Medullary thyroid carcinoma (MTC) is uncommon and accounts for only 5% of all thyroid cancers. MTC was first described in 1959 as a "peculiar" thyroid cancer with nonfollicular histology, amyloid-containing stroma, and a high incidence of lymph node metastases.1 MTC arises from the parafollicular, or calcitonin-secreting, C cells of the thyroid gland. C cells are neural crest cells that are derived embryologically from the ultimobranchial bodies and migrate to the thyroid gland. They are found throughout the thyroid but often concentrate in the uppermost third of the thyroid lobes; therefore, MTC usually originates in this region2 (Figure 6-1).
Photograph of resected thyroid showing medullary thyroid carcinoma (MTC) posteriorly in the uppermost third of both thyroid lobes.
Approximately 25% of patients with MTC have the hereditary form of the disease, which results from germline activating missense mutations in the RET (REarranged during Transfection) proto-oncogene. The remaining 75% of patients with MTC have the sporadic form; however, somatic missense RET mutations may occur in up to 70% of the tumors in patients with sporadic MTC.3
RET is a 21-exon proto-oncogene located on chromosome 10q11.2. It encodes a receptor tyrosine kinase (RET) that functions as a signal transducer to regulate cell growth and survival.4 Germline RET mutations cause the multiple endocrine neoplasia type 2 (MEN2) syndromes, which are inherited in an autosomal dominant fashion.
There are three recognized subtypes of MEN2 (Table 6-1), all of which are characterized by a very high lifetime risk of MTC. MEN2A, or Sipple's syndrome, is the most common subtype of MEN2 and accounts for 80% to 90% of all cases of hereditary MTC. It is characterized by MTC in more than 90% of patients, pheochromocytoma in about 50% of patients, and hyperparathyroidism in about 20% of patients.5 Rarely, MEN2A may be associated with cutaneous lichen amyloidosis (a pruritic plaque that develops on the skin overlying the scapula on the upper back; Figure 6-2)6 or Hirschsprung disease.7
Table 6-1. Clinical Manifestations of the Hereditary Medullary Thyroid Carcinoma Syndromes ||Download (.pdf)
Table 6-1. Clinical Manifestations of the Hereditary Medullary Thyroid Carcinoma Syndromes
|Primary hyperparathyroidism (20%)|
|Cutaneous lichen amyloidosis (rare)|
|Hirschsprung disease (rare)|
|Physical features (e.g., Marfanoid habitus, mucosal neuromas) Ganglioneuromatosis of the GI tract|
|FMTC||MTC in ≤four family members|
|Documented absence of pheochromocytoma and hyperparathyroidism|
|Adequate family history with long-term follow-up|
Cutaneous lichen amyloidosis in a patient with MEN2A. (Courtesy of Dr. Robert F. Gagel, MD Anderson Cancer Center.)