{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T21:31:37Z","timestamp":1779312697463,"version":"3.51.4"},"reference-count":63,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,12,17]],"date-time":"2025-12-17T00:00:00Z","timestamp":1765929600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100006306","name":"Sigrid Jus\u00e9liuksen S\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","award":["230149"],"award-info":[{"award-number":["230149"]}],"id":[{"id":"10.13039\/501100006306","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006306","name":"Sigrid Jus\u00e9liuksen S\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","award":["240158"],"award-info":[{"award-number":["240158"]}],"id":[{"id":"10.13039\/501100006306","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006306","name":"Sigrid Jus\u00e9liuksen S\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","award":["250082"],"award-info":[{"award-number":["250082"]}],"id":[{"id":"10.13039\/501100006306","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100006306","name":"Sigrid Jus\u00e9liuksen S\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","award":["250175"],"award-info":[{"award-number":["250175"]}],"id":[{"id":"10.13039\/501100006306","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008376","name":"Helsingin ja Uudenmaan Sairaanhoitopiiri","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008376","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005878","name":"Terveyden Tutkimuksen Toimikunta","doi-asserted-by":"publisher","award":["333050"],"award-info":[{"award-number":["333050"]}],"id":[{"id":"10.13039\/501100005878","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005878","name":"Terveyden Tutkimuksen Toimikunta","doi-asserted-by":"publisher","award":["363152"],"award-info":[{"award-number":["363152"]}],"id":[{"id":"10.13039\/501100005878","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005878","name":"Terveyden Tutkimuksen Toimikunta","doi-asserted-by":"publisher","award":["365111"],"award-info":[{"award-number":["365111"]}],"id":[{"id":"10.13039\/501100005878","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010711","name":"Sy\u00f6p\u00e4s\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","award":["61\u20106200"],"award-info":[{"award-number":["61\u20106200"]}],"id":[{"id":"10.13039\/501100010711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010711","name":"Sy\u00f6p\u00e4s\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","award":["63\u20106459"],"award-info":[{"award-number":["63\u20106459"]}],"id":[{"id":"10.13039\/501100010711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010711","name":"Sy\u00f6p\u00e4s\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","award":["66\u20106963"],"award-info":[{"award-number":["66\u20106963"]}],"id":[{"id":"10.13039\/501100010711","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010711","name":"Sy\u00f6p\u00e4s\u00e4\u00e4ti\u00f6","doi-asserted-by":"publisher","award":["69\u20107648"],"award-info":[{"award-number":["69\u20107648"]}],"id":[{"id":"10.13039\/501100010711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology CR"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Prostate cancer (PCa) lacks reliable and accurate tissue\u2010based biomarkers to support prognostic stratification and clinical treatment decisions. Current diagnostic assessment, including Gleason grading, has limitations such as interobserver variability and insufficient granularity for disease aggressiveness. Fibroblast activation protein (FAP) and \u03b1\u2010smooth muscle actin (\u03b1SMA) have emerged as putative stromal biomarkers, but their prognostic value in localised PCa has not been validated at scale. In this study, we developed a novel artificial intelligence (AI)\u2010augmented image analysis pipeline tailored for dual\u2010marker immunohistochemistry of FAP and \u03b1SMA, enabling automated, tissue compartment\u2010specific quantification of biomarker expression. This deep learning model was trained and validated using digitised high\u2010resolution whole\u2010slide images of tissue microarrays from three prostatectomy cohorts, comprising 4,097 cores from 835 patients with comprehensive clinical follow\u2010up data. The AI pipeline demonstrated high accuracy in detecting epithelial, stromal, and immune compartments, as well as in quantifying FAP and \u03b1SMA signals. We validated stromal FAP as a robust prognostic marker consistently associated with adverse clinical outcomes, including earlier biochemical recurrence, metastasis, and cancer\u2010specific death. Epithelial FAP and stromal \u03b1SMA showed additional prognostic associations in selected analyses, particularly in MRI\u2010visible tumours. Our findings reinforce the biological and clinical relevance of stromal FAP in the prostate tumour microenvironment. By enabling standardised and scalable biomarker quantification, our newly developed AI\u2010assisted workflow advances the clinical utility of FAP and \u03b1SMA and demonstrates the power of integrating digital pathology with biomarker quantification. This study represents a critical step toward implementing stromal biomarkers in routine PCa diagnostics and underscores the potential of AI\u2010enhanced histopathology in advancing precision oncology.<\/jats:p>","DOI":"10.1002\/2056-4538.70068","type":"journal-article","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T06:05:48Z","timestamp":1766037948000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Validation of fibroblast activation protein and \u03b1\u2010smooth muscle actin as prognostic biomarkers in prostate cancer through\n                    <scp>AI<\/scp>\n                    \u2010assisted image analysis of dual\u2010marker\n                    <scp>IHC<\/scp>"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7510-3483","authenticated-orcid":false,"given":"Jenni","family":"S\u00e4il\u00e4","sequence":"first","affiliation":[{"name":"Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE) University of Helsinki  Helsinki Finland"},{"name":"Research Program in Systems Oncology (ONCOSYS) and iCAN \u2013 Digital Precision Cancer Medicine Flagship University of Helsinki  Helsinki Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timo\u2010Pekka","family":"Lehto","sequence":"additional","affiliation":[{"name":"Research Program in Systems Oncology (ONCOSYS) and iCAN \u2013 Digital Precision Cancer Medicine Flagship University of Helsinki  Helsinki Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Antti","family":"Rannikko","sequence":"additional","affiliation":[{"name":"Research Program in Systems Oncology (ONCOSYS) and iCAN \u2013 Digital Precision Cancer Medicine Flagship University of Helsinki  Helsinki Finland"},{"name":"Department of Urology University of Helsinki and Helsinki University Hospital  Helsinki Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Olli","family":"Kallioniemi","sequence":"additional","affiliation":[{"name":"Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE) University of Helsinki  Helsinki Finland"},{"name":"Science for Life Laboratory, Department of Oncology and Pathology Karolinska Institute  Solna Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tuomas","family":"Mirtti","sequence":"additional","affiliation":[{"name":"Research Program in Systems Oncology (ONCOSYS) and iCAN \u2013 Digital Precision Cancer Medicine Flagship University of Helsinki  Helsinki Finland"},{"name":"Department of Pathology, Diagnostic Center Helsinki University Hospital  Helsinki Finland"},{"name":"Finnish Cancer Institute  Helsinki Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9652-7373","authenticated-orcid":false,"given":"Teijo","family":"Pellinen","sequence":"additional","affiliation":[{"name":"Institute for Molecular Medicine Finland (FIMM), Helsinki Institute of Life Science (HiLIFE) University of Helsinki  Helsinki Finland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,12,17]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2019.08.005"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep43378"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13040628"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.5772\/intechopen.77327"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12061550"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2017.7248"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2015.10.029"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1002\/pros.23867"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/2767-9764.CRC-21-0183"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-020-09909-3"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-018-0275-3"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/s41181-019-0069-0"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12964-023-01151-y"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2015.3197"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0134965"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v18.i8.840"},{"key":"e_1_2_9_18_1","first-page":"855","article-title":"Seprase, a membrane\u2010bound protease, is overexpressed by invasive ductal carcinoma cells of human breast cancers","volume":"11","author":"Kelly T","year":"1998","journal-title":"Mod Pathol"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.113302"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0116683"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes13010135"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12071887"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.4104"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.12.9.2730"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.32193"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.17305\/bjbms.2015.449"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1530\/ERC-12-0085"},{"key":"e_1_2_9_28_1","first-page":"4792","article-title":"Reactive stroma as a predictor of biochemical\u2010free recurrence in prostate cancer","volume":"9","author":"Ayala G","year":"2003","journal-title":"Clin Cancer Res"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1590\/S1677-5538.IBJU.2014.0355"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14122943"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.media.2016.06.037"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-021-00919-2"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.euf.2020.06.016"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2011.328"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1002\/pros.24108"},{"key":"e_1_2_9_36_1","doi-asserted-by":"crossref","unstructured":"PellinenT LuomalaL MattilaKE et al.Fibroblast activation protein defines aggressive EMT\u2010associated cancer cell state and prognosis in localized ccRCC.bioRxiv2024;https:\/\/doi.org\/10.1101\/2024.10.27.620479. [Not peer reviewed].","DOI":"10.1101\/2024.10.27.620479"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncponc0252"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1111\/his.15356"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2024.08.011"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-03405-5"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-024-12980-6"},{"key":"e_1_2_9_42_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.pathol.2024.12.637"},{"key":"e_1_2_9_43_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-1358"},{"key":"e_1_2_9_44_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00432-013-1471-8"},{"key":"e_1_2_9_45_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.00979"},{"key":"e_1_2_9_46_1","first-page":"1952","article-title":"FAP and PSMA expression by immunohistochemistry and PET imaging in castration\u2010resistant prostate cancer: a translational pilot study","volume":"65","author":"Huang RR","year":"2024","journal-title":"J Nucl Med"},{"key":"e_1_2_9_47_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00259-021-05423-y"},{"key":"e_1_2_9_48_1","doi-asserted-by":"publisher","DOI":"10.1177\/1010428317718403"},{"key":"e_1_2_9_49_1","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0215(20010120)95:1<67::AID-IJC1012>3.0.CO;2-U"},{"key":"e_1_2_9_50_1","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djac178"},{"key":"e_1_2_9_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-023-39953-w"},{"key":"e_1_2_9_52_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-15-2973"},{"key":"e_1_2_9_53_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01520-5"},{"key":"e_1_2_9_54_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI157399"},{"key":"e_1_2_9_55_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1560998"},{"key":"e_1_2_9_56_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcmgh.2022.12.005"},{"key":"e_1_2_9_57_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9113697"},{"key":"e_1_2_9_58_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.6163"},{"key":"e_1_2_9_59_1","unstructured":"Aiforia Achieves CE\u2010IVD Mark for Clinical PD\u2010L1 AI Model in Lung Cancer Diagnostics. Imaging Technology News2021. [Accessed 15 August 2025]. Available from:https:\/\/www.itnonline.com\/"},{"key":"e_1_2_9_60_1","unstructured":"Aiforia.Aiforia Releases Another CE\u2010IVD Marked Clinical AI Model \u2013 Expanding Its Diagnostic Pathology Offering to Prostate Cancer2022. [Accessed 23 November 2023]. Available from:https:\/\/www.aiforia.com\/blog\/ce-ivd-prostate-cancer-gleason"},{"key":"e_1_2_9_61_1","doi-asserted-by":"publisher","DOI":"10.1111\/apm.13190"},{"key":"e_1_2_9_62_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.6168"},{"key":"e_1_2_9_63_1","doi-asserted-by":"publisher","DOI":"10.2147\/JMDH.S410301"},{"key":"e_1_2_9_64_1","doi-asserted-by":"publisher","DOI":"10.4103\/0256-4947.51806"}],"container-title":["The Journal of Pathology: Clinical Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/2056-4538.70068","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/2056-4538.70068","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/2056-4538.70068","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T07:36:25Z","timestamp":1769672185000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/2056-4538.70068"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,17]]},"references-count":63,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["10.1002\/2056-4538.70068"],"URL":"https:\/\/doi.org\/10.1002\/2056-4538.70068","archive":["Portico"],"relation":{},"ISSN":["2056-4538","2056-4538"],"issn-type":[{"value":"2056-4538","type":"print"},{"value":"2056-4538","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,17]]},"assertion":[{"value":"2025-04-10","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-27","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-17","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70068"}}