This document provides an overview of glioblastoma multiforme (GBM), the most common and aggressive type of primary brain tumor. It describes the etiology, epidemiology, pathophysiology, presentation, diagnosis through imaging, histologic findings, treatment options including surgery, radiation and chemotherapy, and prognosis. GBM is difficult to treat due to tumor heterogeneity, rapid growth and recurrence. The standard of care involves maximal surgical resection followed by radiation and chemotherapy, but the median survival time remains less than 2 years.

2. Medhat Mustafa, MD,
Department of Neurosurgery
Suez Canal University, Ismailia, Egypt

3. Glioblastoma Multiforme

4. Objectives:
 Describe the etiology of high-grade gliomas.
 Outline the pathogenesis and appropriate evaluation of
high-grade gliomas.
 Desribe the presentation
 Review the management options available for lhigh-grade
gliomas.
 Identify interprofessional team strategies for improving
care coordination and communication to advance cancer,
high-grade gliomas, and improve outcomes.

5. Background
Of the estimated 17,000 primary brain tumors diagnosed in the
United States each year, approximately 60% are gliomas. Gliomas
comprise a heterogeneous group of neoplasms that differ in
location within the central nervous system, in age and sex
distribution, in growth potential, in extent of invasiveness, in
morphological features, in tendency for progression, and in
response to treatments.

6. Etiology
The etiology of glioblastoma remains unknown in most cases.
Familial gliomas account for approximately 5% of malignant gliomas,
and less than 1% of gliomas are associated with a known genetic
syndrome (eg, neurofibromatosis, Turcot syndrome, or Li-Fraumeni
syndrome)
Studies of association with head injury, N-nitroso compounds,
occupational hazards, and electromagnetic field exposure have been
inconclusive

7. Epidemiology
Glioblastoma multiforme is the most frequent primary brain tumor,
accounting for approximately 12-15% of all intracranial neoplasms and
50-60% of all astrocytic tumors. In most European and North American
countries, incidence is approximately 2-3 new cases per 100,000 people
per year
Overall incidence is very similar among countries. Glioblastoma
multiformes are slightly more common in the United States,
Scandinavia, and Israel than in Asia.

8. Glioblastoma multiforme may manifest in persons of any age, but it
affects adults preferentially, with a peak incidence at 45-70 years
males had a slight preponderance over females, with a male-to-female
ratio of 3:2

9. Pathophysiology
Glioblastomas can be classified as primary or secondary.
Primary glioblastoma multiforme accounts for the vast
majority of cases (60%) in adults older than 50 years. These
tumors manifest de novo (ie, without clinical or
histopathologic evidence of a preexisting, less-malignant
precursor lesion), and patients presenting after a short
clinical history, usually less than 3 months.

10. Secondary glioblastoma multiformes (40%) typically
develop in younger patients (< 45 y) through
malignant progression from a low-grade astrocytoma
(WHO grade II) or anaplastic astrocytoma (WHO grade
III).
The time required for this progression varies
considerably, ranging from less than 1 year to more
than 10 years, with a mean interval of 4-5 years

11. Increasing evidence indicates that primary and
secondary glioblastomas constitute distinct
disease entities that evolve through different
genetic pathways, affect patients at different
ages, and differ in response to some of the
present therapies

12. Glioblastoma multiformes occur most often in the
subcortical white matter of the cerebral
hemispheres. In a series of 987 glioblastomas from
University Hospital Zurich, the most frequently
affected sites were the temporal (31%), parietal
(24%), frontal (23%), and occipital (16%) lobes.
Combined frontotemporal location is particularly
typical.

13. Tumor infiltration often extends into the adjacent
cortex or the basal ganglia.
When a tumor in the frontal cortex spreads across the
corpus callosum into the contralateral hemisphere, it
creates the appearance of a bilateral symmetric
lesion, hence the term butterfly glioma.
Sites for glioblastomas that are much less common
are the brainstem (which often is found in affected
children), the cerebellum, and the spinal cord.

14. Some of the more common genetic abnormalities are
described as follows
Mutations in p53, a tumor suppressor gene
Epidermal growth factor receptor (EGFR) gene
Platelet-derived growth factor–alpha (PDGF-alpha) gene
PTEN: PTEN (also known as MMAC and TEP1) encodes a
tyrosine phosphatase located at band 10q23.3

15. Presentation
The clinical history of patients with glioblastoma
multiformes (GBMs) usually is short, spanning less than 3
months in more than 50% of patients, unless the
neoplasm developed from a lower-grade astrocytoma.

16. The most common presentation of patients with
glioblastomas is a slowly progressive neurologic deficit,
usually motor weakness.
However, the most common symptom experienced by
patients is headache.
Alternatively, patients may present with generalized
symptoms of increased intracranial pressure (ICP),
including headaches, nausea and vomiting, and cognitive
impairment.
Seizures are another common presenting symptom.

17. Imaging Studies
Magnetic resonance imaging (MRI)
Magnetic resonance imaging (MRI) with and without contrast is the
study of choice
These lesions typically have an enhancing ring observed on T1-weighted
images and a broad surrounding zone of edema apparent on T2-
weighted images..
A T1-weighted axial MRI without intravenous
contrast. This image demonstrates a
hemorrhagic multicentric tumor (glioblastoma
multiforme [GBM]) in the right temporal lobe.
Effacement of the ventricular system is present
on the right, and mild impingement of the
right medial temporal lobe can be observed on
the midbrain

18. The central hypodense core represents necrosis, the contrast-
enhancing ring is composed of highly dense neoplastic cells
with abnormal vessels permeable to contrast agents, and the
peripheral zone of nonenhancing low attenuation is vasogenic
edema containing varying numbers of invasive tumor cells
A T1-weighted coronal MRI with intravenous
contrast. This image demonstrates the lesion
(glioblastoma multiforme [GBM]) within the
medial temporal lobe and the stereotypical
pattern of contrast enhancement

19. A T2-weighted axial MRI. The
tumor (glioblastoma multiforme
[GBM]) and surrounding white
matter within the right temporal
lobe show increased signal
intensity compared to a healthy
brain

20. A fluid-attenuated inversion
recovery (FLAIR) axial MRI. This
image is similar to the T2-weighted
image and demonstrates extensive
edema in a patient with
glioblastoma multiforme (GBM).

21. Several pathological studies have clearly
shown that the area of enhancement does
not represent the outer tumor border
because infiltrating glioma cells can be
identified easily within, and occasionally
beyond, a 2-cm margin

22. Positron emission tomography (PET) scans and
magnetic resonance (MR) spectroscopy can be
helpful to identify glioblastomas in difficult
cases, such as those associated with radiation
necrosis or hemorrhage.

23. On PET scans, increased regional glucose
metabolism closely correlates with cellularity and
reduced survival.
MR spectroscopy demonstrates an increase in
the choline-to-creatine peak ratio,
an increased lactate peak,
and decreased N- acetylaspartate (NAA) peak in
areas with glioblastomas

24. Magnetic resonance (MR) spectroscopy is
representative of a glioblastoma
multiforme (GBM), demonstrating a high
peak ratio of choline (CHO) to creatine
(CR), a decreased N-acetylaspartate (NAA)
peak, and an increased lactate (LAC) peak.

25. Histologic Findings
Glioblastoma multiformes are composed of poorly
differentiated, often pleomorphic astrocytic cells with
marked nuclear atypia and brisk mitotic activity. Necrosis
is an essential diagnostic feature, and prominent
microvascular proliferation is common

26. Undoubtedly, glial fibrillary acidic protein (GFAP)
remains the most valuable marker for neoplastic
astrocytes.
Although immunostaining is variable and tends to
decrease with progressive dedifferentiation, many
cells remain immunopositive for GFAP even in the
most aggressive glioblastomas.
Vimentin and fibronectin expression are common
but less specific

27. The regional heterogeneity of glioblastomas is
remarkable and makes histopathological diagnosis a
serious challenge when it is based solely on
stereotactic needle biopsies.
Tumor heterogeneity is also likely to play a
significant role in explaining the meager success of all
treatment modalities, including radiation,
chemotherapy, and immunotherapy.

28. Completely staging most glioblastomas is neither practical
nor possible because these tumors do not have clearly
defined margins.
Rather, they exhibit well-known tendencies to invade
locally and spread along compact white matter pathways,
such as the corpus callosum, internal capsule, optic
radiation, anterior commissure, fornix, and subependymal
regions.
Such spread may create the appearance of multiple
glioblastomas or multicentric gliomas on imaging studies

29. Careful histological analyses have indicated that
only 2-7% of glioblastomas are truly multiple
independent tumors rather than distant spread
from a primary site.

30. Despite its rapid infiltrative growth, the glioblastoma
tends not to invade the subarachnoid space and,
consequently, rarely metastasizes via cerebrospinal fluid
(CSF).

31. Hematogenous spread to extraneural tissues is very
rare in patients who have not had previous surgical
intervention, and penetration of the dura, venous
sinuses, and bone is exceptional

32. Treatment
The treatment of glioblastomas remains difficult in that
no contemporary treatments are curative
While overall mortality rates remain high, improved
understanding of the molecular mechanisms and gene
mutations combined with clinical trials are leading to
more promising and tailored therapeutic approaches

33. Multiple challenges remain, including
tumor heterogeneity
tumor location in a region where it is beyond the reach of
local control
and rapid, aggressive tumor relapse.
Therefore, the treatment of patients with malignant gliomas
remains palliative and encompasses surgery, radiotherapy,
and chemotherapy..

34. Because glioblastomas cannot be cured with
surgery, the surgical goals are to
establish a pathological diagnosis,
relieve mass effect,
and, if possible, achieve a gross total resection to
facilitate adjuvant therapy

35. Upon initial diagnosis of glioblastoma
multiforme (GBM), standard treatment
consists of maximal surgical resection,
radiotherapy, and concomitant and adjuvant
chemotherapy with temozolomide

36. While patients are in the hospital, they should
receive postoperative imaging to determine the
extent of surgical resection. Surgical resection is
evaluated best within 3 days of surgery by using
contrast-enhanced MRI.
Contrast enhancement during this period
accurately reflects residual tumor

37. For patients older than 70 years, less aggressive
therapy is sometimes employed, using radiation or
temozolomide alone
A study by Scott et al found that elderly patients
with glioblastoma who underwent radiotherapy had
improved cancer-specific survival and overall
survival compared with those who did not undergo
radiotherapy treatment

38. Evidence suggests that in patients over 60 years old,
treatment with temozolomide is associated with
longer survival than treatment with standard
radiotherapy, and for those over 70 years old,
temozolomide or hypofractionated radiotherapy is
associated with prolonged survival than treatment
with standard fractionated radiotherapy

39. Median time to recurrence after standard therapy
is 6.9 months.
For recurrent glioblastoma multiforme, surgery is
appropriate in selected patients, and various
radiotherapeutic, chemotherapeutic, biologic, or
investigational therapies are also employed

40. Most glioblastomas recur in and around the
original tumor bed, but contralateral and distant
recurrences are not uncommon, especially with
lesions near the corpus callosum.

41. Reoperation is generally considered in the face
of a life-threatening recurrent mass, particularly
if radionecrosis rather than recurrent tumor is
suspected as the cause of clinical and
radiographic deterioration

42. Positron emission tomography (PET) scans and
magnetic resonance (MR) spectroscopy have
proven useful in discriminating between those 2
entities

43. The extent of surgery (biopsy vs resection) has
been shown in a number of studies to affect
length of survival

44. patients with high-grade gliomas who had a gross
total resection had a 2-year survival rate of 19%,
while those with a subtotal resection had a 2-year
survival rate of 0%.

45. The use of functional MRI and diffusion tensor
imaging (DTI) in preoperative planning, as well as
ultrasound, CT scans, and MRI with direct stimulation
during surgery, has allowed for multimodal
neuronavigation and the integration of patient-
specific anatomic and functional data.
Despite these technologies, differentiating between
normal brain and residual tumor continues to be a
major challenge

46. Oral aminolevulinic acid (ALA; Gleolan) was approved by the
US Food and Drug Administration (FDA) in 2017 as an adjunct
for visualization of malignant tissue during surgery in patients
with malignant glioma (suspected WHO grades III or IV on
preoperative imaging).

47. During surgery, an operating microscope adapted
with a blue-emitting light source and filters for
excitation light of wavelength 375-440 nm, and
observation at wavelengths of 620-710 nm is used to
visualize PpIX (an ALA metabolite) accumulation in
tumor cells that shows up as red fluorescence

48. Fluorescence-guided surgery (FGS), an emerging
technology that combines detection devices with fluorescent
contrast agents, may provide more complete and precise
resection of gliomas.
Tozuleristide (BLZ-100), a near-infrared imaging agent
composed of the peptide chlorotoxin and a near-infrared
fluorophore indocyanine green, is a candidate for FGS of
glioma and other tumor types.

49. Even with advances in surgical
resection, the prognosis for patients
with GBM remains poor

50. Aside from extent of surgical resection, other factors
have been associated with increased and overall
survival
Patient age
and Karnofsky Performance Status are widely
recognized as prognostic factors,
with lower age and higher performance status
conferring longer survival

51. Tumors greater than 5–6 cm and those that cross
the mid-line have been associated with negative
outcomes .
Supratentorial and cerebellar tumors, which are more
amenable to surgical treatment, carry a better prognosis
than tumors in the brainstem or diencephalon