Clinicopathological correlates of aspartyl (asparaginyl) β-hydroxylase over-expression in cholangiocarcinoma

Abstract

Aspartyl (asparaginyl) beta-hydroxylase (AAH) expression in surgically resected intrahepatic cholangiocarcinoma significantly correlated with tumor size, growth type, differentiation, vascular invasion, and prognosis after surgery. AAH may have a role in regulating invasive or metastatic tumor cell growth of human intrahepatic cholangiocarcinoma. Recent studies demonstrated increased expression of the AAH gene in the majority of cholangiocarcinomas. The present study was undertaken to determine the relationship between high or low levels of AAH expression and the clinical course of intrahepatic cholangiocarcinoma (ICC). AAH expression was examined in 50 surgically resected primary ICCs, 12 samples of normal liver, and 12 cases of primary sclerosing cholangitis (PSC). The sections were evaluated by immunohistochemical staining with the FB-50 monoclonal antibody to human AAH protein. The sections were examined under code and graded for relative levels of AAH immunoreactivity. The results were analyzed with respect to multiple clinical and histopathological variables to determine correlates of AAH expression in ICCs. Forty-six of the 50 (92%) ICCs had AAH immunoreactivity, whereas the 12 normal liver and 12 PSC specimens were AAH negative. In the ICC specimens, the highest levels of AAH immunoreactivity were detected at the infiltrating margins that interfaced with uninvolved liver tissue, and the lowest levels occurred in the central portions of the tumors. Multivariate analysis demonstrated that high levels of AAH expression were correlated with tumor size (P < 0.05), infiltrative growth pattern (P < 0.01), aggressive histological grade (P < 0.01), vascular invasion (P < 0.05), and poor prognosis (P < 0.05). These findings suggest that AAH has an important role in regulating invasive or metastatic tumor cell growth of human ICC, and that high levels of AAH expression correlate with poor prognosis.