Prognostic impact of spread through air spaces (STAS) in mucin-producing lung adenocarcinoma: a multinational cohort study

INTRODUCTION: Mucin-producing lung adenocarcinoma is a distinct pathological subset, but its prognostic significance, particularly in relation to spread through air spaces (STAS), remains unclear. We used a study-specific analytic framework to separate mucin-producing adenocarcinomas into invasive mucinous adenocarcinoma (IMA) and invasive adenocarcinoma with extracellular mucin production (IAEM), and evaluated their clinicopathological features, prognosis, and the impact of STAS in a multinational cohort. METHODS: A total of 647 surgically resected primary lung adenocarcinomas from five countries were retrospectively analyzed. Histologic subtyping and STAS assessment were performed by expert pathologists using whole-slide images. Survival was evaluated by Kaplan-Meier analysis and log-rank testing. Exploratory RNA sequencing was performed in a subset of IMA cases. RESULTS: Mucin production was observed in 203 cases (31.4%). In univariable analysis, mucin-producing adenocarcinomas showed significantly worse overall survival (OS) than non-mucin-producing tumors; however, mucin status was not independently prognostic in multivariable analysis after adjustment for STAS and pathological stage. STAS was present in 302 cases (46.7%) and was associated with worse OS in all cohorts except Brazil. Mucin-producing adenocarcinomas without STAS showed better outcomes, and no deaths were observed in the small subgroup of STAS-negative IMA in this cohort. RNA sequencing suggested enrichment of gene expression profiles related to gastrointestinal epithelial cell types in IMA. CONCLUSIONS: Across five international cohorts, STAS was associated with adverse prognosis in lung adenocarcinoma, independent of mucin production. In this cohort, STAS-negative IMA was associated with favorable outcomes, suggesting that STAS may refine prognostic stratification in mucin-producing adenocarcinomas.