Anal squamous intraepithelial lesions: Epidemiology, clinical presentation, diagnosis, screening, prevention, and treatment

INTRODUCTION — The anal canal and cervix share embryologic, histologic, and pathologic characteristics. Both develop from the embryonic cloacal membrane and are sites of fusions of endodermal and ectodermal tissue to form a squamocolumnar epithelial junction. Both areas may display normal metaplastic change and abnormal change related to infection with human papillomavirus (HPV) (figure 1). (See "Virology of human papillomavirus infections and the link to cancer".)

HPVs are the most common sexually transmitted agent in the United States. The biology of these viruses has been studied extensively and their link with malignancies is well established, especially with cancers involving the anogenital (cervical, vaginal, vulvar, penile, anal) tract. Anal neoplasia caused by HPV can manifest as preinvasive (squamous intraepithelial lesions [SIL]) or invasive (anal cancer) disease. The epidemiology, clinical manifestations, diagnosis, screening, prevention, and treatment of anal SIL are discussed here. Topics related to invasive anal cancer are discussed separately. (See "Classification and epidemiology of anal cancer" and "Clinical features and staging of anal cancer" and "Treatment of anal cancer".)

HISTOPATHOLOGY AND NOMENCLATURE — Anal SIL and other histopathologic manifestations of human papillomavirus (HPV) infection are most commonly detected at the anal transition zone (ATZ), where the rectal columnar epithelium and anal squamous epithelium meet (figure 2) [1]. Both cytology and histology are used to identify anal SIL. Anal cytology involves the use of a swab to collect a sample of cells without direct visualization of the anal canal. High-resolution anoscopy (HRA), a method of examining the anal canal that uses application of acetic acid, Lugol iodine, and magnification, is performed to obtain a histologic specimen [2]. (See 'Anal cytology' below and 'High-resolution anoscopy' below.)

Cytologically, anal SIL shares features with cervical SIL (also termed cervical intraepithelial neoplasia [CIN]), and both anal and cervical cytology are described using the Bethesda classification system (table 1) [3]. (See "Cervical cancer screening: The cytology and human papillomavirus report".)

Cytology is reported, in order of increasing severity, as negative for SIL, atypical squamous cells of undetermined significance (ASC-US), low-grade SIL (LSIL), atypical squamous cells cannot exclude high-grade SIL (ASC-H), and high-grade SIL (HSIL) [3]. (See 'Anal cytology' below.)

Prior histologic classification of HPV-associated lesions reflected a morphologic continuum in which infection was accompanied by a gradual progression towards invasive cancer [4]. Lesions were termed intraepithelial neoplasia (IN) grades 1, 2, or 3 depending on the severity of the morphologic changes. The nomenclature for IN was further modified depending on the anatomical site of infection. Thus, IN from the anal canal was termed anal intraepithelial neoplasia (AIN) grades 1, 2, or 3.

However, it is now known that a substantial proportion of anal SIL are transient and do not progress to invasive cancer. (See 'Natural history' below.)

Therefore, terminology that reflects a morphologic continuum may be outdated. The College of American Pathologists and the American Society for Colposcopy and Cervical Pathology (ASCCP) have developed more updated guidelines for terminology via the Lower Anogenital Squamous Terminology project. These recommendations reflect the distinction between benign and precancerous SIL and include the use of a two-tiered nomenclature in which LSIL and HSIL are used for both cytology and histopathologic grading across all anogenital sites [5]:

●Histopathologic lesions that were previously classified as AIN 1 correspond to anal LSIL. LSIL is diagnosed when abnormal basaloid cells, characterized by squamous cells with abnormal nuclei and increased nuclear-to-cytoplasmic ratio, extend less than one-third of the thickness of the epithelium above the basal layer [6]. The superficial layers may also show HPV cytopathic effect with koilocytes, enlarged cells with a cytoplasmic halo surrounding the nucleus; their presence is an indication of active HPV replication.

●Lesions previously classified as AIN 3 correspond to anal HSIL. A biopsy is diagnosed as HSIL when the abnormal basaloid cells extend into the upper layers of the squamous epithelium (figure 1).

●The classification of lesions previously described as AIN 2 is dependent on the results of p16 staining, a biomarker of cellular proliferation [5]. Lesions previously classified as AIN 2 that are p16-negative are downgraded to LSIL and lesions previously classified as AIN 2 that are p16-positive are classified as HSIL.

●For lesions in the cervix, it is strongly recommended to qualify a histologic HSIL result by either CIN 2 or CIN 3. Per the 2019 ASCCP guidelines for the management of cervical cytologic and histologic abnormalities, this distinction remains both biologically and clinically important in the cervix [7]. (See "Cervical intraepithelial neoplasia: Terminology, incidence, pathogenesis, and prevention", section on 'Terminology'.)

●Similarly, anal LSIL and HSIL may be further classified by the applicable IN subcategorization (eg, LSIL [AIN 1], HSIL [AIN 2], or HSIL [AIN 3]).

The biologic consequences of anal SIL are analogous to those of cervical SIL. Anal HSIL (corresponding to p16-positive AIN 2 and AIN 3) is considered to be premalignant and may progress to invasive anal cancer [1], whereas anal LSIL [1] (corresponding to AIN 1 and p16-negative AIN 2) is not considered a direct precursor of anal cancer, but it may occur in patients who are also at high risk for concurrent or incident HSIL in the anus and/or other anogenital locations [8]. (See "Invasive cervical cancer: Epidemiology, risk factors, clinical manifestations, and diagnosis", section on 'Pathogenesis'.)

EPIDEMIOLOGY AND RISK FACTORS — A number of risk factors have been identified in the development of anal SIL. The most important of these are anal human papillomavirus (HPV) infection [9,10], sexual behavior [11-13], and HIV, especially in the setting of lower cluster of differentiation 4 (CD4) cell counts [9,14-16]. (See 'HIV' below.)

Approaches to screening for anal SIL in high-risk groups are discussed below. (See 'Who should be screened for anal SIL?' below.)

HPV infection — Human papillomavirus (HPV) infection is necessary but insufficient for the development of SIL, including high-grade SIL (HSIL). HPV are a family of nonenveloped DNA viruses that infect epithelial cells. (See "Human papillomavirus infections: Epidemiology and disease associations".)

About 40 HPV types are sexually transmitted and specifically infect the anogenital and upper digestive tract. Of these, 15 to 20 are oncogenic or high-risk (hr-HPV) strains, and are associated with invasive squamous cell carcinoma at their site of infection. More than 90 percent of cases of anal cancer are associated with hr-HPV infection of the anal canal and/or perianal tissues. In the general population, the association between hr-HPV and anal cancer is primarily with hr-HPV type 16 [17]. Low-risk HPV types are mainly associated with low-grade SIL (LSIL), including genital warts or condyloma acuminata. The low-risk types 6 and 11 are responsible for approximately 90 percent of genital warts [18]. (See "Condylomata acuminata (anogenital warts) in adults: Epidemiology, pathogenesis, clinical features, and diagnosis", section on 'Etiology'.)

Given that anal HPV infection is needed for the development of anal SIL, it is unsurprising that the prevalence of anal SIL correlates well with observed patterns of anal HPV infection [12,17,19-22]. A large meta-analysis of studies evaluating the prevalence of HPV in individuals with a variety of cytopathologic and histopathologic specimens noted a clear association between HPV prevalence and the presence of SIL, with the strength of the association increasing according to lesion severity [17]. The strongest association existed between the prevalence of HPV type 16 and HSIL [17,23]. This observation is consistent with the strong association between HPV type 16 infection and invasive anal cancer. (See "Classification and epidemiology of anal cancer", section on 'Human papillomavirus infection'.)

Despite the strength of this association, not all cases of anal HPV infection, including with hr-HPV types, result in anal SIL. A randomized trial of HPV vaccination in 235 males living with HIV (MLWH) identified anal HSIL in only 38 percent of participants with anal HPV 16 infection [24]. The mechanisms determining whether or not HSIL develops in the presence of hr-HPV infection are incompletely understood.

The spectrum of HPV types with both low-risk and high-risk phenotypes in the anal canal is similar to that described in the cervix. In addition to HPV 16, one group identified 29 individual HPV types and 10 HPV groups from the anal canal of males who have sex with males (MSM), both with and without HIV [25]. (See "Cervical intraepithelial neoplasia: Terminology, incidence, pathogenesis, and prevention", section on 'Types'.)

Some individuals, particularly people living with HIV (PLWH), are more frequently infected with multiple HPV types [12,25]. This has been associated with both the presence of anal SIL, and an increased risk for HSIL compared with infection with a single HPV type or the absence of detectable infection [22,25-27].

Among females, there is significant concordance between cervical and anal HPV infection, particularly at the HPV type-specific level [28]. In a systematic review of studies with paired cervical and anal samples, for females older than age 45 years with cervical HPV 16 infection, the prevalence of HPV 16-positive anal HSIL was as high as 25 percent [29]. This suggests that different anatomical areas can serve as potential reservoirs of infection for each other. (See "Human papillomavirus infections: Epidemiology and disease associations", section on 'Anal infections'.)

Sexual behavior — The following sections describe the impact of sexual behavior on the risk of anal SIL in males and females without HIV. The available information on individuals living with HIV is presented further below. (See 'HIV' below.)

●Males – In men, studies on anal SIL have focused primarily on MSM because they are considered at increased risk of developing anal cancer compared with males who do not have sex with men. Both the number of sexual partners and a history of anal receptive intercourse are associated with anal SIL in MSM:

•In a study of 1262 MSM without HIV, anal SIL, as detected by anal cytology, was present in 20 percent of the population (5 percent with HSIL and 15 percent with LSIL) [12]. The presence of more than five sexual partners as well as the presence of five receptive anal intercourse partners in the previous six months were associated with anal SIL.

•In the same study, the prevalence of SIL did not vary with age, which is consistent with the observation that the prevalence of anal HPV infection is also stable with age [30]. This contrasts with the epidemiology of cervical HPV and SIL, where age-related declines are well documented (see "Cervical intraepithelial neoplasia: Terminology, incidence, pathogenesis, and prevention"). The stable prevalence of anal HPV and SIL over time was postulated to reflect multiple, new, transient infections occurring due to the ongoing presence of multiple sexual partners across different age groups in the urban population studied.

•Although anal cytology can provide relevant information, the gold standard for SIL diagnosis is high-resolution anoscopy (HRA) with targeted biopsies. The Study of the Prevention of Anal Cancer (SPANC), a three-year cohort study in Sydney, Australia, reported a prevalence of LSIL and HSIL of 26.4 and 32.3 percent, respectively, among 396 MSM without HIV who underwent baseline HRA at enrollment [31]. (See 'High-resolution anoscopy' below.)

The prevalence of anal SIL in males without HIV who have sex with females (MSW) is unknown

●Females – While anal HPV infection is known to be common in young, healthy females [32], data on the prevalence of anal SIL in the general female population are more limited since the majority of available studies have focused on females with risk factors for anal cancer, such as HIV. (See "Human papillomavirus infections: Epidemiology and disease associations", section on 'Females'.)

Existing data, however, suggest that despite the high prevalence of HPV infection, anal SIL is relatively rare within the general female population, implying that infections are often transient:

•In female adolescents without HIV, the rate of SIL as detected by abnormal anal cytology was 5.7 percent [33]. The prevalence of abnormal anal cytology in a somewhat older population of healthy females was 4 percent [11].

•Two small studies from Brazil used HRA to evaluate the prevalence of anal SIL in females without risk factors for anal cancer. In the first study of 74 healthy females with negative cervical cytology, 1.4 percent had LSIL and none had HSIL [34]. The second study was comprised of 76 healthy females and similarly found an LSIL prevalence of 2.6 percent and no cases of HSIL [35].

In addition to anal HPV infection [11], risk factors for anal SIL in females include a history of anal receptive intercourse [33,35], number of partners [33], as well as HPV infection and a history of SIL at other genital sites (cervical, vaginal, vulvar) [11,34,35].

Practices unrelated to sexual behavior may also result in anal HPV infection through spread of HPV from the cervicovaginal tract. In a study from Australia, wiping from front to back post-toilet may result in higher rates of anal HPV infection and anal SIL than patting or wiping in the other direction [36,37].

HIV

High-risk HPV and SIL — PLWH are at elevated risk for anal hr-HPV, as well as for anal SIL, including HSIL [13]:

●Males – For MLWH the following data are available:

•A meta-analysis reported a significantly increased prevalence of anal SIL by HRA (63 versus 37 percent), including LSIL (29 versus 11 percent) and HSIL (29 versus 15 percent), in MSM living with HIV (MSMLWH) compared with MSM without HIV [13]. Other studies of MSM undergoing HRA also report an increased prevalence of SIL in MSMLWH compared with MSM without HIV [9,14,31,38,39], or report a high prevalence of anal SIL in MSMLWH [15,27]. The SPANC study provides some of the most recent data on anal SIL prevalence among a large cohort of MSM in Australia who underwent baseline HRA [31]. In that study, the prevalence of anal HSIL was 47.3 percent in MSMLWH versus 32.4 percent in MSM without HIV.

•There are fewer studies reporting data on anal SIL in MSW living with HIV (MSWLWH), but anal HSIL appears to be relatively common in this group:

-A cohort of 50 MSWLWH with intravenous drug use (IVDU) who underwent HRA reported LSIL in eight (16 percent) and HSIL in nine (18 percent) participants [40].

-In a more recent cohort that obtained anal cytology on 218 MSWLWH, 67 (31 percent) had abnormal anal cytology [41]. Of these, 40 underwent HRA, 26 had SIL (65 percent), 8 had HSIL (20 percent), and 1 had invasive anal squamous cell carcinoma.

A low baseline CD4+ cell count as well as a low CD4+ nadir were associated with SIL in the above studies [9,14-16,20,40,41], although high rates of HSIL have been found at all CD4+ strata.

●Females – Among females, HIV is also a risk factor for anal HPV infection and anal SIL:

•Among females living with HIV (WLWH), the prevalence of anal HPV infection appears to be very high. As an example, in the Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy (SUN Study), the prevalence of anal HPV infection in WLWH was 90 percent [22].

The following studies have addressed the prevalence of anal SIL in WLWH:

•Earlier studies in WLWH noted an increased risk of abnormal anal cytology compared with females without HIV [42,43]. One study of 251 WLWH and 68 females without HIV found that the risk for abnormal anal cytology was three times higher in WLWH (26 versus 8 percent [42]). In this cohort, females with abnormal anal cytology were referred for HRA. The prevalence of histologic anal HSIL was also higher in WLWH compared with females without HIV (9 versus 1 percent) [44]. However, the prevalence of anal HSIL was likely underrepresented in this study given the limited sensitivity of anal cytology in identifying people at risk for HSIL. (See 'Anal cytology' below.)

•In a more recent study from the AIDS Malignancy Consortium, which performed HRA on a cohort of 256 WLWH, the prevalence of anal HSIL was much higher than previously reported (27 percent) [45].

•As with MLWH, risk factors for SIL in WLWH include a low CD4+ cell count [42,45] and a low CD4+ nadir cell count [45]. Similar to females in the general population, the presence of anal SIL is associated with cervical hr-HPV as well as abnormal cervical cytology [29,42,45,46] and the number of partners for anoreceptive intercourse.

Invasive anal cancer — In addition to high rates of anal HSIL, an elevated incidence of invasive anal cancer has been clearly documented in PLWH. In the general population, anal cancer incidence, although increasing, is approximately 1.5 per 100,000 person-years [47]. By comparison, in a large linkage study of United States cancer and HIV registries, the incidence of anal cancer in the United States was 50.7 per 100,000 person-years in PLWH [48]. When stratified by gender and sexual behavior, this incidence per 100,000 person-years was 88.7 in MSMLWH, 31.9 in other males with HIV, and 24.2 in WLWH. As with anal HSIL, the risk for anal cancer is higher in PLWH with a low CD4 count nadir [49]. This subject is addressed in more detail elsewhere. (See "Classification and epidemiology of anal cancer", section on 'HIV infection'.)

The high prevalence of anal SIL and the high incidence of anal cancer in PLWH may be due to multiple factors, including a greater likelihood of unprotected sex, a greater likelihood of infection with multiple HPV types, and an impaired mucosal immune response that facilitates HPV replication [12,25].

Impact of potent antiretroviral therapy — The widespread use of potent antiretroviral therapy (ART) has had a profound impact on reducing the incidence of HIV-associated, AIDS-defining malignancies, such as Kaposi sarcoma and diffuse large B cell lymphoma. (See "HIV infection and malignancy: Epidemiology and pathogenesis", section on 'AIDS-defining malignancies'.)

However, the effects of immune reconstitution with ART on non-AIDS-defining malignancies, including anal SIL and anal cancer are less clear. (See "HIV infection and malignancy: Epidemiology and pathogenesis", section on 'Non-AIDS-defining cancers'.)

Initial studies did not show a clear benefit of ART in decreasing the risk for anal HSIL [27] or anal cancer [50], and it was postulated that ART might be associated with an increased incidence of progression of HSIL to anal cancer due to the increased life expectancy of PLWH who take ART [50,51]. More recent work, however, does suggest a modest protective effect of ART [52-55]. The best data come from a large meta-analysis that evaluated the effect of ART on anal HSIL and reported a crude odds ratio of 0.84 (0.72-0.98) for having anal HSIL among PLWH with undetectable viral load compared with PLWH with detectable viremia [52]. Longer time from initiation of ART is associated with increased protection [54,55]; hence, it is possible that earlier studies did not allow for sufficient time to detect a protective effect. The moderate measures of association detected, however, suggest that the impact of ART on SIL may be limited in a population for whom the prevalence is already high. (See "When to initiate antiretroviral therapy in persons with HIV".)

These findings correlate well with recent trends in anal cancer in PLWH, where the incidence rate of anal cancer appears to have plateaued and declined from its peak, but still remains markedly elevated relative to the general population [48]. (See "Classification and epidemiology of anal cancer", section on 'HIV infection'.)

Other risk factors — Other risk factors that have been associated with the development of anal SIL include a history of rectal discharge [9], a history of anogenital warts [9], IVDU [56], current cigarette smoking [56], and iatrogenic immunosuppression (such as following solid organ transplantation) [57-62]. (See "Malignancy after solid organ transplantation", section on 'Anogenital cancers'.)

NATURAL HISTORY — In the cervix, the rates of progression to cervical cancer once cervical SIL (cervical intraepithelial neoplasia [CIN]) is present have been well characterized, largely due to a study in which treatment of SIL was unethically withheld [63]. (See "Cervical intraepithelial neoplasia: Management", section on 'Overview'.)

However, relatively little is known to date about the long-term natural history of anal SIL, which is thought to be more of a dynamic process, with lesions arising and regressing over time [64].

LSIL — Individuals with anal low-grade SIL (LSIL) found during a baseline high-resolution anoscopy (HRA) are at high risk of subsequent diagnosis of anal high-grade SIL (HSIL), and LSIL is considered to represent a marker for risk of HSIL rather than a direct precursor [65-69]. Risk factors for anal HSIL in patients with LSIL include HIV-related immunosuppression with a low cluster of differentiation (CD4) cell count, anal human papillomavirus (HPV) infection, and the presence of multiple HPV types, including the high-risk types [20,67-69]. As noted above, LSIL has been thought to represent a marker of risk for developing incident HSIL at other sites of the anal canal rather than a direct predecessor of HSIL. (See 'Histopathology and nomenclature' above.)

More recent studies have re-evaluated this paradigm by using HRA to follow individual LSIL lesions. As an example, in one study of HIV-positive males who have sex with males (MSM), of the 177 LSIL lesions identified at baseline, 29 (16.4 percent) were reported to progress to HSIL at follow-up [69]. However, given the technically challenging nature of HRA, which includes shifting of redundant mucosa, it is extremely challenging to follow the course of individual lesions over time. Hence, reported findings may have represented incident HSIL at a close location rather than true progression from LSIL to HSIL [64]. Notably, in this study almost 50 percent of LSIL had cleared at two years. Thus, anal lesions showing evidence of LSIL may spontaneously regress, as is well documented in the cervix. (See "Cervical intraepithelial neoplasia: Terminology, incidence, pathogenesis, and prevention", section on 'Age and persistence'.)

HSIL

Regression — Anal high-grade SIL (HSIL) is considered a true cancer precursor with the potential to progress to invasive anal squamous cell carcinoma. Although spontaneous regression of HSIL occurs, HSIL is less likely than anal LSIL to regress spontaneously, regardless of HIV status [14,16]. Lesions containing HPV 16 are the least likely to regress [70].

Despite this, it is increasingly accepted that some proportion of anal HSIL resolve without intervention, but it is not clear how often this happens [16,70-72]:

●A retrospective cohort study comprised primarily of MSM living with and without HIV noted resolution of anal HSIL in 24 percent of participants over a median follow-up of one year [16]. This study defined regression of anal HSIL as the absence of HSIL on follow-up HRA. However, in the absence of follow-up HRA, the presence of a negative anal cytology was considered sufficient evidence of the absence of anal HSIL. Given the limited sensitivity of anal cytology alone to detect anal HSIL, this study may have overrepresented the degree of regression. (See 'Anal cytology' below.)

●More recently, a randomized controlled trial comparing the efficacy of infrared coagulation versus active monitoring to treat anal HSIL found resolution of anal HSIL in 30 percent of participants within the active monitoring arm at one year [71].

●The Study of the Prevention of Anal Cancer (SPANC) study, which evaluated a cohort of MSM with serial HRAs over the course of three years, reported similar regression rates (22 per 100 person-years) in MSM with untreated anal HSIL [70]. (See 'High-resolution anoscopy' below.)

The mechanisms determining HSIL persistence versus regression remain poorly understood. HPV 16 is an important determinant of persistence [70]. Biopsy of lesions, especially when small, may also contribute to HSIL regression [71].

For individuals with anal HSIL, HPV vaccination is recommended within the recommended age range, as it can still provide protection against infection with HPV types not already acquired. However, vaccination has no therapeutic effect on pre-existing HPV infection (ie, it does not induce regression of HSIL), and has no role in preventing the progression of HSIL to invasive anal cancer. (See 'Pre-existing HPV-associated disease' below.)

Risk of progression to anal cancer — There is a heightened risk of developing anal cancer among specific groups, including people living with HIV (PLWH), females with a history of cervical or vulvar HSIL or cancer, and recipients of a solid organ transplant [60]. These groups are also known to have higher risk of anal HSIL. (See 'Epidemiology and risk factors' above.)

Several studies have attempted to quantify the risk of progression and define specific risk factors [8,13,70,73-78]:

●PLWH have a higher progression rate than HIV-negative individuals. The best data in this group come from the control arm of the  in which 4459 persons living with HIV age 35 years or older and who had biopsy-proven HSIL were randomly assigned to HSIL treatment or active monitoring [73]. At a median follow-up of 25.8 months, anal cancer was diagnosed in 21 of 2219 patients undergoing active monitoring (402 cases per 100,000 person-years), and the cumulative incidence of progression to anal cancer at 48 months was 1.8 percent. The time to progression of anal cancer was associated with lesion size (hazard ratio [HR] 5.26, 95% CI 2.54-10.87 for involvement of >50 percent of the anal canal or perianal region versus less) but not nadir CD4 count (HR 1.93, 95% CI 0.88-4.23). Treatment of the HSIL was associated with a significantly lower rate of progression to invasive anal cancer. (See 'Benefit of treatment' below.)

●Data on the risk of progression in people without HIV are limited:

•In a meta-analysis on the prevalence and incidence of anal HSIL and anal cancer in MSM, a theoretical rate of progression was indirectly calculated by dividing the prevalence of HSIL by the incidence of anal cancer [13]. The calculated risk of progression to invasive disease for MSM without HIV was one case of invasive cancer per 4196 males per year (0.02 percent per year).

•In two separate reports from the Surveillance, Epidemiology, and End Results registry, the five-year incidence of anal carcinoma after diagnosis of HSIL was 5.7 and 9.5 percent, respectively [76,79], or approximately 1.2 to 1.9 percent per year [76,79]. Median time from HSIL diagnosis to anal cancer diagnosis was 2.7 years (interquartile range 1.1 to 4.5 years).

•Others note that individuals without HIV who have autoimmune disease or genital warts before or after HSIL diagnosis have an increased risk of progression to invasive disease compared with those without these conditions [77].

CLINICAL MANIFESTATIONS, DIAGNOSIS, AND EVALUATION — For at-risk populations, it is appropriate to discuss the risk of anal SIL and anal cancer and the symptoms (eg, anorectal bleeding, pain, or growths) that should lead to a consultation with a clinician and digital anorectal examination.

Anal SIL is typically asymptomatic, although it may be associated with local symptoms such as pruritus, bleeding, discharge, irritation, and tenesmus. Condylomata (anogenital warts, a manifestation of low-grade SIL [LSIL]), in particular, can present with the above symptoms. When present, anal condylomata are usually clinically obvious and often have a frond-like or plaque-like appearance (picture 1). Other LSIL lesions are generally flat. (See "Condylomata acuminata (anogenital warts) in adults: Epidemiology, pathogenesis, clinical features, and diagnosis", section on 'Clinical manifestations'.)

The diagnosis of anal SIL ultimately requires histopathologic examination of the anal cytology and/or biopsy specimens. The evaluation of symptomatic individuals and asymptomatic individuals at increased risk for anal SIL should begin with a comprehensive medical history and physical examination. Key areas in the medical history include the following:

●History of clinical human papillomavirus (HPV) infection and other sexually transmitted infections

●Sexual history, including specific inquiry about receptive anal intercourse

●HIV serostatus and markers of infection (cluster of differentiation 4 [CD4+] T-cell count/nadir and viral load)

●Previous anal/gastrointestinal conditions

●Local symptoms (pain, itch, bleeding, discharge, irritation, tenesmus)

●Smoking history and recreational drug use

●Medication review, with particular attention to drugs associated with immunosuppression

The physical examination should include the following:

●Visual inspection of the perianal skin (picture 1).

●Digital examination and high-resolution anoscopy (HRA) examination of the anal canal. If anal cytology is planned, it should be performed before the digital or anoscopic examination and in the absence of lubricant. Practice standards for the performance of HRA have been published by the International Anal Neoplasia Society [2].

●Assessment of palpable lymphadenopathy.

Additional information on evaluating anorectal symptoms in males who have sex with males is provided elsewhere. (See "Evaluation of anorectal symptoms in men who have sex with men".)

SCREENING FOR ANAL SIL

Rationale — There are no randomized clinical trials that document the value of screening for anal SIL in at-risk populations [80]. Instead, the rationale for screening relies on the similarities between the anus and cervix, the established success of cervical cytology screening in reducing the incidence of cervical cancer, and the demonstrated benefit of treating HSIL in reducing the rate of progression to invasive anal cancer. (See "Screening for cervical cancer in resource-rich settings" and "Screening for cervical cancer in resource-limited settings".)

Indirect evidence supporting a potential benefit of screening for early detection and treatment of anal SIL in high-risk populations, which is derived from several sources [80]:

●The high incidence of anal cancer in the populations for which screening is proposed. (See "Classification and epidemiology of anal cancer", section on 'Epidemiology and risk factors'.)

●The availability of screening modalities that can effectively diagnose the anal cancer precursor lesion high-grade SIL (HSIL). (See 'Methodology' below.)

●The availability of effective treatments that can ablate HSIL. (See 'Our recommended approach to treatment' below.)

●The significant morbidity and mortality associated with anal cancer and its treatment if it is not prevented by effective screening and treatment. (See "Clinical features and staging of anal cancer" and "Treatment of anal cancer".)

●The cost-effectiveness of screening. (See 'Cost-effectiveness of screening' below.)

●The proven efficacy of screening for and treating cervical HSIL (cervical intraepithelial neoplasia [CIN] 3) in reducing the risk of cervical cancer. (See "Cervical cancer screening: Risk assessment, evaluation, and management after screening", section on 'Rationale and risk estimation'.)

●The demonstration of benefit for treating HSIL to prevent progression to invasive anal cancer in the ANCHOR randomized trial [73]. (See 'Risk of progression to anal cancer' above and 'Benefit of treatment' below.)

Traditional anal screening programs have relied on cytology as the initial screening test. (See 'Anal cytology' below.)

Who should be screened for anal SIL? — The patient populations that are at highest risk of anal cancer are outlined in the table (table 2). The risk-benefit ratio of screening for anal HSIL has not yet been established for any of the groups in this table, although as noted above, data from the ANCHOR trial provides a clear rationale for screening and early identification of HSIL in high-risk individuals.

Our suggested approach — The following represents our approach to screening for anal HSIL in high-risk groups:

●We suggest screening for all males who have sex with males living with HIV (MSMLWH), given the numerous studies that have documented the high prevalence of anal HSIL in males who have sex with males (MSM) with and without HIV [9,12-14,31,38,39,81], as well as the markedly elevated risk of anal cancer in MSMLWH [48,82-84].

●We also suggest screening for other at-risk groups (table 2) even though their risk for anal cancer is likely somewhat lower compared with MSMLWH [60]. Although there are no data to support a benefit for screening in these populations, there is a scientific rationale for anal cytology screening based on the reported high prevalence of anal human papillomavirus (HPV), anal SIL, and anal cancer in MLWH who do not have a history of anal intercourse [40,41], females living with HIV (WLWH) [37,41,42], females without HIV who have cervical infection with HPV 16 [29], and iatrogenically immunocompromised patients, including solid organ transplant recipients [58].

For those who do choose to screen for anal HSIL, variation exists among approaches (eg, frequency and timing of digital and anorectal examination by anoscopy, whether to perform anal cytology and/or HPV testing). These issues are all addressed in detail below. (See 'Methodology' below.)

An important point is that it is not appropriate to offer screening to at-risk populations in the absence of local expertise in the interpretation of screening results, and without availability of a referral infrastructure for high-resolution anoscopy (HRA) with biopsy as well as access to ablative treatments and follow-up. (See 'Methodology' below.)

Timing and frequency of screening — There is no consensus on the optimal time to initiate screening. Given the low incidence of anal cancer among immunosuppressed individuals under the age of 25 years and immunocompetent individuals under the age of 40 years, we generally defer screening PLWH and those with other forms of immune suppression until after 25 years of age and defer screening at-risk immunocompetent individuals until after 40 years of age.

In addition to the lack of guidelines on who and how individuals at risk for anal cancer should be screened, there are no guidelines on how often they should be screened. Based on cost-benefit analyses, many experts, including the authors of this topic, screen at-risk individuals without HIV every two to three years, while PLWH may be screened annually [85,86].

The age at which screening should be discontinued is also not well defined and may vary according to the ongoing risk of an individual. It is possible that anal HPV testing may be helpful in this regard since an individual who is persistently negative for high-risk (hr)-HPV DNA is likely to be at low risk for developing anal cancer in the future.

Methodology — Anal HSIL is typically not palpable, and is unlikely to be discovered on routine digital anorectal examination. Traditional anal HSIL programs have relied on cytology as the initial screening test. Individuals with abnormal cytology are subsequently referred for HRA to examine the anal canal and perianus and identify areas of potential HSIL to biopsy. (See 'Histopathology and nomenclature' above.)

Anal cytology — Anal exfoliative cytology is performed using a water-moistened polyester fiber swab to collect cells prior to anoscopy or anal examination. Polyester fiber is recommended over a cotton swab because it is thought to release its cellular harvest more readily and because it typically has a plastic shaft that will not break during collection. Swabs with scored or wooden shafts that can break off should be avoided [87]. Collection of anal cytology should occur prior to digital anorectal examination or anoscopy to avoid loss of cellular yield and morphology associated with lubrication. It is most commonly performed without direct visualization of the anal canal. The patient is typically positioned in the left lateral position. Next, the moistened swab is gently inserted until it cannot be advanced any further because it has reached the wall of the rectum, thus positioning the swab proximal to the anorectal transformation zone. The swab is then withdrawn with lateral pressure, using a spiral motion to sample the entire circumference of the anal canal. Since the procedure is performed blind, cells from the lower rectum, squamocolumnar transformation zone, and anal canal are sampled.

After removal, the sample may be either fixed conventionally with ethanol or processed using a liquid cytology technique before staining with the Papanicolaou (Pap) method. The latter method is preferable, when available, since it may yield better results among clinicians with limited experience performing anal cytology [9].

Although clinician-collected samples are the norm for anal cytology, self-collected anal cytology may increase patient compliance and decrease cost of screening. Several studies note similar results between self-collected and clinician-collected samples [88-91], although sensitivity may be somewhat better with clinician-collected samples [39].

●Test characteristics in MSMLWH – Test characteristics for anal cytology are best described in MSMLWH, in whom the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) to detect biopsy-proven anal HSIL are approximately 83, 45, 36, and 87 percent, respectively. Individuals with abnormal cytology are subsequently referred for HRA to examine the anal canal and perianus and identify areas of potential HSIL to biopsy. (See 'High-resolution anoscopy' below.)

Studies on the performance characteristics of anal cytology to detect HSIL typically involve HRA as the gold standard against which cytology is compared. Test characteristics have been best studied in MSM, particularly MSMLWH, where performance is comparable to cervical cytology in the detection of CIN [92]. The sensitivity and specificity rates of anal cytology to detect biopsy-proven anal HSIL were 83 and 45 percent, respectively in a meta-analysis of studies evaluating techniques for anal HSIL detection in MSMLWH [93]. PPV and NPV were 36 and 87 percent, respectively. These results are consistent with previous studies [92,94-96], and reflect the use of any cytologic abnormality, including atypical squamous cells of undetermined significance (ASC-US), as the threshold for HRA referral. (See 'Histopathology and nomenclature' above.)

This approach results in reasonable sensitivity and NPV but at the expense of specificity and PPV. Therefore, while a negative cytologic evaluation will not entirely exclude anal HSIL, it is considered acceptable for most patients given the slow progression of anal HSIL, and that fact that overall NPV is expected to increase with serial cytology samples over time. Also worth noting is that 59 percent of MSM and 42 percent of females had abnormal cytology in the above studies, reflecting the large number of HRA referrals that are generated by screening anal cytology [93,97].

While the use of any abnormality on anal cytology as the threshold for HRA referral decreases the overall specificity of anal cytology, any report of HSIL on anal cytology is fairly specific for the presence of histologic (biopsy-documented) HSIL. Thus, the probability of detecting HSIL on HRA-guided biopsy is high when a screening anal cytology reports HSIL [93].

Among MSMLWH, some experts recommend direct referral for HRA without screening anal cytology given the above limitations and the documented high prevalence of anal HSIL in this group [9,13,14,31,38,39], and at least some data suggesting cost effectiveness for HRA in this setting [98]. (See 'Cost-effectiveness of screening' below.)

However, in most practice settings, including those of the authors and editors of this review, there are insufficient resources to perform HRA on all at-risk individuals, and cytology allows clinicians to prioritize those most likely to benefit from HRA, such as individuals with HSIL on cytology, followed by those with low-grade SIL (LSIL).

●Performance in other high-risk populations – Performance data for anal cytology are more limited in other at-risk populations, although one contemporary study of 636 females with a history of lower anogenital tract SIL also reported limited PPV but reasonable NPV for anal cytology in this setting [97].

Molecular diagnostics — Despite the feasibility of molecular diagnostic tests such as hr-HPV DNA detection, HPV E6/E7 mRNA analysis, and P16INK4a and Ki-67 immunostaining to diagnose anal HSIL, a clear benefit for any of these tests over anal cytology has not yet been established in MSM and MSMLWH, and their use cannot be recommended. These diagnostics may perform better in other at-risk populations where the prevalence of anal hr-HPV is lower. In this setting, a substantial proportion of individuals would test negative for hr-HPV and would forego additional work-up.

There has been substantial interest in the application of molecular techniques to detect anal HSIL given some of the limits associated with anal cytology. Testing for hr-HPV subtypes has been studied fairly extensively in MSMLWH even though this test has not been explicitly approved for use in the anal canal. Unfortunately, due to the ubiquitous nature of anal hr-HPV in MSMLWH, the use of hr-HPV testing as an alternative to anal cytology appears to add little benefit [93,99]. In these studies, similar to the performance of anal cytology, sensitivity and NPV using molecular diagnostic tests were reasonably high while specificity and PPV remained limited. While some studies that evaluated testing for hr-HPV or HPV 16 in conjunction with anal cytology found improved performance relative to cytology alone [100,101], but this has not been a consistent finding [99,102]. Biomarkers of cellular proliferation like p16/Ki-67 or E6/E7 mRNA could theoretically also improve test characteristics; however, studies to date have not yet identified improved performance compared with cytology alone [93,102].

In one study of anal HPV testing to screen for anal HSIL in females living with HIV, anal high-risk HPV testing using the Aptima or Hybrid Capture 2 methods demonstrated similar sensitivity to abnormal anal cytology (atypical squamous cells of undetermined significance or higher) to predict anal HSIL with higher specificity [103]. Anal high-risk HPV testing may be an useful alternative strategy to anal cytology for anal HSIL screening among females living with HIV.

High-resolution anoscopy — An abnormal anal cytology screening test should be followed by HRA for a diagnostic biopsy.

HRA refers to the examination of the anal canal and perianus using a colposcope for lighting and magnification, after application of 5% acetic acid and Lugol iodine solutions to identify anal lesions [2]. This procedure allows the clinician to visualize the lesions that represent the source of abnormal cells on cytology screening or HPV if HPV testing was used as the screening test, and obtain biopsy specimens for histopathologic assessment. As in the cervix, anal histopathology is necessary to grade the severity of the disease; this cannot be accurately established with visual evaluation or cytology alone. The goal of the biopsy is to identify HSIL or invasive anal cancer since these may be targeted for treatment. (See "Treatment of anal cancer".)

Although the left lateral decubitus position is typically chosen to facilitate consistent communication, other positions are acceptable as well. Prior to examination, a 4 x 4 gauze swab is wrapped around a Q-tip and soaked in 5% acetic acid. By inserting this Q-tip into the anal canal, the acetic acid is applied evenly prior to visualization. The acetic acid produces a white appearance in areas of abnormal transitional epithelium and facilitates mucosal examination for anoscopy, as it does for cervical colposcopy (picture 2) [104]. (See "Colposcopy".)

The anoscopic changes most often associated with HSIL are similar to those seen in cervical colposcopy [105]. These include the presence of acetowhite change on flat/slightly raised or thickened epithelium (picture 2), with or without abnormal blood vessels (mosaic pattern/punctuation). Tissues with these features that stain negatively with Lugol iodine should be considered highly suspicious for HSIL and biopsied. Tissues that do not take up Lugol stain in the absence of these features may also contain HSIL and should be considered for biopsy, particularly when the patient has HSIL on cytology. A description of specific patterns associated with HSIL on biopsy versus LSIL on biopsy is available [106].

Cost-effectiveness of screening — Several cost-effectiveness analyses suggest that periodic screening of MSM both with and without HIV may be beneficial. Importantly, these studies make assumptions about the efficacy of treatment of anal HSIL to prevent anal cancer, even though no definitive data to demonstrate this are presently available. (See 'Risk of progression to anal cancer' above.)

The following data are available:

●In one study, a state-transition Markov model was developed to calculate lifetime costs, life expectancy, and quality-adjusted life expectancy for no screening versus several screening strategies in a population of MSMLWH [86]. Strategic variables in this model included screening interval and stage of HIV infection. Annual screening for anal SIL increased quality-adjusted life expectancy at all stages of HIV disease.

●A second study of MSM without HIV noted that screening every two to three years provided benefits in both life expectancy and cost-effectiveness [85].

●A more recent model noted that direct referral for HRA in MSMLWH could be cost-effective given the high prevalence of HSIL within this population [98].

●Studies in females at high-risk for anal cancer also suggest that screening with anal cytology is cost-effective [107,108].

Recommendations from expert groups — National guidelines recommending anal screening for precancerous lesions have not been adopted by the United States Public Health Service. Guidelines from other expert groups are variable, and evolving over time:

●Year 2021 guidelines from sexually transmitted infection from an expert advisory group convened by the Centers for Disease Control state that all people living with HIV (PLWH) ≥35 years old have substantially elevated anal SCC risk and should be considered for anal cancer prevention interventions, including screening [109]. Other risk groups include women with a history of HPV-associated genital cancers, solid organ transplant recipients, HIV-negative MSM, and other immunocompromised individuals without HIV infection. Patients who do not fall into an increased risk category should not be screened for anal cancer.

●For PLWH, the HIV Medicine Association of the Infectious Diseases Society of America makes a weak recommendation based on moderate-quality evidence for screening with anal cytology in MSMLWH, WLWH with a history of receptive anal intercourse or abnormal cervical Pap test results, and PLWH with a history of genital warts [110]. (See "Initial evaluation of adults with HIV", section on 'Screening for HPV-associated neoplasia'.)

●The Society of Transplantation Infectious Diseases Community of Practices, recommend yearly anal cytology in solid organ transplant recipients, particularly those with a history of receptive anal intercourse and/or CIN [111].

●The American Society of Colon and Rectal Surgeons recommends consideration of anal HSIL screening in high-risk populations including PLWH, MSM, and females with a history of CIN [112].

PREVENTION — We agree with guidelines from the United States Advisory Committee on Immunization Practices (ACIP), which recommend immunization with the human papillomavirus (HPV) vaccine of all males and females at age 11 to 12 years old, with vaccination starting as early as age 9 and continuing through age 26 [113]. This recommendation extends to all immunocompromised individuals, including people living with HIV (PLWH). The US Food and Drug Administration (FDA) has also approved use of the HPV vaccine for adults ages 27 through 45 years old. While catch-up vaccination is not routinely recommended for older adults, the ACIP recommends shared decision-making in this group between individuals and their providers based on likelihood of benefit [113]. (See "Human papillomavirus vaccination", section on 'Indications and age range'.)

Several vaccines have been developed that are directed against HPV, which vary in the number of HPV types they contain and target, although not all are available in all locations. In the United States, only the 9-valent vaccine (Gardasil-9, which targets HPV types 6, 11, 16, and 18 as well as types 31, 33, 45, 52, and 58) is available. These are all prophylactic vaccines, designed to prevent initial HPV infection and subsequent HPV-associated lesions. In the United States, the 9-valent is specifically approved for prevention of cervical, vulvar, and vaginal cancers in females, and for prevention of anogenital SIL as well as anal, oropharyngeal, and other head and neck cancers in both males and females. (See "Human papillomavirus vaccination", section on 'Choice of vaccine'.)

Data informing the impact of HPV vaccination on anal SIL and anal cancers are more limited than those for cervical disease but suggest efficacy in males, especially males who have sex with males (MSM), and expected efficacy in females. As with cervical infection and disease, prior HPV infection appears to attenuate vaccine efficacy for anal infection and disease. (See "Human papillomavirus vaccination", section on 'Efficacy'.)

The following data are available for anal SIL and anal cancer:

●Males

•A randomized controlled trial of 4065 adolescent boys and young males demonstrated the efficacy of the older quadrivalent HPV vaccine in preventing infection with HPV types 6, 11, 16, and 18 and the development of external HPV-related genital lesions (including perianal SIL and perianal cancer) [114]. (See "Human papillomavirus vaccination", section on 'Efficacy'.)

A planned substudy of the trial analyzed the impact of the HPV vaccine on the development of anal SIL in 602 MSM [115]. The study population consisted of sexually active MSM aged 16 to 26 years who had a history of five or fewer lifetime sexual partners. Individuals with a history or evidence of anal lesions at baseline were excluded, as were participants with HIV at time of enrollment. The primary endpoint was the development of anal SIL associated with HPV types 6, 11, 16, or 18.

Two separate analyses were performed. The intention-to-treat analysis included all participants, regardless of baseline HPV serologic status or baseline anal HPV DNA testing, who received at least one dose of the vaccine and had at least one follow-up visit. The analysis included all documented cases of type-specific anal SIL or type-specific anal cancer after the first vaccine dose. The per-protocol analysis included participants who received all three vaccine doses per study protocol and who had no evidence of HPV infection at baseline and upon completion of the vaccination series (ie, HPV seronegative at baseline and negative anal HPV DNA testing at baseline and one month after completion of the vaccination series). In the per-protocol analysis, only events that occurred at least one month after the completion of the vaccination sequence were counted.

Overall, 598 patients received one or more dose(s) of the vaccine, and 551 of these were eligible for the intention-to-treat analysis:

-The incidence of anal SIL associated with HPV 6, 11, 16, or 18 was decreased by 50 percent in those assigned to the vaccine compared with placebo (6.3 versus 12.6 events per 100 person-years at risk). There was a 50 percent decrease in the incidence of low-grade SIL (LSIL) with the vaccine (5.0 versus 9.9 events per 100 person-years at risk) and a 54 percent decrease in the incidence of high-grade SIL (HSIL; 2.7 versus 6.0 events per 100 person-years at risk). There were no cases of anal cancer in either group.

-The incidence of persistent infection with the relevant HPV types was decreased by 59 percent (8.8 versus 21.6 events per 100 person-years at risk), and the detection of HPV DNA was decreased by 49 percent (15.9 versus 30.9 events per 100 person-years at risk).

The per-protocol analysis included 402 of the 598 males (67 percent) who received all three doses of the vaccine and were seronegative for HPV and had an HPV DNA-negative swab and biopsy specimens on day 1.

The incidence of anal SIL associated with HPV 6, 11, 16, or 18 was decreased by 78 percent in those receiving the vaccine compared with those receiving placebo (1.3 versus 5.8 events per 100 person-years at risk). Magnitude was similar for LSIL and HSIL (73 percent decrease in the incidence of LSIL with the vaccine [1.0 versus 3.9 events per 100 person-years at risk] and a 75 percent decrease in the incidence of HSIL [0.8 versus 3.1 events per 100 person-years at risk]).

These results indicate that the use of the quadrivalent vaccine decreases the incidence of anal SIL in MSM. The higher efficacy in the per-protocol analysis highlights how prophylactic HPV vaccines work best when administered prior to HPV exposure. Routine vaccination, therefore, should ideally occur prior to the onset of sexual activity. (See "Human papillomavirus vaccination", section on 'Optimal timing'.)

•The importance of vaccination prior to sexual initiation was shown in a second trial that addressed the efficacy of HPV vaccination in young (<26 year old) MSMLWH [81]. In this trial, 144 MSMLWH without HSIL at baseline were vaccinated at 0, 2, and 6 months, and screened using cytology, high-resolution anoscopy, serology and HPV testing at screening at months 7, 12, and 24. There were no incident quadrivalent HPV type-associated anal LSIL/HSIL cases among males naïve to those types at baseline, while there were 11.1, 2.2, 4.5, and 2.8 cases per 100 person years for HPV 6, 11, 16, and 18-associated LSIL/HSIL, respectively, among those previously exposed to that type.

●Females

•Among females, there are no direct efficacy data regarding prevention of anal SIL, but bivalent HPV vaccination has been demonstrated to reduce the incidence of anal infection with HPV types 16 and 18, and since the majority of anal cancers in both females and males are related to these subtypes, a beneficial impact of vaccination on anal SIL and anal cancer risk in females is expected and anticipated [116].

●PLWH older than 26 years

•As noted above, a study of 260 MSMLWH aged 18 to 26 emphasized the importance of vaccination before initial sexual activity [81]. A single randomized trial of the quadrivalent HPV vaccine in nearly 600 PLWH older than 26 years demonstrated poor vaccine efficacy (approximately 20 percent compared with placebo) in preventing new persistent anal HPV infection [24]. This likely reflects even higher levels of prior exposure to vaccine HPV types than in the study of younger MSMLWH [81]. Similar to the young males, baseline HPV infection and seropositivity were high, and one-third had existing HSIL. Thus, these findings are consistent with the understanding that the impact of HPV vaccination is reduced among those who have prior HPV infection. (See 'Pre-existing HPV-associated disease' below.)

Pre-existing HPV-associated disease — A history of genital warts, a positive human papillomavirus (HPV) test result, or a history of cervical, vaginal, vulvar, or anal SIL all indicate prior HPV infection but not necessarily with all of the HPV types included in the vaccines. Vaccination is still recommended in individuals within the recommended age range described above, even if they have evidence of prior HPV infection, as it can still provide protection against infection with HPV types not already acquired. However, vaccine efficacy is reduced in such cases, and vaccination has no therapeutic effect on pre-existing HPV infection (including HSIL). (See "Human papillomavirus vaccination", section on 'Optimal timing' and "Human papillomavirus vaccination", section on 'Pre-existing HPV-associated disease'.)

TREATMENT

Our recommended approach to treatment — The availability of treatment modalities for anal SIL varies by geographic location, the presence of clinical expertise and familiarity with this disease, and treatment availability. Modalities are comprised of topical therapies, either clinician or patient applied, as well as office-based ablative therapies. A small subset of patients with HSIL may benefit from treatment in the operating room (high-resolution anoscopy [HRA]-directed surgical ablation).

The following reflects our general approach to treatment:

●Intra-anal high-grade SIL

•For individual small lesions (ie, <1 cm² at the base) or lesions that represent less than 50 percent of the circumference of the anal transition zone (ATZ), reasonable options include application of 80% trichloroacetic acid (TCA), where available, or targeted ablation in the office using infrared coagulation (IRC), radiofrequency ablation (RFA), or electrocautery/hyfrecation. For patients without access to TCA, ablation or surgical management are appropriate alternatives.

TCA is unlikely to be effective with larger lesions, and for more extensive HSIL, local ablation is preferred. If there is concern for stenosis, these procedures may be undertaken in a stepwise manner, with no more than 50 percent of the ATZ circumference treated at any one visit.

Alternatively, use of topical therapies like the immune modulator imiquimod or 5% fluorouracil (FU) may be used in the anal canal. This may result in either complete resolution of the lesions or a reduction in size to where local ablative therapies may then be used.

•Caveats include:

-None of these approaches are approved by the US Food and Drug Administration (FDA).

-Data on the relative efficacy of different treatment agents to reduce or clear HSIL are limited. (See 'Efficacy of available treatment modalities' below.)

●Perianal high-grade SIL – As with anal canal HSIL, small discrete lesions may be treated with TCA, where available, or local ablation. More extensive lesions can be approached initially with application of topical imiquimod or 5% FU prior to considering IRC or ablation.

●Low-grade SIL – In our view, treatment of asymptomatic LSIL, including condylomata, is optional since it is thought to represent a marker of risk for developing incident HSIL rather than a true precancerous lesion. (See 'Histopathology and nomenclature' above.)

However, others may disagree, suggesting that treatment for condylomata not be deferred due to the risk of local progression, which may make them more difficult to treat. (See "Condylomata acuminata (anogenital warts): Management of external condylomata acuminata in adult males", section on 'Indications for treatment'.)

In addition, some patients with LSIL may elect therapy for a variety of reasons, including symptoms (burning, itching, and bleeding) or psychologic distress. Patients with LSIL, including those with treated lesions, should be followed regularly because of the high risk of subsequently developing anal HSIL. (See 'LSIL' above and 'Post-treatment surveillance' below.)

Benefit of treatment — For most patients with HSIL, we suggest treatment rather than observation. Treatment of asymptomatic LSIL is optional, given that these are not considered precancerous lesions. All patients with LSIL should undergo HRA to rule out HSIL and invasive anal cancer, and should be followed regularly for recurrent or incident lesions. Management of anal condylomata is addressed elsewhere. (See "Condylomata acuminata (anogenital warts): Management of external condylomata acuminata in adult males", section on 'Indications for treatment'.)

The benefit of treating HSIL to reduce the risk of invasive anal cancer was shown in the phase III  in which 4459 persons living with HIV age 35 years or older and who had biopsy-proven HSIL were randomly assigned to HSIL treatment or active monitoring [73]. Treatment included office-based ablative procedures, ablation or excision under anesthesia, or the administration of topical fluorouracil or imiquimod. At a median follow-up of 25.8 months, invasive anal cancer was diagnosed in 9 of 2227 treated patients versus 21 of 2219 control patients (173 versus 402 cases per 100,000 person-years), and treatment reduced the risk of progression by 57 percent (95% CI 6-80, p = 0.03). The cumulative incidence of progression to anal cancer at 48 months was 0.9 versus 1.8 percent in the treatment and active monitoring groups, respectively. The rate of trial-related serious adverse events was low overall but higher in the treated group (seven versus one), and included skin ulceration, anal abscess, and treatment-related pain.

Efficacy of available treatment modalities — There are few high-quality studies addressing the efficacy of various treatments for anal SIL and the selection of treatment modality remains largely empiric. The availability of treatment modalities for anal SIL varies by geographic location and presence of clinical expertise and familiarity with this disease. Modalities are comprised of topical therapies, either clinician or patient-applied, as well as office-based ablative therapies. A small subset of patients may benefit from treatment in the operating room (HRA-directed surgical ablation).

Topical therapy — Topical therapies are not specifically FDA approved for treatment of anal SIL. However, they are commonly used off label to treat HSIL. Although there are many potential side effects of local therapies (including erythema, ulceration and bleeding with associated symptoms of irritation/burning and pain, and occasional systemic flu-like symptoms with imiquimod), most are very well tolerated, with only minimal symptoms experienced by the patient.

●TCA – For small lesions (<1 cm² at the base), local application of TCA, where available, by a clinician is a reasonable option. Topical application of TCA is generally well tolerated but can occasionally be painful.

In a retrospective cohort of 72 males living with HIV (MLWH), 98 HSIL were treated using TCA, with an almost 80 percent resolution of HSIL on follow-up. Only two lesions (2 percent) required more than two treatments [117]. Similar results were obtained from another retrospective study of 54 males with and without HIV [118]. In both studies, TCA was more effective in younger patients.

●FU – Other topical therapies, such as fluorouracil (FU), can be self-applied by patients, including topical FU. A 16-week course of self-administered twice-weekly topical FU (5% cream with one gram self-administered intra-anally using a standard anal applicator at each dose) given to 46 males who have sex with males living with HIV (MSMLWH) and who had LSIL or HSIL resulted in a complete response in 18 and a partial response in eight (overall response rate 57 percent) [119]. Efficacy rates were somewhat lower in a subsequent small, randomized-controlled trial comparing FU versus topical imiquimod or electrocautery [120], as described above. (See 'Efficacy of available treatment modalities' above.)

●Imiquimod – A course of self-applied intra-anal imiquimod, an immune modulator, can result in resolution of anal SIL in MSMLWH; however, ablation is probably more effective and associated with fewer treatment-associated side effects [120-122]:

•In a small, randomized-controlled trial, 64 MSMLWH with anal HSIL were randomly assigned to imiquimod or placebo, both applied to the anal canal three times per week for four months [122]. Of the 28 patients given imiquimod, four had complete resolution of SIL and eight had LSIL but no HSIL following completion of treatment. Only 1 of 25 patients on placebo had resolution of the HSIL. At a median follow-up of three years, 61 percent of patients within the treatment group had a sustained absence of HSIL.

•A small randomized trial comparing topical imiquimod versus FU or electrocautery in MSMLWH who had LSIL or HSIL concluded that electrocautery had a higher rate of complete resolution than either topical therapy, and rates of grade 3 to 4 treatment-related side effects were highest with imiquimod [120]. (See 'Choice of therapy' below.)

Infrared coagulation, hyfrecation, argon plasma coagulation, and radiofrequency ablation — Lesions that are too large for TCA can be treated with office-based ablative procedures. As with topical therapy, office-based ablative modalities are not specifically approved by the FDA for treatment of anal HSIL with the exception of RFA. The two most commonly used office-based ablative modalities are IRC and hyfrecation (electrocautery).

●Infrared coagulation – IRC is approved for the treatment of hemorrhoids and anal warts. (See "Home and office treatment of symptomatic hemorrhoids".)

Treatment of anal HSIL with IRC consists of the direct application of a 1.5-second pulse of irradiation in the infrared range to the anal epithelium, which results in tissue destruction to a depth of approximately 1.5 mm. The coagulated tissue can then be debrided using Tischler biopsy forceps. Possible procedure-related complications include immediate and delayed bleeding and infection [123].

Multiple studies have demonstrated the safety and efficacy of IRC in people with HSIL both with and without HIV [71,124-127]. A randomized, open-label trial of 120 PLWH with anal HSIL compared IRC with active monitoring and noted that complete index-HSIL lesion clearance was more frequent in the treatment group than in the monitoring group (62 versus 30 percent at one year, risk difference 32 percent, 95% CI 13-48 percent) [71]. It is worth noting the relatively high rates of persistent HSIL within the treatment group at one year, which is consistent with previous retrospective studies evaluating IRC [125,127]. Additionally, incident metachronous HSIL (lesions at other sites of the anal canal) were common.

●Hyfrecation – Hyfrecation (electrocautery ablation) is also commonly used to treat anal HSIL. Some clinicians prefer it over IRC because it may be faster, particularly for large and keratotic lesions. It is also easier to use than IRC for perianal disease. Its efficacy profile appears to be similar to IRC.

A retrospective series of 232 males who have sex with males (MSM) with and without HIV reported approximately 80 percent efficacy in resolution of anal HSIL lesions following hyfrecation [128]. As with IRC, however, index lesion recurrence and metachronous lesions were common. At a median of 12.2 months postablation (range of follow-up 6.3 to 20.9 months postablation), approximately 45 percent of participants had developed index lesion recurrence, whereas 60 percent had either index lesion recurrence or incident metachronous HSIL. A separate study noted the following risk factors for persistent HSIL following hyfrecation: multiple index lesions, HIV viremia, cigarette smoking, as well as the presence of HPV-16/18 DNA [129].

●APC and RFA – Argon plasma coagulation (APC) and RFA are two less commonly used ablative modalities. APC, a technique used by endoscopists to treat pathologies of the gastrointestinal mucosa, was evaluated in a prospective pilot study of MSMLWH [130]. Sixty-five percent of participants (13 of 20) were clear of HSIL at their 24-month visit, with response rates after the first, second, and third APC treatments of 45, 44, and 67 percent, respectively. As with other treatment modalities, recurrences were common, and equipment cost may be a limiting feature.

RFA has been approved by the FDA for treatment of anal HSIL. This technique provides circumferential ablation of the squamocolumnar junction and has been shown to be effective in a small study performed at a single center [131]. Studies of larger numbers of patients in different centers need to be performed before this technique is widely adopted in the field.

HRA-directed surgical ablation — For lesions that are too large for office-based local ablation, a combination of initial high-resolution anoscopy (HRA)-guided surgical destruction in the operating room and follow-up with office-based ablation may be effective [125]. In general, the HRA-guided surgical destruction is ablation unless there is concern for invasive malignancy, in which case, excision is attempted.

The effectiveness and safety of this approach were illustrated by a retrospective review of the experience with 246 patients treated at the University of California, San Francisco, over a 10-year period [125]. Overall, 200 patients (81 percent) were treated with a single surgical procedure, although 57 percent of these did develop recurrent disease at an average of 19 months after the initial procedure. In 46 patients (19 percent), multiple staged treatments were required for complete lesion ablation. Significant complications were observed in only nine patients (including one with bleeding requiring reoperation, two with anal stenosis, and four with anal fissures).

The high rate of local recurrence, even in patients initially thought to have been completely ablated with a single procedure, mandates careful surveillance following treatment [125]. Nonetheless, most such recurrences can be successfully managed with office-based therapy. (See 'Post-treatment surveillance' below.)

Choice of therapy — As noted previously, only limited data are available comparing different treatment modalities for anal SIL. One relatively small randomized trial compared topical imiquimod, topical FU, and hyfrecation (electrocautery ablation) in 156 MSMLWH who had anal SIL (HSIL in 57 percent) [120]. Hyfrecation resulted in the highest rate of histologic clearance at four weeks following the completion of treatment (18 of 46 [39 percent] versus 13 of 54 [24 percent] for imiquimod and 8 of 48 [17 percent] for FU), and the results with hyfrecation were significantly better than either of the topical therapies. However, recurrence rates were high with all therapies. Among the 50 responders to any form of treatment, 11 (22 percent) recurred by 24 weeks, 22 (46 percent) by 48 weeks, and 30 (72 percent) by 72 weeks. The most common treatment-related side effects were pain, bleeding, and itching, and grade 3 or 4 side effects were more common with topical imiquimod (43 percent versus 27 and 18 percent for FU and hyfrecation, respectively). (See 'Topical therapy' above.)

It is unclear from this study how well each treatment modality performed in the treatment of HSIL compared with all SIL. Furthermore, the results are difficult to generalize to settings where there is variation in the number and/or size of HSIL lesions. A randomized trial comparing FU, versus imiquimod versus placebo in PLWH with anal HSIL is presently underway and should provide further information.

ISSUES SPECIFIC TO PERIANAL HIGH-GRADE SIL — Human papillomavirus (HPV)-related condylomatous perianal disease (ie, low-grade SIL [LSIL]) presents much more frequently to clinicians than does anal canal SIL. Standard therapeutic approaches for these lesions are discussed elsewhere. (See "Condylomata acuminata (anogenital warts): Management of external condylomata acuminata in adult males".)

On the other hand, perianal high-grade SIL (HSIL; including Bowen disease and cutaneous carcinoma in situ) is less well described and recognized. In 1912, Bowen first described the lesions that bear his name as chronic, red or hyperpigmented, well-defined, scaly plaques [132]. Histologic examination shows HSIL without dermal invasion. Perianal HSIL is less often associated with HPV than SIL involving the anal canal, and approximately 5 percent of these lesions progress to invasive squamous cell cancer [133]. Other studies have confirmed the malignant potential of these lesions [134-136]. Treatment modalities for perianal HSIL include electrodessication and curettage, and excisional surgery [137]. Imiquimod or topical fluorouracil (FU) cream may also be tried. (See "Treatment and prognosis of low-risk cutaneous squamous cell carcinoma (cSCC)".)

Anal SIL of varying grades may occur in the perianal skin without classical Bowenoid appearances, and unfortunately, there is a paucity of clinical literature describing the gross or anoscopic appearances of these lesions. As with intra-anal SIL, there are no nationally recognized treatment guidelines for perianal SIL.

POST-TREATMENT SURVEILLANCE — Due to the high rates of recurrence and evolving anal SIL, surveillance with high-resolution anoscopy (HRA) and biopsy of lesions suspicious for high-grade SIL (HSIL) or cancer are required following initial treatment. Although the optimal schedule has not been established, our approach is to follow up in four to six months, including repeat biopsy of the treatment site if there is lesion persistence. Anal cytology may also be useful as an adjunctive test to confirm lesion clearance.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Anal cancer".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology, risk factors, and natural history

•Anal squamous intraepithelial lesions (SIL) are preinvasive anal neoplasia caused by human papillomavirus (HPV) infection. Risk factors for anal SIL include sexual behavior, HIV, and iatrogenic immunosuppression (eg, solid organ transplant recipients). Rates of anal neoplasia are substantially higher among males who have sex with males (MSM), and are particularly high in MSM who are living with HIV (MSMLWH). (See 'Epidemiology and risk factors' above.)

For high-risk populations (table 2), clinicians should discuss the risk of anal SIL and cancer and the symptoms that should lead to a consultation and digital anorectal examination. (See 'Clinical manifestations, diagnosis, and evaluation' above.)

•Anal low-grade SIL (LSIL) is a risk factor for the presence of anal high-grade SIL (HSIL) and/or invasive cancer, rather than a direct precursor. Anal HSIL can progress to invasive anal cancer. (See 'Natural history' above.)

●Screening

•No clinical trials have evaluated the risk benefit ratio of screening for anal SIL; support for screening relies on the similarities between the anus and cervix, the established success of cervical cancer screening, and the demonstrated benefit of treating HSIL in reducing the rate of progression to invasive anal cancer. (See 'Rationale' above.)

•Cytology is used as the initial screening test. Individuals with abnormal cytology are referred for high-resolution anoscopy (HRA) to examine the anal canal and perianus and to biopsy areas of potential HSIL. (See 'Anal cytology' above.)

•Whom to screen (see 'Who should be screened for anal SIL?' above):

-We suggest screening for anal SIL in all MSMLWH (Grade 2C).

-We also suggest screening for other at-risk groups (table 2), even though their risk for anal cancer is likely lower than MSMLWH (Grade 2C).

It is inappropriate to offer screening without local expertise in the interpretation of screening results, and without a referral infrastructure for HRA with biopsy, access to ablative treatments, and follow-up.

•We initiate screening after age 25 in people living with HIV (PLWH) and those with other forms of immunosuppression, and after age 40 for at-risk groups without immunosuppression. At-risk individuals without HIV are typically screened every two to three years, while PLWH may be screened annually. (See 'Timing and frequency of screening' above.)

●Prevention

•HPV vaccination decreases the incidence of infection with the high-risk HPV types associated with cervical and anal cancer. (See 'Prevention' above.)

We agree with the United States Advisory Committee on Immunization Practices (ACIP), which recommends immunization of all males and females starting as early as age 9 and continuing through age 26, and shared decision-making for potential catch-up vaccination in adults ages 27 to 45 years. (See "Human papillomavirus vaccination", section on 'Indications and age range'.)

Vaccination before sexual initiation is most effective. While efficacy is reduced, vaccination is still recommended in individuals with evidence of prior HPV infection, as it can provide protection against infection with HPV types not already acquired. Vaccination has no therapeutic effect on pre-existing HPV infection (including HSIL). (See 'Pre-existing HPV-associated disease' above.)

●Treatment – Data from the ANCHOR trial now demonstrate efficacy of treating anal HSIL to reduce the risk of invasive anal cancer in people living with HIV aged 35 and older. The majority of participants in this study were treated with ablative therapy (hyfrecation), however the optimal treatment modality has not been clearly established. (See 'Benefit of treatment' above.)

The following represents our approach to treatment (see 'Our recommended approach to treatment' above):

•For all patients with anal HSIL, we suggest treatment rather than observation (Grade 2B). Treatment of asymptomatic LSIL is optional, given that these are not considered precancerous. (See 'Benefit of treatment' above.)

•Intra-anal lesions – For patients with one to two small intra-anal HSIL lesions, we suggest a local approach (eg, trichloroacetic acid [TCA], where available) rather than ablation or surgical management (Grade 2C). For patients without access to TCA, ablation or surgical management are appropriate alternatives.

For larger or more numerous lesions, TCA is unlikely to be effective and treatment and other options (ablation with infrared coagulation [IRC], radiofrequency ablation, or electrocautery/hyfrecation) are generally preferred. If there is concern for stenosis, these procedures can be applied over several visits, each treating no more than 50 percent of the anal transition zone circumference.

Although data are limited, an alternative is off-label use of topical imiquimod or fluorouracil [FU] cream, which may result in either complete resolution or a reduction in size to where local therapies may then be used. (See 'Efficacy of available treatment modalities' above.)

For lesions that are too large for office-based local therapy, a combination of initial HRA-guided surgical destruction in the operating room and follow-up with office-based ablation may be effective. (See 'HRA-directed surgical ablation' above.)

•Perianal lesions – Small discrete perianal HSIL lesions may be treated with TCA, where available, or local ablation. More extensive lesions can be approached initially with topical imiquimod or FU cream (see 'Issues specific to perianal high-grade SIL' above) prior to considering IRC or ablation. (See 'Topical therapy' above.)

Although treatment may result in complete regression, recurrences are frequent, and close post-treatment surveillance is necessary. (See 'Post-treatment surveillance' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge Ross D Cranston, MD, PhD, who contributed to an earlier version of this topic review.