Tumor heterogeneity in small hepatocellular carcinoma: Analysis of tumor cell proliferation, expression and mutation of p53 AND ?-catenin

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Abstract
Most hepatocellular carcinomas (HCCs) first occur as well‐differentiated HCCs, from which poorly differentiated HCC cells develop because of dedifferentiation. In this study, we try to clarify the changes of dedifferentiation and cell proliferative activity and their relationship in small HCCs (less than 3.0 cm in diameter) and try to learn the mechanism of these changes by analysing the expressions and genetic changes of proliferation‐related genes p53 and β‐catenin. Of 41 surgically resected small HCCs, 11 were identified to have tumor heterogeneity. DNA from the 11 small HCCs, consisting of 29 intratumoral lesions and 11 noncancerous liver tissues adjacent to HCCs, was extracted from paraffin embedded tissue sections. Exons 5–8 of p53 gene and exon 3 of β‐catenin gene were amplified by polymerase chain reaction and analyzed by direct sequence. The serial sections were also immunostained by anti‐Ki‐67, p53 and β‐catenin antibody. Immunohistochemistry showed that the p53 overexpression was significantly related to the proliferative activities as evaluated by Ki‐67 immunostaining and to the histological differentiation. The expression of β‐catenin was found to be heterogeneously distributed not only in various histological grades of the same tumor but also in areas of the same histological grade. p53 and β‐catenin gene mutations were detected in 1 tumor respectively, both of which were second primary HCCs and also recurred later. The p53 mutation showed the same mutation pattern in heterogeneous subpopulations. β‐catenin mutation was detected only in the less differentiated lesion but not in the well‐differentiated lesion of tumor. In conclusion, our findings suggest that there was histological heterogeneity in small but established HCC, which was accompanied by increased proliferative activity and p53 overexpression. The overexpression of β‐catenin may be related to the proliferative activity and dedifferentiation of HCC.