{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T10:45:15Z","timestamp":1778582715953,"version":"3.51.4"},"reference-count":44,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2021,3,23]],"date-time":"2021-03-23T00:00:00Z","timestamp":1616457600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Biliary tract cancer (BTC) is characterized by an intense stromal reaction and a complex landscape of infiltrating immune cells. Evidence is emerging that tumor-infiltrating neutrophils (TINs) have an impact on carcinogenesis and tumor progression. TINs have also been associated with outcomes in various solid malignant tumors but their possible clinical role in BTC is largely unknown. Tissue samples from patients with sporadic BTC (\u201cspBTC\u201d cohort, N = 53) and BTC in association with primary sclerosing cholangitis (\u201cPSC-BTC\u201d cohort, N = 7) were collected. Furthermore, tissue samples from 27 patients with PSC who underwent liver transplantation (\u201cPSC-LTX\u201d cohort) were investigated. All specimens were assessed for TIN density in invasive and precancerous lesions (biliary intraepithelial neoplasia, BilIN). Most spBTC showed low TIN density (LD, 61%). High TIN density (HD) was detected in 16% of the tumors, whereas 23% were classified as intermediate density (ID); the majority of both HD and ID groups were in T1\u2013T2 tumors (83% and 100%, p = 0.012). TIN density in BilIN lesions did not significantly differ among the three groups. The HD group had a mean overall survival (OS) of 53.5 months, whereas the mean OS in the LD and ID groups was significantly shorter (LD 29.5 months vs. ID 24.6 months, log-rank p &lt; 0.05). The results of this study underline the possible prognostic relevance of TINs in BTC and stress the complexity of the immune cell landscape in BTC. The prognostic relevance of TINs suggests a key regulator role in inflammation and immune landscape in BTC.<\/jats:p>","DOI":"10.3390\/jpm11030233","type":"journal-article","created":{"date-parts":[[2021,3,23]],"date-time":"2021-03-23T14:08:16Z","timestamp":1616508496000},"page":"233","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Tumor Infiltrating Neutrophils Are Frequently Found in Adenocarcinomas of the Biliary Tract and Their Precursor Lesions with Possible Impact on Prognosis"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6182-835X","authenticated-orcid":false,"given":"Vittorio","family":"Branchi","sequence":"first","affiliation":[{"name":"Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3642-3534","authenticated-orcid":false,"given":"Benedict","family":"J\u00fcrgensen","sequence":"additional","affiliation":[{"name":"Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura","family":"Esser","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Gonzalez-Carmona","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9736-1483","authenticated-orcid":false,"given":"Tobias J.","family":"Weism\u00fcller","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christian P.","family":"Strassburg","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonas","family":"Henn","sequence":"additional","affiliation":[{"name":"Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5424-3217","authenticated-orcid":false,"given":"Alexander","family":"Semaan","sequence":"additional","affiliation":[{"name":"Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Philipp","family":"Lingohr","sequence":"additional","affiliation":[{"name":"Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6159-4506","authenticated-orcid":false,"given":"Steffen","family":"Manekeller","sequence":"additional","affiliation":[{"name":"Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Glen","family":"Kristiansen","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u00f6rg C.","family":"Kalff","sequence":"additional","affiliation":[{"name":"Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marieta I.","family":"Toma","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanno","family":"Matthaei","sequence":"additional","affiliation":[{"name":"Department of General, Visceral, Thoracic and Vascular Surgery, University Hospital Bonn, 53127 Bonn, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1001\/jamaoncol.2015.0735","article-title":"The global burden of cancer 2013","volume":"1","author":"Fitzmaurice","year":"2015","journal-title":"JAMA Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21590","article-title":"Cancer statistics, 2020","volume":"70","author":"Siegel","year":"2020","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Saha, S.K., Zhu, A.X., Fuchs, C.S., and Brook, S.G.A. (2016). Forty-year trends in cholangiocarcinoma incidence in the U.S.: Intrahepatic disease on the rise. Oncologist, 21.","DOI":"10.1634\/theoncologist.2015-0446"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"v28","DOI":"10.1093\/annonc\/mdw324","article-title":"ESMO guidelines committee biliary cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up","volume":"27","author":"Valle","year":"2016","journal-title":"Ann. Oncol. Off. J. Eur. Soc. Med. Oncol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1268","DOI":"10.1016\/j.jhep.2014.01.021","article-title":"Guidelines for the diagnosis and management of intrahepatic cholangiocarcinoma","volume":"60","author":"Bridgewater","year":"2014","journal-title":"J. Hepatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1097\/SLA.0b013e318176c4d3","article-title":"Intrahepatic cholangiocarcinoma: Rising frequency, improved survival, and determinants of outcome after resection","volume":"248","author":"Endo","year":"2008","journal-title":"Ann. Surg."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2045","DOI":"10.1002\/hep.26565","article-title":"Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis","volume":"58","author":"Boonstra","year":"2013","journal-title":"Hepatology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1913","DOI":"10.1111\/j.1349-7006.2010.01614.x","article-title":"Significance of alternatively activated macrophages in patients with intrahepatic cholangiocarcinoma","volume":"101","author":"Hasita","year":"2010","journal-title":"Cancer Sci."},{"key":"ref_9","first-page":"130","article-title":"Unveiling the role of tumor reactive stroma in cholangiocarcinoma: An opportunity for new therapeutic strategies","volume":"2","author":"Cadamuro","year":"2013","journal-title":"Transl. Gastrointest. Cancer"},{"key":"ref_10","first-page":"1581","article-title":"Neutrophil\/lymphocyte ratio as a prognostic factor in biliary tract cancer","volume":"50","author":"McNamara","year":"2014","journal-title":"Eur. J. Cancer Oxf. Engl. 1990"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5283","DOI":"10.1007\/s13277-015-3188-6","article-title":"The elevated preoperative neutrophil-to-lymphocyte ratio predicts poor prognosis in intrahepatic cholangiocarcinoma patients undergoing hepatectomy","volume":"36","author":"Chen","year":"2015","journal-title":"Tumour Biol. J. Int. Soc. Oncodev. Biol. Med."},{"key":"ref_12","first-page":"810","article-title":"Prognostic significance of preoperative neutrophil\/lymphocyte ratio and platelet\/lymphocyte ratio in patients with gallbladder carcinoma","volume":"17","author":"Zhang","year":"2015","journal-title":"Clin. Transl. Oncol. Off. Publ. Fed. Span. Oncol. Soc. Natl. Cancer Inst. Mex."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"50963","DOI":"10.18632\/oncotarget.7680","article-title":"Elevated neutrophil-to-lymphocyte ratio is an independent poor prognostic factor in patients with intrahepatic cholangiocarcinoma","volume":"7","author":"Lin","year":"2016","journal-title":"Oncotarget"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1630","DOI":"10.1097\/PAS.0000000000000957","article-title":"C-Reactive Protein (CRP) is a promising diagnostic immunohistochemical marker for intrahepatic cholangiocarcinoma and is associated with better prognosis","volume":"41","author":"Yeh","year":"2017","journal-title":"Am. J. Surg. Pathol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Rapoport, B.L., Steel, H.C., Theron, A.J., Smit, T., and Anderson, R. (2020). Role of the neutrophil in the pathogenesis of advanced cancer and impaired responsiveness to therapy. Molecules, 25.","DOI":"10.3390\/molecules25071618"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1097\/SLA.0000000000002058","article-title":"Tumor-infiltrating neutrophils is prognostic and predictive for postoperative adjuvant chemotherapy benefit in patients with gastric cancer","volume":"267","author":"Zhang","year":"2018","journal-title":"Ann. Surg."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1007\/s10549-019-05336-3","article-title":"Infiltration by myeloperoxidase-positive neutrophils is an independent prognostic factor in breast cancer","volume":"177","author":"Zeindler","year":"2019","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Brierley, J.D., Gospodarowicz, M.K., and Wittekind, C. (2017). TNM Classification of Malignant Tumours, John Wiley & Sons. [8th ed.].","DOI":"10.1002\/9780471420194.tnmc26.pub3"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"701","DOI":"10.1038\/modpathol.3800788","article-title":"Biliary intraepithelial neoplasia: An international interobserver agreement study and proposal for diagnostic criteria","volume":"20","author":"Zen","year":"2007","journal-title":"Mod. Pathol."},{"key":"ref_20","unstructured":"Basturk, O., Aishima, S., and Esposito, I. (2019). Biliary intraepithelial neoplasia. WHO Classification of Tumours: Digestive System Tumours, WHO Classification of Tumours Editorial Board, International Agency for Research on Cancer."},{"key":"ref_21","unstructured":"R Core Team (2020). R: A Language and Environment for Statistical Computing, R Core Team."},{"key":"ref_22","unstructured":"Kassambara, A., Kosinski, M., and Biecek, P. (Survminer: Drawing Survival Curves Using \u201cGgplot2\u201d, 2020). Survminer: Drawing Survival Curves Using \u201cGgplot2\u201d."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.3389\/fonc.2019.01146","article-title":"Tumor associated neutrophils. Their role in tumorigenesis, metastasis, prognosis and therapy","volume":"9","author":"Masucci","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.it.2015.11.008","article-title":"Neutrophils in the tumor microenvironment","volume":"37","author":"Powell","year":"2016","journal-title":"Trends Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.ccr.2009.06.017","article-title":"Polarization of tumor-associated neutrophil phenotype by TGF-\u03b2: \u201cN1\u201d versus \u201cN2\u201d TAN","volume":"16","author":"Fridlender","year":"2009","journal-title":"Cancer Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1038\/nri2808","article-title":"The polarization of immune cells in the tumour environment by TGF\u03b2","volume":"10","author":"Flavell","year":"2010","journal-title":"Nat. Rev. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.trecan.2016.12.006","article-title":"Mouse versus human neutrophils in cancer: A major knowledge gap","volume":"3","author":"Eruslanov","year":"2017","journal-title":"Trends Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"293","DOI":"10.3389\/fmed.2019.00293","article-title":"Inflammation and progression of cholangiocarcinoma: Role of angiogenic and lymphangiogenic mechanisms","volume":"6","author":"Roy","year":"2019","journal-title":"Front. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"69","DOI":"10.3322\/canjclin.56.2.69","article-title":"Chronic inflammation: A common and important factor in the pathogenesis of Neoplasia","volume":"56","author":"Schottenfeld","year":"2006","journal-title":"CA Cancer J. Clin."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1007\/s00432-019-03108-6","article-title":"High density of CD66B in primary high-grade ovarian cancer independently predicts response to chemotherapy","volume":"146","author":"Posabella","year":"2020","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1016\/j.tranon.2019.11.002","article-title":"Prognostic and predictive value of tumor-infiltrating leukocytes and of immune checkpoint molecules PD1 and PDL1 in clear cell renal cell carcinoma","volume":"13","author":"Stenzel","year":"2020","journal-title":"Transl. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/j.jhep.2010.07.044","article-title":"Intratumoral neutrophils: A Poor prognostic factor for hepatocellular carcinoma following resection","volume":"54","author":"Li","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1016\/j.jhep.2010.08.041","article-title":"Peritumoral neutrophils link inflammatory response to disease progression by fostering angiogenesis in hepatocellular carcinoma","volume":"54","author":"Kuang","year":"2011","journal-title":"J. Hepatol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2242","DOI":"10.1002\/hep.25907","article-title":"Overexpression of CXCL5 mediates neutrophil infiltration and indicates poor prognosis for hepatocellular carcinoma","volume":"56","author":"Zhou","year":"2012","journal-title":"Hepatology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1038\/bjc.2013.32","article-title":"Immune cell infiltration as an indicator of the immune microenvironment of pancreatic cancer","volume":"108","author":"Ino","year":"2013","journal-title":"Br. J. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2506","DOI":"10.1245\/s10434-012-2268-8","article-title":"Intratumoral IL-17+ cells and neutrophils show strong prognostic significance in intrahepatic cholangiocarcinoma","volume":"19","author":"Gu","year":"2012","journal-title":"Ann. Surg. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"4961","DOI":"10.3748\/wjg.v21.i16.4961","article-title":"Prognostic value of neutrophil distribution in cholangiocarcinoma","volume":"21","author":"Mao","year":"2015","journal-title":"World J. Gastroenterol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"5466","DOI":"10.1172\/JCI77053","article-title":"Tumor-associated neutrophils stimulate t cell responses in early-stage human lung cancer","volume":"124","author":"Eruslanov","year":"2014","journal-title":"J. Clin. Invest."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/j.immuni.2014.03.013","article-title":"\u0393\u03b4T17 cells promote the accumulation and expansion of myeloid-derived suppressor cells in human colorectal cancer","volume":"40","author":"Wu","year":"2014","journal-title":"Immunity"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1016\/j.ccell.2016.06.001","article-title":"Origin and role of a subset of tumor-associated neutrophils with antigen-presenting cell features in early-stage human lung cancer","volume":"30","author":"Singhal","year":"2016","journal-title":"Cancer Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1016\/j.ejso.2015.05.013","article-title":"Intrahepatic, peri-hilar and distal cholangiocarcinoma: Three different locations of the same tumor or three different tumors?","volume":"41","author":"Ercolani","year":"2015","journal-title":"Eur. J. Surg. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Cardinale, V., Renzi, A., Carpino, G., Torrice, A., Bragazzi, M.C., Giuliante, F., DeRose, A.M., Fraveto, A., Onori, P., and Napoletano, C. (2015). Tumorigenesis and neoplastic progression profiles of cancer stem cell subpopulations in cholangiocarcinomas. Am. J. Pathol., 185.","DOI":"10.1016\/j.ajpath.2015.02.010"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2470","DOI":"10.3748\/wjg.v23.i14.2470","article-title":"Biliary tract cancer stem cells-Translational options and challenges","volume":"23","author":"Mayr","year":"2017","journal-title":"World J. Gastroenterol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1021","DOI":"10.1053\/j.gastro.2011.12.005","article-title":"Genomic and Genetic characterization of cholangiocarcinoma identifies therapeutic targets for tyrosine kinase inhibitors","volume":"142","author":"Andersen","year":"2012","journal-title":"Gastroenterology"}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/11\/3\/233\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:39:37Z","timestamp":1760161177000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/11\/3\/233"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,23]]},"references-count":44,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2021,3]]}},"alternative-id":["jpm11030233"],"URL":"https:\/\/doi.org\/10.3390\/jpm11030233","relation":{},"ISSN":["2075-4426"],"issn-type":[{"value":"2075-4426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,23]]}}}