Subclassifying "Atypia of Undetermined Significance (AUS)" Category in the 2023 Bethesda System for Thyroid Cytopathology: Analyzing K-TIRADS, BRAF V600E Mutation, and Risk of Malignancy

Abstract

The 2023 Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) update refines the atypia of undetermined significance (AUS) category by subclassifying it into AUS-nuclear atypia (AUS-N) and AUS-other atypia (AUS-O) based on risk of malignancy, to enhance clarity of diagnosis and patient management. This study evaluates the impact of AUS subclassification on malignancy risk prediction in thyroid nodules. A total of 118 AUS cases were analyzed for subclassification using the nuclear scoring (NS) system to evaluate nuclear features, along with the ultrasonography-based Korean Thyroid Imaging Reporting and Data System (K-TIRADS) for risk stratification, and BRAF V600E mutation testing. Logistic regression and ROC curve analyses were used to identify predictors of malignancy and to assess model performance. The AUS category was divided into AUS-N and AUS-O, with AUS-N having a significantly higher risk of malignancy (ROM) (78.1%) compared to AUS-O (27.3%). The subcategories AUS-N1, N2, and N5 showed significantly high ROM (96.9%, 71.7%, and 90.0%), whereas AUS-N3 and N4 showed lower ROM (20.0% and 33.3%). The NS system standardized the assessment of nuclear atypia, reducing interobserver variability and improving diagnostic reproducibility. BRAF V600E mutation, present in 28.1% of AUS-N cases but absent in AUS-O cases, was a strong predictor of malignancy. Models integrating imaging, detailed cytologic subclassification, and molecular findings achieved high specificity (81.0-86.5%) but moderate sensitivity (58.0-61.3%). These findings support the use of AUS subclassification and molecular testing for BRAF V600E mutation to improve ROM prediction and are consistent with the 2023 TBSRTC emphasis on tailored risk stratification.

Keywords: BRAF V600E mutation; Atypia of undetermined significance; Nuclear scoring.