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Recent Advances in Chest Medicine |

Diagnosing and Staging Lung Cancer Involving the MediastinumMediastinal Staging FREE TO VIEW

Septimiu Dan Murgu, MD, FCCP
Author and Funding Information

From the Department of Medicine, The University of Chicago, Chicago, IL.

CORRESPONDENCE TO: Septimiu Dan Murgu, MD, FCCP, Department of Medicine, The University of Chicago, 5841 S Maryland Ave, MC 6076, Chicago, IL 60637; e-mail: smurgu@medicine.bsd.uchicago.edu


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(5):1401-1412. doi:10.1378/chest.14-1355
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The purpose of this article is to provide an update on evidence-based methods for mediastinal staging in patients with lung cancer. This is a review of the recently published studies and a summary of relevant guidelines addressing the role of CT scan, PET scan, endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA), and mediastinoscopy as pertinent to lung cancer staging and restaging. The focus is on how these diagnostic methods fit into the best algorithm for patients with chest imaging abnormalities suspected of malignant disease. Several studies, meta-analyses, and systematic reviews specifically targeted the role of PET scan, EBUS-TBNA, and mediastinoscopy for detecting mediastinal lymph node involvement in patients suffering from lung cancer. Based on the recommendations from the currently published guidelines, algorithms of care are proposed for staging and restaging of the mediastinum.

Figures in this Article

In patients with non-small cell lung cancer (NSCLC), accurate mediastinal staging is relevant to determine treatment options, estimate prognosis, and provide a common language when communicating about patients and enrolling them in clinical trials. For the last 4 decades, several lymph node maps have been used to define the clinical and pathologic lymph node involvement in patients with lung cancer by labeling intrathoracic lymph node regions using either anatomic descriptions (eg, right lower paratracheal) or numerical levels (eg, 4R). These maps include those by Naruke, American Thoracic Society (ATS), and Mountain Dressler-ATS (MD-ATS), a modification of the ATS map. The Naruke map had been used by Japanese surgeons and oncologists, whereas the MD-ATS was widely adopted in North America. The International Association for the Study of Lung Cancer (IASLC) has proposed a revision of the TNM staging system in which the N descriptors reconcile the discrepancies between the Naruke and the MD-ATS maps. The most striking discrepancy between the two systems was that level 7 subcarinal lymph nodes in the MD-ATS map corresponded to levels 7 and 10 in the Naruke map. Thus, some tumors were staged as N2 (stage IIIA) according to the MD-ATS map, but they were N1 (stage II) by the Naruke map. Data analyses, treatment options, and outcomes therefore were significantly affected by the choice of a particular lymph node map. This discrepancy illustrates the relevance of having a unified staging system. For mediastinal staging, this is now offered by the IASLC map.

The distinct treatment options and prognosis for any given tumor stage make accurate staging the most relevant step in the management of patients with lung cancer. Staging sequence and completeness prior to curative-intent treatment remain suboptimal. In one study, single (CT scan), bimodality (CT scan plus PET scan or CT scan plus invasive), or trimodality (CT scan, PET scan, and invasive) tests were used to assess for mediastinal metastases. Only 30% of patients had bimodality and 5% had trimodality staging, despite the guidelines recommending for bimodality or trimodality strategies, which have a significantly lower risk of death.1

The Institute of Medicine recommends that patient care should be “STEEEP”: safe, timely, effective, efficient, equitable, and patient-centric. For efficiency, access, and timeliness of an initial procedure in the management of patients with suspected lung cancer, concomitant diagnosis and staging is beneficial because it avoids additional procedures. It is preferable to perform a biopsy at the site that would confer the highest stage (ie, to perform a biopsy of a suspected metastasis or mediastinal lymph node rather than the primary pulmonary lesion).2 Timely staging is relevant, as negative outcomes result from delaying therapy. Distant metastases may become evident on serial CT scans or PET scans in 3% of untreated patients at 4 weeks and in 13% at 8 weeks. Complete restaging, therefore, should be considered if therapy is delayed for 4 to 8 weeks after the diagnosis.3

Safety and effectiveness can be ensured by adherence to the guidelines, which recommend mediastinal lymph node sampling as the first invasive test in patients with suspected lung cancer and mediastinal lymph node involvement without distant metastases. Guideline-consistent care with initial mediastinal sampling results in fewer tests and complications.4 One study compared outcomes of diagnostic strategies in patients with lung cancer with regional spread without distant metastases.4 If the first invasive test involved mediastinal sampling, patients were classified as guideline consistent; otherwise, they were classified as inconsistent. Only 21% of patients had guideline-consistent diagnostic evaluations, and 44% never had mediastinal sampling. Patients who had guideline-consistent care required fewer tests than patients with guideline-inconsistent care, including thoracotomies and CT scan-guided biopsies, although they had more transbronchial needle aspirations. As a consequence, patients with guideline-consistent care had fewer pneumothoraces, chest tubes, hemorrhages, and respiratory failure events.4 Three quality gaps are in fact identified in the care of patients with lung cancer: failure to sample the mediastinum first, failure to sample the mediastinum at all, and overuse of thoracotomy. Furthermore, out of the seven process of care quality indicators related to the evaluation of patients with lung cancer, four are related to staging alone and include mediastinal sampling prior to curative-intent surgery for stage IB or higher.5 Performing a safe, timely, efficient, effective, and patient-centric staging requires a coordinated effort. Guidelines recommend a multidisciplinary lung cancer team involvement early in a patient’s care, which coordinates the optimal approach to staging and specimen acquisition to expedite diagnostic and molecular testing.2,6,7

Contrast-enhanced chest and upper abdominal CT scan is recommended as an initial step for all patients with suspected or confirmed diagnosis of lung cancer suitable for treatment.710 The revised IASLC system is clinician oriented and should be used for staging,8 as it unifies previously used systems and defines the borders of the mediastinal, hilar, and interlobar lymph nodes based on CT scan landmarks.11 To further help clinicians in their routine practice, the American College of Chest Physicians proposed that patients with lung cancer be separated into four categories with respect to the radiographic characteristics of the primary tumor and the lymph nodes based on CT scan findings12 (Fig 1). For group A, tissue diagnosis suffices, as mediastinal involvement is implied. Group B patients need pathologic confirmation of their lymph nodes prior to curative-intent treatment. Groups C and D involve patients with normal mediastinal nodes on CT scan. In group C, the presence of a central tumor or suspected N1 disease on CT scan or PET scan (hilar, interlobar nodes) makes the risk of mediastinal (N2, 3) nodal involvement high (20%-25%) despite normal-sized mediastinal nodes negative on PET scan; thus, further tissue confirmation is needed for this group. For group D, invasive staging is currently not routinely recommended prior to thoracotomy but may be warranted to rule out N1 disease for nonsurgical candidates who will undergo stereotactic body radiation therapy (SBRT). The European Society of Thoracic Surgeons guidelines also recommend invasive staging in patients with the primary tumor size > 3 cm, based on higher probability of N2 disease, even when the CT and PET scans are negative for mediastinal lymph node involvement.13 Spanish Society for Pulmonology and Thoracic Surgery (SEPAR) guidelines recommend invasive staging in patients with low metabolic activity in the primary tumors, as in some adenocarcinomas, since these tumors may be associated with occult N2 disease (ie, pathologic involvement with a negative CT scan and PET scan).8

Figure Jump LinkFigure 1 –  Radiographic characteristics of the primary tumor and associated interlobar, hilar, and mediastinal lymph nodes. The American College of Chest Physicians defines these groups based on CT scan findings; for the purpose of this article, the integrated CT-PET scan findings are illustrated. A, Group A involves patients with mediastinal infiltration; discrete lymph nodes can no longer be discerned or measured. Diagnosis is necessary, but mediastinal involvement is implied, and thus a mediastinal staging procedure is not indicated. B, Group B involves patients with mediastinal node enlargement, in whom the size of the discrete nodes can be measured. These patients require pathologic confirmation (ie, invasive staging). C, D, In Group C, the mediastinal lymph nodes are normal, but there is a high risk for occult N2/N3 disease based on the presence of suspected N1 disease (C) or a central tumor (D). These patients also need invasive staging prior to surgery. E, Group D is composed of patients with a peripheral clinical stage I tumor (the mediastinal, hilar, and interlobar nodes are normal on PET-CT scan). Invasive staging prior to surgery is not recommended in this group unless these patients are considered for stereotactic ablative surgery.Grahic Jump Location

The term “normal mediastinum” by CT scan criteria is used to define the absence of visualized mediastinal lymph nodes or the presence of nonpathologic-size lymph nodes. CT scan criteria have been used to define the probability of malignant involvement of the mediastinal lymph nodes. The most widely used criterion is a short-axis lymph node diameter ≥ 1 cm on a transverse CT scan. There is no universal agreement on these definitions, however, and different organizations use slightly different cutoff values to define discrete suspicious mediastinal lymph nodes. SEPAR defines these as nodes whose smallest diameter is > 15 mm on CT scan with contrast,8 whereas National Institute for Health and Care Excellence defines them as lymph nodes between 10 and 20 mm maximum short axis on CT scan.10 Overall, however, the median sensitivity and specificity of CT scanning for identifying mediastinal lymph node metastasis are 55% and 81%, respectively (Table 1).12 Therefore, lymph nodes < 1 cm seen on the CT scan or nodes that may not be visualized at all may have metastatic involvement once sampled by surgical or needle-based techniques.

Table Graphic Jump Location
TABLE 1 ]  Noninvasive and Invasive Staging Modalities Prior to Thoracotomy

AP = aortopulmonary; EBUS = endobronchial ultrasound; ECM = extended cervical mediastinoscopy; EUS = esophageal ultrasound; MED = mediastinoscopy; − = not accessible; + = Accessible; ± = occasional access, depending on lymph node size and operator technique; VAM = video-assisted mediastinoscopy; VATS = video-assisted thoracic surgery.

a 

Refers to the overall sensitivity for detecting metastasis in the mediastinal lymph nodes but results are not specific for individual lymph node stations.

b 

EUS has access mainly to left-sided lymph nodes.

c 

Access to anterior but not posterior subcarinal (station 7) nodes; MED also has access to stations 1 and 3.

d 

Only accessible by ECM, not by traditional cervical MED.

e 

Only for the lymph nodes on the side of the VATS.

f 

Specific results of VATS for these stations have not been reported.

PET scanning has a higher accuracy than CT scan for the evaluation of mediastinal lymph node involvement from lung cancer. Lymph nodes with higher fluorodeoxyglucose uptake than that of the surrounding normal mediastinal structure are considered as positive. Lymph nodes with equivocally increased fluorodeoxyglucose uptake to a level similar to that of the surrounding normal mediastinal structure are interpreted as negative. This defines a “normal mediastinum” by PET scan criteria. PET scanning also provides information regarding metastatic disease outside the thorax, except for the brain.710 Guidelines recommend the use of PET scan and PET-CT scan for staging in patients who are potential candidates for radical treatment (clinical stage IA-IIIA).7,8,10 PET scan, however, is less sensitive for lymph nodes with diameters between 7 and 10 mm, which in fact, by convention, may be called “normal” on chest CT scan. Mediastinoscopy, endobronchial ultrasound (EBUS), and esophageal ultrasound (EUS)-guided sampling have identified unsuspected mediastinal metastases in patients with normal-sized lymph nodes without increased PET activity (ie, normal mediastinum on CT scan and PET scan).14 Overall, the sensitivity and specificity of PET scan for identifying mediastinal metastasis are approximately 77% and 86%, respectively (Table 21518).12 Thus, tissue sampling is still required to confirm PET scan-positive findings. False positives are seen in patients with active infection and inflammation where there is increased glycolysis. Sarcoidosis, anthracosis, infections, and reactive lymph nodes lead to nodes that are positive on PET scan. In cases of recent lymph node sampling, PET scan may be falsely positive (Fig 2). False-negative PET scans occur when there is impaired blood flow (ie, necrosis) and minimal radiotracer can reach the area or in processes with a low metabolic activity (eg, carcinoid, some adenocarcinomas).

Table Graphic Jump Location
TABLE 2 ]  EBUS-Guided Transbronchial Needle Sampling Technical Aspects

FNA = fine-needle aspiration. See Table 1 legend for expansion of other abbreviation.

a 

Capillary force or action refers to the ability of a medium (usually liquid) to flow in a narrow space (eg, small-gauge needle) against gravity. The medium is lifted up inside the needle as a result of cohesion and adhesive forces between the medium and the inner aspect of the needle. The height of the medium column inside the needle is inversely proportional to the radius of the needle, suggesting that the smaller the needle gauge, the more specimen is collected through the capillary action. The specimen is collected in the needle by nonsuction fine-needle sampling; this results in less nodal trauma and less blood in the smear without compromising specimen cellularity necessary for cytology diagnosis.

Figure Jump LinkFigure 2 –  Diff Quik stains (rapid on-site cytology examination) of endobronchial ultrasound transbronchial needle aspiration specimens from patients with PET scan-positive mediastinal lymph nodes. All these specimens are considered diagnostic. A, Malignant cells suspicious for adenocarcinoma. B, Granuloma. C, Anthracotic pigment and anthracotic histiocytes. D, Abundant normal lymphocytes.Grahic Jump Location

Therefore, PET scanning is not a definitive test. Lymph node sampling improves staging accuracy beyond the ability of PET scanning.12 In the absence of M1 extrathoracic disease, a PET scan showing hypermetabolism in the mediastinal nodes requires confirmation.2,710,19 If the PET scan is negative, tissue confirmation is recommended prior to surgery in any of the following circumstances (Fig 1):

  1. Discrete mediastinal lymph nodes is seen on CT scan.7,8,10,13

  2. Central tumor, usually in contact with the mediastinum7,8,13 (A central tumor was defined as existing within the proximal one-third of the hemithorax, and a peripheral tumor was defined as existing outside the proximal one-third of the hemithorax.)

  3. The tumor has low maximum standard uptake value.8

  4. There is suspicion for N1 disease.7,8,13

  5. Tumor size is > 3 cm.13

Curative-Intent Surgery

For patients with peripheral clinical stage I tumors with negative nodal involvement by CT and PET scan (Fig 1), invasive preoperative evaluation of the mediastinal nodes is not recommended,7,13 based on the evidence that PET scan has a false-negative rate of only 3% to 6% in this population.12 One study, for example, evaluated the role of mediastinoscopy and EUS-fine-needle aspiration (FNA) in patients with no mediastinal nodal disease on PET-CT scan.20 The incidence of unsuspected pathologic N2 (pN2) disease was 2.9% for mediastinoscopy and 3.7% for EUS-FNA. Patients with clinical N1 (cN1) disease suspected on PET-CT scan had a high incidence of unsuspected pN2 disease (17.6% after mediastinoscopy and 23.5% after EUS-FNA), and it was concluded that cytohistologic confirmation is not recommended for cN0, but it is necessary for cN1. Studies demonstrate that preoperative EBUS could upstage patients with small, peripheral tumors and PET-CT scan-negative mediastinum. In these trials, the overall rate of N2 disease that was not detected by PET or PET-CT scan ranged from approximately 5% to 17%.14,2124 These higher rates of detected occult N2 disease in the more recent studies may be partially explained by histologic differences in the study populations and by the changes in the lymph node map in which the area of lymph node station 7 has been widened, allowing detection of additional diseased N2 nodes11 (Fig 3). Future algorithms for staging the normal PET-CT scan mediastinum may also need to take into account biomarkers (eg, carcinoembryonic antigen, carbohydrate antigen 19-9, carbohydrate antigen 125, or cytokeratin 19 fragment), as these may be useful indicators for nodal staging.25 They may impact the decision to proceed with invasive staging.25 For instance, if the N2/N3 node is negative by EBUS but the markers are elevated, surgical staging may be warranted. Although it remains to be determined which marker is most suitable for a specific histologic subtype, biomarker-driven risk stratification of PET-CT scan-normal mediastinum is promising and needs further investigation.

Figure Jump LinkFigure 3 –  Diagram illustrating the mediastinal, hilar, and interlobar lymph node stations relevant for staging and accessible by endobronchial ultrasound transbronchial needle aspiration (stations 2, 4, 7, 10, and 11). The upper and lower borders are based on the revised International Association for the Study of Lung Cancer lymph node map. Station 2R includes nodes extending to the left lateral border of the trachea. The upper border is the apex of the right lung and pleural space and, in the midline, the upper border of the manubrium, and the lower border is the intersection of caudal margin of innominate vein with the trachea. Station 2L includes nodes extending to the left of the left lateral border of the trachea. The upper border is the apex of the left lung and pleural space and, in the midline, the upper border of the manubrium, and the lower border is the superior border of the aortic arch. Station 4R includes right lower paratracheal nodes and pretracheal nodes extending to the left lateral border of trachea. The upper border is the intersection of caudal margin of innominate vein with the trachea, and the lower border is the lower border of azygos vein. Station 7 is the subcarinal nodal station with the upper border composed of the carina of the trachea and the lower border composed of the upper border of the lower lobe bronchus on the left and the lower border of the bronchus intermedius on the right. Station 4L includes nodes to the left of the left lateral border of the trachea, medial to the ligamentum arteriosum. The upper border is the upper margin of the aortic arch, and the lower border is the upper rim of the left main pulmonary artery. Station 10R includes nodes immediately adjacent to the right mainstem bronchus and hilar vessels, including the proximal portions of the pulmonary veins and main pulmonary artery. The upper border is the lower rim of the azygos vein, and the lower border is the interlobar region between the right upper lobe and bronchus intermedius. Station 10L includes nodes immediately adjacent to the left mainstem bronchus and hilar vessels, including the proximal portions of the pulmonary veins and main pulmonary artery. The upper border is the upper rim of the left pulmonary artery, and the lower border is the interlobar region (left upper lobe and left lower lobe). Station 11R superior is composed of the nodes between the right upper lobe bronchus and bronchus intermedius. Station 11R inferior is between the middle and the right lower lobe bronchi. Station 11L is composed of the nodes between the origin of the left upper and lower lobar bronchi. Ao = aorta; PA = pulmonary artery.Grahic Jump Location
Stereotactic Body Radiation Therapy

Open surgery is not feasible in 25% to 35% of patients with stage I NSCLC, and external-beam radiation is offered as a standard treatment. Conventionally fractionated radiotherapy has been the traditional radiation treatment of these patients, but SBRT, also known as stereotactic ablative radiotherapy, is an alternative. SBRT may be more cost effective than conventionally fractionated radiotherapy, wedge resection, or lobectomy for marginally operable patients.26,27 Regional failures, however, occur in up to 15% of patients treated with SBRT.28 This may be because prior to SBRT, patients with medically inoperable NSCLC generally have limited, noninvasive staging.29 At a minimum, however, until more data become available, mediastinal interrogation with EBUS should be performed before patients undergo SBRT. Indeed, mediastinal lymph nodes were found to be positive for metastatic disease in 16% of patients who underwent EBUS prior to SBRT and had no previous radiographic evidence of disease.30 A prospective study is currently testing whether there is a difference in accuracy between CT-PET scan and EBUS-transbronchial needle aspiration (TBNA) for mediastinal staging in patients with NSCLC prior to SBRT.31

The staging technique should be chosen that is most cost efficient, least invasive, and has the least delay in care. Each center should plan the sequence of tests so the initiation of treatment is not delayed.8 Communication among the oncologist, practitioner performing the biopsy, and the pathologist is important to ensure that sufficient tissue is obtained and processed for diagnosis, staging, and genetic alterations.2,7,8

Needle-based techniques currently proven to be accurate for mediastinal staging include EBUS, EUS, and combined EUS/EBUS, with sensitivities of approximately 89%, 89%, and 91%, respectively. These are the tests of first choice to confirm mediastinal involvement in accessible lymph node stations. If negative, as of this writing, they should be followed by surgical biopsy.12 This recommendation is based on the studies of EBUS vs mediastinoscopy3234 and applies to patients with enlarged mediastinal lymph nodes on CT scan or high uptake on PET scan (Fig 4). The preferred first needle technique is EBUS-TBNA, because its diagnostic yield is comparable to that of mediastinoscopy.3234 In fact, EBUS has several advantages over mediastinoscopy: reduced invasiveness; ease of restaging; ability to routinely reach posterior subcarinal, hilar, and interlobar nodal stations (Table 1); and, in some practices, the lack of requirement for general anesthesia. National Institute for Health and Care Excellence guidelines recommend that every cancer network should have at least one center with EBUS and/or EUS and that the local test performance of EBUS and EUS-guided FNA should be the subject of audit.10

Figure Jump LinkFigure 4 –  Staging algorithm that incorporates recommendations from the following published evidence-based guidelines on lung cancer: American College of Chest Physicians (2013), European Society of Thoracic Surgeons (2014), National Comprehensive Cancer Network (2014,) and the Spanish Society for Pulmonology and Thoracic Surgery (2011). EBUS = endobronchial ultrasound; LN = lymph node; SUV = standard uptake value; TBNA = transbronchial needle aspiration; VAM = video-assisted mediastinoscopy.Grahic Jump Location

Studies suggest that the combination of EBUS and EUS allows complementary and near-complete access to all mediastinal lymph node stations12,3335 (Table 1). The sensitivities of surgery, endosonography (EBUS and EUS), and endosonography followed by surgery if the needle technique was negative were 79%, 85%, and 94%, respectively.34 A better understanding of the published data and recent evidence, however, challenge the value of combined EBUS and EUS. EUS must be followed by EBUS for complete staging.36 Lymph node stations 8 and 9, the only ones not accessible by EBUS but accessible by EUS (Table 1), did not contribute to the increased yield of EUS-FNA.37 In addition, it is extremely rare that stations 8 and 9 are involved without concurrent involvement of upper mediastinal nodes (stations 2, 4, or 7).38 In one study of 621 patients who underwent staging according to the European Society of Thoracic Surgeons guidelines, only one of 30 patients with unexpected (ie, negative PET-CT scan) pN2 had involvement in the inferior mediastinum (in station 8). These data do not justify routine exploration of the inferior mediastinum prior to thoracotomy38 and questions the value of routinely performing EUS in addition to EBUS for staging.

Surgical techniques (mediastinoscopy, video-assisted thoracic surgery [VATS]) are used when the suspicion is high (CT or PET scan-positive hilar or mediastinal nodes) and needle techniques are negative2,710,19 (Fig 4). SEPAR recommends mediastinoscopy when three needle-based samples fail to provide a cytopathologic diagnosis or normal lymphatic tissue. In most studies, surgical staging consists of a standard videomediastinoscopy performed in the operating room, under general anesthesia, and patients are discharged to home the same day. The median sensitivity of standard cervical mediastinoscopy is 78%, and median negative predictive value (NPV) is 91% (Table 1).12 The false-negative rate at mediastinoscopy is influenced by: lymph node accessibility, number of stations sampled (3 or 5), and diligence with which the nodes are dissected or sampled. In this regard, lymphadenectomy and videomediastinoscopy have better results than traditional mediastinoscopy, with a median sensitivity of 94%, 89%, and 78%, respectively.12

A surgical staging technique, however, may be the first step for patients with left upper lobe (LUL) tumors because of the predilection for involvement of the aortopulmonary window (APW) nodes (station 5). Invasive assessment of the APW nodes should be performed via Chamberlain, VATS, or extended cervical mediastinoscopy (ECM) if other mediastinal stations are found to be uninvolved.7 These nodes represent the most important group of N2 nodes not accessible by standard cervical mediastinoscopy (Table 1). ECM can be added to explore the subaortic and the paraaortic nodal stations if videomediastinoscopy is deemed to be negative by macroscopic inspection of the biopsied or removed lymph nodes or by frozen section examination of macroscopically suspicious lymph nodes. If videomediastinoscopy reveals N2 or N3 disease in other stations, ECM for station 5 and 6 is not recommended.39 With this procedure, a mediastinoscope is inserted through the suprasternal notch and directed lateral to the aortic arch. In a study of 456 patients with LUL cancers, standard mediastinoscopy accompanied by ECM was found to have a median sensitivity of 71% for identifying station 5, 6 nodal involvement, with a median NPV of 91%.39 VATS has also been used to assess APW lymph nodes, but specific results for stations 5 and 6 have not been reported.12

Most studies on EBUS-TBNA showed a high yield for diagnosis and staging of lung cancer using a sampling technique that involved several (approximately 10-15) needle revolutions inside the node and the use of suction.14,32,34 The current understanding of optimal fine-needle sampling techniques, however, include capillary action and minimal intranodal trauma (Fig 515,40), methods that may increase the purity of the acquired specimens and, thus, their quality, relevant for molecular analysis (Table 2).1518

Figure Jump LinkFigure 5 –  A-C, Lymph node EBUS image patterns. D-G, Images obtained during EBUS-guided TBNA. A, Hypervascular node detected on Doppler mode; this finding may guide the operator to avoid using suction during TBNA to potentially prevent a bloody specimen. B, “Central hilar structure,” defined as a hyperechoic area in the center of the node (arrow), is a sonographic sign that may predict a benign etiology. C, Coagulation necrosis sign is characterized by hypoechoic areas (arrows) inside the node without blood flow (Doppler negative). Sometimes this can occupy the entire node. The presence of coagulation necrosis sign has a high specificity and hazard ratio for prediction of malignancy.40 D, EBUS-TBNA of the 4L lymph node; the needle is seen at the proximal aspect of the node. E, During the same maneuver, the needle is advanced to the distal capsule of the node; this back-and-forth movement from capsule to capsule is warranted, as malignant cells may cluster in subcapsular zones.15 F, EBUS-TBNA using a 25-gauge pro-core needle from a large mass. G, During the same maneuver, by extending the lever of the bronchoscope, the needle direction is changed to sample different areas of the node. See Figure 4 legend for expansion of abbreviations.Grahic Jump Location

Elastography and vascular imaging may be able to further improve the sensitivity in detecting malignant lymph nodes.4143 The power/color Doppler mode allows vascular image pattern classifications of the lymph nodes, which could predict metastatic lymph node involvement. Elastography is an imaging modality already available on certain EBUS processors, which permits the evaluation of the relative stiffness of the tissues. It has already been used in EUS studies for differentiating benign from malignant disease, and the data in EBUS are emerging.42,43 Although in the era of biomarker-driven lung cancer treatment tissue acquisition is still required, these processor functions may allow for selecting the intranodal region that lacks necrosis or has greatest amount of malignant tissue to further increase diagnostic yield, specimen quality, and quantity. In addition, the presence of certain sonographic characteristics may predict the lack of, or the presence of, malignant involvement. Evidence and clinical experience suggest that the presence of a “central hilar structure” on EBUS predicts a benign diagnosis (granulomatous inflammation, reactive lymph node), whereas the “coagulation necrosis sign” predicts malignancy40 (Fig 5). Research is needed to clarify how image patterns can alter posttest probability in cases of nondiagnostic EBUS specimens.

Should the Contralateral (N3), Hilar (Station 10), and Interlobar (Station 11) Nodes Be Sampled During Routine EBUS Staging?

In most trials comparing EBUS with mediastinoscopy for staging NSCLC, stations 2, 4, and 7 were evaluated and sampled by EBUS if they were > 5 mm on the short axis, starting with N3 and ending with N1 nodes. However, contralateral hilar and interlobar (station 10, 11) nodes were not sampled.3234 In one trial of EBUS-TBNA performed in patients with mediastinum negative on PET-CT scan that reports results on stations 10 and 11, none of the patients with confirmed lymph node involvement on EBUS had disease in a contralateral station 10 or 11.14 It is unclear, however, whether the contralateral station 10 and 11 were even sampled. Routinely sampling these stations may not be warranted for the following reasons: (1) in surgical staging, operators routinely sample only contralateral mediastinal (stations 2, 4) and not contralateral hilar and interlobar nodes (stations 10, 11); (2) sampling contralateral station 10 and 11 does not impact staging if a contralateral mediastinal (station 2 or 4) nodes are positive (ie, N3 disease is confirmed by sampling a mediastinal node). If the contralateral mediastinal stations2,4 are negative, and EBUS identifies a contralateral node > 5 mm (as it is often the case in station 11L or 11Rs, even when the CT and PET scans are negative), it is unknown whether these nodes should be routinely sampled. Two arguments favor this strategy: (1) the extremely rare possibility of identifying skipping metastasis to the contralateral hilum/interlobar nodes, and (2) the knowledge of hilar and interlobar N3 disease may affect the radiation field in stage IIIB. Specifically, the dose of radiation and pneumonitis risk are different when these nodes are included in planning. Research is needed to determine the value of this practice.

Should N1 Nodes Be Sampled During Routine EBUS Mediastinal Staging in Surgical Candidates?

Surgical series report that hilar pN1 disease has a worse prognosis than the more peripheral pN1.44 Intralobar pN1 could behave as pN0, and hilar pN1 could have similar prognosis as single-station pN2. Since it affects prognosis, this subdivision of the pN1 group justifies sampling of N1 nodes preoperatively,38 which is possible via EBUS.45 In patients with potentially resectable clinical N0 or N1 NSCLC based on CT and PET scan, EBUS demonstrated a sensitivity, specificity, diagnostic accuracy, and NPV to accurately differentiate between N0 and N1 disease of 76.2%, 100%, 96.6%, and 96.2%, respectively.45 These findings highlight the importance of exploring hilar nodes preoperatively either by EBUS or surgically for prognosis and potential induction therapy to cN1 disease confirmed pathologically.34,38,45

Induction therapy followed by surgery is an option for treating patients with stage IIIA NSCLC with discrete mediastinal node involvement.7 Studies demonstrate the benefit of induction chemotherapy to surgical resection for patients with clinical N2 disease.46 If this approach is chosen, the role of mediastinal restaging after induction therapy remains unclear, but downstaging and complete pathologic response are good prognostic factors. Some authorities suggest that surgery should only be performed in those patients who have a response in the mediastinum to induction therapy. In this regard, both CT and PET imaging for restaging have been shown to be inaccurate.47 Invasive restaging, therefore, is warranted if restaging is to be performed. Restaging of the ipsilateral N2 nodes by VATS has been done, but this is limited by radiation and sometimes anatomy (ie, 4R station), resulting in a sensitivity of only 67% and NPV of 73%.48 A repeat mediastinoscopy has a sensitivity of about 70% to 82% but may pose a technical challenge, and in some series the sensitivity was as low as 30%.12 As a general concept, the less invasive the staging is, the easier the restaging. Because a first-time mediastinoscopy may be the optimal way to accomplish mediastinal restaging, an argument can be made to always use a needle-based technique initially to document N2/3 involvement, as suggested by current guidelines, and to save mediastinoscopy, if needed, for restaging after induction therapy (Fig 6). Two studies, however, show that EBUS has a sensitivity of 64% and 76%, respectively, for restaging,49,50 so that EBUS may be attempted as a first restaging technique. There is still no reliable way of restaging the mediastinum, and none of the above-mentioned methods can be considered preferred. The choice may depend on the availability of EBUS, surgical expertise, and the invasive method used for the initial staging.

Figure Jump LinkFigure 6 –  Proposed restaging algorithm. This algorithm assumes that an adequate initial staging was performed and that patients are considered appropriate candidates for neoadjuvant therapy prior to surgical resection. *Ideally, the first staging procedure should be via EBUS-TBNA to save mediastinoscopy for restaging, if needed. There are data, however, supporting the role of EBUS-TBNA for restaging, which may be preferable, especially when the initial staging was performed via mediastinoscopy. **Repeat mediastinoscopy for restaging may be limited and may not offer a higher yield than EBUS-TBNA. See Figure 4 legend for expansion of abbreviations.Grahic Jump Location

Accurate assessment of mediastinal lymph node involvement in NSCLC is relevant for treatment and prognosis. Recently updated lung cancer guidelines recommend EBUS over surgical staging as a best first test for patients with intermediate and high suspicion of N2, 3 lymph node involvement. These include patients with discrete mediastinal lymph node enlargement on CT or PET scan uptake and patients with radiographically normal mediastinum (by CT and PET scan) and a central tumor, N1 lymph node enlargement, or tumor size > 3 cm. Preoperative invasive staging for clinical stage IA is not currently recommended, but EBUS staging may be warranted in nonsurgical candidates to confirm N0 disease prior to SBRT. EBUS-TBNA is a coordinated sequence of events that includes collection of relevant clinical information, optimal lymph node sampling, specimen preparation and staining, interpretation, communication, and reporting. Advancements in sampling techniques, ultrasound, and needle technology may further improve the diagnostic yield of EBUS and the quality of the samples to guide biomarker-driven lung cancer therapy

Financial/nonfinancial disclosures: The author has reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: I thank Ramon Rami Porta, MD (Thoracic Surgery Service, University Hospital Mutua de Terrassa, Barcelona, Spain) for his input regarding the algorithms for staging and restaging of the mediastinum, and Mark Ferguson, MD (Thoracic Surgery, University of Chicago) and Ravi Salgia (Medical Oncology, University of Chicago) for their assistance in developing the presented guidelines-based staging algorithm.

APW

aortopulmonary window

ATS

American Thoracic Society

EBUS

endobronchial ultrasound

ECM

extended cervical mediastinoscopy

EUS

esophageal ultrasound

FNA

fine-needle aspiration

IASLC

International Association for the Study of Lung Cancer

LUL

left upper lobe

MD-ATS

Mountain Dressler-Amaerican Thoracic Society

NPV

negative predictive value

NSCLC

non-small cell lung cancer

SBRT

stereotactic body radiation therapy

SEPAR

Spanish Society for Pulmonology and Thoracic Surgery

TBNA

transbronchial needle aspiration

VATS

video-assisted thoracic surgery

Farjah F, Flum DR, Ramsey SD, Heagerty PJ, Symons RG, Wood DE. Multi-modality mediastinal staging for lung cancer among medicare beneficiaries. J Thorac Oncol. 2009;4(3):355-363. [CrossRef] [PubMed]
 
NCCN guidelines version 2. National Comprehensive Cancer Network website. 2014; http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site. Accessed May 25, 2014.
 
Mohammed N, Kestin LL, Grills IS, et al. Rapid disease progression with delay in treatment of non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2011;79(2):466-472. [CrossRef] [PubMed]
 
Ost DE, Niu J, S Elting L, Buchholz TA, Giordano SH. Quality gaps and comparative effectiveness in lung cancer staging and diagnosis. Chest. 2014;145(2):331-345. [CrossRef] [PubMed]
 
Mazzone PJ, Vachani A, Chang A, et al. Quality indicators for the evaluation of patients with lung cancer. Chest. 2014;146(3):659-669. [CrossRef] [PubMed]
 
Travis WD, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011;6(2):244-285. [CrossRef] [PubMed]
 
Detterbeck FC, Lewis SZ, Diekemper R, Addrizzo-Harris D, Alberts WM. Executive summary: Diagnosis and management of lung cancer, 3rd ed: American College of Chest physicians evidence-based clinical practice guidelines. Chest. 2013;143(5_suppl):7S-37S. [CrossRef] [PubMed]
 
Sánchez de Cos J, Hernández JH, López MF, Sánchez SP, Gratacós AR, Porta RR; Sociedad Española Neumología y Cirugía Torácica. SEPAR guidelines for lung cancer staging. Arch Bronconeumol. 2011;47(9):454-465. [CrossRef] [PubMed]
 
Vansteenkiste J, De Ruysscher D, Eberhardt WE, et al; ESMO Guidelines Working Group. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(suppl 6):vi89-vi98. [CrossRef] [PubMed]
 
National Institute for Health and Care Excellence Clinical Guideline. 2011. Lung cancer: the diagnosis and treatment of lung cancer. National Institute for Health and Care Excellence website. http://egap.evidence.nhs.uk/lung-cancer-cg121. Accessed September 23, 2014.
 
Rusch VW, Asamura H, Watanabe H, Giroux DJ, Rami-Porta R, Goldstraw P; Members of IASLC Staging Committee. The IASLC lung cancer staging project: a proposal for a new international lymph node map in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol. 2009;4:568-577. [CrossRef] [PubMed]
 
Silvestri GA, Gonzalez AV, Jantz AV, et al. Methods for staging non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5_suppl):e211S-e250S. [CrossRef] [PubMed]
 
De Leyn P, Dooms C, Kuzdzal J, et al. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer. Eur J Cardiothorac Surg. 2014;45(5):787-798. [CrossRef] [PubMed]
 
Herth FJ, Eberhardt R, Krasnik M, Ernst A. Endobronchial ultrasound-guided transbronchial needle aspiration of lymph nodes in the radiologically and positron emission tomography-normal mediastinum in patients with lung cancer. Chest. 2008;133(4):887-891. [CrossRef] [PubMed]
 
Kurimoto N, Osada H, Miyazawa T, Nishisaka T, Muryama M. Targeting the area in metastatic lymph nodes for endobronchial ultrasound guided transbronchial needle aspiration. J Bronchol. 2008;15(3):134-138. [CrossRef]
 
Casal RF, Staerkel GA, Ost D, et al. Randomized clinical trial of endobronchial ultrasound needle biopsy with and without aspiration. Chest. 2012;142(3):568-573. [CrossRef] [PubMed]
 
The Papanicolaou Society of Cytopathology Task Force on Standards of Practice. Guidelines of the Papanicolaou Society of Cytopathology for fine-needle aspiration procedure and reporting. Diagn Cytopathol. 1997;17(4):239-247. [CrossRef] [PubMed]
 
Steinfort DP, Johnson DF, Irving LB. Infective complications from endobronchial ultrasound-transbronchial needle aspiration. Eur Respir J. 2009;34(2):524-525. [CrossRef] [PubMed]
 
Du Rand IA, Barber PV, Goldring J, et al; BTS Interventional Bronchoscopy Guideline Group. Summary of the British Thoracic Society guidelines for advanced diagnostic and therapeutic flexible bronchoscopy in adults. Thorax. 2011;66(11):1014-1015. [CrossRef] [PubMed]
 
Cerfolio RJ, Bryant AS, Eloubeidi MA. Routine mediastinoscopy and esophageal ultrasound fine-needle aspiration in patients with non-small cell lung cancer who are clinically N2 negative: a prospective study. Chest. 2006;130(6):1791-1795. [CrossRef] [PubMed]
 
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Mitera G, Swaminath A, Rudoler D, et al. Cost-effectiveness analysis comparing conventional versus stereotactic body radiotherapy for surgically ineligible stage I non-small-cell lung cancer. J Oncol Pract. 2014;10(3):e130-e136. [CrossRef] [PubMed]
 
Shah A, Hahn SM, Stetson RL, Friedberg JS, Pechet TT, Sher DJ. Cost-effectiveness of stereotactic body radiation therapy versus surgical resection for stage I non-small cell lung cancer. Cancer. 2013;119(17):3123-3132. [CrossRef] [PubMed]
 
Kilburn JM, Lester SC, Lucas JT Jr, et al. Management of mediastinal relapse after treatment with stereotactic body radiotherapy or accelerated hypofractionated radiotherapy for stage I/II non-small-cell lung cancer. J Thorac Oncol. 2014;9(4):572-576. [CrossRef] [PubMed]
 
Grills IS, Mangona VS, Welsh R, et al. Outcomes after stereotactic lung radiotherapy or wedge resection for stage I non-small-cell lung cancer. J Clin Oncol. 2010;28(6):928-935. [CrossRef] [PubMed]
 
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Yasufuku K. Endobronchial ultrasound-guided transbronchial needle aspiration for lymph node staging in patients with non-small cell lung cancer pursuing stereotactic body radiotherapy (SBRT). NCT01786590. ClinicalTrials.gov. Bethesda, MD: National Institutes of Health; 2013. http://clinicaltrials.gov/show/NCT01786590. Updated February 5, 2013.
 
Ernst A, Anantham D, Eberhardt R, Krasnik M, Herth FJ. Diagnosis of mediastinal adenopathy-real-time endobronchial ultrasound guided needle aspiration versus mediastinoscopy. J Thorac Oncol. 2008;3(6):577-582. [CrossRef] [PubMed]
 
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Rusch VW, Crowley J, Giroux DJ, et al; International Staging Committee; Cancer Research and Biostatistics; Observers to the Committee; Participating Institutions. The IASLC Lung Cancer Staging Project: proposals for the revision of the N descriptors in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol. 2007;2(7):603-612. [CrossRef] [PubMed]
 
Yasufuku K, Nakajima T, Waddell T, Keshavjee S, Yoshino I. Endobronchial ultrasound-guided transbronchial needle aspiration for differentiating N0 versus N1 lung cancer. Ann Thorac Surg. 2013;96(5):1756-1760. [CrossRef] [PubMed]
 
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Figures

Figure Jump LinkFigure 1 –  Radiographic characteristics of the primary tumor and associated interlobar, hilar, and mediastinal lymph nodes. The American College of Chest Physicians defines these groups based on CT scan findings; for the purpose of this article, the integrated CT-PET scan findings are illustrated. A, Group A involves patients with mediastinal infiltration; discrete lymph nodes can no longer be discerned or measured. Diagnosis is necessary, but mediastinal involvement is implied, and thus a mediastinal staging procedure is not indicated. B, Group B involves patients with mediastinal node enlargement, in whom the size of the discrete nodes can be measured. These patients require pathologic confirmation (ie, invasive staging). C, D, In Group C, the mediastinal lymph nodes are normal, but there is a high risk for occult N2/N3 disease based on the presence of suspected N1 disease (C) or a central tumor (D). These patients also need invasive staging prior to surgery. E, Group D is composed of patients with a peripheral clinical stage I tumor (the mediastinal, hilar, and interlobar nodes are normal on PET-CT scan). Invasive staging prior to surgery is not recommended in this group unless these patients are considered for stereotactic ablative surgery.Grahic Jump Location
Figure Jump LinkFigure 2 –  Diff Quik stains (rapid on-site cytology examination) of endobronchial ultrasound transbronchial needle aspiration specimens from patients with PET scan-positive mediastinal lymph nodes. All these specimens are considered diagnostic. A, Malignant cells suspicious for adenocarcinoma. B, Granuloma. C, Anthracotic pigment and anthracotic histiocytes. D, Abundant normal lymphocytes.Grahic Jump Location
Figure Jump LinkFigure 3 –  Diagram illustrating the mediastinal, hilar, and interlobar lymph node stations relevant for staging and accessible by endobronchial ultrasound transbronchial needle aspiration (stations 2, 4, 7, 10, and 11). The upper and lower borders are based on the revised International Association for the Study of Lung Cancer lymph node map. Station 2R includes nodes extending to the left lateral border of the trachea. The upper border is the apex of the right lung and pleural space and, in the midline, the upper border of the manubrium, and the lower border is the intersection of caudal margin of innominate vein with the trachea. Station 2L includes nodes extending to the left of the left lateral border of the trachea. The upper border is the apex of the left lung and pleural space and, in the midline, the upper border of the manubrium, and the lower border is the superior border of the aortic arch. Station 4R includes right lower paratracheal nodes and pretracheal nodes extending to the left lateral border of trachea. The upper border is the intersection of caudal margin of innominate vein with the trachea, and the lower border is the lower border of azygos vein. Station 7 is the subcarinal nodal station with the upper border composed of the carina of the trachea and the lower border composed of the upper border of the lower lobe bronchus on the left and the lower border of the bronchus intermedius on the right. Station 4L includes nodes to the left of the left lateral border of the trachea, medial to the ligamentum arteriosum. The upper border is the upper margin of the aortic arch, and the lower border is the upper rim of the left main pulmonary artery. Station 10R includes nodes immediately adjacent to the right mainstem bronchus and hilar vessels, including the proximal portions of the pulmonary veins and main pulmonary artery. The upper border is the lower rim of the azygos vein, and the lower border is the interlobar region between the right upper lobe and bronchus intermedius. Station 10L includes nodes immediately adjacent to the left mainstem bronchus and hilar vessels, including the proximal portions of the pulmonary veins and main pulmonary artery. The upper border is the upper rim of the left pulmonary artery, and the lower border is the interlobar region (left upper lobe and left lower lobe). Station 11R superior is composed of the nodes between the right upper lobe bronchus and bronchus intermedius. Station 11R inferior is between the middle and the right lower lobe bronchi. Station 11L is composed of the nodes between the origin of the left upper and lower lobar bronchi. Ao = aorta; PA = pulmonary artery.Grahic Jump Location
Figure Jump LinkFigure 4 –  Staging algorithm that incorporates recommendations from the following published evidence-based guidelines on lung cancer: American College of Chest Physicians (2013), European Society of Thoracic Surgeons (2014), National Comprehensive Cancer Network (2014,) and the Spanish Society for Pulmonology and Thoracic Surgery (2011). EBUS = endobronchial ultrasound; LN = lymph node; SUV = standard uptake value; TBNA = transbronchial needle aspiration; VAM = video-assisted mediastinoscopy.Grahic Jump Location
Figure Jump LinkFigure 5 –  A-C, Lymph node EBUS image patterns. D-G, Images obtained during EBUS-guided TBNA. A, Hypervascular node detected on Doppler mode; this finding may guide the operator to avoid using suction during TBNA to potentially prevent a bloody specimen. B, “Central hilar structure,” defined as a hyperechoic area in the center of the node (arrow), is a sonographic sign that may predict a benign etiology. C, Coagulation necrosis sign is characterized by hypoechoic areas (arrows) inside the node without blood flow (Doppler negative). Sometimes this can occupy the entire node. The presence of coagulation necrosis sign has a high specificity and hazard ratio for prediction of malignancy.40 D, EBUS-TBNA of the 4L lymph node; the needle is seen at the proximal aspect of the node. E, During the same maneuver, the needle is advanced to the distal capsule of the node; this back-and-forth movement from capsule to capsule is warranted, as malignant cells may cluster in subcapsular zones.15 F, EBUS-TBNA using a 25-gauge pro-core needle from a large mass. G, During the same maneuver, by extending the lever of the bronchoscope, the needle direction is changed to sample different areas of the node. See Figure 4 legend for expansion of abbreviations.Grahic Jump Location
Figure Jump LinkFigure 6 –  Proposed restaging algorithm. This algorithm assumes that an adequate initial staging was performed and that patients are considered appropriate candidates for neoadjuvant therapy prior to surgical resection. *Ideally, the first staging procedure should be via EBUS-TBNA to save mediastinoscopy for restaging, if needed. There are data, however, supporting the role of EBUS-TBNA for restaging, which may be preferable, especially when the initial staging was performed via mediastinoscopy. **Repeat mediastinoscopy for restaging may be limited and may not offer a higher yield than EBUS-TBNA. See Figure 4 legend for expansion of abbreviations.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Noninvasive and Invasive Staging Modalities Prior to Thoracotomy

AP = aortopulmonary; EBUS = endobronchial ultrasound; ECM = extended cervical mediastinoscopy; EUS = esophageal ultrasound; MED = mediastinoscopy; − = not accessible; + = Accessible; ± = occasional access, depending on lymph node size and operator technique; VAM = video-assisted mediastinoscopy; VATS = video-assisted thoracic surgery.

a 

Refers to the overall sensitivity for detecting metastasis in the mediastinal lymph nodes but results are not specific for individual lymph node stations.

b 

EUS has access mainly to left-sided lymph nodes.

c 

Access to anterior but not posterior subcarinal (station 7) nodes; MED also has access to stations 1 and 3.

d 

Only accessible by ECM, not by traditional cervical MED.

e 

Only for the lymph nodes on the side of the VATS.

f 

Specific results of VATS for these stations have not been reported.

Table Graphic Jump Location
TABLE 2 ]  EBUS-Guided Transbronchial Needle Sampling Technical Aspects

FNA = fine-needle aspiration. See Table 1 legend for expansion of other abbreviation.

a 

Capillary force or action refers to the ability of a medium (usually liquid) to flow in a narrow space (eg, small-gauge needle) against gravity. The medium is lifted up inside the needle as a result of cohesion and adhesive forces between the medium and the inner aspect of the needle. The height of the medium column inside the needle is inversely proportional to the radius of the needle, suggesting that the smaller the needle gauge, the more specimen is collected through the capillary action. The specimen is collected in the needle by nonsuction fine-needle sampling; this results in less nodal trauma and less blood in the smear without compromising specimen cellularity necessary for cytology diagnosis.

References

Farjah F, Flum DR, Ramsey SD, Heagerty PJ, Symons RG, Wood DE. Multi-modality mediastinal staging for lung cancer among medicare beneficiaries. J Thorac Oncol. 2009;4(3):355-363. [CrossRef] [PubMed]
 
NCCN guidelines version 2. National Comprehensive Cancer Network website. 2014; http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site. Accessed May 25, 2014.
 
Mohammed N, Kestin LL, Grills IS, et al. Rapid disease progression with delay in treatment of non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2011;79(2):466-472. [CrossRef] [PubMed]
 
Ost DE, Niu J, S Elting L, Buchholz TA, Giordano SH. Quality gaps and comparative effectiveness in lung cancer staging and diagnosis. Chest. 2014;145(2):331-345. [CrossRef] [PubMed]
 
Mazzone PJ, Vachani A, Chang A, et al. Quality indicators for the evaluation of patients with lung cancer. Chest. 2014;146(3):659-669. [CrossRef] [PubMed]
 
Travis WD, Brambilla E, Noguchi M, et al. International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary classification of lung adenocarcinoma. J Thorac Oncol. 2011;6(2):244-285. [CrossRef] [PubMed]
 
Detterbeck FC, Lewis SZ, Diekemper R, Addrizzo-Harris D, Alberts WM. Executive summary: Diagnosis and management of lung cancer, 3rd ed: American College of Chest physicians evidence-based clinical practice guidelines. Chest. 2013;143(5_suppl):7S-37S. [CrossRef] [PubMed]
 
Sánchez de Cos J, Hernández JH, López MF, Sánchez SP, Gratacós AR, Porta RR; Sociedad Española Neumología y Cirugía Torácica. SEPAR guidelines for lung cancer staging. Arch Bronconeumol. 2011;47(9):454-465. [CrossRef] [PubMed]
 
Vansteenkiste J, De Ruysscher D, Eberhardt WE, et al; ESMO Guidelines Working Group. Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(suppl 6):vi89-vi98. [CrossRef] [PubMed]
 
National Institute for Health and Care Excellence Clinical Guideline. 2011. Lung cancer: the diagnosis and treatment of lung cancer. National Institute for Health and Care Excellence website. http://egap.evidence.nhs.uk/lung-cancer-cg121. Accessed September 23, 2014.
 
Rusch VW, Asamura H, Watanabe H, Giroux DJ, Rami-Porta R, Goldstraw P; Members of IASLC Staging Committee. The IASLC lung cancer staging project: a proposal for a new international lymph node map in the forthcoming seventh edition of the TNM classification for lung cancer. J Thorac Oncol. 2009;4:568-577. [CrossRef] [PubMed]
 
Silvestri GA, Gonzalez AV, Jantz AV, et al. Methods for staging non-small cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2013;143(5_suppl):e211S-e250S. [CrossRef] [PubMed]
 
De Leyn P, Dooms C, Kuzdzal J, et al. Revised ESTS guidelines for preoperative mediastinal lymph node staging for non-small-cell lung cancer. Eur J Cardiothorac Surg. 2014;45(5):787-798. [CrossRef] [PubMed]
 
Herth FJ, Eberhardt R, Krasnik M, Ernst A. Endobronchial ultrasound-guided transbronchial needle aspiration of lymph nodes in the radiologically and positron emission tomography-normal mediastinum in patients with lung cancer. Chest. 2008;133(4):887-891. [CrossRef] [PubMed]
 
Kurimoto N, Osada H, Miyazawa T, Nishisaka T, Muryama M. Targeting the area in metastatic lymph nodes for endobronchial ultrasound guided transbronchial needle aspiration. J Bronchol. 2008;15(3):134-138. [CrossRef]
 
Casal RF, Staerkel GA, Ost D, et al. Randomized clinical trial of endobronchial ultrasound needle biopsy with and without aspiration. Chest. 2012;142(3):568-573. [CrossRef] [PubMed]
 
The Papanicolaou Society of Cytopathology Task Force on Standards of Practice. Guidelines of the Papanicolaou Society of Cytopathology for fine-needle aspiration procedure and reporting. Diagn Cytopathol. 1997;17(4):239-247. [CrossRef] [PubMed]
 
Steinfort DP, Johnson DF, Irving LB. Infective complications from endobronchial ultrasound-transbronchial needle aspiration. Eur Respir J. 2009;34(2):524-525. [CrossRef] [PubMed]
 
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