The diagnostic value of apolipoprotein E in malignant pleural effusion associated with non-small cell lung cancer
Introduction
Lung cancer has the highest mortality of all cancers, and its incidence is gradually increasing [1]. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for 80% of all lung cancer cases, and includes squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. Despite substantial improvements in surgical resection, chemotherapy, and radiation therapy, patients with lung cancer remain extremely vulnerable to relapse and death [2]. The cure rate of lung cancer is very low, and the average 5-year survival rate of patients with this cancer is < 15% [3], [4], [5], [6]. Patients with NSCLC often develop a malignant pleural effusion (MPE), which contains proteins from the circulation or from local inflammation or release of epithelial cells [7].
A pleural effusion is an abnormally large volume of fluid around the lung resulting from any of a number of medical conditions. A pleural effusion can be malignant or benign. Benign pleural effusion results from conditions such as tuberculosis or pneumonia, while MPE results from lung cancer and other cancers of the thorax. A cytologic test is the standard basis for diagnosis of MPE, but the positivity rate in known MPE varies considerably (from 11% to 78%) [8]. Thoracoscopy can greatly improve diagnostic sensitivity (90%) [9], but it has a high cost and is associated with injury and other complications and thus is limited in its clinical application.
While cytologic testing is the standard for diagnosis of MPE, it is also laborious and time-consuming. Because the cytologic testing can be sometimes subjective and the positivity rate varies [8], a more reproducible and specific test is needed to improve the diagnostic accuracy. A surrogate biochemical marker that allows differentiation of MPE in NSCLC from pleural effusion due to other diseases would be helpful in guiding and monitoring therapy as well as predicting prognosis. Efforts have been made to find markers that would improve the positivity rate in MPE, including tumor markers. Tumor markers are molecules secreted from tumor cells or produced by the host in response to cancer during the course of cancer genesis, development, invasion, and metastasis. These molecules are released into the blood or pleural effusion; in fact, their concentrations in pleural effusion may be much higher than in serum [10]. Tumor markers can be measured easily and quickly on automated analyzers.
Apolipoprotein E (apoE) is an important plasma lipoprotein that controls transportation and metabolism of cholesterol. It is well known that diseases such as atherosclerosis and Alzheimer disease are associated with different phenotypes and genotypes of abnormal apoE function [11], [12]. Overexpression of apoE has been shown to be related to cancer [13], [14], [15]. Moreover, apoE levels were found to be elevated in pleural effusions of patients with NSCLC [16], [17]. A recent study demonstrated that apoE expression was increased more frequently in lung cancer tissues of patients with MPE-associated lung adenocarcinoma than in those with lung adenocarcinoma or squamous cell carcinoma without MPE, suggesting that there is correlation between apoE and lung adenocarcinoma-associated MPE [18]. However, only limited data are available regarding the value of apoE in diagnosis of NSCLC-associated pleural effusion. Moreover, the diagnostic sensitivity and specificity of apoE in pleural effusion associated with NSCLC have not been well established. In this study, we aimed to determine the clinical role and laboratory diagnostic value of pleural fluid apoE in providing a more reliable and fast diagnosis of MPE in NSCLC, which would assist in guiding and monitoring therapy as well as predicting the course of the disease.
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Participants
Pleural effusion specimens were prospectively collected from 200 patients with lung disease who presented at the First Affiliated Hospital of Wenzhou Medical College, China, between April 2011 and January 2012. Of the 200 patients, 160 were shown to have MPE from NSCLC diagnosed by histologic and immunohistologic analyses. The baseline demographic characteristics of these patients are summarized in Table 1.
The other 40 patients had benign pleural effusion resulting from a disease such as
apoE levels in MPE and benign pleural effusions
Glucose and protein levels were distributed normally, whereas other parameters were not normally distributed as determined by the Shapiro–Wilk test. Differences in age and sex distributions among the groups were not statistically significant (Table 2, Table 3). The median apoE concentration in MPE was 52.5 ng/ml (0.5–414.5 ng/ml), which was higher than that in benign pleural fluid. Levels of CEA, CY211, and protein in MPE were significantly higher than those in benign pleural effusions (Table 2
Discussion
Since the treatment approach and prognosis are distinctly different, it is extremely important to differentiate benign pleural effusion from MPE. Cytologic and pathologic evaluations are the reference standard for distinguishing benign pleural effusion from MPE, but these methods lack sensitivity. In searching for a marker of MPE that might offer greater diagnostic sensitivity, we examined the expression of apoE in pleural effusions. The level of apoE in MPE was significantly higher than that
Acknowledgments
This work was supported by the funds from Wenzhou Municipal Science and Technology Bureau, China (Y20110041).
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These authors contributed equally to this work.