Pediatric Malignant Pleural Effusion


Article Author:
Adebayo Adeyinka


Article Editor:
Noah Kondamudi


Editors In Chief:
Jon Parham
Abigail Frank
Jon Sivoravong


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes


Updated:
6/3/2019 2:05:52 PM

Introduction

The pleural cavity is a thin layer of the sac that is lined with a serous membrane that encloses the lungs and separates it from the thoracic cage. There is an inner layer covering the surface of the lungs called the visceral pleura. The outer layer is the parietal pleural. A minuscule amount of fluid that is approximately 10 microliters thick can be found between the 2 layers. The amount of fluid in the pleural cavity is regulated by a fine balance in the oncotic and hydrostatic pressures between the pleural space and the intravascular components coupled with the perilymphatic drainage. The Frank-Starling law controls this process.

Transudates are formed when there is a disturbance in the fine balance between the production of pleural fluid and its absorption. There are several factors involved in the formation of exudates. Protein and other substances are removed from the pleural cavity via lymphatic lacuna and preformed stoma. Chest wall movement and respiratory dynamics enhance the process of removal of these substances via the lymphatic route.

The pleural cavity also contains cells, some macrophages, red blood cells, and lymphocytes. The amount of fluids and cells in the pleural space can changes considerably in pathologic conditions.

The visceral pleura receives it bloods supply from bronchial circulation whole the parietal pleura receives its supplies from the intercostal arteries make the 2 layers 2 distinct anatomic structures. The visceral part of the pleura does not have any sensory nerve, on the contrary,  the parietal part of the pleura has a rich network of sensory nerve making it very sensitive to painful stimuli. The pleural cavity aids in the mechanics of inspiration and expiration during breathing. Kampmeier's foci are a collection of lymphoreticular and mesothelial cells which acts as “guard” by preventing the entry of undesirable substances from the pleural cavity into the media in the chest wall and mediastinum.

Pleural effusion is the accumulation of fluid in the pleural cavity. The mechanism by which fluid accumulates in the pleural cavity is outlined below:

  • Infection
  • Increased capillary permeability: Exudates
  • Increased hydrostatic pressure or decreased oncotic pressure: Transudates
  • Abnormal lymphatic clearance: Chylous effusion
  • Bleeding: Blood in the pleural cavity: Hemothorax

Etiology

Infection

The most common cause of pleural effusion in the pediatric population is an infection. The infectious agents that can cause pleural effusion are listed below.[1][2][3][4]  

Aerobic Pathogens

  • Streptococcus pneumoniae
  • Hemophilus influenza type B
  • Staphylococcus aureus
  • Moraxella catarrhalis

Anaerobic Pathogens

  • Fusobacterium
  • Bacteroides

Immunocompromised Patients

  • Pneumocystis jiroveci 
  • Mycobacterium tuberculosis

Congestive Heart Failure

The second most common cause of pleural effusion is congestive heart failure in children. Presence of congestive heart failure elevates the left atrial pressure and pulmonary wedge pressure leading to the formation of transudates.

Malignancy

The third leading etiology of pleural effusion in the pediatric population is a malignancy. Malignant pleural effusion develops as a result of the following:

  • Direct invasion of the pleural wall
  • Impairment of lymphatic drainage from the pleural cavity
  • Obstruction of the bronchial tree with the development of bronchial obstruction and atelectasis

Pleural effusion secondary to malignancy can be unilateral or bilateral.

Pleural Effusion Secondary to Malignant Tumor

Malignancy as a cause of pleural effusion in children can be primary malignancy or metastatic malignancy.

Lymphoma

Lymphoma is the most common malignancy associated with pleural effusion. About 13 % of all childhood malignancy is attributable to lymphoma. Lymphoma is also the most common cause of anterior mediastinal mass in children. Approximately 60% of lymphomas are non-Hodgkin lymphoma while the remaining 40% are Hodgkin lymphoma. Patients with lymphoma will usually present with an anterior mediastinal mass. About 5% of patients with Hodgkin or non-Hodgkin lymphoma will develop a pleural effusion.

Leukemia

T-cell lymphoblastic leukemia can also cause a malignant pleural effusion. In about close to 50% to 70% of lymphoblastic leukemia, pleural effusion will develop. Bone marrow biopsy is necessary to differentiate between the 2 types of malignancy.

Germ Cell Tumor (GCT)

GCT accounts for about 6% to 18% of mediastinal masses. Close to 20% of GCT are malignant.They include seminomas and nonseminomatous tumor-like teratocarcinoma, embryonal carcinoma, choriocarcinoma, yolk sac tumor, and mixed types. Encroachment into adjacent structures in the mediastinum can cause respiratory symptoms. Compression of the tracheobronchial tree and obstruction of lymphatic flow by these tumors can result in the development of pleural effusion.

Neurogenic tumor

Neuroblastoma and ganglioneuroma make up about 90% of the posterior mediastinal mass. Growth and expansion can cause mass effect, respiratory distress, and cord compression. Neurogenic tumors generally do not cause pleural effusion.

Chest wall and pulmonary malignancy

These tumors can be primary and metastatic, but it is very difficult to differentiate between the 2. Examples are carcinoids tumor, pleuropulmonary blastoma, and Askin tumor.

Carcinoid tumor 

This type of malignancy is common in older children and adolescents. Reportedly it accounts for about 80% to 85% of primary malignant tumor in children. They can cause compressive atelectasis and pneumonia that can lead to the development of an effusion.

Pleuropulmonary blastoma

This is a rare tumor in pediatrics. It is an embryonal, mesenchymal tumor originating from the lung and pleural cavity. Diagnosis of this malignancy is often late. Three types are histologically recognized.

  • Macro cystic
  • Mixed cystic
  • Solid

This tumor can invade adjacent structures causing pneumonia, spontaneous pneumothorax, and effusion.

Askin tumor

This is a rare form of Ewing Sarcoma or primitive neuroectodermal tumor that can arise from the bones of the rib or chest wall or the lungs. Prognosis is poor in patients with Askin tumor. The tumor can invade adjacent structures like muscle ribs, pleura, and the lungs. It can cause mass effect, with compression of nearby organs and development of pleural effusion.

Epidemiology

Three main conditions cause pleural effusion in children:

  • Infection (50% to 70%)
  • Congestive heart failure (5% to 15%)
  • Malignancy (10% to 15%)

Malignancy is a rare cause of pleural effusion in children. Non-Hodgkin lymphoma is the most common cause of MPE in children.[5][6][7][8]

Pathophysiology

Malignant pleural effusion occurs as a result of disruption of the homeostatic forces that control the flow and fluid in and out of the pleural cavity. The pressure in the pleural cavity is determined by the opposing forces of the elastic recoil of the lung and the pressure from the chest wall. The pleural fluid is not in a state of hydrostatic equilibrium. This is because the vertical gradient of the pleural fluid pressure is not equal to the hydrostatic pressure. This helps to create a movement of fluids in the pleural cavity. Pulmonary and cardiac mechanics also controls the net movement of fluid in the pleural cavity. The fluid in the pleural cavity is an ultrafiltrate from parietal pleura capillaries. The amount of fluid in the pleural cavity is regulated by a filtration rate that is matched by fluid outflow via the lymphatic stomata.

For the development of pleural effusion in malignancy, there must be:

  • An increase in the production of pleural fluid secondary to increased hydrostatic pressure
  • Decreased oncotic pressure or pleural pressure
  • Increased in the permeability of the microvasculature

The increased production of pleural fluid must be such that the lymphatic clearance is impeded by decreased hydrostatic pressure or blockage of lymphatic drainage.

History and Physical

The history and physical examination can help in the diagnosis of malignant pleural effusion. In the history, attention should be focused on the chief complaint.

Chief Complaint

  • Weakness
  • Malaise
  • Fever
  • Weight loss
  • Dyspnea
  • Chest pain

Physical Signs

Other physical signs of malignancy induced pleural effusions are:

  • Tachypnea
  • Tachycardia
  • Diaphoresis
  • Neck mass
  • Chest mass

Physical Examination

Patients should be examined in a position of comfort. Most patients with malignant pleural effusion usually have a mass in the mediastinal cavity that may cause respiratory distress or discomfort. The general appearance of a child with malignant pleural effusion may reveal a diaphoretic, dyspneic patient with mild to moderate respiratory distress.

Auscultation might reveal a pleuritic chest rub in the early stage which might gradually disappear as the accumulation of pleural fluid increases. Excessive accumulation of fluid might the cause displacement of the cardiac apex and the trachea to the contralateral side.

Examination of the affected side might show dullness to percussion with decreased tactile fremitus and egophony. This might be a diagnostic challenge in an uncooperative child.

Evaluation

Evaluation of patients with malignant pleural effusion (MPE) starts with a detailed history, physical examination, and ancillary studies. Eliciting the time of the onset of the symptoms is important. Family history of malignancy might also help in the diagnostic work.

Ancillary Studies

Chest X-ray

In most cases, a chest x-ray can help to confirm the size and location of the pleural effusion. It might not be able to delineate a small effusion. A chest x-ray might also show lobulated pleural thickening, atelectasis, consolidation and mediastinal widening. These radiological findings are highly suggestive of malignancy.

Chest Ultrasonography

This has close to 100% sensitivity in the detection of pleural effusion. The presence of pleural wall thickening of more than 10 mm, nodularity and diaphragmatic wall thickening of greater than 7 mm has high specificity in the diagnosis of MPE.

CAT Scan

CAT scan is a useful imaging study for MPE. It can determine the size, location, and extent of the effusion. CAT scan can also help in the identification of the primary or metastatic tumor causing the effusion. It is more superior in imaging quality than the chest x-ray and chest ultrasonography.

MRI

MRI has a limited role in the diagnostic imaging studies for pleural effusion probably because of poor spatial resolution.

Pleural Thoracentesis

This is a useful test that can serve both diagnostic and therapeutic purpose. If the pleural is hemorrhagic or exudative, a high index of suspicion should be entertained for malignancy. The pleural fluid should be analyzed for the following:

  • pH
  • Protein
  • Glucose
  • Lactate dehydrogenase
  • Red blood cells
  • White blood cells
  • Neutrophils
  • Basophils
  • Eosinophils

Cytology

In about 50% of cases, malignant cells might be detected in pleural fluids. Diagnostic yield is about 40% to 87%.

Using Lights criteria for pleural fluids, MPE is usually an exudate. In some rare cases, MPE might present as a transudate. In MPE, a parapneumonic effusion might develop, and the pleural fluid pH is usually below 7.3 with glucose level less than 60 mg/dl.

Lights Criteria

Lights criteria for exudative pleural fluid:

  • A ratio of the pleural protein to serum protein that is more than 0.5
  • A ratio of the pleural lactate dehydrogenase (LDH) to serum LDH that is more than 0.6
  • LDH of the pleural fluid that is more  than two-thirds the upper limit of serum LDH

Exudative Pleural Effusion

Common causes are a malignancy, parapneumonic effusion, and tuberculosis.

Transudative Pleural Effusion

Common causes are left ventricular failure, liver cirrhosis, and nephrotic syndrome.

Pleural Fluid Cytology

The diagnostic yield of cytology is dependent on several factors.

  • Number of specimens taken
  • Type of fixative solutions
  • Time for specimen transportation
  • Expertise of cytopathologist
  • Histopathology of the specimen
  • Nature and type of primary malignancy
  • Extent of disease
  • The use of cell blocks

The pleural fluid can also be analyzed for tumor markers. This is more commonly done in adults with pulmonary, breast, colon, ovary, and prostate cancer. Tumor markers are substances with a high molecular mass presence of which in the pleural fluid is associated with primary or metastatic malignancy. Tumor markers are useful as:

  • An adjunct in clinical diagnosis
  • Identification of metastases in the pleural cavity
  • Identification of the malignancy primary origin

Common Tumor Markers

  • Carcinoembryonic antigen (CEA)
  • Cancer antigens 15-3 (CA 15-3)
  • CA 72-4
  • CA 125
  • Carbohydrate antigen 19-9 (CA 19-9)
  • Cyfra 21-1
  • Cytokeratin fragment-21-1
  • Stage-specific embryonic antigen-1
  • Nonspecific enolase

Pleural Biopsy

This can be considered as a diagnostic tool. Needle biopsy of pleural tissue combined with fluid cytology of MPE can aid in diagnosis. The procedure can be done under local or general anesthesia.

Thoracoscopy

Thoracoscopy or pleuroscopy can be done using video-assisted thoracoscopy. The technique is relatively simple, and the procedure can be done under local or general anesthesia. Under local anesthesia, procedure can be done with a semi-rigid or rigid thoracoscope.

Diagnostic yield is around 95% to 97%. Finding on endoscopy suggestive of malignancy are pleural ulceration, multiple nodules, and polypoidal masses.

Bronchoscopy

This method is indicated in a patient with MPE with hemoptysis or with suspicion of the primary tumor originating from the bronchopulmonary tree.

Treatment / Management

The management of malignant pleural effusion required a multidisciplinary approach with coordinated care between pediatric hematologist-oncologist, a pediatric surgeon, and interventional radiologist. The most common cause of MPE in a pediatric population is non-Hodgkin lymphoma. The initial treatment which is chemotherapy should be directed towards the primary cause of the effusion.[9][10][11][12]

Thoracocentesis

The main goals of thoracentesis are:

  • Removal of the pleural effusion
  • Clinical improvement in symptoms
  • The prevention of   fluid re-accumulation

Thoracentesis for MPE is for both diagnostic and therapeutic purpose. Most patients with MFE will have a mass in the thoracic cavity causing respiratory compromise and difficulty breathing. Mild effusion can be monitored with serial x-ray and chest ultrasound while the patient is undergoing chemotherapy. For moderate to large effusion, thoracentesis using Seldinger technique can be utilized. For patients with large pleural effusion, it is better to remove the fluid slowly as aggressive removal of pleural fluid might lead to re-expansion pulmonary edema which can also compromise the respiratory status of the patient.

Tube Thoracostomy

For patients with a short life expectancy and recurrent MFE or very young patients under moderate anesthesia, a tube thoracostomy can be performed under local anesthesia. A 7 to 16 Fr chest tube can be utilized for drainage. The tube is usually inserted in the fourth or fifth intercostal space along the anterior or middle auxiliary line. The tube should not be in place for too long because of the risk of infection, bleeding or pneumothorax.

Pleurodesis

After the evacuation of MFE, the next step depending on the life expectancy of the patient is pleurodesis. Pleurodesis is the process of obliteration of the pleural space with the sole purpose of prevention of reaccumulation of pleural fluid. This is for patients who are expected to survive for more than 3 months.

Several agents can be used for pleurodesis.

Chemical Pleurodesis

Agents for chemical pleurodesis include:

  • Bleomycin
  • Tetracycline/doxycycline
  • Corynebacterium parvum extract
  • Silver nitrate
  • Iodopovidone, quinacrine
  • Interferons
  • Interleukin-2

Bleomycin as an agent for pleurodesis has a relatively high success rate in adults, close to 60% to 80\%.

Talc

Talc is also another effective substance that is widely used for pleurodesis. It can be applied as a poudrage or slurry. As a poudrage, talc is introduced into the pleural cavity in the form of a powder to irritate to opposing surface and seal the pleural cavity. A slurry is a combination of talc in 5% dextrose and a local anesthetic agent that can be instilled into the pleural cavity as a sealant.

The procedure can either be done conventionally or with video-assisted thoracoscopy (VAT).

Tunneled Indwelling Pleural Catheter

For a palliative purpose, patients with recurrent MFE can have a tunneled indwelling pleural catheter inserted under local anesthesia or moderate sedation. Intermittent drainage of the catheter can be done by the family member or qualified healthcare professional.

Complications

  • Pneumothorax
  • Hemothorax
  • Empyema
  • Obstruction with the development of tension pleural effusion

This method of palliative treatment has become popular as patients can be managed in an outpatient setting. Consequently, costs are less due to shorter hospitalization and reduced recovery time.

Pleuroperitoneal Shunt

This is a palliative measure that can be used for patients who are not candidates for pleurodesis. The procedure creates a chronic drainage system that connects the pleural and peritoneal cavity. It is rarely used in the pediatric population and only as a palliative measure in adults.

In summary:

  • Thoracentesis: Repeated aspiration of MPE is indicated for patients with a limited lifespan and is justified to provide symptomatic relief
  • Thoracostomy:  Indicated if survival is about a month or more to justify the risk and or benefit of thoracostomy
  • Pleurodesis: Indicated if survival is more tthan2 to 3 months.

Differential Diagnosis

The differential diagnosis of malignant pleural effusion should include other causes of pleural effusion. In pediatrics, the most common cause of pleural effusion is an infection. This is usually pneumonia with parapneumonic effusion. The causative organism for pneumonia and other infectious causes of pleural effusion has been discussed earlier. Pleural effusion from congestive heart failure should also be considered as fluid can accumulate in the pleural cavity from heart failure. Most of the heart failure in the pediatric population is from congenital heart diseases.

Chylothorax can develop pediatric patient with congenital heart disease after surgery. This might be due to:

  • Injury to the thoracic duct
  • Venous or lymphatic congestion
  • Central venous thrombosis

In any case, chylous fluid which has a milky white appearance can accumulate in the pleural fluid and cause significant effusion with respiratory compromise.

In the differential diagnosis, a detailed history and physical examination can help point the clinician in direction. Ancillary studies can assist with the history and physical examination. Thoracentesis with the pleural fluid analysis is especially useful. The Lights criteria can be used to differentiate between an exudate and a transudate. The level of glucose in the pleural fluid is similar to the level in the plasma. In MPE, the pleural fluid glucose level is usually lower than 60 mg/dl. The pH of the pleural fluid is usually lower than 7.3 in MPE. Pleural effusion secondary to infection is exudative in nature while effusion from heart failure is transudative. In MPE, it is sometimes very difficult to distinguish between the 2 types of effusion. However, in close to 95% of the MPE cases, the pleural fluid is exudative. Analysis of pleural fluid for malignant cells can sometimes be helpful albeit with false positive results. In adults, the pleural fluid might be sent for tumor markers to help in the identification of the primary tumor causing the effusion.

Prognosis

The prognosis of MPE depends on the primary tumor causing the effusion.

Complications

The most common complications from MPE are respiratory distress and respiratory failure.

The risk of respiratory failure or cardiovascular collapse is high if MPE is caused by a mediastinal mass compressing the trachea and other vital organs in the mediastinum.

Consultations

Management of MPE requires coordination of care between several subspecialties. The hematologist-oncologist is primarily responsible for the care of the patient and is responsible for the establishment of the initial diagnosis of the tumor. This might be a primary or metastatic that is causing the development of pleural effusion. The hematologist-oncologist initiates chemotherapy and/or radiation therapy. Management of the malignant pleural effusion usually has several options depending on the size, type, and location of the effusion. Thoracentesis, thoracotomy, pleurodesis, and placement of a pleuroperitoneal shunt are the treatment options utilized for MFE. This requires the involvement of either a pediatric surgeon, cardiothoracic surgeon, or interventional radiologist.

Palliative care and rehabilitation is also part of the treatment plan for patients with MFE.

Enhancing Healthcare Team Outcomes

The management of malignant pleural effusion required a multidisciplinary approach with coordinated care between pediatric hematologist-oncologist, a pediatric surgeon, and interventional radiologist. The most common cause of MPE in a pediatric population is non-Hodgkin lymphoma. The initial treatment which is chemotherapy should be directed towards the primary cause of the effusion. [13][14]

The management of the malignant pleural effusion usually has several options depending on the size, type, and location of the effusion. Thoracentesis, thoracotomy, pleurodesis, and placement of a pleuroperitoneal shunt are the treatment options utilized for MFE. This requires the involvement of either a pediatric surgeon, cardiothoracic surgeon, or interventional radiologist.

Palliative care and rehabilitation is also part of the treatment plan for patients with MFE. A pain specialist, oncology nurse and social work must be involved in the care of these patients.


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Pediatric Malignant Pleural Effusion - Questions

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Which of the following findings in pleural fluid of a child would make malignancy the most likely etiology?



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What is the most common cause of a malignant pleural effusion in children?



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A 17-year-old male presents to the emergency department with worsening respiratory symptoms. the patient has no significant past medical or surgical history. He complains that symptoms are worse at night or when he is lying down. Chest x-ray shows a widened mediastinum with a moderate size pleural effusion on the right side of the chest. What tumor most likely responsible for these findings?



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A 13-year-old with non-Hodgkin lymphoma was diagnosed with malignant pleural effusion in the right hemithorax. According to Light's criteria, what is the likely composition of the pleural fluid?



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A 15-year-old male with non-Hodgkin lymphoma was seen in the emergency department because of worsening dyspnea. The chest x-ray shows a widened mediastinum with a moderate size left-sided pleural effusion. What is the mechanism of the pleural effusion in this malignancy?



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Pediatric Malignant Pleural Effusion - References

References

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