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See also Central nervous system-nontumor (future topic), Pituitary (future topic)
Bold and underlined topics are hypertext links
Table of contents for Central Nervous System-tumor
CNS cysts: general, arachnoid, choroid plexus, colloid, dermoid, enterogenous, ependymal, epidermoid, glial, meningeal, neuroepithelial, pineal, simple, syrinx
Tumors: general, approach to diagnosis, WHO classification
Glial tumors
Glioma-general, post-radiation
Astrocytic tumors: general, cystic, granular cell, WHO grading, pilocytic, diffuse, protoplasmic, gemistocytic, anaplastic, glioblastoma, gliosarcoma, pleomorphic xanthoastrocytoma, subependymal giant cell
Oligodendroglial tumors: oligodendroglioma, anaplastic oligodendroglioma
Mixed gliomas: oligoastrocytoma and anaplastic oligoastrocytoma
Ependymal tumors: ependymoma, anaplastic ependymoma, myxopapillary ependymoma, subependymoma
Neuroepithelial tumors of uncertain origin: astroblastoma, chordoid glioma, gliomatosis cerebri
Neuronal and mixed neuronal-glial tumors: ganglion cell tumors-general, gangliocytoma, ganglioglioma, desmoplastic infantile astrocytoma/ganglioglioma, dysembryoblastic neuroepithelial tumor, central neurocytoma, cerebellar liponeurocytoma, extraventricular neurocytoma, papillary glioneuronal tumor, paraganglioma
Nonglial tumors
Embryonal tumors: ependymoblastoma, medulloblastoma, supratentorial PNET, atypical teratoid/rhabdoid tumor, medullomyoblastoma, medulloepithelioma
Choroid plexus tumors: general, papilloma, carcinoma
Pineal tumors: pineal gland-normal, tumors-general, papillary tumor, pineoblastoma, pineocytoma, pineal parenchymal tumor of intermediate differentiation
Meningeal tumors: meningioma, WHO grading, anaplastic, atypical, chordoid, clear cell, invasive, papillary, rhabdoid, secretory; meningioangiomatosis, hemangiopericytoma, melanocytic tumors / melanoma
Germ cell tumors: general, germinoma, embryonal carcinoma, yolk sac tumor, choriocarcinoma, teratoma
Tumors of the sellar region: craniopharyngioma, ganglion cell tumor, pituicytoma, pituitary adenoma, pituitary carcinoma, spindle cell oncocytoma
Lymphoma and other hematopoietic lesions: primary CNS lymphoma, secondary CNS lymphoma, post-transplant lymphoproliferative disorders, anaplastic large cell, angiotropic, diffuse large B cell lymphoma, Erdheim-Chester disease, histiocytic lymphoma/sarcoma, Hodgkin’s, inflammatory pseudotumor, Langerhans cell histiocytosis, leukemia, lymphomatoid granulomatosis, plasma cell granuloma, Rosai-Dorfman
Mesenchymal and other tumors: chondroma, chondrosarcoma, chordoma, epithelioid hemangioendothelioma, fibro-osseous lesions, hemangioblastoma, lipoma, MPNST, neurofibroma, sarcoma, schwannoma, solitary fibrous tumor, textiloma
Metastatic tumors to brain/spinal cord: general, metastatic carcinoma, metastatic choriocarcinoma, metastatic melanoma, paraneoplastic syndromes
Miscellaneous: intraoperative consultation, procedures, grossing, features to report, staging, autopsy
Click here for CNS-nontumor (future topic)
American Journal of Surgical Pathology (AJSP), January 1999 to January 2006
Archives of Pathology and Laboratory Medicine (Archives), January 1999 to December 2005
Human Pathology, January 1999 to December 2005
Modern Pathology, January 1999 to December 2005
Sternberg, S: Diagnostic Surgical Pathology (4th Ed); Lippincott Williams & Wilkins, 2004
Websites: Akron Children’s Hospital, Atlas Interactif de Neuro-Oncologie, Virginia Commonwealth University
Journal search terms: brain, CNS, meninges, spinal cord
Please refer to these primary references for more detailed discussions and photographs
CNS cysts
No solid nodule of tissue
Tumors that commonly are cystic: pilocytic astrocytoma, craniopharyngioma, ganglioglioma, hemangioblastoma, occasionally metastatic carcinoma
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
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
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
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
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
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
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
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
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
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)
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
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
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
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
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)
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
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
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)
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
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)
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 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)
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%)
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
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
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
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,