Lung Cancer in Chronic Obstructive Pulmonary Disease Patients, It Is Not Just the Cigarette Smoke

Pablo Sanchez-Salcedo; Javier J. Zulueta


Curr Opin Pulm Med. 2016;22(4):344-349. 

In This Article

Emphysema and Lung Cancer

Several studies have focused on the impact of emphysema on lung cancer. Our group and Wilson et al., from Pittsburgh, were the first to independently evaluate the role of emphysema (visually assessed on a low-dose CT) on lung cancer risk. Multivariate regression analysis in these studies showed that mere emphysema presence was associated with a three-fold increase in lung cancer risk (relative risk 3.13; 95% CI 1.32–7.44, and relative risk 3.56; 95% CI 2.21–5.73, respectively).[20,21] Interestingly, when emphysema was included in a multiple regression model together with airflow obstruction, only emphysema stood as a significant lung cancer predictor, suggesting that most of the lung cancer risk attributed to COPD could be in fact a result of emphysema per se. This held true even in the absence of airway obstruction.[20,21] In contrast to these results, other studies have found no significant association between emphysema and lung cancer.[19,23] Interestingly, a recent meta-analysis has revealed that the association between emphysema and lung cancer risk is only found when emphysema is assessed visually as opposed to quantifying it automatically with software analysis.[30] The reasons for this paradox are not clearly understood.

The importance of emphysema has also been demonstrated in nonsmoking populations. In 1759 never smokers who died from lung cancer, the presence of emphysema increased the risk of death from lung cancer by 66% (hazard ratio 1.66; 95% CI 1.06–2.59).[31] Furthermore, in a sample of 12 368 never smokers exposed to second-hand smoke who underwent lung cancer screening with low-dose CT in the International Early Lung Cancer Action Program, the prevalence of lung cancer among smokers (current and former) with emphysema was virtually the same as that seen in never smokers with emphysema (2.1 and 2.6%, respectively).[32] This observation was complemented in a multivariate regression analysis, where the presence of emphysema in never smokers increased the risk of prevalent lung cancer six-fold (OR 6.3; 95% CI 2.4–16.9), as compared with never smokers without emphysema. The impact of the presence of emphysema was higher in this population than in current and former smokers (OR 1.8; 95% CI 1.4–2.2, and OR 1.7; 95% CI 1.3–2.2, respectively).[32] The role of alpha-1 antitrypsin (A1AT) deficiency in never smoking populations that could lead to emphysema and thus, an increased lung cancer risk, has been indirectly addressed in a recent study. In 212 lung cancer cases where the A1AT genotype was assessed (30% had an A1AT deficient genotype), SS homozygous individuals showed an increased lung cancer risk. Interestingly, none of the lung cancer cases had evidence of emphysema on CT, suggesting there are other mechanisms of lung cancer development in this population.[33]

Emphysema severity and lung cancer risk has also been the subject of study. Using automated emphysema quantification, the studies by Kishi et al.[19] and Maldonado et al.[23] found no associations. On the other hand, Wilson et al.,[21] and Li et al.,[34] using visual emphysema quantification, found nonlinear significant associations, where mild emphysema better predicted lung cancer than traces or moderate/severe emphysema, respectively. Furthermore, in a lung cancer screening cohort from New York, a linear association between emphysema severity and risk of death from lung cancer was observed. However, the association was only significant for marked emphysema (more than half of the lung parenchyma).[35]

An important feature observed in studies that have assessed emphysema and airflow obstruction is that the highest lung cancer risk occurs in individuals where emphysema and airflow obstruction coexist. Lung cancer incidence density per 1000 person-years was two and 11 times higher in participants who had both diseases, when compared with those who had either emphysema or airflow obstruction, and healthy smokers (no emphysema and no airflow obstruction), respectively.[20] Moreover, for an equal degree of airflow obstruction, the presence of emphysema increased the odds of having lung cancer.[21] de-Torres et al. recently developed and validated a lung cancer screening score to stratify lung cancer risk within patients with COPD. In this score, emphysema showed the strongest association with lung cancer, highlighting the impact of emphysema on patients with airflow obstruction.[36,37]

Research in the field has gone even further to analyze the association between lung cancer location and regional emphysema. By dividing the lungs into different segments and assigning specific emphysema scores to each region (0: no emphysema; 1: <25% emphysema; 2: 25–50% emphysema; 3: 51–75% emphysema; and 4: >75% emphysema), Bishawi et al.[38] observed a correlation between the severity of regional emphysema and the likelihood of developing cancer in that specific location. Conditional regression analysis quantified this risk, where higher regional scores were associated with the presence of a malignant lung nodule (OR 1.34; 95% CI 1.11–1.62).[39] A recent study has also demonstrated an association between regional lung emphysema and larger tumors, along with a worse overall survival in nonsmall cell lung carcinomas.[40]

Similar to what we described for COPD, particular features have been observed in lung cancers that develop in emphysematous lungs. In a sample of 212 stage I lung cancers that underwent surgical resection, higher recurrence rates were observed in patients who had emphysema, an interesting finding considering that tumor characteristics, clinicopathological features from the primary tumor from CT and positron emission tomography, and the surgical procedure performed in each group were virtually the same.[41] In this sense, Murakami and coworkers[42] observed that lung cancers in emphysematous lungs were associated with a more intense intratumoral expression of matrix metalloproteinase 9, increased microvessel density, and a higher tumor proliferative activity than those occurring in patients without underlying pulmonary emphysema.