Anatomic Pathology: Molecular Pathology Diagnostics

• Activating mutations of the RET proto-oncogene are seen in multiple endocrine neoplasia 2A (MEN2A; medullary thyroid carcinoma [MTC], pheochromocytoma and parathyroid hyperplasia), familial medullary thyroid carcinoma (FMTC) and MEN2B (MTC, pheochromocytoma, intestinal ganglioneuromatosis, and marfanoid habitus).

• Most mutations occur in one of eight codons in exons encoding the extracellular cysteine-rich domain of the protein, causing ligand-independent constitutive activation of the tyrosine kinase. More than 80% to 90% of mutations in MEN2A are seen in codon 634. Mutations in the intracellular tyrosine kinase domain account for a smaller number of cases, including most cases of MEN2B.

• Survival in this condition is affected most by MTC, and prophylactic thryroidectomy significantly improves survival in germ line RET mutation carriers. Testing of apparently sporadic cases of MTC has shown germ line mutations in 5% to 10% of cases in different populations, with an increased frequency among younger patients.

• Therefore, testing may uncover FMTC, offering family members the opportunity for presymptomatic testing and potentially life-saving prophylactic thyroidectomy.

• In addition, approximately 25% to 50% of cases of sporadic MTC harbor somatic activating RET mutations, with an increased risk of recurrence.

• Tyrosine kinase inhibitors (TKIs) may be used as targeted therapy for Medullary Thyroid Carcinoma. These include vandetanib, cabozantinib, sorafenib, sunitinib, and motesanib. Vandetanib has been approved for treatment of MTC. Specific mutants, such as those involving the gatekeeper residue V804 (V804M/L mutants) tend to be insensitive to vandetanib.

Pusztaszeri MP, Bongiovanni M, Faquin WC: Update on the cytologic and molecular features of medullary thyroid carcinoma.Adv Anat Pathol 2014;21:31–40

Takami H: Medullary thyroid carcinoma and multiple endocrine neoplasia type 2. Endocr Pathol 2003;14:123–131.

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