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Originally published as JCO Early Release 10.1200/JCO.2005.08.912 on October 11 2005 © 2005 American Society of Clinical Oncology.
Mediastinoscopy: An Endangered Species?Memorial Sloan-Kettering Cancer Center, New York, NY Accurate staging is a critical part of the management of newly diagnosed non–small-cell lung cancer (NSCLC), and of the decision to offer patients induction therapy. During the last decade, the introduction into clinical practice of positron emission tomography (PET) and of endoscopic ultrasound biopsy techniques has again raised the question of when mediastinoscopy, long the gold standard for determining the presence and extent of mediastinal nodal metastases, should be performed. In this edition of the Journal of Clinical Oncology, two articles address this issue. Pozo-Rodriguez et al1 report a prospective study in 132 patients comparing the efficacy of helical computed tomography (CT) and PET in the mediastinal staging of NSCLC. They find that CT and PET have similar accuracies and, when combined, yield a negative predictive probability of .98. Conversely, they note that positive results of either test need to be confirmed pathologically. In the second article, Annema et al2 evaluated endoscopic ultrasound-guided fine-needle aspiration (EUS FNA) in the diagnosis and staging of lung cancer in 242 consecutive patients for whom mediastinoscopy or exploratory thoracotomy were planned. EUS FNA prevented 70% of scheduled surgical procedures, and the accuracy of this procedure in mediastinal staging was found to be 93%. How does the practicing clinician incorporate this information into daily practice? First, it is important to note that these are not the first studies to highlight the utility of PET and EUS in the staging of NSCLC. A literature search yields a plethora of studies of variable quality on both modalities, especially PET.3-8 Table 6 in the article by Pozo-Rodriguez et al1 summarizes some of the most relevant articles published on CT and PET in NSCLC since 1980. However, the authors correctly point out that their trial was more stringently designed than many previous studies, and benefited from the readings of CT and PET being blinded and independent both of each other and of the reference tests. A long follow-up period allowed clinical confirmation of the study findings. Multiple articles already attest to the safety and accuracy of EUS FNA in detecting mediastinal lymph node metastases and mediastinal tumor invasion in NSCLC.9-13 However, Annema et al2 have performed the largest prospective study to date, even though approximately 15% of their patients had EUS FNA performed for reasons other than the initial staging of NSCLC. Therefore, both of these studies are noteworthy by virtue of their size and careful design. Second, these studies reflect the evolving algorithm of staging of NSCLC that is already reducing the use of mediastinoscopy. In many countries, including the United States, PET (and more recently PET-CT) has become a widely accepted study for the initial extent of disease evaluation of NSCLC. Beyond its utility in mediastinal staging, PET provides important prognostic information14 and detects distant metastatic disease, obviating the need for additional bone scanning or imaging of the liver and adrenal glands.15 EUS FNA is not as widely practiced, partly because it is not yet a procedure commonly performed by thoracic surgeons or pulmonary medicine physicians, and partly because it does not provide access anatomically to the right and left paratracheal nodes, which are key to the staging of most NSCLC. However, it is well recognized as an important adjunct in evaluating the periaortic, subcarinal, and periesophageal lymph nodes. Endobronchial ultrasound (EBUS) FNA is just now being introduced into clinical practice outside of Japan and should prove highly effective in diagnosing paratracheal and perhaps even hilar nodal metastases.16 Thus, the staging algorithm of the not-too-distant future could include a contrast CT of the chest and upper abdomen, a PET-CT, brain imaging (as clinically indicated), and an EBUS FNA with or without an EUS FNA. Mediastinoscopy might only be performed in situations where other staging studies are equivocal or when additional tissue is needed for histologic or molecular evaluation. Initial staging with a combination of EUS, EBUS, and PET may also allow mediastinoscopy to be used more freely for restaging after induction therapy in situations where this is important for decisions about subsequent treatment.17 The accuracy of EUS and EBUS FNA for restaging will need to be examined in the future. All mediastinal staging studies should be performed taking into consideration the size and location of the primary tumor. The likelihood of mediastinal nodal metastases is known to be related to the size of the primary tumor, with an incremental risk of 10% to roughly 25% for 1 v 2 v 3 cm tumors. Histologic subtype also influences the risk of nodal metastases, with squamous cell and bronchioloalveolar carcinoma associated with a lower incidence than invasive adenocarcinoma.18-20 The location of the primary tumor also influences the likelihood of nodal metastases, with peripherally located tumors (generally considered to be the outer third of the lung) associated with a lower frequency than more centrally located tumors. The lobar location of the primary tumor dictates the pattern and frequency of mediastinal nodal metastases because of anatomic differences in lymphatic drainage.21-23 Right upper lobe tumors have the highest risk of skip metastases (N2 in the absence of N1 disease) and invariably spread to the right paratracheal lymph nodes (levels 2R and 4R). Right middle and lower lobe tumors and left lower lobe tumors metastasize initially to the subcarinal nodes (level 7), but left lower lobe tumors have a high risk of then metastasizing to the contralateral right paratracheal lymph nodes, whereas right-sided tumors tend to spread to the ipsilateral superior mediastinal nodes. Therefore, cervical mediastinoscopy to exclude stage IIIb (N3) disease is an important part of the staging for left lower lobe NSCLC. Left upper lobe NSCLC has a different pattern of lymphatic drainage, metastasizing first to the aortopulmonary window and periaortic lymph nodes (levels 5 and 6), then to the subcarinal and superior mediastinal nodes. When nodal metastases are confined to levels 5 or 6, these tumors are known to have a relatively better prognosis than other tumor subsets of stage IIIa (N2) disease. All of these factors should be considered when making a decision about the need for invasive staging procedures, whether EUS or EBUS FNA, mediastinoscopy, or—less frequently—videothoracoscopic (VATS) biopsies. No single staging algorithm applies to all NSCLC. Third, it is important to remember that the safety and accuracy of invasive staging procedures is related to the expertise of the physician performing those procedures. This is well recognized by the gastroenterology community with respect to EUS. As pointed out by Annema et al,2 the accuracy of EUS or EBUS FNA is also dictated by the on-site availability of expert review of FNA specimens by a cytopathologist. Thoracic surgeons recognize that the yield from mediastinoscopy varies considerably based on training and experience. Even today, the most inexperienced surgeons will occasionally declare the mediastinum as negative by visual inspection, noting that no lymph nodes were identified. Such findings clearly reflect ignorance that the pretracheal fascial plane needs to be incised to find the paratracheal and subcarinal lymph nodes. Relatively inexperienced surgeons will often biopsy only a couple of lymph nodes from the pretracheal or right paratracheal area, labeling them only as mediastinal lymph nodes, and leaving the oncologist with inadequate information on which to base treatment decisions. Highly experienced surgeons will biopsy the right and left paratracheal and the subcarinal lymph nodes and label all of these accurately by level (eg, 2R, 4R, and so on) for the pathologist. In a normal mediastinum, it is possible for an experienced surgeon to perform a complete subcarinal lymph node dissection via the mediastinoscope, whereas the inexperienced surgeon might not even enter the subcarinal space for fear of injuring the right main pulmonary artery where it abuts the precarinal region. Similar differences in the results of EUS and EBUS will undoubtedly occur during the next decade as these enter routine clinical practice. The reliability of early experience with these staging modalities should be interpreted accordingly. Finally, improvements in systemic therapy are also influencing the use of mediastinoscopy. For many years, adjuvant chemotherapy was thought to have a minimal impact on overall survival. Under these circumstances, it was imperative to distinguish between NSCLC patients who would clearly be considered for induction chemotherapy because of the presence of N2 disease compared with those who would be treated by surgical resection only without adjuvant therapy. Recent large randomized clinical trials have shown that adjuvant platinum-based chemotherapy significantly improves overall survival in patients with stages Ib to IIIa NSCLC.24,25 Consequently, all patients with resectable NSCLC except those with stage Ia disease now receive either induction or adjuvant chemotherapy. Because preoperative treatment usually allows the administration of a higher total dose of chemotherapy, some physicians will consider induction therapy in situations where initial imaging studies clearly show that the tumor is a higher stage than Ia (such as a 6-cm T2 primary tumor or clinically obvious hilar N1 disease) even when there is not pathologic proof of N2 disease. Although there has been no study comparing the efficacy of induction with adjuvant chemotherapy directly, such an approach is rational even if not completely evidence based. In summary, mediastinoscopy remains the gold standard for preresection staging of the mediastinum,26 but may largely be superseded in the future by combinations of PET-CT, EUS FNA, and EBUS FNA. Future studies are needed to define the best use and combinations of these modalities. Stay tuned. The standard of care is evolving. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interest. REFERENCES 1. Pozo-Rodriguez F, Martin de Nicolás JL, Sánchez-Nistal MA, et al: Accuracy of helical CT and FDG-PET for identifying lymph node mediastinal metastases in potentially resectable non–small-cell lung cancer. J Clin Oncol 23:8348-8356, 2005 2. Annema JT, Versteegh MI, Veseliç M, et al: Endoscopic ultrasound guided FNA in the diagnosis and staging of lung cancer and its impact on surgical staging. J Clin Oncol 23:8357-8361, 2005
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17. Lardinois D, Schallberger A, Betticher D, et al: Postinduction video-mediastinoscopy is as accurate and safe as video-mediastinoscopy in patients without pretreatment for potentially operable non-small cell lung cancer. Ann Thorac Surg 75:1102-1106, 2003
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24. Winton T, Livingston R, Johnson D, et al: Vinorelbine plus cisplatin vs. observation in resected non-small cell lung cancer. N Engl J Med 352:2589-2597, 2005
25. Pisters KMW: Adjuvant chemotherapy for non-small cell lung cancer: The smoke clears. N Engl J Med 352:2640-2641, 2005
26. Hammoud ZT, Anderson RC, Meyers BF, et al: The current role of mediastinoscopy in the evaluation of thoracic disease. J Thorac Cardiovasc Surg 118:894-899, 1999 Related Articles
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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