Mutation and Altered Expression of β-Catenin During Gallbladder Carcinogenesis
Department of Pathology, Seoul National University College of Medicine, Korea. American Journal of Surgical Pathology
(Impact Factor: 5.15).
06/2002; 26(6):758-66. DOI: 10.1097/00000478-200206000-00009
Gallbladder carcinoma has two main morphologic developmental pathways: a dysplasia-carcinoma sequence and an adenoma-carcinoma sequence. beta-Catenin is a key regulator of the cadherin-mediated cell adhesion system, and altered expression and mutation of beta-catenin have been identified in many human malignancies. To clarify its role in gallbladder carcinogenesis, we investigated mutation and immunohistochemical expression of beta-catenin in adenomas, dysplasias, and carcinomas. We classified adenomas according to the expression of apomucins and cytokeratin and compared the mutational and expression pattern among each type. beta-Catenin mutations were identified in 58% (14 of 24) of the adenomas, and they were absent from all carcinomas (37 cases) and dysplasias (13 cases). Altered expression of beta-catenin, such as nuclear or cytoplasmic expression and loss of membranous expression, was also significantly higher in adenomas than in dysplasias or carcinomas (p <0.001). Of the adenomas, papillary adenomas and tubular adenomas of intestinal type showed infrequent beta-catenin abnormality, which was similar to the carcinomas. The cytoplasmic and nuclear expression of beta-catenin in carcinomas was correlated with less aggressive tumor behavior; in particular, cytoplasmic expression was associated with improved patient outcome (p = 0.028). Gallbladder adenoma may be a heterogeneous entity, and the majority of adenomas are not responsible for carcinoma progression.
Available from: PubMed Central
- "Using polyp size to decide surgical behavior may, therefore, be misleading. Adenoma is a precancerous disease which could transform to adenocarcinoma in an adenoma-dysplasia-cancer manner (22,23). A protruding type of gallbladder was likely the result of adenoma under continuing stimuli such as gallstones or chronic inflammation. "
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ABSTRACT: The aim of this study was to investigate the differences between images of large adenoma of the gallbladder and the protruding type carcinoma of the gallbladder. A retrospective study was performed on 130 patients who underwent cholecystectomy or biopsy for gallbladder polypoid lesions larger than 10 mm; among them, 20 patients were malignant and 110 patients were benign. Patients' details including ultrasonography (US), computed tomography (CT) and magnetic resonance (MR) findings were analyzed. All patients whose lesions were >15 mm by US, had CT or MR scans to further determine the nature of the lesion; two patients who were suspected to have a malignant lesion due to their large tumor size were benign by histological examination. Distinct differences were found between large adenoma and protruding type of gallbladder carcinoma. There were distinct differences between adenomas and the protruding type gallbladder cancers, and there was a pathological basis for the differences. Benign tumors had a more homogeneous texture, had spaces between the tumor and the gallbladder wall and a relatively normal configuration of the gallbladder wall. Based on these findings, certain lesions could be definitively diagnosed as benign adenomas and could help in treatment strategy.
- "Chang et al. shows that the cytoplasmic and nuclear expression of beta-catenin in carcinomas was correlated with less-aggressive tumor behavior; in particular, cytoplasmic expression was associated with improved patient outcome (P = 0.028). "
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The inactivation of the tumor suppressor gene and activation of the proto-oncogene are key steps in the development of human cancer. p53 and beta-catenin are examples of such genes, respectively. In the present study, our aim was to determine the role of these genes in the carcinogenesis of the gallbladder by immunohistochemistry.
Patients and Methods:
Sections from paraffin-embedded blocks of surgically resected specimens of gallbladder cancer (GBC) (80 cases), chronic cholecystitis (60 cases), and control gallbladders (10 cases) were stained with the monoclonal antibody p53, and polyclonal antibody beta-catenin. Results were scored semiquantitatively and statistical analysis performed. p53 expression was scored as percentage of the nuclei stained. Beta-catenin expression was scored as type of expression–membranous, cytoplasmic, and nuclear staining. Beta-catenin expression was correlated with tumor invasiveness, differentiation, and stage.
Over-expression of p53 was seen in 56.25% of GBC cases and was not seen in chronic cholecystitis or in control gallbladders. p53 expression in gallbladder cancer was significantly higher than in inflammatory or control gallbladders (P < 0.0001). p53 expression increased with increasing tumor grade (P = 0.039). Beta-catenin nuclear expression was seen in 75% cases of gallbladder cancer and in no case of chronic cholecystitis and control gallbladder. Beta-catenin nuclear expression increased with tumor depth invasiveness, and grade (P = 0.028 and P = 0.0152, respectively).
p53 and beta-catenin nuclear expression is significantly higher in GBC. p53 expression correlates with increasing tumor grade while beta-catenin nuclear expression correlates with tumor grade and depth of invasion, thus suggesting a role for these genes in tumor progression of GBC.
Available from: Wenxin Zheng
- "The disruption of intercellular adhesions is an important component of the acquisition of invasive properties in epithelial malignancies. Alterations in the cell-cell adhesion complex, E-Cadherin/β-Catenin, have been implicated in the oncogenesis of carcinomas arising from various anatomic sites and have been correlated with adverse clinico-pathological parameters [10-22]. Epithelial Cadherin (E-Cadherin) is a 120 kDa transmembrane glycoprotein which is involved in both homotypic and heterotypic Ca2+-dependent cellular adhesions [23-26]. "
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ABSTRACT: The disruption of intercellular adhesions is an important component of the acquisition of invasive properties in epithelial malignancies. Alterations in the cell-cell adhesion complex, E-Cadherin/beta-Catenin, have been implicated in the oncogenesis of carcinomas arising from various anatomic sites and have been correlated with adverse clinico-pathologic parameters. In this study, the authors investigated the immunohistochemical expression of E-Cadherin and beta-Catenin in a cohort of early stage cervical cancers to determine its prognostic significance and to investigate differences between the three major histological subtypes.
A tissue microarray of 147 cases of FIGO stage 1A and 1B cervical carcinomas [96 squamous cell carcinomas (SCC), 35 adenocarcinomas (AC), 12 adenosquamous carcinomas (ASQ), 4 miscellaneous types] was constructed from our archived surgical pathology files and stained with monoclonal antibodies to E-Cadherin and beta-Catenin. Cases were scored by multiplying the intensity of staining (1 to 3 scale) by the percentage of cells stained (0-100%) for a potential maximum score of 300. For both markers, "preserved" expression was defined as bright membranous staining with a score of 200 or above. "Impaired" expression included any of the following: negative staining, a score less than 200, or exclusively cytoplasmic or nuclear delocalization.
Impaired expression of beta-Catenin was found in 85.7%, 66.7%, & 58.3% of AC, SCC & ASQ respectively. Impaired expression of E-Cadherin was found in 94.3%, 86.5% & 100% of cases of AC, SCC, & ASQ respectively. The differences between the histologic subtypes were not significant. For the whole cohort, a comparison of cases showing impaired versus preserved of E-Cadherin and beta-Catenin expression showed no significant differences with respect to recurrence free survival, overall survival, patient age, histologic grade, and frequency of lymphovascular invasion or lymph node involvement. There was no correlation between the status of both markers for all three histological subtypes (overall spearman correlation co-efficient r = 0.12, p = 0.14)
Impairment of E-Cadherin and beta-Catenin expression is very frequent in early stage cervical cancers, and alterations in the E-Cadherin/beta-Catenin cell adhesion complex are therefore likely involved in the pathogenesis of cervical carcinomas even at their earliest stages. None of the three major histological subtypes of cervical carcinoma (SCC, ADCA, ADSQ) is significantly more likely than the others to show impairment in E-Cadherin and beta-Catenin expression. Overall, the expression of both markers does not significantly correlate with clinico-pathological parameters of prognostic significance.
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