Guiding Management of Bethesda V Thyroid Nodules: The Role of Molecular Testing

Objective: The 2023 Bethesda System update introduced molecular testing as a management option for Bethesda V cytology nodules, aiming to guide surgical decision-making. This study investigates the correlation between molecular profiling and malignancy aggressiveness. Design: We conducted a retrospective multicenter study involving patients with Bethesda V cytology and confirmed malignant pathology who underwent molecular profiling between 2018 and 2021. Patients: A total of 156 patients with Bethesda V cytology and final malignant histology were included. Measurements: Malignancy aggressiveness was assessed based on histopathological features following 2015 ATA guidelines. Demographic data, pathology results, and genetic variants were analyzed. Molecular profiling results were stratified according to variant risk levels. Results: We identified 161 Bethesda V nodules, of which 153 (95.0%) were malignant on final pathology. Genetic stratification revealed no detected mutations in 39.7% (n = 56), low-risk (n = 49, 31.4%), and intermediate-risk variants (n = 45, 28.8%). Only one patient had a high-risk variant. Patients with intermediate-risk variants had a sixfold risk of aggressive disease compared to those with low-risk variants (49% vs. 8.2%, p < 0.001). RAS mutations were the most common among the low-risk group (68.8%) and BRAF V600E predominated in the intermediate-risk group (93.3%). Conclusions: Our findings suggest that molecular profiling offers insights into risk stratification for Bethesda V thyroid lesions, demonstrating a very low incidence of aggressive pathology in the low-risk molecular group.