Abstract
It is sometimes difficult to distinguish gliomas from other tumors on routine imaging. In this study, we assessed whether 3-T magnetic resonance spectroscopy (MRS) with LCModel software might be useful for discriminating glioma from other brain tumors, such as primary central nervous system lymphomas (PCNSLs) and metastatic tumors. A total of 104 cases of brain tumor (66 gliomas, 20 PCNSLs, 6 metastatic tumors, 12 other tumors) were preoperatively investigated with short echo time (35 ms) single-voxel 3-T MRS. LCModel software was used to evaluate differences in the absolute concentrations of choline, N-acetylaspartate, N-acetylaspartylglutamate, glutamate + glutamine, myo-inositol (mIns), and lipid. mIns levels were significantly increased in high-grade glioma (HGG) compared with PCNSL (p < 0.001). In multivariate logistic regression analysis, mIns was the best marker for differentiating HGG from PCNSL (p < 0.0001, odds ratio 1.9927, 95% confidence interval 1.3628–3.2637). Conventional MRS detection of mIns resulted in a high diagnostic accuracy (sensitivity, 64%; specificity, 90%; area under the receiver operator curve, 0.80) for HGG. The expression of inositol 3-phosphate synthase (ISYNA1) was significantly higher in gliomas than in PCNSLs (p < 0.05), suggesting that the increased level of mIns in glioma is due to high expression of ISYNA1, the rate-limiting enzyme in the mIns-producing pathway. In conclusion, noninvasive analysis of mIns using single-voxel MRS may be useful in distinguishing gliomas from other brain tumors, particularly PCNSLs.
Similar content being viewed by others
Abbreviations
- Cr:
-
Creatine
- FWHM:
-
Full width at half maximum
- Gln:
-
Glutamine
- Glu:
-
Glutamate
- Glx:
-
Glutamine + glutamate
- HGG:
-
High-grade glioma
- IDH:
-
Isocitrate dehydrogenase
- ISYNA1:
-
Inositol 3-phosphate synthase
- Lip:
-
Lipid
- mIns:
-
Myo-inositol
- MRI:
-
Magnetic resonance imaging
- MRS:
-
Magnetic resonance spectroscopy
- NAA:
-
N-Acetylaspartate
- NAAG:
-
N-Acetylaspartylglutamate
- PCNSL:
-
Primary central nervous system lymphoma
- SNR:
-
Signal-to-noise ratio
- 2HG:
-
2-Hydroxyglutarate
References
Stupp R, Pavlidis N, Jelic S (2005) ESMO minimum clinical recommendations for diagnosis, treatment and follow-up of malignant glioma. Ann Oncol 16 Suppl 1: i64–i65. https://doi.org/10.1093/annonc/mdi834
Stupp R (2007) Malignant glioma: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 18(Suppl 2): ii69–ii70. https://doi.org/10.1093/annonc/mdm044
Morris PG, Abrey LE (2009) Therapeutic challenges in primary CNS lymphoma. Lancet Neurol 8:581–592. https://doi.org/10.1016/s1474-4422(09)70091-2
Arrieta O, Saavedra-Perez D, Kuri R, Aviles-Salas A, Martinez L, Mendoza-Posada D, Castillo P, Astorga A, Guzman E, De la Garza J (2009) Brain metastasis development and poor survival associated with carcinoembryonic antigen (CEA) level in advanced non-small cell lung cancer: a prospective analysis. BMC Cancer 9:119. https://doi.org/10.1186/1471-2407-9-119
Christensen TD, Spindler KL, Palshof JA, Nielsen DL (2016) Systematic review: brain metastases from colorectal cancer—incidence and patient characteristics. BMC Cancer 16:260. https://doi.org/10.1186/s12885-016-2290-5
Haldorsen IS, Krossnes BK, Aarseth JH, Scheie D, Johannesen TB, Mella O, Espeland A (2007) Increasing incidence and continued dismal outcome of primary central nervous system lymphoma in Norway 1989–2003 : time trends in a 15-year national survey. Cancer 110:1803–1814. https://doi.org/10.1002/cncr.22989
Guo AC, MacFall JR, Provenzale JM (2002) Multiple sclerosis: diffusion tensor MR imaging for evaluation of normal-appearing white matter. Radiology 222:729–736. https://doi.org/10.1148/radiol.2223010311
Weber MA, Zoubaa S, Schlieter M, Juttler E, Huttner HB, Geletneky K, Ittrich C, Lichy MP, Kroll A, Debus J, Giesel FL, Hartmann M, Essig M (2006) Diagnostic performance of spectroscopic and perfusion MRI for distinction of brain tumors. Neurology 66:1899–1906. https://doi.org/10.1212/01.wnl.0000219767.49705.9c
Yamasaki F, Kurisu K, Satoh K, Arita K, Sugiyama K, Ohtaki M, Takaba J, Tominaga A, Hanaya R, Yoshioka H, Hama S, Ito Y, Kajiwara Y, Yahara K, Saito T, Thohar MA (2005) Apparent diffusion coefficient of human brain tumors at MR imaging. Radiology 235:985–991. https://doi.org/10.1148/radiol.2353031338
Le Bihan D, Breton E, Lallemand D, Grenier P, Cabanis E, Laval-Jeantet M (1986) MR imaging of intravoxel incoherent motions: application to diffusion and perfusion in neurologic disorders. Radiology 161:401–407. https://doi.org/10.1148/radiology.161.2.3763909
Yamashita K, Hiwatashi A, Togao O, Kikuchi K, Kitamura Y, Mizoguchi M, Yoshimoto K, Kuga D, Suzuki SO, Baba S, Isoda T, Iwaki T, Iihara K, Honda H (2016) Diagnostic utility of intravoxel incoherent motion mr imaging in differentiating primary central nervous system lymphoma from glioblastoma multiforme. J Magn Reson Imaging 44:1256–1261. https://doi.org/10.1002/jmri.25261
Jiang S, Yu H, Wang X, Lu S, Li Y, Feng L, Zhang Y, Heo HY, Lee DH, Zhou J, Wen Z (2016) Molecular MRI differentiation between primary central nervous system lymphomas and high-grade gliomas using endogenous protein-based amide proton transfer MR imaging at 3 T. Eur Radiol 26:64–71. https://doi.org/10.1007/s00330-015-3805-1
Aburano H, Ueda F, Yoshie Y, Matsui O, Nakada M, Hayashi Y, Gabata T (2015) Differences between glioblastomas and primary central nervous system lymphomas in 1H-magnetic resonance spectroscopy. Jpn J Radiol 33:392–403. https://doi.org/10.1007/s11604-015-0430-5
Yamasaki F, Takayasu T, Nosaka R, Amatya VJ, Doskaliyev A, Akiyama Y, Tominaga A, Takeshima Y, Sugiyama K, Kurisu K (2015) Magnetic resonance spectroscopy detection of high lipid levels in intraaxial tumors without central necrosis: a characteristic of malignant lymphoma. J Neurosurg 122:1370–1379. https://doi.org/10.3171/2014.9.jns14106
Provencher SW (2001) Automatic quantitation of localized in vivo 1H spectra with LCModel. NMR Biomed 14:260–264
Nagashima H, Tanaka K, Sasayama T, Irino Y, Sato N, Takeuchi Y, Kyotani K, Mukasa A, Mizukawa K, Sakata J, Yamamoto Y, Hosoda K, Itoh T, Sasaki R, Kohmura E (2016) Diagnostic value of glutamate with 2-hydroxyglutarate in magnetic resonance spectroscopy for IDH1 mutant glioma. Neuro-oncology 18:1559–1568. https://doi.org/10.1093/neuonc/now090
Graveron-Demilly D (2014) Quantification in magnetic resonance spectroscopy based on semi-parametric approaches. MAGMA 27:113–130
Tanaka K, Sasayama T, Mizukawa K, Takata K, Sulaiman NS, Nishihara M, Kohta M, Sasaki R, Hirose T, Itoh T, Kohmura E (2015) Combined IDH1 mutation and MGMT methylation status on long-term survival of patients with cerebral low-grade glioma. Clin Neurol Neurosurg 138:37–44. https://doi.org/10.1016/j.clineuro.2015.07.019
Tanaka K, Sasayama T, Irino Y, Takata K, Nagashima H, Satoh N, Kyotani K, Mizowaki T, Imahori T, Ejima Y, Masui K, Gini B, Yang H, Hosoda K, Sasaki R, Mischel PS, Kohmura E (2015) Compensatory glutamine metabolism promotes glioblastoma resistance to mTOR inhibitor treatment. J Clin Invest 125:1591–1602. https://doi.org/10.1172/jci78239
Berridge MJ, Lipp P, Bootman MD (2000) Signal transduction. The calcium entry pas de deux. Science 287:1604–1605
Saiardi A, Bhandari R, Resnick AC, Snowman AM, Snyder SH (2004) Phosphorylation of proteins by inositol pyrophosphates. Science 306:2101–2105. https://doi.org/10.1126/science.1103344
Shen X, Xiao H, Ranallo R, Wu WH, Wu C (2003) Modulation of ATP-dependent chromatin-remodeling complexes by inositol polyphosphates. Science 299:112–114. https://doi.org/10.1126/science.1078068
York JD, Odom AR, Murphy R, Ives EB, Wente SR (1999) A phospholipase C-dependent inositol polyphosphate kinase pathway required for efficient messenger RNA export. Science 285:96–100
Haris M, Cai K, Singh A, Hariharan H, Reddy R (2011) In vivo mapping of brain myo-inositol. Neuroimage 54:2079–2085. https://doi.org/10.1016/j.neuroimage.2010.10.017
Castillo M, Smith JK, Kwock L (2000) Correlation of myo-inositol levels and grading of cerebral astrocytomas. AJNR 21:1645–1649
Hattingen E, Raab P, Franz K, Zanella FE, Lanfermann H, Pilatus U (2008) Myo-inositol: a marker of reactive astrogliosis in glial tumors? NMR Biomed 21:233–241. https://doi.org/10.1002/nbm.1186
Koguchi T, Tanikawa C, Mori J, Kojima Y, Matsuda K (2016) Regulation of myo-inositol biosynthesis by p53-ISYNA1 pathway. Int J Oncol 48:2415–2424. https://doi.org/10.3892/ijo.2016.3456
Seelan RS, Lakshmanan J, Casanova MF, Parthasarathy RN (2009) Identification of myo-inositol-3-phosphate synthase isoforms: characterization, expression, and putative role of a 16-kDa gamma(c) isoform. J Biol Chem 284:9443–9457. https://doi.org/10.1074/jbc.M900206200
Wei L, Hong S, Yoon Y, Hwang SN, Park JC, Zhang Z, Olson JJ, Hu XP, Shim H (2012) Early prediction of response to Vorinostat in an orthotopic rat glioma model. NMR Biomed 25:1104–1111. https://doi.org/10.1002/nbm.2776
Eisenberg F Jr, Parthasarathy R (1987) Measurement of biosynthesis of myo-inositol from glucose 6-phosphate. Methods Enzymol 141:127–143
Mora P, Majos C, Castaner S, Sanchez JJ, Gabarros A, Muntane A, Aguilera C, Arus C (2014) (1)H-MRS is useful to reinforce the suspicion of primary central nervous system lymphoma prior to surgery. Eur Radiol 24:2895–2905. https://doi.org/10.1007/s00330-014-3308-5
Kimura T, Sako K, Gotoh T, Tanaka K, Tanaka T (2001) In vivo single-voxel proton MR spectroscopy in brain lesions with ring-like enhancement. NMR Biomed 14:339–349
Opstad KS, Ladroue C, Bell BA, Griffiths JR, Howe FA (2007) Linear discriminant analysis of brain tumour (1)H MR spectra: a comparison of classification using whole spectra versus metabolite quantification. NMR Biomed 20:763–770. https://doi.org/10.1002/nbm.1147
Choi C, Ganji SK, DeBerardinis RJ, Dimitrov IE, Pascual JM, Bachoo R, Mickey BE, Malloy CR, Maher EA (2011) Measurement of glycine in the human brain in vivo by 1H-MRS at 3T: application in brain tumors. Magn Reson Med 66:609–618. https://doi.org/10.1002/mrm.22857
Acknowledgements
We appreciate those at the Brain Tumor Translational Resource at Kobe University for access to biospecimens and for biorepository support.
Funding
K. Tanaka is supported by grants from the Japanese Ministry of Education, Culture, Sports, Science and Technology (26462181), Takeda Science Foundation and Mochida Memorial Foundation for Medical and Pharmaceutical Research. T. Sasayama, K. Hosoda and E. Kohmura are supported by grants from the Japanese Ministry of Education, Culture, Sports, Science and Technology (25462258, 15K10302 and 25293309, respectively).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Research involving human participants and/or animals
This study was approved by the ethics review boards of our institutions (approval numbers: #1497 for MRS; #1579 for use of tumor samples).
Informed consent
Informed consent was obtained from all patients prior to their inclusion in this study.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Nagashima, H., Sasayama, T., Tanaka, K. et al. Myo-inositol concentration in MR spectroscopy for differentiating high grade glioma from primary central nervous system lymphoma. J Neurooncol 136, 317–326 (2018). https://doi.org/10.1007/s11060-017-2655-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11060-017-2655-x