My, How Things Have Changed in Multiple Endocrine Neoplasia Type 2A!

Abstract

The history of medullary thyroid carcinoma (MTC) has been characterized by several distinct phases. The initial descriptive phase originated with the 1961 report from John Sipple describing the association of thyroid carcinoma and pheochromocytoma (1). Subsequent investigators correctly identified the thyroid malignancy as MTC, showed that the tumor produced the newly discovered hormone calcitonin, and further categorized this syndrome into its two major subtypes—multiple endocrine neoplasia (MEN) types 2A and 2B (2–4). The second phase began in the late 1960s with the use of serum calcitonin measurements to identify MTC and successful treatment of the malignancy by total thyroidectomy and lymph node dissection. In the 1970s and 1980s, investigators questioned whether MTC could be identified in children at risk for inheriting the disease through the use of provocative calcitonin testing and treatment by early thyroidectomy (5, 6). These studies identified well-defined kindreds with MEN2, an essential resource for the genetic linkage analysis to map the causative gene. The third phase began in 1993 with the identification of RET proto-oncogenemutations inMEN2and theuseof this information to identify affected children (7, 8). The fourth phase began in 2002 with the recognition that small organic molecules that inhibit phosphorylation of RET (and other kinase receptors) have therapeutic efficacy for treatment of metastatic MTC (9), leading to recent Food and Drug Administration approval of two agents for this purpose (10, 11). Machens and Dralle (12), in their insightful report published in this issue, summarize their substantial lifetime contributions to this field and, through their experience, chronicle the changes that have occurred over the past 50 years. Perhaps the most significant observation made by the authors in their report has been the impact of early thyroidectomy on the presence of disease and identifiable metastasis, assessed by histological evaluation of the thyroid gland and lymph nodes removed for treatment of MTC. For those non-index patients with American Thyroid Association (ATA)-labeled level C (high-risk) mutations (13), the percentage with MTC found in the thyroid gland at thyroidectomy has fallen from 100% in the 1985–1989 period to 19% in the 2010–2014 period. This dramatic decrease was caused initially by provocative testing that lowered the age of thyroidectomy to an average of 13 years, with a drop from 100% MTC to approximately 50% in the series of cases that encompassed the period from 1971–1988 (6). The decline was further accelerated by the rapid adoption of genetic testing and the acceptance of the recommendation that children with level C mutations undergo thyroidectomy by age 5 or 6 years. Interestingly, there has not been a comparable decline in the MTC or node positivity in the level A or B mutations, a point to which we will return later. Another important observation, highlighted by their data, is the shift in frequency of specific mutations over the past 20 years. In the classic report by Eng et al (14) in 1996, approximately 80% of mutations identified in MEN2 occurred at codon 634 of the RET proto-oncogene (Figure 1). Sipple’s syndrome, or classic MEN2A, the association of MTC, pheochromocytoma, and hyperparathyroidism caused most commonly by a codon 634 RET mutation, came to attention in 1961 (1) because it is a “noisy” syndrome with as many patients initially identified based on the presence of hypercalcemia or pheochromocytoma as MTC, facilitating its identification in the pregenetic era. Subsequent reports by Yip et al (15) in 2003 and Frank-