WHO classification of CNS tumours

The WHO classification of CNS tumours is the most widely accepted system for classifying CNS tumours, now into its 5^th edition, traditionally published in a blue cover (thus "blue book").

Although traditionally based on histological characteristics of the tumours, since the 2016 revised 4^th edition of the 'blue book' the classification increasingly relies on molecular parameters for classification and in some instances has elevated them above histological features ³.  

The 5^th edition referred to as "published in 2021" in many publications and presentations by the primary authors ⁸ is, at the time of writing (September 2021), not yet available neither online nor in print ⁷. Nonetheless, numerous publications outlining the changes that have been incorporated have been made available, beginning with a series of cIMPACT recommendations for the classification of diffuse gliomas ⁶.

Main changes since the 2016 version (revised 4^th edition)

The 5^th edition (2021) builds on the prior version by placing greater emphasis on molecular markers both in terms of classification and grading. This approach, however, results in a fairly heterogeneous classification depending on the specific entity. Some tumours remain primarily assessed histologically while others are entirely on the basis of molecular parameters. 

This will be reflected in a "layered report structure" wherein histological features, grading and molecular information will be combined to form an integrated diagnosis.

• integrated diagnosis
• histopathological classification
• CNS WHO grade
• molecular information

Some important changes to terminology and specific entities are worth highlighting. 

Terminology

Type and subtype

• type replaces "entity"
• subtype replaces "variant" 

For example, meningiomas represent one "type" with numerous "subtypes" e.g. chordoid, rhabdoid, clear cell etc... 

Grading

Grading within tumour types

Unlike other WHO classification systems that graded each tumour based on its own features (i.e. the most low-grade version of a particular tumour was given grade 1, even if it was more aggressive than some other tumour's grade 3 version), in prior editions tumours of the central nervous system where graded (roughly) equivalently so that, in principle, grade I tumours of any type were generally indolent and could be cured if completely resected, whereas grade IV tumours would result in rapid demise ⁸.

As a further step towards bringing the CNS classification of tumours in line with those of other systems, this approach has been mostly abandoned, in favour of grading tumours purely within each "type" ⁸.

Due to the inertia of prior classifications and the desire to avoid additional confusion, however, this has only been adopted in a way that does not overly clash with prior grading. For example, despite grading within tumour types, no grade 1 diffuse astrocytoma, IDH-mutant exists (only grade 2, 3 and 4 are available). Similarly, glioblastoma, IDH-wildtype can only ever be a grade 4 tumour ⁸. 

Arabic numerals

Previously the Roman numerals I, II, III and IV were used for grading. These will be replaced by the Arabic numerals 1, 2, 3 and 4 to bring CNS tumour grades in line with other systems. However, since the features used to grade CNS tumours remain different from those used systemically, it is recommended that the grade be preceded by "CNS WHO", e.g. "meningioma CNS WHO grade 1" ⁸. 

Anaplastic modifier

The term anaplastic, used extensively in the prior classifications has been dropped in favour of grading only. Thus what was previously known as an "anaplastic astrocytoma" is now referred to as an "astrocytoma, IDH-mutant, CNS WHO grade 3" ⁸.

Molecular grading

For the first time, molecular features have been explicitly added to the grading schema, supplanting histological features. For example, EGFR amplification and TERT promoter mutation in IDH mutant astrocytomas ⁸. 

Essential and desirable diagnostic criteria

Each tumour type has been given certain essential diagnostic criteria necessary for a specific diagnosis, as well as additional non-essential but nonetheless desirable criteria ⁸.

Not elsewhere classified (NEC)

In addition to not otherwise specified (NOS), which denotes tumours where complete molecular classification is not available, not elsewhere classified (NEC) has been added to denote tumours that have been fully characterised but that do not fit within the established classification system ^8,9. 

NOTE: This article is in the process of being updated from the revised 4^th edition (2016) to the new 2021 5^th edition. Until this is complete, expect the content below to be a hybrid of the two.  

Main changes since the 2007 version (4^th edition)

The 2016 revised 4^th edition significantly changed the classification of a number of tumour families, introducing a greater reliance on molecular markers. The most notable changes involve diffuse gliomas, in which IDH status (mutated vs. wildtype) and 1p19q co-deletion (for oligodendrogliomas) have risen to prominence. Importantly if histological phenotype and genotype are not-concordant (e.g. looks like diffuse astrocytoma but is 1p19q co-deleted, ATRX-wildtype) then genotype wins, and it is used to determine diagnosis ³. 

Medulloblastomas have also been divided into distinct molecular subgroups. 

Another change is the combining of solitary fibrous tumours of the dura with hemangiopericytoma, which although appearing very different on imaging seem now to be manifestations of the same tumour. 

Structure

Despite a move towards molecular markers for some entities, the classification continues to be organised according to the cell of origin (e.g. ependymal tumours) or anatomical origin (e.g. tumours of the sellar region). 

For entities that now incorporate molecular markers into their definition (e.g. oligodendroglioma IDH-mutant, 1p19q co-deleted) it is recognised that such markers are not always available or identified. In such cases, a 'not otherwise specified (NOS)' option is available (e.g. oligodendroglioma NOS). 

Classification (5th Edition, 2021)​

Gliomas, glioneuronal tumours, and neuronal tumours

Adult-type diffuse gliomas

• Astrocytomaastrocytoma, IDH-mutant
• Oligodendrogliomaoligodendroglioma, IDH-mutant, and 1p/19q-codeleted
• Glioblastomaglioblastoma, IDH-wildtype

Pediatric-type diffuse low-grade gliomas

• Diffusediffuse astrocytoma, MYB- or MYBL1-altered
• Angiocentricangiocentric glioma
• Polymorphouspolymorphous low-grade neuroepithelial tumour of the young
• Diffusediffuse low-grade glioma, MAPK pathway-altered

Pediatric-type diffuse high-grade gliomas

•  Diffuse diffuse midline glioma, H3 K27-altered
•  Diffuse diffuse hemispheric glioma, H3 G34-mutant
•  Diffuse diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype
•  Infant infant-type hemispheric glioma

Circumscribed astrocytic gliomas

• Pilocyticpilocytic astrocytoma
• Highhigh-grade astrocytoma with piloid features
• Pleomorphicpleomorphic xanthoastrocytoma
• Subependymalsubependymal giant cell astrocytoma
• Chordoidchordoid glioma
• Astroblastomaastroblastoma, MN1-altered

Glioneuronal and neuronal tumours

• Gangliogliomaganglioglioma
• Desmoplasticdesmoplastic infantile ganglioglioma (DIG) / desmoplastic infantile astrocytoma
• Dysembryoplasticdysembryoplastic neuroepithelial tumour
• Diffusediffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters (provisional inclusion)
• Papillarypapillary glioneuronal tumour
• rosette-forming glioneuronal tumor
• myxoid glioneuronal tumour
• Rosette-forming glioneuronal tumor
• Myxoid glioneuronal tumour
• Diffusediffuse leptomeningeal glioneuronal tumour
• Gangliocytomagangliocytoma
• Multinodularmultinodular and vacuolating neuronal tumor
• Dysplasticdysplastic cerebellar gangliocytoma (Lhermitte (Lhermitte-Duclos disease)
• Centralcentral neurocytoma
• Extraventricularextraventricular neurocytoma
• Cerebellarcerebellar liponeurocytoma

Ependymal tumours

• Supratentorialsupratentorial ependymoma
• Supratentorialsupratentorial ependymoma, ZFTA fusion-positive
• Supratentorialsupratentorial ependymoma, YAP1 fusion-positive
• Posteriorposterior fossa ependymoma
• Posteriorposterior fossa ependymoma, group PFA
• Posteriorposterior fossa ependymoma, group PFB
• Spinalspinal ependymoma
• Spinalspinal ependymoma, MYCN-amplified
• Myxopapillarymyxopapillary ependymoma
• Subependymomasubependymoma

Choroid plexus tumours

Choroid

• choroid plexus papillomaAtypical
• atypical choroid plexus papillomaChoroid
• choroid plexus carcinoma

Embryonal tumours

Medulloblastoma

• Medulloblastomasmedulloblastomas, molecularly defined
  • Medulloblastomamedulloblastoma, WNT-activated
  • Medulloblastomamedulloblastoma, SHH-activated and TP53-wildtype
  • Medulloblastomamedulloblastoma, SHH-activated and TP53-mutant
  • Medulloblastomamedulloblastoma, non-WNT/non-SHH
• Medulloblastomasmedulloblastomas, histologically defined

Other CNS embryonal tumours

• Atypicalatypical teratoid/rhabdoid tumour
• Cribriformcribriform neuroepithelial tumour (provisional inclusion)
• Embryonalembryonal tumour with multilayered rosettes (ETMR)
• CNS neuroblastoma, FOXR2-activated
• CNS tumour with BCOR internal tandem duplication
• CNS embryonal tumour

Pineal tumours

• pineocytoma
• pineal parenchymal tumour of intermediate differentiation
• pineoblastoma
• papillary tumour of the pineal region
• desmoplastic myxoid tumour of the pineal region, SMARCB1-mutant

Cranial and paraspinal nerve tumours

• Schwannomaschwannoma and schwannoma (intracranial)
• Neurofibromaneurofibroma
• Perineuriomaperineurioma
• Hybridhybrid nerve sheath tumour
• Malignantmalignant melanotic nerve sheath tumour
• Malignantmalignant peripheral nerve sheath tumour
• Paragangliomaparaganglioma

Meningiomas

• meningioma

Mesenchymal, non-meningothelial tumours

Soft tissue tumours

• Fibroblasticfibroblastic and myofibroblastic tumours
  • Solitarysolitary fibrous tumour
• Vascularvascular tumours
  • Hemangiomashemangiomas and vascular malformations
  • Hemangioblastomahemangioblastoma
• Skeletalskeletal muscle tumours
  • Rhabdomyosarcomarhabdomyosarcoma
• Uncertainuncertain differentiation
  • Intracranialintracranial mesenchymal tumour, FET-CREB fusion-positive (provisional inclusion)
  • CIC-rearranged sarcoma
  • Primaryprimary intracranial sarcoma, DICER1-mutant
  • Ewing sarcoma

Chondro-osseous tumours

• Chondrogenicchondrogenic tumours
  • Mesenchymalmesenchymal chondrosarcoma
  • Chondrosarcomachondrosarcoma
• Notochordalnotochordal tumours
  • Chordomachordoma (including poorly differentiated chordoma)

Melanocytic tumours

• Diffusediffuse meningeal melanocytic neoplasms
  • Meningealmeningeal melanocytosis and meningeal melanomatosis
• Circumscribedcircumscribed meningeal melanocytic neoplasms
  • Meningealmeningeal melanocytoma and meningeal melanoma

Hematolymphoid tumours

Lymphomas

• CNS lymphomas
  • Primaryprimary diffuse large B-cell lymphoma of the CNS
  • Immunodeficiencyimmunodeficiency-associated CNS lymphoma
  • Lymphomatoidlymphomatoid granulomatosis
  • Intravascularintravascular large B-cell lymphoma
• Miscellaneous rare lymphomas in the CNS
  • MALT lymphoma of the dura
  • Otherother low-grade B-cell lymphomas of the CNS
  • Anaplasticanaplastic large cell lymphoma (ALK+/ALK−)
  • T-cell and NK/T-cell lymphomas

Histiocytic tumours

• Erdheim-Chester disease
• Rosai-Dorfman disease
• Juvenilejuvenile xanthogranuloma
• Langerhans cell histiocytosis
• Histiocytichistiocytic sarcoma

Germ cell tumours

• Maturemature teratoma
• Immatureimmature teratoma
• Teratomateratoma with somatic-type malignancy
• Germinomagerminoma
• Embryonalembryonal carcinoma
• Yolkyolk sac tumour
• Choriocarcinomachoriocarcinoma
• Mixedmixed germ cell tumour

Tumours of the sellar region

• Adamantinomatousadamantinomatous craniopharyngioma
• Papillarypapillary craniopharyngioma
• Pituicytomapituicytoma, granular cell tumor of the sellar region, and spindle cell oncocytoma
• Pituitarypituitary adenoma/PitNET
• Pituitarypituitary blastoma

Metastases to the CNS

• Metastasesmetastases to the brain and spinal cord parenchyma
• Metastasesmetastases to the meninges