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PubMed This is a summary of 14 peer-reviewed journal articles Updated
Oncology · Penile Cancer

Biological Pathways and Cancer Subtypes

At a Glance

Penile cancer is not a single disease, but a group of different subtypes categorized as either HPV-associated or HPV-independent. Your specific subtype, identified through a biopsy and p16 testing, plays a critical role in determining the aggressiveness of your treatment and your prognosis.

It is common to think of “penile cancer” as a single disease, but modern medicine treats it as a group of different conditions that behave in very different ways. The specific subtype of your cancer is one of the most important factors in determining how aggressive your treatment needs to be and what your long-term outlook looks like.

The Two Main Biological Pathways

The 2022 World Health Organization (WHO) classification now organizes penile cancers into two primary categories based on how they developed [1][2].

1. HPV-Associated (HPV-Driven)

These cancers are caused by a high-risk infection with the Human Papillomavirus (HPV) [1]. To identify this pathway, pathologists use a test called p16 immunohistochemistry.

  • The p16 Marker: If the test shows a “block-like” or “diffuse” staining pattern, it is a strong sign that the cancer is HPV-associated [1][3].
  • Outlook: In general, HPV-associated cancers often have better survival outcomes compared to those that are not related to the virus [4][5].
    (Note: Even if you have an HPV-driven cancer, you may want to ask your doctor if receiving the HPV vaccine post-treatment is beneficial for you, as this is an area of ongoing research and a common patient question [6].)

2. HPV-Independent

These cancers are not caused by a virus. Instead, they often arise from chronic skin inflammation, such as lichen sclerosus [2].

  • Genetic Changes: These tumors often have mutations in a gene called TP53 [2][7].
  • Outlook: These cancers are sometimes more aggressive and may require more intensive monitoring [8][5].

Understanding Your Subtype

Within these two pathways, there are several “flavors” or histological subtypes of Squamous Cell Carcinoma (SCC). Your pathology report will likely list one of these names:

Subtype Risk Level Description & Characteristics
Verrucous Low These are slow-growing and very rarely spread to the lymph nodes. They are usually HPV-independent and have the best overall prognosis [9].
Warty Low to Moderate Often associated with HPV, these tumors have a bumpy, “wart-like” appearance. They generally have a good outlook but require careful monitoring [10].
Basaloid High This is a more aggressive, high-grade subtype that is frequently HPV-associated. It has a higher risk of spreading to the lymph nodes [11].
Sarcomatoid Very High An uncommon but very aggressive form of penile cancer. It tends to grow quickly and has a high potential for spreading to other parts of the body [11].
Usual Type Variable The most common form of penile cancer. Its risk level depends on how aggressive the cells look under the microscope (the grade) [12].

Why the Subtype Matters

Your medical team uses this information to build your roadmap. For example, a patient with a verrucous tumor may only need a local procedure to remove the growth. However, a patient with a basaloid or sarcomatoid tumor will likely need a more comprehensive plan that includes a close evaluation of the lymph nodes and possibly additional therapies like radiation or chemotherapy [13][14]. Always ask your doctor how your specific subtype influences the aggressiveness of your care plan.

Common questions in this guide

What is the difference between HPV-associated and HPV-independent penile cancer?
HPV-associated penile cancers are driven by the Human Papillomavirus and generally have better survival outcomes. HPV-independent cancers usually arise from chronic skin inflammation, such as lichen sclerosus, and can sometimes be more aggressive.
What does a positive p16 test mean on my penile cancer pathology report?
A diffuse or block-like p16 staining pattern on your biopsy is a strong indicator that your cancer is associated with an HPV infection. Doctors use this test to accurately classify your cancer pathway and help predict your overall outlook.
Are all types of penile cancer aggressive?
No, the risk level varies significantly depending on your specific histological subtype. The verrucous subtype is slow-growing and low risk, while basaloid and sarcomatoid subtypes are highly aggressive and carry a greater risk of spreading.
How does my penile cancer subtype affect my treatment plan?
Your tumor's subtype helps your doctors determine the necessary aggressiveness of your care. Low-risk tumors may only require local removal, whereas high-risk subtypes typically demand careful evaluation of the lymph nodes and potentially radiation or chemotherapy.
Should I get the HPV vaccine after being treated for penile cancer?
If you have an HPV-driven cancer subtype, there is ongoing medical research exploring whether the HPV vaccine offers benefits after treatment. This is a common question, and you should ask your oncologist if it is appropriate for your specific situation.

Questions to Ask Your Doctor

Curated prompts to bring to your next appointment.

  1. 1.What specific histological subtype is listed on my pathology report?
  2. 2.Did the p16 testing show a diffuse staining pattern, and what does that mean for my HPV status?
  3. 3.Is my cancer considered a 'high-risk' subtype, such as basaloid or sarcomatoid?
  4. 4.Does the subtype of my cancer change the plan for managing my lymph nodes?
  5. 5.Since I have an HPV-driven subtype, is there any benefit to receiving the HPV vaccine now?

Questions For You

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References

References (14)
  1. 1

    WHO 2022 classification of penile and scrotal cancers: updates and evolution.

    Menon S, Moch H, Berney DM, et al.

    Histopathology 2023; (82(4)):508-520 doi:10.1111/his.14824.

    PMID: 36221864
  2. 2

    Clinicopathological features and reclassification of penile squamous cell carcinoma according to WHO classification 2022 for penile carcinoma with p16 immunohistochemical expression and its prognostic impact.

    Kaushik V, Pai K, Rao A, Sharma S

    Diagnostic pathology 2025; (20(1)):80 doi:10.1186/s13000-025-01676-5.

    PMID: 40611164
  3. 3

    Spectrum of Human Papillomavirus (HPV)-Related Penile Cancer.

    Sali AP, Menon S

    Advances in anatomic pathology 2026; (33(2)):106-116 doi:10.1097/PAP.0000000000000517.

    PMID: 41540754
  4. 4

    Expression of PD-L1, TIGIT, and CD155, and Human Papillomavirus Status in Patients with Advanced Penile Cancer.

    Ulvskog E, Kirrander P, Persson EK, et al.

    European urology open science 2025; (79()):102-110 doi:10.1016/j.euros.2025.07.012.

    PMID: 40822998
  5. 5

    Penile Cancers Attributed to Human Papillomavirus Are Associated with Improved Survival for Node-positive Patients. Findings from a Norwegian Cohort Study Spanning 50 Years.

    Moen CA, Falkenthal TE, Thorkelsen TK, et al.

    European urology oncology 2024; (7(4)):778-785 doi:10.1016/j.euo.2023.10.013.

    PMID: 37949729
  6. 6

    Penile cancer.

    Thomas A, Necchi A, Muneer A, et al.

    Nature reviews. Disease primers 2021; (7(1)):11 doi:10.1038/s41572-021-00246-5.

    PMID: 33574340
  7. 7

    HPV-negative penile squamous cell carcinoma: disruptive mutations in the TP53 gene are common.

    Kashofer K, Winter E, Halbwedl I, et al.

    Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 2017; (30(7)):1013-1020 doi:10.1038/modpathol.2017.26.

    PMID: 28387325
  8. 8

    The Prognostic Role of HPV or p16INK4a Status in Penile Squamous Cell Carcinoma: A Meta-Analysis.

    Mustasam A, Parza K, Ionescu F, et al.

    Journal of the National Comprehensive Cancer Network : JNCCN 2025; (23(2)).

    PMID: 39752880
  9. 9

    Noninfectious Penile Lesions.

    Teichman JMH, Mannas M, Elston DM

    American family physician 2018; (97(2)):102-110.

    PMID: 29365226
  10. 10

    Successful application of aminolevulinic acid/photodynamic therapy in the treatment of condyloma acuminatum in a young child.

    Yin G, Zhang Y, Liu J, et al.

    Photodiagnosis and photodynamic therapy 2022; (38()):102746 doi:10.1016/j.pdpdt.2022.102746.

    PMID: 35123017
  11. 11

    Sarcomatoid carcinoma of the penis: a case report.

    Huang Q, Huang Y, Xiong D, et al.

    Translational andrology and urology 2025; (14(3)):855-862 doi:10.21037/tau-2024-765.

    PMID: 40226050
  12. 12

    The Main Genetic-Molecular Aspects of Penile Cancer.

    Hurtado R, Zender-Poma G, Wang L, Tirado CA

    Journal of the Association of Genetic Technologists 2024; (50(1)):14-18.

    PMID: 38447205
  13. 13

    The Diagnosis and Treatment of Penile Cancer.

    Hakenberg OW, Dräger DL, Erbersdobler A, et al.

    Deutsches Arzteblatt international 2018; (115(39)):646-652.

    PMID: 30375327
  14. 14

    A model of tertiary lymphatic structure-related prognosis for penile squamous cell carcinoma.

    Tang H, Su Z, Huang Q, et al.

    BMC urology 2024; (24(1)):165 doi:10.1186/s12894-024-01532-6.

    PMID: 39090582

This page explains penile cancer subtypes and pathology terminology for educational purposes only. Always consult your urologist or oncologist to interpret your specific pathology report and determine your treatment plan.

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