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CNS neoplasms Flashcards

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1
Q

Gliomas are classified based off of what?

A

• Their resemblance to normal, non-neoplastic glial cells

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2
Q

What are the common gliomas and their WHO grade by definition?

A 
• Pilocytic astrocytoma
		○ Grade I
	• Diffuse astrocytoma
		○ Grade II
	• Anaplastic astrocytoma
		○ Grade III
	• Oligodendroglioma
		○ Grade II
	• Anaplastic oligodendroglioma
		○ Grade III
	• Glioblastoma
		○ Grade IV
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3
Q

What makes a grade I glioma “not so bad”?

A
  • Well demarcated
    • Generally do not upgrade over time
    • Can be surgically-excised if in an anatomically favorable location
    • Treated with surgery alone
    • Usually doesn’t require adjuvant therapies like radiation/chemo
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4
Q

What are the characteristics of pilocytic astrocytoma?

A

• Most common CNS neoplasm of childhood
• found also in young adults
• Cerebellum, optic pathway, hypothalamus, thalamus, spinal cord, temporal lobe
• WHO grade I, does not progress to higher grades (usually)
• Different genetic origins in different anatomical sites
• Histopathology
○ Bipolar neoplastic cells with elongated hairlike processes in parallel bundels
○ Rosenthal fibers, eosinophilic granular bodies
○ May be vascular with calcifications

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5
Q

in what population would you expect a pilocytic astrocytoma to be found?

A
  • Most common CNS neoplasm of childhood

* found also in young adults

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6
Q

What is the histopathology of a pilocytic astrocytoma?

A

• Histopathology
○ Bipolar neoplastic cells with elongated hairlike processes in parallel bundels
○ Rosenthal fibers, eosinophilic granular bodies
○ May be vascular with calcifications

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7
Q

When you see pilocytic astrocytoma, what genetic underpinnings must you think of?

A
  • BRAF:KIAA fusion
    • BRAF fusion
    • The grade I pilocytic astrocytomas by definition have the BRAF fusion
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8
Q

What does the BRAF gene product do?

A
  • Mitogen-activated protein kinase
    • MAPK
    • In the RAS/RAF/MEK/ERK pathway
    • Key in cell proliferation, survival, differentiation and apoptosis
    • Ends up making cyclin D1
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9
Q

What makes the BRAF:KIAA fusion such an advantage for the tumor cell?

A
  • Don’t know what KIAA does alone but fusion leads to ablation of BRAF N-terminal domain
    • Renders BRAF constitutively active and leads to oncogene-induced senescence (OIS)
    • Favorable feature in a slowly growing tumor
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10
Q

What’s up with diffuse astrocytoma?

A

• Mean age 30s-40s
• WHO grade II, may progress to higher grade
• Cerebral hemispheres, rarely posterior fossa
• Histopathology
○ Discohesive monotonous cellular infiltrate in patternless array
○ Fibrillary, protoplasmic, gemistocytic subtypes
○ Occasional microcystic change
○ Rare mitoses, two or more on small stereotactic biopsies = WHO grade III
○ No microvascular proliferation or necrosis
○ Ki67/MIB1 less than 4%
§ Marker of cell cycle
○ Often nuclear p53 IHC+
§ This is unlike oligodendrogliomas

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11
Q

What is the histopathology of diffuse astrocytoma?

A

• Histopathology
○ Discohesive monotonous cellular infiltrate in patternless array
○ Fibrillary, protoplasmic, gemistocytic subtypes
○ Occasional microcystic change
○ Rare mitoses, two or more on small stereotactic biopsies = WHO grade III
○ No microvascular proliferation or necrosis
○ Ki67/MIB1 less than 4%
§ Marker of cell cycle
○ Often nuclear p53 IHC+
§ This is unlike oligodendrogliomas

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12
Q

What are the important IHC markers in diffuse astrocytoma?

A

○ Ki67/MIB1 less than 4%
§ Marker of cell cycle
○ Often nuclear p53 IHC+
§ This is unlike oligodendrogliomas

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13
Q

What makes diffuse astrocytoma a difficult tumor to treat surgically?

A
  • Microcysts and ill-defined borders
    • Surgeon can’t tell where the tumor starts and stops
    • Radiologist can’t tell…you can’t operate on this lesion
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14
Q

What’s up with anaplastic astrocytoma?

A

• Mean age is 45 years
• WHO grade III
• Cerebral hemispheres in adults
• Histopathology
○ Higher cellularity, increased nuclear pleomorphism, hyperchromasia, mitoses compared to WHO grade II astrocytomas
○ No necrosis or microvascular proliferation
○ Ki-67/MIB1 higher than WHO grade II, 5-15%
○ MOST IMPORTANT USE OF MIB1 is in distinguishing WHO grade II astrocytoma from WHO grade III anaplastic astrocytoma

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15
Q

What is the MOST IMPORTANT USE OF MIB1?

A

○ MOST IMPORTANT USE OF MIB1 is in distinguishing WHO grade II astrocytoma from WHO grade III anaplastic astrocytoma

  • less than 4% for grade II
  • 5-15% for grade III
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16
Q

In terms of IDH, what do each of the tumors we discussed have?

A
  • All pilocytic astrocytomas are IDH wildtype
    • All oligodendrogliomas are IDH mutant AND show 1p/19q deletion
    • Diffuse astrocytoma, anaplastic astrocytoma, GBM today SEPARATED into/DEFINED BY IDH mutant and IDH wildtype status
    • GBM - glioblastoma multiformans
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17
Q

What is IDH?

A

• IDH - isocitrate dehydrogenase
• Absolutely essential to know that this is a CNS neoplasm diagnostic marker and it defines certain tumors
*normal function is protection against oxidative damage

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18
Q

If there is a problem in IDH, what is the result?

A

• IDH mutation can lead to too little alpha-ketoglutarate, which is protective against oxidative damage
• If there is too little alpha-ketoglutarate there is a release of HIF1
○ Hypoxia inducible factor
• Leads to angiogenesis really, and promotes the tumor invasion, survival and angiogenesis

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19
Q

What is the utility of the IDH1/2 mutations?

A

• Determining if the lesion is neoplastic vs. non-neoplastic
• Primary CNS tumor vs. non-CNS tumor (metastasis)
○ Remember that metastatic brain lesions are more common than primary
• Marker of astrocytic and oligodendroglial tumors

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20
Q

What is the IDH1 mutation important for?

A
  • Diffuse astrocytomas, anaplastic astrocytomas, GBMs today DEFINED by IDH-mutant or wildtype status
    • All adult oligodendrogliomas defined by presence of LOH 1p,19q AND IDH mutation (either IDH1 or 2)
    • 90% of IDH1 mutations are at position R132H
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21
Q

Where do you find IDH2 mutations?

A

• These are less common and mostly are found in oligodendroglial tumors

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22
Q

What is the utility of an antibody against IDH1 R132H?

Study These Flashcards
A
  • This is 90% of all IDH mutations
    • You would see lots of IDH problems and thus would see oligodendrogliomas well
    • There is a small percentage of gliomas you could miss like the ones with sporadic mutations somewhere else or the rare IDH2 mutations
23
Q

What does IDH1 mutation status have to do with prognosis?

Study These Flashcards
A
  • Strong evidence that negative IDH1 anaplastic astrocytomas do more poorly than those with IDH1 mutation
    • Studies that have stratified IDH1 mutation assessment suggest that IDH is more powerful predictor in high grade gliomas than is grade
24
Q

What are the genetics of diffuse astrocytomas?

Study These Flashcards
A
  • IDH1 mutation
    • No LOH 1p, 19q
      • p53/ATRX mutation
25
What tumors have ATRX gene and what have a loss of it?
• ATRX is lost in diffuse astrocytomas ○ Grade II and III • Retained in oligodendrogliomas, primary GBMs and special glioma types
26
What's up with oligodendrogliomas?
• 5-15% of all gliomas • Mean age of onset is 42 years • WHO grade II • Usually arises in cerebral white matter • Histopathology ○ Low to moderate cellularity occasional mitosis ○ Regular round nuclei with artifactual perinuclear halo ○ Fine capillary network and focal calcification ○ Perineuronal satellitosis, often extensive cortcal infiltration correlating with seizure activity clinically ○ Many cases have intermdiate or mixed oligodendroglial/astrocytic phenotype ○ Both tumor types now know to share common IDH1 mutational lineage, followed by later different and distinctive genetic mutations leading to oligo vs. atrocytic lineage § P53 vs LOH 1p, 19q
27
What is the histopathology common to oligodendrogliomas?
• Histopathology ○ Low to moderate cellularity occasional mitosis ○ Regular round nuclei with artifactual perinuclear halo ○ Fine capillary network and focal calcification ○ Perineuronal satellitosis, often extensive cortcal infiltration correlating with seizure activity clinically ○ Many cases have intermdiate or mixed oligodendroglial/astrocytic phenotype ○ Both tumor types now know to share common IDH1 mutational lineage, followed by later different and distinctive genetic mutations leading to oligo vs. atrocytic lineage § P53 vs LOH 1p, 19q
28
Why do oligodendrogliomas tend to have a mixed astrocytic/oligodendroglial phenotype?
○ Both tumor types now know to share common IDH1 mutational lineage, followed by later different and distinctive genetic mutations leading to oligo vs. atrocytic lineage § P53 vs LOH 1p, 19q
29
A surgical pathology sample (gross) shows a loss of the gray white interface in the cortex. What is the likely culprit?
• Low grade oligodendroglioma will obscure the gray-white interface of the cortex
30
What's up with the anaplastic oligodendroglioma subtype?
• 3.5% of adult supratentorial malignant gliomas • Mean age of onset is 48 years • WHO grade III *expect to see elevated MIB1 presence (more mitoses) • Histopathology ○ Same as classic oligodendroglioma but with incrased cellularity, nuclear atypia and mitoses ○ Occasional vascular proliferation and geographic necrosis is allowed ○ There is a bit more lee-way in the oligodendroglial lineage tumors with necrosis and vascular proliferation ○ IF IT IS ASTROCYTIC, necrosis and vascular proliferation would change the dx to GBM
31
In terms of geographical necrosis and vascular proliferation what is the difference in dx between a tumor of oligodendrocytic and astrocytic lineage?
○ There is a bit more lee-way in the oligodendroglial lineage tumors with necrosis and vascular proliferation ○ IF IT IS ASTROCYTIC, necrosis and vascular proliferation would change the dx to GBM ○ Occasional vascular proliferation and geographic necrosis is allowed in dx of anaplastic oligodendroglioma
32
Oligodendroglial tumors are associated with what particular genetic anomaly?
• 1p and 19q codeletions • Established genetic marker of oligodendroglial tumors • 60-80% of oligodendrogliomas have this • More than 60% of anaplastic oligodendrogliomas have this • Results from unbalanced translocation t(1;19)(q10;10) ○ Lose 1p/19q ○ Preservation of a 1q/19p chromosome ○ Entire chromosome arms typically lost
33
In terms of 1p,19q deletions, what CNS tumors have what abnormalities?
* All pilocytic astrocytomas are IDH wildtype and do NOT have 1p,19q deletions * All oligodendrogliomas are IDH mutant AND show 1p/19q deletion * Diffuse astrocytoma, anaplastic astrocytoma, GBM today SEPARATED into/DEFINED BY IDH mutant and IDH wildtype status * GBM - glioblastoma multiformans
34
What is the utility of discovering a 1p/19q deletion presence/absence?
• Diagnostic: almost never seen in non-oligodendrogliomas ○ Excepting pediatric cases which have different genetics • Prognostic - better survival if deletion is present • Predicitive ○ Better response to procarbazine-lomustine-vincristine (PCV) treatment originally ○ Newer treatment is temozolomide plus radiotherapy and deletion presence predicts better response to this treatment
35
What's up with GBM?
• GBM - glioblastoma multiformans • 15% of all intracranial neoplasms • Mean age of onset primary = 62 years • Mean age of onset secondary = 45 years • Usually involves cerebral hemispheres • WHO grade IV • Histopathology ○ Highly cellular and mitotically active ○ Dedifferentiated elemtns ○ Microvascular hyperplasia - glomeruloid/solid tufts ○ Necrosis ○ Ki-67/MIB1 is over 15% ○ Once diagnsis of GBM is established, controversial as to wheter mitotic rate/MIB1 index provides further diagnostic value ○ Probably due to overwhelming influence of necrosis on prognosis
36
What is the histopathology of GBM?
• Histopathology ○ Highly cellular and mitotically active ○ Dedifferentiated elemtns ○ Microvascular hyperplasia - glomeruloid/solid tufts ○ Necrosis ○ Ki-67/MIB1 is over 15% ○ Once diagnsis of GBM is established, controversial as to wheter mitotic rate/MIB1 index provides further diagnostic value ○ Probably due to overwhelming influence of necrosis on prognosis
37
How do you genetically arrive at secondary glioblastoma?
* IDH (must start out with this) * TP53 mutation/17p loss * (now diffuse astrocytoma) * 9p loss * (now anaplastic astrocytoma) * 10q loss * (now secondary GBM)
38
What are the genetic losses that make a primary GBM?
* 10q loss * PTEN mutation * EGFR amplification * CDKN2A/B deletion
39
What is EGFRvIII?
* 50% of GBMs with EGFR amplification contain EGFRvIII * In-frame deletion of extracellular domain of EGFR, which makes it constitutively active * Helpful for showing the high-grade evilness of GBM
40
Pediatric and adult GBMs are similar in all ways except:
* PTEN mutations and EGFR amplification * These are way more rare in pediatric cases * IDH1 mutations are also rare in children
41
What is the worst of all pediatric brain tumors?
• Pediatric diffuse gliomas • Diffuse intrinsic pointine glioma (DIPG) • Midline non-brainstem high grade glioma (mHGG) • Almost ALL have H3 K27M mutations ○ Histone mutation • Almost 100% fatality and medial survival is 9 months
42
What's up with ganglioglioma?
* WHO grade I * Younger patient population, 8-25 years * Usually supratentorial - temporal lobe * Calcified, cystica nd demarcated, usually little mass effect * Present with seizures pretty often
43
When you see synaptophysin you think…?
* Ganglioglioma | * Neoplastic neurons express synaptophysin and NeuN (nuclear neurofilament)
44
What's up with medulloblastoma?
* Tumor of cerebellum * Peak age of 7 years, most are in children under 16 years old * Male predominance * Present with disturbances of gait, truncal ataxia, lethargy, headache, morning vomiting * Radiation and chemotherapy regimens in treatment of medulloblastoma has improved the 5-year survival rate to 90%
45
You see the word rosette, or a slide with a nice circular clump of tumor cells that look like a blueberry you think…?
* Medduloblastoma * Flexner's rossette (1891) * Wrights rosette (1911) * Bailey's pseudo-rosettes (1926) * All are used to classify medulloblastoma
46
What are the two ways that medulloblastomas are classified by the WHO?
• Genetically defined ○ In particular shh and wnt • Histopathologically defined
47
Can you suspect either a wnt-MB or shh-MB by imaging?
* MB = medulloblastoma * Yes, wnt = cerebellar peduncle/CPA * Lateral cerebellum = shh * You still have to test but you can suspect based off of tumor location
48
What grade are all medulloblastomas?
* WHO grade IV | * They can subclassify by moleuclar criteria: radiation and chemotherapy protocols being modified based on subtype
49
What is important about a choroid plexus papilloma?
* Intraventricular tumor most often * WHO grade I, surgically excisable quite often * Can cause hydrocephalus by CSF overproduction, but that is rare. * Hydrocephalus is usually caused by CSF blockage in this case
50
What's up with the ependymoma?
* WHO grade II * From ependymal cells that line the ventrical and most are found intraventricular * Most are in first 20 years of life * Most are in 4th ventricle * Most present with hydrocephalus * Commonly calcified tumors and protrude up from floor of 4th ventricle * Should see some hairs on them to determine ependymal differentiation * Some form canals or tubes (trying to form 4th ventricle aqueduct)
51
What is a common form of mesenchymal-based tumor that is in the cranial vault?
• Meningiomas • Grade I mostly, but can push on stuff that can be harmful (mass effect) • They may penetrate dura, occlude venous sinuses and invade bone, causing hyperostosis You see hyperostosis in the cranial vault and you think…? • Meningiomas have the ability to invade bone and make a large bony tumor (can't really excise without super specialist help)
52
The 8th cranial nerve is an unfortunately common site of what tumor's growth?
* Schwannoma | * Vestibular schwannomas or acoustic neuromas
53
What are the familial tumor syndromes that concern the CNS?
• Neurofibromatosis type 1 and 2 ○ Type 1 - autosomal dominant § Intra and extracranial schwann cell tumors § Optic gliomas, astrocytomas and meningiomas also occur § Protein is neurofibromin, which inhibits RAS § Located at 17q11.2 ○ Type 2 § Bilateral vestibular schwannomas and multiple meningiomas § Gene on 22q12 § Protein is merlin and regulates cell surface receptor signalling • Tuberous sclerosis ○ Autosomal dominant ○ TSC1 and 2 genes ○ Hamartin and tuberin are gene products ○ Inhibit mTOR which regulates cell size and anabolic growth ○ Characterized by hamartomas and benign neoplasms of the brain and other tissues ○ Sub-ependymal giant cell astrocytoma
54
What are the 5 most common metastatic cancers to the CNS?
Lung, breast, melanoma, kidney and GI Account for 80% of all metastases in CNS Meninges are often a metastatic site as well All are sharply demarcated and form at the gray-white junction Treatment is treating primary tumor and surgical resection from brain

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