Differential prevalence and prognostic significance of spread through air spaces according to oncogenic driver mutations in lung adenocarcinoma.

Abstract

We aimed to characterize the variation in spread through air spaces prevalence by oncogenic driver mutation status in lung adenocarcinoma and to examine whether the prognostic impact of spread through air spaces differs according to driver mutation status. In 4027 surgically resected primary nonmucinous lung adenocarcinomas, we analyzed the prevalence of spread through air spaces according to driver mutation status (EGFR, KRAS, ALK, ROS1) across different tumor sizes and stages. Subsequently, we compared the prognostic value of spread through air spaces for predicting 5-year cumulative incidence of recurrence according to EGFR mutation status. Spread through air spaces was present in 1619 (40.2%) adenocarcinomas, with its prevalence increasing with larger tumor size and higher pathologic stage. Spread through air spaces prevalence varied significantly by driver mutation status, occurring in all ROS1-rearranged tumors (16/16), 80.0% of ALK-rearranged, 56.7% of KRAS-mutated, and 36.6% of EGFR-mutated tumors. Among EGFR-mutated tumors, spread through air spaces was less frequent in those with L858R mutation (30.7%) than in tumors with exon 19 deletion (41.2%) or other subtypes (40.7%) (P < .001). These differences were primarily observed in early-stage (stage I) and small (≤2 cm) tumors. Despite its lower prevalence, spread through air spaces was strongly associated with higher 5-year cumulative incidence of recurrence in the stage IA EGFR-mutated subgroup (16.9% vs 1.7%, P < .001). In contrast, no significant association was found in the EGFR wild-type cases (5.7% vs 3.2%, P = .239). The prevalence and prognostic significance of spread through air spaces varied by driver mutation status, suggesting that the clinical interpretation of spread through air spaces may depend on the molecular context.