Patients harboring anaplastic lymphoma kinase (ALK) or rearranged during transfection (RET) rearrangements are usually diagnosed at a relatively late stage with nodal and distant metastasis, and rapid progression course of ALK/RET fusion-positive lung cancer were well-known. However, clinical characteristics and course of pre-/minimally invasive lung adenocarcinoma harboring ALK or RET fusions are poorly described. Identifying patients with gene fusions at early stage may offer surgical options that could cure those patients.We retrospectively included patients with surgically resected pre-/minimally invasive lung adenocarcinomas harboring epidermal growth factor receptor (EGFR) mutations or ALK/RET rearrangements, and further compared the patient clinical characteristics, nodule natural course, and survival outcomes. Radiological characteristics including ground-glass component, cystic airspace, pleural attachment, etc. were specially assessed for this study. EGFR (exons 18-22) was detected by Sanger sequencing and quantitative real-time polymerase chain reaction (qRT-PCR) was used to analyze the ALK/RET rearrangements. Lung cancer-specific survival (LCSS), relapse-free survival (RFS), and overall survival (OS) were all evaluated.Of 238 patients with pre-/minimally invasive lung adenocarcinomas, 226 patients had EGFR mutations, 7 patients had ALK fusions, and 5 patients had RET fusions. Average age at surgery was 45.3 years for ALK/RET-positive group and 52.6 years for EGFR-positive group (P=0.049). Radiologically, among the 12 patients with ALK/RET fusions, the majority of lesions (10/12) manifested as mixed ground-glass opacities (mGGOs), which was significantly more prevalent when compared with patients with EGFR mutations (83.4% vs. 24.3%, P<0.001). Moreover, a substantial proportion of cystic airspace was found in ALK/RET-positive group but not in EGFR-positive group (66.7% vs. 14.2%, P<0.001). Among four patients with ALK/RET fusions undergoing surveillance over 1 year before surgery, two of them developed rapid radiologic progression. The 5-year LCSS and RFS were 100%, 100% for ALK/RET-positive group, and 100%, 100% for EGFR-positive group, respectively.ALK/RET-positive pre-/minimally invasive lung adenocarcinomas were mostly characterized as mGGOs with cystic airspace developing rapid nodule progression, and no recurrence occurred during long-term follow-up after resection. This provides insights into proper curative surgery timing in the management of patients with gene fusions. However, these findings must be treated with caution and validated in future multi-center studies with larger sample size.2023 Translational Lung Cancer Research. All rights reserved.