CNS5:Oligodendroglioma, IDH-mutant and 1p/19q-codeleted

Primary Author(s)*

Riley Lochner MD, MS, Neuropathology Fellow Houston Methodist/Texas Children’s/MD Anderson Cancer Center

Shashirekha Shetty, PhD, Director, Cytogenetics Laboratory, Center for Human Genetics Laboratory, University Hospitals

Cancer Category/Type

Central nervous system – Diffuse gliomas

Cancer Sub-Classification / Subtype

Oligodendroglioma, IDH-mutant and 1p/19q-codeleted

Definition / Description of Disease

A molecularly defined diffusely infiltrating glioma with IDH1 or IDH2 mutation and codeletion of chromosome arms 1p and 19q[1] .

Oligodendrogliomas are graded morphologically as either CNS WHO grade 2 or CNS WHO grade 3.

In rare cases where molecular studies are unable to be completed or have failed, tumors can be histologically diagnosed as Oligodendroglioma, NOS (not otherwise specified).

Synonyms / Terminology

Anaplastic oligodendroglioma (historical; now known as oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 3).

Oligoastrocytoma (discouraged; oligodendroglioma and astrocytoma are molecularly distinct entities. The diagnosis is reserved for rare cases where a dual genotype is identified, or where molecular testing could not be completed).

Epidemiology / Prevalence

-         Epidemiological statistics should be interpreted with caution as oligodendroglioma is now molecularly defined

  •   A subset of tumor historically diagnosed as oligodendroglioma on morphological grounds may therefore not meet current definition

-         Oligodendrogliomas occur primarily in adults (median age 43 years for CNS WHO grade 2 and 50 years for CNS WHO grade 3)[2]

  •   Slight male preponderance (M:F = 1.2:1[2])

-         Low incidence worldwide

  •   Incidence is changing over time due to refined molecular definition
    •   Incidence rate (cases per 100,000 person-years) for histologically defined oligodendroglioma – 0.10% (Republic of Korea; [3]), 0.50 (France [4]), 0.23 (USA 31675094[2]
    • Incidence rate for histologically defined CNS WHO Grade 3 oligodendroglioma – 0.06% (Republic of Korea[3]), 0.39 (France [4]), 0.11 (USA[2])
  •   CNS WHO grade 2 oligodendrogliomas account for 0.9% of primary brain tumors in US (PMID: 34608945)[2]
  •   CNS WHO grade 3 oligodendrogliomas account of primary brain tumors in the US(PMID: 34608945)[2]

Clinical Features

-         Oligodendrogliomas are most often low-grade, slow growing tumors

  •   Tumors are frequently asymptomatic and are increasingly found incidentally on imaging for other indications[5]

-         Most commonly present with seizures[6]

-         Can present with focal neurologic deficits or cognitive changes secondary to increased cranial pressure, especially in the high grade setting[6]

Signs and Symptoms Seizures[6]

Headache

Signs of increased intracranial pressure

-         Focal neurologic deficits

-         Cognitive changes

Asymptomatic

-         Increasingly an incidental finding on neuroimaging (PMID: 29186201)

Laboratory Findings Not applicable

Sites of Involvement

-         Approximately 60% of oligodendrogliomas occur within the frontal lobes with[1][2]

  •   14-16% in the temporal lobe
  •   10-15% in the parietal lobe
  •   1-6% in the occipital lobe
  •   Less commonly basal ganglia / cerebellum brainstem

-         Leptomeningeal spread and gliomatosis cerebri pattern can rarely occur[7] [8]

-         Rare spinal lesions have been reported but lack genotyping to confirm true oligodendroglioma[9] [10]

-         Extracranial metastasis exceedingly rare (CNS WHO grade 3)[11] [12] [13]

Morphologic Features

-         Classically consist of cells with round, monomorphous nuclei with stippled chromatin and perinuclear halos (artifactual fried-egg appearance)

-         Intervening delicate “chicken wire” vasculature

-         Can contain GFAP-positive minigemistocytes

-         Often contain microcalcifications, especially in low-grade tumors[1]

Immunophenotype


Finding Marker
Positive (universal) Retained nuclear ATRX[14], OLIG2[15], S100[16], MAP2[17], SOX10[18]
Positive (subset) Most positive for IDH1 p.R132H mutation (smaller subset lacking staining have non-canonical IDH mutation, <10%)[19]

Synaptophysin (cytoplasmic dot-like pattern[20])

Negative (universal) Lack diffuse p53[14]
Negative (subset) N/A

Chromosomal Rearrangements (Gene Fusions)

-         Oligodendrogliomas are defined by a t(1;19)(q10;p10) rearrangement that results in 1p/19q whole-arm codeletion

  •   This alteration is now required to make the diagnosis of oligodendroglioma
Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Pathogenic Derivative Prevalence Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
t(1;19)(p10;q10) der[t(1;19)(q10;p10) 100% Yes No No 1p/19q codeletion is the defining mutation of oligodendrogliomas and is required for diagnosis. Prognosis is dependent on histomorphologic grading[21] [22]

Individual Region Genomic Gain/Loss/LOH

Put your text here and fill in the table

Chr # Gain / Loss / Amp / LOH Minimal Region Genomic Coordinates [Genome Build] Minimal Region Cytoband Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
9 Loss chr9:21082471-23839529 [hg38]


9p21.3 No Yes No Loss CDKN2A gene locus associated with shorter survival of grade 3[23] [24]

Characteristic Chromosomal Patterns

Put your text here

Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
Co-deletion of 1p and 19q Yes No No See chromosomal rearrangements table - this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma[21] [22] [25]

Gene Mutations (SNV/INDEL)

Put your text here and fill in the table

Gene; Genetic Alteration Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) Prevalence (COSMIC / TCGA / Other) Concomitant Mutations Mutually Exclusive Mutations Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
IDH1 p.R132H [26] Oncogene (Intrinsically TSG, but is oncogenic in activity) [27] 90%[28] [29] N/A Yes Yes No IDH1 codon 132 mutation required for diagnosis; other most frequent mutation hotspot is IDH2 codon 172
TERT promoter [30] [31] [32] Oncogene 97%[33] N/A Yes Yes, favorable[34] No Teenagers lack TERT promoter mutations[35]
CIC TSG 24% CNS WHO grade 2;

50% CNS WHO grade 3

70% [29] [26]

N/A No Yes No Recurrent missense mutations in HMG-box DNA-binding domain (exon 5) and C1 motif (exon 20) unique to oligodendro-glioma[36]. Shorter time to recurrence with concomintant FUBP1 mut.[37]
FUBP1[38] [39] Both TSG and oncogene [40] 16% CNS WHO grade 2

22% grade 3

20-30%[39]

N/A No Yes No Shorter time to recurrence with concomitant CIC mut.[37]
NOTCH1 [41] TSG 15%[29] N/A No Yes No Shorter survival and worse histology [42] [43]
PIK3CA [44] [45] Oncogene 10%[46] N/A No No Possibly in future[46]
TCF12 TSG 7.5% of CNS WHO grade 3[47]


No Yes No Found recurrently in CNS WHO grade 3 tumors[47]

Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

Epigenomic Alterations

-         IDH-mutant, 1p/19q-codeleted oligodendrogliomas have hypermethylation of multiple CpG islands (PMID: 20399149)

  •   This corresponds to a distinct glioma CpG island methylator phenotype (G-CIMP)
    •   More prevalent in lower grade gliomas
    • Tightly associated with IDH1/2 mutations

Genes and Main Pathways Involved

Put your text here and fill in the table

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
IDH1/2; activating mutation Pathologic upregulation of 2-hydroxyglutarate leading to increased MAPK signaling Increased cell growth and proliferation[27]
TERT promoter; activating mutation Generates de novo ETS transcription factor binding sites upregulating expression Telomere stabilization, cell proliferation and immortalization[30][31] [32]
CIC; inactivating mutation Histone deacetylation upregulates MAPK signaling Increased cell growth and proliferation[48]
FUBP1; activating mutation FUBP1 deficiency alters cells cycle progression, especially in S phase by downregulating cyclin A Increased survival advantage to metabolic stress and chemotherapeutic drugs[38]
NOTCH1; inactivating mutation Affects epidermal growth factor-like domain leading to protein loss of function Induces accelerated cell proliferation[42]

Genetic Diagnostic Testing Methods

-         1p/19q co-deletion

  •   FISH
  •   Multiplex PCR
  •   Chromosomal microarray
  •   Next Generation Sequencing

Familial Forms

-         Germline mutations in POT1 have been associated with familial oligodendroglioma[49]

Links

IDH1

IDH2

References

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Notes

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