The association between thyroid carcinoma and pheochromocytoma (PHEO) was originally reported by Sipple, and in 1968 named as the multiple endocrine neoplasia type 2 syndrome (MEN 2) associated with medullary thyroid carcinoma (MTC).1-4 In 1975, MEN 2B was recognized with a previously reported characteristic phenotype.5,6
Epidemiology and Genetics
MEN 2 is an autosomal, dominant hereditary syndrome, with a 50% risk for offsprings of a carrier to inherit the syndrome. MEN 2 is present in 25% of MTC patients with prevalence of one per 30, 000 individuals.7-12 The MEN 2 genetic disorder includes MEN 2A, familial medullary thyroid carcinoma (FMTC), and MEN 2B. The MEN 2 gene was in 1987 located to chromosome 10q11.2, and in 1993/1994 the varieties of the syndrome, MEN 2A, FMTC, and MEN 2B, were demonstrated to be due to germline missense mutations in the RET (REarranged during Transfection) protooncogene.7-19 The germline RET gene mutations results in expression of abnormally overactive Ret protein in tissues where it is expressed and leads to the specific hereditary syndromes.7 Somatic RET mutations that occur later in life and are limited to C cells are present in 40% to 50% of sporadic MTCs. Founding de novo mutations arise exclusively from the paternal allele in MEN 2B, and in 10% of MEN 2A cases.20,21 Somatic RET mutations have been present in 40% to 50% of sporadic MTC, and in presence of codon 918 mutations been associated with aggressive tumors.22,23 Somatic RET mutations also occur in sporadic PHEO. Somatic RET rearrangements are seen in papillary thyroid carcinoma in children, who have been offers of radiation exposure.
The RET protooncogene with 21 exons encodes a transmembrane tyrosine kinase receptor (Fig. 48-1). The receptor consists of a transmembrane domain, an extracellular domain with a ligand-binding site, and an intracellular tyrosine kinase (TK) domain, and is expressed mainly in neuronal and neuroepithelial cells of neural crest origin.17,24 Mutation in the intracellular catalytic core (mutation of codon 918) has the highest transforming activity, whereas interference with ATP binding (mutations in codons 768, 790, 791, 804, and 891) has low transforming capacity.17,24 Germline “gain-of-function” mutations activate the RET receptor kinase causing thyroid C-cell hyperplasia (CCH), adrenomedullary hyperplasia, and parathyroid hyperplasia.17,24 Age-related progression from CCH to MTC, and development of PHEO, and primary hyperparathyroidism (PHPT) correlate with the transforming capacity of the different RET mutations, but require additional somatic second hits.7,24 MTC is generally the first neoplastic manifestation because of high susceptibility of C cells to the oncogenic RET activation.7,11
RET gene testing should be done prior to surgery in all patients with diagnosed MTC, since 10% of ...