The evaluation of the feasibility and clinical utility of liquid based cytology, human papillomavirus testing and high-resolution anoscopy to screen for anal intraepithelial neoplasia in high-risk groups. Dr Alice Martha Schofield: The University of Manchester for the degree of Doctor of Medicine, January 2016. Background: The increased incidence and natural history of anal cancer in high-risk groups, provides a screening opportunity to detect precancerous lesions, anal intraepithelial neoplasia (AIN), as well as early invasive lesions. The ANALOGY study was performed to strengthen the evidence base required to determine the case for anal screening in terms of the feasibility and clinical utility of liquid based cytology (LBC), high-risk human papillomavirus (HR-HPV) testing and high-resolution anoscopy (HRA) in high-risk groups.Methods: This prospective study offered screening to four cohorts aged over 25 at varying but elevated risk; human immunodeficiency virus (HIV) positive and negative men who have sex with men (MSM), HIV positive women with prior history of abnormal cervical cytology or anogenital warts, HIV negative women who practice anoreceptive sex and transplant recipients (TR). Recruitment commenced in March 2013 and concluded in December 2014, with follow-up until March 2015. All participants underwent testing for HR-HPV, LBC and had HRA performed, sites of abnormality were biopsied. Participants were seen at initial consultation and at a second visit six months later. Immunostaining with Ki67 and p16 antibody was performed on 100 anal tissue biopsies. The cellular positivity of each biomarker were scored by automated and manual methods. H-SCORES of p16 biomarker and block positive staining of AIN2 were quantified and analysed.Results: 409 participants were recruited; 284 MSM (203 HIV positive, 81 HIV negative), nine HIV positive women, four HIV negative women and 112 TR. HR-HPV was highly prevalent in anal samples from MSM (HIV positive 88.0% and HIV negative, 77.8%) and much less so in HIV positive and negative women and TR (19.3%). Despite the high prevalence of cytological abnormality in MSM, almost half of AIN of all grades was associated with negative cytology. AIN3+ on biopsy was found in 4.4% (18/409) of participants; three HIV positive MSM had cancer. One new case of AIN3 was identified at the second visit. Low-grade disease (AIN1/2) was highly prevalent in all groups. Ki67 and p16 biomarker expression increase as the grade of anal disease increased when scored manually. AIN2 histology samples, which demonstrate block positive p16 staining, have an association with an increased H-SCORE.Conclusions: Anal screening in some high-risk groups is clinically feasible in terms of diagnostics with evidence of significant disease prevalence particularly amongst MSM. The high prevalence of HR-HPV infection and frequency of false negative cytology indicates that in terms of sensitivity and specificity, HRA would be the best primary screening tool. The use of Ki67 and p16 in the identification of anal disease appears to have clinical utility, especially in the detection of AIN2; with the majority of samples displaying block p16 staining that corresponded with an increased H-SCORE. The prevalence of AIN3+ in HIV positive MSM lends support for a policy of screening in this group, however limitations of treatment, as well as highly prevalent low-grade lesions of dubious significance, require careful consideration.
|Date of Award||1 Aug 2016|
- The University of Manchester
|Supervisor||Henry Kitchener (Supervisor) & Emma Crosbie (Supervisor)|
- Transplant Recipients
- Anal Cancer, Screening, MSM, HIV positive