GBM

Question 1

What is the pathognomonic finding for GBM?
(presence of this = diagnosis)

Answer 1

Pseudopalisading necrosis

Question 2

What is the median survival of GBM?

Answer 2

14 months

Question 3

What is the treatment paradigm for GBM?

Answer 3

Maximal safe resection with neurological preservation, followed by adjuvant chemoRT as per the Stupp trial

Question 4

What is the epidemiology of GBM?

Answer 4

Most common primary malignant brain tumour in adults (80%)
Median age at dx 64
M:F 1.5:1
White ethnicity > others

Question 5

What are the diagnostic criteria for a GBM as per WHO 2021 classification?

Answer 5

adult patient

diffuse astrocytic tumour

IDH-wildtype

and at least one of the following:

• necrosis
• microvascular proliferation
• TERT promoter mutation
• EGFR gene amplification
• combined gain of whole chromosome 7 and loss of chromosome 10 [+7/-10]

Question 6

What is the MEAN criteria?

Answer 6

Pathology criteria for dx of glioma
More = higher grade

high Mitotic index
Endothelial proliferation
nuclear Atypia
Necrosis

Previously GBM was diagnosed if 3 of these were present

Question 7

What is the ChemoRT aspect of GBM treatment?

Answer 7

RT 60Gy/30# with concurrent Temozolamide (75mg/m^2) daily on RT, and then 150-200mg/m2 adjuvantly for days 1-5 of 28 day cycle for 6 months (shorter if not tolerated)

Question 8

What is the IDH mutation status of GBM as per 2021 WHO classification?

Answer 8

Glioblastoma is defined as a diffuse astrocytic tumour in adults that is IDH-wild type (ie. not mutated).

Grade 4 astrocytoma IDH mutated is a separate entity

Question 9

What proportion of GBMs are de novo vs secondary arising from an existing lower grade tumour?

Answer 9

90% vs 10%

Question 10

What are the three histological variants of GBM as per WHO 2021 classification?

Answer 10

giant cell glioblastoma

gliosarcoma

epithelioid glioblastoma

Question 11

What genetic syndromes are associated with increased risk of GBM?

Answer 11

vast majority of GBM are sporadic

Assoc. with:
NF1
Li fraumeni syndrome
Turcot syndrome
Ollier disease
Maffucci syndrome

Question 12

What parts of the brain does GBM have a predilection for arising in?

Answer 12

Subcortical white matter
Deep grey matter of cerebral hemispheres, esp temporal lobe
Supratentorial white matter is most common location

But can arise anywhere in brain

Question 13

What is a multifocal GBM compared to a multicentric GBM

Answer 13

Multifocal glioblastomas are tumours which have multiple discrete areas of contrast-enhancing tumour embedded with, or connected by, T2/FLAIR signal abnormality. Multifocal glioblastomas are considered to be part of the one tumour.

vs Multicentric: multiple discrete areas of contrast-enhancing tumour without connecting T2/FLAIR signal abnormality. They are considered to represent separate synchronous tumours.

Question 14

What proportion of GBMs are multifocal?

Answer 14

20%

Question 15

Do multifocal have a better or worse prognosis than regular GBM?

Answer 15

Worse prognosis

Question 16

Macroscopic appearance of GBM

Location
Size
Shape
Colour
Edges
Presence/absence of special features e.g. haemorrhage

Answer 16

Glioblastomas are typically poorly marginated, diffusely infiltrating, necrotic masses localised to the cerebral hemispheres.

Supratentorial white matter most common location.

Considerable regional variation in appearance within the tumour is characteristic:
- may be firm or gelatinous.
- Some areas are firm and white
- some are soft and yellow (secondary to necrosis)
- some are cystic with local haemorrhage.

• significant variability in size from only a few centimetres to lesions that replace a hemisphere.
• Infiltration beyond the visible tumour margin is always present.

Question 17

Microscopic appearance of GBM

Answer 17

• Pleomorphic astrocytes with marked atypia and numerous mitoses are seen.
• Varied patterns sometimes within one tumour seen
• Necrosis and microvascular proliferation are hallmarks of glioblastomas.
• Multinucleated giant cells (if dominant feature&raquo_space; giant cell GBM)

Question 18

IHC of GBM

Answer 18

GFAP: positive but of variable intensity

S100: positive

nestin: positive

p53 protein: positive if TP53 mutated

EGFR: positive in 40-98% of cases

IDH-1 R132H: negative (by definition, otherwise not an IDH-wildtype glioblastoma, but rather an astrocytoma, IDH-mutant WHO CNS grade 4)

H3 K27M mutation: negative (if positive then diffuse midline glioma H3 K27-altered)

Question 19

Genetic changes seen in GBM

Answer 19

EGFR gene amplification

TERT promoter mutations

combined gain of whole chromosome 7, loss of chromosome 10 [+7/-10]

alterations of the CDK4/6–RB1 cell-cycle pathway: 80% due to deletions of CDKN2A

Question 20

How does the epidemiology go epithelioid GBM differ from usual GBM?

Answer 20

Epithelioid more common in young adults and young children

Question 21

What are microscopic features of epithelioid GBM?

Answer 21

These tumours are heterogeneous with large epithelioid cells that have abundant eosinophilic cytoplasm, vesicular chromatin, and prominent nucleoli. Rhabdoid cells are also sometimes encountered

Question 22

What are the options for treating GBM?

Answer 22

60Gy/30# with concurrent TMZ

40.05Gy/15# with concurrent TMZ

34GY/10#
25Gy/5#

TMZ mono therapy

Best supportive care

Question 23

Is there benefit to radiotherapy alone in GBM?

Answer 23

Yes-
Laperriere et al. conducted a systematic review which included 6 randomised controlled trials comparing conventional radiation therapy with no radiation therapy.

Patient groups included grade 3 and 4 gliomas. Doses ranged from 50-60 Gy

Survival benefit with post op radiotherapy RR = 0.81, 95% CI:0.74-0.88, p <0.00001

Question 24

What is the evidence supporting use of 60GY/30# with concurrent TMZ followed by adjuvant TMZ in GBM?

Answer 24

Stupp trial
- Between 2000 and 2002, 286 patients were randomised to receive radiation therapy alone (60 Gy in 30 fractions) and 287 patients were randomised to receive radiation therapy (60 Gy in 30 fractions) and continuous daily TMZ (75 mg per square meter of body surface area per day, 7 days per week from the first to the last day of radiation therapy) followed by six cycles of adjuvant TMZ (150 to 200 mg per square meter for 5 days during each 28 day cycle).

• After a median follow up of 28 months, the median survival was 14.6 months in the radiation therapy plus TMZ group versus 12.1 months in the radiation therapy alone group (HR = 0.63, 95% CI:0.52-0.75, p <0.001).
• The 2-year overall survival was 26.5% in the radiation therapy plus TMZ group versus 10.4% in the radiation therapy alone group.
• 2-year progression free survival was 11.2% in the radiation therapy plus TMZ group and 1.8% in the radiation therapy alone group.
• The updated 5-year results showed 5-year survival of 9.8% versus 1.9%

Question 25

In the Stupp trial, what % of patients experienced severe myelosuppression as a result of TMZ?
Severe = grade 3 or 4 tax

Answer 25

16%
(included from start of trial until 7 days after disease progression)

Question 26

Describe a simulation technique for definitive radiation + TMZ for GBM