2. The annual incidence of CNS tumors ranges from 10 to 17 per 100,000 individuals for intracranial
tumors and 1 to 2 per 100,000 individuals for intraspinal tumors; about onehalf to three-fourths
are primary tumors, and the rest are metastatic.
Tumors of the CNS make up a larger proportion of childhood cancers, accounting for as many of
20% of all pediatric tumors. Childhood CNS tumors differ from those in adults in both histologic
subtype and location.
In childhood, tumors are likely to arise in the posterior fossa, whereas tumors in adults are mostly
supratentorial.
Tumors of the nervous system have unique characteristics that set them apart from neoplastic
processes elsewhere in the body.
• These tumors do not have morphologically evident premalignant or in situ stages comparable
to those of carcinomas.
• Even low-grade lesions may infiltrate large regions of the brain, leading to serious clinical
deficits, inability to be resected, and poor prognosis.
• The anatomic site of the neoplasm can influence outcome independent of histologic
classification due to local effects (e.g., a benign meningioma may cause cardiorespiratory arrest
from compression of the medulla).
• Even the most highly malignant gliomas rarely spread outside of the CNS.
3. GLIOMAS
Gliomas are tumors of the brain parenchyma that have long been classified as
astrocytomas, oligodendrogliomas, and ependymomas based on their morphologic
resemblance to different types of glial cells.
With emerging genetic information, it has become clear that the gliomas are a molecularly
distinct family of neoplastic lesions, independent of the histologic patterns. Nonetheless,
histologic patterns continue to inform diagnosis and guide treatment, with refinement based
on molecular characterization.
The diffuse gliomas constitute the vast majority of gliomas that occur in adults, and include
diffuse astrocytomas and oligodendrogliomas.
4. DIFFUSE ASTROCYTOMA
Astrocytomas account for about 80% of adult gliomas.
They are most frequent in the fourth through the sixth decades of life. They usually are found in the
cerebral hemispheres.
The most common presenting signs and symptoms are seizures, headaches, and focal neurologic
deficits related to the anatomic site of involvement.
On the basis of histologic features, astrocytomas are stratified into three groups: diffuse
astrocytoma (grade II), anaplastic astrocytoma (grade III), and glioblastoma (grade IV), with
increasingly grim prognosis as the grade increases.
There is emerging evidence that genetic subtyping provides important additional prognostic
information.
Diffuse astrocytomas can be static for several years, but at some point they progress; the mean
survival is more than 5 years.
Eventually, patients suffer rapid clinical deterioration that is correlated with the appearance of
anaplastic features and more rapid tumor growth.
Other patients present with glioblastoma from the outset. Once the histologic features of
glioblastoma appear, the prognosis is very poor; with treatment (resection, radiotherapy, and
chemotherapy), the median survival is only 15 months.
5. MORPHOLOGICAL FEATURES
Grade II and III astrocytomas are poorly defined, gray, infiltrative tumors that expand and distort the invaded
brain without forming a discrete mass . Infiltration beyond the grossly evident margins is always present.
The cut surface of the tumor is either firm or soft and gelatinous; cystic degeneration may be seen.
In glioblastoma, variation in the gross appearance of the tumor from region to region is characteristic .
Some areas are firm and white, others are soft and yellow (the result of tissue necrosis), and still others show
regions of cystic degeneration and hemorrhage.
Microscopically, low-grade (WHO grade II) astrocytomas are characterized by a mild to moderate increase in the
number of glial cell nuclei, somewhat variable nuclear pleomorphism, and an intervening feltwork of fine, glial
fibrillary acidic protein (GFAP)-positive astrocytic cell processes that give the background a fibrillary appearance.
The transition between neoplastic and normal tissue is indistinct, and tumor cells can be seen infiltrating normal
tissue many centimeters from the main lesion.
Anaplastic astrocytomas show regions that are more densely cellular and have greater nuclear pleomorphism;
mitotic figures are present.
Glioblastoma has a histologic appearance similar to that of anaplastic astrocytoma, as well as either necrosis
(commonly present as serpiginous bands of necrosis with palisaded tumor cells along the border) or
microvascular proliferation
6. OLIGODENDROGLIOMA
Oligodendrogliomas account for 5% to 15% of gliomas and most commonly are detected in the
fourth and fifth decades of life.
Patients may have had several years of antecedent neurologic complaints, often including seizures.
The lesions are found mostly in the cerebral hemispheres, mainly in the frontal or temporal lobes.
The combination of surgery, chemotherapy, and radiotherapy yields an average survival of 10 to
20 years for well-differentiated (WHO grade II) oligodendrogliomas or 5 to 10 years for anaplastic
(WHO grade III) oligodendrogliomas.
7.
8.
9. DIFFUSE ASTROCYTOMAS. (A) GRADE II ASTROCYTOMA IS SEEN AS EXPANDED WHITE MATTER OF THE LEFT CEREBRAL HEMISPHERE
AND THICKENED CORPUS CALLOSUM
AND FORNICES. (B) GLIOBLASTOMA APPEARING AS A NECROTIC, HEMORRHAGIC, INFILTRATING MASS. (C) GLIOBLASTOMA IS A
DENSELY CELLULAR TUMOR WITH NECROSIS AND PSEUDOPALISADING
OF TUMOR CELL NUCLEI ALONG THE EDGE OF THE NECROTIC ZONE.
10. MORPHOLOGY
Well-differentiated oligodendrogliomas (WHO grade II) are infiltrative tumors that form
gelatinous, gray masses and may show cysts, focal hemorrhage, and calcification.
On microscopic examination, the tumor is composed of sheets of regular cells with spherical
nuclei containing finely granular chromatin (similar to that in normal oligodendrocytes)
surrounded by a clear halo of cytoplasm .
The tumor typically contains a delicate network of anastomosing capillaries.
Calcification, present in as many as 90% of these tumors, ranges in extent from microscopic foci
to massive depositions. Mitotic activity usually is low.
Anaplastic oligodendroglioma (WHO grade III) is a more aggressive subtype with higher cell
density, nuclear anaplasia, increased mitotic activity, and often microvascular proliferation.
11. GENETICS AND PATHOGENESIS
Several classes of tumor-causing genetic alterations have been described in gliomas.
• Mutations in isocitrate dehydrogenase (IDH) genes are commonly observed in grade II
astrocytomas and oligodendrogliomas.
These mutations may occur in IDH1 or IDH2 and lead to increased production of 2-
hydroxyglutarate, which interferes with the activity of several enzymes that regulate gene
expression .
• Mutations in the promoter for telomerase, which contribute to the immortalization of tumor
cells , are seen in glioblastomas and other astrocytic tumors.
In tumors with IDH mutations, telomerase mutations are uncommon; instead, these tumors often
have loss of function mutations in ATRX, which normally suppresses recombination events that
can preserve telomere length, a mechanism called alternative lengthening of telomeres.
12. Co-deletion of 1p and 19q chromosomal segments are present in oligodendrogliomas.
The mechanism through which these chromosomal alterations shape tumor morphology and
response to treatment is not known.
• Other genetic alterations, which are also common in tumors outside the CNS, include
mutations that lead to overexpression of the EGF receptor and other receptor tyrosine kinases
or disable p53 or RB (Chapter
13. MIDLINE GLIOMA
Midline gliomas arise most commonly in the brain stem (specifically in the pons) and also
occur in the spinal cord and thalamus.
They are infiltrative and result in significant neurologic impairment because of the disruption
of critical nearby structures.
Although they may not show typical high-grade features such as necrosis or vascular
proliferation, they often behave aggressively.
These lesions typically have acquired point mutations in histone H3, the consequence of which
is loss of a lysine residue that is the target of post-translational modifications that regulate
gene expression, another example of oncogenesis via alteration of the cancer cell “epigenome”.
Precisely how this mutation contributes to cellular transformation remains to be determined.
14. IN OLIGODENDROGLIOMA, TUMOR CELLS HAVE ROUND NUCLEI, OFTEN WITH
A CLEAR CYTOPLASMIC HALO. BLOOD VESSELS IN THE BACKGROUND ARE THIN AND CAN
FORM AN INTERLACING PATTERN
15. PILOCYTIC ASTROCYTOMA
Pilocytic astrocytomas are relatively benign tumors that typically affect children and young
adults.
Most commonly located in the cerebellum, they also may involve the third ventricle, the optic
pathways, the spinal cord, and occasionally the cerebral hemispheres.
There is often a cyst associated with the tumor, and symptoms appearing after the incomplete
resection of the lesions may be associated with cyst enlargement, rather than growth of the solid
component.
Tumors that involve the hypothalamus are especially problematic because they cannot be
resected completely.
A high proportion of pilocytic astrocytomas have activating mutations or translocations
involving the gene encoding the serine-threonine kinase BRAF, which result in activation of the
MAPK signaling pathway.
Pilocytic astrocytomas do not have mutations in IDH1 and IDH2, supporting their distinction
from the low-grade diffuse gliomas.
16. MORPHOLOGY
A pilocytic astrocytoma often is cystic, with a mural nodule in the wall of the cyst; if solid, it is
usually well circumscribed.
The tumor is composed of bipolar cells with long, thin “hairlike” processes that are GFAP-
positive.
Rosenthal fibers, eosinophilic granular bodies, and microcysts are often present, while necrosis
and mitoses are rare.
17. EPENDYMOMA
Ependymomas most often arise next to the ependymalined ventricular system, including
the central canal of the spinal cord.
In the first 2 decades of life, they typically occur near the fourth ventricle and constitute
5% to 10% of the primary brain tumors in this age group.
In adults, the spinal cord is their most common location; tumors in this site are
particularly frequent in the setting of neurofibromatosis type 2 .
The clinical outcome for completely resected supratentorial and spinal ependymomas is
better than for those in the posterior fossa.
18. MORPHOLOGY
In the fourth ventricle, ependymomas typically are solid or papillary masses extending from
the ventricular floor.
The tumors are composed of cells with regular, round to oval nuclei and abundant granular
chromatin.
Between the nuclei is a variably dense fibrillary background. Tumor cells may form round or
elongated structures (rosettes, canals) that resemble the embryologic ependymal canal,
with long, delicate processes extending into a lumen , more frequently present are
perivascular pseudorosettes in which tumor cells are arranged around vessels with an
intervening zone containing thin ependymal processes.
Anaplastic ependymomas show increased cell density, high mitotic rates, necrosis,
microvascular proliferation, and less evident ependymal differentiation.
20. NEURONAL TUMORS
Far less frequent than gliomas, tumors composed of cells with neuronal characteristics are
typically lower-grade lesions that often present with seizures. While some neuronal
differentiation can be observed in many tumors, lesions in this group are primarily composed of
cells that express neuronal markers, such as synaptophysin and neurofilaments.
• Central neurocytoma is a low-grade neoplasm found within and adjacent to the ventricular
system (most commonly the lateral or third ventricle); it is characterized by evenly spaced,
round, uniform nuclei and often islands of neuropil.
21. Dysembryoplastic neuroepithelial tumor is a distinctive, low-grade tumor of children and
young adults that grows slowly, often manifests as a seizure disorder, and carries a favorable
prognosis after resection.
It typically is located in the superficial temporal lobe and consists of small, round neuronal
cells arranged in columns and around central cores of processes.
• Gangliogliomas are tumors with a mixture of glial elements, usually a low-grade
astrocytoma and matureappearing neurons.
Most of these tumors are slow growing, and often manifest with seizures.
About 20% to 50% of gangliogliomas harbor point mutations in the BRAF gene.
22. EMBRYONAL (PRIMITIVE) NEOPLASMS
Some tumors of neuroectodermal origin have a primitive “small round cell” appearance that
is reminiscent of normal progenitor cells encountered in the developing CNS.
Differentiation is often limited, but may progress along multiple lineages. The most common
is the medulloblastoma, accounting for 20% of pediatric brain tumors.
Medulloblastoma
Medulloblastoma occurs predominantly in children and exclusively in the cerebellum. Neuronal
and glial markers are nearly always expressed, at least to a limited extent.
It is highly malignant, and the prognosis for untreated patients is dismal; however,
medulloblastoma is exquisitely radiosensitive.
With total excision, chemotherapy, and irradiation, the 5-year survival rate may be as high as
75%. There are a series of histologic patterns observed in medulloblastoma, which are
informative about prognosis and correlate in part with the underlying genetics
23. MORPHOLOGY
In children, medulloblastomas are located in the midline of the cerebellum; lateral tumors
occur more often in adults.
The tumor often is well circumscribed, gray, and friable and may be seen extending to the
surface of the cerebellar folia and involving the leptomeninges .
Medulloblastomas are densely cellular, with sheets of anaplastic (“small blue”) cells .
Individual tumor cells are small, with little cytoplasm and hyperchromatic nuclei; mitoses are
abundant.
Often, focal neuronal differentiation is seen in the form of rosettes, which closely resemble
the rosettes encountered in neuroblastomas; they are characterized by primitive tumor cells
surrounding central neuropil (delicate pink material formed by neuronal processes).
24. PATHOGENESIS
Genetic analysis of medulloblastoma has revealed several subtypes associated with different
clinical outcomes.
Current approaches separate medulloblastoma into distinct groups with different core
pathogenic pathways or driver mutations.
Examples of oncogenic pathways in these tumors are the following:
• Wnt pathway activation, most commonly associated with gain of function mutations in the
gene for β-catenin; these have the most favorable prognosis of all of the genetic subtypes and
are commonly classic-type tumors.
• Hedgehog pathway activation, most commonly associated with loss of function mutations in
PTCH1, a negative regulator of the Hedgehog; these tumors have an intermediate prognosis, but
the concomitant presence of TP53 mutation confers a very poor prognosis.
• MYC overexpression, due to MYC amplification as well as other changes that result in increased
expression; these tumors have the poorest prognosis.
Clinical trials are ongoing that seek to tailor therapy targeted to molecular alterations, with the
goal of avoiding radiation therapy when possible.
25. MEDULLOBLASTOMA. (A) SAGITTAL SECTION OF A BRAIN SHOWING MEDULLOBLASTOMA
INVOLVING THE SUPERIOR VERMIS OF THE CEREBELLUM. (B) MICROSCOPIC APPEARANCE
OF MEDULLOBLASTOMA, SHOWING MOSTLY SMALL, BLUE, PRIMITIVE-APPEARING TUMOR
CELLS.
26. OTHER PARENCHYMAL TUMORS
PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA
Primary CNS lymphoma, occurring mostly as diffuse large B-cell lymphomas, accounts for 2% of
extranodal lymphomas and 1% of intracranial tumors. It is the most common CNS neoplasm in
immunosuppressed individuals, in whom the tumors are nearly always positive for Epstein- Barr
virus (EBV).
In nonimmunosuppressed populations, the age spectrum is relatively wide, with the incidence
increasing after 60 years of age.
Regardless of the clinical context, primary brain lymphoma is an aggressive disease with a
relatively poor response to chemotherapy as compared with peripheral lymphomas.
Patients with primary brain lymphoma often are found to have multiple tumor nodules within
the brain parenchyma, yet involvement of sites outside of the CNS is uncommon.
Conversely, lymphoma originating outside the CNS rarely spreads to the brain parenchyma;
when this occurs, the tumor usually also involves the CSF or the meninges.
27. MORPHOLOGY
Lesions often involve deep gray structures, as well as the white matter and the cortex.
Periventricular spread is common. The tumors are relatively well defined as compared with
glial neoplasms, but they are not as discrete as metastases.
EBV-associated tumors often show extensive areas of necrosis.
The tumors are nearly always aggressive large B-cell lymphomas, although other histologic
types may be encountered.
Microscopically, malignant lymphoid cells accumulate around blood vessels and infiltrate the
surrounding brain parenchyma. The diagnosis is confirmed by immunohistochemistry for B
cell markers such as CD20, which also is a target of therapeutic antibodies.
28. GERM CELL TUMORS
Primary brain germ cell tumors occur along the midline, most commonly in the pineal and
the suprasellar regions.
They account for 0.2% to 1% of brain tumors in individuals of European descent but in as
many as 10% of brain tumors in individuals of Japanese ethnicity.
They are a tumor of the young, with 90% occurring during the first 2 decades of life.
Germ cell tumors in the pineal region show a strong male predominance.
The most common primary CNS germ cell tumor is germinoma, a tumor that closely
resembles testicular seminoma .
Secondary CNS involvement by metastatic gonadal germ cell tumors also occurs.
29. MENINGIOMAS
Meningiomas are predominantly benign tumors that arise from arachnoid meningothelial cells.
They usually occur in adults and are often attached to the dura.
Meningiomas may be found along any of the external surfaces of the brain as well as within the ventricular
system, where they arise from the stromal arachnoid cells of the choroid plexus.
They often come to attention because of vague nonlocalizing symptoms, or with focal findings referable
to compression of adjacent brain. Most meningiomas are easily separable from underlying brain, but some
tumors are infiltrative, a feature associated with an increased risk for recurrence.
The overall prognosis is determined by the lesion size and location, surgical accessibility, and histologic
grade.
When an individual has multiple meningiomas, especially in association with eighth-nerve schwannomas
or glial tumors, the diagnosis of neurofibromatosis type 2 (NF2) should be considered .
About half of meningiomas not associated with NF2 have somatic lossof- function mutations in the NF2
tumor suppressor gene on the long arm of chromosome 22 .
These mutations are found in all grades of meningioma, suggesting that they are involved in tumor
initiation.
Among sporadic tumors that lack mutations in NF2, several other driver mutations have been identified
including in genes that regulate the Hedgehog pathway as well as in various signaling molecules and
transcription factors.
30. MORPHOLOGY
Meningiomas (WHO grade I) grow as well-defined durabased masses that may compress
the brain but do not typically invade it .
Extension into the overlying bone may be present. The varied histologic patterns include:
meningothelial, named for whorled, tight clusters of cells without visible cell membranes;
fibroblastic, with elongated cells and abundant collagen deposition; transitional, with
features of the meningothelial and fibroblastic types; psammomatous, with numerous
psammoma bodies ; and secretory, with glandlike spaces containing PAS-positive
eosinophilic material.
Atypical meningiomas (WHO grade II) are recognized by the presence of either an
increased mitotic rate, or prominent nucleoli, increased cellularity, patternless growth, high
nucleus-tocytoplasm ratio, or necrosis.
These tumors demonstrate more aggressive local growth and a higher rate of recurrence and
may require therapy in addition to surgery. Some histologic patterns—clear cell and
chordoid—also correlate with more aggressive behavior, as does the presence of brain
invasion.
Anaplastic (malignant) meningiomas (WHO grade III) are highly aggressive tumors that
may resemble a high-grade sarcoma or carcinoma morphologically. Mitotic rates are
typically much higher than in atypical meningiomas.
31. METASTATIC TUMORS
Metastatic lesions, mostly carcinomas, account for approximately one-fourth to one-half of intracranial
tumors.
The most common primary sites are lung, breast, skin (melanoma), kidney, and gastrointestinal tract, which
together account for about 80% of cases. Metastases form sharply demarcated masses, often at the grey-
white matter junction, and elicit local edema .
The boundary between tumor and brain parenchyma is sharp at the microscopic level as well, with
surrounding reactive gliosis.
In addition to the direct and localized effects produced by metastases, paraneoplastic syndromes may
involve the peripheral and central nervous systems, sometimes even preceding the clinical recognition of
the malignant neoplasm.
Many patients with paraneoplastic syndromes have antibodies against tumor antigens. Some of the more
common patterns include the following:
• Subacute cerebellar degeneration resulting in ataxia, with destruction of Purkinje cells, gliosis, and a mild
inflammatory Infiltrate Limbic encephalitis causing a subacute dementia, with perivascular inflammatory
cells, microglial nodules, neuronal loss, and gliosis, all centered in the medial temporal lobe
• Subacute sensory neuropathy leading to altered pain sensation, with loss of sensory neurons from dorsal
root ganglia, in association with inflammation
• Syndrome of rapid-onset psychosis, catatonia, epilepsy, and coma associated with ovarian teratoma and
antibodies against the N-methyl-D-aspartate (NMDA) receptor
32. MENINGIOMA. (A) PARASAGITTAL MULTILOBULAR MENINGIOMA ATTACHED TO THE DURA
WITH COMPRESSION OF UNDERLYING BRAIN. (B) MENINGIOMA WITH A WHORLED
PATTERN OF CELL GROWTH AND PSAMMOMA BODIES.
33. FAMILIAL TUMOR SYNDROMES
Several inherited syndromes caused by mutations in various tumor suppressor genes
are associated with an increased risk for particular types of cancers.
Those with particular involvement of the CNS are discussed here; familial syndromes
associated with tumors of the peripheral nervous system are covered in .
34. METASTATIC MELANOMA. METASTATIC LESIONS ARE DISTINGUISHED GROSSLY
FROM MOST PRIMARY CENTRAL NERVOUS SYSTEM TUMORS BY THEIR MULTICENTRICITY
AND WELL-DEMARCATED MARGINS. THE DARK COLOR OF THE TUMOR NODULES IN THIS
SPECIMEN IS DUE TO THE PRESENCE OF MELANIN.
35. TUBEROUS SCLEROSIS
Tuberous sclerosis is an autosomal dominant syndrome characterized by the development of hamartomas
and benign neoplasms involving the brain and other tissues.
CNS hamartomas variously consist of cortical tubers and subependymal hamartomas, including a larger
tumefactive form known as subependymal giant cell astrocytoma.
Because of their proximity to the foramen of Monro, they often present acutely with obstructive
hydrocephalus, which requires surgical intervention and/or therapy with an mTOR inhibitor .
Seizures are associated with cortical tubers and can be difficult to control with anti-epileptic drugs.
Extracerebral lesions include renal angiomyolipomas, retinal glial hamartomas, pulmonary
lymphangiomyomatosis, and cardiac rhabdomyomas.
Cysts may be found at various sites, including the liver, kidneys, and pancreas.
Cutaneous lesions include angiofibromas, leathery thickenings in localized patches (shagreen patches),
hypopigmented areas (ash leaf patches), and subungual fibromas.
Tuberous sclerosis results from disruption of either TSC1, which encodes hamartin, or TSC2, which encodes
tuberin.
The two TSC proteins form a dimeric complex that negatively regulates mTOR, a kinase that “senses” the
cell’s nutrient status and regulates cellular metabolism.
Loss of either protein upregulates mTOR activity, which disrupts normal feedback mechanisms that restrict
uptake of nutrients and leads to increased cell growth.
36. MORPHOLOGY
Cortical hamartomas are firmer than normal cortex and have been likened in appearance
to potatoes—hence the appellation tubers.
They are composed of haphazardly arranged large neurons that lack the normal cortical
laminar architecture.
These cells may exhibit a mixture of glial and neuronal features, having large vesicular
nuclei with nucleoli (like neurons) and abundant eosinophilic cytoplasm.
Similar abnormal cells are present in subependymal nodules, in which large astrocyte like
cells cluster beneath the ventricular surface.
37. VON HIPPEL–LINDAU DISEASE
In this autosomal dominant disorder, affected individuals develop hemangioblastomas within the
cerebellar hemispheres, retina, and, less commonly, the brain stem, spinal cord, and nerve roots.
Patients also may have cysts involving the pancreas, liver, and kidneys and have an increased
propensity to develop renal cell carcinoma.
The disease frequency is 1 in 30,000 to 40,000.
Therapy is directed at the symptomatic neoplasms, including surgical resection of cerebellar
tumors and laser ablation of retinal tumors.
The affected gene, the tumor suppressor VHL, encodes a protein that is part of a ubiquitin-ligase
complex that degrades the transcription factor hypoxia-inducible factor (HIF).
Tumors arising in patients with von Hippel–Lindau disease generally have lost all VHL protein
function.
As a result, the tumors express high levels of HIF, which drives the expression of VEGF, various
growth factors, and sometimes erythropoietin; the latter effect may produce a paraneoplastic form
of polycythemia.
38. MORPHOLOGY
Hemangioblastoma, the principal neurologic manifestation of the disease, is a highly
vascular neoplasm that occurs as a mural nodule associated with a large, fluid-filled cyst.
These occur most commonly in the cerebellum, but can be found along the spinal cord and
in the retina, and rarely at other sites in the brain.
On microscopic examination, the lesion consists of numerous capillary-sized or somewhat
larger thin-walled vessels separated by intervening stromal cells with a vacuolated, lightly
PAS-positive, lipid-rich cytoplasm.
These stromal cells express inhibin, a member of the TGF-β family, which serves as a useful
diagnostic marker.
