
IL-6
Cytokine-mediated
signaling
OPG
Adhesion-mediated
signaling
↑Differentiation
↑Activity
Osteoblast
DKK-1
PART 4
Oncology and Hematology
Cytokines
IL-6
VEGF
IGF-1
SDF-1®
Endothelial
cells
↑Neoangiogenesis
NF-κB
BMSC
FIGURE 116-4  Pathogenesis of multiple myeloma. Multiple myeloma (MM) cells interact with bone marrow stromal cells (BMSCs) and extracellular matrix proteins via
adhesion molecules, triggering adhesion-mediated signaling as well as cytokine production. This triggers cytokine-mediated signaling that provides growth, survival, and
antiapoptotic effects as well as development of drug resistance. Additional bidirectional interactions lead to inhibition of osteoblast and increase in osteoclast activity,
which leads to bone-related issues in myeloma. Similar interactions with immune microenvironment lead to augmentation of tumor-promoting immune responses and
suppression of tumor protective immune responses, overall allowing myeloma cell growth. (Adapted from G Bianchi, NC Munshi: Blood 125: 3049, 2015.)
necrosis factor [TNF]). The bone lesions are lytic in nature (Fig. 116-5)
and are rarely associated with osteoblastic new bone formation due to
their suppression by dickkopf-1 (DKK-1) produced by myeloma cells.
Therefore, radioisotopic bone scan is less useful in diagnosis than is
plain radiography. The bony lysis results in substantial mobilization
of calcium from bone, and serious acute and chronic complications of
hypercalcemia may dominate the clinical picture (see below). Local­
ized bone lesions may cause pathological fracture or the collapse of
vertebrae, leading to spinal cord compression. The next most common
clinical problem in patients with myeloma is susceptibility to bacterial
infections. The most common infections are pneumonias and pyelone­
phritis, and the most frequent pathogens are Streptococcus pneumoniae,
Staphylococcus aureus, and Klebsiella pneumoniae in the lungs and
Escherichia coli and other gram-negative organisms in the urinary tract.
In ~25% of patients, recurrent infections are the presenting features,
and >75% of patients will have a serious infection at some time in their
course. The susceptibility to infection has several contributing causes.
First, patients with myeloma have diffuse hypogammaglobulinemia if
the M component is excluded. The hypogammaglobulinemia is related
to both decreased production and increased destruction of normal
antibodies. The large M component results in fractional catabolic rates
of 8–16% instead of the normal 2%. Moreover, some patients generate a
population of circulating regulatory cells in response to their myeloma
that can suppress normal antibody synthesis. These patients have very
poor antibody responses, especially to polysaccharide antigens such as
those on bacterial cell walls. Various abnormalities in T-cell function
are also observed including decreased TH1 response, increase in TH17
cells producing proinflammatory cytokines, and aberrant T regulatory
MDSC
pDC
Anergic
Exhausted
Cytotoxic
T cell
CTLA4
PD-L1
PD-1
Proliferatic
p42/44 MAPK
Raf
MEK
BCI-xL
Mcl-1
JAK
STAT3
Drug
resistance
antiapoptosis
Bad
NF-κB
Cyclin D
PI3-K
FKHR
Akt
p21
Cell cycle
Adhesion
molecule
interactions
Migration
PKC
cell function. Granulocyte lysozyme content is low, and granulocyte
migration is not as rapid as normal in patients with myeloma, probably
the result of a tumor product. There are also a variety of abnormalities
in complement functions in myeloma patients. All these factors con­
tribute to the immune deficiency in these patients. Some commonly
used therapeutic agents may significantly affect immune function;
e.g., dexamethasone suppresses immune responses and increases sus­
ceptibility to bacterial and fungal infection, B-cell maturation antigen
(BCMA)–targeting chimeric antigen receptor T (CAR-T) cells and
bispecific antibodies can eliminate plasma cells inducing hypogamma­
globulinemia, and bortezomib predisposes to herpesvirus reactivation.
Renal failure occurs in nearly 25% of myeloma patients, and some
renal pathology is noted in >50%. Of many contributing factors,
hypercalcemia is the most common cause of renal failure. Glomerular
deposits of amyloid, hyperuricemia, recurrent infections, frequent
use of nonsteroidal anti-inflammatory agents for pain control, use of
iodinated contrast dye for imaging, bisphosphonate use, and occa­
sional infiltration of the kidney by myeloma cells all may contribute
to renal dysfunction. However, tubular damage associated with the
excretion of light chains is common. Normally, light chains are filtered,
reabsorbed in the tubules, and catabolized. With the increase in the
amount of light chains presented to the tubule, the tubular cells become
overloaded with these proteins, and tubular damage results either
directly from light chain toxic effects or indirectly from the release
of intracellular lysosomal enzymes. The earliest manifestation of this
tubular damage is the adult Fanconi’s syndrome (a type 2 proximal
renal tubular acidosis), with loss of glucose and amino acids, as well as
defects in the ability of the kidney to acidify and concentrate the urine.
A
B
FIGURE 116-5  Bony lesions in multiple myeloma (MM). A. The skull demonstrates
the typical “punched out” lesions characteristic of MM. The lesion represents a
purely osteolytic lesion with little or no osteoblastic activity (above). B. Positron
emission tomography/computed tomography showing multiple fluorodeoxyglucose
(FDG)-avid lesions in skeleton (left panel) with their resolution on achieving
complete response (CR) (right panel). (Part A courtesy of Dr. Geraldine Schechter;
with permission. Part B courtesy of Dr. Sundar Jagannath; with permission.)
The proteinuria is not accompanied by hypertension, and the protein
is nearly all light chains. Generally, very little albumin is in the urine
because glomerular function is usually normal. When the glomeruli
are involved, nonselective proteinuria is also observed. Patients with
myeloma also have a decreased anion gap [i.e., Na+ – (Cl− + HCO3
−)]
because the M component is cationic, resulting in retention of chloride.
This is often accompanied by hyponatremia that is felt to be artificial
(pseudohyponatremia) because each volume of serum has less water as
a result of the increased protein. Renal dysfunction due to light chain
deposition disease, light chain cast nephropathy, and amyloidosis is
partially reversible with effective therapy. Myeloma patients are sus­
ceptible to developing acute renal failure if they become dehydrated.
Normocytic and normochromic anemia occurs in ~80% of myeloma
patients. It is usually related to the replacement of normal marrow by
expanding tumor cells, to the inhibition of hematopoiesis by factors
produced by the tumor, to reduced production of erythropoietin by
the kidney, and to the effects of long-term therapy. In addition, mild
hemolysis may contribute to the anemia. A larger than expected frac­
tion of patients may have megaloblastic anemia due to either folate or
vitamin B12 deficiency. Granulocytopenia and thrombocytopenia are
rare except when therapy-induced. Clotting abnormalities may be seen
due to the failure of antibody-coated platelets to function properly; the
interaction of the M component with clotting factors I, II, V, VII, or
VIII; antibody to clotting factors; or amyloid damage of endothelium.
Deep venous thrombosis is also observed with the use of thalidomide,
lenalidomide, or pomalidomide. Raynaud’s phenomenon and impaired
circulation may result if the M component forms cryoglobulins, and
hyperviscosity syndromes may develop depending on the physical
properties of the M component (most common with IgM, IgG3, and
IgA paraproteins). Hyperviscosity is defined based on the relative
viscosity of serum as compared with water. Normal relative serum vis­
cosity is 1.8 (i.e., serum is normally almost twice as viscous as water).
Symptoms of hyperviscosity occur at a level greater than 4 centipoises
(cP), which is usually reached at paraprotein concentrations of ~40 g/L
(4 g/dL) for IgM, 50 g/L (5 g/dL) for IgG3, and 70 g/L (7 g/dL) for IgA;
however, chemico-physical properties of the paraproteins may cause it
at lower levels.
CHAPTER 116
Plasma Cell Disorders
Although neurologic symptoms occur in a minority of patients, they
may have many causes. Hypercalcemia may produce lethargy, weak­
ness, depression, and confusion. Hyperviscosity may lead to headache,
fatigue, shortness of breath, exacerbation or precipitation of heart
failure, visual disturbances, ataxia, vertigo, retinopathy, somnolence,
and coma. Bony damage and collapse may lead to cord compression,
radicular pain, and loss of bowel and bladder control. Infiltration of
peripheral nerves by amyloid can be a cause of carpal tunnel syndrome
and other sensorimotor mono- and polyneuropathies. Neuropathy
associated with monoclonal gammopathy of undetermined signifi­
cance (MGUS) and myeloma is more frequently sensory than motor
neuropathy and is associated with IgM more than other isotypes. In
50% of patients with neuropathy, the IgM monoclonal protein is
directed against myelin-associated globulin (MAG). Sensory neu­
ropathy is also a side effect of therapy, specifically thalidomide and
bortezomib.
Many of the clinical features of myeloma, e.g., cord compression,
pathologic fractures, hyperviscosity, sepsis, and hypercalcemia, can
present as medical emergencies. Despite the widespread distribution of
plasma cells in the body, tumor expansion is dominantly within bone
and bone marrow and, for reasons unknown, rarely causes enlargement
of spleen, lymph nodes, or gut-associated lymphatic tissue.
■
■DIAGNOSIS AND STAGING
The diagnosis of myeloma requires marrow plasmacytosis (>10%), a
serum and/or urine M component, and at least one of the myelomadefining events detailed in Table 116-1. Bone marrow plasma cells are
CD138+ and either monoclonal kappa or lambda light chain positive.
The most important differential diagnosis in patients with myeloma
involves their separation from individuals with MGUS or smolder­
ing multiple myeloma (SMM). MGUS is vastly more common than
myeloma, occurring in 1% of the population aged >50 years and in
up to 10% of individuals aged >75 years. The diagnostic criteria for
MGUS, SMM, and myeloma are described in Table 116-1. Although
~1% of patients per year with MGUS go on to develop myeloma, all
cases of myeloma are preceded by MGUS. Non-IgG subtype, abnormal
kappa/lambda free light chain ratio, and serum M protein >15 g/L (1.5
g/dL) are associated with higher incidence of progression of MGUS to
myeloma. Absence of all three features predicts a 5% chance of progres­
sion, whereas higher-risk MGUS with the presence of all three features
predicts a 60% chance of progression over 20 years. The features
PART 4
Oncology and Hematology
TABLE 116-1  Diagnostic Criteria for Multiple Myeloma, Myeloma Variants, and Monoclonal Gammopathy of Undetermined Significance
Monoclonal Gammopathy of Undetermined Significance (MGUS)
Serum monoclonal protein (non-IgM type) <30 g/L
Clonal bone marrow plasma cells <10%a
Absence of myeloma-defining events or amyloidosis that can be attributed to the plasma cell proliferative disorder
Smoldering Multiple Myeloma (Asymptomatic Myeloma)
Both criteria must be met:
• Serum monoclonal protein (IgG or IgA) ≥30 g/L or urinary monoclonal protein ≥500 mg per 24 h and/or clonal bone marrow plasma cells 10–60%
• Absence of myeloma-defining events or amyloidosis
Symptomatic Multiple Myeloma
Clonal bone marrow plasma cells or biopsy-proven bony or extramedullary plasmacytomaa and any one or more of the following myeloma-defining events:
• Evidence of one or more indicators of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:
• Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL)
• Renal insufficiency: creatinine clearance <40 mL/minb or serum creatinine >177 μmol/L (>2 mg/dL)
• Anemia: hemoglobin value of >20 g/L below the lower limit of normal, or a hemoglobin value <100 g/L
• Bone lesions: one or more osteolytic lesions on skeletal radiography, CT, or PET-CTc
• Any one or more of the following biomarkers of malignancy:
• Clonal bone marrow plasma cell percentagea ≥60%
• Involved: uninvolved serum free light chain ratiod ≥100
• >1 focal lesion on MRI studiese
Nonsecretory Myeloma
No M protein in serum and/or urine with immunofixationf
Bone marrow clonal plasmacytosis ≥10% or plasmacytomaa
Myeloma-related organ or tissue impairment (end-organ damage, as described above)
Solitary Plasmacytoma
Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells
Normal bone marrow with no evidence of clonal plasma cellsa
Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion)
Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, or bone lesions (CRAB) that can be attributed to a lymphoplasma cell proliferative
disorder
POEMS Syndrome
All of the following four criteria must be met:
Polyneuropathy
Monoclonal plasma cell proliferative disorder
Any one of the following: (a) sclerotic bone lesions; (b) Castleman’s disease; (c) elevated levels of vascular endothelial growth factor (VEGF)
Any one of the following: (a) organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy); (b) extravascular volume overload (edema, pleural effusion, or
ascites); (c) endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, and pancreatic); (d) skin changes (hyperpigmentation, hypertrichosis, glomeruloid
hemangiomata, plethora, acrocyanosis, flushing, and white nails); (e) papilledema; (f) thrombocytosis/polycythemiag
aClonality should be established by showing κ/λ light chain restriction on flow cytometry, immunohistochemistry, or immunofluorescence. Bone marrow plasma cell
percentage should preferably be estimated from a core biopsy specimen; in case of a disparity between the aspirate and core biopsy, the highest value should be
used. bMeasured or estimated by validated equations. CIf bone marrow has <10% clonal plasma cells, more than one bone lesion is required to distinguish from solitary
plasmacytoma with minimal marrow involvement. dThese values are based on the serum Freelite assay (The Binding Site Group, Birmingham, United Kingdom). The involved
free light chain must be ≥100 mg/L. eEach focal lesion must be ≥5 mm in size. fA small M component may sometimes be present. gThese features should have no other
attributable causes and have temporal relation with each other.
Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging; PET-CT, 18F-fluorodeoxyglucose positron emission tomography with computed tomography;
POEMS, polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes.
responsible for higher risk of progression from SMM to MM are bone
marrow plasmacytosis >10%, abnormal kappa/lambda free light chain
ratio, and serum M protein >30 g/L (3 g/dL). Patients with only one
of these three features have a 25% chance of progression to MM in
5 years, whereas patients with high-risk SMM with all three features
have a 76% chance of progression. Two important variants of myeloma
are solitary bone plasmacytoma and solitary extramedullary plasmacy­
toma. These lesions are associated with an M component in <30% of
the cases, they may affect younger individuals, and both are associated
with median survivals of ≥10 years. Solitary bone plasmacytoma is a
single lytic bone lesion without marrow plasmacytosis. Extramedullary
plasmacytomas usually involve the submucosal lymphoid tissue of the
nasopharynx or paranasal sinuses without marrow plasmacytosis. Both
tumors are highly responsive to local radiation therapy. If an M com­
ponent is present, it should disappear after treatment. Solitary bone
plasmacytomas may recur in other bony sites or evolve into myeloma.
Extramedullary plasmacytomas rarely recur or progress.
■
■LABORATORY INVESTIGATION
Serum protein electrophoresis and measurement of serum immuno­
globulins and free light chains are useful for detecting and character­
izing M spikes, supplemented by immunoelectrophoresis, which is
especially sensitive for identifying low concentrations of M compo­
nents not detectable by protein electrophoresis. A 24-h urine specimen
is necessary to quantitate Bence Jones protein (immunoglobulin light
chain) excretion. The serum M component is IgG in 53% of patients,
IgA in 25%, and IgD in 1%; 20% of patients will have only light chains
in serum and urine. Dipsticks for detecting proteinuria are not reli­
able at identifying light chains, and the heat test for detecting Bence
Jones protein is falsely negative in ~50% of patients with light chain
myeloma. Fewer than 1% of patients have no identifiable M compo­
nent; these patients usually have light chain myeloma in which renal
catabolism has made the light chains undetectable in the urine. In most
of these patients, light chains can now be detected by serum free light
chain assay. Mass spectrometry has been investigated to accurately
assess M protein. IgD myeloma may also present with light chain
disease. About two-thirds of patients with serum M components also
have urinary light chains. The light chain isotype may have an impact
on disease behavior. Whether this is due to some genetically important
determinant of cell proliferation or because lambda light chains are
more likely to cause renal damage and form amyloid than are kappa
light chains is unclear. About half of patients with IgM paraproteins
develop hyperviscosity compared with only 2–4% of patients with
IgA and IgG M components. Among IgG myelomas, it is the IgG3
subclass that has the highest tendency to form both concentration-
and temperature-dependent aggregates, leading to hyperviscosity and
cold agglutination at lower serum concentrations. A standard workup
directed at detecting monoclonal plasma cells and myeloma-defining
events as well as prognosis is detailed in Table 116-2.
A complete blood count with differential may reveal anemia. Eryth­
rocyte sedimentation rate is elevated. Rare patients (~1%) may have
plasma cell leukemia with >2000 plasma cells/μL. This may be seen
in disproportionate frequency in IgD (12%) and IgE (25%) myelomas.
Serum calcium, urea nitrogen, creatinine, and uric acid levels may
be elevated. Serum alkaline phosphatase is usually normal even with
extensive bone involvement because of the absence of osteoblastic
activity. It is also important to quantitate serum β2-microglobulin and
albumin (see below).
Chest and bone radiographs may reveal lytic lesions or diffuse osteo­
penia. Magnetic resonance imaging (MRI) offers a sensitive means to
document extent of bone marrow infiltration and cord or root com­
pression in patients with pain syndromes. 18F-fluorodeoxyglucose
(18F-FDG) positron emission tomography (PET)/computed tomogra­
phy (CT) is a valuable tool to assess bone damage and detect extramed­
ullary sites of the disease (Fig. 116-5). The use of 18F-FDG PET/CT is
now considered standard to distinguish between smoldering and active
TABLE 116-2  Standard Investigative Workup in Multiple Myeloma
(MM)
Investigations to Evaluate for Clonal Plasma Cells
Bone marrow aspirate and biopsy (fine-needle aspiration of plasmacytoma if
indicated)
• Histology
• Clonality by kappa/lambda immunostaining by flow cytometry or
immunohistochemistry
Investigations to Evaluate Clonal Paraprotein
Serum protein electrophoresis and immunofixation
Quantitative serum immunoglobulin levels (IgG, IgA, and IgM)
24-h urine protein electrophoresis and immunofixation
Serum free light chain and ratio
Immunofixation for IgD or IgE in select cases
Investigation to Evaluate End-Organ Damage
Hemogram to assess for anemia.
Chemistry panel for renal function and calcium
Skeletal survey or PET/CT scan to evaluate bone lesions
PET/CT or MRI if smoldering MM or solitary plasmacytoma
Investigation for Risk Stratification
β2-Microglobulin and serum albumin for ISS stage
DNA-sequencing or if not available Fluorescent in situ hybridization for
hyperdipoidy, del17p, t(4;14); t(11;14), t(14;16), t(14;20), amp1q34, and del1p and
p53 mutation on bone marrow sample
LDH
Specialized Investigation in Selected Cases
Abdominal fat pad for amyloid
Serum viscosity if IgM component or high IgA levels or serum M component >7
g/dL
Myd88 and CXCR4 mutation analysis if IgM component
Abbreviations: CT, computed tomography; ISS, International Staging System;
LDH, lactate dehydrogenase; MRI, magnetic resonance imaging; PET/CT, positron
emission tomography/computed tomography.
MM and to confirm a suspected diagnosis of solitary plasmacytoma.
It is also a valuable tool to evaluate response in patients with oligo- or
nonsecretory myeloma.
■
■PROGNOSIS
Serum β2-microglobulin is the single most powerful predictor of sur­
vival and can substitute for staging. β2-Microglobulin is the light chain
of the class I major histocompatibility antigens (HLA-A, -B, -C) on
the surface of every cell. Combination of serum β2-microglobulin and
albumin levels forms the basis for a three-stage International Staging
System (ISS) (Table 116-3) that predicts survival. With the use of highdose therapy and the newer agents, the Durie-Salmon staging system is
unable to predict outcome and is no longer used. High labeling index,
circulating plasma cells, performance status, and high levels of lactate
dehydrogenase are also associated with poor prognosis.
With low proliferative activity of plasma cells, karyotype is now not
recommended in myeloma. Fluorescent in situ hybridization (FISH)
has become a standard investigative technique, and the current recom­
mendation suggests switching to DNA sequencing-based methods.
Chromosome 17p deletion with 20% clonality or TP53 mutation, and
translocations t(4;14), (14;16), or t(14;20) associated with del 1p or
amp1q changes along with high β2-microglobulin with normal renal
function are considered prognostic for high-risk disease, as described
in Table 116-3. Chromosome 13q deletion and t(11;14) are not consid­
ered predictors of high-risk myeloma.
CHAPTER 116
TREATMENT
Multiple Myeloma
Plasma Cell Disorders
MGUS, SMM, AND SOLITARY PLASMACYTOMA
No specific intervention is indicated for patients with MGUS.
Follow-up once a year or less frequently is adequate except in
higher-risk MGUS, where serum protein electrophoresis, complete
blood count, creatinine, and calcium should be repeated every
6 months. A patient with MGUS and severe polyneuropathy is con­
sidered for therapeutic intervention if a causal relationship can be
assumed, especially in the absence of any other potential causes for
neuropathy. Therapy can include plasmapheresis and occasionally
rituximab in patients with IgM MGUS or myeloma-like therapy
TABLE 116-3  Risk Stratification in Myeloma
STANDARD RISK
(75–80%) (EXPECTED
SURVIVAL 8–10+ YEARS)
HIGH RISK (20–25%)
(EXPECTED SURVIVAL
3–4 YEARS)
METHOD
DNA sequencing or
FISH if sequencing not
available
t(11;14)
del(17p) (20% cutoff) and/
or TP53 mut
 
del(13)
t(4;14)/t(14;16)/t(14;20)
with 1q gain and/or 1p del
 
Hyperdiploidy
Del 1p + 1q gain or
biallelic del 1p
Biochemical assessment
 
β2M >5.5 with normal
creatinine
INTERNATIONAL STAGING SYSTEM (ISS)
INTERNATIONAL
STAGING SYSTEM (ISS)
STAGE
MEDIAN SURVIVAL,
MONTHS
β2M <3.5, ALB ≥3.5
I (28%)
II (39%)
β2M <3.5, ALB <3.5 or
β2M <3.5, ALB ≥3.5 or
β2M = 3.5–5.5
III (33%)
β2M >5.5 or β2M <3.5,
ALB <3.5 or β2M = 3.5–5.5
aPercentage of patients presenting at each stage.
Abbreviations: β2M, serum β2-microglobulin in mg/L; ALB, serum albumin in g/dL;
FISH, fluorescent in situ hybridization; LDH, lactate dehydrogenase.
in those with IgG or IgA disease. A subset of patients with MGUS
develop renal dysfunction usually based on renal damage from
the monoclonal antibody. The damage may affect the glomeruli,
tubules, or vessels. No consensus exists on management, but lower­
ing the level of the monoclonal antibody with bortezomib has had
some advocates.
About 10% of patients have SMM and will have an indolent
course demonstrating only slow progression of disease over many
years. For patients with SMM, no specific therapeutic intervention
is indicated in general. But early intervention with lenalidomide
alone or in combination with dexamethasone has been shown to
prevent progression from high-risk SMM to active MM. At present,
patients with SMM only require antitumor therapy when myelomadefining events are identified.
Patients with solitary bone plasmacytomas and extramedullary
plasmacytomas may be expected to enjoy prolonged disease-free
survival after local radiation therapy at a dose of ~40 Gy. Occult
marrow involvement may occur at low incidence in patients with
TABLE 116-4  Standard Therapeutic Agents in Myeloma
CLASS
AGENT
STANDARD DOSAGE AND ADMINISTRATION
COMBINATION
MYELOMA INDICATION
Immunomodulatory
drugs (IMiD)
Thalidomide (T)
Oral 50–200 mg qd
TD, VTD
Newly diagnosed and relapsed
PART 4
Oncology and Hematology
Lenalidomide (R)
Oral 5–25 mg daily × 21 days q 4 weeks
RD, RVD, DaRD, ERD, KRD,
IRD, DaRVD
Pomalidomide (P)
Oral 2–4 mg daily × 21 days q 4 weeks
PD, KPD, DaPD
Relapsed
Proteasome inhibitors
(PI)
Bortezomib (V)
IV or SC 1.3 mg/m2 days 1, 4, 8, 11 OR days 1, 8, 15
VD, VTD, VRD, DaVD, VCD
DaRVD
Carfilzomib (K)
IV 20–56 mg/m2 days 1, 2, 8, 9, 15, 16 q 4 weeks
KD, KRD, KPD, Da KD, Da
KRD, IsaKD
Ixazomib (I)
Oral 4 mg days 1, 8, 15
IRD
Relapsed, maintenance
Antibodies
Daratumumab (Da)
IV or SC 16 mg/kg per week for 8 weeks then every
2 weeks for 16 weeks and then every 4 weeks
thereafter
Elotuzumab (E)
IV 10 mg/kg days 1, 8, 15, and 22 for first two
cycles, then on days 1 and 15; along with RD
Isatuximab (Isa)
IV 10 mg/kg weekly for 4 weeks and then every 2
weeks
Belantamab mafodotin
IV 2.5 mg/kg once every 3 weeks
 
Relapsed or refractory—4 prior
lines of therapy
Selective inhibitor of
nuclear export (SINE)
Selinexor (S)
Oral 80 mg on days 1 and 3 of each week
SVD
Relapsed
Histone deacetylase
inhibitor
Panobinostat (Pa)
Oral 20 mg once every other day for 3 doses/week
for 2 weeks every 21 days
Alkylating agents
Melphalan (M)
Oral 0.25 mg/kg per day for 4 days (with P) every
4–6 weeks
Cyclophosphamide
IV—300–500 mg/m2 weekly × 2 q 4 weeks
Oral—50 mg qd × 21 days
Bendamustine (B)
IV 70–90 mg days 1, 2 OR days 1, 8 q 4 weeks
BD or BVD
Relapsed
Melflufen (Me)
IV 40 mg day 1 (with D 40 mg on days 1, 8, 15, and
22) q 28 days
Glucocorticoid
Dexamethasone (D)
Prednisone (P)
Oral 10–40 mg q week
Oral 1 mg/kg
Cellular therapy
Idecabtagene vicleucel
(Ide-cel)
IV 450 × 106 cells
None
At least two prior lines of therapy
that includes an PI, IMiD and
anti-CD38 antibody
Ciltacabtagene
autoleucel (Cilta-cel)
IV
None
At least one prior line of therapy,
including PI and IMiD and who
are refractory to lenalidomide
Bispecific antibodies
Teclistamab
Anti-BCMA–anti-CD3
Step-up doses of 0.06 mg and 0.3 mg per kilogram
SC days 1, 4 and 1.5 mg per kilogram of body
weight day 8 and q week
None
Relapsed or refractory—4
prior lines of therapy with
prior exposure to PI, IMiD, and
anti-CD38 antibody
Elranatamab
Anti-BCMA–anti-CD3
Step-up doses of 12 and 32 mg on days 1, 4 and
76 mg SC day 8 and then q week for 25 weeks and
then q 2 weeks
Talquetamab
Anti-GPRC5D–anti-CD3
Two step-up doses during first week and then
every week or every other week regimen
solitary bone plasmacytoma. Such patients are usually identified
because their serum M component falls slowly or disappears ini­
tially after local therapy, only to return after a few months. These
patients respond well to systemic therapy.
SYMPTOMATIC MM
Patients with symptomatic myeloma require therapeutic inter­
vention. In general, such therapy has two purposes: (1) systemic
therapy to control myeloma; and (2) supportive care to control
symptoms of the disease, its complications, and adverse effects of
therapy. Therapy can significantly prolong survival and improve the
quality of life for myeloma patients.
The therapy of myeloma includes an initial induction regimen
followed by consolidation and/or maintenance therapy and, on
subsequent progression, management of relapsed disease. All agents
available for use at various stages of the therapy and their doses,
schedules, and combinations are detailed in Table 116-4. Therapy
is partly dictated by the patient’s age and comorbidities, which may
Newly diagnosed, maintenance,
and relapsed
Newly diagnosed and relapsed
Newly diagnosed and relapsed
Dara, DaRD, DaVD, DaPD,
DaKD
Newly diagnosed, maintenance,
and relapsed
ERD, EPD
Relapsed
IsaPD, IsaKD
Relapsed
PaVD
Relapsed
MP, MPT, MPR, MPV,
DaMPV, high-dose M
Newly diagnosed and relapsed
conditioning
VCD
Newly diagnosed and relapsed
MeD
Relapsed or refractory—4 prior
lines of therapy
 
All stages
None
None
Newly diagnosed
Smoldering myeloma
No therapy except on clinical study
or high-risk – Regular follow-up
Myeloma-defining events
Yes
Transplant eligible
Transplant ineligible*
Induction therapy
4-drug regimen with
Dara, R, V or K and
d; 3-drug regimen
without Dara, or VCd
until maximum effect
No response
Alternate
regimen
Response
HDT with ASCT/
consolidation
No response
Relapse
Relapse
Maintenance
Treatment of relapsed disease
2–4 line of alternate regimen
*Due to age or comorbidities.
FIGURE 116-6  Treatment algorithm for multiple myeloma. Alternate regimen indicates combinations including daratumumab, elotuzumab, panobinostat, carfilzomib,
ixazomib, pomalidomide, or other agents. ASCT, autologous stem cell transplantation; C, cyclophosphamide; D, dexamethasone; HDT, high-dose therapy; M, melphalan;
MDE, myeloma-defining events; P, prednisone; R, lenalidomide; RVD-lite, weekly regimen; V, bortezomib.
affect a patient’s ability to undergo high-dose therapy and trans­
plantation (Fig. 116-6).
Three important classes of agents approved for treatment of
newly diagnosed MM are immunomodulatory agents, proteasome
inhibitors, and antibodies targeting CD38. The combination of
lenalidomide with a proteasome inhibitor (bortezomib or carfil­
zomib) and dexamethasone achieves close to a 100% response rate
and a >50% complete response (CR) rate, making this combina­
tion one of the preferred induction regimens in transplant-eligible
patients. Other similar three-drug combinations (bortezomib, tha­
lidomide, and dexamethasone or bortezomib, cyclophosphamide,
and dexamethasone) also achieve >90% response rate. Addition of a
fourth agent, daratumumab or isatuximab, an anti-CD38 antibody,
is providing even deeper responses and such four-drug regimens as
induction therapy are becoming standard of care. Usually between
four and six cycles of these combination regimens are utilized to
achieve initial deep cytoreduction before consideration of highdose therapy with autologous stem cell transplantation.
In patients who are not transplant candidates due to physiologic
age >70 years, significant cardiopulmonary problems, or other
comorbid illnesses, the same three-drug combinations described
above are considered standard of care as induction therapy with
age- and frailty-guided dose and schedule modifications. Com­
bination of daratumumab with lenalidomide and dexamethasone
(DRd) and modified lenalidomide-bortezomib-dexamethasone
(RVD lite) combination achieve high overall response rates (93 and
86%, respectively) and CR rates (47 and 32%, respectively). The
four-drug combinations used in younger patients are also utilized
in healthy older patients with excellent response. In the past, the
combination of melphalan with prednisone (MP) alone or with
thalidomide or bortezomib has been utilized effectively, but with
the availability of newer agents and combinations, MP-based com­
binations are now not utilized.
No
If appearance of MDE
Induction therapy
4-drug regimen with
Dara, R, V or K and d,
Dara Rd, RVd-lite, VCd,
Vd, Rd, VMP until
maximum effect
Response
CHAPTER 116
Maintenance
Treatment of relapsed disease: 5th
line and beyond alternate regimen
Plasma Cell Disorders
HIGH-DOSE THERAPY WITH AUTOLOGOUS STEM CELL
TRANSPLANTATION
High-dose therapy (HDT) and consolidation/maintenance are stan­
dard practice in the majority of eligible patients. In patients who
are transplant candidates and receiving lenalidomide, stem cells
should be collected within 6 months because the continued use
of lenalidomide may compromise the ability to collect adequate
numbers of stem cells. Randomized studies comparing standarddose therapy to high-dose melphalan therapy with hematopoietic
stem cell support have shown that HDT can achieve higher overall
response rates, with up to 25–40% additional CRs and prolonged
progression-free and overall survival; however, few, if any, patients
are cured. Although two successive HDTs (tandem transplanta­
tions) are more effective than single HDT, the benefit is only
observed in the subset of patients who do not achieve a complete
or very good partial response to the first transplantation, which is
a rare subset. Moreover, a randomized study failed to show any sig­
nificant difference in overall survival between early transplantation
after induction therapy versus delayed transplantation at relapse.
These data allow an option to delay transplantation, especially
with the availability of newer agents and combinations. Allogeneic
transplantations may also produce high response rates, but with
significant toxicities. Nonmyeloablative allogeneic transplantation
can reduce toxicity but is recommended only under the auspices
of a clinical trial to exploit an immune graft-versus-myeloma effect
while avoiding attendant toxicity. Due to effective cellular therapies,
allogeneic transplantation is very rarely used.
Maintenance therapy prolongs remissions following standarddose regimens as well as HDT. Several phase 3 studies have
demonstrated improved progression-free survival, and one study
showed prolonged overall survival in patients receiving lenalido­
mide compared to placebo as maintenance therapy after HDT. In
nontransplant candidates, two phase 3 studies showed prolonged
progression-free survival with lenalidomide maintenance after MP
plus lenalidomide or lenalidomide plus dexamethasone induction
therapy. Although concern arises regarding an increased incidence
of second primary malignancies in patients receiving lenalidomide
maintenance, its benefits in reducing the risk of progressive disease
and death from myeloma far outweigh the small increased risk of
second cancers. In patients with high-risk cytogenetics, lenalido­
mide and bortezomib or an oral proteasome inhibitor, ixazomib,
show promise as maintenance combination therapy after trans­
plantation. A phase 3 study has also demonstrated the benefit of
maintenance therapy with daratumumab after HDT.
RELAPSED DISEASE
Relapsed myeloma can be treated with a number of agents includ­
ing lenalidomide and/or bortezomib, if previously not used. The
second-generation proteasome inhibitor carfilzomib and immuno­
modulatory agent pomalidomide have shown efficacy in relapsed
and refractory MM, even MM refractory to lenalidomide and
bortezomib. An oral proteasome inhibitor, ixazomib, has also been
approved in combination with lenalidomide and dexamethasone as
an all-oral regimen for relapsed MM. Four antibodies are approved
for treatment of relapsed MM. Daratumumab targeting CD38
achieves high response rates and improved progression-free sur­
vival as a single agent with further improvement in response
and survival when added to bortezomib and dexamethasone or
lenalidomide and dexamethasone. A formulation of daratumumab
for subcutaneous administration provides decreased toxicity and
improved convenience. Isatuximab, another antibody targeting
CD38, achieves high response rates and improved progression-free
survival in combination with pomalidomide or carfilzomib and
dexamethasone. Elotuzumab, which targets SLAMF7, has shown
significant activity in combination with lenalidomide and dexa­
methasone in relapsed/refractory myeloma but not as a single agent.
Finally, belantamab mafodotin, an antibody-drug conjugate, targets
B-cell maturation antigen (BCMA), which is expressed mainly on
normal plasma cells and myeloma cells and delivers auristatin, a
microtubule inhibitor, to the tumor cells and achieves responses in
relapsed/refractory myeloma. The drug has a unique ophthalmo­
logic toxicity that requires close monitoring. Its efficacy increases
significantly when combined with pomalidomide or proteasome
inhibitor.
PART 4
Oncology and Hematology
Panobinostat, a histone deacetylase inhibitor, in combination
with bortezomib and dexamethasone has been approved for treat­
ment of relapsed/refractory myeloma based on superior response
and progression-free survival compared to bortezomib and dexa­
methasone alone. Two additional newer agents have unique mecha­
nisms of action: selinexor is a first-in-class exportin inhibitor that
blocks export of proteins from the cell nucleus, and melflufen is an
alkylating agent conjugated to a peptide to improve specific delivery
to myeloma cells that express aminopeptidase required for cleaving
of the peptide to deliver the drug intracellularly in myeloma cells.
Both agents have been approved based on their effectiveness in
relapsed/refractory myeloma.
Immunotherapeutic Approaches  Two cellular therapies, both tar­
geting BCMA, are approved for relapsed myeloma. The anti-BCMA
CAR transduced T cell, idecabtagene vicleucel (Ide-cel), is approved
after at least two prior lines of therapy that includes an immu­
nomodulatory agent, a proteasome inhibitor, and an anti-CD38
monoclonal antibody, whereas ciltacabtagene autoleucel (Cilta-cel)
is approved for patients who have received at least one prior line of
therapy, including a proteasome inhibitor and an immunomodula­
tory agent and who are refractory to lenalidomide. In patients with
advanced myeloma with a median of six prior lines of treatment,
81% of patients receiving target dose of Ide-cel responded, and a CR
rate of 33% was observed. Cilta-cel in a similar patient population
achieved 98% overall response with 82% achieving CR. Cytokine
release syndrome and neurotoxicity remain primary toxicities
requiring close monitoring and aggressive management.
Three bispecific antibodies are also approved for treatment of
relapsed and refractory myeloma after four prior lines of thera­
pies. Bispecific antibodies can bind to two different cell surface
targets through two distinct binding domains. One domain binds
to CD3 on human lymphocytes, while the other domain binds to
a cell surface target specific for myeloma cells, bringing the T cells
closer and leading to myeloma cell death. Two bispecific antibodies,
teclistamab and elranatamab, target BCMA, whereas talquetamab
targets a novel cell surface target on myeloma cells, G protein–
coupled receptor class C group 5 (GPRC5D). In patients with
relapsed refractory myeloma, these antibodies result in a 60–70%
response rate, with a quarter of the patients achieving CR. Bispecific
antibodies are associated with toxicities including cytokine release
syndrome, neurotoxicity, and significant susceptibility to infectious
complications. Incorporation of the large number of active agents at
various stages of treatment, including in newly diagnosed patients,
is improving survival as well as quality of life.
THERAPY ENDPOINT
Improvement in the serum M component may lag behind the symp­
tomatic improvement due to longer serum half-life (~3 weeks) of
the immunoglobulin. The fall in M component depends on the rate
of tumor kill and the fractional catabolic rate of immunoglobulin.
Serum and urine light chains with a functional half-life of ~6 h may
fall much quicker within the first week of treatment. Because urine
light chain levels may relate to renal tubular function, they are not
a reliable measure of tumor cell kill in patients with renal dysfunc­
tion. Achieving CR, defined as disappearance of serum and urine
monoclonal protein with normal bone marrow by light microscopy,
has been a standard goal of therapy. However, sequencing or multi­
color flow cytometry–based assessment of minimal residual disease
(MRD) in bone marrow to measure the presence of one myeloma
cell in a million cells is being considered as an important new end­
point, both in newly diagnosed and relapsed patients. Absence of
MRD at this sensitivity predicts for both longer progression-free
survival and longer overall survival. Although patients may not
achieve complete remission, clinical responses may last for long
periods of time in small numbers of patients.
The median overall survival of patients with myeloma is 8+
years, with subsets of younger patients surviving >10 years. The
major causes of death are progressive myeloma, renal failure, sepsis,
or therapy-related myelodysplasia. Nearly a quarter of patients die
of myocardial infarction, chronic lung disease, diabetes, or stroke,
which are all intercurrent illnesses related more to the age of the
patient group than to the tumor.
SUPPORTIVE THERAPY
Herpes zoster prophylaxis is indicated if bortezomib is used, and
neuropathy attendant to bortezomib can be decreased both by its
subcutaneous administration and by administration on a weekly
schedule. Lenalidomide use requires prophylaxis for deep-vein
thrombosis (DVT) with either aspirin or, if patients are at a
greater risk of DVT, warfarin, low-molecular-weight heparin, or
direct-acting anticoagulants DOACs. Patients receiving anti-BCMA
CAR-T cell therapy or bi-specific antibodies may need supplemen­
tation with intravenous γ globulin due to induction of prolonged
hypogammaglobulinemia.
Supportive care directed at the anticipated complications of
the disease may be as important as primary antitumor therapy.
Hypercalcemia generally responds well to bisphosphonates, glu­
cocorticoid therapy, hydration, and natriuresis and rarely requires
calcitonin as well. Bisphosphonates (e.g., pamidronate 90 mg or
zoledronate 4 mg initially once a month for 12–24 months and later
every 2–3 months) reduce osteoclastic bone resorption and pre­
serve performance status and quality of life, decrease bone-related
complications, and may also have antitumor effects. Osteonecrosis
of the jaw and renal dysfunction can occur in a minority of patients
receiving bisphosphonate therapy. Denosumab is an alternative
agent administered intravenously at 120 mg monthly and achieves
a similar level of effect as bisphosphonates to prevent bone-related
complications in myeloma. Treatments aimed at strengthening the
skeleton such as fluorides, calcium, and vitamin D, with or without
androgens, have been suggested but are not of proven efficacy.
Kyphoplasty or vertebroplasty should be considered in patients with
painful collapsed vertebra. Iatrogenic worsening of renal function
may be prevented by maintaining a high fluid intake to prevent
dehydration and enhance excretion of light chains and calcium. In
the event of acute renal failure, plasmapheresis is ~10 times more
effective at clearing light chains than peritoneal dialysis; however,
its role in reversing renal failure remains controversial. Importantly,
reducing the protein load by effective antitumor therapy with agents
such as bortezomib may result in improvement in renal function in
over half of the patients. Use of lenalidomide in renal failure is pos­
sible but requires dose modification because it is renally excreted.
Urinary tract infections should be watched for and treated early.
Plasmapheresis may be the treatment of choice for hyperviscosity
syndromes. Although the pneumococcus is a dreaded pathogen in
myeloma patients, pneumococcal polysaccharide vaccines may not
elicit an antibody response. The pneumococcal conjugate vaccines
are more protective. Prophylactic administration of intravenous
γ globulin preparations is used in the setting of recurrent serious
infections and in patients receiving CAR-T therapy or bispecific
antibodies. Routine chronic oral antibiotic prophylaxis is not war­
ranted. Patients receiving bortezomib or CD38-directed therapies
receive prophylaxis against herpes zoster. Patients with myeloma
and even SMM and MGUS may be at a higher risk of developing
COVID-19 and thus are encouraged to have vaccination for preven­
tion and, if positive for infection, to receive antiviral therapy for
COVID-19. Patients developing neurologic symptoms in the lower
extremities, severe localized back pain, or problems with bowel
and bladder control may need emergency MRI and local radiation
therapy and glucocorticoids if cord compression is identified. In
patients in whom neurologic deficit is increasing or substantial,
emergent surgical decompression may be necessary. Most bone
lesions respond to analgesics and systemic therapy, but certain pain­
ful lesions may respond more promptly to localized radiation. The
anemia associated with myeloma may respond to erythropoietin
along with hematinics (iron, folate, cobalamin). The pathogenesis
of the anemia should be established and specific therapy instituted,
whenever possible.
WALDENSTRÖM’S MACROGLOBULINEMIA
In 1948, Waldenström described a malignancy of lymphoplasmacy­
toid cells that secreted IgM. In contrast to myeloma, the disease was
associated with lymphadenopathy and hepatosplenomegaly, but the
major clinical manifestation was hyperviscosity syndrome. The dis­
ease resembles the related diseases CLL, myeloma, and lymphocytic
lymphoma. It originates from a post–germinal center B cell that has
undergone somatic mutations and antigenic selection in the lymphoid
follicle and has the characteristics of an IgM-bearing memory B cell.
Waldenström’s macroglobulinemia (WM) and IgM myeloma follow a
similar clinical course, but therapeutic options are different. The diag­
nosis of IgM myeloma is usually reserved for patients with lytic bone
lesions and predominant infiltration with CD138+ plasma cells usually
with t(11;14) translocation in the bone marrow. Such patients are at
greater risk of pathologic fractures than patients with WM.
A familial occurrence is common in WM, but its molecular bases
are yet unclear. A distinct MYD88 L265P somatic mutation is present
in >90% of patients with WM and the majority of IgM MGUS. Other
commonly occurring mutations include CXCR4 (30–40%), ARID1A
(17%), and CD79B (8–15%). Presence of MYD88 mutation status is
now used as a diagnostic test to discriminate WM from marginal zone
lymphomas (MZLs), IgM-secreting myeloma, and CLL with plasma­
cytic differentiation. This mutation also explains the molecular patho­
genesis of the disease with involvement of Toll-like receptor (TLR) and
interleukin 1 receptor (IL-1R) signaling leading to activation of IL-1R–
associated kinase (IRAK) 4 and IRAK1 followed by nuclear factor-κB
(NF-κB) activation. MYD88 mutation also triggers Bruton’s tyrosine
kinase (BTK) and hemopoietic cell kinase (HCK)-mediated growth
and survival signaling, which are now important therapeutic targets in
WM. CXCR4 mutations induce AKT and extracellular regulated kinase
1/2 (ERK1/2) signaling. This pathway can lead to development of drug
resistance in the presence of its ligand CXCL12.
The disease is similar to myeloma in being slightly more com­
mon in men and occurring with increased incidence with increasing
age (median age 64 years). The IgM in some patients with macro­
globulinemia may have specificity for myelin-associated glycoprotein
(MAG), a protein that has been associated with demyelinating disease
of the peripheral nervous system and may be lost earlier and to a
greater extent than the better-known myelin basic protein in patients
with multiple sclerosis. Sometimes patients with macroglobulinemia
develop a peripheral neuropathy, and half of these patients are positive
for anti-MAG antibody. The neuropathy may precede the appearance
of the neoplasm. The whole process may begin with a viral infection
that may elicit an antibody response that cross-reacts with a normal
tissue component.
Like myeloma, the disease involves the bone marrow, but unlike
myeloma, it does not cause bone lesions or hypercalcemia. Bone mar­
row shows >10% infiltration with lymphoplasmacytic cells (surface
IgM+, CD19+, CD20+, and CD22+, rarely CD5+, but CD10− and
CD23−) with an increase in number of mast cells. Like myeloma, an
M component is present in the serum in excess of 30 g/L (3 g/dL), but
unlike myeloma, the size of the IgM paraprotein results in little renal
excretion, and only ~20% of patients excrete light chains. Therefore,
renal disease is not common. The light chain isotype is kappa in 80% of
the cases. Patients present with weakness, fatigue, and recurrent infec­
tions similar to myeloma patients, but epistaxis, visual disturbances,
and neurologic symptoms such as peripheral neuropathy, dizziness,
headache, and transient paresis are much more common in macro­
globulinemia. Presence of MYD88 and CXCR4 mutations also affects
disease presentation. Presence of CXCR4 mutations is associated with
higher bone marrow disease burden and higher incidence of hyper­
viscosity. Patients with wild-type MYD88 show lower bone marrow
disease burden.
CHAPTER 116
Plasma Cell Disorders
Physical examination reveals adenopathy and hepatosplenomegaly,
and ophthalmoscopic examination may reveal vascular segmentation
and dilation of the retinal veins characteristic of hyperviscosity states.
Patients may have a normocytic, normochromic anemia, but rouleaux
formation and a positive Coombs test are much more common than in
myeloma. Malignant lymphocytes are usually present in the peripheral
blood. About 10% of macroglobulins are cryoglobulins. These are pure
M components and are not the mixed cryoglobulins seen in rheuma­
toid arthritis and other autoimmune diseases. Mixed cryoglobulins
are composed of IgM or IgA complexed with IgG, for which they are
specific. In both cases, Raynaud’s phenomenon and serious vascular
symptoms precipitated by the cold may occur, but mixed cryoglobu­
lins are not commonly associated with malignancy. Patients suspected
of having a cryoglobulin based on history and physical examination
should have their blood drawn into a warm syringe and delivered to the
laboratory in a container of warm water to avoid errors in quantitating
the cryoglobulin.
TREATMENT
Waldenström’s Macroglobulinemia
A diagnosis of WM requires lymphoplasmacytic infiltrate of any
level in the bone marrow and an IgM monoclonal paraprotein of
any size. Treatment is usually not initiated unless the disease is
symptomatic or increasing anemia, hyperviscosity, lymphadenopa­
thy, or hepatosplenomegaly is present. Control of serious hypervis­
cosity symptoms such as an altered state of consciousness or paresis
can be achieved acutely by plasmapheresis because 80% of the
IgM paraprotein is intravascular. The median survival of affected
individuals is ~50 months. However, many patients with WM
have indolent disease that does not require therapy. Pretreatment
parameters including older age, male sex, general symptoms, and
cytopenias define a high-risk population. BTK inhibitors (ibruti­
nib), alkylating drugs (bendamustine and cyclophosphamide), and
proteasome inhibitors (bortezomib, carfilzomib, and ixazomib),
alone or more frequently in combination with rituximab, are con­
sidered as first-line therapy for symptomatic patients with WM.
Ibrutinib targets the constitutively activated BTK. In patients with
one prior line of therapy, the overall response to ibrutinib was 91%.
Best responses to ibrutinib are observed in patients with mutated
MYD88 and wild-type CXCR4 status, while delayed and lower
response rates to ibrutinib are observed in patients with mutated
CXCR4. At first relapse, in patients with an initial durable response,
either the previous regimen or another primary therapy regimen
can be used. The therapeutic choice is dependent upon the genomic
features, drug availability, and the patient’s clinical profile.
Rituximab can produce an IgM flare, so either plasmapher­
esis should be used before rituximab or its use should be initially
withheld in patients with high IgM levels. Fludarabine (25 mg/m2
per d for 5 days every 4 weeks) is also an effective single agent.
With identification of the MYD88 mutation, novel BTK inhibitors
(acalabrutinib, zanubrutinib, and tirabrutinib), inhibitors targeting
IRAK1/4, and the BCL2 antagonist venetoclax are being explored
for the treatment of WM. HDT plus autologous transplantation has
been utilized in the past, but it is now not recommended due to the
availability of other effective agents.
PART 4
Oncology and Hematology
POEMS SYNDROME
The features of this syndrome are polyneuropathy, organomegaly,
endocrinopathy, M-protein, and skin changes (POEMS). Diagnostic
criteria are described in Table 116-1. Patients usually have a severe,
progressive sensorimotor polyneuropathy associated with sclerotic
bone lesions from myeloma. Polyneuropathy occurs in ~1.4% of
myelomas, but the POEMS syndrome is only a rare subset of that
group. Unlike typical myeloma, hepatomegaly and lymphadenopathy
occur in about two-thirds of patients, and splenomegaly is seen in onethird. The lymphadenopathy frequently resembles Castleman’s disease
histologically, a condition that has been linked to IL-6 overproduction.
The endocrine manifestations include amenorrhea in women and
impotence and gynecomastia in men. Hyperprolactinemia due to loss
of normal inhibitory control by the hypothalamus may be associated
with other central nervous system manifestations such as papilledema
and elevated cerebrospinal fluid pressure and protein. Type 2 diabetes
mellitus occurs in about one-third of patients. Hypothyroidism and
adrenal insufficiency are occasionally noted. Skin changes are diverse:
hyperpigmentation, hypertrichosis, skin thickening, and digital club­
bing. Other manifestations include peripheral edema, ascites, pleural
effusions, fever, and thrombocytosis. Not all the components of
POEMS syndrome may be present initially.
The pathogenesis of the disease is unclear, but high circulating levels
of the proinflammatory cytokines IL-1, IL-6, VEGF, and TNF have
been documented, and levels of the inhibitory cytokine transforming
growth factor β are lower than expected. Treatment of the myeloma
may result in an improvement in the other disease manifestations.
Patients are often treated similarly to those with myeloma. Plas­
mapheresis does not appear to be of benefit in POEMS syndrome.
Patients presenting with isolated sclerotic lesions may have resolution
of neuropathic symptoms after local therapy for plasmacytoma with
radiotherapy. Similar to MM, novel agents and HDT with autologous
stem cell transplantation have been pursued in selected patients and
have been associated with prolonged progression-free survival.
HEAVY CHAIN DISEASES
The heavy chain diseases are rare lymphoplasmacytic malignan­
cies. Their clinical manifestations vary with the heavy chain isotype.
Patients have absence of light chain and secrete a defective heavy chain
that usually has an intact Fc fragment and a deletion in the Fd region.
Gamma, alpha, and mu heavy chain diseases have been described,
but no reports of delta or epsilon heavy chain diseases have appeared.
Molecular biologic analysis of these tumors has revealed structural
genetic defects that may account for the aberrant chain secreted.
■
■GAMMA HEAVY CHAIN DISEASE (FRANKLIN’S
DISEASE)
This disease affects individuals of widely different age groups and
countries of origin. It is characterized by lymphadenopathy, fever,
anemia, malaise, hepatosplenomegaly, and weakness. It is frequently
associated with autoimmune diseases, especially rheumatoid arthritis.
Its most distinctive symptom is palatal edema, resulting from involve­
ment of nodes in Waldeyer’s ring, and this may progress to produce
respiratory compromise. The diagnosis depends on the demonstra­
tion of an anomalous serum M component (often <20 g/L [<2 g/dL])
that reacts with anti-IgG but not anti–light chain reagents. The M
component is typically present in both serum and urine. Most of the
paraproteins have been of the γ1 subclass, but other subclasses have
been seen. The patients may have thrombocytopenia, eosinophilia,
and nondiagnostic bone marrow that may show increased numbers of
lymphocytes or plasma cells that do not stain for light chain. Patients
usually have a rapid downhill course and die of infection; however,
some patients have survived 5 years with chemotherapy. Therapy is
indicated when symptomatic and involves chemotherapeutic combina­
tions used in low-grade lymphoma. Rituximab has also been reported
to show efficacy.
■
■ALPHA HEAVY CHAIN DISEASE
(SELIGMANN’S DISEASE)
This is the most common of the heavy chain diseases. It is closely
related to a malignancy known as Mediterranean lymphoma, a dis­
ease that affects young persons in parts of the world where intestinal
parasites are common, such as the Mediterranean, Asia, and South
America. The disease is characterized by an infiltration of the lamina
propria of the small intestine with lymphoplasmacytoid cells that
secrete truncated alpha chains. Demonstrating alpha heavy chains is
difficult because the alpha chains tend to polymerize and appear as
a smear instead of a sharp peak on electrophoretic profiles. Despite
the polymerization, hyperviscosity is not a common problem in alpha
heavy chain disease. Without J chain–facilitated dimerization, viscos­
ity does not increase dramatically. Light chains are absent from serum
and urine. The patients present with chronic diarrhea, weight loss, and
malabsorption and have extensive mesenteric and paraaortic adenopa­
thy. Respiratory tract involvement occurs rarely. Patients may vary
widely in their clinical course. Some may develop diffuse aggressive
histologies of malignant lymphoma. Chemotherapy may produce longterm remissions. Rare patients appear to have responded to antibiotic
therapy, raising the question of the etiologic role of antigenic stimula­
tion, perhaps by some chronic intestinal infection. Chemotherapy plus
antibiotics may be more effective than chemotherapy alone. IPSID is
recognized as an infectious pathogen–associated human lymphoma
associated with Campylobacter jejuni. It involves mainly the proximal
small intestine, resulting in malabsorption, diarrhea, and abdominal
pain. IPSID is associated with excessive plasma cell differentiation
and produces truncated alpha heavy chain proteins lacking the light
chains as well as the first constant domain. Early-stage IPSID responds
to antibiotics (30–70% complete remission). Most untreated IPSID
patients progress to lymphoplasmacytic and immunoblastic lym­
phoma. Patients not responding to antibiotic therapy are considered
for treatment with combination chemotherapy used to treat low-grade
lymphoma.
■
■MU HEAVY CHAIN DISEASE
The secretion of isolated mu heavy chains into the serum appears to
occur in a very rare subset of patients with CLL. The only features that
may distinguish patients with mu heavy chain disease are the presence
of vacuoles in the malignant lymphocytes and the excretion of kappa
light chains in the urine. The diagnosis requires ultracentrifugation
or gel filtration to confirm the nonreactivity of the paraprotein with
the light chain reagents because some intact macroglobulins fail to
interact with these serums. The tumor cells seem to have a defect in

47 - 117 Amyloidosis
117 Amyloidosis
the assembly of light and heavy chains because they appear to contain
both in their cytoplasm. Such patients are not treated differently from
other patients with CLL (Chap. 107).
■
■FURTHER READING
Corre J et al: Risk factors in multiple myeloma: is it time for a revision?
Blood 137:16, 2021.
Hideshima T, Anderson KC: Signaling pathway mediating myeloma
cell growth and survival. Cancers (Basel) 13:216, 2021.
Hillengass J et al: International myeloma working group consensus
recommendations on imaging in monoclonal plasma cell disorders.
Lancet Oncol 20:e302, 2019.
Kumar S et al: International Myeloma Working Group consensus crite­
ria for response and minimal residual disease assessment in multiple
myeloma. Lancet Oncol 17:e328, 2016.
Moreau P et al: Treatment of relapsed and refractory multiple
myeloma: Recommendations from the International Myeloma Work­
ing Group. Lancet Oncol 22:e105, 2021.
Munshi NC et al: A large meta-analysis establishes the role of MRD
negativity in long-term survival outcomes in patients with multiple
myeloma. Blood Adv 4:5988, 2020.
Raje NS et al: Consensus guidelines and recommendations for infec­
tion prevention in multiple myeloma: A report from the International
Myeloma Working Group. Lancet Haematol 9:e143 2022.
Rajkumar SV et al: International Myeloma Working Group updated
criteria for the diagnosis of multiple myeloma. Lancet Oncol 15:e538,
2014.
Richardson PG et al: Triplet therapy, transplantation, and mainte­
nance until progression in myeloma. N Engl J Med 387:132, 2022.
Robiou du Pont S et al: Genomics of multiple myeloma. J Clin Oncol
35:963, 2017.
Terpos E et al: Treatment of multiple myeloma-related bone disease:
Recommendations from the Bone Working Group of the Interna­
tional Myeloma Working Group. Lancet Oncol 22:e119, 2021.
Treon SP et al: How I use genomics and BTK inhibitors in the treat­
ment of Waldenstrom macroglobulinemia. Blood 143:1702, 2024.
John L. Berk, Vaishali Sanchorawala
Amyloidosis
■
■GENERAL PRINCIPLES
Amyloidosis is the term for a group of protein misfolding disorders
characterized by the extracellular deposition of insoluble polymeric
protein fibrils in tissues and organs. A robust cellular machinery exists
to chaperone proteins during the process of synthesis and secretion, to
ensure that they achieve correct tertiary conformation and function,
and to eliminate proteins that misfold. However, genetic mutation,
incorrect processing, and other factors may favor misfolding, with
consequent loss of normal protein function and intracellular or extra­
cellular aggregation. Many diseases, ranging from cystic fibrosis to
Alzheimer’s disease, are now known to involve protein misfolding.
In the amyloidoses, the aggregates are typically extracellular, and the
misfolded protein subunits assume a common antiparallel, β-pleated
sheet–rich structural conformation that leads to the formation of
higher-order oligomers and then fibrils with unique staining proper­
ties. The term amyloid was coined around 1854 by the pathologist
Rudolf Virchow, who thought that these deposits resembled starch
(Latin amylum) under the microscope.
Amyloid diseases, defined by the biochemical nature of the protein
composing the fibril deposits, are classified according to whether they
are systemic or localized, whether they are acquired or inherited, and
their clinical patterns (Table 117-1). The standard nomenclature is
AX, where A indicates amyloidosis and X represents the protein pres­
ent in the fibril. This chapter focuses primarily on the systemic forms.
AL amyloidosis refers to amyloid composed of immunoglobulin light
chains; this disorder, formerly termed primary systemic amyloidosis,
arises from a clonal B-cell or plasma cell disorder and can be associated
with myeloma or lymphoma. ATTR amyloidosis, the most prevalent
of the familial amyloidoses, refers to amyloid derived from wild-type
or mutated transthyretin (TTR), the transport protein for thyroid
hormone and retinol-binding protein. AA amyloid is composed of the
acute-phase reactant protein serum amyloid A (SAA) and occurs in the
setting of chronic inflammatory or infectious diseases; for this reason,
this type was formerly known as secondary amyloidosis. Aβ2M amyloid
results from misfolded β2-microglobulin, occurring in individuals with
long-standing renal disease who have undergone dialysis, typically for
years. Aβ, the most common form of localized amyloidosis, is found
in the brain of patients with Alzheimer’s disease after abnormal pro­
teolytic processing and aggregation of polypeptides derived from the
amyloid precursor protein.
Diagnosis and treatment of the amyloidoses rest upon the histopath­
ologic identification of amyloid deposits and immunohistochemical,
biochemical, or genetic determination of amyloid type (Fig. 117-1).
In the systemic amyloidoses, the clinically involved organs can be
biopsied, but amyloid deposits may be found in any tissue of the body.
Historically, blood vessels of the gingiva or rectal mucosa were often
examined, but the most easily accessible tissue—positive in more than
80% of patients with systemic amyloidosis—is abdominal fat. After
local anesthesia, fat is aspirated with a 16-gauge needle from the subcu­
taneous layer of the abdominal wall. Fat globules expelled onto a glass
slide can be stained for amyloid by Congo red dye, thus avoiding a sur­
gical procedure. If this material is negative, more invasive biopsies of
the involved organ like kidney, heart, liver, tongue, or gastrointestinal
tract can be considered in patients in whom amyloidosis is suspected.
The regular β-sheet structure of amyloid deposits exhibits a unique
“green” birefringence by polarized light microscopy when stained with
Congo red dye; other regular protein structures (e.g., collagen) appear
white under these conditions. The 10-nm-diameter fibrils can also be
visualized by electron microscopy of paraformaldehyde-fixed tissue.
Once amyloid is found, the precursor protein type must be determined
by immunohistochemistry, immunoelectron microscopy, or extraction
and biochemical analysis employing mass spectrometry; gene sequenc­
ing is used to identify mutants causing hereditary amyloidosis. How­
ever, a mass spectrometry–based analysis of the amyloid-containing
tissues is now considered the best approach, with a reported sensitivity
of 88% and specificity of 96%, which are higher than immunochemical
techniques, and this technique does not require a large panel of antisera
to identify non-AL amyloidosis. The patient’s history, physical find­
ings, and clinical presentation, including age and ethnic origin, organ
system involvement, underlying diseases, and family history, may pro­
vide helpful clues as to the type of amyloidosis. However, there can be
considerable overlap in clinical presentations, and accurate typing of
the amyloidogenic protein is essential to guide appropriate therapy and
offer genetic counseling as appropriate.
CHAPTER 117
Amyloidosis
The mechanisms of fibril formation and tissue toxicity remain con­
troversial. The “amyloid hypothesis,” as it is currently understood, pro­
poses that precursor proteins undergo a process of reversible unfolding
or misfolding; misfolded proteins form oligomeric aggregates, higherorder polymers, and then fibrils that deposit in tissues. Accumulating
evidence suggests that the oligomeric intermediates may constitute the
most toxic species. Oligomers are more capable than fibrils of interact­
ing with cells and inducing formation of reactive oxygen species and
stress signaling. Ultimately, the fibrillar tissue deposits are likely to
interfere with normal organ function. However, direct proteotoxicity
of the soluble oligomers also can lead to organ dysfunction. A more
sophisticated understanding of the mechanisms leading to amyloid
formation and cell and tissue dysfunction will continue to provide new
targets for therapies.
The clinical syndromes of the amyloidoses are associated with rela­
tively nonspecific alterations in routine laboratory tests. Blood counts
are usually normal, although the erythrocyte sedimentation rate is
TABLE 117-1  Amyloid Precursor Proteins and Their Clinical Syndromes
DESIGNATION
PRECURSOR
CLINICAL SYNDROME
CLINICAL INVOLVEMENT
Systemic Amyloidoses
 
 
AL
Immunoglobulin light chain
Primary or myeloma-associateda
Any
AH
Immunoglobulin heavy chain
Rare variant of primary or myeloma-associated
Any
AA
Serum amyloid A protein
Secondary; reactiveb
Renal, heart, other
Aβ2M
β2-Microglobulin
Hemodialysis-associated
Synovial tissue, bone
ATTR
Transthyretin
Familial (mutant)
Age-related (wild type)
AApoAI
Apolipoprotein AI
Familial
Hepatic, renal
AApoAII
Apolipoprotein AII
Familial
Renal
Agel
Gelsolin
Familial
Cornea, cranial nerves, skin, renal
AFib
Fibrinogen Aa
Familial
Renal, vascular
ALys
Lysozyme
Familial
Renal, hepatic
ALECT2
Leukocyte chemotactic factor 2
Undefined
Renal
Localized Amyloidoses
 
 
Aβ
Amyloid β protein
Alzheimer’s disease; Down’s syndrome
Central nervous system
ACys
Cystatin C
Cerebral amyloid angiopathy
Central nervous system, vascular
APrP
Prion protein
Spongiform encephalopathies
Central nervous system
AIAPP
Islet amyloid polypeptide (amylin)
Diabetes-associated
Pancreas
PART 4
Oncology and Hematology
Acal
Calcitonin
Medullary carcinoma of the thyroid
Thyroid
AANF
Atrial natriuretic factor
Atrial fibrillation
Cardiac atria
APro
Prolactin
Endocrinopathy
Pituitary
ASgl
Semenogelin I
Age-related; incidental autopsy or biopsy finding
Seminal vesicles
aLocalized AL deposits can occur in skin, conjunctiva, urinary bladder, and the tracheobronchial tree. bSecondary to chronic inflammation or infection or to a hereditary
periodic fever syndrome such as familial Mediterranean fever.
CLINICAL SUSPICION OF AMYLOIDOSIS
Noninvasive Tissue Biopsy
(Congo red staining of abdominal fat or other tissue)
+
–
Invasive Tissue Biopsy
(Congo red staining of affected major organs)
+
–
No further work-up
Identify
Diagnosis
Mass spectrometry or
IHC of amyloid deposits
Kappa or
lambda light
chain
AL amyloidosis
(Screen for cardiac, renal,
hepatic, autonomic involvement, and factor X deficiency)
Monoclonal protein in
serum or urine
Plasma cell dyscrasia
in bone marrow
Amyloid A
protein
Underlying chronic
inflammatory disease
AA amyloidosis
(Screen for renal,
hepatic involvement)
Transthyretin
Mutant transthyretin
+/– family history
ATTRm familial amyloidosis
(Screen for neuropathy,
cardiomyopathy; screen relatives)
Wild-type transthyretin
(usually males >65, cardiac)
ATTRwt or age-related
amyloidosis
Negative
Mutant ApoAI, ApoAII,
fibrinogen, lysozyme,
gelsolin
Familial amyloidosis of rare type
(Screen for renal, hepatic, GI
involvement)
FIGURE 117-1  Algorithm for the diagnosis of amyloidosis and determination of type. Clinical suspicion:
unexplained nephropathy, cardiomyopathy, neuropathy, enteropathy, arthropathy, and macroglossia. ApoAI,
apolipoprotein AI; ApoAII, apolipoprotein AII; GI, gastrointestinal; IHC, immunohistochemistry.
Cardiac, peripheral and autonomic nerves,
soft tissues, spine, bladder
frequently elevated. Patients with glomerular
kidney involvement generally have proteinuria,
often in the nephrotic range, leading to hypo­
albuminemia that may be severe; patients with
serum albumin levels <2 g/dL generally have
pedal edema or anasarca. Amyloid cardiomy­
opathy is characterized by concentric ventricular
hypertrophy and diastolic dysfunction associated
with elevation of brain natriuretic peptide (BNP)
or N-terminal pro–brain natriuretic peptide
(NT-proBNP) as well as troponin. These car­
diac biomarkers can be used for disease staging,
prognostication, and disease activity monitoring
in patients with AL amyloidosis. Notably, renal
insufficiency can falsely elevate levels of these bio­
markers. Biomarkers of cardiac remodeling—
that is, matrix metalloproteinases and tissue
inhibitors of metalloproteinases—are altered in
the serum of patients with amyloid cardiomy­
opathy. Electrocardiographic and echocardio­
graphic features of amyloid cardiomyopathy are
described below. Patients with liver involvement,
even when advanced, usually develop cholestasis
with an elevated alkaline phosphatase concentra­
tion with minimal alteration of the aminotrans­
ferases and preservation of synthetic function.
In AL amyloidosis, endocrine organs may be
involved, and hypothyroidism, hypoadrenalism,
or even hypopituitarism can occur. Although
none of these findings is specific for amyloidosis,
the presence of abnormalities in multiple organ
systems should raise suspicions of the diagnosis.
■
■AL AMYLOIDOSIS
Etiology and Incidence 
AL amyloidosis is
most frequently caused by a clonal expansion of
bone marrow plasma cells that secrete a monoclonal immunoglobulin
light chains forming amyloid fibrils and deposits in tissues. Whether
the clonal plasma cells produce a light chain that misfolds and leads to
AL amyloidosis or a light chain that folds properly, allowing the cells
to inexorably expand over time and develop into multiple myeloma
(Chap. 116), may depend upon primary sequence of the clonal light
chain or other genetic or epigenetic factors. AL amyloidosis can occur
with multiple myeloma or other B lymphoproliferative diseases, includ­
ing non-Hodgkin’s lymphoma (Chap. 113) and Waldenström’s macro­
globulinemia (Chap. 116). AL amyloidosis is the most common type
of systemic amyloidosis diagnosed in North America. Its incidence has
been estimated at 8–12 cases per 100,000 population; however, ascer­
tainment continues to be inadequate, and the true incidence may be
much higher. AL amyloidosis, like other plasma cell disorders, usually
occurs after age 40 and is often progressive and fatal if untreated.
Pathology and Clinical Features 
Amyloid deposits are usually
widespread in AL amyloidosis and can be present in the interstitium
of any organ outside the central nervous system. The amyloid fibril
deposits are composed of full-length 23-kDa monoclonal immuno­
globulin light chains as well as fragments. Accessory molecules codeposited with light chain fibrils (as well as with other amyloid fibrils)
include serum amyloid P component, apolipoproteins e and A-IV,
glycosaminoglycans, and metal ions. Although all kappa and lambda
light chain subtypes have been identified in AL amyloid fibrils, lambda
subtypes predominate.
AL amyloidosis is often a rapidly progressive disease that presents
as a pleiotropic set of clinical syndromes, recognition of which is key
for initiation of the appropriate workup. Nonspecific symptoms of
fatigue and weight loss are common; however, the diagnosis is rarely
considered until symptoms referable to a specific organ develop. The
kidneys are a frequently involved organ and are affected in 60–70% of
patients. Renal amyloidosis usually manifests as proteinuria, often in
the nephrotic range and associated with hypoalbuminemia, second­
ary hypercholesterolemia and hypertriglyceridemia, and edema or
anasarca. In some patients, interstitial rather than glomerular amyloid
deposition can produce azotemia without proteinuria. The heart is
the other commonly affected organ (70–80% of patients), and cardiac
involvement is the leading cause of death from AL amyloidosis. Early
on, the electrocardiogram may show low voltage in the limb leads with
a pseudo-infarct pattern. Echocardiographic features of disease include
concentrically thickened ventricles and diastolic dysfunction with an
abnormal global longitudinal strain pattern; a “sparkly” appearance
has been described but is often not seen with modern high-resolution
echocardiographic techniques. Poor atrial contractility occurs even
in sinus rhythm, and patients with cardiac amyloidosis are at risk for
development of atrial thrombi and thromboembolic complications.
Cardiac magnetic resonance imaging (MRI) can show increased wall
thickness and characteristic delayed gadolinium enhancement of the
subendocardium. Nervous system symptoms include peripheral sen­
sorimotor neuropathy and/or autonomic dysfunction manifesting as
gastrointestinal motility disturbances (early satiety, diarrhea, constipa­
tion), dry eyes and mouth, impotence, orthostatic hypotension, and/
or neurogenic bladder. Macroglossia (Fig. 117-2A), a pathognomonic
sign of AL amyloidosis, is seen in only ~10% of patients. Liver involve­
ment causes cholestasis and hepatomegaly. The spleen is frequently
involved, and there may be functional hyposplenism in the absence of
significant splenomegaly. Many patients experience “easy bruising” due
to amyloid deposits in capillaries or deficiency of clotting factor X due
to binding to amyloid fibrils; cutaneous ecchymoses appear, particularly
around the eyes, producing another uncommon but pathognomonic
finding, the “raccoon-eye” sign (Fig. 117-2B). Other findings include
nail dystrophy (Fig. 117-2C), alopecia, and amyloid arthropathy with
thickening of synovial membranes in the wrists and shoulders. The
presence of a multisystemic illness or general fatigue along with any
of these clinical syndromes should prompt a workup for amyloidosis.
Diagnosis 
Identification of an underlying clonal plasma cell or
B lymphoproliferative process and a clonal light chain are key to the
A
CHAPTER 117
B
Amyloidosis
C
FIGURE 117-2  Clinical signs of AL amyloidosis. A. Macroglossia. B. Periorbital
ecchymoses. C. Fingernail dystrophy.
diagnosis of AL amyloidosis. Serum protein electrophoresis and
urine protein electrophoresis, although of value in multiple myeloma,
are not useful screening tests if AL amyloidosis is suspected because
the clonal light chain or whole immunoglobulin often is not present in
sufficient amounts to produce a monoclonal “M-spike” in the serum
or light chain (Bence Jones) protein in the urine. However, more than
90% of patients with AL amyloidosis have serum or urine monoclonal
light chain or whole immunoglobulin detectable by immunofixation
electrophoresis of serum (SIFE) or urine (UIFE) (Fig. 117-3A) or by
nephelometric measurement of serum “free” light chains (i.e., light
chains circulating in monomeric form rather than in an immuno­
globulin tetramer with heavy chain). Examining the ratio as well as the
absolute amount of serum-free light chains is essential, as renal insuf­
ficiency reduces light chain clearance, nonspecifically elevating both
isotypes. In addition, an increased percentage of plasma cells in the
bone marrow—typically 5–30% of nucleated cells—is found in ~90%
of patients. Kappa or lambda clonality should be demonstrated by flow
cytometry, immunohistochemistry, or in situ hybridization for light
chain mRNA (Fig. 117-3B). More sensitive mass spectrometry–based
assays can have higher levels of detection for low concentration of
monoclonal protein.
A monoclonal serum protein by itself is not diagnostic of amy­
loidosis, since monoclonal gammopathy of uncertain significance is
common in older patients (Chap. 116). However, when monoclonal
gammopathy of uncertain significance is found in patients with biopsyproven amyloidosis, the AL type should be ruled out. Similarly, patients
thought to have “smoldering myeloma” because of a modest elevation
of bone-marrow plasma cells should be screened for AL amyloidosis if
A
PART 4
Oncology and Hematology
B
FIGURE 117-3  Laboratory features of AL amyloidosis. A. Serum immunofixation
electrophoresis reveals an IgGκ monoclonal protein in this example; serum
protein electrophoresis is often normal. B. Bone marrow biopsy sections stained
by immunohistochemistry with antibody to CD138 (syndecan, highly expressed
on plasma cells) (left) or by in situ hybridization with fluorescein-tagged probes
(Ventana Medical Systems) binding to κ mRNA (center) and λ mRNA (right) in
plasma cells. (Photomicrograph courtesy of C. O’Hara; with permission.)
they have signs or symptoms of renal, cardiac, or neurologic disease.
Accurate tissue amyloid typing is essential for appropriate treatment.
Immunohistochemical staining of the amyloid deposits is useful if
they selectively bind one light chain antibody in preference to the
other; some AL deposits bind antibodies nonspecifically. Commercial
antibodies used for immunohistochemistry may not be accurate in
amyloid typing. Immunoelectron microscopy is more reliable; laser
capture microdissection and tandem mass spectrometry–based typing
of the amyloid precursor protein have become the diagnostic standard.
In ambiguous cases, other forms of amyloidosis should be thoroughly
excluded with appropriate genetic and other testing.
Staging System and Risk Stratification 
The current staging
systems for systemic AL amyloidosis are based on the biomarkers of
plasma cell dyscrasia and cardiac and renal involvement. The Mayo
2004 staging system is based on the levels of NT-proBNP and cardiac
troponins and was modified by European investigators to identify
and classify very-high-risk patients. This cardiac staging system is
the most widely used to determine patient management. This staging
system was modified (Mayo 2012) to include clonal burden, assessed
by dFLC (difference between involved and uninvolved circulating free
light chain) concentration, which has independent ability to predict
survival. Boston University investigators introduced a staging system
incorporating BNP and troponin I that also is able to predict survival.
Patients with AL amyloidosis with a very low (<50 mg/L) dFLC level
have a significantly better outcome irrespective of cardiac stage. A
renal staging system based on 24-h urine protein excretion and esti­
mated glomerular filtration rate (eGFR) predicting the progression to
dialysis at 2 years has also been developed and validated. Several other
biomarkers have been shown to predict outcomes and survival but have
not been incorporated in staging systems yet.
TREATMENT
AL Amyloidosis
Extensive multisystemic involvement typifies AL amyloidosis, and
historically, the median survival without treatment was usually
only ~1–2 years from the time of diagnosis. Marked progress in the
outcome and survival has taken place over the past four decades
with advent of new therapies, increased awareness, and accurate
diagnosis. Current therapies target the clonal bone marrow plasma
cells, using approaches employed for multiple myeloma. High-dose
intravenous (IV) melphalan followed by autologous stem cell trans­
plantation (HDM/SCT) produces complete hematologic responses
in ~40% of treated patients, as determined by loss of clonal plasma
cells in the bone marrow and disappearance of the amyloidogenic
monoclonal light chain, as determined by SIFE/UIFE and free light
chain quantitation. Six to 12 months after achieving a hematologic
response, improvements in organ function and quality of life may
occur. Hematologic responses appear to be more durable after
HDM/SCT than in multiple myeloma, with remissions continuing
in some patients beyond 15 years without additional treatment.
Unfortunately, only ~20–30% of all AL amyloidosis patients are
suitable for aggressive treatment, and even at specialized treat­
ment centers, transplantation-related morbidity and mortality rates
are higher than those for other hematologic diseases because of
impaired organ function at initial presentation. Amyloid cardiomy­
opathy, poor nutritional and performance status, and multiorgan
disease contribute to excess morbidity and mortality. A bleeding
diathesis resulting from adsorption of clotting factor X to amy­
loid fibrils also increases mortality rates; however, this syndrome
occurs in only 5–10% of patients. A randomized multicenter trial
conducted in France compared oral melphalan and dexamethasone
with HDM/SCT and failed to show a benefit of dose-intensive treat­
ment, although the transplantation-related mortality rate in this
study was very high. It has become clear that careful selection of
patients and expert peritransplantation management are essential
in reducing transplantation-related complications.
The best therapy for those who are not eligible to receive
SCT is based on a U.S. Food and Drug Administration–approved
therapy of CyBorD (cyclophosphamide, bortezomib [a protea­
some inhibitor], and dexamethasone) with daratumumab. Patient
characteristics should be considered when choosing a regimen; for
example, treatment with bortezomib plus oral melphalan and dexa­
methasone (MDex) can overcome the effects of both gain of 1q21
(which confers a poorer outcome with oral melphalan) and t(11;14)
(which confers a poorer outcome with bortezomib). Transplantineligible patients in whom bortezomib is contraindicated due to
preexisting peripheral neuropathy can be treated with MDex or
combinations based on immunomodulatory drugs (e.g., lenalido­
mide or pomalidomide). High-risk patients represent ~15–20%
of all individuals with AL amyloidosis and are a challenge owing
to advanced cardiac stage (IIIb) or severe heart failure (New York
Heart Association class III or IV) as they are excluded from most
of the clinical trials.
Novel antifibril monoclonal antibodies are currently undergoing
clinical trials in combination with treatments directed against the
plasma cell dyscrasia (CyBorD plus daratumumab [anti-CD38]) in
patients with newly diagnosed AL amyloidosis. Clinical trials are
essential in improving therapy for this rare disease.
Supportive care is important for patients with any type of amy­
loidosis. For nephrotic syndrome, diuretics and support stockings
can ameliorate edema; angiotensin-converting enzyme inhibitors
should be used with caution and have not been shown to slow
renal disease progression. Effective diuresis can be facilitated with
albumin infusions to raise intravascular oncotic pressure. Conges­
tive heart failure due to amyloid cardiomyopathy is best treated
with diuretics; it is important to note that digitalis, calcium channel
blockers, and beta blockers are relatively contraindicated as they
can interact with amyloid fibrils and produce heart block and wors­
ening heart failure. Amiodarone has been used for atrial and ven­
tricular arrhythmias. Automatic implantable defibrillators appear
to have reduced effectiveness due to the thickened myocardium,
but they may benefit some patients. Atrial ablation is an effective
approach for atrial fibrillation. For conduction abnormalities, ven­
tricular pacing may be indicated. Atrial contractile dysfunction is
common in amyloid cardiomyopathy and associated with increased
thromboembolic complications, prompting considerations of anti­
coagulation even in the absence of atrial fibrillation. Autonomic
neuropathy can be treated with α agonists such as midodrine to
support postural blood pressure; gastrointestinal dysfunction may
respond to motility or bulk agents. Nutritional supplementation,
either oral or parenteral, is also important.
In localized AL amyloidosis, amyloid deposits can be produced
by clonal plasma cells infiltrating local sites in the airways, bladder,
skin, or lymph nodes (Table 117-1). These deposits may respond to
surgical intervention or elimination of the responsible plasma cell
clone by low-dose radiation therapy (typically only 20 Gy); systemic
treatment generally is not appropriate. Patients should be referred
to a center familiar with management of these rare manifestations
of amyloidosis.
■
■AA AMYLOIDOSIS
Etiology and Incidence 
AA amyloidosis can occur in association
with almost any chronic inflammatory state (e.g., rheumatoid arthritis,
inflammatory bowel disease, ankylosing spondylitis, familial Medi­
terranean fever [Chap. 381], or other periodic fever syndromes) or
chronic infections such as tuberculosis, osteomyelitis, or subacute bac­
terial endocarditis. In the United States and Europe, AA amyloidosis
has become less common, occurring in fewer than 2% of patients with
these diseases, presumably because of advances in anti-inflammatory
and antimicrobial therapies. It has also been described in associa­
tion with Castleman’s disease, lymphomas, and renal cell carcinoma,
emphasizing the diagnostic importance of computed tomography (CT)
scanning to look for such tumors as well as serologic and microbiologic
studies. In up to 20% of patients, AA amyloidosis can also be seen with­
out any identifiable underlying disease.
Pathology and Clinical Features 
Organ involvement in AA
amyloidosis usually begins in the kidneys. Hepatomegaly, splenomeg­
aly, and autonomic neuropathy can also occur as the disease progresses;
cardiomyopathy is a late manifestation in ~10–25% of patients. The
symptoms and signs of AA disease cannot be reliably distinguished
from those of AL amyloidosis. AA amyloid fibrils are usually composed
of an 8-kDa, 76-amino-acid N-terminal portion of the 12-kDa precur­
sor protein SAA. This acute-phase protein is synthesized in the liver
and transported by high-density lipoprotein (HDL3) in the plasma.
Several years of an underlying inflammatory disease causing chronic
elevation of SAA levels usually precede fibril formation, although
infections can lead to AA amyloid deposition more rapidly.
TREATMENT
AA Amyloidosis
Primary therapy for AA amyloidosis consists of treatment of the
underlying inflammatory or infectious disease. Treatment that sup­
presses or eliminates the inflammatory state or infection decreases
the circulating levels of SAA, slowing the rate of amyloid fibril
formation. For familial Mediterranean fever, colchicine at a dose
of 1.2–1.8 mg/d is the standard treatment. However, colchicine has
not been helpful for AA amyloidosis of other causes or for other
amyloidoses. Tumor necrosis factor and interleukin 1 and inter­
leukin 6 antagonists can effectively interrupt cytokine signaling
that drives many inflammatory syndromes, inhibiting hepatic SAA
production and limiting AA amyloid deposition. Development of a
fibril-specific agent (eprodisate) that interferes with the interaction
of serum amyloid A protein and glycosaminoglycans to prevent or
disrupt fibril formation failed in phase 3 trials.
■
■ATTR AND OTHER HEREDITARY AMYLOIDOSES
The familial amyloidoses are autosomal dominant diseases in which
mutated or variant plasma proteins misfold or aggregate to form betasheet rich amyloid deposits. These diseases are rare, with an estimated
case incidence of <1/100,000 population in the United States, although
founder effects in remote areas of Portugal, Sweden, and Japan pro­
duce a higher local prevalence of disease. The most prevalent form
of hereditary amyloidosis arises from mutation of the abundant liverderived plasma protein transthyretin (TTR, also known as prealbumin)
and is termed ATTR variant (ATTRv) amyloid. More than 130 TTR
mutations typically conferring one-amino-acid substitutions have been
described, with most inducing clinical ATTR amyloid disease. Toxic
TTR oligomers and ATTR amyloid deposits target peripheral and auto­
nomic nervous systems and the heart. One TTR variant, V122I, occurs
in nearly 4% of the African-American and Afro-Caribbean populations
and is associated with late-onset cardiac amyloidosis. The actual inci­
dence and penetrance of disease in the African-American population
are the subject of ongoing research, but consideration of V122I ATTR
amyloidosis is warranted in African-American patients who present
with concentric cardiac hypertrophy and evidence of diastolic heart
failure, particularly in the absence of a history of hypertension or
valvular disease. Other familial amyloidoses, caused by variant apoli­
poproteins AI or AII, gelsolin, fibrinogen Aα, or lysozyme, are reported
with lower prevalence worldwide. New amyloidogenic serum proteins
continue to be identified periodically, including leukocyte chemotactic
factor LECT2, which is a cause of renal amyloidosis in Hispanic and
Pakistani populations. Although the clustering of ALECT2 cases sug­
gests heritability, no LECT2 gene-coding sequence variations have
been identified.
CHAPTER 117
Amyloidosis
Normal (wild-type) transthyretin can also misfold and aggregate to
form ATTR amyloid, principally expressed in men beginning in the
seventh decade with increasing prevalence with age. Formerly termed
senile systemic amyloidosis, ATTRwt amyloid is reported at autopsy in
25% of hearts from male patients who are 80 years and older. Although
it is unclear why a wild-type protein becomes amyloidogenic, aging
inefficiencies of intracellular quality-assurance mechanisms (termed
the unfolded protein response) likely predispose to secretion of pro­
teins prone to misaggregation. Due to the numbers of aging men
globally, ATTRwt is the most prevalent and rapidly growing form of
amyloidosis in the world today. Data to date characterize ATTRwt
amyloidosis as a disease of aging, not inheritance.
Clinical Features and Diagnosis 
ATTRv amyloidosis has varied
presentations predicted by the specific TTR mutation. Consequently,
kindreds typically express similar disease timing and clinical course.
Apparent sporadic presentations (no recognized family history) often
reflect incomplete penetrance of the TTR mutation and not a sponta­
neous event. ATTRv amyloidosis presents as familial amyloidotic poly­
neuropathy (nerve damage) or familial amyloidotic cardiomyopathy
(heart damage), although the majority of cases exhibit multiorgan dis­
ease. Peripheral neuropathy begins as a length-dependent small-fiber
sensorimotor neuropathy first exhibited in the feet with ascending
progression to the upper extremities. Autonomic neuropathy manifests
as smooth muscle dysmotility (dysphagia, diarrhea, urinary retention),
vascular dysregulation (orthostatic hypotension, erectile dysfunction),
and anhidrosis. Soft tissue disease (carpal tunnel syndrome, tendi­
nopathy, and spinal stenosis) commonly precedes nerve or heart mani­
festations of disease by one to two decades, particularly in ATTRwt
amyloid patients who frequently report bicipital, patellar, or Achilles
tendon rupture. Less common expressions of ATTRv include vitreous
opacities and leptomeningeal amyloid deposition from variant protein
produced by the retinal epithelium and choroid plexus, respectively.
ATTR amyloid involvement of the heart is clinically better tolerated
than AL amyloid cardiomyopathy as reflected by both the time from
heart failure presentation to death in untreated cases of ATTR (median
42–48 months) versus AL (median 6 months) amyloidosis, and the
dramatically greater burden of disease by echocardiographic measures
at symptomatic presentation.
Typical syndromes associated with non-ATTR forms of hereditary
(AF) disease include renal amyloidosis with mutant fibrinogen, lyso­
zyme, or apolipoproteins; hepatic amyloidosis with apolipoprotein AI;
and amyloidosis of cranial neuropathy with corneal lattice dystrophy
pathognomonic of gelsolin (Finnish) amyloidosis. Patients with AF
amyloidosis can present with clinical syndromes that mimic those of
patients with AL disease. Rarely, AF carriers can develop AL disease or
AF patients may have monoclonal gammopathy without AL. Thus, it
is important to screen for plasma cell disorders and for protein muta­
tions in patients with amyloidosis. Although mass spectrometry often
detects amino acid sequence variations, it is not designed to definitively
identify specific protein variations; DNA sequencing is the diagnostic
standard for AF mutations.
TREATMENT
ATTR Amyloidosis
PART 4
Oncology and Hematology
Untreated, survival after onset of ATTR disease is 4–15 years
depending on whether the disease affects primarily the heart or
nervous system, respectively. To date, therapeutic strategies used
to control ATTR amyloidosis include: (1) orthotopic liver trans­
plantation (OLT) to replace the factory of the mutated protein
(only applicable to ATTRv); (2) stabilization of circulating TTR
tetramers, preventing TTR monomer release and amyloid fibril
formation; and (3) TTR gene silencing (RNA interference or anti­
sense oligonucleotide agents), suppressing hepatic TTR production
and subsequent ATTR fibril formation. After nearly 30 years as
the principal treatment, OLT is now rarely employed, limited to
patients with ATTRv amyloid, early peripheral neuropathy (V30M
ATTR), and minimal systemic amyloid burden. Patients with more
extensive amyloid (late V30M and non-V30M TTR mutations)
who undergo OLT often suffer posttransplant disease progression
due to allograft wild-type ATTR complexing on preexisting amy­
loid deposits. The TTR small-molecule thyroxine mimetic agents,
diflunisal and tafamidis, bind to the kinetically stable tetrameric
TTR conformation, limiting release and misfolding of monomeric
protein, which is the critical step in TTR amyloidogenesis. Inter­
national phase 3 randomized controlled trials demonstrate that
TTR stabilizers slow but infrequently stop progression of ATTR
polyneuropathy (diflunisal) and cardiomyopathy (tafamidis). TTR
gene silencers (patisiran, inotersen, vutrisiran, eplontersen) more
reliably halt neurologic disease progression by minimizing produc­
tion of the amyloidogenic protein by the liver. Indeed, 35–60%
of treated patients with familial amyloid polyneuropathy exhibit
improved sensory nerve deficits, a novel finding. Therapeutic drug
trials are underway to examine the safety, tolerability, and effective­
ness of TTR gene silencers for ATTR cardiomyopathy. Preliminary
data suggest TTR gene silencers may promote heart remodeling
and improve systolic function in patients with wild type and variant
ATTR amyloid cardiomyopathy.
Future clinical trials are set to examine the applicability of (1)
one-time CRISPR/cas9 gene editing or (2) ATTR amyloid-depleting
antibodies in patients with either ATTR polyneuropathy or cardio­
myopathy. These antibodies are designed to recognize and bind
nonnative (misfolded) TTR epitopes, mobilizing macrophages and
monocytes to disrupt existing amyloid deposits. Whether disrupt­
ing amyloid deposits renews heart and nerve function will be deter­
mined by the outcome of these pivotal trials.
The extraordinary pace of drug development harnessing cuttingedge science in this orphan disease has extended survival and
improved quality of life. Ironically, these advances expose pre­
viously unrecognized leptomeningeal (brain) and vitreous (eye)
ATTR disease due to their occurrence late in disease, highlighting
the unmet need for effective amyloid treatments that penetrate the
blood-brain barrier.
■
■Aa2M AMYLOIDOSIS
Aβ2M amyloid is composed of β2-microglobulin, the invariant chain
of class I human leukocyte antigens, and produces rheumatologic
manifestations in patients undergoing long-term hemodialysis and,
rarely, in patients with a hereditary form of disease. β2-Microglobulin
is excreted by the kidney, and levels become elevated in end-stage renal
disease. The molecular mass of β2M is 11.8 kDa—above the cutoff of
some dialysis membranes. The incidence of this disease appears to be
declining with the use of newer membranes in high-flow dialysis tech­
niques. Aβ2M amyloidosis usually presents as carpal tunnel syndrome,
persistent joint effusions, spondyloarthropathy, or cystic bone lesions.
Carpal tunnel syndrome is often the first symptom. In the past, persis­
tent joint effusions accompanied by mild discomfort were found in up
to 50% of patients who had undergone dialysis for >12 years. Involve­
ment is bilateral, and large joints (shoulders, knees, wrists, and hips)
are most frequently affected. The synovial fluid is noninflammatory,
and β2M amyloid can be found if the sediment is stained with Congo
red. Although less common, visceral β2M amyloid deposits do occa­
sionally occur in the gastrointestinal tract, heart, tendons, and subcu­
taneous tissues of the buttocks. There are no proven specific therapies
for Aβ2M amyloidosis, but cessation of dialysis after renal allografting
may lead to symptomatic improvement.
SUMMARY
A diagnosis of amyloidosis should be considered in patients with
unexplained nephropathy, cardiomyopathy (particularly with diastolic
dysfunction), neuropathy (either peripheral or autonomic), enter­
opathy, or the pathognomonic soft tissue findings of macroglossia or
periorbital ecchymoses. Pathologic identification of amyloid fibrils can
be made with Congo red staining of aspirated abdominal fat or of an
involved-organ biopsy specimen. Accurate typing by a combination of
immunologic, biochemical, and genetic testing is essential in select­
ing appropriate therapy (Fig. 117-1). Systemic amyloidosis should be
considered a treatable condition, as anti–plasma cell chemotherapy
is highly effective in AL disease and targeted therapies are being
developed for AA and ATTR disease. The combination of precursor
and end-organ amyloid therapeutics potentially provides not only dis­
ease control but also functional and quality-of-life improvements for
patients with amyloidosis. Tertiary referral centers can provide special­
ized diagnostic techniques and access to clinical trials for patients with
these rare diseases.
■
■FURTHER READING
Adams D et al: Efficacy and safety of vutrisiran for patients with
hereditary transthyretin-mediated amyloidosis with polyneuropathy:
A randomized clinical trial. Amyloid 30:1, 2023.
Coelho T et al: Eplontersen for hereditary transthyretin amyloidosis
with polyneuropathy. JAMA 330:1448, 2023.
Griffin JM et al: ATTR amyloidosis: Current and emerging man­
agement strategies: JACC: CardioOncology state-of-the-art review.
JACC CardioOncol 3:488, 2021.
Gustine JN et al: Predictors of hematologic response and survival with
stem cell transplantation in AL amyloidosis: A 25-year longitudinal
study. Am J Hematol 97:1189, 2022.
Kastritis E et al: Daratumumab-based treatment for immunoglobulin
light-chain amyloidosis. N Engl J Med 385:46, 2021.
Maurer MS et al: Patisiran treatment in patients with transthyretin
cardiac amyloidosis. N Engl J Med 389:1553, 2023.
Merlini G et al: Systemic immunoglobulin light chain amyloidosis.
Nat Rev Dis Primers 4:38, 2018.
Staron A et al: Marked progress in AL amyloidosis survival: A 40-year
longitudinal natural history study. Blood Cancer J 11:139, 2021.

48 - 118 Transfusion Therapy and Biology
118 Transfusion Therapy and Biology
Pierre Tiberghien, Olivier Garraud,
Jacques Chiaroni
Transfusion Therapy
and Biology
Transfusion encompasses the use of blood components (BCs) to pre­
vent or treat anemia, hemorrhage, and bleeding disorders. Occasion­
ally, BCs may be used to treat infection or relapse of malignant blood
diseases after allogeneic hematopoietic transplantation. BCs comprise
mainly red blood cell concentrates (RBCCs), platelet concentrates
(PCs), and plasma for transfusion use as opposed to plasma fraction­
ated into medicinal products (such as immunoglobulin, albumin, and
clotting factors). Alongside transfusion safety, ensuring BC quality,
assessing in vivo efficacy, and promoting evidence-based transfusion
practices are critical aspects of transfusion medicine.
Donor medicine does not fall within the scope of this chapter.
While particularly safe, blood donations can cause adverse reactions,
among which are fainting reactions and iron deficiency. These reac­
tions require preventive approaches and appropriate treatment when
needed.
BLOOD COMPONENTS
BC collection and manufacturing processes are described in
Table 118-1. BCs are collected as whole blood or directly as com­
ponents by apheresis. The vast majority of BCs are homologous.
Autologous BCs, collected ahead of planned surgery, are now excep­
tional as they present little to no advantage over homologous BCs.
Nevertheless, such donation may still be of benefit in the presence
of a rare blood group phenotype.
All BCs comply with common quality and performance standards
and guidelines. Quality assurance encompasses well-defined process­
ing steps and stringent BC quality controls as defined by health author­
ities. Reporting of adverse reactions and events associated with blood
collection, BC processing, and transfusion is highly recommended.
With the obvious exception of granulocyte concentrates and mono­
nuclear cells, most BCs are now leukocyte-reduced, and universal
prestorage leukocyte reduction has been recommended. These BCs
contain <1–5.106 donor leukocytes and are associated with reduced
incidence of febrile nonhemolytic transfusion reactions (FNHTRs),
infections with intracellular pathogens such as cytomegalovirus
(CMV), alloimmunization, and immunomodulation.
BCs may undergo additional processing steps. These include irra­
diation to prevent graft-versus-host disease (GVHD) in immunosup­
pressed patients, pathogen reduction to further reduce the risk of
transfusion-transmitted infections, plasma reduction in patients with
severe allergic reactions to BCs, or the manufacturing of specific units
for young children, neonates, or intrauterine transfusion.
BC constituents undergo centrifugation and filtration and are placed
in contact with needles, plastic tubing, and bags, as well as anticoagu­
lants and various additive solutions. BCs are subjected to gas exchanges
that are significantly different from aerobic breathing and are main­
tained at temperatures that are not physiologic, such as 22°C or 4°C. Any
of these elements may contribute to so-called “storage lesions” and to the
presence of bioactive molecules such extracellular vesicles and cell-free
mitochondrial DNA in the BC. The clinical impact of such lesions is still
under investigation with currently no consensus on this issue.
Furthermore, plasma present in BCs contains donor antibodies
(Abs). When directed toward antigens (Ags) present in the recipient,
such as blood group or tissue (human leukocyte antigen [HLA]) Ags,
such Abs may result in adverse events. RBCCs bring only a limited
amount of donor plasma (10–30 mL), unlike PCs and obviously
plasma. The use of platelet additive solution can replace two-thirds of
plasma in PCs, while still leaving the equivalent of one plasma unit of
200 mL per transfused PC.
BLOOD GROUP ANTIGENS AND
ANTIBODIES
Red blood cells (RBCs), as well as other blood constituents such as
platelets and neutrophils, express allogeneic determinants. Transfu­
sion may therefore result in alloimmunization and the production of
alloantibodies (alloAbs). These alloAbs comprise anti-RBC Abs, antiHLA, anti-human platelet Ag (HPA) Abs, and anti-human neutrophil
Ag (HNA) Abs. Anti-RBC immunization may result in hemolysis,
whereas anti-HLA or anti-HPA Abs may result in complications such
as fever and platelet transfusion refractoriness. Furthermore, antiHLA and anti-HNA immunization in the donor may result in a severe
lung disorder called transfusion-related acute lung injury (TRALI).
The Abs against red cell Ags may be IgM or IgG immunoglobulin
classes. Some IgG or IgM can activate complement, and some IgG,
crossing the placental barrier, may induce hemolytic disease of the
fetus and newborn.
Erythrocyte blood groups refer to antigenic molecules that are
expressed on the surface of RBC and other cells, genetically trans­
mitted, and recognized by specific Abs. The polymorphism of such
molecules explains their immunizing potential in situations such as
transfusion, pregnancy, and transplantation. Blood groups can also
interact with the environment and with infectious pathogens, leading
to individual susceptibilities. For example, malaria is less severe in type
O than non-O patients. Currently, ~390 different blood group Ags
have been described, classified within ~45 different systems. Blood
group Ags belong to two broad categories based on their biochemical
nature: carbohydrate blood groups and protein blood groups. RBC Ags
may be the target of autoantibodies (autoAbs) generating autoimmune
hemolytic anemia. Some of them, mostly IgG, are active at 37°C, called
“warm autoAbs,” and are most often directed against Rh Ags, whereas
others, most often IgM, are active at 4°C, called “cold autoAbs,” and
may be directed against ABO, HI, I, i, P, and other Ags.
CHAPTER 118
Transfusion Therapy and Biology
Carbohydrate blood groups are headed by the ABO system, which
comprises two main Ags, A and B, encoded by two alleles, which are
the A and B alleles, respectively. In addition to these active alleles,
there is an inactive allele: O. Depending on the genotype, four different
phenotypes are produced (Table 118-2). Other carbohydrate systems
(H, P1PK, Lewis, I, GLOB and SID) share many characteristics with
the ABO system. The A allele encodes the A enzyme, which binds the
A-type sugar (GalNac) A to the H substrate (expressed by action of
the H enzyme encoded by the H allele, which happens to be inactive
in the Bombay phenotype); sugars are attached to protein substrates on
the surface of the RBC and so forth.
Carbohydrate Ags are ubiquitously distributed in the body. The
ABO Ags, expressed on endothelial cells, are genuine “tissue” groups
and may be involved in graft rejection. These Ags are not specific to
humans but are shared by many species including viruses and bacteria.
The presence of A and B Ags in the environment and, in particular,
on the bacteria of the microbiota explains the synthesis of so-called
“natural” or “regular” Abs, aside from any transfusion or pregnancy.
Such Abs have a major hemolytic capacity as they bind complement
and activate its cascade up to the membrane attack complex. This
imposes donor-recipient stringent compatibility rules for RBCCs and
whole blood transfusion and, albeit less stringently, for plasma and PC
transfusion.
Protein blood groups are headed by the Rh system for RBCs
(Table 118-3). As these Ags are specific to humans, the occurrence
of immunization can only occur upon allogeneic stimulation. Abs
directed against Ags of RBC groups other than ABO must be detected
before RBCC transfusion or transplantation and during pregnancy. Of
the 45 RBC group systems described, five (Rh, Kell, Duffy, Kidd, and
MNS) are routinely investigated due to the clinical significance of Abs
and their frequency. Testing for all five types ensures routine transfu­
sion compatibility of 95%.
The Rh system comprises nearly 56 Ags, the most immunogenic of
which is the D Ag (RH1). The Rh system has two RH∗D and RH∗CE
genes located on chromosome 1. The RH∗D gene codes for the RhD
protein expressing the D Ag (RH1) present in 85%, 93%, and >99%
TABLE 118-1  Blood Components: Collection and Manufacturing Processes
ADDITIONAL
COMPONENT
PROCESSING (OPTIONAL
TO MANDATORY)
RATIONALE
BLOOD OR APHERESIS
COLLECTION AND INITIAL
PROCESSING
BLOOD
COMPONENT
Whole blood collection:
Separation into RBCC and
platelet-rich plasma (PRP) by
slow centrifugation, followed
by high-speed centrifugation
of the PRP to yield one unit
of platelets (most often
subsequently pooled) and one
unit of plasma.
or
RBCC from whole
blood or from
apheresis
Leukocyte reduction
Deleukocytation to
<1–5.106 leukocytes
per unit (highly
recommended): initial
whole blood filtration or
RBC elective filtration
(highly recommended)
Irradiation: X-ray or
gamma, ~25–35 Gy; most
often units not older than
28 days after collection
Separation into a RBCC, a
plasma, and a “buffy coat”
containing leukocytes and
platelets by high-speed
centrifugation, followed by
pooling and slow-speed
centrifugation of the buffy coat
to produce a pooled platelet
unit. Alternatively, the buffy
coat may undergo high-speed
centrifugation to produce a
granulocyte unit that will be
subsequently pooled.
Apheresis collection:
Various apheresis devices
allow for the collection of BCs
either as individual BCs such
as plasma or PC (possibly
double, such as double RBCC)
or combined BCs, such as PC
and plasma, or RBCC, platelets,
and plasma.
Plasma reduction
Prevention of allergic
reactions in patients with
prior severe transfusion
reactions
Pediatric preparation
Adjustment to low-weight
recipients
Cryopreservation
(glycerol)
PART 4
Oncology and Hematology
PC from whole
blood (individual
units or pools of
4–6 units of ABO
identical units) or
from apheresis
Suspension in a platelet
additive solution (PAS).
PAS contains ingredients
such as acetate,
potassium, phosphate,
and magnesium to sustain
platelet storage
Leukocyte reduction
(<1–5.106 leukocytes
per unit) (highly
recommended): initial
whole blood filtration or
PC elective filtration
Pathogen reduction:
Most often nucleic acid
cross-linker and/or UV
illumination
Volume reduction
Prevention of allergic
reactions in patients with
prior severe reactions
Irradiation: X-ray or
gamma, ~25–35 Gy; in
general, on bags no
older than 3 days after
collection
Pediatric
Volume and content adjustment  
 
Cryopreservation (DMSO)
To ensure continuous
availability in remote locations
To ensure availability of
platelets with rare HPA groups
Plasma from whole
blood or from
apheresis
Cryopreservation at –18°C
(most often)
VOLUME AND
CONTENT
STORAGE CONDITIONS
AND DURATION
Reduction of fever and chills
Reduction of intracellular
pathogens (including CMV)
Reduction of
alloimmunization
250–300 mL (including
additive solution, no
more than 40–50 mL of
plasma)
Hemoglobin: 22–40 g/dL
Hematocrit: 50–70%
Hemolysis ≤0.8% at
issuing
4 +/– 2°C
Duration depends on the
additive solution:
25–42 days
After irradiation: 24 h
After plasma reduction:
24 h to 10 days depending
on reduction methodology
GVHD prevention in
immunosuppressed patients
or intrafamily transfusions
 
 
Lesser volume, 10%
reduction in RBC
content
 
Adjusted content
 
Most often to ensure
availability of RBCCs with
a rare blood group for
immunized “public-negative”
recipients or recipients with
complex alloimmunizationsa
Same Hb content
Hematocrit: 40–80%
Glycerol ≤1 g
N2 or –80°C electric
freeze drying
N2: unlimited; –80°C:
30 years
7 days after thawing
in suitable additive
solutions, 24 h without
additive solution
Reduction of fever and chills
Plasma orientation toward
fractionation
From 100 to 700 mL
≥2.1011 platelets
pH ≥6.4
At 20–24°C and under
permanent motion:
3–7 days
or
At 4°C without motion:
up to 14–21 days
If irradiated: <24 h
Reduction of fever and chills
Reduction of intracellular
pathogens (including CMV
infections)
Reduction of
alloimmunization
 
 
Reduction of transfusiontransmitted infections
Prevention of GVHD
 
 
 
 
Prevention of GVHD
 
 
 
6 h after thawing
(depending on
cryopreservation
procedure, may be
resuspended in plasma)
Shelf-life extension
200–300 mL
Coagulation factors,
including fibrinogen
(≥2 g/L), factor VIII
(≥0.5 IU/mL), protein C
and S, antithrombin
1–2 years if
cryopreserved
Up to 28 days if kept
unfrozen
(Continued)
TABLE 118-1  Blood Components: Collection and Manufacturing Processes
ADDITIONAL
COMPONENT
PROCESSING (OPTIONAL
TO MANDATORY)
RATIONALE
BLOOD OR APHERESIS
COLLECTION AND INITIAL
PROCESSING
BLOOD
COMPONENT
Leukocyte reduction
(<1–5.106 leukocytes per
product): Initial whole
blood filtration and/or
plasma elective filtration
Pathogen reduction:
Nucleic acid cross-linker
and/or UV illumination
or solvent detergent
treatment (most often on
pooled products)
Lyophilization
To facilitate transportation
and storage, as well as
immediate availability, in
remote locations
Granulocyte
concentrates from
whole blood (pools
of 10–20 ABOidentical units) or
from apheresisb
Irradiation (mandatory)
Prevention of GVHD
≤650 mL
≤2.1010 granulocytes
Whole blood
Leukocyte reduction with
a platelet-sparing device
Peripheral blood
mononuclear cells
(apheresis)
May undergo
cryopreservation (N2)
Cryoprecipitate
(collected after
thawing and
centrifugation of
plasma)
Resuspension in
plasma (10–15 mL) and
cryopreservation
aAntigen frequency below 1% to 1/1000 of the population and contraindication for using regular blood units, depending on country-specific regulations. bGranulocyte
collection by apheresis requires donor preadministration of steroids and/or hematopoietic growth factor and exposure to heparin and hydroxyethyl starch during the
apheresis procedure.
Abbreviations: BC, blood component; CMV, cytomegalovirus; DMSO, dimethyl sulfoxide; GVHD, graft-versus-host disease; Hb, hemoglobin; HPA, human platelet antigen;
N2, nitrogen gas; N/A, not applicable; RBC, red blood cell; RBCC, red blood cell concentrate; PC, platelet concentrate; UV, ultraviolet.
of individuals of Caucasian, African, and Asian ancestry, respectively.
The RH∗CE gene codes for RhCE proteins expressing C (RH2) and/
or c (RH4), and E (RH3) and/or e (RH4) Ags. The presence of the
D Ag confers Rh “positivity,” while its absence confers Rh “negativ­
ity.” The RH∗D and RH∗CE genes determine eight main haplotypes
(DCe, DcE, Dce, DCE, dce, dCe, dcE, and dCE) whose frequencies
TABLE 118-2  ABO Blood Groups and Antibodies: Transfusion Compatibility
GENOTYPE(S)
ENZYME(S)/IMMUNODOMINANT SUGAR(S)
PHENOTYPE
A/A or A/O
“A” transferase/N-acetylgalactosamine
(GalNac)
A
Anti-B
A or O
A, 0b, Bb, or ABb
A or A,B
B/B or B/O
“B” transferase/galactose (Gal)
B
Anti-A
B or O
B, O, Ab, or ABb
B or A,B
A/B
“A” transferase and “B” transferase
GalNac and Gal
A,B
None
A,B or A or B or O
A,B, Ob, or Ab or Bb
A,B
O/O
Inactive
Unconverted H antigen
O
Anti-A and Anti-B O
0, A, B, or A,B
A or B or A,B or O
aOrder of priority. bWithout high-titer anti-A and/or anti-B antibody.
Abbreviations: PC, platelet concentrate; RBCC, red blood cell concentrate.
(Continued)
VOLUME AND
CONTENT
STORAGE CONDITIONS
AND DURATION
Reduction of fever and chills
Reduction of intracellular
pathogens (including CMV)
Reduction of
alloimmunization
 
 
Reduction of transfusiontransmitted infections
 
 
 
 
Room temperature
≤24 h after the end of
collection
CHAPTER 118
Reduction of posttransfusion
fever and chills
Reduction of intracellular
pathogens (including CMV)
Reduction of
alloimmunization
~520 mL (including
additive solution)
At 2–4°C
21–35 days
Transfusion Therapy and Biology
Increased practicability
Repeated administration
Number of cells
adjusted for a
predetermined number
of T lymphocytes
105–107 CD3+ cells/
recipient kg
N2: unlimited
Never frozen or thawed:
<6 h
N/A
Cold-insoluble plasma
proteins (fibrinogen,
factor VIII, von
Willebrand factor)
12 months
After thawing, may be
stored at 20–24°C for up
to 6 h
differ considerably among different geographical populations. The
high diversity of the Rh Ags includes weak and/or partial expression.
Identifying individuals (especially young females of childbearing
potential and multitransfused patients) with a weak or partial D Ag is
important to adequately select D-positive or -negative RBCs. Molecu­
lar biology is now routinely applied to resolve such situations.
TRANSFUSION COMPATIBILITY REQUIREMENTS
NATURAL
ANTIBODIES
RBCC
PCa
PLASMA
TABLE 118-3  Red Blood Cell Group Systems and Antibodies: Clinical Significance and Transfusion Recommendations
ISBT NO./
SYSTEM
SYMBOL/GENE(S)
ANTIGENS
(NO.)
MAIN ANTIBODIES
(ANTI-)
1/ABO
ABO/ABO
A, B
None to severe; immediate
and/or delayed
2/MNS
MNS/GYPA, GYPB,
(GYPE)
M
None (except in extremely
rare cases if active at 37°C)
N
None (may be
clinically significant
in the case of the rare
N–S–s–U– phenotype)
S, s
None to moderate (rare)
None to severe (rare)
Ag-negative RBCC
U
Mild to severe
Mild to severe (one
reported case requiring an
intrauterine transfusion)
3/P1PK
P1PK/A4GALT
P1
None to moderate; delayed
(rare)
P1, Pk, P (Tja)
None to severe
None to severe
Ag-negative RBCC
4/Rh
RH/RHD, RHCE
D, C, E, c, e
Mild to severe; immediate
or delayed
PART 4
Oncology and Hematology
6 /Kell
KEL/KEL
K
Mild to severe; delayed
Mild to severe (rare)
Ag-negative RBCC
7/Lewis
LE/FUT3
Lea, Leb
None (rare cases of
hemolytic reactions)
8/Duffy
FY/ACKR1
Fya, Fyb
Mild to severe (rare);
immediate/delayed
Fy3, Fy5
Mild to moderate;
immediate (rare)/delayed
9/Kidd
JK/SLC14A1
Jka, Jkb
None to severe; immediate
or delayed
Jk3
None to severe; immediate
or delayed
18/H
H/FUT1
H (Bombay)
None to severe; immediate/
delayed
20/Globoside
GLOB/B3GALNT1
P
None to severe
None to mild
Ag-negative RBCC
Abbreviations: Ab, antibody; Ag, antigen; HDFN, hemolytic disease of the fetus and newborn; IAT, indirect antiglobulin test (indirect Coombs test); ISBT, International Society
of Blood Transfusion; RBCC, red blood cell concentrate.
The Kell system comprises 38 Ags, one of which is routinely deter­
mined: the K antigen (KEL1); 9% and 2% of individuals of Caucasian
and African ancestry are K positive (KEL:1), respectively, whereas 91%
and 98%, respectively, are K negative (KEL:–1). The immunogenicity
of Kell is third behind the ABO and Rh systems. The Kell protein is
linked to another blood group protein called Kx. The rare absence of
this protein (controlled by a gene on X) is associated with a weak KEL
Ag, acanthocytosis, shortened RBC survival, and a progressive form of
muscular dystrophy that includes cardiac defects. This rare condition
is called the McLeod phenotype.
The Duffy system (FY) comprises five Ags, two of which are rou­
tinely tested: the Fya Ag (FY1), coded by the Fya allele, and the Fyb
Ag (FY2), coded by the Fyb allele. Depending on the combination of
alleles, three common phenotypes are expected: Fy (a+b+), which has
the two alleles Fya and Fyb; Fy (a+b–), which has only the Fya allele in
a double dose; and Fy (a–b+), which has only a double dose of the Fyb
allele. A particular phenotype characterized by the absence of the Fya
and Fyb Ags, the Fy(a–b–) phenotype, is exclusive (with some excep­
tions) to individuals of African ancestry where it can reach frequencies
of 70–100% depending on the population. It is linked to the presence
of a double dose of a silent FY*0 allele. This distribution may be related
to the fact that the Fy Ags serve as receptors for Plasmodium vivax
and therefore the Fy(a–b–) phenotype. However, these individuals
may develop Abs against two high-frequency Ags (FY3 and FY5) after
transfusion or pregnancy. They may also have low a granulocyte count
but are not associated with any disease.
The Kidd system (JK) comprises three Ags, two of which are
routinely tested: the Jka Ag (JK1), coded by the Jka allele, and the Jkb
HEMOLYSIS CHARACTERISTICS
RBCC TRANSFUSION
RECOMMENDATIONS
TRANSFUSION
HDFN
None to moderate (rarely
severe)
Ab-negative RBCC
None (except in extremely
rare cases if active at 37°C)
Compatible RBCC (negative
IAT at 37°C)
Ag-negative red cells in the
case of sickle cell disease
None
Compatible RBCC (negative
IAT at 37°C)
Ag-negative RBCC in the
case of N–S–s–U– phenotype
Ag-negative RBCC
None
Compatible RBCC (negative
IAT at 37°C)
Mild to severe
Ag-negative RBCC
None
Compatible RBCC (negative
IAT at 37°C)
Mild to severe (rare)
Ag-negative RBCC
Mild (rare) (no data for
anti-Fy5)
Ag-negative RBCC
Mild to moderate (rare)
Ag-negative RBCC
None to mild
Ag-negative RBCC
Not none
Ag-negative RBCC
Ag (JK2), coded by the Jkb allele. Depending on the combinations of
alleles, three common phenotypes are seen: Jk(a+b+) displaying the
two alleles Jka and Jkb, Jk(a+b–) displaying only the Jka allele in a double
dose, and Jk(a–b+) displaying only a double dose of the Jkb allele. A
particular phenotype is characterized by the absence of the Jka and
Jkb Ags: the Jk(a–b–) phenotype found in Polynesian populations. It
is linked to the presence of a double dose of a silent JK∗0 allele. These
people may develop Abs against the high-frequency anti-JK3 Ag after
transfusion or pregnancy.
The MNS system comprises 50 Ags, four of which are routinely tested.
Two genes (GYPA, GYPB) encode two pairs of so-called “antithetical”
Ags. The M (MNS1) and N (MNS2) pair Ags encoded by the M and
N alleles, respectively, are branched on the glycophorin A molecule.
Their combination will determine whether or not they are present. M+
and N+ subjects have both alleles; an M+, N– subject is homozygous
for the M allele; and an M–, N+ subject is homozygous for the N allele.
The same holds true for the other pair of Ags, S (MNS3) and s (MNS4)
expressed on glycophorin B. Therefore, an M+, N–, S–, s+ subject
(in international nomenclature, this is written as MNS:1,–2,–3,5)
will be homozygous for the M and s alleles. A rare phenotype, S–s–,
found exclusively in individuals of African ancestry, can develop an
Ab against the high-frequency U Ag (MNS5) after transfusion or
pregnancy.
■
■RARE RBC PHENOTYPES
Some patients present with rare genotype/phenotype assortments, and
their RBCs display so-called private Ags or, conversely, lack public
Ags (i.e., widely shared Ags) toward which the patient may develop
an immune response when exposed to these Ags. Public-negative
immunized individuals are virtually impossible to transfuse using
conventional blood bank resources and require access to designated
blood banks that have access to rare blood programs. Their primary
responsibility is to identify and collect blood from donors exhibiting
particular Ag displays on their RBCs or platelets that are uncommon
in the given jurisdiction. Specific ethnic populations may be targeted,
as some may display genotype specificities, such as the Bombay group
in southwestern Indians. Several hemoglobinopathies, such as sickle
cell disease, are more common in individuals of African ancestry. Such
patients may display RBC phenotypes that are uncommon in coun­
tries in the Northern Hemisphere, resulting in difficulties adequately
identifying donors to match the need, as a last resort, for highly valued
cryopreserved BCs.
CLINICAL INDICATIONS AND EFFICACY
ASSESSMENT OF BLOOD COMPONENTS
BCs are life-saving therapies but also scarce resources. Furthermore,
transfusion may result in well-identified adverse reactions as well
as more ill-defined adverse reactions, including inflammation and
therapeutic inefficacy. As highlighted in patient blood management
programs, transfusion should be considered within a multidisciplinary
approach that includes optimization of hematopoiesis and minimiza­
tion of blood loss during surgical interventions. Clinical indications
of BCs as well as means to assess therapeutic efficacy are detailed in
Table 118-4.
ADVERSE REACTIONS TO BLOOD
COMPONENTS
Adverse reactions to transfused BCs are most commonly non-lifethreatening, although serious reactions can present with mild symp­
toms. Transfused patients should be closely monitored for warning
signs suggestive of adverse reactions, as described in Table 118-5.
When an adverse reaction is suspected, the transfusion must be
stopped while the recipient’s clinical status is assessed, and supportive
care is initiated as needed. An average of 37 transfusion-associated
fatalities with possible to definite imputability were reported yearly
to the U.S. Food and Drug Administration (FDA) between 2017 and
2021 among ~15 million transfused BCs. Most frequent causes of
death were transfusion-associated circulatory overload (TACO) (32%),
followed by TRALI (21%), hemolysis (21%), and microbial contamina­
tion (13%).
Adverse reactions to BCs may result in immune and nonimmune
mechanisms. Immune-mediated reactions are often due to recipient
or donor alloimmunization and the presence of preformed recipient or
donor Abs. Nonimmune causes of reactions are from the physical
or chemical properties of BCs or from pathogens present in the BC.
■
■IMMUNE-MEDIATED ADVERSE REACTIONS
Hemolytic Transfusion Adverse Reactions 
Immune-mediated
acute hemolysis occurs when the recipient preformed Abs lyse trans­
fused donor RBCs and may occur during or 24 h after transfusion.
The anti-A or anti-B Abs are responsible for most of the most severe
reactions, which can be fatal. However, alloAbs directed against other
RBC Ags (i.e., Rh, Kell, and Duffy) are also responsible for severe
hemolytic reactions. Such dramatic reactions are usually caused by a
failure in product or patient identification, erroneous blood grouping,
or unidentified anti-RBC alloimmunization in the recipient. Hemoly­
sis, most often of lesser severity, may also occur upon transfusion of
BCs containing incompatible plasma with a large amount of alloAbs
directed against the recipient’s RBCs. This may typically occur after
transfusion of a PC containing ABO-incompatible plasma. Estimated
frequencies of acute and chronic hemolytic adverse reactions are 1–10
and 5–40 per 105 transfused BCs, respectively.
Mechanisms of transfusion hemolytic reactions are described in
Fig. 118-1.
Prevention of hemolytic reactions relies on pretransfusion test­
ing of potential recipients. Testing will include determination of the
ABO D phenotype (and anti-ABO Abs) as well as additional typing
for the other main Rh Ags (CcEe), K Ag of the Kell system, and more
rarely, Duffy (Fya and Fyb), Kidd (Jka and Jkb), and MNS (S and s)
Ags, depending on the clinical setting. These determinations are most
often performed by serology. However, molecular typing is increas­
ingly being used to predict RBC phenotype and facilitate the selection
of a compatible component. Special care must be taken to verify the
patient’s identity and apply adequate tube labeling. A double ABO
determination performed separately may be considered, especially in
the absence of a systematic crossmatch.
Testing will also include the screening and identification of alloAbs
directed against RBC Ags other than ABO. This screen is performed
by mixing patient serum with type O RBCs expressing Ags from
most blood group systems and whose extended phenotype is known.
The specificity of the alloAb is identified by correlating the presence
or absence of Ag with the induced—or not—agglutination. Special
attention should be paid to patients receiving monoclonal Ab treat­
ment that may bind to erythrocytes in vivo (such as anti-CD38 IgG
treatment for multiple myeloma) and therefore interfere with alloAb
screening. Such interference may be offset by sample dithiothreitol
pretreatment.
Crossmatching between the recipient plasma/serum and the selected
RBCs may be performed, especially when the recipient is alloimmu­
nized against RBC or is frequently transfused, as well as in specific
clinical settings such as sickle cell disease, even if the Ab screening is
negative.
CHAPTER 118
The selection of a compatible BC should consider pretransfusion
testing as well as the recipient’s clinical status. In the case of D-negative
patients, every attempt must be made to provide Rh-negative RBCC to
prevent anti-D alloimmunization. In an emergency, D-positive RBCC
can be safely transfused to a D-negative patient who lacks anti-D. How­
ever, an estimated 20–22% of RBCC recipients will become alloimmu­
nized and produce anti-D Abs after transfusion with D-positive RBCs.
Such alloimmunization can occur after PC transfusion, although at a
much lower frequency (~1%). Whenever possible, females with child­
bearing potential (to include prepubertal girls) should be transfused
with D- and K-compatible RBCCs and D-compatible PCs to prevent
alloimmunization and protect a future fetus/newborn from an alloimmunemediated hemolytic disease. D-negative females with childbearing
potential who are transfused with BCs containing D-positive RBCs
should receive anti-D Ab to prevent allosensitization.
Transfusion Therapy and Biology
Hemolysis, most often of lesser severity, may also occur after trans­
fer of alloAbs directed against the recipient’s RBC Ags. Such ABO
“plasmatic” incompatibility, called “minor ABO incompatibility,” will
occur mainly with PC transfusions, where platelets are suspended in
~100–300 mL of plasma (depending on whether part of the plasma is
substituted by additive solution). BCs containing plasma with hightiter anti-A/B Ab may induce a hemolytic reaction. When the transfu­
sion of ABO-identical (vs ABO-compatible) PCs is not feasible, PCs
provided by donors with low-titer anti-A/B only should be preferred.
While there is no universal definition of high-titer Abs, a threshold
titer of 1/64 (as assessed by hemagglutination) may be appropriate.
The use of an additive solution in PCs substantially mitigates this risk.
Lastly, ABO plasmatic incompatibility can lead to the formation of
immune complexes with soluble A and/or B Ags and ensuing inflam­
mation and platelet activation.
Acute hemolytic reactions may present with hypotension, tachypnea,
tachycardia, fever (+1–2°C), chills, chest and back pain, hemoglobin­
uria, and hemoglobinemia. In the most severe cases, disseminated
intravascular coagulation (DIC), acute renal failure, shock, and death
may occur.
Delayed hemolytic reactions, with icterus and persisting or wors­
ening anemia as the main clinical manifestations, result from an
anamnestic response. Such reactions may occur in patients previously
sensitized to RBC Ags who have a negative alloAb screen at the time
of transfusion due to low Ab levels. The alloAb is detectable 1–2 weeks
after the transfusion.
Diagnosis of transfusion-associated hemolysis relies on persis­
tent and/or worsening anemia, depleted plasma haptoglobin levels,
transfusion (not applicable to
CCIa >7.5 to 10 within 1 h and
Prevention and/or resolution
25–30 mL/kg
Sickle cell disease: reduced
Increased Hb (+1 g/dL) and
related symptoms, clinical
4.5 to 5 within 24 h after
COMPONENT
THERAPEUTIC INDICATION
GOAL
DONOR/RECIPIENT COMPATIBILITY
DOSAGE
EFFICACY EVALUATION
Reduction of anemiapercentage of HbS
hematocrit (+3%)
improvement
of bleeding
whole blood–derived PCs)
0.5–0.7 × 1010 platelets/kg
1 unit at a time (250–350
solution), repeated per
mL, including additive
clinical status and Hb
(apheresis or pooled
level
Additional compatibility may be required
compatible (cellular) with low-titer antiHLA compatible (negative lymphocyte
depending on the clinical setting and
ABO identical preferable; if not, ABO
A/B Ab; RhD compatible preferred in
RhC/c/E/e; Kell-compatible RBCCs if
multitransfused whenever possible.
Improve systemic and tissue oxygenation
ABO compatible (cellular) and ABO
childbearing-age females, and if
RhD compatibility in young and
identical when achievable.
PART 4
Oncology and Hematology
premenopausal women
screening results.
multitransfused
improved hemostatic capacity compared with
Replace altered RBCs with donor RBCs and
Cold stored platelets, despite lower in vivo
compensate for hemolysis, prevention of
survival, have maintained and possibly
Correct impaired primary hemostasis,
sickle cell occlusive crisis
including vessel healing
neonates and patients with severe thrombocytopenia
relation with clinical symptoms): <7 g/dL for patients
with preexisting cardiovascular disease (<8 g/dL) as
undergoing orthopedic surgery, cardiac surgery, or
in the absence of fever or infection, ≤10,000/μL to
well as for patients with acute coronary disease
Hb below a given threshold (to be considered in
Platelet level below a given threshold: ≤5000/µL
Thrombocytopenia-related bleeding disorders:
(<9–10 g/dL). Such thresholds do not apply to
Anemia and/or tissue ischemia (treatment or
Not recommended: nutritional anemia (iron,
hemodynamically stable, except for patients
Treatment (cold or room temperature PC) or
and chronic transfusion-dependent anemia.
RBC exchange: Anemia/sickle cell crisis in
hemoglobinopathies (sickle cell disease,
prevention (room temperature PC)
vitamin B12, or folate deficiency)
TABLE 118-4  Blood Components: Clinical Use
thalassemia)
RBCC
Transfusion:
prevention)
blood–derived platelets or
temperature (most often)
single donor apheresis),
PC (from pooled whole
maintained at room
(Continued)
Reduced antibody levels (e.g.,
cold/cryopreserved platelets)
anti-HLA antibodies prior to
ABO compatible (plasma)
45–60 mL/kg
Improved disease-specific
Not determined
Reduced bleeding disorder
recovery in case of TTP)
organ transplantation)
symptomatology (i.e.,
apyrexia and platelet
Infection resolution
ABO compatible (plasma)
10–15 mL/kg
neonates to HPA immunized mother (fetal
refractoriness related to the presence of
neonatal alloimmune thrombocytopenia)
crossmatch) or HLA identical in case of
HPA compatible in thrombocytopenic
anti-HLA Ab
missing elements of coagulation or fibrinolysis
cascade, as well as elements to heal injured
Ab in case of TTP, excess cholesterol, etc.);
and/or immunomodulatory factors such as
Deplete pathogenic elements in the blood
Correct impaired hemostasis by providing
(autoantibodies such as anti-ADAMTS-13
plasma may also bring anti-inflammatory
Provide Abs against relevant pathogens
room temperature stored platelets
vessel endothelium
immunoglobulin
Infectious disease (convalescent plasma containing
Plasma exchange (plasma or combined plasma and
lacking enzyme (e.g., thrombotic thrombocytopenic
20,000/μL if fever or infection; ≤50,000/μL if surgery,
DIC, endoscopy, invasive procedures; ≤80,000/μL if
Pathogenic Ab removal (e.g., anti-HLA Ab prior to
pathogen-specific Abs): Argentina hemorrhagic
Pathogenic Ab removal and supplementation of
fever, viral respiratory infections (experimental)
Coagulation factor–related bleeding disorders
Acute hypovolemic coagulopathy (see below)
Acute hypovolemic coagulopathy (see below)
microangiopathy or Guillain-Barré syndrome)
Immune thrombocytopenia, thrombotic
microangiopathy, and heparin-induced
thrombocytopenia: Not recommended
neurosurgery, eye surgery, or ECMO
kidney transplantation)
Transfusion:
albumin):
Plasma (thawed frozen,
at room temperature,
maintained at 4°C or
never frozen and
freeze-dried)
or at 4°C
4–5 units
Increased plasma fibrinogen
enhancement effect)
N/A
105–107 T lymphocytes/kg
Disease specific (remission)
stabilization until recovery
status
Normovolemia; bleeding
Normovolemia; bleeding
clinical status
Infection resolution (or
from neutropenia)
(0.3–1 g/L)
resolution
resolution
ABO compatible
1–2 × 1010, repeated per
PC ratio, repeated per
compatibility
1 RBCC/1 plasma/0.25
Willebrand factor, and factor XIII
ABO compatibility is not required
10–15 mL/unit, pool of
anti-A/B Ab
Repeated per clinical
clinical status
ABO-identical or group O with low-titer
Standard RBCC, PC, and plasma
transfusion
Appropriate ratio is under investigation; a ratio
of 1 RBCC/1 plasma/0.25 PC (platelet content
relation to granulocytopenia or granulocyte
maintained at 4°C and without an additive
transfusion
Balanced provision of blood components
Correct impaired granulocyte function in
hematopoietic cell transplantation
Graft-versus-leukemia effect (and graft
Provision of fibrinogen, factor VIII, von
of a whole blood) is currently favored
solution and related dilution
Number of platelets transfused x 10
x Body surface area (m )
(
)
(
)
dysfunction
Whole blood
Acute hypovolemic coagulopathy requiring massive
PC, and plasma)
Acute hypovolemic coagulopathy requiring massive
Cryoprecipitate
Acute bleeding coagulopathy, type II (dysfunctional
disease, hemophilia A in the absence of factor VIII
granulocytes (CGD). Neutropenia can be acquired
Donor mononuclear cells
Relapse of malignant hemopathy after allogeneic
factor) or type III (absent factor) von Willebrand
Severe refractory bacterial or fungal infection
(chemotherapy) or congenital. Formal proof of
(mainly soft tissues and lung) in patients with
neutropenia (<100/μL) or with dysfunctional
CCI
Postransfusion count /µL –pretransfusion count /µL
efficacy is lacking.
concentrates
Granulocyte concentrates
Multicomponent (RBCC,
(apheresis or a pool of
whole blood–derived
aCCI calculation:
granulocytes)
Abbreviations: Ab, antibody; CCI, corrected count increment; CGD, chronic granulomatous disease; DIC, disseminated intravascular coagulation; ECMO, extracorporeal membrane oxygenation; Hb, hemoglobin; HLA, human leukocyte
CHAPTER 118
antigen; N/A, not applicable; RBC, red blood cell; RBCC, red blood cell concentrate, PC, platelet concentrate; TTP, thrombotic thrombocytopenic purpura.
Transfusion Therapy and Biology
TABLE 118-5  Transfusion Adverse Reactions: Main Warning Signs
Fever (≥38°C)
+1–2°C within 4 h
FNHTR
Anti-HLA immunization and cognate Ag in the blood product
TRALI (with dyspnea at the forefront)
+1–2°C within 15 min +/–:
• Chills
• Dyspnea
• Hypotension
• Digestive disorders
• Disseminated intravascular coagulation
• Hemoglobinuria
2°C
Transfusion-transmitted bacterial infection
Hypotension (≥30 mmHg decrease in systolic blood pressure)
Hemolytic shock
Anaphylactic shock
Septic shock
TRALI (with dyspnea at the forefront)
Dyspnea
TRALI (within 6 h of transfusion)
TACO (within 12 h of transfusion)
Severe allergy (immediate; within 4 h)
Hemoglobinuria
Intravascular hemolysis
• Immunologic
• Mechanical
• Toxic
• Thermic
PART 4
Oncology and Hematology
Rash
<2/3 of the body within 2–3 h
Minor allergy
2/3 of the body during or within 2–3 h
Severe allergy
2/3 of the body within 5 min
Associated with dyspnea and shock
Icterus
Delayed hemolysis
New alloantibody
Alloimmunization
Rash, diarrhea, and fever occurring 2 days to 6 weeks after transfusion
GVHD
Gum bleeding, purpura 5–12 days after transfusion
Posttransfusion purpura
Cardiac, hepatic, and/or renal insufficiency in frequently transfused patients
Posttransfusion iron overload
Top-down investigation after a blood donor is subsequently found to be infected
Transfusion-transmitted infection
Bottom-up investigation after another recipient of a same blood donation is
found to be infected
Infectious symptoms within 6 months
Abbreviations: Ag, antigen; FNHTR, febrile nonhemolytic transfusion reaction; GVHD, graft-versus-host disease; HLA, human leukocyte antigen; TACO, transfusion-associated
circulatory overload; TRALI, transfusion-related acute lung injury.
hemoglobinemia and hemoglobinuria, and elevated plasma lactate
dehydrogenase and unconjugated bilirubin. The direct antiglobulin test
(DAT, or direct Coombs test) that detects immunoglobulin, and pos­
sibly complement (C3d), on the surface of the recipient’s RBC will most
often be positive (Fig. 118-2). Similarly, a positive indirect antiglobulin
test (IAT, or indirect Coombs test) that detects anti-RBC alloAb in the
serum will also be positive. An elution of the Ab on the surface of the
RBC may allow for the identification of the culprit alloAb.
The management of an immune-mediated acute hemolytic transfu­
sion reaction is mainly supportive. Prompt interruption of the trans­
fusion, biological workup, and a thorough clerical check to prevent
a possible second misidentified transfusion are crucial initial steps.
Vigorous hydration with isotonic saline and diuretics to maintain
urine output is recommended. Although often self-limiting, acute
hemolysis may also require forced alkaline diuresis, correction of elec­
trolyte abnormalities, and pressor support as needed. In patients with
DIC and severe bleeding, PC, plasma, and cryoprecipitate or fibrino­
gen may be required. When transfusion of incompatible RBCCs is
unavoidable, prophylaxis with steroids (100 mg of hydrocortisone)
just before the transfusion and repeated 24 h later and polyvalent
immunoglobulin (1.2–2.0 g/kg per day over 2–3 days, initiated just
before the transfusion) have been successfully used to prevent or
minimize acute and delayed hemolysis. Polyvalent immunoglobulin,
Transfusion-transmitted bacterial infection
Hemolysis
Anaphylaxis
anticomplement (C3) Ab, anti-B-cell Ab, or plasma exchange may be
considered in case of severe posttransfusion hyperhemolysis in sickle
cell patients.
Immune-mediated hemolysis may also occur after allogeneic hema­
topoietic transplantation (most often involving a peripheral blood stem
cell graft) or, more seldomly, solid organ transplantation. Minor ABO
incompatibility, with subsequent red cell destruction in the recipient,
is the most common cause of clinically significant hemolysis in such
cases. Viable donor B lymphocytes, called “passenger lymphocytes,”
transferred passively with the graft, may produce alloAbs (including
anti-D or anti-A1 in an A2 donor) that target recipient red cells. Such
hemolysis has been reported to develop 5–14 days after transplanta­
tion. Reduced-intensity conditioning regimens and cyclosporine as
prophylaxis against GVHD or rejection have been associated with
increased risk. Transfusing RBCs compatible with the graft donor and
the use of GVHD prophylaxis able to target B cells (e.g., methotrex­
ate) have significantly reduced the incidence of passenger lymphocyte
syndrome. Allogeneic hematopoietic transplantation may also result
in acute hemolysis due to incompatible donor-derived red cell (and
precursor) destruction by the recipient alloAbs (i.e., major ABO
incompatibility). Prolonged pure red cell aplasia may occur in such a
situation. Graft deserythrocytation will reduce the risk of early acute
hemolysis.
A Predominantly intravascular acute hemolysis occurring
during or within 24 hours following transfusion
Mastocyte
Cytokines
Chemokines TNFa
IL1, 6, 8
A
C1
C3a/C5a
Anti-A Ab
C5/C9
A
Membrane attack
complex formation
RBC transmembrane pore
Osmotic i.v. hemolysis
B Predominantly extravascular acute or
delayed (3 to 10 days after transfusion)
hemolysis
Macrophage
C1
C3b
RBC lysis
Anti-Jka Ab
Jka
C3b
C3d
C Predominantly extravascular acute or
delayed (3 to 10 days after transfusion)
hemolysis
Macrophage
Anti-D Ab
D
FIGURE 118-1  Mechanisms of transfusion hemolytic reactions. A. Acute responses will involve preexisting antibodies (Abs), naturally occurring anti-A/anti-B IgM or IgG
directed against other RBC antigens (Ags) and resulting from prior sensitization. Upon interaction with cognate antigen on transfused red blood cells (RBCs), recipient
allogeneic Ab (alloAb), mostly natural anti-A/anti-B IgM, may fix and activate complement up to C5/C9. Formation of membrane attack complex (MAC) will create pores in
transfused RBCs with resulting intravascular hemolysis, release of toxic moieties including free hemoglobin responsible for end-organ damage including renal failure, and
tissue factors contributing to occurrence of disseminated intravascular coagulation (DIC). B. Alternatively, complement activation may be incomplete, as typically observed
in a delayed hemolytic transfusion reaction involving neoformed allogeneic IgG. In such cases, complement activation up to C3 results in C3b-mediated opsonization of
RBCs, extravascular hemolysis, and clearance through immunophagocytosis. Anemia and jaundice will be the primary clinical manifestations. C. Lastly, alloAb may not fix
complement while ensuring antibody-dependent cellular cytotoxicity (ADCC)–mediated phagocytosis of targeted RBC. (Adapted from SR Panch et al: Hemolytic transfusion
reactions. N Engl J Med 381:150, 2019.)
Endothelium alterations
Capillar permeability
Vasodilation/Hypotension/Shock
Fever
DIC
Hemoglobinemia
Hemoglobinuria
Albumin
Haptoglobin
HemopexinA
Vasoconstriction
Acute renal failure/
tubular necrosis
Elimination
Nitric oxide
scavenging
Hemoglobin
Dimers
Ferric
heme
CHAPTER 118
Transfusion Therapy and Biology
Unconjugated bilirubin
Albumin
Low-level
hemoglobinemia
Conjugated bilirubin
Partial degradation
of membrane
proteins
Spherocytes
Microspherocytes
Urobilinogen
Stercobilinogen
Unconjugated bilirubin
Albumin
Low-level
hemoglobinemia
Conjugated bilirubin
RBC lysis
Partial degradation
of membrane
proteins
Spherocytes
Microspherocytes
Urobilinogen
Stercobilinogen
Positive
test result
Indirect Coombs test/indirect antiglobulin test
PART 4
Oncology and Hematology
Direct Coombs test/direct antiglobulin test
Positive
test result
Antihuman Abs
Antigens on
the red blood
cell surface
Human
anti-RBC
Abs
FIGURE 118-2  Direct and indirect Coombs test. The direct Coombs/antiglobulin test detects the presence of Abs (or complement) on the surface of erythrocytes. The indirect Coombs/antiglobulin test detects Abs in the serum that may bind
Agglutination of red
blood cells occurs,
because human Abs
are attached to
RBC(s).
Antihuman
Abs are added
to the solution.
Recipient’s Abs that
target the donor’s
RBC(s) form
antibody-antigen
complexes.
to donor erythrocytes. Abs, antibodies; RBC, red blood cell. (Adapted from http://upload.wikimedia.org/wikipedia/commons/1/1c/coombs_test_schematic.png.)
Donor’s blood is
added to the
serum.
Recipient’s
serum is
obtained,
containing
Abs.
Agglutination of RBC(s)
occurs, because human Abs
are attached to RBC(s).
The patient’s washed
RBC(s) are incubated with
antihuman Abs.
Blood sample from a
patient with immunemediated hemolytic
anemia: Abs are
shown attached to
antigens on the RBC
surface.
Polyvalent immunoglobulin may contain high titers of anti-A
(mostly) and/or anti-B Abs and induce acute hemolysis, most often
of limited severity. Such hemolysis is particularly described in group
A or AB children receiving high-dose immunoglobulin, notably for
Kawasaki’s disease, as well as in adults treated for thrombotic thrombo­
cytopenic purpura. A similar mechanism may lead to hemolysis after
anti-D immunoglobulin treatment for immune thrombocytopenia in
RhD-positive patients.
Nonimmune mechanisms of transfusion-associated hemolysis
include thermal (overheated or cold BCs), osmotic (concurrent hypoosmotic perfusion), and mechanical (pressure related to high-flow
transfusion filtering during cell saver processing) mechanisms.
Autoimmune and drug-induced hemolytic anemias may be exacer­
bated by transfusion and can therefore mimic hemolytic transfusion
reactions. Transfusion of RBCs with enzymatic defects may mimic
immune-mediated hemolysis as well. Notably, severe hemolytic reac­
tions in patients receiving long-term transfusions for hemoglobinopa­
thies (mainly sickle cell disease) can precipitate bystander hemolysis, in
addition to clearing transfused red cells. The mechanisms of this hyper­
hemolytic transfusion reaction may be a mediated RBC hemolysis-related
systemic inflammatory response and resulting lysis of red cell precur­
sors by macrophages. This process may be immediate or delayed, with
hemoglobin levels falling below the pretransfusion values, often to
life-threatening levels. Further RBCC transfusion typically exacerbates
ongoing hemolysis, with the exogenous (transfused) allogeneic Ags
probably triggering further nonspecific hemolysis.
Febrile Nonhemolytic Transfusion Reaction 
The most fre­
quent reaction associated with the transfusion of cellular BCs is
FNHTR (up to 300 per 105 BCs). This reaction is characterized by chills
and rigors and a ≥1°C rise in body temperature and is caused by pro­
inflammatory cytokines in the BC or by recipient Abs directed against
donor cell Ags present in the BC. FNHTR is diagnosed when other
causes of fever, notably infection and hemolysis, have been excluded.
Leukocyte reduction, especially prestorage, can prevent the occurrence
of FNHTR. Moreover, the use of additive solutions decreases FNHTR
frequency associated with PC transfusion. Premedication with anti­
pyretics has generally proven ineffective at decreasing the rate of such
reactions and may mask relevant clinical symptoms.
Allergic Reactions 
Most allergic transfusion reactions are mild
and include rash, pruritus, urticaria, and localized edema. More rarely,
allergic reactions may be severe to life-threatening with an anaphylactic
reaction that can involve bronchospasm, respiratory distress, hypoten­
sion, nausea, vomiting, and shock. Frequencies of mild and severe
allergic reactions are ~100 and ~5 per 105 BCs, respectively. Allergic
reactions are related to plasma proteins found in transfused components.
Mild reactions may be treated by temporarily stopping the transfusion
and administering antihistamine drugs. Patients with a history of aller­
gic transfusion reaction may be premedicated with an antihistamine,
although there is no consensus on this issue. Cellular components can
be washed to remove residual plasma for extremely sensitized patients.
Most of the allergic presentation may not depend on preformed Abs
and may be attributable to soluble mediators triggering histamine and
serotonin release from platelets and leukocytes. An anaphylactic reac­
tion may occur after the transfusion of only a few milliliters of the
BC. Treatment includes stopping the transfusion, maintaining vascular
access, and administering adrenaline (0.3–0.5 mg subcutaneously).
Additional treatment with steroids, antihistamine drugs, and bronchodi­
lators may also be required.
Patients who are IgA deficient (<1% of the population) may be sen­
sitized to this immunoglobulin isotype and may be at risk of anaphy­
lactic reactions associated with plasma transfusion. As a precaution,
individuals with severe IgA deficiency should therefore receive, where
available, IgA-deficient plasma and washed cellular BCs. Patients who
have anaphylactic or repeated allergic reactions to BCs should be
tested for IgA deficiency. It should be noted that the importance, or
even the reality, of such a transfusion-related allergic risk is currently
debated.
Graft-Versus-Host Disease 
GVHD is an extremely rare adverse
reaction caused by transfusion, although it is a frequent complication of
allogeneic hematopoietic transplantation. Transfusion-related GVHD
is mediated by engrafted donor T lymphocytes in a recipient unable to
reject such allogenic lymphocytes (as in severely immunosuppressed
patients or patients homozygous for an HLA haplotype shared with
the donor). Such donor T lymphocytes interact with host HLA Ags
and mount an immune response, which is manifested clinically by
the development, 5–10 days after transfusion, of cytopenia, fever, a
characteristic skin rash, diarrhea, and liver function abnormalities.
Transfusion-associated GVHD is highly resistant to treatment with
immunosuppressive therapies as well as ablative therapy followed by
allogeneic bone marrow transplantation and is fatal in >90% of cases.
Prevention in at-risk patients relies on the irradiation of cellular BCs
(minimum of 25 Gy) or treating BCs with pathogen reduction technol­
ogy that will deplete all living cells in the component. At-risk patients
include patients with inherited immune deficiency, patients undergo­
ing autologous or allogeneic hematopoietic transplantation, patients
treated with immunosuppressive drugs such as purine or pyrimidine
analogues, anti-CD52 Ab, or antithymocyte globulin, fetuses receiving
intrauterine transfusions, and recipients of BCs provided by a blood
relative. Because granulocyte concentrates contain a large number of
lymphocytes, they should always be irradiated.
CHAPTER 118
Transfusion-Related Acute Lung Injury 
TRALI is character­
ized by the occurrence or worsening of hypoxia and noncardiogenic
pulmonary edema with bilateral interstitial infiltrates on chest x-ray
during or within 6 h after transfusion, although delayed cases may
occur up to 72 h later. Frequency of TRALI is BC dependent and
ranges, on average, from 0.5 to 10 per 105 BCs. TRALI may be dif­
ficult to distinguish from other causes of hypoxia, such as circulatory
overload, and is among the most common causes of transfusion-related
fatalities. Treatment is supportive only. TRALI usually results from the
transfusion of donor plasma that contains high-titer anti-HLA class II
Abs that bind recipient cognate Ag. Anti-HLA class I and anti-HNA
Abs may also be involved. TRALI mediated by cytokines and chemo­
kines in the absence of an HLA-mediated interaction may occur also.
Leukocytes, especially when primed by either a bacterial moiety such
as lipopolysaccharide or a cytokine/chemokine, aggregate in the pul­
monary vasculature and release inflammatory mediators. The transfu­
sion of plasma and PCs from male donors and nulliparous or parous
female donors without anti-HLA Abs has significantly reduced the risk
of TRALI where implemented. Recipient factors associated with an
increased risk of TRALI include smoking, chronic alcohol use, shock,
liver surgery (transplantation), cancer surgery, mechanical ventilation,
and positive fluid balance.
Transfusion Therapy and Biology
Posttransfusion Purpura 
This rare reaction (~1/105 BCs) is
defined as a thrombocytopenia-related bleeding disorder developing
5–12 days after PC (and more rarely RBCC) transfusion, predominantly
in women. Platelet-specific alloAbs are found in the recipient, most fre­
quently anti-HPA-1a in HPA-1a-negative alloimmunized individuals.
The delayed thrombocytopenia is due to a secondary increased produc­
tion of alloAbs. The mechanisms for the destruction of the patient’s
own platelets remain unclear. Management is mostly supportive but
may require polyvalent immunoglobulin, glucocorticoids, or plasma
exchange. Additional platelet transfusions may worsen the thrombocy­
topenia or be associated with poor increments. Prevention of recurrence
includes use of washed BCs or BCs from HPA-compatible donors.
Alloimmunization/Platelet Refractoriness 
A recipient may
become alloimmunized to a number of Ags on cellular blood elements
and plasma proteins. AlloAbs to RBC Ags are detected during pre­
transfusion testing, and their presence may delay finding Ag-negative
crossmatch-compatible products for transfusion. Women of childbear­
ing age who are sensitized to RBC Ags (i.e., D, c, E, Kell, or Duffy) are
at risk of bearing a fetus with hemolytic disease of the fetus or new­
born. Ag matching is the only pretransfusion selection test to prevent
RBC alloimmunization, which is found to occur with a frequency of
~100/105 RBCC transfusions. Alloimmunization to Ags on leukocytes
and platelets, most often anti-HLA Abs, can result in refractoriness to
PC transfusions (as defined by a low increase in platelet count after
transfusion). Once alloimmunization has developed, HLA-compatible
(crossmatched) PCs should be preferred if available. If not, repeated
PCs at shortened intervals may be considered. Use of leukocytereduced cellular BCs will reduce the incidence of immunization.
Transfusion refractoriness may also result from an anti-HPA alloim­
munization, although less commonly. Recipient factors associated with
platelet refractoriness include fever, splenomegaly, bleeding, DIC, and
medications such as amphotericin B. Notably, cold-stored (and cryo­
preserved) PCs have been found to have preserved hemostatic function
in acutely bleeding patients despite poor platelet increments.
Immunomodulation 
Transfusion of allogeneic blood may be
associated with immunosuppression, as evidenced early on by the
beneficial effect of pretransplant transfusion on kidney graft survival.
The intensity of such an effect is debated and, if present, is most prob­
ably attenuated with leukoreduced BCs. Transfusion-related immu­
nomodulation is indeed thought to be mainly mediated by donor
leukocytes, whether transfused to the recipient or undergoing apopto­
sis during storage. However, leukoreduced RBCCs or PCs still release
immunomodulatory mediators during storage. These mediators, along
with the transfused RBCs or platelets, may exert various, possibly
opposing, immune effects in vivo, including immunosuppression and
inflammation.
PART 4
Oncology and Hematology
■
■NONIMMUNOLOGIC TRANSFUSION ADVERSE
REACTIONS
Fluid Overload 
TACO is a common and underrecognized transfu­
sion adverse reaction. Estimated frequencies vary from ~10 to 100 per
105 BCs. TACO is now the main cause of death from transfusion since
the TRALI risk has been mitigated. Risk factors include older age, renal
failure, preexisting fluid overload, cardiac dysfunction, administration
of a large volume of BCs, and an excessive rate of transfusion in rela­
tion to the patient’s hemodynamic tolerance. TACO results in dyspnea,
hypoxia, bilateral and predominantly alveolar infiltrates on chest x-ray,
frequent systolic hypertension, and elevated brain natriuretic peptide.
Fever may also exist. Prevention involves identifying at-risk patients,
close monitoring, a slow transfusion rate (1 RBCC over 3–4 h), and
use of diuretics in hemodynamically stable patients with a history of
TACO. Treatment requires stopping the transfusion and administrat­
ing oxygen and diuretics.
Massive Transfusion-Associated Reactions/Electrolyte and
Cold Toxicity Reactions 
Reactions related to massive transfu­
sion, i.e., transfusion of 50% of the patient’s total blood volume over 3 h
or >5–10 units of RBCCs (plus associated BCs), include citrate toxic­
ity, hypothermia, hyperkalemia, and dilutional coagulopathy. Citrate,
which is commonly used to anticoagulate BCs, chelates calcium. Hypo­
calcemia, manifested by circumoral paresthesia, and changes in cardiac
function may result from multiple rapid transfusions. Although citrate
is quickly metabolized to bicarbonate, calcium infusion (through a
separate line) may be required. Rapid transfusion of BCs still at 4°C
can result in hypothermia and cardiac dysrhythmias. Use of an inline
warmer will prevent this complication. RBC leakage during storage,
longer storage, and irradiation increase the concentration of potassium
in the unit. Neonates and patients with renal failure or other comor­
bidities (e.g., hyperglycemia or hypocalcemia) are at risk of hyperka­
lemia and resulting acute cardiac toxicity. Treatment includes insulin,
glucose, calcium gluconate, and furosemide, and prevention includes
the use of washed or plasma-reduced RBCCs or a storage age of <7–10 days
and the avoidance of RBCCs stored for >24 h after irradiation.
Iron Overload 
Each RBCC contains 200–250 mg of iron. In fre­
quently transfused recipients, iron accumulation that is left untreated
will affect endocrine, hepatic, and cardiac function. Death may occur
from cardiac failure or arrhythmia. Iron overload can be assessed by
means of serum ferritin measurements, magnetic resonance imaging,
and liver biopsy. Prevention and treatment of this frequently under­
reported transfusion adverse event rely on careful monitoring and iron
chelation.
Hypotensive Reactions 
Acute hypotensive transfusion reactions
are defined as an abrupt drop in blood pressure of >30 mmHg early
after the start of transfusion and resolving quickly once the transfusion
is stopped, without further intervention. Respiratory, gastrointestinal,
or mild allergic reactions may also be present. Estimated frequency is
1–10/105 BCs. These reactions may result from the generation of vaso­
active kinins in the BCs and are more likely to occur in hypertensive
patients taking angiotensin-converting enzyme (ACE) inhibitors who
are therefore less able to metabolize bradykinin. Upon resolution, the
same blood product should not be restarted. Switching from an ACE
inhibitor to an alternative drug should be considered for patients
requiring further transfusions.
Adverse Transfusion Reactions of Uncertain Imputability 
Necrotizing enterocolitis, which is common in preterm and very-lowbirth-weight neonates, has been infrequently described with close tem­
poral association with RBC transfusion. However, the causality of any
association remains to be further ascertained, as does the efficacy of
withholding feeds during transfusion to prevent such a complication.
Posterior reversible encephalopathy syndrome is a rare syndrome char­
acterized by acute reversible neurologic symptoms related to subcorti­
cal vasogenic brain edema. It has been described within 10 days after
RBCC transfusion, mainly in women with severe (and long-standing)
anemia. The prognosis is most often favorable, although irreversible
neurologic disturbance has been described. Prevention may include
avoiding rapid correction of chronic severe anemia. Again, causality
remains to be established.
■
■INFECTIOUS ADVERSE REACTIONS
Donor screening involves the selection of healthy donors without highrisk lifestyles, medical conditions, or exposure to transmissible patho­
gens. Tests are performed on donated blood to detect the presence of
pathogens by testing for relevant Abs or Ags or by directly detecting
infectious agents by nucleic acid amplification. Increasing sensitivity
of testing methods has progressively narrowed the “window” period
early on after infection during which a low-titer undetectable pathogen
may be present in the blood and result in a transfusion-transmitted
infection.
Transfusion-transmitted bacterial infection remains a significant
concern, notably with PCs stored at room temperature, which allows
for bacterial proliferation. However, some gram-negative bacteria such
as Yersinia can grow at 4°C and therefore may be implicated in infec­
tions related to RBCC transfusion. Recipients of contaminated BCs
may develop abrupt (during transfusion and up to several hours after)
fever and chills, which can deteriorate to septic shock, DIC, and death.
Endotoxin formed within the BC may be implicated. After sampling
for bacterial culture, broad-spectrum antibiotics should be promptly
initiated.
Pathogen reduction of PC and plasma, and perhaps soon of RBCCs
as well, offers an additional means of reducing transfusion infection
risks. Although effective for a wide range of pathogens, such processes
are most often ineffective for bacterial spores and nonenveloped
viruses such as hepatitis A virus, parvovirus B19, and hepatitis E virus.
Postdonation information (i.e., fever occurring within 24 h after dona­
tion) allows the involved BCs to be quarantined and may provide an
additional safety measure.
Transfusion-transmitted infections are increasingly rare. However,
new or previously unidentified infectious risks may occur, as high­
lighted by the emergence of the transfusion-associated West Nile virus
infection and babesiosis in early 2000 in the United States, as well
as transfusion-associated hepatitis E in early 2010 in Europe. Such
occurrences require active surveillance programs and the appropri­
ate implementation of mitigation measures such as additional test­
ing, pathogen reduction, and travel-related deferral criteria. Along
with West Nile virus, a number of other arbovirus-related infections
TABLE 118-6  Infectious Transfusion Adverse Events
DONATION PREVALENCE
(/104 BLOOD DONATIONS)
PATHOGEN
Bacteria
Pyogenic bacteria
PC: 10–20
Venipuncture sepsis, diversion of the
initial 10–30 mL of blood, bacterial
detection, pathogen reduction (for PC)
Treponema pallidum
(syphilis)
~1a
Serologyb,c
<0.01
Virus
HIV-1/2
~0.1
Serology, NAT (+/– p24 Ag)b,c
0.1–1d
HBV
~0.5
Serology, NATb,c
<0.5 (3 without NAT)d
HCV
0.2–1.2
Serology, NATb,c
<0.1–1d
HTLV-1/2
0.05–0.1a
Serology, BC leukocyte reduction b,c
0.1–0.3d
HEV
0–10 (in endemic regions)
NAT
Endemic regions: <0.1 with NAT; a transmission
rate from infected donors of ~50% has been
reported
CMV
Undetermined
Serology, BC leukocyte reductionb,c
<0.1 in leukocyte-reduced BCs
Parvovirus B19
~0.5 with viral DNA >106 IU/mL,e
up to 100 overall
West Nile virus
Up to 3 in high season endemic
regionsa
NATb
High season endemic regions: <1 with NAT
Parasitef
Plasmodium (malaria)
~4 (40–>50 in donors from
endemic regions)a
Serology (NAT soon available)
<0.1 in nonendemic regions
Babesia
~90 (in endemic regions)a
Serology (NAT implementation
underway)
Trypanosoma cruzi
(Chagas disease)
~0.14 in donors/mothers from
endemic regionsa
Serology, leukocyte reduction
ND
aAs assessed based on seropositivity, i.e., including a varying percentage of individuals not harboring the pathogen in their blood. bPrevention measures may also include
pathogen reduction (for PC and plasma), cPrevention measures may also include a quarantine of the (cryopreserved) BC pending a negative serology on a subsequent
donation (for plasma), dEstimated residual risk. eTransfusion risk deemed as absent below this threshold, fVisceral leishmaniasis is a transfusion risk as well in endemic
regions, a risk that may be mitigated by leukocyte reduction.
Note. Other pathogens associated with transfusion-transmitted infections at a very low frequency include arboviruses other than West Nile (dengue, Zika virus), hepatitis
A, human herpesvirus-8, Japanese encephalitis virus, tick-borne encephalitis virus complex, and the prion responsible for variant Creutzfeldt-Jakob disease (4 cases in the
United Kingdom, in the context of the bovine spongiform encephalopathy epidemic, before implementation of systematic leukocyte reduction).
Abbreviations: Ag, antigen; BC, blood component; CMV, cytomegalovirus; HBV, hepatitis B virus; HCV, hepatitis C virus; HEV, hepatitis E virus; HTLV, human T-cell leukemia
virus; NAT, nucleic acid detection test; ND, not determined; PC platelet concentrate; RBCC, red blood cell concentrate.
possibly transmissible by blood transfusion are endemic or involved
in epidemic outbreaks. Despite being possibly present in the blood at
asymptomatic phases of the disease, documented cases of transfusiontransmitted infections involving these arboviruses have been very rare
(Zika), often without a discernible clinical impact (Dengue), or absent
(Chikungunya). Route of infection (i.e., intravenous vs mosquito bite),
pathogen dose, storage conditions, recipient immune status, and ongo­
ing treatments may all impact the ability of a pathogen in the donor to
induce a disease in the recipient. Estimated frequencies of transfusionrelevant infections in donors and of transfusion-transmitted infections
are reported in Table 118-6. Such frequencies depend heavily on vari­
ables such as local epidemiology, donor deferral rules, risk reduction
measures, and data reporting, and may vary considerably.
ALTERNATIVES AND PERSPECTIVES
In addition to promoting appropriate transfusion indications, patient
blood management programs have highlighted several transfusionsparing strategies, such as the treatment of iron deficiency before
surgery and minimization of blood loss. Antifibrinolytic agents such
tranexamic acid (TXA) have been shown to be effective in preventing
bleeding complications in various forms of hemorrhage. Erythropoi­
etin stimulates erythrocyte production in patients with anemia from
chronic renal failure and other conditions. Thrombopoietin recep­
tor agonists may reduce platelet transfusion needs resulting from
chemotherapy-induced thrombopenia. Bone marrow transplantation
and gene therapy approaches, including CRISPR-Cas9-mediated gene
PREVENTION MEASURES
(IN ADDITION TO DONOR DEFERRAL)
INFECTION PREVALENCE IN RECIPIENTS
(/106 BLOOD PRODUCTS TRANSFUSED)
Sepsis:
PC: 5–30; with bacterial detection: <1 to 10; with
pathogen reduction: <1
RBCC: <0.2
NAT
Most adults are immune to parvovirus B19; up to
0.12% in seronegative adults has been reported
CHAPTER 118
ND (0.04% donors may be within the serology
window period)
Transfusion Therapy and Biology
editing, dramatically reduce the transfusion needs in patients with
sickle cell or major thalassemia. Stem cell–derived blood cells such as
RBCs or platelets may in the future become a suitable alternative to
rare blood donors.
Importantly, issues surrounding transfusion safety now fully encom­
pass transfusion efficacy. Linked large-scale databases pertaining to
blood donors and transfused patients will also be instrumental in
further assessing and understanding the basis of transfusion safety
and efficacy. Optimal transfusion care will soon require consideration
of new criteria in relation to donor, blood product, and/or recipient
characteristics.
Acknowledgments
The authors are indebted to Jeffery S. Dzieczkowski and Kenneth C.
Anderson who co-authored the chapter in a previous edition and expertly
paved the way for this chapter.
■
■FURTHER READING
Carson JL et al: Red blood cell transfusion 2023 AABB International
guidelines. JAMA 330:1892, 2023.
Delaney M et al: Transfusion reactions: Prevention, diagnosis, and
treatment. Lancet 388:2825, 2016.
Panch SR et al: Hemolytic transfusion reactions. N Engl J Med
381:150, 2019.
Stanworth SJ, Shah A: How I use platelet transfusions. Blood
140:1925, 2022.

49 - 119 Hematopoietic Cell Transplantation
119 Hematopoietic Cell Transplantation
Frederick R. Appelbaum
Hematopoietic Cell
Transplantation
Bone marrow transplantation was the original term used to describe
the collection and transplantation of hematopoietic stem cells, but with
the demonstration that peripheral blood and umbilical cord blood are
also useful sources of stem cells, hematopoietic cell transplantation has
become the preferred generic term for this process. Hematopoietic
cell transplantation is used to treat patients with an abnormal but
nonmalignant lymphohematopoietic system by replacing it with one
from a normal donor. Hematopoietic cell transplantation is also used
to treat malignancy by allowing the administration of higher doses of
myelosuppressive therapy than would otherwise be possible and, in the
setting of allogeneic hematopoietic cell transplantation, by conferring
an immunologic graft-versus-tumor effect. The use of hematopoietic
cell transplantation is increasing, as it becomes safer and applicable to
more diseases and as donor availability expands.
The Worldwide Network for Blood and Marrow Transplantation
(http://www.wbmt.org) estimates that worldwide more than 100,000
transplants were performed in 2022. The frequency of transplanta­
tion varied widely from country to country, with a close association of
transplant rates with gross national income (GNI) per capita. However,
even among countries with similar GNIs per capita, there are substan­
tial differences between countries and regions regarding the frequency
of transplantation, disease indications, and choice of donor type.
PART 4
Oncology and Hematology
THE HEMATOPOIETIC STEM CELL
Several features of the hematopoietic stem cell (HSC) make trans­
plantation clinically feasible, including its remarkable regenerative
capacity, its ability to home to the marrow space following intravenous
injection, and the ability of the stem cell to be cryopreserved (Chap. 101).
Transplantation of a single stem cell can replace the entire lympho­
hematopoietic system of an adult mouse. In humans, transplantation
of a small percentage of a donor’s bone marrow volume regularly
results in complete and sustained replacement of the recipient’s entire
lymphohematopoietic system, including all red cells, granulocytes, B
and T lymphocytes, and platelets, as well as cells comprising the fixed
macrophage population, including Kupffer cells of the liver, pulmonary
alveolar macrophages, osteoclasts, and Langerhans cells of the skin.
Homing of HSCs to their marrow niche initially involves interactions
between P- and E-selectins on marrow sinusoidal endothelium with
integrins including VLA-4 on HSCs. Once tethered to the vascular
endothelium, changes in integrin conformation result in tight adhesion
following which stem cells migrate through the endothelium and extra­
cellular matrix eventually reaching the stem cell niche. This last step is
facilitated by CXCL12 produced by the niche stroma interacting with
the chemokine CXCR4 on HSCs. Human hematopoietic stem cells can
survive freezing and thawing with little, if any, damage, making it pos­
sible to remove and store a portion of the patient’s own bone marrow
for later reinfusion following treatment of the patient with high dose
myelotoxic therapy.
CATEGORIES OF HEMATOPOIETIC CELL
TRANSPLANTATION
Hematopoietic cell transplantation can be described according to the
relationship between the patient and the donor and by the anatomic
source of stem cells. In ~1% of cases, patients have identical twins who
can serve as donors. With the use of syngeneic donors, there is no risk of
graft-versus-host disease (GVHD), and unlike the use of autologous mar­
row, there is no risk that the stem cells are contaminated with tumor cells.
Allogeneic transplantation involves a donor and a recipient who are
not genetically identical. Following allogeneic transplantation, immune
cells transplanted with the stem cells or developing from them can
react against the patient, causing GVHD. Alternatively, if the immuno­
suppressive preparative regimen used to treat the patient before trans­
plant is inadequate, immunocompetent cells of the patient can cause
graft rejection. The risks of these complications are influenced by the
degree of matching between donor and recipient for human leukocyte
antigen (HLA) molecules encoded by genes of the major histocompat­
ibility complex.
HLA molecules are responsible for binding antigenic proteins and
presenting them to T cells. The antigens presented by HLA molecules
may derive from exogenous sources (e.g., during active infections) or
may be endogenous proteins. If individuals are not HLA-matched, T
cells from one individual will react strongly to the mismatched HLA,
or “major antigens,” of the second. Even if the individuals are HLAmatched, the T cells of the donor may react to differing endogenous or
“minor antigens” presented by the HLA of the recipient. Reactions to
minor antigens tend to be less vigorous. The genes of major relevance
to transplantation include HLA-A, -B, -C, and -D; they are closely
linked and therefore tend to be inherited as haplotypes, with only rare
crossovers between them. Thus, the odds that any one full sibling will
match a patient are one in four, and the probability that the patient has
an HLA-identical sibling is 1 − (0.75)n, where n equals the number of
siblings.
With conventional techniques, the risk of graft rejection is 1–3%,
and the risk of severe, life-threatening acute GVHD is ~15% following
transplantation between HLA-identical siblings. The incidence of graft
rejection and GVHD increases progressively with the use of family
member donors mismatched for one, two, or three antigens. Newer
approaches to GVHD prophylaxis, including the use of posttransplant
high-dose cyclophosphamide, have diminished the impact of HLA
mismatching, making transplantation between donor/recipient pairs
who share only one HLA haplotype possible. Since the formation of the
National Marrow Donor Program and other registries, HLA-matched
unrelated donors can be identified for many patients. The genes
encoding HLA antigens are highly polymorphic, and thus the odds of
any two unrelated individuals being HLA identical are extremely low,
somewhat less than 1 in 10,000. However, by recruiting >40 million
volunteer donors, HLA-matched donors can be found for ~60% of
patients for whom a search is initiated, with higher rates among whites
and lower rates among minorities and patients of mixed race. It takes,
on average, 3–4 months to complete a search and schedule and initiate
an unrelated donor transplant. With improvements in HLA typing and
supportive care measures, survival following matched unrelated donor
transplantation is essentially the same as that seen with HLA-matched
siblings.
Allogeneic hematopoietic cell transplantation can be carried out
across ABO blood barriers by removing isoagglutinins and/or incom­
patible red blood cells from the donor graft. However, depending on
the direction of the mismatch, hemolysis of donor cells by persistent
isoagglutinins in the host, or hemolysis of recipient red cells by isoag­
glutinins in the graft or developing from it may occur despite appropri­
ate manipulation of the donor cell product.
Autologous transplantation involves the removal and storage of the
patient’s own stem cells with subsequent reinfusion after the patient
receives high dose myeloablative therapy. Unlike allogeneic transplan­
tation, there is no risk of GVHD or graft rejection with autologous
transplantation. On the other hand, autologous transplantation lacks a
graft-versus-tumor (GVT) effect, and the autologous stem cell product
can be contaminated with tumor cells, which could lead to relapse. A
variety of techniques have been developed to “purge” autologous prod­
ucts of tumor cells, but no prospective randomized trials have shown
that any approach decreases relapse rates or improves disease-free or
overall survival.
Bone marrow aspirated from the posterior and anterior iliac crests
initially was the source of hematopoietic stem cells for transplantation.
Typically, anywhere from 1.5 to 5 × 108 nucleated marrow cells per
kilogram are collected for allogeneic transplantation. Several studies
have found improved survival following both matched sibling and
unrelated transplantation by transplanting higher numbers of bone
marrow cells.
Hematopoietic stem cells circulate in the peripheral blood but in
very low concentrations. Following the administration of a myeloid
growth factor such as granulocyte colony-stimulating factor (G-CSF)
and during recovery from intensive chemotherapy, the concentration
of hematopoietic progenitor cells in blood, as measured either by
colony-forming units or expression of the CD34 antigen, increases
markedly. This makes it possible to harvest adequate numbers of stem
cells from the peripheral blood for transplantation. Donors are typi­
cally treated with 4 or 5 days of hematopoietic growth factor, following
which stem cells are collected in one or two 4-h pheresis sessions. In
the autologous setting, transplantation of >2.5 × 106 CD34 cells per
kilogram, a number that can be collected in most circumstances, leads
to rapid and sustained engraftment in virtually all cases. In the 5–10%
of patients who fail to mobilize enough CD34+ cells with growth fac­
tor alone, the addition of plerixafor, an antagonist of CXCR4, may be
useful. Blocking CXCR4 allows more stem cells to escape the marrow.
When compared to the use of autologous marrow, use of periph­
eral blood stem cells results in more rapid hematopoietic recovery.
Although this more rapid recovery diminishes the morbidity rate of
transplantation, no studies show improved survival.
In the setting of allogeneic transplantation, the use of growth factor–
mobilized peripheral blood stem cells also results in faster engraftment
than seen with marrow but at the cost of more chronic GVHD because
of donor T-cell contamination. With matched sibling donors, the
increased chronic GVHD is more than balanced by reductions in rates
of relapse and nonrelapse mortality, resulting in improved overall sur­
vival. However, in the setting of matched unrelated donor transplanta­
tion, use of peripheral blood results in more chronic GVHD without
a compensatory survival advantage. Nonetheless, because of ease of
collection, peripheral blood continues to be the more commonly used
source of stem cells.
Umbilical cord blood contains a high concentration of hematopoietic
progenitor cells, allowing for its use as a source of stem cells for trans­
plantation. Cord blood transplantation from family members has been
used when the immediate need for transplantation precludes waiting
the 9 or so months generally required for the baby to mature to the
point of donating marrow. Use of cord blood results in slower peripheral
count recovery than seen with marrow but a lower incidence of GVHD,
perhaps reflecting the low number of T cells in cord blood. Multiple
cord blood banks have been developed to harvest and store cord blood
for possible transplantation to unrelated patients from material that
would otherwise be discarded. Currently >800,000 units are cryopre­
served and available for use. The advantages of unrelated cord blood are
rapid availability and decreased immune reactivity allowing for the use
of partially matched units, which is of particular importance for those
without matched unrelated donors. The risks of graft failure and trans­
plant-related mortality are related to the dose of cord blood cells per
kilogram, which previously limited the application of single cord blood
transplantation to pediatric and smaller adult patients. Subsequent trials
have found that for patients without suitable single cord units, the use
of double cord transplants diminishes the risk of graft failure and early
mortality even though only one of the donors ultimately engrafts. Given
the similar survival rates seen with cord blood, matched unrelated, and
haploidentical family member donors, a source of allogeneic stem cells
can now be found for almost every patient in need (Table 119-1).
TABLE 119-1  Probability of Identifying a Donor Based on Stem Cell
Source and Patient Ethnicity
 
UNRELATED ADULT %
UNRELATED CORD %
HAPLOIDENTICAL
Ethnicity
8/8a
7/8a
≥4/6b
 
Caucasian
95
Hispanic
Black
aMatching for HLA-A, -B, -C, and DRB1. bMatching for HLA-A, -B, and DRB1.
THE TRANSPLANT PREPARATIVE REGIMEN
The treatment regimen administered to patients immediately preced­
ing transplantation is designed to eradicate the patient’s underlying
disease and, in the setting of allogeneic transplantation, immunosup­
press the patient adequately to prevent rejection of the transplanted
stem cells. The appropriate regimen therefore depends on the dis­
ease setting and graft source. For example, when transplantation
is performed to treat severe combined immunodeficiency and the
donor is a histocompatible sibling, no preparative regimen is needed
because no host cells require eradication, and the patient is already
too immune incompetent to reject the transplanted graft. For aplastic
anemia, there is no large population of cells to eradicate, and highdose cyclophosphamide plus antithymocyte globulin are sufficient to
immunosuppress the patient adequately to accept the marrow graft. In
the setting of thalassemia and sickle cell anemia, high-dose busulfan is
frequently added to cyclophosphamide to eradicate hyperplastic host
hematopoiesis. A variety of different regimens have been developed
to treat malignant diseases. Most regimens include agents with high
activity against the tumor in question at conventional doses and with
myelosuppression as their predominant dose-limiting toxicity. There­
fore, these regimens commonly include busulfan, cyclophosphamide,
melphalan, thiotepa, carmustine, etoposide, and total-body irradiation
in various combinations.
CHAPTER 119
Although high-dose treatment regimens were the initial approach
to transplantation for malignancies, the realization that much of the
antitumor effect of transplantation derives from an immunologically
mediated GVT response led investigators to ask if reduced-intensity
conditioning regimens might be effective and more tolerable. Evidence
for a GVT effect comes from studies showing that posttransplant
relapse rates are lowest in patients who develop acute and chronic
GVHD, higher in those without GVHD, and higher still in recipients
of T cell–depleted allogeneic or syngeneic marrow. The demonstration
that complete remissions can be obtained in many patients who have
relapsed after transplant by simply administering viable lymphocytes
from the original donor further strengthens the argument for a potent
GVT effect. Accordingly, a variety of alternative regimens have been
studied, ranging from nonmyeloablative, which are the very minimum
required to achieve engraftment (e.g., fludarabine plus 200 cGy totalbody irradiation) and would cause only transient myelosuppression
if no transplant were performed, to so-called reduced-intensity regi­
mens, which would cause significant but not necessarily fatal myelo­
suppression in the absence of transplantation (e.g., fludarabine plus
melphalan). With the use of nonmyeloablative and reduced-intensity
regimens, engraftment is readily achieved with less toxicity than seen
with conventional transplantation. In general, relapse rates are higher
following reduced-intensity conditioning, but transplant-related mor­
tality is lower, favoring the use of reduced-intensity conditioning in
older patients and those with significant comorbidities. High-dose
regimens are favored in those felt able to tolerate the treatment, par­
ticularly if patients have any evidence of measurable disease at the time
of transplantation.
Hematopoietic Cell Transplantation
■
■THE TRANSPLANT PROCEDURE
Marrow is usually collected from the donor’s posterior and sometimes
anterior iliac crests, with the donor under general or spinal anesthesia.
Typically, 10–15 mL/kg of marrow is aspirated, placed in heparinized
media, and filtered through 0.3- and 0.2-mm screens to remove fat and
bony spicules. The collected marrow may undergo further processing
depending on the clinical situation, such as the removal of red cells to
prevent hemolysis in ABO-incompatible transplants, the removal of
donor T cells to prevent GVHD, or attempts to remove possible con­
taminating tumor cells in autologous transplantation. Marrow dona­
tion is safe, with only very rare complications reported.
Peripheral blood stem cells are collected by leukapheresis after
the donor has been treated with hematopoietic growth factors or, in
the setting of autologous transplantation, sometimes after treatment
with a combination of chemotherapy and growth factors. Stem cells
for transplantation are infused through a large-bore central venous
catheter. Such infusions are usually well tolerated, although occasion­
ally patients develop fever, cough, or shortness of breath. These symp­
toms typically resolve with slowing of the infusion. When the stem
cell product has been cryopreserved using dimethyl sulfoxide, patients
sometimes experience short-lived nausea or vomiting due to the taste
(and smell) of the cryoprotectant.
■
■ENGRAFTMENT AND IMMUNE RECONSTITUTION
Peripheral blood counts reach their nadir several days to a week after
transplant as a consequence of the preparative regimen; then cells pro­
duced by the transplanted stem cells begin to appear in the peripheral
blood. The rate of recovery depends on the source of stem cells and
use of posttransplant growth factors. If marrow is the source, recovery
to 100 granulocytes/μL occurs on average by day 16 and to 500/μL by
day 22. Use of G-CSF–mobilized peripheral blood stem cells speed the
rate of recovery by ~1 week compared to marrow, whereas engraftment
following cord blood transplantation is typically delayed by ~1 week.
Use of a myeloid growth factor after transplant accelerates recovery
by 3–5 days. Platelet counts usually recover shortly after granulocytes.
While granulocytes and other components of innate immunity
recover rapidly after hematopoietic cell transplantation, adaptive immu­
nity, which consists of cellular (T cell) and humoral (B cell) immunity,
may take 1–2 years to fully recover. Survival and peripheral expansion
of infused donor T cells is the dominant mechanism for T-cell recovery
in the first months after hematopoietic cell transplantation and results
in mostly CD8+ T cells with a limited repertoire. After several months,
de novo generation of donor-derived CD4+ and CD8+ T cells becomes
dominant, providing a more diverse T-cell repertoire. B-cell counts
recover by 6 months after autologous hematopoietic cell transplantation
and 9 months after allogeneic hematopoietic cell transplantation. In gen­
eral, immune recovery occurs more rapidly after autologous than alloge­
neic hematopoietic cell transplantation and after receipt of unmodified
grafts compared to the setting of in vivo or ex vivo T-cell depletion.
PART 4
Oncology and Hematology
Following allogeneic transplantation, engraftment can be docu­
mented using fluorescence in situ hybridization of sex chromosomes if
donor and recipient are sex-mismatched or by analysis of short tandem
repeat polymorphisms after DNA amplification.
■
■COMPLICATIONS FOLLOWING HEMATOPOIETIC
CELL TRANSPLANTATION
Early Direct Chemoradiotoxicities 
The transplant preparative
regimen may cause a spectrum of acute toxicities that vary according
to the intensity of the regimen and the specific agents used but fre­
quently include nausea, vomiting, and mild skin erythema (Fig. 119-1).
Pancytopenia
Neutropenia
Thrombocytopenia
Regimen-related
toxicities
Mucositis
SOS
Idiopathic pneumonia
Graft-vs-host
disease
Acute GVHD
Chronic GVHD
Infections
Bacterial
Fungal
Viral
Gram positive
Gram negative
Encapsulated bacteria
Candida
Aspergillus
HSV
CMV and adenovirus
VZV
Day 0
Day 30
Day 60
Day 90
Day 180
Day 360
FIGURE 119-1  Major syndromes complicating marrow transplantation. CMV,
cytomegalovirus; GVHD, graft-versus-host disease; HSV, herpes simplex virus; SOS,
sinusoidal obstructive syndrome (formerly venoocclusive disease); VZV, varicellazoster virus. The size of the shaded area roughly reflects the period of risk of the
complication.
High-dose cyclophosphamide can result in hemorrhagic cystitis, which
can usually be prevented by bladder irrigation or with the sulfhydryl
compound mercaptoethanesulfonate (MESNA). Most high-dose pre­
parative regimens will result in oral mucositis, which typically develops
5–7 days after transplant and often requires narcotic analgesia. Use of a
patient-controlled analgesic pump provides the greatest patient satisfac­
tion and results in a lower cumulative dose of narcotic. Keratinocyte
growth factor (palifermin) can shorten the duration of mucositis by
several days following autologous transplantation. Patients begin losing
their hair 5–6 days after transplant and by 1 week are usually profoundly
pancytopenic.
Depending on the intensity of the conditioning regimen, 3–10% of
patients will develop sinusoidal obstruction syndrome (SOS) of the
liver (formerly called venoocclusive disease), a syndrome that results
from direct cytotoxic injury to hepatic-venular and sinusoidal endo­
thelium, with subsequent deposition of fibrin and the development of
a local hypercoagulable state. This chain of events leads to the clinical
symptoms of tender hepatomegaly, ascites, jaundice, and fluid reten­
tion. These symptoms can develop any time during the first month
after transplant, with the peak incidence at day 16. Predisposing fac­
tors include prior exposure to intensive chemotherapy, pretransplant
hepatitis of any cause, and use of more intense conditioning regimens.
The mortality rate of sinusoidal obstruction syndrome is ~30%, with
progressive hepatic failure culminating in a terminal hepatorenal
syndrome. Treatment of severe SOS with defibrotide, a polydeoxyribo­
nucleotide, reduces mortality.
Although most pneumonias developing early after transplant are
caused by infectious agents, in a small percentage of patients, a diffuse
interstitial pneumonia will develop that is a result of direct toxicity of
high-dose preparative regimens. Bronchoalveolar lavage usually shows
alveolar hemorrhage, and biopsies are typically characterized by diffuse
alveolar damage, although some cases may have a more clearly inter­
stitial pattern. High-dose glucocorticoids or anti–tumor necrosis factor
therapies are sometimes used as treatment, although randomized trials
proving their utility have not been reported.
Transplant-associated thrombotic microangiopathy is seen in 5–10%
of patients, appearing on average about 1 month after transplant. The
syndrome is characterized by presence of schistocytes on peripheral
smear, elevated lactate dehydrogenase, thrombocytopenia, and acute
kidney injury and is the result of endothelial injury and complement
activation. Since calcineurin and mTOR inhibitors are thought to
contribute to the pathogenesis of the syndrome, changing immunosup­
pressive regimens is sometimes effective. Patients sometimes respond
to eculizumab.
Late Direct Chemoradiotoxicities 
Two categories of chronic
pulmonary disease occur in patients >3 months after hematopoietic
cell transplantation. Cryptogenic organizing pneumonia is a restrictive
lung disease characterized by dry cough, shortness of breath, and chest
imaging showing a diffuse, fluffy infiltrate. Biopsy shows granula­
tion tissue within alveolar spaces and small airways and no infectious
agents. The disease responds well to corticosteroids and is entirely
reversible. Bronchiolitis obliterans is an obstructive disease presenting
with cough, progressive dyspnea, and radiologic evidence of air trap­
ping. Pathology shows collagen and granulation tissue in and around
bronchial structures and eventually obliteration of small airways. The
disease is usually associated with chronic GVHD, and although it
may respond to increasing immunosuppression, complete reversal is
uncommon.
Other late complications of the preparative regimen include
decreased growth velocity in children and delayed development of
secondary sex characteristics. These complications can be partly
ameliorated with the use of appropriate growth and sex hormone
replacement. Most men become azoospermic, and most postpubertal
women will develop ovarian failure, which should be treated. However,
pregnancy is possible after transplantation, and patients should be
counseled accordingly. Thyroid dysfunction, usually well compen­
sated, is sometimes seen. Cataracts develop in 10–20% of patients and
are most common in patients treated with total-body irradiation and
those who receive glucocorticoid therapy after transplant for treat­
ment of GVHD. Aseptic necrosis of the femoral head is seen in 10% of
patients and is particularly frequent following chronic glucocorticoid
therapy. Both acute and late chemoradiotoxicities (except those due
to glucocorticoids and other agents used to treat GVHD) are less
frequent in recipients of reduced-intensity compared to high-dose
preparative regimens.
Graft Failure 
Although complete and sustained engraftment is
usually seen after transplant, occasionally marrow function either does
not return or, after a brief period of engraftment, is lost. Graft failure
after autologous transplantation can be the result of inadequate num­
bers of stem cells being transplanted, damage during ex vivo treatment
or storage, or exposure of the patient to myelotoxic agents after trans­
plant. Infections with cytomegalovirus (CMV) or human herpesvirus
type 6 have also been associated with loss of marrow function. Graft
failure after allogeneic transplantation can also be due to immunologic
rejection of the graft by immunocompetent host cells. Such rejection
is generally thought to be mostly T-cell–mediated, but the presence
before hematopoietic cell transplantation of donor-specific HLA anti­
bodies in the patient is associated with poor engraftment, leading to
the recommendation for screening for donor-directed anti-HLA anti­
bodies in recipients prior to transplant. Immunologically based graft
rejection is more common following use of less immunosuppressive
preparative regimens, in recipients of T-cell–depleted stem cell prod­
ucts, and in patients receiving grafts from HLA-mismatched donors or
cord blood.
Treatment of graft failure involves removing all potentially myelo­
toxic agents from the patient’s regimen and attempting a short trial
of a myeloid growth factor. Persistence of lymphocytes of host origin
in allogeneic transplant recipients with graft failure indicates immu­
nologic rejection. Reinfusion of donor stem cells in such patients is
usually unsuccessful unless preceded by a second immunosuppressive
preparative regimen. Standard high-dose preparative regimens are
tolerated poorly if administered within 100 days of a first transplant
because of cumulative toxicities. However, reduced-intensity condi­
tioning regimens have been effective in some cases.
Graft-Versus-Host Disease 
Acute GVHD occurs within the
first 3 months after allogeneic transplant with a peak onset around
4 weeks and is characterized by an erythematous maculopapular rash;
by persistent anorexia or diarrhea, or both; and by liver disease with
increased serum levels of bilirubin, alanine and aspartate aminotrans­
ferase, and alkaline phosphatase. Because many conditions can mimic
acute GVHD, the diagnosis usually requires skin, liver, or endoscopic
biopsy for confirmation. In all these organs, endothelial damage and
lymphocytic infiltrates are seen. In skin, the epidermis and hair follicles
are damaged; in liver, the small bile ducts show segmental disruption;
and in intestines, destruction of the crypts and mucosal ulceration may
be noted. A commonly used rating system for acute GVHD is shown
in Table 119-2. Grade I acute GVHD is of little clinical significance,
does not affect the likelihood of survival, and does not require treat­
ment. In contrast, grades II to IV GVHD are associated with significant
symptoms and a poorer probability of survival and require aggressive
TABLE 119-2  Clinical Staging and Grading of Acute Graft-Versus-Host Disease
CLINICAL STAGE
SKIN
LIVER—BILIRUBIN, kmol/L (mg/dL)
GUT
Rash <25% body surface
34–51 (2–3)
Diarrhea 500–1000 mL/d
Rash 25–50% body surface
51–103 (3–6)
Diarrhea 1000–1500 mL/d
Generalized erythroderma
103–257 (6–15)
Diarrhea >1500 mL/d
Desquamation and bullae
257 (>15)
Ileus
OVERALL CLINICAL GRADE
SKIN STAGE
LIVER STAGE
GUT STAGE
I
1–2
II
1–3
III
1–3
2–3
2–3
IV
2–4
2–4
2–4
therapy. The incidence of acute GVHD is higher in recipients of stem
cells from mismatched or unrelated donors, in older patients, and
in patients unable to receive full doses of drugs used to prevent the
disease.
Historically, the standard approach to GVHD prevention was the
administration of a calcineurin inhibitor (cyclosporine or tacrolimus)
paired with an antimetabolite (most commonly methotrexate) follow­
ing transplantation. Prospective randomized trials have demonstrated
the benefit of adding a third drug, either mycophenolate mofetil, abata­
cept, or posttransplant cyclophosphamide, to the two-drug regimen.
Other approaches include the addition of anti–T-cell immune globulin
(ATG) to the GVHD prophylactic regimen or the removal of subsets or
all T cells from the stem cell inoculum.
Despite prophylaxis, significant acute GVHD will develop in ~30%
of recipients of stem cells from matched siblings. Factors associated
with a greater risk of acute GVHD include HLA-mismatching between
recipient and donor, patient and donor age, use of more intense pre­
parative regimens, and use of multiparous women as donors. Presum­
ably, multiparous women have more alloreactivity based on carriage
of genetically disparate fetuses. Disruption of the intestinal microbiota
leading to loss of diversity and overgrowth by a single taxon is associ­
ated with a higher risk of GVHD and transplant-associated mortality.
Biomarkers, including ST2, REG32, and TNF R1, have been identified
that predict the severity of acute GVHD. The disease is usually treated
with prednisone at a daily dose of 1–2 mg/kg. Patients in whom the
acute GVHD fails to respond to prednisone sometimes respond to the
oral JAK2 inhibitor ruxolitinib.
CHAPTER 119
Chronic GVHD occurs most commonly between 3 months and
2 years after allogeneic transplant, developing in 20–50% of recipients.
The disease is more common in older patients, with the use of periph­
eral blood rather than marrow as the stem cell source, in recipients of
mismatched or unrelated stem cells, and in those with a preceding epi­
sode of acute GVHD. The disease resembles an autoimmune disorder
with malar rash, sicca syndrome, arthritis, obliterative bronchiolitis,
and bile duct degeneration with cholestasis. Mild chronic GVHD can
sometimes be managed using local therapies (topical glucocorticoids
to skin and cyclosporine eye drops). More severe disease requires
systemic therapy usually with prednisone, which leads to responses
in 40–60% of patients. Three drugs have received U.S. Food and Drug
Administration approval for the treatment of steroid-resistant chronic
GVHD: ibrutinib, ruxolitinib, and belumosudil. All three are kinase
inhibitors, a class of compounds that reduces growth signals and
activation of key cellular proteins involved with cell activation, migra­
tion, and proliferation. Mortality rates from chronic GVHD average
around 15% but range from 5 to 50% depending on severity. In most
patients, chronic GVHD resolves, but it may require 1–3 years of
immunosuppressive treatment before these agents can be withdrawn
without the disease recurring. Because patients with chronic GVHD
are susceptible to significant infection, they should receive prophylactic
trimethoprim-sulfamethoxazole, and all suspected infections should be
investigated and treated aggressively.
Hematopoietic Cell Transplantation
Although onset before or after 3 months after transplant is often
used to discriminate between acute and chronic GVHD, occasional
patients will develop signs and symptoms of acute GVHD after 3 months
(late-onset acute GVHD), whereas others will exhibit signs and symp­
toms of both acute and chronic GVHD (overlap syndrome). No data
suggest that these patients should be treated differently than those with
classic acute or chronic GVHD.
From 3 to 5% of patients will develop an autoimmune disorder
following allogeneic hematopoietic cell transplantation, most com­
monly autoimmune hemolytic anemia or idiopathic thrombocyto­
penic purpura. Unrelated donor source and chronic GVHD are risk
factors, but autoimmune disorders have been reported in patients
with no obvious GVHD. Treatment is with prednisone, cyclosporine,
or rituximab.
Infection 
Posttransplant patients, particularly recipients of allo­
geneic transplantation, require unique approaches to the problem of
infection. Early after transplantation, patients are profoundly neutro­
penic, and because the risk of bacterial infection is so great, most cen­
ters place patients on broad-spectrum antibiotics once the granulocyte
count falls to <500/μL. Prophylaxis against fungal infections reduces
rates of infection and improves overall survival. Fluconazole is often
used for patients with standard risk, while prophylaxis with mold active
agents (voriconazole, posaconazole, or isavuconazonium) should be
considered for patients at higher risk, such as those with a prior fun­
gal infection. Patients seropositive for herpes simplex should receive
acyclovir or valacyclovir prophylaxis. One approach to infection pro­
phylaxis is shown in Table 119-3. Despite these prophylactic measures,
most patients will develop fever and signs of infection after transplant.
The management of patients who become febrile despite bacterial and
fungal prophylaxis is a difficult challenge and is guided by individual
aspects of the patient and by the institution’s experience.
PART 4
Oncology and Hematology
The general problem of infection in the immunocompromised host
is discussed in Chap. 148.
Once patients engraft, the incidence of bacterial infection dimin­
ishes; however, patients, particularly allogeneic transplant recipients,
remain at significant risk of infection. During the period from engraft­
ment until about 3 months after transplant, the most common causes
of infection are gram-positive bacteria, fungi (particularly Aspergillus),
and viruses including CMV. CMV disease, which in the past was fre­
quently seen and often fatal, can be prevented in seronegative patients
transplanted from seronegative donors using either seronegative
blood products or products from which the white blood cells have
been removed. In seropositive patients or patients transplanted from
seropositive donors, either prophylaxis or preemptive therapy is used.
Letermovir administered over the first 3 months after transplant is
effective as prophylaxis. An alternative approach is to monitor blood
of patients after transplant using polymerase chain reaction assays
for viral DNA and to treat reactivation preemptively with ganciclovir
before clinical disease develops. Foscarnet is effective for some patients
who develop CMV antigenemia or infection despite the use of ganci­
clovir or who cannot tolerate the drug, but it can be associated with
severe electrolyte wasting.
TABLE 119-3  Approach to Infection Prophylaxis in Allogeneic
Transplant Recipients
ORGANISM
AGENT
APPROACH
Bacterial
Levofloxacin
750 mg PO or IV daily
Fungal
Fluconazole
400 mg PO qd to day 75
posttransplant
Pneumocystis jirovecii
Trimethoprimsulfamethoxazole
1 double-strength tablet PO bid
2 days/week until day 180 or off
immunosuppression
Viral
 
 
Herpes simplex
Acyclovir
800 mg PO bid to day 30
Varicella-zoster
Acyclovir
800 mg PO bid to day 365
Cytomegalovirus
Ganciclovir
5 mg/kg IV bid for 7 days, then
5 (mg/kg)/d 5 days/week to
day 100
Pneumocystis jirovecii pneumonia, once seen in 5–10% of patients,
can be prevented by treating patients with oral trimethoprim-sulfa­
methoxazole for 1 week before transplant and resuming the treatment
once patients engraft.
Respiratory viruses that cause community-acquired infections,
including respiratory syncytial virus (RSV), parainfluenza virus, influ­
enza virus, and metapneumovirus, can be life threatening or fatal in
the posttransplant patient. Protection of patients from infected visitors
and staff by avoiding such contacts is critical. Neuraminidase inhibi­
tors are effective for influenza infections. Oral or inhaled ribavirin is
sometimes used for RSV.
The risk of infection diminishes considerably beyond 3 months
after transplant unless chronic GVHD requiring continuous immu­
nosuppression develops. Most transplant centers recommend continu­
ing trimethoprim-sulfamethoxazole prophylaxis while patients are
receiving any immunosuppressive drugs and also recommend careful
monitoring for late CMV reactivation. In addition, many centers rec­
ommend prophylaxis against varicella-zoster, using acyclovir for 1 year
after transplant. Antibody titers to vaccine-preventable diseases (e.g.,
tetanus, polio, mumps, rubella, and encapsulated organisms) decline
after allogeneic or autologous transplantation if the recipient is not
revaccinated. Vaccination begins at 3 months after transplantation for
SAR-CoV-2 and 6 months for influenza (or 3–4 months when seasonal
prevalence is high). Other nonlive routine childhood vaccinations
should be repeated, usually starting at 12 months after transplantation.
Live vaccines (measles, mumps, and rubella [MMR] or MMR plus
varicella [MMR-V]) are generally not administered before 2 years after
hematopoietic cell transplantation.
TREATMENT
Nonmalignant Diseases
Evidence-based indications for hematopoietic cell transplantation
have been published by several organizations and are guided not
only by disease-related factors but also by patient comorbidities,
socioeconomic issues, caregiver and donor availability, and patient
preference.
IMMUNODEFICIENCY DISORDERS
By replacing abnormal stem cells with cells from a normal donor,
hematopoietic cell transplantation can cure patients of a variety of
immunodeficiency disorders including severe combined immu­
nodeficiency, Wiskott-Aldrich syndrome, and Chédiak-Higashi
syndrome. The widest experience is with severe combined immu­
nodeficiency disease, where cure rates of >90% can be expected
with allogeneic transplantation from a suitable related or unrelated
donor when carried out shortly after birth (Table 119-4). Treatment
of severe refractory autoimmune diseases with hematopoietic stem
cell transplantation is also beginning to be explored (see below).
APLASTIC ANEMIA
Transplantation from matched siblings after a preparative regimen
of high-dose cyclophosphamide and antithymocyte globulin cures
95% of patients age <40 years with severe aplastic anemia. Histori­
cally, results in older patients and in recipients of mismatched fam­
ily member or unrelated marrow were less favorable, and therefore,
a trial of immunosuppressive therapy was recommended for such
patients before considering transplantation. However, results with
transplantation have improved leading many to recommend trans­
plantation as initial therapy. Transplantation is effective in all forms
of aplastic anemia including, for example, the syndromes associated
with paroxysmal nocturnal hemoglobinuria and Fanconi’s anemia.
Patients with Fanconi’s anemia are abnormally sensitive to the toxic
effects of alkylating agents, and so less intensive preparative regi­
mens are used in their treatment (Chap. 107).
HEMOGLOBINOPATHIES
Marrow transplantation from an HLA-identical sibling following
a preparative regimen of busulfan and cyclophosphamide can cure
TABLE 119-4  Estimated 3-Year Survival Rates Following
Transplantationa
DISEASE
ALLOGENEIC, %
AUTOLOGOUS, %
Severe combined immunodeficiency
NA
Aplastic anemia
NA
Thalassemia
NA
Acute myeloid leukemia
 
 
  First remission
ID
  Second remission
ID
Acute lymphocytic leukemia
 
 
  First remission
ID
  Second remission
ID
Chronic myeloid leukemia
 
 
  Chronic phase
NA
  Accelerated phase
NA
  Blast crisis
NA
Chronic lymphocytic leukemia
NA
Myelodysplasia
NA
Multiple myeloma—initial therapy
NA
Non-Hodgkin’s lymphoma
 
 
  First relapse/second remission
Hodgkin’s disease
 
 
  First relapse/second remission
aThese estimates are mostly based on results of transplants performed between
2010 and 2020 reported by the Center for International Blood and Marrow Transplant
Research (CIBMTR). The analysis has not been reviewed by their Advisory
Committee.
Abbreviations: ID, insufficient data; NA, not applicable.
80–90% of patients with thalassemia major. The best outcomes can
be expected if patients are transplanted before they develop hepa­
tomegaly or portal fibrosis and if they have been given adequate
iron chelation therapy. Among such patients, the probabilities of
5-year survival and disease-free survival are 95 and 90%, respec­
tively. Although prolonged survival can be achieved with aggressive
chelation therapy, transplantation is the only curative treatment for
thalassemia. Transplantation is potentially curative for patients with
sickle cell anemia. Two-year survival and disease-free survival rates
of 95 and 85%, respectively, have been reported following matched
sibling or cord blood transplantation. Decisions about patient selec­
tion and the timing of transplantation remain difficult, but trans­
plantation is a reasonable option for children and young adults who
have suffered complications of sickle cell anemia including stroke,
recurrent vasoocclusive pain, sickle cell lung disease, or sickle
nephropathy (Chap. 103). As new gene therapies become available,
the indications for allogeneic hematopoietic cell transplantation for
thalassemia and sickle cell disease may change.
OTHER NONMALIGNANT DISEASES
Theoretically, hematopoietic cell transplantation should be able to
cure any disease that results from an inborn error of the lymphohe­
matopoietic system. Transplantation has been used successfully to
treat congenital disorders of white blood cells such as Kostmann’s
syndrome, chronic granulomatous disease, and leukocyte adhesion
deficiency. Congenital anemias such as Blackfan-Diamond anemia
can also be cured with transplantation. Since the penetrance of
some congenital marrow failure states is variable, potential family
member donors should be carefully screened before use to assure
they are not affected. Infantile malignant osteopetrosis is due to an
inability of the osteoclast to resorb bone, and because osteoclasts
derive from the marrow, transplantation can cure this rare inherited
disorder.
Hematopoietic cell transplantation has been used as treatment
for several storage diseases caused by enzymatic deficiencies, such
as Gaucher’s disease, Hurler’s syndrome, Hunter’s syndrome, and
infantile metachromatic leukodystrophy. Transplantation for these
diseases has not been uniformly successful, but treatment early in
the course of these diseases, before irreversible damage to extra­
medullary organs has occurred, increases the chance for success.
Transplantation is being applied as a treatment for severe
acquired autoimmune disorders. These approaches are based on
studies demonstrating that transplantation can reverse autoimmune
disorders in animal models and on the observation that occasional
patients with coexisting autoimmune disorders and hematologic
malignancies have been cured of both with transplantation. A
prospective randomized trial found that patients with severe sclero­
derma have improved event-free and overall survival if treated with
hematopoietic cell transplantation. Randomized studies are explor­
ing a similar approach for patients with multiple sclerosis.
ACUTE LEUKEMIA
Allogeneic hematopoietic cell transplantation cures ~30% of
patients who do not achieve a complete response after induction
chemotherapy for acute myeloid leukemia (AML) and is the only
form of therapy that can cure such patients. Thus, all patients with
AML who are possible transplant candidates should have their
HLA type determined soon after diagnosis to enable hematopoietic
cell transplantation for those who fail to enter remission. Cure
rates of 45–50% are seen when patients are transplanted in sec­
ond remission or in first relapse. The best results with allogeneic
transplantation are achieved when applied during first remission,
with long-term disease-free survival rates averaging 55–60%. Metaanalyses of studies comparing matched related donor transplanta­
tion to chemotherapy for adult AML patients age <60 years show a
survival advantage with transplantation. This advantage is greatest
for those with adverse and intermediate-risk disease but is not seen
in patients with favorable-risk AML. Some centers rely on measure­
ments of minimal residual disease (MRD) as determined by either
multidimensional flow cytometry or molecular methods to further
define transplant candidacy, proceeding with transplantation in
otherwise favorable risk patients if MRD positive and withholding
transplantation in MRD-negative intermediate-risk patients. While
hematopoietic cell transplantation can be performed in patients up
to age 80, prospective trials comparing hematopoietic cell trans­
plantation with chemotherapy are lacking for older patients. Autol­
ogous transplantation has no defined role in the treatment of AML.
CHAPTER 119
Hematopoietic Cell Transplantation
Similar to patients with AML, adults with acute lymphocytic
leukemia who do not achieve a complete response to induction
chemotherapy can be cured in ~30% of cases with immediate
transplantation. Cure rates improve to 40–50% in second remis­
sion, and therefore, transplantation can be recommended for adults
who have persistent disease after induction chemotherapy or who
subsequently relapse. Transplant outcomes in second remission are
improved if carried out when MRD assessments are negative, and
so use of agents such as blinatumomab to achieve an MRD-negative
state before transplantation is recommended. Transplantation in
first remission results in cure rates of about 65%. Transplanta­
tion appears to offer a survival advantage over chemotherapy for
patients with high-risk disease as defined by molecular profiling.
Debate continues about whether adults with standard-risk disease
should be transplanted in first remission or whether transplanta­
tion should be reserved until relapse. Autologous transplantation
is associated with a higher relapse rate but a somewhat lower risk
of nonrelapse mortality when compared to allogeneic transplanta­
tion. Autologous transplantation has no obvious role in treatment
for acute lymphocytic leukemia in first remission, and for secondremission patients, most experts recommend use of allogeneic stem
cells if an appropriate donor is available.
CHRONIC LEUKEMIA
Allogeneic hematopoietic cell transplantation is indicated for
patients with chronic myeloid leukemia (CML) who are in chronic
phase but have failed therapy with two or more tyrosine kinase
inhibitors. In such patients, cure rates of 70% can be expected.
Hematopoietic cell transplantation is also recommended for
patients with CML who present or progress to accelerated phase
or blast crisis, although lower cure rates are seen in such patients
(Chap. 110).
Although allogeneic transplantation can cure patients with
chronic lymphocytic leukemia (CLL), it has not been extensively
studied because of the chronic nature of the disease, the age profile
of patients, and more recently, the availability of multiple effective
therapies. In those cases where it was studied, complete remissions
were achieved in the majority of patients, with disease-free survival
rates of ~65% at 3 years, despite the advanced stage of the disease at
the time of transplant.
MYELODYSPLASIA AND MYELOPROLIFERATIVE
DISORDERS
Between 40 and 65% of patients with myelodysplasia can be cured
with allogeneic transplantation. Results are better among younger
patients and those with less advanced disease. However, patients
with early-stage myelodysplasia can live for extended periods with­
out intervention, and so transplantation is generally reserved for
patients with an International Prognostic Scoring System (IPSS)
score of Int-2 or higher, or for selected patients with an IPSS score
of Int-1 who have other poor prognostic features (Chap. 107). Allo­
geneic hematopoietic cell transplantation can cure patients with
primary myelofibrosis or myelofibrosis secondary to polycythemia
vera or essential thrombocythemia, with 5-year progression-free
survival rates in excess of 65% being reported. It may require many
months for the fibrosis to resolve.
LYMPHOMA
Patients with disseminated intermediate- or high-grade non-Hodgkin’s
lymphoma who have not been cured by first-line chemotherapy
and are transplanted in first relapse or second remission can still
be cured in 50–60% of cases. This represents a clear advantage over
results obtained with conventional-dose salvage chemotherapy. It
is unsettled whether patients with high-risk disease benefit from
transplantation in first remission. Most experts favor the use of
autologous rather than allogeneic transplantation for patients with
intermediate- or high-grade non-Hodgkin’s lymphoma, because
fewer complications occur with this approach and survival appears
equivalent. The use of chimeric antigen receptor T cells targeting
CD19 has been reported to yield results similar to those achieved
with autologous stem cell transplantation. As yet, no consensus has
been reached about how to sequence these two therapies. Although
autologous transplantation results in high response rates in patients
with recurrent disseminated indolent non-Hodgkin’s lymphoma,
the availability of newer agents for this category of patient leaves
the role of transplantation unsettled. Reduced-intensity condition­
ing regimens followed by allogeneic transplantation result in high
rates of complete and enduring complete responses in patients with
recurrent indolent lymphomas.
PART 4
Oncology and Hematology
The role of transplantation in Hodgkin’s lymphoma is similar to
that in intermediate- and high-grade non-Hodgkin’s lymphoma.
With transplantation, 3-year disease-free survival is 40–50% in
patients who never achieved a first remission with standard chemo­
therapy and up to 80% for those transplanted in second remission.
Transplantation has no defined role in first remission in Hodgkin’s
lymphoma.
MYELOMA
Patients with myeloma whose disease progresses after first-line
therapy can sometimes benefit from allogeneic or autologous trans­
plantation. Prospective randomized studies demonstrate that the
inclusion of autologous transplantation as part of initial ther­
apy results in improved disease-free survival and overall survival.
Further benefit is seen with the use of lenalidomide mainte­
nance therapy following transplantation. The use of autologous
transplantation followed by nonmyeloablative allogeneic transplan­
tation has yielded mixed results.
SOLID TUMORS
Patients with testicular cancer in whom first-line platinum-containing
chemotherapy has failed can still be cured in ~50% of cases if
treated with high-dose chemotherapy with autologous stem cell
support, an outcome better than that seen with low-dose salvage
chemotherapy. The use of high-dose chemotherapy with autologous
stem cell support is being studied for several other solid tumors,
including neuroblastoma and pediatric sarcomas. As in most other
settings, the best results were obtained in patients with limited
amounts of disease and in whom the remaining tumor remains sen­
sitive to conventional-dose chemotherapy. Few randomized trials of
transplantation in these diseases have been completed.
POSTTRANSPLANT RELAPSE
Patients who relapse following autologous transplantation some­
times respond to further chemotherapy and may be candidates
for possible allogeneic transplantation, particularly if the remis­
sion following the initial autologous transplant was long. Several
options are available for patients who relapse following allogeneic
transplantation. Treatment with infusions of unirradiated donor
lymphocytes results in complete responses in as many as 75% of
patients with chronic myeloid leukemia, 40% with myelodysplasia,
25% with AML, and 15% with myeloma. Major complications of
donor lymphocyte infusions include transient myelosuppression
and the development of GVHD. These complications depend on the
number of donor lymphocytes given and the schedule of infusions,
with less GVHD seen with lower dose, fractionated schedules.
■
■FURTHER READING
Dadwal SS et al: How I prevent viral reactivation in high-risk patients.
Blood 141:2062, 2023.
DeFilipp Z et al: Hematopoietic cell transplantation in the treatment
of adult acute lymphoblastic leukemia: Updated 2019 evidence-based
review from the American Society for Transplantation and Cellular
Therapy. Biol Blood Marrow Transplant 25:2113, 2019.
Duarte RF et al: Indications for haematopoietic stem cell transplanta­
tion for haematological diseases, solid tumours and immune disor­
ders: current practice in Europe, 2019. Bone Marrow Transplantation
54:1525, 2019.
Jamy O et al: Novel developments in the prophylaxis and treatment of
acute GVHD. Blood 142:1037, 2023.
McDonald GB et al: Survival, nonrelapse mortality, and relapserelated mortality after allogeneic hematopoietic cell transplantation:
Comparing 2003-2007 versus 2013-2017 cohorts. Ann Intern Med
172:229, 2020.
Miller PDE et al: Joint consensus statement on the vaccination of
adult and paediatric haematopoietic stem cell transplant recipients:
Prepared on behalf of the British Society of Blood and Marrow Trans­
plantation and Cellular Therapy (BSBMTCT), the Children’s Cancer
and Leukaemia Group (CCLG), and British Infection Association
(BIA). J Infect 86:1, 2023.
Niederwieser D et al: One and a half million hematopoietc stem cell
transplants: Continuous and differential improvement in worldwide
access with the use of non-identical family donors. Haematologica
107:1045, 2022.
Scott BL et al: Myeloablative versus reduced-intensity conditioning
for hematopoietic cell transplantation in acute myelogenous leuke­
mia and myelodysplastic syndromes: Long-term follow-up of the
BMT CTN 0901 clinical trial. Transplant Cell Ther 27:483, 2021.
Westin J, Sehn LH: CAR T cells as a second-line therapy for large
B-cell lymphoma: A paradigm shift? Blood 139:2737, 2022.
Zeiser R, Lee SJ: Three Food and Drug Administration-approved
therapies for chronic GVHD. Blood 139:1642, 2022.

50 - SECTION 3 Disorders of Hemostasis
SECTION 3 Disorders of Hemostasis
Section 3	 Disorders of Hemostasis
Barbara A. Konkle
Disorders of Platelets
and Vessel Wall
Hemostasis is a dynamic process in which the platelet and the blood
vessel wall play key roles. Platelets are activated upon adhesion to von
Willebrand factor (VWF) and collagen in the exposed subendothelium
after injury. Platelet activation is also mediated through shear forces
imposed by blood flow itself, particularly in areas where the vessel wall
is diseased, and is also affected by the inflammatory state of the endo­
thelium. The activated platelet surface provides the major physiologic
site for coagulation factor activation, which results in further platelet
activation and fibrin formation. Genetic and acquired influences on
the platelet and vessel wall, as well as on the coagulation and fibrino­
lytic systems, determine whether normal hemostasis or bleeding or
clotting symptoms will result.
THE PLATELET
Platelets are released from the megakaryocyte, likely under the influ­
ence of flow in the capillary sinuses. The normal blood platelet count is
150,000–450,000/μL. The major regulator of platelet production is the
hormone thrombopoietin (TPO), which is synthesized in the liver and
other organs. Synthesis is increased with inflammation and specifically
by interleukin 6. TPO binds to its receptor on platelets and megakaryo­
cytes, by which it is removed from the circulation. Thus, a reduction
in platelet and megakaryocyte mass increases the level of TPO, which
then stimulates platelet production. Platelets circulate with an average
life span of 7–10 days. Approximately one-third of the platelets reside
in the spleen, and this number increases in proportion to splenic size,
although the platelet count rarely decreases to <40,000/μL as the spleen
enlarges. Platelets are physiologically very active, but are anucleate, and
thus have limited capacity to synthesize new proteins.
Normal vascular endothelium contributes to preventing thrombosis
by inhibiting platelet function (Chap. 69). When vascular endothelium
is injured, these inhibitory effects are overcome, and platelets adhere
to the exposed intimal surface primarily through VWF, a large multi­
meric protein present in both plasma and in the extracellular matrix of
the subendothelial vessel wall. Platelet adhesion results in the genera­
tion of intracellular signals that lead to activation of the platelet glyco­
protein (Gp) IIb/IIIa (αIIbβ3) receptor and resultant platelet aggregation.
Activated platelets undergo release of their granule contents, which
include nucleotides, adhesive proteins, growth factors, and procoagu­
lants that serve to promote platelet aggregation and blood clot forma­
tion and influence the environment of the forming clot. During platelet
aggregation, additional platelets are recruited to the site of injury,
leading to the formation of an occlusive platelet thrombus. The platelet
plug is stabilized by the fibrin mesh that develops simultaneously as the
product of the coagulation cascade.
THE VESSEL WALL
Endothelial cells line the surface of the entire circulatory tree, totaling
1–6 × 1013 cells, enough to cover a surface area equivalent to about
six tennis courts. The endothelium is physiologically active, control­
ling vascular permeability, flow of biologically active molecules and
nutrients, blood cell interactions with the vessel wall, the inflammatory
response, and angiogenesis.
The endothelium normally presents an antithrombotic surface
(Chap. 69) but rapidly becomes prothrombotic when stimulated,
which promotes coagulation, inhibits fibrinolysis, and activates plate­
lets. In many cases, endothelium-derived vasodilators are also platelet
inhibitors (e.g., nitric oxide), and conversely, endothelium-derived
vasoconstrictors (e.g., endothelin) can also be platelet activators.
The net effect of vasodilation and inhibition of platelet function is to
promote blood fluidity, whereas the net effect of vasoconstriction and
platelet activation is to promote thrombosis. Thus, blood fluidity and
hemostasis are regulated by the balance of antithrombotic/prothrom­
botic and vasodilatory/vasoconstrictor properties of endothelial cells.
DISORDERS OF PLATELETS
■
■THROMBOCYTOPENIA
Thrombocytopenia results from one or more of three processes: (1)
decreased bone marrow production; (2) sequestration, usually in an
enlarged spleen; and/or (3) increased platelet destruction. Disorders of
production may be either inherited or acquired. In evaluating a patient
with thrombocytopenia, a key step is to review the peripheral blood
smear and to first rule out “pseudothrombocytopenia,” particularly in
a patient without an apparent cause for the thrombocytopenia. Pseu­
dothrombocytopenia (Fig. 120-1B) is an in vitro artifact resulting from
platelet agglutination via antibodies (usually IgG, but also IgM and
IgA) when the calcium content is decreased by blood collection in eth­
ylenediamine tetraacetic (EDTA) (the anticoagulant present in tubes
[purple top] used to collect blood for complete blood counts [CBCs]).
If a low platelet count is obtained in EDTA-anticoagulated blood, a
blood smear should be evaluated and a platelet count determined in
blood collected into sodium citrate (blue top tube) or heparin (green
top tube), or a smear of freshly obtained unanticoagulated blood, such
as from a finger stick, can be examined.
CHAPTER 120
Disorders of Platelets and Vessel Wall
APPROACH TO THE PATIENT
Thrombocytopenia
The history and physical examination, results of the CBC, and
review of the peripheral blood smear are all critical components in
the initial evaluation of thrombocytopenic patients (Fig. 120-2).
The overall health of the patient and whether they are receiving
drug treatment will influence the differential diagnosis. A healthy
young adult with thrombocytopenia will have a much more lim­
ited differential diagnosis than an ill hospitalized patient who is
receiving multiple medications. Except in less common inherited
disorders, decreased platelet production usually results from bone
marrow disorders that also affect red blood cell (RBC) and/or white
blood cell (WBC) production. Because myelodysplasia can present
with isolated thrombocytopenia, the bone marrow should be exam­
ined in patients presenting with isolated thrombocytopenia who are
older than 60 years of age or who do not respond to initial therapy.
While inherited thrombocytopenia is uncommon, any prior platelet
counts should be retrieved and a family history regarding thrombo­
cytopenia obtained. A careful history of drug ingestion should be
obtained, including nonprescription and herbal remedies, because
drugs are the most common cause of thrombocytopenia.
The physical examination can document an enlarged spleen,
evidence of chronic liver disease, and other underlying disorders.
Mild to moderate splenomegaly may be difficult to appreciate in
many individuals due to body habitus and/or obesity but can be eas­
ily assessed by abdominal ultrasound. A platelet count of approxi­
mately 5000–10,000 is required to maintain vascular integrity in the
microcirculation. When the count is markedly decreased, petechiae
first appear in areas of increased venous pressure, the ankles and
feet in an ambulatory patient. Petechiae are pinpoint, nonblanching
hemorrhages and are usually a sign of a decreased platelet num­
ber and not platelet dysfunction. Wet purpura, blood blisters that
form on the oral mucosa, are thought to denote an increased risk
of life-threatening hemorrhage in the thrombocytopenic patient.
Excessive bruising is seen in disorders of both platelet number and
function.
Infection-Induced Thrombocytopenia 
Many viral and bacte­
rial infections result in thrombocytopenia and are the most common

51 - 120 Disorders of Platelets and Vessel Wall
120 Disorders of Platelets and Vessel Wall
Section 3	 Disorders of Hemostasis
Barbara A. Konkle
Disorders of Platelets
and Vessel Wall
Hemostasis is a dynamic process in which the platelet and the blood
vessel wall play key roles. Platelets are activated upon adhesion to von
Willebrand factor (VWF) and collagen in the exposed subendothelium
after injury. Platelet activation is also mediated through shear forces
imposed by blood flow itself, particularly in areas where the vessel wall
is diseased, and is also affected by the inflammatory state of the endo­
thelium. The activated platelet surface provides the major physiologic
site for coagulation factor activation, which results in further platelet
activation and fibrin formation. Genetic and acquired influences on
the platelet and vessel wall, as well as on the coagulation and fibrino­
lytic systems, determine whether normal hemostasis or bleeding or
clotting symptoms will result.
THE PLATELET
Platelets are released from the megakaryocyte, likely under the influ­
ence of flow in the capillary sinuses. The normal blood platelet count is
150,000–450,000/μL. The major regulator of platelet production is the
hormone thrombopoietin (TPO), which is synthesized in the liver and
other organs. Synthesis is increased with inflammation and specifically
by interleukin 6. TPO binds to its receptor on platelets and megakaryo­
cytes, by which it is removed from the circulation. Thus, a reduction
in platelet and megakaryocyte mass increases the level of TPO, which
then stimulates platelet production. Platelets circulate with an average
life span of 7–10 days. Approximately one-third of the platelets reside
in the spleen, and this number increases in proportion to splenic size,
although the platelet count rarely decreases to <40,000/μL as the spleen
enlarges. Platelets are physiologically very active, but are anucleate, and
thus have limited capacity to synthesize new proteins.
Normal vascular endothelium contributes to preventing thrombosis
by inhibiting platelet function (Chap. 69). When vascular endothelium
is injured, these inhibitory effects are overcome, and platelets adhere
to the exposed intimal surface primarily through VWF, a large multi­
meric protein present in both plasma and in the extracellular matrix of
the subendothelial vessel wall. Platelet adhesion results in the genera­
tion of intracellular signals that lead to activation of the platelet glyco­
protein (Gp) IIb/IIIa (αIIbβ3) receptor and resultant platelet aggregation.
Activated platelets undergo release of their granule contents, which
include nucleotides, adhesive proteins, growth factors, and procoagu­
lants that serve to promote platelet aggregation and blood clot forma­
tion and influence the environment of the forming clot. During platelet
aggregation, additional platelets are recruited to the site of injury,
leading to the formation of an occlusive platelet thrombus. The platelet
plug is stabilized by the fibrin mesh that develops simultaneously as the
product of the coagulation cascade.
THE VESSEL WALL
Endothelial cells line the surface of the entire circulatory tree, totaling
1–6 × 1013 cells, enough to cover a surface area equivalent to about
six tennis courts. The endothelium is physiologically active, control­
ling vascular permeability, flow of biologically active molecules and
nutrients, blood cell interactions with the vessel wall, the inflammatory
response, and angiogenesis.
The endothelium normally presents an antithrombotic surface
(Chap. 69) but rapidly becomes prothrombotic when stimulated,
which promotes coagulation, inhibits fibrinolysis, and activates plate­
lets. In many cases, endothelium-derived vasodilators are also platelet
inhibitors (e.g., nitric oxide), and conversely, endothelium-derived
vasoconstrictors (e.g., endothelin) can also be platelet activators.
The net effect of vasodilation and inhibition of platelet function is to
promote blood fluidity, whereas the net effect of vasoconstriction and
platelet activation is to promote thrombosis. Thus, blood fluidity and
hemostasis are regulated by the balance of antithrombotic/prothrom­
botic and vasodilatory/vasoconstrictor properties of endothelial cells.
DISORDERS OF PLATELETS
■
■THROMBOCYTOPENIA
Thrombocytopenia results from one or more of three processes: (1)
decreased bone marrow production; (2) sequestration, usually in an
enlarged spleen; and/or (3) increased platelet destruction. Disorders of
production may be either inherited or acquired. In evaluating a patient
with thrombocytopenia, a key step is to review the peripheral blood
smear and to first rule out “pseudothrombocytopenia,” particularly in
a patient without an apparent cause for the thrombocytopenia. Pseu­
dothrombocytopenia (Fig. 120-1B) is an in vitro artifact resulting from
platelet agglutination via antibodies (usually IgG, but also IgM and
IgA) when the calcium content is decreased by blood collection in eth­
ylenediamine tetraacetic (EDTA) (the anticoagulant present in tubes
[purple top] used to collect blood for complete blood counts [CBCs]).
If a low platelet count is obtained in EDTA-anticoagulated blood, a
blood smear should be evaluated and a platelet count determined in
blood collected into sodium citrate (blue top tube) or heparin (green
top tube), or a smear of freshly obtained unanticoagulated blood, such
as from a finger stick, can be examined.
CHAPTER 120
Disorders of Platelets and Vessel Wall
APPROACH TO THE PATIENT
Thrombocytopenia
The history and physical examination, results of the CBC, and
review of the peripheral blood smear are all critical components in
the initial evaluation of thrombocytopenic patients (Fig. 120-2).
The overall health of the patient and whether they are receiving
drug treatment will influence the differential diagnosis. A healthy
young adult with thrombocytopenia will have a much more lim­
ited differential diagnosis than an ill hospitalized patient who is
receiving multiple medications. Except in less common inherited
disorders, decreased platelet production usually results from bone
marrow disorders that also affect red blood cell (RBC) and/or white
blood cell (WBC) production. Because myelodysplasia can present
with isolated thrombocytopenia, the bone marrow should be exam­
ined in patients presenting with isolated thrombocytopenia who are
older than 60 years of age or who do not respond to initial therapy.
While inherited thrombocytopenia is uncommon, any prior platelet
counts should be retrieved and a family history regarding thrombo­
cytopenia obtained. A careful history of drug ingestion should be
obtained, including nonprescription and herbal remedies, because
drugs are the most common cause of thrombocytopenia.
The physical examination can document an enlarged spleen,
evidence of chronic liver disease, and other underlying disorders.
Mild to moderate splenomegaly may be difficult to appreciate in
many individuals due to body habitus and/or obesity but can be eas­
ily assessed by abdominal ultrasound. A platelet count of approxi­
mately 5000–10,000 is required to maintain vascular integrity in the
microcirculation. When the count is markedly decreased, petechiae
first appear in areas of increased venous pressure, the ankles and
feet in an ambulatory patient. Petechiae are pinpoint, nonblanching
hemorrhages and are usually a sign of a decreased platelet num­
ber and not platelet dysfunction. Wet purpura, blood blisters that
form on the oral mucosa, are thought to denote an increased risk
of life-threatening hemorrhage in the thrombocytopenic patient.
Excessive bruising is seen in disorders of both platelet number and
function.
Infection-Induced Thrombocytopenia 
Many viral and bacte­
rial infections result in thrombocytopenia and are the most common
A
PART 4
Oncology and Hematology
B
FIGURE 120-1  Photomicrographs of peripheral blood smears. A. Normal peripheral blood. B. Platelet clumping in pseudothrombocytopenia. C. Abnormal large platelet in
autosomal dominant macrothrombocytopenia. D. Schistocytes and decreased platelets in microangiopathic hemolytic anemia.
Platelet count <150,000/µL
Hemoglobin and white blood count
Normal
Abnormal
Bone marrow examination
Peripheral
blood smear
Platelets clumped: redraw in
sodium citrate or heparin
Fragmented
red blood cells
Normal RBC
morphology;
platelets normal or
increased in size
Microangiopathic
hemolytic anemias
(e.g., DIC, TTP)
Consider:
Drug-induced thrombocytopenia
Infection-induced thrombocytopenia
Idiopathic immune thrombocytopenia
Congenital thrombocytopenia
FIGURE 120-2  Algorithm for evaluating the thrombocytopenic patient. DIC,
disseminated intravascular coagulation; RBC, red blood cell; TTP, thrombotic
thrombocytopenic purpura.
C
D
noniatrogenic cause of thrombocytopenia. This may or may not be
associated with laboratory evidence of disseminated intravascular
coagulation (DIC), which is most commonly seen in patients with
systemic infections with gram-negative bacteria and is seen in patients
ill with COVID-19. Infections can affect both platelet production and
platelet survival. In addition, immune mechanisms can be at work,
as in infectious mononucleosis and early HIV infection. Late in HIV
infection, pancytopenia and decreased and dysplastic platelet produc­
tion are more common. Immune-mediated thrombocytopenia in
children usually follows a viral infection and almost always resolves
spontaneously. This association of infection with immune thrombocy­
topenic purpura is less clear in adults.
Drug-Induced Thrombocytopenia 
Many drugs have been asso­
ciated with thrombocytopenia. A predictable decrease in platelet count
occurs after treatment with many chemotherapeutic drugs due to bone
marrow suppression (Chap. 78). Drugs that cause isolated thrombocy­
topenia and have been confirmed with positive laboratory testing are
listed in Table 120-1, but all drugs should be suspect in a patient with
thrombocytopenia without an apparent cause and should be stopped,
or substituted, if possible. Although not as well studied, herbal and
over-the-counter preparations may also result in thrombocytopenia
and should be discontinued in patients who are thrombocytopenic.
Classic drug-dependent antibodies are antibodies that react with
specific platelet surface antigens and result in thrombocytopenia only
when the drug is present. Many drugs are capable of inducing these
antibodies, but for some reason, they are more common with quinine
and sulfonamides. Drug-dependent antibody binding can be demon­
strated by laboratory assays, showing antibody binding in the presence
TABLE 120-1  Drugs Reported as Definitely or Probably Causing
Isolated Thrombocytopeniaa
Abciximab
Acetaminophen
Amiodarone
Amlodipine
Ampicillin
Carbamazepine
Ceftriaxone
Cephamandole
Ciprofloxacin
Diazepam
Eptifibatide
Furosemide
Gold
Haloperidol
Heparin
Ibuprofen
Lorazepam
Mirtazapine
Naproxen
Oxaliplatin
Penicillin
Phenytoin
Piperacillin
Quinidine
Quinine
Ranitidine
Rosiglitazone
Roxifiban
Sulfisoxazole
Suramin
Tirofiban
Tranilast
Trimethoprim/sulfamethoxazole
Vancomycin
aBased on scoring requiring a compatible clinical picture and positive laboratory
testing. Note, this is not inclusive of newer medications.
Source: Adapted from DM Arnold et al: J Thromb Hemost 11:169, 2013.
of, but not without, the drug present in the assay. The thrombocytope­
nia typically occurs after a period of initial exposure (median length
21 days), or upon reexposure, and usually resolves in 7–10 days after
drug withdrawal. The thrombocytopenia caused by the platelet Gp IIb/
IIIa inhibitory drugs, such as abciximab, differs in that it may occur
within 24 h of initial exposure. This appears to be due to the presence
of naturally occurring antibodies that cross-react with the drug bound
to the platelet.
Heparin-Induced Thrombocytopenia 
Drug-induced throm­
bocytopenia due to heparin differs from that seen with other drugs
in two major ways. (1) The thrombocytopenia is not usually severe,
with nadir counts rarely <20,000/μL. (2) Heparin-induced thrombo­
cytopenia (HIT) is not associated with bleeding and, in fact, markedly
increases the risk of thrombosis. The pathogenesis of HIT is complex.
It results from antibody formation to a complex of the platelet-specific
protein platelet factor 4 (PF4) and heparin or other glycosaminogly­
cans. The anti-heparin/PF4 antibody can activate platelets through the
FcγRIIa receptor and also activate monocytes, endothelial cells, and
coagulation proteins. Many patients exposed to heparin develop anti­
bodies to heparin/PF4 but do not appear to have adverse consequences.
A fraction of those who develop antibodies will develop HIT, and a
portion of those (up to 50%) will develop thrombosis (HITT).
HIT can occur after exposure to low-molecular-weight heparin
(LMWH) as well as unfractionated heparin (UFH), although it is
more common with the latter. Most patients develop HIT after expo­
sure to heparin for 5–14 days (Fig. 120-3). It occurs before 5 days in
those who were exposed to heparin in the prior few weeks or months
HIT only if heparin
in last ~100 days
Risk of HIT
Delayed-onset HIT
occurs rarely
Days of heparin (UFH or LMWH) exposure
FIGURE 120-3  Time course of heparin-induced thrombocytopenia (HIT)
development after heparin exposure. The timing of development after heparin
exposure is a critical factor in determining the likelihood of HIT in a patient. HIT
occurs early after heparin exposure in the presence of preexisting heparin/platelet
factor 4 (PF4) antibodies, which disappear from circulation by ~100 days following a
prior exposure. Rarely, HIT may occur later after heparin exposure (termed delayedonset HIT). In this setting, heparin/PF4 antibody testing is usually markedly positive.
HIT can occur after exposure to either unfractionated (UFH) or low-molecularweight heparin (LMWH).
(<~100 days) and have circulating anti-heparin/PF4 antibodies. Rarely,
thrombocytopenia and thrombosis begin several days after all heparin
has been stopped (termed delayed-onset HIT), and more rarely, spon­
taneous HIT, or autoimmune HIT syndrome, occurs where there is
no history of heparin exposure. A syndrome similar to spontaneous
HIT has been described rarely after COVID-19 vaccination with the
adenovirus-based ChAdOx1-S/nCoV-19 vaccine and termed vaccineinduced immune thrombocytopenia and thrombosis (VITT). Even more
rarely, a similar thrombotic syndrome can follow an adenovirus infec­
tion.  then go to the 4Ts. The “4Ts” are recommended to be used in a
diagnostic algorithm for HIT: thrombocytopenia, timing of platelet
count drop, thrombosis and other sequelae such as localized skin reac­
tions, and other causes of thrombocytopenia not evident. Application
of the 4T scoring system is very useful in excluding a diagnosis of HIT
but will result in overdiagnosis of HIT in situations where thrombocy­
topenia and thrombosis due to other etiologies are common, such as in
the intensive care unit.
LABORATORY TESTING FOR HIT  Because of the prevalence of anti­
heparin antibodies without clinical disease, testing should be done
in individuals who are at intermediate or high risk based on clinical
pretest assessment. HIT (anti-heparin/PF4) antibodies can be detected
using two types of assays. The most widely available are immunoassays
usually with PF4/polyanion complex as the antigen. Because many
patients develop antibodies but do not develop clinical HIT, the test
has a low specificity for the diagnosis of HIT. This is especially true
in patients who have undergone surgery requiring cardiopulmonary
bypass, where approximately 50% of patients develop these antibod­
ies postoperatively. The other assay is a platelet activation assay, most
commonly the serotonin release assay, which measures the ability of
the patient’s serum to activate platelets in the presence of heparin in
a concentration-dependent manner. This test has lower sensitivity
but higher specificity than the enzyme-linked immunosorbent assay
(ELISA). However, HIT remains a clinical diagnosis.
CHAPTER 120
Disorders of Platelets and Vessel Wall
TREATMENT
Heparin-Induced Thrombocytopenia
Early recognition is key in treatment of HIT, with prompt discon­
tinuation of heparin and use of alternative anticoagulants if bleeding
risk does not outweigh thrombotic risk. Thrombosis is a common
complication of HIT, even after heparin discontinuation, and can
occur in both the venous and arterial systems. In patients diagnosed
with HIT, imaging studies to evaluate the patient for thrombosis (at
least lower extremity duplex Doppler imaging) are recommended.
Patients requiring anticoagulation should be switched from
heparin to an alternative anticoagulant. The direct thrombin inhibi­
tor (DTI) argatroban is effective in HITT. The DTI bivalirudin, the
antithrombin-binding pentasaccharide fondaparinux, and direct
oral anticoagulants (DOACs) appear to have efficacy, although
none of these are approved by the U.S. Food and Drug Administra­
tion (FDA) for this indication. Of the DOACs, the most experience
reported is with rivaroxaban. In general, an intravenous DTI should
be used in acutely ill patients with transition to fondaparinux or a
DOAC when they are more stable, which then allows outpatient
treatment. HIT antibodies cross-react with LMWH, and these
drugs should not be used in the treatment of HIT.
Because of the high rate of thrombosis in patients with HIT, anti­
coagulation should be considered, even in the absence of thrombo­
sis. In patients with thrombosis, anticoagulation is continued for
3–6 months, but in patients without thrombosis, the duration of
anticoagulation is less well defined, but should be continued at least
until platelet recovery. An increased risk of thrombosis is present
for at least 1 month after diagnosis; however, most thromboses
occur early, and whether thrombosis occurs later if the patient
is initially anticoagulated is unknown. Introduction of warfarin
alone in the setting of HIT or HITT may precipitate thrombosis,
particularly venous gangrene, presumably due to clotting activation
and severely reduced levels of proteins C and S. Warfarin therapy,
if started, should be overlapped with a DTI, fondaparinux, or a
DOAC and started after resolution of the thrombocytopenia and
lessening of the prothrombotic state.
The rare VITT syndrome is characterized by high D-dimer levels
and thrombosis in unusual sites like the cerebral venous sinuses.
Fatal in about 20%, treatment is usually intravenous gamma globu­
lin (IVIgG) to block platelet activation through Fc receptors, the
pathogenic effect of the anti–PF4-polyanion antibody, and a non­
heparin anticoagulant.
Immune Thrombocytopenic Purpura 
Immune thrombocyto­
penic purpura (ITP; also termed idiopathic thrombocytopenic purpura)
is an acquired disorder in which there is immune-mediated destruction
of platelets and possibly inhibition of platelet release from the mega­
karyocyte. In children, it is usually an acute disease, most commonly
following an infection, and with a self-limited course. In adults, it is a
more chronic disease, although in some adults, spontaneous remission
occurs, usually within months of diagnosis. ITP is termed secondary
if it is associated with an underlying disorder; autoimmune disorders,
particularly systemic lupus erythematosus (SLE), and infections, such
as HIV and hepatitis C, are common causes. The association of ITP
with Helicobacter pylori infection is unclear but appears to have a geo­
graphic distribution.
PART 4
Oncology and Hematology
ITP is characterized by mucocutaneous bleeding and a low, often
very low, platelet count, with an otherwise normal peripheral blood
cells and smear. Patients usually present either with ecchymoses and
petechiae or with thrombocytopenia incidentally found on a routine
CBC. Mucocutaneous bleeding, such as oral mucosa, gastrointestinal,
or heavy menstrual bleeding, may be present. Rarely, life-threatening,
including central nervous system, bleeding can occur. Wet purpura
(blood blisters in the mouth) and retinal hemorrhages may herald lifethreatening bleeding.
LABORATORY TESTING IN ITP  Laboratory testing for antibodies (sero­
logic testing) is usually not helpful due to the low sensitivity and
specificity of the current tests. Bone marrow examination can be
reserved for those who have other signs or laboratory abnormalities
not explained by ITP or in patients who do not respond to initial
therapy. The peripheral blood smear may show large platelets, with
otherwise normal morphology. Depending on the bleeding history,
iron-deficiency anemia may be present.
Laboratory testing is performed to evaluate for secondary causes of
ITP and should include testing for HIV infection and hepatitis C (and
other infections if indicated). Serologic testing for SLE, serum protein
electrophoresis, immunoglobulin levels to potentially detect hypogam­
maglobulinemia, selective testing for IgA deficiency or monoclonal
gammopathies, and testing for H. pylori infection should be consid­
ered, depending on the clinical circumstance. If anemia is present,
direct antiglobulin testing (Coombs’ test) should be performed to
rule out combined autoimmune hemolytic anemia with ITP (Evans’
syndrome).
TREATMENT
Immune Thrombocytopenic Purpura
The treatment of ITP uses drugs that decrease reticuloendothelial
uptake of the antibody-bound platelet, decrease antibody produc­
tion, and/or increase platelet production. The diagnosis of ITP does
not necessarily mean that treatment must be instituted. Patients
with platelet counts >30,000/μL appear not to have increased mor­
tality related to the thrombocytopenia.
Initial treatment in patients without significant bleeding symp­
toms, severe thrombocytopenia (<5000/μL), or signs of impending
bleeding (e.g., retinal hemorrhage or large oral mucosal hemor­
rhages) can be instituted as an outpatient using single agents. Tra­
ditionally, this has been prednisone at 1 mg/kg or a 4-day course
of dexamethasone, 40 mg/d, although Rh0(D) immune globulin
therapy, at 50–75 μg/kg, is also being used in this setting. Rh0(D)
immune globulin must be used only in Rh-positive patients because
the mechanism of action is production of limited hemolysis, with
antibody-coated cells “saturating” the Fc receptors, inhibiting Fc
receptor function. Monitoring patients for 8 h after infusion is
now advised by the FDA because of the rare complication of severe
intravascular hemolysis. IVIgG, which is pooled, primarily IgG
antibodies, also blocks the Fc receptor system, but appears to work
primarily through different mechanism(s). IVIgG has more efficacy
than anti-Rh0(D) in postsplenectomized patients. IVIgG is dosed at
1–2 g/kg total, given over 1–5 days. Side effects are usually related to
the volume of infusion and infrequently include aseptic meningitis
and renal failure. All immunoglobulin preparations are derived
from human plasma and undergo treatment for viral inactivation.
Rituximab, an anti-CD20 (B-cell) antibody, has shown efficacy in
the treatment of refractory ITP, although long-lasting remission
only occurs in approximately 30% of patients. TPO receptor ago­
nists (TPO-RA), administered subcutaneously (romiplostim) or
orally (eltrombopag, avatrombopag), are effective in raising platelet
counts in patients with chronic ITP.
For patients with severe ITP and/or symptoms of bleeding,
hospital admission is required, and combined-modality therapy is
given using high-dose glucocorticoids with IVIgG or anti-Rh0(D)
therapy and, as needed, additional immunosuppressive agents.
For chronic ITP, broad immune therapy and splenectomy are
now generally used less frequently compared to TPO-RAs due
to unfavorable side effects and a negative impact on quality of
life. Newer drugs are under study. In individuals who achieve a
complete response to a TPO-RA, many will maintain a sustained
response off therapy.
In patients who are to undergo splenectomy, vaccination against
encapsulated organisms (especially pneumococcus, but also menin­
gococcus and Haemophilus influenzae, depending on patient age
and potential exposure) is recommended. Accessory spleens are a
very rare cause of relapse.
Inherited Thrombocytopenia 
Thrombocytopenia is rarely
inherited, either as an isolated finding or as part of a syndrome, and
may be inherited in an autosomal dominant, autosomal recessive, or
X-linked pattern. Multiple genetic variants have now been identified in
individuals with isolated thrombocytopenia and cytopenic syndromes,
some of which carry an increased risk of hematologic malignancy.
Many forms of autosomal dominant macrothrombocytopenia are now
known to be associated with variants in the nonmuscle myosin heavy
chain MYH9 gene. These include the May-Hegglin anomaly, and
Sebastian, Epstein’s, and Fechtner syndromes, all of which have distinct
distinguishing features. A common feature of these disorders is large
platelets (Fig. 120-1C). It is important that family history be explored
in any individual with unexplained thrombocytopenia.
■
■THROMBOTIC THROMBOCYTOPENIC PURPURA
AND HEMOLYTIC-UREMIC SYNDROME
Thrombotic thrombocytopenic microangiopathies are a group of dis­
orders characterized by microangiopathic hemolytic anemia (MAHA)
defined by thrombocytopenia and fragmented RBCs (Fig. 120-1D) on
peripheral blood smear, laboratory evidence of hemolysis (elevated lac­
tate dehydrogenase [LDH] and unconjugated bilirubin and decreased
haptoglobin), and microvascular thrombosis. They include thrombotic
thrombocytopenic purpura (TTP) and hemolytic-uremic syndrome
(HUS), as well as syndromes complicating bone marrow transplanta­
tion, certain medications and infections, pregnancy, and vasculitis. In
DIC, although thrombocytopenia and microangiopathy are seen, a
coagulopathy predominates, with consumption of clotting factors and
fibrinogen resulting in an elevated prothrombin time (PT) and often
activated partial thromboplastin time (aPTT). The PT and aPTT are
characteristically normal in TTP or HUS.
Thrombotic Thrombocytopenic Purpura 
TTP was first
described in 1924 by Eli Moschcowitz and characterized by a pentad
of findings that include microangiopathic hemolytic anemia, thrombo­
cytopenia, renal failure, neurologic findings, and fever. The full-blown
VWF and Platelet Adhesion
Blood flow
Protease
No protease
“Ultralarge”
multimers
Normal
multimers
TTP?
FIGURE 120-4  Pathogenesis of thrombotic thrombocytopenic purpura (TTP).
Normally the ultra-high-molecular-weight multimers of von Willebrand factor (VWF)
produced by the endothelial cells are processed into smaller multimers by a plasma
metalloproteinase called ADAMTS13. In TTP, the activity of the protease is inhibited,
and the ultra-high-molecular-weight multimers of VWF initiate platelet aggregation
and thrombosis.
syndrome is less commonly seen now, probably due to earlier diag­
nosis. The introduction of treatment with plasma exchange markedly
improved the prognosis in patients, with a decrease in mortality from
85–100% to 10–30%.
The pathogenesis of inherited (Upshaw-Schulman syndrome) and
idiopathic TTP (ITTP) is related to a deficiency of, or antibodies
to, the metalloprotease ADAMTS13, which cleaves VWF. VWF is
normally secreted as ultra-large multimers, which are then cleaved
by ADAMTS13. The persistence of ultra-large VWF molecules is
thought to contribute to pathogenic platelet adhesion and aggregation
(Fig. 120-4). This defect alone, however, is not sufficient to result in
TTP because individuals with a congenital absence of ADAMTS13
develop TTP only episodically, including during first pregnancy. The
level of ADAMTS13 activity, as well as antibodies to ADAMTS13, can
be detected by laboratory assays, which play a critical role in the dif­
ferential diagnosis of MAHA. ADAMTS13 activity levels of <10% are
diagnostic of TTP.
Idiopathic TTP appears to be more common in women than in
men. No geographic or racial distribution has been defined. TTP is
more common in patients with HIV infection and in pregnant women.
Medication-related MAHA may be secondary to antibody formation
(ticlopidine and possibly clopidogrel) or direct endothelial toxicity
(cyclosporine, gemcitabine, mitomycin C, tacrolimus), although this is
not always so clear, and fear of withholding treatment, as well as lack of
other treatment alternatives, may result in initial application of plasma
exchange. However, withdrawal, or reduction in dose, of endothelial
toxic agents usually decreases the microangiopathy.
TREATMENT
Thrombotic Thrombocytopenic Purpura
TTP is a devastating disease if not diagnosed and treated promptly.
In patients presenting with new thrombocytopenia, with or without
evidence of renal insufficiency and other elements of classic TTP,
laboratory data (PT, aPTT, CBC with platelet count and peripheral
smear, ADAMTS13 activity, LDH, bilirubin, haptoglobin, direct
antiglobulin assay) should be obtained to rule out DIC and to evalu­
ate for evidence of MAHA.
Therapeutic plasma exchange (TPE) remains the mainstay of
treatment of TTP. TPE is continued until the platelet count is
normal and signs of hemolysis are resolved for at least 2 days.
Although never evaluated in clinical trials, the use of glucocorti­
coids seems a reasonable approach but should only be used as an
adjunct to plasma exchange. The addition of rituximab to initial
therapy decreases the risk of relapse. Caplacizumab, an anti-VWF
nanobody, decreases mortality and burden of care when used in
patients with ADAMTS13 <10% or with high clinical probability of
disease. Guidelines from the International Society of Thrombosis
and Hemostasis recommend starting caplacizumab and rituximab
only in individuals with diagnostic ADAMTS13 levels (usually
<10%) and, additionally for rituximab, in patients with evidence of
an inhibitor, given potential side effects and costs.
Patients with persistently low ADAMTS13 have a greater risk of
ongoing sequelae including stroke. There is a significant relapse
rate; in patients treated with TPE, 25–45% of patients relapse within
30 days of initial “remission,” and 12–40% of patients have late
relapses. Relapses are more frequent in patients with severe
ADAMTS13 deficiency at presentation. Treatment of patients with
TTP relapses should be initiated before confirmatory laboratory
assays are available.
CHAPTER 120
Hemolytic-Uremic Syndrome 
HUS is a syndrome character­
ized by acute renal failure, microangiopathic hemolytic anemia, and
thrombocytopenia. It is seen preceded by an episode of diarrhea, often
hemorrhagic in nature, predominantly in children. Escherichia coli
O157:H7 is the most frequent, although not only, etiologic serotype.
HUS not associated with diarrhea is more heterogeneous in presenta­
tion and course. Atypical HUS (aHUS) is usually due to genetic defects
in complement genes or antibodies directed against complementary
regulatory proteins that result in chronic complement activation.
Laboratory testing for DNA variants in complement regulatory genes
is available, although assigning pathogenicity to variants remains chal­
lenging. Currently, a commercially available functional assay is not
available that is diagnostic of the disease.
Disorders of Platelets and Vessel Wall
TREATMENT
Hemolytic-Uremic Syndrome
Treatment of HUS is primarily supportive. In HUS associated with
diarrhea, many (~40%) children require at least some period of
support with dialysis; however, the overall mortality is <5%. In HUS
not associated with diarrhea, the mortality is higher, approximately
26%. Plasma infusion or plasma exchange has not been shown to
alter the overall course in HUS or aHUS, except in patients with
antibodies to factor H. ADAMTS13 levels are generally reported to
be normal in HUS, although occasionally they have been reported
to be decreased. In patients with aHUS, anticomplement therapy
has efficacy in resolution of aHUS and improving or preserving
renal function. Patients with aHUS may initially be treated with
plasma exchange, until the ADAMTS13 level is returned and the
diagnosis is more clear, since aHUS remains a diagnosis of exclu­
sion. However, plasma exchange has not been shown to affect clini­
cal outcomes in aHUS.
■
■THROMBOCYTOSIS
Thrombocytosis is almost always due to (1) iron deficiency; (2)
inflammation, cancer, or infection (reactive thrombocytosis); or (3)
an underlying myeloproliferative process (essential thrombocythemia
or polycythemia vera) (Chap. 108) or, rarely, the 5q– myelodysplastic
process (Chap. 107). Patients presenting with an elevated platelet count
should be evaluated for underlying inflammation and malignancy, and
iron deficiency should be ruled out. Thrombocytosis in response to
acute or chronic inflammation has not been clearly associated with
an increased thrombotic risk. In fact, patients with markedly elevated
platelet counts (>1.5 million), usually seen in the setting of a myelopro­
liferative disorder, have an increased risk of bleeding. This appears to
be due, at least in part, to acquired von Willebrand disease (VWD) due
to platelet-VWF binding and removal from the circulation.
■
■QUALITATIVE DISORDERS OF PLATELET
FUNCTION
Inherited Disorders of Platelet Function 
Inherited platelet
function disorders are thought to be relatively rare, although the preva­
lence of mild disorders of platelet function is unclear, in part because
our testing for such disorders is suboptimal. Rare qualitative disorders
include the autosomal recessive disorders Glanzmann’s thrombasthe­
nia (absence of the platelet Gp IIb/IIIa receptor) and Bernard-Soulier
syndrome (absence of the platelet Gp Ib-IX-V receptor). Both are
inherited in an autosomal recessive fashion and present with bleeding
symptoms in childhood.
Platelet storage pool disorder (SPD) is the classic autosomal domi­
nant qualitative platelet disorder. This results from abnormalities of
platelet granule formation. It is also seen as a part of inherited disorders
of granule formation, such as Hermansky-Pudlak syndrome. Bleeding
symptoms in SPD are variable but often are mild. The most common
inherited disorders of platelet function prevent normal secretion of
granule content and are termed secretion defects. An increasing number
of genetic variants are being found in patients with these disorders,
although assigning pathogenicity remains challenging.
PART 4
Oncology and Hematology
TREATMENT
Inherited Disorders of Platelet Dysfunction
Bleeding symptoms or prevention of bleeding in patients with
severe platelet dysfunction frequently requires platelet transfusion.
Care must be taken to limit the risk of alloimmunization by limit­
ing exposure and using human leukocyte antigen–matched single
donor platelets for transfusion when needed. Recombinant factor
VIIa (rFVIIa) is FDA approved in Glanzmann’s thrombasthenia
and Bernard Soulier syndrome where use can avoid platelet alloim­
munization and antireceptor antibody formation. Platelet disorders
associated with milder bleeding symptoms frequently respond to
desmopressin (1-deamino-8-d-arginine vasopressin [DDAVP]).
DDAVP increases plasma VWF and factor VIII levels; it may also
have a direct effect on platelet function. Particularly for mucosal
bleeding symptoms, antifibrinolytic therapy (tranexamic acid or
ε-aminocaproic acid) is used alone or in conjunction with DDAVP
or platelet therapy.
Acquired Disorders of Platelet Function 
Acquired platelet
dysfunction is common, usually due to medications, either intention­
ally as with antiplatelet therapy or unintentionally as with high-dose
penicillins. Acquired platelet dysfunction occurs in uremia. This is
likely multifactorial, but the resultant effect is defective adhesion and
activation. The platelet defect is improved most by dialysis but may also
be improved by increasing the hematocrit to 27–32%, giving DDAVP
(0.3 μg/kg), or use of conjugated estrogens. Platelet dysfunction also
occurs with cardiopulmonary bypass due to the effect of the artificial
circuit on platelets, and bleeding symptoms respond to platelet transfu­
sion. Platelet dysfunction seen with underlying hematologic disorders
can result from nonspecific interference by circulating paraproteins
or intrinsic platelet defects in myeloproliferative and myelodysplastic
syndromes.
■
■VON WILLEBRAND DISEASE
VWD is the most common inherited bleeding disorder, with preva­
lence of symptomatic disease of 1 in 1000 to 1 in 10,000 individuals.
VWF serves two roles: (1) as the major adhesion molecule that tethers
the platelet to the exposed subendothelium; and (2) as the binding
TABLE 120-2  Laboratory Diagnosis of von Willebrand Disease (VWD)
VWF
ANTIGEN
VWF
ACTIVITY
FVIII
ACTIVITY
MULTIMER
TYPE
aPTT
Nl or ↑
↓
↓
↓
Normal distribution,
decreased in quantity
2A
Nl or ↑
↓
↓ ↓
↓
Loss of high- and
intermediate-MW
multimers
2Ba
Nl or ↑
↓
↓ ↓
↓
Loss of high-MW
multimers
2M
Nl or ↑
↓
↓ ↓
↓
Normal distribution,
decreased in quantity
2N
↑↑
Nl or ↓b
Nl or ↓b
↓↓
Normal distribution
↑↑
↓↓
↓↓
↓↓
Absent
aUsually also decreased platelet count. bFor type 2N, in the homozygous state,
factor VIII is very low; in the heterozygous state, it is only seen in conjunction with
type 1 VWD.
Abbreviations: aPTT, activated partial thromboplastin time; F, factor; MW, molecular
weight; Nl, normal; VWF, von Willebrand factor.
protein for factor VIII (FVIII), resulting in significant prolongation
of the FVIII half-life in circulation. The platelet-adhesive function of
VWF is critically dependent on the presence of large VWF multim­
ers, whereas FVIII binding is not. Most of the symptoms of VWD
are “platelet-like” except in more severe VWD when the FVIII is low
enough to produce symptoms similar to those found in FVIII defi­
ciency (hemophilia A).
VWD has been classified into three major types, with four subtypes
of type 2 (Table 120-2). By far, the most common type of VWD is type 1
disease, with a parallel decrease in VWF protein, VWF function, and
FVIII levels, accounting for at least 80% of cases. Type 1C is a subtype
associated with increased VWF clearance. In type 1 VWD, patients
have predominantly mucosal bleeding symptoms, although procedurerelated and other bleeding is also seen. Bleeding symptoms are uncom­
mon in infancy and usually manifest later in childhood with excessive
bruising and epistaxis. Because these symptoms occur commonly
in childhood, the clinician should particularly note bruising at sites
unlikely to be traumatized and/or prolonged epistaxis requiring medi­
cal attention. Heavy menstrual bleeding is a common manifestation
of VWD. Menstrual bleeding resulting in anemia should warrant an
evaluation for VWD and, if negative, functional platelet disorders and
other bleeding disorders. Type 1 VWD may first manifest with dental
extractions, particularly wisdom tooth extraction, or tonsillectomy.
Not all patients with low VWF levels have bleeding symptoms.
Whether patients bleed or not will depend on the overall hemostatic
balance they have inherited, along with environmental influences
and the type of hemostatic challenges they experience. Although the
inheritance of VWD is autosomal, many factors modulate both VWF
levels and bleeding symptoms. These have not all been defined, but
include blood type, thyroid hormone status, race, stress, exercise, hor­
monal (both endogenous and exogenous) influences, and modulators
of VWF clearance. Patients with type O blood have VWF protein levels
of approximately one-half those of patients with AB blood type, and
in fact, the normal range for patients with type O blood overlaps that
which has been considered diagnostic for VWD. Patients with mildly
decreased VWF levels should be diagnosed with VWD only in the set­
ting of bleeding symptoms and/or a family history of VWD.
Patients with type 2 VWD have functional defects; thus, the VWF
antigen measurement is significantly higher than the test of function. For
types 2A, 2B, and 2M VWD, platelet-binding and/or collagen-binding
VWF activity is decreased. In type 2A VWD, the impaired function is
due either to increased susceptibility to cleavage by ADAMTS13, result­
ing in loss of intermediate- and high-molecular-weight multimers, or
to decreased production of these multimers by the cell. Type 2B VWD
results from gain-of-function DNA variants that result in increased
binding of VWF to platelets in circulation with subsequent increased
ADAMTS13 cleavage and clearance. The resulting VWF in the patients’
plasma lacks the highest molecular-weight multimers, and the platelet
count is usually modestly reduced, but not uniformly. Type 2M occurs
as a consequence of DNA variants that result in a dysfunctional protein
not affecting multimer structure.
Type 2N VWD is due to variants in the VWF gene that affect bind­
ing of FVIII. As FVIII is stabilized by binding to VWF, the FVIII in
patients with type 2N VWD has a very short half-life, and the FVIII
level is markedly decreased. This is sometimes termed autosomal
hemophilia. Type 3 VWD, or severe VWD, describes patients with
virtually no VWF protein and usually FVIII levels <10%. Patients
experience mucosal and joint bleeding, surgery-related bleeding, and
other bleeding symptoms. Some patients with type 3 VWD, particu­
larly those with large VWF gene deletions, are at risk of developing
antibodies to infused VWF.
Acquired VWD or von Willebrand syndrome can be seen in patients
with underlying lymphoproliferative disorders, including monoclonal
gammopathies of underdetermined significance (MGUS), multiple
myeloma, and Waldenström’s macroglobulinemia. It is seen most com­
monly in the setting of MGUS and should be suspected in patients,
particularly elderly patients, with a new onset of severe mucosal
bleeding symptoms. Laboratory evidence of acquired VWD is found
in patients with cardiac valvular disease. Heyde’s syndrome (aortic
stenosis with gastrointestinal bleeding) is attributed to the presence
of angiodysplasia of the gastrointestinal tract in patients with aortic
stenosis. The shear stress on blood passing through the stenotic aortic
valve appears to unfold VWF, making it susceptible to proteolysis.
Consequently, large multimer forms are lost, leading to an acquired
type 2 VWD, but return when the stenotic valve is replaced.
TREATMENT
Von Willebrand Disease
The mainstay of treatment for type 1 VWD is DDAVP (desmopres­
sin), which results in release of VWF and FVIII from endothelial
stores. DDAVP can be given intravenously, by high-concentration
intranasal spray (1.5 mg/mL), or when a concentrated form is
available, by subcutaneous injection. The peak activity when given
intravenously is approximately 30 min, whereas it is 2 h when
given intranasally. The usual dose is 0.3 μg/kg intravenously or two
squirts (one in each nostril) for patients >50 kg (one squirt for those
<50 kg). It is recommended that patients with VWD be tested with
DDAVP to assess their response before using it. In patients who
respond well (increase in laboratory values greater than twofold
with levels >50% for at least 4 h), it can be used for procedures with
minor to moderate risk of bleeding. Depending on the procedure,
additional doses may be needed; it is usually given every 12–24 h.
Less frequent dosing may result in less tachyphylaxis, which occurs
when synthesis cannot compensate for the released stores. The
major side effect of DDAVP is hyponatremia due to decreased free
water clearance. This occurs most commonly in the very young and
the very old, but fluid restriction should be advised for all patients
for the 24 h following each dose.
Some patients with type 2A VWD respond to DDAVP such that
it can be used for minor procedures. For the other subtypes, for
type 3 disease, and for major procedures requiring longer periods
of normal hemostasis, VWF replacement can be given. Virally inac­
tivated VWF-plasma-derived and recombinant factor concentrates
are safer than cryoprecipitate as the replacement product.
Antifibrinolytic therapy using either tranexamic acid (TXA) or
ε-aminocaproic acid is an important therapy, either alone or in an
adjunctive capacity, particularly for the prevention or treatment
of mucosal bleeding. These agents are particularly useful in treat­
ment of heavy menstrual bleeding (TXA 1300 mg every 8 h) and
postpartum hemorrhage, as prophylaxis for dental procedures, and
with DDAVP or factor concentrate for dental extractions, tonsillec­
tomies, and prostate procedures. Antifibrinolytic agents are contra­
indicated in the setting of upper urinary tract bleeding due to the
risk of ureteral obstruction.
■
■DISORDERS OF THE VESSEL WALL
The vessel wall is an integral part of hemostasis, and separation of a
fluid phase is artificial, particularly in disorders such as TTP or HIT
that clearly involve the endothelium as well. Inflammation localized
to the vessel wall, such as vasculitis, and inherited connective tissue
disorders are abnormalities inherent to the vessel wall.
Metabolic and Inflammatory Disorders 
Acute febrile illnesses
may result in vascular damage. This can result from immune com­
plexes containing viral antigens or the viruses themselves. Certain
pathogens, such as the rickettsiae causing Rocky Mountain spotted
fever, replicate in endothelial cells and damage them. SARS-CoV-2
also infects endothelial cells, resulting in activation and damage con­
tributing to COVID-19 pathogenicity. Vascular purpura may occur in
patients with polyclonal gammopathies but more commonly occurs in
those with monoclonal gammopathies, including Waldenström’s mac­
roglobulinemia, multiple myeloma, and cryoglobulinemia. Patients
with mixed cryoglobulinemia develop a more extensive maculopapular
rash due to immune complex–mediated damage to the vessel wall.
Patients with scurvy (vitamin C deficiency) develop painful epi­
sodes of perifollicular skin bleeding as well as more systemic bleed­
ing symptoms. Vitamin C is needed to synthesize hydroxyproline, an
essential constituent of collagen. Patients with Cushing’s syndrome
or on chronic glucocorticoid therapy develop skin bleeding and easy
bruising due to atrophy of supporting connective tissue. A similar
phenomenon is seen with aging, where following minor trauma, blood
spreads superficially under the epidermis. This has been termed senile
purpura. It is most common on skin that has been previously damaged
by sun exposure.
CHAPTER 120
Disorders of Platelets and Vessel Wall
Immunoglobulin A vasculitis, formerly called Henoch-Schönlein
purpura, is a distinct, self-limited type of vasculitis that occurs in chil­
dren and young adults. Patients have an acute inflammatory reaction
with IgA and complement components in capillaries, mesangial tissues,
and small arterioles leading to increased vascular permeability and
localized hemorrhage. The syndrome is often preceded by an upper
respiratory infection, commonly with streptococcal pharyngitis, or is
triggered by drug or food allergies. Patients develop a purpuric rash
on the extensor surfaces of the arms and legs, usually accompanied by
polyarthralgias or arthritis, abdominal pain, and hematuria from focal
glomerulonephritis. All coagulation tests are normal, but renal impair­
ment may occur. Glucocorticoids can provide symptomatic relief but
do not alter the course of the illness.
Inherited Disorders of the Vessel Wall 
Patients with inherited
disorders of the connective tissue matrix, such as Marfan’s syndrome,
Ehlers-Danlos syndrome, and pseudoxanthoma elasticum, frequently
report easy bruising. Inherited vascular abnormalities can result in
increased bleeding. This is notably seen in hereditary hemorrhagic
telangiectasia (HHT, or Osler-Weber-Rendu disease), a disorder where
abnormal telangiectatic capillaries result in frequent bleeding episodes,
primarily from the nose and gastrointestinal tract. Arteriovenous
malformation (AVM) in the lung, brain, and liver may also occur in
HHT. The telangiectasia can often be visualized on the oral and nasal
mucosa. Signs and symptoms develop over time. Epistaxis begins, on
average, at the age of 12 and occurs in >95% of affected individuals by
middle age. Approximately 25% have gastrointestinal bleeding usu­
ally beginning after the age of 50. HHT is caused by pathogenic DNA
variants in a number of genes involved in the TGFβ/BMP signaling
cascade.
■
■FURTHER READING
Boender J et al: A diagnostic approach to mild bleeding disorders. J
Thromb Haemost 14:1507, 2016.
Cines DB, Greinacher A: Vaccine-induced immune thrombotic
thrombocytopenia. Blood 141:1659, 2023.
Connell NT: ASH ISTH NHF WFH 2021 guidelines on the manage­
ment of von Willebrand disease. Blood Adv 5:301, 2021.
Cuker A et al: American Society of Hematology 2018 guidelines for
management of venous thromboembolism: Heparin-induced throm­
bocytopenia. Blood Adv 2:23360, 2018.

52 - 121 Coagulation Disorders
121 Coagulation Disorders
Gomez K: Advances in the diagnosis of heritable platelet disorders.
Blood Rev 56:100972, 2022.
James PD et al: ASH ISTH NHF WFH 2021 guidelines on the diagno­
sis of von Willebrand disease. Blood Adv 5:280, 2021.
Jiang D et al: Changing paradigms in ITP management: Newer tools
for an old disease. Transfus Med Rev 36:188, 2022.
Jokiranta TS: HUS and atypical HUS. Blood 129:2847, 2017.
May J et al: Heparin-induced thrombocytopenia: An illustrated review.
Res Pract Thromb Haemost 7:100283, 2023.
Skeith L et al: A practical approach to evaluating postoperative throm­
bocytopenia. Blood Adv 4:776, 2020.
Vayne C et al: Pathophysiology and diagnosis of drug-induced
immune thrombocytopenia. J Clin Med 9:2212, 2020.
Zheng XL et al: ISTH guidelines for the diagnosis of thrombotic
thrombocytopenic purpura. J Thromb Hemost 18:2486, 2020.
Jean M. Connors
Coagulation Disorders
PART 4
Oncology and Hematology
Deficiencies of coagulation factors have been recognized for centuries.
Patients with genetic deficiencies of plasma coagulation factors exhibit
lifelong recurrent bleeding episodes into joints, muscles, and closed
spaces, either spontaneously or following an injury. The most common
inherited factor deficiencies are the hemophilias, X-linked diseases
caused by deficiency of factor (F) VIII (hemophilia A) or FIX (hemo­
philia B). Rare congenital bleeding disorders due to deficiencies of
other factors, including FII (prothrombin), FV, FVII, FX, FXI, FXIII,
and fibrinogen, are commonly inherited in an autosomal recessive
manner (Table 121-1). Disease phenotype often correlates with the
level of factor activity. While patients can have a congenital deficiency
of FXII accompanied by a significant prolongation in the activated par­
tial thromboplastin time (aPTT), FXII deficiency is not accompanied
by a bleeding phenotype, likely due to redundant paths to activation
of the intrinsic pathway of the coagulation cascade, including direct
activation of FXI by thrombin generated through the extrinsic pathway
(Fig. 121-1). Advances in characterization of the molecular basis of
clotting factor deficiencies have contributed to better understanding
of the disease phenotypes allowing the development of more targeted
TABLE 121-1  Genetic and Laboratory Characteristics of Inherited Coagulation Disorders
CLOTTING
FACTOR
DEFICIENCY
INHERITANCE
PREVALENCE
IN GENERAL
POPULATION
LABORATORY ABNORMALITYa
MINIMUM
HEMOSTATIC
LEVELS
TREATMENT
PLASMA
HALF-LIFE
aPTT
PT
TT
Fibrinogen
AR
1 in 1,000,000
+
+
+
100 mg/dL
Cryoprecipitate
2–4 d
Prothrombin
AR
1 in 2,000,000
+
+
−
20–30%
FFP/PCC
3–4 d
Factor V
AR
1 in 1,000,000
+/−
+/−
−
15–20%
FFPc
36 h
Factor VII
AR
1 in 500,000
−
+
−
15–20%
FFP/PCC
4–6 h
Factor VIII
X-linked
1 in 5000
+
−
−
30%
FVIII concentrates
8–12 h
Factor IX
X-linked
1 in 30,000
+
−
−
30%
FIX concentrates
18–24 h
Factor X
AR
1 in 1,000,000
+/−
+/−
−
15–20%
FFP/PCC
40–60 h
Factor XI
AR
1 in 1,000,000
+
−
−
15–20%
FFP
40–70 h
Factor XII
AR
ND
+
−
−
b
b
60 h
HK
AR
ND
+
−
−
b
b
150 h
Prekallikrein
AR
ND
+
−
−
b
b
35 h
Factor XIII
AR
1 in 2,000,000
−
−
+/−
2%–5%
Cryoprecipitate/FXIII
concentrates
aValues within normal range (−) or prolonged (+). bNo risk for bleeding; treatment is not indicated. cSince platelets contain FV, platelet transfusion can be used as therapy.
Abbreviations: aPTT, activated partial thromboplastin time; AR, autosomal recessive; FFP, fresh-frozen plasma; HK, high-molecular-weight kininogen; ND, not determined;
PCC, prothrombin complex concentrates; PT, prothrombin time; TT, thrombin time.
therapeutic approaches, including the use of small molecules, recom­
binant proteins, or cell- and gene-based therapies.
The two most commonly used tests of hemostasis, the prothrombin
time (PT) and the aPTT, were designed to perform the first screen for
clotting factor deficiency (Fig. 121-1). An isolated prolonged PT sug­
gests FVII deficiency, whereas a prolonged aPTT indicates an intrinsic
pathway factor deficiency, most commonly hemophilia A or B (FVIII
or FIX, respectively) or FXI deficiency (Fig. 121-1). The prolongation
of both PT and aPTT suggests a deficiency of FV, FX, FII, or fibrinogen
abnormalities. A mixing study, in which the addition of normal pooled
plasma to the patient’s plasma, will correct a prolonged aPTT or PT
due to a factor deficiency, and is the next step in determining if there
is a coagulation factor deficiency. If the clotting time does not correct,
it suggests the presence of an inhibitor, an antibody to a specific factor;
however, a mixing study will also detect the presence of anticoagulants.
Many labs have testing methods for detecting inhibitors that neutral­
ize anticoagulants. If the mixing study corrects with normal plasma,
individual factor activity assays are performed to determine which
factor is deficient.
Acquired deficiencies of plasma coagulation factors are more fre­
quent than congenital disorders; the most common disorders include
hemorrhagic diathesis of liver disease, disseminated intravascular
coagulation (DIC), and vitamin K deficiency. In these disorders, blood
coagulation is hampered by the deficiency of more than one clotting
factor, and the bleeding episodes are the result of perturbation of both
primary (e.g., platelet and vessel wall interactions) and secondary
(coagulation) hemostasis.
The development of alloantibodies to coagulation plasma proteins,
clinically termed inhibitors, is a relatively rare disease that often affects
hemophilia A or B and FXI-deficient patients on repetitive exposure to
the missing protein to control bleeding episodes. Inhibitory autoanti­
bodies also occur among subjects without genetic deficiency of clotting
factors and, although rare, can be seen in the postpartum setting, as
a manifestation of underlying autoimmune or neoplastic disease, or
idiopathically. Rare cases of acquired inhibitors to thrombin or FV have
been reported in patients receiving topical bovine thrombin prepara­
tion as a local hemostatic agent in complex surgeries. A mixing study
that does not correct with the addition of normal plasma indicates
the presence of an inhibitor, requiring additional tests to identify the
specificity of the inhibitor and measure its titer. Inhibitor detection
in patients with hemophilia is of particular importance, with yearly
screening performed at most hemophilia treatment centers.
The treatment of coagulation factor deficiencies in the setting of
bleeding requires replacement of the deficient protein(s) using recom­
binant or purified plasma-derived products or fresh-frozen plasma
11–14 d
Intrinsic Pathway
Extrinsic Pathway
Ca2+
aPTT
PT
XIa
XI
IX
IXa
Ca2+
Contact phase
FXIIa
PK
HMWH
VIII
VIIIa
Xa
X
Ca2+
Cross-linked
fibrin clot
FIGURE 121-1  Coagulation cascade and laboratory assessment of clotting factor deficiency by activated partial thromboplastin time (aPTT), prothrombin time (PT),
thrombin time (TT), and phospholipid (PL).
(FFP). Prothrombin complex concentrates (PCCs) are intermediatepurity plasma-derived factor concentrates initially used as sources of
FVIII or FIX for hemophilia patients, but because they contain the
vitamin K–dependent factors, they are also used for warfarin reversal.
Three-factor PCC (3F-PCC) is less frequently used now for warfarin
reversal because these preparations contain low levels of FVII, requir­
ing FFP as a source of FVII. Four-factor PCC (4F-PCC), especially the
one used in the United States, contains FII, FIX, FX, higher levels of
FVII than 3F-PCC, and protein S and protein C.
HEMOPHILIA A AND B
■
■PATHOGENESIS AND CLINICAL MANIFESTATIONS
Hemophilia is an X-linked recessive hemorrhagic disease due to muta­
tions in the F8 gene (hemophilia A or classic hemophilia) or F9 gene
(hemophilia B). The disease affects 1 in 10,000 males worldwide, in all
ethnic groups; hemophilia A represents 80% of all cases. The large size
of the F8 gene makes it more susceptible to mutation events than the
smaller F9 gene. Male subjects are clinically affected; women, who carry
a single mutated gene, are generally asymptomatic. However, increased
bleeding tendencies with procedures are now more commonly appre­
ciated based on F8 or F9 level. Family history of the disease is absent
in ~30% of cases, and in these cases, 80% of the mothers are carriers
of the de novo mutated allele. More than 500 different mutations have
been identified in the F8 or F9 gene. One of the most common hemo­
philia A mutations results from an inversion of the intron 22 sequence,
and it is present in 40% of cases of severe hemophilia A. Advances in
molecular diagnosis now permit precise identification of mutations,
allowing accurate diagnosis of women carriers of the hemophilia gene
in affected families.
Clinically, hemophilia A and hemophilia B are indistinguishable.
The disease phenotype correlates with the activity of FVIII or FIX and
can be classified as severe (<1%), moderate (1–5%), or mild (6–30%).
In the severe and moderate forms, the disease is characterized by bleed­
ing into the joints (hemarthrosis), soft tissues, and muscles after minor
trauma or even spontaneously. Patients with mild disease experience
infrequent bleeding, usually secondary to trauma. Among those with
baseline FVIII or FIX activity >25%, the disease is discovered only with
bleeding after major trauma or during routine laboratory tests, usu­
ally an isolated prolongation of the aPTT that requires mixing study
VII
VIIa/tissue factor
Ca2+
PL
Common Pathway
X
V
Va
PL
Prothrombin
Thrombin
aPTT/PT
Fibrinogen
TT
Fibrin
polymer
Fibrin monomer
CHAPTER 121
XIIIa
Coagulation Disorders
evaluation. FVIII has a short circulating half-life of 25–30 min that
is extended to roughly 12 h when complexed with its carrier protein
von Willebrand factor (VWF). In patients without a known history of
hemophilia, a diagnosis of von Willebrand disease (VWD) needs to
be excluded in patients with a prolonged aPTT and low FVIII activity.
Early in life, bleeding may present after circumcision or rarely as intra­
cranial hemorrhages. The disease is more evident when children begin
to walk or crawl. In the severe form, the most common bleeding mani­
festations are recurrent hemarthroses, affecting primarily the knees,
elbows, ankles, shoulders, and hips. Acute hemarthroses are painful,
and clinical signs are local swelling and erythema. To avoid pain, the
patient may adopt a fixed position, which leads eventually to muscle
contractures. Very young children unable to communicate verbally
show irritability and a lack of movement of the affected joint. Chronic
hemarthroses are debilitating with synovial thickening and synovitis in
response to the intraarticular blood. After a joint has been damaged,
recurrent bleeding episodes result in the clinically recognized “target
joint,” which then establishes a vicious cycle of bleeding, resulting in
progressive joint deformity that in critical cases requires surgery as the
only therapeutic option. Hematomas into the muscle of distal parts of
the limbs may lead to external compression of arteries, veins, or nerves
that can result in compartment syndrome.
Bleeding into the oropharyngeal spaces, central nervous system
(CNS), or retroperitoneum is life-threatening and requires immediate
therapy. Retroperitoneal hemorrhages can accumulate large quantities
of blood with formation of masses with calcification and inflammatory
tissue reaction (pseudotumor syndrome) and also result in damage to
the femoral nerve. Pseudotumors can also form in bones, especially
long bones of the lower limbs. Hematuria is frequent among hemo­
philia patients, even in the absence of genitourinary pathology. It is
often self-limited and may not require specific therapy.
TREATMENT
Hemophilia
Without treatment, severe hemophilia may limit life expectancy.
Advances in the blood fractionation industry during World War II
resulted in the realization that plasma could be used to treat hemo­
philia, but the volumes required to achieve even modest elevation
of circulating factor levels limit the utility of plasma infusion as an
approach to disease management. The discovery in the 1960s that
the cryoprecipitate fraction of plasma was enriched for FVIII, and
the eventual purification of FVIII and FIX from plasma, led to the
introduction of home infusion therapy with factor concentrates in
the 1970s. The availability of factor concentrates resulted in a dra­
matic improvement in life expectancy and quality of life for people
with severe hemophilia. However, the contamination of the blood
supply with hepatitis viruses and HIV resulted in transmission of
these bloodborne infections within the hemophilia population. The
introduction of viral inactivation steps in the preparation of plasmaderived products in the mid-1980s greatly reduced the risk of HIV
and hepatitis; the risks were further reduced by the production of
recombinant FVIII and FIX proteins in the 1990s. It is uncommon
for hemophilic patients born after 1985 to have contracted either
hepatitis or HIV, and for these individuals, life expectancy is now
∼65 years. In fact, since 1998, new infections with viral hepatitis or
HIV have not been reported in hemophilia patients.
Factor replacement for hemophilia has been the mainstay of
therapy for half a century; however, advances including uniquely
functioning molecules and gene therapy have expanded treatment
approaches. Factor replacement has been provided either in response
to a bleeding episode or as prophylactic treatment. Primary prophy­
laxis is defined as maintaining the missing clotting factor at levels
~1% or higher on a regular basis to prevent bleeds, especially the
onset of hemarthroses. Hemophilic boys receiving regular infusions
of FVIII (3 days/week) or FIX (2 days/week) can reach puberty with­
out detectable joint abnormalities. Therefore, prophylactic treatment
has become more common. The Centers for Disease Control and
Prevention reported that >51% of children with severe hemophilia
who are aged <6 years receive prophylaxis, increasing considerably
from 33% in 1995. Although prophylaxis with factor concentrates
is the standard care for children and adults with severe hemophilia,
teenagers and young adults do not always maintain treatment due
to high cost and lifestyle factors including difficulties accessing
peripheral veins for infusions that occur two to three times a week
or potential infectious and thrombotic risks of long-term central
vein catheters.
PART 4
Oncology and Hematology
Treatment of hemophilia bleeds requires the following:
(1) prompt initiation of factor replacement as symptoms often
precede objective evidence of bleeding, especially for classic symp­
toms of bleeding into the joint in a reliable patient, headaches, or
major trauma; and (2) avoidance of antiplatelet drugs.
FVIII and FIX are dosed in units. One unit is defined as the
amount of FVIII (100 ng/mL) or FIX (5 μg/mL) in 1 mL of normal
plasma. One unit of FVIII per kilogram of body weight increases
the plasma FVIII level by 2%. One can calculate the dose needed to
increase FVIII levels to 100% in a 70-kg severe hemophilia patient
(<1%) using the simple formula below. Thus, 3500 units of FVIII
will raise the circulating level to 100%.
FVIII dose (IU) = Target FVIII levels – FVIII baseline levels
  × body weight (kg) × 0.5 unit/kg
The doses for FIX replacement are different from those for
FVIII, because FIX recovery after infusion is usually only 50% of
the predicted value. Therefore, the formula for FIX replacement is
as follows:
FIX dose (IU) = Target FIX levels – FIX baseline levels
  × body weight (kg) × 1 unit/kg
The FVIII half-life of 8–12 h requires injections twice a day to
maintain therapeutic levels, whereas the FIX half-life is longer,
~24 h, so that once-a-day injection is sufficient. In specific situa­
tions such as after surgery, continuous infusion of factor may be
desirable because of its safety in achieving sustained factor levels at
a lower total cost.
Cryoprecipitate is enriched with FVIII protein bound to VWF
(each bag contains ~80 IU of FVIII). This product should be used
only in emergencies when factor concentrates are not available,
although cryoprecipitate may be the only source of FVIII in devel­
oping countries.
Mild bleeds such as uncomplicated hemarthroses or superficial
hematomas require achieving an initial factor level of 30–50%.
Additional doses to maintain levels of 15–25% for 2 or 3 days are
indicated for severe hemarthroses, especially when these episodes
affect the “target joint.” Large hematomas, or bleeds into deep
muscles, require factor levels of 50% or even higher if the clinical
symptoms do not improve, and factor replacement may be required
for a period of 1 week or longer. The control of serious bleeds,
including those that affect the oropharyngeal spaces, CNS, and the
retroperitoneum, requires sustained protein levels of 50–100% for
7–10 days. Prophylactic replacement for surgery is aimed at achiev­
ing normal factor levels (100%) for a period of 7–10 days; replace­
ment can then be tapered depending on the extent of the surgical
wounds. Oral surgery is associated with extensive tissue damage
that usually requires factor replacement for 1–3 days coupled with
oral antifibrinolytic drugs.
NONTRANSFUSION THERAPY IN HEMOPHILIA
DDAVP (1-Amino-8-d-Arginine Vasopressin)  DDAVP is a syn­
thetic vasopressin analogue that causes a transient rise in FVIII and
VWF, but not FIX, by release from stores in vascular endothelial
cells. Patients with moderate or mild hemophilia A should be tested
to determine if they respond to DDAVP before use. DDAVP at
doses of 0.3 μg/kg body weight, over a 20-min period, is expected
to raise FVIII levels by two- to threefold over baseline, peaking
between 30 and 60 min after infusion. DDAVP does not improve
FVIII levels in severe hemophilia A patients because no stores are
available to release. Repeated dosing of DDAVP results in tachyphy­
laxis as storage pools are depleted. After three consecutive doses, if
further therapy is indicated, exogenous FVIII is required.
Antifibrinolytic Drugs  Bleeding in the gums, the gastrointestinal
tract, and during oral surgery can be treated with oral antifibri­
nolytic drugs such as ε-aminocaproic acid (EACA) or tranexamic
acid to prevent fibrin degradation by plasmin. The duration of the
treatment depending on the clinical indication is 1 week or longer.
Tranexamic acid is given at doses of 25 mg/kg three to four times a
day. EACA treatment requires a loading dose of 200 mg/kg (maxi­
mum of 10 g) followed by 100 mg/kg per dose (maximum 30 g/d)
every 6 h. These drugs are not indicated to control hematuria
because of concern for forming an occlusive clot in the lumen of
genitourinary tract structures.
COMPLICATIONS
Inhibitor Formation  The formation of alloantibodies to FVIII
or FIX is the major complication of hemophilia treatment. The
prevalence of inhibitors to FVIII is estimated to be ~30% in severe
hemophilia A patients and 10% among patients with nonsevere
hemophilia A. Inhibitors to FIX are detected in only 3–5%
of all hemophilia B patients. The high-risk group for inhibitor
formation includes severe deficiency (>80% of all cases of inhibi­
tors), familial history of inhibitor, African descent, mutations in
the FVIII or FIX gene resulting in deletion of large coding regions,
or gross gene rearrangements. Inhibitors usually appear early in
life, at a median of 2 years of age, and after 10 cumulative days
of exposure. However, intensive replacement therapy such as for
major surgery, intracranial bleeding, or trauma increases the risk of
inhibitor formation for patients of all ages and severity; all patients
require close laboratory monitoring following these events.
The clinical diagnosis of an inhibitor is suspected when patients
do not respond to factor replacement at therapeutic doses. Inhibi­
tors increase both morbidity and mortality in hemophilia. Because
early detection of an inhibitor is critical to a successful correction
of the bleeding or to eradication of the antibody, most hemophilia
centers perform annual screening with aPTT and mixing studies.
The Bethesda assay uses a similar principle as a mixing study and
defines the specificity of the inhibitor and its titer. The results are
expressed in Bethesda units (BU), in which 1 BU is the amount of
antibody that neutralizes 50% of the FVIII or FIX present in normal
plasma after 2 h of incubation at 37°C. Clinically, inhibitor patients
are classified as low responders or high responders, with response
defined as increase in antibody titer; knowledge of responder
type guides therapy. Therapy for inhibitor patients has two goals:
the control of acute bleeding episodes and the eradication of the
inhibitor. For the control of bleeding episodes, low responders,
those with titer <5 BU, respond well to high doses of human FVIII
(50–100 U/kg), with minimal or no increase in the inhibitor titers.
However, high-responder patients, those with initial inhibitor titer
5 BU or an anamnestic response with increase in the antibody
titer to >5 BU, even if low titer initially, do not respond to FVIII.
The control of bleeding episodes in high-responder patients can be
achieved by using concentrates enriched for prothrombin, FVII,
FIX, FX (PCCs but usually activated PCCs [aPCCs]), and recom­
binant activated FVII (FVIIa), known as “bypass agents” because
they activate coagulation downstream of the inhibited/absent fac­
tor or through a different pathway (Fig. 121-1). For FIX inhibitor
patients, high doses of FIX can be used (<5 BU); however, allergic
or anaphylactic reactions are common in FIX inhibitor patients;
thus, bypass products should be used to treat or prevent bleeding
as well as for those cases of high titer inhibitors. For eradication of
the inhibitory antibody, immunosuppression alone is not effective.
The most effective strategy is immune tolerance induction (ITI)
based on daily infusion of the missing protein until the inhibitor
disappears, typically requiring periods >1 year, with success rates
of ∼60%. The management of patients with severe hemophilia and
inhibitors resistant to ITI is challenging. The use of anti-CD20
monoclonal antibody (rituximab) combined with ITI was thought
to be effective, but although it reduces the inhibitor titers in some
cases, sustained eradication is uncommon.
Other Therapeutic Approaches for Hemophilia A and B  Engi­
neered clotting factors, using fusion to polyethylene glycol (FVIII,
FIX), IgG1-Fc (FVIII, FIX), or albumin (FIX) or other strategies,
extend the plasma half-life of the coagulation factor. A number of
products have been approved for use. These extended half-life prod­
ucts (for FVIII and FIX) facilitate prophylaxis with fewer weekly
injections to maintain circulating levels >1%, decreasing injections
from 3 to 2 days a week in hemophilia A and to once a week for
hemophilia B. Novel approaches to manipulating the coagulation
cascade components, including targeting the natural anticoagulants
and inhibitors of activation of coagulation, have shown promising
clinical trial results but do not yet have regulatory approval.
Emicizumab is an asymmetric bispecific antibody with one
immunoglobulin variable chain region that binds FIXa and another
that binds FX bringing them in close contact and resulting in acti­
vation of FX by FIXa. FXa subsequently cleaves prothrombin to
thrombin—without the need for FVIII (Fig. 121-2). It is effective
in patients with severe hemophilia A with or without inhibitors.
Similar molecules are in development. After initial once-a-week
subcutaneous injections (an improvement over intravenous admin­
istration of factors) for 4 weeks, patients can usually be maintained
with once-a-month dosing to prevent spontaneous bleeds, an over­
whelmingly dramatic improvement in quality of life when com­
pared to even the twice-weekly infusion schedule of “long-acting”
FVIII compounds. Breakthrough bleeds can occur, however, and
need to be carefully managed, as a small number of patients with
inhibitors treated with aPCC or recombinant FVIIa developed
thrombotic events or fatal thrombotic microangiopathy. Routine
aPTT and FVIII activity measurements are inaccurate when emi­
cizumab is present; to detect endogenous or infused FVIII activity,
a chromogenic FVIII activity assay using bovine factor substrates
is required.
These X-linked disorders are ideally suited for gene therapy as
small increases in plasma factor level will result in significant clinical
improvement. FIX has been the most studied as the gene is smaller
Bispecific antibody
Factor X
Factor IXa
EGF2
EGF2
EGF1
EGF1
Gla
Gla
Factor Xa
CHAPTER 121
PS-exposed PL membrane
Coagulation Disorders
FIGURE 121-2  Mechanism of action of emicizumab. Emicizumab is a bifunctional
antibody; the two binding sites recognize different protein sequences, unlike normal
antibodies where both variable regions recognize the same antigen. One arm of
emicizumab recognizes factor IXa and the other factor X. It functions to bring these
two factors in proximity so that factor IXa can activate factor X to factor Xa, which
then cleaves prothrombin to thrombin and activates the clotting cascade. (From T
Kitazawa, M Shima: Emicizumab, a humanized bispecific antibody to coagulation
factors IXa and X with a factor VIIIa-cofactor activity. Int J Hematol 111:20, 2020.)
and easier to package in the viral vectors used. In one approach, the
sequence of a known spontaneous FIX gain-of-function mutation
that has marked increase in specific activity, FIX Padua, is used so
that small increments in plasma level of FIX are also accompanied
by even greater increase in functional activity. The larger FVIII gene
has also been successfully transferred through an adeno-associated
viral vector to a few patients with hemophilia A. The early results
appear promising. Complications include transaminitis and loss
of gene expression for a variety of reasons. Gene therapy using
adenoviral vector approaches have now been approved for patients
with hemophilia A or B. Details on how to implement gene therapy,
selection of appropriate patients, and follow-up monitoring are still
being developed (Chap. 483).
INFECTIOUS DISEASES
Hemophilia patients treated with clotting factor concentrates before
the development of recombinant factors in the 1990s were almost
universally infected with hepatitis C virus (HCV) and HIV, which
became the second leading cause of death. Co-infection of HCV
and HIV, present in almost 50% of hemophilia patients, is an aggra­
vating factor for the evolution of liver disease as correction of both
genetic and acquired (secondary to liver disease) factor deficiencies
may be needed. Effective treatments for both HIV and HCV have
altered the devastating prognosis. In some select cases with cir­
rhosis, liver transplant has been performed, which also is curative
for hemophilia.
EMERGING CLINICAL PROBLEMS IN AGING
HEMOPHILIA PATIENTS
Patients with hemophilia now live well into adulthood, with life
expectancy of patients with severe hemophilia now only ~10 years
shorter than the general male population and near normal in
patients with mild or moderate hemophilia. The older hemophilia
population has distinct needs relating to more severe arthropathy,
chronic pain, and high rates of HCV and/or HIV infections.
Although mortality from coronary artery disease is lower in
hemophilia patients with hypocoagulability decreasing thrombus
formation, atherogenesis is not prevented. Typical cardiovascular
risk factors such as age, obesity, and smoking, along with physical
inactivity, hypertension, and chronic renal disease, are seen in these
patients as in the general population.
Management of an acute ischemic event and coronary revas­
cularization should include collaboration among hematologists,
cardiologists, and internists. Cancer due to HIV- and HCV-related
malignancies is also a concern in this population, with hepato­
cellular carcinoma (HCC) the most common cause of death in
HIV-negative patients. The recommendations for cancer screening
for the general population should be the same for age-matched
hemophilia patients, including routine screening for HCC.
Hemophilia patients benefit from the same preventive and thera­
peutic approaches to minimize the risk of cardiovascular disease
and malignancy as the general population.
MANAGEMENT OF CARRIERS OF HEMOPHILIA
Women carriers of hemophilia with factor levels ~50% of normal
may not have an increased risk for bleeding. However, a wide
range of factor activity (22–116%) due to random inactivation of
the X chromosome (lyonization) can occur and lead to unexpected
bleeding in women with low levels. The factor level of carriers
should be measured to optimize perioperative management. Dur­
ing pregnancy, FVIII levels increase approximately two- to three­
fold in most carriers compared to nonpregnant women, whereas
the FIX increase is less pronounced. After delivery, a rapid fall in
the pregnancy-induced rise of maternal clotting factor levels occurs,
resulting in increased risk for postpartum hemorrhage that can be
prevented by infusion of factor concentrate to levels of 50–70% for
3 days for vaginal delivery and up to 5 days for cesarean delivery.
In mild cases, the use of DDAVP and/or antifibrinolytic drugs is
recommended.
PART 4
Oncology and Hematology
■
■FACTOR XI DEFICIENCY
FXI deficiency, also known as hemophilia C, is a rare autosomal bleed­
ing disorder that occurs at a frequency of one in a million. However,
it is highly prevalent among Ashkenazi and Iraqi Jewish populations,
reaching a frequency of 6% heterozygotes and 0.1–0.3% homozygotes.
More than 65 mutations in the FXI gene have been reported, whereas
fewer mutations (two to three) are found among affected Jewish
populations.
Normal FXI clotting activity levels range from 70–150 U/dL. Levels
vary depending on the presence of heterozygous, homozygous, or dou­
ble heterozygous mutations with levels <1 U/dL seen in the latter two.
Patients with FXI levels <10% of normal have a high risk of bleeding,
but the phenotype does not always correlate with FXI clotting activity.
The family history is informative, with the bleeding risk based on bleed­
ing in kindreds. Clinically, spontaneous bleeding is rare, but mucocu­
taneous bleeding such as bruises, gum bleeding, epistaxis, hematuria,
and menorrhagia are common, especially following trauma. This hem­
orrhagic phenotype suggests that tissues rich in fibrinolytic activity are
more susceptible to FXI deficiency. Postoperative bleeding is common
but not always present, even among patients with very low FXI levels.
FXI replacement is indicated in patients with severe disease for
major surgical procedures. A negative history of bleeding complica­
tions following invasive procedures does not exclude the possibility of
an increased risk for hemorrhage.
TREATMENT
Factor XI Deficiency
Sources of FXI are limited to FFP in the United States, whereas
a plasma-derived FXI concentrate is available in other countries.
FFP at doses of 15–20 mL/kg to increase levels by 10–20% can be
given every other day in the setting of bleeding or major surgery as
FXI has a half-life of 40–70 h. Antifibrinolytic drugs can be used
for minor bleeds and as adjunctive treatment with FXI replace­
ment with the exception of genitourinary tract bleeding. The
development of an FXI inhibitor can be seen in 10% of severely
FXI-deficient patients. Although inhibitors are not associated with
spontaneous bleeding, bleeding with surgery or trauma can be
severe; treatment with PCC/aPCC or recombinant activated FVII
is effective. Data for use of a single very low dose of recombinant
activated FVII (10–15 μg/kg) and an antifibrinolytic agent before
surgery in patients with severe FXI deficiency are good, avoiding
the need for plasma products.
RARE BLEEDING DISORDERS
Inherited disorders resulting from deficiencies of clotting factors other
than FVIII, FIX, and FXI (Table 121-1) occur infrequently. Bleeding
manifestations vary from generally asymptomatic as with dysfibrino­
genemia or FVII deficiency to life-threatening as with FX or FXIII
deficiency. In contrast to hemophilia, hemarthroses are rare, but bleed­
ing in the mucosal tract or after umbilical cord clamping is common.
Individuals heterozygous for plasma coagulation deficiencies are often
asymptomatic. The laboratory assessment for the specific deficient
factor following screening with general coagulation tests (Table 121-1)
identifies the diagnosis.
Replacement therapy using FFP or PCCs for deficiencies provides
adequate hemostasis for bleeds or prophylactic treatment, although
specific concentrates for FX and fibrinogen are available. Cryopre­
cipitate or FXIII concentrate is needed for FXIII deficiency. FVII defi­
ciency, like FXI, has an increased prevalence in the Ashkenazi Jewish
population and is best treated with recombinant FVIIa rather than FFP
or PCCs depending on the severity of bleeding or type of surgery. It
should be noted that deficiency of FXII is associated with significant
prolongation of the aPTT but no bleeding phenotype.
■
■FAMILIAL MULTIPLE COAGULATION
DEFICIENCIES
Several bleeding disorders are characterized by the inherited deficiency
of more than one plasma coagulation factor. To date, the genetic defects
in two of these diseases have been characterized, and they provide new
insights into the regulation of hemostasis by gene-encoding proteins
outside blood coagulation.
Combined Deficiency of FV and FVIII 
Patients with com­
bined FV and FVIII deficiency exhibit ~5% of residual clotting activ­
ity of each factor, yet have a mild bleeding tendency, often following
trauma. A mutation in the lectin mannose binding 1 (LMAN1) gene,
a mannose-binding protein localized in the Golgi apparatus that func­
tions as a chaperone for both FV and FVIII, is responsible. In other
families, mutations in the multiple coagulation factor deficiency 2
(MCFD2) gene have been defined; this gene product forms a Ca2+-
dependent complex with LMAN1, providing cofactor activity for
intracellular mobilization of both FV and FVIII. Replacement therapy
to control or prevent bleeding consists of FFP to maintain FV levels
and DDAVP or FVIII concentrate to achieve FVIII levels of 20–40%.
Alternatively, platelets, which contain FV, can also be used.
Multiple Deficiencies of Vitamin K–Dependent Coagulation
Factors 
Two enzymes involved in vitamin K metabolism have
been associated with combined deficiency of all vitamin K–dependent
proteins, including the procoagulant proteins prothrombin (II), VII,
IX, and X and the anticoagulant proteins C and S. Vitamin K, a fatsoluble vitamin, is a cofactor for carboxylation of the gamma carbon
of the glutamic acid residues in the vitamin K–dependent factors, a
critical step for calcium and phospholipid binding (Fig. 121-3). The
enzymes γ-glutamylcarboxylase and epoxide reductase are critical for
the metabolism and regeneration of vitamin K. Mutations in the genes
encoding the γ-carboxylase (GGCX) or vitamin K epoxide reductase
complex 1 (VKORC1) result in defective enzymes and thus in vita­
min K–dependent factors with reduced activity, varying from 1–30%
Warfarin
Epoxide
reductase
Vitamin K
epoxide
Vitamin K
reduced
Carboxylase
γ-Carboxyglutamic
acid
Glutamic
acid
FIGURE 121-3  The vitamin K cycle. Vitamin K is a cofactor for the formation of
γ-carboxyglutamic acid residues on coagulation proteins. Vitamin K–dependent
γ-glutamylcarboxylase, the enzyme that catalyzes the vitamin K epoxide reductase,
regenerates reduced vitamin K. Warfarin blocks the action of the reductase and
competitively inhibits the effects of vitamin K.
of normal. Patients can have mild to severe bleeding episodes present
from birth. Some patients respond to oral vitamin K1 (5–20 mg/d) or
parenteral vitamin K1 at doses of 5–20 mg/week. For severe bleeding,
replacement therapy with PCC may be necessary.
■
■DISSEMINATED INTRAVASCULAR COAGULATION
In 2001, the International Society on Thrombosis and Haemostasis
(ISTH) defined DIC as “an acquired syndrome characterized by the
intravascular activation of coagulation with loss of localization aris­
ing from different causes that can originate from and cause damage
to the microvasculature, which if sufficiently severe, can produce
organ dysfunction.” Many disparate processes are associated with DIC
(Table 121-2).
The most common causes are bacterial sepsis, although viral and
fungal sepsis can also cause DIC; trauma; obstetric causes such as
abruptio placentae or amniotic fluid embolism; and malignant disor­
ders, especially mucin-producing adenocarcinomas and acute promy­
elocytic leukemia. Activation of inflammatory pathways in response
to infectious pathogens results in increased expression of tissue factor,
activation of neutrophils and monocytes with release of cytokines and
development of neutrophil extracellular traps, and release of poly­
phosphates that engage in cross-talk with the coagulation system to
cause thrombin generation; this process is known as
thrombo-inflammation. Damage to vascular endothe­
lial cells results in the loss of their native antithrom­
botic properties; such damage especially occurs with
sepsis and trauma. Systemic inflammatory response
syndrome (SIRS) and cytokine storm are cytokinemediated exuberant inflammatory responses often
in the setting of infection that are associated with
increased mortality and DIC. Purpura fulminans is a
severe form of DIC resulting in thrombosis of exten­
sive areas of the skin; it affects predominantly young
children following viral or bacterial infection, partic­
ularly those with inherited or acquired hypercoagu­
lability due to deficiencies of the components of the
protein C pathway. Neonates homozygous for protein
C deficiency can develop neonatal purpura fulminans
with or without thrombosis of large vessels.
Red blood cell damage
and hemolysis
Ischemic tissue
damage
Failure of
multiple organs
The central mechanism of DIC is the uncontrolled
generation of thrombin by multiple mechanisms
(Fig. 121-4). Simultaneous disruption of the physi­
ologic anticoagulant mechanisms and abnormal
fibrinolysis further accelerate the process. These
abnormalities contribute to systemic fibrin deposi­
tion in small and midsize vessels. The duration and
intensity of the fibrin deposition can compromise
Vessel patency
FDP D-dimer
FIGURE 121-4  The pathophysiology of disseminated intravascular coagulation (DIC). Interactions
between coagulation and fibrinolytic pathways result in bleeding and thrombosis in the microcirculation
in patients with DIC. FDP, fibrin degradation product.
TABLE 121-2  Common Clinical Causes of Disseminated Intravascular
Coagulation
SEPSIS
IMMUNOLOGIC DISORDERS
• Bacterial:
Staphylococci, streptococci,
• Acute hemolytic transfusion reaction
• Organ or tissue transplant rejection
• Immunotherapy
• Graft-versus-host disease
pneumococci, meningococci,
gram-negative bacilli
• Viral
• Mycotic
• Parasitic
• Rickettsial
TRAUMA AND TISSUE INJURY
DRUGS
• Brain injury (gunshot)
• Extensive burns
• Fat embolism
• Rhabdomyolysis
• Fibrinolytic agents
• Aprotinin
• Warfarin (especially in neonates
with protein C deficiency)
• Prothrombin complex concentrates
• Recreational drugs (amphetamines)
VASCULAR DISORDERS
ENVENOMATION
• Giant hemangiomas (Kasabach-
• Snake
• Insects
CHAPTER 121
Merritt syndrome)
• Large vessel aneurysms (e.g., aorta)
OBSTETRICAL COMPLICATIONS
LIVER DISEASE
• Abruptio placentae
• Amniotic fluid embolism
• Dead fetus syndrome
• Septic abortion
• Fulminant hepatic failure
• Cirrhosis
• Fatty liver of pregnancy
Coagulation Disorders
CANCER
MISCELLANEOUS
• Adenocarcinoma (prostate,
• Shock
• Respiratory distress syndrome
• Massive transfusion
pancreas, etc.)
• Hematologic malignancies (acute
promyelocytic leukemia)
the blood supply of many organs, especially the lung, kidney, liver,
and brain, with consequent organ failure; for example, pulmonary
microvascular thrombosis is a component of adult respiratory distress
syndrome (ARDS). The sustained activation of coagulation and forma­
tion of fibrin can result in consumption of clotting factors and platelets,
which in turn leads to systemic bleeding that can be aggravated by
secondary hyperfibrinolysis that occurs in late stages of DIC.
DIC
Uncontrolled thrombin
generation
Fibrin deposits in the
microcirculation
Consumption of platelets
and coagulation factors
Secondary fibrinolysis
Diffuse bleeding
TABLE 121-3  International Society on Thrombosis and Haemostasis
Criteria for Overt Disseminated Intravascular Congestion (DIC)
PARAMETER
VALUE
POINTS
Platelets
100,000 × 109/L
50–<100 × 109/L
<50 × 109/L
d-Dimera
Normal
Moderate increase
Severe increase
Prothrombin time (PT)
prolonged
<3 s
3–<6 s
6 s
Fibrinogen
1 g/L
<1 g/L
Total Score
 
<5 Low-grade DIC
5 Overt DIC
ad-Dimer assays are not standardized and have different ranges of normal. Check
your institution range of normal to assess degree of increase.
Note: A score of <5 suggests nonovert DIC/low-grade DIC and should be repeated
every 1–2 days. A score of >5 suggests overt DIC; lab values should be repeated
daily to assess critical changes. Not to be used in pregnant patients.
PART 4
Oncology and Hematology
Clinical manifestations of DIC are related to the magnitude of
the imbalance of hemostasis, to the underlying disease, or to both.
The most common clinical findings include petechiae, ecchymoses,
and bleeding ranging from oozing from venipuncture sites to severe
hemorrhage from the gastrointestinal tract, lung, or into the CNS. In
chronic DIC, the bleeding symptoms are discrete and restricted to skin
or mucosal surfaces. The hypercoagulability of DIC manifests as the
occlusion of vessels in the microcirculation resulting in organ failure.
Thrombosis of large vessels and cerebral embolism can also occur.
Hemodynamic complications and shock are common among patients
with acute DIC, due to the underlying disease, with mortality ranging
from 30 to >80%.
Making the diagnosis of DIC can be difficult. The ISTH has devel­
oped a validated scoring tool to aid in the diagnosis of overt DIC with
a separate tool for pregnant women. It incorporates platelet count,
d-dimer level, PT, and fibrinogen level, and assigns points for different
levels of each with the aggregate score helping to make the diagnosis of
DIC (Table 121-3). The peripheral smear should be assessed for schis­
tocytes. The laboratory diagnosis of DIC should prompt a search for
the underlying disease if not already apparent. In critically ill patients,
these tests should be repeated over a period of 6–8 h as patients can
rapidly deteriorate.
Chronic DIC 
Low-grade, compensated DIC can occur in clinical
situations including giant hemangioma, metastatic carcinoma, or late
gestation fetal demise. Plasma levels of fibrin degradation product
or d-dimers are elevated. aPTT, PT, and fibrinogen values are within
the normal range or high. Mild thrombocytopenia or normal platelet
counts are also common findings. Red cell fragmentation is often
detected but at a lower degree than in acute DIC.
Differential Diagnosis 
Distinguishing between DIC and severe
liver disease is challenging and requires serial measurements of the lab­
oratory parameters of DIC. Patients with severe liver disease manifest
laboratory features including thrombocytopenia due to platelet seques­
tration, portal hypertension, or hypersplenism; decreased synthesis of
coagulation factors and natural anticoagulants; and elevated levels of
d-dimer. However, in contrast to DIC, these laboratory parameters in
liver disease do not change rapidly.
Although microangiopathic disorders such as immune thrombotic
thrombocytopenic purpura present with acute onset accompanied by
thrombocytopenia, red cell fragmentation, and multiorgan failure, the
clinical presentation and laboratory findings including presence of an
inhibitor to ADAMTS13 assist in diagnosis (Chap. 120).
TREATMENT
Disseminated Intravascular Coagulation
The morbidity and mortality associated with DIC are primarily
related to the underlying disease. Management of the underlying
disease is required to control and eliminate DIC; however, support
with platelets and coagulation factors may be needed until the incit­
ing cause is under control. Many patients with overt DIC are criti­
cally ill, usually requiring management in the intensive care unit to
treat shock physiology and other manifestations of the underlying
illness.
MANAGEMENT OF HEMORRHAGIC SYMPTOMS
Patients with active bleeding or at high risk of bleeding during inva­
sive procedures or after chemotherapy require transfusion support;
however, transfusion solely to correct mildly to moderately abnor­
mal coagulation parameters is not indicated. Platelet transfusion for
platelet counts <10,000–20,000/μL and replacement of fibrinogen
and coagulation factors with FFP, cryoprecipitate, or fibrinogen
concentrate as a source of fibrinogen are indicated with amounts
determined by the degree of abnormal PT, aPTT, and fibrinogen
levels, as well as severity of bleeding or bleeding risk with invasive
procedures. For these situations, fibrinogen level should be main­
tained at >150 mg/dL and PT prolonged no more than 3 s above the
upper limit of normal. Vitamin K should be given. Patients should
be frequently monitored, and transfusion support adjusted as the
patient’s condition changes and dictates.
REPLACEMENT OF COAGULATION OR
FIBRINOLYSIS INHIBITORS
Anticoagulants such as heparin, concentrates of antithrombin and
thrombomodulin, and antifibrinolytic drugs have all been tried in
the treatment of DIC. Low doses of continuous-infusion heparin
(5–10 U/kg per h) may be effective in patients with low-grade DIC
associated with solid tumors, acute promyelocytic leukemia, or in
a setting with recognized thrombosis. Heparin is also indicated for
the treatment of purpura fulminans. In acute hemorrhagic DIC, the
use of heparin is likely to aggravate bleeding. The use of heparin in
patients with severe DIC, although demonstrating improved coagu­
lation parameters, is not associated with a survival benefit; profes­
sional society recommendations for use vary widely. Although the
use of concentrates of the serine protease inhibitors, antithrombin
and thrombomodulin, for sepsis demonstrated little efficacy in all
treated patients, post hoc analyses of those with sepsis and con­
firmed DIC suggest a survival advantage and require further study.
Activated protein C treatment for septic shock was withdrawn from
the market years ago as findings in clinical practice did not replicate
the mortality advantage seen in the clinical trial; impact on DIC was
not evaluated.
In patients who have DIC characterized by a primary hyperfi­
brinolytic state with concomitant severe bleeding, the administra­
tion of antifibrinolytics may be considered. However, concern for
increasing the risk of thrombosis has led to consideration of con­
comitant use of heparin. Patients with acute promyelocytic leuke­
mia or those with chronic DIC associated with giant hemangiomas
are among the few patients who may benefit from this therapy.
■
■VITAMIN K DEFICIENCY
Vitamin K–dependent proteins are a heterogeneous group, including
clotting factor proteins and proteins found in bone, lung, kidney, and
placenta. Vitamin K mediates posttranslational modification of gluta­
mate residues to γ-carboxylglutamate, which is necessary for calcium
binding and proper assembly on phospholipid membranes (Fig. 121-3).
Inherited mutations with decreased functional activity of the enzymes
GGCX or VKORC1 (see above) result in bleeding disorders. Vitamin K
in the diet is often limiting for the carboxylation reaction; thus,
recycling of the vitamin K by these enzymes is essential to maintain
normal levels of vitamin K–dependent proteins. In adults, severe
vitamin K deficiency due to low dietary intake is rare but is common in
association with the use of broad-spectrum antibiotics or with disease
or surgical interventions that affect the ability of the intestinal tract
to absorb vitamin K, through anatomic alterations or by changing the
fat content of bile salts and pancreatic enzymes in the proximal small
bowel. Chronic liver diseases such as primary biliary cirrhosis also
deplete vitamin K stores. Neonatal vitamin K deficiency and the result­
ing hemorrhagic disease of the newborn have been almost entirely
eliminated by routine administration of vitamin K to all neonates.
Prolongation of PT values is the most common and earliest finding
in vitamin K–deficient patients due to the short half-life of FVII and
occurs before prolongation of the aPTT. Parenteral administration of
10 mg of vitamin K is sufficient to restore normal levels of clotting fac­
tor within 8–10 h. More rapid correction of the coagulopathy requires
replacement with FFP or PCC, with the choice depending on patient
intravascular volume status and need for rapidity of correction. The
reversal of excessive anticoagulant therapy with vitamin K antagonists,
such as warfarin, can be achieved by minimal doses of vitamin K
(1 mg orally or by intravenous injection) for asymptomatic patients.
This strategy can diminish the risk of bleeding while maintaining thera­
peutic anticoagulation for an underlying prothrombotic state. For emer­
gent reversal of warfarin in the setting of life-threatening bleeding or
need for emergency surgery, use of 4F-PPC is the standard of care.
In patients with underlying vascular disease, vascular trauma, atrial
fibrillation, and other comorbidities, re-initiation of anticoagulation
needs to be carefully considered to prevent subsequent thromboem­
bolic complications.
■
■COAGULATION DISORDERS ASSOCIATED
WITH LIVER FAILURE
The liver is the site of synthesis and clearance of most procoagulant
and natural anticoagulant proteins and of essential components of
the fibrinolytic system. Acute liver failure is associated with a high
risk of bleeding due to deficient synthesis of procoagulant factors and
enhanced fibrinolysis; hepatologists refer to this as accelerated intra­
vascular coagulation and fibrinolysis (AICF). Thrombocytopenia is
common in patients with liver disease and may be due to decreased
thrombopoietin that is synthesized in the liver, congestive spleno­
megaly (hypersplenism), or immune-mediated shortened platelet life
span (primary biliary cirrhosis). In addition, several anatomic abnor­
malities secondary to underlying liver disease further increase the risk
of bleeding (Table 121-4). Dysfibrinogenemia is a relatively common
finding in patients with liver disease due to impaired fibrin polymer­
ization. The development of DIC in patients with chronic liver disease
is not uncommon and may enhance the risk for bleeding. Laboratory
TABLE 121-4  Coagulation Disorders and Hemostasis in Liver Disease
Bleeding
Portal hypertension
  Esophageal varices
Thrombocytopenia
  Splenomegaly
  Chronic or acute DIC
Decreased synthesis of clotting factors
  Hepatocyte failure
  Vitamin K deficiency
Systemic fibrinolysis
DIC
Dysfibrinogenemia
Thrombosis
Decreased synthesis of coagulation inhibitors: protein C, protein S, antithrombin
  Hepatocyte failure
  Vitamin K deficiency (protein C, protein S)
Failure to clear activated coagulation proteins (DIC)
Dysfibrinogenemia
Abbreviation: DIC, disseminated intravascular coagulation.
evaluation is mandatory for an optimal therapeutic strategy, either
to control ongoing bleeding or before invasive procedures. Typically,
these patients present with prolonged PT, aPTT, and thrombin time
(TT) depending on the degree of liver damage, thrombocytopenia,
and normal or slight increase in d-dimer. Fibrinogen levels are low
only in fulminant hepatitis, decompensated cirrhosis, advanced liver
disease, or in the presence of DIC. The presence of prolonged TT and
normal fibrinogen and d-dimer levels suggests dysfibrinogenemia.
FVIII levels are often normal or elevated in patients with liver failure,
and decreased levels suggest superimposed DIC. FV is only synthesized
in the hepatocyte and is not a vitamin K–dependent protein; therefore,
reduced levels of FV may be an indicator of liver failure. Normal levels
of FV and low levels of FVII suggest vitamin K deficiency. Vitamin K
levels may be reduced in patients with liver failure due to compromised
storage in hepatocellular disease, changes in bile acids, or cholestasis
that can diminish the absorption of vitamin K. Replacement with intra­
venous vitamin K may improve hemostasis.
Patients with chronic stable liver disease are now recognized to
have rebalanced hemostasis with simultaneous changes in both pro­
coagulant and anticoagulant proteins. Although traditional clinical
laboratory tests may suggest increased bleeding risk, these patients in
fact do not have spontaneous bleeding and often do not need treat­
ment for minor to moderate bleeding risk procedures. If the patient
is bleeding, treatment with FFP was the standard approach to correct­
ing hemostasis in patients with acute liver failure; however, the use of
4F-PCC is now favored due to lower volume, less increase in portal
pressure, reduced risk of circulatory overload, and other complications
associated with FFP transfusion. As in any clinical situation, treatment
should not be given simply to correct laboratory abnormalities in a
patient who is not bleeding or with no need for invasive procedures.
Platelet concentrates are indicated when platelet counts are <10,000–
20,000/μL to control bleeding or immediately before an invasive pro­
cedure if counts are <50,000/μL. Cryoprecipitate is indicated only when
fibrinogen levels are <100–150 mg/mL unless the patient is bleeding, in
which case a higher target is used. The use of antifibrinolytic drugs as
adjuncts to control bleeding in patients with liver failure is not thought
to result in an increased risk of thrombosis; however, their impact on
acute thrombosis propagation is not well studied.
CHAPTER 121
Coagulation Disorders
Liver Disease and Thromboembolism 
Bleeding in patients
with stable liver disease is often mild or even asymptomatic. However,
as the disease progresses, the hemostatic balance is precarious and
easily disturbed; comorbid complications such as infections and renal
failure can rapidly upset this balance (Fig. 121-5). Past assumptions
based on abnormal coagulation tests have been that patients with
liver disease have a decreased risk of thrombosis; however, multiple
factors contribute to hypercoagulability, including decreased levels
of the natural anticoagulant proteins S and C, as well as endothelial
cell changes and hemodynamic changes that result in stasis such that
portal vein thrombosis is common. Patients with liver disease can also
develop deep-vein thrombosis and pulmonary embolism; those with
cirrhosis appear to have a 1.5- to 2-fold increase in the rate of venous
thromboembolism (VTE). Patients with compensated cirrhosis do not
appear to have increased bleeding with the use of VTE prophylaxis or
even therapeutic dose heparin to treat acute portal vein thrombosis
when carefully managed. In the outpatient setting, warfarin is avoided,
but low-molecular-weight heparin and direct oral anticoagulants have
been safely used to treat thrombosis.
Acquired Inhibitors of Coagulation Factors 
An acquired
inhibitor is an immune-mediated disease characterized by the pres­
ence of an autoantibody against a specific clotting factor. Almost half
of patients with an acquired factor inhibitor will have an underlying
autoimmune or immunoproliferative disorder, have a malignancy, or
be peripartum. FVIII is the most common target of antibody forma­
tion and is often referred to as acquired hemophilia A, but inhibitors
to prothrombin (FII), FV, FIX, FX, and FXI are also reported. Acquired
inhibitor to FVIII occurs predominantly in older adults (median age
of 60 years) but occasionally in pregnant or postpartum women with
BLEEDING
THROMBOSIS
Thrombocytopenia
Increased levels of VWF
Abnormal platelet function
Primary
hemostasis
Low production of
thrombopoietin
Decreased levels of
ADAMTS-13
Increased production nitric
oxide and prostacyclin
EQUILIBRIUM
Reduced levels of factors II,
V, VII, IX, X, XI
Elevated levels of FVIII
Coagulation
Decreased levels of protein C,
protein S, antithrombin and
heparin cofactor II
Vitamin K deficiency
Disfibrinogenemia
Inherited thrombophilia
Low levels of α2-antiplasmin,
FXIII and TAFI
Fibrinolysis
Low levels of plasminogen
Elevated level of t-PA
Hemodynamic changes (reduced portal blood flow)
Comorbidity
PART 4
Oncology and Hematology
Vascular damage
(esophageal varices)
Portal hypertension; bacterial infection and renal diseases
FIGURE 121-5  Balance of hemostasis in liver disease. TAFI, thrombin-activated fibrinolytic inhibitor; t-PA, tissue
plasminogen activator; VWF, von Willebrand factor.
no previous history of bleeding. Bleeding episodes occur commonly
in soft tissues, the gastrointestinal or urinary tracts, and skin. In con­
trast to congenital hemophilia, hemarthrosis is rare in these patients.
Retroperitoneal hemorrhages and other life-threatening bleeding may
appear suddenly. The overall mortality in untreated patients ranges
from 8–22%, and most deaths occur within the first few weeks after
presentation. The diagnosis is based on the prolonged aPTT with
normal PT and TT and a mixing study that does not correct with
normal pooled plasma. The Bethesda assay using factor-specific defi­
cient plasma as performed for inhibitor detection in hemophilia will
confirm the diagnosis. Treatment of acquired inhibitors of coagulation
factors requires control of bleeding and eradication of the inhibitor.
Many patients can have life-threatening bleeding. The use of activated
“bypass products” such as aPCC or recombinant FVIIa is required.
The use of recombinant porcine FVIII can be effective for acquired
inhibitors of FVIII. The use of emicizumab to treat acquired FVIII
inhibitors has been reported, and trials in this population are underway
in Europe.
In contrast to inhibitors in patients with congenital factor defi­
ciencies, acquired inhibitors are typically responsive to immune
suppression, and treatment should be initiated early for most cases.
High-dose intravenous γ-globulin and anti-CD20 monoclonal anti­
body are reported to be effective in patients with autoantibodies to
FVIII; however, no firm evidence confirms that these alternatives are
superior to the first line of immunosuppressive drugs (glucocorticoids
and cyclophosphamide), effective in 70% of patients. Relapse of an
inhibitor to FVIII is relatively common (up to 20%) within the first 6
months following withdrawal of immunosuppression; patients should
be followed up regularly for relapse.
Topical plasma-derived bovine and human thrombin are commonly
used during major cardiovascular, thoracic, neurologic, and pelvic
surgeries as well as in trauma patients with extensive burns. Antibody
formation to the xenoantigen or its contaminant (bovine clotting
protein) has the potential to cross-react with human clotting factors,
particularly FV and thrombin, and can result in bleeding that can be
life-threatening. The development of antibodies to FV with the use of
topical preparations of recombinant human thrombin has also been
reported. The clinical diagnosis of these
acquired coagulopathies is rare but is often
complicated by the fact that the bleeding
episodes may be detectable during or imme­
diately following major surgery and could
be assumed to be due to the procedure itself.
Primary
hemostasis
The risk of developing a cross-reacting
antibody is increased by repeated exposure
to topical thrombin preparations. Thus, a
careful medical history of previous surgical
interventions that may have occurred even
decades earlier is critical to assessing risk.
Coagulation
The laboratory abnormalities include a
combined prolongation of the aPTT and
PT that often fails to improve by transfu­
sion of FFP and vitamin K, and a mixing
study that does not correct with normal
pooled plasma. The specificity of the anti­
body is determined by the measurement of
the residual activity of human FV or other
suspected human clotting factor. No assays
specific for bovine thrombin coagulopathy
are commercially available.
Fibrinolysis
No treatment guidelines have been estab­
lished. Platelet transfusions have been used
as a source of FV replacement for patients
with FV inhibitors. FFP and vitamin K sup­
plementation may function as co-adjuvants
rather than as effective treatments for the
coagulopathy itself. Experience with recom­
binant FVIIa as a bypass agent is limited,
and outcomes have been generally poor.
Specific treatments to eradicate the antibodies based on immunosup­
pression with glucocorticoids, intravenous immunoglobulin, or serial
plasmapheresis have been sporadically reported. Patients should be
advised to avoid any topical thrombin sealant in the future.
The presence of lupus anticoagulant can be associated with venous or
arterial thrombotic disease. However, bleeding has also been reported
rarely with lupus anticoagulants due to antibodies to prothrombin,
resulting in hypoprothrombinemia. Both disorders show a prolonged
aPTT that does not correct on mixing. To distinguish acquired inhibi­
tors from lupus anticoagulant, note that the dilute Russell viper venom
time (dRVVT) and the hexagonal-phase phospholipids test will be
negative in patients with an acquired inhibitor and positive in patients
with lupus anticoagulants. Moreover, lupus anticoagulant interferes
with the clotting activity of many factors (FVIII, FIX, FXI, FXII), which
can be assessed in the clinical laboratory; acquired inhibitors are spe­
cific to a single factor.
Acknowledgment
Valder Arruda and Katherine High wrote this chapter in prior editions
and some material from their chapter is included here.
■
■FURTHER READING
Kitazawa T, Shima M: Emicizumab, a humanized bispecific antibody
to coagulation factors IXa and X with a factor VIIIa-cofactor activity.
Int J Hematol 111:20, 2020.
Levi M, Scully M: How I treat disseminated intravascular coagula­
tion. Blood 131:845, 2018.
Menegatti M et al: Management of rare acquired bleeding disorders.
Hematology Am Soc Hematol Educ Program 2019:80, 2019.
Pipe S et al: Delivery of gene therapy in haemophilia treatment centres
in the United States: Practical aspects of preparedness and implemen­
tation. Haemophilia 29:1430, 2023.
Roberts LN: How to manage hemostasis in patients with liver disease
during interventions. Hematology Am Soc Hematol Educ Program
2023:274, 2023.
Srivastava A et al: WFH guidelines for the management of hemo­
philia, 3rd edition. Haemophilia 26:1, 2020.

53 - 122 Arterial and Venous Thrombosis
122 Arterial and Venous Thrombosis
Jane E. Freedman, Joseph Loscalzo
Arterial and Venous
Thrombosis
OVERVIEW OF THROMBOSIS
■
■GENERAL OVERVIEW
Thrombosis is hemostasis “at the wrong place and at the wrong time”
(MacFarlane). The obstruction of blood flow due to the formation of
thrombus may result in tissue anoxia and damage, and it is a major
cause of morbidity and mortality in a wide range of arterial and
venous diseases and patient populations. As reported in 2020, 655,000
Americans die from heart disease each year or about 1 in 4 deaths. In
2020, coronary disease killed 382,820 people and stroke killed 160,747
in the United States with approximately 805,000 suffering from heart
attacks and 795,000 having strokes.
It is estimated that as many as 600,000 people each year have a
pulmonary embolism or deep-venous thrombotic event, and 60,000–
80,000 Americans die of these conditions annually. In the nondiseased
state, physiologic hemostasis reflects a delicate interplay between fac­
tors that promote and inhibit blood clotting, favoring the former. This
response is crucial as it prevents uncontrolled hemorrhage and exsan­
guination following injury. In specific settings, the same processes that
regulate normal hemostasis can cause pathologic thrombosis, leading
to arterial or venous occlusion. Importantly, many commonly used
therapeutic interventions may also alter the thrombotic–hemostatic
balance adversely.
Hemostasis and thrombosis primarily involve the interplay among
three factors: the vessel wall, coagulation and fibrinolytic proteins, and
platelets. Many prevalent acute vascular diseases are due to thrombus
formation within a vessel, including myocardial infarction, throm­
botic cerebrovascular events, and venous
thrombosis. Although the end result is
vessel occlusion and tissue ischemia, the
pathophysiologic processes governing
these pathologies have similarities as well
as distinct differences. While many of the
pathways regulating thrombus formation
are similar to those that regulate hemo­
stasis, the processes triggering or per­
petuating thrombosis may be distinct and
can vary in different clinical and genetic
settings. In venous thrombosis, primary
hypercoagulable states reflecting defects in
the proteins governing coagulation and/or
fibrinolysis or secondary hypercoagulable
states involving abnormalities of blood
vessels and blood flow or stasis lead to
thrombosis. By contrast, arterial thrombo­
sis is highly dependent on the state of the
vessel wall, the platelet, and factors related
to blood flow.
Endothelial cells
Inactive
platelets
ARTERIAL THROMBOSIS
■
■OVERVIEW OF ARTERIAL
THROMBOSIS
In arterial thrombosis, platelets and
abnormalities of the vessel wall typically
play a key role in vessel occlusion. Arterial
thrombus forms via a series of sequential
steps in which platelets adhere to the vessel
wall, additional platelets are recruited, and
thrombin is activated (Fig. 122-1). The
regulation of platelet adhesion, activation,
FIGURE 122-1  Platelet activation and thrombosis. Platelets circulate in an inactive form in the vasculature. Damage
to the endothelium and/or external stimuli activate platelets that adhere to the exposed subendothelial von Willebrand
factor and collagen. This adhesion leads to activation of the platelet, shape change, and the synthesis and release
of thromboxane (TxA2), serotonin (5-HT), and adenosine diphosphate (ADP). Platelet stimuli cause conformational
change in the platelet integrin glycoprotein (GP) IIb/IIIa receptor, leading to the high-affinity binding of fibrinogen and
the formation of a stable platelet thrombus.
aggregation, and recruitment will be described in detail below. In addi­
tion, while the primary function of platelets is regulation of hemostasis,
our understanding of their role in other processes, such as immunity,
metastasis, wound healing, and inflammation, continues to evolve.
■
■ARTERIAL THROMBOSIS AND VASCULAR DISEASE
Arterial thrombosis is a major cause of morbidity and mortality both in
the United States and, increasingly, worldwide. Although the rates have
declined in the United States, the overall burden remains high. Overall,
in 2020, heart disease was estimated to cause about 1 of every 4 deaths
in the United States. In addition to the 605,000 Americans who will
have a new coronary event annually, an additional 200,000 myocardial
infarctions occur in those with previous heart attacks. Although the
rate of strokes has fallen, each year about 795,000 people experience
a new or recurrent ischemic stroke. In 2018, about 1 in 6 deaths from
cardiovascular disease were due to stroke in the United States.
■
■THE PLATELET
Many processes in platelets have parallels with other cell types, such
as the presence of specific receptors and signaling pathways; however,
unlike most cells, platelets lack a nucleus and are unable to adapt
to changing biologic settings by altered gene transcription. Plate­
lets sustain limited protein synthetic capacity from megakaryocytederived and intracellularly transported messenger RNA (mRNA) and
microRNA (miRNA). Most of the molecules needed to respond to
various stimuli, however, are maintained in storage granules and mem­
brane compartments.
CHAPTER 122
Platelets are disc-shaped, very small, anucleate cells (1–5 μm in diam­
eter) that circulate in the blood at concentrations of 200–400,000/μL,
with an average life span of 7–10 days. Platelets are derived from
megakaryocytes, polyploidal hematopoietic cells found in the bone
marrow. The primary regulator of platelet formation is thrombopoietin
(TPO). The precise mechanism by which megakaryocytes produce and
release fully formed platelets is unclear, but the process likely involves
formation of proplatelets, pseudopod-like structures generated by the
Arterial and Venous Thrombosis
Active
platelets
Fibrinogen
GPIIb-IIIa
TxA2
ADP
5-HT
Active
GPIIb-IIIa
Collagen
von Willebrand factor
evagination of the cytoplasm from which platelets bud. After release
into the circulation, (young, large) platelets may continue to divide.
Platelet granules are synthesized in megakaryocytes before thrombo­
poiesis and contain an array of prothrombotic, proinflammatory, and
antimicrobial mediators. The two major types of platelet granules,
alpha and dense, are distinguished by their size, abundance, and con­
tent. Alpha-granules contain soluble coagulation proteins, adhesion
molecules, growth factors, integrins, cytokines, and inflammatory
modulators. Platelet dense-granules are smaller than alpha-granules
and less abundant. Whereas alpha-granules contain proteins that may
be more important in the inflammatory response, dense-granules
contain high concentrations of small molecules, including adenosine
diphosphate (ADP) and serotonin, that influence platelet aggregation
and other related vascular processes, such as vasomotor tone.
Platelet Adhesion 
(See Fig. 122-1) The formation of a thrombus
is initiated by the adherence of platelets to the damaged vessel wall.
Damage exposes subendothelial components responsible for triggering
platelet reactivity, including collagen, von Willebrand factor, fibronec­
tin, and other adhesive proteins, such as vitronectin and thrombos­
pondin. The hemostatic response may vary, depending on the extent
of damage, the specific proteins exposed, and flow conditions. Certain
proteins are expressed on the platelet surface that subsequently regulate
collagen-induced platelet adhesion, particularly under flow conditions,
and include glycoprotein (GP) IV, GPVI, and the integrin α2β1. The
platelet GPIb-IX-V complex adhesive receptor is central both to platelet
adhesion and to the initiation of platelet activation. Damage to the blood
vessel wall exposes subendothelial von Willebrand factor and collagen
to the circulating blood. The GPIb-IX-V complex binds to the exposed
von Willebrand factor, causing platelets to adhere (Fig. 122-1). In addi­
tion, the engagement of the GPIb-IX-V complex with ligand induces
signaling pathways that lead to platelet activation. von Willebrand fac­
tor–bound GPIb-IX-V promotes a calcium-dependent conformational
change in the GPIIb/IIIa receptor, transforming it from an inactive lowaffinity state to an active high-affinity receptor for fibrinogen.
PART 4
Oncology and Hematology
Platelet Activation 
The activation of platelets is controlled by a
variety of surface receptors that regulate various functions in the acti­
vation process. Platelet receptors control many distinct processes and
are stimulated by a wide variety of agonists and adhesive proteins that
result in variable degrees of activation. In general terms, the stimula­
tion of platelet receptors triggers two specific processes: (1) activation
of internal signaling pathways that lead to further platelet activation
and granule release, and (2) the capacity of the platelet to bind to other
adhesive proteins/platelets. Both of these processes contribute to the
formation of a thrombus. Stimulation of nonthrombotic receptors
results in platelet adhesion or interaction with other vascular cells,
including endothelial cells, neutrophils, and mononuclear cells.
Many families and subfamilies of receptors are found on platelets
that regulate a variety of platelet functions. These include the seven
transmembrane receptor family, which is the main agonist-stimulated
receptor family. Several seven transmembrane receptors are found on
platelets, including the ADP receptors, prostaglandin receptors, lipid
receptors, and chemokine receptors. Receptors for thrombin comprise
the major seven transmembrane receptors found on platelets. Among
this last group, the first identified was the protease activation receptor
1 (PAR1). The PAR class of receptors has a distinct mechanism of acti­
vation that involves specific cleavage of the N-terminus by thrombin,
which, in turn, acts as a ligand for the receptor. Other PAR receptors are
present on platelets, including PAR2 (not activated by thrombin) and
PAR4. Adenosine receptors are responsible for transduction of ADPinduced signaling events, which are initiated by the binding of ADP to
purinergic receptors on the platelet surface. There are several distinct
ADP receptors, classified as P2X1, P2Y1, and P2Y12. The activation of
both the P2Y12 and P2Y1 receptors is essential for ADP-induced platelet
aggregation. The thienopyridine derivatives, clopidogrel and prasugrel,
are clinically used inhibitors of ADP-induced platelet aggregation.
Platelet Aggregation 
Activation of platelets results in a rapid
series of signal transduction events, including tyrosine kinase, serine/
threonine kinase, and lipid kinase activation. In unstimulated platelets,
the major platelet integrin GPIIb/IIIa is maintained in an inactive con­
formation and functions as a low-affinity adhesion receptor for fibrino­
gen. This integrin is unique as it is only expressed on platelets. After
stimulation, the interaction between fibrinogen and GPIIb/IIIa forms
intercellular connections between platelets, leading to the formation of
a platelet aggregate (Fig. 122-1). A calcium-sensitive conformational
change in the extracellular domain of GPIIb/IIIa enables the highaffinity binding of soluble plasma fibrinogen as a result of a complex
network of inside-out signaling events. The GPIIb/IIIa receptor serves
as a bidirectional conduit with GPIIb/IIIa-mediated signaling (outsidein signaling) occurring immediately after the binding of fibrinogen.
This binding interaction leads to additional intracellular signaling that
further stabilizes the platelet aggregate and transforms platelet aggrega­
tion from a reversible to an irreversible process (inside-out signaling).
■
■THE ROLE OF PLATELETS AND THROMBOSIS
IN INFLAMMATION
Inflammation plays an important role during the acute thrombotic
phase of acute coronary and other vascular occlusive syndromes. In the
setting of acute upper respiratory infections, people are at higher risk of
myocardial infarction and thrombotic stroke. Patients with acute coro­
nary syndromes have not only increased interactions between platelets
(homotypic aggregates) but also increased interactions between plate­
lets and leukocytes (heterotypic aggregates) detectable in circulating
blood. These latter aggregates form when platelets are activated, often
directly by pathogens, and adhere to circulating leukocytes as part of
their contribution to the immune process. Platelets bind via P-selectin
(CD62P) expressed on the surface of activated platelets to the leukocyte
receptor, P-selectin glycoprotein ligand 1 (PSGL-1). This association
leads to increased expression of CD11b/CD18 (Mac-1) on leukocytes,
which amplifies immunity but may also support further interactions
with platelets partially via bivalent fibrinogen linking this integrin with
its platelet surface counterpart, GPIIb/IIIa. Platelet surface P-selectin
also induces the expression of tissue factor on monocytes, which pro­
motes fibrin formation.
In addition to platelet–monocyte aggregates, the immunomodu­
lator, soluble CD40 ligand (CD40L or CD154), also reflects a link
between thrombosis and inflammation. The CD40 ligand is a trimeric
transmembrane protein of the tumor necrosis factor family and, with
its receptor CD40, is an important contributor to the inflammatory
process, leading both to thrombosis and atherosclerosis. While many
immunologic and vascular cells have been found to express CD40 and/
or CD40 ligand, in platelets, CD40 ligand is rapidly translocated to
the surface after stimulation and is upregulated in the newly formed
thrombus. The surface-expressed CD40 ligand is cleaved from the
platelet to generate a soluble fragment (soluble CD40 ligand).
Links have also been established among platelets, infection, immu­
nity, and inflammation. Bacterial and viral infections are associated
with a transient increase in the risk of acute thrombotic events, such
as acute myocardial infarction and stroke. In addition, platelets con­
tribute significantly to the pathophysiology and high mortality rates
of sepsis. The expression, functionality, and signaling pathways of
Toll-like receptors (TLRs) have been established in platelets. Stimula­
tion of platelet TLR2, TLR3, and TLR4 directly and indirectly activates
the platelet’s thrombotic and inflammatory responses, and live bacteria
induce a proinflammatory response in platelets in a TLR2-dependent
manner, suggesting a mechanism by which specific bacteria and bacte­
rial components can directly activate platelet-dependent thrombosis.
Additionally, viruses, such as SARS-CoV-2, HIV, hepatitis C virus, and
Dengue, are also known to elevate thrombosis; recently, platelets have
been shown to regulate immune responses to viruses via receptors
TLR7 and TLR8.
Risk Factors for Arterial Thrombosis 
In addition to immune
burden, various factors increase the risk of developing arterial thrombo­
sis. Classically, the cardiovascular-dependent risk factors implicated in
thrombosis have been hypertension, high levels of low-density lipopro­
tein cholesterol, and smoking. However, diabetes, pregnancy, age, and
chemotherapeutic agents may also contribute to arterial thrombosis.
Stillbirth and loss of multiple pregnancies may increase the risk of isch­
emic stroke and myocardial infarction, as does hormonal replacement
therapy. Systemic lupus erythematosus and rheumatoid arthritis are
now well-recognized risks for thrombosis, and the former, in particu­
lar, may contribute in the pediatric population. The antiphospholipid
syndrome is also another widely recognized autoimmune prothrom­
botic risk for arterial (and venous) thrombosis.
■
■GENETICS OF ARTERIAL THROMBOSIS
Some studies have associated arterial thrombosis with genetic
variants (Table 122-1A); however, the associations have been
weak and not consistently confirmed in larger series. Platelet
count and mean platelet volume have been studied by genome-wide
association studies (GWAS), and this approach identified signals
located to noncoding regions. Of 15 quantitative trait loci associated
with mean platelet volume and platelet count, one located at 12q24 is
also a risk locus for coronary artery disease.
In the area of genetic variability and platelet function, studies have
primarily dealt with pharmacogenetics, the field of pharmacology
dealing with the interindividual variability in drug response based on
genetic determinants (Table 122-2). This focus has been driven by
the wide variability among individuals in terms of response to anti­
thrombotic drugs and the lack of a common explanation for this vari­
ance. The best described is the issue of “aspirin resistance,” although
heterogeneity for other antithrombotics (e.g., clopidogrel) has also
TABLE 122-1  Heritable Causes of Arterial and Venous Thrombosis
A. Arterial Thrombosis
Platelet Receptors
  β3 and α2 integrins
  Pl A2 polymorphism
  Fc(gamma)RIIA
  GPIV T13254C polymorphism
  GPIb
  Thrombin receptor PAR1-5061 → D
Redox Enzymes
  Plasma glutathione peroxidase, GPx3, promoter haplotype H2
  H2 promoter haplotype
  Endothelial nitric oxide synthase
  –786T/C, –922A/G, –1468T/A
  Paraoxonase
  –107T allele, 192R allele
Homocysteine
  Cystathionine β-synthase 833T → C
  5,10-Methylene tetrahydrofolate reductase (MTHFR) 677C → T
B. Venous Thrombosis
Procoagulant Proteins
  Fibrinogen
  –455G/A, –854G/A
  Prothrombin (20210G → A)
Protein C Anticoagulant Pathway
  Factor V Leiden: 1691G → A (Arg506Gln)
  Thrombomodulin 1481C →T (Ala455Val)
Fibrinolytic Proteins with Known Polymorphisms
  Tissue plasminogen activator (tPA)
  7351C/T, 20 099T/C in exon 6, 27 445T/A in intron 10
  Plasminogen activator inhibitor (PAI-1)
  4G/5G insertion/deletion polymorphism at position –675
Homocysteine
  Cystathionine β-synthase 833T → C
  5,10-MTHFR 677C → T
TABLE 122-2  Genetic Variation and Pharmacogenetic Responses to
Platelet Inhibitors
POTENTIAL GENE
ALTERED
TARGET THERAPEUTIC
CLASS
SPECIFIC DRUG
P2Y1 and P2Y12 CYP2C19,
CYP3A4, CYP3A5
ADP receptor inhibitors
Clopidogrel, prasugrel
COX1, COX2
Cyclooxygenase
inhibitors
Aspirin
PlA1/A2
Receptor inhibitors
Abciximab, eptifibatide,
tirofiban
INTB3, GPIbA
Glycoprotein IIb-IIIa
receptor inhibitors
 
been extensively examined. Primarily, platelet-dependent genetic
determinants have been defined at the level of (1) drug effect, (2) drug
compliance, and (3) drug metabolism. Many candidate platelet genes
have been studied for their interaction with antiplatelet and antithrom­
botic agents.
Many patients have an inadequate response to the inhibitory effects
of aspirin. Heritable factors contribute to the variability; however, ex
vivo tests of residual platelet responsiveness after aspirin administra­
tion have not provided firm evidence for a pharmacogenetic interac­
tion between aspirin and COX1 or other relevant platelet receptors. As
such, currently there is no clinical indication for genotyping to opti­
mize aspirin’s antiplatelet efficiency. For the platelet P2Y12 receptor
inhibitor clopidogrel, additional data suggest that genetics may affect
the drug’s responsiveness and utility. The responsible genetic variant
appears not to be the expected P2Y12 receptor but an enzyme respon­
sible for drug metabolism. Clopidogrel is a prodrug, and liver metabo­
lism by specific cytochrome P450 enzymes is required for activation.
The genes encoding the CYP-dependent oxidative steps are polymor­
phic, and carriers of specific alleles of the CYP2C19 and CYP3A4 loci
have increased platelet aggregability. Increased platelet activity has also
been specifically associated with the CYP2C19*2 allele, which causes
loss of platelet function in select patients. Because these are common
genetic variants, this observation has been shown to be clinically
relevant in large studies. In summary, although the loss-of-function
polymorphisms in CYP2C19 is the strongest individual variable affect­
ing pharmacokinetics and antiplatelet response to clopidogrel, it only
accounts for 5–12% of the variability in ADP-induced platelet aggre­
gation by clopidogrel. In addition, genetic variables do not appear to
contribute significantly to the clinical outcomes of patients treated with
the P2Y12 receptor antagonists prasugrel or ticagrelor.
CHAPTER 122
Arterial and Venous Thrombosis
VENOUS THROMBOSIS
■
■OVERVIEW OF VENOUS THROMBOSIS
Coagulation is the process by which thrombin is activated and
soluble plasma fibrinogen is converted into insoluble fibrin. These
steps account for both normal hemostasis and the pathophysiologic
processes influencing the development of venous thrombosis. The
primary forms of venous thrombosis are deep-vein thrombosis (DVT)
in the extremities and the subsequent embolization to the lungs (pul­
monary embolism), referred to together as venous thromboembolic
disease (VTE). Although the majority of venous thromboembolic
events occur as pulmonary embolism or DVT of the lower extremities,
up to 10% of events may occur in other vascular locations. Venous
thrombosis has both heritable causes (Table 122-1B) and acquired
causes (Table 122-3).
■
■DEEP-VENOUS THROMBOSIS AND
PULMONARY EMBOLISM
It is estimated that DVT or pulmonary embolism (PE) occurs in ∼1–2
individuals per 1000 each year, resulting in 300,000–600,000 new cases
of venous thromboembolism each year in the United States. Approxi­
mately, 60,000–80,000 deaths are attributed to DVT or PE annually. Of
new cases, up to 30% of patients die within 30 days and one-fifth suffer
TABLE 122-3  Acquired Causes of Venous Thrombosis
Surgery
Neurosurgery
Major abdominal surgery
Other
Trauma
Antiphospholipid syndrome
Pregnancy
Long-distance travel
Obesity
Oral contraceptives/hormone replacement
Myeloproliferative disorders
Polycythemia vera
sudden death due to PE; 30% go on to develop recurrent VTE within
10 years. Data from the Atherosclerosis Risk in Communities (ARIC)
study reported a 9% 28-day fatality rate from DVT and a 15% fatality
rate from PE. PE in the setting of cancer has a 25% fatality rate. The
mean incidence of first DVT in the general population is 5 per 10,000
person-years; the incidence is similar in males and females when
adjusting for factors related to reproduction and birth control and
increases dramatically with age from 2–3 per 10,000 person-years at
30–49 years of age to 20 per 10,000 person-years at 70–79 years of age.
PART 4
Oncology and Hematology
■
■OVERVIEW OF THE COAGULATION CASCADE AND
ITS ROLE IN VENOUS THROMBOSIS
Coagulation is defined as the formation of fibrin by a series of linked
enzymatic reactions in which each reaction product converts the sub­
sequent inactive zymogen into an active serine protease (Fig. 122-2).
This coordinated sequence is called the coagulation cascade and is
a key mechanism for regulating hemostasis. Central to the function
of the coagulation cascade is the principle of amplification: owing to
a series of linked enzymatic reactions, a small stimulus can lead to
much greater quantities of fibrin, the end product
that prevents hemorrhage at the site of vascular
injury. In addition to the known risk factors rel­
evant to hypercoagulopathy, stasis, and vascular
dysfunction, newer areas of research have identi­
fied contributions from procoagulant micropar­
ticles, inflammatory cells, microvesicles, and fibrin
structure.
VII
VIIa
The coagulation cascade is primarily initiated
by vascular injury exposing tissue factor to blood
components (Fig. 122-2). Tissue factor may also be
found in bloodborne cell-derived microparticles
and, under pathophysiologic conditions, in leuko­
cytes or platelets. Plasma factor VII (FVII) is the
ligand for and is activated (FVIIa) by binding to tis­
sue factor exposed at the site of vessel damage. The
binding of FVII/VIIa to tissue factor activates the
downstream conversion of factor X (FX) to active
FX (FXa). In an alternative reaction, the FVII/
FVIIa–tissue factor complex initially converts FIX
to FIXa, which then activates FX in conjunction
with its cofactor factor VIII (FVIIIa). Thrombin
can also activate factor XI (FXI) to active FXI
(FXIa), which, in turn, can also activate FIX. FXa
with its cofactor FVa converts prothrombin to
thrombin, which then converts soluble plasma
fibrinogen to insoluble fibrin, leading to clot or
thrombus formation. Thrombin also activates
FXIII to FXIIIa, a transglutaminase that covalently
cross-links and stabilizes the fibrin clot. Formation
of thrombi is affected by mechanisms governing
fibrin structure and stability, including specific
X
Xa
Thrombin
Prothrombin
FIGURE 122-2  Summary of the coagulation pathways. Specific coagulation factors (“a” indicates activated
form) are responsible for the conversion of soluble plasma fibrinogen into insoluble fibrin. This process
occurs via a series of linked reactions in which the enzymatically active product subsequently converts the
downstream inactive protein into an active serine protease. In addition, the activation of thrombin leads to
stimulation of platelets. HK, high-molecular-weight kininogen; PK, prekallikrein; TF, tissue factor.
fibrinogen variants and how they alter fibrin formation, strength,
and structure.
Several antithrombotic factors also regulate coagulation; these
include antithrombin, tissue factor pathway inhibitor (TFPI), heparin
cofactor II, and protein C/protein S. Under normal conditions, these
factors limit the production of thrombin to prevent the perpetuation
of coagulation and thrombus formation. Typically, after the clot has
caused occlusion at the damage site and begins to expand toward adja­
cent uninjured vessel segments, the anticoagulant reactions governed
by the normal endothelium become pivotal in limiting the extent of
this hemostatically protective clot.
■
■RISK FACTORS FOR VENOUS THROMBOSIS
An array of different factors contributes to the risk of VTE; it is notable
that women and men of all ages, races, and ethnicities are at risk for
VTE. The risk factors for venous thrombosis are primarily related to
hypercoagulability, which can be genetic (Table 122-1) or acquired, or
due to immobilization and venous stasis. Independent predictors for
recurrence include increasing age, obesity, malignant neoplasm, and
acute extremity paresis. It is estimated that 5–8% of the U.S. population
has a genetic risk factor known to predispose to venous thrombosis.
Often, multiple risk factors are present in a single individual. Sig­
nificant risk is incurred by major orthopedic, abdominal, or neurologic
surgeries. Cancer patients have an approximately fourfold increased
risk of VTE as compared with the general population, and cancer
patients with VTE have reduced survival. Hospitalized patients have a
greatly increased risk of venous thrombosis with risk factors (increased
age, male, ethnicity) and comorbid conditions, including infection,
renal disease, and weight loss. Community- or hospital-acquired infec­
tion is also associated with increased risk of VTE. Supportive of this
risk, nearly 20% of hospitalized COVID-19 patients were noted to have
coagulation abnormalities as well as increased PE, DVT, and peripheral
thrombotic risk. Moderate risk is promoted by prolonged bedrest;
certain types of cancer; pregnancy; hormone replacement therapy or
oral contraceptive use; and other sedentary conditions, such as longdistance plane travel. It has been reported that the risk of developing
a VTE event doubles after air travel lasting 4 h, although the absolute
XII
PK
XI
HK
TF
XIa
IX
Ca2+
XIa
VIIa/TF
IXa
PL/Ca2+
Activated
platelets
VIII
VIIIa
PL/Ca2+
Va
V
Fibrinogen
Fibrin

54 - 123 Antiplatelet, Anticoagulant, and Fibrinolytic Drugs
123 Antiplatelet, Anticoagulant, and Fibrinolytic Drugs
risk remains low (1 in 6000). The relative risk of VTE among pregnant
or postpartum women is 4.3, and the overall incidence (absolute risk)
is 199.7 per 100,000 woman-years.
■
■GENETICS OF VENOUS THROMBOSIS
(See Table 122-2) Less common causes of venous thrombosis are those
due to genetic variants. These abnormalities include loss-of-function
mutations of endogenous anticoagulants as well as gain-of-function
mutations of procoagulant proteins. Heterozygous antithrombin defi­
ciency and homozygosity of the factor V Leiden mutation significantly
increase the risk of venous thrombosis. While homozygous protein C
or protein S deficiencies are rare and may lead to fatal purpura fulmi­
nans, heterozygous deficiencies are associated with a moderate risk of
thrombosis. Activated protein C impairs coagulation by proteolytic
degradation of FVa. Patients resistant to the activity of activated protein
C may have a point mutation in the FV gene, a mutant denoted factor
V Leiden. Mildly increased risk has been attributed to elevated levels
of procoagulant factors, as well as low levels of tissue factor pathway
inhibitor. Polymorphisms of methylene tetrahydrofolate reductase as
well as hyperhomocysteinemia have been shown to be independent
risk factors for venous thrombosis, as well as arterial vascular disease;
however, many of the initial descriptions of genetic variants and their
associations with thromboembolism are being questioned in larger,
more contemporary studies.
■
■FIBRINOLYSIS AND THROMBOSIS
Specific abnormalities in the fibrinolytic system have been associated
with enhanced thrombosis. Factors such as elevated levels of tissue
plasminogen activator (tPA) and plasminogen activator inhibitor type 1
(PAI-1) have been associated with decreased fibrinolytic activity and
an increased risk of arterial thrombotic disease. Specific genetic vari­
ants have been associated with decreased fibrinolytic activity, including
the 4G/5G insertion/deletion polymorphism in the (plasminogen acti­
vator type 1) PAI-1 gene. Additionally, the 311-bp Alu insertion/dele­
tion in tPA’s intron 8 has been associated with enhanced thrombosis;
however, genetic abnormalities have not been associated consistently
with altered function or tPA levels, raising questions about the relevant
pathophysiologic mechanism. Thrombin-activatable fibrinolysis inhib­
itor (TAFI) is a carboxypeptidase that regulates fibrinolysis; elevated
plasma TAFI levels have been associated with an increased risk of both
DVT and cardiovascular disease.
The metabolic syndrome also is accompanied by altered fibrinolytic
activity. This syndrome, which comprises abdominal fat (central obe­
sity), altered glucose and insulin metabolism, dyslipidemia, and hyper­
tension, has been associated with atherothrombosis. The mechanism
for enhanced thrombosis appears to be due both to altered platelet
function and to a procoagulant and hypofibrinolytic state. One of the
most frequently documented prothrombotic abnormalities reported in
this syndrome is an increase in plasma levels of PAI-1.
In addition to contributing to platelet function, inflammation plays
a role in both coagulation-dependent thrombus formation and throm­
bus resolution. Both polymorphonuclear neutrophils and monocytes/
macrophages contribute to multiple overlapping thrombotic func­
tions, including fibrinolysis, chemokine and cytokine production, and
phagocytosis.
THE DISTINCTION BETWEEN ARTERIAL
AND VENOUS THROMBOSIS
Although there is overlap, venous thrombosis and arterial thrombosis
are initiated differently, and clot formation progresses by somewhat
distinct pathways. In the setting of stasis or states of hypercoagulability,
venous thrombosis is activated with the initiation of the coagulation
cascade primarily due to exposure of tissue factor; this leads to the
formation of thrombin and the subsequent conversion of fibrinogen to
fibrin. In the artery, thrombin formation also occurs, but thrombosis
is primarily promoted by the adhesion of platelets to an injured vessel
and stimulated by exposed extracellular matrix (Figs. 122-1 and 122-2).
There is wide variation in individual responses to vascular injury, an
important determinant of which is the predisposition an individual
has to arterial or venous thrombosis. This concept has been supported
indirectly in prothrombotic animal models in which there is poor
correlation between the propensity to develop venous versus arterial
thrombosis.
Despite considerable progress in elucidating the role of hyperco­
agulable states in VTE, the contribution of hypercoagulability to arte­
rial vascular disease is much less well understood. Although specific
thrombophilic conditions, such as factor V Leiden and the prothrom­
bin G20210A mutation, are risk factors for DVT, PE, and other VTE
events, their contribution to arterial thrombosis is less well defined. In
fact, to the contrary, many of these thrombophilic factors have not been
found to be clinically important risk factors for arterial thrombotic
events, such as acute coronary syndromes.
Clinically, although the pathophysiology is distinct, arterial and
venous thrombosis do share common risk factors, including age,
obesity, cigarette smoking, diabetes mellitus, arterial hypertension,
hyperlipidemia, and metabolic syndrome. Select genetic variants,
including those of the glutathione peroxidase-3 (GPx3) gene, have also
been associated with arterial and venous thrombo-occlusive disease.
Importantly, arterial and venous thrombosis may both be triggered by
pathophysiologic stimuli responsible for activating inflammatory and
oxidative pathways.
CHAPTER 123
The diagnosis and treatment of ischemic heart disease are dis­
cussed in Chap. 284. Stroke diagnosis and management are dis­
cussed in Chap. 318. The diagnosis and management of DVT and
PE are discussed in Chap. 290.
■
■FURTHER READING
Ackermann M et al: Pulmonary vascular endothelialitis, thrombosis,
Antiplatelet, Anticoagulant, and Fibrinolytic Drugs
and angiogenesis in Covid-19. N Engl J Med 383:120, 2020.
Asmis L, Hellstern P: Thrombophilia testing: A systematic review.
Clin Lab 69, 2023.
Becattini C, Aegnelli G: Acute treatment of venous thromboembo­
lism. Blood 135:305, 2020.
Engelmann B, Massberg S: Thrombosis as an intravascular effector
of innate immunity. Nat Rev Immunol 13:34, 2013.
Furie B, Furie BC: Mechanisms of thrombus formation. N Engl J Med
359:938, 2008.
Kaiser R et al: Hemostasis without clot formation: How platelets guard
the vasculature in inflammation, infection, and malignancy. Blood
142;1413, 2023.
Koupenova M et al: Thrombosis and platelets: An update. Eur Heart
J 38:785, 2017.
Jeffrey I. Weitz
Antiplatelet,
Anticoagulant, and
Fibrinolytic Drugs
Thromboembolic disorders are major causes of morbidity and mortal­
ity. Thrombosis can occur in arteries or veins. Arterial thrombosis is
the most common cause of acute myocardial infarction (MI), ischemic
stroke, and limb gangrene. VTE encompasses DVT, which can lead to
postthrombotic syndrome, and PE, which can be fatal or can result in
chronic thromboembolic pulmonary hypertension.
Most arterial thrombi are superimposed on disrupted atheroscle­
rotic plaque because plaque rupture exposes thrombogenic material in
the core to the blood. This material then triggers platelet aggregation
and fibrin formation, which results in the generation of a platelet-rich
thrombus that can temporarily or permanently occlude blood flow.
In contrast, venous thrombi rarely form at sites of obvious vascular
Antithrombotic Drugs
Anticoagulants
Fibrinolytic agents
Antiplatelet drugs
FIGURE 123-1  Classification of antithrombotic drugs.
disruption. Although they can develop after surgical trauma to veins
or secondary to indwelling venous catheters, venous thrombi usually
originate in the valve cusps of the deep veins of the calf or in the mus­
cular sinuses. Sluggish blood flow reduces the oxygen supply to the
avascular valve cusps. Endothelial cells lining these valve cusps become
activated and express adhesion molecules on their surface. Tissue factor–
bearing leukocytes and microvesicles adhere to these activated cells and
induce coagulation. DNA extruded from neutrophils forms neutrophil
extracellular traps (NETs) that provide a scaffold that binds platelets,
promotes their activation and aggregation, and activates factor XII.
Local thrombus formation is exacerbated by reduced clearance of acti­
vated clotting factors because of impaired blood flow. If the thrombi
extend from the calf veins into the popliteal and more proximal veins
of the leg, thrombus fragments can dislodge, travel to the lungs, and
produce PE.
PART 4
Oncology and Hematology
Arterial and venous thrombi are composed of platelets, fibrin, and
trapped red blood cells, but the proportions differ. Arterial thrombi
are rich in platelets because of the high shear in the injured arteries.
In contrast, venous thrombi, which form under low shear conditions,
contain relatively few platelets and are predominantly composed of
fibrin and trapped red cells. Because of the predominance of platelets,
arterial thrombi appear white, whereas venous thrombi are red in color,
reflecting the trapped red cells.
Antithrombotic drugs are used for the prevention and treatment
of thrombosis. Targeting the components of thrombi, these agents
include (1) antiplatelet drugs, (2) anticoagulants, and (3) fibrinolytic
agents (Fig. 123-1). With the predominance of platelets in arterial
thrombi, strategies to attenuate arterial thrombosis focus mainly on
antiplatelet agents, although, in the acute setting, they may include
anticoagulants and fibrinolytic agents. The addition of low-dose
rivaroxaban, an oral factor Xa inhibitor, to dual-antiplatelet therapy
reduces recurrent ischemic events and stent thrombosis in patients
with acute coronary syndrome, whereas its addition to aspirin reduces
the risk of major adverse coronary and limb events in patients with
stable coronary or peripheral artery disease. These findings highlight
the utility of combining low-dose anticoagulants with antiplatelet
agents for secondary prevention in patients at high risk for recurrent
atherothrombotic events.
Anticoagulants are the mainstay of prevention and treatment of
VTE because fibrin is the predominant component of venous thrombi.
Antiplatelet drugs are less effective than anticoagulants in this setting
because of the limited platelet content of venous thrombi. Fibrinolytic
therapy is used in selected patients with VTE. For example, patients
with massive PE can benefit from systemic or catheter-directed fibri­
nolytic therapy. Pharmaco-mechanical therapy is also used to restore
blood flow in patients with extensive DVT involving the iliac and/or
femoral veins.
ANTIPLATELET DRUGS
■
■ROLE OF PLATELETS IN ARTERIAL THROMBOSIS
In healthy vasculature, circulating platelets are maintained in an inac­
tive state by nitric oxide (NO) and prostacyclin released by endothelial
cells lining the blood vessels. In addition, endothelial cells also express
CD39 on their surface, a membrane-associated ecto-adenosine diphos­
phatase (ADPase) that degrades ADP released from activated platelets.
When the vessel wall is damaged, the release of these substances is
impaired and the subendothelial matrix is exposed. Platelets adhere
to exposed collagen via α2β1 and glycoprotein (Gp) V1 and to von
Vascular Injury
Exposure of collagen and VWF
Tissue factor exposure
Platelet adhesion and release
Activation of coagulation
Platelet recruitment and activation
Thrombin generation
Platelet aggregation
Fibrin formation
Platelet-fibrin thrombus
FIGURE 123-2  Coordinated role of platelets and the coagulation system in
thrombogenesis. Vascular injury simultaneously triggers platelet activation and
aggregation and activation of the coagulation system. Platelet activation is initiated
by exposure of subendothelial collagen and von Willebrand factor (VWF), onto
which platelets adhere. Adherent platelets become activated and release ADP
and thromboxane A2, platelet agonists that activate ambient platelets and recruit
them to the site of injury. When platelets are activated, glycoprotein IIb/IIIa on their
surface undergoes a conformational change that enables it to ligate fibrinogen
and/or VWF and mediate platelet aggregation. Coagulation is triggered by tissue
factor exposed at the site of injury. Tissue factor triggers thrombin generation. As a
potent platelet agonist, thrombin amplifies platelet recruitment to the site of injury.
Thrombin also converts fibrinogen to fibrin, and the fibrin strands then weave the
platelet aggregates together to form a platelet/fibrin thrombus.
Willebrand factor (VWF) via Gp Ibα—receptors that are constitutively
expressed on the platelet surface. Adherent platelets undergo a change
in shape, secrete ADP from their dense granules, and synthesize and
release thromboxane A2. Released ADP and thromboxane A2, which
are platelet agonists, activate ambient platelets and recruit them to the
site of vascular injury (Fig. 123-2).
Disruption of the vessel wall also exposes tissue factor–expressing
cells to the blood. Tissue factor binds to factor VII and induces its
activation, and the tissue factor–factor VIIa complex then initiates
coagulation. Activated platelets potentiate coagulation by providing a
negatively charged surface that binds clotting factors and supports the
assembly of activation complexes that enhance thrombin generation.
In addition to converting fibrinogen to fibrin, thrombin serves as a
potent platelet agonist and recruits more platelets to the site of vascular
injury. Thrombin also amplifies its generation by feedback activation
of factors V, VIII, and XI and solidifies the fibrin network by activating
factor XIII, which then cross-links the fibrin strands and renders them
more resistant to degradation.
When platelets are activated, Gp IIb/IIIa, the most abundant recep­
tor on the platelet surface, undergoes a conformational change that
enables it to bind fibrinogen and, under high shear conditions, VWF.
Divalent fibrinogen or multivalent VWF molecules bridge adjacent
platelets together to form platelet aggregates. Fibrin strands, generated
through the action of thrombin, then weave these aggregates together
to form a platelet-rich fibrin clot.
Antiplatelet drugs target various steps in this process. The com­
monly used antiplatelet drugs include aspirin, ADP receptor inhibitors,
which include thienopyridines (clopidogrel and prasugrel) as well as
ticagrelor and cangrelor, dipyridamole, Gp IIb/IIIa antagonists, and
vorapaxar.
■
■ASPIRIN
The most widely used antiplatelet agent worldwide is aspirin. As a
cheap and effective antiplatelet drug, aspirin serves as the foundation
of most antiplatelet strategies.
Mechanism of Action 
Aspirin produces its antithrombotic effect
by irreversibly acetylating and inhibiting platelet cyclooxygenase
Plaque Disruption
Tissue factor
Collagen
VWF
Platelet adhesion and secretion
Aspirin
COX-1
Clopidogrel
Prasugrel
Ticagrelor
Cangrelor
TXA2
ADP
Platelet recruitment and activation
Thrombin
Vorapaxar
GpIIb/IIIa activation
Abciximab
Eptifibatide
Tirofiban
Platelet aggregation
FIGURE 123-3  Site of action of antiplatelet drugs. Aspirin inhibits thromboxane A2
(TXA2) synthesis by irreversibly acetylating cyclooxygenase-1 (COX-1). Reduced
TXA2 release attenuates platelet activation and recruitment to the site of vascular
injury. Clopidogrel and prasugrel irreversibly block P2Y12, a key ADP receptor on
the platelet surface; cangrelor and ticagrelor are reversible inhibitors of P2Y12.
Abciximab, eptifibatide, and tirofiban inhibit the final common pathway of platelet
aggregation by blocking fibrinogen and von Willebrand factor (VWF) binding to
activated glycoprotein (Gp) IIb/IIIa. Vorapaxar inhibits thrombin-mediated platelet
activation by targeting protease-activated receptor-1 (PAR-1), the major thrombin
receptor on human platelets.
(COX)-1 (Fig. 123-3), a critical enzyme in the biosynthesis of throm­
boxane A2. At high doses (~1 g/d), aspirin also inhibits COX-2, an
inducible COX isoform found in endothelial cells and inflammatory
cells. In endothelial cells, COX-2 initiates the synthesis of prostacyclin,
a potent vasodilator and inhibitor of platelet aggregation.
Indications 
Aspirin is widely used for secondary prevention of car­
diovascular events in patients with established coronary artery, cerebral
artery, or peripheral artery disease. Compared with placebo in this
setting, aspirin produces a 25% reduction in the risk of cardiovascular
death, MI, or stroke. Aspirin is no longer used routinely for primary
prevention because recent studies suggest that the risk of gastrointesti­
nal and intracerebral hemorrhage outweigh the benefits. Consequently,
aspirin is only recommended for primary cardiac prevention if the
baseline cardiovascular risk is at least 1% per year over 10 years and
patients are at low risk for bleeding.
Dosages 
Aspirin is usually administered at doses of 75–325 mg
once daily. Higher doses of aspirin are not more effective than lower
aspirin doses, and some analyses suggest reduced efficacy with higher
doses. Because the side effects of aspirin are dose-related, daily aspirin
doses of 75–100 mg are recommended for most indications. When
rapid platelet inhibition is required, an initial aspirin dose of at least
160 mg should be given.
Side Effects 
The most common side effects are gastrointestinal and
range from dyspepsia to erosive gastritis or peptic ulcers with bleeding
and perforation. These side effects are dose related. Use of entericcoated or buffered aspirin in place of plain aspirin does not eliminate
gastrointestinal side effects. The overall risk of major bleeding with
aspirin is 1–3% per year. The risk of bleeding is increased two- to
threefold when aspirin is given in conjunction with other antiplatelet
drugs, such as clopidogrel or ticagrelor, or with anticoagulants, such as
warfarin. When dual or triple therapy is prescribed, low-dose aspirin
should be given (75–100 mg daily). Eradication of Helicobacter pylori
infection and administration of proton pump inhibitors may reduce
the risk of aspirin-induced upper gastrointestinal bleeding in patients
with peptic ulcer disease.
Aspirin should not be administered to patients with a history of
aspirin allergy characterized by bronchospasm. This problem occurs
in ~0.3% of the general population but is more common in those with
chronic urticaria or asthma, particularly in individuals with nasal pol­
yps or chronic rhinitis. Hepatic and renal toxicity are observed with
aspirin overdose.
Aspirin Resistance 
Clinical aspirin resistance is defined as the
failure of aspirin to protect patients from ischemic vascular events. This
is not a helpful definition because it is made after the event occurs. Fur­
thermore, it is not realistic to expect aspirin, which only blocks throm­
boxane A2–induced platelet activation, to prevent all vascular events.
Aspirin resistance has also been described biochemically as a fail­
ure of the drug to produce its expected inhibitory effects on tests of
platelet function, such as thromboxane A2 synthesis or arachidonic
acid–induced platelet aggregation. Potential causes of aspirin resistance
include poor compliance, reduced absorption, drug-drug interaction
with ibuprofen, and overexpression of COX-2. Unfortunately, the tests
for aspirin resistance have not been well standardized, and there is little
evidence that they identify patients at increased risk of recurrent vascu­
lar events, or that resistance can be reversed by giving higher doses of
aspirin or by adding other antiplatelet drugs. Until such information is
available, testing for aspirin resistance remains a research tool.
CHAPTER 123
■
■ADP RECEPTOR ANTAGONISTS
The ADP receptor antagonists include the thienopyridines (clopidogrel
and prasugrel) as well as ticagrelor and cangrelor. All these drugs target
P2Y12, the key ADP receptor on platelets.
Antiplatelet, Anticoagulant, and Fibrinolytic Drugs
Thienopyridines  •  MECHANISM OF ACTION 
The thienopyridines
are structurally related drugs that selectively inhibit ADP-induced
platelet aggregation by irreversibly blocking P2Y12 (Fig. 123-3). Clopi­
dogrel and prasugrel are prodrugs that require metabolic activation by
the hepatic cytochrome P450 (CYP) enzyme system. Prasugrel is about
10-fold more potent than clopidogrel and has a more rapid onset of
action because of better absorption and more streamlined metabolic
activation.
INDICATIONS  When compared with aspirin in patients with recent
ischemic stroke, recent MI, or a history of peripheral arterial disease,
clopidogrel reduced the risk of cardiovascular death, MI, and stroke by
8.7%. Therefore, clopidogrel is more effective than aspirin but is also
more expensive. Clopidogrel and aspirin are often combined to capi­
talize on their capacity to block complementary pathways of platelet
activation. For example, the combination of aspirin plus clopidogrel is
recommended for at least 4 weeks after implantation of a bare metal
stent in a coronary artery and at least a year in those with a drug-eluting
stent. Concerns about late in-stent thrombosis with drug-eluting stents
have led some experts to recommend long-term use of clopidogrel plus
aspirin for the latter indication. The course of dual-antiplatelet therapy
is often shortened in patients at high risk of bleeding with the dropping
of aspirin and continuation of the P2Y12 inhibitor.
The combination of clopidogrel and aspirin is effective in patients
with non-ST-segment elevation MI. Thus, in 12,562 such patients, the
risk of cardiovascular death, MI, or stroke was 9.3% in those random­
ized to the combination of clopidogrel and aspirin and 11.4% in those
given aspirin alone. This 20% relative risk reduction with combination
therapy was highly statistically significant. However, combining clopi­
dogrel with aspirin increases the risk of major bleeding to about 2%
per year. This bleeding risk persists even if the daily dose of aspirin is
≤100 mg. Therefore, the combination of clopidogrel and aspirin should
only be used when there is a clear benefit. For example, this combina­
tion was not proven to be superior to clopidogrel alone in patients with
acute ischemic stroke or to aspirin alone for primary prevention in
those at risk for cardiovascular events.
Prasugrel was compared with clopidogrel in 13,608 patients with
acute coronary syndrome who were scheduled to undergo percutaneous
coronary intervention. The incidence of the primary efficacy endpoint, a
composite of cardiovascular death, MI, or stroke, was significantly lower
with prasugrel than with clopidogrel (9.9% and 12.1%, respectively),
mainly reflecting a reduction in nonfatal MI. The incidence of stent
thrombosis also was significantly lower with prasugrel than with
clopidogrel (1.1% and 2.4%, respectively). However, these advantages
were at the expense of significantly higher rates of fatal bleeding (0.4%
and 0.1%, respectively) and life-threatening bleeding (1.4% and 0.9%,
respectively) with prasugrel. Because patients older than 75 years of age
and those with a history of prior stroke or transient ischemic attack are
at high risk of bleeding, prasugrel should generally be avoided in older
patients, and the drug is contraindicated in those with a history of cere­
brovascular disease. Caution is required if prasugrel is used in patients
weighing <60 kg or in those with renal impairment.
When prasugrel was compared with clopidogrel in 7243 patients
with unstable angina or MI without ST-segment elevation, prasugrel
failed to reduce the rate of the primary efficacy endpoint, which was a
composite of cardiovascular death, MI, and stroke. Because of the neg­
ative results of this study, prasugrel is reserved for patients undergoing
percutaneous coronary intervention. In this setting, prasugrel is usually
given in conjunction with aspirin. To reduce the risk of bleeding, the
daily aspirin dose should be ≤100 mg.
For patients with noncardioembolic stroke or high-risk transient
ischemic attack, the combination of clopidogrel or ticagrelor plus aspi­
rin for 21–30 days followed by aspirin alone thereafter reduces the risk
of stroke, MI, and vascular death by up to 30% compared with aspirin
alone. Therefore, dual antiplatelet therapy is often administered for the
first 3–4 weeks in such patients.
PART 4
Oncology and Hematology
DOSING  Clopidogrel is given once daily at a dose of 75 mg. Loading
doses of clopidogrel are given when rapid ADP receptor blockade is
desired. For example, patients undergoing coronary stenting are often
given a loading dose of 300–600 mg, which produces inhibition of
ADP-induced platelet aggregation in about 4–6 h. After a loading dose
of 60 mg, prasugrel is given once daily at a dose of 10 mg. Patients
older than age 75 years or weighing <60 kg should receive a lower daily
prasugrel dose of 5 mg.
SIDE EFFECTS  The most common side effect of clopidogrel and
prasugrel is bleeding. Because of its greater potency, bleeding is more
common with prasugrel than with clopidogrel. To reduce the risk of
bleeding, clopidogrel and prasugrel should be stopped 5–7 days before
major surgery. In patients taking clopidogrel or prasugrel who present
with serious bleeding, platelet transfusion may be helpful.
Hematologic side effects, including neutropenia, thrombocytopenia,
and thrombotic thrombocytopenic purpura, are rare.
THIENOPYRIDINE RESISTANCE  The capacity of clopidogrel to inhibit
ADP-induced platelet aggregation varies among subjects. This vari­
ability reflects, at least in part, genetic polymorphisms in the CYP iso­
enzymes involved in the metabolic activation of clopidogrel. The most
important of these is CYP2C19. Clopidogrel-treated patients who are
homozygous for the loss-of-function CYP2C192 allele exhibit reduced
platelet inhibition compared with those with the wild-type CYP2C19
allele and experience a higher rate of cardiovascular events. This is
important because estimates suggest that up to 25% of whites, 30% of
African Americans, and 50% of Asians carry the loss-of-function allele,
which would render them resistant to clopidogrel. Even patients with
the reduced-function CYP2C19 alleles may derive less benefit from
clopidogrel than those with the full-function CYP2C19 allele. Con­
comitant administration of clopidogrel with proton pump inhibitors,
which are inhibitors of CYP2C19, produces a small reduction in the
inhibitory effects of clopidogrel on ADP-induced platelet aggregation.
The extent to which this interaction increases the risk of cardiovascular
events remains controversial.
In contrast to their effect on the metabolic activation of clopidogrel,
CYP2C19 polymorphisms appear to be less important determinants
of the activation of prasugrel. Thus, no association was detected
between the loss-of-function allele and decreased platelet inhibition or
increased rate of cardiovascular events with prasugrel. The observation
that genetic polymorphisms affecting clopidogrel absorption or metab­
olism influence clinical outcomes raised the possibility that pharmaco­
genetic profiling might be useful for identifying clopidogrel-resistant
patients and that point-of-care assessment of the extent of clopidogrelinduced platelet inhibition may help detect patients at higher risk for
subsequent cardiovascular events. Clinical trials designed to evaluate
these possibilities have thus far been negative. Although administra­
tion of higher doses of clopidogrel can overcome a reduced response to
clopidogrel, the clinical benefit of this approach is uncertain. Instead,
prasugrel or ticagrelor may be better choices for these patients.
Ticagrelor 
As an orally active inhibitor of P2Y12, ticagrelor differs
from the thienopyridines in that ticagrelor does not require metabolic
activation and it produces reversible inhibition of the ADP receptor.
MECHANISM OF ACTION  Like the thienopyridines, ticagrelor inhibits
P2Y12. Because it does not require metabolic activation, ticagrelor has a
more rapid onset and offset of action than clopidogrel, and it produces
greater and more predictable inhibition of ADP-induced platelet aggre­
gation than clopidogrel.
INDICATIONS  Ticagrelor is indicated for the secondary prevention of
atherothrombotic events in patients with an acute coronary syndrome
treated medically or with percutaneous coronary intervention (PCI)
with or without stent implantation or with coronary artery bypass graft
(CABG) surgery. Ticagrelor is also indicated for up to 3 years for sec­
ondary prevention in patients with a prior history of MI at least 1 year
ago who are at high risk for atherothrombotic events. For patients with
acute coronary syndrome undergoing PCI, guidelines give preference
to ticagrelor over clopidogrel, particularly in higher risk patients.
DOSING  Ticagrelor is initiated with an oral loading dose of 180 mg
followed by 90 mg twice daily. The dose does not require adjustment
in patients with renal impairment, but the drug should be used with
caution in patients with hepatic disease and in those receiving potent
inhibitors or inducers of CYP3A4 because ticagrelor is metabolized in
the liver via CYP3A4. Ticagrelor is usually administered in conjunction
with aspirin; the daily aspirin dose should not exceed 100 mg.
SIDE EFFECTS  In addition to bleeding, the most common side effects
of ticagrelor are dyspnea, which can occur in up to 15% of patients,
and asymptomatic ventricular pauses. The dyspnea, which tends to
occur soon after initiating ticagrelor, is usually self-limiting and mild in
intensity. The mechanism responsible for this side effect is unknown.
To reduce the risk of bleeding, ticagrelor should be stopped at least
5 days before major surgery. Platelet transfusion is unlikely to be of
benefit in patients with ticagrelor-related bleeding or those requiring
urgent surgery because the drug will bind to P2Y12 on the transfused
platelets. Bentracimab, an antibody fragment that binds ticagrelor
and its metabolite with high affinity and rapidly reverses their platelet
inhibitory effects, is under development for ticagrelor reversal before
urgent surgery or intervention or for patients with serious bleeding.
Cangrelor 
Cangrelor is a rapidly acting reversible inhibitor of P2Y12
that is administered intravenously. It has an immediate onset of action,
a half-life of 3–5 min, and an offset of action within an hour. Cangrelor
is licensed for use in patients undergoing PCI and produces rapid ADP
receptor blockade in those who have not received pretreatment with
clopidogrel, prasugrel, or ticagrelor.
Cangrelor is administered as a 30 μg/kg IV bolus before PCI fol­
lowed by an infusion of 4 μg/kg per minute for at least 2 h or for the
duration of the procedure, whichever is longer. When transitioning to
oral P2Y12 inhibitor therapy, ticagrelor can be given at a loading dose of
180 mg at any time during the cangrelor infusion or immediately after
discontinuation. In contrast, loading doses of prasugrel or clopidogrel
(60 and 600 mg, respectively) should only be given after cangrelor
is stopped because cangrelor blocks the interaction of their active
metabolites with P2Y12.
■
■DIPYRIDAMOLE
Dipyridamole is a relatively weak antiplatelet agent on its own, but an
extended-release formulation of dipyridamole combined with lowdose aspirin, a preparation known as Aggrenox, is sometimes used for
secondary prevention in patients with transient ischemic attacks or
ischemic stroke.
MECHANISM OF ACTION  By inhibit­
ing phosphodiesterase, dipyridamole
blocks the breakdown of cyclic adenos­
ine monophosphate (AMP). Increased
levels of cyclic AMP reduce intracellular
calcium and inhibit platelet activation.
Dipyridamole also blocks the uptake of
adenosine by platelets and other cells.
This produces a further increase in local
cyclic AMP levels because the platelet
adenosine A2 receptor is coupled to
adenylate cyclase (Fig. 123-4).
Platelet
INDICATIONS  Dipyridamole
plus
aspirin was compared with aspirin or
dipyridamole alone, or with placebo,
in patients with an ischemic stroke or
transient ischemic attack. The combina­
tion reduced the risk of stroke by 22.1%
compared with aspirin and by 24.4%
compared with dipyridamole. A sec­
ond trial compared dipyridamole plus
aspirin with aspirin alone for secondary
prevention in patients with ischemic
stroke. Vascular death, stroke, or MI
occurred in 13% of patients given com­
bination therapy and in 16% of those
treated with aspirin alone. Another trial randomized 20,332 patients
with noncardioembolic ischemic stroke to either Aggrenox or clopi­
dogrel. The primary efficacy endpoint of recurrent stroke occurred
in 9.0% of those given Aggrenox and in 8.8% of patients treated with
clopidogrel. Although this difference was not statistically significant,
the study failed to meet the prespecified margin to claim noninferior­
ity of Aggrenox relative to clopidogrel. These results have dampened
enthusiasm for the use of Aggrenox.
FIGURE 123-4  Mechanism of action of dipyridamole. Dipyridamole increases levels of cyclic AMP (cAMP) in platelets
by (1) blocking the reuptake of adenosine and (2) inhibiting phosphodiesterase-mediated cyclic AMP degradation. By
promoting calcium uptake, cyclic AMP reduces intracellular levels of calcium. This, in turn, inhibits platelet activation
and aggregation.
Because of its vasodilatory effects and the paucity of data supporting
the use of dipyridamole in patients with symptomatic coronary artery
disease, Aggrenox should not be used for stroke prevention in such
patients. Clopidogrel is a better choice in this setting.
DOSING  Aggrenox is given twice daily. Each capsule contains 200 mg
of extended-release dipyridamole and 25 mg of aspirin.
SIDE EFFECTS  Because dipyridamole has vasodilatory effects, it must
be used with caution in patients with coronary artery disease. Gastroin­
testinal complaints, headache, facial flushing, dizziness, and hypoten­
sion can also occur. These symptoms often subside with continued use
of the drug.
■
■GP IIB/IIIA RECEPTOR ANTAGONISTS
As a class, parenteral Gp IIb/IIIa receptor antagonists have a niche in
patients with acute coronary syndrome. The three agents in this class
are abciximab, eptifibatide, and tirofiban. However, abciximab is no
longer available.
Mechanism of Action 
A member of the integrin family of adhe­
sion receptors, Gp IIb/IIIa is found on the surface of platelets and
megakaryocytes. With about 80,000 copies per platelet, Gp IIb/IIIa
is the most abundant receptor. Consisting of a noncovalently linked
heterodimer, Gp IIb/IIIa is inactive on resting platelets. When platelets
are activated, inside-outside signal transduction pathways trigger a
conformational activation of the receptor. Once activated, Gp IIb/IIIa
binds adhesive molecules, such as fibrinogen and, under high shear
conditions, VWF. Binding is mediated by the Arg-Gly-Asp (RGD)
sequence found on the α chains of fibrinogen and on VWF, and by the
Lys-Gly-Asp (KGD) sequence located within a unique dodecapeptide
domain on the γ chains of fibrinogen. Once bound, fibrinogen and/
or VWF bridge adjacent platelets together to induce platelet aggrega­
tion. Although abciximab, eptifibatide, and tirofiban all target the Gp
IIb/IIIa receptor, they are structurally and pharmacologically distinct
(Table 123-1). Abciximab is a Fab fragment of a humanized murine
Reuptake
Adenosine
X
Dipyridamole
A2 Receptor
Adenylate
cyclase
ATP
Phosphodiesterase
X
AMP
cAMP
Ca2+
Activation and aggregation
inhibited
CHAPTER 123
monoclonal antibody directed against the activated form of Gp IIb/IIIa.
Abciximab binds to the activated receptor with high affinity and blocks
the binding of adhesive molecules. In contrast, eptifibatide and tirofiban
are synthetic small molecules. Eptifibatide is a cyclic heptapeptide that
binds Gp IIb/IIIa because it incorporates the KGD motif, whereas tiro­
fiban is a nonpeptidic tyrosine derivative that acts as an RGD mimetic.
Abciximab has a long half-life and can be detected on the surface of
platelets for up to 2 weeks; eptifibatide and tirofiban have short half-lives.
Antiplatelet, Anticoagulant, and Fibrinolytic Drugs
Indications 
Abciximab and eptifibatide are used in patients under­
going PCIs, particularly those who have not been pretreated with an
ADP receptor antagonist. Tirofiban and eptifibatide are used in highrisk patients with non-ST-segment elevation MI.
Dosing 
All the Gp IIb/IIIa antagonists are given as an IV bolus fol­
lowed by an infusion. The recommended dose of abciximab is a bolus
of 0.25 mg/kg followed by an infusion of 0.125 μg/kg per minute to a
maximum of 10 μg/kg for 12 h. In patients undergoing PCI, eptifiba­
tide is given as two 180 μg/kg boluses given 10 min apart, followed by
an infusion of 2.0 μg/kg per minute for 18–24 h. For patients with acute
coronary syndrome, the second eptifibatide bolus is withheld. Tirofi­
ban is started at a rate of 0.4 μg/kg per minute for 30 min; the drug is
then continued at a rate of 0.1 μg/kg per minute for up to 18 h. Because
eptifibatide and tirofiban are cleared by the kidneys, the doses must
be reduced in patients with renal insufficiency. Thus, the eptifibatide
infusion is reduced to 1 μg/kg per minute in patients with a creatinine
clearance below 50 mL/min, whereas the dose of tirofiban is cut in half
for patients with a creatinine clearance below 30 mL/min.
TABLE 123-1  Features of Gp IIb/IIIa Antagonists
FEATURE
ABCIXIMAB
EPTIFIBATIDE
TIROFIBAN
Description
Fab fragment of
humanized mouse
monoclonal antibody
Cyclical KGDcontaining
heptapeptide
Nonpeptidic RGD
mimetic
Specific for Gp
IIb/IIIa
No
Yes
Yes
Plasma half-life
Short (min)
Long (2.5 h)
Long (2.0 h)
Platelet-bound
half-life
Long (days)
Short (s)
Short (s)
Renal clearance
No
Yes
Yes
Abbreviation: Gp, glycoprotein.
Side Effects 
In addition to bleeding, thrombocytopenia is the most
serious complication. Thrombocytopenia is immune-mediated and is
caused by antibodies directed against neoantigens on Gp IIb/IIIa that
are exposed upon antagonist binding. With abciximab, thrombocyto­
penia occurs in up to 5% of patients. Thrombocytopenia is severe in
~1% of these individuals. Thrombocytopenia is less common with the
other two agents, occurring in ~1% of patients.
■
■VORAPAXAR
An orally active PAR-1 antagonist, vorapaxar blocks thrombin-induced
platelet activation. Vorapaxar has a half-life of about 200 h.
Indications 
When compared with a placebo in 12,944 patients with
acute coronary syndrome without ST-segment elevation, vorapaxar
failed to significantly reduce the primary efficacy endpoint, a compos­
ite of cardiovascular death, MI, stroke, recurrent ischemia requiring
rehospitalization, and urgent coronary revascularization. Moreover,
vorapaxar was associated with increased rates of bleeding, including
intracranial bleeding.
In a second trial, vorapaxar was compared with placebo for
secondary prevention in 26,449 patients with prior MI, ischemic
stroke, or peripheral arterial disease. Overall, vorapaxar reduced
the risk of cardiovascular death, MI, or stroke by 13%, but doubled
the risk of intracranial bleeding. In the prespecified subgroup of
17,779 patients with prior MI, however, vorapaxar reduced the risk
for cardiovascular death, MI, or stroke by
20% compared with placebo (from 9.7% to
8.1%, respectively). The rate of intracranial
hemorrhage was higher with vorapaxar than
with placebo (0.6% and 0.4%, respectively;
p = .076) as was the rate of moderate or
severe bleeding (3.4% and 2.1%, respectively;
p <.0001). Based on these data, vorapaxar is
licensed for patients younger than 75 years
of age with MI or peripheral artery disease
who have no history of stroke, transient
ischemic attack, or intracranial bleeding and
weigh >60 kg.
PART 4
Oncology and Hematology
Factor Xa
A
Unfractionated
heparin
Antithrombin
Dosing 
Vorapaxar is given at a dose of
2.08 mg once daily.
Side Effects 
The major side effect is
bleeding. Platelet transfusion may be of ben­
efit for vorapaxar reversal.
Low-molecularweight heparin
B
ANTICOAGULANTS
There are both parenteral and oral anticoag­
ulants. The parenteral anticoagulants include
heparin, low-molecular-weight heparin
(LMWH), fondaparinux (a synthetic penta­
saccharide), lepirudin, desirudin, bivaliru­
din, and argatroban. Currently available oral
anticoagulants include warfarin; dabigatran
etexilate, an oral thrombin inhibitor; and
rivaroxaban, apixaban, and edoxaban, which
are oral factor Xa inhibitors.
Pentasaccharide
C
■
■PARENTERAL
ANTICOAGULANTS
Heparin 
A
sulfated
polysaccharide,
heparin is isolated from mammalian tis­
sues rich in mast cells. Most commercial
heparin is derived from porcine intestinal
mucosa and is a polymer of alternating
d-glucuronic acid and N-acetyl-d-glucos­
amine residues.
FIGURE 123-5  Mechanism of action of heparin, low-molecular-weight heparin (LMWH), and fondaparinux, a
synthetic pentasaccharide. A. Heparin binds to antithrombin via its pentasaccharide sequence. This induces a
conformational change in the reactive center loop of antithrombin that accelerates its interaction with factor Xa. To
potentiate thrombin inhibition, heparin must simultaneously bind to antithrombin and thrombin. Only heparin chains
composed of at least 18 saccharide units, which corresponds to a molecular weight of 5400, are of sufficient length
to perform this bridging function. With a mean molecular weight of 15,000, all the heparin chains are long enough
to do this. B. LMWH has greater capacity to potentiate factor Xa inhibition by antithrombin than thrombin because,
with a mean molecular weight of 4500–5000, at least half of the LMWH chains are too short to bridge antithrombin
to thrombin. C. Fondaparinux, a synthetic pentasaccharide, only accelerates factor Xa inhibition by antithrombin
because it is too short to bridge antithrombin to thrombin.
MECHANISM OF ACTION  Heparin acts as
an anticoagulant by activating antithrombin
(previously known as antithrombin III) and accelerating the rate at
which antithrombin inhibits clotting enzymes, particularly thrombin
and factor Xa. Antithrombin, the obligatory plasma cofactor for hepa­
rin, is a member of the serine protease inhibitor (serpin) superfamily.
Synthesized in the liver and circulating in plasma at a concentration
of 2.6 ± 0.4 μM, antithrombin acts as a suicide substrate for its target
enzymes.
To activate antithrombin, heparin binds to the serpin via a unique
pentasaccharide sequence that is found on one-third of the chains of
commercial heparin (Fig. 123-5). Heparin chains without this pen­
tasaccharide sequence have little or no anticoagulant activity. Once
bound to antithrombin, heparin induces a conformational change in
the reactive center loop of antithrombin that renders it more readily
accessible to its target proteases. This conformational change enhances
the rate at which antithrombin inhibits factor Xa by at least two orders
of magnitude but has little effect on the rate of thrombin inhibition. To
catalyze thrombin inhibition, heparin serves as a template that binds
antithrombin and thrombin simultaneously. Formation of this ternary
complex brings the enzyme in close apposition to the inhibitor, thereby
promoting the formation of a stable covalent thrombin-antithrombin
complex.
Only pentasaccharide-containing heparin chains composed of at
least 18 saccharide units (which correspond to a molecular weight of
5400) are of sufficient length to bridge thrombin and antithrombin
Pentasaccharide
sequence
Thrombin
together. With a mean molecular weight of 15,000, and a range of
5000–30,000, almost all the chains of unfractionated heparin are long
enough to do so. Consequently, by definition, heparin has equal capac­
ity to promote the inhibition of thrombin and factor Xa by antithrom­
bin and is assigned an anti–factor Xa to anti–factor IIa (thrombin)
ratio of 1:1.
Heparin causes the release of tissue factor pathway inhibitor (TFPI)
from the endothelium. A factor Xa–dependent inhibitor of tissue factor–
bound factor VIIa, TFPI may contribute to the antithrombotic activity
of heparin. Longer heparin chains induce the release of more TFPI
than shorter ones.
PHARMACOLOGY  Heparin must be given parenterally. It is usu­
ally administered SC or by continuous IV infusion. When used for
therapeutic purposes, the IV route is most often employed. If heparin
is given SC for treatment of thrombosis, the dose of heparin must be
high enough to overcome the limited bioavailability associated with
this method of delivery.
In the circulation, heparin binds to the endothelium and to plasma
proteins other than antithrombin. Heparin binding to endothelial
cells explains its dose-dependent clearance. At low doses, the halflife of heparin is short because it binds rapidly to the endothelium.
With higher doses of heparin, the half-life is longer because heparin
is cleared more slowly once the endothelium is saturated. Clearance
is mainly extrarenal; heparin binds to macrophages, which internalize
and depolymerize the long heparin chains and secrete shorter chains
back into the circulation. Because of its dose-dependent clearance
mechanism, the plasma half-life of heparin ranges from 30 to 60 min
with bolus IV doses of 25 and 100 units/kg, respectively.
Once heparin enters the circulation, it binds to plasma proteins
other than antithrombin, a phenomenon that reduces its anticoagulant
activity. Some of the heparin-binding proteins found in plasma are
acute-phase reactants whose levels are elevated in ill patients. Others,
such as high-molecular-weight multimers of VWF, are released from
activated platelets or endothelial cells. Activated platelets also release
platelet factor 4 (PF4), a highly cationic protein that binds heparin
with high affinity. The large amounts of PF4 found in the vicinity of
platelet-rich arterial thrombi can neutralize the anticoagulant activity
of heparin. This phenomenon may attenuate heparin’s capacity to sup­
press thrombus growth.
Because the levels of heparin-binding proteins in plasma vary
from person to person, the anticoagulant response to fixed or weightadjusted doses of heparin is unpredictable. Consequently, coagula­
tion monitoring is essential to ensure that a therapeutic response is
obtained. This is particularly important when heparin is administered
for treatment of established thrombosis because a subtherapeutic anti­
coagulant response may render patients at risk for recurrent thrombo­
sis, whereas excessive anticoagulation increases the risk of bleeding.
MONITORING THE ANTICOAGULANT EFFECT  Heparin therapy can
be monitored using the activated partial thromboplastin time (aPTT)
or anti–factor Xa level. Although the aPTT is the test most often used
for this purpose, there are problems with this assay. aPTT reagents
vary in their sensitivity to heparin, and the type of coagulometer used
for testing can influence the results. Consequently, laboratories must
establish a therapeutic aPTT range with each reagent-coagulometer
combination by measuring the aPTT and anti–factor Xa level in plasma
samples collected from heparin-treated patients. For most of the aPTT
reagents and coagulometers in current use, therapeutic heparin levels
are achieved with a two- to threefold prolongation of the aPTT. Anti–
factor Xa levels also can be used to monitor heparin therapy. With this
test, therapeutic heparin levels range from 0.3 to 0.7 units/mL.
Up to 25% of heparin-treated patients with VTE require
35,000 units/d to achieve a therapeutic aPTT. These patients are
considered heparin resistant. It is useful to measure anti–factor Xa lev­
els in heparin-resistant patients because many will have a therapeutic
anti–factor Xa level despite a subtherapeutic aPTT. This dissociation
in test results occurs because elevated plasma levels of fibrinogen and
factor VIII, both of which are acute-phase proteins, shorten the aPTT
but have no effect on anti–factor Xa levels. Heparin therapy in patients
who exhibit this phenomenon is best monitored using anti–factor Xa
levels instead of the aPTT. Patients with congenital or acquired anti­
thrombin deficiency and those with elevated levels of heparin-binding
proteins may also need high doses of heparin to achieve a therapeutic
aPTT or anti–factor Xa level. If there is good correlation between the
aPTT and the anti–factor Xa level, either test can be used to monitor
heparin therapy.
DOSING  For prophylaxis, heparin is usually given in fixed doses of
5000 units SC two or three times daily. With these low doses, coagula­
tion monitoring is unnecessary. In contrast, monitoring is essential
when the drug is given in therapeutic doses. Fixed-dose or weightbased heparin nomograms are used to standardize heparin dosing and
to shorten the time required to achieve a therapeutic anticoagulant
response. At least two heparin nomograms have been validated in
patients with VTE and reduce the time required to achieve a thera­
peutic aPTT. Weight-adjusted heparin nomograms have also been
evaluated in patients with acute coronary syndromes. After an IV
heparin bolus of 5000 units or 70 units/kg, a heparin infusion rate of
12–15 units/kg per hour is usually administered. In contrast, weightadjusted heparin nomograms for patients with VTE use an initial
bolus of 5000 units or 80 units/kg, followed by an infusion of 18 units/
kg per hour. Thus, patients with VTE appear to require higher doses
of heparin to achieve a therapeutic aPTT than do patients with acute
coronary syndromes. This may reflect differences in the thrombus bur­
den. Heparin binds to fibrin, and the amount of fibrin in patients with
extensive DVT is greater than that in those with coronary thrombosis.
CHAPTER 123
LIMITATIONS  Heparin has pharmacokinetic and biophysical limitations
(Table 123-2). The pharmacokinetic limitations reflect heparin’s propen­
sity to bind in a pentasaccharide-independent fashion to cells and plasma
proteins. Heparin binding to endothelial cells explains its dose-dependent
clearance, whereas binding to plasma proteins results in a variable antico­
agulant response and can lead to heparin resistance.
Antiplatelet, Anticoagulant, and Fibrinolytic Drugs
The biophysical limitations of heparin reflect the inability of the
heparin-antithrombin complex to inhibit factor Xa when it is incor­
porated into the prothrombinase complex, the complex that converts
prothrombin to thrombin, and to inhibit thrombin bound to fibrin.
Consequently, factor Xa bound to activated platelets within plateletrich thrombi has the potential to generate thrombin, even in the face
of heparin. Once this thrombin binds to fibrin, it too is protected
from inhibition by the heparin-antithrombin complex. Clot-associated
thrombin can then trigger thrombus growth by locally activating
platelets and amplifying its own generation through feedback activa­
tion of factors V, VIII, and XI. Further compounding the problem is
the potential for heparin neutralization by the high concentrations of
PF4 released from activated platelets within the platelet-rich thrombus.
SIDE EFFECTS  The most common side effect of heparin is bleeding.
Other complications include thrombocytopenia, osteoporosis, and
elevated levels of transaminases.
Bleeding  The risk of bleeding rises as the dose of heparin is increased.
Concomitant administration of drugs that affect hemostasis, such as
antiplatelet or fibrinolytic agents, increases the risk of bleeding, as does
TABLE 123-2  Pharmacokinetic and Biophysical Limitations of Heparin
LIMITATIONS
MECHANISM
Poor bioavailability at low doses
Binds to endothelial cells and
macrophages
Dose-dependent clearance
Binds to macrophages
Variable anticoagulant response
Binds to plasma proteins whose levels
vary from patient to patient
Reduced activity in the vicinity of
platelet-rich thrombi
Neutralized by platelet factor 4
released from activated platelets
Limited activity against factor Xa
incorporated in the prothrombinase
complex and thrombin bound to fibrin
Reduced capacity of heparinantithrombin complex to inhibit factor
Xa bound to activated platelets and
thrombin bound to fibrin
TABLE 123-3  Features of Heparin-Induced Thrombocytopenia
FEATURES
DETAILS
Thrombocytopenia
Platelet count of ≤100,000/μL or a decrease in platelet
count of ≥50%
Timing
Platelet count falls 5–14 days after starting heparin
Type of heparin
More common with unfractionated heparin than lowmolecular-weight heparin
Type of patient
More common in surgical patients and patients with
cancer than general medical patients; more common in
women than in men
Thrombosis
Venous thrombosis more common than arterial thrombosis
recent surgery or trauma. Heparin-treated patients with serious bleed­
ing can be given protamine sulfate to neutralize the heparin. Protamine
sulfate, a mixture of basic polypeptides isolated from salmon sperm,
binds heparin with high affinity, and the resultant protamine-heparin
complexes are then cleared. Typically, 1 mg of protamine sulfate neu­
tralizes 100 units of heparin. Protamine sulfate is given IV at a maxi­
mum amount of 50 mg per dose. Anaphylactoid reactions to protamine
sulfate can occur, and drug administration by slow IV infusion is rec­
ommended to reduce the risk.
Thrombocytopenia  Heparin can cause thrombocytopenia. Heparininduced thrombocytopenia (HIT) is an antibody-mediated process
that is triggered by antibodies directed against neoantigens on PF4
that are exposed when heparin binds to this protein. These antibod­
ies, which are usually of the IgG isotype, bind simultaneously to the
heparin-PF4 complex and to platelet Fc receptors. Such binding acti­
vates the platelets and generates platelet microparticles. Circulating
microparticles are procoagulant because they express anionic phos­
pholipids on their surface and can bind clotting factors and promote
thrombin generation. The clinical features of HIT are illustrated in
Table 123-3. Typically, HIT occurs 5–14 days after initiation of heparin
therapy, but it can manifest earlier if the patient has received heparin
within the past 3 months. A platelet count <100,000/μL or a 50%
decrease in the platelet count from the pretreatment value should raise
the suspicion of HIT. HIT is more common in surgical patients than in
medical patients and, like many autoimmune disorders, occurs more
frequently in females than in males.
PART 4
Oncology and Hematology
HIT can be associated with thrombosis, either arterial or venous.
Venous thrombosis, which manifests as DVT and/or PE, is more com­
mon than arterial thrombosis. Arterial thrombosis can manifest as
ischemic stroke or acute MI. Rarely, platelet-rich thrombi in the distal
aorta or iliac arteries can cause critical limb ischemia.
The diagnosis of HIT is established using enzyme-linked assays
to detect antibodies against heparin-PF4 complexes or with platelet
activation assays. Enzyme-linked assays are sensitive but can be posi­
tive in the absence of any clinical evidence of HIT. The most specific
diagnostic test for HIT is the serotonin release assay. This test is per­
formed by quantifying serotonin release when washed platelets loaded
with labeled serotonin are exposed to patient serum in the absence or
presence of varying concentrations of heparin. If the patient serum
contains the HIT antibody, heparin addition induces platelet activa­
tion and serotonin release. Management of HIT is outlined in Table
123-4. Heparin should be stopped in patients with suspected or docu­
mented HIT, and an alternative anticoagulant should be administered
TABLE 123-4  Management of Heparin-Induced Thrombocytopenia
Stop all heparins.
Give an alternative anticoagulant, such as argatroban, bivalirudin, fondaparinux,
or rivaroxaban.
Do not give platelet transfusions.
Do not give warfarin until the platelet count returns to its baseline level. If
warfarin was administered, give vitamin K to restore the INR to normal.
Evaluate for thrombosis, particularly deep vein thrombosis.
Abbreviation: INR, international normalized ratio.
to prevent or treat thrombosis. The agents most often used for this
indication are parenteral direct thrombin inhibitors, such as argatroban
or bivalirudin, or factor Xa inhibitors, such as fondaparinux or rivar­
oxaban. A HIT-like syndrome known as vaccine-induced thrombotic
thrombocytopenia was reported as a rare complication after vaccina­
tion with adenovirus COVID-19 vaccines. Characterized by thrombo­
sis and thrombocytopenia that occurred 4–28 days after vaccination,
patients presented with cerebral or splanchnic vein thrombosis as well
as DVT or PE. The diagnosis is established by the detection of antibod­
ies against PF4 and a positive serotonin release assay with added PF4.
Treatment can include intravenous immunoglobulin, steroids, and
plasma exchange to offset the effects of the antibodies against PF4, as
well as anticoagulants such as argatroban, fondaparinux, or rivaroxa­
ban to treat the thrombosis.
Patients with HIT, particularly those with associated thrombosis,
often have evidence of increased thrombin generation that can lead to
consumption of protein C. If these patients are given warfarin without a
concomitant anticoagulant that inhibits thrombin or thrombin genera­
tion, the further decrease in protein C levels induced by the warfarin
can trigger skin necrosis. To avoid this problem, patients with HIT
should be treated with a direct thrombin inhibitor or with fondaparinux
until the platelet count returns to normal levels. At this point, low-dose
warfarin therapy can be introduced, and the parenteral anticoagulant
can be discontinued when the international normalized ratio (INR) has
been therapeutic for at least 2 days. Alternatively, a direct oral antico­
agulant, such as apixaban or rivaroxaban, can be given.
Osteoporosis  Treatment with therapeutic doses of heparin for
1 month can cause a reduction in bone density. This complication
has been reported in up to 30% of patients given long-term heparin
therapy, and symptomatic vertebral fractures occur in 2–3% of these
individuals.
Heparin affects the activity of osteoblasts and osteoclasts and causes
bone loss both by decreasing bone formation and by enhancing bone
resorption.
Elevated Levels of Transaminases  Therapeutic doses of heparin are fre­
quently associated with modest elevations in the serum levels of
hepatic transaminases without a concomitant increase in the level of
bilirubin. The levels of transaminases rapidly return to normal when
heparin is stopped. The mechanism responsible for this phenomenon
is unknown.
Low-Molecular-Weight Heparin 
Consisting of smaller frag­
ments of heparin, LMWH is prepared from unfractionated heparin by
controlled enzymatic or chemical depolymerization. The mean molec­
ular weight of LMWH is about 5000, one-third the mean molecular
weight of unfractionated heparin. LMWH has advantages over heparin
(Table 123-5) and has replaced heparin for most indications.
MECHANISM OF ACTION  Like heparin, LMWH exerts its anticoagu­
lant activity by activating antithrombin. With a mean molecular weight
of 5000, which corresponds to about 17 saccharide units, at least half
of the pentasaccharide-containing chains of LMWH are too short to
bridge thrombin to antithrombin (Fig. 123-5). However, these chains
retain the capacity to accelerate factor Xa inhibition by antithrombin
TABLE 123-5  Advantages of LMWH Over Heparin
ADVANTAGE
CONSEQUENCE
Better bioavailability and longer halflife after subcutaneous injection
Can be given subcutaneously once or
twice daily for both prophylaxis and
treatment
Dose-independent clearance
Simplified dosing
Predictable anticoagulant response
Coagulation monitoring is unnecessary
in most patients
Lower risk of heparin-induced
thrombocytopenia
Safer than heparin for short- or longterm administration
Lower risk of osteoporosis
Safer than heparin for extended
administration
Abbreviation: LMWH, low-molecular-weight heparin.
because this activity is largely the result of the conformational changes
in antithrombin evoked by pentasaccharide binding. Consequently,
LMWH catalyzes factor Xa inhibition by antithrombin more than
thrombin inhibition. Depending on their unique molecular weight
distributions, LMWH preparations have anti–factor Xa to anti–factor
IIa ratios ranging from 2:1 to 4:1.
PHARMACOLOGY  Although usually given SC, LMWH also can be
administered IV if a rapid anticoagulant response is needed. LMWH
has pharmacokinetic advantages over heparin. These advantages
reflect the fact that shorter heparin chains bind less avidly to endothe­
lial cells, macrophages, and heparin-binding plasma proteins. Reduced
binding to endothelial cells and macrophages eliminates the rapid,
dose-dependent, and saturable mechanism of clearance that is a char­
acteristic of unfractionated heparin. Instead, the clearance of LMWH is
dose-independent and its plasma half-life is longer. Based on measure­
ment of anti–factor Xa levels, LMWH has a plasma half-life of ~4–6 h.
LMWH is cleared almost exclusively by the kidneys, and the drug can
accumulate in patients with renal insufficiency.
LMWH exhibits about 90% bioavailability after SC injection.
Because LMWH binds less avidly to heparin-binding proteins in
plasma than heparin, LMWH produces a more predictable dose
response, and resistance to LMWH is rare. With a longer half-life and
more predictable anticoagulant response, LMWH can be given SC once
or twice daily without coagulation monitoring, even when the drug
is given in treatment doses. These properties render LMWH more
convenient to administer than unfractionated heparin. Capitalizing
on this feature, studies in patients with VTE have shown that home
treatment with LMWH is as effective and safe as in-hospital treat­
ment with continuous IV infusions of heparin. Outpatient treatment
with LMWH streamlines care, reduces health care costs, and increases
patient satisfaction.
MONITORING  In most patients, LMWH does not require coagulation
monitoring. If monitoring is necessary, anti–factor Xa levels must be
measured because LMWH preparations have little effect on the aPTT.
Therapeutic anti–factor Xa levels for once-daily and twice-daily dos­
ing of LMWH range from 0.5 to 1.2 units/mL and 1.0 to 2.0 units/mL,
respectively, when measured 3–4 h after drug administration. When
LMWH is given in prophylactic doses, peak anti–factor Xa levels of
0.2–0.5 units/mL are desirable.
Indications for LMWH monitoring include renal impairment and
obesity. LMWH monitoring in patients with a creatinine clearance
≤30 mL/min is advisable to ensure that there is no drug accumula­
tion. Although weight-adjusted LMWH dosing appears to produce
therapeutic anti–factor Xa levels in patients who are overweight, this
approach has not been extensively evaluated in those with morbid obe­
sity. It may also be advisable to monitor the anticoagulant activity of
LMWH during pregnancy because dose requirements can change, par­
ticularly in the third trimester. Monitoring should also be considered
in high-risk settings, such as in pregnant women with mechanical heart
valves who are given LMWH to prevent valve thrombosis, and when
LMWH is used in treatment doses in infants or children.
DOSING  The doses of LMWH recommended for prophylaxis or treat­
ment vary depending on the LMWH preparation. For prophylaxis,
once-daily SC doses of 4000–5000 units are often used, whereas doses
of 2500–3000 units are given when the drug is administered twice
daily. For treatment of VTE, a dose of 150–200 units/kg is given if
the drug is administered once daily. If a twice-daily regimen is used, a
dose of 100 units/kg is given. In patients with unstable angina, LMWH
is given SC on a twice-daily basis at a dose of 100–120 units/kg.
SIDE EFFECTS  The major complication of LMWH is bleeding. Metaanalyses suggest that the risk of major bleeding is lower with LMWH
than with unfractionated heparin. HIT and osteoporosis are less com­
mon with LMWH than with unfractionated heparin.
Bleeding  Like the situation with heparin, bleeding with LMWH is
more common in patients receiving concomitant therapy with anti­
platelet or fibrinolytic drugs. Recent surgery, trauma, or underlying
hemostatic defects also increase the risk of bleeding with LMWH.
Although protamine sulfate can be used as an antidote for LMWH,
protamine sulfate incompletely neutralizes the anticoagulant activity
of LMWH because it only binds the longer chains of LMWH. Because
longer chains are responsible for catalysis of thrombin inhibition by
antithrombin, protamine sulfate completely reverses the anti–factor
IIa activity of LMWH. In contrast, protamine sulfate only partially
reverses the anti–factor Xa activity of LMWH because the shorter pen­
tasaccharide-containing chains of LMWH do not bind to protamine
sulfate. Consequently, patients at high risk for bleeding may be more
safely treated with continuous IV unfractionated heparin than with
SC LMWH. Andexanet alfa, a recombinant factor Xa variant licensed
for reversal of oral factor Xa inhibitors, reverses that anti–factor Xa
activity of LMWH but not its anti–factor IIa activity. The utility of
andexanet for LMWH reversal is uncertain, and it is not licensed for
this indication.
Thrombocytopenia  The risk of HIT is about fivefold lower with LMWH
than with heparin. LMWH binds less avidly to platelets and causes less
PF4 release. Furthermore, with lower affinity for PF4 than heparin,
LMWH is less likely to induce the conformational changes in PF4 that
trigger the formation of HIT antibodies.
LMWH should not be used to treat HIT patients because most
HIT antibodies exhibit cross-reactivity with LMWH. This in vitro
cross-reactivity is more than a laboratory phenomenon because there
are case reports of thrombosis when HIT patients were switched from
heparin to LMWH.
CHAPTER 123
Osteoporosis  Because the risk of osteoporosis is lower with LMWH
than with heparin, LMWH is a better choice than heparin for extended
treatment.
Antiplatelet, Anticoagulant, and Fibrinolytic Drugs
Fondaparinux 
A synthetic analogue of the antithrombin-binding
pentasaccharide sequence, fondaparinux differs from LMWH in sev­
eral ways (Table 123-6). Fondaparinux is licensed for thromboprophy­
laxis in general medical or surgical patients and in high-risk orthopedic
patients and as an alternative to heparin or LMWH for initial treatment
of patients with established VTE. Although fondaparinux is used in
Europe as an alternative to heparin or LMWH in patients with acute
coronary syndrome, the drug is not licensed for this indication in the
United States.
MECHANISM OF ACTION  Fondaparinux has a molecular weight of
1728. Fondaparinux binds only to antithrombin (Fig. 123-5) and is too
short to bridge thrombin to antithrombin. Consequently, fondaparinux
catalyzes factor Xa inhibition by antithrombin and does not enhance
the rate of thrombin inhibition.
PHARMACOLOGY  Fondaparinux exhibits complete bioavailability
after SC injection. With no binding to endothelial cells or plasma
proteins, the clearance of fondaparinux is dose independent, and
its plasma half-life is 17 h. The drug is given SC once daily. Because
fondaparinux is cleared unchanged via the kidneys, it is contraindi­
cated in patients with a creatinine clearance <30 mL/min and should
be used with caution in those with a creatinine clearance <50 mL/min.
DOSING  Fondaparinux produces a predictable anticoagulant response
after administration in fixed doses because it does not bind to plasma
proteins. The drug is given at a dose of 2.5 mg once daily for preven­
tion of VTE. For initial treatment of established VTE, fondaparinux is
TABLE 123-6  Comparison of LMWH and Fondaparinux
FEATURES
LMWH
FONDAPARINUX
Number of saccharide units
15–17
Catalysis of factor Xa inhibition
Yes
Yes
Catalysis of thrombin inhibition
Yes
No
Bioavailability after subcutaneous administration (%)
Plasma half-life (h)
Renal excretion
Yes
Yes
Induces release of tissue factor pathway inhibitor
Yes
No
Neutralized by protamine sulfate
Partially
No
given at a dose of 7.5 mg once daily. The dose can be reduced to 5 mg
once daily for those weighing <50 kg and increased to 10 mg for those
100 kg. When given in these doses, fondaparinux is as effective as
heparin or LMWH for initial treatment of patients with DVT or PE and
is associated with similar rates of bleeding.
Fondaparinux is used at a dose of 2.5 mg once daily in patients
with acute coronary syndrome. When this prophylactic dose of
fondaparinux was compared with treatment doses of enoxaparin in
patients with non-ST-segment elevation MI, there was no difference
in the rate of cardiovascular death, MI, or stroke at 9 days. However,
the rate of major bleeding was 50% lower with fondaparinux than with
enoxaparin, a difference that likely reflects the fact that the dose of
fondaparinux was lower than that of enoxaparin. In acute coronary
syndrome patients who require PCI, there is a risk of catheter throm­
bosis with fondaparinux unless adjunctive heparin is given at the time
of the procedure.
SIDE EFFECTS  Fondaparinux does not cause HIT because it does
not bind to PF4. In contrast to LMWH, there is no cross-reactivity
of fondaparinux with HIT antibodies. Consequently, fondaparinux
appears to be effective for treatment of HIT patients, although large
clinical trials supporting its use are lacking.
The major side effect of fondaparinux is bleeding. Fondaparinux
has no antidote. Protamine sulfate has no effect on the anticoagulant
activity of fondaparinux because it fails to bind to the drug. Andexanet
alfa has been reported to reverse fondaparinux in vitro, but studies
in patients are lacking. Recombinant activated factor VII reverses the
anticoagulant effects of fondaparinux in volunteers, but it is unknown
whether this agent controls fondaparinux-induced bleeding.
PART 4
Oncology and Hematology
Parenteral Direct Thrombin Inhibitors 
Direct thrombin inhibi­
tors bind directly to thrombin and block its interaction with its substrates.
Approved parenteral direct thrombin inhibitors include recombinant
hirudins (lepirudin and desirudin), argatroban, and bivalirudin
(Table 123-7). Lepirudin and desirudin are no longer available.
ARGATROBAN  A univalent inhibitor that targets the active site of
thrombin, argatroban is metabolized in the liver. Consequently, this
drug must be used with caution in patients with hepatic insufficiency.
Argatroban is administered by continuous IV infusion and has a
plasma half-life of ~45 min. The aPTT is used to monitor its anticoagu­
lant effect, and the dose is adjusted to achieve an aPTT 1.5–3 times the
baseline value, but not to exceed 100 s. Argatroban also prolongs the
INR, a feature that can complicate the transitioning of patients from
argatroban to warfarin. This problem can be circumvented by using the
levels of factor X to monitor warfarin instead of the INR. Alternatively,
argatroban can be stopped for 2–3 h before INR determination.
Argatroban is licensed for treatment of patients with HIT or a his­
tory of HIT, including those requiring PCI. In such patients, argatroban
is most useful for those with severe kidney disease because unlike
fondaparinux and bivalirudin, it is not cleared through the kidneys.
BIVALIRUDIN  A synthetic 20-amino-acid analogue of hirudin, bivali­
rudin is a divalent thrombin inhibitor. Thus, the N-terminus of bivali­
rudin interacts with the active site of thrombin, whereas its C-terminus
binds to exosite 1. Bivalirudin has a plasma half-life of 25 min, the
shortest half-life of all the parenteral direct thrombin inhibitors.
Bivalirudin is degraded by peptidases and is partially excreted via the
TABLE 123-7  Comparison of the Properties of Desirudin, Bivalirudin,
and Argatroban
 
DESIRUDIN
BIVALIRUDIN
ARGATROBAN
Molecular mass
Site(s) of interaction
with thrombin
Active site and
exosite 1
Active site and
exosite 1
Active site
Renal clearance
Yes
No
No
Hepatic metabolism
No
No
Yes
Plasma half-life (min)
60 (IV)
120–180 (SC)
kidneys. When given in high doses in the cardiac catheterization labo­
ratory, the anticoagulant activity of bivalirudin is monitored using the
activated clotting time. With lower doses, its activity can be assessed
using the aPTT.
Bivalirudin is licensed as an alternative to heparin in patients under­
going PCI. Bivalirudin also has been used successfully in HIT patients
who require PCI or cardiac bypass surgery.
■
■ORAL ANTICOAGULANTS
For many years, vitamin K antagonists such as warfarin were the only
available oral anticoagulants. This situation changed with the intro­
duction of the direct oral anticoagulants, which include dabigatran,
rivaroxaban, apixaban, and edoxaban.
Warfarin 
A water-soluble vitamin K antagonist initially developed
as a rodenticide; warfarin is the coumarin derivative most often pre­
scribed in North America. Like other vitamin K antagonists, warfarin
interferes with the synthesis of the vitamin K–dependent clotting pro­
teins, which include prothrombin (factor II) and factors VII, IX, and
X. The synthesis of the vitamin K–dependent anticoagulant proteins,
proteins C and S, is also reduced by vitamin K antagonists.
MECHANISM OF ACTION  All of the vitamin K–dependent clotting
factors possess glutamic acid residues at their N termini. A posttransla­
tional modification adds a carboxyl group to the γ-carbon of these resi­
dues to generate γ-carboxyglutamic acid. This modification is essential
for expression of the activity of these clotting factors because it permits
their calcium-dependent binding to negatively charged phospholipid
surfaces. The γ-carboxylation process is catalyzed by a vitamin K–
dependent carboxylase. Thus, vitamin K from the diet is reduced to
vitamin K hydroquinone by vitamin K reductase (Fig. 123-6). Vita­
min K hydroquinone serves as a cofactor for the carboxylase enzyme,
which in the presence of carbon dioxide replaces the hydrogen on the
γ-carbon of glutamic acid residues with a carboxyl group. During this
process, vitamin K hydroquinone is oxidized to vitamin K epoxide,
which is then reduced to vitamin K by vitamin K epoxide reductase.
Nonfunctional
Prozymogens
Functional
Zymogens
γ-glutamyl
carboxylase
O2
CO2
Reduced
vitamin K
Vitamin K
cycle
Oxidized
vitamin K
Vitamin K
reductase
x
CYP1A1
CYP1A2
CYP3A4
CYP2C9
R-warfarin
S-warfarin
Warfarin
metabolism
Warfarin
FIGURE 123-6  Mechanism of action of warfarin. A racemic mixture of S- and
R-enantiomers, S-warfarin is most active. By blocking vitamin K epoxide reductase,
warfarin inhibits the conversion of oxidized vitamin K into its reduced form. This
inhibits vitamin K–dependent γ-carboxylation of factors II, VII, IX, and X because
reduced vitamin K serves as a cofactor for a γ-glutamyl carboxylase that catalyzes
the γ-carboxylation process, thereby converting pro-zymogens to zymogens
capable of binding calcium and interacting with anionic phospholipid surfaces.
S-warfarin is metabolized by CYP2C9. Common genetic polymorphisms in this
enzyme can influence warfarin metabolism. Polymorphisms in the C1 subunit of
vitamin K reductase (VKORC1) also can affect the susceptibility of the enzyme to
warfarin-induced inhibition, thereby influencing warfarin dosage requirements.
Warfarin inhibits vitamin K epoxide reductase (VKOR), thereby
blocking the γ-carboxylation process. This results in the synthesis
of vitamin K–dependent clotting proteins that are only partially
γ-carboxylated. Warfarin acts as an anticoagulant because these par­
tially γ-carboxylated proteins have little or no biological activity. The
onset of action of warfarin is delayed until the newly synthesized clot­
ting factors with reduced activity gradually replace their fully active
counterparts.
The antithrombotic effect of warfarin depends on a reduction in
the functional levels of factor X and prothrombin, clotting factors that
have half-lives of 24 and 72 h, respectively. Because the antithrombotic
effect of warfarin is delayed, patients with established thrombosis
or at high risk for thrombosis require concomitant treatment with a
rapidly acting parenteral anticoagulant, such as heparin, LMWH, or
fondaparinux, for at least 5 days.
PHARMACOLOGY  Warfarin is a racemic mixture of R and S isomers.
Warfarin is rapidly and almost completely absorbed from the gastroin­
testinal tract. Levels of warfarin in the blood peak about 90 min after
drug administration. Racemic warfarin has a plasma half-life of 36–42 h,
and >97% of circulating warfarin is bound to albumin. Only the small
fraction of unbound warfarin is biologically active.
Warfarin accumulates in the liver where the two isomers are metab­
olized via distinct pathways. CYP2C9 mediates oxidative metabolism of
the more active S isomer (Fig. 123-6). Two relatively common variants,
CYP2C92 and CYP2C93, encode an enzyme with reduced activity.
Patients with these variants require lower maintenance doses of war­
farin. Approximately 25% of Caucasians have at least one variant allele
of CYP2C92 or CYP2C93, whereas those variant alleles are less com­
mon in African Americans and Asians (Table 123-8). Heterozygosity
for CYP2C92 or CYP2C93 decreases the warfarin dose requirement
by 20–30% relative to that required in subjects with the wild-type
CYP2C91/1 alleles, whereas homozygosity for the CYP2C92 or
CYP2C93 alleles reduces the warfarin dose requirement by 50–70%.
Consistent with their decreased warfarin dose requirement, subjects
with at least one CYP2C9 variant allele are at increased risk for bleed­
ing. Compared with individuals with no variant alleles, the risk of
warfarin-associated bleeding is almost twofold higher in CYP2C92 or
CYP2C93 carriers.
Polymorphisms in VKORC1 also can influence the anticoagulant
response to warfarin. Several genetic variations of VKORC1 are in
strong linkage disequilibrium and have been designated as non-A
haplotypes. VKORC1 variants are more prevalent than variants of
CYP2C9. Asians have the highest prevalence of VKORC1 variants,
followed by Caucasians and African Americans (Table 123-8). Poly­
morphisms in VKORC1 likely explain 30% of the variability in war­
farin dose requirements. Compared with VKORC1 non-A/non-A
TABLE 123-8  Frequencies of CYP2C9 Genotypes and VKORC1
Haplotypes in Different Populations and their Effect on Warfarin Dose
Requirements
FREQUENCY, %
PERCENTAGE
DOSE REDUCTION
COMPARED WITH
WILD-TYPE
CAUCASIANS
AFRICAN
AMERICANS
(A/A)
ASIANS (A)
GENOTYPE/
HAPLOTYPE
CYP2C9
*1/*1
—
*1/*2
*1/*3
*2/*2
*2/*3
*3/*3
VKORC1
Non-A/non-A
—
Non-A/A
A/A
homozygotes, the warfarin dose requirement decreases by 25 and 50%
in A haplotype heterozygotes and homozygotes, respectively. These
findings prompted the U.S. Food and Drug Administration (FDA) to
amend the prescribing information for warfarin to indicate that lower
initiation doses should be considered for patients with CYP2C9 and
VKORC1 genetic variants. In addition to genotype data, other perti­
nent patient information has been incorporated into warfarin dosing
algorithms. Although such algorithms help predict suitable warfarin
doses, it remains unclear whether better dose identification improves
patient outcome in terms of reducing hemorrhagic complications or
recurrent thrombotic events.
In addition to genetic factors, the anticoagulant effect of warfarin
is influenced by diet, drugs, and various disease states. Fluctuations in
dietary vitamin K intake affect the activity of warfarin. A wide variety
of drugs can alter absorption, clearance, or metabolism of warfarin.
Because of the variability in the anticoagulant response to warfa­
rin, coagulation monitoring is essential to ensure that a therapeutic
response is obtained.
MONITORING  Warfarin therapy is most often monitored using the
prothrombin time, a test that is sensitive to reductions in the levels of
prothrombin, factor VII, and factor X. The test is performed by adding
thromboplastin, a reagent that contains tissue factor, phospholipid, and
calcium, to citrated plasma and determining the time to clot formation.
Thromboplastins vary in their sensitivity to reductions in the levels of
the vitamin K–dependent clotting factors. Thus, less sensitive throm­
boplastins will trigger the administration of higher doses of warfarin to
achieve a target prothrombin time. This is problematic because higher
doses of warfarin increase the risk of bleeding.
CHAPTER 123
Antiplatelet, Anticoagulant, and Fibrinolytic Drugs
The INR was developed to circumvent many of the problems asso­
ciated with the prothrombin time. To calculate the INR, the patient’s
prothrombin time is divided by the mean normal prothrombin time,
and this ratio is then multiplied by the international sensitivity index
(ISI), which is an index of the sensitivity of the thromboplastin used
for prothrombin time determination to reductions in the levels of the
vitamin K–dependent clotting factors. Sensitive thromboplastins have
an ISI near 1.0. Most current thromboplastins have ISI values that
range from 0.9 to 1.4.
Although the INR has helped to standardize anticoagulant practice,
problems persist. The precision of INR determination varies depend­
ing on reagent-coagulometer combinations. This leads to variability
in the INR results. Also complicating INR determination is unreliable
reporting of the ISI by thromboplastin manufacturers. Furthermore,
every laboratory must establish the mean normal prothrombin time
with each new batch of thromboplastin reagent. To accomplish this,
the prothrombin time must be measured in fresh plasma samples from
at least 20 healthy volunteers using the same coagulometer that is used
for patient samples.
For most indications, warfarin is administered in doses that produce
a target INR of 2.0–3.0. An exception is patients with mechanical heart
valves, particularly those in the mitral position or older ball and cage
valves in the aortic position, and valves in any position associated with
atrial fibrillation, where a target INR of 2.5–3.5 is recommended. Stud­
ies in atrial fibrillation demonstrate an increased risk of cardioembolic
stroke when the INR falls below 1.7 and an increase in bleeding with
INR values >4.5. These findings highlight the fact that vitamin K antag­
onists have a narrow therapeutic window. In support of this concept, a
study in patients receiving long-term warfarin therapy for unprovoked
VTE demonstrated a higher rate of recurrent VTE with a target INR of
1.5–1.9 compared with a target INR of 2.0–3.0.
DOSING  Warfarin is usually started at a dose of 5–10 mg. Lower doses
are used for patients with CYP2C9 or VKORC1 polymorphisms, which
affect the pharmacodynamics or pharmacokinetics of warfarin and
render patients more sensitive to the drug. The dose is then titrated to
achieve the desired target INR. Because of its delayed onset of action,
patients with established thrombosis or those at high risk for throm­
bosis are given concomitant initial treatment with a rapidly acting
parenteral anticoagulant, such as heparin, LMWH, or fondaparinux.
Early prolongation of the INR reflects reduction in the functional levels
of factor VII. Consequently, concomitant treatment with the parenteral
anticoagulant should be continued until the INR has been therapeutic
for at least 2 consecutive days. A minimum 5-day course of parenteral
anticoagulation is recommended to ensure that the levels of factor Xa
and prothrombin have been reduced into the therapeutic range with
warfarin.
Because warfarin has a narrow therapeutic window, frequent
coagulation monitoring is essential to ensure that a therapeutic anti­
coagulant response is maintained. Even patients with stable warfarin
dose requirements should have their INR determined every 3–4 weeks
although there are studies suggesting that less frequent monitoring is
feasible. More frequent monitoring is necessary when new medica­
tions are introduced because so many drugs enhance or reduce the
anticoagulant effects of warfarin and when the dosing regimen has
been changed.
SIDE EFFECTS  Like all anticoagulants, the major side effect of warfa­
rin is bleeding. A rare complication is skin necrosis. Warfarin crosses
the placenta and can cause fetal abnormalities. Consequently, warfarin
should not be used during pregnancy.
Bleeding  At least half of the bleeding complications with warfarin
occur when the INR exceeds the therapeutic range. Bleeding compli­
cations may be mild, such as epistaxis or hematuria, or more severe,
such as retroperitoneal or gastrointestinal bleeding. Life-threatening
intracranial bleeding can also occur.
PART 4
Oncology and Hematology
To minimize the risk of bleeding, the INR should be maintained in
the therapeutic range. In asymptomatic patients whose INR is between
3.5 and 10, warfarin should be withheld until the INR returns to the
therapeutic range. If the INR is over 10, oral vitamin K can be admin­
istered at a dose of 2.5–5 mg, although there is no evidence that doing
so reduces the bleeding risk. Higher doses of oral vitamin K (5–10 mg)
produce more rapid reversal of the INR but may render patients tem­
porarily resistant to warfarin when the drug is restarted.
Patients with an increased INR associated with serious bleeding
should be given 5–10 mg of vitamin K by slow IV infusion. Addi­
tional vitamin K should be given until the INR is in the normal range.
Treatment with vitamin K should be supplemented with four-factor
prothrombin complex concentrate, which contains all four vitamin K–
dependent clotting proteins. Prothrombin complex concentrate nor­
malizes the INR more rapidly than transfusion of fresh-frozen plasma.
Warfarin-treated patients who experience bleeding when their INR
is in the therapeutic range require investigation into the cause of the
bleeding. Those with gastrointestinal or genitourinary bleeding often
have underlying disorders.
Skin Necrosis  A rare complication of warfarin, skin necrosis usually is
seen 2–5 days after initiation of therapy. Well-demarcated erythema­
tous lesions form on the thighs, buttocks, breasts, or toes. Typically,
the center of the lesion becomes progressively necrotic. Examination
of skin biopsies taken from the border of these lesions reveals thrombi
in the microvasculature.
Warfarin-induced skin necrosis is seen in patients with congenital
or acquired deficiencies of protein C or protein S. Initiation of warfarin
therapy in these patients produces a precipitous fall in plasma levels of
proteins C or S, thereby eliminating this important anticoagulant path­
way before warfarin exerts an antithrombotic effect through lowering
of the functional levels of factor X and prothrombin. The resultant pro­
coagulant state triggers thrombosis. Why the thrombosis is localized to
the microvasculature of fatty tissues is unclear.
Treatment involves discontinuation of warfarin and reversal with
vitamin K, if needed. An alternative anticoagulant, such as heparin or
LMWH, should be given in patients with thrombosis. Protein C con­
centrate can be given to protein C–deficient patients to accelerate heal­
ing of the skin lesions; fresh-frozen plasma may be of value if protein
C concentrate is unavailable and for those with protein S deficiency.
Occasionally, skin grafting is necessary when there is extensive skin
loss.
Because of the potential for skin necrosis, patients with known
protein C or protein S deficiency require overlapping treatment with
a parenteral anticoagulant when initiating warfarin therapy. Warfarin
should be started in low doses in these patients, and the parenteral
anticoagulant should be continued until the INR is therapeutic for at
least 2–3 consecutive days. Alternatively, treatment with rivaroxaban or
apixaban could be given, although there is limited information about
their efficacy and safety in patients with severe protein C or S deficiency.
Pregnancy  Warfarin crosses the placenta and can cause fetal abnor­
malities or bleeding. The fetal abnormalities include a characteristic
embryopathy, which consists of nasal hypoplasia and stippled epiphy­
ses. The risk of embryopathy is highest if warfarin is given in the first
trimester of pregnancy. Central nervous system abnormalities can also
occur with exposure to warfarin at any time during pregnancy. Finally,
maternal administration of warfarin produces an anticoagulant effect
in the fetus that can cause bleeding. This is of particular concern at
delivery when trauma to the head during passage through the birth
canal can lead to intracranial bleeding. Because of these potential prob­
lems, warfarin is contraindicated in pregnancy, particularly in the first
and third trimesters. Instead, heparin, LMWH, or fondaparinux can
be given during pregnancy for prevention or treatment of thrombosis.
Warfarin does not pass into the breast milk. Consequently, warfarin
can safely be given to nursing mothers.
Special Problems  Patients with antiphospholipid syndrome and those
who need urgent or elective surgery present special challenges.
Although observational studies suggested that patients with thrombo­
sis complicating antiphospholipid syndrome required higher intensity
warfarin regimens to prevent recurrent thromboembolic events, two
randomized trials showed that targeting an INR of 2.0–3.0 is as effec­
tive as higher intensity treatment and produces less bleeding. Moni­
toring warfarin therapy can be problematic in patients with the lupus
anticoagulant because it prolongs the baseline INR; factor X levels can
be used instead of the INR in such patients.
There is no need to stop warfarin before procedures associated with
a low risk of bleeding; these include dental cleaning, simple dental
extraction, cataract surgery, or skin biopsy. For procedures associated
with a moderate or high risk of bleeding, warfarin should be stopped
5 days before the procedure to allow the INR to return to normal lev­
els. Patients at high risk for thrombosis, such as those with mechanical
heart valves, can be bridged with once- or twice-daily SC injections of
LMWH when the INR falls to <2.0. The last dose of LMWH should be
given 12–24 h before the procedure, depending on whether LMWH is
administered twice or once daily. After the procedure, treatment with
warfarin can be restarted.
Direct Oral Anticoagulants 
The direct oral anticoagulants
(DOACs) include dabigatran, which inhibits thrombin, and rivar­
oxaban, apixaban, and edoxaban, which inhibit factor Xa. These drugs
have a rapid onset and offset of action and have half-lives that permit
once- or twice-daily administration. Designed to produce a predictable
level of anticoagulation, the DOACs are more convenient to administer
than warfarin because they are given in fixed doses without routine
coagulation monitoring.
MECHANISM OF ACTION  The DOACs are small molecules that bind
reversibly to the active site of their target enzyme. Table 123-9 sum­
marizes the distinct pharmacologic properties of these agents.
INDICATIONS  All four DOACs are licensed for stroke prevention
in patients with atrial fibrillation except those with mechanical heart
valves or severe rheumatic mitral valve disease, and for treatment of
VTE. Dabigatran, rivaroxaban, and apixaban are licensed for throm­
boprophylaxis after elective hip or knee arthroplasty; edoxaban is only
licensed for this indication in Japan. Finally, low-dose rivaroxaban is
licensed for use with aspirin for secondary prevention in patients with
coronary or peripheral artery disease.
DOSING  For prevention of stroke in patients with atrial fibrillation,
rivaroxaban is given at a dosage of 20 mg once daily, with a reduction to
15 mg once daily in patients with a creatinine clearance of 15–49 mL/
min; dabigatran is given at a dosage of 150 mg twice daily, with a
reduction to 75 mg twice daily in those with a creatinine clearance of
15–30 mL/min; apixaban is given at a dosage of 5 mg twice daily, with
a reduction to 2.5 mg twice daily for patients with at least two of the
TABLE 123-9  Comparison of the Pharmacologic Properties of the Direct Oral Anticoagulants
CHARACTERISTIC
RIVAROXABAN
APIXABAN
EDOXABAN
DABIGATRAN
Target
Factor Xa
Factor Xa
Factor Xa
Thrombin
Prodrug
No
No
No
Yes
Bioavailability
80%
60%
50%
6%
Dosing
qd (bid)
bid
qd
bid (qd)
Half-life
7–11 h
12 h
9–11 h
12–17 h
Renal excretion
33% (66%)
25%
35%
80%
Interactions
3A4/P-gp
3A4/P-gp
P-gp
P-gp
Abbreviations: bid, twice a day; P-gp, P-glycoprotein; qd, once a day.
“ABC” criteria (i.e., age >80 years, body weight <60 kg, and creatinine
1.5 g/dL); and edoxaban is given at a dosage of 60 mg once daily
for patients with a creatinine clearance of 50–95 mL/min and with a
reduction to 30 mg once daily for patients with any one of the follow­
ing criteria: creatinine clearance of 15–50 mL/min, body weight of
60 kg or less, or use of potent P-glycoprotein inhibitors, such as vera­
pamil or quinidine. At doses of 15 or 20 mg once daily, rivaroxaban
must be administered with food to enhance absorption. Apixaban and
edoxaban can be given with or without food. Administration of dabi­
gatran with food may reduce dyspepsia.
For treatment of VTE, dabigatran and edoxaban are started after
patients have received at least a 5-day course of treatment with a par­
enteral anticoagulant such as LMWH. Dabigatran is given at a dose of
150 mg twice daily provided the creatinine clearance is >30 mL/min.
The dosage regimen for edoxaban is identical to that used in patients
with atrial fibrillation. Rivaroxaban and apixaban can be given in alloral regimens; rivaroxaban is started at a dose of 15 mg twice daily for
21 days and is then reduced to 20 mg once daily thereafter, whereas
apixaban is started at a dose of 10 mg twice daily for 7 days and is then
reduced to 5 mg twice daily thereafter. For secondary VTE prevention
after 6 months of full-dose treatment, the dosage of apixaban can be
lowered to 2.5 mg twice daily while the dose of rivaroxaban can be
lowered to 10 mg once daily, doses that have safety profiles like those
of placebo and aspirin, respectively.
Thromboprophylaxis after elective hip or knee replacement surgery
is started after surgery and is often continued for 30 days in patients
undergoing hip replacement and for 10–14 days in patients undergo­
ing knee replacement. Dabigatran is given at a dose of 220 mg once
daily, whereas rivaroxaban and apixaban are given at doses of 10 mg
once daily and 2.5 mg twice daily, respectively. In lower risk patients
undergoing hip or knee replacement surgery, a 5-day course of rivar­
oxaban followed by a 30-day course of aspirin at a dose of 81 mg daily
appears to be as effective and safe as extended thromboprophylaxis
with rivaroxaban.
For secondary prevention of adverse cardiac or limb events in patients
with coronary or peripheral artery disease, rivaroxaban is given at a dose
of 2.5 mg twice daily on top of aspirin (81 or 100 mg once daily).
MONITORING  Although designed to be administered without routine
monitoring, there are situations where determination of the anticoagu­
lant activity of the DOACs can be helpful. These include assessment
of adherence, detection of accumulation or overdose, identification of
bleeding mechanisms, and determination of activity before surgery,
intervention, or reversal. For qualitative assessment of anticoagulant
activity, the prothrombin time can be used for factor Xa inhibitors
and the aPTT for dabigatran. Rivaroxaban and edoxaban prolong the
prothrombin time more than apixaban. In fact, because apixaban has
such a limited effect on the prothrombin time, anti–factor Xa assays are
needed to assess its activity. The effect of the drugs on tests of coagula­
tion varies depending on the time that the blood is drawn relative to
the timing of the last dose of the drug and the reagents used to perform
the tests. Chromogenic anti–factor Xa assays and the diluted thrombin
clotting time or ecarin clot time with appropriate calibrators provide
quantitative assays to measure the plasma levels of the factor Xa inhibi­
tors and dabigatran, respectively.
SIDE EFFECTS  Like all anticoagulants, bleeding is the most com­
mon side effect of the DOACs. The DOACS are associated with less
intracranial bleeding than warfarin, but the higher dose regimens of
dabigatran, rivaroxaban, and edoxaban are associated with more gas­
trointestinal bleeding.
Dyspepsia occurs in up to 10% of patients treated with dabigatran;
this problem improves with time and can be minimized by administer­
ing the drug with food. Dyspepsia is rare with rivaroxaban, apixaban,
and edoxaban.
CHAPTER 123
PERIPROCEDURAL MANAGEMENT  Like warfarin, the DOACs must
be stopped before procedures associated with a moderate or high risk
of bleeding. The drugs should be held for 1–2 days, or longer if renal
function is impaired. Assessment of residual anticoagulant activity
before procedures associated with a high bleeding risk is prudent.
Antiplatelet, Anticoagulant, and Fibrinolytic Drugs
MANAGEMENT OF BLEEDING  With minor bleeding, withholding one
or two doses of drug is usually sufficient. With more serious bleeding,
the approach is like that with warfarin, except that vitamin K adminis­
tration is of no benefit; the anticoagulant and any long-acting antiplate­
let drugs should be withheld, the patient should be resuscitated with
fluids and blood products as necessary, and the bleeding site should
be identified and managed. Coagulation testing or measurement of
the DOAC level will determine the extent of anticoagulation, and
renal function should be assessed so that the half-life of the drug can
be calculated. Timing of the last dose of anticoagulant is important; in
cases of overdose, oral activated charcoal may help prevent absorption
of drug administered in the past 4 h. If >24 h have elapsed since the last
intake, the DOAC is unlikely to be responsible for the bleeding unless
there is marked impairment of renal function.
Anticoagulant reversal should be considered if bleeding continues
despite supportive measures or if the bleeding is life-threatening or
occurs in a critical organ (e.g., intracranial) or in a closed space (e.g.,
the pericardium or retroperitoneum). Idarucizumab is licensed for
dabigatran reversal in such patients or in those requiring urgent sur­
gery or intervention. A humanized antibody fragment, idarucizumab,
binds dabigatran with high affinity to form an essentially irreversible
complex that is cleared by the kidneys. Idarucizumab is given intrave­
nously as a 5-g bolus and is supplied in a box containing two 50-mL
vials, each containing 2.5 g of idarucizumab. Idarucizumab rapidly
reverses the anticoagulant effects of dabigatran and normalizes the
aPTT, diluted thrombin time, or ecarin clot time.
Andexanet alfa is available for reversal of rivaroxaban and apixaban.
A recombinant variant of factor Xa without catalytic activity, andexanet
serves as a decoy to sequester oral factor Xa inhibitors until they are
cleared from the circulation. Low- or high-dose IV andexanet regimens
are used. The low-dose regimen starts with a bolus of 400 mg followed by
an infusion of 4 mg/min for up to 120 min, whereas the high-dose regi­
men starts with a bolus of 800 mg followed by an infusion of 8 mg/min
for up to 120 min. The low-dose regimen is used for reversal of doses
of rivaroxaban or apixaban of 10 mg or 5 mg or less, respectively, or
for any dose of rivaroxaban or apixaban if the last dose was taken >8 h
before presentation. The high-dose regimen is used to reverse rivaroxa­
ban or apixaban doses over 10 and 5 mg, respectively, if the last dose
was taken <8 h since presentation, or if the timing of the last dose of
rivaroxaban or apixaban is unknown.
Andexanet alfa is expensive and is not available in all hospitals.
Because of its cost, andexanet alfa is often reserved for reversal in
patients with life-threatening bleeds such intracranial hemorrhage or
bleeds into a closed space such as retroperitoneal or pericardial bleeds. If
andexanet is unavailable, the results of prospective cohort studies suggest
that four-factor prothrombin complex concentrate (25–50 units/kg) also
is effective at restoring hemostasis. If there is continued bleeding, acti­
vated prothrombin complex concentrate (50 units/kg) or recombinant
factor VIIa (90 μg/kg) can be considered.
Neither andexanet alfa nor four-factor prothrombin complex con­
centrate has been evaluated for reversal in patients requiring urgent
surgery or intervention. Furthermore, andexanet alfa not only reverses
oral factor Xa inhibitors but also reverses heparin and LMWH. This
could be problematic in patients who require cardiac surgery or vas­
cular surgery, procedures where heparin is used routinely. To circum­
vent this problem, most surgical procedures and interventions can be
undertaken without reversal, and four-factor prothrombin complex
concentrate can be given if necessary. For patients requiring surgery to
stop bleeding such as those with a ruptured aortic aneurysm or with
bleeding secondary to polytrauma, upfront four-factor prothrombin
concentrate administration can be considered.
PREGNANCY  As small molecules, the DOACs pass through the pla­
centa. Consequently, these agents are contraindicated in pregnancy,
and when used by women of childbearing potential, appropriate con­
traception is important. DOACs should be avoided in nursing mothers
because small amounts have been found in breast milk.
PART 4
Oncology and Hematology
FIBRINOLYTIC DRUGS
■
■ROLE OF FIBRINOLYTIC THERAPY
Fibrinolytic drugs are used to degrade thrombi and are administered
systemically or can be delivered via catheters directly into the substance
of the thrombus. Systemic delivery is used for treatment of acute MI,
acute ischemic stroke, and most cases of massive PE. The goal of ther­
apy is to produce rapid thrombus dissolution, thereby restoring blood
flow. In the coronary circulation, restoration of blood flow reduces
morbidity and mortality rates by limiting myocardial damage, whereas
in the cerebral circulation, rapid thrombus dissolution decreases the
neuronal death and brain infarction that produce irreversible brain
injury. For patients with massive PE, the goal of thrombolytic therapy
is to restore pulmonary artery perfusion.
Peripheral arterial thrombi and thrombi in the proximal deep veins
of the leg are most often treated using catheter-directed thrombolytic
therapy. Catheters with multiple side holes can be used to enhance drug
delivery. In some cases, intravascular devices that fragment and extract
the thrombus are used to hasten treatment. These devices can be used
alone or in conjunction with fibrinolytic drugs.
■
■MECHANISM OF ACTION
Currently approved fibrinolytic agents include streptokinase; acylated
plasminogen streptokinase activator complex (anistreplase); urokinase;
recombinant tissue-type plasminogen activator (rtPA), which is also
known as alteplase or activase; and two recombinant derivatives of
rtPA, tenecteplase and reteplase. Of these, streptokinase, anistreplase,
and urokinase are no longer available in the United States. All these
agents act by converting plasminogen, the zymogen, to plasmin, the
active enzyme (Fig. 123-7). Plasmin then degrades the fibrin matrix of
thrombi and produces soluble fibrin degradation products.
Endogenous fibrinolysis is regulated at two levels. Plasminogen
activator inhibitors, particularly the type 1 form (PAI-1), prevent
excessive plasminogen activation by regulating the activity of tPA and
urokinase-type plasminogen activator (uPA). Once plasmin is gener­
ated, it is regulated by plasmin inhibitors, the most important of which
is α2-antiplasmin. The plasma concentration of plasminogen is twofold
higher than that of α2-antiplasmin. Consequently, with pharmacologic
doses of plasminogen activators, the concentration of plasmin that is
generated can exceed that of α2-antiplasmin. In addition to degrading
fibrin, unregulated plasmin can also degrade fibrinogen and other clot­
ting factors. This process, which is known as the systemic lytic state,
Plasminogen activators
PAI-1
Plasmin
Plasminogen
α2-antiplasmin
Fibrin degradation
products
Fibrin
FIGURE 123-7  The fibrinolytic system and its regulation. Plasminogen activators
convert plasminogen to plasmin. Plasmin then degrades fibrin into soluble fibrin
degradation products. The system is regulated at two levels. Type 1 plasminogen
activator inhibitor (PAI-1) inhibits the plasminogen activators, whereas α2antiplasmin serves as the major inhibitor of plasmin.
reduces the hemostatic potential of the blood and increases the risk
of bleeding.
The endogenous fibrinolytic system is geared to localize plasmin
generation to the fibrin surface. Both plasminogen and tPA bind to
fibrin to form a ternary complex that promotes efficient plasminogen
activation. In contrast to free plasmin, plasmin generated on the fibrin
surface is relatively protected from inactivation by α2-antiplasmin,
a feature that promotes fibrin dissolution. Furthermore, C-terminal
lysine residues, exposed as plasmin degrades fibrin, provide bind­
ing sites for additional plasminogen and tPA molecules. This creates
positive feedback that enhances plasmin generation. When used phar­
macologically, the various plasminogen activators capitalize on these
mechanisms to a lesser or greater extent.
Plasminogen activators that preferentially activate fibrin-bound
plasminogen are considered fibrin-specific. In contrast, nonspecific
plasminogen activators do not discriminate between fibrin-bound and
circulating plasminogen. Activation of circulating plasminogen results
in the generation of unopposed plasmin that can trigger the systemic
lytic state. Alteplase and its derivatives are fibrin-specific plasminogen
activators, whereas streptokinase, anistreplase, and urokinase are non­
specific agents.
■
■STREPTOKINASE
Unlike other plasminogen activators, streptokinase is not an enzyme
and does not directly convert plasminogen to plasmin. Instead, strep­
tokinase forms a 1:1 stoichiometric complex with plasminogen. Forma­
tion of this complex induces a conformational change in plasminogen
that exposes its active site (Fig. 123-8). The streptokinase-plasminogen
complex then converts additional plasminogen to plasmin.
S
Plasminogen
Streptokinase
S
Plasminogen
Streptokinase
FIGURE 123-8  Mechanism of action of streptokinase. Streptokinase binds to
plasminogen and induces a conformational change in plasminogen that exposes its
active site. The streptokinase/plasmin(ogen) complex then serves as the activator
of additional plasminogen.
Streptokinase has no affinity for fibrin, and the streptokinaseplasminogen complex activates both free and fibrin-bound plasmino­
gen. Activation of circulating plasminogen generates enough plasmin
to overwhelm α2-antiplasmin. Unopposed plasmin not only degrades
fibrin in the occlusive thrombus but also induces a systemic lytic state.
When given systemically to patients with acute MI, streptokinase
reduces mortality. For this indication, the drug is usually given as an
IV infusion of 1.5 million units over 30–60 min. Patients who receive
streptokinase can develop antibodies against the drug, as can patients
with prior streptococcal infection. These antibodies can reduce the
effectiveness of streptokinase.
Allergic reactions occur in ~5% of patients treated with streptoki­
nase. These may manifest as a rash, fever, chills, and rigors. Although
anaphylactic reactions can occur, these are rare. Transient hypotension
is common with streptokinase and has been attributed to plasmin-
mediated release of bradykinin from kininogen. The hypotension usu­
ally responds to leg elevation and administration of IV fluids and low
doses of vasopressors, such as dopamine or norepinephrine.
■
■ANISTREPLASE
To generate this drug, streptokinase is combined with equimolar
amounts of Lys-plasminogen, a plasmin-cleaved form of plasminogen
with a Lys residue at its N terminal. The active site of Lys-plasminogen
that is exposed upon combination with streptokinase is then masked
with an anisoyl group. After IV infusion, the anisoyl group is slowly
removed by deacylation, giving the complex a half-life of ~100 min.
This allows drug administration via a single bolus infusion.
Although it is more convenient to administer, anistreplase offers
few mechanistic advantages over streptokinase. Like streptokinase,
anistreplase does not distinguish between fibrin-bound and circulat­
ing plasminogen. Consequently, it too produces a systemic lytic state.
Likewise, allergic reactions and hypotension are just as frequent with
anistreplase as they are with streptokinase.
When anistreplase was compared with alteplase in patients with acute
MI, reperfusion was obtained more rapidly with alteplase than with anis­
treplase. Improved reperfusion was associated with a trend toward better
clinical outcomes and reduced mortality rate with alteplase. These results
and the high cost of anistreplase dampened the enthusiasm for its use.
■
■UROKINASE
Urokinase is a two-chain serine protease derived from cultured fetal
kidney cells with a molecular weight of 34,000. Urokinase converts
plasminogen to plasmin directly by cleaving the Arg560-Val561 bond.
Unlike streptokinase, urokinase is not immunogenic, and allergic reac­
tions are rare. Urokinase produces a systemic lytic state because it does
not discriminate between fibrin-bound and circulating plasminogen.
Despite many years of use, urokinase has never been systemically
evaluated for coronary thrombolysis. Instead, urokinase is often
employed for catheter-directed lysis of thrombi in the deep veins or
the peripheral arteries. Because of production problems, urokinase is
no longer available.
■
■ALTEPLASE
A recombinant form of single-chain tPA, alteplase has a molecular
weight of 68,000. Alteplase is rapidly converted into its two-chain form
by plasmin. Although single- and two-chain forms of tPA have equiva­
lent activity in the presence of fibrin, in its absence, single-chain tPA
has 10-fold lower activity.
Alteplase consists of five discrete domains (Fig. 123-9); the
N-terminal A chain of two-chain alteplase contains four of these
domains. Residues 4 through 50 make up the finger domain, a region
that resembles the finger domain of fibronectin; residues 50 through
87 are homologous with epidermal growth factor, whereas residues 92
through 173 and 180 through 261, which have homology to the kringle
domains of plasminogen, are designated as the first and second kringle,
respectively. The fifth alteplase domain is the protease domain; it is
located on the C-terminal B chain of two-chain alteplase.
The interaction of alteplase with fibrin is mediated by the finger
domain and, to a lesser extent, by the second kringle domain. The
tPA
F
EGF
K1
K2
P
KHRR
AAAA
F
EGF
K1
K2
P
TNK-tPA
K2
P
r-PA
FIGURE 123-9  Domain structures of alteplase (tPA), tenecteplase (TNK-tPA), and
reteplase (r-PA). The finger (F), epidermal growth factor (EGF), first and second
kringles (K1 and K2, respectively), and protease (P) domains are illustrated. The
glycosylation site (Y) on K1 has been repositioned in tenecteplase to endow it with
a longer half-life. In addition, a tetra-alanine substitution in the protease domain
renders tenecteplase resistant to type 1 plasminogen activator inhibitor (PAI-1)
inhibition. Reteplase is a truncated variant that lacks the F, EGF, and K1 domains.
CHAPTER 123
affinity of alteplase for fibrin is considerably higher than that for fibrin­
ogen. Consequently, the catalytic efficiency of plasminogen activation
by alteplase is two to three orders of magnitude higher in the presence
of fibrin than in the presence of fibrinogen. This phenomenon helps to
localize plasmin generation to the fibrin surface.
Antiplatelet, Anticoagulant, and Fibrinolytic Drugs
Although alteplase preferentially activates plasminogen in the pres­
ence of fibrin, alteplase is not as fibrin selective as was first predicted.
Its fibrin specificity is limited because, like fibrin, (DD)E, the major
soluble degradation product of cross-linked fibrin, binds alteplase
and plasminogen with high affinity. Consequently, (DD)E is as potent
as fibrin as a stimulator of plasminogen activation by alteplase.
Whereas plasmin generated on the fibrin surface results in thromboly­
sis, plasmin generated on the surface of circulating (DD)E degrades
fibrinogen. Fibrinogen degradation results in the accumulation of
fragment X, a high-molecular-weight clottable fibrinogen degradation
product. Incorporation of fragment X into hemostatic plugs formed at
sites of vascular injury renders them susceptible to lysis. This phenom­
enon may contribute to alteplase-induced bleeding.
A trial comparing alteplase with streptokinase for treatment of
patients with acute MI demonstrated significantly lower mortality with
alteplase than with streptokinase, although the absolute difference was
small. The greatest benefit was seen in patients age <75 years with
anterior MI who presented <6 h after symptom onset.
For treatment of acute MI or acute ischemic stroke, alteplase is given
as an IV infusion over 60–90 min. The total dose of alteplase usually
ranges from 90 to 100 mg. Allergic reactions and hypotension are rare,
and alteplase is not immunogenic.
■
■TENECTEPLASE
Tenecteplase is a genetically engineered variant of tPA and was
designed to have a longer half-life than tPA and to be resistant to inac­
tivation by PAI-1. To prolong its half-life, a new glycosylation site was
added to the first kringle domain (Fig. 123-9). Because addition of this
extra carbohydrate side chain reduced fibrin affinity, the existing gly­
cosylation site on the first kringle domain was removed. To render the
molecule resistant to inhibition by PAI-1, a tetra-alanine substitution
was introduced at residues 296–299 in the protease domain, the region
responsible for the interaction of tPA with PAI-1.
Tenecteplase is more fibrin-specific than tPA. Although both agents
bind to fibrin with similar affinity, the affinity of tenecteplase for (DD)
E is significantly lower than that of tPA. Consequently, (DD)E does
not stimulate systemic plasminogen activation by tenecteplase to the
same extent as tPA. As a result, tenecteplase produces less fibrinogen
degradation than tPA.
For coronary thrombolysis, tenecteplase is given as a single IV bolus.
In a large phase III trial that enrolled >16,000 patients, the 30-day mor­
tality rate with single-bolus tenecteplase was like that with accelerateddose tPA. Although rates of intracranial hemorrhage were similar with
both treatments, patients given tenecteplase had fewer noncerebral
bleeds and a reduced need for blood transfusions than those treated
with tPA. The improved safety profile of Tenecteplase likely reflects its
enhanced fibrin specificity.
■
■RETEPLASE
Reteplase is a single-chain, recombinant tPA derivative that lacks the
finger, epidermal growth factor, and first kringle domains (Fig. 123-9).
This truncated derivative has a molecular weight of 39,000. The affinity
of reteplase for fibrin is lower than that of tPA likely because reteplase
lacks the finger domain. Because it is produced in Escherichia coli,
reteplase is not glycosylated. This endows it with a plasma half-life lon­
ger than that of tPA. Consequently, reteplase is given as two IV boluses,
which are separated by 30 min. Clinical trials have demonstrated that
reteplase is at least as effective as streptokinase for treatment of acute
MI, but the agent is not superior to tPA.
CONCLUSIONS AND FUTURE DIRECTIONS
Thrombosis involves a complex interplay among the vessel wall,
platelets, the coagulation system, and the fibrinolytic pathways. Acti­
vation of coagulation also triggers inflammatory pathways that may
exacerbate thrombosis. A better understanding of the biochemistry of
blood coagulation and advances in structure-based drug design have
identified new targets and resulted in the development of novel anti­
thrombotic drugs. Well-designed clinical trials have provided detailed
information on which drugs to use and when to use them. Despite
these advances, however, thromboembolic disorders remain a major
cause of morbidity and mortality. Therefore, the search for better and
safer targets continues.
PART 4
Oncology and Hematology
■
■FURTHER READING
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