Glioblastoma

Glioblastoma, previously known as glioblastoma multiforme (GBM), is the most aggressive and most common type of cancer that originates in the brain, and has a very poor prognosis for survival. Initial signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality changes, nausea, and symptoms similar to those of a stroke. Symptoms often worsen rapidly and may progress to unconsciousness. The cause of most cases of glioblastoma is not known. Uncommon risk factors include genetic disorders, such as neurofibromatosis and Li–Fraumeni syndrome, and previous radiation therapy. Glioblastomas represent 15% of all brain tumors. They are thought to arise from astrocytes. The diagnosis typically is made by a combination of a CT scan, MRI scan, and tissue biopsy. There is no known method of preventing the cancer. Treatment usually involves surgery, usually followed by chemotherapy and/or radiation. The medication temozolomide has been generally advised as part of chemotherapy. However, clinical trial participation, if available, is preferred by current NCCN guidelines. High-dose steroids may be used to help reduce swelling and decrease symptoms. Surgical removal (decompression) of the tumor is linked to increased survival, but only by some months. Despite maximum treatment, the cancer almost always recurs. The typical duration of survival following diagnosis is 10–13 months, with fewer than 5–10% of people surviving longer than five years. Without treatment, survival is typically three months. It is the most common cancer that begins within the brain and the second-most common brain tumor, after meningioma, which is benign in most cases. About 3 in 100,000 people develop the disease per year. About 1 in 170 people develop brain cancer per lifetime. The average age at diagnosis is 64.

Signs and symptoms Common symptoms include seizures, headaches, nausea and vomiting, memory loss, changes to personality, mood or concentration, and localized neurological problems. The kinds of symptoms produced depend more on the location of the tumor than on its pathological properties. The tumor can start producing symptoms quickly, but occasionally is an asymptomatic condition until it reaches an enormous size.

Risk factors The cause of most cases is unclear. The best known risk factor is exposure to ionizing radiation, and CT scan radiation is an important cause. About 5% of cases develop from certain hereditary syndromes.

Genetics Uncommon risk factors include genetic disorders such as neurofibromatosis, Li–Fraumeni syndrome, tuberous sclerosis, or Turcot syndrome. Previous radiation therapy is also a risk. For unknown reasons, it occurs more commonly in males.

Environmental Other associations include exposure to smoking, pesticides, and working in petroleum refining or rubber manufacturing. Glioblastoma has been associated with the viruses SV40, HHV-6, and cytomegalovirus (CMV). Infection with an oncogenic CMV may even be necessary for the development of glioblastoma.

Other Research has been done to see if consumption of cured meat is a risk factor. No risk had been confirmed as of 2003. Similarly, exposure to formaldehyde, and residential electromagnetic fields, such as from cell phones and electrical wiring within homes, have been studied as risk factors. As of 2015, they had not been shown to cause GBM.

Pathogenesis The cellular origin of glioblastoma is unknown. Because of the similarities in immunostaining of glial cells and glioblastoma, gliomas such as glioblastoma have long been assumed to originate from glial-type stem cells found in the subventricular zone. More recent studies suggest that astrocytes, oligodendrocyte progenitor cells, and neural stem cells could all serve as the cell of origin. GBMs usually form in the cerebral white matter, grow quickly, and can become very large before producing symptoms. Since the function of glial cells in the brain is to support neurons, they have the ability to divide, to enlarge, and to extend cellular projections along neurons and blood vessels. Once cancerous, these cells are predisposed to spread along existing paths in the brain, typically along white-matter tracts, blood vessels and the perivascular space. The tumor may extend into the meninges or ventricular wall, leading to high protein content in the cerebrospinal fluid (CSF) (> 100 mg/dl), as well as an occasional pleocytosis of 10 to 100 cells, mostly lymphocytes. Malignant cells carried in the CSF may spread (rarely) to the spinal cord or cause meningeal gliomatosis. However, metastasis of GBM beyond the central nervous system is extremely unusual. About 50% of GBMs occupy more than one lobe of a hemisphere or are bilateral. Tumors of this type usually arise from the cerebrum and may exhibit the classic infiltration across the corpus callosum, producing a butterfly (bilateral) glioma.

Glioblastoma classification Brain tumor classification has been traditionally based on histopathology at macroscopic level, measured in hematoxylin-eosin sections. The World Health Organization published the first standard classification in 1979 and has been doing so since. The 2007 WHO Classification of Tumors of the Central Nervous System was the last classification mainly based on microscopy features. The new 2016 WHO Classification of Tumors of the Central Nervous System was a paradigm shift: some of the tumors were defined also by their genetic composition as well as their cell morphology. In 2021, the fifth edition of the WHO Classification of Tumors of the Central Nervous System was released. This update eliminated the classification of secondary glioblastoma and reclassified those tumors as Astrocytoma, IDH mutant, grade 4. Only tumors that are IDH wild type are now classified as glioblastoma.

Molecular alterations There are currently three molecular subtypes of glioblastoma that were identified based on gene expression:

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