Departments of Pathology Oncology Surgery, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA Department of Surgery, University of Bonn, Bonn, Germany Ludwig Center for Cancer Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA State Key Laboratory of Cancer Biology, Cell Engineering Research Center & Department of Cell Biology, The Fourth Military Medical University, Xi'an, China Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA Department of Pathology, Emory University School of Medicine, Atlanta, GA, USA Department of Oncology, Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Background: Activating point mutations of GNAS at codon 201 have been detected in approximately two thirds of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. Intraductal papillary neoplasms of the bile ducts (IPNBs) morphologically resemble pancreatic IPMNs. This study sought to assess the mutational status of GNAS at codon 201 in IPNBs.
Methods: Thirty-four patients were included. DNA from microdissected IPNBs was subjected to a polymerase chain reaction and ligation method for the detection of GNAS mutations at codon 201 and of KRAS mutations at codon 12. Mutational status was compared with clinical and pathologic data.
Results: The IPNBs had a median diameter of 3.5 cm and were located intrahepatically (n= 6), extrahepatically (n= 13), both intra- and extrahepatically (n= 4) or in the gallbladder (intracystic papillary neoplasms, n= 11). Most exhibited pancreatobiliary differentiation (n= 20), high-grade dysplasia (n= 26) and an associated adenocarcinoma (n= 20). Analysis of GNAS codon 201 identified only one mutant sample in a multifocal intestinal subtype intrahepatic IPNB with high-grade dysplasia. Six lesions harboured a KRAS codon 12 mutation.
Conclusions: GNAS codon 201 mutations are uncommon in IPNBs, by contrast with pancreatic IPMNs. More comprehensive molecular profiling is needed to uncover the pathways involved in IPNB development.
"v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are indicated to be an early event in IPNBs, as shown by several reports [36, 38, 40–42]. The occurrence of these mutations was more common in IPNBs (17.6 to 46.2% of cases) than in BilINs. "
[Show abstract][Hide abstract] ABSTRACT: Intraductal papillary neoplasm of the bile duct (IPNB) is a rare variant of bile duct tumors characterized by papillary growth within the bile duct lumen and is regarded as a biliary counterpart of intraductal papillary mucinous neoplasm of the pancreas. IPNBs display a spectrum of premalignant lesion towards invasive cholangiocarcinoma. The most common radiologic findings for IPNB are bile duct dilatation and intraductal masses. The major treatment of IPNB is surgical resection. Ultrasonography, computed tomography, magnetic resonance image, and cholangiography are usually performed to assess tumor location and extension. Cholangioscopy can confirm the histology and assess the extent of the tumor including superficial spreading along the biliary epithelium. However, pathologic diagnosis by preoperative biopsy cannot always reflect the maximum degree of atypia, because IPNBs are often composed of varying degrees of cytoarchitectural atypia. IPNBs are microscopically classified into four epithelial subtypes, such as pancreatobiliary, intestinal, gastric, and oncocytic types. Most cases of IPNB are IPN with high-grade intraepithelial neoplasia or with an associated invasive carcinoma. The histologic types of invasive lesions are either tubular adenocarcinoma or mucinous carcinoma. Although several authors have investigated molecular genetic changes during the development and progression of IPNB, these are still poorly characterized and controversial.
"GNAS mutations were detected in a half of IPNBs, irrespective of mucin production, phenotypes and the degree of dysplasia in this study. There has been only one study regarding the status of GNAS mutations in IPNBs, in which low frequency (3%) of GNAS mutations in IPNBs was reported, to our knowledge . The mutation sites in GNAS in IPNBs identified in this study are at codon 201 (R201C and R201H) which are common activating mutations in IPMNs and other tumors , . "
[Show abstract][Hide abstract] ABSTRACT: Intraductal papillary neoplasms of the bile duct (IPNB) shows favorable prognosis and is regarded as a biliary counterpart of intraductal papillary mucinous neoplasm (IPMN) of the pancreas. Although activating point mutations of GNAS at codon 201 have been detected in approximately two thirds of IPMNs of the pancreas, there have been few studies on GNAS mutations in IPNBs. This study investigates the status of GNAS and KRAS mutations and their association with clinicopathological factors in IPNBs. We examined the status of GNAS mutation at codon 201 and KRAS mutation at codon 12&13, degree of mucin production and immunohistochemical expressions of MUC mucin core proteins in 29 patients (M/F = 15/14) with IPNB in intrahepatic and perihilar bile ducts (perihilar IPNB) and 6 patients (M/F = 5/1) with IPNB in distal bile ducts (distal IPNB). GNAS mutations and KRAS mutations were detected in 50% and 46.2% of IPNBs, respectively. There was no significant correlation between the status of GNAS mutation and clinicopathological factors in IPNBs, whereas, the status of KRAS mutation was significantly inversely correlated with the degree of MUC2 expression in IPNBs (p<0.05). All IPNBs with GNAS mutation only showed high-mucin production. Degree of mucin production was significantly higher in perihilar IPNBs than distal IPNBs (p<0.05). MUC2 and MUC5AC expression was significantly higher in IPNBs with high-mucin production than those with low-mucin production (p<0.01 and p<0.05, respectively). In conclusions, this study firstly disclosed frequent GNAS mutations in IPNBs, similarly to IPMNs. This may suggest a common histopathogenesis of IPNBs and IPMNs. The status of KRAS mutations was inversely correlated to MUC2 expression and this may suggest heterogeneous properties of IPNBs. IPNBs with high-mucin production are characterized by perihilar location and high expression of MUC2 and MUC5AC, irrespective of the status of GNAS and KRAS mutations.
PLoS ONE 12/2013; 8(12):e81706. DOI:10.1371/journal.pone.0081706 · 3.23 Impact Factor
"Interestingly, the few GNAS1 positive IPNB were all of the intestinal subtype   , alike most GNAS1 mutated pancreatic IPMN [7– 10,18], indicating a possible molecular link with colorectal villous adenomas, where GNAS1 mutations are also commonly found    . Other molecular alterations, identified in IPNBs, but also in cholangiocarcinomas , affect the cell cycle proteins p21 and cyclin D1    . "
[Show abstract][Hide abstract] ABSTRACT: The neoplasms of the biliary tree include the carcinomas of the intra- and extrahepatic bile ducts, the gallbladder and the ampulla. Two types of precancerous lesions precede these adenocarcinomas: the flat and non-tumour forming type that is called biliary intraepithelial neoplasia, and the papillary and tumour-forming type that has been named intraductal papillary neoplasm of the bile duct. Rarely also biliary mucinous cystic neoplasm can give rise to invasive biliary adenocarcinomas. This review discusses the pathological, molecular, epidemiological, clinical and prognostic features of the precancerous biliary lesions, separated according to their origin in the bile ducts, the ampulla and the gall bladder.
Best practice & research. Clinical gastroenterology 04/2013; 27(2):285-97. DOI:10.1016/j.bpg.2013.04.002 · 3.48 Impact Factor
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