High-grade Anal Dysplasia Research Articles

Topical Protease Inhibitor Increases Tumor-Free and Overall Survival in CD4-Depleted Mouse Model of Anal Cancer.

Patients with immunodeficiencies and older age are at an increased risk of anal cancer. Transgenic K14E6/E7 mice with established high-grade anal dysplasia were treated topically at the anus with the protease inhibitor saquinavir (SQV) in the setting of CD4+ T-cell depletion to mimic immunodeficiency. To ensure tumor development, specific groups were treated with a topical carcinogen (7,12-Dimethylbenz[a]anthracene (DMBA)). The treatment groups included the vehicle (control), DMBA only, topical SQV, and topical SQV with DMBA, as well as the same four groups with CD4 depletion. The mice were monitored weekly for tumor development. Upon reaching 20 weeks of treatment, the mice were sacrificed, and their anal tissue was harvested for histological analysis. None of the mice in the SQV or control groups developed overt anal tumors, except three mice that were CD4-depleted. The CD4-depleted mice treated with DMBA had significantly increased tumor-free survival and overall survival as well as decreased tumor-volume growth over time when treated with SQV. These data suggest that topical SQV, in the setting of CD4 depletion and high-grade anal dysplasia, can increase tumor-free and overall survival; thus, it may represent a viable topical therapy to decrease the risk of progression of anal dysplasia to anal cancer.

Intraepithelial CD15 infiltration identifies high-grade anal dysplasia in people with HIV.

Men who have sex with men (MSM) with HIV are at high risk for squamous intraepithelial lesion (SIL) and anal cancer. Identifying local immunological mechanisms involved in the development of anal dysplasia could aid treatment and diagnostics. Here, we studied 111 anal biopsies obtained from 101 MSM with HIV, who participated in an anal screening program. We first assessed multiple immune subsets by flow cytometry, in addition to histological examination, in a discovery cohort. Selected molecules were further evaluated by immunohistochemistry in a validation cohort. Pathological samples were characterized by the presence of resident memory T cells with low expression of CD103 and by changes in natural killer cell subsets, affecting residency and activation. Furthermore, potentially immunosuppressive subsets, including CD15+CD16+ mature neutrophils, gradually increased as the anal lesion progressed. Immunohistochemistry verified the association between the presence of CD15 in the epithelium and SIL diagnosis for the correlation with high-grade SIL. A complex immunological environment with imbalanced proportions of resident effectors and immune-suppressive subsets characterized pathological samples. Neutrophil infiltration, determined by CD15 staining, may represent a valuable pathological marker associated with the grade of dysplasia.

High Grade Anal Dysplasia in People Living with HIV: A Review of the Anal Cancer/HSIL Outcomes Research (ANCHOR) Trial. Implications for Screening and Treatment Strategies to Minimize Anal Cancer in a Very High-risk Population

The rates of AIDS-defining cancers have plummeted for people living with HIV (PLWH) and who have access to highly active antiretroviral therapies. In contrast, as survival of PLWH has improved and now rivals that of age-matched controls, rates of non-AIDS-defining cancers are increasing. Exposure to oncogenic viruses including human papillomavirus (HPV) as well as to traditional carcinogens, such as tobacco and alcohol are among the reasons for many of these cancers. Worldwide, anal cancer rates are increasing, and this is particularly true for high-grade squamous intraepithelial lesions (HSIL) evolving into invasive anal cancer in PLWH. Herein, I briefly review the oncogenic viruses most important in the pathogenesis of AIDS-defining and non-AIDS-defining malignancies and then focus on the link between HPV and anal cancer and efforts to minimize the risk of anal cancer in PLWH. The Anal Cancer/HSIL Outcomes Research (ANCHOR) study is a randomized phase III clinical trial which enrolled nearly 4500 participants across 25 diverse cities in the United States. PLWH who at time of enrollment were 35 years of age or older and who had biopsy-proven HSIL were eligible to take part in the study. The study is the first to show that screening and treating HSIL in a group at high risk for anal cancer can lead to a reduction in anal cancer incidence. Lessons learned from the ANCHOR study may also provide a blueprint for best practices when reaching out and recruiting marginalized groups with cancer into clinical trials. Much work is needed to plan for screening and treatment programs, including better algorithms for referral for high resolution anoscopy (HRA), and increased training to develop a workforce proficient in HRA screening and treatment of anal cancer. The development of progression biomarkers to identify those with HSIL most in need of treatment is essential. Finally, a more detailed analysis of costs and benefits of screen and treat algorithms for this malignancy is necessary for anal cancer screening to be implemented on a global scale.

Topical Protease Inhibitor Decreases Anal Carcinogenesis in a Transgenic Mouse Model of HPV Anal Disease.

Anal cancer is a major health problem. This study seeks to determine if the topical protease inhibitor Saquinavir (SQV), is effective at the prevention of anal cancer in transgenic mice with established anal dysplasia. K14E6/E7 mice were entered into the study when the majority spontaneously developed high-grade anal dysplasia. To ensure carcinoma development, a subset of the mice was treated with a topical carcinogen: 7,12-Dimethylbenz[a]anthracene (DMBA). Treatment groups included: no treatment, DMBA only, and topical SQV with/without DMBA. After 20 weeks of treatment, anal tissue was harvested and evaluated histologically. SQV was quantified in the blood and anal tissue, and tissue samples underwent analysis for E6, E7, p53, and pRb. There was minimal systemic absorption of SQV in the sera despite high tissue concentrations. There were no differences in tumor-free survival between SQV-treated and respective control groups but there was a lower grade of histological disease in the mice treated with SQV compared to those untreated. Changes in E6 and E7 levels with SQV treatment suggest that SQV may function independently of E6 and E7. Topical SQV decreased histological disease progression in HPV transgenic mice with or without DMBA treatment without local side effects or significant systemic absorption.

Prevalence and Predictors of High-Grade Anal Dysplasia in People With HIV in One Southeastern Ryan White HIV/AIDS Program Clinic.

Prevalence of anal cancer is increasing among people with HIV (PWH). Screening for anal cancer involves evaluating cytology and biopsy with high-resolution anoscopy (HRA) if indicated. In this study, we sought to identify the prevalence of abnormal anal cytology and biopsy-proven high-grade dysplasia, defined as anal intraepithelial neoplasia 2 and 3 (AIN2+). Demographic and clinical data were collected from participants age ≥30 years with ≥1 anal Pap smear performed during the study period (12/18/2017-05/29/2021). A subgroup analysis was performed on those with ≥1 HRA. Logistic regression estimated adjusted odds ratios (aORs) for variables of interest such as age, race, gender, presence of HPV strains, and sexual practices. Of 317 participants, 48% (n = 152) had abnormal cytology (93% low-grade squamous intraepithelial lesion [SIL] or atypical cells of undetermined significance [ASCUS] and 7% high-grade SIL). Most with abnormal cytology proceeded to HRA (n = 136/152). Of those with HRA, 62% (n = 84/136) had AIN2+. History of anoreceptive intercourse (aOR 4.62; 95% CI 1.08-23.09; P = .047), HPV 16 (aOR 4.13; 95% CI 1.63-11.30; P = .004), and "other" high-risk HPV strains (aOR 5.66; 95% CI 2.31-14.78; P < .001) were significantly associated with AIN2+. Nearly half of those screened had abnormal cytology, highlighting the high prevalence of anal dysplasia in PWH. Though only 7% had high-grade SIL on cytology, 62% of those biopsied had AIN2+, suggesting that cytology underestimates the severity of dysplasia on biopsy. HPV 16 and "other" high-risk strains were associated with AIN2 + and could be considered for risk-stratifying patients in the screening algorithm.

The use of a topical protease inhibitor, Saquinavir, to alleviate mouse papillomavirus-mediated anal disease

Select protease inhibitors (PI) have been found to be effective in decreasing human papillomavirus oncoprotein expression. This study evaluated whether the topical PI, Saquinavir (SQV), promotes viral clearance in an infectious mouse model with Mus musculus papillomavirus 1 (MmuPV1). NOD scid gamma (NSG) mice were anally infected with ∼4 × 108 viral genome equivalents of MmuPV1 and 120 days post-infection (when majority have high-grade anal dysplasia), began topical treatments: control (mock), 7,12-dimethylbenz(a)anthracene (DMBA) only, once weekly to promote carcinogenesis, 1% SQV only, daily (Monday - Friday), and SQV + DMBA. Viral MmuPV1 load was analyzed from anal lavages pre and post-treatment. Anal tissue was harvested, processed, and evaluated for drug absorption, grade of anal disease, and anal viral RNA. Results suggest that topical SQV promotes decreased viral shedding in female mice treated with SQV.

PANDA: A prospective study of the prevalence of anal dysplasia among women with high-grade cervical, vaginal, and vulvar dysplasia or cancer (107)

<b>Objectives:</b> Infection with high-risk human papillomavirus (HR HPV) is a risk factor for anal cancer, yet no evidence-based anal cancer screening guidelines exist for women with lower genital tract HPV-related dysplasia and/or cancer. We sought to describe the prevalence of anal dysplasia in women with cervical, vaginal, and vulvar dysplasia or cancer. <b>Methods:</b> This cross-sectional study was performed at a tertiary cancer center and its partner public safety-net hospital. Inclusion criteria were ≥21 years of age and a diagnosis of high-grade dysplasia or cancer of the cervix, vagina, or vulva. Women with a history of anal dysplasia or cancer were excluded. Participants underwent anal cytology, as well as anal and cervical HR HPV testing. Participants also underwent cervical cytology and/or colposcopy indicated as part of their standard of care management. Women with abnormal anal cytology were referred for high-resolution anoscopy (HRA). <b>Results:</b> A total of 275 evaluable women were prospectively enrolled between October 2018 and June 2021. The median age was 45 years (range: 21-78). Primary diagnosis was high-grade dysplasia/cancer of the cervix (<i>n</i>=209, 76.0%), vagina (<i>n</i>=25, 9.1%), and vulva (<i>n</i>=41, 14.9%). Five participants (2.0%) were HIV positive. Anal cytology was abnormal in 62 patients (23.8%) and included HSIL (<i>n</i>=1, 1.6%), ASC-H (<i>n</i>=7, 11.3%), ASCUS (<i>n</i>=48,77.4%), and LSIL (<i>n</i>=6, 9.7%). HR anal HPV was detected in 81 patients (32.3%), and included HPV16 in 15 (18.5%), HPV18 in three (3.7%), and other HR HPV types in 63 (77.8%) patients. Nine patients (11.1%) had more than one type of HR anal HPV. HR cervical HPV was detected in 129 patients (47.1%) and included HPV16 in 37 (28.7%), HPV18 in five (3.9%), and other high-risk HPV types in 87 (67.4%) patients. Twelve patients (9.3%) had more than one type of HR cervical HPV. Of those who tested positive for HR HPV, 55 patients (38.5%) had both anal and cervical HR HPV detected. In contrast, 26 (18.2%) had positive anal but negative cervical HR HPV, and 62 (43.4%) had negative anal but positive cervical HR HPV. Anal samples were insufficient for cytology in seven patients (2.6%) and HR HPV testing in 21 patients (7.7%). Of the 62 patients with abnormal anal cytology, 44 (71.0%) underwent HRA. Anal biopsies were performed in 12 patients and showed high-grade anal dysplasia in two patients and were negative in ten patients. Both patients with high-grade anal dysplasia had a primary diagnosis of high-grade cervical dysplasia. There was no association between abnormal anal cytology or positive anal HR HPV testing and the primary site of disease (cervix, vagina, or vulva). There were no cases of anal cancer diagnosed. <b>Conclusions:</b> Our results suggest a high prevalence of anal HR HPV infection and cytologic abnormalities in women with lower genital tract dysplasia or cancer. Further study is needed to determine the rate of progression to high-grade anal dysplasia and cancer to inform appropriate screening guidelines in this population.

PI3K/mTOR inhibition prevents anal cancer in mice with established low-grade anal dysplasia

Low-grade anal dysplasia is a disease that can progress to high-grade anal dysplasia and eventually anal cancer if left untreated. Research has shown that low-grade anal dysplasia is marked by significant autophagic dysfunction. We hypothesized that systemic induction of autophagy, via phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) inhibition, would be effective in preventing anal cancer development in human papillomavirus (HPV) mice (K14E6/E7) with established low-grade anal dysplasia. Mice began treatment at 15 weeks of age, when 75% of mice spontaneously develop low-grade anal dysplasia, and were divided into the following groups: no treatment, systemic LY3023414 (4.5 mg/kg, dual PI3K/mTOR inhibitor) alone, topical 7,12 dimethylbenz[a]anthracene (DMBA) alone, or systemic LY3023414 and topical DMBA. Groups were compared for final histology, PI3K activity, mTOR activity, autophagic induction (light chain 3B (LC3β)), autophagic function (p62 protein), and tumor-free survival. Untreated mice or mice treated with LY3023414 alone did not progress to cancer. There was a statistically significant decrease in the number of mice that developed histologic evidence of cancer when comparing mice that received systemic LY3203414 with topical DMBA versus those that received topical DMBA alone (p = 0.0003). PI3K and mTOR activity decreased in groups treated with systemic LY3023414 and topical DMBA as compared with those treated with topical DMBA alone (p = 0.0005 and p = 0.0271, respectively). LC3β and p62 expression was not statistically altered with systemic LY3023414 treatment. Mice developed less overt tumors and had increased tumor-free survival when treated with systemic LY3023414 in the presence of topical DMBA compared to topical DMBA alone (p = 0.0016 and p < 0.001, respectively). Systemic LY3023414 treatment is effective in anal cancer prevention in the setting of established low-grade anal dysplasia in an HPV-associated mouse model of anal cancer.

Systemic Delivery of a Dual PI3K/mTOR Inhibitor More Effective than Topical Delivery in Preventing Anal Carcinogenesis in an HPV Transgenic Mouse Model.

Anal dysplasia is a growing health concern that over time can result in squamous cell carcinoma (SqCC) of the anus. In this study, we compare a topical versus systemic (oral) administration of LY3023414, a dual PI3K/mTOR inhibitor, to prevent anal carcinogenesis in a Human Papillomavirus (HPV) mouse model of anal cancer. K14E6/E7 transgenic mice were used to model HPV-induced anal carcinogenesis. Mice with varying starting anal histologies (normal histology, low-grade, and high-grade anal dysplasia) were treated topically at the anus or systemically via oral gavage with LY3023414 with or without topical carcinogen for 20 weeks. Mice were monitored for overt anal tumor development and anal tissue was assessed for histology and markers of PI3K and mTOR activity (pAKT and pS6, respectively). LY3023414 treatment, regardless of the mode of delivery, significantly decreased overt tumor development in mice starting with normal histology and low-grade anal dysplasia. Systemic LY3023414 treatment was more effective in delaying tumor onset than topical treatment. Mice treated with systemic LY3023414 had significantly reduced rates of anal SqCC when starting with normal and low-grade anal dysplasia compared to topical treatment. Topical treatment was only effective in reducing SqCC in the setting of low-grade dysplasia. LY3023414 inhibition of pAKT and pS6 expression varied with starting histology. Neither treatment mode was effective in the setting of high-grade anal dysplasia. Systemic LY3023414 treatment was more effective than topical application in delaying the progression of normal anal histology and low-grade dysplasia to anal cancer in HPV-associated mice.

Prevalence of High-Grade Anal Dysplasia and Anal Cancer in Veterans Living With HIV and CD4/CD8 Ratio as a Marker For Increased Risk: A Regional Retrospective Cohort Study.

The Department of Veterans Affairs cares for the largest population of patients with HIV of any healthcare system in the United States. Screening for anal dysplasia/cancer is recommended for all veterans with HIV. Exams are invasive, burdensome, and resource intensive. We currently lack markers of disease to tailor screening. The purpose of this study was to establish the prevalence of advanced anal disease (high-grade dysplasia and anal cancer) and to determine whether CD4/CD8 ratio correlates with risk. This was a retrospective regional cohort study of veterans with HIV. The study was conducted at eight medical centers between 2001 and 2019. Patients with advanced disease were compared with patients with nonadvanced anal pathology. Logistic regression modeling was used to estimate adjusted odds of disease as a function of CD4/CD8. Lowest (nadir) CD4/CD8 and nearest CD4/CD8 ratio in each cohort were evaluated. A total of 2267 veterans were included. Fifteen percent had anal pathology (112 with advanced disease (37 cancer and 75 high-grade), 222 with nonadvanced disease). Nadir and nearest ratio were lower in patients with advanced disease versus nonadvanced (0.24 vs 0.45 (p < 0.001) and 0.50 vs 0.88 (p < 0.001)). In adjusted models, a 1-unit increase in nadir or nearest ratio conferred decreased risk of advanced disease (OR = 0.19 (95% CI, 0.07-0.53); p < 0.001; OR = 0.22 (95% CI, 0.12-0.43); p < 0.001). Using a minimum sensitivity analysis, a cutoff nadir ratio of 0.42 or nearest ratio of 0.76 could be used to risk stratify. This was a retrospective analysis with a low screening rate. In a regional cohort of veterans with HIV, 15% were formally assessed for anal dysplasia. Advanced anal disease was present in 33% of those screened, 5% of the HIV-positive population. A strong predictor of advanced disease in this cohort is the CD4/CD8 ratio, which is a promising marker to stratify screening practices. Risk stratification using CD4/CD8 has the potential to decrease burdensome invasive examinations for low-risk patients and to intensify examinations for those at high risk. See Video Abstract at http://links.lww.com/DCR/B528. ANTECEDENTES:El Departamento de Asuntos de Veteranos atiende a la población más grande de pacientes con el virus de inmunodeficiencia humana (VIH) de cualquier sistema de salud en los Estados Unidos. Se recomienda la detección de displasia / cáncer anal para todos los veteranos con VIH. Los exámenes son invasivos, onerosos y requieren muchos recursos. Actualmente carecemos de marcadores de enfermedad para adaptar la detección.OBJETIVO:Establecer la prevalencia de enfermedad anal avanzada (displasia de alto grado y cáncer anal) y determinar si la relación CD4 / CD8 se correlaciona con el riesgo.DISEÑO:Estudio de cohorte regional retrospectivo de veteranos con VIH.AJUSTE:Ocho centros médicos entre 2001-2019.PACIENTES:Se comparó a pacientes con enfermedad avanzada con pacientes con patología anal no avanzada.PRINCIPALES MEDIDAS DE RESULTADO:Se utilizó un modelo de regresión logística para estimar las probabilidades ajustadas de enfermedad en función de CD4 / CD8. Se evaluó la relación CD4 / CD8 más baja (nadir) y la relación CD4 / CD8 más cercana en cada cohorte.RESULTADOS:Se incluyeron un total de 2267 veteranos. El 15% tenía patología anal (112 enfermedad avanzada (37 cáncer, 75 de alto grado), 222 enfermedad no avanzada). El nadir y el cociente más cercano fueron menores en los pacientes con enfermedad avanzada frente a los no avanzados (0,24 frente a 0,45 (p <0,001) y 0,50 frente a 0,88 (p <0,001)), respectivamente. En modelos ajustados, el aumento de una unidad en el nadir o el cociente más cercano confirió una disminución del riesgo de enfermedad avanzada (OR 0,19 (IC del 95%: 0,07, 0,53, p <0,001)) y (OR 0,22 (IC del 95%: 0,12, 0,43, p <0,001))), respectivamente. Utilizando un análisis de sensibilidad mínima, se podría utilizar un cociente del nadir de corte de 0,42 o el cociente más cercano de 0,76 para estratificar el riesgo.LIMITACIONES:Análisis retrospectivo con una tasa de detección baja.CONCLUSIONES:En una cohorte regional de veteranos con VIH, el 15% fueron evaluados formalmente por displasia anal. La enfermedad anal avanzada estuvo presente en el 33% de los examinados, el 5% de la población VIH +. Un fuerte predictor de enfermedad avanzada en esta cohorte es la relación CD4 / CD8, que es un marcador prometedor para estratificar las prácticas de detección. La estratificación del riesgo usando CD4 / CD8 tiene el potencial de disminuir los exámenes invasivos onerosos para los pacientes de bajo riesgo e intensificar los exámenes para los de alto riesgo. Consulte Video Resumen en http://links.lww.com/DCR/B528.

Incidence of Recurrent High-Grade Anal Dysplasia in HIV-1-Infected Men and Women Following Infrared Coagulation Ablation: A Retrospective Cohort Study.

This single-center, retrospective cohort study sought to estimate the cumulative incidence in HIV-1-infected patients of biopsy-proven high-grade anal intraepithelial neoplasia (HGAIN) recurrence after infrared coagulation (IRC) treatment. The study was based on data from a prospectively compiled database of 665 HIV-1-infected outpatients who attended a hospital Clinical Proctology/HIV Unit between January 2012 and December 2015. Patient records were checked to see which ones had received IRC treatment but later experienced a recurrence of HGAIN. Cytology samples were also checked for the presence of human papilloma virus (HPV). A total of 81 of the 665 patients (12%, 95%CI: 10–15%), of whom 65 were men and 16 women, were diagnosed with HGAIN and again treated with IRC. Of these 81, 20 (25%) experienced recurrent HGAIN, this incidence being true of both men (16/65, 95%CI: 19–57%) and women (4/16, 95%CI: 10–50%). The median time to recurrence was 6 (2–19) months overall, 6 (2–19) months in men, and 4 (2–6) months in women. HPV infection was detected in all patients except two, with HPV-16 being the most common genotype. This rate of incidence of recurrent HGAIN following IRC treatment is consistent with other reports and highlights the importance of continued post-treatment surveillance, particularly in the first year.

CD4/CD8 Ratio as a Novel Marker for Increased Risk of High-Grade Anal Dysplasia and Anal Cancer in HIV+ Patients: A Retrospective Cohort Study.

CD4/CD8 Ratio as a Novel Marker for Increased Risk of High-Grade Anal Dysplasia and Anal Cancer in HIV+ Patients: A Retrospective Cohort Study.

Risk of Invasive Anal Cancer in HIV-Infected Patients With High-Grade Anal Dysplasia: A Population-Based Cohort Study.

The progression rate and predictors of anal dysplastic lesions to squamous cell carcinoma of the anus remain unclear. Characterizing these parameters may help refine anal cancer screening guidelines. This study aimed to determine the rate of progression of high-grade anal dysplasia to invasive carcinoma in HIV-infected persons. Using the Surveillance, Epidemiology, and End Results database linked to Medicare claims from 2000 to 2011, we identified HIV-infected subjects with incident anal intraepithelial neoplasia III. To estimate the rate of progression of anal intraepithelial neoplasia III to invasive cancer, we calculated the cumulative incidence of anal cancer in this cohort. We then fitted Poisson models to evaluate the potential risk factors for incident anal cancer. This is a population-based study. Included were 592 HIV-infected subjects with incident anal intraepithelial neoplasia III. The primary outcome measured was incident squamous cell carcinoma of the anus. Study subjects were largely male (95%) with a median age of 45.7 years. Within the median follow-up period of 69 months, 33 subjects progressed to anal cancer. The incidence of anal cancer was 1.2% (95% CI, 0.7%-2.5%) and 5.7% (95% CI, 4.0%-8.1%) at 1 and 5 years, following a diagnosis of anal intraepithelial neoplasia III. Risk of progression did not differ by anal intraepithelial neoplasia III treatment status. On unadjusted analysis, black race (p = 0.02) and a history of anogenital condylomata (p = 0.03) were associated with an increased risk of anal cancer incidence, whereas prior anal cytology screening was associated with a decreased risk (p = 0.04). The identification of some incident cancer episodes used surrogate measures. In our population-based cohort of HIV-infected subjects with long-term follow-up, the risk of progression from anal intraepithelial neoplasia III to anal squamous cell carcinoma was higher than reported in other studies and was not associated with the receipt of anal intraepithelial neoplasia III treatment. See Video Abstract at http://links.lww.com/DCR/A933.

Clinical results of infrared coagulation as a treatment of high-grade anal dysplasia: a systematic review.

Anal intraepithelial neoplasia (AIN) (or low/high grade squamousintraepithelial neoplasia (L/HSIL))is theprecursor of anal of early invasive anal cancer.Different treatment options for local ablation of localized lesions have been reported.The aim of this study was to analyze the clinical efficacy and safety of infrared coagulation for the treatment of anal dysplasia. A search of the literature was performed in 2019 using PubMed and Cochrane to identify all eligible trials published reporting data on the treatment of anal dysplasia with infrared coagulation. The percentage of squamous cell carcinoma of the the anus thatdeveloped in the follow-up and results on major complications after treatment were the primary outcomes. Twenty-four articles were identified from which 6 were selected with a total of 360 patients included, with a median age of 41.8years. Three studies were prospective and 3retrospective, only one was a randomized trial. All articles included males, 4 articles included HIV-positivewomen and only one article included non HIV infected males.No patient developed major complications after infrared coagulation therapy. Pain was the most common symptom found after the procedure in the different seriesand mild bleeding that did not requiretransfusion was the most common complication occurring in 4to 78% of patients.Median follow-up was between 4.7 and 69months.No patient developed squamous cell carcinoma after infrared treatment. Recurrent HSIL varied from 10to 38%.Two studiesreported results from follow-up of untreated patients showing that between 72 and 93% of them had persistent HSIL at last follow-up and 4.8% developed squamous cell carcinoma. Infrared coagulation is a safe and effective method for ablation of high-grade anal dysplasia that could help prevent anal cancer. Continued surveillance is recommended due to the risk of recurrence.

HPV-SAVE: 9-Valent HPV Vaccine for High-Grade Anal Dysplasia

HPV-SAVE: 9-Valent HPV Vaccine for High-Grade Anal Dysplasia

Pilot Study of Markers for High-grade Anal Dysplasia in a Southern Cohort From the Women's Interagency Human Immunodeficiency Virus Study.

Anal cancer rates have increased, particularly in human immunodeficiency virus (HIV)-infected (HIV+) women. We assessed factors associated with anal precancer in HIV+ and at-risk HIV-negative women from the Atlanta Women's Interagency HIV Study cohort. All participants underwent high-resolution anoscopy and anal cytology and had anal and cervical samples collected. Specimens were tested for 37 human papillomavirus (HPV) types and for FAM19A4 and microRNA124-2 promoter methylation. Binary logistic regression and multivariate analysis were conducted with histologic anal high-grade squamous intraepithelial lesion (A-HSIL) as the dependent variable. Seventy-five women were enrolled: 52 (69%) were HIV+ with three-fourths having undetectable viral load; 64 (86%) were black; mean age was 49 ± 8 years. Forty-nine (65%) anal cytology samples were abnormal, and 38 (51%) of anal samples were positive for at least 1 of 13 high-risk HPV (hrHPV) types. Thirteen (18%) anal biopsies identified A-HSIL. Hypermethylation of FAM19A4 and/or microRNA124-2 was found in 69 (95%) anal samples and 19 (26%) cervical samples. In multivariate analyses, the odds of having A-HSIL were >6 times higher in women with anal hrHPV (adjusted odds ratio [aOR], 6.08 [95% confidence interval {CI}, 1.27-29.18], P = .02) and with positive cervical methylation (aOR, 6.49 [95% CI, 1.66-25.35], P = .007), but not significantly higher in women with positive anal methylation. Anal hrHPV and promoter hypermethylation in the cervix show promise as biomarkers for anal cancer screening in HIV+ and at-risk HIV-negative women. Greater understanding of gene silencing by promoter hypermethylation in anal carcinogenesis is needed.

Prevalence of high-grade anal dysplasia among women with high-grade lower genital tract dysplasia or cancer: Results of a pilot study

ObjectiveTo estimate the prevalence of high-grade anal dysplasia in women with high-grade dysplasia or carcinoma of the cervix, vagina or vulva. MethodsIn this cross-sectional study, participants underwent anal cytology, anal HPV testing with Cervista HPV16/18 and high-resolution anoscopy (HRA). Patients with HSIL (high-grade squamous cell intraepithelial lesion) or greater on anal cytology or anal biopsy were referred to a colorectal surgery specialist for further evaluation. ResultsSeventy-five women were enrolled in the study, including 47 with cervical (cervix group), 10 with vaginal (vagina group), 15 with vulvar (vulva group), 1 with cervical and vaginal, and 2 with vulvar and vaginal disease. The median age in the cervix group (40 years (range 26–69)) was substantially younger than in the vagina (60 years (38–69)) and the vulva (59 years (36–75)) groups. Anal HSIL based on composite endpoints of the most severe cytology or histology result was diagnosed in 6 patients (8.0%). Anal cytology revealed HSIL in 2 (2.7%), atypical squamous cells of undetermined significance (ASCUS) in 12 (16.0%), low-grade squamous cell intraepithelial lesion (LSIL) in 2 (2.7%), and was normal in 59 (78.7%) patients. Anal HPV16/18 test was positive in 15 (20.0%), negative in 48 (64.0%) and insufficient in 12 (16.0%) patients. Of the 6 women with high-grade anal dysplasia, three (50%) had a positive anal HPV16/18 test. No case of anal cancer was observed. ConclusionOur results suggest that the prevalence of anal HSIL is elevated among women with HPV-related lower genital tract dysplasia or cancer. To further support the inclusion of this high-risk group into screening guidelines for anal dysplasia, further studies are necessary to determine what screening strategy is suited to this population.

Expectant Management of High-Grade Anal Dysplasia in People with HIV: Long-term Data.

Both ablation and expectant management of high-grade squamous intraepithelial lesions have been proposed. Expectant management would be reasonable if 1) the rate of high-grade squamous epithelial lesion progression to anal squamous cell carcinoma were low, and 2) anal squamous cell carcinoma arising under surveillance had a better prognosis than anal squamous cell carcinoma presenting without an identified precursor. This study aims to quantify aspects of high-grade squamous epithelial lesion/anal squamous cell carcinoma clinical evolution in a surgical practice. This is a retrospective cohort study. This study was performed in 1 colorectal surgeon's practice over a 20-year period. Consecutive patients with high-grade squamous intraepithelial lesion and anal squamous cell carcinoma were included. We looked at the rate and timing of progression to anal squamous cell carcinoma, and the stage, treatment, and outcome of anal squamous cell carcinoma. We reviewed a comparison group of HIV-positive patients presenting de novo with anal squamous cell carcinoma (no prior history of high-grade squamous intraepithelial lesion). With consideration of only HIV-positive patients, 341 patients had a mean 5.6 years follow-up from high-grade squamous intraepithelial lesion diagnosis to the most recent documented anal examination. Twenty-four of these surveillance patients developed anal squamous cell carcinoma, yielding a progression rate of 1.3% per patient-year. Mean follow-up was 7.3 years from the initial cancer diagnosis to the most recent contact. Forty-seven patients who presented de novo with anal squamous cell carcinoma developed 74 lesions, with a mean follow-up of 5.7 years after initial diagnosis. This de novo group had higher anal squamous cell carcinoma-specific mortality (3% per patient-year vs 0.05%). Our study did not show a significantly higher rate of high stage (stage III or IV) at anal squamous cell carcinoma diagnosis in the de novo group in comparison with the surveillance group (25.5% vs 8.3% (p = 0.09)). This study was retrospective in nature and had a predominately male population. The progression of untreated high-grade squamous intraepithelial lesion to anal squamous cell carcinoma approximates 1% per patient-year. Anal squamous cell carcinoma developing under surveillance tends to be of an earlier stage and to require fewer major interventions than anal squamous cell carcinoma presenting de novo. Cancer-specific mortality was lower for malignancies that developed under surveillance. We suggest that expectant management of patients with high-grade squamous intraepithelial lesion is a rational strategy for preventing anal cancer morbidity. See Video Abstract at http://links.lww.com/DCR/A699.

6 - Pilot study of markers for high-grade anal dysplasia in a southern cohort from the Women's Interagency HIV Study (WIHS)

Background Anal cancer rates have increased in HIV+ women. Factors associated with anal cancer precursor high-grade squamous intraepithelial lesions (HSIL) in HIV+ and at-risk-HIV- women were assessed. Methods HIV+ and HIV- women from the Atlanta WIHS cohort were enrolled in a cross-sectional pilot study. All anal (AS) and cervical (CS) swab samples were analyzed for HPV-genotyping (Linear-Array® HPV-Genotyping Test, LA-HPVGT) and FAM19A4 and microRNA-124-2 promoter methylation. All women underwent high resolution anoscopy with biopsy of suspicious lesions and anal cytology (AC) collection. Logistic regression was conducted with anal HSIL histology (A-HSIL) as the dependent variable. Results 75 women were enrolled: 52(69%) were HIV+ with 3/4 having undetectable viral load, 64(86%) Black, with mean age 49. 44(59%) AC samples were ASCUS/+hrHPV or higher, 38(51%) of all AS were +hrHPV by LA-HPVGT.13 anal biopsies were confirmed A-HSIL. 69(95%) AS and 19(26%) CS tested positive for hypermethylation, respectively. A-HSIL model included ASCUS/+hrHPV or greater on AC and cervical hypermethylation as covariates (Table 1). AS hypermethylation was not associated with A-HSIL. Conclusions Our results suggest AC with hrHPV testing and/or cervical gene promoter hypermethylation measurements as promising non-invasive screening strategies for A-HSIL in both HIV+ and HIV- women. Lack of association between AS hypermethylation and A-HSIL may reflect characteristics of the anal milieu and warrants further investigation.

Risk of Progression of High Grade Anal Dysplasia to Invasive Squamous Cell Carcinoma of the Anus

Risk of Progression of High Grade Anal Dysplasia to Invasive Squamous Cell Carcinoma of the Anus