CYTOKERATIN PATTERNS OF LIVER CARCINOMAS INDUCED BY DIETHYLNITROSAMINE IN MONKEYS

BACKGROUND: Although the general conception is that hepatocyte- and bi le duct-specific cytokeratin (CK) patterns are maintained throughout t he neoplastic process, there is an increasing number of reports showin g deviation from the rule. CK patterns have been found to be similar a cross species barriers, so it could be expected that studying the CK p atterns of experimentally induced liver tumors may contribute to the e lucidation of these controversies. EXPERIMENTAL DESIGN: A CK immunohis tochemical study was carried out on histologic sections from hepatocel lular carcinomas (HCCs) and preneoplastic lesions from 118 monkeys chr onically dosed with diethylnitrosamine (DEN), using mAbs to CK 8, CK 1 8, CR 7, and CK 19. RESULTS: Normal monkey hepatocytes differed from h uman hepatocytes by displaying CK 19 in addition to the CK 8/CK 18 pai rs, whereas the CK pattern of bile duct epithelial cells was identical in monkey and human liver. In association with DEN-induced hepatocarc inogenesis, heterogeneity was observed in the CK expression, both in t he HCCs and nontumorous parts of the livers. The majority of the HCC c ases displayed one of the three CKs normally present in monkey hepatoc ytes, 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 with in the same tumor) was observed in approximately one-fourth of the cas es. There was no correlation between the preservation of the hepatocyt e-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 mor e than half of the cases. In lung metastases, CK 7 was less common, on ly 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-b y-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 f requently in CK 7-negative livers than in positive livers. Proliferati on of CK 7- and CK 19-positive bile ductules and bile ductular-like (o val) cells was frequently associated with the DEN-induced liver injury and hepatocarcinogenesis. CONCLUSIONS: This is the first report on CK expression in monkey liver. The findings show that the hepatocyte spe cific pattern is not always preserved during DEN-induced hepatocarcino genesis and may therefore not be useful in differentiating between HCC s and cholangiocarcinomas.