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

Gloria Zhang1, Karen L Talia2, W Glenn McCluggage3

  • 1Division of Pathology, Diagnostic Institute, Cleveland Clinic, Cleveland, Ohio, USA.

Histopathology
|July 16, 2026
PubMed
Abstract

Insights

Papillary squamous intraepithelial lesions (PSIL) show significant YAP1 activation, suggesting Hippo pathway disruption drives their development. This distinct molecular profile offers new insights into this rare anogenital lesion.

Area of Science:

  • Oncology
  • Molecular Biology
  • Dermatology

Background:

  • Papillary squamous intraepithelial lesion (PSIL) is a rare anogenital lesion linked to low-risk human papillomavirus (HPV).
  • The molecular mechanisms driving PSIL development are not fully understood.
  • Investigating the Hippo pathway, specifically YAP1 activation, may elucidate PSIL pathogenesis.

Purpose of the Study:

  • To investigate YAP1 activation in PSIL.
  • To compare YAP1 activation patterns in PSIL with condyloma and papillary high-grade squamous intraepithelial lesions (HSIL).
  • To explore the molecular profile of PSIL in relation to HPV status.

Main Methods:

  • Immunohistochemistry was used to detect activated YAP1 (act-YAP1) in 36 PSIL, 20 condyloma, and 2 papillary HSIL cases.
  • HPV genotyping and chromogenic in situ hybridization (CISH) were performed to determine HPV status and transcript distribution.
  • Immunoprofiles for p16, p53, Rb1, and CK7 were analyzed.

Main Results:

  • Low-risk HPV, primarily HPV6, was identified in 78.6% of PSIL cases.
  • YAP1 activation was observed in 86.1% of PSILs, with a diffuse pattern similar to papillary HSIL but distinct from condyloma.
  • HPV E6/E7 transcripts showed a diffuse punctate distribution in PSIL, unlike the focal clusters in condyloma.

Conclusions:

  • PSIL exhibits significant YAP1 activation, indicating Hippo pathway dysregulation.
  • These findings suggest a distinct molecular profile for PSIL.
  • Hippo pathway disruption is implicated as a potential driver in the pathogenesis of PSIL.
Keywords:
HPVHippo signalling pathwayYAP1anogenitalcervixpapillary immature metaplasiapapillary squamous intraepithelial lesion

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