title: Intraductal tubulopapillary neoplasms of the bile ducts: clinicopathologic, immunohistochemical, and molecular analysis of 20 cases.
abstract: Intraductal tubulopapillary neoplasm is a well-established entity in the pancreas. A similar, if not identical, tumor occurs also in the biliary tract. We conducted a multicenter study of 20 such lesions, focusing on their clinicopathologic characteristics and molecular profile. Biliary intraductal tubulopapillary neoplasms were seen in patients in their 60s (mean 62 years). The tumors were intrahepatic 70%, extrahepatic 10%, and perihilar 20%; mean tumor size was 6.9 cm. Histologically, all intraductal tubulopapillary neoplasms showed, in addition to their typical tubular pattern, solid areas (70%) or abortive papillae (50%). Necrosis was common (85%), predominantly focal (40%), and with 'comedocarcinoma-like pattern' in 40%. Immunohistochemically, these neoplasms were characterized by the expression of MUC1 (80%) and MUC6 (30%) and by the absence of MUC2 and MUC5AC. Associated invasive carcinomas were present in 16 (80%), mainly conventional tubular adenocarcinoma (50%). The molecular alterations observed included CDKN2A/p16 (intraductal components 44%, invasive 33%) and TP53 (intraductal components 17%, invasive 9%). Mutations in KRAS (intraductal 6%, invasive 0%), PIK3CA (intraductal 6%, invasive 0%), and loss of SMAD4/DPC4 (intraductal 7%, invasive 0%) were rare. No alterations/mutations were identified in IDH1/2, BRAF, GNAS, EGFR, HER2, and β-catenin. Follow-up information was available for 17 patients (85%) with mean follow-up 44 months. Overall combined survival rates showed favorable prognosis: 1 year 100%, 3 years 90%, and 5 years 90%. In conclusion, despite the relatively high incidence of invasive carcinoma (80%), available follow-up suggests that biliary intraductal tubulopapillary neoplasms have an indolent behavior. Molecular analyses highlight the low prevalence of alterations of common oncogenic signaling pathways in intraductal tubulopapillary neoplasm. Further studies using whole-exome sequencing are required to discover yet unknown molecular changes and to understand the carcinogenesis of intraductal tubulopapillary neoplasms.
authors.affiliation: Institute of Pathology, Technische Universität München, München, Germany.
authors.forename: Anna Melissa
authors.initials: AM
authors.lastname: Schlitter
authors.affiliation: Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Kee-Taek
authors.initials: KT
authors.lastname: Jang
authors.affiliation: Institute of Pathology, Technische Universität München, München, Germany.
authors.forename: Günter
authors.initials: G
authors.lastname: Klöppel
authors.affiliation: Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Burcu
authors.initials: B
authors.lastname: Saka
authors.affiliation: Department of Pathology, Ulsan University Hospital, University of Ulsan, College of Medicine, Seoul, Korea.
authors.forename: Seung-Mo
authors.identifier: http://orcid.org/0000-0002-8888-6007
authors.initials: SM
authors.lastname: Hong
authors.affiliation: Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Hyejeong
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Pathology, University Medical Center, Utrecht, The Netherlands.
authors.forename: George Johan
authors.initials: GJ
authors.lastname: Offerhaus
authors.affiliation: Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.affiliation: Department of Diagnostic Pathology, Kobe University, Kobe, Japan.
authors.forename: Yoh
authors.initials: Y
authors.lastname: Zen
authors.affiliation: Institute of Pathology, Technische Universität München, München, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: Konukiewitz
authors.affiliation: Department of Surgery, Technische Universität München, München, Germany.
authors.forename: Ivonne
authors.initials: I
authors.lastname: Regel
authors.affiliation: Institute of Pathology, Technische Universität München, München, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Allgäuer
authors.affiliation: Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Serdar
authors.identifier: http://orcid.org/0000-0002-7852-3851
authors.initials: S
authors.lastname: Balci
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Olca
authors.initials: O
authors.lastname: Basturk
authors.affiliation: Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Reid
authors.affiliation: Institute of Pathology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Irene
authors.initials: I
authors.lastname: Esposito
authors.affiliation: Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA.
authors.forename: Volkan
authors.initials: V
authors.lastname: Adsay
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D000328:Adult; D000368:Aged; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D014408:Biomarkers, Tumor / Q000032:analysis*; D002291:Carcinoma, Papillary / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor