Subclassification of Bethesda Atypical and Follicular Neoplasm Categories According to Nuclear and Architectural Atypia Improves Discrimination of Thyroid Malignancy Risk

Background: Although The Bethesda System for Reporting Thyroid Cytopathology has provided clinicians with a standardized classification scheme for the diagnosis of thyroid fine-needle aspiration cytology (FNAC) specimens, the indeterminate categories of Bethesda III (B3)—atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS)—and Bethesda IV (B4)—follicular neoplasm/suspicious for follicular neoplasm (FN/SFN)—continue to pose challenges with regards to ideal diagnostic and therapeutic management. Having previously demonstrated the presence of nuclear atypia as a high-risk subgroup in B3, the objective of this study was to evaluate the malignancy rates in the B4 subgroup with nuclear atypia. Methods: A retrospective review of all thyroid FNACs diagnosed as B4 (FN/SFN) between 2008 and 2015 was conducted at a tertiary referral center in Singapore. Data on patient demographics, sonographic features, and final histological diagnosis were collected. This was compared to data from a previous analysis on all nodules diagnosed as B3 (AUS/FLUS) over a similar period. Results: A total of 137/309 (44.3%) and 88/111 (79.3%) FNACs diagnosed as B3 and B4, respectively, underwent surgical excision yielding final histopathological diagnoses. The malignancy rate of B4 was 31/88 (35.2%) compared to B3, which was 37/137 (27.0%). Subclassification based on the presence of architectural versus nuclear atypia showed significantly higher malignancy rates in B4 nodules with nuclear atypia (21.8% vs. 57.6%; p < 0.01). These findings corroborate previous results within the B3 category (malignancy rate of 14.7% vs. 36.8%; p < 0.01). The only sonographic features predictive of malignancy were the presence of macrocalcifications in B4 compared to irregularity of margins in B3. Conclusion: The presence of nuclear atypia identifies subgroups with significant differential malignancy risks within both the B3 and B4 categories. This supports the notion that subclassification is a useful risk stratification tool that can guide diagnostic and therapeutic management of indeterminate thyroid nodules with heterogenous risk profiles.