Elsevier

European Urology

Volume 69, Issue 1, January 2016, Pages 166-173
European Urology

Penile Cancer
Genital Human Papillomavirus Infection Progression to External Genital Lesions: The HIM Study

https://doi.org/10.1016/j.eururo.2015.05.032Get rights and content

Abstract

Background

Human papillomavirus (HPV) causes two types of external genital lesions (EGLs) in men: genital warts (condyloma) and penile intraepithelial neoplasia (PeIN).

Objective

The purpose of this study was to describe genital HPV progression to a histopathologically confirmed HPV-related EGL.

Design, setting, and participants

A prospective analysis nested within the HPV Infection in Men (HIM) study was conducted among 3033 men. At each visit, visually distinct EGLs were biopsied; the biopsy specimens were subjected to pathologic evaluation and categorized by pathologic diagnoses. Genital swabs and biopsies were used to identify HPV types using the Linear Array genotyping method for swabs and INNO-LiPA for biopsy specimens.

Outcome measurements and statistical analysis

EGL incidence was determined among 1788 HPV-positive men, and cumulative incidence rates at 6, 12, and 24 mo were estimated. The proportion of HPV infections that progressed to EGL was also calculated, along with median time to EGL development.

Results and limitations

Among 1788 HPV-positive men, 92 developed an incident EGL during follow-up (9 PeIN and 86 condyloma). During the first 12 mo of follow-up, 16% of men with a genital HPV 6 infection developed an HPV 6-positive condyloma, and 22% of genital HPV 11 infections progressed to an HPV 11-positive condyloma. During the first 12 mo of follow-up, 0.5% of men with a genital HPV 16 infection developed an HPV 16-positive PeIN. Although we expected PeIN to be a rare event, the sample size for PeIN (n = 10) limited the types of analyses that could be performed.

Conclusions

Most EGLs develop following infection with HPV 6, 11, or 16, all of which could be prevented with the 4-valent HPV vaccine.

Patient summary

In this study, we looked at genital human papillomavirus (HPV) infections that can cause lesions in men. The HPV that we detected within the lesions could be prevented by a vaccine.

Introduction

Human papillomavirus (HPV) causes penile, oropharyngeal, and anal cancer in men [1]. HPV causes two types of external genital lesions (EGLs): condylomata acuminata, commonly referred to as condyloma or genital warts; and penile intraepithelial neoplasia (PeIN), believed to be a precursor to penile cancer. HPV types 6 and 11 are the most frequently detected types in condyloma (96–100%) [2], [3]. Factors associated with the incidence of condyloma in men include younger age (<30 yr) and a high lifetime number of male or female sexual partners [4], [5]. An estimated $200 million is spent annually in the United States for condyloma treatment, which is often ineffective [5], [6]. Thus, identifying the probability of which commonly occurring genital HPV infections progress to condyloma is of major clinical importance.

Although rare, penile cancer is associated with a high morbidity and mortality. There is large geographic variation in the incidence of penile cancer, with low rates observed in the United States (approximately 1 in 100 000) and the highest rates in Brazil (approximately 5 in 100 000) [7], [8]. Penile cancer most commonly affects men aged 50–70 yr [8]. Few studies have examined PeIN HPV type distribution [9], [10], [11], [12], [13], [14], with most testing only for HPV 16 and 18. Factors associated with penile cancer include lack of circumcision and some sexual behaviors [15], [16]. However, no studies to date have estimated PeIN prevalence or incidence or examined progression of genital HPV infection to PeIN [17].

We are uniquely poised to address these fundamental questions within the HPV Infection in Men (HIM) study. The purpose of this study was to describe genital HPV progression to a histopathologically confirmed EGL, specifically condyloma and PeIN, among otherwise healthy adult men. We estimated the percentage of genital HPV infections that progressed to an EGL and the cumulative incidence rates for EGL development.

Section snippets

Study design and population

The HIM study participants are men aged 18–70 yr living in Tampa, Florida, USA; Cuernavaca, Mexico; and Sao Paulo, Brazil, enrolled between July 2005 and June 2009. A full description of study procedures has been published [18], [19]. Every 6 mo, participants undergo interview, a physical examination, and laboratory analysis. The biopsy and pathology protocol was implemented in February 2009. Men who had two or more study visits after implementation of the protocol were included in this study (n

Results

After excluding men with a prevalent HPV-related EGL, 1788 had a prevalent or incident genital HPV infection during follow-up and were included in this analysis. These 1788 men had a total of 4315 genital HPV infections during follow-up; 1849 were prevalent HPV infections, and 2466 were incident HPV infections. Among the 1788 men with an HPV infection during follow-up, 5% developed an incident EGL (86 men had condyloma and 9 men had PeIN lesions). Age was the only significant demographic

Discussion

Infection with one or more of the 37 HPV types detected at the genitals is common among men aged 18–70 yr. Only 5% of these HPV infections progressed to an EGL during follow-up, rates of progression to an EGL were substantially higher for certain HPV types. Twenty-five percent of men with a genital HPV 6 infection progressed to an HPV 6-positive condyloma, and 23% of men with a genital HPV 11 infection progressed to an HPV 11-positive condyloma, with rapid rates of progression to disease after

Conclusions

Genital HPV 6 and 11 infections were the infections most likely to progress to condyloma, and genital HPV 6, 11, and 16 infections were the infections most likely to progress to PeIN. The quadrivalent (6/11/16/18) HPV (qHPV) vaccine contains the most common HPV types (6/11/16) that we found to progress to EGL. The qHPV vaccine has been shown to be efficacious in preventing condyloma and, likely, PeIN [32]. With the national qHPV vaccine program in Australia, condyloma incidence among men in the

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