Oligodendroglioma

Etiology

OGs are primary brain tumors originating from oligodendrocytes, the glial cells responsible for myelination in the CNS. Initially described by Bailey and Bucy in 1929 for their microscopic resemblance to oligodendrocytes, their exact cellular origin remains debated. The hypothesis that OGs arise either from mature oligodendrocytes or neuroprogenitor cells with glial precursors, which differentiate into oligodendroglial-type cells lacking myelinating capabilities, is supported by shared driver mutations, particularly isocitrate dehydrogenase (IDH) mutations, which are common across various diffuse glioma subtypes and serve as early events in tumorigenesis.[4][5][6][7]

The etiology of OGs is multifactorial, involving genetic, environmental, epigenetic, and cellular factors. Genetically, the hallmark codeletion of chromosomal arms 1p and 19q is diagnostic in 70% to 90% of cases and correlates with better prognosis and therapy responsiveness. Mutations in IDH1 and IDH2 further characterize these tumors, contributing to the glioma CpG island methylator phenotype (G-CIMP), which alters deoxyribonucleic acid (DNA) methylation and promotes growth. Less frequently, mutations in TP53 and ATRX help differentiate OGs from astrocytomas.

While specific environmental exposures, such as ionizing radiation or chemicals in certain industries, may play a role, definitive links remain unproven. Epigenetic changes, including altered DNA methylation and histone acetylation, with dysregulated signaling pathways like platelet-derived growth factor receptor (PDGFR) and the epidermal growth factor receptor (EGFR), further promote tumorigenesis. The tumor microenvironment, influenced by hypoxia, inflammation, and cellular interactions, also contributes to their development. Combining these factors transforms normal oligodendrocytes or their precursors into malignant cells, giving rise to OGs. Research into these mechanisms continues to inform diagnostic and therapeutic advancements, offering hope for improved patient outcomes.

Epidemiology

OGs are uncommon, with an incidence of 0.2 per 100,000 people, and are the third most common primary brain neoplasm following the glioblastoma and the diffuse astrocytoma. OGs comprise approximately 5% of all primary CNS tumors.[5][8][9] These tumors have a slight male predominance, reported from 1.1 to 2, with as low as a 0.92 male-to-female ratio, as seen from the results of a study.[10] OGs have a slight bimodal distribution but are primarily adult neoplasm, with a peak incidence occurring in the fourth and fifth decades and a smaller tumor incidence peak in children aged 6 to 12.[9] OGs in pediatric patients usually demonstrate different molecular markers than are seen in the adult form, raising the issue of whether they represent the same neoplasm.

Pathophysiology

OGs are diffuse gliomas that arise predominantly in the hemispheric cerebral white matter, with 80% to 90% being supratentorial. The frontal lobes are the most commonly affected sites, although involvement of the temporal and parietal lobes is also frequently observed. These tumors are typically located in a cortical-subcortical distribution, with diffuse infiltration into the adjacent white matter. Rarely, OGs can occur in intraventricular or subependymal locations.

Genetic Features

A hallmark of OGs is chromosomal arms 1p and 19q codeletion, which occurs in 70% to 90% of cases. This genetic alteration is diagnostic and associated with better prognosis and enhanced responsiveness to radiotherapy and chemotherapy. Nearly all OGs harbor mutations in the IDH1 or IDH2 genes, producing the oncometabolite 2-hydroxyglutarate. This molecule induces a G-CIMP methylator phenotype, promoting DNA hypermethylation, impairing cellular differentiation, and facilitating tumor growth. Other genetic alterations, such as TP53 mutations or ATRX gene alterations, are less common and help distinguish OGs from other gliomas.

Epigenetic and Cellular Mechanisms

Epigenetic modifications, including DNA hypermethylation and histone changes, further contribute to tumor development by altering gene expression and cell differentiation. Dysregulated signaling pathways, such as those involving PDGFR, EGFR, and phosphoinositide 3-kinase (PI3K), drive tumor cell proliferation, angiogenesis, and resistance to apoptosis. The tumor microenvironment, characterized by hypoxia, inflammation, and immune evasion, plays an additional role in sustaining tumor progression.

Cellular Origin

Historically, OGs were thought to originate from mature oligodendrocytes. However, recent evidence suggests that they arise from neuroprogenitor cells with glial precursor characteristics. These progenitor cells acquire mutations and signaling dysregulation, transforming into malignant cells with an oligodendroglial phenotype.

Histopathology

OGs exhibit distinctive macroscopic and microscopic characteristics that reflect their origin and biological behavior. Macroscopically, OGs are typically gelatinous gray masses with areas of cystic degeneration, calcifications, and occasionally small focal hemorrhages. These features are often observed during surgical resection or imaging studies. Microscopically, OGs are characterized by sheets of uniform, small-to-medium-sized cells with spherical nuclei surrounded by a clear perinuclear halo, creating the classic "fried egg" appearance. This artifact arises from routine histological processing with formalin and paraffin fixation. A network of thin-walled capillaries, described as a "chicken wire" vascular pattern, is a hallmark of these tumors. Scattered calcifications and psammoma bodies are commonly identified.

Occasionally, myelin-like structures are observed on the tumor surface, although they do not meet the criteria for true myelin sheaths.[6] High-grade, anaplastic OGs (WHO grade III) exhibit increased cellular density, significant nuclear atypia, and heightened mitotic activity. These tumors may also display microvascular proliferation, increased blood vessel density, and necrosis, reflecting tumor cells' accelerated growth and proliferation.

Immunohistochemistry aids in differentiating OGs from other gliomas:

• Olig2
  • This transcription factor is associated with oligodendrocyte progenitor cells used in neuronal or oligodendrocytic cell differentiation consistently expressed in OGs.[11]
• Glial fibrillary acidic protein
  • This is commonly expressed in OGs but to a lesser degree than in astrocytomas.[5]
• Myelin basic protein
  • OGs lack basic myelin proteins found in myelin-producing oligodendrocytes and Schwann cells.
• Ki-67
  • This marker for cellular proliferation is low in low-grade OGs but elevated in anaplastic forms.

Molecular features are critical for diagnosis:

• 1p/19q codeletion
  • This defining genetic hallmark seen in 70% to 90% of cases is strongly associated with better prognosis and response to therapy.
• IDH mutations
  • This mutation, found in nearly all OGs, contributes to tumorigenesis through the production of the oncometabolite 2-hydroxyglutarate.
• TERT promoter mutations
  • This is commonly present and involved in telomere maintenance.

OGs are predominantly located in the hemispheric white matter, with 80% to 90% being supratentorial and most commonly found in the frontal lobes. They are diffusely infiltrative, involving adjacent white matter, and less frequently occur in subependymal or intraventricular locations. These histopathological and molecular features facilitate accurate diagnosis and inform prognosis and therapeutic strategies. Advanced understanding of the tumor microenvironment and genetic drivers continues to shape the management of OGs.

History and Physical

History

Patients with OGs often present with nonspecific symptoms such as headaches or more specific findings like seizures, which are among the most common presenting complaints. Seizures are reported in 35% to 91% of cases, making them a hallmark symptom of OG.[9] These seizures may range from focal to generalized and are often refractory to standard antiepileptic therapy, particularly in recurrent or progressive cases. Persistent or progressive headaches may indicate increased intracranial pressure or local mass effect. At the same time, cognitive or personality changes, especially with frontal lobe tumors, can include impaired judgment, memory deficits, or disinhibition.

Depending on the tumor's location, patients occasionally develop focal neurological deficits such as weakness, sensory disturbances, aphasia, or visual field deficits. Increased intracranial pressure symptoms, including nausea, vomiting, and papilledema, may occur in cases with significant mass effects or hydrocephalus. Any patient presenting with new-onset seizures, focal neurological deficits, or unexplained cognitive changes should undergo CNS imaging to evaluate for underlying pathologies, including OGs.

Physical Examination

Findings on physical examination depend on the tumor’s location, size, and mass effect.

• Neurological Examination
  • Seizures
    • May be ongoing or reported as a recurrent issue in the patient’s history
  • Focal neurological deficits
    • Weakness, sensory loss, or aphasia consistent with the affected cortical region
  • Visual field deficits
    • Homonymous hemianopia or quadrantanopia, particularly with temporal or parietal lobe involvement
  • Cognitive and behavioral changes
    • Impaired executive function, personality changes, or memory deficits with frontal lobe lesions
• Signs of increased intracranial pressure
  • Papilledema on fundoscopic examination
  • Sixth nerve palsy due to raised pressure
• Location-specific symptoms
  • Frontal lobe
    • Disinhibition, apathy, or difficulty with planning and judgment
  • Temporal lobe
    • Memory disturbances, auditory hallucinations, or language deficits
  • Parietal lobe
    • Sensory deficits, spatial neglect
  • Occipital lobe
    • Visual field deficits or cortical blindness

Patients with high-grade or anaplastic OGs may present with a rapid onset of symptoms and severe neurological deficits due to the tumor’s fast growth. The history and physical examination provide critical clues for early recognition and guide the need for diagnostic imaging and further management.

Evaluation

Laboratory Tests 

Laboratory investigations for OGs are generally nonspecific but may be performed to assess general health and rule out other conditions. Routine tests like a complete blood count and serum electrolytes can help identify complications such as anemia, infections, or electrolyte disturbances that may arise from the tumor or seizures. However, there are no definitive blood biomarkers for OGs in clinical practice. Genetic markers, such as glial fibrillary acidic protein and Olig2, may be used in research settings to help understand the tumor’s molecular characteristics. These markers are more useful in differentiating OGs from other gliomas, but histological and molecular analysis remains the primary diagnostic approach.

Radiographic Imaging

Computed tomography scan

Computed tomography (CT) is often the initial imaging modality used for patients presenting with nonspecific neurological symptoms, particularly to rule out acute abnormalities such as hemorrhage or ischemia quickly. OGs on CT are typically hypodense or occasionally isodense with the surrounding brain tissue and appear as peripheral masses that may expand the cortical gyri (see Image. Oligodendroglioma, Computed Tomography Scan). Calcifications, seen in up to 90% of OGs, often present in a gyriform pattern, highly suggestive of this tumor type.[12][13] The presence of peritumoral edema and hemorrhage is uncommon, and the degree of contrast enhancement is usually mild, varying by tumor grade.

Magnetic resonance imaging 

Magnetic resonance imaging (MRI) offers a better characterization of the tumor appearance than CT and can help define the OG's true extent and infiltrative nature. T2 weighted sequences will demonstrate a circumscribed heterogeneously hyperintense tumor, often cortical/subcortical in location, and may demonstrate a slight peritumoral hyperintense signal. Within the tumor, there are frequently small areas of cystic change, microhemorrhage, and macroscopic calcifications demonstrated by T2 hypointense signal due to susceptibility signal loss and increased tumor heterogeneity. OGs are hypointense compared to gray matter on T1 weighted imaging, and enhancement in low-grade tumors is variable, ranging from patchy enhancement to moderate enhancement, where the presence of enhancement does not necessarily represent a higher histological grade of OG. An OG typically has facilitated rather than restricted diffusion, with hyperintensity seen on apparent diffusion coefficient maps.

More advanced MRI techniques, such as spectroscopy and perfusion, may complement anatomic imaging and help characterize and grade the tumor type. However, most OGs are low-grade, so these advanced imaging techniques may not provide significant additional information to the more standard anatomic imaging. Spectroscopy shows a mildly elevated choline level and decreased N-acetyl aspartate peaks, seen in most neoplasms, which are more prominent in high-grade tumors than low-grade gliomas due to their increased mitotic activity. Elevated myoinositol and 2-hydroxyglutarate presence may suggest isocitrate dehydrogenase mutation status.[14] 

The presence of elevated lipid and lactate peaks generally suggests a high-grade tumor.[13] T2 weighted dynamic susceptibility contrast perfusion imaging can show elevated cerebral blood flow and cerebral blood volume in higher-grade tumors due to neovascularization compared to low-grade tumors. However, there is a significant degree of overlap between them.[13][15][16] T1 weighted dynamic contrast-enhanced perfusion may show elevated Ktrans, representing leaky vasculature and the diffusion of contrast outside of the capillary endothelium in higher-grade tumors compared to low-grade tumors. Still, again, there is significant overlap where most low-grade tumors do not have significant contrast enhancement.[17][18][19]

Preoperative evaluation of white matter tracts using MRI diffusion tensor imaging sequences and tractography can demonstrate their position and proximity to the tumor. This typically shows displacement of the tracts rather than destruction by the tumor. Additional evaluation with functional MRI can demonstrate the tumor's proximity to the eloquent cortex, including important language, motor, sensory, and visual areas.

Genetic Testing and Histopathology

Histopathologic examination remains essential for definitive diagnosis, as radiographic imaging alone cannot distinguish OGs from other gliomas, especially low-grade tumors. All patients with a tumor will require tissue sampling and histologic examination of that tissue for diagnosis. In 2016, the WHO changed the criteria for classifying CNS tumors to include phenotypic and genotypic analysis. The diagnosis of OG is now determined using molecular markers, and the tumor must possess both an IDH1 or IDH2 mutation and 1p/19q codeletion to be classified as an OG.[2][20] The 1p/19q mutation leads to epigenetic changes and hypermethylation of the genome, demonstrating a distinct biological phenotype associated with improved survival rates.

Tumors that cannot be tested for these genetic markers but would traditionally be diagnosed as OG on histology should be designated OG not otherwise specified (NOS). When a molecular analysis is unavailable, or the molecular diagnosis is equivocal, the diagnosis of OG NOS should be used. Pediatric OG often does not have the characteristics of IDH mutation and 1p/19q codeletion present in their adult counterparts, which may genetically represent a different disease.[5][21][22][23] Further studies on adult and pediatric molecular and genetic markers are ongoing.

Treatment / Management

Treatment of an OG is multifactorial and consists of surgical, chemotherapy, and radiation therapy (RT) treatment methods.

Surgery

Surgical treatments are considered on a case-by-case basis. Tumor location, patient comorbidities, and other surgical risk factors are used to determine the type of surgery that will benefit the optimal patient. Complete or gross total resection of the tumor is the primary treatment of choice for the OG. This approach will increase overall survival time and can occasionally be curative. Therefore, all attempts should be made to achieve this surgical result if possible.[9][24][25][26] Suppose a complete tumor resection cannot be obtained. In that case, a debulking procedure can be performed to help improve neurological symptoms and seizure control and decrease the potential for malignant transformation. This procedure has also increased overall survival time and time to tumor progression.[27] In patients with partially resected low-grade tumors that are being observed and demonstrate increased tumor growth over time, or in patients with concern for malignant transformation to a higher-grade neoplasm, repeat surgical resection is still recommended in an attempt to cure the patient potentially or to confirm the histological grade of the tumor.(A1)

Surgical resection techniques depend on the location of the OG, where the eloquent cortex and vital neurological structures must be preserved. The location of the craniotomy utilized for each approach and access will vary, and some surgeons prefer to perform the resection on an awake patient to stimulate, test, and map adjacent brain parenchyma to help determine the extent of tissue that can safely be removed. Intraoperative imaging techniques, such as intraoperative MRI or ultrasound, have also been used to assist in maximizing the extent of the tumor resection. These adjunct imaging techniques may be more efficacious than standard stereotactic navigation, increase operative time, and require special equipment and training.

Using 5-aminolevulinic acid (5-ALA) fluorescent dye can also be a helpful surgical tool. 5-ALA is a heme precursor that is shown to cause fluorescence in malignant tissue by creating fluorescent porphyrins, which can be visualized intraoperatively. This agent has also been shown to have statistically significant improvement in the extent of resection of high-grade gliomas over conventional stereotactic navigation and is overall similar in efficacy to intraoperative MRI. However, it has only been shown in small sample sizes.[9][28][29][30] Further study and evaluation may be warranted.(A1)

Radiation

RT also plays an important role in treating OG, most often after surgical resection. There does not appear to be a difference in the overall survival between early or delayed postoperative RT. Still, an increased time to progression has been shown with early treatment, in addition to better seizure control following surgery.[31](A1)

Standard focal or limited field hyperfractionated RT is typically employed. The treatment field consists of the surgical resection bed, areas of residual enhancement on T1 postcontrast imaging, and a margin of up to 3 cm, including the adjacent T2/FLAIR signal hyperintensity that may represent infiltrating disease. This margin is modified to minimize the involvement of critical neural structures or if microscopic/infiltrating disease is considered less likely to present.[32] The radiation dose administered has varying recommendation amounts of 45 to 65 Gy in 1.8 to 2 Gy fractions, without significant survival benefit seen between 45 Gy and 59.4 Gy or 54 Gy and 65 Gy treatments. Dosing and the treatment schedule are case-dependent, based on prognosis, with higher doses typically reserved for higher-grade tumors. Hypofractionated doses may be applied in older individuals with poor prognoses, giving fewer, higher single fractions for the same or lower total dose.[12][32][33][34] RT is usually withheld from children to minimize some of the negative long-term side effects of radiation, such as cognitive impairment, personality changes, hypopituitarism, motor and coordination abnormalities, and the development of other neoplasms.[9][35] Adults receiving RT may develop some of these negative effects after therapy or can experience other problems, such as radiation necrosis.(A1)

Chemotherapy

In addition to RT, chemotherapy is a commonly used adjunct, demonstrating increased survival in RT with chemotherapy groups compared to RT alone.[3] There is good evidence that a combination of procarbazine, lomustine, and vincristine (PCV) can be beneficial for treating OGs.[36][37] However, this regimen is typically limited to 6 cycles due to adverse events from the agents.[33][38] These adverse drug events, most often leukopenia and thrombocytopenia, can lead to early discontinuation of the treatment in many patients. For this reason, temozolomide (TMZ) is often the chemotherapy of choice. TMZ is an oral DNA alkylating agent that patients better tolerate than nitrosourea-containing regimens such as PCV. TMZ alone has been shown to occasionally result in a recurrent hypermutated tumor phenotype that is TMZ-resistant. At this time, the combination of RT and chemotherapy affords better overall survival and progression-free survival, but the choice of PCV or TMZ is still debated. Results from recent studies have shown that PCV could lead to better overall survival compared to TMZ in 1p/19q co-deleted patients, advocating for PCV as first-line use chemotherapy in the treatment of OG.[39][40] Currently, the ongoing CODEL study (NCT00887146) assessing outcomes of RT and PCV and RT and TMZ will give a better understanding between these 2 treatment regimens and potentially a determination of superiority. However, results may still be 7 to 10 years in the future.[12][41](A1)

Additionally, noncytotoxic treatment has been approved for recurrent glioblastoma use in the United States, Canada, and Europe. Still, it may also benefit anaplastic OGs that demonstrate increased vascularity, as evidenced by enhancement and peritumoral edema on MRI. Bevacizumab is a monoclonal antibody against vascular endothelial growth factor (VEGF), and these antibodies bind to the VEGF receptors, decreasing neovascularization and vascular permeability and helping to stabilize the blood-brain barrier.[36] This result eventually leads to less peritumoral edema and decreased need for corticosteroids, improving symptoms and progression-free survival as seen in some study results. However, this treatment overall appears limited to recurrent disease, palliative treatment, and in patients with brain radiation necrosis.[42][43]

Differential Diagnosis

Diffuse astrocytoma is the primary differential diagnosis on imaging and is virtually indistinguishable from OG. On imaging studies, diffuse astrocytoma often has less dystrophic calcification and more white matter and less cortical involvement than the OG. However, the main discriminating factors between the 2 tumor types are the genetic markers, where the lack of the 1p/19q deletion occurs in the astrocytoma.

Glioblastoma is an important diagnostic consideration from OG because this tumor carries a much poorer prognosis and is, unfortunately, much more common in adults than children. Glioblastoma will typically demonstrate more avid and heterogeneous enhancement than low-grade OG. Although glioblastoma may be hard to distinguish from the higher grade, it enhances anaplastic OG. Glioblastoma can sometimes have patchy areas of restricted diffusion and areas of central necrosis, which are both uncommon in OG. Calcification is uncommon in glioblastoma and very common in OG. Histologically, glioblastoma will have more aggressive features such as necrosis and neovascularization, and they lack the 1p/19q deletion and are often IDH mutation negative compared to OG on molecular analysis.

Dysembryoplastic neuroepithelial tumors (DNETs) are another low-grade cortical-subcortical-based neoplasm that can look similar to OG in imaging studies. However, DNETs tend to have a more “bubbly” cystic T2 hyperintense appearance and may have adjacent cortical dysplasia. Compared to OGs, which are more often diagnosed in older adults, DNETs are more often found in children and young adults. Ganglioglioma is another cortical-subcortical neoplasm that occurs more often in children and young adults and can be a seizure focus. On MRI, gangliogliomas typically present as cysts with enhancing nodules and are more commonly seen in the temporal lobe than the OG. A multinodular and vacuolating neuronal tumor is a cortical-subcortical lesion that may have imaging overlap with OG and typically appears as a cluster of small bubbly cysts that are T2/FLAIR hyperintense and do not typically enhance. The lesion is typically incidentally found and maybe a malformation/dysplastic lesion instead of a true neoplasm.

Prognosis

Low-grade OGs (WHO Grade II), which by definition have 1p/19q deletion and IDH mutant, have a better prognosis than astrocytomas without these genetic markers.[44] OGs have a median survival time of 10 to 12 years and 5-year progression-free and overall survival rates of 51% to 83%. Younger patients, patients without other comorbidities, and those with a greater extent of tumor resection tend to have a better prognosis.[8][10][24][25][26] The overall and 5-year survival rates decrease with higher-grade anaplastic OGs, where the median survival time is 3.5 years in WHO Grade III tumors.

Complications

Complications from OGs may include seizures, postsurgical complications, and thromboembolic events. Chemotherapeutic adverse events, including myelosuppression limiting treatment with PCV, as well as nausea, vomiting, and other gastrointestinal symptoms that occur with TMZ. The long-term adverse events of radiation therapy include cognitive deficits, gait abnormalities, or radiation necrosis. Residual or recurrent OGs can also undergo malignant degeneration over time.