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Whats new in 2021 WHO classification

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2021 WHO Classification of Tumours of the Central Nervous System: A Review for the Neuroradiologist (General Summary)

  • The fifth edition of the WHO Classification of Tumours of the Central Nervous System (WHO CNS5), published in 2021, incorporates output from the Consortium to Inform Molecular and Practical Approaches to CNS Tumour Taxonomy (cIMPACT-NOW).
  • WHO CNS5 introduces fundamental changes to brain tumour classification, including new tumour families and types, especially in the paediatric population.
  • The key update is a greater emphasis on organizing tumours by molecular type to reflect biology and allow for better planning of treatment.
  • For the first time, WHO CNS5 separates adult-type from paediatric-type diffuse gliomas.
  • The classification proposes a ‘hybrid taxonomy’ that combines histological and molecular techniques to achieve high reproducibility.

Key Points of the Classification

  • The classification places an increased emphasis on molecular data to reach a comprehensive integrated diagnosis.
  • Several new tumour types and subtypes have been introduced, especially within the families of paediatric-type diffuse gliomas and embryonal tumours.
  • Diffuse gliomas are segregated into paediatric-type and adult-type based on their underlying molecular differences.
  • Paediatric diffuse gliomas are now categorized into two families: paediatric-type diffuse low-grade gliomas and paediatric-type diffuse high-grade gliomas.
  • Glioblastomas are defined as adult-type tumours and are IDH-wildtype.
  • Ependymomas are now classified according to a combination of histopathological and molecular features, as well as anatomical location.

Standardising Nomenclature and Grading

  • The term tumour ‘type’ replaces ‘entity’, and the term ‘subtype’ is used instead of ‘variant’.
  • CNS tumour grading now uses Arabic numerals (CNS WHO grades 1–4), replacing the previous Roman numerals.
  • Grading is applied within specific tumour types rather than across different tumour types.

Integrated Layered Diagnosis

  • Molecular and histopathological parameters are presented in a layered report.
  • The classification establishes ‘essential’ and ‘desirable’ criteria for each tumour type to ensure a conclusive integrated diagnosis.
  • The terms ‘not otherwise specified’ (NOS) and ‘not elsewhere classified’ (NEC) may be used if necessary information is unavailable or diagnostic testing is inconclusive, respectively.

Gliomas, Glioneuronal Tumours, and Neuronal Tumours

General

  • A distinction is made between diffuse gliomas based on whether they occur primarily in adults or children, reflecting underlying molecular differences.

Adult-type diffuse gliomas

  • The category has been simplified from 15 entities to three types:
    • Astrocytoma, IDH-mutant (CNS WHO grade 2, 3, or 4): Defined by IDH1 or IDH2 mutations and ATRX loss/mutation or absence of 1p/19q codeletion. The presence of a homozygous deletion of CDKN2A and/or CDKN2B automatically results in CNS WHO grade 4. The term IDH-mutant glioblastoma has been discontinued. Imaging may show T2w-FLAIR mismatch.
    • Oligodendroglioma, IDH-mutant and 1p/19q-codeleted (CNS WHO grade 2 or 3): Diffusely infiltrating tumour often demonstrating a frontal lobe predilection. Typically seen in cortex/subcortical white matter and often shows calcification on CT.
    • Glioblastoma, IDH-wildtype (CNS WHO grade 4): The diagnosis can now be assigned regardless of histology if the tumour is IDH-wildtype H3-wildtype and possesses molecular aberrations typical of glioblastoma (e.g., TERT promoter mutation, EGFR gene amplification, or +7/-10 chromosome copy-number changes). Molecularly defined glioblastomas may lack necrosis or parenchymal enhancement on MRI.

Paediatric-type high-grade diffuse gliomas

  • This family includes four types:
    • Diffuse midline glioma, H3 K27-altered: Infiltrative glioma typically located in the brainstem, pons, thalamus, or spinal cord. Imaging features include T2w hyperintensity and variable enhancement.
    • Diffuse hemispheric glioma, H3 G34-mutant: CNS WHO grade 4 neoplasm of the cerebral hemispheres. Imaging often shows an enhancing tumour with mass effect, haemorrhage, and restricted diffusion.
    • Diffuse paediatric-type high-grade glioma, H3-wildtype and IDH-wildtype: CNS WHO grade 4 malignancy with aggressive, glioblastoma-like histological features. The terms glioblastoma or paediatric glioblastoma are not recommended here. Imaging often shows irregular rim enhancement and restricted diffusion.
    • Infant-type hemispheric glioma: A new type of high-grade astrocytoma typically associated with receptor tyrosine kinase fusions (e.g., NTRK, ROS1, ALK, or MET). These are large masses presenting in early childhood.

Paediatric-type low-grade diffuse gliomas

  • This category was introduced to distinguish tumours driven by activation of the mitogen-activated protein kinase (MAPK) pathway from adult-type low-grade gliomas.
  • New types include: diffuse astrocytoma, MYB- or MYBL1-altered (CNS WHO grade 1); polymorphous low-grade neuroepithelial tumour of the young (PLNTY); and diffuse low-grade glioma, MAPK pathway-altered.
  • Angiocentric glioma (AG), typically associated with MYB-QKI gene fusion, was reclassified into this family (CNS WHO grade 1).

Circumscribed Astrocytic Gliomas

  • The new type is high-grade astrocytoma with piloid features (HGAP):
    • Initially referred to as MC-AAP, this is one of the first tumours defined by a specific methylation profile.
    • Most commonly arises in the posterior fossa (74% in the cerebellum).
  • Astroblastoma, MN1-altered (AB) is a revised type:
    • Characterized by a perivascular growth pattern, astroblastic pseudorosettes, and alteration of the MN1 gene.
    • Generally a well-demarcated, superficial supratentorial lesion, often showing restricted diffusion in the solid components.

Glioneuronal and Neuronal Tumours

  • This family has added three new/provisional types:
    • Multinodular and vacuolating neuronal tumour (MVNT): CNS WHO grade 1 lesion manifesting as multiple discrete nodules along the subcortical ribbon, hyperintense on T2w, typically benign (‘do-not-touch’ lesion).
    • Myxoid glioneuronal tumour: CNS WHO grade 1 neoplasm characterized by PDGFRA gene mutation and a stereotypical location along the septum pellucidum.
    • Diffuse glioneuronal tumour with oligodendroglioma-like features and nuclear clusters (DGONC): A provisional type primarily seen in paediatric patients, often emerging from the temporal lobe.

Ependymal Tumours

  • Classification is based on a combination of histological/molecular features and anatomical location (supratentorial, posterior fossa, spine).
  • New types include supratentorial ependymoma, ZFTA fusion-positive (most common supratentorial subtype in children, associated with poorer outcomes); and supratentorial ependymoma, YAP1 fusion-positive (better prognosis than ZFTA fusion-positive).
  • Posterior fossa ependymomas are separated into Group A (PFA) and Group B (PFB): PFA usually occurs in infants and young children and has a poorer prognosis than PFB.
  • Myxopapillary ependymomas are now classified as CNS WHO grade 2 (previously grade 1).

Embryonal Tumours: Medulloblastoma (MB)

  • MBs are CNS WHO grade 4 lesions and are the most common embryonal brain tumours in children.
  • MBs are classified based on molecular features into four main groups:
    • MB, WNT-activated.
    • MB, SHH-activated, TP53-wildtype.
    • MB, SHH-activated, TP53-mutant.
    • MB, non-WNT/non-SHH (Groups 3 and 4).
  • The prognostic differences are significant (e.g., WNT-MB has favourable outcomes, Group 3 has survival less than 50%).

Embryonal Tumours: Other CNS Embryonal Tumours

  • The term primitive neuroectodermal tumour has been removed.
  • Atypical teratoid/rhabdoid tumour (ATRT) now recognizes three molecular subtypes: ATRT-SHH, ATRT-TYR, and ATRT-MYC.
  • New molecularly defined tumour types include:
    • CNS neuroblastoma, FOXR2–activated.
    • CNS tumour with BCOR internal tandem duplication (CNS tumour BCOR ITD).
    • Cribriform neuroepithelial tumour (CRINET) (provisional type).

Pineal Tumours

  • A new addition is the desmoplastic myxoid tumour of the pineal region, SMARCB1-mutant (no grade assigned yet).

Meningiomas

  • Meningioma is considered a single type with 15 subtypes.
  • Molecular markers are crucial for classification and prognostication; for example, TERT promoter mutations indicate elevated rates of malignant transformation.

Mesenchymal/Non-Meningothelial Tumours

  • The terminology is aligned with the WHO Blue Book on Bone and Soft Tissue Tumours.
  • Haemangiopericytoma has been discontinued and is now referred to as solitary fibrous tumour.
  • New types include intracranial mesenchymal tumour, FET-CREB fusion-positive (provisional); CIC-rearranged sarcoma; and primary intracranial sarcoma, DICER1-mutant.

Tumours of the Sellar Region

  • Adamantinomatous craniopharyngioma and papillary craniopharyngioma are now distinct tumour types.
  • The term pituitary neuroendocrine tumour (PitNET) is introduced for pituitary adenomas.
  • Pituitary blastoma, an embryonal neoplasm of infancy, has been newly added.