Assessing Circulating Tumour DNA (ctDNA) as a Biomarker for Anal Cancer Management: A Systematic Review.

This systematic review investigates the potential of circulating tumour DNA (ctDNA) as a predictive biomarker in the management and prognosis of squamous cell carcinoma of the anal canal (SCCA). PubMed, EMBASE, and Cochrane Central Registry of Controlled Trials were searched until 7 January 2024. Selection criteria included research articles exploring ctDNA in the context of anal cancer treatment response, recurrence risk assessment, and consideration of salvage surgery. A total of eight studies were therefore included in the final review, examining a total of 628 patients. These studies focused on three main themes: SCCA diagnosis and staging, treatment response, and patient outcomes. Significant heterogeneity was observed in terms of patient cohort, study methodology, and ctDNA biomarkers. Four studies provided information on the sensitivity of ctDNA biomarkers in SCCA, with a range of 82-100%. Seven studies noted a correlation between pre-treatment ctDNA levels and SCCA disease burden, suggesting that ctDNA could play a role as a biomarker for the staging of SCCA. Across all seven studies with paired pre- and post-treatment ctDNA samples, a trend was seen towards decreasing ctDNA levels post-treatment, with specific identification of a 'fast elimination' group who achieve undetectable ctDNA levels prior to the end of treatment and may be less likely to experience treatment failure. Residual ctDNA detection post-treatment was associated with poorer patient prognosis. This systematic review identifies the broad potential of ctDNA as a useful and decisive tool in the management of SCCA. Further analysis of ctDNA biomarkers that include larger patient cohorts is required in order to clearly evaluate their potential role in clinical decision-making processes.

Multiple carcinomas in a woman with HIV infection: a case report and literature review.

Non-acquired immunodeficiency syndrome-defining cancers (NADCs) are malignancies in persons living with human immunodeficiency virus (PLWHIV) and are not primarily due to the host's immunodeficiency. There is renewed clinical interest in long-term morbidities in PLWHIV as well as malignancies that occur in this population. We herein describe a 36-year-old woman with a 2-year history of an anal wound and right breast mass. She had been diagnosed with HIV infection prior to the development of these lesions. Clinical and laboratory evaluations led to diagnoses of breast and anal cancers. Chemotherapy and antiretroviral therapy were begun, but the patient discontinued these treatments early and was lost to follow-up. NADCs will continue to be a major clinical issue as the global population ages. This presentation of two NADCs (breast and anal cancers) in a PLWHIV further highlights the burden of multiple malignancies on the depleted health of HIV-infected patients. Early identification and treatment of HIV upon patients' presentation to cancer care sites and screening for NADCs at HIV/AIDS care sites are recommended for improved outcomes.

Assessing the Potential of HPV16 E6 Seroprevalence as a Biomarker for Anal Dysplasia and Cancer Screening-A Systematic Review and Meta-Analysis.

Elevated rates of human papillomavirus (HPV)-related anal high-grade squamous intraepithelial lesions (HSIL) and anal cancer (AC) in populations like men who have sex with men (MSM) living with HIV underscore the need for effective screening. While high-resolution anoscopy-guided biopsy is the gold standard, limited provider availability poses a challenge. This has spurred interest in identifying biomarkers for improved AC prevention. Antibodies against HPV16 oncoprotein E6, known as markers for cervical and oropharyngeal cancers, are the focus of the current study. The systematic review and meta-analysis included six studies meeting inclusion criteria, assessing HPV16 E6 seroprevalence in individuals with anal HSIL or AC. A two-step meta-analysis estimated pooled odds ratios and 95% confidence intervals (CI) for HPV16 E6 seroprevalence and HSIL or AC. Pooled prevalence, sensitivity, specificity, and diagnostic odds ratios were also calculated. This meta-analysis revealed a 3.6-fold increased risk of HSIL for HPV16 E6 seropositive individuals, escalating to a 26.1-fold risk increase for AC. Pooled specificity and sensitivity indicated a high specificity (0.99; 95%CI: 0.99, 0.99) but lower sensitivity (0.19; 95%CI: 0.10, 0.34) for HPV16 E6 serostatus as an AC biomarker. In conclusion, while HPV16 E6 seroprevalence demonstrates specificity as a potential biomarker for HPV-related AC, its utility as a standalone screening tool may be limited. Instead, it could serve effectively as a confirmation test, particularly in high-risk populations, alongside other diagnostic methods. Further research is imperative to explore HPV16 E6 seroconversion dynamics and alternative screening algorithms.

Access to High-Resolution Anoscopy Among Persons With HIV and Abnormal Anal Cytology Results.

This cross-sectional study evaluates use and availability of follow-up anoscopy among persons at highest risk for anal cancer.

Sexual risk characteristics, social vulnerability, and anal cancer screening uptake among men living with HIV in the deep south.

ABSTRACTWithout standard guidelines, there is a critical need to examine anal cancer screening uptake in the South which has the highest HIV incidence in the U.S. We identified factors associated with screening among men living with HIV (MLHIV) at a large academic HIV outpatient clinic in Alabama. Relationships between sociodemographic, clinical, sexual risk characteristics and screening were examined using T-tests, Fisher's exact, Chi-square, and logistic regression analyses. Unadjusted and adjusted odds ratios (AOR) were computed to estimate the odds of screening. Among 1,114 men, 52% had received annual anal cytology (pap) screening. Men who were screened were more likely to have multiple sexual partners compared to men who were not screened (22.8% vs. 14.8%, p = 0.002). Among men with one partner, the youngest were almost five times more likely to be screened compared to middle-aged men (AOR = 4.93, 95% CI: 2.34-10.39). Heterosexual men had lower odds and men who reported unprotected anal sex had higher odds of screening. Our findings suggest a racial disparity, with older black MLHIV being the least likely to be screened. In the South, MLHIV who are older, black, heterosexual, or live in high social vulnerability counties may be less likely to receive annual anal cancer screening.

Deep Learning in High-Resolution Anoscopy: Assessing the Impact of Staining and Therapeutic Manipulation on Automated Detection of Anal Cancer Precursors.

INTRODUCTION: High-resolution anoscopy (HRA) is the gold standard for detecting anal squamous cell carcinoma (ASCC) precursors. Preliminary studies on the application of artificial intelligence (AI) models to this modality have revealed promising results. However, the impact of staining techniques and anal manipulation on the effectiveness of these algorithms has not been evaluated. We aimed to develop a deep learning system for automatic differentiation of high-grade squamous intraepithelial lesion vs low-grade squamous intraepithelial lesion in HRA images in different subsets of patients (nonstained, acetic acid, lugol, and after manipulation). METHODS: A convolutional neural network was developed to detect and differentiate high-grade and low-grade anal squamous intraepithelial lesions based on 27,770 images from 103 HRA examinations performed in 88 patients. Subanalyses were performed to evaluate the algorithm's performance in subsets of images without staining, acetic acid, lugol, and after manipulation of the anal canal. The sensitivity, specificity, accuracy, positive and negative predictive values, and area under the curve were calculated. RESULTS: The convolutional neural network achieved an overall accuracy of 98.3%. The algorithm had a sensitivity and specificity of 97.4% and 99.2%, respectively. The accuracy of the algorithm for differentiating high-grade squamous intraepithelial lesion vs low-grade squamous intraepithelial lesion varied between 91.5% (postmanipulation) and 100% (lugol) for the categories at subanalysis. The area under the curve ranged between 0.95 and 1.00. DISCUSSION: The introduction of AI to HRA may provide an accurate detection and differentiation of ASCC precursors. Our algorithm showed excellent performance at different staining settings. This is extremely important because real-time AI models during HRA examinations can help guide local treatment or detect relapsing disease.

Screening for precancerous anal lesions linked to human papillomaviruses: French recommendations for clinical practice.

In France, about 2000 new cases of anal cancer are diagnosed annually. Squamous cell carcinoma is the most common histological type, mostly occurring secondary to persistent HPV16 infection. Invasive cancer is preceded by precancerous lesions. In addition to patients with a personal history of precancerous lesions and anal cancer, three groups are at very high risk of anal cancer: (i) men who have sex with men and are living with HIV, (ii) women with a history of high-grade squamous intraepithelial lesions (HSILs) or vulvar HPV cancer, and (iii) women who received a solid organ transplant more than 10 years ago. The purpose of screening is to detect HSILs so that they can be treated, thereby reducing the risk of progression to cancer. All patients with symptoms should undergo a proctological examination including standard anoscopy. For asymptomatic patients at risk, an initial HPV16 test makes it possible to target patients at risk of HSILs likely to progress to cancer. Anal cytology is a sensitive test for HSIL detection. Its sensitivity is greater than 80% and exceeds that of proctological examination with standard anoscopy. It is indicated in the event of a positive HPV16 test. In the presence of cytological abnormalities and/or lesions and a suspicion of dysplasia on clinical examination, high-resolution anoscopy is indicated. Performance is superior to that of proctological examination with standard anoscopy. However, this technique is not widely available, which limits its use. If high-resolution anoscopy is not possible, screening by a standard proctological examination is an alternative. There is a need to develop high-resolution anoscopy and triage tests and to evaluate screening strategies.

Unraveling Emerging Anal Cancer Clinical Biomarkers from Current Immuno-Oncogenomics Advances.

Anal squamous cell carcinoma (ASCC) is a rare gastrointestinal malignancy associated with high-risk human papillomavirus (HPV) and is currently one of the fastest-growing causes of cancer incidence and mortality in developed countries. Although next-generation sequencing technologies (NGS) have revolutionized cancer and immuno-genomic research in various tumor types, a limited amount of clinical research has been developed to investigate the expression and the functional characterization of genomic data in ASCC. Herein, we comprehensively assess recent advancements in "omics" research, including a systematic analysis of genome-based studies, aiming to identify the most relevant ASCC cancer driver gene expressions and their associated signaling pathways. We also highlight the most significant biomarkers associated with anal cancer progression, gene expression of potential diagnostic biomarkers, expression of therapeutic drug targets, and emerging treatment opportunities. This review stresses the urgent need for developing target-specific therapies in ASCC. By illuminating the molecular characteristics and drug-target expression in ASCC, this study aims to provide insights for the development of precision medicine in anal cancer.

Anal and Perianal Preneoplastic Lesions.

Anal cancer, mainly squamous cell carcinoma, is rare but increasing in prevalence, as is its precursor lesion, anal squamous dysplasia. They are both strongly associated with human papillomavirus infection. The 2-tiered Lower Anogenital Squamous Terminology classification, low-grade SIL and high-grade SIL, is preferred to the 3-tiered anal intraepithelial neoplasia classification because of better interobserver agreement and clearer management implications. Immunohistochemistry with p16 is helpful to corroborate the diagnosis of squamous dysplasia. Similarly, immunohistochemistry is helpful to differentiate primary Paget disease from secondary Paget disease, which is usually due to anal squamous mucosal/epidermal involvement by primary rectal adenocarcinoma.

The microbiome as a biomarker of anal precancerous lesions in people with HIV.

PURPOSE OF REVIEW: Early detection and treatment of human papillomavirus (HPV)-related anal dysplasia in some high-risk groups can help anal cancer prevention, but new tools to improve diagnostic and risk assessment are needed. Here, we aim to discuss the evidence on the role of the microbiome as a potential biomarker for anal high-grade squamous intraepithelial lesions (HSILs) in people with HIV (PWH). RECENT FINDINGS: This review covers relevant studies on the links between the microbiome and HPV infection, cervical dysplasia/cancer, and anal HPV disease. It focuses on anal samples and precancerous lesions. SUMMARY: The review highlights the promising potential of the anal microbiome as a novel biomarker for precancerous lesions in people with HIV, while also discussing limitations and future research needs.

[Anorectal melanoma : Update on clinical presentation, diagnosis and treatment]. / Anorektales malignes Melanom : Aktuelles zu Klinik, Diagnostik und Therapie.

Anorectal melanomas are a rare malignant type of cancer and pose a diagnostic challenge due to their hidden anatomical location. They are associated with nonspecific clinical symptoms and are therefore often misinterpreted as benign disease. The result is delayed diagnosis in the locally advanced or metastasized stage and an unfavorable prognosis. Given the overall low incidence of the tumor, no consensus guidelines for diagnosis or therapy are established either internationally or nationally at present. The present work intends to provide a comprehensive overview of the clinical aspects, diagnostics, and therapeutic approaches of anorectal melanoma based on the currently available literature.

Acceptability of Anal Human Papillomavirus Home Self-Sampling and Clinician Sampling Among Sexual and Gender Minority Individuals in Milwaukee, Wisconsin: The Prevent Anal Cancer Self-Swab Study.

Purpose: Anal cancer has disproportionately high incidence among sexual minority men. We compared acceptability of home versus clinic human papillomavirus (HPV) anal swabbing. Methods: The Prevent Anal Cancer Self-Swab Study recruited sexual and gender minority individuals in Milwaukee, Wisconsin. Eligible participants were randomized to a home or clinic arm. Home participants received a mailed anal HPV self-sampling kit. Clinic participants attended a clinic appointment where a clinician collected an anal HPV swab. We examined acceptability (overall thoughts, comfort with method, pain, and future willingness to swab) of home versus clinic swabbing using postswab survey responses. Results: A total of 191 individuals completed swabbing and a postswab survey (home = 53.4%, clinic = 46.6%). Mean age was 47 years (range = 25-78). Reported overall thoughts about home (71.6%) and clinic (69.7%) swabbing were mostly positive (p = 0.83). Overall thoughts about the home kit did not differ by participant characteristics, but overall thoughts about clinician swabbing differed by race (p = 0.04) and HIV status (p = 0.002). Nearly all participants (98.4%) reported they were comfortable receiving the kit or getting the swabbing in the clinic, reported little or no pain (98.4%), and reported willingness to undergo swabbing in the future (97.9%). After swabbing, clinic participants reported greater trust that swabbing can give accurate information about anal cancer risk (89.9%) than home participants (69.6%) (p < 0.001), and that swabbing will help them avoid anal cancer (clinic = 79.8%, home = 59.8%) (p = 0.01). Conclusion: Anal swabbing acceptability was high and did not differ between home and clinic. Participants reported high confidence and knowledge using the mailed anal self-sampling kit. Clinical Trial Registration number is NCT03489707.

The impact of body mass index and physical disability on home-based anal self-sampling.

PURPOSE: Self-sampling is increasingly being used in screening programs, yet no studies to date have examined the impact of bodily characteristics on self-sampling experiences. Our objective was to assess whether body mass index (BMI) and physical disability were associated with anal self-sampling difficulty. METHODS: We recruited sexual minority men (SMM) and trans persons in Milwaukee, Wisconsin to participate in an anal cancer screening study. Between January 2020 and August 2022, 240 participants were randomized to a home (n = 120) or clinic (n = 120) screening arm. Home participants received a mailed at-home anal self-sampling kit and were asked to attend a baseline clinic visit where biometric measurements were collected. Participants were asked to complete a survey about their experience with the kit. This research utilized data from participants who used the at-home kit and completed a baseline clinic visit and post-swab survey (n = 82). We assessed the impact of BMI and physical disability on reported body or swab positioning difficulty. RESULTS: Most participants reported no or little difficulty with body positioning (90.3%) or swab positioning (82.9%). Higher BMI was significantly associated with greater reported difficulty with body positioning (aOR = 1.10, 95% CI 1.003-1.20, p = 0.04) and swab positioning (aOR = 1.11, 95% CI 1.02-1.20, p = 0.01). Although not significant, participants who said body positioning was difficult had 2.79 higher odds of having a physical disability. Specimen adequacy did not differ by BMI category (p = 0.76) or physical disability (p = 0.88). CONCLUSION: Anal self-sampling may be a viable option to reach obese persons who may be more likely to avoid screening due to weight-related barriers.

Monitoring Patients With Inflammatory Bowel Disease at High Risk of Anal Cancer.

Anal cancer is a rare but deadly disease that disproportionately affects patients with inflammatory bowel disease (IBD). Rates of adenocarcinoma and human papillomavirus-related squamous cell carcinoma have been consistently demonstrated to be higher in patients with ulcerative colitis and Crohn's disease. Despite this increased risk, uniform screening, diagnosis, and treatment algorithms are lacking. This review describes the most recent literature surrounding anal cancer in the IBD population as well as the unique challenges inherent in diagnosing and treating this population. We conclude by proposing a new screening motif based off literature review and multidisciplinary clinical experience that aims to increase early detection of anal cancers in the IBD population.

Anal cancer screening results from 18-to-34-year-old men who have sex with men living with HIV.

Men who have sex with men living with HIV (MSM LWH) are at highest risk for human papillomavirus (HPV)-associated anal cancer. There is no consensus on the optimal screening initiation age. This study aimed to assess the prevalence and severity of anal HPV disease among MSM LWH under the age of 35, which is a currently proposed screening age threshold. Between 2014 and 2020, 1255 18-to-34-year-old MSM LWH underwent anal cytology screening. 916 were co-tested for high-risk HPV (HR-HPV). 467 underwent high-resolution anoscopy (HRA) and biopsy. Cancer registry data were queried. Predictors of abnormal cytology (ie, ≥ASCUS) and histological high-grade squamous intraepithelial lesions (HSIL) were evaluated using unadjusted logistic regression models. Median age was 28 years (range, 18-34). 19% received at least one dose of HPV vaccine. Abnormal cytology rate was 65%. HR-HPV and HPV16 prevalence were 87% and 30%. Biopsy results were benign (10%), LSIL (43%) and HSIL (47%). No cases of prevalent or incident anal cancers were detected. Findings were similar between age subgroups (18-24, 25-29 and 30-34) except for a higher prevalence of AIN 3 in the 30-34 group (19%). Abnormal cytology was significantly associated with HR-HPV infection. Histological HSIL was associated with HR-HPV infection and cytological LSIL or worse. The absence of anal cancer in a large cohort of MSM LWH under the age of 35, despite high prevalence of anal HR-HPV infection and precancer, supports an age-based anal cancer screening strategy for MSM LWH.

A comprehensive review of anal cancer-with a special focus on anal cytology.

The diagnosis of anal cancer is relatively uncommon, but its incidence has been steadily increasing in high-risk populations. In the 2001 Bethesda System for Reporting Cervical Cytology, anal cytology was introduced as a component. Since then, it has been recognized as a potential tool for screening anal cancer, often in conjunction with high-resolution anoscopy. There are notable similarities between anal cancer and cervical cancer, including the causative role of human papillomavirus. However, there are also significant differences, particularly in terms of disease prevalence. Anal cytology may be used as a primary screening test, and in the event of abnormalities, patients are subsequently directed for high-resolution anoscopy. However, the best approach for anal cancer screening is yet to be determined and uniformly implemented. This comprehensive review article provides an in-depth analysis of the epidemiology and incidence of anal precursor and malignant lesions. It explores the various methods of sample procurement, preparation, interpretation (including sensitivity and specificity), and reporting terminology in anal cytology. The article also addresses the significance of concurrent high-risk human papillomavirus screening in anal cytology and its role in screening programs. Furthermore, it discusses the follow-up, prevention, and subsequent management strategies for anal cancers. By synthesizing current knowledge in these areas, this review aims to provide a comprehensive understanding of anal cytology and its implications in the early detection, prevention, and management of anal neoplasia and cancer.