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

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.

Constitutive Occurrence of E:N-cadherin Heterodimers in Adherens Junctions of Hepatocytes and Derived Tumors

“…Having demonstrated the formation of E:N-cadherin heterodimers in the liver, a feature that is highly preserved during hepatocarcinogenesis, the presence of both cadherins may be used for the differential diagnoses of carcinomas of unknown primary. In line with this, we have previously shown the presence of E- and N-cadherin in cholangiocytes of the biliary tree and derived tumors, suggesting N-cadherin as a marker to distinguish between intrahepatic cholangiocarcinoma and liver metastases of ductal adenocarcinoma of the pancreas [ 89 ]. In conclusion, E- and N-cadherin are suitable markers to identify hepatocytes, cholangiocytes, and derived tumors.…”

N‐cadherin: A diagnostic marker to help discriminate primary liver carcinomas from extrahepatic carcinomas

“…We previously demonstrated that the co‐expression of E‐ and N‐cadherin is a characteristic of hepatocytes, cholangiocytes, and their derived tumors 17,18 . To test the potential of E‐ and N‐cadherin as markers in the differential diagnosis of PLC vs extrahepatic carcinomas, their expression was assessed in a total of 13,295 individual TMA cores comprised of 3359 different tumors (Tables 1 and 2), and compared to previously published analyses of 882 cases of PLC, including HCC and iCCA 17,18 . In a first step, we investigated E‐cadherin (Figure S1) and N‐cadherin (Figure 1) expression via immunohistochemistry (Tables 1, S2, and S3).…”

“…Primary tumors, lymph node metastases, and distant metastases were each separately evaluated. This method, which we have applied in previous studies 17,18 has proven to reflect the most precise gradation of staining intensity for E‐ and N‐cadherin in our experience. Sensitivity and specificity were calculated using Microsoft Excel 2016 (Microsoft Corporation, Redmond, WA).…”

“…According to the literature, EMT, which is characterized by loss of E‐cadherin expression and increased expression of N‐cadherin, has been correlated with tumor invasion and metastasis 8,15 . In previous work, we showed that E‐ and N‐cadherin form cis‐E:N‐cadherin heterodimers in adherens junctions at the basolateral membrane of hepatocytes and cholangiocytes, 16 and that E‐ and N‐cadherin‐expression is retained in iCCA and HCC 17,18 . In fact, regardless of tumor grading, HCC show high N‐cadherin expression in 92% of cases, and co‐expression of E‐cadherin 17,18 .…”

“…Interestingly, N‐cadherin expression gradually declines from HCC and small duct iCCA to large duct iCCA, carcinomas of the extrahepatic bile ducts including perihilar cholangiocarcinomas (pCCAs), and gallbladder carcinomas (GBCs) to pancreatic ductal adenocarcinomas (PDACs). Thus, N‐cadherin immunohistochemistry could be used to distinguish between iCCA and PDAC 17,19–21 . Furthermore, we hypothesized that E‐ and/or N‐cadherin may serve as a valuable marker in differentiating PLC from liver metastases originating from an extrahepatic primary tumor.…”