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INVITED REVIEW SERIES: UPDATE IN INTERVENTIONAL PULMONOLOGY SERIES EDITORS: FABIEN MALDONADO; ERIC S. EDELL; PATRICK J. BARRON AND REX C. YUNG
Multimodality systematic approach to mediastinal lymph node staging in non-small cell lung cancer TIMOTHY M. SAETTELE AND DAVID E. OST Department of Pulmonary Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, USA
ABSTRACT Establishing an accurate diagnosis and stage for nonsmall cell lung cancer has important implications for treatment and prognosis. Ideally, the process should be performed in a way that maximizes the information from each procedure while minimizing the risk to the patient. The concepts of decision analysis and Bayes’ theorem form a basis to develop the strategy. In this framework, the pre-test probability of malignancy is estimated in the lung nodule or mass, the regional lymph nodes and in distant sites. Invasive diagnostic tests are performed in sites with a pre-test probability greater than the testing threshold, beginning with those sites that would yield the highest stage, if positive. Modalities are chosen that are able to biopsy the suspicious sites and present the least amount of risk to the patient. Following each test, the post-test probability of malignancy is calculated to determine if it crosses the testing or test-treatment thresholds. The process continues with further tests until a diagnosis and stage are established. Key words: decision support technique, endobronchial ultrasound, neoplasm staging, non-small cell lung cancer, transbronchial needle aspiration.
Correspondence: David E. Ost, Department of Pulmonary Medicine, The University of Texas M.D. Anderson Cancer Center, Unit 1462, 1515 Holcombe Blvd, Houston, TX 77030, USA. Email: [email protected] The Authors: Dr. Saettele is an interventional pulmonology fellow at The University of Texas M.D. Anderson Cancer Center. His research interests include lung cancer diagnosis and staging and advanced diagnostic bronchoscopy. Dr. Ost is an associate professor in the Department of Pulmonary Medicine, Division of Internal Medicine, at The University of Texas MD Anderson Cancer Center. His areas of interest include diagnosis and staging of lung cancer using endobronchial ultrasound, comparative effectiveness of bronchial stenting, impact of bronchoscopic interventions on quality-adjusted survival and impact of indwelling pleural catheters on quality adjusted survival and health care resource utilization. Received 19 February 2014; invited to revise 3 March 2014; revised 19 March 2014; accepted 29 March 2014. Article first published online: 9 May 2014 © 2014 Asian Pacific Society of Respirology
Abbreviations: CT, computed tomography; EBUS, endobronchial ultrasound; PET, positron emission tomography; TBNA, transbronchial needle aspiration; VATS, video-assisted thoracoscopic surgery.
INTRODUCTION Lung cancer is responsible for more deaths than any other cancer type. About 85% of lung cancer is nonsmall cell lung cancer. Determination of the correct stage of disease has important implications for treatment. Overstaging occurs when a patient is incorrectly labelled as having more advanced disease than is actually present. Conversely, understaging occurs when a patient is thought to have less advanced disease than is present. In both situations, inappropriate treatment may be administered. With overstaging, potentially curative therapies like surgical resection may be withheld in favour of less effective treatments. With understaging, treatment directed at the more limited stage may be futile, increase morbidity and fail to address regional or distant metastases. In addition, since the stage of lung cancer is a key determinant of overall prognosis, any staging errors can lead to an inaccurate estimation of lifespan and the potential for cure. In a patient with possible non-small cell lung cancer, several key concepts should be considered in the diagnosis and staging process. Experienced clinicians intuitively apply these concepts without much formal analysis, but it is useful to address some of these ideas here. For instance, the likelihood that the suspicious nodule or mass represents malignancy is estimated based on individual patient factors and imaging characteristics. Similarly, a probability assessment is made as to the presence of metastases to regional lymph nodes and distant sites. The patient’s overall health status and ability to tolerate potential diagnostic tests and treatments are also considered. Based on these estimates, an overall patient-specific diagnosis and staging strategy is developed that addresses whether biopsies should be Respirology (2014) 19, 800–808 doi: 10.1111/resp.12310
Systematic lung cancer staging
performed, which sites should be biopsied, and which testing modalities should be utilized to establish the correct diagnosis and stage. An evidencebased, systematic approach for determining this strategy is indicated to gather the necessary information with as few procedures and as little risk to the patient as possible. The concepts of decision analysis and Bayes’ theorem form a basis for developing the diagnosis and staging strategy. In this framework, pre-test probabilities are calculated for the likelihood of malignancy being present in the nodule or mass, the regional lymph nodes and at distant sites. At the same time, a testing threshold and a test-treatment threshold are determined based on patient factors, test characteristics and possible treatment risks and benefits. The testing threshold is the distinct probability that separates when observation versus further testing should be performed. If the probability of disease is less than the testing threshold, an observation strategy will be best. The test-treatment threshold is the probability that separates when further testing versus proceeding directly to treatment should be performed. For example, in the case of a lung nodule, when the pre-test probability of malignancy is below the testing threshold, the lesion should be observed with serial chest computed tomography (CT) scans without performing more invasive testing. If the pre-test probability of malignancy is between the testing threshold and test-treatment threshold, then further evaluation is necessary. Finally, if the pretest probability of malignancy in the nodule is above the test-treatment threshold, therapies to treat the nodule (as malignant) are warranted. Similar concepts can be applied to regional lymph nodes and potential distant metastatic sites. Following the performance of any diagnostic test, the post-test probability of malignancy is calculated based on the pre-test probability and the sensitivity and specificity of the test. A positive result on a diagnostic test increases the post-test probability of malignancy, while a negative result decreases the post-test probability. Therefore, the goal of diagnostic testing is to move the post-test probability sufficiently lower or higher such that it falls below the testing threshold or above the test-treatment threshold. Detailed reviews of this topic have been published and are recommended for review.1,2 The purpose of this review is to propose a systematic, multimodality approach to mediastinal lymph node staging in non-small cell lung cancer. It will address the important factors to consider in a patient with suspected lung cancer, highlight the characteristics of the available testing modalities and guide the development of an overall strategy to diagnose and stage non-small cell lung cancer (see Fig. 1).
REVIEW Initial evaluation The evaluation of a patient with a lung nodule or mass begins with determining the pre-test probability that malignancy is present. At the same time, a determina© 2014 Asian Pacific Society of Respirology
801 tion of the patient’s overall health status is made to better understand which potential diagnostic procedures and therapeutic treatments the patient can tolerate. This information, in combination with the patient’s individual preferences, helps determine the testing and test-treatment thresholds. The initial evaluation entails performing a focused history, physical examination and basic laboratory testing looking for abnormalities that support the diagnosis or suggest metastases. Pulmonary function testing is performed to assess the patient’s risk associated with potential lung resection. The chest CT and positron emission tomography (PET) scans are reviewed to further refine the probability of malignancy. In addition to assessing the likelihood that the primary lung lesion is malignant, these imaging modalities allow assessment of the probability that metastases to the regional lymph nodes are present. In addition, whole body PET assesses for extrathoracic metastases as well. Based on all of this information, the likelihood of lung cancer is estimated and the testing and test-treatment thresholds are approximated. Note that experienced clinicians not only estimate the pre-test probability of cancer, they also estimate the pre-test probability of distant metastases and the pre-test probability of regional lymph node metastases. Based on their assessment of the patient’s comorbidities and pulmonary function, they are able to estimate the potential for benefits and harms of treatment. By the end of the initial evaluation, an initial clinical Tumor Node Metastasis (TNM) stage is estimated. In those patients with a pre-test probability for non-small cell lung cancer higher than the testing threshold, further evaluation is warranted.
Assessment for potential distant metastases The search for distant metastases should occur early in the diagnosis and staging process (see Fig. 1). The benefit of biopsying a potential distant metastatic site first is that a positive result establishes the diagnosis and stage with a single test. The pre-test probability for distant metastatic disease is determined based on abnormal findings from the patient’s history, physical exam, lab work and imaging tests. If the pre-test probability for a metastasis at a distant site is above the testing threshold, further evaluation of the suspicious site is indicated. For example, a hypermetabolic liver lesion on a PET scan increases the pre-test probability above the testing threshold, which should prompt further evaluation of the lesion. Similarly, focal neurologic symptoms or findings on exam raise the pretest probability of brain metastases above the testing threshold, and brain imaging is indicated. As with any invasive test, it is necessary to weigh the risks and benefits of biopsying a potential metastatic site. When the risk to benefit ratio is low, biopsy should be performed. In the case of a liver lesion easily accessible by percutaneous needle biopsy, the risk of complications is small and the biopsy is indicated. A positive result raises the post-test probability of malignancy above the test-treatment threshold, establishes the diagnosis and stages the patient with one procedure. Alternatively, the risk of biopsying a suspected brain metastasis identified by magnetic Respirology (2014) 19, 800–808
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TM Saettele and DE Ost
Figure 1 Algorithm to establish the diagnosis and stage of suspected non-small cell lung cancer. Evaluation begins by reviewing the patient’s clinical factors, imaging findings and pulmonary function. The pre-test probability of malignancy in the lung nodule or mass, mediastinal lymph nodes and distant sites is estimated. Biopsies are performed preferentially in sites with intermediate to high pre-test probability of malignancy that, if positive, would establish the diagnosis and stage in a single step. Preference is also given to sites and modalities that involve the least risk to the patient and the highest diagnostic yield. Potential distant metastatic sites are biopsied first, followed by N3 then N2 then N1 regional lymph nodes, then biopsy of the nodule or mass, if needed, until a diagnosis and stage are established. + indicates a positive test result. – indicates a negative test result. CT, computed tomography; EBUS-TBNA, endobronchial ultrasound transbronchial needle aspiration; PET, positron emission tomography; PFT’s, pulmonary function testing.
resonance imaging may outweigh the benefits. In certain cases, such as if the patient is experiencing symptomatic deficits from a brain lesion, surgical resection and biopsy may be indicated. However, if the probability of intracerebral metastases is above the test-treatment threshold already, like in a patient with cerebral lesions on imaging along with suspected widespread metastases in other sites (e.g. bone, liver, adrenals), it may be better to obtain tissue from another site to make the diagnosis and consider empiric treatment of the suspected brain metastases when therapy begins. Also, in the era of personalized medicine, another consideration should be to biopsy Respirology (2014) 19, 800–808
tissue that readily lends itself to molecular characterization, whenever possible. While a positive result from a bone biopsy establishes stage IV disease, it is less likely to provide adequate tissue for genetic testing than tissue obtained at other sites, and another biopsy may be required to obtain suitable tissue.3 All of these concepts are applied generally to potential metastases present at other sites until a diagnosis is made or there are no other sites to biopsy.
Mediastinal lymph node staging If the probability of distant metastases is lower than the testing threshold or biopsy of potential metastatic © 2014 Asian Pacific Society of Respirology
Systematic lung cancer staging
sites is considered too risky, then attention turns to determination of the nodal stage of disease (see Fig. 1). As with assessment for distant metastases, the first step is to determine the pre-test probability of malignancy in the regional lymph nodes. This process is best performed on a per-lymph node station basis. Considering the likelihood of lymph node metastases in each station will help in determining which lymph nodes should be biopsied and which invasive testing modalities should be utilized. Although imaging tests cannot definitively determine whether lymph node metastases are present, they offer important information that can assist in estimating the pre-test probability of metastatic involvement. A lymph node of 1 cm or larger on CT scan is considered abnormal and raises the probability of metastasis in that lymph node above the testing threshold.4 Likewise, increased metabolic activity above the background by PET suggests the presence of malignancy in that lymph node, although a specific abnormal standard uptake value has not been established.5 Note that these are the probability of metastasis being present in that particular lymph node. However, the probabilities of disease in the lymph nodes of a given patient are not independent of each other. If a patient has a central tumour or an enlarged (≥1 cm) or PET-positive N1 lymph node, the pre-test probability of occult N2 or N3 involvement is increased above the testing threshold.6 Occult in this context means that the lymph node actually harbours malignancy but it is ‘negative’ based on size criteria for CT and metabolic activity by PET. Other currently unknown factors may help in determining the likelihood of lymph node metastases and are currently being studied. The decision whether to biopsy lymph nodes is based on the pre-test probability of metastases in the individual lymph node stations. In patients who are surgical candidates, if the pre-test probability of mediastinal lymph node involvement is below the testing threshold, a separate procedure to stage the mediastinum may not be warranted if lymph node dissection will be performed at the time of surgery. This is particularly true in patients with small, peripheral T1 tumours without suspicious lymph nodes on imaging. However, in situations where non-surgical treatments, like stereotactic body radiation therapy, will be utilized and surgical lymph node staging will not be performed, the importance of knowing the status of N1 nodes with higher certainty increases, and the testing threshold for invasive mediastinal staging decreases. In practical terms, this means that invasive mediastinal and hilar lymph node staging becomes more important in patients who will not receive surgical lymph node staging. Based on the pre-test probability of lymph node metastases in each station, a decision is made as to whether invasive mediastinal staging is indicated. Patients who have regional lymph nodes with pre-test probabilities for metastatic involvement between the testing and test-treatment thresholds should go on to have invasive mediastinal staging performed. Alternatively, if no regional lymph nodes have a pre-test probability above the testing threshold, attention © 2014 Asian Pacific Society of Respirology
803 turns to evaluation of the nodule or mass. In the situation where the CT shows extensive tumour invasion into the mediastinum, the pre-test probability for mediastinal involvement is higher than the testtreatment threshold, and further mediastinal staging is not indicated. In this situation, a tissue diagnosis should be established with a procedure that involves the least risk to the patient. In patients with an intermediate to high pretest probability (above the testing threshold) of mediastinal lymph node metastases, the clinician chooses the most appropriate invasive testing modalities to biopsy the suspicious lymph nodes. The choice of which modality to utilize is based on several factors. A modality is chosen that is able to access as many of the suspicious nodal stations as possible (see Table 1). Consideration should also be given to those modalities that can access the highest stage lymph nodes that have a pre-test probability above the testing threshold. For instance, if the pre-test probability for malignancy is above the testing threshold for certain N2 and N3 lymph nodes, the best initial modality is one that can reach those N3 stations. If a modality is chosen that is only able to biopsy the N2 stations but cannot access the N3 stations, another procedure will be needed to sample the suspicious N3 nodes. In addition, the diagnostic characteristics of each test (see Table 2), the risk associated with each modality and the patient’s preferences should be taken into account.
Modalities to biopsy mediastinal and hilar lymph nodes Surgical lymph node dissection and staging through either thoracotomy or video-assisted thoracoscopic surgery (VATS) is the gold standard for lymph node staging. From the right side, surgical staging can reach most of the right side lymph nodes, including stations 2R, 3A/P, 4R, 7, 8, 9, 10R, 11R and more distal stations. From the left, stations 2L, 5, 6, 7, 8, 9, 10L, 11L and more distal stations can be reached. Stations 4L and 3A can also be reached from the left with extensive dissection and increased risk. The diagnostic yield is excellent, with sensitivities and specificities that approach 1.00.7 The disadvantages of VATS or thoracotomy for routine lymph node staging are the invasiveness of the procedures and the lack of access to lymph node stations on the contralateral side. Therefore, this modality is usually reserved for situations in which lobectomy will likely be performed, as it has therapeutic as well as diagnostic implications. Cervical mediastinoscopy was previously considered the pre-treatment procedure of choice to stage the mediastinum. It can routinely access stations 2R/L, 4R/L and anterior station 7 lymph nodes.16 Posterior station 7 lymph nodes are difficult to reach. For video cervical mediastinoscopy, the median sensitivity of the procedure for detecting malignancy is 0.89, and the specificity approaches 1.00.7 Dissection and complete lymphadenectomy increase the diagnostic yield. The procedure is considered low risk and can be performed on an outpatient basis, although it is Respirology (2014) 19, 800–808
804 Table 1
TM Saettele and DE Ost Lymph node stations accessible by invasive staging modality
Lymph Percutaneous node Endobronchial Endoscopic Cervical Anterior needle Right VATS/ Left VATS/ station ultrasound ultrasound mediastinoscopy mediastinoscopy biopsy* thoracotomy thoracotomy 1 2R 2L 3A 3P 4R 4L 5 6 7 8 9 10R 10L 11R 11L 12+
+ + + − + + + − − + − − + + + + ±
− − − − + − + ± − + + + − − − − −
− + + − − + + − − + − − − − − − −
− − − − − − − + + − − − − − − − −
+ + + + + + + + + + + + + + + + +
− + − + + + − − − + + + + − + − +
− − + + − − + + + + + + − + − + +
* Although percutaneous needle biopsy is technically able to reach all nodal stations, it is not practical to biopsy multiple stations with this approach. + indicates an accessible nodal station. − indicates an inaccessible nodal station. ± indicates a nodal station that is sometimes accessible. VATS, video-assisted thoracoscopic surgery.
Table 2 Test characteristics of various mediastinal staging modalities Modality CT7–10 PET7–12 Integrated PET-CT7 Endobronchial ultrasound7,13,14 Endoscopic ultrasound7,15 Cervical video mediastinoscopy7 Anterior mediastinoscopy7 Percutaneous needle biopsy7 VATS7
Sensitivity
Specificity
0.57–0.61 0.79–0.85 0.62 0.88–0.93 0.83–0.89 0.89 0.71 0.94 0.99
0.77–0.82 0.88–0.96 0.90 1.00 0.97–1.00 1.00 1.00 1.00 1.00
CT, computed tomography; PET, positron emission tomography; VATS, video-assisted thoracoscopic surgery.
more invasive than needle-based techniques. The complication rate is around 2.5%, and major complications occur in less than 0.5% of cases.16 Anterior mediastinoscopy, or the Chamberlain procedure, gives access to the station 5 and 6 lymph nodes that are not routinely accessible from a standard cervical mediastinoscopy. The median reported sensitivity of the procedure is 0.71, and the specificity approaches 1.00.7 Imaging-guided percutaneous needle biopsy can technically be used to sample all intrathoracic lymph node stations. However, using this modality to reach multiple stations in a single patient is not practical and carries a higher risk than the use of other modalities. In published series, pneumothorax occurred in 34–48% of patients, and 14–32% of all patients Respirology (2014) 19, 800–808
required placement of a thoracostomy tube.17,18 The performance characteristics of the procedure are excellent, with a median sensitivity of 0.94 and specificity of 1.00.7 Endoscopic ultrasound fine-needle aspiration was the first minimally invasive ultrasound-guided needle-based technique used for mediastinal staging in lung cancer. It allows routine access to stations 4L, 7, 8 and 9 from within the oesophagus. In some patients, the station 5 nodes are within reach as well. In addition, endoscopic ultrasound can sample some abdominal locations that are occasionally involved with metastases, including the left adrenal gland, liver and celiac lymph nodes. In published reviews, its sensitivity for detecting malignancy in these specific locations ranges from 0.83 to 0.89, and its specificity ranges from 0.97 to 1.00.7,15 The procedure is generally performed on an outpatient basis with sedation or under general anaesthesia. Complications occur in less than 1% of patients and are usually minor.15 Endobronchial ultrasound (EBUS) transbronchial needle aspiration (TBNA) has become the modality of choice to stage the mediastinum for many clinicians and is now recommended over surgical staging as the best first test in the American College of Chest Physicians lung cancer guidelines.6 By utilizing the airways to access lymph nodes, it is the only modality able to sample N1, N2 and N3 nodes in a single procedure. Specifically, it can access lymph nodes in stations 1, 2R/L, 3P, 4R/L, 7, 10R/L, 11R/L and some more distal lymph nodes and parenchymal lesions. EBUSTBNA has excellent performance characteristics. In three published systematic reviews, EBUS-TBNA has a sensitivity of 0.88–0.93 and a specificity that © 2014 Asian Pacific Society of Respirology
Systematic lung cancer staging
approaches 1.00 for detecting the correct nodal stage of malignancy.7,13,14 It has an overall complication rate of about 1.4%.19 Major complications include pneumothorax and haemorrhage, which occur in around 0.2% and 0.1% of patients, respectively. The procedure is performed under sedation or general anaesthesia, and patients are discharged home the same day.
Technical aspects of mediastinal staging To maximize their utility, the available evidence should guide the performance of any staging procedure. Much evidence is available supporting the best practices for the needle-based techniques. EBUS-TBNA and endoscopic ultrasound fine-needle aspiration correctly identify lymph node metastases in a significant number of patients with normal appearing mediastinal nodes by CT and PET.20–26 Likewise, using an ultrasound size sampling threshold of 5 mm instead of 10 mm increases the sensitivity of the procedure, as lymph node metastases commonly occur in nodes smaller than 10 mm in diameter. There is no evidence that rapid onsite cytologic evaluation improves the diagnostic yield of the procedure, although it may allow sampling of fewer lymph nodes and shorter procedure times. When rapid onsite evaluation is not available, evidence indicates that three aspirates per lymph node are sufficient to obtain diagnostic tissue, and more needle passes do not increase the diagnostic yield.27 Both techniques produce adequate tissue to perform molecular profiling in most positive samples, although more than three needle passes may be required to collect adequate tissue for analysis.28–30 Anecdotal experience has shown that performing five to eight needle passes is generally sufficient to obtain adequate tissue for genetic testing in a malignant lymph node. Feedback from the rapid onsite cytological assessment can also help ensure the adequacy of the sample. Applying suction to the aspiration needle has a similar diagnostic yield to aspiration performed without suction,31 and there is no difference in specimen adequacy or diagnostic yield between using 21-gauge and 22-gauge needles.32 There is no proven difference in diagnostic yield when the procedures are performed under general anaesthesia versus moderate sedation, although anaesthesia support may facilitate easier biopsy conditions.33 EBUS assessment of the lymph node stations should be performed systematically. To avoid potential overstaging, biopsies should occur from the highest stage lymph nodes (N3) first working to the lower stage nodes (N2, then N1). This practice prevents malignant cells being transferred from a malignant lower stage node to a higher stage sample by a contaminated needle. Stations 11R/L, 4R/L and 7 are assessed in every patient regardless of their appearance on CT and PET. Lymph nodes in these stations are aspirated if they measure 5 mm or larger in short axis. Anecdotal experience has shown that these stations are the ones most commonly involved by metastases. There is ongoing research to verify the validity of this approach. In addition, any other lymph nodes © 2014 Asian Pacific Society of Respirology
805 that have a pre-test probability above the testing threshold and are within reach of EBUS-TBNA are assessed and sampled. The other mediastinal staging procedures should also be performed in a systematic way using the best available evidence to guide them. For instance, cervical mediastinoscopy has the highest yield when lymph node dissection is performed. Ideally, stations 2R/L, 4R/L and 7 are assessed in every patient and biopsies taken from each site. Additionally, when surgical staging is performed at the time of lobectomy, lymph node dissection is superior to selective lymph node sampling, both for diagnostic and treatment purposes.
Assessment of post-test probability Following the performance of a procedure to stage the regional lymph nodes with pre-test-probabilities above the testing threshold, the post-test probability of malignancy in those lymph nodes is estimated (see Fig. 1). Due to the high specificities for all of the invasive tests, a positive biopsy result increases the posttest probability of malignancy to near 1.00 and crosses the treatment threshold, establishing a diagnosis and a stage. However, a negative or nondiagnostic biopsy result in a lymph node with a high pre-test probability may not sufficiently move the post-test probability to below the testing threshold. For example, because the false negative rate of EBUSTBNA is around 0.10, a negative biopsy result in a PET-positive, enlarged mediastinal lymph node in the setting of a large, central mass may not sufficiently rule out metastatic involvement in the node. In this situation, another modality like cervical mediastinoscopy is required to move the post-test probability across one of the thresholds. Following a staging procedure, it is also necessary to reassess the lymph node stations and determine whether other lymph nodes are present with a probability above the testing threshold that would increase the nodal stage or potentially change treatment if positive. If a lymph node fits into this category, then another modality should be performed to sample the node. For instance, consider a patient with a left upper lobe 3.5 cm mass, enlarged lymph nodes in stations 6, 7 and 4R, and no evidence of distant metastases. The patient’s initial clinical stage is T2a N3 M0. EBUS-TBNA is performed as the first test in order to evaluate the suspicious N2 and N3 lymph nodes. Assuming negative results in the standard nodal stations (11R, 4R, 7, 4L and 11L), the post-test probability for malignancy in stations 4R and 7 falls below the testing threshold. However, station 6 still has a pretest probability above the testing threshold, and another modality such as an anterior mediastinoscopy or CT-guided needle biopsy would be indicated for diagnosis and staging. Thoroughness levels for mediastinal staging tests have been proposed.34 These levels were developed from expert opinion and extrapolation of surgical studies and have not been definitively tested. However, they do provide a useful framework for discussion. The definition of thoroughness for surgical Respirology (2014) 19, 800–808
806 Table 3
TM Saettele and DE Ost Classification of the thoroughness of mediastinal staging of lung cancer34
Sampling level Complete
Systematic
Selective
Poor
Surgical staging
Needle-based staging
Complete lymphadenectomy of stations 1, 2R/L, 3, 4R/L, 7, 8; and 5, 6 if left upper lobe tumour Mediastinoscopy with sampling/exploration of 2R/L, 4R/L, 7; and 5, 6 if left upper lobe tumour Mediastinoscopy with biopsy of ≥1 station, and must include any node suspicious by imaging Mediastinoscopy with visual assessment only; no node biopsied or no nodal tissue in samples
Sampling of each visible node in stations 1, 2R/L, 3, 4R/L, 7, 8; and 5, 6 if left upper lobe tumour with ≥3 needle passes per node or rapid onsite cytologic evaluation Sampling of ≥1 node per station from 2R/L, 3, 4R/L, 7, 8; and 5, 6 if left upper lobe tumour with ≥3 needle passes per node or rapid onsite cytologic evaluation Biopsy of ≥1 station, which must include a node suspicious by imaging or ≥1 cm by ultrasound, or ≤3 passes and no rapid onsite cytologic evaluation Visual assessment only; no node biopsied or no lymphatic tissue in aspirates
and needle-based techniques is based on which lymph node stations are assessed, which lymph nodes are biopsied and how the biopsy is performed (see Table 3). For example, with regards to needlebased techniques, complete sampling is defined as biopsying every visible lymph node in each mediastinal nodal station (including stations 1, 2R/L, 3, 4R/L, 7, 8, and stations 5 and 6 if a left upper lobe tumour is present) and performing at least three needle passes per lymph node or using rapid onsite cytologic evaluation. Systematic sampling differs from complete in that nodes from each station are sampled, but not every visible lymph node in each station is biopsied. Selective sampling is defined as biopsy of at least one mediastinal nodal station, including a node suspicious by imaging or at least 1 cm in diameter when assessed by ultrasound, if present. Also, if less than three needle passes are made and rapid onsite evaluation is not available, the sampling classification is considered selective. Finally, poor needle-based sampling defines a staging procedure in which no lymph node is biopsied or lymphatic tissue is absent in the aspirates. The classification of thoroughness for surgical and imagingbased staging modalities are defined similarly, although variations exist with the technical details of each test. The mediastinal staging strategy outlined above is a variation of the ‘systematic’ level of thoroughness. The difference is that not all nodal stations are assessed with a given modality. Certain lymph node stations are always evaluated, and other stations are sampled if they contain lymph nodes with a pre-test probability above the testing threshold. The modality that would give the highest nodal stage, if positive, is the first test that is chosen. Other factors are also considered, like the diagnostic yield, the invasiveness of the test and the patient’s preferences. This approach gives flexibility to the staging strategy and minimizes sampling of lymph node stations that are unlikely to be involved by malignancy. In addition, there is no evidence to suggest that the ‘complete’ level of thoroughness outlined above produces superior results to Respirology (2014) 19, 800–808
‘systematic’ sampling. In fact, ‘complete’ mediastinal staging has the tendency to increase the number of performed procedures, procedure time, risk and cost without proven benefit. Note that the strategy outlined above emphasizes the systematic use of multiple modalities in combination. For example, in a patient with a left upper lobe 3.5 cm mass and enlarged lymph nodes in stations 6, 7 and 4R without evidence of distant metastases, EBUS-TBNA would be the first test. Depending on the results, CT-guided biopsy or anterior mediastinoscopy might be necessary. The question of what is the optimal staging strategy is not answered by choosing a single test, but rather by selecting the proper combination and sequence of tests that together will provide the necessary information to stage and diagnose the patient with the least risk. Too often discussions on staging revolve around which one test is best. That is fundamentally the wrong question. The correct question is which tests in what sequence are appropriate for each particular patient. Thus, the form of the answer is not a single test, but rather must be a method of systematically thinking about the problem in each patient based on individual prior probabilities of disease, benefits and harms.
EVALUATION OF THE LUNG NODULE/MASS After adequate assessment of the regional lymph nodes, if a diagnosis has still not been established, then consideration is given to biopsy of the suspicious nodule or mass. The pre-test probability of malignancy is estimated using clinical factors, like age, smoking history and cancer history, and radiographic characteristics, like tumour location, size and appearance.2,35 If the pre-test probability is below the testing threshold, the patient is observed over time with serial chest imaging examinations per standard guidelines.36 Patients with a pre-test probability of malignancy above the testing threshold should undergo biopsy of the primary lesion to establish a © 2014 Asian Pacific Society of Respirology
Systematic lung cancer staging
diagnosis. If the pre-test probability is above the testtreatment threshold and the patient is appropriate for surgical treatment, then wedge resection followed by completion lobectomy, if the wedge sample is positive, and mediastinal lymph node dissection may be the best choice to establish the diagnosis and stage and treat the patient with a single procedure.
CONCLUSION In summary, decision analysis is a useful tool for developing an overall diagnosis and staging strategy for patients with suspected lung cancer. Determining the pre-test probability of malignancy in the primary nodule or mass, the regional lymph nodes and at distant sites should be at the centre of this process. Attention is given to establishing the diagnosis and stage with as little risk to the patient and with as few procedures as possible. This begins with a search for distant metastases and obtaining tissue from any suspicious site that has an acceptable risk of biopsy. Next, the likelihood of lymph node metastases is estimated, and a modality is chosen to sample lymph nodes with pre-test probabilities above the testing threshold, favouring tests that are less invasive and give the most amount of information. Finally, if a diagnosis and stage are not yet established after systematic examination and sampling of the mediastinal lymph nodes, biopsy or surgical resection of the primary nodule or mass is performed. Following these principles should allow an accurate diagnosis and stage to be established in a safe and efficient way.
REFERENCES 1 Pauker SG, Kassirer JP. The threshold approach to clinical decision making. N. Engl. J. Med. 1980; 302: 1109–17. 2 Ost DE, Gould MK. Decision making in patients with pulmonary nodules. Am. J. Respir. Crit. Care Med. 2012; 185: 363–72. 3 Arcila ME, Oxnard GR, Nafa K, Riely GJ, Solomon SB, Zakowski MF, Kris MG, Pao W, Miller VA, Ladanyi M. Rebiopsy of lung cancer patients with acquired resistance to EGFR inhibitors and enhanced detection of the T790M mutation using a locked nucleic acid-based assay. Clin. Cancer Res. 2011; 17: 1169–80. 4 Pozo-Rodriguez F, Martin de Nicolas JL, Sanchez-Nistal MA, Maldonado A, Garcia de Barajas S, Calero-Garcia R, Pozo MA, Martin-Escribano P, Martin-Garcia I, Garcia-Lujan R et al. Accuracy of helical computed tomography and [18F] fluorodeoxyglucose positron emission tomography for identifying lymph node mediastinal metastases in potentially resectable non-small-cell lung cancer. J. Clin. Oncol. 2005; 23: 8348–56. 5 Cerfolio RJ, Bryant AS, Ojha B, Eloubeidi M. Improving the inaccuracies of clinical staging of patients with NSCLC: a prospective trial. Ann. Thorac. Surg. 2005; 80: 1207–13, discussion 13–4. 6 Verhagen AF, Bootsma GP, Tjan-Heijnen VC, van der Wilt GJ, Cox AL, Brouwer MH, Corstens FH, Oyen WJ. FDG-PET in staging lung cancer: how does it change the algorithm? Lung Cancer 2004; 44: 175–81. 7 Silvestri GA, Gonzalez AV, Jantz MA, Margolis ML, Gould MK, Tanoue LT, Harris LJ, Detterbeck FC. Methods for staging nonsmall cell lung cancer: diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidencebased clinical practice guidelines. Chest 2013; 143: e211S–50S. © 2014 Asian Pacific Society of Respirology
807 8 Dwamena BA, Sonnad SS, Angobaldo JO, Wahl RL. Metastases from non-small cell lung cancer: mediastinal staging in the 1990s–meta-analytic comparison of PET and CT. Radiology 1999; 213: 530–6. 9 Gould MK, Kuschner WG, Rydzak CE, Maclean CC, Demas AN, Shigemitsu H, Chan JK, Owens DK. Test performance of positron emission tomography and computed tomography for mediastinal staging in patients with non-small-cell lung cancer: a meta-analysis. Ann. Intern. Med. 2003; 139: 879–92. 10 Toloza EM, Harpole L, McCrory DC. Noninvasive staging of nonsmall cell lung cancer: a review of the current evidence. Chest 2003; 123: 137S–46S. 11 Birim O, Kappetein AP, Stijnen T, Bogers AJ. Meta-analysis of positron emission tomographic and computed tomographic imaging in detecting mediastinal lymph node metastases in nonsmall cell lung cancer. Ann. Thorac. Surg. 2005; 79: 375–82. 12 Fischer BM, Mortensen J, Hojgaard L. Positron emission tomography in the diagnosis and staging of lung cancer: a systematic, quantitative review. Lancet Oncol. 2001; 2: 659–66. 13 Gu P, Zhao YZ, Jiang LY, Zhang W, Xin Y, Han BH. Endobronchial ultrasound-guided transbronchial needle aspiration for staging of lung cancer: a systematic review and meta-analysis. Eur. J. Cancer 2009; 45: 1389–96. 14 Adams K, Shah PL, Edmonds L, Lim E. Test performance of endobronchial ultrasound and transbronchial needle aspiration biopsy for mediastinal staging in patients with lung cancer: systematic review and meta-analysis. Thorax 2009; 64: 757–62. 15 Micames CG, McCrory DC, Pavey DA, Jowell PS, Gress FG. Endoscopic ultrasound-guided fine-needle aspiration for non-small cell lung cancer staging: a systematic review and metaanalysis. Chest 2007; 131: 539–48. 16 Leyn PD, Lerut T. Conventional mediastinoscopy. Multimed Man Cardiothorac Surg 2005; 2005: 1–10. mmcts 2004 000158. 17 Avritscher R, Krishnamurthy S, Ensor J, Gupta S, Tam A, Madoff DC, Murthy R, Hicks ME, Wallace MJ. Accuracy and sensitivity of computed tomography-guided percutaneous needle biopsy of pulmonary hilar lymph nodes. Cancer 2010; 116: 1974–80. 18 Protopapas Z, Westcott JL. Transthoracic needle biopsy of mediastinal lymph nodes for staging lung and other cancers. Radiology 1996; 199: 489–96. 19 Eapen GA, Shah AM, Lei X, Jimenez CA, Morice RC, Yarmus L, Filner J, Ray C, Michaud G, Greenhill SR et al. Complications, consequences, and practice patterns of endobronchial ultrasound-guided transbronchial needle aspiration: results of the AQuIRE registry. Chest 2013; 143: 1044–53. 20 Herth FJ, Eberhardt R, Krasnik M, Ernst A. Endobronchial ultrasound-guided transbronchial needle aspiration of lymph nodes in the radiologically and positron emission tomographynormal mediastinum in patients with lung cancer. Chest 2008; 133: 887–91. 21 Herth FJ, Ernst A, Eberhardt R, Vilmann P, Dienemann H, Krasnik M. Endobronchial ultrasound-guided transbronchial needle aspiration of lymph nodes in the radiologically normal mediastinum. Eur. Respir. J. 2006; 28: 910–14. 22 Wallace MB, Ravenel J, Block MI, Fraig M, Silvestri G, Wildi S, Schmulewitz N, Varadarajulu S, Roberts S, Hoffman BJ et al. Endoscopic ultrasound in lung cancer patients with a normal mediastinum on computed tomography. Ann. Thorac. Surg. 2004; 77: 1763–8. 23 Fritscher-Ravens A, Davidson BL, Hauber HP, Bohuslavizki KH, Bobrowski C, Lund C, Knofel WT, Soehendra N, Brandt L, Pepe MS et al. Endoscopic ultrasound, positron emission tomography, and computerized tomography for lung cancer. Am. J. Respir. Crit. Care Med. 2003; 168: 1293–7. 24 Yasufuku K, Nakajima T, Motoori K, Sekine Y, Shibuya K, Hiroshima K, Fujisawa T. Comparison of endobronchial ultrasound, positron emission tomography, and CT for lymph node staging of lung cancer. Chest 2006; 130: 710–18. 25 Cornwell LD, Bakaeen FG, Lan CK, Omer S, Preventza O, Pickrell B, Nguyen A, Casal RF. Endobronchial ultrasonography-guided Respirology (2014) 19, 800–808
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transbronchial needle aspiration biopsy for preoperative nodal staging of lung cancer in a veteran population. JAMA Surg 2013; 148: 1024–9. Ost DE, Ernst A, Lei X, Feller-Kopman D, Eapen GA, Kovitz KL, Herth FJ, Simoff M. Diagnostic yield of endobronchial ultrasound-guided transbronchial needle aspiration: results of the AQuIRE Bronchoscopy Registry. Chest 2011; 140: 1557–66. Lee HS, Lee GK, Kim MS, Lee JM, Kim HY, Nam BH, Zo JI, Hwangbo B. Real-time endobronchial ultrasound-guided transbronchial needle aspiration in mediastinal staging of nonsmall cell lung cancer: how many aspirations per target lymph node station? Chest 2008; 134: 368–74. Garcia-Olive I, Monso E, Andreo F, Sanz-Santos J, Taron M, Molina-Vila MA, Llatjos M, Castella E, Moran T, Bertran-Alamillo J et al. Endobronchial ultrasound-guided transbronchial needle aspiration for identifying EGFR mutations. Eur. Respir. J. 2010; 35: 391–5. Santis G, Angell R, Nickless G, Quinn A, Herbert A, Cane P, Spicer J, Breen R, McLean E, Tobal K. Screening for EGFR and KRAS mutations in endobronchial ultrasound derived transbronchial needle aspirates in non-small cell lung cancer using COLD-PCR. PLoS ONE 2011; 6: e25191. Schuurbiers OC, Looijen-Salamon MG, Ligtenberg MJ, van der Heijden HF. A brief retrospective report on the feasibility of epidermal growth factor receptor and KRAS mutation analysis in transesophageal ultrasound- and endobronchial ultrasoundguided fine needle cytological aspirates. J. Thorac. Oncol. 2010; 5: 1664–7.
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TM Saettele and DE Ost 31 Casal RF, Staerkel GA, Ost D, Almeida FA, Uzbeck MH, Eapen GA, Jimenez CA, Nogueras-Gonzalez GM, Sarkiss M, Morice RC. Randomized clinical trial of endobronchial ultrasound needle biopsy with and without aspiration. Chest 2012; 142: 568– 73. 32 Yarmus LB, Akulian J, Lechtzin N, Yasin F, Kamdar B, Ernst A, Ost DE, Ray C, Greenhill SR, Jimenez CA et al. Comparison of 21-gauge and 22-gauge aspiration needle in endobronchial ultrasound-guided transbronchial needle aspiration: results of the American College of Chest Physicians Quality Improvement Registry, Education, and Evaluation Registry. Chest 2013; 143: 1036–43. 33 Kennedy MP, Shweihat Y, Sarkiss M, Eapen GA. Complete mediastinal and hilar lymph node staging of primary lung cancer by endobronchial ultrasound: moderate sedation or general anesthesia? Chest 2008; 134: 1350–1, author reply 1. 34 Detterbeck F, Puchalski J, Rubinowitz A, Cheng D. Classification of the thoroughness of mediastinal staging of lung cancer. Chest 2010; 137: 436–42. 35 Swensen SJ, Silverstein MD, Ilstrup DM, Schleck CD, Edell ES. The probability of malignancy in solitary pulmonary nodules. Application to small radiologically indeterminate nodules. Arch. Intern. Med. 1997; 157: 849–55. 36 MacMahon H, Austin JH, Gamsu G, Herold CJ, Jett JR, Naidich DP, Patz EF Jr, Swensen SJ. Guidelines for management of small pulmonary nodules detected on CT scans: a statement from the Fleischner Society. Radiology 2005; 237: 395–400.
© 2014 Asian Pacific Society of Respirology
INVITED REVIEW SERIES: UPDATE IN INTERVENTIONAL PULMONOLOGY SERIES EDITORS: FABIEN MALDONADO; ERIC S. EDELL; PATRICK J. BARRON AND REX C. YUNG
Multimodality systematic approach to mediastinal lymph node staging in non-small cell lung cancer TIMOTHY M. SAETTELE AND DAVID E. OST Department of Pulmonary Medicine, The University of Texas M.D. Anderson Cancer Center, Houston, USA
ABSTRACT Establishing an accurate diagnosis and stage for nonsmall cell lung cancer has important implications for treatment and prognosis. Ideally, the process should be performed in a way that maximizes the information from each procedure while minimizing the risk to the patient. The concepts of decision analysis and Bayes’ theorem form a basis to develop the strategy. In this framework, the pre-test probability of malignancy is estimated in the lung nodule or mass, the regional lymph nodes and in distant sites. Invasive diagnostic tests are performed in sites with a pre-test probability greater than the testing threshold, beginning with those sites that would yield the highest stage, if positive. Modalities are chosen that are able to biopsy the suspicious sites and present the least amount of risk to the patient. Following each test, the post-test probability of malignancy is calculated to determine if it crosses the testing or test-treatment thresholds. The process continues with further tests until a diagnosis and stage are established. Key words: decision support technique, endobronchial ultrasound, neoplasm staging, non-small cell lung cancer, transbronchial needle aspiration.
Correspondence: David E. Ost, Department of Pulmonary Medicine, The University of Texas M.D. Anderson Cancer Center, Unit 1462, 1515 Holcombe Blvd, Houston, TX 77030, USA. Email: [email protected] The Authors: Dr. Saettele is an interventional pulmonology fellow at The University of Texas M.D. Anderson Cancer Center. His research interests include lung cancer diagnosis and staging and advanced diagnostic bronchoscopy. Dr. Ost is an associate professor in the Department of Pulmonary Medicine, Division of Internal Medicine, at The University of Texas MD Anderson Cancer Center. His areas of interest include diagnosis and staging of lung cancer using endobronchial ultrasound, comparative effectiveness of bronchial stenting, impact of bronchoscopic interventions on quality-adjusted survival and impact of indwelling pleural catheters on quality adjusted survival and health care resource utilization. Received 19 February 2014; invited to revise 3 March 2014; revised 19 March 2014; accepted 29 March 2014. Article first published online: 9 May 2014 © 2014 Asian Pacific Society of Respirology
Abbreviations: CT, computed tomography; EBUS, endobronchial ultrasound; PET, positron emission tomography; TBNA, transbronchial needle aspiration; VATS, video-assisted thoracoscopic surgery.
INTRODUCTION Lung cancer is responsible for more deaths than any other cancer type. About 85% of lung cancer is nonsmall cell lung cancer. Determination of the correct stage of disease has important implications for treatment. Overstaging occurs when a patient is incorrectly labelled as having more advanced disease than is actually present. Conversely, understaging occurs when a patient is thought to have less advanced disease than is present. In both situations, inappropriate treatment may be administered. With overstaging, potentially curative therapies like surgical resection may be withheld in favour of less effective treatments. With understaging, treatment directed at the more limited stage may be futile, increase morbidity and fail to address regional or distant metastases. In addition, since the stage of lung cancer is a key determinant of overall prognosis, any staging errors can lead to an inaccurate estimation of lifespan and the potential for cure. In a patient with possible non-small cell lung cancer, several key concepts should be considered in the diagnosis and staging process. Experienced clinicians intuitively apply these concepts without much formal analysis, but it is useful to address some of these ideas here. For instance, the likelihood that the suspicious nodule or mass represents malignancy is estimated based on individual patient factors and imaging characteristics. Similarly, a probability assessment is made as to the presence of metastases to regional lymph nodes and distant sites. The patient’s overall health status and ability to tolerate potential diagnostic tests and treatments are also considered. Based on these estimates, an overall patient-specific diagnosis and staging strategy is developed that addresses whether biopsies should be Respirology (2014) 19, 800–808 doi: 10.1111/resp.12310
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performed, which sites should be biopsied, and which testing modalities should be utilized to establish the correct diagnosis and stage. An evidencebased, systematic approach for determining this strategy is indicated to gather the necessary information with as few procedures and as little risk to the patient as possible. The concepts of decision analysis and Bayes’ theorem form a basis for developing the diagnosis and staging strategy. In this framework, pre-test probabilities are calculated for the likelihood of malignancy being present in the nodule or mass, the regional lymph nodes and at distant sites. At the same time, a testing threshold and a test-treatment threshold are determined based on patient factors, test characteristics and possible treatment risks and benefits. The testing threshold is the distinct probability that separates when observation versus further testing should be performed. If the probability of disease is less than the testing threshold, an observation strategy will be best. The test-treatment threshold is the probability that separates when further testing versus proceeding directly to treatment should be performed. For example, in the case of a lung nodule, when the pre-test probability of malignancy is below the testing threshold, the lesion should be observed with serial chest computed tomography (CT) scans without performing more invasive testing. If the pre-test probability of malignancy is between the testing threshold and test-treatment threshold, then further evaluation is necessary. Finally, if the pretest probability of malignancy in the nodule is above the test-treatment threshold, therapies to treat the nodule (as malignant) are warranted. Similar concepts can be applied to regional lymph nodes and potential distant metastatic sites. Following the performance of any diagnostic test, the post-test probability of malignancy is calculated based on the pre-test probability and the sensitivity and specificity of the test. A positive result on a diagnostic test increases the post-test probability of malignancy, while a negative result decreases the post-test probability. Therefore, the goal of diagnostic testing is to move the post-test probability sufficiently lower or higher such that it falls below the testing threshold or above the test-treatment threshold. Detailed reviews of this topic have been published and are recommended for review.1,2 The purpose of this review is to propose a systematic, multimodality approach to mediastinal lymph node staging in non-small cell lung cancer. It will address the important factors to consider in a patient with suspected lung cancer, highlight the characteristics of the available testing modalities and guide the development of an overall strategy to diagnose and stage non-small cell lung cancer (see Fig. 1).
REVIEW Initial evaluation The evaluation of a patient with a lung nodule or mass begins with determining the pre-test probability that malignancy is present. At the same time, a determina© 2014 Asian Pacific Society of Respirology
801 tion of the patient’s overall health status is made to better understand which potential diagnostic procedures and therapeutic treatments the patient can tolerate. This information, in combination with the patient’s individual preferences, helps determine the testing and test-treatment thresholds. The initial evaluation entails performing a focused history, physical examination and basic laboratory testing looking for abnormalities that support the diagnosis or suggest metastases. Pulmonary function testing is performed to assess the patient’s risk associated with potential lung resection. The chest CT and positron emission tomography (PET) scans are reviewed to further refine the probability of malignancy. In addition to assessing the likelihood that the primary lung lesion is malignant, these imaging modalities allow assessment of the probability that metastases to the regional lymph nodes are present. In addition, whole body PET assesses for extrathoracic metastases as well. Based on all of this information, the likelihood of lung cancer is estimated and the testing and test-treatment thresholds are approximated. Note that experienced clinicians not only estimate the pre-test probability of cancer, they also estimate the pre-test probability of distant metastases and the pre-test probability of regional lymph node metastases. Based on their assessment of the patient’s comorbidities and pulmonary function, they are able to estimate the potential for benefits and harms of treatment. By the end of the initial evaluation, an initial clinical Tumor Node Metastasis (TNM) stage is estimated. In those patients with a pre-test probability for non-small cell lung cancer higher than the testing threshold, further evaluation is warranted.
Assessment for potential distant metastases The search for distant metastases should occur early in the diagnosis and staging process (see Fig. 1). The benefit of biopsying a potential distant metastatic site first is that a positive result establishes the diagnosis and stage with a single test. The pre-test probability for distant metastatic disease is determined based on abnormal findings from the patient’s history, physical exam, lab work and imaging tests. If the pre-test probability for a metastasis at a distant site is above the testing threshold, further evaluation of the suspicious site is indicated. For example, a hypermetabolic liver lesion on a PET scan increases the pre-test probability above the testing threshold, which should prompt further evaluation of the lesion. Similarly, focal neurologic symptoms or findings on exam raise the pretest probability of brain metastases above the testing threshold, and brain imaging is indicated. As with any invasive test, it is necessary to weigh the risks and benefits of biopsying a potential metastatic site. When the risk to benefit ratio is low, biopsy should be performed. In the case of a liver lesion easily accessible by percutaneous needle biopsy, the risk of complications is small and the biopsy is indicated. A positive result raises the post-test probability of malignancy above the test-treatment threshold, establishes the diagnosis and stages the patient with one procedure. Alternatively, the risk of biopsying a suspected brain metastasis identified by magnetic Respirology (2014) 19, 800–808
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Figure 1 Algorithm to establish the diagnosis and stage of suspected non-small cell lung cancer. Evaluation begins by reviewing the patient’s clinical factors, imaging findings and pulmonary function. The pre-test probability of malignancy in the lung nodule or mass, mediastinal lymph nodes and distant sites is estimated. Biopsies are performed preferentially in sites with intermediate to high pre-test probability of malignancy that, if positive, would establish the diagnosis and stage in a single step. Preference is also given to sites and modalities that involve the least risk to the patient and the highest diagnostic yield. Potential distant metastatic sites are biopsied first, followed by N3 then N2 then N1 regional lymph nodes, then biopsy of the nodule or mass, if needed, until a diagnosis and stage are established. + indicates a positive test result. – indicates a negative test result. CT, computed tomography; EBUS-TBNA, endobronchial ultrasound transbronchial needle aspiration; PET, positron emission tomography; PFT’s, pulmonary function testing.
resonance imaging may outweigh the benefits. In certain cases, such as if the patient is experiencing symptomatic deficits from a brain lesion, surgical resection and biopsy may be indicated. However, if the probability of intracerebral metastases is above the test-treatment threshold already, like in a patient with cerebral lesions on imaging along with suspected widespread metastases in other sites (e.g. bone, liver, adrenals), it may be better to obtain tissue from another site to make the diagnosis and consider empiric treatment of the suspected brain metastases when therapy begins. Also, in the era of personalized medicine, another consideration should be to biopsy Respirology (2014) 19, 800–808
tissue that readily lends itself to molecular characterization, whenever possible. While a positive result from a bone biopsy establishes stage IV disease, it is less likely to provide adequate tissue for genetic testing than tissue obtained at other sites, and another biopsy may be required to obtain suitable tissue.3 All of these concepts are applied generally to potential metastases present at other sites until a diagnosis is made or there are no other sites to biopsy.
Mediastinal lymph node staging If the probability of distant metastases is lower than the testing threshold or biopsy of potential metastatic © 2014 Asian Pacific Society of Respirology
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sites is considered too risky, then attention turns to determination of the nodal stage of disease (see Fig. 1). As with assessment for distant metastases, the first step is to determine the pre-test probability of malignancy in the regional lymph nodes. This process is best performed on a per-lymph node station basis. Considering the likelihood of lymph node metastases in each station will help in determining which lymph nodes should be biopsied and which invasive testing modalities should be utilized. Although imaging tests cannot definitively determine whether lymph node metastases are present, they offer important information that can assist in estimating the pre-test probability of metastatic involvement. A lymph node of 1 cm or larger on CT scan is considered abnormal and raises the probability of metastasis in that lymph node above the testing threshold.4 Likewise, increased metabolic activity above the background by PET suggests the presence of malignancy in that lymph node, although a specific abnormal standard uptake value has not been established.5 Note that these are the probability of metastasis being present in that particular lymph node. However, the probabilities of disease in the lymph nodes of a given patient are not independent of each other. If a patient has a central tumour or an enlarged (≥1 cm) or PET-positive N1 lymph node, the pre-test probability of occult N2 or N3 involvement is increased above the testing threshold.6 Occult in this context means that the lymph node actually harbours malignancy but it is ‘negative’ based on size criteria for CT and metabolic activity by PET. Other currently unknown factors may help in determining the likelihood of lymph node metastases and are currently being studied. The decision whether to biopsy lymph nodes is based on the pre-test probability of metastases in the individual lymph node stations. In patients who are surgical candidates, if the pre-test probability of mediastinal lymph node involvement is below the testing threshold, a separate procedure to stage the mediastinum may not be warranted if lymph node dissection will be performed at the time of surgery. This is particularly true in patients with small, peripheral T1 tumours without suspicious lymph nodes on imaging. However, in situations where non-surgical treatments, like stereotactic body radiation therapy, will be utilized and surgical lymph node staging will not be performed, the importance of knowing the status of N1 nodes with higher certainty increases, and the testing threshold for invasive mediastinal staging decreases. In practical terms, this means that invasive mediastinal and hilar lymph node staging becomes more important in patients who will not receive surgical lymph node staging. Based on the pre-test probability of lymph node metastases in each station, a decision is made as to whether invasive mediastinal staging is indicated. Patients who have regional lymph nodes with pre-test probabilities for metastatic involvement between the testing and test-treatment thresholds should go on to have invasive mediastinal staging performed. Alternatively, if no regional lymph nodes have a pre-test probability above the testing threshold, attention © 2014 Asian Pacific Society of Respirology
803 turns to evaluation of the nodule or mass. In the situation where the CT shows extensive tumour invasion into the mediastinum, the pre-test probability for mediastinal involvement is higher than the testtreatment threshold, and further mediastinal staging is not indicated. In this situation, a tissue diagnosis should be established with a procedure that involves the least risk to the patient. In patients with an intermediate to high pretest probability (above the testing threshold) of mediastinal lymph node metastases, the clinician chooses the most appropriate invasive testing modalities to biopsy the suspicious lymph nodes. The choice of which modality to utilize is based on several factors. A modality is chosen that is able to access as many of the suspicious nodal stations as possible (see Table 1). Consideration should also be given to those modalities that can access the highest stage lymph nodes that have a pre-test probability above the testing threshold. For instance, if the pre-test probability for malignancy is above the testing threshold for certain N2 and N3 lymph nodes, the best initial modality is one that can reach those N3 stations. If a modality is chosen that is only able to biopsy the N2 stations but cannot access the N3 stations, another procedure will be needed to sample the suspicious N3 nodes. In addition, the diagnostic characteristics of each test (see Table 2), the risk associated with each modality and the patient’s preferences should be taken into account.
Modalities to biopsy mediastinal and hilar lymph nodes Surgical lymph node dissection and staging through either thoracotomy or video-assisted thoracoscopic surgery (VATS) is the gold standard for lymph node staging. From the right side, surgical staging can reach most of the right side lymph nodes, including stations 2R, 3A/P, 4R, 7, 8, 9, 10R, 11R and more distal stations. From the left, stations 2L, 5, 6, 7, 8, 9, 10L, 11L and more distal stations can be reached. Stations 4L and 3A can also be reached from the left with extensive dissection and increased risk. The diagnostic yield is excellent, with sensitivities and specificities that approach 1.00.7 The disadvantages of VATS or thoracotomy for routine lymph node staging are the invasiveness of the procedures and the lack of access to lymph node stations on the contralateral side. Therefore, this modality is usually reserved for situations in which lobectomy will likely be performed, as it has therapeutic as well as diagnostic implications. Cervical mediastinoscopy was previously considered the pre-treatment procedure of choice to stage the mediastinum. It can routinely access stations 2R/L, 4R/L and anterior station 7 lymph nodes.16 Posterior station 7 lymph nodes are difficult to reach. For video cervical mediastinoscopy, the median sensitivity of the procedure for detecting malignancy is 0.89, and the specificity approaches 1.00.7 Dissection and complete lymphadenectomy increase the diagnostic yield. The procedure is considered low risk and can be performed on an outpatient basis, although it is Respirology (2014) 19, 800–808
804 Table 1
TM Saettele and DE Ost Lymph node stations accessible by invasive staging modality
Lymph Percutaneous node Endobronchial Endoscopic Cervical Anterior needle Right VATS/ Left VATS/ station ultrasound ultrasound mediastinoscopy mediastinoscopy biopsy* thoracotomy thoracotomy 1 2R 2L 3A 3P 4R 4L 5 6 7 8 9 10R 10L 11R 11L 12+
+ + + − + + + − − + − − + + + + ±
− − − − + − + ± − + + + − − − − −
− + + − − + + − − + − − − − − − −
− − − − − − − + + − − − − − − − −
+ + + + + + + + + + + + + + + + +
− + − + + + − − − + + + + − + − +
− − + + − − + + + + + + − + − + +
* Although percutaneous needle biopsy is technically able to reach all nodal stations, it is not practical to biopsy multiple stations with this approach. + indicates an accessible nodal station. − indicates an inaccessible nodal station. ± indicates a nodal station that is sometimes accessible. VATS, video-assisted thoracoscopic surgery.
Table 2 Test characteristics of various mediastinal staging modalities Modality CT7–10 PET7–12 Integrated PET-CT7 Endobronchial ultrasound7,13,14 Endoscopic ultrasound7,15 Cervical video mediastinoscopy7 Anterior mediastinoscopy7 Percutaneous needle biopsy7 VATS7
Sensitivity
Specificity
0.57–0.61 0.79–0.85 0.62 0.88–0.93 0.83–0.89 0.89 0.71 0.94 0.99
0.77–0.82 0.88–0.96 0.90 1.00 0.97–1.00 1.00 1.00 1.00 1.00
CT, computed tomography; PET, positron emission tomography; VATS, video-assisted thoracoscopic surgery.
more invasive than needle-based techniques. The complication rate is around 2.5%, and major complications occur in less than 0.5% of cases.16 Anterior mediastinoscopy, or the Chamberlain procedure, gives access to the station 5 and 6 lymph nodes that are not routinely accessible from a standard cervical mediastinoscopy. The median reported sensitivity of the procedure is 0.71, and the specificity approaches 1.00.7 Imaging-guided percutaneous needle biopsy can technically be used to sample all intrathoracic lymph node stations. However, using this modality to reach multiple stations in a single patient is not practical and carries a higher risk than the use of other modalities. In published series, pneumothorax occurred in 34–48% of patients, and 14–32% of all patients Respirology (2014) 19, 800–808
required placement of a thoracostomy tube.17,18 The performance characteristics of the procedure are excellent, with a median sensitivity of 0.94 and specificity of 1.00.7 Endoscopic ultrasound fine-needle aspiration was the first minimally invasive ultrasound-guided needle-based technique used for mediastinal staging in lung cancer. It allows routine access to stations 4L, 7, 8 and 9 from within the oesophagus. In some patients, the station 5 nodes are within reach as well. In addition, endoscopic ultrasound can sample some abdominal locations that are occasionally involved with metastases, including the left adrenal gland, liver and celiac lymph nodes. In published reviews, its sensitivity for detecting malignancy in these specific locations ranges from 0.83 to 0.89, and its specificity ranges from 0.97 to 1.00.7,15 The procedure is generally performed on an outpatient basis with sedation or under general anaesthesia. Complications occur in less than 1% of patients and are usually minor.15 Endobronchial ultrasound (EBUS) transbronchial needle aspiration (TBNA) has become the modality of choice to stage the mediastinum for many clinicians and is now recommended over surgical staging as the best first test in the American College of Chest Physicians lung cancer guidelines.6 By utilizing the airways to access lymph nodes, it is the only modality able to sample N1, N2 and N3 nodes in a single procedure. Specifically, it can access lymph nodes in stations 1, 2R/L, 3P, 4R/L, 7, 10R/L, 11R/L and some more distal lymph nodes and parenchymal lesions. EBUSTBNA has excellent performance characteristics. In three published systematic reviews, EBUS-TBNA has a sensitivity of 0.88–0.93 and a specificity that © 2014 Asian Pacific Society of Respirology
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approaches 1.00 for detecting the correct nodal stage of malignancy.7,13,14 It has an overall complication rate of about 1.4%.19 Major complications include pneumothorax and haemorrhage, which occur in around 0.2% and 0.1% of patients, respectively. The procedure is performed under sedation or general anaesthesia, and patients are discharged home the same day.
Technical aspects of mediastinal staging To maximize their utility, the available evidence should guide the performance of any staging procedure. Much evidence is available supporting the best practices for the needle-based techniques. EBUS-TBNA and endoscopic ultrasound fine-needle aspiration correctly identify lymph node metastases in a significant number of patients with normal appearing mediastinal nodes by CT and PET.20–26 Likewise, using an ultrasound size sampling threshold of 5 mm instead of 10 mm increases the sensitivity of the procedure, as lymph node metastases commonly occur in nodes smaller than 10 mm in diameter. There is no evidence that rapid onsite cytologic evaluation improves the diagnostic yield of the procedure, although it may allow sampling of fewer lymph nodes and shorter procedure times. When rapid onsite evaluation is not available, evidence indicates that three aspirates per lymph node are sufficient to obtain diagnostic tissue, and more needle passes do not increase the diagnostic yield.27 Both techniques produce adequate tissue to perform molecular profiling in most positive samples, although more than three needle passes may be required to collect adequate tissue for analysis.28–30 Anecdotal experience has shown that performing five to eight needle passes is generally sufficient to obtain adequate tissue for genetic testing in a malignant lymph node. Feedback from the rapid onsite cytological assessment can also help ensure the adequacy of the sample. Applying suction to the aspiration needle has a similar diagnostic yield to aspiration performed without suction,31 and there is no difference in specimen adequacy or diagnostic yield between using 21-gauge and 22-gauge needles.32 There is no proven difference in diagnostic yield when the procedures are performed under general anaesthesia versus moderate sedation, although anaesthesia support may facilitate easier biopsy conditions.33 EBUS assessment of the lymph node stations should be performed systematically. To avoid potential overstaging, biopsies should occur from the highest stage lymph nodes (N3) first working to the lower stage nodes (N2, then N1). This practice prevents malignant cells being transferred from a malignant lower stage node to a higher stage sample by a contaminated needle. Stations 11R/L, 4R/L and 7 are assessed in every patient regardless of their appearance on CT and PET. Lymph nodes in these stations are aspirated if they measure 5 mm or larger in short axis. Anecdotal experience has shown that these stations are the ones most commonly involved by metastases. There is ongoing research to verify the validity of this approach. In addition, any other lymph nodes © 2014 Asian Pacific Society of Respirology
805 that have a pre-test probability above the testing threshold and are within reach of EBUS-TBNA are assessed and sampled. The other mediastinal staging procedures should also be performed in a systematic way using the best available evidence to guide them. For instance, cervical mediastinoscopy has the highest yield when lymph node dissection is performed. Ideally, stations 2R/L, 4R/L and 7 are assessed in every patient and biopsies taken from each site. Additionally, when surgical staging is performed at the time of lobectomy, lymph node dissection is superior to selective lymph node sampling, both for diagnostic and treatment purposes.
Assessment of post-test probability Following the performance of a procedure to stage the regional lymph nodes with pre-test-probabilities above the testing threshold, the post-test probability of malignancy in those lymph nodes is estimated (see Fig. 1). Due to the high specificities for all of the invasive tests, a positive biopsy result increases the posttest probability of malignancy to near 1.00 and crosses the treatment threshold, establishing a diagnosis and a stage. However, a negative or nondiagnostic biopsy result in a lymph node with a high pre-test probability may not sufficiently move the post-test probability to below the testing threshold. For example, because the false negative rate of EBUSTBNA is around 0.10, a negative biopsy result in a PET-positive, enlarged mediastinal lymph node in the setting of a large, central mass may not sufficiently rule out metastatic involvement in the node. In this situation, another modality like cervical mediastinoscopy is required to move the post-test probability across one of the thresholds. Following a staging procedure, it is also necessary to reassess the lymph node stations and determine whether other lymph nodes are present with a probability above the testing threshold that would increase the nodal stage or potentially change treatment if positive. If a lymph node fits into this category, then another modality should be performed to sample the node. For instance, consider a patient with a left upper lobe 3.5 cm mass, enlarged lymph nodes in stations 6, 7 and 4R, and no evidence of distant metastases. The patient’s initial clinical stage is T2a N3 M0. EBUS-TBNA is performed as the first test in order to evaluate the suspicious N2 and N3 lymph nodes. Assuming negative results in the standard nodal stations (11R, 4R, 7, 4L and 11L), the post-test probability for malignancy in stations 4R and 7 falls below the testing threshold. However, station 6 still has a pretest probability above the testing threshold, and another modality such as an anterior mediastinoscopy or CT-guided needle biopsy would be indicated for diagnosis and staging. Thoroughness levels for mediastinal staging tests have been proposed.34 These levels were developed from expert opinion and extrapolation of surgical studies and have not been definitively tested. However, they do provide a useful framework for discussion. The definition of thoroughness for surgical Respirology (2014) 19, 800–808
806 Table 3
TM Saettele and DE Ost Classification of the thoroughness of mediastinal staging of lung cancer34
Sampling level Complete
Systematic
Selective
Poor
Surgical staging
Needle-based staging
Complete lymphadenectomy of stations 1, 2R/L, 3, 4R/L, 7, 8; and 5, 6 if left upper lobe tumour Mediastinoscopy with sampling/exploration of 2R/L, 4R/L, 7; and 5, 6 if left upper lobe tumour Mediastinoscopy with biopsy of ≥1 station, and must include any node suspicious by imaging Mediastinoscopy with visual assessment only; no node biopsied or no nodal tissue in samples
Sampling of each visible node in stations 1, 2R/L, 3, 4R/L, 7, 8; and 5, 6 if left upper lobe tumour with ≥3 needle passes per node or rapid onsite cytologic evaluation Sampling of ≥1 node per station from 2R/L, 3, 4R/L, 7, 8; and 5, 6 if left upper lobe tumour with ≥3 needle passes per node or rapid onsite cytologic evaluation Biopsy of ≥1 station, which must include a node suspicious by imaging or ≥1 cm by ultrasound, or ≤3 passes and no rapid onsite cytologic evaluation Visual assessment only; no node biopsied or no lymphatic tissue in aspirates
and needle-based techniques is based on which lymph node stations are assessed, which lymph nodes are biopsied and how the biopsy is performed (see Table 3). For example, with regards to needlebased techniques, complete sampling is defined as biopsying every visible lymph node in each mediastinal nodal station (including stations 1, 2R/L, 3, 4R/L, 7, 8, and stations 5 and 6 if a left upper lobe tumour is present) and performing at least three needle passes per lymph node or using rapid onsite cytologic evaluation. Systematic sampling differs from complete in that nodes from each station are sampled, but not every visible lymph node in each station is biopsied. Selective sampling is defined as biopsy of at least one mediastinal nodal station, including a node suspicious by imaging or at least 1 cm in diameter when assessed by ultrasound, if present. Also, if less than three needle passes are made and rapid onsite evaluation is not available, the sampling classification is considered selective. Finally, poor needle-based sampling defines a staging procedure in which no lymph node is biopsied or lymphatic tissue is absent in the aspirates. The classification of thoroughness for surgical and imagingbased staging modalities are defined similarly, although variations exist with the technical details of each test. The mediastinal staging strategy outlined above is a variation of the ‘systematic’ level of thoroughness. The difference is that not all nodal stations are assessed with a given modality. Certain lymph node stations are always evaluated, and other stations are sampled if they contain lymph nodes with a pre-test probability above the testing threshold. The modality that would give the highest nodal stage, if positive, is the first test that is chosen. Other factors are also considered, like the diagnostic yield, the invasiveness of the test and the patient’s preferences. This approach gives flexibility to the staging strategy and minimizes sampling of lymph node stations that are unlikely to be involved by malignancy. In addition, there is no evidence to suggest that the ‘complete’ level of thoroughness outlined above produces superior results to Respirology (2014) 19, 800–808
‘systematic’ sampling. In fact, ‘complete’ mediastinal staging has the tendency to increase the number of performed procedures, procedure time, risk and cost without proven benefit. Note that the strategy outlined above emphasizes the systematic use of multiple modalities in combination. For example, in a patient with a left upper lobe 3.5 cm mass and enlarged lymph nodes in stations 6, 7 and 4R without evidence of distant metastases, EBUS-TBNA would be the first test. Depending on the results, CT-guided biopsy or anterior mediastinoscopy might be necessary. The question of what is the optimal staging strategy is not answered by choosing a single test, but rather by selecting the proper combination and sequence of tests that together will provide the necessary information to stage and diagnose the patient with the least risk. Too often discussions on staging revolve around which one test is best. That is fundamentally the wrong question. The correct question is which tests in what sequence are appropriate for each particular patient. Thus, the form of the answer is not a single test, but rather must be a method of systematically thinking about the problem in each patient based on individual prior probabilities of disease, benefits and harms.
EVALUATION OF THE LUNG NODULE/MASS After adequate assessment of the regional lymph nodes, if a diagnosis has still not been established, then consideration is given to biopsy of the suspicious nodule or mass. The pre-test probability of malignancy is estimated using clinical factors, like age, smoking history and cancer history, and radiographic characteristics, like tumour location, size and appearance.2,35 If the pre-test probability is below the testing threshold, the patient is observed over time with serial chest imaging examinations per standard guidelines.36 Patients with a pre-test probability of malignancy above the testing threshold should undergo biopsy of the primary lesion to establish a © 2014 Asian Pacific Society of Respirology
Systematic lung cancer staging
diagnosis. If the pre-test probability is above the testtreatment threshold and the patient is appropriate for surgical treatment, then wedge resection followed by completion lobectomy, if the wedge sample is positive, and mediastinal lymph node dissection may be the best choice to establish the diagnosis and stage and treat the patient with a single procedure.
CONCLUSION In summary, decision analysis is a useful tool for developing an overall diagnosis and staging strategy for patients with suspected lung cancer. Determining the pre-test probability of malignancy in the primary nodule or mass, the regional lymph nodes and at distant sites should be at the centre of this process. Attention is given to establishing the diagnosis and stage with as little risk to the patient and with as few procedures as possible. This begins with a search for distant metastases and obtaining tissue from any suspicious site that has an acceptable risk of biopsy. Next, the likelihood of lymph node metastases is estimated, and a modality is chosen to sample lymph nodes with pre-test probabilities above the testing threshold, favouring tests that are less invasive and give the most amount of information. Finally, if a diagnosis and stage are not yet established after systematic examination and sampling of the mediastinal lymph nodes, biopsy or surgical resection of the primary nodule or mass is performed. Following these principles should allow an accurate diagnosis and stage to be established in a safe and efficient way.
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