Oligodendroglioma IDH-mutant and 1p/19q-codeleted
In 2021, the World Health Organization published the fifth edition of the Classification of Tumors of the Central Nervous System. This classification incorporates advances in understanding the molecular pathogenesis of brain tumors with histopathology in order to group tumors into more biologically and molecularly defined entities. The previous broad category of adult-type diffuse gliomas has been consolidated into 3 types: astrocytoma, isocitrate dehydrogenase (IDH) mutant; oligodendroglioma, IDH mutant and 1p/19q codeleted; and glioblastoma, IDH wild type. These major changes are driven by IDH mutation status and include the restriction of the diagnosis of glioblastoma to tumors that are IDH wild type; the reclassification of tumors previously diagnosed as IDH-mutated glioblastomas as astrocytomas IDH mutated, grade 4; and the requirement for the presence of IDH mutations to classify tumors as astrocytomas or oligodendrogliomas 1)
IDH-mutant 1p/19q-codeleted grade 3 oligodendroglioma
General information
Key concepts
● slow growing tumor that frequently presents with seizures
● occur primarily in adults, predilection for the frontal lobes
● by definition: a diffusely infiltrating glioma with codeletion of BOTH chromosome arms 1p AND 19q, AND mutation of IDH1 OR IDH2
● histology: classic features of “fried egg” cytoplasm (on permanent pathology) & “chicken wire” vas- culature are unreliable. Calcifications are common
● recommended treatment: as for WHO grade II astrocytic tumors
Arise in the frontal lobe in > 50% of cases.
Histology
Moderately cellular tumor composed of cells resembling oligodendroglial cells (uni- form, round nuclei).
A diffusely infiltrating glioma with IDH1 or IDH2 mutation and codeletion of chromosome arms 1p & 19q.
Tumors show moderate cellularity. Cells with monotonous round nuclei (often in cellular sheets) with an eccentric rim of eosinophilic cytoplasm lacking obvious cell processes are the most consis- tent features.
73% of tumors have microscopic calcifications.58 Isolated tumor cells consistently penetrate largely intact parenchyma; an associated solid tumor component may or may not be present.59 When a solid portion is present, permanent (paraffin) pathology demonstrates lucent perinuclear halos, giving a “fried egg” appearance (actually an artifact of formalin fixation, which is not present on frozen section and may make diagnosis difficult on frozen). A “chicken-wire” vascular pattern has also been described.60 These features are variable.
Nuclear atypia and an occasional mitotic figure is compatible with the diagnosis.5 Compare to WHO grade III anaplastic oligodendroglioma, IDH-mutant 1p/19q codeleted .
16% of hemispheric ODGs are cystic58 (cysts form from coalescence of microcysts from microhe- morrhages, unlike astrocytomas, which actively secrete fluid).
GFAP staining: Since most ODGs contain microtubules instead of glial filaments,61 ODGs usually do not stain for GFAP, although some do. In mixed gliomas, the astrocytic component may stain for GFAP.
CSF metastases
Metastases reportedly occur in 8–14%, mainly as a microscopic finding, but 1% may be a more realistic estimate. Symptomatic spinal metastases (drop mets) are even more uncommon.
Diagnosis
Fluorescein-guided stereotactic biopsy increases the likelihood of definitive neuropathological diagnosis, and the number needed to sample can be reduced by 50% in contrast-enhancing lesions 2)
Treatment
Outcome
Median survival with ODG, IDH-mutant & 1p/19q codeletion is 8 years. Codeletion of 1p/19q by itself is also associated with longer median survival. compared to 6.4 years with diffuse astrocytoma, IDH mutant. Also, WHO grade II is an independent favorable prognosticator compared to WHO grade III ana- plastic ODG.
Case series
Adults with IDH-mutant, 1p/19q codeleted oligodendroglioma (WHO grade 2 or 3) who underwent surgery between 2005 and 2021 were identified. Clinical data, disease characteristics, treatment, and outcomes were collected.
A total of 207 patients with grade 2 and 70 with grade 3 oligodendrogliomas were identified. Median (IQR) follow-up was 57 (87) months. Patients with grade 3 tumors who received adjuvant radiation and PCV had longer median PFS (> 110 months) than patients who received radiation and TMZ (52 months, p = 0.008) or no adjuvant chemoradiation (83 months, p = 0.03), which was not seen in grade 2 tumors (p = 0.8). In multivariate analysis, patients who received PCV chemotherapy (Relative Risk [95% CI] = 0.24[0.05-1.08] and radiotherapy (0.46[0.21-1.02]) trended towards longer PFS, independently of grade.
Adjuvant radiation and PCV are associated with improved PFS over radiation with TMZ in patients with grade 3 molecularly defined oligodendrogliomas, and all-grade patients treated with PCV trended towards decreased risk of recurrence and progression. These results highlight the importance of ongoing clinical trials investigating these treatments 3).
68 patients with oligodendrogliomas treated with radiotherapy +/- chemotherapy. After filtering, 1697 genes were obtained, including 134 associated with progression-free survival: 35 with a better prognosis and 99 with a poorer one. Eight genes (ST3GAL6, QPCT, NQO1, EPHX1, CST3, S100A8, CHI3L1, and OSBPL3) whose risk score remained statistically significant after adjustment for prognostic factors in multivariate analysis were selected in more than 60% of cases were associated with shorter progression-free survival.
They found an eight-gene signature associated with a higher risk of rapid relapse after treatment in patients with oligodendrogliomas. This finding could help clinicians identify patients who need more intensive treatment 4).
Patients treated for a 1p/19q-codeleted and IDH-mutant ODG were evaluated. The patient and tumor characteristics were analyzed for their influence on PFS and OS.
One-hundred-fourteen patients met the inclusion criteria. The median clinical and radiographic follow-up periods were 68.6 and 69.8 months. The median PFS and OS were 66.9 and 236.0 months, respectively. The 2-, 4- and 6-year PFS rates were 89.5%, 76.3%, and 46.0%. The 2-, 4- and 6-year OS rates were 99.0%, 97.9%, and 96.2%. For WHO grade 2 ODG, extent of resection (p = 0.01, hazard ratio (HR) 0.01; p = 0.02, HR 0.02), radiotherapy (p = 0.01, HR < 0.01) and chemotherapy (p = 0.01, HR < 0.01) were associated with a prolonged PFS. For WHO grade 3 ODG, only a combined radiochemotherapy (RCT) lowered the risk of progression in the multivariable analysis (p = 0.02, HR 0.09). Most RCT patients received temozolomide (TMZ) instead of procarbazine, lomustine, and vincristine.
Whereas previous studies often comprise tumors with IDH wild type status and without 1p/19q-codeletion, this homogeneous ODG cohort, as defined by the current WHO classification, demonstrated PFS benefits for various therapies, especially concerning RCT. While this is generally in accordance with comparable studies, more prospective work on homogeneous patient cohorts is required to refine treatment guidelines and to determine the role of TMZ in ODG 5).
Case reports
A case of an oligodendroglioma, IDH-mutant and 1p/19q-codeleted, and LS with a germline pathogenic PMS2 mutation. To our knowledge, this has only been reported in a few cases in the literature. While the family history is less typical of LS, previous studies have indicated the absence of a significant family history in patient cohorts with PMS2 mutations due to its low penetrance. Notably, only a handful of studies have worked on characterizing PMS2 mutations in LS, and even fewer have looked at these mutations in the context of brain tumor development. This report aims to add to the limited literature on germline PMS2 mutations and oligodendrogliomas. It highlights the importance of genetic testing in neuro-oncology 6).