Mediastinal Lymph Node Staging: From Noninvasive to Surgical

Cardiopulmonary Imaging Review Walker et al. Mediastinal Lymph Node Staging Cardiopulmonary Imaging Review Christopher M. Walker 1 Jonathan H. Chung 2 Gerald F. Abbott 3 Brent P. Little 4 Ahmed H. El-Sherief 5 Jo-Anne O. Shepard 3 Michael Lanuti 6 Walker CM, Chung JH, Abbott GF, et al. Keywords: bronchogenic carcinoma, lung cancer, lung carcinoma, lymph node staging DOI:10.2214/AJR.11.7446 Received June 24, 2011; accepted after revision August 12, 2011. Supported by a research grant from Siemens Healthcare (J. H. Chung). Recipient of a gold award at the 2010 annual meeting of the American Roentgen Ray Society, San Diego, CA. The majority of this work was performed at the Massachusetts General Hospital. 1 Department of Radiology, University of Washington Medical Center, Box 357115, 1959 NE Pacific St, Seattle, WA 98195. Address correspondence to C. M. Walker (walk0060@uw.edu). 2 Department of Radiology, National Jewish Health, Denver, CO. 3 Department of Radiology, Massachusetts General Hospital, Boston, MA. 4 Emory University, Atlanta, GA 5 Imaging Institute, Section of Thoracic Radiology, Cleveland Clinic, Cleveland, OH. 6 Division of Thoracic Surgery, Massachusetts General Hospital, Boston, MA. WEB This is a Web exclusive article. AJR 2012; 199:W54 W64 0361 803X/12/1991 W54 American Roentgen Ray Society Mediastinal Lymph Node Staging: From Noninvasive to Surgical OBJECTIVE. The purpose of this review is to describe the current lymph node stations and lymph node staging of non small cell lung carcinoma. Minimally invasive and invasive methods of mediastinal lymph node staging are emphasized, and the relative accuracy and limitations of each modality are described. CONCLUSION. Lung carcinoma remains the most common cause of cancer death in the United States. Accurate staging of lung cancer is imperative for implementing the correct therapy and assessing patient prognosis. L ung cancer is the leading cause of cancer mortality in the United States. It is estimated to have caused 29% of cancer deaths of men and 26% of cancer deaths of women in 2010 [1]. The TNM system is currently used for staging non small cell lung carcinoma (NSCLC). The seventh edition of the TNM system for lung cancer staging was published in 2009 by the International Union Against Cancer and the American Joint Committee on Cancer with important new radiologic implications and changes in staging [2]. It is imperative to accurately stage disease at diagnosis because treatment and prognosis are inherently linked to disease stage. Survival time decreases from a median of 59 months for patients with stage IA disease to 4 months for patients with stage IV disease [3]. Surgical resection is the standard therapy for disease confined to the lung without mediastinal or distant metastasis (i.e., stages I and II) [4, 5]. Thoracic radiation therapy, radiofrequency ablation, and stereotactic body radiation therapy may be used to treat patients with stage I and II disease with comorbidities that preclude safe surgical resection and patients who refuse surgery [6 9]. Treatment of patients with metastatic disease to mediastinal lymph nodes (stages IIIA and IIIB) remains controversial and often includes a combination of chemotherapy and radiation therapy; surgery has an uncertain role [10]. Surgery has been more frequently used at high-volume centers to treat selected patients with stage IIIA disease who have a low tumor and nodal disease burden. Patients with advanced disease (stage IV) are often treated with systemic palliative chemotherapy and targeted molecular therapy. The radiologist plays an important role in diagnosing, staging, and guiding the appropriate workup and treatment of patients with lung cancer. We review the current regional lymph node stations in the context of NSCLC staging. We discuss current modalities and the relative accuracies of noninvasive, minimally invasive, and invasive methods of mediastinal lymph node staging of NSCLC. Particular emphasis is placed on suggesting appropriate nodal targets and the modality best used to sample pathologic lymph nodes. Regional Lymph Node Stations Lymph node locations have been traditionally divided into 14 stations according to a standardized lexicon based on surgical landmarks from mediastinoscopy and thoracotomy [11]. Stations 1 9 correspond to mediastinal nodal groups and represent N2 or N3 disease in the TNM system. Stations 10 14 represent hilar or peribronchial nodal groups and represent N1 or N3 disease in the TNM system. Supraclavicular and suprascalene lymph nodes are not represented in this numbering system because they are extrapleural, but they represent N3 disease in the TNM system of staging lung cancer. A lymph node map has been proposed by the International Association for the Study of Lung Cancer (IASLC) with new nomenclature that regroups previously used lymph W54 AJR:199, July 2012

Mediastinal Lymph Node Staging node stations [12]. The new lymph node map rectifies the differences between the Naruke lymph node classification used in Japan and the Mountain-Dressler classification used in the United States in that it regroups lymph nodes into precise anatomic zones. The main reason for this new classification is that the IASLC found discrepancies between the two existing lymph node classifications in staging of the same lesions. Therefore, the main goal was to unify lymph node staging worldwide while providing precise anatomic definitions of the new nodal zones. For the purposes of this review, the traditional Mountain-Dressler lymph node stations are used with cross-reference to the IASLC nodal map [11]. These stations and zones are anatomically defined in Table 1 and Figure 1. Nodal Staging of Non Small Cell Lung Cancer Nodal metastasis in NSCLC is defined by its relation to the primary tumor (Fig. 2). Category N0 is defined as absence of nodal metastasis; N1, ipsilateral malignancy of hilar or peripheral lymph nodes (Fig. 3); N2, ipsilateral mediastinal or subcarinal malignant lymphadenopathy (Fig. 4); and N3, contralateral involvement of the hilar, peripheral, or mediastinal lymph nodes (Fig. 5). Any malignant supraclavicular or suprascalene lymph nodes are also considered N3 disease (Fig. 6). Staging and prognosis are inherently linked to nodal involvement by tumor [3]. Noninvasive Staging of the Mediastinum CT and PET are the mainstays in noninvasive staging of NSCLC. Identifying nodal disease is of particular importance because some patients with lymph node disease do not benefit from aggressive surgical management. CT and PET are complementary, CT yielding detailed anatomic information and PET results indicating the metabolic activity of lesions. PET has inherently lower spatial resolution than CT. A well-accepted criterion for an abnormal lymph node on CT images is an axial short-axis diameter of 1 cm or greater. Abnormal shape or attenuation of the lymph node may also raise suspicion of metastatic involvement (Fig. 7). CT, however, is relatively inaccurate for identifying pathologic mediastinal lymphadenopathy (sensitivity, 51 64%; specificity, 74 86%) [13 15]. Forty percent of all nodes thought to be malignant according to CT findings are proven to represent benign entities, whereas 20% of nodes without abnormalities are proven to represent metastatic lesions at invasive staging or thoracotomy [13]. However, CT is integral in identification of appropriate lymph node targets, which determines the best invasive or minimally invasive modality for tissue sampling. PET relies on the premise that NSCLC cells have higher glycolytic activity than normal cells [16]. The radiolabeled glucose analog undergoes cellular uptake and phosphorylation, which result in increased radiotracer in malignant cells [17]. PET is superior to CT for identification of mediastinal nodal metastasis; the reported sensitivity is 58 91% and the specificity 78 90% [18 21]. A metaanalysis involving 2865 patients showed PET to have a sensitivity of 74% (95% CI, 0.69 0.79%) and specificity of 85% (95% CI 0.82 0.88%) for identification of nodal metastatic disease in NSCLC [13]. PET is also useful in detecting nodal metastasis in nodes that appear normal according to the CT criteria (Fig. 8). Inflammatory, granulomatous, and infectious tissues may also have a high rate of glycolysis, leading to false-positive findings. Biopsy confirmation of suspicious lesions is recommended for patients being considered for surgery because of the possibility of a false-positive result [22]. A unique situation exists in patients with positive lymph nodes by CT size criteria (> 1 cm) but normal 18 F-FDG PET results. Current surgical practice involves invasive tissue sampling in TABLE 1: Mediastinal Lymph Node Classification [11, 12] Nodal Zone Nodal Station Anatomic Definition Supraclavicular 1 Highest mediastinal nodes lie superior to a line drawn at the upper aspect of the left brachiocephalic vein as it ascends and crosses anteriorly to the midline of the trachea. Upper 2 Upper paratracheal nodes are inferior to station 1 nodes and superior to a horizontal line drawn at the upper portion of the aortic arch. 3 Prevascular and retrotracheal nodes. Prevascular nodes lie anterior to the great vessels and superior to the top of the aortic arch. Retrotracheal nodes are posterior to the trachea and superior to the lower aspect of the azygous vein. 4 Lower paratracheal nodes are usually subdivided into left and right sides, the midline of the trachea being the division. The right and left lower paratracheal nodal groups are inferior to the superior aortic arch and superior to the upper aspect of the right and left upper lobe bronchi, respectively. Aorticopulmonary 5 Subaortic or aorticopulmonary window nodes are lateral to the ligamentum arteriosum, aorta, and left pulmonary artery but remain within the mediastinal pleura. 6 Paraaortic (ascending aortic or phrenic) nodes are anterior and lateral to the ascending aorta and aortic arch but below the superior aspect of the aortic arch. Subcarinal 7 Subcarinal nodes are inferior to the carina and between the mainstem bronchi. Lower 8 Paraesophageal nodes are adjacent to the esophagus and on either side of the midline. 9 Pulmonary ligament nodes lie within the pulmonary ligament. Hilar-interlobar 10 Hilar nodes are the proximal lobar nodes, which are outside the mediastinal pleura and adjacent to the bronchus intermedius and mainstem bronchi. They are inferior to the upper aspect of the upper lobe bronchi. 11 Interlobar nodes are adjacent to proximal lobar bronchi. Peripheral 12 Lobar nodes are adjacent to distal lobar bronchi. 13 Segmental nodes are adjacent to segmental bronchi. 14 Subsegmental nodes are adjacent to subsegmental bronchi. AJR:199, July 2012 W55

Walker et al. these patients to exclude malignant nodal involvement because in this situation nodes are positive in approximately 13% of cases. Normal findings at mediastinoscopy lower this false-negative rate to 3% [23]. PET/CT combines the detailed anatomic information from CT and the metabolic information from PET. PET/CT has been found to be more accurate than either modality alone in the characterization of solitary pulmonary nodules as benign or malignant [24, 25]. Although few studies have been conducted to examine the accuracy of combined PET/CT in mediastinal lymph node staging, the accuracy is at least as good as that of PET alone [26 28]. Invasive Staging of the Mediastinum Biopsy of lymph node disease suspected at CT or PET is often necessary for accurate pathologic staging and to guide appropriate therapy. Many methods exist for invasive mediastinal staging, and they have varying capability for confirming and excluding mediastinal lymph node involvement. The particular invasive test performed relies heavily on the area of expertise and preferences of the thoracic surgeon or pulmonologist performing the procedure. Procedures vary in level of invasiveness and staging accuracy (Fig. 9). We first discuss the more traditional and invasive staging methods followed by newer, minimally invasive staging procedures. Mediastinoscopy Mediastinoscopy is performed in the operating room under general anesthesia, and most patients are discharged from the hospital the same day [29, 30]. Mediastinoscopy can also be performed at the same time as curative surgery through the use of frozen pathologic specimens. This method is beneficial because two separate sessions of general anesthesia are avoided, and definitive treatment can be provided in one hospital stay. The morbidity and mortality rates for this procedure are low but not negligible (2% and 0.08%) [31]. Mediastinoscopy is accomplished through a suprasternal incision by insertion of a mediastinoscope alongside the trachea and biopsy of adjacent lymph nodes. This procedure is optimal for sampling lymph nodes close to the trachea, including the high and low paratracheal, pretracheal, and anterior subcarinal stations (Fig. 10). Inaccessible nodal groups include the posterior subcarinal, inferior mediastinal, aorticopulmonary, and anterior mediastinal stations. A meta-analysis [31] involving more than 6500 patients revealed average sensitivity and specificity for detection of nodal metastasis of 78% and 100%. The false-negative rate was 11%. There are several additional limitations to mediastinoscopy. It is relatively contraindicated for patients with a tracheostomy tube or history of mediastinal irradiation. Many centers also perform mediastinoscopy infrequently, possibly making the procedure technically difficult and not always successful. Extended mediastinoscopy is a specialized procedure performed at a few academic centers and is used to access the aorticopulmonary window. Chamberlain Procedure The Chamberlain procedure, or anterior mediastinotomy, is performed under general anesthesia and involves an incision to the left of the sternum in the second or third intercostal space. It is a selective procedure used to access the aorticopulmonary window lymph node station in patients with left upper lobe malignancies but can also be used to sample most anterior mediastinal lymph nodes. The morbidity and mortality rates of this procedure are extremely low with rare cases of hemorrhage requiring thoracotomy. The reported sensitivity for detecting nodal metastatic disease in suspected cases of aorticopulmonary station metastasis is 87% with a specificity of 100%. The false-negative rate is 10% [31]. Video-Assisted Thoracoscopic Surgery Video-assisted thoracoscopic surgery (VATS) is generally limited to the evaluation of one side of the mediastinum. It requires general anesthesia and hospital admission. VATS has no reported mortality in the setting of mediastinal lymph node staging but carries a complication rate of 0 9% (complications occurred in 12 of 669 patients in one study [31]). This technique also facilitates sampling of an aorticopulmonary window in patients with left upper lobe malignancy. The sensitivity of VATS is estimated to be 75% and the specificity 100%. The falsenegative rate is low at 7% [31]. Minimally Invasive Staging in the Mediastinum Transbronchial Needle Aspiration Transbronchial needle aspiration is blind biopsy through the tracheal or bronchial wall performed on an outpatient basis with minimal morbidity and no reported mortality. The reported major complication rate is low at 0.32%. Complications include pneumothorax and major bleeding, which can occur in patients with both SCLC and NSCLC [32]. Transbronchial needle aspiration is ideal for sampling markedly enlarged lymph nodes in the lower paratracheal station and subcarinal stations (Fig. 11). The overall sensitivity of this technique is 78% and the specificity 99% [31]. Because of a high falsenegative rate of 28%, additional lymph node sampling must be pursued in cases of negative findings [31]. Endobronchial Ultrasound-Guided Needle Aspiration Endobronchial ultrasound (EBUS) needle aspiration is a minimally invasive technique in which bronchoscopy with an attached convex ultrasound probe is used to sample lymph nodes around the trachea and proximal bronchi (highest mediastinal, upper and lower paratracheal, subcarinal, and hilar nodal stations) (Fig. 12). The procedure consists of real-time evaluation of the lymph node architecture and morphologic features to target abnormal-appearing lymph nodes seen during radiographic staging procedures or ultrasound examinations. In a report of 1299 patients, only two complications occurred: an episode of hypoxia and a single pneumothorax that required chest tube placement after the procedure [33]. No procedure-related mortality has been reported. EBUS needle aspiration has been used primarily to sample lymph nodes larger than 2 cm detected with noninvasive staging modalities. In this subset of patients, the average sensitivity is 93% and the specificity 100% [34]. There is a high false-negative rate of 24%, which requires additional lymph node sampling when biopsy findings are normal [31]. Endoscopic Ultrasound-Guided Needle Aspiration Endoscopic ultrasound needle aspiration entails endoscopy for sampling lymph nodes adjacent to the esophagus (Fig. 13). Morbidity is low, only one complication, fever, being reported in 369 patients [31], and there have been no reported deaths in more than 1000 cases. This technique is particularly effective for sampling the aorticopulmonary, subcarinal, esophageal, and the pulmonary ligament stations (Fig. 14). The overall sensitivity and specificity for detecting nodal metastasis in this group of patients with possible metastasis to these nodal groups were W56 AJR:199, July 2012

Mediastinal Lymph Node Staging 84% and 99.5% in a meta-analysis involving more than 1000 patients [31]. The false-negative rate is 19% [31]. The combination of endoscopic ultrasound (EUS) needle aspiration and EBUS needle aspiration allows nodal sampling of all lymph node stations and was found in a study involving 42 patients [35] to have a sensitivity of 93% in the detection of mediastinal nodal disease and a negative predictive value of 97%. The results of that study suggested that combined EBUS- EUS needle aspiration may one day replace mediastinoscopy. The current major limitation to widespread use of EUS-EBUS needle aspiration is lack of availability and experience with these advanced modalities. Electromagnetic Navigation Bronchoscopy Electromagnetic navigation bronchoscopy is a relatively new technique in which 3D virtual bronchoscopy and electromagnetic waves are used to guide biopsy of mediastinal or lung lesions. Use of this technique increases the diagnostic yield over fluoroscopy-guided or blind transbronchial needle aspiration. Predetermined anatomic locations in the trachea and proximal airways are selected at preprocedure 3D virtual bronchoscopy. After planning CT, images are transferred to the navigation system. A sensor is attached to a bronchoscope, and its position in the x-, y-, and z-planes is mapped with an electromagnetic location board located beneath the patient. The previously selected anatomic locations in the airway are identified. The computer then displays the real-time location in relation to the CT images. No procedure-related deaths have been reported. Complications associated with electromagnetic navigation bronchoscopy include procedural hypoxia and a small risk (5%) of pneumothorax. Electromagnetic navigation bronchoscopy is used most frequently for biopsy of peripheral lung nodules. It can also be used to sample the highest mediastinal, paratracheal, pretracheal, subcarinal, hilar, and interlobar lymph node stations (Fig. 15). Electromagnetic navigation bronchoscopy cannot be used to sample the aorticopulmonary or anterior mediastinal nodal stations. Experience with this technique is limited, and few reports exist regarding its sensitivity and specificity, leading to lack of widespread availability. In the most extensive prospective study, 31 lymph nodes were sampled, and a definitive diagnosis was made or benign lymphoid tissue was found in all cases [36]. A retrospective analysis in a community hospital showed a success rate of 94% in the sampling of 71 lymph nodes [37]. Conclusion Lung cancer will continue to be the leading cause of cancer mortality in the United States. Accurate staging of NSCLC is essential for initiating appropriate therapy. 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Mediastinal Lymph Node Staging A A B Fig. 2 Diagram shows lymph node staging of non small cell lung cancer (NSCLC). T = bronchogenic carcinoma. Colored ovals indicate lymph nodes involved with disease: N1 disease with ipsilateral hilar or peripheral lymphadenopathy; N2 disease with ipsilateral mediastinal or subcarinal lymphadenopathy; N3 disease with contralateral hilar, peripheral, or mediastinal nodal disease. Any supraclavicular nodal disease also constitutes N3 disease. Fig. 3 55-year-old man with N1 disease. A, Axial contrast-enhanced CT image shows right upper lobe lobulated nodule (arrow) representing non small cell lung cancer. B, Axial contrast-enhanced CT image shows enlarged right hilar lymph node (arrow). Fig. 4 66-year-old man with N2 disease. A, Axial contrast-enhanced CT image shows right lower lobe mass (arrow) with central area of low attenuation likely due to necrosis. B, Axial contrast-enhanced CT image shows ipsilateral paraesophageal (black arrow) and hilar (white arrow) lymph node disease. Presence of involved ipsilateral mediastinal lymph nodes indicates N2 disease. C, Axial contrast-enhanced CT image at higher level than B shows enlarged ipsilateral right lower paratracheal lymph nodes (arrow). B C AJR:199, July 2012 W59

Walker et al. A A Fig. 7 58-year-old man with necrotic lymph node metastasis from non small cell lung cancer. Axial contrast-enhanced CT image shows enlarged left hilar and subcarinal lymph nodes (arrows). Patient had spiculated left lower lobe mass (not shown). Presence of central low attenuation indicates necrosis and increases specificity of CT for diagnosis of metastatic disease. B B Fig. 5 75-year-old man with N3 disease. A, Axial contrast-enhanced CT image (lung window) shows spiculated right upper lobe mass (arrow). Adjacent centrilobular emphysema is present in both upper lobes. B, Axial contrast-enhanced CT image (mediastinal window) shows multiple enlarged lymph nodes in bilateral paratracheal and aorticopulmonary lymph node stations. It was important to confirm involvement with invasive or semiinvasive staging because presence of N3 disease precludes resection. Fig. 6 63-year-old man with N3 disease. A, Axial contrast-enhanced CT image shows right upper lobe nodule (arrow) proven to represent non small cell lung cancer. Multiple enlarged right hilar and paratracheal lymph nodes are evident. Presence of central area of low attenuation due to necrosis increases specificity of tumor involvement of lymph node. B, Axial contrast-enhanced CT image through level of supraclavicular region shows marked enlargement of ipsilateral supraclavicular lymph node (arrow). Finding constitutes N3 disease, which precludes resection. W60 AJR:199, July 2012

Mediastinal Lymph Node Staging CT Staging Modalities for NSCLC VATS/Thoracotomy Mediastinoscopy Navigational Bronchoscopy EBUS/EUS PET/CT TBNA Cumulative Staging Accuracy Clinical Pathologic Stage Invasiveness A B Fig. 8 Nodes that appear normal according to CT criteria in 72-year-old man in whom PET depicts lymph nodes involved by malignancy with no size enlargement at CT. A, Axial contrast-enhanced CT image (left) shows endobronchial nodule (arrow) in bronchus intermedius. Axial PET image (right) shows focal uptake (arrow) in nodule found to represent small squamous cell carcinoma. B, Axial contrast-enhanced CT image (left) shows multiple right peribronchial lymph nodes (arrows) not enlarged according to size criteria. Axial PET image (right) shows focal uptake in nonenlarged lymph nodes (arrows), consistent with metastatic involvement, which was proven at thoracotomy. Fig. 9 Schematic shows examinations and procedures used in staging of non small cell lung cancer (NSCLC). As invasiveness of procedure increases, ability to more accurately stage NSCLC also increases. Modalities are limited in capability of sampling all lymph node stations and are often complementary. TBNA = transbronchial needle aspiration, EBUS = endobronchial ultrasound, EUS = endoscopic ultrasound, VATS = video-assisted thoracoscopic surgery. AJR:199, July 2012 W61

Walker et al. Fig. 10 Diagram shows lymph nodes adjacent to trachea are best sampled with mediastinoscopy. These nodes (blue) are in upper and lower paratracheal, pretracheal, and anterior subcarinal stations and in upper and subcarinal zones. (Adapted from [11]) Fig. 11 Diagram shows markedly enlarged lymph nodes adjacent to lower trachea (blue) are ideally sampled with transbronchial needle aspiration. These nodes are in lower paratracheal and subcarinal stations and portions of upper and subcarinal zones. (Adapted from [11]) W62 AJR:199, July 2012

Mediastinal Lymph Node Staging Fig. 12 Diagram shows many lymph node stations (blue) can be sampled with endobronchial ultrasound, including nodes in upper and lower paratracheal, prevascular, retrotracheal, subcarinal, hilar, and interlobar stations and upper, subcarinal, and hilar-interlobar zones). (Adapted from [11]) Fig. 14 Diagram shows endoscopic ultrasound accessible nodal groups (blue) are close to esophagus. These nodes are in subcarinal, paraesophageal, and pulmonary ligament stations and in subcarinal and lower zones. Aorticopulmonary station and subaortic station can also be accessed with endoscopic ultrasound. In rare instances, upper and lower paratracheal stations can be accessed with endoscopic ultrasound. (Adapted from [11]) Fig. 13 64-year-old woman with non small cell lung cancer. Endoscopic ultrasound image shows multiple lymph nodes (LN) surrounding esophagus. Presence of hyperechoic center is usually associated with benignity. Endoscopic ultrasound allows realtime ultrasound sampling of suspicious lymph nodes adjacent to esophagus. AJR:199, July 2012 W63

Walker et al. Fig. 15 Diagram shows nodal groups (blue) accessible with electromagnetic navigation bronchoscopy. These nodes include supraclavicular lymph nodes adjacent to trachea; paratracheal, prevascular, retrotracheal, subcarinal, hilar, and interlobar stations; and supraclavicular, upper, subcarinal, and hilar-interlobar zones. (Adapted from [11]) W64 AJR:199, July 2012