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Invasive Mediastinal Staging of Lung Cancer^*

ACCP Evidence-Based Clinical Practice Guidelines (2nd Edition)

^* From the Division of Thoracic Surgery (Dr. Detterbeck), Yale University, New Haven, CT; Division of Pulmonary and Critical Care Medicine (Dr. Jantz), University of Florida, Gainesville, FL; Mayo Clinic (Dr. Wallace), Jacksonville, FL; Division of Pulmonary Medicine (Dr. Vansteenkiste), Catholic University, Leuven Belgium; and Division of Pulmonary and Critical Care Medicine (Dr. Silvestri), Medical University of South Carolina, Charleston, SC.

Correspondence to: Frank C. Detterbeck, MD, FCCP, Division of Thoracic Surgery, Department of Surgery, Yale University, 330 Cedar St, FMB 128, New Haven, CT 06520-8062; e-mail: frank.detterbeck{at}yale.edu

	Abstract

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Background: The treatment of non-small cell lung cancer (NSCLC) is determined by accurate definition of the stage. If there are no distant metastases, the status of the mediastinal lymph nodes is critical. Although imaging studies can provide some guidance, in many situations invasive staging is necessary. Many different complementary techniques are available.

Methods: The current guidelines and medical literature that are applicable to this issue were identified by computerized search and were evaluated using standardized methods. Recommendations were framed using the approach described by the Health and Science Policy Committee of the American College of Chest Physicians.

Results: Performance characteristics of invasive staging interventions are defined. However, a direct comparison of these results is not warranted because the patients selected for these procedures have been different. It is crucial to define patient groups, and to define the need for an invasive test and selection of the best test based on this.

Conclusions: In patients with extensive mediastinal infiltration, invasive staging is not needed. In patients with discrete node enlargement, staging by CT or positron emission tomography (PET) scanning is not sufficiently accurate. The sensitivity of various techniques is similar in this setting, although the false-negative (FN) rate of needle techniques is higher than that for mediastinoscopy. In patients with a stage II or a central tumor, invasive staging of the mediastinal nodes is necessary. Mediastinoscopy is generally preferable because of the higher FN rates of needle techniques in the setting of normal-sized lymph nodes. Patients with a peripheral clinical stage I NSCLC do not usually need invasive confirmation of mediastinal nodes unless a PET scan finding is positive in the nodes. The staging of patients with left upper lobe tumors should include an assessment of the aortopulmonary window lymph nodes.

Key Words: anterior mediastinotomy • bronchoscopy • Chamberlain procedure • clinical staging • endobronchial ultrasound • esophageal ultrasound • mediastinal lymph nodes • mediastinoscopy • N2 • N3 • pathologic staging • staging • transbronchial needle aspiration • transthoracic needle aspiration • video-assisted thoracic surgery

	Introduction

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This chapter addresses invasive procedures for confirmatory staging of the mediastinum in patients with lung cancer. The focus is on patients in whom there is a strong suspicion of lung cancer. Such a presumptive clinical diagnosis is generally possible by an experienced clinician after an assessment of risk factors, and a review of the clinical presentation and the radiographic appearance on a CT scan. If the presence of distant metastatic disease has been ruled out, the status of the mediastinum becomes the crucial factor in selecting the optimal treatment strategy. The initial clinical evaluation (ie, clinical presentation and CT scan findings) already yields a presumptive clinical stage with respect to the mediastinum, which may have been supplemented by a positron emission tomography (PET) scan as well. However, noninvasive imaging tests can provide only a suspicion that involvement of the mediastinal nodes is present or absent, and in many clinical situations confirmation of the status of these nodes by an invasive test is necessary. The reliability of noninvasive tests is discussed in chapter 12 in this supplement. This chapter discusses the performance characteristics of the various invasive staging tests for the mediastinum, how to select a test, and how to interpret the results.

Several invasive tests are available to stage the mediastinum (Table 1 ). These include mediastinoscopy, the Chamberlain procedure (also known as an anterior mediastinotomy), transthoracic needle aspiration (TTNA) of the mediastinum, transbronchial needle aspiration (TBNA), endobronchial ultrasound (EBUS) with needle aspiration (NA), esophageal endoscopic ultrasound (EUS) with NA, and video-assisted thoracic surgery (VATS), which is also known as thoracoscopy. Invasive tests are also sometimes needed to confirm or exclude distant metastases, but these are not discussed in this chapter.

Obviously, in many situations an invasive test can provide both confirmation of the diagnosis and confirmation of the stage at the same time. This fact underlies the importance of not immediately pursuing a diagnostic test in patients but rather thinking through the presumptive diagnosis, the presumptive stage, and the need for further confirmatory staging tests first.

In general, patients with lung cancer can be separated into four groups (Table 2 ) with respect to intrathoracic radiographic characteristics (including both the primary tumor and the mediastinum), as was discussed in chapter 12 on noninvasive staging. Briefly, the groups consist of patients with extensive mediastinal infiltration (radiographic group A), patients with enlargement of discrete mediastinal nodes the size of which can be measured (radiographic group B), patients with normal mediastinal nodes determined by CT scan but with a central tumor or suspected N1 disease (radiographic group C), and patients with normal mediastinal nodes and a peripheral clinical stage I tumor (radiographic group D).

The interpretation and application of the results of invasive staging procedures are difficult because the published data are defined by patients who have undergone a particular test, rather than by radiographic or clinical criteria that could be used prospectively to select patients for a particular approach. The patients who have undergone a particular procedure are a mix of the different radiographic groups just discussed, and often include patients in whom the primary issue was confirmation of the diagnosis, those in whom it was confirmation of nodal involvement, and those in whom it was confirmation of the lack of nodal involvement. Furthermore, the location of suspected nodal involvement influences which test is performed because some nodal stations are easily accessible by one test and not by another. Therefore, the patient cohorts included in series of particular invasive procedures are likely not the same. This makes a comparison of the sensitivity and specificity of the different tests inappropriate. However, we have attempted to make a loose comparison for patients in particular radiographic subgroups, with recognition that this assessment must be taken with a large grain of salt. In addition, the amount of experience is very likely to affect the performance characteristics of a procedure and must also be taken into account in choosing an invasive staging procedure in a specific practice setting. At any rate, it is best to view the different invasive staging tests as complementary and not competitive.

The approach taken in this chapter is to summarize the performance characteristics of each invasive test first, with the recognition that the patients included in studies of a particular test are generally poorly defined, and that direct comparisons between tests are inappropriate. This is followed by a somewhat speculative discussion about which types of patients were included and an analysis of the test results for particular subgroups, whenever this is possible. Finally, the last section uses the available data and the nuances of patient subgroups to attempt to define an integrated approach for use in invasive staging tests of the mediastinum.

It must be emphasized that all of the tests discussed in this chapter are used to refine the clinical stage as defined by the American Joint Committee on Cancer. The clinical stage is the stage that is determined using all information available prior to any treatment, and thus is the most useful staging classification in actual practice. The information available may be limited (ie, involving only a chest CT scan) or extensive (ie, involving invasive procedures). An invasive staging procedure is still considered to be part of clinical staging, even though it may involve a surgical procedure (ie, mediastinoscopy) and evaluation by a pathologist. The pathologic stage is applicable only to patients who have undergone surgical resection, including an accurate assessment of potential areas of spread (such as lymph nodes) by the surgeon and the pathologist. In general, the pathologic stage is viewed as the closest approximation to the true stage, but is useful only for postoperative prognostication, and is not applicable during patient evaluation and selection of a treatment strategy.

	Materials and Methods

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The data presented here are based on a systematic search and evaluation of the published literature from January 1980 through June 2006. Articles published prior to July 2001 were identified according to the criteria laid out in the previous version of the American College of Chest Physicians lung cancer guidelines.¹ Subsequent literature was identified by the authors using the same search strategy and selection criteria (briefly, studies published in the English language, peer-reviewed, nonoverlapping, having at least 20 patients, containing an adequate assessment of the true nodal status, and with the ability to calculate performance characteristics).¹

The data abstraction was performed for patients suspected of having lung cancer (eg, non-small cell lung cancer [NSCLC] and small cell lung cancer [SCLC]). Patients suspected of a diagnosis other than lung cancer were excluded from the study, where possible. A definite diagnosis of any lung cancer in the mediastinal tissues was considered to be positive, while other diagnoses (eg, benign disease or lymphoma) were coded as negative for lung cancer. Equivocal test results were considered to be negative. Biopsies that were aborted or yielded insufficient tissue are included as negative findings and are counted as such in the statistics. The reported feasibility of the test is also reported (ie, the proportion of patients undergoing the test in whom an adequate biopsy was able to be obtained) in order to have an assessment of the technical success rate. The calculation of the subtotal or total summary performance characteristics was accomplished by the calculation of an average of the values (eg, of sensitivity and specificity) from each study; in other words, no weighting according to study size was performed. This was chosen for simplicity, and because a comparison of the results using both methods revealed minimal differences (ie, 1 to 2 percentage points).

Various parameters can be used to assess the reliability of a test, including sensitivity, specificity, and FN and FP rates (typically expressed as a percentage). The latter two measures are sometimes expressed in a less intuitive manner as the converse, known as the negative predictive value (1 – FN rate) or the positive predictive value (1 – FP rate). Sensitivity and specificity are derived from patient populations in whom the true disease status is already known, who either all have or do not have the condition in question. These parameters provide data about how often the test results will be positive or negative for these respective populations. Thus, these measures provide information about the test, because the disease status has already been determined in the patients. In theory, these measures can be used to compare different tests, provided the patient populations in which the tests are used are the same. Unfortunately, particularly with regard to invasive staging tests, the patients selected for different tests are not the same, limiting the value of the measures of sensitivity and specificity. Furthermore, the FN and FP rates are of much greater practical use to the clinician, who must interpret the reliability of a test result (positive or negative) in an individual patient. The clinician does not know the true disease status of the patient, only that the patient falls within the group of those with a negative or positive test result. It is important to point out that the FN rate or FP rate of the test cannot be estimated from the sensitivity or specificity, because these are each derived from different formulas. This is a common misconception that frequently creates confusion and inappropriate interpretation of the test results. The only exception to this fact is in the case of "perfect" test performance (ie, a sensitivity of 100% does, in fact, imply an FN rate of 0%, and a specificity of 100% implies an FP rate of 0%).

This chapter focuses on the clinician’s viewpoint and therefore places an emphasis on the FN and FP rates. The clinician is caring for individual patients. From this perspective, a test is useful if one is comfortable basing treatment decisions on the result, because it is sufficiently predictive of the true disease status in that patient.

	Techniques of Invasive Mediastinal Staging

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Mediastinoscopy
Mediastinoscopy is performed in the operating room, usually under general anesthesia, and in most United States centers patients are discharged from the hospital the same day.²³⁴ The procedure involves an incision just above the suprasternal notch, insertion of a mediastinoscope alongside the trachea, and biopsy of the mediastinal nodes. Rates of morbidity and mortality as a result of this procedure are low (2% and 0.08%, respectively).⁵ Right and left high and low paratracheal nodes (stations 2R, 2L, 4R, and 4L), pretracheal nodes (stations 1 and 3), and anterior subcarinal nodes (station 7) are accessible via this approach. Node groups that cannot be biopsied with this technique include posterior subcarinal nodes (station 7), inferior mediastinal nodes (stations 8 and 9), aortopulmonary window (APW) nodes (station 5), and anterior mediastinal nodes (station 6). The availability of a videomediastinoscope allows better visualization, more extensive sampling (including posterior station 7), and even performance of a complete lymph node dissection through this approach.⁶⁷

The average sensitivity of mediastinoscopy to detect mediastinal node involvement from cancer is approximately 80%, and the average FN rate is approximately 10% (Table 3 ).^{6812131516777879808182838485868788} Several authors^8910111213 have shown that approximately half (range, 42 to 57%) of the FN cases were due to nodes that were not accessible by the mediastinoscope. The FN rate at mediastinoscopy is probably also affected by the diligence with which nodes are dissected and sampled at mediastinoscopy. Ideally, five nodal stations (stations 2R, 4R, 7, 4L, and 2L) should routinely be examined, with at least one node sampled from each station unless none are present after actual dissection in the region of a particular node station. Videomediastinoscopy appears to yield some improvement in sensitivity (90%) and FN rates (7%).⁶¹³¹⁴ The specificity and the FP rates of mediastinoscopy are reported to be 100% and 0%, respectively. Strictly speaking, these values cannot really be assessed because patients with a positive biopsy finding were not subjected to any further procedures (such as thoracotomy) to confirm the results. Nevertheless, it seems reasonable to assume that the FP rate is low. Few studies have reported feasibility, but in general it appears to be quite high.

EUS-NA
EUS-NA of mediastinal lymph nodes through the wall of the esophagus has been performed with a negligible risk of infection or bleeding. Only one complication (transient fever) has been reported among 6 studies involving 369 patients.^171819202122 No mortality has been reported. This technique is particularly useful for inferior pulmonary ligament, esophageal, subcarinal, and APW nodes (stations 9, 8, 7, and 5). Nodes that are anterolateral to the trachea (stations 2R, 2L, 4R, and 4L) are difficult to sample reliably (but are more commonly involved with lung cancer). This procedure requires a skilled endoscopist with specific experience and the necessary equipment, which is becoming more commonly available at many tertiary referral centers.

Sixteen studies^{17181920212223242627282931348990} met the inclusion criteria and assessed the use of EUS-NA in the mediastinal staging of 973 evaluable lung cancer patients (Table 4 ). There are no data regarding the feasibility of EUS-NA, but it is assumed to be high for well-selected patients at experienced centers. For the detection of malignant mediastinal (ie, N2 or N3) lymph nodes, the overall sensitivity was 84%, and the overall FN rate was 19% (range, 0 to 61%). The overall specificity was 99.5%, and the overall FP rate was 0.4%, but only one study²³ truly allowed the evaluation of these performance characteristics because it is the only study in which a positive result was investigated further. In this study, a surgical excision of lymph nodes that were positive, as determined by EUS-NA, was performed; a specificity of 97% and an FP rate of 7% were found.²³ Interestingly, this is the same as the average FP rate for TBNA in those studies that have assessed this.

Some studies^{171920212224252627282930} have reported on more specific groups of patients. Among patients with enlarged lymph nodes seen on CT scan, the sensitivity is 87% and the FN rate is 22% (specificity, 98%; FP rate, 2%). In these studies, the prevalence of N2,3 involvement was 68%. Among patients with normal-sized lymph nodes seen on CT scans, the sensitivity is 66% and the FN rate is 14% (specificity, 100%; FP rate, 0%).²⁴³¹ In these studies, the prevalence of N2 or N3 disease was 36%, which is higher than the expected rate (20 to 25%) based on the CT scan data for normal-sized mediastinal nodes, even for patients with central tumors or cN1 involvement.³² Thus, it can be surmised that many of these patients were selected based on PET scan positivity. Nevertheless, it is reasonable to assume that the performance characteristics of EUS-NA apply broadly to patients with cN0,1 tumors, because the technical issues are probably governed by the size of the nodes and should be relatively unaffected by PET scan results.

Emerging data suggest that the combination of EUS-NA and EBUS-NA may allow complementary and nearly complete access to all mediastinal lymph node stations. One study found a sensitivity of 97% and an FN rate of 2% for combined EUS and EBUS in a population with a prevalence of mediastinal metastases of 42%.³³ The ability to perform both procedures in a single session is appealing, although there are many unresolved issues regarding the training and availability of personnel with combined endoscopic and bronchoscopic expertise.

EUS-FNA is also capable of detecting metastatic disease to subdiaphragmatic sites such as the left adrenal gland, celiac lymph nodes, and the liver. The overall yield is 4% (37 of 834 patients) for such M1 disease detected by EUS-NA.^{1820232426273134} The actual performance characteristics for the detection of M1 disease by EUS-NA cannot be calculated because patients generally do no undergo exploration of the abdomen.

EUS is also capable of evaluating the presence of direct tumor invasion into the mediastinum (T4). Eight studies^{1823242627313435} have evaluated the prevalence of T4 disease, but only one study³⁵ has specifically evaluated the reliability of EUS for T staging. This study found a sensitivity of 88%, a specificity of 98%, an FN rate of 1%, and an FP rate of 30%. Overstaging appeared to occur when a tumor was seen only to invade the mediastinal soft tissues. The FP rate was 0% if a tumor was seen within a blood vessel or the esophagus. Thus, although EUS can be helpful in determining the T stage, the high FP rate, in general, limits the basing of treatment decisions on this test.

The cost of EUS is less than surgical staging procedures, probably due to the ability to perform EUS without general anesthesia in an ambulatory setting. Two studies³⁶³⁷ have suggested that EUS may be more cost-effective compared to mediastinoscopy, although these studies assumed that mediastinoscopy frequently required inpatient hospital admission.

TBNA
TBNA, also known as a Wang NA, can be performed safely with no significant morbidity. It can be performed on an outpatient basis, as is the case with most bronchoscopic procedures. TBNA is used most frequently to assess subcarinal nodes. Paratracheal lymph nodes may also be biopsied with TBNA, but these are sometimes more difficult to access, due to the difficulty in sufficiently angulating the bronchoscope and the needle. It has been reported^38394041 that it is feasible to obtain adequate specimens via TBNA in approximately 80 to 90% of cases.

Seventeen studies^{383940414244919293949596979899100101} met the inclusion criteria for mediastinal staging with TBNA (Table 5 ). The overall sensitivity was 78% with values ranging from 14 to 100%. The average FN rate was approximately 28% (range, 0 to 66%). The reported specificity and FP rates were 100% and 0%, respectively, although few studies confirmed positive TBNA results with further invasive procedures. Occasional FP results have been reported in series⁴²⁴³⁴⁴ in which this has been specifically examined with a confirmatory test (average, 7%).

EBUS-NA
EBUS-NA is a relatively new technique for mediastinal staging. Initially, EBUS was accomplished by introducing a catheter with an ultrasound transducer at the tip of the catheter through the working channel of the bronchoscope. The lymph node was localized with the probe, and the catheter was then withdrawn. The lymph node would then be sampled with TBNA without real-time guidance. More recently, a bronchoscope with a convex ultrasound probe has been developed that allows for real-time ultrasound-guided TBNA.⁴⁵ EBUS-NA can be used to sample the highest mediastinal, upper and lower paratracheal, and subcarinal lymph nodes, as well as hilar lymph nodes.

Eight studies^{4647101102103104105112} met the inclusion criteria for mediastinal staging with EBUS-NA (see Table 6 ). The overall sensitivity was 90%, with values ranging from 79 to 95%. The average FN rate in general was 24% (range, 1 to 37%). One study⁴⁶ with an extremely high FN rate (89%) was excluded from this calculation. This FN rate is explained by an extremely high disease prevalence (98%), because extremely high (or low) prevalence makes the FN rate (or FP rate) unreliable purely on mathematical grounds.³² The specificity and FP rates were 100% and 0%, respectively, but these values are artificial because positive EBUS-NA results were not confirmed.

TTNA
TTNA or biopsy for the diagnosis and staging of the mediastinum is distinct from TTNA of parenchymal masses to achieve a diagnosis. The ability to carry out TTNA for the diagnosis and staging of cancer in the mediastinum has generally been reported to be high (ie, > 90%), although approximately 10% of patients require the placement of a catheter for the evacuation of a pneumothorax.³² The sensitivity has generally been reported to be approximately 90% (see Table 7 ).^{106107108109110}

VATS
Thoracoscopy, also known as VATS, can be used to access mediastinal nodes. This is done under general anesthesia and in general is limited to an assessment of only one side of the mediastinum. Access to the R-sided nodes is straightforward, but access to the L paratracheal nodes is more difficult. Several series have shown the feasibility of this technique. No mortality has been reported from VATS for mediastinal staging, and complications were noted in only 12 of 669 patients (average, 2%; range, 0 to 9%).^{4849505152535455}

The performance characteristics of VATS mediastinal node biopsy for N2 node staging are shown in Table 8 . The sensitivity varies widely, from 37 to 100%. The reason for this variation is not entirely clear. Even if the studies are restricted to patients with enlarged nodes, the sensitivity still ranges from 50 to 100%. The low sensitivity comes primarily from a study by Sebastian-Quetglas et al⁴⁹ This study is the only prospective, multiinstitutional study, and may perhaps be more generally applicable than the results from single institutions with a focused interest and extensive experience. It should be noted that VATS staging was feasible in only 75% of patients in this series. The performance characteristics recorded here are those that apply specifically to determination of mediastinal node status. The FN rate is 15% both in enlarged and normal-sized nodes. In all reports, the specificity is reported as 100% and the FP rate as 0%, but this is technically not evaluable because no further testing was done in the event of a positive VATS result.

Assessment of APW Lymph Nodes
Cancers in the left upper lobe (LUL) have a predilection for involvement of the nodes in the APW (station 5). These nodes are classified as mediastinal nodes and represent the most important group of N2 nodes that are not accessible by standard cervical mediastinoscopy. It has been suggested⁵⁷ that nodes in this region should not be viewed as mediastinal nodes and that the resection of patients should be performed regardless of APW node involvement, making the assessment of these nodes superfluous. This was based on a selected subgroup of 23 completely resected patients who had APW node involvement as the only site of N2 disease. However, the analysis of all of the data in this regard shows that the survival of patients with only APW node involvement is not substantially different than that of patients with involvement of only a single N2 node station in another location.⁵⁸ Therefore, the issue is more a matter of whether patients with involvement of a single mediastinal node station should undergo surgical resection, and not whether APW nodes should be classified as N2 nodes.

The classic way of invasively assessing this area is a Chamberlain procedure (also known as an anterior mediastinotomy), which involves an incision in the second or third intercostal space just to the left of the sternum. Traditionally, an overnight hospital stay has been necessary, but in many institutions this is no longer found to be necessary, especially as surgeons have used visualization between the ribs more frequently as opposed to removal of a costal cartilage. The reliability of this procedure has not been extensively documented, despite its common use. The sensitivity of a Chamberlain procedure in addition to standard cervical mediastinoscopy in patients with LUL tumors is approximately 87%, and the FN rate is approximately 10% (Table 9 ). Two additional studies⁵⁹⁶⁰ regarding this procedure have not really addressed the reliability of the procedure for the staging of NSCLC. In one study,⁵⁹ no actual biopsies were performed in most patients, and the procedure was used to assess resectability (in this series, resectable patients included those with bulky APW nodal involvement). The other study⁶⁰ used anterior mediastinotomy primarily for diagnosis (not staging), and included pulmonary biopsies and evaluation of patients with mediastinal masses. In fact, only a minority of patients included in this study had lung cancer.

The patients included in these series of Chamberlain procedure or extended cervical mediastinoscopy have had potentially operable lung cancer with very few exceptions. These patients are primarily from radiographic group B, with probably a few from group C. The reported results provide data regarding the reliability of these tests for the staging of mediastinal nodes compared to thoracotomy in patients with lung cancer.

Other Staging Procedures
In patients with signs of advanced disease, clinical scenarios often occur that indicate the need for other invasive procedures to be performed, such as NA of a supraclavicular lymph node, thoracentesis or thoracoscopy of a pleural effusion, or NA or biopsy of a metastatic site such as an enlarged adrenal or hepatic mass. The indications for such procedures are covered in more detail in the chapters on diagnosis⁹ and noninvasive staging,¹² and specific recommendations regarding such procedures can be found in these chapters as well. In brief, if an enlarged supraclavicular lymph node or a pleural effusion is present, it is generally prudent to pursue a diagnosis of these lesions. When the clinical presentation is entirely consistent with locally advanced disease (stage IIIb), these procedures are usually indicated because they represent the easiest way to confirm the diagnosis of lung cancer. When the clinical presentation is otherwise not consistent with locally advanced disease, the etiology of these lesions must be established in order to accurately define the stage. However, the procedures used to diagnose an enlarged supraclavicular node (ie, NA or surgical biopsy) are the same regardless of whether the issue is to confirm the diagnosis or to define the stage. Similarly, in patients with a clinical presentation that is consistent with advanced disease (stage IV), an invasive procedure may be indicated as the easiest way to confirm the diagnosis and establish the cell type of the lung cancer. In patients with a solitary site that is suspicious for a distant metastasis or in patients with a clinical presentation that seems inconsistent with advanced disease, an invasive procedure is indicated to accurately define the stage. The procedures used to assess possible distant sites are the same regardless of the clinical presentation, and are dictated primarily by technical and anatomic factors that are specific to the particular patient.

No data are available to assess the sensitivity, specificity, and FN and FP rates of NA of a supraclavicular node. General experience indicates that this procedure is usually successful; in addition, surgical biopsy of such a node is easily accomplished if a NA procedure is not diagnostic. The reliability of procedures to diagnose a pleural effusion is covered in the chapter on diagnosis. Thoracentesis has a sensitivity of approximately 60%; thoracoscopy has a sensitivity of > 95%. Procedures to diagnose suspected distant metastatic sites are too varied to discuss in detail; furthermore, no data are available that expressly assesses the reliability of these tests in patients with lung cancer.

	Approach to Patients

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Mediastinal Infiltration
In patients with extensive mediastinal infiltration, the radiographic evidence of mediastinal involvement is quite universally considered adequate. There are no data to prove this, because invasive confirmation is not done. However, even though staging is not an issue, tissue is needed to confirm the diagnosis and to establish what type of cancer is present (eg, NSCLC vs SCLC). In this case, it does not matter whether tissue is obtained from the primary tumor or from a mediastinal site.

In patients in whom the diagnosis is the primary issue, tissues should be obtained by whatever method is easiest to perform. In other words, the choice of procedure will be governed primarily by patient-specific factors (ie, anatomic, convenience, and comorbidity factors) instead of the performance characteristics of a test. For example, it is still likely that a test of relatively low sensitivity such as sputum cytology or cytology of a pleural effusion will be chosen first simply because it is easiest to perform. It is rare that such a patient will undergo TBNA, EUS-NA, or mediastinoscopy. Details of the performance characteristics of diagnostics tests of the primary tumor are summarized in chapter 9, and performance characteristics of the invasive mediastinal tests are summarized in the tables here. However, as noted above, the determining factor concerning which test to choose will be governed primarily by patient-specific issues.

	Recommendation

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1. For patients with extensive mediastinal infiltration of tumor and no distant metastases, radiographic (CT scan) assessment of the mediastinal stage is usually sufficient without invasive confirmation. Grade of recommendation, 2C

Discrete Mediastinal Lymph Node Enlargement
Many patients present with a CT scan demonstrating the enlargement of discrete mediastinal (N2,3) lymph nodes. An extensive literature³² demonstrates that enlargement seen on CT scan alone carries an FP rate of approximately 40% (see chapter 12). The PET scan literature has only recently become detailed enough to begin to define FN and FP rates in subgroups of patients such as those with discrete nodal enlargement seen on a CT scan. The FP rate for PET scanning in the mediastinum has been widely shown to be around 15 to 20%, although this has not been defined for this particular subgroup of patients. Two metaanalyses⁶⁶⁶⁷ have estimated the PET FN rate to be 13 to 25% in patients with nodal enlargement detected by CT scan, although these estimates are not based on direct data or clearly defined patients. Direct data from studies⁶⁸⁶⁹ in patients with mediastinal or hilar nodal enlargement (radiographic groups B and C combined) have found a PET FN rate of 20 to 28% for N2,3 involvement. Thus, it appears that in patients with enlarged mediastinal nodes detected by CT scanning, the CT scan alone cannot be relied on, and invasive biopsy is needed whether a PET scan finding is positive or negative.

In choosing an invasive staging test, several issues must be considered. First is the availability of different procedures. All of the invasive tests require some specialized experience and skill, and people who perform these procedures only occasionally may not be able to achieve the performance characteristics published in studies performed at high-volume institutions. Second, the location of the suspicious nodes is important, because nodes in one location may be accessible only by a particular approach. There may be factors related to patient comorbidity that may argue against certain approaches, such as mediastinoscopy, which usually requires general anesthesia. However, patients who are unable to tolerate a general anesthetic for such a small procedure as mediastinoscopy are likely not to be well enough to tolerate definitive treatment for lung cancer anyhow. The morbidity and mortality of invasive procedures may be a consideration, although all of the available procedures generally have an excellent safety profile. Finally, cost may be a consideration.

The sensitivity of various invasive mediastinal staging tests in cN2,3 patients appears to be similar. A strict comparison is not justified because the patients undergoing these procedures are not comparable due to differences in how they are selected for a particular procedure (eg, the location of the nodes). The primary issue is the variability in FN rates. If a NA technique is chosen, it must be remembered that a negative result is not very reliable. A NA procedure may well be a good first choice because these procedures are less invasive than mediastinoscopy. However, a negative needle biopsy finding should be followed up in general with mediastinoscopy.

An option for the treatment of patients with stage III NSCLC is induction therapy followed by surgery (see chapter 17). If this approach is chosen, the role of mediastinal restaging after induction therapy is very unclear. However, some people have argued that the approach should include surgery only in those patients who have a response in the mediastinum to induction therapy. It has been shown repeatedly⁷⁰ that CT scan evidence of tumor shrinkage is notoriously misleading. PET scanning for mediastinal restaging has also been shown to have high FP and FN rates.⁷⁰ A repeat mediastinoscopy is generally safe and feasible (82 to 100%) but has mediocre results (sensitivity, 70 to 82%; FN rate, 15 to 25%),^13717273 and most surgeons are uncomfortable with this procedure. Because a first-time mediastinoscopy is probably the best way to accomplish mediastinal restaging, an argument can be made to use a NA technique initially to document N2,3 involvement and to save mediastinoscopy for the restaging procedure after induction therapy. All of this only applies if the adopted treatment policy is one of induction therapy, with subsequent therapy to be determined by the results of mediastinal restaging (despite the lack of data defining the role of surgery and restaging).

	Recommendations

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2. For patients with discrete mediastinal lymph node enlargement (and no distant metastases), invasive confirmation of the radiographic stage is recommended (regardless of whether a PET scan finding is positive or negative in the mediastinal nodes). Grade of recommendation, 1B

3. For patients with discrete mediastinal lymph node enlargement (and no distant metastases), many invasive techniques for the confirmation of the N2,3 node status are suggested as reasonable approaches (eg, mediastinoscopy, EUS-NA, TBNA, EBUS-NA, or TTNA), given the appropriate experience and skill (regardless of whether a PET scan finding is positive or negative in the mediastinal nodes). Grade of recommendation, 1B

4. For patients with discrete mediastinal lymph node enlargement (and no distant metastases), a nonmalignant result from a needle technique (eg, EUS-NA, TBNA, EBUS-NA, or TTNA) should be further confirmed by mediastinoscopy (regardless of whether a PET scan finding is positive or negative in the mediastinal nodes). Grade of recommendation, 1C

Central and Clinical N1 Tumors
Patients with no evidence of mediastinal node enlargement but with a central tumor or N1 node involvement represent another distinct group (group C). It is reasonable to consider patients with central tumors together with those with N1 node enlargement, because it is usually difficult to assess the N1 nodes in the case of a central tumor. Extensive data indicate that the FN rate of a CT scan with respect to the mediastinal nodes is 20 to 25% (see chapter 12 on noninvasive staging).³² More limited data demonstrate that the FN rate for PET scanning in the mediastinal nodes in this situation is similarly high (24 to 83%).^68697475 Thus, invasive staging is required in these patients despite the negative CT scan result and even a negative PET scan result.

In patients with normal-sized mediastinal lymph nodes in whom invasive staging is needed, mediastinoscopy remains the "gold standard." The general experience with mediastinoscopy suggests that the FN rate (approximately 10%) is low in these patients, and those studies¹⁵¹⁶ that have specifically reported on these patients substantiate this. Although it cannot be directly compared to mediastinoscopy, the FN rate (20%) of EUS-NA demonstrates that a significant number of patients with negative EUS-NA finding may still harbor metastases. Subgroup analysis in the study by Wallace et al²⁴ has suggested that approximately one half of these FN cases were due to malignant lymph nodes in the anterior mediastinum, which may be more accessible by mediastinoscopy or, theoretically, EBUS-NA, although to date this area has not been carefully studied. The other half of FN cases were often due to very small deposits that may be more subject to sampling error of the needle or small biopsy methods.

Other methods of mediastinal staging have generally not been used much in this patient population (ie, TTNA, TBNA, and EBUS-NA). However, the performance characteristics of these tests, especially the FN rates, in patients with enlarged mediastinal nodes would suggest that TTNA, TBNA, and EBUS-NA are likely not to perform as well as mediastinoscopy in patients with normal-sized nodes. This is particularly true with regard to the FN rates. Because the goal of invasive staging in this situation is to confirm the absence of mediastinal disease, the FN rate is the parameter of greatest importance. It does not appear that the NA techniques can confirm a negative mediastinum finding with sufficient reliability. EBUS-NA may turn out to be sufficiently reliable to rule out mediastinal node involvement in small nodes, but the data are too preliminary to justify a firm recommendation.⁴⁷

	Recommendations

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5. For patients with a radiographically normal mediastinum (by CT scan) and a central tumor or N1 lymph node enlargement (and no distant metastases), invasive confirmation of the radiographic stage is recommended (regardless of whether a PET scan finding is positive or negative in the mediastinal nodes). Grade of recommendation, 1C

6. For patients with a central tumor or N1 lymph node enlargement (and no distant metastases), invasive staging is recommended. In general, mediastinoscopy is suggested, but EUS-NA or EBUS-NA may be a reasonable alternative if nondiagnostic results are followed by mediastinoscopy. Grade of recommendation, 2C

Peripheral Clinical Stage I Tumors
Patients with peripheral tumors in whom there is no enlargement of N1 or N2,3 nodes seen on CT scans, the FN rate of this radiographic assessment in the mediastinum is approximately 10%.³² The incidence is lower in patients with T1 tumors (9%) than in those with T2 tumors (13%).³² Whether this incidence is viewed as being high enough to justify performing mediastinoscopy or PET scanning is a matter of judgment. A negative PET scan finding in the mediastinum carries a FN rate of approximately 5% (range, 3 to 6%) in this group of patients.^68747576 Thus, invasive staging is probably not needed in this patient group if the findings of a PET scan of the mediastinum are negative. A PET scan is generally not needed in the case of a cT1N0M0 tumor (see chapter 12). Invasive staging of the mediastinum is also generally not indicated in these cases.

If invasive staging is deemed to be necessary, it appears that mediastinoscopy is the best choice because of a low FN rate compared to techniques involving NA. The arguments raised concerning the invasive staging of normal mediastinal nodes in cN1 or central tumors (group C) applies to this group (group D) as well, since these arguments are a function primarily of the size of the mediastinal nodes.

	Recommendations

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7. For patients with a peripheral clinical stage I tumor in whom a PET scan shows uptake in mediastinal nodes (and not distant metastases), invasive staging is recommended. In general, mediastinoscopy is suggested, but EUS-NA or EBUS-NA may be a reasonable alternative if nondiagnostic results are followed by mediastinoscopy. Grade of recommendation, 1C

8. For patients with a peripheral clinical stage I tumor, invasive confirmation of the mediastinal nodes is not needed if the findings of a PET scan of the mediastinum are negative. Grade of recommendation, 1C

Patients With LUL Tumors
Patients with tumors in the LUL deserve special mention because the aortic arch raises technical issues of access to the mediastinal nodes in the APW (station 5). This node station is the most likely mediastinal nodal area to be involved in the case of an LUL tumor, whereas it is extremely unlikely to be involved in patients with a tumor in any of the other lobes. Of course, mediastinal nodal involvement from an LUL tumor can also extend to other node stations such as the subcarinal (station 7) or paratracheal areas (stations 4L, 4R, 2L, and 2 R). A full assessment of potentially involved mediastinal node stations in the case of an LUL tumor requires investigation of the paratracheal and subcarinal nodes, as well as a separate procedure to access the APW area. The technical issues of access to the APW nodes raises questions about whether a separate invasive test for the assessment of these nodes is really necessary.

The definition of radiographic groups (groups A, B, C and D) is the same no matter which lobe of the lung is involved. In addition, the indications for invasive staging of the mediastinum in patients with LUL tumors should follow the same guidelines as in patients with a tumor in a different lobe (patients with enlarged mediastinal nodes, a central tumor or N1 nodal enlargement and a normal mediastinum, or with evidence of PET scan uptake in mediastinal areas should undergo invasive mediastinal staging).

If the usual mediastinal node stations are found to be negative (stations 2R, 4R, 7, 2L, and 4L), it is controversial whether a separate procedure to assess the station 5 area is needed. However, given the lack of clear data that involvement of only this station carries a different prognosis than involvement of a different single mediastinal node station, and with the availability of techniques of assessing the APW area that are easier for patients to undergo (eg, EUS-NA, EBUS-NA, extended cervical mediastinoscopy, and VATS), the guidelines committee favors pursuing an invasive assessment of the APW nodes. A finding of involvement in one mediastinal area may preclude the necessity of biopsying other areas, especially if an additional procedure would be necessary (eg, a positive EUS-NA finding for station 5 may preclude the assessment of paratracheal nodes, or a positive mediastinoscopy result would obviate the need for an anterior mediastinotomy).

A comparative assessment of different invasive tests for APW nodes is not possible. A reasonable extrapolation from the data for other node stations would be to pursue a needle technique for enlarged APW nodes and a surgical biopsy (eg, Chamberlain procedure, VATS, or extended cervical mediastinoscopy) for normal-sized APW nodes. However, it is also a reasonable compromise to accept a negative NA finding without adding an additional surgical biopsy, given the controversy over the need to assess the APW nodes. Modification of these suggestions may be necessary due to the availability of expertise with the invasive procedures. However, it is suggested that referral to a larger center be considered if there is not a fair amount of expertise with at least one invasive APW staging procedure.

	Recommendation

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9. For patients with an LUL cancer in whom invasive mediastinal staging is indicated, as defined by the previous recommendations, it is suggested that invasive mediastinal staging include assessment of the APW nodes (via Chamberlain procedure, thoracoscopy, extended cervical mediastinoscopy, EUS-NA, or EBUS-NA) if other mediastinal node stations are found to be uninvolved. Grade of recommendation, 2C

	Conclusion

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Accurate mediastinal staging is crucial to the selection of the optimal therapy for patients without distant metastases. Imaging studies are not sufficiently reliable in many situations, making invasive staging tests an important part of appropriate staging. Many different invasive staging tests, which should be viewed as complementary to one another because they are applicable to particular nodal stations and patient groups, are available. It is helpful to separate patients into different groups based on the extent of mediastinal involvement by CT scan and whether the primary tumor is central or peripheral. In general, needle techniques are most useful in patients with enlarged mediastinal nodes, while mediastinoscopy remains the "gold standard" in patients with normal-sized nodes.

	Summary of Recommendations

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