Caratteristiche clinico molecolari dei carcinomi tiroidei differenziati ad alto rischio

Background: Differentiated thyroid carcinoma (DTC) is the most common endocrine malignancy, and its incidence is rapidly increasing. Its prognosis is usually excellent, but some patients exhibit an aggressive tumor with poor clinical outcome. The clinical-molecular features that confer an aggressive phenotype in DTC are object of various studies, being the clinical significance of some of them still uncertain. A greater knowledge of clinical, pathological and molecular features of DTC might improve the diagnostic frame and lead to an individualized therapy. The objectives of the study: 1) clinical characterization of high-risk DTC cases; 2) molecular characterization with reference on the study of BRAF, RAS, TP53, PTEN and PIK3CA genes and TERT promoter; 3) correlation between clinical and molecular features; 4) comparison of clinical-molecular profile between high- and low risk DTC. Materials and methods: We studied 119 high-risk patients (max dimension >40mm and/or metastatic) who underwent surgery for diagnosis of DTC between 2007 and 2016. Clinical-molecular features of these patients were compared with those of 144 adult patients, consecutive for molecular study, who underwent surgery for diagnosis of DTC between 2007 and 2010. Results: subjects with metastatic tumor or both metastatic and tumor size larger than 40mm had worse outcome than subjects with tumor larger than 40mm: during the follow-up they had a persistent disease or were dead in 62% and 79% of cases respect to 13% of the latter (p<0,01), they were also more likely to undergo a second treatment (67% and 86% respect to 8%, p<0,01) and had a reduced Disease-Free Survival (DFS) (p<0,01). Among patients with high-risk tumors, we detected BRAF mutations in 26% of cases, RAS mutations in 10% of cases, TERT promoter mutations in 18% of cases, TP53 mutations in 1% of cases, PTEN mutations in 2% of cases, PIK3CA in 3% of cases. No link was found between these mutations and outcome, except for TERT promoter mutations that were linked to a more severe disease. Metastatic subjects had a higher prealence of TERT promoter mutations than subjects with larger size tumors (27% vs 11%, p<0,01). Patients with high-risk cancer had worse clinical-pathological features than low-risk patients, except for the rate of multifocal disease. Regarding the outcome, high-risk patients had poorer clinical outcome, were more likely to have second treatment and had reduced DFS. BRAF gene mutations were more often found in low-risk carcinomas respect to the high-risk ones (61% vs 26%, p40mm, so that TERT mutations (18% vs 3%, p<0,01), particularly among metastatic subjects. Globally, TERT promoter mutations, even in association with other molecular events, are related to older age (67 years vs 47 years, p<0,01), larger tumor size (43mm vs 17mm, p<0,01), tumor extension (T4: 11% vs 4%, p<0,01), distant metastases (56% vs 18%, p<0,01), advanced stage (stage IV: 41% vs 11%, p<0,01), need for a second treatment (27% vs 17%, p<0,01) and worse outcome (persistence/death 69% vs 18%, p