Malignancy Risk, Molecular Mutations, and Surgical Outcomes of Thyroid Nodules Classified as Atypia of Undetermined Significance in the Bethesda System: A Comprehensive Analysis.

OBJECTIVES

Thyroid nodules classified as atypia of undetermined significance (AUS) within the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) present a diagnostic challenge, with a risk of malignancy (ROM) of 5% to 50%. In 2017, TBSRTC introduced AUS subcategories to enhance ROM assessment. This study explores the correlation between AUS subclassification, molecular mutations, and surgical outcomes.

METHODS

Retrospective analysis was performed of 114 AUS cases with molecular profiling by ThyroSeqV3 and surgical follow-up. AUS subcategories as defined by TBSRTC included: AUS-Architectural, AUS-Nuclear, AUS-Nuclear and Architectural, and AUS-Hürthle cell. Pathology diagnoses were categorised as benign, malignant, or borderline, including noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).

RESULTS

Of the 114 nodules, 32.5% were AUS-Architectural, 28.9% AUS-Nuclear and Architectural, 18.4% AUS-Nuclear, 19.3% AUS-Hürthle cell, and 0.9% AUS-Not Otherwise Specified. Papillary carcinoma, predominantly follicular variant, was the most common diagnosis (47.4%), followed by benign lesions (34.2%) and NIFTP (9.6%). RAS family mutations were the most prevalent molecular alteration (34.2%) followed by DICER1, EIF1AX, EXH1 mutations, CNA and GEP (29.8%). THADA fusions, PTEN, TSHR and BRAFK601E mutations were identified in 10.5% of cases, while high-risk mutations such as BRAF V600E, TERT, and TP53 were found in 8.8% of cases. AUS subcategories demonstrated distinct molecular profiles and were linked to varying surgical outcomes.

CONCLUSIONS

AUS subcategorization is associated with specific molecular profiles and surgical outcomes, supporting the subclassification of AUS cases per TBSRTC guidelines for improved risk stratification and clinical management. Further prospective studies with larger cohorts are necessary for validation.