CNS Tumors

Jeffrey W. Oliver, M.D.

 Learning Objectives
• Outline the various families of primary
brain tumors described in class.
• List morphologic features used to grade
fibrillary astrocytomas.
• Describe the typical clinical course of the
three grades of fibrillary astrocytoma, and
compare to that of JPA, PXA, and SEGA.
 Learning Objectives
• Describe the clinical and morphologic
features of JPA, PXA, and SEGA.
• Compare and contrast treatment and
prognosis of oligodendroglioma vs.
fibrillary astrocytomas.
• Name the molecular/cytogenetic
abnormalities of oligodendroglioma and
how they affect prognosis.
 Learning Objectives
• Explain the clinical and morphologic
features of ependymal tumors including the
subtypes myxopapillary ependymoma,
subependymoma, choroid plexus papilloma,
and colloid cyst of 3rd ventricle.
• Describe two pathophysiologic mechanisms
by which choroid plexus papilloma can
cause hydrocephalus.
 Learning Objectives
• List immunophenotypic markers of gliomas,
neuronal tumors, meningiomas, and
Schwann cells.
• Explain the nomenclature of primitive
neuroectodermal tumors.
• Recognize the morphologic features of
medulloblastoma.
 Learning Objectives
• Describe clinical and morphologic features
of primary CNS lymphoma.
• Recognize morphologic features of
meningioma, and list subtypes which are
more likely to recur.
• Name the most common locations of
primary CNS germ cell tumors.
 Learning Objectives
• List the five malignant tumors most likely to
metastasize to the CNS.
• Recognize morphologic features of schwannoma.
• Explain the clinical features and molecular
pathogenesis (where discussed in class) of each of
the following phacomatoses: neurofibromatosis
types I and II, tuberous sclerosis, and Von Hippel-
Lindau syndrome.
 CNS Tumors
• About half primary, half metastatic
• In children, most are infratentorial, in adults most
are supratentorial
• Limitations in resectability
• Benign-appearing tumors can infiltrate
surrounding structures and be lethal
• Even most malignant primary CNS tumors rarely
metastasize outside the CNS
• Meningeal spread common
 Gliomas
• Astrocytomas
• Oligodendrogliomas
• Ependymomas
• All usually at least partially positive for the
glial antigen glial acid fibrillary protein
(GFAP)
 Fibrillary Astrocytoma
• Can occur in children or adults, but more
common in adults
• Symptoms include HA, seizures, or focal
neurologic signs depending on location of
tumor
 Fibrillary Astrocytoma
• Several grading schemes exist, but easiest is
three-tiered system:
• Grade I = low grade fibrillary astrocytoma
• Grade II = anaplastic astrocytoma
• Grade III = glioblastoma multiforme
(GBM)
 Fibrillary Astrocytoma
• Low grade lesions are infiltrative and
destructive, but indolent; mean survival > 5
years; tendency to evolve to higher grade
over time
• GBM is very aggressive despite all forms of
therapy, death usually in 8-10 months
• Gliomatosis cerebri: multiple regions or
entire brain affected
 Fibrillary Astrocytoma
• Can be very small to huge, and can occur
anywhere within the CNS
• Low grade lesions blend almost
imperceptibly into surrounding brain tissue,
are more cellular than normal brain or
gliosis, have fibrillary GFAP-positive
background, and variable amount of nuclear
pleomorphism/atypia
 Anaplastic Astrocytoma
• More cellular and more atypical than low-
grade lesions
• Mitotic figures are present
• When brightly eosinophilic cells
predominate, called gemistocytic
astrocytoma, usually qualifies as anaplastic
astrocytoma
 Glioblastoma Multiforme
• Pleomorphic gross appearance with areas of
hemorrhage and necrosis; often crosses midline
through white matter tracts “butterfly lesions”;
ring enhancing
• More cellular and mitotically active than
anaplastic astrocytoma, but real defining features
are necrosis (sometimes with peripheral
pseudopalisading) and vascular (endothelial)
proliferation
 “Benign” Astrocytomas
• Juvenile pilocytic astrocytoma (JPA),
pleomorphic xanthoastrocytoma (PXA), and
subependymal giant cell astrocytoma
(SEGA)
• More common in children than adults
• Usually benign, but rarely can transform
into more aggressive lesions
 Juvenile Pilocytic Astrocytoma
• Can occur anywhere in CNS, but
cerebellum is most common
• Often cystic with mural nodule
• Bipolar cells with long GFAP-positive
processes, increased number of vessels (but
not endothelial proliferation), Rosenthal
fibers (large red extracellular cigar-shaped
bodies)
Pleomorphic Xanthoastrocytoma
• Almost always superficial temporal lobe in
children to young adults with history of
seizures
• Very atypical astrocytes and foamy cells
• Rosenthal fibers or eosinophilic granular
bodies (smaller red extracellular globules,
probably early Rosenthal fibers)
 Subependymal Giant Cell
Astrocytoma
• Very strong association with tuberous
sclerosis
• Tubers (cerebral hamartomas) probably
evolve into SEGA
• Any subependymal location
• Large (but not really giant) epithelioid
astrocytes without mitotic activity or
necrosis
 Oligodendroglioma
• Most common in 4th-5th decade, often with a
history of seizures
• Most common in white matter of cerebral
hemispheres
• More chemosensitive than astrocytomas,
especially if positive for deletions on
chromosome 1p and 19q
• Average survival = 5-10 years
 Oligodendroglioma
• Well-circumscribed lesions, often with
hemorrhage and calcification
• Sheets of cells with uniform round-oval
nuclei, perinuclear halos, fine capillary
network, calcifications
• Usually at least partially GFAP-positive
 Ependymoma
• Usually arise in periventricular locations, in
children most commonly around 4th
ventricle; in adults usually spinal cord
• Intracranial lesions often give rise to
hydrocephalus, disseminate into CSF, and
have mean survival of 4 years despite
therapy and benign histologic appearance
 Ependymoma
• More well-circumscribed than fibrillary
astrocytomas
• Fairly uniform cells with round-oval nuclei
and fibrillary background
• GFAP-positive fibrillary processes surround
vessels “perivascular pseudorosettes”
• Sometimes cells form true rosettes
 Myxopapillary Ependymoma
• Arises at filum terminale
• Cuboidal ependymal-like cells arranged
around papillary structures within myxoid
background
• Recurrence likely if incompletely resected
 Subependymoma
• Solid periventricular tumors that often
protrude into ventricles
• Benign, and usually asymptomatic, but may
cause hydrocephalus if large enough or in
strategic location
• Clusters of small ependymal-like cells
scattered in a fibrillary background
 Choroid Plexus Papilloma
• Most common in children (usually in lateral
ventricles), but also occur in adults (usually in 4th
ventricle)
• Look like exaggerated normal choroid plexus
• Two mechanisms for making hydrocephalus:
ventricular obstruction & CSF overproduction
• Choroid plexus carcinoma = malignant version,
also more common in children; looks like any
other adenocarcinoma, so difficult to differentiate
from metastatic lesion
 Colloid Cyst of Third Ventricle
• Cystic lesion containing gelatinous material
that hangs from roof of 3rd ventricle
• Most common in young adults
• Hydrocephalus, which often presents as
positional HA
 Neuronal Tumors
• Gangliocytoma
• Ganglioglioma
• Central Neurocytoma
• Dysembryoplastic neuroepithelial tumor
(DNET)
• Positive for neural antigens synaptophysin
and neurofilament
 Gangliocytoma
• Slow growing, usually benign
• Most common in children
• Well-circumscribed, often calcified
• Clumps of large neurons “ganglion cells” in
relatively acellular stroma
 Ganglioglioma
• Similar to gangliocytoma, but also has
astrocytic component
• Usually slow growing, but glial component
sometimes transforms to high grade lesion
with poor prognosis
 Central Neurocytoma
• Usually intraventricular near the foramen of
Munro
• Young to middle-age adults most common
• Mimics oligodendroglioma: sheets of uniform
cells with perinuclear halos, but positive for
neuronal markers and GFAP-negative
• Prognosis is excellent, especially if completely
excised
 Dysembryoplastic
Neuroepithelial Tumor
• A multinodular lesion, usually of temporal
lobe, in children with history of seizures
• Often microcystic with neurons “floating”
in pools of myxoid material and
surrounding glial cells without atypia
• Good prognosis with complete excision
 Primitive Neuroectodermal
Tumors
• Cerebellum – Medulloblastoma
• Cerebral Cortex – Central Neuroblastoma
• Pineal – Pineoblastoma
• Adrenal Medulla – Neuroblastoma
• Retina – Retinoblastoma
• Elsewhere - PNET
 Medulloblastoma
• Usually in children, exclusively in
cerebellum
• Often associated with loss of material from
chromosome 17p; usually in the form of
i(17q)
• Untreated prognosis dismal, but with good
excision and radiation 5 year survival about
75%
 Medulloblastoma
• Usually in midline of cerebellum (but often
lateral cerebellum in adults)
• Very cellular with little cytoplasm,
hyperchromatic nuclei, high mitotic rate;
can express neuronal and/or glial markers;
Homer Wright rosettes
• Propensity for CSF seeding with “drop”
metastases
 Primary CNS Lymphoma
• The most common CNS tumor in
immunosuppressed patients, but can also
occur in immunocompetent patients (mean
age of 60)
• Primary = originally arising in CNS, as
opposed to metastatic spread of lymphoma
from a distant primary site (which is rare)
 Primary CNS Lymphoma
• Usually high-grade B cell lymphoma with
very aggressive behavior and poor response
to chemotherapy
• In immunosuppressed patients, EBV
genome usually present in the tumor cells
 Primary CNS Lymphoma
• Often multifocal, usually fairly well-
circumscribed, often with central necrosis,
periventricular spread common
• Tumor cells accumulate around vessels
 CNS Germ Cell Tumors
• Usually in midline: pineal or suprasellar
area
• Most common in adolescents and young
adults
• Must be differentiated from metastasis
• Histologic types and responses to treatment
parallel those seen in gonads, but CSF
spread may complicate treatment
 Pineocytoma
• Well-differentiated neuronal tumor arising
from pineocytes. No necrosis or mitotic
activity
• As opposed to pineoblastoma, which
resembles medulloblastoma: small cells
with little cytoplasm, high mitotic rate,
necrosis
 Meningioma
• Usually benign tumors arising from
meningothelial cells of arachnoid, usually attached
to dura, but can be intraventricular
• Usually seen in adults
• F:M = 2:1, but 10:1 in spinal meningiomas
• Cells express progesterone receptors and may
grow rapidly during pregnancy
• Increased risk, and often multiple, in patients with
neurofibromatosis type II
 Meningioma
• Rounded dural-based lesions that compress
underlying brain, but are typically easily separated
from it; can present as meningeal plaque; can
invade overlying bone
• Many histologic variants: syncytial, fibroblastic,
transitional, secretory, psammomatous
• Usually positive for epithelial membrane antigen
(EMA)
 Meningioma
• Papillary and clear cell variants have poorer
prognosis, more likely to recur
• Malignant meningioma is rare, and
primarily defined by invasion into
underlying brain tissue, usually also with
mitotic activity, nuclear atypia, and necrosis
 Metastatic Tumors
• Account for about half of all intracranial
tumors
• 5 most common primaries: lung, breast,
melanoma, kidney, GI tract
• Often multiple, and can involve meninges
• Usually sharply circumscribed, often at
gray-white junction
Peripheral Nerve Sheath Tumors
• Schwannoma (Neurilemmoma)
• Neurofibroma
• Malignant Peripheral Nerve Sheath Tumor
(MPNST)
• These can arise within millimeters of the transition
from oligodendroglial to Schwann cell
myelinization, and so can be intracranial
• Positive for Schwann cell marker S-100 protein
 Schwannoma
• Benign tumors arising from Schwann cells
• Symptoms are usually those of nerve
compression
• Sporadic, or associated with
neurofibromatosis type II
 Schwannoma
• If extradural, often arise from large
peripheral nerve trunks
• Intracranial lesions most commonly arise at
cerebellopontine angle, attached to CN
VIII, and present with tinnitus or hearing
loss “acoustic neuroma”
 Schwannoma
• Encapsulated, usually attached to the nerve, but
usually can be separated from it
• Mixture of two growth patterns: relatively cellular
Antoni A areas with palisading nuclei “Verocay
bodies”, and Antoni B areas of less dense
cellularity in myxoid stroma
• Degenerative changes, esp. nuclear atypia in
“ancient schwannomas”
 Solitary/Cutaneous
Neurofibroma
• Small benign nodules in skin, subcutaneous
fat, or peripheral nerve
• Spindle cells in fibrotic stroma
• Can be associated with neurofibromatosis
type I
 Plexiform Neurofibroma
• Almost always associated with
neurofibromatosis type I
• Significant risk of malignant transformation
• Usually arise at large nerve trunks,
commonly multiple
• Spindle cells in a myxoid stroma closely
infiltrate between nerve fibers; cannot be
separated from the nerve
 Malignant Peripheral Nerve
Sheath Tumor
• Invasive, malignant tumor arising from
nerve trunks; multiple recurrences are
usually followed by metastatic disease
• Arise de novo or from malignant
transformation of plexiform neurofibromas
• Strongly associated with neurofibromatosis
type I and history of radiation exposure
 Malignant Peripheral Nerve
Sheath Tumor
• Primarily spindle cells with nuclear atypia,
high mitotic rate, necrosis
• May have mixture of sarcomatous elements,
or be epithelioid
 Neurocutaneous Syndromes
(Phakomatoses)
• Inherited diseases with combination of
hamartomas or neoplasms of skin and
nervous system
• Neurofibromatosis types I & II
• Tuberous Sclerosis
• Von Hippel-Lindau disease
 Neurofibromatosis type I
(von Recklinghausen Disease)
• AD disorder with multiple plexiform and
cutaneous neurofibromas, optic nerve
gliomas, pigmented nodules of the iris
“Lisch nodules,” hyperpigmented macules
“café au lait spots”
• Due to mutations in tumor suppressor gene
NF1 on chromosome 17, which codes for
neurofibromin
 Neurofibromatosis type II
• AD disease, less common than type I, with
bilateral acoustic neuromas and multiple
meningiomas, sometimes glial hamartomas
• Mutations in NF2 gene on chromosome 22,
which codes for the protein merlin (a
cytoskeletal protein)
 Tuberous Sclerosis
• AD disease with cortical hamartomas
“tubers” which can evolve to SEGA, renal
angiomyolipoma, various organ cysts,
subungual fibromas, skin lesions:
angiofibromas, leathery thickening
“shagreen patch,” hypopigmented areas
“ash-leaf patches”
 Tubers
• Firm areas with haphazardly arranged
neurons and large eosinophilic cells which
express both neuronal and glial antigens
• Subependymal lesions may bulge into
ventricles “candle guttering”; may evolve
into SEGA
 Von Hippel-Lindau Disease
• AD disease with hemangioblastomas of
cerebellum & retina, various organ cysts,
and greatly increased risk of renal cell
carcinoma
• Mutations of a tumor suppressor gene on
chromosome 3, which codes for pVHL;
pVHL inhibits the elongation phase of RNA
synthesis
 Hemangioblastoma
• Benign tumors, typically present as a cyst
with a mural nodule
• Very vascular with capillary-sized or
slightly larger vessels, interstitial cells with
lipid-rich vacuolated cytoplasm
• Can mimic metastatic renal cell carcinoma
• 10% have polycythemia due to ectopic
erythropoietin production