Abstract
Even though the incidence of anal cancer among men who have sex with men (MSM) is higher than the incidence of cervical cancer among women, few MSM are identified as high-risk patients in primary care or have received vaccination for human papillomavirus (HPV), the most common sexually transmitted infection worldwide, with 6.2 million new infections each year. The authors review the current literature on diagnosis and basic management of genital, oral, and anal HPV infection. Early diagnosis and treatment of patients with HPV infection is important because this infection causes patients substantial distress even in its benign manifestations. It has also been implicated in a host of cancers, including oral, cervical, penile, and anal cancers and is an independent risk factor for the development of human immunodeficiency virus infection. The incidence of HPV infection drops in women older than 30 years but remains high for MSM in all age ranges. For all of these reasons, physicians should routinely assess the sexual practices of all male patients, especially MSM, and educate them on the HPV infection risks, diagnosis, and treatment options. Physicians can have a significant impact in the primary prevention of HPV by routinely offering HPV vaccination to male patients younger than 26 years.
A major milestone in medicine occurred in 2006 when the Food and Drug Administration approved the first vaccine against human papillomavirus (HPV).
1 In 2009, the Food and Drug Administration subsequently licensed the quadrivalent HPV vaccine for use in boys and young men aged 9 to 26 years.
2 Although the vaccine was initially indicated for young women, HPV infection is highly prevalent in males and is responsible for substantial disease in men, particularly men who have sex with men (MSM).
3,4 For example, HPV infection is an independent risk factor for acquiring human immunodeficiency virus (HIV) infection and some forms of cancer.
5,6 In one study, a majority of the MSM surveyed admitted to having genital warts but did not think they had an HPV infection.
7
Men who have sex with men may be difficult to identify in general practice because many of them do not self-identify as gay or bisexual or are still having sex with women as they develop their sexual identity.
8 Studies indicate that prior estimates of the MSM population were too low and that physicians in general practice can anticipate that 3% of their male patients have had sexual contact with another man in the previous year.
9,10 One study
11 found that 15% of men in a random sample reported some type of sexual contact with another man, irrespective of how they self-identified their sexuality.
In this article we will review the prevalence and basic management of the most common manifestations of HPV infection in MSM, including genital, penile, oral, and anal HPV infection. We will also discuss the possible benefits of offering the HPV vaccine to MSM for the primary prevention of anal carcinoma and HPV transmission to men or women and to reduce the risk of HIV infection.
The Centers for Disease Control and Prevention (CDC) estimates that 20 million individuals are infected with HPV. This number grows larger as 6.2 million new individuals are infected each year, making HPV infection the most common sexually transmitted viral infection worldwide.
12,13 The prevalence of the virus tends to peak after a patient's first sexual encounter (ie, “sexual debut”) and remains high with each new sexual partner among all age groups.
14,15 The risk of developing anal cancer is 17 times higher in gay or bisexual men than in heterosexual men.
3,16 A 2008 meta-analysis of the current literature found that HPV is associated with 85% of anal squamous cell carcinomas in men, 50% of penile cancers, and up to 72% of oropharyngeal cancers.
6 Cancers associated with HPV infection are mostly due to HPV-16 or HPV-18, with numbers roughly approximating the number of cervical cancers in the United States.
17 These findings are particularly worrisome for MSM, because oral sex, anal receptive intercourse, and noninsertive, “safe sex” contact can all result in HPV transmission.
18
The CDC reports that only 1% of sexually active men have visible genital warts at any given time, yet if advanced antibody testing methods are used, up to 73% of healthy men have detectable HPV in the external genital tract.
6,16 Genital warts (condyloma acuminatum, venereal warts) are a common symptom of infection with HPV-6 or HPV-11.
20 Even though condyloma-associated HPV strains 6 and 11 are considered low risk because of their nononcogenic nature, they are still transmissible, incur costs of frequent treatment, and have emotional costs to patients.
19 Both HPV-6 and HPV-11 can cause recurrent respiratory papillomatosis, an uncommon condition in which condylomas develop in the throat, potentially blocking the patient's airway.
6,12
Most genital HPV infection is transmitted by skin-to-skin sexual contact usually involving friction or microtrauma to exposed skin
.20 Subclinical infections are common; exophytic or visible condylomas usually appear 1 to 3 months after exposure but can appear much later.
20 There is no standard method to diagnose genital HPV other than visual inspection and clinician experience. Biopsies are usually not necessary, and HPV DNA sampling is usually not available or practical.
3,20 Generally, genital warts are painless, flesh-colored or pale-pink lesions with cauliflower, velvety, or smooth textures (
Figure 1). Single lesions can be present anywhere on the penile shaft, urethra, scrotum, or perineum and can be symmetric on opposing moist surfaces. Individual condylomas may coalesce in large masses around the penis or perineal area, including the anus.
20,21 For confusing or subclinical lesions, a 5% solution of acetic acid (acetowhite test) can be applied to reveal or whiten inconspicuous lesions, but this is a nonspecific technique and its positive and negative predictive values are unknown.
3,21
Lesions can be confused for other conditions, such as pearly penile papules, molluscum contagiosum, or bowenoid papulosis lesions (
Figure 2), and invasive precancerous lesions.
20 Questionable, atypical, or treatment-resistant lesions should be examined with biopsy for definitive diagnosis. Penile carcinoma is rare but is highly associated with the presence of HPV-16 and the state of being uncircumcised.
4 Patients who are MSM with newly diagnosed condylomas should be screened for other sexually transmitted diseases including HIV infection, hepatitis C virus infection, chlamy - dia, and gonorrhea.
There are a variety of patient- and physician-applied treatments for condylomas, though no treatment is 100% effective. First-line treatments, such as podofilox 0.5% solution or imiquimod 5%, applied directly to the condyloma, are generally safe and convenient for self-application to clinically visible lesions
20,22 (
Figure 3). Physician-applied treatments, such as cryotherapy, podophyllin 20% resin, tricholoracetic acid, and surgical removal are more effective but may also need to be repeated after 1 to 2 weeks
4,22 and require training by the treating physician (
Figure 4 and
Figure 5). Lesions that do not respond to basic therapy or are so extensive that they cause the patient substantial physical or emotion distress should be referred to a specialist for surgery, carbon dioxide laser treatment, or advanced immune-modulating therapies, such as interferon α2b or 5-fluorouracil.
21 The response rates for cryotherapy range from approximately 60% to 90%, compared with 0% to 50% for placebo
24,25 (
Table).
Men who have sex with men have a high risk of developing oral HPV infection. A 2009 study
26 found that oral HPV acquisition was more positively associated with number of recent oral sex and open mouth kissing partners than with the number of vaginal sex partners. Additionally, the prevalence of oral condylomas has increased dramatically since the introduction of highly active antiretroviral therapy among HIV-positive patients, which may be due to immune reconstitution.
27 Human papillomavirus not only causes oral condylomas but is also strongly associated with oropharyngeal cancers and other oral diseases.
28,29 Oral squamous cell carcinoma is the eighth most common cancer in men, and HPV is linked to at least 25% of the cases.
30,31 The incidence of HPV-associated carcinomas of the oropharynx subsantially increased from 1973 to 2004 (annual percentage change, 80%;
P<.001), most likely because of a shift in sexual behaviors, particularly oral sex in young males.
31,32
Common noncancerous oral lesions associated with HPV include oral condylomas (
Figure 6), oral leukoplakia (
Figure 7), and oral lichen planus.
29 Condyloma lesions appear as white or pink sessile, flat, raised, or cauliflowerlike nodules on the mucous membranes or tongue.
21 The most commonly found HPV types are 6, 11, 16, and 18.
21 Oropharyngeal cancers due to HPV occur more commonly among men than among women and account for a large proportion of HPV-associated cancers, second to cervical cancer.
33
Oral condyloma treatment is similar to treatment of lesions in other areas of the body where mucosal surfaces are involved. Cryotherapy, surgical excision, laser treatment and topical 5-fluorouracil are common treatments but should be used by physicians or dentists experienced with their use in this area.
20,27 Ablation of condylomas does reduce transmission,
22 but there is no known way to completely prevent their spread to sexual partners.
Large multicenter studies have shown that 57% of HIV-negative MSM have anal HPV infection, with 26% of them having a high-risk strain.
34 This prevalence persists for MSM across all age groups, whereas the incidence of HPV infection in women tends to peak when women are aged in their late 20s and again after age 55 years.
34 Even though most HPV infections are transient, MSM have more sexual partners, more new sexual partners, and therefore more new exposures to HPV infection after age 30 years than most women.
15,32 HPV-16, one of the types associated with anal neoplasms, is the most common strain found in anal HPV infections among MSM.
18,35
The incidence of anal cancer among MSM is higher than cervical cancer rates among women.
15,34 The latter tend to fall substantially after age 30 years, but MSM are at risk for HPV-associated anal squamous cell intraepithelial lesions throughout their lives in all age groups.
15 Human papillomavirus has been definitively associated with more than 85% of all cancerous or precancerous anal lesions worldwide.
35,36
Condylomas associated with HPV infection can be external or internal, making many lesions difficult to visualize. Patients often report noticing the condylomas after defecation or during sex, particularly if the lesions are in the anal canal, which extends about 3 cm from the anal verge to the anorectal transition zone
37 (
Figure 8). Exophytic condylomas can be managed similarly to other genital warts by using patient- and physician-applied topical treatments, as discussed elsewhere
38 (
Figures 3 through
Figure 5;
Table). The treatment algorithm becomes more complicated with evaluation for the presence of HPV-16 infection, HPV-18 infection, or anal dysplasia.
Anal Papanicolaou tests are increasingly being used to diagnose neoplastic lesions with the same sampling techniques used for cervical Papanicolaou tests.
38 Studies are underway to determine standard guidelines for interpreting anal cytologic findings, but abnormal cells can be easily identified with typical cervical cytology interpretation practices.
4 Patients with abnormal anal cytologic findings should be referred for high-resolution anoscopy, performed by a specialist trained in its use; high-resolution endoscopy, or
anal colposcopy, is an effective way to identify, sample for biopsy, and manage early neoplastic lesions or identify patients who need referral to a colorectal surgeon for management.
38
Physicians who care for MSM should be aware that HPV infection is an independent risk factor for the subsequent development of HIV infection.
5 Patients presenting with HPV infection in any of its forms should be screened for HIV infection at the office visit, preferably with a rapid finger stick or rapid oral HIV test.
5 Higher HIV infection rates are seen among patients already infected with HPV.
5 This association is believed to occur through 2 distinct mechanisms. One mechanism is that sexually transmitted infections such as HPV disrupt normal mucosal anatomic barriers and may allow HIV-infected body fluids direct access to open or bleeding lesions. Another proposed mechanism is that CD4+ T cells and macrophages are recruited in higher numbers to skin surfaces infected with HPV, allowing closer potential contact between HIV-infected fluids and host CD4+ T cells.
5
Men infected with HPV serve as vectors for the spread of the virus to both men and women.
19 It has been demonstrated in recent meta-analyses
36,39,40 that the current HPV vaccine is more than 95% effective against HPV-16 and HPV-18 and could prevent up to 80% of anal carcinomas. The quadrivalent HPV vaccine has also been announced to have 90% efficacy against HPV types 6, 11, 16, and 18 in males aged 16 to 26 years.
41 When an HPV vaccine is approved for males, physicians should be proactive in offering it to their young male patients and all patients who are MSM.
42 Even patients who are knowledgeable about HPV and HIV can and do engage in high-risk sexual behaviors,
43 and MSM may not ask to be screened for HPV or HIV infection.
As knowledge of the HPV vaccine in US communities grows, MSM are increasingly interested about the possibility of being vaccinated. More than 93% of one surveyed group said they would be willing to disclose their sexual history to receive vaccination.
44 Other attitude assessments have determined that young male patients are more willing to be vaccinated if their healthcare provider emphasizes the high prevalence of HPV infection in their communities and the vaccines' threat to their own health more than the patients' risk of transmitting HPV infection to others.
45 A review of the literature shows that acceptance of the HPV vaccine for males is generally high among physicians and patients, but patient acceptance is highly dependent on physicians' offering the vaccine first.
19,46
Historically, physicians have been uncomfortable discussing sexual health issues with patients who are MSM.
8,47 Young gay males may experiment with their sexuality and maintain sexual relationships with both male and female partners, in essence doubling their risk of exposure to and transmission of HPV infection. Given that about 25% of all HPV-associated carcinomas occur in men,
17 widespread vaccination of young men is being considered by the CDC Advisory Committee on Immunization Practices.
42
With the availability of a vaccine that not only could prevent HPV-associated cancer and other diseases but could also help reduce transmission of HIV,
5 physicians have an obligation to incorporate sexual health history and vaccinations into the routine care of their male patients.