title: Clinicopathological study on cholangiolocellular carcinoma suggesting hepatic progenitor cell origin.
abstract: Cholangiolocellular carcinoma (CLC), a subtype of cholangiocellular carcinoma (CC), is thought to originate from the ductules/canals of Hering, where hepatic progenitor cells (HPCs) are located. We investigated the clinicopathological features of 30 CLCs and their relationship to HPCs. We evaluated the expression of hepatocytic markers (hepatocyte paraffin-1, canalicular polyclonal carcinoembryonic antigen, and CD10), biliary/HPC markers (keratin [K]7, K19, and neural cell adhesion molecule), the adenosine triphosphate binding cassette transporters: multidrug resistance protein 1, multidrug resistance-associated protein (MRP)1, MRP3, and breast cancer resistance protein, using immunohistochemistry and electron microscopy. In addition, gene expression profiling of CLC was performed and compared with the profile of hepatocellular carcinoma (HCC) with or without HPC features (K19 expression). In surrounding nontumoral tissue, K7-positive and K19-positive HPCs/ductular reaction were observed. More than 90% of the tumor was composed of CLC areas that showed small monotonous and/or anastomosing glands, strongly positive for K7 and K19. Especially at the tumor boundary, all cases showed a HCC-like trabecular area characterized by canalicular CD10/polyclonal carcinoembryonic antigen expression, and submembranous K7 expression, similar to intermediate hepatocytes. K7-positive/K19-positive HPCs were also seen. Out of 30 cases, 19 showed papillary and/or clear glandular formation with mucin production, representing CC areas. These three different areas showed transitional zones with each other. We observed an increased expression of MRP1, MRP3, and breast cancer resistance protein in the tumor. Electron microscopy findings in HCC-like trabecular areas confirmed the presence of HPCs and intermediate hepatocytes. HPC markers, K7, K19, prominin-1, receptor for stem cell factor c-kit, octamer-4 transcription factor, and leukemia inhibitory factor were upregulated (P < 0.05), while albumin was downregulated in CLC (P = 0.007) toward K19-negative HCCs. Comparison of CLC with K19-positive HCCs indicated a high homology.
  
  
  CONCLUSIONS
  All these findings highly suggest a progenitor cell origin of CLC.
authors.affiliation: Department 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: Bart
authors.initials: B
authors.lastname: Spee
authors.forename: Sara
authors.initials: S
authors.lastname: Vander Borght
authors.forename: Rita
authors.initials: R
authors.lastname: De Vos
authors.forename: Chris
authors.initials: C
authors.lastname: Verslype
authors.forename: Raymond
authors.initials: R
authors.lastname: Aerts
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Yano
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Suzuki
authors.forename: Masanori
authors.initials: M
authors.lastname: Matsuda
authors.forename: Hideki
authors.initials: H
authors.lastname: Fujii
authors.forename: Valeer J
authors.initials: VJ
authors.lastname: Desmet
authors.forename: Masamichi
authors.initials: M
authors.lastname: Kojiro
authors.forename: Tania
authors.initials: T
authors.lastname: Roskams
mesh_terms: D000368:Aged; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000473:pathology* / Q000648:ultrastructure; D001653:Bile Ducts, Intrahepatic / Q000473:pathology* / Q000648:ultrastructure; D018281:Cholangiocarcinoma / Q000235:genetics / Q000473:pathology* / Q000648:ultrastructure; D003346:Corticotropin-Releasing Hormone; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver / Q000473:pathology*; D008112:Liver Glycogen / Q000378:metabolism; D008297:Male; D008854:Microscopy, Electron; D011498:Protein Precursors; D012334:RNA, Neoplasm / Q000235:genetics / Q000302:isolation & purification; D012189:Retrospective Studies; D013234:Stem Cells / Q000473:pathology
chemical_list: D008112:Liver Glycogen; D011498:Protein Precursors; D012334:RNA, Neoplasm; C041645:pro-corticotropin releasing hormone; D003346:Corticotropin-Releasing Hormone