Study Of The Prevention Of Anal Cancer Research Articles

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.

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

ObjectiveGay, 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...

Association of anal symptoms with anal high grade squamous intraepithelial lesions (HSIL) among men who have sex with men: Baseline data from the study of the prevention of anal cancer (SPANC)

BackgroundThe association between anal high-grade squamous intraepithelial lesion (HSIL) and anal symptoms has not been systematically investigated. MethodsThe Study of Prevention of Anal Cancer is a prospective cohort study of men who have sex with men (MSM) ≥ 35 years old in Sydney, Australia. Self-reported symptoms were collected. Anal cytology and high-resolution anoscopy were undertaken. Using baseline visit data, men negative for squamous intra-epithelial lesion (SIL) were compared with men diagnosed with composite-HSIL (cytology and/or histology). Logistic regression analyses were performed to assess the association of symptoms with HSIL. ResultsAmong 414 MSM included (composite-HSIL (n = 231); negative for SIL (n = 183)), 306 (73.9%) reported symptom(s) within the last 6 months. There was no association between any symptom and composite-HSIL. A significant association between anal lump and a larger burden of HSIL (at least 2 intra-anal octants) (anal lump within last month: p = 0.014; anal lump within last 6 months: p = 0.010) became non-significant after adjusting for HIV-status and recent anal warts (anal lump within last month: p = 0.057; anal lump within last 6 months: p = 0.182). ConclusionsAmong MSM age 35 years and older, most anal symptoms are not a useful marker of anal HSIL.

30 - Correlation between HPV16 positivity on anal swab and biopsy-confirmed HSIL caused by HPV16 in the study of the prevention of anal cancer (SPANC)

Background The majority of anal carcinomas are caused by human papillomavirus (HPV) 16. Identifying which of the high-grade squamous intraepithelial lesions (HSIL) are caused by HPV16 may enable targeted management of those most likely to progress. Methods In a natural history study of anal HPV-related lesions in gay and bisexual men, HPV typing of all baseline histologic HSIL was performed utilizing laser capture microdissection (LCM). The results were compared with HPV types detected by Cobas 4800 in matched anal swabs. We calculated the performance of Cobas testing in identifying HSIL caused by HPV16. Results 158 men had both lesion and swab genotyping. Overall 54 men (34%) had HPV16 identified as the causal genotype of at least one HSIL by LCM. 51 of these had HPV16 detected on their anal swabs (sensitivity of 94%). Of the 104 men with non-HPV16 HSIL biopsies, 73 had swabs negative for HPV16 (specificity of 70%). 51 of 82 men with swabs positive for HPV16 had HPV16 positive biopsies (positive predictive value - 62%). 73 of 76 men without HPV16 detected on their swabs had only non-HPV16 HSIL biopsies (negative predictive value (NPV) - 96%). Conclusions In men with prevalent histologic HSIL, Cobas testing of a concurrent anal swab has high sensitivity for detecting those with HPV16-associated HSIL and a high NPV. HPV testing with the Cobas platform may have a role in the identification and management of those with HSIL caused by HPV16 and who are at highest risk of development of anal carcinoma.

Prevalence and predictors of unsatisfactory anal cytology tests in a cohort of gay and bisexual men in Sydney, Australia: baseline findings from the Study of the Prevention of Anal Cancer (SPANC).

Anal cytology has been suggested as a screening test for the anal cancer precursor high-grade squamous intraepithelial lesion (HSIL). We aimed to assess the prevalence and predictors of initial unsatisfactory anal cytology tests ('unsats'). The Study of the Prevention of Anal Cancer is a natural history study of anal human papillomavirus (HPV) and precancerous lesions among gay and bisexual men (GBM) of at least 35 years in Sydney, Australia. At each study visit, an anal swab is collected for cytological testing. Unsats are defined as slides with fewer than 2000 nucleated squamous cells and no abnormal cells. Among 617 GBM enrolled, the median age was 49 (range: 35-79) years and 220 (35.7%) were HIV positive. Initial unsats occurred in 61 (9.9%, 95% confidence interval: 7.6-12.5%), and 29 (4.7%, 95% confidence interval: 3.2-6.7%) remained unsatisfactory on repeat cytology. Initial unsats were associated with fewer lifetime anal-receptive partners with a condom (P=0.007); fewer recent anal-receptive sexual partners without a condom (P=0.005); never having had anal chlamydia (P=0.023) or gonorrhea (P=0.003); HIV-negative status (P=0.002); fewer total (P=0.002), low-risk (P=0.005), and high-risk (P=0.015) HPV types detected; lack of anal HPV18 detection (P=0.001); never having anally douched (P<0.001); and douching with soapy water (P=0.009) among those who douched. Unsats were less common among those with histologic HSIL (P=0.008) and nonsignificantly less common among those with fewer anal canal octants affected by HSIL (P=0.080), but were more common among those who felt more nervous (P=0.020) during the examination. Our findings suggest that unsats are more common among GBM with less receptive anal sexual experience. Avoiding douching with soapy water and strategies to aid patient relaxation during sampling may reduce the unsat rate.

Vaccine-preventable anal human papillomavirus in Australian gay and bisexual men

ObjectiveHPV causes ~90% of anal cancer and HPV16 is the type most commonly associated with anal cancer. Gay and bisexual men (GBM) are at greatly increased risk. We investigated patterns of vaccine-preventable anal HPV in older GBM. MethodsThe Study of the Prevention of Anal Cancer (SPANC) is an ongoing, prospective cohort study of HIV-positive and HIV-negative Australian GBM. Participants completed questionnaires and underwent an anal swab for HPV genotyping using Roche Linear Array. We analysed baseline data from SPANC by HPV type, mean number of types, stratified by age and HIV status. ResultsAnal HPV results from 606 (98.2%) of 617 participants (median age 49 years, 35.7% HIV-positive) showed 525 (86.7%) had ≥1 HPV type and 178 (29.4%) had HPV16. Over one third of participants (214, 35.3%) had no nonavalent vaccine-preventable types detected. Two (0.3%) participants had all quadrivalent types and none had all nonavalent vaccine types. HIV-positive participants (p<0.001) and younger participants (p=0.059) were more likely to have more vaccine-preventable HPV types detected. ConclusionAnal HPV was highly prevalent in this largely community-based GBM cohort. Vaccine-preventable HPV16 was detected in approximately one third of participants. These findings suggest that the potential efficacy of HPV vaccination of older GBM should be explored.

The performance of anal cytology as a screening test for anal HSILs in homosexual men.

Studies regarding the performance of anal cytology in which both the screening test (cytology) and the diagnostic test (high-resolution anoscopy [HRA]) are performed in all members of a screening population are rare. The authors evaluated the performance of liquid-based anal cytology in a cohort of homosexual men in Sydney, New South Wales, Australia. The Study of the Prevention of Anal Cancer (SPANC) is a 3-year prospective study of the natural history of anal human papillomavirus infection in homosexual men aged ≥35 years. At baseline, all participants underwent a liquid-based anal cytology test and HRA at the same clinical visit. Biopsies were obtained for histological assessment if lesions suspicious for human papillomavirus infection were visible during HRA. Using any cytological abnormality as the threshold, the sensitivity, specificity, and positive and negative predictive values were calculated against histologically diagnosed high-grade squamous intraepithelial lesions (HSILs). Among 617 men recruited, the median age was 49 years (range, 35-79 years) and 35.7% were positive for the human immunodeficiency virus. Overall, the sensitivity of cytology was 83.2%, the specificity was 52.6%, the positive predictive value was 45.8%, and the negative predictive value was 86.7%. Specificity improved with increasing age (P for trend =.041). Sensitivity was significantly higher in men with >1 anal octant of biopsy-confirmed HSIL (92.9% vs 77.7%; P = .010), and in those who had ≥10 metaplastic cells present on their cytology slides (87.5% vs 70.2%; P = .007). Anal cytology was found to have a higher specificity in older men while maintaining sensitivity. Sensitivity was higher among those with more extensive HSILs and men with metaplastic cells present on cytology. Cancer Cytopathol 2016;124:415-24. © 2016 American Cancer Society.

S17.4 Using data on pathogenesis and epidemiology to inform anal cancer screening strategies: data from the study of prevention of anal cancer (spanc)

Background HPV vaccination of school-aged boys will prevent anal cancer in future generations. Vaccination of gay men up to age 26 is recommended in several jurisdictions, but vaccination is generally not recommended at older ages because of a concern of possible lack of efficacy due to past or current HPV infection. Anal cancer screening, based on the model of cervical cancer screening, has also been proposed as a means to reduce morbidity. Methods The Study of the Prevention of Anal Cancer (SPANC) is a three-year prospective study of the natural history of anal HPV infection and cancer precursors in HIV-negative and -positive gay men aged ≥35 years. At each visit all men receive an anal swab for cytology and HPV genotyping, followed by high resolution anoscopy-directed biopsy for histological assessment. Results At the end of June 2015, 595 men had been enrolled. Median age was 49 and 35.3% were HIV-positive. Men of all ages enrolled in SPANC were likely to report multiple sexual partners in the past 6 months (overall 73.4% of 35–44 year olds decreasing to 62.1% of 65+ year olds, p trend = 0.03). The prevalence of HPV16, the genotype responsible for >90% of anal cancer, was 29.4% in 35–44, 30.8% in 45–54, 34.2% in 55–64 and 19.0% in 65+ year olds (p trend = 0.54), with no difference by HIV status. The incidence of HPV16 decreased with age from 5.6/100 person years (PY) in 35–44 year olds to 2.9/100PY in 55–64 year olds. There was no incident HPV16 in men aged 65+ (p trend = 0.059). At baseline, the prevalence of anal high grade intraepithelial neoplasia (HSIL) was higher in HIV-positive than in the HIV-negative participants (46.9% vs 32.3%, p Conclusions Gay men in SPANC reported multiple sexual partners across the adult age-range, and incident HPV16 continued to be detected in men up to their seventh decade of life. This suggests that HPV vaccination of adult gay men may prevent infection and have a role in cancer prevention. Anal HSIL is highly prevalent, particularly among HIV-positive men, but there are high rates of clearance without treatment. These data suggest that a screening test which can distinguish persistent from transient HSIL is required. The role of HPV biomarkers in identifying those HSIL lesions most likely to persist should be investigated.

P10.10 T-cells in the anal mucosa of men with high-grade squamous intraepithelial lesions

Introduction The host cellular immune response plays an integral role in controlling human papilloma virus (HPV)-induced precancerous lesions. Anal mucosal cellular immune responses have not been previously studied. Methods The Study of the Prevention of Anal Cancer (SPANC) is a longitudinal natural history study of anal HPV infection in men ≥35 years who have sex with men. 26 participants with anal, high-grade (grade 2 or 3) squamous intraepithelial lesions (HSIL) at study entry had 44 anal biopsies. Lymphoid aggregates in these biopsies were detected by inspection of haematoxylin and eosin-stained sections. Additional sections were immunofluorescently stained to enumerate submucosal and intra-epithelial CD4 + and CD8 + T-cell counts. Whole slide imaging to reveal full tissue architecture at high resolution (x600) was used. Student’s t-test of log 10 -transformed T-cell density was used to compare means; a generalised, linear model was used to determine factors associated with total T-cell density (biopsy-based analysis with intra-subject adjustment). Results Of 26 men with mean age 53 years [standard deviation (SD) 10.5], 7 (27%) were HIV-infected and 17 (68%) had concurrent anal HPV16 in anal swabs. Of 44 biopsies, 26 (59%) revealed HSIL and 24 (55%) had lymphoid aggregates localised in the submucosa adjacent to the epithelium. Presence of lymphoid aggregates was associated with higher CD4 + T-cell density (mean 192 vs. 69 cells/mm 2 , P + T-cell density (106 vs. 62 cells/mm 2 , P = 0.077). A biopsy diagnosed with HSIL was significantly associated with higher total T-cell density [odds ratio (OR) 11.80, 95% confidence interval (CI) 1.51 – 92.08, P = 0.02], as was having anal HPV16 detected (OR 14.08, 95% CI 1.15 – 172.71, P = 0.04). Presence of low-risk HPV genotype (s) was not associated (OR 1.37, 95% CI 0.12 – 15.14, P = 0.80). Conclusion CD4 + T-cell enriched lymphoid aggregates in the anal mucosa were associated with anal HSIL and HPV 16. Disclosure of interest statement Winnie Tong and Jennifer Roberts declare no conflicts of interest. This work was supported by the St Vincent’s Clinic Foundation K&A Collins Cancer Grant 2014. The SPANC study is funded by the National Health and Medical Research Council Program (grant 568971) and the Cancer Council New South Wales Strategic Research Partnership (grant SRP13–11).

High reproducibility of histological diagnosis of human papillomavirus-related intraepithelial lesions of the anal canal

In a natural history study of anal human papillomavirus (HPV) infection and HPV-related lesions, we examined the reproducibility of histological high-grade squamous intraepithelial lesion (HSIL). Three expert anogenital pathologists share the reporting of histological specimens from the Study of the Prevention of Anal Cancer (SPANC), utilising Lower Anogenital Squamous Terminology (LAST) criteria. In total, 194 previously reported biopsies were randomly chosen within diagnostic strata [50 HSIL-anal intraepithelial neoplasia (AIN) 3; 45 HSIL-AIN 2; 49 'flat' low-grade squamous intraepithelial lesion (LSIL); 50 'exophytic' LSIL; and 50 negative for squamous intraepithelial lesion] and reviewed by each of these three pathologists. Consensus was defined as agreement between at least two review diagnoses, using a binary classification of HSIL and non-HSIL, or if consensus was not obtained in this way, it was achieved through a multiheader microscope session by the three pathologists. We found very high agreement between original and consensus diagnoses (Kappa = 0.886) and between each pathologist's review and consensus (Kappas = 0.926, 0.917 and 0.905). Intra-observer agreement for the three pathologists was 0.705, 1.000 and 0.854. This high level of diagnostic reproducibility indicates that the findings of SPANC should be robust and provide reliable information about HPV-related anal canal disease.

The Study of the Prevention of Anal Cancer (SPANC): design and methods of a three-year prospective cohort study

BackgroundThe incidence of human papillomavirus (HPV)-associated anal cancer is increasing in men who have sex with men (MSM). Screening for the presumed cancer precursor, high-grade anal squamous intraepithelial lesions (HSIL) in a manner analogous to cervical cancer screening has been proposed. Uncertainty remains regarding anal HPV natural history and the role of anal cytology and high-resolution anoscopy (HRA) as screening tests. Well-designed cohort studies are required to address these issues.Methods/designThe SPANC study is a prospective study of the epidemiology of low-risk and high-risk anal HPV infection and related cytological and histological abnormalities in HIV-negative and HIV-positive homosexual men aged 35 years and over. The study aims to recruit 600 men from community-based settings in Sydney, Australia. There are six study visits over three years. At the first five visits men undergo a digital ano-rectal examination (DARE), an anal “Papanicolaou” (Pap) test for HPV detection, genotyping and anal cytology, followed by HRA and directed biopsy of any visible abnormalities. The men also complete a behavioural questionnaire before each visit. Questions include a detailed history of sexual behaviour, of anal symptoms, possible anal cancer risk factors and validated quality of life and psychosocial questions. Questionnaires are also completed 2 weeks and 3 months following the provision of test results and include questions on participant experience during the procedure and post-procedure symptoms, including pain and bleeding in addition to quality of life/ psychosocial outcomes.DiscussionRecruitment for the study began in September 2010 and will conclude in mid-2015, with follow up continuing to 2018. Thus far, over 350 men have been recruited from a variety of community-based settings and are broadly representative of the target screening population. The SPANC study is one of only a small number of cohort studies globally to perform HPV, cytology and HRA screening on all participants over multiple time points. The study results will contribute to understanding of the natural history of anal HPV and inform the possible development of guidelines for implementing anal cancer screening programs in this population.

35. Accuracy of anal cytology in predicting histological HSIL: baseline results from the Australian Study of the Prevention of Anal Cancer (SPANC)

Background Anal cytology may form the basis of a future screening program to prevent anal carcinoma. Therefore, the accuracy of anal Papanicolaou tests in detecting histological HSIL needs to be evaluated. Methods: SPANC is a 3-year prospective study in homosexual men aged ≥35 years. At each of five visits, men undergo collection of a ThinPrep® anal cytological sample, high-resolution anoscopy (HRA) and biopsy of any abnormalities. Cytology is reported using the Bethesda system. Histology is reported using lower anogenital squamous terminology. Results: 351 men had a baseline visit by end July 2013. Median age was 49 (range: 35–79) years and 101 (28.8%) men were HIV positive. Anal cytology results were: unsatisfactory in 21 (6.0%), negative in 143 (40.7%), ASC-US in 51 (14.5%), LSIL in 22 (6.3%), ASC-H in 45 (12.8%) and HSIL in 69 (19.7%). 293 of 351 (83.5%) men had baseline histology. The most severe abnormality for each was: negative for SIL in 98 (33.4%), LSIL in 87 (29.7%) and HSIL in 108 (36.9%). Anal cytology sensitivity for histological HSIL (at ASC-US threshold) was 79.0%. Specificity was 53.8%. Positive predictive value (PPV) of any cytological abnormality for histological HSIL was 44.4% and PPV of HSIL cytoprediction was 63.8%. Negative predictive value (NPV) was 84.6%. Overall there was no significant difference between HIV positive and negative men with respect to sensitivity, specificity, PPV or NPV. Conclusions: These results indicate that histological HSIL is common in homosexual men. The finding of any cytological abnormality should prompt HRA. However, both cytology and HRA can miss or underestimate significant lesions in a single screening.

14. Natural history of high-grade squamous intraepithelial lesions (HSIL) in homosexual men: early evidence from the Study of the Prevention of Anal Cancer (SPANC)

Background Screening for the anal cancer precursor HSIL is not recommended in national guidelines. A recent Cochrane review of HSIL treatment concluded there is no evidence of efficacy. In this context, we aimed to describe the natural history of anal HSIL, and association with human papillomavirus (HPV), in a community-recruited cohort of Australian homosexual men. Methods: The SPANC study is a three-year prospective study in men aged ≥35 years. At each visit, men undergo an anal swab for cytology and HPV genotyping (Roche Linear Array), followed by high-resolution anoscopy-aided biopsy. Anal HSIL is defined as having either anal intraepithelial neoplasia grade 2/3 on histology and/or HSIL/ASC-H on cytology. Results: Among 342 men recruited by March 2013, median age was 49 with 29% HIV positive. At baseline, prevalence of anal HSIL was 50% and 44% in the HIV-positive and HIV-negative groups, respectively (P = 0.303). Among those without HSIL at baseline, HSIL incidence was 28/100 person-years in both the HIV-positive and HIV-negative groups (P = 0.920). Among those with HSIL at baseline, the incidence of change to non-HSIL was 41 and 43/100 person-years (P = 0.851). Men with anal HPV16 at baseline were more likely to develop incident HSIL (57 vs 23/100 person-years, P = 0.010), and less likely to change to non-HSIL (18 vs 61/100 person-years, P = 0.001). Conclusions: Anal HSIL was highly prevalent in these homosexual men. Both incidence of HSIL and change to non-HSIL were common, and were closely associated with HPV16 status. HPV16 positivity may identify men with HSIL at higher risk of anal cancer.