{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T04:36:39Z","timestamp":1791606999081,"version":"4.3.4"},"reference-count":33,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,1,30]],"date-time":"2025-01-30T00:00:00Z","timestamp":1738195200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100018722","name":"Jaap Schouten Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100018722","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Histopathology"],"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:sec><jats:title>Aims<\/jats:title><jats:p>Intraductal carcinoma (IDC) is an independent pathological parameter for adverse prostate cancer (PCa) outcome. Although most IDC are believed to originate from retrograde spread of established PCa, rare IDC cases may represent precursor lesions. The actual transition areas between intraductal and invasive cancer, however, have not yet been identified. Our objective was to identify intraductal\u2010invasive PCa transitions using 2\u2010 and 3\u2010dimensional microscopy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and results<\/jats:title><jats:p>Seventy\u2010five samples from 46 radical prostatectomies with PCa were immunohistochemically stained for basal cell keratins. In 35 samples, atypical glands that were indistinguishable from invasive adenocarcinoma (IAC) had focal 34BE12\u2010positive basal cells. These IAC\u2010like glands were present adjacent to IDC and prostatic intra\u2010epithelial neoplasia (PIN) in 21 of 45 (46.7%) and 16 of 58 (27.6%) cases, respectively. Whole\u2010mount confocal imaging of immunofluorescent Ker5\/18 double\u2010stained and cleared 1\u2010mm\u2010thick intact tissues revealed spatial continuity between IDC, IAC\u2010like glands and IAC with a gradual loss of basal cells. In 24 of 35 (68.6%) samples more than one IAC\u2010like focus (median 3.0) was present.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>We identified areas of spatial transition between PIN, IDC and IAC, characterised by remnant basal cells in IAC\u2010like glands. Based on the coexistence of IDC and PIN, the gradual loss of basal cells in IAC\u2010like glands and IAC\u2010like glands\u2019 multifocality, we propose a novel hypothesis on intraductal carcinogenesis, which we term \u2018repetitive invasion, precursor progression\u2019 (RIPP).<\/jats:p><\/jats:sec>","DOI":"10.1111\/his.15414","type":"journal-article","created":{"date-parts":[[2025,1,30]],"date-time":"2025-01-30T11:17:32Z","timestamp":1738235852000},"page":"1091-1100","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Identification of intraductal\u2010to\u2010invasive spatial transitions in prostate cancer: proposal for a new unifying model on intraductal carcinogenesis"],"prefix":"10.1111","volume":"86","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6672-1343","authenticated-orcid":false,"given":"Lucia L","family":"Rijstenberg","sequence":"first","affiliation":[{"name":"Department of Pathology, Erasmus MC Cancer Institute University Medical Centre  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-6269-3002","authenticated-orcid":false,"given":"Hridya","family":"Harikumar","sequence":"additional","affiliation":[{"name":"Department of Pathology, Erasmus MC Cancer Institute University Medical Centre  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2734-0254","authenticated-orcid":false,"given":"Esther I","family":"Verhoef","sequence":"additional","affiliation":[{"name":"Department of Pathology, Erasmus MC Cancer Institute University Medical Centre  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7223-4565","authenticated-orcid":false,"given":"Thierry P P","family":"van den Bosch","sequence":"additional","affiliation":[{"name":"Department of Pathology, Erasmus MC Cancer Institute University Medical Centre  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6765-6720","authenticated-orcid":false,"given":"Roselyne","family":"Choiniere","sequence":"additional","affiliation":[{"name":"Department of Pathology, Erasmus MC Cancer Institute University Medical Centre  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6814-0996","authenticated-orcid":false,"given":"Martin E","family":"van Royen","sequence":"additional","affiliation":[{"name":"Department of Pathology, Erasmus MC Cancer Institute University Medical Centre  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2176-9102","authenticated-orcid":false,"given":"Geert J L H","family":"van Leenders","sequence":"additional","affiliation":[{"name":"Department of Pathology, Erasmus MC Cancer Institute University Medical Centre  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,1,30]]},"reference":[{"key":"e_1_2_9_2_1","volume-title":"WHO classification of tumours: urinary and male genital tumours","author":"Moch H","year":"2022"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.3800702"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-018-0157-9"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/modpathol.2016.49"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0000000000000736"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2014.03.009"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0000000000001497"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.5858\/arpa.2020-0015-RA"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0000000000000794"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/his.13878"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1111\/his.13273"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.4628"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0000000000000465"},{"key":"e_1_2_9_15_1","first-page":"2518","article-title":"Heterogeneous clinicopathological features of intraductal carcinoma of the prostate: a comparison between \u2018precursor\u2010like\u2019 and \u2018regular type\u2019 lesions","volume":"7","author":"Miyai K","year":"2014","journal-title":"Int. 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