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

• Published in: Modern pathology 2014-01, Vol.27 (1), p.73-86
• Main Authors: Schlitter, Anna Melissa, Born, Diana, Bettstetter, Marcus, Specht, Katja, Kim-Fuchs, Corina, Riener, Marc-Oliver, Jeliazkova, Petia, Sipos, Bence, Siveke, Jens T, Terris, Benoit, Zen, Yoh, Schuster, Tibor, Höfler, Heinz, Perren, Aurel, Klöppel, Günter, Esposito, Irene
• Format: Article
• Language: English
• Subjects: 692/420/755; 692/699/67/1504/1329/1326; 692/700/1750; Adult; Aged; Aged, 80 and over; Bile Duct Neoplasms - chemistry; Bile Duct Neoplasms - genetics; Bile Duct Neoplasms - mortality; Bile Duct Neoplasms - pathology; bile duct tumors; Bile ducts; Bile Ducts, Intrahepatic - chemistry; Bile Ducts, Intrahepatic - pathology; Biomarkers, Tumor - analysis; Biomarkers, Tumor - genetics; Biopsy; Cancer; Carcinoma in Situ - chemistry; Carcinoma in Situ - genetics; Carcinoma in Situ - mortality; Carcinoma in Situ - pathology; Carcinoma, Intraductal, Noninfiltrating - chemistry; Carcinoma, Intraductal, Noninfiltrating - genetics; Carcinoma, Intraductal, Noninfiltrating - mortality; Carcinoma, Intraductal, Noninfiltrating - pathology; Cholangiocarcinoma; Cholangiocarcinoma - chemistry; Cholangiocarcinoma - genetics; Cholangiocarcinoma - pathology; Confidence intervals; Cyclin-Dependent Kinase Inhibitor p16 - analysis; Disease Progression; DNA Mutational Analysis; Europe; Female; GNAS; Hospitals; Humans; Immunohistochemistry; intraductal precursor lesion; Kaplan-Meier Estimate; KRAS; Laboratory Medicine; Male; Medical prognosis; Medicine; Medicine & Public Health; Middle Aged; Mutation; Neoplasm Grading; Neoplasm Invasiveness; original-article; Papilloma - chemistry; Papilloma - genetics; Papilloma - mortality; Papilloma - pathology; Pathology; Prognosis; Proportional Hazards Models; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins p21(ras); ras Proteins - genetics; Signal Transduction; Survival analysis; Time Factors; Tumor Suppressor Protein p53 - analysis; Tumors
• ISSN: 0893-3952; 1530-0285
• DOI: 10.1038/modpathol.2013.112

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.