3.Advances in Management of Thyroid Cancer

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Current Problems in Surgery

Current Problems in Surgery 50 (2013) 241–289

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journal homepage: www.elsevier.com/locate/cpsurg

Advances in management of thyroid cancer

Introduction

In this monograph, a comprehensive review of thyroid cancer is presented. This represents
the work of 4 endocrine surgeons all of whom have been or are currently affiliated with CaseWestern Reserve University School of Medicine and have important roots in Cleveland, Ohio.This monograph is a case-based review of primary malignancies of the thyroid gland, in whichthe clinical presentation, diagnosis, treatment, follow-up, outcome, and new advancements areemphasized.
Epidemiology of differentiated thyroid cancer (DTC)

DTC accounts for approximately 2% of all malignancies in the United States. The incidenceof thyroid cancer for all racial and ethnic groups in the United States from 2004-2008 was5.5 per 100,000 in men and 16.3 per 100,000 in women.1 The American Cancer Societyhas reported a dramatic increase in the incidence of thyroid cancer since the mid-1990s.Since 2004, the incidence has increased 5.5% per year in men and 6.6% per year in women,which represents the largest annual percentage increase of any cancer in both men andwomen.2

The American Cancer Society estimated that 56,460 new cases of thyroid cancer would bediagnosed in the United States in 2012; this includes 43,210 women and 13,250 men. It isestimated that there would be 1780 thyroid cancer-related deaths, for an overall 3% mortalityfrom thyroid cancer. From 2004-2008, there has also been a small increase in death rate fromthyroid cancer from 0.47-0.50 per 100,000 in men and from 0.47-0.52 in women, in contrast toa reduction in mortality for most other solid tumors.2

Thyroid cancer has become the fifth most common cancer in women in the United States.1

Thyroid cancer is the second most common cause of cancer in women in the Gulf CooperationCouncil countries of Saudi Arabia, Kuwait, Qatar, and United Arab Emirates3 and the mostcommon cause of cancer in women in Korea.4 The increased incidence in thyroid cancerhas also been observed elsewhere including Europe, Asia, South America, and Australia.5

These statistics are a reflection of the dramatic increase in the incidence of thyroid cancer thathas been observed for the last 4 decades.6,7

The incidence has increased for tumors of all sizes and for all stages.6,8 The largestincrease in incidence, however, has been in cancers smaller than 1 cm and it has beensuggested that the increased incidence in thyroid cancer is related to the increased use ofoffice-based ultrasound and detection of smaller cancers.7 Additionally, ultrasound-guided

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J. Jin et al. / Current Problems in Surgery 50 (2013) 241–289242

fine-needle aspiration (FNA) biopsy of nonpalpable nodules, more frequent use of totalthyroidectomy for treatment of benign disease, and increased pathologic scrutiny with moreextensive thyroid sectioning and histologic examination are likely contributory factors.However, the increased incidence cannot solely be attributed to increased detection becausethe incidence rates of larger and more advanced tumors would be expected to decrease ifcancers were being detected earlier.6 Radiation exposure, from the increased use of computedtomography (CT) and other diagnostic x-rays, may also be an important contributor to theincreased incidence in thyroid cancer. Obesity, dietary nitrosamines, polybrominated diphenylethers, or flame retardants found in plastics, electrical appliances, carpets, and upholstery havealso been suggested as potential contributory factors in the increased incidence of thyroidcancer.9,10

DTC occurs more commonly in women. It is estimated that 3 out of every 4 cases of thyroidcancer occur in women.2 The lifetime risk of developing thyroid cancer in the United States hasbeen reported to be 0.84% in women and 0.30% in men.11 Most women who develop DTC are40-50 years of age and most men are 50-60 years of age.

Papillary thyroid cancer (PTC)

Case

A 23-year-old woman was incidentally found to have enlarged thyroid gland on a work-related physical examination. She denied any symptoms of hypothyroidism or hyperthyroid-ism. She had no compressive symptoms, prior history of head or neck radiation, or familymedical history of thyroid cancer or other endocrinopathies. She had no active medicalproblems and was taking no medications. She smoked 3 cigarettes per day.

On physical examination she was noted to have a 3 cm hard mass in the left lobe of thethyroid gland. She had no palpable dominant nodule in the right lobe of her thyroid gland. Hertrachea was midline. She was noted to have large bulky lymphadenopathy involving the leftlateral neck, corresponding to lymph nodes in levels II-IV. The rest of her physical examinationwas normal.

She had a serum thyroid-stimulating hormone (TSH) level of 2.08 mIU/mL. An ultrasoundexamination revealed a heterogeneous solid nodule in the left lobe of the thyroid gland withill-defined margins and increased vascular flow (Fig 1). The right lobe of the thyroid glandwas normal. Adjacent to the left lobe of the thyroid gland were multiple enlargedheterogeneous lymph nodes in the left internal jugular chain that demonstrated a roundedappearance with microcalcifications and absence of normal echogenic hilum (Fig 2). An FNA

T

CA

IJV

Fig. 1. (A) Large heterogeneous, hypoechoic nodule with irregular borders that is taller than it is wide. Final pathology

revealed a papillary thyroid cancer. (B) Doppler ultrasound study demonstrating increased intranodular vascularity.

T, trachea; IJV, internal jugular vein; CA, carotid artery. (Color version of figure is available online.)

CA

IJVN

Fig. 2. Abnormal, enlarged cervical lymph node with hyperechogenicity, punctate calcifications (arrows), and a rounded

shape N, thyroid nodule; CA, carotid artery; IJV, internal jugular vein. (Color version of figure is available online.)

J. Jin et al. / Current Problems in Surgery 50 (2013) 241–289 243

biopsy of the nodule in the left lobe of thyroid gland and one of the large lymph nodes in thelateral neck was completed. Cytologic analysis of both FNA biopsy specimens revealed PTC.

The patient underwent a total thyroidectomy with a central compartment neck dissection,bilateral transcervical thymectomy, autotransplantation of the right and left inferior para-thyroid glands into the right sternocleidomastoid muscle, and a left lateral compartment neckdissection with removal of lymph nodes from level IIA, III, IV, and VB. The final pathologyrevealed a 3.9-cm well-differentiated, encapsulated, classic PTC involving the left lobe ofthe thyroid gland with 11 of 16 lymph nodes from the central neck and 20 of 30 lymph nodesfrom the lateral neck positive for metastatic PTC (level IIA, 5/8; level III, 9/10; level IV, 5/8;and level VB, 2/4). On the first postoperative day, her serum calcium level was 7.8 mg/dLand intact parathyroid hormone level was 16.7 pg/mL. She was treated with calcium carbonateand calcitriol for 2 weeks, after which her serum calcium normalized. She was startedon a suppressive dose of levothyroxine with plans to keep her serum TSH level less than0.1 mIU/mL. Her serum calcium level normalized and calcium carbonate and calcitriol werediscontinued.

Introduction

The increase in incidence of thyroid cancer is attributed primarily to an increase inincidence of PTC, whereas the incidences of follicular, Hurthle cell, anaplastic, and medullarycancers have remained stable.7 PTC is the most common type of thyroid cancer, accounting forapproximately 85% of all thyroid cancers. In a 2010 study by Cramer and colleagues,12 analysisof thyroid cancer incidence using Surveillance, Epidemiology, and End Results data showed thatpapillary microcarcinoma (o1 cm) increased 19.3% per year from 1973-2006. Although thiswas the highest increase among all PTCs, there was also an increase in incidence of tumorslarger than 1 cm: 12.3% per year for tumors 1-2 cm; 10.3% per year for tumors 2.1-5 cm; and12.0% per year for tumors larger than 5 cm.

Risk factors

In patients who present with a thyroid nodule, multiple factors are associated with anincreased likelihood of malignancy: age less than 15 or older than 45 years, male gender, ahistory of head or neck irradiation, and a family history of thyroid cancer in a first-degreerelative. In patients with a thyroid nodule that is firm and fixed on physical examination orassociated with cervical or supraclavicular lymphadenopathy or vocal cord paralysis, it is morelikely to be cancer. Higher serum TSH levels have also been associated with a greater risk ofmalignancy.13


Radiation exposure

The most important risk factor for the development of DTC is a history of radiation exposureduring childhood and adolescence. This includes radiation treatment for benign diseases suchas facial acne or hirsutism, thymic enlargement, enlarged tonsils and adenoids, tinea capitus,and tuberculous cervical adenitis. Treatment of childhood malignancies including leukemia,Hodgkin’s and non-Hodgkin’s lymphoma, and central nervous system cancer, as well radiationexposure from atomic bombings and radioactive fallout from atomic weapons testing andnuclear power accidents, have been associated with thyroid cancer. Children who survived theatomic bombings of Hiroshima and Nagasaki continue to have a higher-than-normal risk ofthyroid cancer more than 50 years after radiation exposure.14

The practice of using ionizing radiation for treatment for benign head and neck diseaseended in the late 1950s and early 1960s because of the recognition of its carcinogenic effect onthe thyroid. The latency period for development of thyroid cancer varies from 20-50 years andPTC is the predominant histologic type.15 Patients with a thyroid nodule and a history of heador neck irradiation have an approximate 40% incidence of carcinoma and the cancer may befound outside of the index nodule.16 In a Childhood Cancer Survivor Study, 12,547 survivors ofchildhood cancer who received head and neck radiation as part of cancer treatment between1970 and 1986 were followed up until 2005 and 119 survivors were found to have thyroidcancer. The thyroid cancer risk increased linearly with radiation dose up to approximately20 Gy, where the relative risk peaked at 15-fold. Radiation exposure in younger patients (o5years), females, and time since exposure (Z25 years) were found to be significant modifiers forradiation associated thyroid cancer.17

Family history of thyroid cancer

Patients with a family history of thyroid cancer have a higher incidence of thyroidcancer. Familial nonmedullary thyroid cancer (FNMTC) accounts for approximately 5% of allthyroid cancers. FNMTC is defined as DTC occurring in 2 or more first-degree relatives. PTC isthe most common histologic type of FNMTC; Hurthle cell and follicular types are much lesscommon. Compared with sporadic PTC, patients with FNMTC are younger at presentation andare more likely to have multicentric disease, extrathyroidal tumor invasion, and lymph nodemetastases. They are also more likely to develop recurrent disease and have a lower disease-freesurvival.18-20 However, not all studies have found FNMTC to be more aggressive than sporadicPTC.21,22

PTC may occur as part of a familial cancer syndrome (Table 1). Patients with one of thefamilial cancer syndromes have a significantly increased risk of developing DTC. A neckultrasound screening program instituted at the Cleveland Clinic Foundation for patientsdiagnosed with familial adenomatous polyposis (FAP) demonstrated a 5% incidence ofthyroid cancer compared with a 0.2% incidence in the general population, resulting in therecommendation for routine thyroid surveillance of patients with FAP.23 Approximately two-thirds of patients with Cowden disease (PTEN hamartoma tumor syndrome) would develop athyroid neoplasm, which is most commonly a follicular tumor. The lifetime risk of developingthyroid cancer is 35% and follicular cancer is the most common histologic type. Patients with thePTEN mutation and thyroid cancer are younger, with a mean age of 30 years.24 Patients withWerner syndrome primarily develop follicular cancer, but PTC may also occur. Approximately15% of patients with Carney complex develop PTC or follicular thyroid cancer (FC).

The causative gene for nonsyndromic FNMTC has not been identified. Its mode ofinheritance is autosomal dominant with incomplete penetrance. In patients without a knownfamilial syndrome, the risk of thyroid cancer risk is increased 10-fold when a first-degreerelative has thyroid cancer.25 Hemminki and colleagues documented a standard incidence ratioof 3.2 for PTC when a parent had PTC, 6.2 with an affected sibling, and 11.9 when the affectedsibling is a sister.26

Table 1Familial thyroid cancer syndromes.

Familial

syndrome

Other clinical manifestation Gene/chromosome Inheritance

pattern

FAP Adenomatous intestinal polyps with malignant

potential, early age colon cancer, and multiple

extraintestinal manifestations

Inactivating mutation

APC tumor suppressor

gene/5q21

Autosomal

dominant

Gardner’s

syndrome

(variant of FAP)

Adenomatous polyps, supernumerary teeth, fibrous

dysplasia of the skull, osteomas of mandible, desmoid

tumors, fibromas, lipomas, and CHRPE

APC tumor suppressor

gene/5q21

Autosomal

dominant

Cowden’s disease Hamartomas and tumors of breast, thyroid, colon,

endometrium, and brain

PTEN tumor

suppressor gene/

10q22-23

Autosomal

dominant

Carney’s

syndrome

Mucosal pigmentation, myxomas, schwannomas,

pigmented adrenal nodules, pituitary, and testicular

tumors

Activating PRKARI

mutations/17q24

Autosomal

dominant

Werner’s

syndrome

Premature aging, scleroderma-like skin changes,

diabetes mellitus, cataracts, muscle atrophy

WRN/8p11-21 Autosomal

Recessive

FAP, familial adenomatous polyposis; APC, adenomatous polyposis coli; PTEN, phosphatase and tensin homolog;

CHRPE, congenital hypertrophy of the retinal pigment epithelium; WRN, wingless type.


Clinical presentation and diagnosis

In the past, thyroid cancer was most commonly diagnosed as a result of palpable thyroidnodule detected by the patient or on physical examination performed by a healthcare provider.However, with increased recognition of risk factors for thyroid cancer as well as technologicadvancements in ultrasonography and FNA biopsy technique, thyroid cancers are being detectedeven when they are not palpable. Clinically unsuspected thyroid nodules and cancers are beingdetected on imaging studies or during operations for reasons unrelated to the thyroid gland.

The typical patient with PTC is a 40- to 50-year-old woman. Male patients and patients at theextremes of age are less likely to be affected, and may have more aggressive histologic variants ofPTC. Incidentally discovered PTC, found on imaging studies obtained for reasons other thanthyroid disease, is increasing.27 Thyroid nodules with focal increase in 18F-fluorodeoxyglucose(FDG) uptake on positron emission tomography (PET) imaging have a 33% risk of thyroid cancer.28

A firm, fixed, or rapidly enlarging thyroid nodule, hoarseness or vocal cord paralysis, andassociated cervical lymphadenopathy are clinical features raising suspicion for thyroid cancer.Various sonographic characteristics of a thyroid nodule have been associated with highlikelihood of thyroid cancer (Fig 1), including hypoechogenicity, increased intranodularvascularity, irregular infiltrative borders, microcalcifications, and an absent halo sign. Thyroidnodules larger than 1 cm in size or smaller nodules with suspicious sonographic featuresshould be evaluated with FNA biopsy.

FNA biopsy is the gold standard for diagnostic evaluation of a patient with a thyroid nodule.Cytologic features of PTC include large monolayer sheets of follicular epithelial cells in apapillary configuration with large irregular nuclei containing fine, powdery chromatin andnuclear inclusions and grooves (Fig 3). Psammoma bodies may be present, and when seen oncytologic examination of a thyroid nodule, are highly suggestive of PTC. The false-positive ratefor an FNA biopsy diagnosis of PTC is 1%-2%.29 As a result, definitive surgical therapy isrecommended for patients with an FNA biopsy diagnosis of PTC. Patients with PTC may alsohave an FNA biopsy that is interpreted as suspicious for PTC, for which rates of PTC have beenreported to vary from 40%-82%,30 and are best managed with thyroid lobectomy, isthmusec-tomy, frozen section examination, and total thyroidectomy when a diagnosis of PTC isconfirmed histologically.30-32 Patients with a follicular variant (FV) of PTC may have an FNAbiopsy consistent with a follicular neoplasm. A thyroid lobectomy and isthmusectomy isrecommended for patients with a thyroid nodule and an FNA biopsy diagnosis of follicularneoplasm and completion thyroidectomy for a final diagnosis of PTC.

Coarse Chroma�n Pseudoinclusion

Groove

Fig. 3. Fine-needle aspiration cytology specimen demonstrating coarse chromatin, intranuclear grooves, pseudoinclu-

sions, and a psammoma body (inset with arrow), which are cytologic findings consistent with papillary thyroid cancer.

(Color version of figure is available online.)


The evaluation of patients with a thyroid nodule includes a screening of the serum TSH levelto evaluate the functional status of the thyroid gland. Higher serum TSH levels have beenshown to be associated with a higher risk of thyroid cancer.13,33-35 It has also been proposedthat higher serum TSH levels may be associated with a worse prognosis36,37 in patients withthyroid cancer, but this would require further investigation using longitudinal studies.

Once a diagnosis of PTC is made, an ultrasound of the neck is obtained to evaluate thecentral and lateral neck for abnormal lymph nodes. Lymph node metastases from PTC can bedetected on ultrasound in up to 50% of patients.38,39 Microcalcifications, cystic change, loss ofthe fatty hilum, and a rounded rather than an oval contour are all features seen on ultrasoundthat raise suspicion for a metastatic lymph node (Table 2). An abnormal lymph node should bebiopsied for appropriate surgical planning.

Preoperative laryngoscopic examination is important in patients with a diagnosis of thyroidcancer because the status of the vocal cords affects how a cancer that is invading the recurrentlaryngeal nerve is managed. Besides the strap muscles, the recurrent laryngeal nerve is themost common site involved in local invasion from DTC. Resection of the recurrent laryngealnerve is recommended when there is tumor invasion and a documented paralysis of the vocalcord. When the vocal cord is functioning, the tumor should be shaved from the recurrentlaryngeal nerve to preserve its function.

Surgical therapy

There are no prospective randomized studies evaluating the appropriate extent ofthyroidectomy for PTC. Most recommendations for the extent of thyroidectomy for PTC are

Table 2Sonographic features raising suspicion for a metastatic lymph node.

Diameter 41 cm

Loss of the normal fatty hilum

Irregular, rounded contour with long axis to short axis ratio o1.5

Heterogeneous echogenicity

Microcalcifications

Hypervascularity


based on expert opinion or large patient cohorts that have been treated in a nonrandomizedfashion. One of the major advances in the management of PTC has been the categorization ofpatients into low- and high-risk groups based on well-defined prognostic factors, including age,tumor size, tumor differentiation, local invasion, and distant metastases (Table 3). Shaha andcolleagues further refined the risk group definition by identifying an intermediate-risk groupconsisting of patients younger than 45 years of age with high-risk tumors and patients olderthan 45 years of age with low-risk tumors.40 Risk group definition is important for estimationof recurrence and mortality from DTC and for determining the extent of thyroidectomy.

Approximately 10%-20% of patients with PTC are at a high risk for recurrence and mortality.Cady reported a 59% recurrence rate and 46% mortality rate for high-risk DTC.41 Because of thehigh risk of recurrence and mortality, total thyroidectomy is a uniformly accepted therapy forhigh-risk PTC. The treatment of low-risk PTC is more controversial. The National Compre-hensive Cancer Network guidelines have proposed thyroid lobectomy as an alternative to totalthyroidectomy for low-risk PTC, but this may not be the optimal therapy.42

Most experts and published guidelines recommend total thyroidectomy for all patientswith PTC greater than or equal to 1 cm in size.43,44 Total thyroidectomy is also recommendedfor patients with PTC smaller than 1 cm in size when there is nodular disease involvingthe contralateral lobe, regional, or distant metastases, a personal history of head andneck radiation, or a family history of thyroid cancer. The rationale for total thyroidectomy inpatients with PTC is to remove multicentric disease, which is present in 30%-80% ofpatients.45 Total thyroidectomy is associated with the lowest incidence of local and regionalrecurrence.46

Bilimora and colleagues reviewed the data from more than 52,000 patients with PTC fromthe National Cancer Data Base and, adjusting for age, lymph node status, distant metastases,radioiodine use, and year of diagnosis, reported a significantly lower recurrence rate and ahigher survival rate for patients with PTC who underwent total thyroidectomy vs less than totalthyroidectomy.47 Improved survival and lower recurrence rates with total or near-totalthyroidectomy have also been demonstrated in other centers.46,48,49 Other advantages of totalthyroidectomy are that it optimizes the use of serum thyroglobulin (Tg) for detection ofrecurrent cancer and the use of radioiodine for imaging and treatment of metastatic diseaseand it eliminates anaplastic dedifferentiation, which may occur in up to 1% of DTCs. Thyroidlobectomy is best reserved for PTC smaller than 1 cm when it is unifocal without metastasis oraggressive histologic features.

Cady, using the ‘‘age, metastases, extent, and size (AMES)’’ prognostic scheme forclassification of DTC, reported 89% of patients with DTC were in a low-risk group and after amean 20-year follow-up had a 7.7% recurrence rate and a 1.8% mortality rate compared with11% in the high-risk group who had a 59% recurrence rate and 46% mortality rate.41 Shaha andcolleagues, in a review of 1038 patients with DTC treated at Memorial Sloan Kettering CancerCenter with a mean 20-year follow-up, reported that 39% of patients were in the low-risk groupand that they had a 13% recurrence rate, a 2% rate of distant metastases, and mortality of 1%compared with 22% of patients in the high-risk group who had a recurrence rate of 50%, a 34%

Table 3Low- and high-risk groups for recurrence and mortality from DTC based on the age, grade, extent, and size (AGES) and

AMES classification systems (Hay and Cady).

Low risk High risk

Women o50 y Women Z50 y

Men o40 y Men Z40 y

Well-differentiated tumor Poorly differentiated or aggressive variants (tall cell columnar and oxyphilic)

Tumor o4 cm Tumor Z4 cm

Tumor confined to thyroid Local invasion

No distant metastases Distant metastases

AMES, age, metastases, extent, and size.


rate of distant metastases, and a mortality rate of 33%. With only 2% of patients in the low-riskgroup developing distant metastases, the authors questioned the necessity for totalthyroidectomy.40

Cady, Shaha, and Shah have been among the leading proponents for conservative therapy forpatients with DTC in the low-risk group because most patients with low-risk DTC have anexcellent long-term prognosis and the rate of complications is lower than that for totalthyroidectomy. However, when total thyroidectomy can be performed with a complication ratecomparable to thyroid lobectomy, it is the preferred approach for low-risk PTC. Although it mayor may not be associated with an improvement in overall survival, it has been shown tosubstantially reduce local and regional recurrence rates. Hay and colleagues reported areduction in local recurrence from 14%-2% and regional recurrence from 19%-6% and Mazzaferrireported a reduction in overall recurrence from 18.4%-7.1% with near-total or totalthyroidectomy vs thyroid lobectomy.50

In Japan, some clinicians have opted to observe patients with papillary microcarcinomawithout surgical intervention, a practice that is extremely controversial. Ito and colleaguesfrom Japan reported their observation trial for papillary microcarcinoma in 2010 and suggestedthat papillary microcarcinoma without unfavorable features can be safely monitored withoutsignificant disease progression.51 In their study, papillary microcarcinoma was termedunfavorable when there was concern for invasion of the recurrent laryngeal nerve, cytologicfeatures indicative of a tall cell, diffuse sclerosing, or poorly differentiated variant of PTC orlymph node metastases.

When a diagnosis of PTC is made after an initial thyroid lobectomy for an indeterminate,benign, or nondiagnostic FNA biopsy, the decision for a completion thyroidectomy shouldfollow the same management principles used for patients whose diagnosis of cancer was madeprior to operation. Once a decision for completion thyroidectomy is made, patientsshould undergo the procedure within 6 months from the diagnosis of thyroid cancer.Scheumann demonstrated that patients who were operated on within the 6-month period hadsignificantly fewer recurrences, fewer lymph node and hematogenous metastases, and survivedsignificantly longer than those in whom the second operation was delayed for longer than6 months.52

Extrathyroidal tumor spread occurs in approximately 15% of patients with PTC. It isassociated with higher rates of local recurrence and systemic metastases and significantreduction in survival.53,54 The strap muscles, recurrent laryngeal nerve, and trachea are themost common sites of local invasion. The esophagus and larynx are rare sites of local invasion.Patients with strap muscle invasion should be treated with an en bloc resection of the thyroidgland and the involved strap muscles. Resection of a recurrent laryngeal nerve that is invadedby tumor is performed when the nerve is nonfunctioning, as determined by laryngoscopicexamination. Otherwise, the tumor should be shaved off the recurrent laryngeal nerve topreserve its function. There has been no documented case of vocal cord recovery in a patientwith a paralyzed vocal cord from tumor invasion treated with incomplete tumor excision andnerve preservation.55

For patients with tracheal invasion without intraluminal involvement, removal of all grossdisease by tangential shaving of the tumor from the trachea is recommended. Alternatively, awedge of trachea may be resected en bloc when only a small segment of the anterior or lateralwall of the trachea is involved. Complete tracheal resection is reserved for patients with tumorinvasion through the entire wall of the trachea with mucosal involvement.56

Similar to the management of tracheal invasion, patients with esophageal invasion confinedto the muscle layers are treated with a tangential partial resection of the esophageal wall or asmall full-thickness resection of the esophageal wall. The defect is closed with sutures and withor without a muscle, myofascial, or myocutaneous flap. For patients with laryngeal invasionthat can be completely resected, a partial laryngectomy is performed. Total laryngectomy orlaryngopharyngectomy is recommended when partial laryngectomy cannot remove all grossdisease or when more than one-third of the circumference of the cricoid cartilage must beremoved to achieve tumor-free margins.57


Management of lymph node metastases

Approximately 35% of patients with PTC would have macroscopic lymph node metastasesand up to 80% would have microscopic lymph node metastases at the time of initialsurgery.58,59 It is standard practice to perform an ultrasound examination of the neck for allpatients with malignant cytology prior to thyroidectomy.43 Identification of lymph nodemetastases preoperatively may result in the addition of a central and lateral compartment neckdissection at the time of thyroidectomy or both.

Clinically unsuspected lymph node and soft tissue metastases have been identified in 14%-20%of patients with DTC prior to initial surgical therapy.60,61 FNA biopsy of clinically or sono-graphically suspicious (Table 2) lymph nodes should be performed preoperatively. Tg washings offine-needle aspirates from suspicious lymph nodes may be helpful when a cytologic diagnosiscannot be made, particularly when there is scant cellular material.

Lymph node metastases in patients with PTC most commonly involve the lymph nodes inthe central compartment of the neck (level VI). When the lateral neck is involved, it is themiddle (level III) and lower (level IV) jugular lymph nodes that most commonly havemetastatic disease. Younger patients and men are more likely to have cervical lymph nodemetastases.62 The lateral neck is more likely to be involved with metastatic disease, the greaterthe number of central neck nodes that are involved.63,64

Patients with PTC and macroscopic lymph node metastases have higher recurrence rates.39

It has also been shown that patients over 45 years of age with PTC and regional lymph nodemetastases have an increased mortality rate.65,66 There is evidence that lymphadenectomy inpatients with PTC and macroscopic lymph node metastases are associated with reduced ratesof recurrence and improved survival.39,67,68 The clinical significance of microscopic metastasesis less clear. Routine prophylactic central compartment or lateral neck dissection for PTC hasnot been shown to improve survival.

Patients with macroscopic lymph node metastases in the central neck should undergo atherapeutic central compartment neck dissection. Patients with microscopic lymph nodemetastases are treated with radioiodine. It is important to confirm that an enlarged orabnormal lymph node contains metastatic disease either with a preoperative FNA biopsy orwith an intraoperative frozen section examination. Patients with PTC and concomitantHashimoto thyroiditis may have benign reactive lymph nodes, which may be mistaken formetastatic disease, underscoring the importance of confirming metastatic disease prior toperforming a compartment-oriented neck dissection.

A central compartment neck dissection consists of removal of all nodal and fibrofatty tissuebetween the common carotid arteries from the hyoid bone superiorly to the innominate arteryinferiorly. The level VI (prelaryngeal, pretracheal, and paratracheal) and level VII (anteriormediastinal) lymph nodes are removed in a central compartment neck dissection (Fig 4). It isdifficult to preserve the blood supply to the inferior parathyroid glands when performing acentral compartment neck dissection. As a result, it is a good routine practice to autotransplantthe inferior parathyroid glands into the sternocleidomastoid muscle to reduce the risk ofpermanent hypoparathyroidism.

Whether or not to perform a prophylactic central compartment neck dissection for patientswith PTC is controversial. A prophylactic central compartment neck dissection is defined as acompartment-oriented level VI dissection performed in a patient without evidence of lymphnode metastases on preoperative physical examination, imaging studies, or intraoperativeevaluation. Occult micrometastases occur in 31%-62% of patients with PTC,69,70 yet mostmicrometastases remain dormant and rarely become clinically significant. Recurrence in thecentral neck occurs in approximately 2%-3% of patients with clinically node-negative PTC largerthan 1 cm who underwent thyroidectomy alone or thyroidectomy and prophylactic centralcompartment neck dissection.71 Locoregional recurrence has been reported to be equivalent inpatients with or without microscopic lymph node metastases.69

A meta-analysis of retrospective studies examining the outcome of treatment of 1264patients with PTC found no significant difference in overall locoregional recurrence rates (2% vs

Fig. 4. Lymph nodes that are removed during a central compartment neck dissection and a lateral compartment neck

dissection. (Modified from Figure 1 in McHenry CR, Phityakorn R. Difficult Problems in Thyroid Cancer Surgery.

Minerva Chir 2010;65:83-93, with permission.)


3.9%), central neck recurrence (1.9% vs 1.7%), or recurrence in the lateral neck (3.7% vs 3.8%),whether or not a prophylactic central compartment neck dissection was performed.72

Prophylactic central compartment neck dissection has been advocated for accurate staging ofpatients and more selective use of adjuvant radioiodine. This must be balanced with thepotential increased risk of permanent hypoparathyroidism that may occur as a result of theaddition of a central compartment neck dissection.

For patients with thyroid cancer and macroscopic lymph node metastases in the lateralneck, a selective compartment-oriented neck dissection is the preferred approach. In the past, amodified neck dissection, defined as removal of all lymph nodes from levels I-V, withpreservation of the sternocleidomastoid muscle, internal jugular vein, and spinal accessorynerve, was advocated. However, it has subsequently been shown that there is no survivaladvantage to performing a classic modified neck dissection vs a selective neck dissection.73,74 Aselective neck dissection is defined as removal of fewer than all the nodal basins from levelsI-V. We recommend performing a selective compartment-oriented neck dissection, consistingof removal of lymph nodes from levels IIA, III, IV, and VB, for patients with DTC andmacroscopic lymph node metastases in the lateral neck (Fig 5). Modification of the extent ofdissection is based on preoperative ultrasound findings. Excision of enlarged lymph nodes only,known as ‘‘berry picking,’’ is not advocated because of a higher recurrence rate.

Level I lymph nodes, which consist of the submental (IA) and submandibular (IB) lymphnodes, are rarely involved with metastatic thyroid cancer and are not routinely removed.Because of the lower risk for metastases, lymph nodes superior to the spinal accessory nervein level IIB and lymph nodes in the posterior cervical triangle along the spinal accessory nervesuperior to the horizontal plane extending from the cricoid cartilage to the convergenceof the trapezius and sternocleidomastoid muscle (level VA) are also not routinely removedunless they are identified as abnormal by ultrasound or intraoperative evaluation. Avoiding

Fig. 5. The anatomy and boundaries of the compartments involved in a lateral neck dissection for differentiated

thyroid cancer. (Color version of figure is available online.)


dissection of level IIA and VB compartments helps to reduce injury to the spinal accessorynerve.

Level IIA is bounded superiorly by the base of the skull, inferiorly by a horizontal planedefined by the hyoid bone, anteriorly by the posterior edge of the submandibular gland, andposteriorly by the spinal accessory nerve. The lymph nodes in level IIA correspond to lymphnodes along the upper third of the internal jugular vein. Level III and IV lymph nodescorrespond to the lymph nodes along the middle and lower thirds of the internal jugular vein.The boundaries of level III are a horizontal plane corresponding to the hyoid bone superiorly, ahorizontal plane defined by the cricoid cartilage inferiorly, anteriorly by the medial border ofthe carotid artery, and posteriorly by the posterior border of the sternocleidomastoid muscle.Level IV is bounded superiorly by the horizontal plane defined by the cricoid cartilage,inferiorly by the clavicle, anteriorly by the medial border of the carotid artery, and posteriorlyby the posterior border of the sternocleidomastoid muscle. Level VB corresponds to the inferioraspect of the posterior cervical triangle and contains the transverse cervical and supraclavicularlymph nodes. Level VB is bounded superiorly by a horizontal plane extending from the cricoidcartilage to the trapezius muscle, inferiorly to the clavicle, anteriorly by the posterior border ofthe sternocleidomastoid muscle, and posteriorly by the anterior border of the trapezius muscle(Fig 5).

Table 4Complications of lateral neck dissections.

Surgical site infection

Bleeding

Chylous fistula

Nerve injury:

Dissection level I: hypoglossal, lingual, and marginal mandibular

Dissection levels II-V: spinal accessory, greater auricular, cervical sensory roots, phrenic, cervical sympathetic

trunk, vagus, and brachial plexus


Significant complications may occur from a lateral neck dissection (Table 4). Nerve injury isthe most important complication. The spinal accessory nerve may be transected or injuredfrom traction or cautery. Patients may experience shoulder pain and weakness with difficultyin raising their arm, a shoulder droop, or a winged scapula. The most common complicationfrom a lateral neck dissection is numbness of the lateral neck and ear resulting from injury tothe greater auricular nerve and sacrifice of the sensory nerve roots.

Horner syndrome, manifested by ipsilateral ptosis, miosis, and anhidrosis, may result frominjury to the cervical sympathetic chain with dissection posteriomedial to the carotid artery.Phrenic nerve injury may result in paresis or paralysis of the hemidiaphragm and reduction inlung capacity. Hypoglossal, lingual, and marginal mandibular nerve injury may occur withdissection of level I lymph nodes in the submandibular and submental triangles. Injury to thevagus nerve and brachial plexus are uncommon. Injury to the vagus nerve may affect therecurrent laryngeal nerve and result in vocal cord paralysis, or the superior laryngeal nerve andresult in loss of supraglottic sensation with aspiration. Injury to the brachial plexus results inpain, numbness, and weakness that can involve the shoulder, arm, or hand. Chylous fistula mayoccur with interruption of the thoracic duct, which empties into the internal jugular vein at itsjunction with the subclavian vein in the left neck. It also may occur from interruption of thelymphatic duct in the right neck.

Surgical pathology and histologic variants of PTC

Most often PTC is a well-circumscribed, unencapsulated solid gray-white mass withirregular and infiltrative borders. Architectural features that are characteristic of PTC include apapillary growth pattern, elongated-appearing follicles, psammoma bodies, and intratumoralfibrosis. ‘‘Orphan Annie eyes’’ or nuclear clearing, a classic cytomorphologic change associatedwith PTC, occurs as a result of fixation artifact.

Several histologic variants of PTC are recognized based on distinct architectural andcytomorphologic features. Architectural subtypes of PTC include classic, follicular, diffusesclerosing, and cribiform-morular; whereas cytomorphologic subtypes include classic, tall cell,columnar, clear cell, and oncocytic. Tall cell, diffuse sclerosing, and cribiform-morular are moreaggressive variants of PTC.

The FV of PTC is second only to the classic variant of PTC, accounting for approximately 15%-35% of cases.75 It is characterized by an almost exclusive follicular pattern of growth with manyof the features of classic PTC, including oval nuclei, nuclear crowding with a lack of follicularpolarity, clear or pale nuclear chromatin, prominent nuclear grooves, and psammomabodies.76,77 However, there is no consensus on the exact histologic characterization of FVPTC. There has been an increase in the incidence of the FV of PTC as a result of reclassification oflesions once felt to be FC.

Lin and colleagues reported similar 10- and 15-year survival for classic and FV PTC. FV PTChas a significantly lower rate of nodal involvement than the classic type.78 Most patients withFV PTC have a well-encapsulated tumor. Nonencapsulated, diffuse, infiltrative FV PTC is lesscommon and is more likely to have nodal metastases, extrathyroidal extension, positivemargins, and marked intratumoral fibrosis.79


The tall cell variant (TCV) of PTC accounts for approximately 7%-14% of all PTCs.80 The TCVconsists of follicular epithelial cells whose height is twice their width with nuclear featurescharacteristic of PTC and eosinophilic cytoplasm owing to the presence of increasedmitochondria.77,81 Tall cells account for more than 50% of tumor cells. Compared with classicPTC, the TCV is more often associated with metastases, is less likely to concentrate radioiodine,and has a higher rate of recurrence and mortality. Factors that may contribute to a worseprognosis include older age at presentation, larger tumor size, and a higher incidence ofextrathyroidal extension.82 Approximately 80% of patients with the TCV of PTC have BRAFmutations.83-85

Diffuse sclerosing variant (DSV) of PTC is rare with an estimated incidence of 0.75%-5.3%.86

Clinically, DSV of PTC can be confused with Hashimoto thyroiditis because of the diffusethyroid involvement and the presence of serum anti-Tg antibody. Pathologically, it ischaracterized by diffuse involvement of the thyroid parenchyma, sclerosis, abundantpsammoma bodies, prominent squamous metaplasia, and extensive lymphatic permeation.Patients with DSV are usually younger at presentation, have larger tumor size, and higherincidence of lymph node metastases. In a case series of 22 patients with DSV of PTC, 82% hadextrathyroidal extension and lymph node metastases. Although biologically more aggressive,the overall survival is not significantly different compared with classic PTC.86 This result wasreflected similarly in other studies.87,88

The cribiform-morular variant accounts for less than 0.1% of all PTC. It can be seen insporadic cases but most often occurs in patients with FAP syndrome. It occurs predominantly inwomen in their twenties, and can precede the diagnosis of FAP. Histologically, this variant ischaracterized by a combination of cribiform, follicular, papillary, trabecular, solid, and spindlecell growth patterns with morular areas.89 Its peculiar morphologic features are related to thepermanent activation of the WNT (wingless type) signaling pathway, with nuclear andcytoplasmic accumulation of beta-catenin.90 Because of the low number of reported cases, it isdifficult to ascertain whether this variant harbors a significantly worse prognosis comparedwith classic PTC.

Molecular pathogenesis

Biomarkers specific for thyroid cancer have been identified that have diagnostic,therapeutic, and prognostic implications and that have advanced our understanding of thegenetic basis of thyroid cancer. Activating alterations in several genes within the mitogen-activating protein kinase pathway have been identified in the majority of patients with PTC.REarranged during Transfection (RET) oncogene activation in PTC occurs by RET rearrange-ments when the intracellular tyrosine kinase domain of RET is coupled to the N-terminalfragment of different heterologous genes.

RET/PTC1 and RET/PTC3 are the most common gene rearrangements identified in PTC. RETrearrangements occur in 70% of radiation-induced PTC and 40% of sporadic PTC.91 The reportedincidence of RET mutations in patients with PTC has decreased from 33% during the periodfrom 1996-2000 to 17% from 2001-2005 to 9.8% from 2006-2010.92 The higher incidence foundin 1996-2000 may have been related to the post-Chernobyl radioactive fallout. The decrease inincidence in RET mutations over time may be because of better education about radiationexposure and its associated risks.

A point mutation in the BRAF gene at codon 600 is the most common genetic alterationfound in sporadic PTC.93 This point mutation results in a valine to glutamate alteration, leadingto constitutive mitogen-activating protein kinase pathway stimulation. The BRAF V600Emutation has been detected in approximately 45% of PTC and ranges from 23%-83% dependingon different cohorts.94-96 The prevalence of the BRAF V600E mutation in PTC has beendocumented to have progressively increased over time from 28% in 1996-2000 to 49% in 2001-2005 and 58% in 2006-2010.92 The BRAF mutation is most commonly present in the classic andTCVs of PTC. It is rarely seen in the FV of PTC, nor is it very common in radiation-induced PTC.


The BRAF mutation can also occur in thyroid lymphoma, poorly differentiated and anaplasticthyroid cancers (ATCs), and has also been identified in rare cases of benign hyperplasticnodules. It has not been identified in FC or MTC.97 The overall increase in the incidence of BRAFmutation may be the result of environmental factors that cause DNA point mutations. Highiodine intake and air pollutants have been identified as potential sources.

Molecular testing for gene mutations has been increasingly used for diagnostic purposes,especially in the case of the patient with a thyroid nodule and an indeterminate FNA biopsyresult. In a study by Nikiforov and colleagues, 470 nodules were sampled with FNA from 328consecutive patients and were tested for BRAF, RAS, PAX8-PPARg, and RET/PTC mutations.Thirty-two of the 470 (7%) FNA samples were positive for one of the mutations, 31 of whichwere confirmed to be malignant on pathologic examination. Molecular testing had a sensitivityof 62%, but when combined with cytology, the sensitivity increased to 80% with a PPV of 98%.98

In the 10 prospective studies performed since 2004 to test for BRAF mutations in the FNAsamples, the sensitivity of BRAF in detection of malignancy ranged from 27%-83%, but thespecificity was nearly 100%.99 Because of the high specificity, some centers have advocatedinitial definitive total thyroidectomy for patients with nodular thyroid disease and anindeterminate FNA biopsy when genetic testing is positive. The cost associated with moleculartesting has yet to be elucidated, and whether routine molecular testing will become a routineadjunct diagnostic tool to FNA biopsy remains to be seen.

Molecular markers also have significant prognostic implications in the management ofpatients with PTC. The BRAF V600E mutation has been reported to be associated with a higherincidence of extrathyroidal tumor spread, lymph node and systemic metastases, andrecurrence.83 In a study of 500 patients with PTC conducted by Lupi and colleagues, 43% ofthe patients tested positive for BRAF mutation. The BRAF-positive patients were older and had ahigher incidence of extrathyroidal extension, nodal metastases, and multicentricity.100 Usingmultivariate analysis, Kebebew found that the BRAF mutation was independently associatedwith persistent and recurrent PTC. Patients with papillary microcarcinoma and a BRAFmutation had an incidence of extrathyroidal extension and lymph node metastases similar tothat in patients with larger PTCs, suggesting that BRAF mutation positivity may be associatedwith a worse prognosis regardless of tumor size.101

Not all studies have found the BRAF mutation to be a marker of more aggressivedisease.96,102 Two recent reports have demonstrated a significant increase in the frequency ofthe BRAF mutation in patients with PTC over time without an increase in the incidence ofextrathyroidal tumor spread, lymph node metastases, and node or systemic metastases.92

Sancisi and colleagues and others have suggested that the BRAF mutation may not be aninitiating event in BRAF-positive tumors and that BRAF status alone cannot be an independentpredictor of aggressive disease.96

Staging, recurrence, survival, and prognosis

Postoperative staging of PTC is important for determining the need for adjuvant radioactiveiodine (RAI) therapy, the degree of TSH-suppressive therapy with levothyroxine, the methodsand intensity of follow-up, and prognosis. Thyroid cancer staging is based on the AmericanJoint Committee on Cancer (AJCC) TNM staging system (Fig 6). The AJCC TNM staging isintended for prediction of death, and not for recurrence.

In a study by Hundahl and colleagues, the outcome of 42,687 patients who underwentthyroidectomy for thyroid cancer between 1985 and 1995 was determined. The majority of thepatients had stage I (56.9%) or stage II disease (14.4%). Overall, patients with PTC had the best10-year survival rate (93%) when compared with follicular (85%), Hurthle cell (76%), medullary(75%), and anaplastic (10%) cancers.103 Based on the seventh edition AJCC Cancer Stagingsystem, the 5-year disease-specific survival rates for PTC are 100% for stages I and II, 93% forstage III, and 51% for stage IV.104

The incorporation of patient age into the AJCC system favors patients younger than 45 yearsof age. Even in the presence of systemic metastases, patients younger than 45 years are

T0 No evidence of primary tumor.T1 Tumor ≤2 cm in greatest dimension limited to the thyroid.T1a Tumor ≤1 cm, limited to the thyroid.T1b Tumor >1 cm but ≤2 cm in greatest dimension, limited to the thyroid.T2 Tumor >2 cm but ≤4 cm in greatest dimension, limited to the thyroid.T3 Tumor >4 cm in greatest dimension limited to the thyroid or any tumor with minimal extrathyroid extension (e.g.,extension to sternothyroid muscle or perithyroid soft tissues).T4a Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve.

T4b Tumor invades prevertebral fascia or encases carotid artery or mediastinal vessels.

NX Regional lymph nodes cannot be assessed.N0 No regional lymph node metastasis.N1 Regional lymph node metastasis.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 superiormediastinal lymph nodes (Level VII).

M0 No distant metastasis.M1 Distant metastasis.

Primary Tumor (T)

Regional Lymph Nodes (N)

Distant Metastases (M)

Stage T N MPapillary or follicular (differentiated)

YOUNGER THAN 45 YEARS

I Any T Any N M0II Any T Any N M1

45 YEARS AND OLDERI T1 N0 M0II T2 N0 M0III T3 N0 M0

T1 N1a M0T2 N1a M0T3 N1a M0

IVA T4a N0 M0T4a N1a M0T1 N1b M0T2 N1b M0T3 N1b M0T4a N1b M0

IVB T4b Any N M0IVC Any T Any N M1

Stage T N MMedullary carcinoma (all age groups)I T1 N0 M0II T2 N0 M0

T3 N0 M0III T1 N1a M0

T1 N1a M0T2 N1a M0T3 N1a M0

IVA T4a N0 M0T4a N1a M0T1 N1b M0T2 N1b M0T3 N1b M0T4a N1b M0

IVB T4b Any N M0IVC Any T Any N M1

Anaplastic carcinoma c

IVA T4a Any N M0IVB T4b Any N M0IVC Any T Any N M1

Fig. 6. Seventh edition American Joint Committee on Cancer (AJCC) tumor, lymph node, and metastases (TNM) staging

system. (A) TNM staging, and (B) staging for differentiated, medullary, and anaplastic thyroid cancer (http://www.

cancer.gov/cancertopics/pdq/treatment/thyroid/HealthProfessional/page3).


classified under stage II disease. The 1986 study of National Cancer Data Base on PTC showed a10-year disease-specific survival of 95% for patient age less than 45 years, 85% for age 45-59years, 65% for age 60-69 years and 47% in patients older than 70 years.103 However, the AJCCsystem appears to understage younger patients. In a recent study by Tran and colleagues, themortality rate for patients younger than 45 years of age with stage II PTC was 11 times greaterthan that for patients with stage I disease. The survival of patients with stage II PTC in the less

http://www.cancer.gov/cancertopics/pdq/treatment/thyroid/HealthProfessional/page3

http://www.cancer.gov/cancertopics/pdq/treatment/thyroid/HealthProfessional/page3


than 45 years old age group was less than that for older stage II patients, raising concern thatthe AJCC should be revised.105

Although the long-term survival of patients with PTC is generally excellent, the recurrencerate is significant. In a 40-year follow-up study of patients with PTC, Mazzafferi andcolleagues50 reported a 35% recurrence rate. This may be an underestimation of the true rate ofrecurrence because only patients with positive imaging findings or a positive biopsy wereincluded. Those with an elevated serum Tg level but no evidence of disease recurrence onimaging studies were not included. In a follow-up study, Mazzafferi demonstrated that 50% ofall recurrences occurred during the first 5 years following definitive surgical therapy and 75%within the first 10 years.50 Seventy percent of the recurrences occurred in the neck whereas theother 30% occurred in distant sites. Patients at the extremes of age had higher disease-specificrecurrence rates. Patients younger than age 15 years had a recurrence rate of 50% and patientsolder than the age of 60 had a recurrence rate of approximately 40%.

Once distant metastases are detected in patients with PTC, approximately 50% of patientswould die within 5 years. Younger patients with systemic metastases survive longer.106 Forty-nine percent of systemic metastases are to the lung, 25% to the bones, 15% to both the lung andbones, and the remaining are to miscellaneous sites, including the central nervous system,liver, adrenal glands, and skin.

The significance of gender in predicting thyroid cancer prognosis is not completely clear.Men typically present at an older age than women do. The peak age at the time of cancerdiagnosis is 10-20 years later in men than in women. Men have more than twice the frequencyof distant metastases and approximately 30% more regional metastases at the time ofdiagnosis. These differences have been largely attributed to how men and women access thehealthcare systems, with men presenting at a later age and with more advanced stage tumors.So, male gender when corrected for age may not be an independent predictor of outcome forpatients with PTC.

Follicular and Hurthle cell carcinoma (HCC)

Case

A 58-year-old healthy woman was referred for evaluation of a right-sided thyroid nodulethat was felt on routine physical examination by her primary care physician. She wasasymptomatic, denied a history of head or neck irradiation and had no family history of thyroidcancer or other endocrinopathies. On physical examination, she had a firm, mobile 2-cm nodulepalpable in the right lobe of the thyroid gland. Her trachea was midline and she had noabnormal cervical lymphadenopathy. The remainder of her physical examination was normal.

An ultrasound examination demonstrated a well-circumscribed, 2-cm hypoechoic nodulewith smooth borders in the right lobe of the thyroid gland that was hypervascular on Dopplerexamination. There were no additional thyroid nodules. Cytologic analysis of an ultra-sound-guided FNA biopsy was interpreted as a follicular neoplasm. Her serum TSH level was1.50 mIU/mL.

A right thyroid lobectomy and isthmusectomy was performed. There were no abnormal lymphnodes in the central neck. The final pathology revealed a 2-cm follicular carcinoma of the thyroidgland with both capsular and vascular invasion. She underwent a completion thyroidectomy3 months later. Pathology revealed no residual cancer. She subsequently underwent radioiodineablation with 30 mCi of 131I. A follow-up whole-body scan (WBS) was negative. She is onlevothyroxine therapy to maintain her serum TSH level between 0.1 and 0.5 mIU/mL. Twelvemonths after her radioiodine ablation, a TSH-stimulated Tg was less than 2.0 ng/mL.

Follicular thyroid cancer (FC)

FC of the thyroid gland accounts for approximately 11% of all thyroid malignanciesin iodine-sufficient countries and 25%-40% of thyroid malignancies in areas of


iodine deficiency.103 FC is the second most common form of DTC. However, the incidenceof FC has decreased in the United States in relation to the elimination of iodine deficiencyand the more accurate diagnosis of FV of PTC. FC occurs most commonly in the sixthdecade of life, and as with all thyroid malignancies, it is more common in women thanin men.

FC is usually a unifocal tumor. It more commonly spreads hematogenously. Systemicmetastases are present in 10%-15% of patients at the time of diagnosis of FC. Lymph nodemetastases occur in fewer than 10% of patients. Overall 10-year survival for FC is 85%.103 Inpatients with distant metastases, the survival rate drops to 38%-50% at 5 years.107

Diagnosis

Histologically, FC consists of a microfollicular architecture with follicles lined by cuboidalepithelial cells. A benign follicular adenoma has the same architecture. FC tends to be morecellular than a follicular adenoma with more frequent mitoses and a thicker and often irregularcapsule. However, the primary features that distinguish an FC from a follicular adenoma arecapsular and vascular invasion, which cannot be determined based on examination of cellsfrom an FNA biopsy.

Most patients with FC present with a solitary thyroid nodule and the diagnostic evaluationconsists of an ultrasound of the neck, a screening of serum TSH level, and a routine FNA biopsy.Patients with a thyroid nodule and an FNA biopsy interpreted as a follicular neoplasm, as in ourcase, have an approximately 20% likelihood of malignancy, which on final pathology can be FC,FV of PTC, or classic PTC. Although it has been suggested that age greater than 50 years, nodulesize greater than 3 cm, and male gender may be associated with a higher likelihood of FC inpatients with a follicular neoplasm, we and others have not found these to be independentpredictors of malignancy.108 Ultrasound is important to characterize the nodule and also toevaluate the opposite lobe of the thyroid gland for nodular disease. In one study, the absence ofintranodular blood flow using duplex Doppler ultrasonography in a follicular neoplasm wasshown to have a 96% negative predictive value, making it unlikely to be FC.109 Patients with alow serum TSH level should undergo 123I thyroid scintigraphy to exclude a hyperfunctioningnodule, which is much less likely to be malignant, with a reported rate of malignancy of 1% orless.110

Oncogene activation has been demonstrated to play an important role in the pathogenesis ofFC.111 Point mutations in the rat sarcoma (RAS) genes, N-RAS, H-RAS, and K-RAS, occur inapproximately 40% of patients with FC and are responsible for uncontrolled growth.112,113

Paired box gene 8/peroxisome proliferator–activated receptor g (PAX8-PPARg) gene rearrange-ment has been found in 29%-56% of FC and is a cause for loss of inhibitory control of growth.114

MicroRNAs (miR-192, miR-197, miR-328, and miR-346), which alter gene transcription andaffect apoptosis and cell proliferation, have been shown to have greater expression in FC.115

Genetic mutations in p53, c-myc, c-fos, the TSH receptor, and the PTEN suppressor gene havealso been identified as potential factors involved in the pathogenesis of FC.115,116

Molecular profiling is being used in the diagnostic evaluation of patients withan indeterminate FNA biopsy, which include cytologic interpretations consistent withfollicular or Hurthle cell neoplasm and suspicious for PTC. Recently, several mutational panelshave been developed that combine multiple genetic markers to help better define the riskof malignancy for a thyroid nodule based on FNA biopsy. Nikiforov and colleagues,93,98 usinga molecular profiling panel, analyzed more than 1000 patients with thyroid nodulesand indeterminate cytology for BRAF V600E, N-RAS, H-RAS, K-RAS, RET/PTC 1,3, and PAX8/PPARg mutations in FNA biopsy samples. The detection of any mutation conferred a risk ofmalignancy of 87%-95% whereas the risk of cancer in a mutation negative nodule was only 6%-28%. The negative predictive value in this and other studies for the absence of geneticmutations is not high enough to forgo proceeding with a diagnostic thyroid lobectomy andisthmusectomy.


Other investigators have used mRNA expression analysis to measure almost 250,000transcripts in FNA samples and surgical tissues from thyroid nodules and have created amolecular classifier, known as the Veracyte Afirma, gene expression classifier.117 A prospective,multicenter validation of the novel molecular classifier was completed utilizing the Veracytegene expression classifier data analysis of 167 genes in 265 indeterminate thyroid FNA biopsysamples and demonstrated a 92% sensitivity and 52% specificity based on surgical pathology.118

The negative predictive values for follicular lesion of undetermined significance and follicularneoplasms were 95% and 94%, respectively. The results of this study emphasize the potential ofmolecular classification of thyroid nodules using FNA biopsy specimens to reduce theperformance of unnecessary thyroidectomy in patients with benign disease.

Another strategy has been to look for blood-based markers of malignancy that could be usedpreoperatively to assess the risk of malignancy in a thyroid nodule or postoperatively to assessfor recurrence of cancer. TSH receptor and Tg mRNA transcripts identified in the blood havebeen reported to be sensitive and specific for thyroid cancer.119,120 A TSH receptor messengerRNA level greater than 1 mg/mg in the blood of a patient with a follicular neoplasm has beenreported to have a 96% predictive value for cancer and an undetectable level in a patient withno abnormal sonographic findings has been reported to have a 95% predictive value for benigndisease.120 Molecular profiling holds great promise, but will need further refinement to excludesurgery.

Because clinical factors, cytomorphologic criteria, and sonographic features cannotdefinitively distinguish a follicular adenoma from FC, a diagnostic thyroid lobectomy andisthmusectomy is necessary to evaluate for capsular and vascular invasion and make adefinitive diagnosis of FC. Capsular invasion is defined as tumor invasion through the entirecapsule of the tumor. Vascular invasion is a more reliable sign of FC and is defined as tumorpenetration of a large caliber vessel within or immediately outside the capsule of the tumor.76

An FC may also be distinguished from a follicular adenoma on the basis of extrathyroidal tumorspread, lymph node metastases, or systemic metastases.

Pathologic evaluation is important to classify FC as minimally invasive or invasive.Minimally invasive FC has traditionally been described as an encapsulated tumor of the thyroidthat exhibits microscopic penetration of the tumor capsule without evidence of vascularinvasion.76,121,122 Invasive FC has been defined as a tumor with either gross capsularinvasion, extension beyond capsule into the surrounding thyroid parenchyma or vascularinvasion.76,121,122

The distinction between minimally invasive and invasive FC is important because minimallyinvasive FC is a much less aggressive tumor with overall survival rates of 98% or greatercompared with invasive FC, which has a 10-year disease-specific mortality rate of 15%-28%.123

D’Avanzo and colleagues classified FC into minimally invasive, moderately invasive, andwidely invasive variants and reviewed the outcome after a mean 7-year follow-up in 132patients who underwent total thyroidectomy with or without radioiodine treatment.Minimally invasive FC was defined as microscopic capsular invasion only. Moderately invasiveFC was defined by the presence of angioinvasion with or without capsular invasion, and widelyinvasive FC was defined by extensive tumor invasion into the surrounding muscle, fat,or other structures. Twelve of the 132 patients had synchronous distant metastases andwere excluded from the survival analysis. Kaplan-Meier survival curves were dramaticallydifferent for the 3 histologic variants of FC. Recurrence and death occurred in 13% and 11%of patients, respectively, with minimally invasive FC; 20% and 14% of patients, respectively,with moderately invasive FC; and 38% and 62% of patients, respectively with widelyinvasive FC.122

In contrast to D’Avanzo and colleagues, other large centers have had no mortality fromminimally invasive FC. van Heerden and colleagues followed 20 patients with minimallyinvasive FC for 20 years after surgical therapy and no patient developed systemic metastases ordied from FC and only 1 patient developed recurrence.123 Sanders and Silverman followed80 patients with minimally invasive FC for a mean period of 14 years and no patient developeda recurrence or died from FC.124


Surgical therapy

Patients who present with a solitary thyroid nodule that yields a diagnosis of follicularneoplasm on FNA biopsy should undergo a thyroid lobectomy and isthmusectomy. Clinicalfactors, with the exception of a history of head or neck irradiation or disease involving bothlobes of the thyroid gland, do not affect intraoperative decision making regarding the extent ofthyroidectomy.108 Patients with a history of head or neck irradiation or nodular diseaseinvolving the contralateral lobe of the thyroid gland should undergo a total thyroidectomy. Atoperation, the opposite lobe of the thyroid gland should be palpated for concomitant nodulardisease and the central neck examined for abnormal lymph nodes. Patients with FV of PTC andclassic PTC may present with a follicular neoplasm and are more likely to have lymph nodemetastases. A central neck dissection is rarely necessary because lymph node metastases arepresent in fewer than 10% of patients with FC.

Intraoperative frozen section examination of a follicular neoplasm is rarely valuable becausea single pathologic section has a high likelihood of missing a solitary focus of capsularor vascular invasion. Multiple sections of the nodule capsule interface are usually requiredto make a diagnosis of FC. In addition to sampling error, the assessment of capsular orvascular invasion by frozen section examination is limited by the variable thickness andirregularity of the capsule, blood vessel distortion, and collapse and sectioning artifact. Frozensection examination has been shown to have a high false-negative rate and is not costeffective.125

If the final pathologic examination reveals a true microinvasive lesion with a solitary area ofcapsular invasion without angioinvasion or gross extrathyroidal extension, then no additionaltherapy is necessary. Because minimally invasive FC has been shown to be very indolent in itsbehavior, with a disease-free survival similar to that in patients with a follicular adenoma, mostexperts agree that thyroid lobectomy and isthmusectomy is definitive therapy.126 Patients canbe followed up with ultrasound or physical examination or both for the development of anodule in the remaining lobe of the thyroid gland. Patients diagnosed with invasive FC shouldundergo completion thyroidectomy and radioiodine ablation to optimize the use of serum Tgand whole-body scanning for detection of residual or recurrent disease. In contrast to patientswith minimally invasive FC, patients with invasive FC have a 10-year disease-specific mortalityrate of 15%-28%.123

HCC

HCC, first described by Ewing in 1928, is the least common type of DTC, accounting forapproximately 3% of all thyroid cancers.103 It is a follicular cell–derived tumor with TSHreceptors, a functioning TSH adenylate cyclase system, and Tg immunoreactivity.127,128 HCC iscomposed of more than 75% Hurthle cells arranged in a follicular or trabecular pattern withcapsular or vascular invasion.129 Hurthle cells are large polygonal cells that have pleomorphichyperchromatic nuclei and a distinctive eosinophilic granular cytoplasm demonstrated onHematoxylin and Eosin staining, which corresponds to an abundance of mitochondria onelectron microscopy.76,129 HCC, like FC, produces Tg. In contrast to FC, HCC is a more aggressivetumor. It is more often multifocal and bilateral, more likely to have lymph node metastases andextrathyroidal tumor spread, and is less likely to concentrate radioiodine.130 Of all DTCs, HCC isthe most likely to have metastases and has the lowest 10-year survival rate: 76%, comparedwith 85% for FC and 93% for PTC.103

HCC generally manifests in the fifth and sixth decades. Patients with HCC most commonlypresent with a palpable thyroid nodule. They may also present with cervical lymphadenopathyand rarely pulmonary nodules. Approximately 10%-20% of patients would present withsystemic metastases most commonly involving the lung or bones.131 Only 10%-25% of patientswith HCC and metastases concentrate radioiodine, compared with 75% or more of patients withFC.130,132,133


Diagnosis

If FNA biopsy of the thyroid nodule reveals a Hurthle cell neoplasm several potentialdiagnoses can be entertained, including Hashimoto thyroiditis, adenomatous hyperplasia,benign Hurthle cell nodules, Graves disease, oxyphillic variant of PTC and benign Hurthlecell adenoma, and HCC.134 Neoplastic disease accounts for two-thirds of the pathology inpatients with an FNA biopsy consistent with a Hurthle cell neoplasm.134 Hurthle cellneoplasms, also known as oncocytic thyroid neoplasms, are defined as encapsulated tumorscomposed of at least 75% Hurthle cells.129 Hurthle cell neoplasms are similar to follicularneoplasms in that 20% are malignant. A benign Hurthle cell adenoma is distinguished from aHCC based on the presence of capsular or vascular invasion, lymph node metastases, andsystemic metastases.

HCC, like FC, is defined by the presence of capsular or vascular invasion, and thus a diagnosisof HCC cannot be made by FNA biopsy alone. There are some data suggesting that the rate ofcancer found in a Hurthle neoplasm increases with increasing age, male gender, and increasingtumor size.135,136 In one study, 70% of Hurthle neoplasms which were larger than 5 cm weremalignant and all Hurthle cell neoplasms which were larger than 10 cm were malignant.135

Most studies that have evaluated clinical factors for their potential value in predictingcarcinoma and helping to determine the extent of thyroidectomy for patients with Hurthle celland follicular neoplasms have been retrospective studies of patients with a final pathologicdiagnosis of Hurthle cell or follicular adenoma, FC, and HCC as opposed to an analysis of allpatients with an FNA diagnosis of follicular and Hurthle cell neoplasm. They are also surgicalseries with selection bias. In our experience, clinical and cytomorphologic features have notbeen helpful in predicting carcinoma in patients with thyroid nodules and an FNA biopsyconsistent with either a Hurthle cell neoplasm or follicular cell neoplasm. As a result, wecontinue to recommend thyroidectomy in all patients with thyroid nodules and an FNA biopsyconsistent with a Hurthle cell or follicular neoplasm and clinical factors are not used todetermine the extent of thyroidectomy.108

Surgical therapy

If an FNA biopsy of a solitary thyroid nodule yields a diagnosis of Hurthle cell neoplasm, athyroid lobectomy with isthmusectomy should be performed to distinguish nonneoplasticnodules and benign Hurthle adenoma from a HCC. Patients with a history of head or neckirradiation or nodular disease involving the contralateral lobe of the thyroid gland shouldundergo a total thyroidectomy. Similar to follicular neoplasms, intraoperative frozen sectionexamination has not been shown to be useful in distinguishing a Hurthle cell adenoma from aHCC. In one study, frozen section examination was helpful in determining the extent ofthyroidectomy in only 3.3% of cases and in 5% of cases frozen section examination led toadditional unnecessary resection.137 If final pathology reveals a diagnosis of HCC, completionthyroidectomy should be performed in all patients because of its more aggressive behavior anda higher rate of multicentric and bilateral disease.

At the time of surgical resection, the central neck should be examined for abnormal lymphnodes. An abnormal lymph node should be excised and submitted for frozen sectionexamination. This is important because patients with Hashimoto thyroiditis may havenonneoplastic Hurthle cell nodules and abnormally enlarged central neck lymph nodes thatmay be confused with HCC. A central neck dissection should be performed for macroscopiclymph node metastases.

Because of the more aggressive behavior of HCC, we advocate routine radioiodine ablation.Despite the fact that HCC is less likely to concentrate radioiodine, radioiodine ablation willdestroy residual normal cells, which optimizes the value of serum Tg for detection of recurrentdisease. Ten percent to 35% of metastases in patients with HCC will concentrate radio-iodine.130,132,133 If the patient has evidence of residual disease based on high Tg levels or


radiographic evidence of metastatic disease without uptake of 131I on whole-body scanning orboth, additional dosing is not clinically valuable. Tyrosine kinase inhibitors (TKI) are being usedin limited clinical trials for metastatic or locally recurrent radioresistant HCC.

Postoperative treatment and follow-up of patients with DTC

Thyroid hormone therapy

Postoperatively, patients with DTC are treated with levothyroxine (LT4) to reduce serumTSH, which has been shown to stimulate tumor growth, invasion, and angiogenesis. TSH,produced in the anterior pituitary gland, is a 28-kD glycoprotein that is involved in thyroidgrowth and hormone regulation.138 TSH has been shown to upregulate follicular cell growthand is thought to increase follicular cell mitosis by a cyclic adenosine monophosphatemechanism via its interaction with the TSH receptor on the cell surface of follicular cells.139

TSH suppression is important in the long-term management of patients with DTC to preventthe growth or dedifferentiation of residual tumor cells.

TSH suppression has become a routine component in the treatment of DTC. Pujol andcolleagues in a study of 141 patients found that TSH suppression to undetectable levels (TSHo0.05 mU/L) resulted in a longer disease-free survival and lower recurrence rate when comparedwith patients with serum TSH levels greater than 1 mU/L.140 A larger cohort analysis of 683patients with DTC followed up for a median of 4.5 years (range 1-8.5 years) after thyroidresection was performed by Cooper and colleagues with the National Thyroid CancerCooperative Study Group Registry.141 This retrospective study examined patients by cancertype (papillary ¼ 617 and follicular ¼ 66), stage (I and II ¼ low risk, and III and IV¼ high risk),and the extent of TSH suppression. The extent of serum TSH suppression was an independentpredictor of disease progression only in high-risk patients. Mazzaferri and colleagues142 in a30-year retrospective analysis of patients with DTC reported that patients treated with LT4 had25% fewer recurrences and 50% fewer cancer-related deaths than those without adequate LT4therapy and elevated serum TSH levels. Other studies have also shown a survival benefit fromTSH suppression.49

Biondi and colleagues143 agree that LT4 suppression is warranted in patients with high-riskdisease, but question if long-term TSH suppression is necessary in patients who have anundetectable TSH-stimulated Tg level and a negative radioiodine WBS. TSH-suppressive dosesof thyroid hormone are a known cause for atrial fibrillation and other cardiac arrhythmias,spontaneous postmenopausal bone loss, osteoporosis, and exacerbation of underlying ischemicheart disease. Approximately 80% of patients treated for DTC would ultimately have nodemonstrable disease and as a result, replacement rather than suppressive doses of LT4 arepreferable to avoid the potential complications of TSH-suppressive doses. The AmericanThyroid Association Guidelines Taskforce recommends maintaining serum TSH between0.1 and 0.5 mU/L in patients with high-risk DTC who are free of disease, between 0.3 and2.0 mU/L for patients with low-risk DTC, and less than 0.1 mU/L for patients with metastaticdisease.43

Radioiodine remnant ablation

Postoperative radioiodine ablation is advocated for destruction of residual normal ormalignant thyroid cells.43,44,144 It helps facilitate the most effective use of Tg and radioiodinewhole-body scanning for early detection of persistent or recurrent disease. A 30-mCi dose of131I given as an outpatient procedure is recommended and is successful in 80% or more of patientswho have undergone total thyroidectomy.133 Results of remnant ablation with 50-100 mCi of 131Ihave been shown to be equivalent after thyroid hormone withdrawal or administration ofrecombinant human (rhTSH) but may be lower with a 30-mCi dose of 131I.145-147


There is good evidence that radioiodine ablation is valuable in patients with distantmetastases, extrathyroidal tumor spread, and tumor size greater than 4 cm.43 Based onexpert opinion, the American Thyroid Association management guidelines for DTC alsorecommend postoperative 131I ablation for patients with DTC 1-4 cm in size for aggressivehistologic subtypes, lymph node metastases, lymphovascular invasion, and multifocality.131I ablation is also recommended for patients with DTC smaller than 1 cm with associatedhigh-risk features.43 A WBS is obtained 3-7 days after radioiodine administration toevaluate for residual uptake in the thyroid bed and regional lymph node or systemicmetastases.

Follow-up

In general, patients with DTC are followed up every 6 months for the first 2 yearsbecause this is the time when recurrence is highest. Follow-up consists of clinical examinationfor local recurrence in the thyroid bed and abnormal cervical or supraclavicularlymphadenopathy and laboratory studies, including serum levels of TSH, Tg, and anti-Tgantibody (TgAb).

Twelve months after thyroidectomy and radioiodine ablation, an ultrasound of the neck isobtained and serum Tg is measured after thyroid hormone withdrawal or rhTSH admin-istration. A serum TSH level of greater than 30 mU/L indicates adequate stimulation. Astimulated Tg level greater than 2 ng/mL is highly sensitive in identifying patients withpersistent tumor.148,149 In the absence of increased Tg level after TSH stimulation and anegative ultrasound examination, no additional diagnostic testing is needed.

Approximately 25% of patients with DTC will have TgAb,150 which is a cause forboth false-positive and false-negative Tg levels, compromising the clinical utility ofTg monitoring for disease recurrence. TgAb positivity interferes with Tg measurement,causing underestimation of Tg when measured by immunometric assay, and either under-estimation or overestimation when measured by radioimmunoassay.151 Assay methodsperformed on different analytical machines may yield different results and therefore it isbest to follow the changes in the Tg and TgAb levels using the same analytical machine andmethod.

Low-risk patients with an undetectable TSH-suppressed Tg less than 0.1 ng/mL and anegative neck ultrasound are followed with clinical examination, TSH-suppressed Tg and anti-Tg antibody levels, and periodic neck ultrasound. It is estimated that only 0.3%-2.5% of patientswith a TSH-suppressed Tg level less than 0.1 ng/mL would have a rhTSH-stimulated levelgreater than 2 ng/mL.152-155

Ultrasound remains important because there is no absolute level of Tg below whichrecurrent disease can be completely excluded.152 Ultrasound is used for examination of thethyroid bed for local recurrence, and both the central and lateral compartments of the neck forregional lymph node recurrence. Suspicious lymph nodes are biopsied. Measurement of Tg inthe FNA fluid can enhance the sensitivity of diagnosis of metastatic disease. Isolated smallabnormal lymph nodes smaller than 5 mm seen on ultrasound are preferably followed up withserial ultrasound examinations because of the difficulty finding them during operation and thepotential morbidity associated with resection. Biopsy and resection are reserved for patientswith a lymph node that continues to grow. Routine use of WBS is not recommended forsurveillance in this low-risk group.

In low-risk patients who have undergone near-total or total thyroidectomy withoutpostoperative RAI, interpretation of the Tg and TgAb can be challenging. A detectable Tg may beindicative of normal remnant thyroid tissue or persistent or recurrent disease. In a group of 50patients156 with papillary microcarcinoma who underwent total thyroidectomy without RAI,44% had a stimulated Tg level greater than 1 ng/mL. 131I WBSs revealed uptake only in thethyroid bed. Durante and colleagues157 demonstrated that Tg levels in patients who did notundergo RAI fell over time. An undetectable Tg level was present in 60% and 80% of patients


within 1 and 5 years after operation respectively, underscoring the importance of following thetrend in serum Tg and recognizing the value of Tg monitoring in patients who do not undergoradioiodine therapy.

During surveillance, an increase in the previously undetectable Tg level is an indicator ofdisease recurrence. Monitoring TgAb as a surrogate tumor marker is appropriate for patientswith positive TgAb. The de novo appearance, persistence, or increase in TgAb concentration inthe postoperative period represents a significant risk factor for persistent or recurrent disease.During the first year, not all patients will achieve a negative TgAb status. It is normal to see aninitial rise in TgAb after RAI therapy when there is a release of Tg antigen secondary toradioiodine-induced lytic damage of the thyroid cells.158 What is important is to observe agradual decrease of the TgAb level over time. Kim and colleagues found that fewer than 1% ofpatients with more than a 50% drop in TgAb level after 6-12 months of radioiodine treatmenthad disease recurrence whereas 19% of patients in whom TgAb declined less than 50% werediagnosed with recurrence.159

In patients with intermediate- or high-risk PTC and an increasing TSH-suppressed Tg or aTSH-stimulated Tg greater than 2 ng/dL and no evidence of disease on neck ultrasonography, adiagnostic 131I WBS should be performed. A 1-2-mCi dose of 131I should be used to minimizestunning, a phenomenon whereby the pretreatment scanning dose reduces the subsequentuptake of the 131I therapy dose. If the WBS identifies persistent or recurrent disease, atherapeutic dose of 131I is administered.

In patients with negative WBS and mildly elevated stimulated Tg level (o5-10 ng/mL), theAmerican Thyroid Association management guidelines recommend continued surveillancewith TSH-suppressed Tg and neck US at regular intervals.43 If serum Tg continues to rise in theabsence of ultrasonographic findings, further imaging and empiric 131I therapy should beconsidered. CT of the neck, chest, and abdomen, magnetic resonance imaging (MRI) of thebrain, and PET/CT are reserved for patients with an elevated Tg level and a negative ultrasoundof the neck and 131I WBS. The administration of oral or intravenous contrast for CT imaging orboth reduces iodine uptake of metastatic disease, interfering with subsequent RAI scanning andtreatment.

Empiric 131I therapy is controversial. The goals of empiric, high-dose 131I therapy are fortreatment of metastatic disease and for identifying disease foci on a posttreatment WBS thatmay be amenable to further therapy. Pacini and colleagues found that empiric high-dose 131Itherapy was only effective in identification and treatment of lung metastases.144 Others havefailed to show any benefit in the rate of disease remission.160

In patients with a negative WBS and a TSH-stimulated Tg level greater than 5-10 ng/mL,FDG-PET scanning is recommended. DTC that loses its iodine avidity is usually metabolicallyactive and hence would be visualized on PET imaging. PET imaging has a 92% positivepredictive value for patients with negative WBS and elevated stimulated Tg level and a 93%negative predictive value for negative WBS and low Tg level.161-164 The majority of cases thatare missed with PET imaging are small-volume cervical lymph nodes that can often be detectedwith neck ultrasonography. The sensitivity of FDG-PET scanning may be improved withsimultaneous TSH stimulation. However, the clinical benefit of identifying these additionalsmall foci is not clear.165 Patients with metastases that are FDG avid on PET scan are known tohave a worse prognosis.166,167

With improvement in imaging technology, PET imaging with CT or MRI co-localization hasgained popularity over PET imaging alone. The combination of functional and anatomicalimaging allows for better visualization of suspected thyroid cancer metastases. PET/CTscanning has been able to improve the diagnostic accuracy of lymph node and lungmetastases.165,168,169 The recent development of PET/MRI fusion technology has the potentialof replacing PET/CT imaging for detection of metastatic thyroid disease. In a study by Seibothand colleagues,170 one-third of patients had a change in management based on the PET/MRIresults. Nagaiah and colleagues examined PET/MRI vs PET/CT imaging for identificationof remnant thyroid tissue and lymph node metastases prior to patients undergoing RAItherapy for the treatment of high-risk DTC. PET/MRI was superior to PET/CT in differentiating


lymph node metastases and was especially effective for identifying lesions that were smallerthan 1 cm.171

Treatment of systemic metastases

DTC is known to result in distant systemic metastases in approximately 5%-23% ofcases.172,173 The 5-year survival rate in patients with DTC and distant metastases isapproximately 56%.104 Younger patients (age o45 years), solitary distant organ spread, lowertumor burden, radioiodine concentration, and treatment of metastases with 131I are associatedwith better treatment outcomes.172,173 An 131I WBS after withdrawal of thyroid hormone orrhTSH stimulation is the best initial localization test to evaluate for distant metastases. Whenmetastatic DTC maintains its ability to concentrate iodine, high doses of 131I may be used fortreatment of metastatic disease. Tala and colleagues reported no difference in the response rateor 5-year survival rate in patients with metastatic DTC who were treated with 131I followingthyroid hormone withdrawal or TSH stimulation.174

Pulmonary metastases

Pulmonary metastases are the most common site of distant spread for DTC and can occur asdiffuse micrometastases or macronodular disease defined as tumor nodules larger than 1 cm insize. Patients with micrometastases have a more favorable outcome.175 In a study of 394patients with systemic metastases, 241 patients were found to have isolated pulmonarymetastases, 108 had bone metastases, and 72 had combined lung and bone metastases.172 Inthe 241 patients with isolated lung metastases, postoperative CXR revealed micronodules in30%, macronodules (41 cm) in 34%, and was normal in 36%. All patients were treated with 131I,100 mCi in adults and 1 mCi/kg in children. Multivariate analysis revealed that the risk of deathwas highest in patients with macronodular lung disease or multiple bone metastases,intermediate in patients with micronodular lung disease or bone disease visible on plain CXR orskeletal survey, and lowest in patients with lung or bone metastases only seen on radioiodineWBS. In patients with a negative WBS after 131I treatment, 10- to 15-year survival rates havebeen reported to be as high as 89%-92% vs 8%-19% in patients with persistent diseasedemonstrable on 131I WBS despite multiple doses of RAI.172,176

Treatment of pulmonary metastases consists of 131I treatment followed by suppressivedoses of LT4. Empiric dosing of 131I with a 100-200 mCi of 131I or a dosimetric approach to tryand maximize the therapeutic effect and minimize the potential harm to the normal lungparenchyma and bone marrow are utilized. Dosimetry is more complicated, expensive, timeconsuming, and labor intensive. There are, however, some studies which have shown thatdosimetry may help achieve remission in patients when empiric dosing is unsuccessful andmay be safer in pediatric or elderly patients.177,178 Surgical resection is indicated for thesolitary pulmonary metastasis.179

Bone metastases

The second most common site of distant metastases from DTC is bone. The vertebrae, ribs,and pelvis are the most common sites of bone metastases. Bone metastases can be seen in 2%-13% of patients with DTC, occurring in 7%-20% of patients with follicular cancer and 1%-7% ofpatients with PTC.144,176 The increased rate of bone metastases seen in follicular cancer is likelydue to its higher rate of vascular invasion. Overall 10-year survival in patients with bonemetastases is 0%-34% with a mean survival time of only 4 years.176,180 The risk of deathincreases with multiple bony metastases and with increasing age greater than 45 years.173

Patients with bone metastases present with pain from tumor replacement of the marrowcavity or pathologic fracture. Patients may be asymptomatic if the metastases are small.Diagnosis can often be made on a radioiodine WBS. Bone MRI is the most definitive diagnostic


test, with an overall diagnostic accuracy of 91% as compared with a 78% accuracy for an FDG-PET scan.181

Treatment of bone metastases is based on the extent of tumor infiltration as well as patientsymptoms. Most patients are initially treated with TSH-suppressive doses of thyroid hormoneand empiric doses of radioiodine ranging from 100-200 mCi. However, unlike patients withmicronodular lung metastases, patients with bone metastases are rarely cured.

If patients have symptomatic bone metastases other strategies may be employed. Pathologicfractures or vertebral metastases with instability may benefit from bone stabilization incombination with adjuvant radioiodine therapy. An isolated bone metastasis may benefit fromsurgical resection and adjuvant radioiodine treatment. If complete resection can be obtainedthere has been an improved survival seen in some studies.181 External beam irradiation,radiofrequency ablation, intra-arterial embolization, vertebroplasty, kyphoplasty, andbisphosphonates, alone or in combination, may have a role in palliation of patients withpainful bone metastases that are unable to be resected.182

Central nervous system metastases

Brain and spinal cord metastases from DTC are rare. Surgical resection, external beamradiotherapy, and radioiodine are used for treatment of central nervous system metastases.Surgical resection should be considered for lesions that can be completely excised because thismay improve survival. A retrospective analysis of patients with DTC and brain metastasestreated at the M.D. Anderson Cancer Center demonstrated a significantly longer survival timefor patients who underwent surgical resection compared with patients who did not undergoresection (16.7 months vs 3.4 months).183 Patients were not matched for tumor size, age,comorbidities, or other factors, and as a result this study may reflect a bias toward resection ofsmaller, less complicated lesions. However it still demonstrates a role for surgical resection inselected patients with brain metastases. When patients are not amenable to surgical resection,targeted radiotherapy therapy should be considered to minimize the radiation effects to thenormal brain. Radioiodine can be used to treat iodine-avid metastases, but should be precededby external radiation and glucocorticoid administration to reduce the likelihood of centralnervous system edema and increase in tumor that may occur as a result of increased serum TSHlevels.

Clinical trials for 131I-resistant metastatic disease

Metastases that fail to concentrate radioiodine are associated with a worse prognosis.In a study by Schlumberger and colleagues,172 patients with iodine-avid metastases had ahighly significant reduction in relative risk of death compared with patients with metastasesthat did not concentrate radioiodine. Ronga and colleagues reported an overall 10-year survivalrate of 76% for patients with iodine-avid lung metastases compared with 25% in patientswith lung metastases that did not concentrate iodine.184 Alternative therapeutic strategiesare necessary for improving patient outcomes in patients with DTC and iodine-resistantmetastases.

BRAF, Ras, and RET-PTC mutations in patients with DTC lead to downstream alterations inthe genes encoding for the transmembrane tyrosine kinase receptors. This has led to the use ofTKI as a novel treatment regimen. TKI competitively binds to the ATP portion of the tyrosinekinase receptor. Sorafenib, sunitinib, and pazopanib are commercially available TKI that arebeing investigated for treatment of radioiodine-resistant metastases. Axitimib, gefitinib, andmosatenib are TKI that are only available as part of a clinical trial. TKI have been shown tovariably inhibit BRAF receptor, RET/PTC receptor, vascular endothelial growth factor receptor(VEGFR), and platelet-derived growth factor receptor (PDGFR). Each TKI has a different bindingsite to the tyrosine kinase receptor, which has clinical relevance because many tumors becomeresistant to these drugs by the activation of new tyrosine kinases.


The largest clinical trials to date have employed either sorafenib or mosatenib. In 2009,Kloos and colleagues185 reported the results of a phase II trial using sorafenib to treat 56patients with metastatic thyroid cancer not responsive to standard therapeutic regimens.Sorafenib inhibits BRAF, RET, and VEGFR subtypes 2 and 3. In this phase II trial, there were 41patients with PTC, 11 FC/HCC, and 4 ATC. With the exception of patients with ATC, all patientshad undergone thyroidectomy and prior RAI treatment and were not candidates for additional131I therapy; 95% had lung, 10% had bone, and 10 % had other sites of metastases. Tumorburden was assessed by CT, MRI, and PET scans and Response Evaluation Criteria in SolidTumors was used to assess the objective responses. Thirty-two patients were alive at the end ofthe 3-year study and 24 had died of which 20 died because of disease progression. Furtheranalysis was mostly limited to patients with PTC because they had the best overall survival. Nopatients achieved a complete tumor response, 15% had a partial response, 56 % had stabledisease with no further progression as measured by scans or serum Tg levels for at least6 months with a median progression-free survival of 15 months. The therapy was welltolerated in most patients but dose reductions were required because of adverse events such asfatigue, arthralgia, diarrhea, and musculoskeletal pain. Rare side effects were pericardialeffusion and reversible neutropenia.

In a large phase II trial utilizing motesanib to treat 93 patients with progressive locallyadvanced or metastatic DTC that was refractory to standard therapy, similar results werereported. Motesanib inhibits VEGFR subtypes 1-3, PDGFR, and RET. Of the 93 patients, only 32completed the 48-week treatment protocol; 5 died before completing the therapy andtreatment was discontinued because of disease progression in 35 and adverse events in 12patients. A partial response occurred in14% of patients as assessed by Response EvaluationCriteria in Solid Tumors and a decrease in serum Tg levels. Disease was stable at 6 and 12months in 67% and 35% of patients, respectively, and overall survival at 1 year was 73%. Inselected patients with aggressive DTC, TKI hold promise for stabilizing disease and extendingoverall length of survival. TKI have significant toxicities and their use should be restrictedto centers with ongoing trials or experience treating patients with aggressive thyroidcancer.186,187

Other strategies for treatment of refractory metastatic DTC are being directed at reversingiodine resistance.188 Many of these tumors have downregulation of the sodium-iodidesymporter (NIS) rendering the tumor unable to take up and concentrate iodine. Agents suchas retinoic acid, rosiglitazone, trichostatin-A, and lithium are being trialed to either increase NISactivity or reduce iodine excretion from tumor cells in the hope of restoring sensitivity to 131Itherapy.

Other alternative pathways have been discovered that may allow tumors to continue toupregulate growth and differentiation in a TSH-independent pathway utilizing the insulingrowth factor receptor. Studies both in vitro and in vivo show that insulin growth factor-Ireceptor activation can lead to papillary thyroid hyperplasia in mice and that some of thesereceptor subtypes exist in both normal human thyroid follicular cells and in PTC.189,190 Thismay lead to alternative strategies to inhibit tumor growth.

ATC

Case no. 1

A 71-year-old white woman presented with a chief complaint of difficulty swallowing andpressure sensation in her neck that was worse when she laid flat or when her arms were upover her head. She also had hoarseness and difficulty expectorating mucus. She was firstdiagnosed with a ‘‘goiter’’ 21 years prior to her presentation and was started on thyroidhormone. Over the past year she reported that her goiter had increased in size. She deniedany prior history of head or neck radiation. Both her mother and sister had undergonesurgery for benign thyroid disease. Her other medical problems were hypertension andhypercholesterolemia.


The patient was referred for definitive management after having undergone anextensive evaluation. An ultrasound of the thyroid gland demonstrated diffuse hetero-geneity with multiple bilateral nodules. There was marked enlargement of the left lobe ofthe thyroid gland with interval increase in size and additional nodules throughout bothlobes of the thyroid gland compared with an ultrasound exam from 1 year prior. A 24-hour 131I uptake was measured and was only 1.7% and a thyroid scintiscan demonstratedvery little uptake by the thyroid gland. A chest radiograph revealed tracheal impingementand displacement to the right due to the enlarged left lobe of thyroid gland. She had anFNA biopsy of the large neck mass, which was nondiagnostic. No follicular epithelial cellswere identified. There was extensive cellular degeneration and this was felt to beconsistent with a cyst.

On physical examination she had a 6-cm mass involving most of the left lobe of the thyroidgland, the isthmus, and the medial portion of the right lobe of the thyroid gland. The mass wastender to palpation. She had no cervical or supraclavicular adenopathy. Her trachea wasdisplaced to the right.

A total thyroidectomy was performed for a presumed multinodular goiter with a cysticdegeneration that was causing compressive symptoms and tracheal impingement anddisplacement. At operation the patient was noted to have a huge mass involving the entireisthmus and both lobes of the thyroid gland. The mass was adherent to the leftsternothyroid muscle, but there was no obvious invasion. The mass extended substernallyand was filled with a thick amorphous material. The mass was entered during deliveryfrom its retrosternal location resulting in some spillage of the amorphous debris intothe wound.

The weight of the excised thyroid gland was 67 g. There was a large complex cystic-solidnodule that was 5 cm in greatest dimension and was full of necrotic tissue and amorphousdebris. The final pathology revealed anaplastic large cell carcinoma, spindle cell type, withextensive necrosis and chronic inflammation within an adenomatous goiter. The margins ofresection were free of tumor. Imunohistochemical stains confirmed the diagnosis of ATC.Postoperatively, the patient developed transient asymptomatic hypocalcemia with a serumcalcium level of 7.6 mg/dL on the first postoperative day. This was treated with calciumsupplementation. Her serum calcium level was normal at her 2-week follow-up visit and hercalcium supplementation was discontinued.

Although the tumor was completely resected, there was some spillage of the cystcontents intraoperatively. As a result, the patient was referred for evaluation for adjuvantradiotherapy. The patient had additional staging evaluation, which included a CT scan of thechest, abdomen, and pelvis and a bone scan, all of which were negative. She was treated with6000 cGy in 30 fractions to her neck. After 15 years of follow-up, she has no evidence forrecurrent disease.

Case no. 2

A 52-year-old white man presented to the emergency department with progressive bilaterallower extremity weakness, inability to walk, and difficulty urinating. CT of the thoracic spinerevealed osteolytic lesions of the fifth, sixth, and eighth thoracic vertebral bodies. There wascollapse of the fifth vertebral body with a large associated epidural mass (Fig 7). MRI of thethoracic spine demonstrated enhancement of the marrow with infiltrative lesions involving thefifth, sixth, and eighth vertebral bodies which were extending into the epidural space at the T5-6 level. It also demonstrated marked compression of the thoracic spinal cord by an enhancingepidural mass at the T5-6 level (Fig 7). An incidental 4.6-cm mass with course calcificationsinvolving the left lobe of the thyroid gland was also noted (Fig 7).

The patient underwent emergency T5 and T6 laminectomies and corpectomies withinterbody and posterior arthrodesis. A large epidural tumor was also resected. The pathologyrevealed poorly differentiated carcinoma from an unknown primary tumor. Additional historywas obtained and additional physical examination was performed. The patient reported no

T

T

Fig. 7. (A) Axial computed tomographic image demonstrating vertebral body destruction and replacement by tumor;

(B) axial magnetic resonance image demonstrating tumor (T) compression of the spinal cord; (C) sagittal computed

tomographic image demonstrating collapse and rotation of the fifth thoracic vertebrae with spinal cord compression;

and (D) a mass (T) replacing the left lobe of the thyroid gland.


prior head or neck radiation or family history of thyroid cancer or other endocrinopathies. Hehad no prior history of malignancy. He denied any compressive symptoms.

On physical examination, the patient had displacement of his trachea and thyroid cartilageto the right. He had a large hard mass in the left lobe of the thyroid gland that was extendingsubsternally. The right lobe of the thyroid gland was palpable and was firm in character. He hadno associated cervical or supraclavicular adenopathy.

An ultrasound of the thyroid gland revealed a large heterogeneous mass occupying most ofthe left lobe of the thyroid gland measuring 5.8 � 4.7 � 4.4 cm. The mass had cysticand solid components, calcifications, and increased vascularity. His serum TSH level was3.60 mIU/mL. An FNA biopsy of the left neck mass was interpreted as poorly differentiatedcarcinoma. The cytomorphologic features were similar to the malignant cells that wereseen from the epidural mass. The cytopathologist could not give a definitive diagnosis butsuggested that the differential diagnosis included medullary thyroid cancer, Hurthle cellcancer, and ATC.

The patient underwent an en bloc resection of the mass, which included a totalthyroidectomy with a segment of the muscle layer of the esophagus. The pathology revealedATC involving the posterior-medial and posterior-inferior margins. There was perithyroidalextension, vascular invasion, and extensive necrosis. Immunohistochemical studies supportedthe diagnosis of ATC.

The patient’s postoperative course was unremarkable. He was started on thyroid hormonetherapy. He subsequently underwent radiation treatment, which consisted of 3000 cGy in 10fractions to T3 to T10 followed by 3000 cGy in 10 fractions to the neck. Six months followinghis original surgery he died as a consequence of metastatic disease.


Background

ATC is one of the most aggressive solid human cancers with a median survival of 5 monthsafter diagnosis.191 It is the least common type of thyroid cancer, but it carries the highestmortality rate. Less than 3% of all thyroid cancers diagnosed each year are ATC.192-194 Theoverall incidence of ATC worldwide is 1-2 cases for every 1 million individuals. The incidence ofATC is decreasing likely because of increased dietary iodine supplementation and a decrease inendemic goiter, earlier diagnosis, and treatment of DTC before anaplastic dedifferentiationoccurs and better distinction of ATC from poorly differentiated thyroid carcinoma, insularthyroid carcinoma, lymphoma, and undifferentiated MTC.195,196

Presentation

Patients with ATC are older than patients with DTC, typically 60-70 years of age. ATC occursmore often in women. Patients with ATC usually present with a rapidly enlarging tender,painful, firm, and fixed neck mass that on average is greater than 6 cm in size. They commonlyhave compressive symptoms as a result of invasion of the aerodigestive tract. Signs andsymptoms include a rapidly growing central (77%) or lateral (54%) neck mass, dysphagia (40%),voice change or hoarseness (40%), neck pain (26%), and stridor or dyspnea (24%). Patients mayalso present with anorexia, weight loss, fatigue, cough, and hemoptysis. Patients often have along history of a stable goiter that suddenly and rapidly increases in size as was true in our firstcase. Rarely, ATC has been reported to present with superior vena cava syndrome and Hornersyndrome.197 Ninety percent of patients with ATC will present with regional or systemicmetastases.

On physical examination, patients usually have marked bilateral enlargement of the thyroidgland, frequently with substernal extension. The thyroid gland is hard with indistinct borders.The trachea is most often not palpable because of the extent of thyroid enlargement and thefirm character of the gland. Cervical lymph node enlargement is common. Patients may havevocal cord paralysis, facial edema, and venous engorgement.

Distant metastases are present at the time of diagnosis in 25%-66% of patients.198 The lung isthe most common site of distant metastatic spread. ATC also metastasizes to the mediastinum,liver, bones, kidneys, heart, adrenal glands, brain, skin, and the abdominal cavity.198,199 ATC isusually a systemic disease at the time of diagnosis, and as a result all patients with ATC areconsidered to have stage IV disease by the American Joint Commission on Cancer TNM stagingsystem (Fig 6).

Histopathology and diagnosis

ATC is a follicular cell–derived tumor that arises from dedifferentiation of DTC or de novofrom normal thyroid tissue, which rapidly loses its normal differentiation. ATC does not retainany of the functional characteristics of the follicular cell, including synthesis of Tg andradioiodine uptake. Mutations in genes encoding for p53, RAS, BRAF, MIB-1, PIK3CA, Axin 1, andb-catenin may be associated with anaplastic transformation (Fig 8). Mutations in oncogenesand tumor suppressor genes result in underexpression and overexpression of proteins that arevital for cell function.200

ATC cells typically have large, bizarre-shaped nuclei with numerous atypical mitoticstructures that resemble polymorphic mesenchymal sarcoma. This ‘‘dedifferentiation’’ of ATCcan make histologic diagnosis difficult. PAX8 is a transcription factor expressed in the nuclei ofnormal and abnormal thyroid, the kidneys, and the female genital tract tissue. Expression ofPAX8 appears to be preserved in ATC and may help differentiate ATC from head and necksquamous cell carcinomas.201 ATC usually has numerous areas of hemorrhage and necrosisalong with several different histologic patterns, which frequently coexist and do not affect the

NormalThyroid Cell

FollicularAdenoma

PAX8-PPARG? FTC

ATC

PTCPoorly

Differentiated TC

???

RET/PTC rearrangementBRAF mut.RAS mut.

???P53 inact.PI3KCA act.Β-catenin mut.

P53 inact.PI3KCA act.Β-catenin mut.

Fig. 8. Mutations in oncogenes and tumor suppressor genes may result in underexpression and overexpression of

proteins that are vital for cell function and lead to anaplastic transformation. (Color version of figure is available

online.)


already poor prognosis. These patterns include spindle cell, giant cell, squamoid, paucicellular,and carcinosarcoma.

ATC may be diagnosed by an FNA biopsy. However, extensive cellular degeneration or tumornecrosis or both may make it difficult to make an FNA biopsy diagnosis of ATC, which was true inboth the cases that are presented. Ultrasound may be helpful to identify a nonnecrotic area of thethyroid gland to biopsy. A core needle biopsy or incisional biopsy may be needed to obtain enoughtissue for immunohistochemical testing. Useful markers that may distinguish ATC from otherthyroid tumors or sarcomas include cytokeratin, carcinoembryonic antigen (CEA), epithelialmembrane antigen, a-1-chymotrypsin, desmin, vimentin, and anticytokeratin antibodies.202

Imaging

Imaging is important to determine if the ATC is resectable and to evaluate for metastaticdisease. CT of the neck and chest is recommended to assess for tracheal, esophageal, and majorvascular invasion and retrosternal extension. CT of the chest and abdomen, bone scintigraphy,and MRI of the brain are useful to evaluate for distant metastases. FDG-PET imaging may alsobe useful for staging patients with ATC. Poisson and colleagues imaged 20 consecutive patientswith biopsy-proven ATC with FDG-PET combined with CT and noted that ATC cells have a highuptake of FDG.203 The high level of FDG uptake resulted in a higher sensitivity for detection ofcervical and mediastinal lymph node and bone metastases than CT or bone scintigraphy. Thesensitivity of FDG-PET imaging for detection of lung masses was comparable to CT.

Treatment

The optimal treatment strategy for patients with ATC has yet to be determined. The resultsof various treatment strategies come from small retrospective studies that suffer from selection


bias. In many early series of ATC, poorly differentiated thyroid carcinoma, metastases, sarcoma,and primary thyroid lymphoma (PTL) were often incorrectly reported as ATC and reports oflong-term survival were flawed because of misdiagnosis.204 In general, the management of ATCincludes locoregional control and preemptive treatment of gross or occult metastatic disease.

The vast majority of patients with ATC present with locally invasive disease that isunresectable. In the rare patient with ATC that is confined to the thyroid gland, there is a rolefor surgical resection and it may be curative (as was true in our first patient). In all patients whomay have resectable disease, an en bloc resection and total thyroidectomy should beconsidered. Attempts at segmental resection of the carotid artery, trachea, esophagus, pharynx,or larynx should not be performed because this significantly exacerbates the morbidity of theoperation with no clear survival advantage. It is unnecessary to perform a prophylactictracheostomy in the absence of impending airway obstruction as this increases the complexityof care postoperatively and reduces the patient’s overall quality of life.

Radiotherapy is recommended for locoregional control in all patients with ATC, preferablyintensity-modulated radiotherapy. External beam radiotherapy reduces the morbidity andmortality from local invasion. High-dose external beam therapy has also been shown toimprove the length of survival.200 Neoadjuvant therapy has been advocated to convert anunresectable ATC to a resectable one.205

Stage IVA ATC, defined as ATC confined to the thyroid gland, with or without nodalmetastases, and no distant metastases, is rarely encountered in clinical practice. Stage IVB,defined as ATC with gross extrathyroidal extension, with or without lymph node metastases,and no distant metastases, account for approximately 40%-60% of patients. Patients with stageIVA or IVB are candidates for multimodal treatment with some combination of completesurgical resection, radiation therapy, and chemotherapy to improve overall survival. However,in most patients, the ATC is not amenable to curative surgical resection. Patients with stage IVCATC, defined by the presence of distant metastases have the shortest survival. The combinationof intensity-modulated radiation therapy and chemotherapy has been shown to improvesurvival in patients with stage IVA and stage IVB ATC.206 Neoadjuvant chemotherapy andradiotherapy do not improve overall survival in patients with stage IVC disease.207

Consideration should be given to enrolling patients with ATC and gross or occult metastaticdisease in a clinical trial (www.clinicaltrials.gov).

Radiation therapy

Traditional external beam radiation therapy delivers a targeted dosage of radiationto a specific anatomical site. In patients with ATC, high-energy photons result in DNAfragmentation and ultimately cell death through a proposed necroptosis cellular pathway.208

However, it is unclear what the optimal radiotherapy regimen or schedule should be. Dose-related effects of radiation include skin changes, pharyngoesophagitis, tracheitis, andmyelopathy.209,210

Hyperfractionation of external beam radiotherapy is the process whereby multiple smalldosages of radiation are given daily. This process allows for less overall toxicity and thecompletion of an entire radiation therapy course over a shorter time. The theoretical benefit ofthis shortened time is the prevention of accelerated repopulation of ATC cells and an increase inoverall tissue repair. Unfortunately, the recent Hyperfractionated Accelerated Radiotherapytrial for patients with ATC was stopped early because 56% of the patients suffered grade 3 or4 toxicity (erythema, desquamation, dysphagia, and esophagitis) from the radiation.211

The neck is a difficult ‘‘target’’ for external beam radiation because of its natural curvature aswell as interference from the vertebral bodies and trachea. Three-dimensional planning usingCT images helps direct radiation dosages. Intensity-modulated radiation therapy usessophisticated computer algorithms and linear accelerators to shape radiation dosage fields tomore closely align with a patient’s neck anatomy. Images taken during the day of radiationtreatment allow for image-guided radiation therapy, which accounts for any change in tumor

www.clinicaltrials.gov


size from the last time the patient was seen by a radiation oncologist. Intensity-modulated andimage-guided radiation therapy may result in less radiation-related toxicity with better localcontrol.212

Chemotherapy

In general, patients with ATC have a poor response to chemotherapy alone, whichnecessitates combination therapy with radiation and, when possible, surgery. Chemother-apeutic agents that have been used to treat ATC include taxanes or platins and doxorubicin.Taxanes (docetaxel or paclitaxel) are radiosensitizing agents and seem to improve overallresponse to external beam radiation therapy, especially in stage IVB patients.213 Doxorubicinhas known activity against ATC and works in synergy with taxanes.205,209 In general, there aretoo few studies of too few patients with ATC to determine definitively the optimumchemotherapy regimen.

Future targeted therapies

Clinical trials have been initiated to examine various targeted therapies for ATC includinghistone deacetylase inhibitors to induce redifferentiation and restore iodine uptake in ATCcells, monoclonal antibodies to block growth factor receptors, and proteasome inhibitors tostimulate apoptosis.214-216 Other promising targeted therapies include small molecule TKI andantiangiogenesis agents.

Human ATC trials with small molecule TKI include imatinib and sorafenib. Imatinib is aselective c-abl TKI and appears to trigger apoptosis in ATC cells when combined with docetaxelin mice.217 Sorafenib acts on the raf-1 serene/tyrosine kinase and also blocks VEGFR2 andPDGFR-b. Small human trials with these agents have not demonstrated any measurableimprovement in survival, but more research is ongoing.

Several antiangiogenesis and vascular-disrupting agents, including axitinib, fosbretabulin,and combretastatin, are also being tested in ATC patients. Axitinib is an oral, selective inhibitorof VEGFRs 1-3. Fosbretabulin is a tubulin-binding agent that disrupts established tumorvasculature by binding to the colchicine-binding site to inhibit microtubule assembly anddestabilize the cytoskeleton. Finally, combretastatin A4 phosphate is a tubulin-bindingvascular-disrupting agent that inhibits tumor blood flow, blocks the development of newblood vessels, and occludes existing vasculature in ATC cell lines.218

Prognosis

The prognosis of ATC is poor, with a 1-year survival rate of 20% and a 5-year survival rate of5%.219-222 The Surveillance, Epidemiology, and End Results data from 1983-2002 indicate a 2-year survival rate of 33% and a 5-year survival rate of 23% if the ATC is confined to the thyroidand completely resected.219 Age less than 60 years, female gender, and tumor confined to thethyroid gland are associated with increased length of survival.220-222 Higher dose radiationtherapy and greater extent of surgery are also predictive of longer survival and distantmetastases are predictive of higher mortality.200

Sugitani and colleagues developed a prognostic index based on the presence of acutesymptoms or progression of tumor within 1 month, tumor size greater than 5 cm, presence ofdistant metastases at diagnosis, and a WBC count greater than 10,000 mL�1. If prognostic scorewas r1 there was a 62% survival rate at 6 months vs 0% survival rate at 6 months if the scorewas more than 3.223 They applied this prognostic index prospectively and found that patientswith stage IVA or IVB and a prognostic index score greater than 3 should not receivechemotherapy or EBRT as their disease-specific survival was very low and efforts should bemade to maximize their overall quality of life.224


Death from ATC is most often related to distant metastases (as was true for our second case)or airway obstruction. Kitamura and colleagues reviewed 62 fatal cases of ATC and confirmedthat most common cause of death is severe hypoxia from replacement of lung tissue withpulmonary metastases or airway obstruction.225 Other causes of death in ATC patients includetumor hemorrhage and circulatory failure from sepsis, cardiac metastases, disseminatedintravascular coagulation, hypercalcemia, and vena cava stenosis. All patients with ATC shouldhave a consultation from a palliative care team if possible prior to initiating treatments toensure the patient’s quality of life is given the highest priority.

In summary, ATC remains a challenging clinical problem with low overall patient survival.Our case no. 1 represents the rare exception, a long-term survivor from ATC as a result ofincidental detection of a small clinically occult tumor that was confined to the thyroid gland ina patient with a large multinodular goiter. Multimodality therapy that includes resection of allgross disease if feasible, radiosensitizing and adjuvant chemotherapy, and intensity-modulatedand image-guided radiotherapy produces the best results. New therapies for ATC will probablycome from targeted therapies that directly address the multiple genetic derangements of ATC.

MTC

Case

A 30-year-old healthy woman with no significant medical history presented with a right-sided thyroid nodule. She was asymptomatic. She had no prior history of head or neckirradiation and there was no family history of thyroid cancer or known endocrinopathies,sudden death, or thyroid, parathyroid, or adrenal surgery. On physical examination, she had a2.0-cm firm nodule in the right lobe of the thyroid gland. There was no cervical orsupraclavicular lymphadenopathy. Her trachea was midline. The rest of her physicalexamination was normal.

An ultrasound examination demonstrated a 1.8 � 2.9 � 1.3-cm complex, hypoechoicnodule in the right lobe of the thyroid gland. The left lobe and isthmus were normal. There wasno central or lateral compartment lymphadenopathy. An ultrasound-guided FNA biopsy of thethyroid nodule was positive for MTC with positive immunostaining for calcitonin. Serumcalcitonin and calcium levels were 300 pg/mL and 9.5 mg/dL, respectively. A CEA level andplasma metanephrines were all within normal ranges. CT imaging of the neck, chest, andabdomen was normal. RET proto-oncogene testing was negative.

A total thyroidectomy with bilateral central compartment neck dissection was completed.The final pathology revealed a single focus of medullary carcinoma, 1.8 cm in size, that wasconfined to the thyroid gland. There was an incidental 0.2-cm papillary microcarcinoma in theleft lobe of the thyroid gland and a 0.1 cm focus of metastatic MTC in a lymph node that wasattached to lower pole of the right thyroid lobe. The remaining 12 central compartment lymphnodes were negative for metastatic disease.

Postoperatively, her voice was normal. She had no symptoms of hypocalcemia and shewas normocalcemic. Her serum calcitonin level was undetectable and has remained so at the3-years follow-up.

Background

MTC accounts for approximately 4% of all thyroid malignancies.103 MTC was initiallydescribed by Hazard and colleagues.226 In 1966, Williams discovered that MTC originated fromthe parafollicular or ‘‘C’’ cells of the thyroid gland.227 C cells comprise 1% of all cells in thethyroid gland and are primarily concentrated in the upper posterior one-third of each lobe ofthe thyroid gland. Embryologically, the C cells are associated with the ultimobranchial bodiesand migrate from the neural crest to the thyroid gland. The neural crest origin is responsible forthe amine precursor uptake and decarboxylating activity of MTC and its ability to secreteneurohumoral peptides, including calcitonin, CEA, serotonin, adrenocortotrophic stimulating


hormone, chromogranin A, somatostatin, neurotensin, proopiomelanocortin, prostaglandins,kinins, histaminase, and vasoactive intestinal peptide.228

In contrast to DTC, MTC does not produce Tg and it does not respond to TSH suppression. Ccells do not express the sodium-iodide symporter and thus do not concentrate radioiodine.MTC is more aggressive than DTC with a higher rate of recurrence and mortality. MTCcommonly metastasizes to cervical lymph nodes and cure of the disease is dependent onresection of lymph node metastases. MTC is sporadic in 70%-80% of patients and an autosomaldominant inherited disease in 20%-30% of patients, which occurs as a result of germlineactivating missense mutations in the RET proto-oncogene. The RET proto-oncogene is found onchromosome 10q.11.2 and is a 21-exon gene that encodes for a transmembrane tyrosine kinasereceptor.

Patients with sporadic MTC are typically diagnosed later in life with a peak incidencebetween 40 and 60 years of age. These patients usually present with a solitary thyroid noduleor palpable cervical lymphadenopathy and may present with neck pain, dysphagia, dyspnea,cough, choking, and hoarseness with impingement or invasion of the aerodigestive tract orrecurrent laryngeal nerve. Up to 75% of patients with a palpable MTC would have cervicallymph node metastases.182 Patients may present with diarrhea, flushing or Cushing syndrome,which usually occurs in patients with marked hypercalcitoninemia and advanced disease and isrelated to the vasoactive amines that are secreted by the tumor cells. Approximately 5% ofpatients would present with systemic metastases most commonly involving the lungs, liver,and bone.

Sporadic MTC is most often solitary, but up to 30% of patients may have bilateral disease.229

Approximately 10% of patients with sporadic MTCs have a de novo RET germline mutation.230

Somatic mutations or rearrangements involving RET that occur later in life and are limited to Ccells have been identified in 40%-50% of patients with sporadic MTC, which are associated withlymph node metastases, more advanced disease, persistent disease, and lower overallsurvival.228

Patients with hereditary MTC may present as early as the first decade of life and typicallyhave bilateral or multicentric tumors or both. Hereditary MTC is caused by germline gain-of-function mutations in the RET proto-oncogene and is believed to start with C-cell hyperplasia,which progresses to medullary microcarcinoma, macroscopic MTC, and then eventually tolymph node or distant metastases. Somatic mutations are thought to be involved in theprogression to malignancy in an individual with a germline mutation in the RET proto-oncogene. There are 3 distinct hereditary forms of MTC: multiple endocrine neoplasia (MEN)2A (Sipple Syndrome), MEN 2B (Wagenmann-Froboese Syndrome), and familial MTC (FMTC).

MEN 2A is the most common subtype of hereditary MTC accounting for almost 80% ofhereditary MTC. Features of MEN 2A vary with the affected RET codon and include MTC (95%penetrance), unilateral or bilateral pheochromocytoma (�60% penetrance), and primaryhyperparathyroidism (�20% penetrance), which is typically mild and can result frommultiglandular disease or a single adenoma. Less common features include Hirschsprungdisease and cutaneous lichen planus amyloidosis, which can occur, respectively, in 6%-16% and9% of families with MEN 2A.231,232 Patients usually present in the third or fourth decade of life.

FMTC is felt to be a variant of MEN 2A. Patients with FMTC have MTC without otherendocrinopathies are typically older than patients with MEN 2A at the time of diagnosis ofMTC. FMTC is defined as MTC in 4 or more family members without pheochromocytoma orhyperparathyroidism.233 Patients with isolated MTC but less than 4 affected family membersshould be considered as ‘‘unclassified MTC.’’234 Many of these patients would eventually bediagnosed with MEN 2A and as a result, should be appropriately screened until the criteria forMEN 2A or FMTC are met.182,234

MEN 2B is the least common form of hereditary MTC. Patients with MEN 2B have MTC (100%penetrance), unilateral or bilateral pheochromocytoma (450% penetrance), a thin, lanky,Marfanoid habitus with joint laxity, musculoskeletal abnormalities, including pescavusand pectus excavatum, multiple mucosal neuromas, medullated corneal nerve fibers, enlargedlips, eversion of the eyelids, and ganglioneuromas in the gastrointestinal tract and megacolon.


All patients have ganglioneuromas, two-thirds of patients have megacolon and, in contrast toMEN 2A, hyperparathyroidism is not part of the syndrome. The stigmata of MEN 2B precede theonset of MTC. However, in most patients there is a delay in diagnosis until the MTC becomespalpable. MTC occurs at an average age of 10 years and most patients develop metastases inchildhood or adolescence. In at least 50% of patients, MEN 2B occurs as a result of a de novogermline mutation in the RET proto-oncogene.235 It is rare to make a diagnosis of MEN 2Bbased on screening because most patients are index cases resulting from de novo mutationsand most patients with MEN 2B do not have offsprings.

Diagnosis

Although most patients with MTC present with a thyroid nodule, less than 1% of patientswith a thyroid nodule would have MTC. The diagnosis of MTC should be considered in patientswith a family history of MTC, hyperparathyroidism, pheochromocytoma, severe hypertension,sudden death, and Hirschsprung disease. Physical examination should include palpation forunilateral or bilateral disease nodular disease and cervical lymphadenopathy as well asinspection of the tongue, lips, and conjunctivae for mucosal neuromas and evaluation formusculoskeletal abnormalities and other developmental defects. Patients should be examinedfor pruritic skin lesions on the upper back indicative of cutaneous lichen planus amyloidosis.

Immunohistochemical staining of FNA biopsy specimens for calcitonin is performed whenthe cytologic evaluation is consistent with MTC. Cytologically, MTC is characterized bypleiomorphic cells that present singly or in loosely cohesive groups. The cells can be small andround, cuboidal, polygonal, or spindle-shaped with a plasmacytoid appearance containing finecytoplasmic granules that stain positive for calcitonin. Amyloid deposits may be present(presumably derived from transformed calcitonin polypeptides) and are difficult or impossibleto distinguish from colloid on Papanicolau staining and are confirmed by positive Congo redstaining. FNA cytology in patients with MTC may be difficult to distinguish from Hurthle cellneoplasms and ATC emphasizing the importance of immunohistochemical staining andmeasurement of serum calcitonin.76

Patients with an FNA biopsy consistent with MTC should have a basal serum calcitonin level,CEA, calcium and plasma metanephrine levels measured. It is important to exclude apheochromocytoma prior to operation for MTC. If a patient has hypercalcemia, a serumparathyroid hormone level should be measured to establish the diagnosis of primaryhyperparathyroidism.

Mildly elevated calcitonin levels can be seen in patients with C-cell hyperplasia, renaldisease, hypergastrinemia secondary to proton pump inhibitor use, tobacco use, advanced age,and in patients with neuroendocrine tumors from lung, pancreas, or prostate.182 Patients withmildly elevated levels should undergo repeat testing. Calcium-stimulated serum calcitoninlevels may be used to further evaluate patients with mildly elevated calcitonin levels.236 Acalcitonin level in the 20-40 pg/mL range suggests lymph node involvement and a calcitoninlevel greater than 150 pg/mL is associated with distant metastases.236 CEA is predominantlyexpressed in less differentiated cancers and serum levels greater than 30 ng/mL suggestextrathyroidal disease.228

A neck ultrasound with lymph node mapping of both central and lateral neck compartmentsis obtained in all patients with MTC, although it may be falsely negative in up to one-third ofpatients with central compartment lymph node metastases. Additional imaging for metastaticdisease is reserved for patients with basal serum calcitonin levels greater than 150 pg/mL.237

Up to 15% of patients with MTC have distant metastases at the time of diagnosis, mostfrequently in the mediastinum, liver, lungs, or bone. CT imaging of the neck, chest, andabdomen is obtained to evaluate for local tumor invasion and lung, lymph node, and livermetastases.238 FDG-PET may be more sensitive for the identification of neck and mediastinaldisease. MRI is the most sensitive modality for detection of liver metastases. MRI, incombination with bone scintigraphy, is used to evaluate for bone metastases. Diagnostic


laparoscopy may have a role for diagnosis of occult liver metastases prior to initial operation inpatients with serum calcitonin levels greater than 1000 pg/mL. All patients with MTC should beoffered genetic counseling and screening for germline RET mutations. RET proto-oncogenetesting provides important risk information for family members and helps estimate a patient’srisk for developing pheochromocytoma and hyperparathyroidism

Treatment

Surgery is the mainstay of therapy for MTC and consists of 3 separate strategies: prophylacticsurgery for hereditary MTC, surgery for clinically apparent MTC, and palliative surgery for widelymetastatic MTC. Strong correlation exists between the RET codon mutation, the age of onset, andthe risk for aggressive MTC that can be used as a guide to help determine the timing ofprophylactic thyroidectomy (Table 5).182,239,240 The goal of prophylactic thyroidectomy is to treatthe patient before serum basal calcitonin levels increase and before lymph node and systemicmetastases develop so that that the patient can be cured of their disease.

RET proto-oncogene carriers with normal basal calcitonin levels are treated with totalthyroidectomy alone without a central neck dissection. This has important implications forreducing morbidity, related to the minimal working space and the more delicate anatomicalstructures of the infant and child. The predominant complication is permanent hypoparathyr-oidism. Waiting until the patient is older may reduce the morbidity of operation. Thedevelopment of MTC is age-dependent and varies with the RET codon. Therefore, as long asbasal calcitonin levels are normal, consideration may be given to postponing prophylacticsurgery in patients with American Thyroid Association low-risk (A and B) mutations until thestimulated calcitonin levels begin to rise.182 Most patients with MEN 2B have increased basalcalcitonin levels at the time of diagnosis and are treated with total thyroidectomy and a centralcompartment neck dissection. Patients with hereditary MTC and a pheochromocytoma shouldundergo preoperative alpha blockade and adrenalectomy prior to thyroidectomy.

Surgery for clinically apparent MTC, whether sporadic or familial, should include a totalthyroidectomy and a complete central compartment neck dissection. Total thyroidectomy isadvocated because most patients with hereditary MTC and approximately 30% of patients withsporadic MTC would have bilateral disease. Routine bilateral central compartment neckdissection is performed because of the high incidence of lymph node metastases in patientswith clinically apparent MTC. In patients with an incidentally discovered medullarymicrocarcinoma, a central compartment neck dissection may not be necessary.241 Becausethe inferior parathyroid glands are at risk for devascularization or removal during a centralcompartment neck dissection, consideration should be given to autotransplantation of theinferior parathyroid glands into the sternocleidomastoid muscle in patients with sporadic MTC,FMTC, MEN 2B, or in the nondominant forearm in patients with MEN 2A, when there is a riskfor development of hyperparathyroidism.

The role of lateral neck dissection at the time of the initial operation is more controversial.Ipsilateral and contralateral cervical lymph node metastases are present in 14%-80% and

Table 5Recommended management of patients with positive screening for familial MTC and specific RET mutations.

Codons Association Recommended management

883, 918, and 922 MEN 2B Prophylactic total thyroidectomy as soon as it is feasible and within the first

6-12 mo of life.

609, 611, 618, 620,

634, and 819

MEN 2A and

FMTC

Prophylactic total thyroidectomy by 5 y of age.

768, 790, 791, 804,

and 891

MEN 2A and

FMTC

Prophylactic total thyroidectomy may be delayed until stimulated calcitonin

levels increase or before 10 y of age.

MTC, medullary thyroid cancer; RET, Re-arranged during transfection; MEN, multiple endocrine neoplasia; FTMC

familial medullary thyroid cancer.


19%-49% of patients with MTC, respectively.242 Therefore, some surgeons have advocatedbilateral lateral neck dissection for all patients with palpable MTC.243 Other surgeonsrecommend an ipsilateral lateral neck dissection for patients with a palpable MTC, positivecentral compartment lymph nodes, serum calcitonin levels greater than 200 pg/mL, and MTCgreater than 1.0 cm in size.242,244 It is our practice, as well as the practice of other surgeons, toperform a compartment-oriented lateral neck dissection only if there are abnormal lymphnodes present on physical examination, or identified on imaging studies.228,245

Palliative or cytoreductive surgery should be offered to patients who present with advancedMTC. A unilateral thyroidectomy may be the most appropriate therapy for patients with MTCand distant metastases to prevent future airway compromise. Also, patients with diffuselymetastatic disease may develop flushing, weight loss, and diarrhea, which may improve withcytoreductive surgery.

Prognosis and follow-up

Postoperatively, all patients are started on replacement doses of thyroid hormone. In contrast topatients with follicular cell–derived cancers, the C cells do not respond to TSH suppression. Aphysical examination is performed and serum calcitonin and CEA levels are measured at 6-monthintervals to evaluate for persistent or recurrent disease. Patients with normalization of their serumcalcitonin levels postoperatively are less likely to develop recurrent disease. Patients withpersistent calcitonin elevation postoperatively should undergo further imaging evaluation if it hasnot already been done. Patients with a persistent, stable serum calcitonin elevation less than150 pg/mL and a negative imaging evaluation may be followed with ultrasound of the neck aloneand most do well without evidence for clinical or radiographic evidence of recurrence.

Although the risk of recurrence after prophylactic total thyroidectomy is low, patients withhereditary MTC should have a plasma calcitonin and CEA levels monitored annually. Patients with‘‘unclassified MTC,’’ or suspected MEN 2A should be screened for hyperparathyroidism and patientswith ‘‘unclassified MTC,’’ suspected MEN 2A, or MEN 2B should be screened for the development ofpheochromocytoma. The 10-year cause-specific survival with MTC is approximately 75% butdecreases to 45% in patients with lymph node metastases.246 Prognosis most closely correlates withstage of disease (Fig 6) and postoperative serum calcitonin and CEA levels. After adjusting for stageof disease, there is no difference in survival between hereditary and sporadic MTC.237,247 Ten-yearsurvival rates for stages I through IV are 100%, 93%, 71%, and 21%, respectively.246

Calcitonin levels largely correlate with tumor burden and a decrease in postoperativecalcitonin levels to a normal level typically indicates successful removal of all MTC. It may takeseveral months to reach a nadir in the decline of calcitonin, but most patients reach a stablelevel by 72 hours. Mildly elevated, but stable, serum calcitonin levels (o150 pg/mL) can besafely observed. Increased CEA levels combined with stable calcitonin levels may indicateprogressive dedifferentiation of remaining MTC cells and is associated with a worse prognosis.

Rapid calcitonin doubling times, new elevation of serum calcitonin levels, or thedevelopment of palpable disease necessitates a neck ultrasound with FNA biopsy of anysuspicious masses. Evaluation for distant metastases should include a CT scan of the neck,chest, and abdomen, MRI of the liver and bone, bone scintigraphy, and FDG-PET imaging. Livermicrometastases may have a hypervascular, miliary pattern that is too small to be seen on CTimaging and may be best visualized on MRI. FDG-PET and FDG-PET/CT provide both functionaland anatomical information and have a sensitivity of 68% for detection of recurrent ormetastatic MTC.248 The sensitivity of FDG-PET/CT increases to 78%-80% if used selectively inpatients with a serum calcitonin greater than 1000 pg/mL.249

Treatment of persistent or recurrent MTC

In patients with an elevated serum calcitonin level after total thyroidectomy and a properlycompleted central compartment neck dissection, a lateral neck dissection is performed when


abnormal lymph nodes are identified on ultrasound, CT, or FDG-PET scanning. In the absence ofimageable disease, patients with hypercalcitoninemia are followed. Approximately 50% ofpatients with MTC develop recurrent disease. Repeat neck operations are indicated for diseaselimited to the neck when all the disease can be removed, surgical palliation of compressivesymptoms or impending asphyxiation, cytoreductive therapy for palliation of diarrhea orflushing, and for patients who underwent an inadequate initial operation. Repeat central neckdissection may be facilitated by using a lateral approach where the space between the commoncarotid artery and trachea is entered through undissected tissue planes lateral to the strapmuscles.

The role of radiation therapy in the treatment of MTC is limited. The C cells of the thyroidgland do not concentrate radioiodine. As a result, 131I therapy is not utilized. External beamradiation and bisphosphonates have a role in helping to alleviate symptoms secondary to bonemetastases. External beam radiation therapy may also have a palliative role in patients withextensive local disease and involvement of the aerodigestive tract and major vessels. Externalbeam therapy can help achieve locoregional control in patients with high-risk MTC with grossor microscopic residual disease, soft tissue extension, nodal metastases, or mediastinaldisease.250,251 However, it results in no survival benefit and it is associated with significantmorbidity, including severe postradiation fibrosis, mucositis, esophagitis, and dysphagia.251,252

As a result, the risks and benefits must always be considered before recommending radiationtherapy. Conventional chemotherapy has limited efficacy in patients with metastatic MTC.Targeted molecular therapies, most of which are TKI that target RET, VEGF, and epidermalgrowth factor receptors, are being investigated and currently appear to be the best availabletreatment option for locally advanced and metastatic MTC. Vandetanib has been recentlyapproved by the Food and Drug Administration for symptomatic or progressive MTC.Vandetanib administration in patients with locally advanced, unresectable, or metastaticMTC has been shown to produce partial response in 30% and stable disease in 30% of patientsand a 50% reduction in calcitonin levels.253 Other multikinase inhibitors such as sorafenib,axitinib, motesanib, and cabozantinib are also being investigated. New National Institutes ofHealth–funded trials are currently recruiting patients to examine the effects of panobinostat, ahistone deacetylase inhibitor, pasireotide, a somatostatinpeptidomimetic, lithium, and ever-olimus, an inhibitor of the mammalian target of rapamycin (www.clinicaltrials.gov).

PTL case

A 66-year-old woman reported the sudden appearance of a large right-sided neck mass thatwas rapidly increasing in size. She complained of neck pressure, cough, and dyspnea that wasworse when she laid flat. She had a known history of hypothyroidism and was on levothyroxinetherapy. She had no prior history of head or neck radiation. She had a cousin who was treatedfor thyroid cancer.

On physical examination, she had an 8-cm mass in the right lobe of the thyroid gland thatwas extending substernally and was displacing her trachea to the left. She had no cervical orsupraclavicular adenopathy. The rest of her physical examination was normal.

An ultrasound examination of the neck demonstrated a large heterogeneous massmeasuring 8 � 2.9 � 2.9 cm in dimensions that was completely replacing the right lobeand isthmus of the thyroid gland. The left lobe of the thyroid gland was enlarged but there wasno definite dominant nodule appreciated. There were 2 abnormal-appearing right lowercervical lymph nodes with loss of the normal fatty hila. Laboratory evaluation revealed a serumTSH level of 4.88 mIU/mL, an antimicrosomal antibody titer of 805.7 IU/mL, and an anti-Tgantibody of 242.2 IU/mL.

An FNA biopsy of the mass in the right lobe of the thyroid gland revealed an atypicallymphoid cell population that was highly suspicious for a lymphoproliferative disorder. Thepatient underwent an incisional biopsy, which revealed a diffuse large B-cell lymphoma thatwas infiltrating the skeletal muscle. Postoperatively, the patient underwent a stagingevaluation that included a PET-CT scan which demonstrated a large intensely hypermetabolic

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mass in the right neck surrounding the carotid artery, internal jugular vein, and the tracheawith extension into the right superior mediastinum consistent with the patient’s knownlymphoma. There were also 4 separate hypermetabolic skeletal foci 2 in the thoracic spine and2 in the pelvis consistent with bony metastases. A bone marrow biopsy was negative.

The patient was treated with a standard regimen of chemotherapy consisting of rituximab,cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for stage IV diffuse B-cell lymphoma. She was also given prophylactic intrathecal methotrexate. With initiation of theprednisone therapy the patient experienced a rapid reduction in the size of the right-sided neckmass with significant improvement in her compressive symptoms. She completed 6 cycles ofR-CHOP, the first 4 with intrathecal methotrexate. She refused radiation consolidation. At her3-year follow-up she had no evidence for recurrent disease.

Background

PTL is a rare form of thyroid malignancy making up less than 1% of all thyroid malignancieswith an annual incidence rate of 2.1 cases per 1 million persons.254 It accounts for only 2% ofextranodal lymphomas. Like many other thyroid diseases, it has a female predominance with afemale:male ratio of 3:1-4:1, and generally occurs later in life, between the ages of 50 and 80,with a peak incidence in females in their 60s.

Most thyroid lymphomas are derived from a non-Hodgkin’s B-cell lineage (70%-80%) withdiffuse large B cell being the predominant form. Other rare B-cell subtypes include follicularlymphoma, Hodgkin’s lymphoma, small lymphocytic lymphoma, and Burkitt lymphoma. Theremaining 20%-30% of thyroid lymphomas are derived from mucosa-associated lymphoidtissues (MALT) tumors.255 Since the mid-1990s, making the diagnosis of a B cell vs MALT-derived thyroid lymphoma has become important in determining treatment options andprognosis.

Clinical presentation and diagnosis

The most common presentation of PTL is a rapidly enlarging thyroid or neck mass often overthe course of only 2-3 weeks. Although the acute thyromegaly is generally a painless mass, upto 30%-40% of patients complain of local compressive symptoms, including cough, dysphagia,dyspnea, hoarseness, and stridor.256 These symptoms are usually due to local compression bythe tumor on the esophagus and trachea and by involvement of the recurrent laryngealnerve(s). This clinical presentation is similar to patients with ATC or poorly differentiatedthyroid carcinoma. Patients may have a history of hypothyroidism and a preexisting goiter thatsuddenly and rapidly increases in size. The ‘‘B symptoms’’ of lymphoma (fever, night sweats,anorexia, and weight loss) are not typical of PTL unless there is concomitant widespread nodalinvolvement.254

Patients with PTL may have a history of Hashimoto thyroiditis that predates thedevelopment of their lymphoma by 20-30 years. Holm and colleagues have documented thatHashimoto thyroiditis increases the relative risk of developing thyroid lymphoma by a factor of67.257 The exact mechanism of this is not known, but may be similar to other cancers caused bya chronic inflammatory process such as chronic erosive esophagitis leading to Barrettesophagus and esophageal adenocarcinoma.258 Another theory is that the lymphocyticinfiltration seen in Hashimoto thyroiditis provides a lymphocyte population in the thyroidthat can later undergo malignant transformation.259 Nevertheless, a diagnosis of PTL should beconsidered in any patient with Hashimoto thyroiditis and enlarging goiter.

On physical examination, patients usually have marked, firm, bilateral thyroid enlargement,often with substernal extension. The thyroid gland may be fixed to surrounding structures.They may have associated cervical lymphadenopathy

When PTL is suspected, a serum TSH and antimicrosomal antibody levels are obtained andan FNA or core needle biopsy with flow cytometry is performed. An open biopsy with


immunohistochemical studies may be necessary to determine the specific type of lymphoma.The typical morphologic findings of high-grade B-cell lymphomas are large cells withbasophilic cytoplasm and coarse nuclear chromatin, which can usually be identified withsimple Hematoxylin and Eosin staining.260 There are scant to absent follicular cells. However,MALT tumors and some of the less well-characterized B-cell lymphomas may requireimmunohistochemistry and flow cytometry for identification of typical B-cell markers suchas CD19-, CD20-, and CD45-positive cells, and MALT markers such as CD5-, CD10-, and CD23-negative cells. Some institutions have shown the ability to establish these diagnoses on FNAbiopsy in up to 88% of cases,261 but emphasize that core needle biopsy or open incisional biopsymay be necessary to determine the specific cell type of lymphoma.262

Once a diagnosis of PTL is made, a CT scan of the neck, chest, abdomen, and pelvis, FDG-PETscan, and bone marrow biopsy are recommended to determine the stage of the disease.Takashima and colleagues263 found CT scan to be superior to ultrasound in determining thelocal extent of disease and lymph node involvement in both the neck and in other lymph nodebasins. The most widely used staging system of PTL is the Ann Arbor Stage classificationsystem264 (Table 6). Staging is important and plays a role in determining both overall prognosisas well as treatment recommendations. Overall 5-year survival by stage is as follows: stage IE,80%; stage IIE, 50%; and stage III and IVE, o36%.264 Other prognostic factors include tumor size(4 10 cm, worse prognosis), presence of local compressive symptoms, which are indicative oflocal invasion, rapid tumor growth, and histologic subtype. MALT lymphomas tend to be muchmore indolent than their B-cell counterparts. In a large case series by Derringer and colleagues30 patients with MALT lymphomas had a 100% 5-year survival rate whereas B-cell tumors hadan approximate 80% 5-year survival rate.255

Treatment

PTL, like other non-solid organ lymphomas, is both radiosensitive and highly responsive tochemotherapy. However, because of the rarity of this malignancy, there are no randomizedcontrolled studies to help guide therapeutic decision making for thyroid lymphoma. Mostpatients with diffuse B-cell lymphoma are treated with a standard regimen of chemotherapyconsisting of rituximab, a monoclonal antibody directed against CD20 generally present on thecell surface of most B-cell lymphomas, cyclophosphamide, doxorubicin, vincristine, andprednisone (R-CHOP) in combination with external radiation. Patients experience rapid anddramatic reduction in size of the thyroid lymphoma usually within hours after initiation ofprednisone therapy.

The original mainstay for the treatment of PTL was surgical resection or debulking with orwithout radiotherapy. However, the outcomes for this approach were uniformly poor, withmortality rates of 50%-70%, and recurrence rates of at least 50% outside the treated area of theneck and upper mediastinum.265,266 As a result, in the 1980s chemotherapy was added toradiotherapy and the use of surgery was for the most part relegated for diagnosis and palliativetreatment of patients with acute compressive symptoms. In a meta-analysis of more than 200patients with PTL treated with combined chemoradiation, Doria and colleagues demonstrated adramatic reduction in relapse rates from 43% and 37%, respectively, for chemotherapy orradiation therapy alone to 7.7% for combined chemoradiation.267 Similar studies from M.D.Anderson,268 and Matsuzuka and colleagues269 have documented relapse rates of 9% and 0%

Table 6Ann Arbor staging classification of primary thyroid lymphoma (PTL).

IE: PTL with or without extension into the perithyroidal soft tissues.

IIE: PTL with involvement of lymph nodes on the same side of the diaphragm.

IIIE: PTL with involvement of lymph nodes on both sides of the diaphragm.

IVE: PTL with dissemination to other extranodal sites such as liver, spleen, or bone marrow.


with overall 5-year survival rates of 80%-100% using combined chemoradiation. Most patientshad a predominance of B-cell lymphomas.

Up to 80% of patients with MALT of the thyroid gland present with stage I E disease and aretreated with radiation or surgical resection alone. Chemotherapy is used for patients with moreadvanced disease. Some small retrospective studies have borne out this concept. Derringer andcolleagues reported that 30 of their 108 patients with PTL had MALT, 16 were treated withsurgery alone, and 14 had combined radiation and chemotherapy.255 The average 5-yearsurvival rate was 79% and there was no difference in overall survival in either treatment arm.Laing and colleagues reported a 70% disease-free survival in 31 patients with stage I or IIE MALTof the thyroid gland treated with radiation alone.270 As a result, the National ComprehensiveCancer Network recommends radiation or surgery alone for treatment of stage IE MALT of thethyroid gland, with chemotherapy and radiation reserved for more advanced disease.271

Sippel and colleagues have reported that there may still be a role for palliative surgicalresection of PTL.272 In this retrospective study, 27 patients underwent surgical resection ordebulking of their PTL for acute airway obstruction. One patient died on the tenthpostoperative day from a myocardial infarction and 5 patients required tracheostomy, butthe remaining 21 patients had minimal operative morbidity. There was no comparison withpatients who underwent medical therapy alone.

In summary, PTL remains a rare form of thyroid malignancy that precludes formalrandomized studies of treatment protocols, but the existing literature does provide us withsome general guidelines. A rapidly enlarging neck mass of thyroid origin should certainlyprompt a differential diagnosis of PTL vs ATC. Recent advances in cytopathology have allowedaccurate diagnosis of these tumors with the use of fine-needle biopsy and flow cytometry. Coreneedle biopsy and open biopsy may also be necessary for definitive diagnosis. Distinguishing aprimary B-cell lymphoma from MALT should be a priority as it affects treatment and prognosis.Once a diagnosis of PTL is made, CT scan with FDG-PET remains the mainstay of appropriatestaging treated with combined chemotherapy and radiation therapy with surgery reserved forpatients with acute airway obstruction. Surgical intervention for this complex and raremalignancy should be carried out in experienced centers. Surgery or radiation therapy alone orin combination may be considered for early stage MALT lymphomas.

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3.Advances in Management of Thyroid Cancer

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