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Dr. Silvestri is Associate Professor of Medicine, Division of Pulmonary and Critical Care Medicine; Dr. Hoffman is Professor of Medicine, Division of Gastroenterology; and Dr. Reed is Professor of Surgery, Division of Thoracic Surgery, Medical University of South Carolina, Charleston, SC.
Correspondence to: Gerard A. Silvestri, MD, MS, FCCP, Division of Pulmonary and Critical Care Medicine, Medical University of South Carolina, Charleston, SC 29425; e-mail: Silvestri{at}musc.edu
The pulmonologist is the focal point for the diagnosis and staging of lung cancer. Accurate staging is imperative because of the implications that stage has on different treatment modalities and subsequently on survival. Early stage lung cancer is treated with surgery alone. For the majority of patients, locally advanced lung cancer with involvement of the mediastinum is treated with chemotherapy combined with radiotherapy. Finally, metastatic lung cancer is treated with chemotherapy alone. Accurate staging not only allows for the choice of the most appropriate therapy, it predicts survival. For example, early stage lung cancer treated with surgical resection has a 5-year survival on the order of 60 to 75%. However, with metastasis to the mediastinum (stage IIIA disease), the 5-year survival drops to approximately 17%.
Recent advances in technology in both imaging and endoscopic techniques have allowed for greater accuracy in staging lung cancer, but have also led to confusion regarding the indications and timing for each of these staging studies. In this issue of CHEST (see page 442), Fritscher-Ravens and colleagues compare CT, positron emission tomography (PET), and endoscopic ultrasound with fine-needle aspiration (EUS-FNA) for detection of mediastinal metastases in potentially resectable patients with lung cancer. Their study concluded that EUS-FNA is more accurate than both CT and PET scan in detecting abnormal lymph nodes in the mediastinum. The fact that CT is inaccurate is not news. In pooled data of 4,793 patients with lung cancer and an enlarged mediastinal lymph node, the sensitivity was only 60% and the specificity 81%.1 It is the low specificity that is so bothersome. If the pulmonologist were to trust the CT, nearly 20% of patients with lung cancer and mediastinal lymphadenopathy could be precluded from potentially curative surgery, when in fact the lymphadenopathy was not metastatic disease but represented inflammatory adenopathy from some other cause.
PET is a relatively new technology that takes advantage of the fact that malignant tumors have greater glucose utilization than normal tissue. The patient is injected with the radiolabeled glucose analog 18F-fluoro-deoxy-D-glucose that undergoes the same cellular uptake as glucose, but after phosphorylation is not further metabolized and becomes trapped in cells. Accumulation of isotope can then be identified using a PET camera. The sensitivity and specificity of this technology is 85% and 88%, respectively, in pooled data of 1,111 patients.1 Both the sensitivity and specificity in this large series of patients are better than those reported by Fritscher-Ravens et al in their small series. It appears that PET is useful in the preoperative patient with non-small cell lung cancer (NSCLC). Pieterman et al2 reported that in a total of 102 patients, the addition of PET changed the stage in 60 patients, with 42 upstaged and 20 downstaged. Readers should note that PET scans do not provide the necessary anatomic detail of the primary tumor and should be viewed in conjunction with the CT scan.
The advent of endoscopic ultrasound has allowed excellent visualization of the mediastinum, particularly the left-sided mediastinal lymph nodes and the subcarinal space. The procedure itself is nothing more than an upper endoscopy with a special endoscope that has a real-time ultrasound probe attached. The procedure takes anatomic advantage of the fact that the esophagus lies posteriorly and to the left of the trachea and is in the proximity of the lymph nodes between these two structures. Lymph node level 5 (aortopulmonary window), level 7 (subcarina), and inferior mediastinal lymph nodes are particularly easy to access by this method. In the past, the aortopulmonary window would have required an extended cervical mediastinoscopy or a left anterior mediastinotomy (Chamberlain procedure), and thoracoscopy is required for posterior subcarinal and inferior nodes. Once the lymph node in question is visualized, a needle can be passed in real-time and cytologic tissue can be obtained. EUS-FNA can be performed in the outpatient setting with conscious sedation, and the complication rate is virtually nil. As in the article published within this issue, others have reported similar results with EUS-FNA in lung cancer.3 4 5 The only downside to this technology is the inability to access the right side (levels 2R, 4R) and the pretracheal space. In addition to the ability to visualize and sample enlarged lymph nodes, EUS-FNA has the ability to detect malignancy in normal-sized lymph nodes. EUS-FNA in patients without discernable lymphadenopathy was initially reported by Devereaux et al6 to change the TNM stage in 18% of patients, and was reported to have a sensitivity of only 35%. A subsequent study by Wallace and colleagues5 showed a change in stage in 42%. This variability is explained by the techniques used. The higher-yield study obtained samples from any and all levels in which a node was seen, regardless of the lymph node characteristics. This change in technique does prolong the procedure, and further work is being done with computer modeling to determine if there are characteristics of lymph nodes that should guide fine-needle aspiration.
Where does transbronchial needle aspiration (TBNA) fit in? The sensitivity of this technology is 76% with a specificity of 96%.7 The yield is improved with at least seven passes with the TBNA needle and on-site cytopathology.8 TBNA can access the right and left paratracheal space (2R, 4L, 4R) and subcarinal space (level 7). Because TBNA is performed "blindly," the sensitivity is not as high as with EUS-FNA. The accuracy of TBNA may be improved in the future with the addition of endobronchial ultrasound. Wiersema et al9 recently reported that EUS-FNA was superior to TBNA in the diagnosis of mediastinal metastases in NSCLC. While TBNA is not as sensitive as EUS-FNA, it can access the precarinal and right paratracheal areas that are not accessible by EUS-FNA. Unfortunately, TBNA is underutilized by the practicing pulmonologist.10
So how does one choose the appropriate imaging/staging test to be performed in preparation for possible surgery? There are no definitive answers, but our approach is as follows. A thoracic CT is performed in all patients with known or suspected lung cancer to help delineate the characteristics of the primary tumor, assess the best method for biopsy, and assess the mediastinum. In patients who are otherwise surgical candidates and where PET is available, we recommend a PET scan be performed. If the PET finding is negative in the mediastinum and for distant metastatic disease, an argument can be made to go directly to surgery as long as a mediastinal lymph node dissection is performed at the time of resection. If a bronchoscopy is performed to make the initial diagnosis of lung cancer, and the thoracic CT or PET reveals lymphadenopathy in an area where TBNA can access the lymph node, then TBNA should be performed prior to biopsy of the primary tumor so that one does not contaminate the TBNA specimen. If the CT or PET reveals adenopathy in the aortopulmonary window or subcarina, then EUS-FNA is the preferred method for confirmation of malignant spread to the mediastinum. Between EUS-FNA and TBNA, we can now offer minimally invasive mediastinal sampling in the outpatient setting. It is a relatively rare occurrence that mediastinoscopy/mediastinotomy is performed in our institution. Still, this procedure remains the "gold standard" throughout much of the United States and elsewhere.
Perhaps the most important take-home message when staging patients with lung cancer is not to rely solely on imaging studies to assess the mediastinum. Tissue confirmation of metastases to mediastinum is required so that patients with potentially curative cancer are not denied surgery. The emergence of EUS-FNA and PET should assist the clinician in accurately staging the patient with newly diagnosed NSCLC so they can receive the treatment that gives them the best chance for long-term survival.
References
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