CHAPTER (2): MALIGNANT PLEURAL EFFUSION IntroductionPleural 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)

PrevalenceMalignant 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 JB. 2002)

IncidenceMalignant 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. (Joe B. Putnam Jr, 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. (Joe B. Putnam Jr, 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 anifestationsHistory 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 TechniquesChest 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 ThoracentesisBackground 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) Indications 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 JM. 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 BiopsyHistorical 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. 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

2.

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 ThoracoscopyMedical 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. BronchoscopyIntroduction 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. 2. 3. 4. 5. 6. 7. Common reasons to perform a bronchoscopy for diagnosis are: Lung growth, lymph node, atelectasis, or other changes seen on any imaging test Suspected interstitial lung disease Coughing up blood (hemoptysis) Possible foreign object in the airway Cough that has lasted more than 3 months without any ot her explanation 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 To diagnose a lung rejection after a lung transplant (Kraft M. 2011) 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

9.10.

� Treat cancer using a number of different techniques

� Wash out an airway (therapeutic lavage)Risks The main risks from bronchoscopy are: 1. 2. 3. 4. 5. 6. 7. 8. 9. Bleeding from biopsy sites Infection Arrhythmias Breathing difficulties Fever

(Kraft M. 2011)

Heart attack, in people with existing heart disease Low blood oxygen Pneumothorax Sore throat (Reynolds HY. 2011) (Kupeli E, 2010)

6. Surgical BiopsyVideo-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)

TreatmentThe patient ’s 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)