**5. Pleura and fluid characteristics**

Once a pleural effusion is documented, diagnostic or therapeutic thoracentesis should be performed to establish the nature of the effusion. For adequate separation of transudates and exudates in pleural fluid, protein and LDH levels are determined and also the following tests on pleural fluid are recommended: description of the fluid; cell count and differential; glucose; pH particularly if the patient has a parapneumonic effusion; cytology; smears and cultures for bacteria, mycobacteria, and fungi; and adenosine deaminase (ADA) if tuberculous pleuritis is in the differential [32].

Effusions are classified as either exudative or transudative basing on established criteria and now commonly known as Light's criteria: [33]


This defines an exudate if any one of three criteria are met. The overall accuracy of these criteria is 93% to 95% [34, 35]. Light criteria have commonly misclassify effusions when any one of three criteria has a value close to its cutoff point [36]. Although the majority of malignant pleural effusions are exudates, it is important to keep in mind that a few are transudates [37, 38]. These circumstances result from the defective implementation of diagnostic rules that classify pleural effusions or coexisting conditions with transudates, such as hypoalbuminemia, cirrhosis with ascites, or chronic heart failure [39]. This does not suggest that every individual with a transudative pleural effusion should have pleural fluid cytological examination. However, in the appropriate clinical setting and the absence of congestive heart failure or a pleural fluid LDH level close to the exudative range, determination of pleural fluid cytology is suggested [17].

The primary problem with the Light criteria is that they identify 15% to 20% of transudative effusions as exudative effusions [40]. A re-evaluation of Light's criteria demonstrates that Light's criteria have an overall sensitivity for an exudate of near 100%, but a specificity of only approximately 80% [41]. In the search for the ideal test or improvement of Light's criteria; from the first day of Light criteria that were published the most widely accepted and so far have stood the test of time. Based on a meta-analysis of study in order to find the ideal diagnostic criteria, including 1448 patients, an updated version of Light's criteria, the original light studies a slightly modified by the addition of cholesterol as a marker, recommended as the best way to determine exudate. Judged by these criteria, a patient with any of the following criteria is provided, said to be exudates [42]:

**•** Pleural fluid protein greater than 2.9 g/dL

fluid and is superior to CT for characterization of collections for the presence of septations and

Computed tomography (CT) scanning is even more accurate in detecting small effusions, including as little as 2 mL of fluid. The volume of the fluid presence can be best determined radiographically by using three-dimensional reconstruction [26]. Currently, the most useful radiographic study is a chest CT scan. CT scans help to establish the presence of a loculated pleural effusion, allow the evaluation of the pulmonary parenchyma if there is not complete lung compression, and distinguish pleural thickening from effusion. It also provides an excellent way to evaluate the mediastinum for the presence of masses or lymphadenopathy

The role of magnetic resonance imaging (MRI) in the evaluation of pleural effusions is limited; however, it may be beneficial in better characterizing possible tumour involvement of the chest wall or diaphragm [28]. Neither MRI nor CT scan can distinguish transudates from exudates accurately although both can be helpful in evaluating the pleural contents for masses, nodules,

Positron emission tomography (PET scan) with 18F-fluorodeoxyglucose provides less ana‐ tomic information but has the potential advantage of providing diagnostic information about the effusion. This information may prove useful [30]. The true value of a PET scan would be to provide additional information about disease elsewhere, not to give a diagnosis of malig‐ nancy. In addition, diagnosis or treatment of a malignant effusion will depend on the type of

Once a pleural effusion is documented, diagnostic or therapeutic thoracentesis should be performed to establish the nature of the effusion. For adequate separation of transudates and exudates in pleural fluid, protein and LDH levels are determined and also the following tests on pleural fluid are recommended: description of the fluid; cell count and differential; glucose; pH particularly if the patient has a parapneumonic effusion; cytology; smears and cultures for bacteria, mycobacteria, and fungi; and adenosine deaminase (ADA) if tuberculous pleuritis is

Effusions are classified as either exudative or transudative basing on established criteria and

**2.** Ratio of pleural fluid lactate dehydrogenase (LDH) to its serum concentration is greater

**3.** LDH concentration in pleural effusion is greater than two thirds of the upper normal value

**1.** Ratio of pleural fluid protein to serum protein concentration is greater than 0.5

loculations [25].

88 Principles and Practice of Cardiothoracic Surgery

and permits detection of pleural-based nodules [27].

and pleural based thickening once the fluid is removed [29].

cancer, and this cannot be determined with a PET scan [31].

**5. Pleura and fluid characteristics**

now commonly known as Light's criteria: [33]

in the differential [32].

than 0.6

for the serum LDH


The appearance of the pleural fluid obtained by thoracentesis, its consistency and color should be noted. In patients with a known underlying malignancy, it is daily practice not only to obtain the usual tests to differentiate a transudate from an exudate (total protein and lactate dehy‐ drogenase both in the fluid and in the serum) but also to obtain total and differential cell count, pH, glucose level, cholesterol and triglycerides, cytological analysis, hematocrit (if fluid is grossly bloody), and cultures. [37, 38].

Malignant pleural effusions may be serous, serosanguineous, or bloody, and usually are exudative in nature [21]. There are four characteristics features of pleural effusion; suggesting malignancy in patients with undiagnosed pleural effusion: that is to say, [1] a symptomatic period of more than a month, [2] absence of fever, [3] blood-tinged or bloody pleural fluid, or [4] CT findings suggestive of malignancy (pulmonary or pleural masses, pulmonary atelecta‐ sis, or lymphadenopathy) [43].

Despite all the progress in the imaging of the chest, for the diagnosis of MPE cytologic or tissue biopsy is required for approval. Cytology is the simplest definitive and most accurate method to diagnose malignant pleural effusion. Recent data suggests that at least 50 mL of pleural fluid should be studied in order to provide optimal cytological analysis [44, 45].

Diagnostic success of cytology can improve with repeated thoracentesis [46]. Fluids should be concentrated first for optimal detection of malignancy. There is a large variation in diagnostic yields of pleural fluid cytology ranging from 62 to 90% [47, 48]. The sensitivity depends on the type of malignancy, extent of disease, and experience of the cytopathologist [49].

In general, cell counts obtained from the pleural fluid is rarely useful or pathognomonic. Because most cells are normally neutrophils or monocytes, a predominance of lymphocytes (>50%) should make one more seriously entertain the idea of a carcinomatous pleural effusion, and greater than 85% lymphocytes should make one entertain the diagnosis of lymphoma, sarcoidosis, chylothorax, rheumatoid pleurisy, or yellow nail syndrome [66, 67]. An increase in pleural fluid eosinophilia (>10% of nucleated cells) might be associated with benign disease (hemo- or pneumothorax), but also can be associated with all types of malignancy [68]. The

Management of Malignant Pleural Effusion http://dx.doi.org/10.5772/54441 91

Several tumor markers have been used in diagnosing of MPE, but their clinical role has not been firmly established [70]. Higher levels of CEA are seen in squamous cell cancer and adenocarcinoma of lung while higher levels of CA 15-3 are observed in breast cancer [71]. The addition of any tumor marker assay would improve the diagnostic value of cytology [70].

Chromosome analysis has low sensitivity and specificity in diagnosing of MPE [71]. It may be

The molecular biology of pleural effusions has begun to be understood, with vascular endothelial growth factor (VEGF) emerging as a major role player [73]. Because it induces endothelial vasodilatation and enhances the permeability of the mesothelium 50,000 times more potently than histamine, VEGF is thought to be a major, if not the most important, cytokine in the etiology of effusions [74]. VEGF may be a part of the diagnosis of effusion in

MPE has a wide variety of diagnostic methods. Diagnostic methods are often chosen according to health care provider's medical facilities, the clinician's ability and most importantly the patient. In spite of all the advances in today's thoracic imaging confirmation of suspected malignant pleural effusion done by cytological methods or a pleural biopsy, a diagnostic thoracentesis is recommended for any unilateral effusion or bilateral effusion in an individual without obvious evidence of congestive heart failure [75]. Diagnostic thoracentesis is a useful initial approach for patients with MPEs. Thoracentesis takes place in diagnosis of MPE as well as reducing the symptoms. Thoracentesis also helps us in evaluation of the expansion capacity

Traditionally, land selection for thoracentesis is determined by radiographic and physical examination findings [76]. There is no absolute contraindication for thoracentesis. Relative contraindications include a minimal effusion < 1 cm in thickness from the fluid level to the chest wall on a lateral decubitus view, bleeding diathesis, anticoagulation, and mechanical ventilation. There is no increased bleeding in patients with mild-to moderate coagulopathy or thrombocytopenia (prothrombin time or partial thromboplastin time >1.8 times normal,

risk of pneumothorax in patients undergoing mechanical ventilation; if a pneumothorax

, or creatinine >6 mg/dL) [77]. Although it does not seem to increase the

presence of mesothelial cells is not helpful in terms of diagnosis [67, 69]

helpful particularly with MPE secondary to lymphoma and leukaemia [72]

the future.

**6. Diagnosis**

platelets <25,000/mm3

of the lung and relieving acute symptoms.

Cytology of MPE in breast cancer has a sensitivity of 47% [50]. The diagnosis of adenocarci‐ nomas can be established in nearly all patients whereas patients with pleural effusions secondary to Hodgkin's disease, have a positive cytologic examination in less than 25% of cases [51, 52]. Cytology is superior to blind percutaneous pleural biopsy in the diagnosis of malig‐ nant pleural effusion. Blind percutaneous pleural biopsy carries an 8% risk of pneumothorax, and has limited contribution to the diagnosis of patient with suspected malignancy. In a series of 118 patients with pleural effusions and negative cytology, closed pleural biopsy established the diagnosis of malignant pleural effusion in only 17% of the cases [53].

Low diagnostic value of pleural biopsy depends on costal pleural involvement of cancer cells in only half of patients with MPE since initial metastatic disease most commonly occurs on the visceral, mediastinal, and diaphragmatic pleurae [54].

After thoracentesis, pleural biopsy might be indicated in cases with cytological examination undiagnosedor suspected.Diagnosticvalueof conventional closedpleuralbiopsywithAbrams or Cope needles is lower when compared with image-guided and thoracoscopic biopsy techni‐ ques. The specificity of closed needle biopsy for MPE is high, but case series report sensitivities that range from 7% to 72% [53, 55-57]. However, closed pleural biopsy adds little to the cytolog‐ icaldiagnosisinmostcasesandthisisrelatedtothescarceandirregulardistributionofthetumour lesions in the pleural cavity when cytology is negative [54]. The yield of blind needle biopsy is higher when the pleural lesions are diffuse, as in tuberculosis and advanced neoplastic disease. In contrast, thoracoscopy has a very high yield in malignant effusions. It can be performed with localanesthesiaandasingleportofentry,andithasalittlemorecomplicationsthanneedlebiopsy [47]. Contraindications to pleural biopsy include bleeding diathesis, anticoagulation, chest wall infection, and lack of patient cooperation. Important complications include pneumothorax, haemothorax, and vasovagal reactions. A rapid clinical deterioration or increased postproce‐ dure effusion should alert the clinician to a possible haemothorax [58]. Nevertheless, pleural needle biopsy can be performed on outpatient basis [59] whereas thoracoscopy is much more complex and always requires hospitalization.

Normal pleural fluid pH ranges from 7.60 to 7.64. When a diagnostic thoracentesis is per‐ formed, pleural fluid pH is measured at any time. Analysis should be via a blood gas machine, not on litmus paper, because the latter is unreliable and not an acceptable alternative [60]. Approximately one-third of malignant effusions have a pleural fluid pH of <7.30 at presenta‐ tion [61, 62]; this low pH is associated with glucose values of <60 mg/dL [63]. The cause of these low-glucose, low-pH malignant effusion appears to be an increased tumour mass within the pleural space compared with those with a higher pH effusion, resulting in decreased glucose transfer into the pleural space and decreased efflux of the acidic by-products of glucose metabolism, carbon dioxide (CO2], and lactic acid, due to an abnormal pleural membrane [64, 65]. Clinicians should keep in mind that parapneumonic effusions have pH less than 7.3 or puslike looking.

In general, cell counts obtained from the pleural fluid is rarely useful or pathognomonic. Because most cells are normally neutrophils or monocytes, a predominance of lymphocytes (>50%) should make one more seriously entertain the idea of a carcinomatous pleural effusion, and greater than 85% lymphocytes should make one entertain the diagnosis of lymphoma, sarcoidosis, chylothorax, rheumatoid pleurisy, or yellow nail syndrome [66, 67]. An increase in pleural fluid eosinophilia (>10% of nucleated cells) might be associated with benign disease (hemo- or pneumothorax), but also can be associated with all types of malignancy [68]. The presence of mesothelial cells is not helpful in terms of diagnosis [67, 69]

Several tumor markers have been used in diagnosing of MPE, but their clinical role has not been firmly established [70]. Higher levels of CEA are seen in squamous cell cancer and adenocarcinoma of lung while higher levels of CA 15-3 are observed in breast cancer [71]. The addition of any tumor marker assay would improve the diagnostic value of cytology [70].

Chromosome analysis has low sensitivity and specificity in diagnosing of MPE [71]. It may be helpful particularly with MPE secondary to lymphoma and leukaemia [72]

The molecular biology of pleural effusions has begun to be understood, with vascular endothelial growth factor (VEGF) emerging as a major role player [73]. Because it induces endothelial vasodilatation and enhances the permeability of the mesothelium 50,000 times more potently than histamine, VEGF is thought to be a major, if not the most important, cytokine in the etiology of effusions [74]. VEGF may be a part of the diagnosis of effusion in the future.
