Lung cancer is the leading cause of death world wide. Tobacco smoking is the leading cause of deaths in patients of lung cancer. However according to several studies about 25% of lung cancer cases worldwide are not attributable to tobacco smoking. Non tobacco related lung cancer accounts for about 300,000 deaths annually worldwide. Thus, lung cancer in never smokers is the seventh leading cause of cancer deaths inÂ the world. It leads to more deaths world wide than pancreatic or prostate cancers. Although lung cancer in smokers is more common in males, lung cancer in never smokers occurs more frequently among women. In particular, there is a high proportion of never smokers in Asian women diagnosed with lung cancer.
Smoking-related carcinogens act on both proximal and distal airways inducing all the major forms of lung cancer while cancers arising in never smokers usually targetÂ the distal airways. No clear-cut risk factor has emerged that can explain the relatively high incidence of lung cancer in never smokers, however multiple risk factors, including environmental, hormonal, genetic and viral factors, have been implicated in the pathogenesis of lung cancer in never smokers.Â Environmental tobacco smoke (ETS) is a relatively weak carcinogen and can only account for a minority of lung cancers arising in never smokers.
There are four histological types of lung cancer and multiple minor or rare forms. For clinico-pathological reasons they are often divided into the broad categories of small cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). NSCLCs are further divided into three major types, squamous cell carcinoma (SCC), adenocar-cinoma and large cell carcinomas. Large cell carcinomas representsÂ poorly or undifferentiated forms of the other types of cancers, it is a vaguely defined entity, and criteria for its diagnosis vary widely. No clear cut genetic predisposition has been elucidated for the lung cancer in never smokers. Molecular epidemiology studies, in particular of the TP53, KRAS and epidermalÂ growth factor receptor (EGFR) genes, demonstrateÂ different mutationÂ patterns .
As historically lung cancer is considered a disease of the smokers, the clinical threshold for investigating the symptomatic never smoker can be higher, thus delaying the diagnosis such that never smokers present at later stages of disease. In support of this assumption, two recent retrospective studies from the US and Singapore found that a higher proportion of never smokers presented with advanced-stage disease compared with smokers . Also another unforeseen bias could be the predominance of the disease in the female gender .
There are major clinical differences between lung cancers arising in never smokers and smokers and their response to targeted therapies. For example, a multivariate analysis of patients with stages Iâ€“IV adenocarcinoma of the lung identified never smoking as an independent predictor of improved survival (5-year survival 23% for never smokers and 16% for current smokers).
A large population-based analysis of 12,000 patients with NSCLC in southern California also reported significantly improved survival for never smokers (hazard ratio (HR) for death = 1.09 for current and former smokers versus never smokers) .The above-mentioned facts clearly suggest that lung cancer arising in never smokers is a disease distinct from the more common tobacco-associated forms of lung cancer.
Further efforts are needed to identify the major cause or causes of lung cancers arising in never smokers before successful strategies for prevention; early diagnosis and treatment therapies can be implemented.
Risk factor for lung cancers in non-smokers
Environmental tobacco smoke
Residential radonÂ Â
Cooking oil vaporsÂ Â
Indoor coal and woodÂ Â
Viral factors: HPV 16/18Â Â
Lung cancer in never smokers is higher among women, particularly in Asia
Adenocarcinoma is the most frequent lung cancer subtype in never smokers
Some studies suggest that never smokers may present with advanced stage of lung cancer due to a higher clinical threshold for diagnosing lung cancer in non smokers.
Several studies have reported better survival for never smokers than smokers, independent of stage, treatment, co-morbidities and other known prognostic factors.
Note: Never smoker indicates persons with exposure to less than 100 cigarettes in a lifetime.