{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T17:32:25Z","timestamp":1793035945157,"version":"4.5.0"},"reference-count":36,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2023,12,24]],"date-time":"2023-12-24T00:00:00Z","timestamp":1703376000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004504","name":"European Social Fund","doi-asserted-by":"publisher","award":["09.3.3-ESFA-V-711-01-0001"],"award-info":[{"award-number":["09.3.3-ESFA-V-711-01-0001"]}],"id":[{"id":"10.13039\/501100004504","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Despite advances in diagnostic and treatment technologies, predicting outcomes of patients with hepatocellular carcinoma (HCC) remains a challenge. Prognostic models are further obscured by the variable impact of the tumor properties and the remaining liver parenchyma, often affected by cirrhosis or non-alcoholic fatty liver disease that tend to precede HCC. This study investigated the prognostic value of reticulin and collagen microarchitecture in liver resection samples. We analyzed 105 scanned tissue sections that were stained using a Gordon and Sweet\u2019s silver impregnation protocol combined with Picric Acid\u2013Sirius Red. A convolutional neural network was utilized to segment the red-staining collagen and black linear reticulin strands, generating a detailed map of the fiber structure within the HCC and adjacent liver tissue. Subsequent hexagonal grid subsampling coupled with automated epithelial edge detection and computational fiber morphometry provided the foundation for region-specific tissue analysis. Two penalized Cox regression models using LASSO achieved a concordance index (C-index) greater than 0.7. These models incorporated variables such as patient age, tumor multifocality, and fiber-derived features from the epithelial edge in both the tumor and liver compartments. The prognostic value at the tumor edge was derived from the reticulin structure, while collagen characteristics were significant at the epithelial edge of peritumoral liver. The prognostic performance of these models was superior to models solely reliant on conventional clinicopathologic parameters, highlighting the utility of AI-extracted microarchitectural features for the management of HCC.<\/jats:p>","DOI":"10.3390\/cancers16010106","type":"journal-article","created":{"date-parts":[[2023,12,24]],"date-time":"2023-12-24T20:42:30Z","timestamp":1703450550000},"page":"106","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Improving HCC Prognostic Models after Liver Resection by AI-Extracted Tissue Fiber Framework Analytics"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9361-6562","authenticated-orcid":false,"given":"Rokas","family":"Stulpinas","sequence":"first","affiliation":[{"name":"Faculty of Medicine, Institute of Biomedical Sciences, Department of Pathology and Forensic Medicine, Vilnius University, 03101 Vilnius, Lithuania"},{"name":"National Center of Pathology, Affiliate of Vilnius University Hospital Santaros Klinikos, 08406 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1360-6533","authenticated-orcid":false,"given":"Mindaugas","family":"Morkunas","sequence":"additional","affiliation":[{"name":"National Center of Pathology, Affiliate of Vilnius University Hospital Santaros Klinikos, 08406 Vilnius, Lithuania"},{"name":"Vilnius Santaros Klinikos Biobank, Vilnius University Hospital Santaros Klinikos, 08661 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6705-6795","authenticated-orcid":false,"given":"Allan","family":"Rasmusson","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Biomedical Sciences, Department of Pathology and Forensic Medicine, Vilnius University, 03101 Vilnius, Lithuania"},{"name":"National Center of Pathology, Affiliate of Vilnius University Hospital Santaros Klinikos, 08406 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julius","family":"Drachneris","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Biomedical Sciences, Department of Pathology and Forensic Medicine, Vilnius University, 03101 Vilnius, Lithuania"},{"name":"National Center of Pathology, Affiliate of Vilnius University Hospital Santaros Klinikos, 08406 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Renaldas","family":"Augulis","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Biomedical Sciences, Department of Pathology and Forensic Medicine, Vilnius University, 03101 Vilnius, Lithuania"},{"name":"National Center of Pathology, Affiliate of Vilnius University Hospital Santaros Klinikos, 08406 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aiste","family":"Gulla","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Clinical Medicine, Vilnius University, 03101 Vilnius, Lithuania"},{"name":"Faculty of Medicine, Centre for Visceral Medicine and Translational Research, Vilnius University, 03101 Vilnius, Lithuania"},{"name":"Center of Abdominal Surgery, Vilnius University Hospital Santaros Klinikos, 08410 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1690-937X","authenticated-orcid":false,"given":"Kestutis","family":"Strupas","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Clinical Medicine, Vilnius University, 03101 Vilnius, Lithuania"},{"name":"Faculty of Medicine, Centre for Visceral Medicine and Translational Research, Vilnius University, 03101 Vilnius, Lithuania"},{"name":"Center of Abdominal Surgery, Vilnius University Hospital Santaros Klinikos, 08410 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arvydas","family":"Laurinavicius","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Institute of Biomedical Sciences, Department of Pathology and Forensic Medicine, Vilnius University, 03101 Vilnius, Lithuania"},{"name":"National Center of Pathology, Affiliate of Vilnius University Hospital Santaros Klinikos, 08406 Vilnius, Lithuania"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,12,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1053\/j.gastro.2023.01.033","article-title":"Global Epidemiology and Genetics of Hepatocellular Carcinoma","volume":"164","author":"Toh","year":"2023","journal-title":"Gastroenterology"},{"key":"ref_2","unstructured":"Eswaran, S.L., and Reau, N.S. (2023, September 15). Hepatocellular Carcinoma: 5 Things to Know. Available online: https:\/\/www.medscape.com\/viewarticle\/925146?form=fpf."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"310","DOI":"10.3748\/wjg.v28.i3.310","article-title":"Non-alcoholic fatty liver disease and hepatocellular carcinoma: Clinical challenges of an intriguing link","volume":"28","author":"Chrysavgis","year":"2022","journal-title":"World J. Gastroenterol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1016\/S0140-6736(22)01200-4","article-title":"Hepatocellular carcinoma","volume":"400","author":"Vogel","year":"2022","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1978","DOI":"10.1016\/j.cgh.2023.04.015","article-title":"The Global Burden of Liver Disease","volume":"21","author":"Younossi","year":"2023","journal-title":"Clin. Gastroenterol. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"200","DOI":"10.14740\/jocmr4902","article-title":"Prognostic Scores and Survival Rates by Etiology of Hepatocellular Carcinoma: A Review","volume":"15","author":"Vilchez","year":"2023","journal-title":"J. Clin. Med. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1016\/j.hpb.2020.07.010","article-title":"Survival and prognostic factors after transplantation, resection and ablation in a national cohort of early hepatocellular carcinoma","volume":"23","author":"Eilard","year":"2021","journal-title":"HPB"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"681","DOI":"10.1016\/j.jhep.2021.11.018","article-title":"BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update","volume":"76","author":"Reig","year":"2022","journal-title":"J. Hepatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1111\/liv.15180","article-title":"Barcelona Clinic Liver Cancer 2022 update: Linking prognosis prediction and evidence-based treatment recommendation with multidisciplinary clinical decision-making","volume":"42","author":"Mauro","year":"2022","journal-title":"Liver Int."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1111\/liv.14390","article-title":"Collagen biology and non-invasive biomarkers of liver fibrosis","volume":"40","author":"Karsdal","year":"2020","journal-title":"Liver Int."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1038\/s41467-020-20429-0","article-title":"Predicting postoperative peritoneal metastasis in gastric cancer with serosal invasion using a collagen nomogram","volume":"12","author":"Chen","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1186\/s40170-020-00221-w","article-title":"Tumor-associated collagen signatures: Pushing tumor boundaries","volume":"8","author":"Brett","year":"2020","journal-title":"Cancer Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"224","DOI":"10.5005\/jp-journals-10015-1442","article-title":"Tumor-associated collagen signatures: An insight","volume":"8","author":"Pavithra","year":"2017","journal-title":"World J. Dent."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"3229","DOI":"10.7150\/thno.55921","article-title":"Large-scale tumor-associated collagen signatures identify high-risk breast cancer patients","volume":"11","author":"Xi","year":"2021","journal-title":"Theranostics"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s00441-009-0864-0","article-title":"Suprastructures of extracellular matrices: Paradigms of functions controlled by aggregates rather than molecules","volume":"339","author":"Bruckner","year":"2010","journal-title":"Cell Tissue Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1016\/S0016-5085(79)80170-5","article-title":"Collagen Types in Normal and Cirrhotic Liver","volume":"76","author":"Rojkind","year":"1979","journal-title":"Gastroenterology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.addr.2017.07.014","article-title":"The good and the bad collagens of fibrosis\u2014Their role in signaling and organ function","volume":"121","author":"Karsdal","year":"2017","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_18","first-page":"211","article-title":"The role of CAFs and fibrosis in liver cancer","volume":"79","author":"Abrutyn","year":"2015","journal-title":"Annu. Rev. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Zhang, R., Ma, M., Lin, X.H., Liu, H.H., Chen, J., Chen, J., Gao, D.M., Cui, J.F., Ren, Z.G., and Chen, R.X. (2018). Extracellular matrix collagen i promotes the tumor progression of residual hepatocellular carcinoma after heat treatment. BMC Cancer, 18.","DOI":"10.1186\/s12885-018-4820-9"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e146987","DOI":"10.1172\/JCI146987","article-title":"Tumor restriction by type I collagen opposes tumor-promoting effects of cancer-associated fibroblasts","volume":"131","author":"Bhattacharjee","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_21","unstructured":"Burt, A.D., Portmann, B., and Ferrell, L.D. (2012). MacSween\u2019s Pathology of the Liver, Churchill Livingstone\/Elsevier. [6th ed.]."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"14569","DOI":"10.1038\/s41598-021-93566-1","article-title":"Collagen and elastic fibres in acute and chronic liver injury","volume":"11","author":"Hall","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Allaume, P., Turlin, B., Bardou-Jacquet, E., Lor, O., Calderaro, J., Khene, Z.e., Acosta, O., De Crevoisier, R., Rioux-Leclercq, N., and Pecot, T. (2023). Artificial Intelligence-Based Opportunities in Liver Pathology\u2014A Systematic Review. Diagnostics, 13.","DOI":"10.3390\/diagnostics13101799"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1111\/his.15020","article-title":"Augmented liver pathology: Artificial intelligence and the assessment of hepatocellular neoplasms","volume":"83","author":"Burt","year":"2023","journal-title":"Histopathology"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"512","DOI":"10.1111\/his.15001","article-title":"Artificial intelligence-based reticulin proportionate area\u2014A novel histological outcome predictor in hepatocellular carcinoma","volume":"83","author":"Patil","year":"2023","journal-title":"Histopathology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1002\/hep.31750","article-title":"A Machine Learning Approach Enables Quantitative Measurement of Liver Histology and Disease Monitoring in NASH","volume":"74","author":"Pokkalla","year":"2021","journal-title":"Hepatology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1136\/jcp-2022-208614","article-title":"Survey of liver pathologists to assess attitudes towards digital pathology and artificial intelligence","volume":"77","author":"McGenity","year":"2023","journal-title":"J. Clin. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"15474","DOI":"10.1038\/s41598-021-94862-6","article-title":"Tumor collagen framework from bright-field histology images predicts overall survival of breast carcinoma patients","volume":"11","author":"Morkunas","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1007\/s00428-015-1865-x","article-title":"A methodology for comprehensive breast cancer Ki67 labeling index with intra-tumor heterogeneity appraisal based on hexagonal tiling of digital image analysis data","volume":"467","author":"Plancoulaine","year":"2015","journal-title":"Virchows Arch."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1309","DOI":"10.1016\/j.ajpath.2020.01.018","article-title":"Immunogradient Indicators for Antitumor Response Assessment by Automated Tumor-Stroma Interface Zone Detection","volume":"190","author":"Rasmusson","year":"2020","journal-title":"Am. J. Pathol."},{"key":"ref_31","unstructured":"Kingma, D.P., and Ba, J. (2014). Adam: A Method for Stochastic Optimization. arXiv, Available online: https:\/\/arxiv.org\/abs\/1412.6980."},{"key":"ref_32","first-page":"461","article-title":"Primary Carcinoma of the Liver: Histological Study of 27 Cases of Primary Carcinoma of the Liver from Malawi","volume":"85","year":"1977","journal-title":"Acta Pathol. Microbiol. Scand. A"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1016\/S2468-1253(23)00141-3","article-title":"Performance of non-invasive tests and histology for the prediction of clinical outcomes in patients with non-alcoholic fatty liver disease: An individual participant data meta-analysis","volume":"8","author":"Lee","year":"2023","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1136\/flgastro-2023-102415","article-title":"Exploring changing attitudes to non-invasive liver fibrosis tests in secondary care pathways: Comparison of two national surveys","volume":"14","author":"Abeysekera","year":"2023","journal-title":"Frontline Gastroenterol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1200\/JCO.2014.57.9151","article-title":"Assessment of liver function in patients with hepatocellular carcinoma: A new evidence-based approach\u2014The ALBI grade","volume":"33","author":"Johnson","year":"2015","journal-title":"J. Clin. Oncol."},{"key":"ref_36","unstructured":"Council for International Organizations of Medical Sciences (CIOMS) in Collaboration with the World Health Organization (WHO) (2016). International Ethical Guidelines for Health-Related Research Involving Humans, Biomedical Research. [4th ed.]. Available online: https:\/\/cioms.ch\/wp-content\/uploads\/2017\/01\/WEB-CIOMS-EthicalGuidelines.pdf."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/1\/106\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T21:41:21Z","timestamp":1760132481000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/16\/1\/106"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,24]]},"references-count":36,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["cancers16010106"],"URL":"https:\/\/doi.org\/10.3390\/cancers16010106","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,24]]}}}