BERKELEY, CA (UroToday.com) - For men with human papillomavirus (HPV) infection, external genital lesions (EGLs) are cosmetic sequelae of infection with associated psychosocial burden and malignant potential. For the urologist, EGLs present a challenge for timely, definitive management and longitudinal surveillance. For public health interests, EGLs represent an important consequence of viral transmission with far-reaching effects, underscoring the importance of understanding and preventing EGLs. HPVs are definite carcinogens in the vulva, vagina, cervix, anus, penis, and oropharynx. Transmission represents a cancer risk for millions of people in the U.S. and elsewhere, including for penile cancer, where incidence rates are higher in other parts of the world, such as Latin America, Sub-Saharan Africa, and Eastern Europe.
The prospective, international HPV Infection in Men (HIM) Study enrolled male adolescents and young men and demonstrated that administration of the quadrivalent HPV vaccine can prevent infection and EGLs. This and other studies led to the 2011 recommendation from the Centers for Disease Control and Prevention (CDC) for quadrivalent HPV vaccination of boys and men ages 11-22, and for higher-risk men up to age 26. The CDC recommendations for girls and women are similar, focused on ages 13-26. However, current guidelines do not have recommendations for vaccination of older men, a relatively understudied population in terms of HPV infection and EGLs.
In the Journal of Infectious Diseases, Ingles and colleagues report results from the HIM Study (NCT00786760; Epub October 24, 2014). The goals of this large, prospective, multinational study of HPV in 4 000+ healthy men in the U.S., Mexico, and Brazil include assessing incidence, HPV genotype distribution, age, and EGL histologic subtype distribution in men. In this report, men were required to have two or more study visits, at which time they were screened visually for EGLs with 3x magnification. Specimens from suspicious lesions were obtained with surface swabs and shave biopsy. The specimens were examined by the University of South Florida Dematopathology Laboratory for histologic diagnosis and tested for 28 HPV genotypes, including the types included in the quadrivalent vaccine (low-risk types 6 and 11 and high-risk types 16 and 18), as well as the HPV subtypes covered by the recently FDA-approved nonavalent HPV vaccine (6, 11, 16, 18, 31, 33, 45, 52, and 58).
Among the 2 754 men included in the biopsy sub-cohort of the HIM Study, 377 EGLs in 228 men were pathologically confirmed, including in 198 men who developed incident EGLs during the study period. The majority of EGLs identified were condylomas (n=158) or suggestive of condyloma (n=124), with a smaller proportion representing penile intraepithelial neoplasia (PeIN). A key finding of the study was that EGLs tended to decrease in incidence as the age of men increased. The 12-month incidence of any EGL was higher among men < 45 years of age (4.8% and 5.4% among men 18-30 and 31-44 years, respectively) relative to older men (2.5% among men ages 45-73; p=0.030). Similar trends were observed in separate analyses of condylomas and PeIN. For PeIN, all cases were identified in men < 45 years of age.
With regard to HPV genotypes, low-risk types were predominantly associated with lesions identified as condyloma (79.7%) or suggestive of condyloma (75.8%). On the other hand, of the 14 PeIN lesions diagnosed in this cohort, all were associated with HPV, and 85.7% were positive for one or more of the high-risk HPV genotypes (red numbers in Table 1). Interestingly, two of the PeIN lesions were associated with only low-risk types (one with HPV 6 and one with HPV 11), and two of the incident PeIN lesions contained HPV types (HPV 39, 51, 68, 73) targeted by neither vaccine. Counting just the HPV(+) EGLs, the overwhelming majority were positive for one or more types targeted by the quadrivalent (92.4%) or nonavalent (96.9%) vaccine.
Commentary and Discussion
The HIM Study represents a real-world experience of the match between available HPV vaccines and the causative HPV genotypes in incident EGLs in a male population. Our developing understanding of the natural history of penile lesions, and the details of which genotypes of the HPV virus are prevalent, represent fundamental steps to guide vaccine composition and to define target populations. Specifically, it should be noted that while HPV-associated EGL incidence was higher in younger patients, new lesions still were identified in the older cohorts, a group outside current CDC HPV vaccination recommendations. Whether vaccination in older men could prevent the development of these HPV-associated EGLs is an important question. Further, as emphasized by the authors, whether vaccination in childhood or early adulthood provides durable long-term immunogenicity is untested in men. Issues for older men include HPV-associated diseases as well as public health concerns on viral spread.
From the perspective of the urologist, this is an exciting time, the bridging from biological details of the disease towards improved disease control and prevention. Data-driven vaccine design, addressing subtype selection and age administration guidelines, will be a concrete step towards a goal of effective primary prevention of EGLs, virus-associated penile cancers, and HPV-associated diseases of other organs. One may anticipate a growing emphasis on immune-mediated therapy of HPV-associated EGLs, particularly pre-malignant and malignant lesions, with movement beyond conventional excision or topical treatments. For example, an ongoing clinical trial is investigating the use of an HPV 16 and 18 vaccine (NCT01304524) for the treatment of high-grade cervical intraepithelial neoplasia (CIN), a squamous epithelial lesion with HPV genotypic associations similar to EGLs in men. A second immunotherapy example is treatment with tumor infiltrating lymphocytes (TILs) selected for HPV reactivity, with reported regression of metastatic lesions in HPV-associated cervical cancer. Such vaccine strategies for HPV-associated diseases, and a potential for combination with other immune agents in wide development in oncology, represent a novel treatment paradigm for HPV-associated diseases.
Any HPV Type (%)
Low Risk HPV (%)
High Risk HPV (%)
Coinfection Low+High Risk HPV (%)
|Vaccine-4 Coverage (%)||Vaccine-9 Coverage (%)||Vaccine-4 Coverage (%)||Vaccine-9 Coverage (%)|
|Suggestive of Condylomas||77.4||75.8||13.7||12.1||73.4||75.0|
Table 1: HPV Genotypes: Distribution of high & low risk, vaccine coverage.
- Forman D, de Martel C, Lacey CJ, et al. Global burden of human papillomavirus and related diseases. Vaccine 30 Suppl 5:F12-23, 2012
- Giuliano AR, Palefsky JM, Goldstone S, et al. Efficacy of quadrivalent HPV vaccine against HPV Infection and disease in males. N Engl J Med 364:401-11, 2011
- Recommendations on the use of quadrivalent human papillomavirus vaccine in males--Advisory Committee on Immunization Practices (ACIP), 2011. MMWR Morb Mortal Wkly Rep 60:1705-8, 2011
- Markowitz LE, Dunne EF, Saraiya M, et al. Human papillomavirus vaccination: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 63:1-30, 2014
- Ingles DJ, Pierce Campbell CM, Messina JA, et al. Human Papillomavirus Virus (HPV) Genotype- and Age-Specific Analyses of External Genital Lesions Among Men in the HPV Infection in Men (HIM) Study. J Infect Dis, 2014
- Hinrichs CS, Stevanovic S, Draper L, et al. HPV-targeted tumor-infiltrating lymphocytes for cervical cancer. J Clin Oncol 32:5s, 2014 (suppl; abstr LBA3008).
Scott Haake, MD,a Philippe Spiess, MD,b and Mayer Fishman, MD, PhDb as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
aFellow, Medical Oncology & Hematology Fellowship, Moffitt Cancer Center
bDept. of Genitourinary Oncology, Moffitt Cancer Center
No financial conflicts in relation to the pharmaceutical products discussed.
Drs. Spiess and Fishman are members of the Department of Urologic Oncology at the Moffitt Cancer Center and collaborate with Dr. Giuliano and colleagues in projects relating to genitourinary oncology.