13.3.2 Thyroid cancer 2302
13.3.2 Thyroid cancer 2302
SECTION 13 Endocrine disorders
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13.3.2 Thyroid cancer
Kristien Boelaert and Anthony P. Weetman
ESSENTIALS
Thyroid cancers are the most common endocrine malignancies and
their incidence is rising globally, largely due to significant increases in
small, incidentally detected low-risk tumours.
Follicular epithelial cell cancer—the commonest type; usually well
differentiated tumours with an excellent prognosis but occasionally
highly undifferentiated; may be induced by exposure to ionizing ra-
diation; typically present with asymptomatic thyroid enlargement;
usually diagnosed by ultrasonography and fine needle aspiration bi-
opsy; treatment is typically by hemi-or total thyroidectomy, followed
by radio-iodine ablation (administered to remove any remaining
thyroid tissue) and short- to longer-term thyroid-stimulating hor-
mone suppression depending on clinical risk stratification
Medullary thyroid carcinoma—arises from parafollicular C cells;
comprises 3–5% of all thyroid cancers; hereditary autosomal dom-
inant forms associated with germline point mutations in the RET
proto-oncogene; occurs in 20% as part of multiple endocrine
neoplasia (MEN) type 2A or 2B, or as isolated familial medullary
carcinoma; typically presents with a solitary thyroid nodule, accom-
panied in 50% of cases by cervical lymphadenopathy; can be asso-
ciated with unusual hormonal effects, including secretory diarrhoea;
diagnosis often made by fine needle aspiration biopsy and by raised
serum calcitonin concentration; treatment is by total thyroidectomy
(requiring long-term thyroid hormone replacement) and neck dis-
section (if required), followed by monitoring of serum calcitonin
levels and tyrosine kinase inhibitors in advanced cases; Genetic
testing for the presence of RET mutations allows family testing, with
prophylactic thyroidectomy recommended for affected individuals.
Rare thyroid tumours—include (1) anaplastic carcinomas—present as a
rapidly enlarging and fixed thyroid masses, sometimes with local pain; rap-
idly fatal; (2) sarcomas; and (3) primary lymphomas— usually present as a
rapidly enlarging thyroid mass in a patient with Hashimoto’s thyroiditis.
Primary thyroid follicular epithelial tumours
Aetiology
Differentiated thyroid cancers are the most common tumours
arising from thyroid follicular epithelial cells and account for 95% of
all thyroid carcinomas (Table 13.3.2.1).
Papillary carcinomas
Around 85% of all thyroid cancers are papillary carcinomas, and
these carry the best prognosis. Most of these tumours are indo-
lent and harbour mutually exclusive mutations of genes encoding
effectors that signal through the mitogen-activated protein kinase
(MAPK) pathway. BRAF V600E accounts for 60% of these muta-
tions, followed by RAS (15%) and chromosomal rearrangements
(12%) including RET, NTRK, and ALK resulting in aberrant expres-
sion of BRAF or of receptor tyrosine kinases. The remaining 13%
have no known driver mutations. Different mutations are associated
13.3.2 Thyroid cancer 2303 with varying histological subtypes of papillary thyroid cancers and confer distinct patterns of gene expression, signalling, and clinical characteristics. BRAF-mutated papillary thyroid cancers tend to be more aggressive with high frequency of lymph node metastases and recurrence rates. Exposure to ionizing radiation is a risk factor for the devel- opment of papillary thyroid cancer and sharp increases in the incidence of these tumours, especially in young children, were observed following the nuclear reactor accident in Chernobyl in 1986 and following the atomic bomb explosions in Hiroshima and Nagasaki in 1945. Radiation-induced papillary cancers have a high prevalence of fusion oncogenes activating RET or NTRK and RET/ PTC3 is particularly linked to radiation. Low-dose external beam radiation (10–1500 cGy) to the head and neck increases the risk of papillary thyroid cancer over 10 to 30 years. Higher thyroid radi- ation doses, including those arising from radio-iodine given for treatment of hyperthyroidism, are not associated with an increased risk of malignancy because thyroid cells are destroyed rather than transformed. Mutations in the TERT gene have been identified in more aggressive subsets of papillary cancers. Follicular carcinomas Follicular thyroid cancers account for 2–5% of thyroid cancers and usually harbour mutations of either RAS or the PAX8-PPARG fu- sion oncogene. These tumours are also more prevalent in areas of iodine-deficiency and excessive stimulation of thyroid cell growth by thyrotropin (TSH) plays a role in their pathogenesis. Rarely fol- licular carcinomas are associated with activating mutations of the genes encoding the TSH receptor or Gsα protein, similar to those found in toxic adenoma, and it is thought that some follicular carcinomas arise from adenomas. The prognosis of patients with follicular cancers depends on the size of the tumour, the patient’s age, and the degree of angioinvasion which predicts the risk of dis- tant metastases. Hürthle cell cancers These are classified as a variant of follicular carcinomas and are genetically distinct. They may be widely invasive and may behave aggressively, with lung and bone metastases and refractoriness to radio-iodine. Anaplastic carcinomas These may arise from and can coexist with differentiated cancers but can also occur de novo. They have been linked to mutations in TP53 (p53 tumour suppressor gene), the TERT promoter, effectors of the phosphatidylinositol 3-kinase (PI3K)-AKT, mammalian target of rapamycin (mTOR), and genes involved in epigenetic regulation. Germline mutations Several germline variations in chromosomes 9q22.23 and 14q13.3 have been linked with high risk of differentiated thyroid cancers, due to their proximity to genes encoding proteins involved in regulating thyroid development and differentiation including FOXE1 and NKX2-1. Familial forms of papillary and follicular carcinomas exist but are unusual (3–9% of cases), including Cowden’s disease (mul- tiple hamartoma syndrome associated with PTEN mutations OMIM 158350), familial adenomatosis polyposis, including the Gardner syndrome variant (associated with loss of function mutations in the APC gene OMIM 175100), and Werner’s syndrome (adult pro- geria associated with mutation in the WRN gene). Other familial forms may be found in Peutz–Jeghers syndrome (OMIM 175200), the Carney complex (OMIM 160980), and ataxia–telangiectasia (OMIM 208900). Epidemiology Thyroid cancer incidence rates have increased dramatically in most Westernized countries and between 2014–2016 there were an average of 3527 new diagnoses annually in the United Kingdom, rep- resenting more than 155% rise since the early 1990s. In the United States, the incidence of thyroid cancer has more than tripled from 1975 through to 2015, and it is estimated that there will be 52 070 new thyroid cancer cases and 2170 deaths from the disease in 2019. Thyroid cancer is about three times more common in women than in men, and the peak incidence is between 30 and 50 years of age. Most of the recent increase in disease burden is due to the inci- dental detection of small, low-risk tumours, although there is some evidence that other factors including ionizing radiation, obesity, and environmental pollutants may be contributing factors. Papillary microcarcinomas, defined as tumours less than 1 cm in diameter, occur in up to 36% of autopsy specimens and up to 24% of surgical thyroidectomies. Clearly most of these do not significantly impact on long-term outcomes and life expectancy. Clinical features Most patients present with thyroid enlargement in the form of a thy- roid nodule, which is often asymptomatic. This may be noticed by the patient or their relatives, or sometimes the abnormality is de- tected during physical examination for another complaint. The diffi- culty for diagnosis arises because thyroid nodules are frequent, and only about 5% of palpable thyroid nodules are malignant. Diffuse or multinodular thyroid enlargement occurs in around 10% of the population and is four times more common in women than in men. Between 4 and 7% of adults have visible thyroid nodules and these are usually hyperplastic or colloid nodules. Overall, the prevalence of malignancy in thyroid nodules is estimated between 4 and 6.5%. There are usually no symptoms or signs to distinguish benign from malignant nodules because most cancers progress slowly and Table 13.3.2.1 Classification of thyroid malignancies Primary thyroid follicular epithelial tumours Differentiated (papillary, follicular, Hürthle cell) Poorly differentiated Undifferentiated (anaplastic) C-cell epithelial tumours (medullary carcinoma) Primary nonepithelial tumours Lymphoid origin (lymphoma, plasmacytoma) Mesenchymal cell origin (sarcoma) Other (teratoma) Secondary nonthyroidal tumours Metastases Extension of tumour from adjacent structures
SECTION 13 Endocrine disorders 2304 present before disease is advanced. Clinical parameters associated with increased risk of malignancy include male sex and being at the extremes of age (less than 20 or over 60 years). Previous exposure to radiation and a family history of thyroid cancer should also arouse suspicion. A carcinoma is more likely if thyroid enlargement has grown recently or is hard, irregular, or fixed on palpation. Clinical assessment should include careful examination of the cer- vical, submental, and supraclavicular lymph nodes. Late-presenting features include hoarseness, dysphagia, or dyspnoea which may in- dicate local invasion, but these symptoms can occasionally occur with an enlarging benign goitre. Rarely the diagnosis only becomes apparent when metastatic disease is detected in bone or lung. The relatively indolent presentation of papillary and follicular thyroid carcinoma contrasts with that of anaplastic carcinoma, in which a rapidly enlarging and fixed thyroid mass occurs, sometimes with local pain. Extension to the oesophagus, trachea, and/or recur- rent laryngeal nerves is frequent, and the overlying skin may also be infiltrated. Pathology Papillary carcinomas There are several variants of papillary thyroid carcinoma united by their characteristic cytological features. The nuclei are large, clear (‘Orphan Annie’, after the eyes of the cartoon character), and have lon- gitudinal grooves and invaginations of cytoplasm causing a papillary growth pattern (Fig. 13.3.2.1a). One-half of papillary carcinomas contain degenerate calcified papillae, termed psammoma bodies. The tumour is multicentric in up to 80% of cases if the resected thy- roid is examined carefully. Metastasis is via the lymphatics and local lymph nodes are infiltrated in 40 to 50% of cases (more in young patients). Distant metastases are found in less than 5% of patients at presentation, with the lung being the most common site. There are more than 10 different variants of papillary thyroid cancer and those with a less favourable outcome include tall cell, col- umnar cell, and hobnail variants. These tumours generally present at a later age and more advanced stage than classical-type papillary thyroid cancer. Data regarding outcomes of solid variant and scler- osing (including diffuse sclerosing) variants remain controversial. The follicular variant of papillary thyroid carcinoma is a tumour composed of neoplastic follicles rather than papillae, but with fol- licular cells showing nuclear features characteristic of papillary thyroid cancer. There are two main subtypes: infiltrative (non- encapsulated) and encapsulated. The latter form has increased in incidence by an estimated 2-to 3-fold over the past two to three decades and makes up 10–20% of all thyroid cancers currently diagnosed in Europe and North America. These tumours have a very low risk of adverse outcomes and are now termed noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). No additional treatment with surgery or radio-iodine ab- lation is required for these tumours, and no further pathological staging is needed. Follicular carcinomas Follicular carcinoma is characterized by follicular differentiation with a solid growth pattern and without the nuclear features of pap- illary carcinoma. The tumour is encapsulated, but there is invasion of the capsule and vessels, thereby distinguishing it from a follicular adenoma (Fig. 13.3.2.1b). They may be minimally invasive when there is only microscopic capsular invasion, or angioinvasive when there is vascular invasion. The former are indolent tumours with 10-year mortality rates of less than 5%, whereas the latter are asso- ciated with mortality rates of 5–30% depending on the number of invaded blood vessels. (a) (b) (c) Fig. 13.3.2.1 Histopathological features of thyroid follicular epithelial carcinoma. (a) Papillary carcinoma, with psammoma bodies and typical nuclear appearance. (b) Metastatic follicular carcinoma, eroding vertebral bone. (c) Anaplastic carcinoma showing pleomorphic spindle cells. All sections, original magnification ×200. Photomicrographs by courtesy of Dr K. Suvarna.
13.3.2 Thyroid cancer 2305 Hürthle cell cancers Oncocytic (Hürthle cells) cells are characterized by oxyphilic staining due to mitochondrial accumulation, resulting in abundant eosinophilic granular cytoplasm and hyperchromatic nuclei. They are classified into Hürthle cell adenomas or Hürthle cell carcinomas, depending on the presence or absence of capsular and vascular invasion. Poorly differentiated and anaplastic carcinomas Poorly differentiated thyroid cancers are aggressive tumours with partial loss of features of thyroid differentiation occupying a pos- ition between well-differentiated thyroid tumours and completely dedifferentiated anaplastic cancers. They are associated with poor outcomes and 10-year survival rates are around 50%. In anaplastic carcinoma there is no capsule, the cells are atypical, including spindle, multinuclear, and squamoid forms, and mitoses are frequent (Fig. 13.3.2.1c). Investigation and diagnosis Blood tests Thyroid epithelial cancers generally fail to affect thyroid function, but this should be evaluated in all patients presenting with a thyroid nodule; a low circulating TSH concentration strongly suggests an autonomous benign nodule. Anaplastic carcinoma may occasionally cause hypothyroidism, but the most frequent cause of an elevated TSH concentration with a hard, nodular thyroid is Hashimoto’s thyroiditis. Some of the glands in these cases are so irregular that the presence of malignancy may be suspected. Differentiated thy- roid cancer is more common in patients with autoimmune thyroid disease—both Graves’ disease and Hashimoto thyroiditis—and thyroid lymphoma almost always occurs in association with auto- immune thyroiditis. Any dominant or atypical area in a Hashimoto’s goitre therefore requires careful evaluation. Thyroid peroxidase and/or thyroglobulin antibodies are raised in about one-quarter of patients with thyroid follicular epithelial carcinoma, coincident with the presence of a lymphocytic infil- trate which, in turn, is associated with a slightly more favourable prognosis. Although measurement of serum thyroglobulin concentrations is extremely useful in follow-up, as discussed next, this investi- gation is unhelpful in diagnosing thyroid cancer; levels may not be elevated in some patients and, even when elevated, cannot be causally distinguished from those that occur in benign adenoma, multinodular goitre, Graves’ disease, destructive thyroiditis, or Hashimoto’s. Imaging Thyroid nodules may be detected in up to 60% of adults when using high resolution ultrasonography, and they are found incidentally in 16% of cross-sectional CT or MRI scans, 10% of carotid Doppler investigations, and 2–3% of positron emission tomography (PET) scans. FDG-PET positive nodules carry a higher risk of malignancy and require further evaluation. Several ultrasonographic criteria are associated with a higher suspicion for malignancy: current guide- lines combine these into algorithms guiding practitioners regarding the selection of thyroid nodules that warrant further evaluation with fine needle aspiration biopsy. Ultrasonography High-resolution ultrasonography is a very sensitive tool to diag- nose thyroid malignancy and may be specific for the identification of papillary thyroid cancer. Most current guidelines recommend ultrasonography, performed by a competent operator, as the first line imaging tool in patients presenting with thyroid enlargement (Figs. 13.3.2.2 and 13.3.2.3). Ultrasonographic features associated with a higher risk of malignancy are illustrated in Table 13.3.2.2. Ultrasonographic features should be used in summation to identify thyroid lesions that may be malignant and warrant fine needle aspiration biopsy (FNAB). Ultrasonography also increases the yield of FNAB. The presence or absence of abnormal cervical lymph nodes should be documented when undertaking thyroid ultrasonography. Fig. 13.3.2.2 Ultrasound appearances of a cystic thyroid nodule with tiny echogenic foci with subtle ‘ring-down’ or ‘comet tail’ artefact (arrow) due to inspissated colloid. From Scoutt LM, Hamper UM, Angtuaco TL (eds) (2016). Ultrasound. By permission of Oxford University Press, USA. Fig. 13.3.2.3 Ultrasound appearances of papillary thyroid carcinoma. There is a large, solid nodule in the inferior pole of the right lobe of the thyroid with punctate echogenic, nonshadowing microcalcifications (arrows); T, normal thyroid parenchyma. From Scoutt LM, Hamper UM, Angtuaco TL (eds) (2016). Ultrasound. By permission of Oxford University Press, USA.
SECTION 13 Endocrine disorders 2306 In the United Kingdom, a scoring system of U1-5 is recommended to classify thyroid nodules based on ultrasound findings: U1: normal thyroid; U2: benign thyroid lesion; U3: indeterminate thyroid lesion (likely follicular lesion); U4: suspicious thyroid lesion; U5: diag- nostic for thyroid cancer. Nodules graded as U3-5 warrant further cytological evaluation. The US guidelines recommend use of similar system classifying thyroid nodules as benign, very low, low, inter- mediate, or high risk of malignancy, and also take nodule size into account when selecting nodules that warrant FNAB. Radionuclide scanning Radionuclide scanning with 99mTc pertechnetate or radio-iodine (123I or 131I) may be indicated if patients have thyroid enlargement and a low serum TSH concentration. The presence of a ‘hot’ nodule taking up significant amounts of radionuclide with failure of the sur- rounding tissue to take up the tracer is consistent with the presence of an autonomous nodule which is almost invariably benign. Most thyroid cancers fail to take up radionuclide (‘cold’ nodules), but benign lesions may behave in a similar way. Overall radionuclide scanning is not routinely recommended to diagnose thyroid cancer. Fine needle aspiration biopsy Fine needle aspiration biopsy and subsequent cytological evaluation remains the gold standard for the diagnosis of thyroid cancer, with sensitivity and specificity rates of more than 90%. This is now usually performed under ultrasound guidance. In the United Kingdom, the use of the ‘THY classification’ is re- commended: THY1: nondiagnostic (insufficient cells sampled); THY2: nonneoplastic; THY3: neoplasm possible, which is further sub- divided into THY3a: atypical features present, and THY3f: follicular neoplasm; THY4: suspicious of malignancy and THY5: diagnostic of thyroid cancer. US guidelines recommend the use of the Bethesda clas- sification, which is very similar to the United Kingdom system. Surgery is usually required for lesions classified as THY3f, THY4, and THY5 and repeat biopsy should be undertaken for THY1 and THY3a nodules. In all cases the clinical, ultrasonographic, and cytological findings should be considered together and where ap- propriate should be discussed in a multidisciplinary team (MDT) setting, especially if there is nonconcordance between findings. Papillary carcinoma is readily diagnosed by fine needle aspir- ation biopsy, and medullary carcinoma and lymphoma can also be detected by the use of immunohistochemical staining, although lymphoma frequently requires core or open biopsy for confirmation. Follicular carcinomas cannot be distinguished cytologically from follicular adenomas and are usually labelled as THY3F. Many pa- tients with these lesions will undergo diagnostic hemithyroidectomy. However, there is a rapidly growing body of literature describing the use of gene expression classifiers, mutation analysis panels, and protein expression chips to distinguish benign from malignant fol- licular lesions. Some centres, especially in the United States, use mo- lecular analysis of FNAB specimens routinely in decision-making processes regarding the recommendation of surgery for these in- determinate lesions, although this is not common practice in the United Kingdom and most European countries. Thyroid cysts are usually benign and may be aspirated during bi- opsy, although reaccumulation of fluid is common and may indicate presence of malignancy; if this occurs, surgery is usually required for definitive diagnosis. Management of differentiated thyroid cancer Surgical excision The initial form of treatment is surgery, which should be performed by a surgeon with the required training and expertise who is a core member of the multidisciplinary team. Assessment of extrathyroidal extension and presence (or absence) of central compartment and lateral neck lymph node disease through ultrasonography and cross- sectional imaging with CT or MRI is recommended. Thyroid lobectomy is recommended for patients with unifocal papillary microcarcinoma (<1 cm) with no other risk factors. Total thyroidectomy and central compartment lymph node dis- section is recommended for patients with tumours greater than 4 cm in diameter or tumours of any size if associated with any of the following characteristics: multifocal disease, bilateral disease, extrathyroidal spread (pT3 and pT4a), positive familial history, clinically or radiologically involved lymph nodes and/or distant metastases. Tumours between 1 and 4 cm in maximum diameter may be treated with lobectomy or total thyroidectomy, depending on judge- ment by the multidisciplinary team taking additional risk factors into account. Lobectomy is deemed sufficient and central lymph node dissection unnecessary for tumours between 1 and 4 cm in patients aged less than 45 years, with unifocal classical type papillary cancer, without a positive family history, and without extrathyroidal spread or lymph node metastases. Neck dissection is indicated if there is clinical or radiological evidence of lateral compartment lymph node involvement. Postoperative risk stratification UK and US guidelines recommend postoperative staging using the TNM classification (Table 13.3.2.3)/AJCC (American Joint Commission on Cancer) system (Table 13.3.2.4). This classification system predicts the risk of death from dis- ease and is a valuable indicator of overall prognosis, but it does not take individual responses to treatment into account, which may alter prognosis or the risk of recurrence. The British and American Thyroid Association guidelines therefore recommend the use of a three-tier system to predict postoperative risk of re- currence (Table 13.3.2.5). Table 13.3.2.2 Ultrasonographic features of benign and malignant thyroid nodules Benign nodule Malignant nodule Follicular lesion Spongiform/ honeycomb Solid and hypoechoic Hyperechoic/ homogeneous halo benign Purely cystic Irregular margin Hypoechogenicity/loss of halo suspicious Egg shell calcification Intranodular vascularity Iso/hyperechoic (hypoechoic halo) Absence of halo Peripheral vascularity Taller than wide Microcalcifications
13.3.2 Thyroid cancer
2307
Radio-iodine remnant ablation and therapy
for differentiated thyroid cancer
After surgery, radio-iodine is usually administered to remove any
remaining thyroid tissue, which then allows thyroglobulin or 131I
total body scanning to be used in follow-up to detect metastases.
This treatment may also destroy occult carcinoma and, by scan-
ning after ablation, metastatic disease is revealed. Similar to the
multidisciplinary approach recommended for decision-making re-
garding the extent for surgery, a risk-based approach is now recom-
mended when selecting patients requiring radio-iodine remnant
ablation. Patients in the definite indications category are those with
tumours more than 4 cm or tumours of any size with gross thyroidal
extension (pT4) or distant metastases. Remnant ablation is not in-
dicated in patients with tumours not more than 1 cm, unifocal or
multifocal, and in cases where histology reveals classical papillary
or follicular variant or minimally invasive follicular tumours (i.e.
without capsular or angioinvasion).
Indications to treat tumours between 1 and 4 cm with 131-I ab-
lation remain uncertain and MDT discussion and decision-making
is required. Factors favouring intervention include tumours more
than 2 cm, unfavourable histological subtype, widely invasive tu-
mours, more than five resected metastatic lymph nodes, resected
lymph nodes more than 6 mm in maximum diameter, ratio of
positive/negative nodes more than 0.7 and extracapsular nodal
involvement.
Results from two large randomized controlled trials have shown
that an ablative 131-I dose of 1.1 GBq is as effective as 3.7 GBq for
low to intermediate risk tumours, with fewer adverse effects in the
1.1 GBq group. It is recommended that patients with T1-2 and R0 re-
section should receive the lower dosage. For patients with pT3 and/
or N1 disease, the activity of 131-I should be decided by the MDT
on an individual case basis taking all prognostic factors into account.
Iodine exposure, including iodine-containing contrast media, may
prevent accumulation of 131I during treatment. Guidelines regarding
implementation of a low iodine diet prior to radio-iodine ablation
have recently been devised in the United Kingdom (see ‘Further
reading’).
High levels of stimulation by TSH (>30 mU/litre) are required
to produce maximum uptake of 131I. This may be achieved by
levothyroxine withdrawal for 4 weeks, resulting in development of
severe hypothyroid symptoms, or by the administration of recom-
binant human TSH (rhTSH) for 48 hours prior to administration
of radio-iodine, thereby avoiding the need for cessation of thyroid
hormone replacement. If thyroid hormone withdrawal is used, pa-
tients are usually switched to the shorter-acting liothyronine (20 µg
three times daily) as replacement therapy 28 days before 131-I abla-
tion and this treatment is then discontinued 14 days before radio-
iodine administration. Randomized controlled trials have shown
Table 13.3.2.3 TNM classification of thyroid cancer (adapted
from 2014 BTA Guidelines for the management of thyroid cancer)
Primary tumour—T
Tx
Primary tumour cannot be assessed
T0
No evidence of primary tumour
T1
Tumour ≤2 cm limited to the thyroid
T2
Tumour >2 cm but ≤4 cm limited to the thyroid
T3
Tumour >4 cm limited to the thyroid or any tumour with minimal
extrathyroidal extension
T4a
Tumour of any size beyond the thyroid capsule and invading
surrounding tissues
T4b
Tumour invades prevertebral fascia or encases carotid artery or
mediastinal vessels
Regional lymph nodes (cervical and upper mediastinal)—N
Nx
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastases
N1
Regional lymph node metastases
N1a
Metastases to Level VI (pretracheal, paratracheal, and prelaryngeal/
Delphian lymph nodes)
N1b
Metastases to unilateral, bilateral, or contralateral cervical (levels I, II,
III, IV, or V) or retropharyngeal or superior mediastinal lymph nodes
(level VII)
Distant metastases—M
M0
No distant metastases
M1
Distant metastases
Residual tumour—R
Rx
Cannot assess presence of residual primary tumour
R0
No residual primary tumour
R1
Microscopic residual primary tumour
R2
Macroscopic residual primary tumour
Based on the TNM classification tumours are then staged as follows (AJCC/UICC staging
system, Table 13.3.2.4).
Table 13.3.2.4 Staging of differentiated (papillary and follicular)
thyroid carcinomas (adapted from 2014 BTA guidelines for the
management of thyroid cancer)
Patients aged <55
Patients aged ≥55 y
Stage
TNM
description
Stage
TNM
description
I
Any T, any N, M0
I
T2, N0, M0
II
Any T, any N, M1
II
Any T, N1, M0
III
T4a, any N, M0
IVa
T4b, any N, M0
IVb
Any T, any N, M1
Table 13.3.2.5 Postoperative risk stratification for risk of recurrence
of differentiated thyroid cancer (adapted from 2014 BTA Guidelines
for the management of thyroid cancer)
Low risk
Intermediate risk (any)
High risk (any)
No local/distant
metastases
Microscopic tumour
invasion (perithyroidal
soft tissues T3)
Extrathyroidal invasion
All macroscopic
tumour resected
(R0/R1)
Cervical lymph node
metastases N1a/N1b
Incomplete tumour
resection (R2)
No locoregional
tumour invasion
No aggressive
histological features
Aggressive histology,
e.g. Tall cell, insular or
angioinvasion
Distant metastases (M1)
SECTION 13 Endocrine disorders 2308 equal efficacy of 131-I remnant ablation when using thyroid hor- mone withdrawal and rhTSH, with improved quality of life in the rhTSH group due to absence of troublesome hypothyroid symp- toms. The use of rhTSH is therefore recommended in patients with low to intermediate risk tumours (pT1 to pT3, pN0 or Nx, or N1 and M0 and R0). Radio-iodine-avid thyroid cancer metastases may be treated with further radio-iodine therapy; doses between 3.7 and 5.5 GBq are usually administered. Dynamic risk stratification Patients who have undergone total thyroidectomy and remnant ablation with radio-iodine should undergo dynamic risk stratifica- tion to define the response to initial therapy. This is usually done 9–12 months following treatment, when patients are recommended to have a neck ultrasound and measurement of rhTSH stimulated thyroglobulin (Tg). Subsequent intensity and duration of follow-up, as well as targets for TSH suppression, is then based on the assign- ment of patients to different response groups: excellent, indeter- minate, or incomplete response (Table 13.3.2.6). Long-term levothyroxine replacement therapy Following thyroidectomy, it is necessary to maintain euthyroidism through lifelong levothyroxine replacement in all patients who have undergone a total thyroidectomy and, in some patients, fol- lowing lobectomy. Suppression of serum TSH is required in inter- mediate and high-risk patients since thyrotropin is a growth factor for thyroid cells. Following initial treatment with surgery and radio-iodine rem- nant ablation, and before dynamic risk stratification, serum TSH should be suppressed below 0.1 mIU/litre. It is unnecessary to suppress serum TSH in subjects who have undergone less than total thyroidectomy and in those who have not undergone rem- nant ablation. In patients who are stratified into the excellent response category following dynamic risk stratification, serum TSH can be maintained in the lower half of the normal reference range (0.3–2.0 mIU/litre). For historic patients who have not undergone dynamic risk stratification, it is appropriate to keep serum TSH suppressed below 0.1 mIU/litre for 5–10 years and then to allow serum TSH to rise to the lower half of the normal reference range if there is no evidence of recurrence either bio- chemically or structurally. The long-term consequences of serum TSH concentrations suppressed below 0.1 mIU/litre include car- diovascular morbidity and mortality as well as osteoporosis, and evaluation of probability of osteoporotic fragility fracture risk may be required. Systemic therapies for metastatic radio-iodine-refractory thyroid cancer Metastatic thyroid cancer occurs in less than 10% of patients, about two-thirds of whom ultimately present with radio-iodine refractory disease. If patients have radio-iodine avid disease, repeated adminis- tration of radio-iodine therapy every 4–6 months may be beneficial, especially if lung metastases are present. There is little benefit above a cumulative dose of 18.5 GBq. Bone metastases may respond to 131I or external beam radiotherapy, and orthopaedic intervention may be required to stabilize pathological fractures. Palliative external beam radiotherapy has a limited role in controlling locoregional dis- ease when further surgery is ineffective or impractical. Radiotherapy can be used alone or in combination with low-dose chemotherapy. Targeted therapies Improved understanding of the molecular pathogenesis of thyroid cancer has resulted in an explosion of targeted therapies in patients with advanced metastatic thyroid cancer. Two multikinase inhibi- tors, sorafenib and lenvatinib, have been approved for the treat- ment of radio-iodine refractory tumours on the basis of prospective, double-blind randomized placebo-controlled trials that showed longer progression-free survival. Lenvatinib appears to have the greatest efficacy. Significant adverse effects of both drugs often make the maintenance of full dose therapy a challenge. Common adverse effects include hypertension, hand–foot skin reactions, diarrhoea, rash, fatigue, weight loss, and stomatitis. Longer-term effects on quality of life and cumulative toxic effects of these agents remain to be determined. Phase 2 trials using several other multikinase inhibitors have commenced, including sunitinib, pazopanib, axitinib, cabozantinib, and motesanib, all of which have multifunctional actions including antiangiogenic properties. Targeted therapies including RAF-kinase inhibitors used alone or in combination with MEK inhibitors are also being explored in several combination trials. Treatment with selumetinib, a MAPK kinase (MEK) 1 and MEK2 inhibitor, has been shown to produce a clinically meaningful increase in radio- iodine uptake in tumours previously refractory to radio-iodine treatment through loss of the sodium iodide symporter, particu- larly those with a RAS mutation. This is a rapidly developing field and more trials will help address how best to stratify patients for treatment. Follow-up Lifelong follow-up is necessary for papillary and follicular cancer because they may recur many years after apparent cure. As well as monitoring the concentration of serum TSH and performing Table 13.3.2.6 Dynamic risk stratification determining response to treatment (adapted from 2014 BTA Guidelines for the management of thyroid cancer) Excellent response Indeterminate response Incomplete response All the following: Suppressed and stimulated Tg <1 mcg/litre - Neck USS without evidence of disease - Cross-sectional and/or nuclear medicine imaging negative (if performed) Any of the following: Suppressed Tg <1 mcg/ml and stimulated Tg ≥1 and <10 mcg/litre - Neck USS with nonspecific changes or stable lymph nodes (<1 cm) - Cross-sectional and/or nuclear medicine imaging with nonspecific changes, not completely normal Any of the following: Suppressed Tg ≥1 mcg/litre or stimulated Tg ≥10 mcg/litre - Rising Tg values - Persistent or newly identified disease on cross- sectional and/or nuclear medicine imaging USS, ultrasound scan.
13.3.2 Thyroid cancer 2309 careful neck palpation, serum thyroglobulin should be measured. Detectable levels of thyroglobulin after thyroid ablation indicate persistent or recurrent disease. Measuring thyroglobulin levels is especially valuable when the patient is not taking thyroxine replacement, or after recombinant TSH stimulation, as the rise in TSH will promote thyroglobulin production and exaggerate any increase. The use of rhTSH stimulated thyroglobulin is recom- mended as part of dynamic risk stratification, but for low-risk patients (i.e. those who have not undergone radio-iodine rem- nant ablation and those assigned to the excellent response dy- namic risk stratification category), it is appropriate to measure unstimulated Tg while the patient is on levothyroxine therapy. The presence of thyroglobulin antibodies may interfere with thyroglobulin measurements on most assays, hence these anti- bodies should be evaluated by a quantitative method whenever serum Tg is measured. If thyroglobulin is detectable, the patient should have a total body 131I scan and any recurrent disease can then be treated with a therapeutic dose of radioactive iodine (Fig. 13.3.2.4). If the total body scan is negative and serum Tg is consistently raised, cross-sectional imaging and occasionally FDG-PET scanning is indicated. Prognosis Differentiated thyroid cancer Most papillary thyroid cancers are indolent tumours and have an excellent prognosis, with 10-year relative survival rates of more than 98% (Table 13.3.2.7). The risk of death increases with age, hence most prognostic scoring systems take age into account. The 10-year cause-specific survival rate is lower in those with follicular carcinoma, especially if angioinvasion is present, and is only 50% in those with poorly differentiated tumours. Patients who present with or develop metastatic disease (around 10–15% of patients) have poor survival rates which are less than 10% at 10 years, especially in those whose disease becomes refractory to radio-iodine. Anaplastic carcinoma Anaplastic carcinoma (Fig. 13.3.2.5) is usually rapidly fatal. Initial as- sessment should focus on the identification of the small proportion of patients with localized disease and good performance status that Fig. 13.3.2.4 131I scans of three patients. Patient A had undergone near-total thyroidectomy three months previously: two foci of remnant thyroid tissue remain in the neck. Patients B and C had both had thyroidectomy followed by 131I therapy two years previously and been found to have elevated serum thyroglobulin on routine monitoring. In patient B there are numerous iodine-avid lymph node metastases in the neck/mediastinum and bilateral pulmonary metastases. No iodine-avid disease is identified in patient C where there is physiological iodine accumulation in salivary glands, saliva, nasal secretions, and stomach, with excreted iodine in bowel and urinary tract. From Kim CK (ed) (2015). Nuclear medicine and PET/CT cases. By permission of Oxford University Press, USA. Table 13.3.2.7 Ten-year relative survival for differentiated thyroid cancer (adapted from 2014 BTA Guidelines for the management of thyroid cancer) Stage 10-year relative survival (%) I 98.5 II 98.8 III 99.0 IVA 75.9 IVB 62.5 IVC 63
SECTION 13 Endocrine disorders 2310 may benefit from surgical resection and other adjuvant therapies. Surgery may help to relieve obstructive symptoms and external beam radiotherapy is useful in palliation, but the tumour does not take up radio-iodine. The place of chemotherapy (usually doxorubicin com- bined with other drugs) remains unclear. The median survival time for anaplastic carcinoma is 4 to 12 months and those with distant me- tastases at presentation have a median survival time of only 3 months. Prevention In the event of a nuclear accident, prompt administration of stable iodine prevents the uptake of inhaled and ingested radioactive iodine isotopes. Emergency arrangements should be in place close to nuclear installations to provide for distribution of potassium iodate tablets. Advice is available from the World Health Organization (see ‘Further reading’). Special problems in pregnancy A solitary nodule in a pregnant woman should be evaluated by ultra- sonography and fine needle aspiration biopsy. If the biopsy suggests malignancy and the nodule is growing significantly, or if lymph node metastases develop, surgery can be undertaken in the second trimester, but otherwise this is best deferred until after delivery. Regular ultrasound surveillance is required in patients with newly diagnosed thyroid cancer who do not undergo surgery during preg- nancy. Breastfeeding should be discontinued at least 8 weeks before radio-iodine remnant ablation, and pregnancy should be avoided for 6 to 12 months following radio-iodine treatment. The preconception TSH goal in women with pre-existing differ- entiated thyroid cancer, which is determined by risk stratification, should be maintained during pregnancy. It is likely that higher doses of levothyroxine will be required to achieve this. Medullary carcinoma of the thyroid Epidemiology and pathology Medullary carcinoma accounts for 3–5% of all thyroid cancers. About 80% are sporadic with a peak incidence at 40 to 60 years of age. Hereditary autosomal dominant forms occur as part of multiple endocrine neoplasia type 2A (MEN2A) or type 2B (MEN2B) or as isolated familial medullary carcinoma. These forms are associated with germline point mutations in the RET proto-oncogene (different from those in papillary carcinoma) and preneoplastic C-cell hyper- plasia (Table 13.3.2.8). (a) (b) Fig. 13.3.2.5 MRI and CT appearances of anaplastic thyroid carcinoma. Panel (a): transverse fat-saturated T2-weighted MRI image demonstrating a large right-sided mass involving the right thyroid lamina and extending around the posterior margin of the cartilage towards the larynx. Panel (b): CT (bone windows) on the same patient demonstrating the markedly abnormal involved right thyroid lamina with ill definition, permeative destruction, and reactive sclerosis. From Hoskin P, Goh V (eds) (2010). Radiotherapy in practice—imaging. By permission of Oxford University Press. Table 13.3.2.8 Types of medullary carcinoma of the thyroid Type Frequency (%) Associated lesions RET gene mutation Sporadic 80 None RET (in approximately 50%), HRAS, NRAS, or KRAS (in 0–43%) MEN2A 10 Phaeochromocytoma (20–50%), hyperparathyroidism (12–30%) Hirschsprung disease or cutaneous lichen amyloidosis in some 95% of RET mutations in exon 10 (codon 609, 611, 618 or 620) or exon 11 (codon 634) MEN2B 3 Phaeochromocytoma, mucosal neuromas, marfanoid habitus, typical facies, medullated corneal nerves, and aerodigestive tract ganglioneuromatosis RET M918T mutation in more than 95% and RET A833F in the remainder Familial medullary thyroid carcinoma 7 None Broad range of RET mutations MEN, multiple endocrine neoplasia.
13.3.2 Thyroid cancer 2311 The pathological findings are of an encapsulated tumour with round, spindle-shaped, or polyhedral cells arranged in a variety of patterns that have no prognostic significance. There is vari- able fibrosis and three-quarters of tumours show marked depos- ition of amyloid—a feature associated with a good prognosis. Heterogeneous staining for calcitonin, a hormone of C cells, is as- sociated with a poorer outcome, reflecting dedifferentiation. Even the smallest medullary tumours may be associated with local lymph node metastases. Clinical features, diagnosis, and investigation The presentation of sporadic medullary carcinoma is typically with a solitary thyroid nodule, accompanied by cervical lymphadenop- athy in 50% of cases. Lung, liver, or bone metastases are present at diagnosis in 10% of cases. Symptoms due to local invasion or the paraneoplastic production of polypeptides and prostaglandins, such as flushing, diarrhoea, and Cushing’s syndrome, are less common presenting features. The diagnosis is typically made through ultrasonography and fine needle aspiration biopsy. Immunohistochemical staining for calci- tonin in aspirated cells or in washout fluid of the fine needle aspir- ation may be required. Basal serum calcitonin concentrations are almost invariably elevated and confirm the diagnosis. There is con- troversy over the utility of routine serum calcitonin measurement in the work-up of all thyroid nodules; most centres perform aspir- ation biopsy initially. Newly diagnosed patients should be screened for other evidence of MEN and a careful family history is essential. In particular, phaeochromocytoma occurring as part of an inherited cancer syndrome must be excluded before surgery through meas- urement of serum or urine metanephrines or catecholamines. In all cases of confirmed MTC, RET mutation analysis to establish the possible genetic basis for the disease should be performed, even in the absence of a positive family history. Testing genomic DNA for RET mutations in the germline is now widely available and should ideally be carried out on leucocyte DNA from all new patients. The absence of the most common mutations, coupled with a negative family history and the absence of C-cell hyperplasia or multicentric tumours in the resected thyroid, indicates that further family testing is not warranted. When a RET mutation is detected, there is a clear benefit from family testing as prophylactic thyroidectomy in affected individuals improves outcome. However, there are some kindreds in whom familial medullary carcinoma occurs without a recognizable RET mutation and family screening must then be undertaken an- nually, up to the age of 35 to 40 years, using serum calcitonin and carcinoembryonic antigen (CEA) measurements as a guide to the presence of the inherited abnormality. Management Surgery is the primary treatment for patients with sporadic or hereditary medullary thyroid carcinoma and ranges from thy- roid lobectomy in selected patients with sporadic disease to total thyroidectomy with central neck dissection and unilateral or bi- lateral lymph-node compartment dissection. In patients who have inherited a mutated RET allele, the reliable indicator for timing thyroidectomy is the serum calcitonin concentration rather than the specific mutation. Levothyroxine replacement is needed at physiological doses rather than doses that suppress TSH. After surgery, the patient should be monitored by measurement of serum calcitonin concentration. The most accurate measurement of medullary cancer progression and ag- gressiveness is the calcitonin or CEA doubling time (the time it takes for the marker to double). Doubling times that are less than 6 months are associated with a very poor prognosis and those that are more than 2 years are associated with much better long-term survival rates. Although many patients with metastatic or persistent medullary thyroid carcinoma can be monitored, patients with progressive or symptomatic disease should undergo further treatment. Local re- currence with identifiable lymph node involvement should be treated surgically. Standard chemotherapy and radiotherapy regi- mens are largely ineffective. Profuse (secretory) watery diarrhoea is frequently a troublesome feature of extensive disease. This may respond to treatment with loperamide, whereas somatostatin analogues have an inconsistent benefit. Systemic therapy with vandetanib and cabozantinib, RET tyrosine kinase inhibitors with additional inhibitory effects on the vascular endothelial growth factor receptor, increase progression- free survival in locally advanced or metastatic progressive medullary thyroid cancer and provide relief from symptoms. Prognosis Cure, defined as a persistently normal calcitonin level, occurs in only about one-third of patients, but 80 to 90% of patients with an ele- vated calcitonin level and only nodal disease survive for 10 years. Age, stage and size of tumour, and completeness of surgical removal are important prognostic features. Familial medullary carcinoma has the best outcome; in contrast the tumour associated with MEN2B is very aggressive. The overall 10-year survival is around 70%, but is over 90% in those detected early by family screening. Primary thyroid lymphoma Less than 5% of thyroid malignancies are non-Hodgkin’s B-cell lymphoma. The peak incidence is between 50 and 80 years of age, and women are affected three times more frequently than men. The typical presentation is a rapidly enlarging thyroid mass in a patient with Hashimoto’s thyroiditis. The clinical features may suggest anaplastic carcinoma. The diagnosis can be made by fine needle aspiration biopsy and confirmed by large-needle or open bi- opsy. Accurate staging is then necessary to plan treatment, which is with external beam radiotherapy and anthracycline-based chemo- therapy. Intensive treatment has produced 8-year survival rates of over 90%. Rituximab, a monoclonal antibody directed against B cells, has shown some evidence of therapeutic benefit. FURTHER READING Agrawal N, et al. (2015). Integrated genomic characterization of pap- illary thyroid carcinoma. Cell, 159, 676–90. British Thyroid Association (2016). Thyroid Cancer: Low Iodine Diet. http://www.btf-thyroid.org/projects/thyroid-cancer-campaign/ low-iodine-diet Brose MS, et al. (2014). Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a ran- domised, double-blind, phase 3 trial. Lancet, 384, 319–28.
SECTION 13 Endocrine disorders 2312 Cabanillas ME, McFadden DG, Durante C (2016). Thyroid cancer. Lancet, 388, 2783–95. Fagin JA, Wells SA Jr (2016). Biologic and clinical perspectives on thy- roid cancer. N Engl J Med, 375, 2307. Filetti S, et al. (2019). Thyroid cancer: ESMO clinical practice guide- lines for diagnosis, treatment and follow-up. Ann Oncol, pii: mdz400. doi: 10.1093/annonc/mdz400. Harrington KJ, et al. (2001). Gene therapy for prostate cancer: current status and future prospects. J Urol, 166, 1220–33. Haugen BR, et al. (2016). 2015 American Thyroid Association man- agement guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid, 26, 1–133. Haugen BR, et al. (2017). American Thyroid Association guidelines on the management of thyroid nodules and differentiated thyroid cancer task force review and recommendation on the proposed renaming of encapsulated follicular variant papillary thyroid car- cinoma without invasion to noninvasive follicular thyroid neoplasm with papillary-like nuclear features. Thyroid, 27, 481–3. Ho AL, et al. (2013). Selumetinib-enhanced radioiodine uptake in ad- vanced thyroid cancer. N Engl J Med, 368, 623–32. Leboulleux S, et al. (2016). Papillary thyroid microcarcinoma: time to shift from surgery to active surveillance? Lancet Diabetes Endocrinol, 4, 933–42. Morris LG, Tuttle RM, Davies L (2016). Changing trends in the in- cidence of thyroid cancer in the United States. JAMA Otolaryngol Head Neck Surg, 142, 709–11. Perros P, et al. (2014). Guidelines for the management of thyroid cancer. Clin Endocrinol (Oxf), 81 Suppl 1, 1–122. Schlumberger M, et al. (2012). Strategies of radioiodine ablation in patients with low-risk thyroid cancer. N Engl J Med, 366, 1663–73. Schlumberger M, Tahara M, Wirth LJ (2015). Lenvatinib in radioiodine-refractory thyroid cancer. N Engl J Med, 372, 1868. Spitzweg C, Morris JC, Bible KC (2016). New drugs for medullary thy- roid cancer: new promises? Endocr Relat Cancer, 23, R287–97. Tufano RP, et al. (2015). Management of recurrent/persistent nodal disease in patients with differentiated thyroid cancer: a critical re- view of the risks and benefits of surgical intervention versus active surveillance. Thyroid, 25, 15–27. Viola D, et al. (2016). Treatment of advanced thyroid cancer with targeted therapies: ten years of experience. Endocr Relat Cancer, 23, R185–205. Viola D, Elisei R (2019). Management of medullary thyroid cancer. Endocrinol Metab Clin North Am, 48, 285–301. WHO (2011). Ionizing Radiation: Use of Potassium Iodide for Thyroid Protection During Nuclear or Radiological Emergencies. http://www. who.int/ionizing_radiation/pub_meet/tech_briefings/potassium_ iodide/en/
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