The expression of phospho-AKT, phospho-mTOR, and PTEN in extrahepatic cholangiocarcinoma

Purpose: The protein kinase B (AKT) pathway plays a key role in the regulation of cellular survival, apoptosis, and protein translation, and has been shown to have prognostic significance in a number of cancers. We sought to define its role in extrahepatic cholangiocarcinoma. Experimental Design: Two hundred twenty-one extrahepatic cholangiocarcinoma patients with clinicopathologic data, including survival, were arrayed into tissue microarrays. Phosphor-ylated AKT (p-AKT), phosphorylated mammalian target of rapamycin (p-mTOR), and total phosphatase and tensin homolog deleted on chromosome 10 (PTEN) protein expressions were studied with multiplex tissue immunoblotting assay. Results: Expressions of p-AKT and p-mTOR were significantly increased in extrahepatic cholangiocarcinoma cases compared with normal and dysplastic bile duct epithelium (P < 0.05 both). Decreased PTEN expression was observed in patients with increasing depth of invasion (P < 0.05),Tclassification (P < 0.05), and stage grouping (P < 0.05), and the presence of invasion of the pancreas (P < 0.05) and duodenum (P < 0.05). Decreased PTEN expression (P = 0.004) as well as decreased PTEN/p-AKT (P = 0.003) and PTEN/p-mTOR (P = 0.009) expression showed shorter survival by univariate but not by multivariate analysis. Conclusions: The AKT pathway is activated in a subset of extrahepatic cholangiocarcinoma. Elevated PTEN expression correlates with longer survival. Quantitative data obtained by multiplex tissue immunoblotting may provide additional information than assessment of immuno-histochemistry alone. Quantitative analysis of PTEN, PTEN/p-AKT and PTEN/p-mTOR shows differences in survival by univariate analysis.