Mediastinal staging of non-small-cell lung cancer

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1 Expert Review of Respiratory Medicine ISSN: (Print) (Online) Journal homepage: Samjot Singh Dhillon, Jaspreet Kaur Dhillon & Sai Yendamuri To cite this article: Samjot Singh Dhillon, Jaspreet Kaur Dhillon & Sai Yendamuri (2011), Expert Review of Respiratory Medicine, 5:6, , DOI: /ers To link to this article: Published online: 09 Jan Submit your article to this journal Article views: 185 View related articles Full Terms & Conditions of access and use can be found at Download by: [ ] Date: 07 July 2016, At: 15:39

2 CME For reprint orders, please contact Review Mediastinal staging of non-small-cell lung cancer Expert Rev. Respir. Med. 5(6), (2011) Samjot Singh Dhillon 1, Jaspreet Kaur Dhillon 1 and Sai Yendamuri* 2 1 Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA 2 Department of Thoracic Surgery, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA *Author for correspondence: Tel.: Fax: sai.yendamuri@roswellpark.org Accurate mediastinal staging is the hallmark of a sound thoracic oncology program. Mediastinal staging remains the most important validated tool for making treatment decisions for patients with non-small-cell lung cancer. The last few years have seen the emergence of several new techniques to improve mediastinal staging. This article summarizes the current state of the art of this rapidly evolving field. Keywords: endobronchial ultrasound endoscopic ultrasound lung cancer mediastinoscopy staging TEMLA Medscape: Continuing Medical Education Online This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and Expert Reviews Ltd. Medscape, LLC is accredited by the ACCME to provide continuing medical education for physicians. Medscape, LLC designates this Journal-based CME activity for a maximum of 1 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at (4) view/print certificate. Release date: November 14, 2011; Expiration date: November 14, 2012 Learning objectives Describe the general approach to mediastinal staging of NSCLC Describe criteria determining the need for invasive mediastinal staging in patients with NSCLC Describe selection of the best tests to be used for mediastinal staging in patients with NSCLC Financial & competing interests disclosure Editor Elisa Manzotti, Editorial Director, Future Science Group, London, UK Disclosure: Elisa Manzotti has disclosed no relevant financial relationships. CME Author Laurie Barclay, MD, Freelance writer and reviewer, Medscape, LLC Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships. Authors Samjot Singh Dhillon, Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14268, USA Disclosure: Samjot Singh Dhillon has disclosed no relevant financial relationships. Jaspreet Kaur Dhillon, Department of Medicine, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14268, USA Disclosure: Jaspreet Kaur Dhillon has disclosed no relevant financial relationships. Sai Yendamuri, Department of Thoracic Surgery, Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14268, USA Disclosure: Sai Yendamuri has disclosed no relevant financial relationships /ERS Expert Reviews Ltd ISSN

3 Review Dhillon, Dhillon & Yendamuri CME Lung cancer is the leading cause of mortality in both men and women in the USA. Non-small-cell lung cancer (NSCLC) accounts for the majority (84%) of lung cancers [1]. While smallcell cancer is broadly staged as limited stage and extensive stage based on field of radiation, a meticulous Tumor Nodal Metastasis (TNM) system is imperative for classifying NSCLC into distinct stages I IV as the prognosis and treatment of each stage is different [1,2]. This staging paradigm is crucial for making clinical decisions the potential for curative surgical resection, the decision to administer adjuvant chemotherapy, to appropriately enroll patients in clinical trials and to compare outcomes. Incorrect staging of NSCLC results in errors in management including inaccurate prognostic information for the patients, futile and potentially toxic treatment and inaccuracies in research. After excluding distant metastasis, the N staging becomes paramount in making treatment decisions, as patients with N0 and N1 involvement are generally candidates for surgery and patients with N2 disease are usually offered definitive or neoadjuvant chemoradiation. Additionally, a wide variety of investigative procedures and tests are available for mediastinal staging and an in-depth understanding of the potential benefits and pitfalls of each diagnostic test is important to make optimal decisions for work-up of NSCLC patients. This review aims to provide an update on the latest diagnostic tests, procedures and surgical techniques so that they can be used judiciously for ensuring accurate mediastinal staging of NSCLC and to provide optimal work-up prior to treatment. Mapping the mediastinal lymph nodes Understanding the lymphatic drainage of the lung is obviously relevant to staging the mediastinum. Intrapulmonary lymph nodes generally drain through the hilar lymph nodes to the mediastinal lymph nodes, but there is substantial variability in this drainage pattern. Segmental and subpleural lymphatics may drain directly to paratracheal or supraclavicular nodes and crossover lymphatic drainage across the midline is not infrequent [3]. Tumors of the right upper lobe commonly metastasize to the right paratracheal station (4R), those of the left upper lobe to the subaortic and paraaortic (5 and 6) lymph node stations and those of the right middle and both lower lobes spread to the subcarinal (7) station and then to right paratracheal nodes (4R) [4]. Lymph node maps based on tumor drainage patterns have been developed for facilitating staging and patient management. Several different lymph node maps have been used in the past, which hampers the comparison of various research studies. The latest (seventh) TNM system by the International Association for the Study of Lung Cancer has attempted to provide a uniform lymph node map by combining the Naruke map used in Japan and Europe with the Mountain Dressler map used in the USA and readers are encouraged to thoroughly review the new map. The basic N0 N3 station system has been retained and seven distinct nodal zones have been described for future use in survival analysis, although the clinical and survival significance of these nodal zones is not clear currently and the zones are not for current standard nomenclature (Figure 1) [1,4]. Precise radiological, vascular, airway and surgical landmarks for accurate staging that can be unvaryingly recognized by all members of the multidisciplinary team taking care of NSCLC patients were introduced [4]. For example, the N1 and N2 zone in the old map was distinguished by the pleural reflection, which could only be recognized during surgery. The new map uses major thoracic vessels as landmarks to separate these two important zones that can now be easily recognized on imaging studies. Distinct vascular landmarks have been designated to separate upper and lower paratracheal nodes. The subjective landmark of midline of trachea to separate right and left paratracheal nodes has been shifted to the left lateral margins of trachea based on actual lymphatic drainage pattern in the lung and owing to the fact that most of lymph nodes in front of trachea are usually removed en bloc with right paratracheal nodes during surgery. The alteration in landmarks used to identify various lymph node stations has the unintended consequence of making it difficult to compare the new studies with the old ones. The upper boundary of right hilar N1 station has shifted up by utilizing the caudal margin of azygous as the perimeter between right paratracheal and right hilar stations [5]. The N2 subcarinal zone has become bigger. The right paratracheal station has become larger as the boundary between right and left paratracheal stations has been changed from midline of trachea to the left lateral tracheal wall. Thus, a previous metastatic N2 node involvement with left upper lobe NSCLC may now qualify as N3 [5]. Physicians taking care of patients need to recognize these changes while managing patients during this transition. Overall, the new staging system satisfies the long-awaited goal of having a uniform system with clear distinguishing landmarks and will better serve the patients and caregivers in the long term. What constitutes a positive lymph node? It is important for the practicing clinician to be aware of what a positive lymph node means and how the lymph node specimens are processed. There is considerable variability in surgical sampling of lymph nodes that includes selected lymph node biopsy, selective lymph node sampling, systemic nodal dissection, lobe-specific systemic nodal dissection or extended lymph node dissection [3]. The systemic lymph node dissection that involves systematic dissection and removal of all mediastinal tissue containing the lymph nodes within anatomical landmarks is ideally recommended [3]. Unfortunately there is no unanimity about the processing and histopathological examination of these nodes. The European Society of Thoracic Surgeons (ESTS) guidelines recommend that in the presence of gross tumor, one section from the most suspicious site should have hematoxylin and eosin (H and E) staining to look for metastasis and extracapsular extension [3]. If this is negative, then several 2-mm sections of the node in longitudinal plane are recommended, which can improve the rate of detection of metastasis [3]. Each block should be examined separately. Further yield can be improved with serial sectioning and immunohistocytochemistry (IHC) [3]. However, all these techniques to detect less obvious foci of metastasis are arduous, and are not uniformly adhered to. Many times, only limited sections of lymph nodes are reviewed by H and E stain examination. IHC is still not the current standard of care. 836 Expert Rev. Respir. Med. 5(6), (2011)

4 CME Review Supraclavicular zone 1. Low cervical, suprclavicular and sternal notch nodes 1 Upper zone 2R Superior mediastinal nodes 2R. Upper paratracheal (right) 2L 2L. Upper paratracheal (left) 3a. Prevascular Ao 4R 3p. Retrotracheal PA 4L 10R 12R 4R. Lower paratracheal (right) 10L 7 4L. Lower paratracheal (left) 11L 12R 13R Aortic nodes AP zone 11R 5. Subaortic 12L 8 6. Para-aortic (ascending aorta or phrenic) 12R 14R 13L 9 9 Inferior mediastinal nodes Subcarinal zone 8 14L 7. Subcarinal Lower zone 8. Paraesophageal (below carina) 9. Pulmonary ligament N1 nodes Hilar/interlobar zone Hilar 3p 3a Interlobar Peripheral zone 12. Lobar 13. Segmental 14. Subsegmental Figure 1. International Association for the Study of Lung Cancer nodal chart with stations and zones. Adapted with permission courtesy of the International Association for the Study of Lung Cancer. Copyright 2009 Memorial SloanKettering Cancer Center, NY, USA

5 Review Dhillon, Dhillon & Yendamuri CME Metastasis to the lymph nodes does not always occur macroscopically in an easily recognizable fashion. Micrometastasis is the presence of microscopic disease that may escape detection by standard H and E stains. By definition, it is often defined as tumor cells in lymph node measuring mm in greatest diameter [6]. The prevalence of micrometastasis is approximately 19%, but this may in fact may be underestimation due to sampling issues and inability of current techniques to adeptly detect it [6]. Even enhanced techniques, such as IHC, may not be fully successful in detecting micrometastasis. The exact significance of the presence of micrometastasis on the patient prognosis is not yet fully clear, but it may explain the high frequency of recurrence of resected NSCLC. Isolated tumor cells are a term used to describe presence of only a single tumor cell or small cluster of tumor cells <0.2 mm in diameter, which show no stromal reaction or proliferative potential [3,6]. The exact clinical impact of separating such minor foci of metastasis in lymph nodes into micrometastasis and isolated tumor cells is still not clearly understood. However, in future, this may hold promise in predicting patients at high risk of recurrence and selecting candidates for adjuvant chemotherapy. Skip or discontinuous metastasis is the direct metastasis to the mediastinal or N2 nodes, bypassing the intrapulmonary/hilar or N1 nodes. This phenomenon can be seen in approximately 25% (18 38%) of cases, and more so in upper lobe tumors and in adenocarcinomas [4,6 8]. It is uncertain whether skip metastasis occurs owing to unclear pathophysiological mechanisms, direct drainage from intrapulmonary lymphatics or simply represents undetected cases of micrometastases [6]. Methods of mediastinal staging A variety of invasive and noninvasive tests are available to stage the mediastinum. The practising clinician should be well versed in the performance characteristics of each staging modality and be aware of specific limitations and the contexts that can maximize the value of each technique. The practical application of each of these methods also depends on available expertise and the presence of specific resources that can optimize results. Continuous quality assessments should be part of the practice to achieve valid results. Noninvasive methods Noninvasive staging methods, though not confirmatory, provide detailed anatomical information, aid in determining the need for additional invasive staging procedures and assist in deciding the best mode of invasive staging. Chest radiograph Chest radiographs may be helpful in the initial recognition of a tumor and the recognition of bulky mediastinal disease, but is neither sensitive nor specific enough to warrant detailed discussion. CT scan of the chest CT scan of the chest is often the first step in mediastinal staging of NSCLC owing to the benefit of obtaining detailed anatomical information. Intravenous contrast enhancement is desirable, although not mandatory, as it helps to distinguish lymph nodes from vascular structures. A normal-sized mediastinal node is defined as a lymph node with a short axis diameter of 1 cm on a transverse CT scan image. Various CT criteria have been suggested to define features suggestive of malignant involvement, but none including the size criteria are very sensitive or specific. Almost 20% of the lymph nodes smaller than 1 cm are malignant and nearly 40% of lymph nodes larger than 1 cm are benign [9 11]. In one meta-analysis, the pooled sensitivity of chest CTs for detecting mediastinal lymph node metastatic involvement using size criteria is only 51% (95% CI: 47 54%) and pooled specificity is 86% (95% CI: 84 88%) in a population with a median prevalence of 28% [9]. Of note, the specificity of CT scans can be influenced by confounding factors that lead to anatomic changes, such as postobstructive pneumonia [11]. In spite of the low accuracy of CT scan in diagnosing mediastinal nodal metastasis, the anatomical information obtained from a CT scan cannot be underemphasized as it helps with further decision making and appropriate biopsy site direction. Most current guidelines recommend a CT scan in the initial evaluation of NSCLC [9,12]. PET Whole body PET scan provides functional imaging by evaluating the preferential uptake of radiolabeled 18 fluorodeoxyglucose ( 18 F-FDG) by tumor cells and combined PET CT improves this technology further by adding the anatomical details to the functional image [13,14]. A standard uptake value (SUV) cut off of >2.5 is considered abnormal and suggestive of neoplastic involvement [9,15]. However, this criteria has not been uniformly used in all studies. Additionally, there is a concerning variation in the quality of PET reporting among institutions, with some centers not even reporting SUV values this impairs a fair comparison of research studies [13]. A meta-analysis of 44 studies of PET scan (not integrated PET CT) calculated a pooled sensitivity of 74% (95% CI: 69 79%) and specificity of 85% (95% CI: 82 88%) when the median prevalence of mediastinal metastasis is 29% [9]. Thus, based on this, PET has better accuracy than contrast-enhanced CT in staging NSCLC, but is still not good enough to do away with histologic confirmation. Additional criteria to improve accuracy of PET scan in detecting malignant involvement of the mediastinal, such as using a higher cutoff for SUV or using the ratio of maximum SUV of mediastinal node to that of main tumor have been suggested, but these criteria need further validation [16]. The performance of PET scans in specific circumstances appears to be better. PET scan is accurate in the setting of enlarged nodes a meta-analysis by Gould reported a median sensitivity of 100% and specificity of 78% [17]. However, almost 25% of the enlarged nodes can be PET-positive for nonmalignant reasons, such as infection or inflammation, and tissue diagnosis is needed to confirm malignancy. PET is less sensitive but more specific in patients with normal-sized nodes as the same meta-analysis by Gould showed that in the presence of normal-sized nodes, the sensitivity of PET is 82% and the specificity is 93% [17]. False-negative (FN) PET scan can occur in micrometastasis, bronchioalveolar carcinoma, mucoepidermoid carcinomas and in typical carcinoid tumors. 838 Expert Rev. Respir. Med. 5(6), (2011)

6 CME Review Integrated PET CT can assist in detecting lesions not well observed on PET or CT and can provide better anatomical localization and demarcation of adjacent structures [14]. Based on pooled results of several recent studies, PET CT has slightly higher accuracy than PET [14]. It is better in detecting metastatic lesions, provides better anatomical correlation for invasive staging and is more useful in mediastinal restaging than remediastinoscopy (accuracy for restaging: 83 vs 60%, respectively; p < 0.05) and PET or CT alone [14,18]. As the multidetector CT imaging apect of integrated PET CT has improved, it has replaced conventional PET-only scanners. Additional advantages of PET scan include the ability to detect extrathoracic disease that may save futile mediastinoscopy and thoracotomies. It can detect unanticipated stage IV disease in distant sites, such as neck nodes, adrenals, liver and bone (5 20% of cases), and can also obviate the need for a bone scan [9,13,14]. PET also aids in deciding the most appropriate invasive test by helping to identiy the most appropriate sites for biopsy and plan radiation therapy fields. The PET scan continues to be an important recommended test for initial evaluation of lung cancer [9,12]. Recent studies suggest that PET CT prevents unnecessary surgical procedures. Fisher and colleagues randomly assigned 189 NSCLC patients undergoing surgical evaluation for thoracotomy to PET CT and conventional staging (blood work, contrast-enhanced CT chest and upper abdomen bronchoscopy) [19]. These patients subsequently underwent clinically required diagnostic procedures, such as endobronchial ultrasound (EBUS) or endoscopic ultrasound (EUS), and more than 90% patients in each group underwent mediastinoscopy. In the PET CT group, 21 out of 60 thoracotomy procedures (35%) were considered futile as compared with 38 out of 73 (52%) in the conventional staging group (p = 0.05). Another recent randomized Canadian trial of 337 patients by Maziak and colleagues comparing PET CT with conventional staging (CT abdomen and bone scan) in suspected early stage NSCLC on routine CT (all patients also had brain CT or MRI) demonstrated that PET CT correctly upstaged disease in 13.8% of patients as compared with only 6.8% in conventional staging group (p = 0.046) and prevented unnecessary thoracotomies [20]. In this context, it is important to note that studies of PET CT have not clearly shown any improvement in mortality in NSCLC [19,20] and the issue of cost effectiveness is still not fully clear. In spite of its pros and cons, PET CT has been overwhelmingly adopted by the medical community and is recommended by current guidelines in the initial evaluation of all NSCLC patients [9,12]. MRI MRI is not routinely used for mediastinal staging of NSCLC. MRI can detect the difference in intensity between tumor and normal tissue, such as bone, vessels, fat and soft tissue, and is helpful in certain specific situations where the possibility of invasion of mediastinum, major vessels, chest wall, diaphragm or vertebral bodies arises [9]. It is also useful in evaluating superior sulcus tumors for brachial plexus involvement. MRI may have some role in evaluation of subcarinal and A P window nodes due to absence of partial volume average artifact, which can be seen in axial CT imaging [21]. However, the poor spatial resolution sometimes makes it difficult to recognize small discrete individual lymph nodes in a group and may make them look like a single enlarged abnormal node. MRI is also unable to recognize benign patterns of calcifications in nodes [21]. The addition of MRI findings to routine CT imaging has not been shown to improve accuracy of mediastinal lymph node staging [22]. Diffusion-weighted imaging is a MRI technique that provides tissue contrast based on the difference of diffusion of water molecules amongst various tissues. Tumors have less diffusion of water due to increased cellularity, more macromolecular proteins and less extracellular space and hence lower apparent diffusion coefficient [22]. Nomori et al. reported lower rate of false positives (FPs) and a higher accuracy of diffusion-weighted imaging MRI as compared with PET CT in mediastinal staging of NSCLC [23], but these results have not been replicated by others [24]. Further work is needed to determine whether this technology will be useful in routine mediastinal staging of NSCLC. Invasive methods Noninvasive investigations may aid in mediastinal staging but are not accurate enough to make critical management decisions. Even with the best currently available noninvasive staging tests, almost one in every three thoracotomies may be futile [19]. Thus, invasive methods have a vital role in mediastinal staging of NSCLC. The choice of invasive procedure depends on the location of suspected mediastinal nodes, as some nodal stations are more easily accessed by one procedure as compared with another. Therefore, patient cohorts in research studies of various invasive procedures are different owing to selection bias. Two invasive staging tests may have the same sensitivity and specificity, but may have different predictive values based on prevalence of mediastinal lymph node metastasis [25]. Additionally, the proficiency of the physician performing the procedure may also play a part in the varying sensitivity and specificity observed. Thus, comparing the sensitivity and specificity of various invasive procedures of mediastinal staging are fraught with difficulty procedures should be considered complementary rather than competitive [1]. With this background, we present three kinds of summary data in a tabular fashion. Table 1 compares the lymph node station accessible by various staging procedures, Table 2 is an overview of diagnostic yields of common procedures and Table 3 provides a broad comparison of various staging procedures. Cervical mediastinoscopy Cervical mediastinoscopy is the historical gold standard for mediastinal lymph node staging. It is performed in the operating room under general anesthesia and patients are usually discharged on the same day. A small incision is made over the suprasternal notch and dissection is performed out into the pretracheal space up to the carina. Nodes are sampled under direct visualization. Mediastinoscopy typically samples right and left upper and lower paratracheal (2R, 2L, 4R, 4L), and subcarinal (7) stations. The subaortic or aortopulmonary window (5), para-aortic (6), inferior mediastinal (8 and 9), hilar (10) and lobar/intralobar (11 14) 839

7 Review Dhillon, Dhillon & Yendamuri CME Table 1. Lymph node station accessibility of various invasive procedures. stations are inaccessible to routine mediastinoscopy. This method of sampling has the advantage of improved detection of micrometastasis and extracapsular tumor spread. Contraindications are few and include presence of tracheostomy, unstable cervical spine or limited extension of neck due to arthritis. The average sensitivity of mediastinoscopy is 80% and the average FN rate is 10% [1]. Half of the FN cases can be attributed to nodes not accessible by mediastinoscopy and some can be due to operator-related issues. Video mediastinoscopes allow better visualization, more extensive sampling, including better access to posterior subcarinal node, and even complete lymph node dissection (video-assisted mediastinal lymphadenectomy [VAMLA]) and can also help to achieve higher accuracy of staging and better standardization of technique. Sensitivity of 90% Table 2. Overview of common invasive mediastinal staging techniques. Investigation Sensitivity (%) 2R 2L 3a 3p 4R 4L R 10L 11R 11L EBUS EUS +/ +/ + +/ + +/ +/ / +/ EBUS + EUS / EMN TTNA Cervical mediastinoscopy Extended mediastinoscopy Chamberlain + + Left VATS Right VATS VAMLA TEMLA : Accessible; -: Inaccessible; EBUS: Endobronchial ultrasound; EMN: Electromagnetic navigation bronchoscopy; EUS: Endoscopic ultrasound; TEMLA: Transcervical extended mediastinal lymphadenectomy; TTNA: Transthoracic needle aspiration; VAMLA: Video-assisted mediastinal lymphadenectomy; VATS: Video-assisted thoracic surgery. Specificity (%) and FN rate of 7% has been reported [1]. It is recommend that all five nodal stations (stations 2R/L, 4R/L and 7) be examined in a cervical mediastinoscopy and, if nodes are present, at least one node should be sampled from each station [1,12]. Systematic nodal sampling results in more accurate staging than selective sampling while complete lymphadenectomy can detect more multistation disease even though it does not result in a stage shift [26]. Current evidence suggests that the utilization and sampling of mediastinoscopy is suboptimal. A survey of 729 hospitals (11,668 patients of NSCLC) conducted by the American College of Surgeons in 2001 showed that only 27.1% of patients had preoperative mediastinoscopy and that tissue biopsy material was obtained from <50% of these procedures [27]. A Dutch study from one nonteaching university and three community hospitals reported mediastinoscopy sampling per expected standard in only 40% of cases [28]. Another recent retrospective FP (%) FN (%) Median prevalence (%) TBNA EBUS EUS TTNA Cervical mediastinoscopy Chamberlain VATS The values apply only for specific situations and lymph node locations for which the procedures were performed. Values for Chamberlain performed in addition to routine cervical mediastinoscopy. EBUS: Endobronchial ultrasound; EUS: Endoscopic ultrasound; FP: False positive; FN: False negative; TBNA: Transbronchial needle aspiration; TTNA: Transthoracic needle aspiration; VATS: Video-assisted thoracic surgery. The values have been obtained from the information in ACCP guidelines of 2007 [9,38] and updated values for EBUS have been obtained from Gomez et al. [52]. study from the USA suggested that mediastinal lymph node sampling was suboptimal in patients undergoing resection for NSCLC and suboptimal resection was associated with poorer prognosis; likely as a consequence of imprecise staging [29]. The procedure is safe and carries a morbidity of % and mortality of 0 0.2% [30]. The major concern is vascular injury (0.4%) and major bleeding, but that is rare and mostly associated with dissection around station 4R. Other complications include pneumothorax, nerve injury (recurrent laryngeal or phrenic), esophageal or tracheal injury and wound infection [30,31]. Some patients may have concern about the residual neck scar. 840 Expert Rev. Respir. Med. 5(6), (2011)

8 CME Review Table 3. Strengths and weaknesses of common mediastinal staging procedures. Procedure Strengths Weakness CT PET Best anatomic study of thorax Guides the site of biopsy Detects unexpected distant metastasis in 5 20% cases Guides site of biopsy Assists in staging, restaging, treatment response High NPV value for stage I NSCLC Low accuracy for detecting malignant disease False negative in lesions <1 cm or PET-negative tumors 25% false positive TBNA Minimally invasive, simple and cost effective Not well utilized Relatively low yield Yield highly dependent on prevalence EBUS EUS TTNA Cervical mediastinoscopy Minimally invasive Permits direct visualization of node Doppler feature allows identification of vessels and landmarks for nodal stations Excellent access for stations 2, 4, 7, 10 and 11 Allows simultaneous airway inspection and regular bronchoscopy to biopsy lung lesions if needed Minimally invasive Permits direct visualization of nodes Doppler feature allows identification of vessels and landmarks for nodal stations Excellent access to para-esophageal nodes and inferior mediastinum Can access stations 8 and 9 and sometimes 5 and 6, which are generally hard to reach Able to access left adrenal, left lobe of liver and celiac nodes Able to access almost all nodal stations Broad availability Traditional gold standard Excellent for stations 2 and 4 Improved detection of micrometastasis and extracapsular spread Unable to access stations 5, 6, 8 and 9 Special equipment and training needed Unable to access right-sided station 2R and 4R and unable to access stations 10 and 11 Does not allow airway inspections Occasional false positives due to inability to distinguish main tumor from lymph node Special equipment and training needed High risk of pneumothorax Small nodes difficult to biopsy Wide variation in practice pattern of interventional radiologist Limited accessibility of other lymph node stations Not great for posterior subcarinal station Suboptimal sampling common Almost 10% false-negative rate Chamberlain Allows sampling of stations 5 and 6 More invasive Performed by few surgeons VATS TEMLA Allows simultaneous resection of tumor Allows sampling of stations 5 and 6 Allows sampling of inferior mediastinal stations 8 and 9 Allows reliable sampling of almost all nodal stations Can detect micrometastasis and extracapsular spread Permits complete lymphadenectomy Relatively more invasive Anterior and superior mediastinum not well accessed More invasive More postoperative pain than routine mediastinoscopy CT: Computed tomography; EBUS: Endobronchial ultrasound; EUS: Endoscopic ultrasound; NPV: Negative predictive value; NSCLC: Non-small-cell lung cancer; TEMLA: Transcervical extended mediastinal lymphadenectomy; TBNA: Transbronchial needle aspiration; TTNA: Transthoracic needle aspiration; VATS: Video-assisted thoracic surgery. Extended mediastinoscopy Left upper lobe tumors can involve the subaortic (station 5) and para-aortic (station 6) lymph node stations that are not accessible by standard cervical mediastinoscopy. Extended mediastinoscopy enables sampling of these stations. Essentially, after standard mediastinoscopy, the mediastinoscope is directed lateral to the aortic arch and these stations are sampled. It is a challenging procedure performed only in a few centers. Anterior or parasternal mediastinotomy (Chamberlain procedure) Left anterior mediastinotomy involves an incision over the left second or third intercostal space and insertion of mediastinoscope after retraction of left internal mammary artery. It allows biopsy of subaortic (station 5) and para-aortic (station 6) lymph node stations. This procedure is also used to evaluate left upper lobe tumors

9 Review Dhillon, Dhillon & Yendamuri CME VAMLA & transcervical extended mediastinal lymphadenectomy These techniques allow complete bilateral lymph node excision through the cervical mediastinotomy approach. Whereas VAMLA relies on the use of video mediastinoscopy to perform the dissection, transcervical extended mediastinal lymphadenectomy (TEMLA) involves the use of a sternal retractor to increase the mediastinal space to perform an open transcervical dissection [101]. VAMLA can access stations 2, 4, 7 and 8 while TEMLA can access 1, 2, 3a, 3p, 4, 5, 6, 7 and 8 [32,33]. The advantage of complete lymphadenectomy is the potential reduction in the FN rate. In a study by Witte et al., VAMLA performed in 144 patients with resectable lung cancer with a technically adequate dissection was achieved in 86.8%. Additional disease on thoracotomy was identified in only two patients [34]. However, the complication rate was a significant 3.98%, with five recurrent nerve paralyses. In an initial experience, Kuzdzal and colleagues performed TEMLA on 83 patients and reported a sensitivity, specificity and accuracy of the detecting mediastinal node metastases as 90, 100 and 96%, respectively, whereas the positive predictive value was 100% and negative predictive value (NPV) was 95% [33]. The same authors performed a randomized prospective study in NSCLC patients, 21 in the TEMLA arm and 20 in the cervical mediastinoscopy arm [35]. Owing to significantly higher number of FN in cervical mediastinoscopy group (5 vs 0; p = 0.019), the study was terminated prior to the goal of recruiting 100 patients. The sensitivity of mediastinoscopy was 37.5% and NPV was 66.7%, compared with sensitivity of 100% and NPV of 100% in the TEMLA group. An updated series published by Zielinski reported a sensitivity of 94.1%, specificity of 100% and NPV of 97.2% among 256 patients that had TEMLA. The recurrent laryngeal nerve palsy rate was lower at 2.3%, with only 0.8% having permanent recurrent laryngeal nerve palsy [36]. Recent data suggest that TEMLA is better than remediastinoscopy, EBUS and PET CT in restaging NSCLC patients after induction chemotherapy or chemoradiotherapy [37]. While the technique of TEMLA is not very popular yet, the theoretical advantage of complete mediastinal lymphadenectomy and the excellent results in recent studies may make TEMLA the new gold standard of invasive mediastinal staging procedures. However, all the results of TEMLA are from a single institution, similar to VAMLA, and a wider adoption of these techniques with validation of results is essential. Video-assisted thoracic surgery Video-assisted thoracic surgery (VATS) or thoracoscopy is a less invasive alternative to thoracotomy for mediastinal staging. It can assist in T and N staging simultaneously. It is performed under general anesthesia and a scope is passed through a small incision in the chest wall as well as additional working ports allowing dissection of lung and lymph nodes. Nodes on only one side of the mediastinum can be accessed. Lymph node stations 4R/L, 5, 6, 7, 8, 9 and can all be dissected. Many times the primary purpose of VATS may be resection of lung mass, but lymph nodes are sampled initially to determine the exact stage and to decide whether to continue with the resection. Complication rate is low (range: 0 9%) [38]. In a meta-analysis, the pooled sensitivity of VATS was 75%, but the range of sensitivity was wide (37 100%), highlighting differences in expertise in VATS lymphadenectomy [38]. Transthoracic needle aspiration Transthoracic needle aspiration (TTNA) can be performed using fluoroscopy or CT guidance. Almost all mediastinal nodal stations are accessible by TTNA as stations 2, 4, 5 and 6 can be approached using an anterior parasternal approach and stations 4, 7, 8 and 9 can be accessible by a posterior approach [12]. The pooled sensitivity of TTNA for mediastinal lymph node aspiration is 89%, specificity is 100% and FP is 0% when prevalence is 81% [38]. However, in addition to high prevalence, most of these patient cohorts had extensive bulky mediastinal lymphadenopathy and these results are probably only relevant for such patients. The risk of pneumothorax is high and has been reported to be in the range of 10 60% [39]. Presence of extensive bullous disease with the risk of persistent air leak can be a contraindication for the procedure. Conventional transbronchial needle aspiration Transbronchial aspiration of mediastinal nodes involves passing a transbronchial needle aspiration (TBNA) needle through the working channel of a bronchoscope and penetrating the bronchial wall at the expected location of lymph node based on CT correlation. Wang popularized the technique and provided detailed descriptions of several lymph node stations including specific sites to access them from the airway [40]. While a high rate of success with this technique was reported from a few tertiary centers, a meta-analysis on TBNA showed a pooled sensitivity of 39%, specificity of 100% and a FN rate of 28% when the prevalence of mediastinal metastasis is 34% [41]. This analysis suggested that sensitivity was critically dependent on prevalence of mediastinal metastasis. Despite being a useful technique, it has not become popular among physicians. A 1991 American College of Chest Physicians (ACCP) survey of 871 physicians, 98% of whom were pulmonologists, found that only 11.8% of physicians routinely used TBNA for staging malignancies. TBNA received the most negative comments amongst all bronchoscopy procedures. Reasons for not doing TBNA were issues of scope damage, inadequacy of specimens and lack of training. CT guidance, education and experience can improve diagnostic yield [42]. Four to five passes of lymph nodes critical for staging are generally recommended [43]. Rapid onsite cytology may reduce the number of total needle passes and lowers the rate of complications, but does not improve diagnostic yield [44]. Conventional TBNA is safe, easy, inexpensive and useful when performed correctly. Core biopsy with a 19 G needle can be obtained with TBNA and this is a distinct advantage when compared with the more refined EBUS fine-needle aspiration technique. Electromagnetic navigational bronchoscopy-guided TBNA Electromagnetic navigational (EMN) bronchoscopy is a new tool available for airway interventionalists. A virtual bronchoscopy 842 Expert Rev. Respir. Med. 5(6), (2011)

10 CME Review image is generated from CT images and superimposed upon the real tracheobronchial tree during the procedure. The patient is placed in an electromagnetic field and an eight-way steerable flexible catheter with a position sensor (locatable guide) inside a sheath is passed through the regular bronchoscope. The exact position of the sensor when placed within the electromagnetic field is seen on the system monitor, which helps in navigating it to the predetermined target. Once the target is reached, the sheath is secured and the probe is removed. Instruments can be passed through this sheath for specimen collection. Most studies of EMN involve accessing peripheral lung lesions. However the EMN system can also be used to target lymph nodes similar to peripheral lesions. Gildea and colleagues reported a 100% sampling success in all the 31 lymph nodes during one of the initial clinical trials of EMN [45]. However, validation studies of the utility of EMN in this setting are lacking. EMN can be used to sample peripheral lymph nodes (stations 12 14) that may not be accessible by linear EBUS due to the larger size of the scope. Radial EBUS passed through the EMN sheath can be used to confirm the exact location to further improve yield. EBUS-guided TBNA EBUS is a comparatively new minimally invasive technique for mediastinal staging and allows visualization of lymph nodes adjacent to the large airways usually in anterior and superior mediastinum. Two types of EBUS are available: radial probe and linear probe. A 20-MHz radial probe ultrasound with an inflatable balloon can be passed through the working channel of a bronchoscope that can provide a 360 view and has a resolution of less than 1 mm. This is helpful in assessing the bronchial wall to determine the extent of invasion and the surrounding structures including the lymph nodes. However, the radial probe is removed after localization of the lymph node and the TBNA needle is passed through the same working channel and so the ultrasound guidance is not real time. A peripheral probe without a balloon is also available, which helps in accessing peripheral lymph nodes and masses. The convex probe linear EBUS scope has a 7.5-MHz convex transducer at the tip of a flexible bronchoscope. The outer diameter of the insertion tube of the scope is 6.2 mm and that of the tip is 6.9 mm. Therefore, owing to its bigger size, this scope has to be inserted through the mouth or through an endotracheal tube greater than size 8.0. A balloon at the tip can be inflated with normal saline and can be helpful in obtaining a superior view due to better contact with the airway wall. Simultaneous white light and ultrasound images can be viewed, although the white light image is not as good as that of standard bronchoscope. A needle system with a 22 or 21 G needle can be passed through the EBUS scope and introduced into the lymph node under real-time ultrasound guidance, which has several safety knobs/locks to prevent bronchoscope damage. The length of the needle protrusion is 2 cm but can be increased up to 4 cm (conventional TBNA needle length is generally cm). A stylet prevents contamination of the needle when passing through the bronchial wall and helps push the tissue out of the needle hub at the time of specimen collection. The color Doppler feature allows recognition of blood vessels to prevent inadvertent puncture and also helps in recognition of blood vessels as landmarks for the new lymph-node staging system. The procedure can be performed under conscious sedation, monitored anesthesia care, general anesthesia or a laryngeal mask airway. After identifying a lymph node, the needle is advanced and seen entering the node in ultrasound view. Negative pressure is applied with a syringe and the needle is moved back and forth inside the node several times. Variations of this technique include not using negative pressure with a syringe when the initial specimen is bloody or leaving the stylet partially in during sample acquisition [46]. The sample obtained is smeared on glass slides, air dried, fixed with 95% alcohol and stained for rapid on-site cytological analysis or added to cell block medium. The optimal number of passes for getting good diagnostic yield is at least three per lymph node station [47,48]. An expert bronchoscopist and cytologist form the backbone of a successful EBUS program. The EBUS scope can access all mediastinal nodes reachable by cervical mediastinoscopy and has the additional ability to reach the hilar lymph node stations. It can access stations 2, 3p, 4, 7, 10, 11 and at times, 12. Station 3a is anterior to the airway with intervening vasculature and usually not accessible. Owing to its size, the linear EBUS scope generally cannot go beyond the large airways but the peripheral radial probe ultrasound can allow assessment and aspiration of nodes adjacent to distal airways. Several studies have shown high sensitivity and specificity of EBUS for mediastinal lymph node staging, including nodes that are enlarged or are PET positive [47,49 51]. Yasufuku and colleagues studied 102 patients with proven or suspected lung cancer prior to surgery to compare the accuracy of CT, PET and EBUS [49]. They were able to perform EBUS on 147 mediastinal and 53 hilar lymph nodes without any complications. The sensitivity of CT, PET and EBUS-TBNA for correct detection of malignant involvement was 76.9, 80.0 and 92.3%, respectively, and specificity was 55.3, 70.1 and 100%, with diagnostic accuracy of 60.8, 72.5 and 98.0%, respectively. Thus, in this study, EBUS was superior to both CT and PET in mediastinal lymph node staging. The performance of EBUS based on meta-analysis of 12 studies involving 1292 patients (103 of them had radial ultrasound) showed a sensitivity of 93%, specificity of 100%, FN of 9% (range: 1 37%) and FP of 0%, with a mean prevalence of metastatic disease of 63% [52]. Thus, the prevalence of metastatic mediastinal disease in EBUS studies was higher than the typical range of 20 40% reported in studies of other tests/procedures and this fact should be kept in mind when deciding the most appropriate diagnostic procedure for a patient. Few studies have compared EBUS directly with mediastinoscopy. In a commonly quoted prospective crossover trial of 66 patients with suspected NSCLC and enlarged lymph nodes (>1 cm) in the paratracheal and subcarinal area (nodal stations accessible by both procedures), EBUS had better diagnostic yield than mediastinoscopy in per lymph node analysis (91 vs 78%; p = 0.007), but this difference was predominantly due to performance in the subcarinal station [53]. These results may be owing to the fact that the mediastinoscope may not be able to 843

11 Review Dhillon, Dhillon & Yendamuri CME access the posterior subcarinal station well and this may well be operator dependent. Furthermore, the prevalence of metastatic disease in this study cohort was very high at 89%, which could have favored EBUS. Overall, no significant difference was seen in terms of determination of true pathological N staging per patient between in two procedures. PET CT, which is commonly used by clinicians nowadays to direct site of biopsy, was also not utilized for this study. A recent retrospective review showed that eight out of 29 (28%) patients with high risk of N2 disease and negative EBUS had metastatic disease on mediastinoscopy [54]. Prospective trials of EBUS compared with mediastinoscopy are in progress and may shed more light on these issues. Generally, mediastinoscopy is better at determining small foci of metastasis and may allow complete lymphadenectomy [55], while EBUS has the advantage of being less invasive and accessing more nodes, including hilar nodes. It is also important to appreciate the fact that both techniques are operator dependent and studies may be confounded by local expertise. EBUS may be useful in a few other special situations. EBUS has been shown to be useful in staging patients with clinical stage 1 NSCLC and normal mediastinal lymph nodes on CT along with a negative PET scan. Herth and colleagues performed EBUS-TBNA on 156 lymph nodes ranging from 5 to 10 mm on 97 such patients with NSCLC followed by surgical staging [56]. Out of ten patients with confirmed mediastinal metastatic disease, nine were correctly diagnosed by EBUS. The sensitivity, specificity and NPV of EBUS for detecting malignancy in this group with low prevalence were 89, 100 and 98.9%, respectively. Another situation where EBUS has been evaluated is restaging after neoadjuvant therapy. While EBUS has been shown to be safe in restaging the mediastinum after neoadjuvant chemotherapy, the results are poorer when compared with the staging the mediastinum prior to initiation of therapy. In two studies looking at this question [55,57], the NPV of EBUS was 78 and 20%, respectively. Therefore, whenever possible, surgical confirmation is still needed in negative cases. The distinct advantage of EBUS in this situation is the safety of performing the procedure in patients that have had mediastinoscopy prior to the initiation of neoadjuvant therapy, as is often the case. While small case series have demonstrated the safety of remediastinoscopy, most surgeons are reluctant to perform this procedure. Overall, EBUS is a very safe procedure and complications, such as pneumothorax or bleeding have been described only rarely [52]. The risk of bleeding is low; even in cases where major thoracic blood vessels have been intentionally punctured by ultrasound-guided needles to access lymph nodes, no significant bleeding has been reported [58 60]. The major limitation of EBUS is that the amount of tissue obtained is so small that it is prone to sampling and interpretation error. There is a concern of over-staging as some International Association for the Study of Lung Cancer nodal station boundaries are sometimes hard to detect on EBUS/EUS and consequently over-staging can occur when the needle passes through dysplastic or neoplastic airway mucosa or when the main tumor is inadvertently sampled instead of the node [61]. Hopefully, future studies will help further define and refine the role of EBUS in mediastinal staging of NSCLC. With the recent emergence of targeted therapy based on mutation testing, more and more tissue is being requested by pathology. Preliminary studies suggest that it may be possible to perform such analysis on EBUS specimens but further work is needed to clarify this issue [62]. Transesophageal EUS-needle aspiration EUS is similar to EBUS but uses a larger echoendoscope (13 mm) that is inserted into the esophagus to access posterior and inferior mediastinal nodes. Both radial and curvilinear forms are available with an ability to recognize lymph nodes as small as 4 6 mm [63]. A variety of needles ranging from G are available. The procedure is generally performed under conscious sedation. Lymph node stations that can be accessed are level 2L, 4L, 3p, 7, 8 and 9. The inferior border of station 7 is sometimes difficult to observe. Station 5 can occasionally be accessible and some case reports have described accessing station 6 with or without transaortic puncture [59,60,64]. An additional advantage of EUS includes the capability to diagnose M1 disease by accessing retroperitoneal and celiac nodes, lesions in the left lobe of the liver and the left and sometimes even the right adrenal gland. Several studies have shown high sensitivity and specificity of EUS for mediastinal lymph node staging [63,65 67]. A metaanalysis of 16 studies of EUS needle aspiration in diagnosis of mediastinal nodal involvement with NSCLC showed a pooled sensitivity of 84% and pooled specificity of 99.5%, FP of 0.7% and FN of 19% (range: 0 61%) when the mean prevalence is 61% [38]. Size of lymph node, sonographic features and drainage patterns are not helpful in deciding which lymph node to biopsy. When multiple lymph nodes are present, the nodal site that will upstage the patient the most is chosen first and three to five passes per site are suggested for adequate sampling [63]. Central versus peripheral site of aspirate of lymph node and application of suction or no suction do not seem to alter diagnostic yield [68]. EUS has been shown to have better accuracy and higher predictive value than CT and PET for posterior mediastinal nodes (stations 5, 7, 8 and 9) [69]. Even in patients with normal mediastinum by CT criteria, performing EUS precluded surgery in 12% and altered management in 25% of patients [70]. Similar to EBUS, a study of EUS showed that it was superior to mediastinoscopy for subcarinal and paratracheal nodes [67]. However, mediastinoscopy appears to have been performed suboptimally in this study as only 24 out of 60 patients had subcarinal lymph nodes sampled and the sensitivity of mediastinoscopy in the subcarinal region was unacceptably low at 7%. Well-designed, randomized, controlled trials are needed to compare the performance of EUS to mediastinoscopy. Another study implied that the routine addition of EUS to mediastinoscopy improves the performance of either procedure alone by detecting more N2 and T4 disease and can avoid up to 16% of thoracotomies [66]. However, caution should be exercised as some studies have shown that EUS may not be sufficient to diagnose T4 disease and surgical confirmation is also needed [71]. Interestingly, in one study, EUS was able to detect 844 Expert Rev. Respir. Med. 5(6), (2011)