Practical Implications of the Updated WHO Classification of Brain Tumors

Maria Martinez-Lage; Felix Sahm

doi:10.1055/s-0038-1641162

Seminars in Neurology, Table of Contents

Semin Neurol 2018; 38(01): 011-018
DOI: 10.1055/s-0038-1641162

Review Article

Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Practical Implications of the Updated WHO Classification of Brain Tumors

Maria Martinez-Lage

¹Department of Pathology (Neuropathology), Massachusetts General Hospital, Boston, Massachusetts

,

Felix Sahm

²Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany

³Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

› Author Affiliations

Abstract

The updated 2016 WHO classification of Central Nervous System tumors introduced a novel concept of neuropathology diagnostics. Molecular parameters are now included into the definition of several entities. This evolution from a previously purely histology-based classification to an integrated approach of histology and genetic characteristics has implications in daily diagnostic and clinical practice. Both the spectrum of diagnostic workup demanded from the neuropathologist and the range of relevant markers to be considered by clinicians and clinical investigators have increased. This article reviews the major changes in the classification of diffuse gliomas, ependymoma, and medulloblastoma, the practical consequences for diagnostics and clinical trials, and points toward recent developments that potentially will influence the next update of the classification.

Keywords

2016 WHO classification - CNS tumors - glioma - astrocytoma - oligodendroglioma - glioblastoma - molecular diagnosis - IDH - prognosis - diagnosis - medulloblastoma - ependymoma

Full Text

References

References
1 Louis DN, Perry A, Reifenberger G. , et al. The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol 2016; 131 (06) 803-820
2 Louis DN, Perry A, Burger P. , et al; International Society Of Neuropathology–Haarlem. International Society Of Neuropathology–Haarlem consensus guidelines for nervous system tumor classification and grading. Brain Pathol 2014; 24 (05) 429-435
3 Aldape K, Nejad R, Louis DN, Zadeh G. Integrating molecular markers into the World Health Organization classification of CNS tumors: a survey of the neuro-oncology community. Neuro Oncol 2017; 19 (03) 336-344
4 Sahm F, Reuss D, Koelsche C. , et al. Farewell to oligoastrocytoma: in situ molecular genetics favor classification as either oligodendroglioma or astrocytoma. Acta Neuropathol 2014; 128 (04) 551-559
5 Wiestler B, Capper D, Hovestadt V. , et al. Assessing CpG island methylator phenotype, 1p/19q codeletion, and MGMT promoter methylation from epigenome-wide data in the biomarker cohort of the NOA-04 trial. Neuro Oncol 2014; 16 (12) 1630-1638
6 Wiestler B, Capper D, Holland-Letz T. , et al. ATRX loss refines the classification of anaplastic gliomas and identifies a subgroup of IDH mutant astrocytic tumors with better prognosis. Acta Neuropathol 2013; 126 (03) 443-451
7 Weller M, Weber RG, Willscher E. , et al. Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups. Acta Neuropathol 2015; 129 (05) 679-693
8 Louis DN, Ohgaki H, Wiestler OD. , et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007; 114 (02) 97-109
9 Chen L, Voronovich Z, Clark K. , et al. Predicting the likelihood of an isocitrate dehydrogenase 1 or 2 mutation in diagnoses of infiltrative glioma. Neuro Oncol 2014; 16 (11) 1478-1483
10 Reuss DE, Sahm F, Schrimpf D. , 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 2015; 129 (01) 133-146
11 Malzkorn B, Reifenberger G. Practical implications of integrated glioma classification according to the World Health Organization classification of tumors of the central nervous system 2016. Curr Opin Oncol 2016; 28 (06) 494-501
12 Khuong-Quang DA, Buczkowicz P, Rakopoulos P. , et al. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol 2012; 124 (03) 439-447
13 Sturm D, Witt H, Hovestadt V. , et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 2012; 22 (04) 425-437
14 Schwartzentruber J, Korshunov A, Liu XY. , et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 2012; 482 (7384): 226-231
15 Wu G, Broniscer A, McEachron TA. , et al; St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 2012; 44 (03) 251-253
16 Ebrahimi A, Skardelly M, Bonzheim I. , et al. ATRX immunostaining predicts IDH and H3F3A status in gliomas. Acta Neuropathol Commun 2016; 4 (01) 60
17 Kool M, Korshunov A, Remke M. , et al. Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas. Acta Neuropathol 2012; 123 (04) 473-484
18 Pietsch T, Haberler C. Update on the integrated histopathological and genetic classification of medulloblastoma - a practical diagnostic guideline. Clin Neuropathol 2016; 35 (06) 344-352
19 Ellison DW, Kocak M, Dalton J. , et al. Definition of disease-risk stratification groups in childhood medulloblastoma using combined clinical, pathologic, and molecular variables. J Clin Oncol 2011; 29 (11) 1400-1407
20 Ellison DW, Dalton J, Kocak M. , et al. Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups. Acta Neuropathol 2011; 121 (03) 381-396
21 Taylor MD, Northcott PA, Korshunov A. , et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol 2012; 123 (04) 465-472
22 Reuss DE, Kratz A, Sahm F. , et al. Adult IDH wild type astrocytomas biologically and clinically resolve into other tumor entities. Acta Neuropathol 2015; 130 (03) 407-417
23 Brat DJ, Verhaak RG, Aldape KD. , et al; Cancer Genome Atlas Research Network. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 2015; 372 (26) 2481-2498
24 Suzuki H, Aoki K, Chiba K. , et al. Mutational landscape and clonal architecture in grade II and III gliomas. Nat Genet 2015; 47 (05) 458-468
25 Singh D, Chan JM, Zoppoli P. , et al. Transforming fusions of FGFR and TACC genes in human glioblastoma. Science 2012; 337 (6099): 1231-1235
26 Di Stefano AL, Fucci A, Frattini V. , et al. Detection, characterization, and inhibition of FGFR-TACC fusions in IDH wild-type Glioma. Clin Cancer Res 2015; 21 (14) 3307-3317
27 Yoshimoto K, Hatae R, Sangatsuda Y. , et al. Prevalence and clinicopathological features of H3.3 G34-mutant high-grade gliomas: a retrospective study of 411 consecutive glioma cases in a single institution. Brain Tumor Pathol 2017; 34 (03) 103-112
28 Gessi M, Capper D, Sahm F. , et al. Evidence of H3 K27M mutations in posterior fossa ependymomas. Acta Neuropathol 2016; 132 (04) 635-637
29 Jiao Y, Killela PJ, Reitman ZJ. , et al. Frequent ATRX, CIC, FUBP1 and IDH1 mutations refine the classification of malignant gliomas. Oncotarget 2012; 3 (07) 709-722
30 Killela PJ, Pirozzi CJ, Healy P. , et al. Mutations in IDH1, IDH2, and in the TERT promoter define clinically distinct subgroups of adult malignant gliomas. Oncotarget 2014; 5 (06) 1515-1525
31 Pekmezci M, Rice T, Molinaro AM. , et al. Adult infiltrating gliomas with WHO 2016 integrated diagnosis: additional prognostic roles of ATRX and TERT. Acta Neuropathol 2017; 133 (06) 1001-1016
32 Zhang J, Wu G, Miller CP. , et al; St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project. Whole-genome sequencing identifies genetic alterations in pediatric low-grade gliomas. Nat Genet 2013; 45 (06) 602-612
33 Schindler G, Capper D, Meyer J. , 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 2011; 121 (03) 397-405
34 Huether R, Dong L, Chen X. , et al. The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes. Nat Commun 2014; 5: 3630
35 Jones DT, Kocialkowski S, Liu L, Pearson DM, Ichimura K, Collins VP. Oncogenic RAF1 rearrangement and a novel BRAF mutation as alternatives to KIAA1549:BRAF fusion in activating the MAPK pathway in pilocytic astrocytoma. Oncogene 2009; 28 (20) 2119-2123
36 Alexandrescu S, Korshunov A, Lai SH. , et al. Epithelioid glioblastomas and anaplastic epithelioid pleomorphic xanthoastrocytomas--same entity or first cousins?. Brain Pathol 2016; 26 (02) 215-223
37 Broniscer A, Tatevossian RG, Sabin ND. , et al. Clinical, radiological, histological and molecular characteristics of paediatric epithelioid glioblastoma. Neuropathol Appl Neurobiol 2014; 40 (03) 327-336
38 Donson AM, Kleinschmidt-DeMasters BK, Aisner DL. , et al. Pediatric brainstem gangliogliomas show BRAF(V600E) mutation in a high percentage of cases. Brain Pathol 2014; 24 (02) 173-183
39 Kleinschmidt-DeMasters BK, Aisner DL, Birks DK, Foreman NK. Epithelioid GBMs show a high percentage of BRAF V600E mutation. Am J Surg Pathol 2013; 37 (05) 685-698
40 Jones DT, Kocialkowski S, Liu L. , et al. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 2008; 68 (21) 8673-8677
41 Rodriguez FJ, Schniederjan MJ, Nicolaides T, Tihan T, Burger PC, Perry A. High rate of concurrent BRAF-KIAA1549 gene fusion and 1p deletion in disseminated oligodendroglioma-like leptomeningeal neoplasms (DOLN). Acta Neuropathol 2015; 129 (04) 609-610
42 Rodriguez FJ, Perry A, Rosenblum MK. , et al. Disseminated oligodendroglial-like leptomeningeal tumor of childhood: a distinctive clinicopathologic entity. Acta Neuropathol 2012; 124 (05) 627-641
43 Jones DT, Hutter B, Jäger N. , et al; International Cancer Genome Consortium PedBrain Tumor Project. Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet 2013; 45 (08) 927-932
44 Gielen GH, Gessi M, Buttarelli FR. , et al. Genetic analysis of diffuse high-grade astrocytomas in infancy defines a novel molecular entity. Brain Pathol 2015; 25 (04) 409-417
45 Gessi M, Moneim YA, Hammes J. , et al. FGFR1 mutations in Rosette-forming glioneuronal tumors of the fourth ventricle. J Neuropathol Exp Neurol 2014; 73 (06) 580-584
46 Gessi M, Abdel Moneim Y, Hammes J, Waha A, Pietsch T. FGFR1 N546K mutation in a case of papillary glioneuronal tumor (PGNT). Acta Neuropathol 2014; 127 (06) 935-936
47 Pajtler KW, Mack SC, Ramaswamy V. , et al. The current consensus on the clinical management of intracranial ependymoma and its distinct molecular variants. Acta Neuropathol 2017; 133 (01) 5-12
48 Pajtler KW, Witt H, Sill M. , et al. Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups. Cancer Cell 2015; 27 (05) 728-743
49 Mack SC, Witt H, Piro RM. , et al. Epigenomic alterations define lethal CIMP-positive ependymomas of infancy. Nature 2014; 506 (7489): 445-450
50 Witt H, Mack SC, Ryzhova M. , et al. Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell 2011; 20 (02) 143-157
51 Parker M, Mohankumar KM, Punchihewa C. , et al. C11orf95-RELA fusions drive oncogenic NF-κB signalling in ependymoma. Nature 2014; 506 (7489): 451-455
52 Pietsch T, Wohlers I, Goschzik T. , et al. Supratentorial ependymomas of childhood carry C11orf95-RELA fusions leading to pathological activation of the NF-κB signaling pathway. Acta Neuropathol 2014; 127 (04) 609-611
53 Hovestadt V, Remke M, Kool M. , et al. Robust molecular subgrouping and copy-number profiling of medulloblastoma from small amounts of archival tumour material using high-density DNA methylation arrays. Acta Neuropathol 2013; 125 (06) 913-916
54 Sahm F, Schrimpf D, Jones DT. , et al. Next-generation sequencing in routine brain tumor diagnostics enables an integrated diagnosis and identifies actionable targets. Acta Neuropathol 2016; 131 (06) 903-910