Prospective Optimization of Malignancy Risk Prediction in Indeterminate Thyroid Nodules: Diagnostic Synergy of ACR TI-RADS and the 2023 Bethesda System

Abstract

Background: Risk stratification of indeterminate thyroid nodules (Bethesda III-IV) remains difficult and often triggers unnecessary procedures. Ultrasound-based ACR TI-RADS and the 2023 Bethesda System are widely used, but the incremental value of combining them and the role of size thresholds needs prospective validation. Objective: The objective of this study was to prospectively compare the diagnostic performance of ACR TI-RADS and the 2023 Bethesda System, alone and in combination, for predicting malignancy in thyroid nodules, with dedicated analyses of indeterminate lesions (Bethesda categories III-IV), including subtypes of Bethesda III (nuclear atypia vs. other atypia), and the impact of nodule size. Methods: Histopathology was available for 131 nodules. Diagnostic metrics (sensitivity, specificity, PPV, NPV), ROC curves (DeLong comparison), and Youden indices were calculated for individual and combined thresholds; a 16 mm size cut-off was explored. Results: Malignancy was confirmed in 105/131 nodules (80.2%). Bethesda outperformed TI-RADS (AUC 0.87 vs. 0.69; DeLong p = 0.041). Malignancy rates rose with higher categories (e.g., TI-RADS 5: 93.6%; Bethesda category V: 100%; Bethesda category VI: 100%) and were markedly elevated in the histologically confirmed subset for Bethesda category III (32/41; 78.0%) and IV (6/8; 75.0%). The combined requirement of TI-RADS >= 4 and Bethesda >= 4 maximized specificity (96.2%) and PPV (98.4%) with a high Youden J (0.552), supporting a rule-in strategy in category IV of Bethesda. Size alone was a weak discriminator (AUC 0.66); within Bethesda III-IV nodules, malignancy did not differ significantly by the 16 mm threshold (p = 1.00). ROC using continuous tumor size yielded AUC = 0.66; the ROC-derived optimal cut-off was 16 mm. Applying this split produced sensitivity 0.80 and specificity 0.50. Conclusions: Integrating ACR TI-RADS with Bethesda cytology significantly improves specificity and PPV for indeterminate thyroid nodules, supporting a morphology-driven approach over traditional size-based thresholds. Incorporation of combined sonographic-cytologic criteria into management algorithms may reduce unnecessary interventions and optimize patient care.