Few differences were observed in sexuality and health related quality of life as a function of primary surgery and lymphadenectomy. However, (partial) penectomy and lymphadenectomy were associated with more problems with orgasm, body image, life interference and urination. Additional longitudinal studies are warranted to evaluate individual changes with time in these outcomes.

PD-L1 was expressed in 48% of penile carcinomas and mainly in high risk HPV negative tumors. The pattern of expression was a prognostic factor as marginal expression was associated with absent lymph node metastases and diffuse expression was associated with poor survival.

High risk human papillomavirus-DNA was observed in a quarter of penile cancer cases. No relevant increase in high risk human papillomavirus prevalence in recent decades was observed. The presence of high risk human papillomavirus-DNA in penile cancer confers a survival advantage.

Significantly more penile preservation therapies were performed in more recent years. Although patients treated with penile preservation experienced more local recurrences, 5-year cancer specific survival was not jeopardized.

The host’s immune system plays a pivotal role in many tumor types, including squamous cell carcinomas (SCCs). We aim to identify immunological prognosticators for lymph node metastases (LNM) and disease-specific survival (DSS) in penile SCC. For this retrospective observational cohort study, penile SCC patients (n = 213) treated in the Netherlands Cancer Institute, were selected if sufficient formalin-fixed, paraffin-embedded tumor material was available. Analysis included previously described high-risk human papilloma virus (hrHPV) status, immunohistochemical scores for classical and non-classical human leukocyte antigen (HLA) class I, programmed death ligand-1 (PD-L1) expression, and novel data on tumor-infiltrating macrophages and cytotoxic an regulatory T-cells. Clinicopathological characteristics and extended follow-up were also included. Regression analyses investigated relationships of the immune parameters with LNM and DSS. In the total cohort, diffuse PD-L1 tumor-cell expression, CD163+ macrophage infiltration, non-classical HLA class I upregulation, and low stromal CD8+ T-cell infiltration were all associated with LNM. In the multivariable model, only tumor PD-L1 expression remained a significant predictor for LNM (odds ratio (OR) 2.8, p = 0.05). hrHPV negativity and diffuse PD-L1 tumor-cell expression were significantly associated with poor DSS and remained so upon correction for clinical parameters [hazard ratio (HR) 9.7, p < 0.01 and HR 2.8, p = 0.03]. The only immune factor with different expression in HPV+ and HPV− tumors was PD-L1, with higher PD-L1 expression in the latter (p = 0.03). In the HPV− cohort (n = 158), LNM were associated with diffuse PD-L1 tumor-cell expression, high intratumoral CD163+ macrophage infiltration, and low number of stromal CD8+ T-cells. The first two parameters were also linked to DSS. In the multivariable regression model, diffuse PD-L1 expression remained significantly unfavorable for DSS (HR 5.0, p < 0.01). These results emphasize the complexity of the tumor microenvironment in penile cancer and point toward several possible immunotherapy targets. Here described immune factors can aid risk-stratification and should be evaluated in clinical immunotherapy studies to ultimately lead to patient tailored treatment.