Immunohistochemical analysis of the Wnt/β-catenin signaling pathway in pancreatic neuroendocrine neoplasms

Abstract

Aim: To investigate the role of the Wnt/β-catenin pathway in pancreatic neuroendocrine neoplasms (PanNENs).

Methods: Tissue microarrays containing 88 PanNENs were immunohistochemically labeled with antibodies to β-catenin, E-cadherin, adenomatous polyposis coli (APC), chromogranin and synaptophysin. One case had only metastatic tumors resected, whereas others (n = 87) received pancreatectomy with or without partial hepatectomy. Pathology slides, demographic, clinicopathologic, and follow up data were reviewed. Patients' demographics, clinicopathologic features, and immunohistochemical results from 87 primary tumors were compared between patients with low stage (stage I/II) and high stage (stage III/IV) tumors. In addition, correlation of immunohistochemical results from primary tumors with disease-specific survival (DSS) was evaluated.

Results: Strong membranous β-catenin staining in the primary tumor was observed in all 13 stage III/IV PanNENs as compared to 47% (35/74) of stage I/II tumors (P < 0.01). However, the strong membranous β-catenin staining was unassociated with tumor grade or DSS. Decreased membranous β-catenin staining was associated with decreased membranous E-cadherin labeling. Nuclear β-catenin staining was seen in 15% (2/13) of stage III/IV PanNENs as compared to 0% (0/74) of stage I/II tumors (P = 0.02). The case with metastasectomy only also showed nuclear β-catenin staining. Two of the three cases with nuclear β-catenin staining were familial adenomatous polyposis (FAP) patients. Lack of APC expression was seen in 70% (57/81) of the cases, including the 3 cases with nuclear β-catenin staining. Expression of E-cadherin and APC in primary tumor was not correlated with tumor grade, tumor stage, or disease specific survival.

Conclusion: The Wnt/β-catenin pathway was altered in some PanNENs, but did not Impact DSS. PanNENs in FAP patients demonstrated nuclear β-catenin accumulation and loss of APC.

Keywords: Adenomatous polyposis coli; E-cadherin; Familial adenomatous polyposis; Pancreatic neuroendocrine neoplasm; β-catenin.

Figure 1

β-catenin expression in the pancreas and pancreatic neuroendocrine neoplasms (original magnification 200 ×). A: Strong membranous β-catenin staining in the exocrine pancreas and weak membranous staining in pancreatic islets (black arrows); B: Weak membranous β-catenin staining in one pancreatic neuroendocrine neoplasm; C: Strong membranous β-catenin staining in another pancreatic neuroendocrine neoplasm.

Figure 2

A pancreatic neuroendocrine neoplasm from a familial adenomatous polyposis patient (original magnification 200 ×). A: Hematoxylin and eosin stain showing a well differentiated neuroendocrine tumor composed of monomorphic cells with “salt and pepper” chromatin; B and C: Immunohistochemical labeling for synaptophysin (B) and chromogranin (C) showing positive staining; D: Immunohistochemical labeling with β catenin showing β catenin nuclear accumulation and loss of membrane staining; E: Immunohistochemical staining for E-cadherin showing strong E-cadherin membranous expression; F: Immunohistochemical labeling for APC showing loss of APC expression. APC: Adenomatous polyposis coli.

Figure 3

Expression of E-cadherin and adenomatous polyposis coli in the pancreas and pancreatic neuroendocrine neoplasms (original magnification 200 ×). A: Strong membranous E-cadherin labeling in the exocrine pancreas and weak membranous E-cadherin labeling in pancreatic islets (black arrows); B: Weak membranous E-cadherin in one pancreatic neuroendocrine neoplasm; C: Expression of cytoplasmic APC by pancreatic islets (black arrows) but not by the exocrine pancreas; D: Cytoplasmic APC labeling in one pancreatic neuroendocrine neoplasm. APC: Adenomatous polyposis coli.