Central Nervous System

Specimen preparation: save portion for EM; fix tissue and then cut sections of cyst wall; submit as many sections as possible to rule out neoplasm

Micro: no solid nodule of tissue; cyst wall may contain astrocytes, Rosenthal fibers, glial fibrils

DD: abscess (granulation tissue and fibrosis, inflammation); tumors with cystic areas (pilocytic astrocytoma: often in cerebellum; hemangioblastoma: vascular, lipid+, factor VIII+, reticulin outlines each cell), meningeal cyst (on spinal surface, syncytial type cells, collagen+), pineal cyst

Arachnoid cyst

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Subdural or subarachnoid cyst containing CSF

1% of intracranial masses; protrude towards brain or spinal cord; often in middle fossa near temporal lobe

Congenital lesions that arise from split in leptomeninges, also due to trauma or leptomeningitis

Treatment: surgery if symptomatic

Radiologic images: MRI - spinal cord cyst; CT - left temporal lobe cyst

Gross: variable size, but may be vary large; thin transparent wall with clear, colorless fluid; cyst is distinct from leptomeninges and dura

Gross images: cyst of left temporal lobe

Micro: thinner wall than epidural cyst; lined by connective tissue and meningothelial cells

Micro images: thin cyst wall; meningothelial cells

Choroid plexus cyst

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May be present throughout ventricular system, but usually in glomus of lateral ventricles

More frequent in children than adults

Contain CSF

Present in 1-2% of fetuses, <1% associated with trisomy 18

Radiologic images: MR shows small cyst; choroid cyst

Case reports: 53 year old woman with small lesion at foramen of Monro (Am J Neuroradiology 2002; 23:841)

Gross images: cyst at foramen of Monro

Micro: wall composed of connective tissue and epithelial cells

Positive stains: transthyretin

Colloid cyst

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Uncommon; probably due to maldevelopment

Usually ages 20-50 years in third ventricle near foramen of Monro

May cause intermittent positional headaches, hydrocephalus and rarely be fatal if it blocks foramen of Monro

May rupture and mimic abscess or ventriculitis unless colloid is identified

Case reports: 36 year old woman with AIDS, headache and nuchal rigidity (Am J Neuroradiology 2000;21:1470)

Gross: up to 3-4 cm; round, unilocular with thin wall; cyst content after fixation is gray with consistency of soft cartilage

Gross images: colloid cyst; obstruction of foramen of Monro by gelatinous cyst

Micro: fibrous wall lined by simple columnar epithelium (also flattened, cuboidal, squamous) with variable cilia or mucin; also colloid or ghost cells

Micro images: lined by cuboidal or columnar epithelium; epithelium with ciliated and goblet cells resting on collagenous tissue; myelin stain

Positive stains: epithelium - keratin, mucin; contents are PAS+ and Alcian blue+

Negative stains: epithelium - GFAP, vimentin, neurofilament

DD: depending on location enterogenous cyst, ependymal cyst, Rathke cleft cyst

References: eMedicine

Dermoid cyst

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Uncommon; much less common than epidermoid cyst

Midline cerebellum, fourth ventricle, skull, spinal dura, cauda equina

May involve CNS or meninges

May derive from embryonic inclusions of skin at time of closure of neural groove at 3-5 weeks of gestation

May have sinus tract in nasofrontal or occipital regions

Benign; may rupture and cause chemical meningitis and inflammation resembling abscess

Radiologic images: various images

Gross: well defined, round/oval, opaque or pearly; variable size, variable wall thickness; contains greasy material with variable hair; may have solid components

Gross images: cyst from cerebellum with hair and sebaceous material

Micro: fibrous wall lined by keratinizing squamous epithelium with skin adnexa, cyst contains squames, hair, sebum; hair shafts are highlighted with polarized light; rupture may cause granulomatous inflammation with foreign body giant cell reaction

DD: cystic teratoma

References: eMedicine

Enterogenous cyst

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Also called neurenteric cyst

Rare, benign; probably due to maldevelopment

Usually in spinal cord (lower cervical and upper thoracic) presenting with spinal cord or cranial nerve compression; rarely intracranial

Usually intradural or subdural; intradural cysts are usually attached to spinal cord

Infants, children and adults

Cells resemble bronchial epithelium (Appl Immunohistochem Mol Morphol 2004;12:230)

Treatment: complete excision; occasionally is adherent to adjacent structures

Case reports: 78 year old man with cyst in front of medulla (Am J Neuroradiology 2001;22:496), intramedullary cyst of spinal cord presenting during pregnancy (J Neurol Neurosurg Psychiatry 2001;71:528), 43 year old man with cystic mass at cerebellopontine angle (Archives 2003;127:e45)

Gross: usually 1 cm or less

Micro: columnar epithelium with mucin (usually without cilia), resting on collagen layer; resembles intestinal or respiratory epithelium; goblet cells often present; may have squamous metaplasia

Micro images: (1) single layer of ciliated columnar epithelium; (2) figure 1: MRI shows mass at cerebellopontine angle; 2: cyst lining has single or pseudostratified columnal epithelium with focal squamous metaplasia; 3: cells have prominent apical cilia with basal nuclei but no atypia

Positive stains: Alcian blue, mucicarmine, PAS, EMA, CK5/6 (basal cells), CEA

Negative stains: GFAP, S100, NSE, vimentin

EM: well developed stereocilia, distinct basal cells, thin basement membrane

DD: colloid cyst (in third ventricle), ependymal cyst (abuts onto gliotic neuropil, GFAP+), cystic tumors

Ependymal cyst

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Rare; affects brain and spinal cord; usually not midline

Not in communication with ventricle or CSF spaces

Rarely ruptures and causes meningitis

Radiologic images: frontal ependymal cyst

Case reports: 15 year old boy with recurrent, intramedullary cyst at C2-C3 (Neurology India 2003;51:111-free full text)

Gross: resemble arachnoid cyst

Gross images: ependymal cyst

Micro: ciliated columnar cells with underlying fibrosis or fibrillary glia; may have ependymal-like cells or cilia; no mucin production

Micro images: cyst wall is lined by ependymal cells with focal multilayering

Positive stains: GFAP

EM: neuroepithelial origin

Epidermoid cyst

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Also called epidermoid or epidermoid tumor

More common than dermoid cyst (1% of intracranial masses)

Occurs at cerebellopontine angle, temporal lobe, spinal dura, pineal gland, sella, brainstem

Rarely undergoes malignant degeneration

Radiologic images: various images

Case reports: 68 year old man with cyst and sudden death (Am J Forensic Med Path 2002;23:368), woman with cerebellopontine angle cyst that degenerated into squamous cell carcinoma (Neurosurg 2002;97:1237)

Gross: well defined round mass has irregularly nodular capsule with pearly discoloration

Micro: fibrous wall lined by keratinizing squamous epithelium; contains squames but no skin adnexae and no hair

Micro images: fibrous wall with focal squamous epithelium but no skin adnexae

Cytology images: superficial squamous cells

Positive stains: CK8, CK20

DD: dermoid cyst, cystic craniopharyngioma (CK8-, CK20-)

References: eMedicine

Glial cyst

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Often in pineal gland

May cause hydrocephalus and sudden death

Case reports: 22 year old man with sudden death due to hydrocephalus from pineal gland cyst (J Clin Path 1996;49:267-free full text), 19 year old woman with thalamic glial cyst causing hydrocephalus due to hemorrhage (Neurol Med Chir (Tokyo) 1997;37:284)

Micro: wall lined by gliosis, Rosenthal fibers present, variable hemosiderin; no epithelial lining

Micro images: pineal gland cyst adjacent to midbrain; pineal tissue (left) and glial tissue (right)

Positive stains: GFAP

Meningeal cyst

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Also called diverticulum

Overlying hemispheres or in posterior or lateral epidural space in spinal canal

Radiologic images: various images (figures 1-9)

Micro: lined by fibrous tissue resembling dura, no arachnoid membrane

Micro images: fibrocollagenous layer without arachnoid

Neuroepithelial cyst

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Heterogeneous group of lesions with uncertain etiology

Brain and spinal cord, usually older adults

Rarely rupture and cause meningitis; may be associated with seizures or mass effect

Radiologic images: MRI shows large cerebral cyst

Case reports: neuroepithelial cysts of posterior fossa (Can Assoc Radiol J 1996;47:126), causing movement disorders (Can J Neurol Sci 2003;30:393), 4

Treatment: drainage, possibly with placement of drainage device to prevent recurrence

Micro: epithelioid surface with underlying fibrosis or fibrillary glia, but no obvious ventricular or subarachnoid connection

Pineal cyst

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May resemble a cystic tumor

Usually incidental finding present in 2-3% of adults, but may hemorrhage

Large cysts may compress aqueduct

Fine needle aspiration may provide rapid diagnosis (Cancer 2005;105:80)

Radiologic images: various images

Gross images: pineal cyst

Micro: resemble glial cyst; dense gliosis with Rosenthal fibers; may be pinker than surrounding pineal gland (with dark calcifications); may compress pineal tissue and make it appear hypercellular; no epithelial or mesenchymal features

Cytology: small, uniform polygonal cells

Micro images: cyst is separated from partially calcified normal pineal tissue by thick layer of gliofibrillary tissue with Rosenthal fibers #1; #2

DD: pilocytic astrocytoma; also (by Xray) - germ cell tumor, enterogenous cyst, epidermoid cyst, dermoid cyst

References: Ann Diagn Path 1997;1:11

Simple cyst

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Glial cyst in cerebellum

No communication with ventricles

Case reports: 42 year old man (J Neuroradiol 2001;28:209),

Micro: wall lined by gliosis, Rosenthal fibers present, no epithelial lining

Positive stains: GFAP

References: J Neuroradiol 1995;22:48

Syrinx

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Defined as a pathological cavity in the brain or spinal cord, especially in syringomyelia

Dissection of white matter of brainstem or spinal cord NOT continuous with ventricle or spinal canal, and not lined by ependymal cells

Usually from spinal cord (in surgical specimens)

Related to trauma, tumors or abnormalities of cranio-cervical junction

Gross images: syrinx in spinal cord

CNS Tumors

CNS Tumors-general

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13K deaths in US annually (2% of cancer deaths)

Peaks in childhood, then declines to age 25 years, then increases with age

Childhood tumors: 33% in anterior fossa (supratentorial), 67% in posterior fossa (astrocytoma-26%, medulloblastoma/PNET-24%, ependymoma-14%)

Adults: metastases are more common than primary brain tumors but are usually not biopsied; of biopsied tumors, 67% arise in anterior fossa (glioma-33%, meningioma-13%, metastases-12%, pituitary adenoma-5%), 33% in posterior fossa (schwannoma-8%, misc.-33%)

Most common spinal cord tumors are schwannoma, meningioma and ependymoma

Metastasis of primary CNS tumors outside CNS is rare, usually occurs along brain and spinal cord via subarachnoid space or due to surgery related implantation of tumor cells into vessels

Benign appearing tumors may still be infiltrative and difficult to resect

Tumors may arise from neural stem cells, precursors of neurons and glial cells, recently discovered in mature brain

Symptoms: focal deficits, seizures, increased intracranial pressure (due to mass effect, hydrocephalus, cerebral edema), herniation

Intra-axial: within brain and spinal cord

Extra-axial: not within brain and spinal cord (such as meningioma)

Supratentorial: above tentorial membrane - cerebrum

Infratentorial: below tentorial membrane - cerebellum, brainstem or spinal cord

Labeling index/proliferation index: percentage of MIB1+ or PCNA+ nuclei (compared to all nuclei), usually in regions of highest proliferation; useful prognostic indicator (high values associated with poorer prognosis)

Tumors-approach to diagnosis

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Factors to consider:

(1) Neoplasm: yes or no? Yes - hypercellular, composed of atypical fibrillar cells; if no, may be infectious, inflammatory, toxic-metabolic, traumatic, vascular, development or degenerative

(2) Primary or metastatic neoplasm?

(3) Glial, neuronal and other primary tumor considerations

(4) Correlate pathologic diagnosis with age, sex, location and imaging characteristics

Multiple lesions are often metastases, melanoma, medulloblastoma (late) or lymphoma

Differential diagnosis (adopted from Sternberg):

Fibrillar cells: fibrosis, granuloma, astrocytoma, astroblastoma, ependymoma, glioblastoma, gliosarcoma, ganglion cell tumor, central neurocytoma, pineocytoma, polar spongioblastoma, fibroblastic meningioma, MFH, schwannoma, neurofibroma, Langerhans cell histiocytosis, hemangioblastoma, melanoma

Epithelioid cells: xanthogranuloma or gitter cells, oligodendroglioma, choroid plexus tumor, medulloepithelioma, meningioma, chordoma, paraganglioma, pituitary adenoma, endodermal sinus tumor, embryonal carcinoma, hemangioblastoma, craniopharyngioma, metastatic carcinoma, melanoma

Conspicuously different cells: oligoastrocytoma, glioblastoma or gliosarcoma with epithelial metaplasia, ependymoma, ganglion cell tumor, desmoplastic medulloblastoma, transitional meningioma, germinoma, teratoma, choriocarcinoma, desmoplastic carcinoma, melanoma

WHO classification

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Extensively revised in 1993 (1993 classification; reference: Brain Pathol 1993;3:255)

Later revised in 2000 (J Neuropathol Exp Neurol 2002;61:215; WHO book is out of print but US National Cancer Institute has summary)

Neuroepithelial tumors: glial, neuronal, mixed glial-neuronal or nonglial

Glial tumors: astrocytic, oligodendroglial, mixed, ependymal, unknown origin

Glial tumors

Glioma-general

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Includes astrocytoma, ependymoma, glioblastoma, oligodendroglioma and various subtypes / combinations

“Glioma” may be used for frozen section, but is not a final diagnosis

Important to identify oligodendroglial component, due to effectiveness of chemotherapy for these gliomas

Most common CNS tumor

Presence of thrombosed vessels in tumors may predict postoperative systemic thromboses (J Neurosurg 1998;89:200)

Classification of gliomas:

Benign: does not recur; applies to pilocytic astrocytomas, certain gangliogliomas and ependymomas; may still have poor prognosis due to location that makes it difficult to resect completely

Low grade: may recur as high grade and kill patient

Gliomatosis cerebri: diffuse and extensive involvement of CNS associated rarely with gliomas; MRI and biopsy helpful for diagnosis

Micro: biopsies of tumor epicenter have cellularity greater than surrounding brain; biopsies of margin only are difficult to grade; often contain granular calcifications among hypercellular glia; also microcysts and mitotic figures (depending on tumor grade); may have uneven distribution of cellular density that obscures gray-white junction or spawns secondary structures of Scherer (subpial and perineuronal neoplastic glia)

Positive stains: GFAP

Negative stains: collagen, reticulin, fibronectin

Exceptions:

Oligodendroglioma cells have variable GFAP and are Leu7+ and S100+

Xanthoastrocytomas are reticulin+

DD: gliosis (even distribution of cellular density, contracts instead of expanding near hypercellular glia; usually less pleomorphism, no nuclear hyperchromasia, no nuclear cluster formation, no nuclear molding, no mitotic figures, no calcifications)

Post-radiation glioma

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Often 5-25 years after treatment of pituitary adenoma or craniopharyngioma

In children, often follows treatment for acute lymphoblastic leukemia

Usually anaplastic astrocytoma or glioblastoma

Case reports: 48 year old woman with gliosarcoma arising from irradiated anaplastic ependymoma (Hum Path 2004;35:512), arising 11 years after prophylactic brain radiation and intrathecal methotrexate for ALL at age 3 years (Childs Nerv Syst 1988;4:296)

References: Tumori 1994;80:220

Astrocytic tumors

Astrocytic tumors-general

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Most fibrillar of CNS tumors; other fibrillar tumors are tanycytic ependymoma and subependymoma

Low grade astrocytomas resemble gliosis

Affect entire CNS

Usually young adults

Most common primary brain tumor in children

Indicate the grading system used

Brainstem: 20% of primary brain tumors age 20 years and less are astrocytomas; 50% progress to glioblastoma at autopsy

Gross images: mass effect; brainstem glioma #1; #2; infiltrative margin

Micro: hypercellular; nuclei are angular and indent each other; infiltrative margins; often microcystic degeneration (easier to recognize on unfrozen tissue; on frozen section, microcysts contain protein)

Micro images: hypercellular tumor with infiltrative margin (left) vs. normal brain (right)

Positive stains: GFAP (variable)

Cystic astrocytoma

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Not a specific subtype, but a group of entities with similar gross features

Usually low grade unless cysts contain necrotic material

Macroscopic cysts are associated with cerebellar pilocytic astrocytoma

DD: hemangioblastoma

Granular cell astrocytic neoplasms

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Rare morphologic variant of astrocytoma and glioblastoma (not a separate WHO designation)

A degenerative change (AJSP 1996;20:55), not a distinct genetic subtype (Brain Path 2003;13:185)

More aggressive than non granular cell tumors, usually fatal (AJSP 2002;26:750)

Case reports: granular cell appearance due to Rosenthal fibers (Acta Neuropathol (Berl) 1993;86:100)

Micro: prominent population of atypical granular cells (large, round with eosinophilic, PAS+ granules, eccentric nuclei), often with transition to a classic infiltrating glioma; often lymphocytic infiltrate or macrophages

Positive stains: PAS (diastase resistant), S100, GFAP, intercellular reticulin; CD68, EMA and ubiquitin are due to lysosomes

EM: cytoplasmic granules are lysosomes, some autophagic

DD: neuroendocrine tumors, histiocytic lesions, demyelinating disease, infarctions

References: Semin Diagn Pathol 1999;16:91 (review), Clin Neuropathol 2000;19:170, Neuropathol Exp Neurol 1986;45:447 (granular cell glioblastoma), Hum Path 1993;24:805 (granular cell anaplastic astrocytoma)

WHO grading of astrocytomas (2000)

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1: pilocytic - circumscribed, biphasic, bipolar and multipolar cells, Rosenthal fibers, microcysts, granular bodies; no/rare mitotic figures, no/rare vascular proliferation, no/focal necrosis

2: diffuse - moderately hypercellular, monotonous cells, mild nuclear atypia, no/minimal mitotic activity

3: anaplastic - increased cellularity and diffuse infiltration, increased nuclear atypia, increased mitotic activity

4: glioblastoma - vascular proliferation, necrosis, crowded anaplastic cells, marked nuclear atypia, brisk mitotic activity

Pilocytic astrocytoma-grade I

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Pilocytic means “hair like”, due to long, bipolar processes

Most common CNS neoplasm of childhood; incidence of 1/100K; peak age 8-13 years

Better prognosis than diffuse types, particularly if resectable (such as cerebellar tumors)

May be multicentric

Usually involves midline structures in posterior fossa including cerebellum; also third ventricle, thalamus, hypothalamus, neurohypophysis

10 year survival is 100% if supratentorial and gross total resection vs. 74% if subtotal resection

Invasion of subarachnoid space and endothelial proliferation are not poor prognostic factors

Treatment: resection; radiation and chemotherapy for tumors of optic pathway and hypothalamic region; rarely recurs or disseminates

Gross: microcystic or macrocystic; may have mural nodule

Gross images: cerebellar tumor; optic nerve tumor

Micro: bipolar neoplastic cells with elongated hairlike processes that are arranged in parallel bundles and resemble mats of hair; Rosenthal fibers, often associated with eosinophilic protein droplets (resembling foamy macrophages); may have microscopically infiltrative margin; mural nodule may be highly vascular; often calcifications

Rarely malignant degeneration with hypercellularity, mitotic figures and necrosis

Micro images: bipolar cells with Rosenthal fibers #1; #2; #3; various images with case history #1; #2 (with disseminated tumor)

Cytology images: bipolar long astrocytic processes and central Rosenthal fiber

Positive stains: GFAP (strong), PTAH, PAS (protein droplets), alpha-1-antichymotrypsin (protein droplets)

DD: gliosis, hemangioblastoma (cells appear fibrillar on frozen section)

References: Radiographics 2004;24:1693 (review; free full text); Br J Neurosurg 2004;18:613 (adults)

Diffuse astrocytoma-grade II

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Fibrillary, protoplasmic and gemistrocytic (see below) subtypes are called diffuse, but fibrillary is more common

80% of adult primary brain tumors; usually cerebrum, but can be anywhere in CNS

Age 40+ years

May become more anaplastic over time

Grade of small biopsies may not be representative

Median survival is 6-8 years, but rarely has rapid progression and death

Treatment: surgery; average survival is 7 years with wide variability

Poor prognostic factors: high Ki-67, p53, brainstem location

Radiology: mass effect, peritumoral edema

Micro: fibrillary cells contain cellular fibrillar processes and nuclei with greater angularity and density than normal CNS, also intracytoplasmic fibrils and longer cell processes than protoplasmic astrocytomas; microcysts are particularly prominent in protoplasmic subtype, may degenerate into macrocysts; margin gradually diminishes in cellularity and intermingles with normal CNS; may form secondary structures of Scherer

Micro images: smear shows neoplastic astrocytes with cytoplasmic glial processes and variable nuclear atypia; well differentiated tumor, HAM56 negative (no macrophages)

Positive stains: PTAH (fibrillary subtype), GFAP (fibrillary and protoplasmic subtypes)

DD: gliosis, oligodendroglioma (round nuclei with perinuclear halos, chicken wire vessels, mineralization, GFAP negative)

Protoplasmic astrocytoma-grade II

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Rare; 3-4% of supratentorial brain tumors

Variant of diffuse astrocytoma; WHO considers a variant of grade II astrocytoma

Mean age 21 years, often with long history of seizures before diagnosis, male predominance

Often in temporal and frontal lobes

Thought to derive from process-poor protoplasmic astrocytomas

Generally a benign clinical course after resection

Micro: proliferation of glial cells with few cytoplasmic processes; round/oval nuclei, microcystic background, no/rare mitotic figures; no vascular proliferative changes, no necrosis

Micro images: scant or vacuolated cytoplasm with short processes, vesicular nuclei and prominent nucleoli; GFAP+

Positive stains: GFAP (focal/weak or negative)

Negative stains: Ki-67 (<1% staining)

Molecular: no 1p-

DD: microcystic oligodendroglioma (1p-), dysembryoplastic neuroepithelial tumor (associated with cortical dysplasia, usually multifocal or multinodular)

References: Hum Path 2004;35:317, Am J Clin Path 1995;103:705

Gemistocytic astrocytoma-grade II

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Variant of diffuse astrocytoma

May be more aggressive than other grade II astrocytomas (J Neurooncol 2005 [Epub ahead of print], J Neurosurg 1991;74:399)

Restrict diagnosis to cases with at least 20% gemistocytic cells

Case history: congenital brain tumor with various images

Gross images: frontal lobe tumor

Micro: conspicuous (20% of more) gemistocytes (plump cells with abundant, hyaline pink cytoplasm and no/minimal blue Nissl substance, hyperchromatic and angular nuclei at border of cell), perivascular lymphocytic cuffs; infiltrative margins; no neoplastic neurons

Micro images: astrocytes with abundant eosinophilic cytoplasm #1; #2 (arrow points to angulated cytoplasm); #3; #4; #5 (with above case history); GFAP; vimentin

Positive stains: GFAP, vimentin

Molecular: p53 mutations in 82% (Acta Neuropathol (Berl) 1998;95:559)

DD: gliosis (uniform nuclear size, no atypia), astrocytoma with gemistocytes (<20% gemistocytes), ganglioglioma (has neoplastic neurons), subependymal giant cell tumor (larger nuclei, non-infiltrative), oligodendroglioma, anaplastic oligodendroglioma (small cells with small round nuclei)

Anaplastic astrocytoma-grade III

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Rarely associated with hereditary colonic polyposis or neurofibromatosis

Mean survival is 2 years

Case reports: seeding along tract of stereotactic needle (J Neurooncol 2003;61:215), disseminating brainstem tumor resembling an inflammatory process (Hum Path 2005;36:854)

Micro: mitotic figures are part of definition; also have increased cellular density (average distance between a nucleus and its nearest neighbor that it is not actually touching is less than average nuclear diameter), increased nuclear pleomorphism, increased nuclear hyperchromasia; may have individual cells with pyknotic nuclei but no coagulation necrosis or microvascular proliferation (seen in glioblastoma); macrophages often present

Cytology: irregular clusters of tumor cells with scanty ill-defined cytoplasm and fibrillary processes, oval hyperchromatic nuclei; may not see mitotic figures

Micro images: anaplastic astrocytoma #1; #2; #3; H&E and HAM56+ macrophages; p53

Molecular: 19q- in 40%; also p53 mutations

DD: anaplastic oligodendroglioma (may have necrotic foci), ependymoma (perivascular pseudorosettes and true ependymal rosettes)

References: Semin Oncol 2004;31:618 (review), Neurol India 2003;51:276 (cytologic diagnosis-free full text)

Glioblastoma multiforme-grade IV

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Undifferentiated glioma, with possible focal astrocytoma

“Multiforme” due to firm white areas, yellow necrotic areas, hemorrhagic areas and cystic areas

12-15% of adult intracranial tumors, 50-60% of astrocytic neoplasms

Either due to progression from lower grade glioma (often with partial #10 deletion) or de novo with p53 mutation

Usually supratentorial; uncommon in cerebellum, rare in spinal cord

May not be diagnosable on small biopsies

Median survival is 1 year; 5 year survival is <5%; survival may be overstated due to low grade tumors that dedifferentiate to glioblastoma (Cancer 2003;98:1745)

Case reports: giant cell variant with recurrence 8 years later as gliosarcoma (Childs Nerv Syst 2005 Aug; [Epub ahead of print]), cerebellar tumor presenting as gliomatosis cerebri that transformed to glioblastoma (J Neurosurg 2005;102(1 Suppl):72)

Gross: fast growing tumors may have apparent pseudocapsule; usually solitary although may cross midline through corpus callosum, massa intermedia or anterior commissure to produce a “butterfly” lesion; often peritumoral edema

Gross images: cerebral tumor; variegated tumor with necrosis and hemorrhage

Micro: high grade astrocytoma (anaplastic, fibrillar astrocytes) with either coagulation necrosis or microvascular proliferation (formerly “endothelial proliferation”; with thickened vascular walls due to endothelial cell hyperplasia [increase in nuclei in vessel wall] and hypertrophy; also formation of multiple lumina resembling glomerulus); usually hypercellular with mitotic figures (some atypical), multinucleated tumor cells, bizarre nuclei, karyorrhectic cells; may have perinecrotic pseudopalisading of tumor cells around necrotic tumor, secondary structures of Scherer; often coexisting Alzheimer’s disease (Archives 2002;126:1515); often macrophages (Archives 2001;125:637)

Note: examine carefully to determine if low grade tumor also present, suggesting dedifferentiation

Micro images: (1) prominent anaplasia, vascular proliferation and palisading of tumor cells around necrosis #1; #2; (4) anaplastic cells; (6) palisading of cells around necrotic area; (8) various vascular patterns; (10) H&E and HAM56+ macrophages

Cytology images: (1) neoplastic astrocytes with cytoplasmic processes, nuclear atypia and mitotic figures; (2) tufts of vascular proliferation resembling glomeruli; (3) necrosis

Virtual slides: glioblastoma multiforme #1; #2

Positive stains: GFAP, AE1-AE3 (>95%), p53; beta III tubulin, reticulin deposition

Negative stains: CAM5.2, CK7, CK20, BerEP4

Molecular: amplification of EGFR (particularly in small cell variant), mutations of p16, p53 and PTEN; loss of heterozygosity at 10q

DD: malignant meningioma (may contain entrapped GFAP+ glia), metastatic carcinoma (GFAP-, CAM5.2+)

References: Clin Neuropathol 2005;24:163 (CISH to evaluate EGFR amplification in small cell variant), Archives 1999;123:917 (epithelial markers), Hum Path 2005;36:1008 (cystatin C)

Giant cell variant

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5% of glioblastomas

Also affects younger individuals

May have better prognosis than classic glioblastoma

Micro: abundant, bizarre-appearing tumor giant cells, many multinucleated; extensive necrosis, brisk mitotic activity

Micro images: staining vs. pleomorphic xanthoastrocytoma

Positive stains: GFAP, p53

Molecular: p53 mutations in 75-90%, PTEN mutations in 1/3; EGFR amplification is rare

DD: pleomorphic xanthocytoma (more superficial, no/minimal necrosis, no/rare mitotic activity)

References: Archives 2003;127:1187

Pediatric nonbrainstem glioblastomas

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3% of CNS tumors in childhood

Five year survival of 18% or less

Loss of 10q23 (PTEN locus) by FISH is associated with poorer survival (Mod Path 2005;18:1258)

Molecular: polysomy 7 (72%), 10q23- (61%), 9p21- (52%), 1p36- (41%), 1q25+ (25%), polysomy 9 (16%), EGFR amplification (9%), 19q13- (5%), polysomy 19 (5%)

Gliosarcoma-grade IV

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WHO classification includes within glioblastoma

Rare; biphasic CNS tumors with mixture of glioblastoma and sarcoma

May be well circumscribed and resemble meningioma radiologically

May progress to pure sarcoma (GFAP-)

Rarely expresses epithelial markers and lipid

Case reports: 48 year old woman with gliosarcoma arising from irradiated anaplastic ependymoma (Hum Path 2004;35:512); with multifocal, extensive areas of well differentiated carcinoma but with similar cytogenetics, suggesting common origin of both types (Mod Path 2004;17:739), mixed cystic tumor and PNET (Clin Neuropathol 2004;23:218), 80 year old with cerebellar tumor (Archives 2003;127:e345), with malignant fibrohistiocytic, osseous and chondroid elements (Archives 1999;123:358).

Micro: glioblastoma (occasionally oligodendroglioma, rarely ependymoma) plus regions of sarcoma resembling fibrosarcoma or malignant fibrous histiocytoma, rich in reticulin (collagen+, GFAP-)

Cytology: highly cellular; high grade tumor with mesenchymal and glial components; mesenchymal features may be fibrosarcoma, rhabdoid, osteoclastic giant cell, undifferentiated or heterologous elements; rich arborizing vessels, high mitotic rate, necrosis; glial component has pleomorphic round/oval nuclei, gemistocytes in fibrillary stroma (Diagn Cytopathol 2004;30:77)

Micro images: various images #1; #2 with stains; reticulin stain; gliosarcoma with carcinomatous areas

Positive stains: p53 (Arq Neuropsiquiatr 2004;62:608-free full text and images)

DD: glioblastoma with desmoplasia

Pleomorphic xanthoastrocytoma

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WHO grade II; first described in 1979 (Cancer 1979;44:1839)

Rare supratentorial tumor of children and young adults; often involves leptomeninges and cerebral cortex, particularly temporal lobe

Associated with intractable seizures

15-20% progress to malignancy

May be a developmental neuroglial tumor with prominent glioproliferative changes associated with focal cortical dysplasia (J Neurooncol 2004;66:17)

Radiology: large, well circumscribed mass with solid and cystic components or a cyst within a mural nodule

Treatment: gross total resection usually eliminates seizures

Case reports: 49 year old man with seizures (Archives 2003;127:e307), 43 year old woman with rare anaplastic variant initially diagnosed as melanoma (Neuropathology 2005;25:241), 32 year old man whose tumor had pigmented melanotic cells (Archives 2001;125:808), 60 year old man with coexisting ganglioglioma in cerebellum (Archives 2000;124:1707)

Micro: mixture of unusually pleomorphic cells, including neoplastic fibrillar astrocytes (some foamy with lipid), large bizarre forms with multinucleated giant cells and smaller spindle cells; abundant reticulin deposits, chronic inflammatory cells; variable hemorrhage and protein granular degeneration (similar to pilocytic astrocytoma); no necrosis and no mitotic activity, except in tumors “with anaplastic features”

Micro images: (1) pleomorphic cells and cells with lipid #1; #2; #3; #4; (7) GFAP; (8) figure 1: eosinophilic granular bodies (arrows); 2: Rosenthal fibers; 3: atypical cells with granular or foamy cytoplasm and atypical nuclei with pseudoinclusions (arrowhead) and mitotic figures (arrows); 4: multinuclear giant cells with tumor necrosis and nuclear palisading and focal vascular proliferation (arrows; (9) various images/stains in pigmented tumor; (10) staining vs. glioblastoma-giant cell variant

Positive stains: GFAP (100%), S100 (100%), reticulin, class III beta tubulin (73%); neuronal nuclear antigen, neurofilament, often synaptophysin (38%) and CD68

Negative stains: chromogranin, p53 (or focal)

EM: tumor cells are surrounded by basal lamina; neuronal features of microtubules, dense core granules

References: AJSP 2002;26:479 (immunostains), Archives 2003;127:1187 (immunostains)

Subependymal giant cell astrocytoma

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WHO grade I

Usually associated with tuberous sclerosis, an autosomal dominant syndrome of (a) cortical hamartomas/tubers, (b) benign neoplasms (pulmonary and uterine lymphangiomyomatosis, renal angiomyolipoma, cardiac rhabdomyoma), (c) mental retardation and seizures; due to mutations in TSC1 gene on #9q34 (hamartin protein) and TSC2 gene on #16p13.3 (tuberin protein); these tumors are present in 6% of tuberous sclerosis patients

Arises from medial floor of lateral ventricle (site of candle gutterings, subependymal nodules of giant astrocytes)

Grows into lateral ventricle, may obstruct foramen of Monro

Radiologic images: various images

Case reports: 20 year old woman with solitary subependymal giant cell astrocytoma and mutation of TSC2 gene in tumor but not in somatic cells (J Mol Diagn 2005;7:544)

Gross images: tumor of lateral ventricle

Micro: giant astrocytes with abundant, finely granular eosinophilic cytoplasm, large round/oval nuclei and prominent nucleoli; also bright pink cellular processes; may form disoriented fascicles; variable necrosis, endothelial proliferation (often hyalinized or calcified) and mitotic figures; no Nissl substance in cytoplasm

Micro images: large cells with abundant cytoplasm and prominent nucleoli #1; #2; various images

Cytology images: large neoplastic cells with glial and neuronal features

Positive stains: GFAP (variable)

Negative stains: HMB45 (unlike other tuberous sclerosis related lesions)

Oligodendroglial tumors

Oligodendroglioma-grade II

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5-15% of gliomas

Frontal and temporal lobes of middle-aged adults

Patients usually present with seizures

Mean age 42 years (grade II tumors) or 48 years (grade III tumors); 6% occur in infancy/childhood

Pure or mixed with astrocytoma

Rarely invades or originates from dura or adenohypophysis

Usually in cerebral white matter

Metastases are rare; may be associated with delayed or multiple surgery and shunts; usually to bone (75%), cervical lymph nodes (50%), lung or pleura (33%)

Slow growing tumors; mean survival 5 years

Treatment: surgery; combination chemotherapy is helpful

Case reports: 33 year old man with metastases to bone marrow (Archives 2004;128:489)

Gross: more circumscribed than astrocytoma

Gross images: oligodendroglioma

Micro: pure tumors are epithelioid not fibrillar, particularly centrally; tumor cells have perinuclear halo surrounding central, regular and round nuclei (resemble fried egg); may be diffusely infiltrative; fine capillary network resembles chicken wire and has focal calcification, may segregate tumor cells into small lobules; frequent perineuronal gliomatosis; may contain microgemistocytes (nuclei with clumped and marginated chromatin, slightly larger than normal oligodendroglia but smaller than gemistocytic astrocytoma nuclei, GFAP+ short processes); may have limited microvascular proliferation

Cytology: cells with monotonous nuclei, somewhat unclear cytoplasm, long cytoplasmic processes; background granular matrix

Micro images: uniform cells with clear cytoplasm #1; #2; #3; #4; various images; metastatic tumor - figure 1:H&E; 2:GFAP+; 3A/3B:primary tumor

Cytology images: oligodendroglioma

Virtual slides: oligodendroglioma

Note: perinuclear halos are artifacts due to fixation, and are not present in frozen sections

Positive stains: Leu7, S100, MAP2 (strong); variable GFAP

Negative stains: EMA, chromogranin, pituitary hormones

Molecular: 1p-, 19q- are common (50-80% of tumors); associated with favorable response to chemotherapy and longer survival

EM: abundant plasma membrane forms concentric layers mimicking myelin

DD: meningioma (EMA+, does not diffusely infiltrate brain parenchyma, Leu7 negative), pituitary adenomas (chromogranin+, pituitary hormone+), hemangioblastomas (no calcifications), central neurocytoma (more fibrillar), clear cell ependymoma (more fibrillar)

References: Archives 2003;127:1573 (molecular), Mod Pathol 2003;16:708 (FISH), eMedicine

Anaplastic oligodendroglioma-grade III

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Also called malignant oligodendroglioma

3.5% of adult supratentorial malignant gliomas

Mean age of onset is 48 years

Mean survival is 4 years

Tumors with 1p- are particularly sensitive to chemotherapy

Metastasizes to bone marrow

Case reports: metastases to bone marrow (Archives 2004;128:489), 9 year old boy with disseminated tumor via CSF resembling inflammatory process (Hum Path 2005;36:854)

Micro: compared to grade II, have increased cellularity, nuclear atypia, mitotic activity and necrosis; extensive capillary network usually present

Cytology: hypercellular, with loosely cohesive and single cells, moderate pleomorphism, vacuolated background, mitotic activity (Acta Cytol 2003;47:293); bone marrow touch preparations resembles acute leukemia

Micro images: (1) classic and anaplastic oligodendroglioma; (2) anaplastic focus; (3) various images; (4) bone marrow metastasis - figure 1: granular eosinophilic cytoplasm with eccentric nuclei and increased N/C ratio; 2: GFAP+; 3: primary tumor

Cytology images: oligodendroglia type cells with mild pleomorphism and mitotic figure

DD: metastatic carcinoma (renal cell carcinoma, usually no calcifications), leukemia (Acta Cytol 2003;47:467), small cell astrocytoma (Cancer 2004;101:2318), liponeurocytoma (Br J Neurosurg 2004;18:300)

Mixed gliomas

Oligoastrocytoma and anaplastic oligoastrocytoma

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Chemotherapy may not be as helpful as with pure oligodendrogliomas

Diagnosis requires conspicuous oligodendroglioma (MAP2+) and astrocytoma (GFAP+) components

Grade II tumors may transform to grade III tumors, which have more cellularity, nuclear atypia, mitotic figures and pleomorphism

Grade III tumors may resemble glioblastoma (microvascular proliferation or necrosis in astrocytic component)

DD: foamy macrophages (vs. oligodendroglioma with central, neoplastic nuclei, single large perinuclear halo)

Ependymomal tumors

Ependymoma

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WHO grade II if conventional, grade III if anaplastic, grade I if myxopapillary or subependymoma

Arise in ventricles (lined by ependyma) in cerebrum or brainstem, including spinal cord remnant of central canal

3-9% of primary CNS tumors, more common in children/young adults

Glial (GFAP+) and epithelial (true rosettes) derivation

Age 0-20 years: common in fourth ventricle (5-10% of primary brain tumors)

Adults: common in spinal cord; better able to excise completely and generally better prognosis at this site

Cause hydrocephalus from obstruction if in posterior fossa

Poor prognosis due to CSF dissemination (average survival 4 years with surgery and radiation) and inability to excise completely (near pontine and medullary nuclei)

Poor prognostic factor: radiologic residual disease after surgery; higher Ki-67 indices (>20.5%) associated with slightly poorer outcome (AJSP 2004;28:914); for pediatric intracranial tumors, either (a) subtotal resection with tumor p53+ or MIB+ > 5% or (b) complete resection with MIB > 15% in hypercellular areas (Mod Path 2003;16:980)

Treatment: gross total removal of tumor, often is difficult

Case reports: giant cell ependymoma of fourth ventricle (Case of Week #208), giant cell ependymoma of filum terminale (AJSP 1996;20:1091), melanotic ependymoma #1 (AJSP 1990;14:729); #2 (Archives 2003;127:872), collision tumor with malignant triton tumor (Archives 2001;125:1113), cauda equina tumor with features of ependymoma and paraganglioma (Hum Path 1992;23:835)

Gross: may have discrete margin from surrounding brain or spinal cord; grows exophytically into fourth ventricle

Gross images: tumor arising from floor of fourth ventricle #2; #3; #4

Micro: solid or papillary, composed of small blue fibrillar to epithelioid cells with granular chromatin; form perivascular rosettes and less commonly ependymal rosettes; nuclei are round/oval, with prominent light and dark regions, childhood tumors have delicate uniform, lateral, longitudinal and eccentric grooves or clefts extending at least half the nuclear diameter (Archives 1994;118:919); nuclear crowding away from rosettes is more than astrocytoma and less than medulloblastoma/PNET

Ependymal rosettes: formed by ependymal cells resembling cells of embryonic ependymal canal with long, delicate processes extending into a lumen formed by ends of processes; cilia or microvilli may protrude into lumen; lumen may be round or oval, does not have a hypereosinophilic border; ependymal cells are evenly spaced; rosettes associated with ependymoma, but not always present

Homer-Wright (pseudo) rosettes: also called pseudorosettes; fibrillary rosettes with cellular processes in their centers and no lumen; seen in Ewing’s/PNET, medulloblastoma, pineoblastoma, neuroblastoma

Flexner-Wintersteiner rosettes: like ependymal rosettes, but lumen has hypereosinophilic border, composed of cytoplasmic processes resembling photoreceptors and acid mucosubstances; seen in retinoblastoma, occasionally pineoblastoma

Perivascular (pseudo) rosettes: ependymal cell processes directed towards vessel wall, processes become thinner as they extend around blood vessel; more common than ependymal rosettes in ependymoma, but also present in glioma

Micro images: (1) perivascular pseudorosettes #2; #3; #4; #5; (6) ependymal rosettes; (7) canal lined by ependymal cells; (9) pigmented tumor; (10) various gross/micro images

Cytology images: distinct and well organized papillary structures #1; #2

Positive stains: GFAP, vimentin; rarely cytokeratin and EMA

Negative stains: no reticulin or type IV staining fibrils in ependymoma aggregates

EM: EM is necessary to differentiate ependymoma from glioma if rosettes not present; perivascular rosettes, abnormal cilia, intracytoplasmic lumina with variable microvilli and cilia, basal bodies, microvillous inclusions; perinuclear intracytoplasmic intermediate filaments, long junctional complexes; no basement membrane in aggregated ependymoma cells

EM images: (1) interacting cell processes, irregularly contoured nuclei; (2) membrane junctional complex and microrosette; (3) pigmented tumor shows electron dense bodies

Molecular: #22 deletions in 30-70%; inactivation of NF2 or loss of expression of protein in 29-38% of spinal tumors; alterations in protein 4.1 family members is common; loss of 4.1B and 4.1R deletions more common in childhood, intracranial and anaplastic tumors; 4.1G deletions associated with more aggressive disease (Mod Path 2005;18:991, Mod Path 2002;15:526)

DD: glioma (no rosettes, lack cell-cell junctions and intracytoplasmic microvilli-lined lumina)

References: eMedicine, cytogenetics

Clear cell ependymoma

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Uncommon

Usually supratentorial

Age 3-31 years in one study (AJSP 1997;21:820)

Behave similar to classic ependymoma; overall survival of 75% at 5 years

May have extraneural metastases and early recurrence

Case studies: 24 year old woman with intraventricular mass and giant cells, 59 year old man with spinal tumor composed of clear and foamy cells (Neurol Res 2003;25:324), anaplastic supratentorial tumor (J Med Assoc Thai 2004;87:829), tumor of medulla oblongata (Pathol Int 2003;53:297), intramedullary tumor of spinal cord (Neurosurgery 2000;47:1434)

Gross: well demarcated, deeply situated masses; may be dark red or resemble cyst with mural nodule

Micro: noninfiltrative growth, tumor cells have rounded nuclei with perinuclear clear halos and focal perivascular pseudorosettes; may have anaplastic features; often abundant blood vessels

Micro images: above case history with giant cells

Positive stains: GFAP, vimentin, EMA (membrane staining including ring-like)

Negative stains: neuroendocrine markers

EM: features of ependymoma; EM recommended for diagnosis of this variant; shows complex intercellular junctions, surface microvilli and cilia and microrosettes; no secretory granules, no vesicles, no synapses

Molecular: no deletions of 1p, 19q or NF2

DD: oligodendroglioma (vimentin+, EMA+ in cytoplasmic dot-like pattern), central neurocytoma (anti-NEUN+, synaptophysin+), hemangioblastoma (Surg Neurol 1999;51:281)

References: Cancer 2003;98:2232, Neuropathology 2004;24:330, Acta Neuropathol (Berl) 2004;108:24 (stains), Virchows Arch A Pathol Anat Histopathol 1989;415:467

Epithelioid ependymoma

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Not a WHO recognized distinct variant

May have distinct margin with CNS parenchyma resembling nonglial neoplasms

Micro: tightly clustered epithelioid cells resembling multinucleated giant cells in myxoid background; no perivascular pseudorosettes or true rosettes

Positive stains: GFAP (highlights fibrillary processes), vimentin, EMA (variable dot like cytoplasmic staining)

Negative stains: keratin

EM: ependymal features of extensive surface microvilli, some junctions, lumina with microvilli

DD: carcinoma, pituitary adenoma, craniopharyngioma, meningioma

References: Neurosurgery 2003;53:743

Papillary ependymoma

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Rare; resembles choroid plexus papilloma

Case reports: 10 year old girl with cerebral mass and hydrocephalus

Micro: solid regions of ependymoma with growth of tumor cells on each other, not on fibrovascular stroma

Micro images: papillary ependymoma; EMA and GFAP

Positive stains: GFAP, reticulin (accentuates pattern), vimentin, EMA

EM: frequent intercellular microrosettes, microvilli, cilia, zonulae adeherentes

References: J Korean Med Sci 1996;11:415 (free full text)

Tanycytic ependymoma

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Grade II of IV

Within brain or spinal cord (often cervical) parenchyma

Tanyctes are common progenitor cells of both ependymal cells and astrocytes; are elongated, unipolar or bipolar, extend from ventricular lumen to surface of nervous system

Important to distinguish from diffuse astrocytomas, which usually cannot be totally excised

Treatment: gross total excision and radiologic surveillance for recurrence

Case reports: 58 year old man with spinal tumor associated with hematomyelia (Neurol Med Chir (Tokyo) 2005;45:168, free full text), associated with neurofibromatosis 2 (Neurol Med Chir (Tokyo) 2001;41:513-free full text, Clin Neuropathol 2001;20:93), 39 year old woman with cervical intramedullary tumor (Neurochirurgie 2003;49:605), 55 year old woman with intraventricular tumor (J Neurooncol 2005;71:189)

Micro: fibrillar variant of ependymoma; discrete margin with surrounding tissue; features of ependymoma and astrocytoma; elongated spindle cells with round/oval nuclei with distinctly light and dark regions of chromatin (similar to ependymoma) and marked fibrillarity (similar to astrocytoma); have nuclear dense zones and fibrillary zones resembling Verocay bodies, but larger and less linear; rare pseudorosettes

Cytology: cells with long, bipolar glial processes and oval nuclei; may be no pseudorosettes; resembles pilocytic astrocytoma or schwannoma (Diagn Cytopathol 2001;24:289)

Micro images: page 515, within PDF file

Positive stains: GFAP, S100, vimentin

EM: recommended if diagnosis is in doubt; characteristic ependymal features including intracytoplasmic intermediate filaments, prominent intercellular junctions, numerous slender surface microvilli, microvilli lined lumina (Ultrastruct Pathol 1997;21:135)

DD: schwannoma, astrocytoma

References: Acta Neuropathol (Berl) 2001;101:43

Anaplastic ependymoma

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See also ependymoblastoma

Grade III of IV

Rare; usually infants and children

Often cerebrum or cerebellum of children / young adults, but all ages and locations

Infiltrates leptomeninges, spreads along CSF pathways like medulloblastoma

Case reports: 27 year old woman with headaches, supratentorial tumor with giant cells (Mod Path 1998;11:398), 48 year old woman with gliosarcoma arising from anaplastic ependymoma (Hum Path 2004;35:512)

Micro: marked hypercellularity, nuclear atypia and brisk mitotic activity; may have intramural or glomeruloid vascular proliferation, perivascular rosettes; discrete or infiltrative margin; necrosis or pseudopalisading necrosis are not sufficient for diagnosis in otherwise low grade ependymoma

Micro images: focally hypercellular tumor with perivascular pseudorosettes; various images #1; #2

Myxopapillary ependymoma

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Grade I of IV (WHO), but some are aggressive with seeding of CNS (J Neurosurg 2005;102(1 Suppl):59), multiple local recurrences and death

Occur in filum terminale, cauda equina, sacrum and adjacent soft tissue; intracranial primaries (Neurosurgery 2004;55:981) and metastases are rare

2/3 male, mean age 36 years

May bleed into CSF

Radiologic images: intradural extramedullary mass; tumor of filum terminale

Case reports: Case of Week #111, 48 year old woman with back pain (Archives 2004;128:811)

Treatment: gross total resection may be the most predictive factor for outcome (Clin Neuropathol 2008;27:21); incomplete removal may cause local or widespread dissemination and distant metastases

Gross: encapsulated and easily resected or adherent to surrounding tissue and difficult to resect

Gross image (on telfa pad): image

Micro: myxopapillary appearance with bland oval ependymal cells surrounding pseudopapilllary structures of myxoid material, with occasional central vessels; neoplastic cells may also appear elongated with a glial quality; epithelial cells are well differentiated cuboidal to low columnar surrounding a core of hyaline acellular connective tissue with small blood vessels; may be highly myxoid with cords of cells in mucoid matrix resembling chordoma; may be highly fibrous resembling fibrous meningioma or schwannoma; usually no atypia

Myxopapillary ependymoma (continued)

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Cytology: nests and aggregates of epithelioid malignant cells surrounding hyaline globules and branching cords of myxohyaline material

Micro images: papillary structures with core of acellular hyaline material; various images #1; #2; #3; #4; #5; #6; #7; GFAP; gross image from case history; papillary tumor composed of rosette-like structures surrounding a mucoid area with central vessels; radiographs, gross and micro images

Cytology images: papillary structures composed of bland round cells in magenta matrix

Positive stains: GFAP, mucin (PAS or Alcian blue, including vessel walls), vimentin, S100 (50%)

Negative stains: cytokeratin

EM: basal bodies and cilia are present but may be difficult to find; resembles choroid plexus with cells containing nonciliated intracytoplasmic lumina or abnormal arrays of microtubules

DD: chordoma (cords and lobules of physaliphorous cells, keratin+, GFAP-), meningioma (mucin-, GFAP-), schwannoma (mucin-), carcinoma (GFAP-), paraganglioma (cells are more uniform and epithelial and rest on capillary walls, salt and pepper chromatin pattern; secretory granules+, mucin-, GFAP-)

References: Radiographics 2006;26 Suppl 1:S111

Subependymoma

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Grade I of IV; benign behavior

Affects middle-aged to elderly adults, occasionally children

Usually occurs in the fourth ventricle or lateral ventricles, where it is often an incidental finding at autopsy, or in the spinal cord, where it presents as a myelopathy

Cell of origin unknown, but resembles subependymal tissue

Slow growing; 50% have symptoms (associated with larger size or specific locations (J Neurosurg 1978;49:689)

MRI image: intraventricular mass

Case reports: Case of the Week #75, 65 year old woman with ventricular mass, recurrent tumor of temporal horn (J Neurooncol 2003;62:315), spinal cord tumors (Neurol Med Chir (Tokyo) 2002;42:349, Br J Neurosurg 2004;18:548, Pathol Int 2003;53:169)

Treatment: excision is usually curative, occasionally radiation therapy

Gross: well circumscribed, solid, gray-white, sometimes calcified, protrudes into lateral ventricle or 4th ventricle

Micro: clumps of ependymal type cells in dense, fine, glial fibrillary background; mild nuclear pleomorphism, microcystic formations; may be occasional ependymal rosettes; resembles tanycytic ependymoma; no necrosis, no endothelial proliferation

Classify as mixed ependymoma-subependymoma (grade II of IV) if prominent ependymal component

Cytology: microcystic formations, loose fibrillary networks and nuclear clusters with mild pleomorphism (Acta Cytol 2001;45:636)

Micro images: ependymal cells in dense glial background #1; #2; #3; #4; #5; various images #1; #2 - figures D-L

Positive stains: GFAP (100%), NSE (100%), NCAM (100%)

Negative stains: Ki-67 (or rarely positive)

References: J Neurooncol 2005;74:1 (stains), Archives 1999;123:306, Neurol India 2003;51:98 (childhood cases)

Neuroepithelial tumors of uncertain origin

Astroblastoma

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Controversial entity

Rare (<3% primary brain gliomas)

Usually children and young adults (mean age 14 years)

Share features of astrocytoma and ependymoma; express nonfibrillar form of GFAP (so PTAH negative)

Anaplastic histology predicts poor prognosis (J Neurooncol 1998;40:59)

Radiologic images: various images

Treatment: resection (adequate for well-differentiated tumors), more aggressive treatment needed for malignant tumors

Gross: well circumscribed, peripheral, cerebral hemispheric masses

Micro: well circumscribed; perivascular rosettes resembling ependymoma, but with processes remaining thick from cell body to adventitia of vessel; foot processes may thicken near vascular adventitia; also perivascular hyalinization, lack of fibrillarity and pushing borders; limit diagnosis to tumors in which these features predominate (other tumors have these features focally); malignant astroblastomas contain hypercellular and mitotically active regions, often with vascular proliferation or necrosis with pseudopalisading; rare features are signet-ring cells (Neuropathology 2002;22:200)

Micro images: well differentiated and malignant tumors

Positive stains: GFAP, S100, vimentin, focal EMA

Negative stains: PTAH

Molecular: +20q, +19 (Brain Pathol 2000;10:342)

EM: abundant intermediate filaments forming bundles in tumor cytoplasm, membrane junctions and external lamina when cells are in contact with collagen fibers (Surg Neurol 1991;35:116)

References: AJNR Am J Neuroradiol 2002;23:243 (free full text), J Korean Med Sci 2004;19:772 (free full text), Childs Nerv Syst 2005;21:211

Chordoid glioma

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First described in 1998 (J Neuropathol Exp Neurol 1998;57:283)

Uncommon (<50 cases reported)

Low grade neoplasm arising in third ventricle-hypothalamic region

“Glioma” since GFAP+

Often attached to hypothalamic and suprasellar structures (63%)

Usually middle aged women (median age 45 years, 63% female)

WHO 2000 lists as “glial tumor of uncertain origin”

Cells may resemble ependyma of subcommissural organ, present in dorsocaudal third ventricle during embryonic life, which regresses after birth in humans

May have poor outcome despite bland histology (AJSP 2002;26:1330, Neuropathol Appl Neurobiol 2005;31:354)

Radiology: well circumscribed, solid, enhancing mass, 19% are cystic

Treatment: resection; rarely radiotherapy (Surg Neurol 2003;59:424), occasionally recurs due to incomplete excision (16%)

Case reports: 56 year old woman (Archives 2004;128:e141), 60 year old woman (Hum Path 1999;30:723), coexistence with Rathke’s cleft cyst (Pathol Int 2003;53:780)

Micro: chordoma-like features; clusters and cords of epithelioid cells in mucinous matrix; cells have abundant eosinophilic cytoplasm and round/oval nuclei with indistinct nucleoli; also lymphoplasmacytic infiltrates, Russell bodies; may have chondroid metaplasia or papillary formations; no/rare mitotic figures; no vascular proliferation, no necrosis, no whorls, no psammoma bodies

Micro images: (1) H&E and stains; (2) epithelioid tumor cells in chords and clusters within mucinous matrix and lymphoplasmacytic infiltrate; GFAP+

Positive stains: GFAP, vimentin, CD34, EMA (focal), cytokeratin (focal); low Ki-67 index; variable S100

Negative stains: synaptophysin, neurofilament (usually), NSE (usually), desmin, p53

EM: ependymal differentiation; apical pole has microvilli and basal pole has hemidesmosome-like structures connecting cell membranes to basal lamina; also submicroscopic cell body zonation and secretory granules (AJSP 2001;25:401)

DD: chordoid meningioma (whorls, psammoma bodies and nuclear pseudoinclusions, EMA+, GFAP-, well formed desmosomes, 22q-), chordoma (infiltrates bone, physaliphorous cells, EMA+, diffusely keratin+, S100+, GFAP-, mitochondria-rough ER complexes)

References: AJNR Am J Neuroradiol 2001;22:464 (free full text), Brain Pathol 1999;9:617)

Gliomatosis cerebri

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Rare

WHO glade IV of IV

Any age, most common in 20’s and 30’s

Neoplastic glia spread widely throughout the brain, involving 3 or more lobes (WHO definition)

Often involves thalamus and basal ganglia

May also have a focal mass, often a high-grade glioma

Variable clinical presentation - usually change in personality and mental status, hemiparesis, ataxia, papilledema

Poor prognosis - median survival 12 months

More favorable prognosis associated with higher performance status, lower tumor grade, oligodendroglial subtype (J Neurooncol 2005 Sep 10; [Epub ahead of print])

Radiology: MRI (recommended modality) shows diffuse, poorly circumscribed, infiltrating and non-enhancing lesions that expands cerebral white mater and are hyperintense on T2-weighted images

Radiologic images: various images

Treatment: no effective treatment known

Case reports: 39 year old woman with recurrent headache (Archives 2002;126:1130)

Gross: diffuse cerebral swelling with obliteration of structures and thickened corpus callosum

Gross images: frontal section; expanded and discolored corpus callosum and fornix

Micro: diffuse infiltration of brain parenchyma (with preservation of underlying histoarchitecture) by small, immature glial cells resembling astrocytes, oligodendroglia or undifferentiated cells, with occasional bipolar processes and dense, rod-like irregular nuclei; variable cell density and mitotic activity

Micro images: (1) pons shows cellular tumor with markedly pleomorphic tumor and mitotic figures (arrows); (2) moderately pleomorphic glial cells are diffusely infiltrative; (3) optic nerve shows hypocellular tumor with mildly pleomorphic nuclei; (4) small immature glial cells; (5) GFAP+ cells and fibrillary processes; (6) figure 1: CT shows expansion of white matter in left corona radiata; 2: expanded left cerebral hemisphere with midline shift and compression of left lateral ventricle; 3: condensation of malignant cells; 4: relative preservation of neurons and architecture

DD: leptomeningeal gliomatosis (diffuse involvement of leptomeninges by astrocytomas), multifocal glioma (lacks continuity between foci, destructive to normal brain tissue)

References: Radiographics 2003;23:247 (free full text)

Neuronal tumors

Ganglion cell tumors-general

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“Ganglion cell tumor” is not a WHO diagnosis

Most common in temporal lobe, but may arise anywhere

May resemble developmental lesions, cortical dysplasia and tuberous sclerosis

Often have better prognosis than gliomas that they resemble

Identify based on (a) neurons with large nuclei, large nucleoli, basophilic Nissl substance, synaptophysin+, neurofilament+, NeuN+, neurofilament+; (b) cells are neoplastic based on abnormal neuronal clustering, loss of orderly distribution, variably sized neurons in different stages of development, cytologic atypia (binucleation, large and bizarre nuclei, hyperchromasia); (c) Ki-67/MIB1+

Note: ganglion cells and neurons frequently cluster; ganglion cell tumors also often display heavy bands of fibrous tissue or perivascular round cells, Rosenthal fibers and granular bodies

Must also evaluate glial component for neoplasia (use GFAP to check for reactive cells, which cluster at margin of neoplasm)

Types of ganglion cell tumors:

(a) Gangliocytoma: ganglion cells and reactive glia

(b) Ganglioglioma: ganglion cells and glial neoplasm, not anaplastic; grade based on grade of glial component, using similar system as astrocytomas

DD: developmental lesions, cortical dysplasia, tuberous sclerosis; cells from glioblastoma, melanoma and astrocytomas may resemble neurons but lack Nissl substance and stain differently; glial tumors entrapping normal neurons

Gangliocytoma

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Benign

< 0.5% of glial neoplasms

Especially common in temporal lobe and floor of third ventricle

Patients present with seizures

More common in children and young adults

May be sellar, associated with pituitary adenomas (Virchows Arch 1994;425:93)

Case reports: 48 year old woman with acromegaly and intrasellar tumor (Archives 2005;129:415)

Gross images: hypothalamic-infundibular tumor has cells rich in Nissl substance (highlighted by cresyl violet)

Micro: abnormal mature ganglion cells (neurons with abundant cytoplasm containing Nissl substance, large nuclei with prominent nucleoli) and reactive glia; often binucleate or multinucleated cells; no glial atypia; glia cluster near margin of neoplasm

Micro images: (1) nerve cells of variable size and shape; (2) mature neurons with prominent nucleoli #1; (4) tumor attached to dura (arrow); (5) synaptophysin+ cytoplasm and cell processes; (6) intrasellar tumor from above case history composed of ganglion cells and adenohypophyseal cells

Positive stains: synaptophysin, neurofilament; GFAP (reactive glia)

EM: mature neurons with abundant endoplasmic reticulum, mitochondria and neurofilaments; secretory granules in neuronal processes

DD: ganglioglioma

References: Korean J Radiology 2001;2:108 (free full text)

Dysplastic gangliocytoma of cerebellum

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Also called Lhermitte-Duclos disease

Rare, <200 cases described

Hamartomatous lesion, not a neoplasm

May present in childhood; slow enlarges and is usually discovered in adults

Due to or associated with PTEN mutation (Am J Hum Genet 2003;73:1191, free full text)

Associated with Cowden’s disease (OMIM #158350, autosomal dominant disorder with trichilemmomas, hamartomas, intestinal polyposis, palmoplantar keratoses, oral papillomas; increased incidence of breast, GU, CNS and thyroid tumors; due to abnormalities in 10q23)

Treatment: complete excision; occasionally recurs late

Case reports: 16 year old girl with headaches and gait disturbance, with Cowden’s disease (Canadian J Neurologic Sciences 2004;31:542)

Gross: grossly thickened cerebellar cortex

Micro: hyperplastic, disordered granular cell neurons that enlarge cerebellum; granular cells may exist in recognizable layer or be large and dysplastic neuronal cell bodies; axonal hypermyelination of molecular layer; often marked reduction in myelination of central white matter of cerebellar folia; no mitotic figures, no necrosis, no endothelial proliferation

Micro images: (1) thick layer of abnormal nerve cells on surface; (2) deformed nerve cells of variable size, usually with little Nissl substance; (3) abnormal enlarged ganglion cells (arrow); (4) large dysplastic nerve cell bodies; (5) neurons are neurofilament+

References: Clin Neurol Neurosurg 2001;103:105, Acta Neurol Scand 2002;105:137

Ganglioglioma

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Neoplasm with glial and neuronal components

Uncommon, < 1% of intracranial neoplasms

Occurs anywhere in CNS but most common in temporal lobes and cerebellar hemispheres

Usually age 30 years or less

Associated with epilepsy

Radiologic images: temporal lobe tumor

Treatment: gross total resection; rarely recurs, metastases are extremely rare

Case reports: 30 year old man with spinal tumor, 51 year old man with ganglioglioma containing neurofibrillary tangles, 4 year old boy with seizures (Archives 2003; 127:e387), with pleomorphic xanthoastrocytoma (Archives 2000;124:1707, AJSP 1997;21:763), with dysembryoplastic neuroepithelial tumor (Archives 1999;123:247)

Gross: well demarcated; firm, gray-yellow-brown, may be cystic; usually no hemorrhage or necrosis

Micro: clusters of abnormal ganglion cells and low grade glial neoplasm; often perivascular lymphocytes or microcalcification; variable Rosenthal fibers or eosinophilic granular bodies; rare mitotic figures, neurofibrillary tangles

Micro images: (1) mildly atypical glial cells and neurons #1; #2; #3; #4; (6) variable sized astrocytes and nerve cells and calcification; (7) GFAP+ astrocytes and their processes; (8) nesting pattern with delicate vasculature; (9) various images ; #3 (tumor with neurofibrillary tangles); (12) figure 1: MRI shows temporal lobe mass with cystic component; 2: prominent granular bodies, Rosenthal fibers and microcalcifications; 3: like #2 plus large, binucleated ganglion cells and perivascular cuffing; 4: NSE+

Cytology images: ganglion cell with prominent nucleoli and neoplastic astrocytes #1; #2; #3

Positive stains: GFAP (neoplastic glia), synaptophysin, neurofilament, neuron-specific enolase

DD: gangliocytoma, non-neoplastic brain with synaptophysin+ neurons (AJSP 1998;22:550)

References: eMedicine

Anaplastic ganglioglioma

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Due to progression of ganglioglioma

Case reports: dissemination to spinal cord (Surg Neurol 1998;49:445), with sarcomatous component (Neuropathology 2002;22:40), metastases through a ventriculoperitoneal shunt (Pathol Int 1999;49:258), 6 year old girl with mixed ganglion cell tumor-giant cell glioblastoma (Archives 1999;123:342)

Micro: anaplastic glial cells

Positive stains: chromogranin A in ganglion cells, GFAP and vimentin (Acta Neuropathol (Berl) 1992;83:365)

EM: dense core neurosecretory granules and glial filaments

Desmoplastic infantile astrocytoma/ganglioglioma

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WHO grade I of IV

First described in 1987 (J Neurosurg 1987;66:58)

Age 18 months and less; uncommon in older children or adults (J Neurooncol 2005 Sep 9 [Epub ahead of print], Neuropathology 2005;25:150)

Associated with hydrocephalus and rapidly increasing head circumference

Rare (< 0.1% of CNS tumors) intracranial tumor, exclusively supratentorial, usually frontoparietal

Good prognosis, with only rare craniospinal seeding or metastases (AJSP 2002;26:1515, Mod Path 1997;10:945, Australas Radiol 2005;49:433, Pediatr Blood Cancer 2005;45:986)

Radiologic images: large cerebral masses with both cystlike and solid portions (figures 7-8)

Treatment: complete resection; chemotherapy if infiltrative or progressive; residual disease may not grow and may spontaneously regress (Neurosurgery 2003;53:979)

Case reports: 6 month old boy with progressive lethargy, with melanocytic colonization, mixed with conventional ganglioglioma (Mod Path 2001;14:720)

Gross: large (up to 13 cm), partially cystic, firm, superficial; often involves multiple lobes and is focally attached to overlying dura

Gross images: mass at silver probe; resected mass

Micro: well delineated from normal brain; spindled or enlarged astrocytes and occasional abnormal binucleated ganglion-type cells; prominent desmoplastic stroma; may have primitive and mitotically active cells resembling PNET or medulloblastoma; may have focal Schwann cell differentiation

no/rare mitotic figures (except in undifferentiated areas), no necrosis, no vascular proliferation

Desmoplastic infantile astrocytoma: no neurons identified

Micro images: ganglion-type and glial cells is desmoplastic background; various images #1; #2; with melanocytic colonization

Cytology: low cellularity with dispersed or variably sized clusters of large neuronal cells with abundant granular cytoplasm, eccentric, hyperchromatic nuclei with undulating nuclear membranes and occasional binucleation, prominent nucleoli; also astroglial cells with smaller cytoplasmic rim, nuclear hyperplasia and more prominent irregularities in nuclear membranes; may have prominent degenerative changes, foamy macrophages; no vascular structures (CytoJournal 2005, 2:1, free full text)

Cytology images: cytology and H&E

Positive stains: GFAP (glia), reticulin (invests tumor cells), trichrome (stroma); neurons are synaptophysin+, NeuN+, neurofilament+, neuron specific enolase+

EM: astrocytic tumor cells are partly invested by pericytoplasmic basal lamina

DD: fibrous ganglioglioma

References: Childs Nerv Syst 2003;19:292, Brain Pathol 1993;3:275

Dysembryoplastic neuroepithelial tumor (DNET)

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Grade I of IV (benign)

First described by Daumas-Duport in 1988 (Neurosurgery 1988;23:545)

Mixed glioneuronal neoplasm of teenagers/young adults

May arise during embryogenesis

Incidental or associated with chronic complex partial seizures (1-19% of surgical resections for epilepsy)

Either temporal or frontal cortex

Good prognosis after excision with only rare recurrence, even with subtotal excision

Radiologic images: nodular cortical lesion

Treatment: gross total resection usually is curative, usually eliminates or markedly reduces seizures

Case reports: 9 year old boy with headache and occipital mass (Archives 2002;126:991), 31 year old woman with 5 year history of grand mal seizures, with ganglioglioma (Archives 1999;123:247)

Gross: multinodular tumor of cerebral cortex, often in temporal lobe; usually cystic or gelatinous; discrete margin

Drawing: nodular tumor

Micro: bland cells resembling mature oligodendrocytes (Archives 2000;124:123), astrocytes and neurons that appear to float within mucin pools near bundles of axons flanked by oligodendroglia; may be difficult to identify neurons; cells are mature; often accompanied by cortical dysplasia; no/rare mitotic figures

Cytology: floating neurons in clusters or intricate patterns or microcystic; also prominent extracellular mucin; compared to oligodendrogliomas, have larger nuclei, frequent nuclear indentation and multiple small nucleoli (vs. round nuclei with only occasional nucleoli in oligodendrogliomas); also have eosinophilic granular bodies in background (Acta Cytol 2003;47:624), may have bipolar astrocytes, mild nuclear atypia, microcystic change; adjacent cortex may show cortical dysplasia with disturbed lamination and architectural disarray; no/rare necrosis, no/rare endothelial proliferation, uncommon mitotic figures

Micro images: (1) variably sized oligodendroglia and neurons with microcyst formation #1; #2; (3) various images #1; #2; #4; figure 1: moderately cellular with uniform glial cells in somewhat linear pattern; 2: linear fascicles of small glial cells tracking along fine capillaries with axonal fibers; 3: occasional freely suspended neurons

Positive stains: glia-GFAP; oligodendroglia-like cells-S100; mucin-Alcian blue; neurons-NeuN, synaptophysin, neurofilament, neuron specific enolase

EM: oligodendroglial-like cells, elongated processes forming a neuropil-like structure and an expanded mucoid extracellular space (Folia Neuropathol 1999;37:167)

DD: oligodendroglioma (not multinodular, no neurons, no mucin, more polymorphic cells, hyperchromasia, perineuronal satellitosis), ganglioneuroma (more pronounced astrocytes, more collagenous stroma, more pleomorphic neurons), glioma (particularly if midline and intraventricular, AJSP 2001;25:494)

Central neurocytoma - CNS Tumor chapter

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First described in 1982 (Acta Neuropathol 1982;56:151)

Grows from foramen of Monro or septum pellucidum into lateral or third ventricle; often calcified

Most common neoplasm of septum pellucidum in young adults, but still <1% of all CNS tumors

Often presents with increased intracranial pressure due to obstructive hydrocephalus

Similar tumors within CNS parenchyma are called extraventricular neurocytoma

Rare before age 10 years

Radiologic images: intraventricular tumor

Case reports: Case of the Week #119, 32 year old woman with ventricular tumor, 11 year old girl with headaches, sudden death due to acute hemorrhage (Am J Forensic Med Path 1999;20:180), 19 year old girl with malignant tumor (Pathol Oncol Res 1999;5:155); pigmented tumor due to lipofuscin and neuromelanin (AJSP 1999;23:1136)

Treatment: good prognosis after complete surgical excision or gamma knife radiosurgery (Cancer 2007;110:2276), although up to 1/3 recur or progress (Int J Radiat Oncol Biol Phys 2007;67:1145); recurrence associated with incomplete excision, or the presence of necrosis, mitotic activity / increased proliferation rates or microvascular proliferation (Cancer 2000;89:1111, Clin Neurol Neurosurg 2008;110:129)

Gross: well demarcated from surrounding tissue; gray, friable, may be gritty due to microcalcifications

Gross images: various images; ventricular mass #1; #2

Central neurocytoma - CNS Tumor chapter (continued)

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Micro: well developed neuronal features - monotonous bland cells with modest cytoplasm, often empty-appearing “halo” resembling oligodendroglioma, salt and pepper chromatin, embedded in eosinophilic fibrillar matrix with rare Homer Wright rosettes and ganglion cells; usually no infiltrating margin, no/rare necrosis, no endothelial proliferation, no/rare mitotic figures

Cytology: cellular; monotonous round cells with ill-defined cytoplasm, oval nuclei, finely granular chromatin and micronucleoli; background fibrillar matrix; variable histiocytic giant cells with hemosiderin (Acta Cytol 2004;48:194)

Micro images: sheets of non-pleomorphic cells with modest cytoplasm and neuropil #1; #2; #3; #4; #5; #6

case of the week #119 - image #1; #2; #3; #4; #5; #6; #7

Cytology images: monotonous round tumor cells with minimal cytoplasm and fine chromatin, with reactive astrocytes and fibrillar background

Positive stains: synaptophysin, Neu-N (strong, Histopathology 2006;48:438), neuron specific enolase

Negative stains: GFAP (reactive astrocytes are GFAP+), Ki-67 (<2%)

EM: microtubules, 100-200 nm dense core vesicles, clear vesicles, neuritic-type processes; usually no intermediate filaments

DD: glioma (no/few halo cells, no/focal neuronal features, strongly GFAP+), oligodendroglioma (no prominent neuronal features, negative or focal for neuronal markers), clear cell ependymoma (negative for neuronal markers, strongly positive for GFAP, vimentin and EMA)

Cerebellar liponeurocytoma

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Also called lipomatous (lipidized) medulloblastoma or lipomedulloblastoma

Rare; first reported in 1978 (Acta Neuropathol (Berl) 1978;41:261)

Grade I to II of IV

Mean age 50 years; almost always in cerebellum

Better prognosis than medulloblastoma; prognosis may be poorer if mitotic figures present and >10% MIB1+ cells (Neuropathology 2005;25:77), although even cases with low mitotic index may progress (J Neurooncol 2005;71:53)

Considered a mixed neuronal-glial tumor; lipid is apparently due to tumoral lipidization, not adipose metaplasia (AJSP 2001;25:1551)

Case reports: 53 year old woman, 48 year old man with midline cerebellar mass, 62 year old woman (Neurol India 2003;51:274-free full text), 6 year old girl with high labeling index (Hum Path 2002;33:564), recurrent tumor with leptomeningeal invasion but no other aggressive histologic features (Neurosurgery 2003;53:1425)

Micro: neuronal and glial differentiation with lipomatous areas; partly resembles medulloblastoma but with low mitotic activity and less atypia; no necrosis, no pleomorphism, no vascular hyperplasia

Micro images: oligodendrocyte- and adipocyte-like cells #1; #2; various images #1; #2; #3

Positive stains: lipid, neuronal markers (Neu-N, synaptophysin, MAP2), GFAP

References: Brain Pathol 2004;14:281 (genetic profiles), Ultrastruct Pathol 2003;27:109 (EM)

Extraventricular neurocytoma

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Neurocytic tumor within brain parenchyma

Median age 34 years, range 5-76 years

Involves cerebrum

Radiology: circumscribed, solitary, 57% cystic

Poor prognostic factors: incomplete excision, atypical features, high cell proliferation rates; also older patient age

Treatment: total excision prevents recurrence

Case reports: 54 year old woman with atypical neurocytoma with oligodendroglia-like spread (Hum Path 2004;35:1156),

Micro: sheets, clusters, ribbons or rosettes of monotonous tumor cells with round and regular vesicular nuclei and distinct nucleoli embedded in matrix of fine neuropil; ganglion cells in 66%

Atypical if necrosis, vascular proliferation, 3+ mitotic figures/10 HPF

Positive stains: synaptophysin (strong), GFAP (46%; also is staining of entrapped astrocytes at periphery)

EM: neuritic-type processes with microtubules, dense core granules

DD: oligodendroglioma (no ganglion cell differentiation, no salt and pepper chromatin, no neuropil islands; usually more infiltrative, synaptophysin-), ependymoma

References: AJSP 2001;25:1252

Papillary glioneuronal tumor

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Not in WHO classification

Cerebral lesion

Apparently good prognosis

Radiology: contrast-enhancing, cystic

Radiologic images: cystic mass of parieto-occipital lobe

Case reports: 18 year old man with large cystic tumor (Archives 2000;124:1820)

Micro: glial and neural components, focally pseudopapillary; no necrosis, no mitotic figures, no vascular proliferation

Micro images: pseudopapillary pattern, GFAP+, synaptophysin+

Positive stains: GFAP, synaptophysin; low MIB1 index

Negative stains: p53

DD: neurocytoma, pilocytic astrocytoma (Rosenthal fibers, eosinophilic granular bodies), gangliogliomas (atypical ganglion cells, gliomatous component, granular bodies, perivascular lymphoid infiltrate, associated with epilepsy and cortical dysplasia)

Paraganglioma

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Grade I (benign), although rarely metastasizes (J Neurosurg 1991;75:320)

Spinal canal (filum terminale); also temporal bone and posterior fossa

Radiologic images: cauda equina tumor

Treatment: surgery

Micro: nests of neuroendocrine cells (Zellballen) with granular cytoplasm and central bland nucleus; nests are separated by fibrovascular stroma with thin walled vessels; may have focal ganglionic differentiation; no vacuoles

Micro images: tumor of filum terminale

Positive stains: neuroendocrine cells - chromogranin, synaptophysin, cytokeratin; sustentacular cells - S100, GFAP (often, Brain Pathol 2005;15:169)

EM: neurosecretory granules

DD: angiomatous meningioma, myxopapillary ependymoma, hemangioblastoma (mixture of capillary and stromal cells with vacuoles), metastatic renal cell carcinoma

References: Histopathology 1997;31:167, Acta Neurochir (Wien) 1999;141:81, Cancer 1986;58:1720

Nonglial tumors

Embryonal tumors

Ependymoblastoma

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Rare tumor of young children

Micro: highly cellular, numerous multilayer rosettes composed of medium sized, poorly differentiated cells around small cavity; apical surface of internal cell layer forms thickened limiting membrane; cells have round/oval nuclei; high mitotic activity

Micro images: ependymoblastoma

Positive stains: vimentin, S100, rare GFAP

Negative stains: keratin, neurofilament

EM: poorly differentiated cells with scanty cytoplasmic organelles, cells united by junctional complexes, frequent rudimentary or incomplete cilia, few basal bodies and few short intercellular glial-like filaments

References: Histopathology 1988;12:17, Cancer 1985;55:1536

Medulloblastoma

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Major subtype of central primitive neuroectodermal tumor/PNET

Grade IV of IV

Usually cerebellum or roof of fourth ventricle

Children (5-10 years) and adults in 20’s; rarely age 35 or older

20% of brain tumors in children (#2 after pilocytic astrocytoma of cerebellum)

May grow rapidly and cause hydrocephalus, invade subarachnoid space and fourth ventricle early

5% metastasize systemically, commonly to bone

5 year survival is 75% with surgery/radiation

May arise from primitive cells of external granular layer of cerebellum

Large cell variant: also called anaplastic; more aggressive (AJSP 1992;16:687)

Treatment: resection; must also treat entire neuraxis since spreads along CSF pathways (drop metastases to cauda equina are common); tumors are very radiosensitive

Case reports: cartilaginous differentiation (Archives 1989;113:84)

Gross: well circumscribed, gray-pink, soft/friable; involves surface of cerebellar folia and infiltrates leptomeninges

Gross images: cerebellar tumor extending into fourth ventricle

Micro: small round blue cell tumor composed of sheets of undifferentiated cells with minimal cytoplasm, hyperchromatic and anaplastic nuclei, often elongated and carrot-shaped; frequent mitotic figures; similar to pineoblastoma; careful examination reveals fibrillar nature of tumor cells; occasional Homer-Wright rosettes

Micro images: sheets of primitive small blue cells #1; #2; large cell variant #1 with neuronal differentiation; #2; arising on surface of cerebellum; various images

Cytology images: oval blue tumor cells with minimal cytoplasm and indistinct nuclei in fibrillar background with mitotic figure; bone marrow

Positive stains: NSE, synaptophysin, focal GFAP

Molecular: isochromosome (17q) or 17p-; 5-30% overexpress c-myc or N-myc; c-myc overexpression is associated with poor prognosis (Archives 2002;126:540)

Molecular images: i(17)(q10)

EM: neural features

DD: small cell carcinoma, lymphoma (diffusely infiltrates CNS until it mixes with normal and reactive fibrillar cells), peripheral PNET

References: infobiogen-cytogenetics, eMedicine, Mod Path 1990;3:164 (stains)

Desmoplastic medulloblastoma

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Grade IV of IV

May be in lateral cerebellum, not midline

More common in young adults than children (mean age 18 years vs. 6.5 years for classic medulloblastoma in one study, Archives 1989;113:1019)

Associated with nevoid basal cell carcinoma syndrome (Cancer 2003;98:618)

Fibrous reaction may be from leptomeningeal cells in arachnoid space

May have better prognosis than classic medulloblastoma

Case reports: 28 year old man with melanotic tumor (Brain Tumor Pathol 2002;19:93)

Gross: firm consistency

Micro: pale areas lack reticulin compared to reticulin-rich areas of high cellularity

Micro images: clear islands of classic medulloblastoma and dark collagen-rich areas with small tumor cells - #1; #2; reticulin stain

DD: small cell carcinoma

Supratentorial primitive neuroectodermal tumor

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Rare tumor in intracranial cavity, usually cerebral hemisphere

Appears to be a different clinical entity than medulloblastoma (central PNET, cPNET) due to different location (cerebral hemisphere vs. cerebellum), different frequency (10% of frequency of cPNET), survival rate (worse than cPNET), different molecular genetics (14q-, 19q- and 3q- vs. i(17q) in cPNET; different hypermethylation profiles, Hum Path 2005;36:1265)

Usually children and young adults

Treatment: wide excision, adjuvant chemotherapy and radiotherapy

Case reports: tumor cell differentiation due to valproic acid treatment for seizures (Pediatr Hematol Oncol 2004;21:743), 51 year old woman with occipital lobe tumor showing extensive mature adipose tissue (Archives 2001;125:264)

Gross: deep seated tumor with cystic component

Micro: small blue cell tumor with round, hyperchromatic cells, abundant mitotic figures and fibrosis

Micro images: tumor with adipose tissue; figure 3: round, hyperchromatic cells, abundant mitotic figures (arrows) and fibrosis; 4: CD99+

Positive stains: CD99 (strong membrane staining), focal GFAP

Negative stains: CAM5.2, S100, CD45, synaptophysin (usually)

Molecular: t(11;22)(q24;q12); i(17q) is very rare

EM: neuronal or glial differentiation

DD: central PNET/medulloblastoma (no t(11;22), CD99-, synaptophysin+), small cell meningioma, anaplastic glioma, melanoma, lymphoma, rhabdomyosarcoma, atypical teratoid/rhabdoid tumor

References: eMedicine, J Neurooncol 2002;60:43, Hum Path 2005;36:36 (DLC1 expression)

Atypical teratoid / rhabdoid tumor

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Not in WHO classification

Rare; first described in 1987

Infants and young children (mean age 17 months)

Usually posterior fossa or supratentorial

Very aggressive with poor prognosis (mean survival 11 months post-surgery); metastasizes throughout CSF

Radiologic images: various images

Case reports: two infantile cases (Am J Neuroradiol 2004;25:481-free full text), thalamic tumor (Neurol India 2003;51:273-free full text), with ring chromosome 22, 19 year old man with intradural mass at C6-7 (Archives 1999;123:853), with inherited INI1 mutation (Pediatr Blood Cancer 2005 Oct 31 (epub)), monozygotic twins with congenital disseminated malignant rhabdoid tumor in one and a cerebellar tumor resembling medulloblastoma in the other (AJSP 2002;26:266), 12 year old girl with cerebellar tumor with a few rhabdoid cells but different molecular features (Acta Neuropathol (Berl) 2005;110:69)

Micro: large and pleomorphic rhabdoid cells with abundant eosinophilic cytoplasm (pinker than PNET), often filamentous cytoplasmic inclusions and vacuoles; eccentric round nuclei and prominent nucleolus; may have PNET-like areas with small cells; may have mucinous background resembling chordoma; may have epithelioid features with poorly formed glands or Flexner-Wintersteiner rosettes

Cytology: hypercellular; large tissue fragments with papillary appearance of large tumor cells surrounding capillaries; cells are large, round and plasmacytoid or rhabdoid (intermediate size with granular to fibrillary, brightly eosinophilic cytoplasm and variable inclusions; large, eccentric nuclei with single prominent nucleolus); also small, round, primitive, neural type cells with high N/C ratio; also apoptotic bodies, mitotic figures, marked necrosis; variable dystrophic calcification, bizarre, multinucleated giant cells (Cancer 2005;105:65)

Micro images: (1) tumor cells; (2) A: H&E; B: GFAP; C: keratin; D: smooth muscle actin; (3) epithelioid areas, rhabdoid cells and necrosis; (4) various images #1; #6; (10) spinal tumor - figure 1: MRI; 2: tumor infiltrates peripheral nerve roots; 3: rhabdoid tumor cells; 4: EM shows paranuclear whorled arrays of closely packed intermediate filaments

Positive stains: vimentin, EMA, smooth muscle actin; focal GFAP, cytokeratin, neurofilament; variable synaptophysin and chromogranin

Negative stains: INI1 with positive nuclear staining of blood vessels and lymphocytes as positive control (AJSP 2004;28:644, Mod Path 2005;18:951)

Molecular: 22q11.2 deletions involving hSNF5/IN1 gene (similar to choroid plexus tumors, Hum Path 2001;32:156-using FISH, Brain Pathol 2003;13:409)

EM: globular/fibrillar paranuclear inclusions (whorled intermediate filaments)

DD: PNET/medulloblastoma (no rhabdoid cells, no 22q11 deletions, IN1+, Acta Neurochir (Wien) 2003;145:663), composite rhabdoid tumors (with other component, usually INI1+); also ependymoma, choroid plexus carcinoma, occasional germ cell tumors

References: AJSP 1998;22:1083, Brain Pathol 2005;15:23, Atlas of Genetics (all rhabdoid tumors), OMIM 609322

Medullomyoblastoma

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Not in WHO classification; considered a distinct variant of medulloblastoma

Grade IV of IV

Rare midline posterior fossa tumor of children, usually female

Aggressive; survival usually 1 year or less

Treatment: radical surgery and craniospinal radiation

Micro: contains smooth or striated muscle cells and small medulloblastoma-like cells

Micro images: cross striations; medulloblastoma with striated muscle cells

Positive stains (muscle markers): PTAH, desmin, muscle-specific actin; synaptophysin stains neuroectodermal cells

Molecular: alterations in #17 or c-myc amplification

EM: sarcomeres and myofibrils; myoid cells resemble fetal rhabdomyoma (Neurol India 1999;47:178-free full text, Cancer 1984;54:323)

References: Cancer 2004;101:1445

Medulloepithelioma

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Not in WHO classification

Grade IV of IV

Rare; children age 6 years and less; often in eye

Median survival of 5 months

Case reports: 2 year old girl with lesions in 4th ventricle and left cerebellar hemisphere (Case of Week #218), 3 year old boy with cerebral tumor (Neurol India 2003;51:546-free full text), 3 month old boy with long survival (Clin Neuropathol 2002;21:197)

Micro: tubular and papillary epithelial growth pattern; cells have dense and pink material on apical surface; foci of neuroblastic differentiation present; resembles embryonic neural tube

Micro images: epithelial architecture recapitulates early neuroectoderm #1; #2; highly cellular with tubules and papillae lined by columnar cells

DD: metastatic carcinoma, choroid plexus carcinoma

References: J Neurosurg 1996;84:430

Choroid plexus tumors

Choroid plexus tumors-general

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Uncommon (0.4 to 0.6% of intracranial neoplasms)

Usually children

Occurs in any portion of choroid plexus, but usually as papillary neoplasms of lateral ventricle of children and fourth ventricle of adults

In preliminary study, Kir7.1 and stanniocalcin-1 may be sensitive/specific choroid plexus tumor markers (AJSP 2006;30:66)

Choroid plexus papilloma

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Grade I of IV - benign

Rare (<1% of intracranial neoplasms), slow growing tumor commonly in ventricular system and associated with hydrocephalus due to excess production of CSF or direct tumor obstruction of CSF flow

Often causes developmental delay, behavioral problems or epilepsy in children

85% occur at age 10 years or less; often present at birth

Needle biopsy not recommended since histologically resembles normal choroid plexus

10-30% become histologically malignant

High survival unless becomes malignant (then 5 year survival is 26%), although histology does not predict behavior

Radiologic images: various images

Treatment: surgical excision, possibly radiation therapy if incomplete excision

Case reports: case with rhinorrhea as only symptom, 49 year old woman with oncocytic tumor (Archives 2004;128:1448)

Gross: larger than normal choroid plexus; lobulated encapsulated mass

Gross images: fourth ventricle tumor; lobulated vascular mass

Micro: resembles normal choroid plexus with single layer of epithelial cells overlying a fibrovascular core; epithelial cells are more crowded and piled up than normal; mild atypia; may be pigmented, oncocytic, osteogenic, adenomatous, acinar, mucus secreting, tubular; may have vascular stalk that provides mobility within ventricular system

Micro images: (1) papillary architecture at low power; (2) cuboidal / columnar cells overlying fibrovascular core #1; #3; (5) various images #1-pigmented tumor; #3; (8) anaplastic choroid plexus papilloma; (9) oncocytic tumor; (10) cuboidal/columnar cells overlying fibrovascular core; (11) glandular differentiation; (12) CK7+; (13f) atypical features

Cytology images: papillary fronds of choroid plexus tumor with focal calcification

Positive stains: CAM 5.2 (94%), transthyretin (89%), vimentin, S100 (54%); mucin stains, CK7 (usually); focal GFAP (up to 70%), EMA (11-71%); occasionally synaptophysin; fibrovascular core is positive for type IV collagen, reticulin and laminin

Negative stains: p53 (usually), CK20 (usually), BerEP4

DD: papillary ependymoma (more than one layer of cells), metastatic thyroid, breast, kidney or ovarian carcinoma (necrosis and anaplasia present), myxopapillary ependymoma (different location), papillary meningioma (solid and syncytial foci of whorled cells, no mucin)

References: eMedicine, Mod Path 2000;13:638 (CK7/CK20)

Choroid plexus carcinoma

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WHO grade III of IV

Extremely rare

Resembles metastatic carcinoma but usually occurs in children

Associated with germline p53 mutations (Eur J Cancer 2005;41:1597)

Case reports: ventriculoperitoneal shunt related metastases (Neurosurgery 2005;56:E412)

Gross: well circumscribed, brown-red, cauliflower-like mass; variable hemorrhage, necrosis and invasiveness

Gross images: lateral ventricle tumor

Micro: sheets of anaplastic tumor cells with necrosis, frequent mitotic figures; focal papillary areas resemble papilloma but with more crowded and elongated cells

Micro images: markedly pleomorphic cells with loss of papillary pattern; various images #1; #2

Positive stains: EMA, keratin, S100, INI1; GFAP (20%)

DD: atypical rhabdoid tumor (INI1 negative, J Neuropathol Exp Neurol 2005;64:391),

Pineal tumors

Pineal gland-normal

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Also called epiphysis, pineal body

Between superior colliculi at base of brain; 100-180 mg

Develops at month 2 of gestation as diverticulum in diencephalic roof of third ventricle

Replaced by connective tissue after puberty

Produces melatonin, which helps regulate circadian rhythms

Drawings: location in brain #1; #2 (at “p”)

Gross: shaped like a pine cone, midline, attached to posterior end of roof of third ventricle in front of cerebellum, 1 cm long, red-gray

Gross images: local anatomy (horse)

Micro: loose neuroglial stroma with nests of pineocytes containing well-defined neurosecretory (melatonin) granules; also astrocytes; has features of photoreceptors and concretions (“brain sand”)

Micro images: sagittal section #1; #2; #3; #4; concretions; pinealocytes

Positive stains: synaptophysin, retinal S-antigen

Pineal gland tumors-general

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Up to 1% of adult tumors and 3-8% of childhood intracranial tumors

Most tumors are germinomas (resemble seminoma, radiation sensitive); also other germ cell tumors

Frozen sections are challenging

Tumors include those listed below; also astrocytoma, meningioma, metastases, cysts

Tumors often compress aqueduct of sylvius, causing hydrocephalus and requiring ventriculoperitoneal shunting

References: eMedicine

Papillary tumor of pineal region

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First described in 2003 (AJSP 2003;27:505)

4 of 6 were women, ages 19-53 years

May derive from ependymal cells of subcommissural organ (also chordoid glioma)

Radiology: well circumscribed pineal mass

Micro: epithelial-like growth with vessels covered by a layer of tumor cells; cells are large, columnar/cuboidal with clear cytoplasm, round or infolded nuclei at basal pole of tumor cells; may have rosettes

Positive stains: cytokeratin, S100, NSE, vimentin

Negative stains: EMA, GFAP (may be weak)

EM: abundant rough endoplasmic reticulum with distended cisternae filled with secretory product; also microvilli and perinuclear intermediate filaments

DD: pineal parenchymal tumor (synaptophysin+, keratin-, vimentin-)

Pineoblastoma

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Grade IV of IV

Second most common pineal gland tumor after germ cell tumor

Usually age 20 years or less

Frequent CNS metastases or spinal seeding, which is the main cause of death

5 year survival is 58%

Poor prognostic factors: 7+ mitotic figures/10 HPF, presence of necrosis, no neurofilament staining

Case reports: 15 year old girl with midline intracranial mass (Archives 2004;128:707), cases with vertebral metastases (Archives 2001;125:939), osseous metastases (J Neurooncol 2005;74:53)

Treatment: surgery, variable radiation therapy; prognosis is usually poor

Gross: located in pineal gland, may appear well demarcated from surrounding brain tissue but usually infiltrates into surrounding structures

Micro: sheets of densely packed cells with high grade (anaplastic / undifferentiated) features including high N/C ratio with minimal cytoplasm and large hyperchromatic nuclei; also necrosis, frequent mitotic figures; focal nuclear molding; Homer-Wright or Flexner-Wintersteiner rosettes; may have lower grade features of pineocytoma and pineal parenchymal tumor of intermediate differentiation; often infiltrates into surrounding structures

Micro images: (1) highly cellular tumor composed of small, round and poorly differentiated cells #1; #2 with Homer-Wright rosettes; (3) various images #1; #2; #3; (6) figure 1: MRI shows tumor at midline of posterior brain; 2: touch imprint is highly cellular with primitive cells and a few Homer-Wright rosettes (arrow); 3: paraffin section shows highly cellular tumor with perivascular arrangements and Homer-Wright rosettes and frequent mitotic figures (arrows); 4: synaptophysin+

Positive stains: NSE, synaptophysin, retinal S-antigen

Negative stains: GFAP, myoglobin, HHF35

EM: occasional cytoplasmic dense core granules, short immature cell processes, occasional junctional complexes; no definite synapses

DD: medulloblastoma, pineocytoma (better differentiated cells with more cytoplasm, smaller cells, no/rare mitotic figures), glial neoplasms (GFAP+)

Pineocytoma

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Grade I of IV

Mostly adults age 25-35 years, slow growing, average survival 7 years

Gross: well-circumscribed, gray, hemorrhagic

Micro: similar to normal pineal gland’s well differentiated cells but hypercellular; fibrovascular stroma highlights expansive lobules of tumor cells with uniform round nuclei; pinocytomatous rosettes (large, loose, Homer-Wright like rosettes with central fibrillar zones surrounded by neoplastic cells with round nuclei); may have features of neuronal differentiation (ganglion cells); non-infiltrative, no/rare mitotic figures, no necrosis, no/minimal atypia

Micro images: small cells and pineocytomatous rosettes; larger cells resembling pineocytes; various images #1; #2

DD: pineoblastoma (Cancer 1980;45:1408)

Pineal parenchymal tumor of intermediate differentiation

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Features intermediate between pineocytoma and pineoblastoma

10% of pineal parenchymal tumors

Occasionally associated with CNS or extraneural metastasis, but otherwise difficult to predict prognosis

Better survival than pineoblastoma

Micro: marked hypercellularity, but relatively bland nuclear features, no/mild nuclear pleomorphism, no/rare pinocytomatous rosettes, minimal mitotic activity

Molecular: often +4q, +12q, -22 (Genes Chromosomes Cancer 2001;30:99)

References: Brain Pathol 2000;10:49

Meningeal tumors

Meningioma

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Common (20% of brain tumors, 6 per 100K annually)

Derive from arachnoid cap cells (associated with dura mater, choroid plexus)

Grow along external surface of brain or within ventricular system

Difficult to diagnose correctly within choroid plexus, if intraparenchymal, at cerebropontine angle or along spinal cord, due to resemblance to more common tumors at these locations

Slow growing (may grow rapidly during pregnancy), symptoms vague or related to brain compression

Usually adults, 2/3 in brain occur in women, 90% in spinal cord occur in women

Usually solitary; multiple tumors (seen in 1-6%) are occasionally associated with neurofibromatosis 2

Usually benign; not considered malignant even if invades bone and skeletal muscle

May metastasize to lung or mediastinum

Metastases within a meningioma may be from breast cancer or CLL

Difficult to predict recurrence - incomplete resection and grade of tumor are most predictive

Treatment: can merely observe if asymptomatic; resection is usually curative; may recur if incompletely excised

Case reports: Case of the Week #104, intraosseous occipital meningioma (Archives 2001;125:301), 37 year old woman with microcystic meningioma (Archives 2005;129:e173), with leukemic infiltrate (AJSP 2001;25:127)

Gross: rounded, encapsulated and well circumscribed, firm with tiny nodules, well defined dural base, tumor separates readily from brain; may grow en plaque (along dural surface) and cause reactive (hyperostotic) bone changes

Gross images: tumor displaces brain without invading it #1; #2; compression of underlying cortex #1; #2; resected tumor; tumor being resected; adherent to falx cerebri

Micro: distinct margin with CNS parenchyma; whorled clusters of spindle cells, which may secrete collagen, die, calcify and form psammoma bodies (varies by tumor); intranuclear pseudoinclusions common; xanthomatous degeneration, moderate nuclear pleomorphism and metaplasia are common but have no prognostic significance; no necrosis or extensive hemorrhage

Grade I variants:

Angiomatous: grade I of IV; 2% of all meningiomas; vascular component should exceed 50% of total tumor area; may resemble hemangioblastoma or become sclerotic; meningothelial cells are wrapped around small blood vessels; also has large vessels; if entirely hemangioblastic, differentiate from hemangioblastoma by dural attachment and location; no atypia or anaplasia; mean Ki-67 index is 2%; do not recur if entirely resected

Fibroblastic: grade I of IV; firm tumors composed of spindle cells with indistinct cell boundaries; resemble schwannomas, fibrillary astrocytomas and pilocytic astrocytomas but are focally EMA+, often have thick bundles of collagen

Lipomatous: due to lipid accumulation, not lipomatous metaplasia (AJSP 2001;25:769)

Meningothelial: grade I of IV; most common variant; syncytial and epithelial cells, indistinct cell borders and classic whorls; may have sparse psammoma bodies; may appear epithelioid and resemble ependymoma, oligodendroglioma (EMA-, infiltrating margin); EM may be required for diagnosis

Microcystic: grade I of IV; rare to have extensive microcystic formation; cells have elongated processes and loose myxoid background; overall resembles microcysts; has focal “classic” features; variable pleomorphism; no cords or trabeculae; no inflammatory infiltrate; EM shows extracellular microcysts; resembles chordoid meningioma (grade II)

Psammomatous: grade I of IV; found in spinal region; numerous psammoma bodies; also syncytial cells

Transitional: grade I of IV; meningothelial and fibroblastic features; usually prominent whorls, psammoma bodies and clusters of syncytial cells

Other grade I variants: arachnoid trabecular, cartilaginous, lipomatous, lymphoplasmacytic-rich, microcystic, osteogenic, secretory (see below); still have meningothelial features, occasional whorls, finely granular chromatin; meningothelial cells flatten around or encircle vessels; no/rare mitotic figures; EM may be needed to diagnose

Cytology: small to medium sized cells with moderate well defined cytoplasm and short processes; some nuclei have grooves; cells form focal whorls; variable psammoma bodies

Micro images:

angiomatous (trichrome stains) - #1; #2 with microcystic features

fibroblastic variant - #1; #2; #3

lipomatous variant - #1; #2

lymphoplasmacytic rich variant - #1; #2; #3-CD45/LCA+

meningothelial variant - #1; #2; #3; #4 (A-C); occipital tumor; with focal hemosiderin deposition

microcystic variant - #1-lacelike pattern of fibrillary stellate cells with round/oval microcysts; #2 with pleomorphic cells; #3 with pseudo-astrocytic appearance; #4 with strong progresterone receptor+, EMA+

psammomatous - #1

xanthomatous - #1; #2; #3; #4 with cholesterol clefts; #5 with pleomorphic cells

Cytology images: meningothelial tumor #1; #2; whorl; whorl and psammoma body; scattered tumor cells with delicate and wispy cytoplasm

mass at base of skull with inclusions and grooves - image #1; #2; #3; #4

Virtual slides: meningothelial meningioma

Positive stains: vimentin (strong), EMA (70%); S100, ProgR (30%, usually women, tumor may grow during pregnancy), cytokeratin, CEA, PAS+/diastase resistant, IgA, IgM (secretory meningiomas), focal actin in 20% (Archives 1996;120:267)

Negative stains: GFAP, OCT4 (germ cell tumor marker)

Molecular: 22- may indicate aggressive behavior; seen in 50% of meningiomas that are not associated with neurofibromatosis type 2

Molecular images: 22q-; idiotype of deletion

EM: tightly interdigitating cellular processes held together by desmosomes

DD: fibrosis (collagen and reticulin positive), infectious granuloma (organisms and inflammation present)

References: eMedicine, AJSP 2004;28:390 (angiomatous), AJSP 1997;21:375 (oncocytic)

WHO grading of meningiomas

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Grade I - syncytial (meningothelial), fibroblastic (with collagen), microcystic, transitional, psammomatous, angiomatous (includes hemangioblastic, angioblastic), secretory subtypes

Grade II - atypical, clear cell and chordoid subtypes

Grade III - rhabdoid and papillary subtypes, anaplastic/malignant

Grave IV - no meningiomas have this grade

Anaplastic meningioma

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Grade III; also called malignant meningioma

1% of meningiomas

Either denovo, associated with recurrent tumors or associated with prior radiation (J Neurooncol 2005;74:195, Med Pediatr Oncol 1995;24:265)

Associated with aberrant CpG island hypermethylation profile (Hum Path 2005;36:416)

Treatment: resection

Case reports: 61 year old woman with coexisting fibrous and anaplastic meningiomas (J Clin Neurosci 2003;10:622)

Gross: firm, white

Micro: circumscribed and lobulated; exhibit frank histologic features of malignancy far in excess of the abnormalities present in atypical meningiomas; either 20 or more mitotic figures/10 HPF or anaplastic cytology (increased cellularity, hyperchromatic, high N/C ratio, necrosis); invasive front is discrete or proceeds along vessels trapping gliotic areas

Note: invasion alone is insufficient for diagnosis

Micro images: anaplastic foci; pseudopapillary tumor with necrosis and mitotic figures; H&E and cytokeratin

Positive stains: vimentin (100%), Ki-67/MIB1 (high), strong EMA (89%, although often decreases if a recurrence), cytokeratin (75%), strong claudin1 (54%), weak/focal CD99 (15%), weak/focal bcl2 (31%)

Negative stains: BerEP4, CEA, B72.3, CD15

Molecular: 1p- (94%), 14q- (67%), NF2- (100%)

EM: membrane basal-like substance, no desmosomes (Ann Pathol 2000;20:492)

DD: anaplastic glioma, glioblastoma (more invasive margin than meningioma, forms secondary structures of Scherer), hemangiopericytoma (EMA-, CD99+, bcl2+, usually none of above deletions, Hum Path 2004;35:1413), metastatic carcinoma (usually positive for BerEP4, CEA, B72.3, CD15, negative for vimentin, Mod Path 2004;17:1129)

References: Ann Diagn Pathol 2003;7:214 (immunophenotypic changes in recurrences)

Atypical meningioma

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Grade II

5-15% of meningiomas

Either: (a) 4-19 mitotic figures/10 HPF or (b) three of these histologic features: increased cellularity, small cells with high N/C ratio, large and prominent nucleoli, patternless or sheetlike growth, foci of “spontaneous” or geographic necrosis

Note: invasion of dura, bone or soft tissue is not a feature; neither is pleomorphic or atypical nuclei not associated with mitotic activity or necrosis

May be associated with prior irradiation (J Neurosurg 2004;100(5 Suppl Pediatrics):488)

29% recur (vs. 9% of classic meningiomas and 50% of anaplastic meningiomas)

10 year survival is 79%, but 26% will assume a malignant phenotype

In one study, cyclin A and topoisomerase II staining predicted recurrence (Archives 2002;126:1079)

Treatment: gross total resection

Case reports: with lung metastases (J Clin Neurosci 2000;7:69)

Micro images: A: whorls in classic meningioma; B: mitotic figures in atypical variant; various images

DD: meningioma with atypical features (atypical features insufficient for criteria above); necrosis due to preoperative embolization (which is not considered spontaneous)

References: Cancer 2002;94:1538

Chordoid meningioma

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Grade II due to tendency to recur

<1% of all meningiomas

Usually adults (mean age 47 years) with no systemic symptoms, although initial reports were primarily children/young adults with microcytic anemia or dysgammaglobulinemia

Cases with Ki-67 index > 5-10% are more likely to recur

Treatment: complete excision; overall 40% may recur, often when incompletely excised

Case reports: 50 year old woman with progressive headaches (Archives 2004;128:e115), with fever and IL6 production (J Neurosurg;103:555), with IL6 production and Castleman’s disease (J Neurosurg 2005;102:733), tumor at skull base (Australas Radiol 2004 Jun;48:233)

Gross: large, supratentorial

Micro: resembles chordoma with trabeculae / cords of epithelioid and spindle cells with cytoplasmic vacuoles between myxoid collagen, but has meningothelial features and whorls and is cytokeratin negative; often heavy lymphocytic infiltrate with germinal centers

Cytology: cords of polygonal tumor cells with bland nuclei and nuclear pseudoinclusions; occasional loose cells with abundant, metachromatic, pink-purple cells without cytoplasmic vacuoles; also lymphoplasmacytic infiltrate (Acta Cytol 2004;48:259, Acta Cytol 2004;48:397)

Micro images: cells with clear cytoplasm in myxoid stroma; various images #1; #2; EMA+; figure 1: abnormal trabeculae of vacuolated eosinophilic cells in myxoid matrix; 2: small areas of whorled epithelial cells; stroma is Alcian blue+

Cytology images: vacuolated cells

Positive stains: vimentin, EMA

Negative stains: GFAP, keratin, CEA, S100

EM: abundant rough endoplasmic reticulum, intercellular desmosomes, intermediate filaments, complex interdigitating cell processes

DD: chordoma, metastatic carcinoma, myxoid chondrosarcoma, metastatic myxoid meningioma, chordoid glioma

References: AJSP 2000;24:899, AJSP 2003;27:131

Clear cell meningioma

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Grade II due to aggressiveness

More common in lumbar and cerebellopontine areas and in younger patients (mean age 29 years)

More aggressive in skull than spinal cord

Case reports: fourth ventricle tumors (AJSP 2003;27:131), 41 year old woman with L3-L4 intradural lesion (J Spinal Disord Tech 2005;18:539),

Treatment: resection, variable radiation therapy; often recurs

Micro: sheets of polygonal cells with clear cytoplasm; also cells with meningothelial features (vague whorls); often extensive stromal and perivascular hyalinization; no/rare mitotic figures

Cytology: whorled, syncytial architecture composed of spindle to polygonal cells with vacuolated cytoplasm and bland nuclei (Diagn Cytopathol 1998;18:131)

Micro images: extensive vacuoles and fibrous walled vessels; sheets of clear cells with bland nuclear features #1; #2; H&E and EMA+; H&E and stains; vimentin+ cells

Positive stains: PAS+ diastase sensitive (glycogen), vimentin, EMA, progesterone receptor (77%)

Negative stains: S100, CAM 5.2, estrogen receptor, chromogranin A, rare MIB/Ki-67

EM: abundant cytoplasmic glycogen, intermediate filaments, interdigitation of cell membranes, desmosomes, occasional cytoplasmic lumina (Ultrastruct Pathol 1999;23:51)

DD: metastatic renal cell carcinoma (J Clin Neurosci 2005;12:685), oligodendroglioma, hemangioblastoma, seminoma, lipid-rich glioblastoma, ependymoma

References: AJSP 1995;19:493

Invasive meningioma

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Invasion of adjacent cerebral parenchyma or vascular invasion (within tumor); surgical specimen must contain infiltrative interface with the brain to make the diagnosis

Associated with higher risk of recurrence, but does not change the tumor grade

Brain invasion is considered worse than dural invasion (common in low-grade and high-grade meningioma)

SPARC may be associated with invasiveness (Clin Cancer Res 1999;5:237)

Micro images: SPARC in invasive and noninvasive tumors #1; #2; #3

Papillary meningioma

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Grade III due to high rates of local recurrence, metastases and invasion

Rare; tends to occur in children

Difficult to recognize if not associated with dura

Case reports: recurrent cerebellar tumor (AJSP 1999;23:844), associated with prior chemotherapy for ALL (Childs Nerv Syst 2005 Jun 14; [Epub]), tumor of jugular foramen (Brain Tumor Pathol 2004;21:143), 15 year old girl with cystic tumor (Childs Nerv Syst 2005;21:322), rhabdoid and papillary tumor (AJSP 2001;25:964), pleural metastases (Acta Neurol Scand 2000;102:200), spinal tumor (Acta Neurochir (Wien). 2000;142:703)

Micro: papillae composed of syncytial cells making rosettes around vessels; may form by edematous or necrotic loosening of tumor cells surrounding vascular core; usually has areas of classic meningioma and mitotic figures; papillary areas may be focal

Micro images: papillary architecture #1 with fibrovascular core

Positive stains: vimentin, NSE

Negative stains: GFAP, CAM 5.2, EMA (often), S100, synaptophysin

EM: meningioma features; interdigitating cell processes, desmosomes and intermediate filaments (Histopathology 2001;38:318)

DD: papillary ependymoma, choroid plexus papilloma, carcinoma

Rhabdoid meningioma

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Grade III due to marked aggressiveness

Rhabdoid component is often only apparent in recurrences

Case reports: recurrent tumor #1, #2 (Skull Base 2003;13:51, free full text) rhabdoid papillary tumor (AJSP 2001;25:964), without mitotic activity or atypia (Clin Neuropathol 2004;23:16)

Micro: barely cohesive cells with abundant eosinophilic cytoplasm, paranuclear inclusions, eccentric nuclei; also meningothelial features, high mitotic activity

Cytology: abundant large cells with dense eosinophilic cytoplasm, eccentric nuclei, single prominent nucleoli (resembles melanoma or metastatic carcinoma (Diagn Cytopathol 2003;29:297, Diagn Cytopathol 2003;29:292)

Micro images: tumor cells have eosinophilic glossy cytoplasm and eccentric, mildly atypical nuclei; various images

Positive stains: vimentin, EMA, INI1 (Mod Path 2005;18:951), increased Ki-67 index

EM: hyaline perinuclear inclusions contain whorls of intermediate filaments that push nucleus to side

DD: gemistocytic glioma, epithelioid glioma (different location and pattern of brain invasion, negative for vimentin and EMA, different ultrastructure)

References: AJSP 1998;22:1482, AJSP 1998;22:231

Secretory meningioma

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Grade I

May have increased serum CEA

1-9% of all meningiomas; 90% female

Case reports: 46 year old woman (Archives 2000;124:787), 54 year old woman with headache and vomiting, containing lung tumor metastasis (Br J Neurosurg 2002;16:66), with lipomatous component (Brain Tumor Pathol 1999;16:77, Neuroradiology 1998;40:656)

Micro: acini-like structures with PAS+ diastase resistant hyaline inclusions (also called pseudopsammoma bodies) within microvillus lined intracellular lumina; meningothelial cells without atypia; often associated with mast cells and peritumoral edema (Neurosurg Rev 2006;29:41)

Cytology: hypercellular cohesive clusters of uniformly dense cells with eosinophilic cytoplasm, smooth nuclear outlines and even chromatin; also cells with syncytial arrangements, whorls and nuclear pseudoinclusions (Acta Cytol 1999;43:121)

Micro images: cells with lumina containing PAS+ inclusions #1; #2; #3; trichrome; Alcian blue; cytokeratin; H&E and PAS; various images #1; #2

Cytology images: various images #1; #2; #3 (figures 2-4)

Positive stains: CAM 5.2, CEA, CK7, EMA, progesterone receptor, IgA, IgM, CA 19-9

Negative stains: CK20

EM: hyaline inclusions are intracellular and within intercellular lumina lined by microvilli; inclusions contain granular material forming a dense core; microvesicles, dense bodies and lamellar structures

DD: microcystic, clear cell or chordoid meningioma, metastatic carcinoma (usually CK7-, CK20+, Adv Clin Path 1999;3:47)

References: J Clin Neurosci 2001;8:335, Cancer 1997;79:2003, AJSP 1986;10:102

Meningioangiomatosis

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Rare, benign, hamartomatous lesion of children and young adults characterized by leptomeningeal and meningovascular proliferation

Presents with seizures and headaches

Mean age 21-28 years, range 1-70 years

25% associated with neurofibromatosis II

Case reports: 7 year old girl with seizures, 30 year old man with coexisting meningioma, 11 year old boy with seizures (Archives 2003;127:e349), with oligodendroglioma (Archives 1996;120:587), 16 year old boy without stigmata of neurofibromatosis (AJSP 2002;26:125), associated with meningioma (AJSP 1999;23:872), associated with sudden death in otherwise healthy 13 year old boy (Pediatr Dev Pathol 2005;8:240), 16 year old boy without neurofibromatosis but with microsatellite instability of 2 markers flanking the NF2 gene (AJSP 2002;26:125)

Treatment: surgical excision cures most seizures

Gross: thick and opaque leptomeninges with abnormal vessels, but no evidence of neoplasia

Micro: prominent perivascular meningothelial cell proliferation with collagen deposition involving the cortex and sometimes the underlying white matter; also increased cortical vascularity; often leptomeningeal calcification; variable psammoma bodies and osteoid; also variable neurofibrillary tangles; no/rare mitotic activity, no necrosis, no marked pleomorphism

Cytology: numerous thin walled capillaries, bland spindle cells, occasional large cells with prominent nucleoli, variable meningothelial whorls and neurons (Acta Cytol 2001;45:1069)

Micro images: (1) prominent psammoma bodies; (2) figure 2: perivascular meningothelial cells and proliferation of blood vessels; 3: psammoma bodies; (3) degenerative changes; (4) various images #1; #2; #3

Positive stains: vimentin, EMA, focal S100 in 20%, variable CD34

Negative stains: S100

DD: invasive meningioma (infiltrative growth into brain parenchyma with destruction, no prominent vascular component), atypical meningioma (increased mitotic activity and either increased cellularity, high N/C, prominent nucleoli, sheet-like growth or necrosis), desmoplastic infantile astrocytoma (prominent desmoplastic stroma with neuroepithelial cells), schwannoma (encapsulated, Schwann cells in palisading or myxoid patterns, strong S100+, EMA-), vascular malformation (Sturge-Weber syndrome or arteriovenous malformation)

Hemangiopericytoma

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Grade II or III of IV

Formerly called angioblastic meningioma

<1% of all primary CNS tumors

60% men, mean age 43 years

Usually single mass attached to meninges of brain or spinal cord; more often in occipital region attached to venous sinuses

Similar to meningioma - origin from same cells, attaches to outer meninges, does not invade brain

Recent 5 year survival reported as 93% (J Neurosurg 2003;98:1182)

Resembles hemangiopericytomas elsewhere in body, although different molecular phenotype (Mod Path 2001;14:197)

May cause lytic destruction of adjacent bones

60-90% recur, 23-64% metastasize to bone, liver, lung, CNS; mean survival after metastasis is 2 years

Radiology: sharply demarcated tumors attached to dura, with smooth margins and intense contrast enhancement

Case reports: 52 year old woman with pleural metastasis (Archives 2004;128:1061)

Gross: solid, well-demarcated from adjacent brain; red-brown cut surface with vascular spaces; bleeds profusely during excision

Micro: sheets of cells with uniform hypercellularity, cells are homogeneous with abundant cytoplasm, oval nuclei, small nucleoli, moderate pleomorphism; mitotically active, staghorn vascular pattern lined by flat endothelial cells; cells tend to bulge into vascular lumina without bursting through endothelium; mild nuclear atypia, no “ropy” collagen of solitary fibrous tumor

Micro images: sheets of tumor cells; irregular blood vessels #1; #2 (may not be CNS); #3 (may not be CNS); CD34+ and CD31 negative; reticulin stain (may not be CNS); meningeal and soft tissue tumors

Positive stains: pericellular reticulin, type IV collagen or silver stains highlight pericellular basement membrane; strong bcl2 (86%) strong CD99 (85%) factor XIIIa (scattered, 78-100%), Leu7 (70%), CD34 (33%, weak), vimentin (85%), p53 (52%), EMA (33%), variable smooth muscle actin, cytokeratin (20%), desmin (20%), claudin1 (3%)

Negative stains: CD31

EM: extensive basement membrane around every cell; small bundles of intermediate filaments; no desmosomes; no gap junctions

DD: fibrous meningioma (80% EMA+, 80% S100+), glioma, metastatic carcinoma, solitary fibrous tumor (strong CD34 in 100%), anaplastic meningioma (chromosomal deletions, strong EMA+, weak/negative bcl2 and CD99, Hum Path 2004;35:1413)

References: AJSP 1997;21:1354

Melanocytic tumors / melanoma

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Primary intracranial melanocytic tumors are rare - most arise in leptomeninges

In children, associated with neurocutaneous melanosis, a rare congenital syndrome with giant congenital pigmented skin nevi and high rate of CNS melanoma (Semin Cutan Med Surg 2004;23:138)

Two types of pri