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Low-grade epilepsy-associated neuroepithelial tumours — the 2016 WHO classification


Rapid developments in molecular genetic technology and research have swiftly advanced our understanding of neuro-oncology. As a consequence, the WHO invited their expert panels to revise the current classification system of brain tumours and to introduce, for the first time, a molecular genetic approach for selected tumour entities, thus setting a new gold standard in histopathology. The revised 5th edition of the 'blue book' was released in May 2016 and will have a major impact in stratifying diagnosis and treatment. However, low-grade neuroepithelial tumours that present with early-onset focal epilepsy and are mostly seen in children and young adults (previously designated as long-term epilepsy-associated neuroepithelial tumours, LEAT) lack such innovative clinicopathological and molecular genetic tools. The Neuropathology Task Force of the International League against Epilepsy will critically discuss this issue, and will offer perspectives on how to decipher and validate clinically meaningful LEAT entities using the current WHO approach that integrates clinicopathological and genetic classification systems.

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Figure 1: Is it all in one? The histopathological spectrum of nodular growth in low-grade epilepsy-associated neuroepithelial tumours.
Figure 2: Molecular genetic pathways affected in low-grade epilepsy-associated neuroepithelial tumours.
Figure 3: Roadmap to comprehensive clinicopathological and genetic WHO–ILAE classification of epilepsy-associated neuroepithelial tumours.


  1. 1

    Louis, D. N., Ohgaki, H., Wiestler, O. D. & Cavenee, W. K. (eds) WHO Classification of Tumours of the Central Nervous System 5th revised edn (International Agency for Research on Cancer, 2016).

    Google Scholar 

  2. 2

    Louis, D. N. et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 131, 803–820 (2016).

    Article  Google Scholar 

  3. 3

    Louis, D. N. et al. International Society Of Neuropathology — Haarlem consensus guidelines for nervous system tumor classification and grading. Brain Pathol. 24, 429–435 (2014).

    Article  Google Scholar 

  4. 4

    Reuss, D. E. et al. ATRX and IDH1-R132H immunohistochemistry with subsequent copy number analysis and IDH sequencing as a basis for an “integrated” diagnostic approach for adult astrocytoma, oligodendroglioma and glioblastoma. Acta Neuropathol. 129, 133–146 (2015).

    CAS  Article  Google Scholar 

  5. 5

    Jenkins, R. B. et al. A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. Cancer Res. 66, 9852–9861 (2006).

    CAS  Article  Google Scholar 

  6. 6

    Cairncross, J. G. et al. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J. Natl Cancer Inst. 90, 1473–1479 (1998).

    CAS  Article  Google Scholar 

  7. 7

    Reifenberger, G. et al. in WHO classification of Tumours of the Central Nervous System 4th revised edn (eds Louis, D. N., Ohgaki, H., Wiestler, O. D. & Cavanee, W. K.) 60–62 (International Agency for Research on Cancer, 2007).

    Google Scholar 

  8. 8

    Reifenberger, J. et al. Molecular-genetic analysis of oligodendroglial tumors shows preferential allelic deletions on 19q and 1p. Am. J. Pathol. 145, 1175–1190 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. 9

    Stupp, R. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352, 987–996 (2005).

    CAS  Article  Google Scholar 

  10. 10

    Hegi, M. E. et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med. 352, 997–1003 (2005).

    CAS  Article  Google Scholar 

  11. 11

    Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).

    CAS  Article  Google Scholar 

  12. 12

    Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).

    CAS  Article  Google Scholar 

  13. 13

    Capper, D. et al. Application of mutant IDH1 antibody to differentiate diffuse glioma from nonneoplastic central nervous system lesions and therapy-induced changes. Am. J. Surg. Pathol. 34, 1199–1204 (2010).

    Article  Google Scholar 

  14. 14

    Capper, D. et al. Characterization of R132H mutation-specific IDH1 antibody binding in brain tumors. Brain Pathol. 20, 245–254 (2010).

    CAS  Article  Google Scholar 

  15. 15

    Wick, W. et al. NOA-04 randomized phase III trial of sequential radiochemotherapy of anaplastic glioma with procarbazine, lomustine, and vincristine or temozolomide. J. Clin. Oncol. 27, 5874–5880 (2009).

    CAS  Article  Google Scholar 

  16. 16

    Buckner, J. C. et al. Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N. Engl. J. Med. 374, 1344–1355 (2016).

    CAS  Article  Google Scholar 

  17. 17

    Sturm, D. et al. New brain tumor entities emerge from molecular classification of CNS-PNETs. Cell 164, 1060–1072 (2016).

    CAS  Article  Google Scholar 

  18. 18

    Weller, M. et al. MGMT promoter methylation is a strong prognostic biomarker for benefit from dose-intensified temozolomide rechallenge in progressive glioblastoma: the DIRECTOR trial. Clin. Cancer Res. 21, 2057–2064 (2015).

    CAS  Article  Google Scholar 

  19. 19

    Luyken, C. et al. The spectrum of long-term epilepsy-associated tumors: long-term seizure and tumor outcome and neurosurgical aspects. Epilepsia 44, 822–830 (2003).

    Article  Google Scholar 

  20. 20

    Blumcke, I., Aronica, E., Urbach, H., Alexopoulos, A. & Gonzalez-Martinez, J. A. A neuropathology-based approach to epilepsy surgery in brain tumors and proposal for a new terminology use for long-term epilepsy-associated brain tumors. Acta Neuropathol. 128, 39–54 (2014).

    CAS  Article  Google Scholar 

  21. 21

    Castel, D. et al. Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes. Acta Neuropathol. 130, 815–827 (2015).

    CAS  Article  Google Scholar 

  22. 22

    Bodi, I. et al. Two cases of multinodular and vacuolating neuronal tumour. Acta Neuropathol. Commun. 2, 7 (2014).

    Article  Google Scholar 

  23. 23

    Yamaguchi, M. et al. Multinodular and vacuolating neuronal tumor affecting amygdala and hippocampus: a quasi-tumor? Pathol. Int. 66, 34–41 (2016).

    CAS  Article  Google Scholar 

  24. 24

    Nagaishi, M. et al. Localized overexpression of alpha-internexin within nodules in multinodular and vacuolating neuronal tumors. Neuropathology 35, 561–568 (2015).

    CAS  Article  Google Scholar 

  25. 25

    Fukushima, S. et al. Multinodular and vacuolating neuronal tumor of the cerebrum. Brain Tumor Pathol. 32, 131–136 (2015).

    CAS  Article  Google Scholar 

  26. 26

    Huse, J. T. et al. Multinodular and vacuolating neuronal tumors of the cerebrum: 10 cases of a distinctive seizure-associated lesion. Brain Pathol. 23, 515–524 (2013).

    Article  Google Scholar 

  27. 27

    Reifenberger, G. & Louis, D. N. Oligodendroglioma: toward molecular definitions in diagnostic neuro-oncology. J. Neuropathol. Exp. Neurol. 62, 111–126 (2003).

    CAS  Article  Google Scholar 

  28. 28

    Giannini, C. et al. Oligodendrogliomas: reproducibility and prognostic value of histologic diagnosis and grading. J. Neuropathol. Exp. Neurol. 60, 248–262 (2001).

    CAS  Article  Google Scholar 

  29. 29

    van den Bent, M. J. et al. IDH1 and IDH2 mutations are prognostic but not predictive for outcome in anaplastic oligodendroglial tumors: a report of the European Organization for Research and Treatment of Cancer Brain Tumor Group. Clin. Cancer Res. 16, 1597–1604 (2010).

    CAS  Article  Google Scholar 

  30. 30

    Weller, M. et al. Combined 1p/19q loss in oligodendroglial tumors: predictive or prognostic biomarker? Clin. Cancer Res. 13, 6933–6937 (2007).

    CAS  Article  Google Scholar 

  31. 31

    Thom, M., Blumcke, I. & Aronica, E. Long-term epilepsy-associated tumors. Brain Pathol. 22, 350–379 (2012).

    Article  Google Scholar 

  32. 32

    Fisher, R. S. et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 55, 475–482 (2014).

    Article  Google Scholar 

  33. 33

    Kwan, P. et al. Definition of drug resistant epilepsy: consensus proposal by the ad hoc Task Force of the ILAE Commission on Therapeutic Strategies. Epilepsia 51, 1069–1077 (2010).

    CAS  Article  Google Scholar 

  34. 34

    Blumcke, I. et al. International recommendation for a comprehensive neuropathologic workup of epilepsy surgery brain tissue: a consensus Task Force report from the ILAE Commission on Diagnostic Methods. Epilepsia 57, 348–358 (2016).

    Article  Google Scholar 

  35. 35

    Wiebe, S., Blume, W. T., Girvin, J. P. & Eliasziw, M. A randomized, controlled trial of surgery for temporal-lobe epilepsy. N. Engl. J. Med. 345, 311–318 (2001).

    CAS  Article  Google Scholar 

  36. 36

    Jemal, A. et al. Cancer statistics, 2006. CA Cancer J. Clin. 56, 106–130 (2006).

    Article  Google Scholar 

  37. 37

    Blumcke, I. & Wiestler, O. D. Gangliogliomas: an intriguing tumor entity associated with focal epilepsies. J. Neuropathol. Exp. Neurol. 61, 575–584 (2002).

    Article  Google Scholar 

  38. 38

    Thom, M. et al. One hundred and one dysembryoplastic neuroepithelial tumors: an adult epilepsy series with immunohistochemical, molecular genetic, and clinical correlations and a review of the literature. J. Neuropathol. Exp. Neurol. 70, 859–878 (2011).

    CAS  Article  Google Scholar 

  39. 39

    Holthausen, H. & Blumcke, I. Epilepsy-associated tumours: what epileptologists should know about neuropathology, terminology, and classification systems. Epileptic Disord. 18, 240–251 (2016).

    PubMed  Google Scholar 

  40. 40

    Horbinski, C. et al. Isocitrate dehydrogenase 1 analysis differentiates gangliogliomas from infiltrative gliomas. Brain Pathol. 21, 564–574 (2011).

    CAS  Article  Google Scholar 

  41. 41

    Prabowo, A. S. et al. Landscape of chromosomal copy number aberrations in gangliogliomas and dysembryoplastic neuroepithelial tumours. Neuropathol. Appl. Neurobiol. 41, 743–755 (2015).

    CAS  Article  Google Scholar 

  42. 42

    Qaddoumi, I. et al. Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology. Acta Neuropathol. 131, 833–845 (2016).

    CAS  Article  Google Scholar 

  43. 43

    Dougherty, M. J. et al. Activating mutations in BRAF characterize a spectrum of pediatric low-grade gliomas. Neuro Oncol. 12, 621–630 (2010).

    CAS  Article  Google Scholar 

  44. 44

    Schindler, G. et al. Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol. 121, 397–405 (2011).

    CAS  Article  Google Scholar 

  45. 45

    Ramkissoon, L. A. et al. Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1. Proc. Natl Acad. Sci. USA 110, 8188–8193 (2013).

    CAS  Article  Google Scholar 

  46. 46

    Roth, J. J. et al. Diagnostic application of high resolution single nucleotide polymorphism array analysis for children with brain tumors. Cancer Genet. 207, 111–123 (2014).

    CAS  Article  Google Scholar 

  47. 47

    Cruz, G. R. et al. Analysis of KIAA1549–BRAF fusion gene expression and IDH1/IDH2 mutations in low grade pediatric astrocytomas. J. Neurooncol. 117, 235–242 (2014).

    CAS  Article  Google Scholar 

  48. 48

    Prabowo, A. S. et al. BRAF V600E mutation is associated with mTOR signaling activation in glioneuronal tumors. Brain Pathol. 24, 52–66 (2014).

    CAS  Article  Google Scholar 

  49. 49

    Zhang, J. et al. Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat. Genet. 45, 602–612 (2013).

    CAS  Article  Google Scholar 

  50. 50

    Chappe, C. et al. Dysembryoplastic neuroepithelial tumors share with pleomorphic xanthoastrocytomas and gangliogliomas BRAF Mutation and expression. Brain Pathol. 23, 574–583 (2013).

    Article  Google Scholar 

  51. 51

    Rivera, B. et al. Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors. Acta Neuropathol. 131, 847–863 (2016).

    CAS  Article  Google Scholar 

  52. 52

    Korshunov, A. et al. Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. Acta Neuropathol. 118, 401–405 (2009).

    CAS  Article  Google Scholar 

  53. 53

    Wang, M. et al. Monomorphous angiocentric glioma: a distinctive epileptogenic neoplasm with features of infiltrating astrocytoma and ependymoma. J. Neuropathol. Exp. Neurol. 64, 875–881 (2005).

    Article  Google Scholar 

  54. 54

    Holsken, A. et al. Adamantinomatous and papillary craniopharyngiomas are characterized by distinct epigenomic as well as mutational and transcriptomic profiles. Acta Neuropathol. Commun. 4, 20 (2016).

    Article  Google Scholar 

  55. 55

    Johann, P. D. et al. Atypical teratoid/rhabdoid tumors are comprised of three epigenetic subgroups with distinct enhancer landscapes. Cancer Cell 29, 379–393 (2016).

    CAS  Article  Google Scholar 

  56. 56

    Pajtler, K. W. et al. Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups. Cancer Cell 27, 728–743 (2015).

    CAS  Article  Google Scholar 

  57. 57

    Capper, D. et al. Assessment of BRAF V600E mutation status by immunohistochemistry with a mutation-specific monoclonal antibody. Acta Neuropathol. 122, 11–19 (2011).

    CAS  Article  Google Scholar 

  58. 58

    Koelsche, C. et al. Mutant BRAF V600E protein in ganglioglioma is predominantly expressed by neuronal tumor cells. Acta Neuropathol. 125, 891–900 (2013).

    CAS  Article  Google Scholar 

  59. 59

    Majores, M. et al. Tumor recurrence and malignant progression of gangliogliomas. Cancer 113, 3355–3363 (2008).

    Article  Google Scholar 

  60. 60

    Blumcke, I. et al. The CD34 epitope is expressed in neoplastic and malformative lesions associated with chronic, focal epilepsies. Acta Neuropathol. 97, 481–490 (1999).

    CAS  Article  Google Scholar 

  61. 61

    Blumcke, I. et al. The clinico-pathological spectrum of focal cortical dysplasias: a consensus classification proposed by an ad hoc Task Force of the ILAE Diagnostic Methods Commission. Epilepsia 52, 158–174 (2011).

    Article  Google Scholar 

  62. 62

    Blumcke, I. et al. International consensus classification of hippocampal sclerosis in temporal lobe epilepsy: a Task Force report from the ILAE Commission on Diagnostic Methods. Epilepsia 54, 1315–1329 (2013).

    Article  Google Scholar 

  63. 63

    Coras, R. et al. Good interobserver and intraobserver agreement in the evaluation of the new ILAE classification of focal cortical dysplasias. Epilepsia 53, 1341–1348 (2012).

    Article  Google Scholar 

  64. 64

    Blumcke, I. et al. Distinct expression pattern of microtubule-associated protein-2 in human oligodendrogliomas and glial precursor cells. J. Neuropathol. Exp. Neurol. 60, 984–993 (2001).

    CAS  Article  Google Scholar 

  65. 65

    Schramm, J., Luyken, C., Urbach, H., Fimmers, R. & Blumcke, I. Evidence for a clinically distinct new subtype of grade II astrocytomas in patients with long-term epilepsy. Neurosurgery 55, 340–347 (2004).

    Article  Google Scholar 

  66. 66

    Blumcke, I., Luyken, C., Urbach, H., Schramm, J. & Wiestler, O. D. An isomorphic subtype of long-term epilepsy-associated astrocytomas associated with benign prognosis. Acta Neuropathol. 107, 381–388 (2004).

    Article  Google Scholar 

  67. 67

    Zülch, K. J. Histological Typing of Tumours of the Central Nervous System (World Health Organization, 1979).

    Google Scholar 

  68. 68

    Kleihues, P., Burger, P. C. & Scheithauer, B. W. (eds) Histological Typing of Tumors of the Central Nervous System (Springer, 1993).

    Google Scholar 

  69. 69

    Kleihues, P. & Cavenee, W. K. (eds) Pathology and Genetics of Tumors of the Nervous System (International Agency for Research on Cancer, 2000).

    Google Scholar 

  70. 70

    Louis, D. N., Ohgaki, H., Wiestler, O. D. & Cavenee, W. K. (eds) WHO Classification of Tumors of the Central Nervous System 4th revised edn (International Agency for Research on Cancer, 2007).

    Google Scholar 

  71. 71

    Agarwal, S. et al. Extraventricular neurocytomas: a morphological and histogenetic consideration. A study of six cases. Pathology 43, 327–334 (2011).

    Article  Google Scholar 

  72. 72

    Capper, D. et al. Mutation-specific IDH1 antibody differentiates oligodendrogliomas and oligoastrocytomas from other brain tumors with oligodendroglioma-like morphology. Acta Neuropathol. 121, 241–252 (2011).

    Article  Google Scholar 

  73. 73

    Horstmann, S. et al. Genetic and expression profiles of cerebellar liponeurocytomas. Brain Pathol. 14, 281–289 (2004).

    CAS  Article  Google Scholar 

  74. 74

    Bridge, J. A. et al. Identification of a novel, recurrent SLC44A1-PRKCA fusion in papillary glioneuronal tumor. Brain Pathol. 23, 121–128 (2013).

    CAS  Article  Google Scholar 

  75. 75

    Solis, O. E. et al. Rosette-forming glioneuronal tumor: a pineal region case with IDH1 and IDH2 mutation analyses and literature review of 43 cases. J. Neurooncol. 102, 477–484 (2011).

    Article  Google Scholar 

  76. 76

    Gessi, M. et al. FGFR1 mutations in rosette-forming glioneuronal tumors of the fourth ventricle. J. Neuropathol. Exp. Neurol. 73, 580–584 (2014).

    CAS  Article  Google Scholar 

  77. 77

    Gessi, M. et al. Absence of KIAA1549-BRAF fusion in rosette-forming glioneuronal tumors of the fourth ventricle (RGNT). J. Neurooncol. 110, 21–25 (2012).

    CAS  Article  Google Scholar 

  78. 78

    Rodriguez, F. J. et al. Disseminated oligodendroglial-like leptomeningeal tumor of childhood: a distinctive clinicopathologic entity. Acta Neuropathol. 124, 627–641 (2012).

    Article  Google Scholar 

  79. 79

    Rodriguez, F. J. et al. High rate of concurrent BRAF-KIAA1549 gene fusion and 1p deletion in disseminated oligodendroglioma-like leptomeningeal neoplasms (DOLN). Acta Neuropathol. 129, 609–610 (2015).

    Article  Google Scholar 

  80. 80

    Preuss, M. et al. Disseminated oligodendroglial-like leptomeningeal tumors: preliminary diagnostic and therapeutic results for a novel tumor entity [corrected]. J. Neurooncol 124, 65–74 (2015).

    CAS  Article  Google Scholar 

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Members of the ILAE Neuropathology Task Force have been partially supported by the Seventh Framework Programme of the European Commission (DESIRE GA # 602531 to I.B.; EPITARGET GA # 602102 to A.B., and E.A.; EPISTOP # 602391 to E.A.). E.A. has received funding from KIKA (Stichting Kinderen Kankervrij) and Stichting AMC Foundation. T.J. has received funding from the Brain Tumour Charity, Children with Cancer, Great Ormond Street Children's Charity and NIHR. H.M. has received funding from the Japan Epilepsy Research Foundation (JERF) (H25-003).

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Correspondence to Ingmar Blümcke.

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Blümcke, I., Aronica, E., Becker, A. et al. Low-grade epilepsy-associated neuroepithelial tumours — the 2016 WHO classification. Nat Rev Neurol 12, 732–740 (2016).

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