Diagnostic value of tumour markers in pleural effusions.
ABSTRACT: Introduction:We investigated whether tumour markers carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), cancer antigen 125 (CA-125), and cytokeratin 19 fragment (CYFRA 21-1) in pleural effusions and serum can be used to distinguish pleural effusion aetiology. Materials and methods:During the first thoracentesis, we measured pleural fluid and serum tumour marker concentrations and calculated the pleural fluid/serum ratio for patients diagnosed with pleural effusion, using electrochemiluminescence immunoassays. Receiver operating characteristic (ROC) analysis was carried out and the Hanley and McNeil method was used to test the significance of the difference between the areas under ROC curves (AUCs). In order to detect which tumour marker best discriminates between malignant and non-malignant pleural effusions and to establish the predictive value of those markers, discriminant function analysis (DFA) and logistic regression analysis were utilized. Results:Serum tumour markers CYFRA 21-1 and NSE as well as pleural NSE were good predictors of pleural effusion malignancy and their combined model was found statistically significant (Chi-square = 28.415, P < 0.001). Respective ROC analysis showed significant discrimination value of the combination of these three markers (AUC = 0.79). Conclusions:Serum markers showed superiority to pleural fluid markers in determining pleural fluid aetiology. Serum CYFRA 21-1 and NSE concentrations as well as pleural fluid NSE values had the highest clinical value in differentiating between malignant and non-malignant pleural effusions. The combination of these three markers produced a significant model to resolve pleural effusion aetiology.
Project description:The diagnostic value of tumor markers, carcinoembryonic antigen (CEA), cancer antigen (CA) 15-3, CA 19-9, CA 125, cytokeratin fragment (CYFRA), and neuron-specific enolase (NSE) in pleural fluid to differentiate between benign and malignant pleural effusion (MPE) has not yet been clearly established. A review of English language studies using human subjects was performed. Sensitivity and specificity values of the chosen tumor markers were pooled using a random effects model to generate hierarchical summary receiver operator curves to determine the diagnostic performance of each tumor marker. A total of 49 studies were included in the final analysis. Pooled sensitivity and specificity values for chosen tumor markers for diagnosing MPE are as follows: CEA, 0.549 and 0.962; CA 15-3, 0.507 and 0.983; CA 19-9, 0.376 and 0.980; CA 125, 0.575 and 0.928; CYFRA, 0.625 and 0.932; NSE, 0.613 and 0.884. The use of individual tumor markers in diagnosing MPE has many benefits (cost, invasiveness, and so forth). Although these tumor markers exhibit high specificity, the low sensitivity of each marker limits the diagnostic value. We conclude that tumor markers used individually are of insufficient diagnostic accuracy for clinical use. Tumor markers used in various combinations or from serum may have some potential worth further investigation.
Project description:INTRODUCTION: Pleural effusions are a common clinical problem and affect about one million people in the United States and United Kingdom each year. Over 60 causes of pleural effusion have been identified; establishing the definitive aetiology can be difficult, and often requires invasive procedures. Guidelines state that macroscopic examination of the fluid should be the first step in determining the aetiology of a pleural effusion. Papillary thyroid carcinoma is an uncommon cause of malignant pleural effusion, with only 10 cases reported in the literature, their physical characteristics and composition having been rarely described. We describe for the first time a distinctive brown colour of the malignant effusion (despite centrifugation) from a rare case of metastatic papillary thyroid cancer to the pleura, associated with a high pleural fluid iodine content. Such a characteristic may be useful in expediting diagnosis of a malignant pleural effusion in the appropriate clinical context. CASE PRESENTATION: We present the case of a 71-year-old Caucasian man with metastatic papillary thyroid cancer; a large, long-standing, right-sided pleural effusion and a 83-fold higher pleural thyroglobulin level compared to corresponding serum, supporting this malignancy as the cause of the patient's effusion. The pleural fluid had a distinctive pigmentation similar to iodine-containing antiseptic preparations. Biopsy during medical thoracoscopy confirmed metastatic papillary thyroid carcinoma. Analysis of pleural fluid showed a pleural thyroglobulin level over 80 times that of serum levels (29,000?g/L versus 350ug/L). Pleural fluid iodine content was 23,000ug/L and may account for the fluid's distinctive pigment, as iodine is an essential component in thyroglobulin and thyroid hormone synthesis. CONCLUSIONS: Pleural fluid pigmentation may aid diagnosis in the appropriate clinical setting. A distinctive iodine-like brown colour of pleural fluid may represent elevated iodine content and should raise consideration of metastatic thyroid cancer as a cause for a pleural effusion.
Project description:INTRODUCTION:Previous studies have assessed the diagnostic ability of pleural fluid adenosine deaminase (pfADA) in detecting tuberculous pleural effusions, with good specificity and sensitivity reported. However, in North Western Europe pfADA is not routinely used in the investigation of a patient with an undiagnosed pleural effusion, mainly due to a lack of evidence as to its utility in populations with low mycobacterium tuberculosis (mTB) incidence. METHODS:Patients presenting with an undiagnosed pleural effusion to a tertiary pleural centre in South-West England over a 3 year period, were prospectively recruited to a pleural biomarker study. Pleural fluid from consecutive patients with robust 12-month follow up data and confirmed diagnosis were sent for pfADA analysis. RESULTS:Of 338 patients enrolled, 7 had confirmed tuberculous pleural effusion (2%). All mTB effusions were lymphocyte predominant with a median pfADA of 72.0 IU/L (range- 26.7 to 91.5) compared to a population median of 12.0 IU/L (range- 0.3 to 568.4). The optimal pfADA cut off was 35 IU/L, which had a negative predictive value (NPV) of 99.7% (95% CI; 98.2-99.9%) for the exclusion of mTB, and sensitivity of 85.7% (95% CI; 42.2-97.6%) with an area under the curve of 0.88 (95% CI; 0.732-1.000). DISCUSSION:This is the first study examining the diagnostic utility of pfADA in a low mTB incidence area. The chance of an effusion with a pfADA under 35 IU/L being of tuberculous aetiology was negligible. A pfADA of over 35 IU/L in lymphocyte-predominant pleural fluid gives a strong suspicion of mTB.
Project description:BACKGROUND:Pleural effusion (PE) can be divided into benign pleural effusion (BPE) and malignant pleural effusion (MPE). There is no consensus on the identification of lung cancer-associated MPE using the optimal cut-off levels from five common tumor biomarkers (CEA, CYFRA 21-1, CA125, SCC-Ag, and NSE). Therefore, we aimed to find indicators for the auxiliary diagnosis of lung cancer-associated MPE by analyzing and then validating the optimal threshold levels of these biomarkers in pleural fluid (PF) and serum, as well as the PF/serum ratio. PATIENTS AND METHOD:The study has two sets of patients, i.e. the training set and the test set. In the training set, 348 patients with PE, between January 1, 2016 and December 31, 2017, were divided into BPE and MPE based on the cytological diagnosis. Subsequently, the optimal cut-off levels of tumor biomarkers were analyzed. In the test set, the diagnostic compliance rate was verified with 271 patients with PE from January 1, 2018 to July 31, 2019 to evaluate the auxiliary diagnostic value of the aforementioned indicators. RESULT:In the training set, PF CEA at the cut-off value of 5.23 ng/ml was the most effective indicator for MPE compared with other tumor biomarkers (all p?<?0.001). In the test set, PF CEA at the cut-off value of 5.23 ng/ml showed the highest sensitivity, specificity and accuracy, positive and negative predictive value among other tumor biomarkers, which were 99.0%, 69.1%, 91.6%, 90.7%, and 95.9%, respectively. CONCLUSION:PF CEA at the cut-off level of 5.23 ng/ml was the most effective indicator for identifying lung cancer-associated MPE among the five common tumor biomarkers.
Project description:BACKGROUND:Pleural effusion at presentation in Hodgkin lymphoma has been associated with inferior outcome but has not been systematically evaluated. OBJECTIVE:To determine whether pleural effusion at presentation in children with Hodgkin lymphoma is a primary indicator of poor prognosis or secondary to associated factors. MATERIALS AND METHODS:Children's Oncology Group (COG) AHOD0031, a randomized, response-based, centrally reviewed protocol, enrolled 1,712 eligible patients <22 years of age with initial presentation of intermediate risk, biopsy-proven Hodgkin lymphoma; 1,423 had available imaging for retrospective review. We coded effusions as fluid-only or with associated pleural nodule or adjacent lung or bone involvement and correlated this with disease stage, tumor response, large mediastinal adenopathy, and mass effect on the superior vena cava (SVC) and left innominate vein. We recorded change in size and character of effusions post-chemotherapy. RESULTS:Pleural effusions were present in 217, with 204 having fluid-only and 13 having associated solid components. Patients with effusions were more likely to have large mediastinal adenopathy (P<0.0001), be slow early responders (P<0.0001) and have higher relapse rate (P<0.0001). Vascular compression was not significantly correlated with pleural effusion. Of 121 patients with adequate [F-18]2-fluoro-2-deoxyglucose (FDG) positron emission tomography (PET)/CT imaging, no FDG PET avidity was seen in any pleural effusion but was present in solid components. The side of the pleural effusion in those with moderate or large effusions was highly associated with the side of large mediastinal adenopathy (P<0.0001). Statistical analysis indicates that pleural effusion is an independent risk factor for poorer response and relapse. CONCLUSION:Pleural effusion in Hodgkin lymphoma is an important independent poor prognostic indicator for response and relapse.
Project description:In individual patients, especially those who are hospitalized, several conditions often coexist that may be responsible for the development of a pleural effusion and may affect the pleural fluid analysis (PFA). The objective of this study was to investigate the effects of end-stage renal disease and pneumonia on PFA in patients with hydrostatic pleural effusion.In a retrospective analysis of 1,064 consecutive patients who underwent thoracentesis at a university hospital, cell counts and pleural fluid protein, lactate dehydrogenase, pH, and glucose levels were examined in those (n = 300) with clinical evidence of hydrostatic pleural effusion.The 300 patients (28.1%) with pleural effusions had congestive heart failure (CHF), circulatory overload (CO), or both. Expert consensus was achieved in 66 (22%) for CHF as the sole diagnosis (SCHF), 30 (10%) for CHF and coexisting pneumonia (PCHF), and 26 (8.7%) for end-stage renal disease (ESRD) with coexisting CO or CHF. The remaining 178 patients were excluded because of complicating conditions. There were minor, but statistically significant differences in pleural fluid/serum protein ratios in patients with ESRD with coexisting CO or CHF compared with SCHF. Compared with SCHF, there were statistically significant tendencies for higher protein and lactate dehydrogenase concentrations and lower pH levels in those with PCHF. The total nucleated cell count and the absolute neutrophil count were significantly higher in PCHF.ESRD in patients with hydrostatic pleural effusions has a minimal effect on the PFA. Coexisting pneumonia most often results in an exudative effusion in patients with CHF.
Project description:We present a very rare case of right-sided isolated pleural effusion in a patient with severe endometriosis who, in relation to in vitro fertilization (IVF), developed ovarian hyperstimulation syndrome (OHSS). Earlier laparotomy showed grade IV endometriosis including endometriotic implants of the diaphragm. The patient had no known risk factors for OHSS and only a moderate number of oocytes aspirated. She received, however, repeated hCG injections for luteal support. The patient did not achieve pregnancy but was hospitalized due to pain in the right side of the chest and dyspnoea. A chest computed tomography (CT) showed a pleural effusion on the right side. Total of 1000 ml of pleural fluid was drained after a single thoracentesis. After three days, the symptoms and fluid production ceased. Ascites is a common finding in OHSS, but pleural effusions are rare. Further, isolated pleural effusions have not previously been described in a patient with endometriosis. We suggest that the repeated hCG injections induced effusions from the endometriotic lesions at the diaphragm and as a consequence this patient developed isolated hydrothorax.
Project description:Mast cells (MCs) have been identified in various tumors; however, the role of these cells in tumorigenesis remains controversial. Here, we quantified MCs in human and murine malignant pleural effusions (MPEs) and evaluated the fate and function of these cells in MPE development. Evaluation of murine MPE-competent lung and colon adenocarcinomas revealed that these tumors actively attract and subsequently degranulate MCs in the pleural space by elaborating CCL2 and osteopontin. MCs were required for effusion development, as MPEs did not form in mice lacking MCs, and pleural infusion of MCs with MPE-incompetent cells promoted MPE formation. Once homed to the pleural space, MCs released tryptase AB1 and IL-1?, which in turn induced pleural vasculature leakiness and triggered NF-?B activation in pleural tumor cells, thereby fostering pleural fluid accumulation and tumor growth. Evaluation of human effusions revealed that MCs are elevated in MPEs compared with benign effusions. Moreover, MC abundance correlated with MPE formation in a human cancer cell-induced effusion model. Treatment of mice with the c-KIT inhibitor imatinib mesylate limited effusion precipitation by mouse and human adenocarcinoma cells. Together, the results of this study indicate that MCs are required for MPE formation and suggest that MC-dependent effusion formation is therapeutically addressable.
Project description:The diagnosis of malignant pleural effusions may be challenging when cytological examination of aspirated pleural fluid is equivocal or noncontributory. The purpose of this study was to identify protein candidate biomarkers differentially expressed in the pleural fluid of patients with mesothelioma, lung adenocarcinoma, lymphoma, and tuberculosis (TB).A multiplex protein biochip comprising 120 biomarkers was used to determine the pleural fluid protein profile of 29 mesotheliomas, 29 lung adenocarcinomas, 12 lymphomas, and 35 tuberculosis. The relative abundance of these predetermined biomarkers among groups served to establish the differential diagnosis of: malignant versus benign (TB) effusions, lung adenocarcinoma versus mesothelioma, and lymphoma versus TB. The selected putative markers were validated using widely available commercial techniques in an independent sample of 102 patients.Significant differences were found in the protein expressions of metalloproteinase-9 (MMP-9), cathepsin-B, C-reactive protein, and chondroitin sulfate between malignant and TB effusions. When integrated into a scoring model, these proteins yielded 85% sensitivity, 100% specificity, and an area under the curve (AUC) of 0.98 for labeling malignancy in the verification sample. For lung adenocarcinoma-mesothelioma discrimination, combining CA19-9, CA15-3, and kallikrein-12 had maximal discriminatory capacity (65% sensitivity, 100% specificity, AUC 0.94); figures which also refer to the validation set. Last, cathepsin-B in isolation was only moderately useful (sensitivity 89%, specificity 62%, AUC 0.75) in separating lymphomatous and TB effusions. However, this last differentiation improved significantly when cathepsin-B was used with respect to the patient's age (sensitivity 72%, specificity 100%, AUC 0.94).In conclusion, panels of 4 (i.e., MMP-9, cathepsin-B, C-reactive protein, chondroitin sulfate), or 3 (i.e., CA19-9, CA15-3, kallikrein-12) different protein biomarkers on pleural fluid samples are highly discriminative for signaling a malignant versus tuberculous effusion, or lung adenocarcinoma versus mesothelioma, respectively. Cathepsin-B could also be helpful in establishing the presence of a lymphomatous effusion versus that of TB, if the patient's age is simultaneously taken into consideration.
Project description:INTRODUCTION:Serum and fluid laboratory markers are valuable for exploring the aetiologies of pleural effusion (PE) because of their relative non-invasiveness, low cost, objective result and short turnaround time. The diagnostic accuracy of these potential markers needs to be rigorously evaluated before their widespread application in clinical practice. Here, we plan to perform a Study Investigating Markers in PLeural Effusion (SIMPLE). METHODS AND ANALYSIS:This is a prospective and double-blind clinical trial which is being performed at the Affiliated Hospital of Inner Mongolia Medical University, China. Adult patients admitted for the evaluation of aetiology of PE from September 2018 to July 2021 will be enrolled after informed consent. Pleural fluid and serum specimens will be collected and stored at -80°C for the laboratory analysis. The final diagnosis will be concurred with further imaging, microbiology, cytology and biopsy if needed. The results of investigated laboratory markers will be unknown to the clinicians who will make diagnosis and the clinical diagnoses will be unknown to the laboratory technicians who will determine markers. The diagnostic accuracy of investigated markers will be assessed using receiver operating characteristics (ROC) curve analysis, multivariable logistic regression model, decision curve analysis (DCA), net reclassification index (NRI) and integrated discriminatory index (IDI). ETHICS AND DISSEMINATION:The study is approved by the Ethic Committee of the Affiliated Hospital of Inner Mongolia Medical University (NO: 2018011). The results of SIMPLE will be submitted to international scientific peer-reviewed journals or conferences in laboratory medicine or respiratory medicine, thoracic diseases. TRIAL REGISTRATION NUMBER:Chinese Clinical Trial Registry (ChiCTR1800017449); Pre-results.