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LECTURE 7-8 BRAIN TUMORS Functional Cells of CNS 1. Astrocytes a. Gliosis proliferation of astrocytes in damaged areas of the central nervous system i. Most important histopathological indicator of CNS injury! ii. See hypertrophy and hyperplasia 2. Microglia a. Macrophage system of CNS b. Share many surface markers with peripheral monocytes/macrophages (such as CD68) c. With injury form microglial nodules aggregates about small foci of tissue necrosis 3. Ependyma 4. Oligodendrocytes a. Have a dark round nuclei and a perinuclear “halo” 5. Meninges a. Focal nests of arachnoid cells (meningothelial cells) b. often form whorls with central psammoma bodies ***Note: Brain tumors (primary!) do not generally metastasize other cancers though metastasize to the brain though Tumors • 75% of childhood CNS tumors arise within the posterior fossa • 75% of adult CNS tumors arise within the cerebral hemispheres above the tentorium Major Classes of Primary Brain Tumor Gliomas Different Types **Most common group of primary brain tumors • Astrocytomas • Infiltrating • Non-infiltrating • Oligodendrogliomas • Ependymomas Neuronal Tumor Most common tumor containing mature-appearing neurons ganglioglioma - Dysembryoplastic neuroepithelial tumor Central neurocytoma Most of these tumors are slow growing but glial component occasionally become anaplastic Often present as seizure disorder Surgical resection is often effective in controlling seizures Astrocytomas Infiltrating Astrocytomas Non-Infiltrating Astrocytomas Usually in the CEREBRAL HEMISPHERE Usually in the CEREBELLUM 1. Diffuse astrocytoma (grade II/IV) 2. Anaplastic astrocytoma (grade III/IV) 3. Glioblastoma (grade IV/IV) • MOST MALIGNANT • MOST COMMON primary brain tumor MOST COMMON ASTROCYTOMA! • A condition: Gliomatosis cerebri • Multiple regions of the brain (sometimes the entire brain) are infiltrated by neoplastic astrocytes • AGGRESSIVE! • grade III/IV lesion-independent of the appearance of the individual tumor cells • Pilocytic astrocytoma (grade I/IV) Relatively Benign with piloid (hair-like) processes and are characterized by a relatively circumscribed growth pattern Grow very slow!! Treated with resection! Molecular Genetics: Molecular Genetics: Low Grade - mutations affecting p53 - overexpression of platelet-derived growth factor α (PDGF-A) and its receptor High Grade - disruption in RB and p16/CDKNaA Glioblastomas occur in two settings: - Primary glioblastoma (new onset disease) - Secondary glioblastoma (previous low grade) o BOTH stimulate RAS and PI-3 Kinase pathways stimulate growth and survival of tumor cells! - NF1 show functional loss of neurofibromin P53 mutation is rare Clinical Features - Depend on location and growth rate - Mass effect - High grade abnormal vessels that are “leaky” and will show contrast enhancement - Glioblastoma pts poor prognosis Diffuse Astrocytoma Microscopic Examination - Network of fine, GFAP positive astrocytic processes that give the background a fibrillary appearance - Anaplastic Astrocytoma Microscopic Examination - Glioblastoma cellular lesion with a sworling fibrillary appearance to many of the cells Transition between neoplastic and normal tissue is indistinct More densely cellular Gemistocytic Astrocytoma o neoplastic astrocyte shows a brightly eosinophilic cell body from which emanate abundant processes Microscopic Examination (similar to above but additional features) - - necrosis and vascular or endothelial cell proliferation Necrosis in glioblastoma often occurs in a serpentine pattern in areas of hypercellularity (pseudopalisading) Vascular cell proliferation is characterized by tufts of piled-up cells that bulge into the lumen Pilocytic Astrocytoma (non-infiltrating) Macroscopic well circumscribed Microscopic Examination - thin "hairlike" processes that are GFAP-positive and form dense fibrillary meshworks Rosenthal fibers often biphasic narrow infiltrative border with the surrounding brain Oligodendroglioma About 1. 2. 3. 4. Patients usually have several years of neurological complaints Lesions found mostly in CEREBRAL HEMISPHERES Slow growing – well circumscribed – LOW grade malignant tumors BEST over all prognosis!! Gross Examination 1. Well-circumscribed, gelatinous, gray masses, often with cysts, focal hemorrhage, and calcification Microscopic Examination 1. 2. 3. 4. Surrounded by a clear halo of cytoplasm Delicate network of anastomosing capillaries Calcification Perineuronal satellitosis secondary structures often seen with tumor cells 5. WHO grade II/IV lesions Molecular Genetics 1. loss of heterozygosity for chromosomes 1p and 19q 2. Consideration in treatment a. Tumors with loss of 1p and 19q, but without other alterations have consistent, long-lasting responses to chemotherapy and radiation b. Those without loss of 1p and 19q seem to be resistant to therapy Anaplastic Oligodendroglioma 1. WHO grade III/IV 2. Microscopic Examination: increased cell density, nuclear anaplasia, and increased mitotic activity Ependymoma and Paraventricular Mass Lesions – In the first two decades of life they typically occur near the fourth ventricle – Frequent in the setting of neurofibromatosis type 2 Ependymoma Gross Morphology: - Solid or papillary mass extending from the floor of the ventricle Usually makes complete excision impossible Microscopic Examination - rosettes, canals) that resemble the embryologic ependymal canal - perivascular pseudorosettes - GFAP expression Molecular Genetics - NF2 gene of chromosome 22 Clinical Features – Posterior Fossa - Hydrocephalus - CSF dissemination is a common occurrence and portends a poor prognosis - Posterior fossa lesions have the worst overall outcome - clinical outcome for completely resected supratentorial and spinal ependymomas is better Periventricular Lesions General Information: - are usually benign to low-grade lesions - location may cause clinical problems Subependymomas - Choroid Plexus Papillomas - Slow growing nodules attached to ventricular lining protruding into the ventricle Incidental Finding Cause hydrocephalus Most often in LATERAL and FOURTH ventricle Mixture of astrocytic, and ependymal cell clusters surrounded by their fibers - Most common in children o Seen in LATERAL ventricles In adults o Seen in FOURTH ventricles Papillary growths almost exactly recapitulate the structure of the normal choroid plexus Cause hydrocephalus - Most common in TEMPORAL LOBE - Neuronal Tumors Ganglioglioma - Glial component of these lesions usually resembles a low-grade astrocytoma low-grade neuronal neoplasm most commonly the lateral or third ventricles uniform nuclei and often islands of neuropil Cells resemble oligodendroglioma, but ultrastructural and immunohistochemical studies reveal the neuronal lineage of the tumor cells Central neurocytoma Poorly Differentiated Neoplasms - express few phenotypic markers of mature cells of the nervous system and are described as poorly differentiated, or embryonal Medulloblastoma Predominantly in CHILDREN! MOST COMMON Exclusively in the CEREBELLUM!! Neuronal and glial markers may be expressed, but the tumor is often largely undifferentiated Causes Hydrocephalus Usually well circumscribed Metastases to the cauda equina are sometimes termed drop metastases Molecular Genetics: - loss of material from 17p with an abnormal chromosome isochromosome 17q or i(17q) - Signals poor prognosis Clinical Features - HIGHLY malignant - Very radiosensitive! CNS supratentorial primitive neuroectodermal tumors (CNS PNET) Atypical Teratoid/Rhabdoid Tumor • Tumors of similar histology and poor differentiation, resembling medulloblastomas, found in the cerebral hemispheres • Can lead to confusion with the peripheral neuroectodermal tumor, that shares a genetic alteration with Ewing sarcoma Highly malignant tumor of young CHILDREN Occurs equally in the posterior fossa and supratentorial compartments Presence of rhabdoid cells Molecular Genetics: - genetic alterations in chromosome 22 - hSNF5/INI1 gene o Deletions of the locus and loss of nuclear staining for INI1 protein are seen in the majority of tumors Clinical Features - highly aggressive tumors of the very young, usually before the age of 5 - Most patients live less than a year after diagnosis Other Parenchymal Tumors Primary CNS Lymphoma Most common CNS neoplasm seen in immunocompromised patients Usually of B-cell origin Cells involved are usually infected with EBV Often mutifocal Aggressive and poor response to Morphology: - Often involve deep gray matter as well as white matter and cortex - Periventricular spread is common - often show extensive areas of central necrosis - accumulate around blood vessels - B-cell markers, markers of Epstein-Barr viral infection can be used as an aid in diagnosis chemotherapy Germ Cell Tumors • • • • occur along the midline 0.2% to 1% of brain tumors in people of European descent but up to 10% in Japanese people tumors of the young, with 90% occurring during the first two decades tumors in the pineal region show a strong male predominance - - tumors share many features with their counterparts in the gonads metastasis of a gonadal germ cell tumor to the CNS is not uncommon – presence of a non-CNS primary tumor must be excluded before a diagnosis of primary germ cell tumor is made CSF levels of tumor markers including αfetoprotein and β-human chorionic gonadotropin can be used to aid Meningioma General Informaiton 1. benign tumors of adults 2. attached to the dura, that arise from the meningothelial cell of the arachnoid 3. Prior radiation therapy Morphology 1. Usually rounded masses with well-defined dural bases compress underlying brain, but are easily separated 2. encapsulated with thin, fibrous tissue and may have polypoid appearance 3. psammoma bodies that Histology 1. Syncytial ("meningothelial"), appropriately named the whorled clusters of cells that sit in tight groups without visible cell membranes for 2. 3. 4. 5. 6. 7. 8. Fibroblastic, Transitional, Psammomatous, Secretory Microcystic Most meningiomas are easily separable from the brain commonly immunoreactive for epithelial membrane antigen Molecular Genetics 1. loss of chromosome 22, especially the long arm (22q) 2. deletions include the region of 22q12 that harbors the NF2 gene, which encodes the protein merlin Clinical Features 1. 2. 3. 4. 5. 6. 7. 8. Slow-growing compression of underlying brain Common sites of involvement include the parasagittal aspect of the brain conv uncommon in children moderate female predominance usually solitary diagnosis of NF2 should be considered Meningiomas often express progesterone receptors Atypical Meningiomas 1. Higher rate of recurrence and more aggressive local growth a. mitotic index of four or more mitoses per 10 high power fields or at least three atypical features Anaplastic Meningioma 1. Highly aggressive tumor, retaining some histologic evidence of meningothelial origin 2. Mitotic rates are often extremely high Metastatic Tumors 1. Mostly carcinomas 2. Morphology 1. Intraparenchymal metastases form sharply demarcated masses, often at the junction of gray matter and white matter, usually surrounded by a zone of edema Paraneoplastic Syndromes 1. Major underlying mechanism 2. 3. 4. 5. a. development of an immune response against tumor antigens that cross-react with antigens in the central or peripheral nervous systems Subacute cerebellar degeneration a. Destruction of Purkinje cells Limbic encephalitis a. Subacute dementia b. most evident in the anterior and medial portions of the temporal lobe Eye movement disorders a. Most commonly opsoclonus (uncontrolled eye movement), b. often in association with other evidence of cerebellar and brainstem dysfunction The peripheral nervous system can also be affected a. Subacute sensory neuropathy i. Loss of sensory neurons from dorsal root gangli b. Lambert-Eaton myasthenic syndrome