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Molecular testing has emerged as a pivotal tool for the preoperative assessment of cytologically indeterminate thyroid nodules. In this cross-sectional study, we evaluated the diagnostic utility of a targeted next-generation sequencing (NGS) 4-gene panel, including BRAF^V600E, TERT promoter mutations, RET fusions, and NTRK3 fusion, for enhancing the cytological diagnosis of thyroid nodules prior to surgical intervention. A total of 827 thyroid nodules subjected to fine-needle aspiration and subsequent histopathological confirmation were analyzed, among which 773 (93.5%) were classified as malignant or noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). The observed prevalence of molecular alterations was: BRAF^V600E, 68.3% (526/770); TERT promoter mutations, 10.3% (79/770); RET fusions, 10.3% (79/770); and NTRK3 fusion, 3.9% (30/770). Notably, the 4-gene NGS panel demonstrated brilliant diagnostic performance for indeterminate cytological nodules (Bethesda categories III-V), achieving a sensitivity of 87.9%, specificity of 96.3%, positive predictive value (PPV) of 99.7%, negative predictive value (NPV) of 35.9%, and overall accuracy of 88.2%. These findings indicate that the targeted NGS 4-gene panel provides high diagnostic precision in distinguishing benign from malignant nodules. Its implementation offers a cost-effective, efficient molecular diagnostic strategy that may reduce unnecessary diagnostic procedures and facilitate optimized clinical management.