Oligodendroglioma.docx

**Oligodendroglioma, IDH-mutant and 1p/19q-codeleted** **Definition  ** Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, is a diffusely infiltrating glioma with *IDH1* or *IDH2* mutation and codeletion of chromosome arms 1p and 19q (CNS WHO grade 2 or 3). **ICD-O coding  ** 9450/3 Oligodendro...

**Oligodendroglioma, IDH-mutant and 1p/19q-codeleted** **Definition  ** Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, is a diffusely infiltrating glioma with *IDH1* or *IDH2* mutation and codeletion of chromosome arms 1p and 19q (CNS WHO grade 2 or 3). **ICD-O coding  ** 9450/3 Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, grade 2 9451/3 Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, grade 3 **ICD-11 coding  ** 2A00.0Y & XH7K31 Other specified gliomas of brain & Oligodendroglioma, IDH-mutant and 1p/19q-codeleted **Related terminology  ** *Not recommended:* anaplastic oligodendroglioma, IDH-mutant and 1p/19q-codeleted. **Subtype(s)  ** Oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 2; oligodendroglioma, IDH-mutant and 1p/19q-codeleted, CNS WHO grade 3 **Localization  ** Among 5542 histologically defined oligodendrogliomas registered in the Central Brain Tumor Registry of the United States (CBTRUS) database, 59% were located in the frontal lobe, 14% in the temporal lobe, 10% in the parietal lobe, and 1% in the occipital lobe \[\[Central Brain Tumor Registry of the United States \[Internet\]. Chicago (IL): CBTRUS; 2020. Available from: https://cbtrus.org/.\]\]. Among 470 genetically defined CNS WHO grade 3 oligodendrogliomas of the French national POLA network, 62% were frontal tumours, 16% were temporal, 15% were parietal, and 6% were occipital \[\[Portail Epidemiologie France: Health Databases \[Internet\]. Paris (France): Institut thématique Santé Publique - Inserm; 2020. POLA - National POLA Network for the Treatment of High-Grade Oligodendroglial Tumours; updated 2015 Jun 23. Available from: https://epidemiologie-france.aviesan.fr/fr/content/view/full/87575.\]\]. Other studies have also shown a clear predilection for the frontal lobes in IDH-mutant and 1p/19q-codeleted oligodendrogliomas {[[ 26849038 ]](https://www.ncbi.nlm.nih.gov/pubmed/26849038); [[23896377 ]](https://www.ncbi.nlm.nih.gov/pubmed/23896377); [[29016833 ]](https://www.ncbi.nlm.nih.gov/pubmed/29016833)}. Less common locations include the posterior fossa, basal ganglia, and brainstem. Exceptional cases of IDH-mutant and 1p/19q-codeleted oligodendroglioma show widespread intracerebral dissemination corresponding to a gliomatosis cerebri pattern {[[ 26493382 ]](https://www.ncbi.nlm.nih.gov/pubmed/26493382)}. Leptomeningeal spread is occasionally seen in patients with IDH-mutant and 1p/19q-codeleted oligodendroglioma, in particular at recurrence {[[ 31019097 ]](https://www.ncbi.nlm.nih.gov/pubmed/31019097)}. Primary leptomeningeal manifestation of IDH-mutant and 1p/19q-codeleted oligodendroglioma has also been reported {[[ 30210430 ]](https://www.ncbi.nlm.nih.gov/pubmed/30210430)}. Rare cases of intramedullary spinal oligodendroglioma are on record, but data on genotype are usually lacking {[[ 15138790 ]](https://www.ncbi.nlm.nih.gov/pubmed/15138790); [[29021677 ]](https://www.ncbi.nlm.nih.gov/pubmed/29021677)}. Rarely, patients may present with multifocal tumours {[[ 23528979 ]](https://www.ncbi.nlm.nih.gov/pubmed/23528979)}. Individual cases of morphologically defined oligodendrogliomas (not genetically characterized) that developed from ovarian teratomas have been reported {[[ 22496515 ]](https://www.ncbi.nlm.nih.gov/pubmed/22496515)}. **Clinical features  ** Seizures are the presenting symptom in approximately two thirds of patients with IDH-mutant and 1p/19q-codeleted oligodendroglioma {[[ 29186201 ]](https://www.ncbi.nlm.nih.gov/pubmed/29186201); [[28497806 ]](https://www.ncbi.nlm.nih.gov/pubmed/28497806)}. Additional common initial symptoms include headache, other signs of increased intracranial pressure, focal neurological deficits, and cognitive changes. These signs and symptoms are nonspecific and depend on the tumour's location and speed of growth. With advanced imaging becoming more widely available for symptom screening, incidental diagnosis is more frequently reported, accounting for 10% of cases in one study {[[ 29016833 ]](https://www.ncbi.nlm.nih.gov/pubmed/29016833)}. Imaging IDH-mutant and 1p/19q-codeleted oligodendrogliomas usually appear on CT as hypodense or isodense mass lesions that are typically located in the cortex and subcortical white matter {[[ 28723281 ]](https://www.ncbi.nlm.nih.gov/pubmed/28723281)}. Calcifications are commonly seen, but they are not diagnostic; some tumours show intratumoural haemorrhages and/or areas of cystic degeneration {[[ 28723281 ]](https://www.ncbi.nlm.nih.gov/pubmed/28723281)}. MRI typically shows a T1-hypointense and T2-hyperintense mass with indistinct tumour margins. Signal intensities on T1-weighted and T2-weighted MRI are often heterogeneous. Gadolinium contrast enhancement can be detected in \ 70% of CNS WHO grade 3 oligodendrogliomas, where it is associated with microvascular proliferation and less favourable prognosis {[[ 22268087 ]](https://www.ncbi.nlm.nih.gov/pubmed/22268087); [[30529899 ]](https://www.ncbi.nlm.nih.gov/pubmed/30529899); [[30417117 ]](https://www.ncbi.nlm.nih.gov/pubmed/30417117); [[32025725 ]](https://www.ncbi.nlm.nih.gov/pubmed/32025725)}. IDH-mutant and 1p/19q-codeleted oligodendrogliomas showed higher microvascularity (higher rCBV) and higher vascular heterogeneity than IDH-mutant diffuse astrocytomas of corresponding grade {[[ 30712139 ]](https://www.ncbi.nlm.nih.gov/pubmed/30712139)}. Magnetic resonance spectroscopy and radiomics can identify differences in certain features between 1p/19q-codeleted and 1p/19q-intact low-grade diffuse gliomas, but these techniques have limited sensitivity and specificity (\~80% in validation series) and cannot yet replace molecular diagnostics {[[ 18413825 ]](https://www.ncbi.nlm.nih.gov/pubmed/18413825); [[23221948 ]](https://www.ncbi.nlm.nih.gov/pubmed/23221948); [[22433833 ]](https://www.ncbi.nlm.nih.gov/pubmed/22433833); [[31548344 ]](https://www.ncbi.nlm.nih.gov/pubmed/31548344)}. Demonstration of elevated 2-hydroxyglutarate levels by magnetic resonance spectroscopy is a new means of non-invasively detecting IDH-mutant gliomas (including oligodendrogliomas), but it remains technically challenging {[[ 22281806 ]](https://www.ncbi.nlm.nih.gov/pubmed/22281806)}. PET imaging may allow the distinction between CNS WHO grade 2 and 3 IDH-mutant gliomas, but reported series tend to be small and unvalidated {[[ 32382870 ]](https://www.ncbi.nlm.nih.gov/pubmed/32382870)}. Spread IDH-mutant and 1p/19q-codeleted oligodendrogliomas characteristically extend into adjacent brain in a diffuse manner. Like other diffuse gliomas, they occasionally have a gliomatosis cerebri pattern {[[ 26493382 ]](https://www.ncbi.nlm.nih.gov/pubmed/26493382)}. In late-stage disease especially, distant leptomeningeal spread may occur in some patients {[[ 31019097 ]](https://www.ncbi.nlm.nih.gov/pubmed/31019097)}. Rare cases of extracranial metastases of oligodendrogliomas, mostly CNS WHO grade 3, have been reported {[[ 16710746 ]](https://www.ncbi.nlm.nih.gov/pubmed/16710746); [[30526175 ]](https://www.ncbi.nlm.nih.gov/pubmed/30526175); [[31248444 ]](https://www.ncbi.nlm.nih.gov/pubmed/31248444)}. At times, patients with progressive tumours without treatment options may show slow clinical deterioration despite the presence of large enhancing lesions. **Epidemiology  ** The following paragraphs mostly refer to epidemiological data based on histological tumour classification, because population-based data on molecularly defined oligodendrogliomas are not yet available. Thus, the available information must be interpreted with caution as histologically defined oligodendroglial tumours include a considerable subset of gliomas without IDH mutation and 1p/19q codeletion {[[ 24723566 ]](https://www.ncbi.nlm.nih.gov/pubmed/24723566); [[27573687 ]](https://www.ncbi.nlm.nih.gov/pubmed/27573687); [[26354927 ]](https://www.ncbi.nlm.nih.gov/pubmed/26354927)}. Incidence The reported incidence rate (cases per 100 000 person-years) of histologically diagnosed oligodendrogliomas ranges from 0.10 in the Republic of Korea {[[ 20856664 ]](https://www.ncbi.nlm.nih.gov/pubmed/20856664)} to 0.50 in France {[[ 27853959 ]](https://www.ncbi.nlm.nih.gov/pubmed/27853959)}; in the USA, the incidence rate is 0.23 {[[ 31675094 ]](https://www.ncbi.nlm.nih.gov/pubmed/31675094)}. For histologically diagnosed CNS WHO grade 3 oligodendrogliomas, the incidence rate is 0.06 in the Republic of Korea {[[ 20856664 ]](https://www.ncbi.nlm.nih.gov/pubmed/20856664)}, 0.11 in the USA {[[ 31675094 ]](https://www.ncbi.nlm.nih.gov/pubmed/31675094)}, and 0.39 in France {[[ 27853959 ]](https://www.ncbi.nlm.nih.gov/pubmed/27853959)}. Thus, 0.9% of all brain tumours in the USA are CNS WHO grade 2 oligodendrogliomas and 0.4% are CNS WHO grade 3 oligodendrogliomas {[[ 31675094 ]](https://www.ncbi.nlm.nih.gov/pubmed/31675094)}. Approximately one third of all oligodendroglial tumours correspond to CNS WHO grade 3 {[[ 31675094 ]](https://www.ncbi.nlm.nih.gov/pubmed/31675094)}. A decrease in the incidence of oligodendrogliomas from 2000 to 2013 has been reported, a finding probably related to changes in diagnostic criteria over time {[[ 28397028 ]](https://www.ncbi.nlm.nih.gov/pubmed/28397028)}. Age and sex distribution Oligodendrogliomas manifest preferentially in adults, with a median age at diagnosis of 43 years reported in the population-based CBTRUS dataset for patients with histologically defined CNS WHO grade 2 oligodendroglioma and 50 years for those with CNS WHO grade 3 oligodendroglioma {[[ 31675094 ]](https://www.ncbi.nlm.nih.gov/pubmed/31675094)}. The median ages were comparable for patients with IDH-mutant and 1p/19q-codeleted oligodendrogliomas: 41 years for patients with CNS WHO grade 2 tumours and 47 years for patients with CNS WHO grade 3 tumours {[[ 19554337 ]](https://www.ncbi.nlm.nih.gov/pubmed/19554337)}. Overall, histologically defined CNS WHO grade 3 oligodendroglioma shows a slight male predominance, with an M:F ratio of 1.2:1 reported among 5476 patients {[[ 31675094 ]](https://www.ncbi.nlm.nih.gov/pubmed/31675094)}. CNS WHO grade 3 oligodendroglioma is more common in White populations than in Black populations, with an incidence ratio of 2.3:1 {[[ 31675094 ]](https://www.ncbi.nlm.nih.gov/pubmed/31675094)}. Oligodendrogliomas are rare in children, and few data are available on IDH-mutant and 1p/19q-codeleted oligodendrogliomas in this population. In one study, 3 (14%) of 22 tumours with the typical morphological characteristics of oligodendroglioma demonstrated *IDH1* p.R132H mutation and 1p/19q codeletion {[[ 24805856 ]](https://www.ncbi.nlm.nih.gov/pubmed/24805856)}. These 3 patients were aged 16--19 years, indicating that IDH-mutant and 1p/19q-codeleted oligodendrogliomas are rare in children. **Etiology  ** Genetic susceptibility The etiology of IDH-mutant and 1p/19q-codeleted oligodendroglioma is unclear. Most tumours develop sporadically, in the absence of documented familial clustering or a hereditary cancer predisposition syndrome. However, both familial and sporadic gliomas frequently display shared genomic landscapes, and common core pathways might be targeted by both germline and somatic alterations {[[ 30165405 ]](https://www.ncbi.nlm.nih.gov/pubmed/30165405)}. Earlier studies identified SNPs in the *BICRA* (*GLTSCR1*) and *ERCC2* genes as well as the *GSTT1* null genotype with increased risk of oligodendroglioma {[[ 15834925 ]](https://www.ncbi.nlm.nih.gov/pubmed/15834925); [[9429231 ]](https://www.ncbi.nlm.nih.gov/pubmed/9429231)}. Germline mutations of *POT1*, a shelterin complex gene, have been associated with familial oligodendroglioma {[[ 25482530 ]](https://www.ncbi.nlm.nih.gov/pubmed/25482530)}. Cases of familial oligodendroglioma with 1p/19q codeletion have been reported {[[ 18568735 ]](https://www.ncbi.nlm.nih.gov/pubmed/18568735); [[25208478 ]](https://www.ncbi.nlm.nih.gov/pubmed/25208478)}. Given that pathological production of 2-hydroxyglutarate, resulting from somatic mutations in *IDH1* or *IDH2*, is found in all oligodendrogliomas and IDH-mutant astrocytomas, it is of interest that variants (particularly rs5839764) in or near the *D2HGDH* gene, which codes for D-2-hydroxyglutarate dehydrogenase, showed genome-wide association with IDH-mutant gliomas {[[ 32386320 ]](https://www.ncbi.nlm.nih.gov/pubmed/32386320)}. The same study identified rs111976262, located near the *FAM20C* gene, as showing genome-wide association with IDH-mutant, *TERT* promoter--mutant, and 1p/19q-codeleted oligodendrogliomas. Gliomas have been reported in specific hereditary cancer syndromes including germline *BRCA1* mutations, constitutional mismatch repair deficiency syndrome, Lynch syndrome (also known as hereditary non-polyposis colorectal cancer), and hereditary retinoblastoma, yet oligodendrogliomas are uncommon {[[ 8644702 ]](https://www.ncbi.nlm.nih.gov/pubmed/8644702); [[10223463 ]](https://www.ncbi.nlm.nih.gov/pubmed/10223463); [[15340263 ]](https://www.ncbi.nlm.nih.gov/pubmed/15340263); [[23255519 ]](https://www.ncbi.nlm.nih.gov/pubmed/23255519); [[15196536 ]](https://www.ncbi.nlm.nih.gov/pubmed/15196536)}. Patients with the enchondromatosis syndromes Ollier disease and Maffucci syndrome, which are associated with somatic (or postzygotic) IDH mosaicism, present with multiple benign cartilaginous tumours {[[ 22057236 ]](https://www.ncbi.nlm.nih.gov/pubmed/22057236)}. A retrospective cohort study showed that those patients may develop gliomas with an anatomical presentation and a grading distribution similar to those of gliomas in non-syndromic patients, but they are typically younger and more often have multicentric lesions {[[ 27036230 ]](https://www.ncbi.nlm.nih.gov/pubmed/27036230)}. However, none of the gliomas in this enchondromatosis cohort harboured 1p/19q codeletion. Other etiological factors The potential role of viral infections in the etiology of IDH-mutant and 1p/19q-codeleted oligodendroglioma has been debated. Several studies have reported the detection of CMV in gliomas including oligodendrogliomas {[[ 25041908 ]](https://www.ncbi.nlm.nih.gov/pubmed/25041908); [[18351367 ]](https://www.ncbi.nlm.nih.gov/pubmed/18351367)}. However, other studies have concluded that CMV is not present in gliomas {[[ 25155358 ]](https://www.ncbi.nlm.nih.gov/pubmed/25155358)}. Similarly, there have been contradictory findings reported for members of the polyomavirus family (BK virus, JC virus, SV40) {[[ 12429619 ]](https://www.ncbi.nlm.nih.gov/pubmed/12429619); [[8692997 ]](https://www.ncbi.nlm.nih.gov/pubmed/8692997); [[15499616 ]](https://www.ncbi.nlm.nih.gov/pubmed/15499616)}. Whole-genome and RNA sequencing, which provided increased sensitivity and specificity for detecting viral genomes and transcripts, revealed only a low-percentage association between HPV and/or HBV and low-grade gliomas including oligodendrogliomas {[[ 27402152 ]](https://www.ncbi.nlm.nih.gov/pubmed/27402152)}. It was also determined that previous findings of CMV in gliomas were probably a result of laboratory contamination. Dysregulation of the immune system, including immunodeficiency due to HIV infection, posttransplant immunosuppression therapy, or demyelinating disease, has been associated with rare cases of oligodendroglioma {[[ 15361970 ]](https://www.ncbi.nlm.nih.gov/pubmed/15361970); [[12536370 ]](https://www.ncbi.nlm.nih.gov/pubmed/12536370); [[11673595 ]](https://www.ncbi.nlm.nih.gov/pubmed/11673595)}. However, epidemiological data do not indicate an increased incidence of gliomas in patients with autoimmune disease {[[ 23757294 ]](https://www.ncbi.nlm.nih.gov/pubmed/23757294)}. Rat models have shown that nitrosoureas (e.g. ethylnitrosourea and methylnitrosourea) are chemical carcinogens that may induce CNS tumours, including gliomas with an oligodendroglial phenotype {[[ 2696875 ]](https://www.ncbi.nlm.nih.gov/pubmed/2696875)}. However, cancer studies in humans are not available for these compounds. **Pathogenesis  ** Cell of origin The cell (or cells) of origin of IDH-mutant and 1p/19q-codeleted oligodendroglioma remains unknown. Morphology and single-cell RNA-sequencing analysis of human tumours supports the notion that oligodendrogliomas are composed of a mixture of malignant cell types that recapitulate oligodendroglial and astrocytic lineages, as well as neural precursor--like cells {[[ 27806376 ]](https://www.ncbi.nlm.nih.gov/pubmed/27806376)}. Experimental transformation of immortalized human glial cells with *IDH1* p.R132H reprogrammes their cellular lineage and favours the emergence of a neural precursor state {[[ 29180699 ]](https://www.ncbi.nlm.nih.gov/pubmed/29180699)}. Experiments in transgenic mice indicate that gliomas with oligodendroglial histology may originate from different cell types in the CNS, including neural precursor cells, astrocytes, and oligodendroglial precursor cells {[[ 25635044 ]](https://www.ncbi.nlm.nih.gov/pubmed/25635044)}. An oligodendroglioma-like phenotype is commonly found in transgenic brain tumours, despite such tumours showing a variety of targeted cell types and oncogenic events {[[ 12615729 ]](https://www.ncbi.nlm.nih.gov/pubmed/12615729); [[12670909 ]](https://www.ncbi.nlm.nih.gov/pubmed/12670909)}. Studies have suggested that oligodendrogliomas probably originate from oligodendroglial precursor cells {[[ 21156288 ]](https://www.ncbi.nlm.nih.gov/pubmed/21156288); [[21907924 ]](https://www.ncbi.nlm.nih.gov/pubmed/21907924)}. Oligodendroglial precursor cells have also been suggested as the cell of origin in other classes of gliomas and may give rise to either oligodendroglial or astrocytic phenotypes in gliomas, depending on the genes driving transformation {[[ 21737130 ]](https://www.ncbi.nlm.nih.gov/pubmed/21737130); [[25355217 ]](https://www.ncbi.nlm.nih.gov/pubmed/25355217)}. Thus, the interplay between oncogenic events and the cell(s) of origin plays a critical role in determining the resulting glioma phenotype. Genetic profile The entity-defining alterations in oligodendrogliomas are missense mutations affecting *IDH1* codon 132 or *IDH2* codon 172 combined with whole-arm deletions of 1p and 19q. More than 90% of IDH mutations in oligodendrogliomas correspond to the canonical *IDH1* p.R132H mutation; the remaining tumours carry non-canonical mutations, with a higher proportion of *IDH2* mutations in oligodendrogliomas than in astrocytomas (see also [section ]*Astrocytoma, IDH-mutant*) {[[ 19554337 ]](https://www.ncbi.nlm.nih.gov/pubmed/19554337); [[26061751 ]](https://www.ncbi.nlm.nih.gov/pubmed/26061751); [[26061753 ]](https://www.ncbi.nlm.nih.gov/pubmed/26061753); [[29522183 ]](https://www.ncbi.nlm.nih.gov/pubmed/29522183)}. The 1p/19q codeletion has been cytogenetically linked to an unbalanced translocation between chromosomes 1 and 19 that results in loss of the der(1;19)(p10;q10) chromosome, causing whole-arm deletions of 1p and 19q, and retention of the der\[t(1;19)(q10;p10)\] chromosome {[[ 17021403 ]](https://www.ncbi.nlm.nih.gov/pubmed/17021403); [[17047046 ]](https://www.ncbi.nlm.nih.gov/pubmed/17047046)}. Incomplete/partial deletions on either chromosome arm are not compatible with the diagnosis of IDH-mutant and 1p/19q-codeleted oligodendroglioma, but they have been detected in a proportion of IDH-wildtype glioblastomas {[[ 20164239 ]](https://www.ncbi.nlm.nih.gov/pubmed/20164239)}. The vast majority of IDH-mutant and 1p/19q-codeleted oligodendrogliomas carry *TERT* promoter hotspot mutations {[[ 23764841 ]](https://www.ncbi.nlm.nih.gov/pubmed/23764841); [[23530248 ]](https://www.ncbi.nlm.nih.gov/pubmed/23530248); [[24154961 ]](https://www.ncbi.nlm.nih.gov/pubmed/24154961)}. However, IDH-mutant and 1p/19q-codeleted oligodendrogliomas arising in teenagers often lack *TERT* promoter mutation {[[ 30231927 ]](https://www.ncbi.nlm.nih.gov/pubmed/30231927)}. When present, *TERT* promoter mutation is assumed to be an early (i.e. clonal) event in oligodendroglioma development {[[ 25848751 ]](https://www.ncbi.nlm.nih.gov/pubmed/25848751); [[31217899 ]](https://www.ncbi.nlm.nih.gov/pubmed/31217899)}, which remains stable during tumour progression and at recurrence {[[ 28270234 ]](https://www.ncbi.nlm.nih.gov/pubmed/28270234)}. Mechanistically, the *TERT* promoter mutations generate de novo ETS transcription factor binding sites {[[ 23348503 ]](https://www.ncbi.nlm.nih.gov/pubmed/23348503)}, which results in transcriptional upregulation of TERT expression, thereby driving telomere stabilization, cellular immortalization, and proliferation {[[ 32204305 ]](https://www.ncbi.nlm.nih.gov/pubmed/32204305)}. Mutations of *CIC* (the human orthologue of the *Drosophila melanogaster* capicua gene), located in chromosome band 19q13.2, are also frequent in IDH-mutant and 1p/19q-codeleted oligodendrogliomas {[[ 21817013 ]](https://www.ncbi.nlm.nih.gov/pubmed/21817013); [[22072542 ]](https://www.ncbi.nlm.nih.gov/pubmed/22072542)}, with large-scale sequencing studies reporting *CIC* mutations in as many as 70% of oligodendrogliomas {[[ 26061751 ]](https://www.ncbi.nlm.nih.gov/pubmed/26061751); [[26061753 ]](https://www.ncbi.nlm.nih.gov/pubmed/26061753)}. CIC is a constitutive transcriptional repressor of genes essential in development, cellular growth, and metabolism that is relieved by receptor tyrosine kinase signalling {[[ 17255944 ]](https://www.ncbi.nlm.nih.gov/pubmed/17255944); [[32073140 ]](https://www.ncbi.nlm.nih.gov/pubmed/32073140); [[31043608 ]](https://www.ncbi.nlm.nih.gov/pubmed/31043608)}, and it has been associated with various features of neoplastic behaviour {[[ 28827401 ]](https://www.ncbi.nlm.nih.gov/pubmed/28827401); [[27869830 ]](https://www.ncbi.nlm.nih.gov/pubmed/27869830)}. *CIC* mutations in oligodendrogliomas are hemizygous and include almost equal proportions of nonsense or truncating mutations and recurrent missense mutations. The latter are preferentially found in the HMG-box DNA-binding domain in exon 5 and the C1 motif in exon 20. They appear to be unique to oligodendroglioma and not present in other *CIC*-mutant tumour types {[[ 28295365 ]](https://www.ncbi.nlm.nih.gov/pubmed/28295365); [[27869830 ]](https://www.ncbi.nlm.nih.gov/pubmed/27869830); [[16959974 ]](https://www.ncbi.nlm.nih.gov/pubmed/16959974)}. This suggests phenotypic uniqueness of these missense *CIC* mutations in oligodendrogliomas, and that these mutations act cooperatively with IDH mutations to contribute to the pathological upregulation of 2-hydroxyglutarate production {[[ 25277207 ]](https://www.ncbi.nlm.nih.gov/pubmed/25277207)} and activation of the MAPK signalling pathway {[[ 28295365 ]](https://www.ncbi.nlm.nih.gov/pubmed/28295365); [[28278156 ]](https://www.ncbi.nlm.nih.gov/pubmed/28278156)}. Spatial and temporal profiling of oligodendrogliomas, which have a low mutation burden, has also confirmed the presence of clones bearing unique *CIC* mutations, suggesting the presence of selective pressures to escape normal CIC regulatory control {[[ 25848751 ]](https://www.ncbi.nlm.nih.gov/pubmed/25848751); [[27806376 ]](https://www.ncbi.nlm.nih.gov/pubmed/27806376); [[31748746 ]](https://www.ncbi.nlm.nih.gov/pubmed/31748746)}. *CIC* truncating mutations most likely disrupt protein--protein interaction with binding partners including ATXN1L, which appears to result in reciprocal phenotypic alterations {[[ 28178529 ]](https://www.ncbi.nlm.nih.gov/pubmed/28178529); [[30093628 ]](https://www.ncbi.nlm.nih.gov/pubmed/30093628); [[32073140 ]](https://www.ncbi.nlm.nih.gov/pubmed/32073140)}. Approximately 20--30% of IDH-mutant and 1p/19q-codeleted oligodendrogliomas harbour somatic mutations of *FUBP1*, located at chromosome 1p31.1, a region with consistent loss of heterozygosity in these tumours {[[ 21817013 ]](https://www.ncbi.nlm.nih.gov/pubmed/21817013); [[22588899 ]](https://www.ncbi.nlm.nih.gov/pubmed/22588899)}. FUBP1 is a transcriptional regulator essential for normal stem cell self-renewal {[[ 26095368 ]](https://www.ncbi.nlm.nih.gov/pubmed/26095368); [[29606613 ]](https://www.ncbi.nlm.nih.gov/pubmed/29606613)}. It has recently been identified as a pleiotropic regulator of alternative splicing of tumour suppressor genes and oncogenes {[[ 31553912 ]](https://www.ncbi.nlm.nih.gov/pubmed/31553912)}. The combined loss of CIC and FUBP1 protein expression, as a surrogate marker of *CIC* and *FUBP1* nonsense or truncating mutations, has been associated with a shorter time to recurrence in patients with 1p/19q-codeleted oligodendroglioma {[[ 24030748 ]](https://www.ncbi.nlm.nih.gov/pubmed/24030748)}. Approximately 15% of oligodendrogliomas carry mutations in *NOTCH1*, and less commonly in other NOTCH pathway genes {[[ 26061751 ]](https://www.ncbi.nlm.nih.gov/pubmed/26061751); [[25848751 ]](https://www.ncbi.nlm.nih.gov/pubmed/25848751)}. *NOTCH1* mutation was linked to shorter survival in one study {[[ 29016839 ]](https://www.ncbi.nlm.nih.gov/pubmed/29016839)}. Other less commonly mutated genes include epigenetic regulator genes such as *SETD2* (and other histone methyltransferase genes), *PIK3CA*, and genes encoding components of the SWI/SNF chromatin remodelling complex {[[ 26061751 ]](https://www.ncbi.nlm.nih.gov/pubmed/26061751); [[25848751 ]](https://www.ncbi.nlm.nih.gov/pubmed/25848751)}. Genetic alterations associated with tumour progression The number of broad copy-number aberrations increases from CNS WHO grade 2 to CNS WHO grade 3 oligodendrogliomas {[[ 29016839 ]](https://www.ncbi.nlm.nih.gov/pubmed/29016839)}. Deletions on 9p involving the *CDKN2A* and/or *CDKN2B* locus have been associated with CNS WHO grade 3 {[[ 7977648 ]](https://www.ncbi.nlm.nih.gov/pubmed/7977648); [[28030632 ]](https://www.ncbi.nlm.nih.gov/pubmed/28030632)}, contrast enhancement on MRI {[[ 24353325 ]](https://www.ncbi.nlm.nih.gov/pubmed/24353325); [[26385879 ]](https://www.ncbi.nlm.nih.gov/pubmed/26385879)}, and shorter survival {[[ 15099021 ]](https://www.ncbi.nlm.nih.gov/pubmed/15099021); [[26385879 ]](https://www.ncbi.nlm.nih.gov/pubmed/26385879)}. In line with these findings, homozygous *CDKN2A* deletion was indicative of short survival in a prospective cohort study of patients with CNS WHO grade 3 IDH-mutant and 1p/19-codeleted oligodendroglioma {[[ 31832685 ]](https://www.ncbi.nlm.nih.gov/pubmed/31832685)}. Other alterations associated with tumour progression and/or shorter survival include *PIK3CA* mutation {[[ 30975663 ]](https://www.ncbi.nlm.nih.gov/pubmed/30975663); [[15289301 ]](https://www.ncbi.nlm.nih.gov/pubmed/15289301)}, *TCF12* mutation {[[ 26068201 ]](https://www.ncbi.nlm.nih.gov/pubmed/26068201)}, and genetic aberrations causing increased MYC signalling {[[ 27090007 ]](https://www.ncbi.nlm.nih.gov/pubmed/27090007)}. Whereas IDH mutation, 1p/19q codeletion, and *TERT* promoter mutation are clonal alterations in oligodendrogliomas, mutations in *CIC*, *FUBP1*, *TCF12*, and other genes may be subclonal and thus associated with tumour progression {[[ 25848751 ]](https://www.ncbi.nlm.nih.gov/pubmed/25848751); [[31217899 ]](https://www.ncbi.nlm.nih.gov/pubmed/31217899)} Epigenetic changes IDH-mutant and 1p/19q-codeleted oligodendrogliomas show concurrent hypermethylation of multiple CpG islands, corresponding to the glioma CpG island methylator phenotype (G-CIMP){[ 20399149 ]}. This phenomenon has been closely linked to IDH mutation causing increased levels of 2-hydroxyglutarate, which functions as a competitive inhibitor of α-ketoglutarate--dependent dioxygenases, including histone demethylases and the TET family of 5-methylcytosine hydroxylases {[[ 22343901 ]](https://www.ncbi.nlm.nih.gov/pubmed/22343901); [[21251613 ]](https://www.ncbi.nlm.nih.gov/pubmed/21251613)}. This in turn leads to increased histone methylation and G-CIMP {[[ 20399149 ]](https://www.ncbi.nlm.nih.gov/pubmed/20399149); [[22343889 ]](https://www.ncbi.nlm.nih.gov/pubmed/22343889)}. DNA methylation profiles of IDH-mutant and 1p/19q-codeleted oligodendrogliomas differ from those of IDH-mutant but 1p/19q-intact astrocytomas, and they can be used for diagnostic purposes {[[ 29539639 ]](https://www.ncbi.nlm.nih.gov/pubmed/29539639)}. G-CIMP may correlate with epigenetic silencing of multiple genes in oligodendrogliomas, including genes on 1p and 19q, as well as genes on other chromosomes, such as the tumour suppressors *CDKN2A*, *CDKN2B*, and *RB1* {[[ 19333441 ]](https://www.ncbi.nlm.nih.gov/pubmed/19333441)}. *MGMT* promoter methylation is detectable in the majority of oligodendrogliomas {[[ 15455350 ]](https://www.ncbi.nlm.nih.gov/pubmed/15455350)}. At the mRNA level, IDH-mutant and 1p/19q-codeleted oligodendrogliomas typically show a proneural glioblastoma--like gene-expression signature {[[ 18492260 ]](https://www.ncbi.nlm.nih.gov/pubmed/18492260); [[25783747 ]](https://www.ncbi.nlm.nih.gov/pubmed/25783747)}. **Macroscopic appearance  ** Oligodendroglioma typically appears macroscopically as a relatively well-defined, soft, greyish-pink mass located in the cortex and white matter, with blurring of the grey matter--white matter boundary. Local invasion into the overlying leptomeninges may be seen. Calcification is frequent and may impart a gritty texture. Occasionally, densely calcified areas may occur as intratumoural stones. Zones of cystic degeneration, as well as intratumoural haemorrhages, are common. Rare cases with extensive mucoid degeneration look gelatinous. Areas of necrosis may be discernible in CNS WHO grade 3 tumours. **Histopathology  ** Cellular composition Classic oligodendroglioma cells have uniformly round nuclei that are slightly larger than those of normal oligodendrocytes and show an increase in chromatin density or a delicate salt-and-pepper pattern. A distinct nuclear membrane is often apparent. In formalin-fixed, paraffin-embedded tissue, tumour cells often appear as rounded cells with well-defined cell membranes and clear cytoplasm around the central spherical nucleus. This creates the typical honeycomb or fried-egg appearance, which, although artefactual, is a helpful diagnostic feature. This artefact is not seen in smear preparations or frozen sections, and it may also be absent in rapidly fixed tissue and in formalin-fixed, paraffin-embedded sections made from frozen material. Reactive astrocytes are scattered throughout oligodendrogliomas and are particularly prominent at the tumour borders. Oligodendrogliomas may contain tumour cells that look like small gemistocytes with a rounded belly of eccentric cytoplasm that is positive for GFAP, which are termed "minigemistocytes" or "microgemistocytes". Gliofibrillary oligodendrocytes are typical-looking oligodendroglioma cells with a thin perinuclear rim of positivity for GFAP {[[ 6391068 ]](https://www.ncbi.nlm.nih.gov/pubmed/6391068)}. Gliofibrillary oligodendrocytes and minigemistocytes are more commonly seen in CNS WHO grade 3 tumours. GFAP-negative mucocytes or even signet-ring cells are occasionally present, with individual cases reported to consist largely of signet-ring cells {[[ 9194905 ]](https://www.ncbi.nlm.nih.gov/pubmed/9194905)}. Eosinophilic granular cells occur in some oligodendrogliomas {[[ 991110 ]](https://www.ncbi.nlm.nih.gov/pubmed/991110)}. Rare cases with neurocytic or ganglioglioma-like differentiation have also been reported {[[ 20464403 ]](https://www.ncbi.nlm.nih.gov/pubmed/20464403); [[12430711 ]](https://www.ncbi.nlm.nih.gov/pubmed/12430711)}. Occasional CNS WHO grade 3 oligodendrogliomas feature multinucleated giant cells {[[ 24444336 ]](https://www.ncbi.nlm.nih.gov/pubmed/24444336)}, and rare cases contain sarcomatous areas {[[ 23254140 ]](https://www.ncbi.nlm.nih.gov/pubmed/23254140); [[17325476 ]](https://www.ncbi.nlm.nih.gov/pubmed/17325476)}. The presence of these various cellular phenotypes does not preclude an oligodendroglioma diagnosis if the tumour is IDH-mutant and 1p/19q-codeleted. Tumour cells with fibrillary or gemistocytic astrocytic morphology are also compatible with this diagnosis when IDH mutation and 1p/19q codeletion are present. Thus, irrespective of oligodendroglial, oligoastrocytic, astrocytic, or ambiguous features on histology, detection of combined IDH mutation and 1p/19q codeletion indicates an IDH-mutant and 1p/19q-codeleted oligodendroglioma {[[ 26061751 ]](https://www.ncbi.nlm.nih.gov/pubmed/26061751); [[25848751 ]](https://www.ncbi.nlm.nih.gov/pubmed/25848751); [[25783747 ]](https://www.ncbi.nlm.nih.gov/pubmed/25783747)}. Mineralization and other degenerative features Microcalcifications are frequent, found within the tumour itself or in the invaded brain. Calcifications were recorded in 71 (45%) of 157 CNS WHO grade 3 IDH-mutant and 1p/19q-codeleted oligodendrogliomas, {[[ 24723566 ]](https://www.ncbi.nlm.nih.gov/pubmed/24723566)}. Mineralization along blood vessels typically takes the form of small, punctate calcifications, whereas microcalcifications in the brain (called calcospherites) tend to be larger, with an irregular and sometimes laminated appearance. However, this feature is not specific for oligodendroglioma, and because of incomplete tumour sampling, it is sometimes not found histologically even when clearly demonstrated on CT. Areas characterized by extracellular mucin deposition and/or microcyst formation are frequent. Rare tumours are characterized by marked desmoplasia {[[ 21552114 ]](https://www.ncbi.nlm.nih.gov/pubmed/21552114)}. Vasculature Oligodendrogliomas typically show a dense network of branching capillaries resembling chicken wire. In some cases, the capillary stroma tends to subdivide the tumour into lobules. In CNS WHO grade 3 tumours, focal or dispersed pathological microvascular proliferation is frequent. Oligodendrogliomas have a tendency to develop intratumoural haemorrhages. Growth pattern Oligodendrogliomas grow diffusely in the cortex and white matter; however, some tumours feature distinct nodules of higher cellularity against a background of diffuse infiltration. Occasional tumours show a gliomatosis cerebri--like pattern involving more than two cerebral lobes {[[ 26493382 ]](https://www.ncbi.nlm.nih.gov/pubmed/26493382)}. Within the cortex, tumour cells often form secondary structures such as perineuronal satellitosis, perivascular aggregates, and subpial accumulations. Circumscribed leptomeningeal infiltration may induce a desmoplastic reaction. Oligodendrogliomas can have a rare spongioblastic growth pattern consisting of parallel rows of tumour cells with somewhat elongated nuclei forming rhythmic palisades. Occasionally, perivascular pseudorosettes are seen, although some of these are a result of perivascular neuropil formation within foci of neurocytic differentiation {[[ 12430711 ]](https://www.ncbi.nlm.nih.gov/pubmed/12430711)}. These patterns are generally present only focally. Proliferation Mitotic activity is low or absent in CNS WHO grade 2 oligodendrogliomas, but it is usually prominent in CNS WHO grade 3 tumours. Accordingly, the Ki-67 (MIB1) proliferation index is usually low (\ 10% in the large French national POLA cohort of CNS WHO grade 3 tumours {[[ 24723566 ]](https://www.ncbi.nlm.nih.gov/pubmed/24723566); [[27175000 ]](https://www.ncbi.nlm.nih.gov/pubmed/27175000); [[31561286 ]](https://www.ncbi.nlm.nih.gov/pubmed/31561286)}. However, a definitive Ki-67 (MIB1) cut-off value has not been established due to marked variability in staining results between institutions and non-uniform counting approaches. One study reported a Ki-67 index of ≥ 15% as an independent marker of shorter survival in patients with IDH-mutant and 1p/19q-codeleted CNS WHO grade 3 oligodendrogliomas {[[ 31561286 ]](https://www.ncbi.nlm.nih.gov/pubmed/31561286)}. A mitotic count of ≥ 5 mitoses/mm^2^ was also associated with shorter survival but only on univariate, not multivariate, analysis {[[ 31561286 ]](https://www.ncbi.nlm.nih.gov/pubmed/31561286)}. Another study showed that mitotic count was not associated with outcome in patients with IDH-mutant and 1p/19q-codeleted oligodendrogliomas {[[ 25701198 ]](https://www.ncbi.nlm.nih.gov/pubmed/25701198)}. Other proliferation markers, such as PCNA {[[ 10679656 ]](https://www.ncbi.nlm.nih.gov/pubmed/10679656)}, TOP2A {[[ 11419973 ]](https://www.ncbi.nlm.nih.gov/pubmed/11419973)}, MCM2 {[[ 11532161 ]](https://www.ncbi.nlm.nih.gov/pubmed/11532161)}, and MCM6 {[[ 31561286 ]](https://www.ncbi.nlm.nih.gov/pubmed/31561286)}, also correlate with CNS WHO grade and/or survival but do not provide clear advantages over Ki-67 (MIB1). Grading Oligodendrogliomas comprise a continuous spectrum of tumours ranging from well-differentiated, slow-growing neoplasms to frankly malignant tumours with rapid growth. In prior editions of the WHO classification of CNS tumours, two grades were distinguished: oligodendroglioma, CNS WHO grade 2, and oligodendroglioma, CNS WHO grade 3. CNS WHO grade retained prognostic significance in patients with IDH-mutant and 1p/19q-codeleted oligodendrogliomas {[[ 28532485 ]](https://www.ncbi.nlm.nih.gov/pubmed/28532485)}, but the criteria for distinction between grades were not well defined. Histological features that have been linked to higher grade are high cellularity, marked cytological atypia, brisk mitotic activity, pathological microvascular proliferation, and necrosis with or without palisading. CNS WHO grade 3 oligodendrogliomas usually show several of these features. However, the individual impact of each feature is unclear, in particular because most prognostic studies have not previously been confined to IDH-mutant and 1p/19q-codeleted tumours. Microvascular proliferation and brisk mitotic activity, defined as ≥ 2.5 mitoses/mm^2 ^(equating to ≥ 6 mitoses/10 HPF of 0.55 mm in diameter and 0.24 mm^2^ in area) have been reported as indicators of short survival in a study of histologically defined oligodendrogliomas {[[ 11245209 ]](https://www.ncbi.nlm.nih.gov/pubmed/11245209)}. Other studies of 1p/19q-codeleted CNS WHO grade 3 oligodendrogliomas suggested that microvascular proliferation and microvascular proliferation with necrosis are linked to shorter survival than is elevated mitotic activity of ≥ 2.5 mitoses/mm^2^ (equating to ≥ 6 mitoses/10 HPF of 0.55 mm in diameter and 0.24 mm^2^ in area) without microvascular proliferation and necrosis {[[ 24723566 ]](https://www.ncbi.nlm.nih.gov/pubmed/24723566); [[27175000 ]](https://www.ncbi.nlm.nih.gov/pubmed/27175000)}. However, data defining a clear cut-off point for a mitotic count that distinguishes CNS WHO grade 2 from CNS WHO grade 3 of IDH-mutant and 1p/19q-codeleted oligodendrogliomas are not available. Nevertheless, detection of rare mitoses in a resection specimen is not sufficient for diagnosing CNS WHO grade 3 IDH-mutant and 1p/19q-codeleted oligodendroglioma. In borderline cases, proliferation markers like Ki-67 (MIB1) and attention to clinical and neuroradiological features (e.g. rapid symptomatic growth and contrast enhancement) may provide helpful additional information. Homozygous deletion involving the *CDKN2A* and/or *CDKN2B* locus is found in a small subset (\ 30%, to avoid false negative results when assessing 1p/19q codeletion. Immunohistochemical detection of IDH1 p.R132H expression and preserved nuclear ATRX expression, without demonstration of 1p/19q codeletion, is not sufficient to diagnose an IDH-mutant and 1p/19q-codeleted oligodendroglioma, even with classic histology. In IDH-mutant gliomas with preserved nuclear ATRX expression by immunohistochemistry, 1p/19q analysis remains critical for accurate molecular diagnosis. Most IDH-mutant and 1p/19q-codeleted oligodendrogliomas carry *TERT* promoter mutations {[[ 23764841 ]](https://www.ncbi.nlm.nih.gov/pubmed/23764841)}; however, detection of a *TERT* promoter mutation in an IDH-mutant glioma is not sufficient for an oligodendroglioma diagnosis, because rare cases are *TERT*-wildtype, including tumours in teenage patients {[[ 30231927 ]](https://www.ncbi.nlm.nih.gov/pubmed/30231927)}. *TERT* promoter mutations are also observed in a subset of 1p/19q-intact IDH-mutant astrocytomas {[[ 28255664 ]](https://www.ncbi.nlm.nih.gov/pubmed/28255664); [[23955565 ]](https://www.ncbi.nlm.nih.gov/pubmed/23955565)}. DNA methylation array analysis reveals a diagnostic molecular profile by combining the detection of an oligodendroglioma-associated methylation signature and 1p/19q codeletion {[[ 29539639 ]](https://www.ncbi.nlm.nih.gov/pubmed/29539639); [[29967940 ]](https://www.ncbi.nlm.nih.gov/pubmed/29967940)}. Copy-number analysis by FISH also provides information on polysomy of 1q and 19p, which has been detected in subsets of 1p/19q-codeleted oligodendrogliomas of CNS WHO grades 2 and 3 and is associated with shorter survival {[[ 31140557 ]](https://www.ncbi.nlm.nih.gov/pubmed/31140557); [[19808867 ]](https://www.ncbi.nlm.nih.gov/pubmed/19808867); [[22710961 ]](https://www.ncbi.nlm.nih.gov/pubmed/22710961)}. Homozygous deletion of *CDKN2A* has been detected in a small proportion of CNS WHO grade 3 IDH-mutant and 1p/19q-codeleted oligodendrogliomas, but not in those of CNS WHO grade 2, and it was reported to be an independent marker of shorter survival {[[ 31832685 ]](https://www.ncbi.nlm.nih.gov/pubmed/31832685)}. Tumours that cannot be fully analysed for IDH mutation and 1p/19q codeletion but demonstrate classic histological features of oligodendroglioma are classified as oligodendroglioma NOS {[[ 29372318 ]](https://www.ncbi.nlm.nih.gov/pubmed/29372318)}. This indicates that the tumour is a histologically classic oligodendroglioma that will probably exhibit clinical behaviour similar to that of an IDH-mutant and 1p/19q-codeleted oligodendroglioma, but that it could not be molecularly analysed or that its test results were inconclusive or uninformative {[[ 29372318 ]](https://www.ncbi.nlm.nih.gov/pubmed/29372318)}. Tumours that demonstrate oligodendroglial histology but lack IDH mutation and 1p/19q codeletion should not be classified as oligodendroglioma NOS but must be further evaluated to exclude histological mimics, such as dysembryoplastic neuroepithelial tumour, clear cell ependymoma, neurocytoma, polymorphous low-grade neuroepithelial tumour of the young, and pilocytic astrocytoma, as well as molecularly distinct diffuse gliomas that are characterized by *BRAF*, *FGFR1*, *MYB*, or *MYBL1* alterations {[[ 30848347 ]](https://www.ncbi.nlm.nih.gov/pubmed/30848347)}. **Essential and desirable diagnostic criteria  ** See [[\#21469]](https://tumourclassification.iarc.who.int/attachment/45/6/21469)Box 2.02. **Staging  ** Not clinically relevant **Prognosis and prediction  ** Survival data for histologically diagnosed tumours in older studies and population-based registries are confounded by the inclusion of gliomas without IDH mutation and 1p/19q codeletion. Retrospective molecular stratification of older series confirmed that only subsets (30--80%) of tumours corresponded to IDH-mutant and 1p/19q-codeleted oligodendrogliomas {[[ 24723566 ]](https://www.ncbi.nlm.nih.gov/pubmed/24723566); [[27573687 ]](https://www.ncbi.nlm.nih.gov/pubmed/27573687); [[26354927 ]](https://www.ncbi.nlm.nih.gov/pubmed/26354927)}. Overall, IDH-mutant and 1p/19q-codeleted oligodendrogliomas are associated with favourable response to therapy and median survival times of \> 10 years. For example, patients with CNS WHO grade 3 IDH-mutant and 1p/19q-codeleted oligodendroglioma who participated in prospective clinical trials and were treated with a combination of radiotherapy and procarbazine, lomustine, and vincristine (PCV) chemotherapy showed a median survival of ≥ 14 years {[[ 28640702 ]](https://www.ncbi.nlm.nih.gov/pubmed/28640702)}. Oligodendrogliomas generally recur locally but may show leptomeningeal spread. Malignant progression at recurrence is common, although it usually takes longer in oligodendroglioma than in IDH-mutant astrocytoma {[[ 21153680 ]](https://www.ncbi.nlm.nih.gov/pubmed/21153680)}. Clinical factors Clinical factors associated with more favourable outcome include younger patient age at diagnosis, frontal lobe location, presentation with seizures, high postoperative Karnofsky score, and macroscopically complete surgical removal {[[ 18272388 ]](https://www.ncbi.nlm.nih.gov/pubmed/18272388)}. Many of these factors, including age, are confirmed in studies on molecularly defined oligodendroglioma, but limited follow-up remains an issue {[[ 31561286 ]](https://www.ncbi.nlm.nih.gov/pubmed/31561286); [[28532485 ]](https://www.ncbi.nlm.nih.gov/pubmed/28532485)}. Imaging The presence of contrast enhancement on imaging is indicative of worse outcome in IDH-mutant CNS WHO grade 2 and 3 gliomas, including oligodendrogliomas {[[ 30417117 ]](https://www.ncbi.nlm.nih.gov/pubmed/30417117); [[30529899 ]](https://www.ncbi.nlm.nih.gov/pubmed/30529899)}. An increased growth rate on follow-up MRI has been associated with histological features of anaplasia, including microvascular proliferation and higher mitotic count, with contrast enhancement on neuroimaging, and with shorter progression-free survival (PFS) {[[ 32025725 ]](https://www.ncbi.nlm.nih.gov/pubmed/32025725)}. Surgery Greater extent of resection has been associated with longer overall survival (OS) and PFS in patients with CNS WHO grade 2 oligodendroglioma, but it did not prolong the time to malignant progression {[[ 24313617 ]](https://www.ncbi.nlm.nih.gov/pubmed/24313617)}. Studies using volumetric tumour assessment show that extensive resections are associated with improved outcomes. However, leaving some tumour tissue behind appears to have less impact on the survival of patients with oligodendroglioma than on that of patients with IDH-mutant astrocytoma {[[ 29016833 ]](https://www.ncbi.nlm.nih.gov/pubmed/29016833); [[31248860 ]](https://www.ncbi.nlm.nih.gov/pubmed/31248860); [[30206763 ]](https://www.ncbi.nlm.nih.gov/pubmed/30206763)}, perhaps because of the higher sensitivity of oligodendrogliomas to radiotherapy and chemotherapy. Histological features Histological features that have been linked to worse prognosis include necrosis, high mitotic activity, increased cellularity, nuclear atypia, cellular pleomorphism, and microvascular proliferation. However, the prognostic significance of each of these requires re-evaluation in patients with molecularly characterized tumours. In IDH-mutant and 1p/19q-codeleted CNS WHO grade 3 oligodendrogliomas, high mitotic count (≥ 2.5 mitoses/mm^2^, equating to ≥ 6 mitoses/10 HPF of 0.55 mm in diameter and 0.24 mm^2^ in area) was linked to shorter PFS and OS in both univariate and multivariate analyses {[[ 27175000 ]](https://www.ncbi.nlm.nih.gov/pubmed/27175000)}. The presence of microvascular proliferation and/or necrosis was of prognostic significance in cases lacking *CDKN2A* homozygous deletion {[[ 31832685 ]](https://www.ncbi.nlm.nih.gov/pubmed/31832685)}. CNS WHO grading Older studies reported CNS WHO grade as an independent predictor of survival for patients with oligodendroglial tumours {[[ 15193024 ]](https://www.ncbi.nlm.nih.gov/pubmed/15193024); [[11245209 ]](https://www.ncbi.nlm.nih.gov/pubmed/11245209); [[15159478 ]](https://www.ncbi.nlm.nih.gov/pubmed/15159478); [[15977639 ]](https://www.ncbi.nlm.nih.gov/pubmed/15977639)}. However, these studies antedate the molecular criteria for oligodendroglioma. In one study of patients with gliomas with concurrent IDH mutation and *TERT* promoter mutation, patients with grade 2 tumours had longer survival times than those with grade 3 tumours (median OS: 205.5 months vs 127.3 months, respectively) {[[ 24722048 ]](https://www.ncbi.nlm.nih.gov/pubmed/24722048)}. A recent multicentre study observed a median OS of 188 months in patients with grade 2 oligodendrogliomas versus 119 months in patients with grade 3 tumours {[[ 32721633 ]](https://www.ncbi.nlm.nih.gov/pubmed/32721633)}. This difference remained significant in a multivariate analysis. A study of 176 patients with IDH-mutant and 1p/19q-codeleted oligodendrogliomas (CNS WHO grades 2 and 3) also revealed shorter OS for patients with CNS WHO grade 3 tumours {[[ 28532485 ]](https://www.ncbi.nlm.nih.gov/pubmed/28532485)}. In contrast, a retrospective analysis of 212 patients with IDH-mutant and 1p/19q-codeleted oligodendrogliomas did not detect CNS WHO grade as a significant predictor of OS {[[ 25701198 ]](https://www.ncbi.nlm.nih.gov/pubmed/25701198)}. Similarly, data from a combined cohort from Japan and The Cancer Genome Atlas (TCGA) suggested that grading had a limited prognostic role {[[ 25848751 ]](https://www.ncbi.nlm.nih.gov/pubmed/25848751)}. The interpretation of these retrospective studies requires caution because other prognostically relevant factors, such as extent of resection, were not considered, and patients received variable postoperative treatments. Proliferation A study of 220 patients with IDH-mutant and 1p/19q-codeleted CNS WHO grade 3 oligodendroglioma revealed that labelling index values of ≥ 50% for MCM6 and ≥ 15% for Ki-67 correlated with shorter OS in univariate and multivariate analyses {[[ 31561286 ]](https://www.ncbi.nlm.nih.gov/pubmed/31561286)}. The MCM6 and Ki-67 indices also correlated with OS in 30 patients with CNS WHO grade 2 oligodendrogliomas {[[ 31561286 ]](https://www.ncbi.nlm.nih.gov/pubmed/31561286)}. High mitotic count (≥ 2.5 mitoses/mm^2^, equating to ≥ 6 mitoses/10 HPF of 0.55 mm in diameter and 0.24 mm^2^ in area) was associated with an increased growth rate on follow-up MRI and shorter PFS in patients with CNS WHO grade 2 and 3 oligodendrogliomas {[[ 32025725 ]](https://www.ncbi.nlm.nih.gov/pubmed/32025725)}. Genetic alterations Currently available evidence from retrospective studies suggests that the presence of 1q and 19p co-polysomy detected by FISH concurrent with 1p/19q codeletion is associated with earlier recurrence and shorter survival {[[ 31140557 ]](https://www.ncbi.nlm.nih.gov/pubmed/31140557); [[19808867 ]](https://www.ncbi.nlm.nih.gov/pubmed/19808867); [[22710961 ]](https://www.ncbi.nlm.nih.gov/pubmed/22710961)}. Allelic losses on 9p have been detected in about one third of CNS WHO grade 2 IDH-mutant and 1p/19q-codeleted oligodendrogliomas, but they were not associated with shorter survival {[[ 29663171 ]](https://www.ncbi.nlm.nih.gov/pubmed/29663171)}. Other studies reported that allelic losses of 9p21.3 (the *CDKN2A* gene locus) were linked to shorter survival in patients with CNS WHO grade 3 oligodendroglioma {[[ 15099021 ]](https://www.ncbi.nlm.nih.gov/pubmed/15099021); [[26385879 ]](https://www.ncbi.nlm.nih.gov/pubmed/26385879)}. Homozygous deletion involving the *CDKN2A* gene locus is not observed in CNS WHO grade 2 oligodendrogliomas {[[ 29663171 ]](https://www.ncbi.nlm.nih.gov/pubmed/29663171); [[31832685 ]](https://www.ncbi.nlm.nih.gov/pubmed/31832685)}, but it is found in a small subset of CNS WHO grade 3 oligodendrogliomas, in which it has been associated with poor outcome {[[ 31832685 ]](https://www.ncbi.nlm.nih.gov/pubmed/31832685)}. Other alterations that have been linked to less favourable outcome of patients with CNS WHO grade 3 oligodendroglioma include *PIK3CA* mutation {[[ 30975663 ]](https://www.ncbi.nlm.nih.gov/pubmed/30975663); [[15289301 ]](https://www.ncbi.nlm.nih.gov/pubmed/15289301)}, *TCF12* mutation {[[ 26068201 ]](https://www.ncbi.nlm.nih.gov/pubmed/26068201)}, and increased MYC signalling {[[ 27090007 ]](https://www.ncbi.nlm.nih.gov/pubmed/27090007)}. *PTEN* mutation has been associated with shorter survival of patients with CNS WHO grade 2 oligodendroglioma {[[ 29663171 ]](https://www.ncbi.nlm.nih.gov/pubmed/29663171)}. Higher tumour mutation burden was found to predict shorter survival with IDH-mutant gliomas including oligodendrogliomas {[[ 32642696 ]](https://www.ncbi.nlm.nih.gov/pubmed/32642696)}. *CIC* mutation has been reported as a marker of poor prognosis {[[ 26017892 ]](https://www.ncbi.nlm.nih.gov/pubmed/26017892)}, but this finding was not confirmed in other series {[[ 26354927 ]](https://www.ncbi.nlm.nih.gov/pubmed/26354927); [[29663171 ]](https://www.ncbi.nlm.nih.gov/pubmed/29663171)}. No impact on outcome was observed for *CDK4* amplification or *RB1* homozygous deletion {[[ 31832685 ]](https://www.ncbi.nlm.nih.gov/pubmed/31832685)}. Treatment The optimal postoperative treatment of patients with IDH-mutant and 1p/19q-codeleted oligodendrogliomas of CNS WHO grade 2 is a matter of ongoing discussion. After tumour resection, radiotherapy and chemotherapy are often deferred until tumour progression because therapy-associated neurotoxicity is a major concern {[[ 28483413 ]](https://www.ncbi.nlm.nih.gov/pubmed/28483413)}. Patients with symptomatic and progressive tumours, with CNS WHO grade 3 tumours, or with large residual tumours after surgery usually receive immediate further treatment with radiotherapy and/or chemotherapy {[[ 28483413 ]](https://www.ncbi.nlm.nih.gov/pubmed/28483413)}. The European Organisation for Research and Treatment of Cancer (EORTC) 22845 trial showed that adjuvant radiotherapy prolonged PFS but not OS in patients with progressive CNS WHO grade 2 gliomas {[[ 16168780 ]](https://www.ncbi.nlm.nih.gov/pubmed/16168780)}. Long-term follow-up data from randomized trials showed a major increase in OS after radiotherapy plus PCV chemotherapy in patients with CNS WHO grade 3 oligodendrogliomas {[[ 27050206 ]](https://www.ncbi.nlm.nih.gov/pubmed/27050206); [[23071237 ]](https://www.ncbi.nlm.nih.gov/pubmed/23071237); [[23071247 ]](https://www.ncbi.nlm.nih.gov/pubmed/23071247)}. Adjuvant chemotherapy with temozolomide or PCV may also be a feasible therapeutic strategy for patients with progressive CNS WHO grade 2 oligodendroglioma {[[ 15284265 ]](https://www.ncbi.nlm.nih.gov/pubmed/15284265); [[19118062 ]](https://www.ncbi.nlm.nih.gov/pubmed/19118062); [[16541434 ]](https://www.ncbi.nlm.nih.gov/pubmed/16541434); [[25344884 ]](https://www.ncbi.nlm.nih.gov/pubmed/25344884)}.