Pathology of Oligodendrogliomas 

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Oligodendrogliomas are gliomas that arise in the cerebral hemispheres of young and middle-aged adults. The tumors have a propensity to arise in the gray matter or superficial white matter of the frontal lobes, but oligodendrogliomas may also arise in other regions of the central nervous system. These tumors have recently been demonstrated to have a frequent occurrence of loss of heterozygosity for the short arm of chromosome 1 and the long arm of chromosome 19 that, when present, are associated with a good chemotherapeutic responsiveness.

These tumors are designated by the World Health Organization (WHO) as grade II tumors ^[1] ; however, oligodendrogliomas are prone to progress to WHO grade III and cause death. Occasionally a tumor may be encountered with an astrocytic component. Such cases, sharing both oligodendroglial and astrocytic features, are called oligoastrocytomas (see the following image).

Oligodendrogliomas represent approximately 5% of all gliomas, with an incidence of approximately 0.28 per 100,000. The Central Brain Tumor Registry of the United States data reflect a preponderance in white individuals and Hispanics relative to black individuals with a 3-to-1 ratio. ^[2] The tumor also exhibits a male-to-female ratio that ranges from 4:3 to 2:1. ^[3] The most frequently affected age groups are individuals in the fourth to fifth decades. ^[2]

Little is known of the cause(s) of oligodendrogliomas; no pattern of inheritance or familial risk for developing these tumors is known.

Oligodendrogliomas preferentially arise in the cerebral hemispheres of young and middle-aged adults. Histologically, the tumors predominately affect the gray matter or superficial white matter of the frontal lobes. Although these tumors may also arise in other regions of the brain and spinal cord, the latter is rare.

Despite the variable prediagnostic time periods noted in some young adults with oligodendroglioma, the postoperative survival rates seem remarkably uniform, exhibiting survival rates of 75% at a 5 years, 46% at 10-years, and 17% at 15 years in one large study. ^[4] These rates compare favorably with the 81% 2-year survival rates from the Surveillance, Epidemiology, and End Results (SEER) data for all ages. ^[5]

More recent data seem to indicate better survivals, with a 10-year survival rate exceeding 50% for patients with either the well-differentiated or the anaplastic oligodendrogliomas. ^[6] However, age is a significant variable with respect to survival. Patients older than 65 years exhibit a significantly shorter survival rate than younger patients. ^[2] In addition to age, clinical features that are independent variables associated with survival include postoperative Karnofsky performance score, extent of surgical resection, and radiation therapy. ^{[4, 7]}

There are no specific laboratory tests that are helpful in making a diagnosis of oligodendroglioma.

Oligodendrogliomas at presentation are well-delineated, cortically based tumors that, less commonly, may have surrounding edema and may even erode the inner table of the skull. The computed tomography (CT) scan density of the neoplasms at presentation can be either low and attenuated or mixed, isodense, and hyperdense.

CT imaging is preferred over magnetic resonance imaging (MRI), as the MRI features are much more variable. The varieties of imaging include an isointense to hypointense mass on T1-weighted images (T1WI) and a somewhat hyperintense mass on T2-weighted images (T2WI); amorphous areas with dots of T1 hypointensity presumably related to cystic change; and a slightly hyperintense appearance on T2, which may progress to that of a honeycomb appearance (or the cysts may coalesce to form larger nonuniform cysts associated with a solid component resembling a mural nodule). ^[1]

Grossly, the oligodendroglioma tumors are grayish pink, soft, but often well defined. On sectioning, oligodendrogliomas are seen to arise in the superficial aspects of the cerebral hemispheres, occasionally extending to the subarachnoid space as a creamy white mass resembling toothpaste to the operative surgeon. Occasionally, the tumor may arise in the deeper gray matter. The biological reason for the preference of the tumor to arise in the frontal lobe is unknown, but it is not restricted to this lobe.

Bilaterality is associated with crossing of the corpus callosum, and a tendency to spread by subarachnoid or subpial infiltration, in contrast to astrocytomas, in which the astrocytic tumor cells follow the parenchymal white matter tracts. Mucinous change is occasionally noted and may be so extensive as to confer a gelatinous appearance to the tumor.

The oligodendroglioma derives its name from its close histologic resemblance to the benign oligodendroglial cell, with round, central nuclei and oval, water-clear cytoplasm (see the image below), which has been likened to the fried egg with its yolk.

The tumor cells often form dense, hypercellular masses in the subcortical white matter, and they also have a propensity to aggregate around blood vessels and neurons (“satellitosis”) in regions of cortical infiltration (see the following image).

Cortical infiltration may be associated with microcalcifications of blood vessels and neurons, which can sometimes be appreciated radiographically. It should be noted that astrocytomas may occasionally exhibit satellitosis. A concomitant loss of 1p and 19q is rare in cortex infiltrating oligodendrogliomas without satellitosis. ^[4]

Oligodendrogliomas are often associated with delicate arcuate vessels; however, this feature can also be encountered in ischemic cortex and may represent a reaction to tumoral ischemia rather than a nascent feature of the tumor itself. Another histologic feature commonly encountered is the formation of minigemistocytes, characterized by tumor cells with small eccentric droplets of eosinophilic cytoplasm about the size of the nucleus. These glial fibrillary acidic protein (GFAP)-immunoreactive cells have no prognostic significance. Rarely, the tumors may exhibit a focal granular eosinophilic change in the cytoplasm of some cells; such a change also has no diagnostic or prognostic utility.

Fresh cytologic smear preparations of oligodendrogliomas exhibit delicate vessels with small, round nuclei clinging to the vessels. The tumor cells also lack significant cytologic processes.

Occasionally, a tumor may be composed of a mixed population of round nuclei and elongated nuclei having fibrillar cytoplasm and exhibiting satellitosis, or it may demonstrate geographically separate and distinct regions of oligodendroglial and astrocytic (oval to elongated nuclei) morphology (see the following image). Such tumors are best classified as mixed oligoastrocytomas.

There are no specific markers for oligodendrogliomas that can be relied upon to make a diagnosis. However, the tumors are immunoreactive for S100 protein and microtubule-associated protein 2 (MAP2). The transcription factor Olig2, although expressed in oligodendrogliomas, remains nonspecific as an oligodendroglial marker. Recently, alpha-internexin ^[8] and nogo-A ^[9] have been described as markers that appear to correlate with 1p/19 loss status, a marker of good therapeutic response and found in 80% of oligodendroglial tumors.

Approximately 80% of oligodendrogliomas exhibit allelic losses on the short arm of chromosome 1 and the long arm of 19q. These markers have been demonstrated to be of prognostic and theragnostic benefit in that tumors with loss of the full length of the short arm of chromosome 1 (ie, centromeric to telomeric loss) and long arm of chromosome 19 have been shown to be more responsive to chemotherapy and radiotherapy. The allelic losses (co-deletion events) are presumed to occur as somatic events during mitosis in tumors with unbalanced t(1;19)(q10;p10) translocation. ^[10]

Clues to the pathogenetic mechanisms driving oligodendroglioma on 1p and 19q have been provided by an exomic sequencing study of 7 such tumors with these allelic losses. The study revealed 6 cases to exhibit somatic mutations in the CIC gene (homolog of the Drosophila gene capicua) on 19q and 2 tumors to exhibit somatic mutations in the the FUBP1 gene (encoding far-upstream element [FUSE] binding protein) on 1p. ^[11] The frequent losses affecting the CIC gene were subsequently supported by another study. ^[12]

Recently, mutations involving a specific exonal location in the genes isocitrate dehydrogenase 1 and 2 (IDH1, IDH2) have been implicated in the early pathogenesis of all infiltrative gliomas, including oligodendrogliomas and astrocytomas. Mutations in the promoter region of the TERT gene have also been described in oligodendrogliomas, suggesting that a combined mutational approach to these genes may also help in the diagnosis of these tumors. ^[13]

Oligodendrogliomas are largely well circumscribed, but these tumors may occasionally be associated with local multilobar invasion/infiltration to present as gliomatosis cerebri. Distant spread via the cerebrospinal fluid (CSF) is unusual in most gliomas.

Oligodendrogliomas that are associated with a poorer survival include those tumors that exhibit necrosis, significant mitotic activity, and vascular proliferation (see the image below).

These tumors, while maintaining their round, uniform nuclear appearance, will very frequently exhibit scarlet cytoplasm (as shown in the following image), in contrast to the water-clear cytoplasm of the lower grade tumor. The clinical course of these more aggressive oligodendrogliomas is well recognized, and the tumors have been designated by the World Health Organization (WHO) as grade III. ^[1]

The grading of mixed oligoastrocytomas is debatable, ^[14] but most pathologists rely upon the histologic features of the predominant element. Chromosomal studies for deletion of 1p and 19q may also be useful as such tumors frequently exhibit a loss of either 1p or 19q but not both. Therapeutic responsiveness seems to be dependent on the loss of the 1p36 locus. ^[15]

A controversy over the grade of oligoastrocytomas that exhibit vascular proliferation and necrosis has also recently arisen, with issues centered on whether the tumors should be designated as “anaplastic oligoastrocytomas grade IV” or “glioblastomas with oligodendroglial elements.” ^[16] The WHO has chosen the latter designation (glioblastomas with oligodendroglial elements) but noted that that these tumors may have a better clinical prognosis and therapeutic responsiveness than otherwise typical glioblastomas. ^{[1, 10]}

Clear Cell Ependymoma

Extraventricular Neurocytoma

Pilocytic Astrocytoma

Small Cell Glioblastoma

Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, eds. WHO Classification of Tumours of the Central Nervous System. Lyon, France: IARC Press; 2007.

Central Brain Tumor Registry of the United States. Supplement Report: Primary Brain Tumors in the United States, 2004. 2008.

Mork, S. J., Lindegaard, K. F., Halvorsen, T. B., et al. Oligodendroglioma: incidence and biological behavior in a defined population. Journal of Neurosurgery. Dec. 63:881-9. [Medline].

Giannini C, Scheithauer BW, Weaver AL, et al. Oligodendrogliomas: reproducibility and prognostic value of histologic diagnosis and grading. J Neuropathol Exp Neurol. 2001 Mar. 60(3):248-62. [Medline].

Davis FG, Freels S, Grutsch J, Barlas S, Brem S. Survival rates in patients with primary malignant brain tumors stratified by patient age and tumor histological type: an analysis based on Surveillance, Epidemiology, and End Results (SEER) data, 1973-1991. J Neurosurg. 1998 Jan. 88(1):1-10. [Medline].

McLendon RE, Herndon JE 2nd, West B, et al. Survival analysis of presumptive prognostic markers among oligodendrogliomas. Cancer. 2005 Oct 15. 104(8):1693-9. [Medline].

Giannini C, Burger PC, Berkey BA, et al. Anaplastic oligodendroglial tumors: refining the correlation among histopathology, 1p 19q deletion and clinical outcome in Intergroup Radiation Therapy Oncology Group Trial 9402. Brain Pathol. 2008 Jul. 18(3):360-9. [Medline].

Eigenbrod S, Roeber S, Thon N, Giese A, Krieger A, Grasbon-Frodl E. a-Internexin in the diagnosis of oligodendroglial tumors and association with 1p/19q status. J Neuropathol Exp Neurol. 2011 Nov. 70(11):970-8. [Medline].

Marucci G, Di Oto E, Farnedi A, Panzacchi R, Ligorio C, Foschini MP. Nogo-A: a useful marker for the diagnosis of oligodendroglioma and for identifying 1p19q codeletion. Hum Pathol. 2012 Mar. 43(3):374-80. [Medline].

Jenkins RB, Blair H, Ballman KV, et al. A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. Cancer Res. 2006 Oct 15. 66(20):9852-61. [Medline].

Bettegowda C, Agrawal N, Jiao Y, Sausen M, Wood LD, Hruban RH, et al. Mutations in CIC and FUBP1 contribute to human oligodendroglioma. Science. 2011 Sep 9. 333(6048):1453-5. [Medline]. [Full Text].

Yip S, Butterfield YS, Morozova O, Chittaranjan S, Blough MD, An J, et al. Concurrent CIC mutations, IDH mutations, and 1p/19q loss distinguish oligodendrogliomas from other cancers. J Pathol. 2012 Jan. 226(1):7-16. [Medline]. [Full Text].

Killela PJ, Reitman ZJ, Jiao Y, Bettegowda C, Agrawal N, Diaz LA Jr. TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal. Proc Natl Acad Sci U S A. 2013 Apr 9. 110(15):6021-6. [Medline].

McLendon RE, Rasheed A, Wiltshire R, Herndon J. Correlation of 1p-19q-defects in human gliomas with the light microscopic appearance of oligodendroglioma. Mod Pathol. 2004 May. 17(5):604-5. [Medline]. [Full Text].

Pohl U, Cairncross JG, Louis DN. Homozygous deletions of the CDKN2C/p18INK4C gene on the short arm of chromosome 1 in anaplastic oligodendrogliomas. Brain Pathol. 1999 Oct. 9(4):639-43. [Medline].

Scheithauer BW, Fuller GN, VandenBerg SR. The 2007 WHO classification of tumors of the nervous system: controversies in surgical neuropathology. Brain Pathol. 2008 Jul. 18(3):307-16. [Medline].

Roger E McLendon, MD Professor, Director of Surgical Pathology, Chief of Neuropathology, Department of Pathology, Duke University Medical Center

Roger E McLendon, MD is a member of the following medical societies: American Association of Neuropathologists, College of American Pathologists, Society for Neuro-Oncology

Disclosure: Nothing to disclose.

Adekunle M Adesina, MD, PhD Professor, Medical Director, Section of Neuropathology, Director, Molecular Neuropathology Laboratory, Texas Children’s Hospital, Department of Pathology and Immunology, Baylor College of Medicine

Adekunle M Adesina, MD, PhD is a member of the following medical societies: American Association for the Advancement of Science, American Association of Neuropathologists, College of American Pathologists, United States and Canadian Academy of Pathology

Disclosure: Nothing to disclose.

The author would like to acknowledge Dr. Thomas J. Cummings, Dr. Linda Gray and Dr. Allan Friedman for many fruitful collaborative discussions on this topic. Dr. McLendon is supported by grants from NIH 5P50CA108786; NIH P50NS020023; the Pediatric Brain Tumor Foundation; and the Pediatric Brain Tumor Consortium.

Pathology of Oligodendrogliomas 

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