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J Thorac Cardiovasc Surg 2003;126:1900-1904
© 2003 The American Association for Thoracic Surgery
General thoracic surgery |
a,b Division of Nuclear Medicine, Duke University Medical Center, Durham, NC, USA
Read at the Eighty-second Annual Meeting of The American Association for Thoracic Surgery, Washington, DC, May 5-8, 2002.
Received for publication June 3, 2002; revisions received September 9, 2002; accepted for publication September 17, 2002.
* Address for reprints: Thomas A. D'Amico, MD, Duke University Medical Center, Box 3496, Durham, NC 27710, USA
damic001{at}mc.duke.edu
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Abstract |
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 Top Abstract Patients and methodsResultsDiscussionDiscussionReferences |
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METHODS: Between May 1995 and May 2000, positron emission tomography was performed on 1988 patients with known or suspected non–small cell lung cancer at Duke University Medical Center. Cervical mediastinoscopy was subsequently performed in patients without demonstrable evidence of distant metastases. The efficacy of mediastinal staging was analyzed by comparing the prospective results of positron emission tomography with the histopathologic results of mediastinoscopy by nodal station.
RESULTS: In this study 202 patients with non–small cell lung cancer (116 of whom were male) underwent mediastinoscopy after positron emission tomography. Of the 65 patients with positive results of positron emission tomography, only 29 patients had positive results of mediastinoscopy in the corresponding nodal station. Of the 137 patients with negative results of positron emission tomography, 16 patients were demonstrated to have N2 or N3 disease. The sensitivity, specificity, positive and negative predictive values, and accuracy for positron emission tomography were 64.4%, 77.1%, 44.6%, 88.3%, and 74.3%, respectively. Histologic findings in patients with non–small cell lung cancer and false-positive results of mediastinal positron emission tomography included granulomatous inflammation, sinus histiocytosis, and silicosis.
CONCLUSIONS: Positron emission tomography neither confirms nor excludes involvement of the mediastinum in patients with non–small cell lung cancer. Cervical mediastinoscopy with lymph node biopsy remains the criterion standard for mediastinal staging.
The applications of PET in the staging of NSCLC include evaluation of indeterminate pulmonary nodules,3-6 mediastinal staging,7-10 assessment of distant metastases,11,12 and restaging for treatment response and recurrence.13-15 The utility of PET in staging the mediastinum is controversial. Mediastinoscopy has been considered to be the standard for staging of the mediastinum,16,17 but it has been suggested that PET may replace mediastinoscopy in some cases.10 This study is a comparative analysis of PET and mediastinoscopy in staging NSCLC.
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Patients and methods |
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TopAbstractPatients and methodsResultsDiscussionDiscussionReferences |
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PET imaging
All PET studies were performed after fasting for at least 4 hours. PET was performed on an Advance tomographic scanner (GE Medical Systems, Milwaukee, Wis). Transmission scans were obtained over the chest and upper abdomen with rotating germanium 68 pin sources, either before or after isotope administration. Emission images of the chest and upper abdomen were obtained 30 to 60 minutes after the intravenous administration of 10 to 12 mCi of fluorodeoxyglucose F 18 (FDG).
Two-dimensional, non–attenuation-corrected and measured attenuation-corrected images were obtained from the skull base through the proximal thighs. Imaging was performed with reconstruction in the sagittal, axial, and coronal planes. The thoracic images were divided into three regions: lung, hilum, and mediastinum. Serum glucose concentrations were analyzed in all patients before FDG administration, and only patients with glucose concentrations in the normal range underwent PET scan. FDG uptake was considered to be positive in the mediastinum if tracer activity was significantly higher than mediastinal background activity (Figure 1). All studies were interpreted by a nuclear radiologist who was blinded to the histologic results. Results of the PET scans were compared by nodal station with histopathologic results after mediastinoscopy.
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Statistical analysis
The diagnostic efficacy of PET scanning relative to mediastinal lymph node biopsy was calculated with sensitivity, specificity, positive and negative predictive values, and accuracy.
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Results |
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TopAbstractPatients and methodsResultsDiscussionDiscussionReferences |
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Thus 202 patients underwent mediastinoscopy with lymph node biopsy (mean 4.5 stations/patient). There were 116 male and 86 female patients, with a mean age of 64 years (range 31-90 years). The mean interval between PET and mediastinoscopy was 15.4 days. No patients were unavailable for follow-up. Median duration of follow-up was 12.5 months (mean 15 months; range 2-86 months). Before the operation, there were 147 patients with known lung cancer, 51 patients with indeterminate lung nodules, and 5 patients with a lung mass and history of extrapulmonary malignancy in whom the diagnosis of primary lung cancer was suspected. After the operation, there were 151 patients with the diagnosis of lung cancer (Table 1). Histologic subtypes included adenocarcinoma (n = 69), squamous cell carcinoma (n = 45), non–small cell carcinoma (n = 15), large cell carcinoma (n = 8), small cell lung cancer (n = 6) adenosquamous carcinoma (n = 4), atypical carcinoid (n = 3), and bronchoalveolar carcinoma (n = 1).
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Discussion |
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TopAbstractPatients and methodsResultsDiscussionDiscussionReferences |
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PET has also been applied to detect residual or recurrent disease, predominately after treatment with chemotherapy and radiation. In one study, 113 patients with lung cancer had the disease restaged with PET after the completion of initial therapy.15 There was a significant difference in survival between those patients with positive scan results after therapy and those with negative scan results. In the future, it may be possible to assess a patient during treatment with chemotherapy and radiation therapy to estimate treatment response, allowing an earlier opportunity to use an alternate therapy if necessary.
The most effective use of PET to date appears to be in the detection of distant metastases. In one recent series of 105 patients, PET detected unsuspected distant metastases in 26% of patients and changed or influenced the management in 67% of patients with NSCLC.11 In a second series of 102 patients, PET identified distant metastases not found by other methods in 11% of patients and led to upstaging in 42% of cases and downstaging in 20% of cases.12 The ability of PET to detect metastatic disease is unparalleled; the challenge for this application is to define the appropriate population of potentially operable cases in which to obtain PET for cost-effectiveness.19
The success of PET in distant metastatic staging has led to the increased use of PET to stage the mediastinum. PET is clearly superior to CT scanning alone in assessing the mediastinum for malignant disease,20,21 and various algorithms have been suggested that could reduce the use of mediastinoscopy. Anecdotal reports suggest that patients with positive mediastinal PET scan results may be treated as stage III (with definitive chemotherapy and radiation therapy or with induction therapy followed by surgery), without histologic confirmation of N2 disease or exclusion of N3 disease. There is no evidence in the literature to support this approach.
In a recent study, it was proposed that patients with negative CT and mediastinal PET scan results do not require mediastinoscopy before exploration for resection and mediastinal lymph node dissection.10 By this reasonable strategy, the authors concluded that the need for mediastinoscopy would be reduced by 12%. Although this study was carefully analyzed, it is not clear what clinical criteria were applied to perform mediastinoscopy, such as T status. The false-negative rate of PET in this study was not fully addressed. It should also be remembered that if the primary tumor does not have significant FDG uptake, the mediastinal lymph nodes should not be expected to uptake FDG, even if involved.
Our study was undertaken to address two issues. Increasingly, patients are being referred to our institution after treatment decisions have already been made on the basis of the results of a mediastinal PET scan, without histologic confirmation. The first objective was to analyze the group of positive PET scan results to determine the false-positive rate, identifying cases inappropriately staged as IIIa or IIIb. The second objective was to analyze the group of negative PET scan results to determine the false-negative rate, identifying patients with undetected N2 or N3 disease who would be inappropriately treated with surgery primarily.
In this study, 202 patients underwent PET staging (for known or suspected lung cancer) and subsequent mediastinoscopy, constituting the study population. Many of the patients who underwent PET staging were excluded, either because metastatic disease was discovered or because the patients were treated surgically without mediastinoscopy (usually at another institution). The ideal study design would have prospectively registered patients to receive a PET scan followed by mediastinoscopy; because some patients went directly to surgery, selection bias may have limited the denominator in this study, without affecting the numerators: the number of patients with either false-positive or false-negative PET scan results.
Among the 202 patients who underwent PET and subsequent mediastinoscopy, the initial false-positive rate was 55%: of the 65 patients with positive mediastinal PET scan results, 36 had a negative mediastinoscopy. Because the false-negative PET scan results may represent a failure of mediastinoscopy rather than an inaccurate PET study, it is important to include complete follow-up on all potential false-negative results. One patient died after coronary artery bypass grafting, performed before planned pulmonary resection, and 35 underwent exploration. Of these 35 patients, 2 were found to have N2 disease at thoracotomy; thus, the actual false-positive rate was 34 of 65 (52%), although PET did not accurately identify the positive station in one of the patients. Of the remaining 33 patients, 20 are considered to have no evidence of disease, with a median follow-up of 12.5 months. Nine patients had distant metastases develop without evidence of regional nodal recurrence, and 1 patient with died no evidence of disease in the postoperative period. Benign processes that may have contributed to the false-positive PET scan results in patients with cancer include obstruction or pneumonia (n = 6), granulomatous disease (n = 5), and silicosis (n = 1).
From this analysis, it appears that mediastinoscopy failed in only 2 of 65 patients with positive PET scan results (3%). Factors known to be associated with false-positive PET staging include obstructive pneumonia and inflammatory disease.22 It is noteworthy that 4 patients with false-positive PET scan results did not have cancer, and 12 patients with node-negative cancer had benign processes of the mediastinum. A strategy to equate a positive mediastinal PET scan result with stage III disease would result in inappropriate therapy in most (52%) patients in this group.
The false-negative rate in this study was low (11.7%); however, the group included 5 patients with unsuspected N3 disease and 2 patients with small cell lung cancer (all with negative mediastinal lymph nodes on CT and PET), for whom surgical therapy would be considered contraindicated. Although most patients found to have N2 disease had T2 disease (n = 5), there were 3 patients with stage T1 N2 in whom the PET and the CT results were considered negative. A strategy to exclude mediastinoscopy in this group would not be reasonable. Unlike other series, our study did not differentiate scans by standardized uptake values, because our experience has not found that strategy to be advantageous.23 It is possible that subgroups among the patients with negative mediastinal PET scans could be identified for whom the risk of mediastinal metastases is low enough to justify avoiding mediastinoscopy. A cost analysis, including the costs and risks of mediastinoscopy, would be required to answer this question.
PET represents an important advance in the staging of lung cancer. The use of PET in staging the mediastinum must take into account the significance of false-positive and false-negative results. A positive PET scan result does not necessarily represent malignant disease, and histologic confirmation is always warranted. In this setting, PET may be useful to direct biopsies, especially if initial biopsy results are unexpectedly negative.10 A negative PET scan result is relatively powerful (negative predictive value 88.3%). Nevertheless, mediastinoscopy may identify N2 or N3 disease in this group of patients. Mediastinoscopy remains the criterion standard in staging the mediastinum in patients with lung cancer.
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Discussion |
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TopAbstractPatients and methodsResultsDiscussionDiscussionReferences |
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The initial experience and data with PET again suggested that mediastinoscopy is no longer necessary for lung cancer staging. Most of the early PET articles reported accuracy greater than 90%, but Gonzalez-Stawinski and colleagues have shown us more mature results with careful pathologic correlation. In our own experience reported last year, PET correctly differentiated N0-1 disease from N2-3 disease in 91% of patients, with both positive and negative predictive values of 90%. Although this is better than found in this series, it led us to the same conclusion, that there are high enough incidences of both false-positive and false-negative results to support routine mediastinal evaluation by mediastinoscopy.
Dr Gonzalez-Stawinski, I have three questions related to your experience. First, although you performed PET in almost 2000 patients with lung cancer, only 202, or about 10%, had mediastinoscopy after PET. What selection factors excluded the other 90% of patients, and how might this have skewed your results?
Second, you had a surprising incidence of false-positive PET studies, higher than most other reports. Do you think that this is due to setting a low threshold for mediastinal nodal positivity? Do you now use a more quantitative standard uptake value (SUV) threshold to evaluate lymph nodes?
Finally, even T1 tumors with a normal appearing mediastinum have a 10% to 15% incidence of N2 nodal disease. Given your experience showing a low sensitivity for positive mediastinal lymph nodes, have you moved to a strategy of routine mediastinoscopy? I applaud your fine work and your elegant presentation, and I thank you for helping us clarify the value of PET in lung cancer staging.
Dr Gonzalez-Stawinski. Thank you for your kind comments. Let me address the first question in regard to the patients that we excluded. It is true that we excluded 1756 patients. The reason behind that is that we are a center that essentially offers PET scan to an entire region, and a lot of these patients underwent PET scan in our institution without any follow-up or having any therapy afterward. In addition, a large number of patients had stage IV disease, at least as detected by PET scan.
In reference to the use of SUVs, essentially our decision to not use SUVs is based on reports from our own institution published in 1994 in the Journal of Nuclear Medicine by Lowe and coworkers showing that in our hands visual analysis of PET was superior to semiquantitative analysis with SUVs.
Finally, in reference to in which cases we are doing mediastinoscopy, we choose those patients that have T2 or T3 tumors, patients with enlarged lymph nodes, patients who are on protocol studies, and patients who are at high medical risk.
Dr Larry R. Kaiser (Philadelphia, Pa). I enjoyed the article, and it certainly supports some of our own views. You mentioned the size of the lymph nodes. Ned Patz at your institution, who has been one of the leading proponents of PET, has basically stated that PET shouldn't exist in a vacuum, and the combination of the CT scan and PET probably is a better predictor. Have you looked at the size of the lymph nodes? I know you did mediastinoscopy if the nodes were greater than 1 cm, but has there been a better predictive value with PET with the larger nodes?
Also, what has the experience been in your institution with using PET for solitary pulmonary nodules? Are you still optimistic about that? Our own experience has led us to become less enthusiastic, in fact, with solitary nodules.
Dr Gonzalez-Stawinski. Thank you for your questions. With regard to the size of the lymph nodes, in this particular study we did not analyze the size with respect to outcome. And I agree with you regarding the utility of PET for pulmonary nodules; in our own experience, we are less optimistic about the results of PET scan for solitary pulmonary nodules.
Dr Hiran C. Fernando (Pittsburgh, Pa). I congratulate you on your presentation. Two quick questions. In your false-positive cases, what was the incidence of granulomatous inflammation, and in the false-negative cases, what was the incidence of bronchiolar carcinoma?
Dr Gonzalez-Stawinski. Thank you for your question. When we broke down the cases that had benign lesions, we saw 6 patients who had essentially obstructive pneumonia, 5 patients with granulomatous disease, and 1 patient with silicosis.
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