GRADING OF CEREBRAL GLIOMAS: COMBINED ROLE OF MRI STUDIES OF PERFUSION AND SPECTROSCOPY IN COMPARISON WITH THE STUDY OF CONVENTIONAL MRI TECHNIQUE

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1 Acta Medica Mediterranea, 2012, 28: 157 GRADING OF CEREBRAL GLIOMAS: COMBINED ROLE OF MRI STUDIES OF PERFUSION AND SPECTROSCOPY IN COMPARISON WITH THE STUDY OF CONVENTIONAL MRI TECHNIQUE SALVATORE LO MONTE ABSTRACT [Grading dei gliomi cerebrali: ruolo combinato degli studi di RM di perfusione e di spettroscopia a confronto con lo studio in tecnica RM convenzionale] Aim of the study: The purpose of this study is to evaluate the contribution made by MRI studies of perfusion and spectroscopy in the staging of brain gliomas compared to conventional MRI study. Materials and methods: 32 patients suffering from a verified cerebral glioma (patients undergoing to a neurosurgery operation) were subjected to a MR imaging (CMRI) conventional study, of perfusion (PWI) and of spectroscopy (MRS). Gliomas had been classified according to the features highlighted in MRI conventional study (WHO, 2007): 11 low-grade gliomas (WHO I-II), 21 high-grade gliomas (WHO III-IV). Results: It had been identified differences statistically significant (p <.05): between the values of rcbv, obtained by MR study of perfusion, in tumors compared to normal tissue; in relationships NAA/Cr and Cho/Cr, obtained by a MRI study of spectroscopy in low-grade tumors than those with a high degree. Combining the relations between tumoral rcbv than normal tissue and that one of tumoral NAA/Cr is increased the diagnostic accuracy in neoplastic grading. Conclusions: In the evaluation of cerebral gliomas grading the measurements of the values of rcbv and of the ratios of brain metabolites, either individually or in combination, increase the diagnostic accuracy compared to the results achieved with the only study of conventional MRI. Key words: Gliomas, conventional MRI (CMRI), MR perfusion (PWI), MR spectroscopy (MRS). Received Septemper 10, 2012; Accepted Septemper 15, 2012 Introduction WHO, World Health Organization divides the CNS tumors according to the biological behavior and the degree of malignancy, ranging from I to IV grade: Grade I: The growth is slow but expansive, the biological behavior is benign and neoplasia recurring only when excision is incomplete. Grade II: The growth is expansive and / or infiltrating, the biological behavior is half benign. Grade III: The growth is expansive, infiltrative and sometimes destructive, the biological behavior is relatively malignant. Grade IV: The growth is rapid, invasive, destructive, the biological behavior is highly malignant (1-2). The Gliomas are the most common group of primary brain tumors and include: Astrocytomas Oligodendroglioma Ependymomas The Astrocytomas are divided into: INFILTRATING Diffused astrocytoma (Grade II of IV) Anaplastic astrocytoma (Grade III of IV) Glioblastoma (Grade IV of IV) NON INFILTRATING Juvenile pilocytic astrocytoma (Grade I of IV) The Oligodendrogliomas are considered injuries of WHO grade II of IV. The Anaplastic Oligodendrogliomas are of WHO grade III of IV.

2 158 Lo Monte The Ependymomas have a benign and semi benign biological behavior (WHO grade I-II of IV) (1-2). The technological evolution in recent years has marked many milestones in medical science and it has not certainly saved diagnostic imaging that has always been the medical specialty that, more than any other, is the major beneficiary of the continuous optimization of diagnostic available equipment. Magnetic resonance imaging (MRI) is certainly the imaging technique that has taken the biggest advantage from the technological progress characterizing the past decade. Especially in neuroradiological context, the increasing use of high field equipment (1.5 T or more) characterized by very homogeneous fields, with field gradients very perfomants (times of slew rate ever lower) and dedicated multi-channel coils that allow the achievement of signal/noise ratios and higher levels leding to the clinical application of routine of sequences, relatively new but certainly complex, which until a few years ago were confined only experimentally. It has gone from a purely morphological study (MRI Convectional, CMRI) to an ultrastructural one (functional MRI, fmri, also called by some authors the fourth dimension of diagnostic MRI, 4D MR imaging ) (3-4). The protagonists of this revolution are the imaging techniques of diffusion (diffusion weighted imaging, DWI), diffusion tensor (diffusion tensor imaging, DTI), spectroscopy (magnetic resonance spectroscopy, MRS), perfusion (perfusionweighted imaging, PWI) and cortical activation (blood oxygenation level dependent, BOLD) (5-6). These new techniques are increasingly being used routinely as a supplement to conventional protocols study: Nowadays the MRI morphology is in fact the starting and reference point in the neuroradiological diagnostic pathway. Our experience is based on sequences of functional MR spectroscopy (in PRESS technique-sv sequences PROBE-P) and perfusion (in technical DSCE, EPI-GRE T2*) acquired with a 1.5 T scanner (Signa HDxt GE Healthcare, Milwaukee, WI). The purpose of this study is to evaluate the contribution made by MRI studies of perfusion and spectroscopy in the staging of brain gliomas compared to conventional morphological MRI study. Materials and methods Patient populations 32 patients (18 male, mean age 55 y, 14 females, mean age 58 y) with primary brain glioma underwent conventional MR imaging (CMRI), perfusion (PWI) and spectroscopy (MRS ). The protocol included conventional MRI sequences shown in Table 1 (7). The study was carried out with the perfusion technique through DSCE through weighted sequences EPI-GRE T2* (Tab. 2) (8-9). The study was carried out in spectroscopic technique PRESS-SV using sequences PROBE-P (specifications in Table 3) (10-11). Gliomas were classified according to a lowor high-grade and the features highlighted in the study of conventional MRI. The analysis of the data thus acquired was performed on Advantage Workstation (GE Healthcare, Milwaukee, WI) (12-13). For the study of perfusion were calculated maps of CBV, CBF, MTT and TTP parameters using the Brainstat software. The measurements of perfusion values of rcbv were obtained from the regions of maximum perfusion by normalizing the values between tumor tissue and healthy tissue (13-14). For the study of spectroscopy was used the Functool software to determine the ratios of brain metabolites (Cho/Cr, Cho/NAA, NAA/Cr) using a PRESS sequence with TE-SV equal to 35 ms. (15). Statistic analysis TR TE TI FA b value FSE T2 SAG FLAIR T2 Ax FLAIR T2 Cor EPI-DWI Ax GRE T2* Ax FSE T1 Ax, dopo mdv ev. Ax. Sag. e Cor Table 1: protocol of conventional morphology MRI Study. Legend: TR, pulse repetition time, TE, echo time, TI, inversion time, FA, flip angle (7). The tumor grading determined by the three methods was confirmed at histopathologic evaluation. The statistical evaluation was performed using logistic regression analysis and using ROC curves (Receiver Operating Characteristic) in order to determine what parameters were more accurate (sensitivity, specificity, positive predictive values and negative) for the determination of the grading of gliomas.

3 Grading of cerebral gliomas: combined role of MRI studies Specification sequence of perfusion IP-GRE T2 * that we have used Impulses TR EPI-GRE 2400ms TE 60ms FA 90 Matrice 128x128 FOV Thickness of layer Span 20x20-24x24 5mm 6,5mm N of sections 20 N of acquisitions 48 N of total images 960 Tot. acquisition time Time of injection of the contrast bolus Contrast bolus Rate of infusion Bolus of saline Rate of infusion Size of the catheter lm 36s 30s 01,mmol/Kg 3,5-5ml/s 20ml 3,5-5ml/s 18gauge Figures 1, 2, 3, 4, 5, 6: case of low grade glioma. In order from top to bottom and from left to right: Ax T2 FLAIR, PWI (EPI-GRE T2/T2*) with ni ROI of target lesion ROI and n2 the counter-side, map CBV, CBF, MTT, spectrum obtained PROBE-P sequence with SV (TE: 35) ( ). Table 2: Protocols of functional studies ( ). Specification sequence of PSV-PROBE spectroscopy that we have used Impulses TR TE PRESS 35ms 1500ms NEX 8 Tot. acquisition time 4m 30s Legend: EPI, echo planar imaging, GRE, gradient echo, TR, pulse repetition time, TE, echo time, TI, inversion time, FA, flip angle, NEX, number of exications, FOV, field of view. Table 3: Protocols of functional studies ( ). Results Were statistically significant differences (p <.05) between the value of rcbv in tumors compared to normal tissue and in relations NAA/Cr and Cho/Cr in low-grade tumors than those with a high degree. The most accurate parameter for the classification of gliomas is resulted the value of the 'normalized rcbv. Combining the relations between tumoral rcbv than normal tissue and the tumoral NAA/Cr increased further the diagnostic accuracy in the classification of grading tumors. From the analysis of the ROC curves has shown that a ratio between rcbv tumoral compared to normal upper tissue, 1.9 and a tumoral lower ratio NAA/Cr to 0.44 correspond to a higher probability that it is a high grade neoplasia (sensitivity 100%, specificity 98%).

4 160 Lo Monte Conclusions In the evaluation of the grading of cerebral gliomas, the measures of the values of rcbv and relationships of brain metabolites, both individually and in combination, increase the diagnostic accuracy compared to the results obtained with conventional MRI study alone. The rcbv was the main measure of discrimination between low-grade and high grade gliomas than the conventional morphological imaging. The threshold values can represent a further element for optimizing the treatment as well as to predict post-operative outcome of patients. Figures 7, 8, 9, 10, 11: GBM. In order from to bottom and from left to right: Ax TI ESF after intravenous infusion of contrast medium, CBV and CBF maps (ROI 1 and 4 share of solid lesion, 2 and 3 respectively perilesional homo and contralateral) and the respective curves permeability spectrum obtained with sequence PROBE- P SV (TE: 35) ( ). Figure 12: Cut-off rcbv high/low level: 1.9 (Sensor 100%; spec. 83%). Cut-off value of tumoral rcbv compared to normal tissue 1,9 sensitiveness 100 Confidence interval (95%) (83-100) sensitiveness 83,3 Confidence interval (95%) (51,6-97,8) Table 4: Results of analysis rcbv measures. rcbv Average value high-grade tumors(1) rcbv Average value low-grade (0) 4,57(5,04 GBM e 3,85 GA) 1,72 Table 5: Measures of rcbv values. References 1) Giorgio Cittadini, Giuseppe Cittadini, Francesco Sardanelli: Diagnostica per immagini e radioterapia, VI edizione, capitolo XXXII, Neuroradiologia- Marco Rosa e Roberto Carlo Parodi; ) Robbins e Cotran, Le basi patologiche delle malattie, ottava edizione, capitolo 28, Il sistema nervoso centrale, Matthew P. Frosch-Douglas C. Anthony Umberto De Girolami.; ) Rosen BR, Belliveau JW, Vevea JM, Brady TJ. Perfusion imaging with NMR contrast agents. Magn Reson Med 1990; 14 : ) Leon SP, Folkerth RD, Black P. Microvessel density is a prognostic indicator for patients with astroglial brain tumors. Cancer 1996; 77: ) Folkerth RD. Descriptive analysis and quantification of angiogenesis in human brain tumors. J Neurooncol 2000; 50:

5 Grading of cerebral gliomas: combined role of MRI studies ) Folkerth RD. Histologic measures of angiogenesis in human primary brain tumors. Cancer Treat Res 2004; 117: ) Sharma S, Sharma MC, Gupta DK, Sarkar C.., Angiogenic patterns and their quantitation in highgrade astrocytic tumors. J Neurooncol 2006; 79: ) Maeda M, Itoh S, Kimura H, et al. Tumor vascularity in the brain: evaluation with dynamic susceptibility-contrast MR imaging. Radiology 1993; 189: ) Aronen HJ, Gazit IE, Louis DN, et al. Cerebral blood volume maps of gliomas: comparison with tumor grade and histologic findings. Radiology 1994; 191: ) Bruening R, Kwong KK, Vevea MJ, et al. Echo-planar MR determination of relative cerebral blood volume in human brain tumors: TI versus T2 weighting. AJNR Am J Neuroradiol 1996; 17: ) Donahue KM, Krouwer HG, Rand SD, et al. Utility of simultaneously acquired gradientecho and spin-echo cerebral blood volume and morphology maps in brain tumor patients. Magn Reson Med 2000; 43: ) Aronen HJ, Pardo FS, Kennedy DN, et al. High microvascular blood volume is associated with high glucose uptake and tumor angiogenesis in human gliomas. Clin Cancer Res 2000; 6: ) Sugahara T, Korogi Y, Kochi M, Ushio Y, Takahashi M. Perfusion-sensitive MR imaging of gliomas: comparison between gradient- echo and spin-echo echo-planar imaging techniques. AJNR Am J Neuroradiol 2001; 22: ) Wong EC, Buxton RB, Frank LR. Quantitative perfusion imaging using arterial spin labeling. Neuroimaging Clin N Am 1999; 9(2): ) Yang Y, Frank 1A. Hou L, Ye FQ, McLaughlin AC, Duyn IH. Multislice imaging of quantitative cerebral perfusion with pulsed arterial spin labeling. Magn Reson Med 1998; 39 (5): ) Ye FQ, Pekar 11. lezzard P. Duyn 1. Frank 1A. McLaughlin, AC. Perfusion imaging of the human brain at1.5 Tusing a single-shot EPI spin tagging approach. Magn Reson Med 1996; 36(2): ) Calamante F, Thomas DL, Pel GS, Wiersma J, Turner R., Measuring cerebral blood flow using magnetic resonance imagiflg techniques. J Cereb Blood Flow Metab 1999; 19: ) Lev MH, Kulke SF, Sorensen AG, Boxerman JL, Brady TJ, Rosen BR, Buchbinder BR, Weisskoff RIVI. Contrast-to-noise ratio in functional MRI of relative cerebral blood volume with sprodiamide injection. J MagnReson Imaging 1997; 7: Request reprints from: Dr. SALVATORE LO MONTE Via Messina Marine Palermo (Italy)