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Malignant Pleural Effusion

Oncology
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Introduction

Malignant pleural effusion (MPE) indicates advanced disease and incidence is expected to increase with increase in cancer diagnoses and longer survival as cancer therapies evolve. Malignant pleural effusion is most commonly seen in lung cancer, breast cancer, and lymphoma and is associated with poor survival, median of 3-12 months after diagnosis, depending on tumor type, comorbidities, functional status.[1,2] Two prognostic scores, LENT and PROMISE, have been developed and validated, however their utility for clinical decision-making is unclear and further study is needed.[1,3]

Symptoms

Dyspnea is the most common presenting symptom in malignant pleural effusion, driven by the change in the pressure-volume curve affecting the respiratory muscles and resultant change in respiratory mechanics of the chest wall.[4,5]
Dyspnea may occur at rest or with exertion and orthopnea is a frequent associated symptom. Other symptoms may include chest pressure or pain, particularly in cases with pleural or rib metastases, fatigue, cough, or other nonspecific symptoms.

Diagnostic Workup

Imaging
Chest radiograph is often the first imaging modality performed for evaluation of dyspnea or other respiratory symptom. Chest X-ray findings depend on the size of the pleural effusion and range from blunting of the costophrenic angle on posterior-anterior films and lateral films in to presence of a visible meniscus (often seen better on the lateral film) in moderate sized effusion, to complete opacification of the affected hemithorax in cases of large effusion with or without contralateral deviation of the trachea and other mediastinal structures due to the volume-occupying effusion. In cases of opacification of the entire hemithorax, it is imperative to rule out other processes including endobronchial lesion or mucus plug causing airway obstruction (this often causes post-obstructive atelectasis with mediastinal shift toward the affected side due to volume loss). Additional imaging is often needed to determine the cause of radiographic findings in such cases.
Computed tomography of the chest has a sensitivity up to 68% and specificity of up to 80% for diagnosis of pleural involvement of malignancy however MPE is frequently occult on routine CT imaging, requiring further investigation.[6,7]
Ultrasound is recommended by the American Thoracic Society to guide pleural interventions and can help identify puncture site for thoracentesis more accurately than physical exam alone.[8] Utility of ultrasound depends on expertise of the operator and availability of the necessary equipment.[9]
Pathologic diagnosis
Cytologic or histologic diagnosis provides staging and diagnostic information and may help determine treatment options if enough malignant cells are present to conduct tumor mutational analysis, hormone receptor analysis, or immune receptor analysis.
Cytology can be sent from pleural fluid samples with diagnostic yield approximately 60%. Yield may increase with a second cytology sample however this plateaus around 75% with no improvement in diagnostic yield after three samples.[10,11] Pleural fluid is often sent for chemistries in addition to cytology and for culture in cases where infection is suspected. MPE is usually an exudative process with lymphocyte predominance with lactate dehydrogenase greater than two thirds the upper limit of normal or pleural fluid to serum protein ratio greater than 0.6.[4]
Care must be taken to differentiate this from other causes of lymphocytic effusion such as in tuberculosis. Flow cytometry is often needed to diagnose MPE associated with lymphoma and is an acceptable method for immunophenotyping of cytology specimens.[12] Presence of an exudative and lymphocytic pleural effusion can help narrow the diagnosis in cases where cytology is negative or inconclusive. Malignant mesothelioma is difficult to diagnose with cytology as the abnormal cells are often adherent to the pleura and often requires biopsy to make a diagnosis and to evaluate histologic characteristics that correlate with prognosis.[13]
Pleural biopsy in considered the gold standard for diagnosis of pleural malignancy and may be considered if pleural fluid cytology is inconclusive, if more tissue is needed for evaluate for gene expression or receptor status.[11]  Pleural biopsy may be performed via thoracoscopy or video assisted thoracoscopic surgery (VATS) techniques and has sensitivity over 92% for diagnosis of MPE (Miyoshi 2016).[14]

Management

Management of malignant pleural effusion focuses on palliation of symptoms. Treatment choice is made based on patient factors including severity of symptoms, frequency of effusion reaccumulation, performance status, response to systemic therapy, degree of lung expansion after drainage.[15]
In patients with symptoms due to suspected malignant pleural effusion, diagnostic and therapeutic thoracentesis is the first step with drainage of fluid until there is no fluid remaining or until the patient experiences pain or discomfort, whichever comes first. Large-volume thoracentesis may help ascertain whether the patient’s symptoms are relieved with pleural drainage and if the lung is expandable. Patients with known or suspected MPE who are asymptomatic do not need therapeutic pleural interventions as the risks may outweigh any potential benefit.[9]
Management options discussed below are for those patients with symptoms related to known or suspected MPE.
Serial thoracentesis
Thoracentesis requires travel to the designated procedural site and there is a small risk of complication with each procedure. Serial thoracentesis is often performed for management of malignant pleural effusion if patients require infrequent drainage of fluid or in patients with very limited expected survival and in whom more invasive procedures would require hospitalization, or in cases of prohibitive risk. Pleural effusions treated with serial aspiration have a high recurrence rate at one month so this approach is not recommended for patients expected to survive more than four weeks.[15]
Indwelling pleural catheter
Indwelling pleural catheter (IPC) can be placed using ultrasound guidance or using thoracoscopy or VATS techniques and is an option for patients requiring frequent drainage of pleural effusion with longer expected survival who have resources to manage the catheter at home including a relatively clean environment during drainage, reliable access to drainage supplies, and availability of assistance with drainage when placement of the catheter requires another person.  Patients with recurrent symptomatic MPE and no prior pleural intervention reported significant improvement in dyspnea after IPC placement.[16] Patients with nonexpendable lung also reported symptomatic benefit after IPC placement.[17] Patients undergoing IPC placement had decreased length of stay compared to patients undergoing pleurodesis and over 40% of patients with IPC experienced spontaneous pleurodesis after IPC placement allowing for catheter removal.[18-21]
Decreased need for peri-procedural hospitalization combined with a 30% failure rate of pleurodesis leads to a preference for IPC placement over pleurodesis in many centers. IPCs carry a risk of infection which may be limited to cellulitis at the catheter exit site (7.3%), infection of the tunnel, or may extend into the pleural space causing empyema (4.6%).[9]  Most infections can be treated without removal of the catheter and care must be taken during drainage to keep the catheter clean with careful inspection of the exit site and catheter tunnel each time the catheter is drained. Furthermore, dressings must be placed in a sterile manner and the occlusive dressing must remain intact.  IPC is also an option for patients with symptomatic malignant pleural effusion who have nonexpendable lung.
Protocols for IPC Drainage
There is no difference in patient-reported mean daily breathlessness when comparing daily drainage and symptom-guided drainage of IPC indicating similar dyspnea control with both drainage approaches. Daily drainage did lead to increased rates of spontaneous pleurodesis compared to symptom-guided drainage.[22]
Investigation of optimal drainage frequency to achieve spontaneous pleurodesis after IPC placement revealed a daily drainage protocol may lead to higher rates of spontaneous pleurodesis and fewer catheter days compared to every other day drainage.[23]
Individual choice of drainage protocol depends on patients’ goals, severity of symptoms, expected survival, and access to drainage supplies.
Pleurodesis
Pleurodesis, either mechanical or chemical, is a definitive management option for patients with symptomatic malignant pleural effusion with expandable lung. For pleurodesis to be successful, apposition of the visceral and parietal pleura must be achieved.[9,15]  Radiographic confirmation of lung re-expansion is key and may be achieved with radiographs, computed tomography, or ultrasound. Volume of pleural fluid drained is less important than confirmation of lung expansion for pleurodesis.[15]
Chemical pleurodesis can be performed by inserting a chest tube  to drain the pleural effusion causing apposition of the visceral and parietal pleura followed by instillation of a sclerosing agent into the tube to cause inflammation leading to adhesions and obliteration of the pleural space.  Pleurodesis may be performed with small bore or large bore tubes and patients may have less pain with smaller diameter drainage tubes.[11,24,25]
Chemical pleurodesis and associated inflammation leads to exquisite pleuritic pain and admission for pain control with nonsteroidal anti-inflammatory drugs (NSAIDs) and intravenous opioids is needed for this procedure. Use of NSAIDs does not appear to interfere with successful pleurodesis and may be included in pleurodesis periprocedural pain control protocols.[25] Intrapleural lidocaine can also be instilled just prior to sclerosant to provide local anesthetic, taking care not to exceed maximum dose based on body weight. Moderate sedation, when appropriate monitoring equipment and protocols are available, may help alleviate pain and anxiety however there are no studies evaluating pain control around sedation for pleurodesis procedures performed without thoracoscopy.[15]  
Sterile graded talc, either as a slurry or administered via poudrage/insufflation is the most effective sclerosing agent and is recommended in multiple evidence-based guideline publications.[1,8,9,11,15]  Graded talc is used to decrease risk of acute respiratory distress syndrome.[1] Talc may be administered as a poudrage or powder insufflated into the pleural space via thoracoscopy, or as slurry instilled into the pleural space through a chest tube. There is no difference in efficacy between talc poudrage and talc slurry.[28,29]
Bleomycin and antibiotics such as doxycycline are also effective sclerosing agents that are widely available with a similar side effect profile to talc and without significant myelosuppression.[11,15] Studies show less pleural effusion recurrence with talc compared to other agents, however these studies do have some bias and further study is needed.[1,11,30]
Abrasion pleurodesis is achieved via surgical approach with VATS or thoracotomy with abrasion of the pleura and resultant adhesions and obliteration of the pleural space thus preventing accumulation of pleural effusion. The procedure requires hospital admission for chest tube and pain management. In general, surgical pleurodesis procedures show similar efficacy for pleural fluid control and conflicting data around hospital stay and patient outcomes but can be associated with higher rate of adverse events and higher costs.[15,31,32] Pleurectomy is associated with significant risk of infection, hemorrhage and there is insufficient evidence to recommend this as an alternative to the above therapies.[15]
Combined approach with IPC and administration of talc slurry through the IPC may be a viable option for patients with expandable lung as this approach may lead to a higher rate of pleurodesis than with IPC placement alone.[33]

Controversies/Limitations

As with any intervention, limitations vary depending on operator skill and comfort level, equipment and resources available, cost to the patient, and patient preference.
Serial thoracentesis allows for rapid relief of dyspnea with malignant pleural effusion but requires frequent contact with the health care system with associated costs and risks of the procedure, however small.
IPC is associated with less time in the hospital but carries a risk of infection and requires catheter compatible supplies which may be limited in locations with scarce resources and may be cost prohibitive for some patients. Furthermore, IPC sites cannot be submerged in water (even if the occlusive dressing is intact) due to risk of infection and while the dressing is somewhat low profile, it can be difficult to conceal and may interfere with patient’s quality of life, depending on their goals.
Pleurodesis is associated with longer hospitalization and significant peri-procedural pain. Furthermore, failure rate is around 30% in which case further procedures are required. A combined approach for definitive management of malignant pleural effusion may be preferred including placement of IPC with talc pleurodesis in the same procedure.
Discussion with patients about the risks, potential benefits, and their preferences is key when deciding on the optimal management strategy for malignant pleural effusion.

Summary

  • Malignant pleural effusion is associated with poor survival with median of 3 to 12 months after diagnosis. The most common cancers associated with MPE are lung cancer, breast cancer, and lymphoma.
  • Dyspnea is the most common presenting symptom and may occur at rest or with exertion. Other symptoms may be nonspecific and may include fatigue, chest pressure, cough, and orthopnea.
  • Imaging with chest radiograph, computed tomography, or ultrasound is helpful in diagnosing presence of pleural effusion. Complete opacification of one hemithorax on chest radiograph may be due to pleural effusion or endobronchial obstruction from tumor or mucus plug leading to postobstructive atelectasis. In such cases, further investigation may be needed to identify the cause of the radiographic finding before performing a percutaneous drainage procedure.
  • Ultrasound guidance is recommended for percutaneous drainage procedures to help identify the correct entry point and to reduce risk of pneumothorax and solid organ puncture. Utility of ultrasound is dependent on operator expertise and equipment availability.
  • Cytologic or histologic diagnosis of malignant pleural effusion provides staging and diagnostic information and may help determine treatment options.
  • Cytology from pleural fluid has a diagnostic yield of around 60% and plateaus around 75% after three samples. Further sampling does not increase diagnostic yield.
  • Pleural biopsy via thoracoscopy or video assisted thorascopic surgery is considered gold standard for diagnosis of pleural involvement of malignancy and may be considered if pleural fluid cytology is negative or inconclusive, or if further tissue is needed for evaluation of gene expression or receptor status.
  • Management of MPE focuses on symptom palliation and choice of treatment is made based on expected length of survival, degree of lung expansion after fluid drainage, availability of resources, and patient preference.
  • Serial thoracentesis is reserved for patients with expected survival of one month or patients who do not wish to undergo more invasive procedures.
  • Indwelling pleural catheter, placed under ultrasound guidance or thoracoscopy/VATS, is associated with shorter hospital stays and is an option for patients requiring frequent drainage who have resources to care for the indwelling device, and for those with or without full lung expansion.  Multiple drainage protocols exist but daily drainage is associated with increased rates of spontaneous pleurodesis.
  • Chemical pleurodesis is a definitive option for patients with full lung expansion with sterile graded talc being the recommended sclerosing agent. Pleurodesis is associated with peri-procedural pain, fevers, and inflammation often requiring hospitalization for pain control.
  • Surgical options such as abrasion pleurodesis is effective but can be associated with higher costs and adverse events.
  • Discussion with patients about the risks, potential benefits, resources, and their preferences is key when deciding on the optimal management strategy for malignant pleural effusion.

References

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