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Clinical utilization of endobronchial ultrasound (EBUS)
to stage lung cancer
Francisco A. Almeida, MD, MS, FCCPAssociate Staff Member
Respiratory InstituteCleveland Clinic
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Clinical utilization of endobronchial ultrasound (EBUS)
to stage lung cancer
• No conflicts of interest
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EBUS staging in NSCLC
RADIAL-PROBE EBUS
CONVEX-PROBE EBUS
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EBUS staging in NSCLC
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Lymph node map and lung cancer staging
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Rusch V, Asamura H, Watanabe H et al. J Thorac Oncol. 2009;4: 568–577
IASLC Lymph node map
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Detterbeck F, Postmus P, Tanoue L. Chest 2013: 143(5)(Suppl):e191S–e210S
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Yasufuku K, Nakajima T, Motoori K et al. Chest 2006;130;710-718
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EBUS vs Mediastinoscopy
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• Prospective, crossover trial
• Consecutive subjects with clinically suspected NSCLC
• Inclusion criteria:
- Resectable disease
- PET not used and histology unconfirmed at enrollment
- Mediastinal adenopathy (10 mm) on CT had to be confined to lymph node stations 2, 4 or 7
J Thorac Oncol 2008;3:577-582
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• EBUS performed as separate procedure 1 week before mediastinoscopy or at the time of mediastinoscopy
• Only pathologically enlarged nodes on CT biopsied
• Two passes only
• NO ROSE
• Patients with negative EBUS-TBNA and mediastinoscopy: surgical resection
J Thorac Oncol 2008;3:577-582
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J Thorac Oncol 2008;3:577-582
• 66 pts met inclusion criteria
• 120 enlarged nodes
• Mean large node/patient: 1.8 ± 0.1 (1–4)
• 51 pts had surgery
• Overall agreement: 78%
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• Sensitivities:
- EBUS: 87%- Mediastinoscopy: 68%
• In a per patient analysis, the overall diagnostic yield:
- EBUS-TBNA was 59/66 (89%)- Mediastinoscopy was 52/66 (79%; p 0.1)
• Prediction of correct pathologic N stage in the 57 patients with NSCLC:
- EBUS-TBNA: 53/57 (93%) - Mediastinoscopy: 47/57 (82%; p 0.083)
J Thorac Oncol 2008;3:577-582
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Annema T, van Meerbeeck J, Rintoul R et al. JAMA 2010; 304(20):2245-2252
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• Eligibility: patients with potentially resectable NSCLC and indication for mediastinal nodal sampling
- mediastinal nodes with short axis ≥ 10 mm
- PET-positive mediastinal or hilar nodes
- centrally located lung tumor
• 4 participating European hospitals
Annema T, van Meerbeeck J, Rintoul R et al. JAMA 2010; 304(20):2245-2252
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• Patients randomly assigned (1:1) to either
- surgical staging alone (surgical staging group: mediastinoscopy)
- endosonography (combined EUS-FNA and EBUS-TBNA) followed by surgical staging if no nodal metastases
• Patients without evidence of mediastinal Dz following surgical staging in either study group:
- thoracotomy with complete lymph node dissection was performed
• Endosonography of the mediastinum: under moderate sedation
Annema T, van Meerbeeck J, Rintoul R et al. JAMA 2010; 304(20):2245-2252
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• Surgical staging- Sensitivity: 79% (41/52; 95% CI, 66%-88%)- NPV: 86% (66/77; 95% CI, 76-92%)
• Endosonographic staging- Sensitivity: 85% (56/66; 95% CI, 74%-92%)- NPV: 85% (57/67; 95% CI, 75-92%)
(p > .99)
Annema T, van Meerbeeck J, Rintoul R et al. JAMA 2010; 304(20):2245-2252
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• Prospective, controlled trial performed in patients with confirmed or suspected NSCLC who required a mediastinoscopy
• Patients were candidates for surgical resection
• Under general anesthesia: EBUS staging followed by mediastinoscopy on the same setting
• Operator was blinded to EBUS on-site results
• If path negative for N2 or N3 Dz after EBUS and mediastinoscopy: thoracotomy with nodal dissection at the same setting of later
Yasufuku K, MPierre A, Gail Darling G et al. J Thorac Cardiovasc Surg 2011; 142(6):1393-1400
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Yasufuku K, MPierre A, Gail Darling G et al. J Thorac Cardiovasc Surg 2011; 142(6):1393-1400
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Yasufuku K, MPierre A, Gail Darling G et al. J Thorac Cardiovasc Surg 2011; 142(6):1393-1400
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• Mean short axis of the nodes Bx’ed by EBUS-TBNA: 6.9 ± 2.9 mm
• False-negative: 8 on EBUS-TBNA vs 14 on mediastinoscopy
• Sensitivity, negative predictive value, and diagnostic accuracy:
- EBUS-TBNA: 81%, 91%, 93%
- Mediastinoscopy: 79%, 90%, 93% (McNemar’s test, P=.78)
• Minor complications from mediastinoscopy observed in 4 patients (2.6%) (hematoma in 2, left recurrent nerve injury in 1, and wound infection in 1)
Yasufuku K, MPierre A, Gail Darling G et al. J Thorac Cardiovasc Surg 2011; 142(6):1393-1400
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EBUS and PET-CT
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78 out of 102 study patients underwent surgery
Chest 2006;130;710-718
p < 0.00001
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EBUS-TBNA results:
• Small cell lung cancer in 9 (12%)
• Adenocarcinoma in 25 (33%)
• Squamous cell carcinoma in 20 (25%)
• Non small cell lung cancer (unspecified) in 23 (30%) cases
• In 42 (55%) of the 77 cases EBUS-TBNA showed malignancy: primary tissue diagnosis in addition to giving staging information
J Thorac Oncol 2009;4:44-48
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For the 96 cases with definitive reference pathology, the EBUS-TBNA per patient basis:
• Sensitivity: 91% (95% CI 82–95)
• Diagnostic accuracy: 92%
• Specificity: 100% (95% CI 73–100), assuming no FP
• PPV: 100% (95% CI 95–100)
• NPV: 60% (95% CI 36–80)
• EBUS-TBNA obviated the need for further surgical staging procedures in 71%
J Thorac Oncol 2009;4:44-48
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Chest 2009;135;1280-1287
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Chest 2009;135;1280-1287
Normal mediastinum on PET/CT in 61 patients: 9 found to havemediastinal metastasis, 6 on EBUS-TBNASensitivity 75%; Specificity 100%; NPV 94%
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• Stations 2, 4, 7, 10, and 11: short-axis diameter measured in 97 pts
• All visualized nodes 5 to 10 mm were punctured TWICE: 7.9 ± 0.7 mm
• Sensitivity: 89%
• Specificity: 100%
• NPV: 99%
Chest 2008;133;887-891
Missed by EBUS-TBNA
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EBUS scope for “complete” mediastinal staging
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Chest 2010; 138:795-802
Combining EUS-B-FNA + EBUS-TBNA: the proportion of accessible mediastinal nodal stations was increased from 78.6% (372/473) to 84.8% (401/473) (p=0.015)
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Chest 2010; 138:790-794
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EBUS: meta-analysis
Adams K, Shah PL, Edmonds L et al. Thorax 2009;64:757-762Gu P, Zhao Y, Jiang L et al. Eur J Cancer 2009;45(8):1389-1396
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EBUS vs other invasive tests in lung cancer:
- diagnosis and staging
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Almeida F, Casal R, Jimenez C et al, Chest, in press
64%
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Almeida F, Casal R, Jimenez C et al, Chest, in press
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EBUS and NSCLC subtyping and biomarkers
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Navani N, Brown JM, Nankivel M et al. Am J Respir Crit Care Med 2012;185(12):1316-1322
Data not described:-434 final EBUS cancer Dx-Specific subtype in 333 (76.7%)
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Esterbrooka G, Anathhanama S, Plantb PK. Lung Cancer 2013;80(1):30-34
Specific subtype in NSCLC:- 118 of 149 (79.2%)
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EBUS and Biomarkers
EGFR gene mutation analysis
•EBUS-TBNA samples of metastatic AdenoCA of hilar and/or mediastinal lymph node from 156 patients1
- Recut sections of the paraffin-embedded samples yielded tumor cells in 154
- EGFR positive in 42 (26.9%)
- “Enough” tumor for other testing (113): 4 with K-ras and 47 with p53
•EGFR gene analysis feasible in 26 (72.2%) out of the 36 patients2
- EGFR positive in 2 out of 20 patients with adenocarcinoma
1. Nakajima T, Yasufuku K, Nakagawara A et al. Chest; Prepublished online April 28, 2011; DOI 10.1378/chest. 10-31862. Garcia-Olive I, Monso E, Andreo F et al. Eur Respir J 2010; 35: 391-395
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EBUS and Biomarkers
EML4-ALK Fusion Gene Assessment: FISH
•EML4-ALK Fusion Gene Assessment in “metastatic” lymph nodes1
- Re-sliced specimens for histologic examination available in 109 out 112
- ALK positive in 7: all adenoCA and EGFR negative
•EML4-ALK Fusion Gene Assessment in lymph nodes showing adenocarcinoma or NSCLC NOS and negative for EGFR2
- FISH analysis successful in 52 of 55 samples (94.5%)
- ALK positive in 3 of 52 (5.7%)
1. Sakairi Y, Nakajima T, Yasufuku K et al. Clin Cancer Res 2010;16:4938-49452. Neat MJ, Foot NJ, Hicks A et al. Cytopathology 2013 doi: 10.1111/cyt.12060. [Epub ahead of print]
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• EBUS-TBNA, EUS-FNA and histological samples available in 43 patients
- KRAS mutation: 6 patients
- EGFR mutation: 1 patient
- PIK3CA mutation: 1 patient
• 100% concordance between cytological and histological specimens
PLoS ONE 6(3): e17791. doi:10.1371/journal.pone.0017791
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EBUS, ROSE and needle gauge
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Oki M, Saka H, Kitagawa C et al. Respiration 2013 [Epub ahead of print]
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EBUS: 21g vs 22g needle
Oki M, MD, Saka H, Kitagawa C et al. J Bronchol Intervent Pulmonol 2011;18:306-310Nakajima T, Yasufuku, Takahashi R et al. Respirology 2011; 16:90-94
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EBUS: 21g vs 22g needle
Yarmus L , Akulian J, Lechtzin N et al. CHEST 2013; 143(4):1036-1043
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EBUS and ultrasound characteristics
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J Bronchol Intervent Pulmonol 2011;18:322-328
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• Lack of CIV: increase in the likelihood of malignancy [OR, 49.7; 95% confidence interval, 15.1-163.9]
• Presence of a CIV for benign cytology
- Sensitivity: 83.0%
- Specificity: 91.1%
• PPV of CIV predicting nonmalignant cytology: 88.6%
• The presence or absence of a CIV accurately predicted cytology results in 90 out of the 103 LNs sampled (87.4%).
J Bronchol Intervent Pulmonol 2011;18:322–328
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CHEST 2010; 138(3):641-647
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CHEST 2010; 138(3):641-647
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Initial Lung Cancer Evaluation
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Curr Opin Pulm Med 2010; 16(4):307-14
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Summary
• EBUS and mediastinoscopy: both superior to current imaging modalities for NSCLC mediastinal staging
• EBUS and mediastinoscopy appear to be equivalent for mediastinal staging of NSCLC patients: local expertise defines choice
• Standard bronchoscopy + EBUS probably the ideal initial test for diagnosis and staging of lung cancers radiographically limited to the chest
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Summary
• Nodal sonographic characteristics not ready for primetime but may add to EBUS staging (will it increase sensitivity?)
• EBUS alone (in expert hands) is sufficient for the MAJORITY of mediastinal staging cases:
- Combined EBUS and mediastinoscopy provides best yield, and should be viewed as complimentary
• Role of cytology (EBUS) in minimally invasive lung cancer staging is extremely important
- Likely to become the norm in many centers