Prognostic Role of PD-L1 in Penile Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis

Penile squamous cell carcinoma (PSCC) is a rare but aggressive malignancy, with up to 40% of patients presenting with nodal metastasis and poor survival in advanced stages. PD-L1 is an immune checkpoint molecule implicated in tumor immune evasion, yet its prognostic relevance in PSCC remains uncertain. This study aimed to synthesize available evidence on PD-L1 expression, prevalence, and its association with survival and lymph node metastasis.

PubMed, EMBASE, and the Cochrane Library databases were systematically searched for studies published between January 1996 to June 2025. Eligible studies reported PD-L1 expression in tumor tissue and its correlation with overall survival (OS), cancer-specific survival (CSS), or lymph node metastasis (LNM). Hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were pooled using random-effects models. Study quality and risk of bias were assessed using the Newcastle-Ottawa Scale. The protocol was registered with PROSPERO (CRD42019129410).

Overall, 15 retrospective studies were included (n=1,445), and 57% of tumors were PD-L1-positive (IQR, 44%-66%). Among 796 patients, PD-L1 expression was significantly higher in HPV-negative than HPV-positive tumors (42% vs 13.5%). A total of 8 studies (n=930) evaluated OS, 9 studies (n=1,091) assessed CSS, and 5 studies (n=622) investigated LNM. PD-L1 positivity was associated with reduced OS (HR, 1.52; 95% CI, 1.12-2.05; I2=6.8%), reduced CSS (HR, 1.61; 95% CI, 1.16-2.23; I2=38.3%), and higher odds of LNM (OR, 2.94; 95% CI, 1.28-6.78; I2=57.3%). In meta-regression, HPV adjustment significantly strengthened the CSS association (QM=7.13; P=.008; HR, 2.06; 95% CI, 1.21-3.51), accounting for all observed heterogeneity.

This meta-analysis, representing the largest pooled cohort to date, shows that PD-L1 expression is associated with adverse outcomes and greater tumor aggressiveness in PSCC. These findings support further evaluation of PD-L1 as a prognostic biomarker in PSCC and highlight the need for standardized assessment methods.