{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T14:38:51Z","timestamp":1786113531335,"version":"build-2736575974"},"reference-count":60,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T00:00:00Z","timestamp":1780012800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T00:00:00Z","timestamp":1780012800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Histopathology"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Gallbladder carcinoma (GBC) is a rare and highly aggressive malignancy associated with poor clinical outcomes. While most GBCs are adenocarcinomas, only a small subset shows squamous differentiation. Tumours containing more than 25% squamous component are classified as gallbladder adenosquamous carcinomas (GBASC), a rare histological subtype characterized by a significantly worse prognosis than conventional adenocarcinomas. Due to their rarity, the molecular landscape and biological basis underlying the aggressive behaviour of GBASCs remain poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>\n                      In this study, 25 retrospectively collected GBASC cases were comprehensively characterized at both immunohistochemical and molecular levels. Predictive biomarkers including programmed death\u2010ligand 1 (PD\u2010L1), mismatch repair proteins (MMR), human epidermal growth factor receptor 2 (HER2) and claudin 18.2 (CLDN18.2) were evaluated. Nearly all tumours (96%) showed PD\u2010L1 positivity with a combined positive score (CPS) greater than 1. CLDN18.2 expression was identified in 28% of cases, although its confinement to the glandular component may limit its therapeutic applicability. All tumours were mismatch repair proficient (MMRp), and none demonstrated HER2 overexpression, in contrast to a subset of gallbladder adenocarcinomas. Molecular profiling revealed recurrent alterations in\n                      <jats:italic>TP53<\/jats:italic>\n                      (64%),\n                      <jats:italic>KRAS<\/jats:italic>\n                      (16%) and\n                      <jats:italic>CDKN2A<\/jats:italic>\n                      (20%), partially overlapping with the genomic profile of gallbladder adenocarcinomas. However, GBASCs showed a significant enrichment of alterations involving the PI3K pathway, particularly\n                      <jats:italic>PIK3CA<\/jats:italic>\n                      (44%) and\n                      <jats:italic>PTEN<\/jats:italic>\n                      (24%) mutations, representing their most distinctive molecular feature.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Overall, these findings support the recognition of GBASC as a distinct molecular entity potentially requiring dedicated therapeutic strategies.<\/jats:p>\n                  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