Classification of CNS tumours, Classification of brain tumours, WHO 2021 Classification, 2007 WHO Classification, 2016 WHO Classification

1. Classification of brain tumours
Department of Neurosurgery
Dr RE Anto
18/03/2022

2. Contents
• Introduction
• Epidemiology
• Risk factors
• Etiology
• Hereditary sx
• Clinical presentation
• Classification systems
• Benign vs Malignant
• Tumour locations
• WHO Classification System
• Main changes
• References

3. Introduction
• Brain tumour is an abnormal mass of tissue
intracranially, in which cells grow and multiply
uncontrollably, seemingly unchecked by the
mechanisms that control normal cells.
• Multiple classification systems
• Primary vs. Secondary
• Type of cell origin
• Location
• Grading (Benign or Malignant)

4. Epidemiology
• Primary brain tumours are relatively rare: 2% of all cancers in
adults
• NOTE: In paeds: 15-20 % of paediatric cancers
• Great variance in degree of incidence between 1st world and
developing countries
• May be due to differences in resources like imaging modalities and better
registration and data capture systems
• Incidence rises with age
• Males: Female (1.5:1) – except meningiomas (female > male)

5. Davis FG, McCarthy BJ. Current epidemiological trends and surveillance issues in brain tumours. Expert Rev
Anticancer Ther2001;1:395–401.

6. Risk factors
• Develop as a consequence of accumulated genetic alterations
that permit cells to evade normal regulatory mechanisms and
destruction by the immune system
• Seizures may herald development of cerebral tumours by years!
• Risk for any cerebral tumour after first admission for epilepsy is
increased 20-fold
• Highlights the need for continued surveillance of patients with new-
onset seizures

7. Etiology
• Some epidemiological studies suggest increased incidence of astrocytomas
• Petrochemicals eg vinyl chloride
• Electromagnetic radiation
• High dose ionizing radiation
• 10 times risk of meningiomas
• 2.5 times risk for gliomas
• Primary CNS lymphoma
• Viruses eg EBV
• Immunocompromised (transplant patient, AIDS)

8. Hereditary syndromes
• < 5% of all primary CNS tumours
• Neurofibromatosis I and II (MPNST, Optic n glioma, Meningiomas, Vestibular schwannoma)
• Von-Hippel Lindau sx (Haemangioblastoma)
• Tuberous sclerosis (SEGA, Cortical tubers)
• Li-Fraumeni sx (Malignant gliomas, PNET, Medulloblastoma)
• MEN I (Multiple endocrine neoplasia) ( Pituitary adenomas, Malignant schwannoma)
• Turcot sx (GBM, Medulloblastoma)
• Werner’s sx (Meningioma)

9. Clinical Presentation
• Generalized or focal signs.
• Epilepsy: focal or generalized tonic clonic seizures
• Frontal lobe:
• Anosmia
• Dementia
• Urinary incontinence
• Conjugate deviation of eyes
• Aphasia

10. Clinical Presentation
• Temporal lobe:
• Temporal lobe epilepsy
• Auditory hallucinations
• Memory difficulties
• Parietal lobe:
• Hemisensory changes
• Sensory apraxia
• Occipital lobe:
• Visual field changes
• Chiasmatic lesions:
• Visual field changes

11. Clinical Presentation
• Posterior fossa lesions:
• CN Palsies
• Long tract signs
• Obstructive HCP
• Sellar lesions
• Hormone dysfunction
• Acromegaly
• Hyperprolactinemia
• Hypopituitarism
• Hypocortisolemia
• Visual disturbances

12. Classification systems
• Primary:
• Arise from the brain tissue or surrounding
meninges itself
• Glial
• Non-glial (in structures in the brain including
nerves, vessels, glands)
• Secondary:
• Arises from other tumours in the body and
migrate to the brain
• 5-10 times more common than primary CNS
tumours (most common tumours in adults)

15. Benign vs Malignant
• This distinction is less significant than for other systems
• Benign
• Slow-growing tumours
• Low cellularity
• Few mitosis
• No necrosis
• No vascular proliferation
• However, location of these tumours can have lethal consequences
despite its histological classification
• Eg: FM meningioma causing compression of the medulla and causing
cardiorespiratoy arrest

16. Malignant
• Not malignant “metastasize” out of
CNS (rare)
• Morphological Features:
• 1. Nuclear atypia
• 2. Mitosis
• 3. Endothelial Proliferation
• 4. Necrosis
Daumas-Duport C, Scheithauer B, O'Fallon J, Kelly P (1988).
Grading of astrocytomas. A simple and reproducible method.
Cancer 62: 2152-2165.

18. WHO Classification
• 1979: 1st edition – Histological typing of CNS tumours
• 1993: 2nd edition – Reflected advances in immunohistochemistry
• 2000: 3rd edition – Started introduction pathology and genetics
• 2007: 4th edition – used up until 2015 (Youmans 6th edition)
• 2016: Revised 4th edition – substantial revision of 4th edition

19. WHO Classifications (2007/2016)

20. WHO Classifications (2007/2016)
• Formulating concept of how CNS tumours diagnoses are
structured in the molecular era
• Restructured diffuse gliomas, medulloblastomas and
incorporated genetically identified entities.
• Embryonal tumours (removal of PNET)
• Ependymoma genetic variants introduced

21. WHO Classifications (2007/2016)
• Addition of newly recognized entities, variants and patterns:
• IDH-wildtype and IDH-mutant glioblastoma (entities)
• Diffuse midline glioma, H3 K27M–mutant (entity)
• Embryonal tumour with multilayered rosettes, C19MC-altered
(entity)
• Ependymoma, RELA fusion–positive (entity)
• Diffuse leptomeningeal glioneuronal tumor (entity)
• Anaplastic PXA (entity)
• Epithelioid glioblastoma (variant)
• Glioblastoma with primitive neuronal component (pattern)
• Multinodular and vacuolated pattern of ganglion cell tumor (pattern)

22. WHO Classifications (2007/2016)
• Deletion of former entities, variants and terms:
• Gliomatosis cerebri
• Protoplasmic and fibrillary astrocytoma variants
• Cellular ependymoma variant
• “Primitive neuroectodermal tumor”
• Addition of brain invasion as a criteria for atypical meningioma
• Restructuring of solitary fibrous tumour and hemangiopericytoma (SFT/HPC) as one entity and
adapting a grading system to accommodate this change
• Expansion and clarification of entities included in nerve sheath tumors, with addition of hybrid
nerve sheath tumors and separation of melanotic schwannoma from other schwannomas
• Expansion of entities included in hematopoietic/lymphoid tumors of the CNS (lymphomas and
histiocytic tumors

24. 2021 WHO Classification
• 5th edition of WHO Classification of Tumours of the Central
Nervous System (CNS)
• Sixth version of the international standard for the
classification of brain and spinal cord tumours
• Build on the 2016 updated fourth edition and the work of the
Consortium to Inform Molecular and Practical Approaches to
CNS Tumour Taxonomy (cIMPACT-NOW)

25. cIMPACT-NOW
• Consortium to Inform Molecular and Practical Approaches to
CNS Tumour Taxonomy – Not Officially WHO
• Seven updates from 2016-2020

26. Gliomas, glioneuronal tumors, and neuronal
tumours
• 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

27. Gliomas, glioneuronal tumors, and neuronal
tumours
• Circumscribed astrocytic gliomas
• Pilocytic astrocytoma
• High-grade astrocytoma with piloid features
• Pleomorphic xanthoastrocytoma
• Subependymal giant cell astrocytoma
• Chordoid glioma
• Astroblastoma, MN1-altered

28. Glioneuronal and neuronal tumours
• 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

29. Ependymal tumours
• 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

30. Choroid Plexus tumours
• Choroid plexus papilloma
• Atypical choroid plexus papilloma
• Choroid plexus carcinoma

31. Embryonal tumours - 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

32. Other CNS Embryonal tumours
• 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

33. Pineal tumours
• Pineocytoma
• Pineal parenchymal tumor of intermediate differentiation
• Pineoblastoma
• Papillary tumor of the pineal region
• Desmoplastic myxoid tumor of the pineal region, smarcb1-
mutant

34. Cranial and Paraspinal nerve tumours
• Schwannoma
• Neurofibroma
• Perineurioma
• Hybrid nerve sheath tumor
• Malignant melanotic nerve sheath tumor
• Malignant peripheral nerve sheath tumor
• Paraganglioma

35. Meningioma
• Meningothelial
• Fibrous
• Transitional
• Psammomatous
• Angiomatous
• Microcystic
• Secretory
• Lymphoplasmacyte-rich
• Metaplastic
• Chordoid
• Clear Cell
• Atypical
• Papillary
• Rhabdoid
• Anaplastic

36. Mesenchymal, non-meningothelial tumours –
Soft tissue tumours
• 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

37. Chondro-osseous tumours
• Chondrogenic tumors
• Mesenchymal chondrosarcoma
• Chondrosarcoma
• Notochordal tumors
• Chordoma (including poorly differentiated chordoma)

38. Melanocytic tumours
• Diffuse meningeal melanocytic neoplasms
• Meningeal melanocytosis
• Meningeal melanomatosis
• Circumscribed meningeal melanocytic neoplasms
• Meningeal melanocytoma
• Meningeal melanoma

39. Hematolymphoid tumours - 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

40. Germ cell tumors
• Mature teratoma
• Immature teratoma
• Teratoma with somatic-type malignancy
• Germinoma
• Embryonal carcinoma
• Yolk sac tumor
• Choriocarcinoma
• Mixed germ cell tumor

41. 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

42. Metastases to the CNS
• Metastases to the brain and spinal cord parenchyma
• Metastases to the meninges

43. Main changes in 5th edition
• Builds on prior version by placing greater emphasis on molecular
markers in terms of classification and grading
• Heterogenous classification
• Layered report structure
• Integrated diagnosis
• Histopathological classification
• CNS WHO Grade
• Molecular information

44. Grading
• Within tumour 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)
• This approach has been abandoned, in favour of grading tumours within “type”
• Example:
• No Grade 1 Diffuse Astrocytoma, IDH Mutant (only 2,3 or 4)
• Glioblastoma, IDH-wildtype – can only be Grade 4
• Arabic numerals
• Previously – I,II,III,IV (Roman numerals)
• Replaced by Arabic Numerals – 1,2,3,4
• Example: Meningioma, CNS WHO Grade 1

45. Grading
• 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
• Molecular grading
• For the first time, molecular features have been explicitly added to the grading
schema
• May supersede histological features.
• 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

46. Other changes
• NOS (Not Otherwise Specified)
• Diagnostic information (histological or molecular) needed to assign a specific
WHO diagnosis is not available
• Example: not enough tissue available or no resources available
• NEC (Not Elsewhere Classified)
• Results do not readily allow for a WHO diagnosis
• Clinical, histological, or molecular mismatch

47. References
• 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
• 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
• International Agency for Research on Cancer, Otmar D. Wiestler. WHO Classification of
Tumours of the Central Nervous System. (2016) ISBN: 9789283244929
• GreenBerg 9th edition
• Davis FG, McCarthy BJ. Current epidemiological trends and surveillance issues in brain
tumours. Expert Rev Anticancer Ther2001;1:395–401.

48. Thank you