Endobronchial Ultrasonography With a Guide Sheath in the Diagnosis of Benign Peripheral Diseases

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1 Endobronchial Ultrasonography With a Guide Sheath in the Diagnosis of Benign Peripheral Diseases Naofumi Shinagawa, MD, PhD, Kosuke Nakano, MD, Hajime Asahina, MD, PhD, Eiki Kikuchi, MD, PhD, Tomoo Ito, MD, PhD, Yoshihiro Matsuno, MD, PhD, Satoshi Oizumi, MD, PhD, Yasuyuki Nasuhara, MD, PhD, and Masaharu Nishimura, MD, PhD First Department of Medicine, Hokkaido University School of Medicine, Sapporo; and Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan Background. For appropriate treatment, such as the selection of antibiotics or initiation of steroid therapy, correctly diagnosing benign pulmonary diseases located at the periphery is vital. This study assessed the usefulness of bronchoscopy using endobronchial ultrasonography with a guide sheath (EBUS-GS) in the diagnosis of benign pulmonary diseases, especially those presenting peripheral nodular lesions. Methods. We retrospectively reviewed 159 patients with 171 peripheral pulmonary lesions (PPLs) that were subsequently diagnosed as benign diseases. To examine the role of bronchoscopy with EBUS-GS, the contribution of bronchoscopy was classified into 4 categories. We also retrospectively reviewed 24 patients with 25 PPLs that were subsequently diagnosed as benign diseases by bronchoscopy without EBUS-GS (historical control). Results. The ultimate diagnosis of 171 PPLs included 45 cases of mycobacteriosis, 45 cases of bronchiolitis obliterans organizing pneumonia/chronic organized pneumonia (BOOP), 23 cases of bacterial pneumonia, 13 abscesses, 11 cases of sarcoidosis, and 34 other benign diseases. Among them, a definitive diagnosis was obtained by bronchoscopy with EBUS-GS in 99 lesions (58%). Lesions in which the probe was positioned within the lesion had a higher diagnostic yield (64%) than did lesions in which the probe was positioned adjacent to the lesion (52%) or outside the lesion (20%; P 0.01). The diagnostic yield of bronchoscopy with EBUS-GS was higher compared with that of the historical control (58% versus 28%; P 0.04). Conclusions. Bronchoscopy using EBUS-GS is a reasonable option as a diagnostic procedure for PPLs, even if they are suspected to be benign in nature. (Ann Thorac Surg 2012;93:951 7) 2012 by The Society of Thoracic Surgeons For pulmonary peripheral lesions (PPLs), computed tomography and positron emission tomography with fluorodeoxyglucose do not provide a definitive diagnosis. Benign pulmonary diseases include infections, sarcoidosis, and interstitial lung diseases, and it is pivotal to obtain a reliable diagnosis for such diseases. Without a confirmed diagnosis, patients tend to undergo empirical therapy that does not necessarily result in improvement. Surgical biopsy procedures such as video-assisted thoracoscopic surgery (VATS) have become a safe and common procedure, although they still carry a 6% to 7% risk of complications [1]. Therefore, minimally invasive methods are desirable for sampling a tissue specimen for definitive diagnosis, especially for the elderly and patients with poor pulmonary function. A transbronchial approach using a bronchoscope under radiographic fluoroscopic guidance has been the most generally accepted method for diagnosing PPLs since the 1970s [2 4]. The diagnostic yields from transbronchial biopsy (TBB) for benign lesions were reported as 10% to 50%, which is lower than that for malignant lesions [5 7]. Endobronchial ultrasonography (EBUS) has been used for imaging guidance in the TBB of PPLs; the feasibility and effectiveness of TBB using EBUS with a guide sheath (EBUS-GS) has been demonstrated [8, 9]. Several reports have since demonstrated the usefulness of TBB using EBUS [10 12], and the diagnostic yield of TBB using EBUS in PPLs ranges from 58% to 80% [8 12]. However the role of bronchoscopy with EBUS-GS in the diagnosis of benign pulmonary lesions has not been fully examined. We have considered that there are degrees in the contribution of bronchoscopy for the confirmation of benign pulmonary diseases. For example, the detection of bacteria or other pathogens is usually enough for the Accepted for publication Nov 30, Address correspondence to Dr Shinagawa, First Department of Medicine, Hokkaido University School of Medicine, North 15, West 7, Kita-ku, Sapporo , Japan; naofu@med.hokudai.ac.jp. Dr Shinagawa discloses that he has a financial relationship with Olympus Medical Systems by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 952 SHINAGAWA ET AL Ann Thorac Surg EBUS-GS FOR BENIGN PULMONARY LESIONS 2012;93:951 7 confirmation of infectious diseases such as tuberculosis, mycosis, and Pneumocystis jiroveci pneumonia. In contrast, for the diagnosis of pulmonary sarcoidosis, other information, such as the elevation of serum angiotensin-converting enzyme levels or findings on bronchoalveolar lavage, is definitely supportive even with a finding of sampled epithelioid cell granulomas. To provide a guiding principle, we highlight the contribution of bronchoscopy with EBUS-GS in the diagnosis of benign pulmonary nodules. Material and Methods Ethics Committee Approval This study was approved by the institutional review board of Hokkaido University Hospital (project approval number ), and all patients provided written informed consent. Patients We performed a retrospective chart review of patients referred to the Hokkaido University Hospital between April 2003 and June 2010 who underwent EBUS-GS. EBUS-GS was performed for 876 lesions during the study period (Fig 1). Six hundred sixty lesions were finally diagnosed as malignant lesions. Thirty-eight lesions were excluded because the final diagnosis was indefinite. The benign pulmonary diagnoses included various diseases such as mycobacteriosis, pneumonia, abscess, sarcoidosis, mycosis, benign tumor, and pneumoconiosis. We retrospectively reviewed the charts of 159 patients with 171 PPLs that were subsequently diagnosed as benign pulmonary diseases. Transbronchial Biopsy Using EBUS-GS Transbronchial biopsy using EBUS-GS was performed as described previously [13, 14]. A 20-MHz mechanical radial-type probe (UM-S20-17S; Olympus Medical Systems, Tokyo, Japan) with an external diameter of 1.4 mm (1.4-mm probe) was used most often and a 20-MHz mechanical radial-type probe (UM-S20-20R; Olympus Medical Systems) with an external diameter of 1.7 mm (1.7-mm probe) was used for lesions assumed to be reachable. The probe was connected to an endoscopic ultrasonography system (EU-M30S; Olympus Medical Fig 1. Patient disposition. Table 1. Grade of Contribution of Bronchoscopy (Transbronchial Biopsy, Transbronchial Brushing Cytologic Analysis, or Bronchial Washing, or a Combination) in Diagnosing Benign Diseases Grade A: Definitive diagnosis was obtained by bronchoscopy alone Grade B: Definitive diagnosis was obtained by bronchoscopy and clinical features Grade C: Definitive diagnosis was not obtained by bronchoscopy, even with the addition of clinical features, although suspected findings were obtained by bronchoscopy Grade D: Definitive diagnosis was not obtained by bronchoscopy, even with the addition of clinical features; no suspected findings were obtained by bronchoscopy Systems). A flexible fiberoptic bronchoscope with a 2.0- mm diameter working channel (BF-P260F; Olympus Medical Systems) and a guide sheath with an external diameter of 1.9 mm (B ; Olympus Medical Systems) were used for the 1.4-mm probe; a flexible fiberoptic bronchoscope with a greater than or equal to 2.8-mm diameter working channel (BF-1T30 or BF- 1T260; Olympus Medical Systems) and a guide sheath with an external diameter of 2.7 mm (B ; Olympus Medical Systems) were used for the 1.7-mm probe. Using local anesthesia, the bronchoscope was inserted into the target bronchus under direct vision, after which an EBUS probe was inserted into the guide sheath, and the guide sheath covered probe was then inserted through the bronchoscope working channel into the bronchi leading to the area suspected of containing the lesions. Endobronchial ultrasonographic imaging and radiographic fluoroscopy were used to confirm that the probe and guide sheath had reached the lesions. After locating the lesions on the EBUS image, biopsy forceps and bronchial brushes were introduced through the guide sheath. Subsequently, pathologic, cytologic, and culture specimens were obtained under fluoroscopic guidance. If a definitive diagnosis was not obtained by EBUS-GS, the patient underwent additional procedures (VATS or repeated bronchoscopy) or had clinical and radiologic follow-up to confirm the final diagnosis of the lesions. Determination of Grade for Bronchoscopy Contribution The contribution of bronchoscopy with EBUS-GS in diagnosing benign pulmonary diseases with TBB, transbronchial brushing cytologic analysis, bronchial washing, or a combination, was classified into the following 4 grades: grade A, definitive diagnosis obtained by bronchoscopy alone; grade B, definitive diagnosis obtained by bronchoscopy with information about clinical features; grade C, definitive diagnosis not obtained by bronchoscopy even with information about clinical features, although suspected findings were obtained by bronchoscopy; and grade D, no suspected findings obtained by bronchoscopy (ie, normal lung tissue) and no definitive diagnosis obtained (Table 1). Grade A and grade B were defined as positive results that led to a definitive diagnosis of benign pulmonary disease.

3 Ann Thorac Surg SHINAGAWA ET AL 2012;93:951 7 EBUS-GS FOR BENIGN PULMONARY LESIONS 953 Table 2. Contribution of Bronchoscopy in Diagnosis According to Benign Diseases Grade of Contribution of Bronchoscopy Disease n A B C D A B (%) C D (%) Mycobacteriosis (71%) 13 (29%) Tuberculosis (73%) 3 (27%) Nontuberculous mycobacteriosis (71%) 10 (29%) BOOP/COP (44%) 25 (56%) Bacterial pneumonia (52%) 11 (48%) Abscess (92%) 1 (8%) Sarcoidosis (64%) 4 (36%) Radiation pneumonitis (57%) 3 (43%) Eosinophilic pneumonia (50%) 3 (50%) Benign tumor (33%) 4 (67%) Pneumoconiosis (33%) 2 (67%) Angiitis (50%) 1 (50%) Actinomycosis (0%) 2 (100%) Atelectasis (0%) 2 (100%) Pulmonary alveolar proteinosis (100%) 0 (0%) Wegener s syndrome (0%) 1 (100%) Nocardiosis (100%) 0 (0%) Aspergillosis (100%) 0 (0%) Cryptococcus (100%) 0 (0%) Total (58%) 72 (42%) BOOP bronchiolitis obliterans organizing pneumonia; COP chronic organized pneumonia. Historical Control We used the data from patients who underwent conventional bronchoscopy in our institute between July 2001 and February 2003 as a historical control. We retrospectively reviewed 24 patients with 25 PPLs that were subsequently diagnosed as benign pulmonary diseases. Statistical Analysis Statistical analyses were performed with SPSS software, version (SPSS Inc, Chicago, IL). Statistical significance was established at P All analyses were 2-sided. The association of the diagnostic yield with size, location of lesions, size of biopsy forceps, and position of the probe were analyzed using Fisher s exact test. To evaluate the contribution of EBUS-GS for lesions suspected of being benign pulmonary diseases, Pearson s 2 test was used to compare the diagnostic yield with EBUS-GS to that without EBUS-GS. Results Patient Characteristics and Benign Pulmonary Diseases Diagnosed With Bronchoscopy The mean age of 159 patients (97 men, 62 women) was 61.8 years (range, 21 to 85 years). The diameter of the lesions was mm (mean SD; range, 6 to 69 mm); 57 lesions were located in the right upper lobe, 19 lesions were located in the right middle lobe, 42 lesions were located in the right lower lobe, 26 lesions were located in the left upper lobe, and 27 lesions were located in the left lower lobe. We performed biopsies (mean SD; range, 0 to 9) per pulmonary lesion. One hundred seventy-one benign lesions included 45 cases of mycobacteriosis, 45 cases of bronchiolitis obliterans organizing pneumonia (BOOP)/chronic organized pneumonia, 23 cases of bacterial pneumonia, 13 abscesses, 11 cases of sarcoidosis, and 34 other benign diseases (Table 2). Estimation of Bronchoscopy Contribution for Diagnosis of Pulmonary Benign Diseases Regarding the contribution of bronchoscopy in diagnosis, 40 lesions (23.4%) were classified as grade A (eg, diagnosed as mycobacteriosis by pathologic and culture findings in 36 cases, or hamartoma in 2 cases, or pulmonary alveolar proteinosis in 2 cases), 59 lesions (34.5%) were classified as grade B (eg, detection of epithelioid granuloma in sarcoidosis in 7 cases or organization in organized pneumonia in 20 cases), 19 lesions (11.1%) were classified as grade C (eg, detection of nonspecific inflammation in 9 cases), and 53 lesions (31.0%) were classified as grade D (eg, collection of insufficient specimen in 5 cases or detection of normal lung tissue). Figure 2 shows a representative grade A case. Computed tomographic images showed an abnormal nodular shadow in the left upper lobe. We performed TBB using a bronchoscope with EBUS-GS (Fig 2B). The result of TBB showed granulation tissue, and acid-fast bacilli were detected using the Ziehl-Neelsen stain (Fig 2C, 2D). The specimen culture result was positive for Mycobacterium avium. Figure 3 shows a representative grade B case. Computed tomographic images showed a pulmonary nodule (diameter, mm) in the right upper lobe.

4 954 SHINAGAWA ET AL Ann Thorac Surg EBUS-GS FOR BENIGN PULMONARY LESIONS 2012;93:951 7 Fig 2. A case of nontuberculous mycobacteriosis. (A) Computed tomographic scan showed a pulmonary nodule (diameter, mm) in the left lingular segment (S4). (B) Endobronchial ultrasonography showed a low-echoic nodule. (C) Histologic images of biopsy specimens showed caseous necrosis and an epithelioid granuloma (hematoxylin and eosin stain, 40). (D) Using Ziehl-Neelsen staining of specimens from transbronchial brushing cytologic analysis, acid-fast bacilli were detected ( 400). The specimen culture was positive for Mycobacterium avium. We performed EBUS-GS, and the biopsy specimens showed organization in the alveolar space (Fig. 3B, 3C). The specimen culture results were negative. This lesion was diagnosed as an organized pneumonia. With respect to a definitive diagnosis that was defined as grade A or B, bronchoscopy using EBUS-GS provided 99 cases (57.9%) of a confirmed diagnosis for benign peripheral pulmonary diseases. There were no complications in bronchoscopic procedures with EBUS-GS. Among lesions in which diseases could not be diagnosed bronchoscopically, 12 (17%) of 72 underwent VATS, 14 (19%) underwent repeated bronchoscopy, and 46 (64%) were followed for 1 year or more and finally diagnosed as benign diseases. Clinical Features of Peripheral Pulmonary Lesions Related to Diagnostic Yield and Comparison to the Contribution of Bronchoscopy Without EBUS-GS Next, we evaluated the association of the diagnostic yield with size, location of lesions, size of biopsy forceps, and position of the probe (within the lesion versus adjacent to the lesion) (Table 3). Lesions 3 cm or larger (grade A or B; 46/68, 68%) tended to have a higher diagnostic yield than lesions smaller than 3 cm (grade A or B; 53/103, 51%; P 0.08). There were no significant relationships of diagnostic yield (grade A and B) to size, location of the lesions, or diameter of biopsy forceps. Lesions in which the probe was positioned within the lesion on the EBUS image had a higher diagnostic yield (grade A or B; 79/123, 64%) than did lesions in which the probe was positioned adjacent to the lesion (grade A or B; 17/33, 52%) or outside the lesion (grade A or B; 3/15, 20%; P 0.01). We also evaluated the contribution of EBUS-GS when used to diagnose PPLs suspected of being benign pulmonary diseases. Among the PPLs examined between July 2001 and February 2003 (before we started to perform the EBUS-GS procedure), 25 PPLs were suspected of being benign diseases amenable to bronchoscopic procedures without EBUS-GS. The mean diameter of the PPLs was mm (range, 7 to 76 mm) and biopsies were performed times per lesion (mean SD; range, 0 to 6). There was no statistically significant difference in the mean size and numbers of biopsies between the procedure with EBUS-GS and that without EBUS-GS. Without EBUS-GS, the contributions for diagnosis were classified as grade A in 2 lesions (8%), grade B in 5 lesions (20%), grade C in 6 lesions (24%), and grade D in 12 lesions (48%), resulting in a definitive diagnosis (grade A

5 Ann Thorac Surg SHINAGAWA ET AL 2012;93:951 7 EBUS-GS FOR BENIGN PULMONARY LESIONS 955 Fig 3. A case of organized pneumonia. (A) Computed tomographic scan showed a pulmonary nodule (diameter, mm) in the right upper lobe (S1). (B) Endobronchial ultrasonography showed a low-echoic nodule. (C) Histologic images of biopsy specimens showed organization in the alveolar space (hematoxylin and eosin stain, 100). The specimen culture result was negative. or B) in 7 lesions (28%) (Table 4). As a result, the diagnostic yield (grade A or B) of bronchoscopy with EBUS-GS was significantly higher than that of conventional bronchoscopy without EBUS-GS (58% versus 28%, respectively; P 0.04). Comment This report defines the diagnostic yield of benign pulmonary diseases, especially nodular lesions, when using bronchoscopy with EBUS-GS. By applying the classification of the contribution, we have focused on more details of the diagnostic steps in various types of benign pulmonary nodules. In combination with EBUS-GS, we have had a relatively higher diagnostic yield of 58% (grade A or B) for the diagnosis of benign pulmonary nodules. Our study has shown that bronchoscopy with EBUS-GS is effective for diagnosing pulmonary benign diseases. This method seems to enable physicians to avoid unnecessary operations or to select proper antibiotic therapy. Diagnostic yields of bronchoscopy using EBUS in benign disease were reported to be 29% to 69% in previous reports [8 14], but the criteria of such lesions were not standardized. Most of these reports did not mention the Table 3. Contribution of Bronchoscopy in Diagnosing Benign Diseases According to Various Factors Grade of Contribution of Bronchoscopy Factor n A B C D A B (%) C D (%) p Value Lesion diameter 3 cm (68%) 22 (32%) 3 cm (51%) 50 (49%) 0.08 Location Right upper lobe (54%) 26 (46%) Right middle lobe (58%) 8 (42%) Right lower lobe (55%) 19 (45%) Left upper lobe (81%) 5 (19%) Left lower lobe (48%) 14 (52%) 0.23 Guide sheath For 1.7-mm probe (59%) 19 (41%) For 1.4-mm probe (58%) 53 (42%) 0.26 Position of the probe Within (64%) 44 (36%) Adjacent to (52%) 14 (48%) Outside (20%) 12 (80%) 0.01

6 956 SHINAGAWA ET AL Ann Thorac Surg EBUS-GS FOR BENIGN PULMONARY LESIONS 2012;93:951 7 Table 4. Contribution of Bronchoscopy With or Without EBUS-GS in Diagnosing Benign Diseases Grade of Contribution of Bronchoscopy Variable n A B C D A B (%) C D (%) p Value Without EBUS-GS (28%) 18 (72%) With EBUS-GS (58%) 72 (42%) 0.01 EBUS-GS endobronchial ultrasonography with a guide sheath. criteria for diagnosis of benign diseases [8 10, 12 14]. Herth and associates [11] mentioned that a bronchoscopic diagnosis of fibrosis or inflammation was considered nondiagnostic in their report, and we also defined inflammation as grade C. However criteria of diagnosis of benign diseases were not well defined in other studies. Khouri and colleagues [15] reported the criteria for considering a lesion nonmalignant was based on all of the following: successful biopsy visually, no suspicion of cancer in the tissue, adequate material other than normal lung, and absence of endobronchial lesions [15]. They also classified the diagnosis of benign disease into 2 categories: specific benign lesions and nonspecific benign lesions consisting of nonspecific inflammatory changes and fibrosis. We set 4 grades of contribution because we considered that the results of EBUS-GS could be classified into more detailed grades. For example, grade C and grade D were defined as negative in our classification; however they were completely different in view of the accuracy of sampling tissues from target lesions. This new classification of contribution might be instructive for bronchoscopists. Using the classified grades, we have clearly shown that EBUS-GS enabled a higher yield in the diagnosis of benign pulmonary disease. Our main goal in this report was to define retrospectively the efficacy of benign pulmonary diseases, especially nodular lesions, when using bronchoscopy with EBUS-GS. Fraire and associates [16] reported that the diagnostic usefulness of TBB is related to the specimen size, especially in benign diseases. In the present study, we postulated that the size of biopsy specimens would influence the diagnostic yields of benign diseases, but the diagnostic yields did not vary with the diameter of biopsy forceps (59% versus 58%). Endobronchial ultrasonography with a guide sheath has an advantage in confirming the precise location of PPLs by EBUS imaging and in visually obtaining samples from the lesion. In addition, with EBUS-GS, specimens were taken correctly and repetitively from lesions with less risk of complications, because a guide sheath works not only as an introducer but also as a wedge against bleeding. The present study solidified the advantage of EBUS-GS because the examination with EBUS-GS was superior to that without EBUS-GS in the diagnostic yield for the benign diseases examined. Recently, EBUS with transbronchial needle aspiration has been used for both malignant and benign pulmonary lesions. In prospective studies, EBUS transbronchial needle aspiration had a high diagnostic yield and accuracy for the detection of lung cancer and mesothelioma metastases [17, 18]. The technique is also useful for confirming benign diseases such as pulmonary sarcoidosis [19]. Virtual bronchoscopic imaging has been reported as another promising procedure to aid in the diagnosis of benign pulmonary disease [20]. These procedures will continue to have a high yield and be helpful in the diagnosis of pulmonary disease. In conclusion, we have demonstrated that bronchoscopy with EBUS-GS is beneficial in the diagnosis of benign pulmonary lesions by using a new rendering to estimate the contribution of the method. Bronchoscopic examination should be considered for the diagnosis of benign PPLs. 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