Host Nuclear Genome Copy Number Variations Identify High-Risk Anal Precancers in People Living With HIV.

BACKGROUND: People living with HIV (PLWH) have substantially increased incidence of anal precancer and cancer. There are very little data regarding genomic disturbances in anal precancers among PLWH. In this study, specific chromosomal variants were identified in anal squamous intraepithelial lesions. METHODS: Overall, 63 anal biopsy specimens (27 low-grade intraepithelial lesions [LSIL] and 36 high-grade intraepithelial lesions [HSIL]) were collected from PLWH obtained as part of anal cancer screening in our NYC-based health system. Data on patient demographics, anal cytological, and high-risk human papillomavirus (HR-HPV) diagnoses were collected. Specimens were tested for a panel of chromosomal alterations associated with HPV-induced oncogenesis using fluorescence in situ hybridization, and analyses compared the associations of these alterations with clinical characteristics. RESULTS: Gains of 3q26, 5p15, 20q13, and cen7 were detected in 42%, 31%, 31%, and 19% of HSIL compared with 7%, 0%, 4%, and 0% of LSIL, respectively. If at least 1 abnormality was observed, 89% had a 3q26 gain. In lesions with 5p15 gains, 20q13 gains co-occurred in 91% of cases, while cen7 gain only co-occurred with the other 3 alterations. The sensitivity and specificity of any alteration to predict HSIL were 47% (95% CI: 30%-65%) and 93% (95% CI: 76%-99%), respectively. CONCLUSIONS: Genomic alterations seen in HPV-associated cancers may help distinguish anal LSIL from HSIL. 3q26 amplification may be an early component of anal carcinogenesis, preceding 5p16, 20q13, and/or chr7. IMPACT: Insights into potential genomic biomarkers for discriminating high-risk anal precancers are shared.

The other side of screening: predictors of treatment and follow-up for anal precancers in a large health system.

BACKGROUND: Anal cancer disproportionately affects people with HIV (PWH). High-grade squamous intraepithelial lesions (HSIL) are cancer precursors and treating them might prevent anal cancer. Data on adherence to HSIL treatment and surveillance is limited but needed to identify deficiencies of screening strategies. METHODS: We collected data on high-resolution anoscopy (HRA) attendance and outcomes from 2009 to 2019 in a large urban anal cancer-screening program. Patients with an initial HSIL diagnosis were followed for return for HSIL electrocautery ablation within 6 months of index HSIL diagnosis, and follow-up HRA within 18 months of index HSIL diagnosis. We also evaluated predictors of these outcomes in univariable and multivariable analyses. RESULTS: One thousand one hundred and seventy-nine unique patients with an anal HSIL diagnosis were identified and 684 (58%) returned for electrocautery ablation. Of those treated, only 174 (25%) and only 9% of untreated HSIL patients (47 of 495) underwent surveillance HRA within 18 months of index HSIL diagnosis. In multivariable analyses, black patients and PWH regardless of virologic control were less likely to undergo HSIL ablation within 6 months of HSIL diagnosis whereas patients with commercial insurance were more likely to be treated within 6 months of diagnosis. Among treated HSIL patients, PWH with viremia had a lower likelihood of engaging in post-treatment surveillance within 18 months of HSIL diagnosis. DISCUSSION: Even in large specialized anal cancer screening programs adherence to HSIL treatment and surveillance is low. Psychosocial and economic determinants of health may impact retention in care. Addressing both personal and structural barriers to patient engagement may improve the effectiveness of anal cancer screening.

Comparing Anal Cancer Screening Algorithms Using Cytology and Human Papillomavirus DNA Testing in 3 High-Risk Populations.

BACKGROUND: Screening strategies for high-risk human papillomavirus (hrHPV)-associated anal cancer are evolving. Herein, we compare anal cytology to hrHPV DNA testing and 2 novel cytology/hrHPV cotesting algorithms among 3 high-risk populations. METHODS: Anal cytology, hrHPV DNA testing, and high-resolution anoscopy (HRA)-guided biopsy results were analyzed from 1837 participants (1504 HIV-infected men who have sex with men (MSM), 155 HIV-uninfected MSM, and 178 HIV-infected women). Performance to detect histological high-grade squamous intraepithelial lesions (HSIL)/cancer was compared between 4 strategies with distinct HRA referral thresholds: cytology (atypical squamous cells of undetermined significance, ASCUS); hrHPV testing (any hrHPV positive); algorithm A (benign cytology/HPV16/18 positive or ASCUS/hrHPV positive); and algorithm B (benign or ASCUS/hrHPV positive). RESULTS: Histological HSIL/cancer was detected in 756 (41%) participants. Cytology had the lowest sensitivity (0.76-0.89) but highest specificity (0.33-0.36) overall and for each subgroup. Algorithm B was the most sensitive strategy overall (0.97) and for MSM (HIV-infected 0.97; HIV-uninfected 1.00). For women, hrHPV testing and both algorithms yielded higher sensitivity than cytology (0.96, 0.98, and 0.96). Specificity was low for all strategies/subgroups (range, 0.16-0.36). CONCLUSIONS: Screening algorithms that incorporate cytology and hrHPV testing significantly increased sensitivity but decreased specificity to detect anal precancer/cancer among high-risk populations.

Targeted ablation of perianal high-grade dysplasia in men who have sex with men: an alternative to mapping and wide local excision.

BACKGROUND: Perianal high-grade dysplasia (Bowen disease) is traditionally treated with mapping and wide excision with possible grafting rather than local ablation. OBJECTIVE: The aim of this study is to examine the results of high-grade perianal dysplasia ablation. DATA SOURCES: Data for this study were derived from a retrospective chart review at a surgical practice screening and treating patients for high-grade dysplasia between July 1998 and June 2013. STUDY SELECTION: The patients included were men who have sex with men and are undergoing perianal dysplasia ablation. INTERVENTION: Ablation of perianal dysplasia with electrocautery, laser, or infrared coagulation was performed. MAIN OUTCOME MEASURES: The primary outcomes measured were the recurrence of perianal dysplasia postablation and factors affecting recurrence. RESULTS: Seventy HIV-positive and 11 HIV-negative patients enrolled; the median ages were 44.7 and 42.8 years. Median follow-up times for HIV-positive and HIV-negative patients were 4.62 and 3.53 years, and the median numbers of treatments were 4 and 1, p = 0.004. The median number of lesions treated was 1 for both groups. Only 1 HIV-negative patient had a recurrence 8 months after treatment. For HIV-positive patients, the Kaplan-Meier probability of recurrence at 1, 3, and 5 years was 38% (95% CI 26-50), 59% (95% CI 47-72), and 68% (95% CI 55-81) after the first ablation with no difference for subsequent treatments. HIV-positive patients had a relative risk of perianal high-grade squamous intraepithelial lesions of 3.72 (95% CI 2.10-6.60) compared with HIV-negative patients (p ≤ 0.0001). In multivariate analysis, only each increase in intra-anal high-grade squamous intraepithelial lesions significantly increased recurrence (HR 1.13, 95% CI 1.00-1.28, p = 0.002). Only 3 patients with perianal high-grade squamous intraepithelial lesions did not have canal dysplasia. Perianal cancer developed in 3 after being lost to follow-up. LIMITATIONS: This is a retrospective analysis of 1 experienced surgeon's results. No precise way exists to accurately determine the size of the disease. CONCLUSIONS: Perianal dysplasia can be successfully ablated, but recurrence remains high. Almost all patients have anal canal dysplasia. HIV-positive patients are at the greatest risk for disease and recurrence. An increased number of high-grade canal lesions increases recurrence.

Anal condyloma treatment and recurrence in HIV-negative men who have sex with men.

BACKGROUND: Men who have sex with men have increased prevalence of both human papillomavirus and anogenital condyloma. OBJECTIVE: Risk factors for multiple treatment and recurrence of anal condyloma were examined. DESIGN: This is a retrospective study of HIV-negative men who have sex with men who were treated for anal condyloma. SETTINGS: This study was conducted in a private surgical practice. PATIENTS: The patients were HIV-negative men who have sex with men, aged 18 years or older. INTERVENTION(S): Ablation with electrocautery or CO2 laser was performed, as well as excision and topical imiquimod condyloma treatment adjuvant. MAIN OUTCOME MEASURES: Primary clearance, defined as 4 months of condyloma-free survival posttreatment, and recurrence, defined as any anal condyloma diagnosis after primary clearance. RESULTS: Of 231 participants, 207 achieved primary clearance (median age, 32.0 years) and were followed (median, 18.2 months) after primary treatment. Most had intra-anal and perianal condyloma (56%), were treated with electrocautery ablation (79.2%), and required 1 treatment (range, 1-6) for clearance. There were 57 recurrences (median, 12 months). One-third each had minimal, moderate, or extensive disease. Forty-six percent of patients received imiquimod posttreatment adjuvant. High-grade dysplasia was found in 31% at presentation and 43% during follow-up. Factors associated with requiring multiple treatments for clearance were participants having moderate disease (adjusted odds ratio, 6.0 (1.7-21.4)) and receiving imiquimod adjuvant (adjusted odds ratio, 4.7 (2.0-10.6)). No single factor predicted recurrence, but those with moderate disease experienced recurrences significantly sooner (median, 25 months of follow-up). LIMITATIONS: This was a retrospective chart review, it was limited to a single practice, and it excluded those who did not achieve primary clearance. CONCLUSIONS: Most men who have sex with men have intra-anal and perianal condyloma and concomitant high-grade dysplasia is common. Most achieved clearance with 1 treatment. Having both intra-anal and perianal condyloma, increased severity of disease, and imiquimod adjuvant were significant predictors of requiring multiple treatments for clearance. No identified risk factors proved a significant predictor of recurrence.

Random biopsy during high-resolution anoscopy increases diagnosis of anal high-grade squamous intraepithelial lesions.

OBJECTIVE: Random biopsy (RB) of normal appearing cervix during colposcopy increases high-grade dysplasia (HSIL) diagnosis but has not been studied in high-resolution anoscopy (HRA), that is, colposcopy transferred to the anal canal. We investigated the utility of RB during HRA. DESIGN: At HRA, the anal canal was divided into 4 quadrants. Areas suspicious for HSIL had standard biopsy (SB); random biopsies were taken from quadrants without apparent HSIL. Inclusion required ≥1 RB. Two providers performed all procedures (S.E.G., >10 years experience; M.M.G. 3 years experience). RESULTS: Overall, 391 participants enrolled (mean age, 44.7 years); most were male (87.2%), non-Hispanic (69.8%), white (62.7%), and HIV positive (72.9%). Of 1761 biopsies, 883 were RBs (mean, 2.26/participant). HSIL was identified in 252 lesions, and in 132 participants (33.8%). Thirty-two HSILs (12.7%) and 13 participants (9.8%) were diagnosed by RB. RB increased total HSILs identified per participant (mean, 0.65 vs. 0.56; P < 0.001) and participants with HSIL (P < 0.001). Histologically, HSIL diagnoses via SB were no more dysplastic than random biopsies (relative risk, 0.82; range, 0.37-1.8). In multivariable analysis, factors affecting adjusted relative risk (ARR) of HSIL with any biopsy were provider [S.E.G vs. M.M.G.; ARR, 5.9; 95% confidence interval (CI), 1.3 to 25.8] and oncogenic human papillomaviral infection (ARR, 24.3; 95% CI, 2.8 to 213.3). Risk of HSIL on RB alone in multivariate analysis was associated with HSIL via SB (ARR, 3.4; 95% CI, 1.6 to 7.1 or ARR, 1.4; 95% CI, 1.1 to 1.9 per standard HSIL). Provider, HIV status, detectable viral load, age, or prior screening for or treatment of HSIL did not affect the utility of RB. CONCLUSIONS: Addition of RB to HRA significantly increased both the number of HSILs and participants with HSIL identified.