| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
Clinical Investigations |
1 Department of Surgical Oncology, University Hospital of Groningen, Groningen, The Netherlands
2 Department of Nuclear Medicine/PET Center, University Hospital of Groningen, Groningen, The Netherlands
3 Department of Radiology, University Hospital of Groningen, Groningen, The Netherlands
4 Department of Gastroenterology, University Hospital of Groningen, Groningen, The Netherlands
5 Department of Medical Statistics, University Hospital of Groningen, Groningen, The Netherlands
 |
ABSTRACT |
|---|
 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
Key Words: esophageal cancer • 18F-FDG PET • upstaging
|
INTRODUCTION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
|
MATERIALS AND METHODS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
|
Conventional Staging
All patients underwent the best-available conventional staging procedure, including ultrasonography of the neck, CT of the thorax and abdomen, and EUS whenever possible. Cervical ultrasonography revealed no abnormality in the 74 included patients. In 32 patients, the CT scans were performed in our institute on fourth-generation units (SR7000 [Philips Medical Systems] or Somatron Plus 4 spiral CT [Siemens Medical Systems]) and in 42 patients, CT scanning occurred in the referring hospital. After approval of good quality, all scans were revised at the time of initial staging and, recently, all available CT scans were revised again and scored by an experienced oncologic radiologist who was unaware of the previous results.
Visible primary tumors on CT were categorized as T+, invisible as T0, and as T4 in case of suspected invasion in juxtaesophageal structures. Depending on the localization of the primary tumor, suspected nodes were classified as locoregional (N1) or distant metastases (M1a or M1b). Technical details of CT scans in this population are described in Table 2.
|
PET Imaging
18F-FDG was produced as described by Hamacher et al. with a radiochemical purity of >98% (12). For data acquisition we used an ECAT 951/31 with 31 planes over 10.9 cm or an ECAT HR+ positron camera (Siemens/CTI) with 63 planes over a 15.8-cm axial field of view. After fasting overnight, 400–580 MBq 18F-FDG were administered intravenously (6 MBq/kg). Data acquisition started 90 min after injection in whole-body mode, for 5 min per bed position. For attenuation correction, transmission images were obtained for 3 min per bed position. Images were reconstructed using iterative techniques and read from computer monitors. Both corrected and uncorrected images were evaluated for tracer uptake by the primary tumor and categorized as T0 or T+. Depending on the location of hot spots and the distance to the primary tumor, nodes were classified as N0, N1, M1a positive, or M1b positive by translation of PET findings to the TNM system.
Surgery
Surgery was denied when presumed distant metastases on 18F-FDG PET were confirmed pathologically or identified by specific radiographic examination, including bone scintigraphy and MRI, depending on the hot spot localization. All resections included dissections of the posterior mediastinal lymph nodes and abdominal nodes along the celiac, left gastric, splenic, and common hepatic arteries, the so-called 2-field lymphadenectomy. Tumors located near or above the level of the carina were always approached by a right thoracotomy, after initial laparotomy. Tumors of the GEJ and distal esophagus were usually resected by a left thoracoabdominal approach. Resection was not performed in tumors fixed to surrounding vital structures or with distant nodal involvement (celiac trunk, paraaortic or retropancreatic) and initially unsuspected organ metastases. As a rule, macroscopically suspected distant nodes (M1a) and organ lesions (M1b) were biopsied during laparotomy.
Gold Standard
Comparison between traditional staging methods and 18F-FDG PET findings was validated by FNAB or pathologic examination of each resection specimen as the gold standard for each TNM category. Surgical findings strongly suggesting tumor fixation to adjacent structures were regarded as the gold standard for T4 stage. The gold standard for nodal metastases was exclusively obtained by pathologic verification of resection specimens after 2-field lymphadenectomy or surgical node biopsies. The gold standard for M1b disease was based on pathology whenever possible or identification by specific radiographic techniques and clinical or radiographic follow-up of suspected PET lesions during 6 mo after initial staging. The gold standard for the T stage and nodal metastases (N stage) could not always be determined when surgery was denied because of pathologically confirmed M1b metastases identified by 18F-FDG PET.
Statistical Analysis
Sensitivity, specificity, and accuracy to identify nodal and organ metastases were determined and compared between conventional staging methods and 18F-FDG PET. Standard definitions were used to calculate these parameters (13). Differences in sensitivity, specificity, and accuracy were analyzed by McNemar testing for paired variables, corrected for continuity. P < 0.05 was considered to be significant
|
RESULTS |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
Primary Tumor
The gold standard of the T stage (histologically and surgically) could be assessed in 54 patients (73%). In the other 20 patients, the T stage could not be determined adequately because of M1 disease at the time of initial staging or during surgery. The pathologic tumor stage (pT) could be determined in the 40 patients who underwent an esophageal resection (Table 1). Histologic examination revealed 9 pT1, 3 pT2, 25 pT3, and 3 pT4 tumors. Seventeen tumors, 3 after curative intended resection, were considered as T4.
CT demonstrated the primary tumor in 62 of 74 patients (sensitivity, 84%). The nonvisualized tumors (n = 12) were staged as pT1 (n = 4), pT2 (n = 2), and pT3 (n = 1), and the tumor stage could not be determined on CT in the other 5 patients. EUS was successfully performed by visualizing the primary tumor in all 54 patients (sensitivity, 100%). Accuracy for EUS in determining the T stage could be calculated in 42 patients with the gold standard for the T stage. In the other 12 patients, the gold standard of the T stage could not be determined given an overall accuracy of 67% (28/42). Seven tumors were understaged (17%) and 7 others (17%) were overstaged. The primary tumor was visualized in 70 patients by 18F-FDG PET (sensitivity, 95%). The missed tumors were all classified as pT1 and were <0.5 cm at final pathologic examination.
Regional Lymphatic Metastases
The gold standard for regional nodes (N1) could be assessed in 61 patients. Table 3 gives an overview of sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and overall accuracy for the assessment of regional node metastases in the different staging modalities. Forty patients underwent resection with concomitant 2-field lymphadenectomy. The tumor was not resectable in the other patients, but biopsy of suspicious lesions confirmed the presence of nodal metastases. The gold standard of regional nodes could not be assessed in 13 patients. In 6 patients, surgery was denied because of pathologically confirmed M1 disease preoperatively, and 7 patients underwent laparotomy or thoracotomy for locally extended tumors without biopsy of regional nodes.
|
Distant Nodal Disease
The gold standard of distant nodal disease defined as M1a by the TNM staging system could be assessed in 72 patients (Table 4). Two other patients had confirmed M1b disease precluding surgical exploration and, therefore, the gold standard was not accessible in these patients. M1a was present in 24 patients (33%). The involved distant nodes were located around the celiac trunk or paraaortic in 21 patients. One patient also had mediastinal paraaortic involvement, and supraclavicular node metastases were confirmed in 3 patients. Conventional staging methods (CT/EUS) correctly identified M1a disease in 7 patients (sensitivity, 29%; 7/24). The false-negative distant nodes in the remaining 17 patients were located along the abdominal aorta (n = 13), supraclavicular (n = 3), and mediastinal (n = 1). Two patients with suspected regional nodes along the left gastric artery were falsely staged as M1a, precluding resectability by conventional methods. In 1 patient it was based on CT alone and in the other patient EUS was false-positive.
|
|
|
Relation of PET to Tumor and Patient Characteristics on Conventional Staging
We examined whether certain tumor or patient-related characteristics influenced the value of PET in determining the presence of distant metastases. The influence of histologic type (adenocarcinoma vs. squamous cell carcinoma), tumor localization (tubular esophagus vs. GEJ), tumor stages as identified by EUS and quality of CT, and referral from other (nontertiary) hospitals on the outcome of PET were studied. To determine the effect of CT imaging quality, the study group was divided into patients investigated by CT with a resolution of 
5 mm and those staged with a resolution of >5 mm. Moreover, the effect of the acquisition type (multidetector vs. spiral CT) was noted. Finally, the group of patients with adequate EUS was compared with patients in whom EUS results were not available. The main endpoint was the number of patients in each group in which PET provided correct upstaging from M0 to M1 disease. None of the characteristics mentioned earlier had a significant influence, as shown in Table 2.
The results of PET were not related to the histologic type, although a fair comparison was difficult due to a relatively low number of squamous cell carcinomas. Tumor localization, acquisition and type of CT used, and referral of patients from other hospitals had no significant effect on the correct upstaging by PET. In addition, upstaging of PET occurred in the same frequency in the group in which EUS was part of conventional staging compared with the group in which no EUS was performed. However, when patients were divided according to tumor stage as identified by EUS, an interesting phenomenon was seen. All patients, correctly upstaged by PET from M0 to M1 disease, at least had an EUS-confirmed T3 tumor. None of the 11 EUS-staged T1 or T2 N0 tumors turned out to have M1 disease. In this subgroup of patients, PET was false-positive for N1 disease in 6 patients (55%) and false-positive for M1 disease in 1 patient, limiting the additional value of PET in these patients. In contrast, 8 of 41 patients (20%) with T3 or T4 tumors, as determined by EUS, were correctly upstaged as M1 disease with PET.
Overall Prognostic Value
Sensitivity to detect M1 disease defined by distant node or organ metastases was increased with PET (78% [21/27] vs. 37% [10/27], P = 0.012; Table 5). As a whole, 15 of the 74 patients (20%) were correctly upstaged with PET by identification of M1a metastases (n = 10), lymphatic M1b metastases (n = 2), hematogenic (liver) M1b metastasis (n = 1), and a combination of M1a/M1b disease (n = 2). However, with PET, surgery would have been avoided in only 2 of these patients by detecting supraclavicular node metastases. In 4 patients (5%), PET correctly performed downstaging from M1 to M0 disease. False upstaging and downstaging were obtained in 5 patients (7%) and 3 patients (4%), respectively.
|
|
DISCUSSION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
18F-FDG PET does not add much in the detection of regional nodes. Currently available staging methods are of limited value to assess regional node involvement, with the highest reported sensitivity for EUS (70%–90%) (2). The direct vicinity of the primary tumor, obscuring 18F-FDG uptake, probably causes false-negative results in peritumoral N1 nodes. Moreover, small metastatic nodes could cause false negativity by limitations in the spatial resolution. Specificity of 71% (15/21) with PET in assessing regional metastases is comparable with that of other series. Anthracosilicosis in mediastinal nodes, multifocality of the primary tumor, and inhomogeneous uptake of the tracer may cause different hot spots, leading to false-positive results, as shown in 3 of 6 patients in this study. Combining CT, EUS, and PET leads to an increased sensitivity but the number of false-positive N1 nodes also increases, lowering the specificity as found in the literature (14–17).
To identify unsuspected M1 disease, 18F-FDG PET performed better than the combination of CT/EUS. The rate of M1 metastases only detected by 18F-FDG PET in conventionally staged tumors is 10%–20% (5–10,15–18). 18F-FDG PET upstaged the disease in about 20% (15/74) as M1 disease. The accuracy of 69% (51/74) for detecting M1 disease with CT/EUS increased to 86% (64/74) with 18F-FDG PET (Table 5). A combination of all 3 modalities increased the accuracy for detecting M1 disease up to 92% (68/74) as was the result of a more sensitive detection of both distant node and organ metastases. Some considerations must be mentioned about the upstaging role of 18F-FDG PET. First, the difference in detecting M1 disease between conventional staging and 18F-FDG PET is probably high due to a substantial percentage of patients referred to our hospital—a tertiary referral center—after CT was already performed. If CT in the referring center had indicated M1 disease, this patient would not have been referred to our hospital for surgical resection. On the other hand, this phenomenon—the central finding of correct upstaging M1 disease by 18F-FDG PET in a substantial percentage of patients compared with conventional staging—does not explain low sensitivity for detection of distant abdominal nodes (24%).
Second, in 13% of the patients (2/15) who were correctly upstaged by 18F-FDG PET, surgery could be avoided. Both patients had cytologically confirmed cervical node metastases. The other 13 patients needed a laparotomy to confirm distant nodal or liver metastases. This is related to the premise that suspicious hot spots in our study design must be confirmed by cytopathologic examination, avoiding the possibility of denying a curative resection or the risk of tumor progression during possible unnecessary induction treatment. Otherwise, all intraabdominally located M1a lesions demonstrated on PET in our series were confirmed during laparotomy (PPV, 100%). Performing surgery in this group would possibly postpone induction chemotherapy. Furthermore, EUS-guided cytologic biopsies of suspected celiac nodes are a promising technique currently used in this respect (19). A proportion of CT scans was not performed in our institute, limiting standardization of this procedure. The influence on the quality of the conventional staging in this study seems to be small because all CT scans were revised at the time of initial staging and would have been repeated if they were of unacceptable quality. Furthermore, all available CT scans were rescored without knowledge of the results of 18F-FDG PET or the gold standard without increasing sensitivity and accuracy in the assessment of N1 or M1 disease. Although EUS was not acquired in a proportion of patients, increasing the number of EUSs performed in our study would probably not have led to a higher detection of M1 disease because none of the M1a or M1b lesions identified by conventional staging had negative CT scans. Moreover, comparison of the accuracy for the assessment of M1 disease did not differ significantly between referred and nonreferred patients or between patients for whom EUS results were not available (Table 2). Therefore, the central finding of this study—namely, a correct upstaging by 18F-FDG PET in 20% of the patients (15/74)—merely depends on the metabolic reflection of the tumor rather than on the limitations of anatomic staging results of the conventional methods.
The incremental value of 18F-FDG PET will be higher in tumors with a high probability of distant metastatic disease. Eleven of 54 patients, in whom EUS was performed, were staged as T1/T2 N0 M0. In 5 of these 11 patients, PET displayed locoregional hot spots, but none of them was found in resection specimens, representing false upstaging of N1 disease by 18F-FDG PET. Therefore, the additional value of performing PET scans in these low-staged tumors may be questionable. Otherwise, all patients who were correctly upstaged to have M1 disease had T3 N0–N1 tumors, as identified by EUS. Therefore, these results support the arguments for a selective demand of 18F-FDG PET in high-staged esophageal tumors. This option becomes even more attractive at the background of the limited availability of PET scanners. A proposal for such a selective demand of PET based on the staging of these tumors with EUS is given in Figure 3. A well-designed cost-effectiveness study eventually should definitively answer this important question.
|
|
CONCLUSION |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
|
FOOTNOTES |
|---|
For correspondence or reprints contact: John Th.M. Plukker, MD, PhD, Department of Surgical Oncology, University Hospital of Groningen, 9700 RB Groningen, The Netherlands.
E-mail: j.th.plukker{at}chir.azg.nl
|
REFERENCES |
|---|
|
TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONCONCLUSIONREFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  R. G. Berrisford, W.-L. Wong, D. Day, E. Toy, M. Napier, K. Mitchell, and S. Wajed The decision to operate: role of integrated computed tomography positron emission tomography in staging oesophageal and oesophagogastric junction cancer by the multidisciplinary team Eur. J. Cardiothorac. Surg., June 1, 2008; 33(6): 1112 - 1116. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. F. Bruzzi, R. F. Munden, M. T. Truong, E. M. Marom, B. S. Sabloff, G. W. Gladish, R. B. Iyer, T.-S. Pan, H. A. Macapinlac, and J. J. Erasmus PET/CT of Esophageal Cancer: Its Role in Clinical Management RadioGraphics, November 1, 2007; 27(6): 1635 - 1652. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Guo, H. Zhu, Y. Xi, B. Zhang, L. Li, Y. Huang, J. Zhang, Z. Fu, G. Yang, S. Yuan, et al. Diagnostic and Prognostic Value of 18F-FDG PET/CT for Patients with Suspected Recurrence from Squamous Cell Carcinoma of the Esophagus J. Nucl. Med., August 1, 2007; 48(8): 1251 - 1258. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Rizk, R. J. Downey, T. Akhurst, M. Gonen, M. S. Bains, S. Larson, and V. Rusch Preoperative (18)[F]-Fluorodeoxyglucose Positron Emission Tomography Standardized Uptake Values Predict Survival After Esophageal Adenocarcinoma Resection. Ann. Thorac. Surg., March 1, 2006; 81(3): 1076 - 1081. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. J. Cerfolio, A. S. Bryant, B. Ohja, A. A. Bartolucci, and M. A. Eloubeidi The accuracy of endoscopic ultrasonography with fine-needle aspiration, integrated positron emission tomography with computed tomography, and computed tomography in restaging patients with esophageal cancer after neoadjuvant chemoradiotherapy J. Thorac. Cardiovasc. Surg., June 1, 2005; 129(6): 1232 - 1241. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. L. van Westreenen, D. C.P. Cobben, P. L. Jager, H. M. van Dullemen, J. Wesseling, P. H. Elsinga, and J. Th. Plukker Comparison of 18F-FLT PET and 18F-FDG PET in Esophageal Cancer J. Nucl. Med., March 1, 2005; 46(3): 400 - 404. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| JOURNAL OF NUCLEAR MEDICINE TECHNOLOGY | THE JOURNAL OF NUCLEAR MEDICINE |
