[To evaluate the clinicopathologic characteristics and outcome of tumor cells spreading through air spaces in patients with adenocarcinoma of lung].

Objective: To investigate the clinicopathologic features, molecular characteristics and prognosis of spread through air space (STAS) in patients with adenocarcinoma of the lung. Methods: Two hundred and eighty-eight lung adenocarcinoma patients with complete clinicopathologic and follow-up data were included. The patients were divided into STAS positive (178 cases) and negative (110 cases) groups.EGFR and KRAS gene mutations were detected by amplification refractory mutation system (ARMS), and ALK and ROS1 gene fusion were detected by fluorescence in situ hybridization method. The relationship between STAS and clinicopathologic, molecular features, and patient outcome was analyzed. Results: STAS was present in 61.8%(178/288) of lung adenocarcinomas. The positive rate of STAS in tumors >3 cm was significantly higher than that in tumors ≤3 cm (P=0.009), and was significantly higher in tumors with pleural invasion (P<0.01), venous invasion (P<0.01), lymphatic invasion (P<0.01), perineural invasion (P=0.029) and tumors with necrosis (P<0.01). STAS was also correlated with tumor recurrence (P<0.01) and advanced pathologic TNM stage (P=0.002). There was no significant correlation with patients' gender, age and smoking history. Histologically, STAS was present in 58.0%(91/157), 67.6%(50/74), 2/6, 64.3%(27/42) and 8/9 of acinar, papillary, lepidic, solid and micropapillary adenocarcinomas, respectively. In addition, the positive rates of STAS in tumor with micropapillary (>5%) and without micropapillary pattern were 80.9%(55/68) and 55.9%(123/220), respectively (P<0.01). STAS was significantly higher in EGFR negative group (P=0.034), ALK gene rearrangement group (P=0.003) and ROS1 gene rearrangement group (P=0.012), but there was no significant correlation with KRAS mutation. Univariate survival analysis showed that patients with STAS had a shorter progression-free survival (PFS, P<0.01) and overall survival (P=0.013). Multivariate analysis confirmed that STAS was an independent predictor of PFS in lung adenocarcinoma patients (HR: 2.749, 95%CI: 1.550-4.876, P=0.001). Conclusions: The presence of STAS in lung adenocarcinoma suggests high risk of recurrence and invasion and is thus an important prognostic factor. In addition, STAS is associated with EGFR mutation, ALK and ROS1 gene rearrangement.