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Accumulation of pleural fluid is a common clinical problem associated with malignancy. Malignant pleural effusions (MPEs) are the second most common cause of a pleural exudate, with more than 150,000 patients diagnosed annually in the United States alone.1,2 MPEs represent advanced disease and are generally a poor prognostic indicator. Median survival for patients with MPE ranges from 3 to 12 months and depends on the tumor origin.3 In addition, MPEs are a frequent cause of dyspnea and discomfort, which adversely affect a patient’s quality of life. This group of patients requires substantial medical support to manage the burden of their disease, and providing effective therapeutic management remains a challenge. In the United States, there are approximately 126,000 admissions for MPE annually, with a median length of stay of 5.5 days.4 Thirty-day readmission rates are almost 40%, which is approximately 1.5 times higher than for acute myocardial infarction and 2 times higher than for congestive heart failure.5 In addition, palliative measures for patients with MPE are probably underutilized.6
This review is the first of 2 articles focusing on the management of MPE. Here, we discuss the pathophysiology of this disease process and provide an overview of the evaluation and diagnosis of MPE; available therapeutic options for the management of MPE are reviewed in a separate article.
Pathogenesis and Etiology
Normally, the thoracic cavity contains less than 15 mL of pleural fluid. Therefore, the visceral and parietal pleura are usually in close proximity to each other and the space between them is a potential space. Negative intrapleural pressures generated during regular breathing create a gradient for fluid movement into the pleural space from the parietal pleura dictated by Starling forces. Pleural fluid normally has low protein content and is primarily drained back into lymphatics through stomata lining the parietal pleura.7 This system’s ability to remove pleural fluid exceeds normal fluid production by 20- to 30-fold, suggesting that accumulation of excess pleural fluid requires a combination of increased fluid production and/or impaired fluid removal.8
Several mechanisms have been associated with the development of MPE. Pleural involvement by malignancy may occur from direct invasion of the pleural cavity by tumor (eg, lung cancer, breast cancer, chest wall neoplasms) or hematogenous spread of tumor to the pleura (eg, metastasis, non-Hodgkin lymphoma).9,10 Pleural malignancies can produce cytokine and inflammatory mediators, which may directly increase fluid production or indirectly alter vascular permeability.11,12 Tumor cells can also disrupt lymphatic drainage by occluding either pleural stomata or downstream lymphatic drainage. However, tumor involvement of the pleura does not always result in the development of an effusion and is only associated with fluid accumulation in approximately 60% of cases.13,14 MPE have also been strongly associated with mediastinal metastases, likely resulting from obstruction of mediastinal lymphatics.13,15,16
Pleural effusions with negative fluid cytology and pleural biopsies may result from secondary effects of tumor burden without direct pleural involvement and are referred to as paramalignant effusions. Common causes include thoracic duct obstruction (eg, Hodgkin lymphoma), bronchial obstruction, pneumonia, atelectasis, pulmonary embolism, trapped lung, and effects related to radiation or chemotherapy.15
Lung cancer is the most frequent cause of MPE and accounts for approximately one-third of cases. Other common primary tumor sites include breast, lymphoma, ovary, and gastrointestinal. Combined, these etiologies comprise about 75% of cases (Table 1).4,5 Females comprise a greater percentage of patients with MPE mainly due to the prevalence of ovarian and breast cancer. Mesothelioma-related effusions may be more prevalent in certain parts of the world due to associated exposure to asbestos.17 The primary tumor origin remains unknown in approximately 10% of cases.4
Clinical Presentation and Response to Therapeutic Drainage
More than 75% of patients with MPE are symptomatic. Dyspnea is the most common symptom and is present in more than half of patients.15 The mechanism of dyspnea caused by large effusions may not be solely due to impaired lung volumes or gas exchange. Other associated factors include decreased chest wall compliance, mediastinal shift causing decreased volume of the contralateral lung, paradoxical motion of the diaphragm, inefficient muscle length-tension relationships resulting from the stretch of respiratory muscles, and reflex stimulation from the lungs and chest wall.18-20 Other common presenting symptoms include cough, orthopnea, and chest pain. Hemoptysis suggests endobronchial involvement of the large airways. And, given the advanced nature of most MPEs, patients may also present with weight loss and cachexia.
A patient’s degree of symptom palliation and physiologic improvement in response to large-volume fluid removal is important to assess as these are important clinical factors that will influence management decision-making. Upwards of 50% of patients will not have significant palliation because they may be symptom-limited by other comorbid conditions, generalized deconditioning, or incomplete lung re-expansion. Presence of impaired lung compliance during fluid removal is also important to recognize. A trapped lung refers to a lung that cannot expand completely after removal of pleural fluid. Trapped lung may result from pleural-based malignancies or metastases, loculations and adhesions, or bronchial obstruction. Trapped lung is associated with high elastance (Pel) affecting pleural pressure-volume relationships (Figure 1). While clinically often considered together, some authors differentiate the category of incomplete lung expansion into 2 subgroups. In this context, the term trapped lung is used specifically to describe a mature, fibrous membrane that prevents lung re-expansion and is caused by a prior inflammatory pleural condition.21Entrapped lung describes incomplete lung expansion resulting from an active disease process, such as malignancy, ongoing infection, or rheumatologic pleurisy. Differences in pleural manometry can be seen in the 2 subgroups. Pleural manometry can be helpful to monitor for the generation of high negative intrapleural pressures during fluid removal, with negative pressures in excess of –19 cm H2O being suggestive of trapped lung physiology.22 However routine use of pleural manometry has not been shown to avoid the development of procedure-related chest discomfort that develops when the lung is unable to expand in response to the removal of fluid.23
Pleural Fluid Analysis and Pleural Biopsy
While most MPEs are protein-rich exudates, approximately 2% to 5% may be transudates.24,25 MPEs often appear hemorrhagic, so a ratio of pleural fluid to blood serum hematocrit greater than 0.5 is used to distinguish a true hemothorax from bloody-appearing pleural fluid.26 The cell count may be lymphocyte-predominant, but other cell types, such as eosinophils, do not exclude malignancy.27 Fluid may have a low glucose concentration and pH as well.
Thoracentesis with pleural fluid cytology evaluation is the most common method of diagnosis. The diagnostic sensitivity of fluid cytology ranges from 62% to 90%, with variability resulting from the extent of disease and etiology of the primary malignancy.1 If the initial pleural fluid analysis is not diagnostic, repeat thoracentesis can improve the diagnostic yield, but subsequent sampling has diminishing utility. In one series, diagnosis of malignancy was made by fluid cytology analysis in 65% of patients from the initial thoracentesis, 27% from a second procedure, but only 5% from a third procedure.28 At least 50 to 60 mL of pleural fluid should be obtained for pleural fluid cytology, but analysis of significantly larger volumes may not appreciably improve diagnostic yield.29,30
In addition to diagnostic yield, adequate sample cellularity to test for genetic driver mutations has become increasingly important given the rapid development of targeted therapies that are now available. The relative paucity of malignant cells in pleural fluid compared to other types of biopsies can make MPEs difficult to analyze for molecular markers. Newer generation assays have increased sensitivity, with one series reporting that pleural fluid was sufficient in 71.4% of cases to analyze for a panel comprised of EGFR, KRAS, BRAF, ALK, and ROS1 mutations.31 Similarly, fluid analysis from patients with MPEs demonstrated that 71.3% had at least 100 tumor cells, which permitted evaluation for PD-L1, with a concordance of 0.78 when compared to matched parenchymal lung biopsies from the same patient.32
In contrast, pleural biopsy methods may be useful to increase the diagnostic yield when pleural fluid analysis is insufficient. Closed needle biopsy may marginally improve diagnostic yields for malignancy over pleural fluid analysis alone. Diagnostic sensitivity may improve with the use of point-of-care ultrasonography to guide needle placement.33,34 The true value of closed needle biopsy is seen in situations in which there is a high pretest probability to diagnose an alternative disseminated pleural process, such as in tuberculosis, where the diagnostic yield increases substantially with closed needle biopsy of the pleura.33 Otherwise, the diagnosis of lung cancer and mesothelioma is superior with visually guided pleural biopsies, such as medical thoracoscopy or video-assisted thoracoscopic surgery (VATS), with diagnostic yields over 90%.33,35 Testing for genetic driver mutations in pleural biopsies is also substantially improved, with sample adequacy of 90% to 95% for most molecular markers.36,37 Despite the advantages, pleural biopsies are generally reserved for cases when pleural fluid analysis is insufficient or when performed in conjunction with palliative therapeutic interventions due to the increased invasive nature of the procedure.
Predictors of Recurrence and Prognosis
Not all MPEs will progress in size or become symptomatic, and predicting which patients will develop symptoms from their effusions is difficult. Pleural effusions will develop in only a minority of patients with lung cancer, and only a small subset will progress and require therapeutic intervention.38,39 Therefore, management guidelines for malignant pleural effusions discourage empiric intervention for patients with small, asymptomatic effusions.40 However, patients with larger, symptomatic effusions are more likely to have significant and rapid fluid recurrence. In a series of 988 symptomatic patients undergoing drainage, 30% had fluid recurrence within 15 days, 40% within 30 days, 45% within 60 days, and 48% within 90 days.41 Factors associated with fluid recurrence included radiographic size of the effusion, requirement for a larger amount of fluid to be initially drained, and higher pleural fluid lactate dehydrogenase (LDH) level. Negative cytology was associated with lower likelihood for recurrence.
Prognostication of life expectancy is another important clinical assessment which impacts medical decision-making when weighing the risk and benefits of different palliation options. Patient performance status, pleural fluid LDH, serum neutrophil-to-lymphocyte ratio, and tumor origin are independently associated with prognosis in a validated scoring system (Table 2).3 In this study, the overall median survival of patients with MPE was approximately 4.5 months, while the median survival for patients with mesothelioma was 11.3 months, 6.6 months for breast cancer, and 2.5 months for lung cancer and other malignancies. When stratified based on the combination of these 4 variables, patients in the high-risk group had a median survival of just 44 days compared to 130 days for the moderate-risk group and 319 days for the low-risk group. Additional, more complex prediction systems for survival and response to MPE therapies are now emerging and may provide clinicians and patients with additional information useful in medical decision-making.42
Conclusion
MPEs represent advanced stage disease and frequently adversely affect a patient’s quality of life. Ideal therapeutic options, discussed in the second part of this review, should effectively palliate symptoms, provide long-term relief, be minimally invasive with few side effects, minimize hospitalization and reliance on medical assistance, and be cost-effective.
1. Antony VB, Loddenkemper R, Astoul P, et al. Management of malignant pleural effusions. Eur Respir J. 2001;18:402-419.
2. Society AT. Management of malignant pleural effusions. Am J Respir Crit Care Med. 2000;162:1987-2001.
3. Clive AO, Kahan BC, Hooper CE, et al. Predicting survival in malignant pleural effusion: development and validation of the LENT prognostic score. Thorax. 2014;69:1098-1104.
4. Taghizadeh N, Fortin M, Tremblay A. US hospitalizations for malignant pleural effusions: data from the 2012 National Inpatient Sample. Chest. 2017;151:845-854.
5. Yang TS, Hsia DW, Chang DW. Patient- and hospital-level factors associated with readmission for malignant pleural effusion. J Oncol Pract. 2018;14:e547-e556.
6. Ost DE, Niu J, Zhao H, et al. Quality gaps and comparative effectiveness of management strategies for recurrent malignant pleural effusions. Chest. 2018;153:438-452.
7. Miserocchi G. Physiology and pathophysiology of pleural fluid turnover. Eur Respir J. 1997;10:219-225.
8. Sahn SA. State of the art. The pleura. Am Rev Respir Dis. 1988;138:184-234.
9. Khaleeq G, Musani AI. Emerging paradigms in the management of malignant pleural effusions. Respir Med. 2008;102:939-948.
10. Das DK. Serous effusions in malignant lymphomas: a review. Diagn Cytopathol. 2006;34:335-347.
11. Qian Q, Zhan P, Sun WK, et al. Vascular endothelial growth factor and soluble intercellular adhesion molecule-1 in lung adenocarcinoma with malignant pleural effusion: correlations with patient survival and pleural effusion control. Neoplasma. 2012;59:433-439.
12. Kraft A, Weindel K, Ochs A, et al. Vascular endothelial growth factor in the sera and effusions of patients with malignant and nonmalignant disease. Cancer. 1999;85:178-187.
13. Meyer PC. Metastatic carcinoma of the pleura. Thorax. 1966;21:437-443.
14. Light RW, Hamm H. Malignant pleural effusion: would the real cause please stand up? Eur Respir J. 1997;10:1701-1702.
15. Chernow B, Sahn SA. Carcinomatous involvement of the pleura: an analysis of 96 patients. Am J Med. 1977;63:695-702.
16. Musani AI, Haas AR, Seijo L, et al. Outpatient management of malignant pleural effusions with small-bore, tunneled pleural catheters. Respiration. 2004;71:559-566.
17. Roberts ME, Neville E, Berrisford RG, et al; Group BPDG. Management of a malignant pleural effusion: British Thoracic Society Pleural Disease Guideline 2010. Thorax. 2010;65 Suppl 2:ii32-40.
18. Estenne M, Yernault JC, De Troyer A. Mechanism of relief of dyspnea after thoracocentesis in patients with large pleural effusions. Am J Med. 1983;74:813-819.
19. Brown NE, Zamel N, Aberman A. Changes in pulmonary mechanics and gas exchange following thoracocentesis. Chest. 1978;74:540-542.
20. Wang LM, Cherng JM, Wang JS. Improved lung function after thoracocentesis in patients with paradoxical movement of a hemidiaphragm secondary to a large pleural effusion. Respirology. 2007;12:719-723.
21. Huggins JT, Doelken P, Sahn SA. The unexpandable lung. F1000 Med Rep. 2010;2:77.
22. Lan RS, Lo SK, Chuang ML, Yang CT, Tsao TC, Lee CH. Elastance of the pleural space: a predictor for the outcome of pleurodesis in patients with malignant pleural effusion. Ann Intern Med. 1997;126:768-774.
23. Lentz RJ, Lerner AD, Pannu JK, et al. Routine monitoring with pleural manometry during therapeutic large-volume thoracentesis to prevent pleural-pressure-related complications: a multicentre, single-blind randomised controlled trial. Lancet Respir Med. 2019;7:447-455.
24. Porcel JM, Alvarez M, Salud A, Vives M. Should a cytologic study be ordered in transudative pleural effusions? Chest. 1999;116:1836-1837.
25. Ryu JS, Ryu ST, Kim YS, et al. What is the clinical significance of transudative malignant pleural effusion? Korean J Intern Med. 2003;18:230-233.
26. Boersma WG, Stigt JA, Smit HJ. Treatment of haemothorax. Respir Med. 2010;104:1583-1587.
27. Light RW, Erozan YS, Ball WC. Cells in pleural fluid. Their value in differential diagnosis. Arch Intern Med. 1973;132:854-860.
28. Garcia LW, Ducatman BS, Wang HH. The value of multiple fluid specimens in the cytological diagnosis of malignancy. Mod Pathol. 1994;7:665-668.
29. Swiderek J, Morcos S, Donthireddy V, et al. Prospective study to determine the volume of pleural fluid required to diagnose malignancy. Chest. 2010;137:68-73.
30. Abouzgheib W, Bartter T, Dagher H, Pratter M, Klump W. A prospective study of the volume of pleural fluid required for accurate diagnosis of malignant pleural effusion. Chest. 2009;135:999-1001.
31. DeMaio A, Clarke JM, Dash R, et al. Yield of malignant pleural effusion for detection of oncogenic driver mutations in lung adenocarcinoma. J Bronchology Interv Pulmonol. 2019;26:96-101.
32. Grosu HB, Arriola A, Stewart J, et al. PD-L1 detection in histology specimens and matched pleural fluid cell blocks of patients with NSCLC. Respirology. 2019 Jun 17. doi: 10.1111/resp.13614.
33. Koegelenberg CF, Diacon AH. Pleural controversy: close needle pleural biopsy or thoracoscopy-which first? Respirology. 2011;16:738-746.
34. McLaughlin KM, Kerr KM, Currie GP. Closed pleural biopsy to diagnose mesothelioma: dead or alive? Lung Cancer. 2009;65:388-389.
35. Miyoshi S, Sasada S, Izumo T, et al. Diagnostic utility of pleural fluid cell block versus pleural biopsy collected by flex-rigid pleuroscopy for malignant pleural disease: a single center retrospective analysis. PLoS One. 2016;11:e0167186.
36. Vanderlaan PA, Yamaguchi N, Folch E, et al. Success and failure rates of tumor genotyping techniques in routine pathological samples with non-small-cell lung cancer. Lung Cancer. 2014;84:39-44.
37. Albanna AS, Kasymjanova G, Robitaille C, et al. Comparison of the yield of different diagnostic procedures for cellular differentiation and genetic profiling of non-small-cell lung cancer. J Thorac Oncol. 2014;9:1120-1125.
38. Tremblay A RS, Berthiaume L, and Michaud G. Natural history of asymptomatic pleural effusions in lung cancer patients. J Bronchol. 2007;14:98-100.
39. Porcel JM, Gasol A, Bielsa S, et al. Clinical features and survival of lung cancer patients with pleural effusions. Respirology. 2015;20:654-659.
40. Feller-Kopman DJ, Reddy CB, DeCamp MM, et al. Management of malignant pleural effusions. An official ATS/STS/STR clinical practice guideline. Am J Respir Crit Care Med. 2018;198:839-849.
41. Grosu HB, Molina S, Casal R, et al. Risk factors for pleural effusion recurrence in patients with malignancy. Respirology. 2019;24:76-82.
42. Psallidas I, Kanellakis NI, Gerry S, et al. Development and validation of response markers to predict survival and pleurodesis success in patients with malignant pleural effusion (PROMISE): a multicohort analysis. Lancet Oncol. 2018;19:930-939.
Accumulation of pleural fluid is a common clinical problem associated with malignancy. Malignant pleural effusions (MPEs) are the second most common cause of a pleural exudate, with more than 150,000 patients diagnosed annually in the United States alone.1,2 MPEs represent advanced disease and are generally a poor prognostic indicator. Median survival for patients with MPE ranges from 3 to 12 months and depends on the tumor origin.3 In addition, MPEs are a frequent cause of dyspnea and discomfort, which adversely affect a patient’s quality of life. This group of patients requires substantial medical support to manage the burden of their disease, and providing effective therapeutic management remains a challenge. In the United States, there are approximately 126,000 admissions for MPE annually, with a median length of stay of 5.5 days.4 Thirty-day readmission rates are almost 40%, which is approximately 1.5 times higher than for acute myocardial infarction and 2 times higher than for congestive heart failure.5 In addition, palliative measures for patients with MPE are probably underutilized.6
This review is the first of 2 articles focusing on the management of MPE. Here, we discuss the pathophysiology of this disease process and provide an overview of the evaluation and diagnosis of MPE; available therapeutic options for the management of MPE are reviewed in a separate article.
Pathogenesis and Etiology
Normally, the thoracic cavity contains less than 15 mL of pleural fluid. Therefore, the visceral and parietal pleura are usually in close proximity to each other and the space between them is a potential space. Negative intrapleural pressures generated during regular breathing create a gradient for fluid movement into the pleural space from the parietal pleura dictated by Starling forces. Pleural fluid normally has low protein content and is primarily drained back into lymphatics through stomata lining the parietal pleura.7 This system’s ability to remove pleural fluid exceeds normal fluid production by 20- to 30-fold, suggesting that accumulation of excess pleural fluid requires a combination of increased fluid production and/or impaired fluid removal.8
Several mechanisms have been associated with the development of MPE. Pleural involvement by malignancy may occur from direct invasion of the pleural cavity by tumor (eg, lung cancer, breast cancer, chest wall neoplasms) or hematogenous spread of tumor to the pleura (eg, metastasis, non-Hodgkin lymphoma).9,10 Pleural malignancies can produce cytokine and inflammatory mediators, which may directly increase fluid production or indirectly alter vascular permeability.11,12 Tumor cells can also disrupt lymphatic drainage by occluding either pleural stomata or downstream lymphatic drainage. However, tumor involvement of the pleura does not always result in the development of an effusion and is only associated with fluid accumulation in approximately 60% of cases.13,14 MPE have also been strongly associated with mediastinal metastases, likely resulting from obstruction of mediastinal lymphatics.13,15,16
Pleural effusions with negative fluid cytology and pleural biopsies may result from secondary effects of tumor burden without direct pleural involvement and are referred to as paramalignant effusions. Common causes include thoracic duct obstruction (eg, Hodgkin lymphoma), bronchial obstruction, pneumonia, atelectasis, pulmonary embolism, trapped lung, and effects related to radiation or chemotherapy.15
Lung cancer is the most frequent cause of MPE and accounts for approximately one-third of cases. Other common primary tumor sites include breast, lymphoma, ovary, and gastrointestinal. Combined, these etiologies comprise about 75% of cases (Table 1).4,5 Females comprise a greater percentage of patients with MPE mainly due to the prevalence of ovarian and breast cancer. Mesothelioma-related effusions may be more prevalent in certain parts of the world due to associated exposure to asbestos.17 The primary tumor origin remains unknown in approximately 10% of cases.4
Clinical Presentation and Response to Therapeutic Drainage
More than 75% of patients with MPE are symptomatic. Dyspnea is the most common symptom and is present in more than half of patients.15 The mechanism of dyspnea caused by large effusions may not be solely due to impaired lung volumes or gas exchange. Other associated factors include decreased chest wall compliance, mediastinal shift causing decreased volume of the contralateral lung, paradoxical motion of the diaphragm, inefficient muscle length-tension relationships resulting from the stretch of respiratory muscles, and reflex stimulation from the lungs and chest wall.18-20 Other common presenting symptoms include cough, orthopnea, and chest pain. Hemoptysis suggests endobronchial involvement of the large airways. And, given the advanced nature of most MPEs, patients may also present with weight loss and cachexia.
A patient’s degree of symptom palliation and physiologic improvement in response to large-volume fluid removal is important to assess as these are important clinical factors that will influence management decision-making. Upwards of 50% of patients will not have significant palliation because they may be symptom-limited by other comorbid conditions, generalized deconditioning, or incomplete lung re-expansion. Presence of impaired lung compliance during fluid removal is also important to recognize. A trapped lung refers to a lung that cannot expand completely after removal of pleural fluid. Trapped lung may result from pleural-based malignancies or metastases, loculations and adhesions, or bronchial obstruction. Trapped lung is associated with high elastance (Pel) affecting pleural pressure-volume relationships (Figure 1). While clinically often considered together, some authors differentiate the category of incomplete lung expansion into 2 subgroups. In this context, the term trapped lung is used specifically to describe a mature, fibrous membrane that prevents lung re-expansion and is caused by a prior inflammatory pleural condition.21Entrapped lung describes incomplete lung expansion resulting from an active disease process, such as malignancy, ongoing infection, or rheumatologic pleurisy. Differences in pleural manometry can be seen in the 2 subgroups. Pleural manometry can be helpful to monitor for the generation of high negative intrapleural pressures during fluid removal, with negative pressures in excess of –19 cm H2O being suggestive of trapped lung physiology.22 However routine use of pleural manometry has not been shown to avoid the development of procedure-related chest discomfort that develops when the lung is unable to expand in response to the removal of fluid.23
Pleural Fluid Analysis and Pleural Biopsy
While most MPEs are protein-rich exudates, approximately 2% to 5% may be transudates.24,25 MPEs often appear hemorrhagic, so a ratio of pleural fluid to blood serum hematocrit greater than 0.5 is used to distinguish a true hemothorax from bloody-appearing pleural fluid.26 The cell count may be lymphocyte-predominant, but other cell types, such as eosinophils, do not exclude malignancy.27 Fluid may have a low glucose concentration and pH as well.
Thoracentesis with pleural fluid cytology evaluation is the most common method of diagnosis. The diagnostic sensitivity of fluid cytology ranges from 62% to 90%, with variability resulting from the extent of disease and etiology of the primary malignancy.1 If the initial pleural fluid analysis is not diagnostic, repeat thoracentesis can improve the diagnostic yield, but subsequent sampling has diminishing utility. In one series, diagnosis of malignancy was made by fluid cytology analysis in 65% of patients from the initial thoracentesis, 27% from a second procedure, but only 5% from a third procedure.28 At least 50 to 60 mL of pleural fluid should be obtained for pleural fluid cytology, but analysis of significantly larger volumes may not appreciably improve diagnostic yield.29,30
In addition to diagnostic yield, adequate sample cellularity to test for genetic driver mutations has become increasingly important given the rapid development of targeted therapies that are now available. The relative paucity of malignant cells in pleural fluid compared to other types of biopsies can make MPEs difficult to analyze for molecular markers. Newer generation assays have increased sensitivity, with one series reporting that pleural fluid was sufficient in 71.4% of cases to analyze for a panel comprised of EGFR, KRAS, BRAF, ALK, and ROS1 mutations.31 Similarly, fluid analysis from patients with MPEs demonstrated that 71.3% had at least 100 tumor cells, which permitted evaluation for PD-L1, with a concordance of 0.78 when compared to matched parenchymal lung biopsies from the same patient.32
In contrast, pleural biopsy methods may be useful to increase the diagnostic yield when pleural fluid analysis is insufficient. Closed needle biopsy may marginally improve diagnostic yields for malignancy over pleural fluid analysis alone. Diagnostic sensitivity may improve with the use of point-of-care ultrasonography to guide needle placement.33,34 The true value of closed needle biopsy is seen in situations in which there is a high pretest probability to diagnose an alternative disseminated pleural process, such as in tuberculosis, where the diagnostic yield increases substantially with closed needle biopsy of the pleura.33 Otherwise, the diagnosis of lung cancer and mesothelioma is superior with visually guided pleural biopsies, such as medical thoracoscopy or video-assisted thoracoscopic surgery (VATS), with diagnostic yields over 90%.33,35 Testing for genetic driver mutations in pleural biopsies is also substantially improved, with sample adequacy of 90% to 95% for most molecular markers.36,37 Despite the advantages, pleural biopsies are generally reserved for cases when pleural fluid analysis is insufficient or when performed in conjunction with palliative therapeutic interventions due to the increased invasive nature of the procedure.
Predictors of Recurrence and Prognosis
Not all MPEs will progress in size or become symptomatic, and predicting which patients will develop symptoms from their effusions is difficult. Pleural effusions will develop in only a minority of patients with lung cancer, and only a small subset will progress and require therapeutic intervention.38,39 Therefore, management guidelines for malignant pleural effusions discourage empiric intervention for patients with small, asymptomatic effusions.40 However, patients with larger, symptomatic effusions are more likely to have significant and rapid fluid recurrence. In a series of 988 symptomatic patients undergoing drainage, 30% had fluid recurrence within 15 days, 40% within 30 days, 45% within 60 days, and 48% within 90 days.41 Factors associated with fluid recurrence included radiographic size of the effusion, requirement for a larger amount of fluid to be initially drained, and higher pleural fluid lactate dehydrogenase (LDH) level. Negative cytology was associated with lower likelihood for recurrence.
Prognostication of life expectancy is another important clinical assessment which impacts medical decision-making when weighing the risk and benefits of different palliation options. Patient performance status, pleural fluid LDH, serum neutrophil-to-lymphocyte ratio, and tumor origin are independently associated with prognosis in a validated scoring system (Table 2).3 In this study, the overall median survival of patients with MPE was approximately 4.5 months, while the median survival for patients with mesothelioma was 11.3 months, 6.6 months for breast cancer, and 2.5 months for lung cancer and other malignancies. When stratified based on the combination of these 4 variables, patients in the high-risk group had a median survival of just 44 days compared to 130 days for the moderate-risk group and 319 days for the low-risk group. Additional, more complex prediction systems for survival and response to MPE therapies are now emerging and may provide clinicians and patients with additional information useful in medical decision-making.42
Conclusion
MPEs represent advanced stage disease and frequently adversely affect a patient’s quality of life. Ideal therapeutic options, discussed in the second part of this review, should effectively palliate symptoms, provide long-term relief, be minimally invasive with few side effects, minimize hospitalization and reliance on medical assistance, and be cost-effective.
Accumulation of pleural fluid is a common clinical problem associated with malignancy. Malignant pleural effusions (MPEs) are the second most common cause of a pleural exudate, with more than 150,000 patients diagnosed annually in the United States alone.1,2 MPEs represent advanced disease and are generally a poor prognostic indicator. Median survival for patients with MPE ranges from 3 to 12 months and depends on the tumor origin.3 In addition, MPEs are a frequent cause of dyspnea and discomfort, which adversely affect a patient’s quality of life. This group of patients requires substantial medical support to manage the burden of their disease, and providing effective therapeutic management remains a challenge. In the United States, there are approximately 126,000 admissions for MPE annually, with a median length of stay of 5.5 days.4 Thirty-day readmission rates are almost 40%, which is approximately 1.5 times higher than for acute myocardial infarction and 2 times higher than for congestive heart failure.5 In addition, palliative measures for patients with MPE are probably underutilized.6
This review is the first of 2 articles focusing on the management of MPE. Here, we discuss the pathophysiology of this disease process and provide an overview of the evaluation and diagnosis of MPE; available therapeutic options for the management of MPE are reviewed in a separate article.
Pathogenesis and Etiology
Normally, the thoracic cavity contains less than 15 mL of pleural fluid. Therefore, the visceral and parietal pleura are usually in close proximity to each other and the space between them is a potential space. Negative intrapleural pressures generated during regular breathing create a gradient for fluid movement into the pleural space from the parietal pleura dictated by Starling forces. Pleural fluid normally has low protein content and is primarily drained back into lymphatics through stomata lining the parietal pleura.7 This system’s ability to remove pleural fluid exceeds normal fluid production by 20- to 30-fold, suggesting that accumulation of excess pleural fluid requires a combination of increased fluid production and/or impaired fluid removal.8
Several mechanisms have been associated with the development of MPE. Pleural involvement by malignancy may occur from direct invasion of the pleural cavity by tumor (eg, lung cancer, breast cancer, chest wall neoplasms) or hematogenous spread of tumor to the pleura (eg, metastasis, non-Hodgkin lymphoma).9,10 Pleural malignancies can produce cytokine and inflammatory mediators, which may directly increase fluid production or indirectly alter vascular permeability.11,12 Tumor cells can also disrupt lymphatic drainage by occluding either pleural stomata or downstream lymphatic drainage. However, tumor involvement of the pleura does not always result in the development of an effusion and is only associated with fluid accumulation in approximately 60% of cases.13,14 MPE have also been strongly associated with mediastinal metastases, likely resulting from obstruction of mediastinal lymphatics.13,15,16
Pleural effusions with negative fluid cytology and pleural biopsies may result from secondary effects of tumor burden without direct pleural involvement and are referred to as paramalignant effusions. Common causes include thoracic duct obstruction (eg, Hodgkin lymphoma), bronchial obstruction, pneumonia, atelectasis, pulmonary embolism, trapped lung, and effects related to radiation or chemotherapy.15
Lung cancer is the most frequent cause of MPE and accounts for approximately one-third of cases. Other common primary tumor sites include breast, lymphoma, ovary, and gastrointestinal. Combined, these etiologies comprise about 75% of cases (Table 1).4,5 Females comprise a greater percentage of patients with MPE mainly due to the prevalence of ovarian and breast cancer. Mesothelioma-related effusions may be more prevalent in certain parts of the world due to associated exposure to asbestos.17 The primary tumor origin remains unknown in approximately 10% of cases.4
Clinical Presentation and Response to Therapeutic Drainage
More than 75% of patients with MPE are symptomatic. Dyspnea is the most common symptom and is present in more than half of patients.15 The mechanism of dyspnea caused by large effusions may not be solely due to impaired lung volumes or gas exchange. Other associated factors include decreased chest wall compliance, mediastinal shift causing decreased volume of the contralateral lung, paradoxical motion of the diaphragm, inefficient muscle length-tension relationships resulting from the stretch of respiratory muscles, and reflex stimulation from the lungs and chest wall.18-20 Other common presenting symptoms include cough, orthopnea, and chest pain. Hemoptysis suggests endobronchial involvement of the large airways. And, given the advanced nature of most MPEs, patients may also present with weight loss and cachexia.
A patient’s degree of symptom palliation and physiologic improvement in response to large-volume fluid removal is important to assess as these are important clinical factors that will influence management decision-making. Upwards of 50% of patients will not have significant palliation because they may be symptom-limited by other comorbid conditions, generalized deconditioning, or incomplete lung re-expansion. Presence of impaired lung compliance during fluid removal is also important to recognize. A trapped lung refers to a lung that cannot expand completely after removal of pleural fluid. Trapped lung may result from pleural-based malignancies or metastases, loculations and adhesions, or bronchial obstruction. Trapped lung is associated with high elastance (Pel) affecting pleural pressure-volume relationships (Figure 1). While clinically often considered together, some authors differentiate the category of incomplete lung expansion into 2 subgroups. In this context, the term trapped lung is used specifically to describe a mature, fibrous membrane that prevents lung re-expansion and is caused by a prior inflammatory pleural condition.21Entrapped lung describes incomplete lung expansion resulting from an active disease process, such as malignancy, ongoing infection, or rheumatologic pleurisy. Differences in pleural manometry can be seen in the 2 subgroups. Pleural manometry can be helpful to monitor for the generation of high negative intrapleural pressures during fluid removal, with negative pressures in excess of –19 cm H2O being suggestive of trapped lung physiology.22 However routine use of pleural manometry has not been shown to avoid the development of procedure-related chest discomfort that develops when the lung is unable to expand in response to the removal of fluid.23
Pleural Fluid Analysis and Pleural Biopsy
While most MPEs are protein-rich exudates, approximately 2% to 5% may be transudates.24,25 MPEs often appear hemorrhagic, so a ratio of pleural fluid to blood serum hematocrit greater than 0.5 is used to distinguish a true hemothorax from bloody-appearing pleural fluid.26 The cell count may be lymphocyte-predominant, but other cell types, such as eosinophils, do not exclude malignancy.27 Fluid may have a low glucose concentration and pH as well.
Thoracentesis with pleural fluid cytology evaluation is the most common method of diagnosis. The diagnostic sensitivity of fluid cytology ranges from 62% to 90%, with variability resulting from the extent of disease and etiology of the primary malignancy.1 If the initial pleural fluid analysis is not diagnostic, repeat thoracentesis can improve the diagnostic yield, but subsequent sampling has diminishing utility. In one series, diagnosis of malignancy was made by fluid cytology analysis in 65% of patients from the initial thoracentesis, 27% from a second procedure, but only 5% from a third procedure.28 At least 50 to 60 mL of pleural fluid should be obtained for pleural fluid cytology, but analysis of significantly larger volumes may not appreciably improve diagnostic yield.29,30
In addition to diagnostic yield, adequate sample cellularity to test for genetic driver mutations has become increasingly important given the rapid development of targeted therapies that are now available. The relative paucity of malignant cells in pleural fluid compared to other types of biopsies can make MPEs difficult to analyze for molecular markers. Newer generation assays have increased sensitivity, with one series reporting that pleural fluid was sufficient in 71.4% of cases to analyze for a panel comprised of EGFR, KRAS, BRAF, ALK, and ROS1 mutations.31 Similarly, fluid analysis from patients with MPEs demonstrated that 71.3% had at least 100 tumor cells, which permitted evaluation for PD-L1, with a concordance of 0.78 when compared to matched parenchymal lung biopsies from the same patient.32
In contrast, pleural biopsy methods may be useful to increase the diagnostic yield when pleural fluid analysis is insufficient. Closed needle biopsy may marginally improve diagnostic yields for malignancy over pleural fluid analysis alone. Diagnostic sensitivity may improve with the use of point-of-care ultrasonography to guide needle placement.33,34 The true value of closed needle biopsy is seen in situations in which there is a high pretest probability to diagnose an alternative disseminated pleural process, such as in tuberculosis, where the diagnostic yield increases substantially with closed needle biopsy of the pleura.33 Otherwise, the diagnosis of lung cancer and mesothelioma is superior with visually guided pleural biopsies, such as medical thoracoscopy or video-assisted thoracoscopic surgery (VATS), with diagnostic yields over 90%.33,35 Testing for genetic driver mutations in pleural biopsies is also substantially improved, with sample adequacy of 90% to 95% for most molecular markers.36,37 Despite the advantages, pleural biopsies are generally reserved for cases when pleural fluid analysis is insufficient or when performed in conjunction with palliative therapeutic interventions due to the increased invasive nature of the procedure.
Predictors of Recurrence and Prognosis
Not all MPEs will progress in size or become symptomatic, and predicting which patients will develop symptoms from their effusions is difficult. Pleural effusions will develop in only a minority of patients with lung cancer, and only a small subset will progress and require therapeutic intervention.38,39 Therefore, management guidelines for malignant pleural effusions discourage empiric intervention for patients with small, asymptomatic effusions.40 However, patients with larger, symptomatic effusions are more likely to have significant and rapid fluid recurrence. In a series of 988 symptomatic patients undergoing drainage, 30% had fluid recurrence within 15 days, 40% within 30 days, 45% within 60 days, and 48% within 90 days.41 Factors associated with fluid recurrence included radiographic size of the effusion, requirement for a larger amount of fluid to be initially drained, and higher pleural fluid lactate dehydrogenase (LDH) level. Negative cytology was associated with lower likelihood for recurrence.
Prognostication of life expectancy is another important clinical assessment which impacts medical decision-making when weighing the risk and benefits of different palliation options. Patient performance status, pleural fluid LDH, serum neutrophil-to-lymphocyte ratio, and tumor origin are independently associated with prognosis in a validated scoring system (Table 2).3 In this study, the overall median survival of patients with MPE was approximately 4.5 months, while the median survival for patients with mesothelioma was 11.3 months, 6.6 months for breast cancer, and 2.5 months for lung cancer and other malignancies. When stratified based on the combination of these 4 variables, patients in the high-risk group had a median survival of just 44 days compared to 130 days for the moderate-risk group and 319 days for the low-risk group. Additional, more complex prediction systems for survival and response to MPE therapies are now emerging and may provide clinicians and patients with additional information useful in medical decision-making.42
Conclusion
MPEs represent advanced stage disease and frequently adversely affect a patient’s quality of life. Ideal therapeutic options, discussed in the second part of this review, should effectively palliate symptoms, provide long-term relief, be minimally invasive with few side effects, minimize hospitalization and reliance on medical assistance, and be cost-effective.
1. Antony VB, Loddenkemper R, Astoul P, et al. Management of malignant pleural effusions. Eur Respir J. 2001;18:402-419.
2. Society AT. Management of malignant pleural effusions. Am J Respir Crit Care Med. 2000;162:1987-2001.
3. Clive AO, Kahan BC, Hooper CE, et al. Predicting survival in malignant pleural effusion: development and validation of the LENT prognostic score. Thorax. 2014;69:1098-1104.
4. Taghizadeh N, Fortin M, Tremblay A. US hospitalizations for malignant pleural effusions: data from the 2012 National Inpatient Sample. Chest. 2017;151:845-854.
5. Yang TS, Hsia DW, Chang DW. Patient- and hospital-level factors associated with readmission for malignant pleural effusion. J Oncol Pract. 2018;14:e547-e556.
6. Ost DE, Niu J, Zhao H, et al. Quality gaps and comparative effectiveness of management strategies for recurrent malignant pleural effusions. Chest. 2018;153:438-452.
7. Miserocchi G. Physiology and pathophysiology of pleural fluid turnover. Eur Respir J. 1997;10:219-225.
8. Sahn SA. State of the art. The pleura. Am Rev Respir Dis. 1988;138:184-234.
9. Khaleeq G, Musani AI. Emerging paradigms in the management of malignant pleural effusions. Respir Med. 2008;102:939-948.
10. Das DK. Serous effusions in malignant lymphomas: a review. Diagn Cytopathol. 2006;34:335-347.
11. Qian Q, Zhan P, Sun WK, et al. Vascular endothelial growth factor and soluble intercellular adhesion molecule-1 in lung adenocarcinoma with malignant pleural effusion: correlations with patient survival and pleural effusion control. Neoplasma. 2012;59:433-439.
12. Kraft A, Weindel K, Ochs A, et al. Vascular endothelial growth factor in the sera and effusions of patients with malignant and nonmalignant disease. Cancer. 1999;85:178-187.
13. Meyer PC. Metastatic carcinoma of the pleura. Thorax. 1966;21:437-443.
14. Light RW, Hamm H. Malignant pleural effusion: would the real cause please stand up? Eur Respir J. 1997;10:1701-1702.
15. Chernow B, Sahn SA. Carcinomatous involvement of the pleura: an analysis of 96 patients. Am J Med. 1977;63:695-702.
16. Musani AI, Haas AR, Seijo L, et al. Outpatient management of malignant pleural effusions with small-bore, tunneled pleural catheters. Respiration. 2004;71:559-566.
17. Roberts ME, Neville E, Berrisford RG, et al; Group BPDG. Management of a malignant pleural effusion: British Thoracic Society Pleural Disease Guideline 2010. Thorax. 2010;65 Suppl 2:ii32-40.
18. Estenne M, Yernault JC, De Troyer A. Mechanism of relief of dyspnea after thoracocentesis in patients with large pleural effusions. Am J Med. 1983;74:813-819.
19. Brown NE, Zamel N, Aberman A. Changes in pulmonary mechanics and gas exchange following thoracocentesis. Chest. 1978;74:540-542.
20. Wang LM, Cherng JM, Wang JS. Improved lung function after thoracocentesis in patients with paradoxical movement of a hemidiaphragm secondary to a large pleural effusion. Respirology. 2007;12:719-723.
21. Huggins JT, Doelken P, Sahn SA. The unexpandable lung. F1000 Med Rep. 2010;2:77.
22. Lan RS, Lo SK, Chuang ML, Yang CT, Tsao TC, Lee CH. Elastance of the pleural space: a predictor for the outcome of pleurodesis in patients with malignant pleural effusion. Ann Intern Med. 1997;126:768-774.
23. Lentz RJ, Lerner AD, Pannu JK, et al. Routine monitoring with pleural manometry during therapeutic large-volume thoracentesis to prevent pleural-pressure-related complications: a multicentre, single-blind randomised controlled trial. Lancet Respir Med. 2019;7:447-455.
24. Porcel JM, Alvarez M, Salud A, Vives M. Should a cytologic study be ordered in transudative pleural effusions? Chest. 1999;116:1836-1837.
25. Ryu JS, Ryu ST, Kim YS, et al. What is the clinical significance of transudative malignant pleural effusion? Korean J Intern Med. 2003;18:230-233.
26. Boersma WG, Stigt JA, Smit HJ. Treatment of haemothorax. Respir Med. 2010;104:1583-1587.
27. Light RW, Erozan YS, Ball WC. Cells in pleural fluid. Their value in differential diagnosis. Arch Intern Med. 1973;132:854-860.
28. Garcia LW, Ducatman BS, Wang HH. The value of multiple fluid specimens in the cytological diagnosis of malignancy. Mod Pathol. 1994;7:665-668.
29. Swiderek J, Morcos S, Donthireddy V, et al. Prospective study to determine the volume of pleural fluid required to diagnose malignancy. Chest. 2010;137:68-73.
30. Abouzgheib W, Bartter T, Dagher H, Pratter M, Klump W. A prospective study of the volume of pleural fluid required for accurate diagnosis of malignant pleural effusion. Chest. 2009;135:999-1001.
31. DeMaio A, Clarke JM, Dash R, et al. Yield of malignant pleural effusion for detection of oncogenic driver mutations in lung adenocarcinoma. J Bronchology Interv Pulmonol. 2019;26:96-101.
32. Grosu HB, Arriola A, Stewart J, et al. PD-L1 detection in histology specimens and matched pleural fluid cell blocks of patients with NSCLC. Respirology. 2019 Jun 17. doi: 10.1111/resp.13614.
33. Koegelenberg CF, Diacon AH. Pleural controversy: close needle pleural biopsy or thoracoscopy-which first? Respirology. 2011;16:738-746.
34. McLaughlin KM, Kerr KM, Currie GP. Closed pleural biopsy to diagnose mesothelioma: dead or alive? Lung Cancer. 2009;65:388-389.
35. Miyoshi S, Sasada S, Izumo T, et al. Diagnostic utility of pleural fluid cell block versus pleural biopsy collected by flex-rigid pleuroscopy for malignant pleural disease: a single center retrospective analysis. PLoS One. 2016;11:e0167186.
36. Vanderlaan PA, Yamaguchi N, Folch E, et al. Success and failure rates of tumor genotyping techniques in routine pathological samples with non-small-cell lung cancer. Lung Cancer. 2014;84:39-44.
37. Albanna AS, Kasymjanova G, Robitaille C, et al. Comparison of the yield of different diagnostic procedures for cellular differentiation and genetic profiling of non-small-cell lung cancer. J Thorac Oncol. 2014;9:1120-1125.
38. Tremblay A RS, Berthiaume L, and Michaud G. Natural history of asymptomatic pleural effusions in lung cancer patients. J Bronchol. 2007;14:98-100.
39. Porcel JM, Gasol A, Bielsa S, et al. Clinical features and survival of lung cancer patients with pleural effusions. Respirology. 2015;20:654-659.
40. Feller-Kopman DJ, Reddy CB, DeCamp MM, et al. Management of malignant pleural effusions. An official ATS/STS/STR clinical practice guideline. Am J Respir Crit Care Med. 2018;198:839-849.
41. Grosu HB, Molina S, Casal R, et al. Risk factors for pleural effusion recurrence in patients with malignancy. Respirology. 2019;24:76-82.
42. Psallidas I, Kanellakis NI, Gerry S, et al. Development and validation of response markers to predict survival and pleurodesis success in patients with malignant pleural effusion (PROMISE): a multicohort analysis. Lancet Oncol. 2018;19:930-939.
1. Antony VB, Loddenkemper R, Astoul P, et al. Management of malignant pleural effusions. Eur Respir J. 2001;18:402-419.
2. Society AT. Management of malignant pleural effusions. Am J Respir Crit Care Med. 2000;162:1987-2001.
3. Clive AO, Kahan BC, Hooper CE, et al. Predicting survival in malignant pleural effusion: development and validation of the LENT prognostic score. Thorax. 2014;69:1098-1104.
4. Taghizadeh N, Fortin M, Tremblay A. US hospitalizations for malignant pleural effusions: data from the 2012 National Inpatient Sample. Chest. 2017;151:845-854.
5. Yang TS, Hsia DW, Chang DW. Patient- and hospital-level factors associated with readmission for malignant pleural effusion. J Oncol Pract. 2018;14:e547-e556.
6. Ost DE, Niu J, Zhao H, et al. Quality gaps and comparative effectiveness of management strategies for recurrent malignant pleural effusions. Chest. 2018;153:438-452.
7. Miserocchi G. Physiology and pathophysiology of pleural fluid turnover. Eur Respir J. 1997;10:219-225.
8. Sahn SA. State of the art. The pleura. Am Rev Respir Dis. 1988;138:184-234.
9. Khaleeq G, Musani AI. Emerging paradigms in the management of malignant pleural effusions. Respir Med. 2008;102:939-948.
10. Das DK. Serous effusions in malignant lymphomas: a review. Diagn Cytopathol. 2006;34:335-347.
11. Qian Q, Zhan P, Sun WK, et al. Vascular endothelial growth factor and soluble intercellular adhesion molecule-1 in lung adenocarcinoma with malignant pleural effusion: correlations with patient survival and pleural effusion control. Neoplasma. 2012;59:433-439.
12. Kraft A, Weindel K, Ochs A, et al. Vascular endothelial growth factor in the sera and effusions of patients with malignant and nonmalignant disease. Cancer. 1999;85:178-187.
13. Meyer PC. Metastatic carcinoma of the pleura. Thorax. 1966;21:437-443.
14. Light RW, Hamm H. Malignant pleural effusion: would the real cause please stand up? Eur Respir J. 1997;10:1701-1702.
15. Chernow B, Sahn SA. Carcinomatous involvement of the pleura: an analysis of 96 patients. Am J Med. 1977;63:695-702.
16. Musani AI, Haas AR, Seijo L, et al. Outpatient management of malignant pleural effusions with small-bore, tunneled pleural catheters. Respiration. 2004;71:559-566.
17. Roberts ME, Neville E, Berrisford RG, et al; Group BPDG. Management of a malignant pleural effusion: British Thoracic Society Pleural Disease Guideline 2010. Thorax. 2010;65 Suppl 2:ii32-40.
18. Estenne M, Yernault JC, De Troyer A. Mechanism of relief of dyspnea after thoracocentesis in patients with large pleural effusions. Am J Med. 1983;74:813-819.
19. Brown NE, Zamel N, Aberman A. Changes in pulmonary mechanics and gas exchange following thoracocentesis. Chest. 1978;74:540-542.
20. Wang LM, Cherng JM, Wang JS. Improved lung function after thoracocentesis in patients with paradoxical movement of a hemidiaphragm secondary to a large pleural effusion. Respirology. 2007;12:719-723.
21. Huggins JT, Doelken P, Sahn SA. The unexpandable lung. F1000 Med Rep. 2010;2:77.
22. Lan RS, Lo SK, Chuang ML, Yang CT, Tsao TC, Lee CH. Elastance of the pleural space: a predictor for the outcome of pleurodesis in patients with malignant pleural effusion. Ann Intern Med. 1997;126:768-774.
23. Lentz RJ, Lerner AD, Pannu JK, et al. Routine monitoring with pleural manometry during therapeutic large-volume thoracentesis to prevent pleural-pressure-related complications: a multicentre, single-blind randomised controlled trial. Lancet Respir Med. 2019;7:447-455.
24. Porcel JM, Alvarez M, Salud A, Vives M. Should a cytologic study be ordered in transudative pleural effusions? Chest. 1999;116:1836-1837.
25. Ryu JS, Ryu ST, Kim YS, et al. What is the clinical significance of transudative malignant pleural effusion? Korean J Intern Med. 2003;18:230-233.
26. Boersma WG, Stigt JA, Smit HJ. Treatment of haemothorax. Respir Med. 2010;104:1583-1587.
27. Light RW, Erozan YS, Ball WC. Cells in pleural fluid. Their value in differential diagnosis. Arch Intern Med. 1973;132:854-860.
28. Garcia LW, Ducatman BS, Wang HH. The value of multiple fluid specimens in the cytological diagnosis of malignancy. Mod Pathol. 1994;7:665-668.
29. Swiderek J, Morcos S, Donthireddy V, et al. Prospective study to determine the volume of pleural fluid required to diagnose malignancy. Chest. 2010;137:68-73.
30. Abouzgheib W, Bartter T, Dagher H, Pratter M, Klump W. A prospective study of the volume of pleural fluid required for accurate diagnosis of malignant pleural effusion. Chest. 2009;135:999-1001.
31. DeMaio A, Clarke JM, Dash R, et al. Yield of malignant pleural effusion for detection of oncogenic driver mutations in lung adenocarcinoma. J Bronchology Interv Pulmonol. 2019;26:96-101.
32. Grosu HB, Arriola A, Stewart J, et al. PD-L1 detection in histology specimens and matched pleural fluid cell blocks of patients with NSCLC. Respirology. 2019 Jun 17. doi: 10.1111/resp.13614.
33. Koegelenberg CF, Diacon AH. Pleural controversy: close needle pleural biopsy or thoracoscopy-which first? Respirology. 2011;16:738-746.
34. McLaughlin KM, Kerr KM, Currie GP. Closed pleural biopsy to diagnose mesothelioma: dead or alive? Lung Cancer. 2009;65:388-389.
35. Miyoshi S, Sasada S, Izumo T, et al. Diagnostic utility of pleural fluid cell block versus pleural biopsy collected by flex-rigid pleuroscopy for malignant pleural disease: a single center retrospective analysis. PLoS One. 2016;11:e0167186.
36. Vanderlaan PA, Yamaguchi N, Folch E, et al. Success and failure rates of tumor genotyping techniques in routine pathological samples with non-small-cell lung cancer. Lung Cancer. 2014;84:39-44.
37. Albanna AS, Kasymjanova G, Robitaille C, et al. Comparison of the yield of different diagnostic procedures for cellular differentiation and genetic profiling of non-small-cell lung cancer. J Thorac Oncol. 2014;9:1120-1125.
38. Tremblay A RS, Berthiaume L, and Michaud G. Natural history of asymptomatic pleural effusions in lung cancer patients. J Bronchol. 2007;14:98-100.
39. Porcel JM, Gasol A, Bielsa S, et al. Clinical features and survival of lung cancer patients with pleural effusions. Respirology. 2015;20:654-659.
40. Feller-Kopman DJ, Reddy CB, DeCamp MM, et al. Management of malignant pleural effusions. An official ATS/STS/STR clinical practice guideline. Am J Respir Crit Care Med. 2018;198:839-849.
41. Grosu HB, Molina S, Casal R, et al. Risk factors for pleural effusion recurrence in patients with malignancy. Respirology. 2019;24:76-82.
42. Psallidas I, Kanellakis NI, Gerry S, et al. Development and validation of response markers to predict survival and pleurodesis success in patients with malignant pleural effusion (PROMISE): a multicohort analysis. Lancet Oncol. 2018;19:930-939.