Glial tumors / Gliomas Flashcards
Molecular pathways in low-grade gliomas
Categories of glioneuronal tumor
- Adult-type diffuse gliomas
- Pediatric-type diffuse low-grade gliomas
- Pediatric-type diffuse high-grade gliomas
- Circumscribed astrocytic gliomas
- Glioneuronal and neuronal tumors
- Ependymal tumors
Astrocytoma, IDH-mutant
Diffusely infiltrating IDH1/2 mutant glioma.
Frequently with ATRX and/pr TP53 mutations.
1p/19q codeletion disqualifies this diagnosis.
Loss of nuclaer ATRX expression OR ATRX mutation are essential
Available grades: 2, 3, 4
Can occur in any region of the CNS. Imaging features: Poorly defined homogeneous, low-density mass without contrast enhancement.
Morphologically, these range from well-differentiated, low-density, slow-growing tumors to highly anaplastic, hypercellular, rapidly progressive tumors. Gemistocytic differentiation may be seen.
* Grade 2: Well-differentiated fibrillary glial cells without cellular cohesion, often in a microcystic matrix. Normal to mildly increased cellularity. Nuclear characteristics are key: they are enlarged, have irregular nuclear contour, hyperchromasia, and uneven chromatin. Mitotitc activity is absent (you get one grace mitosis per resection specimen, but any more than that and grade 2 is out).
* Grade 3: Increased mitotic activity and histologic anaplasia. Multinucleation may be seen. Any microvascular proliferation or necrosis upgrades to grade 4.
* Grade 4: Microvascular proliferation or necrosis, OR CDKN2A/B homozygous deletion.
Genetics associated with tumor progression: CDKN2A/B loss (usually behave like grade 4 tumors). CDK4 amplification, RB1 loss.
IHC: GFAP + (variable intensity), OLIG2 +
Adult-type diffuse glioma classification simplified
Gemistocytic differentiation
Oligodendroglioma, IDH mutant and 1p/19q codeleted
Available grades: 2, 3 (though criteria for grade 3 are not well defined)
Morphology:
* Grade 2: Classically has “fried egg” appearance, uniformly round nuclei slightly larger than normal oligodendrocytes, salt-and-pepper chromatin, individual tumor cells congregate around neuronal bodies. May have an associated light-blue mucinous matrix.
* Grade 3: Marked cytologic atypia, brisk mitotic activity (>2.5 mitoses per mm^2, microvascular proliferation, necrosis with or without pallisading, CDKN2A/B homozygous deletion.
Essential features:
Diffusely infiltrating glioma with IDH1/2 mutation AND 1p/19q codeletion.
Desirable features: Consistent methylome profile, retention of ATRX, presence of TERT promoter mutation.
Glioblastoma, IDH-wildtype
Genetics: IDH-wildtype, H3-wildtype, often TERT promoter mutated and/or EGFR amplified. +7 or -10 are common karyotype anomalies. Less specific features include RB1 loss, CDKN2A/B homozygous loss, and CDK4 amplification. Many glioblastomas evade apoptosis via TP53 inactivation or MDM2/MDM4 amplification.
Available grades: 4
Location: Most commonly subcortical white matter.
Morphologic features: Highly infiltrative, especially along white matter tracts. Highly proliferative with frequent apoptotic figures. Prominent microvascular proliferation, frequent necrosis. Tend to have myeloid-predominant inflammatory infiltrates. May display substantial pleomorphism, or may be relatively monomorphic - cytology does not help tremendously in this diagnosis. Should be hypercellular in the bulk of the tumor, but may not be at the infiltrative edge.
May display gemistocytic differentiation, epithelial metaplasia (areas of squamous or adenomatous differentiation), or mesenchymal metaplasia (“gliosarcoma”). Small cell glioblastoma and granular cell glioblastoma have also been described.
Essential criteria:
IDH-wildtype, H3 wild-type diffuse astrocytic glioma.
AND at least one of the following:
- Microvascular proliferation
- Necrosis
- TERT promoter mutation
- EGFR amplification
- Monosomy 7
- Trisomy 10
Microvascular proliferation.
Proliferative vessels tend to be multilayered. Florid microvacsular proliferation often shows mitotic figures and glomeruloid forms.
Diffuse astrocytoma, MYB or MYBL1 altered
A neoplasm related to adenoid cystic carcinoma in its affinity for MYB alterations. In both cases, the genetic aberrations involve loss of the C-terminal regulatory domains, resulting in overexpression. Often involves fusion of one of these genes to a fusion partner: MAML2, MMP16, PCDHGA1, QKI.
Available grades: 1
Location: Usually cerebral with cortical and subcortical components.
Morphology: Relatively monomorphic glial cells with bland round-to-oval or spindled nuclei, diffusely disposed in a fibrillary matrix or permeating neuropil. Frequently there is only a very minimal increase in the cellular density of the parenchyma, and it may be difficult to recognize that tissue contains a neoplasm. At low power there may be only a vague angiocentrism or perineuronal satellitism of the cellularity.
Essential features:
Diffuse astrocytoma without histologic features of atypia, without mutations in IDH or H3, and with a structural variant in MYB or MYBL1 OR alternatively an DNA methylation profile aligned with MYB/MYBL1 altered diffuse astrocytomas.
Angiocentric glioma
Low-grade diffuse gliomas almost all bearing the MYB::QKI fusion.
Available grades: 1
Morphology: A diffuse glioma composed mainly of thin, cytologically bland, bipolar cells with granular chromatin aggregating at least partly in perivascular spaces. May be arrayed in a rosette-like pattern or form sleeves lengthwise across vessels.
Pleomorphic xanthoastrocytoma (PXA)
Available grades: 2, 3
Astrocytoma with large, pleomorphic cells which may be multinucleated, spindled, lipidized, and have numerous eosinophilic granular bodies and reticulin deposition.
More common in kids, but can occur at any age. Generally well-circumscribed tumors with compressive symptoms.
Molecular: Characteristically have BRAF V600E (about 80% of cases) and homozygous CDNK2A/B loss. Rare cases may progress to an atypical rhabdoid tumor following loss of SMARCB1.
Polymorphous low-grade neuroepithelial tumor of the young (PLNTY)
Available grades: 1
Indolent cerebral neoplasm characterized by diffuse growth patterns, frequent presence of oligodendroglioma-like components, calcifications, CD34 positivity, and MAPK pathway-activating genetic abnormalities.
Noonan syndrome predisposes (unsurprisingly).
Usually have cortical and subcortical components, and 80% involve the temporal lobes. On imaging, have solid and cystic components, and are densely calcified on CT.
Morphologically, composed of diffuse and compact areas with at least partial oligodendrocyte-like morphology (small, round nuclei with perinuclear haloes) as well as populations displaying obvious variation in nuclear size and shape with wrinkled or grooved nuclei and intranuclear pseudoinclusions. May contain fibrillary, spindled, and pleomorphic forms, as well as rare perivascular pseudorosettes. Calcifications are present and are coarse and confluent. Eosinophilic granular bodies are occasionally seen, but Rosenthal fibers should be absent.
Essential features:
Diffuse growth pattern (at least regionally), oligodendrocytoma-like components (which may be minor), minimal mitotic activity, regional CD34 expression by tumor cells. IDH must be wild-type and there must be unequivocal evidence of BRAF V600E mutation.
Diffuse midline glioma, H3K27 altered
Available grades: 4
Loss of H3K27me3 is characteristic.
Location: In children, preferentially in the brainstem or pons, occasionally bithalamic. In adolescents and adults, preferentially arise unilaterally in the thalamus or spinal cord. Frequently involve the leptomeninges (40% of cases).
Morphology: Diffuse infiltration of brain parenchyma without particular perivascular or perineuronal tropism. Cells are mostly small and monomorphic, but can occasionally be polymorphous, showing astrocytic, piloid, oligodendroglial, giant cell, and undifferentiated or epithelioid cytology. Frequent mitotic figures, microvascular proliferation, and necrosis may be seen, but are not required for diagnosis. Rosenthal fibers and EGBs are not typically seen.
IHC: OLIG2+, MAP+, S100+, GFAP variable. TP53 mutant pattern or ATRX loss may be seen.
Note: EGFR-mutant variants may be GFAP and SOX10 negative, but will be GFAP positive.
Molecular: Most often H3 p.K28M, but can be due to EZHIP overexpression or an EGFR mutation.
Diffuse low-grade glioma, MAPK pathway-altered
Pediatric diffuse glioma with low-grade features, often driven by BRAF V600E or FGFR1 variants.
Location: Seen throughout the craniospinal axis, but especially the cerebral hemispheres.
Morphology: Diffuse astrocytic or oligodendroglial morphology. Tumor cells have absent or minimal minimal mitotic activity, no microvascular proliferation, and no necrosis. There is a genetic alteration in the MAPK pathway without IDH or H3 mutation or CDKN2A deletion.
