2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Glioblastoma: Biology, Genetics, and Behavior
Overview: Glioblastoma (GBM) is a highly malignant, rapidly
progressive astrocytoma that is distinguished pathologically
from lower-grade tumors by necrosis and microvascular hyperplasia.
The global pattern of growth changes dramatically
with the development of GBM histology and is characterized
by hypoxia-driven peripheral expansion from a growing necrotic
core. Necrotic foci present centrally in GBM and are
typically surrounded by “pseudopalisading” cells—a configuration
that is relatively unique and long recognized as an
ominous prognostic feature. Theses pseudopalisades are severely
hypoxic, overexpress hypoxia inducible factor-1 (HIF-1),
and secrete proangiogenic factors, such as vascular endothelial
growth factor (VEGF) and interleukin 8 (IL-8). The microvascular
hyperplasia that emerges in response promotes
peripheral tumor expansion. Recent evidence suggests that
pseudopalisades represent a wave of tumor cells actively
migrating away from central hypoxia that arises following a
GLIOBLASTOMA (GBM; World Health Organization
[WHO] grade 4) is the highest grade astrocytoma and
has a dismal prognosis. 1 Mean survival following the most
advanced treatment, including neurosurgery, radiotherapy,
and chemotherapy is only 60 to 70 weeks. 2 When patients
receive only surgical resection, but are not treated with
adjuvant therapy, mean survival is a mere 14 weeks, underscoring
the tremendous natural growth properties of these
tumors. Lower-grade infiltrative astrocytomas (i.e., WHO
grade 2 and 3 astrocytomas) are also ultimately fatal, but
have substantially slower growth rates and longer survivals
(3 to 8 years). Only once lower-grade tumors have progressed
to GBM do they demonstrate accelerated growth
and rapid progression to death. Those GBMs that progress
from lower-grade gliomas are referred to as “secondary”
GBMs, whereas those GBMs that present without a lowergrade
precursor are termed “primary” or “de novo” GBMs.
De novo tumors account for approximately 90% of all GBMs
and are both clinically and molecularly distinct from secondary
GBMs, as will be discussed below.
Growth Patterns in Grade 2–3 Astrocytomas
Importantly, the biologic properties of GBM (grade 4)
are quite distinct from those of lower-grade astrocytomas
(grade 2 and 3) and suggest that it represents more than an
incremental step in malignancy. The unique neuroimaging
and pathologic features that emerge during the transition to
GBM provide the best insight into potential mechanisms
responsible for the enhanced growth. By magnetic resonance
imaging (MRI), grade 2 and 3 astrocytomas show hyperintense
T2-weighted (or fluid attenuated inversion recovery
[FLAIR]) signal abnormalities, reflecting vasogenic edema
generated in response to diffuse infiltration by individual
tumor cells. Lower-grade tumors expand the involved brain,
but show mild or no contrast enhancement, suggesting an
intact blood-brain barrier and a lack of tumor necrosis.
Radial growth rates are modest, with annual increases in
diameter of 2 to 4 mm/yr. 3 Histologic sections of grade 2–3
tumors reflect the imaging properties: neoplastic cells are
seen diffusely infiltrating between neuronal and glial processes,
leading to architectural distortion and edema. 4-5 As
102
By Daniel J. Brat, MD, PhD
vascular insult. Vaso-occlusive and prothrombotic mechanisms
in GBM could readily explain the presence of pseudopalisading
necrosis in tissue sections, the rapid peripheral
expansion on neuroimaging, and the dramatic shift to an
accelerated rate of clinical progression as a result of hypoxiainduced
angiogenesis. The genetic alterations that coincide
with progression to GBM include amplification of epidermal
growth factor receptor (EGFR), deletion of CDKN2A, and
mutation or deletion of PTEN. Other diagnostic and prognostic
tests used in neuro-oncology include assessment of 1p/19q,
MGMT promoter methylation, IDH1, and p53. More recently,
the Cancer Genome Atlas data have indicated that there are
four robust transcriptional classes of GBM, referred to as
proneural, neural, classical, and mesenchymal. These classes
have genetic associations and may pave the road for future
development of targeted therapies.
astrocytomas progress from the lower end of grade 2 to the
upper end of grade 3, the degree of nuclear anaplasia
increases and the proliferative capacity creeps upward,
resulting in a more densely cellular tumor with greater
malignant potential. Thus, grade 2–3 astrocytomas represent
a continuum of gradually increasing tumor grade and
biologic potential, with clinical behavior generally correlating
with the properties of individual tumor cells.
Changes in Tumor Growth from Grade 2–3
Astrocytomas to Glioblastoma
Tumor dynamics are fundamentally altered in GBM in
comparison to grade 2–3 astrocytomas. Radial growth rates
for GBM can accelerate to values nearly 10 times greater
than those in grade 2 astrocytomas. 3 MRI of GBM typically
reveals a central, contrast-enhancing component (“rimenhancing
mass”) emerging from within the infiltrative
astrocytoma and rapidly expanding outward, causing a
much larger T2-weighted signal abnormality in the tumor’s
periphery.
Studies of cellular proliferation strongly suggest a fundamental
difference in driving biologic forces between the
grade 2–3 astrocytomas and glioblastoma. 6 The most reliable
marker of proliferation is the Ki-67/MIB-1 antibody,
which identifies nuclei of cells in the G1, S, G2, and M
phases of the cell cycle, but is not expressed in the resting
phase, G0. In one study of proliferation in diffuse astrocytomas
of grades 2, 3, and 4, Giannini and colleagues found that
MIB-1 index was highly correlated with survival on multivariate
analysis among grade 2 and 3 astrocytomas. However,
when GBMs (grade 4) were included in the analysis,
proliferation was no longer an independent marker of prog-
From the Department of Pathology and Laboratory Medicine, Winship Cancer Institute,
Emory University School of Medicine, Atlanta, GA.
Author’s disclosure of potential conflicts of interest are found at the end of this article.
Address reprint requests to Daniel J. Brat, MD, PhD, Department of Pathology and
Laboratory Medicine, Emory University Hospital, H-176, 1364 Clifton Rd. NE, Atlanta, GA
30322; email: dbrat@emory.edu
© 2012 by American Society of Clinical Oncology.
1092-9118/10/1-10