The document provides an overview of central nervous system (CNS) tumor classification, grading, incidence, clinical presentation, diagnosis, types, pathobiology, and treatment. It discusses various types of glial and non-glial brain tumors such as glioblastoma, astrocytoma, oligodendroglioma, ependymoma, medulloblastoma, and meningioma. It also covers tumor grading systems, common genetic mutations in brain cancers, surgical resection, radiation therapies including stereotactic radiosurgery, chemotherapy, anti-angiogenic and immunotherapies.

1. 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

3. 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)

4. Brain Tumors Patho-physiology Primary Originating from the brain a normal brain cell (glial cell) becomes malignant and is called a glioma Secondary Originating outside the brain Metastasis-cancer that started elsewhere in the body (e.g. lung or breast) and spread to the brain

5. Morphologic Classification of CNS tumors Based upon the cytologic resemblance of neoplastic cells to normal cells Often used to infer cell of origin Doesn’t always predict the behavior of the neoplastic cells Site of origin Neoplasms Arising within CNS Parenchyma Neoplasms Arising in Accessory CNS Structures Neoplasms Arising in CNS Coverings

6. 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) Astrocytoma-Lowgrade (2) fibrillary

7. CNS Tumor Classification: by site of origin( Pathologic classification) Primary Tumors: Meninges – Meningioma Meningeal Tumors Meningioma Hemangiopericytoma Melanocytic hemiangioblastoma Glial cells: Glioma Astrocytoma & 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 Craniopharyngioma Secondary Tumors - Metastasis , Melanoma breast, lung, GIT.

8. Primary brain tumors: by Cell types (Histologic Classification) Neuron: Gangliocytoma, ganglioglioma medulloblastoma Astrocyte : Astrocytoma, glioblastoma Oligodendrocyte : Oligodendroglioma Ependymal cell : Ependymoma Microglial cell : Tumors derived from microglial cells have not been described. Meningeal cell : Meningiomas are derived from arachnoidal cells and are usually dural-based. Glioblastoma Multiforme Palisading B.V Necrosis

13. Female Male Total

14. 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.

16. Normal Anatomy of Brain (MRI) Supratentorial compartment: Cerebral hemispheres Basal ganglia Thalamic nuclei Lateral ventricles Hypothalamus Corpus callosum Infratentorial compartment: Cerebellum Brain stem 4 th ventricle

17. Glioblastoma MF Adults Children

18. CNS Tumors Incidence: General Features 10% of all tumors. Commonest solid cancers in children.(2 nd to Leuk for all malignancies) Adults - 70% supratentorial Children - 70% infratentorial No/very rare extra-neural spread. Metastasis most common. Adults Children Adults: Astrocytoma & Glioblastoma. Meningioma Metastasis. Children: Astrocytoma Medulloblastoma

20. Clinical Presentation Symptoms caused by mass effect or destruction of normal tissue Symptoms 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

21. Clinical Presentation Nonlocalised Blockage of CSF pathways Weight loss, listlessness, irritability, decreased appetite, lethargy / withdrawn behaviour, headache, vomiting, double vision.

22. Clinical Presentation Infratentorial tumors Symptoms of  ICP Imbalance / Swaying Diplopia, swallowing difficulty Intrinsic brain tumors Diplopia, 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

24. 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

25. Gliomas: Glioblastoma Multiforme (GBM): High grade Astrocytoma - Grade IV Commonest & malignant brain tumor in adults, cerebral supratentorial . Loss of heterozygosity on Chromosome 10 (80%) Most GBMs have lost one entire copy of C – 10 2 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

27. Gliomas:Prognosis for Glioblastoma multiforme Mean survival 12-14 months from diagnosis Mean survival 4-5 months from recurrence 5 year survival rate <5% Recurrence occurs within 2-3 cm of the margins of the original tumor in 80% of patients CNS Tumor- Prognostic Factors Age Tumor type Neurologic functional status Extent of surgery

28. 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.

29. Non-glial tumors Medulloblastoma : Malignant cerebellar tumor of childhood Meningioma : Benign, superficial, well-circumscribed tumor derived from arachnoidal cells Nerve sheath tumors: Schwannoma and neurofibroma, well-circumscribed, encapsulated tumors involving cranial nerves, spinal nerves and other peripheral nerves

30. Non-glial tumors:Medulloblastoma Pediatric Brain Tumors Medulloblastoma: Malignant (40% demonstrate CSF spread) cerebellar (often arises in the posterior fossa) tumor of childhood Medulloblastoma 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.

31. Medulloblastoma Pediatric Brain Tumors Posterior fossa neoplasm – Medulloblastoma Posterior fossa Sagittal Axial

32. 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

34. Tumor Suppression TP53 mutations Most common mutation in human cancer Platelet-derived growth factor receptor (PDGFR)-alpha - over expressed in many gliomas fibrillary astrocytoma oligodendroglioma ependymoma pilocytic 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

35. Patho-biology of CNS tumors

37. Diagnosis Imaging CT scan (plain + contrast) MRI with Contrast (Gd) MRI preferred  sensitivity  resolution  three planer views Classification: Histology Location – Differs from adult brain neoplasms Low grade  Infratentorial  Differential diagnosis Idiopathic intracranial Hypertension Pseudotumor Cerebri Benign Intracranial Hypertension

39. CNS Tumor Treatment modalities Surgery Radiation Chemotherapy Combine d treatment

40. Surgery done for diagnosis and to relieve symptoms when possible Median survival after surgery alone is 3-4 months Resections 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

41. Surface Tumors Meningiomas excised by microsurgical technique: pre-op Post-op Surgical Resection

42. 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.

43. The past*-Whole brain irradiation! Radiation Therapy *2 brain tumors

44. 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.

45. 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.

46. 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.

47. Linear Accelerator Systems Linear Accelerator Scalpel® Peacock System® Novalis® XKnife® CyberKnife®

48. 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.

49. 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.

50. Non-Surgical Treatments of Brain Tumors Immunotherapy. Anti-angiogenic Therapy. Chemotherapy. Endocrinal Therapy- pituitary tumors Gene & Viral Based Therapies.

51. Passive immunotherapy Monoclonal Antibodies : (1) A gainst 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.

52. 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.

53. Vascular Endothelial Growth Factor Pathway Inhibitors 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.

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

55. 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

56. 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.

57. 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 .

58. 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% .

59. 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.

60. 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.

61. Secondary-Brain Tumor 3 treatment options 1. No treatment Death < 1 month 2. Corticosteroids only Corticosteroids produce symptomatic improvement within 24 to 72 hours. Death < 2 months 3. Surgery with Radiation Death 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.

63. 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

64. Total Recall- What you need to know Tumor classification Non-Surgical Treatments CNS tumor types glial & non-glial Clinical Presentation

65. That’s all folks!