The association between emphysema detected on computed tomography and increased risk of lung a systematic review and meta-analysis

Authors: Jiahao Shen, Chen Gao, Xinjing Lou, Ting Pan, Shenghan Wang, Zhengnan Xu, Linyu Wu, Maosheng Xu

Abstract

Background

Lung cancer, chronic obstructive pulmonary disease (COPD), and emphysema share common pathophysiological mechanisms, including diffuse chronic inflammation within lung tissue, oxidative stress, and lung destruction. This study aimed to evaluate the effectiveness of computed tomography (CT) imaging in predicting the risk of lung cancer development in patients with emphysema and COPD.

Methods

The databases of PubMed, Embase, Web of Science, and Cochrane Library were searched to identify studies examining the relationship between CT-detected emphysema, COPD, and the risk of developing lung malignancy. The severity of emphysema (from trace to severe) was assessed visually and quantitatively on CT. COPD severity was classified from Global Initiative for Chronic Obstructive Lung Disease (GOLD) I to GOLD IV. Quality Assessment of Diagnostic Accuracy Studies, version 2 (QUADAS-2) was used to assess risk of bias in the included studies. Pooled odds ratios (ORs) with their corresponding 95% confidence intervals (CIs) were calculated for overall and stratified analyses.

Results

Of the 6,114 studies screened, 12 (22,190 patients) were included. The overall pooled OR for lung cancer associated with CT-defined emphysema was 2.45 (95% CI: 2.01–2.99). In studies employing CT-based evaluation methods, the pooled OR for lung cancer was comparable between visual assessment (2.37; 95% CI: 1.93–2.80) and quantitative assessment (2.38; 95% CI: 1.85–3.05). The risk of lung cancer demonstrated a positive correlation with disease severity in both emphysema and COPD cases.

Conclusions

CT-defined emphysema was linked to an elevated risk of lung cancer, which was observed across various assessments. Moreover, the severity of COPD was found also to be a risk factor for the development of lung cancer.

Introduction

Lung cancer is among the most commonly diagnosed cancers globally and is the leading cause of cancer-related mortality, with approximately 2 million new cases and 1.76 million deaths reported each year (1). Chronic obstructive pulmonary disease (COPD) is characterized by diffuse chronic inflammation within the lung tissue, oxidative stress, and lung destruction. Emphysema, recognized as one of the COPD phenotypes, can also arise from increased cell death in the alveolar walls and/or failure in alveolar wall maintenance (2,3). Lung cancer, COPD, and emphysema share common pathophysiological mechanisms (4), raising interest in the potential link between these conditions.

Chest computed tomography (CT) is a crucial tool for evaluating emphysema with high sensitivity; radiology indicates that pulmonary nodules often present as early signs of lung cancer (5-8). Some previous studies have included emphysema as a risk factor for lung cancer (9-11). Numerous research efforts have explored the relationship between the evaluation of emphysema via chest CT scans and lung cancer, employing both visual assessment and quantitative CT analysis techniques (10-12); nonetheless, the findings have been inconsistent. A 2012 meta-analysis demonstrated that visually assessed emphysema on chest CT scans was independently linked to lung cancer (10), whereas quantitative analysis failed to establish a similar correlation. A 2021 meta-analysis thoroughly examined the relationship between CT-defined emphysema and lung cancer; however, some data were derived from the same study cohort. Additionally, these studies did not consider the confounding factor of COPD, such as performing a stratified analysis based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages. Revising and integrating information from both current and novel research is crucial. Therefore, we aimed to conduct a systematic review and meta-analysis to evaluate the connection among CT-identified emphysema, the severity of COPD, and the likelihood of developing lung cancer. We present this article in accordance with the PRISMA reporting checklist (13) (available at https://qims.amegroups.com/article/view/10.21037/qims-24-1879/rc).

Methods

This systematic review was registered in the International Prospective Register of Systematic Reviews, or PROSPERO (No. CRD42024511856).

Search strategy

A comprehensive search was conducted on 6 June 2024 in the databases of PubMed, Embase, Web of Science, and Cochrane Library. The objective was to identify studies that assessed emphysema severity using chest CT, while also taking COPD status into account. The primary purpose was to investigate the association between these factors and the risk of developing lung malignancies. The reference list of included articles and relevant literature was also manually screened to ensure thoroughness. The search terms used included COPD, emphysema, solitary pulmonary nodule, and lung neoplasm (detailed search terms are provided in Appendix 1).

Definitions of emphysema and COPD

Visual emphysema was characterized by altered lung vasculature and parenchyma presenting with low attenuation in any region of the lungs on a chest CT scan, as assessed by radiologists according to the criteria established by the National Emphysema Treatment Trial (i.e., NETT) or Fleischer Society (14,15). Quantitative assessment was defined as the percentage of low attenuation area (LAA%), representing the proportion of total lung volume below a specified threshold of −950 Hounsfield units (HU) during full inspiration (16). Emphysema severity was classified according to the percentage of lung involvement, categorized as mild (0–25%), moderate (26–50%), and severe (≥51%) (17). Emphysema was also analyzed as a dichotomized variable, classified as normal or abnormal, with abnormal defined as having more than 3% LAA in quantitative analysis or at least a mild grading in visual assessment (17,18).

A postbronchodilator forced expiratory volume in one second to forced vital capacity (FEV1-FVC) ratio of less than 0.70 is required to diagnose COPD. According to the GOLD, the FEV1 percentage is the main indicator of disease severity, which was classified as GOLD I stage (FEV1 ≥80% of predicted), GOLD II (FEV1 of 50–79% of predicted), GOLD III (FEV1 of 30–49% of predicted), or GOLD IV (FEV1 <30% of predicted) (19,20).

Study selection

The data to be extracted included the (I) individuals diagnosed with lung cancer through histopathological evaluation, regardless of the histological type. (II) CT-defined emphysema (assessed by using quantitative CT or visual assessment). (III) COPD GOLD score or emphysema severity would be included if they were reported in articles. The exclusion criteria for our study were as (I) review articles, case studies, letters, editorials, and conference abstracts; (II) non-English-language papers; (III) studies that are not relevant to the topic; (IV) studies on the same cohort; (V) studies lacking assessment of emphysema; and (VI) studies without adjusted effect size.

Data extraction

Two researchers independently performed all data extraction. Conflicts were resolved through consensus or by consulting an external reviewer. In each manuscript, the documented information encompasses a range of factors, organized as authorship, country of origin, and year of publication; smoking status and familial predisposition to lung cancer; the number of individuals examined; the presence of emphysema, COPD, lung nodules, and lung cancer; the distribution of lung cancer histology; assessment of emphysema; severity of emphysema and COPD GOLD grades; outcome indicators, including odds ratios (ORs), risk ratios (RRs), and hazard ratios (HRs), together with their associated 95% confidence intervals (CIs); and variables that were either adjusted for or paired.

Quality assessment

The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) was utilized to assess the methodological quality of every study. QUADAS-2 was structured so that four key domains (patient selection, index tests, reference standard and flow and timing, and applicability) were rated regarding the risk of bias and the concern regarding applicability to the research question (21). Any differences in ratings were settled through consensus.

Statistical analysis

The research was divided into groups based on visual assessment or quantitative evaluation. The principal outcome that was measured was the confirmed diagnosis of lung cancer. In cases where emphysema was observed, the adjusted OR served as the key outcome. RR and HR were treated as OR due to the low occurrence rate of lung cancer (22). If stratified ORs were reported in a study, a combined OR was estimated utilizing a random-effects model. Subgroup analyses were also conducted based on the severity of the emphysema and GOLD score.

The I^2^ statistic was employed to estimate heterogeneity, which was categorized as low, moderate, substantial, or considerable (0–25%, 26–50%, 51–75%, and 76–100%, respectively) (23). Potential sources of variability were investigated through stratified analyses that considered region, sources of participants, and the design of the studies. Funnel plots served to assess any potential publication bias. Both visual inspection and the Egger’s test were utilized to evaluate asymmetry, which may signify publication bias. Subsequently, the trim-and-fill technique was employed to adjust for publication bias and to evaluate the stability of our findings. Additionally, we assessed the robustness of the estimates using a leave-one-out sensitivity analysis, in which each study was removed one at a time, followed by a recalculation of the OR. Finally, a significance level of P<0.05 was used to determine statistical significance. Statistical analysis was performed using Stata Standard Edition, version 18 (StataCorp., College Station, TX, USA).

Results

Literature search

As depicted in Figure 1, 6,114 studies underwent initial screening based on their abstracts and titles. After this screening, 5,658 studies were excluded from further consideration. Upon conducting a full-text screening, one study was excluded due to the repetition of data sources (3). Ultimately, 12 articles met all inclusion criteria for this meta-analysis.

Study characteristics

The total number of samples across 12 studies was 22,190, including 1,649 patients with lung cancer and 827 lung nodules (Table 1). The research encompassed participants from diverse geographical locations, spanning the Americas (six from the USA), Europe (one from Germany, two from Norway, one from Spain), and Asia (two from Japan), with the majority hailing from the USA. There were six prospective studies and six retrospective studies. Sources of participants were derived from either hospitals (five out of 12 studies) or the general population (seven out of 12), with detailed source information provided in Table S1.

Quantitative CT was used in nine studies (24,26-32,35), and visual assessment was used in five (25,26,29,33,34). Emphysema was found in 37% of studies. Two studies featured visual and quantitative assessment (26,29). The definitions of emphysema employed for both visual and quantitative evaluations differed among the studies (Tables 2,3). In terms of quantitative CT evaluation, the HU threshold indicating low attenuation areas ranged between −880 and −950 HU, whereas the cutoffs for LAA% to identify the presence of emphysema spanned from 1% to 10%. Emphysema was categorized as a dichotomized threshold value in 11 studies and a continuous variable in three studies. Two studies allowed for converting a constant emphysema variable to a dichotomous variable (29,31). Moreover, eight studies used the GOLD score to assess COPD severity (24-30,33) (Table 3).

Data synthesis and meta-analysis

The aggregated total estimate for the relationship between lung cancer and emphysema was 2.45 (95% CI: 2.01–2.99) (Figure 2), with consistent results observed in the leave-one-out sensitivity analysis (Figure S1). Low heterogeneity was noted across the studies (I^2^=24.2%; P=0.213). A reasonable degree of symmetry was evident upon visually inspecting the funnel plot (Figure S2), and Egger’s test did not reveal significant publication bias (Egger’s t=1.26; P=0.241) (Figure S3).

Emphysema for lung cancer

The combined OR for lung cancer was 2.37 (95% CI: 1.93–2.80) in research employing visual evaluation, and 2.38 (95% CI: 1.85–3.05) in those utilizing quantitative evaluation. Research utilizing visual assessment exhibited substantial heterogeneity (I^2^=56.4%; P=0.057), whereas studies that applied quantitative assessment demonstrated showed low heterogeneity (I^2^=3.8%; P=0.397) (Figure 3).

Emphysema severity for lung cancer

Emphysema severity was associated with lung cancer as a risk factor, with the overall pooled ORs for lung cancer showing a gradual increase (3.66 for mild and 4.6 for moderate to severe) corresponding to the escalating severity of emphysema. Moderate heterogeneity was noted in research that suggested mild emphysema (I^2^=39.7%) compared with moderate to severe cases (I^2^=0%) (Figure 4).

COPD severity for lung cancer

COPD severity was also associated with lung cancer as a risk factor. The overall pooled ORs for lung cancer gradually increased (1.56, 1.64, 2.02) as the COPD severity increased (GOLD I, GOLD II, GOLD III–IV), respectively. Low heterogeneity was observed for studies that reported GOLD I stage (I^2^=23.3%; P=0.266) compared with GOLD II stage (I^2^=0.0%; P=0.729) and GOLD III–IV stage (I^2^=27.6%; P=0.237) (Figure 5).

Lung cancer confirmed by pathology

All studies confirmed lung cancer through histologic examination, with four studies providing specific histologic distributions (26,29,32,33). Adenocarcinoma was the most prevalent type, accounting for 288 of 613 cases. Two studies reported a total of 827 pulmonary nodules, of which 334 (40%) were confirmed as lung cancer through pathology (31,35).

Sources of heterogeneity

In the supplementary stratified analyses, we examined the possible sources of heterogeneity. The combined ORs were similar between case-control studies (2.54; 95% CI: 1.84–3.51; I^2^=45.7%; P=0.101) and cohort studies (2.21; 95% CI: 1.78–2.75; I^2^=0%; P=0.532). Likewise, the combined ORs were found to be similar for both retrospective (2.13; 95% CI: 1.75–2.59; I^2^=4.5%; P=0.381) and prospective studies (3.10; 95% CI: 2.31–4.17; I^2^=0.0%; P=0.481). Studies based on population showed a moderate degree of heterogeneity (I^2^=41.8%). The pooled OR was 2.74 (95% CI: 2.01–3.73; P=0.127), which is similar to that found in studies conducted in hospital settings (2.24; 95% CI: 1.69–2.97; I^2^=9.8%; P=0.351). Regarding regional differences, the pooled ORs were 2.21 (95% CI: 1.82–2.69; I^2^=10.2%; P=0.351) for America, 2.39 (95% CI: 1.51–3.79; I^2^=0%; P=0.495) for Asia, and 4.10 (95% CI: 2.51–6.71; I^2^=0%; P=0.42) for Europe. As for CT scan parameters, we observed the substantial heterogeneity (I^2^=61.4%) in monophasic CT scan (inspiratory scan only), which had a pooled OR 2.43 (95% CI: 1.57–3.77; P=0.035) comparable to that of dual-phase CT scans (2.72; 95% CI: 1.86–2.97; I^2^=0.0%; P=0.605). As for radiation dose differences, the pooled ORs were 2.21 (95% CI: 1.72–3.59; I^2^=63.4%; P=0.027) for low-dose CT and 2.39 (95% CI: 1.58–3.63; I^2^=0.0%; P=0.792) for standard-dose CT. Additionally, a pooled OR of 2.43 (95% CI: 1.87–3.14; I^2^=24.1%; P=0.253) was observed based on thin CT sections (Appendix 1).

Risk of bias assessment

According to the QUADAS-2 tool, Figure S4 provides a summary of the assessment of this study. Regarding patient selection, the risk of bias was low at 6 (50%) and high at 6 (50%). The risk of bias for the reference standard test was low in nine studies (75%), high in one study (8%), and unclear in two studies (17%). The risk of bias for the index test was low in eight studies (75%) and unclear in four studies (25%). Regarding the flow and timing, the risk of bias was the same as the reference standard.

Discussion

Our systematic review of the literature identified 12 studies that explored the association between COPD and lung cancer. In our meta-analysis, we noted that the population sources in Labaki* et al.’s study were identical to those utilized in the study by Yong et al. (3,34), both of which were derived from the National Lung Screening Trial (NLST). In accordance with the PRISMA statement (13), we selected the study by Yong et al. due to its larger sample size of 16,624 participants, compared to 7,262 participants in the study by Labaki et al.*

This article examined the relationship between emphysema and lung cancer, revealing an overall pooled OR of 2.45 (95% CI: 2.01–2.99). The pooled OR for lung cancer was 2.37 (95% CI: 1.93–2.80) in studies using visual assessment and 2.38 (95% CI: 1.85–3.05) in those using quantitative assessment. The combined ORs for lung cancer progressively rose (3.66 to 4.6) with the escalation of emphysema severity, moving from mild to moderate and then to severe stages. Meanwhile, the overall pooled ORs for lung cancer gradually increased (1.56, 1.64, 2.02) as the COPD severity increased (GOLD I, GOLD II, GOLD III–IV), respectively.

Quantitative CT assessment was discovered to correlate with an increased risk of lung cancer, with a pooled odds ratio of 2.38 (95% CI: 1.85–3.05). Meanwhile, the visual evaluation had higher heterogeneity (I^2^=56.4%), which favors previous studies by Yang et al. (11). It is important to note that each emphysema assessment method has its limitations. Although the visual assessment method was well-developed with standardized criteria (14,17), significant variation was observed both between and within observers. Conversely, when uniform equipment and protocols are employed, the quantitative evaluation is objective, swift, and exceptionally reproducible (17,36,37).

Inconsistent CT scanning parameters across different institutions, such as slice thickness, HU threshold, and LAA% cut-off values also influenced the variability in quantitative CT assessments (36). Conversely, we noted that the definitions of dichotomous emphysema employed for both visual and quantitative evaluations vary among different studies. There is a lack of uniformity in the HU thresholds and the LAA% cutoffs employed to determine the severity of emphysema. Moreover, the current study does not offer standardized guidelines or recommendations for LAA staging classification. These discrepancies may contribute to significant variations in the reported incidence of emphysema. Therefore, it is essential to standardize CT scanning parameters and establish reliable LAA% staging guidelines to ensure the accuracy and consistency of quantitative CT assessments (17,18,36).

Pulmonary function serves as a crucial foundation for GOLD classification. The risk assessment stratification by GOLD also underscores the correlation between airway obstruction and the potential for lung cancer, marking a distinctive aspect of innovation in our article. We found that COPD severity was positively associated with lung malignancy, particularly from the GOLD II to the GOLD III–IV stage. We combined GOLD III and IV classifications due to limited data in some studies. According to the GOLD guideline, GOLD III–IV indicates a predicted FEV1 <50%. Some studies suggest that the disease risk does not increase when the ratio exceeds this threshold (38,39). Meanwhile, the main basis of GOLD grade is spirometry, including FEV1pred% (predicted FEV1). The GOLD grade reflects the airway obstruction status of patients. From GOLD II to GOLD III–IV, there was a 1.6-fold and 2.0-fold increased odds of lung cancer, respectively. Other studies have also reported that the risk of lung cancer increases with the severity of COPD (40).

The interplay among emphysema, COPD, and lung cancer risk is intricate. It is well established that chronic bronchitis, which leads to airway thickening, accounts for the incomplete correlation between emphysema and airflow obstruction. Some studies have evaluated airway thickening using dedicated software, indicating that this metric plays a significant role in the diagnosis of COPD and lung cancer screening. Mets et al. demonstrated that the quantitative evaluation of CT imaging related to emphysema, air trapping, and bronchial wall thickness offers distinct diagnostic insights for COPD. Moreover, inspiratory CT biomarkers alone may suffice to identify patients with COPD in the context of lung cancer screening (41). Additionally, Schreuder et al. developed risk models to predict lung cancer incidence, cardiovascular disease, and COPD mortality, revealing that the utilization of quantitative measures of COPD [including mean lung density, emphysema score, and the square root of wall area of a hypothetical airway with internal perimeter of 10 mm (Pi10)] enhances the prediction accuracy of lung cancer incidence (42). Therefore, integrating these quantitative indicators in future research is essential, as this comprehensive approach may illuminate the complex relationships between emphysema, COPD, and lung cancer.

Although this study performed a meta-analysis of emphysema severity and five studies stratified the severity of emphysema, only one study provided the OR values of trace emphysema. In one study, Nishio* et al.*, only classified emphysema as mild or severe (31). However, several studies have also reported that the risk of lung cancer increases with the severity of emphysema. For example, Yang et al. conducted six emphysema severity studies with 2,730 patients. Comparatively, this research included five studies (1,267 patients) for meta-analysis, with varying degrees of emphysema (11). Inadequate sample size may explain any inconsistencies across different studies. Therefore, the resulting pooled OR values were inadequate to support the meta-analysis due to different evaluation criteria.

Several limitations in this study warrant attention. Firstly, the data incorporated into this meta-analysis lacks sufficient evidence to conclusively establish whether CT-defined emphysema holds a higher independent predictive value than recognized risk factors for emphysema and lung cancer. Secondly, the constrained sample size hindered our ability to conduct a meta-analysis on the severity of emphysema (only one study reported trace emphysema for lung cancer). Thirdly, our evaluation of the risk associated with COPD was incomplete due to some articles lacking adjustments for COPD.

Conclusions

In summary, the diagnosis of emphysema through CT scans was linked to an elevated risk of developing lung cancer. The relationship between CT-defined emphysema and increased lung cancer risk, along with the correlation between the severity of COPD and malignancy, suggests the utility of CT imaging in flagging at-risk individuals. Although emphysema is incurable, CT scanning can be utilized to screen for and monitor early lung cancer, allowing for timely intervention. These strategies increase the window for early intervention in at-risk populations, ultimately allowing for better patient outcomes (Figure 6).

Supplementary