Neuro-oncology

Question 1

What are primary CNS tumours

Answer 1

originated in CNS
most common (vs secondary) in children

Question 2

what are secondary CNS tumours

Answer 2

mets
10x more common than primary tumours
(30% of patients with systemic cancer develop CNS metastases)

Question 3

what are extra-axial CNS tumours (coverings)

Answer 3

Tumours of bone, cranial soft tissue, meninges, nerves

less malignant than intra-axial

Question 4

what are intra-axial CNS tumours (parenchyma)

Answer 4

from normal cell populations of the CNS - flia, neurons and neuroendocrine cells
form other cell types - lymphomas, germ cell tumours

more malignant - WHO grade 2-4 - Infiltrate the tissue of the brain – not encapsulated and they invade the brain tissue

Question 5

aetiology of CNS tumours

Answer 5

unknown
env - radiotherapy to head and neck -> meningioma (and rarely glioma)
genetic predisposition <5% primary - familial syndromes

Question 6

what are familial CNS tumour syndromes - with examples

Answer 6

Autosomal dominant inheritance with frequent de novo mutations

Question 7

signs and symptoms for CNS tumours

Answer 7

subtle in slow growing // short hx for malignant

intracranial HTN - SOL - headache, vomiting, change in mental status

supratentorial - focal neuro deficit, seizures, personality change (frontal lobe)

infratentorial - cerebellar ataxia, long tract signs (brain stem: motor/sensory tracts), cranial nerve palsy (ocular signs)

Question 8

imaging modalities used for CNS tumours

Answer 8

CT-scan
MR-scan – more usual in more chronic
MR-spectroscopy (metabolism)
Perfusion MRI
Functional MRI
PET-scan – more research looking for particular ligand binding

Question 9

Use of imaging in CNS tumours

Answer 9

Assess tumour type
Guide resection & biopsy
Assess post-surgery – have you taken all tumour
Assess response to treatments
Follow-up recurrence and progression

Question 10

mx for cns tumour - surgery

Answer 10

max safe resection with min damage to normal
need margin of normal - might be limited depending on where is in brain

resection - location, size, nymber of lesions

Question 11

mx of CNS tumours - radiotherapy

Answer 11

low and high grade glioma
metastases
some benign

external fractionated radiotherapy, stereotactic radiosurgery

Question 12

mx of cns tumours - chemo

Answer 12

high-grade gliomas (temozolomide – mixed effectiveness) and lymphomas

Biological agents (EGFR inhibitors, PD-L1 inhibitors, etc.)

Question 13

when is craniotomy used for CNS tumours

Answer 13

for debulking
may be sub-total or complete resections - depending where is
remove as much tumour as possible

Question 14

When is open biopsy used for CNS tumours

Answer 14

for inoperable but approachable tumours - 1cm of tissue

usually representative - able to make dx

Question 15

when is stereotactic biopsy used for CNS tumours

Answer 15

if open biopsy not indicated (about 0.5cm of tissue)
tissue may be insufficient esp if heterogenous - might not get definitive dx

Question 16

why do we need tissue dx of cns tumour

Answer 16

for:
* definitive and complete dx
* prognostic and predictive tests
* assessment of treatment response

Histopathology can make a decision while patient is on the table

Question 17

what is involved in the WHO classification of CNS tumours

Answer 17

Tumour type - Putative cell of origin or lineage of differentiation, based on histology, predicts tumour behaviour

Tumour grade – malignancy of the tumour- Tumour aggressiveness

Molecular profile - Most tumour types have molecular markers

Question 18

cell of origin and name of tumour

Answer 18

Astrocytes – astrocytoma
Oligodendrocytes – oligodendroglioma
Ependyma – ependymoma
Neurons- neurocytoma
Embryonal cells – medulloblastoma
Meningothelial cells – meningioma
Schwann cells - schwannoma, neurofibroma

Question 19

grading CNS tumours

Answer 19

startify tumours by outcome ie degree of malignancy
based on morphological criteria:
* proliferative activity (mitotic bodies – number = degree of proliferative activity),
* cell differentiation (wgich cells, are they vascular),
* necrosis (more necrosis = more malignant)

based on predicted natural clinical behaviour (ie doesnt include response to treatment so high grade may now live longer)

Question 20

what are the WHO grades for CNS tumours

Answer 20

Grade 1 – benign – long-term survival
Grade 2 – more than 5 yrs
Grade 3 – less than 5 yrs
Grade 4 – less than 1 yr

Some tumour types have only one possible grade, but others have more than one and tjhey progress

Grades guide treatment – if grade 4 you can lengthen life but do you change the QOL

Question 21

what are diffuse gliomas

Answer 21

infiltrate into the tissue
use structure of tissue eg perivascular, and grow under the meninges

grade >= 2
adults
supratentorial
malignant progressioon

astrocytomas grade 2-4
oligodendrogliomas grade 2-3

Question 22

what are circumscribed gliomas

Answer 22

grades 1-2
children
posterior fossa
rare malignant transfromation

Pilocytic astrocytoma (grade 1)
Subependymal giant cell astrocytoma (grade1)
Ependymomas (usually) – lining of the ventricle, usually well circumscribed

Question 23

what is a pilocystic adenoma

Answer 23

Who grade 1
intraparenchymal tumour
infra-tentoral, posterior fossa

usually 1st and 2nd decade of life - children
20% CNS tumours below 14 yrs - common
cerebellar, optic-hypothalamus, brainstem

BRAF mutation in 70%

MRI - well circumscribed, cystic, enhancing lesion

Question 24

Pilocystic astrocytoma histology

Answer 24

Piloid “hairy” cells
Very often Rosenthal fibres – blue arrow
Slowly growing, low mitotic activity

Question 25

Summarise diffuse gliomas

Answer 25

pts 20-40yrs Astrocytoma (IDH mutant) and Oligodendroglioma (IDH mutant) Pathogenic point mutation in the IDH1/2 gene IDH mutation -> longer survival and a better response to chemotherapy and radiotherapy

Question 26

What is astrocytoma

Answer 26

WHO grade 2-4 pts 20-40yrs cerebral hemispheres point mutation - IDH1/2

Question 27

Histology of astrocytoma

Answer 27

low to moderate cellularity Mitotic activity is low. No vascular proliferation or necrosis. IDH1 mutants can be detected Immunocytochemically – good prognosis progression to higher grades over time

Question 28

summarise glioblastoma multiforme

Answer 28

who grade 4 Most aggressive and most frequent glioma incidence increase with age, most >50yrs median survival - 8mo

Question 29

genetics of glioblastoma multiforme

Answer 29

IDH1 wildtype Common mutations in: TERT, PTEN, EGFR

Question 30

Histology of glioblastoma multiforme

Answer 30

High cellularity Neoangiogenesis – overdeveloped Necrosis Not clean margin – tumour invading the tissue of the brain

Question 31

what are meningiomas

Answer 31

WHO **grade 1-3** 38% primary CNS tumours rare less 40yrs - **increases with age** Originate from **meningothelial cells** of the **arachnoid mater** Any site of craniospinal axis, **can be multiple (NF2)** more accessible to neurosurgeons - **good surgery outcomes** MRI: **extraxial, iso-dense, contrast-enhancing, well circumscribed - not invading parenchyma**

Question 32

grading of meningiomas

Answer 32

**80% Grade 1**: benign, recurrence less than 25% 20% Grade 2: atypical, recurrence 25-50% 1% Grade 3: malignant, recurrence 50-90% **grading is the most useful predictor of recurrence** mainly based on histology, recently molecular markers (**ex TERT mutation, methylome**) Complex histological assessment: proliferation, cell morphology, microscopic brain invasion, etc 15 morphological subtypes, 3 grades

Question 33

how is mitotic activity used to determine grade

Answer 33

Hyperintense nuclear material Count them per high power field Grade depending on how many mitotic bodies find Mitosis per 10HPF (0.16mm2) <4 = grade 1 4-20 = grade 2 >20 = grade 3

Question 34

why do you have to check the interface between meningoma and cortex

Answer 34

Most are sitting between tissue – but have to make sure not invading (even microinvasion)

Question 35

summarise CNS mets

Answer 35

most common CNS tumour incidence increasing because of longer survival. Often multiple, located at grey/white matter junction and/or leptomeningeal disease can be 1st disease presentation - hard to know origin, use immunohistochem poor px because in the brain parenchyma

Question 36

cancers that can give brain mets

Answer 36

any, but commonly: * lung ca, * breast ca, * melanoma, * renal cell ca

Question 37

what is a medulloblastoma

Answer 37

WHO grade 4 embryonal tumour from neuroepithelial cells/neuronal precursors of the cerebellum or dorsal brainstem rare common type in children outcome improved with radio-chemo and subtype stratification

Question 38

histology of medulloblastoma

Answer 38

High grade poorly differentiated Highly proliferated type of tumour 4 histological subtypes: classic, nodular/desmoplastic, extensive nodularity, large cell anaplastic 3 molecular subtypes by transcriptome or methylome profiling: WNT-activated, SHH-activated, nonWNT/nonSHH

Question 39

what is teh methylome profile for CNS tumours

Answer 39

**Most tumours have characteristic patterns of DNA methylation of CpG islands** methylation signiture is stable - **reflect cell of origin - give info on tumour type** The DNA methylation status of a subset of CpG islands is assessed with DNA arrays and compared to a reference dataset (“Classifier”)

Question 40

what is the methylome classifier

Answer 40

Helpful for atypical cases, rare entities, small biopsies, and subtyping: ex medulloblastoma subtypes, meningiomas… Not used for grade/progression or targeted therapy True molecular classification: does not consider the histology