Hippo pathway disruption and <scp>YAP1</scp> 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.