The Efficacy and Value of Proton MR Spectroscopy In Evaluating the Brain Tumours

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1 The New Journal of Medicine 2010;27: Original article The Efficacy and Value of Proton MR Spectroscopy In Evaluating the Brain Tumours Hasan AYDIN 1, Nilay AYDIN OKTAY 1, Serdar S PAH O LU 1, Elif ALTIN 1, Baki HEK MO LU 1 1 D skap Y ld r m Beyazit Research Hospital Department of Radiology, ANKARA ÖZET Proton MR spektroskopinin beyin tümörlerinin de erlendirilmesindeki yarar ve de eri Amac m z beyin tümörlerini s n fland rmada Proton MR Spektroskopinin (H-MRS) yarar n saptamakt r. Multivoksel imajlar (MV-MRS) intrakranial kitle lezyonu olan 33 hastada Philips 1.5 T Achieva MR ünitesinde al nd. Beyin tümörleri dü ük-yüksek grade li glial neoplazmlar, menengiomlar ve metastazlar olarak s n fland r ld. Cho/ NAA, Cho/Cr, Cho/MI oranlar tüm tümör gruplar için hesapland ve bu metabolit oranlar na göre istatiksel analiz yap ld. statiksel analiz ile gruplar aras ndaki fark saptanmaya ve s n fland r lmaya çal ld. Bu üç oran n hepsi GBM grubunda yüksekti. Cho/NAA- Cho/MI oranlar dü ük gradeli neoplazmlarda dü ük, Cho/Cr oran ise menegiomlarda dü üktü. Metastazlarda Cho rezonans nda güçlü elevasyon mevcut olup, ayn zamanda di er üç oran da yüksek olarak saptanm t r. Sonuç olarak MV- MRS de i ik tiplerde beyin tümörlerinin saptanmas nda ve glial neoplazmlar n evrelenmesinde %97 sensitivite ve %87,9 spesifisite ile önemli katk lar sa layabilmektedir. Anahtar Kelimeler : Magnetik Rezonans Spektroskopi, beyin tümörleri, glial neoplazmlar ABSTRACT Our aim was to evaluate the usefulness of proton MR spectroscopy (H-MRS) in categorizing the brain tumours. Multivoxel imaging (MV-MRS) was performed to 33 patients with intra-cranial mass lesions at Philips 1.5 T Achieva MR unit. The brain tumours are classified to; low-high grade glial neoplasms, menengiomas and metastasis. Cho/NAA, Cho/Cr, Cho/MI ratios are calculated for all tumour groups and according to these metabolite ratios by using statistical analysis. We tried to show the differences between groups and tried to categorize them. All three ratios are highest in GBM group, Cho/NAA- Cho/MI ratios are lowest in low-grade gliomas, Cho/Cr ratio is lowest in menengiomas. Metastasis also have strong elevation of Cho resonances and all three ratios are also high in this group. As a conclusion, MV-MRS is a useful tool, provides important informations for the analysis of the brain tumours of different types and for grading glial neoplasms with 97% sensitivity and 87.9% specificity. Key Words : Magnetic Resonance Spectroscopy, brain tumours, glial neoplasms INTRODUCTION Proton magnetic resonance spectroscopy [H MRS), a non-invasive technique, has been helpful in understanding the pathophysiology of different disease processes 1,2. It has been used to observe metabolite changes in different intracranial abnormalities such as tumours, stroke, tuberculomas, multipl sclerosis and metabolic-inherited brain disorders, epilepsy and traumatic injuries 1-3. H- MRS of the human brain assessment has been possible for at least 20 years but its clinical use as a routine part of the initial diagnostic examination for intracranial masses has been slow to develop as it is hard to interpret the images and the spectra of the MRS for neuroradiologists 2. Spectroscopic studies on brain tumours have attempted to characterize the different histologic types and predict the degree of malignancy of masses 1-3. HMRS gives completely different information related to neuronal integrity, cell proliferation or degradation, energy metabolism and necrotic transformation of brain or tumour tissues 2-6. Particularly HMRS is added to routine Brain MRI in order to solve diagnostic problems such as differentiation of neoplastic and nonneoplastic lesions, low and high grade tumours, ischemia and low grade gliomas or separating metastases from primary brain tumours and abcesses 1-3,6. Various spectroscopic methods, including single-voxel (SV-MRS) and multivoxel spectroscopic imaging (MV-MRS) have been used to study tumour biology, grade gliomas, plan treatment and etc 2,3,6,7. In our study, we preferred MV-MRS for all patients to assess the intracranial space occupying lesions. The aim of this study is to establish the clinical application of HMRS in brain tumours with addition to cerebral MRI, distinguish among the types of cerebral neoplasms according to brain metabolites and assessing its reliability in the analysis of cranial masses. MATERIAL AND METHODS 33 patients with intracranial mass lesions suggested by cranial MRI were selected for 37

2 H. Aydın et al. The New Journal of Medicine 2010;27: proton-mr-spectroscopy; 17 male, 16 female with age range 9-85, mean age Informed consent was obtained from all the patients before the study. We have a variety of intracranial tumours that includes high grade glial tumours (Glioblastome multiforme-anaplastic astrocytomas), low-grade glial tumours (Gliomatozis serebriserebelli, gangliogliomas), menengiomas and metastasis in one case. Except for one metastasis and two menengiomas, diagnosis of all the other neoplasms were confirmed pathologically either by biopsy or open-surgery. A patient wits metastazis is still suffering from a known primary neoplasm and the diagnosis of extra-axial menengiomas are based upon the MRI-laboratory and clinical findings. All the MRI and spectroscopic analysis are carried out with a 1.5 T Philips Achieva 16 channel Medical systems-netherland scanner by using a standart head and neck array coil. The MV-MRS was performed by using point-resolved spectroscopy (PRESS) with a volume of interest 5-10 cm 3 depending upon the tumour size. We have positioned the possible voxel within the solid tumoral area avoiding areas of cysts, normal appearing brain parenchyma, scalp or skull base contamination 6-8. Automatic shimming of the linear x, y, z channels was used to optimize field homogeneity, water resonance and water suppression pulse was optimized. Proton spectra were recorded in axial plane with TR;1500 MS, TE;26 and 144 ms, FOV; 24x24 cm, cm section thickness, 256x256 matrix and 24x24 phase encoding. Spectral analysis and postprocessing was carried out by using a software of Philips 8 ch. Achieva Netherland work-shop. Data Analysis Time domain data were multiplied with a Gaussian function of 90 (Centre 0, halfwidth 256 ms), 2D Fourier transformed phase and base-line corrected, quantified by means of frequency domain curve fitting with the assumption of a Gaussian line shape by using the Philips soft-ware ppm is analysed and metabolite signal peaks are centred by as follows; N-Acetyl aspartate (NAA) at 2 ppm, creatine (Cr) at ppm, Phosphocreatine (Cr2) at ppm, Choline (Cho) at 3.2 ppm, lipids (Lip) at ppm, lactate(lac) at ppm, glutamate and glutamine (Glx) at 2.45 ppm, glycine and or myo-inositol (Gly-MI) at ppm 3,4,6,7. Two doublets inverted owing to phase modulation due to J coupling were defined, Lac at 1.4 ppm and alanine (Ala) at 1.5 ppm. At TE 144 ms, Lac can be differentiated from lipids with a narrow bandwidth comparable with the peaks of other metabolites and shows an inverted J-coupled double peak at 1.4 ppm 3,4,6. Water resonance frequency and/or Cr peak were chosen as reference resonances for correction of possible shifting in the frequency domain. Tumour metabolite signal intensities were quantified, normalized by expressing the peak area intensities of the metabolites especially NAA-Cho-Cr as ratios of normal brain parenchymal values to intratumoral metabolites (NAA\Cr, NAA\Cho), Lip and Lac which are not detectable in normal brain, were normalized using the Cr of the contralateral reference spectrum as an internal standart 3,6. All analyses were performed by using a software program (SPSS for Windows, SPSS, Chicago- Illinois). Significance of differences between various cranial mass groups for brain metabolites and metabolite ratios was tested with one-tailed parametric variance analysis test, the sensitivity and the specificity of HMRS between tumour types and space occupying cranial masses was tested by chi-square test-opposite table. Differences of p<0.05 were considered to be statistically significant. RESULTS Datas of 33 patients: Their age were between 9-85 (mean 44). Tumour localizations were right or left frontal, parietal, frontoparietal, temporal, temporooccipital or corpus callosum. Cho/NAA ratios were between , Cho/Cr ratios were between and Cho/MI ratios were between The tumours with regard to MRI results were high grade, moderate glial tm, low grade, menengioma. 30 patients underwent biopsy, as mentioned above metastasis and 2 menengiomas had no histopathologic confirmation. The other histopathologic confirmations were low grade astrositoma, anaplastic astrositoma, glioblastoma multiforme, gliomatosis cerebelly and oligodendroglioma. The spectra from the contralateral brain or from the healthy volunteers revealed a consistent pattern of the four major peaks of NAA, Cr, Cho and MI, no lactate or lipid resonances were visible in these cases. The average Cho/NAA, Cho/Cr, Cho/MI ratios were , , According to H-MRS, we had 7 low-grade (Grade 1-2) gliomas, all low grade gliomas showed increased Cho and reduced NAA resonances, as an average Cho/NAA ratio; (Table 1, Graphic 1). With parametrical variance analysis test for Cho/NAA ratio there was no statistically difference between low-grade tumours among the other brain neoplasms (p>0.05). All low-grade gliomas in this study showed increased Cho and moderately decreased Cr, as an average Cho/Cr 38

3 The New Journal of Medicine 2010;27: H. Aydın et al. ratio (Table 1, Graphic 2). According to Cho/Cr ratio by using one-tailed parametrical variance analysis test, there was a significant statistically difference between low-grade tumours and the other cranial mass groups (p<0.05). As mentioned above, all low-grade glial tumours showed increased Cho and at the same time moderately increased MI, as an average Cho/MI ratio (Table 1, Graphic 3) (Figure 1). Cho/MI ratio in low-grade group is slightly elevated because MI is only present in glial cells and its peak shows the astrogliosis. With respect to Cho/MI ratio, there was no statistically difference between low-grade tumours and the other cranial mass lesions (p>0.05) via the variance parametrical analysis test. Table 1. The Cho/NAA, Cho/Cre and Cho/MI ratios in low grade, moderate and high grade, GBM, menengioma and metastasis Measurement Cho/NAA Ratio Cho/Cre Ratio Cho/MI Ratio Tm Groups Patient Number Mean Std. Deviation Low grade 7 1,54 0,31 Moderate 2 1,92 0,02 High grade 15 3,31 3,04 GBM 5 4,39 1,54 Menengioma 2 1,96 0,33 Metastasis 1 2,88 - Total 32 2,91 2,34 Low grade 7 1,85 0,58 Modarate 2 2,45 0,40 High grade 15 2,24 0,99 GBM 5 4,39 1,58 Menengioma 2 1,39 0,41 Metastasis 1 2,42. Total 32 2,46 1,27 Low grade 7 2,20 1,16 Moderate 2 3,32 0,24 High grade 15 3,46 3,19 GBM 5 6,12 5,37 Menengioma 2 3,46 2,59 Metastasis 1 3,96. Total 32 3,61 3,20 We had 2 moderate gliomas (Grade 2-3) with respect to MV-MRS results, in both cases of moderate-graded gliomas, they showed increased Cho and reduced NAA resonances, as an average Cho/NAA ratio; (Table 1, Graphic 1), increased Cho and decreased Cr, as an average Cho/Cr ratio; (Table 1, graphic 2), increased Cho, normal or minimal decreased MI, as an average Cho/MI ratio (Table 1, Graphic 3). According to Cho/NAA and Cho/MI ratios, there was no statistically difference between moderate grade glial tumours and the other brain neoplasm groups. According to Cho/Cr ratio by using one-tailed parametrical variance analysis test, there was a significant statistically difference between moderate grade gliomas and the other cranial mass groups (p<0.05). Graphic 1. Graphical analysis of Cho/NAA ratio in brain tumoral groups We had 15 high-grade glial neoplasms (Grade 3-4 astrocytomas and anaplastic astrocytomas), they showed increased Cho and highly reduced NAA resonances, as an average Cho/NAA ratio (Table 1, Graphic 1), increased Cho and moderately decreased Cr, as an average Cho/Cr ratio (Table 1, Graphic 2), increased Cho, decreased MI, as an average Cho/MI ratio; (Table 1, graphic 3) (Figure 2). Figure 1. The spectra from the low-grade glial tumours showed increased Cho According to Cho/NAA and Cho/MI ratios, there was no statistically difference between high grade glial tumours and the other brain tumour groups. According to Cho/Cr ratio by using parametrical variance analysis test, there was a significant statistically difference between high grade astrocytomas and the other cranial space occupying mass lesions (p<0.05). In this study there were 5 glioblastome multiforme (GBM) cases (Grade 4 and more), they showed highly increased Cho and highly reduced NAA resonances, as an average Cho/NAA ratio (Table 1, Graphic 1), highly increased 39

4 H. Aydın et al. The New Journal of Medicine 2010;27: Cho and severe decreased Cr, as an average Cho/Cr ratio (Table 1, Graphic 2), highly increased Cho, highly decreased MI, as an average Cho/MI ratio (Table 1, Graphic 3), (Figure 3). According to Cho/NAA and Cho/MI ratios, there was no statistically difference between GBM group and the other cranial brain tumour groups (p>0.05), according to Cho/Cr ratio by using a tailed parametrical variance analysis test, there was a significant statistically difference between GBM and the other cranial neoplasm groups (p<0.05). We have only one metastasis case in this study, it showed increased Cho and highly reduced NAA resonances, as Cho/NAA ratio 2.88 (Table 1, Graphic 1), increased Cho and decreased Cr, as Cho/Cr ratio 2.42 (Table 1, Graphic 2), increased Cho, highly decreased MI, as Cho/MI ratio; 3.96 (Table 1, Graphic 3). According to Cho/NAA and Cho/MI ratios, there was no statistically difference between metastasis group and the other brain tumour groups (p>0.05). According to Cho/Cr ratio by using parametrical variance analysis test, there was a significant statistically difference between metastasis and the other brain neoplasms (p<0.05). Graphic 2. Graphical analysis of Cho/Cre ratio in brain tumoral groups In this paper, we have 2 menengiomas; Extraaxial cranial tumour, they showed increased Cho and reduced NAA resonances, as an average Cho/NAA ratio (Table 1, Graphic 1), increased Cho and slightly decreased Cr, as an average Cho/Cr ratio (Table 1, Graphic 2), increased Cho, decreased MI, as an average Cho/MI ratio (Table 1, Graphic 3). According to Cho/NAA and Cho/MI ratios, there was no statistically difference between menengiomas and the other brain mass lesions. According to Cho/Cr ratio by using parametrical variance analysis test, there was a significant statistically difference between menengiomas and all the other cranial mass groups (p<0.05). Figure 2. The spectra from high-grade glial neoplasms (Grade 3-4 astrocytomas and anaplastic astrocytomas) showed increased Cho and highly reduced NAA resonances Figure 3. The spectra from Glioblastome multiforme (GBM) cases (Grade 4 and more) showed highly increased Cho and highly reduced NAA resonances Graphic 3. Graphical analysis of Cho/MI ratio in brain tumoral groups All the ratios Cho/NAA-Cho/Cr-Cho/MI are highest in GBM group, and at same time highest choline is observed in this group. In low grade glial tumour group the Cho/NAA, Cho/MI ratios are the lowest. Menengiomas have the lowest value for Cho/Cr ratios. In all GMB cases, metas-tasis and in many of the high-grade glial tumours, we had highly elevated lactat and lipid peaks, that is strongly correlated with malignancy 1,3,6. In low grade glial tumours, we have elevated Glx peak additionally. In one patient, MV-MRS showed no mass effect 40

5 The New Journal of Medicine 2010;27: H. Aydın et al. regarding to metabolites but the histo-pathological diagnosis was anaplastic astrocytoma. Except for this case H-MRS datas proved all the mass lesions (32/33). In 7 cases, MV-MRS presented grading faults in glial tumours with regard to biopsy and surgery yields. The sensitivity of MV-MRS is 97% and the specificity of HMRS was 87.9%, calculated by chi-square test opposite table. DISCUSSION H-MRS has a potential for accurate diagnosis without surgical tissue sampling, also serves a significant role before neurosurgical planning. It identifies the extent of tumoral infiltration and provides a more optimal and safe resection 3,6,8,9. MV-MRS also can also help to identify the tumour type and grade, grading of brain tumour and histopathologic classification of brain lesions has important implications for clinical management 6,9. MV-MRS also provides wider anatomical coverage and better spatial resolution to take into account lesion heterogeneity 7,8. In MV-MRS, the resonances of brain metabolites; Cho-Cr-NAA-Lac- Lip-MI-Glx-Ala are briefly analysed for correct diagnosis of brain disorders especially tumours. NAA is a marker of functional neurons and decreases in all kinds of brain damages whether infiltrative-degenerative or destructive processes 1-3,6-11. Cho resonances originate mainly from intermediates of phospholipid metabolism such as phosphocholine and glycerophosphocholine which play an important role in the structure and function of cell membranes-cellular proliferation 1-3,9-11. Cho increases in all tumours due to increased cell membrane synthesis and turnover, reflect the abnormal processes like proliferating tumoral cells 2,3,7,9-11. Creatine-Phosphocreatine are ubiquitous metabolites of ATP/ADP cycle, therefore Cr is considered to be an indicator of energy metabolism, brain tumours generally show decreased Cr levels 3,10,11. Lac is produced under conditions of anaerobic glycolysis, indicates a hypoxic condition as well as glucose consumption, it is more prominent in high grade tumours and GBM 2,3,7,10,11. Lipid usually correlate to the extent of tissue necrosis and generally seen in high-grade neoplasms and metastasis, only observed in short TE spectra because of its short relaxation time. Lip-Lac metabolites routinely were undetectable in healthy brain 2,3,10,11. Glx is an excitatory and inhibitory neurotransmitter. MI is a sugar present in only glial cells and increases in cases of glial activation or proliferation 2,10,11. Ala peak is generally shown in menengiomas and involves in partial oxidation 10,11, but in our cases we had no more precise Ala peaks. In the literature, there were several former studies trying to analyze the efficacy of MV-MRS in brain tumours and most of the authors used Cho/NAA-Cho/Cr ratios to distinguish tumours from non-neoplastic disorders 3,6,9,12. There was a general concordance in previous studies that Cho was the best index for grading cerebral gliomas and its peak obviously increases from low-grade to GBM groups 3,6,9,12,13. In our study we had also similar results, in GBM group the Cho peak was extremely high. The second best discriminator between low-grade glial tumours and malignant gliomas was the amount of lipids while changes of Cr and NAA peaks were less helpful in analyzing the potential malignancy of cerebral tumours 3,6,12. Besides high-grade gliomas, metastases were also shown to have extremely increased Cho and significantly reduced NAA and Cr 3,6,7,13. Although we had only one metastasis case, we had also similar results as shown in the literature. Cho/NAA-Cho/Cr ratios were the valuable tools in determining the malignancy of cranial neoplasms and used by most of the authors 1,3,6,7,9,12,13. In most of the former studies, both ratios increased from low-grade to high-grade gliomas and also extremely higher in metastases and primitive neuroectodermal tumours (PNET) 1,3,6,12,13. We had no PNET type tumour, but both ratios were similarly increased from low-high grade glial tumours and also significantly increased in metastases. In our study, Cho/Cr ratio is the lowest in menengiomas. In the recent studies, most of the authors found out the precise Ala peak in menengiomas-relative decrease of Cr, far more than glial tumours. Increase of Cho resonances not more than GBM or anaplastic astrocytomas and metastasis, generally lactat and lipid peaks were un-remarkable 1,3,6,8,12,13. In our menengioma group, we had a strong elevation of Cho resonance but in contrary to literature, there was no precise Cr decrease and Cho/Cr ratio was the lowest in this group. We didn t see any Ala resonance in both menengioma cases. We tried to make another variation by using Cho/MI ratio in order to categorize tumours according to their potential malignancy which was not frequently seen in the past studies. This ratio was the highest in GBM group and lowest in lowgrade glial tumours. It was also extremely high in higher-grade gliomas and metastasis groups, therefore we can easily conclude that Cho/MI ratio is strongly related with malignancy of the tumours when this ratio gets elevated. At the same time, MI increases in low-grade glial tumours as it is the marker of astrogliosis 2,10,11,13, but in higher grade gliomas-metastases and in more malignant 41

6 H. Aydın et al. The New Journal of Medicine 2010;27: tumours, its peak sharply declines. In our study, Cho/MI ratio was really a diagnostic tool for grading gliomas and categorizing the tumours according to their malignancy rates. As a whole; we found out 97% sensitivity and 87.9% specificity with MV-MRS in determining the types of brain tumours. These values are really quite satisfactory and makes H-MRS, non-invasive technique, a safe trustable diagnostic modality in grading the malignancy of all brain neoplasms 7,9,13. CONCLUSION H-MRS is a non-invasive technique for detecting the presence of cancerous tissue in the brain through its metabolic activity. With its high sensitivity and specificity, MV-MRS is a useful additional procedure for pre-operative grading of glial tumours, differentiating neoplastic to nonneoplastic disorders and for categorization of all cranial space occupying lesions. H-MRS has been discovered as a safe diagnostic technique and gets more importance in clinical medicine. ACKNOWLEDGEMENTS We thank to Mr. Haydar Polat, Egemen Alper and Erdeniz Yurdakul for their brief assistance in handling of those all MV-MRS procedures. REFERENCES 1. Poptani H, Gupta R, Roy R, Pandey R, Jain VK, Chhabra DK. Characterization of Intracranial mass lesions with in vivo Proton MR Spectroscopy. AJNR 1995;16: Sibtain NA, Howe FA, Saunders DE. The clinical value of proton magnetic resonance spectroscopy in adult brain tumours. Clinical Radiology 2007;62: Hartmann W, Herminghaus S, Krings T, Marquardt G, Lanfermann H, Pilatus U, et al. Clinical application of proton magnetic resonance spectroscopy in the diagnosis of intracranial mass lesions. Neuroradiology 2002;44: Kuesel AC, Sutherland GR, Halliday W, Smith JC. H-MRS of high grade astrocytomas;mobile lipid accumulation in necrotic tissue.nmr Biomed 1994;7: Ross B, Michaelis T. Clinical application of magnetic resonance spectroscopy. Magn Reson Q 1994:10: Majos C, Alonso J, Aguilera C, Serrallonga M, Martin JP, Acebes JJ et al. Proton magnetic resonance of human brain tumours; Assessment of differences between tumour types and its applicability in brain tumour categorization. Eur Radiol 2003;13: Nagar VA,Ye J, Xu M, Ng WH, Yeo TT, Ong PL, et al. Multi-voxel MR Spectroscopic Imaging-Distinguishing Intracranial Tumours from Nonneoplastic Diseases. Ann Acad Med Singapore 2007;36: Parmar H, Lim TC, Yin H, Chua V, Khin LW, Raidy T, et al. Multivoxel MR Spectroscopic imaging of the brain: Utility in clinical setting-initial results. Eur J Radiol 2005;55: Magalhaes A, Godfrey W, Shen Y, Hu J, Smith Wl. Proton magnetic resonance Spectroscopy of brain Tumours correlated with pathology. Acad Radiol 2005;12: Callot V, Galanaud D, Le Fur Y, Gouny SC, Ranjeva JP, Cozzone PJ. H-MR spectroscopy of human brain tumours; A practical approach. European Journal of Radiology 2008;67; Papanagiotou P, Backens M, Grunwald IQ, Farmakis G, Politi M, Roth C, et al. MR-Spektroskopie bei Hirntumoren. Radiologe 2007;47: Herminghaus S, Dierks T, Pilatus U, Krings T, Horska A. Determination of histopathological tumour grade in neuro-epithelial brain tumours by using spectral pattern analysis of in vivo spectroscopic data. J Neurosurg 2003;98: Venkatesh SK, Gupta RK, Pal L, Husain N, Husain M. Spectroscopic increase in choline signal, is a non-specific marker for differentiation of infective-inflammatory from neoplastic lesions of the brain. J Magn Reson Imaging 2001;14: Correspondence: Nilay Ayd n Oktay D kap Y ld r m Beyazit Hospital, Ankara naoktay@gmail.com Arrival date : Acceptance date :