N-Cadherin Distinguishes Intrahepatic Cholangiocarcinoma from Liver Metastases of Ductal Adenocarcinoma of the Pancreas

SIMPLE SUMMARY: The differential diagnosis of primary liver cancer versus liver metastases of an extrahepatic primary tumor may be challenging, especially in carcinoma of the pancreatobiliary phenotype, as in intrahepatic cholangiocarcinoma or metastases of ductal adenocarcinoma of the pancreas. Nevertheless, the distinction is of fundamental importance for therapy planning. In the frame of this study, we focus on the differential expression and localization of the cell–cell contact-proteins E-cadherin and N-cadherin, markers for cell differentiation in normal epithelia of the pancreaticobiliary tract as well as in derived tumors, and demonstrate that N-cadherin positivity distinguishes intrahepatic cholangiocarcinoma from liver metastases of ductal adenocarcinoma of the pancreas. We propose that N-cadherin-positivity together with other biliary markers may be used for this important histopathological differential diagnosis and may thus improve the accuracy of cholangiocarcinoma diagnosis. ABSTRACT: Carcinomas of the pancreatobiliary system confer an especially unfavorable prognosis. The differential diagnosis of intrahepatic cholangiocarcinoma (iCCA) and its subtypes versus liver metastasis of ductal adenocarcinoma of the pancreas (PDAC) is clinically important to allow the best possible therapy. We could previously show that E-cadherin and N-cadherin, transmembrane glycoproteins of adherens junctions, are characteristic features of hepatocytes and cholangiocytes. We therefore analyzed E-cadherin and N-cadherin in the embryonally related epithelia of the bile duct and pancreas, as well as in 312 iCCAs, 513 carcinomas of the extrahepatic bile ducts, 228 gallbladder carcinomas, 131 PDACs, and precursor lesions, with immunohistochemistry combined with image analysis, fluorescence microscopy, and immunoblots. In the physiological liver, N-cadherin colocalizes with E-cadherin in small intrahepatic bile ducts, whereas larger bile ducts and pancreatic ducts are positive for E-cadherin but contain decreasing amounts of N-cadherin. N-cadherin was highly expressed in most iCCAs, whereas in PDACs, N-cadherin was negative or only faintly expressed. E- and N-cadherin expression in tumors of the pancreaticobiliary tract recapitulate their expression in their normal tissue counterparts. N-cadherin is a helpful marker for the differential diagnosis between iCCA and PDAC, with a specificity of 96% and a sensitivity of 67% for small duct iCCAs and 50% for large duct iCCAs.