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J Thorac Cardiovasc Surg 2003;126:11-15
© 2003 The American Association for Thoracic Surgery
General thoracic surgery |
a Thoracic Service, Department of Surgery, New York, New York, USAa
b Nuclear Medicine Service, Department of Radiology, New York, New York, USAb
c Biostatistics Service, Department of Epidemiology and Biostatistics,c Memorial Sloan-Kettering Cancer Center, New York, NY, USA
Read at the Eighty-second Annual Meeting of The American Association for Thoracic Surgery, Washington, DC, May 5-8, 2002.
Received for publication May 21, 2002. Received for publication July 17, 2002; revisions received November 25, 2002; accepted for publication December 19, 2002.
* Address for reprints: Raja M. Flores, MD, Thoracic Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA
floresr{at}mskcc.org
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Abstract |
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METHODS: Patients with malignant pleural mesothelioma who underwent fluorodeoxyglucose-positron emission tomography scanning were identified from an institutional database. All patients fasted and received a minimum of 10 mCi of F-18-fluorodeoxyglucose. Whole-body emission studies were acquired, followed by whole-body transmission studies, allowing iterative reconstruction. Blinded review of positron emission tomography scans was performed for clinical staging, which was then correlated with surgical and pathologic findings. Sensitivity and specificity were determined for tumor and nodal status.
RESULTS: From 1998 to 2002, 63 patients underwent positron emission tomography scans, 60 preoperatively and 3 to assess disease recurrence after surgery. Increased fluorodeoxyglucose uptake was seen in all but 1 tumor, which was very early stage (IA). Positron emission tomography findings yielded sensitivities of only 19% and 11% for tumor and nodal status, respectively. However, a high standard uptake value in the primary tumor correlated with the presence of N2 disease. Positron emission tomography correctly identified supraclavicular N3 or M1 disease in 6 patients.
CONCLUSIONS: Positron emission tomography does not identify the local extent of tumor or mediastinal nodal metastases reliably but detects extrathoracic metastases, thereby obviating inappropriate thoracotomy. Further studies of the association between tumor standard uptake value and the presence of N2 disease are warranted.
Malignant pleural mesothelioma (MPM) is an uncommon tumor that is difficult to evaluate radiologically because of its propensity to infiltrate locally along tissue planes. Computed tomography (CT) and magnetic resonance imaging (MRI) are used to stage MPM but often fail to detect tumor invasion of the chest wall and diaphragm, as well as the presence of mediastinal nodal metastases.1,2 The treatment of early stage disease often involves surgical resection by either extrapleural pneumonectomy or pleurectomy/decortication.3,4 However, approximately 20% to 30% of patients undergo exploratory thoracotomy without resection because of the unreliability of current imaging modalities in identifying locally advanced or metastatic disease.2,5 Improved methods of determining resectability are needed to minimize the number of patients subjected to exploratory thoracotomy without resection.
Two studies suggested that MPM shows an increased uptake of fluorodeoxyglucose-positron emission tomography (FDG-PET) scanning, and that PET may be useful in staging this disease.6,7 However, these studies were too small to yield definitive information. We hypothesized that the functional tumor imaging provided by PET scanning might improve locoregional staging in patients undergoing preoperative evaluation or identify otherwise unsuspected extrathoracic disease, thereby avoiding inappropriate surgical exploration. Therefore, we reviewed our experience with FDG-PET scanning in MPM.
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Methods |
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Pet evaluation
PET scans were acquired on dedicated bismuth germinate-based systems, including the GE Advance (GE Medicals Systems, Milwaukee, Wis), Siemens HR+, and Siemens Biograph scanners (CPS Innovations, Knoxville, Tenn). All patients were instructed to fast for 6 hours before the administration of FDG. After a minimum of 45 minutes postinjection of at least 10 mCi of FDG, whole-body emission scans were performed, with rod source-based transmission scans to allow for iterative reconstruction with segmented attenuation correction.
A central review of all PET scans was performed by a single nuclear medicine physician who was blinded to all clinical information. Patients were clinically staged by PET using the International Mesothelioma Interest Group TNM staging system, the staging system for MPM which is now accepted by the American Joint Commission on Cancer and the Union Internationale Contre le Cancer.8-10 The standard uptake value (SUV) was calculated according to standard methods based on the uptake of FDG in grams per milliliter corrected for the injected dose of FDG adjusted for the patient’s weight. To calculate the maximal SUV in the tumor, we thresholded the images electronically such that only the hottest voxel of the tumor was seen. A region of interest was drawn around the hottest voxel on the transaxial slice of the iteratively reconstructed images, and the SUV maximal value, corrected for body weight, was recorded.
Statistical methods
The SUV was calculated for each tumor. The Wilcoxon test was then used to determine the relationship between tumor histologic subtype, and the mean SUV for all tumors was studied. A P value of less than .05 was considered statistically significant.
Sensitivity and specificity on the basis of PET readings were calculated for tumor (T) and nodal (N) status. Sensitivity was defined as the number of patients with positive PET scan results divided by the total number of patients found to have positive results on surgical and pathologic examination. Specificity was defined as the number of patients with negative PET scan results divided by the total number of patients found to have negative results on surgical and pathologic examination. Positive predictive value was defined as the number of true positive findings by PET scan divided by the total number of positive PET scans. Negative predictive value was defined as the number of true negative PET findings divided by the total number of negative PET scan results.
Receiver operator characteristic (ROC) curves were calculated on the basis of SUV for both N and T status. The area under the curve (AUC) was calculated to determine the utility of SUV in predicting each status.
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Results |
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Types of surgical intervention
Sixty patients underwent PET scans before definitive surgical intervention. Three patients underwent PET scans during follow-up to determine disease status after extrapleural pneumonectomy (n = 2) or pleurectomy/decortication (n = 1). Twenty-six patients underwent extrapleural pneumonectomy, 10 patients underwent pleurectomy/decortication, 19 patients underwent exploratory thoracotomy without resection, 1 patient underwent wedge resection after pleurectomy, 2 patients underwent mediastinoscopy, and 2 patients underwent supraclavicular lymph node biopsy. At least 1 month before the PET scan, 10 patients had received induction chemotherapy and 18 patients had prior talc pleurodesis.
The patients who did not have a resection performed had disease invading the mediastinum or chest wall (T4 tumor). This reflects our institutional policy of offering patients exploration whenever preoperative imaging studies indicate potentially resectable disease and not performing an extrapleural pneumonectomy in cases unless all gross tumor can be removed. We have a low threshold for exploration in this patient population because of the inaccuracies of CT scan and MRI in predicting resectability. We consider a patient as unresectable when there is diffuse chest wall invasion or disease invading mediastinal structures (eg, the vena cava) that would not be removed by an extrapleural dissection. Our goal in surgery is to rid the patient of all gross disease. If this is not possible with an extrapleural pneumonectomy, then the procedure is not performed, regardless of the feasibility.
Analysis of PET scan results
Of the patients who underwent PET scans before surgical intervention, 59 of 60 had FDG-18 uptake in the primary tumor. The median SUV of the primary tumor was 6.6 (range 1.7-23). The single patient who had no increased uptake on PET scan was found to have minimal parietal pleural disease (stage IA) at thoracoscopy.
PET findings were correlated with tumor histology. The mean SUV for epithelial tumors (n = 39) was 6.67 (± 2.78) and 7.37 (± 5.82) for the mixed histology tumors (n = 14). These were not significantly different (P = .88). There were only 2 sarcomatous tumors with SUVs of 3.4 and 4.1.
Of the 53 patients who underwent both FDG PET evaluation of T status and surgical and pathologic evaluation, 21 ultimately had unresectable tumors as the result of tumor invading the chest wall or mediastinum (T4 status), as shown in Table 1. The sensitivity of PET in identifying T4 status was 19% (95% confidence interval [CI]: 5%-42%). The specificity was estimated to be 91% (95% CI: 75%-98%). The positive predictive value of PET was 57% (95% CI: 18%-90%), but there were only 7 patients classified as T4 by PET. The negative predictive value, on the other hand, was 63% (95% CI: 48%-77%).
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PET failed to accurately detect disease in 3 patients. One patient had a false-negative scan that failed to detect a 1-cm nodule of mesothelioma; the small size of the nodule on the CT scan was presumed to be the reason for the lack of detection by PET. Two patients had false-positive findings on PET scan (1 patient had a supraclavicular node that showed inflammation, which may have accounted for the false-positive results).
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Discussion |
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The tumor histologic subtype does not seem to influence PET findings. Both epithelial and mixed histology tumors had similar SUVs. Although both of these tumors had lower SUVs than tumors of other histologies, there were too few tumors of sarcomatous subtype for analysis.
Given the lack of spatial localization provided by PET, it is not surprising that we did not reliably identify patients who were unresectable by virtue of T4 disease. The poor sensitivity of PET indicates that it should not be used to make decisions about the resectability of the primary tumor. It remains to be seen whether the newly available combined PET/CT scanners will provide better anatomic tumor definition.
We elected not to evaluate the influence of CT scan on staging. This study was performed specifically to correlate PET scan findings as a single modality with surgical pathologic findings. For staging to be considered, it would have required a retrospective review of different quality CT scanners from different institutions performed at different time periods other than the PET scan. Because the CT scans were performed in a non-uniform fashion, we would not have had the consistency that would be required to answer the specific question in a scientific manner. Combined PET/CT scanners are now available in many institutions and may provide better spatial localization and, therefore, improved staging of locoregional disease. This warrants future investigation.
The SUV was also not a good predictor of the T4 status. On the basis of the ROC curve, it seems that the SUV has no relationship at all to T status. The SUV probably reflects the rate of tumor growth and biology rather than a particular stage at the time of diagnosis.
It has been proposed that PET is useful in the determination of N status.6 Improved nodal staging would be valuable in MPM because of the known adverse impact of N2 disease on prognosis.4 However, our experience indicates that PET also does not reliably predict N status. This is not surprising given the difficulties in spatial resolution within the mediastinum. Pleural tumor involving or abutting the mediastinum will show increased FDG uptake and can easily be misinterpreted as nodal disease. There were a total of 9 patients with N2 disease, and PET did not identify 8. Therefore, any management decision based on PET findings of N2 disease should be confirmed by surgical pathologic evaluation.
A high SUV in the primary tumor seems to correlate with the presence of mediastinal nodal metastasis. This may simply reflect the propensity of more metabolically active tumors to metastasize to mediastinal nodes. This is an interesting preliminary finding. Further investigation is needed to determine if there is a specific SUV level at which mediastinal nodal metastasis is likely to be present. Such information may be of potential use in selecting patients for surgical resection.
Our data indicate that FDG PET may be useful in identifying extrathoracic disease either preoperatively or in the setting of potential tumor recurrence. Although these findings warrant confirmation in a larger number of patients, it is valuable to identify even a small number of patients in whom surgical intervention may be inappropriate.
This experience builds on that reported in previous studies. The number of patients in our study is larger than in previously published studies, but it is still a somewhat heterogenous patient cohort. Additional studies in still larger numbers of patients are warranted. Future studies should investigate our observation that high primary tumor SUV correlates with N2 disease and could validate the lack of correlation between SUV and histologic subtype. Investigations of the accuracy of combined PET/CT scanning should also be undertaken to determine whether this imaging modality leads to better definition of T and N status.
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