Improved diagnostic yield of bronchoscopy in peripheral pulmonary lesions: combination of radial probe endobronchial ultrasound and rapid on-site evaluation

Introduction

Radial probe endobronchial ultrasound (R-EBUS), which was first introduced by Hurter and Hanrath in 1990, has emerged as a powerful tool during transbronchial biopsy (TBB) and brushing of peripheral pulmonary lesions (PPLs) and has increased the diagnostic yield in recent years (1-3). However, several studies have shown that the factors that affect the diagnostic yields using endobronchial ultrasound (EBUS)-guided TBB are the position of the probe, the lesion size, location, computed tomography (CT) scan appearance of the PPLs, and experience of bronchologist (4-8). Inadequate specimen collection is another factor limiting the yield of bronchoscopy (9). Rapid on-site evaluation (ROSE) of cytological material is a highly beneficial adjunct to thyroid, breast, pancreas, and pulmonary/mediastinal mass routine diagnostic method using fine-needle aspiration (FNA), such as ultrasound-guided, CT-guided FNA and endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). The advantages of ROSE include decreasing the number of passes needed for adequate sample, improving the adequacy rate (9-12), and reducing the need for additional sampling with lower risk of procedure complication (9-11). Therefore, ROSE can lead to cost savings for the health system and improve the quality of patient care (13). But, recent studies raised a question about the utility of ROSE for the evaluation of EBUS-TBNA samples in the diagnosis of lung cancer because there was no noticeably difference for diagnostic yield. The role of ROSE during EBUS-TBNA remains questionable because of the high diagnostic yields of EBUS-TBNA regardless of using ROSE (14-16).

However, little is known about whether use of ROSE can affect the diagnostic accuracy of R-EBUS in diagnosing PPLs. The aim of this study was to retrospectively evaluate the effectiveness of the combination of R-EBUS and ROSE in the diagnosis of PPLs, particularly difficult cases. The secondary objective was to define difficult cases with factors that could influence the diagnostic yields.

Patients and methods

Enrolled patients

The patients in this study had undergone bronchoscopy and EBUS to assess PPLs in the China Medical University Hospital (CMUH), Taichung, Taiwan, from December 2012 to December 2014. A total of 1,724 patients had bronchoscopic examinations for various indications during this period. The study was approved by CMUH Internal Review Board (DMR98-IRB-335) and waived the requirement for informed consent. Among 1,724 patients, 815 underwent EBUS for evaluations of PPLs based on CT scan and 107 patients were excluded due to visible endobronchial lesions. PPLs were defined as lesions that were surrounded by pulmonary parenchyma and were endoscopically invisible (i.e., no evidence of endobronchial lesion, extrinsic compression, submucosal tumor, narrowing, inflammation, or bleeding of the bronchus) (3).

Procedures and equipment

All patients underwent bronchoscopy (IT260; Olympus; Tokyo, Japan). EBUS was performed using an endoscopic ultrasound system (EU-M30; Olympus) and a 20-MHz miniature radial probe (UM-S20–20R; Olympus). After premedication with lidocaine local anesthesia, a bronchoscope was introduced transnasally. An EBUS probe was inserted through the working channel into the target bronchus based on radiographic findings. Thus, once the location of the target lesion was identified precisely by EBUS, the EBUS probe was marked with colored tape against the orifice of the working channel of the bronchoscope. Then, the EBUS probe was pulled out slowly. When the EBUS probe transducer reached the orifice of the subsegmental bronchus, the distance between the colored tape on the probe and the orifice of the working channel was measured by an assistant. The EBUS probe was then withdrawn. TBB and brushing were performed without fluoroscopic guidance. No extended working channel (guide sheath) was left in situ (17). Bronchoscopic procedures were performed by two pulmonary attending physicians, each with more than 4 years of training and experience in bronchoscopy.

Rapid on-site specimen evaluations

Bronchoscopy was performed with ROSE every Tuesday and Thursday. Patients were to be received exams with ROSE without any selection criteria. The material from bronchoscopic biopsy or brushing was immediately expressed onto numbered glass slides. Rapid Liu stain was used for specimen staining (18,19). The stained slide was screened by a cytopathologist, who continuously reported the findings and announced when sufficient diagnostic material had been recovered for a provisional diagnosis. The bronchoscopist modified or terminated the sampling process based on the information provided by the cytopathologist.

Definitions

When evaluating the position of the probe against the PPL on the EBUS image, the positions of the probe were divided into the following three patterns, as previously reported (20): (I) within (the probe was located in the bronchus inside the PPL); (II) adjacent to (the probe was located in the bronchus adjacent to the PPL); (III) outside (the probe was located in the bronchus outside the PPL). Bronchus sign positive PPL was defined as the finding on a high-resolution CT scan of a bronchus leading directly to a PPL. Bronchus sign negative PPL was defined as the lesion was only surrounded by pulmonary parenchyma and no bronchus leading directly to the lesion from a high-resolution CT scan (21,22). Pleural effusion surrounding the lesion was defined as the finding on CT scan showing that the lesion was surrounded by pleural effusion.

Statistical analysis

The data were analyzed using SPSS for Windows, version 12.0 (Chicago, IL, USA). Continuous variables were reported as mean ± standard deviation (SD) and compared using two-tailed Student’s t-tests. Categorical variables were reported as the numbers of patients and percentages. Differences between categorical variables were evaluated using Fisher’s exact test. Multivariate stepwise logistic regression analysis was used to identify independent factors related to diagnostic yields of TBB using EBUS in PPLs. All statistical tests were two-sided; P≤0.05 was considered significant. Odds ratios (ORs) and 95% confidence intervals (CIs) were also calculated.

Results

Patients and diagnostic lesions

Of the 815 patients, 526 were males. The mean age was 66±14 years. Table 1 shows the final diagnoses of the patients. Among these 815 patients, 87 patients were undiagnosed due to these patients were negative from R-EBUS and didn’t take any other examination after bronchoscopy. A definite diagnosis was made by R-EBUS-guided TBB or brushing for 627 patients (76.9%). Of the 101 patients with a non-diagnostic EBUS, the diagnosis was established by percutaneous CT-guided biopsy for 57 patients, transthoracic echo-guided biopsy for 18 patients and by video-assisted thoracoscopy (VATS) for 26 patients. The three most common lung malignancies were adenocarcinoma (n=330), squamous cell carcinoma (n=148) and small cell lung cancer (n=62) and the three most common pulmonary infections were tuberculosis (n=66), cryptococcus (n=10), and aspergillus (n=9).

Table 1 Characteristic of 815 PPL patients and proportion of lesions diagnosed by TBB or brushing using EBUS
Full table

Accuracy of ROSE

A total of 279 patients (34.2%) were evaluated by ROSE examinations. Table 2 showed the accuracy of ROSE in predicting final EBUS diagnosis of malignancy. There were no false-positive results with ROSE. However, four cases were falsely-positive evaluated as negative with ROSE, which giving a sensitivity of 98.2%, a specificity of 100%, and diagnostic accuracy of 98.3%.

Table 2 Accuracy of ROSE in predicting final EBUS diagnosis of malignancy
Full table

Diagnostic yield in each group

Table 3 shows the factors that may affect the diagnostic yields from R-EBUS. The first is the size and position of lesion. The lesions of bronchus sign positive PPLs had a significantly higher diagnostic yield than that of bronchus sign negative PPLs (412/472, 87.3% vs. 215/343, 62.7%; P<0.001). A larger size PPLs (size ≥3 cm) also had a significantly higher diagnostic yield than smaller sized PPLs (size <3 cm) (481/564, 85.3% vs. 146/251, 58.2%; P<0.001). Based on the lesion location and size, small PPLs (size <3 cm) with negative bronchus signs had a significantly lower diagnostic yield than larger PPMs (≥3 cm) with positive bronchus signs, small PPLs (<3 cm) with positive bronchus signs or larger PPLs (≥3 cm) with negative bronchus signs: 51.4% vs. 89.7%, 74.7%, and 74.3%, respectively.

Table 3 Diagnostic yields by TBB or brushing using EBUS with and without ROSE, based on the lesion of size and location on CT scan
Full table

Second is the location of the lesion. The yields from the left apical-posterior and right apical segments were significantly lower than those from other locations (87/134, 64.9% vs. 540/681, 79.3%; P<0.001).

Third is the position of probe and if the pleural effusion is surrounded the lesion or not. Lesions within the probe had a higher diagnostic yield (559/642, 87.1%) than the lesion adjacent to the probe (68/173, 39.3%; P<0.001). PPLs with pleural effusion had a lower diagnostic yield than PPLs without pleural effusion (39/67, 58.2% vs. 586/745, 78.7%; P<0.001).

We furthermore compared the above factors that may affect the diagnostic yields from R-EBUS with or without ROSE. A total of 279 patients (34.2%) were evaluated by ROSE examinations. The overall diagnostic yield was 76.9% (627/815). The diagnostic yields of EBUS with ROSE were significantly higher than without ROSE examinations (86.7% vs. 71.8%; P<0.001), particularly for PPLs <3 cm with negative bronchus signs (77.1% vs. 41.7%, P<0.001). ROSE also can significant increase the diagnostic yield, no matter the lesions are in the left apical-posterior and right apical segments (77.4% vs. 56.8%, P=0.015) or at the other location (88.9% vs. 74.5%, P<0.001). The same result is also seen if the position of the probe is within (92.4% vs. 83.9%, P=0.002) or not within (53.7% vs. 34.8%, P=0.031), and if the lesion is surrounded with pleural effusion (75% vs. 46.2%, P=0.044) or not (88.0% vs. 73.8%, P<0.0001).

Figure 1 showed the diagnostic yield according to the size of PPLs. With ROSE examination, there were similar diagnostic yield between the lesion size from 2 cm to more than 10 cm. Low diagnostic yield was observed when the lesion size is less than 2 cm. Without ROSE examination, there were similar diagnostic yield between the lesion size from 3 to 7 cm. Lower diagnostic yield occurred when the PPLs is less than 3 cm or more than 8 cm.

Figure 1 Proportion of lesions diagnosed by TBB or brush using EBUS according to the size of lesions. EBUS, endobronchial ultrasound; TBB, transbronchial biopsy; ROSE, rapid on-site evaluation.

Comparison of procedure

Procedural details in each group are shown in Table 4. Mean procedural time was similar in each group (28.12 vs. 27.7 min, P=0.395). Bronchial alveolar lavages (BAL) for diagnostic of PLLs were significantly fewer in ROSE group than in the non-ROSE group (16.1% vs. 99.1%, P<0.001).

Table 4 Procedural details
Full table

Discussion

As we know, this is the first retrospective study to evaluate ROSE examinations with regard to diagnostic yields for PPLs using R-EBUS without fluoroscopy. This study confirms that ROSE can increase the diagnostic yield of R-EBUS for PPLs, particularly for difficult diagnostic PPLs: lesion size was <3 cm with negative bronchus signs, located in the right apical and left apical-posterior segments, the probe adjacent to the PPLs and PPLs with pleural effusion. Moreover, ROSE examination can also increase diagnostic yield if the lesions size are between 2 to 3 cm or more than 8 cm. Our study also demonstrated that ROSE can reduce the proportion of BAL in diagnosing PPLs, but it was not associated with procedure time.

In our study, the combination of R-EBUS with ROSE had shown higher result with diagnostic yield between 53% and 94%. Overall diagnostic yield of 53–80% with incorporation of R-EBUS into standard bronchoscopy procedures was reported in previous several studies (1,3,4,6,23). Published literature recommends that 72–93% of PPLs could be visualized by R-EBUS (6). There was a strong correlation exists between diagnostic yield and EBUS visualization (1,3,4,6,23). However, EBUS visualization yield always does not translate completely into diagnostic yield of visualized lesions. Definite factors that could account for that deficit have been recommended, mainly number of sequential biopsy samples taken, the quality of the sample obtained, and the effect of probe position in relation to the PPLs (3).

ROSE has proven advantageous in providing real-time feedback to the operator, which has the potential to improve patient care by increasing sample adequacy, diagnostic accuracy, shortening procedure times (by reducing the number of passes and/or number of sampled nodal stations), aiding in the triage of material for ancillary studies (e.g., immunocytochemistry, electron microscopy, and microbiology) and optimizing the use of the procedure room (9-12,24,25). It improves the diagnostic ability of all specialists involved, especially challenging cases that are difficult to access (9). The operator can justify the technique by changing the puncture site, puncture depth or angle based on the ROSE results. The challenging subjects usually have the factors that affect the diagnostic yields.

Previous studies have shown that the diagnostic yield was affected by the position of the EBUS probe, the size and location of the PPLs (3,20,26,27). We can get the similar result. Moreover, we found another factor that influences the diagnostic yield of EBUS, which is pleural effusion occurrence. PPLs with effusion had higher incidence of biopsy the specimen from normal pulmonary parenchyma due to atelectasis, which certainly decreases the diagnostic yield. In Table 3, the combination of ROSE and R-EBUS helps to overcome the factors which affect the diagnostic yield, especially when the size of PPLs are less than 3 cm with negative bronchus signs, the location of PPLs are in the right apical and left apical-posterior segments, the probe are adjacent to the PPLs and PPLs are with pleural effusion. In Figure 1, we focus the ROSE and PPLs size. Schreiber et al. (28) showed that sensitivity of bronchoscopy for the diagnosis of PPLs around 2 cm is reported to range from 33% to 62%. Combination of R-EBUS with ROSE can increase the diagnostic yield if the lesion sizes were 2.0–2.9 cm (46/52, 88.5%), but still low diagnostic yield if the lesions size were 1.0–1.9 cm (10/14, 71.4%). We also find excellent diagnostic yield with ROSE examinations even the PPLs size larger than 7 cm. To our knowledge, once the tumor size became bigger, the tumor had central necrotic part which causes higher false negative results without ROSE. From our limit data, we can conclude that ROSE examination can increase the diagnostic rate for PPLs size less than 3 cm or more than 7 cm.

The increases in sample adequacy and diagnostic accuracy with increased diagnostic yield and greater sensitivity have been described as the main advantages of ROSE (9-12). As the yield of bronchoscopy is typically lowest for PPLs (29), ROSE might be valuable for aspiration of PPLs. From our study when we use R-EBUS to diagnosis the PPLs, ROSE can increase the diagnostic yield than without ROSE (86.7% vs. 71.8%; P<0.001).

To the contrary, the value of ROSE during EBUS-TBNA may be controversial in terms of diagnostic yield because of high diagnostic yield of EBUS-TBNA regardless of using ROSE. It has enabled ‘real-time’ by confirming the position of the needle tip under imaging during the procedure, allowing for a more highly accurate procedure than by the conventional aspiration methods (30). Therefore, the role of ROSE during EBUS-TBNA remains questionable. R-EBUS guided TBB may be quite different from EBUS-TBNA: the former was without real-time ultrasound-guided sampling and specimens obtained using R-EBUS guided TBB forceps are larger than those obtained from EBUS-TBNA. Hence, in our study, false negative rate (1.6%) of ROSE was lower than an EBUS-TBNA study (5.7%) by Nakajima et al. (31). Sensitivity (98.2%) and diagnostic accuracy (98.3%) of ROSE were higher in predicting final R-EBUS diagnosis of malignancy than another EBUS-TBNA study by Oki et al. (sensitivity: 88%, diagnostic accuracy: 89%) (32).

Combination with other techniques for obtaining diagnostic specimens and TBB specimens may raise diagnostic yield, such as BAL and brushings (33). In our practice, the proportion of BAL reduced noticeably in ROSE group, but the diagnostic yield was higher than non-ROSE group. Unnecessary BAL may cause complications such as fever, infection, arrhythmia and hypoxia (34). The result was similar to previous reports, ROSE can avoid the need for additional diagnostic procedures, reduce the complication rate of bronchoscopy without loss in diagnostic yield (9,35). Despite reduction of the proportion of BAL, the ROSE group could not shorten the bronchoscopy time because preparing and reviewing slides for ROSE took time (36).

There are two potential limitations of our study. First, inter-operator and inter-observer variabilities could exist for the pulmonologists who perform the procedures and the cytopathologists who evaluate the specimens. In order to minimize the inter-operator and inter-observer variabilities, bronchoscopic procedures were performed by two well-trained pulmonologists who had more than 8 years of experience, and the stained slides were screened by one cytopathologist who had more than 20 years of experience. Second, our data is a retrospective study. Additional prospective studies shell is conducted to confirm these factors affecting the diagnostic yield with R-EBUS for PPLs.

Conclusions

In conclusions, ROSE can increase the diagnostic yield of PPLs by R-EBUS, particularly difficult cases: PPLs <3 cm with negative bronchus signs, PPLs located in the right apical and left apical-posterior segments, the probe adjacent to the PPLs and PPLs with pleural effusion. Moreover, it can increase diagnostic yield if the PPLs size are more than 7 cm. We believe these results can offer the bronchoscopist to decide which condition should be with ROSE examination or not.

Acknowledgements

None.

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

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