Non-Smoking Lung Adenocarcinoma: Uncovering Divergent Tumor Architectures and Female Predominance in Never-Smokers.

INTRODUCTION: Smoking is the main risk factor for the development of lung adenocarcinoma (LUAD), but a significant and growing proportion of patients develop LUAD without prior tobacco use. It remains unclear how smoking-associated and non-smoking LUAD differ in terms of different growth patterns and tumor grading. METHODS: This retrospective cohort study included all consecutive patients with pathologic stage I non-mucinous lung adenocarcinoma who underwent curative surgery with complete resection (R0) between 2010 and 2020. Patients were stratified by history of smoking. Differences in demographic, pathologic and survival data were analyzed. RESULTS: 507 patients were included in this study. 409 (80.6%) patients were active or former smokers, 98 (19.3%) non-smokers. In the non-smoker group, there was a significantly higher proportion of females (75.5% vs. 45.7% in the smoker group, p < 0.001). Based on the current IASLC grading system, non-smokers had a higher proportion of tumors with favorable tumor grading (grade 1: 19.4% vs. 10.0%, p = 0.010; grade 3: 26.5% vs. 42.1%; p = 0.005). Lepidic-predominant tumors occurred almost twice as frequently in non-smokers as in smokers (19.4% versus 10.5%, p = 0.016). The opposite was true for solid-predominant tumors (6.1% vs. 14.4%, p = 0.027). It is noteworthy that this trend was observed independently in both females and males. With a median follow-up time of 69 months, multivariable Cox regression analysis showed a significant influence of smoking on recurrence-free survival (HR 1.84 [1.14-2.96], p = 0.012). CONCLUSION: Our results highlight that while non-smoking LUAD mostly affects women, the association of favorable histologic subtypes and never-smokers is independent of patient sex. Further research is warranted to clarify the molecular mechanisms associated with this observation.