WHO classification of CNS tumours

The WHO classification of CNS tumours is the most widely accepted system for classifying CNS tumours and was based on the histological characteristics of the tumour. Although the most recent version of the 'blue book' is the 4^th edition from 2007, an update has been released in 2016 ³, which should be considered a replacement for the earlier version. "At this point, a decision to undertake the 5^th edition series of WHO Blue Books has not been made" ³. This 2016 update has, for the first time, included molecular parameters into the diagnostic schema, and in fact, has elevated them in some instances above histological features ³.  

This is a fairly dry article, primarily for reference. For more readable versions, see the article on brain tumours and brain tumours in infancy for general discussion of these topics.

Main changes since previous (2007) version

The most recent update (2016) has 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

• NOS: not otherwise specified 
• four digit code: is from the International Classification of Disease for Oncology (ICD-O)
• /: the number after the slash (/) refers to biological behaviour, not WHO Grade
• *: refers to a 'new' tumour in the classification
• italics: refers to a provisional inclusion

Diffuse astrocytic and oligodendroglial tumours

• WHO grade II
  • diffuse astrocytoma 
    • IDH-mutant - 9400/3
      • ​gemistocytic astrocytoma - 9411/3
    • IDH-wildtype - 9400/3
    • NOS - 9400/3
  • oligoastrocytoma NOS - 9382/3
  • oligodendroglioma  - 9450/3
    • IDH-mutant, 1p19q co-deleted
    • oligodendroglioma NOS
       
• WHO grade III
  • anaplastic astrocytoma - 9401/3
    • IDH-mutant
    • ​IDH-wildtype
    • NOS
  • anaplastic oligoastrocytoma NOS - 9382/3
  • anaplastic oligodendroglioma - 9451/3
    • IDH-mutant, 1p19q co-deleted
    • anaplastic oligodendroglioma NOS
       
• WHO grade IV
  • glioblastoma
    • IDH wildtype - 9440/3
      • giant cell glioblastoma - 9441/3
      • gliosarcoma 9442/3
      • epithelioid glioblastoma - 9440/3
    • IDH mutant - 9440/3 * 
    • NOS - 9440/3
• diffuse midline glioma, H3K27M-mutant *

Other astrocytic tumours

• WHO grade I
  • pilocytic astrocytoma 9421/11 - WHO grade I
  • subependymal giant cell astrocytoma 9384/1 - WHO grade I
     
• WHO grade II
  • pilomyxoid astrocytoma 9425/3 
  • pleomorphic xanthoastrocytoma 9424/3 - WHO grade II
     
• WHO grade III
  • anaplastic pleomorphic xanthoastrocytoma 9424/3 - WHO grade III

Ependymal tumours

• WHO grade I
  • subependymoma - 9383/1
  • myxopapillary ependymoma - 9394/1
     
• WHO grade II
  • ependymoma - 9391/3
    • papillary ependymoma
    • clear cell ependymoma
    • tanycytic ependymoma
    • RELA fusion-positive - 9396/3 *
       
• WHO grade III
  • anaplastic ependymoma - 9392/3

Other gliomas

• WHO grade I
  • angiocentric glioma - 9431/1
    ​
• WHO grade II
  • chordoid glioma of the third ventricle - 9444/1
     
• WHO grade not yet assigned
  • astroblastoma - 9430/3

Choroid plexus tumours

• WHO grade I
  • choroid plexus papilloma - 9390/0
    ​
• WHO grade II
  • atypical choroid plexus papilloma - 9390/1
     
• WHO grade III
  • choroid plexus carcinoma - 9390/3

Neuronal and mixed neuronal-glial tumours

• WHO grade I
  • desmoplastic infantile astrocytoma and ganglioglioma - 9412/1
  • dysembryoplastic neuroepithelial tumour (DNET) - 9413/0
  • dysplastic gangliocytoma of the cerebellum - (Lhermitte-Duclos) - 9493/0
  • gangliocytoma - 9492/0
  • ganglioglioma - 9505/1
  • papillary glioneuronal tumour - 9509/1
  • paraganglioma of the filum terminale - 8680/1
  • rosette-forming glioneuronal tumour of the fourth ventricle - 9509/1
     
• WHO grade II
  • central neurocytoma - 9506/1
  • extraventricular neurocytoma - 9506/1
  • cerebellar liponeurocytoma - 9506/1
     
• WHO grade III
  • anaplastic ganglioglioma - 9505/3
     
• WHO grade unknown
  • diffuse leptomeningeal glioneuronal tumour - no IDC-O code *

Tumours of the pineal region

• WHO grade I
  • pineocytoma - 9361/1
    ​
• WHO grade II or III
  • pineal parenchymal tumour of intermediate differentiation - 9362/3
  • papillary tumour of the pineal region - 9395/3
     
• WHO grade IV
  • pineoblastoma - 9362/3

Embryonal tumours

• WHO grade IV
  • medulloblastoma
    • genetically defined 
      • WNT-activated - 9475/3 *
      • SHH-activated & TP53-mutant - 9476/3
      • medulloblastoma SHH-activated & TP53-wildtype - 9471/3
      • group 3 - 9477/3
      • group 4 - 9477/3
    • histologically defined
      • classic - 9470/3
      • desmoplastic/nodular - 9471/3
      • extensive nodularity - 9471/3
      • large cell/anaplastic - 9470/3
      • NOS - 9470/3
• CNS neuroblastoma 9500/3
• CNS ganglioneuroblastoma 9490/3
• embryonal tumors with multilayered rosettes - 9478/3 * 
  • C19MC-altered
  • NOS
• medulloepithelioma 9501/3
• atypical teratoid / rhabdoid tumour 9508/3
• CNS embryonal tumour with rhabdoid features 8508/3 
• CNS embryonal tumour, NOS 9473/3

Tumours of cranial and paraspinal nerves

• WHO grade I
  • schwannoma (neurilemoma, neurinoma) - 9560/0
    • cellular schwannoma
    • plexiform schwannoma
    • melanotic schwannoma- 9560/1
  • neurofibroma - 9540/0
    • atypical neurofibroma - 9540/0
    • plexiform neurofibroma - 9550/0
  • perineurioma 9571/0
    ​
• WHO grade II, III or IV
  • malignant peripheral nerve sheath tumour (MPNST) - 9540/3 
    • epithelioid
    • with perineural differentiation

Tumours of meningothelial cells

• WHO grade I
  • meningioma - 9530/0
  • meningothelial meningioma - 9531/0
  • fibrous meningioma - 9532/0
  • microcystic meningioma - 9530/0
  • psammomatous meningioma - 9533/0
  • angiomatous meningioma - 9534/0
  • secretory meningioma  - 9530/0
  • metaplastic meningioma  - 9530/0
  • lymphoplasmacyte-rich meningioma - 9530/0
• WHO grade II
  • atypical meningioma - 9539/1
  • clear cell meningioma - 9538/1
  • chordoid meningioma - 9538/1
     
• WHO grade III
  • anaplastic meningioma (malignant) - 9530/3
  • papillary meningioma - 9538/3
  • rhabdoid meningioma - 9538/3
     

Mesenchymal, non-meningothelial tumours

• WHO grade I, II or III
  • solitary fibrous tumour of the dura/haemangiopericytoma - 8815/0 /1 /3
     
• WHO grade I
  • angiolipoma - 8861/0
  • chondroma - 9220/0
  • desmoid-type fibromatosis - 8821/1
  • haemangioblastoma - 9161/1
  • haemangioma - 9120/0
  • hibernoma - 8880/0
  • leiomyoma - 8890/0
  • lipoma - 8850/0
  • myofibroblastoma - 8825/0
  • osteochondroma - 9210/0
  • osteoma 9180/0
  • rhabdomyoma - 8900/0
     
• WHO grade III
  • epithelioid haemangioendothelioma - 9133/3
  • angiosarcoma - 9120/3
  • chondrosarcoma - 9220/3
  • Ewing sarcoma / PNET - 9364/3
  • fibrosarcoma - 8810/3
  • Kaposi sarcoma - 9140/3
  • leiomyosarcoma - 8890/3
  • liposarcoma (intracranial) - 8850/3
  • osteosarcoma - 9180/3
  • rhabdomyosarcoma - 8900/3
  • undifferentiated pleomorphic sarcoma / malignant fibrous histiocytoma - 8830/3

Melanocytic lesions

• primary melanocytic tumours of the CNS
  • meningeal melanocytosis - 8728/0
  • meningeal melanocytoma - 8728/1
  • meningeal melanomatosis - 8728/3
  • meningeal melanoma - 8720/3

Lymphomas

• diffuse large B-cell lymphoma of the CNS - 9680/3
• immunodeficiency-associated CNS lymphomas
  • AIDS-related diffuse large B-cell lymphoma
  • EBV-positive diffuse large B-cell lymphoma, NOS
  • lymphomatoid granulomatosis - 9766/1
• intravascular large B-cell lymphoma - 9712/3
• Low-grade B-cell lymphomas of the CNS
• T-cell and NK/T-cell lymphomas of the CNS
• anaplastic large cell lymphoma
  • ALK-positive - 9714/3
  • ALK-negative - 9702/3
• MALT lymphoma of the dura - 9699/3

Histiocytic tumours

• Erdheim-Chester disease - 9750/1
• histiocytic sarcoma - 9755/3
• juvenile xanthogranuloma
• Langerhans cell histiocytosis - 9751/3
• Rosai-Dorfman disease

Germ cell tumours

• choriocarcinoma - 9100/3
• embryonal carcinoma - 9070/3
• germinoma - 9064/3
• mixed germ cell tumours - 9085/3
• teratoma
  • mature - 9080/0
  • immature - 9080/3
  • with malignant transformation - 9084/3
• yolk sac tumour - 9071/3

Tumours of the sellar region

• WHO grade I
  • craniopharyngioma - 9350/1
    • adamantinomatous  - 9351/1
    • papillary - 9352/1
  • granular cell tumour - 9582/0
  • pituicytoma - 9432/1
  • spindle cell oncocytoma - 8291/0

Entities removed

The following entities are no longer found in the 2016 WHO classification, last seen in the 2007 version. 

• gliomatosis cerebri - 9381/3
• protoplasmic astrocytoma - 9410/3
• fibrillary astrocytoma - 9420/3
• primitive neuroectodermal tumour (PNET) - 9473/3  (now part of ETMR)
• ependymoblastoma - 9392/3 (now part of ETMR)
• cellular variant of ependymoma

Although oligoastrocytomas remain entities, they are now going to be rare, requiring molecularly distinct populations of both components: astrocytes (IDH-mutant, ATRX-mutant, 1p19q-intact) and oligodendroglial cells (IDH-mutant, ATRX-wildtype, 1p19q-co-deleted) ³. 

New entities

The following entities have been introduced in the 2016 WHO classification.

• epithelioid glioblastoma - 9440/3
• diffuse leptomeningeal glioneuronal tumour - no IDC-O code
• diffuse midline glioma, H3K27M-mutant
• embryonal tumour with multilayered rosettes - 9478/3
• ependymoma RELA fusion-positive - 9396/3
• medulloblastoma - WNT - 9475/3

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