bromochloroacetic-acid and Cholangitis--Sclerosing

We examined histologically the bile duct lesions from 53 patients with end-stage primary sclerosing cholangitis (PSC) and compared them with similar lesions found in 25 surgically excised carcinomas of the extrahepatic bile ducts not associated with PSC. Of the 53 cases of PSC, 50 bile ducts were obtained at liver transplantation, two common bile ducts were segmentally resected for almost complete obstruction, and the entire extrahepatic biliary tract of another case was obtained at autopsy. Twenty bile ducts from patients who died without evidence of biliary tract disease served as controls. A modest increase in the number of intramural glands (mild hyperplasia) was noted in 13 cases (24.5%) of PSC. A marked increase in the number of intramural glands (florid hyperplasia) was found in 14 cases (26.4%) of PSC. In one case of florid hyperplasia, there was perineural and intraneural invasion of benign hyperplastic glands, which still maintained their lobular pattern. All cases of florid hyperplasia of intramural glands were accompanied by extensive fibrosis and marked nerve proliferation. Three of 24 (12.5%) invasive adenocarcinomas of the extrahepatic bile ducts showed mild hyperplasia of intramural glands without excessive nerve proliferation. Four invasive adenocarcinomas and one in situ carcinoma of the extrahepatic bile ducts showed florid hyperplasia of intramural glands (16%). The hyperplastic intramural glands were p53 negative and had low proliferative activity as measured by the low MIB-1 labeling index. In contrast, both in situ and invasive carcinoma expressed p53 protein and had a high MIB-1 labeling index. Focal high-grade dysplasia was found in one case of PSC (1.8%) and a small invasive adenocarcinoma in another (1.8%). Hyperplasia of intramural glands of the extrahepatic bile ducts is a reactive process that lacks specificity and is part of the morphologic spectrum of end-stage PSC. The incidence of dysplasia in PSC is low. Small invasive adenocarcinomas may be incidentally found in end-stage PSC, and detecting their presence before liver transplantation may be impossible.

Topics: Adenocarcinoma; Adult; Aged; Bile Duct Neoplasms; Carcinoma in Situ; Cholangitis, Sclerosing; Female; Humans; Immunohistochemistry; Keratin-7; Keratins; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging

Quantitative immunohistochemistry of ERBB-2 and MET receptor proteins and of cyclooxygenase 2 (COX-2) was undertaken to determine if there is a positive correlation between overexpression of either ERBB-2 or MET and up-regulation of COX-2 in human cholangiocarcinogenesis. ERBB-2, MET, and COX-2 immunoreactivities were measured in cancerous parenchyma of 71 archival cases of human cholangiocarcinoma (ChC) compared with hyperplastic small biliary ducts in surrounding nonneoplastic liver and with bile ducts of normal adult human liver. ERBB-2, MET, and COX-2 immunoreactivities were also assessed in both large and small hyperplastic biliary ducts (HBDs) in 27 archival cases of hepatolithiasis and 20 archival cases of primary sclerosing cholangitis (PSC), both of which are risk conditions for human cholangiocarcinogenesis. There was a strong positive correlation between increased ERBB-2, but not MET, and COX-2 immunoreactivity measured in the tumors and risk conditions. Enhanced immunoreactivity for ERBB-2 and COX-2 also correlated directly with tumor differentiation and was highest in well-differentiated tumors. Interestingly, some but not all cases of hepatolithiasis and most cases of PSC showed increased ERBB-2 and COX-2 immunostaining in the large but not small HBDs, whereas strong MET immunostaining was detected in both the large and small ducts. In conclusion, overexpression of ERBB-2 and COX-2 may herald an early carcinogenic event in the human hepatic biliary tract and one that is consistent with a frequent anatomic site of origin of the tumors. The results also suggest ERBB-2 and COX-2 as potentially important targets relevant to chemoprevention or adjunct therapy of ChC.

Topics: Adult; Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Cholangiocarcinoma; Cholangitis, Sclerosing; Cyclooxygenase 2; Humans; Image Processing, Computer-Assisted; Immunohistochemistry; Isoenzymes; Keratins; Membrane Proteins; Prostaglandin-Endoperoxide Synthases; Proto-Oncogene Proteins c-met; Receptor, ErbB-2; Risk Factors; Up-Regulation

Extracellular matrix (ECM) may affect the function and phenotype of hepatocytes. Phenotypic changes of hepatocytes in diseased liver were investigated with reference to ECM composition.. Immunohistochemistry was performed on biopsied liver samples from chronic viral hepatitis (CVH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC) and normal patients, using monoclonal antibodies for laminin, type IV collagen, cytokeratin 19 (CK19) and epithelial glycoprotein (EGP), a protein homologous to nidogen.. In normal controls, both EGP and CK 19 were expressed exclusively on biliary epithelia. Laminin and type IV collagen were expressed around portal bile ducts and blood vessels. Although type IV collagen was expressed in Disse's space, laminin was scarcely expressed. In all pathological livers, both EGP and CK 19 were expressed in proliferated bile ductules. In CVH with piecemeal necrosis, EGP was expressed on periportal hepatocytes, while CK19 expression was limited to a few hepatocytes. Laminin was expressed in Disse's space of periportal sinusoids, where EGP was expressed on hepatocytes. EGP expression on hepatocytes and laminin deposition in Disse's space were rare in PBC and PSC liver.. These results suggest that hepatocytes transform into a phenotype similar to biliary epithelia and, laminin deposition in Disse's space (capillarization of sinusoids) may play a role in this phenotypic change.

Topics: Cholangitis, Sclerosing; Collagen; Extracellular Matrix; Hepatitis, Chronic; Hepatitis, Viral, Human; Humans; Immunohistochemistry; Keratins; Liver; Liver Cirrhosis, Biliary; Liver Diseases; Membrane Glycoproteins; Phenotype

The term oval cell describes small cells with oval nuclei that arise in the periphery of the portal tracts in rat models of hepatocarcinogenesis and injury and can differentiate into either hepatocytes or bile duct cells, ie, are bipotential. The presence of such cells in human liver is controversial. Here, immunolocalization of OV-6 and two biliary markers, cytokeratin 19 (CK-19) and human epithelial antigen 125 (HEA-125) is compared in normal adult human livers and in primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) liver sections. CK-19 and HEA-125 stained bile ducts and ductules in normal liver as well as proliferating ductular structures in diseased livers. OV-6 did not label ducts or ductules in normal liver, but in PBC and PSC stained numerous proliferating ductular and periductular cells and lobular hepatocytes. In PBC, discrete OV-6-positive cells with a mature biliary-cell-like morphology were seen integrated into some intact bile ducts as well as occasional small immature oval-like cells. In addition, in PSC, hepatocytes in regenerating lobules were also strongly stained with OV-6, and on close inspection, in both PBC and PSC, oval cells and small hepatocytes at the margins of the lobules were strongly labeled. In contrast to the rat liver, OV-6 and CK-19 staining did not always co-localize. It is proposed that the small OV-6-positive oval cells are analogous to those seen in rat models and may represent human liver progenitor cells that may differentiate into OV-6-positive ductal cells or lobular hepatocytes.

Topics: Adolescent; Adult; Antibodies, Monoclonal; Antigens, Surface; Biomarkers; CA-125 Antigen; Child; Child, Preschool; Cholangitis, Sclerosing; Humans; Immunoenzyme Techniques; Immunohistochemistry; Infant; Keratins; Liver; Liver Cirrhosis, Biliary; Microscopy, Confocal; Middle Aged; Stem Cells

A cytokeratin immunohistochemical study was performed on 38 liver biopsies from cases of primary biliary cirrhosis, primary sclerosing cholangitis, extrahepatic biliary obstruction or drug-induced liver disease in order to analyse the cytoskeletal changes in detail. On paraffin sections of 27 cases, a variable number of hepatocytes were reactive with a polyclonal anti-cytokeratin antiserum that, in the normal liver, stains bile duct cells only. On cryostat sections of 23 cases, a variable number of hepatocytes were immunoreactive with a monoclonal antibody specifically directed against cytokeratin no. 7 and were most numerous in cases of long-standing cholestasis irrespective of the aetiology. In three cases of primary sclerosing cholangitis and two cases of primary biliary cirrhosis a few hepatocytes were also weakly positive with a monoclonal antibody specific for cytokeratin no. 19. Since cytokeratins no. 7 and no. 19 are, in the normal liver, restricted to bile duct cells, these results further support the concept of 'ductular metaplasia' of hepatocytes, the mechanism of which remains unclear.

Topics: Antibodies, Monoclonal; Autopsy; Biopsy; Chemical and Drug Induced Liver Injury; Cholangitis, Sclerosing; Cholestasis, Intrahepatic; Cytoskeleton; Frozen Sections; Humans; Keratins; Liver; Liver Cirrhosis, Biliary; Liver Diseases; Metaplasia; Paraffin