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.