Nectin-4 expression in upper and lower tract urothelial carcinoma: correlation with early-stage disease and prognostic relevance.

Nectin-4 is a recognized therapeutic target in advanced or metastatic urothelial carcinoma (UC), with the antibody‒drug conjugate enfortumab vedotin (EV) already approved for clinical use. However, the clinicopathological significance of Nectin-4 expression in UC remains controversial. To address this, we analyzed the expression and distribution of Nectin-4 in 147 upper tract UC (UTUC) and 93 bladder UC (BLCA) tissue samples using immunohistochemistry (IHC). High Nectin-4 expression was observed in cancerous regions, with both membranous and cytoplasmic staining patterns identified. Nectin-4 expression was detected in 84% of UTUC and 83% of BLCA cases and was associated with papillary morphology, low tumor grade, early pathological T stage, and a favorable prognosis. Compared with membranous staining, cytoplasmic staining was more frequently observed in advanced-stage UC. In UTUC, Nectin-4 expression correlated with UPK3 and GATA3 expression and inversely associated with PD-L1 and CK5/6. A combined model incorporating Nectin-4, UPK3, GATA3, and PD-L1 expression demonstrated high predictive performance for the patient prognosis. In silico analyses confirmed the association of NECTIN4 expression with a favorable prognosis in both UTUC and BLCA patients using the same cutoff values as the Hiroshima cohort. Bioinformatics analysis of RNA-Seq datasets revealed that the NECTIN4-high group was significantly associated with pathways such as oxidative phosphorylation, lipid metabolism, and chemical carcinogenesis, whereas the NECTIN4-low group was linked to epithelial‒mesenchymal transition (EMT). These findings underscore the clinical value of assessing Nectin-4 protein expression and localization through IHC, which may inform treatment strategies and surveillance protocols for UTUC and BLCA patients.