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The anal Pap test as a screening tool- EDITORIAL
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AIDS:
28 January 2010 - Volume 24 - Issue 3 - p 463-465
Pantanowitz, Liron; Dezube, Bruce J
aDepartment of Pathology, Baystate Medical Center, Tufts University School of Medicine, Springfield, USA
bDepartment of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Correspondence to Liron Pantanowitz, MD, Department of Pathology, Baystate
Medical Center, 759 Chestnut Street, Springfield, MA 01199, USA. Tel: +1 413 794 4195; fax: +1 413 794 3195; e-mail: Liron.pantanowitz@baystatehealth.org
"Although the sensitivity of abnormal cytology to detect HSIL in HIV-positive men has similarly been shown by others to be higher compared with HIV-negative MSM [17], overall anal Pap tests in the HIV-positive population are still an inaccurate predictor of high-grade anal dysplasia on biopsy.
The goal of screening is to detect anal dysplasia early and eradicate AIN, thereby preventing the progression of such lesions to invasive squamous cell carcinoma. The optimum use of HPV testing, and alternative screening methods such as direct visualization or 'optical biopsy' of the anal mucosa (e.g. akin to digital cervicography and speculoscopy), in this setting has yet to be defined. Fortunately, treatment options for anal dysplasia and anal cancer in HIV-infected individuals are expanding, which may lead to decreased morbidity and mortality. Expertise in treating such patients is important to optimize outcomes for patients [18]. Additional studies are needed, including investigations looking at the impact of HPV vaccination on anogenital HPV infection."
The incidence of anal cancer has been rising, with a notable predilection for high-risk groups such as men who have sex with men (MSM) and those individuals infected with HIV. In fact, anal cancer associated with human papilloma virus (HPV) infection has become one of the most common non-AIDS-defining cancers in HIV-infected individuals [1]. The incidence of precursor lesions, called anal intraepithelial neoplasia (AIN), is also markedly increased in HIV-positive men [2], despite the introduction of highly active antiretroviral therapy (HAART) [3]. Current evidence indicates that premalignant high-grade anal squamous lesions can progress to invasive anal carcinoma over time. Therefore, using cervical cancer prevention as a paradigm, anal cytology has been recommended as a primary screening tool for anal dysplasia in at-risk HIV positive men [4].
With the widespread use of anal cytology, an appeal has been made for standardization in cytologic and surgical pathology reporting of anal disease [5]. Currently, different terminology systems are being used for reporting the spectrum of cytological abnormalities in epithelial cells of the anal canal. In the United States, a two-tiered (Bethesda) system has been advocated to report dysplastic anal cytology findings; viz. low-grade squamous intraepithelial lesion (LSIL) and high-grade SIL (HSIL) [6]. In this edition of AIDS, Nathan et al. [7] follow the terminology proposed by the British Society for Clinical Cytology (BSCC), which is closely aligned with the Bethesda system. Indeed, the authors acknowledge that variability in reporting of anal pathology may hinder valuable comparison of findings between groups.
It is recommended that individuals with abnormal cytology diagnosed on an anal Papanicolaou (Pap) test should undergo high-resolution anoscopy (HRA) to identify, biopsy and if feasible treat dysplastic lesions [8]. HRA is somewhat analogous to colposcopy of the cervix. Squamous dysplasia (AIN) of the anal canal diagnosed on histopathologic grounds is considered to represent the gold standard for diagnosis. AIN can be divided into three grades based upon progressively severe cytologic atypia and the level of involvement of the squamous mucosa by dysplastic cells: AIN I (mild dysplasia), AIN II (moderate dysplasia) and AIN III [severe dysplasia or carcinoma in situ (CIS)] [9]. AIN I is considered a low-grade squamous lesion (LGAIN), whereas AIN II and AIN III are considered high-grade squamous lesions (HGAIN). Like the Bethesda system used for reporting anal cytology, a two-tiered system (LGAIN and HGAIN) offers better interobserver reproducibility [5].
The question of whether anal Pap tests are beneficial remains to be satisfactorily answered? Nathan et al. [7] report on their performance of anal cytology in a HRA clinic, demonstrating that for screening purposes anal cytology performs similarly to cervical cytology. Their HRA clinic included HIV-positive MSM and HIV-negative heterosexual individuals. Anal cytology has previously been shown to be a cost-effective screening method for the detection of squamous intraepithelial lesions in populations at high-risk for developing anal carcinoma [10]. Other researchers showed that the annual screening of HIV-positive MSM with anal Pap tests provided an incremental cost-effectiveness ratio of $16 600 per quality-adjusted life year saved. They further demonstrate that this cost is comparable with other widely accepted screening procedures, such as screening for colon cancer in the general population.
In their study, Nathan et al. [7] report that the sensitivity and specificity of anal cytology to detect disease in their patients was 70 and 67%, respectively. Several similar studies evaluated the effectiveness of anal Pap tests by calculating the sensitivity and specificity of anal cytology results compared to histological diagnoses based upon HRA-directed biopsy samples (Table 1) [7,11-16]. Prior experience with anal cytology in the literature clearly reveals that anal Pap tests have low sensitivity and specificity for AIN lesions [4]. The sensitivity in Table 1 ranges from 42-98% and the specificity from 33-96%. Anal cytology is also a poor predictor of the severity of AIN lesions, and frequently does not recognize high-grade anal lesions. Nathan et al. [7] report a poor concordance between their anal cytology and subsequent anal biopsy histology grades. Although the collection of specimens in liquid medium versus conventional smears from the data in Table 1 does not appear to appreciably impact sensitivity and specificity, liquid-based cytology certainly enhances the cytomorphology (e.g. eliminates poor fixation, air drying artifacts, and reduces obscuring fecal contamination) and provides residual vial material (cellularity) for potential ancillary tests (e.g. HPV testing). Nathan et al. [7] show that the sensitivity of anal cytology is dependent upon the area (volume) of anal disease present, sexuality (71% in MSM compared to 58% in heterosexuals), HIV positivity, and immunosuppression (i.e. CD4 cell count), but remains unaffected by the use of antiretroviral treatment. Although the sensitivity of abnormal cytology to detect HSIL in HIV-positive men has similarly been shown by others to be higher compared with HIV-negative MSM [17], overall anal Pap tests in the HIV-positive population are still an inaccurate predictor of high-grade anal dysplasia on biopsy.
The goal of screening is to detect anal dysplasia early and eradicate AIN, thereby preventing the progression of such lesions to invasive squamous cell carcinoma. The optimum use of HPV testing, and alternative screening methods such as direct visualization or 'optical biopsy' of the anal mucosa (e.g. akin to digital cervicography and speculoscopy), in this setting has yet to be defined. Fortunately, treatment options for anal dysplasia and anal cancer in HIV-infected individuals are expanding, which may lead to decreased morbidity and mortality. Expertise in treating such patients is important to optimize outcomes for patients [18]. Additional studies are needed, including investigations looking at the impact of HPV vaccination on anogenital HPV infection.
References
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2. Northfelt DW, Swift PS, Palefsky JM. Anal neoplasia. Pathogenesis, diagnosis, and management. Hematol Oncol Clin North Am 1996; 10:1177-1187.
3. Kreuter A, Wieland U. Human papillomavirus-associated diseases in HIV-infected men who have sex with men. Curr Opin Infect Dis 2009; 22:109-114.
4. 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.
5. Pantanowitz L, Leiman G, Dezube BJ. Screening for anal dysplasia: are we on the same page? AIDS Read 2009; 19:182-183.
6. Darragh TM, Birdsong GG, Luff RD, Davey DD. Anal-Rectal Cytology. In: Solomon D, Nayar R, editors. The Bethesda system for reporting cervical cytology. 2nd ed. New York: Springer; 2004. pp. 169-175.
7. Nathan M, Singh N, Garrett N, Hickey N, Prevost T, Sheaff M. Performance of anal cytology in a clinical setting when measured against histology and high resolution anoscopy findings. AIDS 2009; 24:373-379.
8. Pineda CE, Berry JM, Jay N, Palefsky JM, Welton ML. High-resolution anoscopy targeted surgical destruction of anal high-grade squamous intraepithelial lesions: a ten-year experience. Dis Colon Rectum 2008; 51:829-837.
9. Fenger C, Frisch M, Marti MC, Parc R. Tumours of the anal canal. In: Hamilton SR, Aaltonen LA, editors. World Health Organization classification of tumours. Pathology & genetics. Tumors of the digestive system. Lyon: IARC Press; 2000. pp. 147-155.
10. Goldie SJ, Kuntz KM, Weinstein MC, Freedberg KA, Welton ML, Palefsky JM. 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.
11. Mathews WC, Sitapati A, Caperna JC, Barber RE, Tugend A, Go U. Measurement characteristics of anal cytology, histopathology, and high-resolution anoscopic visual impression in an anal dysplasia screening program. J Acquir Immune Defic Syndr 2004; 37:1610-1615.
12. Panther LA, Wagner K, Proper J, et al. High resolution anoscopy findings for men who have sex with men: inaccuracy of anal cytology as a predictor of histologic high-grade anal intraepithelial neoplasia and the impact of HIV serostatus. Clin Infect Dis 2004; 38:1490-1492.
13. Fox PA, Seet JE, Stebbing J, et al. The value of anal cytology and human papillomavirus typing in the detection of anal intraepithelial neoplasia: a review of cases from an anoscopy clinic. Sex Transm Infect 2005; 81:142-146.
14. Palefsky JM, Holly EA, Hogeboom CJ, Berry JM, Jay N, Darragh TM. Anal cytology as a screening tool for anal squamous intraepithelial lesions. J Acquir Immune Defic Syndr Hum Retrovirol 1997; 14:415-422.
15. Arain S, Walts AE, Thomas P, Bose S. The anal Pap smear: cytomorphology of squamous intraepithelial lesions. Cytojournal 2005; 2:4.
16. Papaconstantinou HT, Lee AJ, Simmang CL, et al. Screening methods for high-grade dysplasia in patients with anal condyloma. J Surg Res 2005; 127:8-13.
17. Berry JM, Palefsky JM, Jay N, Cheng SC, Darragh TM, Chin-Hong PV. Performance characteristics of anal cytology and human papillomavirus testing in patients with high-resolution anoscopy-guided biopsy of high-grade anal intraepithelial neoplasia. Dis Colon Rectum 2009; 52:239-247.
18. Siekas LL, Aboulafia DM. Establishing an anal dysplasia clinic for HIV-infected men: initial experience. AIDS Read 2009; 19:178-186.
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