The cytokeratins phenotype is largely preserved during neoplastic transformation and tumor development. We evaluated the immunoreactivity of biliary epithelial markers keratin 903 and cytokeratin 7 and 19 for intrahepatic cholangiocarcinoma, and compared the results with those for biliary dysplasia and hepatocellular carcinoma. Reactivity with keratin 903 was weakly expressed and increased after the expression of cytokeratin 7 and 19 during human intrahepatic bile duct development. More than 80% of cases of biliary dysplasia showed positive reactivity with keratin 903. Of the 30 cases of hepatocellular carcinoma, 3 (10%), 6 (20%), and 1 (3%) showed positive reactivity with Keratin 903 and cytokeratin 7 and 19, respectively. Among the 73 cases of intrahepatic cholangiocarcinoma, 54 (74%), 66 (90%), and 61 (84%) showed positive reactivity with keratin 903 and cytokeratin 7 and 19, respectively. On clinicopathologic examination of intrahepatic cholangiocarcinomas, reduced keratin 903 reactivity was significantly higher in tumors with an expansive growth pattern (P < .0001), in those with medullary-type stromal reaction (P = .0327), in those without perineural invasion (P = .0001), and in those without lymph node metastasis (P = .0015). In addition, the reactivity with Keratin 903 was directly correlated with expression of cytokeratin 7 and 19 (P = .0153 and P < .0001, respectively). Cases showing reduced keratin 903 reactivity were characterized by a distinctive morphology indicating an hepatocellular carcinoma-like pattern. Multivariate analysis of overall survival revealed that keratin 903 reactivity was a significantly independent prognostic factor. In conclusion, patients with intrahepatic cholangiocarcinoma showing reduced keratin 903 reactivity had a favorable prognosis. Remarkably, the cytokeratin phenotype of intrahepatic cholangiocarcinoma was correlated with the morphologic appearance of intrahepatic cholangiocarcinoma.
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