CLINICAL PRESENTATION

AND DIAGNOSIS IN GLIOMA

Rahmi Ardhini
Neuro-oncology Division, Dept of Neurology,
Medical Faculty Diponegoro University/
dr. Kariadi General Hospital Semarang
4Juli 2020
 Outline
• Introduction
• Diagnosis in Glioma
• Clinical presentation of Low Grade and High
Grade Glioma
ü Generalized symptoms
ü Focal symptoms
• Imaging in Glioma
 INTRODUCTION

• Gliomas is the most common primary CNS tumors,

represent 31% of all and 81% of malignant brain and CNS
tumors
• Arise from glial precursor cells (astrocytes,
oligodendrocytes, ependymal cells)
• Classified according to the World Health Organization
(WHO) into various histologic subtypes and grades
• Devided into Low-grade (grade I-II) and High-grade (III-IV)
 EPIDEMIOLOGY

Clinical characteristics of glioma

Distribution of primary brain and other CNS
glioma based on histology subtypes

Ostrom et al. CBTRUS Statistical Report. 2019

Rasmussen, et al. J Neurooncol. 2017
 GLIOMA EPIDEMIOLOGY
(Dr. Kariadi General Hospital 2015 – 2018)
BASED ON: BASED ON:
Phenotype Phenotype + Genotype
- Morphologic - Morphologic
features features
- Anaplasia grading - Anaplasia grading
- Molecular markers

Greater diagnosis accuracy, improved patient

management, accurate determinations of prognosis
and treatment response
 WHO 2016 Classification of Glioma
Diffuse Astrocytic and Oligodendroglial Tumours Grade
Diffuse astrocytoma, IDH-mutant II
Anaplastic astrocytoma, IDH-mutant III
Anaplastic astrocytoma, NOS III
Glioblastoma, IDH-wildtype IV
Glioblastoma, IDH-mutant IV
Diffuse Midline Glioma, H3K27M-mutant IV
Oligodendroglioma, IDH-mutant and 1p19q-codeleted II
Anaplastic oligodendroglioma, IDH-mutant and 1p19q-codeleted III
Other Astrocytic Tumours
Pilocytic astrocytoma I
Supependymal giant cell astrocytoma I
Pleomorphic xanthoastrocytoma II
Anaplastic pleomorphic xanthoastrocytoma III
Ependymal Tumours
Subependymoma I
Myxopapillary ependymoma I
Ependymoma II
Ependymoma, RELA fusion-positive II or III
Anaplastic ependymoma III
Other Gliomas
Angiocentric glioma I
Chordoid glioma of third ventricle II
Louis, et al. 2016
 The 2016 World Health Organization Classification of
Tumors of the Central Nervous System: a summary

Louis, et al. 2016

DIAGNOSIS IN GLIOMA

ANAMNESIS BIOPSY

Clinical Histolopatology
presentation grading
(Signs &
Symptoms) IMAGING

Brain contrast
CT Scan / MRI
 CLINICAL PRESENTATION
Generalized Symptoms (secondary effects)
Mass effects, Raised intracranial pressure, obstruction

• Headache • Vomiting
• Nausea • Cognitive/ behavioural
• Papilledema changes

Focal Symptoms (direct effects)

Site specific (tumor mass, edema, hemorrhage)
• Motor deficits • Language deficits or aphasia
• Sensory deficits • Seizures
• Visual deficits
 Clinical Presentation in Glioma

TUMOR TYPE
SYMPTOM LOW-GRADE MALIGNANT
GLIOMA GLIOMA
Percent with symptom

Headache 40 50

Seizure 65-95 15-25

Hemiparesis 5-15 30-50

Mental-status 10 40-60
abnormalities

The most common glioma presenting symptoms Symptoms of Brain Tumor

(Posti, et al. Acta Neurol Scand. 2015) (de Angelis, et al. NEJM. 2001)
Clinical characteristics of study population according
to WHO gr I-IV

Variables Groups Grade I Grade II Grade III Grade IV Total

(n=40) (n=247) (n=279) (n=1364) (n=1930)

Focal Yes 20 (50%) 84 (34%) 153 (55%) 978 (72%) 1235

deficit
No 19 (48%) 159 (64%) 120 (43%) 373 (27%) 671

Epileptic Yes 10 (25%) 144 (58%) 127 (45%) 326 (24%) 607
seizure
No 29 (73%) 98 (40%) 144 (52%) 1002 (73%) 1273

Cognitive Yes 5 (13) 60 (24%) 114 (41%) 649 (48%) 828

change
No 33 (82%) 178 (72%) 156 (56%) 689 (50%) 1056

Headache Yes 17 (43%) 55 (22%) 85 (30%) 513 (38%) 670

Venn diagram showing the distribution
No 21 (52%) 184 (75%) 181 (65%) 809 (59%) 1195 of different combination of onset
symptoms in glioma

The most common symptom combination at onset was focal

deficit and cognitive change (29%)

Rasmussen, et al. J Neurooncol. 2017

Clinical presentation of Glioma Patients
dr. Kariadi General Hospital 2015 - 2018
 BRAIN TUMOR HEADACHE (BTH)
§ The prevalence of headache during the course of intracranial tumours were
32% - 71%
§ Headache at presentation being observed in approximately 20%
§ 50% in Low-grade glioma ; 77% in High-grade glioma
§ Characteristic :
Ø Progressive
Ø Worse in the morning (32%)
Ø Aggravated by valsava maneuvers (23%)
Ø Worse with bending over (36%)
§ 48% associated with nausea and vomiting
§ Tension-type or migraine-like headaches

ICHD-3 3rd ed
Headache attributed to intracranial neoplasm is a headache that is usually
progressive, worse in the morning and aggravated by Valsalva maneuvers,
caused by one or more space-occupying intracranial tumors.
Russo, et al. Cephalalgia. 2017
Ranjan S, Schiff D. 2018
Clinical characteristics of brain tumor headaches

Headache
location may have
a localizing value

Ranjan S, Schiff D. 2018

 Pathophysiology of Brain Tumor Headache

ü Stimulation of pain-sensitive structures on or above the tentorium resulted in pain trans-

mitted by CN V located in the anterior half of the head.
ü Stimulation on or below the tentorium resulted in pain over the posterior half of the
head via CN IX and X and the upper three cervical nerves.
Schiff D. 2018
 Clinical and demographic variables in patients with
or without headache at presentation of glioma

Headache p-value
Yes No

Number of patients (%) 12% 88%

Gender 0,856
Male 61% 59% Clinical characteristics of the study
Female 31% 41% population according to WHO grade I–IV
Histology 0,157
Glioblastoma 61% 51% Variables Groups Grade Grade II Grade III Grade IV Total
Other glioma 39% 49% I (n=247) (n=279) (n=1364) (n=1930)
(n=40)
WHO grade 0,166
Grade I/II 21% 29% Headache Total 17 55 85 513 670
Grade III 13% 18% duration (100%) (100%) (100%) (100%) (100%)
Grade IV 66% 53% < 1 4 16 48 356 424 (63%)
month (23%) (29%) (56%) (69%)
Tumor Location 0,038
Supratentorial 79% 88% 1-3 9 21 16 109 155 (23%)
Infratentorial 16% 7% months (53%) (38%) (19%) (21%)
Supra&infratentorial 5% 5% > 3 3 16 13 29 61 (9%)
months (18%) (29%) (15%) (6%)
Tumor site 0,013
Right 52% 41%
Left 27% 46%
Bilateral 21% 13%

Headache type (%)

Brain tumor headache 42%
Worsening of pre-existing headache 11%
Tension-type headache 47%
Migrain-like headache 0%

Russo, et al. Cephalalgia. 2017 Rasmussen, et al. J Neurooncol. 2017

When should you be concerned about a
headache?

Kernick, et al. 2008

 SEIZURES (Glioma-related Epilepsy)
• Glioma-related epilepsy (GRE) is defined as symptomatic epileptic
seizures secondary to gliomas
• Factors affecting GRE incidence
Tumor Type :
Oligodendroglial tumor >> astrocytic tumor

Tumor Type :
ü LGG is highly epileptogenic (65-90%) and the most common initial
symptom
ü In HGG, incidence is 40-64%

Tumor Location :
ü Superficial cortical area
ü Frontal, temporal, insular
ü Eloquent brain area

A new onset seizure in a patient > 40 years of age should be considered

indicative of a brain tumor until proven otherwise. Liang, et al. Cancer Medicine. 2019
Schiff D, et al. 2018
Tonn, et al. 2010
Seizure characteristics in patients with
neuroepithelial tumors

Schiff D, et al. 2018

Seizure Prevalence In Relation to Histopathology and Anatomical Features (Akeret et al. 2019)

Seizure prevalence with unistructural tumors in relation to gyral location

Pathophysiology of Glioma Related Epilepsy

You, et al. Seizure. 2012

DIAGNOSIS FLOWCHART OF GRE

Diagnosis of
Glioma

Liang, et al. Cancer Medicine. 2019

 COGNITIVE DYSFUNCTION IN GLIOMA

§ Neurocognitive function is frequently altered in glioma

§ Cognitive deficits can be subtle (soft sign)
§ Result of a whole brain network disturbance
§ 90% patients have impaired in at least one area of
cognition
§ Plasticity plays a major role in the resilience to
cognitive deficits in brain tumor patients.
§ Executive function impairment (78%), memory and
attention (60%)

Schiff, et al. 2018 ; Heimans, et al. 2012 ; Bergo, et al. 2016

Factors associated cognitive function
PATHOPHYSIOLOGY
 BRAIN COGNITIVE FUNCTION

Celutkiene, et al. 2016

 INTRACRANIAL PRESSURE
Monro-Kellie Doctrine

ICP = Pcerebrum + Pblood + PCSF

CPP = MAP-ICP
Normal ICP = < 15 mmHg (7,5 – 20 cmH2O)

Brain ischemia
Brain Death
Herniation
Symptoms & Signs of Increased Intracranial
Pressure
 BTH ASSOCIATED WITH INCREASED ICP

• 86–95% of patients with increased ICP

• Distinguished from other types of brain tumor
headaches due to their severity, association with
nausea or vomiting and resistance to common
analgesics
• Etiologies :
ü Tumor mass effect
ü Cerebral edema
ü Intratumoral hemorrhage
ü Hydrocephalus
 BRAIN TUMOR EDEMA
Pathophysiology
 PAPILLEDEMA

Increased ICP

Increased CSF pressure

Optic nerve sheath

distension

Axoplasmic stasis

Optic disc swelling

Axon compression

Hypoxia and gliosis

Papilledema

Papil atrophy

Serova, et al. Neuro-Ophthalmology. 2009

 ABDUSCENS NERVE PALSY
• The abduscens palsy can be an early sign of increased
ICP
• Has the longest intracranial course of any cranial nerve
• Patient present with binocular horizontal diplopia
 Cushing Reflex/ Phenomenon

widened pulse pressure (increasing systolic,

decreasing diastolic)
ICP ⬆ à CPP à MAP

Increased blood pressures à activation of

baroreceptors in the aortic arch / compression
of intracranial vagal nerve à parasympathetic
activation à bradycardia

Brainstem dysfunction secondary to increased

ICP
Manifestation : shallow breaths with occasional
periods of apnea

Cushing reflex is the very last hemodynamic response to a systemic sympathetic

activation that follows the acute rise in ICP.
FOCAL NEUROLOGICAL MANIFESTATION
 SITE SPECIFIC SYMPTOMS OF BRAIN TUMOR
Sensory area
Motor area • Sensory deficits (touch,
• Motoric deficits taste, sight, smell, hearing,
(hemiparesis) pain)
Parietal Lobe
Frontal Lobe • Impaired spatial
• Personality changes relationship
(impulsivity, lack of • Hemispatial neglect
inhibition, lack of concern) • Attention
• Delayed initiation • Dysphasia
• Executive dysfunction • Agnosia, alexia,
• Memory disturbance apraxia, agraphia
• Diminished self awareness
• Incontinence
Occipital Lobe
• Alexia
• Hemianopsia
Broca’s area
homonym
• Language deficits
• Achromatopsia
(aphasia)
• Color anomia

Temporal lobe
• Auditory and perceptual Cerebellum
changes Brain stem • Ataxia
• Language deficits
• Diplopia • Vertigo / dizziness
(Wernicke’s aphasia) • Altered
• Memory & learning consciousness
imparment • Cranial nerve
• A homonymous superior palsies
quadrantanopia
Schiff, et al. 2018
 Other Focal Manifestation

• Midline tumors may cause the “3 M” syndrome :

ümaximal disability, Diffuse headache, cognitive or
behavioral changes, and
üminimal signs, and gait/truncal ataxia without
lateralizing findings
ümidline lesion

• Insular glioma can cause nausea and vomiting

IMAGING PROCEDURE
 IMAGING DIAGNOSTIC
1. Magnetic Resonance Imaging (MRI) – contrast enhanced
- Diagnostic procedure of choice
- Higher sensitivity in differentiating tumor tissue
- Allows multiplanar assessment of volumetric size and tumor extension
inti adjacent tissue
2. CT imaging – contrast enhanced
- Use when MRI is contraindicated
- Superior in detecting bone, acute blood, calcification

Advanced technique :
1.Magnetic Resonance Spectroscopy (MRS)
Detection of metabolite levels in and around tumors (choline, NAA,
creatine, lactate
2.MR Perfussion (Dynamic Contrast Enhanced MRI (DCE-MRI)/ Dynamic
Susceptibility Contrast MRI (DSC-MRI) )
Estimation of intravascular volume in tumor
3. Diffusion Tensor Imaging (DTI)
Characterize microstructural changes occurring at tissue or
cellular levels
 IMAGING IN LGG & HGG
LOW-GRADE GLIOMA
CT IMAGE :
ü Non enhancing iso-intense mass
ü Calcification 15-20%
ü 40% mild to moderate inhomogenous contrast enhancement
MRI
ü T1-weighted : iso to hypointense non enhancing mass
ü T2-weighted : hyperintense
ü Enhancement generally minimal

LOW-GRADE GLIOMA
MRI
ü T1-weighted : central area of hypointensity, necrosis, surrounded by
enhancing ring
ü T2-weighted : infiltrating tumor and edema showed hyperintensity
ü The degree of enhancement, necrosis and edema usually less prominent
in anaplastic astrocytoma
Imaging characteristics of Brain Tumors
 LOW GRADE GLIOMA
Axial T1 postcontrast image
shows no enhancement.

Axial FLAIR MR images

demonstrating a hyperintense
mass

Axial T2 shows
hyperintense mass
 Axial FLAIR of a grade II tumor .
Showing a very well-circumscribed margins,
which might suggest a noninfiltrative histology.

Grade II astrocytoma with a widely

infiltrative appearance on imaging
 LOW-GRADE GLIOMA

PILOCYTIC ASTROCYTOMA
(a) An axial T1-weighted image shows a well-circumscribed, hypointense cerebral mass (arrows).
(b) An axial T2-weighted image shows a hyperintense mass w/ peritumoral vasogenic oedema (arrows).
(c) The lesion exhibits low signal on diffusion-weighted imaging
(d) and (e) T1-weighted images demonstrate inhomogeneous enhancement of the mass

Chourmouzi, et al. 2014

a 43-year-old man with low-grade glioma presenting with focal partial seizures in the right arm for
15 days. (A) An expansive lesion with hypointensity on T1-weighted image and (B) hyperintensity on
T2-weighted image and (C) FLAIR image, which does not enhance in (D) the post-contrast-enhanced
T1-weighted image. (E) Axial diffusion-weighted image does not show restricted diffusion

Tonn, et al. 2010

 HIGH GRADE GLIOMA

A 65-year-old man complaining of cognitive impairment with ANAPLASTIC ASTROCYTOMA. (A) Contrast-
enhanced, T1-weighted image shows a round cortical lesion with a slight contrast enhancing in the left
occipitoparietal lobe, with hyperintensity on (B) FLAIR and (C) diffusion-weighted images and restricted
diffusion on (D) ADC maps. (E) The lesion also has hyperperfusion representing neoangiogenesis. (F) Magnetic
resonance spectroscopy shows markedly elevated choline peak and low N-acetylaspartate peak.
Tonn, et al. 2010
 HIGH GRADE GLIOMA

GLIOBLASTOMA. A, Axial postcontrast image demonstrates an irregularly rim enhancing,

centrally necrotic mass in the right frontal lobe. B, Axial T2-weighted image shows edema
surrounding and compression and displacement of the adjacent right lateral ventricle

Berger, et al. 2005

 HIGH GRADE GLIOMA

GLIOBLASTOMA. (A) Axial FLAIR image demonstrates T2 hyperintensity consistent with

infiltrative tumor in the left parietal and occipital lobe. (B) Axial post-gadolinium T1 and (C)
rCBV map demonstrate contrast enhancement and increased cerebral blood volume, indicating
disruption of the blood–brain barrier and high tumor vascularity consistent with high-grade
glioma.
Tonn, et al. 2010
MR Spectroscopy of glioblastoma.
Above. (1-4) corresponding sampled within tumor region (1,3,4) and contralateral
normal region (2). Normal region contains high NAA relative to Cho, Cr, and no Lac.
Below. Intratumoral diffusely elevated Cho, diminished NAA, multifocally elevated
Lac. Tonn, et al. 2010
Outpatient visit priorities
TERIMAKASIH
STATEMENT FROM THE EANO BOARD
Process flowchart for patients with preoperative
glioma-related epilepsy

Liang, et al. Cancer Medicine. 2019