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

1 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.² The 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, 5}

The 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.

2 METHODS

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, 6} Based 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).⁷ The 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.

3 RESULTS

4 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.³ While 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, 11}

These 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.⁷ This 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, 17} As 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.¹⁸

Differences 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.¹⁴ Advocacy 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 toward the highest risk groups will be important to prevent disparities in anal cancer prevention.

We recognize that knowledge gaps exist regarding the harms and benefits of different screening algorithms (e.g., age to initiate/terminate screening, different screening intervals), the tradeoff between disease detection and resource utilization (i.e., HRA capacity), and the impact of incorporating emerging technologies in screening. We also recognize that the impact of screening may differ by HPV vaccination status. In addition, robust data on the clinical performance of screening strategies among risk groups other than those with HIV are lacking. Despite these limitations, recent advances in anal cancer screening and epidemiology research have allowed us to generate current evidence- and consensus-based recommendations. Future studies addressing these questions will be important to provide continued guidance on optimal approaches for anal cancer screening and prevention. Likewise, guidelines for management following treatment for anal HSIL or cancer also need to be developed but were considered beyond the purview of these screening guidelines. IANS is committed to these goals and will continue to review emerging evidence necessary to provide further updates to these anal cancer prevention guidelines.

These consensus recommendations provide a pivotal framework to inform evidence-based anal cancer screening practices for several high-risk populations. Prevention of anal cancer through screening and treatment of anal HSIL has been proven to be effective among high-risk individuals. Of note, in many regions and countries, scarcity of screening and HRA resources may preclude implementation of these guidelines and there will be a need to develop the necessary infrastructure to provide screening and HRA services. In addition, as studies mature, longitudinal data regarding harms and benefits of screening will provide the basis for risk-based screening and management recommendations. These guidelines serve as a foundation for advocacy and expansion of HRA and screening infrastructure, thereby ensuring that anal cancer prevention becomes accessible to all at-risk populations.

AUTHOR CONTRIBUTIONS

Conceptualization: Jay, Stier, Clifford, Palefsky, Goldstone, Hillman, Barroso. Methodology: Jay, Stier, Clarke, Deshmukh, Wentzensen, Palefsky. Formal analysis: Stier, Jay, Clarke, Deshmukh, Wentzensen, Clifford, Palefsky. Visualization: Jay, Stier, Clifford, Palefsky, Goldstone, Hillman. Writing (original draft): Stier, Jay, Clarke, Deshmukh. Writing (Review and editing): Stier, Clarke, Deshmukh, Wentzensen, Liu, Poynten, Cavallari, Fink, Cuming, Rosa-Cunha, La Rosa, Plotzker, Roberts, Jay. The work reported in the paper has been performed by the authors, unless clearly specified in the text.

CONFLICT OF INTEREST STATEMENT

AAD is a consultant for Merck Inc. and Value Analytics Lab and received an honorarium from NIH. SEG is an investigator and consultant for Merck, consultant for THD America, and investigator for Frantz Viral Technologies. VF received honoraria from MSD. LLR is a consultant for MSD. JMP reports potential personal conflicts of interest with Vir Biotechnologies, Roche Diagnostics, Merck and Abbott and reports potential financial conflicts of interest with Sotlight Pharmaceuticals, Atila Biosystems, and Barinthus Biotherapeutics. The other authors declare no conflict of interest.