Brain Tumors Overview

Brain Tumours - Overview

• 2% of all cancers
• 20% of cancers in children under 15 years (leading cause of cancer death)
• Primary or secondary (originating from other parts of the body)

Learning Outcomes

• Classify brain tumors and understand their biological behaviours
• Differentiate brain tumors biologically from other body tumors
• Explain the causes and complications of localized and generalized cerebral edema
• Explain the consequences of raised intracranial pressure
• Describe the pathophysiology of abnormal water accumulation in the brain
• Discuss hydrocephalus

Brain Tumours - Presentation

• Seizures
• Symptoms/signs of raised intracranial pressure
• Symptoms/signs of hydrocephalus
• Focal neurological deficit
• Primary brain tumors rarely metastasize
• Prognosis not solely dependent on tumor grade; tumor site is also crucial (impacts resectability)

Primary Brain Tumours - Cell Types

• Benign: Meningioma, Pineocytoma, Pituitary adenoma, Craniopharyngioma (embryological remnant cells)
• Malignant/malignant potential: Gangliocytoma, Ganglioglioma, Glioma (Astrocytoma, Oligodendroglioma, Ependymoma), Choroid plexus papilloma/carcinoma, Primitive/precursor cells, Schwannoma/Neurofibroma, Medulloblastoma/Embryonal

Footnotes

• Medulloblastoma and other embryonal tumors originate from primitive/immature cells in the developing brain, often located in the cerebellum or brainstem; mostly found in children
• Craniopharyngioma develops from embryonic tissue in the pituitary gland and nearby structures during fetal development

Primary Brain Tumours - Neuroglia

• Most common tumors derived from glial cells (astrocytes and oligodendrocytes)
• Tumors of glial cells are known as Gliomas
• Central Nervous System: Ependymal cells, Oligodendrocytes, Astrocytes, Microglia
• Peripheral Nervous System: Satellite cells, Schwann cells

Grading of Brain Tumours: Glioma

• WHO Grade I (Pilocytic Astrocytoma): Defined by the tumor type; Excellent prognosis (95% survival)
• WHO Grade II: No high-grade features; Median survival of 10 years
• WHO Grade III: Mitosis; Median survival of 3-5 years
• WHO Grade IV: Mitosis, microvascular proliferation, necrosis; Survival usually months, less than 5% survival in 5 years

Molecular Neuropathology

• Useful adjunct to diagnosis
• Makes diagnosis and defines tumor type
• Helps to indicate a tumor grade
• Predicts response to therapy

Common Molecular Abnormalities in Brain Tumours

• BRAF gene fusion/mutation (V600): 90% of posterior fossa pilocytic astrocytomas; BRAF inhibitor therapy often used
• IDH1/2 mutation/1p19q co-deletion: Defines oligodendroglioma; predicts responsiveness to temozolomide
• MGMT methylation: Predicts better responsiveness to temozolomide, in particular glioblastoma/high-grade gliomas
• Histone (H3) mutation: Often worse prognosis, in particular grade 4, particularly paediatric
• Isocitrate dehydrogenase (IDH): Mutations lead to altered DNA methylation and gene expression, promoting tumorigenesis

Opportunities for Targeted Therapies in Brain Tumours

• NTRK gene fusions found in several types of cancers, including glioblastoma; drugs like larotrectinib and entrectinib, shown promising in clinical trials

Case Studies (selected examples)

• Case 1 (14-year-old): Diffuse midline glioma H3K27M MUTANT WHO grade 4 (headache, vomiting)
• Case 2 (39-year-old): Oligodendroglioma grade II (first seizure)
• Case 3 (one-year-old): Atypical teratoid/rhabdoid tumor (AT/RT) WHO grade IV (signs of raised ICP)

H3 K27M Mutant Protein

• Key methylation site, crucial for gene repression; mutation leads to gene repression

Intracranial Pressure

• Brain is confined by the skull, little room for expansion, disturbed by edema, hydrocephalus, tumours
• Initial compensatory response (CSF shifted, blood volume reduced)
• If persistent, swelling leads to vascular compression (cytotoxic edema)

Raised Intracranial Pressure

• Headache (especially postural, nocturnal, early morning; improves when standing)
• Vomiting (especially in children)
• Clouding of consciousness/coma
• Papilloedema

Cerebral Edema

• Vasogenic: Increased vascular permeability, fluid escapes from blood vessels to surrounding tissue
• Cytotoxic: Cellular injury, failure of Na+/K+ pump, water influx, potassium efflux; not associated with increased permeability

Cerebral Herniation

• Displacement of brain tissue due to high intracranial pressure (ICP)
• Types: Uncal, Central, Tonsillar
• Consequences: Further compression & damage to brain tissue & blood supply

Hydrocephalus

• Increased cerebrospinal fluid volume in the ventricular system
• Often associated with tumors in the posterior fossa
• Causes:
• CSF overproduction (e.g., choroid plexus tumor)
• CSF absorption failure (e.g., absence of arachnoid granulations)
• Interference with CSF flow (e.g., neoplasm, malformations, infections, hemorrhage, gliosis)
• Symptoms (common in infants): Enlarging head, bulging fontanelles, vomiting, irritability, sleepiness, Downward eyes ("sunsetting")
• Treatment: Shunt to drain excess cerebrospinal fluid, sometimes medications

Rhabdoid Tumor Predisposition Syndrome (RTPS)

• Diagnosis criteria: rhabdoid tumors, multiple primary tumors or family history
• Germline mutations in SMARCB1 or SMARCA4 are often associated.

Brain Tumors and Cancer Family Syndromes

• Certain cancer syndromes can increase susceptibility to brain tumors.
• Examples include Neurofibromatosis type I and II, von Hippel-Lindau disease, Tuberous sclerosis, Li-Fraumeni syndrome, Cowden syndrome.

Explore the critical aspects of brain tumors, including their classification, symptoms, and biological behaviors. This quiz will help you understand the unique challenges posed by primary and secondary brain tumors, as well as the complications associated with cerebral edema and raised intracranial pressure.