Prognostic and diagnostic value of epithelial to mesenchymal transition markers in pulmonary neuroendocrine tumors

Background: Pulmonary neuroendocrine tumors (Pulmonary NETs) include a wide spectrum of tumors, from the low-grade typical carcinoid (TC) and the intermediate-grade atypical carcinoid (AC), to the high-grade large-cell neuroendocrine carcinoma (LCNEC) and the small-cell carcinoma (SCLC). Epithelial Mesenchymal Transition (EMT) is a process initially recognised during several critical stages of embryonic development, which has more recently been implicated in promoting carcinoma invasion and metastasis. The initial stage of the EMT process begins with the deregulation of adhesion molecules, such as E-cadherin, due to transcriptional repression carried out by factors such as Snail family members, Twist and Foxc2. Methods: Immunohistochemistry for EMT markers and E-cadherin/beta-catenin complex in 134 patients with pulmonary NETs between 1990 -2009. Analysis of potential associations with clinicopathological variables and survival. Results: Pulmonary NETs of high malignant potential (LCNEC and SCLC) had reduced expression of the adhesion molecules and high level expression of transcriptional repressors (Snail1, Snail2, Twist and Foxc2). Snail high expression levels and the loss of E-cadherin/beta-catenin complex integrity had the strongest negative effect on the five-year survival rates. E-cadherin/beta-catenin complex integrity loss independently predicted lymph node involvement and helped in Atypical Carcinoid (AC) vs Typical Carcinoid (TC) differential diagnosis. Importantly, among the TC group, the loss of E-cadherin/beta-catenin complex integrity identified patients with an adverse clinical course despite favourable clinicopathological features. Conclusion: The immunohistochemical determination of E-cadherin/beta-catenin complex integrity loss and EMT markers in the clinical setting might be a potential useful diagnostic and prognostic tool especially among the TC patients.