Anal Cancer Screening in People Living With HIV: A Pilot Study of Primary HPV Screening With Triage Use of p16/Ki67 Dual Stain.

The American Society of Colon and Rectal Surgeons is dedicated to ensuring high-quality patient care by advancing the science, prevention, and management of disorders and diseases of the colon, rectum, and anus. The Clinical Practice Guidelines Committee is composed of society members who are chosen

Cervical determinants of anal HPV infection and high-grade anal lesions in women: a collaborative pooled analysis

Introduction: Anal cancer is increasing in the general population of Puerto Rico. Anal cytology is currently the standardized method for screening among populations at higher risk for developing anal high-grade squamous intraepithelial lesions (HSIL), the precursor lesion of anal cancer. However, studies have shown that anal cytology alone underestimates the anal lesion grade compared to the gold standard test, high-resolution anoscopy (HRA). While studies with both anal histology and cytology confirmed results are limited, the validity of cytology as a screening test seems to improve with more extensive HSILs. We evaluated the validity of anal cytology in detecting HSIL overall and by anal HSIL extension in a clinic-based Hispanic population. Methods: Data from baseline visits and examination from October 2014 to April 2021 of the Anal Neoplasia Clinic at the University of Puerto Rico Comprehensive Cancer Center were analyzed. Individuals who attended the clinic were eligible if they had completed anal cytology testing, HR-HPV typing, and HRA with biopsy. During the baseline visit basic demographic and clinical characteristics were collected. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were estimated by comparing anal cytology results with biopsy results from HRA, overall and by extent of histologically confirmed HSIL, defined as number of octants in the anal canal affected by HSIL (1 vs 2+). Results: Among 431 patients, 67.5% were male and the mean age was 43.57 +/- 13.27 years. Overall, 75.2% were living with HIV and 76.8% tested positive for HR-HPV. Persons diagnosed with any type of squamous intraepithelial lesion (SIL) via anal cytology and histology were 71.46% and 84.22%, respectively. In contrast, while anal HSIL was detected in only 2.09% of individuals through anal cytology, it was detected in 40.37% through biopsy-confirmed histology samples. The overall sensitivity of anal cytology compared to histology was 83.9% (95% CI: 77.6%-89%), whereas the specificity was 37% (95% CI: 31%-43.2%). Among persons with biopsy-confirmed HSIL, when comparing anal cytology to histology by HSIL extension (1 vs. 2+ octants affected) the sensitivity remained similar for both groups (83.7% vs. 84.1%), while specificity was the same with 37%. While the PPV decreased with HSIL extension (32.2% vs. 29.9%) and the NPV increased (86.4% vs. 88.0%), these indicators act as poor predictors of disease status in both groups. Conclusion: In this Hispanic population, anal cytology underestimates biopsy-confirmed HSIL and its performance in detected anal HSIL did not improve with HSIL extension. While future studies with larger sample sizes are needed to further validate research findings, this study emphasizes the need to continue to optimize anal cancer screening methods in high-risk populations. Determining the best way to detect and treat cellular abnormalities will help prevent further disease progression and anal cancer development. AMC-NCI Grant #'s: UM1CA121947, 2U54CA096297-17, R25CA240120. Citation Format: Kandyce G. Keller, Jeslie M. Ramos-Cartagena, MS, Humberto M. Guiot, Cristina Munoz, Yolanda Rodriguez, Vivian Colon-Lopez, Ashish A. Deshmukh, Maribel Tirado-Gomez, Ana Patricia Ortiz. Assessment of the performance of anal cytology as a screening tool for anal high-grade squamous intraepithelial lesions by extent of disease in a clinic-based sample in Puerto Rico [abstract]. In: Proceedings of the AACR Virtual Conference: 14th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2021 Oct 6-8. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2022;31(1 Suppl):Abstract nr PO-254.

Screening to prevent anal cancer: Current thinking and future directions.

Anal high-grade squamous intraepithelial lesions are probable invasive anal squamous-cell cancer precursors, and although unproved, treatment of high-grade squamous intraepithelial lesions may prevent progression to anal squamous-cell cancer. Men who have sex with men are often treated for benign anorectal disorders without consideration given to the possibility of concurrent high-grade squamous intraepithelial lesions or anal squamous-cell cancer. We determined the prevalence of anal high-grade squamous intraepithelial lesions and anal squamous-cell cancer in an urban surgical practice of men who have sex with men referred for treatment of anal condyloma and other benign noncondylomatous anal disorders. One hundred thirty-one HIV-positive and 69 HIV-negative men who have sex with men referred for surgical treatment of presumed benign anorectal disease were evaluated by anal cytology, high-resolution anoscopy, and biopsy. Anal cytology and histology were reported with a modified Bethesda classification. One hundred fifty-seven patients (79 percent) were referred for condyloma, 4 (2 percent) for anal squamous intraepithelial lesions (anal high-grade squamous intraepithelial lesions) diagnosed by primary care providers, and 39 (19 percent) for other benign anorectal disorders. One hundred forty-three patients (93 percent) had abnormal anal cytology, with 107 (54 percent) having high-grade squamous intraepithelial lesions on cytology. Biopsy results revealed 120 patients (60.0 percent) with high-grade squamous intraepithelial lesions and 5 patients (3 percent) with invasive squamous-cell carcinoma. Four of five men with anal squamous-cell cancer were HIV positive. Fourteen men (36 percent) who have sex with men referred for noncondylomatous benign anal disorders had high-grade squamous intraepithelial lesions, and three (8 percent) had anal squamous-cell cancer. High-grade squamous intraepithelial lesions and anal squamous-cell cancer were seen most often at the squamocolumnar junction. Men who have sex with men referred for treatment of either condyloma or noncondylomatous benign anorectal disease had a high prevalence of anal high-grade squamous intraepithelial lesions and anal squamous-cell cancer. All men who have sex with men referred for treatment of benign anorectal disease should have high-resolution anoscopy and aggressive biopsy of all abnormal areas. Treatment of external lesions alone could miss high-grade squamous intraepithelial lesions or anal squamous-cell cancer.

Anal cancer risk: HPV-based cervical screening programmes

The aim of the study was to evaluate the validity of anal cytology against high-resolution anoscopy in the detection of anal high-grade squamous intraepithelial lesions (HSILs) among women in a clinical setting in Puerto Rico, alone and in combination with high-risk human papillomavirus (HR-HPV) typing. A cross-sectional study was done among 128 eligible women who attended the Anal Neoplasia Clinic of the University of Puerto Rico Comprehensive Center between 2014 and 2019. Kappa (κ) coefficient, sensitivity, specificity, positive predictive value, and negative predictive value were calculated using high-resolution anoscopy with biopsy as the criterion standard test. Poisson regression was used to estimate the adjusted prevalence ratio of anal HR-HPV infection. Overall, 71.1% of women were HIV infected and 78.9% had anal HR-HPV infection. Squamous intraepithelial lesions were detected with anal cytology and histology in 70.3% and 81.3% of women, respectively. The κ statistic between the tests (cytology and histology) was 0.32 (p < .05). Measured against the results from histology, the sensitivity of anal cytology alone to detect HSIL was 85.4% (95% CI = 72.2%-93.9%), whereas specificity was 38.8% (95% CI = 28.1%-50.3%). Although the sensitivity of the 2 tests combined (anal cytology and HR-HPV typing) to detect histologically confirmed HSIL increased (100.0%, 95% CI = 92.6%-100.0%), the specificity decreased (16.3%, 95% CI = 9.0%-26.2%). Meanwhile, women with HSIL had a higher prevalence of anal HR-HPV infection than those with no SIL/LSIL (prevalence ratio = 6.23, 95% CI = 1.50-25.83). Anal cytology in combination with HR-HPV typing for the screening of anal intraepithelial neoplasia improved the detection of HSIL in women.

Introduction: Immunosuppressed patients have a higher risk of human papillomavirus (HPV) infection and HPV-related cancers, like anal squamous cell carcinoma (SCC). Information regarding precancerous anal lesions (high-grade anal squamous intraepithelial lesions) in the long-term immunosuppressed patients of pharmacological origin is lacking, especially when high resolution anoscopy (HRA), the most reliable examination tool, is employed. Methods: Retrospective analysis of long-term pharmacologically immunosuppressed patients that have been evaluated and followed with HRA. Results: Data search revealed 48 patients under immunosuppression due to pharmacological agents. In this analysis, we excluded those with multiple causes such as HIV positivity (n=1) and men who have sex with men (n=4). Of the remaining 43 patients, 37 were women, mean age was 49 ±18 years. The most common conditions were Inflammatory bowel disease (n=11, 26%), renal transplantation (n=9, 21%) and systemic lupus erythematosus (n=8, 19%). The most commonly used drugs were prednisolone (n=29), azathioprine (n=21) and tacrolimus (n=9), with a mean duration of immunosuppression of 12±11 years. Twenty-one patients (50%) were current or previous smokers. At the first evaluation with HRA, 23 patients (53%) were diagnosed with anal and/or perianal high-grade squamous intraepithelial lesions (HSIL) and in one case perianal SCC was diagnosed. A mean of 4±2 lesions of the anal canal and a mean of 3±2 lesions of perianus were detected. Considering also the previous history and follow-up with HRA, overall 29 patients (67%) in our series had anal and/or perianal HSIL. Sixteen patients (55%) had both anal and perianal HSIL, 10 (35%) had only anal and 3 patients (10%) only perianal high-grade lesions. In total, 3 patients had perianal SCC, one patient with a previous history and two were detected in the HRA clinic. Prednisolone was a risk factor for anal HSIL (OR=4.7, 95%CI=1.209-18.468, P=0.026) and anal HSIL was a risk factor for perianal HSIL (OR=7.5, 95%CI=1.706-32.676, P=0.008). Conclusion: In our cohort of immunosuppressed patients due to pharmacological agents, anal and perianal HSIL/cancer was common. HRA enabled the detection of these lesions which were likely to be missed by other methods of examination.

Simple SummaryHuman papillomavirus (HPV)-associated cancers, such as anal cancer, are a major risk among people living with HIV (PLWH). High-risk (HR) HPVs are the causal agent of anal precancer and cancer. However, there is a paucity of data regarding the HPV genotypes that cause especially anal cancers and pre-cancers in PLWH. In this study we characterize the specific HPV types in anal tissues, including benign, pre-cancer, and cancer samples from PLWH, and compare them to similar samples from HIV-negative individuals. The results from our study suggest that a broader range of HPV types may play a role in anal cancer in PLWH than in HIV-negative individuals. Proposed screening approaches that include HPV testing might need to differ by HIV status, with extended HPV genotyping included for PLWH.The incidence of anal cancer is increasing, especially in high-risk groups, such as PLWH. HPV 16, a high-risk (HR) HPV genotype, is the most common genotype in anal high-grade squamous intraepithelial lesions (HSIL) and squamous cell carcinoma (SCC) in the general population. However, few studies have described the distribution of HR HPV genotypes other than HPV 16 in the anus of PLWH. HPV genotyping was performed by DNA amplification followed by dot-blot hybridization to identify the HR and low-risk (LR) genotypes in benign anal lesions (n = 34), HSIL (n = 30), and SCC (n = 51) of PLWH and HIV-negative individuals. HPV 16 was the most prominent HR HPV identified, but it was less common in HSIL and SCC from PLWH compared with HIV-negative individuals, and other non-HPV 16 HR HPV (non-16 HR HPV) types were more prevalent in samples from PLWH. A higher proportion of clinically normal tissues from PLWH were positive for one or more HPV genotypes. Multiple HPV infection was a hallmark feature for all tissues (benign, HSIL, SCC) of PLWH. These results indicate that the development of anal screening approaches based on HPV DNA testing need to include non-16 HR HPVs along with HPV 16, especially for PLWH. Along with anal cytology, these updated screening approaches may help to identify and prevent anal disease progression in PLWH.

Human immunodeficiency virus (HIV)-infected women have a higher burden of anal high-grade squamous intraepithelial lesions (HSIL) and anal cancer (AC) compared with HIV-uninfected women. Guidelines for AC screening in this population are heterogeneous. Here we report outcomes and risk factors for anal HSIL following implementation of universal AC screening offered to all HIV-infected women. Data from women who underwent AC screening with anal cytology from April 2009 to July 2014 were analyzed. Routine clinical data included anal and cervical cytology, demographic/behavioral data, and high-resolution anoscopy (HRA) results. We evaluated the association of cytology with HRA results, and predictors of HSIL pathology, and compared rates of HSIL pathology among women meeting screening guidelines to those who did not. Seven hundred forty-five HIV-infected women were screened with anal cytology. Thirty-nine percent had abnormal anal cytology on initial screen and 15% on secondary screen; 208 women underwent HRA following abnormal anal cytology. HSIL was found in 26% and 18% of anal biopsies following initial and secondary screening, respectively. One woman had AC. Cigarette smoking more than doubled HSIL risk. Among women who underwent AC screening despite not meeting existing guideline criteria, 21% and 10%, respectively, were found to have HSIL on biopsy. Neither meeting criteria for screening nor history of receptive anal sex was significantly associated with HSIL. Anal HSIL is common in HIV-infected women. Substantial numbers of HSIL would have been missed by strictly adhering to existing AC screening guidelines. These results support routine screening of all HIV-infected women regardless of human papillomavirus history or sexual practices.

Association of smoking with anal high-risk HPV infection and histologically confirmed anal high-grade squamous intraepithelial lesions among a clinic-based population in Puerto Rico

Given the disproportionately elevated anal cancer risk in high-risk populations, it is important to assess the performance of commonly used anal cancer screening tools to improve the effectiveness of detection and treatment methods. This study evaluates 1) the concordance between anal cytology and histology results and 2) the performance of cytology and high-risk human papillomavirus (HR-HPV) genotyping as screening tools for detecting histologically confirmed anal high-grade squamous intraepithelial lesions (HSIL). Data from the Anal Neoplasia Clinic in Puerto Rico (2014-2021; n = 466) was used. The clinical performance of anal cytology and HR-HPV genotyping to detect HSIL was compared to the gold standard: high-resolution anoscopy-guided biopsy. Sensitivity, specificity, positive predictive value, negative predictive value, and κ coefficients were calculated. A total of 66.95% of the patients were men, 74.0% were people living with HIV, 76.2% had anal HR-HPV infection, and 40.34% had histologically confirmed anal HSIL. The weighted κ statistic between the tests (cytology and histology) was 0.25 (p < .001). The sensitivity and specificity of cytology alone to detect anal HSIL were 84.3% (95% confidence interval [CI], 78.3%-89.1%) and 36.0% (95% CI, 30.3%-42.0%), respectively. Anal HR-HPV genotyping had higher sensitivity (92.2%; 95% CI, 87.4%-95.6%) and similar specificity (34.8%; 95% CI, 29.2%-40.7%) compared to cytology. The two tests combined (positive results following cytology or HR-HPV test) improved sensitivity to detect anal HSIL (97.9%; 95% CI, 94.8%-99.4%), but specificity was compromised (19.2%; 95% CI, 14.7%-24.4%). Although HR-HPV genotyping improved the detection of anal HSIL, HR-HPV testing had lower specificity than anal cytology alone.

The primary obkective was to determine the prevalence of (a) a positive anal cancer screen and (b) histological anal high-grade squamous intraepithelial lesion (HSIL) in women undergoing surveillance for previously diagnosed and treated human papillomavirus (HPV)-associated vulvar HSIL. The secondary objective was to determine the patients' acceptability of the screen. This is a single-institution, cross-sectional pilot study. Women, aged 30 to 80 years, with a history of biopsy-proven vulvar HSIL were invited to undergo screening for anal cancer. Positive screen characterized by abnormalities in any of the following: anal high-risk HPV (HR-HPV); anal cytology; and digital anorectal examination. All women with an abnormal screen were referred for high-resolution anoscopy. All women completed a postscreen questionnaire. Fifty-seven patients were recruited. The median (interquartile range) age was 61.5 (51.0-68.0) years. The prevalence of a positive screen was 56.1% (95% CI = 43.3%-68.2%). Of the 32 screen-positive patients, 12 had both abnormal cytology and HR-HPV, 3 had positive HR-HPV alone, and 17 had abnormal cytology alone. Of the 29 patients with a positive screen who went on to anoscopy, the prevalence of anal HSIL was 33.3% (95% CI = 19.2%-51.2%). The prevalence of anal HSIL among all of those who had screening (N = 57) was 18.2% (95% CI = 10.2%-30.3%). The examination was well tolerated with 100% of patients, indicating that they would have the screening again. Women with vulvar HSIL have an increased risk of developing anal HSIL. Larger studies are needed to define optimal screening protocols as well as algorithms for management in high-risk populations.

The incidence of anal cancer is higher in women than men in the general population and has been increasing for several decades. Similar to cervical cancer, most anal cancers are associated with human papillomavirus (HPV), and it is believed that anal cancers are preceded by anal high-grade squamous intraepithelial lesions (HSIL). Our goals were to summarize the literature on anal cancer, HSIL, and HPV infection in women and to provide screening recommendations in women. A group of experts convened by the American Society for Colposcopy and Cervical Pathology and the International Anal Neoplasia Society reviewed the literature on anal HPV infection, anal SIL, and anal cancer in women. Anal HPV infection is common in women but is relatively transient in most. The risk of anal HSIL and cancer varies considerably by risk group, with human immunodeficiency virus-infected women and those with a history of lower genital tract neoplasia at highest risk compared with the general population. While there are no data yet to demonstrate that identification and treatment of anal HSIL leads to reduced risk of anal cancer, women in groups at the highest risk should be queried for anal cancer symptoms and required to have digital anorectal examinations to detect anal cancers. Human immunodeficiency virus-infected women and women with lower genital tract neoplasia may be considered for screening with anal cytology with triage to treatment if HSIL is diagnosed. Healthy women with no known risk factors or anal cancer symptoms do not need to be routinely screened for anal cancer or anal HSIL.

More than half of people living with HIV in the US are 50+ years old. Despite the benefits of antiretroviral therapy, older individuals with HIV are at higher risk for illnesses than their HIV-negative counterparts. Anal cancer, anal high-grade squamous intraepithelial lesions (HSIL), and anal HPV-16 infection occur most frequently among men who have sex with men living with HIV (MSMLWH). Men aged 60+ are 3-fold more likely to be diagnosed with anal cancer compared with younger men. Despite the increasing risk of anal cancer with age and HIV, little is known about the relationships among aging, HPV infection, HSIL and HIV. The Anal HPV, HIV, and Aging (AHHA) Study is a two-stage project to evaluate the relationships among anal HPV infection, HSIL, HIV infection, and biomarkers of biological aging in MSM or trans women over the age of 50 years. Stage 1 will estimate the cross-sectional prevalence of both anal HPV infection and HSIL, based on outcomes of anal HPV DNA testing, and high-resolution anoscopy with biopsy. We will also study associations with study outcomes and serological biomarkers of inflammation (interleukin-6, C-reactive protein, D-dimer) and with the Veterans Aging Cohort Study Index and the Fried Frailty Phenotype using multivariable models. Participants living with HIV (n = 150) and HIV-negative participants (n = 150) will be enrolled. The 3-year Stage 2 longitudinal sample restricted to HSIL-negative and anal HPV-16 DNA-negative participants will estimate the 3-year incidence of both anal HSIL and anal HPV, stratified by HIV status through Cox proportional hazards regression. The effect of biomarkers of inflammation and markers of aging on study outcomes will be evaluated through multivariable repeated measures models stratified by HIV status. This protocol was approved by the University of California, San Francisco Institutional Review Board (IRB: 16-18966). Results will be disseminated through presentations at national/international scientific conferences and publication in peer-reviewed journals.