Endobronchial ultrasound in real life: primary diagnosis and mediastinal staging of lung cancer in patients submitted to thoracic surgery
© The Author(s). 2016
Received: 13 February 2016
Accepted: 7 July 2016
Published: 19 July 2016
Since the first articles published for over 10 years ago, endobronchial ultrasound (EBUS) has gained a strong scientific backing and has been incorporated into routine medical practice in pulmonology and thoracic surgery centers. How is EBUS performing outside the scientific environment, as a diagnostic and mediastinal staging tool in a subset of patients that undergo thoracic surgery, is an interesting question.
This study evaluated consecutive patients who, during the period from January 2010 to August 2012, were submitted to EBUS and later to thoracic surgery. The samples obtained by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) were compared to surgical samples. The primary endpoint was the proportion of patients with a final diagnosis of non-small cell lung cancer (NSCLC) by EBUS-TBNA correctly subtyped. The secondary endpoint was the negative predictive value (NPV) of EBUS-TBNA for mediastinal staging of lung cancer.
Two hundred eighty seven patients were studied. Considering 84 patients with a final diagnosis of NSCLC by EBUS-TBNA, 79 % (CI 95 % 70.1–87.3) were correctly subclassified. The NPV of EBUS-TBNA for mediastinal staging was 89 % (IC 95 % 84.9–92.7). From a total of 21 false negative cases of mediastinal staging, 16 (76 %) did not undergo positron emission tomography-computed tomography (PET-CT) before the EBUS and in 15 (71 %) the affected lymph node chain was not punctured by EBUS-TBNA. Ten (47 %) patients had only lymph node metastases not directly accessible by the EBUS.
Performed in hospital routine and in patients submitted to thoracic surgery, EBUS-TBNA proved to be a good tool for proper pathological diagnosis of lung cancer. The negative predictive value of 89 % for mediastinal staging of lung cancer is comparable to that reported in previous studies, but the relatively high number of 21 false negative cases points to the need for standardization of routine strategies before, during and after EBUS.
Lung cancer is the malignant tumor with the highest mortality rate among men and women worldwide, with more than 1,4 million deaths a year . The emergence of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), a minimally invasive technique able to provide valuable information for a primary tumor diagnosis and mediastinal staging, significantly changed the approach to lung cancer [2, 3]. Since the first articles published for over 10 years ago , endobronchial ultrasound (EBUS) has gained strong scientific backing [5–7] and has been incorporated into routine medical practice of pulmonology and thoracic surgery centers. Guidelines of respiratory societies reinforce the importance of ultrasound-guided needle techniques in the primary diagnosis and mediastinal staging of lung cancer [8–11]. The success of the technique and the spread of its use around the world make it important to revaluate its performance in “real life”, outside the scientific environment, especially in patients undergoing thoracic surgery, in which the sharpest staging tools are required.
The aim of our study is to determine EBUS performance in patients undergoing thoracic surgery in hospital routine. Using surgical pathology as the gold standard, we calculated the proportion of patients with a final diagnosis of non-small cell lung cancer (NSCLC) by EBUS-TBNA correctly subtyped and the performance of EBUS-TBNA for the mediastinal staging of lung cancer.
The present work is a single-center, retrospective, observational study. All patients who underwent EBUS and thoracic surgery during the period from January 2010 to August 2012 were selected.
The examinations and surgeries took place in the Lungenklinik Hemer, a traditional center for respiratory diseases in Germany. EBUS procedures were performed on hospitalized patients, under general anesthesia. The examination could be accompanied by the presence of a pathologist in the procedure room for rapid on-site evaluation (ROSE) or not. EBUS-TBNA samples were collected using a 22-gauge needle. At least 2 aspirates were obtained from each target lesion. When a pathologist was present, 2 pairs of smears were prepared for ROSE and cytologic examinations. The resulting material (tissue cores, shreds of tissue, cellular components, fluids) was processed using a cell-block technique. If there was no pathologist in the room, all the samples were processed as cell-blocks. Indications for a surgical exploration or resection due to suspicion or confirmation of lung cancer were discussed and had to be approved by a local interdisciplinary clinical session with the mandatory participation of pulmonologists, oncologists, chest surgeons, radiologists and radiotherapists. EBUS-TBNA and surgical samples were analyzed by two different pathology services.
Data collection and statistical analysis were conducted at the Federal University of Rio de Janeiro, Brazil. Through the computer program Teamviewer ® (TeamViewer GmbH, Germany) the authors had remote access to a database provided by the Lungenklinik Hemer to access patient data from local electronic medical records.
Patients who underwent EBUS for any indication in the Lungenklinik Hemer from January 2010 to August 2012 and were subsequently subjected to surgical procedures.
Patients with no lymph node sampling by EBUS-TBNA during an EBUS procedure or patients who did not have histopathologic sampling of mediastinal lymph nodes during surgery.
The primary endpoint was the proportion of patients with a final diagnosis of NSCLC by EBUS-TBNA correctly subtyped as compared to the surgical samples. The secondary endpoint was the negative predictive value (NPV) of EBUS-TBNA for mediastinal staging of lung cancer, according to the 7th edition of the lung cancer staging system of the American Joint Committee on Cancer .
Patient demographics and disease characteristics were summarized using descriptive statistics. For the primary endpoint, the final result of the pathology after surgical resection was used as the gold standard for comparison to EBUS-TBNA samples. This result takes into account the tumor samples present in the lung parenchyma and/or mediastinum. There was no pairing of samples per lymph node site. For the secondary endpoint, the EBUS-TBNA samples were compared only to mediastinal surgical samples (obtained by mediastinoscopy and/or surgical mediastinal lymphadenectomy). The proportion of NSCLC correctly subclassified, the NPV for mediastinal staging and their 95 % confidence intervals (CI) were calculated using standard definitions. All statistical analyses were performed using SPSS® (IBM SPSS Statistics Version 20, United States of America).
Patient demographics, disease and procedure characteristics
Male gender, N (%)
Smoking History, N (%)
COPD, N (%)
Cardiovascular Disease, N (%)
Cancer History, N (%)
Lung Cancer History, N (%)
Instersticial Lung Disease, N (%)
Tumor Location, N, (%)
Right Superior Lobe
Left Superior Lobe
Right Inferior Lobe
Left Inferior Lobe
Total Lymph Nodes punctured, N (mean)
Number of Lymph Nodes punctured per EBUS, N (%)
EBUS with ROSE, N (%)
Additional Biopsy, N (%)
Not performed or not diagnostic
Major Surgical Procedure, N (%)
Right Superior Lobectomy
Left Superior Lobectomy
Right Inferior Lobectomy
Left Inferior Lobectomy
Segmentectomy or wedge resection
NSCLC after surgical exploration, N (%)
238 (82.9 %)
Final Tumor Staging, Nc
IA, N (%)
IB, N (%)
IIA, N (%)
IIB, N (%)
IIIA, N (%)
IIIB, N (%)
IV, N (%)
EBUS-TBNA pathological findings
Absence of pathological findings, N (%)a
Squamous Cell Carcinoma, N (%)
Adenocarcinoma, N (%)
Large Cell carcinoma, N (%)
Adenosquamous Carcinoma, N (%)
NSCLC-NOS, N (%)
Clear Cell Carcinoma, N (%)
Undifferentiated Carcinoma, N (%)
Neuroendocrine Tumor, N (%)
Thymoma, N (%)
Lymphoproliferative Process, N (%)
Sarcomatous Process, N (%)
Anthracosis and Silica, N (%)
Granulomatous Process, N (%)
Inflammatory Process, N (%)
Total, N (%)
287 (100 %)
Mediastinal Lymph Node Staging: EBUS-TBNA X Surgery
EBUS-TBNA N stage
Final N stage
Number of cases
0 or 1
0 or 1
0 or 1
0 or 1
Considering the 4 false positive cases, 2 were surgically classified as N1 and 2 were classified as N0 (all confirmed surgically as NSCLC). In just one of the cases there was a disagreement of the pathological findings of EBUS-TBNA and surgery (EBUS-TBNA suggested adenocarcinoma and surgery confirmed large cell carcinoma). All the 4 cases were submitted to surgical lobectomy and lymph node dissection.
Twenty patients had a mediastinoscopy after the EBUS (4 as the main surgical procedure and 16 as part of the mediastinal staging before surgery). There were 15 true negative, 1 true positive, 4 false negative and no false positive findings comparing mediastinoscopy to final surgical mediastinal staging. Mediastinoscopy did not contribute to a better mediastinal staging than the EBUS in any of the patients. All the 15 true negative cases were also negative by the EBUS. The true positive case was also positive by the EBUS, and one of the 4 false negative mediastinoscopies cases was positive by the EBUS.
Our study evaluated the EBUS-TBNA performance in a key subset of patients with lung cancer: those undergoing thoracic surgery. Despite not representing the majority of patients diagnosed with lung cancer, this is the subgroup in which we need to have the sharpest diagnostic and staging tools to ensure an accurate referral to surgery and expectation of cure. To our knowledge, this is the work with the highest number of patients submitted to surgery who had their EBUS-TBNA results directly compared with the surgical sampling. The use of EBUS was evaluated in a hospital routine, without adherence to study protocols influencing the exam.
The primary endpoint of the study was the proportion of patients with a final diagnosis of NSCLC by EBUS-TBNA correctly subtyped. Our results show that NSCLC was correctly subclassified in 79 % of cases. One of the limitations of existing evidence on EBUS diagnostic performance is that many studies included results of the index test and clinical follow-up in a reference standard test and did not account for the surgical sample being the only possible gold standard. This may have overestimated the result of some studies . Esterbrook et al. showed that EBUS-TBNA samples when made into cell-blocks and subjected to a panel of immunohistochemical stains returned adequate tissue for NSCLC subtyping in 79 %, with a NSCLC-NOS reate of 21 % . In a large, multicenter study, Navani et al. demonstrated that samples from EBUS-TBNA provide sufficient information for subtyping NSCLC in 77 % of the cases .
We chose the NPV of EBUS-TBNA for the mediastinal staging of lung cancer as the secondary endpoint of our study because we consider it to be the most clinically relevant measure in the subset of patients who undergo thoracic surgery. From a total of 238 patients with NSCLC surgically evaluated, 53 had mediastinal metastatic involvement ipsilateral to the target tumor lesion (N2 disease) and 2 had contralateral mediastinal involvement (N3 disease), representing a prevalence of mediastinal nodal involvement of 23 %. The results of our study showed an NPV of 89 %. Probably some of the most important publications of EBUS and mediastinal lymph node staging in patients with potentially resectable NSCLC are the ASTER trial , published in 2010, and the work of Yasufuku et al. , published in 2011. The ASTER trial found an NPV for endosonography staging alone without additional surgical staging of 85 % (prevalence of N2/N3 54 %). Yasufuku showed an NPV of 91 % for EBUS-TBNA (prevalence of N2/N3 disease 35 %).
The sensitivity of 61 % in our work was lower than expected and previously reported. This fact is due to the relatively high number of 21 false negative cases. In reviewing such cases we realize that 16 (76 %) did not undergo PET-CT or it was performed after EBUS and in 15 (71 %) the affected lymph node chain was not punctured by EBUS-TBNA. In the ASTER trial  all patients underwent PET-CT before EBUS. In the discussion of the Lung-BOOST trial , the authors suggest that a PET-CT may not be needed before EBUS-TBNA. In that trial EBUS-TBNA was performed using a systematic aspiration of all visible lymph node stations. Unfortunately, in our study, we are unable to determine if most of the procedures adopted a systematic or selective approach.
In 11 (52 %) patients from the false negative cases, the tumor was located in the left superior lobe and 10 (47 %) had only lymph node metastases not directly accessible by EBUS (lymph node stations 5, 6, 8 and 9). Endoscopic ultrasound (EUS), using the same scope as EBUS, was done in only 6 of our 287 cases. None of the false negative cases underwent also EUS in the same procedure as EBUS. The current consensus is that for a more complete needle-guided ultrasound evaluation of the mediastinum we should associate EBUS and EUS whenever necessary [19, 20]. Perhaps with the more frequent use of EUS in routine practice, some false negative results could have been avoided. However, even though recently showed to be feasible and safe , it would still be difficult to access the lymph nodes in chains 5 (the most often affected) and 6. This points to the need for more cautious strategies in patients susceptible to metastases in these chains, such as patients with tumors in the left superior lobe.
The 4 false positive cases represent patients with NSCLC. Unfortunately we do not have follow-up data, so is difficult to affirm that these are really false positive cases or maybe incorrectly surgically staged patients
The small number of 20 mediastinoscopies already reflects the lower use of this technique in our hospital routine. All mediastinoscopies were performed after EBUS to clarify questionable situations before the final surgical decision. Mediastinoscopy did not contribute to better mediastinal staging than EBUS-TBNA in any of those patients. These findings do not reflect the results of the ASTER trial  or corroborate the current recommendations of the main guidelines of American and European respiratory societies.
Some limitations apply to this study. First, it is a single-center study. We recognize that our results cannot be easily generalized. EBUS was performed in hospitalized patients under general anesthesia. Although this is a standard practice in our service, many procedures, probably the majority, performed in other bronchoscopy services around the world are performed in conscious or moderate sedation. Even tough the World Association for Bronchology and Interventional Pneumology (WABIP) guidelines  state that there is not enough evidence to recommend for or against any type of anesthesia, ideally, we should also have data in patients undergoing the procedure under conscious or moderate sedation. Second; two distinct pathology services have analyzed the samples obtained by EBUS-TBNA and surgery, which may have prevented results of one of the tests influencing the analysis of the other test. But it is difficult to clarify if the differences in pathological classification are due to the quality of the samples or a distinct interpretation by the pathologists. Third, at least 2 aspirates were routinely obtained from each target lesion per EBUS. Lee and colleagues  showed that, in the absence of ROSE, at least 3 aspirates should be obtained from each target lesion in order to provide optimal results from the test. Unfortunately we are not able to identify the number of aspirates that were used in each examination.
In hospital routine and in the subgroup of patients eligible for surgical resection EBUS-TBNA has been proven to be a good tool for the primary diagnosis of lung cancer. The negative predictive value of 89 % for mediastinal staging of lung cancer is comparable to that reported in previous studies, but the relatively high number of false negative cases points to the need for standardization of routine strategies before, during and after EBUS.
CI, confidence interval; EBUS, endobronchial ultrasound; EBUS-TBNA, endobronchial ultrasound-guided transbronchial needle aspiration; EUS, endoscopic ultrasound; GIST, gastrointestinal stromal tumor; NPV, negative predictive value; NSCLC, non-small cell lung cancer; NSCLC-NOS, non-small cell lung cancer not otherwise specified; PET-CT, positron emission tomography-computed tomography; PPV, positive predictive value; ROSE, rapid on-site evaluation; WABIP, World Association for Bronchology and Interventional Pneumology
We thank all the team of the Lungenklinik Hemer by generous support for the implementation of this study.
This study was partly funded by a grant (23038.003721/2013-72) from the Coordination for the Improvement of Higher Education Personnel / CAPES, Ministry of Education, Brazil.
Availability of data and materials
The dataset of this article are stored in the information technology department of the Lungenklinik Hemer and can be made available on request to the corresponding author.
JPSM conceived the study, prepared the first draft of the paper and coordinated the communication between the Lungenklinik Hemer in Germany and the Federal University of Rio de Janeiro in Brazil. FS and AK were responsible for the bronchoscopies in the Lungenklinik Hemer. FS made the supervision of the study in Germany. AK was responsible for the acquisition and organization of the clinical data and eletronical reports. JRLS was responsible for the study design, interpretation of the results and coordination in Brazil. RR made the statistical analysis. MEP contributed to the writing of the introduction and literature revision. APC wrote part of the discussion and conclusion of the study. All authors read and approved the final manuscript.
The authors declare that they have no competing interests.
Consent for publication
Ethics approval and consent to participate
The ethic committees at the Lungenklinik Hemer (Lenkungsgruppe Forschung und Entwicklung Lungenklinik Hemer; Dec 12, 2012) and Federal University of Rio de Janeiro (Comitê de Ética e Pesquisa; # 339.171; Jul 04,2013) approved this study. Because this is a retrospective study, no patient was exposed to additional medical risks and there was no need to informed consent to participate. No individual data are exposed. Collected data were kept in a single computer with security measures to prevent access by unauthorized persons, avoid the release of information from the medical records and ensure secrecy and confidentiality.
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