Medullary Thyroid Carcinoma

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Medullary Thyroid Carcinoma

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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, 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.

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, 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.

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).

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.

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]

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.

[Guideline] Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009 Jun. 19(6):565-612. [Medline]. [Full Text].

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Kebebew E, Greenspan FS, Clark OH, et al. Extent of disease and practice patterns for medullary thyroid cancer. J Am Coll Surg. 2005 Jun. 200(6):890-6. [Medline].

Costante G, Meringolo D, Durante C, Bianchi D, Nocera M, Tumino S, et al. Predictive value of serum calcitonin levels for preoperative diagnosis of medullary thyroid carcinoma in a cohort of 5817 consecutive patients with thyroid nodules. J Clin Endocrinol Metab. 2007 Feb. 92(2):450-5. [Medline]. [Full Text].

Ahmed SR, Ball DW. Clinical review: Incidentally discovered medullary thyroid cancer: diagnostic strategies and treatment. J Clin Endocrinol Metab. 2011 May. 96(5):1237-45. [Medline]. [Full Text].

Machens A, Lorenz K, Dralle H. Individualization of lymph node dissection in RET (rearranged during transfection) carriers at risk for medullary thyroid cancer: value of pretherapeutic calcitonin levels. Ann Surg. 2009 Aug. 250(2):305-10. [Medline].

Trimboli P, Giovanella L, Valabrega S, Andrioli M, Baldelli R, Cremonini N, et al. Ultrasound features of medullary thyroid carcinoma correlate with cancer aggressiveness: a retrospective multicenter study. J Exp Clin Cancer Res. 2014 Oct 25. 33(1):87. [Medline]. [Full Text].

Chang TC, Wu SL, Hsiao YL. Medullary thyroid carcinoma: pitfalls in diagnosis by fine needle aspiration cytology and relationship of cytomorphology to RET proto-oncogene mutations. Acta Cytol. 2005 Sep-Oct. 49(5):477-82. [Medline].

Boostrom SY, Grant CS, Thompson GB, Farley DR, Richards ML, Hoskin TL, et al. Need for a revised staging consensus in medullary thyroid carcinoma. Arch Surg. 2009 Jul. 144(7):663-9. [Medline].

Maxwell JE, Sherman SK, O’Dorisio TM, Howe JR. Medical management of metastatic medullary thyroid cancer. Cancer. 2014 Nov 1. 120 (21):3287-301. [Medline]. [Full Text].

Chatal JF, Campion L, Kraeber-Bodéré F, Bardet S, Vuillez JP, Charbonnel B, et al. Survival improvement in patients with medullary thyroid carcinoma who undergo pretargeted anti-carcinoembryonic-antigen radioimmunotherapy: a collaborative study with the French Endocrine Tumor Group. J Clin Oncol. 2006 Apr 10. 24 (11):1705-11. [Medline].

Ye L, Santarpia L, Gagel RF. Targeted Therapy for Endocrine Cancer: The Medullary Thyroid Carcinoma Paradigm. Endocr Pract. 2009 Jun 22. 1-24. [Medline].

Wells SA, Robinson RF, Gagel H, Dralle JA, Fagin M, Santoro E, et al. Vandetanib (VAN) in locally advanced or metastatic medullary thyroid cancer (MTC): A randomized, double-bind phase III trial (ZETA). J Clin Oncol. 2010. 28:(suppl: abstr 5503. [Full Text].

Wells SA Jr, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012 Jan 10. 30(2):134-41. [Medline].

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Schoffski P, Elisei R, Muller S, Brose MS, Shah MH, Licitra LF, et al. An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients with documented RECIST progression at baseline. Presented at the American Society of Clinical Oncology (ASCO) 2012 Annual Meeting. June 1-5, 2012, Chicago, IL. [Full Text].

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Ahmed SR, Ball DW. Incidentally Discovered Medullary Thyroid Cancer: Diagnostic Strategies and Treatment. J Clin Endocrinol Metab. 2011 Feb 23. [Medline].

[Guideline] Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016 Jan. 26 (1):1-133. [Medline]. [Full Text].

[Guideline] Wells SA Jr, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 Jun. 25 (6):567-610. [Medline]. [Full Text].

[Guideline] NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma. Version l.2016. National Comprehensive Cancer Network. Available at http://www.nccn.org/professionals/physician_gls/pdf/thyroid.pdf. July 8, 2016; Accessed: September 20, 2016.

[Guideline] Gharib H, Papini E, Paschke R, Duick DS, Valcavi R, Hegedüs L, et al. American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association medical guidelines for clinical practice for the diagnosis and management of thyroid nodules: executive summary of recommendations. J Endocrinol Invest. 2010. 33 (5 Suppl):51-6. [Medline]. [Full Text].

Sherman SI. Advances in chemotherapy of differentiated epithelial and medullary thyroid cancers. J Clin Endocrinol Metab. 2009 May. 94(5):1493-9. [Medline].

Schlumberger MJ, Elisei R, Bastholt L, Wirth LJ, Martins RG, Locati LD, et al. Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer. J Clin Oncol. 2009 Aug 10. 27(23):3794-801. [Medline].

Laure Giraudet A, Al Ghulzan A, Aupérin A, Leboulleux S, Chehboun A, Troalen F, et al. Progression of medullary thyroid carcinoma: assessment with calcitonin and carcinoembryonic antigen doubling times. Eur J Endocrinol. 2008 Feb. 158(2):239-46. [Medline]. [Full Text].

Rohmer V, Vidal-Trecan G, Bourdelot A, et al. Prognostic factors of disease-free survival after thyroidectomy in 170 young patients with a RET germline mutation: a multicenter study of the Groupe Francais d’Etude des Tumeurs Endocrines. J Clin Endocrinol Metab. 2011 Mar. 96(3):E509-18. [Medline].

Rowland KJ, Jin LX, Moley JF. Biochemical Cure after Reoperations for Medullary Thyroid Carcinoma: A Meta-analysis. Ann Surg Oncol. 2014 Sep 19. [Medline].

Carlomagno F, Santoro M. Identification of RET kinase inhibitors as potential new treatment for sporadic and inherited thyroid cancer. J Chemother. 2004 Nov. 16 Suppl 4:49-51. [Medline].

Fitze G. Management of patients with hereditary medullary thyroid carcinoma. Eur J Pediatr Surg. 2004 Dec. 14(6):375-83. [Medline].

Gibelin H, Essique D, Jones C, et al. Increased calcitonin level in thyroid nodules without medullary carcinoma. Br J Surg. 2005 May. 92(5):574-8. [Medline].

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Quayle FJ, Moley JF. Medullary thyroid carcinoma: including MEN 2A and MEN 2B syndromes. J Surg Oncol. 2005 Mar 1. 89(3):122-9. [Medline].

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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

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

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: Received salary from Medscape for employment. for: Medscape.

Neetu Radhakrishnan, MD Associate Professor (Adjunct) of Medicine, Division of Hematology/Oncology, University of Cincinnati Medical Center; Hematology/Oncology Medical Director, West Chester Outpatient Clinics

Neetu Radhakrishnan, MD is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology, American Society of Hematology

Disclosure: Nothing to disclose.

Lodovico Balducci, MD Professor, Oncology Fellowship Director, Department of Internal Medicine, Division of Adult Oncology, H Lee Moffitt Cancer Center and Research Institute, University of South Florida Morsani College of Medicine

Lodovico Balducci, MD is a member of the following medical societies: American Association for the Advancement of Science, American Association for Cancer Research, American College of Physicians, American Geriatrics Society, American Society of Hematology, New York Academy of Sciences, American Society of Clinical Oncology, Southern Society for Clinical Investigation, International Society for Experimental Hematology, American Federation for Clinical Research, American Society of Breast Disease

Disclosure: Nothing to disclose.

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

Medullary Thyroid Carcinoma

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