The 2023 Bethesda system is associated with aggressive features and histologic subtype in thyroid cancer

The Bethesda System for Reporting Thyroid Cytopathology (TBS) is the standard framework for interpreting fine-needle aspiration (FNA) specimens. While primarily designed to estimate malignancy risk, whether TBS categories are associated with histologic subtype and tumor aggressiveness remains unclear. We aimed to investigate associations between TBS categories and histologic subtype, molecular alterations, and aggressive pathologic features of thyroid cancer. We conducted a retrospective study of 8595 patients who underwent ultrasound-guided thyroid FNA between January 2016 and February 2025 at Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University. Clinicopathologic characteristics, ultrasonographic features, cytologic diagnoses, molecular testing results, and final histologic outcomes were collected. FNA results were classified according to the 2023 Bethesda System and correlated with aggressive pathologic characteristics, histologic subtypes, and molecular alterations. Of 8595 FNAs, 2960 patients underwent thyroidectomy and were included in histopathologic analysis. TBS distribution was: nondiagnostic (TBS I) 3.5%, benign (TBS II) 60.2%, AUS (TBS III) 8.3%, FN (TBS IV) 3.7%, SM (TBS V) 1.9%, and malignant (TBS VI) 22.4%. Malignancy rates increased stepwise from TBS III (39.7%) to TBS IV (47.6%) to TBS V (78.0%) and TBS VI (99.2%). Higher Bethesda categories were significantly associated with malignant ultrasound features, aggressive histologic subtypes, and adverse pathologic characteristics, including extrathyroidal extension, multifocality, lymphovascular invasion, and lymph node metastasis ( p < 0.05). Classic variant papillary thyroid carcinoma accounted for 70.9% of TBS VI compared with 25.0% of TBS III, 14.4% of TBS IV, and 10.9% of TBS V cases ( p < 0.0001). BRAF V600E mutation frequency increased from 43.4% (TBS III) to 56.9% (TBS V), while high-risk alterations (TERT, TP53, PIK3CA) were predominantly observed in TBS V. Beyond malignancy risk estimation, the 2023 Bethesda System is associated with histologic subtype, molecular alterations, and aggressive pathologic features of thyroid cancer. These findings expand the clinical utility of TBS and support its role in preoperative risk stratification.