Existing algorithms to screen for anal cancer in women living with HIV could be missing many cases of anal high-grade squamous intraepithelial lesions (HSIL) – abnormal tissue changes that may be a precursor to invasive anal cancer – according to a study reported at the recent Conference on Retroviruses and Opportunistic Infections (CROI 2015) in Seattle, USA.
In addition, even though the likelihood of a diagnosis of anal HSIL, or high-grade anal dysplasia, by anal tissue examination increased with the degree of abnormality found on anal cytology (anal Pap testing), HSIL diagnoses were made even for women who had less severe abnormalities in their anal Pap tests according to Fanny Ita-Nagy of Mt. Sinai Icahn School of Medicine, who presented the study findings.
The overall incidence of anal cancer in the US is approximately 1.8 per 100,000 person-years and has been increasing. However, HIV infection increases the risk of anal cancer in both men and women. The incidence of anal cancer among women living with HIV is at least ten times higher than among HIV-negative women, and rates as high as 30 per 100,000 person-years have been reported – similar to the high incidence of cervical cancer seen before the implementation of cervical cytology screening, or routine Pap tests, in the 1950s.
The vast majority of anal cancer, like cervical cancer, is caused by high-risk strains of human papillomavirus (HPV). Studies have shown that people with HIV are more likely to carry high-risk strains and less likely to clear HPV spontaneously. Further, anal HPV infection and dysplasia (abnormal tissue changes) may be more prevalent or persistent in the anus than in the cervix.
Despite the risk, there is no consensus on the best screening algorithms for anal HSIL in women living with HIV. Currently there are two sets of screening guidelines in the US:
- The New York State Department of Health/AIDS Institute 2007 guidelines, which recommend anal cytology screening for three groups: HIV-positive men who have sex with men, women with HIV who have abnormal cervical or vulvar histology, and any HIV-positive person with a history of anogenital warts or condylomata (caused by different types of HPV);
- The HIV Medicine Association of IDSA (HIVMA) 2013 guidelines, which include all of the above criteria and add women with HIV who have a history of receptive anal intercourse.
However, since 2009 Mt. Sinai Medical Center – which provides care to over 3000 people living with HIV, 29% of whom are women – has been offering anal cytology screening to all patients with HIV regardless of previous HPV-associated disease or perceived risk factors. Whenever anyone has abnormal anal cytology, they are referred for high-resolution anoscopy – which includes biopsy of any abnormal tissue found – for diagnosis (performed by a single provider).
The resulting data set provided Ita-Nagy and colleagues with an opportunity to assess the prevalence and associated risk factors for anal HSIL in women living with HIV over the five-year period since the implementation of the screening programme.
A total of 877 women with HIV received anal cytology screening. Of these, 484 (55%) were found to have abnormal anal cytology, defined as having atypical squamous cells of undetermined significance (ASCUS) or a higher degree of abnormality.
Of the women with abnormal cytology, 290 (60%) subsequently underwent anoscopy. Among these women, the mean age was 47 years, the mean CD4 cell count was 572 cells/mm3 and 66% had undetectable HIV viral load. A majority (71%) also had abnormal cervical cytology, 37% had a history of anogenital warts and 66% reported a history of anal sex; 40% were current smokers, 26% were former smokers and 33% had never smoked.
Of the 290 women with anoscopy results, 34.5% had benign findings (either a normal anoscopy or benign histology findings), 38.3% had low-grade squamous intraepithelial lesions (LSIL or mild dysplasia) and 27.2% had HSIL or high-grade dysplasia on biopsies.
As noted, the greater the degree of abnormality on the cytology test, the more likely that HSIL would be found by anoscopy. However, HSIL diagnosis was made by anoscopy even in some women with lower degrees of abnormality on anal cytology.
For instance, 175 women were categorised as having ASCUS (the lowest degree of abnormality on cytology), but anoscopy found that 19% of them had anal HSIL and one was found to have invasive squamous cell carcinoma.
In a univariate analysis, women with a history of anal sex were more likely to have high-grade anal dysplasia (unadjusted odds ratio 1.83, or 83% greater risk); age was a critical factor as well, since cancers are more common in older people. However, in an analysis that adjusted first for age and then for multiple other factors, the only risk factor that was significantly associated with high-grade anal dysplasia was being either a current or former smoker (adjusted odds ratio 1.93, or nearly double the risk).
Looking at the performance of the screening algorithms, 19% of women with abnormal cytology tests would not have met the screening criteria of the New York State Department of Health/AIDS Institute guidelines – of whom 26% were diagnosed with high-grade dysplasia on biopsy (including the one case of invasive anal carcinoma). Likewise, 7% would not have met the HIVMA guidelines criteria, of whom 20% were diagnosed with high-grade dysplasia.
"Screening for anal dysplasia in all HIV-infected women regardless of previous HPV-associated disease or perceived risk factors may be appropriate given the increased risk of anal cancer in this population," concluded Ita-Nagy.
During the following discussion, an audience member suggested that the algorithms might perform better if they included a history of smoking.
A more serious question is whether detection and early treatment of HSIL actually prevents subsequent invasive anal cancer or improves outcomes – particularly because there is a risk of HSIL recurring. One of Ita-Nagy’s colleagues from Mt. Sinai noted that none of the women who had received treatment after high-grade dysplasia was detected in their programme had gone on to develop invasive anal cancer, but that the final answer could only come from a randomised clinical trial.
Fortunately, Joel Palefsky of the University of California at San Francisco and colleagues are currently conducting a multicentre study called ANCHOR that will evaluate the effectiveness of immediate treatment and close follow-up of HIV-positive people with HSIL versus deferring treatment and repeating anoscopy every six months until progression to cancer is detected.