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Table of Contents
Year : 2022  |  Volume : 5  |  Issue : 1  |  Page : 39-42

Tumor growth, angiogenesis, and invasion as clinical hallmarks of glioblastoma: A case report

Department of Neurology, Brain Tumor Center and Neuro-Oncology Unit, Beth Israel Deaconess Medical Center, Boston, MA; Departments of Neurology, Medicine, Neurosurgery and Radiation Oncology, Rhode Island Hospital, Providence, RI, USA

Date of Submission19-Jan-2022
Date of Decision28-Jan-2022
Date of Acceptance10-Feb-2022
Date of Web Publication30-Mar-2022

Correspondence Address:
Dr. Eric T Wong
Division of Hematology/Oncology, Rhode Island Hospital, George 3, 593 Eddy Street, Providence, RI 02903
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/glioma.glioma_2_22

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The clinical hallmarks of tumor growth, angiogenesis, and invasion were identified in a patient with isocitrate dehydrogenase-1 wild-type glioblastoma at initial diagnosis and management issues were examined. The head magnetic resonance imaging (MRI) showed multiple solid and cystic contrast enhancements in the rostral portion of the tumor located within the left motor gyrus and the adjacent brain. Extensive tumor invasion was noted along the left corticospinal tract extending into the cerebral peduncle and pons. After an open craniotomy for tissue biopsy, the patient underwent external beam radiotherapy and concomitant temozolomide, and his motor deficit was stabilized with concurrent bevacizumab infusion while dexamethasone was weaned off. After two cycles of adjuvant temozolomide, the patient experienced worsening motor deficit in the right hand. A repeat gadolinium-enhanced head MRI revealed increased fluid-attenuated inversion recovery hyperintensity in the left cerebral peduncle indicating tumor progression. This case illustrates the extensive invasion from a glioblastoma that cannot be adequately quantified or effectively treated. A wider margin of radiation may be needed to cover microscopic and infiltrative tumor cells. The early use of bevacizumab can also reverse neurological deficits and obviate the long-term use of dexamethasone and insulin in this patient. This study was approved by the Institutional Review Board at Dana Farber Cancer Institute #12-519 onMay 5, 2020.

Keywords: Case report, clinical hallmarks, glioblastoma, invasion

How to cite this article:
Wong ET. Tumor growth, angiogenesis, and invasion as clinical hallmarks of glioblastoma: A case report. Glioma 2022;5:39-42

How to cite this URL:
Wong ET. Tumor growth, angiogenesis, and invasion as clinical hallmarks of glioblastoma: A case report. Glioma [serial online] 2022 [cited 2022 Dec 7];5:39-42. Available from: http://www.jglioma.com/text.asp?2022/5/1/39/341376

  Introduction Top

Tumor growth, angiogenesis, and invasion are clinical hallmarks of glioblastoma readily observable on magnetic resonance imaging (MRI).[1] These characteristics are seen on neuroimaging and they represent the amalgamation of the molecular, biochemical, and cellular traits that give rise to cancer. In 2000, Hanahan and Weinberg introduced six fundamental traits of cancer: (i) evading apoptosis, (ii) self-sufficiency in growth signals, (iii) insensitivity to antigrowth signals, (iv) sustained angiogenesis, (v) limitless replicative potential, and (vi) tissue invasion and metastasis.[2] These Hallmarks of Cancer have been updated and expanded twice, first in 2011 and most recently in 2022.[2],[3],[4] Each successive update incorporated relevant new processes that are appreciated as our knowledge advanced in cancer biology. Specifically, the first update added (i) deregulating cellular energetics, (ii) genome instability and mutation, (iii) avoiding immune destruction, and (iv) tumor-promoting inflammation as emerging hallmarks.[3] The second update included characteristics such as (i) unlocking phenotypic plasticity, (ii) nonmutational epigenetic reprogramming, (ii) polymorphic microbiomes, and (iv) senescent cells that enable cancer cells to survive, proliferate, and wreak havoc in the host.[4] Unfortunately, none of these hallmarks of cancer can be reliably measured on the glioblastoma patient or used as a biomarker to assess treatment efficacy. Therefore, the observable clinical hallmarks of glioblastoma are still tumor growth, angiogenesis, and invasion, which are still relevant for evaluating patients in the clinic.

In this patient, the glioblastoma exhibited all three clinical hallmarks at initial diagnosis. Angiogenesis, demonstrated by gadolinium leakage from immature and hyperpermeable vasculature, occurred at only one part of the tumor and the measurable contrast enhancement does not represent the entire malignancy. This is due to extensive tumor invasion presented as nonenhancing hyperintensity on the fluid-attenuated inversion recovery (FLAIR) MRI sequence in both ipsilateral and contralateral corticospinal tracts. Despite treatment with radiotherapy and concomitant temozolomide, this patient had a rapid progression shortly after completion. The aim of this case is to illustrate these three clinical hallmarks of glioblastoma and identify treatment considerations that are important for tumor invasion.

  Case Report Top

A 77-year-old right-handed Caucasian man, with past medical history of right knee arthroscopy and probable prediabetes, experienced clumsiness and decreased fine finger movements in his dominant right hand. His neurological examination was only significant for motor weakness in the right upper extremity, with strength at 4+/5 proximally and 3/5 distally. His right lower extremity had full strength and no sensory deficit was detectable on his entire right side. Family history was notable for Parkinson's disease and alcoholic liver cirrhosis. The patient was working as an electric lineman for a local utility until his hospitalization and he lived with his wife, who was his primary caretaker. A gadolinium-enhanced MRI of the head, performed 5 days after symptom onset, revealed multiple cystic and solid enhancements at or near the left frontal motor gyrus, together with FLAIR hyperintense signal abnormality in the ipsilateral corticospinal tract extending to the left middle cerebral peduncle and left pons, as well as the contralateral corticospinal tract [Figure 1]. After another 4 days, he underwent a craniotomy for an open biopsy of the enhancing lesions. Histological analysis showed glioblastoma with positive immunohistochemical staining for GFAP, Olig2, and ATRX but negative for isocitrate dehydrogenase-1 (consistent with wild-type R132H status). The Ki-67 staining showed a proliferative index of 40%, while the molecular study was negative for O6-methylguanine-DNA methyltransferase promoter methylation. During his hospitalization, he experienced hyperglycemia and therefore metformin and empagliflozin were started to provide glycemic control. The patient was treated with external beam radiotherapy with concomitant daily temozolomide over 6 weeks to 6000 cGy in 200 cGy per fraction, with the bulk of the radiation delivered to the supratentorial brain [Figure 2]. Bevacizumab at a dose of 5 mg/kg every 2 weeks was initiated 10 days into treatment to facilitate weaning off his dexamethasone. After radiation, he received two cycles of adjuvant temozolomide while continuing bevacizumab. He later developed recurrent right-handed weakness. Repeat gadolinium-enhanced head MRI, performed 2 months after the completion of radiotherapy, revealed increased FLAIR hyperintensity in the left cerebral peduncle, and indicating progressive tumor invasion along the corticospinal tract [Figure 3]. Bevacizumab was discontinued by a local oncologist and the patient was later placed in hospice care. In another 2 months, his weakness progressed to monoplegia in the right upper extremity and significant paresis in the right lower extremity.
Figure 1: Marked glioblastoma invasion on initial head magnetic resonance imaging. Postgadolinium-enhanced T1-weighted axial (A) and coronal (B) sequences demonstrated multiple solid and cystic enhancing tumors within the left motor gyrus and the adjacent brain. The fluid-attenuated inversion recovery axial (C) and coronal (D) sequences showed hyperintense signal abnormality in the left cerebral peduncle (red arrow) as well as the ipsilateral and contralateral corticospinal tracts (black arrows). FLAIR: Fluid-attenuated inversion recovery, MRI: Magnetic resonance imaging

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Figure 2: Dosimetry for glioblastoma treatment in the radiation plan. The bulk of the radiation was delivered to the supratentorial brain as seen in the axial (upper left), coronal (lower left), and sagittal (lower right) views of the dosimetry plan and the dose-volume histogram (right upper). The brainstem received a median of 188.7 cGy with a standard deviation of 660.9 cGy (minimum 54.0 cGy and maximum 4267.8 cGy)

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Figure 3: Increased magnetic resonance imaging signal abnormality in the left cerebral peduncle. Two months after the completion of radiotherapy and daily temozolomide, the patient experienced increased weakness in his right hand. Postgadolinium-enhanced T1-weighted axial (A) and coronal (B) sequences demonstrated pseudo-response of the rostral tumors after bevacizumab treatment. The fluid-attenuated inversion recovery axial sequence (C) showed increased hyperintense signal abnormality in the left cerebral peduncle (red arrow). The fluid-attenuated inversion recovery coronal sequence (D) continued to show stable signal abnormality in the ipsilateral and contralateral corticospinal tracts (black arrows). FLAIR: Fluid-attenuated inversion recovery, MRI: Magnetic resonance imaging

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Informed consent for publication was obtained from the patient and the neuroimaging analysis was performed under an Institutional Review Board-approved protocol at Dana Farber Cancer Institute #12-519 (approval date: May 5, 2020).

  Discussion Top

This patient's glioblastoma has all three observable clinical hallmarks -- tumor growth, angiogenesis, and invasion -- in overdrive. Each one of these biological processes is driven by distinct but interrelated signal transduction pathways. First, despite a lack of activating mutations, amplified epidermal growth factor receptor signaling is still important for promoting tumor growth and proliferation by activating the Ras-Raf-Mek-Erk as well as the PI3 kinase-Akt-mTOR pathways.[5] Second, tumor cells under the condition of hypoxia secrete vascular endothelial growth factor (VEGF-A), which activates VEGF receptor-1 (VEGFR)-1 and VEGFR-2 on endothelial cells and promotes angiogenesis, and that ultimately enables the survival and proliferation of glioblastoma.[6] Lastly, hypoxia also promotes glioma cell invasion into the adjacent brain parenchyma by co-option of existing vasculature.[7] However, the precise molecular driver for glioblastoma cell invasion remains poorly understood, and and this case is limited by a lack of histology that correlates with the MRI findings.

There is no quantitative measure for glioblastoma invasion. Unlike tumor growth and angiogenesis, which can be respectively measured by the response assessment in neuro-oncology criteria and perfusion MRI,[8],[9] tumor cell invasion can cause neurological deficits without observable structural changes on MRI. The invasive front of the tumor often causes little or no change in contrast enhancement or FLAIR signal abnormality. Therefore, invasion into functional neuronal structures of the brain should be considered when the patient's neurological status is worsening, despite stable disease measurements on MRI. There is an attempt to quantify the progression of neurological status by the Neurologic Assessment in Neuro-Oncology scale.[10] Still, neurologic assessment in neuro-oncology is only a qualitative rather than a quantitative measure of the patient's neurological function.

Treatment of this patient's highly invasive glioblastoma may require a wider margin of radiation coverage to include microscopic infiltration. Standard treatment planning includes a 2 cm margin beyond the FLAIR hyperintensity up to 4600 cGy in 23 fractions in phase 1 and an additional boost of 1400 cGy in seven fractions with a 2 cm margin beyond the contrast enhancement in phase 2.[11] However, the bulk of radiotherapy is applied to this patient's supratentorial brain, and the margin of phase 1 and 2 fractions may require further expansion to include infiltrative tumor cells.

Bevacizumab treatment in newly diagnosed glioblastoma patients is controversial. This is because no overall survival benefit was seen from adding this medication to radiotherapy and daily temozolomide in randomized clinical trials.[12] Still, bevacizumab can control cerebral edema while obviating the use of dexamethasone, which could cause hyperglycemia in this patient already at risk for medication-induced diabetes mellitus. When this occurs, he will most likely be placed on injections of insulin, which is a potential growth factor for cancer cells that can accelerate the progression of his glioblastoma. Therefore, early use of bevacizumab in a patient with neurological deficits caused by unresectable glioblastoma may avert the use of dexamethasone for cerebral edema and insulin for secondary diabetes mellitus.

In summary, this patient presents with a highly invasive glioblastoma with an observable tumor growing in the rostral brain associated with solid and cystic enhancements, displaying all three clinical hallmarks of glioblastoma. Notably, the tumor can be seen infiltrating both ipsilateral and contralateral corticospinal tracts. A wider margin of radiation may be needed to cover microscopic and infiltrative tumor cells beyond the standard 2 cm margin from the FLAIR hyperintensity. The early use of bevacizumab can also reverse neurological deficits and obviate the long-term use of dexamethasone and insulin.



Financial support and sponsorship


Institutional review board statement

This study was approved by the Institutional Review Board at Dana Farber Cancer Institute #12-519 on May 5, 2020.

Declaration of patient consent

The author certifies that he has obtained the appropriate patient consent form. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity.

Conflicts of interest

There are no conflicts of interest.

  References Top

Wong ET. Tumor growth, invasion, and angiogenesis in malignant gliomas. J Neurooncol 2006;77:295-6.  Back to cited text no. 1
Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100:57-70.  Back to cited text no. 2
Hanahan D, Weinberg RA. Hallmarks of cancer: The next generation. Cell 2011;144:646-74.  Back to cited text no. 3
Hanahan D. Hallmarks of cancer: New dimensions. Cancer Discov 2022;12:31-46.  Back to cited text no. 4
Oprita A, Baloi SC, Staicu GA, Alexandru O, Tache DE, Danoiu S, et al. Updated Insights on EGFR signaling pathways in glioma. Int J Mol Sci 2021;22:E587.  Back to cited text no. 5
Schmidt T, Carmeliet P. Angiogenesis: A target in solid tumors, also in leukemia?. Hematology Am Soc Hematol Educ Program 2011;2011:1-8.  Back to cited text no. 6
Seano G, Jain RK. Vessel co-option in glioblastoma: Emerging insights and opportunities. Angiogenesis 2020;23:9-16.  Back to cited text no. 7
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 2010;28:1963-72.  Back to cited text no. 8
van Dijken BR, van Laar PJ, Smits M, Dankbaar JW, Enting RH, van der Hoorn A. Perfusion MRI in treatment evaluation of glioblastomas: Clinical relevance of current and future techniques. J Magn Reson Imaging 2019;49:11-22.  Back to cited text no. 9
Ung TH, Ney DE, Damek D, Rusthoven CG, Youssef AS, Lillehei KO, et al. The neurologic assessment in neuro-oncology (NANO) scale as an assessment tool for survival in patients with primary glioblastoma. Neurosurgery 2019;84:687-95.  Back to cited text no. 10
Niyazi M, Brada M, Chalmers AJ, Combs SE, Erridge SC, Fiorentino A, et al. ESTRO-ACROP guideline “target delineation of glioblastomas”. Radiother Oncol 2016;118:35-42.  Back to cited text no. 11
Fine HA. Bevacizumab in glioblastoma – Still much to learn. N Engl J Med 2014;370:764-5.  Back to cited text no. 12


  [Figure 1], [Figure 2], [Figure 3]


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