CLINICAL STUDY Combined RET and Ki-67 assessment in sporadic medullary thyroid carcinoma: a useful tool for patient risk stratification Caterina Mian 1 , Gianmaria Pennelli 2 , Susi Barollo 3 , Elisabetta Cavedon 1 , Davide Nacamulli 1 , Federica Vianello 3 , Isabella Negro 1 , Giulia Pozza 2 , Isabella Merante Boschin 4 , Maria Rosa Pelizzo 4 , Massimo Rugge 2 , Franco Mantero 1 , Maria Elisa Girelli 1 and Giuseppe Opocher 3 1 Endocrinology Unit, Department of Medical and Surgical Sciences, 2 Pathology Unit, Department of Medical Sciences and Special Therapies, 3 Veneto Institute of Oncology – IRCCS, Padova and 4 Special Surgery Unit, Department of Medical and Surgical Sciences, University of Padova, Via Ospedale n.105, 35128 Padova, Italy (Correspondence should be addressed to C Mian; Email: caterina.mian@unipd.it) Abstract 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 (PZ0.01), 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 (PZ0.01), and low overall survival (PZ0.01). 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 O50 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. European Journal of Endocrinology 164 971–976 Introduction Medullary thyroid carcinoma (MTC) is a rare neuro- endocrine cancer originating from parafollicular C cells producing calcitonin (Ct); it accounts for 5–10% of all thyroid carcinomas. About 75% of MTC are sporadic, whereas the remaining are hereditary due to germinal mutations that activate the RET proto-oncogene (1). Total surgical resection is the only effective therapy for MTC. In a far from negligible number of cases, however, the initial diagnosis occurs late, when the cancer has spread beyond the thyroid bed to loco-regional or even distant sites, so only 50% of cancer patients can achieve a biochemical cure after surgery (2, 3). Age at diagnosis and disease stage at the time of initial treatment currently represent the main prog- nostic indicators (2, 4). Although clinical and pathological variables alone may suffice to predict patient outcome in most cases, the variable behavior of MTC in some cases suggests that, in the same clinical and pathological conditions, cancer progression and survival may also be influenced by other biological elements (5, 6). In times of molecular analysis, various genetic factors have been shown to play a part in the risk stratification of MTC patients (7–9). In particular, somatic RET mutations and/or RET polymorphisms were analyzed in several series of sporadic MTC, and RET status was found to correlate with patient outcome (10–12). Recent reports have demonstrated that somatic RET mutations occur in 30–50% of sporadic cases of MTC, and they are a negative predictor of cancer remission and survival (13–15). Such reports were not always homogeneous in terms of the frequency, type, and site of somatic RET mutations, or their association with clinical and pathological features, suggesting that other European Journal of Endocrinology (2011) 164 971–976 ISSN 0804-4643 q 2011 European Society of Endocrinology DOI: 10.1530/EJE-11-0079 Online version via www.eje-online.org Downloaded from Bioscientifica.com at 05/24/2020 12:49:48AM via free access