Accepted Manuscript Trans-Esophageal Pulmonary Nodule Biopsy Using Endoscopic Ultrasound Basil S. Nasir , MD Marcel Edwards , MD Vicky Tiffault , RN Jordan Kazakov , MD Mohammed Khereba , MD Pasquale Ferraro , MD Moishe Liberman , MD, PhD PII:
S0022-5223(14)00736-3
DOI:
10.1016/j.jtcvs.2014.06.007
Reference:
YMTC 8654
To appear in:
The Journal of Thoracic and Cardiovascular Surgery
Received Date: 9 April 2014 Revised Date:
26 May 2014
Accepted Date: 2 June 2014
Please cite this article as: Nasir BS, Edwards M, Tiffault V, Kazakov J, Khereba M, Ferraro P, Liberman M, Trans-Esophageal Pulmonary Nodule Biopsy Using Endoscopic Ultrasound, The Journal of Thoracic and Cardiovascular Surgery (2014), doi: 10.1016/j.jtcvs.2014.06.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
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Trans-Esophageal Pulmonary Nodule Biopsy Using Endoscopic Ultrasound Basil S Nasir MD, Marcel Edwards MD, Vicky Tiffault RN, Jordan Kazakov MD, Mohammed Khereba MD, Pasquale Ferraro MD, Moishe Liberman MD, PhD
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CETOC – CHUM Endoscopic Tracheobronchial and Oesophageal Center, Department of Surgery, Division of Thoracic Surgery, University of Montréal, Montréal, Québec, Canada
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Running Head: EUS Lung Nodule Biopsy Article Word Count: 2782
Key Words: Endoscopic Ultrasound-Guided Fine Needle Aspiration; Lung Neoplasms; Diagnostic Techniques, Respiratory System
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Contact Information:
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MOISHE LIBERMAN, MD, PhD Director - C.E.T.O.C. Division of Thoracic Surgery Centre Hospitalier de l'Université de Montréal 1560 rue Sherbrooke Est 8e CD - Pavillon Lachapelle, bureau D-8051 Montréal, Québec, Canada H2L 4M1 Tel: (514)890-8000 poste 26832 Fax: (514)-412-7855 [email protected]
Presented in part at the 2014 Annual Meeting of the American Association for Thoracic Surgery. Toronto, Ontario. April 2014.
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ABSTRACT
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Objective: Parenchymal pulmonary nodules located in proximity to the mediastinum, vertebral column, major vessels, or behind the heart, can be technically challenging and dangerous to biopsy using traditional image-guided techniques. Endoscopic Ultrasound Fine Needle
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Aspiration (EUS-FNA) can be utilized to access some of these hard to reach lesions. The purpose of this study is to report on our experience with this technique in a consecutive cohort of
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selected patients.
Methods: This was a retrospective cohort study. Eligible patients were identified from a prospective database. A trans-esophageal approach under real-time EUS guidance was performed using a 22-gauge needle. All patients underwent post-procedural chest x-ray and
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were followed-up at thirty days.
Results: Over a 31-month period, 55 patients underwent EUS lung biopsy. Confirmatory visual
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correlation of nodule localization within the lung parenchyma between CT and EUS was
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possible in 100% of cases. Lung nodule distribution was 41.5% right upper lung, 18.9% right lower lung, 28.3% left upper lung, and 11.3% left lower lung. Histologic and cytologic sampling was adequate in 52 of the 55 procedures (94.5%). In all patients with adequate biopsy sampling, accurate pathocytological diagnoses of the target parenchymal nodules were obtained. Accuracy and sensitivity of EUS-FNA were both 94.5%, and consistent with diagnosis on pathological resection, with clinical progression of disease or with both factors. No morbidity resulted from the procedure, nor was observed at 30 days.
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Conclusions: EUS-FNA of parenchymal pulmonary nodules is safe, accurate and allows for
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biopsy of peri-mediastinal lung lesions, which are non-attainable using traditional techniques.
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Abstract Word Count: 249
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Ultramini Abstract
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Endoscopic ultrasound-guided fine needle aspiration can be used to access peri-mediastinal parenchymal pulmonary nodules that are difficult to reach using traditional means. In this study, EUS-FNA of parenchymal pulmonary nodules has been shown to be safe, accurate and
SC
allows for biopsy of peri-mediastinal lung lesions, which are non-attainable using traditional
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techniques.
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INTRODUCTION Lung cancer is the leading cause of cancer deaths in the United States, with an estimated
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incidence of 224,210 new cases in 2014.1 Patients with non-small cell lung cancer (NSCLC) typically present with a lung nodule or mass that may or may not be symptomatic. Recently, the National Lung Screening Trial (NLST) has shown that screening with low dose computed
SC
tomographic (CT) scan is efficacious and associated with reduced mortality.2 As a result, lung
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cancer screening is expected to increase the number of patients presenting for diagnostic evaluation of a pulmonary nodule or mass. In certain patients, tissue for pathologic analysis is required to rule out or rule in malignancy.
Many options exist for obtaining samples from the parenchymal lung nodule for pathologic
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analysis, including transthoracic image-guided needle aspiration (TTNA), transbronchial biopsy, endobronchial ultrasound guided biopsy, navigational bronchoscopic guidance biopsy and thoracoscopic or open lung biopsy. Parenchymal pulmonary nodules located in proximity to the
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mediastinum, in front of the vertebral column, in proximity to major vessels, or behind the heart, can be technically challenging and dangerous to biopsy using traditional image-guided
AC C
techniques. Endoscopic Ultrasound Fine Needle Aspiration (EUS-FNA) has become commonplace for diagnosing mediastinal lymph nodes in lung cancer; however, its utility in biopsying parenchymal pulmonary nodules is not known. This study reports on the largest reported experience with transesophageal needle aspiration of lung nodules using real-time endoscopic ultrasound.
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MATERIALS AND METHODS The study consists of a retrospective cohort study using a prospective interventional endoscopy
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research database. Patients presented to the CHUM Endoscopic Tracheobronchial and Oesophageal Center (C.E.T.O.C.) in the Division of Thoracic Surgery at the Centre Hospitalier de l'Université de Montréal over a 31-month period with a lung mass that was suspicious for either
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a primary or secondary neoplasm of the lung. Patients either had attempts at lung biopsy using traditional techniques which were unsuccessful at obtaining a diagnosis, were not eligible for
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traditional lung nodule biopsy due to anatomy or nodule location, or it was felt to be too dangerous to attempt traditional techniques for lung nodule biopsy. All patients undergoing transesophageal biopsy of an intraparenchymal lung lesion using real-time endoscopic ultrasound (EUS) during the study period were included. The aim of this study was to evaluate
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the rate of successful tissue sampling, accuracy of the diagnostic test and safety.
The Institutional Review Board (IRB) at the Research Center of the Centre Hospitalier de
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l'Université de Montréal approved the electronic prospective database used for this study and
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approved this trial. Patient consent was obtained for entry into the prospective database; the IRB granted a waiver for individual patient consent for this retrospective review.
All patients had standard diagnostic evaluation of their lung lesion with a history, physical examination and standard imaging studies. This included a CT of the chest and upper abdomen with intravenous contrast and 5 mm cuts. Positron emission tomography (PET) scans were undertaken in patients with suspicion for NSCLC. The PET scans were performed from the skull
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base to mid-thigh level. Maximum standardized uptake value (maxSUV) of the primary and of each suspicious lymph node station was determined. The clinical tumor (T), node (N), and
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metastasis (M) stage was recorded. In certain patients, a biopsy was desirable for treatment planning. Such patients included patients with a prior history of treated malignancy, patients with multiple co-morbidities who were high risk for lung resection, and patients considered for
SC
stereotactic body radiation treatment (SBRT). In addition, patients who met criteria for invasive mediastinal staging according to the most recent American College of Chest Physician’s
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guidelines were included if an EUS-guided lung biopsy was undertaken in conjunction with their staging procedure.3 Patients with endobronchial component were excluded, as biopsy of the lesion was undertaken transbronchially. All patients were reviewed for the possibility of a transthoracic or transbronchial needle biopsy by radiologists, pulmonologists and thoracic
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surgeons. In all patients, these procedures were either attempted and found to be nondiagnostic, or not deemed to be safe due to anatomy.
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EUS Technique
A Convex probe EUS scope was utilized to perform real-time transesophageal needle biopsy
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(EUS Linear Scope - GF-UC140P-AL5; Olympus America Inc., Center Valley, PA). A dedicated 22gauge needle (ECHO-1-22, Cook Medical Ireland Ltd., Limerick, Ireland) was used to perform all EUS needle biopsy procedures under real-time ultrasound guidance. No core-needle biopsies were utilized. No transvascular biopsies were performed. Smears were air dried and fixed on a slide. Additional samples were preserved in Cytolyt solution for cell block preparation. We perform as many passes as needed until we are satisfied with the gross appearance of the
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specimen. On average, this requires two to four passes. Rapid on-site evaluation by a cytopathologist was not performed. An upright chest X-ray was obtained in the recovery area
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following the procedure in order to rule-out iatrogenic pneumothorax. Conscious sedation was used in all procedures.
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Definitions and statistical methods
A negative result was defined as a lung nodule labeled as benign by EUS by an adequate needle
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aspiration that identified absence of tumor cells. A false negative was defined as the subsequent identification of malignancy, either by resection or biopsy by another means, within a mass that was deemed negative for malignancy by EUS-FNA. The efficacies (accuracy,
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sensitivity, negative predictive value) of these tests were computed using standard definitions.
RESULTS
Between October 2010 and May 2013, 1165 patients underwent combined endosonographic
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evaluation of biopsy-proven lung cancer or highly suspicious pulmonary lesions using combined endobronchial and endoesophageal ultrasound. Of those, 55 patients underwent planned
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transesophageal real-time ultrasonographic-guided biopsy of a suspicious lung lesion. The demographic data for these patients are included in table 1. For the remaining 1110 patients, none of them had an attempt at a transesophageal lung biopsy. Therefore, no patients had a planned transesophageal biopsy, but not attempted due to anatomical constraints. All patients had a CT scan of the chest and upper abdomen with at least 5 mm collimated cuts.
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In all patients, the lesion was visualized using ultrasonography and correlated with the suspicious lesion on CT. The distribution of location for all the lesions is shown in table 1, with
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the right and left upper lobes being the most common location for lesions within this series. Unsurprisingly, all the lesions were located within the inner third of the thoracic cavity making
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access via the esophagus feasible.
A diagnostic sample was obtained in 52 of the 55 patients, yielding a diagnostic yield of 94.5%.
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In all patients with adequate biopsy sampling, accurate pathocytological diagnoses of the target parenchymal nodules were obtained. Accuracy and sensitivity of EUS-FNA were both 94.5%, and consistent with diagnosis on pathological resection, with clinical progression of disease or with both factors. The distribution of the diagnoses is demonstrated in table 2. NSCLC was the
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most common diagnosis in the series. In all 3 patients with a non-diagnostic sample, additional pathologic analysis was obtained in the form an anatomic lung resection (2 pneumonectomy and 1 lobectomy). In all 3 patients, the final pathology confirmed the presence of NSCLC. There
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were no negative results, and all diagnostic results yielded a diagnosis of malignancy.
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Therefore, the prevalence of malignant disease in this series is 100%.
Nodule volume by EUS compared with CT had a Pearson product-moment correlation coefficient of 0.954 and student t-test of 0.044. Diagnostic accuracy was unaffected by tumor phenotype between non-small cell and small cell lung cancer.
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There were no patients with either pneumothorax or new pleural effusion on post-procedural chest x-ray. There were no immediate or 30-day complications related to the EUS lung biopsy
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procedure. All patients were discharged on the same day following their procedure. There were no readmissions for any procedure-related complications. No patients reported dysphagia or
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odynophagia on long-term follow-up.
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DISCUSSION With the advent of lung cancer screening, the incidence of lung nodules and masses requiring
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evaluation has increased. In the study, we have demonstrated the utility transesophageal ultrasound-guided lung biopsy in establishing a cytopathologic diagnosis in a much selected group of patients requiring biopsy, but where anatomical constraints make traditional means
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unfeasible. We report a diagnostic yield of greater than 90%, albeit in a selected group of
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patients with disease prevalence of 100%.
Regardless of stage, the goal of the initial evaluation is to confirm diagnosis and establish stage of disease with tests that have the highest accuracy with the lowest associated morbidity. Lung
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nodule biopsy options include transthoracic image-guided needle aspiration (TTNA), transbronchial biopsy (TBNA), endobronchial ultrasound guided biopsy, navigational bronchoscopic guidance biopsy and thoracoscopic or open lung biopsy. The choice of
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technique is largely dependent on the location of the lesion in question.
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For peripheral lesions, TTNA has been reported to be safe and efficacious, and is the procedure of choice for biopsy of lung lesions in this subset of patients. Geraghty et al. published their experience with TTNA in 846 patients.5 They described a sensitivity of 91% and specificity of 99%. The incidence of pneumothorax in the series was 38%. This was related partially to needle size, and they concluded that use of a coaxial 18-gauge needle may reduce the incidence of this complication without compromise of the diagnostic accuracy. However, studies on the efficacy
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of TTNA are limited to reports of peripheral lung lesion, and although little data exists for its role in central or hilar lesion, it only seems natural that test performance might be
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compromised. For such central lesions, TBNA has been the preferred approach. Multiple options exist including direct transbronchial biopsy, brush cytology, bronchoalveolar lavage, ultrasound guided and radial-probe endobronchial ultrasound, and more recently
electromagnetic navigational bronchoscopy. The reported sensitivity of TBNA in the setting of a
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visible endobronchial abnormality is 88%.6 However, this included patients with an
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endobronchial abnormality, be it a visible intraluminal lesion or extrinsic compression of a bronchus. Baalkani et al. examined the accuracy of TBNA techniques in relation to the distance from a central bronchus.7 They noted that the sensitivity of TBNA according to distance from the hilum. Yields of bronchoscopy in central, intermediate, and peripherally located lesions
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were 82%, 61%, and 53%, respectively. Thus, TBNA is preferred for central, peribronchial lesions, especially if an endobronchial component is found.
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In certain instances, a suspicious lesion may not be easily classified as a central or peripheral lesion. An example would be the in the patients whose scans are shown in figure 1. These
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lesions are located within the inner third of the thoracic cavity, out of the reach of TTNA in most institutions. However, they are not in a peribronchial location that is amenable to TBNA. These are peripheral lesions that are located adjacent to the mediastinal surface of the lung and are ideal for transesophageal biopsy. This is not a novel technique, and there have been reports in the literature of the use of EUS for biopsy of lung lesions. Araya et al. reported on the use of transesophageal needle biopsy for moleculear diagnosis of lung cancer.8 This study
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included 26 patients undergoing biopsy. The majority of the patients underwent biopsy of mediastinal lesions, however 5 patients had a biopsy of pulmonary nodules without
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complications. The diagnostic yield was 100% for lung cancer for combined transesophageal and bronchoscopic techniques, with an additional diagnostic gain of 69% for EUS and
bronchoscopy, versus bronchoscopy alone. Another study by Bugalho et al. demonstrated the efficacy of transesophageal endosonography in the diagnosis of lung lesions in 51 patients who
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underwent a nondiagnostic attempt using TTNA or TBNA9. The sensitivity, specificity and
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negative predictive value of combined transbronchial and transesophageal ultradound needle biopsy was 89.8%, 100% and 20% respectively. Similar to our study, this was a highly selected group of patients with a prevalence of malignancy of 97.5% and a mean lesion size of 32.1 mm. There are two additional reports of transesophageal EUS-guided lung biopsy using a dedicated
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EUS scope. The first report by Annema et al demonstrated a diagnostic yield of 97% in a group of 32 patients.10 A second study by Varadarajulu et al. reported on EUS-guided needle biopsy of lung lesions after unsuccessful attempts at CT-guided or bronchoscopic sampling to establish a
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tissue diagnosis.11 They demonstrated a 100% diagnostic yield in 18 patients.
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As we have demonstrated in our series, this technique is safe and yields a diagnosis 95% of the time. In the three patients where a diagnosis was not obtained, the result was inconclusive, as opposed to a false negative. This compares very well to contemporary reports of TTNA and TBNA techniques. Furthermore, recent data has shown that endosonographic mediastinal staging is at least as good as surgical staging using mediastinoscopy.12,13 The addition of a EUSguided lung biopsy at the same time during combined endosonographic staging seems logical.
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In a positive result, this may eliminate the need for an additional procedure such as TTNA. There is a theoretical risk of tumor seeding along the needle track. It is difficult to comment on
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such an incidence with a small number of patients and limited long-term follow-up. Anecdotally, however, we have not found any cases where tumor seeding along the needle
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track results in a change in stage or oncologic outcomes.
A comment should be made about the analysis of positive results. The gold standard for
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pathologic diagnosis is surgical resection of the nodule. If a patient underwent resection, then a positive result was confirmed on the final pathology. However, in this cohort, surgical resection was not undertaken in all patients due to advanced stage or medical inoperability. In patients with advanced disease, progression of disease was found on a median follow-up of 5 months.
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The most difficult group is the patients with early stage tumors who were medically inoperable. In all the patients a positive result by EUS was not confirmed and was assumed to be true.
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There are several limitations to this study. The most obvious is the fact that this series is a retrospective analysis that carries all the limitations inherent to such studies. Furthermore, the
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prevalence of malignant disease in this series is 100%. This is a highly selected group of patients with big tumors and significant fluoro-deoxyglucose avidity on PET such that the performance of any test is likely to be good. This raises three issues; the first is whether it is necessary to confirm such masses with a biopsy since the pretest probability is overwhelmingly in favor of malignancy. We believe that a biopsy is not necessary in cases that are resectable in low-risk patients, where the overwhelming likelihood is a primary lung cancer. However, in patients who
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are high risk for resection, or patients in which neoadjuvant or definitive chemotherapy or radiotherapy are indicated, a biopsy is desirable. Another group of patients that benefit from
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biopsy are patients with a history of treated extrathoracic malignancy, where the question is metastatic lesion versus primary lung cancer. In these patients, the treatment plans diverge significantly and a biopsy is indeed helpful in planning care. The second issue is related to the
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first one, insofar as that the cohort represents a highly selected group of patients with large tumors that were central with a prevalence of malignancy of 100%. Since this was our early
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experience we selected patients who had a high probability of success. Thus it is difficult to define the role of EUS-guided lung biopsy in smaller lesions. Now that we have more experience with the technique, we hope that in the future we may publish our results with smaller or more difficult to access lesions. The third issue is how to define the role of EUS lung biopsy in
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comparison to TTNA and TBNA. This is a difficult question to answer since this was not a comparative study, and TTNA or TBNA may certainly have performed well in a subset of patients with 100% prevalence of disease. Rather, EUS is a complimentary technique that can
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be used to confirm disease in case either TTNA or TBNA are not feasible. Patients in this study either had non-diagnostic TTNA or TBNA or were not candidates for TTNA or TBNA due to
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tumor location or patient anatomy.
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CONCLUSION In conclusion, we believe that this study demonstrates the feasibility and safety of EUS lung
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biopsy in patients with primary and secondary lung malignancies that require a tissue diagnosis. At our institution, in cases where a diagnosis is required prior to treatment, percutaneous transthoracic and transbronchial techniques remain the most common means of obtaining
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tissue from lung nodules. We use EUS lung biopsy in selected cases where there is a lesion
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adjacent to the mediastinum, but not located peribronchially such that transbronchial techniques are applicable. We use it mainly in situations where a pre-treatment biopsy will alter treatment, such as high-risk patients, patients with history of treated extrathoracic malignancy or to differentiate small cell lung cancer from NSCLC. We have demonstrated no
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complication in this small series.
Mean age (range)
63 years (39 - 83)
Female (%)
31 patients (56%)
Mean largest dimension on CT
49.3 mm (8 – 110) 2 patients (3.6%)
16-30 mm
10 patients (18%)
> 30 mm
43 (78%)
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S0022-5223(14)00736-3
DOI:
10.1016/j.jtcvs.2014.06.007
Reference:
YMTC 8654
To appear in:
The Journal of Thoracic and Cardiovascular Surgery
Received Date: 9 April 2014 Revised Date:
26 May 2014
Accepted Date: 2 June 2014
Please cite this article as: Nasir BS, Edwards M, Tiffault V, Kazakov J, Khereba M, Ferraro P, Liberman M, Trans-Esophageal Pulmonary Nodule Biopsy Using Endoscopic Ultrasound, The Journal of Thoracic and Cardiovascular Surgery (2014), doi: 10.1016/j.jtcvs.2014.06.007. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
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Trans-Esophageal Pulmonary Nodule Biopsy Using Endoscopic Ultrasound Basil S Nasir MD, Marcel Edwards MD, Vicky Tiffault RN, Jordan Kazakov MD, Mohammed Khereba MD, Pasquale Ferraro MD, Moishe Liberman MD, PhD
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CETOC – CHUM Endoscopic Tracheobronchial and Oesophageal Center, Department of Surgery, Division of Thoracic Surgery, University of Montréal, Montréal, Québec, Canada
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Running Head: EUS Lung Nodule Biopsy Article Word Count: 2782
Key Words: Endoscopic Ultrasound-Guided Fine Needle Aspiration; Lung Neoplasms; Diagnostic Techniques, Respiratory System
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Contact Information:
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MOISHE LIBERMAN, MD, PhD Director - C.E.T.O.C. Division of Thoracic Surgery Centre Hospitalier de l'Université de Montréal 1560 rue Sherbrooke Est 8e CD - Pavillon Lachapelle, bureau D-8051 Montréal, Québec, Canada H2L 4M1 Tel: (514)890-8000 poste 26832 Fax: (514)-412-7855 [email protected]
Presented in part at the 2014 Annual Meeting of the American Association for Thoracic Surgery. Toronto, Ontario. April 2014.
ACCEPTED MANUSCRIPT
ABSTRACT
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Objective: Parenchymal pulmonary nodules located in proximity to the mediastinum, vertebral column, major vessels, or behind the heart, can be technically challenging and dangerous to biopsy using traditional image-guided techniques. Endoscopic Ultrasound Fine Needle
SC
Aspiration (EUS-FNA) can be utilized to access some of these hard to reach lesions. The purpose of this study is to report on our experience with this technique in a consecutive cohort of
M AN U
selected patients.
Methods: This was a retrospective cohort study. Eligible patients were identified from a prospective database. A trans-esophageal approach under real-time EUS guidance was performed using a 22-gauge needle. All patients underwent post-procedural chest x-ray and
TE D
were followed-up at thirty days.
Results: Over a 31-month period, 55 patients underwent EUS lung biopsy. Confirmatory visual
EP
correlation of nodule localization within the lung parenchyma between CT and EUS was
AC C
possible in 100% of cases. Lung nodule distribution was 41.5% right upper lung, 18.9% right lower lung, 28.3% left upper lung, and 11.3% left lower lung. Histologic and cytologic sampling was adequate in 52 of the 55 procedures (94.5%). In all patients with adequate biopsy sampling, accurate pathocytological diagnoses of the target parenchymal nodules were obtained. Accuracy and sensitivity of EUS-FNA were both 94.5%, and consistent with diagnosis on pathological resection, with clinical progression of disease or with both factors. No morbidity resulted from the procedure, nor was observed at 30 days.
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Conclusions: EUS-FNA of parenchymal pulmonary nodules is safe, accurate and allows for
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biopsy of peri-mediastinal lung lesions, which are non-attainable using traditional techniques.
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Abstract Word Count: 249
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Ultramini Abstract
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Endoscopic ultrasound-guided fine needle aspiration can be used to access peri-mediastinal parenchymal pulmonary nodules that are difficult to reach using traditional means. In this study, EUS-FNA of parenchymal pulmonary nodules has been shown to be safe, accurate and
SC
allows for biopsy of peri-mediastinal lung lesions, which are non-attainable using traditional
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EP
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M AN U
techniques.
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INTRODUCTION Lung cancer is the leading cause of cancer deaths in the United States, with an estimated
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incidence of 224,210 new cases in 2014.1 Patients with non-small cell lung cancer (NSCLC) typically present with a lung nodule or mass that may or may not be symptomatic. Recently, the National Lung Screening Trial (NLST) has shown that screening with low dose computed
SC
tomographic (CT) scan is efficacious and associated with reduced mortality.2 As a result, lung
M AN U
cancer screening is expected to increase the number of patients presenting for diagnostic evaluation of a pulmonary nodule or mass. In certain patients, tissue for pathologic analysis is required to rule out or rule in malignancy.
Many options exist for obtaining samples from the parenchymal lung nodule for pathologic
TE D
analysis, including transthoracic image-guided needle aspiration (TTNA), transbronchial biopsy, endobronchial ultrasound guided biopsy, navigational bronchoscopic guidance biopsy and thoracoscopic or open lung biopsy. Parenchymal pulmonary nodules located in proximity to the
EP
mediastinum, in front of the vertebral column, in proximity to major vessels, or behind the heart, can be technically challenging and dangerous to biopsy using traditional image-guided
AC C
techniques. Endoscopic Ultrasound Fine Needle Aspiration (EUS-FNA) has become commonplace for diagnosing mediastinal lymph nodes in lung cancer; however, its utility in biopsying parenchymal pulmonary nodules is not known. This study reports on the largest reported experience with transesophageal needle aspiration of lung nodules using real-time endoscopic ultrasound.
ACCEPTED MANUSCRIPT
MATERIALS AND METHODS The study consists of a retrospective cohort study using a prospective interventional endoscopy
RI PT
research database. Patients presented to the CHUM Endoscopic Tracheobronchial and Oesophageal Center (C.E.T.O.C.) in the Division of Thoracic Surgery at the Centre Hospitalier de l'Université de Montréal over a 31-month period with a lung mass that was suspicious for either
SC
a primary or secondary neoplasm of the lung. Patients either had attempts at lung biopsy using traditional techniques which were unsuccessful at obtaining a diagnosis, were not eligible for
M AN U
traditional lung nodule biopsy due to anatomy or nodule location, or it was felt to be too dangerous to attempt traditional techniques for lung nodule biopsy. All patients undergoing transesophageal biopsy of an intraparenchymal lung lesion using real-time endoscopic ultrasound (EUS) during the study period were included. The aim of this study was to evaluate
TE D
the rate of successful tissue sampling, accuracy of the diagnostic test and safety.
The Institutional Review Board (IRB) at the Research Center of the Centre Hospitalier de
EP
l'Université de Montréal approved the electronic prospective database used for this study and
AC C
approved this trial. Patient consent was obtained for entry into the prospective database; the IRB granted a waiver for individual patient consent for this retrospective review.
All patients had standard diagnostic evaluation of their lung lesion with a history, physical examination and standard imaging studies. This included a CT of the chest and upper abdomen with intravenous contrast and 5 mm cuts. Positron emission tomography (PET) scans were undertaken in patients with suspicion for NSCLC. The PET scans were performed from the skull
ACCEPTED MANUSCRIPT
base to mid-thigh level. Maximum standardized uptake value (maxSUV) of the primary and of each suspicious lymph node station was determined. The clinical tumor (T), node (N), and
RI PT
metastasis (M) stage was recorded. In certain patients, a biopsy was desirable for treatment planning. Such patients included patients with a prior history of treated malignancy, patients with multiple co-morbidities who were high risk for lung resection, and patients considered for
SC
stereotactic body radiation treatment (SBRT). In addition, patients who met criteria for invasive mediastinal staging according to the most recent American College of Chest Physician’s
M AN U
guidelines were included if an EUS-guided lung biopsy was undertaken in conjunction with their staging procedure.3 Patients with endobronchial component were excluded, as biopsy of the lesion was undertaken transbronchially. All patients were reviewed for the possibility of a transthoracic or transbronchial needle biopsy by radiologists, pulmonologists and thoracic
TE D
surgeons. In all patients, these procedures were either attempted and found to be nondiagnostic, or not deemed to be safe due to anatomy.
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EUS Technique
A Convex probe EUS scope was utilized to perform real-time transesophageal needle biopsy
AC C
(EUS Linear Scope - GF-UC140P-AL5; Olympus America Inc., Center Valley, PA). A dedicated 22gauge needle (ECHO-1-22, Cook Medical Ireland Ltd., Limerick, Ireland) was used to perform all EUS needle biopsy procedures under real-time ultrasound guidance. No core-needle biopsies were utilized. No transvascular biopsies were performed. Smears were air dried and fixed on a slide. Additional samples were preserved in Cytolyt solution for cell block preparation. We perform as many passes as needed until we are satisfied with the gross appearance of the
ACCEPTED MANUSCRIPT
specimen. On average, this requires two to four passes. Rapid on-site evaluation by a cytopathologist was not performed. An upright chest X-ray was obtained in the recovery area
RI PT
following the procedure in order to rule-out iatrogenic pneumothorax. Conscious sedation was used in all procedures.
SC
Definitions and statistical methods
A negative result was defined as a lung nodule labeled as benign by EUS by an adequate needle
M AN U
aspiration that identified absence of tumor cells. A false negative was defined as the subsequent identification of malignancy, either by resection or biopsy by another means, within a mass that was deemed negative for malignancy by EUS-FNA. The efficacies (accuracy,
TE D
sensitivity, negative predictive value) of these tests were computed using standard definitions.
RESULTS
Between October 2010 and May 2013, 1165 patients underwent combined endosonographic
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evaluation of biopsy-proven lung cancer or highly suspicious pulmonary lesions using combined endobronchial and endoesophageal ultrasound. Of those, 55 patients underwent planned
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transesophageal real-time ultrasonographic-guided biopsy of a suspicious lung lesion. The demographic data for these patients are included in table 1. For the remaining 1110 patients, none of them had an attempt at a transesophageal lung biopsy. Therefore, no patients had a planned transesophageal biopsy, but not attempted due to anatomical constraints. All patients had a CT scan of the chest and upper abdomen with at least 5 mm collimated cuts.
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In all patients, the lesion was visualized using ultrasonography and correlated with the suspicious lesion on CT. The distribution of location for all the lesions is shown in table 1, with
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the right and left upper lobes being the most common location for lesions within this series. Unsurprisingly, all the lesions were located within the inner third of the thoracic cavity making
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access via the esophagus feasible.
A diagnostic sample was obtained in 52 of the 55 patients, yielding a diagnostic yield of 94.5%.
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In all patients with adequate biopsy sampling, accurate pathocytological diagnoses of the target parenchymal nodules were obtained. Accuracy and sensitivity of EUS-FNA were both 94.5%, and consistent with diagnosis on pathological resection, with clinical progression of disease or with both factors. The distribution of the diagnoses is demonstrated in table 2. NSCLC was the
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most common diagnosis in the series. In all 3 patients with a non-diagnostic sample, additional pathologic analysis was obtained in the form an anatomic lung resection (2 pneumonectomy and 1 lobectomy). In all 3 patients, the final pathology confirmed the presence of NSCLC. There
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were no negative results, and all diagnostic results yielded a diagnosis of malignancy.
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Therefore, the prevalence of malignant disease in this series is 100%.
Nodule volume by EUS compared with CT had a Pearson product-moment correlation coefficient of 0.954 and student t-test of 0.044. Diagnostic accuracy was unaffected by tumor phenotype between non-small cell and small cell lung cancer.
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There were no patients with either pneumothorax or new pleural effusion on post-procedural chest x-ray. There were no immediate or 30-day complications related to the EUS lung biopsy
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procedure. All patients were discharged on the same day following their procedure. There were no readmissions for any procedure-related complications. No patients reported dysphagia or
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odynophagia on long-term follow-up.
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DISCUSSION With the advent of lung cancer screening, the incidence of lung nodules and masses requiring
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evaluation has increased. In the study, we have demonstrated the utility transesophageal ultrasound-guided lung biopsy in establishing a cytopathologic diagnosis in a much selected group of patients requiring biopsy, but where anatomical constraints make traditional means
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unfeasible. We report a diagnostic yield of greater than 90%, albeit in a selected group of
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patients with disease prevalence of 100%.
Regardless of stage, the goal of the initial evaluation is to confirm diagnosis and establish stage of disease with tests that have the highest accuracy with the lowest associated morbidity. Lung
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nodule biopsy options include transthoracic image-guided needle aspiration (TTNA), transbronchial biopsy (TBNA), endobronchial ultrasound guided biopsy, navigational bronchoscopic guidance biopsy and thoracoscopic or open lung biopsy. The choice of
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technique is largely dependent on the location of the lesion in question.
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For peripheral lesions, TTNA has been reported to be safe and efficacious, and is the procedure of choice for biopsy of lung lesions in this subset of patients. Geraghty et al. published their experience with TTNA in 846 patients.5 They described a sensitivity of 91% and specificity of 99%. The incidence of pneumothorax in the series was 38%. This was related partially to needle size, and they concluded that use of a coaxial 18-gauge needle may reduce the incidence of this complication without compromise of the diagnostic accuracy. However, studies on the efficacy
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of TTNA are limited to reports of peripheral lung lesion, and although little data exists for its role in central or hilar lesion, it only seems natural that test performance might be
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compromised. For such central lesions, TBNA has been the preferred approach. Multiple options exist including direct transbronchial biopsy, brush cytology, bronchoalveolar lavage, ultrasound guided and radial-probe endobronchial ultrasound, and more recently
electromagnetic navigational bronchoscopy. The reported sensitivity of TBNA in the setting of a
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visible endobronchial abnormality is 88%.6 However, this included patients with an
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endobronchial abnormality, be it a visible intraluminal lesion or extrinsic compression of a bronchus. Baalkani et al. examined the accuracy of TBNA techniques in relation to the distance from a central bronchus.7 They noted that the sensitivity of TBNA according to distance from the hilum. Yields of bronchoscopy in central, intermediate, and peripherally located lesions
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were 82%, 61%, and 53%, respectively. Thus, TBNA is preferred for central, peribronchial lesions, especially if an endobronchial component is found.
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In certain instances, a suspicious lesion may not be easily classified as a central or peripheral lesion. An example would be the in the patients whose scans are shown in figure 1. These
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lesions are located within the inner third of the thoracic cavity, out of the reach of TTNA in most institutions. However, they are not in a peribronchial location that is amenable to TBNA. These are peripheral lesions that are located adjacent to the mediastinal surface of the lung and are ideal for transesophageal biopsy. This is not a novel technique, and there have been reports in the literature of the use of EUS for biopsy of lung lesions. Araya et al. reported on the use of transesophageal needle biopsy for moleculear diagnosis of lung cancer.8 This study
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included 26 patients undergoing biopsy. The majority of the patients underwent biopsy of mediastinal lesions, however 5 patients had a biopsy of pulmonary nodules without
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complications. The diagnostic yield was 100% for lung cancer for combined transesophageal and bronchoscopic techniques, with an additional diagnostic gain of 69% for EUS and
bronchoscopy, versus bronchoscopy alone. Another study by Bugalho et al. demonstrated the efficacy of transesophageal endosonography in the diagnosis of lung lesions in 51 patients who
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underwent a nondiagnostic attempt using TTNA or TBNA9. The sensitivity, specificity and
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negative predictive value of combined transbronchial and transesophageal ultradound needle biopsy was 89.8%, 100% and 20% respectively. Similar to our study, this was a highly selected group of patients with a prevalence of malignancy of 97.5% and a mean lesion size of 32.1 mm. There are two additional reports of transesophageal EUS-guided lung biopsy using a dedicated
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EUS scope. The first report by Annema et al demonstrated a diagnostic yield of 97% in a group of 32 patients.10 A second study by Varadarajulu et al. reported on EUS-guided needle biopsy of lung lesions after unsuccessful attempts at CT-guided or bronchoscopic sampling to establish a
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tissue diagnosis.11 They demonstrated a 100% diagnostic yield in 18 patients.
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As we have demonstrated in our series, this technique is safe and yields a diagnosis 95% of the time. In the three patients where a diagnosis was not obtained, the result was inconclusive, as opposed to a false negative. This compares very well to contemporary reports of TTNA and TBNA techniques. Furthermore, recent data has shown that endosonographic mediastinal staging is at least as good as surgical staging using mediastinoscopy.12,13 The addition of a EUSguided lung biopsy at the same time during combined endosonographic staging seems logical.
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In a positive result, this may eliminate the need for an additional procedure such as TTNA. There is a theoretical risk of tumor seeding along the needle track. It is difficult to comment on
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such an incidence with a small number of patients and limited long-term follow-up. Anecdotally, however, we have not found any cases where tumor seeding along the needle
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track results in a change in stage or oncologic outcomes.
A comment should be made about the analysis of positive results. The gold standard for
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pathologic diagnosis is surgical resection of the nodule. If a patient underwent resection, then a positive result was confirmed on the final pathology. However, in this cohort, surgical resection was not undertaken in all patients due to advanced stage or medical inoperability. In patients with advanced disease, progression of disease was found on a median follow-up of 5 months.
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The most difficult group is the patients with early stage tumors who were medically inoperable. In all the patients a positive result by EUS was not confirmed and was assumed to be true.
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There are several limitations to this study. The most obvious is the fact that this series is a retrospective analysis that carries all the limitations inherent to such studies. Furthermore, the
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prevalence of malignant disease in this series is 100%. This is a highly selected group of patients with big tumors and significant fluoro-deoxyglucose avidity on PET such that the performance of any test is likely to be good. This raises three issues; the first is whether it is necessary to confirm such masses with a biopsy since the pretest probability is overwhelmingly in favor of malignancy. We believe that a biopsy is not necessary in cases that are resectable in low-risk patients, where the overwhelming likelihood is a primary lung cancer. However, in patients who
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are high risk for resection, or patients in which neoadjuvant or definitive chemotherapy or radiotherapy are indicated, a biopsy is desirable. Another group of patients that benefit from
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biopsy are patients with a history of treated extrathoracic malignancy, where the question is metastatic lesion versus primary lung cancer. In these patients, the treatment plans diverge significantly and a biopsy is indeed helpful in planning care. The second issue is related to the
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first one, insofar as that the cohort represents a highly selected group of patients with large tumors that were central with a prevalence of malignancy of 100%. Since this was our early
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experience we selected patients who had a high probability of success. Thus it is difficult to define the role of EUS-guided lung biopsy in smaller lesions. Now that we have more experience with the technique, we hope that in the future we may publish our results with smaller or more difficult to access lesions. The third issue is how to define the role of EUS lung biopsy in
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comparison to TTNA and TBNA. This is a difficult question to answer since this was not a comparative study, and TTNA or TBNA may certainly have performed well in a subset of patients with 100% prevalence of disease. Rather, EUS is a complimentary technique that can
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be used to confirm disease in case either TTNA or TBNA are not feasible. Patients in this study either had non-diagnostic TTNA or TBNA or were not candidates for TTNA or TBNA due to
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tumor location or patient anatomy.
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CONCLUSION In conclusion, we believe that this study demonstrates the feasibility and safety of EUS lung
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biopsy in patients with primary and secondary lung malignancies that require a tissue diagnosis. At our institution, in cases where a diagnosis is required prior to treatment, percutaneous transthoracic and transbronchial techniques remain the most common means of obtaining
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tissue from lung nodules. We use EUS lung biopsy in selected cases where there is a lesion
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adjacent to the mediastinum, but not located peribronchially such that transbronchial techniques are applicable. We use it mainly in situations where a pre-treatment biopsy will alter treatment, such as high-risk patients, patients with history of treated extrathoracic malignancy or to differentiate small cell lung cancer from NSCLC. We have demonstrated no
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complication in this small series.
Mean age (range)
63 years (39 - 83)
Female (%)
31 patients (56%)
Mean largest dimension on CT
49.3 mm (8 – 110) 2 patients (3.6%)
16-30 mm
10 patients (18%)
> 30 mm
43 (78%)
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