The 2023 Bethesda System Predicts Aggressive Features and Histologic Subtype in Thyroid Cancer

Background: The Bethesda System for Reporting Thyroid Cytopathology (TBS) is the standard framework for interpreting fine-needle aspiration (FNA) specimens, which includes cytologic definitions, diagnostic criteria, and clinical management guideline for each category. Although primarily designed to estimate malignancy risk, whether TBS categories predict histologic subtype and tumor aggressiveness also remains unclear. Our objective was to determine the histologic type and extent of malignancy in thyroid FNAs to expand the utility of the TBS by providing more prognostic information for clinical practice. Methods: A retrospective study of all thyroid FNA cases between January 2016 and February 2025 was conducted 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 TBS and correlated with ultrasound features, molecular alterations, histologic subtypes, and aggressive pathologic characteristics. Results: A total of 8595 patients underwent ultrasound-guided FNA, and TBS diagnostic categories were as follows: nondiagnostic (TBS I) in 3.5% cases, 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%. Final histology demonstrated stepwise increases in malignancy rates from TBS III (39.7%) and 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). Moreover, the classic variant of PTC was identified in 70.9% with malignant FNA cytology compared with 25.0% with AUS, 14.4% with FN, and 10.9% with SM cytology ( p < 0.0001). Molecular profiling revealed increasing frequencies of BRAF V600E mutations across higher Bethesda categories, while high-risk alterations such as TERT, TP53, and PIK3CA mutations were predominantly observed in TBS V. Conclusion: Beyond malignancy risk estimation, the 2023 Bethesda System provides important prognostic information regarding histologic subtype, molecular alterations, and tumor aggressiveness. These findings expand the clinical utility of TBS and support its role as an integrated diagnostic and prognostic tool in thyroid cancer management.