Decrease in E-cadherin is considered a molecular event in dysfunction of the cell-cell adhesion system, triggering invasion and metastasis in many malignancies, including those of endocrine origin. In addition, alterations in the cadherin-catenin system may also be involved in tumorigenesis. E-cadherin and beta-catenin, components of the Wnt signal transduction pathway, may serve as a common switch in central processes that regulate cellular differentiation and growth. The purpose of this study was to examine if abnormalities of the Wnt signaling pathway, specifically, E-cadherin and beta-catenin, occur in pancreatic endocrine tumors (PETs) and correlate these with clinicopathologic parameters. Tissue microarrays were constructed from 57 cases with 4 to 14 cores measuring 1.0 mm from each case. Size of tumor, presence or absences of necrosis, gross invasiveness/demarcation, lymphovascular invasion, and lymph node involvement and liver metastasis were recorded. The mitotic count, expressed per 50 high power fields (HPF) and MIB-1 index of the entire tumor were assessed. All the tissue microarray blocks were stained with commercially available antibodies to E-cadherin (cytoplasmic and extracellular domains), beta-catenin, APC, and GSK-3beta. Twenty-seven were male patients and 30 female, ranging in age from 23 to 80 years (mean, 51.7 y). Six patients had MEN1 syndrome and 1 von Hippel Lindau disease. The tumors ranged in size from 0.8 to 9.8 cm with a mean of 3.4 cm. Sixteen patients had lymph node spread and 7 had liver metastasis. The Ki-67 labeling index ranged from 1% to 30% and the mitotic counts from 0 to 27 per 50 HPF. Thirty of 57 cases (52.6%) cases showed abnormal beta-catenin expression. Thirteen of the 16 cases with lymph node metastasis and all 7 cases with liver spread showed abnormalities of beta-catenin immunostaining. Only 2 cases showed nuclear beta-catenin. The average size of tumors with beta-catenin abnormalities was 4.8 cm. Thirty-four of the 57 (59.6%) cases showed loss of normal membranous immunoreactivity for both antibodies E-cadherin, including nuclear localization in 18 cases with the antibody that recognizes the cytoplasmic domain. E-cadherin decrease and/or loss was identical to beta-catenin with the same 13 cases showing nodal involvement and all 7 cases with liver metastasis displaying aberrant E-cadherin staining. Seven of the 18 cases with nuclear E-cadherin had lymph node spread and 3 liver metastases. The mean size of the 34 cases with abnormal E-cadherin expression was 4.4 cm, compared to the series mean of 3.4 cm. Interestingly, cases with nuclear E-cadherin had a mean size of 5.2 cm. beta-catenin and E-cadherin abnormalities did not correlate with other clinicopathological parameters. All 57 cases showed cytoplasmic immunoreactivity for APC, and cytoplasmic and nuclear positivity for GSK-3beta. APC and GSK-3beta did not show any correlation with beta-catenin or E-cadherin staining. Abnormalities of beta-catenin and E-cadherin immunoexpression are seen in the majority of PETs. Nuclear beta-catenin is rare in PET but nuclear E-cadherin, a previously unrecognized staining pattern in PETs was seen 18 of 57 cases with the antibody detecting the cytoplasmic fragment of E-cadherin. Aberrant expression of both beta-catenin and E-cadherin correlated strongly with lymph node spread and liver metastases.