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Glioneuronal Neoplasms Review



Abbreviations used:

Angiocentric Glioma (AG), Astroblastoma (Astrobla), Anaplastic Astrocytoma (AA), Chrodoid Glioma Third Ventricle (CGTV), Dysplastic Cerebellar Gangliocytoma or Lhemitte-Duclos (DCG), Desmoplastic Infantile Ganglioglioma (DIG), Diffuse Infiltrating Astrocytoma (DIA), Dysembryoplastic Neuroepithelial tumor (DNT), Ependymoma (Ependymo), Ganglioglioma (GG), Glioneuronal Tumor with  Rosetted Islands (GTR), Ganglioneuronal  Glioblastoma (GBM),  Gliomatosis Cerebri (GC), Gliosarcoma (Gliosarc), Granular Cell Astrocytoma (GCA), Granular Cell Tumor (GCT),  Meningeal Gliomatosis (MG), Myxopapillary ependimoma (MPE), Neurocytoma (Neurocyto), Olygodendroglioma (Olygo), Papillary Glioneuronal tumor (PGT),  Pleomorphic Xantoastrocytoma (PXA), Pylocytic Astrocytoma (PA), Pituicytoma (Pitui), Rosette forming glioneuronal tumor of 4th ventricle (RG4),  Subependymal Giant Cell Astrocytoma (SEGA), Subependymoma (SE)

Main References:

AFIP Tumors of Central Nervous System:  Burger and Scheithauer
Ackerman's Surgical Pathology: Rosai
Diagnostic Surgical Pathology: Sternberg
Staying cool in Frozen Room. CAP 2008 conference by Dr Mark Cohen.
Pathology Osler Course, neuropathology section
Robbins Riview of Pathology
Arch Path Lab Med- Vol 135, May 2011: Molecular diagnosis of gliomas.
Multiple other sources  


-Common in kids and very young:   PA,  DIA in brain stem and thalamus, Ependymo in posterior phosa in kids, PXA, Astrobla, AG, GG, DCG, DIG (under 1 year). Some: GBM in thalamus and brain stem.
-Common in adults: Most: DIA hemispheres, AA, GBM, olygo, spinal cord ependymo, GCT, CGTV, central neurocyto (young adults).    
-Common in elderly: Some: DIA, AA, GBM.
-Remainder of the tumors at any age, no predilection.


-3 important hereditary syndromes in brain tumors:
NF1 (chromo 17)  PA (loss of NF alleles in chromo 17)
NF2 (loss of chromo 22) related with  multiple ependymo, most intraspinal.
Tuberous Sclerosis associated with SEGA

-Radiation related: Some gliomas
-Tumors arising from previous tumors: Some GBM are secondary from low grade gliomas, other arise de novo.


-White matter:  Most glial tumors involve white matter,  including DIA and Olygo
-White + Gray matter:  Most: Olygo show dense cortical involvement.  Some:  PA, PXA, DIA and other astrocytomas. GC diffuse effacement of gray white junction at least in 3 lobes.  Some small cells of GBM may spread to brain surface (meninges) and overrun gray matter showing perineuronal satellitosis, subpial and perivascular aggregates. AG predominates in cortex but affect white matter and may go to ventricle.


MAY BE BILATERAL AND/OR MULTIPLE:   DIA in thalamus and Pons involves entire circunference of pons. GC involves at least 3 cerebral  lobes and commonly is bilateral.  Rare cases of GBM.

MAY SPREAD TO MENINGES: Leptomeninges involved with CSF cytology:  Some AA and GBM (common in spinal cord),  ependymo including MPE (5% only)
 -Most superficial meningocerebral lesions breaking pia (leptomeninges) have negative CSF:  Most low grade glyomas,  PA, PXA, GG (desmoplasia if involve subarachnoid space).To determine meningocerebral location look for virchow robin in subaracnoid space and intratumoral muscularized arteries in leptomeninges.
-Dura may be involved: DIG      

MAY SPREAD TO CONTIGUOUS STRUCTURES IN CNS: Some small cells of GBM may spread to cortex, subependymal zones, optic radiation, fornix and corpus callosum (frequent areas of recurrence).  These small cells have high MIB-1.

-Hemispheres (supratentorial) : Most gliomas in adults:  DIA, AA, GBM, GCA, AG, Olygo (cortical gyri), GG (common in temporal lobe but may happen everywhere in neuroaxis), DIG, PXA commonly in temporal lobe. Most DNT  intracortical nodules with bubble appearance. Some PA in young adults
-Brain stem: Common: DIA and GBM in kids expanding and obstructing 4th ventricle, PA is more mesencephalic and exophitic in dorsal midbrain vs  DIA more pontine.
-Infundibulum (neurohypophisis): GCT
-Suprasellar: Pitui
-Thalamus: Common: DIA and GBM in kids.  
-Hypotalamus: Some: PA,
-Corpus Callosum: GBM may spread.
-Optic nerve: Common: PA  Rare: Dissemination of some GBM .
-Hypothalamus: Common: PA, GBM  
-Cerebellum:  Common: PA kids, DIA kids, ependymo kids and DCG (show unilateral mass effect). Rare: PXA. Very rare: GBM
-Cerebellopontine angle: Common: PA Kids (more peduncles), ependymo kids, shwanoma  Rare: PA adults
-Foramen Monro (between 3rd and lateral ventricles): SEGA, SE
-4th ventricle:  PA,  ependymo in kids, SE. Some DNT (most intracortical).
-3rd ventricle: Ependymo, SE, CGTV
-Lateral ventricle: Some: ependymo, central neurocyto (septum pellucidum, the membrane separating lateral ventricles).  
-Spinal cord intramedullary: Common: Ependymo (MPE adults) involving filum terminalis. PA,  DIA, SE. Rare: GBM, PXA
-Localized in leptomeninges only (piaarachnoid): MG. Only seen in meninges, most cases around spinal cord with thickened subaracnoid space and encaseing nerve roots.  
-Retina: Rare:  PXA


-Most tumors initially no specific neurologic deficit product of mass effect depending of location and headache. Late presentation of tumors is common associated with symptoms of increase intracraneal pressure.
-Seizures: Most tumors may produce. Common in superficial tumors like olygo, PA, PXA. Complex seizures in DNT.
-Hidrocephalus: SEGA, SE, CGTV
-Craneal nerve compression: SE
-Amenorrea or hypothyroidism: CGTV (compression of hypothalamus)
-Back pain and numbness in leg:  MPE.
-DCG manifested more for increase preassure than cerebellar symptoms.
-Rare potential to metastasis outside of CNS:  Gliosarc  
-Sex: Primary gliomas more in men. Secondary gliomas more in young women.


-Circumscribed cyst  with mural nodule:  PA, some GG, PXA, extraventricular neurocyto (all WHO grade I or II lesions).
-Contrast enhancing, multicystic or cystic, no mural nodule: PA, PXA. Some intraparenchymal (not intraventricular) ependymos are associated with cyst and contrast enhancing.  In MPE sausage like intraspinal cyst.  In DIG the multicystic mass is superficial and very large (large cysts), attached to dura, with some solid areas around the cysts that are contrast enhancing.
-Solid enhancing with no ring (no central necrosis): AA, GCG (variant of GBM without central necrosis).  Solid well defined  nodule: some GG.
-Ring contrast enhancing : GBM, GCA.  Ring enhancing is due to vascular proliferation and central dark area to necrosis. Very rare: Anaplastic Olygo.
-Contrast enhancing with bubble appearance: astrobla, DNT (bubble like intracortical nodules that may erode skull). -
-Butterfly lesion bridging corpus callosum: GBM.
-Other contrast enhancing: GCT, Pitui, clear cell ependymo (sharp circumscription), ependymoma (broad base in ventricles)

INTRAVENTRICULAR: Most contrast enhancing with exceptions like SE, a intraventricular lesion located in Munro.
-Bright enhancement and no ring probably: SEGA (tuberous sclerosis) or Neurocyto.
-Well defined in 3rd ventricle: CGTV  
-Well circumscribed incorporating septum pellucidum: Central Neurocyto

-Low intensity with no  contrast enhancing: DIA (focal of diffuse enhancing suggest malignant transformation or previous irradiation). AG is bright but not enhancing.
-Edema generating mass: GBM, GCA, Olygo
-Cortical giriform : Olygo.
-Unilateral enalrgement with thickened folia in cerebellum: DCG
-Calcifications: Common: 90% olygo, SEGA, Neurocyto, some SE. Rare: Some PXA, DCG
-GC: Gliomatosis Cerebri is more a radiologic than microscopic definition (micro looks like grade II or III astrocytoma). By definition, 3 cerebral lobes are involved with effacement of gray white junction.  


-Diffuse Infiltrating borders or indisctint margins: Most: DIA, Oligo, AA, GBM, GCA. Comment: Some PXA infiltrate cortex like diffuse astrocytoma and that explain why many PXA recur after excision. Rare: neurocytomas, mainly cerebellar infiltrate glia.
-Well or sharp circumscribed borders (not infiltration of surrounding brain), amenable to complete excision: Common in WHO grade I and II. PA, PXA, GG, Ependymo, Astrobla, DNT, CGTV, central or extraventricular neurocyto. SE are well defined polypoid or multinodular or lobulated lesion protruding into ventricular cavity.  Rare: Some GBM like GCG  very well circumscribed margins.
-Necrosis:   Common: GBM  Possible: Malignant Olygo, malignant ependymo. If parenchymal necrosis occur in grade II gliomas ask about previous radiotherapy. Ischemic infarct like necrosis is possible in any grade II glioma without px significance and even in grade I lesions like PA.
-Hemorrhage:  GBM, Olygo.
-Cyst with fluid and circumscribed mural nodule:  PA, PXA, GG, extraventricular neurocyto
-Large multiple cysts surrounded by very hard woody desmoplastic areas: DIG
-Solid cortical and blister like mucin rich nodules: DNT
-Pseudopapillary surface: MPE


-Grade I:  Reserved for DCG, PA, SE, GCT, Pitui, MPE, gangliocytoma, well diff GG. Well circumscribed tumors. No mitosis. Pleomorphism is possible in PA. DIG is also grade I, even if areas of hypercellularity, small glial cells and mitosis.

-Grade II: No mitosis and low MIB-1 are the most important feature. Sometimes difficult differential with reactive gliosis or normal brain.  Hypercellularity + slight to moderate atypia and hyperchromasia. Even with worrisome pleomorphism (e.g PXA) if no mitosis or high MIB, the lesion is Grade II.  Classified as grade II:   DIA, DIA gemistocytic, CGTV, most PXA, some GC and MG, Infantil PA astrocytoma (myxoid lession with perivascular orientation), most Olygo, most Ependymo>
Central and extraventricular neurocyto are WHO 2. Even with rare event of atypia, pleomorphism, some mitosis and Ki-67 >2% are considered  grade II, probably with greater risk for recurrence.  

-Grade III: Most important pleomorphism, hyperchromasia and hypercellularity with mitosis. If this features hard to find, look for high  MIB-1 > 5%, predicting grade III behavior.  Clasiffied as grade III: AA, AA gemistocytic, anaplastic olygo, GG with anaplastic glia, anaplastic ependymo.
Some capillary vessels may be present but not glomeruloid multilayer vascular proliferation nor necrosis Sometimes classified as grade III: GCA if mixed with areas of AA, GC, MG, PXA if > 5 mitosis (anaplastic PXA)

-Grade IV: Reserved for GBM. Findings of grade III +   necrosis +  Abundant mitosis and/or MIB-1 + vascular proliferation.  Every glioma may have some telangiectatic vessels without multilayer proliferation. Multilayer vascular proliferation: glomeruloid or small/medium vessels with intraluminal multilayer endothelial proliferation.  GCA is considered grade IV if granular cells areas mixed with GBM.  

-Olygo with vascular prolif, mitosis, hypercellularity and necrosis is considered Grade III. Grade IV Olygo is not a correct designantion.  WHO consider designation of GBM with olygo features. No grade is considered for Astrobla (some low grade, some high grade).
-Transformation: If grade II transform to III,  cellularity may decrease but MIB increase (even if mitosis not found).  


-Ice crystal effect on frozen compressing and distorting parenchyma, looking like mycrocysts: This artefact explain why is important to save tissue for permanents. It is present in some  PA, DIA, AA, Olygo, GBM. Do not confound crystal effect with true microcysts (mycrocyst contains proteinaceous eosinophilic material) and is very common in PA and GG.
-Use term low grade infiltrating glioma in frozen for:  DIA, Olygo,
-Marked perinuclear satellitosis with cells showing halos, round nucleus and small nucleoli in frozen favor Olygo. Satellitosis is not synonimun of olygo, and few satallite olygos are always present around neurons.
-In frozen section the key for ependymoma is the pseudovascular rosette. Otherwise may look like astrocytoma.
-GBM vs Mets and Lymphoma: Small cells, small nucleus, small nucleoli and bipolar or fibrilary processes in touch prep  favor GBM. Mets or  lymphomas  larger cells with large nuclei, big nucleoli and no bipolar processes.
-Very careful in PXA confusion with GBM, specially the giant cell GBM that is well circumscribed tumor. Look for absence of necrosis, palisading and mitosis and all additional features of PXA like eosinophilic bodies.
-Look like small blue tumor: Central neurocyto. Touch prep are great to see uniformity, scant cyto, round nucleus, small nucleoli and fine chromatine.
-Floating neurons and olygo like cells in touch: consider DNT.





-Fibrillary background: All astrocytomas, SE, SEGA. GG shows ganglion cells in fibrillar background with astrocytes. Rarely central neurocyto show fibrillar background.
-Biphasic:  PA shows dense compact or solid areas with elongated or piloid (bipolar hairlike astrocytes) and Rosenthal fibers + loose or spongy areas with microcysts. Ependymos are heterogeneous mixing hypercellular areas with pseudorosetes with paucicellular fibrillar areas resembling fibrillary astrocytoma.
-Mixed glioneural:
DNT (ganglion cells  floating in mucous pools + dysplastic neurons combined with fibrillary or pyloid astrocytic background with atypical clusters of astrocytes.
GG (ganglion cells mixed with fibrillary backgrouns and astrocytes and sometimes hidden in fibrous or desmoplastic stroma.  Astrocytic component of GG may be pyloid or oligo like but it is not atypical.
DIG individual ganglion cells, sometimes regionally concentrated in areas are mixed with glial tissue that may show gemistocytes, small cells and in areas is totally desmoplastic and whorled.
Rare cases of central neurocytoma are mixed with ganglion cells (ganglioneurocytoma).
-Neuronal dysplasia: DNT: abnormal lamination and architectural alteration of neurons (lack polarity) + binucleation + polymorphism.
-Hypercellular white matter: Most: DIA (3 times the normal), AA, GBM
-Infiltration of white matter with irregular distribution of tumor cells incorporating astrocytes, oligo, axons and neurons: Most: DIA, AA, GBM, Olygo  Some: PXA  Rare:  PA (some consider PA with trapped neurons a GG).
-Coagulative Necrosis (infarct):   Common: GBM  (granular, coagulative infarct). Possible: Malignant Olygo, malignant ependymo. If parenchymal necrosis occur in grade II gliomas ask about previous radiotherapy. Ischemic infarct like necrosis is possible in any grade II glioma without px significance. Necrosis in PA is hyalinized and homogeneous (not granular or coagulative).  Rare: SEGA
-Pseudopalisading necrosis:  Common: GBM   Possible: Malignant Olygo (grade III), malignant ependymo. Not well developed: some PA.
-Palisading or ribbons without necrosis (rhythmic palisading): Possible in grade III olygo, some PA, SE.  Some DNT ribbons.
-Fascicles:  intersecting bundles and compact architecture in PXA, broad fascicles in some SEGA, fascicles resembling schwanoma with few or negative pseudorosettes in intraspinal ependymo (tanacytic ependymo). Gliosarc, a well circumscribed variant of GBM looks sarcomatoid.
-Septated and micronodular: PA reaching pya (subarachnoid space).
-Pseudopapillary architecture: ependymoma, MPE, some astrobla, some CGTV, PGT
-Microcystic spaces: Common DIA, PA, Olygo, Clear Cell Ependymo, most neurocytic tumors,  SE and GG  Rare: AA, GBM, Reactive gliosis
-Macrocysts: PA, PXA, MPE, DIG
-Subpial and subependymal accumulation of tumoral cells: Some: DIA, AA, GBM, PA (involve pya more by compression than infiltration), PXA, Olygo
-Perineuronal satellitosis of tumoral cells:  favor infiltrating glioma in the set of hypercellularity.  Very common in:  Olygo, Some: DIA, AA, GBM. Not always satellitosis is neoplastic. In neoplastic satellitosis (for example in Olygo) nuclei are more, larger and coarser than non neoplastic satellitosis. Rare: DNT
-Small monomorphic cells: Some GBM (look for necrosis, palisading, vascular proliferation, high MIB-1 and EGFR+), neurocyto
-Multiple well circumscribed hypercellular nodules that may have high MIB-1: Olygo, Ependymo
-Nested epithelioid cells: Rare pattern in CGTV (most cells are chorodoid).


-Eosinophilic nodule of granular cells in infundibulum: GCT
-Sellar tumor with tumor cells similar to normal pituicytes showing some swirling pattern (resemble compact areas of PA or spindle areas or GCT): Pitui
-Floating neurons in mucoid matrix: DNT
-Round mucus pools of perivascular material PAS/ alcian blue +, pseudopapillary areas, mycrocysts with myxoid material,  firbrillary areas, eosinophilic balloons and pyloid/fascicular areas resembling Schwannoma: MPE.
-Intraventricular (Munro), dome shape, low grade, nodular, well circumscribed, microcystis, clustered nuclei and  fibrillar background: SE
-Liver like cords of epithelioid cells separated by blue mucinous myxoid and collagenous material: CGTV
-Look like DIA + psedorossetes (angiocentric) + arrays of subpial tumor cells (but no satellitosis) + zones like schwannoma: AG
-Internal granular of cerebellum replaced by large abnormal vesicular neurons with prominent nucleoli. Tends to be laminar and linear with sharp circumscription with white matter: DCG
-Small round very monomorphic cells, frequetly perivascular with neurocytic rosettes, some halos and microcalcifications (may simulate small blue cell tumors): Central and extraventricular neurocyto.  
-Ganglion cells floating in pools of mucin alcian blue+, microcysts, piloid areas, satellitosis, ribboning and vascular proliferation: DNT.
-PGT : papillas and shows layer of GFAP positive glial cells immediate around the vessels and areas with the neurocytic component.  
-GTR: Look like regular infiltrating glioma mixed with circular islands with finely fibrillar neuropil
-RG4: glial component similar to PA + rosettes with fibrillar cores (neuropil) lined by olygo like cells with fibrillar component.


-Pyloid cells (pyloid gliosis) : Hair cells with bipolar precesses. Common: PA, DNT. It may be response to glial tumors like  spinal cord ependymo or some non glial tumors like craneopharingioma or hemangioblastoma.  Never: Tumors as DIA process are short and coarse, not bipolar.   
-Xanthic cells (xanthomnatous cytoplasm): PXA
-Clear cells :  CG (chordoid features), olygo (perinuclear halos/fried egg), RG4, Clear cell ependymo, RG4.  Rare DIA and GBM show perinuclear halos.
-Gemistocytes:  Abundant eosinofilic cyto and peripheral nuclei. Some: DIA gemistocytic, ependymo, Olygo, SE.  Rare: If AA and GBM  gemistocytic, high mitotic rate is expected. Microgemistocytes: Olygo grade III.
-Ganglion cell component:  All: GG (ganglion cells with dendrites poiting pia, some clustered, may form acinuls like groups).  Some: PXA  Rare: central neurocyto
-Large cells with glassy eosinophilic cyto and eccentric nucleus (morphology between gemistocytes and ganglion cells): SEGA
-Spindle cells: Some: GBM, SEGA
-Epithelioid cells: Most: Astrobla, CGTV. Some: SEGA and Olygo grade III
-Mast cells: Few in SEGA
-Granular cells (spindle or epithelioid): GCT
-Lipidized cells like lipopaghes: Rare: ependymo, central and extraventricular neurocyto may show lipidized cells like adipocytes (liponeurocytoma).
-Epithelial or mesencymal cells: Metaplasia: Glandular or squamous epithelium in GBM (gliosarc). Cartilage, bone or muscle in rare cases of GBM, gliosarc, ependymo, astrobla.  Myoid cells  in cerebellar neurocyto.


-Perivascular cuff of lymphos: Some: DIA (in areas with  gemistocytes), any gemistocytic astrocytoma, some PXA, some GCT, GG.  
-Interstitial lymphos: CGTV. More around virchow robin (subaracnoid): PA, PXA,
-Neutrophils (focal acute supurative inflammation):  Some GBM


-True ependimal canals or rosette :  Rare: Ependymoma. Some: SE, DNT
-Perivascular pseudorossetes (cells surround a fibrillar zone surrounding central vessel):  Most: Ependymo. Astrobla has characteristic perivascular pseudorosette with cells probably astrocytic, not ependymal, with broader processes and less tapered than ependymal cells.  Some: small cell GBM  Rare:   Infantile PA (pylomyxoid ) shows cells inmucopolisacaride matrix orienting around vessels, like ependymo. Vague: SEGA, MPE


-Tumor around muscularized arteries (leptomeninges): PA, PXA,     
-Vascular sclerosis or hialinization: PXA, any slow growing glioma, astrobla, some central or extraventricular neurocyto.
-Vascular proliferation ( vascular proliferation or intravascular hyperplasia + hypertrophy sometimes multilayer or glomeruloid): GBM, anaplastic olygo (grade III), anaplastic ependymo (grade III)  
-Delicate chicken wire pattern of capillaries: Olygo
-Confluent capillary proliferation (inocent glomeruloid masses): No indication of malignancy. Common: GG, PA, DNT


-Naked nuclei: Some: DIA
-Vesicular: SEGA
-Hyperchronmatic: Gemistocytes
-Round nuclei : Most: Olygo (not seen in frozen).  Some: PA, AA, GBM
-Uniform nuclei monotonous with fine chromatin: Olygo (not in frozen), PA. Not seen in:  AA and GBM.
-Elongated nuclei: PA in pyloid areas, areas of spinal cord ependymo (tanacytic ependymo)
-Clefted or grooved: Clear cell ependymo
- Multinucleation:  GBM (mitosis and high MIB-1),  PA (degenerative phenomenon with no mitosis and low MIB-1), some PXA, giant cell ependymoma (degenerative phenomenon in MPE similar to phenomenon that happen in ancient schwanoma, not anaplasia). Some intracraneal ependymos are giant cell ependymos with true anaplasia and WHO grade III. Most GG nuclear atipia with bizarre hyperchromatic or vesicular nuclei and some binucleation. Giant cells : Giant Cell Glioblastoma, variant of GBM. Most GBM cells have small cells.
-Mitosis: Most: AA, GBM, WHO grade III and IV gliomas.   Lack or scant:  No mitosis in WHO grade I or II.  Examples: PA, DIA, PXA, GG


-Small vissible nucleoli: Most: Oligo, central neurocyto. Nucleoli is small in Grade II and III tumors.
-Prominent nucleoli: Except GG and SEGA not commonly identified in gliomas. As a general rure for brain tumors, if prominent nucleoli think in Mets or lympho rather than glioma.   



-Rosenthal (eosinophilic hialine sausage like with blunt end) :  May bee seen in touch prep. Suggest low grade tumor but may happen in reactive conditions or areas adjacent to tumors other tumors like hemangio, craneopha, ependymo, AVM (in areas of pyloid gliosis).  Common:  DIA gemistocytic, PA, PX, GG. Rare: DIA. Not common in high grade gliomas.
-Basocilic intracytoplasmic fibrilary formations: GG
--Eosinophilic granular bodies:  PAS +. May bee seen in touch prep. Suggest low grade tumor but may happen in reactive conditions. Not common in high grade gliomas. Common:  Low grade lesions as PXA, PA, GG, DNT, DIG and extraventricular neurocyto. Also seen in gemistocytic.  Some: ependymo,  extraventricular neurocyto (pyloid areas around neurocytic sheets).  Rare: DIA.
-Round small hypereosinophilic fibrillar balloons: MPE.
-Intracytoplasmic whorls of filaments: Some: Olygo
-Intranuclear cytoplasmic inclusions: SEGA


-Hemosiderin deposits: Ependymoma in Spinal Cord, some SE
-Melanocytic pigment: Very rare: GG, central neurocyto, DNT
-Other tumors with pigmented cells: Some: PXA


90% olygo (laminated microcal),  central and extraventricular neurocyto (commonly perivascular). Some: GBM, PXA, SEGA, ependymo, SE, GG, DNT


-PAS+: Granular cells in GCA and GCT.  Eosinophilic granular bodies in PA, PX, GG. Round spaces of mucin material in MPE.
-Alcian blue: round spaces of perivascular mucinous material in MPE, mucin material where ganglion cells float in DNT.
-Compact aggregates of PAS+ granular cells with some glial process, low mitosis and mixed areas of diffuse high grade astrocytoma: GCA
-Reticulin prominent: Giant Cell Glioblastoma (variant of GBM), hypereosinophilic balloons in MPE. Pericellular reticulin in leptomeninges in PXA-,
-Oil red +: Xanthomatous cells in PXA.


-Myxoid material: MPE, PA infantile (pilomyxoid astrocytoma) and bluish material in CGTV.
-Collagen deposition inside the tumor: Giant Cell Glioblastoma (variant of GBM), longstanding MPE, Astrobla.


-Previously irradiated GBM: Quiescence and radionecrosis:  Paucicellular,  coagulation necrosis, vascular thickening and bizarre cells with marked atypia and abundant cyto (impossible to differentiate between neoplastic astrocytes or reactive astocytes). Rarely  radiation necrosis. Dx recurrence if: Small cells MIB-1 + and/or pseudopalisading.


-S-100: Nuclear and cytoplasmic. Suggestive but not diagnostic of glial origin. Most: Pitui, DIA, AA, PXA and SEGA (diffuse and strong), GBM, Gliosarc,   Olygo, Ependymo, Astrobla.  S-100 is + in normal astrocytes surrounding ganglion cells in GG and DNT.
-GFAP: Positive: Normaly in reactive astrocytes, gemistocytes and microgemistocytes. PA (+ in dense fibrilar areas), DIA, AA, Astrobla, CGTV, Pseudovascular rossetes in Ependymo (true rosette are GFAP neg), GBM, minority of cells in PXA, GCA.
Patterns of GFAP: Positive cell bodies and cytoplasm favor Olygo or mixed glioma. In Gliosarc look for GFAP+ islands of glial component with glassy  or fibrillary cyto. In MG fusiform fascicles GFAP + in leptomeninges without any intraparenchymal glioma detected. GFAP is + in normal astrocytes surrounding ganglion cells in GG and DNT, glial or desmoplastic tissue in DIG and few reactive astrocytes surrounding central or extraventricular neurocyto.  Weak: SEGA, Pitui  Negative: Some small cell variants of GBM, giant cells in GBM, granular cell component of GCA, most GCT.
-Vimentin: Little diagnostic significance  but indicate that specimen is viable.   Present in many gliomas.
-CAM 5.2: Negative: DIA, AA, GBM. Rarely focal: ependymo
-AE1-AE3: Focal very rare: AA, GBM both in neoplastic  and reactive astrocytes, CGTV. Neg:  ependymo (useful for differential with choroid plexus papilloma in pseudopapillary lesions)
-EMA: EMA positive, dot like: Some Ependymo and AG.  Some: Astrobla and CGTV Negative: DIA, AA and most GBM (except if GBM with adenoid or squamous differentiation). Rarely positive: GBM with epithelial differentiation.
-p53: Negative: PXA, Olygo grade II.  Low or weak : PA, DIA, PXA, grade III olygo  High: DIA gemistocytic.
High p53 is possible in all variants of GBM , specially Giant Cell,  secondary and pediatric GBM and Gliosarc. However, not all GBMs are p53+.  Careful with p53 virally infected cells in PML.
-MIB-index:  Low : SEGA, PA, most PXA, most ependymo, most Astrobla, SE. Most DIA index < 2% (except  in some DIA gemistocytic). Although a low grade lession, some MPE  shows MIB-1 index between 2-5%. GG average MIB % is 2.7. Most neurocyto <2%. A central neurocyto > 2% is called atypical, but still is grade II.  High:  commonly more than 5% in AA, GBM, GCA (not in granular cell areas but in areas of mixed high grade astrocytoma). Anaplastic PXA with more 5 mit/HPF or MIB> 2% may behave aggresive, PA with >2% or at least 1 mitosis/250X may transform to malignant. May be high in hypercellular islands of Ependymo or olygo. If anaplastic epencymo >20%, px is poor. Some Astrobla show high MIB-1 (high grade Astrobla).
-EGFR amplified:  Occur  only in primary GBM. Not expected in most secondary GBM, giant cell GBM, gliosarc or other gliomas.
-Neuronal markers: Synaptophisin is the best marker for neurons and ganglion cells. Other neuronal markers that may be + in neurocytes and ganglion cells are: chromogranin, neurofilament protein, Neu1.
Typically synapthophisin + are: GG, DCG, DNT, neuropil in GTR and RG4,  and neurocytic component of PGT y  GTR.  Neoplastic neurons in GGs stain cytoplasmic for synapthophysin and chromogranin (normal neurons only membranous staining or punctate in perikarya). Normal puicytes are positive but pituicytoma is negative
Central and extraventricular neurocyto: fibrillary areas or areas similar to pseudorossetes are synapto + but GFAP neg..
Other tumors commonly + for neuronal markers: PXA if few individual ganglion cells present, few individual cells in SEGA, neuroytic areas or rosettes in Olygo.  
-Alpha 1 antichemotripsina: eosinophilic granular bodies in PA
-CD68: Some Granular cell component of GCA.
-CD34: Some PXA and GG and many CGTV
-Muscle markers: tumors with muscle metaplasia or myoid cells



-Reactive gliosis : In reactive gliosis astrocytes with uniform distribution, abundant cyto, simetric stellate long processes. Sometimes multinucleation and macrophage rich lesion are strong clues of a reactive process.  Reactive gliosis in never hypercellular (cells are more hypertrophic than hyperplastic) with the exception of gliosis around vascular malformations. Differential between gliosis and paucicellular gemistocytic astrocytomas is difficult because cyto in gemistocytes is abundant. Reactive gliosis may be seen around any tumor, inflammation or PML (macrophage rich lesion)
-Foamy macrophage rich lession: always suggest benign, common in demyelinating disease and infarct. Rare in neoplasia.
Thick cut section vs astrocytoma: Hypercellularity but not atypia. MIB-1 negative. No mitosis. Common problem in frozens. Touch prep help to solve the problem.



-Olygo vs low grade astrocytoma: Astrocytoma may show halos but more pleomorphic and hyperchromatic nueclus, more cyto, more process formation, no calcification, less satellitosis. Olygo less process formation with well defined cell borders and no fibrillar background. Monotony always favor olygo, even anaplastic olygo show monotony.  Mitosis always favor astrocytoma (rare in olygo).
-Olygo with microgemistocytes vs astrocytoma rich in gemistocytes: If p53+ favor astrocytoma.
-Olygo vs macrophage rich lessions: demyelinating disease, infarct or lymphoma treated with steroids are rich in histiocytes (CD68+ and PAS+ clear cells).
-Olygo vs Clear cell ependymo:  Clear cell ependymo radiologically and microscopically is sharply circumscribed,  contrast enhancing, show IHC with dot like EMA. Clear cell ependymo commonly Grade III with mitosis and vascular proliferation.
-Olygo vs DNT: Look for floating neurons in mucoid matrix in DNT. DNT is neg for 1p/19q loss.
-Olygo vs Neurocyto: Both round nucleus, halos and calcification. Neurocyto is synapthophysin +


-Ependymo vs DIA: Ependymo with fibrillary areas, abundant gemistocytes and absent perivascular rosettes may simulate DIA.
-Ependymo spinal cord/forth ventricle vs PA: Some PA shows formations similar to pseudorossetes.Mycrocystic pattern is seen in PA but not in Ependymo. Ependymo is well circumscribed and do not infiltrate axons in pons like PA.
-Ependymo vs Central Neurocyto: Pseudorosetes are GFAP +. Neurocyto fibrillar areas resembling pseudorosettes are synaptophysin +, GFAP negative.
-Ependymo vs small cell glioblastoma with perivascular fibrillar areas simulating pseudorossetes: Small Cell Glio infiltrate parenchyma, necrosis, high mitosis, pseudopalisading.
-Ependymo in spinal cord vs Schwanoma : In spinal cord some ependymos resemble Schwanomas with fascicular pattern (tanacytic), fibrous collagenized tissue and  few perivascular rosettes. S-100 strongly + in Schwanoma with GFAP neg or very weak.  Pericelullar reticulin favors Schwanoma.
-Ependymo tanacytic (spinal cord) vs meningioma: Meningioma is EMA+, GFAP neg.
-Ependymo vs SE: Very difficult dx. SE located in Munro. Sometimes both coexist.
-Papillary ependymo vs coroid plexus papilloma: ependymo inside the ventricular system are rarely papillar but never frond like as papilloma.
-SE vs low grade gliomas: SE is a well circumscribed polypoid lesion in foramen Munro that may have fibrillary appearance and microcysts.


-PA vs DIA: PA in cerebellum may resemble DIA.  
-Primary vs Secondary GBM: If young women in cerebral hemisphere or kid in brain stem probably GBM is secondary with not amplified EGFR and non   muted PTEN.
-GCA vs Infarct of demyelinizating disease: Look in GCA for mixed areas of high grade glioma. Compared with foamy histiocytes in infarct or demyelinating disease, granular cells are larger with granular, not foamy cyto.
-GC vs Microgliomatosis: Microgliomatosis is a extremely rare disease. Microglia is CD68+.
-Infundibular GCT vs PA: PA is GFAP +, fibrillar, cells not granular and microcysts present. GCT granular, no microcysts, no fibrillar, most GFAP neg.
-PXA vs others: GBM, specially giant cell GBM that is well circumscribed. Look for absence of necrosis, palisading and mitosis and all additional features of PXA like fascicular compact architecture and eosinophilic bodies.  MFH ruled out if diffuse S-100. PXA not spongy or microcystic areas of PA (PA may have pleomorphic cells but not xanthic change nor pericellular reticulin). Deep areas of PXA may be similar to DIA or gangliogliomas if many ganglion cells trapped (some consider this case a form of ganglioglioma).
-SEGA vs gemistocytic astrocytoma: astrocytoma is intraparenchymal and infiltrative with gemistocytes  smaller than SEGA
-SEGA vs ependimoma: SEGA vague pseudorosettes. Ependymoma no vesicular nuclei or prominent nucleoli.


-Key to differentiate Astrobla from form other gliomas and ependymoma is:  demarcation, vascular hialinization, occur away from ventricle, epithelioid cells, the pseudorosette is not fibrilar and it is more epithelioid
-Key to differentiate Astrobla from Meningioma: If pseudorossetes with papillary features differential may be papillary meningioma. Both EMA+.  Meningioma is dura based and GFAP neg.


CGTV: Clival chordoma is chordoid, dura and bone based with abundant lymphos and plasmos. Chordoid meningioma is GFAP neg. Papillary tumor of pineal region  lacks chordoid architecture and it is GFAP neg or weak.

AG: Due to pseudorosettes may be confused with ependymo and astrobla. If confusion with Olygo, look for satellitosis (present in Olygo but never in AG).

GG:  Infiltrating glioma with trapped neurons: look for satellitosis. Neurons show normal morphology, not atypical

-Meningioangiomatosis:  intracortical non spherical plaque with desmoplastic vascularized stroma trapping neurons.

-PXA vs  GG:  Both eosinophilic granular bodies. Some PXA neoplastic ganglion cells. Immunohistochemistry is key in the dx.

-DCG is not really a mass, it is a dysplastic process in cerebellum.


Very classic, superficial, kid < 1year with gross and radiologic characteristic pattern. PXA may be similar but occur in adults.  In DIG hypercellularity and mitosis may resemble meningeal sarcomas, high grade astrocytomas  or small cell embryonal tumors.

DCG: Easy to differentiate with GG. Tends to be laminar and linear with sharp circumscription with white matter, no cysts, no extension to leptomeninges. If confusion with astrocytoma, IHC resolves problem.   

DNT: due to satellitosis and olygo like cells, may be confused with olygo. DNT is not infiltrative  and grossly is different like well circumscribed mucin like nodule with blisters. Olygo is infiltrative and lack floating neurons. High MIB favor olygo. 1p/19q confirms olygo.
If pyloid background present differential is with PA but they are radiologically, grossly and micro different.  PA more strongly + for GFAP (DNT multiple cortical nodules, bubble like in XRay with ganglion cells and neuronal dysplasia.

Central and extraventricular Neurocyto: Confused with olygo due to halos and calcifications but 1p/19q codeletion is absent. Olygo and Ependymo are completly neg for synaptophisin (central neurocyto is positive in fibrillary areas). Olygo is diffuse, central neurocyto is well circumscribed. Ganglion cells and hialinized vessels not present in olygo.

Ependymos may be paraventricular but not intraventricular like central neurocyto (septum pellucidum). If extraventricular neurocyto, differential with clear cell ependymo is  important  but cells in ependymo shows more nuclear irregularities, more mitosis and clefted nuclei.

Central neuroblastoma is a pediatric tumor, intraparenchymal, not intraventricular.

DNT is a tumor showing ganglion cells floating in pools of mucin with microcysts, piloid areas, satellitosis and vascular proliferation.
In cerebellum the differential of neurocytoma is with medulloblastoma, a tumor more mitosis and nodullarity etc.


-Oligo: chromo 1p and 19q codeletions (loss of arm) performed by FISH or PCR  in paraffin block present in clasic Grade II Olygos with good px.  If both deletions present px better.
- BRAF fusion is the classic abnormality in 80% of PA.
-Any glial tumor, in early stage, when low grade (except PA)  shows isocitrate dehydorgenase mutations (IDH mutations), detected by PCR.
-TP53 Gene Mutation/17p loss is present most Oligoastrocytomas and astrocytomas, any WHO grade. p53 better by IHC.
-9p loss is common in any anaplastic Oligo, AA or Anaplastic Oligoastrocytoma.
-GBM vs AA: 10q loss is present in most GBM (primary or secondary).
- Primary GBM shows PTEN (10q deletion), EGFR amplification by FISH (evaluate signals in chromosome 7)  and CDKN2a deletion.  MIB-1 confirm high grade glioma.
-SEGA: loss heterozigosity chromo 9 or 16
-Not typical molecular or genetic features: Astrobla, CGTV, GG etc.   


-PA:  Some pylomyxoid initially appear aggresive but with time stabilize and simulate usual PA. If not resectable may last 10-20 years.  Optic location and hemisphere excelent px. May recur if hypotalamic, cerebellum, pylomyxoid or infantile.  
-Good px if complete excision possible. Recurrence may happen if not completly excised: PXA, SE, most ependymo including spinal cord MPE, low grade astrobla, DIG, DCG, central and extraventricular neurocyto, AG, DNT.
-SEGA: good px, even in the very rare case of atypia, mitosis and necrosis.
- CGTV is a slow growing lesion but adhere to walls of ventricle and surrounding brain without cleavage for the neurosurgeon (very difficult to resect without neurologic damage).
-Olygo generally not amenable to excision but if 1p/19q loss px is better and survival or 14 years average expected. If 1p/19q loss not detected survival is similar to astrocytoma. Olygo in general better px than astrocytoma.

POTENTIALLY AGGRESIVE: DIA survive 4 to 10 years and many suffer anaplastic transformation to higher grade (specially gemistocytic variants and elderly), PA with MIB > 2% or mitosis, PA in cerebellum in adults commonly overlap with DIA and is grade II or III, anaplastic PXA with more 5 mit/HPF or high MIB aggresive even if completly excised. Px of DNT is not clear, they may be excised but can recur (most are atypical DNT with >2% MIB-1).

AGGRESIVE: Some PA after radiation evolve to GBM. Some anaplastic PXA evolve to GBM. Other lesions with poor px: AA, GBM (even with chemo and radio survival is 12 months, worse in poor, older or brain stem). GCA are very bland benging looking in granular cells areas but are mixed with areas of AA or GBM and therefore px is poor.  MG and GC are diffuse unresectable process with poor px.
Grade III ependymomas in brain parenchyma, clear cell morphology or MIB > 20% poor px.  Anaplastic olygo poor px.
-Astroblasto if high grade (necrosis, mitosis) poor px.

-Associated to aggresive behavior:  gemistocytes (commonly associated with prominent nucleoli and high MIB index).
-No prognostic significance: Ischemic infarct like necrosis in grade II astrocytomas.
-Olygo: Gemistocytes, microgemistocytes, small astrocytic cells, epithelioid cells, hypercellularity and many microcals worse px, generally grade III. Also mixed olygoastrocytoma (mixed glyoma) worse px. Multiple hypercellular clonal nodules is seen in grade II Olygo and it is not an indication of Grade III.


-Grade I and II WHO: Curative if excision posible. In some tumors like for example DNT radiotherapy may be indicated if recurrence.
-Anaplastic PXA with more 5 mit/HPF or high MIB (some consider this lesion grade II) may behave aggresive even if completly excisied and require radiotherapy
-Grade III/IV tumors: Radiotherapy
-Oligo may be treated with chemo as first line.  


-Cerebral Cortex: Normal neurons are triangular in sections, almost never binucleated, show lamination and dendrites extending toward cortical surface. Clusters of neurons are only possible in amigdala (abnormal in other locations). Normally neurons may be surrounded by some small oligodendrocytes. Neuropil of fibrillary background is positive for synaptophysin but individual neurons are positive.   Bipolar elongated thin cells in cortex  highlighted with CD68 are reactive microglia.  Lymphocytes are not expected in cortex. With age subpial, subependimal and perivascular corpora amilacea is normal. Laminations of myelin forming pencil bundles are common in stereotactic bx in basal ganglia and thalamus.
-White Matter: Few scatter neurons are possible in temporal lobe. Short columns of olygodendrocytes may happen and also some clusters of olygodendroglia around vessels and neurons. Large axons may resemble hyphaes. Thick white matter specimens may appear hypercellular.  


-Gemistocyte: Plump astrocyte  with  dense eccentric nuclei, abundant glassy eosinophilic cyto and short delicate processes. They may be reactive or neoplastic. Reactive gemistocytes do not increase in number. In neoplasia they are increased in number and show nuclear atypia.
-Rare variants or findings in GBM:  epithelioid (simulate melanoma or mets), lipid rich, carcinomatous differentiation with papilla,  adenoid or squamoid pattern (simulate mets),  metaplastic bone or cartilage. Gliosarc is a well circumscribed variant of GBM with  with herringhbone or MFH pattern
-Some cases show mixed features of Olygo and Astrocytoma and can be called Mixed gliomas or Olygoastrocytomas.
-Gangliocytoma: for practical purposes in the same cathegory and behavior of Gangliogliomas. It is used for lesions only composed enterily of neurons that resembles cerebral cortex.
-Extraventricular neurocytomas may involve hemisphere, cerebellum and rarely spinal cord. They are similar in morphology and behavior. Cerebellar neurocytomas commonly show lipidized cells and myoid cells positive for muscle markers
-Malignant neuronal and glioneuronal tumors are very rare. Dx of anaplastic ganglioglioma should be made with caution (may be infiltrating glioma trapping normal ganglion cells). Malignant neurocytic tumors without glia are very rare and show atypical neurons with mitosis and high MIB.

Read 16193 times Last modified on Friday, 01 February 2013 21:14
  Andres Angel

I am a board certified pathologist in Anatomic and Clinical Pathology. I have  been working in pathology for 23 years. I finished an AP residency in Colombia in 1992.  After graduation, I worked as a pathologist  for 8 years in a community hospital in Colombia, S.A.  Read More

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