Utility of endobronchial ultrasound-guided-fine-needle aspiration and additional value of cell block in the diagnosis of mediastinal granulomatous lymphadenopathy
Shaesta Naseem Zaidi MD 1, Emad Raddaoui MD 2
1 Department of Histopathology, King Saud University, King Khalid University Hospital, Riyadh, Saudi Arabia
2 Department of Histopathology, King Saud University, King Khalid University Hospital; Department of Histopathology, Al-Faisal University, Riyadh, Saudi Arabia
|Date of Submission||12-May-2015|
|Date of Acceptance||05-Jul-2015|
|Date of Web Publication||22-Sep-2015|
Shaesta Naseem Zaidi
Department of Histopathology, King Saud University, King Khalid University Hospital, Riyadh
Source of Support: None, Conflict of Interest: None
Background: Endobronchial ultrasound-guided transbronchial fine-needle aspiration is a minimally invasive technique for diagnosis of mediastinal lesions. Although most studies have reported the utility of EBUS-FNA in malignancy, its use has been extended to the benign conditions as well. Objective: To evaluate the diagnostic yield and cytologic accuracy of endobronchial ultrasound-guided transbronchial fine-needle aspiration (EBUS-FNA) in cases of clinically and radiologically suspected granulomatous diseases. Patients and Method: From May 2010 to April 2015, 43 of 115 patients who underwent EBUS-FNA at one center for radiologically and clinically suspicious granulomatous lesions, and with no definite histological diagnosis, were included in this retrospective study. Results: When the histological diagnosis was taken as the gold standard, the sensitivity of EBUS-FNA was 85% and specificity was 100% with the positive predictive value of 100. The combined diagnostic sensitivity of EBUS-FNA and transbronchial lung biopsy was 100%. In 4 cases, cell block provided an exclusive morphological diagnosis of sarcoidosis which was noncontributory by EBUS-FNA. Conclusion: Our study supports the use of EBUS-FNA, by virtue of being a safe, minimally invasive, and an outpatient procedure, in the diagnosis of granulomatous mediastinal lymphadenopathy, thereby obviating more invasive testing in a significant number of patients. Also, cell block provides additional data in the diagnosis in these benign mediastinal diseases.
Keywords: Cell block, endoscopic ultrasound guided transbronchial fine-needle aspiration, granulomatous diseases
|How to cite this article:|
Zaidi SN, Raddaoui E. Utility of endobronchial ultrasound-guided-fine-needle aspiration and additional value of cell block in the diagnosis of mediastinal granulomatous lymphadenopathy
. CytoJournal 2015;12:20
|How to cite this URL:|
Zaidi SN, Raddaoui E. Utility of endobronchial ultrasound-guided-fine-needle aspiration and additional value of cell block in the diagnosis of mediastinal granulomatous lymphadenopathy
. CytoJournal [serial online] 2015 [cited 2017 May 24];12:20. Available from: http://www.cytojournal.com/text.asp?2015/12/1/20/165947
Editorial/Peer Review Statement
To ensure the integrity and highest quality of CytoJournal publications, the review process of this manuscript was conducted under a double blind model (authors are blinded for reviewers and vice versa) through automatic online system.
| » Introduction|| |
Granulomas, both noncaseating and caseating, can be seen in a variety of nonneoplastic and neoplastic conditions. In cytopathologic specimens, granulomas can be considered as the diagnostic hallmark of some diseases such as sarcoidosis, or an indicator of a pathologic entity such as Hodgkin's disease and some B- and T-cell lymphomas. Among the most common nonneoplastic conditions that demonstrate granulomas in pathologic specimens are sarcoidosis, tuberculosis (TB), and in other rare diseases like cat scratch disease.
The diagnosis of mediastinal and hilar tuberculous lymphadenopathy is usually challenging owing to its nonspecific clinical and X-ray findings and the low diagnostic yield of sputum examinations. Such methods are effective in diagnosing pulmonary parenchymal TB and not for tuberculous lymphadenitis. The correct diagnosis of these conditions is essential for the proper management of patients as many patients with these conditions can present with diffuse mediastinal lymphadenopathy. 
Endobronchial ultrasound-guided transbronchial fine-needle aspiration (EBUS-FNA) is a recently developed technique and has emerged as a procedure of choice for tissue diagnosis. It is a minimally invasive, safe technique for direct and real-time aspiration of the mediastinal and hilar lymph nodes, and is a less invasive alternative to mediastinoscopy. ,,,, It had gained popularity because of the ability to obtain tissue with less potential complications.
Of all the benign conditions evaluated by EBUS-FNA, sarcoidosis has been the most extensively studied, with many publications which have reported diagnostic sensitivities of 79.5-93%. ,,, This also included our previous study which solely focused on sarcoidosis.  Published data in English literature in general on benign granulomatous diseases, especially tuberculous mediastinal lymphadenopathy are very limited. One report described the utility of EBUS-FNA in the diagnosis of TB in 2 retroviral patients with mediastinal lymphadenopathy,  while 2 other studies have reported sensitivities of EBUS-FNA for diagnosis of tuberculous mediastinal lymphadenopathy of 84.2% (19 patients) and 94% (156 patients). , In the present study, we have included all the cases of mediastinal granulomatous inflammatory diseases encountered in our hospital.
Rapid on-site evaluation is a common practice in many institutions, , including our institution, where it is used to assess adequacy of FNA specimens, may prompt the endoscopist to consider diagnoses related to granulomatous inflammation, which may not have been a consideration initially, and thus direct further investigations accordingly, e.g. sending additional specimens for mycobacterial and fungal smears and cultures. Shidham's method can be applied to the remaining cytology specimen to improve the quality of diagnostic material in cell block sections. 
In our institutional experience, we have found that making a provisional diagnosis of granulomatous disease during rapid on-site evaluation represents a significant challenge and essentially requires review of the cell block specimen. As such, this study is set out to evaluate the utility of EBUS-FNA and additional diagnostic value of cell block in the diagnosis of granulomatous disease at our institution.
| » Patients and methods|| |
At King Khalid University Hospital, Riyadh, EBUS-FNA is often used as the diagnostic test of choice for patients with suspected granulomatous mediastinal lymphadenopathy. In the present study, retrospective chart review was carried out on all the consecutive patients for suspected granulomatous mediastinal lymphadenopathy, diagnosed in our Hospital (hence some cases were duplicate from the previous study),  who underwent EBUS-FNA between May 2010 and April 2015. These cases had enlarged (more than 1 cm) hilar or mediastinal lymph nodes on chest computed tomography (CT), and were clinically and radiologically followed.
EBUS-FNA was conducted by one experienced pulmonologist in the bronchoscopy suite on all the suspected patients with granulomatous mediastinal lymphadenopathy based on chest CT. These patients understood the procedure required to establish the diagnosis, and written informed consent was obtained from all the participants. Local anesthesia with mild conscious sedation was used for the procedure.
Endobronchial ultrasonography was performed using fiberoptic ultrasound bronchoscope with a linear scanning probe (BF-UC260FW, Olympus Medical System, Tokyo, Japan). A dedicated ultrasound scanner (ALOKA SSD-Alpha 10, ALOKA Ultrasound System, Japan) was used for image processing. Targeted lymph node was sequentially sampled with a dedicated 21-gauge needle (NA-201SX-4021, Olympus Medical System, Tokyo, Japan).
Smears were made at the bedside in the bronchoscopy suite.
Preparation of smears
The aspirated material from the needle was expelled on to glass slides by the operating bronchoscopist and smeared by a cytotechnologist. Two to four slides were prepared from each pass, taking care that any clotted material is preserved for cell block. Air dried (for Diff quick staining) and fixed smears (fixed immediately in 95% ethyl alcohol for subsequent Papanicolaou staining) were prepared in an almost equal ratio with more emphasis on fixed smears. Pass number (indicating a specific site of collection) was marked on each slide and site of collection of each pass was noted on a separate paper.
One or two representative of the air dried smears from each pass were immediately stained with rapid Romanowsky (Diff Quick stain from Shandon) and examined under microscope for specimen adequacy assessment, preliminary diagnostic interpretation if necessary, and to suggest additional studies if indicated.
Additional material was collected for ancillary studies polymerase chain reaction (PCR) and was preserved in normal saline (for microbiology). Material collected for cell block was grossly examined before the end of the procedure, and if the collected material was still not enough to make a good cell block, an additional pass was dedicated to cell block only.
Cytology request form was completed by the consultant bronchoscopist, including the details of the procedure and site of the specimen for each pass.
Number of fixed and air dried slides and description of any other material being sent to the laboratory was noted on the request form. Sample was transported to the laboratory as early as possible and processed for staining of remaining slides and preparation of cell block.
Preparation of cell block
Remaining sediment, including any clotted material was fixed immediately in cell block fixative (10% alcohol formalin), centrifuged and transferred to a histology embedding cassette, and the sections (4-5 μ) from paraffin-embedded cell block were cut and stained with hematoxylin and eosin.
All smears and cell block sections were reviewed by an experienced cytopathologist (Dr. ER). The aspirates were considered to be representative if caseating granulomas, noncaseating granulomas, necrosis, or nodal lymphoid tissue were found, or if the aspirate contained other cellular material that resulted in a specific diagnosis.
In cases with subsequent transbronchial core biopsy, tissues were fixed in 10% formalin and thin histologic sections were cut from paraffin-embedded tissue blocks followed by hematoxylin and eosin staining.
In all the patients, the diagnosis of granulomatous inflammation was suspected based on the clinical and radiological findings. The final diagnosis was established based on lymph node aspirate by EBUS-FNA cytology reveling caseating/noncaseating epithelioid cell granulomas [Figure 1] and [Figure 2], clinical and radiological follow-up, and histology in those cases where mediastinoscopy was performed. EBUS-FNA evaluation for sarcoidosis was considered diagnostic if the histology from core specimens of the lymph nodes showed noncaseating granulomatous inflammation and microbiology was negative for the mycobacterial disease.
|Figure 1: Non caseating granuloma, smear shows two well-defined collection of epithelioid histiocytes with no frank evidence of necrosis (Diff Quick stain, original magnification ×200)|
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|Figure 2: Granuloma, high power view, cell block, localized collection of epithelioid histiocytes surrounded by a rim of lymphocytes (H and E, original magnification ×500)|
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A review of all available histologic slides was performed and correlated with the respective cytological diagnoses. Then 2 × 2 tables were prepared to calculate the sensitivity, specificity, and positive and negative predictive values (NPVs), and the Fisher exact test was used to compare differences between groups. Calculations were performed using Statistical Package for the Social Sciences [SPSS 14.0] for Windows (SPSS, Chicago, IL).
| » Results|| |
This study included a total of 43 eligible patients; 29 were males (67.4%) and 14 were females (32.5%). The male: female was 2.07:1. The patients' age ranged from 21 to 79 years old with a mean age of 46.5 years. None of the patients had a known history of cancer, and the radiological appearance was not consistent with malignancy.
Totally, 54 lymph nodes were sampled from 43 patients by EBUS-FNA. The subcarinal lymph node was most frequently sampled followed by para-tracheal lymph nodes.
Cytology slides were available for all the patients, whereas cell block was available for 30 patients. Microbiological analysis (acid-fast Bacilli [AFB] stain and culture) were done in all the cases. PCR: ProbeTec ET DTB (Becton-Dickinson) was carried out in 29 cases.
By EBUS-FNA cytology, granulomas were identified in 34 out of 43 patients (79.0%). Of these, granulomatous lymphadenitis without caseation was seen in 23 cases, caseating granulomatous lymphadenitis in 11 cases of which, active microbacterial TB was present in 6 cases, which were positive for AFB stain and culture (2 cases) and PCR (6 cases).
On cell block histology, out of 30 samples, granulomas were identified in 17 cases, four with additional caseous necrosis; however in 3 cases, only caseous necrosis was present, in the absence of any granuloma. Cell block supported the diagnosis in additional 4 cases which were noncontributory by EBUS-FNA.
Twenty-four cases of 43 cases had corresponding tissue biopsy. Eighteen cases underwent transbronchial biopsy, 2 cases had both transbronchial and endobronchial biopsy, 2 cases had both transbronchial and mediastinal tru-cut lymph node biopsy, 1 case had only mediastinal lymph node tru-cut biopsy, and 1 case had only endobronchial biopsy. Fourteen cases were rendered the diagnosis of sarcoidosis, and 8 cases were consistent with TB. Histology was negative for granuloma in 2 cases. The results are summarized in [Table 1] and [Table 2].
|Table 1: EBUS-FNA results in 43 patients with suspected granulomatous lymphadenitis|
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When the histological diagnosis was taken as the gold standard, the sensitivity of EBUS-FNA was 85% and specificity was 100% with the positive predictive value (PPV) of 100 and NPV of 25%. The combined diagnostic sensitivity of EBUS-FNA and transbronchial lung biopsy (TBLB) was 100%.
| » Discussion|| |
There are various fine-needle aspiration techniques for diagnosing lung and mediastinal lesions, including transesophageal EUS-FNA, EBUS-FNA, conventional transbronchial needle aspiration (TBNA), transthoracic approach, including CT-guided or fluoroscopic guided FNA. A broad range of factors must be considered when selecting a specific diagnostic modality to assess a suspicious lesion. These factors include the clinical and radiological information, sensitivity and specificity of the test, invasiveness of the procedure, safety profile, institutional availability of technology, presence of qualified clinicians, and cost-effectiveness of the procedure.
In a study published by Bugalho et al.,  they demonstrated that in selected patients with central lesions without an endobronchial component, EBUS, and EUS-FNA, performed with one linear ultrasound bronchoscope are accurate methods to diagnose lung cancer. However, the diagnosis of indeterminate pulmonary nodules and masses can constitute a considerable challenge in some cases. Several options are available for the diagnosis of indeterminate pulmonary lesions. CT-guided transthoracic FNA is an effective means of reaching a diagnosis in a wide variety of thoracic lesions, thus, reducing the need for diagnostic thoracotomy. Fluoroscopic guidance is used as the preferred method in some center, when appropriate, since it is both faster than CT and sampling can be performed under direct visualization. 
Until now; TBLB and TBNA have been the primary procedures to diagnose intrathoracic lymphadenopathy with yields of 76-91% and 62-87%,  respectively. However, both procedures are performed blindly because the targeted lymph node or lung lesion are not visualized during a biopsy or fine-needle aspiration.  Instead, aspiration is guided only by knowledge from prior CT imaging and consequently, the technique is considered difficult. 
If the lesion still remains undiagnosed, patients are often referred for more invasive procedures such as mediastinoscopy, thoracoscopy, or even thoracotomy which carry a small but definite risk to the patient, and they are costly. 
Endoscopic ultrasound is a relatively new diagnostic modality which is less invasive, with real-time ultrasound imaging of the target which allows for a quick and reproducible diagnostic examination which is also easy to perform. It is less expensive than more invasive procedures because it allows investigation in an outpatient setting. In addition, it is associated with <1% significant bleeding or pneumothorax. 
The present retrospective study from Saudi Arabia showed that EBUS-FNA is a sensitive, accurate, and safe modality for the evaluation of mediastinal granulomatous lesions. Endoscopic ultrasound-guided transbronchial fine-needle aspiration was introduced in recent years to the Pulmonology Department of our hospital as a new modality to diagnose and stage lung cancer. It now provides an important alternative to evaluate the patients with intrathoracic lymphadenopathy in benign diseases as well. The procedure is well tolerated in the outpatient setting, provides access to the mediastinal and hilar lymph node locations that are commonly involved in TB and sarcoidosis and also allows bronchial washings to be performed at the same procedure.
The histopathological hallmark of granulomatous lymphadenitis is the identification of granulomas which are composed of epithelioid and giant cells with or without central necrosis. The use of cytological assessment of lymph node aspirates in such cases is more controversial because while it may demonstrate epithelioid histiocytes in a background of lymphocytes and plasma cells, the absence of giant cells makes it less specific for true granulomatous disease. 
In the present cohort of patients, the overall sensitivity, NPV, and PPV of EBUS-FNA were 85%, 25%, and 100%, respectively. This is almost the same as a previous study on granulomatous mediastinal lymphadenopathy which reported a sensitivity, NPV, and diagnostic accuracy of 81%, 43%, and 83%, respectively. ,,, Thus, it enabled a definitive diagnosis to be attained in a significant proportion of patients without subjecting them to more invasive investigations which would entail the risks of general anesthesia, surgical morbidity and mortality, and possible chronic tuberculous sinus formation. 
Our data showed the nondiagnostic rate of 20.9% (9/43 cases). There are various factors, which can contribute to the diagnostic yield. Some of them are the skill of the endoscopist, size and station of the lymph nodes, difficult target with fibrotic tissue, and experience of the cytopathology personnel performing on-site material adequacy.
The logistic regression model showed that those EBUS procedures which obtained necrotic granulomas or necrosis alone were more likely to have a positive culture for TB. , It may be postulated that the bacillary load in these lymph nodes is higher in order to cause necrosis, and, therefore, the organism in these patients is more likely to be identified by microbiological investigations. Thus, although EBUS should be targeted toward the peripheral, solid portion of lesions, necrotic specimens should also be obtained in diagnosing TB.
Previous studies have demonstrated that the diagnostic yield for sarcoidosis via EBUS-FNA can be further improved by combining with random endobronchial and TBLB. ,,, We had a similar finding where the addition of TBLB increased our diagnostic sensitivity from 85% to 90%.
We were able to obtain a microbiological culture and Ziehl-Neelsen stain in all the 43 cases, and PCR in 29 out of 43 cases. Two of our cases were AFB smear and culture positive. This is quite lower to previously reported microbiological yield for EBUS-FNA (culture 46%, smear and culture 54%).  PCR was positive in our 6 cases (20.6%) which is slightly lower than previously reported positivity of 35% by Sentürk et al. , Compared to microscopy and culture, which are of low sensitivity and require longer time duration for completion, Mycobacterium TB-PCR can provide confirmatory results in 24-48 h, leading to fast patient diagnosis and management. However, the PCR results should be cautiously interpreted in combination with other clinical and laboratory data. The low microbiological yield in our study is postulated to reflect the variable bacillary load within lymph nodes.
Cell blocks were available from 70% of EBUS-FNA diagnostic procedure. The main contributions of cell blocks to pathology examinations in our study were the improved diagnosis of benign lesions. Four additional cases provided an exclusive morphological diagnosis of sarcoidosis which were noncontributory by EBUS-FNA. This is in concordance with a study reported by Lourido-Cebreiro et al. who found that exclusive diagnosis from cell block was significantly more frequent in benign diseases than the malignant one.  The improved diagnostic yield of the cell block in benign disease is due to the fact that when the specimen is allowed to clot, the cell material from which morphological features are identified is concentrated, and this may aid the diagnosis of granulomatous diseases and lymphoma. 
| » Conclusion|| |
Our study supports the use of EBUS-FNA, by virtue of being a safe, minimally invasive, and an outpatient procedure, in the diagnosis of granulomatous mediastinal lymphadenopathy with a sensitivity and diagnostic accuracy of 85%, thereby obviating more invasive testing in a significant number of patients. Also, cell block can be prepared from a high percentage of cytological specimens from clotted material obtained by EBUS-FNA, and it provides additional data in the diagnosis of node involvement due to benign diseases as well.
However, the optimum use of EBUS-FNA for reaching the confirmed diagnosis depends on the effective collaboration between the cytotechnologist, pathologist, and the bronchoscopist.
| » Competing interests statement by all authors|| |
Declare that we have no competing interests. The authors would like to emphasize that we have not currently or in the past received financial or any other form of support from any of the companies and/or manufacturers mentioned in the article.
| » Authorship statement by all authors|| |
Authors of this article declare that we qualify for authorship as defined by ICMJE. Both authors has participated sufficiently in the work and takes public responsibility for appropriate portions of the content of this article. Both authors read and approved the final manuscript. They acknowledge that this final version was read and approved.
| » Ethics statement by all authors|| |
This study was conducted with approval from Institutional Review Board (IRB) of King Khalid University Hospital, King Saud University, Riyadh, Saudi Arabia. Authors takes responsibility to maintain relevant documentation in this respect.
| » List of abbreviations|| |
0(In alphabetic order
AFB - Acid-Fast Bacilli
CT - Computed Tomography
Endobrochial Ultrasound-Guided Transbronchial Fine-Needle Aspiration
IRB - Institutional Review Board
NPVs - Negative Predictive Value
PCR - Polymerase Chain Reaction
PPV - Positive Predictive Value
TB - Tuberculosis
TBLB - Transbronchial Lung Biopsy
TBNA - Transbronchial Needle Aspiration.
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[Figure 1], [Figure 2]
[Table 1], [Table 2]