Stanley et al. BMC Cancer 2012, 12:398 http://www.biomedcentral.com/1471-2407/12/398 anus and perianus after application of 3-5% acetic acid. However, in comparison to the number of cervical col- poscopists, there are currently far fewer trained experts in HRA and this partly explains why there is even less data published on the prevalence of HGAIN in the gen- eral population. Since there are no recommendations for screening, many patients are either diagnosed serendipit- ously during surgery for benign anal conditions or occa- sionally during colonoscopy or if they present with anal symptoms [25,26]. High grade intra-epithelial neoplasia at all ano-genital sites (anus, cervix, vagina, vulva, penis) is likely to be a precursor to invasive cancer at that site but the potential for progression is best documented in the cervix as a consequence of a large unethical study in which, during the period 1955–1976, definitive treatment of CIN 3 was withheld from a substantial cohort of New Zealand women. The cumulative incidence of cancer of the cer- vix or vaginal vault in this cohort was 31.3% at 30 years as compared with 0.7% receiving adequate treatment [27]. Clearly such a study cannot be duplicated at other sites but progression of AIN to anal SCC has been assessed in small studies with surveillance and treat- ment, but with a relatively short follow up of 5–10 years. Two studies conducted on HIV-negative cohorts stand out. Scholefield’s group [28] has published on a cohort of 35 HIV-negative patients (26 women and 9 men) with AIN 3 and followed up for a median duration of 63 months (range 14 – 120 months). The median age was 43 (range 31 – 62 years). Three of these 35 patients (8.5%) developed invasive carcinoma at the sites of pre- vious AIN 3 disease and all three were systemically im- munosuppressed from long term oral therapy. The authors suggest that immunosuppressed patients (6 in this study – all from long term oral therapy, such as cor- ticosteroids, for various conditions) and those with multifocal AIN (7 in this study) are at higher risk of ma- lignant transformation. This rate of malignant conver- sion is not too dissimilar to that seen in VIN 3 conversion to vulvar cancer (~9% over 5 years) [29]. Another important study has reported on a cohort of 72 patients with AIN, followed for a median of 60 months (range 18–112 months) and with a median age of 49 years (range 18 – 81 years) [30]. 8 patients progressed to invasive SCC, 2 from AIN 2 (10 patients) and 6 from AIN 3 (45 patients). Not one of 17 patients with AIN 1 progressed to cancer during the follow-up period. Twenty-five patients downgraded their lesions. The authors suggest that since 13% of their AIN 3 patients converted to cancer during the follow-up period, it is necessary to keep all AIN 3 under close sur- veillance. However, the data from these 2 small studies show that even with surveillance and treatment, on aver- age 9-13% AIN 3 may progress to invasive disease over Page 3 of 4 5–10 years, comparable to that observed for progression of CIN 3 over similar time periods. However, a recent meta-analysis has indicated that progression rates from HGAIN to anal cancer are ap- proximately one in 600 per year in HIV-positive MSM and one in 4000 per year in HIV-negative MSM patients [31], substantially lower than the one in 80 per year observed in comparable cervical disease [27]. One pos- sible explanation for this discrepancy is that these esti- mates were based on multiple cross-sectional studies and pooled prevalence rates of HGAIN and anal cancer incidence rates, rather than prospective follow-up stud- ies. However, it cannot be excluded that HGAIN might regress more often than CIN 3, perhaps being partially attributable to the fact that HGAIN encompasses both AIN 2 and AIN 3, with AIN 2 probably containing a mixture of HG and LG HPV types. Summary There are strong supportive data for the contention that HGAIN is a precursor lesion to invasive anal carcinoma. However, there are limited data on the prevalence of HGAIN in the general population. There are also some data giving estimates of the natural progression of AIN into invasive cancer over different follow-up periods. Fi- nally, there are current and very recent studies on anal HPV infection in traditionally non-high risk groups con- tinuing to emerge, which help to avoid mere extrapola- tion of data from high-risk groups into the general community. There is now a need for multi-centre pro- spective studies on progression of AIN 3 to cancer and on the effectiveness of treatment to reduce the incidence of anal cancer. Abbreviations HPV: human papillomavirus; HIV: human immunodeficiency virus; CIN: cervical intra-epithelial neoplasia; AIN: anal intra-epithelial neoplasia; MSM: men who have sex with men; VIN: vulvar intraepithelial neoplasia; OR: odds ratio; RR: relative risk; SCC: squamous cell carcinoma. Competing interests MAS acts as consultant to Sanofi Pasteur-MSD, Lyon, France and MAS and PKCG have previously received an educational grant from Sanofi-Pasteur MSD. MAS also acts as consultant to Merck Research Laboratories, Westpoint, USA, and GSK Biologicals, Rixensart, Belgium. This work was supported by grants from the British Skin Foundation (ref: 806), Addenbrooke’s Charities Trust (ref: 25/09CB) and Cancer Research UK (ref: C26262/A8633) to PKCG. Authors’ contributions All authors contributed significantly to the work and have seen and approved the final content of the article. Received: 18 January 2012 Accepted: 1 August 2012 Published: 8 September 2012 References 1. Parkin DM, Bray F: Chapter 2: The burden of HPV-related cancers. Vaccine 2006, 24:11. 2. Abbas A, Yang G, Fakih M: Management of anal cancer in 2010. Part 1: Overview, screening, and diagnosis. Oncology 2010, 24:364–369.