Age and MEN2 outcome

Abstract

genetic tumor syndrome due to mutations of the protooncogene RET [1]. Medullary thyroid cancer (MTC) is the most common feature of MEN2. MEN2 is divided into 2 different entities: MEN2A and MEN2B, the latter including the most aggressive form of MTC: with the earliest age of lymph node metastasis and systemic metastases for MEN2B reported as 1 and 6 years, respectively, due to the presence of the p.M918T RET mutation (which accounts for 95% of all cases of MEN2B) [2]. MEN2A includes high and moderate risks of MTC aggressiveness, leading to a more or less delayed appearance of lymph node and systemic metastases in comparison with MEN2B. To avoid the risk of metastases, the American Thyroid Association has recommended different ages for performing thyroidectomy, based on the RET mutation [3]. For example, patients with MEN2B should be operated before the age of 1 year, while patients with high risk MEN2A should be operated before the age of 5 years. In MEN2, the age at diagnosis of MTC appears to be crucial in defining the chance of remission. In addition to the age at diagnosis, the mutation of RET classically defines the aggressiveness of MTC. For instance, high risk MEN2A-MTC is suggested to be intrinsically more aggressive than moderate risk MEN2A-MTC. However, this hypothesis has recently been challenged: when taking into account the followup from the age at diagnosis and not the overall age at last follow-up, both survival and the risk of distant metastases were not significantly different between high and moderate risk MEN2A MTC. Age at diagnosis was thus considered as the most important marker of MTC outcome in MEN2A, emphasizing the need to perform early thyroidectomies [4]. This point had not previously been evaluated in a large cohort of MEN2B patients. Our large international multicentric study based on 345 patients confirmed that MTC was indeed diagnosed at an earlier age in MEN2B than in MEN2A: however, overall survival was much lower in MEN2B than in MEN2A, when comparing MEN2B and MEN2A patients from their age at diagnosis, suggesting that the p.M918T mutation was per se a strong marker of MTC aggressiveness. This was not surprising since the somatic p.M918T mutation was also found in aggressive forms of non-hereditary MTC, suggesting that this mutaEditorial