Human Papilloma Virus and Anal Squamous Cell Cancer in IBD: Is It Time to Update Our Practice Parameters?

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Anal squamous cell carcinoma (ASCC) remains a relatively rare malignancy, with 8080 new cases diagnosed annually, accounting for only 2% of all colorectal malignancies. However, its incidence has continued to rise over the last 30 years, rising at a rate of 2.2% per year over the last 10 years. Unfortunately, unlike many other malignancies, the mortality rate is rising as well, rising on average 3.2% per year over the last 10 years.1 Both ASCC and the ASCC precursor lesion, anal intraepithelial neoplasia (AIN III) or high-grade squamous intraepithelial lesion (HSIL), are caused by infection with oncogenic strains of human papilloma virus (HPV).2,3 Of particular concern are the HPV oncogenic subtypes HPV 16 and 18, which are also associated with cervical intraepithelial neoplasia.4 HPV is found in <96% of all ASCCs, with HPV 16 being the dominant strain, present in 65% to 89% of the anal cancers,5,6 followed by HPV 18.
HPV is found in <50% of the general population, with a peak incidence in the third decade of life. Fortunately, in 90% of affected people, HPV spontaneously resolves within 2 years.7 Persistent infection is more likely to occur in men aged 18 to 30 years and in high-risk groups, including those who practice anoreceptive intercourse or those who are immunosuppressed. Of particular risk are HIV-infected men who have sex with men (MSM). Because of the clear association of HPV with HSIL and ASCC, 2 of the 4 available vaccines for HPV are now recommended for men with anal neoplasia. Supporting this recommendation are the findings from a recent phase III randomized control trial, which found that the administration of the quadrivalent HPV vaccine (HPV subtypes 6, 11, 16, and 18) to MSM reduced the observed rate of HSIL and eliminated persistent HPV infection in 95% over the 3-year follow-up period.8
Since the introduction of the Papanicolaou (Pap) testing in 1975, the incidence of cervical cancer has decreased by >50%.9 Although the incidence of anal cancer is actually higher in HIV-positive MSM (42 to 131 per 100,000) than the incidence of cervical cancer before Pap testing (35 per 100,000),6 universal screening has not been adopted for anal cancer, even among high-risk populations. This is unfortunate given that HSIL is treatable and, left untreated, may progress to ASCC in 8.5% to 13.0% of patients,2,3 and 5-year survival for stage I, II, IIIA, IIIB, and IV ASCC is 76.9%, 66.7%, 57.7%, 50.7%, and 15.2%.10
Multiple risk factors for ASCC have been described, including a history of anal receptive intercourse, sexually transmitted diseases, number of sexual partners, HPV, smoking, and immunosuppression. Immunosuppressed populations known to be at increased risk for ASCC include solid organ transplant recipients, patients with hematologic malignancies, and HIV-positive patients.11 Given the number of patients with IBD on immunosuppressive medications or with chronic inflammation because of perianal disease, it seems plausible that this patient population may also be at increased risk for HPV, HSIL, and ASCC. Unfortunately, risk factors, incidence of HPV and HSIL, and treatment outcomes for ASCC in patients with IBD come largely from small, single-institution series, unable to power a comparison with patients without IBD.
The largest series to date of anal neoplasia in patients with IBD described that high-risk HPV strains (HPV 16 and 18) and chronic perianal fistulizing Crohn’s disease (>10 y) were associated with ASCC. In fact, 72% of patients with neoplasia had high-risk HPV, and 100% of patients with ASCC had perianal fistulizing disease of >10 years.
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