Classification and pathologic diagnosis of gliomas
- David N Louis, MD
David N Louis, MD
- Massachusetts General Hospital
- Benjamin Castleman Professor of Pathology
- Harvard Medical School
- David Schiff, MD
David Schiff, MD
- Professor of Neurology, Neurological Surgery, and Medicine
- University of Virginia School of Medicine
- Tracy Batchelor, MD, MPH
Tracy Batchelor, MD, MPH
- Giovanni Armenise Professor of Neurology
- Harvard Medical School
- Section Editors
- Jay S Loeffler, MD
Jay S Loeffler, MD
- Section Editor — Neurooncology
- Professor of Radiation Oncology
- Harvard Medical School
- Patrick Y Wen, MD
Patrick Y Wen, MD
- Section Editor — Neurooncology
- Professor of Neurology
- Harvard Medical School
Gliomas account for the great majority of primary tumors that arise within the brain parenchyma. The term "glioma" refers to tumors that have histologic features similar to normal glial cells (ie, astrocytes, oligodendrocytes, and ependymal cells). For each of these types of gliomas, there are neoplasms that span a broad spectrum of biologic aggressiveness.
Historically, the slower-growing lesions, corresponding to World Health Organization (WHO) grades I and II, have been commonly referred to as low-grade gliomas, while the more rapidly progressive tumors are referred to as high-grade gliomas. The WHO classification recommends avoiding the term "low-grade glioma," however, since it lumps together a heterogenous groups of tumors, many of which have significantly different biologic properties, prognoses, and treatment approaches [1,2]. Among grade I and grade II gliomas, for example, current classification favors a distinction between diffuse gliomas (eg, grade II diffuse astrocytoma and oligodendroglioma) and more circumscribed astrocytic tumors (eg, grade I pilocytic astrocytoma).
The classification and diagnosis of gliomas will be reviewed here. Pathogenesis of diffuse gliomas is reviewed separately. (See "Molecular pathogenesis of diffuse gliomas".)
HISTORY OF GLIOMA CLASSIFICATION
The classification and grading of gliomas have evolved over time, beginning in 1926 with a system devised by Bailey and Cushing  and later revised by Kernohan, Ringertz, and others [4-6]. Modern classification of gliomas is based on the World Health Organization (WHO) Classification of Central Nervous System Tumors, first published in 1979 and revised four times since then, most recently in 2016 [1,2].
As of the 2016 edition of the WHO classification, gliomas are classified based not only on histopathologic appearance but also on well-established molecular parameters . The incorporation of molecular features has most notably impacted the classification of astrocytic and oligodendroglial tumors, which are now grouped together as diffuse gliomas, on the basis of growth pattern, behavior, and shared isocitrate dehydrogenase (IDH) genetic status.To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- WHO Classification of Tumours of the Central Nervous System, 4th ed, Louis DN, Ohgaki H, Wiestler OD, Cavenee WK (Eds), IARC, Lyon 2016.
- 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; 131:803.
- Bailey P, Cushing H. A classification of the tumors of the glioma group on a histogenetic basis with a correlated study of prognosis, JB Lippincott, Philadelphia 1926.
- KERNOHAN JW, MABON RF. A simplified classification of the gliomas. Proc Staff Meet Mayo Clin 1949; 24:71.
- RINGERTZ N. Grading of gliomas. Acta Pathol Microbiol Scand 1950; 27:51.
- Daumas-Duport C, Szikla G. [Definition of limits and 3D configuration of cerebral gliomas. Histological data, therapeutic incidences (author's transl)]. Neurochirurgie 1981; 27:273.
- Cancer Genome Atlas Research Network, Brat DJ, Verhaak RG, et al. Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. N Engl J Med 2015; 372:2481.
- Eckel-Passow JE, Lachance DH, Molinaro AM, et al. Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors. N Engl J Med 2015; 372:2499.
- Reuss DE, Mamatjan Y, Schrimpf D, et al. IDH mutant diffuse and anaplastic astrocytomas have similar age at presentation and little difference in survival: a grading problem for WHO. Acta Neuropathol 2015; 129:867.
- Camelo-Piragua S, Jansen M, Ganguly A, et al. Mutant IDH1-specific immunohistochemistry distinguishes diffuse astrocytoma from astrocytosis. Acta Neuropathol 2010; 119:509.
- Horbinski C, Kofler J, Kelly LM, et al. Diagnostic use of IDH1/2 mutation analysis in routine clinical testing of formalin-fixed, paraffin-embedded glioma tissues. J Neuropathol Exp Neurol 2009; 68:1319.
- Hartmann C, Meyer J, Balss J, et al. Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas. Acta Neuropathol 2009; 118:469.
- Visani M, Acquaviva G, Marucci G, et al. Non-canonical IDH1 and IDH2 mutations: a clonal and relevant event in an Italian cohort of gliomas classified according to the 2016 World Health Organization (WHO) criteria. J Neurooncol 2017; 135:245.
- Cairncross JG, Ueki K, Zlatescu MC, et al. Specific genetic predictors of chemotherapeutic response and survival in patients with anaplastic oligodendrogliomas. J Natl Cancer Inst 1998; 90:1473.
- Griffin CA, Burger P, Morsberger L, et al. Identification of der(1;19)(q10;p10) in five oligodendrogliomas suggests mechanism of concurrent 1p and 19q loss. J Neuropathol Exp Neurol 2006; 65:988.
- Jenkins RB, Blair H, Ballman KV, 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 2006; 66:9852.
- 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; 68:8673.
- Dougherty MJ, Santi M, Brose MS, et al. Activating mutations in BRAF characterize a spectrum of pediatric low-grade gliomas. Neuro Oncol 2010; 12:621.
- 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; 121:397.
- Louis DN, Perry A, Burger P, et al. International Society Of Neuropathology--Haarlem consensus guidelines for nervous system tumor classification and grading. Brain Pathol 2014; 24:429.
- Suzuki H, Aoki K, Chiba K, et al. Mutational landscape and clonal architecture in grade II and III gliomas. Nat Genet 2015; 47:458.
- 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; 129:133.
- Wiestler B, Capper D, Sill M, et al. Integrated DNA methylation and copy-number profiling identify three clinically and biologically relevant groups of anaplastic glioma. Acta Neuropathol 2014; 128:561.
- Hartmann C, Hentschel B, Tatagiba M, et al. Molecular markers in low-grade gliomas: predictive or prognostic? Clin Cancer Res 2011; 17:4588.
- Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. Classification of Tumours of the Nervous System, IARC Press, Lyon, France 2007.
- Krouwer HG, Davis RL, Silver P, Prados M. Gemistocytic astrocytomas: a reappraisal. J Neurosurg 1991; 74:399.
- Nobusawa S, Watanabe T, Kleihues P, Ohgaki H. IDH1 mutations as molecular signature and predictive factor of secondary glioblastomas. Clin Cancer Res 2009; 15:6002.
- Yan H, Parsons DW, Jin G, et al. IDH1 and IDH2 mutations in gliomas. N Engl J Med 2009; 360:765.
- Olar A, Wani KM, Alfaro-Munoz KD, et al. IDH mutation status and role of WHO grade and mitotic index in overall survival in grade II-III diffuse gliomas. Acta Neuropathol 2015; 129:585.
- Schneider JH Jr, Raffel C, McComb JG. Benign cerebellar astrocytomas of childhood. Neurosurgery 1992; 30:58.
- Morreale VM, Ebersold MJ, Quast LM, Parisi JE. Cerebellar astrocytoma: experience with 54 cases surgically treated at the Mayo Clinic, Rochester, Minnesota, from 1978 to 1990. J Neurosurg 1997; 87:257.
- Casotto A, Buoncristiani P, Signorini E, Giordana MT. Third ventricle gliomas. Report of 7 cases with benign clinical behaviour. Acta Neurochir (Wien) 1985; 74:43.
- Palma L, Guidetti B. Cystic pilocytic astrocytomas of the cerebral hemispheres. Surgical experience with 51 cases and long-term results. J Neurosurg 1985; 62:811.
- Garcia DM, Fulling KH. Juvenile pilocytic astrocytoma of the cerebrum in adults. A distinctive neoplasm with favorable prognosis. J Neurosurg 1985; 63:382.
- Forsyth PA, Shaw EG, Scheithauer BW, et al. Supratentorial pilocytic astrocytomas. A clinicopathologic, prognostic, and flow cytometric study of 51 patients. Cancer 1993; 72:1335.
- Burkhard C, Di Patre PL, Schüler D, et al. A population-based study of the incidence and survival rates in patients with pilocytic astrocytoma. J Neurosurg 2003; 98:1170.
- Horbinski C, Hamilton RL, Nikiforov Y, Pollack IF. Association of molecular alterations, including BRAF, with biology and outcome in pilocytic astrocytomas. Acta Neuropathol 2010; 119:641.
- Yu J, Deshmukh H, Gutmann RJ, et al. Alterations of BRAF and HIPK2 loci predominate in sporadic pilocytic astrocytoma. Neurology 2009; 73:1526.
- Jacob K, Albrecht S, Sollier C, et al. Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours. Br J Cancer 2009; 101:722.
- Korshunov A, Meyer J, Capper D, et al. Combined molecular analysis of BRAF and IDH1 distinguishes pilocytic astrocytoma from diffuse astrocytoma. Acta Neuropathol 2009; 118:401.
- Lee YY, Van Tassel P, Bruner JM, et al. Juvenile pilocytic astrocytomas: CT and MR characteristics. AJR Am J Roentgenol 1989; 152:1263.
- Coakley KJ, Huston J 3rd, Scheithauer BW, et al. Pilocytic astrocytomas: well-demarcated magnetic resonance appearance despite frequent infiltration histologically. Mayo Clin Proc 1995; 70:747.
- Migliorini D, Aguiar D, Vargas MI, et al. BRAF/MEK double blockade in refractory anaplastic pleomorphic xanthoastrocytoma. Neurology 2017; 88:1291.
- Witt H, Mack SC, Ryzhova M, et al. Delineation of two clinically and molecularly distinct subgroups of posterior fossa ependymoma. Cancer Cell 2011; 20:143.
- Ramaswamy V, Hielscher T, Mack SC, et al. Therapeutic Impact of Cytoreductive Surgery and Irradiation of Posterior Fossa Ependymoma in the Molecular Era: A Retrospective Multicohort Analysis. J Clin Oncol 2016; 34:2468.
- HISTORY OF GLIOMA CLASSIFICATION
- KEY MOLECULAR DIAGNOSTIC TESTS
- IDH1/IDH2 mutations
- 1p/19q codeletion
- ATRX mutation
- TP53 mutation
- H3 K27M mutation
- BRAF alterations
- RELA fusion
- HISTOPATHOLOGIC AND MOLECULAR CLASSIFICATION
- Diffuse astrocytic and oligodendroglial tumors
- - General features
- - IDH-mutant astrocytomas
- - IDH-wildtype astrocytomas and glioblastoma
- - IDH-mutant, 1p/19q-codeleted oligodendrogliomas
- - NOS designation
- Oligoastrocytomas NOS
- Other astrocytic tumors
- - Pilocytic astrocytoma
- - Pleomorphic xanthoastrocytoma
- - Subependymal giant cell astrocytoma
- Ependymal tumors
- Neuronal and mixed neuronal-glial tumors
- INFORMATION FOR PATIENTS