title: Histological diversity in cholangiocellular carcinoma reflects the different cholangiocyte phenotypes.
abstract: Cholangiocellular carcinoma (CC) originates from topographically heterogeneous cholangiocytes. The cylindrical mucin-producing cholangiocytes are located in large bile ducts and the cuboidal non-mucin-producing cholangiocytes are located in ductules containing bipotential hepatic progenitor cells (HPCs). We investigated the clinicopathological and molecular features of 85 resected CCs (14 hilar CCs [so-called Klatskin tumor], 71 intrahepatic CCs [ICCs] including 20 cholangiolocellular carcinomas [CLCs], which are thought to originate from HPCs]) and compared these with the different cholangiocyte phenotypes, including HPCs. Immunohistochemistry was performed with biliary/HPC and hepatocytic markers. Gene expression profiling was performed in different tumors and compared with nonneoplastic different cholangiocyte phenotypes obtained by laser microdissection. Invasion and cell proliferation assay were assessed using different types of CC cell lines: KMC-1, KMCH-1, and KMCH-2. Among 51 ICCs, 31 (60.8%) contained only mucin-producing CC features (muc-ICCs), whereas 39.2% displayed histological diversity: focal hepatocytic differentiation and ductular areas (mixed-ICCs). Clinicopathologically, muc-ICCs and hilar CCs showed a predominantly (peri-)hilar location, smaller tumor size, and more lymphatic and perineural invasion compared with mixed-ICCs and CLCs (predominantly peripheral location, larger tumor size, and less lymphatic and perineural invasion). Immunoreactivity was similar in muc-ICCs and hilar CCs and in mixed-ICCs and CLCs. S100P and MUC1 were significantly up-regulated in hilar CCs and muc-ICCs compared with mixed-ICCs and CLCs, whereas NCAM1 and ALB tended to be up-regulated in mixed-ICCs and CLCs compared with other tumors. KMC-1 showed significantly higher invasiveness than KMCH-1 and KMCH-2.
  
  
  CONCLUSIONS
  Muc-ICCs had a clinicopathological, immunohistochemical, and molecular profile similar to that of hilar CCs (from mucin-producing cholangiocytes), whereas mixed-ICCs had a profile similar to that of CLCs (thought to be of HPC origin), possibly reflecting their respective cells of origin.
authors.affiliation: Departments of Morphology and Molecular Pathology, University Hospitals Leuven, Leuven, Belgium. mina.komuta@gmail.com
authors.forename: Mina
authors.initials: M
authors.lastname: Komuta
authors.forename: Olivier
authors.initials: O
authors.lastname: Govaere
authors.forename: Vincent
authors.initials: V
authors.lastname: Vandecaveye
authors.forename: Jun
authors.initials: J
authors.lastname: Akiba
authors.forename: Werner
authors.initials: W
authors.lastname: Van Steenbergen
authors.forename: Chris
authors.initials: C
authors.lastname: Verslype
authors.forename: Wim
authors.initials: W
authors.lastname: Laleman
authors.forename: Jacques
authors.initials: J
authors.lastname: Pirenne
authors.forename: Raymond
authors.initials: R
authors.lastname: Aerts
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Yano
authors.forename: Frederik
authors.initials: F
authors.lastname: Nevens
authors.forename: Baki
authors.initials: B
authors.lastname: Topal
authors.forename: Tania
authors.initials: T
authors.lastname: Roskams
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001650:Bile Duct Neoplasms / Q000473:pathology*; D001653:Bile Ducts, Intrahepatic; D002135:Calcium-Binding Proteins / Q000032:analysis; D018281:Cholangiocarcinoma / Q000473:pathology*; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000032:analysis
chemical_list: D002135:Calcium-Binding Proteins; D009363:Neoplasm Proteins; C103003:S100P protein, human