Rationale and Objectives
To compare the ability of normalized versus non-normalized metabolite ratios to differentiate recurrent brain tumor from radiation injury using magnetic resonance spectroscopy (MRS) in previously treated patients.
Materials and Methods
Twenty-five patients with previous diagnosis of primary intracranial neoplasm confirmed with biopsy/resection, previously treated with radiation therapy (range, 54–70 Gy) with or without chemotherapy and new contrast enhancing lesion on a 1.5 T magnetic resonance imaging at the site of the primary neoplasm participated in this retrospective study. After MRS, clinical, radiological, and histopathology data were used to classify new contrast-enhancing lesions as either recurrent neoplasm or radiation injury. Volume of interest included both the lesion and normal-appearing brain on the contralateral side. Non-normalized metabolic ratios were calculated from choline (Cho), creatine (Cr), and N-acetylaspartate (NAA) spectroscopic values obtained within the contrast-enhancing lesion: Cho/Cr, NAA/Cr, and Cho/NAA. Normalized ratios were calculated using the metabolic values from the contralateral normal side: Cho/normal creatinine (nCr), Cho/normal N-acetylaspartate (nNAA), Cho/normal choline, NAA/nNAA, NAA/nCr, and Cr/nCr. Results were correlated with the final diagnosis by Wilcoxon rank-sum analysis.
Results
Two of three non-normalized ratios, Cho/NAA (sensitivity 86%, specificity 90%) and NAA/Cr (sensitivity 93%, specificity 70%) significantly associated with tumor recurrence even after correcting for multiple comparisons. Of the six normalized ratios, only Cho/nNAA significantly correlated with tumor recurrence (sensitivity 73%, specificity 40%), but did not remain significant after correcting for multiple comparisons.
Conclusion
Cho/NAA and NAA/Cr were the two ratios with the best discriminating ability and both had better discriminating ability than their corresponding normalized ratios (Area under the curve = 0.92 versus 0.77, AUC= 0.85 vs. 0.66), respectively.
Differentiation between recurrent neoplasm and postradiation change in patients who were treated for primary brain tumors is often difficult, based on conventional magnetic resonance imaging (MRI) features alone. Previous studies suggest that magnetic resonance spectroscopy (MRS) can discern between postradiation changes and recurrent neoplasm in patients treated for a primary brain tumor who have nonspecific contrast-enhancing lesions on follow-up imaging and have shown adequate correlation with pathologic specimens obtained at biopsy and/or resection . Prior investigators evaluating the ability of multivoxel MRS—either two-dimensional (2D) or three-dimensional (3D) chemical shift imaging (CSI)—to differentiate between recurrent neoplasm and postradiation change have suggested that specific standard ratios, such as the choline/creatine (Cho/Cr) or choline/N-acetylaspartate (Cho/NAA), could be used as “cutoffs” to define the different groups .
The key question is which of the different ways to measure ratios and obtaining so called cutoff values works the best?
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Methods
Patient Population
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Table 1
Demographics, Primary Tumor, MRS Diagnosis, Follow-up Interval for the 25 Patients in Whom Normalized Ratios Could be Appropriately Calculated out of 27 Patients in the Original Cohort
Patient Number Age Sex Histology of the Initial Tumor MRS Diagnosis ∗ Final Diagnosis † Reference Standard Months of MRI Follow-up 1 43 M Anaplastic astrocytoma Radiation Radiation Histology 13 2 35 F Oligoastrocytoma Tumor Radiation Histology 27 3 44 M GBM Radiation Radiation Imaging 13 4 54 M Anaplastic oligoastrocytoma Radiation Radiation Imaging 11 5 10 F Oligoastrocytoma Radiation Radiation Imaging 11 6 52 M Oligoastrocytoma Radiation Radiation Imaging 9 7 41 F Anaplastic oligoastrocytoma Radiation Radiation Imaging 11 8 43 F Anaplastic Oligodendroma Radiation Radiation Imaging 19 9 7 F PNET Radiation Radiation Imaging 20 10 64 F Glioblastoma Tumor Tumor Histology 14 11 59 F Low-grade oligoastrocytoma Tumor Tumor Histology 16 12 20 M PNET/glioblastoma Tumor Tumor Histology 27 13 43 M Oligoastrocytoma to GBM Tumor Tumor Histology 12 14 7 M Ependymoma Tumor Tumor Histology 18 15 42 F Anaplastic oligoastrocytoma Tumor Tumor Histology 22 16 24 M Oligoastrocytoma Tumor Tumor Histology 6 17 35 M Astrocytoma Tumor Tumor Imaging 2 18 4 M Medulla glioma Tumor Tumor Imaging 21 19 41 M Oligodendroglioma Tumor Tumor Imaging 18 20 50 M Oligodendroglioma Tumor Tumor Imaging 5 21 36 F Astrocytoma Tumor Tumor Imaging 20 22 32 F Astrocytoma Tumor Tumor Imaging 23 23 ‡ 55 M Pontine glioma Radiation Tumor Imaging 27 24 56 F Neurocytoma Tumor Tumor Imaging — 25 47 M Astrocytoma Radiation Radiation Histology 41
GBM, glioblastoma multiforme; L, left; MRS, magnetic resonance spectroscopy; PNET, primitive neuroectodermal tumor; R, right.
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Table 2
Tumor Location and Metabolic Ratios
Patient Number Tumor Location Cho/Cr Cho/NAA NAA/Cr Cho/nNAA Cho/nCr Cho/nCho Cr/nCr NAA/nNAA NAA/nCr 1 R frontal 1.81 3.19 0.56 1.54 2.52 2.75 1.39 0.48 0.79 2 L Parieto-occipital 2.11 1.29 1.64 0.38 0.89 0.72 0.42 0.29 0.70 3 L corona - radiata 2.24 1.71 1.31 0.79 1.55 1.07 0.69 0.46 0.90 4 R fontal 2.25 1.72 1.31 0.79 1.55 1.07 0.69 0.46 0.90 5 L frontal 1.22 1.05 1.17 0.43 0.70 0.87 0.57 0.41 0.67 6 R frontal 1.58 2.33 0.67 0.81 1.20 1.54 0.76 0.34 0.51 7 R frontal 2.48 1.33 1.86 0.80 1.68 1.34 0.67 0.60 1.26 8 R frontal 1.91 1.27 1.50 0.85 1.53 1.10 0.80 0.66 1.20 9 L frontal 0.86 0.88 0.98 0.92 0.90 1.06 1.05 1.05 1.03 10 R parietal 3.05 3.84 0.79 0.87 1.47 1.23 0.48 0.23 0.38 11 L frontal 0.82 3.42 0.24 0.24 0.48 0.41 0.55 0.07 0.13 12 L frontal 1.46 1.56 0.93 1.18 1.40 1.60 0.96 0.76 0.90 13 R temporal 2.61 1.70 1.54 0.57 0.91 0.66 0.35 0.34 0.53 14 L frontal 2.57 2.25 1.14 0.95 2.27 0.33 0.88 0.42 1.01 15 R temporal 1.90 3.52 0.54 1.96 2.48 2.87 1.30 0.56 0.70 16 L frontal 2.85 2.69 1.06 1.44 2.75 1.72 0.96 0.54 1.02 17 L temporal 2.11 2.71 0.78 0.90 1.33 1.00 0.63 0.33 0.49 18 Pont-med junction 3.87 1.87 2.07 1.09 3.38 1.19 0.87 0.58 1.80 19 L frontal 2.12 2.60 0.82 0.99 2.26 1.86 1.06 0.38 0.87 20 R frontal 2.83 2.63 1.08 4.65 0.78 0.71 0.28 0.18 0.30 21 L frontal 2.51 4.64 0.54 1.23 2.47 2.15 0.99 0.26 0.53 22 L brachium pontis 2.16 2.28 0.94 1.45 1.82 1.30 0.84 0.63 0.80 23 Pons 0.90 1.65 0.55 0.29 0.48 0.37 0.53 0.18 0.29 24 L parietal 2.48 3.29 0.75 0.54 1.08 0.91 0.43 0.16 0.33 25 L frontal 1.09 0.69 1.59 0.22 0.42 0.67 0.38 0.33 0.61
Cho, choline; Cr, creatine; L, left; NAA, N-acetylaspartate; nCho, normal choline; nCr, normal creatinine; nNAA, normal N-acetylaspartate; R, right.
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Lesion Classification
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MRI and MRS Protocol
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Data and Statistical Analysis
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Results
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Table 3
Performance of Non-normalized and Normalized Metabolic Ratios in the Differentiation between Tumor Recurrence and Radiation Change the 25 Patients with Final Diagnosis by Either Histopathology or Imaging Follow-up
Non-normalized Ratios Normalized Ratios Cho/NAA NAA/Cr Cho/Cr Cho/nNAA Cho/nCr Cho/nCho Cr/nCr NAA/nNAA NAA/nCr ROC estimate 0.92 0.85 0.64 0.77 0.71 0.70 0.66 0.62 0.66 ROC 95%CI 0.77–0.99 0.63–0.95 0.45–0.85 0.60–0.93 0.52–0.90 0.46–0.86 0.44-0.84 0.43–0.84 0.4–0.85 % Correctly Classified 88 84 60 60 64 64 52 64 64 Sensitivity 86 93 80 73 73 80 66 86 93 Specificity 90 70 30 40 50 40 30 30 20 (+) Positive Predictive value 93 82 63 65 69 67 59 65 64 (-) Negative Predictive value 82 87 50 50 55 57 37 60 67 Tumor recurrence Mean (SD) 2.81 (0.82) 0.85 (0.40) 2.23 (0.78) 1.01 (0.47) 1.79 (0.85) 1.44 (0.73) 0.81 (0.31) 0.38 (0.20) 0.69 (0.40) Radiation change Mean (SD) 1.39 (0.46) 1.36 (0.33) 1.84 (0.58) 0.66 (0.22) 1.13 (0.41) 0.97 (0.35) 0.64 (0.20) 0.49 (0.22) 0.83 (0.25)P value .0004 ∗ , † .0033 ∗ , † .2441 .02291 ∗ .0759 .0961 .1654 .2918 .1654
Cho, choline; CI, confidence interval; Cr, creatine; L, left; NAA, N-acetylaspartate; nCho, normal choline; nCr, normal creatinine; nNAA, normal N-acetylaspartate; ROC, area under the ROC curve; R, right; ROC, receiver operating characteristic.
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Discussion
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