The clinical and morphological definition of hepatocellular carcinoma (HCC), dysplasia and adenoma suffers from a lack of biological understanding. This is especially important in the histomorphological diagnosis of nodular liver lesions in needle biopsies. Therefore, we constructed a liver tissue micro-array (TMA) and evaluated 48 HCCs, 46 dysplasias, 8 adenomas, 20 cirrhotic specimens and 28 normal liver samples derived from 68 patients. Protein (over)expression by tumor suppressor genes p16, p53 and Rb1 was assessed by immunohistochemistry, the proliferative capacity was examined by immunostaining of Ki67. Further, DNA ploidy status (hyperdiploidy) was measured by fluorescent in situ hybridization (FISH) with a chromosome 1-specific repetitive DNA probe. An abnormal chromosome 1 number, i.e. the percentage of hyperdiploid cells, was 11.0, 13.7, 16.1, 23.7 and 31.3 for normal liver samples, adenomas, cirrhosis, dysplasias and HCCs, respectively. A significant difference was found for HCC versus cirrhosis (P=0.024) or adenoma (P=0.033), a trend (borderline significance) was seen for dysplasia versus cirrhosis (P=0.094). Immunohistochemical protein localisation of p53 and Rb1, as well as Ki67 indicating proliferation, was clearly higher in HCC than in cirrhosis or dysplasia (all P<0.001). Proliferation was also higher in HCC than in adenoma (P=0.025), whereas a trend (borderline significance) was observed for Rb1 overexpression (P=0.063). These data suggest that in the liver cell dysplasia-carcinoma pathway, changes in ploidy are followed by increased proliferation and cell biological perturbations involving p53 and Rb1. Adenomas can be distinguished from carcinomas, but not from dysplasias, based on ploidy and proliferation characteristics.

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Acta Histochemica
Department of Pathology

van Dekken, H, Zondervan, P.E, Verhoef, C, Wink, J.C, van Marion, R, Vissers, K.J, … van Eijck, C.H.J. (2005). Cell biological evaluation of liver cell carcinoma, dysplasia and adenoma by tissue micro-array analysis. Acta Histochemica, 107(3), 161–171. doi:10.1016/j.acthis.2005.03.001