{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T05:15:32Z","timestamp":1778649332281,"version":"3.51.4"},"reference-count":35,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T00:00:00Z","timestamp":1778630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>\n                    We describe a case of metachronous double primary hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) in a 62-year-old male with occult hepatitis B virus (HBV) infection, an extremely rare entity easily misdiagnosed as iCCA recurrence, especially with an alpha-fetoprotein (AFP)-negative phenotype. The patient was initially diagnosed with stage IV iCCA (cT3N0M1) with bone metastases, receiving radiotherapy for primary and metastatic lesions, followed by 2-year sequential apatinib plus camrelizumab, achieving iCCA partial remission. At 56-month follow-up, abdominal CT detected new hepatic lesions, which pathological and immunohistochemical examinations confirmed as\n                    <jats:italic>de novo<\/jats:italic>\n                    HCC rather than iCCA recurrence, with the patient remaining AFP-negative throughout the course. We retrospectively analyzed this case and reviewed relevant literature to discuss its diagnostic clues, potential pathogenesis and therapeutic implications. This case highlights that occult HBV infection, chronic inflammation and liver radiotherapy may synergistically drive multi-pathway hepatocarcinogenesis. Radiotherapy combined with anti-angiogenic and immunotherapy is an effective option for advanced unresectable iCCA. It also emphasizes that active pathological biopsy is essential for new hepatic lesions after iCCA remission to clarify diagnosis and avoid misdiagnosis-induced inappropriate treatment.\n                  <\/jats:p>","DOI":"10.3389\/fonc.2026.1822063","type":"journal-article","created":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T04:50:52Z","timestamp":1778647852000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Metachronous hepatocellular carcinoma after partial response of advanced intrahepatic cholangiocarcinoma treated with radiotherapy combined with apatinib and camrelizumab: a case report"],"prefix":"10.3389","volume":"16","author":[{"given":"Yujuan","family":"Dai","sequence":"first","affiliation":[{"name":"Department of Oncology, The 909th Hospital, School of Medicine, Xiamen University","place":["Zhangzhou, Fujian, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dachao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Oncology, The 909th Hospital, School of Medicine, Xiamen University","place":["Zhangzhou, Fujian, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shufeng","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Oncology, The 909th Hospital, School of Medicine, Xiamen University","place":["Zhangzhou, Fujian, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuehua","family":"Geng","sequence":"additional","affiliation":[{"name":"Department of Pathology, The 909th Hospital, School of Medicine, Xiamen University","place":["Zhangzhou, Fujian, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"XianYing","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Oncology, The 909th Hospital, School of Medicine, Xiamen University","place":["Zhangzhou, Fujian, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nana","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, The 909th Hospital, School of Medicine, Xiamen University","place":["Zhangzhou, Fujian, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiangbin","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Oncology, The 909th Hospital, School of Medicine, Xiamen University","place":["Zhangzhou, Fujian, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,5,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1002\/hep.29913","article-title":"Diagnosis, staging, and management of hepatocellular carcinoma: 2018 practice guidance by the American Association for the Study of Liver Diseases","volume":"68","author":"Marrero","year":"2018","journal-title":"Hepatology"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.4254\/wjh.v6.i12.860","article-title":"Occult hepatitis B virus infection","volume":"6","author":"Kwak","year":"2014","journal-title":"World J Hepatol"},{"key":"B3","doi-asserted-by":"publisher","first-page":"4234","DOI":"10.62347\/PIWA3282","article-title":"Characteristics, diagnosis, treatment and prognosis of double primary hepatic cancer: experience based on a series of 12 cases","volume":"16","author":"Tan","year":"2024","journal-title":"Am J Transl Res"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1111\/jgh.12143","article-title":"Double primary hepatic cancer (hepatocellular carcinoma and intrahepatic cholangiocarcinoma) in a single patient: a clinicopathologic study of 35 resected cases","volume":"28","author":"Cao","year":"2013","journal-title":"J Gastroenterol Hepatol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s12029-021-00637-7","article-title":"Significant response to camrelizumab plus targeted drugs in recurrent intrahepatic cholangiocarcinoma: a case report and literature review","volume":"53","author":"Huang","year":"2022","journal-title":"J Gastrointest Cancer"},{"key":"B6","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1038\/s41575-025-01153-w","article-title":"Cholangiocarcinoma 2026: status quo, unmet needs and priorities","volume":"23","author":"Banales","year":"2026","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.33564","article-title":"N-glycan fingerprint predicts alpha-fetoprotein negative hepatocellular carcinoma: a large-scale multicenter study","volume":"149","author":"Huang","year":"2021","journal-title":"Int J Cancer"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13122871","article-title":"Histological heterogeneity of primary liver cancers: clinical relevance, diagnostic pitfalls and the pathologist's role","volume":"13","author":"Komuta","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B9","doi-asserted-by":"publisher","first-page":"893","DOI":"10.12449\/JCH240508","article-title":"Guidelines for the diagnosis and treatment of primary liver cancer (2024 edition)","volume":"40","year":"2024","journal-title":"J Clin Hepatol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3390\/diagnostics16020314","article-title":"An updated review of combined hepatocellular cholangiocarcinoma: a rare and poorly understood neoplasm","volume":"16","author":"Low","year":"2026","journal-title":"Diagnostics (Basel)"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2020.05.042","article-title":"Occult hepatitis B infection and hepatocellular carcinoma: epidemiology, virology, hepatocarcinogenesis and clinical significance","volume":"73","author":"Mak","year":"2020","journal-title":"J Hepatol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2020-323153","article-title":"Hepatitis B virus integrations promote local and distant oncogenic driver alterations in hepatocellular carcinoma","volume":"71","author":"P\u00e9neau","year":"2022","journal-title":"Gut"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1002\/mco2.70121","article-title":"The Malignant transformation of viral hepatitis to hepatocellular carcinoma: mechanisms and interventions","volume":"6","author":"Yuan","year":"2025","journal-title":"MedComm"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2020.104992","article-title":"HBV induced hepatocellular carcinoma and related potential immunotherapy","volume":"159","author":"Jia","year":"2020","journal-title":"Pharmacol Res"},{"key":"B15","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.jhep.2019.09.007","article-title":"Risk factors for intrahepatic and extrahepatic cholangiocarcinoma: a systematic review and meta-analysis","volume":"72","author":"Clements","year":"2020","journal-title":"J Hepatol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"18199","DOI":"10.1038\/s41598-019-54773-z","article-title":"Somatic mutation signatures in primary liver tumors of workers exposed to ionizing radiation","volume":"9","author":"Goerlitz","year":"2019","journal-title":"Sci Rep"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.9952","article-title":"Surgical resection and radiofrequency ablation initiate cancer in cytokeratin-19+- liver cells deficient for p53 and Rb","volume":"7","author":"Matondo","year":"2016","journal-title":"Oncotarget"},{"key":"B18","doi-asserted-by":"publisher","first-page":"28","DOI":"10.14740\/jmc2387w","article-title":"Combined hepatocellular-cholangiocarcinoma associated with radiofrequency ablation for hepatocellular carcinoma","volume":"7","author":"Takamatsu","year":"2016","journal-title":"J Med cases"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/nature23015","article-title":"Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration","volume":"547","author":"Raven","year":"2017","journal-title":"Nature"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1056\/EVIDoa2200015","article-title":"Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer","volume":"1","author":"Oh","year":"2022","journal-title":"NEJM Evid"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)00727-4","article-title":"Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial","volume":"401","author":"Kelley","year":"2023","journal-title":"Lancet"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1111\/liv.15948","article-title":"Management of intrahepatic and perihilar cholangiocarcinomas: guidelines of the French Association for the Study of the Liver (AFEF)","volume":"44","author":"Neuzillet","year":"2024","journal-title":"Liver Int"},{"key":"B23","doi-asserted-by":"publisher","first-page":"5559","DOI":"10.1038\/s41467-025-60119-3","article-title":"Sintilimab and anlotinib with gemcitabine plus cisplatin in advanced biliary tract cancer: SAGC a randomized phase 2 trial","volume":"16","author":"Li","year":"2025","journal-title":"Nat Commun"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2020-002191","article-title":"Camrelizumab in combination with apatinib in second-line or above therapy for advanced primary liver cancer: cohort A report in a multicenter phase Ib\/II trial","volume":"9","author":"Mei","year":"2021","journal-title":"J Immunother Cancer"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.34372","article-title":"Feasibility and tolerability of sintilimab plus anlotinib as the second-line therapy for patients with advanced biliary tract cancers: an open-label, single-arm, phase II clinical trial","volume":"152","author":"Jin","year":"2023","journal-title":"Int J Cancer"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1158\/2767-9764.CRC-26-0018","article-title":"Lenvatinib plus pembrolizumab for patients with previously treated advanced gastric, biliary tract, or pancreatic cancer: results from the phase II LEAP-005 study","volume":"6","author":"Ponz-Sarvis\u00e9","year":"2026","journal-title":"Cancer Res Commun"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2023.41.16_suppl.e16170","article-title":"The clinical efficacy and safety of sintilimab plus anlotinib for unresectable intrahepatic cholangiocarcinoma (ICC): a prospective, single-arm phase II study","volume":"41","author":"Cheng","year":"2023","journal-title":"J Clin Oncol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2018.36.15_suppl.e16123","article-title":"Efficacy and safety of apatinib in refractory unresectable and metastatic cholangiocarcinoma: a retrospective analysis","volume":"36","author":"Mou","year":"2018","journal-title":"J Clin Oncol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.7150\/jca.53482","article-title":"Apatinib as non-first-line treatment in patients with intrahepatic cholangiocarcinoma","volume":"12","author":"Mao","year":"2021","journal-title":"J Cancer"},{"key":"B30","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1186\/s12885-021-07907-4","article-title":"The efficacy and safety of apatinib treatment for patients with advanced or recurrent biliary tract cancer: a retrospective study","volume":"21","author":"Nie","year":"2021","journal-title":"BMC Cancer"},{"key":"B31","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1186\/s12916-024-03381-4","article-title":"Anti-PD-1 antibody in combination with radiotherapy as first-line therapy for unresectable intrahepatic cholangiocarcinoma","volume":"22","author":"Zhu","year":"2024","journal-title":"BMC Med"},{"key":"B32","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1186\/s40425-019-0692-z","article-title":"Local and abscopal responses in advanced intrahepatic cholangiocarcinoma with low TMB, MSS, pMMR and negative PD-L1 expression following combined therapy of SBRT with PD-1 blockade","volume":"7","author":"Liu","year":"2019","journal-title":"J Immunother Cancer"},{"key":"B33","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1007\/s00262-025-04129-6","article-title":"Local-regional therapy combined with immune checkpoint inhibitors and lenvatinib versus immune checkpoint inhibitors plus chemotherapy in advanced intrahepatic cholangiocarcinoma: a multicenter cohort study","volume":"74","author":"Li","year":"2025","journal-title":"Cancer Immunol Immunother"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2025.1926","article-title":"Adjuvant chemoradiation and immunotherapy for extrahepatic cholangiocarcinoma and gallbladder cancer: a randomized clinical trial","volume":"11","author":"Xiao","year":"2025","journal-title":"JAMA Oncol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.14218\/JCTH.2022.00141","article-title":"Intrahepatic cholangiocarcinoma and hepatocellular carcinoma: real-life data on liver disease, treatment and prognosis","volume":"11","author":"Adhoute","year":"2023","journal-title":"J Clin Transl Hepatol"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1822063\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,13]],"date-time":"2026-05-13T04:51:03Z","timestamp":1778647863000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1822063\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,13]]},"references-count":35,"alternative-id":["10.3389\/fonc.2026.1822063"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1822063","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,13]]},"article-number":"1822063"}}