The most common cancer arising from the brain is the glioblastoma multiforme (GBM). It is also the most deadly,1 representing the most aggressive subtype among the gliomas, a collection of tumors including astrocytomas and oligodendrogliomas. In 1926, Bailey and Cushing, in describing ‘spongioblastoma multiforme’, the label then used for GBM, noted that:
“It is from this group doubtless that the generally unfavorable impression regarding gliomas as a whole has been gained. It is not only the largest single group in the series…but at the same time is one of the most malignant…In the five unoperated cases, the average duration of life from the onset of symptoms was only three months, which speaks well on the whole for the average survival period of twelve months for those surgically treated.
Since their seminal work, the median survival of 12 months has not changed markedly. Both data from the 1960’sand current data confirm that the extent of surgical resection is an important prognostic factor. However, as Bailey and Cushing observed, GBMs have “infiltrating propensities, and…when enucleation is attempted, the growth is found at the depth to spread into and merge with the normal cerebral tissue without recognizable demarcation. In prior eras, radical surgical excisions, including removal of the entire cerebral hemisphere containing the tumor,5 were occasionally attempted, yet patients who survived the hemispherectomy died of recurrent tumor,6 clinically proving the importance of the histologic observation that tumor cells invade throughout the brain. In the modern age, brain imaging may disclose macroscopic tumor in the opposite hemisphere (see Figure 1) or even gliomatosis cerebri—literally a brain full of tumor. In the years leading to up to World War II, the German pathologist Scherer, whose scientific discoveries were tainted by his Nazi activities,7 described ‘secondary structures’8,9 that further characterized invasive tumor cells. These structures are ‘secondary’ because they are dependent for their formation on underlying normal brain structures, as opposed to ‘primary’ structures of the tumor such as pseudopalisading necrosis and microvascular proliferation. Examples include perineuronal and perivascular satellitosis (accumulation of tumor cells around neurons and blood vessels), subpial spread, and intrafascicular tracking such as infiltration along corpus callosum and other white matter tracks.