Atypia of undetermined significance in thyroid cytology: Nuclear atypia and architectural atypia are associated with different molecular alterations and risks of malignancy

Background The Bethesda System for Reporting Thyroid Cytopathology contains an atypia of undetermined significance (AUS) category with heterogeneous and distinct inclusion criteria. The purpose of this study was to investigate differences in malignancy rates and molecular alterations based on the presence of different criteria. Methods A laboratory information search was conducted to identify thyroid fine-needle aspiration specimens signed out as AUS. The cases were reclassified as architectural atypia (3A), cytologic atypia (3C), both architectural and cytologic atypia (3B), or Hurthle cell aspirate (3H). Surgical follow-up and concurrent molecular test results, if available, were collected. Results Five hundred ten specimens, including 258 reclassified as 3A, 40 reclassified as 3B, 119 reclassified as 3C, and 86 reclassified as 3H, were identified. The risks of malignancy for the subcategories were 13.4%, 26.3%, 44.1%, and 13.8%, respectively. Additionally, BRAF V600E mutations were more prevalent in specimens with cytologic atypia (3B/3C), whereas low-risk alterations, including KRAS, PTEN, and PAX8-PPARy2, were more prevalent in those with architectural atypia (3A). Conclusions Subdividing AUS specimens on the basis of the type of atypia can yield categories associated with distinct molecular alterations and risks of malignancy.