{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T12:55:41Z","timestamp":1787316941834,"version":"build-2736575974"},"reference-count":46,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:00:00Z","timestamp":1770768000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82200706, 82503963"],"award-info":[{"award-number":["82200706, 82503963"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2024QH349"],"award-info":[{"award-number":["ZR2024QH349"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To investigate the clinicopathological characteristics, treatment strategies, and prognostic outcomes of biliary neuroendocrine carcinoma (Biliary NEC), and to review the relevant literature to provide further evidence for the clinical management of this rare malignancy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We retrospectively analyzed the clinical data of nine patients who underwent surgical resection and were pathologically diagnosed with biliary NEC at Shandong Provincial Hospital between May 2012 and October 2025. Clinical manifestations, imaging findings, surgical procedures, histopathological and immunohistochemical results (Syn, CgA, CD56, Ki-67), and follow-up outcomes were collected. Overall survival (OS) was estimated using the Kaplan\u2013Meier method. Additionally, published case reports and case series from 2020 onward were reviewed for comparison.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among the nine patients (3 males and 6 females; median age, 65 years; range, 57\u201377 years), the primary tumor sites included the gallbladder (n = 4), hilar bile duct (n = 3), and distal bile duct (n = 2). The main presenting symptoms were abdominal discomfort (n = 6) and jaundice (n = 3). All tumors were poorly differentiated NECs, comprising six small-cell and two large-cell types, with Ki-67 indices ranging from 30% to 80% (median, 70%). Immunohistochemistry showed Syn (+), CgA (\u00b1), and CD56 (\u00b1), with partial expression of SSTR2. All patients underwent curative-intent resection (R0 in 8 and R1 in 1), and four received systemic chemotherapy initiated after documented tumor recurrence. The median follow-up duration was 649 days (range, 67\u2013953 days), and the median OS was 649 days (95% CI: 85\u20131213 days). A review of the literature revealed that systemic chemotherapy, particularly platinum-based regimens, was associated with longer median survival (18 vs. 9 months).<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Biliary NEC is a rare and highly aggressive malignancy with nonspecific clinical manifestations, and its diagnosis relies primarily on histopathological and immunohistochemical evaluation. Surgical resection remains the cornerstone of treatment, while systemic chemotherapy may provide additional survival benefit in selected patients. A high Ki-67 index and lymph node metastasis have been consistently reported as adverse prognostic indicators in biliary neuroendocrine carcinoma, primarily based on evidence from previously published studies. Given the limited sample size of the present case series, our observations should be interpreted as descriptive rather than statistically conclusive. Future multicenter studies incorporating molecular and immunologic profiling are warranted to clarify the biological behavior of biliary NEC and to optimize individualized therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1745019","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T05:26:36Z","timestamp":1770787596000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Clinicopathological characteristics and treatment outcomes of biliary neuroendocrine carcinoma: a single-center case series and literature review"],"prefix":"10.3389","volume":"16","author":[{"given":"Zhipeng","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pancreatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faji","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pancreatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yijie","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Pancreatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Department of Pancreatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shizhe","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Pancreatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheyu","family":"Niu","sequence":"additional","affiliation":[{"name":"Department of Pancreatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pancreatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyang","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Pancreatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaqiang","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pancreatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fengyun","family":"Cui","sequence":"additional","affiliation":[{"name":"Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Pancreatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hengjun","family":"Gao","sequence":"additional","affiliation":[{"name":"Department of Pancreatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pancreatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2019.00038","article-title":"Biliary neuroendocrine neoplasms: clinical profiles, management, and analysis of prognostic factors","volume":"9","author":"Zheng","year":"2019","journal-title":"Front Oncol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1007\/s00268-004-7443-z","article-title":"An analysis of rare carcinoid tumors: clarifying these clinical conundrums","volume":"29","author":"Modlin","year":"2005","journal-title":"World J Surg"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1007\/s00261-025-05204-3","article-title":"Gallbladder neuroendocrine neoplasms: a review","author":"Bhosale","year":"2025","journal-title":"Abdom Radiol (NY)"},{"key":"B4","doi-asserted-by":"publisher","first-page":"28","DOI":"10.32074\/1591-951X-231","article-title":"Neuroendocrine neoplasms of the biliary tree, liver and pancreas: a pathological approach","volume":"113","author":"Luchini","year":"2021","journal-title":"Pathologica"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.12998\/wjcc.v10.i23.8212","article-title":"Gallbladder neuroendocrine carcinoma diagnosis, treatment and prognosis based on the SEER database: A literature review","volume":"10","author":"Cai","year":"2022","journal-title":"World J Clin cases"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1097\/00004728-200607000-00009","article-title":"High-grade neuroendocrine carcinomas of the gallbladder and bile duct: Report of four cases with pathological correlation","volume":"30","author":"Jun","year":"2006","journal-title":"J Comput Assist Tomogr"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.21037\/jgo.2017.10.02","article-title":"Investigation of targetable predictive and prognostic markers in gallbladder carcinoma","volume":"9","author":"Neyaz","year":"2018","journal-title":"J Gastrointest Oncol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3892\/ol.2020.11461","article-title":"Neuroendocrine tumors of the gallbladder","volume":"19","author":"Niu","year":"2020","journal-title":"Oncol Lett"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1111\/his.13975","article-title":"The 2019 WHO classification of tumours of the digestive system","volume":"76","author":"Nagtegaal","year":"2020","journal-title":"Histopathology"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-018-0110-y","article-title":"A common classification framework for neuroendocrine neoplasms: an International Agency for Research on Cancer (IARC) and World Health Organization (WHO) expert consensus proposal","volume":"31","author":"Rindi","year":"2018","journal-title":"Mod Pathol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2022.3395","article-title":"Effectiveness of etoposide and cisplatin vs irinotecan and cisplatin therapy for patients with advanced neuroendocrine carcinoma of the digestive system: the TOPIC-NEC phase 3 randomized clinical trial","volume":"8","author":"Morizane","year":"2022","journal-title":"JAMA Oncol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1186\/s13023-019-1230-2","article-title":"Biliary tract large cell neuroendocrine carcinoma: current evidence","volume":"14","author":"Raiker","year":"2019","journal-title":"Orphanet J Rare Dis"},{"key":"B13","doi-asserted-by":"publisher","first-page":"e28531","DOI":"10.7759\/cureus.28531","article-title":"Rare case of gallbladder neuroendocrine carcinoma","volume":"14","author":"Rennie","year":"2022","journal-title":"Cureus"},{"key":"B14","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1186\/s13000-022-01231-6","article-title":"Mixed neuroendocrine-non-neuroendocrine neoplasm of the gallbladder: case report and literature review","volume":"17","author":"Ren","year":"2022","journal-title":"Diagn Pathol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.31729\/jnma.8444","article-title":"Large cell neuroendocrine carcinoma of gallbladder: A case report","volume":"62","author":"Sah","year":"2024","journal-title":"JNMA J Nepal Med Assoc"},{"key":"B16","doi-asserted-by":"publisher","first-page":"229","DOI":"10.3892\/ol.2023.13815","article-title":"Gallbladder neuroendocrine carcinoma: A report of two cases and literature review","volume":"25","author":"Liao","year":"2023","journal-title":"Oncol Lett"},{"key":"B17","doi-asserted-by":"publisher","first-page":"rjac020","DOI":"10.1093\/jscr\/rjac020","article-title":"Case of resected small-cell neuroendocrine carcinoma of the extrahepatic bile duct","volume":"2022","author":"Sugita","year":"2022","journal-title":"J Surg Case Rep"},{"key":"B18","doi-asserted-by":"publisher","first-page":"e39147","DOI":"10.1097\/MD.0000000000039147","article-title":"Neuroendocrine carcinoma of the gallbladder: A case report and literature review","volume":"103","author":"Yao","year":"2024","journal-title":"Med (Baltimore)"},{"key":"B19","doi-asserted-by":"publisher","first-page":"105940","DOI":"10.1016\/j.ijscr.2021.105940","article-title":"Biliary tree neuroendocrine tumor, an incidental finding","volume":"82","author":"Altiti","year":"2021","journal-title":"Int J Surg Case Rep"},{"key":"B20","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1186\/s40792-022-01386-w","article-title":"Surgical resection of mixed neuroendocrine-non-neuroendocrine neoplasm in the biliary system: a report of two cases","volume":"8","author":"Tamaki","year":"2022","journal-title":"Surg Case Rep"},{"key":"B21","doi-asserted-by":"publisher","first-page":"e939239","DOI":"10.12659\/AJCR.939239","article-title":"Neuroendocrine carcinoma of the extrahepatic bile ducts: A case report","volume":"24","author":"Jevdokimov","year":"2023","journal-title":"Am J Case Rep"},{"key":"B22","doi-asserted-by":"publisher","first-page":"399","DOI":"10.1186\/s12876-020-01550-2","article-title":"Mixed adenoneuroendocrine carcinoma of the hepatic bile duct: a case report and review of the literature","volume":"20","author":"Liu","year":"2020","journal-title":"BMC Gastroenterol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1007\/s12328-024-01982-3","article-title":"Mixed neuroendocrine-non-neuroendocrine neoplasm of the bile duct with long-term prognosis after neoadjuvant chemotherapy","volume":"17","author":"Nakamura","year":"2024","journal-title":"Clin J Gastroenterol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1093\/gastro\/goaa051","article-title":"Small-cell neuroendocrine carcinoma arising from an extra-hepatic bile duct: a case report","volume":"9","author":"Shim","year":"2021","journal-title":"Gastroenterol Rep (Oxf)"},{"key":"B25","doi-asserted-by":"publisher","first-page":"257","DOI":"10.1186\/s12876-021-01777-7","article-title":"Neuroendocrine carcinoma of the common bile duct associated with congenital bile duct dilatation: a case report","volume":"21","author":"Kiya","year":"2021","journal-title":"BMC Gastroenterol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.4240\/wjgs.v16.i5.1449","article-title":"Neuroendocrine carcinoma of the common hepatic duct coexisting with distal cholangiocarcinoma: A case report and review of literature","volume":"16","author":"Chen","year":"2024","journal-title":"World J Gastrointest Surg"},{"key":"B27","doi-asserted-by":"publisher","first-page":"e21912","DOI":"10.1097\/MD.0000000000021912","article-title":"Gallbladder neuroendocrine carcinoma: A single center experience","volume":"99","author":"Chu","year":"2020","journal-title":"Med (Baltimore)"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1080\/00365521.2016.1261938","article-title":"Clinicopathological characteristics of biliary neuroendocrine neoplasms: a multicenter study","volume":"52","author":"Lee","year":"2017","journal-title":"Scand J Gastroenterol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1007\/s12029-015-9745-9","article-title":"Neuroendocrine carcinoma of gall bladder: A series of 19 cases with review of literature","volume":"46","author":"Kamboj","year":"2015","journal-title":"J Gastrointest Cancer"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.654439","article-title":"Biliary neuroendocrine neoplasms: analysis of prognostic factors and development and validation of a nomogram","volume":"11","author":"Zhou","year":"2021","journal-title":"Front Oncol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1245\/s10434-019-07440-6","article-title":"Primary gallbladder neuroendocrine tumors: insights into a rare histology using a large national database","volume":"26","author":"Ayabe","year":"2019","journal-title":"Ann Surg Oncol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1210\/endrev\/bnz004","article-title":"Advances in the diagnosis and management of well-differentiated neuroendocrine neoplasms","volume":"41","author":"Hofland","year":"2020","journal-title":"Endocr Rev"},{"key":"B33","doi-asserted-by":"publisher","first-page":"590","DOI":"10.1038\/s41574-020-0391-3","article-title":"Neuroendocrine neoplasia of the gastrointestinal tract revisited: towards precision medicine","volume":"16","author":"Rindi","year":"2020","journal-title":"Nat Rev Endocrinol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1097\/MCG.0b013e3181d7a6d4","article-title":"Neuroendocrine tumors of the gallbladder: an evaluation and reassessment of management strategy","volume":"44","author":"Eltawil","year":"2010","journal-title":"J Clin Gastroenterol"},{"key":"B35","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1186\/s12957-024-03436-z","article-title":"Clinical diagnosis and treatment of 37 cases of gallbladder neuroendocrine carcinoma","volume":"22","author":"Liu","year":"2024","journal-title":"World J Surg Oncol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1007\/s12029-018-0070-y","article-title":"Neuroendocrine carcinoma of gallbladder: A step beyond palliative therapy, experience of 25 cases","volume":"50","author":"Kanetkar","year":"2019","journal-title":"J Gastrointest Cancer"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.2147\/CMAR.S227501","article-title":"Clinical analysis of 15 cases of gallbladder neuroendocrine carcinoma and comparison with gallbladder adenocarcinoma using a propensity score matching","volume":"12","author":"Yan","year":"2020","journal-title":"Cancer Manag Res"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2020.03.304","article-title":"Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up","volume":"31","author":"Pavel","year":"2020","journal-title":"Ann Oncol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1097\/PAS.0000000000001536","article-title":"Neuroendocrine carcinomas of the gallbladder: A clinicopathologic and immunohistochemical analysis of 34 resected cases","volume":"44","author":"Lee","year":"2020","journal-title":"Am J Surg Pathol"},{"key":"B40","doi-asserted-by":"publisher","first-page":"253","DOI":"10.1186\/s12893-022-01689-7","article-title":"The clinical and prognostic factors for biliary neuroendocrine neoplasm: a study based on the SEER database","volume":"22","author":"Zheng","year":"2022","journal-title":"BMC Surg"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.3390\/jpm13061009","article-title":"Comparative survival benefits of surgery and adjuvant chemotherapy in neuroendocrine carcinoma of the gallbladder: A population-based study with insight into future personalized therapeutic approach","volume":"13","author":"Khan","year":"2023","journal-title":"J Pers Med"},{"key":"B42","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1186\/s40001-019-0363-z","article-title":"Neuroendocrine carcinoma of gallbladder: a case series and literature review","volume":"24","author":"Liu","year":"2019","journal-title":"Eur J Med Res"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mds276","article-title":"Predictive and prognostic factors for treatment and survival in 305 patients with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the NORDIC NEC study","volume":"24","author":"Sorbye","year":"2013","journal-title":"Ann Oncol"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2025.1635630","article-title":"Clinical characteristics and survival outcomes of extrapulmonary neuroendocrine carcinomas: a retrospective study","volume":"16","author":"Xu","year":"2025","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.3390\/cancers15204951","article-title":"Selection of chemotherapy in advanced poorly differentiated extra-pulmonary neuroendocrine carcinoma","volume":"15","author":"Weaver","year":"2023","journal-title":"Cancers (Basel)"},{"key":"B46","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1159\/000527377","article-title":"Clinical analysis of extrapulmonary neuroendocrine carcinoma: A retrospective and single institution experience","volume":"68","author":"Okumura","year":"2023","journal-title":"Chemotherapy"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1745019\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T05:26:36Z","timestamp":1770787596000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1745019\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,11]]},"references-count":46,"alternative-id":["10.3389\/fonc.2026.1745019"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1745019","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,11]]},"article-number":"1745019"}}