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Endoscopic Ultrasound Fine Needle Aspiration in the Diagnosis of Lymphoma

Endoscopic Ultrasound Fine Needle Aspiration in the Diagnosis of Lymphoma Hindawi Publishing Corporation Journal of Oncology Volume 2011, Article ID 785425, 4 pages doi:10.1155/2011/785425 Case Report Endoscopic Ultrasound Fine Needle Aspiration in the Diagnosis of Lymphoma Koen Creemers, Olaf van der Heiden, Jan Los, Joost van Esser, David Newhall, Remco S. Djamin, and Joachim G. Aerts Amphia Hospital, Molengracht 21, 4818 CK Breda, The Netherlands Correspondence should be addressed to Joachim G. Aerts, jaerts@amphia.nl Received 8 October 2010; Revised 9 January 2011; Accepted 19 February 2011 Academic Editor: David Ball Copyright © 2011 Koen Creemers et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In recent years, endoscopic ultrasound techniques with Fine Needle Aspiration (FNA) have become an increasingly used diagnostic aid in the differentiation of mediastinal lymphadenopathy. Endobronchial ultrasound (EBUS) and endoesophageal ultrasound (EUS) are now available for clinicians to reach mediastinal and paramediastinal masses using a minimally invasive approach. These techniques are an established component for diagnosing and staging lung cancer and their benefit in the diagnosis of lymphoma’s has been highlighted in a number of case studies. However, the lack of tissue architecture obtained by cytological FNA specimens decreases the diagnostic accuracy for benign causes of thoracic lymphadenopathies, lymphomas, and histopathological subtyping of lung cancer. Accordingly, our study group have adapted the FNA sampling technique, resulting in tissue fragments that can be used for histopathological examinations. As an illustration, we report a case of follicular non-Hodgkin lymphoma, diagnosed on tissue fragments obtained by adjusted EUS FNA. We believe that this relatively simple adjustment to routine FNA sampling can help to overcome the diagnostic limitations inherent in cytology obtained by routine FNA. 1. Background of studies examining epithelial malignancies have been conducted that highlight this predicament [1–3]. The pathophysiology of mediastinal lymphadenopathy is It has been suggested that the generation of significant multifactorial with both benign and malignant diseases caus- false negative results can be explained by sampling error and detection error. For example, the correct node is sampled ing their presentation. Examples of benign diseases include reactive lymphadenopathy and granulomatous diseases (e.g., but the material obtained does not represent the underlying sarcoidosis, tuberculosis, histoplasmosis). Malignant diseases disease or the radiological suspicious node is not identified correctly during ultrasonography. In addition, only cytology include metastatic spread of carcinoma to the lymph nodes or localisation of lymphoma. is collected when EUS FNA is used and in the specific differ- Recently, the diagnosis of mediastinal lymphadenopathy ential diagnosis of lymphoma, due to the need to perform has been achieved with a combination of endoscopic ultra- immunohistopathological examinations, histological sam- sound and Fine Needle Aspiration (FNA) techniques [1]. pling is preferential [4]. Moreover, in nonsmall cell lung can- Clinicians are able to reach mediastinal and paramediastinal cer, the histopathological subtyping has been recognised as of lymphomas/ masses with endobronchial ultrasound (EBUS) pivotal importance in the choice of chemotherapeutic agents. and endoesophageal ultrasound (EUS) using a minimally In addition, studies have shown how EUS [5]and EBUS [6] can be applied for the diagnosis of lymphoma. Some cen- invasive approach. However, the combination of imaging and FNA tissue sampling is essential because imaging alone is not tres usetrue cut biopsies to acquirelarger tissuespecimens, sufficient for a diagnosis [1]. although it should be noted that this was not incorporated Nonetheless, despite a high diagnostic yield using this into general clinical practice [6]. Some centres also demon- combination technique, the significant number of false nega- strated the net benefit of flow cytometry in increasing the tive findings in the cytology remains problematic. A number diagnostic yield, particularly for lymphoma. However, for a 2 Journal of Oncology multiplicity of reasons this technique cannot be incorporated rial. From this material, there were small tissue fragments into the general handling of all FNA samples [6]. on which the pathologist was able to perform histological Therefore, in the case of mediastinal lymphadenopathy analysis and immunohistochemical tests clearly showing and a suspicion of a lymphoma, current medical practice localisation of the follicular lymphoma. dictates that a surgical biopsy is the preferred diagnostic approach. However, mediastinoscopy is a more invasive pro- 3. EUS Procedure cedure with a higher complication rate when directly com- pared to endoscopic ultrasound techniques [7]. EUS was performed according to published guidelines with Consequently, adaptations to standard EUS-FNA have an Olympus EUS EXERA ultrasonic video gastroscope GF- been developed in order to increase the diagnostic yield UC160P-OL5. After identification of the suspected lymph of EUS-FNA. Subtle adaptations in both our EUS proce- node, the FNA needle was introduced (model Olympus NA- dure and in our handling of samples have allowed us to 200H-8022 needle width 22 Gauge). Following infiltration of obtain histology-like material from EUS-FNA, from which the node, the mandarin was pulled back and in excess of immunohistochemistry can be performed. With the aid of 15 passes into the lymph node were performed before the a case study, we illustrate how we were able to diagnose the needle was finally retracted. The mandarin was reintroduced localisation of a follicular non-Hodgkin lymphoma (NHL) to push any collected tissue fragments, that possessed a on tissue fragments obtained using EUS FNA. “worm-like” appearance, into a cytorich red (CRR) medium. Finally, after the mandarin was removed again, the remaining droplets were collected on glasses by clearing the needle with 2. Case Report air, using a 20cc syringe. A 64-year-old female patient with a 30-pack-year smoking This procedure resulted in the collection of: history was admitted to the outpatient clinic for analyses of (i) “Worm-like” coherent material in the CRR, a hilar and mediastinal lymphadenopathy. Her past medical history revealed a follicular NHL stage IVa diagnosed in (ii) Air dried smeared droplets on glasses, and 2003. This disease presented with iliac lymphadenopathy (iii) Cytospin fluid after the “worm-like” material was and bone marrow localisation. She was initially treated with extracted. palliative radiotherapy for lymphoma in the left iliac area. In 2007, there was clinical evidence of disease progression These materials were then processed and investigated as based on palpable lymph nodes in the right iliac and the left- follows sided supraclavicular areas. A computed tomography (CT) (1) Cytological examination was performed on II and of the abdomen also showed para-aortal lymphadenopathy. She underwent palliative radiotherapy on the right iliac III, using May Grunwald-Giemsa colouring and lymphoma to treat its symptomatic mass effect. In September Shandon EZ Megafunnel (Thermo Fisher) method with Papanicolaou colouring, respectively. 2008, she was admitted for dyspnoea and a loss of appetite and a subsequent CT scan of the thorax, neck, and abdomen (2) The “worm-like” fragments in CRR (I) were added was performed. The CT scan revealed massive left hilar to liquid agar, compressed on the bottom of a mold lymphadenopathy with compression of the surrounding and left for solidification. The solidified agar was then bronchial and venous structures and mediastinal (subcari- taken out from the mold and encased in a cassette. nal) and parasternal lymphadenopathy with a small left The cassette was further processed according to rou- sided pleural effusion. A subsequent positron emission tine histological investigative techniques. The follow- tomography (PET) scan showed multifocal disease activity in ing day, two slices were made at two different levels the pathological areas corresponding to the previous CT scan allowing standard and supplemental histological and and low disease activity in the para-aortal region. Nonethe- immunohistochemical staining to be performed. less, despite these extensive radiological investigations it was not possible to differentiate between progression of NHL or Our approach represents a subtle but significant adapta- another disease pathology such as an underlying primary tion to the routine handling of this material as a smear is not lung carcinoma. made from the “worm-like” fragment. By using our modified Accordingly, a bronchoscopy was performed that showed technique, we can generate two important advantages; firstly, a slightly oedematous bronchial mucosa in the left lower it allows optimal use of the collected material including lobe. Brushing, bronchial lavage and endobronchial biopsies histological investigation. Secondly, it leads to a reduction of the oedematous mucosa with a transbronchial needle aspi- in processing time owing to a reduction in the number of ration (TBNA) of the subcarinal node and a pleuracentesis smears that are made. were performed. Further sampling of the left sternal mass We opted to collect the material in CRR and not dire- with transthoracic FNA was also conducted but all these tests ctly in formalin solution for the following reasons: firstly, failed to deliver a diagnosis. due to the characteristics of CRR (fixation, haemolysis, Therefore, it was deemed necessary to perform an EUS- denaturation of proteins, and compatibility with immuno- FNA with material being obtained from the subcarinal histochemical staining), a specimen of superior quality could lymphoma location 7 and from the possible primary process. be obtained. Secondly, cytological examination could be Both aspirations delivered macroscopic “worm-like” mate- performed on the diagnostic material in the CRR, after the Journal of Oncology 3 Figure 1: True tissue fragment of the material acquired with Figure 3: Immunohistochemical stain CD79A (HE 400×). Micro- adjusted EUS-FNA (HE 200×). scopical report: histological tissue fragments are presented. The image is determined by small lymphatic cells with irregular shaped nucleoli. The chromatine-pattern is enlarged. There is indentation on multiple sides. Some B-lymfoblasts are seen (CD79A/20). The total image is representative of a follicular non-Hodgkin lymphoma. such as sarcoidosis [9]. However, the lack of tissue architec- ture obtained by cytological FNA specimens decreases the diagnostic accuracy, and accordingly suggestions have been proposed to alleviate this problem. One current suggestion is that a true cut needle for obtaining tissue fragments (TCB) should be used. In a small study, Storch et al. [2] demonstrated in a subgroup of 19 patients with a benign disorder, that the combination of FNA and TCB achieved 100% diagnostic accuracy and that Figure 2: True tissue fragment of the material acquired with TCB was superior over FNA (89% versus 68%, resp.) in an adjusted EUS-FNA (HE 400×). accurate diagnosis. Although the use of TCB to retrieve larger histological biopsies has been described in the thorax, it is a “worms” were removed, using the Shandon EZ Megafunnel. new technique and large trials have not yet been conducted This processisparticularly advantageousasitisboth quick that provide satisfactory evidence that this approach is safe. and the equipment is relatively simple to use. Conversely, Evidence for its efficacy and safety has only been provided using an alternative formalin solution would have made the by a few small trials and case reports. Nonetheless, arguably process markedly more complicated. the greatest limitation in EUS-TCB is the necessity that However, it should be noted that in our aforementioned the mediastinal mass must be larger than two centimetres example, the cytological material referred to in II and III did without vascular involvement. Masses that fall outside these not contribute to the diagnosis of lymphoma. Nonetheless, stipulated prerequisitions cannot yield a suitable sample histological tissue fragments that were intact and possessed using EUS-TCB but significantly it can be achieved using structural integrity, as illustrated in Figures 1, 2,and 3,were EUS-FNA. obtained from step I coherent material in CRR. Therefore, a Further techniques to increase the diagnostic yield are subsequent diagnosis of follicular non-Hodgkin lymphoma centred on the handling of the samples. In our approach, could be made after immunohistochemical staining. smears are not created and instead the samples are trans- ferred directly to a medium in an effort to maintain tissue architecture. Moreover, these “worms” that are collected 4. Discussion using our technique can then be used for histopathological Endoscopic ultrasound is a well-established component in analysis. To retrieve these “worms”, the number of needle the diagnosis of lung cancer with most clinicians utilising passes per puncture into the abnormal structure is of EUS as part of their routine diagnostic testing. Furthermore, importance. It was determined that the optimum number of a growing body evidence highlights the additional benefits passes per puncture to obtain the “worm-like” structures was of EBUS [8]. The application of EUS provides minimally at least 10, as less than 10 passes failed to generate sufficient invasive access to the lymph nodes in the posterior medi- data (results not shown). However, it is important to realise astinum, especially on the left side (Mountain-Dressler 2, 4, that a degree of structural integrity is required to collect 5, 6, 7, 8, 9.) and the left-sided adrenal gland. Recent studies the histological material. In necrotic areas, for example, this have shown a high accuracy in diagnosing mediastinal integrity is lacking and it is not always possible to obtain the lymphadenopathy of unknown origin and benign disorders required “worm-like” material that is needed for analysis. 4 Journal of Oncology Theoretically, more passes could be associated with a Trucut biopsy in thoracic lesions: when tissue is the issue,” Surgical Endoscopy and Other Interventional Techniques,vol. higher complication rate but this was not found in our 22, no. 1, pp. 86–90, 2008. series. Previously, we have performed over 300 procedures [3] K. G. Tournoy, M. M. Praet, G. van Maele, and J. P. van Meer- using this technique and only 1 complication occurred and beeck, “Esophageal endoscopic ultrasound with fine-needle this was believed to be related to the puncture itself rather aspiration with an on-site cytopathologist: high accuracy for than the number of passes [10]. Additional testament to the the diagnosis of mediastinal lymphadenopathy,” Chest,vol. safety of this technique is provided in another paper that we 128, no. 4, pp. 3004–3009, 2005. have published that examined the capability of performing [4] R. S. Hoda, L. Picklesimer, K. M. Green, and S. Self, spectroscopy during EUS-FNA. The results showed that no “Fine-needle aspiration of a primary mediastinal large B-cell adverse events were experienced by our study population lymphoma: a case report with cytologic, histologic, and flow [11]. cytometric considerations,” Diagnostic Cytopathology, vol. 32, In the last year, a number of reports on the diagnostic no. 6, pp. 370–373, 2005. [5] A.Ribeiro, D.Pereira,M.P. Escalon, ´ M. Goodman, and accuracy of EUS and EBUS in the diagnosis of lymphoma G. E. Byrne Jr., “EUS-guided biopsy for the diagnosis and have been published [5, 6, 12, 13]. As large randomized classification of lymphoma,” Gastrointestinal Endoscopy,vol. studies are lacking, the interpretation of the results and 71, no. 4, pp. 851–855, 2010. diagnostic yield is confounded by the incidence in the study [6] D. P. Steinfort, M. Conron, A. Tsui et al., “Endobronchial population [14]. ultrasound-guided transbronchial needle aspiration for the Diagnostic yield is also determined in part by the evaluation of suspected lymphoma,” Journal of Thoracic protocols and techniques implemented by the individual Oncology, vol. 5, no. 6, pp. 804–809, 2010. institution. For example, if “on-site” cytology is performed, [7] A.Ernst,D.Anantham, R. Eberhardt, M. Krasnik, and F. in the event that lymphoma is suspected, additional punc- J. F. Herth, “Diagnosis of mediastinal adenopathy-real-time tures should be performed to allow for subsequent flow endobronchial ultrasound guided needle aspiration versus cytometry investigations. mediastinoscopy,” Journal of Thoracic Oncology,vol. 3,no. 6, However, as we have shown that our diagnostic yield pp. 577–582, 2008. [8] R. C.Rintoul,K. G. Tournoy,H.ElDaly etal., “EBUS-TBNA is increased by extracting and sampling the “worm-like” for the clarification of PET positive intra-thoracic lymph material, we no longer perform on-site cytology. nodes-an international multi-centre experience,” Journal of In our case study, conventional diagnostic techniques Thoracic Oncology, vol. 4, no. 1, pp. 44–48, 2009. would have required the use of CT-guided transthoracic [9] K. G.Tournoy, A.Bolly,J.G.Aerts et al., “The value biopsy for sampling the mass in the left lower lobe of the of endoscopic ultrasound after bronchoscopy to diagnose lungs and mediastinoscopy to investigate the mediastinal thoracic sarcoidosis,” European Respiratory Journal, vol. 35, no. lymphomas. Therefore, our modified technique not only 6, pp. 1329–1335, 2010. eliminates the need for these separate procedures, but it also [10] J. G. J. V. Aerts, J. Kloover, J. Los, O. van der Heijden, A. allows both sites to be sampled in one session. Janssens, and K. G. Tournoy, “EUS-FNA of enlarged necrotic The case study provided illustrates the use of our modi- lymph nodes may cause infectious mediastinitis,” Journal of fied technique in diagnosing NHL but its use can be extended Thoracic Oncology, vol. 3, no. 10, pp. 1191–1193, 2008. to provide diagnostic subtyping of nonsmall cell lung cancer. [11] S. C. Kanick, C. van der Leest, R. S. Djamin et al., “Char- acterization of mediastinal lymph node physiology in vivo This application is important because it allows the optimum by optical spectroscopy during endoscopic ultrasound-guided treatment regime for patients to be determined. Our adapted fine needle aspiration,” Journal of Thoracic Oncology, vol.5,no. technique is now currently utilised in a number of other 7, pp. 981–987, 2010. hospitals and this has generated similar results. We now [12] M. Al-Haddad, M. S. Savabi, S. Sherman et al., “Role of endo- have a small series of 6 patients who were diagnosed with scopic ultrasound-guided fine-needle aspiration with flow lymphoma; using this technique, no further investigations cytometry to diagnose lymphoma: a single center experience,” were deemed necessary. In a series of 92 lung cancer patients, Journal of Gastroenterology and Hepatology, vol. 24, no. 12, pp. 75% of samples could be investigated for histological sub- 1826–1833, 2009. typing, morphological examination, immunochemistry, and [13] M. Khashab, M. Mokadem, J. Dewitt et al., “Endoscopic EGFR mutation analysis with EUS-FNA samples. With our ultrasound-guided fine-needle aspiration with or without simple but highly effective adjustments in standard EUS- flow cytometry for the diagnosis of primary pancreatic lymphoma—a case series,” Endoscopy, vol. 42, no. 3, pp. 228– FNA, the diagnostic yield could be increased and the need 231, 2010. for subsequent surgical and radiological sampling could be [14] J. G. J. V. Aerts, M. Delahaye,T.H.van der Kwast, B. Davidson, eliminated. H. C. Hoogsteden, and J. P. van Meerbeeck, “The high post- test probability of a cytological examination renders further References investigations to establish a diagnosis of epithelial malignant [1] S.R.Puli, J. B. K. Reddy, M. L. Bechtold et al., “Endo- pleural mesothelioma redundant,” Diagnostic Cytopathology, vol. 34, no. 8, pp. 523–527, 2006. scopic ultrasound: it’s accuracy in evaluating mediastinal lymphadenopathy? A meta-analysis and systematic review,” World Journal of Gastroenterology, vol. 14, no. 19, pp. 3028– 3037, 2008. [2] I. Storch, M. Shah, R. Thurer, E. Donna, and A. 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Endoscopic Ultrasound Fine Needle Aspiration in the Diagnosis of Lymphoma

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Hindawi Publishing Corporation
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Copyright © 2011 Koen Creemers et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Abstract

Hindawi Publishing Corporation Journal of Oncology Volume 2011, Article ID 785425, 4 pages doi:10.1155/2011/785425 Case Report Endoscopic Ultrasound Fine Needle Aspiration in the Diagnosis of Lymphoma Koen Creemers, Olaf van der Heiden, Jan Los, Joost van Esser, David Newhall, Remco S. Djamin, and Joachim G. Aerts Amphia Hospital, Molengracht 21, 4818 CK Breda, The Netherlands Correspondence should be addressed to Joachim G. Aerts, jaerts@amphia.nl Received 8 October 2010; Revised 9 January 2011; Accepted 19 February 2011 Academic Editor: David Ball Copyright © 2011 Koen Creemers et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In recent years, endoscopic ultrasound techniques with Fine Needle Aspiration (FNA) have become an increasingly used diagnostic aid in the differentiation of mediastinal lymphadenopathy. Endobronchial ultrasound (EBUS) and endoesophageal ultrasound (EUS) are now available for clinicians to reach mediastinal and paramediastinal masses using a minimally invasive approach. These techniques are an established component for diagnosing and staging lung cancer and their benefit in the diagnosis of lymphoma’s has been highlighted in a number of case studies. However, the lack of tissue architecture obtained by cytological FNA specimens decreases the diagnostic accuracy for benign causes of thoracic lymphadenopathies, lymphomas, and histopathological subtyping of lung cancer. Accordingly, our study group have adapted the FNA sampling technique, resulting in tissue fragments that can be used for histopathological examinations. As an illustration, we report a case of follicular non-Hodgkin lymphoma, diagnosed on tissue fragments obtained by adjusted EUS FNA. We believe that this relatively simple adjustment to routine FNA sampling can help to overcome the diagnostic limitations inherent in cytology obtained by routine FNA. 1. Background of studies examining epithelial malignancies have been conducted that highlight this predicament [1–3]. The pathophysiology of mediastinal lymphadenopathy is It has been suggested that the generation of significant multifactorial with both benign and malignant diseases caus- false negative results can be explained by sampling error and detection error. For example, the correct node is sampled ing their presentation. Examples of benign diseases include reactive lymphadenopathy and granulomatous diseases (e.g., but the material obtained does not represent the underlying sarcoidosis, tuberculosis, histoplasmosis). Malignant diseases disease or the radiological suspicious node is not identified correctly during ultrasonography. In addition, only cytology include metastatic spread of carcinoma to the lymph nodes or localisation of lymphoma. is collected when EUS FNA is used and in the specific differ- Recently, the diagnosis of mediastinal lymphadenopathy ential diagnosis of lymphoma, due to the need to perform has been achieved with a combination of endoscopic ultra- immunohistopathological examinations, histological sam- sound and Fine Needle Aspiration (FNA) techniques [1]. pling is preferential [4]. Moreover, in nonsmall cell lung can- Clinicians are able to reach mediastinal and paramediastinal cer, the histopathological subtyping has been recognised as of lymphomas/ masses with endobronchial ultrasound (EBUS) pivotal importance in the choice of chemotherapeutic agents. and endoesophageal ultrasound (EUS) using a minimally In addition, studies have shown how EUS [5]and EBUS [6] can be applied for the diagnosis of lymphoma. Some cen- invasive approach. However, the combination of imaging and FNA tissue sampling is essential because imaging alone is not tres usetrue cut biopsies to acquirelarger tissuespecimens, sufficient for a diagnosis [1]. although it should be noted that this was not incorporated Nonetheless, despite a high diagnostic yield using this into general clinical practice [6]. Some centres also demon- combination technique, the significant number of false nega- strated the net benefit of flow cytometry in increasing the tive findings in the cytology remains problematic. A number diagnostic yield, particularly for lymphoma. However, for a 2 Journal of Oncology multiplicity of reasons this technique cannot be incorporated rial. From this material, there were small tissue fragments into the general handling of all FNA samples [6]. on which the pathologist was able to perform histological Therefore, in the case of mediastinal lymphadenopathy analysis and immunohistochemical tests clearly showing and a suspicion of a lymphoma, current medical practice localisation of the follicular lymphoma. dictates that a surgical biopsy is the preferred diagnostic approach. However, mediastinoscopy is a more invasive pro- 3. EUS Procedure cedure with a higher complication rate when directly com- pared to endoscopic ultrasound techniques [7]. EUS was performed according to published guidelines with Consequently, adaptations to standard EUS-FNA have an Olympus EUS EXERA ultrasonic video gastroscope GF- been developed in order to increase the diagnostic yield UC160P-OL5. After identification of the suspected lymph of EUS-FNA. Subtle adaptations in both our EUS proce- node, the FNA needle was introduced (model Olympus NA- dure and in our handling of samples have allowed us to 200H-8022 needle width 22 Gauge). Following infiltration of obtain histology-like material from EUS-FNA, from which the node, the mandarin was pulled back and in excess of immunohistochemistry can be performed. With the aid of 15 passes into the lymph node were performed before the a case study, we illustrate how we were able to diagnose the needle was finally retracted. The mandarin was reintroduced localisation of a follicular non-Hodgkin lymphoma (NHL) to push any collected tissue fragments, that possessed a on tissue fragments obtained using EUS FNA. “worm-like” appearance, into a cytorich red (CRR) medium. Finally, after the mandarin was removed again, the remaining droplets were collected on glasses by clearing the needle with 2. Case Report air, using a 20cc syringe. A 64-year-old female patient with a 30-pack-year smoking This procedure resulted in the collection of: history was admitted to the outpatient clinic for analyses of (i) “Worm-like” coherent material in the CRR, a hilar and mediastinal lymphadenopathy. Her past medical history revealed a follicular NHL stage IVa diagnosed in (ii) Air dried smeared droplets on glasses, and 2003. This disease presented with iliac lymphadenopathy (iii) Cytospin fluid after the “worm-like” material was and bone marrow localisation. She was initially treated with extracted. palliative radiotherapy for lymphoma in the left iliac area. In 2007, there was clinical evidence of disease progression These materials were then processed and investigated as based on palpable lymph nodes in the right iliac and the left- follows sided supraclavicular areas. A computed tomography (CT) (1) Cytological examination was performed on II and of the abdomen also showed para-aortal lymphadenopathy. She underwent palliative radiotherapy on the right iliac III, using May Grunwald-Giemsa colouring and lymphoma to treat its symptomatic mass effect. In September Shandon EZ Megafunnel (Thermo Fisher) method with Papanicolaou colouring, respectively. 2008, she was admitted for dyspnoea and a loss of appetite and a subsequent CT scan of the thorax, neck, and abdomen (2) The “worm-like” fragments in CRR (I) were added was performed. The CT scan revealed massive left hilar to liquid agar, compressed on the bottom of a mold lymphadenopathy with compression of the surrounding and left for solidification. The solidified agar was then bronchial and venous structures and mediastinal (subcari- taken out from the mold and encased in a cassette. nal) and parasternal lymphadenopathy with a small left The cassette was further processed according to rou- sided pleural effusion. A subsequent positron emission tine histological investigative techniques. The follow- tomography (PET) scan showed multifocal disease activity in ing day, two slices were made at two different levels the pathological areas corresponding to the previous CT scan allowing standard and supplemental histological and and low disease activity in the para-aortal region. Nonethe- immunohistochemical staining to be performed. less, despite these extensive radiological investigations it was not possible to differentiate between progression of NHL or Our approach represents a subtle but significant adapta- another disease pathology such as an underlying primary tion to the routine handling of this material as a smear is not lung carcinoma. made from the “worm-like” fragment. By using our modified Accordingly, a bronchoscopy was performed that showed technique, we can generate two important advantages; firstly, a slightly oedematous bronchial mucosa in the left lower it allows optimal use of the collected material including lobe. Brushing, bronchial lavage and endobronchial biopsies histological investigation. Secondly, it leads to a reduction of the oedematous mucosa with a transbronchial needle aspi- in processing time owing to a reduction in the number of ration (TBNA) of the subcarinal node and a pleuracentesis smears that are made. were performed. Further sampling of the left sternal mass We opted to collect the material in CRR and not dire- with transthoracic FNA was also conducted but all these tests ctly in formalin solution for the following reasons: firstly, failed to deliver a diagnosis. due to the characteristics of CRR (fixation, haemolysis, Therefore, it was deemed necessary to perform an EUS- denaturation of proteins, and compatibility with immuno- FNA with material being obtained from the subcarinal histochemical staining), a specimen of superior quality could lymphoma location 7 and from the possible primary process. be obtained. Secondly, cytological examination could be Both aspirations delivered macroscopic “worm-like” mate- performed on the diagnostic material in the CRR, after the Journal of Oncology 3 Figure 1: True tissue fragment of the material acquired with Figure 3: Immunohistochemical stain CD79A (HE 400×). Micro- adjusted EUS-FNA (HE 200×). scopical report: histological tissue fragments are presented. The image is determined by small lymphatic cells with irregular shaped nucleoli. The chromatine-pattern is enlarged. There is indentation on multiple sides. Some B-lymfoblasts are seen (CD79A/20). The total image is representative of a follicular non-Hodgkin lymphoma. such as sarcoidosis [9]. However, the lack of tissue architec- ture obtained by cytological FNA specimens decreases the diagnostic accuracy, and accordingly suggestions have been proposed to alleviate this problem. One current suggestion is that a true cut needle for obtaining tissue fragments (TCB) should be used. In a small study, Storch et al. [2] demonstrated in a subgroup of 19 patients with a benign disorder, that the combination of FNA and TCB achieved 100% diagnostic accuracy and that Figure 2: True tissue fragment of the material acquired with TCB was superior over FNA (89% versus 68%, resp.) in an adjusted EUS-FNA (HE 400×). accurate diagnosis. Although the use of TCB to retrieve larger histological biopsies has been described in the thorax, it is a “worms” were removed, using the Shandon EZ Megafunnel. new technique and large trials have not yet been conducted This processisparticularly advantageousasitisboth quick that provide satisfactory evidence that this approach is safe. and the equipment is relatively simple to use. Conversely, Evidence for its efficacy and safety has only been provided using an alternative formalin solution would have made the by a few small trials and case reports. Nonetheless, arguably process markedly more complicated. the greatest limitation in EUS-TCB is the necessity that However, it should be noted that in our aforementioned the mediastinal mass must be larger than two centimetres example, the cytological material referred to in II and III did without vascular involvement. Masses that fall outside these not contribute to the diagnosis of lymphoma. Nonetheless, stipulated prerequisitions cannot yield a suitable sample histological tissue fragments that were intact and possessed using EUS-TCB but significantly it can be achieved using structural integrity, as illustrated in Figures 1, 2,and 3,were EUS-FNA. obtained from step I coherent material in CRR. Therefore, a Further techniques to increase the diagnostic yield are subsequent diagnosis of follicular non-Hodgkin lymphoma centred on the handling of the samples. In our approach, could be made after immunohistochemical staining. smears are not created and instead the samples are trans- ferred directly to a medium in an effort to maintain tissue architecture. Moreover, these “worms” that are collected 4. Discussion using our technique can then be used for histopathological Endoscopic ultrasound is a well-established component in analysis. To retrieve these “worms”, the number of needle the diagnosis of lung cancer with most clinicians utilising passes per puncture into the abnormal structure is of EUS as part of their routine diagnostic testing. Furthermore, importance. It was determined that the optimum number of a growing body evidence highlights the additional benefits passes per puncture to obtain the “worm-like” structures was of EBUS [8]. The application of EUS provides minimally at least 10, as less than 10 passes failed to generate sufficient invasive access to the lymph nodes in the posterior medi- data (results not shown). However, it is important to realise astinum, especially on the left side (Mountain-Dressler 2, 4, that a degree of structural integrity is required to collect 5, 6, 7, 8, 9.) and the left-sided adrenal gland. Recent studies the histological material. In necrotic areas, for example, this have shown a high accuracy in diagnosing mediastinal integrity is lacking and it is not always possible to obtain the lymphadenopathy of unknown origin and benign disorders required “worm-like” material that is needed for analysis. 4 Journal of Oncology Theoretically, more passes could be associated with a Trucut biopsy in thoracic lesions: when tissue is the issue,” Surgical Endoscopy and Other Interventional Techniques,vol. higher complication rate but this was not found in our 22, no. 1, pp. 86–90, 2008. series. Previously, we have performed over 300 procedures [3] K. G. Tournoy, M. M. Praet, G. van Maele, and J. P. van Meer- using this technique and only 1 complication occurred and beeck, “Esophageal endoscopic ultrasound with fine-needle this was believed to be related to the puncture itself rather aspiration with an on-site cytopathologist: high accuracy for than the number of passes [10]. Additional testament to the the diagnosis of mediastinal lymphadenopathy,” Chest,vol. safety of this technique is provided in another paper that we 128, no. 4, pp. 3004–3009, 2005. have published that examined the capability of performing [4] R. S. Hoda, L. Picklesimer, K. M. Green, and S. Self, spectroscopy during EUS-FNA. The results showed that no “Fine-needle aspiration of a primary mediastinal large B-cell adverse events were experienced by our study population lymphoma: a case report with cytologic, histologic, and flow [11]. cytometric considerations,” Diagnostic Cytopathology, vol. 32, In the last year, a number of reports on the diagnostic no. 6, pp. 370–373, 2005. [5] A.Ribeiro, D.Pereira,M.P. Escalon, ´ M. Goodman, and accuracy of EUS and EBUS in the diagnosis of lymphoma G. E. Byrne Jr., “EUS-guided biopsy for the diagnosis and have been published [5, 6, 12, 13]. As large randomized classification of lymphoma,” Gastrointestinal Endoscopy,vol. studies are lacking, the interpretation of the results and 71, no. 4, pp. 851–855, 2010. diagnostic yield is confounded by the incidence in the study [6] D. P. Steinfort, M. Conron, A. Tsui et al., “Endobronchial population [14]. ultrasound-guided transbronchial needle aspiration for the Diagnostic yield is also determined in part by the evaluation of suspected lymphoma,” Journal of Thoracic protocols and techniques implemented by the individual Oncology, vol. 5, no. 6, pp. 804–809, 2010. institution. For example, if “on-site” cytology is performed, [7] A.Ernst,D.Anantham, R. Eberhardt, M. Krasnik, and F. in the event that lymphoma is suspected, additional punc- J. F. Herth, “Diagnosis of mediastinal adenopathy-real-time tures should be performed to allow for subsequent flow endobronchial ultrasound guided needle aspiration versus cytometry investigations. mediastinoscopy,” Journal of Thoracic Oncology,vol. 3,no. 6, However, as we have shown that our diagnostic yield pp. 577–582, 2008. [8] R. C.Rintoul,K. G. Tournoy,H.ElDaly etal., “EBUS-TBNA is increased by extracting and sampling the “worm-like” for the clarification of PET positive intra-thoracic lymph material, we no longer perform on-site cytology. nodes-an international multi-centre experience,” Journal of In our case study, conventional diagnostic techniques Thoracic Oncology, vol. 4, no. 1, pp. 44–48, 2009. would have required the use of CT-guided transthoracic [9] K. G.Tournoy, A.Bolly,J.G.Aerts et al., “The value biopsy for sampling the mass in the left lower lobe of the of endoscopic ultrasound after bronchoscopy to diagnose lungs and mediastinoscopy to investigate the mediastinal thoracic sarcoidosis,” European Respiratory Journal, vol. 35, no. lymphomas. Therefore, our modified technique not only 6, pp. 1329–1335, 2010. eliminates the need for these separate procedures, but it also [10] J. G. J. V. Aerts, J. Kloover, J. Los, O. van der Heijden, A. allows both sites to be sampled in one session. Janssens, and K. G. Tournoy, “EUS-FNA of enlarged necrotic The case study provided illustrates the use of our modi- lymph nodes may cause infectious mediastinitis,” Journal of fied technique in diagnosing NHL but its use can be extended Thoracic Oncology, vol. 3, no. 10, pp. 1191–1193, 2008. to provide diagnostic subtyping of nonsmall cell lung cancer. [11] S. C. Kanick, C. van der Leest, R. S. Djamin et al., “Char- acterization of mediastinal lymph node physiology in vivo This application is important because it allows the optimum by optical spectroscopy during endoscopic ultrasound-guided treatment regime for patients to be determined. Our adapted fine needle aspiration,” Journal of Thoracic Oncology, vol.5,no. technique is now currently utilised in a number of other 7, pp. 981–987, 2010. hospitals and this has generated similar results. We now [12] M. Al-Haddad, M. S. Savabi, S. Sherman et al., “Role of endo- have a small series of 6 patients who were diagnosed with scopic ultrasound-guided fine-needle aspiration with flow lymphoma; using this technique, no further investigations cytometry to diagnose lymphoma: a single center experience,” were deemed necessary. In a series of 92 lung cancer patients, Journal of Gastroenterology and Hepatology, vol. 24, no. 12, pp. 75% of samples could be investigated for histological sub- 1826–1833, 2009. typing, morphological examination, immunochemistry, and [13] M. Khashab, M. Mokadem, J. Dewitt et al., “Endoscopic EGFR mutation analysis with EUS-FNA samples. With our ultrasound-guided fine-needle aspiration with or without simple but highly effective adjustments in standard EUS- flow cytometry for the diagnosis of primary pancreatic lymphoma—a case series,” Endoscopy, vol. 42, no. 3, pp. 228– FNA, the diagnostic yield could be increased and the need 231, 2010. for subsequent surgical and radiological sampling could be [14] J. G. J. V. Aerts, M. Delahaye,T.H.van der Kwast, B. Davidson, eliminated. H. C. Hoogsteden, and J. P. van Meerbeeck, “The high post- test probability of a cytological examination renders further References investigations to establish a diagnosis of epithelial malignant [1] S.R.Puli, J. B. K. Reddy, M. L. Bechtold et al., “Endo- pleural mesothelioma redundant,” Diagnostic Cytopathology, vol. 34, no. 8, pp. 523–527, 2006. scopic ultrasound: it’s accuracy in evaluating mediastinal lymphadenopathy? A meta-analysis and systematic review,” World Journal of Gastroenterology, vol. 14, no. 19, pp. 3028– 3037, 2008. [2] I. Storch, M. Shah, R. Thurer, E. Donna, and A. 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