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Nuclear Medicine |
1 From the Departments of Diagnostic and Interventional Radiology (G.A., J.S., T.B., H.K., J.F.D.), Radiation Therapy (S.M.), and Nuclear Medicine (T.B., A.B., L.S.F.), University Hospital Essen, Hufelandstrasse 55, 45122 Essen, Germany; and Department of Thoracic Surgery, Ruhrlandclinic, Essen, Germany (A.T.N.). Received November 28, 2002; revision requested February 6, 2003; revision received March 4; accepted April 14. Address correspondence to G.A. (e-mail: gerald.antoch@uni-essen.de).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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MATERIALS AND METHODS: Twenty-seven patients with NSCLC underwent staging with combined fluorine 18 fluorodeoxyglucose PET and CT. CT, PET, and coregistered PET/CT images were evaluated separately by two different physicians for each imaging modality, and disease stage was determined by using TNM and American Joint Committee on Cancer staging systems. Histopathologic results served as the reference standard. The statistical significance of differences among CT, PET, and PET/CT was determined by using the McNemar test.
RESULTS: Overall tumor stage was correctly classified as 0–IV with CT in 19 patients, with PET in 20 patients, and with PET/CT in 26 patients. PET/CT findings when compared with PET findings led to a treatment change for four patients (15%) and when compared with CT findings led to a treatment change for five patients (19%). Differences in the accuracy of overall tumor staging between PET/CT and CT (P = .008) and between PET/CT and PET (P = .031) were significant. Primary tumor stage was correctly determined in more patients with PET/CT than with either PET alone or CT alone. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of regional lymph node staging, respectively, were 89%, 94%, 89%, 94%, and 93%, with PET/CT; 89%, 89%, 80%, 94%, and 89% with PET; and 70%, 59%, 50%, 77%, and 63% with CT. Fourteen distant metastases were detected in four patients with CT, four were detected in two patients with PET, and 17 were detected in four patients with PET/CT.
CONCLUSION: Use of dual-modality PET/CT significantly increases the number of patients with correctly staged NSCLC and thus has a positive effect on treatment.
© RSNA, 2003
Index terms: Lung neoplasms, 60.3213, 60.33 • Lung neoplasms, CT, 60.12112, 60.12115 • Lung neoplasms, PET, 60.12163 • Lung neoplasms, staging
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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Conventional chest radiography, computed tomography (CT), magnetic resonance imaging, radionuclide scintigraphy, and positron emission tomography (PET) all have been used for NSCLC staging. Although tumor size and infiltration of adjacent structures are accurately assessed with CT (6), PET has been shown to be substantially more sensitive and specific in the detection and characterization of metastases to mediastinal lymph nodes (7–10). The limited anatomic information yielded by PET (11) can be overcome by fusing functional PET data with morphologic CT data. Positional and motion-induced data misregistration, however, renders the image fusion of separately acquired CT and PET image sets unsatisfactory (12).
Accurately fused functional and morphologic data sets are now generated by recently available dual-modality PET/CT imaging systems (13,14). In addition to enhancing accuracy and the ease of image fusion, PET/CT systems facilitate reduced examination times—by up to 30%—by basing attenuation correction on the CT data (14,15). The purpose of this study was to determine the accuracy of dual-modality PET/CT imaging, as compared with PET alone and CT alone, in the staging of NSCLC.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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PET/CT Imaging
Combined PET/CT imaging was conducted by using the biograph system (Siemens Medical Solutions, Hoffman Estates, Ill). CT was performed by using a single-section helical technique with the Somatom Emotion unit (Siemens Medical Solutions, Erlangen, Germany), whereas PET data were collected with a full-ring PET tomograph based on the ECAT EXACT HR+ system (Siemens Medical Solutions, Erlangen, Germany). The PET component of the biograph has an in-plane spatial resolution of 4.6 mm and a transverse field of view of 15.5 cm for one table position. The system generates separate CT and PET data sets that can be fused online by using a syngo-based fusion tool (Siemens Medical Solutions, Erlangen, Germany). Before the injection of fluorine 18 fluorodeoxyglucose as a radioactive tracer, normal blood glucose levels were verified from blood samples.
Whole-body CT images were acquired with 130 mAs, 130 kV, a section width of 5 mm, and a table feed of 8 mm per rotation (gantry rotation time, 800 msec) and encompassed a field of view from the head to the upper thigh. PET and CT image reconstructions were performed at 2.4-mm increments. To ensure the acquisition of fully diagnostic CT data, intravenous and oral contrast agents were administered in all patient examinations. One hundred forty milliliters of an iodinated contrast agent (Xenetix 300, iobitridol [300 mg of iodine per milliliter]; Guerbet, Sulzbach, Germany) was administered intravenously at 3 mL/sec by using an automated injector (model XD 5500; Ulrich Medical Systems, Ulm, Germany). Small-bowel opacification was ensured by administering 1,000 mL of glucose-free barium (Micropaque CT, 1.5 g of barium sulfate per 100 mL; Guerbet); 800 mL was injected for 50 minutes following the fluorodeoxyglucose injection, and the remaining 200 mL was administered immediately before PET/CT scanning to ensure gastric distention.
Whole-body PET images, encompassing the same transverse field of view as the CT images, were acquired 60 minutes after the administration of 350 MBq fluorodeoxyglucose. Patients rested in the supine position during the tracer uptake phase to avoid muscular tracer accumulation. Attenuation correction was based on the CT data (16). PET images were corrected for scatter and iteratively reconstructed.
Image Evaluation
Tumor staging with CT, PET, and PET/CT was based on the newly revised AJCC TNM system for the classification of lung cancer (3). Cancers of stages to IIb are considered resectable, whereas stage IIIb and IV cancers are considered nonresectable. Patients with stage IIIa disease undergo neoadjuvant therapy. The effect of potential differences in tumor staging among CT, PET, and PET/CT on patient treatment was determined on the basis of these therapy recommendations. All data sets were analyzed at a workstation (Systrium Technologies, Minneapolis, Minn) capable of providing interactively multiplanar reformations and any desired window and level settings.
CT, PET, and fused PET/CT images were assessed by three reader teams that consisted of different physicians. Each of the evaluating teams had the same information about the patients’ clinical histories. CT data sets were evaluated in consensus by two radiologists (J.S., J.F.D) with 8 and 11 years of CT experience. Lymph node assessment was based on size: Nodes with a short-axis diameter greater than 10 mm were defined as pathologic. Furthermore, the presence of necrosis within a lymph node was considered a sign of malignancy, regardless of node size.
PET images were assessed in consensus by a radiologist (H.K.) with 3 years of PET experience and a nuclear medicine specialist (L.S.F.) with 5 years of PET experience. They evaluated the PET images qualitatively for regions of focally increased glucose metabolism, as well as quantitatively by determining standardized uptake values (17,18). An increase in glucose uptake to a level greater than that in the surrounding tissue at qualitative analysis and a standard glucose uptake value of more than 2.5 were considered to characterize malignancy.
Fused PET/CT data sets were evaluated in consensus by a third reader team consisting of a radiologist (G.A.) and a nuclear medicine specialist (A.B.), each with 1
years of PET/CT experience. The same criteria used to determine malignancy among the individual CT and PET data sets were applied. However, lymph nodes with increased glucose uptake were deemed positive for metastatic spread even when they were smaller than 1 cm in short-axis diameter. PET-negative lymph nodes were characterized as benign, even when they were larger than 1 cm in short-axis diameter. The three evaluating physician teams were blinded to the results of the other imaging examinations.
Verification of stage of regional lymph node involvement (hereafter N stage) was accomplished either at tumor resection with mediastinal lymph node sampling (n = 16) or at mediastinoscopy (n = 11). None of the patients received treatment during the interval between PET/CT examination and histopathologic verification. Evaluation of local tumor extent (hereafter T stage) was based on data obtained in 16 patients in whom the T stage was verified histopathologically. Verification of distant metastasis stage (hereafter M stage) was accomplished by means of biopsy or radiologic follow-up (mean follow-up period, 142 days). Apart from assessment of tumor stage, CT, PET, and PET/CT images were evaluated for additional clinically important findings.
Surgical Procedures
Mediastinoscopy and tumor resection procedures with mediastinal lymph node dissection were performed by an experienced thoracic surgeon (A.T.N.). Mediastinoscopy was considered to be qualitatively sufficient if bilateral paratracheal and tracheobronchial lymph nodes, as well as subcarinal lymph nodes, were removed and analyzed histopathologically. Thorough mediastinal lymph node dissection was performed during the thoracotomy procedures. Supraclavicular lymph nodes were spared at both mediastinoscopy and thoracotomy.
Data Analysis
The McNemar test for matched pairs proportions was used to determine the statistical significance of differences in overall AJCC stage and in N stage determined with CT, PET, and PET/CT. P < .05 was considered to indicate a statistically significant difference. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the imaging examinations in the assessment of lymph node involvement were determined.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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Compared with CT analysis alone, PET/CT analysis correctly revealed the tumor to be of a higher stage in one patient (4%) and to be of a lower stage in seven patients (26%). This revised staging affected treatment recommendations for five patients: One patient’s treatment status was changed from surgical to nonsurgical, whereas four patients’ treatment statuses were changed from nonsurgical to surgical. For the remaining three patients the revised tumor staging did not lead to a change in the treatment plan.
Compared with PET analysis, analysis based on CT data correctly revealed the tumor to be of a higher stage in three patients (11%) and to be of a lower stage in two patients (7%) (effect on treatment recommendation for one patient). Compared with CT, PET correctly revealed the tumor to be of a higher stage in one patient (4%) and to be of a lower stage in five patients (19%), four of whom consequently had a change in their therapy plan.
Additional Findings
Compared with PET alone, CT alone and combined PET/CT revealed clinically important additional findings in two patients: thrombosis of the right jugular vein diagnosed in conjunction with central pulmonary artery embolism in one patient and local recurrence of rectal carcinoma in the other. Furthermore, in one patient, PET/CT depicted hypopharyngeal carcinoma with local lymph node involvement that was not diagnosed with either CT alone or PET alone.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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Furthermore, the findings of this study reconfirm the superiority of PET over CT in the detection and characterization of mediastinal and hilar lymph node metastases. On the other hand, CT was found to be more accurate in the detection of distant metastases compared with PET, although both examinations were outperformed by combined PET/CT.
Dual-modality PET/CT data enabled more accurate assessment of NSCLC T stage than either PET data alone or CT data alone. This observation reflects inherent limitations of the two imaging modalities when either is used alone. Thus, the limited spatial resolution and the lack of depicted anatomic landmarks limit the ability of PET to enable assessment of either tumor size or potential infiltration of the thoracic wall, mediastinum, or other adjacent structures. CT, on the other hand, frequently does not enable differentiation of tumor tissue from poststenotic atelectasis. This limitation of morphologic imaging examinations can be easily overcome by performing analysis based on PET data, because viable tumor tissue can be differentiated from adjacent structures with this modality. Hence, the integration of morphologic CT and functional PET data sets within a single PET/CT examination enables the most accurate differentiation of veritable tumor tissue relative to all adjacent structures (12,14,19).
The characterization of N stage on CT images is based on lymph node size. Nodes larger than 10 mm in smallest diameter (20) are suspected of harboring disease. The limitations of this size-based node characterization system are well documented: Up to 21% of nodes smaller than 10 mm are malignant, whereas 40% of nodes larger than 10 mm are benign (21–24). PET has been shown to be substantially more sensitive and specific than morphologic size–based evaluation (7–10,25). The present study results support these data by confirming significantly higher accuracy values for N staging with PET than for N staging with CT.
Use of PET/CT resulted in further improved N staging compared with use of PET alone. The difference, however, was not statistically significant. The advantages of PET/CT over PET alone are due to the ability of the dual-modality examination to reveal the exact location of metastatic lymph nodes. Accurate anatomic correlation may be of benefit for differentiating N1 from N2 disease. It is also important in identifying supraclavicular N3 disease, which was present in two of the patients evaluated in this study. In both of these patients, mediastinoscopy did not reveal the supraclavicular lymph nodes, and, thus, understaging of the nodular involvement—as N2 and N0 disease—resulted.
It has been shown that 15% of patients with lesions initially staged as N2 tumors have occult supraclavicular disease that is not detected at clinical examination or mediastinoscopy (26). In these patients, PET/CT is of substantial benefit because performing this examination ensures both accurate detection and exact localization of supraclavicular nodes. On the other hand, increased glucose metabolism in supraclavicular and cervical regions may originate from a second primary malignancy rather than from lymph node involvement of a bronchial carcinoma. Thus, in one patient in this study, focally increased glucose metabolism in the left supraclavicular and cervical regions that was diagnosed as N3 disease with PET was found to be localized in the left hypopharynx at PET/CT. A second primary tumor of the hypopharynx with left supraclavicular lymph node involvement was suspected and later confirmed at histopathologic analysis. Neither the carcinoma of the hypopharynx nor the supraclavicular lymph node metastasis was diagnosed with CT.
In the present study, PET and PET/CT were characterized by a 94% negative predictive value in the detection of mediastinal lymph nodes. These data are corroborated by the results of other studies, which have demonstrated negative predictive values of up to 96% for PET alone (19,24). These values suggest that a diagnosis of N0 disease with either PET or PET/CT does not require additional verification with mediastinal lymph node mapping. The observed positive predictive value of PET, 80%, is well in line with other published reports, most of which still recommend verifying PET-positive findings with mediastinoscopy (8). Although the positive predictive value of PET/CT was higher than that of PET alone, the differentiation between malignancy and focally increased glucose metabolism caused by an inflammatory lymph node reaction remains challenging.
In the detection and localization of distant metastases, CT was superior to PET. Studies with opposite results (8–10,27) are usually based on findings of CT performed without dynamically administered intravenous and oral contrast agents or CT performed with a limited field of view on the z axis. As part of the PET/CT examination, CT images are collected following a state-of-the-art administration of intravenous and oral contrast agents (28). The use of this optimized CT technique may explain the more accurate assessment of distant metastases with CT as compared with the assessment with PET. Furthermore, PET is known to have poor sensitivity to small (10 mm) pulmonary metastases (29), which resulted in false-negative results for two patients in the present study.
Owing to optimized PET and CT components, the PET/CT examination proved superior to both PET alone and CT alone in this study. The advantages of combining accurate detection with exact localization were underscored by the detection of a recurrent rectal carcinoma with PET/CT. Although analysis of the PET images alone falsely revealed the increased FDG uptake as being caused by the bladder, PET/CT facilitated the correct diagnosis.
Eight-month follow-up findings showed all imaging examinations to be falsely negative for distant metastases in one patient. Although metastases may have developed de novo during this time frame, it seems more likely that micrometastases existed at the time of initial PET/CT imaging. The poor sensitivity of PET in the detection of micrometastases has been demonstrated before (7). With a given spatial resolution of 4–6 mm with currently available PET and PET/CT systems, the detection of micrometastases remains challenging. Improving the spatial resolution and sensitivity of PET and PET/CT scanners and developing new, more specific radioactive tracers may help overcome this limitation in the future.
In conclusion, use of dual-modality PET/CT significantly increases the number of patients with correctly staged NSCLC. Our study data demonstrate the positive effect of PET/CT tumor staging on patient treatment as compared with the effects of PET alone and CT alone on treatment.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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Author contributions: Guarantor of integrity of entire study, G.A.; study concepts and design, G.A., J.F.D., A.T.N.; literature research, G.A.; clinical studies, G.A., L.S.F.; data acquisition, G.A., L.S.F., H.K., T.B., S.M.; data analysis/interpretation, G.A., J.S., H.K., L.S.F., A.B., J.F.D.; statistical analysis, G.A.; manuscript preparation, definition of intellectual content, and editing, G.A.; manuscript revision/review and final version approval, all authors
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTS DISCUSSIONREFERENCES |
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