Introduction

Pleural effusion is a frequent complication of advanced malignancy with significant associated morbidity and mortality. Recent advances in the management of malignant pleural effusions (MPE) have changed the morbidity associated with this disease.

Etiology

Malignant pleural effusions (MPE) develop as a direct extension of cancer into the pleural space, or they are due to inflammation induced by malignancy. MPEs are most commonly secondary to lung cancer, with adenocarcinoma type most frequently associated with the development of pleural effusion. Breast cancer is the second most common cause of MPE. Lung cancer and breast cancer account for more than half of cases of MPE.[1] Hodgkin and non-Hodgkin lymphoma is the third most common cause of MPE but is reported to be the most common cause of malignant effusion in young adults.[2] In 5% to 10% of malignant effusions, no primary tumor is identified.[3]

Epidemiology

As of 2000, there have been no epidemiologic studies of MPEs. MPEs have been estimated to affect more than 200,000 patients in the United States annually[4], and it was responsible for 126,825 hospital admissions in 2012.[2],[5] MPE accounts for 36% of all pleural effusions subjected to thoracentesis.

Pathophysiology

Pleural effusions form as the result of 2 mechanisms: the entry rate of liquid into the pleural space must increase through the visceral pleura, and the exit rate must decrease through the parietal pleura wherein the entry rate of liquid thereby exceeds its removal. Increased entry of liquid into the pleural space may be the result of increased filtration across systemic or pulmonary capillaries, while decreased entry of liquid from the pleural space may be secondary to interference with lymphatic function.[4]

An MPE develops as a result of the above mechanisms and can arise from both direct and indirect involvement of cancer. Direct causes of pleural effusion formation include malignancy interfering with the integrity of the lymphatics system or direct tumor involvement of the pleura.[6] An indirect cause of pleural effusion formation includes local inflammatory changes in response to tumor invasion that may cause increased capillary permeability, resulting in increased entry rate of liquid into the pleural space.[7]

History and Physical

Pleural effusion may be the first presentation of malignancy. The most commonly encountered complaint in a patient presenting with an MPE is dyspnea, occurring in more than half of cases. This results from the alteration of respiratory mechanics in which the diaphragm is displaced caudally, and the chest wall is displaced outward. A cough may also be present due to distortion of the lung. Chest pain due to the involvement of the sensory neurons on the parietal and, occasionally, the visceral pleura can occur.[8]

Physical exam findings include decreased breath sounds over the involved hemithorax, dullness to percussion, and decreased tactile fremitus. The development of pleural effusion should have no bearing on oxygenation as it does not alter V/Q dynamics or result in shunting; if a patient with MPE presents with hypoxia, an alternative explanation such as pneumonia, atelectasis related to the endobronchial lesion or pulmonary embolism should be sought.[4]

Evaluation

Investigation with chest radiography should follow the complaint of dyspnea; patients with MPE present with moderate to large effusions with volumes ranging from 500 to 2000 mL. Ten percent of patients present with massive pleural effusion, defined as occupying an entire hemithorax. Large pleural effusions should result in a contralateral mediastinal shift; absence of mediastinal shift implies endobronchial lesion of the ipsilateral mainstem bronchus, disease involvement of pleural surfaces, or fixation of the mediastinum. Chest ultrasonography has 100% sensitivity in the diagnosis of pleural effusion. The appropriate site for performing thoracentesis can be identified using ultrasound. Computed tomography (CT) of the chest is the best modality for visualizing the pleural surfaces in detail, along with lung parenchyma, chest wall, and mediastinum. On CT, pleural thickening greater than 1 cm, irregularity of the pleural space, and pleural nodules can indicate MPE, but approximately 50% of patients with MPE have no pleural abnormalities on CT.[9]

Every patient with free pleural fluid that measures more than 10 mm on the radiograph, ultrasound, or chest CT should have a diagnostic thoracentesis. Therapeutic thoracentesis should be performed in all patients with suspected MPE to assess the degree of relief of dyspnea and rate of recurrence. If dyspnea is not improved with thoracentesis, an alternative diagnosis such as pulmonary embolism, atelectasis, or lymphangitic carcinomatosis should be investigated.

The gross appearance of MPE varies. Malignant disease is the most common cause of bloody effusions, and about half of malignant pleural effusions appear bloody. MPE can otherwise appear clear or cloudy.

As with all pleural effusions, the fluid analysis should include distinguishing between transudate and exudate. Light’s criteria were developed as a means of distinguishing transudative effusions (commonly caused by heart failure, cirrhosis, or renal failure) from exudative effusions (commonly caused by malignancy, infection, pulmonary embolism, and gastrointestinal disease). The identification of transudate or exudate is made by the analysis of the pleural fluid protein and lactate dehydrogenase (LDH) levels. Exudative effusions fulfill at least one of the following criteria: (1) pleural fluid protein/serum protein ratio greater than .50, (2) pleural fluid LDH/serum LDH ratio greater than .60, and (3) pleural fluid LDH greater than two-thirds the upper normal limit for serum. These criteria have 100% sensitivity in diagnosing exudates but can misdiagnose transudates as exudates in up to 25% of cases. If the patient clinically appears to have a transudate (clear, yellow fluid), then additional testing can be performed to further differentiate the two. A serum to fluid protein gradient of greater than 3.1 or serum to fluid albumin gradient of greater than 1.2 indicates a fluid is transudative. The pleural fluid from malignant effusions is almost always an exudate. Rarely, malignant effusions can be transudative, but this is usually related to an underlying condition causing increased hydrostatic pressure resulting in an effusion, such as congestive heart failure, the superior vena cava syndrome, airway obstruction with resultant atelectasis or pneumonia, and low oncotic pressure from underlying malnutrition or cachexia.[10]

Cell differential of pleural fluid typically demonstrates lymphocyte-predominant fluid, although eosinophilic or neutrophilic-predominant effusions do not necessarily preclude effusion secondary to malignancy.

Definitive diagnosis requires the demonstration of malignant cells on cytology sample obtained during thoracentesis. Diagnostic yield is reported to be as high as 60% in patients who undergo thoracentesis for suspected MPE; the diagnostic yield varies with the type of tumor and the extent of tumor involvement of the pleural space. For example, cytology results are more commonly positive in adenocarcinoma than in squamous cell carcinoma due to its greater tendency to invade the pleural space. Cytologic yield does not depend on the size of the effusion. The first thoracentesis is expected to result in diagnosis 65% of the time; one study demonstrated an additional yield of 27% on the second thoracentesis and only 5% on the third. Therefore, if 2 thoracenteses have not yielded cytology and an MPE is highly suspected, thoracoscopy should be pursued as the next step. The diagnostic yield of medical thoracoscopy is considerably higher at 95% but far more invasive than simple thoracentesis.[10]

Finally, during thoracentesis, pleural manometry is encouraged to identify trapped lung physiology. A trapped lung is defined as the inability of the lung to expand due to fibrous visceral peel fully. In patients with MPE, it can be due to endobronchial tumor occlusion or by complete infiltration of the pleura by malignancy. This may be more evident on imaging in those with large pleural effusion without accompanying contralateral mediastinal shift. In the physiology of pleural effusion, pleural pressures are positive. However, the pleural pressure in the trapped lung is negative initially and drops steeply with the removal of fluid.  Those patients with trapped lung are unlikely to benefit from pleurodesis, which will be discussed below.[11]

Treatment / Management

The goal of management of an MPE is palliative; if a patient is asymptomatic, observation is reasonable along with chemotherapy for those primary malignancies that are responsive. However, many patients present with significantly disabling dyspnea. Treatment should aim to relieve dyspnea, minimize discomfort, and limit hospitalization time. Several therapeutic approaches depend on the following factors: (1) the clinical status of the patient, (2) the ability of the lung to fully expand, and (3) the availability of approaches like thoracoscopy.[12]

Serial thoracenteses can be performed for long-term management with the removal of no more than 1.5 liters at a time due to the risk of re-expansion pulmonary edema. This is reasonable in patients who have a prognosis of less than 1 month. However, in those who are expected to live longer, this may not be a practical treatment option. Furthermore, repeated thoracenteses may result in adhesions between parietal and visceral pleura and can limit future thoracoscopic interventions.[12]

Definitive management with pleurodesis, which is a technique to allow for apposition of the parietal and visceral pleura to prevent reaccumulation of pleural effusion, depends on whether the patient has trapped lung. If the patient has trapped lung physiology, they are unlikely to benefit from pleurodesis techniques as the thick fibrous peel surrounding the visceral pleura would prevent apposition of parietal and visceral pleural surfaces.[13] Therefore, patients with an MPE and trapped lung physiology should instead undergo placement of indwelling pleural catheters. These allow ambulatory drainage of pleural fluid daily for relief of symptoms. Several catheters have been developed for this purpose, and studies have shown promising results regarding symptom relief and decreased hospitalizations related to MPEs.[14]. Spontaneous pleurodesis has been reported in some patients. The presence of the catheter in the pleural space stimulates an inflammatory reaction that encourages obliteration of the pleural space.

In those who do not have trapped lung physiology, chemical pleurodesis should be pursued with sclerosants. This can be achieved by placement of chest tube with instillation of talc slurry, which is the most effective of available sclerosants; talc is thought to incite an inflammatory reaction in the pleural space that leads to fibrin formation and apposition of the parietal and visceral pleura. Tetracyclines and bleomycin are alternative sclerosants that can be used.[12]

If the above procedures fail, pleuro-peritoneal shunt or pleurectomy can be performed but have significant cost and morbidity.[12]

Differential Diagnosis

• Acute respiratory distress syndrome

• Asbestos pleural effusion

• Chronic pleural thickening

• Chylothorax

• Congestive heart failure

• Diaphragmatic injury

• Drug-induced pleural disease

• Oesophageal rupture

• Lung neoplasms

• Hypothyroidism

Prognosis

Prognosis in patients with MPE is usually poor. Prognosis is thought to range from 3-12 months, depending on the primary malignancy involved [15].

Pearls and Other Issues

Malignant pleural effusions commonly cause significant dyspnea in advanced malignancy. Diagnosis requires the demonstrated of positive cytology in pleural fluid obtained during thoracentesis; if there is strong suspicion for malignant pleural effusion despite cytology negative on 2 thoracenteses, clinicians should pursue thoracoscopy. Management should focus on palliation of symptoms; this may be through the use of indwelling pleural catheters for those with lungs demonstrated to not expand with therapeutic thoracentesis or pleurodesis with sclerosants like talc.

Enhancing Healthcare Team Outcomes

The management of malignant pleural effusion is with an interprofessional team that includes an oncologist, radiologist, pathologist, palliative care nurses, hospice, thoracic surgeon and a pain specialist. Most of these patients have less than 12 months to live and aggressive measures are unwarranted. The use of sclerotherapy can be used to manage most MPE and surgery should be avoided. A palliative care and hospice nursing team should be involved in the care of these patients; the aim is to make the patient comfortable and pain-free.[15]