Medullary Thyroid Carcinoma

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Background

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.


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

Pathophysiology

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[1] ; prophylactic thyroidectomy can now be offered to specific types of patients with this genetic abnormality (see Prevention).

Epidemiology

Frequency

United States

Medullary carcinoma of the thyroid (MTC) constitutes approximately 4% of all thyroid cancers in the United States.[2] This figure translates into approximately 1000 diagnoses per year.

International

The international incidence of medullary carcinoma of the thyroid is similar to that in the United States.

Mortality/Morbidity

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.[3]

Age

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.

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:

Physical

Causes

Laboratory Studies

Imaging Studies

Procedures

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. 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.[8]

Medical Care

In 2009, the M.D. Anderson Cancer Center provided a paradigm for targeted therapy in medullary thyroid cancer. They explained 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.[9]

Vandetanib (Caprelsa) and cabozantinib (Cometriq) are tyrosine kinase inhibitors approved by the 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.[14, 28, 29]

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.[30]

Surgical Care

Consultations

Medication Summary

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.[12] 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.[13] In addition, sorafenib and sunitinib, which are approved for other malignancies, are being used selectively for patients who do not qualify for clinical trials.[12]

Vandetanib and cabozantinib are tyrosine kinase inhibitors approved by the FDA for treatment of symptomatic or progressive, metastatic medullary thyroid cancer.

Vandetanib (Caprelsa)

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.

Cabozantinib (Cometriq)

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.

Class Summary

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

Further Inpatient Care

Further Outpatient Care

Deterrence/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.[1] 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.

Complications

Prognosis

Author

Anastasios K Konstantakos, MD, Clinical Associate Surgeon, Department of Cardiovascular Surgery, Billings Clinic

Disclosure: Nothing to disclose.

Specialty Editors

Lodovico Balducci, MD, Professor of Oncology and Medicine, University of South Florida College of Medicine; Division Chief, Senior Adult Oncology Program, H Lee Moffitt Cancer Center and Research Institute

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems

Disclosure: Nothing to disclose.

Additional Contributors

Medscape Reference gratefully acknowledges the contributions of Debra J Graham, MD, to previous versions of this article.

References

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

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