Thyroid "atypia of undetermined significance" with nuclear atypia has high rates of malignancy and BRAF mutation.

Background: "Atypia of undetermined significance" (AUS) in the Bethesda System for Reporting Thyroid Cytopathology is a heterogeneous category for cases that cannot be easily classified into benign, suspicious, or malignant. This study evaluated whether cytomorphology-based subcategorization could better predict the malignancy risk in cases designated as AUS, and how the subcategories correlated with BRAF mutation status in thyroid fine-needle aspirates (FNA).

Methods: Of 3589 cases of thyroid FNA diagnosed at the authors' institution in Seongnam, Korea, from January 2010 to December 2011, 331 cases of AUS were reviewed and subcategorized based on cytomorphological features, including nuclear atypia (NA), microfollicle formation (MF), Hürthle cell change (HC), and others (O). The malignancy rate of each subcategory was calculated using cases with histologic follow-up. Pyrosequencing was conducted to detect BRAF mutations.

Results: Malignancy was histologically proven in 23.3% (77 of 331) of cases diagnosed as AUS. In cytomorphology-based subcategories, the rate of malignancy was 30.8% (66 of 214) for AUS-NA, 14.5% (8 of 55) for AUS-O, 4.8% (2 of 42) for AUS-MF, and 5% (1 of 20) for AUS-HC. The BRAF V600E mutation was found in 40% (48 of 120) of AUS-NA, 30.8% (4 of 13) of AUS-HC, 6.7% (1 of 15) of AUS-O, and 2.8% (1 of 35) of AUS-MF.

Conclusions: The AUS-NA subcategory was associated with the highest risk of malignancy and the greatest frequency of BRAF V600E (substitution of valine to glutamic acid at position 600) mutation. These findings suggest that subcategorization of AUS by cytomorphology and BRAF V600E mutation status is important for predicting the risk of malignancy.