- Department of Orthopaedics and Rehabilitation, Yale University School of Medicine, New Haven, CT, USA
- Department of Neurosurgery, NYU School of Medicine, Brooklyn, New York, USA
- Department of Radiation Oncology, NYU School of Medicine, Brooklyn, New York, USA
- Department of Radiology, NYU School of Medicine, Brooklyn, New York, USA
- Kimmel Center for Stem Cell Biology, NYU School of Medicine, Brooklyn, New York, USA
- Brain Tumor Center, NYU School of Medicine, Brooklyn, New York, USA
- Division of Neurosurgery, Maimonides Medical Center, Brooklyn, New York, USA
- Maimonides Cancer Center, Brooklyn, New York, USA
Dimitris G Placantonakis
Department of Neurosurgery, NYU School of Medicine, Brooklyn, New York, USA
Kimmel Center for Stem Cell Biology, NYU School of Medicine, Brooklyn, New York, USA
Brain Tumor Center, NYU School of Medicine, Brooklyn, New York, USA
DOI:10.4103/2152-7806.189296Copyright: © 2016 Surgical Neurology International This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.
How to cite this article: Tyagi V, Theobald J, Barger J, Bustoros M, Bayin NS, Modrek AS, Kader M, Anderer EG, Donahue B, Fatterpekar G, Placantonakis DG. Traumatic brain injury and subsequent glioblastoma development: Review of the literature and case reports. Surg Neurol Int 26-Aug-2016;7:78
How to cite this URL: Tyagi V, Theobald J, Barger J, Bustoros M, Bayin NS, Modrek AS, Kader M, Anderer EG, Donahue B, Fatterpekar G, Placantonakis DG. Traumatic brain injury and subsequent glioblastoma development: Review of the literature and case reports. Surg Neurol Int 26-Aug-2016;7:78. Available from: http://surgicalneurologyint.com/surgicalint_articles/traumatic-brain-injury-subsequent-glioblastoma-development-review-literature-case-reports/
Background:Previous reports have proposed an association between traumatic brain injury (TBI) and subsequent glioblastoma (GBM) formation.
Methods:We used literature searches and radiographic evidence from two patients to assess the possibility of a link between TBI and GBM.
Results:Epidemiological studies are equivocal on a possible link between brain trauma and increased risk of malignant glioma formation. We present two case reports of patients with GBM arising at the site of prior brain injury.
Conclusion:The hypothesis that TBI may predispose to gliomagenesis is disputed by several large-scale epidemiological studies, but supported by some. Radiographic evidence from two cases presented here suggest that GBM formed at the site of brain injury. We propose a putative pathogenesis model that connects post-traumatic inflammation, stem and progenitor cell transformation, and gliomagenesis.
Keywords: Brain tumor, glioblastoma, traumatic brain injury
Glioblastoma (GBM) is the most common and deadly brain malignancy, with over 10000 new cases in the US annually and a median survival of only 14–16 months after surgical resection and concurrent chemoradiotherapy.[
Environmental risk factors for GBM remain poorly defined, with the exception of exposure to ionizing radiation.[
The injury must be severe enough to cause a tissue repair process to commence; The area of the traumatic injury should correspond directly with the location of the subsequent GBM; There should be a gap of at least 1 year between the injury to the brain and the appearance of the tumor. A longer latent period is considered to be a stronger evidence of a causal relationship.
The injury must be severe enough to cause a tissue repair process to commence;
The area of the traumatic injury should correspond directly with the location of the subsequent GBM;
There should be a gap of at least 1 year between the injury to the brain and the appearance of the tumor. A longer latent period is considered to be a stronger evidence of a causal relationship.
Here, we present two patients who developed GBM at the exact same site where they had suffered TBI several years ago. We also review relevant epidemiological studies, which are overall equivocal on the association between TBI and GBM. Finally, we propose a mechanism that could explain the biological link between TBI and gliomagenesis by invoking inflammation as the trigger for oncogenic transformation of neural stem and progenitor cells that migrate to the injured tissue for repair. Chronic inflammation has been shown to be a major predisposing factor for many solid tumors, including, but not limited to, hepatocellular carcinoma and colon cancer.[
We performed literature searches on PubMed to identify epidemiological studies that investigated the link between brain injury and GBM formation. We also collected and analyzed clinical and radiographic data from two patients with a history of TBI, who subsequently developed GBM.
Several epidemiological studies have attempted to analyze the association between GBM formation and the presence of previous TBI. These studies present varying results regarding the strength of correlation and odds ratio for TBI-induced GBM. Nygren et al. performed a population-based cohort study in Sweden, which analyzed over 300,000 patients who were documented to have suffered traumatic brain injury between 1965 and 1994.[
A Taiwanese group analyzed a cohort of 5007 patients who visited ambulatory care centers between 2001 and 2002.[
Gurney et al. performed a multicenter case-control study in which the association between brain injury and tumor formation was analyzed specifically in children.[
A study done by Preston-Martin et al.[
This patient is a 65-year-old left-handed man, who suffered serious head trauma causing a large left frontal contusion at age 54 after a fall at the workplace. At that time, he was placed in a medically induced coma for 3 days. Serial imaging after the injury demonstrated encephalomalacia and gliosis at the site of the contusion [
In preparation for resection of the tumor, a Wada Test revealed bilateral hemispheric language dominance. To avoid damaging language-processing centers, awake language mapping was attempted during planned operative resection. The patient became agitated during language mapping and the surgeon opted to place subdural grid electrodes for extraoperative speech mapping, which revealed no regions associated with language function in the vicinity of the tumor. In a second operative procedure under general anesthesia, he underwent uneventful resection of >90% of the tumor with residual in the left insula. Histopathologic analysis confirmed the diagnosis of GBM. The Ki-67 immunolabeling index using MIB1 antibody was up to 25%. Immunohistochemistry for the R132H mutation in IDH1 was negative.
After surgery, he was treated with concurrent chemoradiotherapy (Stupp protocol). However, the tumor recurred rapidly and he expired within 4 months after surgery.
This patient is a 54-year-old right-handed man who suffered a large contusion and severe injury to the inferior right frontal lobe in an automobile accident at age 47 [
Seven years after the injury, he came again to medical attention due to headaches and confusion. CT imaging indicated a 4 cm heterogeneously enhancing inferior right frontal mass at the site of the brain injury. There was extensive vasogenic edema surrounding the lesion. He underwent right frontal craniotomy for gross total resection of the mass, which was diagnosed as GBM. Immunohistochemistry for the R132H mutation in IDH1 was negative. He was subsequently treated with chemoradiotherapy as per Stupp protocol. As per the most recent follow-up 8 months post-resection, he remains neurologically intact with no evidence for recurrence on CT.
Epidemiological studies are largely equivocal on the link between TBI and subsequent formation of malignant glioma. In fact, large-scale studies have shown no correlation. However, the two presented cases show GBM formation at the site of prior brain injury. Our hypothesis is that, in some patients, an underlying biological vulnerability predisposes them to gliomagenesis after brain trauma. What are the mechanisms that could potentially explain injury-driven gliomagenesis?
We propose that the inflammatory response that ensues after TBI is linked to oncogenic transformation of neural stem and progenitor cells that chemotactically migrate to the injured site in response to inflammation [
Model linking traumatic brain injury to glioblastoma formation. Upon injury to the brain, neural stem cells migrate to the site to enable tissue repair. At the same time, immune cells are recruited. Immune cells release reactive oxygen species (ROS), which can induce mutagenesis and initiate oncogenic transformation of stem cells
Inflammation at the site of brain injury is well-documented in the literature.[
A number of inflammatory cytokines, including IL-1, TNF, IL-10, IL-6, IL-8, and MCP-1, are known to be upregulated in the context of TBI and facilitate recruitment of myeloid immune cells.[
Stem cell migration to injury site
Neural stem cells in the adult brain localize primarily to two neurogenic areas, namely, the subventricular zone of the lateral ventricles and the subgranular zone of the hippocampal dentate gyrus (for review see[
The oncogenic potential of neural stem cells has been suggested by the observation that neurogenic niches in the brain are sensitive to chemical oncogenesis.[
In conclusion, large-scale epidemiological studies have not shown a definitive link between TBI and increased risk of developing GBM. However, the two patients presented here developed GBM at the site of their brain injury several years later. It is, therefore, possible that an underlying biological vulnerability in a subset of patients with TBI may predispose them to gliomagenesis. We propose a putative model that links neuroinflammation to mutagenesis in neural stem and progenitor cells migrating to the site of injury, leading to their neoplastic transformation and glioma initiation. In the future, as molecular mechanisms of gliomagenesis and the brain's response to TBI become clearer, we hope to identify the biological mechanisms that make a subset of patients susceptible to brain tumor formation after injury.
Financial support and sponsorship
N. Sumru Bayin received support from NYSTEM Institutional training grant #CO26880. Dimitris G. Placantonakis received support from NIH/NINDS 1R21NS087241-01, NIH/NINDS 1R21NS088775-01, NIH/NINDS 1R03NS087349-01, NIH/NCI 2P30CA016087-33, NIH/NCATS UL1 TR000038, NYU Cancer Institute, NYU Clinical and Translational Science Institute and the B*Cured Foundation.
Conflicts of interest
There are no conflicts of interest.
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