The immunohistochemical phenotype of dysplastic foci in human liver: correlation with putative progenitor cells

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Abstract

Background/Aims: In previous studies we found strong evidence for the existence and activation in human liver of putative progenitor cells resembling oval cells in rat liver. In view of the known role of rat oval cells in regeneration and hepatocarcinogenesis, we investigated a possible correlation between human putative progenitor cells and different types of dysplastic foci.

Methods: We determined the immunohistochemical phenotype of dysplastic foci found in 20 cirrhotic liver explants of various etiology, using specific antibodies against hepatocyte-type cytokeratin (CK) 8 and CK18, bile duct-type CK7 and CK19, chromogranin-A (chrom-A) and rat oval cell marker OV-6.

Results: All 12 foci of large cell dysplasia had a phenotype similar to that of surrounding parenchyma. Oncocytic foci showed a strong cytoplasmic staining for CK7. Three out of six of these foci contained“progenitor cells”, which are small cells immunoreactive for CK18, CK7, CK19, OV-6, chrom-A and stained more intensely for CK8 than surrounding hepatocytes. Four out of eight glycogen-storing foci contained CK7-positive intermediate hepatocyte-like cells and“progenitor cells”. Sixteen out of 29 small cell dysplastic foci consisted of“progenitor cells” and intermediate hepatocyte-like cells which were immunoreactive for CK7, CK18, OV-6, chrom-A and showed a stronger cytoplasmic positivity for CK8 than surrounding hepatocytes.

Conclusions: Foci of large cell dysplasia show no correlation with putative progenitor cells. Half of the oncocytic and glycogen-storing foci contain“progenitor cells”, while more than half of the foci of small cell dysplasia consist of small cells with the same immunohistochemical phenotype as putative progenitor cells and intermediate hepatocyte-like cells, suggesting that differentiating putative progenitor cells can give rise to foci of small cell dysplasia.

Section snippets

Liver specimens

This study is based on 20 cirrhotic liver specimens, which were resected prior to liver transplantation. These 20 cases were selected out of a group of 75 cirrhotic explant liver specimens because of the presence of dysplastic foci in the paraffin sections stained with hematoxylin and eosin (H&E). Each specimen was received fresh. Tissue samples were fixed in formalin or B5-fixative and embedded in paraffin. A large tissue sample (between 1 cm3 and 2.5 cm3) from each specimen was snap frozen in

Results

Histopathological examination showed that all 20 liver specimens were in an end-stage of cirrhosis. The viral-induced cirrhotic livers showed a mononuclear inflammatory infiltrate of variable density in portal tracts and septa. Variable degrees of interface hepatitis were seen, being mostly focal and mild. In HCV-associated cirrhosis, lymphoid aggregates were recognized. The livers with cirrhosis caused by a vanishing bile duct disease showed a jigsaw-puzzle pattern of cirrhosis with extensive

Discussion

In a previous study we examined the morphology and immunohistochemical phenotype of putative progenitor cells in regenerating liver and cholestatic liver diseases (20). In the present study, we have described cells which have the same immunohistochemical phenotype as the putative progenitor cells (referred to as “progenitor cells”) and discovered that these “progenitor cells” stain more intensely for CK8 than surrounding hepatocytes. Remarkably, this phenotypic pattern of “progenitor cells” is

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