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Ann Thorac Surg 2008;85:1874-1878. doi:10.1016/j.athoracsur.2008.02.031
© 2008 The Society of Thoracic Surgeons
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Original Articles: General Thoracic

Endobronchial Ultrasound-Guided Miniforceps Biopsy in the Biopsy of Subcarinal Masses in Patients with Low Likelihood of Non-Small Cell Lung Cancer

Felix J.F. Hertha, Ross K. Morgan, MDb, Ralf Eberhardt, MDa, Armin Ernst, MD, FCCPa,b,*

a Department of Pneumology and Critical Care Medicine, Thoraxklinik at University Heidelberg, Germany
b Interventional Pulmonology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts

Accepted for publication February 11, 2008.

* Address correspondence to Dr Ernst, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215 (Email: aernst{at}bidmc.harvard.edu).


Dr Ernst discloses that he has a financial relationship with Olympus Ltd.

 

   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
Background: Transbronchial needle aspiration (TBNA) is used to sample mediastinal masses, but the value may be limited by the small specimen size obtained. In benign diseases and hematologic malignancies, the sample size from TBNA is often considered insufficient for diagnosis. We evaluated the safety and efficacy of obtaining histologic specimens from subcarinal masses using a 1.15-mm miniforceps under endobronchial ultrasound (EBUS) guidance and compared the diagnostic yield with TBNA alone.

Methods: Patients being evaluated for subcarinal lesions exceeding 2.5 cm (short axis) and without known or suspected non-small cell lung cancer were included. Bronchoscopy was performed, and EBUS-guided BNA of the lesion was performed first with a 22-gauge needle, followed by the 19-gauge needle. The miniforceps was then passed through the airway into the lesion (three to five passes) under real-time EBUS guidance. Three biopsy specimens were obtained.

Results: The study enrolled 75 patients (41 men; mean age, 51.5 years). Specimens were acquired from each patient using the three techniques and processed separately. A specific diagnosis was made in 36% of patients with the 22-gauge needle, 49% with the 19-gauge needle, and in 88% with the miniforceps. The increase in diagnostic yield with miniforceps was most significant in patients with sarcoidosis (88% vs 36% for TBNA, p = 0.001) or lymphoma (81% vs 35%, p = 0.038). No complications occurred.

Conclusions: Miniforceps biopsy, performed under real-time EBUS guidance, can be used to obtain tissue specimens from subcarinal masses adjacent to the airway. The diagnostic yield for lymphoma and sarcoidosis is superior to TBNA alone, and the procedure appears safe.

Since the introduction of a flexible needle for use through the bronchoscope more than 20 years ago, transbronchial needle aspiration (TBNA) has become an accepted technique for obtaining diagnostic samples from enlarged mediastinal lymph nodes [1, 2]. The reported yield of TBNA ranges widely, however, and largely depends on the prevalence of non-small cell lung cancer in the study population, where it performs well [3]. The recent development of endobronchial ultrasound (EBUS), which permits direct visualization and puncture of mediastinal nodes, has been found to increase further the diagnostic value of TBNA in patients with malignant nodal involvement [4–6].

Difficulties with TBNA, however, arise in diseases in which good histologic specimens are desirable for diagnosis, for example, in lymphoma or in nonmalignant disorders such as sarcoidosis. Although a number of studies have recently reported that EBUS-guided TBNA has a significantly better diagnostic yield for these conditions, in a previous study from our group, a definitive diagnosis of sarcoidosis could only be made in 33% of cases after EBUS-guided TBNA [7]. The specimen sizes obtained with the 22- or 19-gauge TBNA needles, even if a core of tissue is obtained, are frequently considered insufficient by the pathologist to make these diagnoses. As a result, a surgical biopsy, through either mediastinoscopy or video-assisted thoracic surgery, is often necessary.

Until recently, obtaining a biopsy of mediastinal masses through the bronchoscope was hampered by an inability to see outside the airway, which is necessary to both direct the biopsy and prevent the potentially fatal consequence of inadvertent biopsy of large vessels. Prakash [8] previously described passing a lung biopsy forceps through the endobronchial wall blindly into the subcarinal space to sample enlarged subcarinal nodes in cases in which TBNA was unhelpful. Oki and colleagues [9] have also reported their experience in a small number of patients of subcarinal node biopsy through the bronchoscope using a miniforceps and fluoroscopic guidance.

The recently available linear-array EBUS bronchoscope permits the visualization of central mediastinal structures and could thus facilitate real-time safe lymph node biopsy. Here we report a feasibility study performed to assess the utility and safety of an EBUS-guided miniforceps biopsy in the histologic diagnosis of mediastinal masses in the subcarinal location.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
From January 2006 to January 2007, consecutive patients referred for bronchoscopy and with subcarinal masses greater than 25 mm in the short axis on chest computed tomography were enrolled prospectively in the study. Patients with known or suspected non-small cell lung cancer undergoing mediastinal staging for this disease were not included because we and others have previously shown that EBUS-guided TBNA has excellent diagnostic yield in this population [7]. The study was approved by the Hospital Ethics Committee in Heidelberg, where the study was performed by three of the authors (F.H., R.E., and A.E.), and written informed consent was obtained before bronchoscopy from all patients.

The TBNA and miniforceps biopsy of subcarinal lesions, described in detail subsequently, always preceded other bronchoscopic procedures such as washings, brushing, and EB biopsy. All procedures were performed under general anesthesia through a rigid bronchoscope, as is the routine at this institution. The sequence of EBUS-guided procedures was (1) TBNA (22-gauge needle), (2) TBNA with 19-gauge needle, and (3) miniforceps biopsy. Complications were recorded as either minor, which included bleeding controlled with routine bronchoscopic maneuvers, and major, including bleeding requiring transfusion, pneumothorax or pneumomediastinum, respiratory failure, or unscheduled admission.

EBUS-Guided TBNA
A real-time EBUS puncture scope (XBF-UC260F-OL8; Olympus Ltd, Tokyo, Japan) was used in all cases. This has a 6.9-mm outer diameter, a 2.0-mm working channel, and 30° oblique forward-viewing optics. A 7.5-Hz linear US transducer with a maximum penetration of 50 mm is linked to the processor (EU-60, Olympus Ltd). The TBNA samples were obtained by passing a dedicated 22-gauge needle with stylet (XNA-202, Olympus Ltd) through the airway wall and into the mass under real-time US control. Integrated color power Doppler US was used to exclude intervening vessels immediately before needle puncture, when appropriate. Three to four passes were taken from each site.

Transbronchial Needle Aspiration
Transbronchial needle aspiration with a 19-gauge transbronchial needle (Boston Scientific, Natick, MA) was next performed through a flexible bronchoscope with a 2.8-mm working channel. The needle was introduced through the bronchial wall using the jabbing method, as previously described [10], at the site of the original EBUS-guided TBNA puncture. Three to four passes were performed at each site.

Miniforceps Biopsy
For the forceps biopsy, a miniforceps with an external diameter of 1.15 mm (FB-56D-I; Olympus Ltd) was used. The blunt-tipped forceps were inserted into the working channel of the EBUS bronchoscope. Once the tip of the forceps was visualized within the airway lumen, the forceps was advanced slowly toward the puncture site made by the TBNA needle. When the site was reached, the forceps were pushed forcefully through the puncture site in the bronchial wall (Fig 1). Under real-time US control, the forceps were then opened within the lesion and biopsy samples were taken (Fig 2). Because the jaws of the forceps are small, as many passes as necessary were made until 3 specimens were obtained.


Figure 1
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  		Fig 1. Endoscopic view of a lymph node biopsy shows the forceps entering the subcarinal space from the left mainstem.

 

Figure 2
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  		Fig 2. The forceps, which is in an open position, is clearly visible within the lymph node on this endobronchial ultrasound image.

 
Specimen Handling
Aspirates obtained by TBNA needles were air-blown onto glass slides and then air dried and mounted. Rapid onsite cytology was not performed, and the two TBNA samples were processed separately. Tissue specimens obtained by miniforceps were placed immediately in formalin. Samples were also sent in saline solution for culture. Papanicolaou staining, light microscopy, and histologic analysis were performed by a single cytopathologist who was blinded to the gauge of needle used.

Reference Standard: Pathology and Follow-Up
A specific diagnosis made on either TBNA or miniforceps biopsy specimen was considered a true-positive diagnosis. A diagnosis of sarcoidosis was considered if the specimen identified noncaseating granulomas with a compatible clinical phenotype and adequate exclusion of other causes for granulomatous inflammation, including clinical history, follow-up, and a combination of negative tissue staining for acid-fast bacilli and fungal organisms and negative fungal and mycobacterial cultures. In patients in whom bronchoscopy was unrevealing, diagnosis was subsequently made through surgical biopsy specimens of the mediastinum or sampling at another site.

Statistical Analysis
The sensitivity, specificity, and predictive values were calculated using the standard definitions. Groups were compared with {chi}2 analysis. All analyses were done with SPSS 11.5 statistical software (SPSS Inc, Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
These sequential techniques were performed at bronchoscopy in 74 patients (41 men) with a median age of 53 years (range, 27 to 71 years). The specimens obtained were suitable for analysis in all cases. A final diagnosis was available for all patients at follow-up and allowed calculation of the diagnostic yield for each technique of lymph node sampling (Table 1). The mean size of the masses sampled was 3.27 cm (range, 2.5 to 4.2 cm), and no significant correlation was seen between the size of the mass and the likelihood of obtaining a diagnostic specimen with TBNA. A range of three to five passes was necessary to obtain 3 specimens in all patients.


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  		Table 1 Diagnostic Yield of Samples Obtained by Transbronchial Techniques
 
After bronchoscopy, 9 patients (12%) remained undiagnosed and 6 of these underwent a surgical biopsy; 5 had cervical mediastinoscopy and 1 had a video-assisted thoracoscopy (all 6 produced diagnostic tissue). The remaining 3 patients were diagnosed on follow-up by tissue sampling at other sites; 2 of these were found to have sarcoidosis, and the other had Hodgkin disease.

Diagnostic Accuracy
A specific diagnosis was made in 36% of all patients using the 22-gauge needle, in 49% with the 19-gauge needle, and in 88% with the miniforceps. The final diagnoses included sarcoidosis in 25 (33%) and lymphoma in 26 (35%), of which 11 patients (15%) had Hodgkin disease and 15 (20%) had non-Hodgkin lymphoma. Small cell lung cancer was diagnosed in 14 patients (18%). Other diagnoses and diagnostic yields for the EBUS-guided TBNA needle and miniforceps biopsy specimens given in Table 1. There was a significant difference in the diagnostic yield from miniforceps specimens compared with either 19- or 22-gauge TBNA aspirates for both sarcoidosis (p < 0.001) and lymphoma (p < 0.038 for Hodgkin disease and p < 0.001 for non-Hodgkin lymphoma). In patients with small cell lung cancer, the techniques performed equally well, with the 19-gauge needle missing only 1 case of the 14 (93%). The sensitivity, specificity, negative-predictive value, and positive-predictive value for the sampling techniques in lymphoma and sarcoidosis is presented in Table 2


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  		Table 2 Bronchoscopic Sampling Techniques in the Evaluation of Patients With Lymphoma or Sarcoidosis
 
Complications
No clinical complications were identified from the procedure or anesthesia. All patients underwent postprocedural chest roentgenograms at 2 hours, with no complications detected.


   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
Chest physicians are commonly involved in the assessment of patients with mediastinal lymphadenopathy. In the past these patients were commonly referred directly for a surgical biopsy through a mediastinoscopy. The advent of endoscopic and EBUS guidance in the last few years, which increase the yield from TBNA [5–7], as well as a recognition that in practice mediastinoscopy may not be used as well as it could [11], interest has been growing in noninvasive sampling of mediastinal lymph nodes. In particular in the setting of staging of non-small cell lung cancer, where nodal involvement is key to patient management, US-guided aspiration has been found to perform very well, with sensitivities for EUS-guided FNA of 88% to 100% [12, 13] and from 92% to 96% for EBUS-guided TBNA, even where lymph nodes are less than 1 cm in size [14].

The diagnostic value of TBNA in other conditions causing mediastinal lymph node enlargement is less well established. The small sample size obtained may be insufficient for the cytopathologist, particularly in benign disease where cytology may not be very informative. Previous reports in small numbers of patients suggested that forceps biopsy of subcarinal nodes after sequential enlargement of the endobronchial wall puncture site by successive TBNA passages was possible [8, 9]. In this study we showed that transbronchial mediastinal lymph node biopsy performed under real-time US guidance is feasible and safe due to the excellent visualization of mediastinal structures by the EBUS technology. In addition, it performed significantly better than TBNA alone in the diagnostic evaluation of Hodgkin disease, non-Hodgkin lymphoma, and sarcoidosis. In many of the patients in this study, performing miniforceps biopsies obviated the need for mediastinoscopy or transthoracic needle aspiration and their attendant risks.

The yield from TBNA, including EBUS-guided TBNA for sarcoidosis, was low in our study. The sensitivity of 36% is significantly lower than rates of 85% to 91% reported recently by other investigators [15, 16]. The reasons for this are unclear but may relate to use of rapid onsite cytology in those studies, the number of lymph node passes (5 to 7 vs 3 to 4 in our study), and differences in sample processing. In addition, those studies were undertaken in patients with a very high pretest probability of sarcoidosis, which was the final diagnosis in 48 of 50 subjects in the study by Garwood and colleagues [15] and in 61 of the 65 subjects in the study by Wong and colleagues [16]. The sensitivity for EBUS-guided TBNA of 36% for sarcoidosis in the current study is consistent with the 33% we and others previously reported in unselected patient populations [7]. The necessity for adequate tissue specimens in this condition, which clinically and radiologically can mimic granulomatous infection or lymphoma, is obvious.

We found a significant increase in yield for miniforceps biopsy in lymphoma where the yield was 81% compared with 35% for TBNA. The benefit of the larger histologic specimens acquired by miniforceps biopsy is that they permit examination of nodal architecture and immunohistochemistry as well as flow cytometry. Previous studies have found diagnostic yields for endoscopic US-guided FNA of 44% for lymphoma, which increased to more than 80% when immunocytochemistry was also performed on the samples [17]. Immunocytochemistry and flow cytometry were not performed on the samples acquired by aspiration in our study and may have influenced the diagnostic yield. This may also account for the difference in sensitivity of the EBUS-guided TBNA for lymphoma in our study compared with that reported recently by Kennedy and colleagues [18] in which it performed very well.

The high proportion of patients with either lymphoma or sarcoidosis, which together accounted for 68% of patients in our study, would not be expected from an unselected population with mediastinal adenopathy and reflects the exclusion of patients with known or suspected non-small cell lung cancer. The low rates of an infectious etiology, such as tuberculosis, which was the diagnosis in only 2 of our 75 patients, is not surprising. The study site is a tertiary referral center for EBUS-guided TBNA, and infectious causes may have already been excluded before referral.

Although EBUS-guided TBNA alone has excellent sensitivity for diagnosis of metastatic nodal disease, the ability to obtain larger samples through miniforceps biopsy, as described here, may allow more detailed immunohistochemical analysis of lymph node metastases, which may help provide additional prognostic information to guide disease-specific therapy. Our understanding of specific biologic factors that affect the natural history and response to chemotherapy in lung cancers is evolving, and it is likely that increasing efforts will be undertaken to further profile lung tumors in order to direct targeted therapy in the future [19, 20].

No major complications were recorded in this study, although it should be noted that all procedures were done by experienced bronchoscopists in a high-throughput specialist center. All examinations were performed under general anesthesia with the rigid bronchoscope, which is the standard at Thoraxklinik Heidelberg, but there is no reason that this procedure could not be performed with flexible bronchoscopy under moderate sedation.

The primary value of EBUS is in the prevention of complications associated with conventional TBNA, such as inadvertent vascular and mediastinal injury. Here we extend the utility of EBUS in permitting safe mediastinal lymph node biopsy through the bronchial wall into the subcarinal space. Cervical mediastinoscopy has a relatively higher complication rate, with reported mortality of 0.08% to 0.2% and a morbidity rate of 2% to 2.5% [21, 22]. Our complication rate compares favorably, but obviously, larger patient populations would need to be examined to draw a fair comparison. Furthermore, in non-small cell lung cancer, where mediastinoscopy is performed before surgery with curative intent, less than half the patients were found to have lymph node material biopsied [11]; thus, a less invasive way to obtain tissue from the mediastinum would be welcome.

In conclusion, our study establishes a method for real-time biopsy of enlarged mediastinal lymph nodes or masses using the linear-array endobronchial ultrasound scope and a 1.15-mm miniforceps with retrieval of good histologic specimens. The diagnostic yield for lymphoma and sarcoidosis was superior to EBUS-guided TBNA alone and it was safe.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
The endobronchial ultrasound probe was loaned to the authors by Olympus Ltd, Tokyo, Japan, for the duration of this study.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

  1. Wang KP, Brower R, Haponik EF Siegelman S. Flexible transbronchial needle aspiration for staging of bronchogenic carcinoma Chest 1983;84:571-576.[Medline]
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  12. Fritscher-Ravens A, Sriram PV, Bobrowski C, et al. Mediastinal lymphadenopathy in patients with or without previous malignancy: EUS-FNA-based differential cytodiagnosis in 153 patients Am J Gastroenterol 2000;95:2278-2284.[Medline]
  13. Tournoy KG, Praet MM, Van Maele G, Van Meerbeeck JP. Esophageal endoscopic ultrasound with fine-needle aspiration with an on-site cytopathologist: high accuracy for the diagnosis of mediastinal lymphadenopathy Chest 2005;28:3004-3009.
  14. Herth FJ, Ernst A, Eberhardt R, Vilmann P, Dienemann H, Krasnik M. Endobronchial ultrasound-guided transbronchial needle aspiration of lymph nodes in the radiologically normal mediastinum Eur Respir J 2006;28:910-914.[Abstract/Free Full Text]
  15. Garwood S, Judson MA, Silvestri G, Hoda R, Fraig M, Doelken P. Endobronchial ultrasound for the diagnosis of pulmonary sarcoidosis Chest 2007;132:1298-1304.[Medline]
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  17. Ribeiro A, Vazquez-Sequeiros E, Wiersema LM, Wang KK, Clain JE, Wiersema MJ, et al. EUS-guided fine-needle aspiration combined with flow cytometry and immunocytochemistry in the diagnosis of lymphoma Gastrointest Endosc 2001;53:485-491.[Medline]
  18. Kennedy MP, Jimenez CA, Bruzzi JF, et al. Endobronchial Ultrasound Guided Transbronchial Needle Aspiration in the Diagnosis of Lymphoma Thorax 2007.
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