March 15, 2023

Brain Tumors
Epidemiology of CNS tumours................................................................................................................................................................... 1
Risk factors......................................................................................................................................................................................... 2
Pathology of CNS tumours........................................................................................................................................................................... 2
WHO classification of CNS tumours 2021.............................................................................................................................. 2
Molecular classifications.............................................................................................................................................................. 4
Clinical presentation and Diagnosis........................................................................................................................................................ 5
Presentation...................................................................................................................................................................................... 5
Investigations and Diagnosis...................................................................................................................................................... 6
Surgery................................................................................................................................................................................................................ 9
Principle of Surgery........................................................................................................................................................................ 9
Adjuncts............................................................................................................................................................................................... 9
Treatment for High-Grade Glioma......................................................................................................................................................... 10
Adjuvant treatment for GBM.................................................................................................................................................... 10
Adjuvant treatment for Grade III Anaplastic Glioma...................................................................................................... 12
Management of Low-Grade Glioma....................................................................................................................................................... 13
Adjuvant treatment after surgery.......................................................................................................................................... 13
Recurrent Disease........................................................................................................................................................................................ 13
Meningioma.................................................................................................................................................................................................... 14
Epidemiology and Risk factors................................................................................................................................................ 14
Pathology......................................................................................................................................................................................... 14
Neuroimaging findings............................................................................................................................................................... 15
Management................................................................................................................................................................................... 15
Adult Ependymoma..................................................................................................................................................................................... 17
Pituitary adenoma........................................................................................................................................................................................ 18

Reference: NICE guideline,

EPIDEMIOLOGY OF CNS TUMOURS

Distribution of all primary brain and CNS tumours by site

Percent
Histology
Tumours of neuroepithelial tissue 30%
Glioblastoma 15%
Diffuse astrocytoma 2%
Oligodendroglioma 1%
Ependymal tumours 2%
Tumors of nerves (Nerve sheath tumours) 8%
Tumors of meninges (Meningioma) 38%
Lymphomas and hematopoietic neoplasms 2%
Germ cell tumours 0.4%
Tumours of sellar region 16%
Pituitary tumours 15%
Craniopharyngioma 0.8%
Unclassified 5%
Age of diagnosis and Tissue types

 Note: in adults above age 30-40, metastatic brain tumours become more prevalent
 Glioblastoma (the most common primary brain tumour in adult) has a median age of dx at 65.

Risk factors
 Ionizing radiation
o From atomic bomb survivors: latency from five to decades
o From therapeutic brain irradiation, e.g. acute leukemia;
o Higher risk for meningioma
 Neurofibroma
o type 1 = optic nerve glioma, pilocytic astrocytomas, neurofibroma, café-au-lait spots
o type 2 = schwannomas, particularly bilateral acoustic neuromas > meningioma,

PATHOLOGY OF CNS TUMOURS

WHO classification of CNS tumours 2021
 Integrated diagnosis = (1) Histopathology, (2) CNS WHO grade and (3) molecular analysis
o Histopathologic classification = astrocytes, oliogodendrocytes, or mixture of both
o Tumour grade = Grade 2 (Diffuse), Grade 3 (Anaplastic), Grade 4 (GBM)
 Not otherwise specified (NOS) = tumors where complete molecular classification is not available
 Not elsewhere classified (NEC) = fully characterized but do not fit within the classification system

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Tumour classification
Gliomas, glioneuronal tumours and neuronal tumours
Adult-type diffuse gliomas
Astrocytoma, IDH mutant
Oligodendroglioma, IDH mutant,
1p/19q-codeleted
Glioblastoma, IDH WT
Paediatric-type diffuse low-grade gliomas
Diffuse astrocytoma, MYB-altered
Paediatric-type diffuse high-grade gliomas
Diffuse midline glioma, H3 K27
Diffuse hemispheric glioma, H3
G34
Ependymal tumours
Supratentorial ependymoma
Posterior fossa ependymoma
Cranial and paraspinal nerve tumours
Schwannoma
Neurofibroma
Malignant peripheral nerve sheath
Embryonal tumours
Medulloblastoma
Meningiomas
CNS lymphomas
Germ cell tumours
Tumours of the sellar region (e.g. Pituitary adenoma/PitNET)
Grade Features
- Commonly in cerebral hemispheres
- Younger adults (G2-3: 30yo, G4: 45yo)
2-4 - Subtypes = ATRX, TP53, CDKN2A/B mutation
- Tumours with CDKN2A/B homozygous del is G4
- G4 still much better (2x) survival than IDH-WT
- White matter: cerebral cortex (frontal, temporal)
2-3 - More common in frontal and temporal lobes
- Mean survival = 15years
- For low grade IDH WT, should test for TERT
promoter mutation, EGFR gene amplification, gain
of chr 7/ loss of chr 10; if present, upgrade to
glioblastoma, grade 4
4 - By definition, lacks mutation of H3 mutation
- Incidence increases with age and peaks at 45-55yo
- Test for MGMT promoter
- MDM2 overexpression is seen in primary GBM
- Worst prognosis with OS <2yr
1
4 - a/w H3 K27, TP53, ACVR1, PDGFRA, EGFR
- a/w H3 G34, TP53, ATRX
4
- poor prognosis: OS <2yr
2-3
2-3
1-3
3
Histological grade
 IHC staining of GFAP is helpful but not specific
 Grade 2 = lacking brisk mitotic activity, necrosis, and florid microvascular proliferation (MVP)
 Grade 3 = increased mitotic activity
 Grade 4 = presence of florid MVP and/or necrosis

Molecular classifications
IDH1/2 mutations
 Isocitrate dehydrogenase (IDH) type 1/2
 More than 70% of grade 2 and 3 astrocytomas are IDH-mutated
 Less common in paediatric tumours
o .’. in paediatric/ young adults with IDH WT tumours à should further do tests (H3 mut etc.)
 90% form of mutation = IDH1 R132 (IHC)
o Other less common mutations only detected by DNA sequencing – preferred in age<55
 Mutation in IDH1 increases oncogenic metabolite 2-hydroxyglutarate (2HG)
o Leading to increase in histone methylation, G-CIMP exhibition
o Ultimately differentiation, and transcriptional changes
 IDH1/2 mutated tumours have better prognosis
o Signify the tumour developed from a lower grade precursor (e.g. secondary GBM)
 Mutually exclusive with H3 mutations

1p/19q codeletions
 Whole-arm loss of 1p & 19q due to unbalanced translocation between chr 1 and 19
 Defining molecular features of oligodendrogliomas
o Loss of 1p/19q in the setting of IDH1/2 mutations = secondary chromosomal loss
 1p/19q contains tumour suppressor genes
 Tested by FISH, PCR, or cytogenomic array & NGS
 Better prognosis (‘.’ Response to RT and chemo)

ATRX gene mutation

 Closely correlated with IDH1/2 and TP53 mutations
o Mutually exclusive with 1p/19q codeletion
 Suggest astrocytic lineage
 A chromatin regulator gene à alternative lengthening of telomeres (ALT) phenotype
 Loss of nuclear IHC staining for ATRX indicates ATRX mutation
 Loss of ATRX expression has intermediate prognosis
 Rarely (2-3%) found in 1p/19q-codeleted
o Some may suggest omitting ATRX testing if 1p/19q codeletion is present

TP53 mutation
 Suggest astrocytic lineage
 Missense somatic mutation in IDH-mutant astrocytoma
 Usually NOT suggestive of germline TP53 mutation (Li-Fraumeni syndrome)
o Exception: both p53 & IDH1 R132C mutation

CDKN2A/B homozygous deletion

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  Tested on IDH-mutant astrocytoma
 If found positive, upgrade to Grade 4
 One of the most relevant adverse prognostic factors in IDH-mutant astrocytoma
o Even worse prognosis than those with histological grade 4 without such mutation

MGMT promoter methylation

 Methylated (epigenetic silencing) MGMT has better prognosis
o 2-yr OS 50% (vs. unmethylated 12%)
 Better response to alkylating chemotherapy
o partial inability to repair the alkylating chemo-induced DNA damage
 Standard method: methylation-specific PCR +/- IHC (controversial)
 Found in 35% of GBM (but varies up to 60%, due to techniques, and laboratories)
 No diagnostic role

TERT promoter mutations

 May provide further support for diagnosis of oligodendroglioma and GBM
 Mutations in TERT promoter leads to enhanced TERT expression
 Tested by DNA sequencing analysis (e.g. Sanger, PCR, targeted PCR)
 Mutually exclusive with ATRX mutations
o .’. in IDH mutant setting, presence of TERT promoter mut suggests oligodendroglioma
 Also commonly found in GBM with poor outcomes
o For IDH-WT setting, presence of TERT is now Grade 4

H3 K27M mutation
 Present in most diffuse gliomas in the pons, or other midline locations (thalamus/ spinal cord)
 More common in children
 H3F3A K27M mutation detected by IHC

CLINICAL PRESENTATION AND DIAGNOSIS

Presentation
 New episodes and pattern of headache
 Focal seizure
o Tonic-clonic movement (motor), visual disturbance
(occipital), behavioural change (temporal)
o Alarming = first time seizure
o most common presentation for low grade glioma
 Focal neurological deficits progress over time
o Visual defect
o Weakness, sensory hemineglect (frontal/ parietal/
thalamic)
o Aphasia
o Bilateral crossed neurological deficits (brainstem
glioma)
 Changes in personality or cognitive impairment (weeks to
months) (anterior frontal or temporal lobe

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  Obstructive hydrocephalus leading to raised ICP
o Severe morning headache/ during Valsalva manoeuvre, coughing, position change; vomiting,
papillo-oedema
o Risk of Brain herniation

Investigations and Diagnosis

 MRI (with T2W, FLAIR, DWI and T1 pre- & post-contrast sequences) [NICE]
o May consider MR perfusion and MR spectroscopy for high-grade transformation in a tumour
appearing to be low grade on standard structural MRI
 CSF not routinely assessed; EXCET for ependymoma
o For ependymoma, spinal metastasis warrants craniospinal RT

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MRI Imaging features
 Brain metastasis
o Located 80% at the grey-white junction/ subcortical ‘.’ Stopped by BBB
o Vasogenic oedema (finger-like projection), which does NOT affect grey-white junction
o DDx = multiple sclerotic lesions, abscess
 High grade glioma
o T1-hypointense + T2-hyperintense + heterogeneously enhanced
o Can be false positive, with ddx as bacterial abscess, inflammatory disease, ischemia
o Glioblastomas: Thick rim enhancement + central necrotic/ cystic changes
o Oedema shown on T2W/ FLAIR sequence
A: FLAIR sequence and
B: postcontrast T1W
show a large, T2-
hyperintense mass in
left temporal lobe with
heterogenous
enhancement and
central necrosis

 Low-grade tumours are NOT contrast enhanced as much

o Hypointense in T1W
o Compare with T2W may help identify an expansile mass:
A: Low-grade
astrocytomas often do
NOT enhance.
B: The FLAIR sequence
is more useful in
appreciating the true
extent of such
neoplasms

 Meningioma
o Extra-axial lesion: arise from the dura with CSF cleft / smooth border and dural tail
o Contrast enhanced dural mass

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  Primary CNS lymphoma
o Usually T2-hypointense; and more homogenously enhanced; less oedema
o Typical sites = periventricular white matter, basal ganglia, and corpus callosum
o DDx = toxoplasmosis (also in HIV patients)1
Primary CNS lymphoma
has features:
(B) Homogenously
enhanced on contrast
images.
(C) T2 weighed images
show a relatively dark
mass, unlike glioma
Also noted relative lack
of oedema.

 Leptomeningeal metastasis
o Contrast enhanced = thin, linear, serpentine leptomeningeal enhancement
o Other ddx = meningitis

1
To differentiate toxoplasmosis and CNS lymphoma, the solitary areas in lymphoma are much thicker and
homogenously enhanced. Also CNS lymphoma affects periventricular spaces, toxoplasmosis does not.
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MRI for response evaluation
 Pseudo-progression may appear in 4-12 weeks after RT
o Repeat imaging is suggested in 6-8 weeks
 Tumor extension based on: T1 contrast, T2- and FLAIR-weighted MRI
 (Advanced options: PET, MR spectroscopy)

Short summary on different sequences of MRI

T1 T2 FLAIR DWI
Fat is bright Fat is dark T2 + dark free flow water Fluid restriction bright
Water is dark Water is bright Fat is dark But always check ADC to
Flow is dark CSF is dark prevent T2 shine through
Static water is bright
Anatomy Lesions Lesions near ventricles
Edema is bright

Vasogenic vs. Cytotoxic Edema

 Neurovascular unit forming the basic unit of blood-brain barrier
Vasogenic edema Cytotoxic edema
- Plasma escaping into interstitial space - Due to deprived of blood flow (ischemic)
causing leaky BBB - Ischemic neurons, astrocytes,
- Due to neoplasm, abscess, trauma, or even - Take on fluid due to electrolyte imbalance
hypertensive emergency - *Loss of grey-white junction
- Finger-like projection - Best seen on FLAIR (CSF is dark)
- Dose NOT affect the grey matter

SURGERY
Principle of Surgery
[NICE guideline]
 Maximal resection
o Extent of resection = gross total (GTR), subtotal (STR), or no surgery
o Median OS for HGG in 45-59yo = 15 (gross total); 12 (subtotal); 7 months (no surgery)
o Can be aided by 5-ALA
 Preservation of neurological function by:
o Awake craniotomy with language and appropriate functional monitoring
o Intraoperative neurophysiological monitoring
o Intraoperative image guidance
 If surgical resection not appropriate, consider biopsy
 May consider active monitoring without histological diagnosis for lesions radiological features typical of
very low-grade tumour, for example, DNET or optic pathway glioma

Adjuncts
Corticosteroids
 Dexamethasone 8-16mg/day
 For rapid reduction of tumour-associated oedema and improve clinical symptoms
 NOT necessary if no deficits/ raised ICP
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  NOT for prophylaxis during RT
 Rapid tapering is recommended

Anti-epileptic therapy
 NO need for prophylactic use out of perioperative phase
 Preferred agents = Keppra (levetiracetam), lamotrigine, or valproic acid.

TREATMENT FOR HIGH-GRADE GLIOMA

Adjuvant treatment for GBM

Dose and fractionations

 Standard = 60Gy/30Fr with concurrent TMZ (75mg/BSA daily) and up to 6 cycles of TMZ
o Adjuvant TMZ = (4wk post-RT) TMZ (150mg/BSA); 5 days q4wk x 6 cycles
o Boost regimen: 46Gy/23Fr; then boost with 14Gy/7Fr
o For tumour is large/ brainstem involvement, may consider 54-55.8Gy (1.8Gy/Fr)
o Bevacizumab is not recommended
o Septrin prophylaxis given during use of TMZ
 For elderly age >70 with KPS >70: 40Gy/15Fr concurrent with TMZ + up to 12 cycles of adjuvant TMZ
o Even shorter: 25Gy/5Fr
 For patients KPS <70, suggest BSC
o (Leeds: may consider RT 30Gy/6Fr over 2 weeks)

Evidence
 (Stupp trial2) TMZ/RT vs. RT alone= overall median OS (14 vs. 12mo); 2-yr OS (25% vs. 10%)
o MGMT methylation is the strongest prognostic factor: methylated 23mo vs. unmethylated 12mo
o Survival Benefit of TMZ: seen across the board, regardless of MGMT status.
 Lomustine is a less preferred choice than TMZ

2
N Engl J Med 2005; 352:987-996
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 Benefits of TMZ/RT
RT alone TMZ/RT
Methylated MGMT promoter
Median OS (mo) 15 21
Survival at 2 yr (%) 22 46
Unmethylated MGMT promoter
Median OS (mo) 11 12
Survival at 2 yr (%) <2 13

(X) Failed Attempts to Improve Survival

 Dose-dense TMZ (day 1-21 q4wk) (regardless of MGMT status)
 (RTOG 0825; AVAglio) Bevacizumab: prolonged PFS, but NO OS benefits
 (CENTRIC) Cilengitide: selective αvβ3 and αvβ5 integrin inhibitor

For elderly patients >70 [NICE]

 Poor OS of 7-9 months
 If fit, suggest hypo-fractionated RT (40Gy in 15Fr) +/- TMZ
o Standard vs. Hypofractionated RT3 = similar OS (5mo) or KPS
 Better compliance in hypofractionated regimen and less steroid post-treatment
o (EORTC 20174) Hypofractionated RT with TMZ vs. RT alone = OS (9 vs. 7 mo)
o Benefit of TMZ regardless of MGMT status (although stat not sig. for unmethylated)
 For age >70, KPS >70, MGMT methylation positive, may consider TMZ alone x 6 cycles
o (NOA-08) In elderly with MGMT methylated, TMZ alone is better than RT alone
 For KPS <70 and age >70, suggest BSC

Tumour treating field

 [NICE] Do NOT suggest TTF

Radiotherapy planning
 So-called involved-field RT (as opposed to WBRT)
 More than 90% of glioblastomas recur within the irradiated volume

ESTRO-ACROP guideline for GBM volume – single phase

 GTV = T1 contrast-enhancing tumor/ resection cavity plus residual contrast enhancing tumor
 CTV = GTV + 2 cm margin,
o Edited to take into account anatomical barriers to tumor spread
o Such as skull (0 mm, using bone window), ventricles (5 mm), falx (5 mm), tentorium cerebelli
(5mm), visual pathway/optic chiasm & brainstem (0mm)
o Common mistake = fail to trim infra-tentorial component, contralateral side
 For secondary glioblastoma, non-enhancing areas may be a component of the tumour;
o GTV include high signal intensity on T2/FLAIR + contrast enhanced tumour.
 PTV = CTV + 3-5mm margin
 Contour the PRV for critical structures
 Prescribe 100% at isocentre, ensuring 95% isodose surface covers 95% of PTV
 Expect under-dosage to critical OARs
3
DOI: 10.1200/JCO.2004.06.082
4
N Engl J Med 2017; 376:1027-1037
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OAR
Brainstem ≤ 54Gy Cochlea Ideally one side <45Gy
Optic nerves ≤ 54Gy Chiasm <55Gy
Pituitary Dmax <50Gy Lacrimal glands <40 Gy
Eyes Macula <45 Gy Lens Ideally <6Gy; max 10 Gy

Hypofractioned RT (40Gy/15fr) tumour volume

 GTV = contrast-enhancing tumor +/- surgical bed
 CTV = GTV + 1.5cm margin respecting anatomical boundaries
 PTV = CTV + 3-5mm margin

Follow-up
 Repeat MRI 6 weeks after RT (1st assessment)
 Pseudoprogression can happen at 1st assessment
o Repeat MRI 2 months later if suspected pseudoprogression after RT

Adjuvant treatment for Grade III Anaplastic Glioma

 Overall better OS than GBM

Regimen [NICE]
Disease Adjuvant treatment regimen
Grade 3 IDH mutant astrocytoma (AA) RT alone (60Gy), then adjuvant TMZ up to 12 cycles
1p/19q codeletion AOD Sequential RT (60Gy) and 4-6 cycles of PCV
PCV = procarbazine, lomustine (CCNU), vincristine
(Option of giving a few cycles of PCV first for tumour shrinkage)
Other anaplastic glioma No role of PCV5

Common side effects of PCV

- Procarbazine = rash, delayed hypersensitivity (in second cycle), vomit, infertility, cytopenia
- CCNU (Lomustine) = cytopenia (nadir ~30d), vomiting, lung toxicity when accumulate
- Vincristine = vesicant, alopecia, peripheral/ central/ autonomic neuropathy,

Evidence
 (CATNON) Non-1p/19q codeleted anaplastic glioma; RT +/- concurrent TMZ +/- adj. TMZ
o Adjuvant TMZ has OS gain
o No OS gain with concurrent TMZ
 (EORTC 26951) For AOD or AOA, RT/PCV vs. RT alone = 42 vs. 30mo
o PCV given after RT
o More benefit for 1p/19q codeletion
 (RTOG 9402) For AOD or AOA, PCV/RT vs. RT alone = similar OS (4.5 yr)
o Intense PCV given prior RT
o Unplanned analysis= 1p/19q codeletion (14 vs. 7yr); noncodeleted (similar 2.5 yr)
o Less tolerable than EORTC 26951

5
(NOA-04) Neoadjuvant PCV vs. RT first = similar OS / Time to Treatment Failure (TTF) / PFS
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MANAGEMENT OF LOW-GRADE GLIOMA
Adjuvant treatment after surgery
Poor risk factors
 Age >40
 Size >6cm or crossing midline
 Symptomatic
 Astrocytic (IDTwt; and TERT mutated particularly poor)
o 1p/19q codeleted, IDHmt – likely better response to adjuvant chemo PCV

[NICE guideline on adjuvant treatment]

Indications Indications
- Age >40 - Age <40
- Residual tumour on postoperative MRI - (Near) complete resection
- (1p/19q codeleted, IDH-mutated
oligodendroglioma)
RT 54Gy/30Fr, then PCV (Q8wk) x6 cycles Observation
(alternative RT = 50.4Gy/28Fr, or 45Gy/25Fr) Consider RT if progressive disease

Specific management for specific types of Low-Grade Glioma

 For BRAF V600E mutation: consider BRAF and MEK inhibitors
 For SEGA (subependymal giant cell astrocytoma): check tuberous sclerosis; use mTOR inhibitor

Target volume delineation (EORTC 22033-26033)

 GTV = region of high signal intensity on T2 or FLAIR-MRI; or operative cavity + any residual tumour
 CTV = GTV + 1-1.5cm anatomical margin.
o 5mm margin at anatomic boundaries (ventricles, tentorium, meninges, midline)
 PTV = CTV + 3-5 mm

Evidence
 (EORTC 22845) Surgery + RT results in better 5-yr OS (68% vs. 55%)
 (EORTC 22844) adjuvant RT regimen 59.4Gy vs. 45Gy has no statistically significant difference
 (RTOG 98-02) RT+PCV (vs. RT alone) results in better 10-yr OS (60% vs. 50%)
 (EORTC 22033-26033) For high-risk LGG, RT (50.4Gy) vs. TMZ x12, PFS are similar, OS not mature
o IDHmt 1p/19q codel patients has no PFS difference
o But patients with IDHmt 1p/19q non-codel tumours has longer PFS when treated with RT
 Ongoing CODEL trial

Driving
 Low grade glioma = at least 1 year after completion of primary treatment (surgery)
 High grade glioma = at least 2 years after completion of primary treatment (surgery + RT)
 Must also be seizure-free for 1 year

RECURRENT DISEASE
Choice of Treatment
 Chemotherapy: re-treat Temozolomide, PCV; (Carboplatin, NKRT inhibitor Larotrectinib)

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  Surgery: if resectable, or palliative resection if symptomatic
 Alternating electric field therapy for GBM
 Best supportive care

MENINGIOMA
Reference: EANO guideline, NHS guideline

Epidemiology and Risk factors

 Most common intracranial and CNS tumors
 Median age of diagnosis = 65yo (except those wth NF2)
 M: F = 1:3
 Spinal meningiomas comprises 10% of all meningioma
o Mostly in middle-aged adults (40yo). With female predominance (1:9)
Risk factors
 Ionizing radiation/ Incidental radiation exposure
 Genetic predisposition = neurofibromatosis type 2 (NF2) and schwannomatosis
 Up to 60% meningioma associated with NF2

Pathology
WHO classification (based on morphological criteria)
Grading Definition Recurrence
Grade I - Mitotic count <4 per 10 HPF 10-20%
95% - NO brain invasion
- 13 subtypes, e.g. meningothelial, fibrous, angiomatous, psammomatous,
mixed
Grade II - Mitotic count ≥4 per 10 HPF or 30-50%
(4%) - Presence of brain invasion or
- 3 of 5 histological features, e.g. spontaneous necrosis, high cellularity,
small cells, prominent nucleoli, sheeting
- 3 histological subtypes = atypical, clear cells, chordoid
Grade III - Mitotic count ≥20 per 10 HPF or 50-95%
(1%) - Specific histology = anaplastic, rhabdoid, or papillary meningioma
- So-called malignant meningioma
- High risk molecular features = TERT promoter mutation or
homozygous CDKN2A/B deletion

If grading is still uncertain, check MIB-1 staining index (anti-Ki-67):

 0.7% to 2.2% = benign meningiomas
 2.1% to 9.3% = atypical meningiomas
 11.0% to 16.3% = anaplastic meningiomas

Poor prognostic factors

 Mitotic index (>=20/10HPF);
 Loss of chromosome 1p
 Ki-67 LI>12%
 Incomplete excision

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Neuroimaging findings
MRI features
- Extra-axial, dural-based mass
- Isointense on T1, hyperintense in T2
- Strong, homogenous contrast enhancement
CT features
- well-defined extra-axial mass that displaces the normal brain
- sometimes calcified or multilobulated
Typical Atypical
 Smooth contour  Large or disproportionate amount of
 Homogeneous enhancement associated oedema
 Dural tail sign  Intratumoral cystic change
 Calcification  Extensive bone involvement (reactive
 CSF cleft sclerosis, invasion, erosion)
 Brain or leptomeningeal invasion
 Elevated cerebral blood volume

A: Tail sign: tapering dural thickening (arrow) due to direct tumor involvement or reactive change in the
dura, is a highly characteristic sign of meningioma; note also the small reactive arachnoid cyst, reflecting the
extra-axial site of this lesion (arrowhead).
B: Reactive cerebral white matter changes.
C: Bony reactive changes: reactive bone sclerosis, reflected in the increased vault thickness (arrows) is seen
most commonly in patients with multiple meningiomas associated with neurofibromatosis type 2; invasive
tumors such as these can cause problematic extracranial facial masses

Management
Simpson Grading for completeness of surgical resection
Grade Details Symptomatic Recurrence
at 10 years
Grade 1 Complete removal including underlying bone and associated dura 9%
Grade 2 Complete removal and coagulation/ diathermy of dural attachment 19%
Grade 3 Macroscopic tumor removal with small residual foci 29%
Grade 4 Subtotal resection 44%
Grade 5 Simple decompression only 100%

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Management after surgery
Grade Simpson 1-3 Simpson 4-5 No excision Recurrent
1 Active monitor RT if growth may affect Active monitor or RT Consider further
function/ tx options surgery or RT
Otherwise, can observe
2 Monitor or RT Further surgery Active monitor or RT Further surgery
RT if surg not possible Offer RT
3 RT Further surg and offer RT RT Further surgery
Offer RT

UK guideline recommendations
 <2cm tumors rarely grow sufficiently to produce symptoms within 5 years
 Heavily calcified meningiomas rarely grow
 All recurrences of grade 2-3 tumors occurred within 4 years of surgery
 If surgeon judges there is residual, early postop MRI is needed

Management of Grade 1 meningioma

At diagnosis
 For small and asymptomatic G1 meningioma, can offer active monitor
o MRI scans annually for 5 years
o Criteria for intervention = enlarging more rapidly/ atypical features
 For large or symptomatic meningioma, offer surgery; or RT if surgery not feasible
o Primary RT = 54Gy/30Fr; SRS 12-15Gy
o SRS achieves 10-yr RFS of 93%
Postop
 Complete resection (Simpson grade 1) =
o For solitary convexity gr.1, offer MRI 2.5 years later (recurrence rate is 20%)
 For solitary skull base or falcine origin WHO grade 1 tumors
o Regardless of Simpson grades, offer MRI at 1, 2, 3.5 and 5 years postop
 For residual tumor presents:
o May consider adjuvant RT – only improves local control,
o Dose of RT = 50.4Gy/28Fr

Management of Grade 2 meningioma

 FU MRI scans = 6 month, then annually
o May discharge if MRI at 5th year is normal;
o Exception is multiple meningiomas – should have annual scans indefinitely
 For residual tumor, offer adjuvant RT – but still no consensus
o Dose of 54Gy/30Fr or 60Gy/30Fr
o 3-yr OS is >96% and local failure rates 5-15%
o (ROAM EORTC 1308) ongoing trial for G2 meningioma

Management of grade 3 meningiomas

 FU MRI 6-monthly for 3 years then annually
 Adjuvant RT regardless of Simpson = 60Gy/30Fr
o After adjuvant RT, 5-yr PFS of G3 meningioma is 40-50%

EBRT vs. SRS

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 SRS Fractionated EBRT
Size <3-3.5cm Larger (>3.5cm)
Site Away from critical structure (>3mm) Close within 2-4mm of critical structures
Grade Grade 1 Grade 2-3 with less distinct border
Typical Skull base Optic nerve sheath meningioma
sites
Dose/Fr 12-15Gy 50-54Gy, 1.8 Gy per fraction

Meningioma: Target volume delineation

Primary RT
 GTV = tumor bulk + dural tail
o + skull bone if presence of tumor body erosion or hyperostosis
o + foramen extension if skull base meningioma
 CTV = GTV + 0mm margin
Postop RT
 GTV = tumor meningeal base + dural tail + any residual nodular enhancement
 CTV (non-isotropic: growth along the meningeal surfaces)
o Grade 1 = 0-5mm
o Grade 2-3 = 1-2cm

ADULT EPENDYMOMA
Reference: UK guideline 2020,
 Adult ependymoma is more commonly in spine, or supratentorial
 Children ependymoma 90% is intracranial, infratentorial

Pathology
 Classified into 3 grades histologically
 5 WHO distinct entities
o Myxopapillary ependymoma WHO grade I (at cauda equina, conus medullaris)
o Subependymoma WHO grade I (typically located in 4th ventricle)
o Ependymoma WHO grade II
o Ependymoma (RELA fusion-positive): worse prognosis
o Anaplastic ependymoma (WHO grade III)

Investigation
 Craniospinal MRI (2-3 weeks post-surgery) for risk of CSF dissemination
 CSF cytology (after MRI) for all newly diagnosed ependymal tumours

Management
 Surgery with gross total resection (GTR) remains most important treatment
 GTR defined as no residual disease on MRI 3-mo postop

Spinal ependymoma
 GTR is challenging
 Adjuvant RT 50-54Gy if 1) residual disease, and 2) WHO GIII disease
o Should still be considered after GTR ‘.’ technically difficult

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Intra-cranial ependymoma
 GTR is the key
 Grade 1 (Subependymoma) = indolent; either observation or surgery. NO need adjuvant
 Grade 2 = adjuvant RT (54- 59.4Gy) unless GTR
 Grade 3 = adjuvant RT (54- 59.4Gy)
 Craniospinal RT if CSF or spinal dissemination
o Dose for CSI = 36Gy/20Fr with boost to focal lesions of up to 54Gy/30Fr
 Consider proton referral for TYA population

Recurrent disease
 There are no standard salvage options for recurrent ependymoma
 Wherever possible, GTR should be attempted
 Re irradiation should be considered, taking into account interval from previous course of radiotherapy
and previous dose.
 Chemotherapy may be considered = etoposide-platinum, TMZ

PITUITARY ADENOMA
Reference

 Surgical resection for symptomatic non-functioning pituitary macroadenoma

o most surgery is via transsphenoidal endoscopic approach
 Improve visual function in >80%, and hypopituitarism in 30-50%

For recurrent or residual disease

 Residual in 20%, and recurrence chance is 50%-75% in 10 years
o Risk = cavernous sinus invasion
 Repeat resection is indicated for large, symptomatic residual
o But higher operation risk e.g. diabetes insipidus (5%), meningitis (2%), visual deterioration etc.
 Surgical challenging in areas of cavernous sinus, suprasellar region, hypothalamus

Role of RT / SRS
 For recurrent or residual disease, esp. those high risk regions
 SRS 12-20Gy single fraction; IMRT 45-54Gy
 Local control rate ≥90% at 5 years

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