LEARNING OUTCOMES • Describe the pathophysiology of abnormal water accumulation in the brain • Discuss hydrocephalus • Explain the causes and consequences of localised and generalised cerebral oedema • Explain the consequences of raised intracranial pressure • Discuss the basis for the classification of brain tumours and understand their varied biological behaviours. • Explain how brain tumours differ biologically from other tumours in the body Brain Tumours Dr Jane Cryan Summary 1. Brain tumour presentation 2. Cerebral oedema & hydrocephalus 3. Primary vs secondary brain tumours 4. Brain tumour diagnosis 1. WHO grade 2. Molecular tests 5. Unique features brain tumours 6. Tumour syndromes Epidemiology • 2% all cancers • 20% cancers <15yrs • Leading cause of cancer-related death in children Risk Factors for Developing Brain Tumour • Increasing age • History of radiotherapy • Tumour predisposition syndrome Presentation 1. Seizure 2. Symptoms/Signs of raised intracranial pressure 3. Symptoms/ Signs of hydrocephalus 4. Focal neurologic deficit Raised intracranial pressure • Headache (especially postural/ nocturnal/ early morning) • Vomiting (especially children) • Clouding of consciousness/ Coma • Papilloedema Intracranial pressure • Brain & SC exist within rigid compartment defined by skull, vertebral bodies & dura. • +protective environment for delicate structure • -little room for expansion in disease states • Disturbed by cerebral oedema (generalised & local) & hydrocephalus Cerebral oedema = excess fluid in brain Two types 1. Vasogenic oedema = normal blood brain barrier disrupted Æ increased vascular permeability Æ fluid escapes from intravascular to intercellular compartments eg. trauma 2. Cytotoxic oedema = increase in intracellular fluid secondary to cellular (neuronal/ glial/ endothelial) injury eg. hypoxia/ischaemia In practice vasogenic & cytotoxic oedema co-exist. Raised intracranial pressure • Oedema (any cause) ÆSkull behaves as rigid box (infant skull will enlarge) ÆBrain compressed ÆInitial compensatory phase = CSF displaced to spinal compartment; blood volume reduced in cerebral veins ÆSwellingÆ vascular compressionÆ vascular insufficiencyÆ exacerbates high ICP (cytotoxic oedema) —————————————————————–Æ Consequences= Cerebral herniation Other: 4. cerebral ‘fungus’ (craniectomy) 5. upward herniation of cerebellum Extra-cranial herniation through craniectomy defect Extra-cranial herniation through craniectomy defect Complications of brain herniation • Vascular compression – Anterior cerebral artey at falx – Posterior cerebral artery at tentorium – Brainstem Duret haemorrhage = death Focal/ Localised vs Generalised cerebral oedema Definition of hydrocephalus =Increase in CSF volume within the ventricular system NORMAL VENTRICLES HYDROCEPHALUS Causes of hydrocephalus Disturbance of CSF homeostasis (rare) • CSF overproduction (choroid plexus tumour) • Failure of CSF absorption (absence of Arachnoid granulations, various cranial dysplasias) Interference with CSF flow (common) • Neoplasm • Malformation eg congenital stenosis, membrane at foramen of Monro, many more • Infection- scarring • Haemorrhage • Gliosis, any cause eg stroke Neoplasms/ cysts commonly presenting with hydrocephalus • Posterior fossa tumour eg pilocytic astrocytoma, medulloblastoma • Pineal gland neoplasm • SEGA • Hypothalamic pilocytic astrocytoma • Central neurocytoma • Chordoid glioma of 3rd ventricle • Colloid cyst of 3rd ventricle Symptoms/ Signs of hydrocephalus • Infant: enlarging head, bulging fontanelle, vomiting, irritability, sleepiness, downward eyes (sunsetting) • Child: above + headache, blurred vision, poor balance, seizures • Adult: above + poor balance, memory loss, bladder control problems Brain tumour presentation 1. Seizure 2. Symptoms/Signs of raised intracranial pressure 3. Symptoms/ Signs of hydrocephalus 4. Focal neurologic deficit Important facts about brain tumours 1. Can be divided into primary and secondary tumours – Primary tumours arise from cells originating in the nervous system/ its coverings – Secondary tumours are tumours that metastasize from elsewhere in the body – Secondary tumours account for 15% in neurosurgical (rather than autopsy) centres Secondary brain tumours 50% metastases are solitary Metastasize to brain but also meninges and vertebra Breast Lung Colorectal Renal Cell UpperGI Melanoma Ovarian Prostatate Kidney Squamous Cell Thyroid Systemic Lymphoma CNS Primary Unknown Primary 0 5 10 15 20 25 Breast Lung Colorectal Renal Cell UpperGI Melanoma Ovarian Prostatate Kidney Squamous Cell Thyroid Systemic Lymphoma CNS Primary Unknown Primary Surgery for Metastases 18 22 5 6 4 7 2 1 1 2 1 1 1 9 Surgery for Metastases – 2016 Beaumont Hospital Primary brain tumours Neurons Glia= Astrocytes Oligodendrocytes Ependyma Choroid plexus Primitive/ precursor cells Pineal gland Pituitary gland Meninges Embryological remnant cells Nerve Unknown origin: germ cell tumours Know the cells that make up the brain! Primary brain tumours Neurons Gangliocytoma Ganglioglioma Glioma = Astrocytoma Oligodendroglioma Ependymoma Choroid plexus Papilloma/carcinoma Primitive/ precursor cells Medulloblastoma/ Embryonal Pineocytoma Pituitary adenoma Embryological remnant cells Craniopharyngioma Meningioma Nerve Schwannoma/Neurofibroma Know the cells that make up the brain! Embryological remnant cells Unknown origin: germ cell tumours Primary CNS lymphoma Neurons Gangliocytoma Ganglioglioma Glioma = Astrocytoma Oligodendroglioma Ependymoma Choroid plexus Papilloma/carcinoma Primitive/ precursor cells Medulloblastoma/ Embryonal Pineocytoma Pituitary adenoma Embryological remnant cells Craniopharyngioma Meningioma Nerve Schwannoma/Neurofibroma Usually benign Malignant (or potentially malignant) *** Embryological remnant cells Unknown origin: germ cell tumours Primary CNS lymphoma ! Meningioma is the most common benign primary tumour. ! Glioma is the most common malignant primary tumour. – Glioblastoma is the most common glioma. WHO Grade IV Astrocytoma (Glioblastoma Multiforme) [Including; Epitheloid, NOS, Small Cell Atsrocytoma, Giant Cell] 36% Low Grade Meningioma [Including; Angiomatous, Atypical, Meningiothelial, Transitional Type, Mesothelial, Microcystic, Psammomatous, Secretory, Syncytial] 21% High Grade Astrocytoma [Including; Anasplastic, Gemistrocytic, Diffuse Astrocytoma, Pleomorphic Xanthoastrocytoma, Gliosarcoma] 8% Low Grade Schwanoma 7% High Grade Lymphoma 4% Low Grade Astrocytoma 3% Low Grade Ependymoma [Including; Anaplastic, Myxopappillary, Subependymoma] 3% Low Grade Haemangioblastoma [Including Capillary haemangioblastoma] 3% High Grade Glioma 2% Low Grade Oligodendroglioma [Including; NOS] 2% Low Grade Glioma 2% Low Grade Neurofibroma 1% Other Tumour Types 8% Surgery for New Primary CNS Tumours 2016 Beaumont Hospital Tumour Type of New Primary Total Percentage Glioblastoma Multiforme 136 35.79% Low Grade Meningioma 79 20.79% Other Tumour Types* 32 8.42% High Grade Astrocytoma 31 39.24% Low Grade Schwanoma 28 7.37% High Grade Lymphoma 16 4.21% Low Grade Astrocytoma 12 3.16% Low Grade Ependymoma 11 2.89% Low Grade Haemangioblastoma 10 2.63% High Grade Glioma 7 1.84% Low Grade Oligodendroglioma 7 1.84% Low Grade Glioma 6 1.58% Low Grade Neurofibroma 5 1.32% For interest 2. Primary brain tumours rarely metastasize. Spread – secondary structures of Scherer CSF pathway dissemination Important facts about brain tumours Important facts about brain tumours 3. Prognosis is not solely related to grade – Tumour site is very important – Site impacts on resectability – Site impacts on morbidity ie. A ‘benign’ or a ‘low grade’ tumour can kill Optic pathway glioma Pilocytic astrocytoma WHO grade I Morbidity: Blindness, pituitary failure, Meningioma (WHO grade I) Convexity vs skull base ‘Eloquent’ areas Other: dominant hippocampus memory How to predict tumour behaviour? • Grade An example of how to grade a brain tumour: glioma WHO GRADE GLIOMA HISTOLOGIC FEATURES PROGNOSIS WHO Grade I Tumours earn this grade by definition eg PILOCYTIC ASTROCYTOMA Excellent (*site) 5YS 95% WHO Grade II No high grade features Median survival 10yrs WHO Grade III Mitosis Median survival 3-5yrs WHO Grade IV Vascular proliferation +/- Necrosis Survival usually months 5YS <5% HIGH GRADE LOW GRADE Techniques in diagnostic practice IMMUNOHISTOCHEMISTRY Techniques in diagnostic practice Transcription factors X IMMUNOHISTOCHEMISTRY ARRAY COMPARATIVE GENOMIC HYBRIDISATION (aCGH) DNA SEQUENCING PANELS (NGS) FUSION SPECIFIC qPCR METHYLATION The role of Molecular Neuropathology 1. A result can (sometimes) make a diagnosis/ define a tumour (case 1) 2. A result can (sometimes) indicate a tumour grade (case 2) 3. A result can (sometimes) predict responsiveness to therapy (case 3) 4. A result, or more commonly a combination of results, can predict behaviour The following examples will illustrate some of these points Case 1; 1 year old, signs of raised ICP Undifferentiated embryonal tumour INI-1 immunohistochemistry is absent from all tumour cells confirming the presence of SMARCB1 mutation/deletion INI-1; ATYPICAL TERATOID RHABDOID TUMOUR, WHO IV Tumour of infants and young children CSF dissemination Rhabdoid tumour predisposition syndrome in >1/3 cases Case 2: 14yrs headache and vomiting H3K27M H3K27M Diffuse midline glioma, H3K27M MUTANT WHO grade IV Mackay et al., 2017, Cancer Cell 32, 520–537 Case 3: 39yrs, first seizure, non enhancing cortically based SOL 1p19q co-deletion 1p19q co-deletion When present with IDH1/2 mutation, defines oligodendroglioma Predicts responsiveness to PCV therapy when combined with RT Journal of Clinical Oncology 2013 31:3, 337-343 Example: WHO 2016 Adult diffuse glioma = routinely assessed N Engl J Med 2009; 360:765-773 Example: Paediatric low grade glioma MAPK ERK pathway = routinely assessed Any positive molecular result Æplaces a tumour into this oncogenic pathway ÆOpens up important targeted treatment options Summary of some of the more common molecular aberrations in brain tumours Molecular analysis Impact BRAF gene fusion 90% posterior fossa pilocytic astrocyotoma BRAF gene mutation V600 BRAF inhibitor therapy (clinical trials) IDH1/2 mutation Confers better prognosis in glioma (II-IV) 1p19q co-deletion Defines oligodendroglioma MGMT methylation Predicts responsiveness to temozolamide in glioblastoma/ high grade gliomas Histone (H3) mutation Æ Automatically WHO grade IV (paediatrics); dismal prognosis Investigations • Brain imaging: • CT BRAIN followed by • MRI BRAIN with contrast Treatment 1. Surgery – gross total resection (all except lymphoma & germinoma) 2. +/- Radiotherapy (*Cognition) 3. +/- Chemotherapy (BBB challenge) Brain Tumours & Tumour Syndromes Tumour Familial tumour syndrome Neurofibroma, Optic pathway glioma Neurofibromatosis type I Schwannoma (eg. acoustic neuroma) Ependymoma Neurofibromatosis type II (Schwannomatosis) Haemangioblastoma Von Hippel Lindau disease Subependymal giant cell astrocytoma Tuberous sclerosis Glioma/ Embyronal/ Chordoid plexus tumour Li Fraumeni syndrome L’hermitte duclos Cowden syndrome Glioma Turcot syndrome Atypical teratoid rhabdoid tumour ATRT Rhabdoid tumour predisposition syndrome Summary 1. Brain tumour presentation 2. Cerebral oedema & hydrocephalus 3. Primary vs secondary brain tumours 4. Brain tumour diagnosis 1. WHO grade 2. Molecular tests 5. Unique features brain tumours 6. Tumour syndromes. The Clinical Presentation of Brain Tumors Discussion