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HPV-Related Disease in Men: Anal and Penile Cancer (Slides With Transcript)

  • Authors: Joel M. Palefsky, MD, CM, FRCP(C)
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Target Audience and Goal Statement

This activity has been designed for infectious disease specialists, researchers, and other health care professionals who wish to learn more about preventing HPV-related cancers and other diseases.

Upon completion of this activity, participants should be able to:

  1. Describe the epidemiology and pathogenesis of HPV infection at cervical and noncervical body sites.
  2. Define the health care burden of HPV-related anal, penile, and head and neck cancers, and of RRP.
  3. Explain the rationale for and expected public health benefits of widespread HPV vaccination to prevent anal, penile, and head and neck cancers, and RRP.


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  • Joel M. Palefsky, MD, CM, FRCP(C)

    Professor of Medicine; Associate Dean for Clinical and Translational Research; Co-Director, UCSF Clinical and Translational Sciences Institute, University of California, San Francisco, San Francisco, California


    Disclosure: Grants/Research Support: Merck & Co., Inc.

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HPV-Related Disease in Men: Anal and Penile Cancer (Slides With Transcript)

Authors: Joel M. Palefsky, MD, CM, FRCP(C)Faculty and Disclosures


Overview of HPV-Related Disease in Men

  • I'm going to tell you a little bit more about HPV-related disease of the anus and the penis.

  • Slide 1.

    Slide 1.

    (Enlarge Slide)
  • What I'd like to do is tell you about the burden of HPV-associated disease in men, tell you about penile HPV infection and disease, then anal infection and disease, and then talk a little bit about the current thinking about vaccination in men.

  • Slide 2.

    Slide 2.

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  • Here is the slide that led to the data on the question. This is probably an underestimate, but these are the published data. Dr. Gillison will tell you more about why they're probably underestimates, particularly in the oropharynx. But current estimates are about 6900 new HPV-related cases per year in men, and you can see that some of them come from the oral cavity and oropharynx, some of them come from the larynx, and many of them come from the anus and the penis. The proportion of them associated with HPV varies quite widely, with the anus resembling that of the cervix more than the others.

  • Slide 3.

    Slide 3.

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Penile HPV Infection

  • Penile cancer is a cancer that we don't see a lot of here in the developed world, but it does vary in incidence considerably around the world. One of the lowest rates is in Israel, where a high proportion of the men are circumcised. But the rates do go up particularly in countries with high incidences of cervical cancer. For example, you can see in Uganda and in Brazil that the rates of penile cancer are considerably higher than in the United States, roughly a 10-fold ratio.

  • Slide 4.

    Slide 4.

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  • It's quite difficult to make a lot of sense out of the literature on penile HPV infection. That's in part because there is enormous variation in the populations that are studied; the sampling methods have not been standardized the same way they have in the cervix; the anatomic sites vary from study to study and you get different answers depending on which part of the male genital tract you're sampling; and the methods to detect HPV have varied a lot.

  • Slide 5.

    Slide 5.

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  • If you look at the sampling of studies -- and here is an example of 3 of probably the better ones -- you see quite a wide range in the overall prevalence of HPV on the penis. This third one was done by Anna Giuliano's group in the United States and shows one of the higher prevalence of HPV, around 65%. And you can see that you really do have to sample widely if you want to pick up HPV. For instance, in this population, many of whom were circumcised, the shaft is a very common site of HPV infection. People are often surprised when they find out how much anal HPV infection there is in these men, who are predominantly heterosexual. But overall, the numbers do vary, as you can see, quite considerably. And if you look, for instance, under the foreskin specifically, you see quite a bit of HPV infection.

  • Slide 6.

    Slide 6.

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  • As far as risk factors are concerned, again, they're not well understood for the reasons that I summarized earlier, but there are still a few common themes. One of them is that circumcision is protective against HPV infection on the penis. HPV on the penis behaves like an STD in the cervix, with increased number of lifetime sexual partners being associated with it. In 1 study, the number of prostitute contacts was related to it. And in another study, condom use was protective. So overall, our sense is that penile HPV infection behaves much like cervical HPV infection.

  • Slide 7.

    Slide 7.

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Anal HPV Infection

  • What about anal infection? We're looking at the cervical transformation zone here, where the columnar epithelium of the endocervix meets the squamous epithelium of the exocervix. This squamocolumnar junction is a transition zone, which is the primary target of HPV infection. It's essential when we assess the cervix that the entire transition zone or transformation zone be assessed.

  • Slide 8.

    Slide 8.

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  • As it turns out, there is a similar area in the anal canal. That's where the columnar epithelium of the rectum meets the squamous epithelium of the anus. This anal-rectal junction is very similar histologically to the transformation zone of the cervix. To properly assess anal disease, you need to use similar sampling methods, namely cytology, which should ideally cover this area, and visualization with magnification and vinegar using a technique called high-resolution anoscopy.

  • Slide 9.

    Slide 9.

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  • People are talking more about anal cancer these days, and I think with good reason. It's currently better appreciated that the incidence of anal cancer, while not high in the general population, is certainly high in certain risk groups such as MSM (men who have sex with men), where the incidence is not terribly different from the incidence of cervical cancer before we were doing routine Pap smear screening in the cervix. You can see some of these numbers here: before cervical cancer screening, the incidence was 40 to 50 per 100,000; now it is about 8. But before the HIV epidemic in MSM, the incidence of anal cancer was estimated to be 35 per 100,000, and it's at least twice that in HIV-positive MSM. The best estimates are between 75 and 100 per 100,000 in HIV-positive MSM. This is roughly 10 times the current rate of cervical cancer in women.

  • Slide 10.

    Slide 10.

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  • This is what we're trying to prevent here. This was a case that we saw at University of California, San Francisco (UCSF), of a high-grade anal intraepithelial neoplasia (AIN). We didn't treat this person because his disease was too widespread. He came back just a few months later and has an invasive cancer.

  • Slide 11.

    Slide 11.

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  • What we now know is that anal HPV infection is nearly universal amongst HIV-positive MSM. This was just 1 study in San Francisco but it's fairly typical. Even 60% of HIV-negative MSM in the study had anal HPV infection.

  • Slide 12.

    Slide 12.

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  • We wanted to see if these data were generalizable to the rest of the country and did a study to look at the prevalence of anal HPV infection in HIV-negative MSM in 4 different cities around the United States. This was 1400 men. As you can see, not only is the percentage with anal HPV infection similar to what I showed you in the HIV-negative men in San Francisco, but it's also a flat curve throughout life, high but flat. So no matter how old these people are, the prevalence of HPV infection hovers between 50% and 60%.

  • Slide 13.

    Slide 13.

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  • If you look at abnormal anal cytology as a disease marker, you see a similar pattern, and there is a clearer relationship with T cells. The lower the T cells in the pre-HAART (highly active antiretroviral therapy) era, the higher the proportion with abnormal cytology. Even the HIV-negative subjects had a fairly substantial proportion of abnormal anal cytology.

  • Slide 14.

    Slide 14.

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  • Nationally, these numbers are very similar to what we see in San Francisco, with between 18% and 23% of HIV-negative MSM having abnormal anal cytology. Since cytology has limited sensitivity just like cervical cytology does -- the best estimate is that the cytology sensitivity is about 50% -- we're probably underestimating true disease prevalence by about 50%. So the true proportion with disease -- AIN -- is probably closer to 40% to 50%.

  • Slide 15.

    Slide 15.

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  • Unfortunately, this is not a problem that is only restricted to men. We see it in women as well. This is a study that we did in San Francisco comparing the prevalence of anal HPV infections to cervical HPV infection in the same women. These were HIV-positive women and high-risk HIV-negative women -- at high risk for HIV infection. You can see that regardless of which group it is, anal HPV infection is actually more prevalent than cervical HPV infection.

  • Slide 16.

    Slide 16.

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HPV Vaccination in Men

  • Now that we're in the HAART era, the question is, is the problem going to get worse or better? In the more optimistic scenario, we'd like to see regression of high-grade disease to low-grade or nothing when an individual goes on HAART, if there is true immune reconstitution. Conversely, if there is no immune reconstitution -- and we actually don't believe there is going to be because we have evidence to suggest that genetic changes are playing a more important role as the disease progresses to cancer rather than immune suppression -- when somebody goes on HAART, one would expect to see relatively limited improvement in high-grade disease. And if that's so, then we are allowing people to live longer with the high-grade lesion, and in the absence of routine screening those individuals will have longer for their high-grade lesion to progress to cancer. So the concern is, in this scenario, that the incidence of anal cancer would actually increase in the HAART era rather than decrease.

  • Slide 17.

    Slide 17.

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  • Unfortunately, the data point to the second of those 2 scenarios as being the correct one. We started a new study at UCSF several years after HAART was initiated. At baseline in that study, already more than one-half of the men had AIN 2 or 3 despite being on HAART. We repeated the study in 3 different cities around the United States in seropositive women, and at baseline 21% of them had AIN; 8% have had AIN 2/3, and that proportion has grown over time.

    As far as cancer is concerned, there are several pieces of data suggesting that the cancer rates are going up. This is just one, where in a match between the San Francisco AIDS Surveillance Registry and the California Cancer Registry in San Francisco, it was shown by Nancy Hessol that the risk of anal cancer nearly tripled after the introduction of HAART in 1995-1996.

    So we're left with the situation where penile HPV infection is quite common. Fortunately, penile HPV-related cancers are relatively rare. But that is not the case with anal cancers. So there is an argument to be made for reducing disease in men.

  • Slide 18.

    Slide 18.

    (Enlarge Slide)
  • There is one more important thing to consider when thinking about whether or not one should think about vaccination in men. That is, what is their effect on HPV infection in women? What we know is that men are important vectors of HPV infection. I've had discussions with various people about how to title this slide and 1 original version, which I nixed, was, "Men Are the Principal Vectors of HPV Infection." This, of course, is incorrect, since HPV does get spread back and forth between men and women. But men, nevertheless, are a very important piece of the puzzle. Sexual contact with an infected partner is necessary, and there is a strong and consistent association between the numbers of recent and lifetime male sexual partners and detection of HPV in females, not surprisingly. Also consistent with that are data showing that the risk of cervical cancer in a female is associated with her male partner's presence of genital HPV infection, number of extramarital sexual partners, and in 1 study, contact with prostitutes. Also, not surprisingly, since circumcision protects against HPV infection on the penis, it also reduces the risk of cervical cancer in female partners. So, one might anticipate that reduction of penile HPV infection might reduce the risk of cervical and vaginal infection in women.

  • Slide 19.

    Slide 19.

    (Enlarge Slide)
  • The public health rationale in this case comes from the fact that we think that vaccine coverage in girls and women will likely not be complete. If every single at-risk young woman got vaccinated against HPV, then the argument that I just gave you would probably not be very useful. However, we don't think that the coverage is going to be complete, at least not right away. And there are already data to suggest that gender-neutral vaccination has benefits.

  • Slide 20.

    Slide 20.

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  • One of the examples we have of that from the past is rubella. It's a nice analogy because rubella infection occurs in both boys and girls but the consequences are primarily in the girls. In the United Kingdom, they initially started off by vaccinating 10- to 14-year-old girls. They had a fairly flat response initially. They did get somewhere, but it wasn't until they added vaccination to the boys that they truly got rid of new rubella infection in women. This is after they added vaccination in boys, and all of the new cases in the United Kingdom were from immigrants who had not been vaccinated. So they clearly got an extra benefit by vaccinating the boys and the girls even though the disease primarily affects the girls.

  • Slide 21.

    Slide 21.

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  • People have modeled the potential impact of adding vaccination to men on HPV 16/18-related CIN 2/3 incidence in women. They've shown -- this is women-only vaccination in purple and universal vaccination in green -- that one might expect a reduction of about 1.5 million cases of CIN 2/3 sometime in the next 15 to 20 years and beyond.

  • Slide 22.

    Slide 22.

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  • Likewise, if you look at the impact on genital warts, you might see a fairly substantial reduction in genital warts in women if you vaccinated women or if you vaccinated both men and women. The real extra kick comes from vaccinating the boys.

  • Slide 23.

    Slide 23.

    (Enlarge Slide)
  • The rationale, then, to vaccinate with a prophylactic HPV vaccine is from the potential not only to reduce HPV disease burden in the men but also to reduce the transmission of HPV to women, the old-fashioned herd immunity concept.

  • Slide 24.

    Slide 24.

    (Enlarge Slide)
  • Will a vaccine work in boys? There aren't data published yet on the efficacy to prevent infection on the penis or in the anus. There are studies ongoing. But there are some very hopeful indications. One of them was a study that was done of the quadrivalent vaccine in 9- to 15-year-old boys where the outcome was immunogenicity. They showed that in the boys the titers were 2- to 3-fold higher than in young women. This was a pleasant surprise because in many studies men don't respond as robustly from an immunologic standpoint as women do. And the safety profile was favorable.

    The other thing that I think was encouraging was the very high efficacy against external genital lesions, particularly warts in the women. The idea was that the keratinized skin where those genital warts occur may not be as amenable to prevention as internal disease like cervical disease, and those external genital lesions more closely resemble what you might see on the penis. Well, that didn't turn out to be the case. The prevention of external genital lesions was excellent in the women. And that is the kind of skin surface that we see on the penis, and therefore, I think it bodes well for ultimate prevention of penile HPV infection. But we'll need to see the results of those studies.

  • Slide 25.

    Slide 25.

    (Enlarge Slide)

Summary: HPV-Related Disease in Men

  • To summarize, HPV infection does lead to a substantial disease burden in men. HPV can be transmitted from infected men to women and to other men if they are MSM. The immunogenicity data and the similarity of the biology of HPV-associated disease in men and women suggest that vaccination will be effective to prevent HPV infection in men. And hopefully the benefits will include reduction in disease burden in men and enhanced herd immunity to reduce disease burden in women.

  • Slide 26.

    Slide 26.

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