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Intraductal papillary neoplasms of the bile duct: stepwise progression to carcinoma involves common molecular pathways.
Mod Pathol 2014; 27(1):73-86MP

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+Show Affiliations

Institute of Pathology, Technische Universität München, München, Germany.Institute of Pathology, University of Bern, Bern, Switzerland.Molecular Pathology South Bavaria, Trogerstr. 18, München, Germany.Institute of Pathology, Technische Universität München, München, Germany.Department of Visceral Surgery and Medicine, Inselspital, Bern, Switzerland.Institute of Pathology, University Hospital Erlangen, Erlangen, Germany.Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, München, Germany.Institute of Pathology, University of Tübingen, Tübingen, Germany.Department of Internal Medicine, Klinikum rechts der Isar, Technische Universität München, München, Germany.Division of Pathological Anatomy, Hôpital Cochin, Université Paris Descartes, Paris, France.Institute of Liver Studies, King's College Hospital, London, UK.Department of Medical Statistics and Epidemiology, Technische Universität München, München, Germany.Institute of Pathology, Technische Universität München, München, Germany.Institute of Pathology, University of Bern, Bern, Switzerland.Institute of Pathology, Technische Universität München, München, Germany.Institute of Pathology, Technische Universität München, München, Germany.

Pub Type(s)

Comparative Study
Journal Article
Multicenter Study

Language

eng

PubMed ID

23828315

Citation

Schlitter, Anna Melissa, et al. "Intraductal Papillary Neoplasms of the Bile Duct: Stepwise Progression to Carcinoma Involves Common Molecular Pathways." Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc, vol. 27, no. 1, 2014, pp. 73-86.
Schlitter AM, Born D, Bettstetter M, et al. Intraductal papillary neoplasms of the bile duct: stepwise progression to carcinoma involves common molecular pathways. Mod Pathol. 2014;27(1):73-86.
Schlitter, A. M., Born, D., Bettstetter, M., Specht, K., Kim-Fuchs, C., Riener, M. O., ... Esposito, I. (2014). Intraductal papillary neoplasms of the bile duct: stepwise progression to carcinoma involves common molecular pathways. Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc, 27(1), pp. 73-86. doi:10.1038/modpathol.2013.112.
Schlitter AM, et al. Intraductal Papillary Neoplasms of the Bile Duct: Stepwise Progression to Carcinoma Involves Common Molecular Pathways. Mod Pathol. 2014;27(1):73-86. PubMed PMID: 23828315.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Intraductal papillary neoplasms of the bile duct: stepwise progression to carcinoma involves common molecular pathways. AU - Schlitter,Anna Melissa, AU - Born,Diana, AU - Bettstetter,Marcus, AU - Specht,Katja, AU - Kim-Fuchs,Corina, AU - Riener,Marc-Oliver, AU - Jeliazkova,Petia, AU - Sipos,Bence, AU - Siveke,Jens T, AU - Terris,Benoit, AU - Zen,Yoh, AU - Schuster,Tibor, AU - Höfler,Heinz, AU - Perren,Aurel, AU - Klöppel,Günter, AU - Esposito,Irene, Y1 - 2013/07/05/ PY - 2013/02/14/received PY - 2013/05/06/revised PY - 2013/05/11/accepted PY - 2013/7/6/entrez PY - 2013/7/6/pubmed PY - 2014/9/30/medline SP - 73 EP - 86 JF - Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc JO - Mod. Pathol. VL - 27 IS - 1 N2 - 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. SN - 1530-0285 UR - https://www.unboundmedicine.com/medline/citation/23828315/Intraductal_papillary_neoplasms_of_the_bile_duct:_stepwise_progression_to_carcinoma_involves_common_molecular_pathways_ L2 - http://dx.doi.org/10.1038/modpathol.2013.112 DB - PRIME DP - Unbound Medicine ER -