Regional Emphysema of a Non-Small Cell Tumor Is Associated with Larger Tumors and Decreased Survival Rates

Abstract

Rationale: Chronic obstructive pulmonary disease is associated with a worse overall survival in non-small cell lung cancer. Lung emphysema is one component of chronic obstructive pulmonary disease. We hypothesized that emphysema of the tumor region may result in larger tumors and a poorer overall survival.

Methods: We evaluated 304 cases of non-small cell lung cancer from a prospectively enrolled cohort. The lung was divided into equal volumetric thirds (upper, middle, or lower region). Emphysema was defined as percentage of low-attenuation areas less than -950 Hounsfield units (%LAA-950) and measured for each region. Whole-lung %LAA-950 was defined as the emphysema score of the entire lung parenchyma, whereas regional %LAA-950 was the score within that particular region (upper, middle, or lower). The emphysema score of the region in which the tumor occurred was defined as the tumor %LAA-950. Tumor diameter was measured while blinded to characteristics of the lung parenchyma. A proportional hazards model was used to control for multiple factors associated with survival.

Measurements and main results: Increasing tumor %LAA-950 was associated with larger tumors (P = 0.024). Survival, stratified by stage, was significantly worse in those with tumor %LAA-950 greater than or equal to the 50th percentile versus less than the 50th percentile (P = 0.046). Whole-lung %LAA-950 and regional %LAA-950 (e.g., regional emphysema without tumor occurring in the region) were not significantly associated with survival. There were no differences in presenting symptoms or locations of mediastinal or distant metastasis by emphysema score. Increasing tumor %LAA-950 was associated with an increased risk of death (adjusted hazard ratio, 1.36; confidence interval, 1.09-1.68; P = 0.006) after adjustment for age, sex, smoking status, histology, stage, performance status, chemotherapy, radiation, and surgery. Sensitivity analyses revealed no significant difference in the effect size or test of significance for each of the following conditions: (1) exclusion of cases with central tumor location, (2) exclusion of cases where surgery was performed, (3) exclusion of cases where radiation therapy was performed, (4) exclusion of cases where epidermal growth factor receptor tyrosine kinase inhibitors were administered, and (5) inclusion of only stage IV disease.

Conclusions: Increasing emphysema of the region in which a non-small cell lung cancer tumor occurs is associated with increasing tumor size and worse overall survival.

Keywords: emphysema; non–small cell lung cancer.

Figure 1.

(A) Coronal computed tomography image from a non–small cell lung cancer case. (B) Automated densitometric analysis was used to segment out high-attenuation structures (mediastinum, vascular structures, etc.), and the remaining lung regions broken into three equal volumes (upper, middle, and lower). A 1.2-cm lesion is seen in the middle region (although anatomically it exists in the superior segment of the left lower lobe). The tumor percentage of low-attenuation areas less than −950 Hounsfield units (%LAA−950) in this case would be equal to the middle region %LAA−950.

Figure 2.

Axial computed tomography images from two cases with non–small cell lung cancer. (A) A 1.1-cm lesion in a region of 1.6% low-attenuation areas less than −950 Hounsfield units (%LAA−950). Each case was opened into a “blinded” window setting (B) before measurement of the tumor. (C) A 3.9-cm right upper lobe lesion. The tumor %LAA−950 in this region was 24.6%. The “blinded” window setting (D) effectively obscures even large amounts of emphysema, allowing measurement of tumor diameter in an objective manner.

Figure 3.

Illustration of the increase in tumor size by quartile of tumor percentage of low-attenuation areas less than −950 Hounsfield units. Tumors in the upper quartile are 21% larger by diameter (P = 0.024, linear regression for the continuous variable) than those in the lowest quartile. Assuming a spherical configuration, these tumors would be 44% larger by calculated volume.

Figure 4.

Kaplan-Meier survival curves by dichotomized tumor emphysema score (tumor percentage of low-attenuation areas less than −950 Hounsfield units [%LAA−950]), stratified by early- or late-stage disease. Emphysema scores of the region of the tumor greater than or equal to the 50th percentile were associated with a worse overall prognosis than tumors that occurred in regions of lower emphysema (<50th percentile) among both early- and late-stage non–small cell lung cancer (stratified log rank, P = 0.046). Greater emphysema was associated with a poorer prognosis in both strata of non–small cell lung cancer.