Endoscopic Ultrasound-Guided Fine Needle Aspiration for Staging of Malignant Pleural Mesothelioma

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1 Endoscopic Ultrasound-Guided Fine Needle Aspiration for Staging of Malignant Pleural Mesothelioma David C. Rice, MB, BCh, Matthew A. Steliga, MD, John Stewart, MD, PhD, George Eapen, MD, Carlos A. Jimenez, MD, Jeffrey H. Lee, MD, Wayne L. Hofstetter, MD, Edith M. Marom, MD, Reza J. Mehran, MD, Ara A. Vaporciyan, MD, Garrett L. Walsh, MD, and Stephen G. Swisher, MD Departments of Thoracic and Cardiovascular Surgery, Pathology, Pulmonary Medicine, Gastroenterology, Hepatology, Nutrition, and Diagnostic Imaging, The University of Texas, M.D. Anderson Cancer Center, Houston, Texas Background. Radical surgery for malignant pleural mesothelioma does not improve survival in patients with nodal metastases. Imaging is poor at predicting nodal involvement and mediastinoscopy, though frequently used, is of low sensitivity. As endobronchial ultrasound (EBUS) and esophageal endoscopic ultrasound (EUS) are accurate for nodal staging of lung cancer, we hypothesized that they would be at least as sensitive as cervical video-mediastinoscopy for nodal staging of mesothelioma. Methods. Eighty-five patients with mesothelioma who were potential candidates for radical surgery underwent preoperative staging with mediastinoscopy (n 50) or EBUS (n 38). Eleven patients also underwent EUS. Results. Diagnostic yield (specimens containing lymphocytes or tumor cells) was 100% for mediastinoscopy and 84% for EBUS (p < 0.001). Mediastinoscopy identified 7 of 50 (14%) patients with nodal metastases. Thirtyeight (76%) mediastinoscopy-negative patients underwent surgery with nodal sampling and there were 18 false negatives. Endobronchial ultrasound identified 13 of 38 (34%) patients with nodal metastases. Twenty-two (58%) EBUS-negative patients underwent surgery with nodal sampling and there were 10 false negatives. Sensitivity and negative predictive value for mediastinoscopy were 28% and 49%, and 59% and 57% for EBUS. Eleven patients had EUS preoperatively, which revealed infradiaphragmatic nodal metastases in 5 patients. Conclusions. Although this study is retrospective, EBUS had higher sensitivity than either mediastinoscopy or imaging studies for detection of nodal metastases. Nevertheless, the ability to accurately identify nodal involvement preoperatively in patients with mesothelioma remains suboptimal. Esophageal ultrasound may complement EBUS particularly in cases where infradiaphragmatic nodal metastases are suspected. (Ann Thorac Surg 2009;88:862 9) 2009 by The Society of Thoracic Surgeons Accepted for publication May 8, Presented at the Forty-fifth Annual Meeting of The Society of Thoracic Surgeons, San Francisco, CA, Jan 26 28, Address correspondence to Dr Rice, Department of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Box 445, 1515 Holcombe Blvd, Houston, TX 77030; drice@ mdanderson.org. Malignant pleural mesothelioma (MPM) is a highly aggressive disease associated with poor survival and seldom cured despite multimodality treatment. Aggressive therapeutic strategies including extrapleural pneumonectomy (EPP) combined with chemotherapy and adjuvant radiation have been associated with prolonged survival for highly selected subgroups of patients. Patients with nonepithelioid histology, extensive tumors or nodal metastases do not usually benefit from aggressive resection. Although histologic type can be determined by needle aspiration cytology or tissue biopsy, accurate assessment of tumor extent and nodal metastases is problematic. Because transdiaphragmatic invasion or peritoneal carcinomatosis may be missed with radiographic imaging, we routinely perform laparoscopy prior to radical resection [1 3]. Assessment of mediastinal nodal metastases is inaccurate using computed tomography (CT) and positron emission tomography (PET) due to difficulty differentiating lymph nodes from adjacent tumor nodules [4 6]. We have routinely performed cervical videomediastinoscopy (CM) at the time of staging laparoscopy. As previously reported, extended surgical staging identified abdominal involvement or contralateral mediastinal nodal metastases in 13.6% of patients who were radiographically considered resectable [3]. While generally safe, CM requires a cervical incision and is associated with a small risk of recurrent nerve injury, pneumothorax, tracheal injury, hemorrhage and even death [7]. Endobronchial ultrasound (EBUS) and esophageal endoscopic ultrasound (EUS) guided fine needle aspiration (FNA) of mediastinal lymph nodes have been highly effective for staging non-small cell lung cancer (NSCLC) [8 11]. Diagnostic accuracy of these procedures is comparable with CM and they are less 2009 by The Society of Thoracic Surgeons /09/$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 Ann Thorac Surg RICE ET AL 2009;88:862 9 ENDOSCOPIC ULTRASOUND AND MESOTHELIOMA 863 invasive with the added capability of sampling nodal stations beyond the reach of the mediastinoscope. Since 2006 we have performed EBUS for assessment of mediastinal nodes in patients being considered for radical resection of MPM. The utility of EBUS and EUS for the staging of MPM has not previously been described and is the purpose of this study. Material and Methods A retrospective review was performed of the medical records of potentially resectable patients with MPM who underwent preoperative histologic assessment of mediastinal nodes from October 2004 to October The study was approved by the Institutional Review Board of the University of Texas M.D. Anderson Cancer Center and individual patient consent was waived. Patients included in this study were separate from the cohort of patients previously reported on who had undergone extended surgical staging [3]. Prior to mediastinal staging, patients underwent cardiac and physiologic testing as well as CT and PET or PET-CT. Table 1. Patient Demographics and Therapeutic Disposition Variable EBUS (n 38) CM (n 50) p Age (median years) Female 6 (16%) 7 (14%) NS Histology: Epithelioid 32 (84%) 34 (68%) Biphasic 6 (16%) 13 (26%) Sarcomatoid 0 2 (4%) Not specified 0 1 (2%) Clinical stage: I 5 (13%) 3 (6%) NS II 11 (30%) 13 (26%) III 13 (34%) 30 (60%) IV 9 (24%) 4 (8%) Therapy: EPP 17 (45%) 33 (66%) NS PD 5 (13%) 7 (14%) Exploration 1 (3%) 1 (2%) Nonsurgical 15 (39%) 9 (18%) CM cervical video-mediastinoscopy; EBUS endobronchial ultrasound; EPP extrapleural pneumonectomy; NS not significant; PD pleurectomy-decortication. Fig 1. (A) Endobronchial ultrasound-guided fine needle aspiration cytology specimen from a positive node showing malignant epithelioid cells admixed with lymphocytes (Papanicolaou stain). (B) Epithelioid mesothelioma cells showing strong nuclear and cytoplasmic positivity for calretinin. Cervical Mediastinoscopy Mediastinoscopy was performed under general anesthesia using a video-mediastinoscope (Karl Storz, Tuttlingen, Germany). In all cases attempts were made to biopsy nodes from ipsilateral and contralateral paratracheal stations, as well as the subcarinal nodal packet. Biopsies were paraffin embedded, stained with hematoxylin and eosin, and examined by a thoracic pathologist. Endobronchial Ultrasound Endobronchial ultrasound-guided FNA was usually performed at the time of staging laparoscopy by thoracic surgeons. A dedicated flexible ultrasonic bronchoscope was used with a linear scanning 7.5 MHz transducer (UC160F-OL8; Olympus America Inc, Melville, NY) as previously described in the NSCLC population [9]. It scans parallel to the insertion direction of the bronchoscope with a dedicated ultrasound scanner (EU-C60; Olympus America Inc). An examination of all mediastinal lymph node stations accessible by EBUS (stations 1, 2, 4, 7, 10, and 11) was performed. All lymph nodes visualized with ultrasound were measured and those with a short axis 5 mm or greater were sampled with a 22-gauge needle (NA-201SX-4022; Olympus America Inc) designed for the EBUS scope under real-time imaging EBUS guidance. Nodes were readily identifiable as discrete round or oval structures immediately adjacent to the trachea or bronchi. When contralateral (N3) nodes were visualized, they were sampled before N2 nodes. The N1 nodes were not routinely sampled, unless clinically suspicious (short axis 1 cm on CT or 18F-fluorodeoxyglucose [FDG] avid). A minimum of two, but most often three separate aspirations were performed at each nodal station. The aspirated material was applied to glass slides and fixed in

3 864 RICE ET AL Ann Thorac Surg ENDOSCOPIC ULTRASOUND AND MESOTHELIOMA 2009;88:862 9 Table 2. Short Axis Dimensions of Nodes Biopsied Using Endobronchial Ultrasound Variable All (n 93) Diagnostic (n 78) Nondiagnostic (n 15) Tumor (n 21) No Tumor (n 57) Mean (mm) a 11 b 8 Median (mm) Range (mm) a p 0.001, diagnostic versus nondiagnostic specimens (n 98). (n 78). b p 0.001, tumor positive versus tumor negative diagnostic specimens Carnoy s solution (6 parts ethanol [absolute or 95%], 3 parts chloroform, 1 part glacial acetic acid). Additional material was then aspirated into Roswell Park Memorial Institute solution (Sigma-Aldrich, St Louis, MO) and analyzed using cytospin or cell blocks. Fixed specimens were stained with Papanicolaou staining and examined by an on-site cytopathologist to ensure adequate cellular (lymphoid or tumor) material in the specimens (Fig 1). If adequate tissue was not identified after five passes, the procedure was terminated for that node. Specimens were categorized as positive (tumor cells present), negative (lymphoid tissue but no tumor cells), or nondiagnostic (poor cellularity). Esophageal Ultrasound The EUS-FNA was used selectively when suspicious nodes (short axis 1 cm on CT or FDG avid) were identified on imaging studies at sites not accessible to EBUS. The EUS was performed using a radial scanning endoscope (Olympus GF-UM130, GF-UM160; Olympus America Inc, or Pentax EG-3830U, EG-3630UR; Pentax, Tokyo, Japan), a linear array endoscope (Olympus/Aloka GF-UC-130, GF-UC-160P; Aloka Medical Device, Tokyo, Japan or Pentax FG32UA, FG36UX; Pentax Precision Instruments, Orangeburg, NY), an EUS probe (Olympus UM-2R, UM-3R), or a combination of these with a frequency range of 5.0 to 20 megahertz. The EUS-guided fine-needle aspirations were performed using a 22-gauge or 25-gauge needle (EUS needle; Olympus America Inc). In 5 patients, EUS was performed with the EBUS bronchoscope (UC160F-OL8; Olympus America Inc). Therapy Patients with negative mediastinal nodes generally underwent surgical resection (EPP or pleurectomy-decortication [PD], according to the patient s functional status). Patients with N2 disease were treated nonoperatively or with PD. Patients with N3 nodal or distant metastases were treated nonoperatively. Patients undergoing EPP underwent mediastinal node dissection. Nodal sampling was usually (but not uniformly) performed in patients undergoing PD or exploratory thoracotomy. Statistical Analysis Statistical comparisons between patients receiving CM or EBUS were performed using the Student t test, the 2 test, or the Fisher exact test, as appropriate. Malignant cells identified on EBUS, or positive nodes from CM were deemed true positives. If CM confirmed negative mediastinal nodes after EBUS, the results of EBUS were assumed to be a true negative. In the case of negative CM or EBUS, pathologic nodal staging information obtained at thoracotomy was considered the gold standard. Only cases where nodal tissue was resected were used for sensitivity and specificity calculations. The 3 patients who had both EBUS-FNA and CM were excluded from sensitivity calculations for EBUS as definitive pathology was not available for these patients and a negative CM was not considered to be sufficiently reliable. Results Mediastinoscopy and EBUS Eighty-five patients underwent invasive mediastinal staging, 50 (59%) had CM, and 38 (45%) had EBUS. Three (4%) patients underwent both EBUS and CM. The median age was 63 years, and patients who underwent CM were slightly older than patients who had EBUS (median Table 3. Frequency of Nodal Stations Biopsied With Endobronchial Ultrasound Stations Sampled N (% Total) N a (% Patients) Diagnostic (% Total) Tumor (% of Diagnostic Specimens) Tumor (% Patients Examined) 1R 1 (1) 1 (3) 1 (100) 1 (100) 1 (3) 2R 5 (5) 5 (13) 4 (80) 1 (25) 1 (3) 4L 20 (22) 20 (53) 11 (55) 5 (46) 5 (13) 4R 21 (23) 21 (55) 19 (91) 4 (21) 4 (11) 7 38 (41) 38 (100) 36 (95) 10 (28) 10 (26) 11L 5 (5) 5 (13) 4 (80) R 3 (3) 3 (8) 3 (100) 0 0 Total 93 (100) (84%) 21 (27%) 13 (34%) a Each patient generally had multiple nodal stations biopsied.

4 Ann Thorac Surg RICE ET AL 2009;88:862 9 ENDOSCOPIC ULTRASOUND AND MESOTHELIOMA 865 Table 4. Frequency of Nodal Stations Biopsied With Cervical Video-Mediastinoscopy Stations Sampled No. (% Total) No. a (% Patients) Diagnostic (% Total) Tumor (% of Diagnostic Specimens) Tumor (% Patients Examined) 1 3 (2) 3 (6) 3 (100) 0 0 2L 1 (1) 1 (2) 1 (100) 0 0 2R 9 (6) 9 (18) 9 (100) (2) 3 (6) 3 (100) 0 0 4L 41 (27) 41 (82) 41 (100) 0 0 4R 49 (32) 49 (98) 49 (100) 4 (3) 4 (8) 7 46 (30) 46 (92) 46 (100) 6 (4) 6 (12) 10R 1 (1) 1 (2) 1 (100) 1 (1) 1 (2) Total 153 (100%) (100%) 11 (7%) 7 (14%) a Each patient generally had multiple nodal stations biopsied. 63 vs. 61 years, p 0.001). There were 13 (12%) women and no gender differences were observed between EBUS and CM groups. Tumor histology was epithelioid in 66 (78%) patients and there was a nonsignificant trend toward nonepithelioid histology in patients who underwent CM (Table 1). There were no differences in overall final clinical stage after invasive mediastinal staging; however, significantly more patients in the EBUS group were identified as having stage IV tumors compared with the CM group (24% vs 8%, p 0.017) (3 patients who underwent EBUS were diagnosed with infradiaphragmatic nodal metastases by EUS, a procedure not used in the CM cohort). Diagnostic lymphoid tissue was obtained from all patients who underwent EBUS and (or) CM. Mean short axis dimension of lymph nodes sampled in the EBUS group was 8 mm (Table 2). A diagnostic specimen (lymphoid tissue or tumor) was obtained in 78 of 93 (84%) nodal specimens. Lymph nodes yielding diagnostic samples were slightly larger than nondiagnostic nodes (mean 8mmvs6mm,p 0.001), and tumor bearing nodes were larger than benign nodes (mean 11 mm vs 8 mm, p 0.001). Frequencies of specimens obtained from different nodal stations are presented in Tables 3 and 4. Station 7 (subcarinal) was biopsied in all patients and yielded a diagnostic specimen in 95%. Stations 4R and 4L (right and left lower paratracheal) were biopsied in approximately 50% of patients each, but the diagnostic yield was higher for 4R compared with 4L (91% vs 55%). Table 5. Comparison of EBUS, CM, CT, and PET for Mediastinal Staging Variable EBUS (n 31) CM (n 43) CT (n 74) PET (n 67) Sensitivity Specificity Negative predictive value Positive predictive value False negative rate CM cervical video-mediastinoscopy; CT computed tomography; EBUS endobronchial ultrasound; PET positron emission tomography. Twenty-one (27%) mediastinal lymph nodes from 13 (34%) patients contained metastatic tumor. Contralateral (N3) involvement was diagnosed in 1 patient. There were 9 (26%) false negatives among 34 patients in whom confirmatory pathologic staging information was available. Patients who had EBUS had a mean of 2.6 stations biopsied compared with 3.1 stations for patients undergoing CM (p less than 0.001); however, there was a trend toward more tumor-positive nodal stations per patient in the EBUS group (0.55 vs 0.22, p 0.06). Although both ipsilateral and contralateral paratracheal and subcarinal nodal stations were biopsied in most patients, CM revealed N2 disease in only 7 (14%) patients (Table 4). Sensitivity of EBUS for N2 metastases was 52% compared with only 28% for CM, and 38% and 39% for CT and PET, respectively (Table 5). The false negative rate of EBUS- FNA was 32%, and of the 10 false negatives 6 (60%) were at sites accessible to EBUS. Similarly, of 18 false negatives Table 6. Frequency of Nodal Stations Yielding False Negative Results for EBUS and CM. Multiple False Negative Stations May Have Been Present Per Patient Lymph Node Station EBUS (n 10) CM (n 18) EBUS accessible: EBUS inaccessible: Internal mammary 3 Intercostal 1 5 Anterior mediastinal 1 2 Pericardial 1 2 Peridiaphragmatic 2 CM cervical video-mediastinoscopy; ultrasound. EBUS endobronchial

5 866 RICE ET AL Ann Thorac Surg ENDOSCOPIC ULTRASOUND AND MESOTHELIOMA 2009;88:862 9 with CM, 12 (67%) were at stations potentially accessible to CM (Table 6). Esophageal Ultrasound The EUS was performed along with EBUS for preoperative staging in 11 patients with suspicious nodes identified on imaging studies. Of these, metastases to left gastric nodes were documented in 4 patients, and one had metastatic disease in a subdiaphragmatic node. In 6 patients, EUS was performed by the gastroenterology service with dedicated EUS scopes. In 5 cases, the EBUS scope was used after endobronchial staging, by passing the scope into the esophagus with the balloon slightly inflated. Two additional patients had EUS performed during postoperative surveillance after EPP, and metastatic disease in left gastric nodes was documented in both patients. In both cases enlarged nodes had been previously identified on CT scan. Comment Extrapleural nodal involvement occurs in 23% to 52% of patients undergoing surgical evaluation for MPM and adversely affects survival [12, 13]. In most series, patients with node-negative, epithelioid that are able to be completely resected appear to benefit most from radical surgery and survival of resected node-positive patients is about half what it is for patients who are node-negative [13 18]. Furthermore, a recent retrospective study showed no survival benefit to EPP over PD in nodepositive patients [19]. It is therefore logical to attempt to identify nodal metastases preoperatively to optimally stratify patients for appropriate therapy. Radiographic imaging is relatively poor at identifying nodal metastases in patients with MPM. Computed tomographic scanning has an accuracy of approximately 60%, and magnetic resonance imaging has not shown superiority [20, 21]. Although useful for identifying distant disease, the sensitivity of PET for N2 metastases has been reported to be as low as 11% and integrated PET-CT has been shown to be only 30% accurate in determining nodal stage [5, 6]. The high incidence of nodal involvement with MPM, coupled with the low sensitivity of imaging, has led many to recommend mediastinoscopy prior to radical surgery [14, 18, 22]. Although mediastinal staging with CM is 100% specific, we have found the procedure to have a false negative rate of 22% and a sensitivity of only 36% for staging MPM [22] 22. The current series revealed an even higher false negative rate (51%) for CM and a sensitivity of 28%. Others have reported similar results; for instance, Schouwink and colleagues [20] noted 25 patients with negative CM of which 9 (36%) had positive nodes at extrapleural pneumonectomy. Six (24%) patients had metastases at stations not accessible by CM but 3 (12%) were positive at CM accessible stations. Similarly, de Perrot and colleagues [23] found positive nodal disease in 10 of 19 patients (53%) who had been staged as node-negative with CM. Six (32%) patients had N2 disease, and in 4 patients metastases were noted at stations that had been previously biopsied by CM. Edwards and colleagues [24] also reported a high rate of false negatives with CM in 10 of 30 (33%) who underwent EPP. Of 35 patients with N2 metastases, positive nodes were noted at sites inaccessible to CM in 17 (49%). In the current series there were 18 (36%) patients with falsely negative CM and 9 had metastases to N2 stations that had been previously biopsied, despite the fact that diagnostic specimens were obtained in all patients, and most patients had bilateral nodal stations sampled. Endobronchial ultrasound-fine needle aspiration is rapidly gaining acceptance for mediastinal staging of NSCLC [9 11]. It has been shown to be more sensitive than PET and CT for diagnosing N2 disease, is highly specific, and appears to be as accurate as mediastinoscopy, yet is less invasive. The use of EBUS for nodal staging in MPM has not been reported but has several potential attractions. First, the procedure is associated with few, if any serious complications, whereas CM has a small but definite risk of major hemorrhage, recurrent laryngeal nerve paresis, tracheobronchial injury, and even death, none of which have been described with EBUS [7]. Second, CM violates peritracheal tissue planes, potentially making dissection at the time of EPP or PD more difficult. The EBUS-FNA causes minimal trauma to peritracheal tissue. Third, hilar nodes usually inaccessible to CM are easily reached with EBUS. Whether N1 metastases portend the same poor prognosis as positive N2 nodes has been questioned; however, most series have shown no difference in survival between the two [25]. Therefore, preoperative identification of N1 metastases could potentially influence management. For these reasons we investigated the use of EBUS-FNA for preoperative mediastinal staging in MPM. A major limitation of this study is that EBUS and CM were generally performed on different patients and during different time periods. Nevertheless, radiographic staging and treatment indications remained more or less constant during the study period. We identified some noteworthy differences between CM and EBUS. Although CM had a diagnostic yield of 100% and more nodal stations were biopsied per patient compared with EBUS (median 3 vs 2.5), a greater proportion of patients had positive nodes on EBUS (34% vs 10%). Although there were no significant differences in clinical stage between patients having EBUS and those having CM, there was a slightly higher prevalence of nodal metastases in the EBUS group (65% vs 58%, p not significant). Another difference between the two groups that may have influenced the results was the time interval between staging and definitive surgery was slightly longer for the CM group than patients staged with EBUS (mean 57 vs 31 days, p 0.029). Interestingly, the lower diagnostic yield of EBUS (84%) did not lessen the ability to diagnose nodal metastases. In fact, nodes that were nondiagnostic were usually small (median diameter 5 mm), often contralateral, and no false negatives occurred in nodes that were nondiagnostic on EBUS. Although subtle imbalances in stage and nodal prevalence might have contributed to the observed differences in sensitivity of the two

6 Ann Thorac Surg RICE ET AL 2009;88:862 9 ENDOSCOPIC ULTRASOUND AND MESOTHELIOMA 867 procedures, it is also possible that the greater yield of nodal metastases with EBUS might be due to inherent differences in nodal sampling between the two techniques. With EBUS, multiple passes of the needle (about 30 to 50) are taken through each node, perhaps resulting in a more representative sample. Although more nodal tissue is obtained with CM, often only a portion of a node is sampled. This is particularly true with respect to the subcarinal station where usually only the cephalad and anterior portions of the nodal packet are biopsied at CM. In addition, pathologic examination of biopsies from CM usually entails evaluation of one or two representative cuts through the tissue submitted, whereas cytologic specimens obtained with EBUS are smeared and completely visualized. As this study is retrospective, caution should be exercised in interpreting differences between the sensitivities of EBUS and CT and PET. Although radiographic studies were compared only against formal pathology obtained with EBUS, CM, or surgery, there was no uniformity with respect to the radiographic protocols used, scanners, or radiologists interpreting the images. Nonetheless, both CT and PET had relatively low accuracy for determining nodal involvement, which is consistent with our earlier experience as well as that of others [5, 5, 21]. The EBUS allowed accurate measurement of nodes that were sampled and it is important to note that the median short axis dimension of tumor-positive nodes was 8 mm. Only 7 of 21 (33%) nodes were greater than 10 mm in size on short axis which would meet axial CT criteria for nodal enlargement. The smallest positive node biopsied measured 4 mm. This corroborates results from the Leicester group who found no difference in size between nodes that harbored tumor and those that did not, and may explain the relatively low sensitivity of CT and PET for detecting nodal metastases in MPM [22]. Like EBUS, esophageal endoscopic ultrasound has been effective for nodal staging in patients with NSCLC [8, 11, 26] but its use for staging MPM has only recently been reported [27]. Tournoy and colleagues [27] performed EUS on 32 patients with early stage MPM. Pathologic confirmation was possible for 21 patients and EUS diagnosed nodal metastases in 4 (19%). The authors reported a sensitivity of 80%, and similar to our experience with EBUS, mediastinoscopy did not increase the yield of positive nodes. Importantly, one patient had esophageal perforation secondary to EUS-FNA. In our series EUS was used on a selective basis. For patients with suspicious nodes in the periesophageal or infradiaphragmatic region we have found EUS-FNA to be very useful and metastatic disease was confirmed in 5 of 11 patients preoperatively. Esophageal ultrasound, however, is limited in its ability to biopsy right-sided paratracheal nodes, and as the recent report by Tournoy and colleagues shows, is not without potential morbidity. As combined use of EBUS and EUS-FNA has been reported to have higher accuracy than either procedure alone for the staging of lung cancer it seems reasonable to consider a combined approach for the staging of mesothelioma [28]. Despite the fact that EBUS was more sensitive than CM in preoperatively identifying patients with nodal metastases, a significant proportion of patients had occult N2 metastases at the time of surgery. For this reason we have modified our operative approach so that clinical nodenegative patients who are candidates for EPP undergo intraoperative nodal assessment after initial extrapleural mobilization, but prior to pneumonectomy. If frozen section histology reveals nodal metastases then PD is preferred instead of EPP. The question of course arises whether preoperative invasive staging should be performed at all given its low yield. However, in light of the fact that patients with N2 metastases do not benefit from radical resection, it is our belief that every effort should be made to identify these patients prior to thoracotomy. Endobronchial ultrasound and esophageal ultrasound, though not perfect, improve our ability to accurately stage patients preoperatively. References 1. Rusch VW, Venkatraman E. The importance of surgical staging in the treatment of malignant pleural mesothelioma. J Thorac Cardiovasc Surg 1996;111: Conlon KC, Rusch VW, Gillern S. Laparoscopy: an important tool in the staging of malignant pleural mesothelioma. Ann Surg Oncol 1996;3: Rice DC, Erasmus JJ, Stevens CW, et al. Extended surgical staging for potentially resectable malignant pleural mesothelioma. Ann Thorac Surg 2005;80: Marom EM, Erasmus JJ, Pass HI, Patz EF Jr. The role of imaging in malignant pleural mesothelioma. Semin Oncol 2002;29: Flores RM, Akhurst T, Gonen M, Larson SM, Rusch VW. Positron emission tomography defines metastatic disease but not locoregional disease in patients with malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2003;126: Erasmus JJ, Truong MT, Smythe WR, et al. Integrated computed tomography-positron emission tomography in patients with potentially resectable malignant pleural mesothelioma: Staging implications. J Thorac Cardiovasc Surg 2005;129: Lemaire A, Nikolic I, Petersen T, et al. Nine-year single center experience with cervical mediastinoscopy: complications and false negative rate. Ann Thorac Surg 2006;82: Eloubeidi MA, Cerfolio RJ, Chen VK, Desmond R, Syed S, Ojha B. 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: Yasufuku K, Nakajima T, Motoori K, et al. Comparison of endobronchial ultrasound, positron emission tomography, and CT for lymph node staging of lung cancer. Chest 2006; 130: Herth FJ, Eberhardt R, Vilmann P, Krasnik M, Ernst A. Real-time endobronchial ultrasound guided transbronchial needle aspiration for sampling mediastinal lymph nodes. Thorax 2006;61: Detterbeck FC, Jantz MA, Wallace M, Vansteenkiste J, Silvestri GA; American College of Chest Physicians. Invasive mediastinal staging of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007;132: 202S 20S. 12. Sugarbaker DJ, Strauss GM, Lynch TJ, et al. Node status has prognostic significance in the multimodality therapy of diffuse, malignant mesothelioma. J Clin Oncol 1993;11:

7 868 RICE ET AL Ann Thorac Surg ENDOSCOPIC ULTRASOUND AND MESOTHELIOMA 2009;88: Rusch VW, Venkatraman ES. Important prognostic factors in patients with malignant pleural mesothelioma, managed surgically. Ann Thorac Surg 1999;68: Sugarbaker DJ, Flores RM, Jaklitsch MT, et al. Resection margins, extrapleural nodal status, and cell type determine postoperative long-term survival in trimodality therapy of malignant pleural mesothelioma: results in 183 patients. J Thorac Cardiovasc Surg 1999;117: Pass HI, Vogelzang N, Hahn S, Carbone M. Malignant pleural mesothelioma. Curr Probl Cancer 2004;28: Weder W, Kestenholz P, Taverna C, et al. Neoadjuvant chemotherapy followed by extrapleural pneumonectomy in malignant pleural mesothelioma. J Clin Oncol 2004;22: Flores RM, Pass HI, Seshan VE, et al. Extrapleural pneumonectomy versus pleurectomy/decortication in the surgical management of malignant pleural mesothelioma: results in 663 patients. J Thorac Cardiovasc Surg 2008;135: Rice DC, Stevens CW, Correa AM, et al. Outcomes after extrapleural pneumonectomy and intensity-modulated radiation therapy for malignant pleural mesothelioma. Ann Thorac Surg 2007;84: Martin-Ucar AE, Nakas A, Edwards JG, Waller DA. Casecontrol study between extrapleural pneumonectomy and radical pleurectomy/decortication for pathological N2 malignant pleural mesothelioma. Eur J Cardiothorac Surg 2007; 31: Schouwink JH, Kool LS, Rutgers EJ, et al. The value of chest computer tomography and cervical mediastinoscopy in the preoperative assessment of patients with malignant pleural mesothelioma. Ann Thorac Surg 2003;75: Heelan RT, Rusch VW, Begg CB, et al. Staging of malignant pleural mesothelioma: comparison of CT and MR imaging. AJR Am J Roentgenol 1999;172: Pilling JE, Stewart DJ, Martin-Ucar AE, Muller S, O Byrne KJ, Waller DA. The case for routine cervical 20. mediastinoscopy prior to radical surgery for malignant mesothelioma. Eur J Cardiothorac Surg 2004;25: de Perrot M, Uy K, Anraku M, et al. Impact of lymph node metastasis on outcome after extrapleural pneumonectomy for malignant pleural mesothelioma. J Thorac Cardiovasc Surg 2007;133: Edwards JG, Stewart DJ, Martin-Ucar A, Muller S, Richards C, Waller DA. The pattern of lymph node involvement influences outcome after extrapleural pneumonectomy for malignant mesothelioma. J Thorac Cardiovasc Surg 2006; 131: Flores RM, Routledge T, Seshan VE, et al. The impact of lymph node station on survival in 348 patients with surgically resected malignant pleural mesothelioma: implications for revision of the American Joint Committee on Cancer staging system. J Thorac Cardiovasc Surg 2008;136: 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: Tournoy KG, Burgers SA, Annema JT, et al. Transesophageal endoscopic ultrasound with fine needle aspiration in the preoperative staging of malignant pleural mesothelioma. Clin Cancer Res 2008;14: Wallace MB, Pascual JM, Raimondo M, et al. Minimally invasive endoscopic staging of suspected lung cancer. JAMA 2008;299: DISCUSSION DR MARK I. BLOCK (Hollywood, FL): I really enjoyed that, and I congratulate you on extending the minimally invasive endoscopic ultrasound to mesothelioma. I don t see quite as many mesothelioma patients as you do, but I would argue that you should probably do both EUS [esophageal ultrasound] and EBUS [endobronchial ultrasound] routinely rather than selective use of EUS. After all, mesothelioma is a pleural disease, and those paraesophageal, inferior pulmonary ligament, level 8 and 9 nodes are equally likely to be involved. So rather than use it selectively, EUS should be used routinely with EBUS as a combined procedure. I would like to hear your comments. DR STELIGA: You know, when looking at this data, we ve started to discuss that. Not only are they located in EUS accessible areas, but combined with the fact that many positive nodes are small and non-pet [positron emission tomography] avid would suggest that there may be a lot of positive nodes that we re missing. We used EUS only selectively when it was lighting up hot on the PET scan or enlarged, and if we started using it universally in all these patients, we may detect more people with disease in those regions. DR PHILIPPE R. NAFTEUX (Leuven, Belgium): Thank you for this very nice presentation. I have a question. If I caught the paper produced by your group a few years ago using extensive surgical staging, the sensitivity for mediastinoscopy was about 40%. The question is, why is it that low in this study? The second part of the question is, have you ever used laparoscopy to stage the abdomen also for lymph node biopsies? DR STELIGA: The first question, why is it so low in mediastinoscopy in our group. We found only 28%. We reported 36% sensitivity in our earlier series and 28% with mediastinoscopy now. The two studies were based on different time periods and different groups of patients, but I don t think anything had significantly changed between the two ways that we used the video-mediastinoscope to stage patients. And your second question, I m sorry, I didn t catch it. DR NAFTEUX: Did you use laparoscopy to do lymph node biopsy in the belly? DR STELIGA: No, we did not use laparoscopy to do lymph node biopsies in the abdomen. The way we do the laparoscopy is with two ports in the abdomen, one camera port above the umbilicus. We look around, look for any disease in the liver, in the peritoneum or transdiaphragmatic. And if we find no evidence of disease, we lavage the abdomen with saline, approximately a liter of saline and suction it out and send that for cytology. It doesn t happen very often, but when that cytology does come back positive, those patients we ve deemed have advanced disease, and we don t offer them resection. So we do use laparoscopy and peritoneal lavage, but we don t do it for needle biopsy, or for nodal biopsy. Those nodes we can access with EUS, though. In a transesophageal, transgastric way, we ve biopsied celiac nodes and left gastric nodes and found it by that method. DR NAFTEUX: Thank you. DR DANIEL L. MILLER (Atlanta, GA): I have one concern in regards to the EUS biopsies of stations 8 and 9, where you may

8 Ann Thorac Surg RICE ET AL 2009;88:862 9 ENDOSCOPIC ULTRASOUND AND MESOTHELIOMA 869 get a high false positive rate. Because, as you know, the majority of the tumor burden for mesothelioma is usually located very low within the pleural cavity along the recess of the esophagus. I was wondering if that was the only location where you had N2 disease, in stations 8 and 9, which would be falsely positive and therefore up-stage possibly resectable patients? DR STELIGA: I don t know of any data on that. But we have talked about the possibility of biopsying through the esophagus and either going beyond the node or biopsying tumor down there. And we watch very carefully where our needle goes when we pass it with a scope, and we do it under real-time image guidance. And we make sure that the needle lands just in the node (which would be seen as discrete round nodules) and not beyond it in the tumor, which looks like amorphous poorly marginated densities next to the esophagus. DR MILLER: We have tried to do it a couple of times after a talc pleurodesis, and with the tumor burden and talc effect there was no plane to freely biopsy the node without being concerned for a false positive. So I would take caution in your station 8 and 9 data. DR RAFAEL S. ANDRADE (Minneapolis, MN): I m just struggling a little bit with the sensitivity issue: why is it so low for mediastinoscopy and so much better for EBUS? Did you sample the same number of stations on average? Did you check how many stations you sampled with each technique? Are you being more meticulous with EBUS? Something just doesn t add up perfectly, and I don t know exactly what it is. DR STELIGA: When we were looking at our data on this, we looked back at how we were doing our mediastinoscopy, and we had 153 nodes for 50 patients, a little over 3 nodes per patient. Those nodes were all adequately biopsied with mediastinoscopy and had adequate tissue on pathology. Whether we are being more thorough with EBUS, the way we typically did the EBUS was to look at the tracheobronchial nodes, biopsy anything that we could more than 5 mm. Now, we did have 15 nondiagnostic nodes that we tried to biopsy and missed. And we had fewer nodes actually biopsied with EBUS, but we ended up with more positives even though we were biopsying fewer nodes. We were discussing different ways that we can biopsy the node. By biting the node with a little biopsy on mediastinoscopy, you re sampling just a very proximal part of that node. With an EBUS, a needle transgresses the full dimension of the node, and even though you re only taking a smaller amount of tissue, maybe the needle is getting a more representative sample of that node. It s difficult to tell. I m not sure why we were much higher with the EBUS sensitivity, but that may explain it. The Society of Thoracic Surgeons: Forty-Sixth Annual Meeting Mark your calendars for the Forty-Sixth Annual Meeting of The Society of Thoracic Surgeons (STS) to be held at the Greater Fort Lauderdale-Broward County Convention Center, Fort Lauderdale, Florida, from January 25 27, The meeting is open to all physicians, residents, fellows, engineers, perfusionists, physician assistants, nurses, or other interested individuals. Meeting attendees will be provided with the latest scientific information for practicing cardiothoracic surgeons. Attendees will benefit from traditional Abstract Presentations, as well as Surgical Forums, Breakfast Sessions, Surgical Motion Pictures, and Wet Lab sessions. Parallel sessions on Monday and Tuesday will focus on specific subspecialty interests. An advance program with a registration form, hotel reservation information, and details regarding spouse/ guest activities will be mailed to STS members this fall. Nonmembers may contact the Society s secretary, Douglas E. Wood, MD, to receive a copy of the advanced program; however, detailed meeting information will be available on the STS website at Douglas E. Wood, MD Secretary The Society of Thoracic Surgeons 633 N. Saint Clair St, Suite 2320 Chicago, IL Telephone: (312) Fax: (312) sts@sts.org website: by The Society of Thoracic Surgeons Ann Thorac Surg 2009;88: /09/$36.00 Published by Elsevier Inc