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  • Review Article
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Treatment strategies in human papillomavirus-related advanced penile cancer

Nature Reviews Urology volume 22, pages 427–438 (2025)Cite this article

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Abstract

Penile cancer is a rare neoplasm with heterogeneous prevalence influenced by risk factors such as smoking, poor hygiene and human papillomavirus (HPV) infection. Southern Africa, South America and Southeast Asia have the highest incidence of this disease. Penile squamous cell carcinomas (PSCCs) account for the majority of instances of penile cancer, with HPV-related carcinogenesis implicated in up to half of them. Increases in PSCC incidence in industrialized nations parallel the rising high-risk HPV infection rates, particularly HPV-16. Early-stage, localized PSCC is often manageable, but treatment options in advanced disease remain limited, with poor survival outcomes. Emerging evidence suggests that HPV-positive PSCC might exhibit unique therapeutic responses, including increased sensitivity to radiotherapy and chemotherapy, as has been observed in HPV-driven head and neck squamous cell carcinoma. Results of studies in HPV-positive PSCC demonstrate improved responses to chemoradiotherapy and immunotherapy, underscoring the potential for tailored treatments and de-escalation. Additionally, incorporating immunotherapy with radiotherapy in HPV-driven PSCC might provide greater oncological benefits than standard chemotherapy. These observations suggest that treatment strategies for HPV-positive PSCC might benefit from de-escalated chemoradiotherapy regimens or immunotherapy incorporation, potentially optimizing efficacy while minimizing toxic effects. Furthermore, biomarkers such as tumour mutational burden, programmed cell death ligand 1 expression, and genetic alterations could be crucial for predicting treatment response. Comprehensive biomarker assessment and accurate HPV status determination are essential for developing patient-tailored therapeutic strategies. These data provide evidence of the potential benefits of individualized approaches based on tumour biology and biomarker profiles.

Key points

  • Penile cancer is a rare but increasingly diagnosed neoplasm, particularly in regions with high human papillomavirus (HPV) prevalence, and it is substantially influenced by other risk factors such as smoking and poor hygiene.

  • High-risk HPV types, especially HPV-16, are implicated in the majority of penile squamous cell carcinomas (PSCCs), with HPV-related carcinogenesis accounting for up to 50% of instances.

  • Early stages of disease have favourable outcomes, but patients with advanced PSCC with nodal involvement, face limited treatment options and poor survival rates, necessitating innovative therapeutic approaches.

  • Emerging evidence indicates that HPV-positive PSCC might respond more favourably to chemoradiotherapy and immunotherapy than HPV-negative tumours, suggesting the need for tailored treatment strategies.

  • Comprehensive assessment of biomarkers such as tumour mutational burden and programmed cell death 1 ligand 1 expression is crucial for predicting treatment responses and developing personalized therapies for patients with PSCC.

  • De-escalated chemoradiotherapy regimens and the incorporation of immunotherapy into treatment strategies for HPV-positive PSCCs are aimed at enhancing efficacy while reducing toxic effects.

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Fig. 1: Mechanisms of radiosensitivity in HPV-driven cancers.

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Author information

Authors and Affiliations

  1. Division of Experimental Oncology/Unit of Urology, URI, IRCCS Ospedale San Raffaele, Milan, Italy

    Mattia Longoni, Fausto Negri, Andrea Salonia, Giuseppe Basile, Marco Bandini, M. Bandini & G. Basile

  2. University “Vita-Salute” San Raffaele, Faculty of Medicine and Surgery, Milan, Italy

    Mattia Longoni, Fausto Negri, Andrea Salonia, Giuseppe Basile, Marco Bandini, M. Bandini & G. Basile

  3. Department of Urology, The Christie NHS Foundation Trust, Manchester, UK

    Christian D. Fankhauser & C. Fankhauser

  4. Department of Urology, Luzerner Kantonsspital, University of Lucerne, Lucerne, Switzerland

    Christian D. Fankhauser & C. Fankhauser

  5. University of Zurich, Faculty of Medicine and Surgery, Zurich, Switzerland

    Christian D. Fankhauser & C. Fankhauser

  6. Department of Urology, Luzerner Kantonsspital, Lucerne, Switzerland

    Christian D. Fankhauser & C. Fankhauser

  7. Department of Urology, The Royal Free London Foundation Trust, London, UK

    Giuseppe Basile & G. Basile

  8. Department of Radiation Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    Peter A. S. Johnstone

  9. Department of Urology, King’s College Hospital NHS Foundation Trust — London, London, UK

    F. Castiglione

  10. Department of Urology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands

    H. M. De Vries

  11. Department of Urology, IRCCS Istituto Europeo di Oncologia, IEO, Milan, Italy

    G. Fallara

  12. Department of Pathology, Portuguese Oncology Institute of Porto (IPO Porto), Porto, Portugal

    J. Lobo

  13. Cancer Biology and Epigenetics Group, IPO Porto Research Center (GEBC CI-IPOP), Portuguese Oncology Institute of Porto (IPO Porto)/Porto Comprehensive Cancer Center Raquel Seruca (P.CCC) & CI-IPOP@RISE (Health Research Network), Porto, Portugal

    J. Lobo

  14. Department of Pathology and Molecular Immunology, ICBAS — School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal

    J. Lobo

  15. Department of Andrology, University College London Hospitals NHS Foundation Trust, London, UK

    K. H. Pang

  16. Division of Surgery and Interventional Science, University College London, London, UK

    K. H. Pang

  17. Department of Surgery, The Christie NHS Foundation Trust, Manchester, UK

    A. Sachdeva

  18. Division of Cancer Sciences, University of Manchester, Manchester, UK

    A. Sachdeva

  19. Department of Urology and Paediatric Urology, University Medical Center Mainz, Mainz, Germany

    A. Thomas

  20. Department of Urology, Eberhard Karls University Tübingen, Tübingen, Germany

    I. Anselmo da Costa Santiago

  21. Department of Urology, Policlinico Umberto I, Rome, Italy

    L. Antonelli

  22. The Royal Marsden NHS Foundation Trust, London, UK

    W. Cazzaniga

  23. Department of Minimally Invasive and Robotic Urology, University Centre of Excellence in Urology, Wroclaw Medical University, Wroclaw, Poland

    J. Chorbińska

  24. Department of Urology, University Hospitals Leuven, Leuven, Belgium

    L. Elst

  25. Department of Urology, Faculty of Medicine and Health, Örebro University, Örebro, Sweden

    D. Glombik

  26. Department of Urology, University Hospital Zürich, Zurich, Switzerland

    J. B. Grogg

  27. Urology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    S. Nazzani

  28. Università degli Studi di Milano, Milan, Italy

    S. Nazzani

  29. Department of Urology, Faculty of Medicine, University Hospital Cologne, University Cologne, Cologne, Germany

    P. Paffenholz

  30. Department of Minimally Invasive and Robotic Urology, University Center of Excellence in Urology, Wrocław Medical University, Wrocław, Poland

    A. Poterek

  31. Department of Urology, St George’s Healthcare National Health Service Trust, London, UK

    S. Yan

  32. Department of Urology, Fundació Puigvert, Autonoma University of Barcelona, Barcelona, Spain

    A. Territo

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  1. Mattia Longoni
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  2. Christian D. Fankhauser
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  3. Fausto Negri
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  4. Andrea Salonia
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  5. Giuseppe Basile
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  6. Peter A. S. Johnstone
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  7. Marco Bandini
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Consortia

the EAU-YAU Penile and Testis Cancer Working Group

  • C. Fankhauser
  • , M. Bandini
  • , F. Castiglione
  • , H. M. De Vries
  • , G. Fallara
  • , J. Lobo
  • , K. H. Pang
  • , A. Sachdeva
  • , A. Thomas
  • , I. Anselmo da Costa Santiago
  • , L. Antonelli
  • , G. Basile
  • , W. Cazzaniga
  • , J. Chorbińska
  • , L. Elst
  • , D. Glombik
  • , J. B. Grogg
  • , S. Nazzani
  • , P. Paffenholz
  • , A. Poterek
  • , S. Yan
  •  & A. Territo

Contributions

M.L. and G.B. researched data for the article. M.B. and M.L. contributed substantially to the discussion of the content. M.L., F.N. and G.B. wrote the article. M.B., C.D.F., A.S. and P.A.S.J. reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Marco Bandini.

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Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Reviews Urology thanks Rui Medeiros, Suengtaek Choi and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Advanced PSCC

Extensive (T3–T4), regionally advanced (inguinal or pelvic lymph-node involvement) or metastatic (M1) penile squamous cell carcinoma (PSCC), requiring a multidisciplinary approach owing to its poor prognosis.

Chemoradiotherapy

A combined treatment approach using chemotherapy and radiation therapy, which might be more effective in patients with human papillomavirus (HPV)-positive disease than in those who are HPV negative.

Human papillomavirus

(HPV). A group of viruses, some of which are classified as high-risk owing to their potential to cause cancer, particularly penile squamous cell carcinoma.

Immunotherapy

A treatment strategy that harnesses the immune system to fight cancer, showing promise in human papillomavirus (HPV)-positive penile cancer cases.

Penile squamous cell carcinoma

(PSCC). The most common type of penile cancer, accounting for approximately 95% of instances, often linked to human papillomavirus (HPV) infection.

Radiosensitivity

The susceptibility of cancer cells to damage from radiation therapy, with human papillomavirus (HPV)-positive tumours often exhibiting higher radiosensitivity than their HPV-negative counterparts.

Tumour mutational burden

(TME). A measure of the number of mutations within the DNA of a tumour, which can influence the effectiveness of certain therapies, including immunotherapy.

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Longoni, M., Fankhauser, C.D., Negri, F. et al. Treatment strategies in human papillomavirus-related advanced penile cancer. Nat Rev Urol 22, 427–438 (2025). https://doi.org/10.1038/s41585-025-00994-z

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