Definition and classification of low grade glioma. Clinical diagnosis and investigation. Different methods of treatment

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

3. Low Grade Glioma

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

5. Introduction
Tumors of the central nervous system (CNS)
are classified based on their cell lineage of
origin
Gliomas are a type of neuroepithelial
tumors that originate from the supporting
glial cells within the CNS

6. Grade I
(Well differentiated
Grade II
(Anaplastic astrocytoma)
Grade III
(Glioblastoma multiforme
Ringertz
Kernohan Grade I Grade II Grades III and IV
WHO
Grade I
Juvenile pilocytic
astrocytoma
Grade II
Astrocytoma variants
• Fibrillary
• Protoplasmic
• Gemistocytic
Grade III
Anaplastic
astrocytom
a
Grade IV
Glioblastoma variants
• Giant cell
• Gliosarcoma
St Anne-Mayo
Grade I
Score: 0
Grade II
Score: 1
Grade III
Score: 2
Grade IV
Score: 3 or 4
Relationship of the Kernohan system, the ‘three-tiered’ classification system, the WHO
system and the St Anne/Mayo (Dumas-Deport) grading system for astrocytomas.

7. Glial cell tumors are further classified
based on involved cell type, for example,
astrocytomas, ependymomas
oligodendroglioma, and mixed
oligoastrocytomas

8. Low-grade gliomas (LGGs) are typically slow-
growing tumors compared to high-grade gliomas.
Over time, greater than 70% of these can transform
into a higher grade or become aggressive in
behavior within a decade.

9. A study on serial MRI scans before treatment showed that
these lesions typically grow steadily at an average rate of
4.1 mm annually.
The survival is relatively long in low-grade gliomas
compared to the more aggressive types

10. Etiology
There are no known causes of gliomas, and the risk
factors favoring the development are poorly
understood.
Therapeutic irradiation is the only major
environmental factor increasing the risk of all brain
tumors, including low-grade gliomas

11. Epidemiology
the incidence of grade 2 oligodendrogliomas is 0.25,
for astrocytomas is 0.51, and the mixed glioma is
0.20 per 100000 per year in the United States

12. Low-grade gliomas occur more
commonly in the younger age group
between 20 and 40 years
The peak incidence for oligodendrogliomas
is 40 to 45 years, whereas for astrocytomas
is 30 to 40 years.
Low-grade gliomas are slightly more
common in males

13. Pathophysiology
LGGs grow slowly and can be followed over years without
treatment unless they cause symptoms and grow.
Multiple acquired genetic mutations are found in gliomas.
Tumor suppressor protein 53 (p53), phosphatase and
tensin homolog (PTEN), and epidermal growth factor
receptor (EGFR) are involved in the pathogenesis of these
tumors

14. Histopathology
Atypia, anaplasia, microscopic proliferation,
and necrosis are the histological features that
are used to differentiate low-grade from high-
grade tumors.
Well-differentiated and hypercellular glia with
nuclear atypia and rare mitotic activity are the
histological features of LGGs

15. Type of tumor can be differentiated on the basis of the
appearance of cells e.g. fried egg appearance and
pleomorphic giant cells are present in
oligodendrogliomas and astrocytomas respectively
Therefore, histological classification is possible for
these tumors.

16. The most common presenting symptoms in low-
grade gliomas are headache and seizures.
Seizures are especially common in
oligodendrogliomas since these tend to invade the
cortex
History and Physical

17. It is relatively less common for these tumors to
present with focal neurological deficits such as
unilateral weakness or aphasia.
These tumors tend to infiltrate rather than destroy or
compress the cortex, thus not causing any functional
deficit

18. Radiological Evaluation
Magnetic Resonance Imaging (MRI) Brain
Low-grade gliomas appear hypointense on T1 and hyperintense on T2-
fluid attenuated inversion recovery (FLAIR) sequences. Calcification
can be evident on susceptibility-weighted imaging (SWI) sequence.
Low-grade tumors typically do not enhance and, when present is
patchy and not ring-enhancing.
Since contrast enhancement is associated with a breach in the blood-
brain barrier, its presence would favor and indicate a more aggressive
or a higher-grade tumor.

19. Functional MRI, diffusion MRI, perfusion MRI,
MR spectroscopy, and positron emission
tomography help to identify changes in the tumor
and its surrounding microenvironment to monitor
the response to treatments and progression during
the surveillance phase.
In PET scan, the accumulation of
fluorodeoxyglucose can help to distinguish low-
grade from high-grade tumors based on the
uptake

20. Molecular Neuropathology
TP53 has been known to be present in most low-grade
astrocytomas and rare to absent in oligodendrogliomas.
It has also been well known that most of the
oligodendrogliomas have co-deletion of the short arm of
chromosome 1 (1p) and the long arm of chromosome 19
(19q).
Both these mutations (TP53 and 1p/19q co-deletion) are
mutually exclusive in almost all low-grade gliomas

21. The discovery about mutations of IDH, the gene coding for
an enzyme in the Krebs cycle, isocitrate dehydrogenase
being present in over 75% of low-grade glioma has been a
breakthrough
The majority are IDH1 mutations (R132H) and less
commonly IDH2 mutations. These mutations lead to altered
enzyme function, ultimately leading to the production of 2-
hydroxyglutarate, which is an oncometabolite and has a
broad range of effects on gene expression

22. Thus from a molecular neuropathology perspective, low-grade
gliomas may be classified into three categories:
a) group with IDH mutation and 1p/19q co-deletion, which
comprises of oligodendrogliomas,
b) group with IDH mutation and without 1p/19q co-deletion
where most of these have TP53 mutations and ATRX
mutations and comprise of astrocytomas
c) group with neither IDH mutation nor 1p/19q co-deletion.

23. Thus, when a glioma is suspected on clinical
presentation, imaging, and tissue is obtained, it is
strongly recommended to test for IDH mutation and
1p/19q co-deletion to have definitive tumor
classification

24. Treatment
Surgery is indicated in patients with a significant mass
effect, and neurological deficits secondary to the tumor, and
the decision-making becomes obvious

25. The major challenge arises when the tumor
is detected incidentally when an individual
presents with a seizure or other
neurological symptoms like headache,
which is medically controlled and is
otherwise asymptomatic

26. Multiple factors need to be taken into consideration
while making this decision, which includes,
preference of the patient,
prognostic factors like age,
tumor size,
and location

27. For cases where observation is the chosen
strategy, serial imaging should be performed
with a plan to revisit the decision
appropriately based on follow up studies

28. Surgical Management
When surgery is pursued, there is a lack of level 1
evidence about whether resection or a biopsy should
be undertaken.
Based on the overall experience, most authorities in
the field favor a maximal safe resection over
biopsies.
Moreover, the diagnostic accuracy is improved with
resection compared to needle biopsies

29. There are multiple techniques available to
perform gross total resection (GTR) of the
tumors and avoid neurological deficits in
extended surgery or when tumors are not well
demarcated.
These include stereotactic
neuronavigation, intraoperative
MRI, fluorescence-guided glioma surgery, and
intraoperative functional mapping.

30. Radiation and Chemotherapy
The timing and sequence of additional treatment
options like radiotherapy and chemotherapy in the
management of low-grade gliomas is a challenging
question in neuro-oncology.
One prospective study observing patients who have
undergone a gross total resection of the low-grade
glioma and younger than 40 years of age found that
slightly over 50% have recurred within five years
post-surgery

31. When the observation is undertaken in lower-risk
patients, it requires a long-term follow up comparing
MRI scans to the early postoperative scans to
accurately detect changes
patients with low-grade tumors who require
additional treatment should strongly be considered
for combination therapy

32. Regardless of the initial management, low-grade
gliomas ultimately regrow.
Increasing enhancement might develop, and when
operated, the tissue might have transformed into a
high-grade glioma by histopathology.
This phenomenon is called malignant transformation.
Management of patients at this stage would be to treat
the alternative treatment, which they did not receive
previously

33. Prognosis
A spectrum of outcomes is seen in patients with low-
grade gliomas.
Patient groups can be recognized with a median
survival as low as two years to greater than 12 years,
depending on the grade according to the 2016 WHO
CNS classification

34. The clinical prognostic factors include:
 Age: Younger patients do better compared to older patients, with
some studies classifying the age of below and above 40 years
being low and high risk, respectively.
 Symptoms at presentation: Presenting symptoms like
seizures are associated with a good prognosis as well,
likely due to the earlier diagnosis of the condition
leading to close monitoring. This could well be due to
lead-time bias. While fixed neurological deficits are
associated with a poor prognosis.
 Tumor size and area involved: Tumor size is also important, with
larger tumors associated with a poor prognosis and involvement
of corpus callosum is associated with adverse outcomes.

35. Molecular tests allow for a
more refined estimation of
prognosis.

36. The presence of 1p/19q co-deletion is associated with a
favorable diagnosis.
One study showed that the median survival of 1p/19q co-
deleted tumors (oligodendrogliomas) was 12 years
compared to 8 years in non-co deleted gliomas.

37. IDH mutation is also associated with a favorable
prognosis in most low-grade gliomas. A French
study showed an OS of 11 years versus seven years
in gliomas with and without IDH mutation in low-
grade gliomas treated with temozolomide, indicating
a favorable prognosis with chemosensitivity