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An overview of Glioblastoma Multiforme

A brain tumor is an uncontrolled and abnormal proliferation of cells in the brain leading to catastrophic consequences. There are two broad categories of brain tumors namely non-cancerous (benign) and cancerous (malignant) based on the growth pattern, spread, and the frequency of recurrence rate.

Glioblastoma Multiforme

The benign tumor grows locally and is non-spreading or non-metastasizing, whereas malignant tumors grow aggressively and spread to other parts of the body from the site of origin (metastasis). As the brain is the most vital epicenter for all functional control and processes of the body, the uncontrolled proliferation of cells creates havoc in causing symptoms of seizures, vision problems or blurred vision, nausea, headaches, drowsiness, and even paralysis. However, some benign tumors are asymptomatic (without any detectable symptoms). Metastatic brain tumors are also called secondary brain tumors contrary unlike primary brain tumors.

Primary tumors may be classified as glial tumors or gliomas (composed of glial cells) and non-glial tumors (developed on or in the structures of the brain, including nerves, blood vessels, and glands). Central nervous system (CNS) tumors contribute to approximately 2% of all malignancies. About 80% of malignant brain tumors may be gliomas. Glioblastoma multiforme (GBM) is a grade IV glioma, also called glioblastoma, and is one of the most lethal cancers of CNS in adults.

The biopsy-driven histological grading (II-IV) demonstrates different stages of GBM. There is cytologic atypia (II), anaplastic and increased mitotic activity (III), and microvascular proliferation and necrosis (IV). There are further different molecular types of GBM based on mutations. The molecular category of classification based on genetic mutations are namely IDH, MGMT methylation, EGFR, TERT promoter, H3F3A, FGFR fusion, NTRK fusion mutations, and chromosomal aberrations such as gain of 7th chromosome p arm and loss of 10th chromosome q arm, respectively.


Global perspective


Glioblastoma has a global annual incidence of 3.21 per 100,000 population. GBM has an annual incidence of approximately 5.2 per 100,000 population and approximately 16,300 new diagnoses per year in the United States of America. The adult GBM occurs most frequently in the cerebral hemispheres, including both frontal and temporal lobes of the brain. Approximately, 15,000 new astrocytoma cases are diagnosed every year in the U.S.A with a slight male predominance. In the U.S.A., the median age of GBM diagnosis is 64 years which implies that the disease is primarily diagnosed at an older age and is usually uncommon in children. Additionally, the incidence rate of GBM is 2.5 times higher in European Americans than in African Americans and it is found to be more common in non-Hispanics than in Hispanics.


Indian perspective


In India, GBM and other brain cancers are rare in occurrence. Only 2-3 cases out of 100,000 individuals. The CNS malignancies account for approximately 2% of all diagnosed malignancies. In the light of a few studies, there has been a constant agreement on the median age of GBM patients for diagnosis. The median diagnosed age of GBM in India is around 50 years. There is also a decrease in median survival of GBM patients with an increase in age. However, the observations are scanty to give conclusive evidence of such epidemiological figures.


Signs and symptoms


The worsening symptoms are common features of GBM including increased intracranial pressure, along with headache and focal or progressive neurologic deficits. The initial stage presents symptoms such as seizures in as many as 25% of patients; however, more than 50% of the patients experience this seizure at a later stage of the disease. Other common features include nausea or vomiting, a decline in brain function like confusion or memory loss, difficulty with balance, urinary incontinence, vision problems like blurred vision, double vision or loss of peripheral vision, and speech difficulties.


Diagnosis


The diagnosis of glioblastomas primarily depends on imaging techniques such as magnetic resonance imaging (MRI) and computed tomography (CT or CAT scan) followed by biopsy with histopathological confirmation. If a biopsy cannot be performed, then the treatment plan is made based only on the brain scans only. Some more advanced marker-based diagnoses can be made with:​

  • F in-situ hybridization (FISH)

  • Immunohistochemistry (IHC)

  • Quantitative polymerase chain reaction (qPCR)


Management


The detrimental nature and quick progression (median survival of about 15 months) of glioblastomas, make it almost impossible to cure, despite aggressive multimodal treatment strategies. Moreover, the heterogeneous nature of glioblastomas makes it extremely challenging to develop an effective therapeutic approach with a uniform outcome for all patients. The mainstay of glioblastoma treatment is surgery, followed by concomitant radiotherapy as well as chemotherapy. The main purpose of the surgical resection is to reduce the solid tumor tissue within the brain, specifically removing the center of the tumor that may be resistant to radiotherapy and/or chemotherapy, and further reduce intracranial pressure. After the surgical wound has healed considerably, radiotherapy and chemotherapy may be adjuvant or concurrent. Radiotherapy is repeated for a total of 10 to 30 cycles depending on various characteristics of the tumor. Currently, three chemotherapeutic agents named temozolomide (TMZ), bevacizumab, and carmustine have been approved by the FDA to treat GBM patients. Thus, the standard of treatment is chemotherapy with the drug TMZ, (Stupp regimen). In addition, newer generation chemotherapeutic and targeted therapeutic agents are constantly evolvin