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J Thorac Cardiovasc Surg 2000;120:1085-1092
© 2000 The American Association for Thoracic Surgery
General Thoracic Surgery |
From the Departments of Nuclear Medicine, Internal Medicine, Radiology, and Thoracic Surgery, University Hospital Gasthuisberg, Katholieke Universiteit Leuven (KUL), Leuven, Belgium.
Address for reprints: Patrick Flamen, MD, Department of Nuclear Medicine, University Hospital Gasthuisberg, Herestraat 49, 3000 Leuven, Belgium (E-mail: Patrick.Flamen{at}uz.kuleuven.ac.be).
| Abstract |
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| Introduction |
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Recent reports indicated a role for whole-body positron emission tomography (PET) using the radiolabeled glucose analog 18F-fluoro-deoxy-D-glucose (FDG) for preoperative staging of cancer of the esophagus and gastroesophageal junction.
12-16 PET uses a metabolic approach to diagnosis. The depiction of neoplastic foci by FDG-PET relies on the increased accumulation of the radioactive tracer in malignant tissues, which is believed to be the result of an increased expression of glucose transport enzymes in the tumoral cell membrane, together with an increased activity of the enzymes of the first steps of the glycolytic pathway.
17,18 Early reports suggested that PET had a significant advantage over the conventional methods (spiral CT and EUS) for the detection of distant metastases and thus for the diagnosis of nonresectable disease. For assessing locoregional lymph node metastases, PET was as accurate as CDW and more specific. No data are yet available about the potential of PET used in the follow-up of patients after resection of esophageal cancer. The purpose of this study was to investigate the utility of FDG-PET for the diagnosis and staging of disease in patients in whom recurrent esophageal cancer was suspected.
| Methods |
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CDW
In all patients routine CDW was performed in house according to high-standard practice, including spiral CT of chest and abdomen (n = 39), transesophageal EUS (n = 13), and endoscopy (n = 18). In some patients, other sign- or symptom-directed dedicated techniques such as bone scan or spiral CT of the neck were also performed. In 11 patients full passage of the echoendoscope was impossible, precluding accurate EUS diagnosis. These patients underwent an endoscopy. The lesions reported by CDW were classified as equivocal or suspicious for recurrence.
FDG-PET imaging
The PET imaging was performed with a CTI-Siemens 931 or HR+ scanner (CTI, Inc, Knoxville, Tenn) with an axial field of view of 10.1 cm and 15 cm, respectively, and a spatial resolution of 8 and 6 mm, respectively. All patients fasted for 6 hours before the tracer administration. Sixty minutes after the intravenous injection of a 6.5 MBq/kg dose of 18F-FDG (to a maximum of 555 MBq), a whole-body emission scan was performed. The raw imaging data were reconstructed in a 128 x 128 matrix with the use of an iterative reconstruction algorithm.
For the purpose of this study, all PET images were reviewed by two experienced nuclear medicine physicians (A.M. and J.P.C.). At the time of image review, these observers were fully aware of the history of the patients, the type of esophagectomy performed, the location of the esophagogastric anastomosis, and the patients' symptoms. However, the observers were completely blinded to the results of the concurrent CDW and to the follow-up data. In case of diagnostic discordances between the observers, a consensus diagnosis was generated. The PET lesions were classified as equivocal or suspicious for recurrence.
Data analysis
The results of CDW and of FDG-PET were compared with a gold standard that consisted of histologic findings or of clinical and radiologic follow-up. A follow-up of at least 6 months was needed for a definitive negative diagnosis.
For the region-based analysis, recurrences were assigned to 3 regions: (1) the perianastomotic area, located around the esophagogastric anastomosis; (2) the regional area, corresponding to the operative field of the primary esophagectomy, including the mediastinum and upper abdominal compartment, and also the cervical area when a 3-field lymphadenectomy had been performed; and (3) distant areas, if the lesions were located in organs or lymph nodes outside the initial operative field.
The calculations of the accuracies of CDW and PET took into account only those regions for which a gold standard was available. For these calculations, CDW and PET lesions that were classified as equivocal were considered as positive.
The sensitivity, specificity, and accuracy of CDW and FDG-PET were calculated by the standard definitions. McNemar
2 testing was used to compare the sensitivity, specificity, and accuracy of PET and CDW as dependent samples by means of 2 x 2 tables.
| Results |
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The gold standard established cancer recurrence in 33 of 41 (80%) patients.Table II shows the regional distribution of the recurrences and the gold standard used to define the true lesion status. The sensitivity, specificity, and accuracy of CDW and FDG-PET for the diagnosis of perianastomotic recurrence, locoregional recurrence, and distant metastasis are shown inTable III. Overall, sensitivity of FDG-PET was higher than that of CDW (95% vs 85%; P = not significant [NS]). The specificity, on the other hand, was lower (72% vs 86%; P = NS). This resulted in a similar overall accuracy of the two diagnostic approaches (84% vs 86% for PET and CDW, respectively).
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False-positive PET scans were found in 2 patients: both lesions were only moderately intense and were considered as equivocal. The first lesion was located in the anterior mediastinum and was not confirmed by follow-up CT performed 9 months later. The latter lesion was located in the right lung hilus. Histologic examination of the hilar lymph nodes indicated inflammation.
Distant metastases
The gold standard indicated distant metastatic disease in 19 patients: CDW detected lesions in 15 (sensitivity 79%) and FDG-PET in 18 (sensitivity 95%) of these. The PET scan was false-negative in only 1 patient, in whom diffuse miliary peritoneal metastases were found during a diagnostic laparoscopy. Conventional imaging was also false-negative in this patient.
False-positive PET images were found in 2 patients. One had a moderately intense FDG uptake in a spinal location, which was considered as equivocal. Other investigations and a disease-free follow-up of more than 1 year did not confirm the diagnosis of a bone metastasis. Another patient had a moderately intense lesion, also considered as equivocal, located in the periphery of the left lung. The CT of that region showed a thickened pleura and some parenchymatous sequelae of infection.
Regional and distant recurrences
For the diagnosis of a nonperianastomotic recurrence, that is, regional and distant, the sensitivity, specificity, and accuracy of PET were 94%, 82%, and 87% versus 81% (P = NS), 82% (P = NS), and 81% (P = .0771) for CDW. Five lesions were classified as equivocal by PET: 2 regional and 3 distant lesions. The gold standard, available in 4 of them, indicated the absence of recurrent tumor. The 2 regional lesions were located in the lung hilus and in the anterior mediastinum. The 2 distant lesions were located in the lungs and in the bone. After close multidisciplinary correlation with clinical and/or radiographic findings, these lesions were considered as probably inflammatory and, therefore, did not induce any diagnostic or therapeutic change. Importantly, none of the equivocal PET lesions proved to be malignant.
Patient-based analysis
On a patient basis, PET and CDW were completely concordant in 25 of 41 (61%) patients. Of the 16 patients with discordant PET findings, PET improved the diagnosis in 11 patients. According to the degree of potential clinical impact in these patients, the added value of PET was classified as major when a potential treatment could have been installed, withheld, or changed as a consequence of the PET findings; the value was classified as minor in case PET did not significantly change the management of the patient. A major contribution of PET was found in 5 of 41 (12%) patients in whom it correctly diagnosed recurrent disease not detected by CDW. Fig 2 shows the FDG-PET images of such a patient. In 6 other patients, contribution of PET to the correct diagnosis was only minor: in 5 of these patients PET detected more lesions than CDW, and in another patient with equivocal CDW findings FDG-PET correctly excluded a bone metastasis as the cause of a dorsal vertebral collapse.
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| Discussion |
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We believe that the inclusion criteria of this study led to an underestimation of the additional value of PET. Only patients with a clinical or radiologic suggestion of recurrence were referred for a PET scan. The pre-test probability of finding recurrent tumor in these patients is very high. Indeed, 80% of the included patients had recurrent disease, often in advanced stages, leaving only the small fraction of CDW-negative patients to test the additional value of PET. Nevertheless, the very high sensitivity of PET supports the hypothesis that PET could allow an earlier and presumably preclinical diagnosis of esophageal cancer recurrence. It certainly justifies further prospective studies in this respect. Such studies have been reported using CT or EUS as surveillance tools in the year after the primary operation. In a prospective follow-up of patients with routine CT, Barbier and associates
11 showed that the symptom-free interval exeeded the tumor-free interval by 4 months. However, the earlier detection of asymptomatic recurrences had no impact on outcome. More recently, EUS was tested in a similar setting. It was found that EUS performed routinely in the postoperative follow-up detected recurrences in 67% of the asymptomatic patients, on average 3 months before their condition became symptomatic.
21 An important limitation of EUS is that a benign anastomotic stricture precluding passage of an endoscope after cervical esophagogastrostomy will develop in approximately 30% of patients.
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Whether earlier diagnosis of recurrent esophageal cancer would improve patient survival has not been reported yet. The possibility of a survival benefit, however, can be deduced indirectly from results obtained in a study with primary chemotherapy in asymptomatic patients with advanced colorectal cancer, indicating a survival benefit of 6 months.
23 The available therapeutic modalities in recurrent esophageal cancer are radical reresection, palliative resection and bypass, laser thermocoagulation, stenting, chemotherapy, brachytherapy, and radiotherapy, alone or in combination. The choice of a specific therapeutic modality depends on the extent of the recurrence. Our study results indicate that FDG-PET at that point could contribute to patient care because it provides, in one imaging session covering the whole body, an accurate assessment of the extent of disease.
A noteworthy finding in the current study is the high incidence of false-positive PET findings at the perianastomotic region. By reviewing the patients' records, we found that the patients with intense false-positive FDG uptake all had undergone an endoscopic dilation of a benign anastomotic stricture as long as 55 days before the PET scan. Probably the dilation induced a trauma resulting in an inflammatory reaction. False-positive FDG uptake at inflammatory lesions is widely known and remains a major problem in the diagnosis of oncologic patients.
24 Three other patients had only moderate uptake at the anastomosis. In 2 of these patients, a nontumoral stricture was found endoscopically. However, a dilatation had not been performed, and the accumulation of FDG may have been due to proliferating fibroblastic and/or granulomatous tissue at the anastomosis. The other patient underwent scanning less than 2 months after the primary operation. The FDG uptake in this patient probably reflected a normal inflammatory healing process. This means that interpretation of the PET scan at the anastomotic site needs careful correlation with clinical data before a positive diagnosis can be made. The specificity of PET at the regional and distant sites is clearly higher although certainly not perfect. Importantly, all 4 false-positive PET lesions, falsely overstaging the disease in 4 patients, were considered as equivocal by the blinded PET reviewer. The decision to classify these equivocal studies as positive was based on the fact that in other types of tumors these lesions sometimes do indicate the presence of a limited load of neoplastic cells. However, in our experience the clinical impact of these equivocal PET lesions is often relatively limited. Multidisciplinary confrontation of the PET findings with clinical data, together with close correlation of PET and CT images, which was not done in this study, often neutralizes the potential negative impact of these equivocal lesions. Indeed, in our study, the 4 lesions reported as equivocal on PET did not induce any change of patient management because these lesions lacked any clinical or radiologic correlation. The impact of false-positivity of PET would be more pronounced if the technique were used as an early diagnostic maneuver. In that case correlative CT imaging would frequently be necessary to decide on equivocal PET lesions.
We conclude that (1) FDG-PET allows a highly sensitive diagnosis and accurate whole-body staging of symptomatic recurrent esophageal cancer; (2) FDG-PET is not accurate for diagnosis of perianastomotic recurrence owing to frequent false-positive findings based on FDG accumulation in areas of inflammation; (3) a multidisciplinary correlative approach is essential to reduce the potential negative impact of false-positive PET diagnosis on patient care; (4) prospective studies using PET in asymptomatic patients are needed to study the potential benefit of earlier diagnosis of recurrent disease on patient survival and quality of life.
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