Cytokeratin patterns of liver carcinomas induced by diethylnitrosamine in monkeys

Although the general conception is that hepatocyte- and bile duct-specific cytokeratin (CK) patterns are maintained throughout the neoplastic process, there is an increasing number of reports showing deviation from the rule. CK patterns have been found to be similar across species barriers, so it could be expected that studying the CK patterns of experimentally induced liver tumors may contribute to the elucidation of these controversies.

A CK immunohistochemical study was carried out on histologic sections from hepatocellular carcinomas (HCCs) and preneoplastic lesions from 118 monkeys chronically dosed with diethylnitrosamine (DEN), using mAbs to CK 8, CK 18, CK 7, and CK 19.

Normal monkey hepatocytes differed from human hepatocytes by displaying CK 19 in addition to the CK 8/CK 18 pairs, whereas the CK pattern of the bile duct epithelial cells was identical in monkey and human liver. In association with DEN-induced hepatocarcinogenesis, heterogeneity was observed in the CK expression, both in the HCCs and nontumorous parts of the livers. The majority of the HCC cases displayed one of the three CKs normally present in monkey hepatocytes, whereas positive expression of all three CKs (CK 8, CK 18, CK 19) and negative CK 7 was preserved in only 19.5% of the HCC cases. A so-called mixed staining pattern (negative and positive CK staining within the same tumor) was observed in approximately one-fourth of the cases. There was no correlation between the preservation of the hepatocyte-specific CK pattern and the degree of differentiation, tumor grade, or DNA ploidy of the HCCs. In approximately 10% of the primary tumors, CK 7 was expressed in the entire parenchymal cell compartment of the HCC nodules, whereas it was present in a mixed staining pattern in more than half of the cases. In lung metastases, CK 7 was less common, only expressed in approximately one-fourth of the cases. Alterations in the CK patterns were observed in the nonneoplastic hepatocytes of the tumor-bearing monkeys. These included mixed staining patterns in which the CKs appeared as positive and negative regenerating nodules side-by-side. As was observed in the HCCs, CK 7 was more commonly expressed in the nonneoplastic parenchyma in the form of mixed staining pattern than the other three CKs. Moreover, CK 7-negative HCCs occurred more frequently in CK 7-negative livers than in positive livers. Proliferation of CK 7- and CK 19-positive bile ductules and bile ductular-like (oval) cells was frequently associated with the DEN-induced liver injury and hepatocarcinogenesis.

This is the first report on CK expression in monkey liver. The findings show that the hepatocyte specific pattern is not always preserved during DEN-induced hepatocarcinogenesis and may therefore not be useful in differentiating between HCCs and cholangiocarcinomas.