Anal Cancer Prevention (PDQ®)–Health Professional Version

Who Is at Risk?

Human papillomavirus (HPV) infection is the strongest risk factor for anal cancer and is accepted as a causal agent of squamous cell carcinoma of the anus and its precursor lesions.[1] Behaviors or medical conditions that either indicate HPV infection or facilitate HPV transmission or persistence are associated with increased risk. These behaviors and conditions include a history of HPV-related cancers, high-risk sexual practices such as sex between men, receptive anal intercourse and numerous sexual partners, human immunodeficiency virus (HIV) infection, and chronic immunosuppressive states.[2] Cigarette smoking is also a risk factor.[3]

Factors Associated With Increased Risk of Anal Cancer

Interventions Associated With a Decreased Risk of Anal Cancer

Interventions With Inadequate Evidence as to Whether They Reduce the Risk of Anal Cancer

United States

The Surveillance, Epidemiology, and End Results (SEER) Program age-adjusted annual incidence rate of anal cancer in the United States from 2017 to 2021 was 1.9 cases per 100,000 persons per year, and the mortality rate was 0.4 cases per 100,000 persons per year from 2018 to 2022. Incidence rates were slightly higher for women than for men (2.3 vs. 1.6 per 100,000 person-years, respectively), but mortality rates were about the same.[1] In 2024, it is estimated that 10,540 Americans will be diagnosed with anal cancer and 2,190 will die from this disease.[2] Incidence rates increased annually from 2012 to 2021 (average increase, 1.3%), and mortality rates increased annually from 2013 to 2022 (average increase, 5.1%). All incidence and mortality increases were statistically different from zero.[3] The 5-year survival rate has remained fairly constant since 1975, and based on data from 2014 to 2020, it was 70.6%.[1]

World

An estimated 27,000 new cases of anal cancer were diagnosed worldwide in 2008.[4] No global incidence rates, mortality rates, or survival statistics are available.

Precursor Lesions

Squamous cell cancer of the anus is preceded by grade 2 or 3 anal intraepithelial neoplasia (AIN), also referred to as high-grade AIN. Grade 1 AIN is not considered a precursor lesion of anal cancer but may precede high-grade AIN.[4] The cytological terms for low- and high-grade AIN are low-grade squamous cell intraepithelial lesions (LSIL) and high-grade squamous cell intraepithelial lesions (HSIL).[4]

One study reported that 11% of AIN cases progressed to invasive disease over an 8-year period.[5] However, results from another study suggested that progression is much less frequent. Using AIN prevalence and anal cancer incidence data, the investigators estimated hypothetical annual rates of progression from high-grade AIN to anal cancer. For men who have sex with men (MSM) and who are human immunodeficiency virus (HIV) positive, the rate was about 1 case in 600 patients. For HIV-negative MSM, the rate was 1 case in 4,000 patients.[6] Using meta-analysis techniques to combine data from numerous studies worldwide, the investigators estimated that the prevalence of LSIL is 27.5% (95% confidence interval [CI], 21.9%–33.2%) and the prevalence of HSIL is 6.7% (95% CI, 4.4%–9.0%) in HIV-positive MSM. Among HIV-negative MSM, the prevalence of LSIL was 6.6% (95% CI, 1.1%–12.1%), and the prevalence of HSIL was 2.7% (95% CI, 0.0%–5.1%).[6]

Factors Associated With Increased Risk of Anal Cancer

HPV Vaccination

Because human papillomavirus (HPV) is a causal condition for squamous cell anal cancer development, vaccination against the oncogenic strains of HPV before exposure may reduce the risk of anal cancer. Conducted from 2004 to 2008, a multicountry trial randomly assigned 4,065 boys and men to receive either the three-shot quadrivalent HPV vaccine regimen (for HPV-6, -11, -16, and -18) or a three-shot placebo injection regimen. Of the 4,065 patients, 602 reported having sex with male partners in the year before enrollment. Heterosexual participants were between the ages of 16 years and 23 years and had no more than five lifetime female partners. Patients who reported sex with male partners were between the ages of 16 years and 26 years and had no more than five lifetime male or female partners. Persistent infection was defined as detection of the same HPV type in anogenital swabs or biopsy specimens collected on two or more consecutive visits, with an interval of 6 months between visits. In the intent-to-treat analysis, which included participants regardless of their baseline HPV status, the efficacy against persistent HPV-6, -11, -16, and -18 infection was 48% (95% confidence interval [CI], 36.0%–57.6%). Among those who were negative for the four HPV strains of interest at baseline (per the protocol analysis, which included 1,397 intervention-arm and 1,408 control-arm participants), vaccine efficacy against persistent HPV-6, -11, -16, and -18 infection was 90% (95% CI, 69.2%–98.1%).[1]

A nonrandomized, phase II, open-label trial (AMC 072 [NCT01209325]) was conducted in 149 men who have sex with men living with HIV. This study did not show a statistically significant difference between incident-persistent infections in the naïve, per-protocol, and previously exposed per-protocol groups. However, there was a statistically significant reduction in incident HPV-16–associated histological high-grade squamous intraepithelial lesions (HSIL) in the naïve group when compared with the previously exposed group (P = .014). The authors conducted a secondary analysis that compared the per-protocol quadrivalent HPV (qHPV)-type naïve participants in the AMC 072 trial to the original, per-protocol placebo group in the Merck 020 trial. This analysis demonstrated that vaccinated qHPV-naïve AMC-072 participants had significantly reduced disease in a combined analysis of all four qHPV types (5.8 per 100 person-years vs. 0 per 100 person-years; P = .008).[2]

Among the 602 patients who had sex with men, the vaccine efficacy against persistent HPV-6, -11, -16, and -18 infection was 59% (95% CI, 43.0%–71.4%) in the intent-to-treat analysis and 95% (95% CI, 80.4%–99.4%) in the per-protocol analysis. Efficacy against HPV-6, -11, -16 or -18–associated anal intraepithelial neoplasia (AIN) was 50% (95% CI, 25.7%–67.2%) in the intention-to-treat analysis and 77.5% (95% CI, 39.6%–93.9%) in the per-protocol analysis (275 intervention-arm and 276 control-arm participants). Efficacy against HPV-6, -11, -16, or -18–associated high-grade AIN was 54.2% (95% CI, 18.0%–75.3%) in the intent-to-treat analysis and 74.9% (95% CI, 8.8%–95.4%) in the per-protocol analysis (194 intervention-arm and 208 control-arm participants).[3]

Efficacy of the bivalent (HPV-16 and HPV-18) vaccine against anal infection was evaluated in the context of a randomized controlled trial of cervical cancer prevention. Conducted in 6,300 Costa Rican women aged 18 to 25 years at enrollment, the trial compared the efficacy of the three-dose bivalent vaccine with that of a control vaccine. Four years after vaccination, most women were offered the option of providing an anal specimen. Among the 2,103 intervention-arm and 2,107 control-arm participants who provided specimens, vaccine efficacy (i.e., absence of HPV-16 or -18 in the specimen) was 62% (95% CI, 47.1%–73.1%). Among the 1,003 intervention-arm and 986 control-arm participants who provided anal specimens, received the three doses, had no evidence of cervical HPV-16 or -18 infection before vaccination, and were seronegative before vaccination, vaccine efficacy was 84% (95% CI, 66.7%–92.8%).[4]

These data strongly suggest that vaccination against oncogenic HPV strains will lead to reductions in anal cancer. They also suggest that vaccination before exposure will provide the most benefit.

Treatment of Anal HSIL

Until the Anal Cancer–HSIL Outcomes Research (ANCHOR) trial was published, there had not been confirmation that treating anal HSIL decreased an individual's risk for invasive cancer.[5] However, the findings from the ANCHOR trial provided solid evidence that treatment of anal HSIL prevented the incidence of anal cancer. This trial, which was a phase III trial conducted at 25 U.S. sites, included individuals living with HIV who were aged 35 years or older and had biopsy-proven anal HSIL. Participants were randomly assigned in a 1:1 ratio to receive either HSIL treatment or active monitoring without treatment. Nine cases were diagnosed in the treatment group (173 per 100,000 person-years; 95% CI, 90.0–332.0), and 21 cases were diagnosed in the active-monitoring group (402 per 100,000 person-years; 95% CI, 262.0–616.0) after a median follow-up of 25.8 months. The rate of progression to anal cancer was 57% lower in the treatment group than it was in the active-monitoring group (95% CI, 6.0–80.0; P = .03 by log-rank test).

In a recent cohort study of 28,175 individuals being treated for HIV (59.7%, men who have sex with men [MSM]), 227 primary anal cancer cases were diagnosed.[6] Despite the increasing average age of the cohort, crude incidence rates of anal cancer in MSM declined slowly over time from 107.0 per 100,000 person-years (95% CI, 75.7–147.0) in 1996 to 2005 to 93.7 per 100,000 person-years (95% CI, 75.3–115.0) in 2013 to 2020 (P = .49). Crude incidence rates in men who do not have sex with men (non-MSM) and women were generally lower than those in MSM. However, crude incidence rates increased slightly over time from 51.08 per 100,000 person-years (95% CI, 20.54–105.25) to 67.82 per 100,000 person-years (95% CI, 40.83–105.91; P = .52) in non-MSM and from 8.09 per 100,000 person-years (95% CI, 0.20–45.06) to 24.95 per 100,000 person-years (95% CI, 10.03–51.40; P = .29) in women. In addition, the authors compared a subcohort of 3,866 MSM who received high-resolution anoscopy (HRA) screening at least once and treatment for HSIL. Furthermore, if screened individuals had low-grade squamous intraepithelial lesions (LSIL), they continued HRA screening once yearly, and those who had HSIL treatment received HRA screening every 6 months. TNM tumor staging was more favorable (Cochrane-Armitage test for trend, P = .033) in individuals diagnosed with anal cancer during screening. Crude anal cancer–associated 5-year mortality in people living with HIV decreased from 30.4% (1996–2005) to 18.3% (2013–2020; odds ratio, 0.48; P = .070). Anal cancer–related mortality was 3.7% (95% CI, 0.5–23.5) in all men who had been screened and 24.0% (95% CI, 18.1–31.3) in men who had not been screened (P = .023). In men, screening participation (hazard ratio [HR], 0.31; P = .051) and cumulative exposure to CD4 counts of less than 200 cells per µL (HR, 1.11 per year; P = .0022) were independently associated with anal cancer–related mortality.

Even though people living with HIV represent a high-risk population, anal cancer is still rare, and there were few anal cancers in this cohort, rendering conclusions difficult. In particular, there were only 37 anal cancers in non-MSM and only 10 among women. As a result, CIs were wide, and conclusions were suggestive at best. Of note, there are no known randomized controlled trials that provide evidence to support the conclusion of this study.

Data do not support the conclusion that men had improved survival when they were diagnosed with anal cancer after screening or that it is important to screen those who are at high risk of developing anal cancer. The study purported to show reduced mortality after an anal cancer diagnosis among screened men, but the curves in the study's results did not make adjustments for lead-time bias, selection bias, nor the possibility of overdiagnosis bias. The study also suggested that there was a larger proportion of early-stage cases among screened individuals, but the proportional stage shift caused by anal cancer screening is known to be influenced by lead-time and overdiagnosis biases. There was no mention of adjustment for these biases in the study's results. In addition, there was a high proportion of unknown stages, further suggesting that the conclusions in this study were not supported by the data. This is an additional rationale for why the data did not support the conclusion of the study.

Condom Use

Because human papillomavirus (HPV) can be transmitted through microabrasions, as well as through more pronounced exposures such as exchange of certain bodily fluids,[1] restriction of condom use to penetrative activity will not protect against transmission that occurs as part of other sexual contact. Nevertheless, condom use would be expected to reduce some risk of transmission and thus anal cancer risk. Few data that explore these hypotheses exist, and those that do suggest a very modest effect, if any. Of note, the ability of condom use to reduce cervical cancer risk is still uncertain and the subject of debate.[2]

In an Italian cohort of 258 HIV-negative men who have sex with men (MSM), the odds ratio (OR) for infection with high-risk HPV strains was 1.7 (95% confidence interval [CI], 0.52–6.3) for inconsistent or no use of condoms in receptive anal sex, compared with consistent condom use.[3] In a Brazilian cohort that included 176 MSM, the OR for oncogenic HPV infection was 1.8 (95% CI, 0.77–4.35) for men who sometimes used condoms for anal sex and 1.8 (95% CI, 0.58–5.68) for men who never used condoms, compared with men who always used condoms.[4]

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about anal cancer prevention. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Screening and Prevention Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Screening and Prevention Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Screening and Prevention Editorial Board. PDQ Anal Cancer Prevention. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/anal/hp/anal-prevention-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389511]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

Contact Us

More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.