Cmar_a_194344 7845..7855

Francesca Galuppini Matteo Fassan Loris Bertazza Susi Barollo Luciano Cascione Sara WatutantrigeFernando Vanni Lazzarin Paolo Simonato Federica Vianello Massimo Rugge Caterina Mian Gianmaria Pennelli 1Pathology Unit, Department of Medicine (DIMED), University of Padova, Padova 35121, Italy; 2Endocrinology Unit, Department of Medicine (DIMED), University of Padova, Padova 35121, Italy; 3Università Della Svizzera Italiana, Institute of Oncology Research and Swiss Institute of Bioinformatics, Bellinzona 6500, Switzerland; 4Department of Radiotherapy, Istituto Oncologico del Veneto, Padova 35128, Italy Background: The primary goal of papillary thyroid cancer (PTC) management was to stratify patients at preand post-surgical level to identify the small proportion of cases with potentially aggressive disease. Purpose: The aim of our study is to evaluate the possible role of programmed cell death 4 (PDCD4) and BRAF status as prognostic markers in PTC. Patients and methods: We investigate programmed cell death 4 (PDCD4) immunohistochemical expression in 125 consecutive PTCs with median follow-up of 75.3 months (range, 15–98 months) to verify the possible correlation between BRAF status and correlate the classical clinicopathological prognostic factors and PTC outcome with PDCD4 expression. To further support the data, miR-21 expression was tested (by quantitative real-time PCR and in situ hybridization) in a different series of 30 cases (15 PTCs BRAFwt and 15 PTCs BRAFV600E). Moreover, we validated our results using TGCA thyroid carcinoma dataset. Results: We found that 59.8% of the patients showed low-grade PDCD4 nuclear expression and low-grade expression correlated with BRAF V600E. Compared with BRAF 15 wild-type tissue samples, a significant miR-21 up-regulation was associated with BRAF V600E mutations. Lowgrade PDCD4 resulted, and was associated with aggressive histological variants, higher cancer size, extra-thyroidal extension, multifocality, lymph-node metastasis and lymph nodal ratio at the diagnosis. Concerning the outcome, the low-grade PDCD4 expression correlated at univariate and multivariate analysis, with lower levels of recurrence-free survival rate (RFS) and with poor outcome. Moreover, there was significant association between BRAF V600E patients with PDCD4 nuclear loss and lower RFS, whilet here was significant association between BRAF wild-type patients with PDCD4 nuclear expression and better outcome. Conclusion: These results showed that PDCD4 could predict PTC outcome and that the sum of PDCD4 and BRAF alterations increases the prognostic power of BRAF mutation alone.