The vast majority of anal squamous intraepithelial neoplastic lesions, like those in the uterine cervix, are related to sexually transmitted human papillomavirus (HPV) infections of the various subtypes, and these are presumed to be the precursors to invasive anal squamous cell carcinomas. The number of individuals in the population exposed to HPV is high; for example, 3% and 12% of US male and female blood donors, respectively, had positive HPV 16 serology in one study (15). Since there are about 300 million individuals in the United States, if we assume that there are 150 million males and 150 million females, there might be as many as 18 million women and 4.5 million men at risk. Because there were only about 5,260 estimated new cases of anal cancers and about 12,200 new cervical cancers in 2010 (16), this suggests a very low progression rate. However, it is known that individuals infected with human immunodeficiency virus (HIV) are extremely likely to have anal HPV lesions (17,18), so this is the group in whom screening is presently being evaluated, akin to mass cervical screening. Anal HPV lesions in HIV-positive patients can be advanced. One study found that 37% [118/319] of excised condylomas in men who have sex with men (MSM) harbored high-grade anal intraepithelial neoplasia or squamous carcinoma. In the same study, HIV-seropositive men were twice as likely to have high-grade AIN or squamous carcinoma when compared with HIV-negative patients (19). These results are mirrored by those of McCloskey et al., who found AIN in 78% (52% high grade) of excised anal/perianal condylomas of men with HIV infection and in 33% (20% high grade) of condylomas of HIV-negative men. The same study found a
much lower frequency of AIN in condylomas excised from HIV-negative women, 8.3% (2.8% high grade) (20). It is frequently from this HIV-positive population that pathologists receive anal biopsies to evaluate. At least half of the homosexual male HIV population has anal HPV lesions (17,18), and low-grade lesions progressed to high-grade lesions in about 20% of such patients in 2 years in one study (18), but it seems that very few of these
in situ lesions progress to invasive carcinoma; patients most at risk for progression to invasion are those with immunosuppressed states (21). Additionally, women with cervical/perineal dysplasia are at risk for anal dysplasia regardless of a history of anal intercourse or immunosuppression with prevalence ranging from 17.4% to 59.2% (22,23). The main reason to treat these lesions is the aggressive nature of invasive carcinomas in these individuals once invasion ensues. The effect of highly active antiretroviral therapy on these lesions remains unclear, but is not necessarily beneficial (24). Anal intraepithelial lesions are summarized in
Table 5.1. As noted above, their common denominator is HPV, but the factors that determine whether any given infection manifests, such as bowenoid papulosis versus invasive squamous cell carcinoma, remain obscure.
Like the uterine cervix, the anal canal has a transformation zone (
Figs. 5.11 and
5.12). This zone cannot be visualized without the use of anoscopy, so a procedure is required even for cytologic screening. In biopsies obtained from this area (anoscopically at the dentate/pectinate line), it is typical to find fragments of rectal-type mucosa adjoining, or separate from, the lesions in question. The histology of anal squamous intraepithelial lesions is quite similar to that found in the uterine cervix, and is associated with the same HPV types as cervical lesions. Such lesions had been classified as anal intraepithelial neoplasia (AIN) I, AIN II, and AIN III, but now, as for the cervix, most observers prefer to separate low- and high-grade lesions, with the AIN II subsumed under high grade. HPV 16 and 6 are the most common genotypes detected in association with high-grade and low-grade lesions, respectively (25). Variable degree of loss of nuclear stratification and polarity, nuclear pleomorphism and hyperchromatism (with or without keratinization or HPV viral cytopathic changes), and increased mitoses high in the epithelium are the constellation of findings sought on biopsies. HPV viral cytopathic changes are found in either exophytic (condyloma acuminata) (
Figs. 5.13,
5.14 and
5.15, e-Figs. 5.16-5.20) or flat lesions (
Fig. 5.16). Such changes consist of koilocytes and basal zone proliferation, and they account for less than half of the epithelial thickness. These lesions are classified as low grade (
Fig. 5.17, e-Figs. 5.21-5.29). Lesions with higher proliferation of hyperchromatic cells are regarded as high-grade lesions, just as for the uterine cervix (
Figs. 5.18,
5.19,
5.20,
5.21 and
5.22, e-Figs. 5.30-5.36). As in the uterine cervix, dysplasia may be seen extending into colonic glands and should not be mistaken for invasive tumor (
Fig. 5.22, e-Figs. 5.37 and 5.38). Also, as with the uterine cervix, there can be difficulty in separating AIN from reparative features. In these situations, p16 stains can sometimes be helpful. HPV infection is associated with an overexpression of p16,
a cyclin-dependent kinase inhibitor. Lu et al. immunohistochemically studied 29 cases of squamous cell carcinoma of the anorectal region for the expression of p16. The tumor cells exhibited a strong and diffuse nuclear stain (with some cytoplasmic positivity) for p16 in all 29 cases (100%). HPV DNA was detected in every case (100%), with 25 cases (86%) harboring type 16. These and similar other (26) observations indicate that overexpression of p16 is commonly associated with high-risk HPV infection, which may serve as a useful surrogate biomarker for identifying squamous
cell lesions harboring HPV DNA. As such, in intraepithelial lesions, p16 can be a helpful adjunct in separating reactive from AIN lesions (e-Figs. 5.39 and 5.40). When positive, this immunostain is predictive of dysplasia in anal cytology specimens, but the sensitivity and specificity are less than optimal (27). Tandem ki-67 stain can also be helpful. At our
institution, high-grade (AIN II or III) lesions are the threshold for offering treatment, and we sometimes use these stains to confirm an impression of a high-grade lesion. We do not routinely perform HPV testing on such cases, but do so if there is a specific request (e-Fig. 5.20). Interestingly and similarly to some colon cancers, Zhang et al. reported high rates of DNA methylation
in cases of squamous cell carcinoma and high-grade AIN. DNA methylation of the genes
IGSF4 and
DAPK1 was specific for high-grade AIN and squamous cell carcinoma as methylation of these genes was absent in cases of low-grade AIN and in normal mucosa (28). Current treatment options for AIN include electrofulguration, infrared coagulation, immunomodulation therapy with imiquimod 5% cream, and surgical excision.