Endoscopy 2015; 47(06): 545-559
DOI: 10.1055/s-0034-1392040
Guideline
© Georg Thieme Verlag KG Stuttgart · New York

Combined endobronchial and esophageal endosonography for the diagnosis and staging of lung cancer: European Society of Gastrointestinal Endoscopy (ESGE) Guideline, in cooperation with the European Respiratory Society (ERS) and the European Society of Thoracic Surgeons (ESTS)

Peter Vilmann
1  Department of Surgical Gastroenterology, Endoscopy Unit, Copenhagen University Hospital Herlev, Copenhagen, Denmark
,
Paul Frost Clementsen
2  Department of Pulmonary Medicine, Gentofte University Hospital, Hellerup, Denmark
11  Centre for Clinical Education, University of Copenhagen and the Capital Region of Denmark, Copenhagen, Denmark
,
Sara Colella
2  Department of Pulmonary Medicine, Gentofte University Hospital, Hellerup, Denmark
,
Mette Siemsen
3  Department of Thoracic Surgery, Rigshospitalet, Copenhagen Hospital Union, Copenhagen, Denmark
,
Paul De Leyn
4  Department of Thoracic Surgery, University Hospitals Leuven, Belgium
,
Jean-Marc Dumonceau
5  Gedyt Endoscopy Center, Buenos Aires, Argentina
,
Felix J. Herth
6  Department of Pneumology and Critical Care Medicine, Thoraxklinik, University of Heidelberg, Heidelberg, Germany
,
Alberto Larghi
7  Digestive Endoscopy Unit, Catholic University, Rome, Italy
,
Enrique Vazquez-Sequeiros
8  Department of Gastroenterology, University Hospital Ramón y Cajal, Universidad de Alcala, Madrid, Spain
,
Cesare Hassan
7  Digestive Endoscopy Unit, Catholic University, Rome, Italy
,
Laurence Crombag
9  Department of Respiratory Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Daniël A. Korevaar
10  Department of Clinical Epidemiology, Biostatistics and Bioinformatics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
,
Lars Konge
11  Centre for Clinical Education, University of Copenhagen and the Capital Region of Denmark, Copenhagen, Denmark
,
Jouke T. Annema
9  Department of Respiratory Medicine, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands
› Institutsangaben
Weitere Informationen

Corresponding author

Peter Vilmann, MD PhD
GastroUnit, Department of Surgery
Copenhagen University Hospital Herlev
Copenhagen
Denmark   
Telefon: +45-38-682164   

Publikationsverlauf

Publikationsdatum:
01. Juni 2015 (online)

 

This is an official guideline of the European Society of Gastrointestinal Endoscopy (ESGE), produced in cooperation with the European Respiratory Society (ERS) and the European Society of Thoracic Surgeons (ESTS). It addresses the benefit and burden associated with combined endobronchial and esophageal mediastinal nodal staging of lung cancer. The Scottish Intercollegiate Guidelines Network (SIGN) approach was adopted to define the strength of recommendations and the quality of evidence.The article has been co-published with permission in the European Journal of Cardio-Thoracic Surgery and the European Respiratory Journal.

Recommendations

1 For mediastinal nodal staging in patients with suspected or proven non-small-cell lung cancer (NSCLC) with abnormal mediastinal and/or hilar nodes at computed tomography (CT) and/or positron emission tomography (PET), endosonography is recommended over surgical staging as the initial procedure (Recommendation grade A).

The combination of endobronchial ultrasound with real-time guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic (esophageal) ultrasound with fine needle aspiration, with use of a gastrointestinal (EUS-FNA) or EBUS (EUS-B-FNA) scope, is preferred over either test alone (Recommendation grade C). If the combination of EBUS and EUS-(B) is not available, we suggest that EBUS alone is acceptable (Recommendation grade C).

Subsequent surgical staging is recommended, when endosonography does not show malignant nodal involvement (Recommendation grade B).

2 For mediastinal nodal staging in patients with suspected or proven non-small-cell peripheral lung cancer without mediastinal involvement at CT or CT-PET, we suggest that EBUS-TBNA and/or EUS-(B)-FNA should be performed before therapy, provided that one or more of the following conditions is present: (i) enlarged or fluorodeoxyglucose (FDG)-PET-avid ipsilateral hilar nodes; (ii) primary tumor without FDG uptake; (iii) tumor size ≥ 3 cm ([Fig. 3a – c]) (Recommendation grade C).

If endosonography does not show malignant nodal involvement, we suggest that mediastinoscopy is considered, especially in suspected N1 disease (Recommendation grade C).

If PET is not available and CT does not reveal enlarged hilar or mediastinal lymph nodes, we suggest performance of EBUS-TBNA and/or EUS-(B)-FNA and/or surgical staging (Recommendation grade C).

3 In patients with suspected or proven < 3 cm peripheral NSCLC with normal mediastinal and hilar nodes at CT and/or PET, we suggest initiation of therapy without further mediastinal staging (Recommendation grade C).

4 For mediastinal staging in patients with centrally located suspected or proven NSCLC without mediastinal or hilar involvement at CT and/or CT-PET, we suggest performance of EBUS-TBNA, with or without EUS-(B)-FNA, in preference to surgical staging ([Fig. 4]) (Recommendation grade D).

If endosonography does not show malignant nodal involvement, mediastinoscopy may be considered (Recommendation grade D).

5 For mediastinal nodal restaging following neoadjuvant therapy, EBUS-TBNA and/or EUS-(B)-FNA is suggested for detection of persistent nodal disease, but, if this is negative, subsequent surgical staging is indicated (Recommendation grade C).

6 A complete assessment of mediastinal and hilar nodal stations, and sampling of at least three different mediastinal nodal stations (4 R, 4 L, 7) ([Fig. 1], [Fig. 5]) is suggested in patients with NSCLC and an abnormal mediastinum by CT or CT-PET (Recommendation grade D).

7 For diagnostic purposes, in patients with a centrally located lung tumor that is not visible at conventional bronchoscopy, endosonography is suggested, provided the tumor is located immediately adjacent to the larger airways (EBUS) or esophagus (EUS-(B)) (Recommendation grade D).

8 In patients with a left adrenal gland suspected for distant metastasis we suggest performance of endoscopic ultrasound fine needle aspiration (EUS-FNA) (Recommendation grade C), while the use of EUS-B with a transgastric approach is at present experimental (Recommendation grade D).

9 For optimal endosonographic staging of lung cancer, we suggest that individual endoscopists should be trained in both EBUS and EUS-B in order to perform complete endoscopic staging in one session (Recommendation grade D).

10 We suggest that new trainees in endosonography should follow a structured training curriculum consisting of simulation-based training followed by supervised practice on patients (Recommendation grade D).

11 We suggest that competency in EBUS-TBNA and EUS-(B)-FNA for staging lung cancer be assessed using available validated assessment tools (Recommendation Grade D).


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Abbreviations

ACCP: American College of Chest Physicians
CT: computed tomography
CT-PET: integrated computed and positron emission tomography
EBUS-TBNA: endobronchial ultrasound with real-time guided transbronchial needle aspiration
ERS: European Respiratory Society
ESGE: European Society of Gastrointestinal Endoscopy
ESTS: European Society of Thoracic Surgery
EUS: endoscopic (esophageal) ultrasound using the GI scope
EUS-B: endoscopic (esophageal) ultrasound using the EBUS scope
EUS-(B): endoscopic (esophageal) ultrasound using either a GI or the EBUS scope
FDG: fluorodeoxyglucose
FNA: fine needle aspiration
GI: gastrointestinal
NPV: negative predictive value
NSCLC: non-small-cell lung cancer
PET: positron emission tomography
PPV: positive predictive value
RCT: randomized controlled trial
SCLC: small-cell lung cancer
TBNA: transbronchial needle aspiration
TEMLA: transcervical extended bilateral mediastinal lymph adenectomy

Definitions

Combined endosonography
EBUS-TBNA and EUS-(B)-FNA combined

Complete mediastinal nodal staging
All nodes evaluated (in contrast to only analysis of suspected nodes based on CT and/or PET imaging)

Targeted mediastinal nodal staging
Evaluation of the node(s) that is (are) suspicious on CT and/or PET

Centrally located lung tumor
Lung tumor located within the inner third of the chest

Peripherally located lung cancer
Lung tumor located within the outer two thirds of the chest

Lymph node(s) suspicious for malignancy (abnormal mediastinum)
Node with a short axis (> 10 mm) and/or that is FDG-PET-avid


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Introduction

Lung cancer is the most common cause of cancer-related mortality worldwide, causing approximately 1.2 million deaths every year [1]. In Europe, 410 000 new cases of lung cancer and 353 000 related deaths have been estimated to have occurred in 2012. Most cases concern non-small-cell lung cancer (NSCLC) [1]. Accurate staging is mandatory for planning optimal treatment [2]. Surgery or radiotherapy with curative intent is advised in the case of localized disease. Spread to ipsilateral (N2) or contralateral (N3) mediastinal lymph nodes marginalizes the role of surgery as first-line treatment. For disseminated NSCLC and small-cell lung cancer (SCLC), chemotherapy and/or radiotherapy is recommended [3].

Imaging by computed tomography (CT) and/or positron emission tomography (PET) should be obtained to characterize the primary lung lesion and the mediastinum, and to search for metastases. Although the detection of enlarged (at CT, short axis > 10 mm) or fluorodeoxyglucose (FDG)-avid mediastinal lymph nodes at PET increases the probability of malignant involvement [4] [5], nevertheless the accuracy of radiological imaging in mediastinal staging is suboptimal [6] [7] [8]. Therefore, additional mediastinal tissue staging is frequently required to confirm or exclude metastatic mediastinal nodal involvement. This applies not only in patients who present with an abnormal mediastinum [9] [10] [11], but also in those with a normal mediastinum but increased risk of mediastinal involvement because of hilar abnormalities or a centrally located lung tumor [12].

Mediastinoscopy has been demonstrated to have an adequate accuracy for mediastinal nodal staging [13], but is also associated with morbidity and significant costs [13]. Endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and endobronchial ultrasound with real-time guided transbronchial needle aspiration (EBUS-TBNA) represent valuable alternatives to surgical staging (see Box 1; [14] [15] [16] [17] [18]). Both techniques are minimally invasive, safe, well-tolerated, and rarely require general anesthesia [14] [19] [20]. Recently, endosonography has been recommended in guidelines as the initial test of choice over surgical staging [21] [22], because it improves nodal tissue staging, reduces the number of futile thoracotomies [18], and is cost-effective [23] [24]. The integration of the two techniques in a single “combined” endoscopic approach to staging of the mediastinum has been shown to further increase the accuracy as compared with either technique alone [25].

Box 1

Mediastinal nodal staging related to diagnostic reach of endobronchial ultrasound (EBUS) and endoscopic (esophageal) ultrasound (EUS) ([Fig. 1])

No single mediastinal tissue sampling method can reach all mediastinal nodal stations.

The diagnostic yield of EBUS-transbronchial needle aspiration (EBUS-TBNA) is related to those mediastinal and hilar nodes that are located immediately adjacent to the trachea and larger airways. These comprise stations 2 L, 2 R, 4 L, 4 R, and station 7. EBUS, uniquely, can sample tissue from the hilar nodes (station 10) and from the intrapulmonary nodes (stations 11 – 12).

EUS with real-time guided fine needle aspiration using the EBUS scope (EUS-B-FNA) can reach the following locations that are relevant to lung cancer diagnosis and staging [14] [15] [16]: lung tumors close to the esophagus; mediastinal lymph nodes in stations 2 L, 4 L (high and lower left paratracheal nodes); station 7 (subcarinal node); stations 8 and 9 (nodes located in the lower mediastinum); and structures below the diaphragm, i. e., retroperitoneal lymph nodes close to the aorta and the celiac trunk, and tumors in the left liver lobe and the left adrenal gland [17]. Stations 2 R and 4 R (paratracheally to the right) are difficult to reach because the trachea lies between the transducer and the lymph node, limiting visualization of this area. In selected cases of large lymph nodes ( > 2 cm), however, visualization and subsequent sampling is possible.

Stations 5 and 6 can be well visualized by EUS but can rarely be sampled without traversing the pulmonary artery/aorta. These stations are predominantly affected by left upper lobe tumors. Surgical staging by video-assisted thoracic surgery (VATS) is the method of choice for nodes in stations 5 and 6.

The hilar regions (lung tumors and lymph nodes in stations 10, 11, and 12 [right/left]) cannot be reached by EUS-FNA, but they can be sampled using EBUS-TBNA. Combining these two techniques allows sampling of virtually all mediastinal nodal stations [18] (see [Fig. 1]). The frequently affected nodes in locations 4 L and 7 are accessible by both techniques.

Zoom Image
Fig. 1 The complementary nature of endobronchial ultrasound (EBUS) and endoscopic (esophageal) ultrasound (EUS) for nodal staging.

The aim of this Guideline, from the European Society of Gastrointestinal Endoscopy (ESGE) in cooperation with the European Respiratory Society (ERS) and the European Society for Thoracic Surgery (ESTS), is to address the benefit and burden associated with mediastinal nodal staging of lung cancer by combined endobronchial ultrasound (EBUS) and endoscopic esophageal ultrasound (EUS-(B); that is with use of either the GI or the EBUS scope). Additionally the use of EBUS/EUS for the analysis of the primary lung tumor and the left adrenal gland will be addressed, as will training issues.


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Methods

This Guideline has been commissioned by ESGE and produced in cooperation with ERS and ESTS. The guideline development process included meetings, telephone conferences, and internet-based discussions, between October 2012 and December 2014, among members of the Guideline committee who had been selected by the involved societies.

Subgroups were formed, each in charge of a series of clearly defined key questions ([Appendix e1], available online). These working group members identified appropriate search terms and parameters to direct the literature search. A thorough search of MEDLINE (accessed through PubMed), Web of Science, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials was performed. Specific search strategies, including search terms, parameters, and databases searched, are documented for each question in [Appendix e2] (available online). English-language literature concerning the combination of EBUS-TBNA and EUS-(B)-FNA in the diagnosis and in the staging of lung cancer was selected. Literature on the combination of EBUS and EUS as well as on EUS or EBUS alone was selected for review. Initially studies were selected from a period limited to 1990 to October 2013. However, because of delay in the preparation of the manuscript it was decided to additionally include a few important studies published after the search period. Working group members reviewed all abstracts yielded from the literature search and identified the full-text articles they would review in order to address the clinical questions. Members identified the best research evidence available to answer the key questions. The Guideline considers only the linear (not radial) probe technique.

Assessment of level of evidence and grade of recommendations

All selected papers were reviewed independently by two investigators. Disagreements were solved through discussion within the review team. Evidence levels and recommendation grades used in this Guideline were slightly modified from those recommended by the Scottish Intercollegiate Guidelines Network (SIGN) [26] and are described in [Table 1]. The SIGN approach classifies recommendations according to the quality of evidence, taking also into consideration whether the studies were directly applicable to the study population. Evidence tables are detailed in [Appendix e3] (available online).

Table 1

Definitions of categories for evidence levels and recommendation grades used in this Guideline.

Evidence level

1 + + 

High quality meta-analyses, systematic reviews of RCTs,

or RCTs with a very low risk of bias

1 + 

Well conducted meta-analyses, systematic reviews of RCTs,

or RCTs with a low risk of bias

1 – 

Meta-analyses, systematic reviews,

or RCTs with a high risk of bias

2 + + 

High quality systematic reviews of case – control or cohort studies; high quality case – control studies

or cohort studies with a very low risk of confounding, bias, or chance and a high probability that the relationship is causal

2 + 

Well conducted case – control or cohort studies with a low risk of confounding, bias, or chance and a moderate probability that the relationship is causal

2 – 

Case – control or cohort studies with a high risk of confounding, bias, or chance and a significant risk that the relationship is not causal

3

Nonanalytic studies, e. g. case reports, case series

4

Expert opinion

Recommendation grade

A

At least one meta-analysis, systematic review, or RCT rated as 1 + + and directly applicable to the target population

or a systematic review of RCTs

or a body of evidence consisting principally of studies rated as 1 + directly applicable to the target population and demonstrating overall consistency of results

B

A body of evidence including studies rated as 2 + + directly applicable to the target population and demonstrating overall consistency of results

or extrapolated evidence from studies rated as 1 + + or 1 + 

C

A body of evidence including studies rated as 1 – or 2 + directly applicable to the target population and demonstrating overall consistency of results

or extrapolated evidence from studies rated as 2 + + 

D

Evidence level 2 – , 3 or 4

or extrapolated evidence from studies rated as 2 + 

RCT, randomized controlled trial

Caution should be used in developing guidelines and recommendations for diagnostic tests and strategies. Usually, when clinicians consider diagnostic tests, they focus on accuracy (sensitivity and specificity); that is, how well the test classifies patients correctly as having or not having a target disease, as determined by a clinical reference standard. The underlying assumption is, however, that obtaining a better idea of whether a target condition is present or absent will result in improved patient-important outcomes. The best way to assess any diagnostic strategy is a randomized controlled trial (RCT) in which investigators randomize patients to experimental or control diagnostic approaches and measure mortality, morbidity, symptoms, and/or quality of life. When studies were available that compared the impact of alternative diagnostic strategies on patient-important outcomes they were taken into account. Otherwise test accuracy was used as a surrogate for patient-important outcome.

After a final meeting in June 2014, all authors agreed on the final revised manuscript, which was submitted to the official Journals of the Societies. This Guideline was issued in 2015 and will be considered for review in 2019, or sooner if new and crucial evidence becomes available. Any updates of the guideline in the interim will be noted on the websites of ESGE (http://www.esge.com/esge-guidelines.html.), ERS (http://www.ers-education.org/guidelines.aspx) and ESTS (www.ests.org/guidelines_and_evidence/ests_guidelines.aspx).


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Recommendations

Recommendations are shown with a green background.

1. For mediastinal nodal staging in patients with suspected or proven non-small-cell lung cancer (NSCLC) with abnormal mediastinal and/or hilar nodes at computed tomography (CT) and/or positron emission tomography (PET), endosonography is recommended over surgical staging as the initial procedure (Recommendation grade A).
The combination of endobronchial ultrasound with real-time guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic (esophageal) ultrasound with fine needle aspiration, with use of a gastrointestinal (EUS-FNA) or EBUS (EUS-B-FNA) scope is preferred over either test alone (Recommendation grade C). If the combination of EBUS and EUS-(B) is not available, we suggest that EBUS alone is acceptable (Recommendation grade C).
Subsequent surgical staging is recommended, when endosonography does not show malignant nodal involvement (Recommendation grade B).

Background

In patients with (suspected) potentially curable non-small-cell lung cancer (NSCLC), pathologic confirmation of mediastinal lymph nodes is indicated in patients with hilar and/or mediastinal lymph nodes that are enlarged and/or fluorodeoxyglucose (FDG)-avid at positron emission tomography (PET) [27]. This is mandatory because the probability of having lymph node metastases, based on an abnormal mediastinum on computed tomography (CT) or PET imaging, ranges from 50 % to 80 %. The false-positive rate is especially considerable when tumors are accompanied by inflammation [28].


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Review of the studies

Endosonography versus surgical staging

The ASTER study (Assessment of Surgical sTaging versus Endobronchial and endoscopic ultrasound in lung cancer: a Randomized controlled trial) by Annema et al. [18] compared immediate surgical mediastinal staging versus combined endosonography staging (endobronchial ultrasound [EBUS] and endoscopic esophageal ultrasound [EUS] combined) followed by surgical staging if no mediastinal nodal metastases were detected. In detail, 241 patients with enlarged or FDG-avid mediastinal lymph nodes, enlarged or FDG-avid hilar lymph nodes, or a central lung lesion were randomized. The reference standard was surgical pathological staging including mediastinal nodal dissection. The sensitivity for mediastinal lymph node metastasis was 79 % for surgical staging versus 94 % for endosonography followed by surgical staging (P = 0.04), with corresponding negative predictive values (NPVs) of 86 % and 93 % (P = 0.26), respectively. The sensitivity of the combination of EUS and EBUS alone – without subsequent surgical staging – was 85 %; this was not significantly different from immediate surgical staging. Among patients with (suspected) NSCLC, a staging strategy combining endosonography and surgical staging versus immediate surgical staging reduced the percentage of unnecessary thoracotomies from 18 % to 7 % (P = 0.02) [18].

In the ASTER study [18], following a negative endosonography, 65 patients underwent mediastinoscopy which detected 6 additional cases of N2 /N3 disease. In the subgroup of patients with an abnormal mediastinum shown by radiological imaging, after a negative endosonography the post-test probability for lymph node metastasis was 20 % (95 % confidence interval [95 %CI] 12 % – 32 %), and adding a confirmatory mediastinoscopy in these patients with negative endosonography decreased the post-test probability for missed nodal metastases to 5 % (95 %CI 2 % – 20 %) [27]. Therefore, additional surgical staging, especially in this specific subset of patients, is indicated. If negative endosonography results are not followed by confirmatory surgical staging, careful follow-up is mandatory.


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EBUS-TBNA or EUS with fine needle aspiration (FNA) alone

The accuracy of EBUS-TBNA and EUS-FNA separately for assessing mediastinal lymph node metastases has been described in several studies. In a meta-analysis by Gu et al. [29], involving 11 studies and 1299 patients, the pooled sensitivity of EBUS-TBNA in mediastinal staging for lung cancer was 93 % (95 %CI 91 % – 94 %). The reference standard was histopathology in 5 studies, and histopathology or clinical follow-up in 6. In the subgroup of patients with an abnormal mediastinum on the basis of CT or PET, pooled sensitivity was 94 % (95 %CI 93 % – 96 %), which was significantly higher than for the subgroup of patients who were included regardless of CT or PET abnormalities (76 %, 95 %CI 65 % – 85 %).

Concerning EUS-FNA, a meta-analysis by Micames et al. (18 studies, 1201 patients) reported a pooled sensitivity of 83 % (95 %CI 78 % – 87 %) [30]. The reference standard was histopathology in 10 studies, and histopathology or clinical follow-up in 8. The sensitivity was 90 % (95 %CI 84 % – 94 %) in the subgroup of patients with abnormal mediastinal lymph nodes at radiological imaging, and 58 % (95 %CI 39 % – 75 %) among patients without abnormal mediastinal lymph nodes. There was risk of bias in many of the studies included in these meta-analyses. This may have led to overestimations of the sensitivity of the tests.


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EBUS-TBNA and EUS-(B)-FNA combination versus either technique alone

To date, no RCTs have been performed comparing the EBUS plus EUS-(B) combination versus either EBUS-TBNA or EUS-(B)-FNA alone.


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EBUS-TBNA and EUS-(B)-FNA combination studies

We found 11 studies that assessed the accuracy of systematically performing both EBUS and EUS for mediastinal staging in (suspected) lung cancer patients ([Table 2]) [18] [31] [32] [33] [34] [35] [36] [37] [39] [40] [41]. In the prospective comparative study by Wallace et al. [31], TBNA, EBUS-TBNA, and EUS-FNA for mediastinal staging of lung cancer were performed in 138 patients against a reference standard of surgery or clinical follow-up. The overall sensitivity of the combination of EBUS-TBNA and EUS-FNA was 93 %. This was significantly higher than the sensitivities of EBUS-TBNA (69 %), EUS-FNA (69 %), and conventional TBNA (36 %) alone. Vilmann et al. [32] found that the accuracy of EUS-FNA and EBUS-TBNA in combination for the diagnosis of mediastinal cancer was 100 % in 28 patients, against a reference standard of surgery or clinical follow-up. 

Table 2

Studies that systematically assessed the accuracy of endobronchial ultrasound (EBUS) and endoscopic (esophageal) ultrasound (EUS) for mediastinal staging in patients with (suspected) lung cancer.

Author

Reference standard

Test order

Patients, n

Prevalence N2 /N3, %

EBUS

EUS

EBUS + EUS (95 %CI)

Sensitivity (95 %CI)

NPV (95 %CI)

Sensitivity (95 %CI)

NPV (95 %CI)

Sensitivity (95 %CI)

NPV (95 %CI)

Vilmann

2005 [32]

  • Surgery:

    • Pulmonary resection with lymph node exploration

  • Clinical follow-up

EUS – EBUS

28

71 %

0.85 (0.62 – 0.97)

0.72 (0.39 – 0.94)

0.80 (0.56 – 0.94)

0.67 (0.35 – 0.90)

1.00 (0.83 – 1.00)

1.00 (0.63 – 1.00)

Wallace

2008 [31]

  • Surgery:

    • Pulmonary resection with mediastinal exploration

    • Mediastinoscopy

    • Thoracoscopy

  • Clinical follow-up

EBUS – EUS

138

30 %

0.69 (0.53 – 0.82)

0.88 (0.80 – 0.93)

0.69 (0.53 – 0.82)

0.88 (0.80 – 0.93)

0.93 (0.81 – 0.99)

0.97 (0.91 – 0.99)

Annema

2010 [18]

  • Surgery:

    • Pulmonary resection with node dissection

EUS – EBUS

123

54 %

 – 

 – 

 – 

 – 

0.85 (0.74 – 0.92)

0.85 (0.74 – 0.93)

Herth

2010 [34]

  • Surgery:

    • Thoracoscopy

    • Pulmonary resection with node dissection

  • Clinical follow-up

EBUS – EUS-B

139

52 %

0.92 (0.83 – 0.97)

0.92 (0.83 – 0.97)

0.89 (0.79 – 0.95)

0.89 (0.80 – 0.95)

0.96 (0.88 – 0.99)

0.96 (0.88 – 0.99)

Hwangbo

2010 [36]

  • Surgery:

    • Pulmonary resection node dissection

EBUS – EUS-B

143

31 %

0.84 (0.71 – 0.94)

0.93 (0.87 – 0.97)

 – 

 – 

0.91 (0.79 – 0.98)

0.96 (0.90 – 0.99)

Szlubowski

2010 [41]

  • Surgery:

    • Pulmonary resection with node dissection

    • TEMLA

EUS – EBUS

120

23 %

0.46 (0.28 – 0.66)

0.86 (0.78 – 0.92)

0.50 (0.31 – 0.69)

0.87 (0.79 – 0.93)

0.68 (0.48 – 0.84)

0.91 (0.83 – 0.96)

Ohnishi

2011 [33]

  • Surgery:

    • Pulmonary resection with nodal exploration

EBUS – EUS

110

28 %

 – 

 – 

 – 

 – 

0.84 (0.71 – 0.97)

0.94 (0.89 – 0.99)

Kang (1)

2014 [35]

  • Surgery:

    • Pulmonary resection with node dissection

    • Video-assisted thoracic surgery

EBUS – EUS-B

74

46 %

 – 

 – 

 – 

 – 

0.84 (0.66 – 0.95)

0.94 (0.87 – 0.98)

Kang (2)

2014 [35]

  • Surgery:

    • Pulmonary resection with node dissection

    • Video-assisted thoracic surgery

EUS-B – EBUS

74

34 %

0.82 (0.65 – 0.93)

0.87 (0.74 – 0.95)

 – 

 – 

0.85 (0.69 – 0.95)

0.89 (0.76 – 0.96)

Lee

2014 [39]

  • Surgery:

    • Mediastinoscopy

    • Pulmonary resection with mediastinal node dissection

EBUS – EUS-B

37

78 %

0.79 (0.60 – 0.92)

0.57 (0.29 – 0.82)

 – 

 – 

1.00 (0.88 – 1.00)

1.00 (0.63 – 1.00)

Liberman

2014 [40]

  • Surgery:

    • mediastinoscopy

    • (no pulmonary resection with nodal exploration/dissection)

EBUS – EUS

166

32 %

0.72 (0.58 – 0.83)

0.88 (0.81 – 0.93)

0.62 (0.48 – 0.75)

0.85 (0.78 – 0.91)

0.91 (0.79 – 0.97)

0.96 (0.90 – 0.99)

Oki

2014 [37]

  • Surgery:

    • Pulmonary resection with node exploration/ dissection

  • Clinical follow-up

EBUS – EUS-B

146

23 %

0.52 (0.34 – 0.69)

0.88 (0.81 – 0.93)

0.45 (0.28 – 0.64)

0.86 (0.79 – 0.92)

0.73 (0.54 – 0.87)

0.93 (0.86 – 0.97)

NPV, negative predictive value; 95 %CI, 95 % confidence interval; EUS-B, endoscopic (esophageal) ultrasound using the EBUS scope; TEMLA, transcervical extended bilateral mediastinal lymph adenectomy

The diagnostic value of the combined endosonography approach has recently been compared with that of CT-PET for mediastinal nodal staging of lung cancer [33]. Overall, 120 consecutive patients with suspected resectable lung cancer on CT findings (with and without enlarged mediastinal lymph nodes) underwent CT-PET and combined EUS-FNA plus EBUS-TBNA. A final pathological N stage was established in 110 patients. The accuracy of the combination of EUS-FNA plus EBUS-TBNA was significantly higher than that of CT-PET (90.0 % vs. 73.6 %).

Herth et al. [34] analyzed 139 patients who underwent combined EBUS and EUS-B endosonographic staging. The reference standard was surgical confirmation or clinical follow-up. Sensitivity was 89 % for EUS-FNA and 92 % for EBUS-TBNA. The combined approach had a sensitivity of 96 % and an NPV of 96 %.

In a recent RCT [35], 160 patients were randomized to either EBUS-TBNA followed by EUS-B-FNA (group A) or to receive EUS-B-FNA followed by EBUS-TBNA (group B). In both arms, the second procedure was performed on mediastinal nodes inaccessible or difficult to access by the first procedure. No significant differences in final accuracy emerged between groups A and B. However, while in group A, adding EUS-FNA to EBUS-TBNA did not significantly increase the accuracy or sensitivity, in group B, adding EBUS-TBNA to EUS-FNA did significantly increase the accuracy and sensitivity.

Hwangbo et al. [36] evaluated the role of EUS-B-FNA for mediastinal lymph nodes that were inaccessible or difficult to access by EBUS-TBNA in 143 patients, with a reference standard of surgical confirmation. The sensitivity, NPV, and diagnostic accuracy of EBUS-TBNA alone for the detection of mediastinal metastasis were 84.4 %, 93.3 %, and 95.1 %, respectively. The corresponding values for the combination of EBUS-TBNA plus EUS-B-FNA increased to 91.1 %, 96.1 %, and 97.2 %, respectively. The proportion of mediastinal nodal stations accessible by EBUS-TBNA was 78.6 %, and the proportion increased to 84.8 % by combining EUS-B-FNA with EBUS-TBNA (P = 0.015). EUS-B-FNA identified mediastinal metastasis in 3 additional patients.

In a recent prospective NSCLC staging trial in 146 patients, by Oki et al., EBUS was routinely followed by EUS-B. The prevalence of mediastinal nodal metastases was 23 %. The sensitivities of EBUS, EUS-B, and the combination were 52 %, 45 %, and 73 %, respectively, with NPVs of 88 %, 86 %, and 93 %, when using a surgical procedure (or clinical follow-up in a minority of patients) as the reference standard [37]. The subcentimeter size of the lymph nodes in combination with the low prevalence of malignancy might account for the low sensitivity of EBUS. Often small lymph nodes, especially in the left paratracheal station 4 L, are more easily aspirated from the esophagus. In coughing patients, getting a good sample out of these small lymph nodes with EBUS can be troublesome. In this study, patients were turned on their left side for EUS-B; it is questionable whether this is needed as EUS-B is mostly performed with patients in supine position [38].

Lee et al. [39] retrospectively analyzed 37 cases in which EUS-B was performed in addition to EBUS when nodes were inaccessible by EBUS or when tissue sampling by EBUS alone was unsatisfactory. A reference standard of mediastinoscopy or mediastinal lymph node dissection was used. The sensitivity of EBUS compared with the combination was 79 % vs. 100 % (P = 0.008), and in 6 patients (13 %) their disease was upstaged based on EUS-B findings.

In a study by Liberman et al. [40], 166 patients with (suspected) NSCLC underwent EBUS, EUS, and mediastinoscopy in the same setting. The prevalence of mediastinal metastases was 32 %. Against a reference standard of mediastinoscopy, the sensitivity and NPVs were: for EBUS, 72 % and 88 %; for EUS, 62 % and 85 %; and for combined EBUS/EUS, 91 % and 96 %. Endosonography was diagnostic for N2/N3/M1 disease in 24 patients in whom mediastinoscopy findings were negative, preventing futile thoracotomy in 14 % of patients [40].

The combination of EBUS-TBNA and EUS-FNA showed a pooled sensitivity of 86 % (95 %CI 82 % – 90 %) with a 100 % specificity for mediastinal nodal staging in a meta-analysis based on 8 studies (821 patients) [25]. The sensitivity of the combined EBUS and EUS investigations appeared to be higher in the subgroup with mediastinal abnormalities, but pooled data were not provided. Although the authors concluded that “the current evidence suggests that the combined technique is more sensitive than EBUS-TBNA or EUS-FNA alone,” they did not statistically compare results from individual tests with the combined approach.

Random-effects meta-analysis was performed to evaluate the increase in sensitivity provided by the combined approach. Adding EUS-(B)-FNA to EBUS-TBNA for mediastinal nodal staging in a series of patients with established or suspected lung cancer, showed an increase in sensitivity of 13 % (95 %CI 8 % – 20 %) for the combined approach compared with EBUS-TBNA alone (9 studies; [Fig. 2 a]). Adding EBUS-TBNA to EUS-(B)-FNA showed an increase in sensitivity of 21 % (95 %CI 13 % – 30 %) for the combined approach compared with EUS-(B)-FNA alone (7 studies; [Fig. 2 b]). Assuming a prevalence of nodal metastasis of 50 %, these numbers would indicate that in 100 patients, adding EUS-(B)-FNA would avoid further surgical staging in an additional 6.5 cases not identified by initial EBUS-TBNA; conversely, adding EBUS-TBNA would avoid further surgical staging in an additional 10.5 cases not identified by initial EUS-(B)-FNA. Considering that the studies included in these meta-analyses are highly variable regarding quality and study population [25], that some studies included only patients with mediastinal lymph nodes that were not accessible by EBUS-TBNA, that a “complete” EBUS-TBNA or EUS-FNA was not always performed, that the reference standard included imperfect tests in some cases, and in the absence of randomized trials comparing complete staging in single tests with the combined approach, the results of this pooled analysis should be interpreted with caution.

Fig. 2 Endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA) combined with endoscopic (esophageal) ultrasound with real-time guided fine needle aspiration either using the conventional EUS endoscope or using the EBUS scope (that is, EUS-(B)-FNA) for mediastinal nodal staging: comparison of the sensitivity of a single test with that of the combined approach. a Increase in sensitivity of the combined approach compared with EBUS-TBNA alone. b Increase in sensitivity of the combined approach compared with EUS-(B)-FNA alone. Random-effects meta-analysis was performed to evaluate the increase in sensitivity of the combined approach versus a single test. The “Events” columns show the numbers of cases that were detected by the combined approach, but not by a single test. The “Total” columns show the total number of cases, as determined by the reference standard. The “Proportion” column shows the increase in sensitivity of the combined approach versus the single test. Fig. 2a suggests a 13 % (95 % confidence limits [CL] 8 % – 20 %) increase in sensitivity from the combined approach over EBUS-TBNA or alone. Fig. 2b suggests a 21 % (95 %CL 13 % – 30 %) increase in sensitivity from the combined approach over EUS-(B)-FNA alone. Study quality, especially the quality of the reference standard, and the patient populations of included studies vary considerably so the risk of bias may be substantial.

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Safety

Complications of endosonographic procedures are rare. In a 2014 systematic review on adverse events in 16 181 patients undergoing endosonography for mediastinal, hilar, or primary lung tumor analysis, 23 serious adverse events (0.14 %) were reported: 0.3 % for EUS and 0.05 % for EBUS [42]. A systematic review of 13 studies (1536 patients) that reported on the safety of EBUS-TBNA in lung cancer was published in 2009 [43]; no complications were reported in 11 studies, while one study reported no “major complication,” and one study reported rare side-effects, notably cough. In a systematic review [25] of combined EUS-FNA and EUS-TBNA for the staging of mediastinal lymph nodes in lung cancer, severe complications were reported in 2 patients (0.3 %), consisting of pneumothorax and lymph node abscess [25]. A nationwide survey, by the Japan Society for Respiratory Endoscopy, of complications associated with EBUS-TBNA [44] found that, among 7345 procedures performed in 210 facilities, 90 complications occurred (complication rate 1.23 %, 95 %CI 0.97 % – 1.48 %), resulting in one patient death (mortality rate 0.01 %). The most frequent complications were hemorrhage (55 %) and infection (16 %). The reported death was related to cerebral infarction during withdrawal of antiplatelet drugs (replaced by heparin).


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Cost – effectiveness

In the only study that measured actual costs and took health care utilization into account [18], endosonography followed by surgical staging in those with negative test findings proved to be cost-effective over surgical staging alone [18] [24]. The cost – effectiveness gain at 6 months was mainly related to a statistically significant reduction of the post-staging utility with the surgical compared with the combined endoscopic approach, and with a reduction in the overall costs associated with the nonsurgical staging procedure. The higher costs in the “surgical” arm were due to the higher number of thoracotomies that had to be performed in this arm, and not due to mediastinoscopy itself.

In a simulated model of evaluation of lung cancer patients with different prevalences of mediastinal disease, a cost-minimization analysis showed that the combination of EBUS-FNA/EUS-FNA would appear as the most cost-effective approach, compared with bronchoscopy and mediastinoscopy, when the expected prevalence of lymph node metastasis is higher than 32.9 %. This occurs in patients with a finding of abnormal mediastinum at radiological staging [45]. In that model, EUS-FNA alone appeared to be the most cost-effective approach if the prevalence of lymph node metastasis is lower than mentioned above as well as in patients without abnormal lymph nodes on CT [45].

2. For mediastinal nodal staging in patients with suspected or proven non-small-cell peripheral lung cancer without mediastinal involvement at CT or CT-PET , we suggest that EBUS-TBNA and/or EUS-(B)-FNA should be performed before therapy, provided that one or more of the following conditions is present: (i) enlarged or fluorodeoxyglucose (FDG)-PET-avid ipsilateral hilar nodes; (ii) primary tumor without FDG uptake; (iii) tumor size ≥ 3 cm; ([Fig. 3a – c]) (Recommendation grade C).
If endosonography does not show malignant nodal involvement, we suggest that mediastinoscopy is considered, especially in suspected N1 disease (Recommendation grade C).
If PET is not available and CT does not reveal enlarged hilar or mediastinal lymph nodes, we suggest performance of EBUS-TBNA and/or EUS-FNA and/or surgical staging (Recommendation grade C).

3. In patients with suspected or proven < 3 cm peripheral NSCLC with normal mediastinal and hilar nodes at CT and/or PET, we suggest initiation of therapy without further mediastinal staging (Recommendation grade C).

Fig. 3 Schematic representation of peripheral lung cancer with normal mediastinum and with: a ipsilateral hilar node, and tumor < 3 cm; b no fluorodeoxyglucose (FDG) uptake in the tumor, and tumor < 3 cm; c with or without FDG uptake in the tumor, and tumor ≥ 3 cm.

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Background

Patients with small mediastinal lymph nodes without increased FDG uptake present a 6 % – 30 % risk of having mediastinal metastases in the following cases: (i) enlarged or FDG-avid hilar lymph nodes, or small and FDG-avid hilar lymph nodes; (ii) any FDG-cold lung tumor (i. e., pulmonary carcinoid, pulmonary adenocarcinoma in situ; (iii) lung tumor > 3 cm (mainly in the case of adenocarcinoma with high FDG uptake) without any lymph node involvement at CT or PET [9] [10] [11] [21] [46]. Mediastinal staging in those cases should be performed for accurate mediastinal nodal assessment in order to allocate patients appropriately for curative-intent therapy. Mediastinal lymph node metastases are present in less than 6 % of patients with small peripheral tumors that present with neither enlarged nor FDG-avid hilar or mediastinal lymph nodes [27].


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Review of the studies

Data on the accuracy of endosonography for staging in patients without mediastinal involvement on PET and/or CT are scarce. In two abovementioned meta-analyses [29] [30], the sensitivity for mediastinal nodal staging in the subgroup of patients regardless of, or without suspicious lymph nodes at CT or PET was 76 % (95 %CI 65 % – 85 %) for EBUS-TBNA (3 studies, 263 patients) and 58 % (95 %CI 39 % – 75 %) for EUS-FNA (4 studies, 175 patients). Assuming a prevalence of 20 %, these numbers would indicate that 100 patients need to undergo endosonography to detect, respectively, 15.2 and 11.6 cases of mediastinal involvement in whom further surgical staging can be prevented. However, given the wide confidence intervals, especially for EUS, and the varying prevalence, these numbers should be interpreted with caution.

Dooms et al. [47] [48] prospectively evaluated 100 consecutive patients with suspected resectable clinical N1 (cN1) disease, and a normal mediastinum, based on CT-PET with EBUS. The primary outcome was the sensitivity of endosonography to detect N2 disease, against a reference standard of histopathology. A total of 24 patients were diagnosed with N2 disease. The sensitivity from endosonography alone was 38 % and this was increased to 73 % by adding mediastinoscopy. So, in this population, 10 underwent mediastinoscopy to detect a single case with N2 disease missed by endosonography. In this study, EBUS was performed in all patients, while EUS was only added in patients with inaccessible or difficult-to-reach lymph nodes. However, in 8 of the 14 false-negative cases where no EUS was performed, the affected nodes were well within the reach of EUS-(B), being stations 4 L, 7, and 8. Should EUS-(B) have been routinely performed, the sensitivity of endosonography could have been above 70 % [38] [47].

According to a post hoc subgroup analysis of the ASTER trial [27], the prevalence of mediastinal metastases in patients without a suspicious mediastinum at CT-PET imaging was 26 % and the sensitivity of combined EBUS and EUS staging was 71 %, although confidence intervals were wide (36 % – 92 %) because of the small number of patients in this subgroup. In this subgroup of patients, the post-test probability for lymph node metastasis after a negative endosonography was 9 % (95 %CI 4 % – 24 %). After the addition of mediastinoscopy, the post-test probability remained unaffected [27]. In the surgical staging arm of the study, in patients with a non-suspicious mediastinum, the prevalence of mediastinal metastases was 17 % and the sensitivity of surgical staging was 60 % (23 % – 88 %), with a post-test probability of 8 % (95 %CI 3 % – 19 %) after a negative test.

Wallace et al. [31] described a subgroup of 60 patients with negative mediastinal findings at CT and PET who underwent both EBUS and EUS. The sensitivity and NPV were 17 % (95 %CI 2 % – 48 %) and 83 % for TBNA, 50 % (95 %CI 21 % – 79 %) and 89 % for EBUS-TBNA, 67 % (95 %CI 35 % – 90 %) and 92 % for EUS-FNA, and 75 % (95 %CI 43 % – 95 %) and 94 % for combined EBUS – EUS. 

We found only one prospective study [41] that aimed to assess the diagnostic yield of the combined endosonographic approach in patients with NSCLC and a normal mediastinum on CT alone (stage lA – llB). A total of 120 patients underwent the combined approach with both EBUS-TBNA and EUS-FNA followed by transcervical extended bilateral mediastinal lymphadenectomy (TEMLA) and, if negative, pulmonary resection with dissection of the mediastinum as a confirmatory test. The overall sensitivity of the combined approach was 68 %, the NPV was 91 %, and the positive predictive value (PPV) was 91 %, at a prevalence of N2/N3 disease of 22 %. In this study, 120 patients needed to undergo endosonography to detect 19 cases (16 %) in which further surgical staging could be prevented. Additional surgical staging in the remaining 101 patients identified another 9 cases. The overall sensitivity of the combined technique was significantly higher than the sensitivity with EBUS alone (46 %, 95 %CI 28 % – 65 %) and also higher and close to the level of significance when compared with the sensitivity of EUS alone (50 %, 95 %CI 31 % – 69 %).

4. For mediastinal staging in patients with centrally located suspected or proven NSCLC without mediastinal or hilar involvement at CT and/or CT-PET, we suggest performance of EBUS-TBNA, with or without EUS-(B)-FNA, in preference to surgical staging ([Fig. 4]) (Recommendation grade D).
If endosonography does not show malignant nodal involvement, mediastinoscopy may be considered (Recommendation grade D).

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Fig. 4 Schematic representation of centrally located lung cancer with normal mediastinum.

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Background

According to the ESTS guidelines, for centrally located lung tumors exploration of mediastinal lymph nodes is indicated [21]. The false-negative rates of CT and PET imaging for mediastinal staging are high for patients with a centrally located lung tumor (20 % – 25 % and 24 % – 83 %, respectively) [13] [49].


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Review of the studies

There are no diagnostic accuracy studies specifically focusing on the EBUS and EUS-(B) combination for patients with a centrally located lung tumor and a normal mediastinum/hilum. Therefore recommendations are based on the evidence level of expert opinion.

The combination of EBUS-TBNA and EUS-(B)-FNA has been shown to have a high sensitivity and high NPV in the staging of the mediastinal nodes. There are few studies in the literature about the role of endosonography for mediastinal staging of patients with a centrally located tumor [50] [51]. Moreover, it must be noted that there is no agreement in the studies concerning the definition of centrally located lung tumors. In a retrospective cohort of 16 patients who had EUS-FNA of lung mass lesions adjacent to or abutting the esophagus, 10 patients had invasion of the mediastinum by the tumor as shown by EUS, defined as loss of interface between the tumor and the mediastinum, with an irregular border. Out of those 10 patients, 6 had mediastinal lymph nodes. EUS-FNA of the lymph nodes in 3 of those 6 patients did not yield a preliminary diagnosis after 3 needle passes. It was technically difficult to assess the mediastinal lymph nodes in the other 3 patients, because the lung mass was in close proximity and precluded lymph node access [50]. In another study, out of 17 patients undergoing EUS-FNA of a centrally located primary lung neoplasm, EUS identified metastatic lymph node involvement in 3 [51]. The accuracy of EBUS-only for mediastinal staging has already been addressed above [29].

5. For mediastinal nodal restaging following neoadjuvant therapy, EBUS-TBNA and/or EUS-(B)-FNA is suggested for detection of persistent nodal disease, but, if this is negative, subsequent surgical staging is indicated (Recommendation grade C).


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Background

According to current guidelines, stage III NSCLC (N2 /N3), that is, with metastatic involvement of the ipsilateral (stage IIIA-N2) or contralateral (stage IIIB-N3) mediastinal lymph nodes, should be treated with chemoradiation therapy [22] [52]. The role of surgery in stage III (N2/N3) disease is under debate. It has been shown that patients whose disease is downstaged to N0 with chemoradiation therapy, and who subsequently undergo complete surgical resection of the lung tumor, have improved survival in comparison to those patients who undergo surgery with persistent nodal disease [53] [54]. Therefore, if surgery is being considered following chemoradiation therapy, adequate nodal restaging is essential to identify those patients whose disease has downstaged to N0.


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Review of the studies

EUS studies

In 2003, Annema et al. published the first case study with EUS-FNA for mediastinal restaging in 19 NSCLC patients with N2 disease who had been treated with induction chemotherapy. In the absence of regional lymph node metastasis (N0) at EUS-FNA, surgical resection of the tumor with lymph node sampling or dissection was performed. A sensitivity, NPV, and diagnostic accuracy of 75 %, 67 %, and 83 %, respectively, were found [55].

In a retrospective study that included 14 patients with NSCLC and biopsy-proven N2 disease, restaging by EUS-FNA following chemoradiation therapy had a 86 % diagnostic accuracy for predicting mediastinal response [56].

In a prospective study in 28 patients, Stigt et al. re-evaluated the mediastinum after induction therapy, and found a NPV of 91.6 % and accuracy of 92.3 % [57].

Von Bartheld et al. retrospectively analyzed 58 consecutive patients with tissue-proven stage IIIA-N2 or IIIB-N3 NSCLC who underwent EUS-FNA for mediastinal restaging after neoadjuvant chemoradiation therapy. Sensitivity, NPV, false-negative rate, and accuracy of EUS-FNA for mediastinal restaging were 44 %, 42 %, 58 %, and 60 %, respectively. A large percentage (22 %) of nodal metastases found at surgery were in locations beyond the reach of EUS [58].

In a recent retrospective restaging study, EUS and/or EBUS was performed in 88 patients followed by TEMLA if results were negative (n = 78). Significant differences were found between EBUS or EUS and TEMLA for sensitivity (64.3 % and 100 %; P < 0.01) and NPV (82.1 % and 100 %; P < 0.01), in favor of TEMLA [59].


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EBUS studies

Herth et al. retrospectively investigated EBUS-TBNA for restaging the mediastinum following induction chemotherapy in 124 patients with NSCLC. Overall sensitivity, specificity, PPV, NPV, and diagnostic accuracy of EBUS-TBNA for mediastinal restaging after induction chemotherapy were 76 %, 100 %, 100 %, 20 %, and 77 %, respectively [60].

Szlubowski et al. retrospectively analyzed a group of 61 consecutive NSCLC patients with pathologically confirmed N2 disease who underwent neoadjuvant chemotherapy, and in whom EBUS-TBNA was performed for restaging. The sensitivity and negative NPV of the restaging EBUS-TBNA were 67 % and 78 %, respectively [61]. Recently, Szlubowski et al. prospectively assessed the diagnostic utility of combined EBUS-TBNA and EUS-B-FNA for NSCLC restaging after induction therapy in 106 patients with pathologically proven N2 disease. The prevalence of persistent mediastinal lymph node metastases was 51.9 % and the sensitivity, specificity, total accuracy, PPV, and NPV values of the combined approach were 67.3 %, 96.0 %, 81.0 %, 95.0 %, and 73.0 %, respectively. The overall accuracy of the combined approach was higher as compared with EBUS-TBNA and EUS-FNA alone [62].

6. A complete assessment of mediastinal and hilar nodal stations, and sampling of at least three different mediastinal nodal stations (4 R, 4 L, 7) ([Fig. 1], [Fig. 5]) is suggested in patients with NSCLC and an abnormal mediastinum by CT or CT-PET (Recommendation grade D).

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Fig. 5 Schematic representation of sampling of at least three different mediastinal nodal stations.

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Background

For surgical nodal staging by mediastinoscopy, clear recommendations have been made regarding the number and nodes to be sampled [21] [22]. For endosonography, there is no agreement about how many and which lymph node stations should be sampled and which level of thoroughness is necessary for different situations. Some advise a thorough evaluation of all lymph nodes detectable by EBUS and EUS followed by sampling. In many centers, however, the so-called “hit and run” approach is followed, where only the lymph nodes that are suspicious at CT-PET imaging are sampled.

In the recent Guidelines from the American College of Chest Physicians (ACCP) [22], a classification of levels of thoroughness has been developed and could serve as a guide. Four approaches were proposed: A, complete sampling of each node in each major mediastinal node station (2 R, 4 R, 2 L, 4 L, 7, and possibly 5 or 6); B, systematic sampling of each node station; C, selective sampling of suspicious nodes only; D, very limited or no sampling, with only visual assessment.

In line with the ESTS guidelines [21], we recommend that at least three stations should be assessed (subcarinal, left paratracheal, and right paratracheal) and biopsy samples should be taken if possible with EBUS, EUS, or mediastinoscopy. Furthermore, all other abnormal lymph nodes, identified by size or FDG avidity, should be sampled. This “complete” mediastinal staging is based on the concept that identification of one malignant lymph node does not mean that mediastinal staging was optimal.

7. For diagnostic purposes, in patients with a centrally located lung tumor that is not visible at conventional bronchoscopy, endosonography is suggested, provided the tumor is located immediately adjacent to the larger airways (EBUS) or esophagus (EUS-(B)) (Recommendation grade D).

To date, there are limited studies regarding the role of EUS-FNA and EBUS-TBNA in the diagnosis of lung parenchymal masses. A recent retrospective study [63] assessed the diagnostic yield and safety of EUS-FNA of central mediastinal lung masses. In 11 out of 73 patients, the lung mass could not be visualized by EUS. The sensitivity of EUS was 96.7 % when only the visualized masses were considered, but this value dropped to 80.8 % when the 11 nonvisualized masses were also taken into account. Annema et al. [64] conducted a prospective study with 32 patients to assess the feasibility and diagnostic yield of EUS-FNA for the diagnosis of centrally located lung tumors following a nondiagnostic bronchoscopy. EUS-FNA provided a diagnosis of malignancy in 97 % of patients. In 39 % of the patients, EUS-FNA not only established the diagnosis of lung cancer, but also staged patients as having T4 disease, based on tumor invasion; however, the latter was not verified surgically. None of the included patients had mediastinal lymph node involvement at CT scan [64]. Varadarajulu et al. [50] conducted a retrospective study including 18 patients who had undergone EUS-FNA of a lung mass abutting the esophageal wall. A diagnosis was obtained in all patients. Hernandez et al. [51] retrospectively described their experience with EUS-FNA of centrally located primary lung cancers; 17 patients had FNA of both the lung mass and the mediastinal lymph nodes, and all procedures provided an accurate diagnosis of the primary lung lesion.

In a retrospective noncomparative study including 60 patients with a central parenchymal lung lesion suspected to be lung cancer (82 % with a prior nondiagnostic flexible bronchoscopy), Tournoy et al. [65] demonstrated that the sensitivity of EBUS-TBNA was 82 % with a NPV of 23 %. An exploratory analysis showed that the sensitivity for small versus large lesions, when a short-axis cutoff was arbitrarily set at 25 mm, was 78 % (95 %CI 57 % – 91 %) vs. 86 % (95 %CI 68 % – 96 %), respectively (P = 0.50). Verma et al. [15] also recently demonstrated in 37 patients that EBUS-TBNA is an effective way (overall sensitivity 91.4 %) to diagnose parenchymal lesions located centrally close to the airways.

8. In patients with a left adrenal gland suspected for distant metastasis we suggest performance of EUS-FNA (Recommendation grade C), while the use of EUS-B with a transgastric approach is at present experimental (Recommendation grade D).


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Background

The adrenal glands are a predilection site for lung cancer metastases. Distant metastases have significant impact on prognosis and treatment. Adrenal metastases originating from NSCLC have been found in approximately 10 % – 59 % of patients in autopsy series [66].

FDG-PET-CT has a high accuracy (sensitivity of 94 % and specificity of 85 %) for adrenal metastases in patients with lung cancer [67]. However, adrenal glands that are suspicious at FDG-PET-CT can be false-positive [68] and therefore tissue verification is indicated to either confirm or rule out metastatic spread in order to prevent PET/CT-based upstaging in patients.

Traditionally, adrenal masses have been sampled by percutaneous biopsy. A small study involving only 15 patients reported sensitivity and NPV for adrenal biopsy of 73 % and 60 %, respectively [69]. A study involving 79 patients reported an overall complication rate for percutaneous adrenal biopsies of 8.4 % [70], including hemorrhage, pneumothorax, pancreatitis, adrenal abscesses, bacteremia, and needle-tract metastases. Transgastric EUS-guided FNA can be performed during the same session as a mediastinal staging procedure, using the same endoscope.


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Review of the studies

In 1996, Chang reported the first application of EUS and EUS-FNA for left adrenal gland analysis and found that the left adrenal gland was visualized in 30 out of 31 patients (97 %) [71].

In 31 patients with suspected thoracic or gastrointestinal malignancies and enlarged left adrenal gland on abdominal imaging (including 15 patients with lung cancer), Eloubeidi et al. reported that EUS-FNA obtained adequate tissue from the left adrenal gland in all patients [72].

In a mixed series of 119 patients with gastrointestinal or pulmonary disease, who underwent EUS with or without FNA, the left adrenal gland was routinely examined. The overall prevalence of a left adrenal mass was 4/119 (3.4 %), all detected in the cohort of patients (n = 12) with lung cancer [73]. In a retrospective analysis of 40 patients, with established or suspected lung cancer and an enlarged left adrenal gland shown at EUS, the diagnostic yield of EUS-FNA for detecting left adrenal metastases was 95 % [74].

In a retrospective analysis by Schuurbiers et al. of 85 patients with (suspected) lung cancer and a left adrenal gland suspicious for metastasis identified by CT and/or FDG-PET, EUS-FNA demonstrated left adrenal metastases in 62 % and benign adrenal tissue in 29 %. Sensitivity and NPV for EUS-FNA of the left adrenal gland were at least 86 % (95 %CI 74 – 93 %) and 70 % (95 %CI 50 – 85 %), respectively. No complications occurred [75].

Eloubeidi et al. evaluated 59 patients with enlarged adrenal gland(s) on abdominal CT, magnetic resonance imaging (MRI), and/or PET, and known or suspected malignancy. All patients underwent EUS-guided FNA (54 left adrenal gland and 5 right adrenal gland), and adrenal tissue adequate for interpretation was obtained in all patients. On multivariable analysis, altered adrenal gland shape (loss of seagull configuration) was a significant predictor of malignancy [76].

Most literature about EUS of the adrenal gland concerns the left adrenal gland. However there are some reports about transduodenal EUS-guided FNA of the right adrenal gland. It seems feasible and safe in experienced hands [77] [78] [79].

Recently, Uemura and colleagues retrospectively analyzed a consecutive series of 150 patients with potentially resectable lung cancer who were undergoing EUS/EUS-FNA for mediastinal staging of lung cancer. Routinely, both the left and right adrenal glands were assessed. The left adrenal gland was visualized in all patients (100 %) and the right adrenal gland in 87.3 % of patients [79]. Transgastric analysis and FNA of the left adrenal gland using an EBUS scope has been described [77], but its feasibility and safety are under investigation.

Complications of EUS-guided FNA of adrenal glands are rare; an adrenal hemorrhage has been described [80]. However, it should be emphasized, that in the case of signs of a pheochromocytoma, endocrinologic evaluation must be done prior to endosonography.

9. For optimal endosonographic staging of lung cancer, we suggest that individual endoscopists should be trained in both EBUS and EUS-B, in order to perform complete endoscopic staging in one session (Recommendation grade D).


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Background

The quality and safety of endosonography is very dependent on the skills and experience of the operator. Diagnostic yield improves with practice [81], and the number of complications is also associated with operator experience [82]. Despite this, there is a paucity of evidence-based structured training programs, and the important decision about when a trainee is considered competent is often based on an arbitrary number of performed procedures or on subjective impressions.

As the combined staging by EBUS and EUS is superior to staging by a single technique [25], it seems logical that the skills should be present in a single operator [83]. For practical and economic reasons, the majority of procedures will be performed with EBUS scopes for both the endobronchial and esophageal route.

10. We suggest that new trainees in endosonography should follow a structured training curriculum consisting of simulation-based training followed by supervised practice on patients (Recommendation grade D).


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Background

Increased focus on patient safety has put pressure on the traditional apprenticeship model where trainees under supervision practice on patients. Simulation-based training, on phantoms and virtual reality devices, has been suggested for helping trainees surmount the initial, steep part of the learning curve.


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Review of the studies

A systematic review and meta-analysis regarding technology-enhanced simulation, based on 609 papers, found “large effects for outcomes of knowledge, skills, and behaviors and moderate effects for patient-related outcomes” [84]. There are two virtual reality simulators commercially available for EBUS: the GI Bronch Mentor (Simbionix, Cleveland, Ohio, USA) and the AccuTouch Flexible Bronchoscopy Simulator (CAE Healthcare, Montreal, Quebec, Canada). Both simulators can discriminate between novices and experienced operators (indicating construct validity) [85] [86], but there are no published studies exploring the effect of EBUS simulator training on patient care. No software exists for mediastinal sampling using EUS, but EUS-FNA as well as EBUS-TBNA can be practiced on rubber models, animal organs, or live anesthetized animals. A study regarding EBUS-TBNA training found both computer simulation and wet lab simulation to be effective and complementary [87].

However, despite the positive effects of simulation-based training, it is important to remember that no existing simulators are 100 % realistic and not all aspects of a procedure can be practiced. Supervised performance during initial patient encounters is essential, even after a thorough simulation-based training program – self-learning of endosonography should be discouraged [88].

11. We suggest that competency in EBUS-TBNA and EUS-(B)-FNA for staging lung cancer be assessed using available validated assessment tools (Recommendation grade D).


#

Background

Thorough knowledge of (endosonographic) anatomy and its relation to the TNM lung cancer staging system is crucial for the performance of an endosonographic evaluation. Upstaging could prevent the patient from receiving potentially curative therapy, and downstaging may cause the patient to undergo unnecessary surgery and treatments without therapeutic benefit [89]. To avoid this, basic competency must be ensured before trainees are allowed to perform procedures independently.


#

Review of the studies

Early guidelines for gastrointestinal EUS recommend a minimum of 150 total supervised procedures [90], but a more recent study on learning curves showed “substantial variability in achieving competency and a consistent need for more supervision than current recommendations” [91]. It is generally agreed that sampling in the mediastinum is technically easier than in other locations [92] and a study showed that chest physicians achieved satisfactory results after participating in an EUS implementation program for staging lung cancer patients [93]. The only study exploring learning curves for EUS-FNA for lung cancer staging found that acquisition of skills varied between individuals and that 20 procedures were not enough to ensure basic competency [94].

Early guidelines on training requirements for EBUS from the American Thoracic Society/European Respiratory Society and the ACCP respectively recommend minimum numbers of 40 and 50 procedures for initial acquisition of competence [95] [96]. These numbers are based on expert opinions, are arbitrary, and are debated [89] [97]. Studies on EBUS learning curves have shown that performance of 50 procedures does not ensure basic competency [60] [95], and the latest Guidelines from the British Thoracic Society recognise that “Individuals have different learning curves and hence focus should be towards monitoring an individual’s performance and outcomes” [98]. Specific tools for assessment of performance in endosonography [99] [100] could be used for monitoring trainees’ progression, and all programs should continuously monitor their outcomes.

These guidelines from ESGE, ERS, and ESTS represent a consensus of best practice based on the available evidence at the time of preparation. They may not apply in all situations and should be interpreted in the light of specific clinical situations and resource availability. Further controlled clinical studies may be needed to clarify aspects of the statements, and revision may be necessary as new data appear. Clinical consideration may justify a course of action at variance to these recommendations. ESGE guidelines are intended to be an educational device to provide information that may assist endoscopists in providing care to patients. They are not rules and should not be construed as establishing a legal standard of care or as encouraging, advocating, requiring, or discouraging any particular treatment.


#
#

Appendices

Appendix e1

Key questions, level of evidence, and conclusions supporting the Guideline recommendations

Topic

Key questions

Summary of available evidence

Conclusions

Working group recommendation

1 Peripherally located lung cancer with abnormal mediastinum
(enlarged or FDG-PET-avid nodes)

  • What is the sensitivity of EBUS and EUS in combination for mediastinal nodal staging in patients with suspected or proven peripherally located lung cancer and abnormal mediastinum at imaging?

  • Does the combination of EBUS and EUS result in a significant improvement of the sensitivity regarding mediastinal nodal staging in comparison with each of the techniques alone?

  • What is the next investigation when EBUS and EUS show no nodal metastases?

Data were extrapolated from the cited meta-analyses and randomized clinical trials. Other prospective nonrandomized clinical trials were also considered.
No meta-analyses or randomized clinical trials assessed the role of the combined technique only in patients with abnormal mediastinum at imaging.

  • The pooled sensitivity for mediastinal nodal staging for EBUS and EUS performed in combination was 86 % (95 %CI 82 % – 90 %) (evidence level 1 – ).

  • The pooled sensitivities of EBUS or EUS alone were 94 % (95 %CI 93 % – 96 %) and 90 % (95 %CI 84 % – 94 %), respectively (evidence level 1 – ).

  • The sensitivity of EBUS + EUS followed by surgical staging vs. surgical staging: 94 % (95 %CI 85 % – 98 %) vs. 79 % (95 %CI 66 % – 88 %) (evidence level 1 + + ).

A patient with a negative result from complete endosonography should be considered for progression to surgical staging for the confirmation of that result, in order to avoid an unnecessary thoracotomy (evidence level 2 + ).

  • The pooled increase in sensitivity of adding EUS to EBUS is 13 % (95 %CI 8 % – 20 %), and the pooled increase in sensitivity of adding EBUS to EUS is 21 % (95 %CI 13 % – 30 %) (evidence level 1 – ).

According to a recent RCT, the EBUS procedure should be performed first. Starting with EUS-FNA could be a reasonable alternative, especially in patients with low cardiorespiratory function (evidence level 1 + ).

[18] [25] [27] [28] [31] [32] [33] [34] [35] [36] [37] [38]

For mediastinal nodal staging in patients with suspected or proven NSCLC with abnormal mediastinal and/or hilar nodes at CT and/or PET, endosonography is recommended over surgical staging as the initial procedure (Recommendation grade A).

The combination of EBUS-TBNA and EUS-(B)-FNA is preferred over either test alone (Recommendation grade C).
If the combination of EBUS and EUS-(B) is not available, we suggest that EBUS alone is acceptable (Recommendation grade C).

Subsequent surgical staging is recommended, when endosonography does not show malignant nodal involvement (Recommendation grade B).

2 and 3 Peripheral lung cancer without abnormal mediastinal lymph nodes
(no enlarged or FDG-PET-avid nodes)

  • What is the sensitivity of EBUS and EUS in combination for mediastinal staging in patients with suspected or proven peripheral lung cancer and normal mediastinum at radiological imaging?

  • Does the combination of EBUS and EUS result in significant improvement of sensitivity regarding mediastinal nodal staging in comparison with each of the techniques alone?

  • What is the next investigation when EBUS and EUS show negative results?

Data were extrapolated from the cited meta-analyses and randomized clinical trials. Other prospective nonrandomized clinical trials were also considered.
No meta-analyses or randomized clinical trials assessed the role of the combined technique only in patients with normal mediastinum at imaging. The role of routine surgical staging after a negative endosonography should be further investigated.

  • The sensitivity for mediastinal staging of EBUS, only followed by EUS-B in patients with inaccessible or difficult-to-reach nodes, was 38 % in one study, which increased to 73 % by adding mediastinoscopy (evidence level 2 + ).

  • The sensitivity for mediastinal staging for EBUS and EUS performed in combination with two scopes in this group of patients was 68 % in one study (evidence level 2 + ).

  • The sensitivity for mediastinal staging of EBUS and EUS performed in combination with two scopes was 71 % and 75 % in two small subgroup analyses of larger trials (evidence level 2 – ).

  • The pooled sensitivities of EBUS or EUS alone were 76 % (95 %CI 65 % – 85 %) and 58 % (95 %CI 39 % – 75 %), respectively (evidence level 1 – ).

    • No studies investigated the role of combined EBUS and EUS with a single scope in patients with normal mediastinal lymph nodes (evidence level 4).

    • For patients with negative results from complete endosonography, there should be multidisciplinary consideration on whether surgical staging should be undertaken for confirmation of that result, in order to avoid unnecessary thoracotomy (evidence level 2 – ).

[9] [10] [11] [21] [29] [30] [31] [46] [47] [48]

  • For mediastinal nodal staging in patients with suspected or proven non-small-cell peripheral lung cancer without mediastinal involvement at CT or CT-PET, we suggest that EBUS-TBNA and/or EUS-B-FNA should be performed before therapy, provided that one or more of the following conditions is present: (i) enlarged or FDG-PET-avid ipsilateral hilar nodes; (ii) primary tumor without FDG uptake; (iii) tumor size ≥ 3 cm ([Fig. 3a – c]) (Recommendation grade C).

  • If endosonography does not show malignant nodal involvement, we suggest that mediastinoscopy is considered especially in suspected N1 disease (Recommendation grade C).

  • If PET is not available and CT does not reveal enlarged hilar or mediastinal lymph nodes, we suggest performance of EBUS-TBNA and/or EUS-FNA and/or mediastinoscopy for further staging (Recommendation grade C).

  • In patients with suspected or proven < 3 cm peripheral non-small-cell lung cancer with normal mediastinal and hilar nodes at CT and/or PET, we suggest initiation of therapy without further mediastinal staging (Recommendation grade C).

4 and 7 Centrally located lung cancer

  • What is the value of EBUS/EUS in staging of centrally located lesions?

  • What is the value of EBUS/EUS in diagnosing centrally located lesions suspected for lung cancer?

  • No meta-analyses or randomized clinical trials assess the role of the combined technique only in patients with centrally located tumors.

  • In selected cases tumor invasion of the heart, mediastinum and the vessels can be detected (T4) by EUS/EBUS. The advantage of using both techniques is that, in selected cases, the tumor can be reached from the esophagus and/or from the trachea, depending on its location (evidence level 4).

  • The sensitivity for EBUS in diagnosing lung tumors that are invisible by conventional bronchoscopy was 82 % in one study and 91.4 % in another study, and was around 96 % for EUS (evidence level 2 – ).

[12] [13] [15] [21] [27] [29] [49] [50] [51] [63] [64] [65]

For mediastinal staging in patients with centrally located suspected or proven non-small-cell lung cancer without mediastinal or hilar involvement at CT and/or PET, we suggest performance of EBUS-TBNA with or without EUS-(B)-FNA in preference to surgical staging ([Fig. 4]) (Recommendation grade D).

If endosonography does not show malignant nodal involvement, mediastinoscopy may be considered (Recommendation grade D).

For diagnostic purposes, in patients with a centrally located lung tumor that is not visible at conventional bronchoscopy, endosonography is suggested, provided the tumor is located immediately adjacent to the larger airways (EBUS) or esophagus (EUS). (Recommendation grade D).

5 Restaging after neoadjuvant therapy

  • What is the sensitivity and NPV of endosonography (EBUS/ EUS) for mediastinal restaging after induction chemo- and/or radiotherapy in patients with NSCLC?

There are no RCTs on these topics. Few studies have been performed and most have a small sample size. The reference standard, however, is adequate in most studies.

  • Sensitivity and NPV for EUS for mediastinal restaging after induction chemo- and/or radiotherapy in patients with NSCLC range from 44 % to 75 % and from 42 % to 91.6 %, respectively, in 5 studies (evidence level 2 – ).

  • Sensitivity and NPV of EBUS for mediastinal restaging after induction chemo- and/or radiotherapy in patients with NSCLC range from 67 % to 76 % and from 20 % to 78 %, respectively, in 2 studies (evidence level 2 + ).

  • Sensitivity and NPV of combined EBUS-TBNA and EUS-B-FNA for mediastinal restaging after induction chemotherapy in patients with NSCLC were 67 % and 73 %, in one study (evidence level 2 + )

[22] [52] [53] [54] [55] [56] [57] [58] [59] [60] [61] [62]

For mediastinal nodal restaging following neoadjuvant therapy, EBUS-TBNA and/or EUS-(B)-FNA is suggested for detection of persistent nodal disease but, if negative, subsequent surgical staging is indicated (Recommendation grade C).

6 How many lymph nodes should be sampled?

  • How many lymph node stations should be sampled to consider mediastinal staging as “complete”?

For endosonography, there is no agreement about how many and which lymph node stations should be sampled and which level of thoroughness is necessary for different situations.

  • At least three stations should be sampled in patients with high risk of mediastinal lymph node metastases (evidence level 4).

[21] [22]

A complete assessment of mediastinal and hilar nodal stations is recommended, and sampling of at least three different mediastinal nodal stations (4 R, 4 L, 7) ([Fig.1], [Fig.5]) is suggested in patients with NSCLC and an abnormal mediastinum (Recommendation grade D).

8 EUS for adrenal glands

  • What is the feasibility of EUS for detection in the left and right adrenal glands?

  • Are specific EUS imaging characteristics predictive for metastatic involvement?

  • What are the sensitivity and NPV of EUS-FNA of adrenal glands suspicious for metastatic lung cancer involvement?

There are no meta-analyses and no RCTs. The vast majority of studies had a retrospective design. Additionally, only half of the selected studies included patients with lung cancer.

  • EUS of the left adrenal gland is feasible in the vast majority (97 % – 100 %) of patients with lung cancer (evidence level 2 – ).

  • Loss of seagull shape of the adrenal gland on EUS imaging seems to be predictive of malignancy (evidence level 2 – ).

  • Sensitivity of EUS left adrenal gland metastases in patients with lung cancer ranges from 86 % to > 90 %, and NPV ranges from 70 % to > 90 %, but the number of studies is limited. (evidence level 2 – ).

  • Detection and aspiration of the right adrenal gland by EUS is feasible in selected cases (evidence level 2 – ).

  • EUS-FNA of suspicious left adrenal gland is feasible and safe in the absence of clinical signs of a pheochromocytoma (evidence level 4)

[66] [67] [68] [69] [70] [71] [72] [73] [74] [75] [76] [77] [78] [79] [80]

In patients with a left adrenal gland suspected of a distant metastasis, we suggest performance of EUS-FNA, while the use of EUS-B with a transgastric approach is at present experimental (Recommendation grade D).

9 and 10 Training

  • Which steps should be included in the training curriculum for endosonography?

  • What is the impact of simulator-based training on patient care?

We await results from randomized trials exploring the effect of simulation-based training in endosonography. However, we believe that evidence from high quality RCTs from other surgical and endoscopic domains can be extrapolated to endosonography.

  • The quality and the safety of endosonography are dependent on the level of experience of the operator (evidence level 2 – ).

  • The training curriculum for endosonography should include two steps: a simulator-based training followed by supervised practice on patients (evidence level 4-).

  • No data are available about the effects of the simulator-based program for endosonography on patient care (evidence level 4).

[81] [82] [83] [84] [85] [86] [87] [88]

For optimal endosonographic staging of lung cancer, we suggest that individual endoscopists should be trained in both EBUS and EUS-B in order to perform complete endoscopic staging in one session (Recommendation grade D).

We suggest that new trainees in endosonography follow a structured training curriculum consisting of simulation-based training followed by supervised practice on patients (Recommendation grade D).

11 Competence assessment

  • How many procedures must a trainee perform before being being considered competent in endosonography?

All available evidence on acquisition of skills in endosonography show substantial variability between trainees, making it impossible to define a certain number of procedures required for credentialing. Perhaps because of the lack of standardized certification programs in endosonography, there are no studies that actually show that ensuring basic competence and monitoring of outcomes leads to better patient care.

  • There is no standard number of procedures that can be used as a criterion for considering a trainee to be competent (evidence level 4)

  • The acquisition of competence in endosonography varies between operators, but basic competence should be ensured before operators perform the procedures by themselves (evidence level 4).

[16] [17] [61] [88] [89] [90] [91] [92] [93] [94] [95] [96] [97] [98] [99] [100]

We suggest that competence in EBUS-TBNA and EUS-FNA for staging lung cancer be assessed using available validated assessment tools (Recommendation grade D).

95 %CI, 95 % confidence interval; CT, computed tomography; EBUS-TBNA, endobronchial ultrasound with real-time guided transbronchial needle aspiration; EUS-B, endoscopic ultrasound, using the EBUS scope; FDG, fluorodeoxyglucose; FNA, fine needle aspiration; NPV, negative predictive value; PET-CT, positron emission tomography-CT; PPV, positive predictive value; RCT, randomized controlled trial; vs., versus.

Appendix e2

Search strategy for key questions.

1 Search terms: EUS[All Fields] AND EBUS[All Fields] AND staging[All Fields] AND ("lung neoplasms"[MeSH Terms] OR ("lung"[All Fields] AND "neoplasms"[All Fields]) OR "lung neoplasms"[All Fields] OR ("lung"[All Fields] AND "cancer"[All Fields]) OR "lung cancer"[All Fields]) AND combination[All Fields]

2, 3 Search terms: EUS[All Fields] AND EBUS[All Fields] AND staging[All Fields] AND ("lung neoplasms"[MeSH Terms] OR ("lung"[All Fields] AND "neoplasms"[All Fields]) OR "lung neoplasms"[All Fields] OR ("lung"[All Fields] AND "cancer"[All Fields]) OR "lung cancer"[All Fields]) AND combination[All Fields]

4, 5 Search terms: (centrally[All Fields] AND located[All Fields] AND ("lung neoplasms"[MeSH Terms] OR ("lung"[All Fields] AND "neoplasms"[All Fields]) OR "lung neoplasms"[All Fields] OR ("lung"[All Fields] AND "cancer"[All Fields]) OR "lung cancer"[All Fields])) AND (("mediastinum"[MeSH Terms] OR "mediastinum"[All Fields] OR "mediastinal"[All Fields]) AND ("lymph nodes"[MeSH Terms] OR ("lymph"[All Fields] AND "nodes"[All Fields]) OR "lymph nodes"[All Fields] OR ("lymph"[All Fields] AND "node"[All Fields]) OR "lymph node"[All Fields])) AND staging[All Fields] AND ("diagnosis"[Subheading] OR "diagnosis"[All Fields] OR "diagnosis"[MeSH Terms])

6 Search terms: (((EBUS[All Fields] AND EUS[All Fields] AND (combined[All Fields] AND technique[All Fields]) AND ("mediastinum"[MeSH Terms] OR "mediastinum"[All Fields]) AND ("lymph nodes"[MeSH Terms] OR ("lymph"[All Fields] AND "nodes"[All Fields]) OR "lymph nodes"[All Fields] OR ("lymph"[All Fields] AND "node"[All Fields]) OR "lymph node"[All Fields]) AND ("lung neoplasms"[MeSH Terms] OR ("lung"[All Fields] AND "neoplasms"[All Fields]) OR "lung neoplasms"[All Fields] OR ("lung"[All Fields] AND "cancer"[All Fields]) OR "lung cancer"[All Fields])))

7 Search terms: ((("Endoscopic Ultrasound-Guided Fine Needle Aspiration"[Mesh] OR (("Ultrasonography, Interventional"[Mesh] OR Ultrasound[tiab] OR ultrasonograph*[tiab] OR EUS[tiab]) AND ("Biopsy, Fine-Needle"[Mesh] OR Fine Needle[tiab] OR FNA)) OR EUS-FNA[tiab] OR echoendoscop*[tiab] OR echo-endoscop*[tiab]))) AND (("Adrenal Glands"[Mesh] OR adrenal[tiab]))

8 Search terms: ((("Lung Neoplasms"[Mesh] OR lung neoplasm*[tiab] OR lung cancer*[tiab] OR pulmonary neoplasm*[tiab] OR pulmonary cancer*[tiab])) AND ("Combined Modality Therapy"[Mesh] OR neoadjuvant[tiab] OR therapy[tiab] OR treatment[tiab] OR treated[tiab] OR chemotherap*[tiab] OR chemoradiat*[tiab] OR combined modality[tiab])) AND ((("Endoscopic Ultrasound-Guided Fine Needle Aspiration"[Mesh] OR (("Ultrasonography, Interventional"[Mesh] OR Ultrasound[tiab] OR ultrasonograph*[tiab] OR EUS[tiab]) AND ("Biopsy, Fine-Needle"[Mesh] OR Fine Needle[tiab] OR FNA)) OR EUS-FNA[tiab] OR echoendoscop*[tiab] OR echo-endoscop*[tiab])) OR ((Endobronchial ultrasound[tiab] OR EBUS[tiab]) AND (transbronchial needle aspiration*[tiab] OR TBNA[tiab]) OR EBUS-TBNA[tiab]))

Appendix e3

Evaluation of single studies according to the Scottish Intercollegiate Network (SIGN) system [26].

First author, year

Study design

Intervention

Participants

Reference standard

Results

Conclusions

Level of evidence

Limits and comments

Recommendations

Gu,

2009 [29]

Systematic review and meta-analysis

EBUS for mediastinal staging in lung cancer patients

11 studies,
1299 patients

Histopathology in 5 studies, and histopathology or clinical follow-up in 6

EBUS-TBNA:

  • Sensitivity: 0.93 (95 %CI 0.91 – 0.94)

  • Specificity: 1.00 (95 %CI 0.99 – 1.00).

EBUS-TBNA is an accurate, safe and cost-effective tool in lung cancer staging.

Directly applicable

1 –

Limits:

  • Reference standard included clinical follow-up in some studies

1 – 5

The subgroup of patients who were selected on the basis of CT- or PET-positive results had higher pooled sensitivity (0.94, 95 %CI 0.93 – 0.96) than the subgroup of patients without any selection by CT or PET (0.76, 95 %CI 0.65 – 0.85) (P < 0.05).

Only two complications occurred (0.15 %).

The selection of patients who had positive results of suspected lymph node metastasis on CT or PET may improve the sensitivity of EBUS-TBNA.

Micames,

2007 [30]

Systematic review and meta-analysis

EUS for mediastinal staging in lung cancer patients

18 studies,
1201 patients

Histopathology in 10 studies, and histopathology or clinical follow-up in 8

EUS-FNA:

  • Sensitivity: 0.83 (95 %CI 0.78 % – 0.87 %)

  • Specificity: 0.97 (95 %CI 0.96 – 0.98)

The subgroup of patients who were selected on the basis of CT-positive results had higher pooled sensitivity (90 %, 95 %CI 84 % – 94 %) than the subgroup of patients without mediastinal abnormalities on CT (58 %; 95 %CI 39 % – 75 %).

EUS-FNA is a safe modality for the invasive staging of lung cancer that is highly sensitive when used to confirm metastasis to mediastinal lymph nodes seen on CT scans.
In addition, among lung cancer patients with normal mediastinal adenopathy on CT scans, despite lower sensitivity, it has the potential to prevent unnecessary surgery in a large proportion of cases missed by CT scanning.

Directly applicable

1 – 

Limits:

  • Reference standard included clinical follow-up in some studies

1 – 5

Zhang,

2013 [25]

Systematic review and meta-analysis

Accuracy of the combination of EBUS-TBNA and EUS-FNA procedures and clarification of its current role for mediastinal lymph node staging of lung cancer

8 studies,
RCT 1
Prospective 7

822 patients

Surgery in 4 studies, and surgery and clinical follow-up in 4

Combined approach:

  • Sensitivity: 86 %

  • Specificity: 100 %

  • Positive likelihood ratio: 51.77

  • Negative likelihood ratio: 0.15

  • Diagnostic odds ratio (DOR): 416.83

  • Area under the curve (AUC): 0.99

Complications:
1 pneumothorax, 1 lymph node abscess

The combined technique is more sensitive than EBUS-TBNA or EUS-FNA alone.
The diagnostic power of this combined technique is accurate.

1 – 

Directly applicable

Limits:

  • Reference standard included clinical follow-up in some studies

  • Heterogeneity across studies

1, 6

Annema,

2010 [18]

RCT

Multicenter study

Combination of EBUS and EUS (conventional endoscope) in detecting N2 /N3 disease in lung cancer patients

Primary outcome: sensitivity for N2 /N3 disease

Secondary outcome: rate of unnecessary thoracotomy

n = 241
Consecutive patients potentially operable for NSCLC

  • n = 118 surgical staging group

  • n = 123 endosonography staging group, followed by surgical staging

Surgery (thoracotomy with node dissection)

Primary outcome: sensitivity for N2 /N3 metastases:

Sensitivity

  • Surgery alone: 79 %

  • Endosonography (EBUS + EUS) alone: 85 %

  • Endosonography followed by surgical staging: 94 %

NPV

  • Surgery alone: 86 %

  • Endosonography alone: 85 %

  • Endosonography followed by surgical staging: 93 %

Abnormal mediastinum:

  • Sensitivity for endosonography of 86 %, but 97 % when it is followed by surgical staging.

Thoracotomy was unnecessary in 21 patients (18 %) in the surgical group and in 9 patients (7 %) in the endosonography group.

Complication rate was similar in both groups.

Among patients with (suspected) NSCLC, a staging strategy combining endosonography and surgical staging compared with surgical staging alone resulted in greater sensitivity for mediastinal nodal metastases and fewer unnecessary thoracotomies

For statement 1: 1 + + 
Directly applicable

Limits:

  • Only tertiary hospitals

For statement 2 –:
Extrapolated

Limits:

  • Small sample

1, 2, 3, 6

Wallace,

2008 [31]

Prospective comparative study

Single-center study

Combination of EBUS and EUS (regular) in mediastinal lymph node staging in lung cancer

n = 138
consecutive patients

Surgery (thoracotomy with node dissection, lobectomy with mediastinal exploration, mediastinoscopy, or thoracoscopy) or clinical follow-up

The overall sensitivity of the combined technique was 93 % and the NPV was 97 %.

Sensitivity:

  • EBUS alone: 69 %

  • EUS alone: 69 %

  • EBUS + EUS: 93 %

Moreover:

  • If mediastinoscopy had been performed only when results from endosonography were negative, this surgical procedure would have been avoided in 28 % of patients (39 /138).

EBUS-TBNA has higher sensitivity than “blind” TBNA and that EUS plus EBUS may allow near-complete minimally invasive mediastinal staging in patients with suspected lung cancer.
These results require confirmation in other studies but suggest that EUS plus EBUS may be an alternative approach for mediastinal staging in patients with suspected lung cancer.

Suboptimal reference standard

2 + 

Directly applicable

Limits:

  • Not randomized

  • Single-center

Reference standard included clinical follow-up

1, 2, 3, 6

Dooms,

2014 [47]

Prospective multicenter study

Endosonography (EBUS, only followed by EUS-B if patients had inaccessible or difficult to reach lymph nodes) and mediastinoscopy for mediastinal nodal staging of cN1 lung cancer.

n = 100
consecutive patients

Surgery (thoracotomy or video-assisted thoracic surgery [VATS] resection)

Of the 100 patients with cN1 on imaging, 24 patients were diagnosed with N2 disease.

Invasive mediastinal nodal staging with endosonography alone had a sensitivity of 38 %, which was increased to 73 % by adding a mediastinoscopy.
The NPVs were 81 % and 91 %, respectively; 10 mediastinoscopies were needed to detect 1 additional N2 disease missed by endosonography.

Endosonography alone has unsatisfactory sensitivity for detecting mediastinal nodal metastasis in cN1 lung cancer, and the addition of a confirmatory mediastinoscopy is of added value.

2 + 

Limits:

  • EUS-(B) only performed in 25 % of patients

1

Rintoul,

2005 [101]

Prospective comparative study

Single-center study

Combination of EBUS and EUS for mediastinal nodal staging

(EUS has been done only when the assessment of postero-inferior mediastinal lymph nodes was needed)

n = 20
Selected patients underwent EBUS and 7 patients EUS and EBUS

Mediastinoscopy
Clinical follow-up

EBUS-TBNA:
Diagnosis of malignant lymph nodes: 11 out of 18 patients
Negative for N2 /N3: 7 patients:

  • 5 true-negative

  • 2 false-negative

Procedure time:

  • EBUS-TBNA: 30 min

  • EUS-FNA: 45 min

EBUS with real-time TBNA offers improved sensitivity and accuracy for staging of the middle mediastinum, and, combined with endoscopic ultrasound, should allow investigation of the majority of the mediastinum.

2 – 

Not directly applicable

Limits:

  • Small sample of patients;

  • EUS not in all cases

  • Not consecutive patients

  • Reference standard included clinical follow-up

1

Oki,

2014 [37]

Prospective study

EBUS-TBNA was followed by EUS-FNA with a single bronchoscope in the preoperative hilar and mediastinal staging of NSCLC

n = 150 (of whom 146 were included in analysis)

Surgery (resection with node dissection, or resection with node examination), or (in a small number of patients) clinical follow-up

Sensitivity per patient:

  • EBUS-TBNA: 52 %

  • EUS-FNA: 45 %

  • Combined approach: 73 %

Corresponding negative predictive value:

  • EBUS-TBNA: 88 %

  • EUS-FNA: 86 %

  • Combined approach: 93 %

The combined endoscopic approach with EBUS-TBNA and EUS-FNA is a safe and accurate method for preoperative hilar and mediastinal staging of NSCLC, with better results than with each technique by itself.

2 + 

Limits:

  • Single-center

1

Vilmann,

2005 [32]

Prospective cohort study

Single-center study

Combination of EBUS and EUS for mediastinal lymph node staging

n = 33 (of whom 28 were included in analysis)
Selected patients

Surgery (thoracotomy) or clinical follow-up

Diagnostic accuracy: 100 %

EUS-FNA and EBUS-TBNA appear to be complementary methods.
A combined approach with both EUS-FNA and EBUS-TBNA may be able to replace more invasive methods for evaluating lung cancer patients with suspected hilar or mediastinal metastases, as well as for evaluating unclear mediastinal or hilar lesions

2-

Directly applicable

Limits:

  • Small sample of patients

  • Not consecutive patients

  • Reference standard included clinical follow-up

1

Szlubowski,

2010 [41]

Prospective comparative study

Multicenter study

Combination of EBUS and EUS for mediastinal lymph node staging

n = 120

Selected patients

To assess the diagnostic yield of the combined approach in the radiologically normal mediastinum in NSCLC staging.

Surgery (pulmonary resection with node dissection, or transcervical extended bilateral mediastinal lymphadenectomy [TEMLA])

Overall sensitivity: 68 %
Overall NPV: 91 %
Overall PPV: 91 %

Prevalence of N2-N3 disease: 22 %

Station 4R: high rate of false negatives

Station 4L: sensitivity for the combined procedure was 90 %, significantly higher compared with the single techniques alone.

Station 7: sensitivity for the combined procedure was 92 %, significantly higher compared with the single techniques alone.

In the radiologically normal mediastinum, the combined technique is a highly effective and safe technique in NSCLC staging and, if negative, a surgical diagnostic exploration of the mediastinum may be omitted.

2 + 

Directly applicable

2, 3

Varadarajulu,

2004 [50]

Retrospective study

Single-center study

EUS-FNA for diagnosing lung masses adjacent to or abutting the esophagus after unrevealing CT-guided biopsy or bronchoscopy

n = 18 patients

Mean follow-up: 205 days

Diagnostic yield: 100 %, no complication

10 patients had mediastinal invasion.
In 6 out of the 10 patients mediastinal lymph nodes were involved:

  • Station 7: 5 lymph nodes

  • Station 8: 1 lymph nodes

Out of 6, in 3 patients FNA was performed and a diagnosis was not reached; in the other 3, lymph nodes were difficult to reach because of the position of the tumor.

8 patients had no mediastinal invasion; of these EUS-FNA detected a metastasis in only 1 (station 8).

In this study, EUS-guided FNA of lung mass was safe, and it established a diagnosis in all patients with accessible lesions.

2 – 

Directly applicable

Limits:

  • Small sample

  • Retrospective study

4, 5

Szlubowski,

2014 [62]

Prospective study

Combination of EBUS-TBNA and EUS-B-FNA for mediastinal lymph node restaging after induction therapy

n = 106 NSCLC patients with confirmed N2 disease who had undergone induction chemotherapy

Transcervical extended bilateral mediastinal lymphadenectomy (TEMLA)

Sensitivity: 67 %
NPV: 73 %

The combination of EBUS-TBNA and EUS-B-FNA is a reasonable and safe technique in mediastinal restaging in NSCLC patients afterinduction therapy.

2 + 

Directly applicable

Hernandez,

2007 [51]

Review of prospective cohort

Single-center study

EUS-FNA for diagnosing centrally located primary lung cancers

n = 17 patients

9 lesions at hilum
8 lesions in upper lobe

4 /17 had lymph node abnormalities at EUS of which 3 were confirmed for metastases

Clinical follow-up

Diagnostic yield: 100 %

Complication: 1 case of hemoptysis that needed hospitalization

EUS-FNA is a safe, relatively cost-effective, and accurate initial diagnostic modality for the diagnosis of lung lesions adjacent to the esophagus or invading the mediastinum.

2 – 

Directly applicable

Limits:

  • Small sample

  • Retrospective study

4, 5

Vazquez-

Sequeiros,

2013 [63]

Review of prospective cohort

Multicenter study

EUS-FNA after unsuccessful CT-guided lung biopsy or bronchoscopy for diagnosing indeterminate central mediastinal lung masses

n = 73 patients

Mean tumor size in short axis: 26 mm

CT/PET-CT

Tumor close to the cervical/upper part of the esophagus

Clinical follow-up (12 months)

Surgical staging/treatment

Autopsy

62 patients had a diagnosis from the lung infiltrates with EUS (1 hamartoma, 47 NSCLC, 8 SCLC, 6 metastatic cancer).
11 patients had no diagnosis because EUS did not visualize the lung infiltrates.

Sensitivity:

  • in 73 patients: 80.8 %

  • excluding 11 patients: 96.7 %

Complication: 1 tension pneumothorax

Good accuracy and safety of EUS-FNA for evaluation of central mediastinal lung masses

2 + 

Directly applicable

Limits:

  • Only EUS-FNA was considered

  • Only lung tumor

4, 5

Annema,

2005 [64]

Retrospective cohort

Single-center study

EUS-FNA following a nondiagnostic bronchoscopy for diagnosing centrally located lung tumors

n = 32 patients

Mean tumor size at CT: 45 mm

No lymph node involvement

Location:
Left upper lobe: 7
Right upper lobe: 15
Left lower lobe: 7
Right lower lobe: 3

Surgery (only in 11 patients)

  • 31 out of 32 patients (97 %) had a diagnosis of malignancy

  • Only 1 patient had the diagnosis after pneumonectomy (lymphoma)

  • 11 patients underwent operation and were referred to surgery.

  • 39 % of patients were staged as having T4 disease.

EUS-FNA qualifies as the next diagnostic step in patients with suspected lung cancer and a nondiagnostic bronchoscopy if the intrapulmonary mass is located adjacent or near the esophagus.
In these cases, EUS-FNA may replace computed tomography of the chest (CT)-guided biopsies and reduce the number of exploratory thoracotomies.

2-

Directly applicable

Limits:

  • Small sample

4, 5

Tournoy,

2009 [65]

Retrospective

Multicenter study

EBUS-TBNA after a nondiagnostic conventional bronchoscopy for diagnosing central parenchymal lung lesions

n = 60 patients

CT or CT-PET

Mean size of tumor: 25 mm

Transthoracic needle aspiration biopsy or surgical diagnostic procedure (98 % of patients)

The primary tumor was visible with EBUS in all cases.

Lung cancer was diagnosed in 46 patients (77 %)

Overall sensitivity: 82 %

Overall NPV: 23 %

Sensitivity:

  • For lung tumor < 25 mm: 78 %

  • For lung tumor > 25 mm: 86 %

No serious complication

EBUS-TBNA can be considered as a diagnostic test in patients with a centrally located lung lesion after a previous nondiagnostic conventional bronchoscopy.

2-

Directly applicable

Limits:

  • Small sample

4, 5

Verma,

2013 [15]

Review of prospective cohort

Single-center study

EBUS-TBNA for diagnosing central lung parenchymal lesions

n = 37 patients

CT scan

Mean size in short axis: 8 – 82 mm

Surgery (not in all patients)

32 /37 had a final diagnosis

30 /37 had diagnosis of lung cancer

Sensitivity of EBUS-TBNA for detecting:

  • Malignancy: 91.4 %

  • Benign process: 86.5 %

EBUS-TBNA is an effective and safe method for tissue diagnosis of parenchymal lesions that lie centrally close to the airways.
EBUS-TBNA should be considered the procedure of choice for patients with centrally located lesions without endobronchial involvement.

2 – 

Directly applicable

Limits:

  • Surgical reference not done in all patients

Kang,

2013 [35]

Randomized clinical trial

EUS-B-FNA + EBUS-TBNA for mediastinal lymph node staging

Primary outcome:

  • Diagnostic accuracy for N2/N3 disease

Secondary outcomes:

  • Procedure sequence

  • Diagnostic added benefits of the second procedure

  • Procedure time

  • Number of nodal stations aspirated

  • Procedure tolerance

  • Cardiorespiratory parameters

  • Medication requests

  • Complications

n = 162
Consecutive patients were randomized into 2 groups:

  • Group A: 82 patients, EBUS-TBNA then EUS-B-FNA (of whom 74 were included in analysis)

  • Group B: 80 patients, EUS-B-FNA then EBUS-TBNA (of whom 74 were included in analysis

Surgery (open thoracotomy with node dissection, or video-assisted thoracic surgery [VATS])

Primary outcome:

Values achieved with the first procedure, then with the second added:
Group A:

  • Diagnostic accuracy: 91.9 % then 93.2 %

  • Sensitivity: 82.4 %, then 85.3 %

  • NPV: 87 %, then 88.9 %
    These values were not significant.

Group B:

  • Diagnostic accuracy: 86.5 %, then 97.3 %

  • Sensitivity: 60 %, then 92 %

  • NPV: 83.1 %, then 96.1 %
    These values were significant.

Secondary outcomes:

  • Procedure time; number of lymph node stations sampled and number of aspirations; amount of medication, cardiorespiratory parameters; patient tolerance: similar in both groups

  • Complications: hypoxia similar in both groups; in group B, 1 pneumomediastinum was observed after EBUS but did not require specific treatment

Using a combination of EBUS-TBNA and EUS-B-FNA in mediastinal staging, the diagnostic values and the patient satisfaction were not different between group A and group B.
The necessity for EBUS-TBNA following EUS-B-FNA suggests that EBUS-TBNA is a better primary procedure in endoscopic mediastinal staging.

1 + 

Directly applicable

Limits:

  • Suboptimal performance of EUS-B (selective sampling, low number of aspirations, little time spent)

6

Ohnishi,

2011 [33]

Prospective comparative study

Combination of EBUS and EUS for mediastinal lymph node staging

To compare the diagnostic yield of CT-PET and the combination of EBUS/EUS-FNA

n = 120
Consecutive patients

Surgery (resection with N staging)

CT-PET:

  • Accuracy: 73.6 %

  • Sensitivity: 47.4 %

  • Specificity: 87.5 %

  • PPV: 66.7 %

  • NPV: 75.9 %

  • False-negative: 20

EBUS + EUS

  • Accuracy: 90 %

  • Sensitivity: 71.8 %

  • Specificity: 100

  • PPV: 100 %

  • NPV: 86.6 %

  • False-negative: 11

The number of false-negative results was 14 with only EBUS and 20 with only EUS.

The combined endoscopic approach using EUS-FNA and EBUS-TBNA provided excellent diagnostic performance. Therefore, this approach is strongly recommended before surgery or mediastinoscopy to avoid futile thoracotomy and surgical intervention.

2 + 

Directly applicable

6

Hwangbo,

2010 [36]

Prospective study

Single-center study

Combination of EBUS and EUS (single scope) for mediastinal lymph node staging

n = 143
Consecutive patients

Surgery (node dissection)

EBUS alone:

  • Sensitivity: 84.4

  • NPV: 93.3 %

  • Diagnostic accuracy: 95.1 %

EBUS + EUS-B-FNA

  • Sensitivity: 91.1 %

  • NPV: 96.1 %

  • Diagnostic accuracy: 97.2 %
    (not significant values)

Among 473 mediastinal nodal stations having at least one node ≥ 5 mm that were evaluated, the proportion of mediastinal nodal stations accessible by EBUS-TBNA was 78.6 %; the proportion increased to 84.8 % by combining EUS-B-FNA with EBUS-TBNA (P = .015).

Mean procedure time:

  • EBUS-TBNA: 18.9 min

  • EUS-B-FNA: 38 min

Following EBUS-TBNA in the mediastinal staging of potentially operable lung cancer, the accessibility to mediastinal nodal stations increased by adding EUS-B-FNA, and an additional diagnostic gain might be obtained by EUS-B-FNA.

2 + 

Directly applicable

Limits:

  • Single-center

  • EUS-B only used for those nodes not accessible by EBUS

6

Herth,

2010 [34]

Prospective comparative study

Multicenter study

Combination of EBUS and EUS (single scope) for mediastinal lymph node staging

n = 139
Consecutive patients

Surgery (thoracoscopy or open thoracotomy) or clinical follow-up

Sensitivity:

  • EBUS alone: 89 %

  • EUS alone: 92 %

  • Combined approach: 96 %

NPV:

  • EBUS alone: 92 %

  • EUS alone: 82 %

  • Combined approach: 95 %

Mean procedure time:

  • EBUS-TBNA: 14 min

  • EUS-B-FNA: 16 min

No patient intolerance

No complications

The two procedures can be performed with a dedicated linear endobronchial ultrasound bronchoscope in one setting and by one operator.
They are complementary and provide better diagnostic accuracy than either one alone.
The combination may be able to replace more invasive methods as a primary staging method for patients with lung cancer.

2 + 

Directly applicable

Limits:

  • Reference standard included clinical follow-up

6

Lee,

2014 [39]

Retrospective study

EUS-B-FNA was performed after EBUS-TBNA when mediastinal lymph nodes were not accessible using EBUS-TBNA or when tissue sampling using EBUS-TBNA alone was inadequate.

n = 44 (37 included in analysis)

Surgery:

  • Mediastinoscopy

  • Pulmonary resection with mediastinal node dissection

EBUS:

  • Sensitivity: 79 %

  • NPV: 57 %

Combined approach:

  • Sensitivity: 100 %

  • NPV: 100 %

Use of a combination of EBUS-TBNA and EUS-B-FNA can afford better sensitivity and accuracy of mediastinal N-staging compared with use of EBUS-TBNA alone

2 – 

Limits:

  • Reference standard included mediastinoscopy

  • Only included patients with inaccessible nodes during EBUS-TBNA

  • Retrospective study

Liberman, 2014 [40]

Prospective study

Combined EBUS/EUS for mediastinal lymph node staging

n = 166

Surgery:

  • Mediastinoscopy

EBUS:

  • Sensitivity: 72 %

  • NPV: 88 %

EUS:

  • Sensitivity: 62 %

  • NPV: 85 %

Combined approach:

  • Sensitivity: 91 %

  • NPV: 96 %

The combined EBUS/EUS procedure can replace surgical mediastinal staging in patients with potentially resectable NSCLC.

2 – 

Limits:

  • Reference standard included mediastinoscopy

Chang,

1996 [71]

Consecutive patients

Single-center study

EUS: imaging and characterization of left adrenal gland

n = 31

Indication for EUS: diagnosis and staging of GI and lung malignancies.

Radiological follow-up

Left adrenal gland visualized by EUS in 97 % of patients

Technically feasible

2 – 

Not directly applicable

Limits:

  • Small

  • Several GI malignancies

7

Uemura,

2013 [79]

Retrospective cohort study

EUS: Detection rate for right adrenal gland

Diagnostic ability of EUS-FNA for adrenal metastases in lung cancer

n = 150

Indication for EUS: staging of lung cancer

No reference standard

Visualization:

  • Right adrenal gland: 87 %

  • Left adrenal gland: 100 %

Diagnostic accuracy for adrenal metastases 100 %

Technically feasible

2 – 

Directly applicable

Only a few with actual metastasis

7

Eloubeidi,

2004 [72]

Consecutive patients.
Data collection prospectively as an ongoing observational study in one center and by retrospective cohort design at the other center.

EUS-FNA left adrenal gland: feasibility and safety

n = 31

Indications for EUS-FNA: enlarged adrenal gland on imaging and known or suspected malignancies

2 EUS referral centers

No reference standard

Adequate tissue obtained in 100 %.

No complications.

Technically feasible, including aspiration

2 – 

Directly applicable

7

Stelow,

2005 [102]

Retrospective review of cytology files

EUS-FNA of left adrenal gland (1 right adrenal gland):
comparison of EUS-FNA and non-EUS-guided FNA for utility of cell block immunohistochemistry.

n = 22 (24 cases)

Indications for EUS-FNA: in 86 %, staging for malignancies

1 center

No reference standard

Diagnostic material was present in all cases

Technically feasible, including aspiration, to detect left adrenal gland metastases

2 – 

Not directly applicable

7

DeWitt,

2006 [103]

Retrospective case series

EUS-FNA of left adrenal gland: report experience

n = 38

Indication for EUS-FNA: lung mass in 14, left adrenal gland mass in 5, pancreatic mass in 14

1 center

Surgery, clinical and/or radiological follow-up

24 % nondiagnostic

0 % false-negative results in lung cancer cases.

No complications

Technically feasible, including aspiration, to detect and exclude left adrenal gland metastases

2 – 

Not directly applicable

7

Eloubeidi,

2008 [104]

Prospective

EUS-FNA (lymph nodes, pancreatic masses, liver etc): diagnostic accuracy and complications

n = 540

n = 15 for adrenal gland

Indications for EUS-FNA of adrenal gland: unknown

1 center

Death from disease progression; radiological and/or clinical follow-up

Sensitivity: 100 %

NPV: 100 %

Technically feasible, including aspiration, to detect and exclude left adrenal gland metastases

2 – 

Not directly applicable

7

Ang TL,

2007 [73]

Prospective

EUS or EUS-FNA for left adrenal gland

n = 119
Consecutive patients

No reference standard

Overall prevalence of left adrenal gland mass: 3.4 %

EUS-FNA is a safe and useful technique for evaluation of left adrenal gland masses.

2 – 

Not directly applicable

Not all patients had lung cancer

7

Bodtger,

2009 [74]

Retrospective

Evaluation of impact of EUS-FNA of left adrenal gland on TNM staging

n = 40

No reference standard

EUS-FNA of enlarged left adrenal gland altered TNM staging in 70 % of patients, and treatment in 48 %.
Malignant left adrenal gland lesion was found in 28 % of patients and was associated with shorter survival.

EUS-FNA of an enlarged left adrenal gland in patients with known or suspected lung cancer had a significant impact on TNM staging, treatment, and survival.
The impact of routine visualization of the left adrenal gland in lung cancer work-up needs to be prospectively validated.

2 – 

Directly applicable

7

Schuurbiers,

2011 [75]

Retrospective

EUS-FNA sensitivity for left adrenal metastases in lung cancer patients with an adrenal gland suspicious at radiological imaging

n = 85

Imaging, no surgical reference

EUS-FNA findings:

  • 62 % of patients, left adrenal gland metastases

  • 29 %, benign lesions

  • 1 %, colon carcinoma metastasis

  • 1 %, primary adrenocortical carcinoma

In 5.9 %, aspirates had no representative material.

False negatives: 2/85
Sensitivity: 86 %
NPV: 70 %

EUS-FNA is a sensitive, safe and minimally invasive technique to provide tissue proof of left adrenal metastases in patients with (suspected) lung cancer.

2 – 

Directly applicable

7

Von Bartheld,

2011 [58]

Retrospective

Single-center study

EUS-FNA for mediastinal restaging

n = 58

Inclusion: stage III NSCLC and tissue proven lymph node metastases N2 /N3, who underwent EUS-FNA for restaging after chemoradiotherapy

Surgical-pathological staging of nodal metastases

Sensitivity: 44 %

False negative rate: 58 %

NPV: 42 %

For mediastinal restaging of stage III NSCLC, EUS-FNA is a minimally invasive and safe method to confirm persistent nodal metastases but has a low NPV.

2 – 

Directly applicable

8

Stigt,

2009 [57]

Prospective

Single-center study.

EUS-FNA for mediastinal restaging

n = 28

Inclusion: NSCLC stage III and pathologically proven nodal disease.
Restaging was performed on the same nodes after chemoradiotherapy

Thoracotomy with mediastinal lymph node dissection if restaging with EUS showed no tumor cells

NPV: 91.6 %

Diagnostic accuracy: 92.3 %

Restaging with EUS-FNA after induction chemoradiotherapy is well tolerated and reliably predicts the absence of nodal metastasis.
Although changes in mediastinal FDG-PET uptake show a high concordance with EUS-FNA, pathological confirmation is still superior and therefore necessary.

2 – 

Directly applicable

8

Zielinski,

2013 [59]

Retrospective

Single-center study

EBUS-TBNA and/or EUS-FNA for mediastinal restaging

Aim: compare diagnostic yield of EBUS and/or EUS with transcervical extended mediastinal lymphadenectomy (TEMLA)

n = 88

  • 32 EBUS-TBNA

  • 6 EUS

  • 50

Combined EBUS and EUS

Inclusion: NSCLC with previously endosonographically proven metastatic mediastinal nodes and neoadjuvant treatment

TEMLA in the case of negative results of endoscopy

Endosonography:

  • Sensitivity: 64.3 %

  • NPV 82.1 %

The results of this largest reported series comparing endoscopic and surgical primary staging and restaging of NSCLC showed a significantly higher diagnostic yield of TEMLA when compared with that of EBUS or EUS.

2 – 

Directly applicable

8

Annema,

2003 [55]

Prospective

Single-center study

EUS-FNA for mediastinal restaging

n = 19

Inclusion: patients with NSCLC and proven IIIA-N2 disease who had been treated with induction chemotherapy were referred for mediastinal restaging by EUS-FNA

When EUS-FNA restaged the mediastinum as N0, surgical resection of the tumor with lymph node sampling or dissection

PPV: 100 %

NPV: 67 %

Sensitivity: 75 %

Specificity: 100 %

Diagnostic accuracy: 83 %

EUS-FNA qualifies as an accurate, safe and minimally invasive diagnostic technique for the restaging of mediastinal lymph nodes after induction therapy in NSCLC.

2 – 

Directly applicable

8

Varadarajulu,

2006 [56]

Pilot study: Retrospective analysis of prospectively collected data.

Single-center study

EUS-FNA for mediastinal restaging

n = 14

Inclusion: patients with NSCLC and biopsy-proven N2 disease who underwent restaging by EUS following chemoradiation therapy

Those staged as N0 by EUS underwent tumor resection with complete lymph node dissection

Diagnostic accuracy: 86 %

EUS-FNA appears to qualify as an accurate, safe and minimally invasive diagnostic technique for restaging of mediastinal lymph nodes after chemoradiation therapy in NSCLC patients.

2 – 

Directly applicable

8

Herth

2008 [60]

Prospective

EBUS-FNA sensitivity and accuracy for restaging the mediastinum after induction chemotherapy in patients with NSCLC

n = 124
Consecutive patients

Thoracotomy

Sensitivity: 76 %

Specificity: 100 %

PPV: 100 %

NPV: 20 %

Diagnostic accuracy: 77 %

EBUS-TBNA is a sensitive, specific, accurate, and minimally invasive test for mediastinal restaging of patients with NSCLC.
However, because of the low negative predictive value, tumor-negative findings should be confirmed by surgical staging before thoracotomy.

2 + 

Directly applicable

8

Szlubowski,

2010 [61]

Prospective

EBUS-TBNA sensitivity and diagnostic yield in restaging of NSCLC patients after neoadjuvant therapy

n = 61
Consecutive patients

Transcervical extended mediastinal lymphadenectomy (TEMLA)

Sensitivity: 67 %

Specificity: 86 %

Diagnostic accuracy: 80 %

PPV: 91 %

NPV: 78 %

EBUS-TBNA is an effective and safe technique for mediastinal restaging in NSCLC patients.

In patients with negative results of EBUS-TBNA, a surgical restaging of the mediastinum might not be mandatory.

2 + 

Directly applicable

8

Steinfort,

2011 [81]

Prospective

EBUS-TBNA sensitivity for malignancy and evaluation the effect of procedural learning curve on diagnostic sensitivity

n = 215
Consecutive patients (analysis of the first 215 patients undergoing EBUS-TBNA at one institution)

Surgery

Sensitivity for malignancy was 92 %

Significant improvement in diagnostic performance was seen after 20 procedures were completed, and diagnostic accuracy did not peak until after 50 procedures

EBUS-TBNA is able to accurately confirm histologically a large number of disease processes, both malignant and benign, in all clinical indications studied.
The procedure is safe even when carried out by practitioners with minimal prior experience. Diagnostic performance continues to improve beyond performance of 50 cases.

2 – 

9

Stather,

2013 [82]

Retrospective

Determination of the impact of trainee participation during advanced diagnostic bronchoscopy on procedure time, sedation use, and complications

670 procedures; a trainee participated in 512 (84.3 %) examinations

Not applicable

Trainee participation led to:

  • Increased complication rate (4.7 % vs. 1.1 %, P = 0.076)

  • Increased procedure length (58.3 minutes vs. 37.7 minutes, P = 0.001)

  • Increased dose of propofol (178 mg vs. 137 mg, P = 0.002)

Trainee participation in advanced diagnostic bronchoscopy increased procedure time, increased the amount of sedation used, and resulted in a trend to increased complications.

2 – 

9

Cook,

2011 [84]

Systematic review and meta-analysis

To summarize the outcomes of technology-enhanced simulation training for health professions learners in comparison with no intervention

137 randomized studies

Simulation

Not applicable

Pooled effect sizes for:

  • Time skills: 1.14

  • Process skills: 1.09

  • Product skills: 1.18

  • Time behaviors: 0.79

  • Other behaviors: 0.81

  • Direct effects on patients: 0.50

In comparison with no intervention, technology-enhanced simulation training in health professions education is consistently associated with large effects for outcomes of knowledge, skills, and behaviors, and moderate effects for patient-related outcomes.

1 + 

Large heterogeneity (I 2 > 50 %)

10

Konge,

2013 [85]

Prospective comparative

To design an evidence-based and credible EBUS certification based on a virtual-reality EBUS simulator test

n = 22 participants,
divided into 3 groups:

  • Experienced EBUS operators (group 1, n = 6)

  • Untrained novices (group 2, n = 8)

  • Simulator-trained novices (group 3, n = 8).

Not applicable

Successfully sampled lymph nodes and procedure time were the only simulator metrics that showed statistically significant differences.

None of the novices met the pass/fail standard.

Virtual reality simulators could be an important first line in credentialing before trainees proceed to supervised performance on patients.

2 – 

10

Stather,

2011 [86]

Prospective comparative

To validate a computer EBUS simulator in differentiating between operators of varying clinical EBUS experience

n = 22 participants,
divided into groups:

  • A, novice bronchoscopists, no EBUS experience (n = 4)

  • B, expert bronchoscopists, no EBUS experience (n = 5)

  • C, basic clinical EBUS training (n = 9)

  • D, EBUS experts (n = 4)

Not applicable

Significant differences between groups were noted for:

  • Total procedure time

  • Percentage of lymph nodes identified

  • Percentage of successful biopsies.

Group D performed significantly better than all other groups for:

  • Total procedure time

  • Percentage of lymph nodes identified

Group C performed significantly better than groups A and B for:

  • Total procedure time

  • Percentage of lymph nodes identified

  • Percentage of successful biopsies.

An EBUS simulator can accurately discriminate between operators with different levels of clinical EBUS experience.

2 – 

10

Stather,

2012 [87]

RCT

To compare two methods used to teach EBUS-TBNA: wet laboratory (lab) vs. computer EBUS-TBNA simulation

n = 12 participants

  • 6 wet lab group

  • 6 EBUS-TBNA simulator group

Not applicable

No significant differences between the computer EBUS-TBNA simulator group and the wet lab group in procedure time and percentage of successful biopsies.

The computer simulator group performed significantly better than the wet lab group in the percentage of lymph nodes correctly identified.

Wet lab simulation was associated with increased learner confidence in operating the real EBUS-TBNA bronchoscope.

All participants responded that wet lab and computer EBUS-TBNA simulation offered important complementary learning opportunities.

Computer EBUS-TBNA simulation and wet lab simulation are effective methods of learning basic EBUS-TBNA skills, and appeared to be complementary.

1 – 

10

Annema,

2010 [93]

Prospective multicenter trial

To test a training and implementation strategy for EUS for the diagnosis and staging of lung cancer

n = 551
Consecutive patients

Surgery (not in all patients)

Implementation center:

  • EUS sensitivity: 83 %

  • EUS diagnostic accuracy: 89 %

  • Surgery avoided: 51 %

Expert center:

  • EUS sensitivity: 82 %

  • EUS diagnostic accuracy: 88 %

  • Surgery avoided: 54 %

A single complication occurred in each group.

Chest physicians who participate in a dedicated training and implementation program for EUS in lung cancer staging can obtain results similar to those of experts for mediastinal nodal staging.

2 + 

11

Konge,

2013 [94]

Prospective cohort study

To establish whether there is a minimum training requirement for EUS

n = 4 participants
(91 EUS-FNA procedures)

Not applicable

The performances of the participants improved significantly and became more consistent, but were still highly variable even in the latter part of the learning curves.
Only 2 of the participants reached the mean score of experienced operators; this was after 17 and 23 procedures, respectively.

Pulmonologists with knowledge of lung cancer staging and experience in bronchoscopy quickly improved their performance of EUS-FNA.

20 procedures were not enough to secure consistent and competent performance of all trainees.

2 – 

Small sample

11

Konge,

2012 [99]

Prospective comparative study

To explore the reliability and validity of a newly developed EUS Assessment Tool (EUSAT) designed to measure competence in EUS – FNA for mediastinal staging of NSCLC

n = 30 procedures

6 EUS- FNA trainees

6 EUS- FNA experts

Not applicable

Reliability, Cronbach's α:

  • Intra-rater: 0.80

  • Inter-rater: 0.93

The assessment tool demonstrated construct validity by discriminating between trainees and experienced physicians

Competency in mediastinal staging of NSCLC using EUS and EUS – FNA can be assessed in a reliable and valid way using the EUSAT assessment tool.

2 – 

Small sample

11

Davoudi,

2012 [100]

Prospective multicenter comparative study

To assess the validity and the reliability of the EBUS Skills and Tasks Assessment Tool (EBUS-STAT)

24 operators at three levels of EBUS-TBNA experience:

  • 8 beginners

  • 8 intermediates

  • 8 experienced

Not applicable

Intertester reliability between testers was very high (r = 0.9991).

Mean EBUS-STAT scores:

  • Beginners: 31.1/100

  • Intermediates: 74.9/100

  • Experienced: 93.6/100
    Each group differed significantly from the others.

Self-assessments corresponded closely to actual EBUS-STAT scores (r 2 = 0.81).

The EBUS-STAT can be used to reliably and objectively score and classify EBUS-TBNA operators from novice to expert.

2 + 

Small sample

11

Correction: The name of the co-author Enrique Vasquez-Sequeiros was misspelt in the authors’ list. The name should read “Enrique Vazquez-Sequeiros”.

We apologize for this and to the authors.


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Competing interests: Support for educational endosonography courses has been provided to the Academic Medical Center (AMC), Amsterdam, by Hitachi Medical Systems, Pentax, COOK Medical and Symbionix. P. Vilmann is consultant for MediGlobe, Grassau, Germany which produces EUS-FNA needles. J.M. Dumonceau, C. Hassan, D.A. Korevaar, and L. Konge have no competing interests.

Acknowledgment

The contribution of Dr. Paul Frost Clementsen in creating the artwork for [Fig. 1] and [Figs. 3 – 5] is gratefully acknowledged.

Appendix e1 – e3


Corresponding author

Peter Vilmann, MD PhD
GastroUnit, Department of Surgery
Copenhagen University Hospital Herlev
Copenhagen
Denmark   
Telefon: +45-38-682164   


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Fig. 1 The complementary nature of endobronchial ultrasound (EBUS) and endoscopic (esophageal) ultrasound (EUS) for nodal staging.
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Fig. 4 Schematic representation of centrally located lung cancer with normal mediastinum.
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Fig. 5 Schematic representation of sampling of at least three different mediastinal nodal stations.