{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,4]],"date-time":"2026-11-04T00:26:13Z","timestamp":1793751973743,"version":"4.6.1"},"reference-count":34,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T00:00:00Z","timestamp":1737936000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Tokushima University"},{"name":"Heiwa Nakajima Foundation"},{"name":"Takeda Science Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Viral hepatitis, particularly hepatitis B (HBV) and hepatitis C (HCV), is highly prevalent in Mongolia. Moreover, Mongolia has the highest prevalence of hepatitis delta virus (HDV) globally, with over 60% of HBV-infected individuals also co-infected with HDV. Since HBV\/HDV infections accelerate liver disease progression more compared to HBV infection alone, urgent national health measures are required. Method: This study presents a clinicopathological analysis of 49 hepatocellular carcinoma cases surgically resected at the Mongolia\u2013Japan Hospital of the Mongolian National University of Medical Sciences. Results: HBV infection was found in 27 (55.1%) cases of all HCC cases. Immunohistochemical staining of the liver revealed that 14 (28.6%) cases were HDV antigen-positive in the HCC cases. HDV-positive cases exhibited significantly higher inflammatory activity compared to HDV-negative cases, with lymphocytic infiltrates predominantly composed of CD4-positive cells. Furthermore, HDV-positive cells were spatially distinct from HBs antigen-positive cells, suggesting that HDV-infected cells may interfere with HBV replication. No significant differences in fibrosis or in tumor characteristics were observed between the HDV-positive and negative cases. Early diagnosis of HBV\/HDV infections is essential for appropriate treatment and to prevent further domestic transmission of the virus. However, routine testing for HDV infection is rarely conducted in Mongolia. Since HDV-positive cells are morphologically indistinguishable from surrounding HDV-negative cells, routine histopathological analysis may not be sufficient enough to detect HDV infection. Conclusions: Based on this clinicopathological study, CD4 and CD8 immunostaining can be considered an adjunctive diagnostic tool in cases with significant lymphocytic infiltration and hepatocellular damage. Additionally, HDV screening using blood and tissue samples may be recommended to ensure accurate diagnosis.<\/jats:p>","DOI":"10.3390\/cancers17030432","type":"journal-article","created":{"date-parts":[[2025,1,27]],"date-time":"2025-01-27T11:38:49Z","timestamp":1737977929000},"page":"432","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Histopathological Features of Hepatocellular Carcinoma in Patients with Hepatitis B and D Virus Infection: A Single-Institution Study in Mongolia"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1411-7483","authenticated-orcid":false,"given":"Orgil","family":"Jargalsaikhan","sequence":"first","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8503, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenhua","family":"Shao","sequence":"additional","affiliation":[{"name":"Department of Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8503, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4030-1249","authenticated-orcid":false,"given":"Mayuko","family":"Ichimura-Shimizu","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8503, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soichiro","family":"Ishimaru","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8503, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9767-990X","authenticated-orcid":false,"given":"Takaaki","family":"Koma","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8503, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masako","family":"Nomaguchi","sequence":"additional","affiliation":[{"name":"Department of Microbiology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8503, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6750-5439","authenticated-orcid":false,"given":"Hirohisa","family":"Ogawa","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8503, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shotaro","family":"Tachibana","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8503, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Battogtokh","family":"Chimeddorj","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia"},{"name":"Department of Microbiology and Infection Prevention Control, School of Biomedicine, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6176-9313","authenticated-orcid":false,"given":"Khongorzul","family":"Batchuluun","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anujin","family":"Tseveenjav","sequence":"additional","affiliation":[{"name":"Institute of Biomedical Sciences, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9721-2293","authenticated-orcid":false,"given":"Battur","family":"Magvan","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Infection Prevention Control, School of Biomedicine, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bayarmaa","family":"Enkhbat","sequence":"additional","affiliation":[{"name":"Department of Pathology and Forensic Medicine, School of Biomedicine, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6924-8715","authenticated-orcid":false,"given":"Sayamaa","family":"Lkhagvadorj","sequence":"additional","affiliation":[{"name":"Department of Pathology and Forensic Medicine, School of Biomedicine, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia"},{"name":"Surgery Department, Mongolia\u2013Japan Hospital of Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adilsaikhan","family":"Mendjargal","sequence":"additional","affiliation":[{"name":"Surgery Department, Mongolia\u2013Japan Hospital of Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lkhagvadulam","family":"Ganbaatar","sequence":"additional","affiliation":[{"name":"Surgery Department, Mongolia\u2013Japan Hospital of Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minoru","family":"Irahara","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8503, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1484-7777","authenticated-orcid":false,"given":"Masashi","family":"Akaike","sequence":"additional","affiliation":[{"name":"Department of Medical Education, Graduate School of Biomedical Sciences, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8503, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Damdindorj","family":"Boldbaatar","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Bio-Medicine, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0670-9868","authenticated-orcid":false,"given":"Koichi","family":"Tsuneyama","sequence":"additional","affiliation":[{"name":"Department of Pathology and Laboratory Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8503, Japan"},{"name":"Department of Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8503, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,1,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1111\/liv.13018","article-title":"The Adventure of Delta","volume":"36","author":"Rizzetto","year":"2016","journal-title":"Liver Int."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1099","DOI":"10.1128\/jvi.65.3.1099-1104.1991","article-title":"Production of Hepatitis Delta Virus and Suppression of Helper Hepatitis B Virus in a Human Hepatoma Cell Line","volume":"65","author":"Wu","year":"1991","journal-title":"J. Virol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1406","DOI":"10.1158\/1541-7786.MCR-18-0012","article-title":"Molecular Signature and Mechanisms of Hepatitis D Virus-Associated Hepatocellular Carcinoma","volume":"16","author":"Diaz","year":"2018","journal-title":"Mol. Cancer Res."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Cardoso, M.F., and Machado, M.V. (2024). The Changing Face of Hepatitis Delta Virus Associated Hepatocellular Carcinoma. Cancers, 16.","DOI":"10.3390\/cancers16223723"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"S84","DOI":"10.1016\/j.jhep.2016.02.021","article-title":"Mechanisms of HBV-Induced Hepatocellular Carcinoma","volume":"64","author":"Levrero","year":"2016","journal-title":"J. Hepatol."},{"key":"ref_6","unstructured":"WHO (2016). Global Health Sector Strategy on Viral Hepatitis 2016\u20132021, World Health Organization."},{"key":"ref_7","first-page":"491","article-title":"High Prevalence of Hepatitis B, C, and Delta Viruses Among Patients with Chronic Liver Disease in Mongolia","volume":"76","author":"Takahashi","year":"2005","journal-title":"J. Med. Virol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1097\/JCMA.0000000000001073","article-title":"Risk factors associated with hepatitis D virus infection and preventive strategies in Mongolia","volume":"87","author":"Su","year":"2024","journal-title":"J. Chin. Med. Assoc. JCMA"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1016\/j.jhep.2020.04.008","article-title":"The Global Prevalence of Hepatitis D Virus Infection: Systematic Review and Meta-Analysis","volume":"73","author":"Stockdale","year":"2020","journal-title":"J Hepatol."},{"key":"ref_10","unstructured":"Polaris Observatory Collaborators (2024). Adjusted Estimate of the Prevalence of Hepatitis Delta Virus in 25 Countries and Territories. J. Hepatol., 80, 232\u2013242."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1739","DOI":"10.1002\/hep.28957","article-title":"A Novel Quantitative Microarray Antibody Capture Assay Identifies an Extremely High Hepatitis Delta Virus Prevalence Among Hepatitis B Virus-Infected Mongolians","volume":"66","author":"Chen","year":"2017","journal-title":"Hepatology"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Magvan, B., Kloeble, A.A., Ptok, J., Hoffmann, D., Habermann, D., Gantumur, A., Paluschinski, M., Enebish, G., Balz, V., and Fischer, J.C. (2023). Sequence Diversity of Hepatitis D Virus in Mongolia. Front. Med., 10.","DOI":"10.3389\/fmed.2023.1108543"},{"key":"ref_13","unstructured":"WHO (2017). Hepatitis B Vaccines: WHO Position Paper\u2014July 2017. Wkly. Epidemiol. Rec., 92, 369\u2013392."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6550","DOI":"10.1016\/j.vaccine.2009.08.048","article-title":"Epidemiological Serosurvey of Hepatitis B in China\u2014Declining HBV Prevalence Due to Hepatitis B Vaccination","volume":"27","author":"Liang","year":"2009","journal-title":"Vaccine"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1016\/j.jhep.2009.01.002","article-title":"Hepatitis B Vaccination: The Key Towards Elimination and Eradication of Hepatitis B","volume":"50","author":"Chen","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_16","first-page":"163","article-title":"Family Transmission and Rural Hepatitis B Challenges in Mongolia","volume":"31","author":"Shagdar","year":"2019","journal-title":"Asia Pac. J. Public. Health"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.1016\/j.jhep.2009.01.004","article-title":"Hepatitis D: Thirty Years After","volume":"50","author":"Rizzetto","year":"2009","journal-title":"J. Hepatol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1861","DOI":"10.1002\/hep.27403","article-title":"The Impact of Injecting Networks on HCV Transmission in People Who Inject Drugs","volume":"60","author":"Hellard","year":"2014","journal-title":"Hepatology"},{"key":"ref_19","first-page":"499","article-title":"Impact of the \u2018Healthy Liver\u2019 National Programme on HBV Infection in Mongolia","volume":"4","author":"Dagvadorj","year":"2019","journal-title":"Lancet Gastroenterol. Hepatol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/S0168-8278(02)00357-4","article-title":"Histopathological Study of Chronic Hepatitis B and C: A Comparison of Two Scoring Systems","volume":"38","author":"Rozario","year":"2003","journal-title":"J. Hepatol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Lombardo, D., Franz\u00e8, M.S., Caminiti, G., and Pollicino, T. (2024). Hepatitis Delta Virus and Hepatocellular Carcinoma. Pathogens, 13.","DOI":"10.3390\/pathogens13050362"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"John, B.V., Bastaich, D., Amoli, M.M., Wong, R.J., Evon, D.M., Rogal, S.S., Ross, D.B., Morgan, T.R., Spector, S.A., and Villada, G. (2024). Association of Hepatitis Delta Virus Infection and Hepatocellular Carcinoma, Hepatic Decompensation, All-Cause and Liver-Related Death in a National Cohort. Hepatology.","DOI":"10.1097\/HEP.0000000000001162"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Farci, P., Niro, G.A., Zamboni, F., and Diaz, G. (2021). Hepatitis D Virus and Hepatocellular Carcinoma. Viruses, 13.","DOI":"10.3390\/v13050830"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4383","DOI":"10.1038\/s41467-020-18186-1","article-title":"The Genomic Landscape of Mongolian Hepatocellular Carcinoma","volume":"11","author":"Candia","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Smirnova, O.A., Ivanova, O.N., Mukhtarov, F., Valuev-Elliston, V.T., Fedulov, A.P., Rubtsov, P.M., Zakirova, N.F., Kochetkov, S.N., Bartosch, B., and Ivanov, A.V. (2023). Hepatitis Delta Virus Antigens Trigger Oxidative Stress, Activate Antioxidant Nrf2\/ARE Pathway, and Induce Unfolded Protein Response. Antioxidants, 12.","DOI":"10.3390\/antiox12040974"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"882","DOI":"10.1016\/j.jhep.2024.01.035","article-title":"Blocking Viral Entry with Bulevirtide Reduces the Number of HDV-Infected Hepatocytes in Human Liver Biopsies","volume":"80","author":"Allweiss","year":"2024","journal-title":"J. Hepatol."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Oberhardt, V., Hofmann, M., Thimme, R., and Neumann-Haefelin, C. (2022). Adaptive Immune Responses, Immune Escape and Immune-Mediated Pathogenesis During HDV Infection. Viruses, 14.","DOI":"10.3390\/v14020198"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1805","DOI":"10.1053\/j.gastro.2019.01.035","article-title":"Hepatitis D Virus-Specific CD8+ T Cells Have a Memory-Like Phenotype Associated with Viral Immune Escape in Patients with Chronic Hepatitis D Virus Infection","volume":"156","author":"Kefalakes","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1820","DOI":"10.1053\/j.gastro.2019.02.003","article-title":"Mutations in Hepatitis D Virus Allow It to Escape Detection by CD8+ T Cells and Evolve at the Population Level","volume":"156","author":"Karimzadeh","year":"2019","journal-title":"Gastroenterology"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Thiyagarajah, K., Basic, M., and Hildt, E. (2023). Cellular Factors Involved in the Hepatitis D Virus Life Cycle. Viruses, 15.","DOI":"10.3390\/v15081687"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e162404","DOI":"10.1172\/jci.insight.162404","article-title":"Persistent Hepatic IFN System Activation in HBV-HDV Infection Determines Viral Replication Dynamics and Therapeutic Response","volume":"8","author":"Chida","year":"2023","journal-title":"JCI Insight"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Dambadarjaa, D., Radnaa, O., Khuyag, S.O., Shagdarsuren, O.E., Enkhbayar, U., Mukhtar, Y., Tsogzolbaatar, E.O., Nyam, G., Shaarii, S., and Singh, P. (2022). Hepatitis, B, C, and D Virus Infection among Population Aged 10\u201364 Years in Mongolia: Baseline Survey Data of a Nationwide Cancer Cohort Study. Vaccines, 10.","DOI":"10.3390\/vaccines10111928"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1688","DOI":"10.1002\/jmv.20755","article-title":"High Frequency of Hepatocellular Carcinoma in Mongolia; Association with Mono-, or Co-Infection with Hepatitis, C.; B.; and Delta Viruses","volume":"78","author":"Oyunsuren","year":"2006","journal-title":"J. Med. Virol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Khalfi, P., Denis, Z., McKellar, J., Merolla, G., Chavey, C., Ursic-Bedoya, J., Soppa, L., Szirovicza, L., Hetzel, U., and Dufourt, J. (2024). Comparative Analysis of Human, Rodent and Snake Deltavirus Replication. PLoS Pathog., 20.","DOI":"10.1371\/journal.ppat.1012060"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/3\/432\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,8]],"date-time":"2025-10-08T10:37:23Z","timestamp":1759919843000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/17\/3\/432"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,27]]},"references-count":34,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2025,2]]}},"alternative-id":["cancers17030432"],"URL":"https:\/\/doi.org\/10.3390\/cancers17030432","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,27]]}}}