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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.



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.

Differential diagnosis

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).



Case series


Preibisch et al. performed a study in 12 patients with high-grade glioma, where they directly compared the two currently most promising techniques, namely the MR-based relative oxygen extraction fraction (MR-rOEF) and the PET hypoxia marker H-1-(3-[18 F]-fluoro-2-hydroxypropyl)-2-nitroimidazole ([18 F]-FMISO). MR-rOEF was determined from separate measurements of T2 , T2 * and relative cerebral blood volume (rCBV) employing a multi-parametric approach for quantification of the blood-oxygenation-level-dependent (BOLD) effect. With respect to [18 F]-FMISO-PET, besides the commonly used late uptake between 120 and 130 min ([18 F]-FMISO120-130 min ), we also analyzed the hypoxia specific uptake rate [18 F]-FMISO-k3 , as obtained by pharmacokinetic modeling of dynamic uptake data. Since pharmacokinetic modeling of partially acquired dynamic [18 F]-FMISO data was sensitive to a low signal-to-noise-ratio, analysis was restricted to high-uptake tumor regions. Individual spatial analyses of deoxygenation and hypoxia-related parameter maps revealed that high MR-rOEF values clustered in (edematous) peritumoral tissue, while areas with high [18 F]-FMISO120-130 min concentrated in and around active tumor with disrupted blood-brain barrier, i.e. contrast enhancement in T1 -weighted MRI. Volume-of-interest-based correlations between MR-rOEF and [18 F]-FMISO120-130 min as well as [18 F]-FMISO-k3 , and voxel-wise analyses in individual patients, yielded limited correlations, supporting the notion that [18 F]-FMISO uptake, even after 2 h, might still be influenced by perfusion while [18 F]-FMISO-k3 was severely hampered by noise. According to these results, vascular deoxygenation, as measured by MR-rOEF, and severe tissue hypoxia, as measured by [18 F]-FMISO, show a poor spatial correspondence. Overall, the two methods appear to rather provide complementary than redundant information about high-grade glioma biology 8).

Data of 47 consecutive patients with HGG have been collected in our study (25 males, 22 females; mean age: 60.3 years, range: 27-86 years). Fluorescein (5 mg/kg of body weight) was injected intravenously right after the induction of general anesthesia. A YELLOW 560 filter was used on an OPMI Pentero 900 microscope (Carl Zeiss Meditec, Oberkochen, Germany) to complete a microsurgical tumor removal. Glioma resection and quality of life were evaluated preoperative and postoperatively.

Gross total resection (GTR) was achieved in 53.2% (n = 25) of patients. A subtotal resection (STR) (>95%) was achieved in 29.8% (n = 14), while a partial resection (PR) (<95%) was obtained in 17% (n = 8) of patients. Overall, in 83% (n = 39) of patients who underwent fluorescence-guided surgery the resection rate achieved was >95%. No adverse effects correlated to fluorescein have been recorded.

Fluorescein seems to be safe and effective in the resection of HGGs, allowing a high rate of gross total removal of contrast enhanced areas 9).


A retrospective study of 125 HGG patients used three different classification standards of age-groups (≤50 and >50years old, ≤60 and >60years old, ≤45 and 45-65 and ≥65years old) to evaluate the impact of age on prognosis. The primary end-point was overall survival (OS). The Kaplan Meier method was applied for univariate analysis and Cox proportional hazards model for multivariate analysis. Univariate analysis showed a significant correlation between OS and all three classification standards of age-groups as well as between OS and pathological grade, gender, location of glioma, and regular chemotherapy and radiotherapy treatment. Multivariate analysis showed that the only independent predictors of OS were classification standard of age-groups ≤50 and >50years old, pathological grade and regular chemotherapy. In summary, the most appropriate classification standard of age-groups as an independent prognostic factor was ≤50 and >50years old. Pathological grade and chemotherapy were also independent predictors of OS in post-operative HGG patients 10).

Malignant glioma, ie, anaplastic astrocytoma and glioblastoma, is the most common type of primary malignant brain tumor in the People's Republic of China, and is particularly aggressive.

The median survival of patients with newly diagnosed glioblastoma is only 12-14 months despite advanced therapeutic strategies.

Treatment of malignant glioma consists mainly of surgical resection followed by adjuvant radiation and chemotherapy. Temozolomide (TMZ), a second-generation oral alkylating agent, is playing an increasingly important role in the treatment of malignant glioma in Chinese patients. Since the publication of a study by Stupp et al in 2005, which used a protocol of conventional fractionated irradiation with concomitant TMZ followed by standard TMZ for six cycles, many clinical studies in the People's Republic of China have demonstrated that such a treatment strategy has significantly improved efficacy with limited side effects for newly diagnosed glioblastoma after surgery as compared with strategies that do not contain TMZ. However, as a relatively new agent, the history and development of TMZ for malignant glioma is not well documented in Chinese patients. Multicenter, randomized controlled trials including appropriately sized patient populations investigating multiple aspects of TMZ therapy and related combination therapies are warranted in patients with malignant glioma 11).

The Nationwide Inpatient Sample (NIS) database was queried from 2002 to 2011. All adult patients who underwent elective brain surgery for a malignant brain tumor were included. Surgical complications included wrong side surgery, retention of a foreign object, iatrogenic stroke, meningitis, hemorrhage/hematoma complicating a procedure, and neurological complications. A regression model was conducted to estimate the odds ratios (OR) with their 95% confidence intervals (95% CI) of in-hospital mortality for each surgical complication.

A total of 16,530 admissions were analyzed, with 601 (36.2 events per 1000 cases) surgical complications occurring in 567 patients. Over the examined 10-year period, the overall incidence of surgical complications did not change (P=0.061) except for iatrogenic strokes, which increased in incidence from 14.1 to 19.8 events per 1000 between 2002 and 2011 (P=0.023). Patients who developed a surgical complication had significantly longer lengths of stay, total hospital costs, and higher rates of other complications. Patients who experienced an iatrogenic stroke had a significantly increased risk of mortality (OR 9.6; 95% 6.3-14.8) and so were patients with a hemorrhage/hematoma (OR 3.3; 95% CI 1.6-6.6).

In this study of an administrative database, patients undergoing surgery for a malignant brain tumor who suffered from a surgical complication had significantly longer lengths of stay, total hospital charges, and complication rates. Having a surgical complication was also an independent risk factor for in-hospital mortality. Nonetheless, it is unclear whether all surgical complications were clinically relevant, and further research is encouraged 12).

Case reports


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 13).

Ostrom QT, Gittleman H, Fulop J, Liu M, Blanda R, Kromer C, Wolinsky Y, Kruchko C, Barnholtz-Sloan JS. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008-2012. Neuro Oncol. 2015 Oct;17 Suppl 4:iv1-iv62. doi: 10.1093/neuonc/nov189. Epub 2015 Oct 27. PubMed PMID: 26511214; PubMed Central PMCID: PMC4623240.
DeAngelis LM. Brain tumors. N Engl J Med. 2001;344(2):114–123.
Deorah S, Lynch CF, Sibenaller ZA, Ryken TC. Trends in brain cancer incidence and survival in the United States: Surveillance, Epidemiology, and End Results Program, 1973 to 2001. Neurosurg Focus. 2006;20(4):E1.
Surawicz TS, Davis F, Freels S, Laws ER Jr, Menck HR. Brain tumor survival: results from the National Cancer Data Base. J Neurooncol. 1998;40(2):151–160.
G.J. Kitange, K.L. Templeton, R.B. Jenkins Recent advances in the molecular genetics of primary gliomas Curr. Opin. Oncol., 15 (2003), pp. 197–203
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.
Preibisch C, Shi K, Kluge A, Lukas M, Wiestler B, Göttler J, Gempt J, Ringel F, Al Jaberi M, Schlegel J, Meyer B, Zimmer C, Pyka T, Förster S. Characterizing hypoxia in human glioma: A simultaneous multimodal MRI and PET study. NMR Biomed. 2017 Aug 14. doi: 10.1002/nbm.3775. [Epub ahead of print] PubMed PMID: 28805936.
Francaviglia N, Iacopino DG, Costantino G, Villa A, Impallaria P, Meli F, Maugeri R. Fluorescein for resection of high-grade gliomas: A safety study control in a single center and review of the literature. Surg Neurol Int. 2017 Jul 11;8:145. doi: 10.4103/sni.sni_89_17. eCollection 2017. PubMed PMID: 28781922; PubMed Central PMCID: PMC5523479.
Chen JW, Zhou CF, Lin ZX. The influence of different classification standards of age groups on prognosis in high-grade hemispheric glioma patients. J Neurol Sci. 2015 Jun 18. pii: S0022-510X(15)00377-9. doi: 10.1016/j.jns.2015.06.036. [Epub ahead of print] PubMed PMID: 26143529.
Chang L, Su J, Jia X, Ren H. Treating malignant glioma in Chinese patients: update on temozolomide. Onco Targets Ther. 2014 Feb 12;7:235-244. eCollection 2014. Review. PubMed PMID: 24600235.
De la Garza-Ramos R, Kerezoudis P, Tamargo RJ, Brem H, Huang J, Bydon M. Surgical complications following malignant brain tumor surgery: An analysis of 2002-2011 data. Clin Neurol Neurosurg. 2015 Nov 12;140:6-10. doi: 10.1016/j.clineuro.2015.11.005. [Epub ahead of print] PubMed PMID: 26615463.
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.
high_grade_glioma.txt · Last modified: 2018/10/15 11:23 by administrador