Table 2 summarizes baseline characteristics of study participants who underwent HRA by sexual risk group. MSM were significantly younger (median age 42 years) and more likely to have had receptive anal sex (99%). MSM were also significantly less likely to be a former or current tobacco user (54%) and being treated with ART (92%). There was no statistical difference in median CD4+ T-cell counts, overall rates of virologic suppression defined as HIV-1 pVL less than 400 copies/ml, or history of anogenital warts between study groups.
Anal cytology and histology results
Among patients who underwent HRA, there was no significant difference in anal cytology results between risk groups (data not shown; P = 0.06). ASCUS was the most common abnormal cytology diagnosis in patients referred for HRA, found in more than half of all patients, whereas HSIL and ASC-H were the least common and found in less than 10% of patients (Table 3).
When comparing cytology with histology, overall correlation was poor and many patients were found to have HSIL histology with underlying ASCUS and LSIL cytology. Moreover, only one patient with anal cancer had HSIL cytology. However, 87% of patients with HSIL cytology had HSIL or carcinoma on biopsy (Table 3).
Overall, more than two-thirds of patients in all study groups had anal intraepithelial neoplasia (AIN) of any degree with rates varying significantly between sexual risk groups (Fig. 1; P <0.001). The rates of HSIL histology and carcinoma, however, did not differ significantly between groups (Table 3; P = 0.3). When looking at only patients with ASCUS, heterosexual men were significantly less likely to have HSIL histology than either women or MSM (P = 0.04).
There were five cases of anal squamous cell carcinoma (0.7%), four in MSM, one in a heterosexual man, and none in women. All patients had a long history of HIV infection (>16 years) with low nadir CD4+ T-cell counts, and a median age of 43 (range: 40–47). Concomitant cytology yielded ASCUS and LSIL in two patients each, and HSIL in the other patient. Among the four MSM cases, all had intra-anal cancer; two with superficial invasion and two with deep invasion of the muscularis propria. The heterosexual man had perianal, superficially invasive cancer.
It is worth noting that out of 45 women with HSIL histology, 11 (24%) did not have a prior history of abnormal cervical cytology.
Predictors of high-grade squamous intraepithelial lesions or invasive carcinoma
In the unadjusted logistic regression model, RAI was associated with a higher risk of HSIL histology or carcinoma [Table 4; odds ratio (OR) 2.2; 95% confidence interval (CI) 1.3–3.7]. A recent CD4+ T-cell count more than 500/μl was associated with a lower risk of these outcomes (OR 0.6; 95% CI 0.3–0.9). These relationships persisted after adjustment.
In this cohort of HIV-infected persons who underwent HRA for abnormal anal cytology, we find that rates of HSIL are similar among MSM, women, and heterosexual men. This suggests that abnormal anal cytology is a predictor of HSIL in HIV-infected persons irrespective of sexual risk group.
There is a paucity of data regarding prevalence rates of anal dysplasia in HIV-infected women and heterosexual men, despite numerous studies in HIV-infected MSM. The prevalence of HSIL among HIV-infected MSM remains high with a reported prevalence range of 43–52% and appears to be increasing [15–17], suggesting that ART may not have a substantial effect on anal HPV infection and AIN . In 2005, Palefsky et al. reported HRA findings in 357 HIV-infected MSM of whom 81% had dysplasia of any degree and 52% had HSIL, regardless of anal cytology. In a recent series of 403 HIV-infected MSM who underwent HRA mostly based upon abnormal cytology results (only 14.6% had benign cytology), Swedish et al. found a rate of AIN of any degree of 74% and HSIL/cancer in 47.9%. In our cohort of 518 MSM referred for HRA based on abnormal cytology, we found similar rates of AIN overall, but lower rates of HSIL or cancer in MSM (32%) than those observed in previous studies. Our lower rate of HSIL may be related to a potentially different patient population. Operator inexperience causing HSIL underdiagnosis (MG has 3 years of experience performing HRA; the previous studies reported data from more experienced anoscopists) is another possible explanation. However, review of biopsy results by year since initiation of our HRA program did not reveal significant changes in HSIL detection by year (data not shown). Moreover, the majority (87%) of participants with HSIL cytology had concordant HSIL histology suggesting that most HSIL was identified. Unlike patients described in previous studies, those in our cohort had not undergone prior screening or treatment for anal dysplasia . Patients with a history of HSIL have a more than two-fold greater risk for subsequent HSIL than those with no history of HSIL , which could explain the higher rates of HSIL observed in other studies.
There are limited data on rates of AIN in HIV-infected women and significant heterogeneity among studies. An early study of HIV-infected women in France used a limited anoscopy method (without initial anal cytology) and reported dysplasia in 11.3% (4.6% for anal condylomata and 6.7% for LSIL and HSIL combined) of participants . The Women's Interagency HIV Study (WIHS) performed anal cytology on participating women and found 31% with abnormal anal cytology. Less than half of the WIHS participants with abnormal cytology underwent HRA and only 9% had HSIL either by histology or cytology . Much higher rates of HSIL have been reported more recently in the study by Weis et al., in which 31% of 204 HIV-infected women in a Texas public health hospital had abnormal anal cytology; 51 women with abnormal anal cytology underwent HRA, and of those 67% had HSIL. Hou et al. screened 715 HIV-infected women in a large urban hospital finding that 75 (10.5%) had abnormal anal cytology and 29 (38.7%) of those had biopsy-proven HSIL. Mallari et al. performed HRA on 29 HIV-infected women perceived at high risk for anal dysplasia based on a history of HPV-related cervical or vulvar disease; of those 72% had dysplasia of any degree and 34.5% had HSIL. A total of 556 women in our cohort were screened with anal cytology regardless of perceived risk, 233 (42%) had abnormal anal cytology, and 170 women underwent HRA; of those, 67% had dysplasia of any degree and 26% had HSIL, which is slightly lower than the values that other studies have reported. Our data demonstrate that women with abnormal anal cytology have rates of HSIL on HRA comparable with those we observed in MSM. Moreover, even women without a history of cervical dysplasia are at risk and should be screened.
Anal dysplasia in HIV-infected heterosexual men is least studied of all risk groups. In a French cohort of 50 HIV-infected male intravenous drug users (non-MSM), participants underwent anal cytology screening and were offered HRA if cytology was abnormal. Although the exact number of participants with abnormal anal cytology was not mentioned by the authors, 13 men refused HRA and the rate of dysplasia was reported using the highest grade result from either cytology or histology: 36% had dysplasia of any degree and 18% had HSIL . Weis et al. reported HRA findings in 28 HIV-infected men with abnormal anal cytology who did not report a history of RAI and 96% had dysplasia of any degree while 50% had HSIL. In our cohort of 40 HIV-infected heterosexual men undergoing HRA for abnormal cytology, we found that 61% had dysplasia overall and 23% had HSIL, which is lower than what Weis et al. reported, but higher than in the French study.
Although several studies have shown considerable rates of anal HPV infection in the absence of RAI, it remains a major risk factor for anal HPV infection [26–29]. Virtually, all MSM and approximately two-thirds of women in our study reported a history of RAI. RAI more than tripled the risk of HSIL in a multivariate analysis. We do not know whether this high rate of RAI is unique to the women in our cohort or whether other series had high rates as well. Regardless, the high rate of RAI could explain why the women in our cohort have more HSIL than in some prior series. Our data support the concept of RAI as an important mechanism for anal HPV infection with subsequent dysplasia and highlight the importance of taking a thorough sexual history with questions related to RAI in all patients.
As has been shown in various prior studies, we also identified an association between lower CD4+ T-cell counts, lack of HIV-1 virologic suppression, and increased prevalence and incidence of HSIL [30,31]. In lifetime nonsmokers, there was also a trend for lower HSIL risk, though not statistically significant (OR 0.8: CI 0.5–1.1), which is consistent with data reported on the association between cigarette smoking and cervical dysplasia  as well as anal cancer [33,34].
Of 2075 patients screened with anal cytology within the study period, 63% were MSM, 27% women, and 10% heterosexual men, which is not representative of the overall demographics of our clinical sites where approximately 42% are MSM, 29% women, and 29% heterosexual men. It appears that MSM were much more likely to undergo anal cytology screening and we can only speculate on possible reasons. Providers may be more likely to perform anal cytology on patients they perceive to be at highest risk (i.e., MSM); in addition, MSM may be more likely to consent to screening. MSM may also tolerate anal cytology screening better to allow for adequate sampling of the anal canal as is suggested by the observation that MSM had a higher chance of an adequate anal cytology result (87%) compared with women (84%) and heterosexual men (78%; P <0.001). Although all patients with abnormal anal cytology were referred for HRA, only 65% presented for the procedure. Women with abnormal anal cytology were more likely to undergo HRA (73% of all women with abnormal results), when compared with MSM (63%) or heterosexual men (62%; P = 0.01), which is particularly surprising, given the overall poor compliance of women with colposcopy. The observation that almost half of the women and one-third of the heterosexual men screened had abnormal anal cytology, coupled with the fact that all patients with abnormal cytology who underwent HRA had similar rates of HSIL, argues strongly that all HIV-infected patients regardless of gender and sexual risk group should be routinely screened for anal HSIL and cancer and be subject to similar screening recommendations.
Although the number of heterosexual men included in our study was small, the data point out an interesting phenomenon; while overall there was no difference in rates of HSIL histology between sexual risk groups for those with abnormal cytology, it appears that this finding was largely driven by those with LSIL, HSIL, and ASC-H cytology. Heterosexual men with ASCUS cytology, however, had significantly lower rates of HSIL than MSM and women with ASCUS cytology(P = 0.04). Thus, heterosexual men with ASCUS might require a different algorithm for referral to HRA – one similar to what is used for women with ASCUS cervical cytology. It might be better for heterosexual men with ASCUS to be rescreened in 3 months or tested for oncogenic anal HPV subtypes and undergo HRA only if abnormal cytology persists or they test positive for oncogenic HPV. More research on larger numbers of HIV-infected heterosexual men is needed to better understand the optimal approach to anal cancer screening in this group.
Our study had several additional strengths and limitations worth mentioning. It benefited from a large sample of HIV-infected persons of all sexual risk groups with relatively complete ascertainment of study data. Furthermore, all HRA procedures were performed by a single clinician eliminating interobserver variability and variation in examination technique. Additional limitations include the retrospective nature of this series and the lack of standardized review of all pathology specimens by a single reference pathologist. Specimens were read by four pathologists without verification of interpretation or adjudication of discrepancies. Sexual behavior was self-reported and some men classified as heterosexual may not have revealed their true sexual risk factors. In addition, the number of heterosexual men included in this study was relatively low, limiting our power to compare their HSIL rates to those of other sexual risk groups. Furthermore, high-risk HPV testing by molecular methods was not part of routine anal cytology screening during the study period.
While HIV-infected MSM are most likely to have abnormal anal cytology, HIV-infected patients of all sexual risk groups also commonly have abnormal cytology. All HIV-infected patients with abnormal anal cytology have high rates of HSIL. Therefore, anal cancer screening may be warranted in HIV-infected patients regardless of sexual orientation. Further research is needed to more clearly delineate the harms and benefits of anal cancer screening in all HIV-infected patients irrespective of risk group.
K.S. was supported by the National Center for Research Resources (KL2RR029885).
Conflicts of interest
1. Johnson LG, Madeleine MM, Newcomer LM, Schwartz SM, Daling JR. Anal cancer incidence and survival: the surveillance, epidemiology, and end results experience, 1973–2000
2. Shiels MS, Pfeiffer RM, Chaturvedi AK, Kreimer AR, Engels EA. Impact of the HIV epidemic on the incidence rates of anal cancer in the United States
. J Natl Cancer Inst
3. Grulich AE, van Leeuwen MT, Falster MO, Vajdic CM. Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a meta-analysis
4. Shiels MS, Cole SR, Kirk GD, Poole C. A meta-analysis of the incidence of non-AIDS cancers in HIV-infected individuals
. J Acquir Immune Defic Syndr
5. Silverberg MJ, Lau B, Justice AC, Engels E, Gill MJ, Goedert JJ, et al. Risk of anal cancer in HIV-infected and HIV-uninfected individuals in North America
. Clin Infect Dis
6. Fox PA, Seet JE, Stebbing J, Francis N, Barton SE, Strauss S, et al. The value of anal cytology and human papillomavirus typing in the detection of anal intraepithelial neoplasia: a review of cases from an anoscopy clinic
. Sex Transm Infect
7. Sigel K, Dubrow R, Silverberg M, Crothers K, Braithwaite S, Justice A. Cancer screening in patients infected with HIV
. Curr HIV/AIDS Rep
8. Chiao EY, Giordano TP, Palefsky JM, Tyring S, El Serag H. Screening HIV-infected individuals for anal cancer precursor lesions: a systematic review
. Clin Infect Dis
9. Nathan M, Singh N, Garrett N, Hickey N, Prevost T, Sheaff M. Performance of anal cytology in a clinical setting when measured against histology and high-resolution anoscopy findings
10. Goldie SJ, Kuntz KM, Weinstein MC, Freedberg KA, Welton ML, Palefsky JM. The clinical effectiveness and cost-effectiveness of screening for anal squamous intraepithelial lesions in homosexual and bisexual HIV-positive men
11. Lam JM, Hoch JS, Tinmouth J, Sano M, Raboud J, Salit IE. Cost-effectiveness of screening for anal precancers in HIV-positive men
12. Panther LA, Schlecht HP, Dezube BJ. Spectrum of human papillomavirus-related dysplasia and carcinoma of the anus in HIV-infected patients
. AIDS Read
2005; 15:79–82.85-76, 88, 91.
13. Solomon D, Davey D, Kurman R, Moriarty A, O’Connor D, Prey M, et al. The 2001 Bethesda system: terminology for reporting results of cervical cytology
14. Jay N, Berry JM, Hogeboom CJ, Holly EA, Darragh TM, Palefsky JM. Colposcopic appearance of anal squamous intraepithelial lesions: relationship to histopathology
. Dis Colon Rectum
15. Chin-Hong PV, Berry JM, Cheng SC, Catania JA, Da Costa M, Darragh TM, et al. Comparison of patient- and clinician-collected anal cytology samples to screen for human papillomavirus-associated anal intraepithelial neoplasia in men who have sex with men
. Ann Intern Med
16. Palefsky JM, Holly EA, Efirdc JT, Da Costa M, Jay N, Berry JM, Darragh TM. Anal intraepithelial neoplasia in the highly active antiretroviral therapy era among HIV-positive men who have sex with men
17. Palefsky JM, Rubin M. The epidemiology of anal human papillomavirus and related neoplasia
. Obstet Gynecol Clin North Am
18. Heard I, Palefsky JM, Kazatchkine MD. The impact of HIV antiviral therapy on human papillomavirus (HPV) infections and HPV-related diseases
. Antivir Ther
19. Swedish KA, Lee EQ, Goldstone SE. The changing picture of high-grade anal intraepithelial neoplasia in men who have sex with men: the effects of 10 years of experience performing high-resolution anoscopy
. Dis Colon Rectum
20. Goldstone SE, Enyinna CS, Davis TW. Detection of oncogenic human papillomavirus and other predictors of anal high-grade dysplasia in men who have sex with men with abnormal cytology
. Dis Colon Rectum
21. Abramowitz L, Benabderrahmane D, Ravaud P, Walker F, Rioux C, Jestin C, et al. Anal squamous intraepithelial lesions and condyloma in HIV-infected heterosexual men, homosexual men and women: prevalence and associated factors
22. Hessol NA, Holly EA, Efird JT, Minkoff H, Schowalter K, Darragh TM, et al. Anal intraepithelial neoplasia in a multisite study of HIV-infected and high-risk HIV-uninfected women
23. Weis SE, Vecino I, Pogoda JM, Susa JS, Nevoit J, Radaford D, et al. Prevalence of anal intraepithelial neoplasia defined by anal cytology screening and high-resolution anoscopy in a primary care population of HIV-infected men and women
. Dis Colon Rectum
24. Hou JY, Smotkin D, Grossberg R, Suhrland M, Levine R, Smith HO, et al. High prevalence of high grade anal intraepithelial neoplasia in HIV-infected women screened for anal cancer
. J Acquir Immune Defic Syndr
25. Mallari AO, Schwartz TM, Luque AE, Polashenski PS, Rauh SM, Corales RB. Anal cancer screening in HIV-infected patients: is it time to screen them all?
. Dis Colon Rectum
26. Piketty C, Darragh TM, Da Costa M, Bruneval P, Heard I, Kazatchkine MD, Palefsky JM. High prevalence of anal human papillomavirus infection and anal cancer precursors among HIV-infected persons in the absence of anal intercourse
. Ann Intern Med
27. Palefsky JM, Holly EA, Ralston ML, Da Costa M, Greenblatt RM. Prevalence and risk factors for anal human papillomavirus infection in human immunodeficiency virus (HIV)-positive and high-risk HIV-negative women
. J Infect Dis
28. Goodman MT, Shvetsov YB, McDuffie K, Wilkens LR, Zhu X, Ning L, et al. Acquisition of anal human papillomavirus (HPV) infection in women: the Hawaii HPV Cohort study
. J Infect Dis
29. Nyitray AG, Smith D, Villa L, Lazcano-Ponce E, Abrahamsen M, Papenfuss M, Giuliano AR. Prevalence of and risk factors for anal human papillomavirus infection in men who have sex with women: a cross-national study
. J Infect Dis
30. Chin-Hong PV, Vittinghoff E, Cranston RD, Browne L, Buchbinder S, Colfax G, et al. Age-related prevalence of anal cancer precursors in homosexual men: the EXPLORE study
. J Natl Cancer Inst
31. Chin-Hong PV, Palefsky JM. Human papillomavirus anogenital disease in HIV-infected individuals
. Dermatol Ther
32. Holly EA, Cress RD, Ahn DK, Aston DA, Kristiansen JJ, Wu R, Felton JS. Detection of mutagens in cervical mucus in smokers and nonsmokers
. Cancer Epidemiol Biomarkers Prev
33. Daling JR, Weiss NS, Hislop TG, Maden C, Coates RJ, Sherman KJ, et al. Sexual practices, sexually transmitted diseases, and the incidence of anal cancer
. N Engl J Med
34. Daling JR, Madeleine MM, Johnson LG, Schwartz SM, Shera KA, Wurscher MA, et al. Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer
Keywords:© 2014 Lippincott Williams & Wilkins, Inc.
anal cancer; anal cancer screening; anal cytology; anal dysplasia; high-resolution anoscopy; HIV; sexual risk groups