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J Thorac Cardiovasc Surg 2009;137:413-418
© 2009 The American Association for Thoracic Surgery

General Thoracic Surgery

Should endobronchial ultrasonography be part of the thoracic surgeon's armamentarium?

^a University of Pittsburgh, Heart, Lung and Esophageal Institute, Pittsburgh, Pennsylvania
^b Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania
^c School of Dental Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

Received for publication May 2, 2008; revisions received August 19, 2008; accepted for publication September 16, 2008.

^_* Address for reprints: Sebastien Gilbert, MD, UPMC Presbyterian, Suite C-800, 200 Lothrop St, Pittsburgh, PA 15213. (Email: gilberts{at}upmc.edu).

	Abstract

Top Abstract Introduction Materials and Methods Results Discussion Conclusions References

 
Objective: The study objective was to determine the clinical usefulness and accuracy of endobronchial ultrasound-guided needle aspiration of mediastinal and hilar lymph nodes.

Methods: A retrospective analysis of a thoracic surgery unit's experience was performed.

Results: In a period of 19 months, 75 patients underwent the procedure (mean age = 65.5 ± 1.6 years; male to female = 2:1) most commonly for mediastinal lymphadenopathy in the setting of diagnosed or suspected lung cancer. It was diagnostic in 68.9% after rapid on-site evaluation and 74.3% after final cytologic examination. The rapid on-site evaluation and final cytology results were discordant in 16.2% (P < .001). In 50 cases, the needle aspirate cytology could be compared with pathology results. The sensitivity and specificity for the diagnosis of cancer were 85% and 100%, respectively. The false-negative rate endobronchial ultrasound cytology was 8.1%. Mediastinal lymph node station 7 was most commonly biopsied. The stations with the highest diagnostic yield were: 11R, 3, 10L, and 7. Of the patients with a positive positron emission tomography scan with suspected clinical stage III lung cancer, cancer was downstaged in 40% after endobronchial ultrasound.

Conclusion: Endobronchial ultrasound-guided needle aspiration is a clinically useful minimally invasive option for lung cancer staging and evaluation of mediastinal lymphadenopathy. The procedure should be considered complementary to mediastinoscopy.

	Introduction

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To date, thoracic surgeons have played an important role in the evaluation of mediastinal lymphadenopathy and the mediastinal staging of lung cancer. This is in large part due to their ability to safely and reliably perform mediastinoscopy. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a relatively new procedure that is often associated with the emerging field of interventional bronchoscopy. Such technology may result in significant changes to the established approaches to diagnosis and management of thoracic diseases. As more efficacy data become available, EBUS may assume an increasingly important role in the practice of thoracic surgery. Through learning and adaptation, thoracic surgeons will likely continue to expand their therapeutic armamentarium while playing a key role in critically appraising new technology. Our main objectives were to successfully integrate EBUS into our minimally invasive surgical practice and obtain data on its clinical usefulness and accuracy for the evaluation of mediastinal lymph nodes.

	Materials and Methods

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Patients and Personnel
With approval from the institutional review board, a retrospective review of all patients who underwent EBUS-TBNA from October 2006 to April 2008 was completed. Completion of a continuing medical education-approved EBUS course and 5 proctored cases were required to be granted privileges to perform the procedure independently. On-site training was provided to the technicians, therapists, nurses, and doctors involved.

Endobronchial Ultrasound Procedure
The technique and equipment necessary to perform EBUS-TBNA have already been described extensively.¹ Briefly, procedures were performed either transorally with topical anesthesia and monitored intravenous sedation or under general anesthesia with endotracheal intubation. The instrumentation used was manufactured by Olympus (Center Valley, Pa) and included the Evis Exera ultrasonic bronchoscope model BF-UC160F-OL8, the Evis Exera II video processor model CV-180, the Evis Exera II xenon light source model CLV-80, the EUS Exera CLA processor model EU-C60, and 22-gauge aspiration needles with syringe model NA-201SX-4022-A. During ultrasound examination of a lymph node station, the largest identified lymph node amenable to needle puncture was biopsied. A different aspiration needle was used at each lymph node station to avoid potential specimen contamination. All procedures were performed with a cytologist immediately available for rapid on-site evaluation (ROSE) of transbronchial needle aspirates. ROSE was performed on the first specimen retrieved from the aspiration needle after it had been air-dried and stained with Dif-Quick (American Scientific Products, McGaw Park, Ill). Another slide was prepared from the same initial specimen but was fixed in alcohol and processed at a later time using Papanicolaou staining. The remainder of the specimen was retrieved from the needle by reinserting the guide wire and flushing with preservation solution. It was later centrifuged, and the solid component was embedded in paraffin and processed using histology and immunohistochemistry techniques (eg, cytokeratin-7, cytokeratin-20, and thyroid transcription factor-1).

Interpretation of Cytology Results
As determined by the University of Pittsburgh's pathology department, nongynecologic cytology diagnostic categories included negative for malignant cells, atypical cells present, suspicious for malignant cells, and positive for malignant cells. The final cytology report, which became available a few days after the procedure, was reviewed and results of each nodal station biopsy were classified as positive, negative, or nondiagnostic. A result was considered positive only when the cytologic diagnosis was "positive for malignant cells." The results were classified as negative when the specimen was "negative for malignant cells" and the amount of lymphocytes was deemed adequate by the cytologist. All other final cytology results were classified as nondiagnostic. The EBUS-TBNA results were labeled diagnostic if they were either positive or negative. Mediastinoscopy, mediastinal lymph node sampling or dissection, and confirmatory immunohistochemistry panel on a positive EBUS specimen were considered acceptable reference pathologic tests to validate EBUS cytology results.

Statistics
Continuous variables are expressed as the mean value ± standard error of the mean. All tests of significance were 2-sided. Discrete variables were analyzed for statistically significant differences using the Pearson chi-squared method, and continuous variables were analyzed with the independent samples Student t test. Statistical calculations were performed using the Statistical Package for the Social Sciences (version 15, SPPS Inc, Chicago, Ill).

	Results

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Patients
From October 2006 to April 2008 (19 months), EBUS-TBNA was attempted in 76 patients and completed in 75 patients. One patient could not tolerate the procedure because of persistent severe cough despite sedation and topical anesthesia. The procedure was performed under sedation in 38.7% of cases and under general anesthesia with endotracheal intubation in the remainder. The procedures were performed by 4 thoracic surgeons (n = 59; 78.7%) and 1 pulmonologist (n = 16; 21.3%). No operator had previous clinical experience with EBUS. There were 50 men (66.7%) and 25 women (33.3%) aged 65.5 ± 1.6 years (range = 24–87 years). Sixteen patients (21.1%) had previous major pulmonary resection, and 4 patients (5.2%) had a previous mediastinoscopy. Pre-procedure diagnoses included lung cancer (n = 25; 33.3%), lung mass (n = 24; 32%), mediastinal lymphadenopathy (lymph node short axis > 1 cm) (n = 12; 16%), malignancy other than primary lung cancer (n = 12; 16%), and other (n = 2; 2.7%). The indications to perform EBUS-TBNA were mediastinal lymphadenopathy (n = 52; 69.3%), positive mediastinal or hilar lymph node(s) on positron emission tomography (PET) scan without lymphadenopathy (n = 16; 21.4%), mediastinal staging (ie, no lymphadenopathy and negative PET scan) (n = 6; 8%), and other (n = 1; 1.3%). There were no complications, and all patients were discharged within 24 hours of the procedure (98.7% on the same day).

PET/computed tomography (CT) scans were obtained before EBUS-TBNA in 70.6% (n = 53), and 81.1% of the scans (n = 43) were positive in mediastinal or hilar lymph nodes. In patients with a negative PET scan (n = 10), EBUS-TBNA was negative in 7 and nondiagnostic in 3. After subsequent pathologic testing (n = 8), EBUS-TBNA was positive for cancer in 1 of the patients with a negative PET scan. Of the patients with a positive PET scan (n = 43), EBUS-TBNA was positive for cancer in 13 (30.2%), negative in 16 (37.2%), and nondiagnostic in 14 (32.6%). Pathologic testing was available in 29 patients with positive PET scans; of these, 15 (34.9%; 15/43) were positive for cancer and 14 (32.6%; 14/43) were negative. On the basis of a positive mediastinal PET scan, clinical stage III lung cancer was suspected in 20 patients with no history of malignancy. In these patients, EBUS-TBNA was negative in 10 (50%), positive in 6 (30%), and nondiagnostic in 4 (20%). Of the 10 patients in whom EBUS was negative, 2 had positive mediastinal lymph nodes after mediastinoscopy.

Lymph Node Stations
The number of lymph node stations sampled was 1 in 56% (n = 42), 2 in 24% (n = 18), 3 in 18.7% (n = 14), and 4 in 1.3% (n = 1). The lymph node stations sampled were station 7 (n = 42; 56%), station 4R (n = 29; 38.7%), station 10R (n = 20; 26.7%), station 4L (n = 15; 20%), station 10L (n = 7; 9.3%), station 3 (n = 7; 9.3%), station 11R (n = 4; 5.3%), and station 11L (n = 1; 1.3%). Stations 2R and 2L were not sampled in any of the patients. Table 1 summarizes the diagnostic yield at mediastinal stations that were sampled in 10 patients or more. The concordance column reflects the proportion of patients in whom the results were the same on ROSE and final EBUS cytology. The overall mean number of needle passes used to sample lymph nodes was 2.1 ± 0.1 (range, 1–6). The diagnostic yield ranged from 58.6% to 100%, and the stations with the highest yields were 11R, 3, 10L, and 7. For all the sampled stations, there was complete agreement between ROSE and final cytology when the lymph nodes were positive for cancer. When the ROSE was negative, cytology results were concordant in 85.7% to 100%. In the most commonly sampled lymph node stations (Table 1), final cytologic examination yielded a diagnosis in 12.5% to 50% of patients in whom ROSE was deemed nondiagnostic. At the time of final cytologic examination, the cytopathologist has access to additional biopsy material in the form of a slide smear stained with the Papanicolaou method and cell block preparations from centrifuged biopsy material. This may explain the observed difference in diagnostic yield between ROSE and final cytology.

In two thirds of patients (n = 50), the results of EBUS-TBNA could be compared with mediastinoscopy (n = 34; 45.3%), immunohistochemistry (n = 11; 14.7%), or intraoperative mediastinal lymph node sampling (n = 5; 6.7%). In the remaining 25 patients, additional biopsies were not obtained after EBUS for the following reasons: single or multiple lymph node stations found positive for cancer (n = 5; 20%), specific benign diagnosis obtained (eg, sarcoidosis) (n = 5; 20%), not a surgical candidate or declined additional procedures (n = 4; 16%), previous mediastinoscopy (n = 4; 16%), abnormal lymph node not accessible by mediastinoscopy (n = 2; 8%), and other (n = 5; 20%). When the EBUS cytology was nondiagnostic (n = 13; 24%), the pathology was benign in 61.5% (n = 8) and malignant in 38.5% (n = 5). Three of 18 patients (16.6%) with benign cytology were eventually found to have cancer. In all patients in whom EBUS-TBNA cytology was positive for cancer, the pathologic testing was also positive for cancer. More specifically the cytologic diagnosis was correct in 90% of non–small cell lung cancers, 100% of small cell lung cancers and metastatic cancers from a primary other than the lung, and 50% of sarcoidosis cases. In the subgroup of patients with a diagnostic EBUS-TBNA (n = 37), the sensitivity, specificity, positive predictive value, and negative predictive value for the detection of cancer were 85%, 100%, 100%, and 85%, respectively. The false-negative rate of EBUS-TBNA cytology was 8.1%.

Diagnostic Failures
The patient's diagnosis or the indication to perform EBUS-TBNA did not have a significant influence on the overall diagnostic success rate. The presence or absence of lymphadenopathy on CT scan and the PET findings (positive or negative), analyzed alone or in all possible combinations, did not influence the probability of obtaining diagnostic cytology. There was no significant difference in the average number of lymph node stations biopsied between the diagnostic and nondiagnostic EBUS cases. Overall, there was no threshold number of procedures after which the diagnostic rate improved. This was also true for 2 of the operators who each performed more than 20 procedures. The probability of failure to obtain a tissue diagnosis was also independent of the operator's qualifications (surgeon vs pulmonologist).

	Discussion

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In small peripheral lung tumors with no lymphadenopathy, a negative mediastinal PET or PET/CT scan may be helpful in guiding a selective approach to mediastinoscopy. The probability that such patients have mediastinal lymph node metastases is low.² On the other hand, PET scanning has a significant rate of false-positive results for mediastinal lymph node metastases in patients with lung cancer.³ Therefore, it may be best to confirm positive mediastinal PET findings with a lymph node biopsy. This course of action should minimize stage misclassification and ensure that surgical candidates are not denied potentially curative resection. In patients with a positive mediastinal PET scan, EBUS may be helpful in determining whether lymph nodes are truly involved with cancer. If the EBUS-TBNA is positive for cancer, mediastinoscopy may not be necessary as illustrated in Figure 1 . Our preliminary experience seems to support the use of EBUS-TBNA as complementary to mediastinoscopy in obtaining diagnostic tissue from mediastinal lymph nodes. Some investigators may be of the opinion that EBUS, in combination with endoscopic esophageal ultrasound, may eventually render mediastinoscopy obsolete.⁴ They may quote that as many as 54.4% of mediastinoscopies yield no lymphoid tissue on final pathology.⁵ However, this seemingly high proportion would be more accurately interpreted in light of the qualifications of the surgeons performing mediastinoscopy. Unfortunately, this information is not available. The yield of mediastinoscopy seems to be substantially higher in large case series (ie, >3000 patients) published by thoracic surgeons.^6,7

View larger version (15K): [in this window] [in a new window]   Figure 1. Diagnostic approach to the patient with suspected malignant mediastinal lymphadenopathy. CT, Computed tomography; PET, positron emission tomography; LN, lymph node; EBUS, endobronchial ultrasound.

The final cytology report is usually available within a few days of the procedure. In previously published larger (ie, n > 100) EBUS case series, the sensitivity, specificity, positive predictive values, and negative predictive values were 92.3% to 94.6%, 100%, 100%, and 11% to 97.4%, respectively.^11-13 Although only a subset of our patients (66.6%) had pathologic testing in addition to EBUS cytology, we found this proportion to be comparable to published literature (6%–100%).^11-13 Although in our study population, the specificity (100%) was similar to published data, the sensitivity (85%) was slightly lower. The diagnostic yield of cytology was also lower in our study (74.3% vs 93.5%–100%).^11-13 Once again, the lower sensitivity and diagnostic accuracy in our study group may be due to differences in disease prevalence between study populations (44% vs 25.5%–100%). Other potential factors (ie, operator, number of cases, diagnosis, indication, preoperative imaging, and number of stations sampled) did not have a significant influence on diagnostic accuracy.

We realize that the results must be interpreted in light of the limitations inherent to a retrospective study design. We also acknowledge that generalizations regarding diagnostic performance may be limited by the need for subset analysis. Because this was not a prospective research protocol, mediastinoscopy was performed when judged clinically appropriate. At this point in our experience, the results lend support to the use of mediastinoscopy when EBUS-TBNA is negative or nondiagnostic. In selected patients where the cytology is positive for cancer, a specific benign diagnosis is obtained, the operator is confident that the scope was positioned accurately, and the needle puncture sites are in the correct anatomic location, it may be reasonable to forego mediastinoscopy. The relationship between EBUS and mediastinoscopy will likely be refined once more data are available.

	Conclusions

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Our results have guided the design of a clinical pathway for the use of EBUS in the evaluation of patients with abnormal mediastinal lymph nodes on CT or PET scan (Figure 1). Acquired experience with EBUS provides preliminary data and mitigates the potential negative effects of procedural training and learning curve on diagnostic performance. Although the actual needle sampling technique is relatively easy to master, it is our impression that a significant period of adaptation and learning is necessary to understand endobronchial ultrasonography of the mediastinum. The ultrasound image is dynamic rather than static and often presents anatomic relationships in planes that are different from standard CT scanning. Because of operative experience, the thoracic surgeon may be in a favorable position to understand the anatomic relationships displayed during EBUS. Although major societies have recommended at least 40 to 50 supervised procedures to establish basic EBUS competency, this requirement may be less for surgeons who routinely perform bronchoscopy and mediastinal procedures.^14,15 Emerging minimally invasive diagnostic modalities will continue to challenge established approaches. To remain at the forefront of the diagnosis, staging, and management of lung cancer, surgeons should invest the time and effort necessary to evaluate new technology firsthand.

	References

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Sebastien Gilbert David O. Wilson Neil A. Christie James D. Luketich Rodney J. Landreneau Matthew J. Schuchert Permission Requests Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Gilbert, S. Articles by Schuchert, M. J. Search for Related Content PubMed Articles by Gilbert, S. Articles by Schuchert, M. J. Related Collections Lung - cancer