Abstract
Objectives: Peripheral lung nodules containing ground-glass opacity (GGO), which include both pure GGN (nodules that contain only GGO) and part-solid GGN (nodules that contain both GGO and consolidation), are difficult to diagnose by conventional transbronchial biopsy (TBB) because they are not visible by fluoroscopy. Recently developed endobronchial ultrasound (EBUS)-guided TBB is useful for diagnosing these nodules. This study was performed to clarify the contribution of EBUS to the diagnostic yield of TBB for peripheral lung nodules containing GGO.
Methods: We retrospectively reviewed the medical records of 41 patients (21 male, 20 female; median age, 72 years) with peripheral lung pure GGN or part-solid GGN who underwent EBUS-guided TBB.
Results: The median diameter of the target lesions was 18.6 mm (range, 8.8–46.7 mm). There were seven pure GGN lesions and 34 part-solid GGN lesions. The total diagnostic yield was 65.9% (27/41). EBUS images could be obtained (positive) in 30 (73.1%) patients. Among the clinical factors studied, only a positive EBUS finding was significantly associated with a higher diagnostic yield (p=0.018). Diagnostic yield tended to be higher in patients with a positive CT bronchus sign (presence of a bronchus leading directly to the target lesion) and increased consolidation-to-tumor ratio.
Conclusions: EBUS-guided TBB is useful for diagnosing GGN or part-solid GGN. Obtaining positive EBUS findings is important for successful TBB for lesions containing GGO.
Introduction
Recent advances in bronchoscopic procedures, such as endobronchial ultrasound (EBUS)-guided transbronchial biopsy (TBB), have improved the diagnostic yield of peripheral lung lesions.1 As chest computed tomography (CT) screening has become more widespread, smaller peripheral lung lesions have become more readily detected in the daily clinical setting.2 Similarly, peripheral nodules that contain ground-glass opacity (GGO) can be detected by chest CT, but not by conventional chest X-ray. However, nodules that contain only GGO (pure GGN lesions) and nodules that contain both GGO and consolidation (part-solid GGN lesions) are difficult to diagnose by TBB partly because the lesions are often invisible on fluoroscopy.3 Additionally, atypia of tumor cells is relatively low in GGO lesions.4 Therefore, pathological diagnosis of small biopsy samples is sometimes difficult.
We previously reported that the diagnostic yield of EBUS-guided TBB for small peripheral lesions (not only GGO lesions) was significantly associated with the CT bronchus sign (presence of a bronchus leading directly to the target lesion).5 Ikezawa et al.6 reported that EBUS-guided TBB is also useful for diagnosing GGO-predominant lesions. They reported that an aberrant EBUS finding could be obtained in many patients with GGN-predominant lesions. In daily clinical practice, however, aberrant EBUS findings are not always easy to recognize.7 Therefore, the present study was performed to investigate the diagnostic contribution of EBUS during TBB for GGO lesions. We retrospectively reviewed the medical records of patients with pure GGN or part-solid GGN peripheral lung lesions who underwent EBUS-guided TBB in our hospital.
Methods
Patients
We retrospectively reviewed the medical records of consecutive patients who underwent EBUS-guided bronchoscopy for lung lesions containing GGO in Fujita Health University Hospital from April 2015 to March 2017. We selected patients with lesions that contained more than 25% GGO in the tumor on thin-section chest CT (TSCT, 0.5-mm slices) images. The Fujita Health University Institutional Review Board approved this study protocol, which was conducted in accordance with the tenets of the Declaration of Helsinki (approval number: HM 17-060).
Chest CT evaluation
All patients underwent chest TSCT within 1 month before bronchoscopy. TSCT images were generated using a non-enhanced multidetector CT system (Aquilion One Vision Edition; Toshiba Medical Systems, Tokyo, Japan). More than two bronchoscopists carefully evaluated a TSCT image for each patient. We determined the size and location of the lesions and the respective bronchus as well as the number of bronchial branches that reached the target lesion from the trachea before bronchoscopy. We investigated the CT bronchus sign, which was identified as the presence of a bronchus directly leading to the target lesion, as described elsewhere.5 Briefly, we categorized the relationship between the target lesion and the nearest bronchus into three types of CT bronchus signs (A to C). In type A, the responsible bronchus clearly reached the inside of the target lesion. In type C, no bronchus could be detected in relation to the lesion. When the CT findings could be categorized as neither type A nor C (when the responsible bronchus reached only the edge of the target lesion), the CT bronchus sign was categorized as type B. We also evaluated the consolidation-to-tumor ratio (CTR), which was defined as the ratio of the maximum size of consolidation to the maximum tumor size on TSCT (Figure 1).8 A pure GGN tumor was defined as a tumor without a solid component (CTR=0). Part-solid GGN tumors (tumors with both GGO and consolidation) were categorized according to the area of GGO lesions in the tumor (CTR≤25, CTR>25 to CTR≤50, and CTR>50 to CTR≤75) (Figure 2). Two pulmonologists independently evaluated the TSCT images and determined the CTR and CT bronchus sign. When the two bronchoscopists recommended different classifications, the final classification was determined by discussion.
After administration of local pharyngeal anesthesia, all of the patients were sedated with an individually calculated dose of intravenous midazolam, as reported elsewhere.9 TBB using EBUS was performed according to a modification of the standard Kurimoto method.10 A 20-MHz radial type ultrasound probe with an external diameter of 1.4 mm (UM-S20-17S; Olympus Medical Systems, Tokyo, Japan) connected to an endoscopic ultrasonography system (EU-M30S; Olympus Medical Systems) was used in all patients. We mainly used a BF-P260F bronchoscope (Olympus Medical Systems) and a guide sheath with an external diameter of 1.9 mm (K-201 kit equipped with a biopsy forceps and cytological brush; Olympus Medical Systems). According to the size or location of the lesion, the operator could add a biopsy using larger biopsy forceps (FB-231D; Olympus Medical Systems). EBUS findings with hyperechoic fine dots, hyperechoic linear arcs, or a hypoechoic nodule were characterized as positive, and those with a whitish acoustic shadow that represented normal air-filled alveoli were characterized as negative.6 We took at least nine samples. In this study, we determined successful (diagnostic) bronchoscopy when TBB showed evident malignant findings on histological examination, a distinct histological pattern (e.g., epithelioid granuloma or intra-alveolar organization), or the presence of bacteria accompanied by reasonable radiological and clinical findings.
Statistical methods
Statistical analyses were carried out using JMP software (ver. 8.0; SAS Institute, Inc., Cary, NC). Differences in proportions were evaluated with the χ2 test. Spearman’s rank correlation was used to identify the association between two ordinal variables. A p value of <0.05 was considered to indicate statistical significance. All analyses were two-sided.
Results
Patients’ characteristics and details of lesions
Table 1 shows the characteristics of the patients and targeted peripheral lesions containing GGO in this study. Forty-one patients (21 male, 20 female) underwent TBB for pulmonary nodules containing GGO during the study period. The median age of the patients was 72 years (range, 46–80 years). The median diameter of the lesions was 18.6 mm (range, 6.8–46.7 mm). We classified the lesions according to the CTR. Seven (17.1%) lesions had a CTR of 0% (pure GGN lesions), and 68.7% of part-solid GGN lesions had a CTR of ≤50%. Therefore, more than 80% of the studied lesions were GGO-predominant lesions (Figure 1). The number of bronchial branches that reached the target lesion from the trachea ranged from four to eight (median, 6). Type A and B CT bronchus signs (responsible bronchus leading to the lesion) were observed in 34 (82.9%) cases.
Table1
Characteristics of patients and targeted GGO lesions (n=41)
| Variable (patients) |
|
| Age, years |
72 (46–80) |
| Sex |
| Male |
21 (51.2) |
| Female |
20 (48.8) |
| Variable (GGN lesions) |
| Diameter of lesion, mm |
18.6 (8.8–46.7) |
| Location of lesions |
| Upper lobe |
21 (51.2) |
| Lingular lobe or middle lobe |
6 (14.6) |
| Superior segment of lower lobe |
8 (19.5) |
| Lower lobe (except superior segment) |
6 (14.6) |
| Extent of GGO on thin-section CT features |
| Pure GGN |
CTR*=0 |
7 (17.1) |
| Part-solid GGN |
0<CTR≤25 |
16 (39.0) |
|
25<CTR≤50 |
12 (29.3) |
|
50<CTR≤75 |
6 (14.6) |
| Number of branches reaching the lesion |
| Mean |
5.78 |
| 4 |
5 (12.2) |
| 5 |
14 (34.1) |
| 6 |
11 (26.8) |
| 7 |
7 (17.1) |
| 8 |
4 (9.8) |
| CT bronchus sign |
| Type A |
8 (19.5) |
| Type B |
26 (63.4) |
| Type C |
7 (17.1) |
Data are presented as median (range), n (%), or n.
GGO, ground-glass opacity; Pure GGN, nodules containing only GGO; Part-solid GGN, nodules containing both GGO and consolidation; CT, computed tomography; CTR, consolidation-to-tumor ratio
Relevant pathological results were obtained in 65.9% (27/41) of the patients (Table 2). Twenty-four patients had adenocarcinoma and three had benign disease (nontuberculous mycobacteriosis and organizing pneumonia). Nineteen patients with adenocarcinoma underwent subsequent surgical resection, leading to a final pathological classification of adenocarcinoma (lepidic or lepidic-predominant pathology constituted the majority). Surprisingly, we were able to diagnose four cases of adenocarcinoma in situ by EBUS-guided TBB. However, among 14 (34.1%) patients who could not be diagnosed by TBB, 5 underwent surgery, leading to a final diagnosis of adenocarcinoma. Nine patients were closely followed up.
Table2
Final diagnosis of targeted ground-glass opacity-predominant nodules (n=41)
| Diagnosed by EBUS-guided biopsy (n=27, 65.9%) |
| Lung cancer (adenocarcinoma) |
24 |
| Lepidic |
4 |
| Lepidic-predominant |
7 |
| Papillary |
2 |
| Acinar-predominant |
2 |
| Adenocarcinoma in situ |
4 |
| Undetermined |
5 |
| Benign diseases |
3 |
| Nontuberculous mycobacteriosis |
1 |
| Organizing pneumonia |
2 |
| Undiagnosed by EBUS-guided biopsy (n=14, 34.1%) |
| Lung cancer (adenocarcinoma) |
| Papillary |
2 |
| Papillary-predominant |
1 |
| Lepidic-predominant |
1 |
| Adenocarcinoma in situ |
1 |
| Unknown |
9 |
EBUS, endobronchial ultrasound
We evaluated the contribution of clinical factors to the bronchoscopic diagnostic yield (Table 3). The lesion size and location, number of bronchial branches reaching the lesion, and GGO lesion area (pure GGN or part-solid GGN) were not significantly associated with successful bronchoscopic diagnosis. Among factors associated with the bronchoscopic procedures, the use of large forceps and fluoroscopic visibility were not associated with successful diagnosis of GGO lesions by EBUS-guided TBB. However, whether EBUS images of the lesions could be obtained was significantly associated with successful diagnosis (76.7% when positive EBUS findings could be obtained versus 36.4% when they could not; p=0.018). There appeared to be an increase in diagnostic yield as the CTR increased, but this was not statistically significant (p=0.3, χ2 test) (Figure 2). Additionally, as shown in Figure 3, the diagnostic yield tended to increase according to the CT bronchus sign (A>B>C); however, this was also not statistically significant (p=0.064, χ2 test). We found no significant association between the EBUS findings and the CTR or CT bronchus sign.
Table3
Contribution of clinical factors to diagnostic yield
| Total diagnostic yield |
27/41 (65.9%) |
| Variables |
Diagnostic yield |
p value |
| Lesion diameter |
<20 mm |
13/22 (59.1) |
0.32 |
| ≥20 mm |
14/19 (73.7) |
|
| Lesion location |
Upper lobe or superior segment of lower lobe |
17/28 (60.7) |
0.29 |
| Middle or lower lobea |
10/13 (76.9) |
|
| Number of bronchial branches reaching the lesion |
≥6 |
14/22 (63.6) |
0.74 |
| ≤5 |
13/19 (68.4) |
|
| GGO lesion area |
Pure GGN (CTR=0) |
4/7 (57.1) |
0.60 |
| Part-solid GGN (CTR>0) |
23/34 (67.7) |
|
| CT bronchus sign |
Positive (type A+B) |
24/34 (70.6) |
0.169 |
| Negative (type C) |
3/7 (42.9) |
|
| Large forceps useb |
Yes |
15/21 (71.4) |
0.44 |
| No |
12/20 (60.0) |
|
| Visibility on fluoroscopy |
Visible |
4/7 (57.1) |
0.59 |
| Invisible |
23/34 (67.7) |
|
| EBUS finding |
Positive |
23/30 (76.7) |
0.018d |
| Negativec |
4/11 (36.4) |
|
Data are presented as n (%).
GGO, ground-glass opacity; Pure GGN, nodules containing only GGO; Part-solid GGN, nodules containing both GGO and consolidation; CT, computed tomography; CTR, consolidation-to-tumor ratio; EBUS, endobronchial ultrasound
aExcept for superior segment of the lower lobe.
bBiopsy using larger forceps (Olympus FB231D Disposable Biopsy Forceps®).
cNo remarkable ultrasound findings were observed.
dStatistically significant.
Discussion
In recent years, chest CT has been more widely used for both health checks and screening examinations for lung diseases in Japan.11 Although CT provides more information than conventional chest X-ray, it often shows small peripheral lung nodules. Therefore, the widespread use of CT screening may cause another clinical issue regarding how these small nodules can be diagnosed. Recently developed EBUS-related techniques, such as EBUS with a guide sheath and EBUS-guided TBB, are useful for diagnosing such small lung lesions.12 However, the usefulness of EBUS-guided TBB for diagnosis of lesions containing GGO has not been fully determined. Because well-differentiated adenocarcinoma with less atypia often shows GGO density, small TBB specimens are sometimes inadequate for diagnosis. GGO lesions are also frequently invisible on fluoroscopy.7 For these reasons, lesions containing GGO are thought to be difficult to diagnose by TBB. In this study, we showed that the diagnostic yield for GGO lesions by EBUS-guided TBB was acceptable. This suggests that we should perform TBB for diagnosis of lung peripheral lesions containing GGO.
Because GGO lesions in the lung periphery are often well-differentiated adenocarcinoma,13 some clinicians perform surgical resection as the first-choice therapeutic procedure.14 However, our study showed that a small percentage of GGO lesions were benign diseases that did not require surgery. Additionally, a recent increase in the use of chest CT has caused an increase in the number of patients who are unfit for surgery, such as very old patients or those with respiratory insufficiency.15 For these patients, clinicians should choose an alternative therapy such as radiotherapy or administration of anti-cancer drugs. Establishment of a pathological diagnosis is important for these types of patients. Moreover, establishment of a pathological diagnosis is essential for patients to make decisions regarding their own therapy.
Some previous studies have revealed the usefulness of EBUS-guided TBB for diagnosis of lesions containing various proportions of GGO.3,6 These studies showed that the tumor size and CT bronchus sign were significantly associated with an increased diagnostic yield. In the present study, the diagnostic yield tended to be higher for lesions with a positive CT bronchus sign or higher CTR, although the difference was not statistically significant. We speculate that both the CTR and CT bronchus sign may affect the ability to obtain a successful diagnosis by TBB for lesions containing GGO. Our study showed that positive EBUS findings were the only significant factor for successful diagnosis. Ikezawa et al.6 reported abnormal EBUS findings in more than 90% of cases, although the target lesions containing GGO in their study showed details similar to those in our study. These discrepancies between studies may be due to differences in the sample sizes or technical levels in different institutions. However, our study and other studies have shown that EBUS-guided TBB is useful for diagnosis of GGO3 and that careful evaluation of EBUS and CT images is essential.
This study has some limitations. First, because this was a retrospective study, patients were selected for EBUS-guided TBB at the physician’s discretion. Therefore, patient selection bias is likely to be present. Second, the sample size was small. The CT bronchus sign might have been an important factor associated with higher diagnostic yield for GGO lesions if the sample size had been larger. Third, because considerable training is required for EBUS-guided TBB, the technical skills needed for this procedure might differ among institutions. A prospective, multicenter study with a large number of patients is required in the future.
In conclusion, our study shows that EBUS-guided TBB is useful for GGN lung lesions. Obtaining relevant abnormal findings of the target GGN lesions by EBUS may be important to increase the diagnostic yield.
Abbreviations
CT, computed tomography
EBUS, endobronchial ultrasonography
TBB, transbronchial biopsy
TSCT, thin-section computed tomography
GGO, ground-glass opacity
Pure GGN lesions, nodules containing only GGO
Part-solid GGN lesions, nodules containing both GGO and consolidation
CTR, consolidation-to-tumor ratio
Competing Interests
The authors declare that they have no competing interests.
Authors’ Contributions
TH participated in the design of the study, evaluation of the EBUS images, and drafting of the manuscript. TM and TO participated in evaluation of the TSCT findings. YS, SM, TS, and KA helped to draft the manuscript. YG participated in the design of the study. YS, SM, YG, TS, KA, TW, SU, MH, and SI revised the manuscript. KI participated in the design of the study and performed the statistical analysis. All authors read and approved the final manuscript.
Acknowledgments
The authors thank Mrs. Naomi Maeda for her excellent secretarial help. We also thank Mrs. Chikako Hibiya and Ms. Noriko Hiramatsu for their technical assistance.
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