Diffuse Astro, IDH-Mutant

Question 1

Diffuse Astrocytoma, IDH-Mutant:

• Definition
• Grading

Answer 1

• Infiltrating astrocytoma with mutation in either IDH1 or IDH2 gene.
• WHO Grade II

Question 2

The diagnosis of Diffuse Astrocytoma, IDH-Mutant is supported by the presence of what other mutations?

Answer 2

• ATRX

- TP53

Question 3

Diffuse Astrocytoma, IDH-Mutant account for approximately what percentage of all astrocytic brain tumors?

Answer 3

11-15%

Question 4

Diffuse Astrocytoma, IDH-Mutant:

• Age distribution
• M:F

Answer 4

• 38 y/o (mean)

- 1.3:1 (M:F)

Question 5

Diffuse Astrocytoma, IDH-Mutant:

-Localization

Answer 5

• Frontal lobes (Supratentorally)

* Can be located in any region of the CNS

Question 6

Diffuse Astrocytoma, IDH-Mutant - Clinical features:

• Presenting symptoms (2)
• Onset

Answer 6

• Seizures
• Personality changes (frontal lobe)
• Gradual onset

Question 7

Diffuse Astrocytoma, IDH-Mutant - Imaging:

-CT

Answer 7

• Poorly defined, homogenous masses of low density
• NO contrast enhancement
• Calcification and cystic change may be present early in the evolution

Question 8

Diffuse Astrocytoma, IDH-Mutant - Imaging:

-MRI (T1/T2/Gadolinium)

Answer 8

• T1: Hypodensity
• T2: Hyperintensity
• Enhancement not common, tends to appear during progression

Question 9

Diffuse Astrocytoma, IDH-Mutant - Microscopy:

• General
• Classic type

Answer 9

• Well-differentiated fibrillary astrocytes in a background of loosely structured, often microcytic matrix.
• Fibrillary Astrocytoma (no longer listed as a variant)

Question 10

Diffuse Astrocytoma, IDH-Mutant - Microscopy:

• Characteristic features (2)
• Mitosis

Answer 10

• Nuclear atypia
• Moderately increased cellularity
• Mitosis generally absent

Question 11

Diffuse Astrocytoma, IDH-Mutant - Microscopy:

-Nuclear features

Answer 11

• Vesicular with intermediate-sized masses of chromatin

- NUCLEOLUS

Question 12

Diffuse Astrocytoma, IDH-Mutant:

-DDx

Answer 12

-Reactive astrocytosis

Question 13

Histologic features of reactive astrocytes.

Answer 13

• Enlarged nuclei
• Stainable, defined cytoplasm
• Culminating into a Gemistocyte

Question 14

Gemistocyte histologic features.

Answer 14

• Mass of eosinophilic cytoplasm extending into fine processes
• Eccentric nucleus

Question 15

Diffuse Astrocytoma, IDH-Mutant Vs. Reactive Astrocytosis.

Answer 15

• IDH1 positive
• p53 positive
• trisomy 7 (rare)

Question 16

T/F: Reactive astrocytes are rarely all in the same stage of reactivty, so reactions reveal mixtures of astrocytes.

Answer 16

True

-some show enlarged nuclei, others with varying amounts of cytoplasm, most often on a somewhat rarefied background

Question 17

T/F: In diffuse astrocytoma, almost all of the nuclei look identical, and the background is of at least normal density or shows increased numbers of cellular processes.

Answer 17

True

• Microcystic change may be present, but most cells look like one another, without the admixture of gemistocytes more often seen in reactions to injury.
• Pre-existing cell types (e.g. Neurons) are often entrapped.

Question 18

Diffuse Astrocytoma, IDH-Mutant:

-Ki67 proliferation index

Answer 18

<4%

Question 19

T/F: The gemistocytic neoplastic astrocytes show a significantly lower rate of proliferation than does the intermingled small-cell component.

Answer 19

True

Question 20

Diffuse Astrocytomas reliably show what immunophenotype? (2)

Answer 20

• GFAP

- Vimentin

Question 21

What IDH mutation can be demonstrated using IHC?

Answer 21

IDH1 (R132H-mutant)

-90% of all glioma-associated IDH mutations

Question 22

In mutant tumors, what is the staining pattern for IDH1?

Answer 22

Cytoplasmic (stronger)

Nuclear (weaker)

Question 23

Strong nuclear ___ expression is also frequently observed, consistent with the high incidence of ___ mutations in diffuse astrocytomas.

Answer 23

• p53
• TP53

*The use of p53 positivity to reflect TP53 mutation is note entirely sensitive or specific

Question 24

____ expression is almost invariably lost in the setting of ____ mutations, which also feature prominently in Diffuse Astrocytoma.

Answer 24

• ATRX-expression (lost)

- ATRX-mutations

Question 25

T/F: Diffuse gliomas that occur in adults and that do not harbour IDH mutation, regardless of their WHO grade, tend to exhibit more aggressive clinical behavior.

Answer 25

True

Question 26

Glioma-associated IDH1 and IDH2 mutations impart a ___-of-function phenotype to the respective metabolic enzymes ___ and ___, which overproduce the oncometabolite __________.

Answer 26

- Gain-of-function - IDH1/IDH2 - 2-hydroxyglutarate *Glioma-associated IDH1 and IDH2 mutations impart a Gain-of-function phenotype to the respective metabolic enzymes IDH1 and IDH2, which overproduce the oncometabolite 2-hydroxyglutarate.

Question 27

What are the physiological consequences of 2-hydroxyglutarate overproduction?

Answer 27

Effects on epigenomic states and gene regulation

Question 28

IDH mutations induce what?

Answer 28

G-CIMP

Question 29

IDH mutation induced G-CIMP leads to what?

Answer 29

Hypermethylation in gene promoter regions which silence the expression of several important cellular differentiation factors.

Question 30

IDH mutations promote glioma formation by disrupting _______ topology and allowing aberrant chromosomal regulatory interactions that induce oncogene expression, including glioma oncogenes such as ______.

Answer 30

- Chromosomal - PDGFRA *IDH mutations promote glioma formation by disrupting Chromosomal topology and allowing aberrant chromosomal regulatory interactions that induce oncogene expression, including glioma oncogenes such as PDGFRA.

Question 31

___-_____-______ was reported in about 50% of diffuse astrocytomas in the pre-IDH era, but this proportion may be higher amont IDH-mutant diffuse astrocytomas and does not correlate consistently with ____.

Answer 31

- MGMT promoter methylation - G-CIMP *MGMT promoter methylation was reported in about 50% of diffuse astrocytomas in the pre-IDH era, but this proportion may be higher amont IDH-mutant diffuse astrocytomas and does not correlate consistently with G-CIMP.

Question 32

The vast majority of IDH-mutant diffuse astrocytomas, as well as the WHO grade III anaplastic astrocytomas and grade IV glioblastomas that evolve from them, also harbor class-defining mutations in ____ and ____.

Answer 32

- TP53 | - ATRX

Question 33

ATRX encodes an essential _____-_____ protein, and its deficiency has been associated with _______ dysregulation and ______ dysfunction.

Answer 33

- Chromatin-binding - Epigenomic - Telomere *ATRX encodes an essential chromatin-binding protein, and its deficiency has been associated with epigenomic dysregulation and telomere dysfunction.

Question 34

ATRX mutations seem to induce an abnormal ______-_______-_______.

Answer 34

Telomere maintenance mechanism | -known as Alternative lengthening of telomeres.

Question 35

ATRX mutations and alternative lengthening of telomeres are mutually exclusive with what?

Answer 35

Activating mutations in the TERT gene.

Question 36

TERT gene encodes what?

Answer 36

Catalytic component of telomerase.

Question 37

TERT mutations are seen in the vast majority of what? (2)

Answer 37

- Oligodendrogliomas | - IDH-wildtype glioblastomas

Question 38

ATRX deficiency has also been associated with generalized _____-______, which can induce ___-dependent cell death in some contexts.

Answer 38

- genomic instability - p53 *ATRX deficiency has also been associated with generalized genomic instability, which can induce p53-dependent cell death in some contexts.

Question 39

___ mutations in diffuse astrocytoma may enable tumor cell survival in the setting of ____-___.

Answer 39

- TP53 - ATRX loss *TP53 mutations in diffuse astrocytoma may enable tumor cell survival in the setting of ATRX loss.

Question 40

Diffuse Astrocytoma, IDH-Mutant: | -Median survival

Answer 40

10.9 years