Does oncocytic morphology affect the performance of a 7-gene mutation panel in Bethesda IV thyroid nodules? A retrospective single-institution study

Background: Bethesda category IV includes oncocytic (OFN) and non-oncocytic follicular neoplasms (FN). We evaluated whether a 7-gene mutation panel performs differently across these cytomorphologic phenotypes. Methods: We retrospectively reviewed 319 Bethesda IV fine-needle aspirations (2020-2025); cytomorphologic features were assessed in the 285 cases with evaluable 7-gene testing results. Risk of malignancy (ROM) and other diagnostic metrics, including mutation rates and mutation-malignancy association were calculated for FN and OFN. Results: In both FN and OFN we observed RAS-like alterations only. Mutation prevalence was higher in FN (32/112, 28.6%) than in OFN (27/173, 15.6%; OR 2.16, 95% CI 1.21-3.86; p=0.011). In FN, mutation-positive nodules showed a ROM of 50.0% (7/14) vs 14.7% (5/34) in mutation-negative cases (OR 5.80, 95% CI 1.41-23.8; p=0.024). In OFN, ROM was 42.9% (3/7) vs 34.2% (13/38) in mutation-negative cases (OR 1.44, 95% CI 0.28-7.44; p=0.686). Conclusions: A positive 7-gene result was associated with significant risk enrichment in FN, while the association in OFN did not reach significance. The lower mutation prevalence in OFN, together with available evidence that oncocytic tumors are associated with chromosome instability, supports the incorporation of copy number variation analysis as a part of broader panel testing strategy.