CNS tumors - Printer Friendly Version

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

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

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

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

Choroid plexus cyst

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

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

Micro: wall composed of connective tissue and epithelial cells

Positive stains: transthyretin

Colloid cyst

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

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

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

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

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

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

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

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

Rare; affects brain and spinal cord; usually not midline

Not in communication with ventricle or CSF spaces

Rarely ruptures and causes meningitis

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

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

Positive stains: GFAP

EM: neuroepithelial origin

Epidermoid cyst

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

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

Positive stains: CK8, CK20

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

References: eMedicine

Glial cyst

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

Positive stains: GFAP

Meningeal cyst

Also called diverticulum

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

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

References: Neurosurg Focus 2002;13 (spinal extradural meningeal cyst-PDF file, free full text)

Neuroepithelial cyst

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

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

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)

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

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

References: Ann Diagn Path 1997;1:11

Simple cyst

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

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

CNS Tumors

CNS Tumors-general

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

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

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); WHO classification and ICD-O codes-PDF File

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

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

Glial tumors

Glioma-general

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

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

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

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)

Positive stains: GFAP (variable)

Cystic astrocytoma

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

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, free full text)

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)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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), metastatsic 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

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

Positive stains: GFAP, p53

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

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

References: Archives 2003;127:1187

Pediatric nonbrainstem glioblastomas

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

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)

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

DD: glioblastoma with desmoplasia

Pleomorphic xanthoastrocytoma

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”

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

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

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)

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

Positive stains: GFAP (variable)

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

Oligodendroglial tumors

Oligodendroglioma-grade II

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

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

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

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

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

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

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 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

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

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

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

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

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,