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Nuclear Medicine |
1 From the Departments of Nuclear Medicine (R.B.S., N.Y., Z.K., A.F., O.I.), Oncology (N.H., R.E.), Hematology (E.J.D.), and Diagnostic Radiology (D.G.), Rambam Medical Center and the Technion, Israel Institute of Technology, Bat Galim, Haifa 35254, Israel. Supported in part by a grant from the L. Rosenblatt Fund in Cancer Research of the Technion Foundation. Received March 4, 2002; revision requested May 22; final revision received August 29; accepted September 30. Address correspondence to O.I. (e-mail: o_israel@rambam.health.gov.il).
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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MATERIALS AND METHODS: The performance of 67Ga scintigraphy and camera-based FDG PET in the detection of lymphoma was retrospectively evaluated and compared in 84 patients with lymphoma, with 219 suspected sites of disease. Eighty-nine percent of patients were examined during or after treatment. Camera-based FDG PET was initiated by equivocal characterization of the status of disease based on clinical, radiologic, and 67Ga scintigraphic assessment. Findings of 67Ga scintigraphy and camera-based FDG PET were compared on a per-patient and per-site basis for the whole group, for histologic subtypes, and for anatomic locations. Comparison of sensitivity, specificity, and accuracy between the two modalities for detection of lymphoma was performed with the McNemar test.
RESULTS: There was a statistically significant difference in sensitivity, specificity, and accuracy of 67Ga scintigraphy and camera-based FDG PET at both patient- and site-based analysis. 67Ga scintigraphy helped to accurately define disease state in 63% of patients and in 33% of sites, compared with 83% and 87%, respectively, for camera-based FDG PET. For discordant findings between the two modalities, camera-based FDG PET findings were confirmed as true-positive in 71% and as true-negative in 92% of patients. Camera-based FDG PET had a significantly higher detection rate for both nodal and extranodal lymphoma sites. It provided accurate assessment of lymphoma involvement of the skeleton in 93% of sites compared with 29% for 67Ga scintigraphy and excluded active lymphoma in 10 67Ga-positive benign parahilar sites.
CONCLUSION: In this selected group of patients with lymphoma, camera-based FDG PET allowed a significantly more accurate definition of active disease compared with that allowed with 67Ga scintigraphy.
© RSNA, 2003
Index terms: Fluorine, radioactive, 99.12963 • Gallium, radioactive, 99.12962 • Lymphoma, 99.8342, 99.8343 • Lymphoma, PET, 12963 • Lymphoma, SPECT, 99.12962 • Radionuclide imaging, comparative studies, 99.12962, 99.12963
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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The emergence of positron emission tomography (PET) with fluorine 18 fluorodeoxyglucose (FDG) as a powerful functional imaging tool in various malignancies seems to challenge the usefulness of other nuclear medicine procedures. A potential role of FDG PETin the care of patients with lymphoma is suggested in the gradually accumulating data, which indicate FDG avidity of most histologic types of lymphoma and a higher depictability rate of FDG PET over that of CT (9).
In view of the proven role of 67Ga scintigraphy in the management of lymphoma, a systematic comparison with FDG imaging seems needed. In previous studies, these two imaging modalities were analyzed in a small series of patients, often with comparison of suboptimal 67Ga scintigraphic technique vis-à-vis imaging with high-resolution dedicated PET systems (10).
The development of camera-based PET systems with dual-head coincidence imaging provides a less expensive and more accessible alternative to dedicated PET systems (11). The relatively lower cost of camera-based PET compared with that of dedicated PET and improvement in image quality owing to the use of new thick crystal detectors, attenuation correction, and iterative reconstruction algorithms enable a comparable basis for evaluation of 67Ga scintigraphy and FDG PET imaging.
The purpose of our study was to compare the value of the two functional imaging modalities, state-of-the-art 67Ga scintigraphy and camera-based FDG PET, in the evaluation of patients with lymphoma.
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MATERIALS AND METHODS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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Forty-one patients who did not comply with the inclusion criteria were excluded from the study. For 25 of these patients, 67Ga scintigraphy and camera-based FDG PET were performed within more than 60 days of each other; 11 patients had a change in treatment between the two procedures, and five patients underwent 67Ga scintigraphy and camera-based FDG PET only after treatment, with no previous documentation of 67Ga avidity.
The final study population included 84 patients who were retrospectively analyzed. There were 52 male and 32 female patients (median age, 47.5 years; age range, 7–86 years). Twenty-six patients had Hodgkin disease; 17 of them had nodular sclerosis, and eight had mixed cellularity type. The precise Hodgkin disease subtype in one patient could not be determined. Fifty-eight patients had non-Hodgkin lymphoma. According to the Revised European-American Lymphoma classification (12), 32 patients had intermediate- or high-grade non-Hodgkin lymphoma (29 patients with various types of large-cell lymphoma, three with Burkitt lymphoma). Three patients had mantle cell lymphoma. Twenty-three patients had low-grade lymphoma (including 22 patients with various types of follicular lymphoma and one patient with MALT lymphoma). For further analysis, 35 of the 58 patients were considered as having aggressive non-Hodgkin lymphoma, and 23 patients, indolent non-Hodgkin lymphoma. Overall, seven patients had stage I disease, 13 had stage II disease, 17 had stage III disease, and 46 had stage IV disease. The initial stage of disease in one patient with Hodgkin disease was unknown.
67Ga scintigraphy and camera-based FDG PET were performed at various times during the course of disease. Nine studies were performed at baseline before treatment; eight studies, during treatment; 22 studies, at the end of treatment; and 45 studies, during routine follow-up or when recurrence was suspected. Both 67Ga scintigraphy and camera-based FDG PET were performed at least 2 weeks after a cycle of chemotherapy. The temporal distribution of patient evaluation is detailed in Table 1.
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The presence or absence of lymphoma in each suspected lesion was determined at biopsy in 24 sites and with a combination of imaging and clinical follow-up in 195 sites. In 54 of the 219 suspected sites, no evidence of disease was confirmed at a median clinical follow-up of 18.6 months (range, 9–30 months).
Imaging Technique
67Ga scintigraphy was performed according to our routine protocol for lymphoma imaging, as previously detailed (6,7). Adult patients received 8 mCi (296 MBq) and children received 75 µCi (2.77 MBq) of 67Ga citrate per kilogram of body weight. Planar imaging and single photon emission CT (SPECT) were performed at 48 hours. Additional delayed views were obtained 7–14 days after injection, when needed. Scintigraphy was performed with a dual-head digital camera (Helix, Elscint, Haifa, Israel; and VG or MG, GE Medical Systems, Milwaukee, Wis). Three energy peaks of 67Ga at 93, 184, and 300 keV were used. A special collimator (HPC-5; Elscint) designed for 67Ga was used. Whole-body scanning was performed for 20 minutes at 48 hours after injection and for 26 minutes at delayed imaging. SPECT scans of the head, neck, chest, abdomen, and pelvis were obtained in all patients at 48 hours after injection. SPECT was performed by using 360° rotation with 60 projections 6° apart, which resulted in an accumulation of 8.0 x 106 counts for the whole study. A matrix of 64 x 64 and a Metz filter with a cut-off value of 3 and full width at half maximum of 14 were used for reconstruction by using the filtered back-projection method. Images were obtained in the transaxial, sagittal, and coronal planes.
Camera-based FDG PET imaging was performed by using a dual-head variable-angle gamma camera system with coincidence acquisition capabilities (Millenium VG; GE Medical Systems). In 67 studies, the detectors were equipped with 
-inch-thick sodium iodide crystals. Seventeen studies were performed by using detectors with 1-inch-thick crystals. Dual-head coincidence imaging was initiated 60 minutes after intravenous injection of 8–10 mCi (296–370 MBq) of FDG. All patients fasted at least 4 hours before injection. Emission data were acquired for 10 rotations of 360° during 30 minutes. An acquisition matrix of 128 x 128 was used. The data were reformatted into 90 projections and reconstructed iteratively by using coincidence-ordered subsets expectation maximization software (GE Medical Systems).
In 76 patients, the acquisition was performed by using x-ray attenuation correction, and only these images were evaluated. The transmission scanning for attenuation correction was performed by using a low-dose CT scanner, consisting of an x-ray tube and a detector placed on the rotating support of the gamma camera (VG and Hawkeye; GE Medical Systems). The x-ray tube operated at 140 keV and 2.5 mA. Transmission scanning was performed for 10 minutes over 220° with 16 seconds for each section, either before or after the emission scanning. The x-ray images were reconstructed into a 256 x 256 matrix during the acquisition process. The transmission measurements were corrected and logged to produce attenuation measurements, which were reconstructed by using filtered back projection to produce cross-sectional attenuation images in which each pixel represented the attenuation of the imaged tissue.
Camera-based FDG PET images of the head and neck, chest, abdomen, and pelvis were acquired. Images were viewed in the coronal, axial, and sagittal planes and in reprojection three-dimensional cine mode.
Interpretation Criteria
Findings of 67Ga scintigraphy and camera-based FDG PET were defined as positive in the presence of foci of increased uptake in areas unrelated to the normal biodistribution of the radiopharmaceutical. Interpretation of findings of both modalities was performed by the same three experienced nuclear medicine physicians (O.I., N.Y., R.B.S., or Z.K.) with knowledge of medical history and results of anatomic imaging tests and of the previously performed 67Ga scintigraphy. In case of disagreement, the final interpretation was determined by a majority opinion. No quantitative measurements were performed. 67Ga scintigraphic images were reviewed by using both hard copies and the computer screen. Camera-based PET findings were interpreted at the computer screen. The interpretations of findings of both 67Ga scintigraphy and camera-based FDG PET, rendered at the time of the initial reading, were used for comparison.
Results were analyzed separately for each patient and for each suspected site. For patient-based analysis, a true-positive finding was defined as the presence of at least one focus of increased uptake confirmed as active lymphoma. A false-positive finding was defined as a positive scintigraphic finding in a patient with no evidence of disease at further evaluation. A true-negative finding was defined as no abnormal scintigraphic findings, and the patient had no further evidence of disease. A finding was defined as false-negative when no areas of increased uptake were seen in patients with active lymphoma at further evaluation.
For site-based analysis, a true-positive site was defined as increased uptake in a lymphomatous lesion. A false-positive site was defined as an area of increased uptake, with no further evidence of disease. A true-negative site was defined as no uptake in a suspected lesion where disease was excluded at further evaluation. A false-negative site was defined as no increased uptake in a lymphoma lesion. Sixteen patients with negative 67Ga scintigraphic and camera-based FDG PET findings and no evidence of disease were included (as true-negative findings) only in the patient-based analysis and were excluded from the site-based analysis.
Congruence and discongruence patterns of 67Ga scintigraphic and camera-based FDG PET results were analyzed on a per-patient and per-site basis and compared with the final status of disease.
Statistical Evaluation
Statistical analysis was performed on a per-patient and per-site basis for the whole group for different histologic subtypes and different anatomic locations. Sensitivity, specificity, and accuracy of 67Ga scintigraphy and camera-based FDG PET for diagnosis of lymphoma were calculated. Differences between these performance indices in the two modalities were evaluated with the McNemar test. A significance level of .01 was used to partially adjust for multiple testing.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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There were 27 (32%) discordant findings (Fig 1). In 14 patients, findings of FDG PET were positive and those of 67Ga scintigraphy were negative. Ten (71%) of these patients had lymphoma (seven of them had a non–Ga-avid lymphoma, and three patients had single sites of recurrence not detected at 67Ga scintigraphy). In four patients, there was no evidence of lymphoma (one patient each had a hyperplasic thymus, degenerative changes in the spine, uptake in tense cervical muscles, and a granulomatous lesion in the spleen).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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With the increasing availability of FDG PET for routine clinical applications, this modality was found to be highly sensitive in the detection of various malignancies, including lymphoma (16). FDG PET has been found to be superior to CT in initial staging of both nodal and extranodal Hodgkin disease and of non-Hodgkin lymphoma (17–19). Initial reports also suggest that FDG PET is superior to CT in monitoring response to treatment and assessment of residual masses (20–22). Most of these studies present data about use of FDG with dedicated PET systems. Camera-based PET with FDG is a newly developed alternative, is less expensive, and is a more widely available technology (9). Authors of only a few studies have assessed the value of camera-based FDG PET imaging in patients with lymphoma (23–26). Camera-based FDG PET has shown results comparable with those of radiologic imaging methods for staging of Hodgkin disease and non-Hodgkin lymphoma and is more accurate than CT in depicting residual disease after treatment (24–26). The use of attenuation correction and iterative reconstruction algorithms further improves lesion detectability of camera-based FDG PET in patients with lymphoma (23).
There are scarce data in the literature in which the performance of 67Ga scintigraphy and FDG PET is compared in the assessment of lymphoma, with most studies including only small groups of patients. In a first report about five patients, planar FDG imaging with use of a gamma camera with very high-energy collimators depicted lymphoma sites in four patients compared with low-dose planar 67Ga scintigraphy, which depicted lymphoma sites in two patients (27). Planar FDG imaging and 67Ga scintigraphy performed similarly in staging and monitoring lymphoma response to treatment (28).
Authors of further studies have compared dedicated FDG PET with low-dose planar or SPECT 67Ga scintigraphy, making the comparison of these two modalities less accurate (21,26,29,30). Findings in preliminary reports in which camera-based FDG PET and 67Ga scintigraphy were compared indicate a higher tumor-to-background ratio and a higher lesion detectability rate for camera-based PET (10,26,31).
This study is a direct comparison of 67Ga scintigraphy and camera-based FDG PET in the same group, including a large number of patients with lymphoma. Depiction performance is analyzed both on a per-patient and per-site basis and is assessed for the whole study group, as well as separately for different histologic types of disease. In most previous studies, the two tests were assessed for staging of lymphoma in spite of the more important clinical information provided by these two functional imaging modalities during or after therapy. In the present study, 89% of patients evaluated were assessed after the treatment was initiated.
In the present study, we found FDG PET to be significantly better than 67Ga scintigraphy for diagnosis of active lymphoma. For the patient-based analysis, camera-based FDG PET had a statistically significant better sensitivity, specificity, and accuracy for all types of lymphoma. Of 14 patients with results positive at FDG PET but negative at 67Ga scintigraphy, 10 (71%) were confirmed as having true-positive results of lymphoma. Of 13 patients with negative results at FDG PET but positive at 67Ga scintigraphy, 12 (92%) had no evidence of disease.
Differences between FDG PET and 67Ga scintigraphy were more prominent in the site-based analysis. FDG PET defined the nature of suspected sites significantly better than did 67Ga scintigraphy in all types of lymphoma. Overall, 87% of sites were correctly defined as true-positive or true-negative at FDG PET compared with 33% of sites at 67Ga scintigraphy. Of 107 sites positive at FDG PET but negative at 67Ga scintigraphy, 97 (91%) had active lymphoma. Of 35 sites negative at FDG PET but positive at 67Ga scintigraphy, 33 (94%) had no evidence of lymphoma. FDG PET helped correctly characterize suspicious lesions in significantly more sites than did 67Ga scintigraphy in both nodal and extranodal locations.
In the present study, FDG PET provided solutions to some diagnostic dilemmas previously reported for 67Ga scintigraphy. Although superior to CT or bone scintigraphy in the evaluation of bone lymphoma, the specificity of 67Ga scintigraphy is nevertheless hampered by the bone-seeking property of this radiopharmaceutical (32). The correct characterization between viable or treated bone lymphoma or benign bone lesions was made in 42 (93%) of the 45 skeletal sites with FDG PET, while only 13 (29%) of the 45 skeletal sites were accurately defined with 67Ga scintigraphy (Fig 2). Diagnosis of visceral lymphoma involvement with 67Ga scintigraphy is suboptimal (33). Splenic involvement was diagnosed at FDG PET in all five patients, compared with that diagnosed in two patients at 67Ga scintigraphy.
Benign parahilar 67Ga uptake has been described in about 55% of patients with lymphoma, mostly during and after treatment (34). Although quantitative 67Ga scintigraphy may be of value in the differential diagnosis of benign and malignant hilar uptake, clinical decisions are still difficult. In the present study, 10 false-positive sites of benign parahilar uptake at 67Ga scintigraphy were all true-negative at camera-based FDG PET, which was in agreement with findings in previous reports (35).
FDG PET shares certain limitations with 67Ga scintigraphy. Hyperplastic thymus demonstrates increased uptake of both FDG and 67Ga (36), as was seen in the present study in five patients. 67Ga and FDG are both taken up by inflammatory processes (37,38), as was seen in nine sites at FDG PET and in 12 lesions at 67Ga scintigraphy.
The relatively poor results demonstrated with 67Ga scintigraphy in the present study are in contrast with the findings in many past reports in which large numbers of patients were evaluated. The main reason seems to be the referral bias of the present study population. Patients were referred for FDG PET as a result of equivocal 67Ga scintigraphic findings or for further evaluation of non–Ga-avid lymphomas. Performance of 67Ga scintigraphy in this study population was therefore adversely biased because patients were not randomly selected. In addition, in previous reports, performance of 67Ga scintigraphy was evaluated on a per-patient basis, since identification of viable lymphoma rather than exact estimation of the extent of disease is important for further therapeutic decisions.
The better sensitivity and accuracy of camera-based FDG PET over that of 67Ga scintigraphy reported in the present study indicate a potentially more precise and reliable assessment of minimal residual disease during and after therapy with camera-based FDG PET. The important issue of whether the superiority of FDG PET in identifying or excluding lymphoma sites has an effect on patient care needs to be further assessed. It remains to be proven whether results of FDG PET lead to changes in the outcome of patients with lymphoma. The prognostic value of early FDG PET imaging for patient outcome still needs to be assessed. Technical advantages of FDG PET, such as better contrast and resolution, lower dosimetry, shorter scanning time with better patient compliance, as well as improved patient throughput and cost-effectiveness, should also be considered.
Findings of the present comparative study suggest that the differences in imaging results of these two modalities may reflect biologic differences in the interaction of each of the two tracers with lymphomatous tissues. Although both 67Ga and FDG are agents of lymphoma viability, different uptake mechanisms account for their uptake by lymphoma cells. 67Ga uptake involves mainly its specific interaction with transferrin receptors on the surface of lymphoma cells, while FDG uptake reflects a general metabolic process common to most malignant tissues. Differences in the biologic importance of FDG uptake and its dynamics in response to therapy, as compared with 67Ga, should be considered in further clinical studies.
In conclusion, in this selected group of patients, camera-based FDG PET performed significantly better than did 67Ga scintigraphy in defining sites of active lymphoma. The potential benefit of FDG PET imaging compared with that of 67Ga scintigraphy in early detection of treatment failure and recurrent disease and in predicting prognosis should be further assessed.
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FOOTNOTES |
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Author contributions: Guarantor of integrity of entire study, O.I.; study concepts and design, O.I., R.B.S.; literature research, R.B.S.; clinical studies, N.Y., Z.K., N.H., E.J.D., R.E., D.G.; data acquisition, N.Y., Z.K.; data analysis/interpretation, O.I., R.B.S., N.Y., A.F., Z.K.; statistical analysis, A.F.; manuscript preparation and editing, R.B.S., N.Y., O.I.; manuscript definition of intellectual content, revision/review, and final version approval, O.I., R.B.S.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONMATERIALS AND METHODS RESULTS DISCUSSIONREFERENCES |
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