May 2011
Cytopathology And More

Roger B. Lane Jr., MD

Anal cancer and cervical cancer and their precursor lesions are alike in many ways: They are caused by human papillomavirus, they can present clinically as condyloma or as a flat intraepithelial lesion, and they appear similar through the microscope, both cytologically and histologically. This has led to the development of high-resolution anoscopy, which, similar to cervical colposcopy, is used to identify lesions for biopsy, treatment, or both. A recent review article by Teresa Darragh, MD, and Barbara Winkler, MD, compares and contrasts the two diseases (Anal cancer and cervical cancer screening: key differences. Cancer Cytopathol. 2011;1:5–19).

Although anal cancer is much less common in the general population than cervical cancer, anal cancer incidence in high-risk groups is more than double that of cervical cancer incidence before the initiation of Pap screening. The incidence of anal cancer is increasing, while cervical cancer incidence continues to decrease. The success of cervical cancer screening has led to its use as a template for anal cancer screening in high-risk populations. The review by Darragh and Winkler focuses on the key differences between cervical cancer and anal cancer, including the potential role of anal cytology in screening high-risk patient groups, and discusses obstacles and controversies surrounding the implementation of successful anal cancer screening programs.

The article provides an overview of the epidemiology and pathogenesis of anal cancer. The population at highest risk for anal cancer is men who have sex with men (MSM), regardless of HIV status. Other high-risk groups include HIV-positive women and men, other immunosuppressed patients, and women with multicentric lower genital tract squamous intraepithelial neoplasia. The authors also discuss the prevalence of anal intraepithelial neoplasia and HPV infection in different high-risk groups, HPV subtypes associated with anal cancer, and what is known about the natural history of precursor lesions in anal disease.

Darragh and Winkler point out the relative lack of recognition of the risk of anal carcinoma by the public and within the medical community. This has led to underuse of the digital anal-rectal exam, an essential clinical tool in high-risk individuals because most early invasive anal cancers are easily palpable, even in the absence of clinical symptoms. In addition to the digital anal-rectal exam, screening programs may include anal cytology, high-resolution anoscopy, and anal biopsy. There is a detailed summary of previous studies of anal cytology as a screening tool, with discussion of sensitivity, specificity, positive predictive value, and negative predictive value in high-risk groups.

The authors include a summary of anal cytology, including discussion of specimen adequacy, cytologic interpretation, and the possible role of HPV testing. How it differs from cervical cytology is noted, including the higher prevalence of keratinizing lesions and degenerative changes in anal cytology and the finding that anal cytology often under-represents the severity of lesions found on biopsy. They emphasize the uncertain role of HPV DNA testing in screening and triage of anal cancer. In MSM with a diagnosis of atypical squamous cells of undetermined significance (ASC-US) or higher on anal cytology, HPV testing shows a high degree of sensitivity (84 to 100 percent). There is also a high negative predictive value (75 to 100 percent). However, specificity is poor (16 to 18 percent) and the positive predictive value is low (28 to 50 percent). Therefore, it appears unlikely that high-risk HPV testing will play a major role in the highest-risk group, but there are possible useful roles in other at-risk populations with a lower prevalence of HPV.

The authors review high-resolution anoscopy and provide images of low-grade and high-grade lesions of the anal canal. They discuss the shortage of skilled providers of high-resolution anoscopy, along with reasons for the shortage and a review of training resources. This is followed by a review of the histology of anal intraepithelial neoplasia and anal cancer.

The article concludes with a discussion of possible algorithms for triaging and managing patients in anal screening programs. For example, one group has advocated the triage of all patients with ASC-US or higher to high-resolution anoscopy. Others suggest using HPV testing of anal cellular material with indications similar to Pap testing, although the high prevalence of HPV in MSM may obviate the role of HPV testing in the screening and triage of these high-risk patients. Also mentioned is a potential role for HPV genotyping in high-risk patients. Various methods of treating anal intraepithelial neoplasia and anal cancer are reviewed briefly, including ablative techniques and topical therapies. There is a brief discussion of the potential effects that HPV vaccines may have on anal screening models.

In summary, Darragh and Winkler provide an excellent and thorough review of the current state of anal cancer screening. Anal cancer screening and prevention is a relatively new clinical specialty involving many disciplines. The digital anorectal exam is an effective but underused method in high-risk groups. Potentially, screening programs would include cytology, high-resolution anoscopy, and guided biopsy. Each of these tools is imperfect, limited by sensitivity, specificity, and interobserver variability. When used together, they could be a valuable resource for preventing and treating anal cancer and its precursor lesions.