Background Medullary thyroid carcinoma (MTC) is a well-differentiated thyroid tumor that maintains the typical features of C cells. An advanced stage and the presence of lymph node metastases at diagnosis have been demonstrated to be the most important bad prognostic factors. Somatic RET mutations have been found in 40–50% of MTC. Although a relationship between somatic mutations and bad prognosis has been described, data are controversial and have been carried out in small series with short-term follow-ups. The aim of this study was to verify the prognostic value of somatic RET mutations in a large series of MTC with a long follow-up.

Methods We studied 100 sporadic MTC patients with a 10.2 yrs mean follow-up. RET gene exons 10–11 and 13–16 were analyzed. The correlation between the presence/absence of a somatic RET mutation, clinical/pathological features and outcome of MTC patients was evaluated.

Results A somatic RET mutation was found in 43/100 (43%) sporadic MTC. The most frequent mutation (34/43, 79%) was M918T. RET mutation occurrence was more frequent in larger tumors (p=0.03) and in MTC with node and distant metastases (p<0.0001 and p=0.02, respectively), thus, a significant correlation was found with a more advanced stage at diagnosis (p=0.004). A worse outcome was also significantly correlated with the presence of a somatic RET mutation (p=0.002). Among all prognostic factors found to be correlated with a worse outcome, at multivariate analysis only the advanced stage at diagnosis and the presence of a RET mutation showed an independent correlation (p<0.0001 and p=0.01, respectively). Finally, the survival curves of MTC patients showed a significantly lower percentage of surviving patients in the group with RET mutations (p=0.006).

Conclusions We demonstrated that the presence of a somatic RET mutation correlates with a worse outcome of MTC patients, not only for the highest probability to have persistence of the disease, but also for a lower survival rate in a long-term follow-up. More interestingly, the presence of a somatic RET mutation correlates with the presence of lymph node metastases at diagnosis, which is a known bad prognostic factor for the definitive cure of MTC patients.