Medullary carcinoma of the thyroid (MTC) is a distinct thyroid carcinoma that originates in the parafollicular C cells of the thyroid gland. These C cells produce calcitonin.
Sporadic, or isolated, MTC accounts for 75% of cases, and inherited MTC constitutes the rest. Inherited MTC occurs in association with multiple endocrine neoplasia (MEN) type 2A and 2B syndromes, but non-MEN familial MTC also occur.
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.
See the figure below.
Algorithm for the management of a solitary thyroid nodule. FNAB = fine needle aspiration biopsy; US = ultrasonography.
Medullary thyroid cancer (MTC) is usually diagnosed on physical examination as a solitary neck nodule, and early spread to regional lymph nodes is common. Distant metastases occur in the liver, lung, bone, and brain.
Sporadic MTC usually is unilateral. In association with multiple endocrine neoplasia (MEN) syndromes, it is always bilateral and multicentric. 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.
Mutations in the RET (REarranged during Transfection) proto-oncogene, a receptor protein tyrosine kinase encoded on chromosome 10, have been classified into discrete subtypes, which confer varying degrees of risk ; prophylactic thyroidectomy can now be offered to specific types of patients with this genetic abnormality (see Prevention).
Medullary carcinoma of the thyroid (MTC) constitutes approximately 4% of all thyroid cancers in the United States. This figure translates into approximately 1000 diagnoses per year.
The international incidence of medullary carcinoma of the thyroid is similar to that in the United States.
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.
Peak incidence of isolated medullary carcinoma of the thyroid (MTC) occurs in the fifth or sixth decade of life, and the peak incidence of MTC associated with multiple endocrine neoplasia (MEN) 2A or 2B occurs during the second or third decade of life.
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:
Medullary carcinoma of the thyroid (MTC) has a genetic association with multiple endocrine neoplasia (MEN) 2A and 2B; however, it is heritable by a non-MEN mode of transmission. Sporadic MTC occurs in 75% of patients, and familial MTC constitutes the other 25%. Mutations in RET can lead to MTC development in cells derived from neural crest tissue.
According to the American Thyroid Association, preoperative laboratory testing in patients with possible medullary thyroid carcinoma (MTC) has three purposes :
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.[1, 4] 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.
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. 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 many other countries, and DNA testing for RET has replaced this diagnostic method in familial cases.
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.
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).
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.
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.
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.
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. 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.
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.
See Thyroid Cancer Staging for summary tables.
In 2009, the M.D. Anderson Cancer Center provided a paradigm for targeted therapy in medullary thyroid cancer, noting that the discovery of particular genetic abnormalities in genetic tumors reveals specific targets for therapy. In particular, activating mutations of the RET tyrosine kinase receptor in medullary thyroid carcinoma makes MTC a good model for the use of small organic molecule tyrosine kinase inhibitors for treatment of metastatic disease. Clinical trials have shown promising results and tolerable toxicity.
Vandetanib (Caprelsa) and cabozantinib (Cometriq) are tyrosine kinase inhibitors approved by the U.S. Food and Drug Administration (FDA) for progressive, metastatic medullary thyroid cancer. These agents target various tyrosine kinases including MET, RET, and VEGFR-2.
The FDA approval of vandetanib is based on the results of the ZETA study, a phase III, double-blind trial that randomized 331 patients with unresectable locally advanced or metastatic medullary thyroid cancer to vandetanib 300 mg (n=231) or placebo (n=100). Participants randomized to vandetanib showed a statistically significant improvement in progression-free survival (PFS) when compared to those randomized to placebo (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. Median progression-free survival was 16.4 months in the placebo arm and at least 22.6 months in the vandetanib arm. At the primary PFS analysis, no significant overall survival difference was noted.[11, 12, 13]
Approval for cabozantinib was based on the EXAM clinical trial, an international, multicenter, randomized study that included 330 patients with progressive, metastatic medullary thyroid carcinoma. A statistically significant prolongation in progression-free survival 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.
See Thyroid Cancer Treatment Protocols for summarized information.
Surgical treatment goals of medullary thyroid carcinoma (MTC) are as follows:
Sporadic MTC occurring in patients presenting with a palpable thyroid nodule verified by fine-needle aspiration is treated as follows:
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.
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. However, patients with undetectable calcitonin levels, negative RET test findings, and no ultrasonography abnormalities may be conservatively monitored.
Although surgery remains the standard treatment for medullary thyroid carcinoma (MTC), several medications have entered clinical trials. For the most part, these are tyrosine kinase inhibitors that target vascular endothelial growth factor receptors. Partial response rates of up to 30% have been reported in single-agent studies, but prolonged disease stabilization is more common. For example, a phase II study of motesanib—a highly selective inhibitor of vascular endothelial growth factor receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit—has been conducted in 91 patients with MTC. The objective response rate was low, but 81% of patients achieved stable disease during treatment. In addition, sorafenib and sunitinib, which are approved for other malignancies, are being used selectively for patients who do not qualify for clinical trials.
Vandetanib and cabozantinib are tyrosine kinase inhibitors approved by the FDA for treatment of symptomatic or progressive, metastatic medullary thyroid cancer.
Clinical Context: 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.
Clinical Context: 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.
These agents target various tyrosine kinases including MET, RET, and VEGFR-2.
Thyroid hormone therapy and radiotherapy are not as effective as surgical treatment for medullary thyroid carcinoma (MTC). However, positive surgical margins or mediastinal extension may be an indication for adjuvant radiotherapy.
External beam radiotherapy may provide a palliative benefit in controlling symptoms from bony metastases.
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 levels after total thyroidectomy, or above-normal levels after hemithyroidectomy, mandate further assessment with imaging studies, as per American Thyroid Association guidelines. I f 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. 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.
Perform reoperative cervical exploration for isolated recurrent cervical disease (without distant metastases) as demonstrated by ultrasonography or CT scanning.
Identification of distant metastatic disease may depend on 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 the presence of elevated plasma calcitonin levels, elective cervical lymph node dissection or modified radial neck dissection may be performed.
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. 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.
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.
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. 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.