Lung cancer has been linked to the changes in lung function characteristic of chronic obstructive pulmonary disease (COPD) and to the changes in lung morphology seen in emphysema. It seems that a common thread of smoking-induced lung injury can be traced to all three diseases. However, the association is not as straightforward as it may seem; for example, even never-smokers with emphysema have an increased risk of lung cancer. Whether lung cancer, COPD, and emphysema are linked by common genes, mechanisms, causes, or a combination thereof, understanding the associations between them has become a priority for research regarding tobacco-related illnesses. A better delineation of the relationships between these three entities may lead to significant improvements in the effectiveness of lung cancer screening programs, and to reductions in the morbidity and mortality associated with these deadly diseases.
Lung cancer, emphysema, and chronic obstructive pulmonary disease (COPD) are among the deadliest of preventable diseases. Lung neoplasms are the leading cause of cancer deaths worldwide, outnumbering the combined death toll attributable to colon, prostate, and breast cancers.[1,2] COPD, characterized by persistent airflow limitation and chronic inflammation of the airways, is also a leading cause of death, second only to cardiovascular diseases.
Lung cancer, COPD, and emphysema are all caused or aggravated by smoking. While the causal link with tobacco is obvious, and has been made clear by a plethora of scientific studies, the past decade has seen renewed interest in the links between lung cancer, COPD, and emphysema (a chronic lung disease resulting from damage to the alveoli and resulting in breathlessness). Recent evidence provided by screening studies has shown that patients with tobacco-related altered lung function (COPD) or altered morphology (emphysema) are particularly susceptible to lung cancer. Not surprisingly, chronic inflammation has been postulated as the obvious culprit linking COPD and lung cancer. Inflammation causes cellular damage while promoting cell proliferation, hence providing a suitable environment for oncogenic mechanisms to prosper. However, the association between emphysema and lung cancer is not as intuitive, despite its being so powerful that even nonsmokers with emphysema are at risk for lung cancer.
The challenge of finding common pathways is not only academic, but is a major concern in the current era of lung cancer screening, since screening programs are most effective when high-risk populations are selected. A better understanding of the common threads that link emphysema, COPD, and lung cancer might help us make lung cancer screening more cost-effective by enabling us to offer it to smokers with the greatest risk, but also simply make screening more effective—by including younger, less-exposed individuals who are nonetheless at risk, including some nonsmokers.
Evidence Linking Alterations in Lung Function and Morphology With Lung Cancer
The association between altered lung function and lung cancer was first described in the 1980s by Skillrud et al and Tockman et al.[6,7] It is now clear from a growing body of evidence, including a recent meta-analysis, that tobacco-related airflow obstruction conveys an independent two- to fourfold increase in lung cancer risk, even when the cohorts being compared are controlled for smoking.[8-12] This holds true for both men and women. Interestingly, the timing of a COPD diagnosis and disease severity may play a role in the development of lung cancer, and not necessarily in the way one might expect.[13,14] In some studies, lung cancer appears to be more common in patients with a recent COPD diagnosis than in those with longstanding obstructive airway disease, and it may be two to three times more common in cases of mild to moderate obstruction than in more advanced disease—although the data about the latter association are mixed. An increased frequency of lung cancer in patients with less severe COPD seems especially common when screen-detected lung cancers are considered. In one screening study, the vast majority of lung cancers (94%) appeared in patients with early-stage COPD. Even those with altered lung function, but with a forced expiratory volume in 1 second (FEV1) exceeding 90% of predicted values, have twice the risk of smokers without COPD. Indeed, existing evidence appears to support a survivor effect, suggesting that lung cancer may appear early on in the progression of COPD. This finding is important because it suggests that those who stand to benefit most from screening are precisely the ones who might tolerate invasive therapies with curative intent despite a COPD diagnosis. However, not all studies agree, and in any event, the survivor effect can only be partially responsible for this finding, since both the Pittsburgh Lung Screening Study (PLuSS) and data from the National Health and Nutrition Examination Survey suggest the opposite (ie, that lung cancer is more common in patients with moderate to severe airflow obstruction).[9,17]
The evidence linking emphysema and lung cancer is even more intriguing. The widespread availability of CT scanners and the advent of lung cancer screening using low-dose CT have provided ample evidence suggesting that the morphologic changes associated with emphysema may be the single most powerful predictor of lung cancer risk for any given individual. In a study by de Torres et al in patients enrolled in a lung cancer screening program, lung cancer was three times more likely in those with emphysema. Similar results have been reported in other screening cohorts and even by the National Lung Screening Trial (NLST) investigators.[9,18] In the NLST, the presence of emphysema was clearly associated with an increased risk of death from lung cancer (hazard ratio, 1.56; 95% CI, 1.20–2.04). This finding has practical implications for screening, since restricting inclusion criteria by aiming at, for example, the 60% of individuals at highest risk for death from lung cancer would still account for almost 90% of CT-preventable lung cancer deaths while reducing both false-positives and the number needed to screen to prevent one lung cancer death. Unfortunately, the prevalence of both emphysema and COPD in the NLST was low (7% and 5%, respectively). It is likely that the use of emphysema as a screening criterion would provide an additional means of identifying at-risk individuals who might benefit from screening, as evidenced by a landmark study. Emphysema is such a powerful predictor of risk that subjects not meeting NLST age or smoking criteria but who had emphysema might also benefit from screening. Furthermore, it is quite clear from available epidemiologic evidence that even never-smokers with emphysema are at greater risk for lung cancer, suggesting that emphysema by itself, whether smoking-related or not, is a powerful risk factor. Data from the International Early Lung Cancer Action Program (I-ELCAP) screening cohort have shown that never-smokers with emphysema have a sixfold increase in lung cancer risk compared with never-smokers without emphysema. The combined emphysema–pulmonary fibrosis phenotype is also associated with a higher risk of lung cancer, although fibrosis appears to be more carcinogenic than emphysema in some series.
The evidence in favor of emphysema as a putative risk factor for lung cancer independent of tobacco exposure can be contradictory. Some studies favor an association between emphysema severity and lung cancer risk, while others find no such link.[9,22,23] Of note, some studies in which emphysema severity has been determined by quantitative methods have failed to find an association with lung cancer.[10,24] Intriguingly, however, a recent meta-analysis reported that automated quantification of emphysema was inferior to visual assessment, suggesting that the association with lung cancer risk is qualitative, not quantitative. The reasons for the differences between qualitative and quantitative assessments of emphysema and an association with lung cancer are not understood. One possibility is that automatic software quantitation is too sensitive, while visual emphysema determination only identifies areas of obvious parenchymal destruction. Perhaps, as was the case with advanced-stage COPD in some studies, patients with severe emphysema have outlived their chance of developing lung cancer, while it is those with traces of the morphologic changes on CT and preserved lung function who are at greatest risk. In any case, with current technology and knowledge, only visual qualitative determination of emphysema on low-dose CT has a role in assessing a patient’s risk for lung cancer.
The strength of the bond linking emphysema with lung cancer risk may also be dependent on regional lung differences. For example, lung nodules in the upper lobes are more likely to be cancer than those located in the lower lobes. This finding may have more to do with upper lobe–predominant emphysema related to smoking than anything else. In fact, when lung cancer and emphysema coexist, the cancer tends to appear in an area affected by emphysema rather than in a healthier-appearing region of the lung. This is an intriguing finding, given that there is less lung tissue in the emphysematous lung parenchyma for a cancerous clone to appear in than there is in healthier-appearing lung exposed to the same carcinogens. In our opinion, this seemingly counterintuitive finding lends support to the notion that the physiologic processes that are responsible for the morphologic changes typical of emphysema are also involved in lung carcinogenesis.
Finally, it should be noted that the severity of peritumoral emphysema may affect overall survival, suggesting that emphysema is not only associated with lung cancer, but may condition its biology as well. Not surprisingly, recent research has revealed that interactions between lung cancer cells and the surrounding tumor stroma may be responsible for tumor progression and metastasis. A recent study reported that matrix metalloproteinase-9 (MMP-9) expression in intratumoral stromal cells, typical of lung tumors arising in emphysematous lungs, is associated with more aggressive lung cancers. This might explain why lung cancer in a patient with underlying emphysema is associated with a worse prognosis. It seems that emphysema provides the right kind of environment for tumors to develop and progress.
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