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Last week, we asked how you would follow up on an anal Pap smear showing “atypical squamous cells of undetermined significance” (ASCUS) in an HIV-infected man who has sex with men. The case was chosen because it represents a common dilemma in HIV care, one with relatively few definitive data guiding practice and a wide range of practice patterns worldwide. About 20 readers responded, with most recommending high-resolution anoscopy (HRA) and biopsy — even though routine anal Pap smears are not formally recommended in the guidelines for HIV primary care or for preventing opportunistic infections. Now, two HIV specialists describe how they would manage this patient's care.
A 39-year-old HIV-infected man who has sex with men presents for routine care. He has been on tenofovir/FTC/efavirenz (Atripla) since his HIV diagnosis 2 years ago, when he had his first HIV test and was subsequently found to have a CD4 count of 140 cells/mm3. He tolerates this antiretroviral regimen well and maintains perfect adherence. At present, his CD4 count is 490 cells/mm3, his viral load is undetectable, and he has no symptoms of HIV disease. A rectal exam is normal, but an anal Pap smear comes back showing ASCUS.
What would you tell this patient about the significance of the Pap smear result? Would you repeat the test? If so, would you add human papillomavirus (HPV) testing, or do you do that on all anal Pap smears anyway? Is further evaluation — for example, HRA with biopsy — indicated? If so, would you refer the patient to someone else or do the examination yourself? If you refer, what is the specialty of the person doing the evaluation?
This case is an excellent example of the clinical axiom “Know what you're going to do with the results before you order the test.” HIV-infected men who have sex with men (MSM) are at increased risk for HPV infection, and MSM who are coinfected with HIV and HPV are at increased risk for anal dysplasia. The anal Pap smear is now a commonly used technique to screen for this condition. It is well accepted by patients and has been adopted by some providers and institutions as a standard of care. However, we have much to learn about the natural history of anal dysplasia, and the routine use of this test in clinical practice has not been demonstrated to reduce the morbidity and mortality associated with anal cancer. The presumed value of anal Pap smears has been extrapolated from experience with cervical Pap smears, which may or may not be an appropriate comparison.
We have a reasonable understanding of the anal Pap smear's performance. In general, dysplasia can be ruled out in patients with normal cytology results but not in patients with abnormal cells. High-grade dysplasia has been reported with all grades of abnormal cytology, even ASCUS (Clin Infect Dis 2004; 38:1490). For this reason, HRA, with biopsy of any suspicious areas, is generally recommended for all patients with abnormal cytology results on an anal Pap smear.
Before performing an anal Pap smear, I would tell the patient that we are still learning about its optimal role in care, but that any abnormal results will necessitate anoscopy with possible biopsy. In this particular case, I am not sure that a normal result on a repeat test, whether performed immediately or a few months later, would change my approach. Although recent data suggest that a negative HPV DNA test would be reassuring (AIDS 2010; 24:1307), I do not think we know enough about its role in this particular setting to use it for clinical decision making. At our institution, I would refer this patient to the multidisciplinary Dysplasia Clinic, which includes infectious disease, oncology, and surgical staff and has an established protocol for evaluating abnormal anal Pap smears.
Although there is no direct evidence to indicate that use of anal Pap screening reduces morbidity and mortality, the parallels between anal and cervical cancer are hard to ignore. HPV infection causes both diseases, and HIV infection increases risk for both. Routine cervical Pap smears reduce the risk for cervical cancer and associated mortality, so it's not unreasonable to assume that anal Pap testing has similar benefits.
In talking with this patient about his results, I would reassure him that his Pap test shows the lowest grade of abnormality, that anal dysplasia is common in HIV-infected MSM, and that most men with dysplasia will not go on to develop anal cancer.
Our official protocol is to recommend HRA and biopsy for all patients with abnormal Pap smear results. At our institution, HRA was originally performed by an HIV-focused dermatologist. After he left, it was performed by one of our gynecologists. Now, we send patients to a colorectal surgeon in the community who is trained in this procedure. However, I have been bending the rules in patients with ASCUS and monitoring them with yearly Pap smears rather than referring them for HRA. I do this with the understanding that the Pap smear provides an imprecise measurement of the true grade of dysplasia and that those with ASCUS could have higher grades on biopsy. However, I have to weigh that risk with the fact that my patients don't enjoy going through HRA, biopsy, and ablation, that the parallels between anal and cervical dysplasia aren't perfect, and that the protocols around anal Pap smear are written without much evidence backing them up.
I do recommend that patients with low- or high-grade dysplasia undergo HRA and biopsy of abnormal areas. If those biopsies come back showing high-grade dysplasia (anal intraepithelial neoplasia 2 or 3), ablation is performed. Following ablation, our practice has been to resume yearly Pap smears, this time referring for repeat HRA only if cytology results indicate high-grade dysplasia. The logic of this approach has never been clear to me — if the initial pre-HRA Pap smear can miss high-grade dysplasia, then so can the post-HRA one — but my patients aren't eager to undergo the process a second time without the words “high-grade” to motivate them, so I don't argue the point.
Since I began doing routine anal Pap testing about 8 years ago, two of my patients have been diagnosed with anal cancer. The first had refused anal Pap testing year after year but was eventually diagnosed after a mass was discovered during a rectal examination. The second had a concerning mass on a digital exam; a biopsy showed invasive anal cancer, but the anal Pap smear performed on the same day came back normal. Clearly, this test is not perfect, and our protocols for screening are not as data-driven as we'd like them to be. Still, it makes sense to apply the lessons learned from cervical cancer, a similar disease caused by the same pathogen and for which a similar prevention strategy saves lives.