Beate K. Straub

Distinguishing primary liver cancer (PLC), namely hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA), from liver metastases is of crucial clinical importance. Histopathology remains the gold standard, but differential diagnosis may be challenging. While absent in most epithelial, the expression of the adherens junction glycoprotein N‐cadherin is commonly restricted to neural and mesenchymal cells, or carcinoma cells that undergo the phenomenon of epithelial‐to‐mesenchymal transition (EMT). However, we recently established N‐ and E‐cadherin expression as hallmarks of normal hepatocytes and cholangiocytes, which are also preserved in HCC and iCCA. Therefore, we hypothesized that E‐ and/or N‐cadherin may distinguish between carcinoma derived from the liver vs carcinoma of other origins. We comprehensively evaluated E‐ and N‐cadherin in 3359 different tumors in a multicenter study using immunohistochemistry and compared our results with previously published 882 cases of PLC, including 570 HCC and 312 iCCA. Most carcinomas showed strong positivity for E‐cadherin. Strong N‐cadherin positivity was present in HCC and iCCA. However, except for clear cell renal cell carcinoma (23.6% of cases) and thyroid cancer (29.2%), N‐cadherin was only in some instances faintly expressed in adenocarcinomas of the gastrointestinal tract (0%–0.5%), lung (7.1%), pancreas (3.9%), gynecological organs (0%–7.4%), breast (2.2%) as well as in urothelial (9.4%) and squamous cell carcinoma (0%–5.6%). As expected, N‐cadherin was detected in neuroendocrine tumors (25%–75%), malignant melanoma (46.2%) and malignant mesothelioma (41%). In conclusion, N‐cadherin is a useful marker for the distinction of PLC vs liver metastases of extrahepatic carcinomas ( P < .01).