Penile Cancer

Epidemiology & Impact

Penile cancer is rare in developed countries (approximately 2,200 US cases annually) but significant in parts of South America, Africa, and Asia. HPV is detected in approximately 50% of cases and associated with better prognosis. Risk factors include phimosis, chronic inflammation, smoking, and lack of circumcision. Median age is 68.

Risk stratification guides therapy intensity: low-risk tumors (T1a, grade 1-2) can be managed with organ-preserving surgery alone, while high-risk features (lymphovascular invasion, grade 3, perineural invasion) warrant inguinal lymph node dissection. HPV status is emerging as a prognostic biomarker, with HPV-positive tumors having significantly better overall survival. Genomic profiling through Memorial Sloan Kettering IMPACT or Foundation Medicine panels can identify actionable alterations including CDKN2A deletions and PIK3CA mutations. International collaboration through the International Rare Cancers Initiative (IRCI) and the European Association of Urology are advancing prospective data collection for this rare malignancy.

Molecular Biology & Biomarkers

Two molecular pathways: HPV-dependent (50%, p16 overexpression, better prognosis) and HPV-independent (TP53 mutations, CDKN2A loss, worse prognosis). PIK3CA mutations (20%), EGFR amplification, and PD-L1 expression (40-60%) are frequent.

Penile squamous cell carcinoma has two distinct etiological pathways: HPV-driven (30-50% of cases, associated with HPV-16) and non-HPV-driven (associated with lichen sclerosus, chronic inflammation, and phimosis). HPV-positive tumors show p16 overexpression, TP53 wild-type status, and better prognosis. HPV-negative tumors harbor frequent TP53 mutations, CDKN2A loss, NOTCH1/2 mutations, and EGFR amplification. PIK3CA mutations occur in approximately 20% of cases regardless of HPV status. PD-L1 expression is found in 40-60% of penile cancers, supporting checkpoint inhibitor investigation. Tumor mutational burden tends to be moderate, and MSI-high status is rare but actionable when present.

Evolving Treatment Landscape

Localized disease is managed surgically. Advanced disease receives platinum-based TIP chemotherapy. Pembrolizumab has activity in PD-L1-positive or MSI-H tumors. Treatment approaches often extrapolate from head and neck or cervical SCC given shared HPV biology.

Early-stage penile cancer is managed surgically with organ-preserving techniques (Mohs surgery, laser ablation, glansectomy) when feasible. Inguinal lymph node management is critical — sentinel node biopsy guides the need for lymphadenectomy. For locally advanced disease, neoadjuvant chemotherapy (TIP: paclitaxel, ifosfamide, cisplatin) achieves objective response rates of 50% and can render unresectable tumors operable. In metastatic disease, platinum-based combinations remain standard. Pembrolizumab is available for MSI-H/TMB-H tumors under the tumor-agnostic approval. Clinical trials are evaluating EGFR inhibitors, anti-PD-1 combinations, and HPV-directed immunotherapy (therapeutic vaccines). The InPACT trial (NCT02305654) is the largest prospective study evaluating treatment strategies.

Note: There are no tumor-specific FDA-approved novel therapies for penile cancer. Standard treatment includes surgery, radiation, and chemotherapy (TIP: paclitaxel, ifosfamide, cisplatin; or VBM: vincristine, bleomycin, methotrexate). Pembrolizumab is available via the TMB-H tumor-agnostic indication for eligible patients. Checkpoint inhibitors are being studied in clinical trials.

EMA-Approved Therapies for Penile Cancer

The European Medicines Agency (EMA) regulates drug approvals across the European Union. Below are key therapies with comparative information to FDA approvals.

For complete European drug information, visit ema.europa.eu ↗