Malignant pleural effusion (MPE) is one of the most common pleura-associated conditions observed in clinical practice. The development of MPE usually defines advanced cancer with a poor prognosis. Carbohydrate antigen 15-3 (CA 15-3), as an effective pleural fluid biomarker, has been an object of ongoing research in the detection of MPE. The aim of this meta-analysis was to establish the overall diagnostic accuracy of the measurement of pleural CA 15-3 for diagnosing MPE. The databases Medline (using PubMed as the search engine), Embase, Ovid, Web of Science and Cochrane database (up to December 2013) were searched to identify relevant studies. No lower date limit was applied. All literature published in English was reviewed. Sensitivity, specificity, likelihood ratio and diagnostic odds ratio (DOR) were pooled using a random-effect model. Summary receiver operating characteristic (SROC) curve analysis was conducted to evaluate the overall diagnostic value. The methodological quality was assessed in line with the Quality Assessment for Studies of Diagnostic Accuracy statement. Twenty-one studies with a total of 2,861 cases were included in present meta-analysis. The sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR) and DOR of CA 15-3 in the diagnosis of MPE were 0.58 [95% confidence interval (CI), 0.56–0.61], 0.91 (95% CI, 0.90–0.93), 8.93 (95% CI, 4.45–17.93), 0.46 (95% CI, 0.37–0.56) and 24.89 (95% CI, 10.39–59.63), respectively. In addition, the area under the curve (AUC) was 0.84. In conclusion, due to the significantly high specificity of pleural CA 15-3 in detecting MPE, it may play a pivotal role in screening to identify patients who may benefit from further invasive pathologic examination, particularly in those presenting clinical manifestations of MPE but with negative cytological findings of the pleural fluid. However, ruling out MPE by testing CA15-3 alone is not recommended due to its limited sensitivity, and it is recommended that the results of CA15-3 assays are interpreted in parallel with conventional test results and other clinical findings.
CA 15-3; malignant pleural effusion; diagnosis; meta-analysis
Clinical history and physical examination are helpful in indicating the potential causes of pleural effusions (PEs). However, the accurate diagnosis and establishment of the causes of PE is an ongoing challenge in daily clinical practice. The primary aim of this study was to distinguish between infectious PE and malignant PE (MPE) by measuring two major acute phase response biomarkers: prealbumin (PA) and C-reactive protein (CRP). The study was a prospective trial involving 151 patients who were diagnosed with infectious PE or MPE. Patients with infectious PE were divided into two subgroups: tuberculous PE (TBPE) and parapneumonic PE (PNPE). A further 58 patients with PEs that showed no evidence of MPE, TBPE or PNPE were classified as the chronic non-specific PE (NSPE) group. Demographic characteristics and pleural fluids of the subjects were collected consecutively. The discriminative properties of pleural fluid routine biochemistries, and PA and CRP were evaluated. PA, CRP and classical fluid parameters were also applied to classify patients with infectious PE and MPE. Receiver operating characteristics (ROC) analysis established the cutoffs of PA and CRP for discriminating between groups. Pleural fluid PA levels were significantly higher in the MPE group (n=47) than in the infectious PE group (n=104). Pleural fluid CRP levels were significantly higher in the infectious PE group than in the MPE group. Pleural fluid PA levels were identified to be moderately negatively correlated with CRP levels in the MPE group, with a statistically significant correlation coefficient of −0.352. The ROC curve showed that the sensitivity and specificity of PA for the diagnosis of MPE were 0.851 and 0.548, respectively, at the cutoff of 28.3 mg/l. The area under the curve (AUC) was 0.784 (95% CI, 0.707–0.861). Using CRP as a diagnostic parameter resulted in an comparable AUC of 0.810 (95% CI, 0.736–0.885), at the cutoff of 35.2 mg/l. Combinations of PA and CRP resulted in incrementally discriminating values for MPE, with a sensitivity of 0.617 and a specificity of 0.903. The measurement of PA and CRP levels in pleural fluid may be a useful adjunctive test in PE, as a potential differentiator between infectious PE and MPE.
prealbumin; C-reactive protein; pleural effusion
Myelomatous pleural effusion (MPE) is rare in myeloma patients. We present a consecutive series of patients with MPE in a single institution.
We retrospectively reviewed the medical records of 19 patients diagnosed with MPE between 1989 and 2008 at the Asan Medical Center. Diagnoses were confirmed by cytologic identification of malignant plasma cells in the pleural fluid.
Our patients showed dominance of IgA (36.8%) and IgD (31.6%) subtypes. Of 734 myeloma patients, the incidence of MPE was remarkably high for the IgD myeloma subtype (16.7%), compared to the other subtypes (1.4% for IgG and 4.6% for IgA). At the time of diagnosis of MPE, elevated serum β2-microglobulin, anemia, elevated serum lactate dehydrogenase, and elevated creatinine levels were found in 100%, 89.5%, 83.3%, and 57.9% of the patients, respectively. Approximately one-third (31.3%) of the patients had adenosine deaminase (ADA) activities in their pleural fluid exceeding the upper limit of the reported cutoff values for tuberculous pleural effusion (55.8 U/L). Chromosome 13 abnormality was seen in 77.8% of the tested patients. The median survival period from the development of MPE was 2.8 months.
Patients with MPE have aggressive clinical and laboratory characteristics. The preponderance of IgD myeloma in MPE patients is a noteworthy finding because IgD myeloma is a rare subtype. Elevated ADA activity in the pleural fluid is also noteworthy, and may be helpful for detecting MPE. Physicians treating myeloma patients should monitor the development of MPE and consider the possibility of a worse clinical course.
Myelomatous pleural effusion; IgD myeloma; Adenosine deaminase; Chromosome 13 abnormality
Pleural effusions (PE) are a common clinical problem. The discrimination between benign (BPE), malignant (MPE) and paramalignant (PPE) pleural effusions is highly important to ensure appropriate patient treatment. Today, cytology is the gold standard for diagnosing malignant pleural effusions. However, its sensitivity is limited due to the sometimes low abundance of tumor cells and the challenging assessment of cell morphology in cytological samples. This study aimed to develop and validate a diagnostic test, which allows for the highly specific detection of malignant cells in pleural effusions based on the DNA methylation biomarkers SHOX2 and SEPT9. A quantitative real-time PCR assay was developed which enabled the accurate and sensitive detection of SHOX2 and SEPT9 in PEs. Cytological and DNA methylation analyses were conducted in a case control study comprised of PEs from 114 patients (58 cases, 56 controls). Cytological analysis as well as SHOX2 and SEPT9 methylation resulted in 100% specificity. 21% of the cases were cytologically positive and 26% were SHOX2 or SEPT9 methylation positive. The combined analysis of cytology and DNA methylation resulted in an increase of 71% positively classified PEs from cancer patients as compared to cytological analysis alone. The absolute sensitivity of cytology and DNA methylation was not determinable due to the lack of an appropriate gold standard diagnostic for distinguishing between MPEs and PPEs. Therefore, it was unclear which PEs from cancer patients were malignant (containing tumor cells) and which PEs were paramalignant and resulted from benign conditions in cancer patients, respectively. Furthermore, DNA methylation analysis in PEs allowed the prognosis of the overall survival in cancer patients (Kaplan-Meier analysis, log rank test, p = 0.02 (SHOX2), p = 0.02 (SEPT9)). The developed test may be used as a diagnostic and prognostic adjunct to existing clinical and cytopathological investigations in patients with PEs of unclear etiology.
Malignant pleural effusions (MPE) are a common and fatal complication in cancers including lung or breast cancers, or malignant pleural mesothelioma (MPM). MPE animal models and immunotherapy trials in MPM patients previously suggested defects of the cellular immunity in MPE. However only few observational studies of the immune response were done in MPM patients, using questionable control groups (transudate…).
We compared T cell populations evaluated by flow cytometry from blood and pleural effusion of untreated patients with MPM (n = 58), pleural metastasis of adenocarcinoma (n = 30) or with benign pleural lesions associated with asbestos exposure (n = 23). Blood and pleural fluid were also obtained from healthy subjects, providing normal values for T cell populations.
Blood CD4+ or CD8+ T cells percentages were similar in all groups of patients or healthy subjects. Whereas pleural fluid from healthy controls contained mainly CD8+ T cells, benign or malignant pleural effusions included mainly CD4+ T cells. Effector memory T cells were the main T cell subpopulation in pleural fluid from healthy subjects. In contrast, there was a striking and selective recruitment of central memory CD4+ T cells in MPE, but not of effector cells CD8+ T cells or NK cells in the pleural fluid as one would expect in order to obtain an efficient immune response.
Comparing for the first time MPE to pleural fluid from healthy subjects, we found a local defect in recruiting effector CD8+ T cells, which may be involved in the escape of tumor cells from immune response. Further studies are needed to characterize which subtypes of effector CD8+ T cells are involved, opening prospects for cell therapy in MPE and MPM.
Pleura; Effusion; Tumor; Mesothelioma; Immunity; Lymphocytes
Lysophosphatidic acid (LPA) is an important extracellular signal transmitter and intracellular second messenger in body fluids. It can be detected in the ascitic fluid of patients with ovarian cancer. Increasing evidence shows that LPA can stimulate cancer cell proliferation and promote tumor invasion and metastasis. Our study aimed to evaluate the diagnostic value of LPA in differentiating between malignant pleural effusions (MPEs) and benign pleural effusions (BPEs) and to evaluate the association between the level of LPA in MPE and the prognosis of lung cancer patients.
Patients and methods
The level of LPA in the pleural effusions (PEs) of 123 patients (94 MPE, 29 BPE) with lung cancer was evaluated using an enzyme-linked immunosorbent assay. The performance of LPA was analyzed by standard Receiver operator characteristic curve (ROC) analysis methods, using the area under the curve (AUC) as a measure of accuracy. Overall survival (OS) curves and progression-free survival (PFS) curves were based on the Kaplan-Meier method, and the survival differences between subgroups were analyzed using the log-rank or Breslow test (SPSS software). A multivariate Cox proportional hazards model was used to assess whether LPA independently predicted lung cancer survival.
The levels of LPA differed significantly between MPE (22.08±8.72 µg/L) and BPE (14.61±5.12 µg/L) (P<0.05). Using a cutoff point of 18.93 µg/L, LPA had a sensitivity of 60% and a specificity of 83% to distinguish MPEs from BPEs with an AUC of 0.769±0.045 (SE) (P=0.000) (95% CI, 0.68-0.857). In the three pathological types of lung cancer patients with MPE, there were no significant associations between LPA levels and the length of PFS and OS (P=0.58 and 0.186, respectively). Interestingly, in the patients with MPE caused by lung adenocarcinoma there were significant associations between the LPA levels and the PFS and OS (P=0.018 and 0.026, respectively). Multivariate analysis showed that the LPA level was an independent prognostic factor for PFS in lung adenocarcinoma.
Our results indicate that LPA can be used as a new biomarker for the diagnosis of MPE caused by lung cancer and that higher levels of LPA are related to shorter PFS in adenocarcinoma of the lung.
Lysopohsphatidic acid (LPA); malignant pleural effusions (MPEs); lung cancer; diagnosis; prognosis
The diagnosis of malignant mesothelioma is frequently difficult, the most common differential diagnosis being reactive pleural conditions and metastatic adenocarcinoma. Soluble mesothelin levels in serum have recently been shown to be highly specific and moderately sensitive for mesothelioma. As most patients with mesothelioma present with exudative effusions of either the pleura or the peritoneum, a study was undertaken to determine if levels of mesothelin were raised in these fluids and if the increased levels could help to distinguish mesothelioma from other causes of exudative effusion.
Pleural fluid was collected from 192 patients who presented to respiratory clinics (52 with malignant mesothelioma, 56 with non‐mesotheliomatous malignancies and 84 with effusions of non‐neoplastic origin). Peritoneal fluid was collected from 42 patients (7 with mesothelioma, 14 with non‐mesotheliomatous malignancies and 21 with benign effusions). Mesothelin levels were determined in effusion and serum samples by ELISA.
Significantly higher levels of mesothelin were found in effusions of patients with mesothelioma; with a specificity of 98%, the assay had a sensitivity of 67% comparing patients with mesothelioma and those with effusions of non‐neoplastic origin. In 7 out of 10 cases mesothelin levels were raised in the effusion collected 3 weeks to 10 months before the diagnosis of mesothelioma was made; in 4 out of 8 of these, mesothelin levels were increased in the effusion but not in the serum.
Measurement of mesothelin concentrations in the pleural and/or peritoneal effusion of patients may aid in the differential diagnosis of mesothelioma in patients presenting with effusions.
The accurate and timely diagnosis of malignant pleural effusion (MPE) in lung cancer patients is important because MPE has a poor prognosis and is classified as stage IV disease. Molecular biomarkers for pleural effusion, such as circulating extracellular microRNAs (miRNAs) isolated from pleural fluid, may help in the diagnosis of MPE. The present study examined whether miRNAs that are deregulated in lung cancer (miR-134, miR-185, and miR-22) can serve as diagnostic markers for lung adenocarcinoma-associated MPE (LA-MPE).
Materials and Methods
Real-time reverse transcription quantitative polymerase chain reaction was used to measure the expression of the three miRNAs in samples from 87 patients with pleural effusion comprising 45 LA-MPEs and 42 benign pleural effusions (BPEs). The area under the receiver operating characteristic curve (AUC) was then used to evaluate the diagnostic performance of each of the three miRNAs and compare it with that of the common tumor marker, carcinoembryonic antigen (CEA).
The expression of all three miRNAs was significantly lower in LA-MPE than in BPE (p <0.001). The AUCs for miR-134, miR-185, miR-22, and CEA were 0.721, 0.882, 0.832, and 0.898, respectively. Combining CEA with the three miRNAs increased the diagnostic performance, yielding an AUC of 0.942 (95% confidence interval, 0.864 to 0.982), with a sensitivity of 91.9% and a specificity of 92.5%.
The present study suggests that the expression levels of circulating extracellular miR-134, miR-185, and miR-22 in patients with pleural effusion may have diagnostic value when differentiating between LA-MPE and BPE.
Adenocarcinoma; Lung; miR-134; miR-185; miR-22; Pleural effusion
Objective: To investigate the diagnostic accuracy of survivin for malignant pleural effusion (MPE). Methods: Pleural effusion samples were collected from 40 MPE patients and 45 non-MPE patients. Pleural levels of survivin were measured by ELISA. Literature search was performed in Pubmed and Embase to identify studies regarding the usefulness of survivin to diagnose MPE. Data were retrieved and the pooled sensitivity, specificity and other diagnostic indexes were calculated. The summary receiver operating characteristics (SROC) curve was used to determine the overall diagnostic accuracy. Results: The pleural levels of survivin were higher in MPE patients than non-MPE patients (844.17 ± 358.30 vs. 508.08 ± 169.58 pg/ml, P < 0.05), at a cut-off value of 683.2 pg/ml, the sensitivity and specificity were 57.50% and 88.89%, respectively. A total of six studies were included in present meta-analysis, the overall diagnostic estimates were: sensitivity 0.74 (95% CI: 0.59-0.85); specificity, 0.85 (95% CI: 0.79-0.89); positive likelihood ratio, 4.79 (95% CI: 3.48-6.61); negative likelihood ratio, 0.31 (95% CI: 0.19-0.50), and diagnostic odds ratio, 15.59 (95% CI: 7.69-31.61). The area under SROC curve was 0.86 (95% CI: 0.82-0.89). Conclusion: Our study confirms that the pleural survivin plays a role in the diagnosis of MPE. More studies at a large scale should be performed to validate our findings.
Survivin; malignant pleural effusion; diagnosis; meta-analysis
The protein neutrophil gelatinase-associated lipocalin (NGAL) is a mediator synthesized and released by neutrophils. Its physiological function is as yet unclear. Levels in blood increase in several inflammatory diseases. High serum values indicate poor prognosis for several diseases. Pleural effusion may appear as the result of various pathologies. The most common cause is heart failure (HF). Other common causes include parapneumonic (PPE) and malignant (MPE) pleural effusions, and pulmonary embolism. Tubercular effusion (TE) is commonly encountered in Turkey and similar developing countries. The purpose of this study was to investigate the effectiveness of NGAL, a current inflammation marker, in discriminating between different etiological diseases that cause pleural effusion.
The study was performed at the Recep Tayyip Erdoğan University Faculty of Medicine Chest Diseases Clinic. One hundred patients were included in the study, 25 with parapneumonic effusion, 25 with heart failure-related effusion, 25 with tubercular effusion and 25 with cancer-related effusion. NGAL was measured in patients’ serum and pleural fluids.
Serum NGAL levels in PPE (171 ± 56 ng/ml) were significantly higher (p < 0.001) than those in HF (86 ± 31 ng/ml), CA (103 ± 42 ng/ml) and TE (63 ± 19 ng/ml). Pleural NGAL levels were also significantly higher in PPE compared to HF, MPE and TE (p < 0.001). Serum NGAL levels exhibited a positive correlation with white blood cell (WBC), neutrophil, C-reactive protein (CRP), sedimentation, serum LDH, creatinine, pleural leukocyte and pleural neutrophil numbers. The most significant correlation was between NGAL level and WBC (p < 0.001, r = 0.579). Both serum and pleural NGAL levels are highly effective in differentiating patients with PPE from those without PPE (AUC: 0.910 and 0.790, respectively).
NGAL can be used in the diagnosis of diseases with an acute inflammatory course. Serum and pleural NGAL levels can differentiate PPE from other diseases causing pleural fluid with high sensitivity and specificity.
Neutrophil gelatinase-associated lipocalin; NGAL; Pleural effusion; Parapneumonic effusion
Tuberculous pleural effusions (TPEs) and malignant pleural effusions (MPEs) are difficult to differentiate between in certain clinical situations. Interleukin (IL)-33 is a cytokine that participates in inflammatory responses and may have a role in pleural effusions. The present study aimed to investigate the concentrations and potential differential significance of IL-33 in patients with TPE and MPE. IL-33 levels in pleural effusion and serum samples were detected using sandwich enzyme-linked immunosorbent assay in 23 patients with TPE and 21 patients with MPE. The concentration of IL-33 (mean ± standard deviation) in the TPE patients (22.962±0.976 ng/l) was significantly higher than that in the MPE patients (12.603±5.153 ng/l; P<0.001; z=−4.572); however, there was no significant difference in the serum level of IL-33 in the patients with TPE compared with those with MPE (P>0.05). The concentration of IL-33 in the pleural effusions was positively correlated with that in the serum samples in each group (TPE: r=0.563, P=0.05; MPE: r=0.535, P<0.05). The cut-off value of pleural IL-33 for TPE was 19.86 ng/l, which yielded a sensitivity of 0.869, a specificity of 0.905 and an area under the corresponding receiver operating characteristic curve of 0.903. The present study identified that the level of pleural IL-33 is significantly increased in TPEs and may serve as a novel biomarker to differentiate between patients with TPE and MPE.
interleukin-33; pleural effusion; peripheral blood; tuberculous pleurisy; malignant pleural effusion
Lung adenocarcinoma is one of the most frequent causes of malignant pleural effusions (MPE). The presence of MPE bears a poor prognosis. Although epigenetic changes are commonly related to human neoplasia, scarce date is available on patients with MPE. We aimed to estimate the prognostic value of DNA methylation of tumor suppressor genes from pleural fluid. Thirty patients with MPE due to lung adenocarcinoma were prospectively included. Methylation-specific (MS) PCR was used to study the methylation status of the promoter region of tumor suppressor genes p16/INK4a, MGMT, BRCA1 and RARβ in pleural fluid. Clinical data and survival were collected. Survival analysis was performed using Kaplan-Meier plots and Cox regression. Hypermethylation in at least one gene was detected in 25 patients (83.3%). On multivariate analysis factors significantly associated with shorter survival were the lack of hypermethylation in any of the studied genes (hazard ratio = 9.3; p = 0.001), Charlson index ≥ 3 (hazard ratio = 9.6, p = 0.002) and no oncological treatment (hazard ratio = 11.1; p < 0.001). Analysis of aberrant promoter hypermethylation of tumor suppressor genes may be useful in predicting prognosis, but further studies are needed to validate our findings.
lung adenocarcinoma; malignant pleural effusion; DNA hypermethylation; prognosis; survival; treatment; comorbidity
Pleural malignant mesothelioma (MM) is a deadly tumour predominantly associated with asbestos exposure. A reliable diagnostic and prognostic marker for MM will significantly enhance clinical care and is an area of intense research. Soluble mesothelin is the most studied and an FDA-approved biomarker for MM. A recent report showed promising results using fibulin-3 as a new diagnostic marker. The aim of this study was to compare the utility of fibulin-3 versus mesothelin, singly or in combination.
Fibulin-3 and soluble mesothelin were determined by ELISA in the plasma and pleural fluid of 153 patients presenting with a pleural effusion including 82 with MM, 36 with non-MM malignant effusions and 35 with benign effusions. Biomarker concentrations were determined in the plasma of an additional 49 cases with benign asbestos-related disease.
Mesothelin provides better diagnostic accuracy than fibulin-3 for MM whether measured in plasma or pleural effusion: area under the curve (AUC) for plasma was 0.822 (95% CI 0.76 to 0.87) compared with 0.671 (0.61 to 0.73), respectively, and for pleural fluid AUC was 0.815 (0.74 to 0.87) compared with 0.588 (0.51 to 0.67), respectively. Effusion fibulin-3 was an independent significant prognostic factor for survival in MM patients; HR 2.08 (1.14 to 3.82), p=0.017. MM patients with effusion fibulin-3 levels below the median survived significantly longer than those with levels above the median (14.1 vs 7.9 months, p=0.012). Mesothelin and neutrophil to lymphocyte ratio were not significant prognostic markers.
Soluble mesothelin is a superior diagnostic biomarker for MM compared with fibulin-3, whereas fibulin-3 provides superior prognostic information compared with mesothelin.
Many studies have investigated the usefulness of cytokeratin 19 fragments (CYFRA 21-1) in pleural fluid for the differential diagnosis of benign (BPE) and malignant pleural (MPE) effusions. In the present meta-analysis, the reported studies on the diagnosis between CYFRA 21-1 and pleural effusion were assessed to summarize the diagnostic characteristics of CYFRA 21-1 in Chinese patients.
Material and methods
The data sources from the creation of each database up to January 2011 included Medline, Chinese National Knowledge Infrastructure, EMBASE, Cochrane Library, and bibliographies of review and original articles. Through a systematic literature search for publications, the data from 22 studies were summarized based on their discussions on the result of the CYFRA 21-1 assay in pleural effusion and differential diagnosis evaluation in the Chinese population.
A total of 22 studies were available for analysis, and the high CYFRA 21-1 level in MPE was significantly associated with risk for lung cancer (standardized mean difference [SMD] = 1.65, 95% confidence interval [CI] = 1.48–1.82, Z = 18.97, p < 0.00001) compared with BPE. The CYFRA 21-1 level in pleural effusion (13 studies) was significantly higher than that in serum (SMD = 1.10, 95% CI = 0.71–1.48, Z = 5.59, p < 0.00001). The risk for squamous cell carcinoma (SCC) for CYFRA 21-1 was 1.03 (95% CI = 0.64–1.42, Z = 5.15, p < 0.00001) compared with that of adenocarcinoma (8 studies). The sensitivity of CYFRA 21-1 reported in the articles ranged from 46% to 94%, and the specificity ranged from 57% to 100%. The summary measure of the test characteristics derived from the summary receiver operating characteristic curve was 81% for both sensitivity and specificity (17 studies).
The measurement of pleural CYFRA 21-1 is likely to be a useful diagnostic tool for the confirmation of MPE.
meta-analysis; CYFRA 21-1; pleural effusion; lung cancer; differential diagnosis; tumor marker
Pulmonary carcinoma is the main cause of malignant pleural effusions (MPEs). However, there is no satisfactory marker for diagnosing MPEs caused by pulmonary carcinoma. The purpose of this study is to assess the clinical significance of Lunx mRNA detection in diagnosing MPEs caused by pulmonary carcinoma.
A total of 209 patients with pleural effusions were recruited. The patients were diagnosed by cast-off cells, bronchoscopy, and pleural biopsy. The levels of Lunx mRNA in the pleural effusions were determined by real-time PCR. The levels of PH, LDH, glucose, albumin, and CEA were also determined. Patients who accepted chemotherapy underwent Lunx mRNA detection before and after the first chemotherapy session. The patients were divided into four groups according the effect of chemotherapy: complete remission (CR), partial remission (PR), no change (NC), and progressive disease (PD). The patients were also divided into two groups according the change in direction of Lunx mRNA expression after chemotherapy: increased group and decreased group. The patients were followed up to determine survival.
Lunx mRNA was positive in 89 of 106 patients with pleural effusions caused by pulmonary carcinoma. The specificity and sensitivity were 95.9% and 84.9%. The area under the ROC curve was 0.922. Lunx mRNA detection was better than detection using cast-off cells and CEA. All of the Lunx-positive patients with MPEs were diagnosed with pulmonary carcinoma, and all extrapulmonary carcinoma patients were Lunx-negative. The positive predictive value of Lunx mRNA for the source of tumor cells was 100%. Lunx mRNA expression decreased after the first session of chemotherapy in the CR and PR groups, increased in the PD group, there was no change in the NC group. Further analysis indicated the change in direction of Lunx mRNA expression was associated with the overall survival of patients. The patients in the increased group had longer overall survival times than those in the decreased group.
Lunx mRNA is a specific tumor gene that is highly expressed in MPEs caused by pulmonary carcinoma. The changes in Lunx mRNA levels after chemotherapy can predict the prognosis of patients with MPEs caused by pulmonary carcinoma.
Malignant pleural effusion; Pulmonary carcinoma; Lunx mRNA
CYFRA 21-1 assay, measuring cytokeratin 19 fragments, was compared with carcinoembryonic antigen (CEA) assay, as an addition to cytological analysis for the diagnosis of malignant effusions. Both markers were determined with commercial enzyme immunoassays in pleural fluid from 196 patients. Cytological analysis and/or pleural biopsy confirmed the malignant origin of the effusion in 99 patients (76 carcinomas, nine pleural mesotheliomas and 14 non-epithelial malignancies). Effusions were confirmed as benign in 97 patients (33 cardiac failures, 39 infectious diseases--including 12 tuberculosis-- and 25 miscellaneous effusions). Both markers were significantly higher in malignant than in benign effusions. All the patients with non-epithelial malignancies presented CYFRA and CEA values lower than the 95% diagnostic specificity thresholds (100 and 6 ng ml(-1) respectively). The diagnostic sensitivity in the group of carcinomas and mesotheliomas was similar for CYFRA (58.8%) and CEA (64.7%). However, CEA had a significantly higher sensitivity in carcinomas (72.4% vs 55.3%), while CYFRA had a clearly higher sensitivity in mesotheliomas (89.9% vs 0%). Interestingly, 12 out of the 16 malignant effusions with a negative cytology were CEA and/or CYFRA positive. Regarding their high diagnostic sensitivity and their complementarity, CEA and CYFRA appear to be very useful for the diagnosis of malignant pleural effusions when cytology is negative.
BACKGROUND--In conventional cytological diagnosis of pleural effusions the assessment of morphological features plays an important part. However, false negative and false positive results may occur. In this study conventional cytology was compared with flow cytometric DNA analysis and the argyrophil staining technique for nucleolar organiser regions (AgNOR) to characterise benign and malignant effusions. METHODS--Pleural effusions from 71 patients (38 with benign lung disease, 33 with proven adenocarcinoma of lung) were studied by conventional cytology, flow cytometric DNA analysis, and the AgNOR technique. Tumour cell ploidy was determined by flow cytometry. In an attempt to detect the cell proliferative state, flow cytometric S phase fraction and the AgNOR technique were used. The correlations among conventional cytology, flow cytometric DNA ploidy, S phase fraction analysis, and nucleolar organiser regions were investigated. RESULTS--All the 38 benign pleural effusions were diploid. There were 17 (52%) aneuploid and 16 (48%) diploid malignant pleural effusions. Based on these results this type of DNA analysis had a sensitivity of 52% and a specificity of 100%. The mean (SD) numbers of flow cytometric S phase fractions of benign and malignant cases were 5.32 (1.67)% and 12.45 (3.93)% respectively. The mean numbers of S phase fractions of diploid malignant cases were higher than diploid benign cases. In each case the number of AgNORs was counted in 100 cells. The mean number of AgNOR dots per nucleus was 12.57 (3.64) for malignant pleural effusion cells and 3.96 (1.39) for benign pleural effusion cells. The mean number of AgNOR dots was 14.45 (3.36) for aneuploid malignant pleural effusion cells and 10.57 (2.82) for diploid malignant pleural effusion cells. The AgNOR numbers were higher in diploid malignant cells than in diploid benign cells. There was a significant correlation between the S phase fraction determined by flow cytometry and the mean number of AgNORs per nucleus in malignant cases. CONCLUSIONS--Both flow cytometry and the AgNOR methods provide comparable measurements in the diagnosis of pleural effusion. The study also indicates that the AgNOR method, which is rapid and easy to perform, may be a useful adjunct to flow cytometry, S phase fraction analysis and conventional cytology in the routine diagnosis of malignant pleural effusion.
Conventional biomarkers cannot always establish the cause of pleural effusions; thus, alternative tests permitting rapid and accurate diagnosis are required. The primary aim of this study is to assess the ability of pentraxin-3 (PTX3) in order to diagnose the cause of pleural effusion and compare its efficacy to that of other previously identified biomarkers.
We studied 118 patients with pleural effusion, classified as transudates and exudates including malignant, tuberculous, and parapneumonic effusions (MPE, TPE, and PPE). The levels of PTX3, C-reactive protein (CRP), procalcitonin (PCT) and lactate in the pleural fluid were assessed.
The levels of pleural fluid PTX3 were significantly higher in patients with PPE than in those with MPE or TPE. PTX3 yielded the most favorable discriminating ability to predict PPE from MPE or TPE by providing the following: area under the curve, 0.74 (95% confidence interval, 0.63-0.84), sensitivity, 62.07%; and specificity, 81.08% with a cut-off point of 25.00 ng/mL.
Our data suggests that PTX3 may allow improved differentiation of PPE from MPE or TPE compared to the previously identified biomarkers CRP and PCT.
PTX3 Protein; Pleural Effusion
Pleural fluid cytology for malignant cells is the easiest way to diagnose malignant pleural effusion with good sensitivity and specificity. With the introduction of medical thoracoscopy, the use of closed pleural biopsy for the diagnosis of cytology negative malignant pleural effusion is gradually decreasing. However use of thoracoscopy is limited due to its high cost and procedure related complications.
The aim was to assess the usefulness of closed pleural biopsy in the diagnosis of malignant pleural effusion.
Materials and Methods:
Sixty-six patients of pleural effusion associated with malignancy were selected from the patients admitted in the chest ward of a tertiary care hospital over a period of 1 year. Pleural fluid aspiration for cytology and closed pleural biopsy were done in all the patients.
Out of 66 patients, 46 (69%) patients showed malignant cells in pleural fluid cytology examination. Cytology was positive in 35 (52%), 10 (15%), and 1 (1.5%) patients in the first, second, and third samples respectively. Closed pleural biopsy was positive in 32 (48%) patients. Among them, 22 also had positive cytology. Additional 10 cytology negative patients were diagnosed by pleural biopsy. Cytology–histology concordance was seen in 12 patients. Definite histological diagnosis could be achieved in five patients with indeterminate cytology. Pleural biopsy was not associated with any major postoperative complication.
Closed pleural biopsy can improve the diagnostic ability in cytology negative malignant pleural effusion. Closed pleural biopsy has still a place in evaluation of malignant pleural effusion especially in a resource-limited country like India.
Closed pleural biopsy; malignant pleural effusion; pleural fluid cytology
BACKGROUND--Aneuploidy appears to be a highly specific marker for cancer, and measurement of cellular DNA content by flow cytometry is rapid and reliable. This study was undertaken to determine if the addition of DNA analysis improved the sensitivity of cytological diagnosis of malignancy in pleural fluid. METHODS--Pleural effusions from 92 patients were studied by cytological examination and flow cytometry. RESULTS--In 41 patients the final diagnosis was malignancy, there were 40 cases of benign effusions including 22 with pleural tuberculosis, and in the remaining 11 patients with biopsy proven cancer the presence of malignant cells was not found by cytological and histological means in the pleural fluid. Aneuploidy and cytological malignancy were found in 14 samples. There were seven cases with abnormal flow cytometry and negative cytological results. In 12 patients the cytological test results were positive but DNA analysis was normal. Thirty six samples of fluid were both diploid and cytologically negative. Of the 22 tuberculous effusions seven contained aneuploid cells. The sensitivity of DNA and cytological analysis was 51.2% and 63.4%, respectively. The specificity of DNA analysis was 74.5%. CONCLUSIONS--DNA analysis of cells in malignant pleural effusions is both less sensitive and specific than the cytological diagnosis. Flow cytometric analysis is not recommended for routine use in the diagnosis of pleural effusions.
Rationale. The diagnosis of pleural malignant mesothelioma (MM) by effusion cytology may be difficult and is currently controversial. Effusion mesothelin levels are increased in patients with MM but the clinical role of this test is uncertain. Objectives. To determine the clinical value of measuring mesothelin levels in pleural effusion supernatant to aid diagnosis of MM. Methods and Measurements. Pleural effusion samples were collected prospectively from 1331 consecutive patients. Mesothelin levels were determined by commercial ELISA in effusions and their relationship to concurrent pathology reporting and final clinical diagnosis was determined. Results. 2156 pleural effusion samples from 1331 individuals were analysed. The final clinical diagnosis was 183 MM, 436 non-MM malignancy, and 712 nonmalignant effusions. Effusion mesothelin had a sensitivity of 67% for MM at 95% specificity. Mesothelin was elevated in over 47% of MM cases in effusions obtained before definitive diagnosis of MM was established. In the setting of inconclusive effusion cytology, effusion mesothelin had a positive predictive value of 79% for MM and 94% for malignancy. Conclusions. A mesothelin-positive pleural effusion, irrespective of the identification of malignant cells, indicates the likely presence of malignancy and adds weight to the clinical rationale for further investigation to establish a malignant diagnosis.
Since the diagnostic accuracy of conventional examinations for malignant pleural effusion (MPE) is limited, a number of studies have investigated the utility of pleural vascular endothelial growth factor (VEGF) in the diagnosis of MPE. The present meta-analysis aimed to determine the overall accuracy of a VEGF test in the diagnosis of MPE. A systematic review of studies published in English was conducted and the data concerning the accuracy of pleural VEGF assays in the diagnosis of MPE were pooled with random effects models. The overall test performance was summarized using receiver operating characteristic curves. Ten studies, based on 1,025 patients, met the inclusion criteria for the meta-analysis and the summary estimates for VEGF in the diagnosis of MPE were: sensitivity 0.75 [95% confidence interval (CI), 0.72–0.79], specificity 0.72 (95% CI, 0.68–0.76), positive likelihood ratio 2.94 (95% CI, 1.97–4.41), negative likelihood ratio 0.38 (95% CI, 0.27–0.51) and diagnostic odds ratio 9.05 (95% CI, 4.60–17.80). The summary receiver operating characteristic curve indicated that the maximum joint sensitivity and specificity was 0.75; the area under the curve was 0.82. Our findings suggest that the determination of pleural VEGF may improve the accuracy of MPE diagnosis, while the results of VEGF assays should be interpreted in parallel with conventional test results and other clinical findings.
malignant pleural effusion; vascular endothelial growth factor; meta-analysis
Though the possibility of using malignant pleural effusions (MPEs) as alternatives for metastatic pleural tumor tissues (MPTTs) in epidermal growth factor receptor (EGFR) mutation test has been examined, due to the lack of studies comparing the results in matching MPEs and MPTTs, the clinical value of MPEs for advanced adenocarcinoma patients with pleural effusions is not confirmed.
EGFR mutation statuses in matching MPTTs, MPE supernatants and cell blocks, of 41 patients with advanced lung adenocarcinoma as diagnosed by thoracoscopy were analyzed using amplification refractory mutation system (ARMS).
EGFR mutations were detected in 46.3% (19/41) of MPTTs, 43.9% (18/41) of MPE supernatants and 56.3% (18/32) of MPE cell blocks by ARMS analysis. Generally, the same EGFR statuses were identified in both MPTTs and matching MPE cell blocks of 81.3% patients (26/32), whereas MPTTs and matching MPE supernatants of 87.8% (36/41) patients shared the same EGFR status. Compared with EGFR mutation detection in MPTTs, the sensitivity of EGFR mutation detection in MPE-cell blocks was 87.5% (14/16), specificity was 75.0% (12/16), while the sensitivity of EGFR mutation detection in MPE-supernatants was 84.2% (16/19), specificity was 90.9% (20/22).
The high concordance of EGFR mutation statuses between MPEs and MPTTs in lung adenocarcinoma patients with pleural metastasis as determined by ARMS analysis suggests that MPEs, particularly MPE supernatants, may be substitutes for MPTTs in EGFR mutation test.
A panel of tumour markers including carcinoembryonic antigen (CEA), carbohydrate antigen (Ca)15-3, Ca125 and Ca19-9 were measured in the lysate of sediments and in the supernatants of pleural effusions of patients with benign and malignant disease. The tumour markers were also measured in the serum of the same patients. Of these patients, 32 had benign diseases (12 trasudative effusions associated with cirrhosis and 20 with non-malignant exudates: 12 pleuritis and 8 other inflammations) and 103 had malignant effusions (37 breast cancers, 29 lung cancers, 10 ovary cancers, 6 kidney cancers, 11 mesotheliomas and 10 lymphomas). We showed the highest level of CEA in pleural effusions of lung cancer followed by that in pleural effusions of breast cancer; whereas Ca15-3 was very high in the pleural effusions of breast and lung cancer. Concerning the lysate of sediment, CEA was high in the pleural effusions of patients with lung cancer and Ca15-3 in those of patients with breast cancer. The other markers are much less useful. For the remaining tumours, none of the markers tested appear to aid in the diagnosis of disease. In conclusion, our data suggest that the combined determination of tumour markers on supernatants and sediments of pleural effusion may provide additional information on the nature of pleural effusion, especially for cases with negative cytology.
pleural effusions; carcinoembryonic antigen; carbohydrate antigen 15-3; carbohydrate antigen 125
Noninvasive diagnosis of pleural tuberculosis (TB) remains a challenge due to the paucibacillary nature of the disease. As Mycobacterium tuberculosis (MTB)-specific T cells are recruited into pleural space in TB effusion; their indirect detection may provide useful clinical information.
Evaluation of pleural fluid interferon (INF)-γ levels vs Quantiferon–TB Gold In tube assay (QFT- IT) in blood and its adapted variants, using pleural fluid or isolated pleural fluid cells in the diagnosis of pleural TB.
Thirty-eight patients with pleural effusion of unknown etiology presented at Assiut University Hospital, Egypt, were recruited. Blood and pleural fluid were collected at presentation for INF-γ assays. Ex vivo pleural fluid INF-γ levels, QFT-IT in blood and its adapted variants were compared with final diagnosis as confirmed by other tools including blind and/or thoracoscopic pleural biopsy.
The final clinical diagnosis was TB in 20 (53%), malignancy in 10 (26%), and effusion due to other causes in eight patients (21%). Ex vivo pleural fluid INF-γ levels accurately identified TB in all patients and were superior to the QFT-IT assays using blood or pleural fluid (70 and 78% sensitivity, with 60 and 83% specificity, respectively). QFT-IT assay applied to isolated pleural fluid cells had 100% sensitivity and 72% specificity. The optimal cut-off obtained with ROC analysis was 0.73 for TB Gold assay in blood assay, 0.82 IU/ml for the cultured pleural fluid assay, and 0.94 for isolated pleural cells assay.
The ex vivo pleural fluid INF-γ level is an accurate marker for the diagnosis of pleural TB. QFT- IT assay in peripheral blood or its adapted versions of the assay using pleural fluid and/or washed pleural fluid cells had no diagnostic advantage over pleural fluid INF-γ in the diagnosis of pleural TB.
Diagnosis; interferon-γ; interferon-γ release assays; quantiferon–TB gold in tube assay; tuberculous effusion