{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T17:05:53Z","timestamp":1786122353552,"version":"build-2736575974"},"reference-count":30,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"JSPS KAKENHI","doi-asserted-by":"publisher","award":["JP 24K11852"],"award-info":[{"award-number":["JP 24K11852"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Intraductal papillary neoplasm of the bile duct (IPNB) is a premalignant lesion of cholangiocarcinoma. Currently, its tumor immune microenvironment (TIME) remains poorly characterized. Occupational cholangiocarcinoma provides a unique setting wherein multiple IPNBs arise in a background of chronic biliary injury caused by organic solvents. This study evaluated TIME alternations in IPNB lesions in occupational cholangiocarcinoma, focusing on histological subclassifications, phenotypes, invasive status, and tumor size. Methods: Thirteen IPNB lesions in six patients with occupational cholangiocarcinoma were immunohistochemically stained for CD8, CD163, programmed death protein 1 (PD-1), and programmed death ligand 1 (PD-L1). CD8-, CD163-, and PD-1-positive cells were counted in the most densely infiltrated areas. PD-L1 expression was assessed using the combined positive score (CPS), and associations with each status were analyzed. Results: Within the occupational IPNB cohort, type 2 IPNBs demonstrated significantly higher CD8, CD163, and PD-1 expression levels than type 1 IPNBs. Invasive lesions showed significantly higher CD8 expression and CPS than noninvasive lesions. Tumor size was positively correlated with CD163 expression (R = 0.504), CD8 expression (R = 0.627), and CPS (R = 0.569) in the TIME. When stratified by tumor size (&lt;10 vs. \u226510 mm), lesions \u2265 10 mm in size demonstrated significantly higher CD163 expression and CPS. Notably, all lesions with CPS \u22651 were \u226510 mm in size. Conclusions: In IPNB arising from occupational cholangiocarcinoma, tumor enlargement is associated with progressive TIME alterations. Lesions \u2265 10 mm in size may represent a threshold at which immunoediting and invasive potential become more prominent.<\/jats:p>","DOI":"10.3390\/cancers18162539","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T10:12:01Z","timestamp":1786097521000},"page":"2539","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immune Microenvironmental Analysis of Intraductal Papillary Neoplasms of the Bile Duct in Occupational Cholangiocarcinoma: Associations with Tumor Size"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6716-6377","authenticated-orcid":false,"given":"Masahiko","family":"Kinoshita","sequence":"first","affiliation":[{"name":"Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shoji","family":"Kubo","sequence":"additional","affiliation":[{"name":"Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan"},{"name":"Health Education Course, Department of Education, Faculty of Education, Shitennoji University, 3-2-1 Gakuenmae, Habikino 583-8501, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kimika","family":"Kato","sequence":"additional","affiliation":[{"name":"Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Inoue","sequence":"additional","affiliation":[{"name":"Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takuto","family":"Yasuda","sequence":"additional","affiliation":[{"name":"Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kosuke","family":"Hatta","sequence":"additional","affiliation":[{"name":"Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atsushi","family":"Sugimoto","sequence":"additional","affiliation":[{"name":"Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1562-4049","authenticated-orcid":false,"given":"Ryota","family":"Tanaka","sequence":"additional","affiliation":[{"name":"Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Tauchi","sequence":"additional","affiliation":[{"name":"Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sadaaki","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4433-5035","authenticated-orcid":false,"given":"Genki","family":"Watanabe","sequence":"additional","affiliation":[{"name":"Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohei","family":"Nishio","sequence":"additional","affiliation":[{"name":"Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroji","family":"Shinkawa","sequence":"additional","affiliation":[{"name":"Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9534-6973","authenticated-orcid":false,"given":"Takeaki","family":"Ishizawa","sequence":"additional","affiliation":[{"name":"Department of Hepato-Biliary-Pancreatic Surgery, Osaka Metropolitan University Graduate School of Medicine, Osaka 545-8585, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3244-8972","authenticated-orcid":false,"given":"Yasunori","family":"Sato","sequence":"additional","affiliation":[{"name":"Department of Human Pathology, Kanazawa University Graduate School of Medical Sciences, Kanazawa 920-8640, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"key":"ref_1","unstructured":"WHO Classification of Tumors Editorial Board (2019). 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