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© 2002 American Society for Clinical Oncology Clinical Value of Iodine-123-Alpha-Methyl-L-Tyrosine Single-Photon Emission Tomography in the Differential Diagnosis of Recurrent Brain Tumor in Patients Pretreated for Glioma at Follow-UpByFrom the Departments of Nuclear Medicine, Neurosurgery, and Neuropathology, Saarland University Medical Center, Homburg/Saar, Germany. Address reprint requests to Samuel Samnick, PhD, Department of Nuclear Medicine, Saarland University Medical Center, D-66421 Homburg/Saar-Germany; email: rassam{at}med-rz.uni-saarland.de
PURPOSE: To assess the clinical potential of iodine-123-alpha-methyl-L-tyrosine (IMT) and single-photon emission tomography (SPET) in the differential diagnosis of recurrences in patients pretreated for gliomas at follow-up. PATIENTS AND METHODS: Seventy-eight patients were examined after primary therapy over 36 months. Histopathologic diagnoses of all patients was known at first treatment; magnetic resonance and/or computed tomography examination was performed in addition to IMT-SPET. Cerebral SPET images were acquired 20 minutes after intravenous application of 190 ± 10 MBq of IMT. SPET images were classified as positive or negative for recurrent tumor visually and by calculating the ratios between tracer accumulation in the lesion and the unaffected contralateral regions of reference using region of interest. Final diagnoses were based on prospective clinicopathologic findings obtained independently of IMT-SPET. RESULTS: IMT-SPET detected all high-grade recurrent gliomas (grade 4; sensitivity, 100%). A difference could be demonstrated in grade 2 and 3 recurrences (sensitivity, 84% and 92%, respectively). Moreover, benign posttherapeutic lesions (postoperative scars, radiation necrosis) were correctly diagnosed as negative for tumor recurrence. In general, IMT uptake in grade 2 (1.45 ± 0.24) was significantly lower than that in grades 3 (1.70 ± 0.41) and 4 (1.88 ± 0.32). However, it was difficult to evaluate tumor grade only from the IMT accumulation in individual cases. CONCLUSION: IMT-SPET seems highly useful for detecting and delineating recurrent gliomas and differentiating between benign posttherapeutic lesions and malignant tumor tissue. It may be a valuable clinical tool to diagnose recurrences in patients pretreated for gliomas at follow-up. However, it showed limitations in determining histologic tumor grade.
THE MAJOR CLINICAL challenge in the follow-up of patients pretreated for gliomas is the early diagnosis of tumor recurrence. Further therapeutic management strictly depends on the grade of malignancy.1,2 High-grade astrocytomas tend to relapse rapidly after therapy, whereas low-grade gliomas, besides recurrence, sometimes show progression in the grade of malignancy. In the latter patients, confirmation of recurrence and determination of the current tumor grade contribute to the rapid administration of appropriate adjuvant therapy that may result in a fundamental improvement in patients’ individual prognoses. However, the differential diagnosis between recurrent glioma and benign posttherapeutic lesions poses particular problems. Computed tomography (CT) and magnetic resonance imaging (MRI), the two diagnostic techniques most widely used for morphologic imaging of tumors and for monitoring therapeutic response, frequently fail in differentiating recurrence or regrowth of residual tumor from other lesions. Several studies have demonstrated that CT and MRI cannot reliably differentiate viable tumor tissue from tumor-associated edema, postoperative changes, or radiation necrosis.3-5 Therefore, noninvasive imaging methods based on specific markers of tumor tissue and metabolism, such as positron emission tomography (PET) with the glucose analog fluor-18-deoxyglucose (FDG) or radioactively labeled amino acids such as carbon-11-L-methionine (MET) have been shown to be more sensitive in this regard.6,7 However, PET remains expensive and is of only limited availability. Therefore, research has concentrated on the development of radiopharmaceuticals suitable for a widespread clinical application with single-photon emission tomography (SPET). The radioiodinated amino acid iodine-123-alpha-methyl-L-tyrosine (IMT) is currently used for the diagnosis of brain tumors with SPET. IMT has a similar affinity to the neutral amino acid carrier at the blood-brain barrier as L-tyrosine, but it is not metabolized and not incorporated into proteins.8-10 IMT is taken up intensively in brain tumors of different histologic types and grading, while the accumulation in normal brain is low, providing high tumor-to-brain contrast for visualization of the tumor with high accuracy.10,11 Moreover, as shown in in vivo experiments, IMT uptake in brain tumors can be saturated by neutral amino acids, and results from transport inhibition experiments with specific competitive inhibitors indicate that IMT is taken up in brain neoplasms mainly by the specific amino acid transport systems L and ASC.12,13 Meanwhile, the usefulness of IMT-SPET in the diagnosis of primary brain tumors and for radiation planning is established.8-11,14 By contrast, the clinical value of IMT and SPET in the differential diagnosis of recurrent brain tumors has not been examined on a large scale. The aim of the present investigation was to evaluate the clinical potential of IMT-SPET to diagnose recurrences in patients pretreated for glioma using a simplified image analysis as described in previous studies. Stereotactic biopsy, more than noninvasive imaging, remains the gold standard for histologic classification and grading of cerebral gliomas. The potential of IMT-SPET for grading recurrent gliomas is also evaluated and discussed in the present study.
Patients The 78 patients (53 men, 25 women) included in the present investigation were referred over a period of 36 months for routine IMT-SPET because of a suspected recurrent tumor after primary therapy (surgery, radiotherapy, or both) or at follow-up. The period between the last therapeutic intervention and IMT-SPET investigation was at least 6 months. The histopathologic diagnosis of all patients at the time of the first treatment was known, and an MRI and/or CT examination was performed before IMT-SPET. In some cases, FDG-PET of the suspected lesion was performed to determine qualitatively an upgrading after primary therapy. The group studied included 24 patients with an initial diagnosis of astrocytoma grade 2, 15 patients with high-grade 4 glioma (glioblastoma), 16 patients with oligoastrocytoma grade 2, nine patients with oligodendroglioma grade 2, three patients with astrocytoma grade 3, four patients with oligoastrocytoma grade 3, two patients with oligodendroglioma grade 3, and four patients with an initial diagnosis of gliomatosis cerebri, according to the World Health Organization classification.15,16 Exclusion criteria were pregnancy and inability to give informed consent, which was obtained from every patient studied. Patients’ clinical and demographic data are listed in Table 1.
Radiopharmaceutical IMT was prepared as described previously.17,18 Briefly, a mixture of L-alpha-methyltyrosine (3 mg in 150 µL of 1N HCl) and potassium iodate (0.2 mg in 100 µL of H2O) was added to carrier-free sodium [123I]iodide (400 to 1,000 MBq, obtained from Forschungszentrum Karlsruhe, Karlsruhe, Germany) in 8 to 10 µL of 0.1N NaOH solution. After 25-minute reaction time at room temperature, the reaction mixture was diluted with 1N NaOH, which was followed by purification of the resulting IMT by means of isocratic high-performance liquid chromatography (reverse-phase RP-18 column, Nucleosil-100, 250 x 4 mm; Latek, Eppelheim, Germany) with ethanol, water, and acetic acid (10:89:1) as eluent while monitoring ultraviolet and radioactivity. The isolated product fraction was buffered with 0.6 mol/L phosphate buffer (Braun, Mesungen, Germany) and diluted with sterile water (water for injection; Braun) to yield an isotonic and injectable radiopharmaceutical after filtration through a 0.22-µm sterile membrane (Millex GS; Millipore, Molsheim, France). The IMT solution was additionally tested routinely for pyrogens and sterility before use in humans.
IMT-SPET
Image Analysis
Quantitative analysis.
Additionally, we measured target-background ratios (T:B) by ROI technique. For this purpose, loosely defined ROIs were drawn by the two observers on the lesion under study in consecutive slices as previously described,17 and the pixel with maximum IMT uptake was determined automatically. The reference ROI with the same size was defined in the hemispherical half of the brain that was not affected by the tumor or, when the tumor crossed the middle line, by the anterior or posterior half of the brain slice. We use a standardized gray scale describing increased or possibly decreased uptake in the lesion in comparison with the tracer accumulation in the unaffected hemisphere defined as the reference region. Images were classified as positive if IMT activity in the tumor lesion exceeded background activity and as negative if activity was less than or close to background activity (T:B Statistical analysis. The interobserver variability in the qualitative evaluation of the IMT-SPET images was determined by kappa statistics.20 Uptake ratios are provided as mean ± SD. P values of less than .05 were considered significant.
Stereotactic Biopsy All SPET findings were correlated with the histopathologic results obtained by a current stereotactic biopsy and, in three cases, by open surgery. In seven cases, a stereotactic biopsy was not performed for ethical reasons. Therefore, further radiologic examinations, including MRI, CT, and FDG-PET were considered to confirm the IMT-SPET result, in agreement with previous studies.21-24
Seventy-eight consecutive patients (53 men and 25 women; age range, 26 to 73 years) were included in the present investigation. Patient characteristics, tumor types, pretreatment data, results of the visual interpretation, and the individual T:B ratios are given in Table 1. Representative examples of IMT-SPET scans are shown in Figs 1, 2, and 3. The results obtained in a 47-year-old patient with recurrent oligoastrocytoma grade 2 (patient no. 69) are displayed in Fig 1A (IMT-SPET image with increased uptake of IMT in this very lesion) and Fig 1B (T1-weighted MRI scan showing a lesion of decreased enhancement after injection of gadolinium diethylenetriamine penta-acetic acid). Figure 2A (IMT-SPET image) presents the reduced uptake in the right temporal lobe attributable to scar tissue and/or radiation necrosis after surgery and irradiation of a grade 2 oligoastrocytoma in a 67-year-old male patient (patient no. 20). The contrast-enhanced T-1 and T2-weighted MRI scans are shown in Figs 2B and 2C.
Overall, 68 recurrent gliomas and 10 nontumorous lesions were studied. Brain area with glioma showed significantly higher IMT uptake compared with background and nontumorous regions, leading to high T:B ratios. ROIs defined by the two observers in the IMT images showed a high correspondence (P = .002). On the basis of our previous evaluation of IMT in biopsy-controlled patients with recurrent gliomas,17,25 we considered a cutoff of 1.15 (Figs 4 and 5). Of the 78 IMT-SPET studies, 69 were interpreted concordantly by the two observers after visual image analysis. Disagreement was noted in nine cases, which were evaluated by a third observer and semiquantitatively by ROI as defined by consensus, using the MRI/CT images as reference. Maximum and mean tracer uptake was determined and ratios were calculated relative to the reference ROI for the final classification. Four of these cases revealed a TU score of 2 and mean T:B ratio less than 1.15 and were finally categorized as negative for recurrence by consensus (patients no. 16, 18, 42, and 60). The remaining five cases (patients no. 3, 6, 7, 19, and 48) exhibited significantly high T:B ratios (> 1.20) and were visually interpreted positively by the third observer. Therefore, we finally classified these five cases as positive for tumor. Sixty-two of the 66 histopathologically confirmed recurrences were clearly identified by IMT-SPET, yielding a sensitivity of 94%.
Histology was not available for six IMT-SPET–positive patients because of ethical reasons or absence of therapeutic benefit. Recurrence in the suspicious lesions was clearly confirmed by other radiologic examinations, including MRI and FDG-PET. By sorting the recurrences according to Daumas-Duport’s grading of ordinary gliomas, all 25 patients (100%) with grade 4 recurrence, 11 (92%) of 12 patients with grade 3 recurrence, and 16 (84%) of 19 patients with grade 2 recurrence were true-positive. True-negative results were found in all cases of scar and radiation necrosis (100%) as well as in one case of unspecific tissue altering that was histologically considered to be nontumorous. Gliomatosis cerebri and one diffuse glioma could not be detected by IMT-SPET, along with four histologically confirmed low-grade recurrences, which were false-negative. Semiquantitative analysis of the IMT uptake in tumor revealed T:B ratios of 1.45 ± 0.24 in low-grade 2, 1.70 ± 0.41 in low-grade 3, and 1.84 ± 0.32 in high-grade 4 recurrences. In general the T:B ratio of the IMT in low-grade 2 recurrences was lower than that in both low-grade 3 and grade 4 recurrences. However, IMT uptake in some low-grade 2 to 3 recurrences of mixed tumors was not significantly different from that in grade 4 recurrent gliomas. An upgrading from grade 2 to low-grade 3, from grade 2 to high-grade 4, as well from grade 3 to high-grade 4 was found in eight cases, 15 cases, and one case, respectively.
Development of noninvasive techniques to identify quantitative and qualitative differences between normal (or benign) tissue and neoplastic tissue is crucial to the understanding of cancer and to the improvement of cancer treatment. The therapy of cerebral gliomas usually consists of a combination of surgery, radiation therapy, and chemotherapy.26-28 Other therapeutic methods, including radiolabeled specific monoclonal antibodies, brachytherapy, and the boron neutron capture therapy,29-31 have been reported. However, their clinical potential remains to be evaluated. Therapeutic response is usually monitored with CT or MRI. However, CT and MRI are seriously limited when they are used to differentiate recurrence of brain tumor from benign posttherapeutic lesions. One technique that is more sensitive and accurate than CT or MRI is the measure of the physiologic process associated with the utilization of nutrients in tumors using PET. The glucose analog FDG and the amino acid MET have been used extensively to evaluate the metabolic activity of brain tumors by PET.6,7,32 However, the high glucose utilization of gray matter, resulting in a low contrast between tumor tissue and normal gray matter, complicates the identification and the delineation of tumor tissue by FDG-PET. Therefore, difficulties in the visual interpretation and lower sensitivity and specificity values for FDG-PET have been reported, especially in low-grade tumors.10,17 Because of the low uptake in normal brain, tracers of amino acid metabolism may help to overcome these problems. It has been shown that MET, the most intensively studied agent for evaluation of amino acid metabolism of brain tumors, is superior to FDG in definition of tumor extent and detection of recurrences.7,33,34 Moreover, the fact that amino acid imaging is less influenced by inflammation may be advantageous in comparison with FDG-PET and other imaging modalities. Unfortunately, the short half-life of carbon-11 of only 20 minutes restricts the use of this tracer to PET centers with on-site cyclotrons. It was in order to overcome this limitation that the iodine-123–labeled tyrosine IMT was developed. IMT offers widespread application of amino acid studies with SPET, in that SPET cameras and iodine-123 (half-life, 13 hours) are generally available and relatively inexpensive. Moreover, despite the lower resolution and lower sensitivity of SPET compared with PET, IMT-SPET seems to have similar diagnostic potentials as MET-PET for the delineation of cerebral gliomas.35 In a comparative study, IMT-SPET and MET-PET yielded no obvious difference in tumor size and shape, with tumor-brain ratios of both imaging methods showing a significant correlation, especially in the early transport-dominated phase.35 Since IMT uptake in tumor can only be explained by a transport process, this result gives additional support to the hypothesis that transport phenomena play an important role in the increased accumulation of large neutral amino acids in gliomas.18,36 The present study aimed to determine in a larger series of patients whether IMT-SPET could be used for early diagnosis of cerebral tumor recurrences and for evaluating the current tumor grade. Therefore, we evaluated 78 patients pretreated for gliomas by IMT-SPET. The IMT-SPET finding was correlated with actual histopathology for the final diagnosis. However, in seven of our patients, a histologic diagnosis was not available because stereotactic biopsy or reoperation could not be justified in all patients with brain tumor recurrence due to possible side effects of these invasive procedures and the absence of a therapeutic benefit. In these patients, a distinction between recurrences and benign posttherapeutic lesions was based on radionuclide imaging and other radiologic techniques. In six of the seven patients, the suspicious lesions with high IMT uptake exhibited high FDG uptake and contrast enhancement on MRI scan, clearly confirming recurrences. These cases were ultimately classified as positive, in agreement with previous studies.21-24 In the last case, IMT-SPET (T:B ratio, 1.05), MRI (T1), and FDG-PET, which was performed to determine qualitatively an upgrading after primary therapy, failed to confirm recurrent glioma. Therefore, we classified this case (patient no. 54) as negative for recurrent tumor in the final diagnosis. The present evaluation showed that IMT is highly useful both for detecting recurrences and for differentiating between tumor tissue and nonneoplastic posttherapeutic lesions. IMT-SPET was true-positive in all cases (100%) of high-grade (grade 4) recurrent gliomas. Differences were demonstrated in low-grade tumor recurrences. True-positive results by IMT-SPET were found in 92% of grade 3 and 84% of grade 2 recurrences. IMT-SPET accurately distinguished all scars and radiation necrosis from tumor in the present study. This is an important clinical finding, since differentiation of brain tumor recurrences from benign posttherapeutic lesions remains a serious clinical problem. One potential value of amino acid imaging in gliomas remains its accurate clarification of tumor extension. Our results demonstrated that IMT-SPET allows reliable definition of tumor extent, at least to some extent, even in low-grade recurrences. This finding is in agreement with results obtained in primary brain tumors and consistent with previous reports, confirming the clinical advantages of IMT-SPET compared with FDG-PET and MRI,10,11,14,16 as well as with 201Tl, another radiopharmaceutical proposed for brain tumor imaging by SPET.37,38 A further important issue in evaluating the clinical utility of radionuclide imaging in oncology is the in vivo determination of tumor grade. Despite the occurrence of sampling errors,39 which limits histopathologic analysis, stereotactic biopsy remains the gold standard in the classification and grading of brain tumors. The role of IMT-SPET for in vivo tumor grading is controversial. IMT-SPET could differentiate high-grade tumors from benign lesions with high accuracy.9 However, the sensitivity decreased significantly, separating high-grade from low-grade tumors.9 In general, T:B ratios in the present evaluation were lower in grade 2 recurrences than in grade 3 and grade 4 recurrences. However, in some cases, no significant differences in the tumor uptake of IMT could be accurately defined among the different grades of malignancy. An upgrading from low-grade oligoastrocytoma (grade 2) to anaplastic oligodendroglioma (grade 3) could not be accurately differentiated from upgrading of an astrocytic tumor to a glioblastoma. Therefore, our results indicate that IMT-SPET does not support a sufficient in vivo grading at follow-up of patients pretreated for gliomas, confirming our previous results on selected biopsy-controlled patients with brain tumor recurrences.16,25 In conclusion, the present investigation demonstrates that IMT-SPET is a valuable clinical tool for rapid diagnosis of brain tumor recurrences in the follow-up of patients pretreated for glioma. The specificity of the method seems very promising, even in low-grade recurrences and in regions of the brain with no contrast enhancement in morphologic imaging. However, IMT-SPET shows limitations in classification and determination of the tumor grade, especially in cases of mixed tumor recurrences. In these cases, histopathologic evaluation of the tumor grade, if possible, remains necessary. Therefore, we see the primary application of IMT-SPET as routine identification or exclusion of tumor recurrences.
We thank Christian Chapot, MD, for MRI interpretation and the technologists of the Division of Nuclear Medicine at Saarland University Hospital for their valuable technical assistance.
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
3 was considered to be pathologic and was classified as positive for tumor tissue. In cases of discordant interpretation, further evaluations were considered for the final classification, including an evaluation by a third independent observer and a definition of region of interest (ROI) by consensus. 
1.10 ± 0.05). For further analysis and in case of discordance, an ROI was defined by consensus using the MRI images as a reference. Results of both investigators were compared with each other and with the results obtained by ROI as defined by consensus, including the determination of the mean and SD of the T:B ratio and of the tumor size. 
