Our prospective analysis indicates that among women, there is a different effect of smoking dose across histologic types of lung cancer, with greater variation in risk for smoking duration than for the number of cigarettes smoked/day. Upon cessation, the risk for small cell carcinoma drops more rapidly than the other histologic types.
Quitting smoking clearly reduces the risk of developing any type of lung cancer, compared with continuing. Our findings showing the decline in risk after quitting is strongest for small cell carcinoma (followed by squamous cell carcinoma, large cell carcinoma, and adenocarcinoma, respectively), is supported by previous studies assessing the relation of cessation and risk of lung cancer by histologic type, as well as those studies indicating that this histologic type is most associated with smoking.7,13
This finding is meaningful as small cell carcinoma of the lung has the most aggressive clinical course of all pulmonary tumors, with a median survival of 16-24 months with current forms of treatment for patients with limited-stage disease.14-16
The strength of the association with tobacco smoke may differ by histologic type due to lower exposure of tobacco smoke particles to sites that are more peripheral in the respiratory tract. Squamous and small cell carcinoma occur mainly in the large central bronchi, an area highly exposed to tobacco smoke, compared to adenocarcinoma, located in the peripheral sections of the lung, and large cell carcinoma, located in the peripheral and subpleural regions.17
Although cigarette design changes and smoking behavior may have allowed adenocarcinoma to become more strongly associated with cigarette smoking than it has been in the past, through an increase in the dose of potent tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)18,19
and smoker compensation (more frequent puffs per cigarette, larger puff volumes, deeper inhalation),20
the effect of smoking duration still has a substantially different effect across histologic types compared to the number of cigarettes smoked/day. Our finding that smoking duration is a more important predictor than smoking intensity for lung cancer, is supported by two large studies,21,22
and this duration effect may account for most of the difference in the effect of smoking between histologic types, obscured when using pack-years.23,24
Some other aspects of smoking do not seem to have different effects on the histologic types, such as age at starting smoking. However, as 63% of our cohort began smoking between 18 and 21 years of age, and less than 5% started at 30 years of age or later, there may not have been enough variability to detect a different effect of age at starting smoking according to histologic type. Our results also indicated that the association between cigarettes smoked/day by former smokers and risk of the four histologic types are similar when modeled as continuous variables. Former smokers who quit smoking before 1976 only provided information on the amount of cigarettes smoked before quitting; thus, we cannot fully capture the smoking history of a former smoker, which may prevent us from precisely estimating the risks associated with smoking intensity for this group.
Five recent prospective cohort studies examined cigarette smoking and subsequent risk of lung cancer by histologic type, although none formally compared risk estimates across the histologic types. Among current male smokers in the Japanese Public Health Center Study, the magnitude of relative risk was greater for smoking duration than the number of cigarettes smoked/day when modeling these variables simultaneously, similar to our results, and a more rapid increase in risk with increasing duration was observed for squamous cell and small cell carcinomas combined (n=101; Ptrend, duration
= 0.06), compared to adenocarcinoma (n=78; Ptrend, duration
In the Norwegian male cohort, a more rapid increase in risk with increasing cigarettes per day was observed for small cell (n=45) and squamous cell carcinoma (n=99), compared with adenocarcinoma (n=42).26
Both studies had too few cases in women to provide separate estimates by histologic type and only had smoking information reported by participants at baseline.
Among current male smokers in the Korean24
and Japanese studies,25
and female and male smokers in the Copenhagen cohort,27
risk increased with higher pack-years for adenocarcinoma, squamous cell carcinoma and small cell carcinoma, but a steeper increase was observed for squamous and small cell carcinoma. In the Iowa Women’s Health Study, there was a more consistent risk reduction with smoking cessation for squamous/small cell carcinoma than with adenocarcinoma. Compared with current heavier smokers (≥ 20 pack-years), there was a significantly lower risk of squamous/small cell carcinoma (n=39) but a non-significantly lower risk of adenocarcinoma (n=31) among former heavier smokers in the first 10 years of smoking cessation.7
None of these studies evaluated large cell carcinoma.
In our study, repeated measures on smoking status collected every two years have mitigated misclassification due to changes in smoking status over time. Follow-up is very high in the Nurses’ Health Study and there are high rates of histologic confirmation of primary lung cancer. The accuracy of the classification of lung cancer by histologic type may not be perfectly consistent. However, as standard diagnostic criteria are applied, the classifications of cell type are likely to be reasonably accurate. One study compared reports to the Iowa Cancer Registry with an independent uniform review by 2 board certified surgical pathologists, and found that the histologic type diagnosis obtained by the registry was reasonably reliable, with an overall percent exact agreement of 72%.28
Small cell carcinoma had the highest sensitivity (94.1%) while large cell carcinoma had the lowest sensitivity (21.9%), explained in part by the absence of specific features that would permit a diagnosis of adenocarcinoma or squamous carcinoma. Specificity was lowest for adenocarcinoma (84.4%). Inaccuracy in the classification of histologic type may prevent us from observing a difference in risk for the various smoking factors across the four histologic types of lung cancer.
Depth of inhalation and tar content were not accounted for in this analysis. Data on tar is not available in this cohort; however, there is evidence that compensatory changes are observed with “reduced yield” cigarettes, such as increasing the number of cigarettes smoked/day, reducing the benefit of lower-tar cigarettes and potential for residual confounding by tar content.29,30
We only had data on depth of inhalation for current smokers, and this aspect was only queried on two early questionnaires, so we could not account for changes in smoking inhalation behavior over follow-up. As most adenocarcinoma occurs in the periphery of the lung, which could indicate deeper inhalation, there may be different effects of inhalation across the histologic types. The data on inhalation in the study by Prescott et al. suggest that inhalation may modify the effect of pack-years, showing that an increase in risk of lung cancer with increasing pack-years is stronger for inhalers compared to non-inhalers.27
We did not include exposure to passive smoke in this analysis; however, passive smoke exposure is unlikely to be an important factor among ever smokers.
In summary, our findings indicate that smoking is a cause of all major types of lung cancer in women, with the risk of small cell and squamous cell carcinoma increasing most rapidly with increasing smoking duration. The risk of all types of lung cancer examined decreases after quitting, with risk of small cell carcinoma decreasing most rapidly after cessation. These results are fully appreciated at long durations of smoking and smoking cessation. Preventing smoking initiation and encouraging smoking cessation should continue to be the focus of public health efforts to reduce lung cancer incidence and mortality.
“What this paper adds”
Smoking increases risk of all major histologic types of lung cancer. Case-control and cohort studies have previously looked at this association across histologic type, but have not used formal statistical tests to evaluate heterogeneity. Due to a limited number of cases, some cohort studies combined histologic types or did not perform histologic analyses in women. Utilizing repeated measures of smoking status, and the high follow-up rates in the Nurses’ Health Study, this study is the largest cohort study to evaluate the relation between aspects of smoking and risk of lung cancer by histologic type in women, while applying new statistical techniques.
Our prospective analysis indicates that among women, there is a different effect of smoking dose across histologic types of lung cancer, with greater variation in risk for smoking duration than for the number of cigarettes smoked per day. Upon cessation, the risk for small cell carcinoma drops more rapidly than the other histologic types. These different results by histologic type are fully appreciated at long durations of smoking and smoking cessation. Preventing smoking initiation and encouraging smoking cessation should continue to be the focus of public health efforts to reduce lung cancer incidence and mortality.