Alexander Chen
Pleural Effusion
GENERAL PRINCIPLES
· A pleural effusion is the abnormal accumulation of fluid in the pleural space. The pleural space normally contains only a small amount of fluid that is not radiographically apparent.
· Effusions are categorized into two types: transudates and exudates. This differentiation is defined by laboratory testing and identifies effusions secondary to diseases that do not directly damage the pleural surfaces (transudates) versus diseases that do directly damage the pleural surfaces (exudates). This designation is important since the management of the two types of effusions is distinctly different.
o Transudative pleural effusions result from alteration of hydrostatic and oncotic factors that increase the formation or decrease the absorption of pleural fluid (e.g., increased mean capillary pressure [heart failure] or decreased oncotic pressure [cirrhosis or nephrotic syndrome]).
o Exudative pleural effusions occur when damage or disruption of the normal pleural membranes or vasculature (e.g., tumor involvement of the pleural space, infection, inflammatory conditions, or trauma) leads to increased capillary permeability or decreased lymphatic drainage.
· When transudative effusions are identified, the underlying systemic disease should also be identified (heart failure [HF], liver disease, kidney disease) and treatment should be directed toward the primary disorder.
· Exudative effusions frequently indicate a process (malignancy, infection, etc.) that directly injures the pleura and deserves further investigation and therapy, typically focused on the pleural space.
· Pleural effusions occur in a wide variety of disease states; however, 90% of pleural effusions are the result of only five diseases: HF (36%), pneumonia (22%), malignancy (14%), pulmonary embolism (PE) (11%), and viral disease (7%).1
DIAGNOSIS
Clinical Presentation
· The underlying cause of the effusion typically dictates the symptoms, although patients may be asymptomatic. Pleural inflammation, abnormal pulmonary mechanics, and worsened alveolar gas exchange produce symptoms and signs of disease.
· Inflammation of the parietal pleura leads to pain in locally involved areas (intercostal) or referred distributions (e.g., shoulder pain from phrenic nerve).
· Dyspnea is frequent and may be present out of proportion to the size of the effusion. Cough can occur.
· Clinical signs of pleural effusion include chest pain, dyspnea, and cough, though these are neither sensitive nor specific for diagnosing a pleural effusion.
· Unfortunately, a definitive diagnosis based upon pleural fluid analysis is possible in less than half of all effusions. Therefore, it is important to define the clinical setting of a pleural effusion with a thorough history and physical examination to aid in diagnosis.
· Obtain a detailed history with review of systems to identify symptoms of HF, underlying malignancy, PE, myocardial infarction, surgery or trauma, connective tissue diseases, or other underlying or recent infections.
· Social history focused on smoking history and possible TB exposures.
· Family history focused on malignancy, heart disease, and connective tissue diseases.
· Signs of a pleural effusion on physical exam include asymmetric chest wall expansion, dullness to percussion, diminished breath sounds, and the presence of a pleural rub.
Diagnostic Testing
Imaging
· Prior to any invasive diagnostic or therapeutic procedure, the patient should undergo imaging to confirm the presence, character, and size of the effusion.
· Pleural effusions are often initially detected by plain chest radiography (CXR).
o Effusions are seen as blunting of the costophrenic angle or opacification of the base of the hemithorax without loss of volume of the hemithorax (which would suggest atelectasis) or presence of air bronchograms (which would suggest pneumonia).
o CXR can also detect masses or infiltrates that may give clues to an etiology.
o Decubitus chest films are frequently obtained to demonstrate that at least a portion of the fluid is not loculated and therefore, amenable to thoracentesis (see Table 19-1 and Figure 19-1).
· Computed tomography (CT) with contrast given by PE protocol is recommended if PE is suspected.
o CT without contrast is adequate for the evaluation of pleural effusion if PE is clinically less likely.
o CT can be used to further define masses, lymphadenopathy, or other abnormal findings on chest radiography.
o CT with contrast given by standard protocol (in which the images are timed such that the contrast bolus is in the systemic vasculature) helps differentiate pleural fluid from lung masses and atelectatic lung; it also serves to identify and define the extent of pleural fluid thickening and pleural nodularity.
· Ultrasound is one of the best modalities to assess for pleural fluid loculations.
o It provides real-time guidance for pleural procedures and can reduce both the complications and failure rate of thoracentesis.
o Ultrasound of the pleural space may be used to characterize pleural fluid as well as pleural space anatomy (e.g., presence of septations and adhesions).
o Ultrasound of the pleural space may guide management for pleural drainage procedures, as in tube thoracostomy versus thoracentesis for loculated pleural effusions and surgical versus medical management for complex septated pleural effusions.
TABLE 19-1 Indications for Thoracentesis
Figure 19-1 Evaluation of the unknown pleural effusion. CHF, congestive heart failure; CT, computed tomography; PE, pulmonary embolism.
Diagnostic Procedures
Thoracentesis
· Once a pleural effusion has been identified, the clinician must decide whether to sample the pleural fluid for either diagnostic or therapeutic benefit or both. Table 19-1 shows indications for thoracentesis, while Figure 19-1 is a schematic for the evaluation of an unknown effusion.
· If a patient has significant symptoms of dyspnea, cough, pain, or a supplemental oxygen requirement, a therapeutic thoracentesis is warranted.
· Thoracentesis can be performed safely, in the absence of disorders of hemostasis, on effusions that demonstrate a >10 mm on a lateral decubitus film.
· Loculated effusions can be localized with ultrasonography or CT scan.
· The most common serious complications of thoracentesis are pneumothorax, bleeding, and introduction of infection into the pleural space.
· Proper technique and sonographic guidance minimize the risk of complications.
· Pleural fluid appearance may be helpful in diagnostic and therapeutic considerations.
o Red-tinged or serosanguineous pleural effusions indicate the presence of blood. This is either due to the procedure (and therefore should clear with continued aspiration) or from the primary disorder (commonly malignancy, PE, or trauma).
o The presence of gross blood should lead to the measurement of a pleural fluid hematocrit. Hemothorax is defined as a pleural fluid blood hematocrit ratio of more than 0.5, and chest tube drainage should be implemented.
o Malodorous fluid or frank pus is consistent with an empyema, and tube thoracostomy should occur immediately.
o Turbid or milky fluid should prompt evaluation for chylothorax.
· The most important aspect of pleural fluid analysis is the laboratory evaluation, allowing the designation of a pleural effusion as either transudate or exudate using Light criteria (Table 19-2) or Heffner criteria (Table 19-3).1–3 Of note, in patients who have an exudative effusion by chemical criteria, but high clinical suspicion for heart, liver, or kidney disease, then a serum to pleural fluid albumin gradient should be checked. A gradient of >1.2 g/dL suggests that the pleural fluid is likely due to congestive heart failure (CHF), liver, or kidney disease.4
o The most frequently used criteria for defining pleural fluid as either exudate or transudate is Light criteria.1 These criteria have a 97.9% sensitivity for detecting an exudative effusion.5 At the time of thoracentesis, a simultaneous measurement of serum lactate dehydrogenase (LDH) and protein must be sampled to properly use the criteria.
o Heffner criteria have a similar sensitivity to Light criteria (98.4%) and do not require simultaneous blood work for interpretation.3
· High cell counts are more typically seen in exudative effusions; however, this is not a component of Light criteria.
o A high neutrophil count is suggestive of an infectious process, especially bacterial, and should prompt consideration of an empyema.6
o Eosinophilia (>10% of total nucleated cell count) is suggestive of air or blood in the pleural space.7 If neither of these is present, consideration should be given to fungal or parasitic infection, drug-induced disease, PE, asbestos-related disease, and Churg-Strauss syndrome.8
o Lymphocytosis (>50% of the total nucleated cell count) is suggestive of malignancy or tuberculosis.6
o Mesothelial cells, when present, argue against the diagnosis of tuberculosis.
o Plasma cells in abundance suggest multiple myeloma.
· Routine stains should be obtained to quickly determine if an effusion is infected and to direct antibiotic therapy if indicated (Table 19-4). Staining for acid-fast bacilli and culture for tuberculosis are performed when clinically indicated.
· A glucose concentration <60 mg/dL is probably due to tuberculosis, malignancy, rheumatoid arthritis, or a parapneumonic effusion.9–11 For parapneumonic effusions, with a glucose <60 mg/dL, tube thoracostomy should be considered (Table 19-4).
· Pleural fluid with a low pH usually corresponds to a low glucose and a high LDH; otherwise, the low pH may be due to poor sample collection technique (proper pH testing on pleural fluid involves anaerobic collection in a heparinized syringe and stored on ice).
o A pH of <7.3 is seen with empyema, tuberculosis, malignancy, collagen vascular disease, or esophageal rupture.
o For parapneumonic effusions with a pH < 7.2, tube thoracostomy should be considered (Table 19-4).8,12
· Cytology is positive in approximately 60% of malignant effusions.13 Priming the fluid collection bag with unfractionated heparin may increase the yield. Of note, the volume of pleural fluid analyzed does not impact the yield of cytologic diagnosis.14
· An elevation in amylase suggests pancreatic disease, malignancy, or esophageal rupture but should not be routinely measured unless there is a clinical suspicion.15 Malignancy and esophageal rupture have salivary amylase elevations and not pancreatic amylase elevations.
· Turbid or milky fluid should prompt an investigation for chylothorax. The fluid should be centrifuged. If the cloudiness clears, then the appearance was merely secondary to cells and debris. If the supernatant does not clear and instead remains turbid, then pleural lipids should be checked. Elevation of triglycerides (>110 mg/dL) suggests that a chylothorax is present,2,8 usually due to a disruption of the thoracic duct from trauma, surgery, or malignancy (e.g., lymphoma). Chylomicrons in the pleural fluid will confirm this.
TABLE 19-2 Light Criteria for Definition of an Exudate
TABLE 19-3 Heffner Criteria for Definition of an Exudate
TABLE 19-4 Indication for Tube Thoracostomy in Parapneumonic Effusions
Other Diagnostic Procedures
· When there is clinical suspicion for a certain diagnosis, other invasive procedures may be useful.
· Closed pleural biopsy typically adds little to the diagnostic yield of thoracentesis, except in the diagnosis of tuberculosis. For tuberculous effusions, pleural fluid cultures alone are positive in only 20% to 25% of cases. However, the combination of pleural fluid studies and pleural biopsy (demonstrating granulomata or organisms) is 90% sensitive in establishing TB as the etiology of the effusion.
· Diagnostic thoracoscopy has largely replaced closed pleural biopsy. Thoracoscopy allows visually directed biopsies, thus increasing the diagnostic yield for malignancy, while maintaining the high diagnostic yield for TB.
Differential Diagnosis
· Transudative pleural effusions usually have low protein and LDH. The glucose level is usually similar to the serum level, and the pH is generally higher than blood pH. Most transudates are clear, straw colored, nonviscous, and odorless. White blood cell (WBC) count is usually <100 cells/HPF, and the RBC count is usually <10,000 cells/HPF. Transudates should lead to further evaluation of the heart, liver, and kidney with therapy directed accordingly.
· Exudative pleural effusions usually have high-protein or LDH values and meet one of Light criteria as described above. Diagnosis of the etiology of the pleural fluid should proceed with a careful history and physical followed by pleural fluid analysis. There is a broad differential for exudative pleural effusions, and once a diagnosis is determined, therapy should be directed toward the cause.
o Parapneumonic effusions are exudates that develop secondary to pulmonary infections.
§ Patients with pneumonia and an effusion should undergo rapid diagnostic testing because an infected pleural space (empyema) needs to be treated without delay.
§ In an uncomplicated parapneumonic effusion, bacterial infection in the pleural space is presumed to be absent, pH > 7.2, and glucose >60 mg/dL.
§ In complicated parapneumonic effusions, bacterial invasion of the pleural space is assumed to be present, pH < 7.2, glucose <60 mg/dL, and/or Gram stain and/or culture positive. Empyema is any uncomplicated parapneumonic effusion that appears grossly purulent.
§ Complicated parapneumonic effusions and empyema should be managed with chest tube drainage when indicated based on the size, presence of loculations, gross appearance of the fluid, or biochemical analysis of the pleural fluid (Table 19-4).12
§ Antibiotics should be administered broadly and then narrowed as directed by culture data.
§ Multiple chest tubes are sometimes required to adequately drain the pleural space.
§ Failure to adequately and quickly drain the pleural space can lead to organization of the pleural fluid and formation of a thick pleural “rind,” which may necessitate surgical removal (known as decortication).
o Malignant pleural effusions arise from tumor involvement of the pleura or mediastinum. In addition, patients with cancer are at increased risk of pleural effusions from other secondary causes such as PE, postobstructive pneumonia, chylothorax, and drug and radiation reactions. It may be appropriate for some patients with stable effusions without significant symptoms to avoid further invasive procedures and observe only.
TREATMENT
· Therapeutic thoracentesis may improve patient comfort and relieve dyspnea.
o Repeated thoracenteses are reasonable if they achieve symptomatic relief and if fluid reaccumulation is slow.
o The incidence of reexpansion pulmonary edema is approximately 1% and is related to changes in pleural pressure more so than the absolute volume of pleural fluid that is removed.16
o Unfortunately, 95% of malignant effusions recur, and the median time to recurrence is <1 week.
· Pleurodesis is an effective procedure indicated for a recurrent pleural effusion in a patient whose symptoms were relieved with initial drainage but has rapid reaccumulation.
o Chemicals used for pleurodesis include talc, doxycycline or minocycline, and bleomycin (considered less effective and more expensive).
o Chemical sclerosant is instilled into the pleural space to promote fusion of the visceral and parietal pleura (pleurodesis).
o Systemic analgesics and lidocaine added to the sclerosing agent should be used to reduce the significant discomfort associated with this procedure.17
o If chest tube drainage remains high (>100 mL/day) >2 days after the initial pleurodesis, a second dose of sclerosing agent can be administered.
· A chronic indwelling pleural catheter (e.g., PleurX catheter) can provide good symptomatic control of an effusion via intermittent patient-controlled drainage.
o The PleurX catheter is better at controlling symptoms than doxycycline pleurodesis.18
o Furthermore, repeated drainage leads to pleurodesis in roughly 50% of patients, allowing the catheter to be removed.
o Chronic indwelling catheters can be used for palliation with trapped lung compared when chemical pleurodesis is ineffective due to incomplete apposition of the visceral and parietal pleura.
· Pleurectomy or mechanical pleural abrasion of the pleural lining can promote pleurodesis. This requires thoracotomy and should be reserved for patients with a good prognosis who have had ineffective pleurodesis by other means.
· Chemotherapy and mediastinal radiotherapy may control effusions in responsive tumors, such as lymphoma or small cell bronchogenic carcinoma.
Solitary Pulmonary Nodule
GENERAL PRINCIPLES
· The solitary pulmonary nodule (SPN) is defined as a ≤3 cm isolated, spherical, well-circumscribed lesion completely surrounded by aerated lung without associated atelectasis, hilar enlargement, or pleural effusion.19,20
· A lesion >3 cm is referred to as a pulmonary mass, and the probability of malignancy is much higher.19,20 Some authorities also distinguish subcentimeter nodules as <8 to 10 mm, which are much less likely to be malignant.19
· The large majority of SPNs are discovered incidentally on plain CXR or chest CT obtained for other reasons.19
· The prevalence of SPNs is highly dependent on the characteristics of the population studied (e.g., age, smoking status) and the technique used (e.g., CXR or CT). It has been reported to range from 0.2% to 7% for CXRs and 8% to 51% for CT.19,21–23 Some SPNs detected on CXR will be false positives.
· Importantly, long-term survival is dramatically better after resection of a malignant SPN compared to that for advanced lung cancer.
· Screening high-risk patients with low-dose CT scans significantly decreases lung cancer–attributed mortality in this patient population.24
· The rate of malignancy in patients with SPNs varies greatly depending on study populations and methods of detection used. Characteristics that increase the risk of malignancy will be discussed below. Table 19-5 outlines a differential diagnosis for SPN.
TABLE 19-5 Partial Differential Diagnosis of the SPN
DIAGNOSIS
Clinical Presentation
· The vast majority of patients with a SPN will be asymptomatic with regard to the nodule itself. Age, smoking status, history of extrathoracic cancer, and history of prior lung cancer are perhaps the most important historical features that increase the likelihood that an SPN is malignant.19,20,25–28
· Patients should also be asked about constitutional symptoms that may be due to malignancy or infection such as fever, chills, sweats, weight loss, anorexia, weakness, fatigue, and malaise.
· The physical examination is usually normal with regard to the SPN. Nonetheless, a careful pulmonary examination is indicated.
Diagnostic Testing
Chest Radiography
· CXR factors suggestive of malignancy are as follows19,21,25,26,29:
o Likelihood of malignancy increases rapidly with size. Those <1 cm are not usually malignant, but SPNs >2 cm often are malignant.
o Upper lobe lesions, particularly on the right, are more likely to be malignant.
o Irregular or spiculated margins increase the likelihood of malignancy. Smooth margins are more likely to be benign, and scalloped margins have intermediate likelihood.
o Stippled and/or eccentric calcifications are associated with malignancy. Laminated, central, and dense calcifications suggest a granuloma, while the “popcorn” pattern suggests hamartoma. Patients with obviously benign calcifications do not need to be evaluated further.
o The doubling time for malignant SPNs is usually between 20 and 300 days, often <100 days. One doubling time equates to an approximately 30% increase in diameter. Based on these assumptions, most authorities agree that SPNs that are stable in size for 2 years are less likely to be malignant. Because of the importance of growth rate, it is critical to compare with previous CXRs or CTs. Slowly growing bronchoalveolar cancers are known to exist, and they may subsequently become more aggressive. This seems to be particularly true of lesions with a ground-glass appearance, and lengthier follow-up may be indicated in these cases.30
· The American College of Chest Physicians (ACCP) recommends that clinicians estimate the pretest probability of malignancy before ordering further imaging studies or biopsy.19 When appropriate, this may be done qualitatively using all of the factors discussed above. Several prediction models have been developed.25,31,32 The prediction model developed by Swensen et al.33 has been validated but is no more accurate than expert clinician assessment. In this model, the independent predictors are age (OR 1.04 for each year), current or past smoking (OR 2.2), history of cancer diagnosed ≥5 years ago (OR 3.8) (patients with cancer <5 years ago were excluded); and nodule diameter (OR 1.14 for each mm), spiculation (OR 2.8), and upper lobe location (OR 2.2).25
Chest Computed Tomography
High-resolution chest CT is clearly more sensitive and specific for detection and characterization of SPNs. The ACCP recommends that all patients with an indeterminate SPN on CXR have high-resolution CT of the chest performed.18 If there are any prior chest CTs, these should be reviewed. In addition to the radiographic features discussed above, CT characteristics suggestive of malignancy include the following19–21,29,34,35:
· Vascular convergence.
· Dilated bronchus leading into the nodule.
· Pseudocavitation.
· Thick (>15 mm), irregular-walled cavitation.
· Dynamic contrast enhancement >15 Hounsfield units (HU).
· Fat attenuation (−40 to −120 HU) is strongly suggestive of hamartoma or lipoma. Some metastatic malignancies (e.g., liposarcoma or renal cell carcinoma) may occasionally contain fat.
Positron Emission Tomography
· Fluorodeoxyglucose positron emission tomography (18F-FDG PET) may also be used to further characterize SPNs.36 Reviews have estimated the sensitivity to be 87% to 96.8% and specificity 77.8% to 83%.37 Sensitivity is less for subcentimeter (<8 to 10 mm) SPNs.
· It is important to recognize that false negatives can occur, and if clinical suspicion still exists, a biopsy should be strongly considered.
· The ACCP recommends 18F-FDG PET for patients with low-to-moderate pretest probability and an SPN >8 to 10 mm with indeterminate (i.e., not clearly benign) CT characteristics.19 In some centers, PET and CT can be combined in a single scan.
Further Evaluation
· Once the clinical and imaging characteristics are known, the choice of subsequent management can be a close call between risk and benefit. Alternatives include observation with serial radiographs, biopsy, and surgery. Each of these has advantages and disadvantages that depend greatly on the likelihood of malignancy.
· Observation is appropriate for those with a very low likelihood of malignancy (<5%). Reasonable follow-up consists of serial high-resolution CT scans at 3, 6, 12, and 24 months. Any sign of growth is presumptive evidence of malignancy. If the lesion is stable after 2 years, then the risk of malignancy is very low.19
· Observation with serial CT scans may also be appropriate for SPNs >8 to 10 mm:
o With a low likelihood (<30% to 40%) of malignancy and a negative 18F-FDG PET scan or dynamic contrast enhancement <15 HU
o With a nondiagnostic biopsy and a negative 18F-FDG PET scan
o If the patient declines aggressive evaluation19
· Biopsy is recommended for SPNs >8 to 10 mm in patients who would be appropriate candidates for surgical cure when:
o The clinical likelihood of malignancy and results of imaging studies are not in agreement (e.g., high clinical suspicion but a negative 18F-FDG PET scan)
o A specific treatment is available for a benign diagnosis (e.g., fungal infection)
o The patient wants biopsy confirmation prior to committing to surgery (this may be most useful when the risks of surgery are high).18
· Usually, the preferred biopsy technique is CT-guided transthoracic needle aspiration, especially for more peripheral lesions. Sensitivity and specificity are variable and depend on multiple factors including lesion size, expertise of the radiologist, availability of an onsite cytopathologic examination, needle size, and number of needle passes.19,21,29,34,38–40 The reported rate of pneumothorax is variable, ranging from approximately 12% to 44%. Most do not require chest tube placement. Factors associated with pneumothorax include increased lesion depth, smaller SPN size, emphysema, smaller needle-pleural angle, lateral biopsy site, and lesion site near a fissure.19,41–46
· Bronchoscopic biopsy may be a viable alternative in specific situations (e.g., central lesions, lesions adjacent to a bronchus, an air bronchogram is in the lesion) when there is available expertise.19
· Newer technology including radial probe endobronchial ultrasound, electromagnetic navigation, and virtual bronchoscopy may improve the diagnostic yield of bronchoscopy for peripheral nodules over conventional bronchoscopic methods.47,48
· Surgical management is recommended for indeterminate SPNs >8 to 10 mm in appropriate surgical candidates when the clinical likelihood is moderate to high, the 18F-FDG PET is positive, and the patient prefers to undergo a definitive procedure.18 There are typically two surgical options:
o Thoracotomy is the most definitive approach particularly for more centrally located SPNs that are not accessible by other techniques.
o Video-assisted thoracoscopic surgery (VATS) is a minimally invasive technique with a lower mortality rate. It is usually the preferred method for SPNs in the peripheral third of the lung.
· Stereotactic body radiation therapy (SBRT) is a nonsurgical approach to managing early-stage lung cancer using highly focused radiation for patients who are not surgical candidates and offers local control rates similar to those achieved with surgery in this patient population.
REFERENCES
1.Light RW, Macgregor MI, Luchsinger PC, et al. Pleural effusions: the diagnostic separation of transudates and exudates. Ann Intern Med 1972;77:507–513.
2.Light RW. Pleural Diseases, 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2007.
3.Heffner JE, Brown LK, Barbieri CA. Diagnostic value of tests the discriminate between exudative and transudative pleural effusions. Primary Study Investigators. Chest 1997;111:970–980.
4.Roth BJ, O’Meara TF, Cragun WH. The serum-effusion albumin gradient in the evaluation of pleural effusions. Chest 1990;98:546–549.
5.Romero S, Candela A, Martin D, et al. Evaluation of different criteria for the separation of pleural transudates from exudates. Chest 1993;104:399–404.
6.Light RW, Erozan YS, Ball WC Jr. Cells in pleural fluid. Their values in differential diagnosis. Arch Intern Med 1973;132:854–860.
7.Spriggs AI, Boddington MM. The Cytology of Effusions: Pleural, Pericardial, and Peritoneal and of Cerebrospinal Fluid, 2nd ed. New York: Grune & Stratton; 1968.
8.Light RW. Clinical practice. Pleural effusions. N Engl J Med 2002;346:1971–1977.
9.Balbir-Gurman A, Yigla M, Nahir AM, et al. Rheumatoid pleural effusion. Semin Arthritis Rheum 2006;35:368–373.
10.Rodriguez-Panadero F, Lopez Mejias J. Low glucose and pH levels in malignant pleural effusions. Diagnostic significance and prognostic value in respect to pleurodesis. Am Rev Respir Dis 1989;139:663–667.
11.Heffner JE, Brown LK, Barbieri C, et al. Pleural fluid chemical analysis in parapneumonic effusions. A meta-analysis. Am J Respir Crit Care Med 1995;151:1700–1708.
12.Colice GL, Curtis A, Deslauriers J, et al. Medical and surgical treatment of parapneumonic effusions: an evidence-based guideline. Chest 2000;118:1158–1171.
13.Prakash UB, Reiman HM. Comparison of needle biopsy with cytologic analysis for the evaluation of pleural effusion: analysis of 414 cases. Mayo Clin Pro 1985;60: 158–164.
14.Sallich SM, Sallach, JA, Vazquez E, et al. Volume of pleural fluid required for diagnosis of pleural malignancy. Chest 2002;122:1913–1917.
15.Branca P, Rodriguez RM, Rogers JT, et al. Routine measurement of pleural fluid amylase is not indicated. Arch Intern Med 2001;161:228–232.
16.Feller-Kopman D, Berkowitz D, Boiselle P, et al. Large volume thoracentesis and the risk of re-expansion pulmonary edema. Ann Thorac Surg 2007;84:1656–1662.
17.Walker-Renard PB, Vaughn LM, Sahn SA. Chemical pleurodesis for malignant pleural effusions. Ann Intern Med 1994;120:56–64.
18.Putman JB, Light RW, Rodriguez RM, et al. A randomized comparison of indwelling pleural catheter and doxycycline pleurodesis in the management of malignant pleural effusion. Cancer 1999;86:1992–1999.
19.Gould MK, Fletcher, J, Iannettoni MD, et al. Evaluation of patients with pulmonary nodules: when is it lung cancer?: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007;132:108S–130S.
20.Ost D, Fein AM, Feinsilver SH. Clinical practice. The solitary pulmonary nodule. N Engl J Med 2003;348:2535–2542.
21.Wahidi MM, Govert JA, Goudar RK, et al. Evidence for the treatment of patients with pulmonary nodules: when is it lung cancer?: ACCP evidence-based clinical practice guidelines (2nd edition). Chest2007;132:94S–107S.
22.Henschke CI, McCauley DI, Yankelevitz DF, et al. Early Lung Cancer Action Project: overall design and findings from baseline screening. Lancet 1999;354:99–105.
23.Holin SN, Dwork RE, Glaser S, et al. Solitary pulmonary nodules found in a community-wide chest roentgenographic survey. Am Rev Tuberc 1959;79:427–439.
24.The National Lung Screening Trial Research Team. Reduced lung cancer mortality with low-dose computed tomographic screening. N Engl J Med 2011;365:395–409.
25.Swensen SJ, Silverstein MD, Ilstrup DM, et al. The probability of malignancy in solitary pulmonary nodules. Application to small radiologically indeterminate nodules. Arch Intern Med 1997;157:849–855.
26.Gould MK, Ananth L, Barnett PG. A clinical model to estimate the pretest probability of lung cancer in patient with solitary pulmonary nodules. Chest 2007;131:383–388.
27.Schultz EM, Sanders GD, Trotter PR, et al. Validation of two models to estimate the probability of malignancy in patients with solitary pulmonary nodules. Thorax 2008;63:335–341.
28.Mery CM, Pappas AN, Bueno R, et al. Relationship between a history of antecedent cancer and the probability of malignancy for a solitary pulmonary nodule. Chest 2004;125:2175–2181.
29.Winer-Muram HT. The solitary pulmonary nodule. Radiology 2006;239:34–49.
30.Aoki T, Nakata H, Watanabe H, et al. Evolution of peripheral lung adenocarcinomas: CT findings correlated with histology and tumor doubling time. AJR Am J Roentgenol 2000;174:763–768.
31.Gurney JW. Determining the likelihood of malignancy in solitary pulmonary nodules with Bayesian analysis. Part I. Theory. Radiology 1993;186:405–413.
32.Gurney JW, Lyddon DM, McKay JA. Determining the likelihood of malignancy in solitary pulmonary nodules with Bayesian analysis. Part II. Application. Radiology 1993;186:415–422.
33.Swensen SJ, Silverstein MD, Edell ES, et al. Solitary pulmonary nodules: clinical prediction model versus physicians. Mayo Clin Proc 1999;74:319–329.
34.Jeong YJ, Yi CA, Lee KS. Solitary pulmonary nodules: detection, characterization, and guidance for further diagnostic workup and treatment. AJR Am J Roentgenol 2007;188:57–68.
35.Swensen SJ, Viggiano RW, Midthun DE, et al. Lung nodule enhancement at CT: multicenter study. Radiology 2000;214:73–80.
36.Herder GJ, van Tinteren H, Golding RP, et al. Clinical prediction model to characterize pulmonary nodules: validation and added value of 18F-fluorodeoxyglucose positron emission tomography. Chest2005;128:2490–2496.
37.Gould MK, Maclean CC, Kuschner WG, et al. Accuracy of positron emission tomography for diagnosis of pulmonary nodules and mass lesions: a meta-analysis. JAMA 2001;285:914–924.
38.Lacasse Y, Wong E, Guyatt GH, et al. Transthoracic needle aspiration biopsy for the diagnosis of localized pulmonary lesions: a meta-analysis. Thorax 1999;54:884–893.
39.Wallace MJ, Krishnamurthy S, Broemeling LD, et al. CT-guided percutaneous fine-needle aspiration biopsy of small (≤1-cm) pulmonary lesions. Radiology 2002;225:823–828.
40.Ohno Y, Hatabu H, Takenaka D, et al. CT-guided transthoracic needle aspiration biopsy of small (<20 mm) solitary pulmonary nodules. AJR Am J Roentgenol 2003;180:1665–1669.
41.Kazerooni EA, Lim FT, Mikhail A, et al. Risk of pneumothorax in CT-guided transthoracic needle aspiration biopsy of the lung. Radiology 1996;198:371–375.
42.Cox JE, Chiles C, McManus CM, et al. Transthoracic needle aspiration biopsy: variable that affect risk of pneumothorax. Radiology 1999;212:165–168.
43.Yeow KM, See LC, Lui KW, et al. Risk factors for pneumothorax and bleeding after CT-guided percutaneous coaxial cutting needle biopsy of lung lesions. J Vasc Interv Radiol 2001;12:1305–1312.
44.Ko JP, Shepard JO, Drucker EA, et al. Factors influencing pneumothorax rate at lung biopsy: are dwell time and angle of pleural puncture contributing factors? Radiology 2001;218:491–496.
45.Saji H, Nakamura H, Tsuchida T, et al. The incidence and the risk of pneumothorax and chest tube placement after percutaneous CT-guided lung biopsy: the angle of the needle trajectory is a novel predictor. Chest2002;121:1521–1526.
46.Yeow KM, Su IH, Pan KT, et al. Risk factors of pneumothorax and bleeding: multivariate analysis of 660 CT-guided coaxial cutting needle lung biopsies. Chest 2004;126:748–754.
47.Eberhardt R, Anantham D, Herth F, et al. Electromagnetic navigation diagnostic bronchoscopy in peripheral lung lesions. Chest 2007;131:1800–1805.
48.Kurimoto N, Miyazawa T, Okimasa S, et al. Endobronchial ultrasonography using a guide sheath increases the ability to diagnose peripheral pulmonary lesions endoscopically. Chest 2004;126:959–965.