Oligodendroglioma: Clinical Presentation, Pathology, Molecular Biology, Imaging, and Treatment

Oligodendroglioma: Clinical Presentation, Pathology, Molecular Biology, Imaging, and Treatment features the latest "cutting-edge" molecular biology, molecular therapeutics, imaging, immunotherapy, and research methods on the topic of oligodendrogliomas. The most detailed and comprehensive resource on the subject, it provides up-to-date information on clinical presentation, pathology, molecular biology, and treatment methods, including immunotherapy. This book is a critical for students, physicians and researchers in the fields of neuroscience, neuro-oncology, neurosurgery, radiation oncology, medical oncology, and others working in research or with patients.

• Provides the most up-to-date information regarding the clinical presentation, pathology, molecular biology, and methods for the treatment of oligodendroglioma brain tumors, including surgical therapy, radiotherapy, molecular therapeutics, chemotherapy, and immunotherapy
• Broadly appeals to anyone interested in the field of neuro-oncology and the treatment of patients with oligodendrogliomas
• Useful to clinicians interested in a thorough overview of the basic science and treatment of oligodendrogliomas
• Includes a section on immunotherapy, with updates on the use of vaccines and immune-based treatment approaches applied to oligodendrogliomas

• Language: English
• Publisher: Academic Press
• Release date: Jun 18, 2019
• ISBN: 9780128131596

Book preview

oligodendrogliomas.

Section A

Clinical presentation and quality of life

Chapter 1

Clinical presentation in adults—Brain

Ugonma N. Chukwueke*,†; David Reardon*,‡    * Center for Neuro-Oncology, Dana-Farber Cancer Institute, Boston, MA, United States

† Department of Neurology, Harvard Medical School, Boston, MA, United States

‡ Department of Medicine, Harvard Medical School, Boston, MA, United States

Abstract

Oligodendroglioma and anaplastic oligodendroglioma were traditionally known as World Health Organization (WHO) grade II and III tumors, classified based on their histologic appearance. There have been advances in the evolution of genetic and epigenetic technologies, and as such, the collective understanding of the molecular underpinnings of these tumors has also evolved. The recent revision of the WHO Classification of Brain Tumors categorizes these entities by integrating the genotypic and phenotypic characteristics. The diagnosis of oligodendroglioma and anaplastic oligodendroglioma now requires the co-occurrence of alterations in isocitrate dehydrogenase (IDH) and deletion of chromosome arms 1p and 19q. Consistent with most primary adult tumors, there is a predilection for the supratentorial compartment, as most oligodendroglioma and anaplastic oligodendroglioma are found in the cortex. Growth is typically indolent, accounting for the clinical presentation in most cases. Seizure is the most common presenting feature of oligodendroglioma, for which many factors have been proposed as the underlying etiology of epileptogenesis, including mutant IDH. The presence of IDH mutation and 1p/19q co-deletion is thought to predict more favorable treatment response and survival outcomes to treatment with chemotherapy and radiation.

Keywords

Oligodendroglioma; Low-grade glioma; Isocitrate dehydrogenase (IDH); 1p/19q; Seizure; Supratentorial; World Health Organization (WHO) classification of brain tumors

Epidemiology

Oligodendroglioma and anaplastic oligodendrogliomas are rare primary brain tumors. Traditionally classified as World Health Organization (WHO) grade II and III tumors, among adults in the United States, oligodendroglioma and anaplastic oligodendroglioma account for 1% and 0.5% of brain and central nervous system (CNS) tumors annually.¹ Median age at the time of diagnosis of oligodendroglioma and anaplastic oligodendroglioma are 43 and 50 years, respectively (Fig. 1). Consistent with trends observed in malignant primary brain tumors, these tumors occur more commonly in men as compared to women. From the standpoint of race, the incidence of oligodendroglioma and anaplastic glioma is higher in non-Hispanic whites in comparison to other ethnic groups, although survival outcomes in blacks have been reported to be poorer relative to other races, even with similar treatment regimens.¹ To date, there have been few studies examining the impact of race on primary brain tumors, so the underpinnings of this disparity are poorly understood.²

Fig. 1 Distribution of primary brain and other CNS gliomas by histology subtypes ( N  = 100,619), CBTRUS statistical report: NPCR and SEER, 2010–2014.

In the United States, there are expected to be > 1000 new cases of oligodendroglioma and > 600 anaplastic oligodendroglioma over the next 2 years.¹ Additionally, it is expected that the incidence of primary brain tumors will continue to rise, notably in regions of higher economic development. Europe has the highest incidence of brain cancer with an annual age-standardize rate (ASR) of 5.5 per 100,000 persons. The lowest ASR is in sub-Saharan Africa at 0.8 per 100,000 persons. It is unclear whether the rising incidence and disparity between developed and developing nations are true or may be an observation effect, correlated with increasing availability of technology, allowing for timely evaluation and diagnosis. An additional consideration may be variability in data collection and surveillance.³

Despite investigation of multiple potential risk factors for the development of glioma, including oligodendroglial tumors specifically, more investigation is still warranted. Ionizing radiation has been studied frequently for its association with risk of intracranial malignancy. Longitudinal analyses of incidence of neoplasm in populations in Hiroshima and Nagasaki showed an elevated risk of glioma; however, without achieving statistical significance.³ Similarly, work by Sadetzki et al. noted the incidence of glioma in individuals being treated with irradiation for tinea capitis has doubled, in comparison to population and sibling controls.⁴ Additionally observed was a dose–response relationship.

In 2011, McCarthy et al. reviewed data pooled from seven case–control studies (five in the United States and two in Scandinavia) to identify possible risk factors for the development of oligodendroglial tumors (oligodendroglioma, anaplastic oligodendroglioma, and mixed glioma).⁵ Among the factors identified included: history of asthma/allergy (decreased), family history (increased), and personal history of chicken pox (decreased). Ongoing work is required to further characterize whether these are reliable factors in reducing or enhancing the risk of tumor development, specifically, in oligodendroglial tumors.

This chapter will focus on the clinical presentation of oligodendroglioma in adults in the brain, with subsequent sections dedicated to discussion of these tumors in the pediatric population and other CNS structures.

Tumor classification

Until 2016, oligodendroglioma and anaplastic oligodendroglioma were defined exclusively by their histologic appearance. As they are derived from oligodendrocytes, the feature most consistent with a malignant process was the presence of a small, round nucleus surrounded by a halo of cytoplasm (fried egg), with calcifications and branching vessels. Anaplastic oligodendroglioma are further characterized by high cellularity and mitotic rate, with microvascular proliferation. The category of mixed oligoastrocytoma was previously included to capture tumors which were felt to morphologically harbor characteristics of both astrocytoma and oligodendroglioma.

In 2016, the WHO Classification of Brain Tumors was revised to reflect the emerging understanding and significance of the molecular characteristics of primary brain tumors. Inclusion of molecular-genetic alterations in the diagnosis of diffuse glial tumors is mandated by this scheme. In cases where testing is unavailable or incomplete, tumors may be assigned as not otherwise specified or NOS.⁶ The historical paradigm of distinguishing gliomas solely on morphological features (mitotic rate, anaplasia, and vascular proliferation) has evolved into a system of classification based on both phenotypic and genotypic features. Additionally, the integration of histology and genetics allows for increased accuracy of diagnosis, as well as clarity in predicting the behavior of the tumors from a prognostic standpoint. For an integrated diagnosis of oligodendroglioma and anaplastic oligodendroglioma, in addition to the noted histological characteristics, co-occurrence of mutation in isocitrate dehydrogenase (IDH)-1 (cytoplasmic) or IDH-2 (mitochondrial) and deletion of the short arm of chromosome 1p and long arm of 19q (1p/19q co-deletion) are required. Over 90% of the IDH mutations result in a substitution of arginine (R) for histidine (H) at codon 132 or R132H.⁷ Most WHO grade II and III tumors will harbor IDH mutations.⁶

While the prognostic difference between IDH-mutant and IDH wild-type gliomas has been established, whether this is also true in comparing histological grades II and III is under investigation.⁸,⁹ In this revised system, the categories of oligoastrocytoma and glioblastoma with oligodendroglioma component (GBMO) are no longer included, as molecularly they are like astrocytoma or oligodendroglioma and it is recommended that they should be assigned to either group, whenever possible.¹⁰ The inclusion of IDH mutation is critical in both understanding the molecular characteristics and natural history of oligodendroglioma and anaplastic tumors. This alteration is also informative in the collective understanding of clinical manifestations of disease, providing insight into management of tumor and associated neurologic symptoms such as seizure.

Clinical features

Although considered malignant primary brain tumors, there may be heterogeneity in how aggressive these tumors behave.³ Symptoms and signs of either oligodendroglioma or anaplastic oligodendroglioma are largely contingent upon factors including: lesion size and location (supra- vs infratentorial), as well as the rate of growth. Consistent with other primary brain tumors in the adult population, there is a predilection for the supratentorial compartment with oligodendrogliomas. Most tumors are found in the cortex, with preference for the white matter, primarily frontal, followed by temporal, parietal, and occipital lobes, less frequently.¹¹ Infratentorial, spinal, and leptomeningeal spread have been reported to occur, however, rarely.¹² Although no longer considered in the revised 2016 WHO Classification of Brain Tumors, a gliomatosis or multifocal pattern may be seen; however, this has been more likely associated with tumors of astrocytic origin.

Unlike IDH wild-type gliomas, oligodendroglial tumors are indolent with respect to growth trajectory and behavior, thus accounting for associated clinical manifestations. In comparison to high-grade tumors, in which symptoms may progress over a period of days or weeks, the pattern observed in oligodendroglioma is over the course of months to years. Acute development of focal deficit, such as in association with ischemic or hemorrhagic stroke, is thought to be rare. Features of elevated intracranial pressure typically observed with high-grade glioma, such as nausea, syncope, or papilledema, are also less likely to occur but have been reported in single case reports.¹³ Given the infiltrative nature of growth, these tumors may be identified during workup for other neurologic symptoms.

The most common presenting feature of oligodendroglioma is seizure, which is characteristic of low-grade glioma in general, occurring in up to 90% of patients.¹⁴ This is a cause of tumor-related morbidity and reduction in quality of life. Seizures in patients with underlying tumors are localization-related or symptomatic, with semiology being determined by the involved cortical structure.¹⁵ Like nontumor-related epilepsy, seizures may be focal in onset with evolution into a generalized event, or generalized from initial onset. Status epilepticus occurs in at least 10% of patients with glioma.¹⁶ As they are a warning sign for the presence of pathology, initial presentation with seizure represents a positive prognostic factor.¹⁷ Other factors may contribute to epileptogenesis in addition to tumor and location, such as its genetic profile and indolent growth pattern.¹⁷,¹⁸ It is likely due to these and other underlying factors, which make treatment of tumor-related seizures challenging. Pharmacoresistant seizures have been associated with temporal or insular cortex location or partial-onset semiology.¹⁹ Factors which may predict postoperative seizure control include: presence of generalized seizures, surgery < 1 year after presentation, gross total resection, and preoperative seizure control with anti-seizure medication.²⁰

Mutant IDH and seizure

One proposed mechanism for increased seizure activity is the presence of IDH mutations, which results in the formation of 2-hydroxyglutarate (2-HG), a substrate with structural characteristics like glutamate, an excitatory neurotransmitter. The presence of 2-HG is thought to activate N-methyl-d-aspartate (NMDA) receptors, thus contributing to epileptogenesis.¹⁶ In an autosomal recessive disorder, L-2-hydroxyglutarate-acidurea (2HGA), 2-HG levels are elevated in serum, urine, and CSF with clinical manifestations including refractory seizures.²¹

The IDH mutations have been demonstrated to be associated with better survival, frontal lobe location, and seizures as initial presentation.²² An alternate explanation for high likelihood of seizure in this population is the role of IDH in increasing glutamate concentrations in glioma cells, primarily in the extracellular space. This has been correlated with higher seizure frequency and tumor progression.¹⁶ Recent work by Chen et al. has proposed an alternative mechanism for the effect of IDH and 2-HG, as not being limited to the tumor cells, but have an impact on cortical neurons.²³ The release of 2-HG by glioma cells leads to direct activation of neuronal NMDA receptors with downstream effects resulting in excitatory postsynaptic potentials and increased likelihood of action potentials.²³ There are ongoing clinical trials investigating the benefit of IDH inhibitors in the treatment of glioma; the impact of these agents on seizure control will also warrant additional investigation.

Prognosis and survival outcomes

Despite the indolent growth and behavior of oligodendroglial tumors, characterized by slow changes radiographically and clinically, it is expected that most patients will ultimately deteriorate. A 5-year survival for adult [age > 40 according to SEER (surveillance, epidemiology and end results) data] oligodendroglioma and anaplastic oligodendroglioma are 74.9% and 51.1%, respectively.¹ Prior to current understanding of the molecular features of oligodendroglioma, clinical criteria were established to predict prognosis and expected behavior of disease including age, tumor size and extent, histology, and the presence or absence of neurologic deficit.²⁰,²⁴ From these factors, a prognostic aggregate score of 0–5 was calculated with each factor being worth 1 point with high-risk being classified as scores ≥ 3 and low-risk as ≤ 2. The following were considered high-risk features: age ≥ 40, tumor diameter ≥ 6 cm, tumor crossing midline, astrocytoma histology, and the presence of neurologic deficit.²⁰

RTOG 9802

In the RTOG 9802 trial, overall survival (OS) was evaluated in 251 patients with supratentorial WHO grade II gliomas who were randomized to either postoperative radiation or postoperative radiation followed by a chemotherapy regimen [procarbazine, lomustine (also called CCNU), and vincristine—PCV], for those who met high-risk criteria: age ≥ 40 or age 18–39 with either biopsy or subtotal resection. As this investigation preceded the revised CNS tumor classification scheme, histologies in this cohort included oligodendroglioma, astrocytoma, and mixed oligoastrocytoma. The recently published data were collected with median follow-up time of 11.9 years, in which the survival benefit was most apparent in the combined radiation and chemotherapy treatment cohort with median survival (OS) of 13.3 years vs 7.8 years.²⁵ Median progression-free survival (PFS) was also prolonged in the same cohort of 10.4 vs 4.0 years.²⁵ Within treatment groups, the survival benefit was enhanced in patients with oligodendroglial histology (pure or mixed) in comparison to astrocytoma (Figs. 2 and 3).

Fig. 2 Overall survival, according to treatment group.

Fig. 3 Progression-free survival, according to treatment group.

EORTC 26951 and RTOG 9402

In EORTC 26951, patients were randomized to either radiation alone or radiation and adjuvant PCV.⁷ Of 368 patients, 80 had 1p/19q co-deleted tumors; within this subset, PFS was prolonged in the radiation and chemotherapy group with a median of 157 months, as compared to 50 months with radiation alone.⁷ In this cohort, OS was also prolonged, having yet to be achieved in the co-deleted group treated with radiation and chemotherapy vs radiation alone, in which median OS was 112 months.

In RTOG 9402, 291 patients with anaplastic oligodendroglioma or anaplastic oligoastrocytoma were randomly assigned to either PCV followed by radiation (n = 148) or radiation alone without chemotherapy (n = 143). There was no difference in median survival between treatment groups: 4.6 years for PCV and radiation as compared to 4.7 years for radiation alone. However, between treatment groups, patients with co-deleted tumors were found to have longer OS than the retained population (14.7 years vs 2.6 years). This effect was magnified when comparing outcomes of the treatment regimens. Among those with co-deleted tumors, the combination of PCV and radiation increased median OS, 14.7 vs 7.3 years. There was no difference in OS in patients with retained tumors when comparing PCV and radiation vs radiation treatment alone. The result of these two cooperative group studies was the opening of a new trial in 2016, in which radiation with adjuvant chemotherapy (PCV) was compared to radiation with concurrent and subsequent adjuvant temozolomide in patients with anaplastic oligodendroglioma.

References

1 Ostrom Q.T., Gittleman H., Liao P., et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2010–2014. Neuro Oncol. 2017;19(suppl_5):v1–v88.

2 Shin J.Y., Yoon J.K., Diaz A.Z. Racial disparities in anaplastic oligodendroglioma: an analysis on 1643 patients. J Clin Neurosci. 2017;37:34–39.

3 Ostrom Q.T., Gittleman H., Stetson L., Virk S., Barnholtz-Sloan J.S. Epidemiology of intracranial gliomas. Prog Neurol Surg. 2018;30:1–11.

4 Sadetzki S., Chetrit A., Freedman L., Stovall M., Modan B., Novikov I. Long-term follow-up for brain tumor development after childhood exposure to ionizing radiation for tinea capitis. Radiat Res. 2005;163(4):424–432 Erratum in: Radiat Res. 2005; 164(2):234.

5 McCarthy B.J., Rankin K.M., Aldape K., et al. Risk factors for oligodendroglial tumors: a pooled international study. Neuro Oncol. 2011;13(2):242–250.

6 Louis D.N., Perry A., Reifenberger G., et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131(6):803–820.

7 van den Bent M.J., Brandes A.A., Taphoorn M.J., et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J Clin Oncol. 2013;31(3):344–350.

8 Olar A., Wani K.M., Alfaro-Munoz K.D., et al. IDH mutation status and role of WHO grade and mitotic index in overall survival in grade II-III diffuse gliomas. Acta Neuropathol. 2015;129(4):585–596.

9 Killela P.J., Pirozzi C.J., Healy P., et al. Mutations in IDH1, IDH2, and in the TERT promoter define clinically distinct subgroups of adult malignant gliomas. Oncotarget. 2014;5(6):1515–1525.

10 Rogers T.W., Toor G., Drummond K., et al. The 2016 revision of the WHO classification of central nervous system tumours: retrospective application to a cohort of diffuse gliomas. J Neurooncol. 2018;137:181–189.

11 Mulligan L., Ryan E., O'Brien M., et al. Genetic features of oligodendrogliomas and presence of seizures. The relationship of seizures and genetics in LGOs. Clin Neuropathol. 2014;33(4):292–298.

12 Strickland B.A., Cachia D., Jalali A., et al. Spinal anaplastic oligodendroglioma with oligodendrogliomatosis: molecular markers and management: case report. Neurosurgery. 2016;78(3):E466–E473.

13 Roncone D.P. Papilloedema secondary to oligodendroglioma. Clin Exp Optom. 2016;99(6):507–517.

14 van Breemen M.S., Wilms E.B., Vecht C.J. Epilepsy in patients with brain tumours: epidemiology, mechanisms, and management. Lancet Neurol. 2007;6(5):421–430.

15 Rosati A., Tomassini A., Pollo B., et al. Epilepsy in cerebral glioma: timing of appearance and histological correlations. J Neurooncol. 2009;93(3):395–400.

16 Kerkhof M., Vecht C.J. Seizure characteristics and prognostic factors of gliomas. Epilepsia. 2013;54(Suppl 9):12–17.

17 Vecht C.J., Kerkhof M., Duran-Pena A. Seizure prognosis in brain tumors: new insights and evidence-based management. Oncologist. 2014;19(7):751–759.

18 Beaumont A., Whittle I.R. The pathogenesis of tumour associated epilepsy. Acta Neurochir. 2000;142(1):1–15 Review.

19 Rudà R., Bello L., Duffau H., Soffietti R. Seizures in low-grade gliomas: natural history, pathogenesis, and outcome after treatments. Neuro Oncol. 2012;14(Suppl 4):iv55–64.

20 Pignatti F., van den Bent M., Curran D., et al. Prognostic factors for survival in adult patients with cerebral low-grade glioma. J Clin Oncol. 2002;20(8):2076–2084.

21 Craigen W.J., Jakobs C., Sekul E.A., et al. D-2-hydroxyglutaric aciduria in neonate with seizures and CNS dysfunction. Pediatr Neurol. 1994;10(1):49–53.

22 Sanson M., Marie Y., Paris S., et al. Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. J Clin Oncol. 2009;27(25):4150–4154.

23 Chen H., Judkins J., Thomas C., et al. Mutant IDH1 and seizures in patients with glioma. Neurology. 2017;88(19):1805–1813.

24 Gorlia T., Wu W., Wang M., et al. New validated prognostic models and prognostic calculators in patients with low-grade gliomas diagnosed by central pathology review: a pooled analysis of EORTC/RTOG/NCCTG phase III clinical trials. Neuro Oncol. 2013;15(11):1568–1579.

25 Buckner J.C., Shaw E.G., Pugh S.L., et al. Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N Engl J Med. 2016;374(14):1344–1355.

Chapter 2

Clinical presentation of spinal oligodendrogliomas

Lily C. Pham*; David Cachia†; Akash J. Patel*; Jacob J. Mandel*    * Department of Neurology and Neurosurgery, Baylor College of Medicine, Houston, TX, United States

† Department of Neurosurgery, Medical University of South Carolina, Charleston, SC, United States

Abstract

Initially defined in 1926 by Bailey and Cushing, oligodendrogliomas are exceedingly rare gliomas arising from oligodendrocytes. Spinal oligodendrogliomas are even rarer still representing 1.59% of all oligodendrogliomas with only 60 cases reported in the literature. There is a mild predilection toward males (1.33 times more likely to occur in males than in females), and these tumors are 2.5 times more prevalent in Caucasians compared to African-American populations. Clinical presentation of spinal oligodendroglioma is often dependent on the location of the tumor and age of presentation. The majority of spinal oligodendrogliomas arise in the thoracic region (36.3%), followed by the lumbar (18.2%), cervical (18%), thoracolumbar (12.1%), cervicothoracic (9.1%) regions, and the whole spinal cord (8%). The average size of a primary oligodendroglioma is 3.5 (± 1.8) vertebral levels. The most common presenting symptoms are weakness/paresis (69.5%), pain—including acute back pain, neck pain, and sciatic pain (50%), and sensory changes—including paresthesia and numbness (45%). In addition to the location of the tumor in the spinal cord, exhibiting signs also depend on whether the tumor is intramedullary, intradural-extramedullary, or extramedullary. The typical age of presentation is between 30 and 40 years, with the majority of patients presenting in adulthood. Spinal oligodendrogliomas in the pediatric population tend to present as scoliosis, regression of motor developmental milestones, gait disturbance, and sensory deficits. Patients presenting with a history of symptoms referable to the spinal cord and/or a concerning neurological exam should undergo prompt imaging with an MRI (magnetic resonance imaging) of the spine with and without contrast.

Keywords

Oligodendroglioma; Spinal cord; Tumor

Introduction

Initially defined in 1926 by Bailey and Cushing, oligodendrogliomas are exceedingly rare gliomas arising from oligodendrocytes.¹ Based on the most recent report from the Central Brain Tumor Registry of the United States 2010–2014, oligodendrogliomas make up 1.4% of all primary brain tumors, and represents 4.7% of all malignant primary brain tumors and other central nervous system tumors.² Within the already rare classification of oligodendrogliomas, spinal oligodendrogliomas are even rarer still representing 1.59% of all oligodendrogliomas. Primary intramedullary oligodendrogliomas represented 0.8%–4.7% of spinal cord and filum terminale tumors.³ Historically, the majority of spinal oligodendrogliomas arise in the thoracic region (36.3%), followed by the lumbar (18.2%), cervical (18%), thoracolumbar (12.1%), cervicothoracic (9.1%) regions, and the whole spinal cord (8%).⁴,⁵ The average size of a primary oligodendroglioma is 3.5 (± 1.8) vertebral levels.⁵

The first description of a spinal oligodendroglioma was in 1931 by Kernohan et al.⁶ Since then, approximately 60 reported cases of spinal oligodendrogliomas have been documented in the literature. The typical age of presentation is between 30 and 40 years of age, with the majority of patients presenting in adulthood.³ There is a mild predilection toward males (1.33 times more likely to occur in males than in females), and these tumors are 2.5 times more prevalent in Caucasians than in African-American populations.² Rarely, spinal oligodendroglioma are also diagnosed in children. Since 1942, there have been five reported cases of spinal oligodendroglioma in children.⁷ Usually, cases in the pediatric population have a poorer prognosis and a shorter duration of symptoms prior to presentation.⁷,⁸

Spinal oligodendrogliomas are often suspected based on history, clinical symptoms, physical examination, and subsequent imaging, then diagnosed following surgery based on histopathology. Only recently have cases with histopathologic diagnosis of oligodendrogliomas undergone tissue analysis and molecular characterization through gene deletions and by DNA analysis. Officially, oligodendrogliomas are now identified by an IDH (isocitrate dehydrogenase) gene family mutation and 1p/19q chromosomal co-deletion according to the 2016 World Health Organization (WHO) Classification of Tumors of the Nervous System.⁹ Because of this fact, it is unclear how many of the 60 previously reported cases in the literature would still be classified as oligodendrogliomas based on current WHO diagnostic criteria.⁹

Clinical presentation

Clinical presentation of spinal oligodendroglioma is dependent on the age of presentation and the location of the tumor. The duration of symptoms reported prior to presentation has been variable, spanning from months to years. In the reported cases in the literature (Table 1), the most common presenting symptoms are weakness/paresis (69.5%), pain—including acute back pain, neck pain, and sciatic pain (50%), and sensory changes—including paresthesia and numbness (45%). While early presenting symptoms are related to the location of the tumor in the cord (cervical vs thoracic vs lumbar vs whole cord), symptomatology also differs depending on whether the tumor is intramedullary, intradural-extramedullary, or extramedullary (Fig. 1). Intramedullary tumors rarely produce pain and often occur with sensory dysesthesia and numbness with early loss of sphincter control, whereas pain, usually back or neck pain, is the presenting symptoms of extramedullary tumor and is only associated with loss of sphincter control if it is found in the lumbosacral region.⁵⁰,⁵¹ In addition, primary intramedullary oligodendroglioma is more likely to be associated with meningeal spread and intracranial hypertension leading to fluctuating symptoms due to spontaneous hemorrhage.⁴¹ Spinal oligodendrogliomas in the pediatric population tend to present as scoliosis, regression of motor developmental milestones, gait disturbance, and sensory deficits.³,⁵,⁷,³⁰,³¹,³⁷–⁴¹,⁴³,⁴⁶

Table 1

XR, X-ray; MRI, magnetic resonance imaging; TMZ, temozolomide; RT, radiation treatment; VPS, ventriculoperitoneal shunt.

Fig. 1 Historic classification of spine tumors based on myelography: (A) normal, (B) extradural extramedullary, (C) intradural extramedullary, and (D) intradural intramedullary. Adapted with permission from Mechtler LL, Nandigam K. Spinal cord tumors: new views and future directions. Neurol Clin., 2013;31(1):241–268.

Based on the available information from the 60 case reports in the literature, the distribution of spinal oligodendroglioma is: 25% cervical, 28.3% thoracic, 13.3% thoracolumbar, 13.3% lumbosacral, and 5% whole cord, with 15.7% unaccounted for due to poor documentation (Tables 1 and 2). In all, 66.6% of these cases were intramedullary tumors, 10% were intradural extramedullary, and 3.3% had both intramedullary and extramedullary components. The other 20% did not report location of the tumor in relation to the spinal cord and dura. These numbers are roughly similar to historically reported statistics in previous large case reports when taking into account the small number of overall cases in literature.³,⁸,⁵⁰,⁵¹

Table 2

RT, radiation treatment; TMZ, temozolomide; IDH, isocitrate dehydrogenase; WT, wild type; MGMT, O⁶-methylguanine–DNA methyltransferase.

Details regarding outcome is limited depending on the length of follow-up at the time of the case report. However, based on the available data, 13.3% showed progression/recurrence, 31.6% of patients had died by the time of follow-up, and 33.3% had no progression or recurrence at the time of follow-up. The earliest documented death following initial presentation was within 6 days, and the longest span of time without progression or recurrence was 31 years.³,¹⁶ Of note, the survival rate of spinal oligodendrogliomas appears much more dismal in pediatric cases compared to adult cases. Most cases of primary oligodendroglioma in children result in death within 3–23 months after initial presentation, with the longest survival time being 7 years.⁷ All of the reported cases without progression or recurrence were adults. Time to disease progression or death in the adult population ranges between months and years, without a clear pattern. Due to the infiltrative nature of spinal oligodendrogliomas, only a total of 6 cases out of 60 received a gross total resection.³,¹⁶,⁴³,⁴⁴,⁵¹ There were no reported deaths in cases that received gross total resections. Most were either symptomatically stable or had oscillating symptoms without significant progression following surgery. Due to the rarity of the diagnosis of spinal oligodendrogliomas, there have been no randomized prospective studies to guide treatment. Recent studies of intracranial oligodendrogliomas have shown the benefit of using radiation and chemotherapy [procarbazine, CCNU, and vincristine (PCV); temozolomide] following diagnosis in patients with a 1p/19q co-deletion.²⁴,⁵² Yet despite similar histopathologic appearance it remains unclear whether spinal oligodendrogliomas are analogous molecularly to intracranial oligodendrogliomas. Treatment with radiation therapy and/or chemotherapy following surgical resection is therefore of unknown benefit, but should be considered in all patients unable to undergo a gross total resection.

Imaging

Magnetic resonance imaging (MRI) of the spine is the recommend diagnostic study for patients suspected of a spinal cord tumor. Spinal MRIs are capable of offering outstanding definition of the spinal cord and adjacent structures. The MRI is used to determine the exact location of the tumor in the spinal cord, whether the lesion is intramedullary, intradural-extramedullary, or extramedullary, and if it enhances following the injection of gadolinium contrast.⁵³

Oligodendrogliomas typically appear on MRI as isointense to the spinal cord on T1-weighted images, hyperintense on T2-weighted and FLAIR images (Fig. 2), and demonstrate heterogeneous contrast enhancement.⁵⁴ Calcifications and hemorrhages may also be noted on imaging.⁴³ Syringomyelia (a process where a cyst or cavity develops within the spinal cord) has also been appreciated in several cases.⁵,¹⁷,²³,⁴⁸

Fig. 2 Hyperintense intradural extramedullary mass ( red arrow ) on T2 weighted images with cystic components (A). Post-op MRI of the lumbosacral region revealing no residual tumor (B). Adapted with permission from Gürkanlar D, et al., Primary spinal cord oligodendroglioma. Case illustration. Neurocirugia (Astur). 2006;17(6):542–543.

Alternatively, myelography or standard X-ray (XR) of the spine can often be used to diagnose spinal cord tumors. Myelography is an examination where a radiocontrast is injected into the cervical or lumbar spine followed by X-ray or computed tomography evaluation. Although it has largely fallen out of favor in lieu of the more detailed MRI, CT myelography can be performed in patients with contraindications to MRI such as a pacemaker. As with myelography, earlier case reports of spinal oligodendrogliomas utilized XR imaging of the affected spinal region. The most notable XR findings of spinal oligodendroglioma are scattered calcifications, which can be found in 28%–40% of the time within the tumor body.³,⁸,¹² However, XR imaging alone is no longer favored as the level of detail of the spinal cord and related structures on XR pale in comparison to that of a MRI.

Other studies

Pathology

Macroscopically, the classic gross appearance of spinal oligodendroglioma is described as a translucent, gelatinous solid tumor that appears to be gray, pink, and yellow in color.⁴³,⁵¹ These tumors are also easily friable and are often hemorrhagic on gross resection due to their close association with spinal vasculature.³,⁴³ The firm outward appearance is due to the high cellularity of oligodendroglial tumors, and the densely packed small cells at a microscopic level.⁵⁵

Microscopically, the key features of spinal oligodendroglioma are similar to oligodendrogliomas found in the brain. These features were originally described by Bailey and Bucy in 1929 as uniform polyhedral cells with honeycomb appearance, inside the cells are perinuclear clear halos surrounding a round and dark-staining/hyperchromatic nucleus, resembling a fried egg.⁵¹,⁵⁵ Further, these cells have multifocal calcifications without any associated necrosis or significant presence of glial fibrils.³¹,⁴³,⁵¹

Lumbar puncture

Prior to the advent of MRIs many patients presenting with oligodendrogliomas received lumbar punctures. While there are no pathognomonic CSF (cerebrospinal fluid) findings related to oligodendrogliomas, it has been noted that CSF protein levels are pathologically elevated. A study examining these levels found that the mean value of CSF protein was 1397 mg% (50–5000), with further elevation in lumbar tumors at 2850 mg%.³ With improvement in imaging capabilities, lumbar punctures are no longer indicated as part of the initial workup for patients with spinal oligodendrogliomas.

Molecular signatures

Based on the latest WHO classification published in 2016, oligodendrogliomas are now identified by IDH gene family mutation and 1p/19q co-deletion.⁹,⁵⁵ The IDH gene mutations have been observed in patients with prolonged survival and give rise to changes in cellular metabolism affecting chromatin remodeling and transcription. The presence of the IDH gene mutation is a predictive factor in survival time, especially when considered in conjunction with a 1p/19q co-deletion.⁵⁶

1p/19q co-deletion in oligodendroglial tumors was originally described in 1994 by Reifenberger et al.⁵⁷ Since then subsequent studies have shown that the presence of this translocation between 1p and 19q arms is associated with increased chemotherapy sensitivity, and ultimately improved outcome.²⁴,⁵⁸ In the spinal oligodendroglioma literature, only five reported cases have utilized molecular signatures in addition to the histopathological diagnosis.⁴,¹¹–¹³ This low number is due to the rarity of the tumor, difficulty of obtaining substantial tissue due to eloquent location of the tumor, and the availability of genetic testing at the time of the report. As many mixed gliomas also exhibit a 1p/19q co-deletion and are IDH mutants, it is possible that there will now be an increase in the diagnosis of spinal oligodendrogliomas, simply based on molecular signatures.⁵⁵ Alternatively, it remains unclear how many cases of spinal oligodendrogliomas previously reported in the literature would still be classified as oligodendrogliomas because of their potential absence of IDH mutation or 1p/19q co-deletion.

Unlike intracranial gliomas, which have been reported to have an IDH mutation 75% of the time, the rate of IDH mutations in infratentorial and spinal gliomas has reported to be much lower.⁵⁹,⁶⁰ A recent study of 44 patients with infratentorial or spinal cord grade 2 and 3 diffuse gliomas found only 7% were positive for IDH1 mutation, all of the cases with the mutation localizing to the brainstem.⁶⁰ None of the nine spinal cord gliomas (three diffuse astrocytomas, two WHO grade 2 oligodendrogliomas, and four anaplastic astrocytomas) were found to be IDH1 mutated by immunohistochemistry.⁶⁰ Therefore, it remains unclear how many of the cases previously reported in the literature would still be classified as oligodendrogliomas, if the diagnosis is dependent on the tumors having a molecular signature of a 1p/19q co-deletion and IDH mutation, in addition to oligodendroglial histopathology.

Due to the rarity of diagnosis and lack of molecular testing performed in the past for spinal oligodendrogliomas, an international registry and further molecular research is needed to help elucidate the nature of spinal oligodendrogliomas.

Conclusion

Spinal oligodendrogliomas are extremely rare, with only 60 reported cases. Clinical presentation of spinal oligodendroglioma is often dependent on the age of presentation and the location of the tumor, with the majority of spinal oligodendrogliomas arising in the thoracic region. The most common presenting symptoms are weakness/paresis, pain, and sensory changes. In addition to the location of the tumor in the spinal cord, presenting signs also depend on whether the tumor is intramedullary, intradural-extramedullary, or extramedullary. Patients presenting with a history of symptoms referable to the spinal cord and/or a concerning neurological examination should undergo prompt imaging with an MRI of the spine with and without contrast.

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