Medullary thyroid carcinoma
Medullary Thyroid Carcinoma (MTC)
Medullary thyroid carcinoma (MTC) is rare. It is accounts for about 5% of all thyroid cancers. Medullary thyroid carcinoma occurs in sporadic or hereditary (25% of cases) forms, as part of multiple endocrine neoplasia type 2 (MEN 2) syndromes or as the familial medullary thyroid carcinoma-only syndrome (FMTC). It is more aggressive type of the thyroid cancer. Affected individuals initially develop primary C-cell hyperplasia (CCH) that progresses to early invasive medullary microcarcinoma, and eventually develop grossly invasive macroscopic medullary thyroid carcinoma. Medullary thyroid carcinoma is spread to neck lymph nodes and by blood to other organs, such as lung, liver, bones and brain. The spread is depend on size of the tumor.
MEN 2A is defined as the presence of medullary thyroid carcinoma, pheochromocytoma, and primary hyperparathyroidism (PHPT) associated with a germline RET mutation. Familial medullary thyroid carcinoma is a clinical variant of MEN 2A in which medullary thyroid carcinoma is the only manifestation. MEN 2B is defined as the presence of medullary thyroid carcinoma, marfanoid habitus, medullated corneal nerve fibers, ganglioneuromatosis of the gut and oral mucosa, and pheochromocytoma associated with a germline RET mutation. The severity of medullary thyroid carcinoma could be classified as following from most favorable to most aggressive: FMTC, following by MEN 2A, following by sporadic medullary thyroid carcinoma, and the worst one is MEN 2B related medullary thyroid carcinoma.
Medullary thyroid carcinoma is the only thyroid cancer that can be diagnosed by blood test, checking for calcitonin level. With medullary thyroid carcinoma preoperative diagnosis by FNA biopsy is helpfull but may very difficult to establish. Usual description of FNA thyroid biopsy reveals findings of "malignancy", "cancer cells" or "follicular neoplasm". When diagnosis is suspected then blood calcitonon llevel should be checked. CEA level is also part of preoperative blood work, but it is not specific for medullary thyroid carcinoma only and can be elevated with other cancers. If this is a familial cancer syndrome, such as MEN 2A (Sipple’s syndrome), familial medullary thyroid carcinoma (FMTC), or MEN 2B, genetic testing of the blood for the RET proto-oncogene is indicated. Findings of RET-protooncogene mutation can lead to an early diagnosis of medullary thyroid carcinoma and, subsequently, earlier surgery to remove thyroid gland and lymph nodes.
All patients with a personal medical history of primary C cell hyperplasia, medullary thyroid carcinoma, or MEN 2 should be offered germline RET testing. All people with a family history consistent with MEN 2 or FMTC, and at risk for autosomal dominant inheritance of the syndrome, should be offered RET testing. For MEN 2B this should be done shortly after birth. For MEN 2A and FMTC this should be done before 5 years of age
American Thyroid Association have established guidelines for the diagnosis and treatment of patients with medullary thyroid carcinoma. These guidelines recommend primary complete surgical extirpation of disease with total thyroidectomy and varying level lymphadenectomy. Bilateral compartment-oriented neck surgery achieved biochemical cure in at least half the patients with calcitonin less than 1,000 pg/ml but not in patients with levels higher than 10,000 pg/ml
Stage of disease and age at diagnosis were found to be the strongest predictors of survival for patients with medullary thyroid carcinoma. Unfavorable risk factors include: older age, elevated calcitonin and CEA level, extrathyroidal invasion, lymph nodes metastasis, distant metastasis, and inability to achieve gross resection during the first surgery.
The 10-year disease-specific survival of medullary thyroid carcinoma is about 75%. Using a prior TNM classification system, 10-year survival rates for stages I, II, III, and IV are 100%, 93%, 71%, and 21%, respectively.
1) Roman S, Lin R, Sosa JA. Prognosis of medullary thyroid carcinoma: demographic, clinical, and pathologic predictors of survival in 1252 cases. Cancer. 2006 Nov 1;107(9):2134-42.
2) Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, Moley JF, Pacini F, Ringel MD, Schlumberger M, Wells SA Jr. Medullary thyroid cancer: management guidelines of the American Thyroid Association. American Thyroid Association Guidelines Task Force, Thyroid. 2009 Jun;19(6):565-612.
3) A. Machens, H. Dralle, J Clin Endocrinol Metab 95: 2655–2663, 2010
4) A. Machens, H. Dralle, CLINICS 2012;67(S1):113-118
5) Shifrin, AL., Xenachis, C., Fay, A., Matulewicz, T., Y.-H. Kuo, Vernick, JJ, “One hundred and seven family members with the rearranged during transfection V804M proto-oncogene mutation presenting with simultaneous medullary and papillary thyroid carcinomas, rare primary hyperparathyroidism, and no pheochromocytomas: Is this a new syndrome-MEN 2C?” Surgery. 2009, Dec 146(6):998-1005
6) Shifrin, AL., Xenachis, C., Fay, A., Matulewicz, T., Y.-H. Kuo, Vernick, JJ. The First Letter to the Editos: “One hundred and seven family members with the rearranged during transfection V804M proto-oncogene mutation presenting with simultaneous medullary and papillary thyroid carcinomas, rare primary hyperparathyroidism, and no pheochromocytomas: Is this a new syndrome-MEN 2C?” Surgery., 2010 Jun; 147(6):896-898.
7) Shifrin, AL., Xenachis, C., Fay, A., Vernick, JJ.. The Second Letter to the Editor: “One hundred and seven family members with the rearranged during transfection V804M proto-oncogene mutation presenting with simultaneous medullary and papillary thyroid carcinomas, rare primary hyperparathyroidism, and no pheochromocytomas: Is this a new syndrome-MEN 2C?” Surgery. 2010 Sep;148(3):611-2.
8) Shifrin, AL, Ogilvie J, Stang, M, Xenachis, C., Fay, A., Matulewicz, T., Y.-H. Kuo, Vernick, JJ. “Single nucleotide polymorphisms act as modifiers and correlate with the development of medullary and simultaneous medullary/papillary thyroid carcinomas in two large, non-related families with the RET V804M proto-oncogene mutation”. Surgery. 2010 Dec;148(6):1274-81.
9) A. Shifrin, A. Fay, J. Ogilvie, Y-H Kuo.Title: Letter to the Editor. Response to "Single nucleotide polymorphisms and development of hereditary medullary thyroid cancer in V804M RET families: Disease modification or linkage disequilibrium?" Surgery. 2012 Jun;151(6):902-3.