Introduction

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominantly inherited disorder characterized by medullary thyroid carcinoma (MTC), pheochromocytoma (PC), and primary parathyroid hyperplasia (PPH). While the penetrance of MTC is nearly 100%, there is much inter- and intra-family variability in the other clinical manifestations of this disorder. An MEN2 syndrome is often first suspected when a patient is found to have one or more of these tumors and especially at a young age. MEN2 is subclassified into three distinct syndromes: MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC). Although these syndromes are rare, early identification enables adequate treatment and evaluation of family members. Because the predisposing gene is known (the RET proto-oncogene), molecular testing by DNA mutation analysis is now available for detecting pre-symptomatic patients with MEN2. Early detection and treatment improves life expectancy and quality of life.

Medullary thyroid carcinoma (MTC)

MTC is a neuroendocrine tumor of the parafollicular or C-cells of the thyroid gland, accounting for approximately 3 to 5% of all thyroid carcinomas. C-cells are neuroendocrine cells derived from the ultimobranchial bodies (transient embryonic structures), which fuse with the posterior lobes of the thyroid; C-cells make up only about 0.1% of the thyroid mass. Multi-centric hyperplasia of the parafollicular C-cells is the hallmark of MEN2, with a penetrance approaching 100%. C-cell hyperplasia (CCH) clearly is a precursor lesion of MTC (see Figure 66.1). Nearly all MEN2 patients develop clinically apparent MTC, often early in life (1). A characteristic feature of thyroid C-cells and MTC is the production of the blood calcium-lowering peptide hormone calcitonin (2–4). The diagnoses of CCH and MTC are based upon microscopy criteria (histopathology, see Figure 66.1; 5). Neoplastic CCH and MTC in MEN2 are caused by a germline mutation in the RET proto-oncogene; MTCs in MEN2 patients are multi-centric and concentrated in the upper third of the thyroid gland (see Figure 66.2), reflecting the normal distribution of parafollicular thyroid C-cells.