WHO classification of CNS tumors
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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.
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 and incorporates most of the recommendations made in the cIMPACT-NOW publications 6. This approach, however, results in a fairly heterogeneous classification depending on the specific entity. At one end of the spectrum, some tumors remain primarily assessed histologically while at the other end, some are assessed 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.
CNS WHO grade
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
Other WHO classification systems generally grade each tumor independently; i.e. the most low-grade version of a particular tumor is given grade 1 regardless of how aggressive it is relative to other diagnoses.
In contrast, in prior editions of the WHO classification of CNS tumors, entities were graded (roughly) equivalently so that 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, at least aspirationally, 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 astrocytoma, IDH-mutant exists (only grades 2, 3 and 4 are available). Similarly, glioblastoma, IDH-wildtype can only ever be a grade 4 tumor 8.
It should also be noted that generally there is shift towards placing less importance on grade as it is often less relevant than location or available therapies. For example, medulloblastoma, WNT activated, despite being a grade 4 tumor, if treated has a good prognosis far better than other medulloblastoma types.
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
Pediatric-type diffuse low-grade gliomas
Pediatric-type diffuse high-grade gliomas
Circumscribed astrocytic gliomas
Glioneuronal and neuronal tumors
diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (provisional inclusion)
supratentorial ependymoma, ZFTA fusion-positive
supratentorial ependymoma, YAP1 fusion-positive
posterior fossa ependymoma, group PFA
posterior fossa ependymoma, group PFB
spinal ependymoma, MYCN-amplified
Choroid plexus tumors
medulloblastomas, molecularly defined
medulloblastoma, SHH-activated and TP53-wildtype
medulloblastoma, SHH-activated and TP53-mutant
medulloblastomas, histologically defined
Other CNS embryonal tumors
cribriform neuroepithelial tumor (provisional inclusion)
CNS embryonal tumor
Cranial and paraspinal nerve tumors
Mesenchymal, non-meningothelial tumors
Soft tissue tumors
fibroblastic and myofibroblastic tumors
skeletal muscle tumors
intracranial mesenchymal tumor, FET-CREB fusion-positive (provisional inclusion)
primary intracranial sarcoma, DICER1-mutant
diffuse meningeal melanocytic neoplasms
circumscribed meningeal melanocytic neoplasms
Miscellaneous rare lymphomas in the CNS
Germ cell tumors
teratoma with somatic-type malignancy
yolk sac tumor
mixed germ cell tumor
Tumors of the sellar region
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
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- 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).