N-cadherin as a diagnostic marker to discriminate primary from metastatic liver carcinomas

The differential diagnosis between the primary liver cancer hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA) from liver metastases is of crucial therapeutic importance, but the histopathologic diagnosis may be challenging. We previously identified the adherens junction glycoproteins N- and E-cadherin as hallmarks of normal hepatocytes, cholangiocytes and derived tumors. In line with literature, we showed that N-cadherin is restricted to neural and mesenchymal cells, whereas epithelia are vastly negative, with the exception of liver carcinoma and carcinoma during the phenomenon of epithelial to mesenchymal transition. Therefore, we hypothesized that N-cadherin may distinguish between carcinoma derived from the liver versus other origin. During this study, we evaluated E- and N-cadherin in 2,489 different tumors using immunohistochemistry, and compared our results with previously published 882 cases of primary liver cancers including 570 HCCs and 312 iCCAs. Most carcinomas irrespective of their origin showed strong positivity for E-cadherin. A strong staining reaction with antibodies against N-cadherin was present in HCC and iCCA. With the exception of clear cell renal cell carcinoma (23.6% of cases), N-cadherin was rarely expressed in adenocarcinomas of the gastrointestinal tract (0-0.5%), lung (7.1%), pancreas (3.9%), gynecological organs (0-7.4%) and breast (2.2%) nor urothelial (9.4%) or squamous cell carcinoma (0-5.6%). Furthermore, N-cadherin was frequently detected in tumors of endocrine origin such as thyroid cancer (29.2%), neuroendocrine tumors (25-75%), as well as in malignant melanoma (46.2%) and malignant mesothelioma (41%). In conclusion, N-cadherin is a useful marker for the distinction of primary versus metastatic liver carcinoma (p<0.01).