High-grade Anal Intraepithelial Neoplasia Research Articles

Trends in the occurrence of high‐grade anal intraepithelial neoplasia in San Francisco: 2000‐2009

Although screening of human immunodeficiency virus (HIV)-positive individuals for anal intraepithelial neoplasia (AIN; a precursor of anal cancer) has been practiced in San Francisco among HIV health care providers since the early 1990s, to the authors' knowledge no study to date has focused on evaluating recent AIN trends. Cases of high-grade AIN 3 and invasive anal cancer from 2000 to 2009 were obtained from the San Francisco/Oakland Surveillance, Epidemiology, and End Results (SEER) population-based cancer registry. Age-standardized rates of AIN 3 and anal cancer were calculated overall and by demographic characteristics (sex, race, and age group). Log-linear regression calculated annual percent change in rates during 2000 to 2009, and rate ratios (RRs) and 95% confidence intervals (95% CIs), evaluated differences in rates during 2000 through 2004 and 2005 through 2009. During 2000 through 2009, the majority of AIN 3 cases occurred among men (1152 of 1320 men; 87.3%). Rates of AIN 3 during the corresponding period increased by 11.48% per year (P < .05) among men and were stable among women. Comparing rates among men during 2000 to 2004 with those during 2005 to 2009, the largest increases were noted among those aged 50 years to 64 years (RR, 2.47; 95% CI, 1.93-3.17) and among black individuals (RR, 3.49; 95% CI, 2.14-5.85). During the same period, anal cancer rates were stable among men and women. Rates of AIN 3 increased in San Francisco during 2000 through 2009, in conjunction with an anal cytology screening program for high-risk groups, whereas rates of invasive anal cancer were unchanged. Continued surveillance is necessary to evaluate the impact of screening and human papillomavirus vaccination on the prevention of human papillomavirus-related AIN and anal cancer.

Current treatment options for management of anal intraepithelial neoplasia.

Anal squamous cell cancer is an uncommon malignancy caused by infection with oncogenic strains of Human papilloma virus. Anal cancer is much more common in immunocompromised persons, including those infected with Human immunodeficiency virus. High-grade anal intraepithelial neoplasia (HGAIN), the precursor of anal cancer, is identified by clinicians providing care for patients with anorectal disease, and is increasingly being identified during screening of immunosuppressed patients for anal dysplasia. The traditional treatment for HGAIN has been excision of macroscopic disease with margins. This approach is effective for patients with small unifocal HGAIN lesions. Patients with extensive multifocal HGAIN frequently have recurrence of HGAIN after excision, and may have postoperative complications of anal stenosis or fecal incontinence. This led to the suggestion by some that treatment for HGAIN should be delayed until patients developed anal cancer. Alternative approaches in identification and treatment have been developed to treat patients with multifocal or extensive HGAIN lesions. High-resolution anoscopy combines magnification with anoscopy and is being used to identify HGAIN and determine treatment margins. HGAIN can then be ablated with a number of modalities, including infrared coagulation, CO2 laser, and electrocautery. These methods for HGAIN ablation can be performed with local anesthesia on outpatients and are relatively well tolerated. High-resolution anoscopy-directed HGAIN ablation is evolving into a standard approach for initial treatment and then subsequent monitoring of a disease which should be expected to be recurrent. Another treatment approach for HGAIN is topical treatment, principally with 5-fluorouracil or imiquimod. Topical therapies have the advantage of being nonsurgical and are well suited for treating widespread multifocal disease. Topical treatments have the disadvantage of requiring extended treatment courses and causing a symptomatic inflammatory response. Successful treatment requires adherence to a regime that is uncomfortable at best and at worst painful. Topical treatments can be successful in motivated adherent patients willing to accept these side effects.

Will local ablation of high grade anal intraepithelial neoplasia prevent invasive anal cancer?

Will local ablation of high grade anal intraepithelial neoplasia prevent invasive anal cancer?

Anal intraepithelial neoplasia in a sexually transmitted diseases outpatient clinic: correlation with cytological screening

High-grade anal intraepithelial neoplasia (AIN) is currently considered a precursor of anal cancer. The population most susceptible to AIN is men who have sex with men (MSM), especially if they are infected by HIV. We analysed the population diagnosed with AIN and evaluated anal cytology as a method of screening the at-risk population. We undertook a retrospective review of patients diagnosed with AIN by means of a surgical biopsy between 2008 and 2010. We analysed the risk factors of the population affected and the degree of agreement with the cytology performed previously. During the study period 41 patients were diagnosed with AIN and seven with anal canal carcinoma in situ; 77% were men, most MSM. A history of receptive anal intercourse was found in 81% of the patients and in 71% there was an association with anogenital warts; 32 patients were HIV-positive, most of them men. Of the patients with anal dysplasia of any type in the cytology, 90% had some grade of AIN or carcinoma in situ in the later biopsy. The degree of agreement between the cytology and the biopsy was 94% in the high-grade dysplasias and 50% in the low-grade dysplasias. Anal cytology in at-risk populations has a high degree of agreement with the biopsy when performed surgically, though less in low-grade dysplasias, which must always be studied. More studies evaluating the degree of progression of AIN to anal cancer are necessary.

Treatment of high-grade anal dysplasia in high-risk patients: outcome at an urban community health centre

Human immunodeficiency (HIV)-infected patients and men who have sex with men (MSM) have a higher rate of high-grade anal intraepithelial neoplasia (HGAIN), a likely precursor to anal cancer. This retrospective study describes the outcome of treating MSM with incident biopsy-proven HGAIN in an urban community health setting with access to outpatient ablation or operative treatment. The main outcome was freedom from HGAIN at follow-up. One hundred and fifty-three met inclusion criteria; 86 (56%) were HIV-infected. Eighty (52%) received outpatient ablation, 49 (61%) had a follow-up within nine months. Among those, 26 (53%) were free of high-grade disease, 19 (39%) had high-grade disease; and 4 (8%) had unknown grading. In a logistic regression model, a lower extent of anal disease (1 quadrant versus 2, 3 or 4 quadrants) at the time of treatment was significantly associated with a lower probability of high-grade disease (P value 0.04). HGAIN could be managed in a community health setting; however, systems are needed to ensure follow-up care.

Anal cytology as a predictor of anal intraepithelial neoplasia in HIV‐positive men and women

Human immunodeficiency virus (HIV)-infected individuals have increased risk of anal intraepithelial neoplasia (AIN) and squamous cell carcinoma (SCC). Cytologic screening is invaluable in the detection of cervical neoplasia, therefore many clinicians have adopted anal cytology as part of anal cancer screening in patients at high-risk for anal neoplasia. The purpose of this study is to determine whether anal cytology is a valuable screening test for identifying AIN in HIV+ patients. The cohort included 228 HIV+ patients who underwent anal cancer screening with collection of 318 anal cytology specimens between January 2006 and December 2009. Of this group, 74 (32.5%) patients had associated anal biopsies within a 6-month period, with a total of 89 comparison cases. The anal cytology samples were classified using the 2001 Bethesda System terminology. The sensitivity of anal cytology in detecting ASC-US, AIN 1-3 or SCC was 93%. Cytology was 88% sensitive for detecting low-grade AIN (AIN 1), but only 20% sensitive for detecting high-grade AIN (AIN 2-3) or SCC. Atypical squamous cells of undetermined significance cases were distributed evenly between low- and high-grade AIN, with two cases having normal histology. Only six cases had negative cytology, all of which were associated with AIN on biopsy, for a false negative rate of 7%. Anal cytology is a good predictor of AIN, as confirmed by the high degree of sensitivity. However, there is poor correlation between the cytological and histological grade of AIN. Cytology underestimates the grade of dysplasia compared to the corresponding biopsy.

9. Cellular immune response to anal dysplasia in HIV-positive men on highly active antiretroviral therapy

Background The role of the cellular immune response to anal dysplasia progression is poorly understood. Extrapolated from the cervical model, CD4+ (killed by HIV) and CD8+ cells may have crucial anti-tumour activity. We report pilot data on key immune responses in HIV+ patients on HAART with anal dysplasia. Methods: High-resolution anoscopy and biopsies were performed. Ten tissue biopsies with high-grade anal intraepithelial neoplasia (HGAIN) were stained with immunohistochemistry for CD4+, CD8+, CXCL12+ and FOXP3+, and compared with 10 samples with low-grade anal intraepithelial neoplasia (LGAIN). Serum CD4+ and CD8+ counts were available. Tissue photographs were obtained and analysed utilising MetaXpress software. Results: In all dysplastic tissue, we found a higher number of CD4+, CD8+ and FOXP3+ cells in the subepithelium than epithelium. In HGAIN, the number of FOXP3+, intraepithelial CD4+ cells, and the ratio of intraepithelial to serum CD4+ were higher than in LGAIN. CXCL12+ staining was more abundant in HGAIN. CD4+ cells outnumbered CD8+ cells in all dysplastic tissue. Conclusions: The higher CD4+ to CD8+ ratio in HGAIN may be explained by the excess demand for antitumour activity, which is known to be a function of CD4+ cells against HPV-dysplasia in the analogous cervical dysplasia model. Cytotoxic CD8 cells, although known to have an important anti-tumour role, were less abundant in our study. The pro-tumour FOXP3+ cells, being more abundant in HGAIN, may have a key role in the progression of anal dysplasia. Strategies to block CXCL12+ may be useful in the treatment of HPV-related dysplasia.

30. Recognising and treating anal cancer: training medical students and physicians in Puerto Rico

Background Knowledge about epidemiology, diagnosis and treatment of anal neoplasia is limited among medical students and physicians from Puerto Rico (PR). Methods: Educational activity (1.5 contact hours) about anal cancer for a group of medical students, residents and faculty from the University of PR (n = 50). A 6-item pre- and post-test on anal cancer was given to assess the change in knowledge. Results: Thirty-four participants (68%) answered the survey. Overall, 78.8% had not received training in anal cancer screening and 93.9% were interested in receiving this training. Most (75.8%) were interested in participating in a clinical trial. An increase in the test scores was observed after the activity (pre-test: 3.4 ± 1.2; post-test: 4.7 ± 0.71). Three items showed an increment in the post-test that assessed participants’ knowledge regarding: (1) current status of guidelines for the screening/treatment of patients with HPV-related anal disease; (2) that anal intraepithelial neoplasia (AIN) 2 is considered to be a form of high-grade AIN (HGAIN); and (3) that warty growths in the anus are not necessarily a manifestation of HGAIN. Conclusions: This educational activity increased the participants’ knowledge of anal cancer and revealed that most of them were interested in future training and in collaborating in clinical trials. Training physicians from PR on anal cancer and clinical trials is essential to encourage recruitment of Hispanic patients in these studies now that the guidelines in anal cancer screening and treatment are on their way to being defined.

7. High prevalence of human papillomavirus (HPV) infection and high-grade anal intraepithelial neoplasia in HIV-seropositive women, the EVVA study

Background Women living with HIV are at increased risk of anal HPV infection, anal intraepithelial neoplasia (AIN) and anal cancer. This study will describe the burden of infection and of high-grade AIN (AIN-2,3) in a population of HIV-infected women living in Montreal, Canada. Methods: HIV-seropositive women aged ≥18 years old are recruited in the cohort study EVVA. Participants are followed every 6 months for 2 years with questionnaires, cervical/anal HPV testing, cervical/anal cytology and high-resolution anoscopy (HRA). Results: Of the 116 first participants, 88 (75.9%, 95% confidence interval (CI) 67.3–82.8) were infected by HPV in the anal canal. In contrast, 58 of these participants (50%, 95% CI 41.1–59.0) had cervical HPV infection). The most frequent types were HPV16 (n = 19), HPV51 (n = 18), HPV81 and HPV62 (n = 15 each), and HPV45 and HPV58 (n = 14 for each). An average of 2.3 ± 3.1 HPV types (median of 1) were detected per anal sample. Of the 89 participants with satisfactory cytology, 5 had high-grade squamous intraepithelial lesions. HRA from 95 women revealed 17 AIN2,3 (17.9%, 95% confidence interval (CI) 11.4–26.9), 43 AIN1 (45.3%, 95% CI 35.6–55.3), and only 35 without AIN (36.8%, 95% CI 27.8–46.9). Biopsies from 4 women gave undetermined results. Conclusions: Our study revealed that anal HPV infection was more frequently detected than cervical infection in HIV-seropositive women. Prevalent AIN2,3 is a significant problem in women infected with HIV. Prospective follow-up of women with AIN1 will disclose the proportion of women with progressive AIN.

34. One lesion, one virus: individual components of high-grade anal intraepithelial neoplasia in HIV+ men contain a single HPV type

Background Anal intraepithelial neoplasia (AIN) is present in the majority of HIV+ men who have sex with men (MSM). The main aetiological factor is human papilloma virus (HPV). We analysed whether HPV PCR genotyping of whole tissue sections (WTS) and subsequent laser capture microdissection (LCM) detects type-specific HPV DNA in individual areas of HGAIN, and compared these lesional HPV genotypes with HPV types in anal swabs. Methods: DNA was isolated from anal swabs and WTS of 31 HGAIN biopsies obtained from 21 HIV+ MSM and analysed by the SPF10 PCR/LiPA25 HPV genotyping system. In case of multiple HPV types per WTS, PCR was repeated in selected areas of AIN obtained by LCM. Results: A single HPV type was observed in 15 (48%) of 31 WTS. In the 16 WTS with multiple HPV types, LCM-isolated dysplastic areas were studied. In 14 of the 16 WTS, one single HPV type was demonstrated within each discrete area of the lesion, resulting in a total of 29 (15+14) biopsies in which a single HPV type was found in (all components of) the lesion. HPV 16 was found in 14 of 31 biopsies (45%). In almost half the biopsies, lesional HPV types were not detected in the anal swabs. Conclusions: WTS PCR and subsequent LCM PCR is accurate in detecting lesion-specific HPV types in HGAIN and in 94% of the biopsies a single HPV was found in (each component of) the HGAIN lesion. In the majority, HPV16 was not the causative type and HPV genotyping of anal swabs was not useful in detecting the lesion-specific type.

Anal cytological abnormalities are poor predictors of high-grade intraepithelial neoplasia amongst HIV-positive men who have sex with men

Although anal squamous cell carcinomas (ASCC) are rare in the general community, rates of ASCC among HIV-positive men who have sex with men (MSM) approach those of major cancers in the general community, such as colorectal and lung cancers. Anal cytology and high-resolution anoscopy (HRA) have been proposed as methods for the diagnosis of high-grade anal intraepithelial neoplasia (HGAIN), the precursor of ASCC. To determine the prevalence of anal disease among HIV-positive MSM, we investigated anal cytological and histological findings in men from a large HIV clinic in Sydney, Australia. This was a single-centre study conducted between October 2008 and January 2010. Participants self-collected cytology specimens, and those yielding abnormal cytology results of atypical cells of undetermined significance, atypical cells of undetermined significance - possibly high-grade (ASC-H) and high-grade squamous intraepithelial lesions (HSIL) were offered HRA. In addition, of those yielding low-grade squamous intraepithelial lesions results, a systematically selected group (25%) were offered HRA. Of the 1339 HIV-positive MSM who attended the clinic during the study period, 291 (31.8%) were finally included in the study, 262 yielded technically satisfactory cytological results and 101 (36.7%) participants underwent HRA. HGAIN was identified in 55 (54.5%) of the 101 men undergoing HRA. HGAIN was diagnosed in 28 (52.7%) without cytological ASC-H or HSIL results. Despite the poor correlation between anal cytological and histological findings, high levels of HGAIN were identified in HIV-positive MSM attending this clinical service.

Treatment of High-Grade Anal Intraepithelial Neoplasia With Infrared Coagulation in a Primary Care Population of HIV-Infected Men and Women

High-grade anal intraepithelial neoplasia, the putative anal carcinoma precursor, is more common in HIV-infected persons. The ideal treatment for these lesions has not been established. The aim of this study was to evaluate the effectiveness of infrared coagulation treatment for high-grade anal intraepithelial neoplasia. This is a prospective cohort study. Patients with high-grade anal intraepithelial neoplasia either received infrared coagulation treatment or voluntarily did not receive treatment and were reevaluated at a subsequent time point. This investigation was performed at a Ryan White-funded clinic located in the United States. HIV-infected men and women with biopsy-confirmed high-grade anal intraepithelial neoplasia were included. The primary outcome measured was the histology collected by high-resolution anoscopy-directed biopsy. The study included 124 patients. Of 42 patients who either delayed treatment or were not treated, 37 (88%; 95% CI = 74%-96%) still had high-grade anal intraepithelial neoplasia on reevaluation and 2 (5%; 95%CI = 1%-16%) had squamous-cell carcinoma. Of 98 patients who received infrared coagulation treatment, 73 (74%; 95% CI = 65%-83%) patients had no evidence of high-grade anal intraepithelial neoplasia on their first posttreatment evaluation, and none had progressed to squamous-cell carcinoma (p < 0.0001 in comparison with untreated). Upon completing all initial and, if necessary, follow-up treatment, 85 (87%; 95% CI = 78%-93%) patients treated by infrared coagulation had no evidence of high-grade anal intraepithelial neoplasia and none had progressed to squamous-cell carcinoma. The study population may not be representative of the general population, the study environment was uncontrolled, and patients were not randomly assigned to treatment. Infrared coagulation is an effective treatment for high-grade anal intraepithelial neoplasia.

Human papillomavirus genotype attribution and estimation of preventable fraction of anal intraepithelial neoplasia cases among HIV-infected men who have sex with men.

The prevention of human papillomavirus (HPV)-induced anal cancer in high-risk populations such as human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) remains an urgent priority, given rising incidence rates despite widespread antiretroviral therapy use. HPV genotypes and anal disease prevalence, by cytology and histopathologic findings, were evaluated among 363 HIV-infected MSM. We modeled fractions of high-grade anal intraepithelial neoplasia (HGAIN) attributable to individual carcinogenic HPV genotypes and estimated the range of the proportion of HGAIN cases potentially preventable by prophylactic HPV vaccines. HPV16 was the most common genotype overall (26.4% of cases) and among HGAIN cases (55%). Prevalence of multiple (≥ 2) carcinogenic HPV genotypes increased from 30.9% in cases of AIN grade <1 to 76.3% in cases of AIN grade 3 (P(trend) < .001). The fractions of HGAIN cases attributable to carcinogenic HPV16/18 targeted by currently licensed bivalent and quadrivalent HPV vaccines ranged from 12% to 61.5%, and the fractions attributable to carcinogenic HPV16/18/31/33/45/52/58 targeted by an investigational nonavalent HPV vaccine ranged from 39% to 89.4%. Our analytical framework allows estimation of HGAIN cases attributable to individual HPV genotypes in the context of multiple concurrent HPV infections, which are very common among HIV-infected MSM. Our results suggest that licensed and investigational HPV prophylactic vaccines have the potential to prevent a substantial proportion of HGAIN cases in this population.

P16 as an Adjunct Test for the Detection of High-Grade Anal Intraepithelial Neoplasia in Anal Paps

Our goal was to assess the usefulness of the p16 immunohistochemical stain as adjunct to detect high-grade anal intraepithelial neoplasia (AIN) in anal Paps, which are increasingly used for screening of populations at high risk for AIN in the United States. Although published data indicate there are populations at high …

P16 as an Adjunct Test for the Detection of High-Grade Anal Intraepithelial Neoplasia in Anal Paps

Our goal was to assess the usefulness of the p16 immunohistochemical stain as adjunct to detect high-grade anal intraepithelial neoplasia (AIN) in anal Paps, which are increasingly used for screening of populations at high risk for AIN in the United States. Although published data indicate there are populations at high …

Anal Intraepithelial Lesions in Women With Human Papillomavirus–Related Disease

This study aimed to determine the prevalence of anal intraepithelial lesions in women with histologic diagnosis of intraepithelial lesions of the lower genital tract. This was a cross-sectional study conducted at the Lower Genital Tract and Colposcopy Unit of Hospital de Clínicas "José de San Martín," University of Buenos Aires, Argentina. A total of 481 women with histologically confirmed low-grade and high-grade cervical, vaginal, or vulvar intraepithelial lesions were evaluated between 2005 and 2011. They were referred for cytologic samples and examination with high-resolution anoscopy. We obtained biopsy specimens of any suspicious colposcopic images. Of a total of 481 patients, 404 (84%) were immunocompetent, 31 (6.4%) were HIV+, and 46 (9.6%) had other causes of immunosuppression. Moreover, of the 481 patients, 134 (27.86%) had anal intraepithelial neoplasia (AIN); 28 (5.82%) had high-grade AIN and 106 (22%) had low-grade AIN. Women with high-grade cervical intraepithelial neoplasia (CIN 2, 3) had 2 times the odds of developing AIN compared with women with low-grade CIN (CIN 1) (odds ratio = 1.91, 95% confidence interval = 1.1-3.6). Regarding localization, we found statistically significant difference between the frequency of vulvar and anal lesions. Women with vulvar condylomata and vulvar intraepithelial neoplasia (VIN) may be more likely to develop AIN. Immunocompetent women with CIN, vaginal intraepithelial neoplasia, or VIN may also present high-grade or low-grade anal intraepithelial lesions so we should consider AIN as part of multicentric disease of the lower genital tract. Cervical intraepithelial neoplasia, VIN, condyloma accuminatta, and vaginal intraepithelial neoplasia could be warning signs of anal intraepithelial lesions.

HPV infection, anal intra-epithelial neoplasia (AIN) and anal cancer: current issues

BackgroundHuman papillomavirus (HPV) is well known as the major etiological agent for ano-genital cancer. In contrast to cervical cancer, anal cancer is uncommon, but is increasing steadily in the community over the last few decades. However, it has undergone an exponential rise in the men who have sex with men (MSM) and HIV + groups. HIV + MSM in particular, have anal cancer incidences about three times that of the highest worldwide reported cervical cancer incidences.DiscussionThere has therefore traditionally been a lack of data from studies focused on heterosexual men and non-HIV + women. There is also less evidence reporting on the putative precursor lesion to anal cancer (AIN – anal intraepithelial neoplasia), when compared to cervical cancer and CIN (cervical intraepithelial neoplasia). This review summarises the available biological and epidemiological evidence for HPV in the anal site and the pathogenesis of AIN and anal cancer amongst traditionally non-high risk groups.SummaryThere is strong evidence to conclude that high-grade AIN is a precursor to anal cancer, and some data on the progression of AIN to invasive cancer.

Anal cancer screening – Authors' reply

In our meta-analysis of the natural history of human papillomavirus (HPV) infection in men who have sex with men (MSM),1 we concluded that anal cancer screening and treatment of high-grade anal intraepithelial neoplasia (AIN) should occur within a research setting. Joel Palefsky and Luis F Borroso have taken issue with this conclusion.

High Prevalence of High Grade Anal Intraepithelial Neoplasia in HIV-Infected Women Screened for Anal Cancer

There is no consensus on optimal screening for anal cancer (AC) in HIV+ women. Seven hundred fifteen unique asymptomatic women in a high-prevalence HIV+ community were screened for AC with anal cytology and triage to high-resolution anoscopy after routine screening was implemented in a large urban hospital system. Of these, 75 (10.5%) had an abnormal anal cytology and 29 (38.7%) of those with an abnormality had high-grade anal intraepithelial neoplasia (AIN). Women with poorly controlled HIV were significantly more likely to have high-grade AIN (P = 0.03). Given the high rate of AIN in screened HIV-infected women, routine AC screening in all HIV-infected women should be strongly considered.

Nylon-flocked swab collection method better predicts high-grade AIN than does dacron swab method

Author(s): Wiley, Dorothy; Bolan, Robert; Voskanian, Alen; Young, Stephen; Elashoff, David; Hsu, Hilary; Masongsong, Emmanuel; Barman, Provaboti; Detels, Roger