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Ann Thorac Surg 1997;64:770-776
© 1997 The Society of Thoracic Surgeons

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Original Article: General Thoracic

Improvement in Staging of Esophageal Cancer With the Addition of Positron Emission Tomography

Division of Cardiothoracic Surgery, Department of Surgery, and Division of Nuclear Medicine, Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri

	Abstract

Top Footnotes Abstract Introduction Material and Methods Computed Tomography PET Imaging Patient Management Esophagectomy and Specimen... Correlation of CT and... Results Patients With Unresectable... Patients With Resectable Tumors Comment References

 
Background. Positron emission tomography with the glucose analogue 2-[¹⁸F]fluoro-2-deoxy-D-glucose (FDG) has been used to detect and stage a variety of malignancies. We hypothesized that FDG–positron emission tomography would improve staging of patients with esophageal cancer and thereby facilitate selection of candidates for resection.

Methods. Fifty-eight patients (42 men and 16 women) with biopsy-proven esophageal cancer were evaluated with both FDG–positron emission tomography and computed tomography.

Results. In all but 2 patients, increased FDG uptake was identified at the site of the primary tumor. Six patients were not operative candidates. Seventeen patients were not candidates for resection because of metastatic disease. Positron emission tomography identified the metastatic disease in all 17 (12 of whom underwent confirmatory biopsy), whereas computed tomography was positive for metastases in only 5. The remaining 35 patients underwent surgical exploration, were judged to have resectable disease and had esophagectomy. Pathologic examination of resected specimens identified lymph node metastases in 21 patients. These nodes were detected by positron emission tomography in 11 patients and by computed tomography in 6.

Conclusions. Positron emission tomography improved staging and facilitated selection of patients for operation by detecting distant disease not identified by computed tomography alone.

	Introduction

Top Footnotes Abstract Introduction Material and Methods Computed Tomography PET Imaging Patient Management Esophagectomy and Specimen... Correlation of CT and... Results Patients With Unresectable... Patients With Resectable Tumors Comment References

 
See also page 776.

Accurate preoperative staging is a difficult and important problem in determining therapy for patients with esophageal cancer. Esophagectomy is the mainstay of treatment of those patients with early-stage disease and resectable tumors; it offers both a chance for cure and substantial palliation from debilitating symptoms, but it is associated with major morbidity and mortality. Although late survival after resection in patients with occult metastatic and locally advanced disease is dismal, recent advances in the nonoperative management of such patients have led to combined chemotherapy and radiotherapy regimens that provide symptomatic improvement and, perhaps, survival equivalent to that achieved by esophagectomy [1–3].

As a result of these recent advances, the approach toward a patient with esophageal cancer is changing. Accurate preoperative staging is critical for identification of those patients most likely to benefit from surgical intervention and those for whom primary nonoperative therapy is indicated. Current modalities used in the staging of esophageal cancer include computed tomography (CT), endoscopic ultrasonography, and, occasionally, magnetic resonance imaging. These techniques pro-vide high-resolution anatomic images of areas of interest from which conclusions about histology are derived. Although these methods are reported to provide combined accuracy of 70% to 90% in identification of metastatic disease [4–6], there remain a substantial number of patients who are found to have advanced disease at the time of operation.

Positron emission tomography (PET) is a well-established imaging technique that has potential applications in the staging of malignancies [7, 8]. Images are generated based on accumulation of a radiopharmaceutical and reflect tissue metabolism. By comparison, CT, magnetic resonance imaging, and endoscopic ultrasonography are anatomic imaging tools. The functional images of PET are not only complementary to the images obtained by more traditional modalities but may be more sensitive because they reflect alterations in tissue metabolism that generally precede anatomic change. Fluorine 18, a radionuclide that decays by positron emission, can be used to label the glucose analogue 2-deoxyglucose to produce 2-[¹⁸F]fluoro-2-deoxy-D-glucose (FDG), which is taken up by cellular glucose transport mechanisms and phosphorylated through the action of hexokinase. Unlike glucose-6-phosphate, however, FDG-6-phosphate cannot be further metabolized by either the glycogen-synthetic or glycolytic pathways and becomes metabolically "trapped" within cells that lack substantial amounts of glucose-6-phosphatase (eg, brain, myocardium, and most tumors). Thus, FDG preferentially accumulates in cells with high rates of glucose utilization, thereby enabling their detection by PET [7].

Warburg [9] first described the increase in metabolism associated with malignant transformation. Those observations have been substantiated by subsequent reports and form the basis for imaging of cancer with FDG-PET [10]. Since its first application in the detection of primary brain tumors, PET has been increasingly used in oncology not only for its ability to detect primary malignant tumors (including breast, lung and colorectal carcinomas, melanoma, and several other solid-organ cancers) but also for its ability to detect both regional and distant metastases, distinguish benign from malignant tissue or recurrent cancer from treatment-related scarring, and document response to therapy [7, 8, 11]. An important advantage of FDG-PET is its ability to generate whole-body images.

Use of FDG-PET in the assessment of patients with esophageal cancer has been reported anecdotally [12]. Because nonoperative staging for this disease is both difficult and critical in guiding therapy, we undertook to assess the utility of FDG-PET by studying a consecutive series of patients seen with cancer of the esophagus. We hypothesized that the functional images generated by PET would improve detection of metastatic disease and thereby facilitate selection of candidates for resection.

	Material and Methods

Top Footnotes Abstract Introduction Material and Methods Computed Tomography PET Imaging Patient Management Esophagectomy and Specimen... Correlation of CT and... Results Patients With Unresectable... Patients With Resectable Tumors Comment References

 
Patients
Between April 1994 and October 1996, 59 patients with biopsy-proven esophageal cancer were seen and evaluated by the Thoracic Surgical Service at Washington University Barnes-Jewish Hospital. Diagnosis was confirmed by pathologic review of either submitted slides or fresh biopsy specimens. All patients underwent routine evaluation, including history and physical examination, chest radiography, electrocardiography, barium swallow, esophagogastroduodenoscopy, and CT of the chest and upper abdomen. Tests performed elsewhere were repeated if the data and results were incomplete, unavailable, dated, or, in the case of computed tomographic scans, of suboptimal quality. Esophagogastroduodenoscopy was performed on all patients considered surgical candidates, and additional studies such as bronchoscopy, head CT, bone scintigraphy, or magnetic resonance imaging were obtained as clinically indicated. Fifty-eight patients had FDG-PET as part of the staging workup. One patient did not undergo FDG-PET and was excluded from the study. A detailed comparison of the PET and CT results with pathologic findings for 36 of the patients in this study has been reported separately [13].

	Computed Tomography

Top Footnotes Abstract Introduction Material and Methods Computed Tomography PET Imaging Patient Management Esophagectomy and Specimen... Correlation of CT and... Results Patients With Unresectable... Patients With Resectable Tumors Comment References

 
All patients underwent contrast-enhanced CT of the chest and upper abdomen. Twenty-seven patients had scans performed elsewhere; the hard-copy images were available and of acceptable quality. The remaining 31 patients had CT at this institution with a Siemens Somatom Plus S scanner. After administration of both oral and intravenous contrast agents, 10-mm contiguous images were obtained from the neck to below the level of the liver. Extent of the primary tumor, thickness of the esophageal wall, tumor invasion of adjacent structures, and presence of lesions suggestive of metastases to distant sites were recorded. All CT examinations were interpreted without prior knowledge of the findings on FDG-PET.

	PET Imaging

Top Footnotes Abstract Introduction Material and Methods Computed Tomography PET Imaging Patient Management Esophagectomy and Specimen... Correlation of CT and... Results Patients With Unresectable... Patients With Resectable Tumors Comment References

 
The method of Toorongian and associates [14] was used to produce FDG on-site. The PET scans were performed with a Siemens ECAT EXACT scanner, capable of simultaneous collection of 47 transverse slices over a total span of 16.2 cm, with a typical reconstructed spatial resolution on clinical images of approximately 10 mm (full width, half maximum). Patients fasted for at least 4 hours prior to scanning, and blood samples taken immediately before scanning were analyzed for glucose to confirm normoglycemia. All images were obtained with the patient supine. Approximately 40 minutes after intravenous administration of 10 to 15 mCi of FDG, a series of three to five overlapping, 47-slice emission images (each of 10 to 15-minute duration) was performed. A 2-minute transmission scan was done with a rotating ⁶⁸Ge/⁶⁸Ga rod source immediately after each emission scan. Attenuation correction of the emission scan was performed using the segmentation method [15]. To ensure adequate clearance of bladder activity, a Foley catheter was inserted into the urinary bladder at the beginning of the PET study. To minimize renal pelvicalyceal activity, which might obscure structures in the upper abdomen, approximately 1,500 mL of normal saline solution was infused slowly throughout the study, and unless contraindicated, 20 mg of furosemide was administered intravenously 20 minutes after injection of FDG.

Image processing and reconstruction were performed on a SUN computer workstation. Images were displayed in three orthogonal projections and as whole-body reprojection images for visual interpretation. All PET images were evaluated qualitatively by at least two experienced nuclear medicine physicians, and there was 100% agreement between the observers. The criteria applied were those routinely used in scintigraphic imaging. On the basis of knowledge of normal biodistribution of the radiopharmaceutical, foci of abnormal radiotracer accumulation were identified. All lesions were graded as definitely or probably abnormal (categorized as representing tumor), equivocal, or normal (in the case of an abnormality identified on radiography for which no corresponding abnormality was present on PET). Preliminary PET interpretation was performed without prior knowledge of the CT findings. Subsequently, for final interpretation, the PET images were compared with the CT images, and patient management was based on the combined interpretation.

	Patient Management

Top Footnotes Abstract Introduction Material and Methods Computed Tomography PET Imaging Patient Management Esophagectomy and Specimen... Correlation of CT and... Results Patients With Unresectable... Patients With Resectable Tumors Comment References

 
All information relevant to staging and management of each patient was presented at a multidisciplinary conference involving thoracic surgeons, medical and radiation oncologists, radiologists, nuclear medicine physicians, pathologists, and nurse coordinators. Staging decisions were based on the TNM classification (Union Internationale Contre Cancer, 1988), and consensus was sought regarding the performance of additional testing and the therapeutic plan. The PET findings were considered part of the staging workup. Biopsies of sites suspected of containing metastatic disease were performed by fine-needle aspiration, mediastinoscopy, or, in one case, laparotomy.

Patients were classified as inoperable if their risk at operation was considered prohibitive secondary to their medical condition, the tumor was characterized as technically unresectable because of its location (eg, a tumor located in the cervical or proximal thoracic esophagus where achieving a negative proximal margin would be unlikely), or they declined surgical intervention. Patients with evidence of distant disease were considered not to be operative candidates and were classified as unresectable. Patients presumed to have resectable disease, including patients with involvement of local-regional nodes, were offered esophagectomy. Patients who had not already received medical or radiation therapy prior to referral were offered neoadjuvant therapy consistent with current protocols. The treatment plan represented a consensus individualized for each patient.

	Esophagectomy and Specimen Analysis

Top Footnotes Abstract Introduction Material and Methods Computed Tomography PET Imaging Patient Management Esophagectomy and Specimen... Correlation of CT and... Results Patients With Unresectable... Patients With Resectable Tumors Comment References

 
All esophagectomies were performed at this institution, with choice of operative approach left to the individual surgeon. At operation, biopsy specimens of suspicious lesions and lymph nodes were taken, and a determination of resectability was made. Standard transhiatal esophagectomy was the most common procedure performed, with particular care taken to complete visualization of the posterior mediastinum through the enlarged esophageal hiatus and to removal of all accessible lymph nodes. Other approaches used included the Ivor Lewis esophagectomy (right thoracotomy and laparotomy with anastomosis in the chest), McKeown esophagectomy (right thoracotomy followed by laparotomy and left neck incision with a cervical anastomosis), and a left thoracoabdominal approach with an additional left neck incision for creation of a cervical anastomosis. In all cases, a complete thoracic esophagectomy including the esophagogastric junction was performed. The specimens were removed en bloc and regions of particular interest marked. Identification and dissection of lymph nodes from the specimen were performed by the pathologist, and frozen sections of the proximal and distal margins were obtained to ensure complete resection. The gastric remnant was used for reconstruction in each instance.

	Correlation of CT and PET Results With Pathologic Findings

Top Footnotes Abstract Introduction Material and Methods Computed Tomography PET Imaging Patient Management Esophagectomy and Specimen... Correlation of CT and... Results Patients With Unresectable... Patients With Resectable Tumors Comment References

 
The documented final reports from all preoperative studies were reviewed in conjunction with pathologic findings from biopsy material and surgical specimens. Pathologic stage was determined on the basis of accepted TNM classification guidelines. Proximity to the primary tumor was used to define adjacent and nonadjacent lymph nodes. For example, with a distal third/esophagogastric junction tumor, subcarinal and gastrohepatic lymph nodes were classified as nonadjacent and adjacent, respectively, but when associated with a middle-third tumor, would be considered adjacent and nonadjacent, respectively. For the purpose of correlating pathologic with CT and PET findings, celiac lymph nodes were considered to be nonadjacent, and supraclavicular lymph nodes represented a site of distant metastasis (M1 disease). Equivocal statements in the radiologic reports, such as "may represent," were interpreted as negative results, whereas more definitive statements were considered positive. Patients are referred to by their number, assigned in alphabetic order by last name.

	Results

Top Footnotes Abstract Introduction Material and Methods Computed Tomography PET Imaging Patient Management Esophagectomy and Specimen... Correlation of CT and... Results Patients With Unresectable... Patients With Resectable Tumors Comment References

 
Patient Characteristics
Fifty-eight patients (42 men and 16 women) were evaluated by PET as part of the staging workup. Mean age was 62.4 years (range, 44 to 84 years). Adenocarcinoma was the most common histology (34 patients); in the remaining patients, the diagnoses were squamous cell carcinoma (22), squamous cell carcinoma with neuroendocrine features (1), and mixed adenosquamous carcinoma (1). Positron emission tomography demonstrated increased activity in the known primary tumor in all but 2 patients (patients 29 and 51), both of whom had small T1 lesions confined to the mucosa.

After the initial evaluation, 6 patients were classified as inoperable (Table 1). Two of them declined surgical intervention; both had evidence of regional nodal metastases by PET, but only 1 had positive findings by CT. The other 4 patients were thought to have technically unresectable disease because of the proximal extent of the tumor.

	Patients With Unresectable Tumors

Top Footnotes Abstract Introduction Material and Methods Computed Tomography PET Imaging Patient Management Esophagectomy and Specimen... Correlation of CT and... Results Patients With Unresectable... Patients With Resectable Tumors Comment References

View larger version (117K): [in this window] [in a new window]   Fig 1. . Representative positron emission tomographic image from a patient in the unresectable group. Computed tomography demonstrated only the distal esophageal primary tumor. This coronal 2-[18F]fluoro-2-deoxy-D-glucose–positron emission tomographic image shows uptake by the primary tumor and by the myocardium (large arrows). In addition, foci of uptake in the mediastinum and supraclavicular regions (small arrows) are identified. Biopsy specimen of the supraclavicular lymph node demonstrated metastatic esophageal cancer.

	Patients With Resectable Tumors

Top Footnotes Abstract Introduction Material and Methods Computed Tomography PET Imaging Patient Management Esophagectomy and Specimen... Correlation of CT and... Results Patients With Unresectable... Patients With Resectable Tumors Comment References

There were few false-positive studies. Fourteen patients had no evidence of nodal disease at either adjacent or nonadjacent sites on final pathology. Computed tomography suggested involvement of adjacent nodes for 3 of these patients, and PET was false-positive in 3 different patients: 2 at an adjacent site only and 1 at both adjacent and nonadjacent sites.

	Comment

Top Footnotes Abstract Introduction Material and Methods Computed Tomography PET Imaging Patient Management Esophagectomy and Specimen... Correlation of CT and... Results Patients With Unresectable... Patients With Resectable Tumors Comment References

 
Optimal management of patients with cancer of the esophagus depends on accurate staging. Those few patients with limited disease and early-stage tumors clearly benefit from esophagectomy, whereas those with locally advanced disease have a poor prognosis despite aggressive attempts at resection, and those with distant metastatic disease are incurable. We studied a consecutive series of patients seen with esophageal cancer to determine the potential for PET to improve staging. Their evaluations were conducted along generally accepted guidelines, including the routine use of CT. All results, including those of PET, were used in the setting of a multidisciplinary conference to formulate individualized plans for therapy. Consequently, we were able simultaneously to assess the value of PET in staging and in therapeutic decision-making. With the exception of 2 patients who had small, early-stage tumors, FDG-PET clearly identified the primary tumor in all patients in this study, substantiating the physiologic premise behind the use of FDG-PET to detect esophageal cancer.

Three groups of patients emerged: those for whom esophagectomy was not an option for reasons unrelated to staging (inoperable); those in whom staging identified evidence of metastatic disease and who would therefore not sustain a survival benefit from esophagectomy (unresectable); and those in whom staging suggested that resection was possible and offered the possibility of cure. Because there were no staging-related pathologic specimens obtained by biopsy or at operation for patients in the inoperable group, evaluation of the effectiveness of PET in those 6 patients is difficult. However, review of both CT and PET results does indicate that PET tended to suggest involvement of regional nodal stations not delineated by CT.

The most important finding in this study was that the addition of PET to the staging workup improved our ability to classify patients as having either resectable or unresectable disease and therefore facilitated selection of patients for operation. Positron emission tomography identified metastases that were either not appreciated by CT or were more accessible for biopsy than those shown by CT (see Table 2). Of the 17 patients classified as having unresectable disease, PET supplied additional useful information in 12, 20% of the overall study population. In many cases, PET identified disease in sites readily accessible for biopsy, such as supraclavicular lymph nodes or liver, and in others, it demonstrated completely unsuspected metastases. For these patients, PET clearly altered the course of therapy, as they otherwise would have undergone operation with the intent to perform esophagectomy in the presence of occult metastatic disease.

All patients characterized as having resectable disease proved to be in that category at operation, although the majority were ultimately staged with regionally advanced disease. To evaluate correlation of CT and PET results with pathologic findings, nodal stations were described as either adjacent or nonadjacent. This classification was necessary because of the poorer spatial resolution of PET compared with CT. As a result, the ability to distinguish between involved nodes and the intense uptake of FDG in a primary tumor could be limited by their proximity. This is generally not a consideration in the use of PET for staging lung cancer, where sensitivity and specificity of up to 100% for the evaluation of mediastinal lymph nodes have been documented [11]. In the case of a mediastinal primary tumor, presumably PET would be better at identifying nonadjacent than adjacent nodes. Although characterization of nodal regions as adjacent or nonadjacent is relatively imprecise, review of the results reveals that PET was able to identify nodal metastases in both groups and that PET was superior to CT in both groups. Positron emission tomography predicted metastatic involvement in more than half of all patients with involved adjacent lymph nodes (11/21), almost twice as many as CT alone (6/21). Combined, CT and PET predicted nodal metastases in 14 patients. When considered together, results from both the resectable and unresectable groups demonstrate that addition of PET to the staging workup dramatically improved detection of metastases. Of the total 38 patients with metastatic disease, CT alone identified only 17 (45%), whereas PET plus CT identified 31 (82%), an improvement of more than 80%.

As with all imaging modalities, PET has both advantages and limitations. As already discussed, one of its primary advantages is the ability to generate images on the basis of tissue metabolism, thus complementing the results of anatomic imaging tools such as CT and ultrasonography. Further, PET can provide images of the entire body in three dimensions, thereby offering the potential to replace multiple studies, such as brain CT or magnetic resonance imaging and bone scintigraphy, with a single test. There also exists the possibility of detecting second primary tumors, as happened in 1 patient in this study. Because FDG-PET demonstrates tissues with increased glucose uptake, false-positive results can occur at sites of inflammation [16]. Given the prevalence of mediastinal and pulmonary involvement by granulomatous inflammation, we anticipated potential difficulties in evaluating the mediastinum. Nevertheless, only three false-positive tests were identified. In an attempt to distinguish benign from malignant lesions, many investigators have used a semiquantitative measure of FDG activity, the standardized uptake value, to generate threshold levels that indicate malignancy [7, 11]. We have found this approach to be of limited usefulness in differentiating active inflammatory disease from malignant involvement of lymph nodes in the thorax. In addition, quantitative analysis has not been proved to be more reliable than qualitative visual assessment of the images [16]. Last, the widespread use of PET is limited by the availability and cost of the equipment. Few centers possess the scanning equipment, and the relatively short half-life of the radiopharmaceuticals limits the distance a PET scanner can be from the nearest cyclotron. This is likely to improve as PET gains widespread acceptance as an important imaging tool for a variety of clinical indications.

Ideally, the best method for analysis of PET as a staging modality would be comparison of PET and CT findings with meticulous pathologic analysis of each patient in a prospective fashion. This study is limited by the absence of pathologic material in every patient: many patients did not undergo resection, and most esophagectomies were performed by the transhiatal route, an approach generally considered less thorough at mediastinal lymphadenectomy. Further, potential sites of metastatic disease, such as supraclavicular lymph nodes, were not routinely sampled in the absence of a positive study. As a result, it is possible that metastatic disease not detected by PET or CT was missed. Although important for the ultimate assessment of sensitivity of PET, this consideration does not affect the central finding of our investigation—that in 20% of the patients in this study, PET detected otherwise unsuspected metastases that indicated an unresectable extent of disease and thus prevented unnecessary exploration and futile esophagectomy.

Patients with cancer of the esophagus present a vexing management problem because staging is critical for prognosis yet can be difficult to accomplish reliably. We have found that the addition of FDG-PET to the staging workup substantially improved our ability to identify those patients for whom esophagectomy would not have been appropriate. In addition, FDG-PET proved to be useful for improving detection of regional nodal metastases, identifying a group of patients for whom trials of neoadjuvant therapy may be the best approach. The use of FDG-PET warrants further systematic evaluation in the staging of patients with esophageal cancer.

	Footnotes

Top Footnotes Abstract Introduction Material and Methods Computed Tomography PET Imaging Patient Management Esophagectomy and Specimen... Correlation of CT and... Results Patients With Unresectable... Patients With Resectable Tumors Comment References

 
Presented at the Thirty-third Annual Meeting of The Society Thoracic Surgeons, San Diego, CA, February 3-5, 1997.

Address reprint requests to Dr Patterson, Division of Cardiothoracic Surgery, Washington University School of Medicine, 3108 Queeny Tower, One Barnes Hospital Plaza, St. Louis, MO 63110.

	References

Top Footnotes Abstract Introduction Material and Methods Computed Tomography PET Imaging Patient Management Esophagectomy and Specimen... Correlation of CT and... Results Patients With Unresectable... Patients With Resectable Tumors Comment References

 

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