Lecture Outline• CNS Tumor classification and grading-pathologic,

histologic and prognostic • Incidence- male / female; adult / pediatric• Clinical Presentation/diagnosis• CNS tumor types, glial/non-glial tumors ; Prognosis• Patho-biology• Treatment-surgery, radiation,non-surgical treatment• Brain Tumor prevention• Exam prep-what to know!

Glioblastoma Cerebrum

What is a brain tumor?Brain tumors are abnormal growths of tissue

found inside the skull. which can be cancerous or non-cancerous.

Brain tumors are the second most common cause of death from neurological disease, after stroke.

Brain tumors can be benign or malignant:Benign brain tumors do not contain cancer cells.Malignant brain tumors contain cancer cells.Brain tumors by grade - from low grade (grade I-slow growing) to high grade (grade IV-fast growing).

Glioma : high grade (IV)

Brain Tumors Patho-physiology

PrimaryOriginating from the brain a

normal brain cell (glial cell) becomes malignant and is called a glioma

SecondaryOriginating outside the

brainMetastasis-cancer that

started elsewhere in the body (e.g. lung or breast) and spread to the brain

Morphologic Classification of CNS tumorsBased upon the cytologic resemblance of

neoplastic cells to normal cellsOften used to infer cell of originDoesn’t always predict the behavior of the

neoplastic cells

Site of originNeoplasms Arising within CNS ParenchymaNeoplasms Arising in Accessory CNS StructuresNeoplasms Arising in CNS Coverings

Astrocytoma-Lowgrade (2) fibrillary

Histologic Classification of Glial Tumors (World Health Organization 2000)

Astrocytic Tumors (Astrocytes-The most abundant type of macroglial cell, astrocytes (also called astroglia) have numerous projections that anchor neurons to

their blood supply)

Pilocytic (grade 1) Diffuse/Fibrillary (Grade 2) Anaplastic (grade 3) Glioblastoma Multiforme (grade 4)

Oligodendroglial tumors and mixed variants (Oligodendrocytes are cells that coat axons in the CNS with their cell membrane forming a specialized membrane differentiation called myelin, producing the so-called myelin sheath. The myelin sheath provides insulation to the axon that allows electrical signals to propagate more efficiently)

Oligodendroglioma, well differentiated (grade 2) Anaplastic oligodendroglioma (grade 3) Mixed oligodendroglioma/astrocytoma (grade 2) Mixed anaplastic oligodendroglioma/astrocytoma (grade 2)

CNS Tumor Classification: by site of origin(Pathologic classification)

Primary Tumors:Meninges – Meningioma

Meningeal Tumors MeningiomaMeningioma Hemangiopericytoma Melanocytic hemiangioblastoma

Glial cells: GliomaAstrocytoma & Glioblastoma. Oligodendroma, Mixed gliomas (oligoastrocytoma)ependymoma.Nerve sheath – Schwanoma, Neurofibroma.

Embryonal – Medulloblastoma, neuroblastoma, teratoma.Blood vessels – angioma, angiosarcoma etc.

Tumors of the Sellar Region Epithelial, Pituitary & Pineal gland tumors: Pituitary ademoma CraniopharyngiomaSecondary Tumors - Metastasis, Melanoma breast, lung, GIT.

Primary brain tumors: by Cell types (Histologic Classification)

1. Neuron: Gangliocytoma, ganglioglioma medulloblastoma2. Astrocyte: Astrocytoma, glioblastoma3. Oligodendrocyte: Oligodendroglioma4. Ependymal cell: Ependymoma5. Microglial cell: Tumors derived from microglial cells have

not been described.6. Meningeal cell: Meningiomas are derived from

arachnoidal cells and are usually dural-based.

Palisading

B.V

Necrosis

Glioblastoma Multiforme

Female

Male

Total

POPULATION WITH BRAIN TUMORS!Brain tumors are the second leading cause of

cancer related deaths in males ages 20-39 Brain tumors are the fifth leading cause of cancer-

related deaths in women ages 20-39 Lifetime Risk:Males have a 0.66% lifetime risk of being

diagnosed with a primary malignant brain tumor and a 0.50% chance of dying from a brain tumor.

Females have a 0.54% lifetime risk of being diagnosed with a primary malignant brain tumor and a 0.41% chance of dying from a brain tumor.

Normal Anatomy of Brain (MRI)

Supratentorial compartment:Cerebral hemispheresBasal gangliaThalamic nucleiLateral ventriclesHypothalamusCorpus callosum

Infratentorial compartment:CerebellumBrain stem4th ventricle

Glioblastoma MF

Adults

Children

CNS Tumors Incidence: General Features10% of all tumors.Commonest solid cancers in children.(2nd to Leuk for all

malignancies)Adults - 70% supratentorialChildren - 70% infratentorialNo/very rare extra-neural

spread.Metastasis most common. AdultsAdults

ChildrenChildren

Adults:Astrocytoma & Glioblastoma.MeningiomaMetastasis.

Children:AstrocytomaMedulloblastoma

Clinical PresentationSymptoms caused by mass effect or destruction of normal

tissueSymptoms

Headache (80%)Seizures (30%)

Neurological Deficits

Change in mental status/Personality Changes Slowing of Motor Function/Hemiplegia Hallucinations Memory Impairment Vision Impairment

Depends on:• Location / age• Non localised• Localised• Size

Clinical Presentation

Nonlocalised Blockage of CSF pathways

Weight loss, listlessness, irritability, decreased appetite, lethargy / withdrawn behaviour, headache, vomiting, double vision.

Clinical Presentation

Infratentorial tumorsSymptoms of ICPImbalance / SwayingDiplopia, swallowing

difficultyIntrinsic brain tumorsDiplopia, swallowing and

breathing difficulty, weakness limbs, swaying ICP

Supratentorial tumors

Weakness of limbs, loss of sensation, abnormal vision, learning difficulty, memory loss,

Deep midline tumors

Obesity, visual complaints, growth abnormalities.

Localised

Gliomas: Gliomas are neoplasms of glial cells. Commonest both in adults and children Benign * to Aggressively malignant.

Astrocytoma (anaplastic-Grade III & G.B.M-Grade IV)

Ependymoma - Rare, 4th ventricle. Oligodendroglioma - Benign, adults, rare

Gliomas: Glioblastoma Multiforme (GBM):High grade Astrocytoma - Grade IVCommonest & malignant brain tumor in adults, cerebral

supratentorial.Loss of heterozygosity on Chromosome 10 (80%)Most GBMs have lost one entire copy of C – 102 types: Primary (worst) or Secondary from low grade

astrocytomas (better prog).spreads quickly to other parts of the brain. For this

reason, can be difficult to treat.Variants: giant cell GBM, gliosarcoma

Gliomas:Prognosis for Glioblastoma multiformeMean survival 12-14 months from diagnosisMean survival 4-5 months from recurrence5 year survival rate <5%Recurrence occurs within 2-3 cm of the margins of the

original tumor in 80% of patients

CNS Tumor-Prognostic FactorsAgeTumor typeNeurologic functional statusExtent of surgery

•These tumors begin in the ependyma,the cells that line the passageways in the brain where special fluid that protects the brain and spinal cord (cerebrospinal fluid) is made and stored.

•They are a rare glioma and can be found anywhere in the brain or spine.

• Most commonly they arise in the cerebrum, the main part of the brain.

•Ependymomas may spread from the brain to the spinal cord via cerebrospinal fluid

Gliomas: Ependymal Tumors

MRI image shows an ependymoma (arrow) in the right lateral ventricle.

Non-glial tumorsMedulloblastoma: Malignant cerebellar tumor of

childhoodMeningioma: Benign, superficial, well-circumscribed

tumor derived from arachnoidal cellsNerve sheath tumors: Schwannoma and neurofibroma,

well-circumscribed, encapsulated tumors involving cranial nerves, spinal nerves and other peripheral nerves

Non-glial tumors:Medulloblastoma Pediatric Brain TumorsMedulloblastoma: Malignant (40% demonstrate CSF spread)

cerebellar (often arises in the posterior fossa) tumor of childhoodMedulloblastoma is the most common malignant brain tumor in

children, comprising 14.5% of newly diagnosed cases and the second most common malignancy among children <20 yo.

The incidence of childhood medulloblastoma is higher in males (62%) than females (38%).

Overall 10 year survival is 60%, 40 % relapse (median survial 5 months).

Clinical signs:Headache, vomiting, increased intracranial pressure

(Hydrocephalus), Increasing head circumference often is the only presenting symptom in infants

Cerebellar signs :Medulloblastoma most commonly is located midline. Therefore,

unilateral dysmetria (lack of coordination of movement typified by the undershoot or

overshoot of intended position with the hand, arm, leg, or eye) is less common than either truncal ataxia (gross lack of coordination) or a wide-based gait.

Medulloblastoma Pediatric Brain Tumors

Posterior fossa neoplasm – Medulloblastoma

SagittalAxial

Posterior fossa

Non-glial tumors: Meningioma Arise from arachnoid granulations of venous sinuses.

Attached to dura. Females common (2:1) Slow growth, well differentiated. Does not invade brain

(Benign).

Meninges

Tumor Suppression TP53 mutationsMost common mutation in human cancer

Platelet-derived growth factor receptor (PDGFR)-alpha - over expressed in many gliomasfibrillary astrocytomaoligodendrogliomaependymomapilocytic astrocytoma

Epidermal Growth Factor Receptor (EGFR) glioblastoma

Loss of heterozygosity (LOH) involving 1p and 19q is a common genetic alteration in oligodendroglioma

Patho-biology of CNS tumors

Patho-biology of CNS tumors

Diagnosis

ImagingCT scan (plain + contrast)

MRI with Contrast (Gd)

MRI preferred sensitivityresolution three planer views

Classification: Histology Location – Differs from

adult brain neoplasms Low grade Infratentorial

Differential diagnosisIdiopathic intracranial Hypertension-Pseudotumor Cerebri- Benign Intracranial Hypertension

CNS Tumor Treatment modalities

SurgeryRadiationChemotherapyCombined treatment

Surgery done for diagnosis and to relieve symptoms when possible

Median survival after surgery alone is 3-4 monthsResections are suboptimal secondary to preservation of

normal brain tissue-Goal is to remove as much tumor without causing neurologic dysfunction

Re-excision at recurrence an option in patients with good performance status

Rationale behind resection: -to obtain definitive histologic diagnosis -to palliate symptoms from local tumor effect -to potentially provide better tumor control with radiation/chemotherapy -to provide tissue for molecular/genetic analysis

for prognostication and research -to provide improved survival

Surgical Resection

Surface TumorsMeningiomas excised by microsurgical technique: pre-op

Post-op

Surgical Resection

Pre-Operative CT scan showing a big tumor on the surface of the brain compressing the brain significantly

Post Operative CT Scan showing successful removal of the tumor

Surgical Resection•Neurosurgery alone -showed limited success as a management of brain tumors.

•Collected data on symptoms before and after surgical resection report that 32% had an improvement in their symptoms, 58–76% were not different, and 9–26% had a worsening in their symptoms.

The past*-Whole brain irradiation! Radiation Therapy

*2 brain tumors

The present-Stereotactic Radiosurgery

• Definition: It refers to precisely localizing a target with application of ionizing radiation energy, aiming at accurate & complete destruction of this target, without significant concomitant or late radiation damage to adjacent tissues. The total dose of radiation is typically delivered in one fraction.

• Performed by: (1) Gamma Knife. (2) Linear accelerator system.

Gamma Knife• A head frame is attached to the patient’s skull and the

patient is positioned within the helmet. • Inside the helmet, multiple fixed cobalt sources are

arranged to intersect at a given point.

In Gamma Knife(1) There is a need to attach a frame to the skull. (2) Limitation of use to lesions above foramen magnum.(3) Inability to fractionate the dose.

Linear Accelerator Systems

(1) Linear Accelerator Scalpel®(2) Peacock System®(3) Novalis®(4) XKnife®(5) CyberKnife®

In Linear Accelerator system (CyberKnife)(1) There is a need to put a mask on the skull. (2) Used for lesions any where in the body.(3) The dose can be fractionated.

Radiosurgery for Brain Metastasis

• Gamma Knife or CyperKnife is now being used in brain metastasis as:

(A) A primary management OR (B) Booster treatment with whole brain radiation therapy.

• Although the size limitation on treatable lesions that preferred to be < 4 cm, tumor control rates of 90% can be expected if 1-4 lesions are irradiated with a peripheral dose of 20 gray (Gy), SI unit of absorbed radiation or more. In such cases, true recurrence is rare.

Non-Surgical Treatments of Brain Tumors

• Immunotherapy.• Anti-angiogenic Therapy.• Chemotherapy.• Endocrinal Therapy- pituitary

tumors• Gene & Viral Based Therapies.

Passive immunotherapy

• Monoclonal Antibodies : (1) Against epidermal growth factor receptor mutant

variant III. (2) Against vascular endothelial growth factor such as

Bevacizumab. (3) For delivery of Radionucleotides.

• Immunotoxins: Plant and bacterial toxins that are conjugated to either

antibodies or peptide ligands. They are designed to selectively deliver these toxins to the tumors.

Anti-angiogenic Therapy

• GBM over-express VEGF • Vascular Endothelial Growth Factor Pathway

Inhibitors: (1) Ligand Inhibitors (2) Receptor Inhibitors

• Non-Vascular Endothelial Growth Factor Pathway Inhibitors.

• Endothelial Cell Migration Inhibitors.

Vascular Endothelial Growth Factor Pathway Inhibitors

(1) Ligand Inhibitors: as Bevacizumab & Aflibercept. High radiographic response & 6-month progression-free survival were observed with the combination of bevacizumab and conventional chemotherapy.

(2) Receptor Inhibitors: as Cediranib & Vatalanib. They showed good radiographic response & powerful anti-edema effect.

Recurrent glioblastoma (A) treated with bevacizumab and chemotherapy (irinotecan) : showing marked reduction in enhancement after 4 weeks of therapy (B).

Non-Vascular Endothelial Growth Factor Pathway Inhibitors

• Epidermal Growth Factor Receptor Inhibitors: Gefitinib & Erlotinib.

• Platelet Derived Growth Factor Receptor Inhibitors: Imatinib & Dasatanib.

• VEGF Inhibitors: • Thalidomide blocks VEGF induced angiogenesis

Thalidomide (800-1200mg/day) & Lenalidomide. • Protein Kinase C Inhibitors: Enzastaurin, Taboxifen. GBM expresses high levels of PKC activity In vitro glioma cells are sensitive to inhibitors of PKC Inhibit PKC in glioma cell lines in micromolar concentrations

Endothelial Cell Migration Inhibitors: Cilengitide showed 6-month progression-free survival in

65% of patients with good tumor penetration after intravenous administration.

Metronomic Chemotherapy: It is a conventional chemotherapy administered at low

doses. It targets mainly tumor vasculature and delays tumor growth.

Chemotherapy• Chemotherapy has played primarily an adjuvant role in

treatment of brain tumors due to efficacy limitations related to drug-delivery issues & inherent tumor chemoresistance.

• Recent developments in chemotherapy of brain tumors include the combination of cytotoxic, cytostatic and targeted therapies.

Cytotoxic Chemotherapy

• Nitrosureas: were the mainstay of adjuvant therapy. They were used either alone as carmustine (BCNU) & lomustine (CCNU) or in combination with other agents as in PCV (procarbazine, CCNU & vincristine).

• Nitrosurea-based chemotherapy: after its addition to radiotherapy, it showed a modest but significant prolongation of survival. There was an absolute increase in 1-year survival of 6% and in 2-year survival of 5%.

• Temozolomide: is an oral alkylating agent that can cross the intact blood-brain barrier with excellent toxicity profile.

• Novel oral cytotoxic agent (imidazotetrazine-related to dacarbazine).

• Rapid absorption with 100% bioavailability.• Good CSF penetration (20-40%)• Well tolerated with good safety profile

• Temozolomide: was FDA approved for treatment of recurrent anaplastic astrocytoma only, whereas the European authorities approved the drug for both anaplastic astrocytoma and glioblastoma.

• Temozolomide’s approved schedule or standard regimen was a dose of 150– 200 mg/m2/day for 5 days of every 28-day cycle.

• Concomitant chemo-radiotherapy followed by single-agent adjuvant treatment with temozolomide was associated with a significant improvement in median survival and also it was well tolerated in all patients.

• Concomitant chemo-radiotherapy is the current standard of care for glioma patients, as well as the early introduction of chemotherapy appears to be the key to improve outcome.

Secondary-Brain Tumor3 treatment options

1. No treatment Death < 1 month

2. Corticosteroids onlyCorticosteroids produce symptomatic improvement within 24 to 72 hours.

Death < 2 months 3.Surgery with RadiationDeath 3-6 months. Radiation to the whole brain is often used to treat tumors that have

spread to the brain, especially if there is more than one tumor. Surgery may be used for metastatic brain tumors when there is a single lesion and when

there is no cancer elsewhere in the body. Some may be completely removed. Tumors that are deep or that infiltrate brain tissue may be debulked (removing much of the tumor's mass to reduce its size).

Surgery may reduce pressure and relieve symptoms in cases when the tumor cannot be removed.

Chemotherapy for brain metastases is not as helpful as surgery or radiation for many types of cancer.

Medications for some symptoms of a brain tumor may include the following: Corticosteroids such as dexamethasone to reduce brain swelling, has little

mineralocorticoid activity and lower risk for infection & cognitive impairment Osmotic diuretics such as urea or mannitol to reduce brain swelling Anticonvulsants such as phenytoin to reduce seizures Pain medication Antacids or antihistamines to control stress-ulcers.

CNS tumor prevention The only risk factor that's been proven to

increase the risk of brain tumors is exposure to high-dose ionizing radiation.

Persons who have been previously treated with radiation

Avoid the use of alcohol and smoking.Limit consumption of processed meats which

tend to have high levels of nitrates.People who have been in close proximity to a

nuclear blast.Healthy lifestyle

Total Recall-What you need to know

Tumor classificationNon-Surgical Treatments CNS tumor types glial & non-glialClinical Presentation

That’s all folks!That’s all folks!