Taiki Fujiwara

The utility of sonographic features during endobronchial ultrasound-guided transbronchial needle aspiration for lymph node staging in patients with lung cancer: a standard endobronchial ultrasound image classification system.

BACKGROUND Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive procedure with a high yield for lymph node staging of lung cancer. The aim of this study was to assess the utility of sonographic features of lymph nodes during EBUS-TBNA for the prediction of metastasis in patients with lung cancer and to establish a standard endobronchial ultrasound (EBUS) image classification system. METHODS Digital images of lymph nodes obtained during EBUS-TBNA in patients with lung cancer were categorized according to the following characteristics: (1) size (short axis) less or more than 1 cm, (2) shape (oval or round), (3) margin (indistinct or distinct), (4) echogenicity (homogeneous or heterogeneous), (5) presence or absence of central hilar structure, and (6) presence or absence of coagulation necrosis sign. The sonographic findings were compared with the final pathologic results. RESULTS A total of 1,061 lymph nodes were retrospectively evaluated in 487 patients. The accuracy of predicting metastatic property for each category was as high as 63.8% to 86.0%. A multivariate analysis revealed that round shape, distinct margin, heterogeneous echogenicity, and presence of coagulation necrosis sign were independent predictive factors for metastasis. Two hundred eighty-five of the 664 lymph nodes (42.9%) having at least one metastatic feature of the four categories were pathologically proven metastatic, and 96.0% of lymph nodes (381/397) were proven not metastatic when all four categories were determined as benign. CONCLUSIONS Sonographic features of lymph nodes based on the new EBUS imaging classification may be helpful in the prediction of metastatic lymph nodes during EBUS-TBNA.

The role of EBUS-TBNA for the diagnosis of sarcoidosis – comparisons with other bronchoscopic diagnostic modalities

BACKGROUND The diagnosis of sarcoidosis requires both compatible clinical features and pathologic findings as a means to exclude other differential diagnoses. The utility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for diagnosis of sarcoidosis has been reported, although its indication remains unclear for cases of suspicious sarcoidosis. To clarify the role of EBUS-TBNA for the diagnosis of sarcoidosis, we compared three diagnostic modalities: EBUS-TBNA, transbronchial lung biopsy (TBLB) and bronchoalveolar lavage fluid analysis (BAL). METHODS Thirty-eight patients with suspicious sarcoidosis who had enlarged hilar and/or mediastinal lymph nodes on chest CT were retrospectively reviewed. Patients with malignancies or prior established diagnosis of sarcoidosis were excluded. BAL was initially performed followed by TBLB and finally EBUS-TBNA at the same setting. Microbacterial examinations were also performed from all samples. RESULTS Pathological findings compatible with sarcoidosis were obtained in 32 patients. The remaining 6 patients were diagnosed as one case each of chronic eosinophilic pneumonia, atypical mycobacterial infection and tuberculosis, and the remaining three were pathologically indefinite cases. Clinically, 35 patients were diagnosed with sarcoidosis. The diagnostic accuracy of sarcoidosis was significantly better by EBUS-TBNA (91.4%, p<0.001) compared to the other two modalities. According to chest roentgenogram classifications, there were 31 stage I patients and 4 stage II patients. For stage I patients, EBUS-TBNA was significantly better (90.3%, p<0.001), but each modality showed 100% accuracy for stage II patients. CONCLUSION It is recommended that EBUS-TBNA is added to the conventional diagnostic modalities for patients with suspicious stage I sarcoidosis on chest roentgenogram.

Role of endobronchial ultrasound-guided transbronchial needle aspiration in the management of lung cancer

Endobronchial ultrasound (EBUS) is a promising new modality first introduced during the early 1990s. The radial probe EBUS was initially developed seeking for high-resolution imaging of processes in the airway wall and outside the airways. The structure of special importance was lymph nodes, walls of the central airways, and the mediastinum. After the development of miniaturized radial probes with flexible catheters having a balloon at the tip, it has been applied to aid bronchoscopists during biopsy of patients with respiratory diseases. In particular, the role of EBUS in transbronchial needle aspiration (TBNA) has been established. Radial probe EBUS-guided TBNA has increased the yield of TBNA of mediastinal lymph nodes, although it was still not a real-time procedure with target visualization. New convex probe EBUS (CP-EBUS) with the ability to perform real-time EBUS-guided TBNA (EBUS-TBNA) has emerged to overcome these problems. Indications for EBUS-TBNA are (1) lymph node staging in lung cancer patients; (2) diagnosis of intrapulmonary tumors; (3) diagnosis of unknown hilar and/or mediastinal lymphadenopathy; and (4) diagnosis of mediastinal tumors. Case series using EBUS-TBNA for mediastinal lymph node staging in lung cancer have reported a high yield, ranging from 89% to 98% (average 94.5%). To date, there are no reports of major complications related to EBUS-TBNA. EBUS-TBNA is a novel approach with a high diagnostic yield that is safe. The aim of this article was to review the current role of EBUS-TBNA for the management of lung cancer patients.

Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration for the Diagnosis of Intrapulmonary Lesions

Background: The diagnosis of centrally located intrapulmonary tumors not visible on bronchoscopy may be a challenge. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been shown to be useful for the evaluation of mediastinal lymph nodes. However, there have been no reports of the utility of EBUS-TBNA for the diagnosis of intrapulmonary tumors. Objectives: The purpose of this study was to evaluate the usefulness of EBUS-TBNA for the diagnosis of intrapulmonary tumors located adjacent to the central airway. Methods: From December 2002 to June 2007, 35 patients with pulmonary masses located close to the central airways were accessed by EBUS-TBNA. Conventional bronchoscopic biopsy before EBUS-TBNA was nondiagnostic in 25 of the 35 cases. Patients with endobronchial lesions were excluded from this study. Results: EBUS-TBNA was performed in 19 peritracheal and 16 peribronchial lesions. Cytologic and/or histologic samples were diagnostic in 33 of 35 patients. The final diagnoses of the pulmonary masses were lung cancer in 26 cases (1 small cell lung cancer, 25 non-small cell lung cancer), metastatic lung tumors in 5, and BALT lymphoma in one. The sensitivity and the diagnostic accuracy of EBUS-TBNA for the diagnosis of unknown pulmonary masses was 94.1% and 94.3%, respectively. Conclusions: Intrapulmonary lesions not assessable by conventional bronchoscopic procedures can easily be assessed and diagnosed by EBUS-TBNA as long as it is within the reach of the EBUS-TBNA scope. EBUS-TBNA is a real-time procedure with a high yield which can be applied for the diagnosis of lung tumors.

Molecular characterization of chronic obstructive pulmonary disease-related non-small cell lung cancer through aberrant methylation and alterations of EGFR signaling.

BackgroundThe aim of this study was to evaluate the molecular influence of chronic obstructive pulmonary diseases (COPD) on the pathogenesis of non-small cell lung cancer (NSCLC).Materials and MethodsThe methylation profiles of 12 genes, and the epidermal growth factor receptor (EGFR) and KRAS mutations were determined for samples from 229 NSCLC patients. In addition, protein expression of EGFR and HER2 in 116 NSCLCs was analyzed based on the presence or absence of COPD.ResultsIL-12Rβ2 and Wif-1 methylation and HER2 overexpression were more frequent events in the COPD group. Eighty nonmalignant lung tissues had no correlation with any molecular changes between the COPD and the non-COPD group. EGFR mutation was significantly higher in the non-COPD group, while EGFR expression was inversely correlated with %FEV1.0. In the COPD group, unmethylated SPARC and sFRP-2 genes or a negative CpG island methylator phenotype (CIMP) was a negative prognostic factor, while methylation of p16INK4A and WNT antagonist genes was a negative prognostic factor in the non-COPD group.ConclusionsNovel characteristics of COPD-related NSCLC were identified by examination of methylation profiles and alterations of EGFR signaling. In consideration of the high sensitivity to smoking in patients with COPD, NSCLC with COPD might be a distinct population of smoke-related NSCLC, the genetic profile of which is quite different from non-COPD NSCLC.

Rapid On-Site Cytologic Evaluation During Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration for Nodal Staging in Patients With Lung Cancer

BACKGROUND The utility of rapid on-site evaluation (ROSE) during endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for lymph node staging in lung cancer is still controversial. The aim of this study was to assess the role of ROSE during EBUS-TBNA and the interpretation of its results. METHODS We performed a retrospective chart review of patients with suspected or diagnosed lung cancer who underwent EBUS-TBNA for lymph node staging. The slides were air-dried and Diff-Quik (American Scientific Products, McGaw Park, IL) staining was used for ROSE. Additional smears were prepared for Papanicolaou staining and any remaining sample was placed in 10% formalin for histologic evaluation. The results of ROSE were compared with the results of the final pathologic diagnosis. RESULTS EBUS-TBNA was performed in 438 patients on 965 lymph nodes. Eighty-four lymph nodes (8.7%) were determined insufficient for definitive diagnosis by final cytologic evaluation. However 45 of the 84 lymph nodes were able to be diagnosed by histologic examination. The non-diagnostic sampling rate was 4.0%. There were no false-positive results on ROSE; however 25 cases (5.7%) were falsely evaluated as negative on ROSE. The concordance rate for staging between ROSE and final pathologic diagnosis was 94.3%. The sensitivity, specificity, negative predictive value, and diagnostic accuracy rate of EBUS-TBNA for correct lymph node staging was 96.5%, 100%, 89.8%, and 98.2%, respectively. CONCLUSIONS ROSE during EBUS-TBNA for material adequacy showed a low rate of non-diagnostic sampling. There was a high agreement between the on-site and final pathologic evaluation during EBUS-TBNA; however immediate diagnosis should be approached with caution.

Utility of endobronchial ultrasound-guided transbronchial needle aspiration in the diagnosis of mediastinal masses of unknown etiology.

BACKGROUND Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been reported to be useful for lymph node staging in lung cancer. The role of EBUS-TBNA in the diagnosis of mediastinal masses of unknown etiology has not been described. The purpose of the current study was to investigate the clinical utility of EBUS-TBNA in the diagnosis of mediastinal masses of unknown etiology. METHODS Retrospective chart review of our EBUS-TBNA database between 2002 and 2007 was performed. Mediastinal masses of unknown origin in the absence of known pulmonary malignancy were included in the study. Final diagnoses were determined by EBUS-TBNA, surgery and (or) clinical follow-up. The EBUS-TBNA results were classified into two categories: (1) malignant mediastinal and (2) benign mediastinal. RESULTS A total of 140 patients with mediastinal masses of unknown origin without the presence of lung cancer or other pulmonary malignancy were identified. Final diagnosis was available in all patients by means of EBUS-TBNA, surgery, mediastinoscopy, or other diagnostic or long-term follow up. The final diagnoses were 40 malignant mediastinal and 100 benign mediastinal. The EBUS-TBNA was diagnostic in 131 of 140 patients (93.6%) for all disease categories (malignant 87.5%, benign 96.0%). The EBUS-TBNA was successful in directing subsequent workup and (or) therapy in 94 of 140 patients (67.1%). The EBUS-TBNA was uneventful and there were no complications. CONCLUSIONS Endobronchial ultrasound guided transbronchial needle aspiration is a safe and minimally invasive approach for sampling of mediastinal tissues. It should be considered for evaluation of mediastinal masses of unknown origin early in the diagnoses process. It spares more invasive procedures for tissue sampling of the mediastinum.

Narrow band imaging with high-resolution bronchovideoscopy: A new approach for visualizing angiogenesis in squamous cell carcinoma of the lung

OBJECTIVES We investigated the ability of a high-resolution bronchovideoscopy system with narrow band imaging (NBI) to detect blood vessel structures in squamous cell carcinoma (SCC) of bronchi, as well as squamous dysplasia. METHODS Seventy-nine patients with either abnormal sputum cytology or lung cancer were entered into the study. First, high-resolution bronchovideoscopy with white light was performed. Observations were repeated using NBI light to examine microvascular structures in the bronchial mucosa. Spectral features of the RGB (red/green/blue) sequential videoscope system were changed from a conventional RGB filter to the new NBI filter. The wavelength ranges of the NBI filter were: 400-430 nm (blue), 400-430 nm (green) and 520-560 nm (red). RESULTS The following were clearly observed with NBI with high-resolution bronchovideoscopy: increased vessel growth and complex networks of tortuous vessels of various sizes, in squamous dysplasia; some dotted vessels, in addition to increased vessel growth and complex networks of tortuous vessels, in ASD; several dotted vessels and spiral or screw type tumor vessels of various sizes and grades, in SCC. Capillary blood vessel and/or tumor vessel mean diameters of ASD, CIS, microinvasive and invasive carcinoma were 41.4+/-9.8 microm, 63.7+/-8.2 microm, 136.5+/-29.9 microm and 259.4+/-29.6 microm, respectively. These results indicated a statistically significant increase of mean vessel diameters in the four groups (P<0.0001). CONCLUSION NBI with high-resolution bronchovideoscopy was useful for detecting the increased vessel growth and complex networks of tortuous vessels, dotted vessels and spiral or screw type tumor vessels of bronchial mucosa. This may enable detecting the onset of angiogenesis during multi-step carcinogenesis of the lung.

Lymph Node Staging by Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration in Patients With Small Cell Lung Cancer

BACKGROUND Surgical treatment of small cell lung cancer (SCLC) is limited to stage I disease. Therefore, accurate lymph node staging is mandatory in SCLC patients. The purpose of this study was to evaluate the utility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for the evaluation of mediastinal and hilar lymph node metastasis in patients with SCLC. METHODS Forty patients with untreated SCLC who underwent EBUS-TBNA for lymph node staging between November 2002 and September 2008 were retrospectively analyzed. The convex probe endobronchial ultrasonography was used for EBUS-TBNA. Lymph nodes assessed by the convex probe endobronchial ultrasonography were aspirated until EBUS-TBNA revealed malignant cells by rapid on-site cytology. RESULTS Endobronchial ultrasound-guided transbronchial needle aspiration was successfully performed in all patients, and revealed lymph node status as follows: N0, 13 cases; N1, 5 cases; and N2, 22 cases. Among the 13 N0 cases, 9 patients underwent surgery, whereas 4 patients did not undergo surgical intervention because of enlargement of subaortic or paraaortic lymph nodes (stations 5 and 6) that precluded EBUS-TBNA assessment (n = 3) or poor performance status (n = 1). Pathologic examination of dissected nodes confirmed an N0 diagnosis in 8 patients, whereas 1 patient had hilar lymph node metastasis (N1). The sensitivity, specificity, and diagnostic accuracy rate of EBUS-TBNA were 96.4%, 100%, and 97.2%, respectively. The overall 5-year survival rate for the 9 patients who underwent surgery was 77.8%. CONCLUSIONS Endobronchial ultrasound-guided transbronchial needle aspiration has a high diagnostic yield for the evaluation of mediastinal and hilar lymph node metastasis in SCLC and has a high impact on patient management.

Assessment of chemosensitivity-related aberrant methylation of nonsmall cell lung cancer by EBUS-TBNA

BackgroundMultigene aberrant methylation profiling may predict response to chemotherapy in lung cancer. The purpose of this study was to analyze the feasibility of detecting aberrant methylation in biopsy samples obtained by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). MethodsLymph node samples from 30 patients with nonsmall cell lung cancer diagnosed as metastatic carcinoma by EBUS-TBNA were analyzed. Histologic cores obtained by EBUS-TBNA were separately stored at −80°C. DNA was extracted from EBUS-TBNA samples and bisulfate modification was performed. We evaluated the methylation status of a panel of 6 genes (FANCF, Reprimo, TMS1/ASC, activated protein-2α, CHFR, and ATM) using methylation-specific polymerase chain reaction. Twenty-four patients with adenocarcinoma or squamous cell carcinoma metastasis received platinum-based combination chemotherapy. We reviewed their response to chemotherapy in correlation to the methylation status. ResultsBisulfate modification was successfully performed in all samples using DNA obtained from EBUS-TBNA samples by checking p16 unmethylation expression. Aberrant methylation was detected as follows: 9 cases of FANCF (30.0%), 14 cases of Reprimo (46.7%), 10 cases of TMS1/ASC (33.3%), and 19 cases of activated protein-2α (63.3%). In response to chemotherapy, there were 1 complete response, 6 partial response, 12 stable disease, and 5 progressive disease (PD) cases. The number of methylated genes was significantly smaller in the PD group than in the non-PD groups (P=0.0435). ConclusionsAberrant methylation analysis can be performed in metastatic lymph nodes sampled by EBUS-TBNA. EBUS-TBNA allows for genetic evaluations of tumor cells and may help to guide the most effective treatment strategies in the near future.