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.
Journal of the National Comprehensive Cancer Network : JNCCN. 2026 Jul 09 [Epub ahead of print]
Nadine Mahmoud, Arfa Mustasam, Justin Miller, Alyssa Lakhram, Firas Hatoum, Zachary J Thompson, Youngchul Kim, Gabriel Roman Souza, Jeffrey S Johnson, Houssein Safa, Philippe E Spiess, Jad Chahoud
1Department of Internal Medicine, Saint Louis University, St. Louis, MO., 2Department of Genitourinary Oncology, H. Lee Moffitt Cancer Center, Tampa, FL., 3University of South Florida Health Morsani College of Medicine, Tampa, FL., 4Department of Biostatistics and Bioinformatics, Moffitt Cancer Center, Tampa, FL., 5Department of Hematology Oncology, Baylor College of Medicine, Houston, TX., 6Department of Genitourinary Oncology, OrlandoHealth Cancer Institute, Orlando, FL.