The incidence of anal squamous cell carcinoma is increasing. The populations at greatest risk for developing anal carcinoma are men who have sex with men (MSM), regardless of HIV status, and HIV positive patients of either sex.

Rate of Incidence
The incidence of anal carcinoma in homosexual men prior to the AIDS epidemic was estimated to be as high as 36.9 per 100,000, which is similar to the incidence of cervical carcinoma prior to the use of Pap screening.¹

The current incidence in this high-risk population is estimated to be as high as 70/100,000.^1,2 The National Cancer Institute estimates that 5,260 new cases of anal cancer will be diagnosed in 2010, and that 720 men and women will die of the disease. Data for the current year are not yet available.

The increased incidence of anal carcinoma accompanies the widespread use of highly active antiretroviral therapy (HAART) for the management of HIV.¹ This therapy increases the lifespan of HIV positive patients.

The rate of progression of high-grade anal intraepithelial neoplasia (AIN) to invasive squamous cell carcinoma is not known, but the increased lifespan allows sufficient time for the development of AIN and anal carcinoma. Prior to the advent of HAART, HIV positive patients most likely succumbed to AIDS before anal carcinoma developed.

Anal and Cervical Carcinoma
AIN and anal carcinoma are analogous to cervical intraepithelial neoplasia (CIN) and cervical carcinoma.^2,4 Both AIN and CIN are associated with Human Papilloma Virus (HPV) infection.

Low-risk HPV infection results in low-grade intraepithelial lesions and condyloma. High-risk HPV types are associated with the development of high-grade intraepithelial lesions and carcinoma.⁴

Both AIN and CIN arise in metaplastic epithelium and share similar morphology and cytologic and histologic grading systems.⁵ High-grade CIN is known to be the precursor lesion of cervical squamous cell carcinoma.

Based on the natural history of CIN and the similarities between AIN and CIN, AIN is considered to be the precursor lesion of anal squamous cell carcinoma.⁵ Additional evidence to support this assumption is the increased incidence of anal carcinoma in populations with a high prevalence of high-grade AIN.

ADVANCE thanks JulieAnn Nagle Warner, MD (Click image to view larger photo.)

Screening
The success of cervical cancer screening has been used as a model for anal cancer screening. Anal cancer screening strategies utilize anal cytology, high-resolution anoscopy (i.e., analogous to colposcopy), and directed biopsy to guide diagnosis and treatment.

There are currently no national guidelines for the frequency of screening, but in 2007, the New York State Department of Public Health AIDS Institute recommended annual digital anal-rectal exams and anal cytologic screenings in HIV-positive MSM, any patient with a history of anogenital condyloma and women with abnormal cervical and/or vulvar histology.⁶

Proper anal cytology screening involves sampling from the anal verge to the rectal vault. It is important to sample the area of squamous metaplasia that is analogous to the transformation zone of the cervix. Most AINs arise in this area because immature squamous metaplastic cells are susceptible to infection by HPV.

Liquid-based cytology is the preferred screening method due to increased cellular yield, improved preservation, elimination of air-drying artifact, and reduction in fecal material that may obscure cellular detail on conventional cytology specimens.⁷

Anal cytology is interpreted and reported using the Bethesda 2001 guidelines, modified for this body site. The terminology, criteria, and management guidelines are similar to those utilized in cervical cytology specimens. 

Sampling
Limited literature exists on what constitutes an adequate anal-rectal sample. According to Bethesda guidelines, minimal cellularity is at least 2,000 to 3,000 nucleated squamous cells. The presence of the anal transformation zone (i.e., glandular and/or squamous metaplastic cells) is not necessary for an adequate sample, but should be indicated on the report as a quality indicator.⁸ 

As in the cervical screening model, anal cytology is used to identify precursor lesions.  AIN is often underdiagnosed on the basis of cytology, and an abnormal cytology result of ASC-US (i.e., atypical squamous cells of undetermined significance) or higher suggests the possibility of high-grade AIN.^{9, 10} If an abnormality is detected, high resolution anoscopy and directed biopsy are required for accurate grading. 

The role of HPV DNA testing in the screening and triage of anal carcinoma is unclear.  High-risk HPV testing for triage of abnormal anal cytology specimens in MSM is reportedly very sensitive with a high negative predictive value, but there is low specificity and a low positive predictive value. 6 

In addition, in the highest risk population (i.e., HIV-positive MSM) there is a high prevalence of high-risk HPV. Therefore, it is unlikely that high-risk HPV testing will be useful in that population, but may be useful in triaging patients in other at-risk populations with a lower prevalence of anal HPV infection.

JulieAnn Nagle Warner is a medical doctor at Rochester General Hospital in Rochester, NY. Learn more about the ASCT at www.asct.com

References

1. Arain S, Walts AE, Primi T, Shikha B. The Anal Pap smear: Cytomorphology of quamous Intraepithelial Lesions. Cytojournal 2005, 2:4.
2. Darragh TM. Anal Cytology for Anal Cancer Screening: Is it Time Yet? Diagnostic Cytopathol 2004;30:371-374.
3. Chiao EY, Giordano TP, Palefskg JM, Tyring S and Serag HE. Screening HIV-Infected Individuals for Anal Cancer Precursor Lesions: A Systemic Review. CID 2006;43:223-233.
4. Palefsky JM, Holly EA, Gonzales J, Berline J, Ahn DK and Greenspan JS. Detection of Human Papillomavirus DNA in Anal Intraepithelial Neoplasia and Anal Cancer. Cancer Res 1991;51:1014-1019.
5. Palefsky JM, Holly EA, Hogeboom CJ, et al. Anal Cytology as a Screening Tool for Anal Squamous Intraepithelial Lesions. J AIDS Hum Retrovir 1997;14:415-422.
6. Darragh TM, Winkler B. Anal Cancer and Cervical Cancer Screening:  Key Differences. Cancer Cytopathol 2011;119:5-19.
7. Darragh TM, Winkler B. The ABCs of Anal Rectal Cytology. CAP Today. 2004 May, 1-5.
8. Solomon D, Nayar R. The Bethesda System for Reporting Cervical Cytology: Definitions, Criteria, and Explanatory Notes. 2nd ed. New York: Springer-Verlag; 2004.
9. Palefsky JM, Holly EA, Ralston ML, Jay N, Berry JM, and Darragh TM. High Incidence of Anal High-Grade Squamous Intra-epithelial Lesions Among HIV-positive and HIV negative Homosexual and Bisexual Men. AIDS 1998; 12: 495-503.
10. 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. CID 2004;38:1490-1492.