Alteration of the E-cadherin/β-catenin cell adhesion system is common in pulmonary neuroendocrine tumors and is an independent predictor of lymph node metastasis in atypical carcinoids

BACKGROUND. To the authors' knowledge, little is known regarding the role of E-cadherin/β-catenin system dysregulation in pulmonary neuroendocrine tumors. METHODS. E-cadherin and β-catenin immunoreactivity was evaluated in 10 hyperplastic neuroendocrine tumorlets and 210 neuroendocrine tumors, including 96 typical carcinoids (CTs), 35 atypical carcinoids (ACTs), 49 large cell neuroendocrine carcinomas (LCNECs), and 30 small cell lung carcinomas (SCLCs). RESULTS. Normal and hyperplastic bronchial neuroendocrine cells expressed E-cadherin/β-catenin with an orderly distribution along the cell membrane. Neuroendocrine tumors retained β-catenin expression in all tumors and E-cadherin in most tumors, with the exception of 2% of LCNECs, 3% of SCLCs and 9% of ACTs. E-cadherin showed a prevalent membrane-associated, linear immunoreactivity in CTs, whereas membrane-disarrayed and cytoplasmic staining was seen in most ACTs, LCNECs, and SCLCs (P < 0.001). β-Catenin exhibited similar immunoreactivity patterns according to tumor type and a close association with E-cadherin subcellular distribution (P < 0.001). Nuclear accumulation of β-catenin was found only in seven LCNECs and in two SCLCs. In ACTs, disarrayed immunoreactivity for E-cadherin and/or β-catenin was associated with a nontrabecular growth pattern, altered expression of the cell-motility marker fascin, and lymph node metastases. Furthermore, a disarrayed E-cadherin distribution pattern was associated with the pathologic lymph node classification and the number of involved lymph nodes. Multivariate analysis confirmed that a disarrayed E-cadherin or β-catenin pattern was an independent predictor of lymph node metastases in patients with ACT. CONCLUSIONS. The subcellular compartmentalization of the E-cadherin/β- catenin complex was altered in pulmonary neuroendocrine tumors. This likely affects the tumor growth pattern and cell motility of ACT and was correlated with the occurrence of lymph node metastases.