title: Intraductal papillary neoplasms of the bile duct: stepwise progression to carcinoma involves common molecular pathways.
abstract: Intraductal papillary neoplasms of the bile duct are still poorly characterized regarding (1) their molecular alterations during the development to invasive carcinomas, (2) their subtype stratification and (3) their biological behavior. We performed a multicenter study that analyzed these issues in a large European cohort. Intraductal papillary neoplasms of the bile duct from 45 patients were graded and subtyped using mucin markers and CDX2. In addition, tumors were analyzed for common oncogenic pathways, and the findings were correlated with subtype and grade. Data were compared with those from 22 extra- and intrahepatic cholangiocarcinomas. Intraductal papillary neoplasms showed a development from preinvasive low- to high-grade intraepithelial neoplasia to invasive carcinoma. Molecular and immunohistochemical analysis revealed mutated KRAS, overexpression of TP53 and loss of p16 in low-grade intraepithelial neoplasia, whereas loss of SMAD4 was found in late phases of tumor development. Alterations of HER2, EGFR, β-catenin and GNAS were rare events. Among the subtypes, pancreato-biliary (36%) and intestinal (29%) were the most common, followed by gastric (18%) and oncocytic (13%) subtypes. Patients with intraductal papillary neoplasm of the bile duct showed a slightly better overall survival than patients with cholangiocarcinoma (hazard ratio (cholangiocarcinoma versus intraductal papillary neoplasm of the bile duct): 1.40; 95% confidence interval: 0.46-4.30; P=0.552). The development of biliary intraductal papillary neoplasms of the bile duct follows an adenoma-carcinoma sequence that correlates with the stepwise activation of common oncogenic pathways. Further large trials are needed to investigate and verify the finding of a better prognosis of intraductal papillary neoplasms compared with conventional cholangiocarcinoma.
authors.affiliation: Institute of Pathology, Technische Universität München, München, Germany.
authors.forename: Anna Melissa
authors.initials: AM
authors.lastname: Schlitter
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Diana
authors.initials: D
authors.lastname: Born
authors.affiliation: Molecular Pathology South Bavaria, Trogerstr. 18, München, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Bettstetter
authors.affiliation: Institute of Pathology, Technische Universität München, München, Germany.
authors.forename: Katja
authors.initials: K
authors.lastname: Specht
authors.affiliation: Department of Visceral Surgery and Medicine, Inselspital, Bern, Switzerland.
authors.forename: Corina
authors.initials: C
authors.lastname: Kim-Fuchs
authors.affiliation: Institute of Pathology, University Hospital Erlangen, Erlangen, Germany.
authors.forename: Marc-Oliver
authors.initials: MO
authors.lastname: Riener
authors.affiliation: Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Petia
authors.initials: P
authors.lastname: Jeliazkova
authors.affiliation: Institute of Pathology, University of Tübingen, Tübingen, Germany.
authors.forename: Bence
authors.initials: B
authors.lastname: Sipos
authors.affiliation: Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, München, Germany.
authors.forename: Jens T
authors.initials: JT
authors.lastname: Siveke
authors.affiliation: Division of Pathological Anatomy, Hôpital Cochin, Université Paris Descartes, Paris, France.
authors.forename: Benoit
authors.initials: B
authors.lastname: Terris
authors.affiliation: Institute of Liver Studies, King's College Hospital, London, UK.
authors.forename: Yoh
authors.initials: Y
authors.lastname: Zen
authors.affiliation: Department of Medical Statistics and Epidemiology, Technische Universität München, München, Germany.
authors.forename: Tibor
authors.initials: T
authors.lastname: Schuster
authors.affiliation: Institute of Pathology, Technische Universität München, München, Germany.
authors.forename: Heinz
authors.initials: H
authors.lastname: Höfler
authors.affiliation: Institute of Pathology, University of Bern, Bern, Switzerland.
authors.forename: Aurel
authors.initials: A
authors.lastname: Perren
authors.affiliation: Institute of Pathology, Technische Universität München, München, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Klöppel
authors.affiliation: Institute of Pathology, Technische Universität München, München, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Esposito
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001650:Bile Duct Neoplasms / Q000737:chemistry* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000737:chemistry / Q000473:pathology; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D001706:Biopsy; D002278:Carcinoma in Situ / Q000737:chemistry* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000737:chemistry* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D018281:Cholangiocarcinoma / Q000737:chemistry / Q000235:genetics / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000032:analysis; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005060:Europe; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D010212:Papilloma / Q000737:chemistry* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D016016:Proportional Hazards Models; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction; D013997:Time Factors; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D018631:ras Proteins / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins