Molecular Mechanisms of Cholangiocarcinogenesis: Are Biliary Intraepithelial Neoplasia and Intraductal Papillary Neoplasms of the Bile Duct Precursors to Cholangiocarcinoma?

Bickenbach, Kai; Galka, Eva; Roggin, Kevin K.

doi:10.1016/j.soc.2008.12.001

Cited by 39 publications

(43 citation statements)

References 43 publications

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“…In the biliary tract, the physiological expression of MUC1 occurs only in early fetal development (16) . However, this mucin may be expressed again in CC, as demonstrated in 97% of cases studied by Sasaki et al (15) , this findings were also confirmed by other authors (1,22) . We also point out that this mucin was expressed in cholangiocarcinoma regardless of the degree of histological differentiation, contrary to that observed by other authors (10) , which showed lower expression in the well-differentiated CC.…”

Section: Resultssupporting

confidence: 73%

“…CC pathogenesis is mainly related to chronic inflammation of the ductal epithelium, which is very common in the diseases mentioned above, with subsequent continuous proliferation and malignant transformation of its cells (13) . In cholangiocarcinoma, similarly to that observed in both bowel and gastric adenocarcinoma, the carcinogenesis process comprises from reactive and dysplastic changes in the epithelium to invasive cancer (1) . Besides the recognition of morphological changes that precede invasive cancer, recent studies reveal that during the cholangiocarcinogenesis process, molecular and phenotypic changes of the ductal epithelium occur (22) .…”

mentioning

confidence: 87%

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Mucins and NCAM (CD56) in intrahepatic cholangiocarcinogenesis

Esperança¹,

Camacho²,

Monteiro³

et al. 2014

Jornal Brasileiro De Patologia E Medicina Laboratorial

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Introduction: Cholangiocarcinoma is the second most common malignant neoplasm of the hepatobiliary system. During cholangiocarcinogenesis phenotypic changes occur in the ductal epithelium, including the expression of mucins (MUC). However, the evaluating studies of the expression of mucins in the different stages of cholangiocarcinogenesis are scarce. CD56 has also contributed in differentiating benign ductal proliferation and cholangiocarcinoma; however, its expression has not been evaluated in dysplastic epithelium of the bile duct yet. Objective: To assess immunohistochemical profile of (MUC) 1, 2, 5, 6, and CD56 in cholangiocarcinoma, pre-neoplastic and reactive lesions in the epithelium of intrahepatic bile ducts. Material and methods: Immunohistochemical expression of MUC 1, 2, 5, 6, and CD56 were studied for 11 cases of cholangiocarcinoma and 83 intrahepatic bile ducts (67 reactive and 16 dysplastic). Variables were considered significant when p < 0.05. Results: The expression of MUC1 occurred in about 90% of the cholangiocarcinomas, contrasting with the low frequency of positive cases in reactive and dysplastic bile ducts (p < 0.001). However, there was no statistically significant difference in the expression of MUC5, MUC6 and CD56 between the reactive or dysplastic lesions and cholangiocarcinoma. The anti-MUC2 antibody was negative in all cases. Conclusions: MUC1 contributed for the differential diagnosis between cholangiocarcinoma and pre-neoplastic and reactive/regenerative lesions of intrahepatic bile ducts, and it should compose the antibodies panel aiming at improvement of these differential diagnoses. In contrast, MUC2, MUC5, MUC6 and CD56 were not promising in differentiating all the phases of cholangiocarcinogenesis.

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Section: Resultssupporting

confidence: 73%

mentioning

confidence: 87%

Mucins and NCAM (CD56) in intrahepatic cholangiocarcinogenesis

Esperança¹,

Camacho²,

Monteiro³

et al. 2014

Jornal Brasileiro De Patologia E Medicina Laboratorial

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“…Reported mutation rates show a high range between intrahepatic and extrahepatic cholangiocarcinoma and between different studies. 45 Intraductal papillary neoplasms of the bile duct and cholangiocarcinoma share, therefore, similarities in the respective molecular carcinogenesis but also display differences, 28,45 as for example regarding the role of TP53 inactivation, which represents an early event in intraductal papillary neoplasms of the bile duct and a late event in cholangiocarcinoma development. 29 Further evaluation of the molecular differences between cholangiocarcinomas originating from biliary intraepithelial neoplasia and intraductal papillary neoplasm of the bile duct might help to understand the distinct morphology and natural history of these two precursors of bile duct carcinoma.…”

Section: Discussionmentioning

confidence: 99%

“…24 Therefore, little is known about the prognostic relevance of the histological subtypes 17,23 and the oncogenic pathways underlying the development of these tumors, especially of those occurring sporadically in Western countries. [25][26][27][28][29] In this study, we analyzed a large series of intraductal papillary neoplasms of the bile duct from the patients of European origin, with focus on molecular genetic changes in relation to morphology, distribution of different subtypes and their prognostic relevance. The data were then correlated with the biology of the tumors.…”

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confidence: 99%

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

Schlitter

Born

Bettstetter³

et al. 2014

Modern Pathology

132

131

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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 highgrade 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, b-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 ¼ 0.552). The development of biliary intraductal papillary neoplasms of the bile duct follows an adenomacarcinoma 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.

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“…Analogous to the pancreas, two precursor pathways have been pathologically identified in the biliary tree, comprising non-papillary biliary intra-epithelial neoplasia (bilIN) lesions, and IPBNs. 20 Although molecular analyses of either of the two biliary precursor lesions are limited, the available information suggests underlying differences in terms of genetic alterations, as well as clinical distinctions in the invasive carcinomas arising in the respective contexts. [21][22][23] Emerging evidence suggests a number of similarities between IPMNs and IPNBs.…”

Section: Discussionmentioning

confidence: 99%

GNAS Codon 201 mutations are uncommon in Intraductal Papillary Neoplasms of the Bile Duct

Matthaei¹,

Wu²,

Molin³

et al. 2012

Z Gastroenterol

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Abstracth pb_504 677..683Background: 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.

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Molecular Mechanisms of Cholangiocarcinogenesis: Are Biliary Intraepithelial Neoplasia and Intraductal Papillary Neoplasms of the Bile Duct Precursors to Cholangiocarcinoma?

Cited by 39 publications

References 43 publications

Mucins and NCAM (CD56) in intrahepatic cholangiocarcinogenesis

Mucins and NCAM (CD56) in intrahepatic cholangiocarcinogenesis

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

GNAS Codon 201 mutations are uncommon in Intraductal Papillary Neoplasms of the Bile Duct

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