Approach to the Patient: Hereditary Medullary Thyroid Carcinoma.

Abstract

Medullary thyroid carcinoma is a rare neuroendocrine tumor originating from calcitonin-secreting parafollicular C cells of the thyroid gland. Approximately 25% of cases in adults are hereditary medullary thyroid carcinoma (hMTC), arising from activating, germline pathogenic variants in the REarranged during Transfection (RET) proto-oncogene and causing the syndromes multiple endocrine neoplasia (MEN) types 2A and 2B. A paradigmatic feature of MEN2 is its robust genotype-phenotype correlations, which predict the disease spectrum and age of onset of hMTC and other clinical manifestations. Advances in genetic testing and systemic therapies and an improved understanding of the natural course of MEN2 have transformed the clinical presentation of hMTC from advanced-stage disease to early detection in asymptomatic RET pathogenic variant carriers. The management of hMTC has similarly evolved from aggressive, one-size-fits-all surgical approaches to personalized strategies informed by genotype, biochemical markers, and imaging findings. Risk-reducing early thyroidectomy remains the cornerstone of metastatic hMTC prevention, with the timing of surgery tailored to the specific pathogenic variant and clinical context. Additionally, recent advances in targeted systemic therapies offer promising options for patients with recurrent and/or metastatic disease. This "Approach to the Patient" article explores the diagnostic evaluation, surgical decision-making, systemic treatment options, and follow-up of patients with hMTC, emphasizing the critical role of multidisciplinary care in optimizing outcomes for patients and their families.