Evolution of Untreated Anal High-grade Squamous Intraepithelial Lesions in High-risk Men: A Prospective 5-year...

Histologically-confirmed anal high-grade squamous intraepithelial lesions (hHSIL) are targets for diagnosis and treatment in anal cancer screening programmes. However, long-term natural history of untreated hHSIL remains poorly understood.

In the APACHES study, 513 HIV-positive men who have sex with men aged ≥35 years underwent three annual visits for anal cytology, HPV testing, and high-resolution anoscopy with biopsies to detect hHSIL. hHSIL were not treated but monitored every six months for up to five years. Methylation markers, ASCL1 and ZNF582, were assessed in biopsies at hHSIL diagnosis. hHSIL regression probability was estimated using Cox proportional hazards models, adjusted hazard ratios (aHR) and Kaplan-Meier survival curves.

Of 127 untreated hHSIL, 21% regressed within 1 year, 41% within 2 years, and 75% within 5 years. None progressed to cancer during follow-up. Regression was significantly less likely for hHSIL with concurrent high-grade anal cytology (aHR = 0.41; 95% CI: 0.19-0.88), 12-month persistent HPV16 infection in anal swabs (aHR = 0.46; 95% CI: 0.21-0.97), or positivity for both ASCL1 and ZNF582 (aHR = 0.39; 95% CI: 0.18-0.82). 5-year regression probability ranged from ∼30% for ASCL1/ZNF582-positive hHSIL with high-grade cytology, to ∼90% for ASCL1/ZNF582-negative hHSIL without high-grade cytology. hHSIL regression was not influenced by age, smoking, or HIV-related markers.

Only one quarter of untreated hHSIL persisted at 5 years, representing lesions with the highest anal cancer risk. Methylation markers ASCL1/ZNF582 were the strongest predictors of persistent hHSIL and, combined with HPV testing and cytology, may inform prioritisation for diagnosis and treatment in anal cancer screening programmes.