Cytology and HPV testing for anal HSIL screening
Anal cancer disproportionately affects certain groups like men who have sex with men (MSM), people living with HIV (PLWH), and women with a history of lower genital tract neoplasia (LGTN). Interest exists in determining how to identify and treat those with the anal cancer precursor, high-grade squamous intraepithelial lesion (HSIL), prior to malignancy. Anal cytology has traditional been used to identify individuals at-risk for HSIL. The presence of any abnormality is followed by referral for high-resolution anoscopy (HRA), a procedure that uses a colposcope to examine the anal canal and perianus. When identified, treatment of anal HSIL typically involves ablation with electrocautery or infrared coagulation.
Studies describing the performance of anal cytology have focused on MSM, particularly MSM living with HIV (MSMLWH). One recent such study compared anal cytology with same-day HRA in 375 MSM without HIV and 213 MSMLWH.1 Results were consistent with previous reports and notable for low specificity and positive predictive value (PPV), but reasonable sensitivity and negative predictive value (NPV) (Table 1). Low specificity and PPV reflects the use of any cytological abnormality including atypical squamous cells of undetermined significance (ASC-US) as the threshold for HRA referral. Increasing the severity required for referral would improve these values but at the expense of sensitivity and NPV. Performance data are more limited in other at-risk populations, although a recent study of 636 women with LGTN also reported limited PPV but reasonable NPV (Table 1).2 Thus, while a negative cytology does not entirely exclude HSIL, its use is considered acceptable given the slow progression of anal HSIL and that overall NPV will increase with serial cytologies over time. These studies also show a high PPV for biopsy-proven HSIL when the cytology shows HSIL. 59% of MSM and 42% of women had abnormal cytologies in the aforementioned studies, reflecting the large number of HRA referrals generated by cytology. This has prompted interest in determining whether newer molecular techniques like high-risk HPV (hr-HPV) testing can improve performance, particularly specificity.
Hr-HPV testing has been primarily studied for anal HSIL detection in MSMLWH, despite the absence of FDA-approval for use in the anus. A meta-analysis reported limited specificity and PPV but high sensitivity and NPV (Table 1).3
This reflects the ubiquitous nature of anal hr-HPV in MSMLWH such that its identification does not add significant discriminatory power. While biomarkers of cellular proliferation like p16/Ki-67 or E6/E7 mRNA could theoretically improve test characteristics, their use was similarly not associated with improved performance compared with cytology alone.3 Thus, cytology remains the mainstay of anal HSIL screening, although molecular testing may perform better in populations with lower prevalence of anal hr-HPV. It may also be a valuable alternative when access to pathologists for cytology interpretation is limited. Other approaches to testing including combinations of cytology with detection of specific HPV genotypes such as HPV 16 or 18 may be useful. There is also interest in other molecular markers of HSIL that could be used in combination with cytology or HPV testing, such as E6/E7 oncoprotein detection or methylation markers.
Despite our ability to identify and treat anal HSIL, there are no national guidelines recommending screening. This is partly due to the absence of trials demonstrating the efficacy of anal HSIL treatment in preventing anal cancer. Furthermore, the absolute incidence of anal cancer remains low in the general population such that widespread screening may be of limited benefit. Existing guidelines instead are focused on high-risk groups. The HIV Medicine Association recommends anal cytology for certain PLWH: MSM, women with a history of receptive anal intercourse or abnormal cervical cytology, and PLWH with genital warts.4 In women, expert opinion concluded that HIV and LGTN were the most compelling indications for screening.5 Thus, it is reasonable to perform anal cytology in these groups with prior counseling about the high probability of abnormal results and HRA referral. Cytology or other tests to detect anal HSIL should be avoided if the infrastructure to treat anal HSIL is unavailable, and instead, a yearly digitoanorectal exam to detect palpable anal cancer can be performed.
DISCLOSURE The author declares nothing to disclose.
References
1. Jin F, Grulich AE, Poynten M et al. The performance of anal cytology as a screening test for anal HSILs in homosexual men. Cancer Cytopathol 2016;124(6):415-24. Available from: https://pubmed.ncbi.nlm.nih.gov/26915346/
2. Albuquerque A, Sheaff M, Stirrup O et al. Performance of Anal Cytology Compared With High-Resolution Anoscopy and Histology in Women With Lower Anogenital Tract Neoplasia. Clin Infect Dis 2018;67(8):1262-1268. Available from: https://pubmed.ncbi.nlm.nih.gov/29659752/
3. Dias Goncalves Lima F, Viset JD, Leeflang MMG et al. The Accuracy of Anal Swab-Based Tests to Detect High-Grade Anal Intraepithelial Neoplasia in HIV-Infected Patients: A Systematic Review and Meta-analysis. Open Forum Infect Dis 2019;6(5):ofz191. Available from: https://pubmed.ncbi.nlm.nih.gov/31123696/
4. Aberg JA, Gallant JE, Ghanem KG et al. Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis 2014;58(1):1-10. Available from: https://pubmed.ncbi.nlm.nih.gov/24235263/
5. Moscicki AB, Darragh TM, Berry-Lawhorn JM et al. Screening for Anal Cancer in Women. J Low Genit Tract Dis 2015;19(3 Suppl 1):S27-42. Available from: https://pubmed.ncbi.nlm.nih.gov/26103446/
OTHER ARTICLES INCLUDED IN THE HPW SPECIAL ISSUE ON ANAL CANCER:
J Palefsky. Screening for anal high-grade squamous intraepithelial lesions and anal cancer- has its time come?
EA Stier. Anal HPV infection: risk groups and natural history
JP Terlizzi, SE Goldstone. Treatment for anal high grade squamous intraepithelial lesions
J Kauffmann. The modern anal neoplasia clinic
JC Wang. Treatment for anal cancer
GB Ellsworth, TJ Wilkin. Early HPV vaccination could reduce anal cancer incidence
TM Darragh. Pathology of anal squamous intraepithelial lesions and cancer: similarities and differences from cervical pathology
JM Berry-Lawhorn. Groups at high risk of anal cancer
RJ Hillman. Digital anal rectal examination (DARE) for anal cancer prevention
A Curran. Current guidelines recommendations for anal HPV-related disease screening
N Jay. Practising and training for high resolution anoscopy
IM Poynten, F Jin, AE Grulich. Anal squamous intraepithelial lesions: risk groups and natural history
