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Dynamics of DLGG and Clinical Implications

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Diffuse Low-Grade Gliomas in Adults

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Abstract

Diffuse low-grade glioma is defined by a common morphotype on histological analysis. However, these tumors exhibit a wide heterogeneity in their degree of biological aggressivity, resulting in a large range of survival times. Several factors at diagnosis have been found to identify different subgroups of prognosis, but there is growing evidence that the intrinsic dynamics of the tumor – that can be evaluated over a short initial follow-up – plays a major role in predicting overall prognosis at an individual scale. We will review our current knowledge of DLGG dynamics on molecular, histological, radiological, and clinical scales. In particular, we emphasize the importance of estimating the initial radiological dynamics from two successive morphological MRI. Finally, we describe how the spontaneous dynamics can be modified by the different treatment modalities, including surgery, chemotherapy, and radiotherapy.

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Notes

  1. 1.

    We do not know whether this is a random process or whether some biological law governs the spatiotemporal dynamics of these events.

  2. 2.

    PET imaging with different molecular markers will not be discussed here considering the limited number of longitudinal studies. We refer the reader to the PET imaging chapter for the interest of these techniques in DLGG.

References

  1. Aaronson NK, Taphoorn MJ, Heimans JJ, Postma TJ, Gundy CM, Beute GN, Slotman BJ, Klein M. Compromised health-related quality of life in patients with low-grade glioma. J Clin Oncol. 2011;29(33):4430–5.

    Article  PubMed  Google Scholar 

  2. Alimenti A, Delavelle J, Lazeyras F, Yilmaz H, Dietrich PY, de Tribolet N, Lovblad KO. Monovoxel 1H magnetic resonance spectroscopy in the progression of gliomas. Eur Neurol. 2007;58(4):198–209.

    Article  PubMed  Google Scholar 

  3. Berger MS, Deliganis AV, Dobbins J, Keles GE. The effect of extent of resection on recurrence in patients with low grade cerebral hemisphere gliomas. Cancer. 1994;74(6):1784–91.

    Article  PubMed  CAS  Google Scholar 

  4. Bettegowda C, Agrawal N, Jiao Y, Sausen M, Wood LD, Hruban RH, Rodriguez FJ, Cahill DP, McLendon R, Riggins G, Velculescu VE, Oba-Shinjo SM, Marie SK, Vogelstein B, Bigner D, Yan H, Papadopoulos N, Kinzler KW. Mutations in CIC and FUBP1 contribute to human oligodendroglioma. Science. 2011;333(6048):1453–5.

    Article  PubMed  CAS  Google Scholar 

  5. Bian W, Khayal IS, Lupo JM, McGue C, Vandenberg S, Lamborn KR, Chang SM, Cha S, Nelson SJ. Multiparametric characterization of grade 2 glioma subtypes using magnetic resonance spectroscopic, ­perfusion, and diffusion imaging. Transl Oncol. 2009;2(4):271–80.

    PubMed  Google Scholar 

  6. Brasil Caseiras G, Ciccarelli O, Altmann DR, Benton CE, Tozer DJ, Tofts PS, Yousry TA, Rees J, Waldman AD, Jager HR. Low-grade gliomas: six-month tumor growth predicts patient outcome better than admission tumor volume, relative cerebral blood volume, and apparent diffusion coefficient. Radiology. 2009;253(2):505–12.

    Article  PubMed  Google Scholar 

  7. Cha S, Tihan T, Crawford F, Fischbein NJ, Chang S, Bollen A, Nelson SJ, Prados M, Berger MS, Dillon WP. Differentiation of low-grade oligodendrogliomas from low-grade astrocytomas by using quantitative blood-volume measurements derived from dynamic susceptibility contrast-enhanced MR imaging. AJNR Am J Neuroradiol. 2005;26(2):266–73.

    PubMed  Google Scholar 

  8. Chang EF, Smith JS, Chang SM, Lamborn KR, Prados MD, Butowski N, Barbaro NM, Parsa AT, Berger MS, McDermott MM. Preoperative prognostic classifi­cation system for hemispheric low-grade gliomas in adults. J Neurosurg. 2008;109(5):817–24.

    Article  PubMed  Google Scholar 

  9. Chang EF, Clark A, Jensen RL, Bernstein M, Guha A, Carrabba G, Mukhopadhyay D, Kim W, Liau LM, Chang SM, Smith JS, Berger MS, McDermott MW. Multiinstitutional validation of the University of California at San Francisco Low-Grade Glioma Prognostic Scoring System. Clinical article. J Neurosurg. 2009;111(2):203–10.

    Article  PubMed  Google Scholar 

  10. Chen X, Dai J, Jiang T. Supratentorial WHO grade II glioma invasion: a morphologic study using sequential conventional MRI. Br J Neurosurg. 2010;24(2):196–201.

    Article  PubMed  Google Scholar 

  11. Correa DD, Shi W, Thaler HT, Cheung AM, DeAngelis LM, Abrey LE. Longitudinal cognitive follow-up in low grade gliomas. J Neurooncol. 2008;86(3):321–7.

    Article  PubMed  Google Scholar 

  12. Danchaivijitr N, Waldman AD, Tozer DJ, Benton CE, Brasil Caseiras G, Tofts PS, Rees JH, Jager HR. Low-grade gliomas: do changes in rCBV measurements at longitudinal perfusion-weighted MR imaging predict malignant transformation? Radiology. 2008;247(1):170–8.

    Article  PubMed  Google Scholar 

  13. Daumas-Duport C, Tucker ML, Kolles H, Cervera P, Beuvon F, Varlet P, Udo N, Koziak M, Chodkiewicz JP. Oligodendrogliomas. Part II: a new grading system based on morphological and imaging criteria. J Neurooncol. 1997;34(1):61–78.

    Article  PubMed  CAS  Google Scholar 

  14. Daumas-Duport C, Varlet P, Tucker ML, Beuvon F, Cervera P, Chodkiewicz JP. Oligodendrogliomas. Part I: patterns of growth, histological diagnosis, clinical and imaging correlations: a study of 153 cases. J Neurooncol. 1997;34(1):37–59.

    Article  PubMed  CAS  Google Scholar 

  15. Duffau H, Pallud J, Mandonnet E. Evidence for the genesis of WHO grade II glioma in an asymptomatic young adult using repeated MRIs. Acta Neurochir (Wien). 2011;153(3):473–7.

    Article  Google Scholar 

  16. Duffau H. The challenge to remove diffuse low-grade gliomas while preserving brain functions. Acta Neurochir (Wien). 2012;154(4):569–74.

    Article  Google Scholar 

  17. Glunde K, Bhujwalla ZM, Ronen SM. Choline metabolism in malignant transformation. Nat Rev Cancer. 2011;11(12):835–48.

    PubMed  CAS  Google Scholar 

  18. Gomori E, Pal J, Kovacs B, Doczi T. Concurrent hypermethylation of DNMT1, MGMT and EGFR genes in progression of gliomas. Diagn Pathol. 2012;7(1):8.

    Article  PubMed  CAS  Google Scholar 

  19. Goze C, Bezzina C, Goze E, Rigau V, Maudelonde T, Bauchet L, Duffau H. 1P19Q loss but not IDH1 mutations influences WHO grade II gliomas spontaneous growth. J Neurooncol. 2012;108(1):69–75.

    Article  PubMed  Google Scholar 

  20. Guillevin R, Menuel C, Duffau H, Kujas M, Capelle L, Aubert A, Taillibert S, Idbaih A, Pallud J, Demarco G, Costalat R, Hoang-Xuan K, Chiras J, Vallee JN. Proton magnetic resonance spectroscopy predicts proliferative activity in diffuse low-grade gliomas. J Neurooncol. 2008;87(2):181–7.

    Article  PubMed  CAS  Google Scholar 

  21. Guillevin R, Menuel C, Vallee JN, Francoise JP, Capelle L, Habas C, De Marco G, Chiras J, Costalat R. Mathematical modeling of energy metabolism and hemodynamics of WHO grade II gliomas using in vivo MR data. C R Biol. 2010;334(1):31–8.

    Article  PubMed  Google Scholar 

  22. Guillevin R, Menuel C, Abud L, Costalat R, Capelle L, Hoang-Xuan K, Habas C, Chiras J, Vallee JN. Proton MR spectroscopy in predicting the increase of perfusion MR imaging for WHO grade II gliomas. J Magn Reson Imaging. 2011;35(3):543–50.

    Article  PubMed  Google Scholar 

  23. Guillevin R, Menuel C, Taillibert S, Capelle L, Costalat R, Abud L, Habas C, De Marco G, Hoang-Xuan K, Chiras J, Vallee JN. Predicting the outcome of grade II glioma treated with temozolomide using proton magnetic resonance spectroscopy. Br J Cancer. 2011;104(12):1854–61.

    Article  PubMed  CAS  Google Scholar 

  24. Hlaihel C, Guilloton L, Guyotat J, Streichenberger N, Honnorat J, Cotton F. Predictive value of multimodality MRI using conventional, perfusion, and spectroscopy MR in anaplastic transformation of low-grade oligodendrogliomas. J Neurooncol. 2010;97(1):73–80.

    Article  PubMed  Google Scholar 

  25. Ishii N, Tada M, Hamou MF, Janzer RC, Meagher-Villemure K, Wiestler OD, Tribolet N, Van Meir EG. Cells with TP53 mutations in low grade astrocytic tumors evolve clonally to malignancy and are an unfavorable prognostic factor. Oncogene. 1999;18(43):5870–8.

    Article  PubMed  CAS  Google Scholar 

  26. Jbabdi S, Mandonnet E, Duffau H, Capelle L, Swanson KR, Pelegrini-Issac M, Guillevin R, Benali H. Simulation of anisotropic growth of low-grade gliomas using diffusion tensor imaging. Magn Reson Med. 2005;54(3):616–24.

    Article  PubMed  Google Scholar 

  27. Jiang Z, Le Bas JF, Grand S, Salon C, Pasteris C, Hoffmann D, Bing F, Berger F, Chabardes S, Liu C, Krainik A. Prognostic value of perfusion MR imaging in patients with oligodendroglioma: a survival study. J Neuroradiol. 2011;38(1):53–61.

    Article  PubMed  CAS  Google Scholar 

  28. Kier EL, Staib LH, Davis LM, Bronen RA. MR imaging of the temporal stem: anatomic dissection tractography of the uncinate fasciculus, inferior occipitofrontal fasciculus, and Meyer’s loop of the optic radiation. AJNR Am J Neuroradiol. 2004;25(5):677–91.

    PubMed  Google Scholar 

  29. Law M, Yang S, Wang H, Babb JS, Johnson G, Cha S, Knopp EA, Zagzag D. Glioma grading: sensitivity, specificity, and predictive values of perfusion MR imaging and proton MR spectroscopic imaging compared with conventional MR imaging. AJNR Am J Neuroradiol. 2003;24(10):1989–98.

    PubMed  Google Scholar 

  30. Lev MH, Ozsunar Y, Henson JW, Rasheed AA, Barest GD, Harsh GR, Fitzek MM, Chiocca EA, Rabinov JD, Csavoy AN, Rosen BR, Hochberg FH, Schaefer PW, Gonzalez RG. 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 [corrected]. AJNR Am J Neuroradiol. 2004;25(2):214–21.

    PubMed  Google Scholar 

  31. Mandonnet E, Delattre JY, Tanguy ML, Swanson KR, Carpentier AF, Duffau H, Cornu P, Van Effenterre R, Alvord Jr EC, Capelle L. Continuous growth of mean tumor diameter in a subset of grade II gliomas. Ann Neurol. 2003;53(4):524–8.

    Article  PubMed  Google Scholar 

  32. Mandonnet E, Capelle L, Duffau H. Extension of paralimbic low grade gliomas: toward an anatomical classification based on white matter invasion patterns. J Neurooncol. 2006;78(2):179–85.

    Article  PubMed  Google Scholar 

  33. Mandonnet E, Pallud J, Fontaine D, Taillandier L, Bauchet L, Peruzzi P, Guyotat J, Bernier V, Baron MH, Duffau H, Capelle L. Inter- and intrapatients comparison of WHO grade II glioma kinetics before and after surgical resection. Neurosurg Rev. 2010;33(1):91–6.

    Article  PubMed  Google Scholar 

  34. Mandonnet E, Duffau H, Bauchet L. A new tool for grade II glioma studies: plotting cumulative time with quality of life versus time to malignant transformation. J Neurooncol. 2011;106(1):213–5.

    Article  PubMed  Google Scholar 

  35. Martino J, Taillandier L, Moritz-Gasser S, Gatignol P, Duffau H. Re-operation is a safe and effective therapeutic strategy in recurrent WHO grade II gliomas within eloquent areas. Acta Neurochir (Wien). 2009;151(5):427–36; discussion 436.

    Article  Google Scholar 

  36. Matsukado Y, Maccarty CS, Kernohan JW. The growth of glioblastoma multiforme (astrocytomas, grades 3 and 4) in neurosurgical practice. J Neurosurg. 1961;18:636–44.

    Article  PubMed  CAS  Google Scholar 

  37. McGirt MJ, Chaichana KL, Attenello FJ, Weingart JD, Than K, Burger PC, Olivi A, Brem H, Quinones-Hinojosa A. Extent of surgical resection is independently associated with survival in patients with hemispheric infiltrating low-grade gliomas. Neuro­surgery. 2008;63(4):700–7; author reply 707–8.

    Article  PubMed  Google Scholar 

  38. McKnight TR, Lamborn KR, Love TD, Berger MS, Chang S, Dillon WP, Bollen A, Nelson SJ. Correlation of magnetic resonance spectroscopic and growth characteristics within Grades II and III gliomas. J Neurosurg. 2007;106(4):660–6.

    Article  PubMed  CAS  Google Scholar 

  39. Ohgaki H, Kleihues P. Genetic pathways to primary and secondary glioblastoma. Am J Pathol. 2007;170(5):1445–53.

    Article  PubMed  CAS  Google Scholar 

  40. Pallud J, Devaux B, Daumas-Duport C, Oppenheim C, Roux FX. Glioma dissemination along the corticospinal tract. J Neurooncol. 2005;73(3):239–40.

    Article  PubMed  CAS  Google Scholar 

  41. Pallud J, Mandonnet E, Duffau H, Kujas M, Guillevin R, Galanaud D, Taillandier L, Capelle L. Prognostic value of initial magnetic resonance imaging growth rates for World Health Organization grade II gliomas. Ann Neurol. 2006;60(3):380–3.

    Article  PubMed  Google Scholar 

  42. Pallud J, Duffau H, Razak RA, Barbarino-Monnier P, Capelle L, Fontaine D, Frenay M, Guillet-May F, Mandonnet E, Taillandier L. Influence of pregnancy in the behavior of diffuse gliomas: clinical cases of a French glioma study group. J Neurol. 2009;256(12):2014–20.

    Article  PubMed  Google Scholar 

  43. Pallud J, Capelle L, Mandonnet E. Comment on parameters of low-grade glioma as predictors. Radiology. 2010;256(3):1014.

    Article  PubMed  Google Scholar 

  44. Pallud J, Fontaine D, Duffau H, Mandonnet E, Sanai N, Taillandier L, Peruzzi P, Guillevin R, Bauchet L, Bernier V, Baron MH, Guyotat J, Capelle L. Natural history of incidental World Health Organization grade II gliomas. Ann Neurol. 2010;68(5):727–33.

    Article  PubMed  Google Scholar 

  45. Pallud J, Mandonnet E, Deroulers C, Fontaine D, Badoual M, Capelle L, Guillet-May F, Page P, Peruzzi P, Jouanneau E, Frenay M, Cartalat-Carel S, Duffau H, Taillandier L. Pregnancy increases the growth rates of World Health Organization grade II gliomas. Ann Neurol. 2010;67(3):398–404.

    PubMed  Google Scholar 

  46. Pallud J, Varlet P, Devaux B, Geha S, Badoual M, Deroulers C, Page P, Dezamis E, Daumas-Duport C, Roux FX. Diffuse low-grade oligodendrogliomas extend beyond MRI-defined abnormalities. Neurology. 2010;74(21):1724–31.

    Article  PubMed  CAS  Google Scholar 

  47. Pallud J, Llitjos J, Dhermain F, Varlet P, Dezamis E, Devaux B, Souillard-Scemama R, Sanai N, Koziak M, Page P, Schlienger M, Daumas-Duport C, Meder J, Oppenheim C, Roux F. Dynamic imaging response following radiation therapy predicts long-term outcomes for diffuse low-grade gliomas. Neuro Oncol. 2012;14(4):496–505.

    Article  PubMed  Google Scholar 

  48. Pallud J, Mandonnet E. Letter to the Editor: Incidental low-grade gliomas. J Neurosurg. 2012 Dec 21. [Epub ahead of print].

    Google Scholar 

  49. Perry JR, Cairncross JG. Glioma therapies: how to tell which work? J Clin Oncol. 2003;21(19):3547–9.

    Article  PubMed  Google Scholar 

  50. Peyre M, Cartalat-Carel S, Meyronet D, Ricard D, Jouvet A, Pallud J, Mokhtari K, Guyotat J, Jouanneau E, Sunyach MP, Frappaz D, Honnorat J, Ducray F. Prolonged response without prolonged chemotherapy: a lesson from PCV chemotherapy in low-grade gliomas. Neuro Oncol. 2010;12(10):1078–82.

    Article  PubMed  Google Scholar 

  51. Porporato PE, Dhup S, Dadhich RK, Copetti T, Sonveaux P. Anticancer targets in the glycolytic metabolism of tumors: a comprehensive review. Front Pharmacol. 2011;2:49.

    Article  PubMed  Google Scholar 

  52. Potts MB, Smith JS, Molinaro AM, Berger MS. Natural history and surgical management of incidentally discovered low-grade gliomas. J Neurosurg. 2012;116(2):365–72.

    Article  PubMed  Google Scholar 

  53. Pouratian N, Asthagiri A, Jagannathan J, Shaffrey ME, Schiff D. Surgery Insight: the role of surgery in the management of low-grade gliomas. Nat Clin Pract Neurol. 2007;3(11):628–39.

    Article  PubMed  Google Scholar 

  54. Price SJ. Advances in imaging low-grade gliomas. Adv Tech Stand Neurosurg. 2010;35:1–34.

    Article  PubMed  Google Scholar 

  55. Ricard D, Kaloshi G, Amiel-Benouaich A, Lejeune J, Marie Y, Mandonnet E, Kujas M, Mokhtari K, Taillibert S, Laigle-Donadey F, Carpentier AF, Omuro A, Capelle L, Duffau H, Cornu P, Guillevin R, Sanson M, Hoang-Xuan K, Delattre JY. Dynamic history of low-grade gliomas before and after ­temozolomide treatment. Ann Neurol. 2007;61(5):484–90.

    Article  PubMed  CAS  Google Scholar 

  56. Sanai N, Berger MS. Glioma extent of resection and its impact on patient outcome. Neurosurgery. 2008;62(4):753–64; discussion 264–6.

    Article  PubMed  Google Scholar 

  57. Scherer H. The forms of growth in gliomas and their practical significance. Brain. 1940;63:1–35.

    Article  Google Scholar 

  58. Shah AH, Madhavan K, Heros D, Raper DM, Iorgulescu JB, Lally BE, Komotar RJ. The management of incidental low-grade gliomas using magnetic resonance imaging: systematic review and optimal treatment paradigm. Neurosurg Focus. 2011;31(6):E12.

    Article  PubMed  Google Scholar 

  59. Smith JS, Chang EF, Lamborn KR, Chang SM, Prados MD, Cha S, Tihan T, Vandenberg S, McDermott MW, Berger MS. Role of extent of resection in the long-term outcome of low-grade hemispheric gliomas. J Clin Oncol. 2008;26(8):1338–45.

    Article  PubMed  Google Scholar 

  60. Soffietti R, Baumert BG, Bello L, von Deimling A, Duffau H, Frenay M, Grisold W, Grant R, Graus F, Hoang-Xuan K, Klein M, Melin B, Rees J, Siegal T, Smits A, Stupp R, Wick W. Guidelines on management of low-grade gliomas: report of an EFNS-EANO* Task Force. Eur J Neurol. 2010;17(9):1124–33.

    Article  PubMed  CAS  Google Scholar 

  61. Sorensen AG, Patel S, Harmath C, Bridges S, Synnott J, Sievers A, Yoon YH, Lee EJ, Yang MC, Lewis RF, Harris GJ, Lev M, Schaefer PW, Buchbinder BR, Barest G, Yamada K, Ponzo J, Kwon HY, Gemmete J, Farkas J, Tievsky AL, Ziegler RB, Salhus MR, Weisskoff R. Comparison of diameter and perimeter methods for tumor volume calculation. J Clin Oncol. 2001;19(2):551–7.

    PubMed  CAS  Google Scholar 

  62. van den Bent M, Wefel J, Schiff D, Taphoorn M, Jaeckle K, Junck L, Armstrong T, Choucair A, Waldman A, Gorlia T, Chamberlain M, Baumert B, Vogelbaum M, Macdonald D, Reardon D, Wen P, Chang S, Jacobs A. Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas. Lancet Oncol. 2011;12(6):583–93.

    Article  PubMed  Google Scholar 

  63. Watanabe T, Nobusawa S, Kleihues P, Ohgaki H. IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol. 2009;174(4):1149–53.

    Article  PubMed  CAS  Google Scholar 

  64. Yan H, Bigner DD, Velculescu V, Parsons DW. Mutant metabolic enzymes are at the origin of gliomas. Cancer Res. 2009;69(24):9157–9.

    Article  PubMed  CAS  Google Scholar 

  65. Yan H, Parsons DW, Jin G, McLendon R, Rasheed BA, Yuan W, Kos I, Batinic-Haberle I, Jones S, Riggins GJ, Friedman H, Friedman A, Reardon D, Herndon J, Kinzler KW, Velculescu VE, Vogelstein B, Bigner DD. IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360(8):765–73.

    Article  PubMed  CAS  Google Scholar 

  66. Yip S, Butterfield YS, Morozova O, Chittaranjan S, Blough MD, An J, Birol I, Chesnelong C, Chiu R, Chuah E, Corbett R, Docking R, Firme M, Hirst M, Jackman S, Karsan A, Li H, Louis DN, Maslova A, Moore R, Moradian A, Mungall KL, Perizzolo M, Qian J, Roldan G, Smith EE, Tamura-Wells J, Thiessen N, Varhol R, Weiss S, Wu W, Young S, Zhao Y, Mungall AJ, Jones SJ, Morin GB, Chan JA, Cairncross JG, Marra MA. Concurrent CIC mutations, IDH mutations, and 1p/19q loss distinguish oligodendrogliomas from other cancers. J Pathol. 2012;226(1):7–16.

    Article  PubMed  CAS  Google Scholar 

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  1. Department of Neurosurgery, Lariboisière Hospital, 2 rue Ambroise Paré, 75010, Paris, France

    Emmanuel Mandonnet MD, PhD

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  1. , INSERM U1051, Institute for Neurosciences of Montpelli, av. Augustin Fliche 80, Montpellier, 34295, France

    Hugues Duffau

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Mandonnet, E. (2013). Dynamics of DLGG and Clinical Implications. In: Duffau, H. (eds) Diffuse Low-Grade Gliomas in Adults. Springer, London. https://doi.org/10.1007/978-1-4471-2213-5_17

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