Because of the frequent clinical observation of pulmonary scars in the proximity of lung cancers, it has been speculated that scars may induce lung cancer. The PLCO Trial, a large prospective study of the effectiveness of CXRs in screening for lung cancer, provided a framework for us to evaluate this hypothesis. We observed increased risks of lung cancer following a CXR diagnosis of pulmonary scarring, confirming findings of a previous analysis of PLCO data that explored associations between a range of pulmonary abnormalities and several outcomes.15
To our knowledge, our study is the first to use CXRs to relate the laterality of pulmonary scarring to the risk of lung cancer and to characterize the temporal sequence between scarring and the subsequent development of cancer.
It is notable that the elevated risk was found for cancers that were ipsilateral, but not contralateral, to the scarring and/or fibrotic lesions. This finding supports the hypothesis that scarring is associated with a localized process of tissue damage and repair that may contribute to development of cancer. The absence of an increased risk of contralateral cancer argues against the alternative explanation that scarring is a marker for a systemic disease process that increases cancer risk more broadly. Indeed, the greater risk of lung cancer in persons with bilateral scarring (compared with those who had only unilateral scarring) can be explained by the fact that the former group has 2 lungs at increased risk of cancer (instead of only 1), rather than by a difference in the disease process between the 2 groups. Likewise, lung cancer risk was especially high in persons with diffuse scarring, but this elevation arose because diffuse scarring was largely bilateral, while the magnitude of lung cancer risk ipsilateral to the scarring was actually similar for diffuse and discrete scarring.
Another important finding of our study regards the temporal pattern of lung cancer in relation to scarring. Previous evidence has been inconclusive on whether scarring causes or results from the cancer (ie, reverse causality). We found that lung cancer risk in relation to pulmonary scarring remained elevated for 12 years following CXR detection of scarring and was similar in magnitude in each time interval. Although reverse causality could still play a role, we saw no association between detection of the 2 conditions (scarring and lung cancer) on the same baseline film, and an elevated risk of lung cancer related to scarring was observed even when we excluded subjects who had baseline CXRs suggestive of lung cancer. Indeed, reverse causality becomes less likely as an explanation for the associations seen during extended follow-up () because it seems improbable that a lung cancer that had caused a scar would have remained otherwise silent for many years subsequently.
After considering alternative explanations, we suggest that our observations are consistent with a possible pathway connecting pulmonary scarring (or closely associated lung processes, such as inflammation) and the subsequent development of lung cancer. To put our findings into context, there are other lines of evidence that support a role for pulmonary inflammation and scarring in the development of lung cancer.22
Fibrotic processes may induce or promote lung cancer by causing excessive or persistent localized inflammation at sites of wounding and repair.10
Inflammatory processes have been shown to contribute to damage of the lung epithelium.9
Cytokines such as tumor necrosis factor and interleukin 1, secreted by infiltrating macrophages and lymphocytes, stimulate the production of other cytokines as well as proliferation of lung epithelial cells.9
Inflammatory cells also produce reactive oxygen species that can induce chromosomal strand breaks, leading to DNA mutations when inaccurate repairs accumulate.23
Consistent with these findings, inflammatory injury due to pulmonary scarring is characteristic of inflammatory lung diseases, such as COPD and pneumonia, which are themselves associated with an increased risk of lung cancer independent of smoking.2-6
High serum levels of C-reactive protein, which is a marker of inflammation, have been shown to be associated with an elevated risk of lung cancer.24
Finally, recent evidence links polymorphisms in inflammation-related genes, such as interleukin 1α and interleukin 1β, to altered susceptibility to lung cancer.25
A limitation of our study was the reliance on CXRs to diagnose the presence of scarring. Investigators from the PLCO Trial previously reported only fair agreement in scarring diagnoses across successive CXRs, which were interpreted independently of one another (ie, κ=0.40 for paired CXRs obtained at different times and interpreted by different radiologists).15
This level of agreement is similar to that for other CXR diagnoses, such as COPD and emphysema (κ=0.38) and bone and soft tissue lesions (κ=0.45).15
Without a reference test, we could not estimate the sensitivity and specificity of CXRs for detecting true pulmonary scarring lesions. Another limitation of our study was that we were not able to fully characterize the relationship between locations of the scars and subsequent cancers owing to different descriptive classifications because scarring was reported according to the region of the lungs on a single-view posteroanterior CXR, whereas cancers were localized according to the lobe of the lungs.
The association of scarring and lung cancer appeared stronger for lesions in the right lung than in the left lung. We believe that this difference could be due to misclassification of nonscar lesions as scars in the left lung. There were many more scars reported in the left lung, particularly in the lower part, than in the right lung. The position of the heart in the left lung partly obscures the left lower lobe on the CXR, which may cause difficulty in distinguishing scarring from other lesions, such as linear atelectasis. Also, pleural scarring (eg, due to asbestosis) can be mistaken for scarring within the lung itself, and this error may occur more commonly in the left hemithorax than in the right because of the unique anatomy of the left lung. Alternatively, one could hypothesize that some types of scarring common in the left lower lobe may not be related to cancer risk. For example, in patients with cardiac disease or following abdominal surgery, the left lower lung often becomes atelectatic, which may lead to scarring over time. Because we did not have strong evidence that the biological effects of scarring would differ for the 2 lungs, we considered the 2 lungs together in our analyses. To the extent that the results for the left lung may have reflected a stronger likelihood of misclassification of scars and perhaps less deleterious scarring processes, combining the analyses for the 2 lungs would have underestimated the HRs for ipsilateral cancer. More generally, we note that the difficulties with CXR diagnosis of scarring that we discuss herein together serve to attenuate the apparent association between scarring and cancer and that future detailed evaluations with a better imaging modality (eg, computed tomography) would be expected to provide more definitive evidence regarding this association.
As the major risk factor for lung cancer, cigarette smoking contributed to some of the excess of lung cancer risk associated with scarring. Scarring was more common among current and former smokers and was related to the cumulative amount of tobacco use. However, an association between scarring and lung cancer persisted even after adjustment for smoking. Likewise, we observed a similarly elevated HR associated with scarring across strata of smoking status or previous diagnosis of COPD, which is more prevalent among smokers. We therefore believe that the increased lung cancer risk among individuals with pulmonary scarring is not entirely explained by smoking habits. We were unable to examine other medical conditions or exposures, such as work-related exposures, as the source of scarring because such data were not collected in the trial.
Our conclusions were supported by a number of strengths of the study, which included prospective collection of CXR and lung cancer data and a large sample size. Although diffuse fibrosis frequently manifests clinically with respiratory symptoms, less extensive pulmonary fibrosis is usually clinically silent. This situation has complicated the systematic study of scarring and its potential adverse outcomes. Thus, a strength of our study was that it incorporated CXR diagnoses of scarring and/or fibrosis from mostly asymptomatic subjects, who received a CXR examination for screening purposes rather than evaluation of scar-related symptoms. Also, detection bias was minimized because lung cancer in subjects with and without scarring would be equally likely to be detected by CXR screening and subsequent evaluation.
In conclusion, our findings provide support for a model whereby pulmonary scarring and localized inflammation promote subsequent development of lung cancer. Lung scarring can result from a variety of infections, environmental exposures, and pulmonary diseases. Further research is needed to elucidate the biological mechanisms underlying the associations between pulmonary scarring, inflammation, and lung cancer. Additional research is also necessary to determine whether asymptomatic persons with CXR-detected pulmonary scarring would benefit from clinical monitoring for the development of lung cancer.