Hashimoto Thyroiditis Modifies the Association Between Nuclear Atypia and Malignancy in Bethesda III Thyroid Nodules.

Abstract

Background: Nuclear atypia is associated with an increased risk of malignancy in Bethesda III thyroid nodules; however, reactive nuclear changes related to Hashimoto thyroiditis (HT) may complicate its interpretation. We investigated whether HT modifies the association between nuclear atypia and malignancy in Bethesda III nodules. Methods: This retrospective single-center study included 426 surgically selected patients with Bethesda III nodules who underwent thyroidectomy between January 2015 and August 2026. HT was defined by postoperative histopathology. The association between nuclear atypia and malignancy was evaluated according to HT status. Effect modification was assessed using an HT × nuclear atypia interaction term in unadjusted and multivariable logistic regression models. Results: HT was present in 199 (46.7%) patients. Malignancy was less frequent in patients with HT than in those without HT (26.1% vs. 38.8%, p = 0.006), whereas nuclear atypia was more frequent (91.0% vs. 45.8%, p < 0.001). In patients without HT, nuclear atypia was strongly associated with malignancy and remained an independent predictor after multivariable adjustment (adjusted OR 13.24, 95% CI 5.46-32.10; p < 0.001). In patients with HT, nuclear atypia was not associated with malignancy (OR 0.68, 95% CI 0.24-1.94; p = 0.466). The HT × nuclear atypia interaction was significant in both unadjusted (OR 0.040, p < 0.001) and adjusted models (OR 0.031, p < 0.001). Conclusions: HT significantly modified the association between nuclear atypia and malignancy in Bethesda III nodules. Nuclear atypia strongly predicted malignancy in the absence of HT but not in its presence. Given the postoperative definition of HT, prospective validation using preoperative HT indicators is required before clinical application.