Update on Multiple Endocrine Neoplasia Type 2: Focus on Medullary Thyroid Carcinoma

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant hereditary cancer syndrome caused by missense gain-of-function mutations in the RET proto-oncogene on chromosome 10. Specific RET mutations can predispose toward a particular phenotype and clinical course, with strong genotype–phenotype correlations. MEN2 is highly penetrant in medullary thyroid carcinoma (MTC), and it can be associated with bilateral pheochromocytoma and primary hyperparathyroidism. Two different clinical variants of MEN2 are known: MEN2A, which includes the familial subtype, and MEN2B. Treatment includes early thyroidectomy. Recommendations on the timing and extent of surgery are based on the RET mutation risk categories (moderate-, high-, or highest-risk) regarding the age of MTC onset. Early identification of patients with hereditary MTC has improved treatment outcomes. Previously, MTC was diagnosed based on clinical tumors; in contrast, with genetic screening, MTC can be diagnosed at preclinical disease states. This approach has resulted in a high cure rate and a much better prognosis for MTC. However, classification into one of the three RET mutation risk groups for predicting aggressiveness and prognosis has had limited impact. Increasing evidence has shown that patients with RET mutations in different risk classifications exhibit a broad spectrum of MTC aggressiveness during follow-up, with no relevant difference in survival. The specific germline activating mutation of the RET proto-oncogene appears to be the first determinant of the age of MTC onset, but, presumably, different regulatory events determine long-term tumor behavior.