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1.  Suitability of Endobronchial Ultrasound-guided Transbronchial Needle Aspiration Specimens for Subtyping and Genotyping of Non–Small Cell Lung Cancer 
Rationale: The current management of advanced non–small cell lung cancer (NSCLC) requires differentiation between squamous and nonsquamous subtypes as well as epidermal growth factor receptor (EGFR) mutation status. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is increasingly used for the diagnosis and staging of lung cancer. However, it is unclear whether cytology specimens obtained with EBUS-TBNA are suitable for the subclassification and genotyping of NSCLC.
Objectives: To determine whether cytology specimens obtained from EBUS-TBNA in routine practice are suitable for phenotyping and genotyping of NSCLC.
Methods: Cytological diagnoses from EBUS-TBNA were recorded from 774 patients with known or suspected lung cancer across five centers in the United Kingdom between 2009 and 2011.
Measurements and Main Results: The proportion of patients with a final diagnosis by EBUS-TBNA in whom subtype was classified was 77% (95% confidence interval [CI], 73–80). The rate of NSCLC not otherwise specified (NSCLC-NOS) was significantly reduced in patients who underwent immunohistochemistry (adjusted odds ratio, 0.50; 95% CI, 0.28–0.82; P = 0.016). EGFR mutation analysis was possible in 107 (90%) of the 119 patients in whom mutation analysis was requested. The sensitivity, negative predictive value, and diagnostic accuracy of EBUS-TBNA in patients with NSCLC were 88% (95% CI, 86–91), 72% (95% CI, 66–77), and 91% (95% CI, 89–93), respectively.
Conclusions: This large, multicenter, pragmatic study demonstrates that cytology samples obtained from EBUS-TBNA in routine practice are suitable for subtyping of NSCLC and EGFR mutation analysis and that the use of immunohistochemistry reduces the rate of NSCLC-NOS.
PMCID: PMC3378660  PMID: 22505743
endobronchial ultrasound; non–small cell lung cancer; adenocarcinoma; EGFR mutation; NSCLC-NOS
2.  Screening for EGFR and KRAS Mutations in Endobronchial Ultrasound Derived Transbronchial Needle Aspirates in Non-Small Cell Lung Cancer Using COLD-PCR 
PLoS ONE  2011;6(9):e25191.
EGFR mutations correlate with improved clinical outcome whereas KRAS mutations are associated with lack of response to tyrosine kinase inhibitors in patients with non-small cell lung cancer (NSCLC). Endobronchial ultrasound (EBUS)-transbronchial needle aspiration (TBNA) is being increasingly used in the management of NSCLC. Co-amplification at lower denaturation temperature (COLD)–polymerase chain reaction (PCR) (COLD-PCR) is a sensitive assay for the detection of genetic mutations in solid tumours. This study assessed the feasibility of using COLD-PCR to screen for EGFR and KRAS mutations in cytology samples obtained by EBUS-TBNA in routine clinical practice. Samples obtained from NSCLC patients undergoing EBUS-TBNA were evaluated according to our standard clinical protocols. DNA extracted from these samples was subjected to COLD-PCR to amplify exons 18–21 of EGFR and exons two and three of KRAS followed by direct sequencing. Mutation analysis was performed in 131 of 132 (99.3%) NSCLC patients (70F/62M) with confirmed lymph node metastases (94/132 (71.2%) adenocarcinoma; 17/132 (12.8%) squamous cell; 2/132 (0.15%) large cell neuroendocrine; 1/132 (0.07%) large cell carcinoma; 18/132 (13.6%) NSCL-not otherwise specified (NOS)). Molecular analysis of all EGFR and KRAS target sequences was achieved in 126 of 132 (95.5%) and 130 of 132 (98.4%) of cases respectively. EGFR mutations were identified in 13 (10.5%) of fully evaluated cases (11 in adenocarcinoma and two in NSCLC-NOS) including two novel mutations. KRAS mutations were identified in 23 (17.5%) of fully analysed patient samples (18 adenocarcinoma and five NSCLC-NOS). We conclude that EBUS-TBNA of lymph nodes infiltrated by NSCLC can provide sufficient tumour material for EGFR and KRAS mutation analysis in most patients, and that COLD-PCR and sequencing is a robust screening assay for EGFR and KRAS mutation analysis in this clinical context.
PMCID: PMC3176319  PMID: 21949883
3.  TBNA with and without EBUS: a comparative efficacy study for the diagnosis and staging of lung cancer 
Journal of Thoracic Disease  2014;6(5):416-420.
Conventional transbronchial needle aspiration (TBNA) has been around for over 30 years with sensitivities approaching 70-90%. Recent development of endobronchial ultrasound (EBUS) TBNA demonstrated even higher sensitivities among experts. However EBUS-TBNA is more costly and less available worldwide than conventional TBNA. A comparison study to determine the efficacy of TBNA with and without EBUS in the diagnosis and staging of lung cancer is described.
A total of 287 patients with mediastinal and hilar lymphadenopathy presenting for diagnosis and/or staging of lung cancer at enrolling institutions were included. Equal numbers of punctures were performed at the target lymph node stations using conventional TBNA techniques followed by EBUS-TBNA at the same sites. Patients and puncture sites that were biopsied by both methods and were positive for lung cancer were compared to establish efficacy of each technique on the same patients.
In 253 patients at least one pair of specimens were obtained by conventional TBNA and EBUS-TBNA. In 83 of these patients malignancy was diagnosed. Among the 83 patients with a diagnosis of a malignancy there was no significant difference in the diagnostic yield of conventional TBNA versus EBUS-TBNA. When comparing diagnosis of malignancy for each lymph node sampled, there were a significantly greater number of positive (diagnostic for malignancy) lymph nodes sampled by EBUS-TBNA.
Recommendations for current practice depend on individual centers and bronchoscopist comfort level with TBNA (with or without EBUS). In our study, no significant difference was seen between the techniques for the diagnosis and staging of individual patients.
PMCID: PMC4015015  PMID: 24822097
Bronchoscopy; transbronchial needle aspiration (TBNA); endobronchial ultrasound (EBUS); lung cancer
4.  Usefulness of High Suction Pressure for Sufficient Tissue Collection During Endobronchial Ultrasound Guided Transbronchial Needle Aspiration 
PLoS ONE  2013;8(12):e82787.
The optimal suction pressure during endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) remains to be determined. The aim of this study was to compare suction pressures for performance in collecting sufficient tissue specimens from mediastinal and hilar lymph nodes during EBUS-TBNA.
Retrospective analysis of consecutive patients with mediastinal and hilar lymphadenopathy who underwent EBUS-TBNA over a 3-year period. Results from patients who underwent EBUS-TBNA using a dedicated 20-mL VacLoc (Merit Medical Systems, Inc, South Jordan, UT) syringe (conventional method, group C) were compared with results from patients in whom a disposable 30-mL syringe (high pressure group, group H) was used. The yield for sufficient histologic specimen retrieval and amount of tissue obtained were compared between the 2 groups.
Of 178 patients who underwent EBUS-TBNA, 131 had lung cancer confirmed by EBUS-TBNA: 35 in group C and 96 in group H. There were 7 patients in group C and 6 in group H who received final diagnoses by cytology alone. There were 28 in group C and 90 in group H who were diagnosed by both cytology and histology. There was a statistically significant difference between the groups in terms of the rate of sufficient sampling for histological specimens (p = 0.04). The H group revealed a tissue area approximately twice that of the C group (p = 0.003). There were no major procedure-related complications in either group.
Higher suction pressures with larger syringe volumes during EBUS-TBNA may be useful for safely collecting sufficient tissue specimens.
PMCID: PMC3855538  PMID: 24340058
5.  Contribution of cell blocks obtained through endobronchial ultrasound-guided transbronchial needle aspiration to the diagnosis of lung cancer 
BMC Cancer  2012;12:34.
Conventional smears of samples obtained by endobronchial ultrasound with real-time transbronchial needle aspiration (EBUS-TBNA) have proven useful in lung cancer staging, but the value of additional information from cell-block processing of EBUS-TBNA samples has only been marginally investigated. This study focussed on the contribution of cell block analysis to the diagnostic yield in lung cancer.
Patients referred for lung cancer diagnosis and/or staging by means of EBUS-TBNA were enrolled, the adequacy of the obtained samples for preparing cell blocks was assessed, and the additional pathologic or genetic information provided from cell block analysis was examined.
In 270 lung cancer patients referred for EBUS-TBNA (mean age, 63.3 SD 10.4 years) 697 aspirations were performed. Cell blocks could be obtained from 334 aspirates (47.9%) and contained diagnostic material in 262 (37.6%) aspirates, providing information that was additional to conventional smears in 50 of the 189 samples with smears that were non-diagnostic, corresponding 21 of these blocks to malignant nodes, and allowing lung cancer subtyping of 4 samples. Overall, cell blocks improved the pathologic diagnosis attained with conventional smears in 54 of the 697 samples obtained with EBUS-TBNA (7.7%). Cell blocks obtained during EBUS-TBNA also made epithelial growth factor receptor mutation analysis possible in 39 of the 64 patients with TBNA samples showing metastatic adenocarcinoma (60.1%). Overall, cell blocks provided clinically significant information for 83 of the 270 patients participating in the study (30.7%).
Cell-block preparation from EBUS-TBNA samples is a simple way to provide additional information in lung cancer diagnosis. Analysis of cell blocks increases the diagnostic yield of the procedure by nearly seven per cent and allows for genetic analysis in a sixty per cent of the patients with metastatic adenocarcinoma.
PMCID: PMC3292510  PMID: 22264305
Cell block; Endobronchial ultrasound; Transbronchial needle aspiration; Lung cancer
6.  Endobronchial Ultrasound–guided Transbronchial Needle Aspiration Prevents Mediastinoscopies in the Diagnosis of Isolated Mediastinal Lymphadenopathy 
Rationale: Patients with isolated mediastinal lymphadenopathy (IML) are a common presentation to physicians, and mediastinoscopy is traditionally considered the “gold standard” investigation when a pathological diagnosis is required. Endobronchial ultrasound–guided transbronchial needle aspiration (EBUS-TBNA) is established as an alternative to mediastinoscopy in patients with lung cancer.
Objective: To determine the efficacy and health care costs of EBUS-TBNA as an alternative initial investigation to mediastinoscopy in patients with isolated IML.
Methods: Prospective multicenter single-arm clinical trial of 77 consecutive patients with IML from 5 centers between April 2009 and March 2011. All patients underwent EBUS-TBNA. If EBUS-TBNA did not provide a diagnosis, then participants underwent mediastinoscopy.
Measurements and Main Results: EBUS-TBNA prevented 87% of mediastinoscopies (95% confidence interval [CI], 77–94%; P < 0.001) but failed to provide a diagnosis in 10 patients (13%), all of whom underwent mediastinoscopy. The sensitivity and negative predictive value of EBUS-TBNA in patients with IML were 92% (95% CI, 83–95%) and 40% (95% CI, 12–74%), respectively. One patient developed a lower respiratory tract infection after EBUS-TBNA, requiring inpatient admission. The cost of the EBUS-TBNA procedure per patient was £1,382 ($2,190). The mean cost of the EBUS-TBNA strategy was £1,892 ($2,998) per patient, whereas a strategy of mediastinoscopy alone was significantly more costly at £3,228 ($5,115) per patient (P < 0.001). The EBUS-TBNA strategy is less costly than mediastinoscopy if the cost per EBUS-TBNA procedure is less than £2,718 ($4,307) per patient.
Conclusions: EBUS-TBNA is a safe, highly sensitive, and cost-saving initial investigation in patients with IML.
Clinical trial registered with (NCT00932854).
PMCID: PMC3423452  PMID: 22652031
endobronchial ultrasound; mediastinal lymphadenopathy; sarcoidosis; tuberculosis; lymphoma
7.  Endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of intrathoracic lymph node metastases from extrathoracic malignancies 
Intrathoracic lymph node enlargement is a common finding in patients with extrathoracic malignancies. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a technique that is commonly used for lung cancer diagnosis and staging but that has not been widely investigated for the diagnosis of enlarged mediastinal and lobar lymph nodes in patients with extrathoracic malignancies. We conducted a retrospective study of 117 patients with extrathoracic malignancies who underwent EBUS-TBNA for diagnosis of intrathoracic lymph node enlargement from October 2005 to December 2009 and compared the EBUS-TBNA findings with the final diagnoses. EBUS-TBNA diagnosed mediastinal metastases in 51 of the 117 (43.6 %) cases and gave an alternate diagnosis or ruled out the presence of malignancy in 35 (56.4 %). Fourteen of these 35 patients underwent further surgical investigation, while the remaining 21 had clinical and radiological follow-up for 18 months. No false negatives were found in the surgery group. In the follow-up group, 13 patients had stable or regressive lymphadenopathy, and eight developed clinicoradiological progression and were assumed to have been false negatives by EBUS-TBNA. The sensitivity and negative predictive value of EBUS-TBNA were 86.4 and 75 %, respectively. Immunohistochemical staining (IHC) was performed in 80.4 % of the samples obtained by EBUS-TBNA. In samples obtained from ten patients with metastatic breast cancer, estrogen receptor expression was successfully assessed in eight patients and progesterone receptor and human epidermal growth factor receptor 2 in four. EBUS-TBNA is an accurate procedure for the diagnosis of thoracic lymph node metastases in patients with extrathoracic malignancies and should be an initial diagnostic tool in these patients. Furthermore, EBUS-TBNA can obtain high-quality specimens from metastatic lymph nodes for use in molecular analyses.
PMCID: PMC3616225  PMID: 23196318
Endobronchial ultrasound; Transbronchial needle aspiration; EBUS-TBNA; Mediastinal lymph node metastases; Extrathoracic malignancy; Immunohistochemistry
8.  Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration for the Diagnosis of Central Lung Parenchymal Lesions 
Yonsei Medical Journal  2013;54(3):672-678.
The purpose of this study was to evaluate the usefulness of convex probe endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for detecting malignancy in parenchymal pulmonary lesions located adjacent to the central airways.
Materials and Methods
We retrospectively reviewed the diagnostic performance of EBUS-TBNA in consecutive patients with high clinical suspicion of a centrally located primary lung cancer who had undergone EBUS-TBNA at the Samsung Medical Center between May 2009 and June 2011.
Thirty-seven patients underwent EBUS-TBNA for intrapulmonary lesions adjacent to the central airways. Seven lesions were located adjacent to the trachea and 30 lesions were located adjacent to the bronchi. Cytologic and histologic samples obtained via EBUS-TBNA were diagnostic in 32 of 37 (86.4%) of patients. The final diagnosis was lung cancer in 30 patients (7 small cell lung cancer, 23 non-small cell lung cancer), lymphoma in one and malignant fibrous histiocytoma in one patient. The diagnostic sensitivity of EBUS-TBNA in detecting malignancy and detecting both malignancy and benignity was 91.4% and 86.5%, respectively. Two patients experienced minor complications.
EBUS-TBNA is an effective and safe method for tissue diagnosis of parenchymal lesions that lie centrally close to the airways. EBUS-TBNA should be considered the procedure of choice for patients with centrally located lesions without endobronchial involvement.
PMCID: PMC3635626  PMID: 23549813
Bronchoscopy; endobronchial ultrasound; transbronchial needle aspiration; lung cancer; parenchymal lesion
9.  Endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of non-lymph node thoracic lesions 
Annals of Thoracic Medicine  2013;8(1):14-21.
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has shown excellent diagnostic capabilities for mediastinal and hilar lymphadenopathy. However, its value in thoracic non-lymph node lesions is less clear. This study was designed to assess the value of EBUS-TBNA in distinguishing malignant from benign thoracic non-lymph node lesions.
From October 2009 to August 2011, 552 patients underwent EBUS-TBNA under local anesthesia and with conscious sedation. We retrospectively reviewed 81 of these patients who had tracheobronchial wall-adjacent intrapulmonary or isolated mediastinal non-lymph node lesions. On-site cytological evaluation was not used. Immunohistochemistry (IHC) was performed to distinguish the origin or type of malignancy when necessary.
EBUS-TBNA was performed in 68 tracheobronchial wall-adjacent intrapulmonary and 13 isolated mediastinal non-lymph node lesions. Of the 81 patients, 77 (95.1%, 60 malignancies and 17 benignancies) were diagnosed through EBUS-TBNA, including 57 primary lung cancers, 2 mediastinal tumors, 1 pulmonary metastatic adenocarcinoma, 7 inflammation, 5 tuberculosis, 3 mediastinal cysts, 1 esophageal schwannoma, and 1 focal fibrosis. There were four false-negative cases (4.9%). Of the 60 malignancies, there were 9 (15.0%) which originally had no definite histologic origin or type. Thus, IHC was performed, with 7 (77.8%) being subsequently confirmed. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of EBUS-TBNA in distinguishing malignant from benign lesions were 93.4% (60/64), 100% (17/17), 100% (60/60), 81.0% (17/21), and 95.1% (77/81), respectively.
EBUS-TBNA is a safe procedure with a high sensitivity for distinguishing malignant from benign thoracic non-lymph node lesions within the reach of EBUS-TBNA, with IHC usually providing a more definitive diagnosis.
PMCID: PMC3573552  PMID: 23439919
Endobronchial ultrasound; immunohistochemistry; lung cancer; thoracic lesion; transbronchial needle aspiration
10.  Genomic Characterisation of Small Cell Lung Cancer Patient-Derived Xenografts Generated from Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration Specimens 
PLoS ONE  2014;9(9):e106862.
Patient-derived xenograft (PDX) models generated from surgical specimens are gaining popularity as preclinical models of cancer. However, establishment of PDX lines from small cell lung cancer (SCLC) patients is difficult due to very limited amount of available biopsy material. We asked whether SCLC cells obtained from endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) could generate PDX lines that maintained the phenotypic and genetic characteristics of the primary tumor. Following successful EBUS-TBNA sampling for diagnostic purposes, we obtained an extra sample for cytologic analysis and implantation into the flanks of immunodeficient mice. Animals were monitored for engraftment for up to 6 months. Histopathologic and immunohistochemical analysis, and targeted next-generation re-sequencing, were then performed in both the primary sample and the derivative PDX line. A total of 12 patients were enrolled in the study. EBUS-TBNA aspirates yielded large numbers of viable tumor cells sufficient to inject between 18,750 and 1,487,000 cells per flank, and to yield microgram quantities of high-quality DNA. Of these, samples from 10 patients generated xenografts (engraftment rate 83%) with a mean latency of 104 days (range 63–188). All but one maintained a typical SCLC phenotype that closely matched the original sample. Identical mutations that are characteristic of SCLC were identified in both the primary sample and xenograft line. EBUS-TBNA has the potential to be a powerful tool in the development of new targeting strategies for SCLC patients by providing large numbers of viable tumor cells suitable for both xenografting and complex genomic analysis.
PMCID: PMC4156408  PMID: 25191746
11.  Utility of on-site evaluation of endobronchial ultrasound-guided transbronchial needle aspiration specimens 
CytoJournal  2011;8:20.
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is an integral tool in the diagnosis and staging of malignant tumors of the lung. Rapid on-site evaluation (ROSE) of fine needle aspiration (FNA) samples has been advocated for as a guide for assessing the accuracy and adequacy of biopsy samples. Although ROSE has proven useful for numerous sites and procedures, few studies have specifically investigated its utility in the assessment of EBUS-TBNA specimens. The intention of this study was to explore the utility of ROSE for EBUS-TBNA specimens.
Materials and Methods:
The pathology files at our institution were searched for all EBUS-TBNA cases performed between January 2010 and June 2010. The data points included number of sites sampled per patient, location of site(s) sampled, on-site evaluation performed, preliminary on-site diagnosis rendered, final cytologic diagnosis, surgical pathology follow-up, cell blocks, and ancillary studies performed.
A total of 294 EBUS-TBNA specimens were reviewed and included in the study; 264 of 294 (90%) were lymph nodes and 30 of 294 (10%) were lung mass lesions. ROSE was performed for 140 of 294 (48%) specimens. The on-site and final diagnoses were concordant in 104 (74%) and discordant in 36 (26%) cases. Diagnostic specimens were obtained in 132 of 140 (94%) cases with on-site evaluation and 138 of 154 (90%) without on-site evaluation. The final cytologic diagnosis was malignant in 60 of 132 (45%) cases with ROSE and 46 of 138 (33%) cases without ROSE, and the final diagnosis was benign in 57 of 132 (47%) with ROSE and 82 of 138 (59%) without ROSE. A cell block was obtained in 129 of 140 (92%) cases with ROSE and 136 of 154 (88%) cases without ROSE.
The data demonstrate no remarkable difference in diagnostic yield, the number of sites sampled per patient, or clinical decision making between specimens collected via EBUS-TBNA with or without ROSE. As a result, this study challenges the notion that ROSE is beneficial for the evaluation of EBUS-TBNA specimens.
PMCID: PMC3229807  PMID: 22145008
EBUS-TBNA; endobronchial; on-site; ROSE
12.  Rapid KRAS, EGFR, BRAF and PIK3CA Mutation Analysis of Fine Needle Aspirates from Non-Small-Cell Lung Cancer Using Allele-Specific qPCR 
PLoS ONE  2011;6(3):e17791.
Endobronchial Ultrasound Guided Transbronchial Needle Aspiration (EBUS-TBNA) and Trans-esophageal Ultrasound Scanning with Fine Needle Aspiration (EUS-FNA) are important, novel techniques for the diagnosis and staging of non-small cell lung cancer (NSCLC) that have been incorporated into lung cancer staging guidelines. To guide and optimize treatment decisions, especially for NSCLC patients in stage III and IV, EGFR and KRAS mutation status is often required. The concordance rate of the mutation analysis between these cytological aspirates and histological samples obtained by surgical staging is unknown. Therefore, we studied the extent to which allele-specific quantitative real-time PCR with hydrolysis probes could be reliably performed on EBUS and EUS fine needle aspirates by comparing the results with histological material from the same patient. We analyzed a series of 43 NSCLC patients for whom cytological and histological material was available. We demonstrated that these standard molecular techniques can be accurately applied on fine needle cytological aspirates from NSCLC patients. Importantly, we show that all mutations detected in the histological material of primary tumor were also identified in the cytological samples. We conclude that molecular profiling can be reliably performed on fine needle cytology aspirates from NSCLC patients.
PMCID: PMC3050927  PMID: 21408138
13.  Combined Endobronchial and Transesophageal Approach of an Ultrasound Bronchoscope for Mediastinal Staging of Lung Cancer 
PLoS ONE  2014;9(3):e91893.
We evaluated the utility of a combined approach using endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and transesophageal bronchoscopic ultrasound-guided fine-needle aspiration (EUS-FNA-B/E) for mediastinal staging of lung cancer.
An EBUS-TBNA database was analyzed retrospectively. EUS-FNA-B/E was performed after EBUS-TBNA when mediastinal lymph nodes were not accessible using EBUS-TBNA or when tissue sampling using EBUS-TBNA alone was inadequate.
During the study period, 44 patients were enrolled. EBUS-TBNA and EUS-FNA-B/E were performed on 79 and 52 lymph nodes, respectively. The sensitivity, specificity, and accuracy of mediastinal N-staging using EBUS-TBNA alone were 79%, 100%, and 84%, respectively. The sensitivity, specificity, and accuracy of mediastinal N-staging using a combination of EBUS-TBNA and EUS-FNA-B/E were 100%, 100%, and 100%, respectively. Significant differences in sensitivity (P = 0.008) and accuracy (P = 0.004) of mediastinal N-staging were evident when EBUS-TBNA alone and the combined procedure were compared. The nodal stage shifted higher after use of the EUS-FNA-B/E procedure in six cases (13%). No serious complication associated with the procedures was noted.
Use of a combination of EBUS-TBNA and EUS-FNA-B/E can afford better sensitivity and accuracy of mediastinal N-staging compared with use of EBUS-TBNA alone. Such combined procedures should be considered for examination of lesions that are inaccessible or difficult to access by EBUS-TBNA.
PMCID: PMC3954842  PMID: 24632834
14.  BRIEF REPORT: Adequacy of lymph node transbronchial needle aspirates using convex probe endobronchial ultrasound for multiple tumor genotyping techniques in non-small-cell lung cancer 
Adequate tumor acquisition is essential to identify somatic molecular alterations in non-small-cell lung cancer (NSCLC), such as EGFR mutations and ALK translocations. The success and failure rates for tumor genotyping of tissue obtained from fine needle aspirates of nodal tissue using a convex probe endobronchial ultrasound (CP-EBUS) and other diagnostic modalities in routine NSCLC care have not been described.
Clinicopathologic data, tumor genotype success and failure rates were retrospectively compiled and analyzed from 207 patient-tumor samples sent for routine tumor genotype in clinical practice, including 42 patient-tumor samples obtained from hilar or mediastinal lymph nodes using CP-EBUS.
The median age was 65 years, 62.3% were women, 77.8% were white, 26.6% were never smokers, 73.9% had advanced NSCLC and 84.1% had adenocarcinoma histology. Tumor tissue was obtained from CP-EBUS-derived hilar or mediastinal nodes in 42 cases (20.2% of total). In this latter cohort, the overall success rate for EGFR mutation analysis was 95.2%, for KRAS mutation 90.5%, and for ALK FISH 90.5%. In the complete 207 tumors, the success rate for EGFR was 92.3%, for KRAS 91.8%, and for ALK 89.9%. The failure rates were not significantly different when comparing CP-EBUS-derived nodal tissue versus all other samples or versus surgical biopsies of mediastinal nodes, but were significantly lower than image-guided percutaneous transthoracic core-needle biopsies.
The success rate of multiple tumor genomic analyses techniques for EGFR, KRAS and ALK gene abnormalities using routine lung cancer tissue samples obtained from hilar or mediastinal lymph nodes by means of CP-EBUS exceeds 90%, and this method of tissue acquisition is not inferior to other specimen types. Tumor genotype techniques are feasible in most CP-EBUS-derived samples and therefore further expansion of routine tumor genotype for the care of patients with NSCLC may be possible using targeted sample acquisition through CP-EBUS.
PMCID: PMC3800048  PMID: 24128714
lung cancer; non-small-cell lung cancer; endobronchial ultrasound; EBUS; mediastinoscopy; never smokers; epidermal growth factor receptor; EGFR; anaplastic lymphoma kinase; ALK; KRAS; tumor genotype; failure; bone specimen; core biopsy; transbronchial needle aspiration; computed tomography; molecular testing
15.  Nodal Stations and Diagnostic Performances of Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration in Patients with Non-Small Cell Lung Cancer 
There are no accurate data on the relationship between nodal station and diagnostic performance of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). We evaluated the impact of nodal station and size on the diagnostic performance of EBUS-TBNA in patients with non-small cell lung cancer (NSCLC). Consecutive patients who underwent EBUS-TBNA of mediastinal or hilar lymph nodes for staging or diagnosis of NSCLC were included in this retrospective study. Between May 2009 and February 2010, EBUS-TBNA was performed in 373 mediastinal and hilar lymph nodes in 151 patients. The overall diagnostic sensitivity, specificity, accuracy and negative predictive value (NPV) of EBUS-TBNA were 91.6%, 98.6%, 93.8%, and 84.3%, respectively. NPV of the left side nodal group was significantly lower than those of the other groups (P = 0.047) and sensitivity of the left side nodal group tended to decrease (P = 0.096) compared with those of the other groups. Diagnostic sensitivity and NPV of 4L lymph node were 83.3% and 66.7%, respectively. However, diagnostic performances of EBUS-TBNA did not differ according to nodal size. Bronchoscopists should consider the impact of nodal stations on diagnostic performances of EBUS-TBNA.
PMCID: PMC3247774  PMID: 22219613
Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration; Lymph Nodes; Mediastinum; Non-Small Cell Lung Cancer
16.  Usefulness of Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration for Diagnosis of Sarcoidosis 
Yonsei Medical Journal  2013;54(6):1416-1421.
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is an accurate and minimally invasive technique used routinely for investigation of mediastinal and hilar lymphadenopathy. However, few studies have addressed its role in comparison to the traditional diagnostic approaches of transbronchial lung biopsy (TBLB), endobronchial biopsy (EBB), and bronchoalveolar lavage (BAL) in the diagnosis of sarcoidosis. We evaluated the usefulness of EBUS-TBNA in the diagnosis of sarcoidosis compared to TBLB, EBB, and BAL.
Materials and Methods
Consecutive patients with suspected sarcoidosis (stage I and II) on chest radiography and chest computed tomography were included. All 33 patients underwent EBUS-TBNA, TBLB, EBB, and BAL during the same session between July 2009 and June 2011. EBUS-TBNA was performed at 71 lymph node stations.
Twenty-nine of 33 patients, were diagnosed with histologically proven sarcoidosis; two patients were compatible with a clinical diagnosis of sarcoidosis during follow-up; and two patients were diagnosed with metastatic carcinoma and reactive lymphadenopathy, respectively. Among 29 patients with histologically proven sarcoidosis in combination with EBUS-TBNA, TBLB, and EBB, only EBUS-TBNA and TBLB revealed noncaseating granuloma in 18 patients and one patient, respectively. The overall diagnostic sensitivities of EBUS-TBNA, TBLB, EBB, and BAL (CD4/CD8 ≥3.5) were 90%, 35%, 6%, and 71%, respectively (p<0.001). The combined diagnostic sensitivity of EBUS-TBNA, TBLB, and EBB was 94%.
EBUS-TBNA was the most sensitive method for diagnosing stage I and II sarcoidosis compared with conventional bronchoscopic procedures. EBUS-TBNA should be considered first for the histopathologic diagnosis of stage I and II sarcoidosis.
PMCID: PMC3809855  PMID: 24142646
Endobronchial ultrasound; transbronchial needle aspiration; sarcoidosis; mediastinal lymphadenopathy
17.  Utility of endobronchial ultrasound-guided transbronchial needle aspiration in patients with tuberculous intrathoracic lymphadenopathy: a multicentre study 
Thorax  2011;66(10):889-893.
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has emerged as an important tool for the diagnosis and staging of lung cancer but its role in the diagnosis of tuberculous intrathoracic lymphadenopathy has not been established. The aim of this study was to describe the diagnostic utility of EBUS-TBNA in patients with intrathoracic lymphadenopathy due to tuberculosis (TB).
156 consecutive patients with isolated intrathoracic TB lymphadenitis were studied across four centres over a 2-year period. Only patients with a confirmed diagnosis or unequivocal clinical and radiological response to antituberculous treatment during follow-up for a minimum of 6 months were included. All patients underwent routine clinical assessment and a CT scan prior to EBUS-TBNA. Demographic data, HIV status, pathological findings and microbiological results were recorded.
EBUS-TBNA was diagnostic of TB in 146 patients (94%; 95% CI 88% to 97%). Pathological findings were consistent with TB in 134 patients (86%). Microbiological investigations yielded a positive culture of TB in 74 patients (47%) with a median time to positive culture of 16 days (range 3–84) and identified eight drug-resistant cases (5%). Ten patients (6%) did not have a specific diagnosis following EBUS; four underwent mediastinoscopy which confirmed the diagnosis of TB while six responded to empirical antituberculous therapy. There was one complication requiring an inpatient admission.
EBUS-TBNA is a safe and effective first-line investigation in patients with tuberculous intrathoracic lymphadenopathy.
PMCID: PMC3361304  PMID: 21813622
18.  Current status and clinical applicability of endobronchial ultrasound-guided transbronchial needle aspiration 
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has played a key role in the diagnosis of mediastinal, paratracheal, and peribronchial lesions, as well as in lymph node staging for lung cancer. Despite its minimally invasive character, EBUS-TBNA has demonstrated a diagnostic yield comparable with that of established surgical methods. It has therefore gained credibility and has become a routine procedure at various referral centers. A successful EBUS-TBNA procedure requires careful planning, which includes a thorough review of the radiological imaging and special care during specimen collection and preparation, as well as technical expertise, experience with the procedure itself, and knowledge of the potential complications inherent to the procedure. The most common indications for EBUS-TBNA include lymph node staging for lung cancer and the diagnostic investigation of mediastinal/hilar masses and lymph node enlargement. Recently, tumor biomarkers in malignant samples collected during the EBUS-TBNA procedure have begun to be identified, and this molecular analysis has proven to be absolutely feasible. The EBUS-TBNA procedure has yet to be included on the Brazilian Medical Association list of medical procedures approved for reimbursement. The EBUS-TBNA procedure has shown to be a safe and accurate tool for lung cancer staging/restaging, as well as for the diagnosis of mediastinal, paratracheal, and peribronchial lesions/lymph node enlargement
PMCID: PMC4075814  PMID: 23670509
Endoscopic ultrasound-guided fine needle aspiration; Lung neoplasms; Neoplasm staging
19.  Complications associated with endobronchial ultrasound-guided transbronchial needle aspiration: a nationwide survey by the Japan Society for Respiratory Endoscopy 
Respiratory Research  2013;14(1):50.
With the recent widespread use of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), there have been occasional reports on complications associated with its use. Previous reviews on EBUS-TBNA have been limited to studies by skilled operators, thus the results may not always be applicable to recent clinical practice. To assess the safety of EBUS-TBNA for the staging and diagnosis of lung cancer in Japan, a nationwide survey on its current usage status and complications associated with its use was conducted by the Japan Society for Respiratory Endoscopy (JSRE).
A questionnaire about EBUS-TBNA performed between January 2011 and June 2012 was mailed to 520 JSRE-accredited facilities.
Responses were obtained from 455 facilities (87.5%). During the study period, EBUS-TBNA was performed in 7,345 cases in 210 facilities (46.2%) using a convex probe ultrasound bronchoscope, for 6,836 mediastinal and hilar lesions and 275 lung parenchymal lesions. Ninety complications occurred in 32 facilities. The complication rate was 1.23% (95% confidence interval, 0.97%-1.48%), with hemorrhage being the most frequent complication (50 cases, 0.68%). Infectious complications developed in 14 cases (0.19%) (Mediastinitis, 7; pneumonia, 4; pericarditis, 1; cyst infection, 1; and sepsis, 1). Pneumothorax developed in 2 cases (0.03%), one of which required tube drainage. Regarding the outcome of the cases with complications, prolonged hospitalization was observed in 14 cases, life-threatening conditions in 4, and death in 1 (severe cerebral infarction) (mortality rate, 0.01%). Breakage of the ultrasound bronchoscope occurred in 98 cases (1.33%) in 67 facilities (31.9%), and that of the puncture needle in 15 cases (0.20%) in 8 facilities (3.8%).
Although the complication rate associated with EBUS-TBNA was found to be low, severe complications, including infectious complications, were observed, and the incidence of device breakage was high. Since the use of EBUS-TBNA is rapidly expanding in Japan, an educational program for its safe performance should be immediately established.
PMCID: PMC3655828  PMID: 23663438
Breakage; Bronchoscopic ultrasound; Bronchoscopy; Infection; Lung cancer; Mediastinitis; Mortality; Pulmonary intervention; Safety; Survey
20.  EBUS-TBNA Provides Highest RNA Yield for Multiple Biomarker Testing from Routinely Obtained Small Biopsies in Non-Small Cell Lung Cancer Patients - A Comparative Study of Three Different Minimal Invasive Sampling Methods 
PLoS ONE  2013;8(10):e77948.
Multiple biomarker testing is necessary to facilitate individualized treatment of lung cancer patients. More than 80% of lung cancers are diagnosed based on very small tumor samples. Often there is not enough tissue for molecular analysis. We compared three minimal invasive sampling methods with respect to RNA quantity for molecular testing.
106 small biopsies were prospectively collected by three different methods forceps biopsy, endobronchial ultrasound (EBUS) guided transbronchial needle aspiration (TBNA), and CT-guided core biopsy. Samples were split into two halves. One part was formalin fixed and paraffin embedded for standard pathological evaluation. The other part was put in RNAlater for immediate RNA/DNA extraction. If the pathologist confirmed the diagnosis of non-small cell lung cancer(NSCLC), the following molecular markers were tested: EGFR mutation, ERCC1, RRM1 and BRCA1.
Overall, RNA-extraction was possible in 101 out of 106 patients (95.3%). We found 49% adenocarcinomas, 38% squamouscarcinomas, and 14% non-otherwise-specified(NOS). The highest RNA yield came from endobronchial ultrasound guided needle aspiration, which was significantly higher than bronchoscopy (37.74±41.09 vs. 13.74±15.53 ng respectively, P = 0.005) and numerically higher than CT-core biopsy (37.74±41.09 vs. 28.72±44.27 ng respectively, P = 0.244). EGFR mutation testing was feasible in 100% of evaluable patients and its incidence was 40.8%, 7.9% and 14.3% in adenocarcinomas, squamouscarcinomas and NSCLC NOS subgroup respectively. There was no difference in the feasibility of molecular testing between the three sampling methods with feasibility rates for ERCC1, RRM1 and BRCA1 of 91%, 87% and 81% respectively.
All three methods can provide sufficient tumor material for multiple biomarkers testing from routinely obtained small biopsies in lung cancer patients. In our study EBUS guided needle aspiration provided the highest amount of tumor RNA compared to bronchoscopy or CT guided core biopsy. Thus EBUS should be considered as an acceptable option for tissue acquisition for molecular testing.
PMCID: PMC3812131  PMID: 24205040
21.  The Role of Convex Probe Endobronchial Ultrasound Guided Transbronchial Needle Aspiration in the Diagnosis of Malignant Mediastinal and Hilar Lymph Nodes 
Iranian Journal of Radiology  2012;9(4):183-189.
In the diagnosis of malignant lymph nodes (LNs) and staging of lung cancer, sampling of mediastinal and hilar LNs is essential. Mediastinoscopy is known as the gold standard. Convex probe (CP) endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) is a noninvasive and highly sensitive diagnostic method in mediastinal and hilar LN sampling.
Evaluating the role of CP-EBUS-guided TBNA in the diagnosis of mediastinal and hilar LNs suspicious of malignancy.
Patients and Methods
One hundred twenty patients with a known lung malignancy or hilar/mediastinal LNs detected by thoracic computed tomography (CT) and/or positron emission tomography (PET)-CT suspicious for malignancy were included in this prospective study. The procedure was performed by Olympus 7.5 MHz CP endoscope and EU C2000 processor by the oral route under topical anesthesia and conscious sedation. After visualization of LNs, their dimensions were recorded. Aspiration was considered as “insufficient” if there were inadequate lymphocytes on the smears. Diagnosis of “malignancy” on cytologic examination was considered as the “final diagnosis”. If diagnosis was negative for malignancy, more invasive procedures were performed to confirm the diagnosis.
Twenty four females and 96 male patients (mean age, 57.8 ± 9.1) were included. A total of 177 LN stations were aspirated in 120 patients. In 82 patients, the diagnosis was malignant by EBUS-guided TBNA and in the remaining 38; the diagnosis was established by further invasive procedures. Of the 38 EBUS-guided TBNA negative patients, 28 were diagnosed as non-malignant and 10 were malignant. The sensitivity, diagnostic accuracy and negative predictive value of CP EBUS-guided TBNA were 89.1%, 91.6% and 73.6%, respectively. No major complications were seen.
As an alternative method to mediastinoscopy, EBUS-guided TBNA is a safe and noninvasive procedure with high sensitivity in the diagnosis of malignant mediastinal LNs.
PMCID: PMC3569549  PMID: 23407664
Ultrasonography; Lung Cancer; Mediastinal Neoplasms; Lymph Nodes
22.  False positive endobronchial ultrasound-guided real-time transbronchial needle aspiration secondary to bronchial carcinoma in situ at the point of puncture: a case report 
Since the development of endobronchial ultrasound-guided real-time needle aspiration (EBUS-rt-TBNA) no false positive (FP) cases have been described. We present the first FP case for EBUS-rt-TBNA secondary to a carcinoma in situ (CIS) in the bronchial point of puncture. A 66-years-old male was referred to our Institution because of a mass in left lower lobe. The bronchoscopy did not show any endobronchial lesion. The cytology of the washing confirmed an unspecified non-small cell lung cancer. An EBUS-rt-TBNA for staging was carried out. No mediastinal nodes over 5 mm length were found but one single left hilar node at station 11 L was sampled. The cytology of the TBNA showed lymphocytes and neoplastic squamous cells. The patient underwent thoracotomy. On the surgical specimen no metastasis on any of the nodes resected were detected but a CIS on the bronchial resection margin was described. A bronchial biopsy confirmed CIS on the bronchial stump. The reported case depicts an unusual situation, we consider EBUS-rt-TBNA an accurate technique if minimal requirements are met
PMCID: PMC3499306  PMID: 22892016
Lung Cancer; Endobronchial Ultrasound; Staging; False Positive; Carcinoma in situ
23.  The role of Endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) for qualitative diagnosis of mediastinal and hilar lymphadenopathy: a prospective analysis 
BMC Cancer  2011;11:100.
Recently EBUS-TBNA, which has a sensitivity of 94.6%, specificity of 100% and diagnostic accuracy rate of 96.3% as previously reported, has been widely used for patients with mediastinal and hilar lymphadenopathy or suspected lung cancer to get accurate diagnosis. The purpose of the current study was to evaluate the usefulness of EBUS-TBNA in obtaining cytological and histological diagnosis of mediastinal and hilar lymph nodes compared to the results obtained with conventional mediastinoscopy as previously reported, and to assess the relationship of diagnostic accuracy and number of passes and size of lymph nodes.
101 patients with mediastinal and hilar lymphadenopathy or suspected lung cancer in our institution were included in this prospective study. EBUS-TBNA was performed in all cases. The final diagnosis was confirmed by cytology, surgical results, and/or clinical follow-up for at least 6 months. Sensitivity, specificity, accuracy, and positive and negative predictive values were calculated using standard formulas.
In 101 patients, EBUS-TBNA was successfully performed to obtain samples from 225 lymph nodes, 7 lung masses, 1 mediastinal mass and 2 esophageal masses. 63 malignant tumors and 38 benign diseases were confirmed. Epidermal growth factor receptor mutation was detected in 10 biopsy samples, and epidermal growth factor receptor mutation was detected in 4 cases. With respect to the correct diagnosis of mediastinal and hilar lymphadenopathy, EBUS-TBNA had a sensitivity of 95.08%, specificity of 100%, positive predictive value of 100%, negative predictive value of 93.02%, and overall accuracy of 97.02%. The relationship of diagnostic accuracy and number of lymph node passes or size of lymph nodes was both insignificant (p = 0.27; p = 0.23). The procedure was uneventful without complications.
EBUS-TBNA is an accurate and safe tool in diagnosis of mediastinal and hilar lymphadenopathy. It cannot completely replace mediastinoscopy, it may indeed reduce the number of mediastinoscopy procedures. In some cases, it can necessarily be the first-line procedure before mediastinoscopy.
PMCID: PMC3076261  PMID: 21418631
24.  Efficient utilization of EBUS-TBNA samples for both diagnosis and molecular analyses 
OncoTargets and therapy  2014;7:2061-2065.
The assessment of an increasing number of molecular markers is becoming a standard requirement from endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) specimens. However, it is unclear how many needle passes should be performed and the amount of lung cancer cells that should be sent for molecular analyses. The objective of this study was to determine if it is feasible to divide the material obtained by EBUS-TBNA to allow for molecular analysis without compromising the accuracy of mediastinal staging.
We aimed to determine if dividing EBUS-TBNA specimens has a negative impact on either histopathological diagnosis or molecular analysis.
EBUS-TBNA was performed in 249 enlarged lymph nodes. Negative or ambiguous histopathological results were confirmed by surgical means and clinical follow-up over 6 months. The tissue obtained by EBUS-TBNA was placed onto a glass slide and divided for histopathological workup and molecular analysis. The number of passes was recorded. Both the accuracy of the mediastinal lymph node staging and the applicability of the sample division for molecular analysis were assessed.
Each lymph node was punctured an average of 3.18 times and division of the obtained material for diagnosis and molecular analysis was feasible in all cases. The sensitivity and accuracy of the mediastinal lymph node staging were 96.6% and 97.6%, respectively. A cytokeratin (CK)-19-mRNA concentration–based molecular test was feasible in 74.1% of cases.
Dividing EBUS-TBNA samples for both histopathological diagnosis and molecular testing is feasible and does not compromise the accuracy of mediastinal staging. This method may be an alternative to taking additional needle passes for molecular analyses.
PMCID: PMC4234164  PMID: 25419143
lung cancer; molecular marker; CK-19-mRNA; lymph node sampling
25.  Utility of Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration in Diagnosis of Intrathoracic Lymphadenopathy in Patients with Human Immunodeficiency Virus Infection 
BioMed Research International  2015;2015:257932.
Objective. Intrathoracic lymphadenopathy (LAD) in patients with Human Immunodeficiency Virus (HIV) infection is common, with wide-ranging diagnoses, from benign to malignant causes. Endobronchial Ultrasound-guided Transbronchial Needle Aspiration (EBUS-TBNA) is a relatively new technology with established applications in lung cancer, sarcoidosis, and tuberculosis. We sought to find out whether the addition of EBUS-TBNA to the diagnostic algorithm for LAD in HIV patients will reduce the need for mediastinoscopy. Methods. Retrospective chart review of all EBUS-TBNA procedures performed in our centre from August 2008 to December 2012. Results. 513 patients had EBUS-TBNA performed during this period. We identified nine HIV-infected patients who had LAD of unknown cause and underwent EBUS-TBNA. The procedure reduced the need for mediastinoscopy in eight patients (89%). Conclusions. Potential mediastinoscopies can be avoided by utilising EBUS-TBNA in HIV patients with LAD.
PMCID: PMC4310302  PMID: 25654091

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