The epithelial-mesenchymal transition phenotype is associated with the frequency of tumor spread through air spaces (STAS) and a High risk of recurrence after resection of lung carcinoma

Objectives: The prognostic value of spread through air spaces (STAS) in lung carcinoma has been validated in independent cohorts. Epithelial-mesenchymal transition (EMT) is a biological process that promotes the migration and invasiveness of tumor cells. To investigate the role of the EMT phenotype in the occurrence of STAS, we analyzed patients with therapy-naive lung adenocarcinoma and squamous cell carcinoma undergoing lobectomy (n = 635). Materials and Methods: STAS was defined by the presence of tumor cells within air spaces in the lung parenchyma beyond the edge of the main tumor. The expression of E-cadherin, vimentin, and (R)-catenin was evaluated by immunohistochemistry using tissue microarray. Tumors were classified into three EMT phenotypes (epithelial, intermediate, and mesenchymal). Recurrence-free probability and overall survival were analyzed using the log-rank test and the Cox proportional hazards model. Results: STAS was less frequently observed in tumors with epithelial phenotype than in those with non-epithelial phenotype (p = 0.034), and more frequent in patients with nuclear beta-catenin-positive tumors (p < 0.001). The EMT phenotype was an independent prognostic factor of recurrence (mesenchymal vs. epithelial: hazard ratio [HR] = 2.27, p =0.014; mesenchymal vs. intermediate: HR = 2.13, p = 0.019). Conclusion: We have demonstrated that in patients with resected lung carcinoma, STAS was less frequent in tumors with an epithelial phenotype than in those with non-epithelial phenotype, and that the nuclear translocation of beta-catenin was associated with a higher rate of STAS. The mesenchymal state was an independent predictor of high risk of recurrence in patients with STAS.