Background
Chronic inflammation plays a key role in carcinogenesis via disordered necrotic cell death, subsequent epithelial proliferation, and suppressed immunity [
1]. Like other organs, chronic inflammation in the lung, such as chronic obstructive pulmonary disease (COPD), is associated with an increased risk of lung cancer, mainly related to repeated airway epithelial injury and accompanied high cell turnover rates [
2‐
4].
Bronchiectasis (BE) is a representative chronic inflammatory airway disease characterized by abnormal and permanent dilatation of the bronchi, accompanied by high levels of inflammatory cytokines [
5]. Unlike COPD, however, the impact of the inflammation accompanying BE on lung cancer remains unclear.
Considering reports on the influence of inflammatory signaling in carcinogenesis, chronic inflammation caused by BE might be associated with an increased risk of lung cancer because of the local effects of chronic inflammation caused by repeated airway injury and impaired mucociliary clearance. If this postulate holds, it is reasonable to think that the incidence or prevalence of cancer should be increased close to the pre-existing BE in location [
3,
6,
7].
However, there are only limited data on an association between BE and the risk of lung cancer. A few studies reported that patients with BE had elevated levels of serum transforming growth factor-β1 (TGF-β1), which is a potential protective factor against carcinogenesis [
5,
8,
9]. In patients with cystic fibrosis showing radiological features of BE, the cystic fibrosis gene mutation was inversely associated with some malignancies [
10]. This supports the hypothesis that the association between BE and lung cancer is different from the previously reported role of inflammation in lung cancer carcinogenesis.
The aim of this study was to assess the association between BE and the risk of lung cancer by analyzing the lobar location of lung cancer in patients with underlying BE.
Discussion
This study assessed the association between pre-existing BE and newly diagnosed lung cancer in terms of the lobar distribution. It revealed that the presence of pre-existing BE was associated with a significantly lower risk of lung cancer in the same lobe. These results are interesting and suggest another aspect of the relationship between chronic inflammatory airway diseases and lung cancer. In addition, our data also provide information about the prevalent location of lung cancer and BE in patients which the two diseases coexist. Compared to lung cancer, which most commonly involved the right upper lobe, BE most commonly involved the left lower lobe. To our knowledge, this would be the first description of the association between BE and lung cancer by location of the disease detected using CT at the level of lung lobes [
6,
17].
There is limited evidence for the pathophysiological mechanism of the protective effect of BE in local carcinogenesis shown in our study. However, indirect biological plausibility exists. There are reports of elevated serum TGF-β1 levels in patients with BE [
5]. In normal and premalignant cells, TGF-β enforces homeostasis and tumor-suppressive effects by regulating cell-autonomous cytostasis, differentiation, and apoptosis. In addition to its direct inhibitory effects, TGF-β can restrict epithelial cell proliferation and carcinogenesis by blocking the production of paracrine factors in the stromal cells [
8,
9]. Other plausibility includes the
CTFR gene. A case–control study suggested that the ΔF508 deletion in the
CFTR gene in patients with cystic fibrosis, which shows radiological features of BE, is an important protective variant for lung cancer risk [
10]. However, more research is needed to identify a biological mechanism that can clearly explain our findings.
Since previous studies report a positive association between the chronic inflammation in COPD or smoking and the risk of squamous cell carcinoma, it is notable that the majority of patients in our study were diagnosed with adenocarcinoma [
2,
18]. Moreover, among the patients diagnosed with lung cancer, 46 % were never-smokers, and 65 % had no or mild emphysema. The high proportion of adenocarcinoma, never-smokers, and non-emphysematous subjects among the diagnosed lung cancer patients suggests that the majority of lung cancers in patients with pre-existing BE occurs independently of chronic inflammation. These findings can support our theory that the chronic inflammation caused by BE is not associated with an increased risk of lung cancer.
Previous epidemiological reports have aimed to evaluate the association between prior lung diseases and the risk of lung cancer. They showed that some chronic respiratory diseases, including bronchitis and emphysema, are positively associated with the risk of lung cancer [
17,
19]. However, these efforts focused mainly on evaluating diseases and chronic inflammation associated with smoking, a major contributor to lung cancer. To date, the mechanism of airway inflammation in BE, and the association between BE and lung cancer remains unclear. Recently, a nationwide cohort study from Taiwan reported that patients with underlying BE had a 2.36-fold increased risk of lung cancer compared to patients without BE. However, this study has limitations in confirming the disease status only by the diagnosis codes provided from the registered hospitals, and including only inpatients as subjects diagnosed with BE, who had significantly higher rate of comorbidities possibly related to cancer. Moreover, the study used a database that did not contain information on smoking status of the participants, which is a possible strong confounding factor when evaluating risk of lung cancer. The study also could not provide any information about the severity or location of BE and the histological type of lung cancer, which is important when discussing the possible effects of BE and inflammation on the risk of lung cancer [
20]. Although our study included a relatively small number of subjects, we were able to obtain detailed information about the diagnosed BE and lung cancer for each patient, and the data on the location of BE and lung cancer made it possible to perform analyses within levels of lung lobes. Results of our study are in concordance with a recent case–control study from South Korea which reported that the concomitant presence of BE was associated with a lower risk of lung cancer in COPD patients [
21]. Although BE is a representative chronic inflammatory airway disease causing permanent dilatation of the bronchi and is accompanied by high levels of inflammatory cytokines, our results suggest that the chronic inflammation caused by BE might produce different cytokines compared with other airway diseases and acts in a different way in carcinogenesis of the lung.
The main strength of our study is that the presence of lung cancer and BE was assessed with chest CT, a precise means of evaluating the location of the disease at the level of the lung lobes. In addition, because we analyzed the association between the two diseases by location within patients known to have both diseases, the possible confounding factors of the risk of lung cancer in each patient (e.g., age, gender, and smoking status) could be ignored in our study.
To interpret our results correctly, we should consider the limitations of this study. First, given its retrospective design, by selecting patients who were diagnosed with lung cancer, there might have been selection bias enrolling patients at higher risk of, or more susceptible to, lung cancer. However, since the study design was powered to evaluate the association between BE and lung cancer by the locations of the two diseases within each subject, rather than an epidemiology study evaluating a certain population, possible selection bias is not expected to have contributed to the significant results of our study. Second, our data contains no detailed clinical information on the history of BE (e.g. frequency of exacerbations, type of infection, length of follow up, and received treatments), which can be an important issue when discussing the role of chronic inflammation in BE. Lastly, due to the limited data collected on the field of inflammation and carcinogenesis related BE, the validity of the potential explanations on our findings and the role of chronic inflammation might be low. Nevertheless, considering the limited data and difficulty to perform large-scaled studies on the association between BE and lung cancer, our results still would provide novel and relevant information, and motivation for further studies.
Although this study was not a longitudinal study following BE patients, it is reasonable to believe that in the patients evaluated in our study, BE preceded the development of lung cancer since BE is generally accepted to be a chronic condition following infection in childhood, while lung cancer usually develops within years of the initial diagnosis [
22]. Moreover, patients were excluded if they had BE secondary to mechanical effects caused by lung cancer. Therefore, despite the retrospective design, we insist that our results represent a temporal relationship between BE and lung cancer, rather than a coincidental finding.
Acknowledgements
This study was non-financially supported by a multidisciplinary research grant-in-aid from the Seoul Metropolitan Government Seoul National University (SMG-SNU) Boramae Medical Center.