Elsevier

The Lancet Oncology

Volume 13, Issue 5, May 2012, Pages e221-e229
The Lancet Oncology

Personal View
Mediastinal staging of lung cancer: novel concepts

https://doi.org/10.1016/S1470-2045(11)70407-7Get rights and content

Summary

Clinical TNM staging is the standard method used to decide treatment for patients with non-small-cell lung cancer. Although integrated fluorodeoxyglucose (FDG) PET CT increases the accuracy of staging, it only guides direct tissue sampling. Histological assessment of mediastinal lymph nodes has traditionally been done with mediastinoscopy, a surgical procedure. Endobronchial and oesophageal ultrasound-guided lymph node sampling have been assessed as additions or alternatives to mediastinoscopy. We review endosonography and surgical staging, and show that both have a place in the mediastinal staging of lung cancer. We conclude that mediastinal tissue staging should preferentially start with a complete endosonographic assessment. A surgical mediastinoscopy should be reserved for those in whom the endosonography result is negative. Further refinement of this recommendation is likely in the near future because data suggest that the confirmatory mediastinoscopy is particularly useful for patients with enlarged or FDG-avid lymph nodes.

Introduction

Pulmonary resection is the treatment of choice for patients with localised non-small-cell lung cancer (NSCLC) who have no evidence of mediastinal nodal metastasis. The treatment of patients with NSCLC metastases restricted to the ipsilateral mediastinal (N2) lymph nodes is controversial. Definitive concomitant chemoradiotherapy is appropriate, although neoadjuvant therapy followed by surgery if mediastinal lymph nodes become free of tumour (nodal downstaging) is practised in some centres. However, almost all clinicians agree that immediate operation on stage IIIA N2 NSCLC is not appropriate. Patients with contralateral mediastinal lymph node metastases (N3) should not have an operation. Therefore, in the absence of extrathoracic, contralateral lung, or pleural cavity metastasis, assessment of the mediastinum becomes crucial for operable patients with resectable NSCLC.1, 2, 3, 4

The correlation between mediastinal lymph node size and the presence of nodal metastasis has been investigated for more than 25 years.5 Lymph nodes with a short-axis diameter of less than 10 mm in axial CT scans are more likely to be benign than are enlarged nodes. However, roughly 40% of all nodes deemed to be malignant by CT are benign and 20% of nodes deemed to be benign by CT are malignant.6 CT has moderate test characteristics, with a sensitivity of 51% (95% CI 47–54) and a specificity of 86% (84–88).6 Attempts have been made to identify subgroups in which CT would eliminate the need for other tests. For example, 9% of patients with peripheral tumours less than 3 cm without enlarged mediastinal lymph nodes have a mediastinal node metastasis, making the need for invasive staging debatable.2

Routine use of fluorodeoxyglucose (FDG) PET detects unexpected distant metastases in 10–15% of patients with NSCLC and unanticipated mediastinal lymph node metastases in 10%.7, 8, 9 Operations providing little or no benefit are avoided when patients are staged with FDG PET.9, 10 FDG PET assessment of mediastinal lymph nodes in NSCLC has a sensitivity of 74% (69–79) and a specificity of 85% (82–88).6 FDG PET has a poor sensitivity for small lymph nodes (20% false negatives [1–sensitivity]) and a poor specificity for large lymph nodes (20% false positives).11 The combination of node size and metabolic characteristics provided by integrated FDG PET CT has improved the accuracy of staging by better anatomic localisation of FDG hotspots. However, for most patients, integrated FDG PET CT does not eliminate the need for invasive testing.12, 13, 14 As with CT, subgroups in which FDG PET CT might be sufficient have been sought.11 Mediastinal nodal metastases are detected in less than 6% of patients with small peripheral tumours without enlarged or FDG-avid hilar or mediastinal lymph nodes; a 33% improvement compared with a cohort staged with CT only.2, 15 Most clinicians use these criteria to rule out mediastinal involvement and proceed with thoracotomy.2, 15, 16, 17

Sampling of mediastinal lymph nodes is still necessary in two groups of patients with resectable lung cancer (figure 1). The first group has mediastinal lymph nodes suspected of containing metastases on the basis of either size (short axis ≥10 mm) or FDG uptake (abnormal mediastinum by imaging). Nodal metastasis in this group ranges from 50% to 80%. The second group has small mediastinal lymph nodes without increased FDG uptake (normal mediastinum by imaging), but still has a 6–30% prevalence of mediastinal metastases because of a centrally located primary tumour, enlarged or FDG-avid hilar lymph nodes, or a primary tumour and lymph nodes that are not FDG avid.18, 19, 20, 21

Mediastinoscopy and endoscopic techniques have been assessed in these two groups. Because the prevalence of malignant nodal metastases differs between patients with an abnormal mediastinum by imaging (up to 80%) and a normal mediastinum (up to 30%), selective approaches might be necessary to obtain the best clinical mediastinal staging.

In this Personal View, we provide an overview of the data for an evidence-based recommendation for mediastinal tissue staging in patients with NSCLC. We focus on the development of a clinical management strategy based on the optimum combination of endosonography and surgical staging. We also discuss future developments that will likely establish different staging pathways for patient subgroups.

Section snippets

Surgical staging of the mediastinum

Mediastinal assessment by tissue verification as part of pre-operative staging is the most accurate method to establish the clinical N stage. For more than 50 years, this procedure has been done by cervical mediastinoscopy (originally with a lighted hollow tube, and later with a videoscope). Experts agree that ideally five (at least three) mediastinal nodal stations4—paratracheal left (stations 2L and 4L), paratracheal right (stations 2R and 4R), and subcarinal (station 7)—should be examined,

Endosonography to stage the mediastinum

Paratracheal and subcarinal lymph nodes identified by CT can be sampled by a transbronchial (Wang) needle passed through the working channel of a flexible bronchoscope. Although the endoscopist does not have an image when using this procedure, cytologic sampling effectively identifies metastases. For the confirmation of malignant nodal metastases, sensitivity varies between 39% and 78% and depends on the nodal size and the operator's experience.27 However, systematic assessment of the

Comparisons of staging techniques

On the basis of the available data, if the initial EUS-FNA or EBUS-TBNA is negative, cervical mediastinoscopy seems a reasonable approach to optimise mediastinal nodal staging.2, 3 However, the results from individual trials with patients selected to maximise the benefit of the technique being assessed might bias towards improved outcomes. As such, generalisation of these results to the broader population is risky. A good example is the number of mediastinal lymph nodes sampled compared with

Optimisation of indications for endosonography and surgical mediastinoscopy

Substantial evidence shows that initiation of mediastinal staging with complete endosonography is the optimum approach. A subsequent surgical staging procedure (mediastinoscopy) is advised for all patients whose biopsy samples do not show nodal metastases.2, 3, 45 However, the existence of a single optimum strategy to stage all patients with NSCLC is unlikely. The European ESTS and UK NICE guidelines anticipated this scenario by acknowledging that diagnostic procedures do not perform equally in

Do all patients with a negative endosonography require a mediastinoscopy?

Attempts to identify homogeneous subgroups likely to benefit from a particular sequence of staging techniques have not been on the basis of direct comparisons.16, 17 However, the suggestion to confirm negative endosonography findings with an additional surgical medias-tinoscopy if the clinical suspicion of mediastinal malignancy based on imaging is high, while proceeding to immediate resection after a negative EBUS and EUS when suspicion of malignant mediastinal nodes is low, was ahead of its

Integration of data into practice

Complete assessment of the mediastinal lymph nodes is integral to optimum clinical staging (figure 4). Therefore, at least three stations should be assessed and biopsy samples taken if possible (subcarinal, left paratracheal, and right paratracheal lymph nodes), irrespective of size or FDG uptake. Furthermore, all other abnormal lymph nodes, identified by size or FDG avidity, should be sampled. This proposal extends the staging algorithms of ESTS and ACCP and is based on the concept that

Conclusion

Mediastinal tissue staging of patients with NSCLC is a dynamic specialty in which imaging (CT and FDG-PET combined with CT) and biopsy techniques (invasive surgery and minimally invasive endoscopic approaches) are being investigated. Complete endosonographic assessment (oesophageal and endobronchial) of the mediastinum as the first (minimally) invasive staging procedure is a new concept that improves staging. Surgical staging of the mediastinum is indicated if the endosonographic assessment is

Search strategy and selection criteria

We searched PubMed, Embase (OVID version), Web of Science, and the Cochrane library, with the combination of subject headings: “endoscopic ultrasound (EUS)”, “endobronchial ultrasound (EBUS)”, “lung cancer”, and “cancer staging”. All databases were queried, taking into account the terminology differences between these databases (eg, “lung neoplasm” in PubMed, “lung tumor” in Embase). For the different concepts, all relevant keyword variations were used, not only keyword variations in the

References (48)

  • KG Tournoy et al.

    Endoscopic and endobronchial ultrasonography according to the proposed lymph node map definition in the seventh edition of the tumor, node, metastasis classification for lung cancer

    J Thorac Oncol

    (2009)
  • CG Micames et al.

    Endoscopic ultrasound-guided fine-needle aspiration for non-small cell lung cancer staging: a systematic review and metaanalysis

    Chest

    (2007)
  • P Gu et al.

    Endobronchial ultrasound-guided transbronchial needle aspiration for staging of lung cancer: a systematic review and meta-analysis

    Eur J Cancer

    (2009)
  • KG Tournoy et al.

    The yield of endoscopic ultrasound in lung cancer staging: does lymph node size matter?

    J Thorac Oncol

    (2008)
  • FJ Herth et al.

    Endobronchial ultrasound-guided transbronchial needle aspiration of lymph nodes in the radiologically and positron emission tomography-normal mediastinum in patients with lung cancer

    Chest

    (2008)
  • A Ernst et al.

    Diagnosis of mediastinal adenopathy-real-time endobronchial ultrasound guided needle aspiration versus mediastinoscopy

    J Thorac Oncol

    (2008)
  • FJ Herth et al.

    Combined endoesophageal–endobronchial ultrasound-guided, fine-needle aspiration of mediastinal lymph nodes through a single bronchoscope in 150 patients with suspected lung cancer

    Chest

    (2010)
  • B Hwangbo et al.

    Transbronchial and transesophageal fine-needle aspiration using an ultrasound bronchoscope in mediastinal staging of potentially operable lung cancer

    Chest

    (2010)
  • F Detterbeck et al.

    Classification of the thoroughness of mediastinal staging of lung cancer

    Chest

    (2010)
  • JRJ Handy et al.

    What happens to patients undergoing lung cancer surgery? Outcomes and quality of life before and after surgery

    Chest

    (2002)
  • NICE guidelines

  • P De Leyn et al.

    ESTS guidelines for preoperative lymph node staging for non-small cell lung cancer

    Eur J Cardiothorac Surg

    (2007)
  • HI Libshitz et al.

    Mediastinal lymph node size in lung cancer

    AJR Am J Roentgenol

    (1984)
  • W De Wever et al.

    Detection of extrapulmonary lesions with integrated PET/CT in the staging of lung cancer

    Eur Respir J

    (2007)
  • Cited by (74)

    • Indications for invasive mediastinal staging for non–small cell lung cancer

      2018, Journal of Thoracic and Cardiovascular Surgery
    • Upfront surgery as first-line therapy in selected patients with stage IIIA non–small cell lung cancer

      2018, Journal of Thoracic and Cardiovascular Surgery
      Citation Excerpt :

      Therefore, preoperative lymph node condition in these patients had little impact on our surgical procedure selection. Invasive mediastinal staging of lung cancer through mediastinoscopy endobronchial ultrasound-guided transbronchial needle aspiration or endoscopic ultrasound-guided needle aspiration not included in our treatment strategy, although most physicians believed that it was an important part of modern thoracic surgical oncology.29,30 Only initially unresectable patients received invasive mediastinal staging operations, whereas those patients with positive pathologic confirmations were initially given chemotherapy or induction chemotherapy.

    • EUS and EBUS in Non-Small Cell Lung Cancer

      2018, Endosonography, Fourth Edition
    View all citing articles on Scopus
    View full text