Penile cancer

Overview

• Epidemiology: rare in the US (~1:100,000 men per year, ~2,200 cases/yr); higher in developing countries. Mostly older men.
• Histology: squamous cell carcinoma (>90%). Rare variants: verrucous, papillary, warty (↑ with HPV), basaloid (↑ with HPV), and sarcomatoid carcinoma. HPV-related and HPV-unrelated pathways (HPV-related ~50%).
• Risk factors: HPV (16, 18), HIV, uncircumcised (phimosis), poor hygiene, smoking, balanitis, chronic inflammation, penile trauma, lichen sclerosus, PUVA therapy. Circumcision is protective (↓ risk).
• Precursor lesions (CIS): erythroplasia of Queyrat on the glans, Bowen disease on the shaft.

Workup & risk-stratified node assessment

• Biopsy of primary lesion + bilateral inguinal exam; HPV / p16 testing.
• Imaging: pelvic MRI/CT, CT chest, PET-CT for advanced or node-positive disease.
• Clinically node-negative, stratify by primary:
  • Low risk (pTis, Ta, or T1a grade 1): no additional imaging required; surveillance.
  • Intermediate risk (pT1a grade 2): SLNBx or ILND or surveillance.
  • High risk (≥pT1b): SLNBx or ILND.
• Palpable/suspicious inguinal node: obtain prompt image-guided FNA or core biopsy and stage (no routine empiric antibiotic trial, which delays staging; reserve antibiotics for clear infection); if positive, ILND and add staging imaging; if negative with persistent suspicion, repeat FNA or excisional biopsy.

Staging & stage-based management

Inguinal node management (high-yield)

• cN0 + high-risk primary: SLNB or modified ILND.
• cN+: ILND (uni/bilateral); add pelvic LND if >2 inguinal LN+ or ENE.
• Bulky N2/N3 or pelvic LN: neoadjuvant TIP (paclitaxel + ifosfamide + cisplatin) × 4 → consolidation surgery.
• Adjuvant chemoRT or chemo for ≥pN2 or ENE.

Recurrence & metastatic disease

• Local recurrence: penectomy vs a second penis-preserving treatment.
• Inguinal recurrence: neoadjuvant chemotherapy followed by ILND (poor prognosis).
• Distant metastatic: TIP is standard 1L; pembrolizumab for MSI-H or high-TMB tumors; cetuximab + paclitaxel (penile SCC is often EGFR+). Pembrolizumab/cemiplimab have modest activity in PD-L1+ or pretreated disease.

2024-2025 updates

• InPACT (NCT02305654): phase 3 in inguinal node-positive penile SCC, randomizing upfront ILND vs neoadjuvant chemo (TIP) → ILND vs neoadjuvant chemoradiation → ILND, with a second randomization to prophylactic pelvic LND (InPACT-pelvis). Primary endpoint OS; accrual closed, results pending. Neoadjuvant TIP for bulky cN2 to N3 remains guideline standard based on phase 2 data.
• NCT04475016 (Sun Yat-sen, single-arm phase 2, completed): neoadjuvant TIP + nimotuzumab (anti-EGFR) + toripalimab (anti-PD-1) in locally advanced penile SCC (T4 or N3); primary endpoint pCR. Investigational.
• HERCULES (Maluf JAMA Oncol 2025): phase 2 pembrolizumab + cisplatin (or carboplatin)/5-FU in advanced penile SCC, ORR ~40%, mOS ~10 mo. Supports IO/chemo combo in metastatic 1L; not yet FDA-labeled but NCCN-listed option.

High-yield penile pearls

• HPV-related in ~50%; p16/HPV testing routine.
• Inguinal LN management is critical: SLNB or ILND based on risk.
• TIP regimen is the preferred chemo (neoadjuvant and metastatic).
• Organ preservation when oncologically safe.