HPV and Penile Cancer: Perspectives on the Future Management of HPV-Positive Disease

March 15, 2016

Over the past 5 years, several studies have investigated the molecular profiling of penile carcinomas, examining both genomic and epigenetic alterations. These studies have revealed distinct molecular pathways associated with HPV status.

Human papillomavirus (HPV) infection can be considered a major pandemic, causing both benign and malignant disease around the world. It is the most frequently acquired sexually transmitted disease, with more than 6 million new cases transmitted annually in the United States.[1] HPV is implicated in the oncogenesis of at least 5% of all cancers, including cervical, head and neck, anal, and penile cancers.

Recently, Alemany et al[2] undertook the largest epidemiologic study to date of HPV’s role in penile cancer, examining 1,010 penile cancer specimens from 25 countries. The team detected HPV DNA in approximately 40% to 50% of invasive penile cancer cases and in up to 90% of high-grade squamous intraepithelial lesions. The high-risk oncogenic subtypes 16 and 18 accounted for most of this disease and were detected in over 60% of HPV-positive specimens.

In this issue of ONCOLOGY, Drs. Stratton and Culkin provide an excellent in-depth review of HPV and penile cancer,[3] including both premalignant and malignant penile lesions. This review understandably did not mention lichen sclerosus as a further potential pathway leading to invasive penile cancer. Previously, controversy surrounded HPV’s role in conjunction with lichen sclerosus, but current evidence suggests that lichen sclerosus is an HPV-independent carcinogenic factor.[4,5]

As the review discusses, the College of American Pathologists’ most recent classification system for penile intraepithelial neoplasms (PeIN) has two distinct categories of PeIN: (1) “differentiated,” referring to PeIN with no HPV association and most commonly caused by lichen sclerosus, and (2) “undifferentiated,” referring to bowenoid/warty PeIN with a high association with HPV.[6] These distinctions are important, as future targeted therapies will depend on overall HPV status.

Over the past 5 years, several studies have investigated the molecular profiling of penile carcinomas, examining both genomic and epigenetic alterations. These studies have revealed distinct molecular pathways associated with HPV status. Recently, McDaniel et al[7] performed targeted genomic profiling of 60 fixed penile carcinomas and revealed several distinct recurrent mutations. In the HPV-positive cohort, low levels of TP53 and CDKN2A alterations were found, which were consistent with findings from genomic profiling of other HPV-induced malignancies, including oropharyngeal and cervical squamous cell carcinomas. One explanation for this is that during HPV infection, there is no genetic drive for alterations in these genes, as they become inactivated by the viral oncogenes E6 and E7, respectively. Feber et al[8] undertook methylome analysis of 50 cases of penile carcinoma and found that HPV infection was associated with widespread loss of DNA methylation. This methylation signature was distinct from that of the HPV-negative tumors. Furthermore, they found differentially methylated regions containing several candidate genes-eg, GRAMD4, a tumor suppressor gene. Gene ontology analysis found that a significant proportion of those genes found in differentially methylated regions belong to the Wnt signaling pathway.

Further work is needed to validate the potential targets uncovered in these molecular studies. Patients with penile cancer who have lymph node metastases still have only a few options, with mostly only platinum or taxane-based chemotherapeutic agents available, resulting in poor 5-year disease-specific survival rates. Future work should validate these targets, with targeted therapies in mind, such as epidermal growth factor receptor and mammalian target of rapamycin inhibitors.

The best method of combating HPV-related disease is to prevent it in the first place. This can now be achieved by routine vaccination using a quadrivalent or, more recently, a 9-valent HPV vaccine, which is routinely offered to young women in many countries. Stratton and Culkin highlight the important effect that HPV vaccination could have on the future epidemiology and treatment of penile cancer. HPV vaccination for high-risk HPV subtypes should now be considered in all young men as well as young women. It has the potential to improve herd immunity with regard to infection with all strains of HPV present in the vaccines, and thus to protect the population at large from both benign and malignant HPV-induced lesions.

In the near future, therapeutic HPV DNA vaccines will also be able to treat patients with HPV-positive disease. The first one in development, GTL001, is currently being evaluated in a phase II international randomized controlled trial across seven European countries.[9] We are awaiting these results, which will be published within the next 6 months. Further research is needed on HPV vaccination’s possible role in the treatment of HPV penile carcinomas. This affordable adjunct to treatment could potentially improve outcomes for all patients with HPV-associated penile carcinomas. The option of vaccination as treatment adds further weight to the argument that all penile tumors should be typed for HPV status, as we are now on the threshold of an era in which this information will directly affect the treatment and management of these patients.

Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.


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2. Alemany L, Cubilla A, Halec G, et al. Role of human papillomavirus in penile carcinomas worldwide. Eur Urol. 2016 Jan 4. [Epub ahead of print]

3. Stratton KL, Culkin DJ. A contemporary review of HPV and penile cancer. Oncology (Williston Park). 2016;30:245-9, 252.

4. Gutierrez-Pascual M, Vicente-Martin FJ, Lopez-Estebaranz JL. Lichen sclerosus and squamous cell carcinoma. Actas Dermosifiliogr. 2012;103:21-8.

5. Mannweiler S, Sygulla S, Winter E, Regauer S. Two major pathways of penile carcinogenesis: HPV-induced penile cancers overexpress p16ink4a, HPV-negative cancers associated with dermatoses express p53, but lack p16ink4a overexpression. J Am Acad Dermatol. 2013;69:73-81.

6. Velazquez EF, Amin MB, Epstein JI, et al. Protocol for the examination of specimens from patients with carcinoma of the penis. Arch Pathol Lab Med. 2010;134:923-9.

7. McDaniel AS, Hovelson DH, Cani AK, et al. Genomic profiling of penile squamous cell carcinoma reveals new opportunities for targeted therapy. Cancer Res. 2015;75:5219-27.

8. Feber A, Arya M, de Winter P, et al. Epigenetics markers of metastasis and HPV-induced tumorigenesis in penile cancer. Clin Cancer Res. 2015;21:1196-206.

9. Esquerré M, Momot M, Goubier A, et al. Bivalent adenylate cyclase (CYA)-based therapeutic vaccines: eradication of tumor cells expressing different antigens over time. Cancer Res. 2015;75(15 suppl):abstr 2507.