Medullary carcinoma of the thyroid is an uncommon type of thyroid cancer that arises from the parafollicular or C-cells thyroid, which produces the hormone calcitonin. (Papillary thyroid cancer, arising from the glandular cells, is the most common type of thyroid cancer.) Three distinct but related familial cancer syndromes together are responsible for approximately one-fourth of the incidence of medullary carcinoma of the thyroid; the remaining three-fourths are sporadic. The three inherited syndromes include multiple endocrine neoplasia (MEN) types 2A and 2B and familial medullary thyroid cancer (FMTC). MEN 2A and MEN 2B differ from each other (and from MEN 1) in the spectrum and frequency of accompanying endocrine malignancies and other disorders. In contrast, FMTC is defined as being in a family with the repeated occurrence of medullary thyroid cancer in the absence of other endocrine malignancies or disorders MEN 2A, MEN 2B, and FMTC are all dominantly inherited. Point mutations of the germline RET gene, located on chromosome 10, are associated with inheritance of MEN 2A, MEN 2B, or FMTC.
Medullary thyroid cancer is curable surgically if detected before it has spread to regional lymph nodes. However, lymph node involvement at diagnosis may be found in up to 75% of patients for whom a thyroid nodule is the first sign of disease. Surveillance by annual biochemical monitoring has been used to identify those with the inherited disease before it progresses beyond the earliest stages. The development of invasive medullary thyroid cancer usually is preceded by C-cell hyperplasia, which can be detected by hypersecretion of calcitonin in response to a chemical challenge. Recently, genetic assays for RET mutations have been used as an alternative to annual biochemical testing for C-cell hyperplasia, in patients with a known family history of MEN 2A, 2B, or FMTC. Annual biochemical screening can be stopped in those patients who test negative for mutations. Patients who test positive may undergo immediate thyroidectomy or postpone thyroidectomy until biochemical tests suggest evolving medullary cancer. Genetic assays have also been used to determine if new cases of medullary thyroid cancer without a family history are truly sporadic in origin. A positive test in this setting should initiate evaluation of family members. In addition, a positive test may prompt screening for pheochromocytoma, a component of MEN 2A and 2B, in the affected patient.