Glioblastoma Differential Diagnosis

Glioblastoma Differential Diagnosis

Tumors are classically distinguished based on biopsy of the tumor itself, as well as a radiological interpretation using diverse MRI modalities.

As its historical name glioblastoma multiforme implies, glioblastoma is a histologically diverse, World Health Organization grade IV astrocytic neoplasm. In spite of its simple definition of presence of vascular proliferation and/or necrosis in a diffuse astrocytoma, the wide variety of cytohistomorphologic appearances overlap with many other neoplastic or non-neoplastic lesions 1).

General imaging differential considerations include:

Intracranial metastases

may look identical

both may appear multifocal

metastases usually are centered on grey-white matter junction and spare the overlying cortex rCBV in the ‘edema‘ will be reduced

Primary central nervous system lymphoma should be considered especially in patients with AIDS, as in this setting central necrosis is more common otherwise usually homogeneously enhancing

Cerebral abscess central restricted diffusion is helpful, however, if GBM is hemorrhagic then the assessment may be difficult presence of smooth and complete SWI low-intensity rim presence of dual rim sign

Anaplastic astrocytoma should not have central necrosis consider histology sampling bias

Tumefactive demyelination lesion can appear similar often has an open ring pattern of enhancement usually younger patients

Subacute cerebral infarction history is essential in suggesting the diagnosis should not have elevated choline should not have elevated rCBV

Cerebral toxoplasmosis especially in patients with AIDS

In a study, Samani et al. of the overarching goal are to demonstrate that primary glioblastomas and secondary (brain metastases) malignancies can be differentiated based on the microstructure of the peritumoral region. This is achieved by exploiting the extracellular water differences between vasogenic edema and infiltrative tissue and training a convolutional neural network (CNN) on the Diffusion Tensor Imaging (DTI)-derived free water volume fraction. They obtained 85% accuracy in discriminating extracellular water differences between local patches in the peritumoral area of 66 glioblastomas and 40 metastatic patients in a cross-validation setting. On an independent test cohort consisting of 20 glioblastomas and 10 metastases, we got 93% accuracy in discriminating metastases from glioblastomas using majority voting on patches. This level of accuracy surpasses CNNs trained on other conventional DTI-based measures such as fractional anisotropy (FA) and mean diffusivity (MD), which have been used in other studies. Additionally, the CNN captures the peritumoral heterogeneity better than conventional texture features, including Gabor filter and radiomic features. The results demonstrate that the extracellular water content of the peritumoral tissue, as captured by the free water volume fraction, is best able to characterize the differences between infiltrative and vasogenic peritumoral regions, paving the way for its use in classifying and benchmarking peritumoral tissue with varying degrees of infiltration 2).


Gokden M. If it is Not a Glioblastoma, Then What is it? A Differential Diagnostic Review. Adv Anat Pathol. 2017 Nov;24(6):379-391. doi: 10.1097/PAP.0000000000000170. PMID: 28885262.

Samani ZR, Parker D, Wolf R, Hodges W, Brem S, Verma R. Distinct tumor signatures using deep learning-based characterization of the peritumoral microenvironment in glioblastomas and brain metastases. Sci Rep. 2021 Jul 14;11(1):14469. doi: 10.1038/s41598-021-93804-6. PMID: 34262079.

Glioblastoma treatment

Glioblastoma treatment

The gold standard for High-Grade Glioma treatment recommends beginning chemoradiation within 6 weeks after. glioblastoma surgery.

The standard of care management for newly diagnosed glioblastoma multiforme (GBM) includes surgeryradiationtemozolomide (TMZ) chemotherapy, and tumor treating fields 1).

From 2005 chemotherapy with temozolomide, according to Stupp protocol 2) , particularly in patients that demonstrate MGMT promoter methylation.

Conflicting reports have emerged regarding the importance of the time interval between these 2 treatments and there is no clear association between duration from surgery to initiation of chemoradiation on overall survival (OS). 3).

Treatment consists of maximal safe resectionradiotherapy, and chemotherapy. Trials of patients with newly diagnosed grade III glioma have shown survival benefit from adding chemotherapy to radiotherapy compared with initial treatment using radiotherapy alone. Both temozolomide and the combination of procarbazinelomustine, and vincristine provide survival benefit. In contrast, trials that compare single modality treatment of chemotherapy alone with radiotherapy alone did not observe survival differences. Currently, for patients with grade III gliomas who require postsurgical treatment, the preferred treatment consists of a combination of radiotherapy and chemotherapy 4).

After treatment, all patients have to undergo brain magnetic resonance imaging procedure quarterly or half-yearly for 5 years and then on an annual basis. In patients with recurrent tumor, wherever possible re-resection or re-irradiation or chemotherapy can be considered along with supportive and palliative care. High-grade malignant glioma should be managed in a multidisciplinary center

see CATNON trial.

The criteria used to assess extent of resection (EOR) have an impact on findings of association between EOR and survival. Current assessment of EOR mainly relies on pre and postoperative contrast-enhanced T1 weighted images (CE-T1WI).

This method is subject to several inherent limitations, including failure to evaluate nonenhancing components of glioma.

To solve this problem, fluid attenuated inversion recovery (FLAIR) imaging is added in the RANO criteria 5).

From the introduction of the first standard of care (SOC) established in 2005 in patients with a new diagnosis of GBM, a great number of trials have been conducted to improve the actual SOC, but the real turning point has never been achieved or is yet to come. Surgical gross total resection, with at least one more reoperation, radiation therapy plus concomitant and adjuvant temozolomide chemotherapy currently remains the current SOC for patients with GBM 6).

Antiepileptic medications may increase radiosensitivity, and therefore improve clinical outcomes, specifically in glioblastoma multiforme patients 7).

The recommended treatment for MGMT promoter unmethylated glioblastoma (GBM) is radiation therapy with concurrent/adjuvant temozolomide (TMZ).

Although overall survival (OS) is the standard for determining GBM treatment efficacy, using OS as an endpoint when studying new therapeutic strategies can be problematic because of potential influence of therapies prior to or subsequently following the therapy being studied. For example, it is difficult to definitively conclude that bevacizumab has no efficacy in GBM when a large percentage of patients in the placebo arms in both III trials studying efficacy of bevacizumab (i.e. AVAglio and RTOG 0825) eventually crossed over and received bevacizumab (31% in AVAglio) 8) and 48% in RTOG-0825 9). If bevacizumab increased OS when given at any time during treatment, we may expect both treatment arms to have similar median OS since most patients eventually were treated with bevacizumab, disguising any therapeutic effects of the drug. Together, these results suggest OS may not be a suitable endpoint when studying new therapeutics or when there is a high chance of cross over in the control arm 10).

To overcome the limitations associated with using OS as the primary endpoint in studies involving new therapeutics, progression free survival (PFS) and objective response rate (ORR) should be considered important end points 11).

see Glioblastoma surgery.

Glioblastoma Maximal Safe Resection

Glioblastoma radiochemotherapy.

see Glioblastoma chemotherapy

see Glioblastoma multiforme antiangiogenic therapy.

see Molecular targeted therapy of glioblastoma.

GBM is one of the most active areas of research. Significant efforts are being made to look beyond basic morphology.

The retrospective analysis of the AVAglio trial reported 4.3 months incremental survival in the proneural glioblastoma subgroup 12).

Hence, patient selection and personalization of treatment should be done with more appropriateness in future. However, the complexity of performing these molecular assays in the lab appears to be labor and cost intensive and may limit routine use. In this context, a simplified model incorporating MGMT methylation, human telomerase (TERT) methylation, and IDH mutation may be formulated to dictate the optimum treatment. Treatment personalization may further be refined with the incorporation of these molecular factors along with patient factors like age, performance status, etc., (molecular-clinical profiling). A Large number of newer drugs and virus based therapy are being evaluated in different phase III and phase II trials as well.

The subventricular zone (SVZ) forms the lining the lateral ventricles and represents the origin of neural and some cancer stem cells. Gupta et al. reported on dose volume parameters of SVZ in 40 patients of adult GBM. Dose to the ipsilateral SVZ dose was found to be an independent predictor of survival in multivariate analysis in this study. Although a novel finding, this requires further validation in a prospective study 13).

Citalopram with standard RT and Temozolomide TMZ

RT alone versus RT and TMZ for elderly

CCNU/TMZ combination therapy versus standard TMZ (MGMT-methylated cases)

Standard RT plus concomitant and adjuvant OSAG 101 (Theraloc°) plusTMZ versus standard RT plus concomitant and adjuvant TMZ

Rindopepimut/GM-CSF with adjuvantTMZ in EGFvall-positive GBM CDX110-04

DCVax-L, autologous dendritic cells pulsed with tumor Iysate antigen 020221

Adjuvant TMZ with or without Interferon-alpha NCT 01765088

Adjuvant RT and temozolomide with or without Velipari b NCT 02152982

CCNU – Lomustine; TMZ -Temozolomide; MGMT – O‘-methylguanine—DNA methyltransferase; GBM – Glioblastoma multiforme; RT – Radiotherapy,-

GM-CSF -Granulocyte-monocyte colony stimulating factor,- EGFRvIII – Epidermal growth factor receptor variant III.

see Glioblastoma immunotherapy.

ALK inhibitor for Glioblastoma.

Alternating electric field therapy for Glioblastoma

Extensive dominant lobe glioblastoma

Butterfly glioblastoma.

Glioblastoma in elderly patients

Karnofsky performance score < 70

Multicentric glioblastoma.

see Recurrent glioblastoma treatment.

Hyperbaric oxygen therapy for Glioblastoma


Stupp R, Taillibert S, Kanner A et al (2017) Effect of tumortreating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA 318:2306–2316

Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO; European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups; National Cancer Institute of Canada Clinical Trials Group. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005 Mar 10;352(10):987-96. PubMed PMID: 15758009.

Osborn VW, Lee A, Garay E, Safdieh J, Schreiber D. Impact of Timing of Adjuvant Chemoradiation for Glioblastoma in a Large Hospital Database. Neurosurgery. 2018 Nov 1;83(5):915-921. doi: 10.1093/neuros/nyx497. PubMed PMID: 29092047.

van den Bent MJ, Smits M, Kros JM, Chang SM. Diffuse Infiltrating Oligodendroglioma and Astrocytoma. J Clin Oncol. 2017 Jul 20;35(21):2394-2401. doi: 10.1200/JCO.2017.72.6737. Epub 2017 Jun 22. Review. PubMed PMID: 28640702.

Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, et al: Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol 28:1963–1972, 2010

Montemurro N. Glioblastoma Multiforme and Genetic Mutations: The Issue Is Not Over Yet. An Overview of the Current Literature. J Neurol Surg A Cent Eur Neurosurg. 2019 Sep 24. doi: 10.1055/s-0039-1688911. [Epub ahead of print] PubMed PMID: 31550738.

Julie DAR, Ahmed Z, Karceski SC, Pannullo SC, Schwartz TH, Parashar B, Wernicke AG. An overview of anti-epileptic therapy management of patients with malignant tumors of the brain undergoing radiation therapy. Seizure. 2019 Jun 12;70:30-37. doi: 10.1016/j.seizure.2019.06.019. [Epub ahead of print] Review. PubMed PMID: 31247400.

Chinot OL, Wick W, Mason W, Henriksson R, Saran F, Nishikawa R, Carpentier AF, Hoang-Xuan K, Kavan P, Cernea D, Brandes AA, Hilton M, Abrey L, Cloughesy T. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):709-22. doi: 10.1056/NEJMoa1308345. PubMed PMID: 24552318.

Gilbert MR, Dignam JJ, Armstrong TS, Wefel JS, Blumenthal DT, Vogelbaum MA, Colman H, Chakravarti A, Pugh S, Won M, Jeraj R, Brown PD, Jaeckle KA, Schiff D, Stieber VW, Brachman DG, Werner-Wasik M, Tremont-Lukats IW, Sulman EP, Aldape KD, Curran WJ Jr, Mehta MP. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N Engl J Med. 2014 Feb 20;370(8):699-708. doi: 10.1056/NEJMoa1308573. PubMed PMID: 24552317; PubMed Central PMCID: PMC4201043.

Ellingson BM, Wen PY, Cloughesy TF. Modified Criteria for Radiographic Response Assessment in Glioblastoma Clinical Trials. Neurotherapeutics. 2017 Apr;14(2):307-320. doi: 10.1007/s13311-016-0507-6. Review. PubMed PMID: 28108885; PubMed Central PMCID: PMC5398984.

Lamborn KR, Yung WK, Chang SM, Wen PY, Cloughesy TF, DeAngelis LM, Robins HI, Lieberman FS, Fine HA, Fink KL, Junck L, Abrey L, Gilbert MR, Mehta M, Kuhn JG, Aldape KD, Hibberts J, Peterson PM, Prados MD; North American Brain Tumor Consortium. Progression-free survival: an important end point in evaluating therapy for recurrent high-grade gliomas. Neuro Oncol. 2008 Apr;10(2):162-70. doi: 10.1215/15228517-2007-062. Epub 2008 Mar 4. PubMed PMID: 18356283; PubMed Central PMCID: PMC2613818.

Sandmann T, Bourgon R, Garcia J, Li C, Cloughesy T, Chinot OL, et al. Patients with proneural glioblastoma may derive overall survival benefit from the addition of bevacizumab to first line radiotherapy and temozolomide: Retrospective analysis of the AV Aglio trial. J Clin Oncol. 2015:pii–JCO.2015.61.5005. Epub ahead of print.

Mallick S, Gandhi AK, Rath GK. Therapeutic approach beyond conventional temozolomide for newly diagnosed glioblastoma: Review of the present evidence and future direction. Indian J Med Paediatr Oncol. 2015 Oct-Dec;36(4):229-37. doi: 10.4103/0971-5851.171543. Review. PubMed PMID: 26811592; PubMed Central PMCID: PMC4711221.

Glioblastoma overall survival

Glioblastoma overall survival

In glioblastomaprogression-free survival (PFS) and overall survival (OS) are strongly correlated, indicating that PFS may be an appropriate surrogate for OS. Compared with OS, PFS offers earlier assessment and higher statistical power at the time of analysis 1).

Increasing the extent of resection (EOR) of GBM is associated with prolonged survival 2)

Also, adjuvant radiochemotherapy showed higher survival rates in patients with complete resection (EOR ≥ 90%), compared with partial resection (EOR < 90%) 3).

Glioblastoma IDH Mutant is associated with better outcome and increased overall survival 4).

Overall estimates of survival among patients with glioblastoma have at least doubled since 2005 to 18% at 2 years and 11% at 3 years. This may reflect treatment response to modern therapeutic approaches. However, longer-term survival remains poor and there appears to be a lack of improvement in 5-year survival 5).

Magnetic resonance perfusion imaging parameter obtained on 3-Tesla and the Ki-67 labeling index predict the overall survival of glioblastoma 6).

MR image derived texture features, tumor shape and volumetric features, and patient age were obtained for 163 patients. OS group prediction was performed for both 2-class (short and long) and 3-class (short, medium and long) survival groups. Support vector machine classification based recursive feature elimination method was used to perform feature selection. The performance of the classification model was assessed using 5-fold cross-validation. The 2-class and 3-class OS group prediction accuracy obtained were 98.7% and 88.95% respectively. The shape features used in this work have been evaluated for OS prediction of GBM patients for the first time. The feature selection and prediction scheme implemented in this study yielded high accuracy for both 2-class and 3-class OS group predictions. This study was performed using routinely acquired MR images for GBM patients, thus making the translation of this work into a clinical setup convenient 7).


Han K, Ren M, Wick W, Abrey L, Das A, Jin J, Reardon DA. Progression-free survival as a surrogate endpoint for overall survival in glioblastoma: a literature-based meta-analysis from 91 trials. Neuro Oncol. 2013 Dec 12. [Epub ahead of print] PubMed PMID: 24335699.

Sanai N, Polley MY, McDermott MW, Parsa AT, Berger MS (2011) An extent of resection threshold for newly diagnosed glioblastomas. J Neurosurg 115:3–8. jns1099810.3171/2011.7.jns10238

Stummer W, van den Bent MJ, Westphal M (2011) Cytoreductive surgery of glioblastoma as the key to successful adjuvant therapies: new arguments in an old discussion. Acta Neurochir 153:1211– 1218.

Ohgaki H, Kleihues P. The definition of primary and secondary glioblastoma. Clin Cancer Res. 2013 Feb 15;19(4):764-72. doi: 10.1158/1078-0432.CCR-12-3002. Epub 2012 Dec 3. PMID: 23209033.

Poon MTC, Sudlow CLM, Figueroa JD, Brennan PM. Longer-term (≥ 2 years) survival in patients with glioblastoma in population-based studies pre- and post-2005: a systematic review and meta-analysis. Sci Rep. 2020 Jul 15;10(1):11622. doi: 10.1038/s41598-020-68011-4. PMID: 32669604; PMCID: PMC7363854.

Fudaba H, Momii Y, Matsuta H, Onishi K, Kawasaki Y, Sugita K, Shimomura T, Fujiki M. Perfusion parameter obtained on 3-Tesla magnetic resonance imaging and the Ki-67 labeling index predict the overall survival of glioblastoma. World Neurosurg. 2021 Feb 7:S1878-8750(21)00183-2. doi: 10.1016/j.wneu.2021.02.002. Epub ahead of print. PMID: 33567368.

Sanghani P, Ang BT, King NKK, Ren H. Overall survival prediction in glioblastoma multiforme patients from volumetric, shape and texture features using machine learning. Surg Oncol. 2018 Dec;27(4):709-714. doi: 10.1016/j.suronc.2018.09.002. Epub 2018 Sep 10. PMID: 30449497.
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