Reduced Nectin-4 expression in lymph node metastases of penile squamous cell carcinoma: a paired primary–metastatic analysis

Objective To evaluate Nectin-4 expression in primary and matched metastatic penile squamous cell carcinoma (PSCC) lesions and to assess its associations with clinicopathological features and survival outcomes. Methods We analyzed 123 patients with pathologically confirmed PSCC treated at our hospital between 2018 and 2024. Nectin-4 expression was assessed by immunohistochemistry using the H-score (0-300) in primary tumors and 30 matched lymph node metastases, and associations with pathological features, paired primary-metastatic differences, and survival outcomes were analyzed. Results Nectin-4 was widely expressed in PSCC. Higher Nectin-4 expression was observed in less aggressive tumors. Expression was higher in T1 than in T2 stage (95% CI 19.10-79.28; P < 0.01) and decreased from G1 to G3, with significant differences between G1 and G2 (95% CI 0.39-63.83; P = 0.047) and between G1 and G3 (95% CI 24.41-170.43; P = 0.009). Expression in primary tumors was not significantly associated with nodal status. In paired samples, lymph node metastases showed lower H-scores than their matched primary tumors (95% CI 3.52-72.82; P = 0.032). Low Nectin-4 expression was associated with shorter overall survival in Kaplan-Meier and univariable Cox analyses, but it was not independently associated with survival after multivariable adjustment. Conclusions Nectin-4 expression in PSCC is higher in early, better-differentiated tumors and lower in lymph node metastases. Low Nectin-4 expression was associated with poorer overall survival, although it was not an independent prognostic factor. These findings suggest that Nectin-4 may have prognostic relevance and potential value as a therapeutic target in PSCC.