To allocate patients with non small cell lung cancer

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1 SECTION I: LUNG CANCER DETECTION AND ANALYSIS Endobronchial and Endoscopic Ultrasound-Guided Fine-Needle Aspiration: A Must for Thoracic Surgeons Shawn S. Groth, MD, and Rafael S. Andrade, MD Division of General Thoracic and Foregut Surgery, Department of Surgery, University of Minnesota, Minneapolis, Minnesota A thoracic surgeon facile in endobronchial ultrasoundguided fine-needle aspiration (EBUS-FNA) and endoscopic ultrasound-guided fine-needle aspiration (EUS- FNA) can accurately sample mediastinal lymph nodes (MLNs) for histologic assessment of mediastinal adenopathy and for thoracic malignancy staging. Although mediastinoscopy is the gold standard for histologic MLN assessment, EBUS-FNA and EUS-FNA have emerged as useful, less-invasive sampling techniques that offer access to a wider range of MLN stations than mediastinoscopy and can be used to biopsy suspicious lesions within (ie, peribronchial masses) and outside the mediastinum (ie, left adrenal gland masses, liver lesions, and enlarged celiac lymph nodes). The negative predictive value of EBUS-TBNA and EUS-FNA in patients with malignancy is somewhat lower than the negative predictive value of mediastinoscopy. Therefore, we recommend that nonmalignant EBUS or EUS cytologic findings should be confirmed with a surgical MLN biopsy (ie, mediastinoscopy or thoracoscopy) if the pretest probability of malignancy is high. (Ann Thorac Surg 2010;89:S ) 2010 by The Society of Thoracic Surgeons To allocate patients with non small cell lung cancer (NSCLC) to the most appropriate treatment regimen, accurate cancer staging, which includes an assessment for mediastinal lymph node (MLN) metastasis, is essential. Currently, the combination of computed tomography (CT) and positron emission tomography (PET) is the most efficacious method to clinically stage the mediastinum. Integrated PET/CT scans have a sensitivity of 60% to 85%, a specificity of 84% to 94%, and an accuracy of 78% to 96% for screening for MLN metastases [1 5]. However, because of the potential for false-positive or false-negative PET/CT findings, tissue diagnosis is required for all potential surgical candidates, regardless of PET/CT findings. Mediastinoscopy is the gold standard for histologic evaluation of mediastinal adenopathy and for thoracic malignancy staging. As demonstrated by large singleinstitution series, standard cervical mediastinoscopy has excellent sensitivity (86% to 93%), diagnostic accuracy (93% to 96%), and negative predictive value (NPV; 80% to 99%) [6 12]. It is associated with a very low morbidity rate (0.6% to 1.1%) and an extremely low mortality rate (0.05% to 0.2%) [8, 9]. However, mediastinoscopy is invasive and allows access to only a limited number of American Thoracic Society MLN stations (1, 2, 3, 4, and 7) [13]. Consequently, interest is growing in alternative, less-invasive MLN biopsy techniques that provide access to a wider range of MLN stations. Presented at the 2 nd International Bi-Annual Minimally Invasive Thoracic Surgery Summit, Boston, MA, October 9 10, Address correspondence to Dr Andrade, Division of General Thoracic and Foregut Surgery, University of Minnesota, Department of Surgery, MMC 207, 420 Delaware St SE, Minneapolis, MN 55455; andr0119@umn.edu. Transbronchial Needle Aspiration Transbronchial needle aspiration (TBNA) is less invasive than mediastinoscopy and allows access to a wider range of MLN stations (2, 3, 4, 7, 10, and 11) [14, 15]. However, conventional TBNA is performed blindly (without precise knowledge of the location of the MLN being biopsied), resulting in wide variability in diagnostic yield (40% to 75%) and poor sensitivity (17% to 61%), precluding its use as a screening technique for MLN metastases [16 18]. Endobronchial Ultrasound-Guided Fine-Needle Aspiration Recently, endobronchial ultrasound-guided fine-needle aspiration (EBUS-FNA) has generated considerable interest as a simple and precise method to improve the diagnostic yield of conventional TBNA [19 23]. Like conventional TBNA, EBUS-FNA allows histologic assessment of a wider range of MLN stations (2, 3, 4, 7, 10, and 11) than mediastinoscopy (stations 1, 2, 3, 4, and 7). As demonstrated in a randomized clinical trial, EBUS-FNA results in significantly greater diagnostic yield (80%) as compared with conventional TBNA (71%) [20]. Moreover, the development of a linear scanning probe now allows real-time procedure guidance [24 30], resulting in improved sensitivity and accuracy. Drs Groth and Andrade have no conflicts of interest to disclose by The Society of Thoracic Surgeons /$36.00 Published by Elsevier Inc doi: /j.athoracsur

2 S2080 MINIMALLY INVASIVE THORACIC SURGERY SUMMIT 2009 GROTH AND ANDRADE Ann Thorac Surg EBUS/EUS FOR THORACIC SURGEONS 2010;89:S Endobronchial Ultrasound-Guided Fine-Needle Aspiration Technique ANESTHESIA. The method of anesthesia administration (general anesthesia versus conscious sedation) will depend almost entirely on the choice of the bronchoscopist and the patient. We prefer to perform EBUS-FNA under general endotracheal anesthesia. Advantages of using general anesthesia (as compared with conscious sedation) include (1) improved patient comfort during the procedure, (2) less difficulty with oxygenation and ventilation, (3) enhanced ability to thoroughly evaluate the mediastinum, (4) ability to use intermittent apnea to facilitate EBUS-FNA of small paratracheal MLN ( 10 mm), (5) technical ease, and (6) the option to perform any alternative biopsy (ie, mediastinoscopy, thoracoscopy, or transesophageal endoscopic ultrasound-guided fine-needle aspiration [EUS-FNA]) in the same anesthetic setting, if necessary. Disadvantages of general anesthesia include (1) side effects from anesthetic agents (eg, systemic hypotension and nausea), (2) upper airway trauma from intubation, and (3) longer postanesthesia recovery time (as compared with conscious sedation). Because of comorbidities, some patients may not be able to tolerate general anesthesia. However, histologic MLN staging in these patients is of less relevance because these patients are less likely to be candidates for definitive cancer therapy. Ideally, an 8.5-mm (or larger) endotracheal tube (ETT) should be used. In our experience, it is very uncommon (because of the patient s anatomy) not to be able to use this size of an ETT. The size of the ETT is important, as the diameter of the ultrasound bronchofibervideoscope is slightly larger than the diameter of a standard adult fiberoptic bronchoscope. The ultrasound bronchofibervideoscope will fit through an 8-mm ETT. However, because the ultrasound bronchofibervideoscope is 6.2 mm in diameter (leaving little room [1.8 mm] to ventilate the patient), intermittent removal of the bronchoscope may be required for proper ventilation. The bronchoscopist should position the ETT so that the cuff is just below the glottis to allow for good apposition of the bronchofibervideoscope to the tracheal wall. Poor apposition of the bronchofibervideoscope to the tracheal wall will lead to inappropriate ultrasound imaging. On rare occasions, we deflate the ETT cuff and pull it into the glottis to allow for EBUS-FNA of station 2 MLNs. Alternatively, a laryngeal mask airway may be used, which is particularly helpful in patients with station 2 MLNs. Disadvantages of laryngeal mask airways are cost and interference with the option of performing an EUS if needed (because the laryngeal mask airway blocks the hypopharynx). Endobronchial ultrasound-guided fine-needle aspiration can be performed using conscious sedation and topical anesthesia without compromising the diagnostic capacity of EBUS-FNA. In a series of 502 patients, the accuracy of MLN staging using EBUS-FNA was similar whether it was performed under general anesthesia (94.8%) or conscious sedation (94%); the sensitivity was also unaffected by the anesthesia technique (general anesthesia, 95%; conscious sedation, 94%) [24]. BRONCHOFIBERVIDEOSCOPE. At this time, the only available bronchofibervideoscope on the North American market is manufactured by Olympus (Olympus Exera; Olympus Imaging American Inc, Center Valley, PA). This videoscope is equipped with a linear scanning probe, which allows real-time procedure guidance unlike (earlier) radial scanning probes to be performed, thereby allowing accurate access to MLNs. Integrated color Doppler flow acquisition allows easy identification of vascular structures. To improve acoustic coupling and optimize image acquisition, a water-filled balloon can be used. A 22G aspiration needle is used for FNA. TECHNIQUE. The patient s most-recent CT or PET/CT should be available in the operating room for review during EBUS-FNA. To ensure that all MLNs of interest noted on the CT scan are sampled, we measure the short axis of every MLN of interest and compare it with the CT measurement, thereby ensuring that we are sampling the MLN of interest. The ultrasonographic characteristics of the MLN are noted (ie, echogenicity and shape). Once the MLN has been located with the ultrasound probe, we perform an FNA of MLNs from all accessible stations (regardless of the size, echogenicity, and shape of the MLN). Under real-time EBUS guidance, we perform a total of 10 to 15 needle passes (using a 22G needle). Each target MLN is accessed three times to maximize the diagnostic yield [31]. In our experience, we have been able to obtain diagnostic tissue from MLNs as small as 4 mm. If three attempts fail to yield adequate tissue, an alternative MLN biopsy technique (ie, EUS-FNA, mediastinoscopy, thoracoscopy, or thoracotomy) should be performed in the same anesthesia setting if the pretest probability of malignancy is high. LEARNING CURVE. To establish proficiency with EBUS-FNA, the American College of Chest Physicians recommends that initial training should consist of at least 50 supervised EBUS-FNA procedures [32]; the European Respiratory Society and the American Thoracic Society recommend that the first 40 procedures should be supervised [33]. However, we demonstrated that a sensitivity of 96% and accuracy of 98% can be achieved by thoracic surgeons after a learning curve of about 10 procedures [34]. CYTOLOGY OF ENDOBRONCHIAL ULTRASOUND-GUIDED FINE- NEEDLE ASPIRATION SPECIMENS. Although not available at all institutions, we believe that rapid on-site cytology is essential for the safe and expeditious evaluation of NSCLC patients because it facilitates rapid clinical decision making. If the cytology specimen is inadequate or not diagnostic, it allows the surgeon to determine (in the same anesthesia setting) whether additional MLN tissue using EBUS-FNA (or an alternative MLN biopsy technique) is required. Without rapid on-site cytology, there is a risk that the patient could be subject to an additional procedure (and anesthesia) at a later date if the MLN sample is not diagnostic. As determined by the cytologist, the adequacy of cytology specimens is defined by the presence of lymphocytes: 40 lymphocytes per high-powered field or clusters of pigmented macrophages are strong predictors

3 Ann Thorac Surg MINIMALLY INVASIVE THORACIC SURGERY SUMMIT 2009 GROTH AND ANDRADE 2010;89:S EBUS/EUS FOR THORACIC SURGEONS S2081 of an adequate cytology specimen [35]. Indeed, the absence of lymphocytes has a significant negative impact on the NPV of EBUS-FNA specimens [36]. Bronchial epithelial cells in MLN cytology specimens can pose a diagnostic dilemma because their presence can be caused by either bronchial contamination or metastases. Characteristic cytology features that favor contamination (the presence of cilia, normal morphology, cellular uniformity, and absence of mitoses) can be obscured by dysplastic bronchial epithelium, chemotherapy or radiation therapy (which can alter the bronchial epithelial architecture), air-drying, and poor fixation or preservation [35]. Because the learning curve for pathologists can be steep, a cytopathologist experienced with EBUS-FNA is essential to interpret challenging cytology findings [37]. RESULTS. Endobronchial ultrasound-guided fine-needle aspiration is a safe technique for thoracic malignancy staging [28] and assessing mediastinal adenopathy [29]. More than 1,000 EBUS-FNA procedures have now been reported in the literature, all without significant complications [24, 26, 27, 30, 38]. Endobronchial ultrasound-guided fine-needle aspiration is superior to radiographic staging techniques. In a prospective comparative study of 102 NSCLC patients, EBUS-FNA had superior sensitivity, specificity, and diagnostic accuracy as compared with either CT or standalone PET [30]. The superior diagnostic ability of EBUS-FNA for MLN staging in NSCLC patients (as compared with CT and PET) was substantiated in a anther recent report of 100 NSCLC patients with clinical stage I disease; EBUS-FNA detected MLN metastases in 9% of these patients, despite negative CT (all MLNs 10 mm) and PET findings (maximum standardized uptake value 2.5) [39]. Therefore, we recommend sampling all accessible MLN stations (by EBUS-FNA) for all patients, regardless of PET/CT findings. Experienced bronchoscopists have demonstrated that EBUS-FNA is associated with excellent sensitivity (85% to 99%) and diagnostic accuracy (92% to 99%; Table 1) [24 30, 40, 41]. Although these results appear similar to mediastinoscopy, a formal comparison has not been reported in the literature. Nonetheless, despite real-time image guidance for FNA, the NPV (60% to 99%) appears to be lower than that for mediastinoscopy (80% to 99%) [6 12, 24 30]. Consequently, we recommend confirming all negative EBUS-FNA findings if there is sufficient concern for malignant pathologic diagnosis. Endoscopic Esophageal Ultrasound-Guided Fine-Needle Aspiration Endoscopic esophageal ultrasound-guided fine-needle aspiration is another well-established diagnostic procedure that allows access to a wider range of MLN stations (2R, 2L, 4L, 7, 8, and 9) than mediastinoscopy. Furthermore, unlike mediastinoscopy and EBUS, EUS-FNA can be used to biopsy left adrenal gland and hepatic lesions. Experienced operators may also sample MLN station 5 by means of a transpulmonary artery puncture. Technique We perform EUS-FNA after completion of EBUS-FNA with the same EBUS scope and in the same anesthetic setting. The EBUS scope is adequate to image and sample left lobe liver lesions and gastrohepatic and celiac lymph nodes. However, the EBUS scope is not appropriate to sample the left adrenal gland. Patients with a left adrenal mass that require endoscopic biopsy should be evaluated with a formal videoendoscope. As compared with current bronchofibervideoscopes, videoendoscopes offer a wider array of biopsy needles (including core needles). Results A recent systematic review and meta-analysis of 1,201 patients from 18 studies who underwent EUS-FNA for NSCLC staging demonstrated that EUS has a sensitivity of 83% (95% confidence intervals, 78% to 87%) [42].Inour experience, EUS is helpful when access or visualization of MLN stations is difficult by means of EBUS, because the esophagus has a more pliable wall than the tracheobronchial tree and air within the tracheobronchial tree can result in poor transmission of ultrasound waves. Also, EBUS-FNA of MLNs from patients with centrally located squamous cell cancers with widespread airway dysplasia or carcinoma in situ may result in false-positive findings; EUS-FNA avoids that risk. Endobronchial and Endoscopic Esophageal Ultrasound-Guided Fine-Needle Aspiration The combination of EBUS-FNA and EUS-FNA provides near complete mediastinal staging (without a skin incision) and may soon become the standard of care. Several small studies have been published on the use of the combination of EBUS-FNA and EUS-FNA for NSCLC Table 1. Diagnostic Efficacy of Endobronchial Ultrasound-Guided Fine-Needle Aspiration in Patients With Malignancy Author Year N Sensitivity Specificity PPV NPV Accuracy Yasufuku et al [28] % 100% 100% 89.5% 96.3% Herth et al [24] % 100% 100% 14% 94.8% Vincent et al [27] % 100% 100% 97% 98.7% Groth et al [34] % 100% 100% 92.5% 97.8% Omark Petersen et al [41] % 90% Gilbert et al [40] % 100% 100% 80.6% 91.7% NPV negative predictive value; PPV positive predictive value.

4 S2082 MINIMALLY INVASIVE THORACIC SURGERY SUMMIT 2009 GROTH AND ANDRADE Ann Thorac Surg EBUS/EUS FOR THORACIC SURGEONS 2010;89:S staging; excellent sensitivity (93%), NPV (97%), and accuracy (about 100%) have been reported [43, 44]. Unlike pulmonologists and gastroenterologists who perform EBUS or EUS, thoracic surgeons have the unique opportunity to streamline patient care, owing to their ability to perform any necessary additional diagnostic (ie, mediastinoscopy, thoracoscopy, or thoracotomy) or therapeutic procedures (ie, pulmonary resection or chemotherapy port placement) in the same anesthesia setting. We performed at least one additional procedure in 50% of our patients at the same time as EBUS-FNA. Consequently, it is critical for thoracic surgeons to become proficient with both EBUS and EUS. Endobronchial and Endoscopic Esophageal Ultrasound-Guided Fine-Needle Aspiration for Restaging the Mediastinum Patients with resectable sage IIIA (N2) NSCLC who have completed neoadjuvant therapy require mediastinal restaging before final consideration for surgical resection, as patients with residual N2 disease may not benefit from surgery [45, 46]. The current gold standard for restaging the mediastinum is repeat mediastinoscopy. A timetested technique, repeat mediastinoscopy is technically more challenging than initial mediastinoscopy (because of scarring from the initial procedure). Furthermore, as compared with initial mediastinoscopy, repeat mediastinoscopy (after induction therapy) is associated with lower sensitivity (repeat, 29% to 73% versus initial, 86% to 93%) and diagnostic accuracy (repeat, 60% to 85% versus initial, 93% to 96%) [6 12, 47 49]. Because of these limitations of repeat mediastinoscopy, EBUS-FNA is an attractive alternative. In a recent review of 124 NSCLC patients with biopsy-proven N2 disease who completed induction chemotherapy, EBUS-FNA had a sensitivity of 76% (versus 95% for initial EBUS- FNA), an NPV of 20% (versus 14% for initial EBUS-FNA), and a diagnostic accuracy of 77% (versus 95% for initial EBUS-FNA) [24, 50]. Although neoadjuvant therapy reduces the sensitivity and accuracy of EBUS-FNA, these results compare favorably with repeat mediastinoscopy, but a formal comparison has not been reported in the literature. The diagnostic efficacy of EUS-FNA for mediastinal restaging has also been assessed in several small series. These studies demonstrated that an NPV of 67% to 91.7% and an accuracy of 83% to 92.3% can be achieved after induction therapy [51, 52]. Similar to EBUS-FNA, these results compare favorably with repeat mediastinoscopy, but a formal comparison has not been reported in the literature. 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