Combined RET and Ki-67 assessment in sporadic medullary thyroid carcinoma: a useful tool for patient risk stratification

Objective: Medullary thyroid carcinoma (MTC) derives from the parafollicular C cells, being sporadic in 75% of cases and familial in 25%, due to RET proto-oncogene germinal mutations. In sporadic forms, stage at diagnosis is the most important negative prognostic factor. The aim of this study was to evaluate the prognostic impact of molecular and immunohistochemical markers in sporadic MTC. Design and methods: We studied 60 patients with sporadic MTC. For each case, we sought RET somatic mutations in the primary cancer and in lymph node metastases. The primary cancer also underwent immunohistochemical examination for Ki-67. Results: A somatic RET mutation was found in 38% of patients, being M918T in 52% of them. We observed a statistically significant association between RET mutations and male gender (P < 0.01), tumor size (P < 0.05), lymph nodes (P < 0.05) and distant metastases (P < 0.001), advanced stage (P < 0.05), increased risk of persistent disease (P=0.01), and low overall survival (P < 0.01). High Ki-67 levels were similarly associated with extra-thyroid spread (P < 0.05), lymph nodes (P < 0.05) and distant metastases (P < 0.001), advanced stage (P=0.01), and low overall survival (P=0.01). Combining somatic RET analysis with Ki-67 assessment seems to be useful for increasing the specificity of Ki-67 assessment alone and identifying patients with a more aggressive cancer: in our series, only the patients who died during the follow-up had both a somatic RET mutation and a Ki-67 expression level > 50 cells/mm(2). Conclusions: The combined evaluation of RET and Ki-67 could act as an adjuvant prognostic marker useful for ameliorating the initial risk stratification of patients with sporadic MTC.