The goal of anal cancer screening is similar to that of cervical cancer screening, namely, to identify and treat HGAIN before the development of cancer. Cytology is the primary screening tool for detection of HPV-associated disease in the anus. The cytology technique is simple and can easily be performed in the context of an office visit. Although anal cytology is typically performed by clinicians, patient self-collected anal cytology has also been evaluated. Self-collected specimens offer the advantage of convenience and privacy, are acceptable to patients, and have been used for rectal specimens to screen for other sexually transmitted diseases [19
]. Though specimen adequacy rates for cytology are slightly lower for self-collected samples, sensitivity for detection of anal intraepithelial neoplasia (AIN) is comparable [11
]. Samples that are inadequate because of scant cellularity may also be repeated.
To perform cytology, a rayon or polyester swab is first moistened with tap water and then inserted blindly as far as possible, with gentle pressure and rotation until it reaches the entire rectum. Synthetic fiber swabs are preferred over cotton because cells cling to cotton, decreasing cellular yield. The swab is then rotated 360 degrees while gentle pressure is applied to the walls of the anal canal as the swab is gradually withdrawn. The swab can then be placed in liquid cytology media or smeared on a glass slide (conventional cytology). Both liquid-based and conventional cytology are acceptable modalities with similar cellular yield and adequacy rates [21
Anal cytology is categorized according to the Bethesda system for cervical cytology: normal, atypical squamous cells of undetermined significance—ASC-US, low-grade squamous intraepithelial lesion—LSIL, high-grade squamous intraepithelial lesion—HSIL, atypical squamous cells, cannot rule out HSIL—ASC-H [22
]. Anal histology is graded according to severity; mild abnormalities are graded as AIN I, and moderate to severe abnormalities are graded as AIN II or AIN III (HGAIN). Although a cytologic diagnosis of HSIL is nearly always associated with HGAIN diagnosed on biopsy, HGAIN is also frequently associated with mildly abnormal cytologic diagnoses (ASC-US, LSIL) [23
]. Therefore, we recommend that individuals with abnormal cytology findings of ASCUS or worse be referred for high-resolution anoscopy (HRA) with biopsy. Individuals with HGAIN on biopsy should subsequently be treated (Fig. ).
Fig. 1 Protocol for screening of anal intraepithelial neoplasia (AIN). ASC-H—atypical squamous cells, cannot rule out HSIL; ASC-US—atypical squamous cells of undetermined significance; HSIL—high-grade squamous intraepithelial lesion; (more ...)
If resources for HRA are limited, then cytology can be used for triage: patients with HSIL or ASC-H cytology should be prioritized for HRA, followed by patients with LSIL, and finally by those with ASC-US. Cytology can also be useful as a quality control measure for the anoscopist, because individuals with HSIL on cytology should have HGAIN on biopsy. If no AIN or only low-grade AIN is detected in an individual with HSIL cytology, we recommend repeat HRA to ensure the high-grade lesion was not missed.
Multiple studies have examined the operating characteristics of anal cytology. The reported sensitivity to detect AIN on HRA among different high-risk populations (including HIV-positive MSM) is between 69% and 93%, with specificity ranging from 32% to 64% [24
]. Among HIV-negative MSM, cytology is generally less sensitive but more specific than in HIV-positive MSM, with sensitivity reported as about 50% to 60% and specificity of 76% to 84% [11
]. The predictive value of cytology can be improved through repeated testing; in a large, prospective, cohort study by Palefsky et al. [26
], the positive predictive value of cytology improved from 38% to 78% and the negative predictive value improved from 46% to 79% after consecutive testing for 2 years.
Although cervical HPV testing is regularly used as an adjunct to triage women with mildly abnormal cervical cytology test results, the role of anal HPV testing as an adjunct to anal cytology is unclear. Based on limited data, it appears that in HIV-positive MSM, using HPV testing as an adjunct to cytology for detection of HGAIN is highly sensitive but has poor specificity and poor positive predictive value [27
]. HPV testing may be more useful in HIV-negative MSM, because the presence of oncogenic HPV infection, especially HPV-16, is highly specific for HGAIN on biopsy [25
•]. HPV testing may also be useful among populations with a lower prevalence of anal HPV infection than HIV-positive MSM (eg, HIV-negative MSM) for its negative predictive value.
Because of the high prevalence of AIN in certain populations, some researchers have advocated foregoing cytology and using HRA as a primary screening test. This consideration is reasonable, given that a single negative cytology result has a poor negative predictive value in populations with a high prevalence of disease (eg, HIV-positive MSM). However, given the insufficient availability of HRA, we believe that use of cytology to triage individuals to HRA and biopsy is the appropriate approach to AIN or anal cancer screening in most settings.
Currently, no national consensus exists on an optimal method and frequency for anal cancer screening. Guidelines from the Centers for Disease Control and Prevention acknowledge that cytology is used by many experts to screen for AIN in HIV-positive individuals [28
••]. Screening HIV-positive MSM annually and screening HIV-negative MSM every 2 years appears to be cost-effective, with a cost of about $16,000 per quality-adjusted life year (QALY) saved; this is comparable to other commonly used preventive health measures [29
]. However, modeling studies conducted under different assumptions in the United Kingdom demonstrate much higher costs per QALY for MSM, thus the issue of cost efficacy must be analyzed separately in health care systems where screening may be used [31
An important caveat regarding our recommendation for anal cytology screening is that screening should only be instituted if treatment is available for individuals with HGAIN. If expertise is not available to perform HRA and treat HGAIN, then, at a minimum, high-risk patients should receive an annual digital rectal exam (DRE) to feel for masses in the anal canal. Although no data exist on the performance of DRE in detecting anal cancer, DRE is easy to perform and offers the potential benefit of detecting anal cancers at an early and treatable stage.