Abstract

Background: This study aims to investigate the diagnostic value of endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) procedure in malign and benign diseases.

Methods: Two hundred twenty-eight patients (165 males, 63 females; mean age 58.1 years; range 22 to 84 years) who were performed EBUS-TBNA between April 2011 and January 2013 were retrospectively analyzed. Midazolam sedation was applied in all patients. The diagnostic verification of the samples collected from lymph nodes was carried out by surgical intervention or clinical and radiological follow-up.

Results: In a total of 228 EBUS-TBNA procedures, 1,447 aspirations (average 6.47 for each patient, range 1-12) were applied to 635 lymph nodes (average 2.78 for each patient, range 1-6). In 98.6% of the patients (225/228), the samples were histopathologically appropriate. The histopathological examination identified 88 reactive hyperplasias (39%), 82 neoplastic diseases (36%), 39 granulomatous diseases (17%) (tuberculosis compatible in four patients), and five patients with suspicion of malignant diseases (2%). The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy rates were 91.7%, 100%, 100%, 88.9%, and 95%, respectively. No mortality was observed associated with EBUS-TBNA procedure.

Conclusion: This study suggests that EBUS-TBNA is a reliable method with high diagnostic value in the evaluation of the mediastinal and hilar lymph nodes.

Noninvasive diagnostic tools, such as computed tomography (CT) and positron emission tomography (PET), are frequently used as standard imaging methods in the evaluation of mediastinal lymph nodes. However, using these two methods to differentiate between those that are malignant and those that are benign is still not possible in clinical evaluations.[1,2] In these situations, evaluating the pathological lymph nodes with accuracy is possible through the use of a mediastinoscopy, the current gold standard. However, this method is invasive, requires hospitalization and general anesthesia, and has low complication risks, although at relatively low rates.[3-5] In recent years, transbronchial needle aspiration (TBNA) with real time endobronchial ultrasound (EBUS) has been routinely used to histopathologically evaluate the mediastinal and hilar lymph nodes. It is a minimally invasive technique with high diagnostic accuracy and can also be used to collect samples for cytological evaluation. In addition, meta-analyses have shown that the sensitivity of the EBUS-TBNA method is above 88%.[6-8] The aim of this study was to evaluate the diagnostic performance and process reliability of the EBUS-TBNA method in the cytological evaluation of patients with mediastinal and hilar lymph nodes and examine the clinical features of these cases.

Methods

The clinical and pathological features of 228 patients (165 males, 63 females; mean age 58.1 years; range 22-84 years) who received EBUS-TBNA between April 2011 and January 2013 were retrospectively analyzed. All the patients gave their informed consent to be included in the study before the procedure was performed.

The patients underwent EBUS-TBNA because of suspected mediastinal lymph node metastasis based on the CT (short axis of lymph node >1 cm) or PET/CT (FDG uptake ≥2.5) results.[9] The EBUS-TBNA team consisted of an implementing physician, an anesthesia technician, a nurse, and an auxiliary staff member. Intravenous midazolam (0.05 mg/kg) was used for conscious sedation after a minimum of four hours of fasting, and we introduced the BF-UC180F linear ultrasound bronchoscope (Olympus Medical Systems Corp., Tokyo, Japan) and used either the singleuse 22-gauge (22G) EBUS-TBNA aspiration needle (Olympus Medical Systems Corp., Tokyo, Japan) or the Echo Tip® Ultra Endobronchial High Definition Ultrasound Needle (Cook Medical. Bloomington, IN, USA) during the procedure.

In the cancer patients, if there were multiple lymph node involvement, we started with the lymph node stations that presented with the worst prognosis (N3 prior to N2) to prevent cross-contamination. In addition, if multiple lymph node stations were biopsied, a single TBNA needle was used for each station after flushing the working channel with normal saline. The goal was to perform an accurate staging with a single needle.

The minimum diameter of the lymph nodes that were localized by EBUS-TBNA and biopsied was 5 mm. For each patient, a minimum of two lymph node stations were evaluated, and for each one, a maximum of five aspirations were conducted. The “Doppler ultrasound mode” was used as necessary to differentiate this tissue from the biopsy tissue taken from the vascular structure.

The aspiration materials on which this procedure was performed were both fixed by 95% ethyl alcohol, and the cell blocks were prepared using the CytoRich Red® preservative fluid (Tripath Imaging, Inc., Burlington, NC). During the EBUS-TBNA procedure, no on-site cytopathologist was available in the bronchoscopy department of the hospital, so the appropriateness of the cytological materials was defined by the presence of lymphocytes, pigmented macrophages, histiocyte clusters, and neoplastic cells. The aspirates with an insufficient number of lymphoid cells, crush artifacts, or erythrocytes along with those only bronchial cells were considered to be inappropriate for a diagnosis. In the biopsy material, the presence of lymphoid tissue (lymphocytes, histiocytes, anthracosis residue, or macrophages) or neoplastic cells was interpreted as being suitable for diagnosis. The unsuitable aspiration materials were reviewed again by another cytopathologist, but the diagnosis did not change.

The sensitivity, specificity, and positive and negative predictive values of the EBUS-TBNA were analyzed according to the aspiration results and had been confirmed either by the surgical intervention or clinical and radiological treatment.

Results

The lymph node aspiration was conducted in the following lymph node stations: subcarinal (n=261), lower paratracheal (n=215), hilar (n=152), and upper paratracheal (n=7). A total of 635 evaluated lymph nodes (mean of 2.78 lymph nodes per patient; range 1-6), and 1,447 lymph node aspirations (mean of 6.47 per patient; range 1-12) were performed. However, EBUS-TBNA was not carried out on any patient WHO had possible hilar lymph node metastases without any possible metastatic mediastinal lymph nodes. Additionally, no hilar lymph node metastases were detected by EBUS-TBNA without the presence of any mediastinal lymph node metastases.

In the majority of the patients who underwent EBUS-TBNA, the primary diagnoses were bronchial carcinoma (n=106, 46.5%), pure mediastinal lymphadenopathy (n=65, 28.5%), and an undiagnosed pulmonary mass with clinically abnormal mediastinal lymph nodes (n=22, 10%). These pulmonary masses were not diagnosed by conventional fiberoptic bronchoscopy or transthoracic fine needle aspiration because they were not available at our facility. There were 19 patients (8.5%) with metastatic non-pulmonary carcinoma, and 10 with breast carcinomas (4%) along with three with colonic carcinomas (1.5%), and these were the most common primary tumors that metastasized to the mediastinal lymph nodes. The characteristics of the patients are shown in Table 1.

Table 1: Patient characteristics

All of the patients in the study who had been primarily diagnosed with non-small cell lung cancer (NSCLC) were surgical resection candidates if they had no locally advanced diseases. When the post-EBUS cytopathological results were analyzed, 88 (39%) were diagnosed with reactive lymph nodes, 82 (36%) with metastatic lymph nodes, and 39 (17%) with granulomatous disease. In addition, false negative results were confirmed during the surgery in 11 of the remaining 18 patients.

When the cytopathological results of the 22 patients that underwent EBUS-TBNA for an undiagnosed pulmonary mass with clinically abnormal mediastinal lymph nodes were evaluated, the results revealed bronchial carcinoma in 13 patients (eight with squamous cell carcinoma and five with small cell carcinoma), metastatic lymph nodes (NSCLC with no subgroup assignment) in one patient, reactive hyperplasia in six others, granulomatous disease in one, and suspicious material in another.

The cytopathological results of the five patients who underwent the EBUS-TBNA procedure due to a paratracheal mass were analyzed, and NSCLC (2 squamous cell carcinoma and 1 spindle cell carcinoma) was identified in three patients, small cell carcinoma in one, and granulomatous disease compatible with tuberculosis (TB) in another.

The 121 patients (53%) identified with a specific disease (metastatic or granulomatous disease) were not confirmed surgically. However, confirmation for 65 patients (28%) with reactive lymph nodes occurred via a surgical procedure and for 43 (19%), it took place via clinical or radiological monitoring for at least six months. In all of the patients being monitored, the lymph nodes had either remained stable or receded (Table 2). In the 54 patients (54.5%) diagnosed with reactive hyperplasia by EBUS who received surgical intervention, the diagnosis did not change; however, in the remaining 11 patients (11.1%), the reactive hyperplasia that had been diagnosed by this technique was identified as granulomatosis in five cases and malignant disease in six others via invasive surgical interventions. The overall false negativity rate was 5% (11/228). Three of these false negative patients had less than two aspirations, and the short axis of the lymph nodes was smaller than 1 cm in two others. The highest rate of false negative results by EBUS was obtained from the right paratracheal lymph nodes (station 4R) (Table 3). Furthermore, seven upper paratracheal lymph nodes (station 2R) were diagnosed as reactive hyperplasia, and this was confirmed during the surgical intervention.

Table 2: Cytopathological results of the mediastinal and hilar lymph nodes in study patients

Table 3: Characteristics of the false negative cases

Afterwards, a histopathological analysis found granulomatous disease. Moreover, the angiotensin receptor blocker (ARB) culture results of the material conducted by EBUS-TBNA were positive.

In the patients with benign diseases, the sensitivity, specificity, positive predictive values, negative predictive values, and diagnostic accuracy for the EBUS-TBNA procedure were 88.6%, 100%, 100%, 94.6%, and 96.2%, respectively, but for those with malignant diseases, the rates were 93.2%, 100%, 100%, 93.6%, and 96.6%. In addition, the overall rates for these values were 91.7%, 100%, 100%, 88.9%, and 95.0%, respectively.

In five patients, TBNA was performed once per lymph node due to problems that occurred during the procedure. Three had hemoptysis, one suffered a hypertensive attack, and another had cardiac arrhythmia. For the patients with hemoptysis, the mild endobronchial bleeding was controlled with a cold saline and adrenaline solution before the procedure was completed, whereas the hypertensive attack and cardiac arrhythmia were treated with medication. No mortality was associate with the EBUS-TNBA procedure.

Table 4: Diagnostic performance of the study population

Discussion

Conventional TBNA, a blinded technique performed using a fiberoptic bronchoscope, has been used for more than 30 years.[10] Although this method can be used to take samples from the hilar and mediastinal lymph nodes, it is more effective in the subcarinal and right paratracheal stations.[11-14] Moreover, identifying the small lymph nodes (target visualization) and performing biopsies on these lymph nodes with the conventional EBUS-TBNA procedure is difficult. Additionally, Cetinkaya et al.[15] found that in conventional EBUS-TBNA, the sensitivity and diagnostic rates were high in cases with negative histopathological results.

A mediastinoscopy is a surgical method which requires general anesthesia and hospitalization, and it has minimal mortality and morbidity risks. Some studies that have been conducted in recent years have shown that the EBUS-TBNA procedure and mediastinoscopies, which are regarded as the gold standard for the histopathological diagnosis of mediastinal lymph nodes, have the same diagnostic accuracy rates, especially in the second, fourth, and seventh stations.[16,17]

In their study, Yasufuku et al.,[18] stated that 41 (39%) out of the 105 patients who received EBUSTBNA due to hilar and/or mediastinal adenopathies avoided surgery. Mediastinoscopies were performed on 29 of the patients, thoracotomies on eight, and thoracoscopies on four others.

In our study, 121 (53%) out of the 228 patients had a specific granulomatous or malignant disease which was diagnosed via EBUS-TBNA making the need for surgical intervention to confirm the diagnosis unnecessary. However, this type of confirmation was necessary for 28% (n=65) of the remaining patients because of the presence of reactive hyperplasia, suspicion of a disease, or the use of inappropriate materials. In addition, 19% (n=43) were monitored.

After the first presentation of the EBUS-TBNA procedure in the literature, studies stating that it was accurate and reliable for the cytopathological evaluation of both mediastinal and hilar lymph nodes were published.[19,20] Additionally, some studies have also proposed that the learning period for this technique is relatively short.[21-23]

In the meta-analysis by Varela-Lema et al.[24] that analyzed 14 scientific articles that focused on patients diagnosed with lung cancer, they determined that the sensitivity ranged from 85-100% and the negative predictive values varied from 11-97.4%. Three studies assessed the clinical applicability of the EBUS-TBNA technique in the diagnosis of sarcoidosis and found that it was used diagnostically in 88-93% of the patients. In another meta-analysis, Gu et al.,[7] evaluated a total of 1,299 cases with lung cancer and determined that the sensitivity of the EBUS-TBNA procedure was 93%. Furthermore, a review of this approach performed on patients suspected of having sarcoidosis found that it had a sensitivity of between 85 and 93%.[25] In our study, the diagnostic value of EBUS-TBNA was relatively low, but this was most likely due to the pathologist’s lack of experience. Cetinkaya et al.[26] attributed their high diagnosis rates for benign diseases to the importance of convex probe (CP)-EBUS guidance. In this study, the overall diagnostic accuracy of EBUS-TBNA was consistent with the findings of these studies.

In the patients with both benign and malignant diseases, negative predictive value and diagnostic value as 91.7%, 88.9% and 95% respectively.

Song et al.[27] showed that a d efinitive diagnosis for the evaluation of nodal metastases from an extrapulmonary malignancy was achieved by EBUSTBNA in 61.4% (n=35) of 57 patients, allowing them to avoid surgery. Furthermore, Parmaksız et al.[28] evaluated mediastinal a nd hilar l ymph nodes in 48 patients with a history of an extrathoracic malignancy and demonstrated that EBUS-TBNA could be used to accurately diagnose mediastinal lymph node metastases. We had 19 patients (8.3%) with extrathoracic malignancies.

In our study, EBUS-TBNA was performed on 19 patients with an extrapulmonary malignancy, and five of these (26%) had a malignant disease that negated the need for more invasive surgical techniques while surgical intervention revealed that 11 (58%) had benign lymph nodes and three (16%) had false negative results.

The usefulness of rapid on-site evaluation (ROSE) throughout endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for lymph node staging in patients with lung cancer is still debatable. Chandra et al.[8] stated that the sensitivity of EBUS-TBNA was not dependent on ROSE or the size of the needle that was used. Furthermore, Nakajima et al.[29] validated that ROSE done during EBUS-TBNA for material adequacy showed a low rate of nondiagnostic sampling, but there was a high consonance between the on-site and final pathological evaluations. Nevertheless, careful attention should be paid to the immediate diagnosis. At our institution, we do not perform ROSE; hence, the EBUS-TBNA technique was repeated until an adequate amount of material was collected. Our clinical experience has also shown that in this subjective evaluation, a correlation does not always exist between the amount of material taken and the diagnosis gained by EBUSTBNA. Furthermore, the researchers in our study used two different brands of transbronchial needles that were the same size, but no difference was seen in terms of applicability.

In the study by Medford et al.,[25] because of the current inferior negative predictive value of EBUSTBNA, they deemed that a mediastinoscopy was still required for the clarification of negative nodes associated with this technique. However, Zhang et al.[30] found that the diagnostic yield of EBUS-TBNA was still lower than that of transcervical mediastinoscopy and that it appears to not be as dependable for the safe elimination of mediastinal nodal metastases. Therefore, they encouraged the use of a transcervical mediastinoscopy to confirm negative EBUS-TBNA results.

Nowadays, the matter at hand is whether the EBUSTBNA procedure should replace a mediastinoscopy. With that in mind, it should be noted that a mediastinoscopy is considered to be the gold standard for the histological evaluation of mediastinal lymph nodes, and the European Society of Thoracic Surgeons (ESTS) guidelines recommended that negative EBUSTBNA results should be verified via surgery or other techniques.[1]

Conclusion

The EBUS-TBNA procedure is a non-invasive technique that can be performed using conscious sedation without the need for general anesthesia, and it requires no hospitalization. In addition, this procedure is reliable and has high diagnostic accuracy rates when pathological mediastinal and/or hilar lymph nodes are evaluated. Therefore, we believe that the opportunity to examine both hilar and interlobar lymph nodes could make this technique a viable choice before invasive interventions are carried out.

Declaration of conflicting interests
The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Funding
The authors received no financial support for the research and/or authorship of this article.

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