GLIOBLASTOMA MULTIFORME (GBM)

 

Glioblastoma multiforme (GBM) is one of the most aggressive types of cancer. It exhibits rapid cellular growth and highly invasive behavior. GBM is the most common primary intracranial tumor with a very poor prognosis representing 57% of all gliomas.

GBM can be divided into Isocitrate dehydrogenase (IDH) wild type, which is clinically defined as primary or de novo glioblastoma and also corresponds to approximately 90% of GBM cases, and IDH mutant, corresponding to secondary glioblastoma that progressively develops from low-grade astrocytoma and frequently manifests in patients aged 40-50 years old. GBM remains and incurable disease with a median survival rate o 15 months.

 

Classification of Glioblastoma multiforme

Glioblastoma multiforme can be classified into four known subtypes with specific alteration in NF1 and PDGFRA/IDH1. The four types of GBM are Proneural, Neural, Classical and Mesenchymal subtypes.

 

Ethiology of Glioblastoma multiforme

Many genetic and environmental factors have been studied in glioblastoma multiforme, however, no risk factor that accounts for a large proportion of GBM has been identified. An exposure to high ionizing radiation is the only confirmed risk factor of GBM. It has also been reported that relatively low doses of radiation that are used to treat tinea Capitis and skin hemangioma in children have also been associated with relative risks for gliomas.

Furthermore, patients who received treatment for Acute lymphoid leukemia (ALL) are more prone to develop GBM, which could be a result of complications arising from the leukemia or the chemotherapeutic agents used to treat ALL. There is no concluding association between GBM and environmental factors such as smoking, dietary risks factors, cell phones or electromagnetic field. Few studies have however shown the possible role of ovarian steroid hormones in development of GBM.

 

Epidemiology of Glioblastoma Multiforme

Although GBM is a rare tumor with global incidence of less than 10 per 100,000 persons, its poor prognosis with survival rate of 14-15 months after diagnosis makes it a crucial public health issue. GBM accounts for 50% of all gliomas in all age groups. It is primarily diagnosed in adults with a median age but is rare among children.

The ratio of GBM incidence is higher in men as compared to women. It is also more prevalent in the western world than in developing nations. And blacks are less prone to GBM. GBM incidence is higher in other ethnic groups, including, Asians, Latinaos, and Whites.

 

Pathogenesis of Glioblastoma Multiforme

The most frequent location for GBM is the cerebral hemisphere, with 95% of these tumors arising in supratentorial region, while only a few percentage of tumors occur in cerebellum, brain stem, and spinal cord.

 

Genetic and molecular pathogenesis of Glioblastoma Multiforme

Based on clinical characteristic, GBM can be subdivided into primary and secondary GBMs. Primary GBM arise de novo without clinical and histological evidences of precursor lesion. In contrast, secondary GBMs progress slowly from preexisting lower-grade astrocytoma.

Primary GBM is marked by epidermal growth factor receptor (EGFR) gene mutation and amplification, over expression of mouse double minute 2 (MDM2), deletion of p16 and loss of heterozygosity (LOH) of chromosome 10q holding phosphatase and tensin homolog (PTEN) and TERT promoter mutation.

Genetic and molecular pathogenesis of secondary Glioblastoma Multiforme

The molecular pathogenesis of secondary GBM include over expression of platelet-derived growth factor A and platelet-derived growth factor receptor alpha (PDGFA/PDGFRα), retinoblastoma (RB), LOH of 19q and mutation of IDH1/2, TP53 and ATRX.

An assimilated analysis of the numerous genetic abrasions has shown that these genetic lesion are grouped into three main signaling pathways; they are (I) receptor tyrosine kinase (RAS/PI3K), (II) P53 pathway and (III) RB signaling pathway.