Malignant Pleural Effusion

What every physician needs to know:

Malignant pleural effusion (MPE) is a common clinical problem that results in disabling breathlessness for patients with advanced malignancy. It represents disseminated disease and confers a poor prognosis. Patients often require multiple invasive procedures in order to gain a diagnosis and manage their symptomatic pleural effusions, which impacts their quality of life.

The diagnosis can be elusive, particularly in the context of malignant mesothelioma, where interpretation of pleural fluid cytology and pleural biopsies is a challenging specialist field. Radiological techniques, including ultrasound, CT, MRI and PET, can help characterize the disease further. Thoracoscopic techniques, which are increasingly used to gain a tissue diagnosis, have the advantage of draining the fluid and performing a pleurodesis in the same setting.

Indwelling pleural catheters, which continue to gain in popularity, allow successful management in the community with intermittent fluid drainage performed without the need for a hospital admission. Alternative methods of managing malignant effusions include chest tube drainage with pleurodesis and surgical decortication.

Classification:

Primary Pleural Malignancy

• Mesothelioma

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Secondary Pleural Malignancy

• Lung

• Breast

• Ovary

• Hematological

• GI tract

• Urogenital

• Skin (melanoma)

• Unknown primary

Are you sure your patient has a malignant pleural effusion? What should you expect to find?

Symptoms

The clinical history of patients with malignant pleural effusion (MPE) can be variable. Most patients will be symptomatic, although up to 25 percent may be asymptomatic, with the effusion discovered incidentally during imaging for another reason.

Respiratory symptoms include breathlessness, cough and chest pain. Dyspnea, which can vary greatly in its severity, may be progressive as the effusion enlarges. Breathlessness is often noted on exertion and may be exacerbated when the patient lies on the contralateral side to the effusion. Breathlessness is related to mechanical restriction of the chest wall and diaphragmatic movements by the fluid, along with mediastinal shift. Therefore, symptoms may improve significantly once a thoracocentesis is performed. Breathlessness may also be exacerbated by co-existing pathology due to the underlying malignancy, such as pulmonary embolism (PE), endobronchial obstruction by the tumour or lymphangitic spread in the underlying lung.

With an isolated pleural effusion, the cough is usually dry. In the context of co-existing infection or endobronchial tumour, patients may have a cough productive of purulent sputum or even hemoptysis, although these symptoms cannot be directly attributed to the effusion itself.

Chest pain is not a common finding in malignant pleural effusion except in certain situations. Pleuritic chest pain may suggest a co-existing pathology, such as PE. Chronic, diffuse chest wall pain, a common finding in mesothelioma, may be severe and may develop early in the disease course, sometimes prior to the development of an effusion. Pathological fractures caused by bone metastases to the spine, ribs or sternum can also cause significant pain. Chest wall invasion by tumor, particularly involving the ribs or parietal pleura, can also be very painful.

Patients may complain of constitutional symptoms related to the underlying cancer, such as weight loss, fevers and sweating (a particular feature of mesothelioma), poor appetite, lethargy and fatigue. Early satiety can be caused by the pleural effusion, as the fluid results in diaphragmatic flattening, which can compress the stomach.

Symptoms attributed to primary tumor depend on the primary tumor site. A thorough review of systems may help to identify previously unreported symptoms that highlight a potential primary source.

Signs

Clinical signs of a pleural effusion are present when more than 300ml of pleural fluid has accumulated in the pleural cavity. Malignancy is the most common cause of massive pleural effusion and, if this is the case, clinical signs may be obvious.

Chest signs consistent with the pleural effusion include reduced expansion, dull percussion note, reduced breath sounds, and reduced vocal resonance.

In large pleural effusions, mediastinal shift usually occurs away from the side of the effusion unless co-existing bronchial obstruction is present, in which case the mediastinum may be central or shifted toward the effusion.

Signs of underlying malignant disease to be aware of on examination include:

• clubbing

• cachexia

• lymphadenopathy

• breast masses

• organomegaly or abdominal masses

• adenexal masses

• skin lesions

Beware: there are other diseases that can mimic malignant pleural effusion

The differential diagnosis for a unilateral pleural effusion is broad so clinical findings and investigations will help to guide the clinician to the diagnosis. Specific diagnoses that may mimic malignancy include:

• Tuberculosis. Often described as the great mimic, TB is often confused with malignancy at presentation because of its similar constitutional symptoms. A high degree of diagnostic suspicion is required, as the diagnosis of TB pleuritis may be elusive.

• Benign asbestos pleural effusion (BAPE). In patients who present with a pleural effusion in the context of previous asbestos exposure, benign asbestos pleural effusion is in the differential diagnosis. However, the effusion is usually small, and it tends to occur with a shorter time lag after asbestos exposure than mesothelioma does. BAPE is a diagnosis of exclusion, so careful clinical and radiological follow-up is required before making the diagnosis.

In the context of underlying malignancy, effusions can develop indirectly for reasons other than pleural tumor involvement. Examples of these effusions, which are often described as para-malignant effusions, include:

• pulmonary emboli, which causes increased permeability of the pulmonary capillaries and increased pressure in the pulmonary circulation, resulting in a pleural effusion

• parapneumonic effusion resulting from bronchial obstruction and subsequent post-obstructive pneumonia

• chylothorax from trauma or obstruction to the thoracic duct

• hypoalbuminaemia, causing a transudative effusion

• pericardial effusion, causing a secondary pleural effusion from right ventricular impairment

• superior vena cava obstruction, resulting in increased hydrostatic pressure in the SVC and thoracic duct and subsequent pleural effusion

• mediastinal lymph node enlargement secondary to tumor, resulting in impaired pleural fluid resorption.

How and/or why did the patient develop a malignant pleural effusion?

The mechanisms involved in the development of malignant pleural effusion are thought to be multiple, and the pathogenesis may vary depending on the type of tumor. Spread of tumor to the pleura may occur by various mechanisms, including:

• direct invasion of the pleura by tumor from nearby structures, such as the breast, the lung, or mediastinal structure

• haematogenous spread of tumor from distant primary

• invasion of the pulmonary vasculature by tumor with subsequent embolization of tumor cells to the visceral pleura

The precise mechanism by which pleural fluid develops in MPE is not fully understood. An excess of pro-inflammatory cytokines, particularly vascular endothelial growth factor (VEGF), have been implicated in the process. VEGF is thought to stimulate angiogenesis and to increase vascular endothelium permeability, resulting in increased pleural fluid accumulation. Further research is required to clarify the role of VEGF in this process.

Tumor can also block lymphatic drainage of the pleural fluid, leading to reduced resorption from the pleural cavity and contributing to fluid build-up. Other mechanisms unrelated to pleural tumor infiltration may also contribute to the effusion (as described above).

Which individuals are at greatest risk of developing malignant pleural effusion?

Mesothelioma has a close association with previous asbestos exposure, with crocidolite (blue) and amosite (brown) asbestos fibers posing the highest risk because of their slender, amphibole shape, although exposure to chrysotile (white) asbestos still poses a significant risk. There is a latency period, which may be as short as fifteen years but can be up to sixty-five years, between exposure and development of the disease. In most cases, the exposure is occupational. Other potential risk factors for mesothelioma include exposure to erionite (a naturally occurring fibrous substance found in Turkey) and exposure to ionizing radiation.

Certain tumors, including lung, breast, urogenital, ovarian, haematological, GI tract, and skin (melanoma), are more likely to metastasize to the pleura, and in this context the development of MPE represents disseminated malignancy. Specific risk factors depend on the type of malignant cell involved.

With regard to clinical predictors suggestive of underlying pleural malignancy at presentation, a prospective study of patients undergoing thoracoscopy for an undiagnosed effusion found that predictors of an underlying malignant process included symptom duration of more than one month, absence of fever, blood-tinged pleural fluid, and a CT chest suggestive of malignancy.

What laboratory studies should you order to help make the diagnosis, and how should you interpret the results?

Blood tests

LDH/Total Protein – The majority of MPE are exudates, and the measurement of blood LDH and total protein is necessary to apply Light’s criteria. However, up to 10 percent of malignant effusions are transudates, so the diagnosis of MPE must still be considered in the context of transudative effusions.

Anaemia, hypercalcaemia, low albumin – These tests may see non-specific findings that may raise the suspicion of underlying malignancy.

Tumor markers – Measurement of tumor markers have no routine role for the investigation of an undiagnosed pleural effusion due to their poor negative predictive value. Individually, tumour markers have a low sensitivity in diagnosing malignant pleural effusion, and the use of panel of tumour marker has a lower pooled sensitivity (50%) than pleural cytology. However, their measurement may be helpful in some situations, particularly if there is a diagnostic suspicion of a specific malignancy.

Mesothelin, a glycoprotein that can be measured in blood and pleural fluid, has been evaluated as a potential biomarker of mesothelioma. A meta-analysis on the use of serum mesothelium demonstrated a sensitivity of 32% and specificity of 95% in diagnosing mesothelioma. Its use is limited by the number of false negative results, particularly in sarcomatoid mesothelioma, with a negative result of limited value. However, a high serum mesothelin level should prompt further investigation and may also be of value patients with suspicious cytology who are not fit to undergo a biopsy. Its role in disease monitoring and response to chemotherapy has yet to be defined.

Pleural Fluid Tests

Biochemistry – LDH, Protein, Glucose – When compared with serum levels, LDH and total protein of pleural fluid can be used to differentiate transudates and exudates. A low pleural fluid glucose may be a non-specific finding in MPE.

pH – Approximately a third of malignant pleural effusions have a low pH. This is thought to be due to impaired glucose, hydrogen ion, and carbon dioxide transfer across the diseased pleura, resulting in a lower pleural fluid glucose concentration and a lower pH, rather than local acid production. pH may be lower in mesothelioma compared with secondary pleural malignancies because of the extensive pleural thickening, which exacerbates the problems with glucose and hydrogen ion flux.

In the context of malignancy, a pleural fluid pH lower than 7.3 is a marker of more extensive disease, a poorer prognosis, and a lower chance of successful pleurodesis when compared with those malignant effusions with a normal pH. However, a recent meta-analysis has shown that pH alone is not sufficient to select patients for pleurodesis, so this decision should be made in conjunction with other factors, such as performance status and type of tumor.

Differential cell count – A differential cell count on the pleural fluid may help guide the clinician to a specific diagnostic pathway. Malignant pleural effusions are most commonly lymphocytic, but they may be neutrophilic or eosinophilic, and although the differential cell count may help narrow the differential diagnosis, it will not make the diagnosis of MPE. Other causes of a lymphocytic effusion include TB, lymphoma, cardiac failure, and other chronic disease processes, such as rheumatoid arthritis, sarcoidosis, and yellow nail syndrome.

Cytology/lymphocyte subsets – Pleural fluid cytology, a quick and easy method of obtaining material for analysis, can potentially confirm the diagnosis of malignant pleural effusion by identification of malignant cells. Sixty percent of MPE will have positive cytology, although this figure is lower in mesothelioma. Once malignant cells have been identified, immunocytochemistry can be used to differentiate malignant cell type. In the context of an undiagnosed lymphocytic effusion where lymphoma is suspected, flow cytometry of the pleural fluid can help to identify abnormal lymphocyte subsets.

What imaging studies will be helpful in making or excluding the diagnosis of malignant pleural effusion?

Chest X Ray

The chest radiograph is a useful initial test in malignant pleural effusion (See Figure 1). The effusion may vary in size, with as little as 200ml of fluid causing some blunting of the costophrenic angle on x-ray. A massive pleural effusion occurs when one hemithorax is completely or almost completely opacified on the chest x-ray, and this is usually associated with mediastinal shift away from the side of the effusion and diaphragmatic inversion. The most common cause of massive pleural effusion is malignancy.

Figure 1.

Other signs on the chest radiograph may suggest a malignant cause for the effusion. In the context of a large effusion, mediastinal shift toward the side of the effusion should alert the clinician to the possibility of bronchial obstruction, which may be caused by malignancy. Other diagnostic clues on the chest radiograph include the presence of a pulmonary or mediastinal mass, lymphadenopathy, or lytic bony lesions.

Ultrasound

The use of ultrasound in the investigation of pleural disease has increased in recent years. Nodularity or thickening of the diaphragm or pleura and the presence of liver metastases can be useful signs on ultrasound to differentiate benign from malignant effusions with a high specificity. Other features, such as septations within the effusion, echogenicity, and swirling within the fluid suggest the effusion is an exudate, although these findings are less specific for malignancy. Ultrasound also allows for the detection of smaller effusions than may be evident on chest radiography.

Ultrasound improves the safety of pleural interventions, such as thoracentesis, reducing the rates of pneumothoraces by 16% and haemorrhage by 39%. It is also used in image-guided biopsies, with thoracic ultrasound (TUS) guided biopsies demonstrating similar diagnostic yields as those performed under CT guidance, whilst avoiding ionizing radiation. TUS guided pleural biopsies have also been shown to be effective when performed by respiratory physicians.

Computed tomography (CT)

Contrast-enhanced CT scanning has a critical role in the investigation of malignant pleural disease, as it provides information on the likelihood and extent of pleural malignancy, as well as the primary cause and tumor stage. The pleura may appear nodular, irregular, and thickened on CT, and it commonly enhances with contrast. These findings are highly specific for a malignant process, although differentiating between malignant cell type on the basis of CT is more difficult. See Figure 2.

Figure 2.

On occasion, CT may identify an occult primary tumor elsewhere–such as in the bowel, the breast, or the lung–and other features, such as lymphadenopathy, bony deposits, and adrenal and liver metastases, may help with disease staging. In addition, CT may detect other paramalignant causes of an effusion, such as pulmonary emboli and superior vena cava obstruction.

As with ultrasound, CT is also commonly used to direct biopsies of the pleura, with an improved diagnostic yield compared to blind pleural biopsies.

Magnetic resonance imaging (MRI)

The precise role for MRI in the investigation of malignant pleural disease is still subject to debate. MRI signal intensity on T2-weighted images differentiates malignant and benign pleural thickening with a level of accuracy similar to that of CT, so it may be useful in difficult cases where there is ambiguity about the CT results. MRI visualizes soft tissue, such as the diaphragm and chest wall well, allowing for careful delineation of local infiltration, but respiratory and cardiac motion artifact may impair image quality and the views of other thoracic structures. For example, images of the lungs themselves are poorer than they are using CT.

In mesothelioma, the use of gadolinium contrast and different phase sequences may allow more precise evaluation of local disease invasion than other imaging modalities and hence may be useful to accurately stage the disease. Early studies suggest that the use of MRI may also have a role in monitoring response to chemotherapy in mesothelioma.

FDG PET

PET scanning using 18-fluorodeoxyglucose (FDG) is still under evaluation in pleural disease. A recent meta-analysis determined that FDG PET had a sensitivity of 81% and specificity of 74% in diagnosing pleural malignancy. Despite success as an imaging modality in other thoracic malignancies, in the context of pleural disease its use is limited by the high false positive rate in other common pleural conditions, such as empyema and following talc pleurodesis. That said, FDG PET is considered to have a good negative predictive value in young people, who are at lower risk of pleural malignancy. FDG PET has also been used in conjunction with CT to differentiate benign asbestos related pleural disease from mesothelioma, and it is under evaluation for monitoring disease response and prognostication in mesothelioma. It may also have a role in determining the optimal site for radiologically guided biopsy, a hypothesis under investigation in the Target trial (www.isrctn ISRCTN14024829).

What non-invasive pulmonary diagnostic studies will be helpful in making or excluding the diagnosis of malignant pleural effusion?

No specific non-invasive pulmonary studies will help make the diagnosis of malignant pleural effusion. Lung function testing may be necessary to risk-stratify patients prior to performing a surgical procedure to gain a histological diagnosis.

What diagnostic procedures will be helpful in making or excluding the diagnosis of malignant pleural effusion?

Pleural fluid aspiration

Pleural fluid aspiration is the best initial invasive investigation in a suspected malignant effusion. With direct ultrasound guidance, pleural fluid aspiration is a predominantly safe and minimally invasive procedure that can be performed quickly and easily with minimal discomfort to the patient. It can provide symptomatic relief from breathlessness caused by the effusion if sufficient fluid is aspirated. Cytological results can be available quickly, and alternative differential diagnoses, such as pleural infection, can be investigated.

Malignant cells are identified by cytology in about 60 percent of malignant pleural effusions, so a significant proportion of patients will still have to undergo a more invasive test to finalize the diagnosis. The yield of pleural fluid cytology is less in mesothelioma, where cytology may appear benign or may mimic alternative malignant conditions, particularly adenocarcinoma, so a biopsy is usually required to clarify the diagnosis.

Blind pleural biopsy

Pleural biopsy is the mainstay of diagnosis, particularly in mesothelioma, where cytology can be falsely negative or misleading. Blind pleural biopsies using are not recommended, as the yield is only marginally superior to that of pleural fluid cytology, and the procedure may be associated with significant pain and complications. The yield from an image-guided biopsy in suspected malignancy is much higher than that in a blind biopsy (80% with a CT-guided biopsy compared to 47% with a blind pleural biopsy in a recent randomized trial). Blind pleural biopsies also have a higher complication rate than CT-guided biopsies, and pain, pneumothorax, and vasovagal reactions are common. In addition, there is a small (<1%) but relevant risk of serious hemorrhage.

Image-guided pleural biopsy

CT-guided biopsy using a tru-cut needle has a sensitivity of nearly 90 percent, and even small areas of pleural thickening can be successfully biopsied in areas that a closed pleural biopsy cutting needle would not reach. Specific areas of pleural thickening can be targeted, and in general, patients can be discharged from the hospital the same day as the procedure. There is a risk of iatrogenic pneumothorax, so spirometry is often requested prior to the procedure to ensure there is sufficient respiratory reserve should iatrogenic pneumothorax occur. CT-guided biopsy may be particularly useful if local anesthetic thoracoscopy is not possible and the patient is not fit for the general anesthetic required for a surgical biopsy.

Pleuroscopy (local anesthetic thoracoscopy)

Pleuroscopy has the benefit of being able to visualize the pleural cavity directly and to allow biopsies, complete fluid drainage, and pleurodesis to be performed in one procedure. It is performed under sedation, is generally well tolerated, has a low complication rate, and can be performed with only a short in-patient stay. The diagnostic yield is high (95% in recent studies) and comparable to that of a surgical VATS biopsy, but it removes the need for a general anesthetic.

Surgery

In cases in which the lung is tethered or the effusion is heavily septated, preventing the lung from collapsing during a local anesthetic thoracoscopy, a surgical procedure may be necessary to obtain diagnostic material. Video-assisted thoracoscopic surgery (VATS) has the benefit of allowing the surgeon to perform other techniques at the same time, such as breaking down loculations or performing a decortication or pleurodesis at the end of the procedure. Larger biopsies are also possible, and a more comprehensive view of the pleural cavity is obtained than is possible with local anaesthetic thoracoscopy.

However, the procedure requires a general anesthetic and an induced pneumothorax, so patients with severe underlying lung disease and the elderly may not be able to tolerate it. The diagnostic yield of a VATS is high, and complications are rare. If the visceral and parietal pleura are completely opposed and tethered together, a VATS may not be possible, necessitating a larger operative procedure, such as a thoracotomy.

In the context of mesothelioma, malignant cells may be seeded into the subcutaneous tissues during invasive pleural procedures, and tumor can spread along the procedure track, resulting in painful procedure tract metastases (PTM). A randomised control trial examining the utility of prophylactic radiotherapy in patients with mesothelioma undergoing large bore thoracic intervention found no decrease in incidence in the rate of PTM compared to deferred radiotherapy, providing evidence against the use of routine prophylactic radiotherapy in prevention of PTMs.

What pathology/cytology/genetic studies will be helpful in making or excluding the diagnosis of malignant pleural effusion?

Cytology

Pleural fluid cytology is the initial investigation of choice in patients with a suspected malignant effusion, as it identifies malignant cells in about 60 percent of patients with the condition, and it is minimally invasive. Diagnostic yield increases if both a smear and a cell block are prepared from the pleural fluid sample.

Differentiating between the primary tumor type can be challenging, as cytological appearances can be similar, so additional stains are required in order to define the cell type conclusively. This is a particular problem in mesothelioma, where cells may mimic atypical mesothelial cells or metastatic adenocarcinoma. In this context, even in the hands of an experienced cytologist, cytology can be misleading or inaccurate, so a pleural biopsy should be obtained if mesothelioma is suspected and the patient is fit enough. Immunocytochemistry to identify patterns of cell surface marker expression is useful to confirm the malignant cell type.

Lymphocyte subsets

Flow cytometry can be used in conjunction with pleural fluid cytology to identify abnormal proliferation of specific lymphocyte subsets. Flow cytometry has a particular role in undiagnosed lymphocytic effusions where lymphoma is suspected.

Histology

Histological evaluation of a pleural biopsy can offer significant additional information when the cytology has been inconclusive. A large specimen, which also allows for improved characterization of tumor structure and morphology, can be obtained by various methods described above. Interpretation of pleural histology is notoriously challenging because benign and malignant conditions may share some histological features and because differentiating between malignant cell types can be difficult, especially on small tissue samples.

Particularly in mesothelioma, histological features may be similar to those of benign reactive mesothelial hyperplasia and fibrous pleuritis. Immunohistochemistry assists in differentiating between them, as well as in identifying the presence of malignant features, particularly local invasion.

In addition, adenocarcinoma can resemble mesothelioma, both macroscopically and microscopically, and differentiating between the two relies on immunohistochemistry. Positivity for calretinin (a calcium-binding protein present on mesothelial cells), CK 5/6, and epithelial membrane antigen (EMA) on the tumor epithelium is found in mesothelioma. In cases of adeoncarcinoma, carcinoembryonic antigen (CEA), CD15, and thyroid transcription factor 1 (TTF1) may be positive. Hence, a full panel of immunostains should be performed on tissue to confirm the precise diagnosis.

If you decide the patient has malignant pleural effusion, how should the patient be managed?

The treatment modalities available to patients with malignant pleural effusions are expanding, and they depend on patient choice, clinical condition, and availability. Strategies focus on removal of the pleural fluid and attempts to prevent further fluid reaccumulation. There are no current therapies that target the underlying problem of excess fluid production, but this is the subject of ongoing research.

Factors which influence the choice of intervention include patient preference, prognosis, rate of fluid recurrence, anticipated chemo-sensitivity and the presence of trapped lung or septated effusion. Definitive management strategies such as chest drain with talc pleurodesis or indwelling pleural catheters have been shown to be equally effective, allowing the patient and treating clinician to decide a strategy that suits the patients wishes and disease process best.

It is recognised that various other factors can significantly contribute to the dyspnea in patients with a MPE (e.g., co-existing cardio-respiratory co-morbidities, pulmonary embolism or bronchial obstruction) and a combined diagnostic and therapeutic aspiration as part of the patient’s initial management can help determine whether the patient’s symptoms improve with removal of pleural fluid.

Thoracentesis

Thoracentesis allows quick relief of symptoms and provides fluid for cytology to make a diagnosis and although it may successfully manage a patients symptoms on a temporary basis, in the vast majority of cases of malignant pleural effusion, the fluid will reaccumulate, requiring a more conclusive intervention to be performed later. If large volumes of fluid are removed quickly, there is a risk of re-expansion pulmonary edema, which can be potentially serious. Over many years, studies have evaluated the use of pleural manometry to monitor intrapleural pressure changes during fluid removal; theoretically, if drainage is stopped when the intrapleural pressure falls below a certain level, the occurrence of re-expansion pulmonary edema may be reduced.

In certain situations, repeated therapeutic pleural aspirates may be performed to control patients’ symptoms. This may be necessary if the underlying condition is predicted to respond quickly to chemotherapy (such as in some cases of lymphoma), if a patient would be unable to tolerate a more conclusive procedure, if the prognosis is less than three months, or if fluid reaccumulation is very slow. However, repeated thoracenteses may induce a further inflammatory response within the pleura, increasing the risk of development of a septated and loculated effusion, which may become subsequently more difficult to treat.

Chest drainage and pleurodesis

Chest drainage and pleurodesis have been the mainstays of treatment of malignant effusions for many years. Fluid is drained using an intercostal chest tube, and after complete drainage, a pleurodesis agent is instilled into the pleural cavity via the chest tube in an attempt to seal the pleural cavity and prevent fluid reaccumulation. This technique allows the lung to re-expand and relieves breathlessness and if pleurodesis is successful, it can provide long-term relief of symptoms. However, pleurodesis is not universally successful, with success rates in clinical trials ranging from 70-90 percent. The rate of successful pleurodesis in routine practice is perceived to be at the lower end of this estimate.

Parietal and visceral pleura apposition is essential for pleurodesis to be effective, so if the lung cannot fully expand to fill the chest cavity (i.e. if it is ‘trapped’) because of a visceral pleural “peel: or endobronchial obstruction, pleurodesis will be ineffective. A low pleural fluid pH may also be a marker of potential pleurodesis failure; however, this marker cannot be used in isolation for patient selection.

The agents that have been adopted for pleurodesis include talc, bleomycin, tetracycline, and mustine. Talc can be administered at the time of thoracoscopy via poudrage or through the chest tube as a slurry. In the largest study to date to compare the two administration methods, no significant difference was found with regard to pleurodesis efficacy. However, in a subgroup analysis, patients with underlying lung and breast cancer appeared to have a higher success rate with talc poudrage. A recent Cochrane review examining types of scleroscent, concluded talc poudrage was the more effective pleurodesis agent, though it could not confirm superiority over talc slurry or doxycycline. The side effects of pleurodesis include pain, fever, and breathlessness. Acute respiratory distress is a rare but well documented side effect of talc pleurodesis, which is caused by small talc particles being absorbed into the systemic circulation. Graded talc, which remains within the pleural cavity poses a lower risk of acute respiratory distress.

The TIME-1 study examined the use of analgesia and drain size on pleurodesis efficacy. It found that there was no significant decrease in pain scores or pleurodesis rates in patients that used NSAIDS compared to opioids, although the NSAIDs cohort required more rescue medications. While large-bore chest drains (24Fr) were associated with higher pain scores than small-bore drain (12Fr), they demonstrated lower pleurodesis failure and complications rates.

Fibrinolytics

In a subgroup of patients who have heavily septated or loculated malignant effusions, pleurodesis is less effective than in those with a simple effusion, as the discrete pockets of fluid created by the septations prevent complete drainage of the effusion and, thus, visceral and parietal pleural apposition. Despite encouraging results from earlier studies using intrapleural fibrinolytics to break down septations and loculations, to allow complete drainage prior to pleurodesis, a recent randomised control trial demonstrated that intrapleural urokinase did not improve dyspnea or pleurodesis success when compared to placebo in non-draining MPEs.

Indwelling pleural catheters (IPC)

In patients with trapped lung and in those who wish to avoid an in-patient hospital stay, long-term indwelling pleural catheters are commonly used, as they allow frequent drainage of pleural fluid in the community. The procedure, which is performed under local anesthetic (and sedation in some cases) as a day case procedure, is usually well tolerated. The majority of patients gain good symptomatic relief of breathlessness once the IPC is inserted. Early complications include bleeding, although the risk of serious bleeding is less than 1 percent, and pain.

Later, there is a small risk of infection (both skin cellulitis and empyema), catheter blockage, and tracking of tumor along the catheter insertion tract. In up to half of patients with an IPC, spontaneous pleurodesis occurs, allowing the catheter to be removed with no recurrence of the effusion. Indwelling pleural catheters have a particular role in trapped lung, where chest drain and pleurodesis is ineffective because of failure of pleural apposition.

The TIME-2 study demonstrated that IPC insertion was just as effective at relieving breathlessness as chest drain with talc pleurodesis. The AMPLE trial demonstrated than IPC insertion led to fewer bed days when compared talc slurry.

Surgery

On occasion, a surgical decortication may be necessary to break down intrapleural loculations and septations and to release underlying trapped lung in order to improve patients’ symptoms of breathlessness. Patients must be well enough to tolerate general anesthesia, and usually the procedure can be performed by a video-assisted thoracoscopic surgery (VATS) approach. However, some patients may require a thoracotomy. Pleurodesis can also be performed at the time of surgery to prevent fluid reaccumulation.

What is the prognosis for patients managed in the recommended ways?

The involvement of the pleura in a malignant process is a sign of advanced disease, so treatment is palliative. Current management strategies to remove fluid and prevent reaccumulation do not alter the prognosis but do allow improved quality of life by improving symptoms of breathlessness. Depending on the underlying tissue type, various palliative treatments, including chemotherapy, which may improve prognosis, may be available.

Prognosis depends on the underlying tumor cell type, with breast and ovarian carcinoma having the best prognosis, and patients with lung cancer having a shorter survival. The first validated prognostic score system, the LENT score, uses patient factors (performance status), pleural fluid characteristics (pleural LDH), blood test results (neutrophil-lymphocyte ratio) and tumour type to classify patients in low, medium and high risk score. Low risk patients have been showed to have a median survival of 319 days compared to 44 days in the high risk group.

What other considerations exist for patients with malignant pleural effusion?

Because of the close association between mesothelioma and previous asbestos exposure, many patients are eligible for financial compensation. The systems and funds available will depend on patient circumstances, the history of asbestos exposure, and the country of residence. It is important that patients with a new diagnosis of mesothelioma are made aware of this potential financial support to allow them to pursue compensation should they wish to do so.

Involvement of the palliative care team may be required for patients with malignant pleural effusions in order to improve symptom control and provide practical and emotional support for patient and their families. Palliative care input is considered more effective if it is initiated earlier rather than later, so palliative care should be considered early in the patient’s disease course if possible.

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