Originally, glioblastoma was thought to be derived from and composed of primitive embryonal cells, or, in the late decades of the twentieth century, to arise through anaplasia of maturing astrocytes. However, these views have been called into question because models of malignant transformation of neural stem cells or of glial progenitor cells explain many of the characteristics and behavior of gliomas. The location, cellular and genetic heterogeneity, and manner of growth and spread of these tumors are consistent with an origin in a primitive cell. Sanai and colleagues have summarized the case for stem cell origin, but this notion is not universally accepted and potential deficiencies in this theory are noted by Reid and coworkers. The genetic or epigenetic events that putatively lead to a malignant evolution of these progenitor cells are not known but some aspects are discussed below. Ironically, this is a reversion to the idea of the early last century that posited an embryonal origin of glioma. Furthermore, there is a configuration of genetic markers that may promote the transformation of a lower grade glioma into glioblastoma.
The natural history of untreated glioblastoma is well characterized. Fewer than 20 percent of patients survive for 1 year after the onset of symptoms and only about 10 percent live beyond 2 years (Shapiro). Age is an important prognostic factor; fewer than 10 percent of patients older than age 60 years survive for 18 months, in comparison to two-thirds of patients younger than age 40 years. Survival with anaplastic astrocytoma is somewhat better, typically 3 to 5 years. Cerebral edema and increased intracranial pressure are usually the causes of death. Survival rates with treatment are discussed in the following text.
(anaplastic) glioma without many of the special histologic features of glioblastoma. The natural progression is for these astrocytomas to progress to glioblastoma and there may be certain constellations of mutations that promote such transformations.
The diagnosis of both of these tumor types must be confirmed by a stereotactic biopsy or by a craniotomy that aims to remove as much tumor as is feasible at the same time.
Genetics of gliomas Among the first detectable changes in glioblastoma are mutations acquired in the act of neoplastic cell division that inactivate the tumor suppressor gene p53 on chromosome 17p; over 50 percent of astrocytomas have deletions within this gene. Other early changes include overexpression of genes that control growth factors or their receptors as noted below. After the tumor develops, progression to a more malignant grade of astrocytoma or to a glioblastoma may be triggered by defects causing overexpression of the epidermal growth factor gene. In fact, it is striking that analysis of the patterns of these defects in some tumors correlates with the staging and aggressive characteristics of these tumors. The events that lead to their accumulation are not clear, as noted below. Also, mutations in the genes that code for isocitrate dehydrogenase (IDH1 and 2) are common in gliomas and oligodendrogliomas and their presence relates to slower tumor progression.
Furthermore, mutations in the paired 1p/19q region, EGFR, ATRX, TERT promoter and a number of other subsidiary genes influence the behavior of gliomas, treatment response (see below), and have greatly altered modern classification as already noted. As noted below, epigenetic characteristics, especially of MGMT methylation, are also involved in the response to antitumor agents, specifically temozolomide. A systematic approach to understanding these mutations is shown in Fig. 30-3. In the modern conceptualization, there is a hierarchy of mutations that determine tumor behavior.