BACKGROUND.To propose ‘never‐smoking nonsmall cell lung cancer (NSCLC)’ as a separate entity, the clinicopathologic differences of operable NSCLC between never‐smoking patients and patients with a history of smoking were investigated.METHODS.The medical records of 1405 patients with primary NSCLC who underwent a complete resection at the study institution from 1974 through 2004 were reviewed for clinicopathologic variables and postoperative survival.RESULTS.The proportion of never‐smoking patients with NSCLC has been significantly increasing over 30 years, from 15.9% in the 1970s to 32.8% in the 2000s. A significantly greater proportion of female patients or adenocarcinoma patients was found in the ‘never‐smoking NSCLC’ group in comparison to the ‘smoking NSCLC’ group (85.8% vs 11.2% and 87.8% vs 49.1%, respectively). The proportion of pathologic stage IA disease for the ‘never‐smoking NSCLC’ group was significantly higher than that for the ‘smoking NSCLC’ group (40.1% vs 25.4%; P < .0001). With regard to both overall and cancer‐specific survival, the ‘never‐smoking NSCLC’ patient group was significantly superior to the ‘smoking NSCLC’ group. In addition to smoking status, the factors found to be significantly associated with the postoperative survival rate were sex, histologic type, T classification, and N classification by univariate analyses. A multivariate analysis revealed never‐smoking status to be an independent prognostic factor in addition to pathologic T and N classification.CONCLUSIONS.The differences in the clinicopathologic factors and survivals between the ‘never‐smoking NSCLC’ patient group and the ‘smoking NSCLC’ group suggest that NSCLC in never‐smokers should be considered a separate disease entity. Cancer 2008. © 2008 American Cancer Society.

Recent interest in lung cancer without a history of tobacco smoking has led to the classification of a distinct disease entity of 'non-smoking-associated lung cancer'. In this review article, we have made an overview of the recent literature concerning both the epidemiology and clinical features of lung cancer in never smokers, and have brought 'non-smoking-associated lung cancer' into relief. The etiology of lung cancer in never smokers remains indefinite although many putative risk factors have been described including secondhand smoking, occupational exposures, pre-existing lung diseases, diet, estrogen exposure, etc. Non-small cell lung cancer (NSCLC) in never smokers is clinically characterized by an increased incidence in females and a higher occurrence of adenocarcinoma in comparison to NSCLC in ever smokers in both surgical patients and non-resectable advanced-stage patients. Furthermore, the prognosis of never-smoking NSCLC is better than that of smoking-related NSCLC in both surgical patients and non-resectable advanced-stage patients. Recently recognized novel gene mutations such as EGFR (epidermal growth factor receptor) mutations are largely limited to never smokers or light smokers, and the expression of this gene is responsible for the clinical efficacy of gefitinib, an epidermal growth factor receptor-tyrosine kinase inhibitor. NSCLC with the EML4 (echinoderm microtubule-associated protein-like 4)-ALK (anaplastic lymphoma kinase) fusion gene is also more likely to occur in never smokers and in those with adenocarcinoma histology, and is expected to benefit from ALK inhibitors. In consideration of the future increase in never-smoking NSCLC or 'non-smoking-associated lung cancer', both clinical trials and investigations are needed.

A positive association between Brachyury and Slug and IL-8, and a negative association with E-cadherin may lead to invasiveness and metastasis in primary lung carcinoma. Brachyury mRNA expression is a significant predictor of poor prognosis in primary lung carcinoma.

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