Lung cancer location drives lateralized ventilation loss and adverse outcome

Evidence suggests that the hypoxic tumor microenvironment (TME) contributes to the initiation and progression of non-small cell lung cancer (NSCLC). However, the degree to which tumor growth affects ventilation in the ipsilateral lung, and the clinical significance of this functional change, is not well understood. This study aimed to measure ventilation impairment on the tumor-bearing side using ventilation-perfusion scintigraphy (VPS) and to evaluate its association with patient survival.

This retrospective study included 365 patients with pathologically confirmed NSCLC diagnosed between 2009 and 2020. Tumor location and bilateral pulmonary ventilation were evaluated using VPS. Ipsilateral ventilation impairment was determined by comparing the relative ventilation contributions of each lung. Subgroup analyses were performed by histological subtype, tumor size, and anatomical location. Survival outcomes were assessed using Kaplan-Meier analysis and univariate Cox regression.

Quantitative VPS analysis showed that pulmonary ventilation on the tumor-bearing side was significantly lower than on the contralateral side (χ² = 17.74, p < 0.001), a pattern consistently observed in both LSCC (χ² = 16.30, p < 0.001) and LUAD (χ² = 4.81, p = 0.028) subgroups. Further analysis confirmed an association between tumor presence and reduced ipsilateral ventilation: in patients with right-sided tumors, ventilation was 4.08% ± 1.34% lower than in unaffected right lungs (52.74% vs. 56.82%, p = 0.003); a similar difference was observed in left-sided tumors (43.19% vs. 47.26%, p = 0.003). Subgroup analysis indicated significant impairment in LSCC (left lung: 42.51% vs. 49.02%, p = 0.002; right lung: 50.97% vs. 57.50%, p = 0.002), while LUAD showed a similar but non-significant trend (p > 0.05). Stratified analysis by tumor size demonstrated a consistent decline in ventilation across different tumor volumes. Spearman correlation analysis suggested that ipsilateral ventilation impairment was not solely explained by space-occupying effects (left lung: ρ = -0.225, p = 0.011; right lung: ρ = -0.322, p < 0.001). Survival analysis showed that patients with tumors in the lower-ventilated lung had a significantly higher risk of mortality (HR = 2.40, 95% CI: 1.28-4.51, p = 0.017).

This study is the first to systematically demonstrate that pulmonary ventilation is significantly reduced in the tumor-bearing lung of patients with NSCLC. This reduction is not solely explained by the space-occupying effect of the tumor, but may also reflect a more complex interaction between tumor biology and regional pulmonary function. In addition, the presence of a tumor in the lower-ventilated lung was associated with worse prognosis. These findings support the potential value of functional imaging in prognostic assessment and suggest that ventilation metrics may serve as functional biomarkers for risk stratification in NSCLC.