WHO classification of CNS tumors

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

Although traditionally based on histological characteristics of the tumors, 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 (October 2021), not yet available either online or in print ⁷. Nonetheless, numerous publications outlining the changes that have been incorporated have been made available, beginning with a series of cIMPACT-NOW recommendations for the classification of diffuse gliomas ⁶.

Main changes in the 5^th edition (2021)

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 tumors 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 tumor types

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

As a further step towards bringing the CNS classification of tumors in line with those of other systems, this approach has been mostly abandoned, in favor of grading tumors 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 tumor 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 tumor 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 tumor grades in line with other systems. However, since the features used to grade CNS tumors 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 favor 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, and may supersede histological features. For example, an IDH-wildtype astrocytoma with low-grade histologic features can be considered grade 4 (glioblastoma) in the presence of EGFR amplification, TERT promoter mutation or the combined gain of chromosome 7 and loss of chromosome 10 [+7/-10] ⁸. 

Essential and desirable diagnostic criteria

Each tumor 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 tumors where complete molecular classification is not available, not elsewhere classified (NEC) has been added to denote tumors that have been fully characterized but that do not fit within the established classification system ^8,9. 

Main changes in the revised 4^th edition (2016)

The 2016 revised 4^th edition significantly changed the classification of a number of tumor 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 tumors of the dura with hemangiopericytoma, which although appearing very different on imaging seem now to be manifestations of the same tumor. 

Structure

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

Classification (5^th edition, 2021)​

Gliomas, glioneuronal tumors, and neuronal tumors

Adult-type diffuse gliomas

• astrocytoma, IDH-mutant
• oligodendroglioma, IDH-mutant, and 1p/19q-codeleted
• glioblastoma, IDH-wildtype

Pediatric-type diffuse low-grade gliomas

• diffuse astrocytoma, MYB- or MYBL1-altered
• angiocentric glioma
• polymorphous low-grade neuroepithelial tumor of the young
• diffuse low-grade glioma, MAPK pathway-altered

Pediatric-type diffuse high-grade gliomas

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

Circumscribed astrocytic gliomas

• pilocytic astrocytoma
• high-grade astrocytoma with piloid features
• pleomorphic xanthoastrocytoma
• subependymal giant cell astrocytoma
• chordoid glioma
• astroblastoma, MN1-altered

Glioneuronal and neuronal tumors

• ganglioglioma
• desmoplastic infantile ganglioglioma (DIG) / desmoplastic infantile astrocytoma
• dysembryoplastic neuroepithelial tumor
• diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (provisional inclusion)
• papillary glioneuronal tumor
• rosette-forming glioneuronal tumor
• myxoid glioneuronal tumor
• diffuse leptomeningeal glioneuronal tumor
• gangliocytoma
• multinodular and vacuolating neuronal tumor
• dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease)
• central neurocytoma
• extraventricular neurocytoma
• cerebellar liponeurocytoma

Ependymal tumors

• supratentorial ependymoma
  • supratentorial ependymoma, ZFTA fusion-positive
  • supratentorial ependymoma, YAP1 fusion-positive
• posterior fossa ependymoma
  • posterior fossa ependymoma, group PFA
  • posterior fossa ependymoma, group PFB
• spinal ependymoma
  • spinal ependymoma, MYCN-amplified
• myxopapillary ependymoma
• subependymoma

Choroid plexus tumors

• choroid plexus papilloma
• atypical choroid plexus papilloma
• choroid plexus carcinoma

Embryonal tumors

Medulloblastoma

• medulloblastomas, molecularly defined
  • medulloblastoma, WNT-activated
  • medulloblastoma, SHH-activated and TP53-wildtype
  • medulloblastoma, SHH-activated and TP53-mutant
  • medulloblastoma, non-WNT/non-SHH
• medulloblastomas, histologically defined

Other CNS embryonal tumors

• atypical teratoid/rhabdoid tumor
• cribriform neuroepithelial tumor (provisional inclusion)
• embryonal tumor with multilayered rosettes (ETMR)
• CNS neuroblastoma, FOXR2-activated
• CNS tumor with BCOR internal tandem duplication
• CNS embryonal tumor

Pineal tumors

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

Cranial and paraspinal nerve tumors

• schwannoma and schwannoma (intracranial)
• neurofibroma
• perineurioma
• hybrid nerve sheath tumor
• malignant melanotic nerve sheath tumor
• malignant peripheral nerve sheath tumor
• paraganglioma

Meningiomas

• meningioma

Mesenchymal, non-meningothelial tumors

Soft tissue tumors

• fibroblastic and myofibroblastic tumors
  • solitary fibrous tumor
• vascular tumors
  • hemangiomas and vascular malformations
  • hemangioblastoma
• skeletal muscle tumors
  • rhabdomyosarcoma
• uncertain differentiation
  • intracranial mesenchymal tumor, FET-CREB fusion-positive (provisional inclusion)
  • CIC-rearranged sarcoma
  • primary intracranial sarcoma, DICER1-mutant
  • Ewing sarcoma

Chondro-osseous tumors

• chondrogenic tumors
  • mesenchymal chondrosarcoma
  • chondrosarcoma
• notochordal tumors
  • chordoma (including poorly differentiated chordoma)

Melanocytic tumors

• diffuse meningeal melanocytic neoplasms
  • meningeal melanocytosis
  • meningeal melanomatosis
• circumscribed meningeal melanocytic neoplasms
  • meningeal melanocytoma
  • meningeal melanoma

Hematolymphoid tumors

Lymphomas

• CNS lymphomas
  • primary diffuse large B-cell lymphoma of the CNS
  • immunodeficiency-associated CNS lymphoma
  • lymphomatoid granulomatosis
  • intravascular large B-cell lymphoma
• Miscellaneous rare lymphomas in the CNS
  • MALT lymphoma of the dura
  • other low-grade B-cell lymphomas of the CNS
  • anaplastic large cell lymphoma (ALK+/ALK−)
  • T-cell and NK/T-cell lymphomas

Histiocytic tumors

• Erdheim-Chester disease
• Rosai-Dorfman disease
• juvenile xanthogranuloma
• Langerhans cell histiocytosis
• histiocytic sarcoma

Germ cell tumors

• mature teratoma
• immature teratoma
• teratoma with somatic-type malignancy
• germinoma
• embryonal carcinoma
• yolk sac tumor
• choriocarcinoma
• mixed germ cell tumor

Tumors of the sellar region

• adamantinomatous craniopharyngioma
• papillary craniopharyngioma
• pituicytoma, granular cell tumor of the sellar region, and spindle cell oncocytoma
• pituitary adenoma (pitNET)
• pituitary blastoma

Metastases to the CNS

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

History and etymology

The International Agency for Research on Cancer (IARC) is the specialized cancer agency of the World Health Organization and commissions and publishes the "WHO classification of tumors" series. Please note that the term "blue book" is used for all books in the series not just the CNS tumor book ¹⁰.