Medullary thyroid gland carcinoma arises from dysfunction of calcitonin-producing C-cells in the thyroid gland. The condition is categorized as sporadic in the majority of cases, with familial forms accounting for approximately 10 to 20 percent of all MTC diagnoses. Per expert review, familial cases arise from heritable gain-of-function variants in a cancer predisposition gene that is central to C-cell biology; these familial variants follow an autosomal dominant pattern of transmission. Family members of an affected individual who carry the same heritable variant are considered at substantially elevated risk for MTC development, per expert review. In individuals with familial forms, disease expression is typically bilateral and multifocal, in contrast to the more commonly unifocal presentation of sporadic cases. Per expert review, a somatic variant in the same cancer predisposition gene—occurring in the absence of an inherited germline change—is identified in a substantial proportion of sporadic cases as well, suggesting a shared molecular pathway. Penetrance of heritable variants in familial forms is not complete, and disease expression can vary even within families carrying the same variant, according to expert review. Specific gene identities are not detailed in the known_genes field of this packet.

Diagnosis of medullary thyroid gland carcinoma involves clinical, biochemical, histological, and, where applicable, molecular genetic evaluation. Per expert review, an elevated plasma calcitonin concentration serves as a sensitive and specific marker raising diagnostic suspicion, and provocative testing using intravenous calcium administration may be performed to assess stimulated calcitonin secretory capacity. Histological evaluation remains central to establishing the diagnosis; MTC is characterized histologically by the presence of C-cells extending beyond the basement membrane and infiltrating thyroid follicles. Immunohistochemistry for calcitonin expression is used as a pathologic diagnostic adjunct, per expert review. Per expert review, familial forms may be suspected in individuals presenting with relevant endocrine tumor history or a positive family history, and molecular genetic testing of the relevant cancer predisposition gene is performed in all individuals with a clinical diagnosis—genotype-specific information guides management decisions and enables cascade testing in family members. Calcitonin stimulation testing is used for biochemical surveillance in individuals with known heritable variants who have not undergone prophylactic thyroid surgery, per expert review.

Surgery is the primary and preferred treatment for medullary thyroid gland carcinoma. Per expert review, standard surgical management involves removal of the thyroid gland with concurrent cervical lymph node dissection. For individuals with familial forms who carry an identified heritable variant, prophylactic thyroidectomy prior to the development of invasive carcinoma is a recognized preventive intervention; timing is guided by variant-specific risk stratification, per expert review. External beam radiation therapy or intensity-modulated radiation therapy may be considered for cases with incomplete tumor resection or extrathyroidal extension with positive margins, according to expert review.

Two systemic agents are currently FDA-approved for use in this condition. Selpercatinib (RETEVMO), approved in April 2024, is an FDA-approved option for individuals with this condition. Vandetanib (CAPRELSA), approved in April 2011, is a second FDA-approved systemic agent. Per expert review, multikinase inhibitors and RET-selective inhibitors—including agents in these approved classes—have demonstrated improvement in progression-free survival in some individuals with metastatic or unresectable advanced disease. Consideration of systemic therapy typically occurs in the context of disease that cannot be managed surgically.

Multidisciplinary care involving specialists in endocrinology, endocrine surgery, and medical genetics is described in management literature for this condition, per expert review. Supportive care addressing hypothyroidism following thyroidectomy with thyroid hormone replacement therapy is a standard component of post-surgical management, per expert review.

The prognosis for medullary thyroid gland carcinoma is influenced by the extent of disease at diagnosis, particularly the presence and extent of lymph node metastases, and the presence of distant spread. Per expert review, a substantial proportion of individuals presenting with a palpable thyroid mass or diarrhea already have cervical lymph node metastases at the time of diagnosis, which significantly influences disease course and treatment planning. Among individuals who undergo total thyroidectomy and regional nodal dissection, recurrent disease occurs in a notable proportion, according to expert review. Outcomes depend on tumor stage, the presence of distant metastases to organs such as the liver, lungs, or bone, and individual response to systemic therapy. Advances in targeted systemic treatment approaches have contributed to improved management options for individuals with advanced disease. In familial forms, regular biochemical surveillance through calcitonin and CEA testing enables earlier detection of recurrence and identification of biochemical disease in at-risk family members, per expert review.

Numerous certified active trial records are present for medullary thyroid gland carcinoma, spanning multiple phases and encompassing diverse intervention types including drug therapy, biologic approaches, procedural research, and natural history investigation. Research directions under active evaluation include the clinical application of multikinase inhibitors, targeted molecular agents, immune checkpoint inhibitors, and novel immunologic strategies such as CAR-T cell approaches in this tumor type, with active enrollment occurring across multiple academic and cooperative group settings, per expert review. Natural history characterization studies are also enrolling individuals with this condition to better define disease trajectories across familial and sporadic presentations. Active clinical trials for this condition are listed on ClinicalTrials.gov.