90 - Pleuropulmonary Amebiasis
Editors: Shields, Thomas W.; LoCicero, Joseph; Ponn, Ronald B.; Rusch, Valerie W.
Title: General Thoracic Surgery, 6th Edition
Copyright 2005 Lippincott Williams & Wilkins
> Table of Contents > Volume II > Section XVI - Carcinoma of the Lung > Chapter 105 - Diagnosis and Staging of Lung Cancer
Chapter 105
Diagnosis and Staging of Lung Cancer
Carolyn E. Reed
Gerard A. Silvestri
Once the radiographic (see Chapter 104) or clinical presentation (see Chapter 103) raises the possibility of lung cancer, the physician must proceed in an expeditious manner to confirm a diagnosis. The choice of approach will be influenced by lesion characteristics (e.g., size, location), presence or absence of symptoms (e.g., hemoptysis, obstructive pneumonia), and evidence of extrathoracic disease. The evaluation should establish the diagnosis as well as determine the extent or stage of the cancer. This information is critical for treatment decisions and discussion of prognosis with the patient. At times, the diagnosis and stage can be determined by a single test (e.g., liver biopsy, thoracentesis of a pleural effusion). In most cases, careful evaluation of the tumor status (T), nodal status (N), and evidence of metastatic disease (M) requires consideration of a variety of noninvasive and invasive procedures. The staging should be performed in a cost-effective manner.
DIAGNOSIS OF LUNG CANCER
Sputum Cytology
Since the advent of fiberoptic bronchoscopy, the use of sputum cytology for diagnosis of lung cancer has declined dramatically. However, this diagnostic technique should be considered in certain cases because it has no risk to the patient and is inexpensive. Sputum cytology is most beneficial when the lesion is central or the patient presents with hemoptysis. Travis and colleagues (1996) have reviewed the literature and suggest the diagnostic yield of sputum cytology increases from 52% to 87% when the sample is an induced collected sputum sample rather than spontaneous expectoration and when three samples are obtained rather than one.
Fiberoptic Bronchoscopy
Fiberoptic bronchoscopy is used to diagnose, stage, and, in some cases, treat lung cancer. Diagnostic techniques include endobronchial forceps biopsy, endobronchial brushing, bronchial washing, bronchoalveolar lavage (BAL), and transbronchial needle aspiration (TBNA).
Fiberoptic bronchoscopy is the diagnostic procedure of choice for patients with centrally located lung masses. Such a mass may be present as an endobronchial exophytic lesion or a bronchial submucosal or infiltrative lesion, or may cause extrinsic bronchial compression. The diagnostic yield of fiberoptic bronchoscopy for a central bronchogenic carcinoma is overall about 70% but approaches 100% when the lesion is visualized. Three to four biopsy specimens maximize diagnostic yield. Bronchial brushing or TBNA may increase the diagnostic potential if a lesion is submucosal or compressive. Bronchial washing with 30 to 50 mL normal saline solution is often added to routine biopsy and brushing, but Arroglia and Matthay (1993) reported that it seldom increases diagnostic accuracy. If performed, washing should be done after biopsy and brushing because it yields more cells.
As reviewed by Savage and colleagues (2001), TBNA offers several advantages over routine forceps, biopsy, or cytology brushing. TBNA may be useful when lesions are considered high risk for bleeding, when an infiltrative lesion requires an acute angle for adequate tissue penetration, when a peribronchial lesion narrows the bronchus, and when the tumor is necrotic.
The use of fiberoptic bronchoscopy for peripheral lesions is less well validated. In the review of Arroglia and Matthay (1993), the diagnostic yield of transbronchial biopsy, brush, and washing with the use of biplane fluoroscopy varied between 40% and 80%. Size is the most important factor influencing diagnostic yield. Transbronchial biopsy of lesions that are greater than 4 cm in diameter has a diagnostic yield of approximately 80%, whereas lesions less than 2 cm in diameter have a yield of approximately 30%. As reported by Reichenberger and associates (1999) and earlier by Shure and Fedullo (1983), use of TBNA can increase diagnostic yield. Pirozynski (1992) found that performing BAL with 100 to 200 mL normal saline may provide a higher diagnostic yield for peripheral lesions than routine washings, giving
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the highest yield in bronchoalveolar cell carcinoma (80%).
The complication rate of fiberoptic bronchoscopy is low and includes cough, hypoxemia, cardiac arrhythmia, bleeding, pneumothorax, and iatrogenic infection. Major bleeding (more than 50 mL) occurs in 27% or less of patients. Pneumothorax after biopsy of a central lesion is extremely rare.
Transthoracic Fine-Needle Aspiration
Transthoracic fine-needle aspiration (FNA) has been the procedure of choice for the diagnosis of peripheral pulmonary nodules measuring less than 3 cm in diameter, particularly those lesions lateral to the midclavicular line. FNA biopsy can be performed using fluoroscopic, computed tomographic (CT), or ultrasonographic guidance. CT-guided FNA is commonly used for lesions measuring 0.5 to 1.5 cm. Salazar and Westcott (1993) reported an accuracy between 80% and 95% in the diagnosis of lung cancer cases. The presence of an on-site cytopathologist improves the diagnostic yield. Addition of a core needle biopsy to FNA increases the specificity of obtaining a definitive benign diagnosis. Unfortunately, a negative or nondiagnostic FNA does not reassure the clinician that the patient does not have cancer because up to 30% of these patients have malignant lesions discovered at surgery. A repeat transthoracic FNA is diagnostic in 35% to 65% of these patients.
The most common complications of transthoracic FNA are bleeding (hemoptysis, hematoma, and hemothorax) and pneumothorax. As reviewed by Savage and colleagues (2001), postbiopsy bleeding is usually self-limited, and severe bleeding is seen almost exclusively with core biopsy. Minor hemoptysis occurs in 5% to 10% of cases. The incidence of pneumothorax is dependent on type of biopsy (core versus FNA), depth and size of lesion, number of biopsy attempts, and presence of emphysema, among other factors. Chest tube placement is required in 5% to 25% of patients sustaining a pneumothorax.
After nondiagnostic bronchoscopy, the surgeon must decide whether to proceed with transthoracic FNA or with more invasive diagnostic approaches such as video-assisted thoracic surgery (VATS) or thoracotomy. Swensen and colleagues (1997) identified three clinical characteristics and three radiologic characteristics that were independent predictors of malignancy (Table 105-1). In patients who have these characteristics, FNA only delays surgery, and a more aggressive approach is warranted. However, there are circumstances in which FNA is recommended to avoid surgery:
The patient is a high operative risk
The patient has a low risk of malignancy based on clinical and radiologic characteristics
A definite benign diagnosis is considered likely
The patient prefers to have a diagnosis of cancer before proceeding to the operating room
The patient is not an operative candidate, but tissue confirmation is needed before definitive treatment with radiation therapy or chemotherapy or both
Table 105-1. Characteristics of Solitary Pulmonary Nodules Predicting Malignancy | |
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Video-Assisted Thoracic Surgery
For patients with peripheral indeterminate pulmonary nodules, wedge excision via VATS offers an alternative to transthoracic needle biopsy. When clinical or radiologic [i.e., CT lesion enhancement greater than 20 Hounsfield units or positive uptake on positron emission tomographic (PET) scan] characteristics suggest a high likelihood of malignancy, this more invasive diagnostic technique is warranted. Mack and colleagues (1993a) reported the results of 242 patients undergoing thoracoscopic excisional biopsy as the primary diagnostic method for indeterminate solitary pulmonary nodules. Such lesions were defined as less than 3 cm in diameter, noncalcified, and located in the outer one-third of the lung parenchyma. Only two patients required thoracotomy to locate the nodules; a definitive diagnosis was obtained in all patients.
Before performing VATS, the CT scan should be carefully examined to determine the likelihood that the nodule can be located at thoracoscopy. If the nodule is pleural based and larger than 1 cm, visualization of the nodule can be anticipated. If the nodule is immediately subpleural, effacement of the lung parenchyma around the nodule as the lung collapses aids in detection. For nodules deeper than 1 cm below the pleural surface or less than 1 cm in diameter, several techniques can be helpful, as described by Mack and associates (1993b). The CT scan may indicate subtle pleural puckering, or soft tissue windows may reveal the nodule adjacent to the fissure. A blunt grasping instrument may be used for palpation of the lung and give the surgeon a partial tactile sense. A finger inserted through a port site placed over the lesion as guided by CT can palpate a partially inflated lung. More precise techniques to mark the lesion include needle localization preoperatively under CT guidance (similar to breast needle localizations), injection of barium contrast as described by Moon and colleagues (1999), or placement of a microcoil as described by Lizza and associates (2001) with subsequent wedge excision using intraoperative fluoroscopic guidance. Shennib and Bret (1992) reported the use of intraoperative transthoracic ultrasonography to locate lung lesions during VATS.
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Thoracotomy
When other noninvasive diagnostic techniques have been unsuccessful and the lesion has features suggestive of malignancy, open thoracotomy should be performed. If the lesion is deep within a lobe and cannot be removed easily and completely by a wedge excision, true-cut needle biopsy should be performed.
Algorithm for Diagnosing Lung Cancer
The choice of diagnostic technique is dependent on a variety of factors, including size of lesion, location, procedural invasiveness, and local physician preference and expertise. When the likelihood of malignancy is high, such as positive uptake on PET scan without other findings, excision by VATS may be most cost-effective. Subsequent VATS lobectomy or conversion to open thoracotomy and lobectomy can immediately be carried out. Figure 105-1 illustrates a diagnostic algorithm modified from that of Savage and colleagues (2001).
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Fig. 105-1. Algorithm for diagnosing lung cancer. Adapted from Savage C, Morrison RJ, Zwischenberger JB: Bronchoscopic diagnosis and staging of lung cancer. Chest Surg Clin N Am 11:701, 2001. With permission. |
STAGING OF LUNG CANCER
The staging of lung cancer is critical for planning treatment strategies, defining prognostic subgroups, and comparing research data and the results of clinical trials. Staging provides a common language of communication for physicians caring for the patient. The staging process should be accurate and reproducible.
Over the last two decades the staging system for non small cell lung cancer (NSCLC) has undergone significant changes in an attempt to minimize variability of prognosis within each group and correlate different treatment strategies for different stage groups. Mountain (1997) has refined the TNM staging system to increase specificity in stage classification and decrease the heterogeneity of end results existing for the TNM categories within stage groups.
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This system used a database of 5,319 patients with primary lung cancer treated at the M. D. Anderson Cancer Center from 1975 to 1988 or by the North American Lung Cancer Study Group from 1977 to 1982. The TNM descriptors are detailed in Table 105-2.
Mountain and Dresler (1997) recommended a classification of regional lymph node stations that unified the system developed and reported by Naruke and colleagues (1978) and the system advocated by the American Thoracic Society and the North American Lung Cancer Study Group. The schema was adopted by the American Joint Committee on Cancer (AJCC) and the Prognostic Factors TNM Committee of the Union Internationale Contre le Cancer at the 1996 annual meeting. The regional lymph node stations are illustrated in Fig. 105-2 (see Color Fig. 105-2) and defined in Table 105-2. All N2 nodes are contained within the mediastinal pleural envelope and are single-digit numbers. According to the location of the primary tumor, ipsilateral N2 nodes are designated right or left. Midline prevascular and retrotracheal lymph nodes are considered ipsilateral. All N1 nodes (numbered 10 through 14) lie distal to the mediastinal pleural reflection and are within the visceral pleura. Stage grouping in Mountain's (1997) revised system is shown in Table 105-3 and Fig. 105-3 (see Color Fig. 105-3).
Table 105-2. TNM Definitions | ||||||||||||||||||||||||||||||||||||||
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The Noninvasive Staging of Lung Cancer
Computed Tomography for Intrathoracic Staging
Computed tomography of the chest is the most widely used imaging modality for staging lung cancer. CT scan is almost always obtained after an abnormality is discovered on plain chest radiograph. Clinical scenarios exist for which chest radiography alone may suffice (e.g., multiple metastatic pulmonary nodules in a patient with a poor performance status or gross rib destruction with chest wall invasion). However, because plain chest radiography is not sensitive enough to detect mediastinal lymphadenopathy or chest wall or pleural invasion, CT scan of the chest is almost always necessary.
For evaluation of the primary tumor, CT scan has difficulty distinguishing between T3/T4 tumors and T1/T2 tumors. In fact, in a study by Webb and colleagues (1991), CT was only able to discriminate between advanced chest wall tumors and primary tumors in 62% of the cases. When rib destruction was present or there was a definite chest wall mass, the CT had a better predicted value. The surgeon cannot rely solely on the CT scan for central tumors that may invade the mediastinum. The sensitivity of CT for invasion of the mediastinum is low, in the range of 60% to 75%. Occasionally, invasion of a vessel can be detected by CT scan. Given this low sensitivity, there are occasions when surgical exploration is the only way to definitively stage for tumor invasion into the mediastinum (T4 disease). It was initially thought that magnetic resonance (MR) imaging would be useful in detecting mediastinal and chest wall invasion. However, the sensitivity and specificity of this technique are not significantly higher than CT scan alone. MR imaging is useful in evaluating superior sulcus (Pancoast's) tumors for involvement of the brachial plexus, spinal cord, chest wall, and subclavian artery.
The use of CT scan to detect mediastinal lymphadenopathy is fraught with difficulties. Although CT scan is an excellent tool for detecting enlarged lymph nodes, it cannot differentiate benignity from malignancy. Lymph nodes in the mediastinum are considered enlarged if they are greater than 1 cm in short-axis diameter. The finding of an enlarged lymph node in the mediastinum in patients with a known primary lung cancer does not ensure that those lymph nodes will have metastatic deposits. False-positive lymph nodes are especially common in patients with postobstructive pneumonia secondary to their primary lung cancer. Patients with other underlying diseases, such as sarcoidosis, may
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have abnormally enlarged mediastinal lymph nodes. When lymph node enlargement is detected by CT scan, the onus is on the clinician to prove that the lymph node has a metastatic deposit. It must be emphasized that enlarged lymph glands on CT alone should not preclude a patient from a potentially curative resection. In addition, a CT scan of the chest can be helpful in directing the clinician to the most appropriate staging procedure for lymph node biopsy.
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Fig. 105-2. Regional lymph node stations. (See Color Fig. 105-2.) |
Table 105-3. Revised Stage Grouping for Lung Cancer | |||||||||||||||||||||||||||||
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Recently, the American College of Chest Physicians completed an evidence-based review of the staging characteristics of CT for staging the mediastinum in patients with NSCLC. Toloza and colleagues (2003) pooled the results of 20 studies that included 3,829 evaluable patients. The pooled sensitivity and specificity of CT were 0.57 [95% confidence interval (CI), 0.49 0.66] and 0.82 (95% CI, 0.77 0.86), respectively. Thus, 18% of enlarged mediastinal lymph nodes detected on CT scan will be secondary to benign causes, reinforcing the need to sample these nodes prior to excluding a patient from potentially curative surgery.
In patients with no evidence of mediastinal lymphadenopathy by CT scan, there is some controversy as to
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whether an invasive mediastinal staging study (i.e., mediastinoscopy) should be performed prior to surgery. While up to 15% of these patients with negative CT will, in fact, have microscopic deposition in a lymph node at surgery, this group generally has up to a 30% 5-year survival when patients undergo complete resection.
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Fig. 105-3. TNM staging of lung cancer. (See Color Fig. 105-3.) From Lababede O, Meziane MA, Rice TW: TNM staging of lung cancer. Chest 115:233, 1999. With permission. |
Positron Emission Tomography for Staging Lung Cancer
Perhaps the most significant advance in the staging of lung cancer over the last several years is the use of PET. This imaging modality takes advantage of the biologic activity of tumor cells. Cancer cells have an increased cellular uptake of glucose and higher rate of glycolysis compared with normal cells. The radiolabeled glucose analogue fluorodeoxyglucose (FDG) undergoes the same cellular uptake as glucose, but after phosphorylation it is not further metabolized and is thus trapped in cells. Accumulation of this isotope can then be detected under a PET camera. The specific criteria for an abnormal PET scan include either a standard uptake value (SUV) of greater than 2.5 or uptake in a lesion that is greater than the background uptake in the mediastinum. PET scans, therefore, provide the clinician with information on the functional activity of a lesion rather than the strictly anatomic information that a CT scan can provide. The two imaging modalities are complementary, and one cannot necessarily replace the other. Combined PET CT scanners have been developed, and studies are underway to establish sensitivities and specificities in staging. The explosion of research on the utility of PET for the diagnosis and staging of lung cancer can be divided into three categories: the solitary pulmonary nodule and mass, staging the mediastinum, and the search for occult metastatic disease.
Positron Emission Tomography for Nodules and Masses
With nearly 150,000 solitary pulmonary nodules (SPNs) detected by chest radiograph each year, it would be advantageous to have a diagnostic tool to help differentiate benign from malignant disease. Although CT of the chest will give anatomic information and is useful in the description of the nodule (calcified, spiculated, etc.), it is neither sensitive nor specific for the differentiation of benignity from malignancy in most cases. PET is extremely sensitive and relatively specific for solitary pulmonary nodules and masses. Gould and colleagues (2001) performed a meta-analysis of 40 studies inclusive of 1,474 patients with SPNs evaluated by PET. The overall sensitivity for malignancy
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was 96.8%, with a specificity of 77.8%; for detecting benign disease, the sensitivity was similar (96%) but the specificity was higher (88%). For the clinician, a negative PET should dissuade one from proceeding to thoracotomy because the likelihood of malignancy is low. The few false positives seen are usually slow-growing bronchoalveolar cell carcinomas or pulmonary carcinoids. An abnormal PET does not guarantee malignancy. Slightly more than 20% of the PET scans performed for SPNs are false positives because benign lesions, including focal pneumonias and granulomatous and inflammatory diseases (e.g. sarcoidosis), can also utilize glucose at a rate mirroring malignancy and thus be detectable by PET. Positron emission tomography is not accurate for nodules smaller than 1 cm because of the spatial resolution of the current technology.
Mention should be made of the recent use of technetium Tc 99m depreotide single-photon emission computed tomographic (SPECT) imaging for the differential diagnosis of solitary pulmonary nodules. Technetium Tc 99m depreotide is a synthetic cyclic six amino acid peptide analogue of somatostatin and has been found to bind avidly and specifically to non small cell tumors, according to Goldsmith and Kostakoglu (2000). Blum and colleagues (1999) found that 12 (85.7%) of 14 positive studies were true positives, with a 14.2% false-positive rate due to uptake in an inflammatory lesion in two patients. Of the 16 patients whose lesion revealed no uptake, there was initially a single false-negative result (0.06%). This modality's value in detecting metastatic disease is as yet undetermined, and its true value in the prospective evaluation of the solitary nodule must be further evaluated by additional studies.
Positron Emission Tomography for Mediastinal Staging
Because the accuracy of CT scan for differentiating benign from malignant mediastinal lymphadenopathy is dismally low (sensitivity 0.57 and specificity 0.82), it was the hope of clinicians that the functional information provided by PET would improve upon CT. A recent meta-analysis by Toloza and colleagues (2003) has confirmed this hope. Combining 18 studies and 1,045 patients, the pooled sensitivity and specificity of PET for the detection of malignancy in the mediastinum were 0.84 (95% CI, 0.78 0.89) and 0.89 (95% CI, 0.83 0.93), respectively. There has only been one multicenter randomized trial of the utility of PET in staging the mediastinum for patients with known lung cancer prior to surgery. The PLUS trial reported by van Tinteren and associates (2002) randomized patients to conventional evaluation alone versus PET followed by conventional workup. The group that utilized PET detected more mediastinal metastases and distant metastatic disease, and subsequently more patients avoided a futile thoracotomy. One of us (GAS) and colleagues (2003) recommended a PET scan (where this technology is available) to stage the mediastinum in the ACCP lung cancer guidelines on noninvasive staging.
Positron Emission Tomography for Detection of Metastatic Disease
The use of PET for the detection of distant metastatic disease has been insufficiently studied to make any firm recommendations. An immediate problem is that PET cannot be used to accurately detect metastases in the brain because the background utilization of glucose by the brain is so high that it can obscure the findings of metastatic disease. This poses a significant obstacle because the brain is a common repository for metastatic disease in patients with lung cancer. Both Pieterman (2000) and van Tinteren (2002) and their associates have documented unexpected metastatic disease in about 10% of patients who were otherwise candidates for surgery. Unfortunately, there is little description of whether or not patients underwent an expanded clinical evaluation that would have predicted metastatic disease. As reported by one of us (GAS) and co-workers (1995), previous research has shown that when the clinical evaluation is negative, patients do not require further imaging using conventional CT and nuclear medicine studies of the brain, bone, and abdomen. There has yet to be a study that compares clinical evaluation to PET scan findings for detection of silent metastases.
In summary, PET is likely to assume an increasing role in the diagnosis and staging of lung cancer. A negative PET is helpful because the sensitivity is high, making the likelihood of finding cancer with a negative PET low. One must be wary of a positive PET because a significant number of false positives exist. The false positives are usually due to infectious etiologies or inflammatory adenopathy. Tissue confirmation of an abnormal PET scan is the rule so that patients are not precluded from a potentially curative surgery. Further research is needed to decide on the appropriate role for PET in both early-stage lung cancer and the detection of metastatic disease. One should also consider that this technology is relatively new and that the test characteristics may drop off as this technology diffuses into practice and further research is undertaken.
The Noninvasive Search for Metastatic Disease
As is often the case, a careful history and physical examination provide valuable information that may guide the physician in locating metastatic disease. For example, the recent onset of severe pain in the midhumerus may prompt a bone scan that reveals uptake in the area of the pain consistent with metastasis. A more difficult decision arises when the patient has a normal clinical evaluation, and the clinician must consider the likelihood that metastatic disease will be discovered by CT or radionuclide scan. This introduces the concept of the negative predictive value (NPV) of a test, which, in the context of the clinical evaluation, is defined as the probability of a negative scan for metastatic disease given a negative clinical evaluation. A high NPV of the clinical evaluation in patients with newly diagnosed lung cancer would imply that if the
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clinical evaluation were normal, then the probability of a positive CT or radionuclide scan for metastatic disease would be low. One of us (GAS) and colleagues (1995) found the NPV of the clinical evaluation to be quite high when compared with subsequent staging scans of the head and abdomen and with radionuclide bone scan. This is particularly true if an extensive clinical evaluation was performed (Table 105-4). The most common metastatic sites for NSCLC are the brain, bone, and abdomen (liver and adrenal glands). The meta-analysis by one of us (GAS) and colleagues (1995) has been recently updated by Toloza and associates (2003), who confirmed the findings in a larger series of patients.
Specific Considerations
Cranial Metastases
The finding of brain metastases is not uncommon in patients with lung cancer. They are present in 10% of patients at the time of diagnosis and in 30% to 50% of patients by autopsy series. When a comprehensive clinical evaluation is performed, the median negative predictive value of the clinical evaluation was 0.94 (95% CI, 0.91 0.96) in the pooled studies of 1,784 patients reported by Toloza and associates (2003). If the clinical evaluation was comprehensive, the finding of asymptomatic brain metastases in a patient with primary lung cancer was 3% or less in the analysis by one of us (GAS) and colleagues (1995).
Two subgroups of asymptomatic patients may have a higher incidence of cranial metastases. Kormas and associates (1992) found that patients with known N2 disease detected on chest CT or at the time of surgery had a higher incidence of clinically silent cranial metastases. In addition, one of us (GAS) and colleagues (1995) reported in the meta-analysis that adenocarcinoma carries a higher likelihood of asymptomatic brain metastases than does squamous cell carcinoma. However, Tanaka and co-workers (1999) retrospectively studied 754 patients with stage I and II NSCLC and found a 1% rate of silent metastases and no difference in the rate of metastases among different histologies.
Table 105-4. Extended Clinical Evaluation Suggesting Metastatic Disease in Patients with Lung Cancer | |
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A cost-effectiveness study by Colice and colleagues (1995) found that, overall, it was not cost-effective to perform a CT scan if the clinical evaluation was negative. A positive clinical finding on cranial CT does not necessarily equate with true metastases. Patchell and associates (1990) studied 54 patients with known primary cancers elsewhere and presumed cranial metastases seen by CT scan; 6 (11%) studies were indeed false-positive scans. The patient who has a solitary brain lesion discovered on cranial CT may warrant biopsy of this lesion before exclusion from potentially curative thoracotomy.
With the reported increased sensitivity of MR imaging, investigators have hypothesized that clinically silent cranial metastases would be discovered more frequently using this modality. Cole and colleagues (1994) performed preoperative cranial CT scans in 42 patients with lung cancer and normal neurologic examinations. This was followed by MR imaging for comparison. Neither modality detected a metastatic lesion; however, benign pathology was detected more frequently by MR imaging.
Currently, the consensus is to perform a cranial CT during the staging evaluation if the patient has positive findings that suggest the presence of cranial disease (e.g., headaches, seizures). Cranial CT should also be performed prior to thoracotomy in patients with nonspecific findings that suggest widespread disease (e.g., weight loss, anemia) if metastatic disease has not been documented elsewhere. Patients who have N2 disease documented prior to surgery may warrant a head CT scan.
Bone Metastases
Lung cancer metastasis to the bone occurs frequently and is found in up to 30% of patients at autopsy. Radionuclide bone scan is often positive in patients with bone metastases. Only 5% to 15% destruction of bone is necessary before neoplastic deposits are detected by bone scanning, according to Rogers (1993). However, false-positive bone scan or radionuclide bone scans also occur because patients in this age group can have a history of coexistent trauma, osteoporosis, or benign lesions. The clinical evaluation is useful in deciding whether to order a radionuclide bone scan. Common clinical findings of bone metastases include bone pain, pathologic fracture, and an elevated alkaline phosphatase or serum calcium level. One of us (GAS) and associates (1995) found that the median negative predictive value for the clinical evaluation was 92%. This included data from over 600 patients. Of the seven studies included in that meta-analysis, several documented the fact that false-positive scans were common. The updated meta-analysis by Toloza and associates (2003) also points out
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that there is heterogeneity in the studies, and the pooled NPV they reported was 0.90 (95% CI, 0.86 0.93).
The radionuclide bone scan has its greatest utility in patients who have a positive clinical evaluation. The patient who has multiple areas of uptake consistent with metastases needs no further evaluation. However, an isolated area of uptake may require further evaluation, including plain radiographs to assess for pathologic fracture. In the absence of plain radiographic abnormality or local signs of symptoms, biopsy of a suspected osseous metastasis becomes a challenging problem.
Robinson and associates (1998) reported on the use of an intraoperative gamma probe directed biopsy of ribs and sternum in 10 patients following a standard dosage of technetium Tc 99m oxidronate 6 to 12 hours prior to surgery. The technique proved to be easy and highly accurate (100% sensitivity) to localize areas of abnormal radioisotope uptake. Of note is that in only one of five asymptomatic patients with known lung cancer did biopsy confirm metastasis. This low yield of positivity is confirmed by Ichinose and associates (1989), who found a 55% false-positive rate in routine bone scans in asymptomatic patients with lung cancer.
Abdominal Metastases
Lung cancer may metastasize to both the adrenal glands and liver. Because adrenal metastases are generally considered to be clinically silent, it has been common practice to extend the chest CT through the adrenal glands to evaluate them for the presence of metastatic disease. However, an abnormally enlarged adrenal gland does not necessarily represent metastatic disease. Adrenal adenomas occur in 2% to 10% of the general population. Oliver and colleagues (1984) showed that an enlarged adrenal gland was more likely to be an adenoma than metastatic disease in the preoperative patient with non small cell lung cancer. One of us (GAS) and associates (1992) discovered that the likelihood of adrenal metastases noted on abdominal CT was zero in patients with a normal clinical evaluation. All patients who ultimately had adrenal metastases had findings that suggested the presence of metastatic disease.
The recurring problem of false-positive scans occurs in patients who have liver abnormalities noted on CT scan. Liver metastases occur in up to 5% of patients with lung cancer. However, a benign pathology of the liver is common, and abnormalities visualized in the liver during abdominal CT are more likely to be benign than malignant. Thus, additional studies to rule out the presence of metastases may become necessary, including ultrasound to evaluate cystic lesions and bolus contrast CT to establish the presence of a hemangioma. Occasionally, a CT-guided percutaneous liver biopsy may be performed.
Combining patients from 12 studies totaling more than 1,201 patients in which a clinical evaluation was performed prior to the abdominal CT scan, Toloza and associates (2003) reported that the clinical evaluation performed well, with a median negative predictive value of 0.95 (95% CI, 0.93 0.96). It can therefore be argued that since the likelihood of abdominal metastases in patients who have a negative clinical evaluation is low and testing may result in a false-positive abdominal CT scan, routine CT scans through the abdomen in patients with NSCLC and a negative clinical evaluation should not be performed. Any abnormal finding suggestive of metastatic disease discovered during the clinical evaluation should be followed by a chest CT that is extended through the abdomen unless the symptoms are referent to a specific organ system (e.g., severe headache). A complete staging algorithm for the evaluation of metastatic disease is shown in Fig. 105-4.
SUMMARY OF EXTRATHORACIC STAGING
A compelling argument can be made for performing an expanded clinical evaluation during the pretreatment workup of patients with lung cancer. There is a need to be
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compulsive in the assessment, as pointed out by Guyatt and colleagues (1999), who found that thoracic surgeons who detected and documented subtle neurologic findings had patients who were more likely to subsequently present with central nervous system metastases. A randomized trial performed by the Canadian Lung Oncology Group (2001) addressed the issue of the need for extrathoracic staging tests. The trial randomized patients to either surgery or a full metastatic workup prior to surgery. The results showed no statistical difference in the primary end point, which was thoracotomy with recurrence. The recommendations are as follows:
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Fig. 105-4. Staging algorithm for lung cancer. |
Patients with a negative clinical evaluation need not have further testing.
Patients with either organ-specific or nonspecific findings indicative of metastatic disease, even if they are subtle, require further testing.
Patients with known or suspected N2 disease should have extrathoracic staging prior to surgical resection.
INVASIVE INTRATHORACIC STAGING
Mediastinal nodal status is the major prognostic factor in assessing resectability of lung cancer. The need to perform invasive mediastinal staging on every patient is controversial. It is accepted that histologic evaluation of enlarged lymph nodes identified by CT scan is required to confirm staging. McLoud and associates (1992) found that 37% of nodes 2 to 4 cm in diameter did not contain metastatic disease at thoracotomy. Likewise, false-positive PET scans can result from granulomatous and other infectious disease processes, and further evaluation of the mediastinum with sampling of the abnormal lymph node station should be undertaken. Both CT and PET scans can guide the location of node biopsy and therefore help direct the choice of biopsy technique.
On the other hand, peripheral T1N0M0 tumors with a negative mediastinum by CT scan are unlikely to have mediastinal metastases. Positivity in this setting is variably reported as between 5% to 15%. Squamous histology lowers the odds of positivity. The Canadian Lung Cancer Oncology Group (1995) reported that selective mediastinoscopy in patients with enlarged lymph nodes was more cost-effective than invasive mediastinal staging. The need for invasive mediastinal staging for a peripheral T1 tumor and negative mediastinum by PET needs further investigation. Kernstine and associates (2002) reported that N2 disease was still found at thoracotomy in 2% to 8% of cases if PET scans were negative. Vesselle and coauthors (2002) reported that PET understaged the mediastinum in 8 (6.8%) of 118 patients. Gonzalez-Stawinski and colleagues (2003) compared PET scanning to mediastinoscopy results and found that 11.7% of patients (16 of 137) with a negative mediastinal PET had N2 or N3 disease demonstrated at mediastinoscopy.
Other predictors of N2 disease may be useful in making a decision to perform invasive mediastinal staging. For patients with T3 tumors or central adenocarcinomas, Daly and colleagues (1993) reported a high incidence of positive mediastinal lymph nodes and a low negative predictive value for CT. If resection is contemplated for a peripheral clinical T1N0M0 SCLC, mediastinoscopy is warranted because of the propensity of early spread to mediastinal lymph nodes. Accurate evaluation of the outcomes of clinical trials using adjuvant therapy in the setting of N2 disease requires invasive staging for pathologic confirmation.
Transbronchial Needle Aspiration
Transbronchial needle aspiration (TBNA) offers the opportunity to stage the mediastinum at the time of diagnostic bronchoscopy. The sensitivity of TBNA for diagnosing malignant adenopathy depends on the transbronchial needle size, the size and location of the adenopathy, and the cancer histology. Sensitivity is increased with SCLC. Schenk and colleagues (1993) compared the use of 19- and 22-gauge needles in malignant mediastinal adenopathy greater than 1 cm and confirmed that the yield increased with the larger needle from 53% to 86%. In a prospective study by Harrow and colleagues (2000), overall sensitivity of TBNA was found to be at least 57% for lymph nodes greater than 1 cm, and specificity was 99%. In this study, right-sided tumors and right paratracheal and subcarinal adenopathy were predictive of a positive TBNA biopsy. In a study by Chin and colleagues (2002), a plateau in the yield from TBNA occurred after seven aspirates. The rate of success for enlarged subcarinal (64%) and right paratracheal lymph nodes (38%) was similar to those reported in other studies. Shure and Fedullo (1984) reported an association between malignant carinal aspirates and the presence of an endobronchial tumor (24%) or abnormal-appearing carina (widening or mucosal erythema) at bronchoscopy (38%).
The technique of TBNA has been well described by Wang (1995) and Dasgupta and Mehta (1999), but does require increased bronchoscopic expertise. The major complication is damage to the working channel of the bronchoscope. To avoid false-positive results, suctioning prior to TBNA should be avoided, TBNA should be performed prior to other procedures, the needle should not be passed through the primary lesion, and removal of mucosal secretions prior to needle insertion should be done by rinsing. The presence of an on-site cytopathologist is associated with a higher yield for obtaining a malignant diagnosis: 71% versus 25% in the series reported by Chin and co-workers (2002).
Transthoracic Fine-Needle Aspiration
Sampling of N2 and N3 lymph nodes can be obtained by CT scan guided transthoracic FNA. Even nodes in proximity to the aorta and pulmonary artery can be needled with safety, as reported by Wang (1995), because of the relatively
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fixed anatomy and the direct visualization provided by CT.
The most significant complication of transthoracic FNA is major bleeding. History of a bleeding disorder or pulmonary hypertension is a contraindication to this approach. The most common complication is pneumothorax, and Salazar and Wescott (1993) quote a frequency of 25% to 33%.
Mediastinoscopy
Cervical mediastinoscopy allows exploration of lymph nodes in the paratracheal and pretracheal regions, in the tracheobronchial angles, and in the anterior aspect of the subcarinal space. It is considered the standard for assessing superior mediastinal lymph node metastases. Ginsberg (1987) reported that in two analyses of 2,259 mediastinoscopies, the total complication rate was 2.0%. There were no deaths. Only 0.3% of life-threatening complications (hemorrhage, tracheal nerve injury, or esophageal injury) required surgical intervention, consisting of thoracotomy or sternotomy. Recurrent nerve injury and pneumothorax occurred in 0.9% of mediastinoscopies.
The false-negative rate of mediastinoscopy is generally less than 10%, and there should be no false positives. Funatsu and colleagues (1992) reported that the sensitivity of mediastinoscopy was lowest for subcarinal lymph nodes (64.0%). The false-negative results were low for the paratracheal regions (1% to 2%) but were 6.1% for the subcarinal lymph nodes. Ideally, all five lymph node stations (2R, 4R, 2L, 4L, 7) should be dissected and sampled if positive lymph nodes are found. Mediastinoscopy is commonly an outpatient procedure.
Although not frequently performed at most institutions, mediastinoscopy can be extended to evaluate the subaortic (level 5) and paraaortic (level 6) regions. This extension is created by finger dissection in the space superolateral to the aorta between the innominate artery and left common carotid artery. In 100 consecutive cases in which standard and extended mediastinoscopies were performed, Ginsberg and colleagues (1987) found a sensitivity of 69% and a false-negative rate of 11% for detection of N2 and N3 disease. Lopez and colleagues (1994) reported 100% specificity and 83.3% sensitivity in a prospective study of 50 cases. Similar findings were reported by Freixinet Gilart and associates (2000) in 93 patients with enlarged aortopulmonary window lymph nodes (sensitivity 81%; false-negative rate 9%).
Anterior Mediastinotomy
For left upper lobe tumors, evaluation of the subaortic and lateral aortic areas for N2 disease is required for complete staging. As a more frequent alternative to extended mediastinoscopy, biopsy can be achieved using an anterior mediastinotomy (the Chamberlain procedure). The technique may include a left vertical parasternal incision as originally described by McNeil and Chamberlain (1966), an excision of the second intercostal cartilage, or an incision in the second or third intercostal space. Biopsy of stations 5 and 6 lymph nodes is achieved by inserting the mediastinoscope in the extrapleural plane. For left upper lobe tumors, a cervical mediastinoscopy is performed in addition to the Chamberlain procedure to rule out contralateral disease and yields a sensitivity of about 87% and false-negative rate of 10%.
Video-Assisted Thoracic Surgery
Video-assisted thoracic surgery is an alternative to the Chamberlain procedure. Not only does it allow biopsy of nodes in levels 5 and 6, but it also allows access to paraesophageal (level 8) and inferior pulmonary ligament (level 9) lymph nodes. On the right side, video-assisted thoracic surgery permits exploration of upper and lower paratracheal lymph nodes, subcarinal nodes, and paraesophageal and inferior pulmonary lymph nodes. Landreneau and associates (1993) reported the use of thoracoscopic mediastinal exploration in 40 patients with CT-enlarged aortopulmonary window, right periazygos, or subcarinal lymph nodes. Thoracoscopic nodal sampling was 100% sensitive and 100% specific in diagnosing the mediastinal adenopathy.
An added benefit to using video-assisted thoracic surgery to stage the mediastinum is the ability to view the tumor and explore the pleural cavity. Unsuspected pleural seeding may be discovered. As noted by Roviaro and associates (1995), dissection maneuvers can allow evaluation of operability when a lesion is suspected to be contacting, compressing, or invading hilar or mediastinal structures. In their experience, video-assisted thoracic surgery revealed causes of inoperability and avoided unnecessary thoracotomy in 8.3% of cases.
Esophageal Endoscopic Ultrasonography
Endoscopic ultrasonography (EUS) allows the depiction of lesions in and around the gastrointestinal tract, including adjacent lymph nodes. With the development of the linear array echoendoscope, EUS/FNA of lymph nodes became possible. One of us (GAS) and colleagues (1996) demonstrated an accuracy of 89% when assessing subcarinal, aortopulmonary, or inferior mediastinal lymph nodes designated by the radiologist as abnormal. Figure 105-5 shows an EUS/FNA of an enlarged subcarinal lymph node. In a series of 82 patients with mediastinal lymphadenopathy reported by Wiersema and colleagues (2001), the sensitivity, specificity, and accuracy of EUS/FNA in distinguishing benign from malignant mediastinal lymph nodes were 96%, 100%, and 98%, respectively. In this series, all 29 patients with NSCLC were correctly staged with EUS/FNA. Gress and associates (1997) reported an accuracy of 96% in 24
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patients. Wallace and colleagues (2001) from our institution have published a large series of 121 patients undergoing EUS/FNA for staging of NSCLC. Advanced mediastinal disease was identified in 75 (77%) of 97 patients with carcinoma of the lung and enlarged mediastinal nodes by CT, thus avoiding further invasive staging. EUS/FNA also detected mediastinal disease in 10 (42%) of 24 patients without mediastinal adenopathy by CT.
 |
Fig. 105-5. FNA guided by endoscopic ultrasonography of an enlarged subcarinal lymph node. The needle is shown entering the lymph node. |
The inability of EUS/FNA to access levels 2R, 4R, and the pretracheal space means that the technology should still be viewed as complementary to other techniques. Fritscher-Ravens and colleagues (2003) reported a prospective triple-blinded trial of 33 NSCLC patients who had CT, PET, and EUS/FNA for mediastinal staging. EUS/FNA had a sensitivity of 81%, compared with 57% for CT and 73% for PET.
EUS/FNA is performed under conscious sedation in an outpatient setting, and the complication rate is virtually nil. Using a decision-analysis model, Aabakken and colleagues (1999) showed that EUS/FNA is a cost-effective technique compared with mediastinoscopy and mediastinotomy.
Endobronchial Ultrasound
The role of endobronchial ultrasound in the diagnosis of both bronchial and mediastinal pathology is undergoing study. As discussed by Burgers and colleagues (2001), technical aspects still need to be addressed. At present, ultrasound guidance for mediastinal staging is performed by first passing an ultrasound probe down the working channel of the bronchoscope to localize the lymph node. Mediastinal lymph nodes as small as 3 mm can be detected. Once localized, the probe is withdrawn and TBNA performed in standard fashion. Unfortunately, no unique ultrasound features predict presence of metastatic disease. In a prospective randomized controlled trial reported by Shannon and colleagues (1996), the sensitivities of ultrasound-guided TBNA and standard TBNA were equally high (82% and 90%, respectively) although ultrasound-guided TBNA decreased the number of aspirates needed for diagnosis.
Intraoperative Staging
Presurgical staging must be confirmed by intraoperative staging. The tumor is usually easily assessed upon opening the chest. Extrapleural dissection should be performed if there is adhesion to the parietal pleura. If the plane is not clearly defined, chest wall or mediastinal invasion beyond the parietal pleura must be assumed.
Careful assessment of the parietal pleura for tumor studding should be done immediately after opening the chest. Palpation of the non tumor-bearing lobe or lobes should be performed to assess for satellite tumor nodules. Suspicious lesions are sent for frozen section.
Palpation of the mediastinal lymph nodes should precede resection. Although mediastinal node dissection or systemic sampling is usually performed at the completion of pulmonary resection, it should be done first if positive mediastinal nodes will alter treatment plans. Gaer and Goldstraw (1990) reported that intraoperative palpation of lymph nodes had a positive predictive value of only 64.1% but a negative predictive value of 96.0%.
SPECIFIC CLINICAL ENTITIES
Diagnostic Approach to Occult Lung Cancer
Occasionally patients will present with hemoptysis and a negative chest radiograph. If they have a significant smoking history and are over 40 years old, Colice (1997) estimates that 6% will eventually have the diagnosis of lung cancer established. The diagnostic strategy that uses the least number of tests to diagnose the lung cancer begins with sputum cytology. Colice (1997) reported little role for CT scan as an initial test in patients with hemoptysis and a normal chest radiograph. If sputum cytology is positive for malignant cells, fiberoptic bronchoscopy with airway inspection should be performed. If a visible endobronchial lesion is not identified for biopsy, the patient should have the bronchoscopy performed under general anesthesia so that cytologic brushing of each subsegment of the lungs can be undertaken. When a positive cytologic brush result is obtained, the procedure should be repeated in the affected area. Surgical resection is recommended when two positive results are obtained from the same lobe.
Asymptomatic Solitary Pulmonary Nodules
It is estimated that nearly 150,000 asymptomatic solitary pulmonary nodules (SPN) are detected each year in the
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United States. The number of nodules has increased with the emergence of high-resolution CT scan and may explode if the use of low-dose CT for lung cancer screening is found to be efficacious. A lesion measuring less than 3 cm is defined as a nodule. Nodules are by definition not associated with atelectasis or adenopathy. Masses are defined as greater than 3 cm and have a much higher probability of malignancy.
The differential diagnosis of an SPN is broad and includes infectious, inflammatory, and neoplastic diseases. Although most nodules are benign, primary malignancy is found in about 35% of nodules, and metastatic solitary metastases account for another 23%, as reported by Swanson (1999) and Leef (2002) and their colleagues and by Yankelevitz and Henschke (2000). Radiographic and clinical characteristics (see Table 105-1) can help characterize the lesion as benign or malignant. However, none of these methods is 100% accurate, and thus the onus is upon the clinician to disprove cancer.
It has long been held that there are two reliable indicators of benign disease. The first is the absence of growth by radiograph over a 2-year period. The second is the presence of benign calcification. Swensen and colleagues (1990) suggest that if prior roentgenograms demonstrate a stable lesion over a 2-year period or if a particular pattern of calcification (diffuse, central, laminar, or popcorn ) exists, a benign diagnosis can be affirmed and an observation only approach is justified. If the patient is younger than 30 to 35 years, has no previous history of malignancy, and is a nonsmoker, again an observation only approach is appropriate. If chest films indicate growth, the doubling time of the volume of the mass may yield useful information. Nathan and associates (1962) reported that in patients over 40 years, a doubling time of a solitary nodule of less than 37 days or one greater than 465 days represented a benign lesion. A 25% increase in the diameter of a nodule represents an approximate doubling of the volume of the mass.
High-resolution CT scan can be helpful in determining calcium content, contour, and internal characteristics. Zwirewich and colleagues (1991) compared edge and internal composition of benign nodules with those of malignant nodules. Spiculation of the margin was present in 55% of the benign and 87% of the malignant nodules; pleural tags were present in 27% and 58%, respectively; and bubblelike areas of low attenuation (air bronchograms, cavitation, or tumor necrosis) were observed in 25% of the malignant and only 9% of the benign nodules.
When a solitary noncalcified nodule less than 3 cm in diameter is found in a patient 25 years or older with no current or past evidence of extrapulmonary malignancy and with no knowledge of prior films documenting stability of the lesion, the burden is on the physician to disprove malignancy. Given the test characteristics of PET (described previously) and the fact that additional information regarding the mediastinum and possibly metastatic disease can be garnered from this noninvasive study, we would recommend a PET scan where available. Where PET is not available, a bolus contrast CT scan will suffice. A negative scan would help the physician to recommend observation and follow-up imaging. If the nodule is amenable to thoracoscopic resection, this procedure has 100% sensitivity and 100% specificity. As Mack and colleagues (1993a) have demonstrated, operative mortality should be zero and the complication rate should be under 5%. Most patients have already had a CT scan for evaluation, and if thoracoscopy demonstrates malignancy, definitive therapy can be undertaken.
We rarely perform transthoracic needle aspiration for a solitary pulmonary nodule except in special circumstances previously discussed. In Calhoun and associates' (1986) series of 397 consecutive patients undergoing transthoracic needle aspiration, 132 patients had a no cancer diagnosis, and 29% were subsequently found to have a malignancy. Because of such a high yield of nondiagnostic results, we favor a more aggressive approach.
REFERENCES
Aabakken L, et al: Cost-efficacy of endoscopic ultrasonography with fine-needle aspiration vs mediastinotomy in patients with lung cancer and suspected mediastinal adenopathy. Endoscopy 31:707, 1999.
Arroglia AC, Matthay RA: The role of bronchoscopy in lung cancer. Clin Chest Med 14:87, 1993.
Blum JE, Handmaker H, Rinne NA: The utility of a somatostatin-type receptor binding peptide radiopharmaceutical (P829) in the evaluation of solitary pulmonary nodules. Chest 115:224, 1999.
Burgers JA, et al: Endobronchial ultrasound. Lung Cancer 34:S109, 2001.
Calhoun P, et al: The clinical outcome of needle aspirations of the lung when cancer is not diagnosed. Ann Thorac Surg 41:592, 1986.
Canadian Lung Oncology Group: Investigation for mediastinal disease in patients with apparently operable lung cancer. Ann Thorac Surg 60:1382, 1995.
Canadian Lung Oncology Group: Investigating extrathoracic metastatic disease in patients with apparently operable lung cancer. Ann Thorac Surg 71:425, 2001.
Chin R Jr, et al: Transbronchial needle aspiration in diagnosing and staging lung cancer: how many aspirates are needed? Am J Respir Crit Care Med 166:377, 2002.
Cole FH Jr, et al: Cerebral imaging in the asymptomatic preoperative bronchogenic carcinoma patient: is it worthwhile? Ann Thorac Surg 57:838, 1994.
Colice GL: Detecting lung cancer as a cause of hemoptysis in patients with a normal chest radiograph: bronchoscopy vs CT. Chest 111:877, 1997.
Colice GL, et al: Cost-effectiveness of head CT in patients with lung cancer without clinical evidence of metastases. Chest 108:1264, 1995.
Daly BD, et al: N2 lung cancer: outcome in patients with false-negative computed tomographic scans of the chest. J Thorac Cardiovasc Surg 105:904, 1993.
Dasgupta A, Mehta AC: Transbronchial needle aspiration: an underused diagnostic technique. Clin Chest Med 20:39, 1999.
Freixinet Gilart J, et al: Extended cervical mediastinoscopy in the staging of bronchogenic carcinoma. Ann Thorac Surg 70:1641, 2000.
Fritscher-Ravens A, et al: Mediastinal lymph node involvement in potentially resectable lung cancer: comparison of CT, positron emission tomography, and endoscopic ultrasonography with and without fine-needle aspiration. Chest 123:442, 2003.
Funatsu T, et al: The role of mediastinoscopic biopsy in preoperative assessment of lung cancer. J Thorac Cardiovasc Surg 104:1688, 1992.
Gaer JAP, Goldstraw P: Intraoperative assessment of nodal staging at thoracotomy for carcinoma of the bronchus. Eur J Cardiothorac Surg 4:207, 1990.
Ginsberg RJ: Evaluation of the mediastinum by invasive techniques. Surg Clin North Am 67:1025, 1987.
Ginsberg RJ, et al: Extended cervical mediastinoscopy. A single staging procedure for bronchogenic carcinoma of the left upper lobe. J Thorac Cardiovasc Surg 94:673, 1987.
P.1547
Goldsmith SJ, Kostakoglu L: Nuclear medicine imaging of lung cancer. Radiol Clin North Am 38:511, 2000.
Gonzalez-Stawinski GV, et al: A comparative analysis of positron emission tomography and mediastinoscopy in staging patients with non-small cell lung cancer. J Thorac Cardiovasc Surg 125:1900, 2003.
Gould MK, et al: Accuracy of positron emission tomography for diagnosis of pulmonary nodules and mass lesions: a meta-analysis. JAMA 285:914, 2001.
Gress FG, at al: Endoscopic ultrasonography, fine-needle aspiration biopsy guided by endoscopic ultrasonography and computed tomography in the preoperative staging of non-small cell lung cancer: a comparison study. Ann Intern Med 127:604, 1997.
Guyatt GH, et al: Surgeons' assessment of symptoms suggesting extrathoracic metastases in patients with lung cancer. Ann Thorac Surg 68:309, 1999.
Harrow EM, et al: The utility of transbronchial needle aspiration in the staging of bronchogenic carcinoma. Am J Respir Crit Care Med 161:601, 2000.
Ichinose Y, et al: Preoperative examination to detect distant metastasis is not advocated for asymptomatic patient with stages 1 and 2 non-small cell lung cancer. Chest 96:1104, 1989.
Kernstine KH, et al: Can FDG-PET reduce the need for mediastinoscopy in potentially resectable nonsmall cell lung cancer? Ann Thorac Surg 73:394, 2002.
Kormas P, Bradshaw JR, Jeyasingham K: Preoperative computed tomography of the brain in non-small cell bronchogenic carcinoma. Thorax 47:106, 1992.
Lababede O, Meziane MA, Rice TW: TNM staging of lung cancer. Chest 115:233, 1999.
Landreneau RJ, et al: Thoracoscopic mediastinal lymph node sampling: useful for mediastinal lymph node stations inaccessible by cervical mediastinoscopy. J Thorac Cardiovasc Surg 106:554, 1993.
Leef JL III, Klein IS: The solitary pulmonary nodule. Radiol Clin North Am 40:123, 2002.
Lizza N, et al: Thoracoscopic resection of pulmonary nodules after computed tomographic-guided coil labeling. Ann Thorac Surg 71:986, 2001.
Lopez L, et al: Extended cervical mediastinoscopy: prospective study of fifty cases. Ann Thorac Surg 57:555, 1994.
Mack MJ, et al: Techniques for localization of pulmonary nodules for thoracoscopic resection. J Thorac Cardiovasc Surg 106:550 1993a.
Mack MJ, et al: Thoracoscopy for the diagnosis of the indeterminate solitary pulmonary nodule. Ann Thorac Surg 56:825, 1993b.
McLoud TC, et al: Bronchogenic carcinoma: analysis of staging in the mediastinum with CT by correlative lymph node mapping and sampling. Radiology 182:319, 1992.
McNeil TM, Chamberlain JM: Diagnostic anterior mediastinotomy. Ann Thorac Surg 2:532, 1966.
Moon SW, et al: Fluoroscopy-aided thoracoscopic resection of pulmonary nodule localized with contrast media. Ann Thorac Surg 68:1815, 1999.
Mountain CF: Revisions in the international system for staging lung cancer. Chest 111:1710, 1997.
Mountain CF, Dresler CM: Regional lymph node classification for lung cancer staging. Chest 111:1718, 1997.
Naruke T, Suemasu K, Ishikawa S: Lymph node mapping and curability of various levels of metastases in resected lung cancer. J Thorac Cardiovasc Surg 76:832, 1978.
Nathan MH, Collins VP, Adams RA: Differentiation of benign and malignant pulmonary nodules by growth rate. Radiology 79:221, 1962.
Oliver TWJ, et al: Isolated adrenal masses in nonsmall cell bronchogenic carcinoma. Radiology 153:217, 1984.
Patchell RA, et al: A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med 322:494, 1990.
Pieterman RM, et al: Preoperative staging of non-small-cell lung cancer with positron-emission tomography. N Engl J Med 343:254, 2000.
Pirozynski M: Bronchoalveolar lavage in the diagnosis of peripheral, primary lung cancer. Chest 102:372, 1992.
Reichenberger F, et al: The value of transbronchial needle aspiration in the diagnosis of peripheral pulmonary lesions. Chest 116:704, 1999.
Robinson LA, et al: Intraoperative gamma probe-directed biopsy of asymptomatic suspected bone metastases. Ann Thorac Surg 65:1426, 1998.
Rogers LF: Secondary malignancies in bone. In Juhl JH, Crummy AB (eds): Paul and Juhl's Essentials of Radiologic Imaging. Philadelphia: Lippincott, 1993, p. 164.
Roviaro GC, et al: Videothoracoscopic staging and treatment of lung cancer. Ann Thorac Surg 59:971, 1995.
Salazar AM, Westcott JL: The role of transthoracic needle biopsy for the diagnosis and staging of lung cancer. Clin Chest Med 14:99, 1993.
Savage C, Morrison RJ, Zwischenberger JB: Bronchoscopic diagnosis and staging of lung cancer. Chest Surg Clin N Am 11:701, 2001.
Schenk DA, et al: Comparison of the Wang 19-gauge and 22-gauge needle in the mediastinal staging of lung cancer. Am Rev Respir Dis 147:1251, 1993.
Shannon JJ, et al: Endobronchial ultrasound-guided needle aspiration of mediastinal adenopathy. Am J Respir Crit Care Med 153:1424, 1996.
Shennib H, Bret P: Intraoperative transthoracic ultrasonographic localization of occult lung lesions. Ann Thorac Surg 55:767, 1992.
Shure D, Fedullo PF: Transbronchial needle aspiration of peripheral masses. Am Rev Respir Dis 128:1090, 1983.
Shure D, Fedullo PF: The role of transcarinal needle aspiration in the staging of bronchogenic carcinoma. Chest 86:693, 1984.
Silvestri GA, et al: The relationship of clinical findings to CT evidence of adrenal metastases in the staging of bronchogenic carcinoma. Chest 102:1748, 1992.
Silvestri G, Littenberg B, Colice GL: The clinical evaluation for detecting metastatic lung cancer: a meta-analysis. Am J Respir Crit Care Med 152:225, 1995.
Silvestri G, et al: Endoscopic ultrasound with fine-needle aspiration in the diagnosis and staging of lung cancer. Ann Thorac Surg 61:1441, 1996.
Silvestri G, et al: The noninvasive staging of non-small cell lung cancer: the guidelines. Chest 123:147S, 2003.
Swanson SI, et al: Management of the solitary pulmonary nodule: role of thoracoscopy in diagnosis and therapy. Chest 116:532S, 1999.
Swensen SJ, et al: An integrated approach to evaluation of the solitary pulmonary nodule. Mayo Clin Proc 65:173, 1990.
Swensen SJ, et al: The probability of malignancy in solitary pulmonary nodules. Application to small radiologically indeterminate nodules. Arch Intern Med 157:849, 1997.
Tanaka K, et al: Extrathoracic staging is not necessary for non-small-cell lung cancer with clinical stage T1 2 N0. Ann Thorac Surg 68:1039, 1999.
Toloza E, Harpole L, McCrory DC: Noninvasive staging of non-small cell lung cancer: a review of the current evidence. Chest 123:137S, 2003.
Travis WD, Linden J, MacKay B: Classification histology, cytology and electron microscopy. In Pass HI, et al. (eds): Lung Cancer Principles and Practice. Philadelphia: Lippincott-Raven, 1996, p. 361.
van Tinteren H, et al: Effectiveness of positron emission tomography in the preoperative assessment of patients with suspected non-small-cell lung cancer: the PLUS multicentre randomised trial. Lancet 359:1388, 2002.
Vesselle H, et al: The impact of fluorodeoxyglucose F 18 positron-emission tomography on the surgical staging of non-small cell lung cancer. J Thorac Cardiovasc Surg 124:511, 2002.
Wallace MB, et al: Endoscopic ultrasound-guided fine needle aspiration for staging patients with carcinoma of the lung. Ann Thorac Surg 72:1861, 2001.
Wang KP: Transbronchial needle aspiration and percutaneous needle aspiration for staging and diagnosis of lung cancer. Clin Chest Med 16:535, 1995.
Webb WR, et al: CT and MR imaging in staging non-small cell bronchogenic carcinoma: report of the Radiologic Diagnostic Oncology Group. Radiology 178:705, 1991.
Wiersema MJ, et al: Evaluation of mediastinal lymphadenopathy with endoscopic US-guided fine-needle aspiration biopsy. Radiology 219:252, 2001.
Yankelvitz DF, Henschke CI: Lung cancer: small solitary pulmonary nodules. Radiol Clin North Am 38:1, 2000.
Zwirewich CV, et al: Solitary pulmonary nodule: high resolution CT and radiologic-pathologic correlation. Radiology 179:469, 1991.
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