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High rates of anal dysplasia in HIV-infected men who have sex with men, women, and heterosexual men

Gaisa, Michaela; Sigel, Keithb; Hand, Jonathana; Goldstone, Stephenc

doi: 10.1097/QAD.0000000000000062
Clinical Science

Objective: To determine rates of anal dysplasia in a cohort of HIV-infected men who have sex with men (MSM), women, and heterosexual men with abnormal anal cytology.

Design/methods: We evaluated histologic findings in 728 HIV-infected MSM, women, and heterosexual men referred for high-resolution anoscopy (HRA) after abnormal anal cytology in a single-center cohort study. Using multivariable logistic regression, we evaluated predictors of high-grade squamous intraepithelial lesion (HSIL) histology or invasive carcinoma including age, sexual behavior, receptive anal intercourse (RAI), anogenital warts, smoking status, antiretroviral therapy, CD4+ T-cell count, and HIV-1 plasma viral load.

Results: A total of 2075 HIV-positive patients were screened with anal cytology and 62% of MSM, 42% of women, and 29% of heterosexual men had abnormal findings (P <0.001). Of the 728 HIV-infected patients with abnormal anal cytology who underwent HRA, 71% were MSM, 23% women, and 6% heterosexual men. HSIL/cancer was found in 32% of MSM, 26% of women, and 23% of heterosexual men (P = 0.3). There were five cases of anal squamous cell carcinoma (0.7%), four in MSM and one in a heterosexual man. In a multivariable adjusted analysis, biopsy-proven HSIL/cancer was associated with RAI [odds ratio (OR) 2.2; 95% confidence interval (CI) 1.3–3.7]. CD4+ T-cell counts more than 500/μl conferred a lower risk of HSIL/cancer (OR 0.5; 95% CI 0.3–0.9).

Conclusion: Rates of anal HSIL histology are high in HIV-infected patients of all sexual risk groups with abnormal anal cytology. Consequently, all HIV-infected patients may warrant anal cancer screening.

aDivision of Infectious Diseases

bDivision of General Internal Medicine

cDepartment of Surgery, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Correspondence to Stephen E. Goldstone, 420 West 23rd St., New York, NY 10011, USA. Tel: +1 212 242 6500; e-mail:

Received 10 April, 2013

Accepted 3 September, 2013

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The incidence of anal cancer is increasing among both women and men at a rate of approximately 2% per year [1]. The National Cancer Institute reports the current anal cancer incidence rate among US men to be 1.5 and among women to be 1.9 per 100 000 persons-years (, Accessed 27 August 2013). HIV infection appears to be a key factor in the human papillomavirus (HPV)-associated, malignant transformation of the anal mucosa. Two meta-analyses of cancer incidence studies have reported an approximately 30-fold increased risk of anal cancer in HIV-infected persons [2–4]. HIV-infected men who have sex with men (MSM) are at highest risk of developing anal cancer. In a recent study of 13 North American cohorts, anal cancer incidence rates per 100 000 person-years ranged from 131 for HIV-infected MSM to 46 in ‘other’ HIV-infected men and 30 in HIV-infected women [5]. Particularly in men, the rising incidence of anal cancer in the United States is strongly correlated with the HIV epidemic [2].

Analogous to the cervix, high-grade squamous intraepithelial lesions (HSILs) are thought to be the precursors of anal squamous cell carcinoma [1]. Effective screening for and treatment of cervical dysplasia have decreased cervical cancer mortality. Similar strategies have been proposed for screening and treatment of anal HSIL to prevent anal cancer [6]. Anal cytology is interpreted in accordance with the same guidelines as cervical cytology, and colposcopy has been adapted to the anal canal as high-resolution anoscopy (HRA). High-grade lesions of the cervix and anus appear very similar both grossly and histologically. Screening for anal cancer has not routinely been recommended in the general population, but the increased burden of disease in HIV-infected persons suggests that screening may have benefit. As a result, in 2007 the New York State Department of Health's AIDS Institute recommended annual anal cytology screening for HIV-infected MSM, HIV-infected persons with a history of anogenital condylomata, and HIV-infected women with abnormal cervical/vulvar histology (

A commonly proposed screening algorithm for anal dysplasia is anal cytology followed by HRA for patients with abnormal cytology [7]. Performance characteristics of anal cytology for the detection of dysplastic lesions have been variable, with reported sensitivity ranging from 69 to 93%, and specificity ranging from 32 to 59% [8], with rates varying as a function of the patient's volume of anal dysplasia, HIV serostatus, and CD4+ T-cell count [9]. Anal cytology screening has been shown to be cost-effective in HIV-infected MSM [10]. A more recent Canadian cohort study, however, found that primary screening of HIV-infected MSM with HRA rather than cytology was the most cost-effective approach [11]. While the majority of studies evaluating anal cancer screening have focused on HIV-infected MSM, there are limited data evaluating these screening techniques in heterosexual men and women [12].

At the Mount Sinai Medical Center (MSMC) and its affiliated clinical sites, all HIV-infected patients are offered anal cytology screening and, if abnormal, are referred for HRA. The MSMC serves a hospital-based clinic population of over 3000 HIV-infected patients; of those, approximately 42% are MSM, 29% are women, and 29% are heterosexual men.

In this study, we determined the rates of anal dysplasia in a cohort of HIV-infected MSM, women, and heterosexual men with abnormal anal cytology, in addition to risk factors for anal dysplasia observed in this population.

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This single-center cohort study used data from a treatment database of HIV-infected outpatients engaged in care at three clinical sites. All HIV-infected patients, regardless of gender and sexual behavior, were offered anal cytology screening and referred for HRA if anal cytology was abnormal. Patients with benign or inadequate anal cytology were not routinely referred for HRA and were not included in our final analysis. Our primary analytic sample included 728 individual patients with abnormal anal cytology who underwent HRA between April 2009 and August 2012.

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Sample collection

Anal cytology was introduced to the routine clinical practice of our HIV clinics in 2009. Most commonly, the patients’ primary HIV care provider collected cytology samples after receiving uniform instructions on sample collection. Briefly, a moistened, nonlubricated polyester swab or cytobrush was inserted blindly 5–6 cm into the anal canal to collect cells from the anal verge to above the squamocolumnar junction. The cells were preserved in liquid-based cytology medium for processing. Results were reported in accordance with the Bethesda system for cervical cytology: benign, atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesion (LSIL), HSIL, or atypical squamous cells, cannot rule out HSIL (ASC-H) [13]. Patients with abnormal cytology were referred for HRA.

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High-resolution anoscopy

All procedures were performed by a single provider (M.G.) who is an infectious disease specialist trained in HRA. HRA was performed in an ambulatory setting using previously described techniques [14]. After treatment with 3% acetic acid and Lugol's iodine, the squamocolumnar junction, the distal anal canal, and the anal margin were visualized under magnification to look for abnormal vascular patterns and other potential signs of HSIL or cancer, including ulceration, mass effect, and friability. Areas suspicious for HSIL or cancer were biopsied. Anal histology was reported according to severity of mucosal dysplasia as benign, LSIL, HSIL, and invasive carcinoma. If no lesion was seen, then no biopsy was taken and the patient was scored as having a ‘benign’ examination. Random biopsies of normal appearing tissue were not performed in this study.

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Data collection and statistical analysis

Only patients who had both abnormal anal cytology and HRA were included in the final analysis. In cases in which a patient had more than one anal cytology sample or HRA performed, patient information was counted only once using their highest grade histology result and preceding cytology. Data collected included age, sexual behavior, current antiretroviral therapy (ART), CD4+ T-cell count, and HIV-1 plasma viral load (pVL). Patient history of receptive anal intercourse (RAI), smoking, and anogenital warts was also collected. Demographics and clinical characteristics among study groups were compared using χ 2 tests for categorical variables and nonparametric tests for continuous variables. We then stratified the cohort into three risk groups of MSM, women, and heterosexual men for comparison. Unadjusted and adjusted logistic regression models were used to evaluate predictors of a combined outcome of HSIL histology or invasive carcinoma. Predictors used in the unadjusted and adjusted models included age, sexual behavior, RAI, anogenital warts, current/former versus lifetime nonsmoking status, use of ART, CD4+ T-cell count defined as 500 cells/μl or less versus more than 500 cells/μl, and undetectable HIV-1 pVL defined as less than 400 copies/ml.

Less than 5% of the sample had missing data on smoking status; we imputed these values using a multiple imputation method. Our findings did not significantly differ after imputation, and we report the results of our imputational analysis. All analyses were performed in STATA version 11 (Stata Corporation, College Station, Texas, USA). This study was approved by the Institutional Review Board of the Icahn School of Medicine at Mount Sinai.

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Patient characteristics

During the study period, 2075 HIV-positive patients underwent anal cytology screening (Fig. 1; 1301 MSM, 556 women, and 218 heterosexual men). Rates of abnormal cytology results were significantly different when compared by sexual risk group (Table 1; P <0.001) and were highest in MSM (62%), followed by women (42%) and heterosexual men (29%). Of the 1114 patients with abnormal anal cytology, 728 (65%) underwent HRA. 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).

Fig. 1

Fig. 1

Table 1

Table 1

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.

Table 2

Table 2

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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).

Table 3

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.

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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.

Table 4

Table 4

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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 [18]. In 2005, Palefsky et al. [16] 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. [19] 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 [19]. Patients with a history of HSIL have a more than two-fold greater risk for subsequent HSIL than those with no history of HSIL [20], 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 [21]. 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 [22]. Much higher rates of HSIL have been reported more recently in the study by Weis et al. [23], 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. [24] 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. [25] 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 [26]. Weis et al. [23] 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 [32] 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.

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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.

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K.S. was supported by the National Center for Research Resources (KL2RR029885).

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Conflicts of interest

None declared.

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anal cancer; anal cancer screening; anal cytology; anal dysplasia; high-resolution anoscopy; HIV; sexual risk groups

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