Postgraduate Course 10 Malignant pleural effusion management · Notability - €3.99 ... Malignant pleural effusion management ... of malignant pleural effusions, and how to use these
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ERS International Congress Amsterdam
26–30 September 2015
Postgraduate Course 10
Malignant pleural effusion management
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AIMS: To understand the new roles that molecular biology and histo-/cytopathology play in the diagnosis and management (treatment and prognosis) of malignant pleural effusions, and how to use these techniques (processing and data interpretation) in clinical practice. TARGET AUDIENCE: Trainees, pulmonary physicians, thoracic surgeons, pathologists, molecular biologists, and scientists.
CHAIRS: P. Astoul (Marseille, France), M. Skrzypski (Sopot, Poland)
COURSE PROGRAMME PAGE
09:30 Which material in which disease? 5 S. Fernandez Bussy (Santiago, Chile)
10:15 How to send your material to pathology 82 P. Schnabel (Homburg/Saar, Germany)
11:00 Break
11:30 Interpretation of the results in the clinic 83 A. Scherpereel (Lille, France)
12:15 Atypical mesothelial hyperplasia and other pitfalls in MPE diagnosis 102 F. Galateau-Salle (Caen, France)
Faculty disclosures 108
Faculty contact information 109
Answers to evaluation questions 110
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“Tumor markers seem to be a promising alternative and have been proposed to aid in the differentiation of the PE etiology. These include carcinoembryonic antigen (CEA), cancer antigens: CA- 125, CA 15-3, CA 19-9, CA 72-4, cytokeratin fragments (CYFRA 21-1), neuron specific enolase (NSA), and squamous cell carcinoma antigen (SCCA). However, the clinical value of these markers is still unclear.”
Eur J Med Res (2009) 14(Suppl. IV): 128-133
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“Pleural fluid (mean volume 50 ml) and blood samplesfor tumor marker measurements were collectedduring the first thoracentesis. They were centrifuged at2000 rpm for 10 min and the supernatant was frozenat -20°C until assayed. Concentrations of CEA, CA-125, CYFRA 21-1, and NSE were measured usingelectrochemiluminescence immunoassays on RocheElecsys 1010 analyzer (Roche Diagnostics; Mannheim,Germany).”
Eur J Med Res (2009) 14(Suppl. IV): 128-133
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“The diagnostic utility was calculated for: 1) singletumor marker level in the pleural fluid (P) and serum(S); 2) single marker pleural fluid/serum level ratio(R); 3) a combination of four markers in the pleuralfluid and serum. In the last case, the result was considered positive when the level of at least two markers was higher than the respective marker cut-off value.”
Eur J Med Res (2009) 14(Suppl. IV): 128-133
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Eur J Med Res (2009) 14(Suppl. IV): 128-133
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Eur J Med Res (2009) 14(Suppl. IV): 128-13317
“The median pleural fluid concentrations of the investigatedtumor markers were significantly higher in malignant exudates compared with non-malignant effusions, with the exception of CA-125 which was similar. An analysis of the serum concentrations revealed comparable values of CA-125 and NSE in both groups, while the CEA and CYFRA 21-1 levels were significantly higher in malignant effusions. The pleuralfluid/serum concentration ratios were similar for all markers in both investigated groups, with the exception of CEA which was significantly higher in the malignant group.”
Eur J Med Res (2009) 14(Suppl. IV): 128-133
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Eur J Med Res (2009) 14(Suppl. IV): 128-133
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Eur J Med Res (2009) 14(Suppl. IV): 128-133
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“CEA in PE proved to be the marker with the highest diagnosticaccuracy. The area under curve (AUC) in the ROC analysis for this parameter was 0.83. Previous studies which included this marker revealed the following AUC values: 0.97; 0.84, and 0.72 [3, 9, 10]. The diagnostic accuracy for serum measurements in our study was lower and equaled to 0.65.”
Eur J Med Res (2009) 14(Suppl. IV): 128-133
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“CYFRA 21-1 is another marker with a high diagnosticyield, but contrary to the three other markersthe serum, rather than plural fluid, level of CYFRA21-1 shows a higher overall diagnostic accuracy.CYFRA 21-1, soluble fragments of cytokeratin 19, isexpressed by all histological types of lung cancer, especially by squamous lung cancer [12]. Similarly toCEA, increased levels of CYFRA 21-1 in the pleural fluid may result from impaired lymphatic drainage orcancer involvement of the pleura. In our study, theAUC for this marker in serum was 0.78.”
Eur J Med Res (2009) 14(Suppl. IV): 128-133
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“Studies in which lung cancer was the predominantcause of PE, revealed a higher diagnostic yield of thisparameter. Serum CYFRA 21-1 has been found usefulfor the diagnosis of lung cancer, particularly of thesquamous cell type. However, Dejsomritrutai et al [14]found that CYFRA 21-1 is a good marker also in apopulation of patients with PE caused by adenocarcinoma.These authors reported CYFRA 21-1 sensitivity of 81.5% and 74.1% in serum and the pleural fluid, respectively.The specificity of this marker was also high and reached as much as 97.1% for both serum and PE.”
Eur J Med Res (2009) 14(Suppl. IV): 128-133
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“We found a high sensitivity, but low diagnostic accuracy,for NSE. NSE is a known marker of small cellcarcinoma. The sensitivity of pleural fluid NSE concentration was as high as 94.4%, while for the serummeasurements it was 80.6%. However, the specificityof this marker was relatively low, thus the AUC reached 0.65 for pleural fluid and 0.62 for serum.”
Eur J Med Res (2009) 14(Suppl. IV): 128-133
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“CA-125 is particularly useful in detecting the recurrenceof ovarian cancer [15], although the marker isalso observed in malignancies of the endometrium,lung, breast, and gastrointestinal tract. In our patients,the accuracy of CA-125 measurement in PE andserum was 0.64 and 0.60, respectively.”
Eur J Med Res (2009) 14(Suppl. IV): 128-133
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“In the present study, a combination of four markers (CEA,CA-125, CYFRA 21-1, and NSE), with a cut-off for two or more markers, gave sensitivity and specificity of 91.7% and 86.8% for pleural measurements, 86.1% and 71.1% for serum, and 100% and 60.5% for the pleural fluid/ serum ratio, respectively. The AUC calculated from the ROC analysis achieved as much as 0.89, 0.82, and 0.88 for the pleural fluid, serum, and pleural fluid/serum ratio, respectively. It seems that the pleural fluid/serum marker ratio does not add anyessential clinical information. A meta-analysis by Lianget al [16] showed similar results with the combinationsof different tumor markers, e.g., the AUC for CEA/CA-125 was 0.86 and for CEA/ CYFRA 21-1 - 0.93.”
Eur J Med Res (2009) 14(Suppl. IV): 128-133
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Tuberc Respir Dis 2014;76:211-217
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Tuberc Respir Dis 2014;76:211-217
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“First, measurement of pleural CEA is likely to be a useful diagnostic tool for confirming MPE and is useful for the differential diagnosis between malignant pleural mesothelioma and metastatic lung cancer. A high level of pleural CEA seems to rule out malignant mesothelioma. Second, CA 15-3, CA 19-9, and CYFRA 21-1 are highly specific but insufficiently sensitive to diagnose MPE, and the combination of two or more tumor markers appears to increase the diagnostic sensitivity. Therefore, the results of tumor marker assays should be interpreted in parallel with clinical findings and with the results of conventional tests.”
Tuberc Respir Dis 2014;76:211-217
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“Vascular endothelial growth factor (VEGF) as a diagnostic biomarker of MPE because of the high levels of VEGF present in MPE14. VEGF is thought to be the key mediator in the formation of MPE via increased vascular permeability and vascular leakage of fluid. A recent meta-analysis based on 1,025 patients in 10 studies concluded that VEGF might play a role in the diagnosis of MPE, while its diagnostic value is not satisfactory (Table 2)15. Mesothelin and fibulin-3 in pleural effusion have also been introduced as potential new biomarkers to detect pleural mesothelioma at an earlier stage.”
Tuberc Respir Dis 2014;76:211-217
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“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.” 44
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“The present meta-analysis suggested that the diagnostic value of CA 15-3 for MPE was far from perfection. Combining CA 15-3 with other markers may be an appropriate method for improving the diagnostic accuracy. The study by Romero et al found that the sensitivity and specificity of carcinoembryonic antigen combined with CA 15-3 in pleural fluid were 71% and 96%, respectively, which was better than testing CA 15-3 alone (15). Another study reported that the combination of thymidine kinase with CA 15-3 and procalcitonin appeared to be an optimal combination, nearly enabling differential diagnosing in all types of effusion”
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“The diagnosis of malignant pleural effusion (MPE) is often challengingbecause differentiating MPE from benign effusion can be difficultusing the currently available tools derived from thoracentesis; onlyapproximately 50–70% of patients with MPE can be diagnosed bycytological examination of the pleural fluids [1]. Therefore, varioustumor markers found in pleural effusions, including carcinoembryonicantigen (CEA), Cyfra 21-1, CA125, CA19-9, neuron-specific enolase, andsquamous cell carcinoma antigen, have been investigated for their abilityto differentiate malignant from benign pleural effusions [5–7]. However,the sensitivity of these tests is relatively low, and false-positive resultshave been described in almost all series. Thus, it is necessary to identifyand evaluate more sensitive biological markers for MPE diagnosis [8].The ideal marker would be office-based, rapid, and inexpensive andwould have high sensitivity and specificity in the target population; thismight reduce the burden and expense of frequent biopsies of the pleura.”
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“Background: Survivin in pleural effusion is a promising marker for the diagnosis of malignant pleural effusion.Methods: Based on the principles and methods of Cochrane systematic reviews, PubMed, EMBASE, Web of Knowledge (ISI), the Cochrane Library, and China National Knowledge Infrastructure (CNKI) databases were searched to identify studies that assessed the diagnostic value of survivin in pleural effusion for malignant pleural effusion. Stata 12 and Meta-disc 1.4 software were used to test the heterogeneity and to perform the meta-analysis.Results: Our search returned 167 articles, ofwhich ten fulfilled the inclusion criteria. These studies included a total of 614 patients with malignant pleural effusion and 430 patients with benign pleural effusion as controls. The summary assessments revealed that the pooled sensitivity was 0.86 (95% CI: 0.82 0.88) and the pooled specificity was 0.92 (95% CI: 0.89–0.94). The positive likelihood ratio was 8.76 (95% CI: 5.41–14.20), the negative likelihood ratio was 0.16 (95% CI: 0.13–0. 20) and the diagnostic odds ratio (DOR) was 59.72 (95% CI: 39.60–90.05). The area under the curve (AUC) for the pleural effusion survivin tests was 0.9485, and the *Q index estimatefor these tests was 0.8885.Conclusions: Survivin in pleural effusion has potential diagnostic value with advanced sensitivity and specificity and it can be used as adjunct tool for non-invasive diagnosis of malignant pleural effusion.”
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“Survivin is a 12-amino acid protein (16.5 kDa) that islocated at chromosomal region 17q25. Survivin is an inhibitor of programmed cell death and mediates the suppression of apoptosis byinhibiting caspases 3 and 7, the terminal effectors in apoptotic protease cascades [10]. The survivinpromoter is highly active in human tumorcells, but not in normal cells, and is up-regulated by hypoxia in tumors [11]. It is undetectable in normal differentiated tissues but is notably expressed in patients with lung cancer, breast cancer, bladder cancer, multiple myeloma, and lymphoma.”
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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 from1331 individuals were analysed.The final clinical diagnosis was 183 MM,436 non-MM malignancy, and 712 nonmalignant effusions. Effusion mesothelinhad a sensitivity of 67% forMM 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 presenceof malignancy and adds weight to the clinical rationale for further investigation to establish a malignant diagnosis.
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Purpose of reviewMalignant mesothelioma is an asbestos-induced, aggressive tumour, which frequently presents with pleural effusion. There are over 60 reported causes that can result in the development of a pleural effusion.Currently, there are no tumour biomarkers in widespread clinical use for the differential diagnosis of mesothelioma from other diseases. With the incidence of mesothelioma expected to continue to increase, it is timely to review the current status of effusion-based biomarkers for mesothelioma diagnosis.Recent findingsThe majority of recent studies have evaluated soluble mesothelin in effusions in a diagnostic setting for mesothelioma. However, at high specificity, the sensitivity of the assay is limited to approximately 60% at the time of diagnosis. There is considerable research effort directed toward the identification of new markers for mesothelioma through a variety of genomic, proteomic and immunomic based platforms. One of the few new biomarkers to be identified through a biomarker discovery pipeline and evaluated in pleural effusions is fibulin-3. Preliminary results on the diagnostic accuracy of fibulin-3 have been inconsistent.SummaryTo date, soluble mesothelin remains the best available biomarker for mesothelioma and a positive result is clinically useful in patients with pleural effusions in whom the diagnosis is uncertain.
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At a histopathologic level, there are essentially four circumstances in which immunophenotypic study plays animportant role in the recognition of mesothelioma.
(1) Mesothelioma versus adenocarcinoma
(2) Sarcomatoid mesothelioma versus primary or metastaticpleural sarcoma versus metastatic sarcomatoidCarcinoma
(3) Mesothelioma versus reactive mesothelial hyperplasia
(4) Desmoplastic sarcomatoid mesothelioma versus fibrouspleuritis
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Each of the above-cited diagnostic questions requires a different panel of immunohistochemical reagents. In cases of suspected spindle-cell or desmoplastic mesothelioma, these should include antibodies to keratin and calretinin; other markers are necessary only to subtypetruly mesenchymal keratin-negative neoplasms.
Recently, antibodies to cytokeratins 5/6 have beenadvocated as contextually specific markers for mesothelioma. Ordoñezfound that 40 cases of mesothelioma were positive for keratins 5/6, whereas adenocarcinomas of the lung were negative. Nevertheless, the selected analyses have also found that 11 to 14% of nonpulmonary adenocarcinomas show focal reactivity for cytokeratins 5/6.
Cytokeratins 7, 8, 18, and 19 are seen in all mesotheliomas and adenocarcinomas, whereas cytokeratins 5, 6, 14, and 17 are observed in some mesotheliomas but not adenocarcinomas. Unfortunately, the latter markers are absent in sarcomatoid tumors.
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Carcinoembryonic antigen: Virtually all pleural mesotheliomas lack CEA, whereas the vast majority of pulmonary adenocarcinomas expressthat marker.
CD15 has a high level of specificity for adenocarcinomaamong all epithelial tumors. Nevertheless, occasional mesotheliomas (usually primary peritoneal lesions) may show focal staining for this marker.
B72.3This antibody recognizes a widely distributed epithelial determinant (tumor-associated glycoprotein-72), which is a cell-membrane glycoprotein. Irrespective of their sites of origin, a majority of adenocarcinomas show reactivity with B72.3.
Ber-EP4 is another generic epithelial marker that was originally thought to be specific for adenocarcinomas. It is now apparent that roughly 20%of mesotheliomas demonstrate Ber-EP4 reactivity as well.
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Calretinin is a cytoplasmic and nuclear calcium-binding protein. In contrast to most antibodies used for the evaluation of possible mesotheliomas, labeling for calretinin represents positive support for that diagnosis. This marker is present in more than 85% of mesotheliomas of the epithelial type.
The authors’ own experience is that the majority of sarcomatoid lesions are, in fact, positive for calretinin.
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Aquaporin-1 (AQP1) is a molecule involved in the growth of MM cells, and yetis a factor reported to correlate with improved survival rates for MM with an epithelioid component, in comparison to AQP1-poor MM, as assessed from AQP1 expression by epithelioid MM cells only (apart from co-expression by stromal endothelial cells in addition to the tumour cells).
Prognostic factors for MM include not only the histological subtypes, butother independent variables that include (among others), AQP1 expression by mesothelioma cells, the clinical status of the patient, the serum neutrophil:lymphocyte ratio and blood thrombocytosis
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Mesothelial Hyperplasia VsEpitheliod Mesothelioma
Husain A., et al., Arch Pathol Lab Med 2013;137:647-66777
Epitheliod Mesothelioma VsLung AdenoCa
Husain A., et al., Arch Pathol Lab Med 2013;137:647-66778
Sarcomatoid Mesothelioma VsSCC and TCC
Scherpereel A, et al. Eur Respir J 2010;35:479-95
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Fibrous Pleurisy vs SarcomatoidMesothelioma
Husain A., et al., Arch Pathol Lab Med 2013;137:647-667