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: 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
• Journal: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc (Mod Pathol) Vol. 27 Issue 1 Pg. 73-86 (Jan 2014) ISSN: 1530-0285 [Electronic] United States
• PMID: 23828315 (Publication Type: Comparative Study, Journal Article, Multicenter Study)

Chemical References

• Biomarkers, Tumor
• Cyclin-Dependent Kinase Inhibitor p16
• KRAS protein, human
• Proto-Oncogene Proteins
• TP53 protein, human
• Tumor Suppressor Protein p53
• Proto-Oncogene Proteins p21(ras)
• ras Proteins

Topics

• Adult
• Aged
• Aged, 80 and over
• Bile Duct Neoplasms (chemistry, genetics, mortality, pathology)
• Bile Ducts, Intrahepatic (chemistry, pathology)
• Biomarkers, Tumor (analysis, genetics)
• Biopsy
• Carcinoma in Situ (chemistry, genetics, mortality, pathology)
• Carcinoma, Intraductal, Noninfiltrating (chemistry, genetics, mortality, pathology)
• Cholangiocarcinoma (chemistry, genetics, pathology)
• Cyclin-Dependent Kinase Inhibitor p16 (analysis)
• DNA Mutational Analysis
• Disease Progression
• Europe
• Female
• Humans
• Immunohistochemistry
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Mutation
• Neoplasm Grading
• Neoplasm Invasiveness
• Papilloma (chemistry, genetics, mortality, pathology)
• Prognosis
• Proportional Hazards Models
• Proto-Oncogene Proteins (genetics)
• Proto-Oncogene Proteins p21(ras)
• Signal Transduction
• Time Factors
• Tumor Suppressor Protein p53 (analysis)
• ras Proteins (genetics)