Anal Intraepithelial Neoplasia Grade Research Articles

Impact of screening programme to prevent anal cancer in high-risk patients with HIV.

We assessed the impact of a nationwide screening programme to reduce the risk of anal cancer in a large cohort of high-risk patients with HIV. From a large database from one referral centre, all high-risk patients with HIV (men who have sex with men, history of anal or genital warts, or previous cervix human papillomavirus-related lesions) who were eligible to enter the French anal cancer screening programme (2011-2020) were retrospectively included. Adherence to the screening programme was defined as no interval >18 months between two visits. Standardized management included perianal visualization and standard anoscopy with biopsies of macroscopic abnormalities. Overall, 700 patients with HIV were included (median follow-up 8.4 years [interquartile range 4.3-9.2] and 1491.6 patient-years), and 336 had one or more proctology visit. A total of 13 patients were diagnosed with anal squamous cell carcinomas. The risk of anal cancer was higher with anal intra-epithelial neoplasia grade 3 (AIN3; hazard ratio [HR] 44.5 [95% confidence interval {CI} 11.2-176.6], p < 0.001), AIN2 (HR 11.9 [95% CI 2.1-66.9], p = 0.005), or high-grade dysplasia (HR 23.4 [95% CI 7.9-69.1], p < 0.001) than with low-grade dysplasia or no lesion. Among the patients who were strictly adherent to the screening programme (4.6% [32/700]), we did not report any AIN or anal cancer, but we also did not observe any significant reduction in the risk of anal cancer (p = 0.51), AIN3 (p = 0.28), high-grade dysplasia (p = 0.19), or any AIN lesions (p = 0.10) compared with non-adherent patients. In contrast, screened patients were more likely to be diagnosed with anal warts (HR 3.71 [95% CI 2.14-6.42], p < 0.001). Macroscopic high-grade dysplasia lesions are associated with a higher risk of developing anal cancer. Despite finding no cases of cancer during the screening programme, we also did not demonstrate a clear benefit from our screening programme for the prevention of anal cancer in high-risk patients with HIV.

Electrocautery ablation of high-grade anal intraepithelial lesions: A protocol for a clinical trial

Background: Anal cancer is predominantly caused by the human papillomavirus. The use of high-resolution anoscopy (HRA) for screening, followed by appropriate therapeutic interventions, is progressively being acknowledged as a standardized procedure to manage anal cancer. Commonly, lesions identified as potentially high-grade squamous intraepithelial lesions undergo biopsy and receive treatment if classified as anal intraepithelial neoplasia (AIN) grade 2 or 3. Numerous studies have underscored the substantial efficacy of electrocautery ablation in treating grade 2 or 3 AIN. However, relapse within and outside the targeted areas after intervention is a clinical problem. Postintervention recurrence within and beyond the initial targeted areas presents a significant clinical challenge. Most healthcare facilities in Japan do not offer electrocautery ablation. An initial pilot study demonstrated the safety and efficacy of electrocautery ablation. Consequently, we aimed to scrutinize the effectiveness and safety profile of electrocautery ablation procedures using a larger sample size. Methods: This single-arm, open-label intervention trial aims to examine the efficacy and safety associated with electrocautery ablative treatments by utilizing high-frequency medical instruments. The cohort will comprise patients diagnosed with grade 2 or 3 AIN who will then undergo ablative treatments. Subsequent follow-ups will be scheduled at intervals of 6, 12, 24, and 36 months posttreatment, incorporating HRA-guided sextant biopsies to monitor disease progression. To minimize the chances of overlooking the lesions before and after the treatment phase, systematic HRA-guided sextant biopsies will be performed. Within the scope of this study, a sextant biopsy necessitates a minimum of 6 biopsy procedures in various directions, irrespective of any abnormalities detected during HRA inspections. The principal objective of this study is to ascertain the 12-month recurrence rate, with secondary objectives focusing on monitoring adverse events and recurrence rates at the 6-, 24-, and 36-month time points. Conclusion: This study aims to provide substantial data concerning the effectiveness and safety parameters of electrocautery ablation as a viable alternative treatment for patients with grade 2 or 3 AIN.

Severe anal intraepithelial neoplasia trends and subsequent invasive anal cancer in the United States.

Anal intraepithelial neoplasia grade III is a precursor to squamous cell carcinoma of the anus for which rates are nearly 20-fold higher in people with HIV than in the general population in the United States. We describe trends in anal intraepithelial neoplasia grade III diagnosis and risk of squamous cell carcinoma of the anus following anal intraepithelial neoplasia grade III by HIV status and sex. We used data from a population-based linkage between cancer and HIV registries in 11 US states; Puerto Rico; and Washington, DC, during 1996-2019. We identified all individuals with a diagnosis of anal intraepithelial neoplasia grade III and determined their HIV status. We estimated the average annual percentage change of anal intraepithelial neoplasia grade III using Poisson regression stratified by HIV status and sex. We estimated the 5-year cumulative incidence of squamous cell carcinoma of the anus following an anal intraepithelial neoplasia grade III diagnosis stratified by sex, HIV status, and prior AIDS diagnosis. Among people with HIV, average annual percentage changes for anal intraepithelial neoplasia grade III were 15% (95% confidence interval [CI] = 12% to 17%) per year among females and 12% (95% CI = 11% to 14%) among males. Average annual percentage changes for those without HIV were 8% (95% CI = 7% to 8%) for females and 8% (95% CI = 6% to 9%) for males. Among people with HIV, a prior AIDS diagnosis was associated with a 2.7-fold (95% CI = 2.23 to 3.40) and 1.9-fold (95% CI = 1.72 to 2.02) increased risk of anal intraepithelial neoplasia grade III diagnosis for females and males, respectively. Five-year cumulative incidence of squamous cell carcinoma of the anus following anal intraepithelial neoplasia grade III for people with HIV with a prior AIDS diagnosis were 3.4% and 3.7% for females and males, respectively. Rates of anal intraepithelial neoplasia grade III diagnoses have increased since 1996, particularly for people with HIV, likely influenced by increased screening. A prior AIDS diagnosis was strongly associated with risk of anal intraepithelial neoplasia grade III diagnosis.

Treatment of precancerous anal lesions in HIV patients: should they be treated or monitored?

Treatment of precancerous anal lesions in HIV patients: should they be treated or monitored?

Automated In Vivo High-Resolution Imaging to Detect Human Papillomavirus-Associated Anal Precancer in Persons Living With HIV.

In the United States, the effectiveness of anal cancer screening programs has been limited by a lack of trained professionals proficient in high-resolution anoscopy (HRA) and a high patient lost-to-follow-up rate between diagnosis and treatment. Simplifying anal intraepithelial neoplasia grade 2 or more severe (AIN 2+) detection could radically improve the access and efficiency of anal cancer prevention. Novel optical imaging providing point-of-care diagnoses could substantially improve existing HRA and histology-based diagnosis. This work aims to demonstrate the potential of high-resolution microendoscopy (HRME) coupled with a novel machine learning algorithm for the automated, in vivo diagnosis of anal precancer. The HRME, a fiber-optic fluorescence microscope, was used to capture real-time images of anal squamous epithelial nuclei. Nuclear staining is achieved using 0.01% wt/vol proflavine, a topical contrast agent. HRME images were analyzed by a multitask deep learning network (MTN) that computed the probability of AIN 2+ for each HRME image. The study accrued data from 77 people living with HIV. The MTN achieved an area under the receiver operating curve of 0.84 for detection of AIN 2+. At the AIN 2+ probability cutoff of 0.212, the MTN achieved comparable performance to expert HRA impression with a sensitivity of 0.92 ( P = 0.68) and specificity of 0.60 ( P = 0.48) when using histopathology as the gold standard. When used in combination with HRA, this system could facilitate more selective biopsies and promote same-day AIN2+ treatment options by enabling real-time diagnosis.

A systematic review and meta-analysis of cytology and HPV-related biomarkers for anal cancer screening among different risk groups.

To inform optimal approaches for detecting anal precancers, we performed a systematic review and meta-analysis of the diagnostic accuracy of anal cancer screening tests in different populations with elevated risk for anal cancer. We conducted a literature search of studies evaluating tests for anal precancer and cancer (anal intraepithelial neoplasia grade 2 or worse, AIN2+) published between January 1, 1997 to September 30, 2021 in PubMed and Embase. Titles and abstracts were screened for inclusion and included articles underwent full-text review, data abstraction and quality assessment. We estimated the prevalence of AIN2+ and calculated summary estimates and 95% confidence intervals (CI) of test positivity, sensitivity and specificity and predictive values of various testing strategies, overall and among population subgroups. A total of 39 articles were included. The prevalence of AIN2+ was 20% (95% CI, 17-29%), and ranged from 22% in men who have sex with men (MSM) living with HIV to 13% in women and 12% in MSM without HIV. The sensitivity and specificity of cytology and HPV testing were 81% and 62% and 92% and 42%, respectively, and 93% and 33%, respectively for cytology and HPV co-testing. AIN2+ risks were similar among those testing positive for cytology, HPV, or co-testing. Limited data on other biomarkers (HPV E6/E7 mRNA and p16/Ki-67 dual stain), suggested higher specificity, but lower sensitivity compared with anal cytology and HPV. Our findings provide important evidence for the development of clinical guidelines using anal cytology and HPV testing for anal cancer screening.

A nationwide longitudinal study on risk factors for progression of anal intraepithelial neoplasia grade 3 to anal cancer.

Little is known about risk factors for progression of high‐grade anal intraepithelial neoplasia (AIN) to anal squamous cell carcinoma (ASCC). In this large, population‐based study, we assess the role of factors related to immune status for the risk of ASCC among individuals from the general population with a diagnosis of AIN3. Individuals diagnosed with AIN3 during 1985‐2016 were identified in the Danish Pathology Registry and followed for subsequent development of ASCC. The study population was linked to the National Patient Registry, the Danish Prescription Registry and the Danish HIV Cohort Study for information on autoimmune disease, genital warts and HIV status. To study the progression rate, Cox regression models with hazard ratios (HR) and 95% confidence intervals (CI) were applied with time since AIN3 as the underlying time scale and with adjustment for age at AIN3 diagnosis, year of AIN3 diagnosis and sex. The study population comprised 1222 individuals with AIN3 contributing 12 824 person‐years of follow‐up. Ninety‐seven individuals (7.9%) developed ASCC. Individuals registered with an autoimmune disease or genital warts before and/or after the AIN3 diagnosis had an increased rate of progression to ASCC compared to individuals without these conditions. People living with HIV had a higher progression rate than HIV‐negative individuals (HR = 4.25; 95% CI: 1.87‐9.65) with the highest progression rate among those with CD4 count ≤200 cells/μL. These associations may be caused by an interplay between HPV infection and immunosuppression.

Automated Evaluation of p16/Ki-67 Dual-Stain Cytology as a Biomarker for Detection of Anal Precancer in Men Who Have Sex With Men and Are Living With Human Immunodeficiency Virus.

Human papillomavirus-related biomarkers such as p16/Ki-67 "dual-stain" (DS) cytology have shown promising clinical performance for anal cancer screening. Here, we assessed the performance of automated evaluation of DS cytology (automated DS) to detect anal precancer in men who have sex with men (MSM) and are living with human immunodeficiency virus (HIV). We conducted a cross-sectional analysis of 320 MSM with HIV undergoing anal cancer screening and high-resolution anoscopy (HRA) in 2009-2010. We evaluated the performance of automated DS based on a deep-learning classifier compared to manual evaluation of DS cytology (manual DS) to detect anal intraepithelial neoplasia grade 2 or 3 (AIN2+) and grade 3 (AIN3). We evaluated different DS-positive cell thresholds quantified by the automated approach and modeled performance compared with other screening strategies in a hypothetical population of MSM with HIV. Compared with manual DS, automated DS had significantly higher specificity (50.9% vs 42.2%; P < .001) and similar sensitivity (93.2% vs 92.1%) for detection of AIN2+. Human papillomavirus testing with automated DS triage was significantly more specific than automated DS alone (56.5% vs 50.9%; P < .001), with the same sensitivity (93.2%). In a modeled analysis assuming a 20% AIN2+ prevalence, automated DS detected more precancers than manual DS and anal cytology (186, 184, and 162, respectively) and had the lowest HRA referral rate per AIN2+ case detected (3.1, 3.5, and 3.3, respectively). Compared with manual DS, automated DS detects the same number of precancers, with a lower HRA referral rate.

Incidence of human papillomavirus-related anogenital precancer and cancer in women with diabetes: A nationwide registry-based cohort study.

In this register-based cohort study, we estimated the incidence of human papillomavirus (HPV)-related anogenital precancer and cancer in women with diabetes compared with women without diabetes. We followed all women living in Denmark born 1916 to 2001 (n = 2 508 321) for individual-level information on diabetes (Type 1 or 2 [T1D or T2D]), diagnoses of cervical, vaginal, vulvar and anal intraepithelial neoplasia Grade 2 or 3 (IN2/3) and cancer and other covariates from nationwide registries. We used Poisson regression to model the incidence rates of anogenital IN2/3 and cancer as a function of diabetes status, age, HPV vaccination, education, calendar year, and cervical cancer screening status. Incidence rate ratios (IRRs) were estimated for diabetes overall, and separately for T1D and T2D, compared with women without diabetes. Women with diabetes had higher rates of vulvar IN2/3 (IRR = 1.63; 95% confidence interval [CI]: 1.41-1.88), vulvar cancer (IRR = 1.61; 95% CI: 1.36-1.91) and vaginal cancer (IRR = 1.79; 95% CI: 1.27-1.91) than women without diabetes. Similar patterns were observed for anal IN2/3, anal cancer and cervical cancer, although not statistically significant. In contrast, women with diabetes had lower rates of cervical IN2/3 (IRR = 0.74; 95% CI: 0.69-0.79) than women without diabetes. Patterns were generally similar in women with T1D and T2D, although cancer rates were higher in women with T2D. In conclusion, the incidence of most anogenital precancers and cancers were increased in women with diabetes. However, women with diabetes had lower incidence of cervical precancer. Our findings could be explained by biological mechanisms and/or behavioral factors, such as smoking and less frequent cervical screening participation.

Human Papillomavirus Genotypes in Anal High-Grade Squamous Intraepithelial Lesion (HSIL): Anal Intraepithelial Neoplasia Grades 2 (AIN2) and 3 (AIN3) Are Different.

Anal high-grade squamous intraepithelial lesion (HSIL) can be histomorphologically categorized into anal intraepithelial neoplasia (AIN) grade 2 (AIN2) and grade 3 (AIN3). Different risk factors for these two categories have been described. We investigated whether there were also differences in lesion-specific human papillomavirus (HPV) genotypes. The Study of the Prevention of Anal Cancer (SPANC) recruited 617 gay and bisexual men (GBM); 36% of participants were HIV positive. At baseline, 196 men (31.8%) had histologic HSIL lesions. Tissue was available for genotyping in 171, with a total of 239 HSIL lesions (183 AIN3 and 56 AIN2). Using laser capture microdissection, each lesion revealed a maximum of one genotype. High-risk HPV (HR-HPV) genotypes were found in 220 (92.1%) HSIL lesions, with no significant difference between AIN3 (93.4%) and AIN2 (87.5%). AIN3 lesions had significantly more HPV16 (42.1%) than AIN2 lesions (12.5%; P < 0.001) and AIN2 lesions had significantly more non-16 HR-HPV types (75.0%) than AIN3 lesions (51.4%; P = 0.002). These associations were similar for HIV-negative men with HPV16 in 51.1% AIN3 and 18.2% AIN2 (P = 0.001) and non-16 HR-HPV in 40.0% AIN3 and 75.8% AIN2 (P < 0.001). For HIV-positive men, HPV16 remained more frequently detected in AIN3 (33.3% vs. 4.4% for AIN2; P = 0.004), but there was no difference between AIN3 and AIN2 for non-16 HR-HPV (62.4% vs. 73.9%; P = 0.300). As HPV16 has the strongest link with anal cancer, the subcategorization of HSIL may enable stratification of lesions for anal cancer risk and guide anal HSIL management. Stratification of anal cancer risk by histologic HSIL grade.

Risk of vulvar, vaginal and anal high-grade intraepithelial neoplasia and cancer according to cervical human papillomavirus (HPV) status: A population-based prospective cohort study

ObjectivesAll cervical cancers and some vulvar, vaginal and anal cancers are caused by high-risk human papillomavirus (hrHPV). However, little is known about the association between cervical HPV infection and subsequent intraepithelial neoplasia and cancer at other anogenital sites. In this prospective cohort study, we estimated the risk of vulvar, vaginal and anal intraepithelial neoplasia grade 2/3 or cancer (VIN2+, VaIN2+, AIN2+) according to cervical hrHPV status. MethodsLiquid-based cervical cytology samples were collected from 40,399 women screened against cervical cancer in Copenhagen, Denmark, during 2002–2005. Samples were tested for hrHPV using Hybrid Capture 2 (HC2) and genotyped using INNO-LiPA. We linked the cohort with Danish nationwide registries to identify cases of VIN2+, VaIN2+ and AIN2+ during up to 15 years of follow-up. We estimated age-adjusted hazard ratios (HRs) using Cox regression and cumulative incidences using Aalen-Johansen's estimator. ResultsWomen with cervical HPV16 infection had increased hazard of VIN2+ (HR = 2.6; 95% confidence interval [CI], 1.2–5.5), VaIN2+ (HR = 23.5; 95% CI, 6.8–81.6) and AIN2+ (HR = 3.7; 95% CI, 1.1–12.2) compared with HC2 negative women. Women with other hrHPV types than HPV16 also had increased hazard of VaIN2+ (HR = 7.1; 95% CI, 2.3–22.3) and a borderline statistically significantly increased risk of AIN2+ (HR = 2.2; 95% CI, 0.9–4.9) compared with HC2 negative women. The 10-year cumulative incidences of VIN2+, VaIN2+ and AIN2+ in women with cervical HPV16 were 0.3% (95% CI, 0.2%–0.7%), 0.2% (95% CI, 0.1%–0.5%) and 0.1% (95 CI, 0.0%–0.4%). ConclusionsCervical HPV16 infection is associated with increased risk of VIN2+, VaIN2+ and AIN2+.

347 Successful Removal of Anal Condyloma With Endoscopic Submucosal Dissection (ESD): A Novel Indication for ESD

INTRODUCTION: Endoscopic submucosal dissection (ESD) is a novel procedure that utilizes advanced surgical techniques to remove gastrointestinal tumors without the invasive nature of surgery. While there are many advantages to this procedure, one limitation that remains is that the standardization of ESD technique is yet to be well-defined, particularly in Western nations. Here, we present a case of a patient with a 30-mm anal condyloma who had complete resection of the pre-malignant lesion through ESD. CASE DESCRIPTION/METHODS: A 73-year-old female presented for screening colonoscopy. She was found to have an anal lesion on exam, biopsies showed anal condyloma with low-grade dysplasia. Given the extension of the lesion to the distal rectum, the decision was to perform dissection of the anal condyloma from the anorectal canal. Initially, the lesion was marked 5-6 mm away from its border, to allow for dissection with clear margins. In the next step, a 25-gauge needle was used to inject a solution containing Hetastarch and methylene blue. This was done to raise the lesion away from the muscularis propria layer. A circumferential incision was made, beginning at the anal aspect of the lesion. To make the final dissection, a dissection knife with an insulated ceramic tip was used in the forward view. This allowed for secure separation of the lesion in one piece, without any tissue injury. DISCUSSION: A 30 mm anal condyloma was procured. Pathology showed an anal condyloma with anal intraepithelial neoplasia grade I (AIN1). The lesion was negative for any high-grade dysplasia or carcinoma. Peripheral and deep margins were free of the lesion. The patient had mild rectal pain for three days after the procedure, which completely resolved with the application of lidocaine gel. ESD is a highly effective resection tool and should be considered for treatment of rectal condylomatous lesions. Watch the video: http://bit.ly/2LXfpkp

Human papillomavirus-related anogenital premalignancies and cancer in renal transplant recipients: A Danish nationwide, registry-based cohort study.

In this registry-based cohort study, we estimated the risk of human papillomavirus (HPV)-related anogenital premalignancies and cancer in renal transplant recipients (RTRs) compared to a nontransplanted comparison cohort. We identified all first-time RTRs in Denmark during 1990-2015 in a nationwide nephrology register. For each RTR, we randomly selected 50 age- and sex-matched non-RTRs from the background population. The study population was followed for diagnoses of cervical, vaginal, vulvar, penile and anal intraepithelial neoplasia grades 2-3 (IN2/3) and cancer for up to 27 years. We estimated hazard ratios (HRs) of anogenital IN2/3 and cancer in RTRs vs. non-RTRs by Cox regression separately for men and women using age as underlying timescale, adjusting for income, education, HPV vaccination and immunocompromising conditions. We included 4,261 RTRs and 213,673 non-RTRs. RTRs had increased hazard of cervical (HR = 2.1, 95% CI: 1.7-2.8), vaginal (HR = 35.0, 95% CI: 13.9-87.7), vulvar (HR = 16.4, 95% CI: 10.4-25.8), penile (HR = 21.9, 95% CI: 11.1-43.5) and anal (women: HR = 51.1, 95% CI: 28.0-93.1; men: HR = 39.0, 95% CI: 16.7-91.1) IN2/3. The HRs of anogenital cancers were also increased at most sites. The HR of anogenital IN2/3 in female RTRs tended to be higher during graft function than during dialysis. In female RTRs aged <40 years at transplantation, 10-15% had cervical IN2/3 and 5-12% had vaginal/vulvar/anal IN2/3 within 20 years after transplantation, compared to 4-8 and 0.2-0.4%, respectively, of female non-RTRs. In conclusion, RTRs had substantially higher risk of HPV-related anogenital premalignancies and cancer than non-RTRs.

Condyloma Acuminatum of Urinary Bladder: Relation to Squamous Cell Carcinoma.

Condyloma acuminatum rarely occurs in the urinary bladder and is considered to be a risk factor for squamous cell carcinoma, although there are only a few publications with limited cases. We studied 51 cases of condyloma acuminatum of the urinary bladder from transurethral resections of the urinary bladder of 38 patients from the consult files of one of the authors. Transurethral resections of the urinary bladder were obtained from 25 males with a median age of 73 years (range: 41 to 87 y) and 13 females with a median age of 68 years (range: 30 to 86 y). The follow-up period ranged from 15 months to 20 years (median: 6 y). Bladder lesions were accompanied by urethral lesions in 4 men. Eight patients (8/38; 21.0%) had a history of immunosuppression. Seven patients (7/8; 87.5%) from this group had multiple and/or recurrent condylomas. One patient (1/38; 2.6%) with renal transplantation had 10 separate bladder condylomas over time. One patient (1/38; 2.6%) had extensive anogenital condylomas and anal intraepithelial neoplasia grade 3. One patient (1/8; 12.5%) with renal transplantation presented with a solitary condyloma with synchronous squamous cell carcinoma in situ. Three female patients (3/38; 7.9%) had a history of premalignant vagina/cervix lesions. In total, 17 patients (17/38; 44.7%) had squamous cell carcinoma of the bladder, either invasive or in situ. In all cases, the squamous cell carcinoma (either in situ or invasive) was diagnosed either concurrent with the diagnosis of bladder condyloma or within 1 year of the condyloma diagnosis). In total, 9 of 38 (23.7%) patients had invasive squamous cell carcinoma with or without in situ squamous cell carcinoma. Eight of 38 (21.0%) patients had squamous cell carcinoma in situ only (without a definitive invasive component-in 3 cases invasive squamous cell carcinoma could not be excluded with certainty). In total, 19 patients (19/38; 50%) were positive for either low-risk human papillomavirus (LR-HPV) or high-risk human papillomavirus (HR-HPV) or both (3 were positive for both LR-HPV and HR-HPV, 12 patients for only LR-HPV, and 4 for only HR-HPV). Of the 19 patients that were negative for both LR-HPV and HR-HPV, 9 of 19 (47.4%) patients had associated squamous cell carcinoma. Of the 12 patients with only LR-HPV, 4 (33.3%) had associated squamous cell carcinoma (either invasive or in situ). Of the 7 patients with HR-HPV (with or without LR-HPV), 4 (57.1%) has associated squamous cell carcinoma. In summary, condyloma acuminatum of the urinary bladder shows a strong association with squamous cell carcinoma of the bladder, regardless of the condyloma's HPV in situ hybridization results. Immunosuppression is associated with condylomas of the bladder. It is important to distinguish bladder condylomas from papillary urothelial carcinoma, given their different risks for panurothelial disease and risk of squamous cell carcinoma. Recognition of bladder condylomas histologically is often challenging given their rarity, and that they can be negative for both LR-HPV and HR-HPV. The lack of a history of other anogenital human papillomavirus-related lesions further increases the difficulty in establishing the correct diagnosis.

Utility of Stathmin-1 as a Novel Marker in Evaluating Anal Intraepithelial Neoplasia (AIN).

The aim of this study is to determine whether immunohistochemistry for Stathmin-1 enhances diagnostic accuracy of anal dysplasia. The study included 40 biopsies with diagnosis of benign anal transitional zone (n=10), low-grade anal intraepithelial neoplasia (AIN) (AIN1, n=10), and high-grade AIN (AIN2, n=10, AIN3, n=10). The cases were selected to represent classic features. Immunohistochemistry for Stathmin-1, p16, and Ki-67 was performed and assessed for distribution within epithelial thickness. Stathmin-1 was expressed only in the basal layer of benign anal epithelium. Similar pattern of distribution was seen in all low-grade AIN cases (100%). In total, 40% of AIN2 showed Stathmin-1 staining pattern similar to AIN1. The other 60% of cases showed staining extending into the middle third of the epithelial thickness. Of AIN3 cases, 20% showed staining confined to the lower third epithelium, 20% showed staining extending to the middle third, and 60% showed staining extending into the upper third epithelium. The pattern of stain distribution suggested that staining extending above the lower one-third of the epithelial thickness discriminates between low-grade and high-grade AIN. With this cutoff, the sensitivity for the diagnosis of high-grade AIN was 70%, specificity was 100%, positive predictive value equaled 100%, and negative predictive value equaled 77%. P16INK4a showed 100% sensitivity for AIN2 and AIN3, whereas Ki-67 had 100% sensitivity for any AIN grade. In conclusion, Stathmin-1 has excellent specificity for the diagnosis of high-grade AIN; however, Stathmin-1 alone may not be sufficiently sensitive. Use in conjunction with other sensitive markers, such as p16 or Ki-67 may be considered.

5-Year Prospective Evaluation of Cytology, Human Papillomavirus Testing, and Biomarkers for Detection of Anal Precancer in Human Immunodeficiency Virus-Positive Men Who Have Sex With Men.

Human papillomavirus (HPV)-related biomarkers have shown good cross-sectional performance for anal precancer detection in human immunodeficiency virus-positive (HIV+) men who have sex with men (MSM). However, the long-term performance and risk stratification of these biomarkers are unknown. Here, we prospectively evaluated high-risk (HR) HPV DNA, HPV16/18 genotyping, HPV E6/E7 messenger RNA (mRNA), and p16/Ki-67 dual stain in a population of HIV+ MSM. We enrolled 363 HIV+ MSM between 2009-2010, with passive follow-up through 2015. All had anal cytology and a high-resolution anoscopy at baseline. For each biomarker, we calculated the baseline sensitivity and specificity for a combined endpoint of high-grade squamous intraepithelial lesion (HSIL) and anal intraepithelial neoplasia grade 2 or more severe diagnoses (HSIL/AIN2+), and we estimated the 2- and 5-year cumulative risks of HSIL/AIN2+ using logistic and Cox regression models. There were 129 men diagnosed with HSIL/AIN2+ during the study. HR-HPV testing had the highest positivity and sensitivity of all assays, but the lowest specificity. HPV16/18 and HPV E6/E7 mRNA had high specificity, but lower sensitivity. The 2- and 5-year risks of HSIL/AIN2+ were highest for those testing HPV16/18- or HPV E6/E7 mRNA-positive, followed by those testing dual stain-positive. Those testing HR-HPV- or dual stain-negative had the lowest 2- and 5-year risks of HSIL/AIN2+. HPV-related biomarkers provide long-term risk stratification for anal precancers. HR-HPV- and dual stain-negativity indicate a low risk of HSIL/AIN2+ for at least 2 years, compared with negative anal cytology; however, the high positivity of HR-HPV in HIV+ MSM may limit its utility for surveillance and management in this population.

Clinical evaluation of anal intraepithelial neoplasia: are we missing the boat?

Anal intraepithelial neoplasia (AIN) is dysplasia in the epithelium of the anus and is a pre-malignant condition associated with a low rate of progression to invasive squamous cell carcinoma (SCC). The natural history of progression for AIN to anal SCC is poorly defined. This study aims to review our experience with AIN and investigate the natural history of progression. Data on all patients with AIN from January 2005 to December 2015 were retrospectively reviewed. Three separate databases were searched - Colorectal, Radiation Oncology and Infectious Diseases. All databases were cross-referred to obtain a complete but non-duplicated data set. Electronic charts were reviewed to obtain clinical information. Twenty-eight patients were identified with AIN of various grades. There were 25 males, three females. Twenty of the male patients were human immunodeficiency virus (HIV) positive. Mean length of follow up was 56 months. Complete regression of AIN to normal was noted in 13 patients (46%). Four patients had persisting AIN III with no evidence of regression or malignant transformation. Nine patients with pre-existing AIN developed SCC (32%). Seven were positive for HIV infection (all males). Median time to progression was 36 months. None of the patients demonstrated clear linear pattern of progression of AIN to SCC. High grade AIN may progress to anal SCC and surveillance is indicated. The exact natural history of progression for AIN is difficult to predict. There is no linear progression over time evident. HIV patients with AIN are at higher risk of developing SCC.

Efficacy, effectiveness and safety of vaccination against human papillomavirus in males: a systematic review

BackgroundHuman papillomavirus (HPV) vaccination is safe and effective in preventing cervical cancer in females. As HPV infections can also induce cancers of the anus, penis and oral cavity, male vaccination is also advocated, but systematic reviews on efficacy and safety in males are lacking.MethodsWe performed a systematic review on the efficacy, effectiveness and safety of HPV vaccination in males of any age. MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and ClinicalTrials.gov were searched from inception to April 2017.ResultsWe identified 5196 articles and seven studies (four randomized controlled trials (RCTs), three non-randomized studies) were included, comprising a total of 5294 participants. Vaccine efficacy against at least 6-month persisting anogenital HPV 16 infections was 46.9% (95% confidence interval (CI) 28.6–60.8%), whereas efficacy against persisting oral infections was 88% (2–98%). A vaccine efficacy of 61.9% (21.4–82.8%) and 46.8% (− 20 to –77.9%) was observed against anal intraepithelial neoplasia grade 2 and grade 3 lesions, respectively. No meaningful estimates were available on vaccine efficacy or effectiveness against penile intraepithelial neoplasia grade 2 or 3, and no data were identified for anal, penile or head and neck squamous cell cancer. In participants who were HPV-seronegative and PCR-negative at enrolment, efficacy against all outcomes was higher as compared to seropositive and/or PCR-positive individuals. Risk of bias was low in three RCTs and high in one, while the three non-randomized studies were at serious to critical risk of bias. Grading of Recommendations Assessment, Development and Evaluation evidence quality was moderate to low for most outcomes.ConclusionsHPV vaccination in males is moderately effective against persistent anogenital HPV infection and high-grade anal intraepithelial lesions in studies where the population consists mainly of HPV-infected males. Vaccine effectiveness was high in study groups comprising HPV-naïve males. This supports a recommendation for vaccination of boys before the onset of sexual activity with the goal of establishing optimal vaccine-induced protection. Mathematical modelling studies will still be needed to assess the effects of adding males to existing HPV vaccination programs in females.Trial registrationProspective Register for Systematic Reviews (PROSPERO) registration CRD42016038965.

18 - Identification of productive and transforming anal intraepithelial neoplasia using immunohistochemical markers p16INK4a and HPV E4

Background Immunohistochemical (IHC) biomarkers enable standardised, reproducible grading of anal intraepithelial neoplasia (AIN) based on progression of HPV infection from transient productive infection to complete neoplastic transformation. We investigated the expression of IHC biomarker HPV E4, a marker of productive HPV infection, in different grades of AIN caused by low-risk (lr) and high-risk (hr) HPV infection. Methods A reference grading of AIN was established using expert, consensus, subjective HE diagnoses supported by p16 expression for 183 anal biopsies: normal squamous epithelium 37, AIN1 67, AIN2 43, AIN3 36. Causative HPV genotype of the worst lesion was identified using laser capture microdissection and SPF10-PCR. Results Most AIN1 lesions were caused by lrHPV (72%) whereas most AIN2 (84%) and AIN3 (92%) was caused by hrHPV. None of the normal biopsies showed E4 positivity and 49% (33/67) of AIN1, 56% (24/43) of AIN2 and 3% (1/36) of AIN3 showed E4 positivity. While the large majority of E4 positive AIN1 (26/33) and AIN2 (16/24) lesions showed extensive positivity, the E4 positive AIN3 lesion showed only focal, superficial E4 positivity. HPV E4 positivity was seen in lesions caused by lr and hr HPV. Conclusions Our results show that when using HPV E4 in addition to p16, productive infections among both low-grade and high-grade AIN can be identified. Studies that further explore progression and regression in transforming (E4 negative) and productive (E4 positive) high-grade AIN, are necessary.

HPV genotypes detected by linear array and next-generation sequencing in anal samples from HIV positive men who have sex with men in Mexico.

The incidence of anal cancer has been rising, especially in HIV+ patients and has been associated with HPV infection. HIV+ patients are more at risk of HPV coinfection and are seven times more likely to have persistent HPV infection; moreover, HIV+ men have an increased risk of developing anal cancer compared to HIV+ women. The development of screening strategies for the detection of HPV in HIV+ men is of major importance; however, there is not enough information about the HPV genotypes and variants that are colonizing the anal epithelia of HIV+ men in diverse geographical regions. Therefore, this work was aimed at identifying HPV genotypes present in the anal epithelium of HIV+ men who have sex with men (MSM), with or without anal lesions (n=75). For HPV genotyping, two approaches were performed: Linear Array HPV Genotyping Test and next-generation sequencing (NGS). In general, the six most frequent HPV genotypes found by Linear Array were HPV6, 62, 61, 81, 16 and 51. On the other hand, employing NGS, a total of 36 HPV genotypes belonging to both alpha and beta genera were found. The genotypes with the greatest number of reads, according to the diagnostic group, were: HPV81, 45, 6, 51 and 61 in MSM without anal lesions (WAIN); HPV6, 61, 70, 62 and 66 in MSM with atypical lesions (AAL); HPV6, 11, 66, 81 and 61 in MSM with anal intraepithelial neoplasia grade I (AIN I); and HPV16, 81, 58, 61 and 52 with AIN III. Additionally, a great diversity of L1 variants was observed, especially in genotypes HPV16, 58, 61, 52, 45 and 59.