Glial and Glioneuronal Tumors

Glial and Glioneuronal Tumors
Neuropathology 4/18/2016 Megan Mantica, PGY3

Diffuse Fibrillary Astrocytoma Pilocytic Astrocytoma Subependymal Giant Cell Astrocytoma Pleomorphic Xanthoastrocytoma Oligodendroglioma Ependymoma Subependymoma Ganglioglioma

Diffuse Fibrillary Astrocytoma
Diffuse infiltrative glioma displaying predominantly astrocytic features Clinical Features: Grade II-IV; 40% primary intracranial tumors Incidence 4/100,000, median age astrocytoma, anaplastic astrocytoma, GBM Symptoms: new onset seizure, deficits based on location, ICP (HA, N/V, papilledema) Imaging: Grade II astrocytomas commonly non-enhancing, ill-defined, predominantly subcortical hemispheric masses Anaplastic astrocytomas may show punctate or irregular foci contrast enhancement GBM typically ring-enhancing, central low density necrosis, crosses corpus callosum (“butterfly lesions”) Prognosis/Treatment: Survival inversely proportional to patient age; Grade II 5-10Y survival, Grade II 2-3Y, Grade IV 1 Y Astrocytomas worse prognosis than oligoastro and oligos Treatment: gross total resection, RT + TMZ (for grade III, IV)

A. Diffuse Astrocytoma, grade II, T2 ill-defined margins
B. GBM, T1 ring enhancing lesion, crosses corpus callosum C. Radiation necrosis

Gross Findings: Ill-defined borders, foci of tumor grossly invisible Most common in WM or deep gray matter (thalamus, BG); blurring of corticomedullary and gray-white junction Mass effect w/ MLS, blunting sulci, compression of ventricles Variegated appearance w/ foci of necrosis and hemorrhage s/o GBM

Microscopic Features Immunohistochemical Hypercellular, infiltrative Hyperchromic oval-spindled nuclei w/ irreg countours Nuclear atypia Mitotic features, increased proliferation in high grade tumors Endothelial hyperplasia/necrosis in GBM GFAP: usually positive S-100 protein: positive; less specific, more sensitive than GFAP for glial Cytokeratin, EMA, HMB-45, melan A, LCA: negative Neurofilament highlights entrapped axons, c/w an infiltrative pattern p53 protein: positive in > 50% MIB-1 (Ki-67) labeling index roughly proportional to grade

Genetics DDx Mutations p53 in 40-50% in astrocytomas, anaplastic astrocytomas and secondary GBM EGFR amplification in 30-40% primary GBM 10q deletion/LOH in majority of GBM Loss of p16 in anaplastic astros and GBM Oligo/oligoastrocytoma Metastatic carcinoma or melanoma CNS lymphoma Radiation necrosis Reactive gliosis

Coagulative necrosis w/ dystrophic calcification
B-D. Vascular changes with fibrinoid necrosis (B), hyalinization (C), and telengiectasia (D)

enlarged, irreg contoured nuclei
Perineuronal satelitosis and perivascular aggregation of tumor cells C. Geminocytic component in Grade II D. Moderate cellularity, mitotic activity E. Ki-67 immunostain

G. GFAP staining H. Synaptophysin immunoreactivity I. Endothelial hyperplasia in GBM J. Pseudopalisading necrosis in GBM

GBM Permanent H&E GFAP Ki67 P53 Intraop

Pilocytic Astrocytoma
Benign astrocytic neoplasm w/ hair-like processes and circumscribed growth pattern Clinical Features: 2% primary intracranial neoplasms Incidence 0.3/100,000 Located in cerebellum, optic pathway, hypothalamus/3rd ventricle, tectum, spinal cord Predominantly in children, median age 13Y Associated with NF1 (optic pathway, brainstem) Imaging: Cyst w/ enhancing mural nodule Well demarcated Diffuse or fusiform enlargement of optic nerve/chiasm Prognosis/Treatment: 80% 20 year survival Most surgically curable RT for subtotal resected or recurrent tumors

Gross Findings Microscopic Findings Cystic, well demarcated Spongy appearance d/t microcysts or hypervascularity Pilomyxoid astrocytomas are solid/gelatinous and may infiltrate parenchyma Dense and loose appearance, sharply cicrumscribed Piloid astrocytic cells, long thin hair-like processes Round-oval nuclei Rosenthal fibers, PAS+ eosinophilic granular bodies characteristic Mitotic figures uncommon Infarct-like necrosis in 5-10% GFAP: positive S-100: positive

Genetics DDx Reduced expression of neurofibromin (protein product of NF1 gene) assoc w/ NF1, not sporadic tumors Gain of Chr 6 and 10 Frequent BRAF gene fusions Diffuse astrocytoma Oligo/oligoastro Pleomorphic xanthoastrocytoma Ganglioglioma Monomorphous pilomyxoid astrocytoma DNET Reactive pilocytic gliosis

Spindled astrocytes w/ long-thin processes; loose microcystic foci
Dense foci w/ rosenthal fibers Eosinophilic granular bodies Pilomyxoid astrocytoma Perivascular arrangement of tumor cells

JPA Permanent H&E GFAP Ki67 P53 Intraop

Subependymal Giant Cell Astrocytoma
Benign or hamartomatous astrocytic and partially neuronal intraventricular tumor Clinical Features: < 1% primary intracranial tumors Lateral or 3rd ventricles near foramen of Monro Symptoms – obstructive hydrocephalus, ICP Almost exclusively seen in Tuberous Sclerosis Imaging: Enhancing intraventricular mass, well demarcated Often calcified May be seen with other s/s of TS (tubers, candle gutterings, gray matter heterotopia) Prognosis/Treatment: Most surgically curable, excellent prognosis

CTH w/ contrast: enhancing intraventricular mass near foramen of Monro w/ obstructive hydrocephalus; calcified tuber L frontal

Gross Findings Microscopic Features Solid, well demarcated, often calcified Candle gutterings (resemble wax drippings) throughout ventricular surface Epithelioid, gemistocyte-like, spindled cells arranged in sweeping fascicles Dysmorphic cells with neuron-like nuclei and astrocyte-like cytoplasm Perivascular pseudorosettes Mitotic figures/necrosis uncommon GFAP: positive in subset of cells S-100: positive Synaptophysin, neurofilament, NeuN, chromogranin: positive in subset of cells

Genetics DDx No significant alterations known Gemistocytic astrocytoma Ependymoma Intraventricular meningioma Central neurocytoma Subependymoma

Perivascular pseudorossettes
Neuronal-like nuclei and astrocyte-like cytoplasm

SEGA Permanent H&E GFAP Ki67 Intraop

Pleomorphic Xanthoastrocytoma
Variant of astrocytoma w/ reticulin deposition and increased pleomorphism Clinical Features: < 1% primary intracranial tumors Temporal lobes Children, young adults Chronic seizure disorder Imaging: Cyst with enhancing mural nodule, but may be solid Superficial cortex, may attach to overlying dura Well demarcated, often calcified Prognosis/Treatment: Grade II good prognosis; 15-20% malignant transformation to Grade III and may die of disease Many surgically curable; adjuvant therapy for subtotal resection, recurrent, or anaplastic tumors

Well demarcated, partially cystic, enhancing, mass lesion

Gross Findings Microscopic Features Solid and rubbery; may have a cystic component Demarcated , often calcified Pleomorphic with mixed glial and mesenchymal-like features Spindled and atypical gemistocyte-like or epithelioid cells PAS-+ eosinophilic granular bodies Increased intercellular reticulin deposition Rosenthal fibers (periphery of the tumor ) Xanthomatous (clear and foamy) astrocytes in ¼ tumors Mitotic figures and necrosis are uncommon GFAP + in subset cells S-100 positive Ki-67 index usually low

Genetics DDx No significant alterations known GBM/gliosarcoma Malignant fibrous histiocytoma/pleomorphic sarcoma Ganglioglioma Pilocytic astrocytoma w/ increased atypia Meningioma

A. Spindled cells and lipidized astrocytes
B. Pleomorphism w/ multinucleated giant cells C. PAS+eosinophilic granular bodies D. Dense intercellular reticulin network

Oligodendroglioma Diffusely infiltrative glioma w/ predmoninantly oligodendroglioma features Clinical Features: 10-25% diffuse gliomas, 0.6/100,000, M:F 3:2 Cerebral hemisphers, frontal lobe predominance Median age 40-45Y Focal neuro deficits, ICP, seizures Imaging: Non-enhancing masses (grade II), anaplastic oligos (grade III) typically enhancing Intratumoral calcifications common Prognosis/Treatment: Grade II 10-15Y survival, grade III 3-5Y Oligo better prognosis than astrocytomas Gross total resection; RT for subtotal resection, anaplasia, older age Chemo

Oligodendroglioma Gross Findings Microscopic Features
Ill-defined borders Tumor center in cortex or corticomedullary junction; blurring of G-W junctions MLS, blunting sulci, compression of venticles Foci of necrosis/hemorrhage suggest anaplasia Hypercellular, uniformly round nuclei Clear perinuclear halos “fried egg” appearance Microcalcifications common Branching capillary network resembling “chicken-wire” GFAP: negative S-100: positive Cytokeratins, EMA, HMB-45: negative P53 protein negative

Oligodendroglioma Genetics DDx
Co-deletion 1p/19q in 50-80% associated with increased survival and treatment responsiveness Loss of p16 in anaplastic/recurrent oligo Astrocytoma/oligoastro Small cell glioblastoma DNET Pilocytic astrocytoma Clear cell ependymoma Cntral neurocytoma Extraventricular neurocytoma Metastatic clear cell carcinoma CNS lymphoma Clear cell meningioma

Chicken-wire capillary network, uniformly round nuclei, clear perinuclear halos “fried egg” appearance Perineuronal satellitosis D. Gliofibrillary oligos characterized by perinuclear rims of GFAP positive

Grade III – increased mitotic activity
Endothelial hyperplasia

Ependymoma Well circumscribed malignant glioma with ependymal features
Clinical Features: 3-9% primary brain tumors overall; 6-12% in children, 30% in infants Most common glioma of spinal cord (50-60% all cases) 0.3/100,000 Posterior fossa (children), spinal cord (adults) Peak age 0-16 and 30-40Y Imaging: Enhancing, solid, well-demarcated mass Spinal tumors intra-axial sausage shape expansion of cord; associated with adjacent syrinx May have calcifications/hemorrhage Prognosis/Treatment: Better prognosis: older age, spinal cord rather than intracranial, extent of resection Surgical resection followed by RT

Ependymoma Gross Findings Microscopic Features
Well circumscribed, soft, tan-red mass Hemorrhage/necrosis may be present Associated syrinx Sharp demarcation Perivascular pseduorosette Ependymal rosettes in 5-10% Round-oval nuclei, clear vacuoles in signet ring cells represent enlarged intracellular lumina EM: long zipper-like desmosomes/intercellular junctions GFAP: positive S-100: positive

Ependymoma Genetics DDx Aneuploidy seen in Grade I and II
NF2 with increased susceptibility for spinal ependymomas 22q loss, 1q gain common Diffuse astrocytoma Astroblastoma Oligo PNET Choroid plexus papilloma Pilocytic astrocytoma

Sharp tumor-brain interface
Perivascular pseudorossettes Ependymal rosettes Hypercellularity, high mitotic infex in anaplastic ependymomas

Papillary Clear cell Tanycytic Myxopapillary involving filum terminale

E. Myxopapillary ependymoma of filum terminale

Subependymoma Benign intraventricular glioma w/ clusters of ependymal-like nuclei embedded in dense fibrillary matrix Clinical Features: <1% primary brain tumors 4th ventricle > lateral ventricles; rare spinal cord Onset middle age-elderly Asymptomatic, incidental detection, may have obstructive hydrocephhalus Imaging: Non-enhancing nodular intraventricular mass Foci of calcification, hemorrhage or both Spinal tumors intraaxial sausage shaped expansion of cord; associated syrinx Prognosis/Treatment: Excellent prognosis, benign Mixed ependymoma-subependymomas have malignant potnetial and should be treated as ependymomas

Subependymoma Gross Findings Microscopic Features
Firm, well-circumscribed, nodular/lobulated tan-red mass Hemorrhage/calcifications Associated syrinx Sharp demarcation Microcytic spaces, hyalinized vessels Round-oval nuclei in cellular clusters, dense fibrillary matrix Normal ependymal lining overlying tumor GFAP: positive S-100: positive Ki-76 low

Subependymoma Genetics DDx No consistent alterations Ependymoma
Diffuse astrocytoma

Subependymoma with nodularity
Clusters of nuclei embedded in dense fibrillary matrix

Ganglioglioma Mature glioneuronal neoplasm w/ dysmorphic ganglion cells in combination w/ glial element Clinical Features: <2% primary brain tumors; 0.2/100,000 Superficial temporal lobes Dysplastic cerebellar gangliocytoma associated w/ Cowden’s syndrome (hamartomas, risk of breast/thyroid/endometrial cancers) Children, young adults Seizures Imaging: Cystic mass w/ enhancing mural nodule common Calcifications Minimal mass effect/edema Prognosis/Treatment: Benign Surgical resection +/- RT for anaplastic cases

Well demarcted, cystic, enhancing temporal lobe mass

Ganglioglioma Gross Findings Microscopic Features
Well-circumscribed, firm intracrotical mass Cystic component Heavy calcification in some Dysmorphic, haphazardly arranged ganglion cells Binucleate neurons in some Eosinophilic granular bodies Rosenthal fibers Increased reticulin and collagen Synaptophysin, chromagranina, neurofilament: positive GFAP: positive in astrocyte elements S-100: positive Ki-67 low

Ganglioglioma Genetics DDx No consistent alterations
Pilocytic astrocytoma Pleomorphic xanthoastrocytoma Diffuse astrocytoma DNET

Clustered ganglion cells
Perivascular lymphocytic cuffing, eosinophilic granular bodies, dysmorphic neurons, binucleate

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