The WHO classification of CNS tumours is the most widely accepted system for classifying CNS tumours, now into its 5th edition, traditionally published in a blue cover (thus "blue book").
Although traditionally based on histological characteristics of the tumours, 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.
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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 tumours 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.
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
Other WHO classification systems generally grade each tumour independently; i.e. the most low-grade version of a particular tumour 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 tumours, entities were graded (roughly) equivalently so that 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, at least aspirationally, 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 astrocytoma, IDH-mutant exists (only grades 2, 3 and 4 are available). Similarly, glioblastoma, IDH-wildtype can only ever be a grade 4 tumour 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 tumour, if treated has a good prognosis far better than other medulloblastoma types.
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 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 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.
Main changes in the revised 4th edition (2016)
The 2016 revised 4th 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 haemangiopericytoma, 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).
Classification (5th edition, 2021)
Gliomas, glioneuronal tumours, and neuronal tumours
Adult-type diffuse gliomas
Paediatric-type diffuse low-grade gliomas
Paediatric-type diffuse high-grade gliomas
Circumscribed astrocytic gliomas
Glioneuronal and neuronal tumours
desmoplastic infantile ganglioglioma (DIG) / desmoplastic infantile astrocytoma
diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters (provisional inclusion)
dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease)
Ependymal tumours
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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 tumours
Embryonal tumours
Medulloblastoma
-
medulloblastomas, molecularly defined
medulloblastoma, SHH-activated and TP53-wildtype
medulloblastoma, SHH-activated and TP53-mutant
medulloblastoma, non-WNT/non-SHH
medulloblastomas, histologically defined
Other CNS embryonal tumours
cribriform neuroepithelial tumour (provisional inclusion)
CNS embryonal tumour
Pineal tumours
Cranial and paraspinal nerve tumours
Meningiomas
Mesenchymal, non-meningothelial tumours
Soft tissue tumours
-
fibroblastic and myofibroblastic tumours
-
vascular tumours
-
skeletal muscle tumours
-
uncertain differentiation
intracranial mesenchymal tumour, FET-CREB fusion-positive (provisional inclusion)
primary intracranial sarcoma, DICER1-mutant
Chondro-osseous tumours
-
chondrogenic tumours
mesenchymal chondrosarcoma
-
notochordal tumours
chordoma (including poorly differentiated chordoma)
Melanocytic tumours
-
diffuse meningeal melanocytic neoplasms
-
circumscribed meningeal melanocytic neoplasms
Hematolymphoid tumours
Lymphomas
-
CNS lymphomas
-
Miscellaneous rare lymphomas in the CNS
other low-grade B-cell lymphomas of the CNS
Histiocytic tumours
Germ cell tumours
mature teratoma
immature teratoma
teratoma with somatic-type malignancy
yolk sac tumour
mixed germ cell tumour
Tumours of the sellar region
Metastases to the CNS
History and etymology
The International Agency for Research on Cancer (IARC) is the specialised cancer agency of the World Health Organisation and commissions and publishes the "WHO classification of tumours" series. Please note that the term "blue book" is used for all books in the series not just the CNS tumour book 10.