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7. 8. Brain Tumors Neurons are the principal functional unit of brain tumors There are multiple different types with different properties, sizes, and structures. Astrocytes branching multipolar cytoplasmic processes containing glial fibrillary acidic protein (GFAP); Gliosis is the most imp histopathologic indicator of CNS injury, and is characterized by both hypertrophy and hyperplasia Microglia macrophage system of the CNS with monocytes/macrophages (e.g. CD68) surface markers. Following an injury microglia cells aggregates about small foci of tissue necrosis (microglial nodules) Ependyma Ciliated columnar epithelial cells lining the ventricles; do not have specific patterns of rxn Oligodendrocytes dark round nuclei and a perinuclear “halo” (whereas astrocytes are larger, less dense, oval) Meninges form focal nests of arachnoid cells (meningothelial cells) over arachnoid villa and in adults they form whorls w/central psammoma bodies CNS TUMORS: Dx of these tumors depend upon locations. Typically does’t metastasize (dependent on unique features of each tumor): Glioma – most common & rarely metastasizes outside CNS (Grades I-IV according to biologic behavior - based on WHO grading scheme) o Astrocytoma o Oligodendroglioma o Ependymomas Glial tumors w/benign histo features – may infiltrate large brain areas poor prognosis (not feasible to resect these tumors w/o compromising neuro functions) Prognosis of tumors in CNS depends on location Through the CSF, the subarachnoid space provides a pathway for spread Meningioma Infiltrating Astrocytoma, Oligodendroglioma Pilocytic Astrocytoma, Medulloblastoma Ependymomas and periventricular lesions Ganglioglioma Glioma Astrocytomas Diffuse Astrocytoma (Fibrillary Astrocytoma) Etiology/Characteristics Grade II - Infiltrative Anaplastic Astrocytoma Grade III - Infiltrative Glioblastoma (Glioblastoma multiform) - Infiltrative * Most malignant form of astrocytoma and the most common primary brain tumor Pilocytic Astrocytoma - Non-infiltrating * Most common astrocytoma Grade IV Lower grade: p53 and α(PDGF-A) w/receptor Higher grade: RB and p16/CDKNaA Older pts will typically have primary form Younger pts will typically have secondary form - Both leads to ↑tyrosine kinase receptor activity and the activation of the RAS and PI-3 kinase pathways Grade I/IV Typically in children and young adults * Occurrence in presence of NF1 shows functional loss of neurofibromin Histo - Network of fine GFAP + astrocytic processes that give a fibrillary appearance - Cellular lesion w/sworling fibrillary appearance - Hard to differentiate btwn normal and neoplastic cells - Densely cellular - Gemistocytic astrocytoma used if bright eosinophilic cell body seen - Similar to anaplastic astrocytoma - Necrosis (in hypercellular areas - serpentine pattern) - Endothelial/vascular cell proliferation (tufts of piled up cells) - Thin "hairlike" GFAP + processes that form dense fibrillary meshworks - Rosenthal fibers - Often biphasic Gross Poorly defined, gray, infiltrative tumor (goes past the midline) Clinical Info & Dx & Tx Usually @ cerebral hemispheres Sxms - Seizures, HA, and focal neurologic deficits relative to the anatomic site Varies * Gliomatosis cerebri: Affects multiple regions… sometimes the entire brain; Grade III Piloid (hair-like) processes and are characterized by a relatively circumscribed growth pattern Dx - High-grade astrocytomas have abnormal vessels that are "leaky" and therefore demonstrate contrast enhancement on imaging studies Tx - Poor prognosis Benign (relative to others) & slow growth Tx – resection Dx – histo rarity of p53 mutation or other genetic Δ compared to others Other Gliomas Oligodendroglioma Etiology/Characteristics Grade II @ cerebral hemispheres Slow growing, low grade malignant tumor Genetic - Loss of heterozygosity for chromosomes 1p and 19q Histo - Surrounded by a clear halo of cytoplasm - Anastomosing capillaries - Calcification - Perineural satellitosis - Anaplastic Oligodendroglioma Grade III ↑ cell density, nuclear anaplasia, and ↑ mitotic activity Ependymoma Grade II Typically @ 4th ventricle Spinal ones are associated w/ NF2 - Resembles embryologic ependymal canal - Perivascular pseudorosettes - GFAP + in most Solid or papillary mass; Well demarcated from adjacent brain Mixture of astrocytic, and ependymal cell clusters surrounded by their fibers Nodules protruding into the lateral/4th ventricle Sxms – normally asymptomatic; may cause hydrocephalus Papillary growths recapitulate the structure of the normal choroid plexus Clinically presents with hydrocephalus - Paraventricular Lesions Subependymoma Benign to low grade lesions Slow growing - Choroid plexus papilloma - Most commonly in children – lateral ventricles - Adults – 4th ventricle Gross Well-circumscribed, gelatinous, gray masses, often with cysts, focal hemorrhage, and calcification Clinical Info & Dx & Tx Sxms – Multiple years of neuro complaints Best prognosis among gliomas Tx – In tumors w/loss of 1p & 19q genes longlasting response to chemo In tumors w/o loss of these genes resistant Sxms – CSF dissemination, 2ndary hydrocephalus Tx – Complete excision (good prognosis); if CSF dissemination-poor prognosis and if posterior fossa lesion-worst outcome) Neuronal Tumors Gangliocytomas – entirely neuronal tumors Tumors Ganglioglioma Etiology/Characteristics Contains mature-appearing neurons (ganglions) – usually admixed glial neoplasm Mostly slow growing, but the glial comp becomes anaplastic Histo - Bi-nucleate forms are frequent; - Glial component resembles astrocytoma Gross Commonly @ temporal lobe Clinical Info & Dx & Tx Lesions containing mixtures of neuronal and glial elements present as a seizure disorder Tx – surgical resection Central neurocytoma @ lateral or 4th ventricle Low grade neuronal neoplasm - uniform nuclei and often islands of neurophil - Resembles oligodendroglioma Medulloblastoma Commonly in children (near vermis, whereas in adults more lateral) Genes – loss of material from 17p poor prognosis - May express neuronal and glial markers CNS supratentorial primitive neuroectodermal tumors (CNS PNET) Can lead to confusion with the peripheral neuroectodermal tumor, that shares a genetic alteration with Ewing sarcoma Similar histology and poor differentiation, resembling medulloblastomas, found in the cerebral hemispheres Atypical Teratoid/Rhabdoid Tumor Genes – alterations in chromosome 22 (>90%) or hSNF5/INI1 gene Presence of rhabdoid cells (resembles rhabdomyosarcoma) * Drop metastases = metastasis to cauda equina Dx - ultrastructural and immunohistochemical studies reveal the neuronal lineage Poorly differentiated or embryonal Exclusively in cerebellum @ posterior fossa and supratentorial compartments May lead to hydrocephalus Highly malignant, but radiosensitive Highly malignant tumor of young CHILDREN, usually before the age of 5 Prognosis – most live less than a yr Brain Parenchymal tumors: Tumors Primary CNS Lymphoma (2ndary CNS lymphoma is very rare – occasionally by CSF/nerve roots) Germ Cell Tumors Meningioma Atypical Meningioma Anaplastic Meningioma Etiology/Characteristics Arises from B-cells, often multifocal (rarely involves structures outside CNS) Periventricular spread is common 0.2% to 1% of brain tumors in Europeans but 10% in Japanese. 90% affected by 20yo. If tumor @ pineal region – male predominance May metastasize from gonadal germ cell tumor Grade I Predominantly benign tumors of adults Arises from the meningothelial cell of the arachnoid Risk factor: - Prior radiation therapy - Loss of chromosome 22 (esp. 22q) NF2 gene merlin protein loss Grade II Higher rate of recurrence Grade III Histo Malignant cells accumulate around blood vessels Patterns observed: Numerous calcified psammoma bodies Syncytial – whorled cluster of cell Fibroblastic – collagen deposits Transitional – btwn above 2 Secretory Microcystic Gross Often involves deep gray matter as well as white matter and cortex Well defined, but not as discrete as metastases and often show extensive areas of central necrosis Clinical Info & Dx & Tx Common in immunosuppressed pt (Epstein-Barr virus) - Poor response to chemo Occurs along the midline Dx – 1st-exclude non-CNS primary tumor 2nd-α-fetoprotein and βhuman chorionic gonadotropin markers Attached to the dura; Rounded mass, well-defined dural base - compressing underlying brain; Surface of mass – encapsulated by thin, fibrous tissue w/polypoid appearance Sxms – Slow growing, normally parasagittal aspect of the brain convexity; usually solitary; Dx - B-cell markers or Epstein-Barr markers Tx – Surgery - easily separable from the brain Dx – Immunoreactive for epithelial membrane Ag Mitotic index of four or more mitoses per 10 high power fields or at least three atypical features More aggressive local growth Histo evidence of meningothelial origin Mitotic rates - extremely high Highly aggressive Metastatic Tumors: Mostly carcinomas Morphology: 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 Immune response against tumor Ag that cross-react with Ag in the CNS or PNS In CNS a. Subacute cerebellar degeneration Destruction of Purkinje cells b. Limbic encephalitis Subacute dementia, commonly @ temporal lobe c. Eye movement disorders opsoclonus, may be associate w/evidence of cerebellar and brainstem dysfunction In PNS: a. Subacute sensory neuropathy Loss of sensory neurons from dorsal root gangli b. Lambert-Eaton myasthenic syndrome