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

Epithelioid ependymoma

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

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

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

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)

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

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

Myxopapillary ependymoma

top

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

Poor prognosis if extends into subarachnoid space and surround roots of cauda equina, or if unresectable

May bleed into CSF

Case reports: 40 year old man with cauda equina mass, 38 year old man with saccrococcygeal mass; 48 year old woman with back pain (Archives 2004;128:811)

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

Micro: papillary elements in myxoid background with ependymal cells; two cell types - epithelial and fibrillar cells, but only after careful searching; 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

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

Positive stains: GFAP, mucin (including vessel walls), vimentin, S100 (50%)

Negative stains: cytokeratin

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

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

Subependymoma

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)

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)

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

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)

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)

Positive stains: GFAP, S100, vimentin, focal EMA

Negative stains: PTAH

Molecular: +20q, +19 (Brain Pathol 2000;10:342, free full text-PDF file)

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

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

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, free full text)

Gliomatosis cerebri

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

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

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

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

“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

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)

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

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

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

Ganglioglioma

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

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

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

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

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)

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

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

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)

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)

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

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

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

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

First described in 1982

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

Rare before age 10 years

Good prognosis after complete surgical excision

May recur if incomplete excision or if necrosis, mitotic activity / increased proliferation rates or microvascular proliferation present (Cancer 2000;89:1111)

Case reports: 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)

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

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 with 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)

Positive stains: synaptophysin, Neu-N, neuron specific enolase

Negative stains: GFAP (reactive astrocytes are GFAP+), Ki-67 (<1%)

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

DD: glioma, oligodendroglioma, clear cell ependymoma

Cerebellar liponeurocytoma

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

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

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

Extraventricular neurocytoma

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

Not in WHO classification

Cerebral lesion

Apparently good prognosis

Radiology: contrast-enhancing, cystic

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

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

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

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

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

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

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

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

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

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

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)

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

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

DD: small cell carcinoma

Supratentorial primitive neuroectodermal tumor

Also called peripheral PNET / Ewing’s sarcoma

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: 46 year old man with right cavernous sinus tumor (Archives 2005;129:e11), 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), in cauda equina (Hum Path 2000;31:999)

Gross: deep seated tumor with cystic component

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

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, Mod Path 2002;15:673 (meningeal peripheral PNET), J Neurooncol 2002;60:43, Hum Path 2005;36:36 (DLC1 expression)

Atypical teratoid / rhabdoid tumor

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

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)

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, free full text-PDF file)

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, free full text-PDF file (molecular), Atlas of Genetics (all rhabdoid tumors), OMIM 609322

Medullomyoblastoma

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

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

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: 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

DD: metastatic carcinoma, choroid plexus carcinoma

References: J Neurosurg 1996;84:430

Choroid plexus tumors

Choroid plexus tumors-general

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

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

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

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

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

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

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

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

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

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

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

Positive stains: synaptophysin, retinal S-antigen

Pineal gland tumors-general

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

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

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

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

Grade II 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

DD: pineoblastoma (Cancer 1980;45:1408)

Pineal parenchymal tumor of intermediate differentiation

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, free full text

Meningeal tumors

Meningioma

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: 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

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; menigothelial 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

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

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

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

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

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

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)

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

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)

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

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: intraspinal familial tumor in mother and child-PDF file, 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)

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

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)

Papillary meningioma

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

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

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)

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

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)

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

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)

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 cellularlity, 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

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

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

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 primary leptomeningeal melanoma (diffuse or nodular); both are aggressive with metastases to liver and bones

Focal leptomeningeal melanosis is common; usually melanocytes are sparse in leptomeninges, but more numerous over anterior/lateral cord, brainstem and base of brain

Case reports: metastasizing melanocytoma-like leptomeningeal tumor, 11 year old girl with malignant blue nevus of ear associated with large multinodular blue nevus at same location and 2 intracranial melanocytic tumors with different grade of malignancy, probably representing metastases (Hum Path 2004;35:1292), intraventricular melanoma (AJNR Am J Neuroradiol 1999;20:691-free full text)

Gross: melanocytomas are unilocular and nodular attached to dura

Micro: melanocytomas are hypercellular with cells in nests or sheets; oval nuclei with fine chromatin and prominent nucleoli; no/rare mitotic figures, usually no hemorrhage, necrosis or CNS invasion

Positive stains: vimentin, S100, HMB45

Negative stains: EMA

EM: basal lamina around cell groups, no desmosomes

DD: metastatic melanoma, melanotic meningioma (EMA+, desmosomes), melanotic schwannoma (basal lamina surrounds each cell)

References: AJSP 1999;23:745

Germ cell tumors

Germ cell tumors-general

<2% of intracranial neoplasms in children or adults < 20 years old in US (50 new cases annually in US); higher frequency in Japan and Taiwan

95% are midline in pineal or suprasellar regions, 10% involve both regions

Sacrococcygeal teratoma occurs at base of spine

Specimens are usually biopsies, not surgical resections

Divided into germinomas and non-germinomas

Germinomas have better prognosis than non-germinomas (Pediatr Neurol 2002;26:369)

Radiation therapy rarely causes cortical laminar necrosis (Pediatr Blood Cancer 2005;44:412)

References: eMedicine, National Cancer Institute (USA), Childs Nerv Syst 1999;15:578, Oncologist 2000;5:312 (free full text)

Germinoma

Most common intracranial germ cell neoplasm

Often teenagers and young adults; 2/3 male

May be mixed with other germ cell tumors

May derive from ectopic rests, transformation of resident germ cells or migration of germ cells late in development

Most common site is pineal region; also anterior or posterior third ventricle, rarely fourth ventricle

Rarely associated with dysgenetic syndromes

Immunostains useful because biopsy is often small

Relatively good prognosis (5-10 year survival is 75-95%) vs. 25-40% for non-germinoma germ cell tumors (Pediatr Neurol 2002;26:369)

Very sensitive to radiotherapy and chemotherapy; nongerminomatous germ cell tumors are less radiosensitive

Metastases may be due to surgical displacement of tumor; spinal cord metastases occur in 10-15% of patients

Staging:

T1: Smaller than 5 cm in diameter and located in the suprasellar, intrasellar, or pineal region

T2: Larger than 5 cm in diameter and located in the perisellar region

T3: May be smaller than 5 cm in diameter but invades and encroaches on the third ventricle

T4: Extends into the anterior, middle, or posterior fossa

N: not indicated for CNS tumors

M0: No evidence of gross subarachnoid or hematogenous metastasis

M1: Microscopic tumor cells found in the CSF

M2: Gross nodular seeding in the ventricular system or cranial subarachnoid spaces

M3: Gross nodular seeding in the spinal subarachnoid spaces

M4: Metastasis outside the cerebrospinal axis

Case reports: intramedullary tumor (free full text), 23 year old man with headaches and visual difficulties (Archives 2003;127:497)

Treatment: resection difficult due to high collagen content; radiation therapy helpful

Gross: soft, gray-pink, homogenous; variable encapsulation; usually poorly circumscribed and infiltrative

Micro: resembles seminoma/dysgerminoma; large, epithelioid cells with abundant PAS+ cytoplasm, large, round nuclei and irregular and pleomorphic nuclei; may have prominent nests of lymphocytes with occasional granulomatous inflammation that may obscure tumor cells (Neurol Med Chir (Tokyo) 2005;45:415); lymphocytes may smear in small biopsies; frequent mitotic activity and necrosis; syncytiotrophoblasts in 14%; less anaplasia than embryonal carcinoma; no cells intermediate in size between lymphocytes and large germinoma cells

Cytology: loose fragments or single large pleomorphic and polygonal cells with vacuolated cytoplasm, enlarged oval nuclei and prominent nucleoli; frequent mitotic figures, naked nuclei, foamy background; also smashed lymphoid cells with streaking

Positive stains: PLAP, PAS+ cytoplasm, CD117/c-kit, OCT4 (strong, often diffuse)

Negative stains: keratin, EMA, hCG and AFP (except for syncytiotrophoblasts)

EM: glycogen in cytoplasm, sparse cytoskeletal elements, prominent nucleoli

DD: embryonal carcinoma (25% are PLAP+), carcinoma (usually metastatic, keratin+, EMA+, 13% are PLAP+)

References: eMedicine #1, #2 (pineal germinoma), AJSP 2005;29:368 (OCT4 staining)

Embryonal carcinoma

Prognosis poorer than germinoma

May be associated with precocious puberty

Characterized by rapid and bulky growth and spread to liver and lungs; 60% have metastases at presentation

Treatment: chemotherapy, radiation therapy, surgery

Positive stains: alpha-fetoprotein

Yolk sac tumor

Rare intracranial tumor, usually in pineal or suprasellar regions

Also called endodermal sinus tumor

Prognosis poorer than germinoma (median survival 2 years or less)

Case reports: 22 year old man with Down’s syndrome and pineal tumor with solid pattern (free full text), 15 year old girl with frontal lobe tumor (free full text)

Gross: usually large

Micro: tubulopapillary structures with vacuolated cuboidal cells, cystic spaces with eosinophilic hyaline bodies, and Schiller-Duval bodies

Positive stains: alpha-fetoprotein

References: J Neurosurg 1999;90:133

Choriocarcinoma

Prognosis poorer than germinoma - median survival 22 months in cases with high hCG levels (Neurooncol 2004;66:225)

Serum levels of hCG are helpful

Case reports: neonatal intracranial tumor in one month old infant who died from extensive intracerebral hemorrhage, presumed from a placental metastasis (Archives 1990;114:1079), 8 year old boy with precocious puberty (J Paediatr Child Health 1993;29:464)

Micro: syncytiotrophoblasts (large multinucleated cells) and cytotrophoblasts

Positive stains: hCG

DD: metastatic choriocarcinoma (from gonads or placenta)

Teratoma

Tissue derived from ectoderm, endoderm and mesoderm (at least 2 of 3 germinal layers)

Usually well differentiated / grade I of IV

Incidence varies with age: 30-50% of congenital brain tumors, 2% of brain tumors in infants and children, 0.5% at all ages

Congenital cases are usually fatal; may replace cerebral hemispheres (Pediatr Pathol 1987;7:333)

Mature teratomas: have well differentiated tissue from all three germinal layers, including neuroectoderm, including epithelium that is solid, cystic, glandular or tubular, cartilage or other mesenchymal elements, glial and neuronal tissue

Immature teratomas: have less differentiated tissue from any of the three germinal layers; 50% with intracranial tumors die within one year

Poor prognosis: tissue resembling medulloepithelioma, neuroblastoma, retinoblastoma or ependymoblastoma

Pineal teratomas are more common in males, but saccrococcygeal teratomas are more common in females

Must sample thoroughly for correct diagnosis

Growing teratoma syndrome: enlarging teratoma after tumor treatment (Neurosurgery 2005;56:188)

Treatment: newborns - complete surgical excision (difficult)

Case reports: 27 week fetus with immature intracranial teratoma causing skull rupture and death (Archives 2004;128:102), congenital tumor of lateral ventricle (Neurol India 2001;49:170-free full text; Neurol Res 2005;27:53-free full text)

References: J Pediatr Hematol Oncol 2004;26:712 (associated with perioperative coagulopathy)

Tumors of the sellar region (see also Pituitary chapter)

Craniopharyngioma

Grade I of IV

Relatively rare; usually children (6-10% of intracranial malignancies), usually in sellar region near third ventricle

300 new cases per year in US, 1/3 are ages 0-14 years

Tumors may also have features of Rathke pouch cysts, and may arise from epithelial remnants of Rathke’s pouch that are trapped in pituitary stalk

Grows slowly and damages hypothalamus (causing endocrine abnormalities), compresses optic chiasm (causing bitemporal hemianopsia), blocks third ventricle (causing hydrocephalus)

Histologically benign but frequently recurs due to incomplete excision; rarely metastasizes or transforms to squamous cell carcinoma

Adamantinous subtype: usually children (ages 5-14 years); associated with beta-catenin mutations

Papillary subtype: usually older adults (ages 50+)

Case reports: metastatic tumor (Archives 2000;124:1356; AJNR Am J Neuroradiol 1999;20:1059-free full text), 47 year old woman with headaches and visual blurring, 12 year old girl with sphenoid sinus tumor (Archives 2005;129:e73)

Gross: solid and cystic; contents of adamantinomatous tumors resemble motor oil (color due to blood proteins, protein and cholesterol crystals secondary to hemorrhage)

Micro: either adamantinomatous (pediatric type), papillary (adult type) or mixed Adamantinomatous: relatively poorly circumscribed, nests and trabeculae of epithelium in fibrocollagenous stroma; peripheral cells show nuclear palisading; central cells are loose and termed “stellate reticulum”, often shows abundant keratin with “wet” appearance, may undergo cystic degeneration, calcification, xanthogranulomatous reaction; cyst fluid contains cholesterol crystals, cholesterol clefts, reactive giant cells; variable necrosis, inflammation and Rosenthal fibers; no keratohyaline granules

Papillary: well-circumscribed, composed of cores of fibrovascular stroma lined by well differentiated squamous epithelium that may separate to form pseudopapillae; resembles squamous papilloma; no stellate reticulum, no “wet” keratin, no calcification, no xanthogranulomatous inflammation; cystic fluid does not resemble motor oil

Negative stains: CK8, CK20 (Archives 2002;126:1174)

DD: metastatic carcinoma (usually no calcifications, no squamous epithelium), pilocystic astrocytoma (if only gliosis is sampled, more cellular, has microcysts), Rathke cleft cysts (CK8+, CK20+; both negative in craniopharyngioma)

References: eMedicine #1 (pediatric); #2, AJSP 1984;8:57

Ganglion cell tumor of pituitary

Rare; hamartomatous or neoplastic ganglion cells in sella turcica

May be associated with pituitary adenoma or hyperplasia

May be associated with acromegaly or Cushing’s syndrome or be apparently nonfunctioning

May represent neuronal differentiation of pituitary adenoma

Micro: adenoma with ganglion cell areas

References: AJSP 2000;24:607

Pituicytoma

Also called infundibuloma

Rare low grade glioma of sella and suprasellar region

May be derived from neurohypophyseal pituicytes (a specialized glial cell of the stalk and posterior lobe of the pituitary gland with supportive role for vasopressin and oxytocin-producing neurons)

Mean age 48 years, range 30-83 years; 6 of 9 were men

Visual symptoms, headaches or hypopituitarism

Radiology: solid, discrete, contrast enhancing masses within sella or suprasellar space

Treatment: total resection; may recur if incompletely excised

Case reports: 66 year old man with other endocrine neoplasms also (Archives 2001;125:527)

Micro: sheet, fascicles or storiform arrangement of plump bipolar spindle cells with abundant, slightly fibrillar eosinophilic cytoplasm without vacuoles and without granulation, mildly pleomorphic and oval nuclei with pinpoint nucleoli; rich capillary network with vessels often surrounded by radiating spindle cells; no infiltration of adjacent tissue, no Rosenthal fibers, no granular bodies, no granular axonal dilations (Herring bodies, normally present in neurohypophysis), no/rare mitotic figures

Positive stains: vimentin, S100, variable GFAP; low Ki-67 labeling index

Negative stains: synaptophysin, neurofilament, collagen type IV (not present between tumor cells), usually EMA

EM: bipolar spindle cells with abundant intermediate filaments; no meningothelial or ependymal features

DD: normal neurohypophysis (has axons, Herring bodies, perivascular anucleate zones with axonal terminations), pituitary adenomas (synaptophysin+, often chromogranin+, S100-, GFAP-), meningioma (whorls, psammoma bodies, nuclear inclusions, collagen deposition; EMA+, S100+ in fibrous variant, GFAP-; well defined desmosomes and interdigitating cell membranes), schwannoma (biphasic, hyalinized vessels, pericellular reticulin), benign fibrous histiocytoma (S100-), granular cell tumor, pilocytic astrocytoma

References: AJSP 2000;24:362

Pituitary adenoma

May grow into base of brain and resemble oligodendroglioma, ependymoma or meningioma

May be nonfunctional, particularly if gonadotropin-producing (no increase in plasma hormones)

Invasion of sella is associated with prolactin production (Arch Neurol 1977;34:742)

Most glow slowly and are considered benign, but others with benign histologic features invade the cavernous sinus, sphenoid sinus and base of brain

Often classified by hormone production (growth hormone, prolactin, TSH, ACTH, FSH or alpha-glycoprotein subunit)

Adenoma with uncertain malignant potential: high Ki-67, p53+ or invasive but not metastatic

Case reports: large tumor invading into cavernous sinuses (Neurol India 2005;53:105-free full text), ectopic pituitary adenoma with malignant transformation after multiple relapses (AJSP 2002;26:1078)

Positive stains: chromogranin, pituitary peptide hormones

EM: neurosecretory granules

Pituitary carcinoma

0.2 to 0.5% of adenohypophyseal tumors

Considered to derive from pituitary adenomas

Defined as tumors that have metastasized, since cannot differentiate based on histology (like other endocrine tumors)

Usually secrete ACTH or prolactin; “silent” pituitary tumors rarely metastasize

Highly aggressive, eventually causing death

Case reports: ectopic pituitary adenoma with malignant transformation after multiple relapses (AJSP 2002;26:1078)

Micro: may have nuclear pleomorphism with prominent nucleoli, mitotic activity

Positive stains: may have high Ki-67 labeling index, p53

DD: pituitary adenoma

References: AJSP 2003;27:477

Spindle cell oncocytoma of adenohypophysis

Described in 2002 (AJSP 2002;26:1048)

Mean 62 years, range 53-71 years

Associated with panhypopituitarism and variable visual field defect

Benign; no recurrence if totally excised

May derive from adenohypophyseal folliculostellate cells

Radiology: suprasellar extension; resembles pituitary adenoma; no dural involvement

Micro: fascicles of spindle cells with granular and eosinophilic cytoplasm; no/rare mitotic figures; no necrosis

Positive stains: vimentin, EMA, S100, galectin3

Negative stains: pituitary hormones, synaptophysin, chromogranin, GFAP, CAM 5.2, smooth muscle actin, CD34, CD68

EM: mitochodria rich in lamellar cristae; intermediate junctions and desmosomes, rough endoplasmic reticulum; no secretory granules

DD: metastatic extracranial oncocytic tumor, pituitary adenoma with oncocytic change (keratin+, synpatophysin+, neurosecretory granules+; chromogranin+, S100-, vimentin-, EMA-), meningioma with oncocytic change (EMA+ but intrasellar extension is rare; also whorls, interdigitation of cell membrane, S100- [except in fibrous meningioma]), ectopic salivary gland rests undergoing oncocytic transformation

Lymphoma and other hematopoietic lesions

Primary CNS lymphoma

Formerly called reticulum cell sarcoma or diffuse histiocytic lymphoma

By definition, occurs first in CNS without evidence of systemic lymphoma

<2% of brain tumors

Usually in cerebrum, but also elsewhere

May develop subsequent systemic lymphoma

Increased incidence (1000x) with AIDS and immunosuppression; also older immunocompetent patients

Most are high grade, diffuse large B cell lymphoma; other subtypes are rare (plasmacytoma, angiotropic lymphoma, Hodgkin’s lymphoma, MALT); but high incidence of T cell subtypes in Korea (17%, similar in Japan, vs. <5% elsewhere, AJSP 2003;27:919)

Steroid pre-treatment causes necrosis and makes diagnosis difficult

Pathogenesis uncertain since CNS lacks a regular lymphatic system

In previously healthy individuals, arise at age 50+ years, 60% male vs. mean age 10 years with inherited immunodeficiency, 37 years for transplant recipients, 39 years for AIDS patients

Often present with focal neurologic deficits (50-80%), neuropsychiatric symptoms (20-30%), increased intracranial pressure (10-30%), seizures (5-20%), eye symptoms (5-20%)

Usually discrete masses; rarely presents as diffuse, infiltrating condition without a cohesive mass, called lymphomatosis cerebri, associated with rapidly progressive dementia (Hum Path 2005;36:282)

CSF cytology helpful in diagnosing lymphoma of dura, leptomeningeal space or nerve roots

Radiology: bilateral, symmetric, subependymal, high signal foci on CT/MRI are suggestive; AIDS cases have multifocal, ring-enhancing lesions with central necrosis, resembling toxoplasmosis

Poor prognostic factors: multiple lesions, periventricular or meningeal involvement, associated immunodeficiency, age 60+ years, preoperative Karnofsky score 70 or less (J Clin Oncol 2003;21:266), expression of p53, c-myc or bcl6 in immunocompetent patients in one study (Archives 2003;127:208)

Survival: in immunocompetent patients treated with radiotherapy and chemotherapy, 2 year overall survival in 40-75% and 5 year overall survival in 25-45%; AIDS patients have median survival of 2-6 months, increasing to 13 months with multimodal therapy

Treatment: radiotherapy and chemotherapy

Case reports: Waldenstrom macroglobulinemia with CNS involvement (Archives 2002;126:1243), AIDS+ man with EBV+, KSHV+ primary effusion lymphoma in subarachnoid space (Hum Path 1999;30:981), 89 year old woman with peripheral T-cell lymphoma of cytotoxic/suppressor phenotype (AJSP 2003;27:682, 21 year old woman with B cell lymphoblastic lymphoma in middle cranial fossa (Surg Neurol 2004;62:80),)

Gross: single or multiple, discrete or infiltrative, often deep-seated and periventricular; tissue may be variegated, friable, granular, necrotic, hemorrhagic, gray-tan and resemble infarct or glioblastoma; tumors of dura mimic meningioma

DD: toxoplasmosis, glioblastoma (more nuclear and cellular pleomorphism, vascular proliferation, necrosis with pseudopalisading of tumor cells, GFAP+, CD45-, CD20-), metastatic lymphoma (tumor outside CNS), inflammatory lesions, metastatic carcinoma (more cohesive, no perivascular deposition, keratin+, CD45-, CD20-), demyelinating disorder (macrophage rich with preservation of axons), infarct (macrophage rich, axonal destruction)

References: eMedicine, National Cancer Institute (USA), RadioGraphics 1997:17

Secondary CNS lymphoma

Defined as peripheral lymphoma with secondary involvement of CNS

9% of lymphoma patients in one study (Eur J Cancer Clin Oncol 1989;25:703); CSF involvement in 9% of mantle cell lymphomas (Mod Path 2002;15:1073)

May involve dura, leptomeninges, cranial or peripheral nerves, vessels or CNS parenchyma

Short median survival of 5 months (Ann Hematol 2006;85:45)

Post-transplantation lymphoproliferative disease (PTLD)

Associated with organ transplantation or immunosuppression

CNS involvement in 19% of cases of PTLD, associated with high mortality (88% at 6 months in one study)

Almost all are high grade lymphomas (AJCP 2004;121:246)

Lymphoma cases are usually EBV+

Case reports: EBV+ low-grade lymphoproliferative disorder in 7 year old, HIV+ girl (not post-transplant, Archives 1999;123:83), clonally distinct EBV+ abdominal and CNS lesions (Hum Path 1999;30:1262)

Anaplastic large cell lymphoma

Rare in CNS (either primary or secondary)

Aggressive (rapidly fatal)

Favorable prognostic factors: ALK1+, young age (AJSP 2003;27:487)

Case reports: 46 year old AIDS patient with ALK negative tumor (Archives 2004;128:324), CD30+, ALK+ tumor (An Oncol 2002;13:1827-free full text), CNS relapse in patient without initial CNS disease (J Pediatr Hematol Oncol 2003;25:975), 2 year old boy (Med Pediatr Oncol 1997;28:132), leptomeningeal seeding with hydrocephalus after chemotherapy (Acta Haematol 1996;95:135), early detection of relapse with low CSF involvement (Pediatr Blood Cancer 2005;44:400)

Micro: large lymphoid cells with abundant cytoplasm and pleomorphic nuclei, often horseshoe or kidney-shaped; usually necrosis and mitotic activity; variants include small cell and lymphohistiocytic

Positive stains: CD30, ALK1 (often)

Molecular: T cell receptor gene rearrangements; t(2;5) involving ALK1 and NPM

DD: Hodgkin’s lymphoma, CD30+ T cell lymphomas, metastatic tumors, mycobacterial infection (Hum Path 1999;30:978)

Angiotropic lymphoma

Also called malignant angioendotheliomatosis, intravascular lymphoma

Uncommon cause of primary CNS lymphoma

Presents as rapidly progressive dementia with multifocal neurologic deficits, usually ages 60+ years

Mean survival 9-13 months

May present with CNS mass lesion (Pathol Int 2004;54:231)

Treatment: chemotherapy; may be curative

Case reports: 47 year old man with presumed CNS vasculitis (AJNR Am J Neuroradiol 2002;23:239-free full text); causing spinal cord stroke with paraplegia (AJNR Am J Neuroradiol 2004;25:1831), causing cauda equina syndrome (Clin Neurol Neurosurg 1992;94:311)

Micro: large, noncohesive, pleomorphic lymphoid cells (diffuse large B cell lymphoma type) within small and intermediate blood vessels

Positive stains: CD45, usually B cell markers; also bcl2

DD: intravascular dissemination of angiosarcoma (AJSP 1997;21:1138)

References: Hum Path 2000;31:220

Diffuse large B cell lymphoma

By definition, primary CNS disease arises exclusively in central nervous system with no obvious lymphoma outside CNS at diagnosis

5-10% of CNS neoplasms in patients ages 75+ (Hum Path 2003;34:1137)

2-12% of AIDS patients at autopsy

Usually EBV- in immunocompetent patients vs. EBV+ in AIDS patients

Mean age: 10 years old if inherited immunodeficiency, 37 years for post-transplant, 39 years for AIDS patients

Favorable prognostic factors: single lesion, no periventricular or meningeal involvement, no immunodeficiency, age < 60 years, Karnofsky score > 70; also negative for p53, c-myc and bcl6 in one study (Archives 2003;127:208)

Median survival: 17-45 months if immunocompetent and chemoradiation therapy; 13.5 months with AIDS and multimodal therapy

Post-transplant: present nonspecifically, progress rapidly, stereotactic brain biopsy has significant mortality, survival is poor (Neuro-oncol 2000;2:229)

Case reports: dural tumor presenting as intracranial mass (Archives 2000;124:1700), 49 year old man with progressive dementia, cryoglobulin deposition within tumor bed in immunocompetent patient (Hum Path 2003;34:720)

Micro: dense cellular aggregates of atypical lymphoid cells with dense perivascular aggregates; may infiltrate parenchyma diffusely, mix with gliosis and resemble glioma; often smearing of lymphoma cells with needle biopsy

Positive stains: CD20, CD79a, monoclonal immunoglobulin; trichrome, type IV collagen and GFAP are helpful in identifying lymphoma invasion of vessels and parenchyma and differentiating from desmoplasia; may have reactive CD3+ T cells

Molecular: immunoglobulin gene rearrangement

References: Archives 2004;128:595

DD: PNET (synaptophysin+), undifferentiated small cell carcinoma (keratin+), Langerhans cell histiocytosis (abundant cytoplasm, reniform nuclei, S100+, CD1+), tuberculoma (J Neurol Neurosurg Psychiatry 2004;75:1636-free full text), progressive multifocal leukoencephalopathy (Rinsho Ketsueki 2000;41:507)

Erdheim-Chester disease of CNS

Very rare (<100 cases reported), nonfamilial, neoplastic, xanthogranulomatous, non-Langerhans cell systemic histiocytosis first identified by William Chester in 1930

Usually associated with disease of long bones

Etiology not well understood

Mean age 57 years, range 25-76 years, no gender preference

Three year survival is 50-65%; prognosis usually depends on extent of extraosseous disease

Rarely involves CNS; usually hypothalamus and posterior pituitary (causing diabetes insipidus), retroorbital space; may affect dura

Case reports: 55 year old woman with tumors attached to pituitary, tentorium and brainstem (Clin Neuropathol 2003;22:246), brain stem infiltration by both Langerhans cell histiocytosis and Erdheim- Chester disease (Clin Exp Pathol 1999;47:71)

Micro: diffuse infiltration with large, foamy histiocytes, lymphoid aggregates, fibrosis, rare Touton-like giant cells

Cytology: lymphohistiocytic elements and large multinucleated cells with abundant cytoplasm, vesicular nuclei and prominent nucleoli (Diagn Cytopathol 2004;31:420)

Positive stains: CD68 and factor XIIIa (strong), S100 (weak or negative)

Negative stains: CD1a

EM: lipid droplets in cytoplasm but no Birbeck granules

DD: meningiomas (AJNR Am J Neuroradiol 2004;25:134-free full text, J Neurol Neurosurg Psychiatry 1999;66:72-free full text)

References: J Neurosurg 1997;86:888 (2 CNS cases); not CNS - AJSP 1999;23:17, Hum Path 2000;31:734, Hum Path 1999;30:1093

Histiocytic lymphoma/sarcoma

Very rare

Often fever, weight loss, hepatosplenomegaly and intestinal obstruction

Case reports: occipital lobe mass also involving meninges as a thick exudate (AJSP 2003;27:258)

Micro: large groups or sheets of large cells with abundant eosinophilic cytoplasm, pleomorphic vesicular nuclei, distinct nucleoli; also necrosis, neutrophils (variable abscesses) and chronic inflammatory cells, hemophagocytosis; no infiltration of vascular walls

Positive stains: CD68, lysozyme, HAM56; Ki-67 index > 20%; variable S100

Negative stains: myeloperoxidase, dendritic markers, CD30, ALK1, CD3, CD20, CD21/CD35, CD1a, ALK1, GFAP, cytokeratin

Molecular: no t(2;5); polyclonal

EM: abundant cytoplasm with irregularly folded or multisegmented nuclei, lysosomes; no Birbeck granules, no interdigitating cell processes, no cell junctions

DD: other lymphomas and histiocytic neoplasms (use immunohistochemistry), inflammatory processes

References: AJSP 2001;25:1372

Hodgkin’s lymphoma

Case reports: 54 year old with intracerebral disease without dural attachment (AJSP 1999;23:477)

Inflammatory pseudotumor

Also called spindle cell pseudotumor, plasma cell granuloma, inflammatory myofibroblastic tumor

Rare, nonneoplastic lesion

May be intracranial extension of extracranial tumor

Usually in lung and airways; rarely intracranial or within spinal cord affecting young men

Treatment: complete resection, variable radiation therapy or steroids; may recur

Case reports: 70 year old man with intracranial tumor (Archives 2003;127:e220), 38 year year old man receiving steroids for sarcoidosis with Mycobacterium avium intracellulare (AJSP 1999;23:1294)

Micro: inflammatory proliferation of polyclonal plasma cells with variable lymphocytes, neutrophils, eosinophis and histiocytes; fibrovascular background; variable giant cells, calcifications, circular fibrosis of small veins

Stains: plasma cells are polyclonal; acid fast bacilli if due to Mycobacteria

DD: plasmacytoma, lymphoplasmacyte-rich meningioma (has areas of classic meningioma, EMA+), lymphoma (monoclonal)

References: Hum Path 2003;34:253

Langerhans cell histiocytosis

Rare lytic skull lesion or parasellar mass

Children and young adults

May arise from primary histiocytic proliferation with secondary atrophy or from demyelination and gliosis of unknown origin (J Child Neurol 2000;15:150)

Case reports: 29 year old woman with post-traumatic frontal bone mass, 13 year old girl with temporal bone mass, brain stem infiltration by both Langerhans cell histiocytosis and Erdheim- Chester disease (Clin Exp Pathol 1999;47:71), necrotic, hemorrhagic, focally infiltrative (but benign) tumor (Clin Neuropathol 1993;12:179),

Micro: cells with abundant eosinophilic cytoplasm and reniform (kidney / coffee bean shaped) nuclei with grooves; variable collagen, gliosis and infiltrating T cells; may be partially infiltrative of surrounding CNS parenchyma or circumscribed granulomas

Positive stains: S100, CD1a; also CD68 (macrophages and giant cells)

Negative stains: GFAP

EM: Birbeck granules

References: Brain 2005;128(Pt 4):829, Neurosurg Rev 1996;19:247

Leukemia

See also Leukemia chapter

Usually diagnosed by CSF cytology

Blast crises of >300K may be associated with parenchymal or meningeal mass lesions and intravascular leukostasis, particularly in AML

Case reports: acute monocytic leukemia presenting as temporal lobe mass (Archives 1999;123:327), AML relapse presenting as cerebellar granulocytic sarcoma / myeloblastoma (Mod Path 1999;12:1186)

Lymphomatoid granulomatosis

Lymphoproliferative disorder with features of inflammation, vasculitis and neoplasm; usually B cell disorder with reactive T cells

Has high rate of CNS involvement (20-50%), often associated with pulmonary disease

Rarely is isolated to CNS

May progress to lymphoma, particularly in AIDS patients

Micro: angiocentric inflammation due to atypical lymphocytes with vessel wall destruction; usually no well formed granulomas

Positive stains: EBV (Mod Path 1990;3:435)

References: AJNR Am J Neuroradiol 2001;22:1283 (free full text)

Rosai-Dorfman disease

Also called sinus histiocytosis with massive lymphadenopathy

Often (25-43%) has extranodal involvement

Rare (100 cases/year in US), and isolated CNS findings are extremely rare

Benign, but may be associated with systemic disease

Children and young adults (mean age 41 years, range 22-63 years)

CNS tumors usually associated with dura

Treatment: surgical biopsy or excision

Case reports: 50 year old woman with leptomeningeal disease, dural based masses, 48 year old woman with dural based intracranial tumor (Archives 2001;125:1115), relapsing intracranial disease treated with radiation (J Neurol Neurosurg Psychiatry 2001;71:538-free full text), 68 year old woman with isolated dural disease (AJNR Am J Neuroradiol 2003;24:515-free full text)

Micro: proliferation of variably sized, pale staining histiocytes, the larger ones may exhibit emperipolesis (engulf intact lymphocytes); often extensive lymphoplasmacytic infiltrate and collagen

Cytology: Rosai-Dorfman histiocytes (voluminous pale pink cytoplasm, single or multiple nuclei, large and hyperchromatic, with lymphagocytosis); also scattered lymphoid aggregates with loose mixture of lymphocytes, plasma cells and classic histiocytes (Acta Cytol 2003;47:1111)

Positive stains: CD68, S100

Negative stains: CD1a

DD: Langerhans cell histiocytosis, inflammatory pseudotumor, meningioma-lymphocytoplasmic rich subtype, nodular sclerosing Hodgkin’s lymphoma

References: Mod Path 2001;14:172, Clin Neuropathol 2005;24:112 (isolated CNS disease)

Mesenchymal and other tumors

Chondroma

Arises from bones of skull

Rarely in meninges or CNS parenchyma

Angiography: vascular mass displacing adjacent cortical vessels (GE medcyclopaedia)

Case reports: intracranial chondroma (AJNR Am J Neuroradiol 1997;18:889-free full text), arising from falx (AJNR Am J Neuroradiol 1997;18:573-free full text), associated with previous depressed skull fracture (Acta Neurochir (Wien) 2005;147:343), intradural convexity chondroma (W V Med J 2000;96:612), cystic falcine chondroma (Br J Neurosurg 1999;13:426)

Micro: mature hyaline cartilage

References: eMedicine

Chondrosarcoma

Classic subtype

Case reports: parafalcine tumor (AJNR Am J Neuroradiol 2003;24:245-free full text)

Mesenchymal chondrosarcoma

Rare

Intracranial or spinal meninges or cauda equina

Children or young adults

Treatment: surgery; radiation may be more helpful than chemotherapy (J Exp Clin Cancer Res 2005;24:317)

Case reports: craniocervical junction (Clin Neurol Neurosurg 1990;92:343), 13 year old girl with huge intracranial tumor (Kaohsiung J Med Sci 2004;20:240), with rhabdomyosarcomatous differentiation (Br J Neurosurg 2001;15:419)

Micro: dimorphic pattern of well differentiated cartilage with abrupt boundary from undifferentiated stroma composed of small round/oval cells resembling lymphoma, hemangiopericytoma or Ewing’s sarcoma/PNET; occasional spindle cells; minimal pleomorphism, no/rare mitotic figures

Positive stains: vimentin (100%), S100 (100% in cartilaginous component), cytokeratin (25%), GFAP (25%)

Molecular: usually diploid

DD: small blue cell tumors (Ewing’s/PNET, lymphoma, small cell osteosarcoma; all usually lack chondroid lobules)

References: Cancer 1996;77:1884

Myxoid chondrosarcoma

Case reports: intracranial tumor (Acta Neurochir (Wien) 2002;144:735), tumor of jugular foramen (Clin Neuropathol 2004;23:232)

Micro: rows of cuboidal cells in myxoid background, resembling chordoma

Positive stains: S100, vimentin

Negative stains: keratin

Molecular: t(9;22)(q22-31;q11-12): TEC/CHN and EWS genes

Poorly differentiated chondrosarcomas

Rare

Usually involve meninges

Micro: cartilage production may be sparse

Positive stains: S100, but many other CNS tumors are S100+

DD: other sarcomas, meningeal gliomatosis, carcinomatosis (lack cartilage production)

Chordoma

Rare malignant midline bone tumor arising from fetal notocord, usually within vertebral bodies, but possibly also in intervertebral discs or presacral soft tissue

May arise from benign notocordal tumors (Mod Path 2005;18:1005)

Usually males, age 40-60 years

Slow growing with repeated recurrences, eventually fatal, perhaps 10 years later; late distant metastases to skin, bone, ovary (Archives 1990;114:208)

May dedifferentiate to high grade sarcoma with poorer prognosis

Invasiveness may be due to cathepsin K expression (Hum Path 2000;31:834)

Sites: 50% sacrococcygeal (ages 40-59 years), 35% spheno-occipital / clivus (particularly children, image of clivus), 15% thoraco-lumbar spine

Sacrococcygeal: sacrum destroyed by osteolytic tumor; may extend into retroperitoneum, presents as palpable extrarectal mass

Spheno-occipital: presents as nasal, paranasal or nasopharyngeal mass involving cranial nerves

Posterior mediastinum: Xray presentation is well-circumscribed, encapsulated soft tissue mass separate from spine (Hum Path 1995;26:1354)

Poor prognostic factors: large tumor size, positive surgical margins, tumor necrosis, high proliferative activity, areas of dedifferentiation; also up regulation of N cadherin and down regulation of E cadherin (AJSP 2005;29:1422)

Treatment: radical excision, radiation

Case reports: spheno-occipital tumor evolving to acute pontocerebellar hemorrhage (Archives 1989;113:1075), chordoma of distal ulna (chordoma periphericum, AJSP 2001;25:263), lumbosacral tumor with high grade malignant cartilaginous and spindle cell components (AJSP 1990;14:384)

Gross: soft, gelatinous, hemorrhagic, gray

Micro: cords and lobules of physaliferous (bubbly) cells; lobules separated by fibrous septa; cells may be very large, have vacuolated cytoplasm, prominent vesicular nucleus; usually extensive mucoid stroma; also small tumor cells with small nucleus; rare mitotic figures

Positive stains: S100, keratin (CK 8/18, CK19, AE1-AE3), EMA, 5' nucleotidase, glycogen, neural-type cadherin (Archives 2002;126:425), variable CK903, vimentin, CEA and lysozyme

Negative stains: CK7, CK20

Molecular: aneuploid

EM: mitochondria-endoplasmic reticulum complexes, parallel bundles of crisscrossing tubules, desmosomes (Archives 1993;117:1055)

DD: metastatic renal cell carcinoma (not lobulated, S100 negative) or other carcinoma, chondrosarcoma (not midline, no fibrous septa, EMA and keratin negative), signet cell adenocarcinoma of rectum, myxopapillary ependymoma (negative for epithelial markers), parachordoma (soft tissue tumor composed of epithelioid cells, smaller “glomoid” cells and spindle cells, negative for CK7, CK19, CK20, CEA), chordoid meningioma (keratin-), hemangioblastoma (mucin-)

References: Archives 1988;112:553 (stains), Mod Path 1997;10:545 (keratin stains), Archives 2004;128:1457 (physaliferous cells), more information

Chondroid chordoma

Chordoma with prominent cartilaginous component - a controversial entity

Usually spheno-occipital region

Better prognosis than classic chordoma

Some consider them to be chondrosarcomas

Micro: matrix of amorphous blue ground substance with lacunae containing enlarged and slightly atypical cells; admixed areas of conventional chordoma

Cytology: low cellularity with loose round or stellate cells in myxoid background; cells have variably vacuolated cytoplasm, round/oval nuclei, mild cellular pleomorphism (Diagn Cytopathol 1999;21:335; Acta Cytol 1997;41:913)

Positive stains: both components - keratin, EMA, vimentin; often S100, occasionally CEA

EM: well formed tonofilament desmosome complexes, crystalline tubular structures within prominent and dilated rough endoplasmic reticulum, intracytoplasmic glycogen aggregates, abundant fibrillogranular matrix (AJSP 1983;7:625)

References: AJSP 1992;16:1144

Epithelioid hemangioendothelioma

Rare; usually cerebral hemispheres

Intermediate grade between hemangioma (benign) and angiosarcoma (high grade)

All ages, but 2/3 male

Usually unifocal

Favorable prognosis with complete resection; may recur or seed neuraxis; deaths are rare

Radiologic: associated with peritumoral vasogenic edema and homogenous contrast enhancement

Treatment: surgical excision, possibly radiation therapy (if incomplete excision) or alpha-interferon

Case reports: 49 year old woman with suprasellar tumor (Archives 2004;128:1289)

Micro: histiocytoid, epithelioid and spindled areas with intracytoplasmic lumina; vascular lumina are not apparent or focal; often chronic inflammatory cells, eosinophils and mast cells; variable mitotic figures; no dilated vascular spaces of cavernous hemangioma; no significant hemorrhage; no marked atypia

Positive stains: CD31, CD34, factor VIII related antigen

EM: endothelium with Weibel-Palade bodies, abundant intermediate filaments, surrounded by basal lamina

Molecular: t(1;3)(p36.3;q25) in some cases (involves PAX7)

DD: metastatic tumor from known primary (Eur Respir J 2004;23:483) or undisclosed primary (J Neurooncol 2004;67:337)

References: AJSP 1996;20:707

Fibro-osseous lesions

Also called calcifying pseudoneoplasms of neural axis

Uncommon

May be associated with dura along vertebral column

Probably reactive

Treatment: wide excision

Micro: various combinations of palisading spindle cells, epithelioid cells and multinucleated cells in fibrous stroma and bone; nodular chondromyxoid-like matrix

References: AJSP 1999;23:1270

Hemangioblastoma

WHO Grade I of IV (benign); slow growing and indolent, but symptoms due to mass effect and peritumoral edema

1-2% of intracranial tumors

Often in cerebellum; also spinal cord, meninges

Either part of von Hippel-Lindau disease (25-30%, inherited mutation of VHL gene on 3p25-26; autosomal dominant, hemangioblastomas of cerebellum and retina, cysts of liver and pancreas, pheochromocytoma, kidney tumors) or sporadic (often with somatic mutation of VHL gene)

Loss of VHL promotes increased production of vascular endothelial growth factor and erythropoietin

May be associated with loss of unknown tumor suppressor gene at 22q13 (Hum Path 2004;35:1105)

VHL patients often have new multiple, small, remote tumors (Brain Tumor Pathol 2004;21:75)

Case reports: cerebral tumor (Archives 2003;127:e382), intradural extramedullary spinal mass, 27 year old woman with cerebellar mass

Gross: well circumscribed mural nodule (containing tumor) associated with large fluid filled cyst

Note: obtain frozen section from mural nodule, NOT cyst wall

Micro: proliferation of capillaries with variable sized, closely packed, thin walled vessels and large neoplastic stromal cells with pink to clear foamy cytoplasm with fine vacuoles containing PAS+ lipid; nuclei are hyperchromatic; cyst wall has gliosis and Rosenthal fibers (resembling pilocytic astrocytoma); numerous mast cells in tumor mass (Folia Neuropathol 1999;37:138), usually no atypia; no fibrillar cells, no necrosis, no/rare mitotic figures

Cytology: nonfibrillar stromal cells with large nuclei and vacuoles

Positive stains: stroma is positive for NSE, lipid (at frozen section), reticulin, CD34; also VEGF, inhibin alpha (AJSP 2003;27:1152); occasionally erythropoietin, GFAP, S100

Negative stains: EMA, keratin, CD10 (Mod Path 2005;18:788)

EM: variable secretory granules

DD: endocrine neoplasm (no endocrine gland of origin nearby), fibrillary astrocytoma (at frozen section due to bursting from lipid), renal cell carcinoma (nuclear atypia, large nucleoli, mitotic figures, cytokeratin+, EMA+, NSE-, inhibin-)

References: eMedicine (VHL); molecular-VHL

Lipoma

Rare; either congenital malformation or no other pathologic findings (Clin Neurol Neurosurg 2005 May 11; [Epub ahead of print])

Often midline near corpus callosum, quadrigeminal plate, hypothalamus, spinal canal, cauda equina, tuber cinereum

Causes headache, seizures or no symptoms

Associated with epidermal nevus syndrome (Neuropediatrics 2000;31:175), encephalocraniocutaneous lipomatosis (Am J Med Genet 2000;91:261), Goldenhar-Gorlin syndrome (Childs Brain 1984;11:285), agenesis of corpus callosum (Pediatr Neurol 2005;32:94)

May be due to focal disturbances in cerebral cortical development (AJNR Am J Neuroradiol 2000;21:1718-free full text, Acta Neuropathol (Berl) 2005;109:339)

Case reports: parietal lipomeningocele (Neurol Med Chir (Tokyo) 2005;45:112-free full text), 10 year old with lipoma of tuber cinereum (Archives 2005;129:708)

Micro: mature adipose tissue; also Schwann cells, bone, cartilage, hamartomatous blood vessels

References: Archives 2003;127:1475 (lipomatous choristomas of cranial nerve VIII)

Malignant peripheral nerve sheath tumor (MPNST)

Grade III or IV

Locally aggressive, metastasizes late

Usually arises in peripheral nerves, usually is a transformed plexiform neurofibroma (associated with neurofibromatosis 1), but may also be associated with radiation therapy or arise denovo; only rarely arises from malignant degeneration of schwannomas

Very rare in cranial cavity; rarely involves cranial nerves V and VIII

Case reports: trigeminal nerve tumor with loss of S100+ at recurrence (Acta Neurochir (Wien) 2000;142:591), collision tumor of MPNST with rhabdomyoblastic differentiation (triton tumor) and ependymoma at cerebellopontine angle (Archives 2001;125:1113)

Gross: fusiform or plexiform enlargement of nerve with thin capsule; homogeneous gray cut surface

Micro: infiltrates nerve (important criteria since histologic features vary) and soft tissue with necrosis; also marked hypercellularity (varies within tumor) with cells having spindle-shaped nuclei with tapered ends, nuclear pleomorphism, brisk mitotic activity with abnormal forms

Patterns: fibrosarcoma, MFH, Schwann cells, triton tumor (rhabdomyosarcoma regions), chondrosarcoma

Positive stains: p53; variable S100

DD: metastatic MPNST (Neurol Med Chir (Tokyo) 2000;40:116-free full text, Folia Neuropathol 2004;42:43, Clin Neuropathol 1990;9:290-pigmented spinal tumor)

Epithelioid MPNST

Very rare; aggressive

Case reports: tumor of mandible and skull base (J Craniofac Surg 1997;8:417), cerebral metastasis from forearm tumor (Neurosurgery 1991;29:906)

Micro: tumor cells have distinct cell borders and epithelial cell nests

Cytology: discohesive cells with plasmacytoid or epithelioid appearance (Diagn Cytopathol 1997;17:200)

Positive stains: S100

Negative stains: cytokeratin

Neurofibroma

Benign (grade I)

Arises within nerves and infiltrates them

Having multiple tumors or plexiform subtype is associated with neurofibromatosis 1

Case reports: plexiform tumor of cauda equina (Surg Neurol 2005;63:182), lateral wall of cavernous sinus (Aust N Z J Surg 1988;58:594), combined neurofibroma-granular cell tumor of middle cranial fossa (Pathol Res Pract 1978;163:378)

Gross: fusiform enlargement of nerve from which it arises

Micro: spindled Schwann cells with wire like collagen fibrils mixing with axons, stromal mucosubstances, mast cells, Wagner-Meissner corpuscles, fibroblasts; no Antoni A or B areas; vessels are thin walled without perivascular hemosiderin

Positive stains: S100, Leu7, variable GFAP

Negative stains: EMA, cytokeratin

Sarcoma (other than chondrosarcoma)

Very rare (<1% of CNS tumors); more likely to be another tumor that is misdiagnosed

Usually cerebral, but may be cerebellar or spinal cord

Median age 28 years, range 3-63 years

Often associated with prior radiation therapy (such as for craniopharyngioma or pituitary adenoma); these sarcomas cause rapid death from local invasion

Better prognosis if low grade, but even high grade sarcomas have better survival than glioblastoma multiforme (AJSP 2002;26:1056)

Case reports: meningeal sarcomas with meningothelial and leiomyoblastic differentiation (AJSP 2000;24:1273), 15 month old boy with hypomelanosis of Ito and primary meningeal rhabdomyosarcoma (Archives 2000;124:762), follicular dendritic cell sarcoma (J Neurosurg 2003;99:1089), 9 year old boy with fibrosarcoma (J Neurooncol 2004;68:161)

Gross: median size 4 cm (1-8 cm)

Micro: fibrosarcoma, MFH or undifferentiated subtypes are most common; often high grade; no glial or meningothelial features

Negative stains: EMA, GFAP

DD: lymphoma, PNET, giant cell glioblastoma

References: fibrosarcoma (Neurol India 2000;48:396-free full text), Ewing’s sarcoma in CNS (Clin Neuropathol 2005;24:184; Acta Neurochir (Wien) 1991;113:48)

Schwannoma

Also called neurilemoma; improperly designated as acoustic “neuroma”

Benign (grade I)

7% of intracranial neoplasms

More common in older adults, women

Derived from Schwann cells (neural crest derivation)

Tend to arise on and compress peripheral aspects of nerves, 90% on CN VIII (“acoustic schwannoma”); rare on CN V or VII or other cranial nerves

In spinal cord, usually attached to dorsal spinal nerve root, and may extend into cord

Bilateral CN VIII tumors: associated with neurofibromatosis type 2 (NF2); NF2 patients also have tumors at unusual locations, meningeal proliferations and gliomas; poorer prognosis is associated with tumors 2 cm or larger and earlier age at onset (J Neurosurg 2003;99:480)

Symptoms associated with compressed nerve (tinnitus or hearing loss with CN VIII)

Treatment: radiation therapy may cause malignant transformation, particularly in children or NF patients (J Med Genet 2005 Sep 9; [Epub ahead of print])

Case reports: intracranial subfrontal tumor (Neurol India 2004;52:248-free full text), patient with spinal and intracranial melanotic schwannomas (J Neurooncol 2004;68:249), intracerebral tumor (Pathol Int 2005;55:514)

Gross: firm gray masses; may have cystic and xanthomatous change and hemorrhage; attached to nerve, but can be separated from it; does not invade but can displace brainstem and spinal cord

Micro: circumscribed and often encapsulated; biphasic (less common at cerebellopontine angle); composed of uniformly spindled Schwann cells with Antoni A (cellular fascicular) and Antoni B (myxoid; vacuolated) regions; vessel walls with perivascular hemosiderin; variable Verocay bodies (eosinophilic cores and nuclear palisading); cells are spindled with ill defined cytoplasm, dense chromatin; no axons, no mitotic figures

Degenerative changes (ancient change) - nuclear pleomorphism, xanthomatous change, vascular hyalinization; common but no significance

May have Rosenthal fibers or eosinophilic granular bodies (Archives 1997;121:1207)

Positive stains: S100, Leu7; type 4 collagen (stains abundant parenchymal reticulin), CD34 (Antoni B areas), calretinin (Antoni A areas); silver stain shows minimal axons; variable GFAP

Negative stains: EMA, cytokeratin, CD31, ER, PR, BCL2

Molecular: 22q- due to mutations of neurofibromatosis 2 gene in these patients

EM: continuous basement membranes along exterior surface of cells

DD: fibroblastic meningioma (whorls, psammoma bodies, EMA+), solitary fibrous tumor, tanycytic ependymoma (no abundant parenchymal reticulin), subependymoma, astrocytoma (no abundant parenchymal reticulin), hemangiopericytoma

References: eMedicine (Schwannoma, cranial nerve)

Solitary fibrous tumor

Rare; often not recognized when found in dura

Usually dural based lesion of cranium or spinal canal; occasionally lateral ventricle or spinal cord

May recur (if inadequately resected); rarely metastasizes but still has indolent course

Treatment: gross total resection; may recur if incomplete resection (Clin Neuropathol 2005;24:252)

Case reports: 67 year old man with tumor at spinal nerve root (Archives 2004;128:335), quadriplegic patient with recurrent paraspinal tumor (Archives 2002;126:987), 61 year old woman with malignant tumor, meningeal tumor, 53 year old woman with solitary fibrous tumor and salivary gland heterotopia at cerebellopontine angle (AJSP 2004;28:139), infiltrative tumor involving cavernous sinus, sphenoid sinus and pituitary fossa (Ann Diagn Pathol 2003;7:169), brain invasive tumor (Int J Surg Pathol 2002;10:217), with CSF dissemination (J Neurosurg 2004;101:1045), tumor of hypoglossal nerve (AJNR Am J Neuroradiol 2003;24:343-free full text)

Gross: smooth surface, no capsule; white-tan, firm, slightly rubbery, compresses adjacent parenchyma

Micro: haphazard (patternless) arrangement of monomorphic spindle cells with abundant ropy collagen mixed with tumor cells; may have alternating hypo- and hypercellular areas with perivascular hyalinization or myxoid degeneration; usually has hemangiopericytoma-like vascular pattern; no mitotic figures or necrosis

May have more aggressive behavior if hypercellular, pleomorphism, mitotic activity, necrosis (Brain Pathol 2001;11:485)

Positive stains: CD34, CD99, BCL2, vimentin; variable ER, PR

Negative stains: EMA, S100, smooth muscle actin, desmin, keratin, CD31

EM: resemble fibroblasts

DD: hemangiopericytoma (80% recurrence rate, often causing death, has delicate prominent pericellular reticulin fibers, usually no dense collagen bands, focal CD34+), fibrous meningioma (cellular whorls and psammoma bodies, more common, no dense collagenous bands, usually EMA+, S100+, weak/negative CD34 staining), schwannoma (alternating Antoni A and B areas, strongly S100+)

References: Archives 2003;127:432, Am J Clin Pathol 1996;106:217 (meningeal tumors)

Textiloma

Also called gossypiboma, gauzoma, muslinoma

Foreign body tumor composed of nonresorbable or resorbable substances used for hemostasis in neurosurgical procedures

Micro: core of degenerating hemostatic agent with surrounding inflammation

DD: recurrent tumor (by MRI), radiation necrosis

References: Archives 2004;128:749

Metastatic tumors to CNS

Metastases to CNS - general

Most common brain tumor seen in community hospitals are metastases (50% of intracranial tumors in hospitalized patients)

Primary is usually known - melanoma or carcinoma, occasionally germ cell tumor

80% from lung, breast, skin (melanoma), kidney, GI

Common with choriocarcinoma

Common presentation is adult with seizures or ataxia

Dural metastases are often from breast and prostate, but also unusual primaries; may have survival of 2+ years (Archives 2001;125:880)

Case reports: metastatic salivary gland pleomorphic adenoma to spinal cord (Archives 2003;127:887)

Gross: sharply demarcated lesion at gray-white matter junction, surrounded by edema

Metastatic carcinoma to CNS

Metastases to brain: lung, breast, kidney, GU

Metastases to vertebral column: often prostate, breast or hematopoietic neoplasm

Metastases with unknown primary: lung, colon, kidney

Rarely produces carcinomatous meningitis, with poor prognosis

Multiple lesions are suggestive of metastasis vs. primary CNS tumor

Usually to cerebrum, but no distinct patterns

Favorable prognostic factors: single metastasis, younger age, surgical resection of metastasis, primary in lung (non-small cell), breast, melanoma, renal cell or ovary

Meningeal carcinomatosis: represents 4-8% of metastatic brain tumors; diffuse spread of tumor in subarachnoid space; associated with carcinoma of lung and breast and ALL; poor prognosis; repeat lumbar punctures and immunocytochemistry may be helpful in differentiating from aseptic meningitis (Archives 2000;124:759)

Case reports: meningeal carcinomatosis - from gallbladder carcinoma (Archives 2001;125:1120), from renal collecting duct carcinoma (Archives 1999;123:638); from melanoma (Hum Path 2003;34:625), from contralateral adenoid cystic carcinoma of external ear canal (Archives 2002;126:87)

Micro: epithelial cells with discrete cell boundaries, pushing margin except for small cell carcinoma (infiltrative)

Recommended stain panels: TTF1 (lung and thyroid), cytokeratin and CAM 5.2, CK7, CK20, PSA

Breast carcinoma: CK7+, CK20-, CAM5.2+ but TTF1 negative

Lung adenocarcinoma: CK7+, CK20-, CAM5.2+ but TTF1+

Colon carcinoma: CK7-, CK20+, TTF1 negative

Renal cell carcinoma: RCC+, CAM5.2+, vimentin+

DD: glioblastoma, anaplastic glioma (no distinct borders, have fibrillary cytoplasmic processes), meningioma (syncytial borders), hemangioblastoma vs. renal cell carcinoma, PNET vs. metastatic small cell carcinoma (nonfibrillar cells), melanoma

References: Hum Path 2002;33:642 (TTF1), eMedicine

Metastatic choriocarcinoma to CNS

Primaries frequently metastasize to CNS

Often is hemorrhagic

Rarely occurs during pregnancy (Obstet Gynecol 2003;102:1380, J Neurosurg 2002;97:477)

Positive stains: beta hCG

References: Cancer 1983;52:1728. Neurol India 2001;49:231-free full text

Metastatic melanoma to CNS

Melanoma has high rate of CNS metastases (10-40% in clinical studies, higher in autopsy studies)

Melanoma is third most common cause of cerebral metastases in most series (after lung and breast primaries)

Metastases may be multiple

To make the diagnosis, must consider melanoma in advance

Poor survival (mean 3 months) after metastases detected

Case reports: initial presentation as extensive metastatic leptomeningeal melanomatosis (Hum Path 2003;34:625)

Gross: well circumscribed nodules, solid or partially cystic; marked peritumoral edema; variable hemorrhage or necrosis

Micro: variable pigment, epithelial or spindle cells

Positive stains: S100 (not specific), HMB45, MelanA/MART1

DD: melanocytoma (benign cells normally in arachnoid), primary melanoma

References: eMedicine

Paraneoplastic syndromes

Nervous system dysfunction associated with cancer but without direct tumor invasion, infection or vascular complications of neural tissue

May precede clinical recognition of tumors

Occurs in <1% of cancer patients; usually small cell carcinoma of lung, breast cancer, ovarian cancer

Often due to autoantibodies

May respond to treatment of the underlying tumors

Cerebellar degeneration: destruction of Purkinje cells (antibody mediated) with perivascular lymphocytes; causes progressive bilateral leg and arm ataxia, dysarthria, variable vertigo and diplopia; associated with breast, gynecologic, Hodgkin’s lymphoma, small cell carcinoma of lung; often associated with anti-Yo antibody in serum or CSF

References: Brain 2003;126(Pt 6):1409-free full text

Lambert-Eaton myasthenic syndrome: destruction of neuromuscular junction (presynaptic terminals) by small cell lung cancer; due to IgG antibody

Limbic encephalitis: associated with subacute dementia - perivascular inflammatory cuffs, microglial nodules, neuronal loss, gliosis of temporal lobe, resembles infectious process; also in brainstem; most common with small cell lung cancer

Myelopathies: necrotizing myelopathy due to leukemia, lymphoma, lung carcinoma; myelitis due to Anti-Hu antibody associated with small cell lung carcinoma

Opsoclonus/myoclonus (spontaneous chaotic eye movements): affects brain stem, but site unknown; due to breast and small cell lung cancer; also neuroblastoma; may be associated with anti-Ri autoantibody

Peripheral neuropathy: most common paraneoplastic syndrome; may be associated with anti-Hu antibody in lung cancer patients

Primary lateral sclerosis: rarely caused by breast cancer; 50% develop lower motor neuron signs eventually

Retinal degeneration: destruction of photoreceptors; due to small cell carcinoma and gynecologic tumors

Stiff-man syndrome: destruction of spinal interneurons by amphiphysin antibody; usually breast cancer, also lung cancer and thymoma

Subacute sensory neuropathy: may occur with limbic encephalitis; loss of sensory neurons from dorsal root ganglia, associated with inflammation; due to small cell lung cancer

References: Neurol Neurosurg Psychiatry 1997;63:133-free full text (paraneoplastic encephalomyelitis)

Subacute motor neuronopathy: degeneration of anterior horn cells; rare, painless lower motor neuron weakness of extremities; associated with lymphoma

Case reports: neuropathy associated with lymphoma and IgM antibodies against disialosyl residues (Muscle Nerve 2005;32:216)

DD: metabolic brain disease, meningeal carcinomatosis, progressive multifocal leukoencephalopathy

References: Washington University, eMedicine, J Neurol Neurosurg Psychiatry 2004;75 Suppl 2:ii43-free full text

Miscellaneous

Intraoperative consultation / frozen sections

Indications: (a) determine if lesional tissue is present, (b) determine if adequate sampling, (c) provide preliminary information to assist neurosurgeon (see below), (d) perform special techniques (culture, B5 for lymphoma, touch preparations)

Need not give definitive diagnosis

Should not grade astrocytic glial neoplasm unless is clearly a glioblastoma (since tumors often have variable grades)

For some tumors, attempts at total resection are made (meningioma, schwannoma, solitary metastases, cysts, ependymoma, hemangioblastoma, cerebellar pilocytic astrocytoma, craniopharyngioma), so intraoperative consultation may be helpful

Recommended to assess undefined lesions by both frozen section and cytologic preparation

Cytologic preparation: adds fine nuclear detail, reveals glial-type processes or epithelioid features of carcinomas; shows discohesiveness associated with pituitary adenoma, oligodendroglioma, medulloblastoma or lymphoma; may be more accurate than frozen section (Stereotact Funct Neurosurg 1995;65:187)

Recommended to obtain touch preparations (touch glass slide to wet tissue, fix before it dries, then stain)

Artifacts: long empty cavities in parenchyma (due to cryostat) vs. microcysts which contain cells and eosinophilic proteinaceous material)

References: Archives 2005;129:1635, Archives 1997;121:481, Mod Path 1988;1:378, J Neurol Neurosurg Psychiatry 1988;51:332, Archives 2005;129:1653 (assessment of pediatric tumors)

Procedures

Either primary biopsy to determine diagnosis; secondary biopsy to determine diagnosis or monitor therapy effect; or therapeutic resection

Primary biopsy: may be able to totally resect meningiomas, carcinomas, adenomas, schwannomas, pilocytic astrocytomas, ependymomas

Stereotactic needle biopsy: through small hole in skull; tissue may be nondiagnostic (necrotic, may have missed lesion); important for pathologist to indicate if lesional tissue is obtained; perform cytology by touching slide to gauze; report presence of large vessel to neurosurgeon

Secondary biopsy: repeat biopsies of lesion or its immediate vicinity; avoid by monitoring primary biopsy with intraoperative consultation

Post-therapy biopsy: must know nature of prior therapy

Therapeutic resection: if tumor was not previously completely excised; may be gross total resection (100% removal of known mass), radical subtotal (95-99% removal), subtotal (75-95% removal), partial (10-75% removal); compare to prior slides to determine treatment response (fibrosis, necrosis)

Grossing

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Evaluate the arachnoid, gray and white matter

Section, if possible, from the arachnoid through the gray to the white matter

Sample interface between the lesion and normal appearing brain

EM helpful for poorly differentiated or unusual tumors (clear cell ependymoma), toxic-metabolic disease, infection; recommended to save tissue for EM in challenging cases

Infarcts: section perpendicular to surface of brain, submit sections of arachnoid, gray and white matter; save gray matter for EM if considering CADASIL or mitochondrial disease

Hematopoietic lesions: also B5, cell culture media (for flow cytometry), touch preparations, flash frozen tissue for molecular analysis

Infectious disorders: recommended that surgeon obtain cultures from sterile operating field

Toxic-metabolic disorders: recommend fixation of gray and white matter in formalin, glutaraldehyde, frozen tissue bank

Gross features of various disease entities

Abnormal mass: solid tissue not identifiable as gray or white matter

Cyst wall: flat tissue from 0 to 3 mm thick - compare to surgeon’s impression or radiographs

Gliosis: often yellow or gray and firm

Necrosis: soft, friable, often cavitates

Semiliquid or gelatinous masses: usually tumors, including oligodendroglioma, lymphoma, pituitary adenoma

Vascular malformation: vessels larger than usual aggregate of arachnoid vessels, often associated with hemorrhage, may involve meninges or parenchyma

Margins: usually impossible to assess due to piecemeal nature of resection or infiltrative growth pattern; may be able to determine for childhood pilocytic astrocytoma of cerebellum, cerebral dysembryoplastic neuroepithelial tumor, meningioma

Safety: recommended that surgeon contact lab if patient is HIV+ (use cytology, not frozen section) or may have Creutzfeldt-Jakob disease (decline frozen sections since cannot decontaminate cryostat); decontaminate cryostat used for HIV+ tissue by replacing blade, removing frozen debris and wiping surfaces with 10% bleach in water; for CJD specimens that are sectioned, recommended to place cassettes in formalin for 24 hours, then transfer to 100% formic acid for one hour, then return to fresh formalin for 48 hours, then process; label cassettes with pencil (formic acid dissolves ink), wrap needle biopsies in lens paper, handled embedded tissue as if infectious, dispose of blade, section waste, wipe microtome and cutting station with bleach, incinerate all towels, gloves and waste

References: Univ of Pittsburgh grossing manual

Features to report-excludes pituitary neoplasms

* Specimen type

* Specimen size (greatest dimension, additional dimensions are optional)

* Tumor site

* Tumor size (greatest dimension, additional dimensions are optional)

* Histologic type

* Histologic grade (WHO I-IV, other, cannot be determined, not applicable)

* Margins (involved, uninvolved, cannot be assessed, not applicable)

* Results of additional studies performed (electron microscopy, cytogenetics, molecular testing, immunohistochemistry)

* mandatory to report for accreditation purposes by American College of Surgeons Committee on Cancer

Link to College of American Pathologist protocols

References: Archives 2001;125:1162

Staging

No TNM classification exists for CNS tumors [AJCC Cancer Staging Manual (6th Ed) for these reasons:

For T component, histology and location are more important than tumor size

For N component, brain and spinal cord have no lymphatics, so lymph nodes cannot be staged

For M component, most patients die before metastatic disease is identified (except for CSF seeding)

Generally favorable prognostic factors: younger age, total resection vs. subtotal resection; higher Karnofsky performace scale

Autopsy

Standard CNS sections: spinal cord (2-3 levels), medulla, pons, midbrain, cerebellum, hypothalamus, basal ganglia, hippocampus, thalamus, parietal cortex, occipital cortex, cingulate gyrus, superior temporal gyrus, paracentral cortex, pituitary

Sample gross description:

The scalp and skull are entered in a standard biparietal, post-auricular manner. Then dura is intact and the sagittal sinus is patent. The pre-fixation brain weight is __ grams. The formalin fixed brain weights __grams. The cerebral and cerebellar hemispheres are symmetrical with no masses, areas of discoloration or gross lesions identified. There is no evidence of midline shift. There is no uncal, subfalcine or tonsillar softening or grooving. The sulci/gyri are unremarkable, with no atrophy identified. The leptomeninges are thin, translucent and without hemorrhage. The circle of Willis is intact, with no atherosclerotic plaque. Coronal sections of the cerebral hemispheres show well delineated gray and white matter structures. The ventricles are symmetric and not dilated. Distal blood vessels are unremarkable.

Axial sections of the midbrain, pons and medulla are symmetrical with well delineated gray and white matter structures. The substantia nigra and locus ceruleus are well pigmented. The aqueduct and fourth ventricle are unremarkable. Parasagittal sections of the cerebellum show well delineated white and gray matter structures with prominent folia.

The pituitary is removed from the sella and is grossly unremarkable. The spinal cord is removed by an anterior approach. Axial sections of the spinal cord are symmetric with well delineated gray and white matter.

Sample microscopic description:

The spinal cord shows ... The midbrain, pons and medulla show mild neuronal loss and gliosis consistent with the patient’s age. The cerebellum, basal ganglia and thalamus are unremarkable. The hippocampus shows no senile plaques or neurofibrillary tangles. The cerebral neocortex is unremarkable.

End of Central Nervous System-tumor chapter/outline

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