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
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
C-reactive protein (CRP) has been implicated in various inflammatory and advanced malignant states. Increased serum CRP (s-CRP) levels have been shown to be associated with independent prognostic factors for survival in patients with advanced lung cancer. However, only few studies have focused on the role of CRP in pleural effusions. This study aimed to evaluate the diagnostic and prognostic value of pleural CRP (p-CRP) in lung cancer patients with malignant pleural effusion (MPE).
Materials and Methods
Pleural effusion (PE) samples were collected from patients with MPE (68 lung cancers; 12 extrathoracic tumors), and from 68 patients with various benign conditions (31 with pneumonia; 37 with tuberculosis). Concentrations of p- and s-CRP were measured by enzyme-linked immunosorbent assay. CRP level in pleural fluid and its association with survival were examined.
p-CRP levels correlated with s-CRP levels (r=0.82, p<0.0001). For the differential diagnosis of MPE and benign PE, the area under the receiver operating characteristic curve was greater for p-CRP (0.86) than for s-CRP (0.77). High p-CRP expression significantly correlated with shorter overall survival (p=0.006). P-CRP was independent prognostic factor significantly associated with overall survival on multivariated analysis (p=0.0001). The relative risk of death for lung cancer patients with high p-CRP levels was 3.909 (95% confidence interval, 2.000-7.639).
P-CRP is superior to s-CRP in determining pleural fluid etiology. Quantitative measurement of p-CRP might be a useful complementary diagnostic and prognostic test for lung cancer patients with MPE.
Pleural CRP; diagnosis; prognosis; lung cancer; pleural effusion
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
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.
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.
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
The aim of this study was to investigate the diagnostic value of interleukin 22 (IL-22) and carcinoembryonic antigen (CEA) in tuberculous pleural effusions (TPEs) and malignant pleural effusions (MPEs). Pleural effusion samples from 56 patients were classified on the basis of diagnosis as TPE (n=28) and MPE (n=28). The concentration of IL-22 was determined by ELISA. Lactate dehydrogenase (LDH), adenosine dehydrogenase (ADA) and CEA levels were also determined in all patients. A significant difference was observed in the levels of ADA and CEA (P<0.01), but not in the levels of LDH (P>0.05) between TPE and MPE. The concentration of IL-22 in TPE was significantly higher compared to MPE (P<0.01). With a threshold value of 49 pg/ml, IL-22 had a sensitivity of 82.14% (23/28) and a specificity of 96.43% (27/28) for differential diagnosis. The combined detection of IL-22 and CEA had a sensitivity of 100% (28/28) and a specificity of 96.43% (27/28) to distinguish TPE from MPE. TPEs showed significantly higher levels of IL-22 compared to MPEs. The combined detection of IL-22 and CEA may be more valuable in the differential diagnosis between TPE and MPE.
interleukin 22; carcinoembryonic antigen; pleural effusion; differential diagnosis
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
Interferon-γ (IFN-γ) plays a crucial role in Mycobacterium tuberculosis induced pleural responses. Interleukin (IL)-33 up-regulates the production of IFN-γ. We aimed to identify whether an association between pleural IL-33 levels and tuberculous pleurisy exists and determine its diagnostic value.
Pleural IL-33, ST2 (a receptor of IL-33), adenosine deaminase (ADA), and IFN-γ, as well as serum IL-33 and ST2 were measured in 220 patients with pleural effusions (PEs). Patients with malignant (MPEs), parapneumonic (PPEs), tuberculous (TPEs), and cardiogenic (CPEs) pleural effusions were included.
Pleural and serum IL-33 levels were highest or tended to be higher in patients with TPEs than in those with other types of PEs. The median pleural fluid-to-serum IL-33 ratio was higher in TPE cases (≥ 0.91) than in other PE cases (≤ 0.56). Pleural IL-33 levels correlated with those of pleural ADA and IFN-γ. However, the diagnostic accuracies of pleural IL-33 (0.74) and pleural fluid-to-serum IL-33 ratio (0.75) were lower than that of ADA (0.95) or IFN-γ (0.97). Pleural ST2 levels in patients with MPEs were higher than in patients with TPEs. Serum ST2 levels did not differ among the groups.
We identified an association between elevated pleural IL-33 levels and tuberculous pleurisy. However, we recommend conventional pleural markers (ADA or IFN-γ) as diagnostic markers of TPE.
Interleukin-33; ST2; Tuberculosis; Pleural effusion
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.
Sometimes etiological diagnosis of pleural effusion is difficult despite cytological, biochemical and microbiological tests and labeled as undiagnosed exudative pleural effusions.Aim of present study was to make an etiological diagnosis of pleural effusion.
Materials and Methods:
Study group included patients of exudative pleural effusion where etiological diagnosis could not be yielded by conventional cytological, biochemical and microbiological investigations. Pleural tissue was obtained by Cope’s pleural biopsy needle and or thoracoscopy. Pleural biopsy was subjected to histopathology, ZN staining and culture to find the mycobacterium tuberculosis.
Out of 25 patients, 17 (68%) and 8 (32%) were male and female, respectively. Age ranged from 15 to 65 years (mean 31.72). Mean value of serum and pleural fluid LDH was 170.56 U/L and 1080.28 U/L, respectively. Histopathology of 9 (36%) showed epitheloid granuloma with caseation necrosis. In other 9 (36%) patients, epitheloid granulomas (with or without giant cells) was reported. In 5 (20%) patients, histopathology report was of nonspecific chronic inflammation. Histopathology was reported as normal in one case; it turned out to be a case of malignancy. In two (8%) patients, pleural tissue obtained was inadequate for opinions; however, other tests revealed malignancy in one and tuberculosis in other. Ziehl-Neelsen (ZN) stain was positive for AFB in two patients and culture of pleural tissue showed presence of Mycobacterium tuberculosis in three patients.
The role of percutaneous closed needle biopsy of pleura among patients of undiagnosed exudative pleural effusion is still accepted as a diagnostic tool, as this may lead to a specific diagnosis among 76% of cases. This is of particular importance in a developing country like India where the facilities of thoracoscopy and imaging guided cutting needle biopsies are not easily available.
Closed needle pleural biopsy; pleural biopsy; undiagnosed pleural effusion
The cause of pleural effusion was studied in 300 consecutive patients by clinical examination and laboratory tests. The three most common causes were found to be cancer 117 cases (metastatic 65, bronchogenic 34, mesothelioma 10, lymphoma 7, other 1); tuberculous infection 53; and bacterial infection 38. The cause was not found in 62 patients. Cancer diagnosis was established by cytological examination of pleural fluid (63), closed pleural biopsy (37), and open pleural biopsy (11). Tuberculosis was diagnosed by culture of pleural fluid (12), closed pleural biopsy (38), and open pleural biopsy (3). In cases of empyema 12 Gram-positive and two Gram-negative cocci and two anaerobes were identified. The various causes and the usefulness of the different investigative procedures are discussed, and the data evaluated in the light of current knowledge about mechanisms of transfer through the pleural space.
The aim of this study is to determine the level of serum cytokeratin19 fragment (cyfra21-1) in patients with benign or malignant pleural effusion and evaluation the sensitivity and specificity of this tumor marker.
Method & Material
We prospectively evaluated 98 patients (39 malignant, 54 benign and the results were inconclusive in 5) with pleural effusion. The diagnosis of malignant pleural effusion was defined by cytological or histological results. We used serum cyfra21-1 criteria from literature of Roch company. Level of the marker was determined using electrochemiluminescence.
There was statistically significant difference between mean of serum cyfra21-1 levels of benign (3.9±7.6) and malignant(19.5± 30) pleural effusion (p=0.01). In addition the sensitivity, specificity, positive predictive value and negative predictive value of serum cyfra21-1 at the cut off point of 3.3 ng/ml , was 84% , 61%, 61% and 84 % respectively.
Serum cyfra21-1 is useful as a measure in differentiating malignant from benign pleural effusion.
Cyfra21-1; pleural effusion; malignancy
To evaluate the suitability of malignant pleural effusion (MPE) and plasma as surrogate samples for epidermal growth factor receptor (EGFR) mutation detection, and compare three different detection methods.
Matched tissue and plasma samples were collected from patients with advanced non-small cell lung cancer (NSCLC) (stage IIIB/IV adenocarcinoma/adenosquamous carcinoma), with matched MPE samples collected from a subgroup. DNA was extracted from tissue, MPE cell block, MPE supernatant and plasma before mutation detection by amplification refractory mutation system (ARMS) (all samples), Sanger sequencing and mutant-specific immunohistochemistry (IHC) (tissue and MPE cell blocks only).
Sensitivity of MPE cell block, MPE supernatant and plasma versus tissue: 81.8% (9/11), 63.6% (7/11) and 67.5% (27/40); specificity was 80.0% (8/10), 100% (10/10) and 100% (46/46), respectively. Sensitivity of Sanger sequencing versus ARMS: 81.8% (27/33) for tissue, 40% (4/10) for MPE cell blocks; specificity was 100% (36/36 and 12/12) for both. Sensitivity of mutant-specific IHC versus ARMS: 54.8% (17/31) for tissue, 50.0% (6/12) for MPE cell blocks; specificity was 97.1% (34/35) and 100% (14/14), respectively.
MPE and plasma are valid surrogates for NSCLC tumour EGFR mutation detection when tissue is not available. ARMS is most suitable for mutation detection in tissue and MPE cell blocks; however, mutant-specific IHC could be a complementary method when DNA-based molecular testing is unavailable.
Egfr; Diagnostics; Lung Cancer
Minimally invasive investigations, such as pleural fluid cytological assessment and closed percutaneous pleural biopsy, are often performed first in the investigation of suspected malignant pleural effusions. Malignant pleural effusions can be diagnosed with pleural fluid cytology alone in most cases; however, closed pleural biopsy is performed to increase the diagnostic yield when pleural fluid cytology is negative. This additional yield is at the expense of increased complication rates. We report a 64-year old man with a negative pleural fluid cytology but suspected malignant pleural effusion who underwent a closed pleural biopsy, which was complicated by pneumothorax, pneumomediastinum and severe subcutaneous emphysema. Pulmonary laceration by the pleural biopsy needle is the most likely aetiology of these complications. Our case report highlights an infrequent but significant complication of closed percutaneous pleural biopsy.
Pleural effusion remains the most common manifestation of pleural pathology. Sometimes it is difficult to differentiate between tubercular and malignant pleural effusion in spite of routine biochemical and cytological examination of pleural fluid.
This study aims to evaluate the role of pleural biopsy to determine the etiology of pleural effusion and to correlate it with the biochemical and cytological parameters of pleural fluid.
Settings and Design:
Seventy two consecutive patients of pleural effusion were selected from the out patient and indoor department of a tertiary hospital of Kolkata. It was a prospective and observational study conducted over a period of one year.
Materials and Methods:
Biochemical, cytological and microbiological evaluation of pleural fluid was done in all cases. Those with exudative pleural effusions underwent pleural biopsy by Abram’s needle. Subsequently, the etiology of effusion was determined.
Malignancy was the most common etiology, followed by tuberculosis. Pleural biopsy was done in 72 patients. Pleural tissue was obtained in 62 cases. Malignancy was diagnosed in 24, tuberculosis in 20 and non-specific inflammation in 18, on histopathological examination. Out of 20 histological proven tuberculosis cases adenosine de-aminase (ADA) was more than 70 u/l in 11 cases.
In our study, malignancy is more common than tuberculosis, particularly in elderly. When thoracoscope is not available, pleural fluid cytology and pleural biopsy can give definite diagnosis. Pleural fluid ADA ≥ 70 u/l is almost diagnostic of tuberculosis, where pleural biopsy is not recommended.
Malignancy; pleural biopsy; pleural effusion; tuberculosis
Background and objective
Recent evidence suggests that YKL-40 is a relatively new biomarker of inflammation and it is involved in the pathogenesis of several pulmonary diseases. Details of serum and pleural YKL-40 in pleural effusions however, remain unknown. We aimed to assess whether serum and pleural YKL-40 is an accurate biomarker of pleural effusions.
This clinical study was prospective, observational and cross-sectional. The concentrations of serum and pleural fluid YKL-40 and conventional pleural marker levels were measured in 80 subjects with pleural effusions, including 23 transudates caused by congestive heart failure (CHF), and 57 exudates including 23 parapneumonic, 22 malignant and 12 tuberculous pleural effusions (TBPEs).
Median pleural fluid YKL-40 levels were higher in exudates than in transudates (219.4 and 205.9 ng/mL, respectively, P<0.001). High pleural YKL-40 levels, with a cutoff value of >215 ng/mL, yielded a 73% sensitivity, 73% specificity, likelihood ratio 2.8 for diagnosing exudate, with an area under the curve of 0.770 [95% confidence intervals (CI): 0.657-0.884]. Pleural YKL-40/serum YKL-40 ratio >1.5 yielded a 75% sensitivity, 72% specificity and likelihood ratio 2.6 for diagnosing TBPE, with an area under the curve of 0.825 (95% CI: 0.710-0.940).
High concentrations of pleural YKL-40 level may help to differentiate exudate from transudate and a high pleural YKL-40/serum YKL-40 ratio may be helpful in seperating TBPE from non-tuberculous effusions.
Exudate; pleural effusion; transudate; tuberculosis; YKL-40
Malignant pleural mesothelioma (MPM) is a highly aggressive neoplasm primarily arising from surface serosal cells of the pleura and is strongly associated with asbestos exposure. Patients with MPM often develop pleural fluid as initial presentation. However, cytological diagnosis using pleural fluid is usually difficult and has limited utility. A useful molecular marker for differential diagnosis particularly with lung cancer (LC) is urgently needed. The aim of the present study was to investigate the diagnostic value of soluble mesothelin-related protein (SMRP) in pleural fluid. Pleural fluids were collected from 23 patients with MPM, 38 with LC, 26 with benign asbestos pleurisy (BAP), 5 with tuberculosis pleurisy (TP) and 4 with chronic heart failure (CHF), and the SMRP concentration was determined. All data were analyzed by using non-parametric two-sided statistical tests. The median concentration of SMRP in MPM, LC, BAP, TP and CHF were 11.5 (range 0.90–82.80), 5.20 (0.05–36.40), 6.65 (1.45–11.25), 3.20 (1.65–6.50) and 2.03 (1.35–2.80) nmol/l, respectively. The SMRP concentration was significantly higher in MPM than in the other diseases (P=0.001). The area under the ROC curve (AUC) values of the MPM diagnosis was 0.75 for the differential diagnosis from the other groups. Based on the cut-off value of 8 nmol/l, the sensitivity and specificity for diagnosis of MPM were 70.0 and 68.4%, respectively. These results indicate that the SMRP concentration in pleural fluid is a useful marker for the diagnosis of MPM.
mesothelin; mesothelioma; asbestos
To evaluate the value of pleural fluid alkaline phosphatase and pleural fluid/serum alkaline phosphatase ratio for the purpose of differentiating tuberculous from nontuberculous pleural effusion.
Materials and Methods:
A total of 60 indoor patients, admitted to our hospital, having pleural effusion and suffering from varying etiologies, were included in this study. According to the final diagnosis, these 60 patients were divided into two groups: Tuberculous (30) and nontuberculous (30) pleural effusion.
The mean pleural alkaline phosphatase and pleural fluid/serum alkaline phosphatase ratio was significantly higher in tuberculous compared to nontuberculous pleural effusion. (P < 0.0001). In receiver operating characteristic curve analysis, sensitivity and specificity values were 90% and 80% for a cut-off value of 71 IU/L for pleural alkaline phosphatase activity; and were 90% and 86.66% for a cut-off value of 0.51 for pleural fluid/serum alkaline phosphatase ratio.
From this study it is concluded that alkaline phosphatase activity remains a useful test in differentiation of tuberculous from nontuberculous pleural effusion.
Alkaline phosphatase; differentiation; pleural effusion; tuberculosis
After pneumonia, cancer involving the pleura is the leading cause of exudative pleural effusion. Cytologic examination of pleural effusions is an important initial step in management of malignant effusions. The aim of this study is to evaluate the spectrum of uncommon malignant pleural effusions in a chest disease center in Turkey.
Materials and Methods:
A retrospective study of samples of pleural effusions submitted to Ataturk Chest Diseases and Chest Surgery Education and Research Hospital Department of Pathology between March 2005 and November 2008 was performed.
Out of a total of 4684 samples reviewed 364 (7.8%) were positive for cancer cells. Of the malignant pleural effusions 295 (81%) were classified as adenocarcinoma or carcinoma not otherwise specified (NOS). Pleural effusion specimens revealing a diagnosis other than adenocarcinoma/carcinoma NOS were: 32 (8.8%) malignant mesotheliomas, 14 (3.8%) small cell carcinomas, 13 (3.5%) hematolymphoid malignancies and 10 (2.7%) squamous cell carcinoma. Hematolymphoid malignancies included non- Hodgkin lymphoma (diffuse B large cell lymphoma, mantle cell lymphoma), multiple myeloma, chronic myeloid leukemia, and acute myeloid leukemia.
Despite that adenocarcinoma is the most common cause of malignant pleural effusions, there is a significant number of hematological and non-hematological uncommon causes of such effusions. Cytopathologists and clinicians must keep in mind these uncommon entities in routine practice for an accurate diagnosis.
Cytopathology; differential diagnosis; malignant; pleural effusion; uncommon causes
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
The concentration of ferritin was measured in the pleural fluid of 108 patients with pleural effusions. In all groups of patients the ferritin concentration was higher in pleural fluid than in serum. The greatest differences, with up to 100 times more ferritin in the pleural fluid, were found for patients with rheumatoid pleurisy, malignant effusions, and empyema. In patients with non-malignant inflammatory pleural effusions the concentration of ferritin in pleural fluid correlated significantly with other pleural fluid indices of inflammation: there was a positive correlation with lactate dehydrogenase activity and a negative correlation with concentrations of glucose and complement components C3 and C4. Ferritin was detected immunocytochemically only in the macrophages found among the pleural fluid cells. Our study shows that large amounts of ferritin accumulate locally in the pleural cavity in certain types of pleural inflammation. The accumulation is probably partly the result of increased local reticuloendothelial system activity. Determination of the concentration of ferritin in pleural fluid may provide corroborative information for differential diagnosis and may further our understanding of the pathogenetic events that lead to the perpetuation of inflammatory activity in pleural effusions.
The relationship between interleukin 6 (IL-6) levels and clinical parameters was studied in 25 patients with malignant pleural mesothelioma. The serum levels of IL-6, C-reactive protein, alpha1-acid glycoprotein and fibrinogen were significantly higher in mesothelioma than in lung adenocarcinoma with cytology-positive pleural effusion. Serum IL-6 levels correlated with the levels of the acute-phase proteins. We demonstrated a high incidence of thrombocytosis (48%) and a significant correlation between platelet count and the serum IL-6 level. The level of IL-6 in the pleural fluid of patients with mesothelioma was significantly higher than in the pleural fluid of patients with adenocarcinoma, and was about 60-1400 times higher than in the serum. However, even higher levels of IL-6 in the pleural fluid and of thrombocytosis were found in patients with tuberculous pleurisy. These results indicate that large amounts of IL-6 from the pleural fluid of patients with mesothelioma leak into the systemic circulation and induce clinical inflammatory reactions. These profiles are not specific to mesothelioma as similar profiles are found in patients with tuberculous pleurisy. However, the detection of a markedly increased level of IL-6 in pleural fluid argues against a diagnosis of adenocarcinoma.
Increase in reactive oxygen metabolites (ROM) and free radicals is an important cause of cell injury. In this study, we investigated whether determination of ROM in pleural fluids of patients with malignant and non-malignant pleural effusions can be used as a tumor marker indicating malignant effusions in the differential diagnosis.
Sixty subjects with exudative pleural effusion and 25 healthy individuals as the control group were included in the study. Of the subjects with pleural effusion, 50% were malignant and 50% were non-malignant. ROM was studied in the pleural fluids and sera of the subjects with pleural effusion and in the sera of those in the control group. The ROM values of smokers and non-smokers were compared in each group. The Student’s t-test and the Mann-Whitney U test were used in order to detect differences between groups for descriptive statistics in terms of pointed features. The statistical significance level was set at 5% in computations, and the computations were made using the SPSS (ver.13) statistical package program
It was determined that the difference between the ROM values of subjects with malignant and non-malign pleural effusions and the sera of the control group was significant in the malignant group compared to both groups (P = 0.0001), and the sera ROM values of patients with non-malignant pleural effusion were significant compared to the control group (P = 0.0001), and the ROM values of smokers were significant compared to non-smokers in each of the three groups (P = 0.0001).
These findings indicate that sera ROM levels are increased considerably in patients with exudative effusions compared to that of the control group. This condition can be instructive in terms of serum ROM value being suggestive of exudative effusion in patients with effusions. Furthermore, the detection of pleural ROM values being significantly higher in subjects with malignant pleural effusions compared to non-malignant subjects suggests that ROM can be used as a tumor marker in the differential diagnosis of pleural effusions of unknown origin.
Malignant pleural effusion; non-malignant pleural effusion; reactive oxygen metabolites