Download path 1330 to 1343 [5-6

Path 1330-1343
CNS Tumors
 Most of childhood CNS tumors arise in posterior fossa; most tumors of adults arise in cerebral hemispheres
above tentorium
 Because of infiltrative behavior, often not feasible to resect glial neoplasms completely w/o compromising
neurologic function
 Even most highly malignant gliomas rarely metastasize outside CNS
o Subarachnoid space provides pathway for spread, so seeding along brain and spinal cord can occur in
neoplasms that extend into CSF
 When tumors recur, often progress to higher histologic grade and acquire different name (each grade has
different name)
Gliomas
 Gliomas – most common group of primary brain tumor; include astrocytomas, oligodendrogliomas, and
ependymomas
 Infiltrating astrocytomas – majority of adult primary brain tumors
o Diffuse astrocytoma (grade II) develops to anaplastic astrocytoma (grade III) to glioblastoma (grade IV)
o Grade I is pilocytic astrocytoma (non-infiltrating)
o Gross appearance of diffuse astrocytoma is poorly defined, gray, infiltrative tumor that expands and
distorts invaded brain; cut surface either firm or soft and gelatinous; cystic degeneration may exist
 Tumor may be well demarcated from surrounding brain tissue, but infiltration beyond outer
margins always present
 Characterized by mild to moderate increase in glial cellularity, variable nuclear pleomorphism,
and intervening felt-work of fine, GFAP-positive astrocytic processes that give background
fibrillary appearance
 Transition between neoplastic and normal tissue indistinct, and tumor cells seen infiltrating
normal tissue some distance from main lesion
o Anaplastic astrocytoma shows regions more densely cellular and have greater nuclear pleomorphism;
mitotic figures observed
 Gemistocytic astrocytoma – tumors where predominant neoplastic astrocyte shows brightly
eosinophilic cell body from which emanate abundant, stout processes
o Glioblastoma – variation in gross appearance; some areas firm and white, some soft and yellow (due to
necrosis), some show regions of cystic degeneration and hemorrhage
 Have necrosis and vascular or endothelial cell proliferation
 Necrosis often occurs in serpentine pattern in areas of hypercellularity
 Tumor cells collect along edges of necrotic regions (pseudopalisading)
 Vascular cell proliferation characterized by tufts of piled-up cells that bulge into lumen (double
layer of endothelial cells is minimal); with marked vascular cell proliferation, tuft forms ball-like
structure (glomeruloid body)
 VEGF produced by malignant astrocytes in response to hypoxia; contributes to vascular change
o Gliomatosis cerebri – multiple regions of brain infiltrated by neoplastic astrocytes; because of
widespread infiltration, process follows aggressive course; considered grade III independent of
appearance of individual tumor cells
o Mutations affecting p53 and overexpression of PDGF-A and its receptor predispose to infiltrating
astrocytomas
 Transition to higher grade astrocytoma associated with disruption of RB & p16/CDKNaA
o Primary glioblastoma typically in older patients as new onset disease; usually have amplification of
MDM2 (gene that encodes inhibitor of p53); amplified mutated EGFR genes that encode aberrant forms
of EGFR (EGFRvIII)
o Secondary glioblastoma seen in younger patients with history of lower-grade astrocytoma; usually have
p53 mutations; increased signaling through PDGF-A receptor
o Both primary and secondary glioblastoma mutations lead to increased receptor tyrosine kinase activity
and activation of RAS and PI-3 kinase pathways, which stimulate growth and survival of tumor cells
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Combos of mutations that activate RAS and PI-3 kinase and inactivate p53 and RB present in
majority of primary glioblastomas
o Mass effects like edema occur beyond immediate adjacent area to tumor
o High-grade astrocytomas have abnormal vessels that are leaky and demonstrate contrast enhancement
on imaging studies
o Prognosis for glioblastoma very poor
o Methylation of promotor for gene encoding DNA repair enzyme MGMT predicts responsiveness to DNA
alkylating drugs (since MGMT critical for repair of chemotherapeutically induced DNA modification)
o Treatment of primary glioblastoma patients with tyrosine kinase inhibitors that target EGFR helps some
o Mean length of survival after diagnosis is 15 months
Pilocytic astrocytomas (grade I) relatively benign; occur in children and young adults; usually in cerebellum (can
be in floor and walls of 3rd ventricle, optic nerves, and occasionally cerebral hemispheres)
o Often cystic
o Tumor composed of bipolar cells with long, thin hair-like processes that are GFAP-positive and form
dense fibrillary meshworks
o Rosenthal fibers and eosinophilic granular bodies often present
o Often biphasic with loose microcystic pattern in addition to fibrillary areas
o Increase in number of blood vessels, often with thickened walls or vascular cell proliferation, seen but
doesn’t imply unfavorable prognosis
o Necrosis and mitosis uncommon
o Narrow infiltrative border with surrounding brain
o Symptomatic recurrence of incompletely resected lesions often associated with cyst enlargement rather
than growth of solid component
o Tumors that extend into hypothalamic region from optic tract have more ominous clinical course
because of location
o Rarely have genetic changes
o Those that occur in settings of NF1; show functional loss of neurofibromin; not observed in sporadic
Pleomorphic xanthoastrocytoma – occurs most often in temporal lobe of younger people, usually with history of
seizures; neoplastic astrocytes (sometimes lipidized); often express neuronal and glial markers
o Presence of abundant reticulin deposits, relative circumscription, and chronic inflammatory cell
infiltrates, along with absence of necrosis and mitotic activity confirms this diagnosis
o Usually low-grade (grade II) with 5 year survival of 80%
Brainstem glioma – occur earlier in life
o Intrinsic pontine gliomas – most common with aggressive course and short survival
 Separated into low-grade diffuse fibrillary astrocytomas and glioblastomas
o Tumors (often exophytic) arising in cervicomedullary junction region; less aggressive course
o Tectal gliomas – benign
Oligodendroglioma – more common in middle-age; patients may have several years of neurologic complaints,
often including seizures; mostly in cerebral hemispheres with predilection for white matter
o Well-circumscribed, gelatinous, gray masses, often with cysts, focal hemorrhage, and calcification
o Tumors composed of sheets of regular cells with spherical nuclei containing finely granular chromatin
(similar to normal oligodendrocytes) surrounded by clear halo of cytoplasm
o Typically contains delicate network of anastomosing capillaries
o Calcification present in most tumors
o As tumor cells infiltrate cortex, often formation of secondary structures, often with tumor cells arrayed
around neurons (perineuronal satellitosis)
o Mitotic activity usually difficult to detect; proliferation indices low
o Grade II lesions
o Anaplastic oligodendrogliomas – grade II; characterized by increased cell density, nuclear anaplasia,
increased mitotic activity, and necrosis; changes found in nodules
 Discrete round cells with cytoplasmic GFAP and nuclei that resemble other elements of tumor;
microgemistocytes differ from gemistocytic astrocytes because they lack abundant processes
 Intermediate filaments restricted to small lump of cytoplasm
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Some high-grade oligodendroglial tumors show patterns indistinguishable from glioblastoma
(because of appearance and worse behavior, these are grouped with glioblastomas)
o Most common genetic alterations are loss of heterozygosity for chromosomes 1p and 19q; additional
genetic alterations tend to accumulate with progression to anaplastic oligodendroglioma
 More common include loss of 9p, 10q, and mutation in CDKN2A
 EGFR gene amplification not seen, but increased EGFR protein levels seen
 Tumors with loss of 1p and 19q have consistent, long-lasting responses to chemotherapy and
radiation; those with additional genetic changes have shorter-lived responses, and those w/o
loss of 1p and 19q resistant to therapy
o Better prognosis than astrocytomas; average survival of 5-10 years
o Progression from low to higher-grade lesions occurs over 6 years
o Oligoastrocytomas and anaplastic oligoastrocytomas – neoplasms consisting of distinct regions of
oligodendroglioma and astrocytoma; tumors monoclonal and show either 1p/19q deletion or p53
mutation
Ependymomas arise next to ependyma-lined ventricular system; earlier in life near 4th ventricle; later in life
spinal cord; tumors particularly frequent in setting of neurofibromatosis type 2 (NF2)
o In 4th ventricle, typically solid or papillary masses extending from floor of ventricle; proximity of vital
pontine and medullary nuclei makes complete extirpation impossible
o In intra-spinal tumors, sharp demarcation sometimes makes total removal feasible
o Composed of cells with regular, round to oval nuclei and abundant granular chromatin; between nuclei,
variably dense fibrillary background
o Tumor may form gland-like round or elongated structures (rosettes, canals) that resemble embryologic
ependymal canal, with long delicate processes extending into lumen
o Perivascular pseudorosettes – tumor cells arranged around vessels with intervening zones consisting of
thin ependymal processes directed toward wall of vessel
o GFAP expression found in most ependymomas
o Most well differentiated and behave as grade II lesions
o Anaplastic ependymomas (grade III) have increased cell density, high mitotic rates, areas of necrosis,
and less evident ependymal differentiation
o Myxopapillary ependymomas – occur in filum terminale and contain papillary elements in myxoid
background, admixed with ependymoma-like cells
 Cuboidal cells, sometimes with clear cytoplasm, arranged around papillary cores containing CT
and blood vessels
 Myxoid areas contain neutral and acidic mucopolysaccharides
 Prognosis depends on completeness of surgical resection
 If tumor extends into subarachnoid space and surrounds roots of cauda equina, recurrence likely
o NF2 gene commonly mutated in ependymomas in spinal cord, but not other sites
 Supratentorial lesions have alterations in chromosome 9
o Posterior fossa ependymomas often manifest with hydrocephalus secondary to progressive obstruction
of 4th ventricle
o CSF dissemination common occurrence and portends poor prognosis
o Posterior fossa lesions have worst overall outcome, particularly in younger children; 5-year survival 50%
 Clinical outcome for completely resected supratentorial and spinal ependymomas better
Tumors immediately below ependymal lining of ventricle or in association with choroid plexus
o With exception of rare choroid plexus carcinoma, mostly benign low-grade lesions
o Subependymomas – solid, sometimes calcified, slow-growing nodules attached to ventricular lining and
protruding into ventricle; may cause hydrocephalus; usually asymptomatic, incidental findings
 Most often found in lateral and 4th ventricles; characteristic appearance with clumps of
ependymal-appearing nuclei scattered in dense fine glial fibrillary background
o Choroid plexus papillomas can occur anywhere along choroid plexus; most common in children in lateral
ventricles and in adults in 4th ventricle
 Papillae have CT stalks covered with cuboidal or columnar epithelium
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Usually present with hydrocephalus due to obstruction of ventricular system by tumor or
overproduction of CSF
o Choroid plexus carcinomas resemble adenocarcinoma; usually found in children
o Colloid cyst of 3rd ventricle – non-neoplastic lesion most often in young adults; attached to roof of 3rd
ventricle, where it can obstruct one or both foramina of Monro, causing non-communicating
hydrocephalus; headache important clinical symptom
 Cyst has thin, fibrous capsule and lining of low to flat cuboidal epithelium; contains gelatinous
proteinaceous material
Neuronal Tumors
 Ganglioglioma – CNS tumor of mature-appearing neurons (ganglion cells); usually admixed glial neoplasm
o Slow-growing; glial component occasionally becomes anaplastic and disease progresses rapidly
o Lesions that contain mixtures of neuronal and glial elements often present as seizure disorder
o Surgical resection of tumor usually effective in controlling seizures
o Most commonly found in temporal lobe and often have cystic component
o Neoplastic ganglion cells irregularly clustered and have random orientation of neuritis
o Binucleate forms frequent
o Glial component usually resembles low-grade astrocytoma, lacking mitotic activity and necrosis
 Dysembryoplastic neuroepithelial tumor – low-grade tumor of childhood that often presents as seizure disorder;
relatively good prognosis after surgical resection
o Typically in superficial temporal lobe; often attenuation of overlying skull
o Typically form multiple discrete intracortical nodules of small, round cells, arranged in columns around
central cores of processes; associated with myxoid background (specific glioneuronal element)
o Well-differentiated floating neurons that sit in pools of mucopolysaccharides-rich fluid of myxoid
background
o Surrounding nodules, may be focal cortical dysplasia and sometimes low-grade astrocytoma
o Lesions that show both specific element and glial component are complex
 Central neurocytoma – typically low-grade neuronal neoplasm found in ventricular system (lateral or 3rd
ventricle); evenly spaced round uniform nuclei and often islands of neuropil
o Differentiated from oligodendroglioma by studies that reveal neuronal lineage of tumor cells
Poorly Differentiated Neoplasms
 Medulloblastoma – occurs primarily in children and exclusively in cerebellum; neuronal and glial markers may be
expressed, but tumor largely undifferentiated
o Located in midline of cerebellum in children; lateral locations more often in adults
o Rapid growth may occlude flow of CSF, leading to hydrocephalus
o Tumor often well circumscribed, gray, and friable; may be seen extending to surface of cerebellar folia
and involving leptomeninges
o Extremely cellular with sheets of anaplastic cells
o Individual tumor cells small with scant cytoplasm and hyperchromatic nuclei frequently elonagated or
crescent shaped
o Mitoses abundant; markers of cellular proliferation (Ki-67) detected in high percentage of cells
o May express neuronal (neurosecretory granules or Homer Wright rosettes) and glial (GFAP) phenotypes
o Desmoplastic variant characterized by areas of stromal response, marked by collagen and reticulin
deposition and nodules of cells forming pale islands that have more neuropil and show greater
expression of neuronal markers
o At edges of main tumor mass, cells have propensity to form linear chains of cells infiltrating through
cerebellar cortex to aggregate beneath pia, penetrate pia, and seed into subarachnoid space
o Dissemination through CSF common, presenting as nodular masses elsewhere in CNS, including
metastases to cauda equina (drop metastases)
o Most common genetic alteration is loss of 17p (abnormal chromosome derived from duplication of 17q)
 Loss of 17p signals poor prognosis
o MYC amplification associated with more aggressive clinical course
o SHH-patched pathway (involved in control of normal proliferation of cerebellar granule cells) WNT
signaling pathway (including APC and β-catenin), and Notch signaling pathway mutations can predispose
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Tumors with increased TRKC have better clinical outcome, as do those with nuclear accumulation of βcatenin
o Tumor highly malignant, but exquisitely radiosensitive; with excision and radiation, 5-year survival 75%
 CNS supratentorial primitive neuroectodermal tumors (CNS PNETs) – similar histology and poor degree of
differentiation resembling medulloblastomas; genetically distinct from medulloblastoma or PNS PNET
 Atypical teratoid/rhabdoid tumor – highly malignant; occurs in posterior fossa and supratentorial compartments
in nearly equal proportions in young children
o Presence of rhabdoid cells resembling rhabdomyosarcoma defining characteristic
o Cytoplasm of rhabdoid cell contains intermediate filaments and is immunoreactive for epithelial
membrane antigen and vimentin; may be positive for smooth muscle actin and keratins
 No desmin or myoglobin
o Islands of tumor with rhabdoid differentiation mixed with small-cell component as well as mesenchymal
and epithelial patterns
o Mitotic activity prominent
o Genetic alterations on chromosome 22; hSNF5/INI1 encodes protein that is part of large complex
involved in chromatin remodeling; functional deletions of locus and loss of nuclear staining for INI1
protein seen in majority of tumors
o Nearly all tumors occur before age 5, and most patients live less than a year after
Other Parenchymal Tumors
 Primary CNS lymphoma – most common CNS neoplasm in immunosuppressed tumors
o Primary brain lymphoma often multifocal within brain parenchyma; nodal, bone marrow, or extra-nodal
involvement outside CNS rare and late complication
o Lymphoma arising outside CNS rarely involves brain parenchyma
o Usually manifested by presence of malignant cells in CSF and around intradural nerve roots, occasionally
with infiltration of superficial areas of cerebrum or spinal cord by malignant cells
o Most of B-cell origin; nearly all tumors latently infected with Epstein-Barr virus
o Aggressive with relatively poor response to chemotherapy compared with peripheral lymphomas
o Lesions frequently multiple and often involve deep gray matter as well as white matter and cortex
o Tumors relatively well defined but not as discrete as metastases; often show extensive areas of central
necrosis
o Diffuse large-cell B-cell lymphomas most common histologic group
o Within tumor, malignant cells infiltrate parenchyma of brain and accumulate around blood vessels
o Reticulin stains show infiltrating cells separated by silver-staining material (hooping); characteristic of
primary brain lymphoma; most cells also express BCL-6
 Intravascular lymphoma – tumor cells grow intraluminally within small vessels, often involves brain with other
regions of body; can result in widespread microscopic infarcts
 Primary brain germ cell tumors occur along midline, most commonly in pineal and suprasellar regions
o Germ cells may come from rests that remain in CNS or migrate there from other sites late in
development
o Metastasis of other germ cell tumor to produce brain germ cell tumor uncommon
o CSF levels of tumor markers (α-fetoprotein and β-hCG) used to diagnose and track response to therapy
 Pineocytes – have features of neuronal differentiation
o Pineocytomas – well-differentiated lesions with areas of neuropil, cells with small round nuclei, and no
evidence of mitoses or necrosis
o Pineoblastomas – high-grade tumors w/little evidence of neuronal differentiation, densely packed small
cells w/necrosis, and frequent mitotic figures
o High-grade pineal tumors affect children more; lower-grade lesions found more often in adults
o Highly aggressive pineoblastoma commonly spreads throughout CSF space; occurs w/increased
frequency in individuals w/germline mutations in RB (trilateral retinoblastoma)
o Gliomas found in pineal region arising from glial stroma of gland
Meningiomas
 Predominantly benign tumors of adults, usually attached to dura; arise from meningothelial cell of arachnoid
 Found along any external surface of brain or ventricular system (from stromal arachnoid cells of choroid plexus)
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Prior radiation therapy risk factor for development
Metastases, solitary fibrous tumors, and range of poorly differentiated sarcomas can grow as dural-based mass
Usually rounded masses w/well-defined dural bases that compress underlying brain but easily separated from it
Extension into overlying bone may be present
Surface of mass usually encapsulated with thin, fibrous tissue and may have bosselated or polypoid appearance
May grow en plaque (tumor spreads in sheet-like fashion along surface of dura); commonly associated with
hyperostotic reactive changes in overlying bone
 Lesions range from firm and fibrous to finely gritty; may contain numerous calcified psammoma bodies
 No gross evidence of necrosis or extensive hemorrhage
 Relatively low risk of recurrence or aggressive growth; grade I
 Can be syncytial (meningothelial; whorled clusters of cells that sit in tight groups w/o visible cell membranes),
fibroblastic (elongated cells and abundant collagen deposition between them), transitional (share features of
syncytial and fibroblastic types), psammomatous (w/psammoma bodies formed from calcification of syn ytial
nests of meningothelial cells), secretory (PAS-positive intracytoplasmic droplets and intracellular lumens), or
microcystic (loose, spongy appearance)
 Xanthomatous degeneration, metaplasia (often osseous), and moderate nuclear pleomorphism common
 Atypical meningiomas (grade II) – may require radiation therapy in addition to surgery; distinguished by
presence of either higher mitotic index or at least 3 atypical features (increased cellularity, small cells with high
nuclear-to-cytoplasmic ratio, prominent nucleoli, patternless growth, or necrosis)
o Clear cell and chordoid patterns considered grade II because of more aggressive behavior
 Anaplastic (malignant) meningioma (grade III) has appearance of high-grade sarcoma, but retains some
histologic evidence of meningothelial origin
 Papillary meningioma (pleomorphic cells arranged around fibrovascular cores) and rhabdoid meningioma
(sheets of tumor cells w/hyaline eosinophilic cytoplasm containing intermediate filaments) have such high
propensity to recur, they are grade III
 Some tumors infiltrate brain with broad pushing edges or single cells; invasion associated with increased risk of
recurrence, but doesn’t change histologic grade
 Commonly immunoreactive for epithelial membrane antigen
 Keratin restricted to lesions with secretory pattern; also positive for carcinoembryonic antigen
 Most commonly have loss of 22q; deletions include deletion of NF2 gene (encodes protein merlin)
 Common sites of involvement include parasagittal aspect of brain convexity, dura over lateral convexity, wing of
sphenoid, olfactory groove, sella turcica, and foramen magnum
 Uncommon in children
 Spinal meningiomas cocmmonly psammomatous
 If lesions multiple, consider diagnosis of NF2; more likely to be dissemination from single tumor rather than
distinct tumors
 Often express progesterone receptors and may grow more rapidly during pregnancy
Metastatic Tumors
 Mostly carcinomas; most common primary sites are lung, breast, melanomas, kidney, and GI tract
 Choriocarcinomas have high likelihood of metastasizing to brain
 Meninges frequent site of involvement in metastatic disease
 Intraparenchymal metastases form sharply demarcated masses, often at junction of gray matter and white
matter, usually surrounded by zone of edema (melanoma not always)
o Nodules of tumor often have central areas of necrosis surrounded by reactive gliosis
o Meningeal carcinomatosis with tumor nodules studding surface of brain, spinal cord, and intradural
nerve roots associated with carcinoma of lung and breast
Paraneoplastic Syndromes
 May involved PNS and CNS, sometimes preceding clinical recognition of malignant neoplasm
 Majority underlying mechanism of paraneoplastic syndromes is development of immune response against
tumor antigens that cross-react with antigens in CNS or PNS
 Some tumor types associated with multiple types of autoantibodies
 Various patterns of encephalomyelitis
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Subacute cerebellar degeneration – destruction of Purkinje cells, gliosis, and mild inflammatory infiltrate
Limbic encephalitis – subacute dementia with perivascular inflammatory cuffs, microglial nodules, some
neuronal loss, and gliosis, most evident in anterior and medial portions of temporal lobe, resembling
infectious process
o Eye movement disorders, most commonly opsoclonus, often in association with other evidence of
cerebellar and brainstem dysfunction; in children most commonly associated with neuroblastoma
o Subacute sensory neuropathy found in association with limbic encephalitis; marked by loss of sensory
neurons from DRG in association with lymphocytic inflammation
o Lambert-Eaton myasthenic syndrome caused by antibodies against voltage-gated Ca2+ channel in
presynaptic elements of NMJ; seen in absence of malignancy as well
Peripheral Nerve Sheath Tumors
 Arise from cells of PNS (Schwann cells, perineurial cells, and fibroblasts
o Many express Schwann cell characteristics (S-100 antigen and potential for melanocytic differentiation)
 Transition between myelination by oligodendrocytes and myelination by Schwann cells that occurs w/in several
mm of substance of brain; PNS tumors can arise in dura as well as along PNS nerves
 Schwannoma – benign tumors arise from neural crest-derived Schwann cell and cause symptoms by local
compression of involved nerve or adjacent structures
o Component of NF2; sporadic schwannomas commonly associated with inactivating mutations of NF2
o Loss of merlin consistent finding in all schwannomas; merlin normally restricts cell-surface expression of
growth factor receptors (such as EGFR) through interactions involving actin cytoskeleton; in absence,
cells hyperproliferate in response to growth factors
o Well-circumscribed, encapsulated masses attached to nerve but can be separated from it
o Firm, gray masses that may have areas of cystic and xanthomatous change
o Mixture of Antoni A pattern of growth (elongated cells with cytoplasmic processes arranged in fascicles
in areas of moderate to high cellularity and scant stromal matrix; nuclear-free zones of processes lying
between regions of nuclear palisading are Verocay bodies) and Antoni B pattern (tumor less densely
cellular and consists of loose meshwork of cells, microcysts and myxoid stroma)
 Both areas, cells have elongated shape and regular oval nuclei
o BM deposits encasing single cells and collagen fibers
o Axons largely excluded from tumor, though they may become entrapped in capsule
o Can have nuclear pleomorphism, xanthomatous change, and vascular hyalinization
o Malignant change extremely rare, but local recurrence can follow incomplete resection
o Commonly occur at cerebellopontine angle, affecting vestibular branch of CN VIII
o Sensory nerves preferentially involved
o When extradural, most commonly found in association with large nerve trunks, where motor and
sensory modalities intermixed
 Neurofibromas – can present as discrete localized masses (cutaneous neurofibroma or solitary neurofibroma) or
as infiltrative lesion growing within and expanding peripheral nerve (plexiform neurofibroma)
o Presence of either multiple neurofibromas or plexiform neurofibromas suggests neurofibromatosis type
1 (NF1)
o Cutaneous neurofibroma – skin lesions grow as nodules, sometimes with overlying hyperpigmentation;
may become large and pedunculated; risk of malignant transformation extremely small
 Present in dermis and subcutaneous fat; well-delineated but unencapsulated; composed of
spindle cells
 Adnexal structures sometimes enwrapped by edges of lesions
 Stroma highly collagenized and contains little myxoid material
o Plexiform tumors may result in significant neurologic deficits when they involve major nerve trunks;
significant potential for malignant transformation
 Large nerve trunks most commonly involved; frequently multiple
 Affected nerves irregularly expanded as each of fascicles infiltrated by neoplasm
 Not possible to separate lesion from nerve
 May have poorly defined borders as fingers of tumor and individual neoplastic cells insert
themselves between nerve fibers
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Lesion has loose, myxoid background with low cellularity; Schwann cells (elongated nuclei and
extensions of pink cytoplasm), larger multipolar fibroblastic cells, and sprinkling of inflammatory
cells (including mast cells)
 Often areas of collagen bundles (shredded carrot appearance)
 Axons can be demonstrated within tumor
 Product of NF1 gene (neurofibromin) stimulates activity of GTPase that inhibits RAS activity
 Malignant peripheral nerve sheath tumors highly malignant; locally invasive, frequently with multiple
recurrences and eventual metastatic spread
o Most commonly associated with medium to large nerves rather than CNs or distal small nerves
o About ½ arise in setting of NF1 either from transformation of plexiform neurofibroma or following
radiation therapy
o NF1 function lost at early stage of development; subsequent alterations often disrupt both p53 and RBdependent pathways for regulation of cell proliferation
o Lesions poorly defined tumor masses that frequently infiltrate along axis of parent nerve and invade
adjacent soft tissues
o Patterns reminiscent of fibrosarcoma or pleomorphic sarcoma may be found
o Can have areas that resemble Schwann cells
o Fascicle formation may be present
o Mitoses, necrosis, and extreme nuclear anaplasia common
o Wide variety of divergent histologic patterns may be admixed, including epithelial structures,
rhabdomyoblastic differentiation (Triton tumors), cartilage, and bone
o Epithelioid malignant schwannomas – aggressive variants with tumor cells with visible cell borders; grow
in nests; immunoreactive for S-100 but not keratin
Familial Tumor Syndromes
 Cowden syndrome – dysplastic ganglioglicytomas of cerebellum (Lhermitte-Duclos disease) caused by mutations
in PTEN resulting in increased activity of AKT and mTOR pathways
 Li-Fraumeni syndrome – medulloblastomas caused by mutations in p53
 Turcot syndrome – medulloblastoma or glioblastoma caused by mutations in APc or mismatch repair genes
 Gorlin syndrome – medulloblastoma caused by mutations in PTCH gene resulting in upregulation of SHH
signaling pathways
 Neurofibromastosis type 1 – autosomal dominant disorder; characterized by neurofibromas (plexiform and
solitary), gliomas of optic nerve, pigmented nodules of iris (Lisch nodules), and cutaneous hyperpigmented
macules (café au lait spots)
o Propensity for neurofibromas, particularly plexiform, to undergo malignant degeneration at higher rate
o NF1 gene encodes neurofibromin (large protein with GTPase-activating domain that inhibits RAS)
o Tumor cells lack NF1 expression due to biallelic inactivation of gene
 Neurofibromatosis type 2 – autosomal dominant disorder resulting in range of tumors, most commonly bilateral
CN VIII schwannomas and multiple meningiomas
o Gliomas (typically ependymomas of spinal cord) occur
o Many have non-neoplastic lesions that include nodular ingrowth of Schwann cells into spinal cord
(schwannosis), meningioangiomatosis (proliferation of meningeal cells and blood vessels that grows into
brain), and glial hamartia (microscopic nodular collections of glial cells at abnormal locations)
o NF2 commonly mutated in sporadic meningiomas and schwannomas
o Merlin shows structural similarity to series of cytoskeletal proteins; regulates membrane receptor
signaling, including contact growth inhibition
 Tuberous sclerosis complex – autosomal dominant syndrome; characterized by development of hamartomas
and benign neoplasms involving brain and other tissues
o Hamartomas in CNS take form of cortical tubers and subependymal nodules
o Subependymal giant-cell astrocytomas – low grade neoplasms that appear to develop from
hamartomatous nodules in same location
o Cortical tubers often epileptogenic; surgical resection beneficial when medical management difficult
o Other lesions include renal angiomyolipomas, retinal glial hamartomas, pulmonary
lymphangioleiomyomatosis, and cardiac rhabdomyomas
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Cysts can be found in liver, kidneys, and pancreas
Cutasneous lesions include angiofibromas, localized leathery thickenings (shagreen patches),
hypopigmented areas (ash-leaf patches), and subungual fibromas
o TSC1 encodes protein hamartin
o More commonly, TSC2 mutated (encodes tuberin)
o Tuberin and hamartin bind, forming complex that inhibits mTOR (key regulator of protein synthesis and
other aspects of anabolic metabolism); mTOR controls cell size, and tumors associated with tuberous
sclerosis have voluminous amounts of cytoplasm, particularly giant-cell astrocytomas in CNS, and
cardiac rhabdomyomas
o Cortical and subependymal tubers associated with intact copy of allele; subependymal giant-cell
astrocytomas have biallelic loss
o Treatment symptomatic
o Cortical hamartomas of tuberous sclerosis firm areas of cortex; composed of haphazardly arranged
neurons that lack normal laminar organization of neocortex
o Some large cell shave appearances between glia and neurons (large vesicular nuclei with nucleoli
(neurons) with abundant eosinophilic cytoplasm (gemistocytic astrocytes), often with intermediate
filaments of both neuronal (neurofilament) and glial (GFAP) types)
o Large astrocyte-like cells cluster beneath ventricular surface; drop-like masses bulge into ventricular
system, giving rise to candle-guttering
o Subependymal giant-cell astrocytomas unique to tuberous sclerosis
Von Hippel-Lindau disease – autosomal dominant disease; develop hemangioblastomas and cysts involving
pancreas, liver, and kidneys; propensity to develop renal cell carcinoma and pheochromocytoma
o Hemangioblastomas most common in cerebellum and retina
o Gene is VHL (tumor suppressor gene that encodes pVHL, which is component of ubiquitin ligase complex
that downregulates HIF-1 (transcription factor involved in regulating expression of erythropoietin and
other growth factors))
o Dysregulation of erythropoietin responsible for polycythemia can be in association with
hemangioblastomas
o Missense mutations in VHL (not other types of mutations) associated with pheochromocytomas
o Highly vascularized neoplasms that occur as mural nodule associated with large fluid-filled cyst; lesions
consists of mixture of variable proportions of capillary-size or somewhat larger thin-walled vessels with
intervening stromal cells of uncertain histogenesis characterized by vacuolated, lightly PAS-positive,
lipid-rich cytoplasm and indefinite immunohistochemical phenotype
 Neoplastic element of hemangioblastoma based on presence of second hit in previously normal
VHL allele
o Therapy directed at symptomatic neoplasms, including resection of cerebellar hemangioblastomas and
laser therapy for retinal hemangioblastomas