Risk stratification in stage I invasive non-mucinous lung adenocarcinoma based on high-risk histopathologic features

High-risk histopathologic features (HRHFs) are recognized adverse markers in stage I lung adenocarcinoma (LUAD), but there is no simple way to integrate them into routine postoperative risk assessment. We aimed to develop and validate a pathology-only risk score based on four prespecified HRHFs.

Consecutive patients with pathologic stage I invasive non-mucinous LUAD who underwent R0 resection at a tertiary center (training cohort, n = 373) and two external hospitals (validation cohort, n = 257) were retrospectively analyzed. IASLC Grade 3, spread through air spaces (STAS), visceral pleural invasion (VPI) and lymphovascular invasion (LVI) were entered together into a multivariable Cox model for disease-free survival (DFS). Regression coefficients were translated into a points-based HRHF score (2 points for Grade 3; 1 point each for STAS, VPI and LVI; range 0-5), then grouped into low (0), intermediate (1-2) and high (≥3) risk strata. Discrimination was assessed in the training and combined external cohorts.

All four HRHFs showed adverse associations with DFS and remained in the multivariable model. The pathology-only predictor achieved 5-year time-dependent AUCs of 0.75 in the training and 0.73 in the validation cohort. The three-level HRHF score preserved most of this performance and produced clearly separated 5-year DFS across strata (training: 98.6%, 90.9%, 79.3%; validation: 96.5%, 91.8%, 71.7% for low, intermediate and high risk, respectively).

Four routinely reported HRHFs can be combined into a simple score that stratifies DFS risk within pathologic stage I invasive non-mucinous LUAD and may support more consistent, risk-aligned follow-up and adjuvant therapy discussions.