Familial Medullary Thyroid Cancer Syndromes: MEN 2A, MEN 2B, FMTC

MEDULLARY THYROID CARCINOMA (MTC) is a highly aggressive malignant neoplasm of the thyroid gland that arises from the thyroid C cell and occurs either sporadically or as a part of the inherited autosomal dominant multiple endocrine neoplasia (MEN) type 2A (MEN 2A), and MEN type 2B (MEN 2B), and familial medullary thyroid carcinoma (FMTC) syndromes. Classic MEN 2A syndrome consists of MTC in up to 90% of the patients, pheochromocytoma in 57%, and primary hyperparathyroidism (PHPT) in 15% to 30% of patients. MEN 2B consists of MTC, pheochromocytoma, a marfanoid habitus, and ganglioneuromas of the intestinal tract mucosa.

The Familial Medullary Thyroid Carcinoma subtype comprises approximately 10–20% of cases of MEN 2. Familial Medullary Thyroid Carcinoma is typically viewed as a variant of MEN 2A. Familial Medullary Thyroid Carcinoma is diagnosed in families with four or more cases of MTC in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia, or with RET proto-oncogen testing in the blood.

MEN 2A, MEN 2B and Familial Medullary Thyroid Carcinoma syndromes develop as result of a missense mutation in the REarranged during Transfection (RET) proto-oncogene, which encodes for a tyrosine kinase receptor. This mutation results in the development of C-cell hyperplasia (CCH), which then progresses to invasive MTC. RET mutations were classified based on risk for aggressive MTC at the Seventh International Workshop on MEN.3 More recently, the American Thyroid Association (ATA) stratified RET mutations into 1 of 4 risk levels (A--D), in which level D mutations carry the greatest risk.

The American Thyroid Association Guidelines Task Force has classified RET mutations based on their risk for aggressive MTC. The classification may be used in predicting phenotype and recommendations for age at which to perform prophylactic thyroidectomy and to begin biochemical screening for pheochromocytoma and hyperparathyroidism.

Prophylactic thyroidectomy is the primary preventive measure for individuals with an identified germline RET mutation. According to the consensus statement from the American Thyroid Association Guidelines Task Force, the age at which prophylactic thyroidectomy is performed can be guided by the codon position of the RET mutation. Thyroidectomy for CCH, before progression to invasive MTC, may allow surgery to be limited to thyroidectomy with sparing of lymph nodes

For all individuals with a RET mutation who have not had a thyroidectomy, annual biochemical screening is recommended with immediate thyroidectomy if results are abnormal. Annual serum calcitonin screening should begin for children with MEN 2B at age 6 months and at age 3–5 years for those with MEN 2A or Familial Medullary Thyroid Carcinoma.

Approximately 50% of individuals diagnosed with MTC who have undergone total thyroidectomy and neck nodal dissections have recurrent disease.

Genetic counseling must be done for any patient with RET mutation.

References:

1) Eng C, Clayton D, Schuffenecker I, Lenoir G, Cote G, Gagel RF, et al. The relationship between specific RET protooncogene mutations and disease phenotype in multiple endocrine neoplasia type 2. International RET mutation consortium analysis. JAMA 1996;276:1575-9.

2) American Thyroid Association Guidelines Task Force, Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid 2009;19:565-612.

3) Response to "Single nucleotide polymorphisms and development of hereditary medullary thyroid cancer in V804M RET families: disease modification or linkage disequilibrium?". Shifrin AL, Fay A, Kuo YH, Ogilvie J. Surgery. 2012 Jun;151(6):902-3.

4) Single nucleotide polymorphisms act as modifiers and correlate with the development of medullary and simultaneous medullary/papillary thyroid carcinomas in 2 large, non-related families with the RET V804M proto-oncogene mutation. Shifrin AL, Ogilvie JB, Stang MT, Fay AM, Kuo YH, Matulewicz T, Xenachis CZ, Vernick JJ. Surgery. 2010 Dec;148(6):1274-80;

5) One hundred and seven member family 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? Shifrin AL, Fay AM, Xenachis CZ, Vernick JJ. Surgery. 2010 Sep;148(3):611-2.

6) 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? Shifrin AL, Xenachis C, Fay A, Matulewicz TJ, Kuo YH, Vernick JJ. Surgery. 2009 Dec;146(6):998-1005.

7) Jessica Moline and Charis Eng, Multiple endocrine neoplasia type 2: An overview. Genet Med 2011:13(9):755–764