Brain tumors, a neurologist view Lectures for medicine students

1. BRAIN TUMORS
Assist.Prof. Ines Strenja MD, PhD
neurologist
NEUROLOGY DEPARTMENT
CLINICAL HOSPITAL RIJEKA

2. • Brain tumors are a diverse group of
neoplasms arising from different cells
within the central nervous system (CNS) or
from systemic cancers that have
metastasized to the CNS.

3. •Classification
•Epidemiology
•Clinical picture
•Diagnostics
•Treatment

4. Brain Tumor Characteristics
 Start in the brain and grow steadily there.
 Very rarely spread to other organs through the bloodstream.
 Are named for the anatomic location of tumor and/or the cells from
which they arise, each having a certain function essential to normal
physiological functioning of the brain.
For example:
• Brain Stem Gliomas arise in the lowest part of the brain.
• Meningiomas arise in the meninges.
• Gliomas arise from glial cells that support the CNS.
• Astrocytomas arise from astrocytes
• Ependymomas arise from ependymal cells which line the ventricles
• Oligodendrogliomas arise from oligodentdrocyte cells which make up the
fatty substance called myelin that covers nerves like electrical insulation.

5. CNS tumor classification
• Based on the location (topography)
• Based on morphology ( histology)
• Based on the biological behavior ( malignant
or benign)

6. • Skull bones
• Meninges
• Neurons
• Neuroglia - macroglia
(astrocytes and
oligodendrocytes), ependymal
cells and microglia
• Blood vessels
• Pituitary
• Pineal gland
• The rest of the embryonic
epithelium
Tumors inside the skull
(origin)

8. Spinal tumors
(origin)
• Spinal cord parenchyma
• Spinal sheaths (meninges)
• Spinal nerve root
• Spinal blood vessels
• Parts of the vertebrae

10. Biological behavior of tumors
 Criteria for establishing the stages of tumor malignancy
• Cell pleomorphism
• Nuclear atypia
• Mitotic index
• Vascular proliferation
• Necrosis
 Tumor Behavior
Benign Tumors - Slow growing, Distinct borders, Rarely, spread
Malignant Tumors - Usually rapid growing, Invasive Life threatening
Borderline Malignant Tumors – Rare, Likely to Recur following Surgical Resection,
May become Life threatening

11. 1. Tumors of Neuroepithelial Tissue
2. Tumors of Cranial and Spinal Nerves
3. Tumors of the Meninges
4. Lymphomas and Hematopoietic Neoplasm
5. Germ Cell Tumor
6. Tumors of the Sellar Regions( pituitary /craniopharyngioma)
7. Metastatic Tumors
For the past century, the classification of brain tumors has been based largely on
concepts of histogenesis: Light microscopic features in hematoxylin and eosin
sections, immunohistochemical expression of proteins an ultrastructural
characterization.
WHO IV. classification of brain tumors 2007. and updates of
CNS tumors 2016. godine

12. WHO 2007.
IV. revision

13. WHO classification of malignancy - IV stages based on :
 mitotic activity
Necrosis status
Cell pleomorphism ( higher stage, higher mlg)

16. WHO 2016.
Update
.

19. Figure 2. Diagnostic schema for WHO World Health Organization grades II and III infiltrating gliomas in adults.
Johnson DR. Published Online: October 13, 2017
https://doi.org/10.1148/rg.2017170037
In primary brain malignant tumors, the presence of a genetic mutation is particularly important -
isocitrate dehydrogenase mutation (IDH1 / 2 mutation) and 1p / 19q chromosomal codellation.
Thus, a completely new diagnosis of glioblastoma multiforme in relation to the presence of IDH1
mutations would be: Glioblastoma, IDH mutant or wild type.

21. TYPES OF BRAIN TUMORS

22. BRAIN TUMOR INCIDENCE
• The proportion of brain tumors is 2% of all tumors
• The frequency of various tumor types and grades varies by
age group..f.e.
• Meningiomas and glial tumors (eg, glioblastoma,
astrocytoma, oligodendroglioma) account for
approximately two-thirds of all primary brain tumors in
adults
• 50% of children's brain tumors are infratentorial
• 4/5 intracranial tumors
• 1/3 of brain tumors are malignant
• The frequency increases with age, most tumors occur in
the 6th decade of life!

23. EPIDEMIOLOGY OF BRAIN TUMOR
 Rates of incidence for primary brain tumors in the Republic of
Croatia based on methodologically similar research projects
are between 4,57 – 15,8/100.000. (28,3/100.000 in Valle
d’Aosta, Italy)
 Generally higher rates of incidence are associated to countries
with highly efficient and organisied epidemiological and
medical services (diagnostics, higher amount of autopsies
 USA 29,9/100 000 - adults, 5.9/100 000 - children
 Malignant tumor 60% children vs 30% adults

25. • Glioms – most common tumors (30%)
• Glioblastoma as a majority
• Meningeoma (40%)
• Frequency of metastatic forms of brain tumors
increases with age (50% above the age of 40)
• Gender ratio (M- F) - 0,9-2,6 – difference between
specific histologic types based on the gender (Glioma
more common in M, meningeoma in F)
• Incidence rates differ based on age
• Mortality data on individuals with brain tumors
indicate that younger patients have a significantly
better prognosis compared with older individuals

26. Incidence by age…

27. CNS tumors aged 0 to 19
• Malignant brain and other CNS
tumors are the most common
cancer site in children up to
age 14 years, followed by
leukemia and soft tissues, and
the most common cause of
cancer death
• The CNS is the third most
common cancer site among
adolescents and young adults

28. Copyrights apply

29. Copyrights apply

30. Copyrights apply

31. Incidence by age – CNS tumors in adults

32. Risk factors for brain tumors
 Ionizing radiation is the only firmly established
environmental risk factor for brain tumors. Cohort
studies of atomic bomb survivors and childhood
cancer survivors have demonstrated that cranial
radiation is associated with increased risk for a
variety of brain tumors, including meningiomas,
gliomas, and nerve sheath tumors
 The association between forms of nonionizing
radiation, such as low-frequency electromagnetic
fields and radiofrequency fields, and cancer is less
clear, and the data do not support an important role
for these types of radiation as risk factors for brain
tumors.

33. Risk factors for brain tumors…
 There is no solid evidence of the influence of environmental
factors or the workplace on the occurrence of brain tumors,
although the connection in some workers, such as miners, oil
workers, rubber workers--
 Infections / Toxoplasma g. Astrocyte and meningioma in 2
studies /
 Ionizing radiation of the skull possible cause of meningioma,
glioma or neurinoma - glioma or neurinoma - for 5 years
continuously
 Head irradiation and rdg imaging of teeth may be associated
with a risk of developing gliomas and meningiomas
 Chemical substances (herbicides, pesticides); some viruses
(experiment)
 Exposure to electromagnetic fields is cited in the literature
as a potential risk factor but there is no conclusive evidence

34.  Corle C, Makale M, Kesari S. Cell phones and glioma risk: a review of the
evidence. J Neurooncol 2012; 106:1.
 Musicco M, Sant M, Molinari S, et al. A case-control study of brain
gliomas and occupational exposure to chemical carcinogens: the risk to
farmers. Am J Epidemiol 1988; 128:778.
 Piel C, Pouchieu C, Tual S, et al. Central nervous system tumors and
agricultural exposures in the prospective cohort AGRICAN. Int J Cancer
2017; 141:1771.

35. Genetic role CNS tumor development
 A small proportion of brain tumors are due to
genetic syndromes that confer an increased risk of
developing tumors of the nervous system. These
include neurofibromatosis type 1 (NF1),
neurofibromatosis type 2 (NF2), von Hippel-Lindau
syndrome, Li-Fraumeni syndrome, familial
adenomatous polyposis, and the basal cell nevus
syndrome. Genetic susceptibility has also been
noted to play a role in determining risk of brain
tumors, although collectively these variants do not
account for a large proportion of risk.

36. 5% of patients have a predisposing genetic
syndrome for cancer
Neurofibromatosis is an autosomal dominant
disease, there are 2 types:
Type 1 (von Recklinghausen's disease) is the
most common, and causes neurological,
cutaneous and sometimes orthopedic
manifestations. TNF gene on chromosome 22
Type 2 Neurofibromatosis is manifested
primarily

37. von Recklinghausen's disease
Neurofibromatosis
•5% of patients have a predisposing genetic
syndrome for cancer
•Neurofibromatosis is an autosomal
dominant disease, there are 2 types:
Type 1 (von Recklinghausen's disease)
is the most common, and causes
neurological, cutaneous and sometimes
orthopedic manifestations. NF1 on
chromosome 17
Type 2 Neurofibromatosis is manifested
primarily congenital bilateral neuromas of
the auditory nerve, NF2 on chromosome 22

38.  Possible causative factors that require further
investigation include allergies, nonionizing
radiation, physical and acoustic trauma, and
certain infection….
 Holdhoff M, Guner G, Rodriguez FJ, et al. Absence of Cytomegalovirus in
Glioblastoma and Other High-grade Gliomas by Real-time PCR,
Immunohistochemistry, and In Situ Hybridization. Clin Cancer Res 2017; 23:3150.
 Taha MS, Abdalhamid BA, El-Badawy SA, et al. Expression of cytomegalovirus in
glioblastoma multiforme: Myth or reality? Br J Neurosurg 2016; 30:307.

39. • Clinical course
 Slow clinical course is shown by astrocytomas,
oligodendrogliomas, meningiomas, acoustic neuromas,
pituitary adenomas
 Rapid clinical course has glioblastoma multiforme and
metastatic tumors!
• Symptoms and signs two groups:
 Symptoms of increased intracranial pressure
 Focal symptoms and signs

40. CLINICAL MANIFESTATIONS
 Patients with brain tumors may present with
generalized and/or focal signs and symptoms
or they may be asymptomatic
 General symptoms (signs of increased ICP)
 Focal symptoms

41. The way the symptoms occur can be different:
 Combination of progressive focal symptoms and
symptoms of elevated intracranial pressure (IP)
 Only signs of increased intracranial pressure
 Generalized epileptic seizures
 Apoplectiform onset with loss of consciousness and
focal signs

42. Pathophysiology of CNS tumors
Expansion – tumor enlargement
around the central core with
compromised and susceptible to
destruction
Infiltration – spreading of the
tumor and ingrowth in the
proximal tissue, capable of
spreading to a significant distance

43. General symptoms
 Headache
 Vomiting
 Edema of the optic nerve papilla (fundus)
 Changes in heart rhythm (bradycardia,
tachycardia, arrhythmia)
 Respiratory rhythm changes
 Mental changes symptoms- irritability,
behavioral changes
 Epileptic seizures

44. Edem p.n.o.

45. Brain edema around the tumor …
• Vasogenic edema – increase of
capillary permeability due to a
blood brain barrier disfunction
• Edema leeds to increase of
intracranial pressure (ICP)
• Obstruction CSF
• Focused neurological disorders
• Epileptic seizures
• Hypophyisis function disorder

46. Headache
 Headache is a common manifestation of brain tumors and a
presenting symptom in up to half of patients, usually dull and
constant, but occasionally throbbing.
 Symptom severity tends to progress over time. Severe headaches
are infrequent unless increased intracranial pressure (ICP) or
meningeal irritation is present.
 Patients may report worsening of headache after a change in body
position, such as bending over, or with maneuvers that raise
intrathoracic pressure, such as coughing, sneezing, or the Valsalva
maneuver.
 Tumor-related headaches may be worse at night and may awaken
the patient
 Other features suggestive of a brain tumor or other causes of
secondary headache in a patient complaining of headaches include
new and progressive symptoms, morning nausea and vomiting,
a significant change in prior headache pattern, and an
abnormal neurologic examination.

47. Seizures
 Focal seizures are among the most common
symptoms of primary and metastatic brain tumors
 Seizures affect 50 to 80 % of patients with primary
brain tumors and 10 to 20 % of patients with
metastatic tumors
 Among primary brain tumors, low-grade tumors are more
likely to cause seizures than high-grade tumors.
 The clinical manifestations of focal seizures depend
upon tumor location…frontal lobe tumors may cause
focal tonic-clonic movements involving one extremity,
while seizures originating within the occipital lobe may
cause visual disturbances. Temporal lobe seizures,
with abrupt sudden behavioral changes may occur with
or without typical preseizure auras, such as abnormal
smell, taste, or gastrointestinal symptoms…
 Focal-onset seizures Generalized tonic-

49. FOCAL SIMPTOMS

50. Increased intracranial pressure (ICP) - FACTS
 Increased ICP can arise either from a large
mass or from restriction of cerebrospinal fluid
(CSF) outflow causing hydrocephalus.
 Symptoms may be subtle or consist of the
classic triad of headache, nausea, and
papilledema.
 Intratumoral bleeding
 Peritumoral edema
 The mechanism of brain autoregulation is lost,
cerebral perfusion is reduced, the end result is brain
herniation!

51. The types of brain herniation
• (1) cingulate gyrus herniation, (subfalcine herniation), occurs below the
falx cerebri.
• (2) lateral tentorial herniation (temporal uncus herniation), is the
herniation of medial edge of the temporal lobe (uncus) through the
tentorial notch.
• (3) central tentorial herniation, is a vertical displacement of the brainstem
and diencephalon through the tentorial notch.
• (4) cerebellar tonsil herniation, is the protrusion cerebellar tonsil through
the foramen magnum.
• (5) herniation of brain-tissue through the craniotomy defect.

52. Frequency of bleeding within the tumor
• Glioblastoma
• Astrocyte
• Oligodendroglioma
• Ependyma
• Meningioma
• Schwan
• Medulloblastoma
• Hemangioblastoma
• Craniopharyngioma
• Pituitary adenoma
• Papilloma plexus
chorioidalalis
6,3
2,5
8,3
6,6
1,3
0,0
1,4
0,0
3,3
15,8
16,7

53. Frequency of calcifications within the tumor

56. Glioma
Glioma is the most common form of central nervous system
(CNS) neoplasm that originates from glial cells
45% of all intracranial tumors
They are formed by the proliferation
of glial cells
Degrees of malignancy from I-IV
55% of gliomas are astrocytomas
Pilocytic astrocytoma has a survival
of 10 years!
Glioblastoma multiforme (grade IV)
very malignant, cystic degeneration
and bleeding into the tumor are
common, survival 1 year

57. Astrocytoma

58. Glioblastoma

59. Oligodendroglioma
 Most often in the 6th decade of
life
 Contains higher amounts of
calcium (craniogram)
 Slow-growing glial tumor, more
common in men
 More often in the frontal lobe
 Often butterfly spreading to
another hemisphere of the brain
 Low-grade oligodenrogliomas
with the most epileptogenic
tumors

60. Ependymoma
 Ependymoma is a type of tumor that
can form in the brain or spinal cord.
 Most often occurs in young children,
can occur at any age
 They arise most frequently in
the fourth ventricle and
cause hydrocephalus by blocking CSF
flow
 Very often they can give droplet
metastases via cerebrospinal fluid to
other parts of the CNS
 Only 45% of children survive 5 years,
poor prognosis!
 Spinal ependymoma

61. Medulloblastoma
 Childhood tumor, , ¾ up to 9
years, more common in boys
with a worse prognosis in them
 Posterior cranial fossa
 Very malignant. Hypocephalus
develops early with morning
sickness and vomiting, double
vision, and symptoms of
cerebellar dysfunction with
truncal ataxia, Nystagmus
 Survival time 1 year.
 Tendency to metastasize via
cerebrospinal fluid
 TH. Surgery, radiotherapy,
chemotherapy, immunotherapy

62. Primary CNS lymphoma
 PCNSL is now known to be a formof
extranodal, high-grade non-Hodgkin
B-cell neoplasm, usually large cell or
immunoblastic type. Rare <2% BT
 It originates in the brain,
leptomeninges, spinal cord, or eyes;
typically remains confined to the
CNS; and rarely spreads outside the
nervous system.
 Corticosteroids are avoided during
the initial workup, because their
administration may have a direct
antitumor effect on B-cell lymphoma
and cause dramatic reduction in MRI
abnormalities, making biopsy and
histologic confirmation more diff.

63. Meningeoma
 Benign tumor that arises from the
meninges
 Middle age
 Slow growth
 Malignant alteration
 Most common form of BT, about
80% Grade I, which is usuallybe
cured by surgery. <1% aggresive!
MOST COMMON SITES: parasagittal
(falks) (25%), convexity (19%),
sphenoid bone (17%), suprasellar
(tuberculum) (9%), posterior
cranial fossa (9%), olfactory groove
(8%).

64. Brain metastases
 Cerebral hemispheres 80%
 Cerebelum 15 &
 Brain stem 5%

66. DIAGNOSIS
• Anamnesis and heteroanamnesis
• Detailed neurological examination
• Neuroradiological diagnostics
- CT, MRI, MRS (Magnetic Resonance Spectroscopy), MRA
• Histopathology
• Cytological analysis of cerebrospinal fluid (primary, metastases..)
• Stereotactic brain tumor biopsy

67. (A) Axial T1-weighted MRI showing edematous left temporal lobe with loss of sulci
and gray-white demarcation.
(B) After gadolinium infusion, a circular 2.5 cm x 2.5 cm area of irregular contrast
enhancement is seen in the left temporal lobe (arrow).
GLIOBLASTOMA

68. Left temporal glioblastoma
Brain MRI in a 53-year-old male presenting with several weeks of headaches and word-finding
difficulties. FLAIR (A) and postcontrast T1-weighted images (B) show a large, T2-hyperintense
mass in the left temporal lobe with heterogeneous enhancement and central necrosis. Pathology
confirmed a WHO grade IV glioblastoma.
MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery; WHO: World
Health Organization.

69. MRI appearance of low-grade oligodendroglioma
Brain MRI in a 40-year-old male presenting with first-time generalized tonic-clonic seizure.
Pathology confirmed a WHO grade II oligodendroglioma, IDH1 mutant, 1p19q-codeleted.
(Panel A) Axial FLAIR image showing a T2-hyperintense, expansile mass in the right frontal
lobe.
(Panel B) Post-contrast axial T1-weighted image showing no appreciable contrast
enhancement.

70. CT and MRI appearance of diffuse intrinsic pontine
glioma
(A) Axial unenhanced CT of the brain shows diffuse, symmetric low attenuation expansion of the pons
(arrows). There is mass effect on the ventral aspect of the fourth ventricle (arrowhead).
(B) An axial T2-weighted image reveals a large pontine mass associated with diffuse high signal
intensity (arrows). An area of signal heterogeneity within the tumor likely reflects necrosis (dashed
arrow).
(C) A sagittal Gd-enhanced T1-weighted image shows non-enhancement of the central necrotic region
(asterisk), enhancement of the region surrounding the necrosis (arrow), and non-enhancement of the
rest of the tumor (dashed arrow).
CT: computed tomography; MRI: magnetic resonance imaging; Gd: gadolinium.

71. The MRI examination in the transverse plane is from a 63-year-old
female with primary CNS lymphoma.
• The T1 weighted sequence (A)
reveals a single mass that
infiltrates the splenium of corpus
callosum [a relatively common
location for primary CNS
lymphoma] (arrow), abutting the
third ventricle anteriorly. The
mass enhances homogeneously
following gadolinium
administration (B), is relatively
dark on T2 weighted images (C),
and reveals restricted diffusion
on the diffusion weighted
sequence (bright, D). The reader
should note the relative lack of
edema on flair studies. These
features are consistent with the
diagnosis of primary lymphoma
of the brain.

72. CNS metastasis from melanoma
Axial images of a brain magnetic resonance imaging (MRI) study demonstrating an
intracerebral metastasis in a patient with melanoma. Following the injection of contrast
(B) the lesion enhances with a ring-like pattern.
(A) Pre-contrast.
(B) Post-contrast.
• Systemic cancers
most likely to
metastasize to the
CNS include lung
cancer, melanoma,
and breast cancer.

73. Intracranial meningioma
• A 70-year-old woman presented
with a several-week history of
confusion. Panels (A, B): Non-
contrast and contrast-enhanced
head CT shows a large bifrontal
lesion with calcifications and
surrounding edema.
• Panels (C, D): Non-contrast and
contrast-enhanced T1-weighted
axial MR images of the head also
demonstrate large flow voids
representing blood vessels in the
center of the tumor.
• Panel (E): Non-contrast T1-
weighted sagittal MR image.
Panel (F): Contrast-enhanced T1-
weighted coronal MR image.

75. Brain MRI tumefactive demyelination
Axial FLAIR image (A) demonstrates a large demyelinating lesion in the left frontal lobe
with mass effect that shows peripheral enhancement on post-contrast T1-weighted
image (B).
MRI: magnetic resonance imaging; FLAIR: fluid-attenuated inversion recovery.

76. Therapy
 The choice of treatment depends on the type of
tumor, localization, stage of the disease, age and
general condition of the patient
 Radical surgery Maximum reduction + radiation
 Radiosurgery
 Primary radiation + symptomatic (antiedematous,
antiepileptic) + Cytostatics
 Chemotherapy
 Immunotherapy

77. The pathological diagnosis of CNS tumors is a multi-step process starting with tumor tissue and
in some cases also blood samples being analyzed with multiple tests to provide an integrated
diagnosis. Evaluation and discussion of the pathological diagnosis by a multidisciplinary board of
specialists from radiology, surgery, oncology, and (neuro)pathology is crucial for translating the
findings into optimal therapeutic management for individual patients.

78. Modern oncology
1. RADIOTHERAPY
2. CHEMOTHERAPY
3. SURGERY
4. IMUNOTHERAPY!

79. RADIOTHERAPY
 Cobalt, a linear accelerator, a
radiotherapy device, or the
implantation of radioactive
material into the tumor itself.
 2 -4 weeks after surgery.
 Irradiation is carried out by
external beams of radiation up to a
total dose of 50 to 60 Gy in 25 to
30 fractions.
 Side effects of radiotherapy: acute
(edema and elevated ICP) and in
case of radiation overdose later
chronic side effects that are
irreversible, cerebral radionecrosis,
brain atrophy and dementia!!

80. RADIOSURGERY - GAMMA KNIFE
 a device by which, with 201 radioactive air from a CO - 60
source, it is precisely directed to the area of ​​the brain for the
treatment of tumors

81. RADIOSURGERY

82. Spinal Tumors
 Intramedular
 Ekstramedular
- intradural
- ekstradural
- ekstravertebral
 10% of CNS tumors
 Rare among children and elderly

83. Pathophysiological features of spinal
tumors
• Compression, iritation and straining of
spinal nerve roots
• Compression and dislocation of spinal
marrow
• Invasion and destruction of spinal marrow
• Spinal bloodstream disfunction
• Obstruction of CSF

84. Clinical picture of spinal ekstramedullar tumors
 Pain and paresthesia (roots)
 Motoric disorders with muscle
hypothrophy with lesions
 Pyramidal lesion (spastic paralysis)
 Sphincter dysfunction
 Spinal cord necrosis – symptoms
of complete transversal lesion with
paraplegia and kompletne
transverzalne lezije s paraplagijom
i complete loss of sensations

85. Clinical picture of spinal intramedullar tumors
 Sphincter disorders (more often
retention)
 With their infiltrative growth,
they affect several segments of
the spinal cord
 Various sensory disturbances
(similar to syringomyelia)

86. SPINAL METASTASES
 Metastatic lesions are most
common tumors of the spine
(95-98%)
 5-10% of the patients with
cancer develop spine metastases
 All age groups with highest age
incidence in between 40 and 65
years
 Male:Female – 3:2
 Vertebral body affected first
 Approximately 70% of patients
who die of cancer have evidence
of vertebral metastases on
autopsy
INTRASPINALNE METASTAZE
21%
15%
10%
10%
9%
7%
5%
4%
4%
15%
dojka
pluća
prostata
limforetikular
sarkom
bubreg
gastrointestinalni
melanom
nepoznat primarni
mješano

87. Different diagnosis of spinal tumors
 Epidural haematoma
 Epidural abscess
 Spondylosis
 Discopathy
 Noncompressive diseases (MS,
vascular or inflammatory
diseases)
 DIAGNOSTICS
• CT
• MRI
• Myelography
• Native rtg
• Spinal angiography

88. Immunotherapy as a new therapeutic option!
• Immunotherapy is the latest branch of modern oncology that
uses the body's immune system, either directly or indirectly, to
fight cancer.
• Monoclonal antibodies against immune system molecules
(Immune anti-checkpoint blockade therapy)

89. Checkpoint receptors such as cytotoxic T-lymphocyte antigen 4 (CTLA-4)
and programmed cell death receptor-1 (PD-1) (PD-1L) suppress T cell
activation, proliferation and function, thereby promoting proliferation.

91. Figure 1. Summary of the different malignant brain tumors , their name-derived cell
of origin,