High-grade glioma

High-grade gliomas (HGGs), are the most common intrinsic brain tumors in adults hallmarked by rapid proliferation, hypervascularization and an invasive growth pattern.

The process of malignant transformation (MT) of low grade glioma (LGG) to HGG is poorly understood but likely involves the activation of signaling programs that suppress apoptosis.

see High grade glioma classification

High grade gliomas represent a widely heterogeneous group of tumors, the most frequent of which is glioblastoma multiforme.

Its annual incidence has risen over the last decades, particularly amongst elderly people.

Approximately 89,000 new primary brain tumors are diagnosed in the United States each year, for which 27% are gliomas and 32.8% are malignant gliomas 1).

High-grade gliomas are the most common primary malignant brain tumor in adults 2) 3) 4).

While there has been progress in understanding the molecular genetics of these tumors 5) , the cell type(s) of origin are still uncertain, and the molecular determinants of disease aggressiveness are not well understood. A better understanding of the cellular origin and molecular pathogenesis of these tumors may identify new targets for treatment of these neoplasms.

Intratumoral hypoxia is thought to be a main contributor to tumorigenesis and angiogenesis of these tumors. Because HIF1A is the major mediator of hypoxia-regulated cellular control, inhibition of this transcription factor may reduce glioblastoma growth.

Dissemination of high-grade gliomas (WHO grade IV) has been investigated poorly so far.

Usually, low-grade gliomas show no increase in tumor rCBV, whereas high-grade gliomas demonstrate high relative cerebral blood volume (rCBV) that in some cases even extends outside the contrast-enhancing portions of the tumor 6).

see Stereotactic biopsy of high grade glioma.

They require MGMT, isocitrate dehydrogenase (IDH) and 1p19q status, the determination of these molecular diagnostics should be prioritized

A 58-year-old male with slight left hemiparesis. The radiological evaluation with contrast administred magnetic resonance imaging (MRI) scan demonstrated a right temporo-parietal ring enhancing mass lesion surrounded by edema which was resembling a typical glioma.

The patient was operated on via a temporo-parietal craniotomy and an arteriovenous malformation surrounded by abnormal glial tissue was observed during the exposure. A nidus supplied by several branches arising from the middle cerebral artery (MCA) was obvious. The venous drainage of the malformation was to the superficial venous system. The observed arterial feeders and the draining vein were coagulated and the nidus was macroscopically totally excised. The frozen examination from surrounding glial tissue revealed a high grade glioma. The tumor was also macroscopically totally excised. Postoperatively, the cerebral angiogram demonstrated a right temporal arteriovenous malformation with a centrally excised nidus. The remaining major feeders involved the angular gyrus and the posterior temporal arteries. The venous drainage was to the straight and sigmoid sinuses.

The final histopathological examination of the specimen revealed an arteriovenous malformation surrounded by a high grade glioma.

The patient refused a second operation for total removal of the AVM. Postoperatively, he is doing well with improvement of his left hemiparesis 7).

see High grade glioma treatment.

see High grade glioma outcome.

see High grade glioma case series.


Temozolomide (TMZ) for malignant gliomas is traditionally dosed in 5 out of a 28-day cycle, however alternative regimens exist, including dose-dense. Continuous daily dosing is available, but the acceptable dose and duration of therapy is unknown.

Zhou et al. document a 40-year-old male with recurrent anaplastic astrocytoma, IDH mutant and MGMT promotor methylation negative, who has well-tolerated continuous daily TMZ for 20 months at 100 mg per day for nearly the length of this period. A trial at 80 mg per day demonstrated disease progression with response upon return to 100 mg per day. Prior to the daily TMZ, the patient underwent three surgical resections, radiation therapy with concurrent TMZ according to the EORTC NCIC protocol, and subsequently bevacizumab in combination with use of the Optune device. Long-term survival of patients with recurrent malignant gliomas is uncommon, and currently no standard treatment strategies exist for these patients. We present this case to demonstrate the tolerability and dose dependency of prolonged daily TMZ dosing as a therapeutic option for recurrent anaplastic astrocytomas 8).

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Hu L. S. et al. Correlations between perfusion MR imaging cerebral blood volume, microvessel quantification, and clinical outcome using stereotactic analysis in recurrent high-grade glioma. AJNR Am J Neuroradiol 33, 69–76, 10.3174/ajnr.A2743 (2012).
Ziyal IM, Ece K, Bilginer B, Tezel GG, Ozcan OE. A glioma with an arteriovenous malformation: an association or a different entity? Acta Neurochir (Wien). 2004 Jan;146(1):83-6; discussion 86. Epub 2003 Dec 5. PubMed PMID: 14740271.
Zhou Z, Howard TA, Villano JL. Long-term daily temozolomide with dose-dependent efficacy in MGMT promotor methylation negative recurrent high-grade astrocytoma. Cancer Chemother Pharmacol. 2017 Aug 8. doi: 10.1007/s00280-017-3415-5. [Epub ahead of print] PubMed PMID: 28791452.
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