International Anal Neoplasia Society's consensus guidelines for anal cancer screening.

The International Anal Neoplasia Society (IANS) developed consensus guidelines to inform anal cancer screening use among various high-risk groups. Anal cancer incidence estimates by age among risk groups provided the basis to identify risk thresholds to recommend screening. Guided by risk thresholds, screening initiation at age 35 years was recommended for men who have sex with men (MSM) and transgender women (TW) with HIV. For other people with HIV and MSM and TW not with HIV, screening initiation at age 45 years was recommended. For solid organ transplant recipients, screening initiation beginning from 10 years post-transplant was recommended. For persons with a history of vulvar precancer or cancer, screening initiation was recommended starting within 1 year of diagnosis of vulvar precancer or cancer. Persons aged ≥45 years with a history of cervical/vaginal HSIL or cancer, perianal warts, persistent (>1 year) cervical HPV16, or autoimmune conditions could be considered for screening with shared decision-making, provided there is adequate capacity to perform diagnostic procedures (high-resolution anoscopy [HRA]). Anal cytology, high-risk (hr) human papillomavirus (HPV) testing (including genotyping for HPV16), and hrHPV-cytology co-testing are different strategies currently used for anal cancer screening that show acceptable performance. Thresholds for referral for HRA or follow-up screening tests are delineated. These recommendations from IANS provide the basis to inform management of abnormal screening results, considering currently available screening tools. These guidelines provide a pivotal foundation to help generate consensus among providers and inform the introduction and implementation of risk-targeted screening for anal cancer prevention.

Performance of Human Papillomavirus Attribution Algorithms to Predict Causative Genotypes in Anal High-Grade Lesions.

BACKGROUND: Gay and bisexual men (GBM) are at increased risk of human papillomavirus (HPV)-associated anal high-grade squamous intraepithelial lesions (HSILs). Understanding the fractions of HSILs attributable to HPV genotypes is important to inform potential impacts of screening and vaccination strategies. However, multiple infections are common, making attribution of causative types difficult. Algorithms developed for predicting HSIL-causative genotype fractions have never been compared with a reference standard in GBM. METHOD: Samples were from the Study of the Prevention of Anal Cancer. Baseline HPV genotypes detected in anal swab samples (160 participants) were compared with HPV genotypes in anal HSILs (222 lesions) determined by laser capture microdissection (LCM). Five algorithms were compared: proportional, hierarchical, maximum, minimum, and maximum likelihood estimation. RESULTS: All algorithms predicted HPV-16 as the most common HSIL-causative genotype, and proportions differed from LCM detection (37.8%) by algorithm (with differences of -6.1%, +20.9%, -20.4%, +2.9%, and +2.2% respectively). Fractions predicted using the proportional method showed a strong positive correlation with LCM, overall (R = 0.73 and P = .002), and by human immunodeficiency virus (HIV) status (HIV positive, R = 0.74 and P = .001; HIV-negative, R = 0.68 and P = .005). CONCLUSIONS: Algorithms produced a range of inaccurate estimates of HSIL attribution, with the proportional algorithm performing best. The high occurrence of multiple HPV infections means that these algorithms may be of limited use in GBM.

Vulvar High-Grade Squamous Intraepithelial Lesions and Cancer as a Risk Factor for Anal Cancer: A Review.

OBJECTIVES: Anal squamous cell carcinoma (ASCC) has a higher incidence described in certain groups, namely, in women with vulvar high-grade squamous intraepithelial lesions (vHSILs) and/or human papillomavirus squamous cell carcinoma (VSCC). This review describes terminology, vHSIL, and VSCC in their association with ASCC and the published recommendations for early detection of this cancer in these women. MATERIALS AND METHODS: A narrative review was conducted by the authors on vHSIL and VSCC as risk factors for ASCC. RESULTS: The ASCC and VSCC incidence are increasing. Women with vHSIL and/or VSCC can present with ASCC at diagnosis, being one of the highest-risk groups. Suspicious symptoms include rectal bleeding, pain, and a sensation of an anal mass. Digital anorectal examination can help detect early ASCC. Sensitivity of anal cytology in women with vHSIL and VSCC seems low, with the exception of immunosuppressed women with genital neoplasia (cervix, vagina, and vulva). There are still insufficient data on high-resolution anoscopy in women with vHSIL and/or VSCC as a screening method. CONCLUSIONS: Clinicians need be aware that women with vHSIL and VSCC comprise one of the highest-risk groups for ASCC. Inquiring suggestive symptoms of ASCC and a digital anorectal examination can help in the early detection of this type of cancer.

HIV, Immune Dysfunction, and the Natural History of Anal High-Risk Human Papillomavirus Infection in Gay and Bisexual Men.

BACKGROUND: Incidence of anal cancer is highest in gay and bisexual men (GBM). Better understanding of the natural history of anal high-risk human papillomavirus (hrHPV) infection is needed for anal cancer prevention. METHODS: The Study of the Prevention of Anal Cancer was a 3-year study of Australian GBM, aged 35 years or older. We examined incidence, clearance, and risk factors for 13 hrHPV types at baseline and 3 annual visits. RESULTS: In 525 men with ≥ 2 visits, 348 (66.3%) acquired ≥ 1 incident hrHPV infection. HPV16 incidence rates were similar, but non-16 hrHPV incidence was higher in HIV-positive (51.8/100 person years [PY]) than HIV-negative men (36.5/100 PY, P < .001). Annual clearance rates of HPV16 (13.21/100 PY, 95% confidence interval, 10.53-16.56) were lower than for other hrHPV types. hrHPV clearance rates were not associated with HIV overall but were significantly lower in those with a lower nadir CD4 (<200 cells/µL) for HPV16 (P = .015) and other hrHPV types (P = .007). CONCLUSIONS: Higher incidence of non-16 hrHPV types, coupled with lower clearance of non-16 hrHPV types in those with past impaired immune function, is consistent with the greater role of non-16 hrHPV in anal cancer in HIV-positive people. AUSTRALIA NEW ZEALAND CLINICAL TRIALS REGISTRY: ANZCTR365383.

The Natural History of Anal High-grade Squamous Intraepithelial Lesions in Gay and Bisexual Men.

BACKGROUND: Gay and bisexual men (GBM) are disproportionately affected by anal cancer. Prevention is hindered by incomplete understanding of the natural history of its precursor, anal high-grade squamous intraepithelial lesions (HSIL). METHODS: The Study of the Prevention of Anal Cancer, conducted between 2010 and 2018, enrolled human immunodeficiency virus (HIV)-positive and HIV-negative GBM aged ≥35 years. Anal cytology and high-resolution anoscopy (HRA) were performed at baseline and 3 annual visits. A composite HSIL diagnosis (cytology ± histology) was used. Cytological high-grade squamous intraepithelial lesions (cHSIL) incidence and clearance rates were calculated with 95% confidence intervals (CIs). Predictors were calculated using Cox regression with hazard ratios (HRs) and 95% CIs. RESULTS: Among 617 men, 220 (35.7%) were HIV-positive, median age 49 years. And 124 incident cHSIL cases occurred over 1097.3 person-years (PY) follow-up (11.3, 95% CI 9.5-13.5 per 100 PY). Significant bivariate predictors of higher incidence included age <45 years (HR 1.64, 95% CI 1.11-2.41), HIV positivity (HR 1.43, 95% CI .99-2.06), prior SIL diagnosis (P-trend < .001) and human papillomavirus (HPV)16 (HR 3.39, 2.38-4.84). Over 695.3 PY follow-up, 153 HSIL cleared (clearance 22.0, 95% CI 18.8-25.8 per 100 PY). Predictors were age < 45 years (HR 1.52, 1.08-2.16), anal intraepithelial neoplasia (AIN)2 rather than AIN3 (HR 1.79, 1.29-2.49), smaller lesions (HR 1.62, 1.11-2.36) and no persistent HPV16 (HR 1.72, 1.23-2.41). There was 1 progression to cancer (incidence 0.224, 95% CI .006-1.25 per 100 PY). CONCLUSION: These data strongly suggest that not all anal HSIL detected in screening requires treatment. Men with persistent HPV16 were less likely to clear HSIL and are more likely to benefit from effective HSIL treatments. CLINICAL TRIALS REGISTRATION: Australia New Zealand Clinical Trials Registry (ANZCTR365383).

Prevalence of anal cytological abnormalities and high-risk human papillomavirus prevalence in kidney transplant recipients: A cross-sectional study.

BACKGROUND: Transplant recipients are at high-risk of anal squamous cell cancer. We aimed to estimate the prevalence of high-risk human papillomavirus (HPV) and high-grade squamous intraepithelial lesion (HSIL) and assess characteristics associated with results METHODS: We recruited kidney transplant recipients in a single-center, 2015-2018. Participants completed a clinical questionnaire and received an anal-swab sent for HPV-DNA and cytological testing RESULTS: A total of 97 (74%) of 125 recipients approached consented to participate. Participants were median 47 (IQR 40-55) years, 60% male and median 4.5 (IQR .9-13) months-since-transplant. Of 86 assessable samples, at least one HPV genotype was detected in 15 (17%) participants; 1 (1%) HPV16, 8 (9%) other high-risk HPV. Of 76 assessable cytology samples, 9 (12%) showed evidence of abnormality; 1 (1%) HSIL, 1 (1%) atypical-squamous-cells, cannot exclude HSIL. Both HSIL recipients had high-risk HPV and biopsy confirmed HSIL. High-risk HPV was detected in six (9%) recipients with normal cytology. History of sexually transmitted infection, and abnormal cervical pap smear in women, was associated with high-risk HPV and HSIL CONCLUSIONS: High-risk HPV and HSIL testing may identify kidney transplant recipients at higher risk of anal cancer. Longitudinal studies are needed to describe the natural history of anal cancer in transplant recipients.

Self-reported anal symptoms and their association with anal pathology among gay and bisexual men: a cross-sectional observational analysis.

Background Anal symptoms may indicate serious pathology. Receptive anal intercourse (RAI) and sexually transmissible infections (STIs) may contribute to a higher prevalence of symptoms among gay and bisexual men (GBM). This study investigated associations with anal symptoms among GBM. METHODS: The Study of the Prevention of Anal Cancer was a longitudinal study of anal human papillomavirus and related lesions in Sydney, Australia. GBM aged ≥35 years were recruited from community settings between September 2010 and August 2015. Information about anal symptoms (discharge, itch, pain defecating, lump, bleeding, 'sores', tearing, tenesmus), STIs and sexual behaviours was collected. High-resolution anoscopy (HRA) and STI testing were performed. Logistic regression analyses on baseline data were performed to assess associations with each symptom. RESULTS: Among 616 participants (median age 49 years, 35.9% HIV positive), 35.3% reported at least one anal symptom within the past week and 65.3% were diagnosed with fistula, fissure, ulcer, warts, haemorrhoids and/or perianal dermatoses at HRA. Anal symptoms were not associated with anal chlamydia, gonorrhoea, warts or syphilis. Self-reported 'sores' were associated with previous anal herpes simplex virus (HSV; P < 0.001). 'Sores' (P < 0.001), itch (P = 0.019), discharge (P = 0.032) and lump (P = 0.028) were independently associated with ulceration. Among participants diagnosed with fissure, fistulae, haemorrhoids and perianal dermatoses, 61.9%, 100%, 62.0% and 63.9% respectively were asymptomatic. Only self-reported anal tear was independently associated with recent RAI. CONCLUSIONS: Previous anal HSV was the only STI associated with any symptom. Anal pathology was highly prevalent, but often asymptomatic. Anal symptoms do not appear to be useful markers of most anal pathology in GBM.

Detection of high-grade cervical disease among women referred directly to colposcopy after a positive HPV screening test varies with age and cytology findings.

Australia's new HPV-based cervical screening program is based on an algorithm that incorporates reflex cytology to guide decisions about further follow-up with colposcopy and, if indicated, biopsy. We reviewed results for 2300 women referred directly for colposcopy after their first positive HPV screening test, to determine the proportion that had underlying histological high-grade abnormality (HGA). Overall, HGA was detected in 24.3% of women. Among HPV16/18 positive women, 18.0% had HGA, increasing from 6.6% among women with negative cytology to 79.7% among women with high-grade squamous lesion or worse, or any glandular lesion on cytology (HSIL+; P-trend < .001). For this latter group, the proportion with HGA was higher among HPV16/18 positive women than among those positive for other oncogenic types (68.8%; P = .029). Among women with ASC-H cytology, 51.8% had HGA, with no difference between HPV groups (P = .314). In analyses by age-groups, detection of HGA was highest, at 36.4%, among women younger than 35 years, then decreased significantly to 5.9%, among women aged 65 to 74 years (P-trend < .001). The relationship of decreasing HGA detection with increasing age was strong for women with negative cytology, and those with ASC-H cytology (P-trend < .001 for each). For women with HSIL+ cytology, detection of HGA was high and stable, regardless of age (P-trend = .211). This report describes the first follow-up colposcopy findings in Australia's new HPV-based cervical screening program. The results demonstrate the additional value of reflex cytology in managing HPV positive women and suggest that further refinement of the risk-based algorithm to account for age may be warranted.

Psychological and utility-based quality of life impact of screening test results for anal precancerous lesions in gay and bisexual men: baseline findings from the Study of the Prevention of Anal Cancer.

OBJECTIVE: Gay, bisexual and other men who have sex with men (GBMSM), particularly HIV-positive GBMSM, are at increased anal cancer risk compared with the general population. This study examined the psychological and quality of life (QoL) impact of receiving abnormal anal cancer screening results during the baseline visit of the Study of the Prevention of Anal Cancer (SPANC). METHODS: SPANC was a prospective cohort study of the natural history of anal human papillomavirus (HPV) and associated abnormalities in GBM aged 35 years and over. Participants completed questionnaires including aspects of health-related QoL (HR-QoL) and psychosocial functioning at baseline. Participants underwent procedures including an anal swab for cytology, and high-resolution anoscopy with biopsy of any possibly HPV-related abnormality. Questionnaires were readministered 2 weeks and 3 months after participants were given cytology and histology results. Perceived test result served as the study factor. RESULTS: Participants with perceived abnormal results (n=232) reported poorer HR-QoL (mean difference=1.8; p=0.004) and lower utility-based QoL (mean difference=0.02; p=0.018) 2 weeks after screening than individuals with perceived normal results (n=268). These differences did not persist at 3-month follow-up. A greater proportion of participants who perceived their results as abnormal reported feeling worse than usual about their anal health and anal cancer fear (p's<0.001), experienced more intrusive thoughts about their results (p's≤0.006) and felt more likely to develop cancer than other gay men their age (p's≤0.025) at both time points than those with perceived normal results. CONCLUSIONS: Providing abnormal results may cause psychological distress and impact HR-QoL, with sustained intrusive thoughts, increased cancer worry and perceived cancer risk. The potential for psychological harm needs to be considered when implementing anal cancer screening programmes.

Prevalence, incidence and predictors of anal Chlamydia trachomatis, anal Neisseria gonorrhoeae and syphilis among older gay and bisexual men in the longitudinal Study for the Prevention of Anal Cancer (SPANC).

OBJECTIVES: Sexually transmitted infection (STI) notifications are increasing among older individuals. Many older gay and bisexual men (GBM) are sexually active and have multiple partners. We aimed to investigate the prevalence, incidence and predictors of anal chlamydia, anal gonorrhoea and syphilis in older GBM. METHODS: The Study for the Prevention of Anal Cancer (SPANC) was a prospective cohort study of HPV infections and related anal lesions among community-recruited GBM age ≥ 35 years in Sydney, Australia. At baseline and subsequent annual visits, recent STI diagnoses were collected via questionnaire ('interval diagnoses') and STI testing occurred ('study visit diagnoses'). Baseline STI prevalence was calculated using study visit diagnoses. Incidence of anal chlamydia and gonorrhoea was calculated using interval and study visit diagnoses. Syphilis incidence was calculated using interval diagnoses. Univariate and multivariate analysis using Cox proportional hazards were undertaken to investigate the association between risk factors and incident STI. RESULTS: Among 617 GBM, the median age was 49 years (range 35-79) and 35.8% (n=221) were HIV-positive. At baseline, STI prevalence was: anal chlamydia 2.3% (n=14); anal gonorrhoea 0.5% (n=3) and syphilis 1.0% (n=6). During 1428 person-years of follow-up (PYFU), the incidence (per 100 PYFU) of anal chlamydia, anal gonorrhoea and syphilis was 10.40 (95% CI 8.82 to 12.25), 9.11 (95% CI 7.64 to 10.85) and 5.47 (95% CI 4.38 to 6.84), respectively. In multivariate analysis, HIV-positivity, higher number of recent condomless receptive anal intercourse partners and baseline methamphetamine use were associated with each STI. Sex with 'fuck-buddies' was associated with anal chlamydia and gonorrhoea. Age was not associated with any STI. DISCUSSION: There was a high incidence of STI among SPANC participants. Age should not be used as a proxy for sexual risk and older GBM require a detailed sexual behaviour and recreational drug use history. Interventions that specifically target STI risk among older GBM should be considered.

Routine cervical screening by primary HPV testing: early findings in the renewed National Cervical Screening Program.

OBJECTIVES: To report human papillomavirus (HPV) testing patterns and rates of oncogenic HPV-positivity for specimens submitted during the first 6 months after the National Cervical Screening Program switched from cytology- to primary HPV-based screening. DESIGN, PARTICIPANTS: Retrospective cross-sectional review of 195 606 specimens submitted for HPV testing, 1 December 2017 - 31 May 2018. SETTING: Large community-based general pathology laboratory in metropolitan Sydney. MAIN OUTCOME MEASURES: Prevalence of oncogenic HPV types (all, HPV16/18, non-HPV16/18) by reason for HPV test (primary screening, non-screening); for oncogenic HPV-positive women in the age band recommended for primary HPV screening (25-74 years), prevalence of cytologic abnormality and rates of 12-month follow-up and colposcopy recommendations. RESULTS: 195 606 samples were received: 157 700 (80.6%) for primary screening, 37 906 (19.4%) for non-screening tests. Oncogenic HPV was detected in 8.1% of screening tests (95% CI, 7.9-8.2%) and 20.9% of non-screening tests (95% CI, 20.5-21.3%); 35.5% (95% CI, 34.7-36.4%) of women of recommended screening age with positive oncogenic HPV screening test results also had a cytologic abnormality. The proportion of HPV16/18-positive samples with high grade abnormality was 15.3% (95% CI, 14.2-16.6%); for samples positive for other oncogenic HPV types, the proportion was 6.3% (95% CI, 5.8-6.8%). Repeat HPV testing after 12 months was recommended for 5.4% (95% CI, 5.3-5.5%) and direct colposcopy for 2.6% (95% CI, 2.5-2.7%) of screened women aged 25-74 years. CONCLUSIONS: High grade cytologic abnormalities were more common in women positive for HPV16/18, supporting their higher risk classification. Colposcopy referral rates were higher than during primary cytology-based testing, as predicted by clinical trial and modelling data. The prevalence of HPV was much higher in non-screening than in primary screening samples. Our findings indicate the renewed program is performing as expected during the initial HPV screening round.

Endocervical adenocarcinoma in situ presenting in fundal endometrial polyp: the mother of all skip lesions.

A 38-yr-old woman, with a previous history of low grade squamous intraepithelial lesion in the cervix, presented with heavy menstrual bleeding. At hysteroscopy, a fundal polyp was removed from the right cornu which displayed many glands lined by atypical, mitotically active epithelium with features characteristic of endocervical adenocarcinoma in situ (AIS) of intestinal subtype. Subsequent cervical liquid-based cytology and colposcopically directed biopsies revealed no causative lesion, but residual PreservCyt from the ThinPrep vial tested positive for high risk HPV type other than HPV 16 and 18. Further biopsies from the endocervical canal and base of the resected polyp showed intestinal type AIS, while all those from the intervening anterior and posterior endometrial lining exhibited normal endometrium only. Genomic DNA extracted from the endometrial polyp and second set of endocervical biopsies tested positive for HPV 31, an uncommon cause of endocervical glandular neoplasia. Endocervical AIS typically arises in the transformation zone but may be found exclusively in the endocervical canal and rarely as high as 30 mm from the ectocervix. Contiguous spread into the lower uterine segment is known to occur, as are proximate so-called skip lesions. However, finding a 'skip' lesion 80 mm from the transformation zone poses an interesting pathogenetic conundrum as well as a therapeutic dilemma in a young patient desirous of retaining fertility. Issues relating to pathogenesis include necessary metaplasia of the endometrial glandular epithelium to 'susceptible' endocervical type epithelium within the polyp or metastatic implantation of transformed endocervical glandular cells onto the polyp. The current management plan involves regular hysteroscopic surveillance of the uterine cavity.

Screening for Anal Cancer in Women.

OBJECTIVE: The incidence of anal cancer is higher in women than men in the general population and has been increasing for several decades. Similar to cervical cancer, most anal cancers are associated with human papillomavirus (HPV), and it is believed that anal cancers are preceded by anal high-grade squamous intraepithelial lesions (HSIL). Our goals were to summarize the literature on anal cancer, HSIL, and HPV infection in women and to provide screening recommendations in women. METHODS: A group of experts convened by the American Society for Colposcopy and Cervical Pathology and the International Anal Neoplasia Society reviewed the literature on anal HPV infection, anal SIL, and anal cancer in women. RESULTS: Anal HPV infection is common in women but is relatively transient in most. The risk of anal HSIL and cancer varies considerably by risk group, with human immunodeficiency virus-infected women and those with a history of lower genital tract neoplasia at highest risk compared with the general population. CONCLUSIONS: While there are no data yet to demonstrate that identification and treatment of anal HSIL leads to reduced risk of anal cancer, women in groups at the highest risk should be queried for anal cancer symptoms and required to have digital anorectal examinations to detect anal cancers. Human immunodeficiency virus-infected women and women with lower genital tract neoplasia may be considered for screening with anal cytology with triage to treatment if HSIL is diagnosed. Healthy women with no known risk factors or anal cancer symptoms do not need to be routinely screened for anal cancer or anal HSIL.

Comprehensive Cardiovascular Risk Factor Control With a Mobile Health Cardiovascular Risk Self-Management Program.

BACKGROUND: Mobile health technology's impact on cardiovascular risk factor control is not fully understood. This study evaluates the association between interaction with a mobile health application and change in cardiovascular risk factors. METHODS AND RESULTS: Participants with hypertension with or without dyslipidemia enrolled in a workplace-deployed mobile health application-based cardiovascular risk self-management program between January 2018 and December 2022. Retrospective evaluation explored the influence of application engagement on change in blood pressure (BP), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and weight. Multiple regression analyses examined the influence of guideline-based, nonpharmacological lifestyle-based digital coaching on outcomes adjusting for confounders. Of 102 475 participants, 49.1% were women. Median age was 53 (interquartile range, 43-61) years, BP was 134 (interquartile range, 124-144)/84 (interquartile range, 78-91) mm Hg, TC was 183 (interquartile range, 155-212) mg/dL, LDL-C was 106 (82-131) mg/dL, and body mass index was 30 (26-35) kg/m2. At 2 years, participants with baseline systolic BP ≥140 mm Hg reduced systolic BP by 18.6 (SEM, 0.3) mm Hg. At follow up, participants with baseline TC ≥240 mg/dL reduced TC by 65.7 (SEM, 4.6) mg/dL, participants with baseline LDL-C≥160 mg/dL reduced LDL-C by 66.6 (SEM, 6.2) mg/dL, and participants with baseline body mass index ≥30 kg/m2 lost 12.0 (SEM, 0.3) pounds, or 5.1% of body weight. Interaction with digital coaching was associated with greater reduction in all outcomes. CONCLUSIONS: A mobile health application-based cardiovascular risk self-management program was associated with favorable reductions in BP, TC, LDL-C, and weight, highlighting the potential use of this technology in comprehensive cardiovascular risk factor control.

Anal and perianal squamous carcinomas and high-grade intraepithelial lesions exclusively associated with "low-risk" HPV genotypes 6 and 11.

Anal squamous cell carcinomas are predominantly associated with high-risk human papillomaviruses (HPVs), particularly HPV 16, similar to cervical, vaginal and vulvar cancers. Although the presence of "low-risk" HPVs, in particular genotypes 6 and 11, have occasionally been reported in various HPV-related anogenital cancers, the overall distribution of these genotypes in the anal canal and perianal tissue may differ to that in the cervix. In addition, although the majority of anal and perianal cancers are associated with HPV, some are not; hence, confirmation of direct association of the virus within a lesion is important. Using laser capture microdissection, anal and perianal invasive carcinomas and high-grade squamous intraepithelial lesions (HSILs) in biopsies previously associated with HPV 6 or 11 alone were isolated from tissue sections and HPV genotype tested. Of seven cases tested, four invasive carcinomas were positive for HPV 6 only, one invasive carcinoma was negative for HPV and two HSILs were positive for HPV 11 only. All samples were confirmed as HPV 16/18 negative using two different DNA targets (E6 and L1). From these results, we confirm that HPV 6 and 11 can occasionally be associated with high-grade lesion and anal cancer.

Anal cancer: a 20-year retrospective study from Australia.

BACKGROUNDS: Anal cancer is an uncommon condition, occurring at higher rates in specific subpopulations. Clinical experience is limited and substantial changes have recently occurred in our understanding of this condition. We, therefore, set out to characterize patients presenting with anal cancer and investigate whether there have been any changes over the past 20 years. METHODS: Retrospective audit of cases identified from pathology and clinical databases during the period 1 January 2000 to 31 December 2019. RESULTS: Two hundred and sixteen patients had anal squamous cell carcinomas, comprising 160 (74%) males and 56 (26%) females. Mean age at initial diagnosis was 55.1 ± 11.20 for males and 60.6 ± 15.18 for females (P = 0.02). At initial diagnosis, HIV-positive cases were significantly younger than HIV negative cases (mean 52.2 ± 9.35 vs. 62.8 ± 11.61, P < 0.001); 46% of cases were classified as intra-anal, 29% perianal and 25% both; 52% were > 2 cm at diagnosis. At presentation, intra-anal cases were larger and more advanced than perianal cases (P = 0.049). Compared with the period 2000-2009, anal cancers presented more commonly in 2010-2019 (148 vs. 76), were more likely to occur in HIV-negative people and to be diagnosed at a similar stage. CONCLUSION: The number of anal cancer cases almost doubled over the study period and people living with HIV presented 10 years younger than others. Perianal cases presented earlier than those originating in intra-anal locations. Together with the large size at diagnosis, this suggests the potential value of screening, particularly for intra-anal cancers in those at high risk.

Possible Reactivation of Latent Anal Human Papillomavirus Associated with Markers of Immune Dysfunction in Gay and Bisexual Men.

BACKGROUND: It is unknown whether reactivation of human papillomavirus (HPV) after latency occurs in the anus. We measured incidence and predictors of incident anal HPV in sexually inactive gay and bisexual men (GBM) as a surrogate of HPV reactivation. METHODS: The Study of the Prevention of Anal Cancer collected data on sexual behavior, anal cytology, HPV DNA, histology and HPV serology. HPV incidence during periods when zero sexual partners were reported in the last six months at both the current and previous annual visit ("no sexual activity") was analyzed by Cox regression using the Wei-Lin-Weissfeld method to determine univariable predictors. RESULTS: Of 617 men enrolled, 525 had results for ≥2 visits, of whom 58 (11%) had ≥ one period of "no sexual activity". During sexually inactive periods, there were 29 incident high risk HPV infections in 20 men, which occurred more commonly in older men (Ptrend = 0.010), HIV-positive men (HR = 3.12; 95% CI, 0.91-16.65), longer duration of HIV (Ptrend = 0.028), history of AIDS defining illness (P = 0.010), lower current (P = 0.010) and nadir CD4 count (P = 0.014). For 18 of 29 infections with available results, 12 men remained type-specific HRHPV L1 seronegative. None were consistently seropositive. A new diagnosis of HSIL occurred in only two men, caused by an HPV type other than the incident type. CONCLUSIONS: Our findings suggest that in sexually inactive GBM, anal HRHPV incidence is relatively common, and is associated with increasing age and immune dysfunction, a pattern consistent with HPV reactivation. IMPACT: Reactivation of anal HPV may occur.

Comparison of four assays for human papillomavirus detection in the anal canal.

OBJECTIVE: Anal cancer is preceded by high-risk human papillomavirus (HRHPV) infection, predominantly HPV16. No HPV assay is licenced for use in anal screening. We aimed to determine the sensitivity and specificity of four anal canal swab HPV assays to predict high-grade squamous epithelial lesions (HSIL). METHODS: In a cohort of Australian HIV-positive and negative gay and bisexual men, we compared the sensitivity and specificity of detection of 13 anal HRHPV genotypes by Linear Array (LA), Cobas 4800, EuroArray, and Anyplex II HPV28 (+ and ++ cut offs), compared their ability to predict prevalent anal HSIL, and compared anal canal HRHPV detection with HRHPV isolated from HSIL using laser capture microdissection (LCM). RESULTS: A total of 475 participants had baseline results available for all four assays (166, 35.0% HIV positive), and 169 participants had a diagnosis of cytological and/or histological HSIL. The HPV16 and any HRHPV detection were highest with Anyplex II HPV28 (+) (156, 32.8% 95% CI 28.6-37.2 and 359, 75.6%, 95% CI 71.5-79.4, respectively). For detection of concurrent HSIL and HPV16, the assay sensitivity was similar, ranging from 49.1%, 95% CI 41.4-56.9 (Anyplex II HPV28 ++) to 55.0%, 95% CI 47.2-62.7 (Anyplex II HPV28 +). For concurrent HSIL and any HRHPV detection, EuroArray was more specific than Anyplex II HPV28 (+) (45.9% 95% CI 40.2-51.7 vs 36.7%, 95% CI 31.3-42.4, p = 0.021) and had comparable specificity with Anyplex II HPV28 (++) (45.9% vs 47.2%, 95% CI 41.5-53.0, p = 0.75). All assays had high sensitivities for predicting HPV16 detected on LCM (92.5-97.5%). Anyplex II HPV28 and EuroArray were significantly more sensitive than LA for lesions caused by non-HPV16 HRHPV types on LCM. DISCUSSION: Anyplex II HPV28 and EuroArray detected more non-16 HRHPV genotypes than LA. Increasing the Anyplex II HPV28 cutoff improved specificity without compromising sensitivity for detection of concurrent HSIL.

Gene methylation of CADM1 and MAL identified as a biomarker of high grade anal intraepithelial neoplasia.

Human papillomavirus (HPV) is detected in up to 96% of anal squamous cell cancers, where screening programs needed. However, the best methodology is still undetermined. Host DNA methylation markers CADM1, MAL and miR124 have been identified in cervical disease, but not anal disease. Anal swabs varying by disease grade were assessed for DNA methylation of CADM1, MAL and miR124-2. Each marker was compared across disease grades, stratified by HPV and HIV status. Receiver operating characteristic curves identified the predictive value of significant gene candidates. CADM1 methylation was significantly higher in high-grade squamous intraepithelial lesions (HSIL) compared with low-grade (LSIL) (p = 0.005) or normal (p < 0.001) samples with 67.2% correctly identified as HSIL. MAL methylation was significantly (p = 0.002) increased in HSIL compared with LSIL in HIV positive participants with 79.8% correctly indicated as HSIL. Gene miR124-2, showed no difference between disease grades. Biomarkers with established diagnostic value in cervical disease have limited utility in the prediction of anal disease, with CADM1 identified as a marker with screening potential in a gay and bisexual men (GBM) population and MAL in HIV positive GBM population. New markers specific to the anal mucosa are required to improve triage of high-risk individuals.