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BACKGROUND

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Medullary thyroid cancer (MTC) is a well-differentiated neuroendocrine tumor arising from the calcitonin-producing parafollicular cells, also known as C cells. C cells are derived from neural crest cells that form the ultimobranchial bodies of the fourth and fifth branchial pouches. During thyrogenesis, the ultimobranchial bodies fuse with the thyroid laterally and as a result, C cells are concentrated in the upper poles of the thyroid. In addition to calcitonin, MTC may secrete carcinoembryonic antigen (CEA), adrenocorticotrophic hormone (ACTH), and occasionally somatostatin. Symptoms related to hormone hypersecretion such as diarrhea, flushing, or Cushing’s syndrome may be the presenting manifestation and are usually representative of advanced disease.

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Medullary thyroid cancer accounts for 3% to 4% of all thyroid cancers, and up to 13% to 14% of thyroid cancer-related deaths. Unlike differentiated thyroid carcinoma (DTC) of follicular-cell origin, the incidence of MTC has been stable despite improvements in diagnostic and genetic tests.1 MTC can be hereditary and part of the multiple endocrine neoplasia type 2 (MEN2) or familial MTC (FMTC) syndrome in 20% to 25% of cases, but is more often sporadic (75% to 80%). Overall 10-year survival for MTC patients is 75%, and poor prognostic variables include older age (>65 years) and advanced American Joint Committee on Cancer (AJCC) stage at presentation.1,2

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The diagnosis of sporadic MTC usually occurs during routine evaluation of a solitary thyroid nodule, and the incidence of MTC in nodular thyroid disease ranges from 0.3% to 1%. The mean age at diagnosis is 50 years, and although thyroid nodules are more frequent in women, sporadic MTC is diagnosed in both genders with equal frequency.1 There are no known risk factors for the development of MTC except for a family history of MEN2 or MTC.3

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MEN2 was initially described by Dr Sipple in 1961 when he identified an association between thyroid cancer and pheochromocytoma (Pheo). Seven years later, Steiner et al4 recognized primary hyperparathyroidism (PHP) as an additional manifestation, and labelled the constellation of endocrinopathies as multiple endocrine neoplasia 2. MEN2 is inherited in an autosomal dominant pattern, and is composed of three clinical variants: MEN2A, MEN2B, and FMTC (Table 34-1).3,5 In addition to MTC, Pheo, and PHP, MEN2A is also characterized by Hirshsprung’s disease and cutaneous lichen amyloidosis. The clinical manifestations of MEN2B are different from MEN2A, and include MTC, Pheo, musculoskeletal abnormities such as marfanoid habitus, mucosal neuromas that affect the lips, tongue, and conjunctivae, and ganglioneuromas of the urinary and intestinal tracts. The diagnosis of FMTC requires MTC in at least four multigenerational family members without PHP or Pheo. In MEN2A/2B, the penetrance of MTC is nearly 95%, but may be lower in FMTC kindreds. All hereditary MTC variants are caused by germline mutations in the RET proto-oncogene.6

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Table Graphic Jump Location
TABLE 34-1:

Manifestations Associated with Inherited MTC Syndromes3,5

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