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Invasive Staging of Non-small Cell Lung Cancer*: A Review of the Current Evidence FREE TO VIEW

Eric M. Toloza, MD, PhD; Linda Harpole, MD, MPH; Frank Detterbeck, MD, FCCP; Douglas C. McCrory, MD, MHS
Author and Funding Information

*From the Departments of Surgery (Dr. Toloza) and Medicine (Dr. Harpole), and the Center for Clinical Health Policy Research (Dr. McCrory), Duke University Medical Center, Durham; the Department of Veterans Affairs Medical Center, Durham; and Department of Surgery (Dr. Detterbeck), University of North Carolina, Chapel Hill, NC.

Correspondence to: Eric Toloza, MD, PhD, Duke Thoracic Oncology, DUMC Box 3048, Durham, NC 27710; e-mail: toloz001@mc.duke.edu



Chest. 2003;123(1_suppl):157S-166S. doi:10.1378/chest.123.1_suppl.157S
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Study objectives: To determine the test performance characteristics of transbronchial needle aspiration (TBNA), transthoracic needle aspiration (TTNA), endoscopic ultrasound-guided needle aspiration (EUS-NA), and mediastinoscopy in staging non-small cell lung cancer (NSCLC).

Design, setting, and participants: Systematic search of MEDLINE, HealthStar, and Cochrane Library databases to July 2001 and print bibliographies. Included were studies comparing staging results of TBNA, TTNA, EUS-NA, or mediastinoscopy against either tissue histologic confirmation or long-term clinical follow-up (≥ 1 year). Patients included were those with NSCLC or small cell lung cancer.

Measurement and results: For patients with lung cancer, the pooled sensitivity for TBNA was 0.76, the pooled specificity was 0.96, and the negative predictive value (NPV) was 0.71. For TTNA, the pooled sensitivity was 0.91, with an NPV of 0.78. EUS-NA had a pooled sensitivity of 0.88, a pooled specificity of 0.91, and an NPV of 0.77. For standard cervical mediastinoscopy, the pooled sensitivity was 0.81, with an NPV of 0.91. The addition of either extended cervical mediastinoscopy or anterior mediastinotomy to standard cervical mediastinoscopy appeared to improve the sensitivity of any of the procedures alone.

Conclusions: Invasive clinical staging of NSCLC can be performed effectively by TBNA, TTNA, EUS-NA, or mediastinoscopy. Selection of the appropriate study is dependent on the degree of suspicion for metastatic disease, the patient’s comorbid illnesses, and the availability and performance characteristics of procedural options.

The primary aim of intrathoracic staging in non-small cell lung cancer (NSCLC) is the evaluation of mediastinal lymph node involvement. Accurate assessment of mediastinal lymph node status affects a patient’s prognosis and treatment plan, as the presence of mediastinal lymph node involvement indicates the presence of stage IIIA or IIIB lung cancer. This suggests either inoperability and/or the need for treatment by chemotherapy and/or radiotherapy. Recently, induction therapy followed by surgery has been suggested for stage IIIA NSCLC.13 Since mediastinal lymph node involvement is found in 30 to 44% of patients with newly diagnosed lung cancer, testing is required to rule in or rule out such disease.

Noninvasive techniques to evaluate mediastinal nodes rely on either lymph node size (CT, endoscopic ultrasound) or metabolism (positron emission tomography) to detect cancerous involvement. However, while noninvasive tests can identify nodes suspicious for cancer, they do not provide definitive tissue diagnosis and often are not sufficient for initiation of nonsurgical treatment. Thus, invasive tests are often required to further evaluate nonresectability.

Invasive techniques utilize needle biopsy or surgical open biopsy to obtain tissue samples to confirm the diagnosis of metastatic disease. Needle biopsy techniques include transbronchial needle aspiration (TBNA), transthoracic needle aspiration (TTNA), and endoscopic ultrasound-guided needle aspiration (EUS-NA). Surgical open biopsy can be performed by standard cervical mediastinoscopy, extended cervical mediastinoscopy, or anterior mediastinotomy.

TBNA is performed with the aid of bronchoscopy. A needle catheter is passed through the working channel of the bronchoscope and guided to the area of the tracheobronchial tree overlying the mediastinal lymph node of interest. The needle catheter, which comes in varying gauges, is then advanced through the tracheal or carinal wall into the mediastinal lymph node, and an aspiration biopsy obtained. Larger-gauge needles may be used in an attempt to obtain a “core” of tissue for histologic examination. Several passes may be performed until an adequate specimen is obtained. Bedside or on-site cytopathologic examination of needle aspiration specimens may improve the yield of TBNA, as the rapid evaluation of collected specimens would give the interventionalist feedback as to the need for further aspirations. This technique is limited by being a blind biopsy and by the difficulty of sampling more than a few nodal stations. Guidance by emerging imaging techniques, such as real-time CT-fluoroscopy, endobronchial ultrasound, and virtual bronchoscopy (using three-dimensional images reconstructed from routine helical CT scans), may improve the yield of TBNA and are under investigation. The main complications of TBNA include those inherent to bronchoscopy, such as laryngospasm, and those specific to the biopsy, such as endobronchial bleeding.

TTNA is performed with the aid of CT or, less often, with fluoroscopic guidance. The biopsy needle is passed percutaneously and guided to the mediastinal node of interest from which an aspiration biopsy is obtained. Similar to TBNA, TTNA may require several passes of the needle to obtain an adequate specimen, and bedside cytopathologic examination of collected specimens may minimize the number of needle passes necessary to yield a diagnosis. As with TBNA, larger-gauge needles may also be used in attempt to obtain a core of tissue for histologic examination. TTNA is radiologically guided, but like TBNA, is limited in its ability to sample more than a few nodal stations. The main complications of TTNA are pneumothorax and intrathoracic bleeding.

EUS-NA is performed with the aid of esophagoscopy. A biopsy needle catheter is passed through the working channel of the endoscope, through the esophageal wall, and guided ultrasonographically toward mediastinal nodes of interest. Similar to both TBNA and TTNA, several passes of the needle may be needed to obtain adequate specimens, and bedside cytopathologic examination of collected specimens may minimize the number of needle passes necessary to yield a diagnosis. This technique is guided by ultrasound, but it too is limited in its ability to sample more than a few nodal stations. One advantage of endoscopic ultrasound is that the simultaneous qualitative assessment of the mediastinal nodes provided by ultrasound analysis for features such as necrosis may aid in the selection of nodes to biopsy that are more likely to be malignant.

Standard cervical mediastinoscopy is a surgical open-biopsy technique that involves making a small incision above the suprasternal notch. Dissection is carried down to the pretracheal fascia, beneath which a mediastinoscope is passed into the mediastinum toward the carina. Blunt dissection paratracheally, bilaterally, and subcarinally exposes the mediastinal lymph nodes, which can then be sampled under direct vision. All four paratracheal lymph node stations (levels 2R, 2L, 4R, and 4L) and the anterior subcarinal lymph node station (level 7) can be easily sampled in this fashion. This procedure does require general anesthesia and carries risks of bleeding and left laryngeal nerve injury.

Extended cervical mediastinoscopy is an extension of the standard cervical mediastinoscopy that allows biopsy of the aortopulmonary window (level 5) and preaortic (level 6) lymph node stations. Anterior mediastinotomy also allows biopsy of the aortopulmonary window and preaortic lymph node stations. However, extended cervical mediastinoscopy is performed through the same cervical incision as the standard cervical mediastinoscopy. The mediastinoscope is passed between the brachiocephalic artery and the left carotid artery over the aortic arch to the aortopulmonary window. In contrast, anterior mediastinotomy requires a separate incision parasternally, usually at the level of the second or third intercostal space. Both procedures are associated with a risk of bleeding. Extended cervical mediastinoscopy has an additional risk of embolic stroke, while anterior mediastinotomy often results in violation of the pleura or injury to the internal mammary artery. Both procedures allow biopsy of the lymph nodes under direct vision, but extended cervical mediastinoscopy has the added advantage of allowing access to the paratracheal and subcarinal lymph nodes for biopsy without additional incisions.

To evaluate the usefulness of TBNA, TTNA, EUS-NA, mediastinoscopy, and mediastinotomy in determining the presence or absence of metastatic disease in mediastinal lymph nodes, we analyzed published studies that reported the ability of the various invasive methods to correctly establish the pathologic stage of newly diagnosed or suspected lung cancer. In this review, needle aspiration is considered a type of biopsy. The terms needle aspiration and needle biopsy are, thus, considered interchangeable.

Key Questions

Two key questions were identified: (1) What are the sensitivities and specificities of TBNA, TTNA, EUS-NA, mediastinoscopy, and mediastinotomy in patients with lung cancer for detecting malignancy in mediastinal lymph nodes? (2) How accurate are negative lymph node biopsies obtained by TBNA, TTNA, EUS-NA, mediastinoscopy, and mediastinotomy in predicting the absence of nodal metastases in patients with lung cancer?

Study Identification

Computerized searches of the MEDLINE bibliographic database (January 1991 to July 2001), HealthStar, and the Cochrane Library were performed. Key words used for the search included lung neoplasm, bronchial neoplasm, mediastinoscopy, neoplasm staging, neoplasm metastasis, lymphatic metastasis, biopsy, needle biopsy, CT, mediastinum radiography, emission-CT, and sensitivity and specificity. In addition, we searched the reference lists of included studies, selected textbooks, practice guidelines, systematic reviews, and meta-analyses in order to ensure that all relevant studies were identified. Only articles published in English were considered.

Pertinent studies published between 1980 and 1991 were identified through a previously published search4 that included MEDLINE, a review of the table of contents of 10 medical journals (Annals of Thoracic Surgery; Cancer; CHEST; International Journal of Radiation Oncology, Biology, and Physics; Journal of Clinical Oncology; Journal of Thoracic and Cardiovascular Surgery; Lung Cancer; Radiology; Seminars in Oncology; and Thorax), and a review of the reference lists of other articles. The 10 journals were chosen because they contain approximately 75% of lung cancer research articles. Studies from this period were excluded if they involved patients who were subsequently included in a larger group described in a more recent publication.

Selection Criteria

Titles and abstracts, and the full text of all articles passing the title-and-abstract screen, were evaluated independently by at least two of the authors for inclusion or exclusion based on five criteria: (1) publication in a peer-reviewed journal; (2) study size of > 20 patients (except for studies involving mediastinoscopy, which required a study size of > 50 patients); (3) patient group not included in subsequent update of the study; (4) confirmation of mediastinal nodal biopsy results by histology at the time of resection, or by long-term clinical follow-up (≥ 1 year) if the patient did not go on to resection; and (5) availability of original data so that sensitivities, specificities, and positive and negative predictive values (NPVs) could be independently calculated. Only articles meeting all five of these criteria were included for further analysis.

Data Abstraction

Data were abstracted from included studies and tabulated separately by type of invasive procedure (TBNA, TTNA, EUS-NA, mediastinoscopy, or mediastinotomy). The data were abstracted and analyzed three ways. First, abstracted data were analyzed for all patients undergoing invasive techniques, regardless of the indication (eg, suspected lung cancer, lymphoma, etc.). In this case, a definitive diagnosis of any malignancy was considered positive, and a definitive benign diagnosis was considered negative. The limitation of this approach is that sensitivities and specificities may vary by the diseases in the studied population, and thus the summary results may not directly apply to a specific population.

In the second case, the abstraction was performed for patients suspected of having lung cancer. In this case, a definitive diagnosis of any lung cancer (eg, NSCLC, SCLC) was considered positive. Patients suspected of a diagnosis other than lung cancer were excluded, where possible. This analysis assesses an invasive technique for its ability to stage lung cancer. Patients with both NSCLC and SCLC were included in the analyses for several reasons: (1) separation of NSCLC and SCLC, histologically, was often inconsistent in the 1980s; (2) some patients suspected of having NSCLC at presentation are later found to have SCLC; and (3) if detected early, SCLC patients can be treated surgically and are therefore offered the same staging algorithm as NSCLC patients for the purpose of determining treatment options.

Finally, data abstraction was performed for patients with a confirmed diagnosis of NSCLC. In this case, a definitive diagnosis of NSCLC was considered positive, and any other biopsy result was negative. This approach allows for an assessment of the performance of an invasive test for staging patients with NSCLC. The rationale for this analysis was that NSCLC behaves and is usually treated differently from SCLC. However, as in the case described above, some SCLC patients may not have been accurately identified as such and may have been included in the analyses.

Either tissue histologic confirmation or, if that was unavailable, long-term clinical outcome (whether the patient survived at least 1 year with no evidence of disease) was utilized as the reference or “gold standard.” If neither tissue confirmation nor clinical outcome was available, then the patient was excluded from further analysis.

Biopsy specimens that contained atypical, but not decidedly malignant, cells were considered negative. Biopsy attempts that were aborted (often due to a complication), those that could not locate nodal tissue, and those that yielded insufficient material for cytologic examination were considered to be negative. Patients for whom an adequate sample was not obtained were included in the calculations of sensitivity and specificity, as they are part of the pool of patients on whom the procedure is being performed. However, we excluded patients for whom a sample was not obtained when calculating the NPV, so that the reported NPVs estimate the probability that an adequate negative biopsy result is truly negative.

Positive invasive clinical staging tests usually obviate the need for therapeutic surgical exploration and resection. Therefore, false-positive rates are often not available for these tests. All positive biopsy data were, thus, considered true-positive results. Biopsy results that were determined to be “suspicious” for malignancy were also considered to be positive.

Statistical Analysis

Sensitivity is the percentage of people with the disease who are detected by the test. It is calculated as the number of true-positives divided by the sum of the number of true-positives and false-negatives. Specificity is the percentage of people without the disease who were correctly labeled by the test as not diseased. It is calculated as the number of true-negatives divided by the sum of true-negatives and false-positives. The positive predictive value (PPV) is the likelihood that a patient with a positive test result actually has the disease. It is calculated as true-positives divided by the sum of true-positives and false-positives. The NPV is the likelihood that a patient with a negative test result actually does not have the disease. It is calculated as true-negatives divided by the sum of true-negatives and false-negatives. Both the PPV and the NPV vary with the prevalence of disease, which is the frequency of disease in the population. The prevalence can be calculated as the number of patients with either true-positive or false-negative results divided by the total number of patients.

Summary sensitivity and specificity, and their respective confidence intervals (CIs), were calculated using the Meta-Test (New England Medical Center; Boston, MA) statistical software for meta-analysis of diagnosis tests.5 Summary PPV, NPV, and prevalence were calculated based on the total number of true-positive, false-negative, false-positive, and true-negative results summed across studies; however, studies in which all subjects had mediastinal disease were excluded from these calculations.

As described above, data were abstracted and analyzed three ways. However, the results obtained by all three methods were essentially the same; therefore, we present results for scenario two, which assesses the ability of an invasive procedure to adequately stage patients with suspected lung cancer (either NSCLC or SCLC). In this scenario, patients enrolled in the study but suspected of having a diagnosis other than lung cancer were not considered evaluable and were excluded, where possible. Moreover, if neither tissue confirmation nor clinical outcome was available as reference by which the test result is compared, then the patient was not considered evaluable and was excluded as well.

Mediastinal Staging by TBNA

Twelve studies using TBNA to stage the mediastinum met the inclusion criteria (Table 1 ).617 They included a total of 910 evaluable patients, of whom 906 patients (99.7%) were confirmed to have lung cancer. The overall sensitivity of TBNA was 0.76 (95% CI, 0.72 to 0.79), and the specificity was 0.96 (95% CI, 0.91 to 1.00). The average NPV was 71% (range, 36 to 100%) and was associated with an average prevalence of 70%. However, the prevalence among studies varied between 30% and 88%. The two studies with an NPV < 45% each had a prevalence of > 85%, suggesting that the NPV is underestimated when the prevalence is high. One study included a large number of patients but did not include sufficient original data to calculate the NPV and was, therefore, excluded.18 Another study had a high proportion of unverified negative aspirates; these patients were excluded from the analysis.7

Mediastinal Staging by TTNA

Five studies using TTNA to stage the mediastinum met the inclusion criteria (Table 2 ).1923 These studies involved a total of 215 evaluable patients, of whom 207 patients (96%) were confirmed to have lung cancer. The overall sensitivity of TTNA was 0.91 (95% CI, 0.74 to 0.97). The overall NPV was 78% (range, 42 to 100%). As with TBNA, the NPV of TTNA was inversely correlated with prevalence, which was 83% overall and varied from 65 to 91%.

Mediastinal Staging by EUS-NA

Five studies met the inclusion criteria and assessed the use of EUS-NA in mediastinal staging of 215 evaluable lung cancer patients (Table 3 ).2428 When EUS-NA was used to stage the mediastinum, the overall sensitivity was 0.88 (95% CI, 0.82 to 0.93), and the overall specificity was 0.91 (95% CI, 0.77 to 0.97). The overall PPV was 98% (range, 96 to 100%), and the overall NPV was 77% (range, 68 to 100%), with an overall prevalence of disease of 69% (range, 63 to 79%). There was little variability in performance characteristics among the included studies.

Mediastinal Staging by Mediastinoscopy or Mediastinotomy

Fourteen included studies, involving 5,687 evaluable patients, assessed mediastinal staging by standard cervical mediastinoscopy (Table 4 ).2942 The overall sensitivity was 0.81 (95% CI, 0.76 to 0.85). The overall NPV was 91% (range, 58 to 97%), with a prevalence of 37% (range, 21 to 54%).

In addition, two studies, assessing 206 evaluable patients with lung cancer, met the inclusion criteria for assessing extended cervical mediastinoscopy alone or with standard cervical mediastinoscopy.4344 The addition of extended cervical mediastinoscopy to standard cervical mediastinoscopy allows the sampling of lymph node stations 5 and 6. In the two included studies, the overall sensitivity of standard cervical mediastinoscopy alone (range, 33 to 52%) and extended cervical mediastinoscopy alone (range 45 to 51%) increased (range, 69 to 76%) when the two procedures were combined (Table 5 ). The slightly higher sensitivity of the extended cervical mediastinoscopy alone compared to standard cervical mediastinoscopy alone may be due to a higher proportion of left upper lobe primary tumors in these series. The overall NPV of standard or extended mediastinoscopy alone ranged from 62 to 84%, but increased to a range of 82 to 89% when the two procedures were combined. The overall prevalence in these two studies ranged from 29 to 42%.

Anterior mediastinotomy, or the Chamberlain procedure, is able to assess only lymph node stations 2R, 4R, and 3 when performed through the right chest, and only lymph node stations 5 and 6 when performed through the left chest, thus limiting its ability to evaluate the mediastinum. However, anterior mediastinotomy is an alternative approach to the extended cervical mediastinoscopy. Two studies assessed both anterior mediastinotomy alone (84 lung cancer patients) and anterior mediastinotomy in combination with standard cervical mediastinoscopy (71 lung cancer patients).38,42,45 The overall sensitivity for detecting mediastinal lymph node involvement of anterior mediastinotomy alone (range, 63 to 86%) and standard cervical mediastinoscopy alone (range, 68 to 73%) increased to 87% when the two procedures were combined (Table 6 ).

Clinical staging is based on all information obtained about the primary tumor, its draining lymph node basins, and potential distant sites of metastasis prior to treatment initiation. Accurate clinical staging is paramount not only for estimating a patient’s life expectancy and 5-year survival probability, but also because it directly impacts on the selection of appropriate therapy.

Clinical staging has been shown to differ markedly from pathologic staging at the time of resection. In a large prospective study, 24% of patients were clinically overstaged and 20% understaged when compared with pathologic staging.46Another study found that when applying pathologic staging, 19% of clinically staged N0 patients were actually N1, and another 24% were N2.47Additionally, a study of clinical N2 patients found that 44% were inappropriately staged, with 38% actually being N0 or N1, and 6% being N3.48

While clinical staging of N1 nodes may be difficult, this is currently of minor importance, as therapy remains surgical resection. In contrast, metastatic involvement of mediastinal lymph nodes would upstage a lung cancer patient from the primarily surgical stages I and II to possibly surgical stage IIIA or the primarily nonsurgical stage IIIB. Moreover, studies demonstrating the benefits of neoadjuvant chemotherapy and radiation therapy prior to surgical resection of stage IIIA patients make it even more important that patients be staged appropriately at the time of presentation, with confirmation of the presence of N2 (surgical stage IIIA) or the absence of N3 nodal (nonsurgical stage IIIB) involvement.13 While studies such as the Bimodality Lung Oncology Trial support induction therapy prior to surgery for patients with N1 disease, the use of neoadjuvant chemotherapy with or without radiation therapy for stage II patients is currently only done under protocol settings.49

When selecting a test for staging a patient with known or suspected lung cancer, two issues need to be considered. First, one needs to select a test that will assess the mediastinum for involved or uninvolved nodes. This requires a test with a high sensitivity and specificity. Second, one needs to be able to accurately interpret the test results for an individual patient. For example, what is the likelihood that a negative test result means a patient is free of mediastinal disease or, conversely, that a positive test confirms metastatic disease? This issue is addressed by the PPVs and NPVs of a test. However, the NPVs and PPVs of a test are affected by the prevalence of disease. Thus, patients may be approached differently depending on the initial degree of suspicion regarding mediastinal involvement. A patient suspected of having metastases would require a test to confirm the diagnosis with high sensitivity. In contrast, a patient suspected of having early stage disease would require a test to rule out advanced disease with high specificity.

In this analysis, TTNA, EUS-FNA, and mediastinoscopy were all shown to have similar sensitivities. However, the higher sensitivity demonstrated in studies utilizing TTNA and EUS-FNA to assess the mediastinum may be biased by the fact that these studies are usually performed in patients for whom there is radiographic evidence of mediastinal lymphadenopathy accessible by a biopsy needle. This selection bias is likely to result in fewer false-negative results, yielding a higher sensitivity. Mediastinoscopy often is performed in the absence of enlarged lymph nodes on radiologic imaging, yet still yields equivalent sensitivity to TTNA and EUS-FNA. Despite similar sensitivities, the NPVs are quite different. Mediastinoscopy has an NPV of 91% vs 71 to 78% for needle aspiration, and thus provides greater confidence in a negative biopsy result. Additionally, mediastinoscopy has the added advantages of being able to obtain relatively larger specimens from a greater number of nodal stations under direct vision than any of the needle biopsy techniques.

There have been suggestions that a fine needle aspiration, which is generally considered a cytologic evaluation, and a needle biopsy, which is generally considered to provide a core of tissue that can be histologically evaluated, have different diagnostic yields. Since needle aspiration is, in fact, a type of biopsy, this review does not distinguish between the terms needle aspiration and needle biopsy, which are used inconsistently in the literature. Even the terms cytology needle and histology needle do not necessarily specify needle size, and vice versa. “Cytology” or “aspiration” needles usually refer to 20- to 22-gauge needles but can be as large as 17-gauge. “Histology” or “core” needles usually refer to 18- to 19-gauge needles but may be as small as 20-gauge or as large as the 14-gauge Tru-cut needle. To add to the confusion, “slotted” aspiration needles are purported to obtain larger specimens than “standard” aspiration needles of the same gauge. The small numbers of patients in the few studies reviewed in this meta-analysis did not permit the comparison of diagnostic yields of cytology needles vs histology needles.

That said, the use of larger needles has been reported to improve diagnostic yield but may be more difficult.13,15 Schenk and coworkers13,15 reported that TBNA with an 18- or 19-gauge needle resulted in an 80 to 86% sensitivity compared to a 53% sensitivity with a 22-gauge needle. The use of larger needles may be limited by lymph node size and location. Smaller gauge needles were preferred for lymph nodes < 10 mm in short-axis diameter and for lymph nodes adjacent to the heart and great vessels.7,23 The larger, 14-gauge Tru-cut needles were only considered for lymph nodes with a 20-mm minimal diameter.20 The experience of the practitioner performing the needle biopsy has a significant impact on the diagnostic yield, even when comparing equivalently sized lymph nodes using equivalently sized needles.7 Some practitioners obtain both cytology and histology specimens, while others obtain histology specimens only if the cytology specimens are inadequate, which may improve the sensitivity of the test.13,15 Diagnostic yield may also be improved by flushing histology needles to obtain additional cytology specimens and by collecting any specimens retained in the hub of cytology needles.

Determination of adequacy of the cytology specimen often relies on a cytopathologist being present on-site to prepare and evaluate the specimen immediately, which was often not the case in the studies reviewed. On-site determination of cytologic adequacy would allow termination of the procedure to minimize the risk of potential complications or, conversely, would dictate the need for additional needle passes to improve diagnostic yield. There was inadequate data to determine if the method of processing cytologic specimens altered the diagnostic yield, but on-site determination would be facilitated by immediate smearing of the specimens onto slides, drying and fixation compared to fixation in fluid followed by centrifugation onto slides. Schenk and coworkers15 have suggested that histology needles obviate the need for cytopathologic support, as the specimens are large enough for the practitioner, who is performing the biopsy, to grossly determine adequacy prior to formalin-fixation, paraffin-embedding and sectioning.

The higher sensitivity of EUS-NA and TTNA relative to TBNA is likely due to their ability to reach more nodal stations, particularly in the inferior mediastinum, than TBNA, and even mediastinoscopy. In addition, EUS-NA and TTNA both utilize imaging techniques to direct the biopsy needle to the target lymph node. Another advantage of EUS-NA is its ability to estimate the probability of metastatic involvement of a particular lymph node through its echogenic pattern.

Rong and Cui9 suggested that TBNA guidance by standard CT may improve diagnostic yield, but they used a very low (20%) historical baseline diagnostic yield of non–CT-guided TBNA for comparison. Standard CT guidance is also time-consuming and imparts significant radiation exposure. Real-time CT-fluoroscopic guidance,6,5051 endobronchial ultrasound guidance,52and virtual bronchoscopic guidance (using three-dimensional CT reconstructions)53 may improve the yield of TBNA with fewer complications, especially for small or otherwise inaccessible lymph nodes, but these emerging imaging techniques are still under investigation.

Extended cervical mediastinoscopy and anterior mediastinotomy were shown to have lower sensitivities and NPVs than the other invasive tests. This may be due to their ability to reach only aortopulmonary lymph node stations. However, extended cervical mediastinoscopy or anterior mediastinotomy may be a useful adjunct to cervical mediastinoscopy, as it adds lymph node stations 5 and 6 to the number of stations that would otherwise be evaluable by mediastinoscopy alone, as demonstrated by the improved sensitivity and NPV of the combined tests (Tables 5, 6).

A limitation of this current study is that the relative performance characteristics of the reviewed invasive procedures for staging the mediastinum have not been established through direct comparisons. The studies included in the analyses were not randomized trials, but rather prospective or retrospective evaluations of the performance of the applied invasive tests. Patient selection bias is inherent in this study design, as the selection of patients for studies is based on size and location of the lymph node and the associated risks of the procedure. Without performing a randomized trial of invasive staging techniques for patients with lung cancer, one cannot definitely say which test is best for all patients.

In summary, the invasive clinical staging of NSCLC can be performed effectively by several methods, including TBNA, TTNA, EUS-NA, and mediastinoscopy. Although at this point mediastinoscopy appears to have the best performance characteristics, selecting the correct test for a presenting patient should incorporate an assessment of the patient’s comorbid illnesses, the degree of suspicion for metastatic disease, the location of the suspicious nodes, the availability of a procedure at the patient’s institution, and the experience and results obtained by the performing physicians at the institution for the considered procedure.

Abbreviations: CI = confidence interval; EUS-NA = endoscopic ultrasound-guided needle aspiration; NPV = negative predictive value; NSCLC = non-small cell lung cancer; PPV = positive predictive value; SCLC = small cell lung cancer; TBNA = transbronchial needle aspiration; TTNA = transthoracic needle aspiration

Supported by a contract from the American College of Chest Physicians.

Table Graphic Jump Location
Table 1. Accuracy of TBNA of the Mediastinum in Patients with Lung Cancer
* 

Not defined because all subjects had mediastinal disease.

Table Graphic Jump Location
Table 2. Accuracy of TTNA of the Mediastinum in Patients With Lung Cancer
* 

Not defined because all subjects had mediastinal disease.

Table Graphic Jump Location
Table 3. Accuracy of EUS-NA of the Mediastinum in Patients With Lung Cancer
* 

Not defined because all subjects had mediastinal disease.

Table Graphic Jump Location
Table 4. Accuracy of Standard Cervical Mediastinoscopic Biopsies in Patients With Lung Cancer
Table Graphic Jump Location
Table 5. Accuracy of Extended Cervical Mediastinoscopic Biopsies in Patients With Lung Cancer
Table Graphic Jump Location
Table 6. Accuracy of Anterior Mediastinotomy Biopsies in Patients With Lung Cancer
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Protopapas, Z, Westcott, JL Transthoracic needle biopsy of mediastinal lymph nodes for staging lung and other cancers.Radiology1996;199,489-496
 
Böcking, A, Klose, KC, Kyll, HJ, et al Cytologic vs histologic evaluation of needle biopsy of the lung, hilum and mediastinum: sensitivity, specificity and typing accuracy.Acta Cytol1995;39,463-471
 
de Gregorio Ariza, MA, Alfonso Aguiran, ER, Villavieja Atance, JL, et al Transthoracic aspiration biopsy of pulmonary and mediastinal lesions.Eur J Radiol1991;12,98-103
 
Moinuddin, SM, Lee, LH, Montgomery, JH Mediastinal needle biopsy.AJR Am J Roentgenol1984;143,531-532
 
Westcott, JL Percutaneous needle aspiration of hilar and mediastinal masses.Radiology1981;141,323-329
 
Wiersema, MJ, Vazquez-Sequeiros, E, Wiersema, LM Evaluation of mediastinal lymphadenopathy with endoscopic US-guided fine-needle aspiration biopsy.Radiology2001;219,252-257
 
Wallace, MB, Silvestri, GA, Sahai, AV, et al Endoscopic ultrasound-guided fine needle aspiration for staging patients with carcinoma of the lung.Ann Thorac Surg2001;72,1861-1867
 
Fritscher-Ravens, A, Soehendra, N, Schirrow, L, et al Role of transesophageal endosonography-guided fine-needle aspiration in the diagnosis of lung cancer.Chest2000;117,339-45
 
Gress, FG, Savides, TJ, Sandler, A, et 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 Med1997;127,604-612
 
Silvestri, GA, Hoffman, BJ, Bhutani, MS, et al Endoscopic ultrasound with fine-needle aspiration in the diagnosis and staging of lung cancer.Ann Thorac Surg1996;61,1441-1445discussion 1445–1446
 
Ebner, H, Marra, A, Butturini, E, et al Clinical value of cervical mediastinoscopy in the staging of bronchial carcinoma.Ann Ital Chir1999;70,873-879
 
Hammoud, ZT, Anderson, RC, Meyers, BF, et al The current role of mediastinoscopy in the evaluation of thoracic disease.Thorac Cardiovasc Surg1999;118,894-899
 
Gdeedo, A, Van Schil, P, Corthouts, B, et al Prospective evaluation of computed tomography and mediastinoscopy in mediastinal lymph node staging.Eur Respir J1997;10,1547-51
 
De Leyn, P, Schoonooghe, P, Deneffe, G, et al Surgery for non-small cell lung cancer with unsuspected metastasis to ipsilateral mediastinal or subcarinal nodes (N2 disease).Eur J Cardiothorac Surg1996;10,649-654discussion 654–655
 
Aaby, C, Kristensen, S, Nielsen, SM Mediastinal staging of non-small-cell lung cancer: computed tomography and cervical mediastinoscopy.ORL J Otorhinolaryngol Relat Spec1995;57,279-285
 
Dillemans, B, Deneffe, G, Verschakelen, J, et al Value of computed tomography and mediastinoscopy in preoperative evaluation of mediastinal nodes in non-small cell lung cancer: a study of 569 patients.Eur J Cardiothorac Surg1994;8,37-42
 
Jolly, PC, Hutchinson, CH, Detterbeck, F, et al Routine computed tomographic scans, selective mediastinoscopy, and other factors in evaluation of lung cancer.Thorac Cardiovasc Surg1991;102,266-270discussion 270–271
 
Riordain, DS, Buckley, DJ, Aherne, T Mediastinoscopy as a predictor of resectability in patients with bronchogenic carcinoma.Ir J Med Sci1991;160,291-292
 
Ratto, GB, Frola, C, Cantoni, S, et al Improving clinical efficacy of computed tomographic scan in the preoperative assessment of patients with non-small cell lung cancer.Thorac Cardiovasc Surg1990;99,416-425
 
Page, A, Nakhle, G, Mercier, C, et al Surgical treatment of bronchogenic carcinoma: the importance of staging in evaluating late survival.Can J Surg1987;30,96-99
 
Luke, WP, Pearson, FG, Todd, TR, et al Prospective evaluation of mediastinoscopy for assessment of carcinoma of the lung.Thorac Cardiovasc Surg1986;91,53-56
 
Brion, JP, Depauw, L, Kuhn, G, et al Role of computed tomography and mediastinoscopy in preoperative staging of lung carcinoma.J Comput Assist Tomogr1985;9,480-4
 
Coughlin, M, Deslauriers, J, Beaulieu, M, et al Role of mediastinoscopy in pretreatment staging of patients with primary lung cancer.Ann Thorac Surg1985;40,556-60
 
Deneffe, G, Lacquet, LM, Gyselen, A Cervical mediastinoscopy and anterior mediastinotomy in patients with lung cancer and radiologically normal mediastinum.Eur J Respir Dis1983;64,613-619
 
Freixinet Gilart, J, Garcia, PG, de Castro, FR, et al Extended cervical mediastinoscopy in the staging of bronchogenic carcinoma.Ann Thorac Surg2000;70,1641-1643
 
Ginsberg, RJ, Rice, TW, Goldberg, M, et al Extended cervical mediastinoscopy: a single staging procedure for bronchogenic carcinoma of the left upper lobe.Thorac Cardiovasc Surg1987;94,673-678
 
Best, LA, Munichor, M, Ben-Shakhar, M, et al The contribution of anterior mediastinotomy in the diagnosis and evaluation of diseases of the mediastinum and lung.Ann Thorac Surg1987;43,78-81
 
Bulzebruck, H, Bopp, R, Drings, P, et al New aspects in the staging of lung cancer: prospective validation of the International Union Against Cancer TNM classification.Cancer1992;70,1102-1110
 
Fernando, HC, Goldstraw, P The accuracy of clinical evaluative intrathoracic staging in lung cancer as assessed by postsurgical pathologic staging.Cancer1990;65,2503-2506
 
Watanabe, Y, Shimizu, J, Oda, M, et al Aggressive surgical intervention in N2 non-small cell cancer of the lung.Ann Thorac Surg1991;51,253-261
 
Pisters, KM, Ginsberg, RJ, Putnam, JB, Jr, et al Induction chemotherapy before surgery for early-stage lung cancer: a novel approach.Thorac Cardiovasc Surg2000;119,429-439
 
Goldberg, SN, Raptopoulos, V, Boiselle, PM, et al Mediastinal lymphadenopathy: diagnostic yield of transbronchial mediastinal lymph node biopsy with CT fluoroscopic guidance; initial experience.Radiology2000;216,764-767
 
White, CS, Weiner, EA, Patel, P, et al Transbronchial needle aspiration: guidance with CT fluoroscopy.Chest2000;118,1630-1638
 
Shannon, JJ, Bude, RO, Orens, JB, et al Endobronchial ultrasound-guided needle aspiration of mediastinal adenopathy.Am J Respir Crit Care Med1996;153(4 pt 1),1424-1430
 
McAdams, HP, Goodman, PC, Kussin, P Virtual bronchoscopy for directing transbronchial needle aspiration of hilar and mediastinal lymph nodes: a pilot study.AJR Am J Roentgenol1998;170,1361-1364
 

Figures

Tables

Table Graphic Jump Location
Table 1. Accuracy of TBNA of the Mediastinum in Patients with Lung Cancer
* 

Not defined because all subjects had mediastinal disease.

Table Graphic Jump Location
Table 2. Accuracy of TTNA of the Mediastinum in Patients With Lung Cancer
* 

Not defined because all subjects had mediastinal disease.

Table Graphic Jump Location
Table 3. Accuracy of EUS-NA of the Mediastinum in Patients With Lung Cancer
* 

Not defined because all subjects had mediastinal disease.

Table Graphic Jump Location
Table 4. Accuracy of Standard Cervical Mediastinoscopic Biopsies in Patients With Lung Cancer
Table Graphic Jump Location
Table 5. Accuracy of Extended Cervical Mediastinoscopic Biopsies in Patients With Lung Cancer
Table Graphic Jump Location
Table 6. Accuracy of Anterior Mediastinotomy Biopsies in Patients With Lung Cancer

References

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Ratto, GB, Mereu, C, Motta, G The prognostic significance of preoperative assessment of mediastinal lymph nodes in patients with lung cancer.Chest1988;93,807-813
 
Schenk, DA, Bower, JH, Bryan, CL, et al Transbronchial needle aspiration staging of bronchogenic carcinoma.Am Rev Respir Dis1986;134,146-148
 
Gasparini, S, Zuccatosta, L, Zitti, P, et al Integration of TBNA, and TCNA in the diagnosis of peripheral lung nodules: influence on staging.Ann Ital Chir1999;70,851-855
 
Protopapas, Z, Westcott, JL Transthoracic needle biopsy of mediastinal lymph nodes for staging lung and other cancers.Radiology1996;199,489-496
 
Böcking, A, Klose, KC, Kyll, HJ, et al Cytologic vs histologic evaluation of needle biopsy of the lung, hilum and mediastinum: sensitivity, specificity and typing accuracy.Acta Cytol1995;39,463-471
 
de Gregorio Ariza, MA, Alfonso Aguiran, ER, Villavieja Atance, JL, et al Transthoracic aspiration biopsy of pulmonary and mediastinal lesions.Eur J Radiol1991;12,98-103
 
Moinuddin, SM, Lee, LH, Montgomery, JH Mediastinal needle biopsy.AJR Am J Roentgenol1984;143,531-532
 
Westcott, JL Percutaneous needle aspiration of hilar and mediastinal masses.Radiology1981;141,323-329
 
Wiersema, MJ, Vazquez-Sequeiros, E, Wiersema, LM Evaluation of mediastinal lymphadenopathy with endoscopic US-guided fine-needle aspiration biopsy.Radiology2001;219,252-257
 
Wallace, MB, Silvestri, GA, Sahai, AV, et al Endoscopic ultrasound-guided fine needle aspiration for staging patients with carcinoma of the lung.Ann Thorac Surg2001;72,1861-1867
 
Fritscher-Ravens, A, Soehendra, N, Schirrow, L, et al Role of transesophageal endosonography-guided fine-needle aspiration in the diagnosis of lung cancer.Chest2000;117,339-45
 
Gress, FG, Savides, TJ, Sandler, A, et 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 Med1997;127,604-612
 
Silvestri, GA, Hoffman, BJ, Bhutani, MS, et al Endoscopic ultrasound with fine-needle aspiration in the diagnosis and staging of lung cancer.Ann Thorac Surg1996;61,1441-1445discussion 1445–1446
 
Ebner, H, Marra, A, Butturini, E, et al Clinical value of cervical mediastinoscopy in the staging of bronchial carcinoma.Ann Ital Chir1999;70,873-879
 
Hammoud, ZT, Anderson, RC, Meyers, BF, et al The current role of mediastinoscopy in the evaluation of thoracic disease.Thorac Cardiovasc Surg1999;118,894-899
 
Gdeedo, A, Van Schil, P, Corthouts, B, et al Prospective evaluation of computed tomography and mediastinoscopy in mediastinal lymph node staging.Eur Respir J1997;10,1547-51
 
De Leyn, P, Schoonooghe, P, Deneffe, G, et al Surgery for non-small cell lung cancer with unsuspected metastasis to ipsilateral mediastinal or subcarinal nodes (N2 disease).Eur J Cardiothorac Surg1996;10,649-654discussion 654–655
 
Aaby, C, Kristensen, S, Nielsen, SM Mediastinal staging of non-small-cell lung cancer: computed tomography and cervical mediastinoscopy.ORL J Otorhinolaryngol Relat Spec1995;57,279-285
 
Dillemans, B, Deneffe, G, Verschakelen, J, et al Value of computed tomography and mediastinoscopy in preoperative evaluation of mediastinal nodes in non-small cell lung cancer: a study of 569 patients.Eur J Cardiothorac Surg1994;8,37-42
 
Jolly, PC, Hutchinson, CH, Detterbeck, F, et al Routine computed tomographic scans, selective mediastinoscopy, and other factors in evaluation of lung cancer.Thorac Cardiovasc Surg1991;102,266-270discussion 270–271
 
Riordain, DS, Buckley, DJ, Aherne, T Mediastinoscopy as a predictor of resectability in patients with bronchogenic carcinoma.Ir J Med Sci1991;160,291-292
 
Ratto, GB, Frola, C, Cantoni, S, et al Improving clinical efficacy of computed tomographic scan in the preoperative assessment of patients with non-small cell lung cancer.Thorac Cardiovasc Surg1990;99,416-425
 
Page, A, Nakhle, G, Mercier, C, et al Surgical treatment of bronchogenic carcinoma: the importance of staging in evaluating late survival.Can J Surg1987;30,96-99
 
Luke, WP, Pearson, FG, Todd, TR, et al Prospective evaluation of mediastinoscopy for assessment of carcinoma of the lung.Thorac Cardiovasc Surg1986;91,53-56
 
Brion, JP, Depauw, L, Kuhn, G, et al Role of computed tomography and mediastinoscopy in preoperative staging of lung carcinoma.J Comput Assist Tomogr1985;9,480-4
 
Coughlin, M, Deslauriers, J, Beaulieu, M, et al Role of mediastinoscopy in pretreatment staging of patients with primary lung cancer.Ann Thorac Surg1985;40,556-60
 
Deneffe, G, Lacquet, LM, Gyselen, A Cervical mediastinoscopy and anterior mediastinotomy in patients with lung cancer and radiologically normal mediastinum.Eur J Respir Dis1983;64,613-619
 
Freixinet Gilart, J, Garcia, PG, de Castro, FR, et al Extended cervical mediastinoscopy in the staging of bronchogenic carcinoma.Ann Thorac Surg2000;70,1641-1643
 
Ginsberg, RJ, Rice, TW, Goldberg, M, et al Extended cervical mediastinoscopy: a single staging procedure for bronchogenic carcinoma of the left upper lobe.Thorac Cardiovasc Surg1987;94,673-678
 
Best, LA, Munichor, M, Ben-Shakhar, M, et al The contribution of anterior mediastinotomy in the diagnosis and evaluation of diseases of the mediastinum and lung.Ann Thorac Surg1987;43,78-81
 
Bulzebruck, H, Bopp, R, Drings, P, et al New aspects in the staging of lung cancer: prospective validation of the International Union Against Cancer TNM classification.Cancer1992;70,1102-1110
 
Fernando, HC, Goldstraw, P The accuracy of clinical evaluative intrathoracic staging in lung cancer as assessed by postsurgical pathologic staging.Cancer1990;65,2503-2506
 
Watanabe, Y, Shimizu, J, Oda, M, et al Aggressive surgical intervention in N2 non-small cell cancer of the lung.Ann Thorac Surg1991;51,253-261
 
Pisters, KM, Ginsberg, RJ, Putnam, JB, Jr, et al Induction chemotherapy before surgery for early-stage lung cancer: a novel approach.Thorac Cardiovasc Surg2000;119,429-439
 
Goldberg, SN, Raptopoulos, V, Boiselle, PM, et al Mediastinal lymphadenopathy: diagnostic yield of transbronchial mediastinal lymph node biopsy with CT fluoroscopic guidance; initial experience.Radiology2000;216,764-767
 
White, CS, Weiner, EA, Patel, P, et al Transbronchial needle aspiration: guidance with CT fluoroscopy.Chest2000;118,1630-1638
 
Shannon, JJ, Bude, RO, Orens, JB, et al Endobronchial ultrasound-guided needle aspiration of mediastinal adenopathy.Am J Respir Crit Care Med1996;153(4 pt 1),1424-1430
 
McAdams, HP, Goodman, PC, Kussin, P Virtual bronchoscopy for directing transbronchial needle aspiration of hilar and mediastinal lymph nodes: a pilot study.AJR Am J Roentgenol1998;170,1361-1364
 
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