0
Original Research: COPD |

Are Airflow Obstruction and Radiographic Evidence of Emphysema Risk Factors for Lung Cancer?: A Nested Case-Control Study Using Quantitative Emphysema Analysis FREE TO VIEW

Fabien Maldonado, MD; Brian J. Bartholmai, MD; Stephen J. Swensen, MD; David E. Midthun, MD, FCCP; Paul A. Decker, MS; James R. Jett, MD, FCCP
Author and Funding Information

From the Division of Pulmonary and Critical Care Medicine (Drs Maldonado, Midthun, and Jett), Division of Radiology (Drs Bartholmai and Swensen), and Division of Biostatistics (Mr Decker), Mayo Clinic, Rochester, MN.

Correspondence to: Fabien Maldonado, MD, Division of Pulmonary and Critical Care Medicine, Gonda 18 South, Mayo Clinic, 200 1st St SW, Rochester, MN 55905; e-mail: Maldonado.Fabien@mayo.edu


For editorial comment see page 1289

Funding/Support: This study was funded by the Mayo Clinic Foundation and the Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2010 American College of Chest Physicians


Chest. 2010;138(6):1295-1302. doi:10.1378/chest.09-2567
Text Size: A A A
Published online

Objectives:  Several studies have identified airflow obstruction as a risk factor for lung cancer independent of smoking history, but the risk associated with the presence of radiographic evidence of emphysema has not been extensively studied. We proposed to assess this risk using a quantitative volumetric CT scan analysis.

Methods:  Sixty-four cases of lung cancer were identified from a prospective cohort of 1,520 participants enrolled in a spiral CT scan lung cancer screening trial. Each case was matched to six control subjects for age, sex, and smoking history. Quantitative CT scan analysis of emphysema was performed. Spirometric measures were also conducted. Data were analyzed using conditional logistic regression making use of the 1:6 set groups of 64 cases and 377 matched control subjects.

Results:  Decreased FEV1 and FEV1/FVC were significantly associated with a diagnosis of lung cancer with ORs of 1.15 (95% CI, 1.00-1.32; P = .046) and 1.29 (95% CI, 1.02-1.62; P = .031), respectively. The quantity of radiographic evidence of emphysema was not found to be a significant risk for lung cancer with OR of 1.042 (95% CI, 0.816-1.329; P = .743). Additionally, there was no significant association between severe emphysema and lung cancer with OR of 1.57 (95% CI, 0.73-3.37).

Conclusions:  We confirm previous observations that airflow obstruction is an independent risk factor for lung cancer. The absence of a clear relationship between radiographic evidence of emphysema and lung cancer using an automated quantitative volumetric analysis may result from different population characteristics than those of prior studies, radiographic evidence of emphysema quantitation methodology, or absence of any relationship between emphysema and lung cancer risk.

Figures in this Article

Lung cancer is the most common cause of cancer deaths worldwide, with an estimated 1.2 million deaths per year. In the United States, lung cancer is responsible for more deaths than the next three most common cancers: colon, breast, and prostate cancer. The dismal prognosis of lung cancer, the absence of early symptoms, and the potential for curative resection surgery in the initial stages of the disease should theoretically position lung cancer as an ideal candidate for screening programs.1

After large screening trials based on serial chest radiographs and sputum examinations failed to show mortality reduction in the 1970s, investigators pursued trials based on low-dose screening CT scanning.2,3 Analysis of the data provided by these prospective, single-arm, observational CT scan screening studies has shed some light on the epidemiologic characteristics of lung cancer, specifically with respect to the risk factors associated with the disease.4-6 Although these studies have shown that CT scanning detects a high percentage of stage I cancers, mortality benefit from CT scanning is yet to be clarified by randomized controlled trials.

Cigarette smoking is the main risk factor for lung cancer and is believed to be responsible for 85% of all lung cancers, increasing the risk by tenfold. Several studies have evaluated airflow obstruction and radiographic evidence of emphysema as independent predictors of lung cancer after adjustment for age, sex, and smoking history, with varying results.4-7 Although data on airflow obstruction as an independent risk factor have been widely published in the literature, only a few studies suggest that radiographic evidence of emphysema, detected qualitatively or semiquantitatively, may be an additional risk factor independent of airflow obstruction.4,6,7 Several other studies have suggested that a clinical diagnosis of emphysema may be an independent predictor of lung cancer, but the diagnosis of emphysema in these studies is typically self-reported, hence subject to inaccuracy and bias.8,9 It has been suggested that automated quantitative assessment of radiographic evidence of emphysema may be a valid way to evaluate this association.10

Preliminary data from the lung cancer screening trial by Swensen et al only included 24 lung cancer cases (of which 22 were prevalent and two were incident)3 and suggested that airflow obstruction was independently associated with increased risk for lung cancer, whereas radiographic evidence of emphysema, quantified by automated CT scan analysis from three-dimensional (3-D) volumetric reconstructions, was not.5 The technique for quantitative assessment of radiographic evidence of emphysema in that study used simple “density mask” software and has since been refined, resulting in marked improvements in sensitivity and specificity. In particular, the anatomic extraction techniques have been optimized to more accurately include the entire lung volume as well as exclude counting normal structures, such as the air in tracheobronchial tree. We analyzed our completed study data using this more advanced technology to clarify the relationship between lung cancer, airflow obstruction, and the automated quantification of radiographic evidence of emphysema.

Participants

The lung cancer screening trial at the Mayo Clinic, Rochester, Minnesota, enrolled patients at high risk for lung cancer between January 1, 1999, and December 31, 1999.3 Patients were men and women ≥ 50 years or age with a life expectancy of 5 or more years, current or former smokers (> 20 pack-years and having quit < 5 years prior to enrollment) and not using supplemental oxygen. Patients with a history of cancer within 5 years (other than nonmelanoma skin cancer, in situ cervical cancer, or localized prostate cancer) were excluded. The study protocol was approved by the institutional review board. Sixty-six patients were diagnosed with lung cancer from a total of 1,520 patients enrolled and followed for 4 years. Radiographic data were not technically analyzable for two of the 66 cases, leaving the 64 cases included in this study.

Quantitative CT Scan Analysis

CT scans were performed with General Electric High-Speed Advantage scanner (GE Medical Systems; Milwaukee, WI) in the helical mode without contrast material. This CT scan protocol included low-dose acquisition (40 mA at 120 kilovolt [peak]) of the entire lungs in a single full inspiration with 5-mm slice thickness and overlapping reconstruction at an interval of 3.5 mm using a standard reconstruction algorithm, following a validated acquisition protocol.11 Automated selective extraction of the lungs, trachea, and main bronchi from the CT scan volume was performed. High-density intraparenchymal structures excluded by the dynamic threshold-based lung extraction technique (including intraparenchymal blood vessels, fissures) were reincorporated in the calculations of final lung volumes based on the technique of “hole closing” to more accurately represent true lung volumes than simple threshold-based extraction techniques (Fig 1). Median 3-D filtration of the CT scan datasets was performed with a 3 × 3 × 3 neighborhood as a processing step prior to emphysema quantification. The median filter was used to remove noise and other spurious features of single pixel extent while preserving overall image quality, to reduce the contribution of image noise to the emphysema counts and increase the accuracy of emphysema volume in these low-dose CT scans with overlapping slices.12-14

Figure Jump LinkFigure 1. Multiplanar reconstruction and three-dimensional rendering of the results of automated extraction of lungs and tracheobronchial tree from CT scan volume, with quantification of low-density emphysema regions. A, Axial CT scan of the chest with detected emphysema regions shown in blue. B, Three-dimensional visualization of anatomic segmentation of lungs from CT scan of the chest. Right lung is shown in red, left lung is green, tracheobronchial tree is yellow, and overlay of detected emphysema is blue. C, Coronal reformat CT scan of the chest with detected emphysema regions shown in blue. D, Sagittal reformat CT scan of the chest with detected emphysema regions shown in blue.Grahic Jump Location

Quantitative measures of lung density were performed and a threshold of -900 Hounsfield units (HU) was chosen to estimate emphysema volume in the extracted lung volume. The volume of low attenuation voxels was then divided by the total lung volume to obtain the percentage of emphysema.

Spirometry

Spirometry was performed using a Puritan Bennett Renaissance pneumotach-based flow spirometer (Mallinckrodt; St Louis, MO) according to the standards set by the American Thoracic Society/European Respiratory Society. Flows were expressed as percentage of predicted using the reference equations of Crapo et al.15

Statistical Analysis

All analyses were performed using the 1:6 matched set of 64 cases and 377 control subjects selected from participants of the lung cancer screening trial without evidence of cancer. There were seven cases that had only five matches. These additional control subjects were excluded from the study because their data sets could not be processed or because of significant artifacts (such as beam hardening from metal in the thorax, significant image noise from large patient size, patient motion, problems with the CT scan acquisition, protocol deviation, or loss of image data since the acquisition in 1999). Conditional logistic regression was used to assess whether percent predicted FEV1, FEV1/FVC, or the percentage of emphysema were risk factors for lung cancer. Percent predicted FEV1 was analyzed as a continuous variable and also as a categorical variable using the categories: ≥ 81%, 61% to 80%, 41% to 60%, and ≤ 40%.4 FEV1/FVC was analyzed as a continuous variable and also as a categorical variable using the categories: ≥ 71%, 61% to 70%, 51% to 60%, and ≤ 50%. Percentage of emphysema was analyzed as a continuous variable and also as a categorical variable. ORs with corresponding 95% CIs were calculated where appropriate. In all cases, two-sided tests were used with P values ≤ .05 considered statistically significant.

Sixty-four case subjects (39 women and 25 men) were matched with 377 control subjects (233 women and 144 men). Thirty-five cases were incident cancers (detected after the initial CT scan).3 Cases and control subjects were matched (1:6) for sex, age, and pack-years of smoking history. The demographic characteristics of the patients included in the study are summarized in Table 1. Mean age in years ± SD was 62.7 ± 6.5 for the cases and 62.4 ± 6.2 for the control subjects. Smoking history in pack-years ± SD was 57.2 ± 21.7 for the cases and 56.7 ± 21.1 for the control subjects. There were more current than former smokers in both cases and control subjects (P = .736). The majority of lung cancer cases were adenocarcinomas (53%). Other cell types included squamous cell carcinoma (21%), small cell carcinoma (12%), non-small cell carcinomas not otherwise specified (7%), and large cell neuroendocrine and mixed large and small cell carcinomas (3%). One cancer type was unknown and two patients with cancer detected on prevalence CT scan had an additional new primary lung cancer on an incidence CT scan.

Table Graphic Jump Location
Table 1 —Patient Demographics

Conditional logistic regression was used to determine whether airflow obstruction and/or radiographic evidence of emphysema are predictors of lung cancer independent of age, smoking history, and sex. The findings of the analyses are presented in Table 2.

Table Graphic Jump Location
Table 2 —Conditional Logistic Regression Results

Data were analyzed using conditional logistic regression making use of the 1:6 matched set group subjects of 64 case subjects and 377 control subjects matched for sex, age, and smoking history. FEV1, FEV1/FVC, and percentage of emphysema were analyzed both as continuous variables and also categorically using the categories specified. When analyzed as a continuous variable the ORs presented for FEV1 and FEV1/FVC correspond to a decrease of 10 percentage points. When analyzed as a continuous variable the ORs presented for spiral CT scan variables correspond to an increase of 50 units. For categorical variables, the OR is presented for each category relative to the reference group, which is indicated using an OR of 1.0.

a 

Entries are No. (%) unless otherwise indicated.

Analyzed as a continuous variable, the percent predicted FEV1 (FEV1%) was associated with lung cancer, with an OR of 1.15 (95% CI, 1.00-1.32; P = .046), OR corresponding to a decrease of 10 percentage points in predicted FEV1. When analyzed as a categorical variable, more severe degrees of airflow obstruction were associated with an increased likelihood of lung cancer with ORs of 2.84 (95% CI, 1.09-7.38) for FEV1% < 40% of predicted. FEV1/FVC ratio was also independently associated with lung cancer both as a continuous variable (OR, 1.29; 95% CI, 1.02-1.62; OR corresponding to 10 percentage points) and a categorical variable with increased likelihood of lung cancer with lower FEV1/FVC values (OR, 2.67; 95% CI, 1.15-6.17 for FEV1/FVC < 50%).

Analyzed as a continuous variable, the percentage of volume of emphysema as quantified by automated CT scan analysis was not significantly associated with lung cancer, with an OR of 1.04 (95% CI, 0.82-1.33; P = .743). There was also no significant correlation between severe emphysema (as determined by percentage of emphysema volume > 15%) and lung cancer, with an OR of 1.57 (95% CI, 0.73-3.37).

When analyzed by sex, the association between lung cancer and FEV1% as a continuous variable was still statistically significant for men (P = .0423) and not significant for women (P = .406), but there was still no statistically significant relationship between lung cancer and percentage of volume of emphysema (P = .907 for men and P = .914 for women). There was also no statistically significant association between lung cancer and percentage volume of emphysema when analyzing prevalent and incident cases separately (P > .05). Overall total lung volume was significantly higher in lung cancer cases than in control subjects (5,396.5 mL ± 1,478.9 mL vs 5,042.0 mL ± 1,293.7 mL; P = .013).

Our nested case-control study corroborates that airflow obstruction, particularly severe airflow obstruction with FEV1% < 40% of predicted, is predictive of lung cancer independent of age, sex, and smoking history as characterized by pack-years. However, the association between lung cancer and radiographic evidence of emphysema, as quantified by automated CT scan analysis, was not statistically significant for any degree of severity of emphysema.

Our study confirms numerous reports suggesting that airflow obstruction is an independent risk factor for lung cancer.16-18 Several potential explanations have been suggested to explain this phenomenon, including impaired ciliary clearance in areas of small airway inflammation with pooling of particles and prolonged exposure to inhaled carcinogens, as well as shared pathogenic mechanisms between COPD and lung cancer. The role of chronic airway inflammation induced by cigarette smoke is an active area of research. Several pathways, such as the nuclear factor-κB pathway, have been found to be activated by cigarette smoke and are implicated in both local inflammation and tumorigenesis. Reactive oxygen species are direct products of lung inflammation and promote DNA alterations that may ultimately lead to lung cancer.19,20 The association of other pulmonary inflammatory conditions, such as TB, sarcoidosis, and pulmonary fibrosis with lung cancer, supports this hypothesis.21,22 Smoking histories are, however, notoriously unreliable, and it is possible that residual confounding variables, such as smoking or other potential exposures, were not adjusted for in these studies, which could have biased their results.

In our study, the degree of radiographic evidence of emphysema was not found to be an independent risk factor for lung cancer, in contradiction to the findings of two recently published cohort studies.4,6 The major difference in these conflicting reports is that our methodology for quantifying emphysema was automated and by definition blinded and reproducible. We confirm the findings of the previous study3 using an improved methodology for automated emphysema quantitation, increasing the power considerably by including a significantly increased number of cases (64 vs 24).5

Strengths and Limitations of the Study

To the best of our knowledge, our study is the first to use automated CT scan analysis with 3-D filtering and voxel density to analyze the association between radiographic evidence of emphysema and lung cancer. This technique has been found to correlate well with radiologist assessment of emphysema and physiologic data, and to provide reproducible and blinded assessment across CT scan studies.23,24 This technique virtually eliminated any subjectivity in the estimation of emphysema, an expressed concern in prior studies6; it is interesting to note that the majority of patients with lung cancer and emphysema in the report by Wilson et al6 had either trace or mild emphysema and that the association with lung cancer, although statistically significant, did not appear to be linear (no dose-response effect) when all degrees of severity were considered. The smaller study by de Torres et al4 (23 lung cancers in 1,166 participants) did not analyze severity of emphysema as a predictor of lung cancer given that only the presence or absence of emphysema as a dichotomous variable was used. In our study, radiographic evidence of emphysema was analyzed as a continuous variable, thereby theoretically increasing its power by capturing variability of the data that would be lost with categorical variables. In addition, we believe that the markedly improved algorithms used in the present study increased the sensitivity and specificity of the quantitative analysis of radiographic evidence of emphysema, also leading to increased power. Specifically, a dynamic threshold was used to assure accurate extraction of the lungs as well as the iterative tracheal extraction process excluding normal structures from the emphysema counts. The differences in emphysema quantification technique used, in addition to the markedly increased sample size compared with the previous report, are likely responsible for the lower percentage of captured emphysema volume.5 Although our study was smaller than that of Wilson et al6 (64 cases of lung cancer vs 99), it remains one of the largest studies assessing the relationship between radiographic evidence of emphysema and lung cancer. The nested case-control design of our study may have decreased its power slightly; however, 1:6 matching was used and adds strength. Another notable strength was that our patients were part of a large cohort study, which enabled all data to be accumulated in a prospective fashion with only one of 1,520 participants lost to follow-up.3

An important aspect to consider is that the thickness of the CT scan slices in our study was higher (5 mm) than that used in the study by Wilson et al6 (2.5 mm). These thicker CT scan slices explain the higher threshold (-900 HU) used to capture radiographic evidence of emphysema in our study, a threshold established for higher slice thickness such as those used in our study, but higher than those chosen in most recent reports using high-resolution CT scans.25-27,28,29 The optimal threshold to accurately quantify emphysema depends on both slice thickness and the CT scan reconstruction algorithm used. The threshold of -900 HU has been shown to correlate with radiologist assessment and physiology in prior studies using automated quantification of emphysema with higher slice thickness and the standard body algorithm, such as the images used in this study.25-27 The suggestion by Wilson et al6 that the association between radiographic evidence of emphysema and lung cancer exists for any degree of emphysema would imply that this association may not be linear (no dose-response relationship). In this context, missing some patients with traces of emphysema because of density averaging could have obscured this relationship. One final noteworthy limitation of the study is the absence of postbronchodilator pulmonary function testing data. Hence, our study of the association of airflow obstruction and risk of lung cancer may have captured a heterogeneous population of patients (rather than only patients with COPD).30

The results obtained in our study contrast sharply with other published data presented in studies with similar study design. The proportion of radiographic evidence of emphysema, as well as age and smoking history, was similar to the study by Wilson et al6 but substantially higher than in the study by de Torres et al.4 The main differences in methodology and results are summarized in Table 3. One notable difference was the predominance of female patients in our study (61% of cases and 62% of control subjects) when compared with the studies by Wilson et al6 (48.6%) and de Torres et al4 (26%). This is an important consideration because for a given stage of COPD based on the GOLD (Global Initiative for Chronic Obstructive Lung Disease) criteria, women have been shown to demonstrate less radiographic evidence of emphysema than men.31 Although we could not identify a statistically significant association between radiographic evidence of emphysema and lung cancer in the subgroup of men in our study, the number of male patients was only 25, which may not have yielded sufficient power to detect this association. This hypothesis could also in part explain the apparent discordance noted between airflow obstruction and radiographic evidence of emphysema in our study. A recent study on radiographic evidence of emphysema in the absence of airflow obstruction again showed that women tend to have less radiographic evidence of emphysema after adjustment for age, BMI, smoking history, and FEV1 and FVC.32 It is also conceivable, though speculative, that emphysema may share pathogenic mechanisms with only certain types of lung cancer. It is believed that there are significant differences in lung cancer based on sex, both pathologically and genetically.33 Whether the genetic predisposition to emphysema is shared by a subgroup of lung cancers only remains to be determined. Finally, it is possible that the pathogenic determinants of the “emphysema” phenotype of COPD may be substantially different than in patients with “chronic bronchitis,” and perhaps predispose differently to the risk of lung cancer, which could explain the differences observed in our study. Indeed, radiographic evidence of emphysema is not uncommon in smokers with normal pulmonary function studies.30,34

Table Graphic Jump Location
Table 3 —Comparison of Three Recent Studies Assessing Airflow Obstruction and Radiographic Evidence of Emphysema as Independent Risk Factors for Lung Cancer

AdenoC = adenocarcinoma; F = female; M = male; SCC = small cell carcinoma; SqCC = squamous cell carcinoma.

In conclusion, we confirm prior observations suggesting a significant association between airflow obstruction and lung cancer, whereas radiographic evidence of emphysema, as quantified by a validated automated methodology, was not found to be an independent risk factor. Whether this observation can be explained by the different population included in our study, the methodology used in this study, or the absence of any relationship between radiographic evidence of emphysema and lung cancer risk is unclear. Based on these results, further research is warranted in order to clarify the relationship between airflow obstruction/emphysema and lung cancer, particularly with respect to possible gender differences and to clarify the pathogenic determinants of the association observed.

Author contributions:Dr Maldonado: contributed to the design of the study, data collection, and writing the manuscript.

Dr Bartholmai: contributed to the design of the study, data collection, and writing the manuscript.

Dr Swensen: contributed to the design of the study and writing the manuscript.

Dr Midthun: contributed to the design of the study and writing the manuscript.

Mr Decker: contributed to the statistical work.

Dr Jett: contributed to the design of the study and writing the manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Bach PB, Jett JR, Pastorino U, Tockman MS, Swensen SJ, Begg CB. Computed tomography screening and lung cancer outcomes. JAMA. 2007;2979:953-961. [CrossRef] [PubMed]
 
Henschke CI, Yankelevitz DF, Libby DM, Pasmantier MW, Smith JP, Miettinen OS. International Early Lung Cancer Action Program Investigators International Early Lung Cancer Action Program Investigators Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med. 2006;35517:1763-1771. [CrossRef] [PubMed]
 
Swensen SJ, Jett JR, Hartman TE, et al. CT screening for lung cancer: five-year prospective experience. Radiology. 2005;2351:259-265. [CrossRef] [PubMed]
 
de Torres JP, Bastarrika G, Wisnivesky JP, et al. Assessing the relationship between lung cancer risk and emphysema detected on low-dose CT of the chest. Chest. 2007;1326:1932-1938. [CrossRef] [PubMed]
 
Kishi K, Gurney JW, Schroeder DR, Scanlon PD, Swensen SJ, Jett JR. The correlation of emphysema or airway obstruction with the risk of lung cancer: a matched case-controlled study. Eur Respir J. 2002;196:1093-1098. [CrossRef] [PubMed]
 
Wilson DO, Weissfeld JL, Balkan A, et al. Association of radiographic emphysema and airflow obstruction with lung cancer. Am J Respir Crit Care Med. 2008;1787:738-744. [CrossRef] [PubMed]
 
Mizuno S, Takiguchi Y, Fujikawa A, et al. Chronic obstructive pulmonary disease and interstitial lung disease in patients with lung cancer. Respirology. 2009;143:377-383. [CrossRef] [PubMed]
 
Schwartz AG, Cote ML, Wenzlaff AS, et al. Chronic obstructive lung diseases and risk of non-small cell lung cancer in women. J Thorac Oncol. 2009;43:291-299. [CrossRef] [PubMed]
 
Turner MC, Chen Y, Krewski D, Calle EE, Thun MJ. Chronic obstructive pulmonary disease is associated with lung cancer mortality in a prospective study of never smokers. Am J Respir Crit Care Med. 2007;1763:285-290. [CrossRef] [PubMed]
 
Dubinett SM, Aberle DR, Tashkin DP, Mao JT. The partners—airflow obstruction, emphysema, and lung cancer. Am J Respir Crit Care Med. 2008;1787:665-666. [CrossRef] [PubMed]
 
Coxson HO. Computed tomography and monitoring of emphysema. Eur Respir J. 2007;296:1075-1077. [CrossRef] [PubMed]
 
McCollough C, Zhang J, Bruesewitz M, Bartholmai B. Optimization of CT image reconstruction algorithms for the Lung Tissue Research Consortium (LTRC). 2006 Progress in Biomedical Optics and Imaging. Proceedings SPIE International Society for Optical Engineering. 2006;61432:614330
 
Park YS, Seo JB, Kim N, et al. Texture-based quantification of pulmonary emphysema on high-resolution computed tomography: comparison with density-based quantification and correlation with pulmonary function test. Invest Radiol. 2008;436:395-402. [CrossRef] [PubMed]
 
Schilham AMR, van Ginneken B, Gietema H, Prokop M. Local noise weighted filtering for emphysema scoring of low-dose CT images. IEEE Trans Med Imaging. 2006;254:451-463. [CrossRef] [PubMed]
 
Crapo RO, Morris AH, Gardner RM. Reference spirometric values using techniques and equipment that meet ATS recommendations. Am Rev Respir Dis. 1981;1236:659-664. [PubMed]
 
Skillrud DM, Offord KP, Miller RD. Higher risk of lung cancer in chronic obstructive pulmonary disease. A prospective, matched, controlled study. Ann Intern Med. 1986;1054:503-507. [PubMed]
 
Tockman MS, Anthonisen NR, Wright EC, Donithan MG. Airways obstruction and the risk for lung cancer. Ann Intern Med. 1987;1064:512-518. [PubMed]
 
Wasswa-Kintu S, Gan WQ, Man SF, Pare PD, Sin DD. Relationship between reduced forced expiratory volume in one second and the risk of lung cancer: a systematic review and meta-analysis. Thorax. 2005;607:570-575. [CrossRef] [PubMed]
 
Azad N, Rojanasakul Y, Vallyathan V. Inflammation and lung cancer: roles of reactive oxygen/nitrogen species. J Toxicol Environ Health B Crit Rev. 2008;111:1-15. [CrossRef] [PubMed]
 
Stathopoulos GT, Sherrill TP, Cheng DS, et al. Epithelial NF-kappaB activation promotes urethane-induced lung carcinogenesis. Proc Natl Acad Sci U S A. 2007;10447:18514-18519. [CrossRef] [PubMed]
 
Engels EA, Shen M, Chapman RS, et al. Tuberculosis and subsequent risk of lung cancer in Xuanwei, China. Int J Cancer. 2009;1245:1183-1187. [CrossRef] [PubMed]
 
Le Jeune I, Gribbin J, West J, Smith C, Cullinan P, Hubbard R. The incidence of cancer in patients with idiopathic pulmonary fibrosis and sarcoidosis in the UK. Respir Med. 2007;10112:2534-2540. [CrossRef] [PubMed]
 
Hersh CP, Washko GR, Jacobson FL, et al. Interobserver variability in the determination of upper lobe-predominant emphysema. Chest. 2007;1312:424-431. [CrossRef] [PubMed]
 
Rogers RM, Coxson HO, Sciurba FC, Keenan RJ, Whittall KP, Hogg JC. Preoperative severity of emphysema predictive of improvement after lung volume reduction surgery: use of CT morphometry. Chest. 2000;1185:1240-1247. [CrossRef] [PubMed]
 
Archer DC, Coblentz CL, deKemp RA, Nahmias C, Norman G. Automated in vivo quantification of emphysema. Radiology. 1993;1883:835-838. [PubMed]
 
Kauczor HU, Heussel CP, Fischer B, Klamm R, Mildenberger P, Thelen M. Assessment of lung volumes using helical CT at inspiration and expiration: comparison with pulmonary function tests. AJR Am J Roentgenol. 1998;1714:1091-1095. [PubMed]
 
Stern EJ, Frank MS. CT of the lung in patients with pulmonary emphysema: diagnosis, quantification, and correlation with pathologic and physiologic findings. AJR Am J Roentgenol. 1994;1624:791-798. [PubMed]
 
Madani A, Van Muylem A, de Maertelaer V, Zanen J, Gevenois PA. Pulmonary emphysema: size distribution of emphysematous spaces on multidetector CT images—comparison with macroscopic and microscopic morphometry. Radiology. 2008;2483:1036-1041. [CrossRef] [PubMed]
 
Bankier AA, De Maertelaer V, Keyzer C, Gevenois PA. Pulmonary emphysema: subjective visual grading versus objective quantification with macroscopic morphometry and thin-section CT densitometry. Radiology. 1999;2113:851-858. [PubMed]
 
Stratelis G, Fransson SG, Schmekel B, Jakobsson P, Mölstad S. High prevalence of emphysema and its association with BMI: a study of smokers with normal spirometry. Scand J Prim Health Care. 2008;264:241-247. [CrossRef] [PubMed]
 
Dransfield MT, Washko GR, Foreman MG, Estepar RS, Reilly J, Bailey WC. Gender differences in the severity of CT emphysema in COPD. Chest. 2007;1322:464-470. [CrossRef] [PubMed]
 
Sverzellati N, Calabro E, Randi G, et al. Sex differences in emphysema phenotype in smokers without airflow obstruction. Eur Respir J. 2009;336:1320-1328. [CrossRef] [PubMed]
 
Patel JD. Lung cancer in women. J Clin Oncol. 2005;2314:3212-3218. [CrossRef] [PubMed]
 
Lee G, Walser TC, Dubinett SM. Chronic inflammation, chronic obstructive pulmonary disease, and lung cancer. Curr Opin Pulm Med. 2009;154:303-307. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1. Multiplanar reconstruction and three-dimensional rendering of the results of automated extraction of lungs and tracheobronchial tree from CT scan volume, with quantification of low-density emphysema regions. A, Axial CT scan of the chest with detected emphysema regions shown in blue. B, Three-dimensional visualization of anatomic segmentation of lungs from CT scan of the chest. Right lung is shown in red, left lung is green, tracheobronchial tree is yellow, and overlay of detected emphysema is blue. C, Coronal reformat CT scan of the chest with detected emphysema regions shown in blue. D, Sagittal reformat CT scan of the chest with detected emphysema regions shown in blue.Grahic Jump Location

Tables

Table Graphic Jump Location
Table 1 —Patient Demographics
Table Graphic Jump Location
Table 2 —Conditional Logistic Regression Results

Data were analyzed using conditional logistic regression making use of the 1:6 matched set group subjects of 64 case subjects and 377 control subjects matched for sex, age, and smoking history. FEV1, FEV1/FVC, and percentage of emphysema were analyzed both as continuous variables and also categorically using the categories specified. When analyzed as a continuous variable the ORs presented for FEV1 and FEV1/FVC correspond to a decrease of 10 percentage points. When analyzed as a continuous variable the ORs presented for spiral CT scan variables correspond to an increase of 50 units. For categorical variables, the OR is presented for each category relative to the reference group, which is indicated using an OR of 1.0.

a 

Entries are No. (%) unless otherwise indicated.

Table Graphic Jump Location
Table 3 —Comparison of Three Recent Studies Assessing Airflow Obstruction and Radiographic Evidence of Emphysema as Independent Risk Factors for Lung Cancer

AdenoC = adenocarcinoma; F = female; M = male; SCC = small cell carcinoma; SqCC = squamous cell carcinoma.

References

Bach PB, Jett JR, Pastorino U, Tockman MS, Swensen SJ, Begg CB. Computed tomography screening and lung cancer outcomes. JAMA. 2007;2979:953-961. [CrossRef] [PubMed]
 
Henschke CI, Yankelevitz DF, Libby DM, Pasmantier MW, Smith JP, Miettinen OS. International Early Lung Cancer Action Program Investigators International Early Lung Cancer Action Program Investigators Survival of patients with stage I lung cancer detected on CT screening. N Engl J Med. 2006;35517:1763-1771. [CrossRef] [PubMed]
 
Swensen SJ, Jett JR, Hartman TE, et al. CT screening for lung cancer: five-year prospective experience. Radiology. 2005;2351:259-265. [CrossRef] [PubMed]
 
de Torres JP, Bastarrika G, Wisnivesky JP, et al. Assessing the relationship between lung cancer risk and emphysema detected on low-dose CT of the chest. Chest. 2007;1326:1932-1938. [CrossRef] [PubMed]
 
Kishi K, Gurney JW, Schroeder DR, Scanlon PD, Swensen SJ, Jett JR. The correlation of emphysema or airway obstruction with the risk of lung cancer: a matched case-controlled study. Eur Respir J. 2002;196:1093-1098. [CrossRef] [PubMed]
 
Wilson DO, Weissfeld JL, Balkan A, et al. Association of radiographic emphysema and airflow obstruction with lung cancer. Am J Respir Crit Care Med. 2008;1787:738-744. [CrossRef] [PubMed]
 
Mizuno S, Takiguchi Y, Fujikawa A, et al. Chronic obstructive pulmonary disease and interstitial lung disease in patients with lung cancer. Respirology. 2009;143:377-383. [CrossRef] [PubMed]
 
Schwartz AG, Cote ML, Wenzlaff AS, et al. Chronic obstructive lung diseases and risk of non-small cell lung cancer in women. J Thorac Oncol. 2009;43:291-299. [CrossRef] [PubMed]
 
Turner MC, Chen Y, Krewski D, Calle EE, Thun MJ. Chronic obstructive pulmonary disease is associated with lung cancer mortality in a prospective study of never smokers. Am J Respir Crit Care Med. 2007;1763:285-290. [CrossRef] [PubMed]
 
Dubinett SM, Aberle DR, Tashkin DP, Mao JT. The partners—airflow obstruction, emphysema, and lung cancer. Am J Respir Crit Care Med. 2008;1787:665-666. [CrossRef] [PubMed]
 
Coxson HO. Computed tomography and monitoring of emphysema. Eur Respir J. 2007;296:1075-1077. [CrossRef] [PubMed]
 
McCollough C, Zhang J, Bruesewitz M, Bartholmai B. Optimization of CT image reconstruction algorithms for the Lung Tissue Research Consortium (LTRC). 2006 Progress in Biomedical Optics and Imaging. Proceedings SPIE International Society for Optical Engineering. 2006;61432:614330
 
Park YS, Seo JB, Kim N, et al. Texture-based quantification of pulmonary emphysema on high-resolution computed tomography: comparison with density-based quantification and correlation with pulmonary function test. Invest Radiol. 2008;436:395-402. [CrossRef] [PubMed]
 
Schilham AMR, van Ginneken B, Gietema H, Prokop M. Local noise weighted filtering for emphysema scoring of low-dose CT images. IEEE Trans Med Imaging. 2006;254:451-463. [CrossRef] [PubMed]
 
Crapo RO, Morris AH, Gardner RM. Reference spirometric values using techniques and equipment that meet ATS recommendations. Am Rev Respir Dis. 1981;1236:659-664. [PubMed]
 
Skillrud DM, Offord KP, Miller RD. Higher risk of lung cancer in chronic obstructive pulmonary disease. A prospective, matched, controlled study. Ann Intern Med. 1986;1054:503-507. [PubMed]
 
Tockman MS, Anthonisen NR, Wright EC, Donithan MG. Airways obstruction and the risk for lung cancer. Ann Intern Med. 1987;1064:512-518. [PubMed]
 
Wasswa-Kintu S, Gan WQ, Man SF, Pare PD, Sin DD. Relationship between reduced forced expiratory volume in one second and the risk of lung cancer: a systematic review and meta-analysis. Thorax. 2005;607:570-575. [CrossRef] [PubMed]
 
Azad N, Rojanasakul Y, Vallyathan V. Inflammation and lung cancer: roles of reactive oxygen/nitrogen species. J Toxicol Environ Health B Crit Rev. 2008;111:1-15. [CrossRef] [PubMed]
 
Stathopoulos GT, Sherrill TP, Cheng DS, et al. Epithelial NF-kappaB activation promotes urethane-induced lung carcinogenesis. Proc Natl Acad Sci U S A. 2007;10447:18514-18519. [CrossRef] [PubMed]
 
Engels EA, Shen M, Chapman RS, et al. Tuberculosis and subsequent risk of lung cancer in Xuanwei, China. Int J Cancer. 2009;1245:1183-1187. [CrossRef] [PubMed]
 
Le Jeune I, Gribbin J, West J, Smith C, Cullinan P, Hubbard R. The incidence of cancer in patients with idiopathic pulmonary fibrosis and sarcoidosis in the UK. Respir Med. 2007;10112:2534-2540. [CrossRef] [PubMed]
 
Hersh CP, Washko GR, Jacobson FL, et al. Interobserver variability in the determination of upper lobe-predominant emphysema. Chest. 2007;1312:424-431. [CrossRef] [PubMed]
 
Rogers RM, Coxson HO, Sciurba FC, Keenan RJ, Whittall KP, Hogg JC. Preoperative severity of emphysema predictive of improvement after lung volume reduction surgery: use of CT morphometry. Chest. 2000;1185:1240-1247. [CrossRef] [PubMed]
 
Archer DC, Coblentz CL, deKemp RA, Nahmias C, Norman G. Automated in vivo quantification of emphysema. Radiology. 1993;1883:835-838. [PubMed]
 
Kauczor HU, Heussel CP, Fischer B, Klamm R, Mildenberger P, Thelen M. Assessment of lung volumes using helical CT at inspiration and expiration: comparison with pulmonary function tests. AJR Am J Roentgenol. 1998;1714:1091-1095. [PubMed]
 
Stern EJ, Frank MS. CT of the lung in patients with pulmonary emphysema: diagnosis, quantification, and correlation with pathologic and physiologic findings. AJR Am J Roentgenol. 1994;1624:791-798. [PubMed]
 
Madani A, Van Muylem A, de Maertelaer V, Zanen J, Gevenois PA. Pulmonary emphysema: size distribution of emphysematous spaces on multidetector CT images—comparison with macroscopic and microscopic morphometry. Radiology. 2008;2483:1036-1041. [CrossRef] [PubMed]
 
Bankier AA, De Maertelaer V, Keyzer C, Gevenois PA. Pulmonary emphysema: subjective visual grading versus objective quantification with macroscopic morphometry and thin-section CT densitometry. Radiology. 1999;2113:851-858. [PubMed]
 
Stratelis G, Fransson SG, Schmekel B, Jakobsson P, Mölstad S. High prevalence of emphysema and its association with BMI: a study of smokers with normal spirometry. Scand J Prim Health Care. 2008;264:241-247. [CrossRef] [PubMed]
 
Dransfield MT, Washko GR, Foreman MG, Estepar RS, Reilly J, Bailey WC. Gender differences in the severity of CT emphysema in COPD. Chest. 2007;1322:464-470. [CrossRef] [PubMed]
 
Sverzellati N, Calabro E, Randi G, et al. Sex differences in emphysema phenotype in smokers without airflow obstruction. Eur Respir J. 2009;336:1320-1328. [CrossRef] [PubMed]
 
Patel JD. Lung cancer in women. J Clin Oncol. 2005;2314:3212-3218. [CrossRef] [PubMed]
 
Lee G, Walser TC, Dubinett SM. Chronic inflammation, chronic obstructive pulmonary disease, and lung cancer. Curr Opin Pulm Med. 2009;154:303-307. [CrossRef] [PubMed]
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543