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* From the Department of Pneumology and Critical Care Medicine (Drs. Eberhardt and Herth), Thoraxklinik, University of Heidelberg, Heidelberg, Germany; and the Department of Interventional Pulmonology (Drs. Anantham, Feller-Kopman and Ernst), Beth Israel Deaconess Medical Center, Harvard University Medical School, Boston, MA.
Correspondence to: Armin Ernst, MD, FCCP, Chief, Interventional Pulmonology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston MA 02215; e-mail: aernst{at}bidmc.harvard.edu
Abstract
Background: Electromagnetic navigation bronchoscopy (ENB) with biopsy under fluoroscopic guidance has enhanced the yield of flexible bronchoscopy in the diagnosis of peripheral lung lesions. However, the accuracy of ENB navigation suggests that the addition of fluoroscopy is redundant.
Objectives: Data were prospectively collected to determine the yield of ENB without fluoroscopy in the diagnosis of peripheral lung lesions.
Method: ENB was performed via flexible bronchoscopy (superDimension/Bronchus system; superDimension Inc; Plymouth, MN). Biopsy specimens were obtained through the extended working channel after navigation. Fluoroscopy was not utilized, but post-transbronchial biopsy chest radiographs were obtained to exclude pneumothorax. The primary end point was diagnostic yield, and the secondary end points were navigation accuracy, procedure duration, and safety. Analysis by lobar distribution was also performed to assess performance in different lobes of the lung.
Results: Ninety-two peripheral lung lesions were biopsied in the 89 subjects. The diagnostic yield of ENB was 67%, which was independent of lesion size. Total procedure time ranged from 16.3 to 45.0 min (mean [± SD] procedure time, 26.9 ± 6.5 min). The mean navigation error was 9 ± 6 mm (range, 1 to 31 mm). There were two incidences of pneumothorax for which no intervention was required. When analyzed by lobar distribution, there was a trend toward a higher ENB yield in diagnosing lesions in the right middle lobe (88%).
Conclusions: ENB can be used as a stand-alone bronchoscopic technique without compromising diagnostic yield or increasing the risk of pneumothorax. This may result in sizable timesaving and avoids radiation exposure.
Key Words: electromagnetic navigation bronchoscopy • peripheral lung lesion • solitary pulmonary nodule • transbronchial lung biopsy
The yield of flexible bronchoscopy in the diagnosis of peripheral lung lesions and solitary pulmonary nodules is limited. The reported sensitivity for peripheral bronchogenic carcinoma ranges from 36 to 86% and is dependent on lesion size.12 Pilot studies have shown that electromagnetic navigation bronchoscopy (ENB) may enhance this yield (Table 1 ). The reported yields have ranged from 69 to 82%, and appear to be independent of lesion size and lobar distribution.345
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The accuracy of ENB navigation has been proven in animal studies6 and against fluoroscopically verified reference points in humans.7 Nevertheless, all preceding diagnostic studies utilizing ENB also used fluoroscopy to guide biopsies. The role of ENB as a stand-alone technology is still unproven, and concerns remain that biopsy instruments may dislodge an accurately positioned EWC when replacing the sensor probe.5 Data were prospectively collected and retrospectively analyzed to determine the yield of ENB without fluoroscopy in the diagnosis of peripheral lung lesions and solitary pulmonary nodules.
Materials and Methods
Eighty-nine patients underwent ENB at our two centers between February 2005 and August 2006. Inclusion criteria were subjects above the age of 18 years, who signed informed consent forms and were candidates for elective bronchoscopy. They all had evidence of peripheral lung lesions or solitary pulmonary nodules with no evidence of endobronchial pathology. Pregnant patients and those with implantable pacemakers or defibrillators were excluded. The institutional review boards of both of the participating centers approved this study.
The primary end point was diagnostic yield. If the ENB-guided biopsy yielded a definitive histologic diagnosis, this was considered to be ENB success. If the ENB-guided biopsy result was nondiagnostic, then additional procedures such as CT scan-guided transthoracic needle aspiration biopsy or surgery was undertaken to make the diagnosis. This was considered to be ENB failure. However, if an ENB-guided biopsy yielded a plausible negative diagnosis and if patients were unable or unwilling to undertake further diagnostic testing, clinical and radiologic follow-up was used to monitor stability. This follow-up extended to a mean (± SD) duration of 16.1 ± 1.8 months (range, 6 to 22 months) until the submission of data. If the lesions remained stable, then the negative ENB-guided biopsy result was considered a success. Analysis by lobar distribution was performed to identify any differences in yield by lesion location.
Secondary end points included the ability of the ENB system to navigate accurately to the lesions, as displayed by the location of the sensor tip on the ENB screen. The duration of each phase of the procedure was also documented to assess the time burden of ENB on diagnostic bronchoscopy. Finally, the safety of the procedure was assessed by reporting all complications.
ENB Procedure
One ENB system (superDimension/Bronchus; superDimension Inc; Plymouth, MN) was used for the procedures. All patients underwent noncontrast CT scans of the chest with slice thicknesses of 2 to 3.5 mm and slice intervals of 1 to 2.5 mm (with an overlap of 1 mm). The initial planning phase involved importing the CT scan data into the software (superDimension) using the standard format (Digital Imaging and Communications in Medicine; Rosslyn, VA). Registration points were marked by identifying five to seven prominent anatomic landmarks on the virtual bronchoscopy images. The center of the target lesion was also marked.
The patient was then placed on the electromagnetic location board (470 x 560 mm). Bronchoscopy was performed via the oral route using an adult therapeutic bronchoscope (model IT160; Olympus; Tokyo, Japan) with a 2.8-mm working channel. General anesthesia was used in 55 patients, and moderate sedation (using bolus IV midazolam and fentanyl) was used in 34 patients. All patients were given adequate amounts of local anesthesia for the airways using topical lidocaine to avoid coughing. Endobronchial mapping was achieved when the virtual fiducial registration points were linked to the actual position in the patient’s thorax. The software documented the registration error, which represents the radius of the expected difference in location between the tip of the sensor probe in the actual patient and where the tip is expected to be. The registration error could then be reduced by either repositioning a misplaced landmark or by eliminating the landmarks with the greatest deviation. The sensor probe width is 1.9 mm and has a working length of 972 mm.
Navigation was completed by wedging the bronchoscope in the suspected bronchial segment and steering the sensor probe together with the EWC to the lesion using the multiplanar CT scan images and the "tip-view" orientation. The EWC has a working length of 945 mm and requires a minimum bronchoscope instrument channel width of 2.0 mm. The navigation error is the closest distance between the sensor probe and the lesion center.
After navigation to the lesion was complete, specimens were obtained through the EWC by washings, with transbronchial needle, brush, or forceps biopsy, or a combination, depending on the judgment of the four attending interventional pulmonologists who performed all of the procedures. Rapid on-site cytopathologic evaluation was not used. All patients received a postprocedure chest radiograph to identify any iatrogenic pneumothorax after transbronchial lung biopsy.
Statistical Analysis
Statistical analyses were performed using a statistical software program (SAS; SAS Institute; Cary, NC). Continuous variables are expressed using mean and SD. Dichotomous variables are summarized as simple proportions. Comparisons of continuous variables were performed in univariate analyses with the Student t test when two sample means were compared, and analysis of variance when multiple sample means were compared. The Fisher exact test was used for comparing proportions. A two-tailed p value of < 0.05 indicated statistical significance.
Results
Ninety-two peripheral lung lesions were biopsied in the 89 subjects, of whom 39 (44%) were female. The mean age was 67 ± 12 years (age range, 29 to 95 years). The mean size of lesions was 24 ± 8 mm (range, 10 to 58 mm); the mean number of forceps biopsies performed was 5 ± 1 (range, 0 to 11). A single patient had no forceps biopsies because the navigation error was 31 mm despite multiple attempts. This was attributed to the possible absence of a bronchus leading to the lesion. The bronchial washings were negative; however, the surgical diagnosis was consistent with non-small cell carcinoma.
Diagnostic Yield
The overall diagnostic yield of ENB was 67%. This appeared to be independent of size (Table 2
). The sensitivity, specificity, positive predictive value, and negative predictive value for malignant disease were 60%, 100%, 100%, and 44%, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value for benign disease were 91%, 100%, 100%, and 97%, respectively. ENB yielded a definitive histologic diagnosis in 52 lesions (57%). In 24 patients with 26 lesions, further diagnostic testing yielded an alternative diagnosis when ENB was nondiagnostic. The final diagnoses from either ENB or alternative testing are listed in Table 3
. A further 14 lesions were followed up for clinical and radiologic stability for a mean duration of 16.1 ± 1.8 months (range 6 to 22 months). To date, 10 lesions proved to have true-negative results and were designated as ENB successes. The histologic reading on these patients was chronic inflammation. A single patient died 6 months after undergoing the procedure with a clinical diagnosis of disseminated malignancy. Two patients had radiologic findings that were consistent with malignancy but declined further biopsy procedures because of age, comorbidities, and potential risks. One other patient had the clinical course of a chronic pulmonary infection, and the lesion cleared with antibiotics. These four patients were designated as ENB failures. When analyzed by lobar distribution, there was a suggestion of a higher ENB yield in diagnosing lesions in the right middle lobe, but, because of the small sample size, this did not reach statistical significance (Table 2).
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Procedure Details
The mean number of registration points used in planning was 8 ± 1 (range, 5 to 9). The mean registration error was 4.6 ± 1.8 mm (range 1.8 to 10.4 mm). In 34 patients, registration was repeated at the operator’s discretion to improve accuracy, and this resulted in a mean reduction of registration error of 1.5 ± 1.7 mm. The mean navigation error was 9 ± 6 mm (range 1 to 31 mm).
Total procedure time ranged from 16.3 to 45.0 min (mean time, 26.9 ± 6.5 min). The mean registration time was 3.2 ± 2.3 min (range, 0.8 to 15.0 min), and the mean navigation time was 4.5 ± 3.4 min (range 0.3 to 15.0 min). Procedure timing and registration/navigation error by lobar distribution showed no lobar variation (Table 2).
Safety
There were two cases of pneumothorax that were discovered on the postprocedure chest radiograph. The first patient had a left lower lobe lesion that was 26 mm in its largest dimension and had six forceps biopsy specimens along with bronchial washings and brush specimens taken. The second patient had two lesions in the right lower lobe that were 12 and 19 mm in size. This patient had a total of nine forceps biopsy specimens taken from the two lesions, as well as washings and brush specimens. The two pneumothoraces were described by the reporting radiologists to be tiny and apical. Both patients were asymptomatic. No intervention or hospitalization was necessary. Another 81-year-old patient required postprocedure endotracheal intubation and temporary mechanical ventilation (< 24 h) for hypercapnic respiratory failure that was related to the sedation given. In one further case, repeated insertion and removal of the biopsy forceps perforated the EWC.
Discussion
In this largest series to date, we have shown that ENB can be used as an independent bronchoscopic technique without the need for fluoroscopy when compared with other available studies. There was no compromise in the diagnostic yield and no increased risk of pneumothorax. This yield was attributable to the small registration error (< 5 mm) and navigation error (< 10 mm) that occurred. Our pneumothorax rate (2 of 89 patients; 2%) compares favorably with those of preceding studies,35 in which the observed rate was 3% and pleural drainage was necessary. There also appears to have been a marked reduction in procedure time compared to clinical data from a prior study,5 which reported a mean total ENB time of 51 ± 13 min. This makes the procedure time more feasible in terms of the delivery of moderate sedation by nonanesthesiologists.
Our diagnostic yield was independent of lobar distribution, although a larger series may prove that the trend toward a better yield in the right middle lobe may indeed be significant. The upper lobes tend to have sharper angles in the bronchial tree that may be challenging to navigate even with a steerable sensor probe. The EWC ends close to the tip of the sensor probe and makes it less flexible. This reduces the range of deflection and, consequently, the ability to navigate. It can also make the probe flip into a different position when negotiating some tight angles in the bronchi.3 Furthermore, these tight angles may result in the EWC being more easily dislodged when stiffer biopsy devices like forceps are passed through them.5 Navigation in the lower lobes is more affected by diaphragmatic movement during breathing and could result in larger errors than recorded. This is because the planning data are based on CT scan images acquired in a single breathhold.3
The size of the lesion did not prove to be a determinant in diagnostic yield. The improved yield of ENB compared to conventional transbronchial lung biopsy in small lesions (ie, those < 20 mm in diameter) can be attributed to the improved precision in navigation. The lack of further gains in the yield with larger lesions may be due to the fact that these larger lesions tend to distort and occlude the airways leading up to them. This could result in the sensor probe ending up adjacent to the lesion rather than within the lesion. Navigation to the margin of the lesion rather than to the center and the utilization of biopsy tools like transbronchial needle aspiration biopsy may be able to overcome this.3
The design of this study did not allow direct comparisons with other techniques, and only historical comparisons are possible. A randomized controlled trial within the same institution utilizing ENB with or without fluoroscopy is needed to make definitive conclusions about the comparative yield. In our series, there were also variations in the number of biopsy specimens obtained and the biopsy instruments used, such as forceps, brushes, or needles. This is reflective of the clinical pretest suspicion, the CT scan characteristics of the lesions (ie, solid vs infiltrative), as well as the patients’ tolerance of sedation. The fact that not all patients who were designated as ENB successes had a definitive final histologic diagnosis is yet another limitation. However, this represents true clinical conditions in which a surgical or even transthoracic needle aspiration poses significant risks to elderly patients with limited pulmonary reserve. Our patients were followed up for nearly 2 years, at which time they would be considered to have stable lesions according to recommended guidelines.89
This study has shown the yield, safety, and timesaving with use of the ENB system without the need for fluoroscopy. This system elininates radiation exposure and could reduce procedure costs. The diagnostic utility of the use of ENB in the biopsy of peripheral lung lesions appears to be equivalent to other advanced techniques like endobronchial ultrasound.1011121314 These techniques have pushed bronchoscopic biopsy yields closer to those achieved by CT scan-guided transthoracic needle biopsy and surgery. Given the relative comfort15 and safety16 of flexible bronchoscopy, and the recognized risks of both CT scan-guided17181920 and surgical biopsies,2122 there is an impetus to develop and refine these techniques. The expanded role of lung cancer screening, in which the vast majority of lesions is benign, makes this all the more important.23 The future of ENB may see improved means of specimen collection with dedicated instruments. Multimodality diagnosis by combining ENB with other bronchoscopic and imaging techniques may further enhance the diagnostic yield.
Acknowledgements
Dr. Roger Davis from Department of Medicine, Beth Israel Deaconess Medical Center (Boston, MA) assisted with the statistical analysis. Robert Garland from Interventional Pulmonology, Beth Israel Deaconess Medical Center (Boston, MA) assisted with data collection.
Footnotes
Abbreviations: ENB = electromagnetic navigation bronchoscopy; EWC = extended working channel
A portion of these data has been accepted as an abstract for the 2007 American Thoracic Society International Conference.
The locatable sensor probes at both Thoraxklinik and Beth Israel Deaconess Medical Center were provided free of charge by superDimension/Bronchus. superDimension/Bronchus has supported CME courses at the Thoraxklinik Heidelberg and Harvard University through unrestricted educational grants. Dr. Ernst was a member of the Scientific Advisory Board of superDimension/Bronchus and had been reimbursed for time and travel expenses related to that function. Dr. Ernst also had stock options, which have been returned in the past. Dr. Ernst was not involved in the consenting process of patients. Drs. Eberhardt, Anantham, Herth, and Feller-Kopman have reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Received for publication December 15, 2006. Accepted for publication February 27, 2007.
References
2-cm) subpleural pulmonary lesions: short- versus long-needle-path CT-guided biopsy: comparison of diagnostic yields and complications. Radiology 2005;234,631-637This article has been cited by other articles:
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  D. Makris and K. I. Gourgoulianis Electromagnetic Navigation Diagnostic Bronchoscopy and Transbronchial Biopsy Chest, March 1, 2008; 133(3): 829 - 830. [Full Text] [PDF]
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