, Volume 50, Issue 9, pp 759–767 | Cite as

Prognostic value of choline and creatine in WHO grade II gliomas

  • Elke Hattingen
  • Peter Raab
  • Kea Franz
  • Heiner Lanfermann
  • Matthias Setzer
  • Rüdiger Gerlach
  • Friedhelm E. Zanella
  • Ulrich Pilatus
Diagnostic Neuroradiology



The purpose of this study was to evaluate whether proton magnetic resonance spectroscopy (1H-MRS) predicts survival time, tumor progression, and malignant transformation in patients with WHO grade II gliomas.

Materials and methods

1H-MRS and MR imaging (MRI) were performed before surgery in 45 patients with histologically proven WHO grade II gliomas. Metabolite concentrations of choline-containing compounds (Cho) and creatine/phosphocreatine (tCr) were normalized to contralateral brain tissue. Spectroscopic data as well as the extent of tumor resection, contrast enhancement, size and histopatholocical type of the tumor, age, sex, and first neurological symptoms of the patients were analyzed for survival, tumor progression, and malignant transformation for a follow-up period of 1 to 5 years.


The normalized tCr of WHO grade II gliomas was a significant predictor for tumor progression (p = 0.011) and for malignant tumor transformation (p = 0.016). Further, contrast enhancement of the tumor (p = 0.014) at the time of diagnosis was significant for malignant tumor transformation and extent of tumor resection for the tumor progression (p = 0.007). All other parameters failed to predict any of the three endpoints.


Normalized values of tCr in WHO grade II gliomas may have prognostic implications for this group of gliomas. As a rule of the thumb, low-grade gliomas with decreased tCr (relative tCr values below 1.0) may show longer progression-free times and later malignant transformation than low-grade gliomas with regular or increased tCr values.


1H-MR spectroscopy WHO grade II gliomas Creatine Choline Progression Malignant transformation 


Conflict of interest statement

The authors declare that they have no conflict of interest.


  1. 1.
    Karim AB, Afra D, Cornu P, Bleehan N, Schraub S, De Witte O, Darcel F, Stenning S, Pierart M, Van Glabbeke M (2002) Randomized trial on the efficacy of radiotherapy for cerebral low-grade glioma in the adult: European Organization for Research and Treatment of Cancer Study 22845 with the Medical Research Council study BRO4: an interim analysis. Int J Radiat Oncol Biol Phys 52:316–324PubMedGoogle Scholar
  2. 2.
    Shimizu H, Kumabe T, Tominaga T, Kayama T, Hara K, Ono Y, Sato K, Arai N, Fujiwara S, Yoshimoto T (1996) Noninvasive evaluation of malignancy of brain tumors with proton MR spectroscopy. AJNR Am J Neuroradiol 17:737–747PubMedGoogle Scholar
  3. 3.
    Kuznetsov YE, Caramanos Z, Antel SB, Preul MC, Leblanc R, Villemure JG, Pokrupa R, Olivier A, Sadikot A, Arnold DL (2003) Proton magnetic resonance spectroscopic imaging can predict length of survival in patients with supratentorial gliomas. Neurosurgery 53:565–574PubMedCrossRefGoogle Scholar
  4. 4.
    Reijneveld JC, van der Grond J, Ramos LM, Bromberg JE, Taphoorn M (2005) Proton MRS imaging in the follow-up of patients with suspected low-grade gliomas. Neuroradiology 47:887–891PubMedCrossRefGoogle Scholar
  5. 5.
    Tedeschi G, Lundbom N, Raman R, Bonavita S, Duyn JH, Alger JR, Di Chiro G (1997) Increased choline signal coinciding with malignant degeneration of cerebral gliomas: a serial proton magnetic resonance spectroscopy imaging study. J Neurosurg 87:516–524PubMedGoogle Scholar
  6. 6.
    Pignatti F, van den Bent M, Curran D, Debruyne C, Sylvester R, Therasse P, Afra D, Cornu P, Bolla M, Vecht C, Karim AB, European Organization for Research and Treatment of Cancer Brain Tumor Cooperative Group; European Organization for Research and Treatment of Cancer Brain Tumor Cooperative Group and Cancer Radiotherapy Cooperative Group (2002). Prognostic factors for survival in adult patients with cerebral low-grade glioma. J Clin Oncol 20:2076–2084PubMedCrossRefGoogle Scholar
  7. 7.
    Murphy PS, Leach MO, Rowland IJ (1999) Signal modulation in (1)H magnetic resonance spectroscopy using contrast agents: proton relaxivities of choline, creatine, and N-acetylaspartate. Magn Reson Med 42:1155–1188PubMedCrossRefGoogle Scholar
  8. 8.
    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 21:233–241PubMedCrossRefGoogle Scholar
  9. 9.
    Provencher SW (1993) Estimation of metabolite concentrations from localized in vivo proton NMR spectra. Magn Reson Med 30:672–679PubMedCrossRefGoogle Scholar
  10. 10.
    Michaelis T, Merboldt K, Bruhn H, Hänicke W, Frahm J (1993) Absolute concentrations of metabolites in the adult human brain in vivo: quantification of localized proton MR spectra. Radiology 187:219–227PubMedGoogle Scholar
  11. 11.
    Li BS, Wang H, Gonen O (2003) Metabolite ratios to assumed stable creatine level may confound the quantification of proton brain MR spectroscopy. Magn Reson Imaging. 21:923–928PubMedCrossRefGoogle Scholar
  12. 12.
    Li X, Lu Y, Pirzkall A, McKnight T, Nelson SJ (2002) Analysis of the spatial characteristics of metabolic abnormalities in newly diagnosed glioma patients. J Magn Reson Imaging 16:229–237PubMedCrossRefGoogle Scholar
  13. 13.
    Galanaud D, Chinot O, Nicoli F, Confort-Gouny S, Le Fur Y, Barrie-Attarian M, Ranjeva JP, Fuentès S, Viout P, Figarella-Branger D, Cozzone PJ (2003) Use of proton magnetic resonance spectroscopy of the brain to differentiate gliomatosis cerebri from low-grade glioma. J Neurosurg 98:269–276PubMedGoogle Scholar
  14. 14.
    Panigrahy A, Krieger MD, Gonzalez-Gomez I, Liu X, McComb JG, Finlay JL, Nelson MD Jr, Gilles FH, Blüml S (2006) Quantitative short echo time 1H-MR spectroscopy of untreated pediatric brain tumors: preoperative diagnosis and characterization. AJNR Am J Neuroradiol 27:560–572PubMedGoogle Scholar
  15. 15.
    Urenjak J, Williams SR, Gadian DG, Noble M (1993) Proton nuclear magnetic resonance spectroscopy unambiguously identifies different neural cell types. J Neurosci 13:981–989PubMedGoogle Scholar
  16. 16.
    Dringen R, Verleysdonk S, Hamprecht B, Willker W, Leibfritz D, Brand A (1998) Metabolism of glycine in primary astroglial cells: synthesis of creatine, serine, and glutathione. J Neurochem 70:835–840PubMedCrossRefGoogle Scholar
  17. 17.
    Kinoshita Y, Kajiwara H, Yokota A, Koga Y (1994) Proton magnetic resonance spectroscopy of brain tumors: an in vitro study. Neurosurgery 35:606–613PubMedCrossRefGoogle Scholar
  18. 18.
    Gillies RJ, Barry JA, Ross BD (1994) In vitro and in vivo 13C and 31P NMR analyses of phosphocholine metabolism in rat glioma cells. Magn Reson Med 32:310–308PubMedCrossRefGoogle Scholar
  19. 19.
    Shimizu H, Kumabe T, Shirane R, Yoshimoto T (2000) Correlation between choline level measured by proton MR spectroscopy and Ki-67 labeling index in gliomas. AJNR Am J Neuroradiol 21:659–665PubMedGoogle Scholar
  20. 20.
    Herminghaus S, Pilatus U, Moller-Hartmann W, Raab P, Lanfermann H, Schlote W, Zanella FE (2002) Increased choline levels coincide with enhanced proliferative activity of human neuroepithelial brain tumors. NMR Biomed 15:385–392PubMedCrossRefGoogle Scholar
  21. 21.
    Ackerstaff E, Pflug BR, Nelson JB, Bhujwalla ZM (2001) Detection of increased choline compounds with proton nuclear magnetic resonance spectroscopy subsequent to malignant transformation of human prostatic epithelial cells. Cancer Res 61:3599–3603PubMedGoogle Scholar
  22. 22.
    Miller BL, Chang L, Booth R, Ernst T, Cornford M, Nikas D, McBride D, Jenden DJ (1996) In vivo 1H MRS choline: correlation with in vitro chemistry/histology. Life Sci 58:1929–1935PubMedCrossRefGoogle Scholar
  23. 23.
    Gupta RK, Cloughesy TF, Sinha U, Garakian J, Lazareff J, Rubino G, Rubino L, Becker DP, Vinters HV, Alger JR (2000) Relationships between choline magnetic resonance spectroscopy, apparent diffusion coefficient and quantitative histopathology in human glioma. J Neurooncol 50:215–226PubMedCrossRefGoogle Scholar
  24. 24.
    Zhang K, Li C, Liu Y, Li L, Ma X, Meng X, Feng D (2007) Evaluation of invasiveness of astrocytoma using 1H-magnetic resonance spectroscopy: correlation with expression of matrix metalloproteinase-2. Neuroradiology 49:913–919PubMedCrossRefGoogle Scholar
  25. 25.
    Di Costanzo A, Scarabino T, Trojsi F, Giannatempo GM, Popolizio T, Catapano D, Bonavita S, Maggialetti N, Tosetti M, Salvolini U, d’Angelo VA, Tedeschi G (2006) Multiparametric 3T MR approach to the assessment of cerebral gliomas: tumor extent and malignancy. Neuroradiology 48:622–631PubMedCrossRefGoogle Scholar
  26. 26.
    Möller-Hartmann W, Herminghaus S, Krings T, Marquardt G, Lanfermann H, Pilatus U, Zanella FE (2002) Clinical application of proton magnetic resonance spectroscopy in the diagnosis of intracranial mass lesions. Neuroradiology 44:371–381PubMedCrossRefGoogle Scholar
  27. 27.
    Lev MH, Ozsunar Y, Henson JW, Rasheed AA, Barest GD, Harsh GR 4th, Fitzek MM, Chiocca EA, Rabinov JD, Csavoy AN, Rosen BR, Hochberg FH, Schaefer PW, Gonzalez RG (2004) Glial tumor grading and outcome prediction using dynamic spin-echo MR susceptibility mapping compared with conventional contrast-enhanced MR: confounding effect of elevated rCBV of oligodendrogliomas. AJNR Am J Neuroradiol 25:214–221PubMedGoogle Scholar
  28. 28.
    White ML, Zhang Y, Kirby P, Ryken TC (2005) Can tumor contrast enhancement be used as a criterion for differentiating tumor grades of oligodendrogliomas. AJNR Am J Neuroradiol 26:784–790PubMedGoogle Scholar
  29. 29.
    Shaw E, Arusell R, Scheithauer B, O'Fallon J, O'Neill B, Dinapoli R, Nelson D, Earle J, Jones C, Cascino T, Nichols D, Ivnik R, Hellman R, Curran W, Abrams R (2002) Prospective randomized trial of low- versus high-dose radiation therapy in adults with supratentorial low-grade glioma: initial report of a North Central Cancer Treatment Group/Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group study. J Clin Oncol 20:2267–2276PubMedCrossRefGoogle Scholar
  30. 30.
    Tofts PS, Benton CE, Weil RS, Tozer DJ, Altmann DR, Jäger HR, Waldman AD, Rees JH (2007) Quantitative analysis of whole-tumor Gd enhancement histograms predicts malignant transformation in low-grade gliomas. J Magn Reson Imaging 25:208–214PubMedCrossRefGoogle Scholar
  31. 31.
    Karim AB, Maat B, Hatlevoll R, Menten J, Rutten EH, Thomas DG, Mascarenhas F, Horiot JC, Parvinen LM, van Reijn M, Jager JJ, Fabrini MG, van Alphen AM, Hamers HP, Gaspar L, Noordman E, Pierart M, van Glabbeke M (1996) A randomized trial on dose-response in radiation therapy of low-grade cerebral glioma: European Organization for Research and Treatment of Cancer (EORTC) Study 22844. Int J Radiat Oncol Biol Phys 36:549–556PubMedGoogle Scholar
  32. 32.
    Lote K, Egeland T, Hager B, Stenwig B, Skullerud K, Berg-Johnsen J, Storm-Mathisen I, Hirschberg H (1997) Survival, prognostic factors, and therapeutic efficacy in low-grade glioma: a retrospective study in 379 patients. J Clin Oncol 15:3129–3140PubMedGoogle Scholar
  33. 33.
    Scerrati M, Roselli R, Iacoangeli M, Pompucci A, Rossi GF (1996) Prognostic factors in low grade (WHO grade II) gliomas of the cerebral hemispheres: the role of surgery. J Neurol Neurosurg Psychiatry 61:291–296PubMedCrossRefGoogle Scholar
  34. 34.
    Berger MS, Deliganis AV, Dobbins J, Keles GE (1994) The effect of extent of resection on recurrence in patients with low grade cerebral hemisphere gliomas. Cancer 74:1784–1791PubMedCrossRefGoogle Scholar
  35. 35.
    Eyre HJ, Crowley JJ, Townsend JJ, Eltringham JR, Morantz RA, Schulman SF, Quagliana JM, al-Sarraf M (1993) A randomized trial of radiotherapy versus radiotherapy plus CCNU for incompletely resected low-grade gliomas: a Southwest Oncology Group study. J Neurosurg 78:909–914PubMedGoogle Scholar
  36. 36.
    Soffietti R, Chio A, Giordana MT, Vasario E, Schiffer D (1989) Prognostic factors in well-differentiated cerebral astrocytomas in the adult. Neurosurgery 24:686–692PubMedCrossRefGoogle Scholar
  37. 37.
    Van Veelen ML, Avezaat CJ, Kros JM, van Putten W, Kros JM (1998) Supratentorial low grade astrocytoma: prognostic factors, dedifferentiation, and the issue of early versus late surgery. J Neurol Neurosurg Psychiatry 64:581–587PubMedGoogle Scholar
  38. 38.
    Shaw EG, Scheithauer BW, O'Fallon JR (1997) Supratentorial gliomas: a comparative study by grade and histologic type. J Neurooncol 31:273–278PubMedCrossRefGoogle Scholar
  39. 39.
    Okamoto Y, Di Patre PL, Burkhard C, Horstmann S, Jourde B, Fahey M, Schüler D, Probst-Hensch NM, Yasargil MG, Yonekawa Y, Lütolf UM, Kleihues P, Ohgaki H (2004) Population-based study on incidence, survival rates, and genetic alterations of low-grade diffuse astrocytomas and oligodendrogliomas. Acta Neuropathol 108:49–56PubMedCrossRefGoogle Scholar
  40. 40.
    Van den Bent MJ, Afra D, de Witte O, Ben Hassel M, Schraub S, Hoang-Xuan K, Malmström PO, Collette L, Piérart M, Mirimanoff R, Karim AB, EORTC Radiotherapy and Brain Tumor Groups and the UK Medical Research Council (2005) Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytomas and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet 366:985–990PubMedCrossRefGoogle Scholar
  41. 41.
    Wiedermann D, Schuff N, Matson GB, Soher BJ, Du AT, Maudsley AA, Weiner MW (2001) Short echo time multislice proton magnetic resonance spectroscopic imaging in human brain: metabolite distributions and reliability. Magn Reson Imaging 19:1073–1080PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Elke Hattingen
    • 1
  • Peter Raab
    • 1
    • 3
  • Kea Franz
    • 2
  • Heiner Lanfermann
    • 3
  • Matthias Setzer
    • 2
  • Rüdiger Gerlach
    • 2
  • Friedhelm E. Zanella
    • 1
  • Ulrich Pilatus
    • 1
  1. 1.Institute of NeuroradiologyJohann Wolfgang Goethe University of Frankfurt/MainFrankfurt/MainGermany
  2. 2.Department of NeurosurgeryJohann Wolfgang Goethe University of Frankfurt/MainFrankfurt/MainGermany
  3. 3.Institute of NeuroradiologyMedizinische Hochschule Hannover (MHH)HannoverGermany

Personalised recommendations