OverviewThere are 3 main histologic types of thyroid carcinoma: differentiated (including papillary, follicular, and Hürthle), medullary, and anaplastic (aggressive undifferentiated tumor). Of 53,856 patients treated for thyroid carcinoma between 1985 and 1995, 80% had papillary, 11% had follicular, 3% had Hürthle cell, 4% had medullary, and 2% had anaplastic thyroid carcinoma.1 These NCCN guidelines focus on medullary thyroid carcinoma (MTC). Another NCCN guideline addresses papillary, follicular, Hürthle cell, and anaplastic thyroid carcinomas (see NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma [to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org]).MTC derives from the neuroendocrine parafollicular calcitonin-producing (C) cells of the thyroid.2–4 Sporadic MTC accounts for approximately 80% of all cases of the disease. The remaining cases consist of inherited tumor syndromes, such as multiple endocrine neoplasia type 2A (MEN 2A), which is the most common type; MEN 2B; or familial MTC.5,6 Sporadic disease typically presents in the fifth or sixth decade. Familial forms of the disease tend to present at earlier ages.2Because the C cells are predominantly located in the upper portion of each thyroid lobe, patients with sporadic disease typically present with upper pole thyroid nodules. Metastatic cervical adenopathy appears in approximately 50% of patients at initial presentation. Symptoms of upper aerodigestive tract compression or invasion are reported by up to 15% of patients with sporadic disease.7Symptoms from distant metastases in the lungs or bones occur in 5% to 10% of patients. The ability of the tumor to...
Overview

There are 3 main histologic types of thyroid carcinoma: differentiated (including papillary, follicular, and Hürthle), medullary, and anaplastic (aggressive undifferentiated tumor). Of 53,856 patients treated for thyroid carcinoma between 1985 and 1995, 80% had papillary, 11% had follicular, 3% had Hürthle cell, 4% had medullary, and 2% had anaplastic thyroid carcinoma.1 These NCCN guidelines focus on medullary thyroid carcinoma (MTC). Another NCCN guideline addresses papillary, follicular, Hürthle cell, and anaplastic thyroid carcinomas (see NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma [to view the most recent version of these guidelines, visit the NCCN Web site at www.NCCN.org]).

MTC derives from the neuroendocrine parafollicular calcitonin-producing (C) cells of the thyroid.24 Sporadic MTC accounts for approximately 80% of all cases of the disease. The remaining cases consist of inherited tumor syndromes, such as multiple endocrine neoplasia type 2A (MEN 2A), which is the most common type; MEN 2B; or familial MTC.5,6 Sporadic disease typically presents in the fifth or sixth decade. Familial forms of the disease tend to present at earlier ages.2

Because the C cells are predominantly located in the upper portion of each thyroid lobe, patients with sporadic disease typically present with upper pole thyroid nodules. Metastatic cervical adenopathy appears in approximately 50% of patients at initial presentation. Symptoms of upper aerodigestive tract compression or invasion are reported by up to 15% of patients with sporadic disease.7

Symptoms from distant metastases in the lungs or bones occur in 5% to 10% of patients. The ability of the tumor to secrete measurable quantities of calcitonin, occasionally along with other hormonally active peptides (i.e., adrenocorticotrophic hormone [ACTH] or calcitonin-gene related peptide [CGRP]), can contribute to the development of diarrhea, Cushing's syndrome, or facial flushing in many patients with advanced disease. The risk for concomitant or subsequent development of pheochromocytoma and hyperparathyroidism must always be considered.2

Epidemiology

Thyroid nodules are approximately 4 times more common in women than in men. Palpable nodules increase in frequency throughout life, reaching a prevalence of approximately 5% in the United States population aged 50 years and older.810 Nodules are even more prevalent when the thyroid gland is examined at autopsy or surgery, or when using ultrasonography; 50% of the thyroids so studied have nodules, which are almost always benign.9,11 New nodules develop at a rate of approximately 0.1% per year, beginning in early life, but develop at a much higher rate (∼2% per year) after exposure to head and neck irradiation.12,13

F1NCCN Clinical Practice Guidelines in Oncology: Medullary Carcinoma

Version 1.2010, 01-14-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 5; 10.6004/jnccn.2010.0040

F2NCCN Clinical Practice Guidelines in Oncology: Medullary Carcinoma

Version 1.2010, 01-14-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 5; 10.6004/jnccn.2010.0040

F3NCCN Clinical Practice Guidelines in Oncology: Medullary Carcinoma

Version 1.2010, 01-14-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 5; 10.6004/jnccn.2010.0040

F4NCCN Clinical Practice Guidelines in Oncology: Medullary Carcinoma

Clinical trials: The NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are category 2A unless otherwise noted.

Citation: Journal of the National Comprehensive Cancer Network J Natl Compr Canc Netw 8, 5; 10.6004/jnccn.2010.0040

By contrast, thyroid carcinoma is uncommon. For the United States population, the lifetime risk for being diagnosed with thyroid carcinoma is less than 1% (0.83% for women, 0.33% for men).14 Approximately 37,200 new cases of thyroid carcinoma were estimated to be diagnosed in the United States in 2009.15 The 10-year disease-specific survival rate for patients with MTC is approximately 75%.2

In 2009, approximately 1630 cancer deaths will occur among persons with thyroid carcinoma in the United States.15 Anaplastic thyroid carcinoma is almost uniformly lethal; however, most thyroid carcinoma deaths are from papillary, follicular, and Hürthle cell carcinomas, which account for nearly 95% of all thyroid carcinoma cases. Although thyroid carcinoma occurs more often in women, mortality rates are higher for men, probably because men are usually older at diagnosis.14,16

Thyroid Nodule Evaluation

Patients with MTC can be identified using pathologic diagnosis or prospective genetic screening. Separate paths are included in the guidelines algorithm (see page 516) depending on the method of identification used. MTC must be distinguished from the other types of thyroid carcinoma (see page 515). The American Thyroid Association (ATA) recently published a guideline on MTC.2

Fine-needle aspiration (FNA) is the preferred procedure for evaluating suspicious thyroid nodules.10,17 The Society of Radiologists in Ultrasound wrote a consensus statement on managing thyroid nodules identified at thyroid ultrasonography. Their recommendations describe which nodules should undergo FNA based on nodule size and ultrasound characteristics, and on clinical features that might predict risk for morbidity from an undiagnosed malignancy.18 Suspicious criteria by ultrasound include central hypervascularity, microcalcifications, and irregular borders.

Although more than 50% of all malignant nodules are asymptomatic, the pretest probability of malignancy in a nodule increases considerably when signs or symptoms are present (see page 514).19 For example, the likelihood that a nodule is malignant increases approximately 7-fold if it is very firm, fixed to adjacent structures, rapidly growing, associated with enlarged regional lymph nodes, and causing vocal cord paralysis, or if symptoms of invasion into neck structures are present.19,20 Family history of thyroid cancer is also indicative of malignancy. If 2 or more of these features are present, the likelihood of thyroid cancer is virtually assured; however, this is a rare situation.20

A patient's age and gender also affect the probability of malignancy. The risk for malignancy is higher in patients younger than 15 years and in men. Other factors that increase the suspicion of malignancy include 1) a history of head and neck irradiation; 2) a history of diseases associated with thyroid carcinoma, such as familial adenomatous polyposis (formerly called Gardner's syndrome), Carney complex, Cowden's syndrome, and MEN 2A or 2B; 3) evidence of other thyroid cancer–associated diseases or syndromes, such as hyperparathyroidism, pheochromocytoma, marfanoid habitus, and mucosal neuromas (MEN2B), which make the presence of MTC more likely; or 4) the presence of suspicious findings detected with imaging, such as focal 18-fluorodeoxyglucose (FDG) uptake on PET, or central hypervascularity, irregular border, and/or microcalcifications on ultrasound.21

Initial Workup of Thyroid Nodule

In patients who are clinically euthyroid, FNA of the nodule and clinically suspicious lymph nodes is recommended as the first diagnostic test before any imaging studies are performed.8,10 Ultrasound of the thyroid and central neck is also recommended.22 Ultrasound of the lateral neck can also be performed (category 2B). Ideally, the serum thyrotropin (thyroid-stimulating hormone [TSH]) results should be known before FNA is performed. This is often impractical, however, and FNA may be performed during the initial office visit. Recent data show that higher TSH levels are associated with risk for differentiated thyroid cancer.23

Some clinicians, especially in Europe,24 recommend obtaining serum calcitonin levels from all patients with thyroid nodules. However, controversy exists surrounding the cost-effectiveness of this practice in the United States, especially in the absence of confirmatory pentagastrin stimulation testing and the assumptions used in cost-effective analyses. The ATA is equivocal about measuring serum calcitonin.10,25 A recent study showed that calcitonin screening may be cost effective in the United States.26 However, false-positive calcitonin readings that can result from minimal calcitonin elevations can only be ruled out with pentagastrin testing, and pentagastrin is not available in the United States.

Cytologic examination of an FNA specimen is typically categorized as 1) carcinoma (papillary, medullary, or anaplastic) or suspicious for malignancy; 2) follicular or Hürthle cell neoplasm; 3) follicular lesion of undetermined significance; 4) thyroid lymphoma; 5) benign (i.e., nodular goiter, colloid goiter, hyperplastic/adenomatoid nodule, Hashimoto's thyroiditis); or 6) insufficient biopsy (nondiagnostic; see page 515). These diagnostic categories for FNA results reflect the National Cancer Institute's State of the Science conference held in 2007 (http://www.cytojournal.com/content/5/1/6).

Pathology and cytopathology slides should be reviewed at the treating institution by a pathologist with expertise in diagnosing thyroid disorders. Although FNA is a very sensitive test, particularly for papillary, false-negative results are sometimes obtained; therefore, a reassuring FNA should not override concerns in the presence of worrisome clinical findings.27 Medullary carcinoma may occasionally require additional immunohistochemical studies (e.g., calcitonin) to confirm the diagnosis (http://www.cytojournal.com/content/5/1/6). Hürthle cell neoplasms can sometimes mimic medullary carcinoma cytologically and on frozen section, and sometimes anaplastic thyroid cancer can be difficult to discriminate from other primary thyroid malignancies (i.e., MTC, thyroid lymphoma) or poorly differentiated cancer metastatic to the thyroid.28 Metastatic renal carcinoma can mimic a follicular neoplasm, melanoma can mimic medullary carcinoma, and metastatic lung cancer can mimic anaplastic carcinoma of the thyroid (http://thyroidfna.cancer.gov/pages/conclusions/).

Sporadic MTC

Sporadic MTC is usually suspected after FNA of a solitary nodule (see page 515). Reports suggest that approximately 3% of patients with nodular thyroid disease will have an increased serum calcitonin level when measured with a sensitive immunometric assay; 40% of these patients will have MTC at thyroidectomy.2931 However, the NCCN does not recommend routine measurement of the basal serum calcitonin concentration for evaluating patients with nodular thyroid disease because of the expense incurred by screening all thyroid nodules to find only a few cases of MTC, the lack of confirmatory pentagastrin stimulation testing, and the resulting need for thyroidectomy in some patients who actually have benign thyroid disease.32,33

Inherited MTC

In kindreds known to have inherited MTC, prospective family screening with testing for mutant RET (rearranged during transfection) genes can identify disease carriers long before clinical symptoms or signs are noted.24 The traditional approach of stimulating secretion of calcitonin with either pentagastrin or calcium infusion is no longer recommended, because elevated calcitonin is not a specific or adequately sensitive marker for MTC34 and pentagastrin is no longer available in the United States. Serum intact parathyroid hormone levels and calcium levels are measured when MEN 2A is suspected (see page 518). Compared with sporadic disease, the typical age of presentation for familial disease is the third or fourth decade, without gender preference. In MEN 2A, signs or symptoms of hyperparathyroidism or pheochromocytoma rarely present before those of MTC, even in the absence of screening.

All familial forms of MTC and MEN 2 are inherited in an autosomal dominant fashion. Mutations in the RET proto-oncogene are found in at least 95% of kindreds with MEN 2A and 88% of familial MTC.3,4,35 Familial MTC is now viewed as a variant of MEN 2A.2 The RET proto-oncogene codes for a cell membrane–associated tyrosine kinase receptor for a glial, cell line–derived neurotrophic factor. Mutations associated with MEN 2A and familial MTC have been primarily identified in several codons of the cysteine-rich extracellular domains of exons 10, 11, and 13, whereas MEN 2B and some familial MTC mutations are found within the intracellular exons 14 through 16.2 Somatic mutations in exons 11, 13, and 16 have also been found in at least 25% of sporadic MTC tumors, particularly the codon 918 mutation that activates the tyrosine kinase function of the receptor and is associated with poorer prognosis.

Approximately 6% of patients with what appears to be clinically sporadic MTC carry a germline mutation in RET, allowing new kindreds to be identified among many previously undiagnosed affected individuals.36,37 Genetic testing for RET proto-oncogene mutations should be encouraged for all patients with newly diagnosed clinically apparent sporadic MTC, and for screening children and adults in known kindreds with inherited forms of MTC. Genetic counseling should be considered.

Generally accepted approaches to preoperative workup include measurement of serum markers (basal calcitonin and serum carcinoembryonic antigen [CEA]) and screening patients with germline RET proto-oncogene mutations for pheochromocytoma (MEN 2A and 2B) and hyperparathyroidism (MEN 2A). Before undertaking surgical therapy for MTC, coexisting pheochromocytoma must be diagnosed and prospectively treated to avoid hypertensive crisis during surgery. Pheochromocytoma can be removed through laparoscopic adrenalectomy.2

Preoperative neck ultrasound is recommended. Contrast-enhanced CT of the chest and mediastinum or MRI can be considered if the patient has N1 disease or calcitonin greater than 400 pg/mL.2 Vocal cord mobility can also be evaluated.

Staging

The TNM criteria for clinicopathologic tumor staging are based on tumor size, the presence or absence of extrathyroidal invasion, locoregional nodal metastases, and distant metastases (see the staging table, available online, in these guidelines, at www.NCCN.org [ST-1]; 6th edition AJCC staging manual).38 An MTC tumor 2 cm or less in diameter without evidence of disease outside the thyroid gland is classified as stage I. Any larger tumor (> 2 ≤ 4 cm) limited to the thyroid without nodal or distant metastases is classified as stage II. The presence of level 6 nodal metastases, minimal extrathyroidal invasion, or tumor size greater than 4 cm is classified as stage III. A tumor extending beyond the perithyroid soft tissues, involving lymph nodes beyond level 6, or spreading to distant metastatic sites is classified as stage IV. Note that staging for MTC has slightly changed in the recent AJCC update (i.e., 7th edition AJCC staging manual), which was effective January 1, 2010.39 In the 7th edition, T3,N0,M0 has been downstaged from stage III to stage II.

Note that all follow-up studies reporting on AJCC-TNM staging have referred to the 5th edition40 and not the 6th or 7th editions.38,39 In one study with a median follow-up period of only 4 years, mortality from MTC was 0% for stage I, 13% for stage II, 56% for stage III, and 100% for stage IV disease.41

However, the TNM staging classification lacks other important prognostic factors.42 Notably absent is the age at diagnosis. Patients younger than 40 years at diagnosis have 5- and 10-year disease-specific survival rates of approximately 95% and 75%, respectively, compared with 65% and 50% for those older than 40 years.7,42 Controlling for the effect of age at diagnosis, the prognosis of patients with inherited disease (who typically are diagnosed at an earlier age) is probably similar to those with sporadic disease.43,44 Despite an even younger typical age at diagnosis, however, patients with MEN 2B who have MTC are more likely than those with either MEN 2A or familial MTC to have locally aggressive disease.44

Other factors that may be important for predicting a worse prognosis include 1) the heterogeneity and paucity of calcitonin immunostaining of the tumor;45 2) a rapidly increasing CEA level, particularly in the setting of a stable calcitonin level;46 and 3) postoperative residual hypercalcitoninemia.41 A study comparing different staging systems found that the EORTC system incorporating age, gender, and distant metastases had the greatest predictive value; however, the AJCC staging system was deemed to be the most appropriate.42,47 Codon analysis is useful for predicting prognosis.2,48 Presence of an exon 16 mutation, either within a sporadic tumor or associated with MEN 2B, is associated with more aggressive disease.49 More than 95% of patients with MEN 2B have a mutation in exon 16 (codon 918), whereas 2% to 3% have a mutation in exon 15 (codon 883).50

Surgical Management

Surgery is the main treatment for MTC, because no known curative systemic therapy exists. MTC cells do not concentrate radioactive iodine, and MTC does not respond well to conventional cytotoxic chemotherapy. Therefore, radioiodine imaging cannot be used, and radioiodine treatment is not effective in these patients. Postoperative levothyroxine is indicated for all patients; however, TSH suppression is not appropriate, because C cells lack TSH receptors. Thus, TSH should be kept in the normal range through adjusting the levothyroxine dose.2

Even with patients who have apparently sporadic disease, the possibility of MEN 2 should dictate that a RET proto-oncogene mutation is absent or that hyperparathyroidism and pheochromocytoma should be excluded preoperatively. Pheochromocytomas should be removed (e.g., laparoscopic adrenalectomy) with α-adrenergic blockade (phenoxybenzamine) or α-methyltyrosine before surgery on the thyroid to avoid hypertensive crisis during surgery. Forced hydration and α-blockade are necessary to prevent hypotension after the tumor is removed. After institution of α-blockade and hydration, β-adrenergic blockade may be necessary to treat tachyarrhythmia.

For all patients with MTC whose tumor is 1 cm or larger or who have bilateral thyroid disease, total thyroidectomy and bilateral central neck dissection (level VI) are indicated. For those who have a tumor smaller than 1 cm and have unilateral thyroid disease, total thyroidectomy is recommended and neck dissection can be considered (see page 516).7 Given the risks associated with thyroidectomy in very young children, referral is advised to a surgeon and team experienced in pediatric thyroid surgery.

If a patient with inherited disease is diagnosed early enough, the recommendation is to perform a prophylactic total thyroidectomy by age 5 years or when the mutation is identified (in older patients), especially in patients with codon 609, 611, 618, 620, 630, or 634 RET (risk level B) mutations.2,51 Note that C634 mutations are the most common mutation.2 Total thyroidectomy is recommended in the first year of life or at diagnosis for patients with MEN 2B or carriers of codon 883 RET, 918 RET, or compound heterozygous (V804M + E805K, V804M + Y806C, or V804M + S904C) RET mutations (see page 517), because these mutations are associated with the highest risk for MTC (i.e., level D).2

However, for patients with codon 768, 790, 791, 804, and 891 RET (risk level A) mutations, the lethality of MTC may be lower than with other RET mutations.52 In patients with these level A RET mutations, annual basal calcitonin testing and ultrasound are recommended; total thyroidectomy and central node dissection may be deferred if these tests are normal, there is no family history of aggressive MTC, and the family agrees (see page 517).2,53

Delaying thyroidectomy may also be appropriate for children with risk level A mutations because of the late onset of MTC development.2,54 A study found no evidence of persistent or recurrent MTC 5 years or more after prophylactic total thyroidectomy in young patients with RET mutations for MEN 2A; longer follow-up is necessary to determine if these patients are cured.55

Variations in surgical strategy depend on the risk for locoregional node metastases and whether simultaneous parathyroid resection for hyperparathyroidism is necessary. A bilateral central neck dissection (level VI) can be considered for all patients with MEN 2B. For those with MEN 2A who undergo prophylactic thyroidectomy, therapeutic ipsilateral or bilateral central neck dissection (level VI) is recommended if they have an increased calcitonin or CEA test or if ultrasound shows a thyroid or nodal abnormality. Similarly, more extensive lymph node dissection (levels II–V) is considered for patients with primary tumors 1 cm or larger in diameter (> 0.5 cm for patients with MEN 2B) or central compartment lymph node metastases (see page 518).

For patients with a concurrent diagnosis of hyperparathyroidism in MEN 2A or familial MTC, surgeons should leave or autotransplant the equivalent mass of 1 normal parathyroid gland if multiglandular hyperplasia is present. Cryopreservation of resected parathyroid tissue should be considered to allow future implantation in the event of iatrogenic hypoparathyroidism. Disfiguring radical node dissections do not improve prognosis and are not indicated. In the presence of grossly invasive disease, more extended procedures with resection of involved neck structures may be appropriate. Function-preserving approaches are preferred.

Surgical Complications: The most common significant complications of thyroidectomy are hypoparathyroidism and recurrent laryngeal nerve injury, which occur with higher frequency after total thyroidectomy. Transient clinical hypoparathyroidism after surgery is common in adults56 and children57,58 undergoing total thyroidectomy.

However, the rates of persistent hypocalcemia are reported to be much lower in the hands of experienced thyroid surgeons. In a review of 7 published surgical series, the average rates of long-term recurrent laryngeal nerve injury and hypoparathyroidism, respectively, were 3% and 2.6% after total thyroidectomy, and 1.9% and 0.2% after subtotal thyroidectomy.59 One study reported hypocalcemia in 5.4% of patients immediately after total thyroidectomy, persisting in only 0.5% of patients 1 year later.60

When experienced surgeons perform thyroidectomies, complications occur at a lower rate. A study of 5860 patients treated in the state of Maryland found that surgeons who performed more than 100 thyroidectomies per year had the lowest overall complication rate (4.3%), whereas those who performed fewer than 10 thyroidectomies a year had 4 times as many complications.61

Adjuvant Radiation Therapy

External-beam radiation therapy (RT) has not been adequately studied as adjuvant therapy in medullary carcinoma. Although slight improvements have been reported in local disease-free survival after external-beam RT for selected patients, such as those with extrathyroidal invasion or extensive locoregional node involvement,62 most centers do not have extensive experience with adjuvant RT for this disease. When external-beam RT is used, 40 Gy is typically administered in 20 fractions to the cervical, supraclavicular, and upper mediastinal lymph nodes over 4 weeks, with subsequent booster doses of 10 Gy in 5 fractions to the thyroid bed.63 Postoperative adjuvant RT to the neck and mediastinum may be considered for patients with gross extrathyroidal extension (T4a or T4b) with positive margins after resection of all gross disease and moderate- to high-volume disease in the central or lateral neck lymph nodes with extranodal soft tissue extension. However, this practice is rarely recommended in children (see pages 517 and 518).2 External-beam RT can also be given to palliate painful or progressing bone metastases.2

Persistently Increased Calcitonin

Basal serum concentrations of calcitonin and CEA should be measured 2 or 3 months postoperatively. Approximately 80% of patients with palpable MTC and 50% of those with nonpalpable but macroscopic MTC who undergo supposedly curative resection have serum calcitonin values indicative of residual disease. Patients with residual disease may benefit from further evaluation to detect either residual resectable disease in the neck or the presence of distant metastases. Patients with detectable basal calcitonin or elevated CEA who have negative imaging and are asymptomatic may be followed up (see page 519).

Patients with a basal serum calcitonin value greater than 1000 pg/mL and with no obvious MTC in the neck and upper mediastinum probably have distant metastases, most likely in the liver. However, occasionally patients have relatively low serum CEA and calcitonin levels but have extensive metastatic disease; initial postoperative staging imaging is therefore not unreasonable despite the absence of very high serum markers.

The prognosis for patients with postoperative hypercalcitoninemia depends primarily on the extent of disease at initial surgery. In a study of 31 patients (10 patients with apparently sporadic disease, 15 with MEN 2A, and 6 with MEN 2B), the 5- and 10-year survival rates were 90% and 86%, respectively.64

Two studies have reported higher mortality rates for patients with high postoperative serum calcitonin values, with more than 50% of patients experiencing a recurrence during a mean follow-up of 10 years.41,65 Routine lymphadenectomy or excision of palpable tumor generally fails to normalize the serum calcitonin concentrations in these patients; therefore, some clinicians have focused on detecting and eradicating microscopic tumor deposits with a curative intent in patients without distant metastases. Extensive dissection to remove all nodal and perinodal tissue from the neck and upper mediastinum was first reported to normalize the serum calcitonin levels in 4 of 11 patients at least 2 years postoperatively.66 In subsequent larger studies, 20% to 40% of patients undergoing microdissection of the central and bilateral neck compartments were biochemically cured, with minimal perioperative morbidity.67,68

When repeat surgery is planned for curative intent, preoperative assessment should include locoregional imaging (e.g., ultrasonography of the neck and upper mediastinum) and attempts to exclude patients with distant metastases, which may involve contrast-enhanced CT or MRI of the neck, chest, and abdomen.68

Postoperative Management and Surveillance

Calcitonin is very useful for surveillance, because it is produced in the parafollicular cells. Therefore, measurements of serum calcitonin and CEA levels are the cornerstone of postoperative assessment for residual disease (see page 519). For patients with a detectable basal calcitonin or elevated CEA level, neck imaging is recommended. Patients with undetectable calcitonin levels can be followed up with annual measurements of serum markers, reserving additional studies or more frequent testing for significantly rising calcitonin or CEA. Nonetheless, the likelihood of significant residual disease is very low in patients with an undetectable basal calcitonin level using a sensitive assay. If the patient has MEN 2, annual screening for pheochromocytoma (MEN 2B or 2A) and hyperparathyroidism (MEN 2A) should be performed. For some low-risk RET mutations (e.g., codons 768, 790, 804, or 891), less frequent screening may be appropriate.

Patients with detectable serum markers should undergo contrast-enhanced CT or MRI of the neck, chest, and abdomen with a liver protocol. Bone scan, FDG-PET scan, or MRI of axial skeleton should be considered in patients with very elevated calcitonin levels.2 The panel recognizes that many different imaging modalities may be used to examine for residual or metastatic tumor, but evidence is insufficient to recommend any particular choice or combination of tests.2

For asymptomatic patients with detectable markers in whom imaging fails to identify foci of disease, the panel recommends conservative surveillance with repeat measurement of the serum markers every 6 to 12 months. For asymptomatic patients with abnormal markers and repeated negative imaging, continued observation or consideration of cervical reoperation is recommended if primary surgery was incomplete. For patients with increasing serum markers, more frequent imaging may be considered. Outside of clinical trials, no therapeutic intervention based on abnormal markers alone is recommended.

Recurrent or Persistent Disease

When locoregional disease is identified in the absence of distant metastases, surgical resection is recommended with or without postoperative RT. If symptomatic progressive or unresectable locoregional disease is present, then RT can be considered. Distant metastases that are causing symptoms (e.g., those in bone) could be considered for palliative resection, ablation (e.g., radiofrequency, embolization), or other regional treatment (see page 520). These interventions may be considered for asymptomatic distant metastases (especially for progressive disease), but observation is acceptable given the lack of data on alteration in outcome. In the setting of disseminated symptomatic metastases, the guidelines recommend 1) a clinical trial (preferred); 2) RT for focal symptoms; 3) consideration of small molecule kinase inhibitors (i.e., sorafenib or sunitinib) if clinical trials are not available or appropriate;6971 4) systemic chemotherapy, using dacarbazine or combinations including dacarbazine;72,73 4) consideration of bisphosphonate therapy for bone metastases; and 5) best supportive care.

In patients with metastatic MTC, sorafenib reduces symptoms caused by hypercalcitonemia and metastases.69 Recently, stable disease rates of approximately 50% and clinical benefit rates of approximately 70% have been seen with motesanib diphosphate (AMG-706) in sporadic, metastatic MTC, and with vandetanib in hereditary metastatic MTC.74,75 In addition, clinical response was seen in 6 of 8 patients treated with a combination of sorafenib and the farnesyltransferase inhibitor tipifarnib.76 Sunitinib was associated with clinical response in 2 patients published as case reports.70,77

Ongoing clinical trials are studying the effectiveness of novel multitargeted therapies, including sunitinib,70,78 sorafenib,76,79 XL 184,80,81 and pazopanib (GW786034). Several recent published reviews have examined novel therapies and the therapeutic approach to the management of aggressive MTC.8284

Of interest, calcitonin levels decreased dramatically after vandetanib therapy, which did not correlate directly with changes in tumor volume; thus, calcitonin may not be a reliable marker of tumor response in patients undergoing RET inhibitor therapy.75 A study in patients with progressive metastatic MTC assessed treatment using pretargeted anti-CEA radioimmunotherapy with 131I;85 overall survival was improved in the subset of patients with calcitonin doubling times of less than 2 years.

Individual Disclosures for the NCCN Medullary Carcinoma Panel

T1

Medullary Carcinoma Clinical Practice Guidelines in Oncology

NCCN Categories of Evidence and Consensus

Category 1: The recommendation is based on high-level evidence (e.g., randomized controlled trials) and there is uniform NCCN consensus.

Category 2A: The recommendation is based on lower-level evidence and there is uniform NCCN consensus.

Category 2B: The recommendation is based on lower-level evidence and there is nonuniform NCCN consensus (but no major disagreement).

Category 3: The recommendation is based on any level of evidence but reflects major disagreement.

All recommendations are category 2A unless otherwise noted.

Clinical trials: The NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

Please Note

These guidelines are a statement of consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. The National Comprehensive Cancer Network makes no representation or warranties of any kind regarding their content, use, or application and disclaims any responsibility for their applications or use in any way.

These guidelines are copyrighted by the National Comprehensive Cancer Network. All rights reserved. These guidelines and the illustrations herein may not be reproduced in any form without the express written permission of the NCCN © 2010.

Disclosures for the NCCN Medullary Carcinoma Guidelines Panel

At the beginning of each NCCN guidelines panel meeting, panel members disclosed any financial support they have received from industry. Through 2008, this information was published in an aggregate statement in JNCCN and online. Furthering NCCN's commitment to public transparency, this disclosure process has now been expanded by listing all potential conflicts of interest respective to each individual expert panel member.

Individual disclosures for the NCCN Medullary Carcinoma Guidelines Panel members can be found on page 530. (The most recent version of these guidelines and accompanying disclosures, including levels of compensation, are available on the NCCN Web site at www.NCCN.org.)

These guidelines are also available on the Internet. For the latest update, please visit www.NCCN.org.

NCCN Medullary Carcinoma Panel Members

*R. Michael Tuttle, MD/Chairð

Memorial Sloan-Kettering Cancer Center

Douglas W. Ball, MDð

The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

David Byrd, MD¶

University of Washington/Seattle Cancer Care Alliance

Gilbert H. Daniels, MDð

Massachusetts General Hospital Cancer Center

Raza A. Dilawari, MD¶

St. Jude Children's Research Hospital/University of Tennessee Cancer Institute

Gerard M. Doherty, MD¶

University of Michigan Comprehensive Cancer Center

Quan-Yang Duh, MD¶

UCSF Helen Diller Family Comprehensive Cancer Center

Hormoz Ehya, MD≠

Fox Chase Cancer Center

William B. Farrar, MD¶

The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute

Robert I. Haddad, MD†

Dana-Farber/Brigham and Women's Cancer Center

Fouad Kandeel, MD, PhDð

City of Hope Comprehensive Cancer Center

*Richard T. Kloos, MDðφ

The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute

Peter Kopp, MDð

Robert H. Lurie Comprehensive Cancer Center of Northwestern University

Dominick M. Lamonica, MDþφ

Roswell Park Cancer Institute

Thom R. Loree, MD¶

Roswell Park Cancer Institute

William M. Lydiatt, MD¶

UNMC Eppley Cancer Center at The Nebraska Medical Center

Judith McCaffrey, MDζ

H. Lee Moffitt Cancer Center & Research Institute

John A. Olson, Jr., MD, PhD¶

Duke Comprehensive Cancer Center

Lee Parks, MDð

Vanderbilt-Ingram Cancer Center

John A. Ridge, MD, PhD¶

Fox Chase Cancer Center

Jatin P. Shah, MD¶

Memorial Sloan-Kettering Cancer Center

*Steven I. Sherman, MDð

The University of Texas M. D. Anderson Cancer Center

Cord Sturgeon, MD¶

Robert H. Lurie Comprehensive Cancer Center of Northwestern University

*Steven G. Waguespack, MDð

The University of Texas M. D. Anderson Cancer Center

Thomas N. Wang, MD¶

University of Alabama at Birmingham Comprehensive Cancer Center

Lori J. Wirth, MD†

Massachusetts General Hospital Cancer Center

KEY:

*Writing Committee Member

Specialties: ðEndocrinology; ¶Surgery/Surgical Oncology; ≠Pathology; †Medical Oncology; φNuclear Medicine; þInternal Medicine; ζOtolaryngology

References

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    CheungKRomanSAWangTS. Calcitonin measurement in the evaluation of thyroid nodules in the United States: a cost-effectiveness and decision analysis. J Clin Endocrinol Metab2008;93:21732180.

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    YehMWDemircanOItuartePClarkOH. False-negative fine-needle aspiration cytology results delay treatment and adversely affect outcome in patients with thyroid carcinoma. Thyroid2004;14:207215.

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Article Sections

Figures

  • View in gallery
    NCCN Clinical Practice Guidelines in Oncology: Medullary Carcinoma

    Version 1.2010, 01-14-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

  • View in gallery
    NCCN Clinical Practice Guidelines in Oncology: Medullary Carcinoma

    Version 1.2010, 01-14-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

  • View in gallery
    NCCN Clinical Practice Guidelines in Oncology: Medullary Carcinoma

    Version 1.2010, 01-14-10 ©2010 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

  • View in gallery
    NCCN Clinical Practice Guidelines in Oncology: Medullary Carcinoma

    Clinical trials: The NCCN believes that the best management for any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. All recommendations are category 2A unless otherwise noted.

References

  • 1.

    HundahlSAFlemingIDFremgenAMMenckHR. A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985–1995 [see comments]. Cancer1998;83:26382648.

    • Search Google Scholar
    • Export Citation
  • 2.

    KloosRTEngCEvansDB. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid2009;19:565612.

  • 3.

    GagelRFHoffAOCoteGJ. Medullary thyroid carcinoma. In: Braverman LE Utiger RD eds.Werner and Ingbar's The Thyroid: A Fundamental and Clinical Text 9th ed.Philadelphia: Lippincott Williams & Wilkins; 2005:967988.

    • Search Google Scholar
    • Export Citation
  • 4.

    GagelRFCoteGJ. Pathogenesis of medullary thyroid carcinoma. In: Fagin JA ed.Thyroid Cancer. Boston/Dordrecht/London: Kluwer Academic; 1998:85103.

    • Search Google Scholar
    • Export Citation
  • 5.

    GertnerMEKebebewE. Multiple endocrine neoplasia type 2. Curr Treat Options Oncol2004;5:315325.

  • 6.

    RaueFFrank-RaueK. Multiple endocrine neoplasia type 2: 2007 update. Horm Res2007;68(Suppl 5):101104.

  • 7.

    SaadMFOrdonezNGRashidRK. Medullary carcinoma of the thyroid. A study of the clinical features and prognostic factors in 161 patients. Medicine (Baltimore)1984;63:319342.

    • Search Google Scholar
    • Export Citation
  • 8.

    MazzaferriEL. Thyroid carcinoma: Papillary and follicular. In: Mazzaferri EL Samaan NA eds.Endocrine Tumors. Cambridge: Blackwell Scientific Publications; 1993:278333.

    • Search Google Scholar
    • Export Citation
  • 9.

    HegedusL. Clinical practice. The thyroid nodule. N Engl J Med2004;351:17641771.

  • 10.

    CooperDSDohertyGMHaugenBR. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid2006;16:109142.

    • Search Google Scholar
    • Export Citation
  • 11.

    EzzatSSartiDACainDRBraunsteinGD. Thyroid incidentalomas. Prevalence by palpation and ultrasonography. Arch Intern Med1994;154:18381840.

    • Search Google Scholar
    • Export Citation
  • 12.

    RonELubinJHShoreRE. Thyroid cancer after exposure to external radiation: a pooled analysis of seven studies. Radiat Res1995;141:259277.

    • Search Google Scholar
    • Export Citation
  • 13.

    SchneiderABBekermanCLelandJ. Thyroid nodules in the follow-up of irradiated individuals: comparison of thyroid ultrasound with scanning and palpation. J Clin Endocrinol Metab1997;82:40204027.

    • Search Google Scholar
    • Export Citation
  • 14.

    HornerMJRiesLAKrapchoM. SEER Cancer Statistics Review 1975–2006. Bethesda, MD: National Cancer Institute; 2009. Available at: http://seer.cancer.gov/csr/1975_2006/results_merged/sect_26_thyroid.pdf. Accessed March 15 2010.

    • Search Google Scholar
    • Export Citation
  • 15.

    JemalASiegelRWardE. Cancer statistics, 2009. CA Cancer J Clin2009;59:225249.

  • 16.

    MazzaferriELJhiangSM. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med1994;97:418428.

    • Search Google Scholar
    • Export Citation
  • 17.

    LayfieldLJCibasESGharibHMandelSJ. Thyroid aspiration cytology: current status. CA Cancer J Clin2009;59:99110.

  • 18.

    FratesMCBensonCBCharboneauJW. Management of thyroid nodules detected at US: Society of Radiologists in Ultrasound consensus conference statement. Radiology2005;237:794800.

    • Search Google Scholar
    • Export Citation
  • 19.

    MazzaferriEL. Thyroid cancer in thyroid nodules: finding a needle in the haystack. Am J Med1992;93:359362.

  • 20.

    HammingJFGoslingsBMvan SteenisGJ. The value of fine-needle aspiration biopsy in patients with nodular thyroid disease divided into groups of suspicion of malignant neoplasms on clinical grounds. Arch Intern Med1990;150:113116.

    • Search Google Scholar
    • Export Citation
  • 21.

    ChanBKDesserTSMcDougallIR. Common and uncommon sonographic features of papillary thyroid carcinoma. J Ultrasound Med2003;22:10831090.

    • Search Google Scholar
    • Export Citation
  • 22.

    KoikeENoguchiSYamashitaH. Ultrasonographic characteristics of thyroid nodules: prediction of malignancy. Arch Surg2001;136:334337.

  • 23.

    HaymartMRRepplingerDJLeversonGE. Higher serum thyroid stimulating hormone level in thyroid nodule patients is associated with greater risks of differentiated thyroid cancer and advanced tumor stage. J Clin Endocrinol Metab2008;93:809814.

    • Search Google Scholar
    • Export Citation
  • 24.

    HenryJFDenizotAPucciniM. Early diagnosis of sporadic medullary cancers of the thyroid: value of systematic assay of calcitonin. Presse Med1996;25:15831588 [in French].

    • Search Google Scholar
    • Export Citation
  • 25.

    CooperDSDohertyGMHaugenBR. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid2009;19:11671214.

    • Search Google Scholar
    • Export Citation
  • 26.

    CheungKRomanSAWangTS. Calcitonin measurement in the evaluation of thyroid nodules in the United States: a cost-effectiveness and decision analysis. J Clin Endocrinol Metab2008;93:21732180.

    • Search Google Scholar
    • Export Citation
  • 27.

    YehMWDemircanOItuartePClarkOH. False-negative fine-needle aspiration cytology results delay treatment and adversely affect outcome in patients with thyroid carcinoma. Thyroid2004;14:207215.

    • Search Google Scholar
    • Export Citation
  • 28.

    AsaSLBedardYC. Fine-needle aspiration cytology and histopathology. In: Clark OH Noguchi S eds.Thyroid Cancer: Diagnosis and Treatment. St Louis: Quality Medical Publishing; 2000:105126.

    • Search Google Scholar
    • Export Citation
  • 29.

    PaciniFFontanelliMFugazzolaL. Routine measurement of serum calcitonin in nodular thyroid diseases allows the preoperative diagnosis of unsuspected sporadic medullary thyroid carcinoma. J Clin Endocrinol Metab1994;78:826829.

    • Search Google Scholar
    • Export Citation
  • 30.

    NiccoliPWion-BarbotNCaronP. Interest of routine measurement of serum calcitonin: study in a large series of thyroidectomized patients. The French Medullary Study Group. J Clin Endocrinol Metab1997;82:338341.

    • Search Google Scholar
    • Export Citation
  • 31.

    OzgenAGHamuluFBayraktarF. Evaluation of routine basal serum calcitonin measurement for early diagnosis of medullary thyroid carcinoma in seven hundred seventy-three patients with nodular goiter. Thyroid1999;9:579582.

    • Search Google Scholar
    • Export Citation
  • 32.

    HorvitPKGagelRF. The goitrous patient with an elevated serum calcitonin—what to do?J Clin Endocrinol Metab1997;82:335337.

  • 33.

    HodakSPBurmanKD. The calcitonin conundrum—is it time for routine measurement of serum calcitonin in patients with thyroid nodules?J Clin Endocrinol Metab2004;89:511514.

    • Search Google Scholar
    • Export Citation
  • 34.

    PapiGCorselloSMCioniK. Value of routine measurement of serum calcitonin concentrations in patients with nodular thyroid disease: a multicenter study. J Endocrinol Invest2006;29:427437.

    • Search Google Scholar
    • Export Citation
  • 35.

    KouvarakiMAShapiroSEPerrierND. RET proto-oncogene: a review and update of genotype-phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors. Thyroid2005;15:531544.

    • Search Google Scholar
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