Brain Tumors

Neurology Brain Tumors December 17-19, 2007 WHO Histologic Classification of Tumors of the CNS 1. Tumors of Neuroepithelial Tissue 2. Tumors of Cranial and Spinal Nerves 3. Tumors of the Meninges 4. Tumors of Uncertain Histogenesis - Ex: Hemangioblastoma from primitive vascular structures 5. Lymphomas and Hematopoietic Neoplasm 6. Germ Cell Tumor - Ex: Germinoma – common in pineal gland area 7. Cysts and Tumor-like lesions - Usually in the third ventricle 8. Tumors of the Sellar Regions 9. Local Extension from Regional Tumors 10. Metastatic Tumors Note: Brain tumors are mostly derived from glial cells rather than the neural cells. Tumors of the CNS can be:
Primary
Secondary (metastatic) may lodge into the ff structures: - Brain parenchyma – most common area of metastases - Leptomeninges – pia mater & arachnoid - Dural space Benign Malignant - A tumor can be benign histologically. However, due to location, for example in an eloquent area, it can become malignant if it causes signs & symptoms Extramedullary (Extraaxial) - Meningioma - Pituitary adenoma - Vestibular schwanomma Intramedullary (Intraaxial) – mostly manifesting as seizures - Glioma – glial cell tumor in the brain parenchyma - Primary CNS Lymphoma - Metastatic Intraventricular Look at it now! ☺ ** When you see a lymphoma in the brain parenchyma, it is primary CNS tumor. When you see a lymphoma in the leptomeninges, it is usually a metastatic lesion.

Clinical Presentation - Depends on location of the tumor and rate of growth of the tumor - Insidious onset - Slowly progressive tumors - Headache - Usually becoming severe & slowly progressive, tumor should be a suspect - Seizure - Adult onset seizures – tumors should be suspected - Childhood onset seizures – tumors are rare but signs of focal neurologic deficits should make one suspicious of a tumor - Mental, behavioral and personality changes - Also when becoming severe & slowly progressive, suspect a brain tumor - Lateralizing or focal neurologic deficits - Increased ICP ** To reiterate, the onset of brain tumors is insidious & the course is slowly progressive. (As oppose to stroke, which has an acute onset & a rapid clinical course) Cerebral Dysfunction - Seizure - Language disorder—aphasia (motor area lesion: Broca’s aphasia; sensory lesion: Wernicke’s aphasia) - Organic mental, behavioral personality changes - Contralateral lesion of the cerebrum manifests the following: - Hemiparesis with Babinski reflex & cranial nerve deficits - Hemisensory deficits - Homonymous hemianopsia/quadrantanopsia **The nature of the contralateral manifestations of a cerebral lesion is due to the decussation of the corticobulbar & corticospinal tracts coming from the cerebrum. Cerebellar Dysfunction - Hemisphere lesion - Ipsilateral limb ataxia - intention tremor - dysmetria - dysdiadochokinesia - Vermis lesion - truncal ataxia - no limb ataxia ** An example of a vermis tumor is medulloblastoma in children which manifests with truncal ataxia.

** Of the most common primary brain tumors, only glioma is intramedullary in location. Meningioma, pituitary adenoma & vestibular schwannoma (2nd, 3rd & 4th most common, respectively) are all extramedullary)

** With the cerebellum in close relation to the 4th ventricle, a lesion appearing in the cerebellum may compress this ventricle & cause obstructive hydrocephalus.

Age Incidence - Adults - Supratentorial: 80-85% - Intratentorial: 15-20% - Children - Intratentorial: 60% - Supratentorial: 40%

Brainstem Dysfunction - “Crossed motor or sensory syndrome” - Ipsilateral cranial nerve deficits - Contralateral hemiparesis with Babinski - Ipsilateral limb ataxia - Internuclear ophthalmoplegia—median longitudinal fasciculus syndrome

** Therefore, cerebral tumors are more common in adults while cerebellar & brainstem tumors are more common in children. **Boundary between supratentorial & infratentorial is the tentorium cerebelli.

Increased ICP Headache/vomiting with: a. Papilledema - The abducens n. has the longest intracranial route making it vulnerable to alterations even if ICP is in the upper portion above the pons b. Diplopia with internal squint (lateral rectus palsy secondary to abducens nerve lesion) - As a focal lesion, lateral rectus palsy will localize the lesion in the pons or pontine glioma - But when associated with ↑ ICP, lesion may be cerebral, cerebellar or in the brainstem due to the long route of the abducens nerve c. Deterioration in the level of consciousness d. Bulging fontanel, separation of sutures, rapid enlarging head size

I. GLIOMAS Most common primary brain tumor 50% of all symptomatic brain tumors Incidence increases with advancing age Peak in 8th and 9th decades No known environmental factors No behavioral lifestyle choices Ionizing radiation: the only clear risk factor Originate from glial cells or their stem cell precursors Include: a. Astrocytoma b. Oligodendroglioma c. Ependymoma - WHO Classification Basis a. Increased cellularity b. Nuclear atypia c. Endothelial proliferation d. Necrosis - Can be located anywhere – from the cerebrum, cerebellum or brainstem. If it appears in the brainstem, the most common location is the pons.

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Temporal Profile of Brain Abnormalities - Onset of Illness - Course of Illness Vascular

Toxin & Metabolic

Neurologic Impairment

Infection

Neoplasm

Degenerative

1

2 3 4 5 6 7 2 3 4 2 3 4 5 6 2 Days

Weeks

Months

3

Years

Ancillary Procedures - Skull X-ray - EEG - Perimetry, audiometry - Cerebral angiographs - CSF examination - Its role is questionable in brain tumors. Usually there is normal sugar content but protein is elevated because the tumors release proteases that destroy the BBB allowing proteins to come in. - Neuroimaging studies - Cranial/Spinal CT Scan with or without contrast Treatment of Brain Tumors - Surgery - Radiotherapy - Gamma knife: indicated for tumors <3.2cm - Very expensive - Chemotherapy

A. Astrocytoma - Most common glioma - Cerebral astrocytoma (more in adults) - Behavioral changes - Seizures - Hemiparesis - Language difficulty - Cerebellar astrocytoma (more in children) - Hemisphere - Ataxia - Brain stem (children) - Pons - CN deficits Grade WHO Designation I

Pilocytic astrocytoma

II

Astrocytoma

III

Anaplastic astrocytoma Glioblastoma multiforme

IV

II

Oligodendroglioma

III

Anaplastic Oligodendroglioma

II

Ependymoma

III

Anaplastic ependymoma

Criteria for Tumor Type Bipolar & multi-polar astrocytes, long processes, microcytes Well-diff fibrillary or neoplastic astrocytes -

Bounded tumor cells, “fried egg” appearance, network of branching capillaries -

Perivascular pseudorosettes

Criteria for Grade Piloid cells, Rosenthal fibers, eosinophilic granular bodies, low cellularity Nuclear atypia, increased cellularity Nuclear atypia & mitosis Nuclear atypia, mitosis + endothelial proliferation & necrosis Nuclear atypia occasional mitosis

Nuclear atypia Mitosis, Microvascular proliferation Necrosis Well delineated, moderately cellular & ependymal rosettes Microvascular proliferation, pseudopalisading necrosis

Grade I: Pilocytic Astrocytomas - Primary in children & young adults - Focal astrocytoma may be associated with neurofibromatosis type I (NF-I) - Unusually excellent prognosis Grade II: Diffuse or Fibrillary Astrocytoma - Most common in the cerebral hemisphere in young adults - Low grade or benign histologically - Infiltrative – usually a problem because the tumor cannot be resected completely if this is a characteristic of the tumor - Complete resection not possible - Latent potential for malignant transformation Grade III: Anaplastic Astrocytoma Grade IV: Glioblastoma multiforme - Grades III and IV are high-grade gliomas - 20% of all intracranial tumors - 55% of gliomas - 80% of gliomas of the cerebral hemispheres in adults - Peak incidence middle to late adulthood - Males/females = 1.61 - No familial predilection Glioblastoma Multiforme - CSF seeding: - Malignant cells in the CSF may form: a. Distant foci in spinal roots b. White spread meningeal gliomatosis - CSF seeding implies that GBM can go to the CSF spaces such as the subarachnoid space & communicate with the ventricular system - Extraneural metastasis - To bone & lymph nodes (very rare) after a craniotomy - Pseudopalisading around the necrosis is common in GBM - Can cross the midline in a “butterfly” pattern: this shows the aggressive nature of this tumor because the midline is composed of a tough dura Anaplastic Astrocytoma - Have increased pleomorphism, enlarged nuclei and most importantly, increased proliferative activity that is reflected as increased mitotic activity. - There should be NO necrosis or endothelial proliferation. Presence of either/both is suggestive of worse biological behavior. Imaging: High- and Low-Grade Gliomas - High-grade or malignant gliomas: appear as contrastenhancing mass lesions which arise in white matter & are surrounded by edema - Low-grade gliomas: typically non-enhancing lesions that diffusely infiltrate brain tissue & may involve a large region of brain - Low-grade gliomas are usually best appreciated on T2weighted MRI scans. Prognosis of Astrocytomas - Median survival - GBM: 1 year - Anaplastic astrocytoma: 3 years - Low-grade astrocytoma: 5 years - Others survive a decade or more - Most die from transformation of tumor to higher grade B. Oligodendroglioma - Derived from oligodendrocytes or their precursors - Oligodendrocytes produce the white matter in the brain - 5-7% of all intracranial gliomas - Most often in the 3rd and 4th decades - Males:females = 2:1 - Found primarily in cerebral hemispheres, within the brain parenchyma - Highly infiltrative - May metastasize distantly in ventricular & subarachnoid spaces like the GBM (CSF seeding) - Round regular “fried-egg” cells

- Calcification: common - Usually GFAP negative (glial fibrillary acidic protein staining) - Highly infiltrative - Majority are low-grade lesions which have the potential to transform over time to anaplastic oligodendroglioma - May acquire astrocytic features which may develop into GBM - Radiosensitive & Chemosensitive - Radiotherapy: standard treatment for anaplastic oligodendroglioma - Correlated with loss of heterozygosity of chromosome 1p19q (1p/19q LOH or deletion) - Many respond to chemotherapeutic agents - PCV regimen: Procarbazine, Lomustine, and Vincristine

“fried egg cells of oligodendroglioma” Prognosis of Oligodendroglioma Median Survival - Low-grade oligodendrogliomas: 8-16 years - Anaplastic oligodendrogliomas: 5 years - Tumors that have 1p/19q LOH—best prognosis - Many pxs die from malignant transformation of the tumor C. Ependymoma - Arise from ependymal cells (an intraventricular tumor) - More common in children - 10% pediatric intracranial tumors - 5% of adult intracranial tumors - Most common in the 4th ventricle - Ataxia, vertigo, increased ICP - May grow in brain parenchyma without obvious attachment to the ventricular system - Spinal lesions more common in adults - Intracranial ependymomas predominate in children Histological Characteristics of Ependymoma - Perivascular pseudorosettes - Tumor cells arranges themselves radially around blood vessels - Ependymal or Homer-Wright Rosettes - Tumor cells arrange themselves around a central lumen - GFAP positive - Loss of chromosome 22 particularly 22q - CSF seeding (“drop metastasis”) - From the 4th ventricle to the subarachnoid space down to the spinal cord causing spinal cord manifestations Cranial MRI - Heterogenous well-delineated lesion with prominent contrast enhancement - Occasional hemorrhage and calcification Prognosis - 5-year survival: 40-50% - 10-year survival: 47-68% - Better prognosis: - Young age - Infratentorial - Gross total excision - Low-grade histology

II. MENINGIOMA - Second most common primary brain tumor - Originate from arachnoid cells (meningoepithelial cap cells normally seen in arachnoid villi) - 20% of all intracranial tumors (with asymptomatic cases—40% or more) - 7% of all posterior fossa tumors - 3-12% of cerebellopontine angle tumors - Most diagnosed in 6th % 7th decades - Female: Male—3:2 to 2:1 - Multiple in 5-15% (NF-2) - 90% intracranial - 10% intraspinal - Spinal meningioma: 10x in women - All familial meningiomas occur with NF-2 - Rare in children (more in boys) - Rare with dural attachments - Usually Intraventricular or posterior fossa - Commonly with sarcomatous changes - Frequently with NF-2 Etiology of Meningioma - Radiotherapy - Only established risk factor for meningioma - Radiation-induced tumors tend to occur over convexities - multiple - histologically malignant - more likely to recur - Head trauma: not a confirmed risk factor - Viral infection (SV-40): data are unconvincing - Estrogen receptors marginally present: less affinity for estrogen as the receptor in breast cancer - That is why meningioma can grow during pregnancy - Progesterone receptors - Expressed in 80% of women with meningiomas - Expressed in 40% of men with meningiomas Pathology - Nodular tumors occasionally meningiomas en plaque (sheer-like formation) - Highly vascular - Encapsulated and attached in the dura (blood supply from external carotid artery) - Hyperostosis of adjacent bone (bone proliferation) Histological Characteristics - Benign - Typical features: - Whorls of arachnoid cells surrounding a central hyaline material that eventually calcifies to form PSAMMOMA BODIES - No characteristic cytologic marker WHO Classification of Meningioma - Cellularity, cytologic atypia, mitosis, necrosis A. Typical or benign B. Atypical or malignant (rare) - other histologic features of anaplasia often present: mitosis, pleomorphism, necrosis - aggressive (+brain invasion) - systemic metastases in 50% * Bone * Liver * Lung

Clinical Manifestations - Some are asymptomatic—found incidentally by MRI - But may have symptoms: - Tumor location: by compression of underlying neural structures - Sites of predilection - Cerebral convexity (Sylvian & parasagittal areas) - Falx cerebri - Skull base - Olfactory groove - Sphenoid ridge - CP angle - Tuberculum sella

This is the parasagittal area of the brain: lower extremities are affected when a lesion occurs here

** A convulsion affecting the lower extremities, suspect a meningioma in the parasagittal area. ** Base of the skull = CN can be found here Cranial CT Scan - Isointense or slightly hyperintense - Smooth, sometimes lobulated distinct margins with dural tail attachments - Strong and homogenous enhancement - Edema is variable - Hyperostosis—20% - Isointense (65%) or hypointense (35%) in T1 and T2 - Intense and homogenous enhancement with gadolinium Angiography - Hypervascular mass - If preoperative, perform embolization to reduce the risk of intraoperative bleeding MR Angiography & Venography - Has replaced standard angiography Growth Rate of Meningioma - Less than 1 cm per year (very slow growth but can recur) - Tumor doubling time: 1.27 to 14.35 years Surgery - Complete excision may cure many meningiomas - The extent of resection is the most important in determining recurrence - For recurrence: reresection Radiation Therapy - Residual tumor after surgery - Recurrent tumor - Atypical or malignant histology Hemangiopericytoma - Meningeal tumor derived from pericytes (smooth muscle cells associated with small blood vessels)

III. TUMORS OF THE PITUITARY GLAND - Third most common primary brain tumor - Often asymptomatic - Incidence at autopsy: 1.7 – 24% - Most common in adults in the 3rd and 4th decade - 10% incidence in children & adolescents - Not hereditary except MEN-1 (multiple endocrine neoplasia) Pathology - Microadenoma - Less than 1cm - Symptoms due to excess hormone secretion (or hyperfunctioning) a. Growth hormone b. Gonadotropin c. Thyroid hormone d. Adrenal hormone e. Prolactin hormone - Macroadenoma - More than 1cm - Symptoms due to compressing normal pituitary gland and neural structure causing hypofunctioning - Endocrine Active (Secretory) - Prolactinoma - Most common secretory intrasellar endocrine active tumor - Secreted either by microadenoma or macroadenoma - Growth hormone - Before closure of epiphysis → gigantism - After closure of epiphysis → acromegaly - ACTH: Cushing’s Syndrome - FSH and LH - Endocrine Inactive (Non-secretory or null cell adenoma) - 10% mixed secretory tumor - Histological characteristics: - Almost all are histologically benign - Pituitary CA: rare - Macroadenomas - May invade dural bone - May infiltrate surrounding structure - Locally invasive pituitary adenomas are nearly always histologically benign - Pleomorphism and mitotic figure insufficient for diagnosis of carcinoma (may be seen in benign adenomas) - Invasive character independent of growth rate - Pituitary Carcinoma - Highly invasive - Rapidly growing & anaplastic - Unequivocal diagnosis relies on presence of distant metastasis Clinical Manifestations of Tumors of the Pituitary Gland  Mass effect (of the growing tumor) - Compression of neural and vascular structures - Headache - Hypopituitarism - Visual symptoms - visual loss - visual field abnormality: bitemporal hemianopsia is the most common - Papilledema is rare - May enlarge with pregnancy - 5% of pituitary adenoma present with pituitary apoplexy Optic chiasm - Between hypothalamus & sella turcica - When this is compressed → bitemporal hemianopsia Optic nerve - When this is compressed → ipsilateral blindness Optic tract - When this is compressed → contralateral homonymous hemianopsia Diaphragma sella - The dura that covers sella turcica

- As tumor grows forward to the sella → compress the basal dura → headache → affected pain-sensitive intracranial structures - Basal dura is a pain-sensitive intracranial structure  Hypothalamus + thalamus - Form the lateral wall of the 3rd ventricle - Any pathology in the ventricular system will cause accumulation of CSF proximal to the block → hydrocephalus  Suprasellar region – region of the hypothalamus - An example of a suprasellar tumor is a craniopharyngoma in children & adults - A craniopharyngoma can compress the third ventricle & cause the ff: (hydrocephalus with signs of increased ICP) - Headache - Vomiting - Papilledema - Nowadays, pituitary adenoma usually does not grow until the region of the hypothalamus because visual problems prompt consult & diagnosis. - Papilledema is also rare because it manifests late in the course of the tumor. Before that happens, patient must have been diagnosed already - Obstructive hydrocephalus: rare because of diagnosis at visual problem level  Pituitary Apoplexy - Hemorrhage or infarction of pituitary adenoma - Sudden onset of headache, nausea, vomiting, visual loss, diplopia, altered mental status - Diagnosis by CT or MRI - Treatment  emergency surgery Note: **If px has amenorrhea check the ff structures: - Ovary: estrogen & progesterone problem - Pituitary gland: may be the problem due to FSH and LH hyposecretion - Hypothalamus: may be the problem due to GnRH hyposecretion - If px is not pregnant, by visual examination, she may have bilateral hemianopsia or monocular blindness. Therefore ruling out pregnancy. **A pituitary tumor need not to be a microadenoma to secrete endocrine hormone. Macroadenoma can also secrete hormones. Diagnosis - X-ray – will show you ballooning of the sella turcica - Cranial MRI - Best way to evaluate pituitary pathology Treatment - Surgery Transsphenoidal approach: procedure of choice - Hormone replacement - Radiation Treatment Complementary to surgery in preventing progression or recurrence - Radiosurgery NOT used for: - large tumors - tumors less than 3 mm distance from optic apparatus

IV. VESTIBULAR SCHWANNOMA - A.k.a acoustic neuroma or acoustic neurofibroma - Used to be called acoustic schwannoma, but the lesion is in the vestibular apparatus, not in the acoustic portion or the cochlea - 4th most common tumor - Arises from schwann cells of the vestibular branch of the 8th cranial nerve - 5-10% of intracranial tumors - Most common tumor of the cerebellopontine angle (next is meningioma) - Peak age: 40-60y/o - F:M—2:1 - Bilateral tumors in less than 5% Defining characteristic of NF-2 - Grows slowly Less than 2mm per year - Many tumors are large and even cystic before they become asymptomatic ** 2 components of the CN VIII is the acoustic & vestibular portion. ** When thinking of a cranial nerve deficit due to a tumor, the tumor must be in the base of the brain or base of the skull Clinical Manifestations of Vestibular Schwannoma - Usually based on the affected nerve - Progressive unilateral hearing loss - A more persistent or consistent finding in schwannomas - If your suspicion is a schwannoma & px presents with unilateral hearing loss, the px may be deaf for the rest of his life. - As compared to a meningioma, which is also a CP angle tumor, unilateral hearing loss may not be present or may disappear. In schwannoma, hearing loss is persistent - Unsteady gait (dysequilibrium/vertigo): 20% - As the schwannoma grows very slowly, the brain may have the capability of adjusting. So, initially, vertigo may manifest. But after some time, vertigo may disappear. - Facial numbness (CN V): 30% - Facial weakness (CN VII): 9% - Tinnitus: 70% - Decreased corneal reflex - Closing of the eye lids may be inappropriate due to affectation of the CN V - Tumor encroaching on acoustic regionpx becomes deaf - Tumor usually grows up to press on 5th cranial nerve (causes facial numbness), medially to compress 7th cranial nerve (causes facial weakness) - Usually doesn’t involve the 6th cranial nerve first - Common cranial nerves involved in vestibular schwannoma (in order): CN VIII, VII, V (875) Remember this! Listen to this! Very Nice!☺ CN II, III – pupillary reflex, localize at the midbrain CN V and VII – corneal reflex, localize at the pons CN IX – gag reflex, localize at the medulla Cerebellopontine Angle (CPA) Tumors 1. Vestibular Schwannoma 2. Meningioma (2nd most common; pxs not deaf) 3. Cholesteatoma (Epidermoid) 4. Trigeminal Neuroma: does not involve 8th CN. Therefore, no cochlear dysfunction; only consider due to proximity

Schwannoma Eccentric placement in nerve fascicle Gross total resection normally possible

Neurofibroma Hallmark tumor of NF-1 Plexiform neurofibroma cordlike enlargement of nerve twigs Spindle cells, axons, myxoid background Patent nerve intermingles with tumor Harder to remove because the tumor is together with the nerve

Histologic Characteristics - Antoni A: areas with densely packed tumor cells - Antoni B: areas with loose pattern of stellate cells with long irregular processes - Notice the whirly swirly pattern and how the cell nuclei are closely bunched together almost as if they’re forming a fence - Schwannomas are benign spindle cell tumors that occur along the ropes of peripheral nerves. They can usually be removed without damaging the nerve itself. Malignant Schwannoma - Can be difficult to diagnose and are usually >5cm in diameter by the time they are brought to the attention of a medical professional and identified. - Similar to most other types of cancers, the tumors are treated with one or more of the ff: surgery, chemotherapy or radiotherapy. - The 5yr survival rate associated with malignant schwannomas is low, primarily due to poor response of the tumors to available tx and metastasis to the lungs & other areas of the body. - Good prognosis: young px relatively small tumors which are completely removed via surgical means Diagnosis - Gadolinium-enhanced MRI Best technique for diagnosis Hyperintense on T2 MRI Treatment - Surgery - Radiosurgery: excellent alternative for tumors less than 3cm in diameter V. LYMPHOMA Look! But you have to understand! ☺ - Lymphoma can be primary in the CNS or they can be metastatic - When they are primary, it is usually in the brain parenchyma >90% of the time - When metastatic, it usually goes to the leptomeninges Metastatic Lymphomas (CNS) - Almost exclusively with Non-Hodgkin’s Lymphoma - They usually metastasize to the ff: 1. Leptomeninges - Most common location of a metastatic lymphoma intracranially - Composed of the pia & the arachnoid which surrounds the subarachnoid space - Therefore, a metastatic lymphoma in the leptomeninges is a tumor in the subarachnoid space - Therefore, from the SAS it can travel to the other ventricle 2. Epidural space – 3-5% 3. Rarely brain parenchyma - <1%

Hodgkin’s Lymphoma - Metastasize to the epidural space → epidural spinal cord compression - Rarely leptomeningeal & brain parenchyma Primary CNS Lymphomas (PCNSL) - Most common site is the brain parenchyma in the cerebrum - In contrast to what has been always known, CNS lymphoma can also develop in immunocompetent individuals, not only to those who are immunocompromised A. Immunocompetent - 3% of all intracranial neoplasms - 7% of all malignant lymphomas - Peak incidence: 5th-7th decade - M:F—3:2 - Pathology: - Single or multiple parenchymal brain lesions (>90%) - Primary leptomeningeal lymphoma - Primary intramedullary lymphoma of spinal cord (rarest) - Primary ocular lymphoma (uvea or vitreous lesions) - 98%: B-cell tumors - 2%> T-cell tumors - Grossly: - Fleshy with ill-defined borders - Histologically: - Cells are closely packed with characteristic perivascular concentration - Neuroimaging: - Single or multiple lesions often periventricular - Most common in supratentorial, particularly frontal lobe - CAT Scan: isodense or hyperdense pre-contrast - MRI - Hypointense on T1 relative to gray matter borders; NOT well-demarcated - On contrast: dense & homogenous on Immunocompetent - Edema: mild to moderate - MRI may show diffuse ependymal spear not appreciated on CT B. Immunocompromised - Pxs with or who underwent: AIDS Renal transplantation Ataxia telangiectasia Rheumatoid arthritis Wiskott-Aldrich Syndrome IgA deficiency - Occurs in the 3rd and 4th decades - Almost always multiple. Do not have the typical periventricular location - Increased preponderance of the immunoblastic - Hemorrhage, necrosis & calcifications are common - Neuroimaging with contrast-ring enhancement (corresponding to necrosis)

Treatment - Corticosteroids: cytotoxic effect on lymphomas  will decrease in size - Surgery is not helpful therapeutically - Radiation PCNSL is highly responsive to radiotherapy - Chemotherapy PCNSL is chemosensitive VI. VASCULAR TUMORS
Histologically indistinguishable a. Hemangioblastoma - confined to posterior fossa in the cerebellum - no dural attachment (meningioma is the one with dural attachment) b. Angioblastic meningioma - located above & below the tentorium - has significant dural attachment - identical in other meningiomas c. Hemangiopericytoma - derived from pericytes (smooth muscle cells of small blood vessels) - recognized elsewhere in the body Hemangioblastoma - Composed of primitive vascular elements - 1-2% of intracranial neoplasms - All ages are affected but more frequently in young & middleaged adults - Predominantly males - 20% familial - 10-20% part of von Hippel-Lindau Disease Hemangioblastoma Angiomatosis of retina Cysts of kidneys and pancreas Occasional renal cell carcinoma & capillary nevi of skin - Adult with cerebellar tumor same as pilocytic astrocytoma (cystic tumor)  hemangioblastoma - Any tumor encroaching on vestibular system will cause obstructive effects. Therefore, increase ICP. - Predominantly in the cerebellum (most common in the paramedian cerebellar hemisphere) - Large cysts with yellow proteinaceous fluid - Resemble the cyst & mural nodule of cystic cerebellar astrocytoma but with distinctive vascular appearance & angiogram - May be multiple Vertebral angiogram showing hemangioblastoma Clinical Features of Cerebellar Masses - Headache - Papilledema - Ataxia: focal neurologic deficit of hemangioblastoma - Polycythemia Erythropoietic substance from cystic fluid Diagnosis: CT angiogram Treatment: surgery - evacuation of cyst - removal of mural nodule

Diagnosis - Histologic confirmation from: Brain CSF Vitreous humor - Gross & microscopic pathology and clinical manifestations are identical in immunocompetent & immunocompromised pxs - Use tissue biopsy for differentiation

Look at this! Very nice! ☺ - If I ask you what is the cerebellar tumor in adults that is assoc with polycythemia, the answer is Hemangioblastoma. - What will be the focal deficit of Hemangioblastoma? Limb ataxia

Clinical Manifestations (symptoms of space-occupying lesions) - Headache - Personality change - Lateralizing on focal neurologic deficits

** Any cerebellar tumor because of the anatomic location of the cerebellum in relation to the 4th ventricle, they are assoc with increased ICP because they will compress on the 4th ventricle. → obstructive hydrocephalus

Cerebellar Dysfunction - Hemisphere lesion Ipsilateral limb ataxia - intention tremor - dysmetria - Dysdiadochokinesia - Vermis lesion Truncal ataxia No limb ataxia Note: Most common location of medulloblastoma is the vermis which is common in children. Prognosis of Hemangioblastoma - Good alive 5-20 years after surgery - High incidence of recurrence If partial resection Multiple tumors METASTASIS Brain parenchymal metastasis Leptomeningeal metastasis Dural metastasis I. BRAIN PARENCHYMAL METASTASIS - Most common part: cerebrum (followed by the cerebellum) - Tumor in cerebellum in adults often Metastatic - Usually found with disseminating systematic disease - In some the intracranial disease appears before the systemic cancer - Non-small cell lung cancer: most common primary lesion leading to brain metastasis - Melanoma and small cell lung cancer have the greatest propensity to metastasize in the brain - 2 most common metastasis to the brain 1. lungs 2. breast - Other primary cancers that commonly spread to the brain: Renal cancer GI cancer - Tumors that rarely spread to the brain: Prostate cancer (usually to the bone) Uterine cancer } seldom Pancreatic cancer } metastasize - Hemorrhagic metastasis to the brain - Lung cancer – most common - Melanoma - Thyroid - Choriocarcinoma Clinical Findings - Symptoms similar to any space-occupying lesion - Subacute course over 1-2 weeks - Occasionally acute and stroke-like in intratumoral hemorrhage ** If I ask you in the quiz, systemic cancer commonly metastasize intracranially in the: a. cerebrum b. cerebellum c. brainstem ** When does brain metastases become acute? When there is intratumoral hemorrhage Diagnosis
Cranial MRI with Gadolinium Solitary or multiple Lesions are contrast enhancing diffusely when small and ring enhancing when large with well defined borders ** Most of the time, solitary tumor in the brain seen in the MRI can be both primary or metastatic. But multiple brain tumors are mostly metastatic lesions.

Treatment - Whole brain radiotherapy: relief of neurologic symptoms in 80% - At least 48hrs of Dexamethasone (16mg/day) before WBRT is delivered - Chemotherapy: Limited role Only at recurrence after surgical & radiotherapeutic options exhausted - Median survival is only 4-6months II. LEPTOMENINGEAL METASTASIS - Most common tumor that metastasize in the leptomeninges is metastatic lymphoma - 8% of pxs with cancer - Hematologic malignancies: acute lymphocytic leukemia, Non-Hodgkin’s lymphoma - Solid tumor: Breast Ca, Lung Ca, Melanoma, GI Cancer Clinical Findings - Multi-level signs & symptoms affecting 3 main areas: Cerebrum Cranial nerve Spinal roots & cord - CSF examination: (+) tumor cells (-) tumor marker (CA 15-3 for breast cancer) Diagnosis - MRI of the spine - (+) subarachnoid tumor 1. enhancing tumor in cortical sulci 2. subependymal enhancement 3. enhancing cranial nerves 4. tumor nodules in cauda equina Treatment - Therapy 1. Radiotherapy to symptomatic suites 2. Intrathecal chemotherapy - contraindicated in uncontrolled high ICP Prognosis - Median survival: 4% up to 6 months III. DURAL METASTASIS - From direct extension of a calvarial metastasis or from the overlying bone - 2 most common tumors that go to the bone is prostate CA for males & breast cancer for females - May present with painless, growing skull lesion with headache, seizure & hemiparesis - MRI may show a tumor similar to meningioma - Treatment: focal radiotherapy EMBRYONAL TUMORS Medulloblastomas Supratentorial Primitive Neuroectodermal Tumors Atypical Teratoid/Rhabdoid Tumors I. PRIMITIVE NEUROECTODERMAL TUMORSS (PNETS) - Arise fro primitive progenitor cells which are pluripotent, uncommitted neuroectodermal cells with capacity for differentiation along ependymal, neuronal, glial or even retinal cells - Therefore, a PNET can differentiate into anything! - Most common malignant pediatric tumor occurring predominantly in the posterior fossa (medulloblastoma) but also in the pineal (pinealoblastoma) or other CNS locations (cortical or spinal PNETS) - PNETS arising from distinct locations cannot be distinguished histologically - Histologic appearance is of small round cell tumor with glial or other types of differentiation in some cases. High cellularity, mitotic rate and tendency for leptomeningeal dissemination

- There mat be positive staining for both neurofilament protein & glial fibrillary acidic protein (GFAP) but also for synaptophysin which is more specific for PNET - Medulloblastomas (posterior fossa PNETS) have significantly better prognosis than other PNETS. II. MEDULLOBLASTOMAS (Posterior Fossa PNETS) - Specifically PNET of the cerebellum - Derived from fetal external granular cells of the cerebellum or rests in the posterior medullary velum - 30% of Infratentorial tumors in children but uncommon in adults - Typically involve the cerebellar vermis; grow to fill the 4th ventricle and may infiltrate the floor of the ventricle and adjacent structure (brainstem) - Vermis lesion → truncal ataxia - Filling the 4th ventricle → ↑ ICP - May arise laterally especially in older pxs - Median age: 5 years Clinical Features - Increased ICP - Unsteadiness (truncal) - Symptoms duration: less than 3 months - Recent onset of head tilt from ophthalmoparesis or incipient cerebellar herniation Diagnosis of Medulloblastomas - Cranial CAT scan Isodense or hyperdense Enhance homogenously With hydrocephalus May include small cysts, calcification & hemorrhage - MRI Tumor extent PNET can produce leptomeningeal dissemination, CSF seeding & drop metastasis Treatment - Surgery - Postoperative radiation therapy Prognosis - 5-year disease-free survival rate: 55% CRANIOPHARYNGOMAS - From rests of embryogenic tissue located in the Rathke’s pouch (anlage of the anterior pituitary gland) - Any age; even late adulthood - 6-10% of intracranial tumors in children - More common in children - Suprasellar calcification is present seen by plain x-rays - Small well-circumscribed solid nodules to huge multilocular cysts with turbid fluid that may contain cholesterol crystals - Histologically benign - In region of hypothalamus or 3rd ventricle → ↑ ICP - Many with papilledema due to location in hypothalamus near 4th ventricle (?) Clinical Manifestations - Short stature - Hypogonadism - Hypothyroidism - Diabetes insipidus - Visual loss - Increased ICP: because of its proximity to the hypothalamus & ventricles - CT: calcification; bony expansion of the sella, non-adherent - Plain skull x-ray: may see suprasellar calcification Treatment - Drain cyst, resect non-adherent tumor - Postoperation radiotherapy - Gross total resection

GERM CELL TUMORS (GCT) 1. Germinomas 2. Non-germinomas (very malignant) - Embryonal-cell carcinoma - Endodermal sinus tumor (yolk sac tumor) - Choriocarcinoma - Teratocarcinoma 3. Benign Gram Cell Tumors (intermediate malignancies) - Epidermoids - Dermoids - Teratomas By location: 1. Pineal GCT: almost exclusively in boys 2. Suprasellar GCT: boys = girls Note: - Suprasellar tumor → craniopharyngoma - Tumor in the hypothalamus, if you don’t have any suspicions, might be a glioma - The pineal gland, when it enlarges, it grows towards the iter causing obstructive hydrocephalus - The pinealoma can also compress the superior colliculus which will make an individual unable to look up. This is a part of the Parinaud’s syndrome A. Germinomas - Half of intracranial GCT - Histologically identical to testicular seminoma & ovarian dysgerminomas - Arise in the midline, pineal area, suprasellar - Highly malignant - Occasionally seed the CSF B. Nondysgerminoma GCT - Highly malignant - More aggressive than dysgerminoma - Metastasize to the CSF more frequently than germinoma - Endodermal sinus tumors Contain yolk sac element that produces alphafetoprotein (AFP) - Choriocarcinomas Contain cyst and syncytiotrophoblastic cells that produce β-hCG High levels of β-hCG and AFP in the CSF indicate the presence of malignant germ cell element C. Pineal Gland Tumors - 1% of all intracranial tumors in USA - 4-7% of all intracranial tumors in Asia where GCT are common - Here in the Phil., most common is germinoma Clinical Manifestations - Increased ICP - Direct compression of brain stem and cerebellum Parinaud’s Syndrome - paralysis of upgaze (common manifestation) - light near pupillary dissociation - nystagmus - ataxia & dysmetria - Endocrine Secondary effect of hydrocephalus or tumor spread to the hypothalamic region Precocious puberty Precocious pseudopuberty hypothalamic-gonadal axis not mature Diagnosis - MRI with gadolinium Definite histologic diagnosis for optimal patient - Radiotherapy Very radiosensitive All pxs with pineablastoma NGGCT & disseminated germinomas require neuraxis radiotherapy - Chemotherapy Most benefit with pinealoblastoma are NGGCT

Prognosis Germinomas: 80-90% 5-year survival rate following surgery and radiotherapy

DERMOID TUMORS - Cystic mass with yellow cystic fluid from sebaceous gland secretion TERATOMAS - Infants & young children - Mature teratomas are lobulated and cystic containing differentiated tissues such as bone, cartilage, teeth, air or intestine - Immature & malignant teratomas: less common - Tend to occur in the pineal region - Parinaud syndrome, hydrocephalus - 4% of childhood intracranial tumors - Rx: Surgical resection CHORDOMAS - Derived from remnants of the embryonic notochord: gives rise to nucleus polposus - Sacrococcygeal, clivus elsewhere along the spinal column - Less than 1% of CNS tumors - Remain asymptomatic until adult - Multiple cranial nerve palsies, erosion of skull base - Rx: Surgical resection, postoperative radiation therapy EPIDERMOIDS (Cholesteatomas) - Most common embryonal CNS tumor - 2% of all intracranial tumors - Arise within skull tables or adjacent to the dura - Suprasellar region, cerebellopontine angle, skull base, brainstem - Encapsulated, pearly appearance may contain cyst fluid with cholesterol crystals - MRI: Low T1, high T2 signal - Treatment: surgical resection CHOROID PLEXUS TUMORS - Lateral ventricle - Most diagnosed before 2 years - Hydrocephalus - Excess CSF production (which is the cause of hydrocephalus) COLLOID CYSTS OF THE 3RD VENTRICLE - Arise from the anlage of the paraphysis - Grow in the anterior superior portion of 3rd ventricle - Small white cysts filled with homogenous gelatinous material - Become symptomatic during adulthood - Intermittent hydrocephalus - Rx: surgical excision Indirect Neurologic Complications of Cancer (Nonmetastatic or Paraneoplastic) - Vascular disorders - Infections - Metabolic & nutritional disorders - Side effects of therapy: - Chemotherapy - Radiation Therapy - Surgery & other diagnostic or therapeutic procedures - “Remote” or paraneoplastic syndromes - May have an autoimmune pathogenesis

Paraneoplastic Neurologic Syndromes - Subacute cerebellar degeneration - Anti-Yo (anti-Purkinje cell) auto-Ab - Tumors of ovary, fallopian tube, lung - Opsoclonus/myoclonus - Anti-Ri - Tumors of breast, fallopian tube, small cell lung - Limbic encephalitis - Subacute motor neuropathy - Anti-Hu - Tumors of small cell lung, Hodgkin, other lymphomas - Lambert-Eaton myasthenic syndrome - Anti-voltage (VGCG) Ca channel - Tumors of small cell lung, Hodgkin, other lymphomas - Encephalomyelitis - Cerebellar degeneration - Encephalomyelitis - Anti-Hu, Anti-Ma - Tumors of small cell lung, neuroblastoma, prostate, breast, Hodgkin, testicular - Stiffman syndrome - Antiamphiphysin - Breast 4 most common primary brain tumor in adults (In decreasing frequency) 1. Glioma (astrocytoma) 2. Meningioma 3. Pituitary adenoma 4. Vestibular schwannoma 4 most common infratentorial brain tumors in children 1. Cerebellar hemisphere astrocytoma – 30-40% 2. Vermis medulloblastoma – 30-40% 3. Brainstem gliomas – 10-20%; pontine astrocytoma 4. Ependymoma (4th ventricle) – 10-20% Supratentorial brain tumors in children 1. Suprasellar region – 20-30% - Craniopharyngoma - Chiasmatic & hypothalamic glioma - Germinoma 2. Pineal/parapineal region – 10% - Germinoma 2 most common sites of germinoma - Pineal gland - Suprasellar

This transcription is a combination of Dr. Conde’s & Dr. Poblete’s lecture. Transcribed by: Denise Zaballero ☺ Slides from: Fred Monteverde JB Villegas Jun Minagawa Additional notes from: Cecile Ong Emy Onishi Mitzel Mata Patriccia Mendiola Recorded lecture from: Lala Nieto We all have a sickness that cleverly attaches and multiplies --Dig, Incubus