Advancing anal cancer prevention Screening strategies and biomarkers for risk stratification

The incidence of anal cancer is on the rise. It is preceded by precancerous lesions (HSIL), making screening possible. Treating HSIL reduces the risk of progression to anal cancer by half. In the Netherlands, screening is offered to groups at an increased risk, like men living with HIV, but current methods are complex, burdensome for patients, and limited by capacity shortages. Furthermore, most HSIL do not progress to cancer leading to overtreatment. This thesis addresses these challenges and aims to guide improvements in anal cancer screening implementation.
In Part 1, we evaluated existing anal swab tests (cytology and HPV testing) as initial screening tools and explored multiple algorithms using these tests. Although these tests are suitable for screening, significant improvements are necessary. We also surveyed expert opinions to establish performance criteria for future tests.
In Part 2, we investigated methylation markers as a novel approach to enhance anal cancer screening. We showed that they could complement current screening tests, as well as determine cancer risk in anal HSIL, reducing unnecessary treatments. A reproducible methylation test was developed and is being validated in a prospective cohort study.
In Part 3, we explored the local immune system of the anal mucosa. We found that patients whose lesions progressed to cancer had more immunosuppressive macrophage profiles.
In conclusion, this thesis proposes improvements to anal cancer screening by refining current tools, developing methylation markers, and exploring immune mechanisms of progression. These findings may support more effective, personalized, and resource-efficient prevention strategies.