The role of cytology (Pap tests) and human papillomavirus testing in anal cancer screening

Salit, Irving Ea,b; Lytwyn, Alicec,d; Raboud, Janeta,b; Sano, Mariea; Chong, Sylviad; Diong, Christinaa; Chapman, Williame; Mahony, James Bf,d; Tinmouth, Jilla,b,g

doi: 10.1097/QAD.0b013e328339e592
Clinical Science

Objective: To assess anal oncogenic human papillomavirus (HPV) and anal cytology as screening tests for detecting high-grade anal intraepithelial neoplasia (AIN 2+), as this is an immediate anal cancer precursor.

Design: Cross-sectional study of 401 HIV-positive men who have sex with men (MSM). The endpoint was histologically confirmed AIN 2+ obtained by high-resolution anoscopy. Cytology and biopsy specimens were assigned random numbers and independently assessed by two pathologists.

Methods: We did concomitant anal cytology, anal HPV testing and HRA with directed biopsies without knowing the results of each intervention. The main outcome measures were the sensitivity, specificity, negative predictive value and positive predictive value of anal cytology and oncogenic HPV for the detection of AIN 2+.

Results: Cytology was abnormal in 67% of patients: high-grade squamous intraepithelial lesion, 12%; low-grade squamous intraepithelial lesion, 43% and atypical squamous cells of undetermined significance, 12%. Biopsies were abnormal in 68% of patients: AIN 2+, 25% and AIN 1, 43%. HPV was detected in 93% with multiple HPV types in 92% and oncogenic HPV types in 88%. Test performance characteristics for the detection of AIN 2+ using any abnormality on anal cytology were: sensitivity 84%, specificity 39%, negative predictive value 88% and positive predictive value 31%; using oncogenic HPV: sensitivity 100%, specificity 16%, negative predictive value 100% and positive predictive value 28%.

Conclusion: Anal cytology and HPV detection have high sensitivity but low specificity for detecting AIN 2+. HIV-positive men who have sex with men have a high prevalence of AIN 2+ and require high-resolution anoscopy for optimal detection of high-grade anal dysplasia.

Author Information

aUniversity Health Network, Toronto General Hospital, Canada

bUniversity of Toronto, Toronto, Canada

cHenderson Hospital, Canada

dMcMaster University, Hamilton, Canada

eSt. Joseph's Hospital, Toronto, Canada

fSt. Joseph's Healthcare, Hamilton, Canada

gSunnybrook Medical Centre, Toronto, Ontario, Canada.

Received 30 November, 2009

Revised 7 February, 2010

Accepted 17 February, 2010

Correspondence to Irving E. Salit, MD, University Health Network, Toronto General Hospital, 200 Elizabeth Street, Eaton 13N-215, Toronto, ON M5G 2C4, Canada. E-mail:

Article Outline
Back to Top | Article Outline


Squamous cell anal cancer is infrequent but has been increasing in the general population; currently, the rate is approximately one per 100 000 [1]. It occurs at much higher rates in HIV-positive men who have sex with men (MSM) (approximately 60–160/100 000) [2–5] and in other immunocompromised persons such as transplantation recipients [6]. Rates of anal cancer among HIV-infected MSM are comparable to rates of cervical cancer in women prior to the initiation of routine screening for cervical dysplasia [7]. Combination antiretroviral therapy (cART) has markedly reduced HIV-related opportunistic infections and mortality [8] but malignancies are now a major cause of morbidity in HIV-infected individuals [9]; these include AIDS-defining malignancies such as non-Hodgkin lymphoma and non-AIDS-defining malignancies such as anal cancer [2,4,10].

Anal cancer shares features with cervical cancer. Both are human papillomavirus (HPV)-associated squamous cell cancers, which occur at a squamocolumnar transition zone [11,12], and both are believed to arise from precancerous dysplastic lesions, which are nearly identical histologically [13,14]. These precancerous changes can be detected by cytologic sampling using Papanicolaou smears and by colposcopy or the analogous procedure in the anal canal, high-resolution anoscopy (HRA) with directed biopsy [14,15].

The use of these methods to detect cervical cancer and its precursors has been studied extensively [16] and are well recognized by healthcare practitioners. Although less well known, these methodologies have also been applied to the anus [17–20]. In high-risk populations, such as HIV-infected MSM, screening to prevent anal cancer may be warranted. However large, well designed, methodologically sound studies are required in order to determine the optimal screening strategy. In the current study, we investigate the test characteristics of anal cytology and HPV testing for the detection of histologically confirmed high-grade anal intraepithelial neoplasia (AIN 2+), as this is an immediate anal cancer precursor that likely requires treatment.

Back to Top | Article Outline


Study design

In this cross-sectional study, anal cytology, HPV testing and HRA were performed at the initial visit. In addition, participants completed a questionnaire on demographics, symptoms and risk behaviors at this visit. The test characteristics of anal cytology, HPV testing for the detection of AIN 2+ at HRA or both were determined using the data from the initial visit.

This study is registered at #NCT00188292.

Back to Top | Article Outline

Participants were part of the Toronto Research for Anal Cancer Evaluation (TRACE) anal cancer screening study [20] and were enrolled between December 2001 and November 2005. All were HIV-infected men aged 18 years or more with a history of anal receptive intercourse and who were attending tertiary care hospital HIV clinics or primary care clinics in Toronto, Canada. Patients were excluded if they had a history of anal cancer. At entry, none of the participants had known previous anal cytologic studies or anal biopsies, so no prior results were available to us. The presence or absence of any symptoms, including anal symptoms, did not affect eligibility.

Back to Top | Article Outline
Screening studies

At the initial visit, participants had concomitant anal cytology (Pap smears), HPV testing and HRA with directed biopsies. Additional visits, examinations and treatments were arranged for participants who had high-grade histologic or cytologic abnormalities. Two anoscopists (I.E.S. and J.T.) had received formal training in HRA and they examined all the participants. The biopsies were processed in a routine manner and three deeper levels were cut from each paraffin-embedded specimen. Evaluation of anal cytology and detection of oncogenic HPV by Hybrid Capture 2 Assay (Digene Corporation, Gaithersburg, Maryland, USA) was performed on a specimen that was collected by vigorously rotating a Dacron-tipped swab in the anal canal and that was then placed in liquid-based ThinPrep (Cytyc, Boxborough, Massachusetts, USA). The results from the Hybrid Capture 2 Assay were used to determine the test characteristics of HPV detection. Another anal swab was tested for HPV genotypes using the Linear Array HPV Genotyping Test (Roche Diagnostics, Indianapolis, Indiana, USA).

Cytology and biopsy specimens were assigned computer-generated random numbers and were independently assessed by two gynecologic pathologists (A.L. and W.C.) each with over 20 years of pathology experience. The pathologists were masked to each other's interpretations, to the corresponding cytology specimen of the biopsy being examined, to the corresponding histology of the cytology being examined and to clinical and other laboratory information. After all specimens were reported, the pathologists met at a multiheaded microscope and reached consensus on any specimen for which there had not been agreement in the independent review.

The cytology was classified according to the modified Bethesda system for cervical cytology [21]. Biopsies were classified as normal, AIN 1, AIN 2/3 or invasive carcinoma. Perianal lesions were excluded from the analysis.

HRA was done using a plastic anoscope with visualization of the anal squamocolumnar junction using 6–15× magnification after sequential mucosal staining with 3% acetic and Lugol's iodine [15]. Biopsies were taken by endoscopic forceps from areas that appeared abnormal [15]. Abnormal areas were those that were acetowhite, had abnormal-looking vessels or were Lugol's negative.

Demographic characteristics, symptoms in the previous 12 months, risk behaviors and duration of HIV (number of years since the first positive antibody test) were obtained from the questionnaire, which was completed by each participant without assistance from study personnel. The most recent CD4 cell count, viral load and previous medical history including current antiretroviral regimen were obtained from the participant's clinical record.

Back to Top | Article Outline

Demographic characteristics were summarized for the study population using frequency and percentage for categorical variables and median and interquartile range for continuous variables. We calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of cytology and presence of oncogenic HPV on Hybrid Capture testing to detect histologically confirmed AIN 2+ on a per patient basis. If the anal canal at HRA appeared normal, no biopsy was taken and the anal canal for that patient was designated as ‘Normal’. If biopsies were taken, patient status was designated by the consensus diagnosis of the most severe histologic lesion in that patient.

Back to Top | Article Outline
Sample size

The predetermined primary outcome was the sensitivity of any anal cytologic abnormality to detect histologically confirmed intraanal AIN 2, AIN 3 or invasive squamous cell carcinoma (AIN 2+). The cytologic test was defined as positive if at least atypical squamous cells of undetermined significance (ASCUS) was present, that is, if either ASCUS, low-grade squamous intraepithelial lesion (LSIL) or high-grade squamous intraepithelial lesion (HSIL) was present. On the basis of this primary outcome and assuming a sensitivity of 70%, we estimated that we would need a sample size of 100 patients with AIN 2+ to be able to determine the sensitivity with a 95% confidence interval (CI) of ±10%. As the prevalence of AIN 2+ was estimated to be 25% in this population, we planned to enroll 400 patients in order to obtain 100 patients with AIN 2+.

Back to Top | Article Outline

The study was approved by the Research Ethics Board of the University Health Network and was carried out in accordance with the Declaration of Helsinki of 1975, as revised in 1983.

Back to Top | Article Outline



We enrolled 401 patients. The median age was 44 years with a median CD4 cell count of 390 cells/μl, median viral load less than 50 copies/ml, 76% were on cART and they had been HIV positive for a median of 14.0 years. Only 31.0% had an AIDS-defining illness and 18.0% had a CD4 cell count of less than 200 cells/μl. Ninety-two percent reported at least one gastrointestinal symptom, most commonly mild bowel irregularity or blood noted on wiping (Table 1).

Back to Top | Article Outline
Prevalence of human papillomavirus, cytologic or histologic abnormalities

At their initial visit, all patients had anal cytology, HPV testing and anal biopsy if indicated by the HRA appearance. Cytology was abnormal in 67% of patients: HSIL, 12%; LSIL, 43% and ASCUS, 12% (Table 2). The biopsies from the first visit were abnormal in 68% of patients and the worst grade of lesion was AIN 2+, 25% and AIN 1, 43%. No invasive cancers were initially identified. In order to assess whether there might have been a learning effect whereby the anoscopists would have detected more AIN 2+ later in the study, we examined that trend over time. The rate of AIN 2+ detection was 25 per 100 (25%) for the first 100 patients and 73 per 301 (24%) for the remaining patients.

HPV was detected in 93% of patients with multiple HPV types in 92%. Oncogenic HPV types were found in 352 of 400 (88%): HPV 16 (38%), HPV 18 (20%), HPV 31(16%), HPV 33 (15%), HPV 53 (20%), HPV 52 (18%), HPV 68 (12%) and HPV 56 (12%).

Back to Top | Article Outline
Test characteristics of oncogenic human papillomavirus and cytology at the initial visit

Using a threshold for abnormal of at least ASCUS (≥ASCUS), abnormal cytology detected histologically confirmed intraanal AIN 2+ with a high sensitivity but with low specificity (Table 3). Using this definition, abnormal cytology failed to detect only 16 of 98 (16%) AIN 2+, whereas 186 of 268 (69%) of abnormal cytologic results were not associated with AIN 2+. If abnormal cytology was defined as HSIL, the sensitivity of cytology dropped, whereas the specificity markedly increased. HSIL on cytology missed 77 of 98 (79%) of histologic AIN 2+, whereas 26 of 47 (55%) of cytologic HSIL results were unassociated with presence of AIN 2+ histologically. Furthermore, the test characteristics of abnormal anal cytology did not differ if we excluded the first 100 patients (data not shown). As these rates did not differ, we used the data for the whole group in all analyses.

All patients with AIN 2+ were positive for oncogenic HPV; conversely, none of the patients who were negative for oncogenic HPV had AIN 2+. If we used a combination of any abnormal cytology and oncogenic HPV as a predictor of AIN 2+, there was minimal improvement in the test characteristics compared with using the cytology alone (sensitivity 84 vs. 84% and specificity 43 vs. 39%).

Forty-nine men had anal cytology which showed ASCUS and 42 (86%) of them were test positive for oncogenic HPV. Nine men with ASCUS cytology had biopsy-proven AIN 2+, and all nine were oncogenic HPV positive. Therefore, in patients with ASCUS on cytology, oncogenic HPV testing had a sensitivity of 100% (95% CI 70–100) and a specificity of 17.5% (95% CI 8.7–32.0) for high-grade AIN.

Back to Top | Article Outline


In the current study, we have analyzed anal cytology (Pap testing) and HPV detection in MSM as screening methods for detection of high-grade intraepithelial neoplasia (AIN 2+), as these lesions are most likely to lead to anal cancer and treatment of these lesions may potentially prevent cancer. We found a high prevalence (24%) of histologic AIN 2+ in our high-risk population at initial screening. However, anal cytology only showed HSIL in 12%, suggesting that it is an insensitive test (if done once) for detection of high-grade histologic disease. High-risk (oncogenic) HPV types were present in almost 90% of our patients; as most of the patients denied recent sexual activity, many of these are likely long-standing persistent infections. Persistent oncogenic cervical HPV infection is a strong risk factor for the occurrence of high-grade cervical intraepithelial neoplasia (CIN) and progression to invasive cancer [22] and this situation is likely similar for anal cancer in MSM.

Anal cancer rates are increasing in the general population in both men and women and rates are particularly high in HIV-positive MSM [1–5] likely due to exposure to HPV through multiple partners [5] and prolonged immune deficiency, which permits persistence of HPV. In the era of cART, survival in persons with HIV has dramatically improved, as deaths from opportunistic infections and AIDS-defining malignancies are markedly diminished [8]. Despite its undisputed efficacy in preventing many HIV-related complications, there is mounting evidence that cART not only fails to protect against anal precancers and cancers [2–4,23,24] but also that the incidence of anal cancer is increasing [1,3,25,26]. Because of this increasing burden of anal cancer, there is an urgent need to find effective ways of screening to prevent anal cancer in HIV-infected MSM.

In immunocompetent persons, high-grade anal dysplasia progresses to invasive malignancy in an important proportion of cases (14% over a period of 8 years) [13]. In anal and cervical cancers, precancerous lesions appear to transition through similar cellular stages that can be detected by anal or cervical cytology (Pap tests) or biopsy. Although there are no randomized controlled trials to support screening to prevent cervical cancer, ecological studies have shown that cervical Pap testing and colposcopy with treatment of abnormalities has been associated with a marked reduction in cervical cancer [16] and countries without effective screening have high rates of cervical cancer [27].

HIV-positive MSM have a high prevalence of anal dysplasia (AIN) and it seems likely that these lesions are anal cancer precursors. Given the strong parallels with cervical cancer, it would seem intuitive that detection and removal of these high-grade anal lesions (AIN 2+), particularly in HIV-infected MSM, might reduce anal cancer rates even though this is unproven. In HIV-uninfected persons, anal cancer detection at an earlier stage improves survival [28,29] so early cancer detection in HIV-infected patients may also be beneficial [30,31]. Anal cancer screening seemed to prolong quality-adjusted life expectancy as demonstrated in a state-transition Markov model and it should be done every 12–24 months depending on the prevalence of anal dysplasia [32]. Even though a number of centers do screen for anal cancer and precancer in high-risk MSM, the optimal methods and strategies are uncertain.

Potential screening tests in MSM such as anal cytology or anal HPV detection are simple to do, much cheaper, less time-consuming and require less expertise than HRA. Cervical Pap testing for women, at the threshold of ASCUS or greater to detect CIN 2 or greater, only has a sensitivity of 50% [33] but it is a simple strategy that can be done repeatedly and it has been responsible for the dramatic decrease in cervical cancer incidence [34]. The incremental benefit of repeated anal Pap testing in HIV-positive MSM is not known.

Cervical oncogenic HPV detection in women is more sensitive but may be less specific than cervical Pap testing for detecting CIN 2/3 [35]. In our population, we found similar test characteristics for anal oncogenic HPV testing in MSM. Although the absence of oncogenic HPV completely predicted that AIN 2+ was not present (NPV = 100%), the usefulness of this test is limited because of the extremely high prevalence of oncogenic HPV infection in this population.

In women who show cervical ASCUS cytology on Pap smear, oncogenic HPV testing is helpful to identify those who should undergo colposcopic examination [36]. We found that among HIV-positive MSM, testing for anal oncogenic HPV in those with ASCUS had very low specificity for detection of AIN 2+; HPV testing in this context is unlikely to be useful, as the HPV prevalence is so high. Indeed, in women, cervical oncogenic HPV testing is also not recommended when cytology shows LSIL, as the HPV prevalence in these women is also over 80% [36].

In the current study, anal Pap testing using ASCUS as the threshold was sensitive in detecting AIN 2+ but there were so many abnormal Pap tests that only a small number were excluded from requiring HRA. If we used HSIL as a threshold to predict AIN 2+, specificity was increased but substantial numbers of men with histological AIN 2+ were missed as a result of the very poor sensitivity of the Pap test. Because of the high prevalence of AIN 2+ in HIV-positive MSM and because of the suboptimal test characteristics of one-time cytological and HPV testing, it can be argued that HRA should be a first-line screening strategy in this high-risk population; however, anal cytology may provide complementary information [37]. Clinicians interested in screening their HIV-positive MSM must also take costs, availability of local expertise in doing HRA and the willingness of patients to have this procedure into consideration when selecting a screening strategy.

The strengths of the current study are: we could effectively compare liquid-based anal cytology, HPV detection and HRA, as these were done simultaneously on all patients and the results reported independently to avoid bias; histologically proven AIN 2+ was used as the reference standard; over 400 patients were enrolled and followed prospectively and cytologic and histologic results were independently assessed by two pathologists. We focused on AIN 2+ detection because CIN 2+ constitutes the threshold for treatment in the cervix [38].

The implementation of anal cancer screening programs is hampered by the lack of data from randomized control trials. Nevertheless, the data presented here on the detection of AIN will be useful in evaluating the utility of early anal cancer screening in HIV-positive MSM. Future studies should focus on treatment and the effectiveness of screening in the prevention of anal cancer, including the cost-effectiveness, in other high-risk groups such as women with previous gynecologic malignancy and transplant recipients.

Back to Top | Article Outline


Ontario HIV Treatment Network (grant #ROGB184) and the Canadian Cancer Society (grant #18164) funded the capital costs, research assistant and operating costs. J.S. was supported by a Career Scientist Award from the Ontario HIV Treatment Network.

I.S. and J.T. did all the anoscopic examinations; M.S. organized the anal cancer screening treatments and database; A.L. and W.C. assessed all the pathology specimens; J.R. and C.D. did statistical analyses; J.B.M. and S.C. performed HPV analyses; study conception and design was done by I.S., A.L., J.R., J.B.M., W.C. and J.T.

There are no conflicts of interest.

Back to Top | Article Outline


1. Chiao EY, Krown SE, Stier EA, Schrag D. A population-based analysis of temporal trends in the incidence of squamous anal canal cancer in relation to the HIV epidemic. J Acquir Immune Defic Syndr 2005; 40:451–455.
2. Silverberg MJ, Chao C, Leyden WA, Xu L, Tang B, Horberg MA, et al. HIV infection and the risk of cancers with and without a known infectious cause. AIDS 2009; 23:2337–2345.
3. Crum-Cianflone NF, Hullsiek KH, Marconi VC, Ganesan A, Weintrob A, Barthel RV, et al. Anal cancers among HIV-infected persons: HAART is not slowing rising incidence. AIDS 2010; 24:535–543.
4. van Leeuwen MT, Vajdic CM, Middleton MG, McDonald AM, Law M, Kaldor JM, Grulich AE. Continued declines in some but not all HIV-associated cancers in Australia after widespread use of antiretroviral therapy. AIDS 2009; 23:2183–2190.
5. D'Souza G, Wiley DJ, Li X, Chmiel JS, Margolick JB, Cranston RD, et al. Incidence and epidemiology of anal cancer in the multicenter AIDS cohort study. J Acquir Immune Defic Syndr 2008; 48:491–499.
6. Patel HS, Silver AR, Northover JM, Patel HS, Silver ARJ, Northover JMA. Anal cancer in renal transplant patients. Int J Colorectal Dis 2007; 22:1–5.
7. Qualters JR, Lee NC, Smith RA, Aubert RE. Breast and cervical cancer surveillance, United States, 1973–1987. MMWR Surveill Summ 1992; 41:1–15.
8. Walensky RP, Paltiel AD, Losina E, Mercincavage LM, Schackman BR, Sax PE, et al. The survival benefits of AIDS treatment in the United States. J Infect Dis 2006; 194:11–19.
9. Grulich AE. Update: cancer risk in persons with HIV/AIDS in the era of combination antiretroviral therapy. AIDS Read 2000; 10:341–346.
10. Silverberg MJ, Neuhaus J, Bower M, Gey D, Hatzakis A, Henry K, et al. Risk of cancers during interrupted antiretroviral therapy in the SMART study. AIDS 2007; 21:1957–1963.
11. De Ruiter A, Mindel A. Anal intraepithelial neoplasia. Eur J Cancer 1991; 27:1343–1345.
12. Bjorge T, Engeland A, Luostarinen T, Mork J, Gislefoss RE, Jellum E, et al. Human papillomavirus infection as a risk factor for anal and perianal skin cancer in a prospective study. Br J Cancer 2002; 87:61–64.
13. Watson AJM, Smith BB, Whitehead MR, Sykes PH, Frizelle FA. Malignant progression of anal intra-epithelial neoplasia. ANZ J Surgery 2006; 76:715–717.
14. Palefsky JM, Holly EA, Hogeboom CJ, Ralston ML, DaCosta MM, Botts R, et al. Virologic, immunologic, and clinical parameters in the incidence and progression of anal squamous intraepithelial lesions in HIV positive and HIV negative homosexual men. J Acquir Immune Defic Syndr 1998; 17:314–319.
15. Jay N, Berry JM, Hogeboom CJ, Holly EA, Darragh TM, Palefsky JM. Colposcopic appearance of anal squamous intraepithelial lesions: relationship to histopathology. Dis Colon Rectum 1997; 40:919–928.
16. Quinn M, Babb P, Jones J, Allen E. Effect of screening on incidence of and mortality from cancer of cervix in England: evaluation based on routinely collected statistics. BMJ 1999; 318:904–908.
17. Chin-Hong PV, Berry JM, Cheng S-C, Catania JA, Da Costa M, Darragh TM, et al. Comparison of patient- and clinician-collected anal cytology samples to screen for human papillomavirus-associated anal intraepithelial neoplasia in men who have sex with men. Ann Intern Med 2008; 149:300–306.
18. Chiao EY, Giordano TP, Palefsky JM, Tyring S, El Serag H. Screening HIV-infected individuals for anal cancer precursor lesions: a systematic review. Clin Infect Dis 2006; 43:223–233.
19. Lytwyn A, Salit I, Raboud J, Chapman W, Darragh T, Winkler B, et al. Interobserver agreement in the interpretation of anal intraepithelial neoplasia. Cancer 2005; 103:1447–1456.
20. Salit IE, Tinmouth J, Chong S, Raboud J, Diong C, Su D, et al. Screening for HIV-associated anal cancer: correlation of HPV genotypes, p16, and E6 transcripts with anal pathology. Cancer Epidemiol Biomarkers Prev 2009; 18:1986–1992.
21. Solomon D, Davey D, Kurman R, Moriarty A, O'Connor D, Prey M, et al. The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA 2002; 287:2114–2119.
22. Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S. Human papillomavirus and cervical cancer. Lancet 2007; 370:890–907.
23. Palefsky JM, Holly EA, Ralston ML, Da Costa M, Bonner H, Jay N, et al. Effect of highly active antiretroviral therapy on the natural history of anal squamous intraepithelial lesions and anal human papillomavirus infection. J Acquir Immune Defic Syndr 2001; 28:422–428.
24. Palefsky JM, Holly EA, Efirdc JT, Da Costa M, Jay N, Berry JM, et al. Anal intraepithelial neoplasia in the highly active antiretroviral therapy era among HIV-positive men who have sex with men. AIDS 2005; 19:1407–1414.
25. Piketty C, Selinger-Leneman H, Grabar S, Duvivier C, Bonmarchand M, Abramowitz L, Costagliola D, et al. Marked increase in the incidence of invasive anal cancer among HIV-infected patients despite treatment with combination antiretroviral therapy. AIDS 2008; 22:1203–1211.
26. Hessol NA, Pipkin S, Schwarcz S, Cress RD, Bacchetti P, Scheer S. The impact of highly active antiretroviral therapy on non-AIDS-defining cancers among adults with AIDS. Am J Epidemiol 2007; 165:1143–1153.
27. Gakidou E, Nordhagen S, Obermeyer Z. Coverage of cervical cancer screening in 57 countries: low average levels and large inequalities. PLoS Med 2008; 5:e132.
28. Goldman S, Auer G, Erhardt K, Seligson U. Prognostic significance of clinical stage, histologic grade, and nuclear DNA content in squamous- cell carcinoma of the anus. Dis Colon Rectum 1987; 30:444–448.
29. John M, Flam M, Palma N. Ten-year results of chemoradiation for anal cancer: focus on late morbidity. Int J Radiat Oncol Biol Phys 1996; 34:65–69.
30. Edelman S, Johnstone PA, Edelman S, Johnstone PAS. Combined modality therapy for HIV-infected patients with squamous cell carcinoma of the anus: outcomes and toxicities. Int J Radiat Oncol Biol Phys 2006; 66:206–211.
31. Chiao EY, Giordano TP, Richardson P, El-Serag HB, et al. Human immunodeficiency virus-associated squamous cell cancer of the anus: epidemiology and outcomes in the highly active antiretroviral therapy era. J Clin Oncol 2008; 26:474–479.
32. Goldie SJ, Kuntz KM, Weinstein MC, Freedberg KA, Welton ML, Palefsky JM, et al. The clinical effectiveness and cost-effectiveness of screening for anal squamous intraepithelial lesions in homosexual and bisexual HIV-positive men. JAMA 1999; 281:1822–1829.
33. Cuzick J, Clavel C, Petry KU, Meijer CJ, Hoyer H, Ratnam S, et al. Overview of the European and North American studies on HPV testing in primary cervical cancer screening. Int J Cancer 2006; 119:1095–1101.
34. Miller AB, Chamberlain J, Day NE, Hakama M, Prorok PC. Report on a workshop of the UICC project on evaluation of screening for cancer. Int J Cancer 1990; 46:761–769.
35. Arbyn M, Sasieni P, Meijer CJ, Clavel C, Koliopoulos G, Dillner J. Clinical applications of HPV testing: a summary of meta-analyses. Vaccine 2006; 24 (Suppl 3):S3/78–S3/89.
36. The ASCUS-LSIL Triage Study (ALTS) Group. Results of a randomized trial on management of cytology interpretations of atypical squamous cells of undetermined significance. Am J Obstet Gynecol 2003; 188:1383–1392.
37. Nahas CSR, da Silva F, Edesio V, Segurado AAC, Genevcius RFF, Gerhard R, et al. Screening anal dysplasia in HIV-infected patients: is there an agreement between anal Pap smear and high-resolution anoscopy-guided biopsy? Dis Colon Rectum 2009; 52:1854–1860.
38. Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D, et al. 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ. Am J Obstet Gynecol 2007; 197:340–345.

anal cancer; anoscopy; cancer screening; HIV; human papillomavirus

© 2010 Lippincott Williams & Wilkins, Inc.