Intraductal papillary neoplasms of the bile duct: Stepwise progression to carcinoma involves common molecular pathways

Anna Melissa Schlitter, Diana Born, Marcus Bettstetter, Katja Specht, Corina Kim-Fuchs, Marc Oliver Riener, Petia Jeliazkova, Bence Sipos, Jens T. Siveke, Benoit Terris, Yoh Zen, Tibor Schuster, Heinz Höfler, Aurel Perren, Günter Klöppel, Irene Esposito

Research output: Contribution to journalArticlepeer-review

117 Scopus citations

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.

Original languageEnglish
Pages (from-to)73-86
Number of pages14
JournalModern Pathology
Volume27
Issue number1
DOIs
StatePublished - Jan 2014

Keywords

  • GNAS
  • KRAS
  • bile duct tumors
  • intraductal precursor lesion

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