Medullary Thyroid Carcinoma
- Author: Anastasios K Konstantakos, MD; more...
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.
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.
[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].
Hundahl SA, Cady B, Cunningham MP, Mazzaferri E, McKee RF, Rosai J, et al. Initial results from a prospective cohort study of 5583 cases of thyroid carcinoma treated in the united states during 1996. U.S. and German Thyroid Cancer Study Group. An American College of Surgeons Commission on Cancer Patient Care Evaluation study. Cancer. 2000 Jul 1. 89(1):202-17. [Medline].
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].
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].
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].
Solomon B, Rischin D. Progress in molecular targeted therapy for thyroid cancer: vandetanib in medullary thyroid cancer. J Clin Oncol. 2012 Jan 10. 30(2):119-21. [Medline].
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].
Ducic Y, Oxford L. Transcervical elective superior mediastinal dissection for thyroid carcinoma. Am J Otolaryngol. 2009 Jul-Aug. 30(4):221-4. [Medline].
Ahmed SR, Ball DW. Incidentally Discovered Medullary Thyroid Cancer: Diagnostic Strategies and Treatment. J Clin Endocrinol Metab. 2011 Feb 23. [Medline].
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].
Chi DD, Moley JF. Medullary thyroid carcinoma: genetic advances, treatment recommendations, and the approach to the patient with persistent hypercalcitoninemia. Surg Oncol Clin N Am. 1998 Oct. 7(4):681-706. [Medline].
Evans DB, Fleming JB, Lee JE, et al. The surgical treatment of medullary thyroid carcinoma. Semin Surg Oncol. 1999. 16:50-63. [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].
Hyer SL, Newbold K, Harmer C. Familial medullary thyroid cancer: clinical aspects and prognosis. Eur J Surg Oncol. 2005 May. 31(4):415-9. [Medline].
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].
Rosenthal MS, Pierce HH. Inherited medullary thyroid cancer and the duty to warn: revisiting Pate v. Threlkel in light of HIPAA. Thyroid. 2005 Feb. 15(2):140-5. [Medline].
Shaha AR. Management of the neck in thyroid cancer. Otolaryngol Clin North Am. 1998. 31:823-31.
Udelsman R, Lakatos E, Ladenson P. Optimal surgery for papillary thyroid carcinoma. World J Surg. 1996. 20:88-93. [Medline].
You YN, Lakhani V, Wells SA Jr, Moley JF. Medullary thyroid cancer. Surg Oncol Clin N Am. 2006 Jul. 15(3):639-60. [Medline].