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Glioblastoma (GBM)

Glioblastoma (GBM)

Glioblastomas (also called GBM) are malignant Grade IV tumors, where a large portion of tumor cells are reproducing and dividing at any given time. They are nourished by an ample and abnormal tumor vessel blood supply. The tumor is predominantly made up of abnormal astrocytic cells, but also contain a mix of different cell types (including blood vessels) and areas of dead cells (necrosis). Glioblastomas are infiltrative and invade into nearby regions of the brain. They can also sometimes spread to the opposite side of the brain through connection fibers (corpus callosum). It is exceedingly rare for glioblastomas to spread outside of the brain. 

Glioblastomas may arise de novo, meaning they begin as a Grade IV tumor with no evidence of a lower grade precursor. De novo tumors are the most common form of glioblastoma and tend to be more aggressive and tend to affect older patients. Alternatively, secondary glioblastomas may progress from a lower-grade astrocytic tumors (Grade II or Grade III) and evolve into Grade IV tumors over time. In general, these tumors tend to be slower growing initially, but can progressively become aggressive. 

Glioblastomas are usually diagnosed as either IDH-wildtype or IDH-mutant (please see the Genetic Profile section below for more information). IDH-wildtype glioblastomas are more common, tend to be more aggressive, and have worse prognosis than IDH-mutant glioblastomas. 

Location:

Glioblastomas are generally found in the cerebral hemispheres of the brain, but can be found anywhere in the brain.  IDH mutant glioblastomas tend to arise preferentially in the frontal lobe

Symptoms:

Patients with glioblastomas develop symptoms rapidly due to mass effect from the tumor itself or from the fluid surrounding the tumor (edema) that causes further brain swelling. For example, common symptoms at diagnosis are related to the increased pressure in the brain (nausea, vomiting, and severe headaches which are typically worse in the morning). Patients can also present with neurological symptoms which are dependent on the tumor location (for example, weakness or sensory changes of face, arm or leg, balance difficulties and neurocognitive/memory issues). Other common presentation includes seizures. 

Treatment:

Glioblastoma can be difficult to treat since some cells may respond well to certain therapies, while others may not be affected at all. Because of this, the treatment plan for glioblastoma may combine several approaches.  

The first step in treating glioblastoma is a surgical procedure to make a diagnosis, to relieve pressure on the brain, and to safely remove as much tumor as possible. Glioblastomas are diffuse and have finger-like tentacles that infiltrate the brain, which makes them very difficult to remove completely. This is particularly true when the tumors are growing near important regions of the brain that control functions such as language and movement/coordination.   

Radiation and chemotherapy are used to slow down the growth of residual tumor after surgery and for tumors that cannot be removed with surgery. Additional treatments such as angiogenesis inhibitors may be used for tumors that recur or those that are non-responsive as a second-line agent. Tumor Treating Fields (TTFields) may be also be offered especially for recurrent tumors in adults.  

Prognosis:

With standard treatment, median survival for adults with glioblastoma, IDH-wildtype, is approximately 11-15 months.   

There are factors that can contribute to improved prognosis, such as younger age at diagnosis (less than 50 years), near-complete removal of the tumor in surgery. Important molecular markers are determined after biopsy or surgery, which provide information for diagnosis and prognosis.  For patients with IDH mutant glioblastoma, the prognosis is significantly better (median survival of 27 – 31 months) compared to IDH wildtype glioblastoma (median survival 11-13 months) after diagnosis. Another marker, methylation of a gene called MGMT promoter is also an important marker. MGMT is important for the stability of genes in all cells. When it is methylated, it is inactivated. This makes cancer cells more sensitive to certain chemotherapy drugs such as temozolomide because the DNA gets so damaged that the cells die.   

Incidence:

Glioblastomas represent about 15% of all primary brain tumors.  Glioblastomas are slightly more common in men than in women. IDH mutant glioblastomas account for approximately 10% of all glioblastomas.   

Age Distribution:

The median age at diagnosis for glioblastoma is 64 years of age, and risk increases with age. IDH mutant glioblastomas develop in patients significantly younger with a median age of 48 years old. Glioblastomas are rare in children. 

Risk Factors:

A very small percentage of glioblastomas are inherited as part of other syndromes such as Turcot Syndrome, Li-Fraumeni syndrome, and Neurofibromatosis type 1. The vast majority of glioblastomas occur randomly, without inherited genetic factors. The only confirmed risk factor is ionizing radiation to the head and neck region. Studies of environmental and genetic factors contributing to glioblastomas have so far been inconclusive or negative. However, there appears to be a decreased risk among individuals with a history of allergies. 

Genetic Profile:

Glioblastomas are currently diagnosed as IDH-wildtype, IDH-mutant, or rarely as Glioblastoma NOS when IDH status cannot be determined.  

Glioblastoma, IDH-wildtype tumors  

IDH-wildtype glioblastomas harbor a great deal of genetic abnormalities:  

  • Alterations of large pieces of chromosomes can occur and can increase or decrease the number of copies of certain genes that are found in those pieces
  • Gain of chromosome 7p in combination with loss of chromosome 10q is the most common genetic alteration in glioblastoma. This is associated with an increase in the Epidermal Growth Factor Receptor (EGFR) and a decrease in the tumor suppressor gene PTEN. 
  • Glioblastomas may also have too few copies of chromosomes 9, and 13. 
  • Genes can also become mutated. Some common mutations in IDH-wild-type glioblastoma include:
  • PTEN is a tumor suppressor, which can become inactive or absent when mutated
  • EGFR stimulates cell division and can be stuck in the “on” position when it is 
  • TheTERT gene increases longevity in cells. Mutations of the TERT promoter make this gene more active, allowing the cancer cells to continue to divide. 
  • There can be alterations in other cell growth signaling pathways including PDGFRA, PI3 Kinase, and Met, which stimulate the cancer cells to grow and divide.
  • Alterations in other tumor suppressor pathways are also common including p53, retinoblastoma, and CDKN2A. These genes would normally block uncontrolled growth, but the alterations block the function of these genes.

Glioblastoma, IDH-mutant tumors:   

  • Have mutated genes
  • All of these tumors have a mutation in the IDH1 or IDH2 gene. This changes the way the cells make and use energy, which changes many aspects of how the cells function. 
  • ATRX, which is involved in turning genes off, can be mutated, causing it to not function properly
  • The tumor suppressor gene, p53can also be mutated, resulting in loss of control over tumor growth. 
  • Loss of a large piece of chromosome19, known as 19q, is also common for this tumor type.  
  • The DNA in these tumors tends to be hypermethylated, meaning that genes are inappropriately turned off. 
  • The way that chromosome interact is frequently altered, causing oncogenes such as PDGFRA to be over expressed.
Glioblastoma (GBM) Brochure Glioblastoma (GBM) Brochure | Spanish