{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,2]],"date-time":"2026-08-02T15:23:26Z","timestamp":1785684206976,"version":"3.56.0"},"reference-count":14,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T00:00:00Z","timestamp":1694649600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T00:00:00Z","timestamp":1694649600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001787","name":"University of South Australia","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100001787","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Virchows Arch"],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>High-grade prostatic intraepithelial neoplasia (HGPIN) is a well-characterised precursor lesion in prostate cancer. The term atypical intraductal proliferations (AIP) describes lesions with features that are far too atypical to be considered HGPIN, yet insufficient to be diagnosed as intraductal carcinoma of the prostate (IDCP). Here, a panel of biomarkers was assessed to provide insights into the biological relationship between IDCP, HGPIN, and AIP and their relevance to current clinicopathological recommendations. Tissue samples from 86 patients with prostate cancer were assessed by routine haematoxylin and eosin staining and immunohistochemistry (IHC) with a biomarker panel (Appl1\/Sortilin\/Syndecan-1) and a PIN4 cocktail (34\u03b2E12+P63\/P504S). Appl1 strongly labelled atypical secretory cells, effectively visualising intraductal lesions. Sortilin labelling was moderate-to-strong in &gt; 70% of cases, while Syndecan-1 was moderate-to-strong in micropapillary HGPIN\/AIP lesions (83% cases) <jats:italic>versus<\/jats:italic> flat\/tufting HGPIN (\u2264 20% cases). Distinct biomarker labelling patterns for atypical intraductal lesions of the prostate were observed, including early atypical changes (flat\/tufting HGPIN) and more advanced atypical changes (micropapillary HGPIN\/AIP). Furthermore, the biomarker panel may be used as a tool to overcome the diagnostic uncertainty surrounding AIP by supporting a definitive diagnosis of IDCP for such lesions displaying the same biomarker pattern as cribriform IDCP.<\/jats:p>","DOI":"10.1007\/s00428-023-03643-1","type":"journal-article","created":{"date-parts":[[2023,9,14]],"date-time":"2023-09-14T03:25:57Z","timestamp":1694661957000},"page":"723-728","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Distinct patterns of biomarker expression for atypical intraductal proliferations in prostate cancer"],"prefix":"10.1007","volume":"485","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3891-7696","authenticated-orcid":false,"given":"Carmela","family":"Martini","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica M.","family":"Logan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra","family":"Sorvina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarita","family":"Prabhakaran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin S Y.","family":"Ung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian R. D.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shane M.","family":"Hickey","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert D.","family":"Brooks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"kConFab Consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria C.","family":"Caruso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja","family":"Klebe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Litsa","family":"Karageorgos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John J.","family":"O\u2019Leary","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brett","family":"Delahunt","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hemamali","family":"Samaratunga","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas A","family":"Brooks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2023,9,14]]},"reference":[{"key":"3643_CR1","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1038\/modpathol.3800053","volume":"6","author":"DG Bostwick","year":"2004","unstructured":"Bostwick DG, Liu L, Brawer MK, Qian J (2004) High-grade prostatic intraepithelial neoplasia. Rev Urol 6:171\u2013179. https:\/\/doi.org\/10.1038\/modpathol.3800053","journal-title":"Rev Urol"},{"key":"3643_CR2","doi-asserted-by":"publisher","first-page":"469","DOI":"10.1016\/j.eururo.2022.07.002","volume":"82","author":"GJ Netto","year":"2022","unstructured":"Netto GJ, Amin MB, Berney DM et al (2022) The 2022 World Health Organization classification of tumors of the urinary system and male genital organs-part B: prostate and urinary tract tumors. Eur Urol 82:469\u2013482. https:\/\/doi.org\/10.1016\/j.eururo.2022.07.002","journal-title":"Eur Urol"},{"key":"3643_CR3","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1097\/PAS.0000000000000794","volume":"41","author":"RA Hickman","year":"2017","unstructured":"Hickman RA, Yu H, Li J et al (2017) Atypical intraductal cribriform proliferations of the prostate exhibit similar molecular and clinicopathologic characteristics as intraductal carcinoma of the prostate. Am J Surg Pathol 41:550\u2013556. https:\/\/doi.org\/10.1097\/PAS.0000000000000794","journal-title":"Am J Surg Pathol"},{"key":"3643_CR4","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1111\/bju.15568","volume":"129","author":"J Morote","year":"2022","unstructured":"Morote J, Schwartzmann I, Celma A et al (2022) The current recommendation for the management of isolated high-grade prostatic intraepithelial neoplasia. BJU Int 129:627\u2013633. https:\/\/doi.org\/10.1111\/bju.15568","journal-title":"BJU Int"},{"key":"3643_CR5","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1111\/his.13878","volume":"75","author":"RB Shah","year":"2019","unstructured":"Shah RB, Nguyen JK, Przybycin CG et al (2019) Atypical intraductal proliferation detected in prostate needle biopsy is a marker of unsampled intraductal carcinoma and other adverse pathological features: a prospective clinicopathological study of 62 cases with emphasis on pathological outcomes. Histopathology 75:346\u2013353. https:\/\/doi.org\/10.1111\/his.13878","journal-title":"Histopathology"},{"key":"3643_CR6","doi-asserted-by":"publisher","first-page":"1851","DOI":"10.1158\/1541-7786.MCR-14-0074","volume":"12","author":"IR Johnson","year":"2014","unstructured":"Johnson IR, Parkinson-Lawrence EJ, Shandala T et al (2014) Altered endosome biogenesis in prostate cancer has biomarker potential. Mol Cancer Res 12:1851\u20131862. https:\/\/doi.org\/10.1158\/1541-7786.MCR-14-0074","journal-title":"Mol Cancer Res"},{"key":"3643_CR7","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1002\/pros.22777","volume":"74","author":"IR Johnson","year":"2014","unstructured":"Johnson IR, Parkinson-Lawrence EJ, Butler LM, Brooks DA (2014) Prostate cell lines as models for biomarker discovery: performance of current markers and the search for new biomarkers. Prostate 74:547\u2013560. https:\/\/doi.org\/10.1002\/pros.22777","journal-title":"Prostate"},{"key":"3643_CR8","doi-asserted-by":"publisher","first-page":"37919","DOI":"10.18632\/oncotarget.6114","volume":"6","author":"IR Johnson","year":"2015","unstructured":"Johnson IR, Parkinson-Lawrence EJ, Keegan H et al (2015) Endosomal gene expression: a new indicator for prostate cancer patient prognosis? Oncotarget 6:37919\u201337929. https:\/\/doi.org\/10.18632\/oncotarget.6114","journal-title":"Oncotarget"},{"key":"3643_CR9","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.pathol.2022.08.001","volume":"55","author":"C Martini","year":"2023","unstructured":"Martini C, Logan JM, Sorvina A et al (2023) Aberrant protein expression of Appl1, Sortilin and Syndecan-1 during the biological progression of prostate cancer. Pathology 55:40\u201351. https:\/\/doi.org\/10.1016\/j.pathol.2022.08.001","journal-title":"Pathology"},{"key":"3643_CR10","doi-asserted-by":"publisher","unstructured":"Sorvina A, Martini C, Prabhakaran S et al (2023) Appl1, Sortilin and Syndecan-1 immunohistochemistry on intraductal carcinoma of the prostate provides evidence of retrograde spread. Pathology. https:\/\/doi.org\/10.1016\/j.pathol.2023.05.004","DOI":"10.1016\/j.pathol.2023.05.004"},{"key":"3643_CR11","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3390\/cancers15123215","volume":"15","author":"JM Logan","year":"2023","unstructured":"Logan JM, Hopkins AM, Martini C et al (2023) Prediction of prostate cancer biochemical and clinical recurrence is improved by IHC-assisted grading using Appl1, Sortilin and Syndecan-1. 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Mod Pathol 26:587\u2013603. https:\/\/doi.org\/10.1038\/modpathol.2012.201","journal-title":"Mod Pathol"},{"key":"3643_CR14","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1111\/his.13273","volume":"71","author":"RB Shah","year":"2017","unstructured":"Shah RB, Yoon J, Liu G, Tian W (2017) Atypical intraductal proliferation and intraductal carcinoma of the prostate on core needle biopsy: a comparative clinicopathological and molecular study with a proposal to expand the morphological spectrum of intraductal carcinoma. Histopathology 71:693\u2013702. https:\/\/doi.org\/10.1111\/his.13273","journal-title":"Histopathology"}],"updated-by":[{"DOI":"10.1007\/s00428-023-03666-8","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2023,9,29]],"date-time":"2023-09-29T00:00:00Z","timestamp":1695945600000}}],"container-title":["Virchows Archiv"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00428-023-03643-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00428-023-03643-1\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00428-023-03643-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,29]],"date-time":"2024-10-29T12:10:13Z","timestamp":1730203813000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00428-023-03643-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,9,14]]},"references-count":14,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2024,10]]}},"alternative-id":["3643"],"URL":"https:\/\/doi.org\/10.1007\/s00428-023-03643-1","relation":{"correction":[{"id-type":"doi","id":"10.1007\/s00428-023-03666-8","asserted-by":"object"}]},"ISSN":["0945-6317","1432-2307"],"issn-type":[{"value":"0945-6317","type":"print"},{"value":"1432-2307","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,9,14]]},"assertion":[{"value":"2 August 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 August 2023","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 September 2023","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 September 2023","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 September 2023","order":5,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Correction","order":6,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"A Correction to this paper has been published:","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"https:\/\/doi.org\/10.1007\/s00428-023-03666-8","URL":"https:\/\/doi.org\/10.1007\/s00428-023-03666-8","order":8,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Ethics approval for sample access and use of de-identified human prostate tissues from the kConFab was obtained through the institutional review board, Human Research Ethics Committee of the University of South Australia (Application IDs: 201907 and 0000036070). The study was performed in accordance with the Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"D.A.B and J.J.O\u2019L are shareholders for Envision Sciences Pty Ltd and benefit from this company\u2019s research funding. D.A.B and I.R.D.J have a patent WO2014197937A1 that has been licensed by UniSA Ventures to Envision Sciences Pty Ltd for commercialisation. DAB is named as inventor on an additional patent, PCT\/AU2020\/050925, involving the invention used in this manuscript, which is owned by Envision Sciences Pty Ltd. C.M, J.M.L, A.S, S.P, B.S-Y.U, and I.R.D.J are employed by the University of South Australia using funding from Envision Sciences Pty Ltd.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}