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1.WHO CNS Tumors > Diffuse Astro, IDH-Mutant > Flashcards

Diffuse Astro, IDH-Mutant Flashcards

1
Q

Diffuse Astrocytoma, IDH-Mutant:

  • Definition
  • Grading
A
  • Infiltrating astrocytoma with mutation in either IDH1 or IDH2 gene.
  • WHO Grade II
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2
Q

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

A
  • ATRX

- TP53

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3
Q

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

A

11-15%

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4
Q

Diffuse Astrocytoma, IDH-Mutant:

  • Age distribution
  • M:F
A
  • 38 y/o (mean)

- 1.3:1 (M:F)

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5
Q

Diffuse Astrocytoma, IDH-Mutant:

-Localization

A
  • Frontal lobes (Supratentorally)

* Can be located in any region of the CNS

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6
Q

Diffuse Astrocytoma, IDH-Mutant - Clinical features:

  • Presenting symptoms (2)
  • Onset
A
  • Seizures
  • Personality changes (frontal lobe)
  • Gradual onset
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7
Q

Diffuse Astrocytoma, IDH-Mutant - Imaging:

-CT

A
  • Poorly defined, homogenous masses of low density
  • NO contrast enhancement
  • Calcification and cystic change may be present early in the evolution
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8
Q

Diffuse Astrocytoma, IDH-Mutant - Imaging:

-MRI (T1/T2/Gadolinium)

A
  • T1: Hypodensity
  • T2: Hyperintensity
  • Enhancement not common, tends to appear during progression
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9
Q

Diffuse Astrocytoma, IDH-Mutant - Microscopy:

  • General
  • Classic type
A
  • Well-differentiated fibrillary astrocytes in a background of loosely structured, often microcytic matrix.
  • Fibrillary Astrocytoma (no longer listed as a variant)
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10
Q

Diffuse Astrocytoma, IDH-Mutant - Microscopy:

  • Characteristic features (2)
  • Mitosis
A
  • Nuclear atypia
  • Moderately increased cellularity
  • Mitosis generally absent
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11
Q

Diffuse Astrocytoma, IDH-Mutant - Microscopy:

-Nuclear features

A
  • Vesicular with intermediate-sized masses of chromatin

- NUCLEOLUS

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12
Q

Diffuse Astrocytoma, IDH-Mutant:

-DDx

A

-Reactive astrocytosis

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13
Q

Histologic features of reactive astrocytes.

A
  • Enlarged nuclei
  • Stainable, defined cytoplasm
  • Culminating into a Gemistocyte
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14
Q

Gemistocyte histologic features.

A
  • Mass of eosinophilic cytoplasm extending into fine processes
  • Eccentric nucleus
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15
Q

Diffuse Astrocytoma, IDH-Mutant Vs. Reactive Astrocytosis.

A
  • IDH1 positive
  • p53 positive
  • trisomy 7 (rare)
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16
Q

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

A

True

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

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17
Q

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.

A

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.
18
Q

Diffuse Astrocytoma, IDH-Mutant:

-Ki67 proliferation index

A

<4%

19
Q

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

A

True

20
Q

Diffuse Astrocytomas reliably show what immunophenotype? (2)

A
  • GFAP

- Vimentin

21
Q

What IDH mutation can be demonstrated using IHC?

A

IDH1 (R132H-mutant)

-90% of all glioma-associated IDH mutations

22
Q

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

A

Cytoplasmic (stronger)

Nuclear (weaker)

23
Q

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

A
  • p53
  • TP53

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

24
Q

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

A
  • ATRX-expression (lost)

- ATRX-mutations

25
Q

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.

A

True

26
Q

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

A
  • 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.

27
Q

What are the physiological consequences of 2-hydroxyglutarate overproduction?

A

Effects on epigenomic states and gene regulation

28
Q

IDH mutations induce what?

A

G-CIMP

29
Q

IDH mutation induced G-CIMP leads to what?

A

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

30
Q

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

A
  • 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.

31
Q

___-_____-______ 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 ____.

A
  • 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.

32
Q

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 ____.

A
  • TP53

- ATRX

33
Q

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

A
  • Chromatin-binding
  • Epigenomic
  • Telomere

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

34
Q

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

A

Telomere maintenance mechanism

-known as Alternative lengthening of telomeres.

35
Q

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

A

Activating mutations in the TERT gene.

36
Q

TERT gene encodes what?

A

Catalytic component of telomerase.

37
Q

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

A
  • Oligodendrogliomas

- IDH-wildtype glioblastomas

38
Q

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

A
  • genomic instability
  • p53

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

39
Q

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

A
  • TP53
  • ATRX loss

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

40
Q

Diffuse Astrocytoma, IDH-Mutant:

-Median survival

A

10.9 years

1.WHO CNS Tumors (1 decks)

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