Endoscopic Ultrasound-Guided Fine- Needle Aspiration for Non-small Cell Lung Cancer Staging* A Systematic Review and Metaanalysis

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1 CHEST Endoscopic Ultrasound-Guided Fine- Needle Aspiration for Non-small Cell Lung Cancer Staging* A Systematic Review and Metaanalysis Carlos G. Micames, MD; Douglas C. McCrory, MD; Darren A. Pavey, MD; Paul S. Jowell, MD; and Frank G. Gress, MD Original Research INTERVENTIONAL PULMONOLOGY Background: Endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) is a minimally invasive alternative technique for mediastinal staging of non-small cell lung cancer. A metaanalysis was performed to estimate the diagnostic accuracy of EUS-FNA for staging mediastinal lymph nodes (N2/N3 disease) in patients with lung cancer. Methods: Relevant studies were identified using Medline (1966 to November 2005), CINAHL, and citation indexing. Included studies used histology or adequate clinical follow-up (> 6 months) as the gold standard, and provided sufficient data for calculating sensitivity and specificity. Summary receiver operating characteristic curves metaanalysis was performed to estimate the pooled sensitivity and specificity. Results: In 18 eligible studies, EUS-FNA identified 83% of patients (95% confidence interval [CI], 78 to 87%) with positive mediastinal lymph nodes (pooled sensitivity) and 97% of patients (95% CI, 96 to 98%) with negative mediastinal lymph nodes (pooled specificity). In eight studies that were limited to patients who had abnormal mediastinal lymph nodes seen on CT scans, the sensitivity was 90% (95% CI, 84 to 94%) and the specificity was 97% (95% CI, 95 to 98%). In patients without abnormal mediastinal lymph nodes seen on CT scans (four studies), the pooled sensitivity was 58% (95% CI, 39 to 75%). Minor complications were reported in 10 cases (0.8%). There were no major complications. Conclusions: EUS-FNA is a safe modality for the invasive staging of lung cancer that is highly sensitive when used to confirm metastasis to mediastinal lymph nodes seen on CT scans. In addition, among lung cancer patients with normal mediastinal adenopathy seen on CT scans, despite lower sensitivity, it has the potential to prevent unnecessary surgery in a large proportion of cases missed by CT scanning. (CHEST 2007; 131: ) Key words: biopsy; diagnostic tests; endoscopic ultrasound; endosonography; fine needle; lung cancer; metaanalysis; neoplasm staging; sensitivity and specificity Abbreviations: CI confidence interval; DOR diagnostic odds ratio; EUS endoscopic ultrasound; FDG fluorodeoxyglucose; FNA fine-needle aspiration; NSCLC non-small cell lung cancer; PET positron emission tomography Lung cancer is the most common cause of cancerrelated mortality in the United States, with an estimated annual incidence of 174,000 cases and 162,000 deaths. 1 Treatments are largely based on *From the Division of Gastroenterology (Drs. Micames, Pavey, Jowell, and Gress), Duke University Medical Center, and the Center for Clinical Health Policy Research (Dr. McCrory), Duke University, Durham, NC. The authors have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article. histology (small cell vs non-small cell) and the presence of mediastinal lymph node involvement or metastases distant from the tumor. Accurate staging Manuscript received June 8, 2006; revision accepted September 8, Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( org/misc/reprints.shtml). Correspondence to: Carlos G. Micames, MD, Duke University Medical Center, Division of Gastroenterology, Box 3913, Durham, NC 27710; Carlos.micames@duke.edu DOI: /chest CHEST / 131 / 2/ FEBRUARY,

2 is very important as it guides prognosis, and for this reason it is a prerequisite for clinical trials that compare different therapies. Nearly half of all patients with lung cancer have mediastinal disease at diagnosis. Metastases to ipsilateral or subcarinal nodes (N2) are classified as stage IIIA disease. Management of stage IIIA disease is more controversial, but many centers treat it with radiation and chemotherapy, with surgery performed under investigational protocols. Direct mediastinal invasion (T4) or metastasis to contralateral mediastinal nodes (N3) is classified as stage IIIB disease. The 5-year survival rate is 5%, and patients are generally offered treatment with chemoradiotherapy without surgery. Endoscopic ultrasound (EUS) is a promising invasive imaging test that is gaining acceptance as a tool for staging lung cancer. EUS was originally developed for the local staging of GI cancers, but it also provides excellent access to the posterior mediastinum through the esophageal wall. 2 Early studies 3 described the morphology of benign and malignant lymph nodes in terms of size, shape, echogenicity, and edge characteristics. The addition of the technique of EUS-guided fine-needle aspiration (FNA) significantly improved both sensitivity and specificity in the detection of malignant lymph nodes by EUS. 4 The aim of this study was to perform a metaanalysis of the data published to date on the use EUS-FNA for mediastinal staging of non-small cell lung cancer (NSCLC). Materials and Methods Study Selection and Data Abstraction A literature search was performed using PubMed and CINAHL from January 1966 to November The following search terms were used: endoscopic ultrasound OR endosonography; and biopsy, fine-needle OR fine-needle aspiration. Titles and abstracts were reviewed by two independent investigators (CGM and DAP). Full articles of appropriate studies were retrieved for detailed evaluation. We included studies in any language that included the following; (1) used EUS-FNA in adult patients ( 18 years old) with suspected or previously diagnosed NSCLC for staging of mediastinal lymph nodes; (2) enrolled at least 10 participants who had undergone EUS-FNA for mediastinal staging; (3) utilized histopathology or adequate clinical follow-up ( 6 months) as the reference standard; and (4) presented data sufficient to allow the calculation of sensitivity and specificity. Two investigators (CGM and DAP) independently extracted data from each article. Disagreements were resolved by consensus. The accuracy of EUS-FNA in participants with enlarged mediastinal lymph nodes present or absent on chest CT scan was calculated from articles that provided these data. EUS-FNA performance was calculated from data extracted per each individual patient, instead of per lymph node station. Study Quality We reviewed the studies for quality using items from the Standards for Reporting of Diagnostic Accuracy statement. 5 Components of this statement that were utilized to judge study quality included the following: prospective design; consecutive enrollment of a series of patients; reference standard and its rationale; expertise of index test operators; blinding of index test operators to results of prior tests (ie, CT scans and/or positron emission tomography [PET] scans); assurance that all participants underwent reference testing; and reporting of any adverse events related to performing the index test and/or the reference standard. A standardized data extraction sheet was used. Statistical Analysis A2 2 contingency table was constructed for each study. Participants were classified as having a positive or negative EUS-FNA finding and as having malignant or benign mediastinal lymph nodes. The reference standard was defined as the presence or absence of malignancy in mediastinal lymph nodes obtained through mediastinoscopy or thoracotomy, or the progression of disease during clinical follow-up. EUS-FNA samples reported as being inconclusive or nondiagnostic were considered to be a true-negative finding if no malignancy was found during surgery, or a false-negative finding if lymph node metastasis was confirmed. Cases with benign diagnoses made by EUS-FNA (eg, sarcoidosis or tuberculosis) were counted as true negative findings if no metastases were detected during surgery or if there was a lack of progression during clinical follow-up. The sensitivity and specificity of EUS-FNA was determined for its ability to distinguish mediastinal lymph node involvement (stations 1 to 9, or N2/N3 by TNM classification) from hilar, intrapulmonary (stations 10 to 14, or N1), or no lymph node involvement (N0). 6 Patients without detectable nodes on EUS or small, nonsuspicious nodes in which aspirates were not obtained were also staged as N0. Summary receiver operating characteristic curve metaanalysis with inverse-variance weighting and continuity correction for zero cells was performed, and was used to estimate the pooled sensitivity and specificity. All analyses were performed using a statistical software package (dr-roc, version 2.0; dr 2 Consulting; Glenside, PA). Comparisons of diagnostic accuracy between subgroups were made by comparing the diagnostic odds ratio (DOR) between subgroups of interest using analysis of variance. These analyses were performed using the PROC GLM procedure (SAS, version 9.1; SAS Institute; Cary, NC). p Values of 0.05 were considered to be statistically significant. To assess for the presence of publication bias, an inverted funnel plot was constructed of SE vs the estimated effect size (ie, DOR) for each study. Results Combining the search terms resulted in a total of 101 articles (Fig 1). Seventy-seven articles were excluded after reviewing the title and abstract. Eight articles were excluded after reviewing the full article Two additional studies 15,16 were identified from the references of articles obtained from this literature search and review articles. A total of 18 studies were included in the metaanalysis (Table 1). All of the studies retrieved for the metaanalysis were published in English. One 540 Original Research

3 Figure 1. Results of search strategy. study was published in both Danish and English. 27,33 The median number of participants per study was 59 (range, 24 to 212 participants). The mean age of participants was 63 years, and the median proportion of male participants was 63% (range, 53 to 86%). The median prevalence of malignant lymph nodes was 65% (range, 33 to 85%). Study Details and Quality Of the 18 studies, 16 studies 15,17 27,29 32 enrolled patients prospectively. Two studies 16,28 were retrospective database reviews. Three studies 17,18,26 enrolled patients in a consecutive manner, but only one study 26 met all of our criteria for assessing study quality, including the blinding of EUS operator to prior test results. Ten studies 17 19,21,24 26,28,31,32 used histopathology alone as a reference standard. The remaining studies 15,16,20,22,23,27,29,30 used a compound reference standard composed of histopathology or adequate clinical follow-up. Only one study 18 performed surgery to confirm positive EUS-FNA results. The remaining studies considered malignant cytology obtained by EUS-FNA as a true-positive result or required evidence of clinical progression in addition to positive EUS-FNA results. Three articles 17,19,24 did not report adverse events related to performing EUS-FNA. EUS- FNA procedures were performed by one to three experienced operators and utilized either a 22-gauge or a 23-gauge needle. Lymph node stations examined by EUS-FNA differed betweens studies (Table 1). Half of the studies utilized a radial echoendoscope initially to evaluate for the presence or absence of mediastinal lymphadenopathy, followed by the use of a curvilinear echoendoscope for FNA of the target lesion. 15,16,19,21,22,24,29,31,32 The remaining studies 17,18,20,23,25 28,30 performed both the initial evaluation and FNA using the curvilinear echoendoscope. Patient enrollment and the influence of selection bias differed among studies. Four studies did not appear to have referral bias as they prospectively enrolled consecutive patients with proven lung cancer who had been referred for preoperative staging of the mediastinum using EUS-FNA, 18,26 or had enrolled patients without enlarged mediastinal CHEST / 131 / 2/ FEBRUARY,

4 Table 1 Characteristics of the Included Studies* Study/Year Publication Type No. LN on CT Scan, % N2/N3 Prevalence, % Sensitivity, % Specificity, % Reference Standard Stations Examined by EUS Silvestri et al 32 /1996 Prospective Histopathology 5, 7, 8, 9 Gress et al 31 /1997 Prospective Histopathology All within EUS reach Williams et al 16 /1999 Retrospective Histopathology and 5, 7 follow-up ( 6 mo) Fritscher-Ravens et al 30 / Prospective Histopathology and All within EUS reach 2000 follow-up Wiersema et al 29 /2001 Prospective Histopathology and All within EUS reach follow-up ( 12 mo) Wallace et al 28 /2001 Retrospective Histopathology All within EUS reach Larsen et al 27 /2002 Prospective Histopathology and All within EUS reach follow-up ( 12 mo) Fritscher-Ravens et al 26 / Consecutive Histopathology All within EUS reach 2003 Kramer et al 25 /2004 Prospective Histopathology All within EUS reach Wallace et al 24 /2004 Prospective Histopathology All within EUS reach Savides and Perricone 15 / Prospective Histopathology and All within EUS reach 2004 follow-up ( 12 mo) Eloubeidi et al 22 /2005 Prospective 104 NA Histopathology and All within EUS reach follow-up ( 6 mo) LeBlanc et al 21 /2005 Prospective Histopathology All within EUS reach Larsen et al 20 /2005 Prospective Histopathology and 2, 4, 7 follow-up ( 12 mo) Caddy et al 19 /2005 Prospective Histopathology All within EUS reach Annema et al 18 /2005 Consecutive Histopathology All within EUS reach Tournoy et al 23 /2005 Prospective 60 NA Histopathology and All within EUS reach follow-up ( 5 mo) Annema et al 17 /2005 Consecutive Histopathology All within EUS reach *LN on CT Scan enlarged mediastinal lymph nodes (ie, 1 cm) on CT scan; NA not available. Lymph node stations within reach of transesophageal EUS: 2L, 4L, 5, 7, 8, and 9. lymph nodes on CT scans who were being considered for surgery. 21,24 Six studies 17,19,23,25,30,31 enrolled patients with enlarged mediastinal lymph nodes seen on CT scan or positive PET scan regardless of whether they were located in regions accessible to EUS-FNA. The remaining studies 15,16,20,22,27 29,32 were the most prone to selection bias as they included patients who had been referred for EUS-FNA based on prior imaging (CT or PET scanning) that revealed lesions within easy reach of EUS, mainly the posterior mediastinum and adjacent to the esophagus. All participants who were enrolled in the study underwent reference testing in 10 studies. 15,16,22,23,25,26,28,29,31,32 Approximately 80% of participants who were enrolled underwent reference testing in seven studies ,24,33 One study 30 enrolled only 51% of eligible subjects in the analysis. All eligible participants included in this study underwent EUS-FNA for suspected lung cancer without a confirmed diagnosis after undergoing transbronchial biopsy. Specific numbers and reasons for exclusion were not provided (Table 2). Diagnostic Accuracy A total of 1,201 patients were included in the analysis from the 18 eligible nonoverlapping studies. EUS-FNA had a pooled sensitivity of 83% (95% confidence interval [CI], 78 to 87%) and a specificity of 97% (95% CI, 96 to 98%) [Fig 2]. Results for sensitivity in individual studies ranged from 36 to 100% (Fig 3). The lowest sensitivity occurred in the two studies 21,24 that enrolled patients with no enlarged mediastinal lymph nodes seen on CT scans. The prevalence of malignant lymph nodes was 33% for both, which was lower than that in any other study. Only one study 18 had a specificity result below 100%. Participants who were enrolled in this study underwent mediastinoscopy regardless of the result of prior EUS-FNA results. This was the only study that verified positive findings obtained during EUS- FNA by histopathology. It revealed two false-positive EUS-FNA findings, which occurred while sampling a suspected subcarinal lymph node that was not confirmed to be malignant after mediastinoscopy and thoracotomy. Seven studies 15 17,19,27,30,31 enrolled only patients 542 Original Research

5 Figure 2. Summary receiver operating characteristic curve for EUS-FNA in all studies. Πmean threshold point on the summary receiver operating characteristic curve. with enlarged lymph nodes seen on CT scans. Several studies included participants with and without enlarged lymph nodes seen on CT scans, but only one study 28 provided sufficient data to calculate sensitivity and specificity separately between groups. A total of 560 participants with mediastinal adenopathy seen on CT scans were enrolled into the study. The pooled sensitivity was 90% (95% CI, 84 to 94%), and the specificity was 97% (95% CI, 95 to 98%) [Fig 4]. Two studies 21,24 enrolled patients without enlarged mediastinal lymph nodes seen on CT scans, and two more studies 26,28 provided sufficient information to calculate the sensitivity and specificity for this subgroup. In these four studies, enrolling a total of 175 cases, the pooled sensitivity was 58% (95% CI, 39 to 75%). The pooled specificity was 98% (95% CI, 96 to 99%). This difference in diagnostic accuracy between studies enrolling patients with adenopathy seen on CT scans and those without adenopathy was statistically significant (p 0.01). Several investigators 15,16,19,23,24,28,31,32 performed EUS-FNA and used an on-site cytopathologist to determine the adequacy of the sample. These eight studies included a total of 459 cases, with a pooled sensitivity of 88% (95% CI, 80 to 93%) and a specificity of 98% (95% CI, 96 to 99%). Studies without an on-site cytopathologist, 17,18,20,22,26,27,29,30 including two studies 21,25 with an on-site cytotechnician, had a slightly lower pooled sensitivity (80%; 95% CI, 72 to 86%). Pooled specificity remained unchanged (97%; 95% CI, 96 to 98%). The diagnostic accuracy of the nine studies performing an initial examination with a radial echoendoscope revealed a sensitivity of 84% (95% CI, 76 to 90%) and a specificity of 98% (95% CI, 97 to 99%). The remaining studies that utilized only a curvilinear echoendoscope showed resulted for a pooled sensitivity of 82% (95% CI, 75 to 88%) and a specificity of 97% (95% CI, 95 to 98%). The difference in diagnostic accuracy for these two subgroups was not statistically significant (p 0.26 and 0.38, respectively). To examine the effect of different reference standards, we compared the DOR between studies that used histopathology exclusively as the reference standard with those using a compound reference standard of histopathology and clinical follow-up. Both of the two studies 21,24 that included only patients without enlarged mediastinal lymph nodes seen on CT scans confirmed their results using histopathology. They were excluded from this analysis as this would confound the effect of the reference standard with that of mediastinal lymph node status. 21,24 The remaining eight studies 17 19,25,26,28,31,32 enrolled a total of 617 patients, resulting in a pooled sensitivity of 79% (95% CI, 70 to 85%) and a specificity of 97% (95% CI, 95 to 98%). Eight studies, 15,16,20,22,23,27,29,30 enrolling 448 cases, used a compound reference standard of histopathology and clinical follow-up that resulted in a pooled sensitivity of 93% (95% CI, 88 to 96%) and a specificity of 98% (95% CI, 96 to 99%). This difference in diagnostic accuracy was statistically significant (p 0.01). Despite the differences between the studies, a statistical test for heterogeneity among all studies was not significant ( 0.77). Since we found no evidence of heterogeneity, we chose the fixed-effects model. The DOR between the random-effects model and the fixed-effects model were nearly identical. Pooled estimates for sensitivity, specificity, positive predictive value, and negative predictive value for the groups of studies are shown in Table 3. An inverted funnel plot showed no evidence of publication bias (Fig 5). Adverse Events Minor complications were reported in 10 cases (0.8%). These included one patient with a fever that developed 24 h after performing EUS-FNA and resolved a day later after initiating oral antibiotic therapy. 29 The rest were reported by Eloubeidi et al, 22 including one patient with self-limited stridor during the procedure, six patients who reported having a sore throat, one patient with nausea and vomiting, and one patient with cough at the 1-week CHEST / 131 / 2/ FEBRUARY,

6 Table 2 Patients Who Did Not Undergo Reference Standard Testing Study/Year Participants* Enrolled, % Reasons for Exclusion Fritscher-Ravens et al 30 / /69 51 Not available Larsen et al 27 / /34 85 No mediastinoscopy done (2), and no thoracotomy following negative EUS-FNA and mediastinoscopy (3) Wallace et al 24 / /87 79 Not surgical candidates (10), and treatment started without surgical staging (8) LeBlanc et al 21 / /76 88 Lost to follow-up (5), distant metastasis (3), and synchronous esophageal cancer (1) Larsen et al 20 / /60 88 T4 tumors (4), distant metastasis (1), clinical deterioration precluding further staging (1), and local progression (1) Caddy et al 19 / /36 94 Not available Annema et al 18 / / Inadequate or no mediastinoscopy (5), distant metastasis (1), clinical deterioration (1), and change of management (1) Annema et al 17 / / PET in N2 nodes (2), pleural extension (3), distant metastasis (5), clinical deterioration (4), death (1), neoadjuvant treatment administered (2), patient refusal (1), and T4 tumors (9) *Values are given as No. of patients enrolled/total No. Values in parentheses are the No. of patients. follow-up. There were no major complications reported in any of the studies. Discussion In this metaanalysis, we found that EUS-FNA is an accurate method for the invasive staging of NSCLC. Its sensitivity is higher when used to confirm metastasis to lymph nodes in patients with suspected N2 or N3 disease seen on CT scans. Patients without enlarged mediastinal adenopathy seen on CT scans had a 35% prevalence of malignant mediastinal lymph nodes. The performance of EUS- FNA in this group is useful given the ability of this technique to sample nodes as small as 3 mm and to identify metastases found in normal-sized lymph nodes, reducing the number of unnecessary mediastinoscopies and futile thoracotomies. Our results compare favorably to results reported in the literature of other modalities used for mediastinal staging. The sensitivity of EUS-FNA was 90% in patients with enlarged mediastinal lymph nodes seen on CT scans, results that are similar to those of fluorodeoxyglucose (FDG)-PET scans. If lymph nodes did not appear to be enlarged on CT scans, the sensitivity for EUS-FNA was lower than that for FDG-PET scans (58% and 82%, respectively). The specificity for EUS-FNA results was higher than that for FDG-PET scan findings (97% and 90%, respectively), particularly when the CT scan showed enlarged lymph nodes (97% and 78%, respectively). 34 Given the high false-positive rate caused by benign lesions with high metabolic activity such as granulomatous disease and pneumonia, the confirmation of a positive FDG-PET scan finding by obtaining a tissue diagnosis is recommended. EUS-FNA is a minimally invasive alternative technique with a high accuracy for confirming positive FDG-PET scan results. 11 Table 3 Diagnostic Accuracy and Heterogeneity* Variables Sensitivity Specificity NPV PPV Heterogeneity Prevalence Overall 83 (78 87) 97 (96 98) 78 (73 83) 98 (97 99) CT scan Positive findings 90 (84 94) 97 (95 98) 78 (68 86) 99 (98 99) Negative findings 58 (39 75) 98 (96 99) 81 (74 88) 94 (83 98) On-site cytopathology 88 (80 93) 98 (96 99) 71 (63 78) 98 (97 99) No on-site cytopathology 80 (72 86) 97 (96 98) 76 (69 82) 98 (96 99) Radial EUS 84 (76 90) 98 (97 99) 86 (80 91) 98 (96 99) Linear EUS only 82 (75 88) 97 (95 98) 71 (63 78) 98 (97 99) Histopathology 79 (70 85) 97 (95 98) 66 (58 74) 98 (97 99) Histopathology and follow-up 93 (88 96) 98 (96 99) 91 (85 94) 98 (97 99) *Values are given as % (95% CI), unless otherwise indicated. NPV negative predictive value; PPV positive predictive value. p Value of the Q-statistic. 544 Original Research

7 Figure 3. Individual study estimates of sensitivity and 1-specificity of EUS-FNA for identifying metastasis to mediastinal lymph nodes (N2/N3 disease). Error bars 95% CI. The average sensitivity of cervical mediastinoscopy is 80%. False-negative results usually occur in stations that are not accessible, including the subcarinal lymph nodes (station 7), paraesophageal lymph nodes (stations 8 and 9), the aortopulmonary window lymph nodes (station 5), and the anterior mediastinal lymph nodes (station 6). An extended cervical mediastinoscopy with an anterior mediastinotomy (Chamberlain procedure) permits evaluation of the aortopulmonary window lymph nodes, but false-negative rates remain at 9 to 11%. 35 In comparison, EUS-FNA was superior to mediastinoscopy for diagnosing mediastinal disease in the paratracheal lymph nodes (stations 2 and 4) and subcarinal lymph nodes (station 7) in one study. 20 Using a decision-analysis model, EUS-FNA has also been shown to be a more cost-effective technique than mediastinoscopy and mediastinotomy in patients with abnormal lymph nodes seen on CT scans. 36 Annema et al 18 found a higher sensitivity for EUS-FNA compared to cervical mediastinoscopy, which was attributed to a majority of missed metastases located in the subcarina (station 7). This prospective, nonrandomized study also found that 16% of thoracotomies could have been avoided by using EUS-FNA in addition to mediastinoscopy, suggesting a complementary role for these two procedures. In addition, a definitive malignant cytologic diagnosis obtained by EUS-FNA was accepted as final proof of metastatic disease in all of the studies included, except for one. 18 This study found two falsepositive FNA results obtained from left lower lobe tumors interpreted by the EUS operators as being subcarinal lymph nodes. The remaining studies attempted to confirm positive EUS-FNA results by observing disease progression during follow-up or by the response to chemoradiotherapy. Exact details were not well documented and likely explain the perfect specificity for all of these studies. Despite its low rate, this issue of false-positive EUS-FNA findings is of concern. This makes the accurate localization of hilar tumors and distinction from lymph nodes by both CT scan and EUS of the utmost importance. The major limitation of EUS-FNA in lung cancer staging is the inability to assess nodes in the anterior mediastinum, resulting in an imperfect sensitivity. This is due to the fact that ultrasound cannot penetrate air-filled structures, so nodes immediately anterior to the trachea (ie, levels 2R, 4R, 3, and 6) are not well visualized. More recent studies 7,37 utilizing a prototype real-time endobronchial ultrasound bronchoscope with the ability to perform FNA have shown promising results and may overcome this limitation. Combined use with transesophageal EUS was shown to be complementary and highly accurate for the diagnosis of mediastinal lesions. 7,37 Studies CHEST / 131 / 2/ FEBRUARY,

8 Figure 4. Individual study estimates of sensitivity and 1-specificity of EUS-FNA for identifying N2/N3 disease in studies that included patients with or without enlarged mediastinal lymph nodes on CT scan. Error bars 95% CI. evaluating the diagnostic accuracy of this combined approach for mediastinal staging are currently ongoing. Another cause of false-negative findings is nodal micrometastasis or the selective involvement of different nodes in the same group. This problem can be minimized by the practice of sampling all suspicious posterior mediastinal lymph nodes, starting with those having the biggest impact on management, the contralateral nodes, the testing results of which would, if positive, denote stage IIIB disease. The status of the anterior mediastinal lymph nodes would then be irrelevant, and further invasive staging procedures would be avoided. Most studies included in this metaanalysis had a similar sensitivity, ranging from 87 to 100%. Four studies were identified as having results that were inconsistent with the remaining studies. Two stud- Figure 5. Inverted funnel plot. 546 Original Research

9 ies 21,24 enrolled only patients without mediastinal adenopathy seen on CT scans and had a lower prevalence of metastases to mediastinal lymph nodes. Kramer et al 25 had 31% of EUS-FNA samples result in inconclusive cytologic diagnosis, which led to a sensitivity of 73%. Approximately two thirds of patients with samples yielding inconclusive cytology findings were found to have malignant disease during surgery, accounting for 84% of false-negative findings for EUS-FNA. This study did not have an on-site cytopathologist, and the number of attempted passes was not provided. Several features seen with EUS can help to determine whether a lymph node is malignant. These features include the following: diameter 5to10 mm on the short axis; round, sharp, distinct margins; and hypoechoic texture. An increasing number of features increases the probability of that lymph node being malignant. 3 However, only 23 to 25% will have all four echo features, and their reliability for predicting malignant involvement in lung malignancies is lower than that for GI cancers. 4,38 There was significant variability in the terms of EUS criteria used to decide on proceeding with FNA. Six of the studies included in this metaanalysis required the presence on EUS of at least one criterion before performing FNA on a particular lymph node. LeBlanc et al 21 performed FNA only on lymph nodes with at least two endosonographic criteria for malignancy. This can decrease sensitivity because it assumes that some lymph nodes are benign and thus that FNA is not needed to confirm the diagnosis. One study 31 required the presence of all four criteria, resulting in a sensitivity of 93%. However, all patients enrolled in the study had mediastinal adenopathy seen on CT scans and a high prevalence of lymph node metastases. In summary, EUS-FNA is an accurate, cost-effective, and safe means of evaluating patients with lung cancer. EUS-FNA is useful in providing the histologic confirmation of cancer in cases in which bronchoscopy has been nondiagnostic. EUS-FNA may be the investigation of choice for staging patients with NSCLC who are surgical candidates, even in those without evidence of mediastinal lymphadenopathy seen on CT or PET scans. Its main limitation is the inability to visualize mediastinal lymph nodes anterior to the trachea, heart, and great vessels. The use of EUS-FNA as a staging modality for NSCLC may avoid the need for further staging in up to 30% of patients, thereby avoiding the risks associated with more invasive staging. References 1 Jemal A, Siegel R, Ward E, et al. Cancer statistics, CA Cancer J Clin 2006; 56: Wiersema MJ, Hassig WM, Hawes RH, et al. Mediastinal lymph node detection with endosonography. Gastrointest Endosc 1993; 39: Catalano MF, Sivak MV Jr, Rice T, et al. Endosonographic features predictive of lymph node metastasis. Gastrointest Endosc 1994; 40: Bhutani MS, Hawes RH, Hoffman BJ. A comparison of the accuracy of echo features during endoscopic ultrasound (EUS) and EUS-guided fine-needle aspiration for diagnosis of malignant lymph node invasion. Gastrointest Endosc 1997; 45: Bossuyt PM, Reitsma JB, Bruns DE, et al. The STARD statement for reporting studies of diagnostic accuracy: explanation and elaboration. Ann Intern Med 2003; 138:W1 W12 6 Mountain CF, Dresler CM. Regional lymph node classification for lung cancer staging. Chest 1997; 111: Vilmann P, Krasnik M, Larsen SS, et al. Transesophageal endoscopic ultrasound-guided fine-needle aspiration (EUS- FNA) and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) biopsy: a combined approach in the evaluation of mediastinal lesions. Endoscopy 2005; 37: Rintoul RC, Skwarski KM, Murchison JT, et al. Endobronchial and endoscopic ultrasound-guided real-time fine-needle aspiration for mediastinal staging. Eur Respir J 2005; 25: Larsen SS, Vilmann P, Krasnik M, et al. Endoscopic ultrasound guided biopsy performed routinely in lung cancer staging spares futile thoracotomies: preliminary results from a randomised clinical trial. Lung Cancer 2005; 49: Eloubeidi MA, Tamhane A, Chen VK, et al. Endoscopic ultrasound-guided fine-needle aspiration in patients with non-small cell lung cancer and prior negative mediastinoscopy. Ann Thorac Surg 2005; 80: Annema JT, Hoekstra OS, Smit EF, et al. Towards a minimally invasive staging strategy in NSCLC: analysis of PET positive mediastinal lesions by EUS-FNA. Lung Cancer 2004; 44: Varadarajulu S, Hoffman BJ, Hawes RH, et al. EUS-guided FNA of lung masses adjacent to or abutting the esophagus after unrevealing CT-guided biopsy or bronchoscopy. Gastrointest Endosc 2004; 60: Emery SC, Savides TJ, Behling CA. Utility of immediate evaluation of endoscopic ultrasound-guided transesophageal fine needle aspiration of mediastinal lymph nodes. Acta Cytol 2004; 48: Fritscher-Ravens A, Davidson BL, Hauber HP, et al. Endoscopic ultrasound, positron emission tomography, and computerized tomography for lung cancer. Am J Respir Crit Care Med 2003; 168: Savides TJ, Perricone A. Impact of EUS-guided FNA of enlarged mediastinal lymph nodes on subsequent thoracic surgery rates. Gastrointest Endosc 2004; 60: Williams DB, Sahai AV, Aabakken L, et al. Endoscopic ultrasound guided fine needle aspiration biopsy: a large single centre experience. Gut 1999; 44: Annema JT, Versteegh MI, Veselic M, et al. Endoscopic ultrasound-guided fine-needle aspiration in the diagnosis and staging of lung cancer and its impact on surgical staging. J Clin Oncol 2005; 23: Annema JT, Versteegh MI, Veselic M, et al. Endoscopic ultrasound added to mediastinoscopy for preoperative staging of patients with lung cancer. JAMA 2005; 294: Caddy G, Conron M, Wright G, et al. The accuracy of EUS-FNA in assessing mediastinal lymphadenopathy and staging patients with NSCLC. Eur Respir J 2005; 25: Larsen SS, Vilmann P, Krasnik M, et al. Endoscopic ultrawww.chestjournal.org CHEST / 131 / 2/ FEBRUARY,

10 sound guided biopsy versus mediastinoscopy for analysis of paratracheal and subcarinal lymph nodes in lung cancer staging. Lung Cancer 2005; 48: LeBlanc JK, Devereaux BM, Imperiale TF, et al. Endoscopic ultrasound in non-small cell lung cancer and negative mediastinum on computed tomography. Am J Respir Crit Care Med 2005; 171: Eloubeidi MA, Cerfolio RJ, Chen VK, et al. Endoscopic ultrasound-guided fine needle aspiration of mediastinal lymph node in patients with suspected lung cancer after positron emission tomography and computed tomography scans. Ann Thorac Surg 2005; 79: Tournoy KG, Praet MM, Van Maele G, et al. Esophageal endoscopic ultrasound with fine-needle aspiration with an on-site cytopathologist: high accuracy for the diagnosis of mediastinal lymphadenopathy. Chest 2005; 128: Wallace MB, Ravenel J, Block MI, et al. Endoscopic ultrasound in lung cancer patients with a normal mediastinum on computed tomography. Ann Thorac Surg 2004; 77: Kramer H, van Putten JW, Post WJ, et al. Oesophageal endoscopic ultrasound with fine needle aspiration improves and simplifies the staging of lung cancer. Thorax 2004; 59: Fritscher-Ravens A, Bohuslavizki KH, Brandt L, et al. Mediastinal lymph node involvement in potentially resectable lung cancer: comparison of CT, positron emission tomography, and endoscopic ultrasonography with and without fine-needle aspiration. Chest 2003; 123: Larsen SS, Krasnik M, Vilmann P, et al. Endoscopic ultrasound guided biopsy of mediastinal lesions has a major impact on patient management. Thorax 2002; 57: Wallace MB, Silvestri GA, Sahai AV, et al. Endoscopic ultrasound-guided fine needle aspiration for staging patients with carcinoma of the lung. Ann Thorac Surg 2001; 72: Wiersema MJ, Vazquez-Sequeiros E, Wiersema LM. Evaluation of mediastinal lymphadenopathy with endoscopic USguided fine-needle aspiration biopsy. Radiology 2001; 219: Fritscher-Ravens A, Soehendra N, Schirrow L, et al. Role of transesophageal endosonography-guided fine-needle aspiration in the diagnosis of lung cancer. Chest 2000; 117: 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 Med 1997; 127: Silvestri GA, Hoffman BJ, Bhutani MS, et al. Endoscopic ultrasound with fine-needle aspiration in the diagnosis and staging of lung cancer. Ann Thorac Surg 1996; 61: Larsen SS, Krasnik M, Vilmann P, et al. Endoscopic ultrasound-guided biopsy of suspected malignancy in the mediastinum has a major impact on the clinical decision process. Ugeskr Laeger 2002; 164: Gould MK, Kuschner WG, Rydzak CE, et al. Test performance of positron emission tomography and computed tomography for mediastinal staging in patients with non-smallcell lung cancer: a meta-analysis. Ann Intern Med 2003; 139: Detterbeck FC, DeCamp MM Jr, Kohman LJ, et al. Lung cancer. Invasive staging: the guidelines. Chest 2003; 123: 167S 175S 36 Aabakken L, Silvestri GA, Hawes R, et al. Cost-efficacy of endoscopic ultrasonography with fine-needle aspiration vs. mediastinotomy in patients with lung cancer and suspected mediastinal adenopathy. Endoscopy 1999; 31: Krasnik M, Vilmann P, Larsen SS, et al. Preliminary experience with a new method of endoscopic transbronchial real time ultrasound guided biopsy for diagnosis of mediastinal and hilar lesions. Thorax 2003; 58: Vazquez-Sequeiros E, Levy MJ, Clain JE, et al. Routine vs. selective EUS-guided FNA approach for preoperative nodal staging of esophageal carcinoma. Gastrointest Endosc 2006; 63: Original Research