Preoperative serum inflammation-based scores in medullary thyroid cancer.

INTRODUCTION: Neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII) are prognostic factors in several tumours, though little is known in medullary thyroid cancer (MTC). OBJECTIVE: To evaluate the association between preoperative NLR, PLR and SII with MTC clinicopathological and molecular features, and their predictive value for lymph node and distant metastasis. METHODS: We retrospectively analysed 75 patients with MTC who underwent surgery at our institution. The familial form of MTC was found in 12% of patients. RESULTS: In our cohort, 56% were females, the median age at diagnosis was 57 years (44-69), the median tumour diameter was 25mm (15-50); 21.3% were multifocal and 34.7% had extrathyroidal extension. Lymph node and distant metastasis were observed in 36 (48.0%) and 8 (10.7%) patients, respectively. Higher NLR was associated with preoperative calcitonin, angioinvasion, extrathyroidal extension, moderate/severe fibrosis; higher PLR was associated with extrathyroidal extension and advanced T stages; lower SII and NLR were associated with biochemical cure after surgery. Increased PLR, NLR and SII were associated with advanced MTC stages. In the univariate analysis, only NLR was associated with lymph node metastasis (odds ratio (OR)=2.69, 95% confidence interval (CI): 1.50-5.84; p=0.004); however, in the multivariate model, NLR was no longer a predictive factor for lymph node metastasis. None of these serum inflammatory markers predicted the occurrence of distant metastasis. CONCLUSION: In conclusion, NLR, PLR and SII are associated with aggressive MTC, but do not predict lymph node or distant metastasis.

Cell cycle deregulation and TP53 and RAS mutations are major events in poorly differentiated and undifferentiated thyroid carcinomas.

BACKGROUND: Anaplastic thyroid carcinomas (ATCs) are among the most lethal malignancies, for which there is no effective treatment. OBJECTIVE: In the present study, we aimed to elucidate the molecular alterations contributing to ATC development and to identify novel therapeutic targets. DESIGN: We profiled the global gene expression of five ATCs and validated differentially expressed genes by quantitative RT-PCR in an independent set of tumors. In a series of 26 ATCs, we searched for pathogenic alterations in genes involved in the most deregulated cellular processes, including the hot spot regions of RAS, BRAF, TP53, CTNNB1 (ß-catenin), and PIK3CA genes, and, for the first time, a comprehensive analysis of components involved in the cell cycle [cyclin-dependent kinase (CDK) inhibitors (CDKI): CDKN1A (p21(CIP1)); CDKN1B (p27(KIP1)); CDKN2A (p14(ARF), p16(INK4A)); CDKN2B (p15(INK4B)); CDKN2C (p18(INK4C))], cell adhesion (AXIN1), and proliferation (PTEN). Mutational analysis was also performed in 22 poorly differentiated thyroid carcinomas (PDTCs). RESULTS: Expression profiling revealed that ATCs were characterized by the underexpression of epithelial components and the up regulation of mesenchymal markers and genes from TGF-ß pathway, as well as, the overexpression of cell cycle-related genes. In accordance, the up regulation of the SNAI2 gene, a TGF-ß-responsive mesenchymal factor, was validated. CDKN3, which prevents the G1/S transition, was significantly up regulated in ATCs and PDTCs and aberrantly spliced in ATCs. Mutational analysis showed that most mutations were present in TP53 (42% of ATCs; 27% of PDTCs) or RAS (31% of ATCs; 18% of PDTCs). TP53 and RAS alterations showed evidence of mutual exclusivity (P = .0354). PIK3CA, PTEN, and CDKI mutations were present in 14%-20% of PDTCs, and in 10%-14% of ATCs. BRAF, CTNNB1, and AXIN1 mutations were rarely detected. CONCLUSION: Overall, this study identified crucial roles for TP53, RAS, CDKI, and TGF-ß pathway, which may represent feasible therapeutic targets for ATC and PDTC treatment.