common in females than males. PTC is especially prevalent in iodine-sufficient regions of the world

while follicular carcinoma has relatively higher incidence in iodine-deficient regions. Papillary

carcinoma arises from the follicular cells, is characterized by papillary architecture, calcifications,

psammoma bodies, squamous metaplasia, and fibrosis. Cytology is diagnostically important and typical

findings include large, overlapping nuclei that are optically clear (Orphan Annie nuclei) and intranuclear

grooves. Greater than 30% of PTC is multicentric and found throughout the thyroid. Although

multifocality does not signify a worse prognosis, this characteristics may support the rationale for total

thyroidectomy. The incidence of cervical lymph node metastases varies across series and is influenced

by whether lymphadenectomy is performed for prophylactic or therapeutic reasons. Central neck (level

VI) lymphadenectomy performed prophylactically (in the absence of clinically detectable metastasis)

demonstrates metastasis in 30% to 80%, however the clinical relevance of micrometastatic disease is

debatable. Therapeutic neck dissection for clinically positive lymph node macrometastasis is

recommended as the standard of care.12 Distant metastases occur in 1% to 8% of patients with PTC

typically presenting as pulmonary nodules.39 At least 70% of PTC take up radioiodine and RAI scanning

and ablation are important parts of the treatment strategy. As a whole, the prognosis for PTC is

excellent, especially in those patients with tumors that define a low risk for recurrence.

Variants of Papillary Carcinoma. The follicular variant of PTC essentially combines the histologic and

architectural appearance of follicular tumors with the cytologic features of papillary carcinoma. In

terms of treatment and biologic behavior, this variant behaves in the same manner as classic PTC. The

dilemma caused by this variant is that in contrast to classic PTC it is very difficult to diagnose on frozen

section analysis. It is often interpreted as a follicular lesion with the final diagnosis deferred until

formal histopathology, to identify the atypical features, is complete. More aggressive variants of

papillary carcinoma include tall cell, columnar, and diffuse sclerosing types, which also exist along the

spectrum of dedifferentiation. The tall cell variant is associated with more extrathyroidal extension,

angiolymphatic invasion and lymph node involvement resulting in higher rates of recurrence.40

5 Papillary Microcarcinoma. PTCs less than 1 cm in size are considered microcarcinomas (occult or

incidental tumors). They may be multifocal and are usually clinically silent until thyroidectomy is

performed for another indication. Although they are by definition malignant, this group of tumors

requires a different set of considerations based on their biologic behavior and patient outcome.

Prognosis is exceptionally good, with a 0.4% cause-specific mortality rate.41 A solitary microcarcinoma

found after lobectomy is considered adequately treated with lobectomy alone and completion

thyroidectomy or radioiodine scanning are not typically indicated. Somewhat in contrast, if these

microcarcinomas are diagnosed preoperatively, which may be difficult because of their small size,

thyroid resection is usually recommended. Some groups, however, have chosen to follow these patients

closely with US and have shown that only 8% significantly increase in size, 3.8% develop new lymph

node metastasis and 6.8% progress to clinical disease over 10-year observation period and that patients

older than 60 years and those with contraindications to thyroidectomy may be the best candidates for

this observational strategy.41,42 However, there have also been reports of lymph node metastasis in

papillary microcarcinoma and occult primary tumors not identified on histopathology, suggesting that a

small subset of microcarcinomas have potential for more aggressive behavior.

Molecular Markers in Thyroid Cancer

6 Molecular testing of thyroid tumors to help characterize thyroid tumors in the pre- and postoperative

setting is becoming increasingly useful. Mutations in the MAPK pathway including BRAFV600E, RAS

and RET are present in the majority of papillary thyroid cancer while RAS mutations and the PAX8–

PPARγ rearrangement are common in follicular thyroid cancer. In the preoperative assessment of

thyroid nodules, molecular testing of FNA samples can identify presence of these mutations and if

present may be useful in determining the need for and the extent of thyroidectomy and nodal

dissection.43 Mutation of the BRAF gene in papillary carcinomas is estimated to be present in up to 60%

of cases and is associated with a more aggressive phenotype and increased recurrence and mortality.44

Follicular Carcinoma

FTC accounts for approximately 10% of thyroid cancers. Again, there is a female-to-male predominance,

and the incidence begins to increase in the fifth decade of life. Determination that a follicular

lesion/neoplasm is a carcinoma is contingent not only on the specific cellular architecture, but also on

the findings of vascular and capsular invasion. This determination is rarely able to be made on FNA or

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frozen section and often requires final surgical histopathology analysis.45 FTC is often more advanced

and locally infiltrative of muscles and perithyroidal vascular structures at the time of diagnosis

compared with PTC. Because of this difference in stage at diagnosis, the overall 10-year survival for

patients with FTC is slightly worse than for those with PTC, but when patients are matched for age and

stage with PTC, this difference largely disappears.46 In contrast to PTC, follicular cancers are usually

solitary. FTC tends to spread hematogenously and approximately one-third of patients have distant

metastases of the lung and bone at the time of diagnosis. Lymph node involvement is less common than

in PTC and is limited to only about 10% of patients. At least 80% of FTC will take up radioiodine,

making this an important consideration in postoperative imaging and adjuvant treatment.

Minimally Invasive Follicular Carcinoma. Follicular neoplasms with demonstrable capsular invasion,

but no vascular invasion, are classified as minimally invasive follicular cancers. These patients have an

excellent prognosis, conceptually equivalent to patients with incidental papillary microcarcinomas. If

such a tumor is found after hemithyroidectomy, completion thyroidectomy and radioiodine therapy are

generally not indicated.47

Hürthle Cell Carcinoma

Malignant Hürthle cell neoplasms account for less than 5% of thyroid carcinomas, are more prevalent in

women than men, affect patients slightly older than those with PTC or FTC and are more often

associated with lymph node metastases and distant metastases. Hürthle cells are frequently present on

FNA cytology and the possibility of HCC is included in the diagnostic differential for these nodules.

Patients with Hashimoto disease or colloid nodules commonly contain Hürthle cells; however, it is the

nodule that contains almost entirely Hürthle cells that raises concern for HCC. If HCC is suggested by

FNA cytology, a diagnostic thyroid lobectomy is required to definitively establish the nature of the

tumor. Hürthle cell cancers can have higher rates of lymph node metastasis and more aggressive nature

compared to PTC and FTC therefore many surgeons advocate total thyroidectomy for any Hürthle cell

carcinoma. Despite a likely follicular cell origin, only around 10% of HCC tumors take up radioiodine.

Surgery therefore is the mainstay of treatment and total thyroidectomy is often combined with central

compartment lymphadenectomy and perhaps modified radical neck dissection if lateral compartment

lymph node involvement is present.

Anaplastic Carcinoma

Although it formerly accounted for a larger fraction of thyroid malignancies, undifferentiated or

anaplastic cancer now accounts for just 1% to 2% of thyroid cancers. Most commonly, it occurs in

elderly patients with a long-standing history of a goiter. There is significant evidence to infer that most

anaplastic thyroid cancers of the spindle cell or giant cell type arise from transformation of follicular or

papillary carcinoma. Anaplastic thyroid carcinoma is one of the most aggressive and rapidly lethal

malignancies known. Nearly all are too far advanced at the time of diagnosis to be adequately treated

by currently available therapies. The diagnosis may be made by appropriate clinical suspicion (rapidly

growing firm thyroid mass) and FNA; however, core-needle or incisional/excisional biopsy may be

required. If airway compromise is present or impending, operation may include debulking and

tracheostomy. Occasionally, a small anaplastic cancer is found that is confined to the thyroid or is

minimally invasive to surrounding tissues. Aggressive resection may be legitimately considered,

especially in a young patient. The long-term prognosis for these patients, however, is usually limited by

metastatic disease, which may not be apparent at diagnosis. Adjuvant or primary palliative therapy

consisting of chemotherapy and external beam radiotherapy is frequently employed. It is common to see

a measurable response early in therapy, but eventual tumor progression is typical. Chemotherapeutic

regimens often include some combination of taxane (paclitaxel or docetaxel) and/or doxorubicin and/or

platin (cisplatin or carboplatin), however, the overall impact is often very limited.48 Radiation therapy

can be used as primary treatment often in combination with chemotherapy or as adjuvant treatment

following surgery with typical total radiation doses of 40 to 60 Gy. Most often, chemotherapy and

radiotherapy follow an operation performed for diagnosis or airway protection, but such a regimen may

also be used occasionally as neoadjuvant therapy before an attempt at resection is undertaken. A recent

trial suggested a trend toward improved survival when combretastatin A-4 (fosbretabulin), a tubulinbinding compound, was added to carboplatin/paclitaxel in the treatment of anaplastic cancer

postthyroidectomy.49 Median survival for anaplastic thyroid cancer remains low at 5 months with a 20%

1-year survival for all patients.

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Staging of Differentiated Thyroid Cancer

A number of patient factors have been investigated to predict risk and prognosis for patients with DTC,

such as age, gender, tumor size, involvement of lymph nodes, extrathyroidal invasion, tumor grade or

histologic features, and completeness of surgical removal. Although there are differences in these

systems, in general, they agree that younger patients with smaller tumors have an excellent prognosis

with decreased risk of recurrence and death compared with older patients. One early prognostic staging

scheme was the AGES system (age, histologic grade, extrathyroidal disease [invasion and distant

metastases], and tumor size).50 Although useful, the scheme was later modified to exclude histologic

tumor grade because there was no uniform agreement on DTC grading by pathologists. Another system

is the AMES system (age, metastases, extrathyroidal invasion, and tumor size), which was originally

described for patients with DTC.51 The main criticism of this scheme is that it was defined based on a

patient population that included both papillary and follicular thyroid carcinomas, and that there was no

accounting for those patients with low-risk versus high-risk FTC. Another useful prognostic system is the

MACIS scoring system (metastases, age, completeness of resection, extrathyroidal invasion and distant

metastases, and tumor size). This system calculates a composite score based on these factors, then

stratifies prognosis in proportion to these scores (<6.00 is very low risk and >8.00 represents greatly

increased risk).52 The European Organization for Research on Treatment of Cancer (EORTC) based its

prognostic scoring system on a multivariate analysis of patients with all types of thyroid malignancies

and found that patients with scores of less than 50 had a 5-year survival rate of 95%, whereas those

with scores greater than 109 had a 5-year survival rate of 5%.53 This system has not been universally

adopted for use in DTC because the high-risk, poor-prognostic group contained a large fraction of

patients with anaplastic thyroid cancer. The familiar TNM system (tumor size, nodal status, and distant

metastases) is also used to provide prognostic information for patients. When used for thyroid cancer,

the TNM system has been modified to account for the risk-reducing influence of low patient age such

that patients <45 years are limited to stage I and II diseases. (Table 75-75). This system can provide

consistency when comparing patients across different series. This system, like all prognostic scoring

systems, still has limited utility in guiding initial treatment decisions (e.g., extent of resection) because

the important components are unable to be determined until after resection. All patients with anaplastic

cancer are considered to have stage IV disease which is further subcategorized into IVa (confined to

thyroid), IVb (extrathyroidal extension), and IVc (metastatic disease).

STAGING

Table 75-2 Tumor, Node, Metastasis Staging System for Differentiated Thyroid

Carcinoma (Papillary and Follicular Types)

Medullary Carcinoma

MTC arises from the parafollicular C cells and accounts for about 5% to 7% of all thyroid malignancies.

Approximately 75% occur in a sporadic fashion and 20% to 25% are familial due to multiple endocrine

neoplasia (MEN) types 2A and 2B or familial medullary thyroid carcinoma (FMTC) syndrome. These are

autosomal dominant inherited endocrinopathies related to a group of specific mutations of the RET

protooncogene on chromosome 10q11.2 (Table 75-3). The familial forms of MTC have different degrees

of aggressiveness: FMTC has the most indolent course, MEN 2B has the most aggressive course, and

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MEN 2A is intermediate. Most sporadic MTC is relatively slow growing and may be quite indolent and

typically do not present before 30 years of age. However, a subset of patients with sporadic MTC have a

much more aggressive course. Approximately 20% of patients thought to have sporadic MTC may in

fact be index cases of FMTC. Therefore, any patient with a new diagnosis of MTC should have genetic

testing for the RET protooncogene mutations associated with MEN 2 and FMTC. Appropriate screening

for pheochromocytoma (which would be treated prior to thyroidectomy) and hyperparathyroidism are

required. The variability in biologic behavior in sporadic and FMTC accounts for the overall 10-year

survival rate of approximately 50% for all patients combined.

FNA can be diagnostic for medullary cancer, especially if the specimen is stained for calcitonin. MTC

is unique in that calcitonin and carcinoembryonic antigen (CEA) are specific tumor markers used for

diagnosis and to guide subsequent follow-up. The degree of calcitonin elevation roughly corresponds to

extent of disease and levels >400 pg/mL should prompt evaluation for extracervical metastasis with

cross-sectional imaging. Overall, MTC is more aggressive than other DTCs and is more likely to

metastasize such that 50% to 75% of patients with sporadic MTC have nodal metastases at the time of

diagnosis. Nodal metastasis is correlated with tumor size and contralateral cervical metastases are

synonymous with systemic disease.54 Distant metastases commonly involve the liver, lungs, and bone.

The treatment strategy for MTC is somewhat distinguished from that of PTC or FTC. Due to the high

likelihood of lymph node metastases and the fact that radioiodine is not available as an effective

adjuvant therapy, a more extensive initial surgical resection is warranted. With few exceptions, the

minimum appropriate operation for MTC is a total thyroidectomy with central compartment

lymphadenectomy (level VI).55 Patients with lymph node involvement in the lateral compartment

should undergo total thyroidectomy with central and lateral neck dissection which includes lymph node

levels II, III, IV, V and VI. Following initial surgery, an undetectable serum calcitonin is associated with

persistent or recurrent disease, while levels which are detectable but <150 pg/mL are often associated

with locoregional disease. Experience with remedial neck dissections in an attempt to decrease

calcitonin to the normal range or render it undetectable have shown varying results and requires an

appropriate search for distant metastases before such an operation is planned.56 This may include

imaging tests such as CT scanning, US, somatostatin receptor scintigraphy scanning, selective venous

sampling for calcitonin levels, and laparoscopy to investigate for hepatic metastases. For most patients,

the strategy of observation by clinical examination, biochemical markers (with determination of

calcitonin doubling time), and imaging tests is adopted with interval reassessment for resectable

regional and metastatic diseases. Resection can be considered for symptomatic lesions and those in a

location whereby ongoing growth could cause significant morbidity (e.g., tracheoesophageal groove).

Hepatic resections for isolated bulky metastatic deposits can provide palliation. Treatment of clinically

significant distant or unresectable disease with targeted agents including vandetanib (an inhibitor of

RET kinase, vascular endothelial growth factor receptor [VEGFR], and epidermal growth factor [EGFR])

has shown promise in the context of the general ineffectiveness of traditional cytotoxic chemotherapy.57

Somatostatin analogs may also be useful in slowing the growth of the tumor in some patients. External

beam radiotherapy may be useful for locoregional tumor control, especially in those patients with

evidence of locally aggressive or residual tumor after resection;58 however, this should not be employed

until appropriate surgical options have been exhausted. The TNM staging system for MTC is outlined in

Table75-4.

CLASSIFICATION

Table 75-3 Disease Phenotypes Related to Mutation of the RET Protooncogene

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7 All patients with MTC (not already known to have familial mutation) should undergo evaluation for

germline RET mutations. The best use of genetic testing is to identify the specific mutation in the

affected family member, which then guides testing of the progeny. When other kindred members with

the mutation are identified, prophylactic thyroidectomy may be performed before malignancy develops

with the timing of this guided by the particular codon mutation (Table 75-4).55 The thyroid resection

must be absolutely complete because the region of thyroid remnant after a near-total or subtotal

thyroidectomy is the region that is most densely populated with C cells. The association of primary

hyperparathyroidism and MEN 2A should be considered during preoperative planning and enlarged

parathyroid glands encountered at the time of thyroidectomy should be removed. A subtotal

parathyroidectomy or total parathyroidectomy and autotransplantation (similar to that which would be

considered for MEN 1) are excessive options for the parathyroid disease encountered in MEN 2A and,

instead, resection may be guided by morphologic changes in the parathyroid glands and intraoperative

parathyroid hormone monitoring. Children identified to have MEN 2B should undergo thyroidectomy

and central compartment lymph node dissection as soon as the diagnosis is made, definitely by 2 years

of age, but even by 6 months of age as guided by mutation analysis (Table 75-5).59 If MTC is already

evident at the time of RET mutation diagnosis (as opposed to only C-cell hyperplasia), patients should

also undergo ipsilateral neck dissection.

STAGING

Table 75-4 Tumor, Node, Metastasis Staging System for Medullary Thyroid

Carcinoma

Thyroid Lymphoma

8 Primary thyroid lymphomas are rare tumors that account for fewer than 5% of thyroid malignancies.

The majority are classified as non-Hodgkin lymphomas of B-cell origin. Nearly all arise from within a

background of Hashimoto thyroiditis. Most patients present with a rapidly enlarging thyroid mass and

compressive symptoms (e.g., dyspnea, dysphagia, choking, and pain) and have a history of

hypothyroidism. Modern immunophenotypic analysis often allows for diagnosis with a small amount of

tissue obtained by FNA or core-needle sampling. Surgery is typically utilized only to establish the

diagnosis with open biopsy if needle biopsy is insufficient. Definitive treatment of thyroid lymphoma

includes chemotherapy and radiation. Patients with diffuse large B-cell lymphoma are generally treated

with combination chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP]

with rituximab) followed by radiation therapy for stage IE or IIE disease.60 In those with pure marginal

zone B-cell lymphoma (MALT), some have advocated for single-modality therapy (chemotherapy or

radiation) given its more indolent behavior, but this still remains controversial and would be limited to

those with localized disease.61

TREATMENT

Table 75-5 Age of Prophylactic Thyroidectomy Based on Genotype/Phenotype

Correlation in Medullary Thyroid Carcinoma

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