CHAPTER (2): MALI GNANT PLEURAL EFFUSI ON

I ntroduction
Pleural effusions are a significant public health problem. Diagnosis of over 1 million
pleural effusions is estimated to occur yearly in the United States. Patients with pleural
effusions are frequently symptomatic with dyspnea and loss of function. Treatment goals
for these patients should focus on relief or elimination of dyspnea, restoration of normal
activity and function, minimization or elimination of hospitalization, and efficient use of
medical care resources. (Antunes G, Neville E. 2000)

Prevalence

Malignant pleural effusions occur commonly in patients with cancer. The malignancies
responsible for more than 75% of all of pleural effusions in order of frequency are lung,
breast, lymphoma, and ovarian cancer. In a general hospital setting, 25% of all pleural
effusions are malignant. In patients with an existing diagnosis of cancer, this increases to
30 to 70% if the fluid is an exudate. (Putnam J B. 2002)

I ncidence

Malignant pleural effusions are a common clinical problem in patients with neoplastic
disease. In one postmortem series, malignant effusions were found in 15% of patients who
died with malignancies .Although there have been no epidemiologic studies, the annual
incidence of malignant pleural effusions in the United States is estimated to be greater than
150,000 case. Malignant pleural effusion is also one of the leading causes of exudative
effusion; studies have demonstrated that 42 to 77% of exudative effusions are secondary to
malignancy. (American Thoracic Society 2000)

Etiology and Pathogenesis
Pleural effusions occur between two membranes: the visceral (inner) layer of the pleura
attached to the lungs, and the parietal (outer) layer attached to the chest wall. The pleural
space normally is nonexistent and is lubricated by a slight amount of pleural fluid (10 20
cc) that provides lubrication between the pleura. Fluid (sera) continuously moves from the
parietal pleura through the pleural space to be absorbed by the visceral pleura. The fluid is
then drained into the lymphatic system. The fluid in the pleural space is minimized by a
balance of Starling forces, oncotic pressure in the circulation, and negative pressure in the
lymphatics of the lungs. (J oe B. Putnam J r, MD.; 2002)

In patients with primary malignancies, metastasis to the pleural space
may cause significant shifts or fluid imbalance from derangements in the
Starling forces that regulate the reabsorption of fluid within the pleural
space. Movement of pleural fluid across the pleural space may involve over 5 to 10 L/d,
and derangements in this movement may increase the normal amount of pleural fluid from
5 to 50 cc to a more significant amount. Other disease processes may also significantly

affect the ability of the body to manage its intrapleural fluid. (J oe B. Putnam J r, MD

2002)

Pleural effusions may occur in patients with:

1. Increased capillary permeability caused by inflammation, infection, or pleural metastasis.

2. Increased hydrostatic pressure as results from congestive heart failure.

3. Decreased oncotic pressure from hypoalbuminia.

4. Increase in the normal negative pressure (more negative intrathoracic press ure) secondary
to atelectasis.
5. Impaired or decreased lymphatic drainage secondary to obstruction of the normal
lymphatic channels by tumor, radiation, or chemotherapy induced fibrosis. (Mountain CF.
1997)
Diagnostic Approaches

1. Clinical M anifestations

History

A detailed medical history should be obtained from all patients presenting with a
pleural effusion, as this may help to establish the etiology. History of chronic hepatitis or
alcoholism with cirrhosis suggests hepatic hydrothorax or alcohol-induced pancreatitis
with effusion. Recent trauma or surgery to the thoracic spine raises the possibility of a CSF
leak. The patient should be asked about a history of cancer, even remote, as malignant
pleural effusions can develop many years after initial diagnosis. An occupational history
should also be obtained, including potential asbestos exposure, which could predispose the
patient to mesothelioma or asbestos pleural effusion. The patient should also be asked
about medications they are taking. (Sahn SA. 2006)

Dyspnea

Dyspnea is the most common symptom associated with pleural effusion and is related
more to distortion of the diaphragm and chest wall during respiration than to hypoxemia.
In many patients, drainage of pleural fluid alleviates symptoms despite limited
improvement in gas exchange. Drainage of pleural fluid may also allow the underlying
disease to be recognized on repeat chest radiographs. Note that dyspnea may be caused by
the condition producing the pleural effusion, such as underlying i ntrinsic lung or heart
disease, obstructing endobronchial lesions, or diaphragmatic paralysis, rather than by the
effusion itself. (Khaleeq G, Musani AI . 2008)

Cough

Cough in patients with pleural effusion is often mild and nonproductive. More severe
cough or the production of purulent or bloody sputum suggests an underlying pneumonia
or endobronchial lesion. (Khaleeq G, Musani AI . 2008)
Chest pain

The presence of chest pain, which results from pleural irritation, raises the likelihood of an
exudative etiology, such as pleural infection, mesothelioma, or pulmonary infarction. Pain
may be mild or severe. It is typically described as sharp or stabbing and is exacerbated
with deep inspiration. Pain may be localized to the chest wall or referred to the ipsilater al
shoulder or upper abdomen, usually because of diaphragmatic involvement. Pain often
diminishes in intensity as the pleural effusion increases in size. (Froudarakis ME. 2008)

Additional symptoms

Other symptoms in association with pleural effusions may suggest the underlying
disease process. Increasing lower extremity edema, orthopnea, and paroxysmal nocturnal
dyspnea may all occur with congestive heart failure. Night sweats, fever, hemoptysis, and
weight loss should suggest TB. Hemoptysis also raises the possibility of malignancy, other
endotracheal or endobronchial pathology, or pulmonary infarction. An acute febrile
episode, purulent sputum production, and pleuritic chest pain may occur in patients with an
effusion associated with pneumonia. (Wong CL, Holroyd-Leduc J .; 2009)

Physical Examination


Physical findings in pleural effusion are variable and depend on the volume of the
effusion. Generally, there are no physical findings for effusions smaller than 300 mL. With
effusions larger than 300 mL, findings may include the following:

Dullness to percussion, decreased tactile fremitus, and asymmetrical chest
expansion, with diminished or delayed expansion on the side of the effusion, are the
most reliable physical findings of pleural effusion. (Wong CL, Holroyd-Leduc J ,
2009)
Mediastinal shift away from the effusion - This is observed with effusions of greater
than 1000 mL; displacement of the trachea and mediastinum toward the side of the
effusion is an important clue to obstruction of a lobar bronchus by an endobronchial
lesion, which can be due to malignancy or, less commonly, to a nonmalignant cause,
such as a foreign body.
Diminished or inaudible breath sounds.

Egophony ("e" to "a" changes) at the most superior aspect of the pleural effusion.

Pleural frictions rub. (Kalantri S, et al. 2007)


Other physical findings, as follows, may suggest the underlying cause of the pleural
effusion:

Peripheral edema, distended neck veins, and S3 gallop suggest congestive heart
failure. Edema may also be a manifestation of nephrotic syndrome; pericardial
disease; or, combined with yellow nails, the yellow nail syndrome.
Cutaneous changes with ascites suggest liver disease.

Lymphadenopathy or a palpable mass suggests malignancy. (Sahn SA. 2006)










2. Imaging Techniques


Chest CT scanning with contrast should be performed in all patients with an
undiagnosed pleural effusion, if it has not previously been performed, to detect thickened
pleura or signs of invasion of underlying or adjacent structures. The 2 diagnostic
imperatives in this situation are pulmonary embolism an d tuberculous pleuritis. In both
cases, the pleural effusion is a harbinger of potential future morbidity. In contrast, a short
delay in diagnosing metastatic malignancy to the pleural space has less impact on future
clinical outcomes.. (Gurung P, et al.; 2011)

Most patients presenting with malignant pleural effusions have some degree of dyspnea
on exertion and their chest radiographs show moderate to large pleural effusions ranging
from approximately 500 to 2,000 ml. While only 10% of patients have massive pleural
effusions on presentation, malignancy is the most common cause of massive pleural
effusion. Massive pleural effusions are defined as those effusions occupying the entire
hemithorax. About 15% of patients, however, will have pleural effusions < 500 ml in
volume and will be relatively asymptomatic. An absence of contralateral mediastinal shift
in these large effusions implies fixation of the mediastinum, main stem bronchus occlusion
by tumor (usually squamous cell lung cancer), or extensive pleu ral involvement (as seen
with malignant mesothelioma). (American Thoracic Society 2000)

Computerized tomography (CT) scans of patients with malignancies may identify
previously unrecognized small effusions. They may also aid in the evaluation of patie nts
with malignant effusions for mediastinal lymph node involvement and underlying
parenchymal disease, as well as in demonstrating pleural, pulmonary, or distant
metastases; identification of pleural plaques suggests asbestos exposure. Ultrasonography
may aid in identifying pleural lesions in patients with malignant effusions and can be
helpful in directing thoracentesis in patients with small effusions and avoiding
thoracentesis complications. (Benard F, et al.; 1998)

The role of magnetic resonance imaging (MRI) in malignant effusions appears limited,
but MRI may be helpful in evaluating the extent of chest wall involvement by tumor.
There is little information available on the utilization of fluorodeoxyglucose positron
emission tomography (PET scanning) in malignant pleural effusions, although it has been
reported as helpful in evaluating the extent of disease in malignant mesothelioma. (Bittner

RC, Felix R.; 1998)


Diagnostic Thoracentesis


Background

Thoracentesis (thoracocentesis) is a core procedural skill for hospitalists, critical care
physicians, and emergency physicians. With proper training in both thoracentesis itself and
the use of bedside ultrasonography, providers can perform this procedure safely and
successfully. Before the procedure, bedside ultrasonography can be used to determine the
presence and size of pleural effusions and to look for loculations. During the procedure, it
can be used in real time to facilitate anesthesia and then guide needle placement. (Duncan
DR, Daniels CE. 2009)

I ndications

Thoracentesis is indicated for the symptomatic treatment of large pleural effusions (see the
images below) or for treatment of empyemas. It is also indicated for pleural effusi ons of
any size that require diagnostic analysis. (Porcel J M. 2009)




















Figure (1): chest X-ray showing large left pleural effusion before and after

thoracocentesis.


Transudative effusions result from decreased plasma oncotic pressures and increased
hydrostatic pressures. Heart failure is by far the most common cause, followed by liver
cirrhosis and nephrotic syndrome. (Chaiyakunapruk N. et al.; 2002)



Exudative effusions result from local destructive or surgical processes that cause increased
capillary permeability and subsequent exudation of intravascular components into potential
spaces. Causes are manifold and include pneumonia, empyema, cancer, pulmonary
embolism, and numerous infectious etiologies. (Chaiyakunapruk N. et al.; 2002)



Contraindications

Relative contraindications to diagnostic thoracentesis include a small volume of fluid (<

1 cm thickness on a lateral decubitus film), bleeding diathesis or systemic anticoagulation,
mechanical ventilation, and cutaneous disease over the proposed puncture site. Mechanical
ventilation with positive end-expiratory pressure does not increase the risk of
pneumothorax after thoracentesis, but it increases the likelihood of severe complications
(tension pneumothorax or persistent bronchopleural fistula) if the lung is punctured.

(Duncan DR, 2009)
Complications
Complications of diagnostic thoracentesis include pain at the puncture site, cutaneous or

internal bleeding, pneumothorax, empyema, and spleen/liver puncture. Pneumothorax
complicates approximately 12-30% of thoracentesis but requires treatment wit h a chest
tube in less than 5% of cases. Use of needles larger than 20 gauge increases the risk of a
pneumothorax complicating the thoracentesis. In addition, significant chronic obstructive
or fibrotic lung disease increases the risk of a symptomatic pneumothorax complicating the
thoracentesis. (Duncan DR, 2009)


3. Closed Pleural Biopsy


Historical view

Pleural diseases involve the parietal and visceral pleura and may be of either
inflammatory or malignant origin, often resulting in pleural effusions. The diagnostic
evaluation of pleural effusions includes chemical and microbiological studies, as well as
cytological analysis, which can provide further information about the etiological disease
process. However, 40% of pleural effusions remain undiagnosed after an initial
thoracocentesis. (Salyer WR, 1975)

Pleural biopsy is recommended for evaluation and exclusion of infectious etiologies
such as tuberculosis or malignant disease, particularly malignant mesothelioma.
Connective tissue disorders such as rheumatoid disease can also present with pleural
involvement, requiring pleural biopsy for diagnosis. In addition, pleural thickening in the
absence of pleural effusion may require further histological evaluation. It is important to
understand that the etiology of pleural effusion remains unclear in nearly 20% of cases.

(Prakash UB, Reiman HM. 1985)


Various biopsy techniques are available to diagnose pleural disease. These range from
older techniques, such as blind or closed pleural biopsy, to newer techniques including
image-guided and thoracoscopic biopsy. The latter techniques have higher diagnostic yield
and provide better diagnostic sensitivity. In addition, the use of immunohistochemistr y
provides increased diagnostic accuracy. (Koss MN, 1998)


Indications and results


Indications for pleural biopsy include the following:

1. Recurrent pleural effusion of unknown etiology.

2. Pleural mass or thickening. (Ernst A, 2003)

Normal Results

The pleural tissues appear normal, without signs of inflammation, infection, or cancer.
Normal value ranges may vary slightly among different laboratories. (Broaddus VC, Light
RW. 2010)

Abnormal Results

Abnormal results may reveal cancer (including primary lung cancer, malignant
mesothelioma, and metastatic pleural tumor), tuberculosis, a viral disease, a fungal disease,
a parasitic disease, or collagen vascular disease. (Broaddus VC, Light RW. 2010)

Complications
The flexible-rigid pleuroscope is considered to be a safe procedure, with no morbidity or
mortality observed in a study of 51 patients. The major concern of the procedure is pleural
hemorrhage from underlying intercostal blood vessels. (Lee P, Hsu A, 2007)

Immediate pressure using forceps and a small piece of gauze can be applied to control
bleeding. If bleeding is significant, an additional incision should be considered to access
the pleural cavity in order to perform tissue cauterization. If bleeding is not controlled with
direct pressure and cauterization, ligation of the bleeding vessels with endoclips should be
considered. Ongoing bleeding may require thoracotomy. Other common complications
include prolonged air leak, subcutaneous emphysema, post procedure wounds infections
including empyema, and chest wall metastasis from mesothelioma. (Lee P, Mathur PN,
2010)


4. Medical Thoracoscopy

Medical thoracoscopy/pleuroscopy is a minimally invasive procedure that allows
access to the pleural space using a combination of viewing and working instruments. It
also allows for basic diagnostic (undiagnosed pleural fluid or pleural thickening) and
therapeutic procedures (pleurodesis) to be performed safely. This procedure is distinct
from video-assisted thoracoscopic surgery, an invasive procedure that uses sophisticated
access platform and multiple ports for separate viewing and working instruments to access
pleural space. It requires one-lung ventilation for adequate creation of a working space in
the hemithorax. Complete visualization of the entire hemithorax, multiple angles of attack
to pleural, pulmonary (parenchymal), and mediastinal pathology with the ability to
introduce multiple instruments into the operative field allows for both basic and advanced
procedures to be performed safely. (Chen LE, et al. 2002)
Complications of medical thoracoscopy/pleuroscopy are uncommon. They include
bleeding, infection of the pleural space, and injury to intrathoracic organs, atelectasis, and
respiratory failure. (Seijo LM, Sterman DH. 2001)

5. Bronchoscopy


Introduction

Bronchoscopy allows a doctor to examine inside your airway for any abnormality such
as foreign bodies, bleeding, a tumor, or inflammation. The doctor uses either a rigid
bronchoscope or flexible bronchoscope. (Prakash UB. 1999)


Indications

1. Common reasons to perform a bronchoscopy for diagnosis are:
2. Lung growth, lymph node, atelectasis, or other changes seen on any imaging test

3. Suspected interstitial lung disease

4. Coughing up blood (hemoptysis)

5. Possible foreign object in the airway

6. Cough that has lasted more than 3 months without any ot her explanation

7. Infections in the lungs and bronchi that cannot be diagnosed any other way or need a
certain type of diagnosis
8. Inhaled toxic gas or chemical

9. To diagnose a lung rejection after a lung transplant (Kraft M. 2011)

10. You may also have a bronchoscopy to treat a lung or airway problem, such as to:


Remove fluid or mucus plugs from your airways

Remove a foreign object from your airways

Widen (dilate) an airway that is blocked or narrowed

Drain an abscess
Treat cancer using a number of different techniques

Wash out an airway (therapeutic lavage) (Kraft M. 2011)


Risks
The main risks from bronchoscopy are:

1. Bleeding from biopsy sites

2. Infection

3. Arrhythmias

4. Breathing difficulties

5. Fever

6. Heart attack, in people with existing heart disease

7. Low blood oxygen

8. Pneumothorax

9. Sore throat (Reynolds HY. 2011) (Kupeli E, 2010)

6. Surgical Biopsy


Video-assisted thoracic surgery (VATS) procedures usually require general anesthesia
and single-lung ventilation. The surgeon may undertake a more extensive pro cedure than
medical thoracoscopy, using several ports, and often combining diagnosis with treatment.
VATS is contraindicated and open biopsy is preferred when the patient cannot tolerate
single-lung ventilation (e.g., patient undergoing mechanical ventilat ion, prior contralateral
pneumonectomy, or abnormal airway anatomy precluding placement of double -lumen
endotracheal tube), if the pleural space contains adhesions that would prevent the safe
insertion of the examining thoracoscope, and if there is insuffi cient expertise to deal with
the complications of the procedure. Adhesions may be evident preoperatively on chest
radiographs or on pleural ultrasound and may lead to the decision to undertake open
biopsy. Often, however, this situation is appreciated for the first time at a VATS
examination, and the surgeon must therefore be ready to convert to an open procedure.
Adhesions frequently result from previous pleurodesis attempts but may also follow
repeated thoracentesis for diagnosis or therapy. (McKneally MF, Lewis RJ .; 1992)


Treatment

The patients symptoms, functional status, life expectancy, and the type of tumor
responsible for MPE should be kept in mind when considering therapeutic options as
discussed later. In MPE associated with breast cancer and s mall cell lung cancer,
chemotherapy may be all that is required. Similarly, radiation may suffice for the MPE
associated with lymphoma, precluding any further intervention. (Khaleeq G, Musani A.
2008)

Therapeutic thoracentesis should be performed in each case, not only to establish a
cytological diagnosis, but also to document symptomatic improvement and the presence or
absence of trapped lung. Lack of symptomatic improvement after thoracentesis may
dissuade one from further interventions. A diagnosis of t rapped lung should prompt one to
consider strategies other than chest tube insertion and talc pleurodesis, such as indwelling
pleural catheters. Symptomatic, recurrent, and recalcitrant (to chemotherapy or radiation
therapy) MPEs should be addressed with a definitive, palliative care plan. (Pien GW, Gant
M, 2001)