Prognostic impact of smoking in non-small cell lung cancer: histology-specific findings from a retrospective cohort study

Background: Smoking negatively influences postoperative outcomes in non-small cell lung cancer (NSCLC), but its prognostic effect may differ by histologic subtype. However, whether this impact varies between adenocarcinoma (ADC) and squamous cell carcinoma (SqCC) remains poorly understood. We aimed to quantify this difference using a pre-specified interaction analysis.

Methods: We retrospectively analyzed 8,103 patients who underwent curative-intent resection for pathologic stage I–III NSCLC between 2011 and 2022. Smoking status was categorized as never versus ever (smoking history). Overall survival (OS) and recurrence-free survival (RFS) were evaluated using multivariable Cox models with a smoking × histology interaction term and additional stage-stratified analyses.

Results: In the primary multivariable interaction model, smoking history was associated with worse OS in the reference ADC subgroup [hazard ratio (HR): 1.33; 95% confidence interval (CI): 1.10–1.60; P=0.003]. Histology-specific analysis showed that smoking history was associated with worse OS in ADC subgroup (HR: 1.24; 95% CI: 1.02–1.50; P=0.03), whereas in SqCC subgroup, the estimate was imprecise and binary smoking history did not clearly discriminate prognosis (HR: 1.01; 95% CI: 0.67–1.50; P=0.98). The smoking × histology interaction for OS was not significant (interaction HR: 0.74; 95% CI: 0.50–1.09; P=0.12).

Conclusions: Smoking history was associated with worse postoperative OS, with the most consistent prognostic signal observed in ADC subgroup. In SqCC cohort, binary smoking history showed limited prognostic discrimination, likely reflecting near-universal smoking exposure rather than absence of biological relevance. Smoking status should be interpreted within histologic context during postoperative risk assessment.