- Email: [email protected]
Endoscopic Mediastinal Staging in Lung Cancer Is Superior to “Gold Standard” Surgical Staging
Endoscopic Mediastinal Staging in Lung Cancer is Superior to “Gold Standard” Surgical Staging Ilyes Berania, MD, Jordan Kazakov, MD, Mohamed Khereba, MD, Eric Goudie, MD, Pasquale Ferraro, MD, Vicky Thiffault, RN, and Moishe Liberman, MD, PhD Department of Surgery, Division of Thoracic Surgery, CHUM Endoscopic Tracheobronchial and Oesophageal Center, University of Montr eal, Montr eal, Qu ebec, Canada
Background. The objective was to evaluate whether endobronchial ultrasonography (EBUS) or endoscopic ultrasonography (EUS) staging techniques of the mediastinum for lung cancer can change the treatment plan compared with the “gold standard” of surgical staging. Methods. Patients were retrospectively identified from a prospectively collected database. Endoscopic staging was compared with the “gold standard” cervical mediastinoscopy (CM). In cases where mediastinoscopy was not performed, EBUS/EUS was compared with “ideal” CM, a virtual procedure, which was assumed to have 100% rates of sensitivity and specificity. Results. EBUS was performed in 324 patients (99%), EUS in 295 patients (90%), and CM in 101 patients (31%); 226 patients (69%) were assumed to have undergone a virtual ideal CM and a virtual surgical mediastinal staging; 108 positive biopsies (33.0%) with endosonography had sampling of targets that were out of the scope of CM.
Distant metastatic disease was diagnosed by EBUS/EUS in 7 patients (2.1%); 22 patients (6.7%) had positive targets outside the reach of the CM or virtual CM. If the 14 patients who had positive stations 5, 6, 10, and 11 are excluded (accessible with anterior mediastinotomy or extended cervical mediastinoscopy), there were 6 patients (1.8%) in whom endosonography upstaged the patient over ideal surgical mediastinal staging. In 20 patients (6.1%), ultrasound-guided biopsy made the diagnoses, which changed the treatment plan over CM and ideal CM. Conclusions. Combined EBUS- and EUS-guided biopsies can access more targets, including lung and distant metastasis, and thus have the potential to upstage patients compared with mediastinoscopy and change the treatment plan.
M
ediastinal staging is a critical step in the preoperative evaluation of patients with non-small cell cancer [1]. Accurate cancer staging allows for appropriate disease management in terms of selecting candidates for surgical resection versus nonsurgical modalities [2]. In addition, lymph node assessment represents a valuable prognostic factor [3]. Noninvasive mediastinal staging with computed tomography and positron emission tomography scans have significant false negative and false positive rates, and imaging modalities therefore require confirmatory lymph node biopsy for tissue diagnosis. Currently, cervical mediastinoscopy (CM) is considered the “gold standard” procedure for the mediastinal staging of lung cancer staging [4]. Over the past decade, the increased use of minimally invasive endosonographic techniques, including endobronchial ultrasound (EBUS) and endoscopic ultrasound (EUS), has been recognized as an alternative method to surgical staging [5]. Currently, some prefer needle-sampling techniques over surgical
staging as a best first test for mediastinal lymph node staging in lung cancer [6]. Real-time imaging with combined EBUS and EUS allows detection and sampling of hilar and mediastinal lymph nodes beyond the reach of standard mediastinoscopy. EBUS allows for visualization and biopsy of hilar (station 10), interlobar (station 11), and lobar (station 12) lymph nodes, and EUS gives access to the aortopulmonary window (station 5), paraaortic (station 6), paraesophageal (station 8), inferior pulmonary ligament nodes (station 9), and intraabdominal targets including the liver and adrenal sites [7]. Because of the additional sites that are accessible through endosonography, these techniques may allow for a more complete preoperative staging compared with CM. The aim of this study was to evaluate whether EBUS or EUS or both used in the preoperative staging of lung cancer contributes to changes in the treatment plan compared with conventional gold standard surgical staging.
Accepted for publication Aug 26, 2015.
Patients and Methods
Presented at the 2014 Annual Meeting of the American Thoracic Society, San Diego, CA, May 16–21, 2014.
Subjects
Address correspondence to Dr Liberman, Division of Thoracic Surgery, Centre Hospitalier de l’Universit e de Montreal, 1560 rue Sherbrooke E, 8e CD, Pavillon Lachapelle D-8051, Montr eal, QE H2L 4M1, Canada; e-mail: [email protected].
Ó 2015 by The Society of Thoracic Surgeons Published by Elsevier
(Ann Thorac Surg 2015;-:-–-) Ó 2015 by The Society of Thoracic Surgeons
Patients were retrospectively identified from a prospective interventional endoscopy database at the Centre Hospitalier de l’Universit e de Montr eal (CHUM) Endoscopic Tracheo-Bronchial and Oesophageal Center, Division of 0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2015.08.070
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BERANIA ET AL ENDOSCOPIC MEDIASTINAL STAGING IN LUNG CANCER
Thoracic Surgery. Database data were complemented by manual chart review of the electronic medical record of all patients at CHUM including official pathology and cytopathology reports. The Institutional Ethics Review Board of the Centre de Recherche du CHUM approved the study. Data collection included assessment of staging procedures (EBUS, EUS, or CM), biopsy sites, imaging reports (positron emission tomography, computed tomography, and positron emission tomography/ computed tomography scan), final pathologic diagnosis, and demographic data (age and sex).
Surgical Staging CERVICAL MEDIASTINOSCOPY. Endoscopic staging was compared with CM staging. Cervical mediastinoscopy is a surgical staging procedure that allows access to the superior mediastinum. Lymph node biopsies were performed with the use of a mediastinoscope that was introduced through a suprasternal incision. The CM assessed the upper paratracheal (2R/2L), lower paratracheal (4R/4L), and subcarinal (7) lymph node stations. In cases where mediastinoscopy was not performed, EBUS/EUS was compared with “ideal” CM, a virtual procedure, which was assumed to have 100% rates of sensitivity and specificity. Ideal CM assessed all stations reached by CM. SURGICAL MEDIASTINAL STAGING. Patients assigned to virtual CM were also assumed to have undergone an ideal surgical mediastinal staging (SMS), with access (in addition to stations assessed with ideal CM) to subaortic (station 5) and paraaortic (station 6) lymph nodes (through extended cervical mediastinoscopy or anterior mediastinotomy), and to hilar (station 10) and interlobar (station 11) stations (through extended cervical mediastinoscopy). Results of the EBUS and EUS procedures were compared with those of CM, virtual CM, and virtual SMS in terms of the addition of staging information, upstaging, and change of treatment plan. IDEAL VIRTUAL STAGING. Patients who have not undergone surgical staging were assigned to virtual, or ideal, staging. This theoretical group of patients served as a comparator to endoscopic staging procedures. Virtual ideal surgical procedures assumed that patients underwent CM or SMS that reached all accessible stations, with 100% sensitivity and specificity.
Endosonography-Guided Needle Aspiration Biopsies All fine-needle aspiration specimens were evaluated by dedicated cytopathologists in the Department of Pathology at CHUM. Results were evaluated for (1) positivity; (2) negativity (no tumor cells, presence of normal lymphocytes); and (3) inadequacy (no tumor cells, no lymphocytes). A minimum of two passes was performed into each lymph node. The procedures were performed under local anesthesia with moderate sedation or under general anesthesia. Endosonographic data were prospectively recorded during the staging procedure. Lung cancer staging was based on the American Joint Committee on Cancer staging manual, seventh edition [8].
Ann Thorac Surg 2015;-:-–-
Results Lung cancer diagnosis was reported in 327 patients who have undergone EBUS or EUS or both between January 2009 and December 2013 in our health care center. The EBUS and EUS were performed in 324 patients (99%) and 295 patients (90%), respectively. The CM was performed on 101 patients (31%), and 226 patients (69%) who did not undergo CM were assumed to have undergone ideal surgical staging (ideal CM and ideal SMS). Overall, 181 patients (55.4%) in the cohort were male and 146 (44.6%) were female. The mean age was 65.3 years (SD 9.8). One hundred eight patients (33.0%) who underwent endosonography had sampling of thoracic targets that were outside the scope of standard CM. Among these, lymph node stations 5, 6, 8, 9, 10, and 11 were positive in 25 (23.1%), 4 (3.7%), 16 (14.8%), 2 (1.9%), 14 (13.0%), and 11 (10.2%) cases, respectively. Biopsy specimens were obtained from positive lung masses with EBUS and EUS in 22 patients (20.4%) and 14 patients (13.0%), respectively (Table 1). Ultrasound-guided biopsies assessed extrathoracic stations that include liver, adrenal glands, and abdominal lymph nodes. These stations led to the diagnosis of metastatic disease in 7 patients (2.1%; Table 2). In total, 22 patients (6.7%) had positive targets outside the reach of CM or ideal CM. With the exclusion of 14 patients who had positive stations 5, 6, 10, and 11 (accessible through SMS), there were 6 upstaged patients (1.8%) over ideal SMS (Table 3). There was a change in treatment plan for 20 patients (6.1%) and 12 patients (3.7%) with combined endoscopic staging compared with ideal CM and ideal SMS, respectively (Table 4).
Comment In the present study, we compared minimally invasive ultrasonographic biopsy techniques with gold standard cervical mediastinoscopy for non-small cell lung cancer staging. Our findings suggest that combined EBUS and Table 1. Positive Thoracic Biopsies Out of Scope of Standard Cervical Mediastinoscopy Positive Biopsies Target Stations 5 6 8L 8R 9L 9R 10L 10R 11L 11R PLL
EBUS
EUS
Total
2 . . . . . 3 11 6 5 22
23 4 7 9 1 1 . . . . 14
25 4 7 9 1 1 3 11 6 5 36
EBUS ¼ endobronchial ultrasonography; EUS ¼ endoscopic ultrasonography; L ¼ left; PLL ¼ parenchymal lung lesion; R ¼ right.
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BERANIA ET AL ENDOSCOPIC MEDIASTINAL STAGING IN LUNG CANCER
Table 2. Positive Distant Metastatic Sites
Table 4. Patients With Change in Treatment Plan
Positive Distant Metastasis
n (%)
Distant stations, n ¼ 8 Left adrenal gland Liver mass Gastrohepatic ligament lymph node
5 (62.5) 2 (25.0) 1 (12.5)
EUS may be superior to surgical staging for the assessment of mediastinal lymph node stations and preoperative lung cancer staging. Past reports suggest equal or better accuracy for endoscopic compared with surgical approaches for lung cancer staging. In a prospective controlled trial, Yasufuku and colleagues [9] noted similar sensitivity, negative predictive value, and diagnostic accuracy of 81%, 91%, and 93%, respectively, for EBUS, and 79%, 90%, and 93%, respectively, for mediastinoscopy. In a randomized controlled multicenter trial, Annema and colleagues [10] showed that combined endosonography followed by surgical staging compared with surgical staging alone resulted in greater sensitivity for mediastinal nodal metastases and fewer unnecessary thoracotomies. A prospective controlled trial conducted in our center demonstrated that endoscopic staging was diagnostic for N2/N3/M1 disease in 24 patients in whom SMS findings were negative, thereby preventing futile thoracotomy for 14% of patients [11]. A systematic review and meta-analysis of 8 studies by Zhang and associates[12] also showed that combined endoscopic techniques are more sensitive than EBUS– transbronchial-needle aspiration or EUS–fine-needle aspiration alone, and the diagnostic power of the combined technique is more accurate [12]. Now, EUS can also mimic anterior mediastinotomy or left video-assisted thoracoscopic surgery for access to stations 5 and 6. Liberman and colleagues [13, 14] described a novel technique for direct access to the paraaortic (station 6) lymph node region through the proximal esophagus, an area Table 3. Patients Upstaged by Nodal Sampling With Endobronchial Ultrasonography and Endoscopic Ultrasonography Compared With Cervical Mediastinoscopy/ Ideal Cervical Mediastinoscopy and Ideal Surgical Mediastinal Staging Upstaged Patients CM/ideal CM Nodal stage, n ¼ 22 1 2 3 Ideal SMS Nodal stage, n ¼ 6 1 2 3 CM ¼ cervical mediastinoscopy;
n (%)
7 (31.8) 11 (50.0) 4 (18.2)
0 (0.0) 2 (33.3) 4 (66.7) SMS ¼ surgical mediastinal staging.
Patients With Change of Plan
n (%)
Compared with CM or ideal CM Nodal stage, n ¼ 20 0 1 2 3 Compared with ideal SMS Nodal stage, n ¼ 12 0 1 2 3 CM ¼ cervical mediastinoscopy;
3
2 0 14 4
(10.0) (0.0) (70.0) (20.0)
2 0 9 1
(16.7) (0.0) (75.0) (8.3)
SMS ¼ surgical mediastinal staging.
thought to be unreachable endoscopically without traversing the aorta or the pulmonary artery, thus increasing the endoscopic access. One advantage to endosonography is the lack of need for general anesthesia as these procedures can be done under local anesthesia and moderate sedation. That also has a cost impact as operating room costs are avoided. Another advantage of ultrasound-guided biopsies is the increased accessibility to mediastinal and hilar lymph node stations not accessible with SMS. In the present study, we noted greater access to positive lymph node stations with EBUS and EUS that were out of the reach of cervical mediastinoscopy. The results of the present study also revealed that half of the endosonography upstaged patients were classified as N2 lymph node positive, defined as ipsilateral mediastinal or subcarinal lymph node metastasis [15]. Some patients in this group benefited from neoadjuvant therapy before surgical resection [15] and other patients were spared futile lung resection. Moreover, the combined endoscopic approach was able to diagnose distant metastatic disease in 2% of the patients of the cohort, avoiding an additional procedure or undiagnosed M1 disease. Diagnosis of advanced disease (stage IV) allows patients to receive palliative support and avoid unnecessary additional treatments [16]. In the present study, detection rates of distant metastatic disease were lower than in previous reports. Silvestri and associates [6] observed that EUS needle aspiration was capable of detecting metastatic disease in subdiaphragmatic sites such as the left adrenal gland, celiac lymph nodes, and the liver, with an overall yield of 4%. This difference may be explained by patient referral patterns as the patients in this cohort were referred to a thoracic surgery interventional endoscopy center, and that may have contributed to the lower overall stage of the cohort. In the current study, compared with ideal CM and ideal SMS, patient treatment plans were changed for 20 patients (6.1%) and 12 patients (3.7%), respectively, based on the findings from combined endosonographic staging. Appropriate detection and cancer staging prevents unnecessary thoracotomies and their potential complications
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Ann Thorac Surg 2015;-:-–-
for nonsurgical candidates. Sharples and associates [17] demonstrated, in a randomized control trial, a reduction of futile thoracotomy by 13% when comparing the endosonography group and the surgical staging group. The current study also demonstrated superior accuracy of real-life EBUS and EUS in comparison with ideal virtual procedures (virtual CM and virtual SMS), which were falsely assigned perfect detection rates (100% accuracy). Therefore, we can assume that even greater differences could have been observed under true clinical settings with the use of CM. Nevertheless, a limitation of our study is that real surgical comparison was performed in only 30% of our group. Surgical mediastinal staging has been shown to be associated with a negative predictive value and accuracy of 89% compared with endoscopic mediastinal staging and rates of 92% and 91%, respectively, at time of thoracotomy or video-assisted thoracoscopic surgery [11]. The economic impact of lung cancer staging represents another factor in favor of minimally invasive staging. Past studies suggest that EBUS and EUS are less expensive than mediastinoscopy. A prospective randomized controlled study by Sharples and colleagues [18] noted lower costs over a 6-month period with endosonographic staging. Harewood and colleagues [19] also observed lower costs with EBUS and EUS compared with SMS, with a greater difference observed in N2/N3 disease. Minimally invasive techniques are progressively replacing traditional surgical methods for lymph node biopsy in lung caner. Nevertheless, surgical staging remains a valuable tool [20, 21]. For instance, biopsies of small lymph nodes (less than 5 mm) are thought to be less reliable with the use of EBUS–transbronchial-needle aspiration. Although these nodes most frequently suggest benign pathology, they may require surgical sampling [22]. Although endosonographic staging appears as effective as surgical staging for positive lymph node detection, its lower negative predictive rate may require further surgical sampling for negative results for a definite diagnostic confirmation in centers with less experience with these techniques [4]. In conclusion, the present study confirms that endosonography in the staging of non-small cell lung cancer can access more lymph node targets and thus has the potential to improve accuracy compared with cervical mediastinoscopy and surgical mediastinal staging. These findings support the gradual transition from traditional surgical staging to endoscopic staging.
4. De Leyn P, Lardinois D, Van Schil PE, et al. ESTS guidelines for preoperative lymph node staging for non-small cell lung cancer. Eur J Cardiothorac Surg 2007;32:1–8. 5. Detterbeck FC, Jantz MA, Wallace M, Vansteenkiste J, Silvestri GA. Invasive mediastinal staging of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007;132(Suppl):202–20. 6. Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods for staging non-small cell lung cancer. Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143(Suppl):e211–50. 7. Harris CL, Toloza EM, Klapman JB, Vignesh S, Rodriguez K, Kaszuba FJ. Minimally invasive mediastinal staging of nonsmall-cell lung cancer: emphasis on ultrasonographyguided fine-needle aspiration. Cancer Control 2014;21:15–20. 8. Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC cancer staging manual. 7th ed. New York: Springer-Verlag; 2010. 9. Yasufuku K, Pierre A, Darling G, et al. A prospective controlled trial of endobronchial ultrasound-guided transbronchial needle aspiration compared with mediastinoscopy for mediastinal lymph node staging of lung cancer. J Thorac Cardiovasc Surg 2011;142:1393–400. 10. Annema JT, Van Meerbeeck JP, Rintoul RC, et al. Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial. JAMA 2010;304:2245–52. 11. Liberman M, Sampalis J, Duranceau A, Thiffault V, Hadjeres R, Ferraro P. Endosonographic mediastinal lymph node staging of lung cancer. Chest 2014;146:389–97. 12. Zhang R, Ying K, Shi L, Zhang L, Zhou L. Combined endobronchial and endoscopic ultrasound-guided fine needle aspiration for mediastinal lymph node staging of lung cancer: a meta-analysis. Eur J Cancer 2013;49:1860–7. 13. Liberman M, Duranceau A, Grunenwald E, et al. New technique performed by using EUS access for biopsy of paraaortic (station 6) mediastinal lymph nodes without traversing the aorta (with video). Gastrointest Endosc 2011;73:1048–51. 14. Liberman M, Duranceau A, Grunenwald E, Thiffault V, Khereba M, Ferraro P. Initial experience with a new technique of endoscopic and ultrasonographic access for biopsy of paraaortic (station 6) mediastinal lymph nodes without traversing the aorta. J Thorac Cardiovasc Surg 2012;144:787–92. 15. Mountain CF, Dresler CM. Regional lymph node classification for lung cancer staging. Chest 1997;111:1718–23. 16. Uy KL, Darling G, Xu W, et al. Improved results of induction chemoradiation before surgical intervention for selected patients with stage IIIA-N2 non-small cell lung cancer. J Thorac Cardiovasc Surg 2007;134:188–93. 17. V azquez-Sequeiros E, Gonzalez-Panizo-Tamargo F, Barturen A, et al. The role of endoscopic ultrasound guided fine needle aspiration (EUS-FNA) in non small cell lung cancer (NSCLC) patients: SEED-SEPD-AEG joint guideline. Rev Esp Enferm Dig 2013;105:215–24. 18. Sharples LD, Jackson C, Wheaton E, et al. Clinical effectiveness and cost-effectiveness of endobronchial and endoscopic ultrasound relative to surgical staging in potentially resectable lung cancer: results from the ASTER randomised controlled trial. Health Technol Assess 2012;16:1–75; iii–iv. 19. Harewood GC, Pascual J, Raimondo M, et al. Economic analysis of combined endoscopic and endobronchial ultrasound in the evaluation of patients with suspected non-small cell lung cancer. Lung Cancer 2010;67:366–71. 20. Wallace MB, Pascual JM, Raimondo M, et al. Minimally invasive endoscopic staging of suspected lung cancer. JAMA 2008;299:540–6. 21. Szlubowski A, Zieli nski M, Soja J, et al. A combined approach of endobronchial and endoscopic ultrasoundguided needle aspiration in the radiologically normal mediastinum in non-small-cell lung cancer staging—a prospective trial. Eur J Cardiothorac Surg 2010;37:1175–9. 22. Rusch VW. Mediastinoscopy: an obsolete procedure? J Thorac Cardiovasc Surg 2011;142:1400–2.
References 1. Ernst A, Eberhardt R, Krasnik M, Herth FJ. Efficacy of endobronchial ultrasound-guided transbronchial needle aspiration of hilar lymph nodes for diagnosing and staging cancer. J Thorac Oncol 2009;4:947–50. 2. Rusch VW, Crowley J, Giroux DJ, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol 2007;2:603–12. 3. Hammoud ZT, Anderson RC, Meyers BF, et al. The current role of mediastinoscopy in the evaluation of thoracic disease. J Thorac Cardiovasc Surg 1999;118:894–9.
Background. The objective was to evaluate whether endobronchial ultrasonography (EBUS) or endoscopic ultrasonography (EUS) staging techniques of the mediastinum for lung cancer can change the treatment plan compared with the “gold standard” of surgical staging. Methods. Patients were retrospectively identified from a prospectively collected database. Endoscopic staging was compared with the “gold standard” cervical mediastinoscopy (CM). In cases where mediastinoscopy was not performed, EBUS/EUS was compared with “ideal” CM, a virtual procedure, which was assumed to have 100% rates of sensitivity and specificity. Results. EBUS was performed in 324 patients (99%), EUS in 295 patients (90%), and CM in 101 patients (31%); 226 patients (69%) were assumed to have undergone a virtual ideal CM and a virtual surgical mediastinal staging; 108 positive biopsies (33.0%) with endosonography had sampling of targets that were out of the scope of CM.
Distant metastatic disease was diagnosed by EBUS/EUS in 7 patients (2.1%); 22 patients (6.7%) had positive targets outside the reach of the CM or virtual CM. If the 14 patients who had positive stations 5, 6, 10, and 11 are excluded (accessible with anterior mediastinotomy or extended cervical mediastinoscopy), there were 6 patients (1.8%) in whom endosonography upstaged the patient over ideal surgical mediastinal staging. In 20 patients (6.1%), ultrasound-guided biopsy made the diagnoses, which changed the treatment plan over CM and ideal CM. Conclusions. Combined EBUS- and EUS-guided biopsies can access more targets, including lung and distant metastasis, and thus have the potential to upstage patients compared with mediastinoscopy and change the treatment plan.
M
ediastinal staging is a critical step in the preoperative evaluation of patients with non-small cell cancer [1]. Accurate cancer staging allows for appropriate disease management in terms of selecting candidates for surgical resection versus nonsurgical modalities [2]. In addition, lymph node assessment represents a valuable prognostic factor [3]. Noninvasive mediastinal staging with computed tomography and positron emission tomography scans have significant false negative and false positive rates, and imaging modalities therefore require confirmatory lymph node biopsy for tissue diagnosis. Currently, cervical mediastinoscopy (CM) is considered the “gold standard” procedure for the mediastinal staging of lung cancer staging [4]. Over the past decade, the increased use of minimally invasive endosonographic techniques, including endobronchial ultrasound (EBUS) and endoscopic ultrasound (EUS), has been recognized as an alternative method to surgical staging [5]. Currently, some prefer needle-sampling techniques over surgical
staging as a best first test for mediastinal lymph node staging in lung cancer [6]. Real-time imaging with combined EBUS and EUS allows detection and sampling of hilar and mediastinal lymph nodes beyond the reach of standard mediastinoscopy. EBUS allows for visualization and biopsy of hilar (station 10), interlobar (station 11), and lobar (station 12) lymph nodes, and EUS gives access to the aortopulmonary window (station 5), paraaortic (station 6), paraesophageal (station 8), inferior pulmonary ligament nodes (station 9), and intraabdominal targets including the liver and adrenal sites [7]. Because of the additional sites that are accessible through endosonography, these techniques may allow for a more complete preoperative staging compared with CM. The aim of this study was to evaluate whether EBUS or EUS or both used in the preoperative staging of lung cancer contributes to changes in the treatment plan compared with conventional gold standard surgical staging.
Accepted for publication Aug 26, 2015.
Patients and Methods
Presented at the 2014 Annual Meeting of the American Thoracic Society, San Diego, CA, May 16–21, 2014.
Subjects
Address correspondence to Dr Liberman, Division of Thoracic Surgery, Centre Hospitalier de l’Universit e de Montreal, 1560 rue Sherbrooke E, 8e CD, Pavillon Lachapelle D-8051, Montr eal, QE H2L 4M1, Canada; e-mail: [email protected].
Ó 2015 by The Society of Thoracic Surgeons Published by Elsevier
(Ann Thorac Surg 2015;-:-–-) Ó 2015 by The Society of Thoracic Surgeons
Patients were retrospectively identified from a prospective interventional endoscopy database at the Centre Hospitalier de l’Universit e de Montr eal (CHUM) Endoscopic Tracheo-Bronchial and Oesophageal Center, Division of 0003-4975/$36.00 http://dx.doi.org/10.1016/j.athoracsur.2015.08.070
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BERANIA ET AL ENDOSCOPIC MEDIASTINAL STAGING IN LUNG CANCER
Thoracic Surgery. Database data were complemented by manual chart review of the electronic medical record of all patients at CHUM including official pathology and cytopathology reports. The Institutional Ethics Review Board of the Centre de Recherche du CHUM approved the study. Data collection included assessment of staging procedures (EBUS, EUS, or CM), biopsy sites, imaging reports (positron emission tomography, computed tomography, and positron emission tomography/ computed tomography scan), final pathologic diagnosis, and demographic data (age and sex).
Surgical Staging CERVICAL MEDIASTINOSCOPY. Endoscopic staging was compared with CM staging. Cervical mediastinoscopy is a surgical staging procedure that allows access to the superior mediastinum. Lymph node biopsies were performed with the use of a mediastinoscope that was introduced through a suprasternal incision. The CM assessed the upper paratracheal (2R/2L), lower paratracheal (4R/4L), and subcarinal (7) lymph node stations. In cases where mediastinoscopy was not performed, EBUS/EUS was compared with “ideal” CM, a virtual procedure, which was assumed to have 100% rates of sensitivity and specificity. Ideal CM assessed all stations reached by CM. SURGICAL MEDIASTINAL STAGING. Patients assigned to virtual CM were also assumed to have undergone an ideal surgical mediastinal staging (SMS), with access (in addition to stations assessed with ideal CM) to subaortic (station 5) and paraaortic (station 6) lymph nodes (through extended cervical mediastinoscopy or anterior mediastinotomy), and to hilar (station 10) and interlobar (station 11) stations (through extended cervical mediastinoscopy). Results of the EBUS and EUS procedures were compared with those of CM, virtual CM, and virtual SMS in terms of the addition of staging information, upstaging, and change of treatment plan. IDEAL VIRTUAL STAGING. Patients who have not undergone surgical staging were assigned to virtual, or ideal, staging. This theoretical group of patients served as a comparator to endoscopic staging procedures. Virtual ideal surgical procedures assumed that patients underwent CM or SMS that reached all accessible stations, with 100% sensitivity and specificity.
Endosonography-Guided Needle Aspiration Biopsies All fine-needle aspiration specimens were evaluated by dedicated cytopathologists in the Department of Pathology at CHUM. Results were evaluated for (1) positivity; (2) negativity (no tumor cells, presence of normal lymphocytes); and (3) inadequacy (no tumor cells, no lymphocytes). A minimum of two passes was performed into each lymph node. The procedures were performed under local anesthesia with moderate sedation or under general anesthesia. Endosonographic data were prospectively recorded during the staging procedure. Lung cancer staging was based on the American Joint Committee on Cancer staging manual, seventh edition [8].
Ann Thorac Surg 2015;-:-–-
Results Lung cancer diagnosis was reported in 327 patients who have undergone EBUS or EUS or both between January 2009 and December 2013 in our health care center. The EBUS and EUS were performed in 324 patients (99%) and 295 patients (90%), respectively. The CM was performed on 101 patients (31%), and 226 patients (69%) who did not undergo CM were assumed to have undergone ideal surgical staging (ideal CM and ideal SMS). Overall, 181 patients (55.4%) in the cohort were male and 146 (44.6%) were female. The mean age was 65.3 years (SD 9.8). One hundred eight patients (33.0%) who underwent endosonography had sampling of thoracic targets that were outside the scope of standard CM. Among these, lymph node stations 5, 6, 8, 9, 10, and 11 were positive in 25 (23.1%), 4 (3.7%), 16 (14.8%), 2 (1.9%), 14 (13.0%), and 11 (10.2%) cases, respectively. Biopsy specimens were obtained from positive lung masses with EBUS and EUS in 22 patients (20.4%) and 14 patients (13.0%), respectively (Table 1). Ultrasound-guided biopsies assessed extrathoracic stations that include liver, adrenal glands, and abdominal lymph nodes. These stations led to the diagnosis of metastatic disease in 7 patients (2.1%; Table 2). In total, 22 patients (6.7%) had positive targets outside the reach of CM or ideal CM. With the exclusion of 14 patients who had positive stations 5, 6, 10, and 11 (accessible through SMS), there were 6 upstaged patients (1.8%) over ideal SMS (Table 3). There was a change in treatment plan for 20 patients (6.1%) and 12 patients (3.7%) with combined endoscopic staging compared with ideal CM and ideal SMS, respectively (Table 4).
Comment In the present study, we compared minimally invasive ultrasonographic biopsy techniques with gold standard cervical mediastinoscopy for non-small cell lung cancer staging. Our findings suggest that combined EBUS and Table 1. Positive Thoracic Biopsies Out of Scope of Standard Cervical Mediastinoscopy Positive Biopsies Target Stations 5 6 8L 8R 9L 9R 10L 10R 11L 11R PLL
EBUS
EUS
Total
2 . . . . . 3 11 6 5 22
23 4 7 9 1 1 . . . . 14
25 4 7 9 1 1 3 11 6 5 36
EBUS ¼ endobronchial ultrasonography; EUS ¼ endoscopic ultrasonography; L ¼ left; PLL ¼ parenchymal lung lesion; R ¼ right.
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BERANIA ET AL ENDOSCOPIC MEDIASTINAL STAGING IN LUNG CANCER
Table 2. Positive Distant Metastatic Sites
Table 4. Patients With Change in Treatment Plan
Positive Distant Metastasis
n (%)
Distant stations, n ¼ 8 Left adrenal gland Liver mass Gastrohepatic ligament lymph node
5 (62.5) 2 (25.0) 1 (12.5)
EUS may be superior to surgical staging for the assessment of mediastinal lymph node stations and preoperative lung cancer staging. Past reports suggest equal or better accuracy for endoscopic compared with surgical approaches for lung cancer staging. In a prospective controlled trial, Yasufuku and colleagues [9] noted similar sensitivity, negative predictive value, and diagnostic accuracy of 81%, 91%, and 93%, respectively, for EBUS, and 79%, 90%, and 93%, respectively, for mediastinoscopy. In a randomized controlled multicenter trial, Annema and colleagues [10] showed that combined endosonography followed by surgical staging compared with surgical staging alone resulted in greater sensitivity for mediastinal nodal metastases and fewer unnecessary thoracotomies. A prospective controlled trial conducted in our center demonstrated that endoscopic staging was diagnostic for N2/N3/M1 disease in 24 patients in whom SMS findings were negative, thereby preventing futile thoracotomy for 14% of patients [11]. A systematic review and meta-analysis of 8 studies by Zhang and associates[12] also showed that combined endoscopic techniques are more sensitive than EBUS– transbronchial-needle aspiration or EUS–fine-needle aspiration alone, and the diagnostic power of the combined technique is more accurate [12]. Now, EUS can also mimic anterior mediastinotomy or left video-assisted thoracoscopic surgery for access to stations 5 and 6. Liberman and colleagues [13, 14] described a novel technique for direct access to the paraaortic (station 6) lymph node region through the proximal esophagus, an area Table 3. Patients Upstaged by Nodal Sampling With Endobronchial Ultrasonography and Endoscopic Ultrasonography Compared With Cervical Mediastinoscopy/ Ideal Cervical Mediastinoscopy and Ideal Surgical Mediastinal Staging Upstaged Patients CM/ideal CM Nodal stage, n ¼ 22 1 2 3 Ideal SMS Nodal stage, n ¼ 6 1 2 3 CM ¼ cervical mediastinoscopy;
n (%)
7 (31.8) 11 (50.0) 4 (18.2)
0 (0.0) 2 (33.3) 4 (66.7) SMS ¼ surgical mediastinal staging.
Patients With Change of Plan
n (%)
Compared with CM or ideal CM Nodal stage, n ¼ 20 0 1 2 3 Compared with ideal SMS Nodal stage, n ¼ 12 0 1 2 3 CM ¼ cervical mediastinoscopy;
3
2 0 14 4
(10.0) (0.0) (70.0) (20.0)
2 0 9 1
(16.7) (0.0) (75.0) (8.3)
SMS ¼ surgical mediastinal staging.
thought to be unreachable endoscopically without traversing the aorta or the pulmonary artery, thus increasing the endoscopic access. One advantage to endosonography is the lack of need for general anesthesia as these procedures can be done under local anesthesia and moderate sedation. That also has a cost impact as operating room costs are avoided. Another advantage of ultrasound-guided biopsies is the increased accessibility to mediastinal and hilar lymph node stations not accessible with SMS. In the present study, we noted greater access to positive lymph node stations with EBUS and EUS that were out of the reach of cervical mediastinoscopy. The results of the present study also revealed that half of the endosonography upstaged patients were classified as N2 lymph node positive, defined as ipsilateral mediastinal or subcarinal lymph node metastasis [15]. Some patients in this group benefited from neoadjuvant therapy before surgical resection [15] and other patients were spared futile lung resection. Moreover, the combined endoscopic approach was able to diagnose distant metastatic disease in 2% of the patients of the cohort, avoiding an additional procedure or undiagnosed M1 disease. Diagnosis of advanced disease (stage IV) allows patients to receive palliative support and avoid unnecessary additional treatments [16]. In the present study, detection rates of distant metastatic disease were lower than in previous reports. Silvestri and associates [6] observed that EUS needle aspiration was capable of detecting metastatic disease in subdiaphragmatic sites such as the left adrenal gland, celiac lymph nodes, and the liver, with an overall yield of 4%. This difference may be explained by patient referral patterns as the patients in this cohort were referred to a thoracic surgery interventional endoscopy center, and that may have contributed to the lower overall stage of the cohort. In the current study, compared with ideal CM and ideal SMS, patient treatment plans were changed for 20 patients (6.1%) and 12 patients (3.7%), respectively, based on the findings from combined endosonographic staging. Appropriate detection and cancer staging prevents unnecessary thoracotomies and their potential complications
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BERANIA ET AL ENDOSCOPIC MEDIASTINAL STAGING IN LUNG CANCER
Ann Thorac Surg 2015;-:-–-
for nonsurgical candidates. Sharples and associates [17] demonstrated, in a randomized control trial, a reduction of futile thoracotomy by 13% when comparing the endosonography group and the surgical staging group. The current study also demonstrated superior accuracy of real-life EBUS and EUS in comparison with ideal virtual procedures (virtual CM and virtual SMS), which were falsely assigned perfect detection rates (100% accuracy). Therefore, we can assume that even greater differences could have been observed under true clinical settings with the use of CM. Nevertheless, a limitation of our study is that real surgical comparison was performed in only 30% of our group. Surgical mediastinal staging has been shown to be associated with a negative predictive value and accuracy of 89% compared with endoscopic mediastinal staging and rates of 92% and 91%, respectively, at time of thoracotomy or video-assisted thoracoscopic surgery [11]. The economic impact of lung cancer staging represents another factor in favor of minimally invasive staging. Past studies suggest that EBUS and EUS are less expensive than mediastinoscopy. A prospective randomized controlled study by Sharples and colleagues [18] noted lower costs over a 6-month period with endosonographic staging. Harewood and colleagues [19] also observed lower costs with EBUS and EUS compared with SMS, with a greater difference observed in N2/N3 disease. Minimally invasive techniques are progressively replacing traditional surgical methods for lymph node biopsy in lung caner. Nevertheless, surgical staging remains a valuable tool [20, 21]. For instance, biopsies of small lymph nodes (less than 5 mm) are thought to be less reliable with the use of EBUS–transbronchial-needle aspiration. Although these nodes most frequently suggest benign pathology, they may require surgical sampling [22]. Although endosonographic staging appears as effective as surgical staging for positive lymph node detection, its lower negative predictive rate may require further surgical sampling for negative results for a definite diagnostic confirmation in centers with less experience with these techniques [4]. In conclusion, the present study confirms that endosonography in the staging of non-small cell lung cancer can access more lymph node targets and thus has the potential to improve accuracy compared with cervical mediastinoscopy and surgical mediastinal staging. These findings support the gradual transition from traditional surgical staging to endoscopic staging.
4. De Leyn P, Lardinois D, Van Schil PE, et al. ESTS guidelines for preoperative lymph node staging for non-small cell lung cancer. Eur J Cardiothorac Surg 2007;32:1–8. 5. Detterbeck FC, Jantz MA, Wallace M, Vansteenkiste J, Silvestri GA. Invasive mediastinal staging of lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 2007;132(Suppl):202–20. 6. Silvestri GA, Gonzalez AV, Jantz MA, et al. Methods for staging non-small cell lung cancer. Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143(Suppl):e211–50. 7. Harris CL, Toloza EM, Klapman JB, Vignesh S, Rodriguez K, Kaszuba FJ. Minimally invasive mediastinal staging of nonsmall-cell lung cancer: emphasis on ultrasonographyguided fine-needle aspiration. Cancer Control 2014;21:15–20. 8. Edge S, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A. AJCC cancer staging manual. 7th ed. New York: Springer-Verlag; 2010. 9. Yasufuku K, Pierre A, Darling G, et al. A prospective controlled trial of endobronchial ultrasound-guided transbronchial needle aspiration compared with mediastinoscopy for mediastinal lymph node staging of lung cancer. J Thorac Cardiovasc Surg 2011;142:1393–400. 10. Annema JT, Van Meerbeeck JP, Rintoul RC, et al. Mediastinoscopy vs endosonography for mediastinal nodal staging of lung cancer: a randomized trial. JAMA 2010;304:2245–52. 11. Liberman M, Sampalis J, Duranceau A, Thiffault V, Hadjeres R, Ferraro P. Endosonographic mediastinal lymph node staging of lung cancer. Chest 2014;146:389–97. 12. Zhang R, Ying K, Shi L, Zhang L, Zhou L. Combined endobronchial and endoscopic ultrasound-guided fine needle aspiration for mediastinal lymph node staging of lung cancer: a meta-analysis. Eur J Cancer 2013;49:1860–7. 13. Liberman M, Duranceau A, Grunenwald E, et al. New technique performed by using EUS access for biopsy of paraaortic (station 6) mediastinal lymph nodes without traversing the aorta (with video). Gastrointest Endosc 2011;73:1048–51. 14. Liberman M, Duranceau A, Grunenwald E, Thiffault V, Khereba M, Ferraro P. Initial experience with a new technique of endoscopic and ultrasonographic access for biopsy of paraaortic (station 6) mediastinal lymph nodes without traversing the aorta. J Thorac Cardiovasc Surg 2012;144:787–92. 15. Mountain CF, Dresler CM. Regional lymph node classification for lung cancer staging. Chest 1997;111:1718–23. 16. Uy KL, Darling G, Xu W, et al. Improved results of induction chemoradiation before surgical intervention for selected patients with stage IIIA-N2 non-small cell lung cancer. J Thorac Cardiovasc Surg 2007;134:188–93. 17. V azquez-Sequeiros E, Gonzalez-Panizo-Tamargo F, Barturen A, et al. The role of endoscopic ultrasound guided fine needle aspiration (EUS-FNA) in non small cell lung cancer (NSCLC) patients: SEED-SEPD-AEG joint guideline. Rev Esp Enferm Dig 2013;105:215–24. 18. Sharples LD, Jackson C, Wheaton E, et al. Clinical effectiveness and cost-effectiveness of endobronchial and endoscopic ultrasound relative to surgical staging in potentially resectable lung cancer: results from the ASTER randomised controlled trial. Health Technol Assess 2012;16:1–75; iii–iv. 19. Harewood GC, Pascual J, Raimondo M, et al. Economic analysis of combined endoscopic and endobronchial ultrasound in the evaluation of patients with suspected non-small cell lung cancer. Lung Cancer 2010;67:366–71. 20. Wallace MB, Pascual JM, Raimondo M, et al. Minimally invasive endoscopic staging of suspected lung cancer. JAMA 2008;299:540–6. 21. Szlubowski A, Zieli nski M, Soja J, et al. A combined approach of endobronchial and endoscopic ultrasoundguided needle aspiration in the radiologically normal mediastinum in non-small-cell lung cancer staging—a prospective trial. Eur J Cardiothorac Surg 2010;37:1175–9. 22. Rusch VW. Mediastinoscopy: an obsolete procedure? J Thorac Cardiovasc Surg 2011;142:1400–2.
References 1. Ernst A, Eberhardt R, Krasnik M, Herth FJ. Efficacy of endobronchial ultrasound-guided transbronchial needle aspiration of hilar lymph nodes for diagnosing and staging cancer. J Thorac Oncol 2009;4:947–50. 2. Rusch VW, Crowley J, Giroux DJ, et al. The IASLC Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol 2007;2:603–12. 3. Hammoud ZT, Anderson RC, Meyers BF, et al. The current role of mediastinoscopy in the evaluation of thoracic disease. J Thorac Cardiovasc Surg 1999;118:894–9.