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The complimentary role of transbronchial lung cryobiopsy and endobronchial ultrasound fine needle aspiration in the diagnosis of sarcoidosis
Respiratory Medicine 131 (2017) 65e69
Contents lists available at ScienceDirect
Respiratory Medicine journal homepage: www.elsevier.com/locate/rmed
The complimentary role of transbronchial lung cryobiopsy and endobronchial ultrasound fine needle aspiration in the diagnosis of sarcoidosis Alejandro Adolfo Aragaki-Nakahodo a, *, Robert P. Baughman b, Ralph T. Shipley c, Sadia Benzaquen a a b c
Interventional Pulmonology, Division of Pulmonary and Critical Care Medicine, University of Cincinnati, Cincinnati, OH 45219, USA Department of Medicine, University of Cincinnati, Cincinnati, OH 45219, USA Department of Radiology, University of Cincinnati, Cincinnati, OH 45219, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 17 May 2017 Received in revised form 25 July 2017 Accepted 2 August 2017 Available online 4 August 2017
Purpose: Transbronchial lung cryobiopsy (TBLC) is a novel technique that has proved to be useful in diagnosing various interstitial lung diseases (ILD). The use of TBLC to diagnose sarcoidosis in an unselected patient population is unknown, and could be complimentary to endobronchial ultrasound fine needle aspiration (EBUS-FNA). Methods: A retrospective analysis of 36 patients in a single, tertiary-care, academic medical center was conducted to describe the yield of both EBUS-FNA and TBLC in the diagnosis of suspected sarcoidosis over a three year period. A grading system to evaluate the presence and extent of specific radiographic features on computed tomography chest imaging studies was compared to the results of EBUS-FNA and TBLC. Complications associated with the procedures were also noted. Results: The overall diagnostic yield in our cohort (all pathologic diagnosis considered) was 80.6% (29 out of 36 patients had a definite pathologic diagnosis). Eighteen patients referred for possible sarcoidosis had a positive bronchoscopic specimen confirming the diagnosis of sarcoidosis. For those patients with a pathologic diagnosis of sarcoidosis, the diagnostic yield for EBUS-FNA and TBLC was 66.7% each (12 out of 18 patients), while the combined diagnostic yield for EBUS-FNA and TBLC increased to 100%. For all cases, the pneumothorax rate was 11.1%. Conclusions: TBLC appears to be a safe and complimentary technique to diagnose sarcoidosis and could be considered part of the diagnostic armamentarium in bronchoscopic centers. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Sarcoidosis Lung biopsy Transbronchial lung cryobiopsy Endobronchial ultrasound fine needle aspiration
1. Background Sarcoidosis is a multisystem disorder of unknown cause. It frequently presents with bilateral hilar and mediastinal adenopathy, pulmonary infiltrates, and ocular and skin lesions. The diagnosis is established when clinicoradiological findings are supported by histological evidence of noncaseating epithelioid cell granulomas [1]. Even with tissue confirmation, diagnosis is never secure and follow-up over a number of years is required to be fully confident of the diagnosis [2].
* Corresponding author. Interventional Pulmonology, Pulmonary and Critical Care Medicine, University of Cincinnati, 231 Albert Sabin Way, ML0564 MSB 6365, Cincinnati, OH 45267, USA. E-mail address: [email protected] (A.A. Aragaki-Nakahodo). http://dx.doi.org/10.1016/j.rmed.2017.08.003 0954-6111/© 2017 Elsevier Ltd. All rights reserved.
The ATS/ERS/WASOG Statement on Sarcoidosis written in 1999 recommends transbronchial lung biopsy (TBLB) as the procedure of choice for tissue diagnosis [1]. However, the diagnostic yield of TBLB ranges 40%e90% [3e6]. Factors influencing yield of TBLB include chest X ray (CXR) appearance and experience of the operator. Specimens from TBLB may lack sufficient quality due to crush artifact and are generally too small for diagnosis of diffuse lung disease [7]. If TBLB is negative, other diagnostic modalities include endobronchial ultrasound bronchoscopy (EBUS) [8e10], the more invasive video assisted thoracoscopic surgical (VATS) lung biopsy, or open lung biopsy (OLB). VATS lung biopsy is costly, requires general anesthesia, in-patient care and has a mortality rate ranging 0%e4.4% [11e13]. OLB probably has a similar complication rate at least [14]. Transbronchial lung cryobiopsy (TBLC) is a novel technique
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PaƟents referred for possible sarcoidosis N=37
Did not have TBLC because of pulmonary hypertension N=1
Underwent both TBLC and EBUS-FNA N=36
Sarcoidosis N=18
AlternaƟve granulomatous disease
Other intersƟƟal lung disease diagnosed
N=3
N=8
Non diagnosƟc N=7
TBLC posiƟve
TBLC posiƟve
TBLC posiƟve
TBLC posiƟve
N=12
N=0
N=8
N=0
EBUS-FNA posiƟve
EBUS-FNA posiƟve
EBUS-FNA posiƟve
EBUS-FNA posiƟve
N=12
N=2
N=0
N=0
Fig. 1. Outcome of all patients. TBLC ¼ transbronchial lung cryobiopsy; EBUS-FNA ¼ endobronchial ultrasound guided fine needle aspiration. Alternative granulomatous disease: 1 patient with EBUS-FNA culture positive for M. tuberculosis; 1 patient with BAL positive for M. kansasii; 1 patient with EBUS-FNA compatible with mantle cell lymphoma (confirmed with VATS excision of right paratracheal lymph node station) Other ILD diagnosed: 7 patients with RB-ILD, 1 patient with emphysema.
under investigation to overcome limitations of TBLB and could be complimentary to EBUS. It has proved useful in diagnosing various interstitial lung diseases (ILD) [15e17]. 2. Methods A retrospective analysis of patients with suspected sarcoidosis in a single, tertiary-care, academic medical center who had been referred for bronchoscopic evaluation was performed. All patients were considered for both endobronchial ultrasound-guided fine needle aspiration (EBUS-FNA) and TBLC. Cases were seen over a three year period (October of 2013 and October of 2016). The following data was extracted from the patients' charts: age, gender, body mass index, radiographic data, procedure and pathology reports, and complications. All patients were classified by the American Society of Anesthesiologists (ASA) scoring system prior to the procedure. Clinical data, post procedural outcomes, pathologic diagnosis and outpatient follow-up (at least 6 months after lung biopsy) were recorded. This retrospective chart review protocol had been approved by the University of Cincinnati Institutional Review Board (Study #: 2016-0867). All patients underwent bronchoscopy under general anesthesia through a laryngeal mask airway (LMA). Alternatively, if a patient had features suggestive of a difficult airway or had baseline home oxygen >4L per minute, an endotracheal tube (ETT) was used. Bronchoscopies were performed by board certified interventional pulmonologists at the University of Cincinnati Medical Center. Our cryobiopsy technique has been described previously [18]. The final diagnosis was made based on clinical presentation, radiographic information, pathologic examination, and clinical course of patients. Patients diagnosed with sarcoidosis met ATS/ ERS/WASOG criteria, with alternative diagnosis excluded. The pathologic diagnosis of sarcoidosis was confirmed with
histological evidence of noncaseating epithelioid cell granulomas, and the following: - Negative bacterial, fungal and mycobacterial stains/cultures. - Cytology samples negative for disease processes other than sarcoidosis. Radiologic evaluation of patients with suspected sarcoidosis was done with computed tomography (CT) chest imaging. A thoracic radiologist (RTS) reviewed the CT chest scans, blinded to results of bronchoscopy. The pattern and extent of disease was described with a grading system based on a Likert score: none, mild, moderate and severe, for five different CT chest findings: adenopathy; bronchovascular bundle thickening (large airway bundles); centrilobular nodularity (small airway bundles and/or ground glass opacities); pleural nodularity (along peripheral and fissural pleura); and fibrosis. CT chest studies were also classified according to the Scadding criteria [19]. See pictures section for representative imaging studies and yield of EBUS-FNA, TBLC or both combined (see Fig. 2). Complications associated with the bronchoscopic procedure included acute respiratory failure, acute coronary syndromes, new cardiac arrhythmias requiring short or long term therapy, pneumonia, lobar atelectasis, pneumothorax, bleeding, thromboembolic disease, and death, regardless of cause, within 30 days of the procedure. Bleeding at time of bronchoscopy was classified using a modification of a previously reported scale [18]. Bleeding was scored as Grade 0: traces of blood not requiring suctioning; Grade 1: mild bleeding that only requires suctioning and hemostatic wedging up to 2 min (two 1-min cycles); Grade 2: moderate bleeding requiring hemostatic wedging for 3 or more minutes; Grade 3: severe bleeding requiring topical instillation of epinephrine or cold saline;
A.A. Aragaki-Nakahodo et al. / Respiratory Medicine 131 (2017) 65e69
67
Fig. 2. Proposed CT grading criteria and representative imaging. a)Adenopathy (severe). Both TBLC and EBUS-FNA were positive. b)Bronchovascular thickening (severe). Only EBUS-FNA was positive.
or Grade 4: life threatening bleeding that requires hemodynamic support, transfusion of blood products, selective mainstem intubation, bronchial blocker, hospital admission and/or surgical intervention. The total number of TBLC for each lobe (upper, middle/lingula, and lower) was recorded. The mean measurement for a patient's TBLC sample was calculated from the total biopsies' measurements divided by the total number of TBLC samples. Statistics: Results were expressed as mean with standard deviation and median with value range as appropriate. We also tested the EBUS-FNA and TBLC results with other variables with the Chisquare test and Fisher's exact test. A p value of <0.05 was considered significant. 3. Results A total of 37 patients were identified. One patient was excluded from the analysis as he did not undergo TBLC due to severe pulmonary hypertension. Of the remaining 36, the mean age of the patients was 47 years and 70% were female. Average BMI was 31.3 (± 9.9). The predominant races in this study were Caucasian (55%) and African-American (42%). All patients were referred to rule out sarcoidosis. On average, patients had 5 TBLC (2 in the upper lobe, 1 in the middle/lingula, and 2 in the lower lobe). The mean cryobiopsy measurement was 5.1 mm (± 1.4 mm). The overall diagnostic yield in our cohort (all pathologic diagnosis considered) was 80.6% (29 out of 36 patients had a definite pathologic diagnosis). 50% (18 out of 36 patients) had a tissue diagnosis of sarcoidosis. Of the remaining 18 cases, 3 had alternative granulomatous disease (1 patient with Mycobacterium tuberculosis infection, 1 patient with Mycobacterium kansasii infection,
and 1 patient with mantle cell lymphoma); 8 patients had other diffuse lung disease diagnosis (7 had respiratory bronchiolitisinterstitial lung disease, 1 had emphysematous changes); 7 patients had non-diagnostic biopsies. Fig. 1 summarizes the overall yield of our study population. For those patients with a pathologic diagnosis of sarcoidosis, the diagnostic yield for EBUS-FNA and TBLC was 66.7% each (12 out of 18 patients), while the combined diagnostic yield for EBUS-FNA and TBLC increased to 100% (Table 1). Retrospective review of the CT chest was performed in the 34 patients in whom the films were available for re-review. The findings according to our proposed classification and further Scadding stage classification can be seen in Tables 2 and 3. A total of 28 patients had some level of adenopathy on CT scan. For those who had sarcoidosis, EBUS was highly diagnostic. For those who had an alternative diagnosis, EBUS was less useful. The diagnostic yield for EBUS-FNA and TBLC per Scadding criteria is presented in Table 4. There was difference between a positive EBUS-FNA and the presence of significant lymphadenopathy (Stage 1 or 2: 11/14 (78.6%)) vs the absence of lymphadenopathy (Stages 0, 3, or 4: 1/4 (25%)). It is worth noting that from our 7 patients with non-diagnostic TBLC samples, 5 had only mild mediastinal/hilar adenopathy (Scadding stage 1), while the other 2 had mild mediastinal/hilar adenopathy and some degree of centrilobular nodularity (Scadding stage 2). See Table 5. All patients had minor bleeding that was controlled with bronchoscopic wedging through an LMA (24 out of 36 patients had bleeding grade 1). No cases required the use of a bronchial blocker. Complications included 4 patients with iatrogenic pneumothorax (11.1%) that resolved with a small bore chest tube placement, with an average hospital stay of 2.5 days.
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Table 1 Diagnostic yield for sarcoidosis (n ¼ 18).
TBLC positive TBLC negative
Table 5 EBUS yield by presence/absence of adenopathy.
EBUS-FNA positive
EBUS-FNA negative
6 6
6 0
TBLC ¼ transbronchial lung cryobiopsy; EBUS-FNA ¼ endobronchial ultrasound guided fine needle aspiration.
EBUS-FNA positive EBUS-FNA negative
Adenopathy (Scadding stages 1, 2)
No adenopathy (Scadding stages 0, 3, 4)
11 3
1 3
EBUS-FNA ¼ endobronchial ultrasound guided fine needle aspiration.
Table 2 Proposed CT chest classification.a Adenopathy
Bronchovascular bundle thickening
Centrilobular nodularity
Pleural nodularity
Fibrosis
Number with CT finding
28
9
16
9
6
Sarcoidosis cases Number (%) EBUS-FNA positive
15 12/15 (80%) 9/15 (60%)
6 4/6 (66.7%) 5/6 (83.3%)
8 6/8 (75%) 6/8 (75%)
7 5/7 (71.4%) 5/7 (71.4%)
4 1/4 (25%) 3/4 (75%)
13 2/13 (15.4%) 6/13 (46.2%)
3 1/3 (33.3%) 2/3 (66.7%)
8 0/8 (0%) 6/8 (75%)
2 0/2 (0%) 1/2 (50%)
2 0/2 (0%) 1/2 (50%)
Number (%)TBLC positive
Non-sarcoidosis cases Number (%)EBUS-FNA positive Number (%)TBLC positive
TBLC ¼ transbronchial lung cryobiopsy; EBUS-FNA ¼ endobronchial ultrasound guided fine needle aspiration. a Any grade (mild, moderate or severe) was included 2 patients' imaging studies not included.
Table 3 CT chest classification (Scadding criteria).a Stage 0
Stage 1
Stage 2
Stage 3
Stage 4
Total cases
2
13
14
3
2
Sarcoidosis cases Number (%) EBUS-FNA positive
1 0/1 (0%) 1/1 (100%)
7 5/7 (71.4%) 4/7 (57.1%)
6 6/6 (100%) 4/6 (66.7%)
2 0/2 (0%) 2/3 (66.7%)
2 1/2 (50%) 1/2 (50%)
1 0/1 (0%) 1/1 (100%)
6 1/6 (16.7%) 1/6 (16.7%)
8 1/8 (12.5%) 5/8 (62.5%)
1 0/1 (0%) 1/1 (100%)
0 0 (0%) 0 (0%)
Number (%) TBLC positive
Non-sarcoidosis cases Number (%) EBUS-FNA positive Number (%) TBLC positive
TBLC ¼ transbronchial lung cryobiopsy; EBUS-FNA ¼ endobronchial ultrasound guided fine needle aspiration. a 2 patients imaging studies not included.
Table 4 Diagnostic yield of TBLC and EBUS-FNA by Scadding criteria (CT chest evaluation). Scadding stage (CT)
TBLC positive
EBUS-FNA positive
Total patients
0 1 2 3 4
1 4 4 2 1
0 5 6 0 1
1 7 6 2 2
TBLC ¼ transbronchial lung cryobiopsy; EBUS-FNA ¼ endobronchial ultrasound guided fine needle aspiration.
4. Discussion Flexible bronchoscopy is a safe technique to demonstrate granulomatous inflammation in the diagnostic workup of a suspected case of sarcoidosis. We recently reviewed the different modalities to diagnose sarcoidosis [20]. There is growing interest in
the TBLC technique. For sarcoidosis, the value of TBLC could be avoiding OLB in atypical cases, and the ability to procure bigger tissue samples for genetic testing. The diagnostic yield of EBUS-FNA in patients with a pathologic diagnosis of sarcoidosis was within the range of prior publications [8e10,20]. The addition of TBLC increased the yield. The value of combining bronchoscopic techniques has been noted previously, including a recent meta-analysis: Goyal et al. [21], for example, described the diagnostic yield of the following: endobronchial biopsy (EBB): 36%, conventional transbronchial needle aspiration (cTBNA): 48%, transbronchial lung biopsy (TBLB): 70%, and endobronchial ultrasound fine needle aspiration (EBUS-FNA): 74.5%. When combined in 2 different groups, the diagnostic yield increased: cTBNA þ EBB þ TBLB (85.5%) vs EBUS-FNA þ EBB þ TBLB (93%). In our case series, the diagnostic yield for TBLC was 66.7%, which approximates the diagnostic yield of TBLB described by Goyal et al. (70%). The value of TBLC was specifically helpful in cases without significant adenopathy with/without parenchymal abnormalities. This has been reported by others with the use of TBLB. We postulated that the diagnostic yield for EBUS-FNA and TBLC could be related to CT chest findings. However, no specific CT chest finding as described above, was statistically significant. Since the sample size of this study was fairly small, future studies seem warranted. Pneumothorax (11.1%) was a significant adverse event, easily managed with a small-bore chest tube and a short inpatient stay at our hospital as compared to SLB, in which 100% of the cases patients stay in the hospital post operatively with at least one chest tube in place. The pneumothorax rate for TBLC in our cohort was higher than the usual 5% rate estimated for TBLB. We believe this may be related in part, to the low number of patients in our cohort. In our institutional experience with TBLC for diffuse interstitial lung disease (total of 74 patients, including patients with atypical presentation of sarcoidosis cases), the pneumothorax rate was lower, 6.7% [18].
A.A. Aragaki-Nakahodo et al. / Respiratory Medicine 131 (2017) 65e69
We found that TBLC appears to be a safe and complimentary technique to diagnose sarcoidosis and could be considered part of the diagnostic armamentarium in bronchoscopic centers of excellence. Based on our study, we recommend considering EBUS-FNA sampling on any lymphadenopathy when its largest diameter is > 5 mm under EBUS examination. In conclusion, we found the overall diagnostic yield for EBUSFNA and TBLC was 100% in patients with a final diagnosis of sarcoidosis. TBLC appeared to be useful to diagnose sarcoidosis even in the absence of typical parenchymal disease. Further randomized controlled trials should clarify the value of TBLC in the diagnosis of sarcoidosis. Conflict of interest declaration All authors disclose no relationships/conditions/circumstances that present potential conflict of interest while preparing this manuscript. Source(s) of support None. References [1] G.W. Hunninghake, U. Costabel, M. Ando, et al., ATS/ERS/WASOG statement on sarcoidosis. American thoracic society/european respiratory society/world association of sarcoidosis and other granulomatous disorders, Sarcoidosis Vasc. Diffuse Lung Dis. 16 (2) (1999 Sep) 149e173. [2] P. Govender, J.S. Berman, The diagnosis of sarcoidosis, Clin. Chest Med. 36 (2015) 585e602. [3] M. Halme, A. Piilonen, E. Taskinen, et al., Comparison of endobronchial and transbronchial biopsies with high-resolution CT (HRCIT) in the diagnosis of sarcoidosis, APMIS 109 (4) (2001) 289e294. [4] R.M. Hsu, A.F. Connors Jr., J.F. Tomashefski Jr., et al., Histologic, microbiologic, and clinical correlates of the diagnosis of sarcoidosis by transbronchial biopsy, Arch. Pathol. Lab. Med. 120 (4) (1996) 364e368. [5] M. Oki, H. Saka, C. Kitagawa, et al., Prospective study of endobronchial ultrasound-guided transbronchial needle aspiration of lymph nodes versus transbronchial lung biopsy of lung tissue for diagnosis of sarcoidosis, J. Thorac.
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Cardiovasc Surg. 143 (2012) 1324e1329. [6] R.A. Roethe, R.B. Byrd, D.R. Hafermann, Transbronchoscopic lung biopsy in sarcoidosis. Optimal number and sites for diagnosis, Chest 77 (3) (1980) 400e402. [7] A. Babiak, J. Hetzel, G. Krishna, et al., Transbronchial cryobiopsy: a new tool for lung biopsies, Respiration 78 (2009) 203e208. [8] M. Oki, H. Saka, C. Kitagawa, et al., Real-time endobronchial ultrasoundguided transbronchial needle aspiration is useful for diagnosis sarcoidosis, Respirology 12 (2007) 863e868. [9] S. Garwood, M.A. Judson, G. Silvestri, et al., Endobronchial ultrasound for the diagnosis of pulmonary sarcoidosis, Chest 132 (2007) 1298e1304. [10] A. Tremblay, D.R. Stather, P. MacEachern, et al., A randomized controlled trial of standard vs endobronchial ultrasonography-guided transbronchial needle aspiration in patients with suspected sarcoidosis, Chest 136 (2009) 340e346. [11] L. Tiito, U. Heiskanen, R. Bloigu, et al., Thoracoscopic lung biopsy is a safe procedure in diagnosing usual interstitial pneumonia, Chest 128 (2005) 2375e2380. [12] D. Morris, V. Zamvar, The efficacy of video-assisted thoracoscopic surgery lung biopsies in patients with interstitial lung disease: a retrospective study of 66 patients, J. Cardiothorac. Surg. 9 (2014) 45. [13] M.E. Kreider, J. Hansen-Flaschen, N.N. Ahmad, et al., Complications of videoassisted thoracoscopic lung biopsy in patients with interstitial lung disease, Ann. Thorac. Surg. 83 (3) (2007) 1140e1144. [14] W. Nguyen, K.C. Meyer, Surgical lung biopsy for the diagnosis of interstitial lung disease: a review of the literature and recommendations for optimizing safety and efficacy, Sarcoidosis Vasc. Diffuse Lung Dis. 30 (1) (2013) 3e16. [15] G.L. Casoni, S. Tomassetti, A. Cavazza, et al., Transbronchial lung cryobiopsy in the diagnosis of fibrotic interstitial lung diseases, PLoS One 9 (2) (2014) e86716. [16] V. Pajares, C. Puzo, D. Castillo, et al., Diagnostic yield of transbronchial cryobiopsy in interstitial lung disease: a randomized trial, Respirology 19 (6) (2014) 900e906. [17] J. Kropski, J. Pritchett, W. Mason, et al., Bronchoscopic cryobiopsy for the diagnosis of diffuse parenchymal lung disease, PLoS One 8 (11) (2014) e78674. [18] T. Sriprasart, A. Aragaki, R.P. Baughman, et al., A single US center experience of transbronchial lung cryobiopsy for diagnosing interstitial lung disease with a 2-scope technique, J. Bronchology Interv. Pulmonol. 24 (2) (2017) 131e135. [19] M.A. Judson, R.P. Baughman, A.S. Teirstein, et al., Defining organ involvement in sarcoidosis: the access proposed instrument. ACCESS research group. A case control etiologic study of sarcoidosis, Sarcoidosis Vasc. Diffuse Lung Dis. 16 (1) (1999) 75e86. [20] S. Benzaquen, A. Aragaki, Bronchoscopic modalities to diagnose sarcoidosis, Curr. Opin. Pulm. Med. (2017 Jun 5), http://dx.doi.org/10.1097/ MCP.0000000000000398 [Epub ahead of print]. [21] A. Goyal, D. Gupta, R. Agarwal, et al., Value of different bronchoscopic sampling techniques in diagnosis of sarcoidosis. A prospective study of 151 patients, J. Bronchol Interv. Pulmonol. 21 (2014) 220e226.
Contents lists available at ScienceDirect
Respiratory Medicine journal homepage: www.elsevier.com/locate/rmed
The complimentary role of transbronchial lung cryobiopsy and endobronchial ultrasound fine needle aspiration in the diagnosis of sarcoidosis Alejandro Adolfo Aragaki-Nakahodo a, *, Robert P. Baughman b, Ralph T. Shipley c, Sadia Benzaquen a a b c
Interventional Pulmonology, Division of Pulmonary and Critical Care Medicine, University of Cincinnati, Cincinnati, OH 45219, USA Department of Medicine, University of Cincinnati, Cincinnati, OH 45219, USA Department of Radiology, University of Cincinnati, Cincinnati, OH 45219, USA
a r t i c l e i n f o
a b s t r a c t
Article history: Received 17 May 2017 Received in revised form 25 July 2017 Accepted 2 August 2017 Available online 4 August 2017
Purpose: Transbronchial lung cryobiopsy (TBLC) is a novel technique that has proved to be useful in diagnosing various interstitial lung diseases (ILD). The use of TBLC to diagnose sarcoidosis in an unselected patient population is unknown, and could be complimentary to endobronchial ultrasound fine needle aspiration (EBUS-FNA). Methods: A retrospective analysis of 36 patients in a single, tertiary-care, academic medical center was conducted to describe the yield of both EBUS-FNA and TBLC in the diagnosis of suspected sarcoidosis over a three year period. A grading system to evaluate the presence and extent of specific radiographic features on computed tomography chest imaging studies was compared to the results of EBUS-FNA and TBLC. Complications associated with the procedures were also noted. Results: The overall diagnostic yield in our cohort (all pathologic diagnosis considered) was 80.6% (29 out of 36 patients had a definite pathologic diagnosis). Eighteen patients referred for possible sarcoidosis had a positive bronchoscopic specimen confirming the diagnosis of sarcoidosis. For those patients with a pathologic diagnosis of sarcoidosis, the diagnostic yield for EBUS-FNA and TBLC was 66.7% each (12 out of 18 patients), while the combined diagnostic yield for EBUS-FNA and TBLC increased to 100%. For all cases, the pneumothorax rate was 11.1%. Conclusions: TBLC appears to be a safe and complimentary technique to diagnose sarcoidosis and could be considered part of the diagnostic armamentarium in bronchoscopic centers. © 2017 Elsevier Ltd. All rights reserved.
Keywords: Sarcoidosis Lung biopsy Transbronchial lung cryobiopsy Endobronchial ultrasound fine needle aspiration
1. Background Sarcoidosis is a multisystem disorder of unknown cause. It frequently presents with bilateral hilar and mediastinal adenopathy, pulmonary infiltrates, and ocular and skin lesions. The diagnosis is established when clinicoradiological findings are supported by histological evidence of noncaseating epithelioid cell granulomas [1]. Even with tissue confirmation, diagnosis is never secure and follow-up over a number of years is required to be fully confident of the diagnosis [2].
* Corresponding author. Interventional Pulmonology, Pulmonary and Critical Care Medicine, University of Cincinnati, 231 Albert Sabin Way, ML0564 MSB 6365, Cincinnati, OH 45267, USA. E-mail address: [email protected] (A.A. Aragaki-Nakahodo). http://dx.doi.org/10.1016/j.rmed.2017.08.003 0954-6111/© 2017 Elsevier Ltd. All rights reserved.
The ATS/ERS/WASOG Statement on Sarcoidosis written in 1999 recommends transbronchial lung biopsy (TBLB) as the procedure of choice for tissue diagnosis [1]. However, the diagnostic yield of TBLB ranges 40%e90% [3e6]. Factors influencing yield of TBLB include chest X ray (CXR) appearance and experience of the operator. Specimens from TBLB may lack sufficient quality due to crush artifact and are generally too small for diagnosis of diffuse lung disease [7]. If TBLB is negative, other diagnostic modalities include endobronchial ultrasound bronchoscopy (EBUS) [8e10], the more invasive video assisted thoracoscopic surgical (VATS) lung biopsy, or open lung biopsy (OLB). VATS lung biopsy is costly, requires general anesthesia, in-patient care and has a mortality rate ranging 0%e4.4% [11e13]. OLB probably has a similar complication rate at least [14]. Transbronchial lung cryobiopsy (TBLC) is a novel technique
66
A.A. Aragaki-Nakahodo et al. / Respiratory Medicine 131 (2017) 65e69
PaƟents referred for possible sarcoidosis N=37
Did not have TBLC because of pulmonary hypertension N=1
Underwent both TBLC and EBUS-FNA N=36
Sarcoidosis N=18
AlternaƟve granulomatous disease
Other intersƟƟal lung disease diagnosed
N=3
N=8
Non diagnosƟc N=7
TBLC posiƟve
TBLC posiƟve
TBLC posiƟve
TBLC posiƟve
N=12
N=0
N=8
N=0
EBUS-FNA posiƟve
EBUS-FNA posiƟve
EBUS-FNA posiƟve
EBUS-FNA posiƟve
N=12
N=2
N=0
N=0
Fig. 1. Outcome of all patients. TBLC ¼ transbronchial lung cryobiopsy; EBUS-FNA ¼ endobronchial ultrasound guided fine needle aspiration. Alternative granulomatous disease: 1 patient with EBUS-FNA culture positive for M. tuberculosis; 1 patient with BAL positive for M. kansasii; 1 patient with EBUS-FNA compatible with mantle cell lymphoma (confirmed with VATS excision of right paratracheal lymph node station) Other ILD diagnosed: 7 patients with RB-ILD, 1 patient with emphysema.
under investigation to overcome limitations of TBLB and could be complimentary to EBUS. It has proved useful in diagnosing various interstitial lung diseases (ILD) [15e17]. 2. Methods A retrospective analysis of patients with suspected sarcoidosis in a single, tertiary-care, academic medical center who had been referred for bronchoscopic evaluation was performed. All patients were considered for both endobronchial ultrasound-guided fine needle aspiration (EBUS-FNA) and TBLC. Cases were seen over a three year period (October of 2013 and October of 2016). The following data was extracted from the patients' charts: age, gender, body mass index, radiographic data, procedure and pathology reports, and complications. All patients were classified by the American Society of Anesthesiologists (ASA) scoring system prior to the procedure. Clinical data, post procedural outcomes, pathologic diagnosis and outpatient follow-up (at least 6 months after lung biopsy) were recorded. This retrospective chart review protocol had been approved by the University of Cincinnati Institutional Review Board (Study #: 2016-0867). All patients underwent bronchoscopy under general anesthesia through a laryngeal mask airway (LMA). Alternatively, if a patient had features suggestive of a difficult airway or had baseline home oxygen >4L per minute, an endotracheal tube (ETT) was used. Bronchoscopies were performed by board certified interventional pulmonologists at the University of Cincinnati Medical Center. Our cryobiopsy technique has been described previously [18]. The final diagnosis was made based on clinical presentation, radiographic information, pathologic examination, and clinical course of patients. Patients diagnosed with sarcoidosis met ATS/ ERS/WASOG criteria, with alternative diagnosis excluded. The pathologic diagnosis of sarcoidosis was confirmed with
histological evidence of noncaseating epithelioid cell granulomas, and the following: - Negative bacterial, fungal and mycobacterial stains/cultures. - Cytology samples negative for disease processes other than sarcoidosis. Radiologic evaluation of patients with suspected sarcoidosis was done with computed tomography (CT) chest imaging. A thoracic radiologist (RTS) reviewed the CT chest scans, blinded to results of bronchoscopy. The pattern and extent of disease was described with a grading system based on a Likert score: none, mild, moderate and severe, for five different CT chest findings: adenopathy; bronchovascular bundle thickening (large airway bundles); centrilobular nodularity (small airway bundles and/or ground glass opacities); pleural nodularity (along peripheral and fissural pleura); and fibrosis. CT chest studies were also classified according to the Scadding criteria [19]. See pictures section for representative imaging studies and yield of EBUS-FNA, TBLC or both combined (see Fig. 2). Complications associated with the bronchoscopic procedure included acute respiratory failure, acute coronary syndromes, new cardiac arrhythmias requiring short or long term therapy, pneumonia, lobar atelectasis, pneumothorax, bleeding, thromboembolic disease, and death, regardless of cause, within 30 days of the procedure. Bleeding at time of bronchoscopy was classified using a modification of a previously reported scale [18]. Bleeding was scored as Grade 0: traces of blood not requiring suctioning; Grade 1: mild bleeding that only requires suctioning and hemostatic wedging up to 2 min (two 1-min cycles); Grade 2: moderate bleeding requiring hemostatic wedging for 3 or more minutes; Grade 3: severe bleeding requiring topical instillation of epinephrine or cold saline;
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Fig. 2. Proposed CT grading criteria and representative imaging. a)Adenopathy (severe). Both TBLC and EBUS-FNA were positive. b)Bronchovascular thickening (severe). Only EBUS-FNA was positive.
or Grade 4: life threatening bleeding that requires hemodynamic support, transfusion of blood products, selective mainstem intubation, bronchial blocker, hospital admission and/or surgical intervention. The total number of TBLC for each lobe (upper, middle/lingula, and lower) was recorded. The mean measurement for a patient's TBLC sample was calculated from the total biopsies' measurements divided by the total number of TBLC samples. Statistics: Results were expressed as mean with standard deviation and median with value range as appropriate. We also tested the EBUS-FNA and TBLC results with other variables with the Chisquare test and Fisher's exact test. A p value of <0.05 was considered significant. 3. Results A total of 37 patients were identified. One patient was excluded from the analysis as he did not undergo TBLC due to severe pulmonary hypertension. Of the remaining 36, the mean age of the patients was 47 years and 70% were female. Average BMI was 31.3 (± 9.9). The predominant races in this study were Caucasian (55%) and African-American (42%). All patients were referred to rule out sarcoidosis. On average, patients had 5 TBLC (2 in the upper lobe, 1 in the middle/lingula, and 2 in the lower lobe). The mean cryobiopsy measurement was 5.1 mm (± 1.4 mm). The overall diagnostic yield in our cohort (all pathologic diagnosis considered) was 80.6% (29 out of 36 patients had a definite pathologic diagnosis). 50% (18 out of 36 patients) had a tissue diagnosis of sarcoidosis. Of the remaining 18 cases, 3 had alternative granulomatous disease (1 patient with Mycobacterium tuberculosis infection, 1 patient with Mycobacterium kansasii infection,
and 1 patient with mantle cell lymphoma); 8 patients had other diffuse lung disease diagnosis (7 had respiratory bronchiolitisinterstitial lung disease, 1 had emphysematous changes); 7 patients had non-diagnostic biopsies. Fig. 1 summarizes the overall yield of our study population. For those patients with a pathologic diagnosis of sarcoidosis, the diagnostic yield for EBUS-FNA and TBLC was 66.7% each (12 out of 18 patients), while the combined diagnostic yield for EBUS-FNA and TBLC increased to 100% (Table 1). Retrospective review of the CT chest was performed in the 34 patients in whom the films were available for re-review. The findings according to our proposed classification and further Scadding stage classification can be seen in Tables 2 and 3. A total of 28 patients had some level of adenopathy on CT scan. For those who had sarcoidosis, EBUS was highly diagnostic. For those who had an alternative diagnosis, EBUS was less useful. The diagnostic yield for EBUS-FNA and TBLC per Scadding criteria is presented in Table 4. There was difference between a positive EBUS-FNA and the presence of significant lymphadenopathy (Stage 1 or 2: 11/14 (78.6%)) vs the absence of lymphadenopathy (Stages 0, 3, or 4: 1/4 (25%)). It is worth noting that from our 7 patients with non-diagnostic TBLC samples, 5 had only mild mediastinal/hilar adenopathy (Scadding stage 1), while the other 2 had mild mediastinal/hilar adenopathy and some degree of centrilobular nodularity (Scadding stage 2). See Table 5. All patients had minor bleeding that was controlled with bronchoscopic wedging through an LMA (24 out of 36 patients had bleeding grade 1). No cases required the use of a bronchial blocker. Complications included 4 patients with iatrogenic pneumothorax (11.1%) that resolved with a small bore chest tube placement, with an average hospital stay of 2.5 days.
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Table 1 Diagnostic yield for sarcoidosis (n ¼ 18).
TBLC positive TBLC negative
Table 5 EBUS yield by presence/absence of adenopathy.
EBUS-FNA positive
EBUS-FNA negative
6 6
6 0
TBLC ¼ transbronchial lung cryobiopsy; EBUS-FNA ¼ endobronchial ultrasound guided fine needle aspiration.
EBUS-FNA positive EBUS-FNA negative
Adenopathy (Scadding stages 1, 2)
No adenopathy (Scadding stages 0, 3, 4)
11 3
1 3
EBUS-FNA ¼ endobronchial ultrasound guided fine needle aspiration.
Table 2 Proposed CT chest classification.a Adenopathy
Bronchovascular bundle thickening
Centrilobular nodularity
Pleural nodularity
Fibrosis
Number with CT finding
28
9
16
9
6
Sarcoidosis cases Number (%) EBUS-FNA positive
15 12/15 (80%) 9/15 (60%)
6 4/6 (66.7%) 5/6 (83.3%)
8 6/8 (75%) 6/8 (75%)
7 5/7 (71.4%) 5/7 (71.4%)
4 1/4 (25%) 3/4 (75%)
13 2/13 (15.4%) 6/13 (46.2%)
3 1/3 (33.3%) 2/3 (66.7%)
8 0/8 (0%) 6/8 (75%)
2 0/2 (0%) 1/2 (50%)
2 0/2 (0%) 1/2 (50%)
Number (%)TBLC positive
Non-sarcoidosis cases Number (%)EBUS-FNA positive Number (%)TBLC positive
TBLC ¼ transbronchial lung cryobiopsy; EBUS-FNA ¼ endobronchial ultrasound guided fine needle aspiration. a Any grade (mild, moderate or severe) was included 2 patients' imaging studies not included.
Table 3 CT chest classification (Scadding criteria).a Stage 0
Stage 1
Stage 2
Stage 3
Stage 4
Total cases
2
13
14
3
2
Sarcoidosis cases Number (%) EBUS-FNA positive
1 0/1 (0%) 1/1 (100%)
7 5/7 (71.4%) 4/7 (57.1%)
6 6/6 (100%) 4/6 (66.7%)
2 0/2 (0%) 2/3 (66.7%)
2 1/2 (50%) 1/2 (50%)
1 0/1 (0%) 1/1 (100%)
6 1/6 (16.7%) 1/6 (16.7%)
8 1/8 (12.5%) 5/8 (62.5%)
1 0/1 (0%) 1/1 (100%)
0 0 (0%) 0 (0%)
Number (%) TBLC positive
Non-sarcoidosis cases Number (%) EBUS-FNA positive Number (%) TBLC positive
TBLC ¼ transbronchial lung cryobiopsy; EBUS-FNA ¼ endobronchial ultrasound guided fine needle aspiration. a 2 patients imaging studies not included.
Table 4 Diagnostic yield of TBLC and EBUS-FNA by Scadding criteria (CT chest evaluation). Scadding stage (CT)
TBLC positive
EBUS-FNA positive
Total patients
0 1 2 3 4
1 4 4 2 1
0 5 6 0 1
1 7 6 2 2
TBLC ¼ transbronchial lung cryobiopsy; EBUS-FNA ¼ endobronchial ultrasound guided fine needle aspiration.
4. Discussion Flexible bronchoscopy is a safe technique to demonstrate granulomatous inflammation in the diagnostic workup of a suspected case of sarcoidosis. We recently reviewed the different modalities to diagnose sarcoidosis [20]. There is growing interest in
the TBLC technique. For sarcoidosis, the value of TBLC could be avoiding OLB in atypical cases, and the ability to procure bigger tissue samples for genetic testing. The diagnostic yield of EBUS-FNA in patients with a pathologic diagnosis of sarcoidosis was within the range of prior publications [8e10,20]. The addition of TBLC increased the yield. The value of combining bronchoscopic techniques has been noted previously, including a recent meta-analysis: Goyal et al. [21], for example, described the diagnostic yield of the following: endobronchial biopsy (EBB): 36%, conventional transbronchial needle aspiration (cTBNA): 48%, transbronchial lung biopsy (TBLB): 70%, and endobronchial ultrasound fine needle aspiration (EBUS-FNA): 74.5%. When combined in 2 different groups, the diagnostic yield increased: cTBNA þ EBB þ TBLB (85.5%) vs EBUS-FNA þ EBB þ TBLB (93%). In our case series, the diagnostic yield for TBLC was 66.7%, which approximates the diagnostic yield of TBLB described by Goyal et al. (70%). The value of TBLC was specifically helpful in cases without significant adenopathy with/without parenchymal abnormalities. This has been reported by others with the use of TBLB. We postulated that the diagnostic yield for EBUS-FNA and TBLC could be related to CT chest findings. However, no specific CT chest finding as described above, was statistically significant. Since the sample size of this study was fairly small, future studies seem warranted. Pneumothorax (11.1%) was a significant adverse event, easily managed with a small-bore chest tube and a short inpatient stay at our hospital as compared to SLB, in which 100% of the cases patients stay in the hospital post operatively with at least one chest tube in place. The pneumothorax rate for TBLC in our cohort was higher than the usual 5% rate estimated for TBLB. We believe this may be related in part, to the low number of patients in our cohort. In our institutional experience with TBLC for diffuse interstitial lung disease (total of 74 patients, including patients with atypical presentation of sarcoidosis cases), the pneumothorax rate was lower, 6.7% [18].
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We found that TBLC appears to be a safe and complimentary technique to diagnose sarcoidosis and could be considered part of the diagnostic armamentarium in bronchoscopic centers of excellence. Based on our study, we recommend considering EBUS-FNA sampling on any lymphadenopathy when its largest diameter is > 5 mm under EBUS examination. In conclusion, we found the overall diagnostic yield for EBUSFNA and TBLC was 100% in patients with a final diagnosis of sarcoidosis. TBLC appeared to be useful to diagnose sarcoidosis even in the absence of typical parenchymal disease. Further randomized controlled trials should clarify the value of TBLC in the diagnosis of sarcoidosis. Conflict of interest declaration All authors disclose no relationships/conditions/circumstances that present potential conflict of interest while preparing this manuscript. Source(s) of support None. References [1] G.W. Hunninghake, U. Costabel, M. Ando, et al., ATS/ERS/WASOG statement on sarcoidosis. American thoracic society/european respiratory society/world association of sarcoidosis and other granulomatous disorders, Sarcoidosis Vasc. Diffuse Lung Dis. 16 (2) (1999 Sep) 149e173. [2] P. Govender, J.S. Berman, The diagnosis of sarcoidosis, Clin. Chest Med. 36 (2015) 585e602. [3] M. Halme, A. Piilonen, E. Taskinen, et al., Comparison of endobronchial and transbronchial biopsies with high-resolution CT (HRCIT) in the diagnosis of sarcoidosis, APMIS 109 (4) (2001) 289e294. [4] R.M. Hsu, A.F. Connors Jr., J.F. Tomashefski Jr., et al., Histologic, microbiologic, and clinical correlates of the diagnosis of sarcoidosis by transbronchial biopsy, Arch. Pathol. Lab. Med. 120 (4) (1996) 364e368. [5] M. Oki, H. Saka, C. Kitagawa, et al., Prospective study of endobronchial ultrasound-guided transbronchial needle aspiration of lymph nodes versus transbronchial lung biopsy of lung tissue for diagnosis of sarcoidosis, J. Thorac.
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