Continuing Education Activity

Malignant Pleural effusions (MPE), with an incidence of 150,000 new cases a year, have long been recognized as a cause of significant morbidity in advanced cancer patients. More recently, the presence of a loculated pleural effusion has been identified as an independent risk factor for poor prognosis. A variety of therapeutic options exist for the management of MPE. Spengler, in 1901 was the first to perform chemical pleurodesis with the use of hypertonic glucose. Since then, there has been controversy over the ideal agent for performing chemical pleurodesis. However, Talc has been recognized as the most widely used and studied agent. This activity provides a conceptual understanding of the interprofessional team's etiology, pathophysiology, evaluation, and management of MPE.

Objectives:

• Describe the pathophysiology of malignant pleural effusion.
• Review the clinical findings of malignant pleural effusion.
• Outline Investigations strategies involved in the management of malignant pleural effusion.
• Review the associated complications of the various therapeutic procedures utilized for the management of malignant pleural effusion.

Introduction

Malignant pleural effusion is characterized by the presence of malignant cells in the pleural fluid.[1] The presence of MPE denotes systemic dissemination of cancer and has been staged as M1a disease, as per the American Joint committee on Cancer TNM staging system.[2] The identification of malignant cells in pleural lavage fluid, performed in patients without a coexistent pleural effusion, has been identified as an indicator of micro-metastatic disease and associated with a higher recurrence rate and poorer survival.[3] Both the parietal and visceral pleura may be involved by the tumor directly or via the blood-borne spread.[4] While the parietal pleura may be involved by secondary spread from the visceral pleura, direct seeding has also been described.[5] 

The pathophysiology is attributed to a disturbance of the Starling forces that govern and dictate fluid biomechanics within the pleural space.[6] While pleural fluid production is governed by the difference in the hydrostatic and oncotic pressure between the pulmonary circulation and pleural space, absorption is determined by lymphatic vessels in the parietal pleura.[7] Excess fluid may accumulate as a result of an inability to drain the fluid from the pleural space, which has been postulated to arise as a result of the clogging of the stomata within the parietal pleura or metastatic involvement of hilar and mediastinal lymph nodes.[8]

Lung cancer, breast cancer, and hematological malignancies are the major malignancies associated with direct, contiguous, or hematogenous pleural involvement. From 50 to 55 percent of patients with pleural involvement develop effusion.[9] Wet pleural involvement is associated with a poorer prognosis (as compared to dry pleural disease).[10] Between 42 and 77 percent of effusions in cancer patients have been documented to be exudative in nature. There has been a gradual increase in the incidence of eosinophilic pleural effusions (defined as exudative pleural effusions containing more than 10 percent eosinophils), which can be attributed to a malignant etiology in recent years, with an attempt to delineate malignant eosinophilic pleural effusion as a separate entity.[11][12] While malignant involvement of the pleura may be one cause of effusion in a patient with cancer, other etiologies also need to be considered among the differential.[13]

Malignant pleural effusions must be differentiated from paramalignant pleural effusions, which are not caused by direct pleural involvement by the tumor.[14] A trapped lung is an entity characterized by the failure of a chronically non-expanded lung to re-expand following drainage of the pleural fluid, which may be caused by extensive involvement of the visceral pleura.[15] Septated Pleural effusions which are characterized by the development of septated fibrin pockets, may represent an underlying cause of failure to achieve successful drainage and complete resolution of dyspnea.[16] 

The treatment of recurrent malignant pleural effusions represents a significant financial burden.[17] Dyspnea is the most common presenting complaint associated with the development of pleural involvement by the tumor.[18] Goals of management include palliation of symptoms, with minimal impact on the quality of life while ensuring cost-effectiveness of the treatment.[19] 

Therapeutic approaches vary widely given the broad range of treatment options. However, there has been a concerted effort in recent times to move towards patient-related outcomes compared to successful pleurodesis as markers of successful palliation.[20] The role of vascular endothelial growth factor and host-tumor cell interactions in the pleural microenvironment (consisting of inflammatory, mesothelial and endothelial cells) has been the subject of growing scrutiny.[21][22][23] Novel immunotherapy approaches have been targeted towards understanding the role of the CD8+ T-cell response and the associated immune responses to translocated microbial pathogens in the pathogenesis of this condition.[21]

Etiology

Anatomical factors - Normal pleural space lies between the parietal and the visceral pleura. While the parietal pleura lines the inner thoracic wall, including the bilateral medial mediastinum, subcostal right and left diaphragmatic leaflets, inner ribs, and associated musculature, the visceral pleura lies in close approximation with the lung parenchyma. The visceral and parietal pleurae join at the hilum.[24] Close apposition and maintenance of negative pressure within the intrapleural space ensure adherence of visceral to parietal pleura. Pleural fluid under normal physiological conditions also promotes the sliding motion of the parietal over the visceral pleura.[25] 

The normal fluid volume in the pleural space measures ten ml/0.13 (0.26 +/- 0.1) ml/kg body weight.[26] Intrinsic factors (direct infiltration by tumor cells, hormonal disequilibrium, and anatomical disruption) and extrinsic factors (limitation of respiratory motion, blockage of pleural stomata, and mechanical compression) interfere with the ability of the pleural lymphatics to function effectively. Both intrinsic and extrinsic factors contribute to a decreased pleural fluid resorption, with resultant accumulation of excess fluid in the pleural space.[24]

Physiological factors - Both increased production and decreased reabsorption have been associated with the development of MPE.[27]

Molecular factors - Molecules predisposing to the development of pleural vessels' hyperpermeability, which leads to overproduction of pleural fluid, comprise three different classes of chemical mediators.[28] The first class consists of inflammatory cytokines such as interleukin 2, tumor necrosis factor, and interferon.[29] The second group comprises pro-angiogenic molecules such as angiopoietin 1 and 2. At the same time, the third includes molecules such as vascular endothelial growth factor, chemokine (C-C motif ligand), matrix metalloproteinases, and osteopontin, which have been implicated directly in the pathogenesis of increased vascular permeability.[30][31]

Genetic factors - Mutations in KRAS, EGFR, MET, BRAF, PIK3CA, and RET, have been identified to be associated with the development of MPE.[32][33]

Impact on Respiratory Physiology - The development of pleural effusion has been associated with hypoxemia and a reduction in the partial pressure of oxygen. The occurrence of a mild intrapulmonary shunt also predisposes to the development of reduced arterial oxygenation. A dramatic relief in the sensation of breathlessness following a successful thoracentesis procedure has also led to an added emphasis on the impact of pleural fluid accumulation on respiratory dynamics. Activation of mechanoreceptors in response to pleural fluid accumulation, in response to stretch, cough, and altered lung volumes have been shown to underlie the pathophysiology of dyspnea in MPE. Both alterations in hemi-diaphragmatic movement and paradoxical movement of the diaphragm have been identified. Shifts in inspiratory muscle pressure-volume curves predisposing to an unfavorable pressure-volume interdependence between increased thoracic volume and pressure have resulted in the accumulation of pleural fluid. Alterations in the length-tension relationship have also been shown to predispose to dyspnea.[34][35]

Epidemiology

Malignant pleural effusion is seen in up to 15 percent of all cancer patients.[33] The annual incidence of MPE approaches 100,000 cases in Europe and 150,000 cases in the United States. Effusions usually signify an advanced stage of the malignancy, with an overall survival approaching 3 to 12 months after initial diagnosis.[36] The 5-year survival of lung cancer patients with wet pleural disease is estimated to be 3 percent.[37] While small cell carcinoma cells directly invade the pleura, non-small cell lung cancer causes indirect impairment of the function of pleural lymphatics.[38][39] 

Ipsilateral pleural involvement is seen in 90 percent of cases of lung cancer.[40] Contralateral pleural effusion is seen in 10 percent of cases.[41] Between 2 and 11 percent of breast cancer patients present with malignant pleural effusion, which is usually caused by direct dissemination via pleural lymphatics. Most cases of breast cancer-associated MPE are associated with triple-negative disease and are associated with a poor prognosis.[42] An elevated KI-67 in the pleural fluid has also been associated with a poor outcome.[43][44]

Pleural effusion in ovarian cancer may represent a comparatively better prognosis when compared to other tumors. Fifteen percent of patients may present with the wet pleural disease as the first sign of cancer.[45] Positive pleural fluid cytology represents FIGO stage IV-a disease.[46] While more than three-fourths of the patients present with the ipsilateral disease, one-fourth of the cases may show bilateral involvement. MPE is seen in both Hodgkin’s as well as Non-Hodgkin’s disease.[47][48][49] 

While 20 percent of patients with Hodgkin’s lymphoma may present with MPE at the time of diagnosis, effusions may represent a disease progression in around 60 percent of patients. It is associated with a poor prognosis and may represent chemotherapy-resistant disease.[50] Diffuse large B cell lymphoma and follicular lymphoma represent leading causes of Non-Hodgkin’s lymphoma presenting with MPE.[49] 

Both infiltrations of the pleural space and tumor-immune cell interactions in the pleural microenvironment represent underlying pathophysiologic mechanisms.[49][51] MPE associated with the unusually aggressive malignant mesothelioma is seen in nearly 50 to 94 percent of cases and represents a distinct biologically active disease process that protects the tumor from chemotherapy and promotes tumor growth.[52] Bilateral pleural effusions are seen in 15 percent of non-critically ill patients and 55 percent of the critically ill patient population.[53][54]

History and Physical

A succinct clinical history is useful in identifying the various etiologies of malignant pleural effusions. Identifying various comorbidities (pulmonary, renal, cardiac, and hepatic) is useful in determining the patient's physiological reserve and may have management implications.

Symptoms - Clinical presentation depends upon the extent of effusion, rapidity of development, and physiological reserves of the patient.[55]

Dyspnea - Dyspnea is the most common presenting complaint in a patient with an underlying pleural effusion, seen in more than 50 percent of all cases. Mechanical factors such as a decrease in chest wall compliance, altered biomechanics resulting from a contralateral shift of the mediastinum, decrease in ipsilateral lung volume, activation of compensatory reflex phenomenon (from chest wall receptors), and caudal displacement of the diaphragm have been identified as contributory factors.[34] A sense of breathlessness that is out of proportion to the amount of collected fluid may be seen due to coexistent lung collapse, pulmonary arterial hypertension, and ventilation-perfusion mismatch.[19][56] 

Assessment of dyspnea in cancer can be performed using the unidimensional and multidimensional scale (which factor in functional impairment).[57] While a numerical rating scale and visual analog scale have been commonly used to measure dyspnea, oxygen cost diagram, borg scale, modified Borg scale, and St. George respiratory symptom assessment questionnaire has also been used.[58][59][60][61] 

Other tools used in assessing dyspnea include dyspnea interview schedule, pulmonary functional status scale, and baseline dyspnea index.[62] Non-pharmacological approaches in the management of dyspnea in advanced disease focus upon the subjective experience of breathlessness. The added emphasis on the need to quantify the impact of dyspnea on functional activities of daily living necessitates the use of multidimensional scales in assessing breathlessness. A minimal clinically important difference (MCID) of approximately ten on a visual analog scale of 100 is used to signal a clinically significant improvement in chronic breathlessness in clinical trials.[63]

Pain - Chest wall pain signifies the presence of underlying chest wall involvement or malignant pleural mesothelioma.[64] Visceral pain from pleural involvement may also increase upon taking a deep breath (pleuritic).[65] A dull aching pain may be more common than the classically described pleuritic pain. Radiation of pain to the right shoulder may signal diaphragmatic involvement. Chest pain might also signal localized involvement of the chest wall or rib fractures.

Cough - May be productive and associated with hemoptysis. Denotes underlying pleural inflammation, which may accompany tumor involvement of the pleura or bronchial involvement by the tumor. Constitutional symptoms such as loss of appetite, loss of weight, easy fatiguability, and lethargy might indicate the advanced stage of the disease.[56][66]

Symptomatology related to paraneoplastic manifestations - Muscle weakness - Lambert Eaton Myasthenic syndrome (small-cell lung cancer).[67] Drowsiness, obtundation, seizures - hyponatremia related to the syndrome of inappropriate antidiuretic hormone (SIADH) (hyponatremia).[68] Confusion, Increased frequency of micturition - hypercalcemia (squamous cell lung cancer).[69] Cushing striae, obesity, buffalo hump, muscle weakness (proximal myopathy) - Cushing syndrome due to ectopic ACTH production (small cell lung cancer).[70] 

Headache, engorged veins in the anterior chest wall, dyspnea, altered voice, confusion, obtundation, swelling of face, swelling of the arm - superior vena cava obstruction (small cell lung cancer).[71] Miosis, ptosis, anhidrosis, apparent enophthalmos - Horner syndrome - superior sulcus tumor/Pancoast tumor (adenocarcinoma).[72] Hypertrophic pulmonary osteoarthropathy - most commonly associated with non-small cell lung cancer.[73][74]

Occupational history - History of occupational asbestos exposure should be sought.[75]

Family history - A family history of malignancy may offer a clue to the diagnosis of an underlying malignancy.

Past medical history - A review of medications should also be performed as medications such as amiodarone, nitrofurantoin, and methotrexate can be associated with the development of exudative effusions.[76]

Clubbing - Presence of Lovibond sign, Schamroth sign, and Distal phalangeal (DPD) to interphalangeal depth (IPD) ratio of more than 1 are physical signs required for establishing a diagnosis.[77][78] Depth at the nail bed (DPD) is compared with depth at the interphalangeal fold. Values of more than one are considered indicative of a diagnosis of finger clubbing (irrespective of the patient's age). Measurements are made using a Harpenden skinfold caliper.[79] Tissue hypoxia, chronic inflammation, and abnormal vascularization have been shown to underlie the pathogenesis of clubbing.[80]

Physical Examination

Inspection - Asymmetrical chest wall expansion, tracheal shift, intercostal fullness, Trail's sign, scars of previously performed thoracocentesis or biopsies, a predominance of abdominal breathing.[81]

Evaluation (General Physical Examination) - Poor performance status may signal an urgent need for imminent palliation. Prognostication may be performed using a palliative prognostic scale which is a component of the palliative prognostic index (PPI). A score more than 4.5 on the PPI may signal a survival lesser than six weeks.[82] Pallor, clubbing (hypertrophic pulmonary osteoarthropathy), left supraclavicular lymphadenopathy (Trosier sign) may signal an advanced stage of illness.

Percussion - Dullness is usually observed on percussion. The percussion note has been traditionally described as being woody dull. 

Joseph Leopold Auenbrugger is regarded as the inventor of direct percussion, which has been replaced mainly by the digitodigital method of percussion. Percussion is preferentially performed with the patient sitting up. Topographic comparative percussion is performed in the apical regions, fourth and fifth intercostal spaces (right middle lobe and lingular lobe), and basal areas of the lung.

Cardinal Rules of Percussion

The pleximeter finger (middle finger of the left hand) should be in firm apposition to the chest wall, while the remaining fingers should be kept off the chest wall. The tip of the middle finger of the right hand or the plessor should strike the middle phalanx of the pleximeter finger swiftly at a right angle. Percussion must be performed in the intercostal spaces. Percussion may be performed directly over the clavicle. Percuss should proceed from a more resonant to a less resonant area. Percussion from a resonant towards a flat area is also considered acceptable. This ensures that a difference between the two areas is felt (if present). While performing the percussion act, the plessor finger should strike the middle phalanx of the pleximeter finger at a right angle. The sudden movement of the plessor finger should originate at the relaxed wrist. It is advised to keep the long axis of the pleximeter finger parallel to the border of the organ being percussed. The note should be compared in similar areas between both sides.

The force of the stroke of the plessor finger depends upon patient factors (age, sex, and built), tissue type, differential diagnoses being considered, the area being examined, and thickness of the chest wall. Damping of the percussion stroke can be avoided by withdrawing the plessor finger immediately after striking the middle phalanx. Both the sound and the feeling of the percussion note are considered crucial to formulating a differential diagnosis. Heavy percussion causes large areas of the lung to resonate (as a result of which it is possible to miss small areas of impaired note) and should be avoided.[83][84]

Auscultation - Diminished or absent breath sounds are present on auscultation. A pleural rub is usually heard in dry pleurisy.[56]

Egophony (E to A change) - Change in the timber of voice from E to A (but not pitch or volume). They are usually heard as a high-pitched nasal sound and described by Laennec as the bleating of a goat. It is characterized by the intensity and suddenness with which it appears—usually confined over a small area on one side of the chest. An absence of similar change in sound over the contralateral side should be used before making a definitive diagnosis. Underlying mechanism - accumulation of fluid enhances the transmission of high-frequency sounds while filtering out low-frequency sounds.  

Whispering pectoriloquy - Pectoriloquy is defined as the increased resonance of voice while passing through the lung structures. Whispered sound is heard clearly after placing a stethoscope over the patient's chest. Both whispered pectoriloquy, as well as egophony, are heard at the upper border of the pleural effusion. 

Summary - Physical findings of dullness to percussion and decreased vocal fremitus have been used clinically to diagnose pleural effusion. The presence of dullness on percussion makes the diagnosis likely. A chest radiograph is required to confirm the diagnosis. In the presence of a low clinical suspicion of a diagnosis, the absence of a reduced vocal fremitus decreases the likelihood of diagnosis. A chest radiograph is usually not advised without a finding of reduced vocal fremitus on physical examination.[56] 

According to Auenbrugger and Forbes, dullness is a prerequisite for diagnosing pleural effusion, although this particular physical finding might be challenging to discern in bilateral pleural effusion. Percussive sounds have been shown to penetrate up to a maximum depth of 6 cm (2 cms of chest wall and 4 cm of fluid). At least 500 ml of fluid should be present in the pleural cavity to yield positive findings on physical examination. The finding of significant tachypnea, significantly decreased chest expansion, absent tactile fremitus, absent breath sounds, contralateral tracheal or mediastinal shift (presence of Trail's sign, tracheal deviation), bulging intercostal spaces, and presence of egophony has been shown to correlate with accumulation of more than 1500 ml of fluid in the pleural space.[85]

Evaluation

Imaging

Chest radiograph - A posteroanterior chest radiograph is considered a first-line investigation for the initial evaluation of a patient with signs and symptoms of pleural effusion in the setting of cancer.[86] A minimum quantity of 200 ml of fluid is required in the pleural space for the diagnosis to be made on a posteroanterior chest radiograph. In comparison, 50 ml of fluid may be visible on a lateral chest radiograph.[87] Blunting of the costophrenic angle on the PA view requires the presence of 175 ml of fluid.[88] The fluid volume of fewer than 500 ml (detected in roughly 10 to 15 percent effusions) has not been associated with symptoms.[19] 

Blunting of costophrenic angle, mediastinal shift, Crowding of the ribs, elevation of the hemidiaphragm may be radiographic findings that point towards a diagnosis.[86] A massive effusion is defined as the one that occupies an entire hemithorax and is more commonly associated with mediastinal shift and diaphragmatic inversion.[86] The presence of a massive effusion, loculation, and loss in volume of lung ipsilateral to the site of involvement has been associated with an increased suspicion of an underlying malignant etiology.[89] A mass lesion may also be visualized in the case of a lung primary. Hilar prominence may be suggestive of a central lesion or lymphadenopathy. An absence of a mediastinal shift may represent underlying fibrosis (fixity of the mediastinum) or extensive pleural involvement (malignant pleural mesothelioma).[90]

Thoracic Ultrasound - Thoracic Ultrasonography has a higher sensitivity than chest radiography.[91] Ultrasonography may help diagnose smaller amounts of fluids and as a guide to performing diagnostic and therapeutic procedures.[92] Using 3.5 - 5 MHz transducer probes can provide a good depth of penetration and optimum spatial resolution. The diagnosis of septations (loculated collections), hemothorax, and organized collections may be made.[93] An ultrasound may also be used to distinguish between an effusion, consolidation, and thickened pleura.[86] Pleural metastases may be characterized as relatively small lenticular hypoechoic masses, in close apposition to the chest wall or masses with complex echogenicity.[94] 

The shred sign can be used to diagnose pulmonary non-translobar consolidation with a sensitivity of 90 percent and specificity of 98 percent.[95] Lung movement may be visualized as pleural sliding, which may be lost with the development of post-procedure pneumothorax.[96] The presence of pleural thickening (more than 1 cm), presence of pleural nodularity/irregularity, visceral pleural thickening, diaphragmatic thickening more than 7 mm may be other indicators of the presence of malignancy.[94] 

Evidence supports the use of pre-procedural ultrasonography in identifying the optimal site for thoracentesis.  A grading system proposed by Smargiassi et al. uses the description of anatomical extent, visible radiological landmarks, and a number of intercostal spaces involved to stratify the extent of pleural effusion. A large pleural effusion is classified as one where the upper lung lobe is partially displaced, includes atelectasis of the lower lobe or partial atelectasis of the upper lobe, and involves three to four intercostal spaces. A massive pleural effusion is characterized by the full collapse of the lung, atelectasis of the whole lung with hilum visible, and involvement of four or more intercostal spaces.[97] The use of thoracic ultrasound has also been associated with reducing the incidence of hemothorax and pneumothorax following thoracentesis.[98] Ultrasound imaging also has a role in the rapid identification of post-procedural pneumothorax.

Contrast-Enhanced Chest Computed Tomography - Mediastinal lymph node involvement and associated parenchymal disease may be better visualized on computed tomography, considered the gold standard screening in those with underlying pleural malignancy.[99] Circumferential pleural thickening, pleural nodularity, thicken of parietal pleura in excess of 1 cm, and mediastinal pleural involvement are all considered pointers of a diagnosis of malignancy. The use of CT scanning is characterized by high specificity (at the cost of poor sensitivity). Other potential limitations include an inability to distinguish between malignant pleural mesothelioma and pleural metastasis. Nodular pleural thickening, mediastinal pleural thickening, circumferential thickening encasing the lung, and thickening of parietal pleura in excess of one centimeter may also be useful markers in the identification of malignant pleural involvement.[100] 

A CT scan scoring system proposed by Pocel et al. for differentiation between malignant and benign conditions includes the following parameters – the presence of pleural lesions measuring more than 1 cm, hepatic metastasis, pulmonary mass or nodule measuring more than 1 cm, pericardial effusion, absence of loculations and absence of cardiac silhouette enlargement. A score of more than 7 out of 10 can be used to detect malignancy with a sensitivity and specificity of 88 and 94 percent, respectively.[101] 

Dual-energy spectral CT imaging, which can generate material decomposition images, monochromatic image sets with fast kilovoltage switching, has been shown to have added utility in distinguishing benign from malignant pleural lesions. A combination of patient age, clinical history, and information on CT value measurement (at both high and low energy levels), and the effective atomic number obtained in a single spectral scan have been found to be useful in identifying malignant pleura disease.[102]

Positron Emission Tomography/Dynamic Imaging - While early or indolent disease may give rise to false negatives, inflammatory pleural involvement, rheumatoid disease, pleurodesis procedure performed may be associated with false-positive results.[103] Dynamic imaging may have some utility in characterizing mixed lesions (pleural asbestosis, malignant pleural mesothelioma) and targeting specific areas within the pleura.[104] While Bury et al. were the first to propose its utility in the characterization of pleural disease, a score consisting of unilateral masses/nodules showing increased, pleural thickening, multiple nodules, presence of effusion showing increased F18-FDG uptake, and presence of extrapulmonary malignancy has been proposed in distinguishing benign from malignant disease with a sensitivity and specificity of 83 and 92 percent respectively.[105]

Magnetic Resonance Imaging - MRI offers better soft tissue resolution as compared to Computed tomographic scanning. MR Imaging possesses a higher sensitivity in detecting chest wall and diaphragmatic involvement.[106][107] The exclusion of MRI-based imaging from diagnostic algorithms can be attributed to higher costs, limited availability, and difficulty in imaging the lung parenchyma. Diffusion-weighted imaging has been shown to be useful in differentiating between benign and malignant pleural diseases.[108]

Histopathological Diagnosis

Diagnostic Thoracentesis - The standard panel of tests that needs to be performed on a pleural fluid sample includes PF protein, glucose, pH, lactate dehydrogenase, cytology, and microbiology.[109] A volume of 40 to 60 cc of pleural fluid is considered optimum to make a diagnosis o MPE.[110] While the yield of pleural fluid analysis approaches 6 to 32% for the diagnosis of mesothelioma, it has been shown to have a comparatively higher sensitivity in diagnosing Adenocarcinoma (80%).[111][112] While primarily an exudate, transudative effusion may be seen in 5 to 10% of cases.[113] Repeat procedures may increase the yield by a third; however, more than two repeat procedures have not been found to be more productive.[114]

Pleural Fluid Analysis - Normal physicochemical characteristics include pH between 7.60 and 7.64, protein levels of less than 2 percent (2 gm/dl), less than 100 WBC’s per cubic millimeter, Glucose content similar to that of plasma, LDH level less than half of that present within the plasma. The following parameters can be used in making a diagnosis of malignant etiology underlying the accumulation of pleural fluid – pH less than 7.30, LDH levels greater than 1000 U/l, reduced pleural fluid glucose concentration (30 to 50 mg/dl), lymphocyte values greater than 50 to 70%.[109][115] 

Pleural fluid tumor marker levels have been used in the diagnosis of MPE. Carcinoembryonic Antigen, mucin, and Leu 1 have been shown to be elevated in effusions with an underlying malignant etiology.[48] While the standard Light’s criteria which are used to distinguish between exudative and transudative effusion include pleural fluid protein and LDH levels, additional criteria which can be used to identify exudative effusions include gross appearance (cloudy), specific weight (>1.020), Total proteins (2.9 g/dl), cholesterol levels, Computed tomographic scan attenuation parameters, and Serum-pleural fluid albumin gradient.[116] 

An issue that continues to remain a deterrent in diagnosing malignant effusion by the use of conventional cytology remains the differentiation of malignant cells from reactive mesothelial cells.[117] The inability to study the tissue architecture due to a paucity of tissue specimens also remains an issue that needs to be addressed. Overcrowding of cells and processing artifacts may also contribute to the low yield.[118] The cytocentrifuge or millipore filter can be used for the evaluation of malignant cells in the pleural fluid.[119]

Pleural Fluid Cell Block - Cell-block technique for processing fluids was first introduced in 1896.[120] Retention of tissue fragments vital to make a diagnosis is considered a potential advantage over conventional cytology.[121] Various methods used to prepare a cell block include the formalin method, agar method, and thrombin clot method.[122] The underlying principle involves the formation of a gel due to cross-linking of proteins that do not get dissolved upon the processing of tissue samples.[123] A better preservation of the antigenicity and cytomorphological characteristics is an additional advantage of this technique. The increase in sensitivity of the procedure may be attributed to higher cellularity, preservation of cellular architecture, and morphological patterns of malignant cells. Immunohistochemistry analysis and special staining can also be performed on the cell block specimen.[124]

Pleural Biopsy- Given the low diagnostic yield of conventional cytology and the lack of standard protocols which advocate the use of the cell block technique, a pleural biopsy may be considered in patients with cytology negative effusions.[125] A closed pleural biopsy is usually performed using the Abrams, Cope, Vim Silverman, or cutting needle biopsy.[126] This procedure has a lower yield in early-stage tumors and the non-homogenous distribution of tumors. Ease of performance and resource-intensive nature is the primary reason for preferring this procedure over techniques such as medical thoracoscopy. An increase in yield is noted when this procedure is combined with cytological techniques.[121] A diagnostic yield approaching 60 percent has been reported with the use of Blind closed pleural biopsy. The addition of imaging techniques (Ultrasonography and Computed tomography) may help improve diagnostic yields.[127]

Image-Guided Biopsies - Both ultrasound-guided and CT-guided biopsies have been used in obtaining representative pleural samples for diagnostic purposes.[128] Both have shown sensitivity in the range of 70 to 90 percent. Imaging guided biopsy can increase the sensitivity of diagnosing MPE to 80 percent.

Thoracoscopy - Medical thoracoscopy is recommended when the thickness of effusion is less than 10 mm on a CT scan.[118] It improves diagnostic accuracy as it allows for direct visualization of the area of interest and tumor tissue sampling. Major pathological changes observed in the diseased pleura include nodules, adhesions, plaques, ulcers, and hyperemia. Thoracoscopy has been shown to have a complication rate of less than 8 percent when performed by trained professionals. Transient chest pain due to the indwelling catheter, cough, and a feeling of discomfort in the chest associated with re-expansion of the lung following drainage of a large amount of fluid have been reported following medical thoracoscopy. 

Pleural Manometry - German physician Heinrich Quincke was the first to pioneer pleural manometry to measure the pressure within the pleural space in 1878. Techniques used to measure pleural pressures include a hemodynamic electronic transducer, electronic manometer, and U tube water manometer. Hemodynamic electronic transducers provide the most reliable and accurate measures of intrapleural pressures. The thickness of the normal pleural space is 20 micrometers, and 50 ml of fluid in the pleural space is required to ensure that the effect of local deformation forces on the measurement of pleural pressures can be nullified. Pressure within the pleural space is influenced by elastic forces of the chest wall, lung, and effusion volume. Gravity, ventilatory pressures, forces produced due to cardiac contraction and associated with lymphatic drainage play a role in generating pleural pressures. Lan et al. were the first to describe the utility of manometry in optimizing pleurodesis in those with malignant pleural effusion. Although real-time manometry has been proposed as a means of identifying an un-expandable lung following thoracentesis. However, there has been a lack of consensus on specific pressure cut-offs that can be used to distinguish between normal and unexpanded lung.

Treatment / Management

A definitive procedure is defined as one aimed at providing long-term relief from symptoms associated with pleural effusion.[129] For this reason, serial thoracentesis is not considered a definitive procedure in the joint guidelines published by the European Respiratory Society and the European Association of Cardiothoracic Surgery.[18]

Thoracentesis

Incidence of recurrence after a single procedure has been identified as 4.2 days, with a rate of recurrence approaching 98 percent 30 days within the period of completion of the procedure. A thoracentesis does not aim to prevent fluid re-accumulation or allow continued drainage. Thoracentesis confirms the presence of fluid, but can also be used to confirm lung re-expansion following pleural fluid drainage.[93] Though no absolute contraindications to thoracentesis have been mentioned, the following precautions have been advised, small fluid accumulations and ongoing positive pressure ventilation may predispose to the development of pneumothorax, both thrombocytopenia and uncorrected coagulopathy have been associated with the development of bleeding.[93][130] 

Tension pneumothorax which may also be associated with hemodynamic compromise, may also be seen with the performance of thoracentesis in those receiving positive pressure ventilation.[93][131] Requisite sedation and analgesia have been recommended in the pediatric population to ensure minimal movements during the procedure.[132] Excessive movements during the procedure have been shown to predispose to an increased incidence of damage to vascular structures and underlying lung parenchyma.[133] The presence of skin infection at the site of needle insertion may predispose to the entry of microorganisms into the pleural space.[134]

Anatomical Localization 

The normal site for the aspiration of pleural fluid is the seventh intercostal space in the posterior axillary line (near the tip of the scapula).[135] Laceration of the posterior intercostal artery poses a major risk of bleeding during the procedure.[136] The posterior intercostal artery runs within the subcostal groove along the posterior border of the rib with the neurovascular bundle.[137] A site above the rib should be chosen to avoid the bundle.[92] A decrease in the effective, safe space has been documented in the elderly, along with a considerable variation in the course (mean distance from the spine).[93] It has also been demonstrated that variability in the course of the posterior intercostal artery increases in more posterior positions.[138]

Procedure 

While adults may undergo the procedure in the upright, seated, or lateral position, pediatric patients may be held in the burping position by an assistant.[139] The site of needle insertion is prepared with chlorhexidine. Draping is done to ensure access to the anatomical area of interest. The skin entry site is localized using the available anatomical landmarks and confirmed with ultrasound.[140] The needle is then advanced, under all aseptic precautions perpendicular to the skin, to infiltrate the underlying subcutaneous tissue and reach the periosteum, which may be infiltrated with the local anesthetic agent. The needle needs to be advanced over the superior border of the rib to avoid injury to the neurovascular bundle, which lies along the lower border of the upper rib (within the intercostal space). Gentle aspiration may be carried out till pleural fluid has been obtained.[140] 

The depth of insertion where access to the fluid is first obtained should be noted, and an over-the-needle catheter is inserted for atraumatic removal of the fluid. Attachment of a three-way stopcock along with tubing may facilitate the drainage of large volumes of fluid.[141] Use of a heparinized syringe which needs to be kept closed till the measurement has been completed) may be indicated if the measurement of pH has been planned.[142] Cessation of a procedure should be considered at the onset of the development of pleuritic chest pain, chest tightness, and significant cough, which might signal underlying damage to the lung parenchyma.[143][144][143] 

Large volume thoracentesis has been defined as the removal of more than one liter of pleural fluid.[145] It has been postulated that tolerance to thoracentesis can be improved by allowing slower drainage or by draining with the aid of gravity and not employing a technique that involves rapid evacuation with suction.[144]

Repeat thoracentesis has been advocated in patients with a slower accumulation of fluid, expected to have resolution with systemic therapies, advanced disease, poor performance status, and limited life expectancy. Patients undergoing systemic treatment for the underlying malignancy, which might be thought to prevent the re-accumulation of fluid (such as those with small cell lung cancer, lymphoma, or EGFR mutated adenocarcinoma), may also be potential candidates for undergoing repeated thoracentesis.[146] 

A delay in performing pleurodesis may also be associated with extensive disease (signifying an increased pleural tumor burden), which might decrease the effectiveness of pleurodesis, and development of a trapped lung, which might act as a contraindication to pleurodesis.[18] In patients with a mediastinal shift, monitoring of pleural pressure during the performance of a procedure or removal of a smaller amount of fluid (300-500 ml) at a given time may be necessary to prevent the development of complications related to a precipitous fall in pleural pressure.[147][148] 

While there is consensus that volumes in excess of 1.5 liters are associated with the development of re-expansion pulmonary edema, some groups advocate the removal of 1200 to 1800 ml of pleural fluid safely within a single setting.[149][150] In cases where simultaneous monitoring of pleural pressures using intrapleural catheters is being performed, it should be ensured that negative pleural pressure generated during the procedure should not increase beyond -20 mm of Hg. Real-time ultrasonographic guidance is being used increasingly during the procedure to minimize the rate of development of complications such as pneumothorax.[151] Bilateral concurrent thoracentesis under ultrasonographic guidance has been performed safely, without the risk of developing pneumothorax in patients with bilateral pleural effusions.[53][98]

Complications 

While pneumothorax remains a real concern, the development of pain, shortness of breath, and vasovagal syncope have also been noted [98]. The occurrence of cough is known to commonly occur during the procedure. However, only cough severe enough to cause significant discomfort is considered an indication to terminate the procedure.[144] Other authors propose the termination of the procedure at the onset of coughing, as this has been shown to denote pulmonary injury. Rare complications include bleeding, re-expansion pulmonary edema, and organ puncture.[152] Repeat thoracentesis has also been shown to be associated with complications of hypoproteinemia, empyema, pneumothorax, and loculated pleural effusion.[93] History of receiving radiotherapy or superior vena cava obstruction also predisposes to the presence of dilated venous channels, which might predispose to vascular injury.[153]

Re-expansion Pulmonary Edema

Pinault, in 1853, was the first to describe the occurrence of edema following thoracentesis.[150] Drainage of more than 1.5 liters of fluid has been associated with the development of re-expansion pulmonary edema. Re-expansion pulmonary edema has been shown to develop frequently in the first hour following thoracentesis and tends to occur within 24 hours in most patients. Although unilateral edema is a common occurrence, bilateral cases have been described. Increased capillary permeability due to hypoxia-mediated endothelial injury, free radical-mediated injury, surfactant depletion, pulmonary arterial pressure changes, a sudden increase in blood flow, and a sudden expansion of capillary blood have been identified as factors known to underlie the development of pulmonary edema. High perfusion associated with pulmonary vasoconstriction in response to hypoxic injury in areas that have been exposed to an abrupt variation in pressures, decreased lymphatic flow, and venous constriction has also been proposed to underlie the etiopathogenesis.[152] 

Among measures that have been shown to prevent the development of this phenomenon, avoidance of the application of negative intrapleural pressures and prevention of lung collapse for prolonged periods has been afforded foremost importance.[154] The chronicity of the collection, presence of bronchial obstruction, and technique of re-expansion have also been postulated to affect development.[155] It may be asymptomatic on presentation (with radiological features only), associated with breathlessness, or symptoms of acute respiratory distress syndrome.[156][149] Cough, pink frothy expectoration, and cyanosis may denote severe lung involvement. Infection is considered a close differential.[155] Though the patient may demonstrate initial worsening during the first one or two days, the pathological process is considered to be self-resolving and usually resolves within 3 to 5 days of occurrence.[157]

Untreated pulmonary edema may be associated with a poorer outcome and has been estimated to be potentially lethal in 20 percent of cases.[158] Lung injury predisposes to the development of edema and atelectasis.[159][160] The degree of intrapulmonary shunting, ventilation-perfusion mismatch, decreased compliance, and presence of intra-alveolar fluid determine the grade of severity.[161] Hypotension may accompany sufficient accumulation of fluid within the pulmonary interstitium.[162] 

Patchy ground-glass opacities, consolidation, interlobar septal thickening, and intralobular interstitial thickening have been described on high-resolution computed tomography of the chest.[163] Bronchovascular bundle thickening and ill-defined ground-glass opacities have been described less commonly. Supportive management is advised to ensure adequate oxygenation and perfusion till the resolution of lung injury.[164][165] This may include serial chest radiographs (showing non-specific initial findings of unilateral opacification of air spaces), arterial blood gas analysis, supplemental oxygen treatment in the event of hypoxia, and intubation and mechanical ventilation (positive end-expiratory pressure ventilation) in the presence of severe pulmonary involvement.[166] The management of hypotension may require intravenous volume expansion (use of parenteral fluids), inotropes, and plasma expanders.[158] The use of diuretics is contraindicated due to a propensity to worsen fluid depleted state. Adequate positioning with lateral decubitus position (on the affected side) may reduce shunting and improve oxygenation.[165]

Chemical Pleurodesis

Lucius Splengler, in 1901 was the first to perform chemical pleurodesis, which involves obliteration of the pleural space with the creation of an artificial symphysis between the visceral and parietal pleura. Inflammatory reaction within the pleural space leads to the activation of the coagulation cascade with the formation of fibrogenic cytokines that promotes the development of pleurodesis by the formation of collagen.[167] Beneficial effects of pleurodesis have been observed within weeks or months of the procedure. The procedure is aimed at preventing the re-accumulation of fluid within the pleural space.[168] Pleurodesis is usually offered to advanced cancer patients who are not deemed feasible for receiving systemic cancer-directed treatment as a palliative intervention.[169] 

Active pleurodesis can be achieved with the creation of a direct injury to the pleura with mechanical or physical methods such as mechanical injury or abrasion to the pleura during video-assisted thoracoscopic surgery or the formation of intrapleural adhesions with the use of chemical agents such as talc, bleomycin, povidone-iodine, and Corynebacterium parvum. Antibiotics (Tetracycline, doxycycline, erythromycin, minocycline) as well as antiseptics (silver nitrate, iodopovidine), chemotherapeutic agents (mitomycin, bleomycin, cytarabine, doxorubicin, mitoxantrone), microorganisms (Corynebacterium parvum, Streptococcus pyogenes (OK432), and autologous blood have been used for performing chemical pleurodesis. Both pleural catheters, as well as medical thoracoscopy, have been used to introduce sclerosing agents into the pleural cavity. Life expectancy and patient factors play a crucial role in determining acceptability to the procedure.[170] 

Two major contraindications to pleurodesis include the presence of a non-re-expanded or trapped lung and loculated pleural effusion. The type of cancer, the extent of pleural involvement, and the type of sclerosant used for pleurodesis determine the degree of effectiveness of pleurodesis.[169]

Procedure Details

Pleurodesis can be performed through a 28-32 French gauge chest tube or a pigtail catheter in a premedicated patient (provided adequate analgesia).[171] In practice, some clinicians recommend that non-steroidal anti-inflammatory drugs, selective cyclooxygenase-2 inhibitors, and corticosteroids are avoided 48 hours before and five days following the procedure to avoid interference with the fibrotic pleural response to the sclerosant.[172] Greater than 150 ml/day aspirate, radiograph demonstrating residual fluid, suspicion of pleural infection, and a lack of informed consent are considered contraindications to the procedure. Inflation of the lung should be confirmed by auscultation and chest radiograph.[86] 

Specific risks of bleeding, pain, procedure failure rates (approaching 20 percent) should be explained to the patient.[151] The risk of acute respiratory distress syndrome with the use of talc as a sclerosing agent has been shown to be less than 1 percent.[173] A combination of lidocaine and a sclerosing agent is instilled through the chest tube/indwelling pleural catheter into the pleural space. The dose of lidocaine in a single patient should not exceed 3 mg/kg and altered pharmacokinetics keeping in mind the sarcopenic status of the advanced cancer patient. A practical consideration with the use of talc involves the need to agitate the solution, as it may be difficult to dissolve, and the need to stop moving the container/syringe once the slurry has been prepared to prevent precipitation (of talc particles).[174]

Flushing of the catheter with normal saline should be performed after the installation of the slurry.[175] While some authorities recommend that the patient be rotated in all directions (up to 1 hour) to ensure uniform distribution of the sclerosant, others advise against the practice. There is some variability in the withholding time of the sclerosant mixture in the pleural space after clamping of the drain, with values ranging from 1 to 6 hours.[176][177] The drain should be unclamped subsequently and removed 24 to 48 hours after ensuring lung re-expansion and drainage of the pleural cavity.[41] 

Respiratory rate, temperature, pain intensity, pulse rate, oxygen saturation, blood pressure, and characteristics of the fluid drained should be monitored. A post-procedure chest radiograph should be performed to rule out pneumothorax and confirm the eradication of pleural fluid. Drain or catheter may be removed after 24 to 48 hours of sclerosant administration and following confirmation of a normal chest radiograph, decrease in the amount of pleural fluid drainage to less than 100 ml, and absence of air leak.[41][178][41] 

Patients in the recently concluded TAPPS trial were discharged following a pleurodesis procedure (talc slurry or thoracoscopic talc insufflation) when the total pleural fluid drain output was lesser than 250 ml per day.[179] Although there is no role of prophylactic radiotherapy in preventing procedure tract metastases, local palliative radiotherapy may be indicated in the presence of painful nodules in patients with malignant pleural mesothelioma.[180]

Efficacy of pleurodesis has been defined as complete response with an absence of pleural fluid re-accumulation, partial with residual pleural fluid or fluid re-accumulation which remained asymptomatic and did not require a repeat drainage procedure, and failure where additional procedures have been required, up to six months (follow up period depends upon the patient's survival).[181] Chest pain followed by fever has been reported as the commonest complications following pleurodesis.[182] Occurrence of ARDS with the use of talc and visual loss with large quantities of povidone-iodine has also been reported.[182] The use of povidone-iodine as an effective sclerosant is indicated in cases where talc is not available or its use contraindicated.[177] Thoracoscopic talc poudrage was introduced by Bethune in 1934 as a method of producing adhesiolysis prior to lobectomy, while the use of thoracoscopic talc slurry in humans was reported for the first time by Chambers.[183][184]

Contraindications to the performance of talc pleurodesis in recurrent pleural effusion may include pregnancy, previous intrapleural procedures or history of irradiation to the hemithorax, changes in systemic therapy in the previous two months, chylous or bilateral pleural effusions.[178] Talc can be administered in the pleural cavity in the form of a slurry (admixed with normal saline) or insufflated in a powdered form via a medical thoracoscopic procedure (single port of entry).[185] 

Medical grade talc has been shown to activate pleural mesothelial cells to produce significantly higher levels of basic fibroblast growth factor.[186] bFGF has been hypothesized to be the chemical mediator responsible for pleurodesis [186]. Thoracoscopic talc insufflation provides the opportunity to directly visualize the pleura, perform adhesiolysis and address loculated pleural effusions.[187] TTI may be effective in those who have undergone prior ipsilateral surgery or attempted adhesiolysis and in case of the trapped lung.[185] TTI has also been shown to be associated with a higher incidence of respiratory complications in the form of atelectasis, pneumonia, and respiratory failure.[184]

Risk factors for a failed pleurodesis include a history of prior irradiation and a chest tube in place for more than ten days.[188] Underlying causes for a failure of the procedure include uneven distribution of the agent within the lung, failure of the lung to re-expand following the procedure, and high tumor burden with low fluid pH.[41] High tumor burden may be defined by the presence of multiple pleural nodules on all aspects of visceral and parietal pleura and adherence of the lobes within themselves and with the parietal pleura.[94] Prior thoracic irradiation might also increase the risk of the development of pleuro-cutaneous fistula.[189] 

No differences between the two procedures of talc installation (thoracoscopy guided Tac insufflation and bedside chest drain associated Talc slurry) with respect to the primary outcome indicator of Pleurodesis failure post 90 days of randomization have been reported in the recently concluded TAPPS trial.[190] The TAPPS trial results seem to provide definitive evidence of the equivalence of the two procedures as no significant differences were noted in the secondary outcome measures of Pleurodesis failure up to the final outcome visit (180 days), mortality, length of hospital stay, radiological clearance of effusion and patient-reported outcomes.[190] Talc poudrage has been shown to be less cost-effective when compared to talc slurry.[191]  Another potential drawback of thoracoscopic talc insufflation would be the inability to perform this procedure safely under local anesthetic guidance in advanced cancer patients considered to be frail.[191] 

Indwelling Pleural Catheter 

Placement of indwelling pleural catheters is considered a safe and efficient method for drainage of pleural effusions in those with smaller or loculated recurrent pleural collections.[192] The increasing use of bedside imaging modalities has only aided the emergence of this treatment modality as a viable option for achieving palliation of distressing respiratory symptoms.[193] This procedure has also been shown to have good tolerability in advanced cancer patients.[192] While the presence of a catheter (foreign body) within the pleural cavity promotes inflammation leading to auto-pleurodesis (between the visceral and parietal pleura), rapid re-expansion of the lung is aided by the negative suction pressure created by the vacuum bottles.[193][194] 

Bertolaccini et al. point out the lower rate of complications and advocate early implantation of indwelling pleural catheters to repeated needle thoracentesis.[195] Both the AMPLE and ASAP 2 trials have demonstrated higher rates and shorter times to auto-pleurodesis in those treated with an indwelling pleural catheter and aggressive drainage compared to those treated with an IPC and alternate day drainage.[196] Malignant pleural effusion unsuitable for pleurodesis, recurrent pleural effusions after pleurodesis, and trapped lung have been considered as conventional indications for the insertion of an indwelling pleural catheter. The presence of multiloculated effusions, infection at the insertion site, malignant skin infiltration at the insertion site, and coagulopathy are considered potential contraindications to indwelling pleural catheter insertion.[195] Pleural empyema, accidental dislodgement, drain malfunction, and spontaneous fracture have been reported as potential complications.[192]

Comparison of Various Modalities of Treatment 

According to the results of a meta-analysis performed by Sivakumar et al., comparing patient-related outcomes with thoracoscopic talc insufflation, talc slurry, and indwelling pleural catheters, all procedures were shown to have a comparable effect upon the improvement in health-related quality of life parameters over the course of 12 weeks.[197] A lack of insufficient long-term data has been identified as a potential drawback due to high attrition rates.[197] The authors concluded that the evidence on the comparative efficacy of these three procedures is marred by the lack of randomized control trials in this setting.[197] 

Successful outpatient rapid pleurodesis has been demonstrated using thoracoscopy and talc slurry with the insertion of a tunneled pleural catheter in the same setting.[169]\ In a prospective randomized control trial conducted by Reddy et al., those undergoing rapid pleurodesis with a combination of procedures were discharged on the same day (of the procedure).[169] A trial by Olfert et al. was also able to demonstrate the efficacy of the indwelling pleural catheter as a cost-effective treatment method.[198] A median time to achieve pleurodesis of 4 days has been reported using drug-eluting indwelling pleural catheters by Bhatnagar et al.[199] 

The results of the ongoing SWIFT trial are expected to provide further insight into the efficacy and safety profile of drug-eluting pleural catheters. The sclerosant used in these trials consists of a slow-release coating of silver nitrate.[199] A Cochrane network meta-analysis performed by Dipper et al. showed that 20/100 patients post talc pleurodesis, 19/100 post talc slurry, and 52/100 bleomycin required a repeat procedure.[200] The results suggest the superiority of talc poudrage and Talc Slurry over other methods of performing pleurodesis, enlists catheter site infection (cellulitis) and pleural infection as possible complications of IPC insertion.[200] 

This network meta-analysis supports the use of Bedside graded talc as the sclerosant of choice, given the years of experience with the use of this modality.[200] The authors go on to opine that the search for a single ideal procedure for the management of a complex problem is liable to prove futile.[200] The importance of taking patient preferences into consideration while taking into account practical issues in the real-life setting (patient and family experience) might represent a sensible way forward. 

Special Scenarios

Trapped Lung 

Trapped lung is used to describe an advanced state of lung pathology in a patient with a history of malignant pleural effusion, which is characterized by the absence of the lung to fully expand, the failure of the visceral pleura to appose to the parietal pleura with the persistence of a residual hollow cavity.[18] Though the terminology lung entrapment has been used to characterize the failure of the lung to re-expand in the presence of an active pleural process with the formation of a visceral pleural peel, a trapped lung has also been used to denote a similar pleural pathophysiological process that has occurred in the remote past.[18] Growth factor (TGF-beta) production leads to an increase in fibroblast proliferation and collagen production, which leads to fibrotic reorganization of the visceral pleura.[201] A ventilation-perfusion mismatch due to the altered respiratory ventilatory dynamics leads to dyspnea which has a potentially adverse impact on the quality of life.[202] 

Trapped lung may result from pleural thickening, which limits the movement of the visceral pleura, which may precede the development of a fibrinous exudate around the lung.[167] Potential causes include direct infiltration with malignant cells or development of fibrotic tissue within the visceral pleura, presence of pleural carcinomatosis, radiation-induced fibrotic transformation, and proximal endobronchial obstruction causing distal lung collapse or chronic atelectasis with a concomitant malignant or para-malignant pleural effusion.[195] 

The radiological finding of pneumothorax ex vacuo, which has been characterized by the failure of the lung to expand after drainage of pleural fluid, might represent a manifestation of trapped lung. Thoracic ultrasonography might be useful in differentiating between pleural thickening, pleural fluid, and consolidation.[203] Non-expandable lung/Unexpanded Lung (NEL/UL) is a clinical entity defined by the apposition of the lung to less than 25 to 50 percent of the chest wall.[202] This entity represents a potentially reversible condition that might revert to its original state with the institution of anti-tumor therapy. It might also represent a scenario where a lung that has been unable to re-expand due to the prolonged period of the collection will re-expand fully after the drainage of effusion.[204] 

All cases of non-expandable lung do not meet the criteria for a trapped lung.[204] Patients with a NEL have been shown to develop auto-pleurodesis with the use of an indwelling pleural catheter.[205] Diagnosis is made upon clinical examination. Occurrence of severe dull or sharp pleuritic chest pain and cough during thoracentesis and thoracic ultrasonography has been used to diagnose trapped lung. Though VATS-assisted thoracoscopy has been used as a definitive modality for diagnosis, the measurement of pleural fluid elastance by using pleural manometry also represents a promising approach.[195] 

Pleural fluid elastance is measured by the decrease in pleural fluid pressures in cm of water after removing 500 ml of fluid by thoracentesis.[129] In a trapped lung with Malignant pleural effusion, the pleural pressure is low and tends to drop significantly as fluid is removed.[195] Pleural fluid elastance of more than 14.5 cm H2O per liter has been shown to represent a pleural space mechanical abnormality.[206] The following strategies have been considered potentially beneficial in managing trapped lung - Indwelling pleural catheter, surgical pleurectomy/decortication, pleuroperitoneal shunting, and intrapleural fibrinolysis.[18]

Persistent Air Leaks 

The possibility of developing pneumothorax after ultrasound-guided thoracentesis is small (3 to 4 percent) but significant.[151] A small fraction of those who develop pneumothorax will require chest tube insertion.[207] An air leak manifests as a collection of air bubbles in the drainage bag connected to the chest drain.[208] A persistent air leak is defined as one that exists for more than 5 to 7 days following a chest tube insertion.[209] Communication between the sterile pleural space and the tracheobronchial tree in the form of alveolar pleural fistulous communication or bronchopleural fistula may be the underlying cause.[210] 

Wait and watch/ expectant management - The American College of Chest Physicians has advised a period of conservative management for four days, during which the fistulous communication is expected to close on its own.[210] A thoracic surgery opinion with consideration of pleurodesis might be indicated in the event of failure of watchful management.[208] Minimally invasive approaches - less invasive approaches may be considered in those who are not surgical candidates and those who refuse surgical management.[209] Autologous blood patch pleurodesis, Heimlich valve, Endobronchial valves, tissue adhesives, and occlusive devices may also be used to obliterate the communication.[211] Definitive surgical approach-VATS or open thoracotomy with chemical or mechanical pleurodesis or pleurectomy has been defined as the definitive surgical approach.[208]

Septated Pleural Effusion

Fibrin-rich effusion fluids can lead to the development of pockets within the effusion.[16] Significant adhesions have been demonstrated in almost 40 percent of patients on thoracoscopy by Bielsa et al.[212] Significant adhesions are defined as those that obstruct more than one-third of the field of view in thoracoscopy.[213] In patients undergoing chest drain insertion, an increasing number of septations have been associated with the failure to achieve adequate relief in dyspnea.[16][214] 

There is a need to differentiate septations from vascularized adhesions which might develop when fibrinous septations become infiltrated with fibroblasts and undergo organization with the laying down of collagen fibrils.[16] However, these terms have been used interchangeably in literature and need to be defined, emphasizing the impact of these pathologies on the prognosis. The severity of the septations or organized adhesions has been defined by an ultrasound-based grading system that characterizes them based upon the nature and number of adhesions.[16] 

Significant adhesions may represent a potential cause of failure to drain an effusion effectively.[16] Fibrous septations and adhesions may be differentiated based on thoracoscopy.[215] While fibrinous adhesions can be divided easily, dense organized adhesions usually show the presence of blood vessels on them on thoracoscopy.[215] A computed tomographic scan is not useful to visualize septations directly, although indirect evidence of septations such as air pockets may be seen.[215] Adhesiolysis with the intrapleural instillation of fibrinolytics has been used to facilitate drainage of septated pleural effusion.[216]

TIME 3 trial demonstrated no clinically significant improvement in dyspnea or time to pleurodesis failure rates over one year with intrapleural streptokinase instillation in non-draining malignant septated pleural effusions.[217]. No significant differences were reported between the urokinase and placebo groups in quality of life parameters at any time during the study.[217] Although the study has been critiqued for the possible impact of fibrinolytic agents on the efficacy of repeat procedures, these concerns remain unproven.[217] It has been explained that given the short half-life of these agents, any substantial impact on the efficacy of repeat drainage and pleurodesis procedures is not expected.[217][216] 

Another concern with the use of fibrinolytics remains the possibility of hemorrhage into the pleural fluid, which has been attributed to the presence of friable vessels within the hemorrhagic fluid due to neo-angiogenesis.[216][217] However, the risk of bleeding has remained minimal with the concomitant use of an indwelling pleural catheter and does not seem to represent a substantial concern.[216] The authors conclude that though better lung re-expansion can be achieved using intrapleural thrombolytic agents, the rates of successful pleurodesis continue to remain unaltered.[217] The failure to relieve dyspnea in this patient subset has prompted a rethink on using drainage catheters in this setting. Alternative methods for palliation of breathlessness in advanced cancer have been advocated.[217]

Malignant Eosinophilic Pleural Effusion

MEPE has been defined by the presence of more than 10 percent of eosinophils in the differential white blood cell count in the first thoracentesis, and the presence of exudative effusion along with histological confirmation of malignancy.[11] Repeated thoracentesis, blood/ air in the pleural space, and drug interactions may be confounding factors that need to be ruled out before a diagnosis of eosinophilic pleural effusion can be made conclusively.[11] Lung cancer (non-small cell adenocarcinoma, squamous cell carcinoma), metastasis to the lung, Non-Hodgkin lymphoma, and dysgerminoma are the common etiologies underlying MEPE.[218] 

The formation of MEPE involves two steps, accumulation and migration.[219] Accumulation of eosinophils occurs due to increased production within the bone marrow while the migration is promoted by the firm cytoadherence of these eosinophils to endothelial cells.[219] Increased production of cytokines such as IL-33, 4, 5, which have been shown to have chemoattractant properties that aid in eosinophilic migration, has been reported in patients with non-small cell lung cancer.[219] Tumor homing eosinophils have also been shown to secrete chemokines which stimulate the expansion of T cells within the tumor microenvironment. Eosinophils have been shown to enhance the maturation of dendritic cells in the tumor microenvironment, which overcome tumor tolerance and have been associated with better prognosis.[219][220] 

Though cancer-directed therapies have been shown to control pleural fluid formation in Small cell lung cancer, strategies that positively impact survival are yet to be developed.[146] Measures to palliate symptoms are similar to the ones employed for non-eosinophilic malignant pleural effusion. The percentage of eosinophils may represent an important marker of prognosis, and further research on this topic has been advocated. 

Hemorrhagic Malignant Pleural Effusion

This occurs with a frequency of 47 to 50 percent. HMPE is usually characterized by the presence of a pronounced degree of dyspnea, higher incidence of chest pain, deterioration in general physical condition, co-occurrence with large effusion, and thickening with parietal pleural effusion.[221] Cytological analysis usually reveals an increased percentage of malignant cells in the pleural fluid. Thickened parietal pleura with hemorrhagic nodules may be visualized on thoracoscopy.[221] Talc pleurodesis and thoracoscopic talc poudrage have been found to be less effective.[221] HMPE is usually associated with poor survival and higher rates of pleurodesis.[221]

Palliative Symptom Directed Management of Dyspnea in Advanced Cancer 

Dyspnea has been defined as a subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity.[222] Ambrosino et al. have suggested that differences in language, culture, race, and gender can influence the subjective experience of breathlessness.[223] Refractory breathlessness has been defined as an experience that persists despite optimal treatment of the underlying condition and has been associated with a shortened life expectancy.[224] Refractory breathlessness is especially frightening for patients and families and results in the use of acute hospital services.[225] The term chronic breathlessness syndrome has been suggested to delineate a syndrome that consists of breathlessness that persists despite optimal management of the underlying pathophysiology.[226]

The feeling of breathlessness in advanced cancer has been explained by a mismatch between afferent sensory information sent by the afferent receptors and the Respiratory motor command from the cortex and brainstem.[227] The biopsychosocial model and the breathing, thinking, functioning models have been used to explain the physiopathology of dyspnea in advanced cancer.[228][225] It is important to understand that one's experience of breathlessness is derived from interactions among multiple factors that include physiological, psychological, social, and environmental factors.[223] The sensation of dyspnea may by itself induce secondary, physiological, and behavioral responses.[229] Only a weak correlation has been observed between the degree of physiological impairment (such as hypoxemia or forced expiratory volume in 1 second and a person's subjective sensation of breathlessness, which might make the symptom difficult to treat.[230] 

Patient-reported outcomes are considered the gold standard in the assessment of breathlessness.[231] While unidimensional tools such as NRS and VAS may be used, assessing the subjective experience of the patient and its impact on functional outcomes is of utmost importance.[232][225] The London chest activities of daily living scale (LCADL) have been shown to effectively measure the impact of breathlessness of functional and social activity in patients with refractory breathlessness in advanced disease.[233] Episodic breathlessness should be identified and characterized as a separate entity and managed according to prescribed guidelines.[234]

Management of chronic breathlessness syndrome usually requires specialist palliative medicine input. Palliative interventions, which may include pharmacological and non-pharmacological management, are provided through a series of visits across many settings.[225] In patients with breathlessness in advanced cancer in patients with malignant pleural effusion unable to achieve relief with other definitive procedures, non-pharmacological measures may be advised. Among the non-pharmacological interventions, the use of a handheld fan directed towards the face, breathing retraining techniques, a trial of mobility aids, encouragement of self-management by the use of activity pacing, relieving positions and distraction techniques, participation in exercise-based rehabilitation programs, and complementary and alternative treatment strategies have been recommended.[225] Among pharmacological options, only opioids and oxygen are useful. Correct dosing of opioids is an important consideration, and doses between 10 and 30 mg of extended-release morphine sulfate have been used. Rescue dose or IR morphine of about 1/6 of the patient's total daily morphine dose may be considered for episodes of exacerbation of breathlessness if required.[225]

Supplemental oxygen (Palliative oxygen therapy) is indicated in patients with chronic severe hypoxemia (partial pressure of oxygen (PaO2) less than 7.3kPa, corresponding to a SpO2 >88%).[235][225] There is a lack of evidence from clinical trials to support the use of benzodiazepines for the relief of breathlessness, and these are not advised in the first-line setting.[236] They may be used to alleviate anxiety associated with air hunger in the second or third-line setting when opioids have not been shown to be effective.[236] Steroids have been advised in the management of breathlessness refractory to other treatment options.[237] 

The use of non-invasive ventilation may improve both oxygenation and hypoventilation and support chest wall muscles.[225] A trial of non-invasive ventilation should be considered in chronic severe breathlessness, especially in patients with acute hypercapnic respiratory failure.[225] Refractory breathlessness is also recognized as an indication to provide Palliative sedation at the end of life.[238] The use of palliative sedation for refractory symptoms at the end of life can be justified by the ethical doctrine of double effect, which was developed by the Roman Catholic church and whose origins date back to the Salamanticensis theologians of the sixteenth and seventeenth century.[239]

Caregiver Distress

A substantial body of data demonstrates that carers of someone suffering from chronic breathlessness experience profound anxiety, isolation, exhaustion, and poor sleep.[225] This distress is heightened when they witness their loved ones having an episode of breathlessness. A feeling of powerless (inability to help) and exhaustion from the extra physical work adds to the genesis and propagation of this symptomatology. Psychoeducation, provision of psychological support may be important.[225] Recognition and acknowledgment of symptoms seem to be useful first steps in the management of caregiver distress.[240] 

The phenomenon of compassion fatigue (Burnout and secondary traumatic stress) in healthcare professionals involved in caring for patients with terminal life-limiting illnesses also needs to be recognized.[241] Preparatory grief and existential suffering might also represent issues specific to the advanced cancer patient often approaching the end of their life, which might require the intervention of a specialist palliative medicine team.[242]

Differential Diagnosis

Clinical differential diagnoses - Raised hemidiaphragm (phrenic nerve palsy, liver enlargement), pleural thickening (secondary to previous tuberculosis, empyema), plaques, consolidation, and lobar collapse, 

Radiological differential diagnoses - The differential includes pleural thickening, plaques (benign and malignant), pseudo-plaques, and inferior pulmonary ligament. Pseudo-plaques are defined as plaque-like lung opacities formed by small nodules and contiguous with the visceral pleura. These are formed by small coalescent nodules, commonly seen in sarcoidosis, coal workers pneumoconiosis, and silicosis. 

Histopathological differential diagnoses - Non-specific pleuritis - cytology negative exudative pleural effusion without a definable etiology after histopathological analysis.[36] Possible etiologies might include radiation-induced pleuritis and chemotherapy-induced pleuritis. From 3 to 12 percent of patients with non-specific pleuritis are diagnosed with a pleural malignancy upon regular surveillance. 

Prognosis

LENT, modified LENT, and the PROMISE scores have been developed to predict patients with MPE [243]. A lack of inclusion of newer targeted therapies within its purview has been pointed out as a potential drawback of the use of older prognostication systems.[244] 

The LENT score consists of the following four parameters - pleural fluid lactate dehydrogenase, Eastern Cooperative Oncology Group performance status, neutrophil to lymphocyte ratio, and Ttmor type[244]. The PROMISE score uses a more diverse range of biomarkers to predict the three-month mortality and success rate of pleurodesis in this cohort of patients.[245] Relative protein expression of Tissue Inhibitor of metalloproteases - 1, cadherin 1, platelet-derived growth factor, Vascular endothelial growth factor, and interleukin 4 are the biomarkers used for prognostication in the PROMISE model.[246] 

The SELECT score uses the following markers for predicting the 90-day survival in these patients - Sex, Eastern Cooperative Oncology Group, Leucocyte count, EGFR status, chemotherapy, and primary tumor type.[247] The SELECT score has been shown to perform better than the LENT and PROMISE in prognosticating survival.[247] The modified LENT score has been shown to compare with the SELECT score in prognosticating survival.[244] 

It has also been suggested that prognostication in this domain needs to be individualized, emphasizing developing systems that include patient preferences, newer targeted therapy, immunotherapy approaches, and symptom burden within their purview.[33] Prognostication in advanced disease may involve using various tools such as the Palliative prognostic index, which consists of the palliative performance scale, edema, dyspnea, reduced oral intake, and delirium. A score of more than 4.5 is usually associated with a survival of fewer than six weeks. Chest tube drainage, chemical pleurodesis, thoracoscopy guided talc drainage have been recommended over repeated procedures due to the risk of developing adhesions with the performance of repeat thoracentesis.[33][247] 

Patients with an actionable mutation with non-small cell lung cancer and malignant pleural effusion have been associated with a similar risk of recurrence when compared to those without an actionable mutation.[248] In a study by Scwalk et al., Larger pleural effusion size, pleural fluid lactate dehydrogenase, and positive cytological examination results have been associated with a higher recurrence rate of pleural effusions.[248]

Complications

Trapped lung, persistent air leaks after chest tube insertion (for iatrogenic pneumothorax), and septated effusion are all potential complications. Complications of treatment have been mentioned in the article elsewhere. These include complications associated with procedures used for draining pleural fluid (thoracoscopic talc poudrage, talc slurry, tunneled catheter insertion, and pleurodesis). MPE does not have a cure, and the goals of treatment include palliation of symptoms. The financial difficulty related to repeated procedures in families strained by the economic hardships brought on by cancer treatment also needs to be recognized.[249]

Pearls and Other Issues

Paramalignant pleural effusion - needs to be distinguished from malignant pleural effusion due to different prognostic implications. Pathophysiological processes underlying the development of para-malignant pleural effusions may include tumor-associated obstruction, chylous effusion associated with obstruction of the thoracic duct, pulmonary embolism-related effusion, effusion secondary to hypoalbuminemia (driven by a low colloidal osmotic pressure). Superior vena caval obstruction may be seen, both as a late adverse effect of radiotherapy to the mediastinum and increased systemic venous pressures due to local effects of the tumor.[14]

Treatment-related effusions - Radiotherapy, conventional chemotherapy (bleomycin, procarbazine, cyclophosphamide, and methotrexate), targeted therapy (dasatinib), and immunotherapy.[19]

Other causes of pleural fluid accumulation - Congestive heart failure, hepatic decompensation, and renal failure.

Tumor clonal evolution owing to pharmacological pressure to anticancer treatment has been shown to underlie the differences in mutations in the primary tumor and the pleural metastases. Personalized MPE therapy based upon the actionable mutation discovered in the malignant pleural cells might represent the future of definitive treatment[33]. Crizotinib has been shown to be effective in reducing the amount of pleural effluent in a patient with adenocarcinoma of the lung with ALK mutation by Sun et al.[250] 

The utility of intrapleural immune stimulants is also being explored as both a potential anti-tumor and sclerosant treatment. Ren et al. have demonstrated increased survival in patients undergoing pleurodesis with Staphylococcus aureus bioproduct mixture due to its immune-stimulating effect on T cells, which might predispose to tumor cell apoptosis in malignant mesothelioma.[251]

Enhancing Healthcare Team Outcomes

Interdisciplinary management of malignant pleural effusion is an essential component of the comprehensive management of advanced cancer patients. Management of medical issues in advanced cancer may play an important role in improving the patient's survival along with a significant impact on quality of life. Dyspnea is one of the key symptoms that have been shown to have a substantial impact on the advanced cancer patient's quality of life.

It is pertinent to treat correctable causes of breathlessness before proceeding to pharmacological measures that function by decreasing the patient's perception of discomfort (due to breathlessness). The degree of aggressiveness of treatment is a contentious but important region that requires family participation. Therapeutic interventions for the management of malignant pleural effusion may be delivered by Medical oncologists, Respiratory medicine physicians, Surgical oncologists, and Palliative medicine experts.

Management of Pleural effusion in the advanced cancer patient at the end of life is a challenge that demands a relook a the conventional role of a palliative medicine consult. The advanced cancer patient with a unique set of physical (medical and surgical), psychological, social, and spiritual issues presents a unique challenge for inpatient admission in the palliative medicine ward. The European Society of Medical Oncology has proposed using the term patient-centered care to encompass both palliative and supportive care provision. Their definition of the patient-centered approach includes Assessment, monitoring, and interventions, management of cancer-related symptoms, along with management of anti-cancer treatment-related complications. These guidelines remain the only official set of guidelines that acknowledge the role of the supportive and palliative medicine expert in the management of this medical condition directly.