Internal medicine

Penile cancer

Disease

Prostate cancer

Cancer

Oncology

Immunosuppression

Localized disease

Radiation therapy

Medicine

Nature Reviews Disease Primers

Penile squamous cell carcinoma (PSCC) is a rare cancer with orphan disease designation and a prevalence of 0.1–1 per 100,000 men in high-income countries, but it constitutes up to 10% of malignancies in men in some African, Asian and South American regions. Risk factors for PSCC include the absence of childhood circumcision, phimosis, chronic inflammation, poor penile hygiene, smoking, immunosuppression and infection with human papillomavirus (HPV). Several different subtypes of HPV-related and non-HPV-related penile cancers have been described, which also have different prognostic profiles. Localized disease can be effectively managed by topical therapy, surgery or radiotherapy. As PSCC is characterized by early lymphatic spread and imaging is inadequate for the detection of micrometastatic disease, correct and upfront surgical staging of the inguinal lymph nodes is crucial in disease management. Advanced stages of disease require multimodal management. Optimal sequencing of treatments and patient selection are still being investigated. Cisplatin-based chemotherapy regimens are the mainstay of systemic therapy for advanced PSCC, but they have poor and non-durable responses and high rates of toxic effects, indicating a need for the development of more effective and less toxic therapeutic options. Localized and advanced penile cancers and their treatment have profound physical and psychosexual effects on the quality of life of patients and survivors by altering sexual and urinary function and causing lymphoedema. This Primer discusses the epidemiology of penile cancer and mechanisms underlying its development, including HPV infection. The authors explain contemporary and possible future diagnostic and management approaches in localized and advanced disease and highlight important considerations around the quality of life of affected patients.