Hereditary Medullary Thyroid Carcinoma (MTC)

MTC
  • Hereditary MTC:
    • Is unique in many ways among inherited cancer syndromes:
      • MTC is founded on the following findings:
        • The hereditary variant:
          • Affecting as many as 25% of MTC patients:
            • Is more frequent than many other common hereditary tumors.
        • Unlike many other hereditary tumors:
          • Hereditary MTC features a strong genotype-phenotype correlation:
            • That is utilized worldwide for risk assessment
            • This genotype-dependent, age-related tumor progression:
              • Not only underlies the development of:
                • Hereditary MTC
                • But also the formation of:
                  • MEN 2–associated pheochromocytoma and hyperparathyroidism (HPT).
      • Disease progression from C-cell hyperplasia to MTC:
        • Requiring the acquisition of somatic mutations for malignant progression:
          • Is a stochastic sequence of events not fully under the control of a gene carrier’s genetic makeup.
      • Serum calcitonin:
        • A sensitive diagnostic marker of MTC, better reflects a gene carrier’s stage of C-cell disease than his or her underlying germline mutation in the RET (REarranged during Transfection) proto-oncogene:
          • We may now tailor the timing and extent of surgical intervention in the neck to the gene carrier’s stage of disease through consideration of serum calcitonin levels.
      • Lymph node metastases are indicative of progressive disease:
        • Portending a worse prognosis for sporadic and hereditary MTC alike.
      • Although multifocal tumor growth:
        • More common in hereditary than sporadic MTC:
          • 65% versus 8%:
            • No difference in biochemical cure and survival between hereditary and sporadic disease has been found after adjusting for extent of disease.
      • MEN 2B is a special and virulent variant of MEN type 2:
        • Characterized by the presence of MTC in early infancy.
        • More than 90% of MEN 2B RET gene carriers:
          • Harbor de novo germline mutations.
          • Such de novo germline mutations are rare in other MTC syndromic settings such as familial MTC (FMTC) and MEN 2A.
          • DNA-based screening of families for the MEN 2B trait for early detection of hereditary MTC hence is rarely an option.
          • Intriguingly, there are some early clues in MEN 2B infants:
            • Notably tearless crying and pseudo-Hirschsprung’s disease:
              • These clinical signs may help identify gene carriers before they develop the more characteristic MEN 2B stigmata