Histo: Neuro-Oncology

Question 1

How much more common are secondary brain tumours than primary brain tumours?

Answer 1

Brain metastases are 10x more common that primary tumours

Question 2

Describe the locational classification of brain tumours.

Answer 2

Extra-axial (coverings):

• bone
• meninges
• nerves
• cranial soft tissue

Intra-axial (parenchyma):

• Derived from normal cell populations of the CNS (e.g. glia, neurones, neuroendocrine, vessels)
• Derived from other cell types (e.g. lymphomas, germ cell tumours)

Question 3

List the different cell types within the CNS that can give rise to brain tumours.

Answer 3

• Neurones
• Astrocytes
• Oligodendrocytes
• Ependyma
• Choroid plexus epithelium
• Meningothelial cells
• Embryonal cells

Question 4

What is the aetiology of CNS tumours

Answer 4

Largely unknown

• Environmental: radiation associated with meningioma
• Genetic predispostion: familial CNS tumour syndromes

Question 5

What is the most common genetic syndrome associated with brain tumours?

Answer 5

Neurofibromatosis

Question 6

What is the inheritance pattern of neurofibromatosis?

Answer 6

Autosomal dominant

Question 7

Where are the genes that cause neurofibromatosis located?

Answer 7

• NF1 = 17q11
• NF2 = 22q12

Question 8

What tumours are associated with following Familial CNS Tumour Syndromes:

• NF1
• NF2
• Brain Tumour polyposis syndrome 1
• Gorlin syndrome
• Von Hippel Lindau syndrome

Answer 8

• NF1 - neurofibroma, astrocytoma
• NF2 - bilateral vestibular schwanoma, meningioma
• BTP1 - malignant glioma
• Gorlin syndrome - medulloblastoma
• VHL - haemangioblastoma

AD inheritance

Question 9

What are some common signs of CNS tumours

Answer 9

Raised ICP:

• Headache (worse in morning, coughing, lying down)
• Vomiting
• Altered mental status

Question 10

List some manifestations of brain tumours that are:

1. Supratentorial
2. Subtentorial

Answer 10

Supratentorial

• Focal neurological deficit
• Seizures
• Personality changes

Subtentorial

• Cerebellar ataxia
• Long tract signs (e.g. hyperreflexia)
• Cranial nerve palsies

Question 11

What are some neuroimaging modalties

Answer 11

• CT
• MRI
• MR spectroscopy - assess tumour metabolic activity
• Perfusion MRI
• fMRI
• PET

Question 12

Outline the management options for brain tumours.

Answer 12

Surgery - aim for maximal safe resection with minimal damage to the patient. Debulking may be performed and biopsies may be taken.

Radiotherapy - used for gliomas and metastases

Chemotherapy - mainly for high-grade gliomas and lymphomas

Question 13

What is the role of histopathology and molecular pathology

Answer 13

• Definitive diagnosis
• Prognostic tests
• Assessement of treatment response

Question 14

What is the WHO classification of brain tumours based on?

Answer 14

• Tumour type (cell of origin)
• Tumour grade (aggressiveness/degree of malignancy)
• Molecular profile - most tumour types have specific molecular markers

NOTE: metastases are not graded

Question 15

What are some criteria that tumour grade is based on?

Answer 15

• Mitotic activity
• Degree of cell and tissue differentiation
• Degree of necrosis

Question 16

Outline the meaning of the different WHO grades for brain tumours.

Answer 16

• Grade I = benign, long-term survival
• Grade II = death in > 5 years
• Grade III = death in < 5 years
• Grade IV = death in < 1 years

NOTE: grades I and II are low

GRADE GUIDES Mx

Question 17

Which brain tumours are staged?

Answer 17

None

Except medulloblastoma

Question 18

What is the most common type of primary brain tumour?

Answer 18

Glial tumours, specifically astrocytoma

Question 19

How are the types of glial tumours seen in children and adults different?

Answer 19

Diffuse gliomas

• Mainly seen in adults
• Supratentorial
• Malignant progression
• Astrocytomas, oligodendrogliomas

Circumscribe gliomas

• Mainly seen in children
• Posterior fossa
• Rarely undergo malignant transformation
• Astrocytomas, ependymomas

Question 20

Which genetic mutations are associated with gliomas in adults and in children?

Answer 20

• Diffuse infiltration (adults) - IDH1/2
• Circumscribed gliomas (children) - MAPK (BRAF)

Question 21

List some examples of circumscribe gliomas.

Answer 21

• Pilocytic astrocytoma (MOST COMMON)
• Ependymoma
• Subependymal giant cell astrocytoma

Question 22

List some key features of pilocytic astrocytomas (WHO grade 1)

Answer 22

• Mainly occurs in children (1st and 2nd decade of life)
• Associated with NF1
• Often located cerebellar, optic hypothalamus, or brainstem
• BRAF mutation in 70% of cases

Question 23

What is the hallmark histological feature of pilocytic astrocytoma?

Answer 23

• Piloid (hairy) cell
• Often see Rosenthal fibres and granular bodies
• Slow-growing with low mitotic activity

Question 24

List some key features of astrocytoma (WHO grade 2, 3, and 4)

Answer 24

• Usually affects adults 20-40 years old
• Cerebral hemispheres are the most common site in adults
• Can progress to become a higher grade (malignant progression)
• IDH1/2 mutation in 80% of cases

Question 25

Describe the histology of astrocytoma (WHO grade 2, 3, and 4)

Answer 25

* Low cellularity and mitotic activity * No vascular proliferation or necrosis * IDH mutants can be detected with immunocytochemistry

Question 26

What can astrocytomas eventually become?

Answer 26

Glioblastoma (after 5-7 years) *Grade IV astrocytoma*

Question 27

What is the most aggressive form of astrocytoma

Answer 27

Glioblastoma multiforme (WHO stage 4)

Question 28

List some key features of glioblastoma multiforme.

Answer 28

* Grade IV * Most patients \> 50 years * Affects cerebral hemispheres * most freq glioma * median survival 8months

Question 29

Describe the histology of GBM

Answer 29

* High cellularity and high mitotic activity * Neoangiogeneis * Necrosis

Question 30

What does glioblastoma multiforme tend to arise from?

Answer 30

**90% arise *de novo*** and have wildtype IDH 10% occur secondary to astrocytoma and have **IDH mutation**

Question 31

What is the second most common primary intracranial tumour after gliomas?

Answer 31

Meningioma

Question 32

List some key features of meningioma.

Answer 32

* Mainly low grade (I and II) * Rare in patients <40, incidence increases with age * Can be multiple (e.g. in NF2) 80% - grade 1 (benign) 20% - grade 2 (atypical) 1% - grade 3 (malignant)

Question 33

What cell type does meningioma originate from

Answer 33

Meningioepithelial cells of **arachnoid mater**

Question 34

Which histological feature of meningioma is important in determining grade?

Answer 34

**Mitotic activity** (number of mitoses per 10 high power fields) * Grade 1: \< 4 * Grade 2: 4-20 * Grade 3: \> 20 NOTE: brain invasion is also an important thing to assess (presence of brain invasion makes it grade II)

Question 35

How does grade of meningioma affect the management options?

Answer 35

Grade II and III requires radiotherapy as well as surgery

Question 36

What is a medulloblastoma?

Answer 36

* Embryonal tumour originating from neuroepithelial precursors of the **cerebellum and dorsal brainstem** * They are **always found in the cerebellum**

Question 37

Describe the histological appearnce of medulloblastoma.

Answer 37

**Small blue** round cell tumour with expression of neuronal markers (very little differentiation) NOTE: snaptophysin is an example of a neuronal marker

Question 38

Describe the role of methylome profiling

Answer 38

* Most tumours have characteristic DNA methylation patterns of CpG islands * This methylation signatures is stable and can be used to identify the tumour cell origin

Question 39

Which tumours most commonly metastasise to the brain?

Answer 39

* Lung * Breast * Melanoma * Renal cell

Question 40

How can the origin of brain metastases be identified

Answer 40

Immunohistochemistry

Question 41

Where in the brain do metastases tend to be found?

Answer 41

* At the grey-white junction * This is because the cerebral blood vessels become smaller as they enter the white matter so neoplastic emboli get caught here

Question 42

What mutation is associated with a better prognosis?

Answer 42

IDH mutation found in IDH mutant diffuse gliomas

Question 43

Useful predictor of recurrence in **meningiomas**?

Answer 43

Tumour grade based on: * histology * molecular markers