High-Grade Cerebral Glioma Characterization: Usefulness of MR Spectroscopy and Perfusion Imaging Associated Evaluation

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1 The Neuroradiology Journal 25: 57-66, High-Grade Cerebral Glioma Characterization: Usefulness of MR Spectroscopy and Perfusion Imaging Associated Evaluation I. Aprile 1, C. Torni 1, P. Fiaschini 1, M. Muti 2 1 Department of Neuroradiology, 2 Department of Oncologic Radiotherapy, S. Maria General Hospital; Terni, Italy Key words: brain tumours, gliomas characterization, magnetic resonance perfusion imaging, magnetic resonance spectroscopy, magnetic resonance comparative studies SUMMARY The aim of our study was to evaluate if both spectroscopy and perfusion magnetic resonance (MR) imaging are necessary to differentiate high grade gliomas from low grade tumour, or if only one of these techniques is sufficient. Sixty-five patients with cerebral glioma were retrospectively evaluated. All patients were studied both with spectroscopy and perfusion imaging. In 43 cases histological examination showed a high grade glioma while a low grade glioma was found in 22 patients. For every patient spectroscopic maximum Cho/NAA ratio and lactate presence was established maximum relative CBV value was evaluated by perfusion MR. Both for Cho/NAA and rcbv threshold values were obtained by means of ROC curves. Then diagnostic sensitivity and specificity for high grade gliomas identification was evaluated for spectroscopic data only (Cho/NAA and lactate presence that was considered a high grade glioma marker), for perfusional data only (rcbv) and finally for both spectroscopic and perfusional data together. Sensitivity was significantly highest evaluating both spectroscopic and perfusional data together (89.7%) in comparison with spectroscopy (74.4%) or perfusion (79.4%) alone. Instead specificity was slightly lower with all data (91.7%) in comparison with spectroscopy (95.8%) and perfusion (95.8%) alone. In conclusion, to characterize high grade gliomas it is more useful to evaluate spectroscopic and perfusional data together with respect only one of these techniques alone. Introduction Even when Magnetic Resonance (MR) is carried out using conventional morphological sequences, also after contrast media administration, there is no certainty regarding the precise detection of high grade gliomas, with respect to low grade tumours. In many cases the diagnosis can be reasonably certain, especially with regard to glioblastomas, even if morphological reports are often uncertain 1,2. Both MR perfusion and spectroscopy provide enough quantitative data to detect the malignancy grade of cerebral gliomas 3-6. Even if perfusion is a minimally invasive application because it uses a double dose of contrast media, spectroscopy involves a long study that requires high levels of patient compliance and considerable availability of time. Therefore, it is important to establish whether both methods are necessary for a correct diagnosis. The purpose of this study was to evaluate whether both techniques - perfusion and spectroscopy - are essential or if the quantitative data of either method give a precise enough detection of high grade gliomas compared to low grade ones. Materials and Methods Patients We performed a retrospective study on 65 patients with past clinical records of cerebral gliomas. They had all undergone a biopsy or a resection operation with a subsequent histological diagnosis of the neoplastic type (Table 57

2 High-Grade Cerebral Glioma Characterization: Usefulness of MR Spectroscopy and Perfusion Imaging Associated Evaluation I. Aprile 1). They consisted of 42 males and 23 females ranging in age from 19 to 89 years (the mean age of the patients was 54.12). Table 1 Distribution of the cases by histological diagnosis. Gangliocytoma 3 Pilocytic astrocytoma 2 Grade I astrocytoma 4 Grade II astrocytoma 10 Grade II oligodendroglioma 3 Grade III astrocytoma 10 Grade III oligodendroglioma 1 Glioblastoma 32 Sequences All examinations were performed on a 1.5 Tesla MR scanner with 23 mt/m gradients (Gyroscan ACS-NT PT 3000, Philips Medical System, Amsterdam, The Netherlands). All patients underwent both a spectroscopic investigation and a cerebral perfusion evaluation. In addition, a study of the brain was performed on all patients with a conventional technique of fast spin echo (FSE) images and fluid attenuated inversion recovery (FLAIR) T2-weighted images, spin echo (SE) T1-weighted images with and without contrast agent. Finally, two fast sagittal and coronal FSE T2-weighted images were also performed on those patients who had undergone spectroscopy for a better definition of the plane of interest. Spectroscopic study was carried out on most patients (50 cases) using chemical shift imaging (CSI) and acquiring a localized scan at the lesion s equator. The remaining 15 patients underwent investigation with single voxel acquisition as the lesions were localized in areas where multi-voxel acquisition had proved difficult (cerebellum, brainstem or in supratentorial cortico-subcortical site). In any case a voxel of a minimum mm size was acquired, making sure that it only contained the neoplastic tissue in order to avoid the partial volume effect. For each patient the following sequences were acquired: Spin echo (SE) axial T1-weighted images (TR 560 ms, TE 14 ms, matrix, 230 mm field of view (FOV), two excitations (NEX), 5 mm scan thickness). Fast spin-echo (FSE) axial proton density and T2-weighted images (TR 2000 ms, TE 8.8 and 110 ms, matrix, 230 mm FOV, 2 NEX, 5 mm scan thickness, 16 ETL). Fluid attenuated inversion recovery (FLAIR) axial T2-weighted images (TR 6000 ms, TE 100 ms, matrix, 230 mm FOV, 2 NEX, 5 mm scan thickness, 21 ETL). PRESS sequences spectroscopic CSI with water suppression and acquisition of images with matrix, TR 2000 ms, TE 288 ms, Hz 1000 spectral bandwidth. Single voxel sequences were acquired with the same technical parameters. Post contrast 3D PRESTO axial images (GRE-EPI T2*) for the study of cerebral perfusion (TR 20 ms, TE 29 ms, FA 8, matrix, 230 mm FOV, 1 NEX) with 40 dynamic phases and a time resolution of 1.67 s. Images acquired post-contrast with axial, coronal and sagittal scans: SE T1-weighted image technique (TR 560 ms, TE 14 ms, matrix, 230 mm FOV, 2 NEX, 5 mm scan thickness). The contrast medium (Gadoteridol, Pro- Hance, Bracco, Milan, Italy) was injected via intravenous injection with an 18 Gauge needle through an automatic injector at a 5 ml/s flow rate. In all patients the contrast media dose was 0.25 mmol/kg (a bolus of 0.2 mmol/kg preceded by a pre-bolus of 0.05 mmol/kg). Both spectroscopic and perfusion images were subsequently processed and converted in coloured maps on a dedicated workstation (Philips Easy Vision). Quantitative Analysis Perfusion and spectroscopy imaging quantitative data were analysed blindly by two experienced neuroradiologists using a dedicated post-processing workstation. Perfusion CBV maps were evaluated by detecting the normalised maximum value of the lesion in relation to the contralateral normal white matter value (rcbv). With reference to spectroscopy, the maximum Cho/NAA ratio of a voxel selected in the solid tumour area was calculated. In addition, the presence of lactate peak was also taken into account. Lastly, we estimated diagnostic sensitivity and specificity of the techniques aiming at the identification of high grade (grade III and IV) gliomas in comparison to low malignity grade lesions (grade I and II). Both for perfusion and spectroscopy data a threshold value was established by means of ROC (Receiver Operating Characteristic) curves (Figure 1). Quantitative rcbv analysis was carried out adopting a threshold value of 3, whereas a threshold value of 1.85 was adopted 58

3 The Neuroradiology Journal 25: 57-66, 2012 A B Figure 1 ROC curves of rcbv (A) and Cho/NAA ratio (B). for Cho/NAA analysis. Above these values the lesion was considered at a high grade. Lactate peak presence was considered a marker for high grade lesions. In the evaluations of more associated parameters (Cho/NAA + lactate presence; Cho/NAA + lactate presence + rcbv) the discrimination analysis method 7 was used to evaluate the ROC curve of more parameters associated with one another. Lastly, sensitivity and specificity values of the parameters associated in couples and triples were calculated in correspondence to the optimized threshold of that ROC curve. The discrimination analysis allows the definition of the discrimination function, that is the relative weight of every variable in the combination of couples or triples. It also allows the discrimination threshold, that is the discrimination function value beyond which the result of each case is considered to be positive. In our case the result was for the associated evaluation of rcbv, Cho/NAA and lactate presence, whereas it was for the associated evaluation of Cho/NAA and lactate presence. Therefore, we first evaluated sensitivity and specificity values obtained from the analysis of perfusion imaging (rcbv) data. Secondly we evaluated those values relating to spectroscopy data (as a couple: Cho/NAA association + lactate presence) and lastly those relating to the combined perfusion and spectroscopy data sets (Cho/NAA + lactate presence + rcbv). The data evaluation was based on sensitivity and specificity terms. Results The perfusional and spectroscopic data of all patients are reported in Table 2. Grade I and II gliomas tended to have low rcbv and Cho/ NAA values (Figures 2 and 3) while high grade ones showed higher rcbv and Cho/NAA values with, in some cases, lipids peak detection (Figure 4). Diagnostic sensitivity and specificity with regard to the evaluation of data referring to perfusion (rcbv), those referring to spectroscopy (Cho/NAA in association with the evaluation of lactate presence) and lastly to the evaluation of all the data analysed together (rcbv in association with evaluation of Cho/NAA rcbv and lactate presence) are reported in Table 3. The evaluation of rcbv with perfusion imaging was highly specific: only one low grade tumour presented values higher than threshold value 3. Even the evaluation of spectroscopy parameters provided higher specificity values (Table 3). The evaluation of all available data in joint association (perfusion + spectroscopy) noticeably increased the diagnostic sensitivity and caused a slight reduction in specificity (Table 3). 59

4 High-Grade Cerebral Glioma Characterization: Usefulness of MR Spectroscopy and Perfusion Imaging Associated Evaluation I. Aprile Table 2 All patients perfusional and spectroscopic data; rcbv values below 2 were considered normal. Patient Histology rcbv Cho/NAA Lip 1 gangliocytoma normal gangliocytoma normal gangliocytoma normal pilocytic astrocytoma pilocytic astrocytoma grade I astrocytoma normal grade I astrocytoma normal grade I astrocytoma normal grade I astrocytoma normal grade II astrocytoma normal grade II astrocytoma normal grade II astrocytoma normal grade II astrocytoma normal grade II astrocytoma grade II astrocytoma normal grade II astrocytoma normal grade II astrocytoma normal grade II astrocytoma grade II astrocytoma normal grade II oligodendroglioma normal grade II oligodendroglioma normal grade II oligodendroglioma grade III astrocytoma grade III astrocytoma grade III astrocytoma grade III astrocytoma normal grade III astrocytoma normal grade III astrocytoma grade III astrocytoma normal grade III astrocytoma grade III astrocytoma normal grade III astrocytoma grade III oligodendroglioma glioblastoma glioblastoma glioblastoma glioblastoma glioblastoma glioblastoma normal glioblastoma glioblastoma normal glioblastoma glioblastoma glioblastoma glioblastoma glioblastoma glioblastoma glioblastoma glioblastoma normal glioblastoma glioblastoma glioblastoma glioblastoma glioblastoma glioblastoma glioblastoma glioblastoma glioblastoma glioblastoma glioblastoma glioblastoma glioblastoma glioblastoma glioblastoma glioblastoma

5 The Neuroradiology Journal 25: 57-66, 2012 Table 3 MR perfusion and spectroscopy diagnostic sensibility and specificity in the detection of high grade gliomas. rcbv Cho/NAA+Lac Cho/NAA+Lac+rCBV Sensitivity 79.4% 74.4% 89.7% Specificity 95.8% 95.8% 91.7% Discussion It is necessary to identify the lesion type in patients who have undergone MR for the detection of suspected cerebral tumour. It would be equally important to consider the presence of tumoral tissue infiltrating beyond the enhancement area to be able to differentiate metastases from gliomas. As a final step, it would be necessary to define the malignancy grade by differentiating low grade gliomas (I and II grade) from those at a high grade (III and IV grade) 1-3,8,9. In some cases the morphological study itself, with and without contrast, accomplishes differential diagnoses between low and high grade tumours. Glioblastomas often have typical morphologic characteristics (corpus callosum involvement, conspicuous vasogenic edema, necrotic aspect), different from low grade astrocytic gliomas. However, in many cases the differential diagnosis is not easy, especially among gliomas of II and III grade with low or no enhancement after contrast 1-3. Gliomas characterisation is important firstly because it precisely assesses the risk/benefit relationship of the surgical operation. Secondly, it is generally known that, in some cases, the histological examination can underestimate the tumour malignancy grade in the case of biopsy or partial ablation. In this case both perfusion and spectroscopy imaging can be useful to detect the lesion malignancy grade correctly, in addition to identifying accurately the most malignant part of the lesion for a proper biopsy sampling. Perfusion imaging provides brain vascular maps that identify cerebral tissues on the basis of several hemodynamic parameters. The parameter that most effectively relates to histological characteristics of cerebral gliomas is CBV that is proportional to the volume of microvessels supplying an area of interest In this case, therefore, the malignancy grade is proportional to the density of the lesion s microvessels. Spectroscopy, on the other hand, detects the concentration of some metabolites, always in specific lesion areas. The glioma malignancy grade is directly proportional to the choline peak (which is produced during the synthesis of biological membranes and is, therefore, a marker of replicating cells) and is inversely proportional to that of N-acetyl aspartate which, instead, is a marker of normal neurons For this reason the glioma malignancy grade is directly proportional to the Cho/NAA ratio. Furthermore, spectroscopy detects the presence of lactate as a necrosis marker. When the lactate peak is present it characterizes high grade gliomas, even if the report can be unspecified because necrosis can also be present in non-neoplastic lesions Diffusion is the third advanced MR technique that can be employed to characterize gliomas. With this technique the MR signal depends on water molecule diffusivity and it is, therefore, inversely proportional to cell density. With this reasoning some authors tried to identify high grade gliomas with respect to those at a low grade, where high grade lesions are characterized by a lower diffusivity 21. More recent studies, however, have not confirmed the initial findings and there is often an excessive overlap between the two tumour groups with consequent impossibility of definitite detection 22. Therefore, the advanced MR techniques that currently provide reliable quantitative data for gliomas characterization are perfusion and spectroscopy Yang et al. 27 evaluated 17 cerebral gliomas with diffusion, perfusion and spectroscopy to detect their malignancy grade. They only assessed the average of the numeric data resulting from the three techniques in the analysis of the two types of tumours. Important differences both with reference to apparent diffusion coefficient (ADC) as well as to rcbv and Cho/ NAA relationship were spotted. They are, however, data of little importance due to the low number of test cases. In 2003 Law et al. 28 published a paper on the characterization of high grade gliomas. This study was accomplished with a high number of cases (160 cases) and represents the first important reference point in the evaluation of the diagnostic indications of perfusion and spectroscopy. The authors evaluated the diagnostic sensitivity and specificity of both perfusion (rcbv) and spectroscopy (Cho/NAA) separately, as 61

6 High-Grade Cerebral Glioma Characterization: Usefulness of MR Spectroscopy and Perfusion Imaging Associated Evaluation I. Aprile A B C D Figure 2 Cerebellar low grade astrocytoma. FLAIR image (A) and post-contrast sequence (B) without tumour enhancement. In CBV maps (C) the lesion is iso-hypoperfused in comparison to controlateral cerebellar lobe, while spectroscopy (D) shows high choline and low NAA peak s height. 62

7 The Neuroradiology Journal 25: 57-66, 2012 A B C D Figure 3 Pilocytic astrocytoma. T2-weighted (A) and post-contrast image (B) with depiction of tumour solid tissues. Medially there is a part of the lesion hyperperfused (arrow) in CBV maps (C) and also in spectroscopic imaging (D) a voxel with high Cho peak was showed (arrow). Both in morphologic and in perfusional and spectroscopic images this low grade tumour mimic high grade aspects. 63

8 High-Grade Cerebral Glioma Characterization: Usefulness of MR Spectroscopy and Perfusion Imaging Associated Evaluation I. Aprile A B C D Figure 4 High grade (III) cerebellar astrocytoma. T2-weighted (A) and post-contrast image (B) with intense lesion s enhancement. In CBV maps (C) the tumour is isoperfused to controlateral lobe, while spectroscopy (D) shows Cho peak increasing and NAA one decreasing with respect to creatine. 64

9 The Neuroradiology Journal 25: 57-66, 2012 well as of both methods together. The results are similar to ours with reference to spectroscopy and the associated evaluation of perfusion and spectroscopy. With reference to perfusion evaluation we recorded high specificity (95.8%) and less sensitivity (79.4%), whereas Law et al. 28 obtained high sensitivity (95%) and low specificity (57.5%) using, however, a limit value lower than ours (1.75 vs 3). Another difference from our study is that they did not evaluate lactate as a marker of high malignancy grade gliomas. A study carried out in analysed 44 gliomas with a 3 Tesla device. Again, important differences between gliomas at low and high grade were detected using only spectroscopy (Cho/NAA), even if in this study did not calculate diagnostic sensitivity and specificity. Another interesting work 30 with a high number of cases (150 cases) spotted a statistically important difference between gliomas at low and high grade both with perfusion (rcbv) and with spectroscopy (NAA/Cr and Cho/Cr), but also in this case diagnostic sensitivity and specificity had not been considered. A recent study by Fayed et al. 31 evaluated the malignity level of 24 tumours both with spectroscopy (Cho/Cr) and with perfusion (rcbv) obtaining good results in relation to both diagnostic sensitivity and specificity. In the range of cases, metastases were also included in addition to gliomas. Batra et al. 32 evaluated only gliomas with little enhancement after contrast, therefore excluding glioblastomas that generally undergo strong enhancement. The number of cases was low (22 cases), but the work is interesting because it included only gliomas of II and III grade that are the most difficult to differentiate with conventional morphological sequences, even using a contrast agent. Also in this case they found statistically significant differences between the two types of tumour both with perfusion (rcbv) and with spectroscopy (Cho/Cr). Finally, we wish to comment on oligodendrogliomas. It is well-known that low grade oligodendrogliomas tend to have rcbv values similar to III grade oligodendrogliomas 33. For this reason, unlike astrocytomas, perfusion cannot be used to detect malignant tumours from those with a low malignancy. However, other studies have contradicted this statement and have, in fact, emphasized that there is a statistically significant rcbv difference between grade II oligodendrogliomas and anaplastic oligodendrogliomas 34. For this reason study data resulting from general range of cases including all types of gliomas could not be very specific for the presence of oligodendrogliomas. On the basis of some literature articles, oligodendrogliomas could have vascularization characteristics, assessed with perfusion RM, different from astrocytomas. In our study we evaluated three low grade oligodendrogliomas that in all cases presented maximum rcbv values lower than the 3 limit value and hence were correctly characterized. Therefore, in our range of cases perfusion imaging diagnostic specificity was not reduced by the presence of II grade oligodendrogliomas, as they presented vascularization characteristics similar to those of low grade astrocytomas. Our work analysed results from a range of cases of 65 gliomas, all being studied with both techniques. Unlike other similar studies, our study also evaluated the presence of lactate as a marker of malignant gliomas. In this way we obtained very good diagnostic sensitivity values mainly concerning data evaluation of spectroscopy and perfusion in association (89.7%). On the contrary, when we isolated perfusion data from those resulting from spectroscopy, in both cases we obtained good specificity values (95.8%), with less sensitivity (Table 2). In our range of cases we preferred to consider all gliomas, including glioblastomas (IV grade), even though it would been more interesting to assess only gliomas of I, II and III grade. However, if we had excluded IV grade gliomas, the range of cases would have been too limited (33 cases). In conclusion, perfusion and spectroscopy are both useful to detect the malignancy grade of gliomas, and both techniques should be employed. Perfusion and spectroscopy, when individually evaluated, have got good specificity (Table 3), but joint evaluation of both techniques has clearly improved diagnostic sensitivity by slightly reducing specificity. 65

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