International Anal Neoplasia Society's consensus guidelines for anal cancer screening

The International Anal Neoplasia Society (IANS) developed consensus guidelines to inform anal cancer screening use among various high‐risk groups. Anal cancer incidence estimates by age among risk groups provided the basis to identify risk thresholds to recommend screening. Guided by risk thresholds, screening initiation at age 35 years was recommended for men who have sex with men (MSM) and transgender women (TW) with HIV. For other people with HIV and MSM and TW not with HIV, screening initiation at age 45 years was recommended. For solid organ transplant recipients, screening initiation beginning from 10 years post‐transplant was recommended. For persons with a history of vulvar precancer or cancer, screening initiation was recommended starting within 1 year of diagnosis of vulvar precancer or cancer. Persons aged ≥45 years with a history of cervical/vaginal HSIL or cancer, perianal warts, persistent (>1 year) cervical HPV16, or autoimmune conditions could be considered for screening with shared decision‐making, provided there is adequate capacity to perform diagnostic procedures (high‐resolution anoscopy [HRA]). Anal cytology, high‐risk (hr) human papillomavirus (HPV) testing (including genotyping for HPV16), and hrHPV‐cytology co‐testing are different strategies currently used for anal cancer screening that show acceptable performance. Thresholds for referral for HRA or follow‐up screening tests are delineated. These recommendations from IANS provide the basis to inform management of abnormal screening results, considering currently available screening tools. These guidelines provide a pivotal foundation to help generate consensus among providers and inform the introduction and implementation of risk‐targeted screening for anal cancer prevention.

der women (TW) with HIV.For other people with HIV and MSM and TW not with HIV, screening initiation at age 45 years was recommended.For solid organ transplant recipients, screening initiation beginning from 10 years post-transplant was recommended.For persons with a history of vulvar precancer or cancer, screening initiation was recommended starting within 1 year of diagnosis of vulvar precancer or cancer.Persons aged ≥45 years with a history of cervical/vaginal HSIL or cancer, perianal warts, persistent (>1 year) cervical HPV16, or autoimmune conditions could be considered for screening with shared decision-making, provided there is adequate capacity to perform diagnostic procedures (high-resolution anoscopy [HRA]).
Anal cytology, high-risk (hr) human papillomavirus (HPV) testing (including genotyping for HPV16), and hrHPV-cytology co-testing are different strategies currently used for anal cancer screening that show acceptable performance.Thresholds for referral for HRA or follow-up screening tests are delineated.These recommendations from IANS provide the basis to inform management of abnormal screening results, considering currently available screening tools.These guidelines provide a pivotal foundation to help generate consensus among providers and inform the introduction and implementation of risk-targeted screening for anal cancer prevention.
anal cancer, anal cancer screening, anal cytology, anal HPV

What's new?
Recently, treatment of anal high-grade squamous intraepithelial lesions (HSIL) was found to reduce anal cancer risk in people living with HIV.However, there are no current comprehensive anal cancer screening guidelines.The International Anal Neoplasia Society (IANS) recommendations provide evidence-based consensus guidance for which populations should be offered anal cancer screening and for management of abnormal screening results, considering currently available screening tools.The IANS guidelines provide a basis for expansion of anal cancer screening infrastructure to all at-risk populations.

| INTRODUCTION
Almost all squamous cell carcinomas of the anus (hereinafter, anal cancers) are caused by human papillomavirus (HPV) and are preceded by high-grade squamous intraepithelial lesions (HSIL), which are screening-detectable precancerous lesions.Worldwide, nearly 30,500 new anal cancer cases occurred in 2020. 1 Although rare among the general population, anal cancer disproportionately affects several specific populations, including people with HIV (PWH), men who have sex with men (MSM), solid organ transplant recipients (SOTR), and women with a history of vulvar cancer or precancer. 2The elevated anal cancer incidence among these and other high-risk groups warrants the development of risk-targeted anal cancer screening recommendations.
Screening guidelines for anal cancer prevention have been developed by several organizations worldwide, largely targeting PWH (see Supporting information, Appendix 1).These guidelines differ with respect to whom to screen, at what age to initiate screening, preferred screening test(s), and how to manage abnormal results.
Most of these recommendations were developed before the recently published Anal Cancer/HSIL Outcomes Research (ANCHOR) study addressed a key uncertainty regarding the effectiveness of treatment for anal precancer by showing that treating anal HSIL reduces anal cancer risk among PWH. 3 In addition to the ANCHOR study findings, more data on the risk of anal cancer among other groups and the performance of anal cancer screening tests have accumulated over time, providing a critical foundation to generate evidence-based anal cancer screening guidelines. 2,4,5e International Anal Neoplasia Society (IANS) is the leading professional organization committed to providing the highest quality evidence, recommendations, and standards of care for the prevention and early detection of anal cancer.To develop consensus guidelines for anal cancer prevention and early detection, IANS convened a task force to assess the needs, develop evidence-based guidance, and address knowledge gaps for anal cancer screening.
In 2018, IANS assembled a task force (TF) of 17 international experts representing 6 countries with a wide range of professional expertise including epidemiology, decision science, pathology, public policy, infectious diseases, gynecology, colorectal surgery, and high resolution anoscopy (HRA) providers.The IANS TF determined three priority areas for guidelines development which became the basis to convene three working groups that evaluated: (1) anal cancer incidence by risk group to identify populations who would benefit from screening, (2) current clinical practice, including screening tools, HRA and treatment of HSIL, and (3) the performance of available anal cancer screening tests and approaches.The initial findings were presented at the IANS Scientific Meeting in June 2019 and subsequently evolved into three recent publications. 2,4,6Based on these results, the IANS TF deliberated in a further series of meetings and online surveys among IANS members to establish (1) which populations to screen based on the evaluation of anal cancer incidence in different groups (2) which screening tools to recommend, and (3) management of results and threshold for HRA referral.To include more diverse representation by discipline, geography, providers of under-represented populations, and community advocates, the task force was expanded to 60 persons representing 19 countries (Supporting information, Appendix 2).The IANS TF assigned recommendation strength (A-E) and quality of evidence (I-III) using the same grading system applied to the US multi-organizational cervical cancer screening and management guidelines where applicable (see Supporting information, Appendix 3). 7The finalized guidelines were sent to the IANS' membership and other stakeholders for a public comment period of 2 weeks in March 2023.These guidelines were then approved by the IANS task force committee members and the IANS Board of Directors.

| Populations to screen and timing of screening
Anal cancer incidence estimates by risk group and age were evaluated to identify populations and age ranges to recommend for screening (Table 1). 2,5The observed anal cancer incidence estimates from the United States (US) and other countries were categorized into two groups by the TF.Risk Category A included high-risk groups with an incidence of at least 17 per 100,000 (defined as 10-fold greater incidence compared with the general US population-1.7 per 100,000 person-years [py]). 8A second tier (Risk Category B) were those groups with higher incidence compared with the general US population but who did not reach the Category A incidence threshold.
The TF developed specific recommendations for Risk Category A groups.Recommendations for Risk Category B are currently limited to shared decision-making, but updates will be considered when more data on screening outcomes, particularly, harms and benefits, in these populations become available.

Population-Risk category When
Anal cancer incidence Abbreviations: HSIL, high grade squamous intraepithelial lesion; MSM, Men who have sex with men; MSW, Men who have sex with women; TW, Transgender women.a Shared decision-making is defined as the process in which a health care provider and patient work together to make a health care decision.The optimal decision considers evidence-based information regarding available options, the provider's knowledge and experience, and the patient's values and preferences.
3.1.1| Risk Category A (incidence ≥10-fold compared to the general population) Persons with HIV MSM and transgender women (TW) with HIV (age ≥35 years).This risk group presents the highest anal cancer incidence, which begins to peak at a relatively younger age (>70 per 100,000 py among persons aged ≥35 years). 2 Strong evidence on effectiveness of anal HSIL treatment among PWH aged ≥35 years and initial data suggesting that anal HSIL treatment before age 35 may cause more harm than benefit, supports the recommendation for screening initiation starting at age 35 years. 3,9,10ile data for TW are currently lacking, analogous clinical recommendations were considered appropriate by the TF.
Men who have sex with women (MSW) and women with HIV (age ≥45years).Among MSW and women with HIV, anal cancer incidence increases with age, reaching >10-fold compared with the general population at age ≥45 years, 2 supporting the recommendation of screening initiation at age 45 years for this population.
MSM and TW not with HIV (aged ≥45 years) Among MSM not with HIV, anal cancer incidence peaks at age ≥60 years (34 per 100,000 py) but begins to increase at 45 years (reaching 10-fold compared with the general population [i.e., ≥18 per 100,000 py]), supporting the recommendation for screening initiation at age 45 years. 5While data for TW are currently lacking, analogous clinical recommendations were considered appropriate by the TF.

History of vulvar cancer or precancer
Anal cancer incidence is high among individuals with a history of HPV-associated vulvar cancer (absolute incidence of 48 per 100,000 py) and those with a history of HPV-associated vulvar precancer (42 per 100,000 py). 2 Screening initiation within 1 year after diagnosis of HPV-associated vulvar precancer and cancer was considered appropriate.

SOTR (10-year post-transplantation)
Among SOTR recipients, anal cancer incidence exceeds the risk threshold of ≥10-fold after 10 years from transplantation (incidence of 24.5 per 100,000 py among men and 49.6 per 100,000 py among females), 2 supporting the recommendation for screening initiation 10 years post-transplantation.Although it was recognized that the incidence for women with SOTR increases earlier than for men with SOTR, the TF recommended a singular simplified strategy for this risk group.
3.1.2| Risk Category B (incidence less than 10-fold higher than the general population) Persons with a history of cervical/vaginal HSIL or cancer, perianal warts, persistent (>1 year) cervical HPV16, and autoimmune conditions (including but not limited to rheumatoid arthritis, Systemic Lupus Erythematosus, Crohn's Disease, Ulcerative Colitis on systemic therapy) 11 have incidences of anal cancer that are less than 10 per 100,000 but elevated compared with the general population. 11,12ese risk groups (Risk Category B), which did not reach the benchmark (≥10-fold the general population), could be included for screening with shared decision-making, provided there is adequate capacity for HRA.The TF voted not to include women with a history of vulvar warts in risk category B. For additional comments on the screening populations, see Supporting information, Appendix 4a.

| Screening tests for anal HSIL and cancer
Screening tests and management strategies for the detection of anal HSIL are summarized in Tables 2 and 3. Based on findings from the systematic review and meta-analysis of diagnostic studies, conducted primarily among PWH, anal cytology, hrHPV testing (including genotyping for HPV16), and hrHPV-cytology co-testing are all strategies currently used for anal cancer screening and show acceptable performance. 4A positive screening result can be further stratified with triage strategies including sending abnormal cytology specimens for hrHPV testing, or sending hrHPV positive specimens for cytology, though data were sparse for some of these test combinations.Data on longitudinal performance (beyond 2-3 years) of screening were also lacking.We include management options for settings with limited HRA capacity using higher specificity thresholds, ensuring that individuals with the highest risk of anal HSIL are prioritized for immediate referral to HRA.The TF defined sufficient HRA capacity as the availability of HRA evaluation within 6 months of an abnormal screening test for the eligible population; whereas limited capacity indicates a longer wait time until HRA can be provided.These screening strategies are intended for populations with access to HRA.In the absence of HRA availability, screening should be limited to digital anal rectal exam (DARE) for detection of anal cancer. 13,14For additional comments on screening tools, see Supporting information, Appendix 4b.

| Digital anal rectal exam
The DARE should be performed at all screening visits following the collection of samples for cytology and/or hrHPV testing.The DARE provides screening for early anal cancers that may be detectable by palpation.If HRA referral is not available, it is recommended that the DARE be performed routinely in populations identified for anal cancer screening.

| DISCUSSION
The IANS recommendations provide evidence-based consensus guidance for which populations should be offered anal cancer screening and for management of abnormal screening results, utilizing currently available screening tools.Historically, the controversy regarding anal cancer screening focused on the rarity of anal cancer in the general population and the lack of evidence on the effectiveness of treatment for anal precursor lesions to prevent progression to anal cancer.The ANCHOR study confirmed that the detection and treatment of HSIL in PWH is effective for anal cancer prevention. 3While the low incidence of anal cancer does not support screening in the general population, several recent studies defined other specific populations at elevated risk and assessed the performance of various screening tests, providing the necessary foundation to generate this evidence-and risk-based screening guidance. 2,4,5,11ese guidelines primarily focus on populations with an anal cancer incidence ≥10-fold compared with the general population.These recommendations also provide guidance for other populations with increased incidence of anal cancer but less than a 10-fold increased incidence (Risk Category B, e.g., women with a history of cervical precancer or cancer or patients with auto-immune diseases).For these populations, given their relatively lower risk, the TF recommended shared decision-making as an approach for individuals concerned about their potential risk, provided there is adequate HRA capacity.
Risk category B also included populations with an unknown incidence of anal cancer, for example, perianal warts.Recommendations for these groups were made by consensus expert opinion.
Several screening approaches, including cytology and hrHPV testing with different triage strategies have been evaluated for anal cancer screening in different populations.Currently, there are not enough data on comparative effectiveness or evaluating the harms and benefits of these strategies to recommend a preferred option.Further, longitudinal studies evaluating different screening approaches are lacking, making it difficult to recommend evidence-based intervals for screening and management.For example, most anal cancer screening studies have been cross-sectional and the few prospective studies were limited to 2-3 years follow-up with varying designs and cohorts unlike the robust longitudinal data (e.g., 10 or more year outcomes for cervical cytology and HPV testing results) available for cervical cancer screening. 7This precludes recommending screening intervals beyond the observation periods of 1-3 years.Ultimately, with more data, a risk-based approach with clinical action thresholds can be developed for anal screening similar to the current approach for cervical screening. 16,17As more long-term clinical follow-up data and evidence from mathematical modeling studies become available, anal cancer prevention guidelines will be updated.
It is critical to emphasize the implementation aspects of anal cancer screening programs.An effective screening program would rely on initial screening with DARE and anal swab collection (for cytology and/or hrHPV) provided by primary care providers, gynecologists, HIV providers, or other specialists who interface with at-risk populations.
Cytopathologists with expertise in cervical pathology should be able to accommodate the increase in anal cytology and biopsy specimen volume.Screening providers should have access to HRA clinics and adequate follow-up to ensure patients' successful participation in their care.The impact of screening on preventing anal cancers will be largely dependent on achieving high compliance with screening recommendations, follow-up treatment, and surveillance. 18fferences in the organization of national health care systems, economic resources and cultural barriers pose particularly difficult challenges to standardize screening practices for the prevention of anal cancer worldwide.Screening strategies implemented in regions lacking resources or infrastructure should be tailored to ensure that those at the highest risk of anal cancer receive the immediate and the best available approach while developing strategies to improve access for others.
Even among high resource settings, the major challenge to the implementation of anal cancer screening guidelines is the limited availability of HRA infrastructure for referral of patients with abnormal screening results.Currently, most HRA providers are located in large cities in the United States, 19 Western Europe and Australia; and much of the world has very limited (if any) access to HRA providers.HRA requires significant training and costly equipment. 14Advocacy for sufficient funding and capacity-building is critical for clinics to support the necessary infrastructure for creating or expanding HRA practices.
In particular, equitable distribution of screening resources targeted Screening tests for anal high-grade squamous intraepithelial lesion (HSIL) and cancer.Management of screening test results.ASC-H, atypical squamous cells cannot exclude high grade; ASC-US, atypical squamous cells of undetermined significance; hr, high risk; HRA, high resolution anoscopy; HSIL, high grade squamous intraepithelial lesion; LSIL, low grade squamous intraepithelial lesion; NILM, negative for intraepithelial lesion or malignancy.Low HRA capacity is defined as greater than 6 month wait for HRA referral for an abnormal screening test.
(LSIL) or ASC-US, and repeat testing in 12-24 months with NILM results.Triage using hrHPV testing of individuals with ASC-US or LSIL cytology can reduce the need for immediate referral to HRA and is acceptable for anal cancer screening (CII).HPV testing is not necessary for individuals with ASC-H or HSIL cytology.HRA referral is3.2.2 | hrHPV alone or with cytology triagehrHPV alone is acceptable for anal cancer screening (BII).Immediate HRA referral is recommended for individuals testing hrHPV positive;In settings with limited HRA capacity, it is acceptable to only refer individuals testing positive for HPV16 to immediate HRA, with repeat testing in 12 months recommended for individuals testing positive for other hrHPV types.Repeat screening in 24 months is recommended for individuals testing hrHPV negative.T A B L E 2Abbreviations: ASC-US, atypical squamous cells of undetermined significance; hr, high risk; HRA, high resolution anoscopy; HSIL, high grade squamous intraepithelial lesion; MSM, men who have sex with men.T A B L E 3 a