Tumour Markers In Pleural Fluid Research Articles

Tumor markers determination in malignant pleural effusion: pearls and pitfalls.

Serum and pleural fluid tumor markers are well-recognized auxiliary diagnostic tools for malignant pleural effusion (MPE). Here, we discuss some pearls andpitfalls regarding the role of tumor markers in MPE management. The following issues are discussed in this article: What is the appropriate clinical scenario for evaluating pleural tumor markers? Which tumor markers should be advocated for diagnosing MPE? Can extremely high levels of tumor markers be employed to establish a diagnosis of MPE? Does the serum-to-pleural fluid ratio of a tumor marker have the same diagnostic efficacy as the measurement of that marker alone in the pleural fluid? Can tumor markers be usedto estimate the risk of specific cancers? What should beconsidered when interpreting the diagnostic accuracy of tumor markers? How should tumor marker studies be performed? We addressed these issues with published works, particularly systematic reviews and meta-analyses.

The prevalence of tumour markers in malignant pleural effusions associated with primary pulmonary adenocarcinoma: a retrospective study

ABSTRACT Background Oncological treatment of primary pulmonary adenocarcinoma (AC) includes drugs targeting the pathways involving programmed death-ligand 1 (PD-L1), epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK). The aim of the study was to report the prevalence of these tumour markers in pleural fluid with cytology positive for pulmonary AC and the potential influence of volume pleural fluid tested. Methods We retrospectively reviewed all thoracenteses performed in a two-year period at our interventional unit at Department of Respiratory Medicine at Zealand University Hospital Naestved, Denmark. ALK and PD-L1 testing was done using immunohistochemistry and EGFR testing using next-generation sequencing. We included pleural fluid specimens containing malignant cells originating from primary pulmonary AC and with at least one tumour marker requested by the clinicians. Results When screening 927 pleural fluid specimens, we identified 57 in accordance with the inclusion criteria. PD-L1, ALK and EGFR were obtained in 35/55 (64%), 38/57 (67%) and 26/47 (55%), respectively. The prevalence did not increase when analysing volumes > 50 mL (p = 0.21–0.58) Conclusion Tumour markers in pleural fluid specimens containing cells from pulmonary AC can be demonstrated in more than half of the cases. Therefore, supplementary invasive procedures than thoracentesis could potentially await these analyses.

The diagnostic value of pleural fluid homocysteine in malignant pleural effusion

Pleural fluid homocysteine (HCY) can be useful for diagnosis of malignant pleural effusion (MPE). There are no published studies comparing the diagnostic accuracy of HCY with other tumour markers in pleural fluid for diagnosis of MPE. The aim was to compare the accuracy of HCY with that of carcinoembryonic antigen (CEA), cancer antigen (CA) 15.3, CA19.9 and CA125 in pleural fluid and to develop a probabilistic model using these biomarkers to differentiate benign (BPE) from MPE. Patients with pleural effusion were randomly included. HCY, CEA, CA15.3, CEA19.9 and CA125 were quantified in pleural fluid. Patients were classified into two groups: MPE or BPE. By applying logistic regression analysis, a multivariate probabilistic model was developed using pleural fluid biomarkers. The diagnostic accuracy was determined by receiver operating characteristic (ROC) curves and calculating the area under the curve (AUC). Population of study comprised 133 patients (72 males and 61 females) aged between 1 and 96 years (median = 70 years), 81 BPE and 52 MPE. The logistic regression analysis included HCY (p<0.0001) and CEA (p = 0.0022) in the probabilistic model and excluded the other tumour markers. The probabilistic model was: HCY+CEA = Probability(%) = 100×(1+e-z)-1, where Z = 0.5471×[HCY]+0.3846×[CEA]-8.2671. The AUCs were 0.606, 0.703, 0.778, 0.800, 0.846 and 0.948 for CA125, CA19.9, CEA, CA15.3, HCY and HCY+CEA, respectively. Pleural fluid HCY has higher accuracy for diagnosis of MPE than CEA, CA15.3, CA19.9 and CA125. The combination of HCY and CEA concentrations in pleural fluid significantly improves the diagnostic accuracy of the test.

Tumor markers in pleural fluid as prognostic factor in patient with lung cancer and pleural effusion

Tumor markers in pleural fluid as prognostic factor in patient with lung cancer and pleural effusion

Ratio of carcinoembryonic antigen in pleural fluid and serum for the diagnosis of malignant pleural effusion.

Background:Tumour markers in pleural fluid and their diagnostic value are subject to debate. Although there are several studies on this topic, standardized cut-off values do not exist. In this study we investigated the potential of a ratio of carcinoembryonic antigen (CEA) in pleural fluid and serum, serving as an individual marker for pleural cancer manifestation.Methods:A total of 201 consecutive patients with unclear pleural effusion were included in the study; 98 were diagnosed with malignant pleural effusion and 103 had an effusion due to other, benign reasons. CEA levels in pleural fluid and serum were measured.Results:By using receiver operating characteristics analysis, at the cut-off of 1.0, the CEA ratio showed a specificity of 92% and sensitivity of 85%, with a positive predictive value of 91% and a negative predictive value of 87%. These results are higher than in previous investigations on different pleural tumour markers and their combination.Conclusions:The CEA ratio is a useful tool in predicting pleural carcinosis. Elevated results in cytology-negative patients should lead to further investigations, such as repeated cytological examination or thoracoscopy.

Diagnostic Accuracy of Combinations of Tumor Markers for Malignant Pleural Effusion: An Updated Meta-Analysis

Background: The role of combinations of tumor markers such as carcinoembryonic antigen (CEA), carbohydrate antigens (CA) 125, 15-3, and 19-9, and CYFRA 21-1 (a fragment of cytokeratin 19) in diagnosing malignant pleural effusion (MPE) has not been clearly established. Objectives: This meta-analysis was performed to establish the overall diagnostic accuracies of combinations of these pleural fluid tumor markers for MPE. Methods: The PubMed, Ovid, Embase, Web of Science, and Cochrane bibliographic databases were searched. Sensitivity, specificity, and other measures of the accuracy of combinations of pleural CEA, CA 125, CA 15-3, CA 19-9, and CYFRA 21-1 in the diagnosis of MPE were pooled after a systematic review of English-language studies. Results: Twenty studies met the inclusion criteria. For pleural fluid tumor marker combinations including more than 3 studies, the summary estimates of the sensitivity/specificity for diagnosing MPE were as follows: CEA + CA 125, 0.65/0.98; CEA + CA 15-3, 0.64/0.98; CEA + CA 19-9, 0.58/0.98; CEA + CYFRA 21-1, 0.82/0.92; and CA 15-3 + CYFRA 21-1, 0.88/0.94. Conclusions: In patients with undiagnosed pleural effusion, the combinations of positive pleural CEA + CA 15-3 and CEA + CA 19-9 are highly suspicious for pleural malignancy, but the sensitivity of these tests is poor. Therefore, their routine role in the diagnostic algorithm of these patients is questionable, and management decisions should depend on positive cytological or biopsy results from the pleura.

Diagnostic value of tumour markers Ca-125 and CEA in the diagnostics of malignant pleural fluids

Abstract The significance of carbohydrate (cancer) antigen 125 (Ca-125) and carcinoembryonic antigen (CEA) tumour markers levels in differential diagnostics of malignant and benign pleural effusion was studied. Within this prospective study, 121 patients with fluids of various aetiology in the pleural cavity were analysed. Malignant pleural effusion was detected in 55 patients, parapneumonic effusion in 28 patients, transudative effusion of cardiac origin in 31 patients, pancreatitis in one patient and tuberculous pleurisy in five patients. The highest accuracy in diagnosis of malignancy was observed for Ca-125 and CEA levels in the pleural fluid: 75.2% at cut-off value ≥1452 U/mL and 76.9% at cut-off value ≥6.58 ng/mL, respectively. We conclude that the level of tumour markers in pleural fluid has additional diagnostic significance in the differential diagnosis of malignant and benign pleural effusions.

Pleural fluid tumour markers in malignant pleural effusion with inconclusive cytologic results.

The presence of tumour cells in pleural fluid or tissue defines an effusion as malignant. Cytology analysis of the pleural fluid has about 60% diagnostic sensitivity. Several tests have been proposed to improve diagnosis-among them, the concentrations of tumour markers in pleural fluid. We evaluated whether the concentrations of tumour markers in pleural fluid could improve the diagnosis of malignant pleural effusion (mpe) when cytology is doubtful. Lymphocytic pleural fluids secondary to tuberculosis or malignancy from 156 outpatients were submitted for cytology and tumour marker quantification [carcinoembryonic antigen (cea), cancer antigen 15-3 (ca15-3), carbohydrate antigen 19-9 (ca19-9), cancer antigen 72-4 (ca72-4), cancer antigen 125 (ca125), and cyfra 21-1). Oneway analysis of variance, the Student t-test or Mann-Whitney test, and receiver operating characteristic curves were used in the statistical analysis. Concentrations of the tumour markers cea, ca15-3, ca125, and cyfra 21-1 were higher in mpes than they were in the benign effusions (p < 0.001), regardless of cytology results. The markers ca19-9 and ca72-4 did not discriminate malignant from benign effusions. When comparing the concentrations of tumour markers in mpes having positive, suspicious, or negative cytology with concentrations in benign effusions, we observed higher levels of cea, ca15-3, cyfra 21-1, and ca125 in malignant effusions with positive cytology (p = 0.003, p = 0.001, p = 0.002, and p = 0.001 respectively). In pleural fluid, only ca125 was higher in mpes with suspicious or negative cytology (p = 0.001) than in benign effusions. Given high specificity and a sensitivity of about 60%, the concentrations of tumour markers in pleural effusions could be evaluated in cases of inconclusive cytology in patients with a high pre-test chance of malignancy or a history of cancer.

High levels of tumor markers in pleural fluid correlate with poor survival in patients with adenocarcinomatous or squamous malignant effusions

Background The aim of this study was to determine whether several pleural fluid (PF) tumor markers, either alone or in combination, could be used to predict survival time of patients with malignant pleural effusion secondary to adenocarcinoma or squamous cell carcinoma. Methods A total of 224 patients with confirmed metastatic pleural malignancies due to adenocarcinoma or squamous cell carcinoma were enrolled. PF tumor markers were determined either by electrochemiluminescence immunoassay (CEA, CA 15-3, CYFRA 21-1) or microparticle enzyme immunoassay (CA 125) technologies. Cutoff points that predicted death during the first month after diagnoses, with a specificity of 60%, were selected for each marker, using receiver operating characteristic analysis. Results In patients with adenocarcinomatous or squamous malignant effusion, the combination of PF CA 125 ≥ 1000 U/mL and CYFRA 21-1 ≥ 100 ng/mL predicted a lower survival (4 vs. 11.7 months, p = 0.03; and 0.3 vs. 8.4 months, p = 0.003 respectively). This tumor marker combination remained as an independent predictor of poor outcome when adjusted for age and tumor type. Conclusion High PF tumor marker levels identify a subgroup of patients with a shorter median survival.

Clinical value of CYFRA21-1, NSE, CA15-3, CA19-9 and CA125 assay in the elderly patients with pleural effusions

The aim of this study was to evaluate the individual and combined diagnostic value of five tumour markers in the elderly patients with pleural effusions. Serum and pleural fluid levels of cytokeratin fragment 19 (CYFRA21-1), neuron-specific enolase (NSE), carbohydrate antigen 15-3 (CA15-3), carbohydrate antigen 19-9 (CA19-9) and carbohydrate antigen 125 (CA125) were assayed in 32 elderly patients with malignant pleural effusions resulting from advanced lung cancer and in 30 elderly patients with benign pleural effusions by ELISA. Serum levels of CYFRA21-1, NSE, CA15-3, CA19-9 and CA125 in patients with malignant pleural effusions were 12.84 +/- 6.48 microg/l, 22.07 +/- 11.25 microg/l, 65.74 +/- 30.26 kU/l, 56.32 +/- 25.6 kU/l and 71.86 +/- 31.45 kU/l, respectively, and were significantly higher than those in patients with benign pleural effusions (p < 0.01). Pleural fluid levels of CYFRA21-1, CA15-3, CA19-9 and CA125 except NSE in patients with malignant pleural effusions were 18.64 +/- 8.15 microg/l, 59.31 +/- 27.35 kU/l, 48.24 +/- 21.56 kU/l and 62.16 +/- 27.79 kU/l, respectively, and were significantly higher than those in patients with benign pleural effusions (p < 0.01). The parallel combined testing of five tumour markers in serum increased the diagnostic sensitivity to 90.6%, and serial combined testing increased the diagnostic specificity to 93.3%. The sensitivity (%) and specificity (%) of these tumour markers in pleural fluid were as follows: CYFRA21-1, 84.4/90; CA15-3, 62.5/73.3; CA19-9, 37.5/66.7; CA125, 56.3/70; for differentiating malignant effusions from benign effusions. When CYFRA21-1 and CA15-3 combined, the sensitivity and specificity were increased (100% and 90% respectively). Serum and pleural fluid levels of the five tumour markers shows certain values in the diagnosis and differentiate diagnosis for malignant pleural effusions in the elderly patients from benign. The combined assay of five tumour markers in serum and the CYFRA21-1 combined with CA15-3 in pleural fluid were helpful and can increase the sensitivity and specificity in diagnosing malignant pleural effusions.

Diagnostic Value of CYFRA 21-1, CEA, CA 19-9, CA 15-3, and CA 125 Assays in Pleural Effusions: Analysis of 116 Cases and Review of the Literature

Levels of tumor markers in pleural effusions may help to establish the diagnosis of pleural malignancy, but the precise diagnostic value of each marker remains unclear. The aim of this study was to assess the diagnostic value of five common pleural fluid tumor markers, carcinoembryonic antigen (CEA), cytokeratin fragment (CYFRA) 21-1, cancer antigen (CA) 15-3, CA 19-9, and CA 125, and to review the literature from the past 15 years. Pleural fluid samples were collected prospectively from 116 patients and assayed for CEA, CYFRA 21-1, CA 15-3, CA 19-9, and CA 125 levels. A MEDLINE search of the English-language literature from the past 15 years was also done. Effusions were classified as benign or malignant on the basis of their definitive pathologic or cytologic diagnoses. The levels of all pleural tumor markers were statistically significantly higher in the malignant group than in the benign group. The marker with the highest accuracy was CEA (85.3%); CA 15-3, CYFRA 21-1, and CA 19-9 had similar accuracies (75.2%, 72.4%, and 71.5%, respectively), and CA 125 had the lowest accuracy (40.5%). On univariate analysis, tumor-marker combinations did not result in a greater accuracy than that of CEA alone. On multivariate logistic regression, CA 15-3 and CYFRA 21-1 were significant predictors of malignancy. Among the nine reports in the literature comparing 11 different tumor markers, CEA, CA 15-3, and CYFRA 21-1 yielded the best results. We conclude that pleural fluid analysis should include CEA for the diagnosis of malignancy. CA 15-3 and CYFRA 21-1 may serve as alternative options.

Use of a Panel of Tumor Markers (Carcinoembryonic Antigen, Cancer Antigen 125, Carbohydrate Antigen 15–3, and Cytokeratin 19 Fragments) in Pleural Fluid for the Differential Diagnosis of Benign and Malignant Effusions

The diagnostic value of tumor markers in pleural fluid is subject to debate. The aim of this study was to evaluate the diagnostic performance of several tumor markers in common use for detecting malignant pleural disease. Blinded comparison of four tumor markers in pleural fluid with a confirmatory diagnosis of malignancy by pleural cytology or thoracoscopic biopsy. Two teaching hospitals in Spain. A total of 416 patients (166 with definite malignant effusions, 77 with probable malignant effusions, and 173 with benign effusions) were enrolled. Among them, there were 42 patients recruited from one of the participant centers with thoracoscopic facilities, who had false-negative fluid cytology findings and malignancy confirmed by medical thoracoscopy. Tumor markers in pleural fluid were determined either by electrochemiluminescence immunoassay (carcinoembryonic antigen [CEA], carbohydrate antigen 15-3 [CA 15-3], cytokeratin 19 fragments [CYFRA 21-1]) or microparticle enzyme immunoassay (cancer antigen 125 [CA 125]) technologies. Cutoff points that yielded 100% specificity (ie, all patients with benign effusions had levels below this cutoff) were selected for each marker. Malignant pleural effusions (PEs) had higher levels of pleural fluid markers than did effusions due to benign conditions. At 100% specificity, a pleural CEA > 50 ng/mL, CA 125 > 2,800 U/mL, CA 15-3 > 75 U/mL, and CYFRA 21-1 > 175 ng/mL had 29%, 17%, 30%, and 22% overall sensitivities, respectively. The combination of the four tumor markers reached 54% sensitivity, whereas the combined use of the cytology and the tumor marker panel increased the diagnostic yield of the former by 18% (95% confidence interval, 13 to 23%). More than one third of cytology-negative malignant PEs could be identified by at least one marker of the panel. No single pleural fluid marker seems to be accurate enough as to be introduced in the routine workup of PE diagnosis. However, a tumor marker panel may represent a helpful adjunct to cytology in order to rule in malignancy as a probable diagnosis, thus guiding the selection of patients who might benefit from further invasive procedures.

Evaluation of seven tumour markers in pleural fluid for the diagnosis of malignant effusions

Carcinoembryonic antigen (CEA), carbohydrate antigens 15–3, 19–9 and 72–4 (CA 15–3, CA 19–9 and CA 72–4), cytokeratin 19 fragments (CYFRA 21–1), neuron-specific enolase (NSE) and squamous cell carcinoma antigen (SCC) were evaluated in pleural fluid for the diagnosis of malignant effusions. With a specificity of 99%, determined in a series of 121 benign effusions, the best individual diagnostic sensitivities in the whole series of 215 malignant effusions or in the subgroup of adenocarcinomas were observed with CEA, CA 15–3 and CA 72–4. As expected, a high sensitivity was obtained with SCC in squamous cell carcinomas and with NSE in small-cell lung carcinomas. CYFRA and/or CA 15–3 were frequently increased in mesotheliomas. Discriminant analysis showed that the optimal combination for diagnosis of non-lymphomatous malignant effusions was CEA + CA 15–3 + CYFRA + NSE: sensitivity of 94.4% with an overall specificity of 95%. In malignant effusions with a negative cytology, 83.9% were diagnosed using this association. The association CYFRA + NSE + SCC was able to discriminate adenocarcinomas from small-cell lung cancers. Regarding their sensitivity and their complementarity, CEA, CA 15–3, CYFRA 21–1, NSE and SCC appear to be very useful to improve the diagnosis of malignant pleural effusions. © 1999 Cancer Research Campaign

Utility of tumour markers in the diagnosis of neoplastic pleural effusion

Approximately 20% of pleural effusions are caused by neoplastic processes. Although cytology is the most specific routine diagnostic procedure, its sensitivity of 50–60% is insufficient, and thus diagnosis is usually carried out by more invasive techniques such as pleural biopsy, thoracoscopy or thoracotomy. The object of this study is to evaluate the use of determining some tumour markers in pleural fluid obtained by thoracocentesis for diagnosis of neoplastic pleural effusion. Patients (271) with pleural effusions were classified in five groups: I: neoplasms n = 88; II: tuberculosis n = 63; III: parapneumonics n = 53; IV: miscellaneous exudates n = 39 and V: transudates n = 28. The tumour markers studied were: carcinoembryonic antigen (CEA), CA 125, squamous cell carcinoma antigen (SCC), and neuron specific enolase (NSE). The tumour makers had the following diagnostic efficiencies for neoplastic origin of the pleural effusion: CEA 76% (sensitivity 31%, specificity 93%); CA 125 66% (70% and 61%); SCC 65% (48% and 80%) and NSE 53% (30% and 89%). The diagnostic efficiencies for pulmonary neoplastic origins were 68% for NSE (sensitivity 83%, specificity 53%); 65% for SCC (54% and 75%); 63% for CEA (80% and 48%) and 61% for CA 125 (79% and 42%). We believe that the routine testing of tumour markers in pleural fluid obtained by thoracocentesis would greatly increase diagnostic effectiveness and could avoid the practice of more aggressive diagnostic techniques on the patient.