Malignant Pleural Effusions

I. Problem/Condition.

The main symptom of malignant pleural effusions (MPE) is shortness of breath (57%), typically progressive exertional dyspnea followed by cough (43%). Chest pain is more common in patients with mesothelioma. However, some patients have no symptoms and the effusion is only found on imaging. There are >150,000 new cases of MPE in the United States each year. Lung cancer is responsible for approximately one-third of cases of MPE, followed by breast cancer, ovarian cancer, and lymphoma. Most of the MPE are secondary to adenocarcinoma.

In general, having MPE portends a poor prognosis for a patient with malignancy, with median survival after diagnosis between 4-9 months. Patients with poor performance status have median survival as low as 30 days. However, MPE can be associated with malignancies where patients have longer survival (breast cancer, Hodgkin’s disease or lymphoma).

II. Diagnostic Approach.

A. What is the differential diagnosis for this problem?

The differential for MPE includes pleural effusions from other causes. Other diagnoses to consider include heart failure, cirrhosis, pulmonary embolism, rheumatologic conditions that could cause a pleurisy, trauma or procedure (endoscopy or esophageal dilatation) and infectious causes of pleural effusion. These diagnoses can usually be distinguished based on the clinical history and exam, as well as pleural studies.

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MPE can be distinguished from many other clinical conditions by history and an exudative pleural fluid with cytology positive for malignancy. It is important to keep in mind that while MPE tend to be exudates, there is a small percentage (5-10%) that are transudative.

B. Describe a diagnostic approach/method to the patient with this problem.

When a patient presents with progressive dyspnea and a pleural effusion that has not been diagnosed in the past, a good clinical history will be key in guiding diagnosis and treatment. A unilateral pleural effusion in a patient with a history of cancer or a significant smoking history with weight loss and other alarming symptoms would be very different from a patient who presents with dyspnea, found to have bilateral pleural effusions and also symptoms of lower extremity swelling and orthopnea.

If a patient presents with progressive dyspnea and is found to have a unilateral pleural effusion on exam and has no history of heart failure, the first diagnostic and therapeutic approach is to pursue a diagnostic and therapeutic thoracentesis. Not only will the thoracentesis provide pleural fluid for analysis, it will also demonstrate whether or not the patient has any symptomatic relief from removal of fluid which can help guide treatment in patients with MPE.

1. Historical information important in the diagnosis of this problem.

  • How long has the dyspnea been occurring?

  • Any history of cancer, congestive heart failure, or cirrhosis?

  • Any history of trauma to the chest?

  • Any recent GI procedures (particularly endoscopy or esophageal dilatation)?

  • Any history of fevers or chills, productive cough, or sick contacts?

  • History of weight loss, night sweats or hemoptysis?

  • History of smoking or other significant cancer exposures (asbestos, etc.)?

  • Associated other symptoms, swelling in the lower extremities, orthopnea, weight gain?

  • Any history of calf swelling, prolonged immobilization, surgeries, or other risk factors for pulmonary embolism?

  • Has this ever occurred before?

  • Any history of or risk factors for tuberculosis?

  • Has the patient had age appropriate cancer screening in the past?

  • Any history of rash, joint pain, hair loss?

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

Look at the patient’s general appearance (e.g., well-appearing or cachetic-appearing). Other exam findings that may be helpful are abnormalities on the lung exam, elevated jugular venous distention or other signs of heart failure, unilateral or bilateral lower extremity swelling, any swollen lymph nodes, and abdominal distention with a fluid wave indicative of ascites. Clubbing in a patient with a history of smoking is an alarming sign for lung cancer.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

Imaging can be helpful to establish the presence of an effusion. Effusions of at least 200 milliliters can be seen on chest x-ray, and a lateral decubitus film can show if the effusion is free flowing. Ultrasound can help to diagnose loculated effusion as well as help to detect pleural thickening and pleural nodularity which can be suggestive of malignant nature of effusion. Chest computed tomography (CT) can be used to evaluate loculated effusions. Chest CT will also be able to better evaluate for underlying pathology in the lung.

Pleural studies will be key in diagnosing MPE. Studies that should be sent on pleural fluid on initial evaluation include:

  • LDH (with corresponding serum LDH at the time of thoracentesis)

  • Total protein (with corresponding serum total protein at the time of thoracentesis)

  • pH

  • Albumin (with corresponding serum albumin)

  • Cell count and differential including hematocrit if the fluid is bloody

  • Cytology (yield is variable, single specimen has yield of 60% in MPE associated with adenocarcinoma which increases up to 80% on second sample and then plateaus; at least 50 mL of fluid should be set for optimal analysis). However, MPE associated with malignant mesothelioma has very poor diagnostic yield – in the range of 20-70% based on visceral pleural invasion.

  • Glucose

  • Cholesterol – MPE in cases of lymphoma can present chylothorax.

  • Amylase

Tumor markers from the pleural fluid are not helpful in diagnosing MPE.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

Most MPEs are exudative. Around 3-5% malignant pleural effusion can be transudative in nature.

The most common way used to distinguish transudate and exudate are Lights criteria:

Light’s criteria – one of the following criteria being fulfilled usually means exudate:

  • Pleural fluid total protein/serum total protein >0.5

  • Pleural fluid LDH/serum LDH >0.6

  • Pleural fluid LDH >2/3 the upper limit of normal for serum LDH level

Alternatively, 2 and 3 criteria rules have been proposed to diagnose exudative effusion in the absence of concurrent blood testing:

  • 2 criteria rule: LDH > 0.45 times the upper limit of normal serum values and/or pleural fluid cholesterol > 45 mg/dl

  • 3 criteria rule: 2 criteria rule and/or pleural fluid protein > 2.9 g/dl

Bloody fluid is consistent with malignancy, but there are other diagnoses that can cause bloody appearing fluid (pulmonary infarction, pulmonary embolism).

In general, pleural fluid with protein level <3 g/dl indicates transudate, >3 g/dl indicates exudate but only if the serum total protein is in the normal range. When the pleural protein level is between 2.5 g/dl and 3.5 g/dl, Light’s criteria is recommended to make the distinction.

If the clinical scenario fits transudate but the pleural fluid is exudative by Light’s criteria, looking at the pleural and serum albumin can be helpful. If the serum albumin is >1.2 g/dl higher than the pleural fluid albumin level, this can also be suggestive of transudate but this criteria should not be used alone.

Low pleural glucose (<60 mg/dl) is generally associated of either a parapneumonic or malignant effusion (less commonly, effusions related to rheumatologic conditions and tuberculosis can also lead to a low pleural glucose).

Low pH (<7.20) is associated with parapneumotic or malignant effusion. Patients with MPE who have pH <7.35 and/or glucose < 60 mg/dl tend to have a worse prognosis as well.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

If there is a free-flowing effusion seen on chest x-ray with decubitus film, then proceeding to a thoracentesis is reasonable unless there is concern for loculated effusion. Further chest imaging is not necessary unless evaluating for the underlying pathology of the effusion (it may be reasonable to pursue chest CT if there is concern for malignancy).

Because PET scan has low sensitivity (81%) and low specificity (74%), it should not be used as a diagnostic modality to differentiate between malignant and benign pleural effusion.

III. Management while the Diagnostic Process is Proceeding.

A. Management of Clinical Problem Malignant Pleural Effusions.

The first step in both diagnosis and management is thoracentesis with removal of up to 1-1.5 L of pleural fluid when possible. Removal of more than 1.5 liters can lead to re-expansion pulmonary edema. Young patients and those with a history of lung collapse are at increased risk of developing re-expansion pulmonary edema. A minimum of 50-60 ml of pleural fluid should be sent on 2 occasions to achieve diagnostic accuracy up to 80%. Thoracentesis will aid in diagnosis by providing pleural fluid for studies, but also help to determine if fluid removal will improve the patient’s symptoms.

If thoracentesis fails to reveal a malignant effusion and it is exudative, thoracoscopic pleural biopsy (sensitivity of 95-97%) is preferred over closed pleural biopsy (sensitivity ∼40%) to diagnose a malignant nature of the effusion.

Once the diagnosis of MPE is made, management depends on the patient’s prognosis and performance status. These decisions should be made in conjunction with the oncologist and/or surgeon.

If the patient does not have significant symptoms from the MPE, the patient may not require any interventions at that time.

For patients with life expectancy <30 days and/or poor performance status, repeat thoracentesis may be the only option for the patient.

For patients with a longer life expectancy, treatment depends on a few factors. If the patient does not have relief of symptoms from thoracentesis, this may be secondary to lung non-reexpansion or the patient’s symptoms may not be from the pleural effusion. If the patient has lung non-reexpansion, pleurodesis may not be successful and other treatment options should be considered. If the patient has lung re-expansion and continues to have symptoms, other etiologies for the symptoms should be considered, such as lymphangitic spread or malignant airway obstruction.

For those patients with longer life expectancy who have symptomatic relief from thoracentesis and who have lung re-expansion, the following are treatment options:

  • In-dwelling tunneled pleural catheter

– A catheter is placed with intermittent outpatient drainage. This can be performed as an outpatient and the procedure itself is well-tolerated. It is minimally invasive and not too burdensome, even for those with poor performance status. It tends not to interfere with a patient’s ongoing cancer treatment. Pleurodesis can occur with this method in anywhere from 40-70% of patients in a few weeks. Tunneled pleural catheter procedure can be combined with pleurosocopy and talc pleurodesis to enhance the efficacy. Efficacy of tunneled pleural catheter to achieve pleurodesis is slightly lower than thoracoscopic pleurodesis. However, if a patient’s expected survival is less than 3 months, then a tunneled pleural catheter may be cost-effective compared to pleuroscopic pleurodesis. Complication rates are not significantly different from those of talc pleurodesis. Another advantage of a tunneled catheter is that it can be used in patients with a “trapped lung” who have symptomatic benefit with thoracentesis (in these situations, talc pleurodesis will not be effective).

  • Chest tube thoracostomy

– Tends to occur as an inpatient, can be performed at the bedside under local anesthesia. Pleurodesis can be performed after re-expansion of the lung. Pleurodesis is generally done with talc insufflation.

  • VATS (video-assisted thoracic surgery)

– Performed in the operating room, usually with general anesthesia and endotracheal intubation. Usually, the pleural fluid is evacuated and a sclerosant is insufflated into the pleural space.

  • Medical pleuroscopy and talc pleurodesis

– Is an alternative to VATS. Can be done under moderate sedation without endotracheal intubation. This is particularly useful for undiagnosed pleural effusion as pleural biopsy can be done with medical pleursocopy before talc insufflation.

For more refractory patients:

  • Pleurectomy

– Removal of the pleura. A major surgical procedure, tends to only be used in patients who have failed other measures or in patients with malignant pleural mesothelioma.

  • Pleuroperitoneal shunt

– A shunt is placed to transfer pleural fluid to the peritoneal cavity. Generally only used for patients who have a chylous effusion refractory to other treatments or patients who cannot have pleurodesis because of lung non-reexpansion after thoracentesis.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.

The most common side effect with pleurodesis are fever and pain. Other rare complications include: local site infection depending on how the pleurodeis is done, empyema, acute lung injury/acute respiratory distress syndrome.

Since most MPEs return within 30 days, a long-term plan for follow-up and management of symptomatic pleural effusions should be made with the patient’s outpatient oncologist if only a thoracentesis is pursued in the hospital. While thoracentesis will provide short-term relief of symptoms, if long-term issues are not addressed, the patient may return to the hospital with symptoms.

IV. What's the evidence?

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Uzbeck, MH, ALmeida, FA, Sarkiss, MG, Morice, RC, Jimenez, CA, Eapen, GA, Kennedy, MP.. “Management of malignant pleural effusions”. Adv Ther.. vol. 27. 2010. pp. 334-347.

Christie, NA.. “Management of pleural space: effusions and empyema”. Surg Clin N Am.. vol. 90. 2010. pp. 919-934.

Neragi-Miandoab, S.. “Malignant pleural effusion, current and evolving approaches for its diagnosis and management”. Lung Cancer.. vol. 54. 2006. pp. 1-9.

Light, RW.. “Pleural effusion”. N Engl J Med.. vol. 346. 2002. pp. 1971-1977.

Porcel, JM, Hernández, P, Martínez-Alonso, M, Bielsa, S, Salud, A.. “Accuracy of fluorodeoxyglucose-PET imaging for differentiating benign from malignant pleural effusions: a meta-analysis”. Chest. vol. 147. February 1, 2015. pp. 502-12.

Perricone, G.. “Re expansion pulmonary edema after thoracentesis”. NEJM. vol. 370. 2014. pp. e19

Swiderek, J. “Prospective study to determine the volume of pleural fluid required to diagnose malignancy”. Chest. vol. 137. 2010; Jan. pp. 68-73.

Olden, AM. “Treatment of malignant pleural effusion: PleuRx catheter or talc pleurodesis? A cost-effectiveness analysis”. J Palliat Med.. vol. 13. 2010 Jan. pp. 59-65.

Puri, V. “Treatment of malignant pleural effusion: a cost-effectiveness analysis”. Ann Thorac Surg.. vol. 94. 2012. pp. 374-9.

Fysh, ET.. “Indwelling pleural catheters reduce inpatient days over pleurodesis for malignant pleural effusion”. Chest. vol. 142. 2012 Aug. pp. 394-400.