# 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