Medullary, Anaplastic, and Metastatic Cancers of the Thyroid

Medullary, Anaplastic, and Metastatic Cancers of the Thyroid Susan C. Pitt and Jeffrey F. Moley Thyroid cancer is the most common endocrine malignancy accounting for nearly 95% of endocrine cancers according to the American Cancer Society. In 2009, more than 37,000 adults are projected to be diagnosed with thyroid cancer in the United States, and more than 1,600 people will die from the disease (www.cancer.org). A disproportionate number of these deaths will be accounted for by the rarer, but more aggressive thyroid malignancies, including medullary, anaplastic, and metastatic cancers of the thyroid. For these patients, surgical management is the only potentially curative treatment option. However, a significant amount of research is being conducted on novel therapeutic agents. This article reviews the pathology, epidemiology, clinical presentation, diagnosis, and treatment options of medullary, anaplastic, and metastatic cancers of the thyroid with an examination of emerging therapies. Semin Oncol 37:567-579 © 2010 Elsevier Inc. All rights reserved.

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n 2009, the American Cancer Society estimated that 37,200 new cases of thyroid cancer would be diagnosed in the United States, and 1,630 people would die from the disease.1 These diagnoses include several types of thyroid malignancies—papillary, follicular, Hürthle cell, medullary, and anaplastic thyroid cancer, primary thyroid lymphoma, and secondary metastases to the thyroid. The most common thyroid diagnosis is differentiated thyroid cancer (DTC), which is comprised of two main histological subtypes: papillary and follicular. Together, papillary and follicular thyroid cancers make up 80% to 90% of all cases.2 Papillary thyroid cancer (PTC) is the most prevalent histological subtype of thyroid cancer, accounting for about 80% of all cases.2 Fortunately, the prognosis for patients diagnosed with PTC is very favorable, with a 10-year survival rate of greater than 95% (Table 1).2,3 Approximately 10% to 12% of thyroid neoplasms are thus follicular thyroid cancers (FTCs), which also are associated with excellent long-term survival rates (92% 10year survival).2,4 Therefore, the majority of patients with a new thyroid cancer diagnosis can expect a positive outcome. In a given year, less than 15% of newly diagnosed thyroid malignancies will be medullary, anaplastic, or Washington University School of Medicine, St. Louis, MO. Address correspondence to Jeffrey F. Moley, MD, Washington University School of Medicine, Campus Box 8109, St. Louis, MO 63110. E-mail: [email protected] 0270-9295/ - see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1053/j.seminoncol.2010.10.010

metastatic cancer to the thyroid.2,5 Medullary thyroid cancer (MTC) accounts for approximately 5% of thyroid carcinomas and arises from calcitonin-secreting parafollicular C cells.6 The survival at 10 years is less than that observed in patients with DTC, since approximately 75% to 80% of patients are alive at this time point.3,4 Thus, MTC represents a disproportionate number of deaths accredited to thyroid cancer (13.4%).6,7 Anaplastic thyroid cancer (ATC) comprises an even smaller portion of all thyroid carcinomas, making up only 0.5% to 1.7% of diagnosed cases.4 The survival for patients with these tumors is also the worst, with at most 14% alive 10 years after diagnosis.4 Metastases to the thyroid are even rarer and likely represent less than 1% of thyroid malignancies. The prognosis for these patients depends on the histological subtype of the primary tumor and extent of metastasis. Nonetheless, the overall survival of patients with secondary thyroid malignancies is almost certainly worse than that of patients with DTC.

MEDULLARY THYROID CANCER With the increasing incidence of PTCs and stable incidence of other histological subtypes, MTC likely comprises only 5% of all thyroid cancers currently.2,7 While up to 25% of MTCs are hereditary, the majority of cases (75%) are sporadic.8,9 Hereditary forms of MTC include both types of multiple endocrine neoplasia 2 (MEN 2A and MEN 2B) and familial MTC (FMTC). Mutations of the RET (Rearranged during Transfection) proto-oncogene on chromosome 10q11 are present in more than 95% of hereditary MTCs and about 25% of

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Table 1. Classification, Incidence, and Survival of Thyroid Malignancy by Cell Origin

Cell Origin Follicular cells

Cancer Type Differentiated Papillary Follicular Hürthle cell Undifferentiated Anaplastic

Incidence (%) 80 10 2

10-Year Survival (%) 98 92 76

1

3.5

Medullary

5

75–80

Metastases Lymphoma

1 1

Variable 95

Parafollicular C cells Non-thyroid

sporadic MTCs.10 Dominant-activating or gain-of-function mutations in the RET proto-oncogene lead to the constitutive activation of receptor tyrosine kinases and downstream pathways involved in cell survival and proliferation.11,12 MTC is an uncommon, slow-growing neuroendocrine tumor that originates from parafollicular C cells, which secrete the hormone calcitonin. C-cell hyperplasia is a premalignant lesion frequently seen in patients with familial forms of MTC.13–16 On gross pathology, MTCs are grey, firm nodules that may be multifocal or bilateral, especially in familial forms of the disease.8 Microscopically, these tumors have a fine granular eosinophilic cytoplasm and central nuclei inside polygonal cells that are uniform throughout the tumor specimen.8 Stromal amyloid also may be seen and is highly characteristic of MTC but is observed in a minority of cases (30%).8

Clinical Presentation and Diagnosis of MTC The clinical presentation of MTC varies to some extent depending on whether the patient has a sporadic or hereditary form of the disease. Sporadic MTC usually presents with a solitary, palpable thyroid nodule.17 These patients typically have unifocal disease and a somatic RET mutation about 25% of the time.8,9 Other symptoms may be present, such as dyspnea, hoarseness, coughing, or dysphagia, but are less common. Patients also may complain of diarrhea, which can occur secondary to elevated levels of calcitonin.8 Palpable disease in the lateral neck from metastasis also can be observed. Once a palpable thyroid nodule has become clinically evident, more than 50% patients have already developed lymph node metastases.18 The central compartment, comprised of the pretracheal and paratracheal nodes (level VI), is the most common site of nodal disease. Metastasis to the ipsilateral jugular chain nodes in the lateral compartment (levels II–V) is

the next most frequent location of lymphatic spread, followed by contralateral cervical nodes, and then level VII nodes in the anterior mediastinum.18,19 Distant metastases from hematogenous dissemination of tumor cells also are observed in the lungs, liver, bone, and brain. Therefore, symptoms such as abdominal discomfort, bone pain, or mental status changes can be observed as well. Presentation of patients with hereditary MTC may be different because of known family history, previous genetic testing, or diagnosis of an alternate disease in the syndrome. MEN 2A is the most common, comprising almost 80% of the hereditary MTCs and consists of MTC, pheochromocytoma, and hyperparathyroidism. In MEN 2A patients, MTC has 100% penetrance and is multifocal and bilateral. Pheochromocytoma and hyperparathyroidism are observed with approximately 40% and 20% penetrance, respectively.20,21 In rare instances, lichen planus amyloidosis and/or Hirschsprung’s disease can be seen with the MEN 2A syndrome. MEN 2B also has 100% penetrance of MTC and 40% penetrance of pheochromocytoma but is characterized by a marfanoid body habitus, mucosal neuromas, gastrointestinal ganglioneuromatosis, and megacolon.20 FMTC is not associated with other diseases and is typified by the development of MTC alone. To avoid diagnostic error, FMTC criteria are stringent and require 10 or more carriers of the RET mutation in the family and multiple MTC diagnoses after the age of 50.20,22,23 Hereditary MTCs are transmitted in an autosomal dominant fashion and develop due to missense germline mutations of the RET proto-oncogene on chromosome 10q11 that are present in more than 95% of cases.10,17 The RET gene serves a critical role in the development of the renal and enteric nervous systems and codes for a transmembrane receptor tyrosine kinase. Dominant-activating or gain-of-function mutations

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Table 2. Hereditary RET Mutations by Clinical Syndrome and ATA Risk Level

Clinical Syndrome

ATA Risk Level

MEN 2A

A (lowest) B

MEN 2B

FMTC

C D (highest) A B C D

A

B C D

RET Codons 609, 790, 791, 804, 891 611, 618, 620, 633, 634, V804M ⫹ V778I C634R — — — — 883, 918, V804M ⫹ E805K/Y806C/ S904C, 922* 532, 609, 768, 790, 791, 804, 891, 912 633, 634 C634R —

Abbreviations: ATA, American Thyroid Association; MEN, multiple endocrine neoplasia; familial medullary thyroid carcinoma. Bolded codons are the most common mutations observed. *Brandi ML, et al.20

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tant metastatic disease. Fine needle aspiration (FNA) is the diagnostic test of choice, and immunohistochemical staining for calcitonin facilitates this diagnosis.8,9 Furthermore, serum calcitonin levels should be obtained and are useful for following individuals with recognized MTC or screening those at-risk for hereditary MTC as well.8,9 Additional studies that are recommended by the National Comprehensive Cancer Network (NCCN) 2010 Practice Guidelines in Oncology include serum calcium and carcinoembryonic antigen (CEA) levels, a neck ultrasound (US), genetic analysis for RET mutations, and evaluation of the vocal cords.26 Screening for pheochromocytoma by measuring plasma or urine metanephrines and catecholamines is additionally recommended. If the serum calcium is elevated, parathyroid hormone levels should be examined. Once the diagnosis is made, genetic counseling should be considered. If the calcitonin level is greater than 40 pg/mL, US of the neck to evaluate lymph nodes should be obtained. If the patient has palpable nodal disease or a calcitonin level greater than 400 pg/mL, a computed tomography (CT) scan or magnetic resonance imaging (MRI) of the chest and mediastinum is recommended.26 On CT scan, MTC classically has calcifications that can be readily identified. For the hereditary MTC syndromes, genetic screening should be done immediately after birth in MEN 2B offspring, and before the age of 5 years for MEN 2A and FMTC offspring.8,26 Staging for MTC is outlined in Table 3.

Treatment of MTC in the RET proto-oncogene lead to continual autophosphorylation of specific tyrosine residues.12 These changes in turn induce constitutive activation of intracellular signal transduction pathways involved in cell survival and proliferation. MEN 2A and FMTC are initiated frequently by a single point mutation at one of six cysteine codons, triggering constitutive dimerization and activation of the RET kinase.11,12,20,24,25 Mutations within the tyrosine kinase domain itself are identified in FMTC.11,20,25 In addition, germline mutations occur commonly within one of two specific sites in the kinase catalytic domain in MEN 2B.12 Table 2 lists several of the more common RET mutations that are seen in hereditary MTC by their syndrome and risk level. Diagnosis of MTC is similar to that of other thyroid cancers with a few additions. A thorough history and physical with a complete family history should be performed with special attention paid to the characteristic features (ie, marfanoid habitus) and alternative diagnoses (ie, hypertensive episodes and headaches in pheochromocytoma) seen in the hereditary MTC syndromes. Assessment of the patient should note the thyroid nodule size, mobility or fixation, presence of additional nodules or cervical lymphadenopathy, and any physical abnormality that could be related to dis-

Once a patient has been staged and undergoes thorough evaluation, the mainstay of treatment for MTC is surgical resection, largely because these tumors do not concentrate iodine and have shown poor response to conventional radioactive iodine, chemotherapy, and external-beam radiation regimens. In recent years, both the American Thyroid Association (ATA) and the NCCN Practice Guidelines in Oncology were updated for MTC, but they differ slightly.26,27 For neoplasms that are less than 1 cm and unilateral, a total thyroidectomy is recommended and a central neck dissection of level VI lymph nodes should be considered.26 For MTCs that are ⱖ1 cm and/or multifocal, a total thyroidectomy with a bilateral central neck dissection is the primary treatment. If ipsilateral or contralateral cervical lymph nodes are clinically or radiologically apparent, ipsilateral or bilateral modified neck dissection, respectively, is advocated. Furthermore, if a large tumor burden is encountered in the central neck, an ipsilateral modified neck dissection should be considered even in the absence of palpable disease. At our institution, in the absence of palpable lymphadenopathy, preoperative ultrasonic evaluation of the neck guides, whether an ipsilateral or contralateral neck dissection, is necessary.18 Machens et al have

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Table 3. Medullary Thyroid Cancer Staging (2010 AJCC Seventh Edition)

TNM Staging for MTC Primary tumor (T) Note: All categories may be subdivided: (s) solitary or (m) multifocal tumor. If multifocal, the largest tumor determines the T classification TX Primary tumor cannot by assessed T0 No evidence of primary tumor T1a Tumor ⱕ 1 cm in greatest dimension 1b Tumor ⬎ 1 – 2 cm T2 Tumor ⬎ 2 – 4 cm T3 Tumor ⬎ 4 cm and limited to the thyroid or T1 – 3 with minimal extrathyroid extension T4a Any T that extends beyond the thyroid capsule and invades the subcutaneous soft tissue, larynx, trachea, esophagus, or recurrent laryngeal nerve T4b Any T that invades prevertebral fascia or encases the carotid artery or mediastinal vessels Regional lymph nodes (N) Note: Includes central compartment, lateral cervical, and upper mediastinal nodal basins. NX Regional lymph nodes cannot be assessed N0 No regional lymph node involvement N1a Regional lymph nodes metastasis to level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph nodes) N1b Metastasis to unilateral, contralateral, or bilateral cervical or superior mediastinal lymph Nodes Distant metastasis (M) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis Stage I II III IVA IVB IVC

TNM T1a,b T2 T3 T1–3 T4a T1– 4a T4b Any T

N0 N0 N0 N1a N0 –1a N1b Any N Any N

M0 M0 M0 M0 M0 M0 M0 M1

Abreviation: TNM, tumor-node-metastasis.

previously shown that the presence of both ipsilateral and contralateral MTC nodal involvement is directly correlated with the extent of disease in the central neck.28,29 In addition, their data also indicated that the risks of ipsilateral and contralateral nodal metastases in the absence of central compartment disease are 10% and 5%, respectively. Therefore, thorough evaluation of the entire neck is prudent both preoperatively and intraoperatively. The ATA guidelines specifically support a mandatory skilled neck US that includes the superior mediastinum, as well as the central and bilateral lateral neck compartments.27 Because the sensitivity and specificity of surgeon-performed examination in

the operating room are only 64% and 74%, respectively, radiological assessment is critical.18 For patients with germline RET mutations, alternative management guidelines exist and include prophylactic therapies to prevent MTC development.26,27 Even within a given syndrome, the recommendations vary because of the diverse levels of penetration of the RET mutations and, thus, risk for MTC. Table 2 lists the codons and their risk levels by hereditary disease. MEN 2B has the most aggressive RET mutations with the highest risk of MTC and, therefore, screening after birth is performed.20 In infants with mutations at codons 883, 918, or 922 or compound heterozygous

Medullary, anaplastic, and metastatic cancers of the thyroid

RET mutations (V804M with E805K, Y806C, or 904C), total thyroidectomy with or without bilateral central neck dissection during the first year of life (or at diagnosis if later) is the appropriate surgical management.26 This technically challenging procedure should be performed only by surgeons experienced in thyroid and parathyroid operations in children. If a tumor greater than 0.5 cm is present, then central and ipsilateral functional neck dissections should be contemplated.26 For FMTC or MEN 2A patients (RET mutations at codons 609, 611, 618, 620, 630, 634, 768, 790, 791, 804, or 891), a total thyroidectomy by age 5 or 6 or when the mutation is identified (if later) is recommended.26 An ipsilateral or bilateral central neck dissection (level VI) is additionally recommended in the presence of palpable or radiologically identifiable lymphadenopathy or elevation of calcitonin level greater than 40 pg/mL. When a patient has already developed primary hyperparathyroidism prior to surgical intervention, then an appropriate parathyroidectomy dependent on the etiology of the underlying disease (adenoma v hyperplasia) can be performed at the time of thyroidectomy. The difficulty of reoperative parathyroidectomy should be kept in mind when hyperplasia is present. In these cases, we prefer a total parathyroidectomy with forearm autotransplantation and cryopreservation of parathyroid tissue. For MEN 2A and 2B in cases with a concurrent diagnosis of a pheochromocytoma, the pheochromocytoma should be treated first.27 Several technical considerations must be kept in mind to avoid complications during total thyroidectomy (which include hypoparathyroidism and recurrent laryngeal nerve injury). In addition to the standard thyroidectomy mobilization, a central neck dissection excises all lymphatic tissue between the carotid arteries laterally, the hyoid bone superiorly, and the innominate vessels inferiorly.18,30 –33 This commonly required widened area of exploration makes preservation of parathyroid function a major priority. The lower parathyroids are frequently directly connected to level VI nodes and, thus, must be excised and autotransplanted into the sternocleidomastoid muscle or forearm muscle.20,34,35 If the vascular pedicles of the glands have not been compromised, then the parathyroids may remain in situ, but devascularization is frequently required to perform an adequate and complete thyroidectomy with central compartment lymphadenectomy. Temporary hypoparathyroidism with hypocalcemia is observed in approximately 14% of patients, while permanent hypoparathyroidism is much less common (1.7% in one study).36,37 In experienced hands, the risk of permanent recurrent laryngeal nerve injury varies depending on whether a lymph node dissection is (2.7%) or is not (0.7%) performed.36 Postoperative management and surveillance of MTC patients relies heavily on serum calcitonin measurements, which should be checked preoperatively as a

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baseline. Following thyroidectomy, the calcitonin level typically requires approximately 72 hours to reach a new steady state.8 In patients with undetectable calcitonin levels and normalized CEA, annual measurement of both markers is advocated with consideration for a yearly cervical US as well. For those with MEN 2 syndromes, pheochromocytoma and hyperparathyroidism (MEN 2A only) screening also should be performed. If a significant rise in the calcitonin or CEA level is observed, then additional imaging is indicated to look for locally recurrent or metastatic disease (chest and abdomen). These imaging modalities include ultrasound of the neck, CT, MRI, fluorodeoxyglucose positron emission tomography (FDG-PET), or bone scan (contrastenhanced CT of the neck, chest, and abdomen with liver protocol). Because hepatic metastases are usually small (⬍3 cm) with a miliary pattern, these nodules are frequently overlooked on standard cross-sectional imaging and may require diagnostic laparoscopy to identify them.34,38 For those patients who have a detectable basal calcitonin or elevated CEA when measured postoperatively, a neck US is advised with additional imaging if the calcitonin is ⱖ150 pg/mL.26 If the patient is asymptomatic with negative imaging, then surveillance calcitonin and CEA every 6 months is advised. Any rise in these serum levels should prompt a metastatic work-up. When postoperative surveillance identifies persistent or recurrent MTC, management is operative when possible, but may necessitate multimodality and investigative therapies.8,39 For locoregional persistence or recurrence of MTC in the absence of distant metastases (with documented negative work-up), surgical resection is indicated.26,27 Durable biochemical normalization of calcitonin can be attained in more than 25% of these patients.32,34,39,40 If the isolated locoregional disease is unresectable and focally symptomatic, radiotherapy should be considered.26 Surgical resection or alternative regional treatments, such as radiofrequency ablation (RFA) or chemoembolization, also should be entertained for palliation in patients with symptomatic distant metastases. Asymptomatic distant metastatic MTC can be observed or treated similarly to patients with symptomatic disease. When disseminated distant disease is present, alternative therapies include clinical trial enrollment, small molecule tyrosine kinase inhibitor such as sorafenib or sunitinib, and dacarbazinebased chemotherapy.13,26,41– 48 Bisphosphonates may be used when bony metastases are present. A recent report on the effectiveness of the small molecule inhibitor vendatinib in patients with metastatic hereditary MTC reported a response rate of up to 30%.48

Prognosis and Survival of Patients With MTC In patients with MTC, the strongest predictors of survival are the stage of the disease, the age at diagnosis, and the extent of surgery.3,7,49 In a large study using

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the Surveillance, Epidemiology, and End Results (SEER) registry, SEER stage (localized, regional, or distant MTC) was strongly associated with survival, and those with distant metastases had a 4.5 times increased risk of dying compared to patients with localized disease.49 The worst prognosis was observed in patients older than 65 years at the time of diagnosis. In addition, patients who undergo surgery do better than similar patients who forego such a procedure, and total thyroidectomy patients survive longer than those with a lobectomy alone. Interestingly, this analysis also revealed that adjuvant radiotherapy was adversely associated with survival. Additional factors that have been associated with an improved outcome include female gender, well-differentiated histology, smaller tumor size, intrathyroidal tumor (confined to capsule), lack of lymph node involvement, and lower post-thyroidectomy calcitonin.3,7,49,50 The survival for patients with MTC is worse than that observed for DTCs but has improved over the last 20 to 30 years. The mean survival time from diagnosis of MTC was 8.6 years in a SEER database review from 1973 to 2002.49 The overall 5- and 10-year survival rates for MTC have been reported to be between 80%–97% and 75%– 88%, respectively, with the higher numbers coming from more recent reviews.4,50 Relative 5-year survivals by the 3rd/4th American Joint Cancer Committee (AJCC) stage of MTCs diagnosed between 1985 and 1990 were 98%, 98%, 73%, and 40% for stages I, II, III, and IV, respectively.4 More recently, Boostrom et al reported 5-year overall survival rates according to the sixth edition of the AJCC staging for MTC for stages I to IV to be approximately 100%, 99%, 96%, and 82%, respectively.51 More long-term survival data with respect to the most recent staging system have yet to be analyzed. Nonetheless, the prognosis for MTC patients appears to be improving with more appropriate surgical therapy and multiple clinical trials investigating novel treatments.

ANAPLASTIC THYROID CANCER ATC is a rare albeit highly aggressive tumor that is derived from the follicular cells of the thyroid (Table 1). This diagnosis accounts for less than 2% of all thyroid cancers.4,52 Unlike PTC and FTC, which are well-differentiated thyroid tumors with the same cellular origin, ATC cells are poorly differentiated and fail to retain any of the biological features of the original follicular cells.30 Histologically, ATCs can have various subtypes that may coexist, including giant cell, spindle cell, and squamoid cell tumors. Because these carcinomas are dedifferentiated, ATCs lose the ability to uptake iodine and synthesize thyroglobulin. These tumors also exhibit the most malignant behavior of all thyroid tumors and, thus, have the worst prognosis.4,30 Fortunately, the incidence of ATC has slightly decreased in

S.C. Pitt and J.F. Moley

recent years.53,54 It is postulated that this change is due to a combination of occurrences, including the increased incidence and earlier recognition of differentiated thyroid cancers thereby reducing the possibility of dedifferentiation, as well as the enhanced supplementation of dietary iodine worldwide. The pathophysiology of ATCs indicates that these tumors arise within well-differentiated thyroid cancers in approximately 1% of cases, especially in incompletely treated PTC and FTC lesions.55 In addition, many of these tumors develop in patients with longstanding goiters and, therefore, have a higher incidence in areas with endemic goiters.56 Molecular studies indicate that ATCs frequently have mutations of the RAS oncogene and may arise from RAS-mutated FTCs.57– 60 In addition, p53, a well-known tumor-suppressor gene, is commonly highly mutated in ATCs and may be involved in the process by which PTCs or FTCs become dedifferentiated.57,61– 63 Recent data also suggest that alterations in the oncogene BRAF may play a role in the progression of BRAF-mutated PTCs to ATCs.57 Further research is needed to delineate whether any of these mutations may be targets for future molecular therapies.

Clinical Presentation and Diagnosis of ATC Patients with ATC typically present with a rapidly growing thyroid mass and symptoms secondary to mechanical compression on or direct local invasion into surrounding structures.54,64 The tumor may infiltrate into cervical fat, the trachea, neck musculature, the esophagus, and/or the larynx, which has the potential to cause asphyxiation (Figure 1). Therefore, complaints such as a sore throat, neck pain, odynophagia, dysphagia, coughing, otalgia, dyspnea, dysphonia, stridor, hoarseness, or voice changes along with a palpable thyroid mass may be observed. ATC is up to three times more common in females than males and is typically diagnosed in the elderly, with a peak incidence in the sixth and seventh decades.3,53,65– 67 A recent SEER analysis of patients diagnosed with ATC between 1983 and 2002 reported a median age of 70 years with a range of 30 to 94 years.65 At presentation, these lesions are typically large, with a mean reported size of approximately 7 to 8 cm, but they can range from 3 cm up to 20 cm.30,53,65,68 More than half of patients will have extrathyroidal tumor extension and/or metastases to the lymph nodes or distant sites, most commonly the lungs or bone.52,56,65,69 Furthermore, less than 14% of patients are reported to have ATC that is confined within the thyroid capsule.30,65,70 Therefore, the clinical picture of an elderly patient with a rapidly enlarging neck mass that is firm and fixed to surrounding structures is highly indicative of ATC. Like MTC, the diagnosis of ATC is made by FNA cytology. If an FNA is suspicious for ATC, then histol-

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Figure 1. Anaplastic thyroid cancer (ATC) is a rapidly growing neoplasm that often presents with infiltration into cervical fat and musculature invading or displacing the trachea (A). This airway compression causes pain, dyspnea, and stridor as was seen in this patient with ATC (B).

ogy from a core biopsy should be obtained.26 These tests should always be accompanied by a thorough history and physical examination. Recommended laboratory studies include a complete blood cell count (CBC), serum calcium, and serum thyroid-stimulating hormone (TSH).26 Because of the aggressive nature of ATC, initial imaging should include a CT scan of the head, neck, chest, abdomen, and pelvis both to define the local extent of disease and to identify distant metastases.26,30,53,55,71 An FDG-PET or bone scan also can be considered to isolate sites of metastatic disease. The most recent AJCC Staging Manual classifies all ATCs as T4 and stage IV tumors, regardless of their actual overall tumor burden, due to the highly invasive quality and dismal prognosis of ATCs (Table 4).

Treatment of ATC A consensus on the management of patients with ATC has not been reached largely because the effectiveness of various therapies, in terms of prolonging survival, remains unclear. A combination of surgery, radiotherapy, and chemotherapy may improve local control and survival.72–77 Although the majority of patients are not eligible for surgical resection at the time of diagnosis, surgery continues to be the only curable treatment for ATC. Appropriate surgical management includes a total or near-total thyroidectomy accompanied by the resection of involved local and regional structures, as well as any clinically or radiographically involved lymph nodes. For postoperative surgical patients, as well as the majority of patients with ATC who are unresectable, NCCN guidelines preferentially recommend enrollment in a clinical trial, although combined radiotherapy (potentially hyperfractionated) with chemotherapy is an alternative.26 Referral to a clinical trial is the preferred therapy because standard

treatments lack efficacy. Several clinical trials are currently recruiting patients with ATC or have recently completed recruiting (www.clinicaltrials.gov). These trials include investigation of novel agents, among others, such as imatinib, a Bcr-Abl protein tyrosine kinase inhibitor; sorafenib, a tyrosine kinase inhibitor; combrestatin, a natural stilbenoid phenol that inhibits ␤-tubulin, combined with paclitaxel/carboplatin; bevacizumab, a monoclonal antibody to vascular endothelial growth factor (VEGF), combined with doxorubicin; pazopanib, a tyrosine kinase inhibitor with anti-angiogenesis properties; and pemetrexed, a folate antimetabolite, plus paclitaxel.69,78 – 81 Gene therapy also is being examined.

Table 4. Anaplastic Thyroid Cancer Staging

(2010 AJCC Seventh Edition) TNM Staging for ATC Primary tumor (T) All ATCs are considered T4 tumors T4a Intrathyroidal tumor (surgically resectable) T4b Extrathyroidal tumor (surgically unresectable) The N and M classifications are the same for ATC and MTC (see Table 3) All anaplastic carcinomas are stage IV Stage IVA IVB IVC

TNM T4a T1– 4a T4b Any T

N0 –1a N1b Any N Any N

M0 M0 M0 M1

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In patients who choose to forgo clinical trial enrollment or when registration is not possible, combined radiation with chemotherapy is advocated. Radiotherapy has been administered in the neoadjuvant setting in attempt to increase the rate of resectability.69,74,75 However, the role of radiation in addition to surgical resection is less clear. A survival benefit to external-beam radiotherapy has been shown in postoperative patients with extracapsular disease that is limited to adjacent tissues (locally invasive disease).65,72,80 An improvement in local control with acceleration of hyperfractionated radiation with concurrent chemotherapy (doxorubicin) also has been reported.69 In addition, a survival benefit has been seen in patients without surgery when a radiotherapy dose greater than 45 Gy is used.74 For patients with disease confined to the capsule, the benefit of adjuvant radiation is less clear. Radiotherapy has been used alone or in combination with various chemotherapeutic agents, including cisplatin, bleomycin, and melphalan.53 Doxorubicin has shown the greatest effectiveness, and is being investigated in many current clinical trials along with paclitaxel and other agents (www.clinicaltrials.gov). In patients with advanced ATC, surveillance and palliative procedures may be necessary to provide the best supportive care. FDG-PET or bone scintigraphy at regular intervals may be indicated in patients with a longer survival and relatively good health.82 Some advocate surveillance tracheoscopy and esophagoscopy every few months to look for signs of invasion. Such procedures are clearly warranted in patients with worsening of local symptoms. For those patients with impending airway obstruction who are not in imminent danger of dying, a palliative tracheostomy can be considered. In addition, tracheal stenting or interventional bronchoscopy using a Nd-YAG laser are alternatives in patients with inoperable ATC and tracheal obstruction. Nevertheless, in these patients with ATC, the treatment will most likely be multimodality, potentially experimental, and only rarely curative.

Prognosis and Survival of Patients With ATC The prognosis for patients with ATC is universally poor, although rare cases of long-term survivors have been reported.3,53,54,65,71,83 Several factors have been associated with an improved prognosis, including younger age at diagnosis (⬍45 years), disease confined to the thyroid, and surgery for patients with locoregional disease.53,67,68,70,84 In a study of SEER data from 1983 to 2002, characteristics that portended a worse outcome on univariate analysis were female gender, older age, extracapsular extension of disease or distant metastasis, tumor size greater than 7 cm, and lymph node involvement.65 However, multivariate analysis of the same data identified older age, extent of disease, and size over 7 cm to be the most significant determi-

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nants of worse survival. Others have found similar results with complete tumor resection or potentially curative surgery being the principal feature associated with survival.52,73 The survival for patients with ATC is significantly worse than that of MTC. Despite making up less than 2% of all thyroid malignancies, ATC accounts for greater than 50% of all deaths from thyroid cancer.53 In a recent SEER review, the median survival for patients with ATC was 4 months, which is consistent with reports that range from 3 to 10 months.65 Overall survival for this same group of patients was 7.5% at 5 years, although the literature suggests the 5-year survival rate may be as low as 1% or as high as 14%.3,52,65,67–70,74,84 When analyzed by stage according to the Sixth AJCC edition for ATC, patients diagnosed between 1983 and 2002 had 22.9%, 10.1%, and 0% 5-year overall survivals at stages IVA, IVB, and IVC, respectively.65 These dismal survival rates for patients with ATC reinforce the need for improvements in systemic therapies and enrollment in multi-institutional, prospective clinical trials. Furthermore, early detection and surgical intervention is necessary to impact the prognosis of these patients.

METASTATIC CANCERS OF THE THYROID Metastases to the thyroid are extremely rare despite the gland’s extensive relative vascularity and are observed most commonly in patients with renal cell carcinoma (RCC), breast, lung, or colon cancer, and melanoma among others.85–91 The incidence of clinically significant metastatic disease has not been well established due to the infrequency with which patients present. In surgical case series examining patients operated on for malignant thyroid neoplasms, 1.4% to 2.1% have been from metastasis to the thyroid.88,92,93 However, autopsy studies of patients with metastatic tumors have reported higher rates of spread to the thyroid ranging from 0.5% to 24.2%.87,94 –96 In an analysis by Shimaoka et al, the frequency of metastasis to the thyroid also varied by primary tumor, with 39% of melanoma patients having secondary thyroid neoplasms, but only 12% of RCC patients developing the same.94 However, less than 10% of those patients studied had clinically detectable thyroid disease.94 When considering clinical significance, metastatic RCC is likely the most common tumor with thyroid metastasis, although no clear consensus exists.85,86,89,92,93 Table 5 is a more comprehensive account of tumors that can metastasize to the thyroid, but it does not provide a completely exhaustive record.85–94,97 Multiple single case reports have been published on tumors with thyroid metastases.30,90,97

Presentation and Diagnosis of Metastases to the Thyroid In patients with metastatic disease to the thyroid, symptoms such as a dysphagia, hoarseness, stridor, or a

Medullary, anaplastic, and metastatic cancers of the thyroid

Table 5. Sample of Primary Tumors With Reported Thyroid Metastases

Melanoma Breast ductal carcinoma Renal clear cell carcinoma Lung adenocarcinoma Squamous cell carcinoma of the head and neck Squamous cell carcinoma of the esophagus Squamous cell carcinoma of the cervix Colon adenocarcinoma Pancreatic neuroendocrine tumors Pleomorphic liposarcoma Hepatocellular carcinoma Leiomyosarcoma Merkel cell carcinoma Paraganglionoma

palpable mass may be present, but many are asymptomatic with a nodule being detected on routine physical examination or incidentally on imaging studies such as FDG-PET.85,89,92–94 Any patient with a thyroid nodule and history of a primary cancer should be considered to have potential metastatic disease.89 Previous studies have described disease-free intervals of over 15 years between the time of primary diagnosis and the appearance of thyroid metastasis.91–93 Diagnostic work-up should include a systematic history and physical examination, an assessment of thyroid function, and FNA of the suspicious thyroid nodule.91 Measurement of serum TSH is usually sufficient to determine the patient’s thyroid function. However, measurement of free thyroxine (T4) or triiodothyronine (T3) levels also may be necessary. FNA is highly accurate in these patients and is the diagnostic procedure of choice allowing for the preoperative diagnosis of a secondary thyroid neoplasm.89,91 If FNA identifies a metastatic cancer, further work-up should be performed to evaluate the extent of metastatic disease. Depending on the histology of the primary neoplasm, CT, MRI, FDG-PET, bone scan, or additional imaging modalities may be indicated.

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apy depends on multiple factors such as histology, the presence of additional metastases, and tumor biology. Therefore, each case should be treated individually as thyroidectomy may be appropriate in some patients but not in others. Indications for surgical intervention include solitary thyroid metastases with proven negative work-up for occult metastases and palliation of symptoms related to compression or airway compromise.89,98 For solitary metastasis to the thyroid in the absence of additional metastatic disease, most would argue that thyroidectomy is the treatment of choice.85,89 However, the extent of thyroid resection is debatable seeing that a lobectomy with ipsilateral isthmusectomy or subtotal thyroidectomy may suffice for patients with a solitary unilobar mass that appears many years after the primary tumor as is commonly seen with clear cell cancers of the kidney. In the case of bilobar or multifocal disease, a total thyroidectomy is recommended. Lymphadenectomy should be reserved for those individuals with preoperative macroscopic lymphadenopathy detected by physical examination or US. Emphasis on the need for a thorough preoperative evaluation in patients suspected of having isolated metastases to the thyroid is imperative to avoid unnecessary surgery on those with a poor prognosis.98 The effectiveness of additional therapeutic modalities depends largely on the histology of the primary tumor. External beam radiation therapy and chemotherapy are certainly the most frequently employed alternatives to surgical management, and immunotherapy has been used as well.91 Breast and non-small cell lung cancers are more radiosensitive tumors with thyroid metastases, while RCC and melanoma tend to be radioresistant. Furthermore, tumor-specific treatments, such as the use of tamoxifen in breast cancer metastases, also can be employed.89 Involvement of radiation and medical oncology specialists in patients who have no clear indication for or benefit from thyroidectomy is essential. Treatment of patients with widespread metastases will likely require a multidisciplinary approach and possible enrollment in multi-institutional, randomized controlled clinical trials.

Treatment of Metastases to the Thyroid

Prognosis and Survival of Metastases to the Thyroid

Treatment of secondary thyroid cancer also depends on the tumor histology in addition to the extent of metastatic disease, presence of symptoms or airway compromise, and the availability of alternative (nonsurgical) therapies. No guidelines or consensus exist that address the management of this disease and thus the recommendations that have been made are based on expert opinion and retrospective reviews. Arguments exist both in favor of and against surgical excision. Because of the vast potential types of metastases, ther-

Metastases to the thyroid comprise a variety of primary tumor types and can originate from nearly every organ in the body. Therefore, like the treatment of these tumors, the prognosis and survival for these patients depends significantly on the histology of the primary cancer and the extent of metastatic disease. Nonetheless, multiple case series have analyzed these patients as a group and attempted to identify prognostic variables. In general, patients with secondary thyroid cancers were thought to have a poor prognosis,

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although recent data suggest that the survival is similar to that of patients with the same stage and primary tumor.99 In patients with isolated metastases to the thyroid gland, thyroidectomy has been shown to prolong survival in some series, while others have failed to show a similar benefit.85,86,98,99 In addition, patients with nodular thyroid metastases as opposed to thyroid infiltration tend to have an improved outcome.98 On the other hand, a delay in the diagnosis of thyroid metastases and the presence of widespread disease are associated with reduced survival.88 The survival of patients with metastases to the thyroid is difficult to ascertain because of the rarity of this disease, the lack of population-based data analysis, and the multitude of different primary carcinomas each with varying biology and prognosis. In one review of 43 cases that include primary tumors of the kidney, lung, breast, uterus, and esophagus, the mean survival ranged from 25 to 34 months in nonsurgical and thyroidectomy patients, respectively.89 However, when examining just patients with lung cancer, the time from diagnosis of thyroid metastases to death has consistently been reported as less than 3 months.91,100 On the contrary, long-term survival and cure have been documented in patients with RCC and other isolated metastases, with disease-free survival of up to 10 years in some cases.85 In an analysis of 10 patients with isolated disease, the median survival was not yet reached at a median follow-up of 5.2 years.85 The wide range of survival that has been observed in these patients reinforces the need to take into account the individual characteristics of both the patient and the tumor in any discussion of prognosis or survival with patients who have metastases to the thyroid.

SUMMARY Early diagnosis and thorough surgical resection is integral to the management of patients with MTC, ATC, and metastases to the thyroid. These tumors almost always display a more aggressive tumor biology than is seen in patients with DTCs. Additional disease burden is commonly encountered in the cervical lymph nodes or at distant sites. Therefore, curative resection is unable to be achieved in a significant number of these patients. As such, the prognosis and overall survival is poorer when compared to the more common thyroid carcinomas—PTC and FTC. Medullary, anaplastic, and metastatic cancers to the thyroid together comprise less than 10% of all malignant thyroid tumors, but they account for the majority of deaths, emphasizing the need for innovative research and novel therapeutic strategies for these patients. Furthermore, multi-institutional, randomized controlled trials should be performed to advance our medical knowledge more rapidly. Fortunately, the prognosis in patients with MTC,

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ATC, and secondary thyroid malignancies appears to be improving.

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