WHO classification of CNS tumors
Citation, DOI & article data
The WHO classification of CNS tumors is the most widely accepted system for classifying CNS tumors, now into its 5th edition, traditionally published in a blue cover (thus "blue book").
Although traditionally based on histological characteristics of the tumors, since the 2016 revised 4th 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 5th 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 5th edition (2021)
The 5th 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.
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 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.
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.
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.
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 4th edition (2016)
The 2016 revised 4th 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.
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 (5th 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
- 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
- multinodular and vacuolating neuronal tumor
- dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease)
- central neurocytoma
- extraventricular neurocytoma
- cerebellar liponeurocytoma
- 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, MYCN-amplified
- myxopapillary ependymoma
Choroid plexus tumors
- 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 parenchymal tumor of intermediate differentiation
- papillary tumor of the pineal region
- desmoplastic myxoid tumor of the pineal region, SMARCB1-mutant
Cranial and paraspinal nerve tumors
- schwannoma and schwannoma (intracranial)
- hybrid nerve sheath tumor
- malignant melanotic nerve sheath tumor
- malignant peripheral nerve sheath tumor
Mesenchymal, non-meningothelial tumors
Soft tissue tumors
- fibroblastic and myofibroblastic tumors
- vascular tumors
- skeletal muscle tumors
- uncertain differentiation
- intracranial mesenchymal tumor, FET-CREB fusion-positive (provisional inclusion)
- CIC-rearranged sarcoma
- primary intracranial sarcoma, DICER1-mutant
- Ewing sarcoma
- chondrogenic tumors
- mesenchymal chondrosarcoma
- notochordal tumors
- diffuse meningeal melanocytic neoplasms
- circumscribed meningeal melanocytic neoplasms
- CNS lymphomas
- Miscellaneous rare lymphomas in the CNS
- 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
- embryonal carcinoma
- yolk sac tumor
- 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
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.
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- 2. David N., M.D. Louis (Editor), Hiroko Ohgaki (Editor), Otmar D. Wiestler (Editor) et al. Pathology and Genetics of Tumours of the Nervous System. (2006) ISBN: 9789283224303 - Google Books
- 3. Louis D, 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(6):803-20. doi:10.1007/s00401-016-1545-1 - Pubmed
- 4. International Agency for Research on Cancer, Otmar D. Wiestler. WHO Classification of Tumours of the Central Nervous System. (2016) ISBN: 9789283244929 - Google Books
- 5. Thom M, Liu J, Bongaarts A et al. Multinodular and Vacuolating Neuronal Tumors in Epilepsy: Dysplasia or Neoplasia? Brain Pathol. 2018;28(2):155-71. doi:10.1111/bpa.12555 - Pubmed
- 6. Louis D, Wesseling P, Aldape K et al. CIMPACT-NOW Update 6: New Entity and Diagnostic Principle Recommendations of the CIMPACT-Utrecht Meeting on Future CNS Tumor Classification and Grading. Brain Pathol. 2020;30(4):844-56. doi:10.1111/bpa.12832 - Pubmed
- 7. IARC WHO classification of tumour - 5th edition volume titles - accessed Feb 2021
- 8. Louis D, Perry A, Wesseling P et al. The 2021 WHO Classification of Tumors of the Central Nervous System: A Summary. Neuro-Oncology. 2021;23(8):1231-51. doi:10.1093/neuonc/noab106 - Pubmed
- 9. Louis D, Wesseling P, Paulus W et al. CIMPACT-NOW Update 1: Not Otherwise Specified (NOS) and Not Elsewhere Classified (NEC). Acta Neuropathol. 2018;135(3):481-4. doi:10.1007/s00401-018-1808-0 - Pubmed
- 10. IARC’s Mission: Cancer research for cancer prevention. https://www.iarc.who.int/about-iarc-mission/. https://www.iarc.who.int/about-iarc-mission/ (accessed 16 October 2021).