Endobronchial Ultrasound and Lymphoproliferative Disorders: A Retrospective Study

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1 Endobronchial Ultrasound and Lymphoproliferative Disorders: A Retrospective Study Seher Iqbal, MD,* Zachary S. DePew, MD,* Paul J. Kurtin, MD, Anne-Marie G. Sykes, MD, Geoffrey B. Johnson, MD, Eric S. Edell, MD, Thomas M. Habermann, MD, and Fabien Maldonado, MD Division of Pulmonary and Critical Care Medicine, Department of Laboratory Medicine and Pathology, Department of Diagnostic Radiology, and Department of Hematology, Mayo Clinic, Rochester, Minnesota Background. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been shown to have excellent diagnostic performance for mediastinal staging of lung cancer. The utility of EBUS- TBNA for the diagnosis of lymphoproliferative disorders involving the mediastinum or hila, or both, is unclear. Methods. A retrospective analysis was completed of all patients diagnosed with a lymphoproliferative disorder involving the mediastinum or hila, or both, who underwent an EBUS-TBNA within 3 months of the diagnosis. Results. Sixty-five patients with mediastinal or hilar lymph node, or both, involvement of their lymphoproliferative disorder underwent EBUS-TBNA within 3 months of their diagnosis. The initial EBUS-TBNA was nondiagnostic in 34 (52%), 11 were subsequently diagnosed by mediastinoscopy, and the remaining 23 were diagnosed by biopsy of a distant site, with involvement of the mediastinum or hilum assumed from preestablished radiographic criteria. A EBUS-TBNA specimen in 31 patients (48%) was interpreted as consistent with or suspicious for a lymphoproliferative disorder. The overall sensitivity of EBUS-TBNA for establishing a definitive diagnosis was 25 of 65 (38%). The sensitivity was lower for new patients, at 7 of 32 (22%), and better for patients with recurrence, at 18 of 33 (55%). Conclusions. Contrary to previous studies, our findings suggest that EBUS-TBNA does not provide sufficient diagnostic material for accurate lymphoproliferative disorder subtyping in a significant number of patients and performs especially poorly when evaluating new patients. Mediastinoscopy should still be considered as the initial diagnostic procedure of choice when the clinical suspicion for a lymphoproliferative disorder is high, unless the patient is being evaluated for a recurrence of prior disorder. (Ann Thorac Surg 2012;94:1830 4) 2012 by The Society of Thoracic Surgeons Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is increasingly used in the initial evaluation of isolated mediastinal and hilar lymphadenopathy. EBUS-TBNA has been shown to have excellent diagnostic accuracy for the mediastinal staging of non-small cell lung cancer and to be cost-beneficial compared with mediastinoscopy as an initial approach in this context [1 8]. EBUS-TBNA has also been shown to have excellent performance characteristics for the diagnosis of benign etiologies of mediastinal lymphadenopathy, including sarcoidosis [5, 9 11]. The utility of EBUS-TBNA for the diagnosis of lymphoproliferative disorders affecting the mediastinal and hilar lymph nodes is less clear. For the purposes of this report, the term lymphoproliferative disorder (LPD) applies to B-cell chronic lymphocytic leukemia, T-cell prolymphocytic leukemia, Hodgkin lymphoma, and malignant lymphomas with B-cell and T-cell lineage. The sensitivity of EBUS-TBNA for the diagnosis of LPDs has been reported between 57% and 91% [12 14]. As such, it has been suggested that EBUS-TBNA could be Accepted for publication Aug 17, *These authors contributed equally to this manuscript. Address correspondence to Dr Maldonado, Mayo Clinic, Division of Pulmonary and Critical Care Medicine, 200 First St SW, Rochester, MN 55905; maldonado.fabien@mayo.edu. considered as the initial diagnostic approach in patients with isolated mediastinal or hilar lymphadenopathy suspicious for a LPD. However, in addition to being limited by small sample size, 20% to 25% of the patients diagnosed with a LPD by EBUS-TBNA in these studies required subsequent analysis of a surgical biopsy specimen to establish a specific histologic diagnosis. Although a presumptive diagnosis of a LPD can be established in most patients by EBUS-TBNA, the current standard of care for lymphoma treatment is based on diagnosis and classification by World Health Organization criteria [15]. This can only be established when sufficient tissue is available for pathologic evaluation. To clarify the utility of EBUS-TBNA in this setting, we reviewed our institutional experience with use of EBUS-TBNA for the diagnosis of LPDs. The purpose of this study was to evaluate the adequacy of specimens obtained by EBUS-TBNA for the specific diagnosis of a LPD in a cohort of patients ultimately diagnosed with mediastinal or hilar involvement by a LPD. Patients and Methods This study was approved by the Institutional Review Board of the Mayo Clinic College of Medicine (IRB 2012 by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc

2 Ann Thorac Surg IQBAL ET AL 2012;94: EBUS-TBNA FOR LYMPHOPROLIFERATIVE DISEASES # ). The Mayo Clinic Lymphoma Database identified all patients diagnosed with a LPD from June 2006 through August This cohort was crossreferenced with our EBUS-TBNA database to determine which of these patients had an EBUS-TBNA procedure with sampling of mediastinal or hilar lymphadenopathy, or both, performed within 3 months of their diagnosis. Of the 3,040 patients who were diagnosed with a LPD during the inclusion timeframe, 129 (4%) had undergone evaluation with EBUS-TBNA within 3 months of the diagnosis for isolated mediastinal or hilar lymphadenopathy, or both. A retrospective analysis of their medical records was completed with extraction of the following data: demographics, history of malignancy, location of all lymph nodes sampled during EBUS-TBNA, and pathologic (histologic/cytologic) results from the EBUS-TBNA and all subsequent procedures. Nodal stations were initially defined according to the 1997 International Staging System until the updated International Association for the Study of Lung Cancer lymph node map was published in 2009, which was used thereafter [16, 17]. Review of the electronic medical records determined that 65 of the 129 patients (50%) had an active diagnosis of a LPD based on mediastinal or hilar lymphoid tissue acquired during EBUS-TBNA or another surgical intervention. For a more conservative analysis, mediastinal or hilar lymph nodes from patients diagnosed on the basis of biopsy specimens from sites other than the chest were assumed to be involved if considered highly suspicious by radiographic criteria (see below). The remaining 64 patients (50%) had a history of LPD, negative EBUS- TBNA, and no subsequent biopsy specimens demonstrating evidence of recurrent disease. These patients remained in remission after continued surveillance for 1 year after EBUS-TBNA. Radiographic Review All relevant imaging studies completed within 6 months of EBUS-TBNA were retrospectively reviewed by 2 radiologists, 1 with expertise in thoracic radiology (A.G.S.) and 1 with expertise in nuclear radiology (G.B.J). The diagnostic quality of all reviewed radiographic studies was adequate based on criteria that included subjective image quality, slice thickness, positron emission tomography-computed tomography (PET-CT) protocol variables, and patient serum glucose level. CT imaging features considered benign included a normal fatty hilum and nodular calcification (unless previously irradiated). CT imaging features considered malignant included a short-axis dimension exceeding 10 mm, focal low density suggestive of necrosis, surrounding fat infiltration suggestive of pericapsular invasion, and hilar lymph nodes with convex margins that deformed the surrounding structures. For PET-CT imaging, a modified London criterion was used where scores of 1, 2, or 3 were considered negative, and scores of 4 or 5 were considered positive for malignancy [18]. PET-CT features considered benign included fluorodeoxyglucose uptake at or below the level of surrounding 1831 vascular structures, a standardized uptake value maximum of less than that of the patient s normal liver and greater than 70 Hounsfield units on the CT component. Fluorodeoxyglucose uptake on PET imaging was required to be focal in nature with a corresponding CT imaging abnormality to be considered positive for malignancy. Owing to the potential for artifactual alterations in fluorodeoxyglucose uptake, clinical discretion was used when (1) EBUS-TBNA was performed within 7 days before PET-CT imaging, (2) chemotherapy was given within 14 days before PET-CT imaging, (3) patients were on continued steroid therapy, or (4) patients had received previous radiation to the area in question. Each lymph node region sampled by EBUS-TBNA was evaluated separately and defined as involved by a LPD if it met the above mentioned criteria by CT or PET-CT imaging. Pathologic Review All EBUS-TBNA tissue samples from cases determined to represent a diagnosis of a LPD by aforementioned criteria were reviewed without knowledge of clinical or radiographic data by an experienced hematopathologist (P.J.K.) to determine if (1) the acquired tissue was sufficient to establish the diagnosis of a specific LPD and (2) if subtyping of the LPD by World Health Organization lymphoma classification criteria was sufficient to independently determine appropriate therapeutic management. Materials reviewed included cytology preparations and tissue sections stained with hematoxylin and eosin. Immunoperoxidase stains, performed by standard methods, were applied in selected cases. Primary antibodies directed against the following antigens were used: cluster of differentiation (CD) 2, CD3, CD4, CD5, CD7, CD8, CD10, CD15, CD20, CD23, CD30, CD43, CD45, activin receptor-like kinase-1, paired box protein-5, and T-cell leukemia/lymphoma 1. Because tissue was limited, the antibody panels selected for each case reflected the morphologic differential diagnosis and were not uniformly applied to each case. All lymphomas and leukemias were classified by the World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues criteria [15]. We compared the review pathology results with the initial pathology results reported in the electronic medical records. EBUS-TBNA Procedures All procedures were completed using conscious sedation. Patients were intubated with an uncuffed wire spiral endotracheal tube over a conventional flexible videobronchoscope (Olympus BF-P160/BF-Q180, Olympus America Inc, Center Valley, PA), which was then used for routine airway inspection before EBUS-TBNA. The conventional bronchoscope was then exchanged for the linear-array ultrasonic bronchoscope (Olympus BF- UC160F-0L8). Comprehensive and systematic ultrasound examinations of the mediastinum and hila were performed, followed by TBNA of lymph nodes, at the discretion of the proceduralist, with a 21-gauge needle. All biopsy specimens were obtained with a minimum of

3 1832 IQBAL ET AL Ann Thorac Surg EBUS-TBNA FOR LYMPHOPROLIFERATIVE DISEASES 2012;94: Fig 1. Diagram illustrates the procedure by which diagnosis was made, the number of recurrent cases, and final diagnosis. (BCL B-cell lymphoma; EBUS-TBNA endobronchial ultrasound-guided transbronchial needle aspiration; HL Hodgkin lymphoma; LPD lymphoproliferative disease; MALT mucosa associated lymphoid tissue lymphoma; PTLD posttransplant lymphoproliferative disorder; SLL/CLL small lymphocytic lymphoma/chronic lymphocytic leukemia; TCL T-cell lymphoma.) three needle passes, unless two needle passes resulted in visible core obtained with each pass [19]. Flow cytometry was not used to favor histologic evaluation because subtyping of LPDs is not possible by flow cytometry. Molecular genetic analysis and fluorescence in situ hybridization were performed when appropriate. Results Of the 3,040 patients who were diagnosed with a LPD during the inclusion time frame, 129 (4%) had undergone evaluation with EBUS-TBNA within 3 months of the diagnosis for isolated mediastinal or hilar lymphadenopathy, or both. Of these patients, 65 were considered to have mediastinal or hilar involvement, or both, by the LPD based on histologic lymph node examination (n 42) or a combination of other biopsy specimens and positive radiographic criteria (n 23). A history of a LPD was present in 30 of these patients (46%). All EBUS- TBNA results and final diagnoses are shown in Figure 1. A review of the medical records revealed that the EBUS-TBNA biopsy specimen was nondiagnostic in 34 of the 65 patients (52%), and 11 (32%) underwent mediastinoscopy to establish the diagnosis. Of these 11 patients, 8 (73%) had a new diagnosis of a LPD, and the remaining 3 had a recurrence of a prior LPD. Of the remaining 23 of 34 patients (68%), the diagnosis was determined by analysis of a specimen from a biopsy performed at a distant site, and mediastinal or hilar involvement, or both, was assumed from the previously established radiographic criteria. A new diagnosis of a LPD was established in 15 of 23 patients (65%), with the remaining 8 (45%) representing recurrence of a prior LPD. An endobronchial mucosal biopsy specimen was obtained in 8 patients at the time of the bronchoscopy that established the diagnosis, despite a negative EBUS- TBNA. Other biopsy sites included the pancreas (n 1), jejunum (n 1), liver (n 1), colon (n 1), bone marrow (n 1), and lymph nodes in the cervical (n 4), inguinal (n 3), or axillary (n 2) regions. One patient demonstrated recurrent disease at autopsy. In 31 of 65 patients (48%), an EBUS-TBNA specimen was interpreted as consistent with or suspicious for a LPD. Of these 31 patients, the specimen was sufficient for definitive diagnosis in 25 (81%), and 18 of these 25 (72%) had a history of a LPD and were assumed to have the same subtype as before. The remaining 6 patients (19%) required subsequent mediastinoscopy, 2 for further subtyping of the LPD and management guidance, and 4 to establish a diagnosis of a LPD after detection of atypical or suspicious cells during EBUS-TBNA. If only the patients for whom pathologic tissue confirmation was available are considered (EBUS-TBNA or mediastinoscopy), 25 of 42 (60%) had specimens acquired by EBUS-TBNA that established a definitive diagnosis of a specific LPD, whereas the remainder required mediastinoscopy. In contrast, if we also include the 23 patients who met the radiographic criteria for mediastinal or hilar involvement, or both, only 25 of 65 patients (38%) had EBUS-TBNA specimens sufficient for definitive diagnosis. Upon independent review of the slides, discordance occurred between initial and blinded review in 6 patients for whom the reviewing pathologist determined that the EBUS-TBNA specimens were insufficient for diagnosis of a LPD. Four of these patients had a history of a LPD, were assumed to have recurrence of their prior subtype, and were treated accordingly. One of the remaining 2 patients was diagnosed on the basis of molecular genetic evidence of a clonal immunoglobulin gene rearrangement, without histologic or phenotypic findings of lymphoma. This patient underwent subsequent mediastinoscopy for de-

4 Ann Thorac Surg IQBAL ET AL 2012;94: EBUS-TBNA FOR LYMPHOPROLIFERATIVE DISEASES finitive diagnosis and treatment. The other patient underwent a concurrent endobronchial mucosa biopsy during the EBUS-TBNA, and the specimen demonstrated B-cell lymphoma that likely influenced the initial EBUS- TBNA pathologic results. Therefore, our expert blinded review suggests that in the absence of any clinical history or radiographic data, the overall sensitivity of EBUS- TBNA for accurately diagnosing a LPD is 19 of 65 (29%). Comment Contrary to previous studies suggesting that EBUS- TBNA may be an appropriate initial investigation for the diagnosis of isolated mediastinal or hilar lymphadenopathy suspicious for a LPD, our study demonstrates that EBUS-TBNA does not provide adequate pathologic tissue samples for accurate characterization and subtyping of LPDs in a significant number of cases. Sensitivity of EBUS-TBNA for the definitive diagnosis of a LPD was at best 60% when only cases with pathologic confirmation were taken into account; however, a more conservative analysis, including cases in which involvement of the mediastinum or hila was assumed based on established radiographic criteria, resulted in a sensitivity of only 29%. Furthermore, 62% of patients were exposed to the attendant risks of a subsequent invasive procedure (eg, mediastinoscopy, excisional lymph node biopsy, endoscopy) to establish a definitive diagnosis and guide therapy. In the patients for whom EBUS-TBNA was able to establish a definitive diagnosis of a LPD, 72% were presumed to have a recurrence of a prior established LPD, suggesting that EBUS-TBNA may have limited utility in establishing new diagnoses of LPDs but may have a role in evaluating patients for possible recurrence of a prior LPD. Four of the 6 instances in which a discrepancy was found in the independent blinded pathology review were recurrences, suggesting that clinical history and radiographic data likely influenced the interpretation of the EBUS-TBNA specimen. All of these specimens were noted to have inadequate material, with minimal cellularity accompanied by increased tissue distortion upon independent review. Establishing a new 1833 diagnosis of a LPD is highly dependent on sufficient pathologic tissue samples, which our data would suggest is not routinely attainable by EBUS-TBNA. However, EBUS-TBNA may be a reasonable initial diagnostic tool in patients with a history of a prior LPD when the detection of malignant cells is usually sufficient to establish recurrence and guide therapy. Three previous smaller studies have suggested a higher overall sensitivity from 57% to 91% for EBUS- TBNA in the diagnosis of LPDs [12 14]. However, the analysis published by Kennedy and colleagues [12] reporting a sensitivity of 91% in 11 patients did not account for the fact that 2 of these patients required mediastinoscopy for subtyping of their LPD. A more conservative analysis of their data would suggest a sensitivity of 8 of 11 (73%) for definitive diagnosis of a LPD by EBUS-TBNA. In addition, 8 of their 11 patients had a history of a LPD. This was similar in the study by Marshall and colleagues [13], in which 6 of the 8 patients definitively diagnosed with a LPD by EBUS-TBNA were recurrent cases. In another study, by Steinfort and colleagues [14], only 2 of the 21 patients diagnosed with a LPD by EBUS-TBNA were recurrent; however, the reported overall sensitivity in their study was lower, at 57%. Our overall sensitivity of 38% for all patients is lower than in these reports. However, our sensitivity for diagnosing recurrent cases of LPDs using EBUS-TBNA alone was 18 of 33 (55%), which compares favorably with the prior reports predominately composed of patients with recurrence. However, our sensitivity for diagnosing new LPDs was only 7 of 32 (22%), suggesting that EBUS-TBNA is not the procedure of choice for initial evaluation of patients in whom there is significant clinical suspicion for a LPD involving the mediastinum or hilum (Fig 2). This is further supported by a recent study published by Navani and colleagues [20] reporting a sensitivity of only 33% for the definitive diagnosis of lymphoma involving the mediastinum, although the low number of patients with lymphoma in that study arguably precludes definitive conclusions [21]. We acknowledge several limitations to our study. First, this retrospective analysis limited the study to patients Fig 2. Diagram illustrates the method by which diagnosis was made for new vs recurrent cases. (Dx diagnosis; EBUS-TBNA endobronchial ultrasound-guided transbronchial needle aspiration; LPD lymphoproliferative disease; Med mediastinoscopy.)

5 1834 IQBAL ET AL Ann Thorac Surg EBUS-TBNA FOR LYMPHOPROLIFERATIVE DISEASES 2012;94: who were ultimately diagnosed with LPD on the basis of EBUS-TBNA, mediastinoscopy, or specimens from other biopsies. We could not retrospectively identify all mediastinal or hilar lymphadenopathy suspicious for a LPD, limiting our analysis to sensitivity (and not specificity). However, our primary goal was to determine how often a definitive diagnosis of a LPD precise enough to allow for determination of specific management could be established by EBUS-TBNA. Another limitation is the small sample size of our study. However, even when considering only those patients with mediastinal or hilar tissue confirmation, our study remains the largest series reported. Finally, we did not use flow cytometry routinely when evaluating EBUS-TBNA specimens. The entire tissue specimens were used for histologic assessment and immunohistochemistry. The experience of our hematopathology group has been that this approach optimizes the opportunity for establishing accurate subtyping of LPDs based on morphology and immunoarchitecture in small specimens, a necessity for appropriate therapeutic decision making. In summary, our results suggest that EBUS-TBNA may not provide adequate pathologic specimens in most of the patients with mediastinal or hilar lymphadenopathy in whom a new diagnosis of a LPD is suspected. In our opinion, other alternatives should be considered. Mediastinoscopy, which provides significantly larger pathology specimens, should continue to be considered as the initial diagnostic procedure of choice in these patients. Alternatively, EBUS-TBNA could be considered a suitable alternative when recurrence of a prior LPD is suspected or when the clinical suspicion of a LPD is low. 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