Cancer Risk Stratification of Anal Intraepithelial Neoplasia in Human Immunodeficiency Virus-Positive Men by Validated Methylation Markers Associated With Progression to Cancer.

BACKGROUND: High-grade anal intraepithelial neoplasia (HGAIN; AIN2-3) is highly prevalent in HIV+ men, but only a minority of these lesions progress towards cancer. Currently, cancer progression risk cannot be established; therefore, no consensus exists on whether HGAIN should be treated. This study aimed to validate previously identified host cell DNA methylation markers for detection and cancer risk stratification of HGAIN. METHODS: A large independent cross-sectional series of 345 anal cancer, AIN3, AIN2, AIN1, and normal control biopsies of HIV+ men was tested for DNA methylation of 6 genes using quantitative methylation-specific PCR. We determined accuracy for detection of AIN3 and cancer (AIN3+) by univariable and multivariable logistic regression analysis, followed by leave-one-out cross-validation. Methylation levels were assessed in a series of 10 anal cancer cases with preceding HGAIN at similar anatomic locations, and compared with the cross-sectional series. RESULTS: Methylation levels of all genes increased with increasing severity of disease (P < .05). HGAIN revealed a heterogeneous methylation pattern, with a subset resembling cancer. ZNF582 showed highest accuracy (AUC = 0.88) for AIN3+ detection, slightly improved by addition of ASCL1 and SST (AUC = 0.89), forming a marker panel. In the longitudinal series, HGAIN preceding cancer displayed high methylation levels similar to cancers. CONCLUSIONS: We validated the accuracy of 5 methylation markers for the detection of anal (pre-) cancer. High methylation levels in HGAIN were associated with progression to cancer. These markers provide a promising tool to identify HGAIN in need of treatment, preventing overtreatment of HGAIN with a low cancer progression risk.

Multizonal anogenital neoplasia in women: a cohort analysis.

BACKGROUND: There is currently a lack of information on full anogenital evaluation of women with a previous history of anogenital neoplasia. METHODS: Retrospective analysis of the Homerton Anogenital Neoplasia Service records from January 2012 to March 2017, to identify all new referrals of women with previous anogenital neoplasia, who had had at least one complete examination of all anogenital sites. Multizonal anogenital disease (MZD) was defined as the presence of high-grade squamous intraepithelial lesions (HSIL)/carcinoma concurrently at two or more of the following sites/zones: perianus, anal canal, vulva, vagina or cervix. RESULTS: 253 women were included, mean age was 47 (SD=15) years and median duration of follow-up was 12 (IQR=21) months. Fifty-six women (22%) were diagnosed with MZD at first assessment and/or during follow-up. Current smokers (RR=1.84, 95% CI 1.21-2.79, p=0.004) and women on immunodulators/immunosuppressive drugs (RR=2.57, 95% CI 1.72-3.86, p<0.001) had an increased risk for MZD. The risk was lower for women without a previous history of anogenital high-grade lesions/cancer compared to those with this history (RR=0.06, 95% CI 0.01-0.45, p=0.006). CONCLUSIONS: Multizonal assessment was important to diagnose occult areas of disease and should be especially considered in current smokers, pharmacologically immunocompromised and those with a previous history of anogenital HSIL/cancer.

Burden of anal squamous cell carcinoma, squamous intraepithelial lesions and HPV16 infection in solid organ transplant recipients: A systematic review and meta-analysis.

The number of solid organ transplant recipients (SOTR), and their life expectancy, is increasing, with higher risk for long-term complications from immunosuppression. We carried out a systematic review describing the burden of anal squamous cell carcinoma (SCC), and its surrogates, in SOTR. We conducted mixed effect model-based meta-analyses evaluating incidence of anal SCC (standardized incidence ratio [SIR] vs general population, and absolute incidence rate [IR]), prevalence of anal squamous abnormalities, and human papillomavirus (HPV) 16. Generalized I2 statistics were calculated, quantifying heterogeneity. Anal SCC incidence in SOTR was elevated vs the general population (pooled SIR = 6.8, 95% confidence interval [CI], 4.3-10.9; 6 studies including 241 106 SOTR; I2  = 82.3%), with an absolute IR of 12.3 (95% CI, 10.4-14.7) per 100 000 person-years (5 studies including 1 079 489 person-years; I2  = 0%). Prevalence of abnormal anal cytology was 12.9% (95% CI, 9.2%-17.7%; 6 studies including 328 SOTR; I2  = 17.4%). For histology, the pooled prevalence estimate of anal squamous intraepithelial lesions was 22.4% (95% CI, 17.3%-28.5%; 3 studies including 214 SOTR; I2  = 0%), with 4.7% (95% CI, 2.5%-8.5%; I2  = 0%) high-grade squamous intraepithelial lesions. Pooled anal HPV16 prevalence was 3.6% (95% CI, 1.6%-7.8%; 4 studies including 254 SOTR; I2  = 17.6%). There was substantial and consistent evidence of elevated anal SCC incidence in SOTR.

High-Resolution Anoscopy Surveillance After Anal Squamous Cell Carcinoma: High-Grade Squamous Intraepithelial Lesion Detection and Treatment May Influence Local Recurrence.

BACKGROUND: Local recurrence is a significant risk after anal squamous cell carcinoma. OBJECTIVES: This study aimed to examine the occurrence of high-grade squamous intraepithelial lesions and local recurrence after anal cancer at surveillance with high-resolution anoscopy. DESIGN: This is a retrospective observational study. SETTING: This study was conducted at an anogenital neoplasia referral center. PATIENTS: There were 76 anal/perianal cancers from 1998 to 2018. Sixty-three patients were eligible and 3 were excluded, for a total of 60 patients; 35 of 60 (58%) patients were male. INTERVENTION: High-resolution anoscopy after chemoradiation or excision only for anal squamous cell carcinoma was performed. MAIN OUTCOME MEASURES: The primary outcomes measured were local recurrence and high-grade squamous intraepithelial lesion detection rates. RESULTS: Sixty patients, 27% HIV positive, underwent surveillance over a median 42 (range 7-240) months of follow-up. Seven had had a prior local recurrence at study entry so were analyzed separately. Thirty of 53 underwent chemoradiation (57%) and 23 of 53 underwent excision alone (43%); 33 had perianal cancer and 20 had anal cancer. Ten of 30 of the chemoradiation group had had stage 1 (33%) disease in comparison with 22 of 23 of the excision only group (96%, p < 0.001). OUTCOMES: High-grade squamous intraepithelial lesions were detected in 4 of 30 (13%) patients after chemoradiation and in 17 of 23 (74%) patients after excision only (p < 0.001). Twenty of 21 (95%) high-grade lesions were treated with ablation. Six of 7 (86%) patients with prior local recurrence had high-grade squamous intraepithelial lesions over a median of 21 months follow-up. One local recurrence (T1N0M0) occurred during surveillance after primary chemoradiation (0.56/1000 person-months), none occurred after excision only, and 2 of 7 with prior local recurrence developed further local recurrence (6.86/1000 person-months). All 3 local recurrences occurred after treatment of high-grade squamous intraepithelial lesions. There were no metastases, abdominoperineal excisions, or deaths from anal squamous cell carcinoma. LIMITATIONS: Retrospective data were used for this study. CONCLUSIONS: High-grade squamous intraepithelial lesions after anal squamous cell carcinoma are more common after excision only than after chemoradiation. Local recurrence is low in this high-resolution anoscopy surveillance group in which high-grade squamous intraepithelial disease was ablated. Excision of small perianal cancers appears safe; however, a subset of patients is at excess risk. See Video Abstract at http://links.lww.com/DCR/B285. VIGILANCIA POR ANOSCOPÍA DE ALTA RESOLUCIÓN EN CASOS DE CARCINOMA ANAL A CÉLULAS ESCAMOSAS: LA DETECCIÓN Y TRATAMIENTO DE UNA LESIÓN INTRAEPITELIAL ESCAMOSA DE ALTO GRADO (HSIL) PUEDE INFLUIR EN LA RECURRENCIA LOCAL: La recurrencia local tiene un riesgo significativo después del carcinoma anal a células escamosas.Evaluar la aparición de lesiones intraepiteliales escamosas de alto grado (HSIL) y su recurrencia local durante la vigilancia con anoscopía de alta resolución en casos de cancer anal.Estudio observacional retrospectivo.Centro de referencia de neoplasia anogenital.Se diagnosticaron 76 cánceres anales / perianales entre 1998 y 2018. Un total de 63 pacientes fueron elegidos, 3 excluidos (n = 60), 35/60 (58%) fueron varones.Anoscopía de alta resolución después de la quimio-radioterapia, o solo excisión en casos de carcinoma anal a células escamosas.Recurrencia local primaria y tasas de detección de lesión intraepitelial escamosa de alto grado.Sesenta pacientes, 27% VIH positivos, fueron sometidos a vigilancia durante una mediana de 42 (rango 7-240) meses de seguimiento. Siete habían tenido una recurrencia local antes de ser incluidos en el estudio, por lo que se analizaron por separado. Treinta de 53 se sometieron a quimio-radioterapia (57%) y 23/53 solo a excisión (43%). 33 eran lesiones perianales, 20 de canal anal. 10/30 del grupo de quimio-radioterpia se encontraban en Fase 1 (33%) comparados con 22/23 del grupo de excisión (96%, p <0.001).Se detectaron lesiones intraepiteliales escamosas de alto grado en 4/30 (13%) después de la quimio-radioterapia, y en 17/23 (74%) solo después de la excisión (p < 0.001). 20/21 (95%) lesiones de alto grado fueron tratadas con ablación. Seis de siete (86%) con recurrencia local previa tenían lesiones intraepiteliales escamosas de alto grado durante una mediana de seguimiento de 21 meses. Se produjo una recurrencia local (T1N0M0) durante la vigilancia después de la quimio-radioterapia primaria (0.56/1000 persona-meses), ninguna después de la excisión sola y 2/7 con recurrencia local previa desarrollaron una recurrencia local adicional (6.86/1000 persona-meses). Las 3 recidivas locales ocurrieron después del tratamiento de las lesiones intraepiteliales escamosas de alto grado. No hubieron metástasis, excisiones abdominoperineales o muertes por carcinoma anal a células escamosas.Datos retrospectivos.Las lesiones intraepiteliales escamosas de alto grado en casos de carcinoma escamocelular anal son más comunes después de la excisión sola que después de la quimio-radioterapia. La recurrencia local es baja en este grupo de vigilancia de anoscopía de alta resolución en el que se retiró la enfermedad intraepitelial escamosa de alto grado. La excisión de pequeños cánceres perianales parece segura; sin embargo, un subconjunto de pacientes tiene un riesgo excesivo. Consulte Video Resumen en http://links.lww.com/DCR/B285. (Traducción-Dr. Xavier Delgadillo).

International Anal Neoplasia Society Guidelines for the Practice of Digital Anal Rectal Examination.

OBJECTIVE: The aim of the study was to develop recommended techniques and quality assurance metrics for the practice of Digital Anal Rectal Examination (DARE). MATERIALS AND METHODS: The International Anal Neoplasia Society undertook a literature review and, using the AGREE II technique, developed guidelines for performing DARE. RESULTS: A consensus was formed regarding the optimum conditions and characteristics of DARE. Several Quality Assurance metrics were developed. CONCLUSIONS: Digital Anal Rectal Examination is a cheap and potentially universally available technique, which has the potential to facilitate the early diagnosis of anal cancers, when they are most amenable to treatment. These guidelines provide a basis for teaching the technique and may be used as for evaluation research.

Performance of Anal Cytology Compared With High-Resolution Anoscopy and Histology in Women With Lower Anogenital Tract Neoplasia.

Background: Information on the performance of anal cytology in women who are high risk for human papillomavirus-related lesions and the factors that might influence cytology are largely lacking. Methods: Retrospective study including all new referrals of women with a previous history of anogenital neoplasia from January 2012 to July 2017, with concomitant anal cytology and high-resolution anoscopy with or without biopsies. Results: Six hundred and thirty six anal cytology samples and 323 biopsies obtained from 278 women were included. Overall sensitivity and specificity of "any abnormality" on anal cytology to predict any abnormality in histology was 47% (95% confidence interval [CI], 41%-54%) and 84% (95% CI, 73%-91%), respectively. For detecting high-grade squamous intraepithelial lesions (HSIL)/cancer, sensitivity was 71% (95% CI, 61%-79%) and specificity was 73% (95% CI, 66%-79%). There was a poor concordance between cytological and histological grades (κ = 0.147). Cytology had a higher sensitivity to predict HSIL/cancer in immunosuppressed vs nonimmunosuppressed patients (92% vs 60%, P = .002). The sensitivity for HSIL detection was higher when 2 or more quadrants were affected compared with 1 (86% vs 57%, P = .006). A previous history of vulvar HSIL/cancer (odds ratio [OR], 1.71, 1.08-2.73; P = .023), immunosuppression (OR, 1.88, 1.17-3.03; P = .009), and concomitant genital HSIL/cancer (OR, 2.51, 1.47-4.29; P = .001) were risk factors for abnormal cytology. Conclusions: Women characteristics can influence the performance of anal cytology. The sensitivity for detecting anal HSIL/cancer was higher in those immunosuppressed and with more extensive disease.

p16 immunostaining in histological grading of anal squamous intraepithelial lesions: a systematic review and meta-analysis.

p16 is the most widely studied biomarker in lower anogenital tract squamous intraepithelial lesions and, currently the only recommended biomarker for histological grade assessment. The aim of this systematic review and meta-analysis was to evaluate p16-positive rates according to anal squamous intraepithelial lesions/anal intraepithelial neoplasia (AIN) grade. Two investigators independently searched four electronic databases: PubMed, Web of Sciences, Scopus, and Embase from inception until August 2017. Studies that evaluated p16 immunostaining in histological samples of anal and/or perianal squamous intraepithelial lesions and defined a p16-positive result as diffuse block staining with nuclear or nuclear plus cytoplasmic staining were included. A meta-analysis was performed using a random effects model. Fifteen studies consisting of 790 samples were included. The proportion of p16 expression increased with the severity of histological grade. p16 positivity was 2% (95% CI: 0.2-5%) in normal histology, 12% (95% CI: 2-27%) in low-grade squamous intraepithelial lesions (LSILs)/AIN1 (excluding condylomas), 7% (95% CI: 2-13%) in all LSIL (AIN1/LSIL/condyloma), 76% (95% CI: 61-88%) in AIN2, and 90% (95% CI: 82-95%) in AIN3. For anal high-grade squamous intraepithelial lesions (HSILs), in studies using a two-tiered nomenclature, p16 positivity was 84% (95% CI: 66-96%) and for all HSIL (AIN2, AIN3, HSIL combined) it was 82% (95% CI: 72-91%). In summary, p16 positivity in anal squamous intraepithelial lesions appears to be in a similar range to the commonly described cervical squamous intraepithelial lesions, however, for anal low-grade lesions positivity seems to be lower.

The acceptability of high resolution anoscopy examination in patients attending a tertiary referral centre.

BACKGROUND: High resolution anoscopy (HRA) examination is regarded as the best method for the management of anal high grade squamous intraepithelial lesions to prevent anal squamous carcinoma. However, little is known about the acceptability of this procedure. This analysis looks at patient experience of HRA examination and ablative treatment under local anaesthetic. METHODS: Patients took part in anonymised feedback of their experience immediately after their HRA examinations and/or treatments. A standard questionnaire was used that included assessment of pain and overall satisfaction scores as well as willingness to undergo future HRA examinations. RESULTS: Four hundred four (89.4%) responses were received and all responses were analysed. The group consisted of 119 females (29.4%) and 261 males (64.6%) with median age of 45 years (IQR = 19) and 45 years (IQR = 21) respectively, and included 58 new cases, 53 treatment cases and 202 surveillance cases. 158 patients (39.1%) had at least one biopsy during their visits. The median pain score was 2 [Inter Quartile Range (IQR) 3] on a visual analogue scale of 0 to 10, where 0 indicated no pain / discomfort and 10 indicated severe pain. The median pain score was 2 (IQR 2) in men and 4 (IQR = 3) in women [Dunn's Test = 4.3, p < 0.0001] and 3 (IQR 4.5) in treatment cases. Problematic pain defined as a pain score of ≥7 occurred more frequently in women (14%) than in men (6%), [Chi square test (chi2) = 5.6, p = 0.02]. Patient satisfaction with the care they received, measured on a scale of 0 (not happy) to 10 (very happy) found the median score to be 10 with 76% reporting a score of 10. Out of 360 responses, 98% of women and 99% of men said that they would be willing to have a future HRA examination. CONCLUSIONS: In this cohort, the overall pain scores were low and similar across appointment types. However, women had a higher pain score, including troublesome pain levels. Despite this, both women and men were equally satisfied with their care and were willing to have a future examination. The results of the analysis show that the procedure is acceptable to patient groups. A small number of women may need general anaesthesia for their examinations/treatment.

Anal High-Grade Squamous Intraepithelial Lesions in Pharmacologically Immunocompromised Patients Followed in a Referral Center.

BACKGROUND: Information is lacking regarding anal/perianal precancerous lesions in referral cohorts of pharmacologically immunocompromised patients. OBJECTIVE: The aim of this study is to evaluate the prevalence of anal/perianal high-grade squamous intraepithelial lesions in a referral cohort of patients on immunomodulator/immunosuppressive medications, who were assessed and followed with high-resolution anoscopy. DESIGN: This is a retrospective study. SETTING: This study was conducted in a single anal neoplasia service from January 2012 to June 2017. PATIENTS: Patients on chronic immunomodulator/immunosuppressive medications were included. Cases of concomitant immunosuppression due to HIV infection were excluded, and immunosuppression due to chemotherapy was not considered for this analysis. INTERVENTION: High-resolution anoscopy was performed. MAIN OUTCOME: The primary outcome measured was the prevalence of anal/perianal high-grade squamous intraepithelial lesions in a referral cohort of pharmacologically immunocompromised patients. RESULTS: Fifty-four patients were included, of whom 40 were women (74%), with a mean age of 48 ± 17 years. A total of 232 high-resolution anoscopy examinations were performed in this cohort. At the first evaluation, 28 patients (52%) were diagnosed with anal and/or perianal high-grade squamous intraepithelial lesions (including 2 cases of perianal squamous cell carcinoma); 11 cases (20%) were new diagnoses. Ten of 46 patients (22%) with follow-up developed a new lesion (high-grade/cancer) during a median follow-up period of 17 (interquartile range, 6-28) months. Overall, 37 patients (69%) in our cohort had anal/perianal high-grade squamous intraepithelial lesions ever diagnosed (including previous history, first visit, and follow-up); 5 patients had perianal squamous cell carcinoma. At our center, 6% of the new referrals were known to be pharmacologically immunocompromised patients. LIMITATIONS: The retrospective nature of this study, the heterogeneity of the cohort, and the absence of human papillomavirus testing were limitations of this study. CONCLUSIONS: The presence of anal and/or perianal high-grade squamous intraepithelial lesions or cancer detected by high-resolution anoscopy in this referral population was high, and the detection of new lesions suggests that long-term follow-up is needed. Patients on immunomodulator/immunosuppressive drugs represented only a small percentage of the new referrals to our center. See Video Abstract at http://links.lww.com/DCR/A748.

Human papillomavirus infection: protocol for a randomised controlled trial of imiquimod cream (5%) versus podophyllotoxin cream (0.15%), in combination with quadrivalent human papillomavirus or control vaccination in the treatment and prevention of recurrence of anogenital warts (HIPvac trial).

BACKGROUND: Anogenital warts are the second most common sexually transmitted infection diagnosed in sexual health services in England. About 90% of genital warts are caused by human papillomavirus (HPV) types 6 or 11, and half of episodes diagnosed are recurrences. The best and most cost-effective treatment for patients with anogenital warts is unknown. The commonly used treatments are self-administered topical agents, podophyllotoxin (0.15% cream) or imiquimod (5% cream), or cryotherapy with liquid nitrogen. Quadrivalent HPV (qHPV) vaccination is effective in preventing infection, and disease, but whether it has any therapeutic effect is not known. METHODS AND DESIGN: To investigate the efficacy of clearance and prevention of recurrence of external anogenital warts by topical treatments, podophyllotoxin 0.15% cream or imiquimod 5% cream, in combination with a three-dose regimen of qHPV or control vaccination. 500 adult patients presenting with external anogenital warts with either a first or subsequent episode of anogenital warts will be entered into this randomised, controlled partially blinded 2 × 2 factorial trial. DISCUSSION: The trial is expected to provide the first high-quality evidence of the comparative efficacy and cost-effectiveness of the two topical treatments in current use, as well as investigate the potential benefit of HPV vaccination, in the management of anogenital warts. TRIAL REGISTRATION: The trial was registered prior to starting recruitment under the following reference numbers: International Standard Randomized Controlled Trial Number (ISRCTN) Registry - ISRCTN32729817 (registered 25 July 2014); European Union Clinical Trials Register (EudraCT) - 2013-002951-14 (registered 26 June 2013).

2016 IANS International Guidelines for Practice Standards in the Detection of Anal Cancer Precursors.

OBJECTIVES: To define minimum standards for provision of services and clinical practice in the investigation of anal cancer precursors. METHODS: After initial face to face meetings of experts at the International Papillomavirus meeting in Lisbon, September 17 to 21, 2015, a first version was drafted and sent to key stakeholders. A complete draft was reviewed by the Board of the International Anal Neoplasia Society (IANS) and uploaded to the IANS Web site for all members to provide comments. The final draft was ratified by the IANS Board on June 22, 2016. RESULTS: The essential components of a satisfactory high-resolution anoscopy (HRA) were defined. Minimum standards of service provision, basic competencies for clinicians, and standardized descriptors were established. Quality assurance metrics proposed for practitioners included a minimum of 50 HRAs per year and identifying 20 cases or more of anal high-grade squamous intraepithelial lesions (HSILs). Technically unsatisfactory anal cytological samples at first attempt in high-risk populations should occur in less than 5% of cases. Where cytological HSIL has been found, histological HSIL should be identified in ≥ 90% of cases. Duration of HRA should be less than 15 minutes in greater than 90% of cases. Problematic pain or bleeding should be systematically collected and reported by 10% or lesser of patients. CONCLUSIONS: These guidelines propose initial minimum competencies for the clinical practice of HRA, against which professionals can judge themselves and providers can evaluate the effectiveness of training. Once standards have been agreed upon and validated, it may be possible to develop certification methods for individual practitioners and accreditation of sites.

Human papillomavirus genotype detection and viral load in paired genital and urine samples from both females and males.

The ability to detect type-specific high risk HPV (HR-HPV) infections in samples from females and males is important for monitoring the epidemiology of HPV and the impact of vaccination. Type-specific detection concordance between paired urine and genital samples from females (n = 264) undergoing routine colposcopy and males (n = 88) attending a genito-urinary medicine clinic was evaluated using an in-house genotyping assay. The overall inter-rater agreement (κ) was 0.781 for female pairs and 0.346 for male pairs. Female urine had sensitivity for detection of HPV16/18 and HR-HPV of 75% and 84%, respectively, while male urine had sensitivities of 13% and 28%, respectively. Genital samples had a higher HPV DNA copy number than urine although a small proportion (10%) of urine samples had a higher copy number than the corresponding genital sample. The proportion of females with normal cytology positive for HPV16/18 was 19%, increasing to 57% in moderate or severely dyskaryotic samples. The same trend was seen in the corresponding urine (19-43%) compounded by the reduced sensitivity of this sample type. The HPV16 viral load in female genital samples, but not in urine, was weakly associated with cervical disease stage. Despite reduced sensitivity, urine appears to be an appropriate surrogate sample for type-specific HPV detection in females for epidemiological objectives. The lower sensitivity and lack of association between viral load and disease stage in urine suggest that urine may not be useful for clinical management of HPV infection. The utility of urine for type-specific detection in males is less certain.

Anal cancer and precancerous lesions: a call for improvement.

Anal squamous cell carcinoma is the most common type of anal cancer and is largely associated with anal human papillomavirus infection. The incidence of anal squamous cell carcinoma is increasing, and although still uncommon in the general population, a high incidence has been noted in specific population groups (eg, patients with HIV, men who have sex with men [MSM], recipients of solid organ transplants, women with genital neoplasia, and patients with systemic lupus erythematosus or inflammatory bowel disease). The higher incidence among individuals who are HIV-positive makes anal squamous cell carcinoma one of the most common non-AIDS-defining cancers among HIV-positive individuals. Anal cancer screening in high-risk groups aims to detect high-grade squamous intraepithelial lesions, which are considered anal precancerous lesions, and for which identification can provide an opportunity for prevention. A blind anal cytology is normally the first screening method, and for patients with abnormal results, this approach can be followed by an examination of the anal canal and perianal area under magnification, along with staining-a technique known as high-resolution anoscopy. Digital anorectal examination can enable early anal cancer detection. Several societies are in favour of screening for HIV-positive MSM and recipients of transplants. There are no current recommendations for screening of anal precancerous lesions via endoscopy, but in high-risk groups, a careful observation of the squamocolumnar junction should be attempted. Several treatments can be used to treat high-grade squamous intraepithelial lesions, including argon plasma coagulation or radiofrequency ablation, which are largely limited by high recurrence rates. Gastroenterologists need to be aware of anal squamous cell carcinoma and anal precancerous lesions, given that patients at high risk are frequently encountered in the gastroenterology department. We summarise simple procedures that can help in early anal squamous cell carcinoma detection.

Imiquimod versus podophyllotoxin, with and without human papillomavirus vaccine, for anogenital warts: the HIPvac factorial RCT.

BACKGROUND: The comparative efficacy, and cost-effectiveness, of imiquimod or podophyllotoxin cream, either alone or in combination with the quadrivalent HPV vaccine (Gardasil®, Merck Sharp & Dohme Corp., Merck & Co., Inc., Whitehouse Station, NJ, USA) in the treatment and prevention of recurrence of anogenital warts is not known. OBJECTIVE: The objective was to compare the efficacy of imiquimod and podophyllotoxin creams to treat anogenital warts and to assess whether or not the addition of quadrivalent human papillomavirus vaccine increases wart clearance or prevention of recurrence. DESIGN: A randomised, controlled, multicentre, partially blinded factorial trial. Participants were randomised equally to four groups, combining either topical treatment with quadrivalent human papillomavirus vaccine or placebo. Randomisation was stratified by gender, a history of previous warts and human immunodeficiency virus status. There was an accompanying economic evaluation, conducted from the provider perspective over the trial duration. SETTING: The setting was 22 sexual health clinics in England and Wales. PARTICIPANTS: Participants were patients with a first or repeat episode of anogenital warts who had not been treated in the previous 3 months and had not previously received quadrivalent human papillomavirus vaccine. INTERVENTIONS: Participants were randomised to 5% imiquimod cream (Aldara®; Meda Pharmaceuticals, Takeley, UK) for up to 16 weeks or 0.15% podophyllotoxin cream (Warticon®; GlaxoSmithKlein plc, Brentford, UK) for 4 weeks, which was extended to up to 16 weeks if warts persisted. Participants were simultaneously randomised to quadrivalent human papillomavirus vaccine (Gardasil) or saline control at 0, 8 and 24 weeks. Cryotherapy was permitted after week 4 at the discretion of the investigator. MAIN OUTCOME MEASURES: The main outcome measures were a combined primary outcome of wart clearance at week 16 and remaining wart free at week 48. Efficacy analysis was by logistic regression with multiple imputation for missing follow-up values; economic evaluation considered the costs per quality-adjusted life-year. RESULTS: A total of 503 participants were enrolled and attended at least one follow-up visit. The mean age was 31 years, 66% of participants were male (24% of males were men who have sex with men), 50% had a previous history of warts and 2% were living with human immunodeficiency virus. For the primary outcome, the adjusted odds ratio for imiquimod cream versus podophyllotoxin cream was 0.81 (95% confidence interval 0.54 to 1.23), and for quadrivalent human papillomavirus vaccine versus placebo, the adjusted odds ratio was 1.46 (95% confidence interval 0.97 to 2.20). For the components of the primary outcome, the adjusted odds ratio for wart free at week 16 for imiquimod versus podophyllotoxin was 0.77 (95% confidence interval 0.52 to 1.14) and for quadrivalent human papillomavirus vaccine versus placebo was 1.30 (95% confidence interval 0.89 to 1.91). The adjusted odds ratio for remaining wart free at 48 weeks (in those who were wart free at week 16) for imiquimod versus podophyllotoxin was 0.98 (95% confidence interval 0.54 to 1.78) and for quadrivalent human papillomavirus vaccine versus placebo was 1.39 (95% confidence interval 0.73 to 2.63). Podophyllotoxin plus quadrivalent human papillomavirus vaccine had inconclusive cost-effectiveness compared with podophyllotoxin alone. LIMITATIONS: Hepatitis A vaccine as control was replaced by a saline placebo in a non-identical syringe, administered by someone outside the research team, for logistical reasons. Sample size was reduced from 1000 to 500 because of slow recruitment and other delays. CONCLUSIONS: A benefit of the vaccine was not demonstrated in this trial. The odds of clearance at week 16 and remaining clear at week 48 were 46% higher with vaccine, and consistent effects were seen for both wart clearance and recurrence separately, but these differences were not statistically significant. Imiquimod and podophyllotoxin creams had similar efficacy for wart clearance, but with a wide confidence interval. The trial results do not support earlier evidence of a lower recurrence with use of imiquimod than with use of podophyllotoxin. Podophyllotoxin without quadrivalent human papillomavirus vaccine is the most cost-effective strategy at the current vaccine list price. A further larger trial is needed to definitively investigate the effect of the vaccine; studies of the immune response in vaccine recipients are needed to investigate the mechanism of action. TRIAL REGISTRATION: Current Controlled Trials. Current Controlled Trials ISRCTN32729817 and EudraCT 2013-002951-14. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 47. See the NIHR Journals Library website for further project information.

The HIPvac [Human papillomavirus infection: a randomised controlled trial of Imiquimod cream (5%) versus Podophyllotoxin cream (0.15%), in combination with quadrivalent human papillomavirus or control vaccination in the treatment and prevention of recurrence of anogenital warts] trial compared two commonly used creams to treat genital warts: 0.15% podophyllotoxin cream (Warticon^®; GlaxoSmithKlein plc, Brentford, UK) and 5% imiquimod cream (Aldara^®; Meda Pharmaceuticals, Takeley, UK). It also investigated whether or not a vaccine used to prevent human papillomavirus infection, quadrivalent human papillomavirus vaccine (Gardasil^®, Merck Sharp & Dohme Corp., Merck & Co., Inc., Whitehouse Station, NJ, USA), could help treat warts or prevent them from coming back in patients whose warts had been cleared. The HIPvac trial was a randomised controlled trial involving 503 patients with warts attending sexual health clinics in England and Wales. The creams and the vaccine were well tolerated; there was some soreness where the cream was applied, but no unexpected side effects. When deciding which treatment was better, we looked at whether or not the warts had cleared by 16 weeks after starting treatment and, if cleared, whether or not they returned by 48 weeks. We compared the creams against each other, and the addition of vaccine against no vaccine (a placebo injection). Patients were allowed to have cryotherapy (freezing treatment) as well, if the investigator advised this. We also calculated the value for money of each type of treatment. The two creams were very similar in how well they worked to clear the warts. One difference was that podophyllotoxin cream worked slightly quicker. The number of patients given cryotherapy was about the same for both types of cream. We had expected that recurrence of warts after treatment with imiquimod cream might be less than after treatment with podophyllotoxin cream, but, in fact, the two creams were similar. Quadrivalent human papillomavirus vaccine did not improve clearance of warts or reduce the chance of recurrence, but the result remains inconclusive. If we had been able to recuit 1000 participants as originally planned, we might have been able to be more certain about whether there was any benefit of vaccination. Further research would be needed to investigate any possible effect. The two creams offered similar value for money in treating warts. Giving patients the vaccine in addition to the cream is not good value for money at its current list price, given the uncertainty about the benefit it offers.

Improved screening for anal neoplasia by immunocytochemical detection of minichromosome maintenance proteins.

PURPOSE: Early detection of anal intraepithelial neoplasia (AIN) and anal squamous cell carcinoma (SCC) by screening will improve clinical outcome. Assessment of anal cytology samples using routine Papanicolaou testing suffers from shortcomings in sensitivity and/or specificity, suggesting that screening tests based on biomarkers may be of value. We tested the suitability in this context of minichromosome maintenance (MCM) proteins, accurate markers of the deregulated cell cycle entry that characterizes malignancy and premalignancy. EXPERIMENTAL DESIGN: We undertook an initial immunohistochemical study of 54 anal tissue samples and validated our findings using an independent prospective cohort study of 235 anal cytology samples from 144 subjects. RESULTS: In the progression from normal anal epithelium through AIN to SCC, there was increasing expression of MCM2 and MCM5, including in the superficial epithelial third, the source of the majority of cells collected by anal swab. The median labeling indices (LI) for MCM2 and MCM5 in the superficial third of AIN2/3 and SCCs combined were 90.2% and 84.0%, respectively. MCM LIs in the superficial layers were significantly greater than LIs for Ki67, an alternative marker of cell cycle entry (P<0.0001). By immunocytochemistry using a mixture of anti-MCM2 and anti-MCM5 antibodies, immunopositive cells were readily identified in anal cytology samples, even at low magnification. MCM testing showed sensitivity for AIN2/3 of 84% (95% confidence interval, 75,93) and for AIN1/viral changes of 76% (68, 84), with overall specificity (for any lesion) of 77% (64, 90). CONCLUSIONS: MCMs are promising biomarkers for improving detection of AIN and SCC in anal cytology samples.