HER2 expression and clinicopathological correlates across immunohistochemical phenotypes of urothelial carcinoma: a retrospective single-center study

Background Human epidermal growth factor receptor 2 (HER2) is a treatment target in urothelial carcinoma (UC), but the features of tumors with HER2 overexpression are not well defined. This study evaluated the clinicopathological factors related to HER2 expression and compared its frequency and tumor characteristics among immunohistochemical (IHC) phenotypes. Methods This retrospective study enrolled 280 patients with pathologically confirmed UC at our institution between 2021 and 2025. Tumor sections were evaluated for HER2, CK5/6, and CK20 expression by IHC. Tumors were grouped as HER2 IHC 0/1 + or 2+/3+, and were classified as luminal, basal, double-positive, or double-negative based on CK5/6 and CK20 expression. Factors related to IHC 2+/3 + expression were assessed by univariable and multivariable logistic regression. Results HER2 IHC 2+/3 + staining was observed in 191 tumors (68.2%). HER2 IHC 2+/3 + was associated with age > 60 years, high-grade histology, abnormal p53 expression, Ki-67 index ≥ 30%, and IHC phenotypes (all P < 0.05). In multivariate analysis, luminal type (OR=3.848, P < 0.001), double-positive type (OR=3.429, P = 0.021), and age > 60 years (OR=1.888, P = 0.033) remained independently associated with HER2 IHC 2+/3 + . Conclusions HER2 IHC 2+/3 + expression was common in UC and was associated with age, histologic grade, Ki-67 index, abnormal p53 expression and IHC phenotypes. These findings describe differences in HER2 expression across CK5/6- and CK20-defined IHC phenotypes.