title: Prognostic impact of tumour-infiltrating immune cells on biliary tract cancer.
abstract: BACKGROUND
  Biliary tract cancers (BTC) are relatively rare malignant tumours with poor prognosis. It is known from other solid neoplasms that antitumour inflammatory response has an impact on tumour behaviour and patient outcome. The aim of this study was to provide a comprehensive characterisation of antitumour inflammatory response in human BTC.
  
  
  METHODS
  Tumour-infiltrating T lymphocytes (CD4+, CD8+, and Foxp3+), natural killer cells (perforin+), B lymphocytes (CD20+), macrophages (CD68+) as well as mast cells (CD117+) were assessed by immunohistochemistry in 375 BTC including extrahepatic (ECC; n=157), intrahepatic (ICC; n=149), and gallbladder (GBAC; n=69) adenocarcinomas. Overall and intraepithelial quantity of tumour-infiltrating immune cells was analysed. Data were correlated with clinicopathological variables and patient survival.
  
  
  RESULTS
  The most prevalent inflammatory cell type in BTC was the T lymphocyte. Components of the adaptive immune response decreased, whereas innate immune response components increased significantly in the biliary intraepithelial neoplasia - primary carcinoma - metastasis sequence. BTC patients with intraepithelial tumour-infiltrating CD4+, CD8+, and Foxp3+ T lymphocytes showed a significantly longer overall survival. Number of total intraepithelial tumour-infiltrating Foxp3+ regulatory T lymphocytes (HR: 0.492, P=0.002) and CD4+ T lymphocytes (HR: 0.595, P=0.008) were tumour grade- and UICC-stage-independent prognosticators. The subtype-specific evaluation revealed that the tumour-infiltrating lymphocytic infiltrate is a positive outcome predictor in ECC and GBAC but not in ICC.
  
  
  CONCLUSIONS
  Our findings characterise the immune response in cholangiocarcinogenesis and identify inflammatory cell types that influence the outcome of BTC patients. Further, we show that BTC subtypes show relevant differences with respect to density, quality of inflammation, and impact on patient survival.
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Goeppert
authors.forename: L
authors.initials: L
authors.lastname: Frauenschuh
authors.forename: M
authors.initials: M
authors.lastname: Zucknick
authors.forename: A
authors.initials: A
authors.lastname: Stenzinger
authors.forename: M
authors.initials: M
authors.lastname: Andrulis
authors.forename: F
authors.initials: F
authors.lastname: Klauschen
authors.forename: K
authors.initials: K
authors.lastname: Joehrens
authors.forename: A
authors.initials: A
authors.lastname: Warth
authors.forename: M
authors.initials: M
authors.lastname: Renner
authors.forename: A
authors.initials: A
authors.lastname: Mehrabi
authors.forename: M
authors.initials: M
authors.lastname: Hafezi
authors.forename: A
authors.initials: A
authors.lastname: Thelen
authors.forename: P
authors.initials: P
authors.lastname: Schirmacher
authors.forename: W
authors.initials: W
authors.lastname: Weichert
mesh_terms: D000230:Adenocarcinoma / Q000175:diagnosis* / Q000276:immunology / Q000401:mortality / Q000601:surgery; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001661:Biliary Tract Neoplasms / Q000175:diagnosis* / Q000276:immunology / Q000401:mortality / Q000601:surgery; D015496:CD4-Positive T-Lymphocytes / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000473:pathology; D005260:Female; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000473:pathology / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016019:Survival Analysis; D046888:Tissue Array Analysis