MEDULLARY THYROID CARCINOMA (MTC)
MTC, which is a carcinoma of the parafollicular C cells, is a proven component cancer of multiple endocrine neoplasia type 2 (MEN 2), caused by germline mutations in the RET proto-oncogene. While C cell hyperplasia was believed to be pathognomonic for MEN 2, once RET was identified as the MEN 2 susceptibility gene, it was discovered that this association no longer holds true, and indeed C cell hyperplasia can be found in truly sporadic MTC (Eng et al. 1995a, b; Marsh et al. 1996b).
The etiology of sporadic MTC is also not well known. Among all presentations of MTC, clinical epidemiological studies have shown that 25 % can be attributable to MEN 2. Occult germline mutations in the RET proto- oncogene can be found in 5–15 % of apparently sporadic MTC, that is, without obvious syndromic features or family history (Blaugrund et al. 1994; Eng et al. 1995a, b; Wohlik et al. 1996; Schuffenecker et al. 1997). Due to these accumulating data, the general recommendations, such as from the American Thyroid Association Management Guidelines, are to offer RET mutation analysis to all presentations of MTC regardless of age, presence of syndromic features, or family history (Kloos et al. 2009).
Somatic RET mutations have been reported to occur in 10–80 % of sporadic MTC (Eng et al. 1994, 1995a, b; Hofstra et al. 1994; Marsh et al. 1996a). The great majority of somatic RET mutations are M918T. Of note, somatic mutations have been found to occur in patches or subpopulations even within a single Tumours (Eng et al. 1996a, b, 1998). Up to 80 % of sporadic MTC harbor at least one subpopulation with somatic M918T mutation (Eng et al. 1996a, b). It remains controversial whether somatic M918T in the primary Tumours portends a poor prognosis. Unfortunately, because some studies have used mixed primary and metastatic Tumours (e.g., Schilling et al. 2001), and because of the presence of subpopulations and the varied mutation detection technologies employed, whether M918T status is associated with prognosis remains unknown. Nonetheless, one well-designed study did not show a difference in clinical outcome with or without somatic M918T (Marsh et al. 1996b). In general, MEN 2-associated MTC do not carry somatic intragenic RET mutation as a second genetic event (Eng et al. 1995a, b). However, there are rare instances of somatic M918T occurring in MEN 2-associated MTC (Marsh et al. 1996a). It is also believed that duplication of the mutated REt allele in MEN 2A-associated MTC may contribute to carcinogenesis (Koch et al. 2001). A recent study of a relatively small series of sporadic MTC found that half of all somatic RET mutation- negative MTC harbored somatic mutations in HRAS, but not in other RAS family members (Moura et al. 2011).