Clinical utilization of
endobronchial ultrasound (EBUS)
to stage lung cancer
Francisco A. Almeida, MD, MS, FCCP
Associate Staff Member
Respiratory Institute
Cleveland Clinic
Clinical utilization of
endobronchial ultrasound (EBUS)
to stage lung cancer
• No conflicts of interest
EBUS staging in NSCLC
RADIAL-PROBE
EBUS
CONVEX-PROBE EBUS
EBUS staging in NSCLC
Lymph node map and lung
cancer staging
IASLC Lymph node map
Rusch V, Asamura H, Watanabe H et al. J Thorac Oncol. 2009;4: 568–577
Detterbeck F, Postmus P, Tanoue L. Chest 2013: 143(5)(Suppl):e191S–e210S
Yasufuku K, Nakajima T, Motoori K et al. Chest 2006;130;710-718
EBUS vs Mediastinoscopy
• 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
• 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
• 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%
J Thorac Oncol 2008;3:577-582
• 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
Annema T, van Meerbeeck J, Rintoul R et al. JAMA 2010; 304(20):2245-2252
• 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
• 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
• 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
• 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
Yasufuku K, MPierre A, Gail Darling G et al. J Thorac Cardiovasc Surg 2011; 142(6):1393-1400
Yasufuku K, MPierre A, Gail Darling G et al. J Thorac Cardiovasc Surg 2011; 142(6):1393-1400
• 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
EBUS and PET-CT
p < 0.00001
78 out of 102 study patients underwent surgery
Chest 2006;130;710-718
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
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
Chest 2009;135;1280-1287
Normal mediastinum on PET/CT in 61 patients: 9 found to have
mediastinal metastasis, 6 on EBUS-TBNA
Sensitivity 75%; Specificity 100%; NPV 94%
Chest 2009;135;1280-1287
• 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
EBUS scope for “complete”
mediastinal staging
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)
Chest 2010; 138:795-802
Chest 2010; 138:790-794
EBUS: meta-analysis
Adams K, Shah PL, Edmonds L et al. Thorax 2009;64:757-762
Gu P, Zhao Y, Jiang L et al. Eur J Cancer 2009;45(8):1389-1396
EBUS vs other invasive tests in
lung cancer:
- diagnosis and staging
64%
Almeida F, Casal R, Jimenez C et al, Chest, in press
Almeida F, Casal R, Jimenez C et al, Chest, in press
EBUS and NSCLC subtyping and
biomarkers
Data not described:
- 434 final EBUS cancer Dx
- Specific subtype in 333 (76.7%)
Navani N, Brown JM, Nankivel M et al. Am J Respir Crit Care Med 2012;185(12):1316-1322
Specific subtype in NSCLC:
- 118 of 149 (79.2%)
Esterbrooka G, Anathhanama S, Plantb PK. Lung Cancer 2013;80(1):30-34
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.
2.
Nakajima T, Yasufuku K, Nakagawara A et al. Chest; Prepublished online April 28, 2011; DOI 10.1378/chest. 10-3186
Garcia-Olive I, Monso E, Andreo F et al. Eur Respir J 2010; 35: 391-395
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.
2.
Sakairi Y, Nakajima T, Yasufuku K et al. Clin Cancer Res 2010;16:4938-4945
Neat MJ, Foot NJ, Hicks A et al. Cytopathology 2013 doi: 10.1111/cyt.12060. [Epub ahead of print]
• 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
EBUS, ROSE and needle gauge
Oki M, Saka H, Kitagawa C et al. Respiration 2013 [Epub ahead of print]
EBUS: 21g vs 22g needle
Oki M, MD, Saka H, Kitagawa C et al. J Bronchol Intervent Pulmonol 2011;18:306-310
Nakajima T, Yasufuku, Takahashi R et al. Respirology 2011; 16:90-94
EBUS: 21g vs 22g needle
Yarmus L , Akulian J, Lechtzin N et al. CHEST 2013; 143(4):1036-1043
EBUS and ultrasound
characteristics
J Bronchol Intervent Pulmonol 2011;18:322-328
• 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
CHEST 2010; 138(3):641-647
CHEST 2010; 138(3):641-647
Initial Lung Cancer Evaluation
Curr Opin Pulm Med 2010; 16(4):307-14
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
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