Medullary Thyroid Carcinoma 

Updated: May 18, 2021
Author: Anastasios K Konstantakos, MD; Chief Editor: Neetu Radhakrishnan, MD 

Overview

Practice Essentials

Medullary carcinoma of the thyroid (MTC) accounts for less than 5% of thyroid cancer. MTC arises from the C cells of the thyroid, which do not accumulate radioiodine, and it secretes calcitonin (Ctn), which is used as a tumor marker. Sporadic, or isolated, MTC accounts for 75% of cases and the remaining 25% are part of multiple endocrine neoplasia type 2 (MEN2), an autosomal-dominant syndrome caused by germline-activating mutations in the RET proto-oncogene.[1] These features allow early recognition of sporadic MTC using Ctn screening in patients with thyroid nodules and preclinical diagnosis of patients with MEN2 by RET gene analysis. 

Outcome depends on extent of disease, nature of tumor biology, and overall efficacy of surgical treatment.

Advances in genetic testing in have revolutionized the management of this disease, by allowing risk stratification of patients with inherited mutations and identifying molecular targets for therapy. Prophylactic thyroidectomy is indicated for patients who carry mutations that put them at risk for aggressive MTC.  

Surgery remains the standard of care for localized disease and for oligometastatic disease. Several tyrosine kinase inhibitors are approved for use in progressive, metastatic MTC, and a variety of agents have entered clinical trials. External beam radiotherapy is used in certain situations.

See Treatment and Medication.

See the figure below.

Algorithm for the management of a solitary thyroid Algorithm for the management of a solitary thyroid nodule. FNAB = fine needle aspiration biopsy; US = ultrasonography.

For patient education resources, see  Thyroid Cancer.

Pathophysiology

Medullary thyroid cancer (MTC) is usually diagnosed on physical examination as a solitary neck nodule. Early spread to regional lymph nodes is common. Distant metastases occur in the liver, lung, bone, and brain.

Sporadic MTC usually is unilateral. MTC in association with multiple endocrine neoplasia (MEN) syndromes is always bilateral and multicentric, with presentation earlier in life. MTC typically is the first abnormality observed in both MEN 2A and 2B syndromes.

In addition to producing calcitonin, MTC cells can produce several other hormones, including corticotropin, serotonin, melanin, and prostaglandins. Moreover, paraneoplastic syndromes (eg, carcinoid syndrome, Cushing syndrome) can occur in these patients.

Etiology

Sporadic MTC occurs in 75% of patients, and inherited MTC constitutes the rest. MTC is the dominant component of the multiple endocrine neoplasia (MEN) type 2 syndromes, MEN2A and MEN2B. MEN2A accounts for 95% of the cases. The following four variants have been recognized:[2]

  • Classical MEN2A - The most common variant. MTC is uniformly present; pheochromocytoma, primary hyperparathyroidism, or both occur less frequently.
  • MEN2A with cutaneous lichen amyloidosis (CLA) - CLA may present in young patients, before the onset of clinically evident MTC
  • MEN2A with Hirschsprung disease
  • Familial medullary thyroid carcinoma (FMTC) - MTC only, in the absence of a family history of pheochromocytoma or hyperparathyroidism

Mutations in RET, a transmembrane proto-oncogene located on chromosome 10q11.2, are responsible for MEN2. Although its function is still unknown, the protein produced by RET is critical during embryonic development of the enteric nervous system and kidneys. RET consists of 3 domains, including a cysteine-rich extracellular receptor domain, a hydrophobic transmembrane domain, and an intracellular tyrosine kinase catalytic domain.

RET germline mutations are present in virtually all patients with MEN2A and  MEN2B, and somatic RET mutations are present in approximately 50% of sporadic MTCs. In sporadic MTC that is RET mutation–negative, mutations in genes involving the RAS pathway—HRAS, KRAS, or (rarely) NRAS—are often found.[2, 3]

Epidemiology

Thyroid cancer represents approximately 3% of new malignancies occurring annually in the United States, with an annual incidence of approximately 14 per 100,000. Of these cancer diagnoses, 2% to 3% are medullary thyroid carcinoma (MTC), which translates into approximately 1080-1620 new diagnoses per year.[4]                  

Unlike the rising incidence rates of papillary thyroid cancer and other differentiated thyroid cancers, incidence rates for MTC (as well as follicular) thyroidcancers have remained relatively stable over the past 30 years.The incidence rate of MTC in Europe is 0.11 per 100,000 person-years, with no noted substantial differences by race/ethnicity and sex.[5]

Peak incidence of isolated MTC occurs in the fifth or sixth decade of life. The peak incidence of MTC associated with multiple endocrine neoplasia (MEN) 2A or 2B occurs during the first to third decade of life.[6]

Prognosis

Prognosis depends on patient age, histologic grade, and status of surgical resection. Patients with a worse prognosis tend to be older, have higher-grade lesions, and have undergone incomplete surgical resection of the lesion. The 5-year relative survival for stages I to III is about 93% compared to 28% for stage IV.[6]

Isolated medullary carcinoma of the thyroid (MTC) typically demonstrates a relatively indolent biologic progression. While regional lymph node metastases are possible, the lesion may not spread outside of the cervical region until several months later. MTC associated with multiple endocrine neoplasia (MEN) syndromes may have a more aggressive course, which also depends on associated comorbidity (eg, pheochromocytoma).

Despite advances in genetic screening for the RET proto-oncogene, preliminary population studies have yet to show a definitive impact on disease prognosis.[7]

A study by Rohmer et al concluded that disease-free survival (DFS) in younger patients (>21 y) with hereditary MTC was best predicted by TNM staging and preoperative basal CT level of less than 30 pg/mL.[8]  Basal CT findings, class D genotype, and age were the key factors in deciding peroperatively timely surgery.

In a meta-analysis of 27 studies involving 984 MTC patients who underwent reoperation, Rowland and colleagues found that normalization of calcitonin after reoperation occurred in 16.2% of patients overall. Patients who underwent targeted selective lymph node removal procedures showed normalization of calcitonin in 10.5% of cases, while normalization was seen in 18.6% of those who underwent compartment-oriented procedures.[9]  

Permanent hypoparathyroidism and recurrent laryngeal nerve palsy reportedly occur in less than 2% of virgin neck dissections. Reoperation is associated with a considerably higher risk of these injuries.

 

Presentation

History

A specific constellation of symptoms of medullary thyroid carcinoma (MTC) is not usually noted; however, one or more of the following symptoms may be observed:

  • Patients may describe a lump at the base of the neck, which may interfere with or become more prominent during swallowing

  • Patients with locally advanced disease may present with hoarseness, dysphagia, and respiratory difficulty

  • Although uncommon, patients may present with various paraneoplastic syndromes, including Cushing or carcinoid syndrome

  • Diarrhea may occur from increased intestinal electrolyte secretion secondary to high plasma calcitonin levels

  • Distant metastases (eg, lung, liver, bone) may result in weight loss, lethargy, and bone pain

Physical Examination

Physical examination may demonstrate a dominant thyroid nodule at the base of the neck. Palpable cervical lymphadenopathy signifies disease that has progressed locally. Icterus, and rarely, bone tenderness may occur in patients with systemic metastases. 

Cutaneous lichen amyloidosis in MEN 2A patients manifests as multiple pruritic, hyperpigmented, lichenoid papules in the scapular area of the back. Men2B patients may have a marfanoid habitus with mucosal neuromas.

Labile hypertension may be seen in those with an associated pheochromocytoma.

 

DDx

 

Workup

Laboratory Studies

Calcitonin

Obtain serum calcitonin levels. Calcitonin is the principal biochemical marker in MTC; it is used for detection, staging, postoperative management, and prognosis. The higher that the calcitonin levels are above normal, the greater the likelihood of MTC; basal levels of >100 pg/mL have been found to have 100% positive predictive value for MTC.[10] Very rarely, patients with clinically apparent MTC may not have elevated calcitonin levels.

Occult MTC is rare, but clinically significant. If calcium stimulation testing cutoff data become well-validated, calcitonin screening is likely to be more widely used in the diagnostic workup for thyroid nodules in the United States.[11]

Machens et al found that in RET carriers who are at risk for MTC but have not yet undergone treatment, calcitonin levels can be used to determine the need for lymph node dissection.[12] In their study of 308 RET carriers, all patients with node-positive MTC had elevated basal calcitonin levels (91.4 pg/mL or higher); no patients with normal pretherapy calcitonin levels had lymph node metastasis. These researchers suggest that unless clinical evidence indicates a need for it, RET carriers with normal pretherapeutic basal calcitonin levels may forgo lymph node dissection.

Traditionally, a pentagastrin-induced rise in calcitonin secretion has been used to diagnose MTC; however, pentagastrin is not available in the United States, and DNA testing for RET has replaced this diagnostic method in familial cases. However pentagastrim stimulation testing is used in European countries to further delineate extent of disease. 

In addition to occurring in medullary thyroid cancer (MTC), elevated calcitonin results may also be seen in patients with any of the following:

  • Hypercalcemia
  • Hypergastrinemia
  • Neuroendocrine tumors
  • Renal insufficiency
  • Papillary and follicular thyroid carcinomas
  • Goiter
  • Chronic autoimmune thyroiditis
  • Prolonged treatment with omeprazole (greater than 2 to 4 months), beta-blockers, and glucocorticoids

Also, the presence of heterophilic antibodies to calcitonin can falsely elevate serum calcitonin levels.

With treatment, serum calcitonin concentration falls slowly in some patients, with the nadir not being reached for several months. However, in patients who are surgically cured, calcitonin levels begin to rapidly decline within the first postoperative hour. Therefore, normal calcitonin levels within the first few weeks may indicate biochemical remission, although the converse is not true. Elevated levels in the immediate postoperative period do not necessarily indicate persistent disease.

Carcinoembryonic antigen

Carcinoembryonic antigen (CEA) is not a specific biomarker for MTC, and assessment of CEA levels is not useful for early detection of MTC. Serum CEA levels are useful for evaluating disease progression in patients with clinically evident MTC and for monitoring patients following thyroidectomy.[2]

Elevated CEA levels can also occur in patients with any of the following:

  • Heterophilic antibodies
  • Gastrointestinal tract inflammatory disease
  • Benign lung disease
  • Nonthyroid malignancies (eg, lung cancer, colon cancer)
  • Cigarette smoking

Screening studies in patients with MEN

Consider a 24-hour urinalysis for catecholamine metabolites (eg, vanillylmandelic acid [VMA], metanephrine) to rule out concomitant pheochromocytoma in patients with MEN type 2A or 2B. Pheochromocytoma must be treated before MTC.[2]

Obtain screening for the development of familial MTC in family members of patients with a history of MTC or MEN 2A or 2B. Screen all family members for missense mutation in RET in leukocytes. Finding a RET mutation in an asymptomatic family member should lead to discussion and pursuit of a prophylactic total thyroidectomy (see Treatment).

Imaging Studies

Patients in whom medullary thyroid carcinoma (MTC) is diagnosed or suspected on the basis of fine needle aspiration findings or calcitonin levels should undergo preoperative ultrasonography to detect lymph node metastases. The study should be performed by an experienced operator and should include the superior mediastinum and the central and lateral neck compartments.[2]

In a study of 134 patients with MTC, suspicious findings on preoperative ultrasonography were associated with disease aggressiveness. Patients judged to be at risk for malignancy on the basis of ultrasound (n= 89) more often had metastatic lymph nodes and extrathyroid invasiveness. Suspicious ultrasound results were significantly correlated with advanced stage disease, with an odds ratio of 5.5. Mean serum calcitonin values before and after surgery were significantly higher in the suspicious ultrasound group.[13]

Patients with regional lymph node involvement or calcitonin levels >400 pg/mL should undergo preoperative computed tomography (CT) scanning of the chest and neck, as well as three-phase, contrast-enhanced, multidetector liver CT or contrast-enhanced magnetic resonance imaging (MRI) to detect metastatic disease.[2]  The liver is the most common site of metastases in patients with MTC, occurring in approximately 45% of patients with advanced disease. Liver metastases are best identified with three-phase contrast-enhanced liver CT or contrast-enhanced liver MRI. 

The sensitivity of FDG-PET scanning for detecting metastatic disease is variable but improves with higher calcitonin levels (sensitivity 78% for basal calcitonin value above 1000 pg/mL, versus 20% for levels below 1000 pg/mL in one study. Imaging with 111-In-octreotide or 99m-Tc-DMSA is not currently recommended for routine initial screening for metastatic disease.

Procedures

Fine-needle aspiration (FNA) yields cytologic information, allowing diagnosis of MTC.[14] The sensitivity of FNA is improved by the addition of immunohistochemical staining for calcitonin.

Histologic Findings

Grossly, medullary thyroid carcinoma (MTC) resembles a well-circumscribed off-white nodule with a rough texture. Microscopically, it contains nests of round or ovoid cells without follicle development because these cells originate from the calcitonin-producing parafollicular C cells of the thyroid. A fibrovascular stroma is usually intercalated between cells. Sometimes, amyloid material, consisting of calcitonin prohormone, may occur in the MTC stroma. Perhaps most importantly, immunohistochemical diagnosis of MTC can be made by demonstrating calcitonin using radioactive calcitonin antiserum against MTC cells.

Staging

A 2009 article argued that using the 1997 TNM staging criteria is more accurate for medullary thyroid carcinoma than the 2002 criteria in terms of assessing prognosis. Under the 2002 criteria, a significantly higher percentage of patients were classified as having stage IV disease. The authors indicated that elevated calcitonin that remains stable often does not indicate a poor outcome, and patients with lymph node metastases but no distant disease would be better classified as having stage III cancer.[15]

See Thyroid Cancer Staging for summary tables.

 

Treatment

Approach Considerations

The primary treatment for medullary thyroid carcinoma (MTC) is extensive and meticulous surgical resection. Thyroid hormone therapy is not as effective as surgical treatment for MTCs, which are neuroendocrine tumors of thyroid parafollicular cells that do not concentrate iodine. Radiation therapy is also less effective; however, positive surgical margins or mediastinal extension may be an indication for adjuvant radiotherapy, and external beam radiotherapy (EBRT) may provide a palliative benefit in controlling symptoms from bony metastases.

In cases of metastasis, the approach depends on the severity and rate of progression of disease. Metastatic MTC can be treated with limited surgical resection, EBRT in certain situations, or medical management with tyrosine kinase inhibitors (TKIs) or other agents. 

Metastatic disease

Asymptomatic metastatic tumors (generally less than 1 to 2 cm in diameter) growing in diameter less than 20% per year should be monitored for progression, with imaging every 6 to 12 months.

For other patients, first-line treatment is surgery or palliative EBRT. If they are not candidates for surgery or radiotherapy, systemic treatment as part of a clinical trial may be the best option.

Other options include tyrosine kinase inhibitor (TKI) therapy, such as with cabozantinib, vandetanib, sorafenib, or sunitinib. Selpercatinib, a RET-specific TKI, received accelerated approval by the US Food and Drug Administration (FDA) in May 2020 for adults and children aged 12 years or older for advanced or metastatic RET-mutant MTC who require systemic therapy.[16]

Cytotoxic agents are used for metastatic MTC only if the patient is unable to participate in clinical trials or experiences intolerance or failure of TKIs. Most regimens combine dacarbazine with other agents, including vincristine, 5-fluorouracil, cyclophosphamide,  streptozocin, or doxorubicin. No one combination has demonstrated a significant advantage over others.[17]  

Radioimmunotherapy using anti–carcinoembryonic antigen/anti-diethylenetriamine pentaacetic acid (DTPA)–indium recombinant bispecific antibody (BsMAb), followed 4 days later by a 131I-labeled bivalent hapten, resulted in a median overall survival of 110 months compared with 60 months in a contemporaneous untreated cohort.[18]

Peptide receptor radionuclide therapy produces a cytotoxic effect through the binding of a radiolabeled ligand to its respective receptor expressed on a tumor’s surface. Phase 2 trials in patients with metastatic MTC whose tumors expressed somatostatin or cholecystokinin (CCK) receptors have demonstrated some benefit.[17]

Medical Care

In 2009, the M.D. Anderson Cancer Center provided a paradigm for targeted therapy in MTC, demonstrating that activating mutations of the RET (rearranged during transfection) tyrosine kinase receptor in MTC made this disease a good model for the use of TKIs for treatment of metastatic cases.[19] Several TKIs have since entered clinical practice. Vandetanib (Caprelsa) and cabozantinib (Cometriq), which target various tyrosine kinases, including MET, RET, and VEGFR-2, are approved for progressive, metastatic MTC. Selpercatinib (Retevmo) and pralsetinib (Gavreto) are approved for MTC that has RET mutations.

FDA approval of vandetanib was based on the results of the phase III ZETA study, in which participants randomized to vandetanib (n=231) showed a statistically significant improvement in progression-free survival (PFS) compared with those randomized to placebo (n=100): median PFS was at least 22.6 months in the vandetanib arm, versus 16.4 months in the placebo arm (hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.24-0.53; P <  0.0001). This difference reflects a 65% reduction in risk for disease progression. At the primary PFS analysis, no significant difference in overall survival (OS) was noted.[20, 21, 22]

Approval for cabozantinib was based on the EXAM clinical trial, an international, multicenter, randomized study that included 330 patients with progressive, metastatic MTC. A statistically significant prolongation in PFS was seen with cabozantinib compared with placebo (11.2 vs 4.0 months; P <  0.0001). Partial responses were observed only among patients in the active treatment arm (27% vs 0%; P < 0.0001), and more patients in the cabozantinib group than in the placebo group were alive and free of disease progression at 1 year (47.3% vs 7.2%). Median duration of response was 14.7 months.[23]

Selpercatinib is the first RET targeted therapy to be approved by the FDA for MTC. It is indicated for advanced or metastatic RET-mutant MTC in adults and children aged 12 years or older who require systemic therapy. Accelerated approval for MTC was based on the open-label LIBRETTO-001 phase I/II clinical trial (n = 143). The objective response rate (ORR) was 69% in cabozantinib/vandetanib treatment–experienced patients (n = 55) and 73% in treatment-naïve patients (n = 88). The phase III confirmatory trial (LIBRETTO-531) is in progress.[16]

Pralsetinib was approved by the FDA for adult and pediatric patients aged 12 years and older with advanced or metastatic RET-mutant MTC who require systemic therapy. Efficacy was evaluated in the ARROW trial, a multicenter, open label, multicohort clinical trial. In the 55 patients with advanced or metastatic RET-mutant MTC who were previously treated with cabozantinib or vandetanib, the ORR was 60% (95% CI: 46%, 73%); the rate of duration of response (DOR) of 6 months or longer was 79%. Efficacy was also evaluated in 29 treatment-naïve patients with RET-mutant MTC: in this arm, the ORR was 66% (95% CI: 46%, 82%); DOR lasting 6 months or longer was 84%.[24]

See Thyroid Cancer Treatment Protocols for summarized information.

Surgical Care

Surgical treatment goals of medullary thyroid carcinoma (MTC) are as follows:

  • Provide local control of the cancer
  • Maintain laryngoesophageal function (speech and swallowing)
  • Tailor surgical treatment according to the type of MTC presentation (ie, sporadic, familial)

Sporadic MTC

Sporadic MTC occurring in patients presenting with a palpable thyroid nodule verified by fine-needle aspiration is treated as follows:

  • Perform a total thyroidectomy and central neck dissection for cases of symptomatic (clinically detected) MTC.

  • For patients with microscopic involvement of regional lymph nodes, advocate a central neck dissection, which involves complete dissection of structures and removal of node-bearing tissue between the hyoid bone and innominate vessels, sternothyroid resection, removal of paratracheal lymph nodes, and possible thymectomy.

  • Autograft an inferior parathyroid gland that is histologically confirmed as cancer-free into the sternocleidomastoid or forearm muscle.

  • In palpable lymph node disease, perform a modified radical neck dissection. For increasing calcitonin levels, a reoperative neck dissection may be indicated.

  • In a 2009 retrospective review of elective superior mediastinal neck dissections for thyroid carcinomas, the authors concluded that "elective transcervical superior mediastinal dissection was commonly positive in patients with papillary, medullary, and anaplastic thyroid carcinomas. A transcervical approach may be safely performed without sternotomy to the level of the brachiocephalic vein." They pointed out that further studies are needed to determine the impact of elective superior mediastinal lymph node dissections on survival.[25]

Familial MTC

Prophylactic thyroidectomy is indicated for carriers of RET mutations who have no apparent disease but are at risk for aggressive MTC. Guidelines from the American Thyroid Association classify RET carriers into four risk levels, on the basis of the particular mutation involved. The age at which thyroidectomy is recommended corresponds to the level of risk and varies from as soon as possible within the first year of life (for those at highest risk) to beyond 5 years of age, provided that stringent criteria are met.[2]

Perform a total thyroidectomy with a central neck dissection or modified radial neck dissection for patients with clinically detectable disease evidenced by increased calcitonin levels, thyroid nodule on ultrasonography, or findings on physical examination. MTC is diagnosed after thyroidectomy in approximately 10-15% of cases.

Patients with persistently elevated serum calcitonin levels, positive RET findings, or nodal disease are good candidates for completion thyroidectomy and lymph node dissection.[26] However, patients with undetectable calcitonin levels, negative RET test findings, and no ultrasonography abnormalities may be conservatively monitored.

Consultations

Consultations may include the following:

  • General physician
  • Head and neck surgeon
  • Endocrinologist
  • Geneticist, for cases of inherited MTC such as in patients with MEN2 syndromes.
  • Oncologist

Prevention

Management guidelines from the American Thyroid Association (ATA) recommend prophylactic thyroidectomy for individuals with documented RET mutation who are at risk for aggressive medullary thyroid carcinoma.[2]  The ATA has proposed schedules for the recommended age of RET testing, first ultrasound, serum calcitonin level, and prophylactic surgery, depending on the level of risk; in those at highest risk, surgery is recommended within the first year of life.

Long-Term Monitoring

Measure calcitonin and carcinoembryonic antigen (CEA) levels after thyroidectomy. Patients with undetectable calcitonin—or, in patients with sporadic MTC who have undergone hemithyroidectomy, calcitonin levels within the normal reference range—should have follow-up testing every 6-12 months.

Detectable CEA levels after total thyroidectomy, or above-normal levels after hemithyroidectomy, mandate further assessment with imaging studies, as per American Thyroid Association guidelines. If calcitonin becomes detectable after total thyroidectomy but imaging studies do not identify disease or if calcitonin levels rise after hemithyroidectomy, doubling time of calcitonin and CEA levels may be used to assess tumor progression.[27]  In one study, 94% of patients with doubling times shorter than 25 months had progressive disease and 86% of patients with doubling times longer than 24 months had stable disease.[28]

Further intervention may include the following:

  • Perform reoperative cervical exploration for isolated recurrent cervical disease (without distant metastases) identified by ultrasonography or CT scanning
  • Identification of distant metastatic disease may require laparoscopy with probe ultrasonography to detect liver surface lesions and bone scanning to detect osseous disease
  • Selective hepatic venous sampling for liver metastases is an experimental procedure that is used to detect intrahepatic lesions with greater sensitivity
  • If metastatic workup findings are negative in a patient with elevated plasma calcitonin levels, elective cervical lymph node dissection or modified radial neck dissection may be performed.

For patients with undetectable calcitonin and normal CEA levels, post-surgical followup may include the following:

  • Physical examination twice yearly for 2 years and then yearly thereafter
  • Measurement of serum calcitonin and CEA levels twice yearly for 2 years and then yearly thereafter
  • Neck ultrasound 3 to 12 months postoperatively (depending on the extent of lymph node involvement prior to surgery) to establish a baseline; additional imaging is not required unless the calcitonin or CEA values rise during follow-up

Calcitonin values that remain ≥150 pg/mL 2 to 6 months after surgery increase the likelihood that the patient may have distant metastases. These patients should undergo neck ultrasound and additional imaging (eg, CT or MRI of neck, chest, and abdomen; bone scan or bone MRI in patients suspected of having skeletal metastases) to identify possible distant metastases. Adjuvant radiation has not been shown to influence 10 yr survival rates, however.

 

Guidelines

Guidelines Summary

Guidelines Contributor: Kemp M Anderson Medical University of South Carolina College of Medicine

The following organizations have released guidelines for the diagnosis and/or management of thyroid cancer:

  • American Thyroid Association (ATA) [29, 2]
  • National Comprehensive Cancer Network (NCCN) [6]
  • American Association of Clinical Endocrinologists/American College of Endocrinology/Associazione Medici Endocrinologi (AACE/ACE/AME)(diagnosis only) [30]
  • European Society for Medical Oncology (ESMO) [5]
  • Japan Associations of Endocrine Surgeons [31]

Prevention

The familial medullary thyroid carcinoma (MTC) syndromes consist of multiple endocrine neoplasia (MEN) types 2A and 2B and familial MTC. They are inherited in an autosomal dominant fashion. Children inheriting any of these syndromes have a 100% risk of developing MTC.

MEN 2A (Sipple syndrome) consists of MTC, pheochromocytoma (in 50% of patients), and hyperparathyroidism (10-20% of patients). MEN 2B consists of MTC, pheochromocytoma (in 50% of patients), marfanoid habitus, and ganglioneuromatosis. FMTC consists of MTC alone.

MTC in MEN 2B has the most aggressive biologic features. In this situation, MTC usually develops around 10 years of age, and it has a high propensity for rapid growth and metastasis. MTC in MEN 2A can appear in the first decade of life, and it almost always develops by the second decade. MTC in FMTC usually develops during adulthood.

Genetic testing is now the mainstay in the diagnosis of the familial MTC syndromes. Germline RET proto-oncogene mutations (on chromosome arm 10q) discovered in these syndromes include the following[2] :

  • MEN 2A – Majority of cases show substitutions of conserved cysteine residues in exons 10 and 11
  • MEN 2B – 95% of cases show threonine-for-methionine substitution in codon 918 of exon 16.
  • Familial MTC - Most commonly seen with mutations in exons 10, 13 & 14

Guidelines from the American Thyroid Association (ATA) recommend prophylactic thyroidectomy for individuals that have a documented RET mutation and are at risk for aggressive medullary thyroid carcinoma.[2] Japan Associations of Endocrine Surgeons guidelines do not uniformly recommend prophylactic total thyroidectomy for carriers of RET mutations who have not developed MTC; outcomes to consider are the prognosis, surgical complications, and health considerations from the patient's perspective.[31]

The original ATA guidelines stratified risk level of RET carriers into four categories, A through D, based upon the increasing aggressiveness of the particular mutation. Due to some confusion and lack of uniformity with other staging guidelines, the revised ATA guidelines[2] transition category D to “highest risk” (HST), transition category C to “high risk” (H), and combine categories B and A into “moderate risk”. The risk stratification, screening schedules, and prophylactic thyroidectomy schedules are described in the table below.

Table. Revised ATA MTC Risk Levels and Pediatric Recommendations (Open Table in a new window)

Risk Level

RETcodon Mutation

Possible Diagnoses

Prophylactic Thyroidectomy

Recommendations

Follow-up

Highest Risk (HST)

M918T+All MEN2B

MEN2B

Within the first year of life or the first months of life based upon specialist and parental discussions. The ability to identify and preserve or transplant parathyroid glands determines level VI dissection.

Physical exam, neck US, serum Ctn, and serum CEA every 6 mos first year, then annually; begin screening for pheochromocytoma at age 11 yr

High Risk (H)

C634, A883F

MEN2A

At or before age 5 yr, to be determined on the basis of serum Ctn

Physical exam, neck US, serum Ctn, and serum CEA every 6 mos first year, then annually. Begin screening for pheochromocytoma at age 11.

Moderate Risk (MOD)

All other mutations

MEN2A

When serum Ctn becomes elevated or in childhood to avoid lengthy evaluation period.

Evaluate every 6 months for 1 year. Annual follow-ups thereafter if serum Ctn is normal or undetectable. Begin screening for pheochromocytoma at age 16 yr

CEA=carcinoembryonic antigen;  Ctn=calcitonin; MEN=multiple endocrine neoplasia; US=ultrasound

Diagnosis

All the guidelines advocate ultrasound evaluation of thyroid nodules along with measurement of serum thyroid-stimulating hormone (TSH) levels to determine whether a fine needle aspiration biopsy (FNAB) is indicated. A routine measurement of serum thyroglobulin (Tg) for the initial evaluation of thyroid nodules is not recommended because Tg levels are elevated in most benign thyroid conditions.[29, 6, 30, 5]

Although all the guidelines recommend FNAB as the procedure of choice in the evaluation of solid thyroid nodules, there is variance in the size of the nodule as an indication for FNAB, as follows[29, 6, 30]

  • >0.5 cm in diameter (ATA) [29]
  • ≥1 cm if suspicious sonographic features are present; ≥1.5 cm if no suspicious sonographic features are present (NCCN) [6]
  • ≥1 cm if high risk; > 2 cm if intermediate risk; > 2 cm if low risk and increasing in size or associated with a risk history and before thyroid surgery or minimally invasive ablation therapy (AACE/ACE/AME) [30]
  • >1 cm, with the decision to aspirate guided by lesion size and sonographic appearance (ESMO) [5]

In its 2016 revised guidelines, AACE/ACE/AME included the following additional recommendations for FNAB for evaluation[30] :

  • Nodules < 0.5 cm in diameter should be monitored with US, irrespective of their sonographic appearance 
  • Nodules 0.5 - 1cm that are associated with suspicious sonographic features, consider either FNA sampling or watchful waiting on the basis of the clinical setting and patient preference
  • US-guided FNA is recommended for the following nodules: Subcapsular or paratracheal lesions; suspicious lymph nodes or extrathyroid spread; in patients with a positive personal or family history of thyroid cancer; or, coexistent suspicious clinical findings (e.g., dysphonia)

AACE/ACE/AME, ESMO and NCCN suggest a serum calcitonin assay as an optional test,[6, 30, 5]  but the ATA guidelines make no recommendation on the routine measurement of serum calcitonin because of insufficient evidence.[2] AACE/ACE/AME, ATA and NCCN guidelines recommend radionuclide imaging in patients with a low TSH level.[6, 2, 30]

Patients with medullary thyroid carcinoma (MTC) can be identified by pathologic diagnosis or by prospective genetic screening. According to the revised ATA guidelines, an FNAB result suspicious for MTC should prompt the following[29] :

  • Ultrasound of the neck
  • Serum calcitonin assay
  • Serum carcinoembryonic antigen (CEA) measurement
  • DNA analysis for  RET germline mutation

Although calcitonin is a valuable tumor marker in patients with MTC, the 2015 Revised ATA guidelines note that clinical judgment should be exercised in the interpretation of calcitonin test results. Serum levels can be falsely high or low in a variety of clinical diseases, can be elevated in children under 3 years of age, and can be higher in males than females.[2]

The NCCN recommends the following diagnostic procedures when FNAB results indicate MTC[6] :

  • Basal serum calcitonin level
  • CEA level
  • Pheochromocytoma screening
  • Serum calcium assay
  • Consider genetic counseling
  • Screen for germline RET proto-oncogene mutations (exons 10, 11, 13-16)
  • Thyroid and neck ultrasound (including central and lateral compartments), if not previously done
  • Consider evaluation of vocal cord mobility (ultrasound, mirror indirect laryngoscopy, or fiberoptic laryngoscopy)
  • Consider contrast-enhanced CT of chest and mediastinum or MRI or 3‑phase CT of live
  • if N1 disease or calcitonin >400 pg/mL
  •  Consider Ga‑68 DOTATATE PET/CT; if not available, consider bone scan and/or skeletal MRI

Primary Treatment

The National Comprehensive Cancer Network (NCCN) guidelines recommend total thyroidectomy and bilateral central neck dissection (level VI) for all patients with medullary thyroid carcinoma (MTC) whose tumor is ≥1 cm or who have bilateral thyroid disease, as well as the following[6] :

  • Therapeutic ipsilateral or bilateral modified neck dissection for clinically or radiologically identifiable disease (levels II–V)
  • Prophylactic ipsilateral modified neck dissection for high volume or gross disease in the adjacent central neck may be considered

Total thyroidectomy is recommended and neck dissection can be considered for those whose tumor is < 1 cm and for unilateral thyroid disease

ATA guidelines recommend surgical treatments as follows[2]

  • Total thyroidectomy and dissection of the lymph nodes in the central compartment for patients with MTC and no evidence of lymph node metastases (level VI); 
  • Dissection of lymph nodes in the lateral compartments (levels II–V) may be considered based on serum calcitonin (Ctn) levels in patients with MTC and no evidence of neck or distant metastases
  • Total thyroidectomy, dissection of the central lymph node compartment (level VI), and dissection of the involved lateral neck compartments (levels II–V) for patient with MTC confined to neck and cervical lymph nodes.
  • When preoperative imaging is positive in the ipsilateral lateral neck compartment but negative in the contralateral neck compartment, contralateral neck dissection should be considered if the basal serum calcitonin level is greater than 200 pg/mL

External beam radiation therapy (EBRT) is an option for treatment of incomplete tumor resection when further surgical resection is no longer possible[6] . EBRT can also be considered for adjuvant treatment for extrathyroidal extension (T4a or T4b) with positive margins.[6, 2]

Radioiodine (131I) therapy is not effective.[6]

Suppression of thyroid-stimulating hormone (TSH) is not appropriate; TSH is kept in the normal range by adjusting levothyroxine dose.[2, 6]

The ATA and NCCN guidelines recommend removal of pheochromocytoma prior to surgery for MTC to prevent a possible hypertensive crisis.[2, 6]  Pheochromocytoma should be resected by laparoscopic or retroperitoneoscopic adrenalectomy. Subtotal adrenalectomy to preserve adrenal cortical function should be considered as an alternative procedure. Patients with no adrenal glands require glucocorticoid and mineralocorticoid replacement therapy and should be carefully monitored to ensure that their steroid levels are adequate. Patients should be educated regarding the risk of adrenal crisis and wear a bracelet or a necklace indicating that they have no adrenal glands and are on corticosteroid replacement therapy. Glucocorticoid supplementation will be required if they become severely ill or are injured.[2]

ESMO guidelines recommend preoperative ulltrasound (US) for all patients with MTC.[5] In US-positive patients, total thyroidectomy and bilateral central neck dissection plus therapeutic neck dissection of involved levels is recommended, plus contalateral lateral neck dissection if the serum Ctn level is > 200 pg/mL. In US-negative patients, treatment recommendations vary according to Ctn levels, as follows:

  • Ctn < 20 pg/mL - Total thyroidectomy
  • Ctn 20-50 pg/mL - Total thyroidectomy with or without bilateral central neck dissection
  • Ctn 50-200 pg/mL - Total thyroidectomy with bilateral central neck dissection and ispilateral lateral neck dissection (at least IIA-III-IV)
  • Ctn 200-500 pg/mL - Total thyroidectomy with bilateral central neck dissection and bilateral lateral neck dissection (at least IIA-III-IV)
  • Ctn > 500 pg/mL - Work up for distant metastasis: If M0, total thyroidectomy with bilateral central neck dissection and bilateral lateral neck dissection (at least IIA-III-IV); if M1, neck surgery based on disease progression and symptoms

Advanced or Metastatic Disease

Vandetanib and cabozantinib have been approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of patients with locally advanced/metastatic MTC. ESMO guidelines recommend vandetanib and cabozantinib as the first-line systemic treatments for progressive metastatic MTC.[5] Similarly, ATA guidelines recommend using vandetanib or cabozantinib as single-agent first-line systemic therapy in patients with advanced progressive MTC.[2]

For asymptomatic recurrent or metastatic MTC, the NCCN recommends the following treatment options[6] :

  • Active surveillance
  • Resection, if possible or ablation or vandetanib (category 1) or cabozantinib (category 1), if not resectable and progressing

For symptomatic or progressing recurrent or metatstaic MTC, NCCN recommends the following treatment options[6] :

  • Vandetanib (category 1) or cabozantinib (category 1) or clinical trial orother small-molecule kinase inhibitors or Decarbazine (DTIC)-based chemotherapy 
  • External beam radiation therapy (EBRT)/Intensity modulated radiation therapy (IMRT) for local symptoms

For bone metastases, NCCN and ATA guidelines recommend  bisphosphonate or denosumab therapy.[6, 2]

ATA guidelines recommend performing brain imaging in patients with metastatic MTC who have neurologic symptoms, including patients who are candidates for systemic therapy. Patients with isolated brain metastases are candidates for surgical resection or EBRT (including stereotactic radiosurgery). Whole-brain EBRT is indicated for multiple brain metastasis.[2]   

 

Surveillance

If, in the 2-3 months postoperatively, the basal calcitonin level remains undetectable and the CEA level remains within the reference range, NCCN guidelines recommend the following for active surveillance[6] :

  • Annual serum calcitonin and CEA testing
  • Consider ultrasound of the central and lateral neck compartments
  • Perform additional studies or more frequent testing if the calcitonin or CEA rises significantly
  • No additional imaging is required if the calcitonin and CEA levels remain stable
  • For MEN2B or MEN2A, perform annual biochemical screenings for pheochromocytoma and hyperparathyroidism (MEN2A)

ESMO guidelines recommend pstoperative assessment 30–60 days after surgery with serum Ctn and CEA and neck ultrasound (US), with use of other imaging modalities depending on the stage and serum Ctn and CEA levels.[5] The subsequent surveillance protocol depends on the results of that assessment, as follows:

  • Excellent response (Ctn and CEA undetectable or within normal range, no structural evidence of disease) - Serum Ctn every 6 months for 1 year, then annually; repeat neck US depending on Ctn levels (abnormal values should prompt imaging studies)
  • Biochemical incomplete response (detectable Ctn and abnormal CEA, but no structural evidence of disease) - Serum Ctn and CEA every 3 to 6 months to determine doubling times (doubling times < 24 months are associ-ated with progressive diseasec); neck US every 6-12 months depending on Ctn and CEA doubling times; other imaging modalitiesa depending on Ctn and CEA levels and doubling times
  • Structural incomplete response (structural evidence of disease, regardless Ctn and CEA levels) - If disease is stable, serum Ctn and CEA every 3-6 months to determine doubling times; neck US every 6-12 months, depending on Ctn and CEA doubling times; other imaging modalities, depending on Ctn and CEA levels and their doubling times; in progressive symptomatic disease, locoregional therapy if single lesion, systemic therapy with cabozantinib or vandetanib if multiple lesions
 

Medication

Medication Summary

Although surgery remains the standard treatment for medullary thyroid carcinoma (MTC), several tyrosine kinase inhibitors (TKIs) are approved by the US Food and Drug Administration (FDA) for treatment of advanced or metastatic MTC. These include the multitarget TKIs vandetanib and cabozantinib, and the RET tyrosine kinase inhibitor selpercatinib.

Tyrosine Kinase Inhibitors

Class Summary

These agents target various tyrosine kinases including MET, RET, and VEGFR-2.

Vandetanib (Caprelsa)

Tyrosine kinase inhibitor (TKI) with selective activity against RET, VEGFR-2, and EGFR. Indicated for treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease.

Cabozantinib (Cometriq)

Cabozantinib is a tyrosine kinase inhibitor that targets RET, MET, VEGFR-1, -2, and -3, KIT, TrkB, FLT-3, AXL, and TIE-2 pathways; these tyrosine kinases are involved in both normal cellular function and pathologic processes (eg, oncogenesis, metastasis, tumor angiogenesis, and maintenance of tumor microenvironment). It is indicated for treatment of progressive, metastatic medullary thyroid cancer.

RET Kinase Inhibitors

Class Summary

Genomic alterations in rearranged during transfection (RET) kinase, which include fusions and activating point mutations, lead to overactive RET signaling and uncontrolled cell growth.

Selpercatinib (Retevmo)

Selpercatinib is a kinase inhibitor of wild-type rearranged during transfection (RET) and multiple mutated RET isoforms, as well as vascular endothelial growth factor receptors (VEGFR1, VEGFR3). It is indicated for advanced or metastatic RET-mutant MTC in adults and children aged 12 years or older who required systemic therapy.

Pralsetinib (Gavreto)

A once-daily therapy designed to selectively target RET alterations. Indicated for advanced or metastatic rearranged during transfection (RET)-mutant MTC in adult and pediatric patients ≥12 years who require systemic therapy, or with advanced or metastatic RET fusion-positive thyroid cancer who require systemic therapy and who are radioactive iodine-refractory (if radioactive iodine is appropriate).