Hippo pathway disruption and YAP1 activation in anogenital papillary squamous intraepithelial lesion

Aims Papillary squamous intraepithelial lesion (PSIL), also known as papillary immature metaplasia, is a rare anogenital lesion associated with low‐risk human papillomavirus (HPV) infection. The molecular pathogenesis of PSIL remains unclear. This study aims to investigate the activation of YAP1, a Hippo pathway co‐activator, in PSIL and compare it to condyloma and papillary HSIL. Methods and results YAP1 activation was evaluated by immunohistochemistry using an antibody specific for activated/unphosphorylated YAP1 (act‐YAP1) in 36 PSIL cases, 20 condyloma and 2 papillary HSIL cases. HPV genotyping and chromogenic in situ hybridization (CISH) were performed to determine HPV status. Low‐risk HPV, predominantly HPV6, was detected in 78.6% of PSILs. CISH revealed a diffuse fine punctate distribution of low‐risk HPV E6/E7 transcripts in PSIL, distinct from the large focal clusters seen in condyloma, but similar to high‐risk HPV in HSIL. All PSILs showed non‐block p16 expression. Act‐YAP1 immunostaining demonstrated YAP1 activation in 86.1% of PSILs (72.2% diffuse, 13.9% focal), resembling the pattern in papillary HSIL but differing from condyloma, which exhibited nuclear act‐YAP1 only in basal and granular layers. No significant associations were found between YAP1 activation and HPV status or immunoprofiles of p16, p53, Rb1 and CK7. Conclusions PSILs demonstrate prominent YAP1 activation, implicating Hippo pathway disruption as a potential driver of PSIL pathogenesis. These findings support a distinct molecular profile of PSIL and provide insight into the biological mechanisms underlying this rare lesion.