Clinicopathological Significance of Syndecan-1 in Cholangiocarcinoma: A Study Based on Immunohistochemistry and Public Sequencing Data

Goeppert

Hausen

et al. 2022

Cancers

Self Cite

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.

Section: Immunohistochemistrymentioning

confidence: 99%

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

Goeppert

Hausen

et al. 2022

Cancers

Self Cite

“…Subsequently, slides were digitalized by a whole slide scanner at 40×, with a pixel size of 0.2278 × 0.2278 µm (Nanozoomer, Hamamatsu Photonics, Hamamatsu, Japan). IHC stains for E- and N-cadherin were manually evaluated by scoring the intensity of staining from 0 (no staining) to 3 (strong staining), as described before [ 37 ]. The mean value was calculated for patients with the same entity.…”

Section: Methodsmentioning

confidence: 99%

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

Ridder

Schindeldecker

et al. 2022

Cells

Self Cite

Cell–cell junctions are pivotal for embryogenesis and tissue homeostasis but also play a major role in tumorigenesis, tumor invasion, and metastasis. E-cadherin (CDH1) and N-cadherin (CDH2) are two adherens junction’s transmembrane glycoproteins with tissue-specific expression patterns in epithelial and neural/mesenchymal cells. Aberrant expression has been implicated in the process of epithelial–mesenchymal transition (EMT) in malignant tumors. We could hitherto demonstrate cis-E:N-cadherin heterodimer in endoderm-derived cells. Using immunoprecipitation in cultured cells of the line PLC as well as in human hepatocellular carcinoma (HCC)-lysates, we isolated E-N-cadherin heterodimers in a complex with the plaque proteins α- and β-catenin, plakoglobin, and vinculin. In confocal laser scanning microscopy, E-cadherin co-localized with N-cadherin at the basolateral membrane of normal hepatocytes, hepatocellular adenoma (HCA), and in most cases of HCC. In addition, we analyzed E- and N-cadherin expression via immunohistochemistry in a large cohort of 868 HCCs from 570 patients, 25 HCA, and respective non-neoplastic liver tissue, and correlated our results with multiple prognostic markers. While E- or N-cadherin were similarly expressed in tumor sites with vascular invasion or HCC metastases, HCC with vascular encapsulated tumor clusters (VETC) displayed slightly reduced E-cadherin, and slightly increased N-cadherin expression. Analyzing The Cancer Genome Atlas patient cohort, we found that reduced mRNA levels of CDH1, but not CDH2 were significantly associated with unfavorable prognosis; however, in multivariate analysis, CDH1 did not correlate with prognosis. In summary, E- and N-cadherin are specific markers for hepatocytes and derived HCA and HCC. E:N-cadherin heterodimers are constitutively expressed in the hepatocytic lineage and only slightly altered in malignant progression, thereby not complying with the concept of EMT.

“…Precursor lesions were classified accordingly. Depending on tumor location, as previously stated, we subdivided perihilar cholangiocarcinoma (pCCA) from iCCA [38]. pCCA was defined as primarily located in the hilus region at the common hepatic duct, possibly extending to the right or left hepatic duct.…”

Section: Histology and Immunohistologymentioning

confidence: 99%

“…Due to the wide range of tumor cell morphology, a semiquantitative representation was omitted. Tissue microarrays (TMA) were generated as previously described [38]. The collection of human tumor samples and data were in compliance with the ethical guidelines of the Declaration of Helsinki and approved by the Institutional Ethics Committee (permit numbers 837.280.17 (11114) and 2021-15819).…”

Section: Histology and Immunohistologymentioning

confidence: 99%

Integrative Analysis of Intrahepatic Cholangiocarcinoma Subtypes for Improved Patient Stratification: Clinical, Pathological, and Radiological Considerations

Müller

Bartsch

et al. 2022

Cancers

Self Cite

Intrahepatic cholangiocarcinomas (iCCAs) may be subdivided into large and small duct types that differ in etiology, molecular alterations, therapy, and prognosis. Therefore, the optimal iCCA subtyping is crucial for the best possible patient outcome. In our study, we analyzed 148 small and 84 large duct iCCAs regarding their clinical, radiological, histological, and immunohistochemical features. Only 8% of small duct iCCAs, but 27% of large duct iCCAs, presented with initial jaundice. Ductal tumor growth pattern and biliary obstruction were significant radiological findings in 33% and 48% of large duct iCCAs, respectively. Biliary epithelial neoplasia and intraductal papillary neoplasms of the bile duct were detected exclusively in large duct type iCCAs. Other distinctive histological features were mucin formation and periductal-infiltrating growth pattern. Immunohistochemical staining against CK20, CA19-9, EMA, CD56, N-cadherin, and CRP could help distinguish between the subtypes. To summarize, correct subtyping of iCCA requires an interplay of several factors. While the diagnosis of a precursor lesion, evidence of mucin, or a periductal-infiltrating growth pattern indicates the diagnosis of a large duct type, in their absence, several other criteria of diagnosis need to be combined.