Preoperative CT Morphology and Tumor Extracellular Volume Fraction for Identifying Air-Space Spread in 1 - 3 cm Solid Lung Adenocarcinoma

Abstract

Background: Spread through air spaces (STAS) is associated with recurrence after limited resection of lung adenocarcinoma; however, reliable preoperative assessment remains challenging. Objectives: This study investigated whether routine computed tomography (CT) morphology and tumor CT-derived extracellular volume fraction (CT-ECV) contribute to the preoperative identification of STAS in 1 - 3 cm CT-solid lung adenocarcinomas. Patients and Methods: This retrospective study included 104 surgically resected tumors, of which 53 (51.0%) showed STAS. Twelve prespecified preoperative variables were analyzed using least absolute shrinkage and selection operator (LASSO) logistic regression with repeated nested stratified five-fold cross-validation. A full-cohort stratified 10-fold analysis was performed to describe variable retention at the minimum-error and one-standard-error penalty levels. Out-of-fold discrimination and calibration were assessed using the area under the receiver operating characteristic curve (AUC), Brier score, calibration intercept and slope, and a bootstrap confidence band. Interobserver agreement and CT-ECV remeasurement reproducibility were assessed using Cohen's kappa, the intraclass correlation coefficient (ICC), and Bland-Altman analysis. Results: At the minimum-error penalty, LASSO retained peripheral ill-defined opacity, tumor CT-ECV, and vascular convergence; at the one-standard-error penalty, only peripheral ill-defined opacity was retained. The out-of-fold AUC was 0.632 (95% confidence interval [CI], 0.522 - 0.737), and the mean fold-specific AUC was 0.628 ± 0.122. Calibration was limited (Brier score, 0.237; calibration intercept, 0.016; calibration slope, 0.645). Interobserver agreement for peripheral ill-defined opacity was almost perfect (kappa, 0.919; 95% CI, 0.834 - 0.981). Region-of-interest-based CT-ECV remeasurement on the same CT examinations showed good relative agreement (ICC, 0.890) but wide absolute limits of agreement (−8.62% to 8.91%). Conclusion: In surgically resected 1 - 3 cm CT-solid lung adenocarcinoma, peripheral ill-defined opacity was the most stable contributor to STAS assessment, whereas CT-ECV was less consistent. Modest discrimination and calibration limit clinical utility and support the need for validation in larger, multicenter cohorts before application beyond this population.