Description of the Evidence
Incidence, mortality, and survival
The Surveillance, Epidemiology, and End Results (SEER) age-adjusted annual incidence rate of anal cancer in the United States for the period from 2006 to 2012 was 1.7 cases per 100,000 persons per year, and the mortality rate was 0.2 cases per 100,000 persons per year. Incidence rates were slightly higher for women than for men (1.9 vs. 1.5 per 100,000 person-years, respectively), but mortality rates were the same. In 2015, it is estimated that 7,270 new cases of anal cancer will be diagnosed, and 1,010 deaths will be caused by this disease in the United States. Incidence rates increased annually from 2001 to 2010 (average increase, 2.4%) and mortality rates increased annually over the same time period (average increase, 3.4%). The annual percent increase in incidence was greater for women (2.7%) than for men (2.1%), but the increase in mortality was greater for men (4.0%) than for women (3.1%). All incidence and mortality increases were statistically different from zero. Five-year survival has remained fairly constant since 1975 and on the basis of data from 2003 to 2009, is 66%.
An estimated 27,000 new cases of anal cancer were diagnosed worldwide in 2008. No global incidence rates, mortality rates, or survival statistics are available.
About 85% of anal cancers in the United States have squamous cell histology or a histologic variant. Nearly all other anal cancers are adenocarcinomas. Human papillomavirus (HPV) vaccination, HPV screening, and screening for the presence of anal cancer precursor lesions will probably change the histologic distribution of anal cancer in years to come, as HPV is implicated only in squamous cell carcinomas, and identification of precursor lesions is expected to reduce invasive squamous cell disease.
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. The cytologic terms for low- and high-grade AIN are low-grade squamous cell intraepithelial lesions (LSIL) and high-grade squamous cell intraepithelial lesions (HSIL).
One study reported progression of 11% of AIN cases to invasive disease over an 8-year period, although 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 in men who have sex with men (MSM) and who are human immunodeficiency virus (HIV) positive to be about 1 case in 600 and 1 case in 4,000 for HIV-negative MSM. 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).
Factors associated with increased risk of anal cancer
Anal HPV infection
HPV infection is the strongest risk factor for anal cancer. About 90% of anal cancers occur in individuals with detectable HPV infection. HPV infection with oncogenic HPV strains is accepted as a causal agent and necessary condition for development of squamous cell carcinoma of the anus and its precursor lesions. In a 2009 meta-analysis of about 1,000 invasive squamous cell lesions, HPV-16 was present in about two-thirds and HPV-18 was present in about 5%. Because 85% of anal cancers have a squamous cell carcinoma histology or histologic variant, it is probable that elimination of oncogenic HPV infection would nearly eradicate anal cancer.
HPVs are typically cleared rapidly in healthy individuals. Persistence of the oncogenic HPV strains is more likely in persons with compromised immune systems; therefore, risk of squamous cell anal cancer is much higher in these individuals. Behaviors that facilitate transmission of HPVs also increase risk. While these conditions or behaviors will probably have, at most, little independent effect on squamous cell anal cancer risk (that is, in the absence of HPV), very limited data that fully address this hypothesis are available.
Given the paucity of cases of anal adenocarcinoma and other nonsquamous histologic subtypes, it is unknown what role, if any, HPV plays in development of these lesions.
Behaviors or medical conditions that may either indicate HPV infection, or facilitate HPV transmission or persistence
History of cervical, vaginal, and vulvar cancer
Cancers of the cervix, vagina, and vulva are HPV-related cancers. Long-term registry-based monitoring of cervical, vaginal, and vulvar cancer survivors demonstrates an increase in anal cancer risk for these individuals, although the magnitude of the relationship varies.[13-16] For survivors of invasive cervical cancer, the standardized incidence ratio (SIR) for anal cancer was 3.1 (95% CI, 1.9–4.9) in a cohort of more than 100,000 cervical cancer survivors from Denmark, Finland, Norway, Sweden, and the United States, and was 6.2 (95% CI, 4.1–8.7) in the SEER registry data from 1973 to 2007 (more than 1 million person-years). In the latter cohort, the SIR for women with in situ cervical cancer was 16.4 (95% CI, 13.7–19.2). In an analysis of data from the Swedish Family-Cancer Database, which used data from 1958 to 1996, SIRs were 3.8 (95% CI, 2.9–4.7) among the women with in situ cervical cancer and 3.9 (95% CI, 2.3–6.0) among the women with invasive cervical cancer. In the aforementioned multicountry cohort, the anal cancer SIR for in situ and invasive vaginal cancer were 7.6 (95% CI, 2.4–15.6) and 1.8 (95% CI, 0.2–5.3), respectively; the anal cancer SIR for in situ and invasive vulvar cancer were 22.2 (95% CI, 16.7–28.4) and 17.4 (95% CI, 16.7–28.4), respectively.
Persons with cancer of the oropharynx  and penis, two other HPV-associated cancers, are hypothesized to be at increased risk of anal cancer. From 1973 to 2007 (more than 1 million person-years), it was estimated that the observed-to-expected ratio for anal cancer among people with oropharyngeal cancer was twofold (significantly different from one). In that same data source, it was also estimated that no anal cancers occurred after penis cancer, although the expected number of cases was 0.36.
HIV infection/acquired immunodeficiency syndrome (AIDS)
The association between HIV infection and anal cancer is strong. One meta-analysis indicated a 30-fold increase in anal cancer in HIV-infected people, compared with the general population (SIR, 28.8; 95% CI, 21.6–38.3). A nationwide Danish cohort study with data from 1995 to 2009 observed an even stronger association (incidence rate ratio, 77.9; 95% CI, 36.2–167.7). This association between HIV infection and anal cancer is confounded or modified by other factors associated with anal cancer, such as HPV status, high-risk behaviors, and level of immunocompromise. For example, the magnitude of the association between HIV infection and anal cancer risk varies by sexual preference. In one study, the highest SIR and the highest incidence rate were observed for HIV-positive MSM, compared with HIV-negative men (SIR, 80.3; 95% CI, 42.7–151.1); the incidence rate for HIV-positive MSM is 131 per 100,000 person-years. The SIR for HIV-positive men who did not have sex with men was lower but nonnegligible (SIR, 26.7; 95% CI, 11.5–61.7; incidence rate, 46 per 100,000 person-years). In the same study, 30 of 8,842 HIV-positive women had anal cancer diagnoses (incidence rate, 2 per 100,000 person-years) but none of the 11,653 HIV-negative women were diagnosed with anal cancer; thus, no SIR could be calculated, and the incidence rate was zero. Among men with anal cancer, the Danish study observed a mortality rate ratio of 3.2 (95% CI, 1.1–9.2) for HIV-positive men compared with men in the general population.
Anal HPV infection is common in HIV-positive individuals. Studies suggest an HPV prevalence of 85% to 95% among HIV-positive MSM, 76% to 90% in HIV-positive women, and 60% in heterosexual men who are HIV positive.
In a cohort of almost 7,000 men with AIDS, 28 anal cancers occurred, and the odds ratios (OR) suggested relatively modest elevations (about twofold) in risk as the prevalence of high-risk behaviors increased. However, the only statistically significant OR relating to sexual practices was for seven or more unprotected anal receptive sexual partners during the time between study onset and the third study visit (OR, 4.0; 95% CI, 1.1–14.6). In a cohort of nearly half a million AIDS patients, intravenous drug use was associated with anal cancer (SIR, 11.7; 95% CI, 4.2–25.5 for men and SIR, 38.0; 95% CI, 10.3–97.3 for women). Current cigarette smoking, relative to never smoking, has also been observed to increase anal cancer risk in HIV-positive individuals (OR, 2.6; 95% CI, 1.3–5.3).
Anal cancer risk is positively associated with severity of immunosuppression in HIV-positive and AIDS patients. When combined antiretroviral therapy (cART) became available in 1996, the incidence of anal cancer among these patients was expected to decrease. While decreases have been observed for other HIV-associated cancers, such trends have not been observed for anal cancer. It has been proposed that timing of cART treatment influences the risk of anal cancer, and that to be effective against anal cancer, cART must be administered to those with HPV infection earlier in the course of infection than has been clinically practiced. One study suggests that immunosuppression levels 6 to 7 years before anal cancer diagnosis may be more strongly associated with odds of developing the disease than immunosuppression levels in the 12 months before anal cancer diagnosis.
Investigators reported ORs for CD4+ counts 6 to 7 years before anal cancer diagnosis as follows:
- For counts of 350 to 499: OR = 2.8 (95% CI, 0.6–13.0).
- For counts of 200 to 349: OR = 5.9 (95% CI, 1.5–23.0).
- For counts lower than 200: OR = 14.0 (95% CI, 3.9–50.9).
ORs for CD4+ counts in the 12 months before diagnosis were as follows:
- For counts of 350 to 499: OR = 2.0 (95% CI, 0.9–4.6).
- For counts of 200 to 349: OR = 2.2 (95% CI, 1.1–4.6).
- For counts lower than 200: OR = 4.6 (95% CI, 1.8–11.4).
Similar patterns were observed for CD8+ cell counts and for CD4+/CD8+ ratios.
High-risk sexual practices
Sexual practices that confer elevation in anal cancer risk include receptive anal intercourse, numerous sexual partners, and sex between men. These are practices that are known or believed to increase anal exposure to oncogenic strains of HPV. Because HPV and HIV infection are highly correlated with high-risk sexual practices, few data exist that assess the independent effects of sexual behaviors. Before the HIV/AIDS era, the epidemiology of anal cancer received little attention; it was only as the concurrent emergence of AIDS and the increase in anal cancer occurred that sexual practices were investigated as possible risk factors.
Regardless of the underlying reason, MSM have the highest rates of anal cancer when compared with other men and women. As previously mentioned, HIV-positive MSM have the highest anal cancer rates (about 50 per 100,000 person-years), but HIV-negative MSM have significantly higher rates than do men in the general population; their incidence is estimated to be 5 per 100,000 person-years. Case-control studies have observed a modest (about twofold) increase in risk for women who practice receptive anal intercourse;[27,28] however, one study found the association to exist only among women who first had anal intercourse before age of 30 years (OR, 3.4; 95% CI, 1.7–6.6). In the same study, adjusted ORs for both men and women increased with increasing lifetime number of sexual partners. The OR associated with 10 or more partners was 4.5 (95% CI, 2.7–7.4) for women and 2.5 (95% CI, 1.1–5.5) for men. Increased risk for both men and women has been observed with a history of anal warts and certain other sexually transmitted diseases.
Chronic immunosuppressive states other than HIV infection
Chronic immunosuppression in general is thought to increase risk of anal cancer because of its impact on the ability to clear HPV infection. Organ transplant recipients are at elevated risk of anal cancer because immunosuppressant medications are used to prevent organ rejection. Three large transplant cohort studies have observed SIRs for anal cancer of 2.8 (95% CI, 1.5–4.6), 5.8 (95% CI, 4.7–7.2), and 10.3 (95% CI, 2.8–26.6). Autoimmune disorders are hypothesized to increase risk of anal cancer because of the condition, the treatment, or both, but the rarity of anal cancer and relative rarity of many of these disorders have led to conflicting findings or limited data. A cohort study of the Denmark National Patient Registry that included nearly 30 years’ experience observed statistically significant 3-fold increases in risk for Crohn disease (SIR, 3.1; 95% CI, 1.2–6.4) and psoriasis (SIR, 3.1; 95% CI, 1.8–5.1), as well as a 9-fold increase for polyarteritis nodosa (SIR, 8.8; 95% CI, 1.5–29.0) and a 12-fold increase in Wegener granulomatosis (SIR, 12.4; 95% CI, 2.1–40.8).
Cigarette smoking was among the first risk factors for anal cancer to be identified. In 1987, a case-control study of 58 men and 90 women observed a ninefold increase in risk (relative risk [RR], 9.4; 95% CI, 2.3–38.5) for men and an eightfold increase in risk for women (RR, 7.7; 95% CI, 3.5–17.2) for current smokers after adjustment for number of sexual partners. RRs for former smokers were not statistically significant and less than twofold. Another case-control study of 306 patients suggested that current cigarette smoking may be an independent risk factor for anal cancer because adjustment for HPV status and number of sexual partners dampened but did not eliminate the significant associations observed in the 1987 study; the OR for men was 3.9 (95% CI, 1.9–8.0) and for women was 3.8 (95% CI, 2.3–6.2). Given the rarity of anal cancer, studies have not been able to rigorously explore whether risk of anal cancer varies by other aspects of smoking history, such as pack-years smoked and time since cessation. The latter would be of particular interest, given the observation of strong risk in current smokers but no risk in former smokers.
Interventions Associated With a Decreased Risk of Anal Cancer
Because 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; those reporting 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% CI, 36.0%–57.6%). Among those who were negative for the four HPV strains of interest at baseline (per the protocol analysis, which included1,397 intervention 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%).
Among the 602 subjects 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 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 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 and 208 control-arm participants).
Efficacy of the bivalent (HPV-16 and -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 and 2,107 control-arm participants who provided specimens, vaccine efficacy (that is, absence of HPV-16 or -18 in the specimen) was 62% (95% CI, 47.1%–73.1%). Among the 1,003 intervention and 986 control-arm participants who provided anal specimens, received the three doses, had no evidence of cervical HPV-16 or -18 infection, and were seronegative before vaccination, vaccine efficacy was 84% (66.7%–92.8%).
These data strongly suggest that vaccination against oncogenic strains will lead to reductions in anal cancer. They also suggest that vaccination before exposure will provide the most benefit.
Interventions With Inadequate Evidence as to Whether They Reduce the Risk of Anal Cancer
Because HPV can be transmitted through microabrasions, as well as through more pronounced exposures such as exchange of certain bodily fluids, 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 provide some reduction in 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.
In an Italian cohort of 258 HIV-negative MSM, the OR for inconsistent or no use of condoms in receptive anal sex, relative to consistent use, was 1.7 (95% CI, 0.52–6.3) for infection with high-risk HPV strains. 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.
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