A.
CENTRAL NERVOUS SYSTEM
63 Cancer of the Central Nervous System
Jay F. Dorsey, Ryan D. Salinas, Mai Dang, Michelle Alonso-Basanta,
Kevin D. Judy, Amit Maity, Robert A. Lustig, John Y.K. Lee,
Peter C. Phillips, and Amy A. Pruitt
S UMMARY OF K EY P OI N T S
Incidence
• 78,980 new primary brain tumors will
be diagnosed in the United States in
2018, of which approximately
one-third will be malignant.
• 3,560 new childhood (ages 0–19
years) primary benign and malignant
CNS tumors will be diagnosed in
2018. Brain tumors are now the most
commonly diagnosed malignancy
among children at a rate of 5.47 per
100,000 population, surpassing
leukemia (5.0 per 100,000).1
• Radiation exposure is the most
established risk factor for brain
tumors. Hereditary syndromes
including neurofibromatosis types 1
and 2, tuberous sclerosis, von
Hippel-Lindau disease, and
Li-Fraumeni syndrome are
associated with a higher risk of brain
tumors.
Pathology and Classification
• Taking all age groups into account,
histologic types of CNS tumors
include meningiomas (36.6%),
glioblastomas (14.9%), other
astrocytomas (5.6%), nerve sheath
tumors (8,2%), tumors of the
pituitary (15.9%), oligodendrogliomas
(1,5%), ependymomas (1.8%), and
embryonal tumors including
medulloblastomas (1%).
• Among children aged 14 years or
younger, histologic tumor types
include pilocytic astrocytomas
(18%), glioblastomas (2.8%), other
astrocytomas (8.5%), ependymal
tumors (5.8%), oligodendrogliomas
(0.7%), embryonal tumors including
medulloblastomas (13.8%),
craniopharyngiomas (4%), and germ
cell tumors (3.8%).
906
• Most brain tumors are supratentorial;
notable exceptions include brainstem
gliomas, cerebellar pilocytic
astrocytomas, medulloblastomas,
and ependymomas that involve the
posterior fossa.
• Glioblastoma (World Health
Organization grade IV astrocytoma)
and brainstem gliomas in children
carry the poorest prognosis. Pilocytic
astrocytomas carry the best
prognosis. In 2016, the World Health
Organization reclassified brain
tumors to include molecular
diagnostics based on genetic
mutations, which can clarify
prognosis and guide
treatment.
Clinical Manifestations
• General signs and symptoms from
mass effect, increased intracranial
pressure, edema, or shift or
destruction of surrounding brain
tissue may include changes in
personality and cognitive function,
headaches, nausea, vomiting,
seizures, and papilledema.
• Focal signs and symptoms may
include focal seizures, visual
changes, speech abnormalities, gait
abnormalities, and cranial nerve
deficits.
• Posterior fossa tumors often
compress the fourth ventricle,
causing hydrocephalus, and
frequently manifest with ataxia and
intractable nausea and vomiting.
• Brainstem gliomas often manifest
with a combination of cranial nerve
palsies and “long tract” signs such
as hemianesthesia or hemiparesis
coupled with ataxia in cases with
cerebellar involvement.
• Pineal region tumors (germ cell
tumors, pineocytomas,
pineoblastomas, and gliomas of this
region) may compress the aqueduct
of Sylvius, causing hydrocephalus.
Compression of the pretectal area
produces Parinaud syndrome, with
paralysis of upgaze, ptosis, and loss
of pupillary light reflexes, along
with retraction-convergence
nystagmus.
Diagnostic Studies
• Magnetic resonance imaging with
gadolinium contrast is the most
sensitive technique.
• Computed tomography scanning is
good for visualizing intratumoral
calcifications and bone erosion but
poor at visualizing the posterior
fossa.
• Positron emission tomography and
advanced magnetic resonance
imaging techniques may help
discriminate between tumor
recurrence and radiation necrosis or
pseudoprogression.
• Magnetic resonance spectroscopy
may help distinguish a high-grade
tumor from a low-grade tumor or
radiation necrosis.
Therapy
• For most brain tumors, tissue
diagnosis is required (an exception
may be selected brainstem
gliomas).
• Treatment for brain tumors is highly
dependent on histologic type.
For many tumors (e.g., gliomas,
meningiomas, primitive
neuroectodermal tumors [PNETs],
and ependymomas), maximal
surgical resection that is safely
feasible is the primary treatment.
 Cancer of the Central Nervous System • CHAPTER 63 907

• For some tumors (e.g.,
glioblastomas, PNETs, and germ cell
tumors), radiation therapy is an
essential adjunct treatment after
surgery.
• For some tumors (e.g., acoustic
neuromas and glomus tumors), either
irradiation or surgery can offer management of many brain
successful control; the decision tumors (e.g., glioblastomas,
between the two is based germ cell tumors, anaplastic
on assessment of adverse oligodendrogliomas, PNETs, and
effects. CNS lymphomas).
• Chemotherapy is assuming an
increasingly important role in the

The World Health Organization (WHO) classification of central
nervous system (CNS) tumors is based on tumor histology and cellular
origin and was established to provide a common classification and
grading system of human CNS tumors that is accepted and used
worldwide. The WHO divides brain tumors into classes: neuroepithelial
tumors, tumors of the cranial and paraspinal nerves, tumors of the
meninges, lymphomas and hematopoietic neoplasms, and germ cell
tumors and tumors of the sellar region.2 The different histologic types
of CNS tumors are shown in Table 63.1. Meningiomas, glioblastomas,
and astrocytomas constitute more than half of all CNS tumors. The
frequency of different histologic tumor types varies with age, as shown
in Fig. 63.1. The incidence of all brain tumors is highest in the 75- to
84-year-old age group. The incidence of meningiomas increases with
increasing age, whereas for gliomas and pituitary adenomas the incidence
increases with age but then declines at the highest age category (see
Fig. 63.1A). Certain histologic types, such as germ cell tumors,
medulloblastomas, and pilocytic astrocytomas, are far more common
in children than in adults (Table 63.2; See Fig. 63.1B).
For most patients with primary CNS tumors, surgery usually is the
initial therapy. Radiation therapy is often an important component
of treatment after surgery, but for management of malignant disease,
chemotherapy has an expanding role. A great deal of knowledge has

80
All primary tumors
70
Rate per 100,000 person-years

Gliomas
60 Meningioma
Nerve sheath tumors
50 Pituitary adenoma
Lymphoma
40

30

20

10

0
A (0–14) 0–19 20–34 35–44 45-54 55–64 65–74 75–84 85+

6
Rate per 100,000 person-years

0
B 0–4 5–9 10–14 15–19

All primary tumors

Figure 63.1 • Age-specific incidence of primary central nervous Gliomas
system tumors by histologic type. (A) Selected histologic types Embryonal tumors, including medulloblastoma
among all age groups. (B) Selected histologic tumor types in children.
(Data from Central Brain Tumor Registry of the United States. Pilocytic astrocytoma
Primary brain tumors in the United States, Statistical Report, 2012. Ependymoma/
Hinsdale, IL: Central Brain Tumor Registry of the United States; Anaplastic ependymoma
2012. Data were collected between the years 2004 and 2008.)
908 Part III: Specific Malignancies

Table 63.1 Primary Central Nervous System Tumors: Distribution by Histologic Type
FREQUENCY (%) OF PRIMARY CNS TUMORS BY HISTOLOGY
WHO 2016 Classification of Primary CNS Tumors Grade In All Age Groupsa Among Young Adultsb
Tumors of neuroepithelial tissue 29.3 28
Astrocytic tumors
Pilocytic astrocytoma I 1.4 2.8
Pilomyxoid astrocytoma
Subependymal giant cell astrocytoma I
Pleomorphic xanthoastrocytoma II
Anaplastic pleomorphic xanthoastrocytoma III
Diffuse astrocytoma II 2.2
Diffuse astrocytoma, IDH-mutant
Diffuse astrocytoma, IDH–wild type
Diffuse astrocytoma NOS
Anaplastic astrocytoma III 1.7
Anaplastic astrocytoma, IDH-mutant
Anaplastic astrocytoma, IDH–wild type
Anaplastic astrocytoma, NOS
Glioblastoma IV 14.9 4.4
Glioblastoma IDH–wild type
Glioblastoma IDH-mutant
Glioblastoma, NOS
Diffuse midline glioma H3K27M-mutant IV
Oligodendroglial tumors 1.0 3.5
Oligodendroglioma II
IDH-mutant and 1p/19q codeleted
Anaplastic oligodendroglioma III
IDH-mutant and 1p/10q-codeleted
Ependymal tumors
Ependymoma II 1.8 3.5
Ependymoma RELA fusion positive II or III
Anaplastic ependymoma III
Subependymoma I
Myxopapillary ependymoma I
Other gliomas
Angiocentric glioma I
Chordoid glioma of third ventricle II
Neuronal and mixed neuronal-glial tumors 1.2
Dysembryoplastic neuroepithelial tumor
Gangliocytoma I
Ganglioglioma I
Anaplastic ganglioglioma III
Dysplastic gangliocytoma of cerebellum (Lhermitte-Duclos) I
Desmoplastic infantile astrocytoma and ganglioglioma I
Papillary glioneuronal tumor I
Rosette-forming glioneuronal tumor I
Central neurocytoma II
Extraventricular neurocytoma II
Cerebellar liponeurocytoma II
Tumors of the pineal region 0.2
Pineocytoma I
Pineal parenchymal tumor of intermediate differentiation II or III
Pineoblastoma IV
Papillary tumor of the pineal region II or III
 Cancer of the Central Nervous System • CHAPTER 63 909

Table 63.1 Primary Central Nervous System Tumors: Distribution by Histologic Type—cont’d
FREQUENCY (%) OF PRIMARY CNS TUMORS BY HISTOLOGY
WHO 2016 Classification of Primary CNS Tumors Grade In All Age Groupsa Among Young Adultsb
Embryonal tumors 1.0 1.6
Medulloblastoma (all subtypes) IV
Embryonal tumor with multilayered rosettes, C19MC-altered IV
Medulloepithelioma IV
CNS embryonal tumor, NOS IV
Atypical teratoid or rhabdoid tumor IV
CNS embryonal tumor with rhabdoid features IV
Tumors of cranial and paraspinal nerves 8.3 8.6
Schwannoma (neurilemmoma, neurinoma) I
Neurofibroma I
Perineuroma I
Malignant peripheral nerve sheath tumor II, III, IV
Tumors of the meninges 37.8
Tumors of meningiothelial cells
Meningioma I 36.6 15.9
Atypical meningioma II
Anaplastic (malignant) meningioma III
Other neoplasms related to the meninges
Solitary fibrous tumor, hemangiopericytoma I, II, or III
Hemangioblastoma, hemangioma I 3.5
Lymphomas and hematopoietic neoplasms 2.0 1.5
Germ cell tumors 0.4 1.3
Tumors of the sellar region 16.7 32.2
Craniopharyngioma I 0.8 1.2
Tumors of the pituitary I 15.9 31
Granular cell tumor I
Pituicytoma I
Spindle cell oncocytoma I

a
Frequency among all patients with primary brain and CNS tumors espectively (N = 368,117). Data from CBTRUS Statistical Report: Primary Brain and Other Central Nervous
System Tumors Diagnosed in the United States in 2010–2014 (Ostrom et al. 2016).
b
Frequency among young adults (15–34 years of age) with primary brain and CNS tumors (N = 54,388, respectively).
CNS, Central nervous system; IDH, isocitrate dehydrogenase; NOS, not otherwise specified; WHO, World Health Organization.
Data from Ostrom, Quinn T., et al. “CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2009–2013.”
Neuro-oncology 18.suppl_5 (2016): v1–v75.

been amassed during the past two decades regarding the biology
of brain tumors that should lead to improved treatments in the
near future.
EPIDEMIOLOGY
An estimated 79,270 new cases of primary CNS tumors were expected
to be diagnosed in the United States in 2017.1 Approximately 25,850
of these tumors were expected to be malignant, representing 1.4% of
all primary malignant cancers diagnosed in the United States.3
Malignant CNS tumors were expected to cause approximately 17,000
deaths in 2017.
On the basis of data provided by the Surveillance, Epidemiology,
and End Results (SEER) Program, Deorah and colleagues3 found
that the incidence of brain cancer increased until 1987, when the
annual percentage of change reversed direction. Elderly persons
experienced an increase in brain cancer until 1985, but their rates
were stable thereafter. Overall, however, the incidence of glioblastoma
has been increasing, with survival only modestly improved during the
past decade.4
Ionizing radiation is one of the few factors shown to have a strong
association with the development of brain tumors. Exposure to ionizing
radiation represents the most important exogenous risk factor for
childhood brain tumors. Prenatal diagnostic x-ray exposure increases
the risk of childhood brain tumors,5 and various reports describe the
occurrence of gliomas, meningiomas, and other brain tumors in children
who received radiation therapy to the head for tinea capitis and for
prior malignancies.6–9 A dose of 1 to 2 Gy of radiation, which was
used to treat tinea capitis in Israeli children, was associated with an
increased risk of the development of brain tumors—specifically,
meningiomas, gliomas, and nerve sheath tumors.10 A dose-response
correlation in the induction of brain tumors was seen, with a relative
risk of 3.0 at a dose of 1 Gy. Tumors developed at least 6 years after
irradiation, with a mean interval greater than 15 years. Even lower
doses of radiation delivered with radium-226 that were used to treat
hemangiomas in Swedish infants (with a mean dose to the brain of
910 Part III: Specific Malignancies

brain tumors in humans (reviewed by Berleur and Cordier18). The

Table 63.2 Primary Central Nervous System relationship of human cytomegalovirus (HCMV) and gliomas remains
Tumors of Childhood: Distribution by controversial. The HCMV and gliomas symposium held in April 2011
Histologic Type resulted in consensus that sufficient evidence exists to conclude that
HCMV viral gene expression exists in most, if not all, malignant
FREQUENCY (%)
gliomas and that HCMV could influence the phenotype of malignant
Age 0–14 Yr Age 15–19 Yr gliomas by interacting with signaling pathways.19 Other authors who
Histologic Tumor Type (n = 16,653) (n = 6869) have used the data regarding cytomegalovirus (CMV) seroprevalence
Pilocytic astrocytoma 18 9.4 in the United States from the National Health and Nutrition
Examination Surveys, 1988 to 2004, have concluded that a possible
Glioma malignant NOS 14.3 5.1
CMV-glioblastoma association could not be corroborated with CMV
Embryonal tumors, including 13.8 3.6 seropositivity rates.20
medulloblastoma Also lacking is conclusive evidence that occupational exposure to
All other 10.2 11.5 industrial chemicals leads to the development of brain tumors, although
Other astrocytomas 8.5 7.4 a number of studies have suggested such a link (reviewed by Wrensch
Neuronal and mixed 6.6 7.9 and coworkers).21 Some of the chemicals that can induce brain tumors
neuronal-glial tumors in laboratory animals, such as polycyclic aromatic hydrocarbons, can do
Ependymal tumors 5.8 3.9
so only when administered by direct contact or transplacentally, but not
by inhalation or dermal contact; the latter two modes of exposure are
Nerve sheath tumors 4.9 5.9 more relevant in the occupational setting. Specific chemicals that have
Tumors of the pituitary 4.5 27.8 been examined include cosmetics containing N-nitroso compounds,
Craniopharyngioma 4.0 2,1 organic solvents, chemicals used in the manufacture of synthetic rubber,
Germ cell tumors 3.8 4.1 formaldehyde, phenols, polycyclic aromatic compounds, polyvinyl
Glioblastoma 2.8 3,3
chloride, and pesticides. Although many chemicals can induce brain
tumors in laboratory animals, no definitive associations have been found
Meningioma 1.6 5.0 in humans. For example, N-nitroso compounds, which commonly
Oligodendroglioma 0.7 1.6 are present in foods, are known to be neurocarcinogenic in animals.
Oligoastrocytic tumors 0.4 0.8 Oxidants in the environment can cause DNA damage, so it has been
Lymphoma 0.2 0.4 hypothesized that antioxidants, such as vitamin E, found in certain
foods may protect against the development of cancers. Epidemiologic
NOS, Not otherwise specified. studies, however, have provided mixed support for the idea that the
Data from Ostrom, Quinn T., et al. “CBTRUS statistical report: primary brain and intake of N-nitroso compounds, antioxidants, or specific nutrients in
other central nervous system tumors diagnosed in the United States in 2009–2013.” foods can influence the risk of developing brain tumors.18
Neuro-oncology 18.suppl_5 (2016): v1–v75. A great deal of interest has emerged in a possible association between
the use of cell phones and the risk of brain tumors. In a case-control
study, Inskip and coworkers were unable to show a correlation between
7 cGy) were found to be associated with an excess risk of intracranial the duration of cell phone use and the development of gliomas,
tumors, including pituitary adenomas, gliomas, meningiomas, and meningiomas, and acoustic neuromas.22 Other large case-control studies
nerve sheath tumors.11 also have failed to find any association between cell phone use and
A large amount of data has been accumulated on the incidence of the risk of developing brain tumors.23–25 A meta-analysis of nine
brain tumors in patients who received cranial irradiation for the case-control studies revealed no increased risk in analog or digital
treatment of acute lymphoblastic leukemia (ALL). The estimated cellular phone users.26 Nevertheless, some still claim that there is a
cumulative risk of secondary malignant brain tumors after childhood link between cell phone use and brain tumors.27 In addition, the
ALL therapy is 0.5% at 10 years after completion of therapy.12 In a International Agency for Research on Cancer (IARC), a WHO agency,
study from St. Jude Children’s Research Hospital, the actuarial 20-year has classified radiofrequency electromagnetic fields as “possibly carci-
probability of developing a brain tumor in these patients was 1.4%.13 nogenic to humans.”28
The probability of developing a high-grade glioma was greater in Other factors that have been analyzed for their possible relationship
children younger than 5 years of age at diagnosis than in those 6 years to the development of brain tumors include a history of head trauma
of age or older (1.08% versus 0.45%; P = .045). An apparent dose- and injury, drugs and medications, allergies, seizures, smoking and
response correlation was observed; the 20-year risk of developing a alcohol consumption, and exposure to power-frequency electromagnetic
brain tumor was 3.2% in patients who received more than 30 Gy, fields. None of these factors, however, has been conclusively shown
versus 1.03% in patients who received 21 Gy or less (P = .015). No to be important (reviewed by Wrensch and associates21).
CNS malignancies were seen in patients who did not receive cranial Most brain tumors represent sporadic cases; however, familial
irradiation. The latency period between irradiation and the diagnosis clustering has been noted. It is estimated that hereditary syndromes
of a brain tumor ranged from 5.9 to 29 years (median, 12.6 years) account for 2% of childhood brain tumors, although this may be an
but was longer for meningiomas (median, 19 years) than for high-grade underestimate because hereditary syndromes may be undiagnosed in
gliomas (median, 9.1 years). Very similar results regarding the frequency a number of cases.29 Some hereditary syndromes known to be associated
of brain tumors, latency, and dependence on prior cranial irradiation with brain tumors are listed in Table 63.3 (reviewed by Kimmelman
were seen in studies from the German Berlin-Frankfurt-Munster group14 and Liang30). Some of the associations are extremely strong. Nearly
and the Children’s Cancer Study Group.15 The types of brain tumors 70% of all optic pathway gliomas occur in patients with neuro-
that have been reported in these series include gliomas, meningiomas, fibromatosis type 1 (NF1), and acoustic neuromas commonly occur
and medulloblastomas. Patients who received cranial irradiation for in patients with NF2. In addition, hereditary immunosuppression
ALL also often received intrathecal chemotherapy. It has been suggested disorders such as Wiskott-Aldrich syndrome, treatment-associated
that cranial irradiation and intrathecal chemotherapy may work immunosuppression as in organ-transplant recipients, and exogenous
synergistically to increase the incidence of glial tumors.16,17 immunosuppression as in human immunodeficiency virus (HIV)
Viruses can induce brain tumors in animals in the experimental infection are known to be associated with an increased risk of primary
setting; however, no conclusive data point to viruses as a cause of central nervous system lymphoma (PCNSL).
 Cancer of the Central Nervous System • CHAPTER 63 911

Table 63.3 Hereditary Syndromes Associated With Brain Tumors

Chromosomal
Syndrome Associated CNS Tumors Gene Locus Defective Protein and Normal Function
Neurofibromatosis type 1 Optic pathway gliomas, NF1 17q11-12 Neurofibromin; GTPase-activating protein that
meningiomas, neuromas negatively regulates Ras
Neurofibromatosis type 2 Bilateral acoustic neuromas, NF2 22q12 Merlin; related to membrane cytoskeleton linker
meningiomas, gliomas protein 4.1 superfamily
Tuberous sclerosis Cerebral hamartomas TSC1 9q34 Hamartin
Subependymal giant cell TSC2 16p13 Tuberin; associates with hamartin; both are involved in
astrocytoma (SEGA) signaling downstream of Akt
von Hippel-Lindau syndrome Hemangioblastomas VHL 3p25-29 VHL protein; degrades HIF-1α
Li-Fraumeni syndrome Malignant gliomas TP53 17p13 p53; maintains genomic stability
Cowden syndrome Meningiomas PTEN 10q23 PTEN; lipid phosphatase, counters PI3 kinase activation
Gorlin syndrome (nevoid basal Medulloblastomas PTCH 9q22 Cell surface receptor; regulates normal brain
cell carcinoma syndrome) development
Turcot syndrome Medulloblastomas APC 5q21 APC; part of Wnt/β-catenin signaling pathway
Malignant gliomas hMLH1 3p21 Involved in mismatch repair
Malignant gliomas PMS2 7p22 Involved in mismatch repair
Familial retinoblastoma Pineoblastomas RB 13q14 Rb protein; regulates entry into S phase
Ataxia-telangiectasia CNS lymphoma ATM 11q22-23 ATM protein; involved in DNA damage sensing
Multiple endocrine neoplasia Pituitary adenomas MEN1 11q13 Menin
syndrome 1

APC, Adenomatous polyposis coli; ATM, ataxia-telangiectasia mutated; CNS, central nervous system; GTPase, guanosine triphosphatase.

TUMOR BIOLOGY
Cell Proliferation
Normal cells rely on growth factors secreted in their local environment
to stimulate their growth. However, many CNS tumors have developed
the ability to express their own growth factors along with the respective
receptors, resulting in an autocrine loop that allows for self-stimulation.31
Platelet-derived growth factor receptor alpha (PDGFRα), for example,
is overexpressed in all grades of astrocytomas, but only higher-grade
tumors overexpress the ligands PDGFA and PDGFB.32 Insulin-like
growth factors and their receptors both are expressed in brain tumors,
including gliomas and meningiomas.33 The epidermal growth factor
receptor (EGFR) is amplified or overexpressed in 50% of glioblasto-
mas,31 and expression of transforming growth factor–α (TGF-α), a
ligand that binds to this receptor, is increased in many gliomas.34,35
Both scatter factor (also known as hepatocyte growth factor) and its
receptor c-Met are expressed in gliomas, with the highest level of
expression seen in the most malignant tumors.36
As a result of increasing expression of receptors and ligands, increased
signaling occurs in many brain tumors, resulting in activation of many
different pathways that are important in proliferation (reviewed by
Rao and James34). The best studied of these pathways is the mitogen-
activated protein kinase (MAPK) pathway, which involves Ras and
Raf. Another pathway that has attracted much attention is the
phosphatidylinositol 3 (PI3) kinase pathway, which leads to activation
of Akt. Mutation of PTEN, which occurs in 30% to 40% of glio-
blastomas, also can lead to increased Akt activation.37
Ras activation commonly is seen in human astrocytomas and
neurofibromas despite the fact that these tumors rarely contain Ras
mutations. In astrocytomas, Ras activation probably occurs through
activation of growth factor receptors such as EGFR and PDGFR.38
Other mechanisms of activation of aberrant G proteins have been
identified in other CNS tumors (reviewed by Woods and coworkers39).
In NF1, loss of expression of neurofibromin, an inactivator of Ras,
is seen (see Table 63.3). This loss of neurofibromin leads to the increased
Ras activation seen in NF1-associated astrocytomas. Pituitary adenomas
often show activation of the alpha subunit of the large heterotrimeric
Gs protein, resulting in mitogenic signaling.
The Wnt pathway has been shown to play a role in glioma
tumorigenesis. Investigators have shown that the Wnt-specific secretory
protein Evi is overexpressed in astrocytomas.40 Furthermore, the same
researchers showed that the depletion of this protein in glioma cells
leads to decreased cell proliferation and apoptosis. In addition, silencing
of Evi in glioma cells leads to reduced cell migration and the ability
to form tumors in vivo.40 Involvement of Wnt/β-catenin signaling in
gliomas has been reviewed by Zhang and colleagues.41
Cell proliferation is intimately tied to cell cycle regulation. Mutations
in the p16/Cdk4 or Cdk6/cyclin D/Rb pathway or the p21/p53/
Mdm2/p19ARF pathway are common in many brain tumors, particularly
gliomas.
Invasion
Many brain tumors, particularly gliomas, display an invasive phenotype
with infiltration of tumor cells into surrounding tissues, making a
cure very difficult to achieve. In fact, tumor recurrence was reported
in one case even after resection of the entire hemisphere in which a
glioma was located.42 The process of invasion involves several steps:
detachment of the invading cell from the primary tumor mass, adhesion
to extracellular matrix (ECM), degradation of ECM, and cell motility
and contractility.43 The details of the mechanisms of glioma invasion
are only beginning to be understood. Numerous molecules associated
with invasion have been found to be upregulated in gliomas, including
tenascin-C, secreted protein acidic and rich in cysteine (SPARC),
various integrins, and matrix metalloproteinases (reviewed by Demuth
and Berens44).
Some controversy exists regarding deregulated Rho guanosine
triphosphatase (GTPase) signaling in brain tumors. For example,
although RhoA and RhoB are reduced in some astrocytic tumors,
912 Part III: Specific Malignancies
some studies report Rho-dependent lysophosphatidic acid–induced
migration in glioma cells. Expression of another member of the
Rho subfamily, Rac1, has been found to be reduced in astrocytic
tumors; in addition, this protein has been shown to be overex-
pressed and to have induced invasion in medulloblastoma tumors.
The role of Rho GTPases has been reviewed by Khalil and
El-Sibai.45
Angiogenesis and Hypoxia
For a tumor to grow beyond a certain size, it must develop a blood
supply. The vasculature of normal brain, which is composed of endo-
thelial cells, pericytes, and astrocytes, is highly specialized. Together
these cells form the blood-brain barrier, which selectively restricts
exchange of molecules between the intracerebral and extracerebral
circulatory systems. As primary brain tumors or brain metastases grow,
the integrity of the blood-brain barrier is compromised.46–49
A number of growth factors are known to be important in angio-
genesis. The most prominent of these is vascular endothelial growth
factor (VEGF), which is overexpressed in many brain tumors. In one
study, increasing VEGF expression correlated with increasing malignant
grade in astrocytomas, oligodendrogliomas, and ependymomas.50 In
this study it also was found that increased expression of the VEGF
receptors Flt-1 and KDR in tumor vasculature correlated with increasing
VEGF expression and malignant grade. Hypoxia and acidosis have
been shown to independently regulate VEGF transcription in brain
tumors in vitro and in vivo.51 In addition, both tumor suppressors
and oncogenes, hormones, cytokines, and other signaling molecules
have been shown to regulate VEGF expression.49,52–55 Growth factors
other than VEGF that may play a role in angiogenesis in gliomas
include members of the TGF-β family, PDGF, placental growth factor,
basic fibroblast growth factor, and scatter factor/hepatocyte scatter
factor.56 Angiogenesis can also be negatively regulated by factors such
as thrombospondins 1 and 2 (TSP1 and TSP2). TSP1 is positively
regulated by p53, and thus loss of p53, which commonly occurs
in gliomas, can lead to decreased TSP1 expression and increased
angiogenesis.
Angiogenesis is particularly prominent within glioblastomas. Among
the characteristic features of these tumors are endothelial proliferation
and neovascularization. A variety of growth factors that can increase
angiogenesis are expressed by glioblastomas, with the foremost being
VEGF. VEGF, also known as vascular permeability factor, is a potent
inducer of capillary permeability. The high levels of VEGF expression
in glioblastomas may be responsible for the edema associated with
these tumors. Some evidence indicates that genetic changes common
to glioblastomas, such as EGFR activation and PTEN mutation, may
contribute to high levels of VEGF expression, perhaps through activa-
tion of the PI3 kinase pathway.57–59
Despite expressing high levels of VEGF, glioblastomas contain
significant regions of hypoxia, which may be a cause of treatment
resistance. Hypoxia has been shown to be present in malignant gliomas
with both polarographic needle electrode measurement60,61 and binding
of the 2-nitroimidazole EF5.62 Hypoxia, as measured by binding of
EF5, has been shown to correlate with more rapid tumor recurrence.62
Evidence indicates that hypoxia is involved in many aspects of tumor
growth, including induction of angiogenesis, increased invasion and
metastases, resistance to chemotherapy, resistance to radiotherapy,
increased brain tumor stem cell population, and stem cell genetic
instability.63
The histologic features of glioblastoma are consistent with this
notion of hypoxia, including the presence of pseudopalisading necrosis
and proliferative blood vessels. Pseudopalisades seen within glioblas-
tomas represent a wave of tumor cells actively migrating away from
central hypoxia and are thought to arise as a result of vasoocclusion
and intravascular thrombosis.64 High VEGF levels and robust neo-
vascularization may be explained by hypoxia-induced VEGF simulation
of new vessels.
Stem Cells
The tumor stem cell hypothesis may help explain the resistance of
glioblastoma to current therapies. The tumor stem cell hypothesis
suggests that a subset of tumor cells, called tumor stem cells, stemlike
cells, or tumor-initiating cells, are endowed with characteristics of normal
stem cells, such that they can self-renew and are able to produce a
variety of cell types. Because the stemlike cells have properties different
from the cells constituting most of the tumor, a different approach
to eradicating these stemlike cells may be necessary.
Identification of glioblastoma stemlike cells has proved to be
challenging. Early studies showed differences between CD133+ and
CD133− glioma cells, including differences in tumor-forming capacity
in xenografts.65 However, other studies have shown that CD133− stem-
like cells may also be capable of forming tumors, although these two
cell populations exhibit distinct molecular profiles and growth
characteristics.66
Efforts are being made to elucidate transduction pathways that
influence tumorigenicity and are unique to glioma stemlike cells to
allow treatments to target these pathways. It has been demonstrated
that glioma stemlike cells may be relatively radioresistant as a result
of overexpression of DNA damage repair proteins, including the
checkpoint kinases Chk1 and Chk2.67 The cells may be made more
radiosensitive by using specific inhibitors of Chk1/Chk2. Piccirillo
and colleagues68 showed that CD133+ glioblastoma stem cells have
a functional bone morphogenetic protein receptor pathway. By exposing
mice implanted with orthotopic glioblastomas to bone morphogenetic
protein 4, these researchers were able to cause the CD133+ cells to
differentiate toward glial cells and reduce tumor growth. These two
strategies have the potential to be used to target stem cells in glio-
blastomas. Another potential strategy is to target the tumor stroma,
which provides a specialized niche for tumor cells. Calabrese and
associates69 showed that stem cells in brain tumors occupied a peri-
vascular niche and could be targeted by antiangiogenic therapy.
Other potential targets include signal transducer and activator of
transcription 3 (STAT3), a transcription factor activated by interleukin
(IL)-6, a molecule that is overexpressed in glioblastoma. STAT3 is
constitutively active in numerous cancers, including glioblastoma.
Expression of a dominant negative mutant STAT3 or silencing STAT3
with a lentivirus have been shown to reduce proliferation of a glio-
blastoma cell line.70 Other groups are investigating nanotechnology
to target glioma stemlike cells. Some investigators have used iron
oxide nanoparticles conjugated to a glioblastoma-specific target of
EGFRvIII in an animal model,71 whereas others have used curcumin
nanoparticles to inhibit glioblastoma and medulloblastoma cell prolifera-
tion in culture.72 Glioblastoma stemlike cells have been reviewed in
detail by Nduom and colleagues73 and by Tabatabai and Weller.74 The
stemlike cell hypothesis also applies to other brain tumor histologic
types. The roles of medulloblastoma and ependymoma tumor-initiating
cells have been reviewed by Manoranjan and colleagues75 and Poppleton
and Gilbertson, respectively.76
CLINICAL PRESENTATION
Pathophysiology of Signs and Symptoms
Parenchymal brain tumors produce clinical signs and symptoms by
three main mechanisms, each of which has important implications
for therapy. First, infiltration along nerve fiber tracts is typical of
primary brain tumors such as low-grade astrocytomas and oligoden-
drogliomas. The first clinical manifestation may be seizures. Normal
brain tissue may be present within areas appearing abnormal on
magnetic resonance imaging (MRI), and functional mapping may be
necessary for safe resection of these slowly growing tumors.77–80 Second,
displacement of brain tissue with production of vasogenic edema is
typical of cerebral metastases. Such tumors sometimes can be resected
or irradiated focally with less risk to adjacent normal brain tissue than

is the case with infiltrating tumors. Third, rapidly growing aggressive
tumors such as high-grade astrocytomas may enlarge as a mass and
also destroy surrounding neuropil to such an extent that surgical
resection, although helpful for the reduction of mass effect and intra-
cranial pressure (ICP), may not alleviate local symptoms and signs.
Intracranial neoplasms usually produce progressive symptoms.
Location and rate of growth determine both general and specific
localizing symptoms and signs. Thus a patient with a low-grade glial
tumor may have seizures for many years or may exhibit behavioral
alteration for many months before focal signs develop. With a more
aggressive glial neoplasm, headache and focal signs may develop over
a few weeks. Apoplectic onset is associated with hemorrhage or the
development of hydrocephalus.
Brain tumor symptoms may be general, localizing, or falsely local-
izing. General symptoms include headache, lethargy, nausea, vomiting,
and nonspecific cognitive or balance difficulties. These symptoms may
be manifestations of increased ICP from a combination of expanding
tumor volume and the production of associated vasogenic cerebral
edema. Tumors also may cause raised ICP by obstruction of the
ventricular system or blockage of the venous sinuses. Abrupt headache
and exacerbation of neurologic signs may accompany the plateau
waves of sudden increased ICP.
Sustained ICP in excess of 200 mm H2O causes brain shifts that
can displace brain tissue through fixed intracranial openings, producing
life-threatening herniation syndromes (Fig. 63.2). The uncal herniation
syndrome is caused by tumors arising in the lateral aspect of the
brain, most commonly the temporal lobe. An early, consistent sign
of compressive uncal herniation is a unilaterally dilated pupil due to
compression of the ipsilateral third cranial nerve, which is followed by
extraocular movement abnormalities consistent with an oculomotor
Falx cerebri
Cingulate
gyrus
Third
ventricle
Hippocampal
gyrus
Tentorium
cerebelli
Foramen Cerebellar
magnum tonsil
Figure 63.2 • Intracranial herniation syndromes evoked by supratentorial
masses. The tumor and its edema (arrows) have produced the following (curved
arrows): cingulate gyrus herniation under the falx cerebri; diencephalic herniation
across the midline compressing the ipsilateral ventricle and producing the
hydrocephalus in the contralateral ventricle; hippocampal gyrus herniation
through the tentorial notch compressing the posterior cerebral artery and
brainstem; and herniation of the cerebellar tonsils through the foramen magnum.
Cancer of the Central Nervous System • CHAPTER 63 913
palsy. The posterior cerebral artery may be compressed against the
tentorium, leading to homonymous hemianopia. Brainstem compression
can cause compression of the contralateral cerebral peduncle against
the edge of the tentorium, causing what is known as the Kernohan
notch phenomenon.81 Patients with uncal herniation initially may
be awake, but progression to obtundation, coma, and death may
occur rapidly.
The central herniation syndrome results from tumors that arise
along the midline axis of the brain, especially those deep in the basal
ganglia and thalamus regions. The initial signs and symptoms are due
to diencephalic compression. The syndrome often first manifests with
an alteration in the level of alertness and behavior. Some patients
become agitated, whereas others become very drowsy. Hemisensory
or hemiparetic deficits and periodic Cheyne-Stokes respirations may
develop in these patients. Initially with diencephalic compression,
pupils are small (1–3 mm), but as the syndrome progresses to compress
the midbrain and upper pons, the pupils dilate moderately and fix at
midposition (3–5 mm). As the syndrome progresses, patients become
progressively lethargic and apathetic and Cushing’s signs of hypertension
and bradycardia may develop as a result of direct compression of the
hemodynamic control nuclei within the brainstem.82,83
Tonsillar herniation may be caused by an expanding mass in the
posterior fossa. Tonsillar herniation results in the cerebellar tonsils
being pushed through the foramen magnum. The syndrome is character-
ized by posterior headache, vomiting, stiff neck, and sometimes
opisthotonic posturing. Other features may include dysconjugate eye
movements and syncope with cough or sudden postural change. As
a result of direct compression of the medulla and its respiratory center,
irregular breathing and acute apnea may develop.
These herniation syndromes can rapidly progress from the onset
of symptoms to death. They can be precipitated by medical procedures.
Lumbar puncture may lead to tonsillar herniation, and ventriculostomy
may result in upward herniation in which the brainstem is forced up
through the tentorial notch. A high index of suspicion is required to
successfully diagnose and treat this condition with emergency intubation
and administration of appropriate therapy (see the section on treatment
of brain tumor symptoms).
General Signs and Symptoms
Headache results from traction on pain-sensitive structures of the
intracranial contents, including the large cerebral vessels, the dura
and meninges, the venous sinuses, cranial nerves V and IX, and the
second and third cervical nerve roots. Headache is the most common
symptom of a brain tumor and occurs in approximately 50% of
patients at some time during the course of the illness. Headache more
frequently accompanies rapidly growing than slowly growing tumors.
Tumors located in neurologically noneloquent brain areas such as the
nondominant frontal and temporal lobes may manifest with headache
as the sole clinical manifestation. The “classic” brain tumor–associated
headache often is worse in the morning and lateralized to the affected
side of the brain. Brain tumor–associated headache may be worsened
by coughing or straining. A majority of patients with brain tumors,
however, do not have these classic symptoms but instead have headaches
that are deep, aching, and difficult to distinguish from tension-type
headache. Headaches from posterior fossa tumors are localized to the
back of the head or neck, whereas headaches from tumors of the
anterior and middle cranial fossae may be referred to the forehead or
eye, at times being misconstrued as a sinus headache.
Brain tumor–associated cognitive changes initially may be subtle
and frequently are misdiagnosed as depression or, in the older patient,
age-associated forgetfulness or early Alzheimer disease. Frontal lobe
tumor location is the most common site for tumors producing these
symptoms as the initial manifestation of a neoplasm.
Several other symptoms may emerge that roughly parallel cognitive
decline and are of poor localizing value by themselves. Dysphagia is
a common complaint, and caregivers may note that the patient with
914 Part III: Specific Malignancies
cognitive impairment seems to take a long time to chew and swallow.
Oral candidiasis is a potential complicating issue in patients undergoing
long-term corticosteroid therapy, and appropriate treatment should
be instituted. Similarly, incontinence tends to parallel the degree of
cognitive impairment. Urinary retention may occur in patients with
bifrontal brain disease or with spinal cord problems. Opiate medications
may exacerbate the urologic problems.
Seizures occurring for the first time in adults are more likely to be
due to focal brain pathology, particularly neoplasms, than are seizures
occurring in childhood. Intracranial tumors produce generalized
tonic-clonic seizures, secondarily generalized tonic-clonic seizures, and
partial, localization-related seizures. Seizures are more common in
persons with cortical tumors than in persons with infratentorial or
deep thalamic lesions, and they occur more often in low-grade
astrocytomas, oligodendrogliomas, or oligoastrocytomas (60%–80%)
than in high-grade gliomas (20%–40%) or cerebral metastases
(15%–20%)84,85 Seizures occur at some time in 25% to 50% of patients
with brain tumors. Seizure frequency may increase during radiation
treatment and continue at an increased frequency for several months
thereafter because of localized swelling.
Papilledema—that is, swelling of the optic nerve head with engorge-
ment of retinal veins—usually indicates raised ICP. Currently, papil-
ledema is seen in fewer than 20% of patients at presentation, down
from 59% in the 1971 report by Huber.86 The development of
papilledema is dependent on the location of the tumor and the rate
of growth.
Vomiting with or without nausea may occur as a result of direct
simulation of emetic centers in the floor of the fourth ventricle. This
mechanism explains the nausea and vomiting seen with raised ICP,
particularly when the rise in pressure has been rapid and is associated
with hemorrhage or herniation. Patients with posterior fossa tumors
frequently experience nausea and vomiting. More commonly, however,
nausea is a nonlocalizing symptom, and thus the differential diagnosis
must include adverse drug reactions from antiepileptic drugs (AEDs),
analgesics, or other concurrent medications and gastritis from high-dose
corticosteroid treatment.
Localizing Signs of Intracranial Tumors
Focal clinical signs of an intracranial tumor reflect the location of the
mass and its associated vasogenic edema, which often is of much
greater volume. This chapter does not provide a detailed discussion
of every possible localizing sign but rather focuses on the general
principle of neurologic localization and the specific emergent syndromes
that should be recognized because of their localizing and management
importance.
Disorders associated with frontal lobe lesions include early impair-
ment of intellectual function and language function if the dominant
frontal lobe is involved. Patients with bilateral frontal tumors appear
to lack initiative and spontaneity—a state called abulia. Such patients
may have an impaired gait with difficulty initiating walking. Personality
changes include inattentiveness, apathy, depression, and the less
common disinhibition and inappropriate affect leading to socially
inappropriate behaviors. As tumors enlarge to involve the motor cortex,
contralateral motor problems, such as hemiparesis or monoparesis,
may develop.
Receptive language, auditory discrimination, and memory all are
important functions of the dominant temporal lobe. Patients with
nondominant temporal lobe tumors may have seizures involving visual,
olfactory, or gustatory hallucinations. Deep temporal tumors may
cause a contralateral visual field cut (superior quadrantanopia).
The parietal lobe is demarcated from the frontal lobe by the central
sulcus. Parietal lobe functions include tactile perceptions; integration
of sensory, visual, and auditory information; and visual discrimination
in the inferior contralateral quadrant. When tumor involves the
nondominant parietal lobe, inattention to the deficit (anosognosia)
may be a prominent feature of the presentation.
Tumors in the occipital lobes cause a contralateral quadrantic or
hemianopic defect, sometimes with sparing of central macular vision.
Tumors of the brainstem cause a great many focal deficits early in
their course. Typically, a combination of cranial nerve palsies and long
tract signs such as hemianesthesia or hemiparesis coupled with ataxia
reflecting cerebellar involvement give a clue to the localization. Patients
with brainstem tumors experience difficulty with swallowing and speech
articulation and are at risk for aspiration.
Cerebellopontine (CP) angle tumors such as acoustic neuromas
impair function of the eighth cranial nerve and produce unilateral
hearing loss, tinnitus, and, later, vertigo. Involvement of adjacent
cranial nerves VII and V leads to facial palsy and facial anesthesia.
Later cerebellar dysfunction reflects tumor growth in this area.
Tumors of the pituitary and suprasellar region produce endocri-
nologic abnormalities either by hormonal production by secretory
adenomas or by impingement on hypothalamic-pituitary connections.
Visual defects reflect chiasmatic involvement. The most common
pituitary region field defect is a bitemporal hemianopia.
Pineal region tumors (e.g., germ cell tumors, pineocytomas,
pineoblastomas, gliomas of this region) may compress the aqueduct
of Sylvius, causing hydrocephalus. Compression of the pretectal area
produces a characteristic syndrome (Parinaud syndrome) with paralysis
of upgaze, ptosis, and loss of pupillary light reflexes, along with
retraction-convergence nystagmus.
Many primary tumors are capable of diffuse infiltration of the
meninges. Gliomas, lymphomas, and oligodendrogliomas all may
invade the subarachnoid space. They produce variable cranial nerve
and spinal root dysfunction and diffuse headache, and sometimes lead
to communicating hydrocephalus. Elevated levels of cerebrospinal
fluid (CSF) protein, low levels of CSF glucose, and positive results
on cytologic studies are the diagnostic hallmarks.
On occasion, the clinician will be faced with symptoms that appear
to give a clue to the patient’s tumor site but in fact are false localizing
symptoms. Palsies of the abducens nerve (cranial nerve VI) may reflect
brainstem involvement but commonly are a nonlocalizing sign of
raised (or, much less commonly, low) ICP. Ocular pain is of little
localizing value because it may reflect any of the structures innervated
by the first division of the fifth cranial nerve. Thus eye pain may
reflect any process in the anterior or middle cranial fossa. Diplopia
may result from cranial nerve invasion by brainstem or leptomeningeal
tumor but also can be caused by excess levels of AEDs.
Posterior head pain may reflect posterior fossa disease but also may
come from the upper cervical segments, and spinal cord tumor or
caudal extension of a primary brainstem tumor should be considered
if the patient reports pain in the occiput. Another sign of cervical
cord disease is bilateral upper limb weakness or numbness.
Gait disorders pose another potential hazard for falsely localizing
signs and symptoms. A frontal lobe gait ataxia may mimic basal ganglia
or even cerebellar disease. The affected patient walks slowly, with a
wide-based gait, and seems to have difficulty initiating movements.
Proximal leg weakness may reflect spinal metastases from intracranial
or systemic tumor, but probably the most common cause of proximal
leg weakness is corticosteroid-induced myopathy.
Treatment of Brain Tumor Symptoms
Acute Raised Intracranial Pressure
The most immediate life-threatening syndromes are the herniation
syndromes, but rapid increase in vasogenic edema also mandates
aggressive treatment of evolving neurologic signs and symptoms.
If the patient’s condition is rapidly deteriorating, intubation and
hyperventilation aiming for a pressure of carbon dioxide (Pco2) of
25 to 30 mm Hg are required. Mannitol is administered intravenously
at a loading dose of 1 to 2 g/kg, followed by 0.5 to 1 g/kg every 6
hours as needed to control ICP. Mannitol may be transiently effective,
but a rebound pressure increase sometimes develops after 24 to 48
hours. Intravenous dexamethasone at a loading dose of 10 mg followed

by 4 to 10 mg every 6 hours is also appropriate initial treatment,
but the full effect of corticosteroid therapy takes 24 to 72 hours.
Although it is frequently given every 6 hours, dexamethasone has
a long half-life and can be given in a twice-daily dosing regimen.
Electrolytes and glucose levels must be monitored, and gastritis pro-
phylaxis is required. Acute neurosurgical interventions include ICP
monitoring devices and ventricular drainage or tumor decompression
in patients with obstruction. Fluid management requires avoidance of
hyponatremia.
Chronically Increased Intracranial Pressure
Dexamethasone in doses of 8 to 40 mg per day upregulates angiopoietin
1 to stabilize the blood-brain barrier and downregulates VEGF.87–89
Controlling the edema also helps to control headache, nausea, and
seizures. Because chronically raised ICP can cause visual loss, careful
ophthalmologic follow-up evaluation with visual field assessment is
essential. Acetazolamide therapy for symptomatic plateau waves has
been useful for some patients with raised ICP from intracerebral or
leptomeningeal tumor.90
In the doses required to treat cerebral edema, corticosteroids produce
many adverse effects that range from the easily managed gastritis
symptoms and glucose intolerance to insomnia, steroid psychosis,
intractable hiccoughs, and disabling myopathy. The psychosis may
readily respond to reduction of the steroid dose and the addition of
neuroleptic agents. Treatment of the steroid myopathy, however, will
require weeks of physical therapy with attempts at steroid reduction.
Anecdotal reports suggest that substitution of a nonfluorinated steroid
such as methylprednisolone for fluorinated steroids such as dexa-
methasone may help minimize the weakness.91
Many patients with brain tumors are treated with corticosteroids
for prolonged periods and are thus susceptible to infection, particularly
with Pneumocystis jiroveci, which carries a 50% mortality rate. Among
solid tumors, primary and metastatic brain tumors have the highest
rate of Pneumocystis infection, which occurs in 2% of patients and
proves fatal to 40% of these patients.92 The mean duration of steroid
therapy before infection was 7 months, with a mean dexamethasone
equivalent dose of 1 to 2 mg per day.93 In view of these statistics,
prophylaxis with one double-strength tablet of trimethoprim-
sulfamethoxazole three times a week should be provided for patients
with brain tumors during steroid administration and for 1 month
afterward. Alternatives for patients who are allergic to trimethoprim-
sulfamethoxazole include aerosolized pentamidine, dapsone, or ato-
vaquone. Withdrawal of corticosteroids after use for more than 2
weeks may result in an adrenal insufficiency state with symptoms of
lethargy, hypotension, electrolyte imbalance, arthralgias, and diffuse
weakness. Chronic glucocorticoid supplementation with hydrocortisone,
10 to 20 mg per day, is essential for these patients.94,95 A VEGF
inhibitor such as bevacizumab or cediranib may provide an alternative
treatment for controlling peritumoral edema.96
Seizures
Neurooncologists often find themselves working closely with epileptolo-
gists as they seek to control seizures with minimal adverse effects.
Because patients with brain tumors frequently require corticosteroids,
analgesics, anxiolytics, and antiemetics, drug-drug interactions make
the management of epilepsy complex.
The potential interaction of AEDs with other medications required
for patients who have a brain tumor has led to reconsideration of the
prophylactic use of antiseizure drugs. Cytochrome P450 enzyme–
inducing drugs such as phenytoin and carbamazepine are now used
less frequently because of their side effects.
A rash develops in approximately 20% of patients with gliomas
who are treated with phenytoin or carbamazepine and cranial irradiation;
the most serious and sometimes life-threatening reaction, Stevens-
Johnson syndrome, occurs in a few patients. Treatment is controversial,
but often the corticosteroid dose is doubled as AEDs are withdrawn
abruptly.
Cancer of the Central Nervous System • CHAPTER 63 915
In view of all of the potential hazards of AEDs, it is worthwhile
to consider whether their prophylactic use is justified in the brain
tumor population with several studies showing mixed results regarding
efficacy.97–99 For all of these reasons, a practice parameter published
by the Quality Standards Subcommittee of the American Academy
of Neurology concluded that no benefit could be established for routine
prophylactic use of AEDs in patients with brain tumors.100 However,
the advent of AEDs that do not induce hepatic enzymes has recently
caused some neurologists to reconsider prophylactic use of seizure
medicines in high-risk patients, particularly those with hemorrhagic
metastases, such as patients with melanoma.
Of the newer agents, levetiracetam (Keppra) has emerged as a first
line antiepileptic agent in patients with brain tumors. Its therapeutic
window is wider than that of phenytoin, as the level is not affected
by chemotherapy drugs, and it does not alter the metabolism of any
chemotherapeutic agents. Transitioning from phenytoin to levetiracetam
in glioma-related seizures did not elicit significant differences in seizure
freedom, suggesting safety in switching to levetiracetam.101,102 However,
the clinician must be familiar with some adverse effects specific to
these drugs (summarized in Table 63.4) to be able to diagnose symptoms
accurately, eliminate the offending drug, and avoid unnecessary
diagnostic and therapeutic interventions. One of the most common
adverse side effects of levetiracetam is irritability and aggression.
Lacosamide is an alternative first-line103 or add-on therapy104 to
levetiracetam with similar efficacy. Use of lacosamide as monotherapy
or in combination with levetiracetam may be considered in patients
who are experiencing adverse side effects.
Deep Venous Thrombosis
Deep venous thrombosis (DVT) is extremely common in patients
with brain tumors, with a reported incidence of 28% to 45%.100,105
The risk is greatest in the postoperative period and in patients with
hemiplegia.
For prophylaxis, low-molecular-weight heparin drugs have a good
safety profile in the neurosurgical population.106 Prophylaxis with
enoxaparin, 40 mg, administered subcutaneously daily, plus use of
external compression stockings has been found to be superior to the
use of compression stockings alone for the prevention of venous
thromboembolism after neurosurgery.107
Patients with brain tumors who have diagnosed DVT or pulmonary
embolism (PE) will often receive inferior vena cava filters to prevent
further thromboembolic complications. However, retrospective studies
have demonstrated a low risk of hemorrhage relative to a 60% rate
of complications. Complications included PE, filter thrombosis, and
postphlebitic syndrome.109
Although no absolute guidelines are available, most neurosurgeons
would be reluctant to institute full anticoagulation in these patients
within 2 weeks of surgery. Because most primary and secondary brain
tumors pose a continuing risk of thromboembolism, lifelong antico-
agulation is recommended.
Table 63.4 Adverse Effects of Antiepileptic Drugs:
Special Issues in Patients With Brain
Tumors
Drug Potential Adverse Effect(s)
Oxcarbazepine Hyponatremia (confusion, seizures)
Gabapentin Sedation, ataxia, weight gain
Depakote Weight gain, platelet dysfunction
Topiramate Memory and word-finding problems, weight loss
Zonisamide Sedation
Levetiracetam Psychosis, irritability, lethargy
916 Part III: Specific Malignancies

No clear-cut guidelines exist for the use of direct thrombin inhibitors
in patients with brain tumors, and the lack of agents to reverse
anticoagulation is a drawback in this population of patients who may
need urgent surgical intervention. However, the recent development
of new reversal agents may lead to changes in practice patterns, given
the inherent decreased risk of intracranial hemorrhage with direct
thrombin inhibitors.
DIAGNOSTIC IMAGING
Magnetic Resonance Imaging
MRI is the study of choice for evaluating brain tumors. The increased
tissue contrast resolution provides exquisite anatomic definition, which
is accentuated after administration of gadolinium contrast material.
Therefore when possible, MRI sequences should be performed before
and after administration of contrast material. Much like with the use
of iodinated contrast material in computed tomography (CT) imaging,
tumor-related disruption of the blood-brain barrier allows interstitial
leakage of contrast material, and depending on scanning parameters,
it may appear as increased (spin echo T1) or decreased (gradient echo
imaging) signal. Gadolinium enhancement can be crucial in identifying
leptomeningeal disease, which appears as thickened, enhancing areas
of the dura and leptomeninges. The absence of bony artifacts common
with CT has enabled MRI to provide exceptional information regarding
brain tumors, particularly in the posterior fossa. In addition, localization
of the lesion is precise because MRI is usually reconstructed in three
orthogonal planes.
Multiple sequences may be obtained from the MRI scans, highlight-
ing different properties of both brain and tumor. Of particular interest
are the T2-weighted and fluid-attenuated inversion recovery (FLAIR)
images. These sequences highlight tumor-related vasogenic edema
and nonenhancing portions of the tumor, which appear as areas of
increased T2 signal compared with normal brain. Evaluating this signal
pattern is very important in assessing the degree of mass effect, because
the increased signal may represent the true limits of a glial tumor, as
tumor cells are invariably present in the nonenhancing tissue sur-
rounding the enhancing component.110 This phenomenon provides
the rationale for extending the irradiated zone in standard external
beam radiation therapy to include the edematous volume of brain
plus a margin. The presence of an edema pattern extending into the
corpus callosum implies direct tumor invasion into the corpus callosum.
The extremely compact fiber tracts passing through the corpus callosum
impede passage of edematous fluid, and thus any increased T2 signal
that is present is likely created by tumor infiltration. This point is
very important to keep in mind in assessing the extent of tumor.
Endothelial proliferation with neovascularity is a hallmark of
malignancy in brain neoplasms. Both MRI and CT perfusion imaging
can be performed in combination with conventional MRI examinations
to determine the extent of neovascularity. The correlation between
relative cerebral blood volume (rCBV) and grade of malignant glioma
appears to be very good.112 Perfusion imaging with dynamic susceptibil-
ity contrast-enhanced MRI is especially helpful in distinguishing grade
III from grade IV malignant gliomas, but it can also be used to dis-
tinguish gliomas from other neoplasms such as intracranial metastases
(Fig. 63.3).113,114 It has been shown that anaplastic astrocytomas that

A B C

D E F
Figure 63.3 • Differentiation of tumor types with perfusion magnetic resonance imaging (MRI). Axial T1-weighted postgadolinium magnetic resonance
image demonstrating a metastasis from a lung carcinoma in one patient (A) and glioblastoma multiforme in another (D). Respective axial T2-weighted images
demonstrate moderate edema with questionable involvement of the corpus callosum genu by the metastasis (B) and splenium of the corpus callosum by the
glioblastoma (E). Perfusion magnetic resonance image demonstrates hypovascularity in the peritumoral region, with only a minor increase in perfusion at the
rim of enhancing tumor (C, white arrow), consistent with vasogenic edema without infiltrating tumor, compared with (F), which demonstrates increased perfusion
in the peritumoral region, implying hypervascularity consistent with infiltrating high-grade glioma. (From Law M. Perfusion and MRS for brain tumor
diagnosis. In: Edelman RR, Hesselink JR, Zlatkin MB, Crues JV, eds. Clinical Magnetic Resonance Imaging. Vol. 3. 3rd ed. Philadelphia: WB Saunders; 2006.)
 Cancer of the Central Nervous System • CHAPTER 63 917

enhance have a higher vascularity index than do nonenhancing
anaplastic astrocytomas. Perfusion imaging may enable monitoring
of the antiangiogenic effects of treatment in brain tumors. Furthermore,
perfusion imaging is also useful in determining vascularity in benign
tumors such as meningiomas, a phenomenon that may be associated
with disease progression.115
Functional MRI techniques have been used to identify areas of
brain activity in real time, which is quite useful in identifying regions
of eloquent brain adjacent to tumors.116,117 By identifying language
and motor areas adjacent to tumors, one can determine the extent of
surgical resection that can be carried out while attempting to preserve
functional activity.118 It is now possible to import functional MRI
images into frameless stereotactic units that are used for intraoperative
surgical planning.119 Through use of discrete motor, sensory, language,
or visual paradigms, the functional activity of relevant cortical brain
can be imaged. One limitation to functional MRI scanning is its
inability to identify subcortical white matter tracts adjacent to the
gray matter activated by the investigated activity. For this reason,
diffusion tensor imaging (DTI) is increasingly being used to map
subcortical white matter tracts. It has been shown that combining
DTI with conventional anatomic images of the lesion of interest
facilitates extended resection of tumor while preserving function.120
A great deal of interest has centered on the capability of clinical MRI
scanners to perform magnetic resonance spectroscopy (MRS) to evaluate
molecular components of a defined voxel within the brain tissue.
Today’s smaller voxel sizes allow a much greater degree of selectivity
in evaluating components of a tumor. MRS of malignant gliomas
has been evaluated extensively, and the presence or absence of five
metabolites provides the most useful information. N-acetylaspartate
(NAA) is a marker of healthy neurons, whereas increases in choline
are associated with high cellular turnover. Creatine serves as an
internal marker and is related to the energy state of the tumor. A
lipid peak indicates the presence of necrosis and suggests higher-grade
malignancy, whereas lactate indicates the presence of hypoxia.121,122
Malignant gliomas exhibit a higher choline peak relative to creatine
and a lower NAA peak relative to choline, with increasing grade of
malignancy (Fig. 63.4). Lipid and lactate peaks, which also constitute
markers of malignancy, can be seen both in primary gliomas and in
metastatic tumors. MRS can help determine whether an enhancing
region in a previously treated tumor bed represents active tumor or
radiation necrosis. MRS is also used to monitor treatment effects over an
extended period.
MRI has the capability to specifically identify vascular structures.
As noninvasive techniques, magnetic resonance angiography (MRA)
and magnetic resonance venography can be useful in evaluating major
vessels at the base of the skull in preparation for surgical treatment
of skull base tumors.
Computed Tomography
A CT scan usually is the first study obtained in a patient with a
neurologic complaint. In part because of its extensive availability and
rapid acquisition times, CT provides a robust screening tool. Hemor-
rhagic lesions can be seen as a result of the increased density of
extravasated blood products in comparison with surrounding tissues.
Infarcts manifest acutely as edematous hypodense tissue and can be

Cho After resection

NAA
Cho Cr

Normal-appearing spectrum Histologically proved Presumed necrosis

tumor

Post contrast Choline NAA NAA + Cho

Figure 63.4 • Magnetic resonance imaging/magnetic resonance spectroscopy (MRI/MRS) studies of World Health Organization grade II oligoastrocytoma.
Axial T1-weighted postgadolinium MRI performed the day before surgery (top left panel) revealed an area of hypodensity that did not enhance (bottom left
panel). MRS image (middle panel) shows an area of high choline (Cho; 1.8 times greater than adjacent brain) and low N-acetylaspartate (NAA) levels, in
addition to a smaller region of no significant metabolite levels, which is presumed to be necrosis. The resection was limited to a region of elevated choline
with no significant Cr, Creatine. (From Vigneron D, Bollen A, McDermott M, et al. Three-dimensional magnetic resonance spectroscopic imaging of histologically
confirmed brain tumors. Magn Res Imaging. 2001;19:93.)
918 Part III: Specific Malignancies

confused with tumors, especially low-grade gliomas, which may not
enhance with contrast agents. However, cytotoxic edema associated
with infarcts often involves both gray and white matter, whereas
vasogenic edema as a result of the presence of tumor predominately
involves the white matter. Iodinated contrast agents may be useful to
differentiate tumor from the surrounding edematous brain tissue
because disruption of the blood-brain barrier permits leakage of the
contrast agent into the interstitial space. The pattern of ring enhance-
ment of tumors may be difficult to distinguish from the ring enhance-
ment of a cerebral abscess, although brain tumors are far more common
than brain abscesses in the United States. Infarcted brain tissue may
also enhance after administration of contrast material. This finding
is most common 2 to 3 weeks after a stroke, and thus clinical history
should complement image interpretation.123
CT has limitations in evaluating structures near the irregular bony
surfaces of the skull base because of volume averaging and streak
artifact. This limitation makes interpretation in and around the skull
base and in the posterior fossa (the region between the tentorium and
the foramen magnum) difficult. Nevertheless, CT is the study of
choice in patients who cannot undergo MRI, such as patients with
claustrophobia, implanted pacemakers, defibrillators, or other metal
devices that preclude imaging with MRI.
Imaging of Supratentorial Gliomas
WHO grade I (pilocytic) astrocytomas show enhancement on CT
and MRI scans. By contrast, WHO grade II astrocytomas typically
are poorly defined, hypodense, or isodense lesions on CT scans and
do not enhance. Either localized or homogeneous enhancement,
however, can be seen in up to 30% to 40% of cases, with calcification
in 5% to 10% of cases.124,125 MRI shows low signal intensity on
T1-weighted images and high signal intensity on T2-weighted images
(Fig. 63.5A–B). Grade III anaplastic astrocytomas and grade IV
glioblastomas typically enhance with contrast, although in one study,
enhancement was not seen in 40% of the former and in 4% of the
latter (see Fig. 63.5C–D)126 The region of enhancement typically has
a ringlike appearance surrounding an area of necrosis. The perimeter
of the enhancing region does not define the border of the tumor, and
malignant cells may be present beyond this perimeter. T2-weighted
MRI images show abnormalities that are more extensive than those

A B

C D
Figure 63.5 • Magnetic resonance imaging: low-grade astrocytoma versus glioblastoma. (A) World Health Organization (WHO) grade II astrocytoma.
T1-weighted postgadolinium axial image shows no enhancing mass; however, a region of hypodensity is seen. (B) A corresponding fluid-attenuated inversion
recovery (FLAIR) image of the tumor in (A) shows abnormality consistent with edema. (C) WHO grade IV glioblastoma. A T1-weighted postgadolinium
axial image shows the presence of a large mass compressing the right lateral ventricle. A rim of enhancement with central necrosis is typical of these tumors.
(D) A corresponding FLAIR image of the tumor in (C) shows extensive peritumoral edema.

seen on a contrast-enhanced CT scan or a T1-weighted MRI scan.
In one study in which stereotactic biopsy findings were correlated
with radiologic findings in patients with gliomas, isolated tumor cells
often were found as far away as the region showing increased signal
intensity on T2-weighted images.110 Perfusion MRI can measure rCBV
and cerebral blood flow, which can be used to determine tumor grade
and to assess progression after treatment.127
At least 50% of oligodendrogliomas show calcifications, which can
be appreciated on plain films of the skull and on CT scans.128 Enhance-
ment of oligodendrogliomas can be seen on CT and MRI scans but
is often mild and poorly defined.
Positron Emission Tomography
Positron emission tomography (PET) imaging uses a radioactive
isotope analogue of glucose, fluorine-18 fluorodeoxyglucose (FDG),
to image glucose metabolism. Because glucose is the sole fuel for brain
tissue, this metabolic imaging allows visualization of brain physiology.
Because glioblastomas, untreated PCNSL, oligodendrogliomas, and
malignant meningiomas have increased glucose metabolism compared
with normal brain tissue, these tumors have greater FDG avidity and
will be PET positive. Anaplastic astrocytomas, oligodendrogliomas,
meningiomas, and metastatic tumors show variable FDG uptake (Fig.
63.6), whereas low-grade gliomas and radiation necrosis show little
to no FDG uptake. PET imaging using targeted tracers, such as the
somatostatin-receptor ligand gallium-68 DOTATOC in meningiomas,
might be more useful for tumors in which FDG is too variable for
accurate delineation.129
Challenges to Imaging Modalities
Complicating assessment of chemotherapy in patients with a brain
tumor is the observation that corticosteroids also often reduce MRI
contrast enhancement and relieve symptoms, making it difficult to
distinguish chemotherapy effects from corticosteroid effects. For almost
20 years, standard response criteria have been the Macdonald criteria,
which use two-dimensional measurements of enhancing tumor and
account for corticosteroid use and clinical status. However, it has been
recognized that reliance on contrast enhancement is a limitation in
many anaplastic gliomas. Two situations in particular have led to the
development of a new set of response criteria (Response Assessment
Figure 63.6 • Positron emission tomography (PET) scan of recurrent glioma. The patient had undergone surgical resection of an anaplastic oligodendroglioma
15 months earlier. Areas of contrast enhancement on T1-weighted magnetic resonance imaging (MRI) scan (left) have high fluorodeoxyglucose (FDG) accumula-
tion, consistent with recurrent high-grade tumor on the coregistered FDG-PET image (right). (From Hagge RJ, Wong TZ, Coleman RE. Positron emission
tomography. Brain tumors and lung cancer. Radiol Clin North Am. 2001;39:874.)
Cancer of the Central Nervous System • CHAPTER 63 919
in Neuro-Oncology, or RANO). First, pseudoprogression is defined as
an increase in contrast enhancement or edema on MRI without true
tumor progression, a phenomenon made more common by the addition
of temozolomide to radiotherapy.130,131 The first postradiation MRI
image shows increased contrast enhancement in up to 50% of patients
(Fig. 63.7), in half of whom the enhancement eventually subsides.
The phenomenon may be asymptomatic but can also cause neurologic
decline. Failure to recognize pseudoprogression may cause the physician
to prematurely terminate effective therapy.132,133 Second, pseudoregression
refers to a decrease in contrast enhancement on MRI without true
response, a phenomenon increasingly seen in patients treated with
VEGF pathway antiangiogenic agents.134 Infiltrative tumor may be
distinguished from radiation-related FLAIR and T2 signal MRI changes
by diffusion-weighted MRI sequences that show diffusion restriction
in areas infiltrated by neoplastic cells.135
Some of the important features of the updated RANO criteria
that are just now being implemented in clinical trials include precise
definitions of measurable disease, exclusion of patients within the first
3 months after radiotherapy from clinical trials to avoid confounding
chemotherapy failure with pseudoprogression, and inclusion of stable
or decreased nonenhancing disease as a criterion for tumor response
in patients who have received antiangiogenic therapy.
Similarly, confusion may arise when neuroimaging documents
enlargement of a mass after stereotactic radiosurgery (SRS) that may
progress over many months. Because PET scanning may not reliably
distinguish radiation necrosis from tumor progression, the results of
concurrent chemotherapy may be ambiguous. Multicentric recurrence
outside original radiation fields and after temozolomide appears to
be more common when patients have positive O6-methylguanine
DNA-methyltransferase (MGMT) promoter methylation status.136,137
Lumbar Puncture
Lumbar punctures are not commonly used for the diagnosis of brain
tumors owing to the low yield of the procedure in primary gliomas.
Leptomeningeal seeding from supratentorial malignant gliomas is
usually an end-stage finding. Once life-threatening conditions such
as mass effect have been excluded, lumbar puncture may be performed
for confirmation of leptomeningeal disease. Lumbar puncture remains
part of the staging workup for some primary brain tumors, such as
medulloblastoma and CNS lymphoma.
920 Part III: Specific Malignancies
Figure 63.7 • Pseudoprogression after chemoradiation. Gadolinium-enhanced T1 magnetic resonance image before chemoradiation in a patient with
anaplastic astrocytoma (left). First posttreatment scan (right) 8 weeks after completion of radiation and temozolomide therapy shows enlargement of a ring-
enhancing mass that correlated with clinical deterioration. Symptoms and magnetic resonance imaging findings had regressed on the next scan 6 weeks later
(not shown).
SURGERY: GENERAL CONSIDERATIONS
The successful resection of a brain tumor requires removing the tumor
while minimizing injury to the surrounding normal brain. The approach
to removal of brain tumors follows the mantra of real estate agents:
“location, location, location.” Deep tumors that are in noneloquent
regions of brain can be easily accessed and removed, whereas superficial
tumors may not be easily resectable because of their location within
extremely eloquent brain tissue.
The goals of surgery are to (1) establish the histology of the lesion,
which is frequently better achieved via surgical resection over stereotactic
biopsy because greater tissue sampling reduces the risk of sampling
error; (2) debulk the mass effect of the tumor to correct a neurologic
deficit and to prevent imminent death in patients with large tumors
and early herniation syndromes; and (3) achieve surgical cure when
possible (as in WHO I gliomas) or, when the lesion is infiltrative and
surgical cure is impossible, to debulk the tumor to increase the efficacy
of radiation therapy and chemotherapy, which produce the best response
rate when they are used with minimal tumor burden.
The most common presenting manifestations in patients with
glioma are headache and seizures.135 Debulking large tumors will reduce
dural stretch, thus decreasing headaches. The incidence of seizures in
patients with malignant gliomas can be decreased by at least 75%
with attempts at gross total resection.136 Recovery from other neurologic
deficits such as hemiparesis, visual field loss, or aphasia will depend
on whether the deficit is due to mass effect or due to infiltration and
damage to neural tracts.
Another rationale for maximal debulking is to reduce the cellular
burden in order to increase efficacy of both radiation therapy and
chemotherapy following resection. Extent of resection in primary glial
tumors has been found to correlate with survival.138–140
RADIATION THERAPY: GENERAL
CONSIDERATIONS
Radiation is commonly used to treat many different types of brain
tumors. The radiation oncologist must decide on many factors in the
treatment plan for an individual patient, including treatment volume,
dose, fractionation, and normal tissue constraints. Treatment techniques
including three-dimensional conformal therapy, stereotactic radio-
therapy, and intensity-modulated radiation therapy are being used in
a majority of patients with brain tumors. Proton therapy, which is
increasingly available in the United States, may be used for specific
cases, especially for pediatric brain tumors and for tumors at the base
of the skull. Heavy ion therapy, such as with carbon ions, is used in
a few centers worldwide.
Radiation Therapy: Technical Details
Treatment planning starts with a review of the MRI scan to identify
the target volumes. The appropriate volume to be irradiated varies
according to the tumor type. Most brain tumors including gliomas
and meningiomas are treated with focal radiation to the lesion plus
a margin. The actual abnormality seen on imaging studies is termed
the gross tumor volume (GTV). Additional tissue surrounding the
GTV that is thought to potentially contain tumor cells is included
in the clinical target volume (CTV). For some tumors such as glio-
blastoma, which can be highly infiltrative, the CTV includes the area
of edema as demonstrated on the FLAIR or T2 sequences plus up to
a 2.5-cm margin. For other tumors that do not infiltrate, such as
meningiomas, pituitary adenomas, acoustic neuromas, and cranio-
pharyngiomas, the CTV typically would be much tighter than that
used for glioblastomas. An additional volume is included around the
CTV to take into account day-to-day setup error and to allow for
buildup of dose, resulting in the planning target volume (PTV).
Treatment planning begins with CT simulation of the patient with
appropriate immobilization devices. Fig. 63.8 shows thermoplastic
mask and bite-block immobilization devices. A previously obtained
MRI image or an MRI image obtained at the time of simulation may
be fused with the CT images in the treatment planning system to
facilitate better target volume delineation. Computerized treatment
planning is then used to generate radiation beam angles, blocks, and
dose distributions.
Most brain tumors are treated with focal radiation therapy, and
often brain metastases and some leukemias and lymphomas require
whole-brain radiotherapy; however, for some tumors, such as primitive
neuroectodermal tumors (PNETs) and metastatic germ cell tumors
of the CNS, it may be necessary to include the entire craniospinal

A B
Figure 63.8 • Patient immobilization devices for radiation therapy delivery. (A) Thermoplastic mask head-immobilization device. (B) Bite-block head
immobilization device. (From Gunderson LL, Tepper JE. Clinical Radiation Oncology. 2nd ed. Philadelphia: WB Saunders; 2006.)
axis in the irradiated zone. Proton therapy for craniospinal irradiation
has the advantage of reducing dose to the vertebral bodies and essentially
eliminating the exit dose through the thorax, abdomen, and pelvis.141
E-Fig. 63.1 shows sample treatment plans for craniospinal irradiation
using three-dimensional conformal radiotherapy, tomotherapy, and
proton beam techniques.142
Stereotactic Radiotherapy
Stereotactic radiotherapy is a technique for delivering high-dose
radiation to a target volume with very tight margins, thereby sparing
surrounding normal tissues. This technique can be implemented
with various devices, including (1) a Gamma Knife machine,
which, depending on the model, typically contains 192 or 201 fixed
cobalt-60 sources that converge to a single point; (2) a conventional
linear accelerator (“linac”) outfitted with additional hardware so it
can deliver focused radiation, generally with three to five arcs; (3)
CyberKnife, which is a radiosurgery system composed of a linac
mounted on a robot and directed under image guidance; and (4)
delivery of charged particles such as protons, which, because of their
physical properties, deposit energy in a narrower region than is possible
with x-rays.
Stereotactic radiation can be delivered in a single large fraction;
this technique is termed stereotactic radiosurgery, although no surgery
is performed. A stereotactic head frame often is screwed to the skull.
The head frame permits three-dimensional localization and immobiliza-
tion of the head during treatment, thereby allowing delivery of radiation
with precision to a very tightly defined volume defined with MRI
imaging. The usual dose of single-fraction radiation used in SRS
ranges from 12 to 24 Gy and is based on the histologic tumor type
and the volume of tissue irradiated. The doses used are based on the
likelihood of tumor control and the risk of development of radiation
necrosis.
Stereotactic radiotherapy also can be delivered in a fractionated
regimen over several days or weeks. CyberKnife does not require the
use of a head frame but instead uses real-time image tracking while
patients are immobilized with a face mask.
Intensity-Modulated Radiation Therapy
Intensity-modulated radiation therapy uses multiple segmented fields
with inverse treatment planning algorithms. In addition to defining
the doses to be delivered to the GTV and CTV, dose constraints are
placed on normal structures to limit their radiation exposure. Con-
straints include the maximum or mean dose to the entire structure,
Cancer of the Central Nervous System • CHAPTER 63 921
limits to a portion of the structure, and the maximum point dose
within the structure. The most common mechanism of delivering this
dose is use of multiple fields, typically five to nine, with use of a special-
ized blocking apparatus called a multileaf collimator to divide each
field into multiple beamlets. From 50 to more than 100 beamlets
may be used.
Heavy Charged Particle Radiation Therapy
The delivery of charged particles, primarily protons, has been used
to treat brain tumors. The potential benefit of protons is the result
of their physical properties, which are different from those of photons.
The advantage of proton radiation therapy compared with photon
radiation therapy is the reduction of the total dose to the patient as
a result of the absence of an exit dose. This attribute results in a
decreased dose to the normal part of the brain, which may decrease
acute and long-term toxicities, which is particularly important in
pediatric patients.
Adverse Effects After Irradiation of the Brain
or Spine
Acute and Early Delayed Effects After Cranial Irradiation
A variety of adverse effects may occur after irradiation of the CNS
(reviewed by Schultheiss and associates143). These effects can be divided
into acute, which occur during the treatment; delayed early, which
occur within a few months of radiation; and late, which occur months
to years later.
Acute effects of cranial irradiation include fatigue, nausea, headaches,
anorexia, and alopecia. Patients may experience nausea within hours
after the administration of the radiation and headaches during the
course of treatment. Nausea and headaches are thought to be caused by
radiation-induced edema and can be ameliorated with corticosteroids.
Nausea usually is well controlled with antiemetics such as ondansetron,
granisetron, or prochlorperazine. In patients receiving craniospinal
radiation, the nausea and anorexia may be compounded by radiation
that the upper gastrointestinal tract receives as an exit dose from the
spinal field. Hair loss generally starts after the scalp has received 20
to 30 Gy. It usually is not permanent, but regrowth of hair may
take months, and the new hair often is thinner than the original
hair or even of a different color. In areas that receive a high dose
of radiation, especially with tangentially directed fields, alopecia
may be permanent. Other acute adverse effects of cranial irradiation
may include accumulation of cerumen in the ear canals and serous
otitis media.
 Cancer of the Central Nervous System • CHAPTER 63 921.e1
921.e1

100%

A B 30%

100%

C D 30%

100%

E F 30%

E-Figure 63.1 • Sample treatment plan for craniospinal irradiation showing dose distributions in sagittal and axial views for (A–B) three-dimensional
conformal radiotherapy, (C–D) tomotherapy, and (E–F) proton beam therapy. (From Yoon M, Shin DH, Kim J, et al. Craniospinal irradiation techniques:
a dosimetric comparison of proton beams with standard and advanced photon radiotherapy. Int J Radiat Oncol Biol Phys. 2011;81:3.)
922 Part III: Specific Malignancies
The most common delayed early effect from radiation is the
somnolence syndrome, which is characterized by excessive drowsiness,
nausea, and irritability.144 If this syndrome occurs, it generally does
so 1 to 3 months after radiation has been completed. This syndrome
is thought to be due to transient, diffuse demyelination. It usually is
seen after whole-brain irradiation but also can develop after limited-field
irradiation. The syndrome resolves spontaneously, but steroids can
shorten its duration. Delayed early effects occurring after cranial
irradiation can also take the form of focal neurologic signs due to
intralesional reactions related to tumor response or perilesional reactions
related to edema or demyelination.
Late Effects
The pathophysiology of late effects from CNS irradiation is poorly
understood. Some of the effects may be caused by degenerative changes
in the supporting glial cells, whereas others may be caused by vascular
changes due to endothelial cell loss and capillary occlusion. The clinical
and imaging manifestations of these changes may include cognitive
deficits and neurobehavioral changes, pituitary-hypothalamic dysfunc-
tion, and brain necrosis.
Radiation Necrosis of the Brain
One of the most serious late effects of cranial irradiation is brain
necrosis, which may cause significant and persistent neurologic
injury.145,146 Histopathologic changes seen in radiation necrosis include
coagulative and liquefactive necrosis, mostly in white matter, and
associated endothelial thickening, vascular hyalinization, fibrinoid
deposition, and calcification.147 It may produce progressive cerebral
edema and mass effect requiring prolonged corticosteroid use or surgery.
Radiation necrosis may be confused with tumor growth, resulting in
the inappropriate use of antitumor therapies. The onset of radiation
necrosis includes behavioral changes, such as lethargy and dementia,
headache and papilledema, and seizure. Clinical signs and symptoms
are usually identified 2 to 3 years after irradiation, although confirmed
cases have been detected as early as 9 months and as late as 16 years
after completion of radiation therapy. The signs and symptoms are
strongly related to the site of radiation necrosis; however, the most
common clinical signs are focal motor deficits.
Accurate data regarding the incidence of brain necrosis based
on CT and MRI findings come from a randomized trial of irra-
diation for low-grade gliomas.148 In this study, the 2-year actuarial
incidence of brain necrosis was 2.5% for patients receiving 50.4 Gy
and 5% for those receiving 64.8 Gy. A retrospective review of 426
patients treated for glioma with radiation found that radionecrosis
developed in 4.9% of patients.149 The risk of necrosis increased
with longer survival and with increasing dose of radiation. The
use of adjuvant chemotherapy was associated with increased risk of
radiation necrosis.
Often radiation necrosis is difficult to distinguish from recurrent
tumor with CT or MRI, which may show increased signal intensity
on T2-weighted images and contrast enhancement on T1-weighted
images.150 As discussed earlier in the section on diagnostic imaging, PET
scanning with FDG may help distinguish viable tumor from necrotic
tissue.151–153 Advanced MRI techniques may also help differentiate tumor
from necrosis. On MRS, NAA is significantly reduced in patients with
radiation necrosis, whereas changes in choline and creatine are more
variable. A high choline level is more consistent with disease progression,
whereas a decreased creatine level is generally associated with radiation
injury.147 Ratios of metabolites are considered, and pooling ratios of
different metabolites may be helpful in differentiating tumor from
necrosis.155 Perfusion imaging techniques that measure rCBV may also
help differentiate recurrence from necrosis by allowing for indirect
assessment of tumor angiogenesis and vascularity. Hyperperfusion is seen
with tumor recurrence, and necrosis is associated with ischemia-related
change.147 Still, rCBV may be increased in areas of radiation-induced
inflammation. Advanced MRI techniques of late radiation-induced
injury are reviewed by Pružincová and colleagues.155
Management of radiation necrosis may be either medical or surgical.
Corticosteroids may counteract the vascular endothelial damage and
also decrease the inflammatory response.156 Other therapies, such as
hyperbaric oxygen,157 anticoagulants,158 and vitamins159 have met with
varying degrees of success, and no large trials have been conducted
to support their use.160 A promising therapy for brain necrosis is the
anti-VEGF agent bevacizumab, which may result in decreased vessel
permeability. A double-blind placebo-controlled trial of 14 patients
with CNS radiation necrosis showed that patients receiving the antibody
demonstrated a radiographic response, whereas those treated with
placebo did not demonstrate a response. Important to note, all patients
treated with bevacizumab showed clinical improvement.161 Surgical
exploration often is necessary not only to establish a diagnosis but
also as a therapeutic intervention to reduce mass effect and edema.
This results in clinical improvement in the majority of patients.147
Neurocognitive Deficits After Cranial Irradiation
Neurocognitive deficits often are observed after cranial irradiation,
especially in young children. Many of the sequelae appear several
years after treatment of children with brain tumors, which mandates
long-term follow-up. Sequential assessments of neurocognitive
function demonstrated progressive deterioration during 6 years after
radiotherapy in children with ALL who were treated with 18 Gy
of whole-brain irradiation.162 Numerous studies of neurocognitive
function in children after whole-brain irradiation for ALL have been
performed.163–167 In summary, these findings show that whole-brain
irradiation can lead to decline in neurocognitive function, an effect
that appears to be greater in younger children and with higher doses of
radiation (e.g., 24 Gy) but can be seen after treatment with 18 Gy.162
It also is possible that an interaction between methotrexate (intrathecal
or high-dose systemic) and whole-brain irradiation causes these late
effects.167 In one study, serial intelligence quotient (IQ) examinations
were used to follow 44 pediatric patients with medulloblastoma who
were treated with postoperative radiation therapy with or without
chemotherapy. At a mean of 5.2 years from completion of radiotherapy,
the mean estimated full-scale IQ was greater than one standard
deviation below the expected population norm, and a mean loss of
2.55 estimated full-scale IQ points occurred per year. This study
suggests that the decline in IQ was not because of a loss of previously
known skills and information, but rather an inability to acquire new
skills and information at a rate comparable with healthy control
subjects.168
In a North Central Cancer Treatment Group (NCCTG) randomized
study of a dose of 64.8 versus 50.4 Gy for treatment of low-grade
gliomas,148 data regarding cognitive performance were collected
prospectively. With a median follow-up time of 7.4 years in survivors,
the vast majority of patients with normal baseline findings on the
Mini Mental State Examination (MMSE) maintained normal findings
after undergoing radiotherapy.169 Patients with abnormal MMSE results
before radiotherapy were more likely to have an improvement in
cognitive abilities than deterioration after being treated with radio-
therapy. Armstrong and coworkers170 conducted prospective, compre-
hensive, longitudinal neuropsychologic testing on 26 adult patients
with low-grade supratentorial brain tumors, mostly gliomas, who had
been treated with radiotherapy. Nine patients underwent testing 6
years after being treated with radiotherapy. No declines were noted
on most neurocognitive tests. Results in 7 of the 37 neuropsychologic
tests showed improvement over 6 years. However, declines emerged
only after 5 years on selected tests of cognitive function such as visual
memory.
Some evidence indicates that adults treated with brain radiotherapy
may experience long-term cognitive sequelae. One study aimed to
differentiate causes of cognitive disability—either the tumor itself or
various treatments, including radiotherapy, surgery, or medication—in
a population of patients with a low-grade glioma at a mean of 6 years
from diagnosis. Their findings suggest that the tumor had the greatest
deleterious effect on cognitive functioning and that radiotherapy

resulted in long-term cognitive disability mostly when high doses per
fraction (>2 Gy) were used.171 An update of this study, which assessed
cognitive abnormalities at a mean of 12 years after diagnosis, showed
that patients who were treated with radiation therapy had greater
deficits than did control subjects who did not undergo radiotherapy.
The patients who underwent radiation therapy had more deficits in
attention functioning at follow-up, regardless of fraction dose, and
they also performed worse in tests of executive functioning and
information processing speed.172
Data regarding treatment of these cognitive deficits in brain tumor
survivors are limited and conflicting. In a randomized trial of 83
childhood survivors of ALL or malignant brain tumors who had
problems with academic achievement, the use of methylphenidate
was investigated, and it was revealed that the drug at least temporarily
reduced some attentional and social deficits.173 However, a phase III
placebo-controlled trial in patients with a brain tumor failed to show
that prophylactic use of methylphenidate improved quality of life or
cognitive function.174 A phase II trial of the acetylcholinesterase inhibitor
donepezil in patients who received radiation for brain tumors showed
improved cognitive functioning, mood, and health-related quality of
life after a 24-week course of the drug.175 Cranial transplantation of
human stem cells is a treatment currently under investigation in the
laboratory. Radiation-induced depletion of stem cells in the brain,
especially in the area of the hippocampus, may be partially responsible
for radiation-induced cognitive deficits. Using rats subjected to cranial
irradiation, researchers have transplanted human embryonic stem
cells176 or human neural stem cells177 into the hippocampal formations.
Animals receiving stem cells showed superior performance on
hippocampal-dependent cognitive tasks.
Young age also is an important risk factor for leukoencephalopathy,
which can affect all age groups. Histologically, multifocal white matter
destruction with loss of myelin can be seen, especially in the periven-
tricular regions; MRI scans show these periventricular abnormalities.
CT scans also may reveal the presence of intracerebral microcalcifications
due to mineralizing microangiopathy. The clinical expression of
leukoencephalopathy ranges from mild evidence of white matter injury
on neuroimaging studies to severe necrotizing leukoencephalopathy
with profound neurologic impairment and, in some cases, death. Mild
or subclinical cases are more common than severe necrotizing leuko-
encephalopathy. The bulk of the experience comes from children who
received 24 Gy of whole-brain radiation along with high doses of
intravenous and intrathecal methotrexate. The frequency of leukoen-
cephalopathy is low in patients who receive cranial radiotherapy and
intrathecal methotrexate or cranial irradiation and intravenous
methotrexate but may be as high as 45% in patients who receive all
three treatments.178 In general, methotrexate is most toxic when given
during or after radiation.
Cranial irradiation can result in arterial vascular problems such as
vessel obliteration or narrowing, resulting in a strokelike syndrome.179
These complications are rare, but when they occur they are more
likely to happen after irradiation of the parasellar region.
Endocrine Deficits After Cranial or Spinal Irradiation
Endocrine problems are common after cranial irradiation, particularly
in children.180–182 Such problems include growth hormone (GH)
deficiency and thyroid and gonadal dysfunction.
The hypothalamus is more radiosensitive than the pituitary
gland and is responsible for endocrine dysfunction at lower doses.
At higher doses (>40 Gy), however, both the anterior pituitary gland
and the hypothalamus contribute to endocrine dysfunction. Of all the
hormones, GH is the most likely to show deficiency after irradiation
and is seen in a majority of children who have received whole-brain
irradiation. One study found that in children with ALL who received
a dose of 24 Gy to the whole brain, 56% experienced GH deficiency,
whereas no such problems were seen in children who received a
dose of 18 Gy, at least 4 years later.183 The latency of onset is dose
dependent and is shorter with higher doses.184 Growth may be further
Cancer of the Central Nervous System • CHAPTER 63 923
impaired by spinal irradiation, which directly affects the vertebral body
growth center.
Precocious puberty may occur after relatively low doses, on the
order of 18 Gy.185 Deficiencies in other hormones, such as gonado-
tropins, thyroid-stimulating hormone (TSH), and adrenocorticotropic
hormone (ACTH), are rare after doses lower than 40 Gy.181 Thyroid
dysfunction is common in patients with brain tumors who are treated
with high-dose radiotherapy.186 Constine and associates studied
endocrine function in 32 patients with brain tumors not involving
the hypothalamic-pituitary region who received 39.6 to 70.2 Gy to
this region.187 Hypothalamic or pituitary hypothyroidism developed
in 65% of the patients. Fourteen of 23 postpubertal patients (61%)
had evidence of hypogonadism manifesting with oligomenorrhea, low
estradiol levels, or low testosterone levels. Half of the patients had
mild hyperprolactinemia. Subtle abnormalities in adrenal function
were seen in 35% of patients.
In patients receiving craniospinal radiation, hypothyroidism also
may occur as a result of the exit dose to the thyroid gland. In one
study, the incidence of hypothyroidism was 15% or 33% (P = .013),
respectively, for patients receiving cranial or craniospinal irradiation.188
The mean spinal dose was 29 Gy, and the exit dose to the thyroid
gland ranged from 10 to 15 Gy.
Optic Neuropathy After Cranial Irradiation
Irradiation of tumors that are close to the optic nerves or chiasm may
result in a sufficient dose to these structures to cause concern about
the development of optic neuropathy. Two major classes of optic
neuropathy are recognized: anterior optic neuropathy and retrobulbar
optic neuropathy.189 The former is thought to be due to vascular injury
affecting the nerve head inside the globe anterior or adjacent to the
lamina cribrosa. This vascular injury is associated with swelling of the
optic head, in contrast with retrobulbar optic neuropathy, which is
due to more proximal injury to the optic nerve. Diagnostic criteria
for retrobulbar optic neuropathy include (1) visual loss (monocular
or binocular) accompanied by corresponding visual field defects, (2)
funduscopic examination, which often shows a pale optic disc but
without edema, (3) onset 6 months to several years after radiation
therapy that delivered a significant dose to the optic nerve and chiasm,
and (4) no radiologic evidence of visual pathway compression.190 MRI
scans may show pathologic contrast enhancement of the region of
the optic nerve and chiasm that received a high dose of radiation.191
Parsons and colleagues189 examined radiation-induced optic neu-
ropathy in patients receiving radiation treatment for primary extracranial
head and neck tumors. Of 215 optic nerves at risk, these investigators
found anterior optic neuropathy in 5 nerves and retrobulbar optic
neuropathy in 12 nerves. No injuries were observed in 106 optic
nerves that underwent irradiation with less than 59 Gy. The 15-year
actuarial risk of optic nerve neuropathy after administration of 60 Gy
or more was 11% when daily fractions less than 1.9 Gy were used,
versus 47% when 1.9 Gy or more was used.
Although these data suggest that the optic nerve–chiasm tolerance
is at least 59 Gy, their population did not include patients with
intracranial tumors compressing the optic nerve and chiasm. It is
possible in the latter situation that the tolerance of the optic nerve
and chiasm is lower as a result of ischemic injury. In some patients
with pituitary adenomas or craniopharyngiomas treated with radiation,
optic neuropathy developed after doses as low as 45 to 50 Gy, although
in many of these patients the daily fraction size was greater than
2 Gy.190,192,193 On the basis of these results, most investigators currently
recommend limiting the dose to the optic chiasm and nerve to 50 Gy
in 1.8- to 2-Gy fractions in the treatment of pituitary adenomas or
craniopharyngiomas. For other brain tumors requiring higher doses,
most radiation oncologists would restrict the dose to the optic nerve
and chiasm to 54 Gy or lower. In one series in which the risk of optic
neuropathy after SRS was examined, a risk of 1.1% for patients receiving
12 Gy or less was found, and the risk was increased in patients who
received previous or concurrent external beam radiation therapy.194 A
924 Part III: Specific Malignancies
conservative estimate for single-dose tolerance of the optic nerve and
chiasm in SRS is 8 Gy.195 Adherence to these guidelines should keep
the risk of radiation-induced optic neuropathy extremely low (1% or
less) but unfortunately will not completely eliminate it. Possible
treatments include use of hyperbaric oxygen, corticosteroids, or
anticoagulation, but none is particularly effective.196
Second Malignant Neoplasms Developing After
Cranial Irradiation
Second malignant neoplasms including malignant gliomas and
meningiomas remain relatively uncommon consequences of radiation
therapy for brain tumors.197 Concern exists that the addition of adjuvant
chemotherapy may increase the risk of second malignancies in long-term
survivors of childhood brain tumors.16,17 This outcome may be especially
true after prolonged use of alkylating agents and etoposide with or
without irradiation.
Myelopathy After Spinal Irradiation
A delayed early effect that can be seen after irradiation of the cervical
spine is Lhermitte syndrome, which is characterized by an electric
shock–like sensation precipitated by forward neck flexion.198 The
symptoms typically start weeks to a few months after completion of
radiation therapy. They are maximal at first but abate with time,
without the development of any objective signs. The paresthesias most
commonly occur in the lumbosacral region but also can involve the
upper and lower extremities and the upper back. This transient form
of Lhermitte syndrome can occur at radiation doses within accepted
spinal cord tolerance and is not associated with any permanent late
sequelae. The pathogenesis is thought to involve an inhibitory effect
on oligodendrocytes that results in transient reversible demyelination.
A more ominous form of Lhermitte syndrome can manifest after a
longer latency period after completion of radiation therapy (at least
a year), which then progresses to chronic radiation myelopathy.
Chronic myelopathy is the most catastrophic late effect that can
occur after spinal cord irradiation. Nearly half of the affected patients
will die from complications.199 A biphasic distribution in the latency
period from irradiation to the onset of myelopathy has been observed.
The early peak is from 12 to 14 months, and the second peak is from
24 to 28 months. The pathologic insults that lead to myelopathy
include damage to oligodendroglial cells, causing demyelination and
white matter necrosis, and death of endothelial cells, resulting in
vascular injury. In some patients, partial neurologic dysfunction
develops; others progress to complete paraplegia or quadriplegia. No
clinical or radiologic findings are pathognomonic for radiation-induced
myelopathy. Therefore the diagnosis usually is made by a combination
of (1) neurologic abnormalities corresponding to a level just below
the irradiated region, (2) a history of spinal cord irradiation with a
high total dose (greater than 45 Gy) at least 6 months before the
onset of signs and symptoms, (3) MRI findings of increased signal
intensity on T2-weighted images in the irradiated region,200 and (4)
exclusion of other etiologic factors. The MRI findings in spinal cord
myelopathy can mimic tumor recurrence with gadolinium enhancement
on MRI.
The probability of development of chronic radiation myelopathy
is dependent not only on the total dose delivered to the spinal cord
but also on the fraction size. Larger fraction sizes are associated with
more severe later effects (Schultheiss and associates143). Using standard
fraction sizes (1.8–2 Gy per day), a commonly observed limit for dose
to the spinal cord is 45 Gy. In a study of the incidence of myelitis
after irradiation of the cervical cord, Marcus and Million201 found
that of 1112 patients, chronic radiation myelopathy developed in
only 2 (0.18%). This complication developed in 2 out of 471 patients
(0.43%) receiving between 45 and 50 Gy. No patients who received
between 40 and 45 Gy or who received more than 50 Gy developed
myelopathy. The investigators’ conclusion was that even with doses
of up to 50 to 55 Gy to the cervical cord, the likelihood of development
of chronic myelopathy was extremely low. Even if the spinal cord dose
is limited to 45 Gy, myelitis may still develop. This report cited
published cases in which myelitis developed with doses less than 45 Gy
or even less than 40 Gy, given in 1.8- to 2-Gy daily fractions. Such
cases, however, are extremely rare, with an estimated risk of 0.2% or
less for the development of chronic myelopathy at this dose.143 No
effective treatment exists for this condition, and only case reports are
found in the literature suggesting possible instances of benefit with
growth factors, anticoagulation, and bevacizumab.
GENERAL PRINCIPLES OF CHEMOTHERAPY
Chemotherapy for brain tumors involves many of the same problems
as chemotherapy for systemic cancer, including lack of specificity,
intrinsic or developing cellular resistance, intolerance of normal tissue
to drug toxicity, synergistic toxicity between chemotherapy and radiation
therapy, and systemic toxicity. Brain tumor therapy also is associated
with specific problems of drug delivery across the blood-brain or
blood-tumor barrier. Cerebral edema may impede drug delivery, and
corticosteroids that effectively treat the edema may “repair” tumor
vessels and impede the delivery of chemotherapy to the tumor. Radiation
therapy also may result in endovascular changes, and the sequencing
of chemotherapy administration with irradiation remains an area of
active investigation. Thus a recurring disappointment in clinical
chemotherapy trials has been the failure to translate promising preclini-
cal chemotherapy findings into meaningful improvement in patient
survival.
Clinical criteria for chemotherapeutic success can be confusing.
Performance status, measured in many clinical trials with the Karnofsky
Performance Scale (KPS), is affected by tumor site, presence of seizures,
and adverse effects of AEDs and steroids. Therefore an appropriate
measure of chemotherapeutic efficacy should not be median survival
alone. Median progression-free survival (PFS) or 6-month PFS and
reduction in seizure frequency, corticosteroid requirement, and focal
deficits all are parameters that must be measured. For long-term
survivors, cognitive impairment and other serious acute and chronic
neurologic toxicities of cytotoxic chemotherapy and newer molecular
strategies factor into the assessment of chemotherapeutic program
efficacy.202
Finally, chemotherapy of primary brain tumors for approximately
the past 20 years has been designed on the assumption that the problem
is one of local control, with few recurrences outside the original tumor
site.203 With longer survival periods and better local tumor control,
however, a higher rate of multicentric cerebral and even leptomeningeal
disseminated disease has been noted among patients with high-grade
glial tumors, and oncologists may need to design future systemic
regimens with these considerations in mind. Recent studies with an
antibody specific to a mutation of the isocitrate dehydrogenase (IDH1)
biomarker identified single tumor cells remote from the presenting
mass and lend credence to the notion that what may appear to be
focal glioma may represent systemic brain disease.204,205
An important consideration in the chemotherapy of brain tumors
is the ability of the drugs to cross the blood-brain barrier. This physi-
ologic barrier defines the restricted transport between blood and the
CNS of water-soluble, ionized molecules larger than about 200 daltons.
The blood-brain barrier is formed by the endothelial cells of brain
capillaries, with some contribution from astrocytes. Brain capillaries
differ from capillaries elsewhere in the body by the presence of tight
intercellular junctions. Tight junctions consist of a protein complex
of two groups, the transmembrane proteins occludin and claudin,
and junction-associated molecules and cytoplasmic scaffolding and
regulatory proteins. The brain’s extracellular or interstitial fluid is an
ultrafiltrate essentially identical to CSF. Capillaries of the choroid
plexuses are fenestrated, allowing access of large protein molecules
into the plexus stroma. The epithelial cells separating stroma from
CSF, however, have apical tight junctions. The brain lacks a lymphatic
system. Brain tumors and their associated blood vessels have altered

expression and function of membrane transporters and enzymes leading
to vasogenic edema and inflammation.206,207
These features of the blood-brain barrier and the blood-CSF barrier
exclude entry of large molecules such as proteins and limit entry of
smaller molecules to their ability to cross the lipid bilayer of cells.
Lipid-soluble molecules such as nicotine, ethanol, heroin, and the
alkylating agents bis-chloroethylnitrosourea (BCNU; carmustine) and
temozolomide (Temodar) pass readily across the blood-brain barrier.
Another function of the blood-brain barrier may be that of pumping
out chemicals potentially harmful to the brain. P-glycoprotein, a
blood-brain barrier protein, is present in the membrane of some brain
tumor cells and serves to reduce the intracellular concentration of
several chemotherapeutic agents.
Quantitative examination of the blood-brain barrier and the brain-
tumor barrier has resulted in new avenues of investigation for brain
tumor chemotherapy. Methotrexate entry into brain tumors can be
enhanced by intraarterial delivery, but the use of hyperosmolar mannitol
for this purpose results in a far greater increase of drug entry into
normal brain tissue than into tumor. Human and rat studies of BCNU,
cisplatin, and other agents after blood-brain barrier disruption in both
primary glial tumors and PCNSL have demonstrated significant
toxicity.208,209 Intraarterial delivery of such drugs has been largely
abandoned.
In brain tumors, the degree to which the tight endothelial cell
junctions of the blood-brain barrier are disrupted and vascular perme-
ability is thereby increased varies even within individual tumors. The
persistence of a relatively intact barrier impedes entry of some water-
soluble chemotherapeutic agents into areas of tumor, leading investiga-
tors to look for methods of opening the blood-brain barrier that are
less toxic than intraarterial mannitol, but efforts have not been suc-
cessful.210 Radiation-induced blood-brain barrier disruption may offer
another avenue to deliver chemotherapy to brain tumors. For example,
evidence suggests that radiation therapy may offer a unique window
extending from 1 week after the initiation of radiotherapy to 1 month
after the completion of treatment during which a pharmaceutical
agent has maximum access to high-grade gliomas.211
SUPRATENTORIAL GLIOMAS
Clinical Considerations
Patients with supratentorial gliomas may have general signs and
symptoms such as changes in mental status, seizures, headaches,
papilledema, and nausea and vomiting, as discussed earlier. They also
may have focal signs and symptoms, dependent on tumor location,
as discussed previously.
The incidence of low-grade astrocytomas is highest between the
ages of 20 and 40 years and decreases in patients older than 50 years.
Oligodendrogliomas display a similar age-related frequency. Conversely,
high-grade astrocytomas, including glioblastomas, increase in frequency
with increasing age (see Fig. 63.1).
A history of seizures also is extremely common in patients with
oligodendrogliomas, occurring in 70% to 90%. The duration of
symptoms can be prolonged. In a study by Ludwig and colleagues,212
55% of patients had symptoms for longer than 1 year before diagnosis,
and 37% had symptoms for longer than 3 years. A few patients had
symptoms for 10 to 15 years before diagnosis.
Most glioblastomas have a very short symptomatic history at
presentation, on the order of days or weeks. Tumors that seem to
progress more slowly with a longer antecedent history of seizures or
cognitive decline may have progressed from a lower-grade glial neoplasm
and thus are considered secondary glioblastomas.
Pathologic Classification of Supratentorial Gliomas
Astrocytomas arise from astrocytes, the supporting cells of the CNS.
Glial fibrillary acidic protein is expressed in the cytoplasmic processes
Cancer of the Central Nervous System • CHAPTER 63 925
that extend from the astrocytes, and thus antibodies against this protein
can be used in immunohistochemical studies.
Over the years, many different histopathologic staging systems
have been used.213–215 Historically systems classify tumors in up to
four categories with increasing malignancy. The most widely used
system today for classification of astrocytomas is part of the WHO
classification of tumors of the CNS, which was last updated in 2016.216
Compared with the 2007 classification, which relied solely on histologic
characteristics, the 2016 WHO classification of tumors of the CNS
now also uses molecular data to define CNS tumors. Notable changes
include the removal of oligoastrocytoma as a distinct entity and the
subclassification of tumors based on IDH1 mutation status, which
confers a better prognosis in both high-grade and low-grade astrocy-
tomas. The 2016 CNS WHO classification uses the classical histologic
features to make an initial diagnosis, which is then refined on the
basis of molecular testing (Fig. 63.9).
Histologic Classification of Supratentorial Gliomas
The category of grade I astrocytic tumors is reserved for subependymal
giant cell astrocytoma and pilocytic astrocytoma, which are the most
benign in terms of histologic characteristics; they are generally curable
with surgery alone. Because grade I astrocytomas are more common
in children than in adults, they are discussed in greater detail later in
the section on childhood brain tumors. The remaining categories are
grade II (diffuse astrocytomas), grade III (anaplastic astrocytomas),
and grade IV (glioblastomas).
Diffuse astrocytomas (grade II) are poorly defined gray tumors
that expand the parenchyma and obliterate normal gray matter–white
matter boundaries217 (Fig. 63.10). Microscopically, increased numbers
of irregularly distributed astrocytes with mildly atypical nuclei are
noted (Fig. 63.11A). Tumor cells can be seen infiltrating into normal
brain tissue. Diffuse astrocytomas often are classified into one of three
subtypes: fibrillary (the most common subtype), protoplasmic, or
gemistocytic.218 Fibrillary astrocytomas are composed of tightly
interlacing bundles of small, spindle-shaped cells amid a predominantly
fibrillar matrix. Gemistocytic astrocytomas contain plump cells with
distinct, round pink cytoplasm arranged on a more delicately interlacing
fibrillar matrix. Protoplasmic astrocytomas are composed of small,
round, regular cells with indistinct cytoplasmic boundaries arranged
on a loosely fibrillar stroma.
Microscopically, anaplastic astrocytomas (WHO grade III)
are distinguished from grade II tumors by their greater cellular-
ity, increased nuclear pleomorphism, and, of greatest importance,
mitotic activity (see Fig. 63.11B). In both these and grade IV
glioblastomas, tumor cells can be seen infiltrating into surrounding
normal brain tissue, often at a great distance from the primary tumor
mass. Histologically, glioblastomas are distinguished from anaplastic
astrocytomas by the presence of endothelial proliferation or necrosis
(Fig. 63.12). The necrosis can form a serpentine pattern referred to
as pseudopalisading, in which tumor cells crowd around the edges
of the necrotic region. The presence of necrosis is of particular
importance in grading gliomas and has been associated with shorter
survival.219
Grade IV astrocytomas (glioblastomas) show areas of hemorrhage,
necrosis, and cystic change on gross examination (Fig. 63.13). Glio-
blastoma can manifest with multicentric disease, but this occurs in
less than 5% of cases as determined at the autopsy of patients with
untreated tumors.203
In addition to pathologic grading by morphology, immunohisto-
chemical techniques have been developed to measure cell kinetics
based on the idea that faster-growing tumors are more malignant.
Ki-67 (MIB-1) or proliferating cell nuclear antigen is a measure of
cellular proliferation. Bromodeoxyuridine (BUdR) or iododeoxyuridine
incorporation into tumor cells can help measure the proportion of
cells in the S phase of mitosis. The predictive power of all three of
these techniques has been compared with that for clinical parameters.220
926 Part III: Specific Malignancies

Histology Astrocytoma Oligoastrocytoma Oligodendroglioma Glioblastoma

IDH status
IDH mutant IDH wild-type IDH mutant IDH wild-type

1p/19q and Glioblastoma, IDH mutant

other genetic ATRX loss*
1p/19q codeletion
parameters TP53 mutation*
Glioblastoma, IDH wild-type

Diffuse astrocytoma, IDH mutant

Oligodendroglioma, IDH mutant and 1p/19q codeleted Genetic testing not done
or inconclusive

After exclusion of other entities:

Diffuse astrocytoma, IDH wild-type
Oligodendroglioma, NOS

Diffuse astrocytoma, NOS

Oligodendroglioma, NOS
Oligoastrocytoma, NOS
Glioblastoma, NOS

Figure 63.9 • Molecular classification based on 2016 WHO classification. Both IDH1 mutation status and 1p19q status have become defining feature
in the molecular WHO classification of gliomas. *, Characteristic but not required for diagnosis; IDH, isocitrate dehydrogenase; NOS, not otherwise specified.
(From Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary.
Acta Neuropathol. 2016;131[6]:803–820.)

Immunohistochemical stains for genetic changes found in glial tumors

Figure 63.10 • Diffuse low-grade astrocytoma, gross specimen. A World
Health Organization grade II astrocytoma arises diffusely and infiltrates the
right frontal lobe. Gross determination of the tumor’s boundaries is almost
impossible, but the tumor is evident as an ill-defined area of enlargement,
with loss of distinction between the gray and white matter. (From Maher EA,
McKee AC. Neoplasms of the central nervous system. In: Skarin AT, ed.
Dana-Farber Cancer Institute Atlas of Diagnostic Oncology. 3rd ed. St Louis:
Mosby; 2003.)
are increasingly used to assess prognosis.
The different grades of astrocytoma carry very different prognoses.
With WHO grade I (pilocytic) astrocytomas, a cure rate greater than
90% after surgical resection alone can be expected. By contrast, with
WHO grade IV tumors, the median survival period is 1 to 2 years,
even after aggressive combined-modality therapy. With WHO grade
III tumors, long-term survival rates on the order of 20% are usual,
but the median survival period is approximately 2 years. WHO grade
II tumors carry a better prognosis than grade III tumors; nevertheless,
recurrence with a higher-grade tumor is common with grade II tumors,
although recurrence may take 6 to 8 years to occur.
Most oligodendrogliomas occur in the cerebral hemispheres (80%),
but they can rarely occur in the lateral and third ventricles. Oligo-
dendrogliomas arise from oligodendrocytes, which produce myelin.
They often involve the subcortical white matter, with extension into
the cerebral cortex. On gross examination, oligodendrogliomas are
often soft and gelatinous and better circumscribed than astrocytomas.217
They frequently contain calcifications. Despite their gross appearance
suggesting that they are contained, they can infiltrate surrounding
tissues, including the subarachnoid space and leptomeninges.
Because of fixation artifact, oligodendrogliomas appear micro-
scopically as sheets of cells with nuclei surrounded by a clear halo of
cytoplasm, giving the cells the appearance of a “fried egg” (Fig. 63.14A).
Unlike astrocytomas, oligodendrogliomas lack fibrillary cytoplasmic
processes. Calcifications are present in 90% of these tumors. A common
finding is a network of capillaries, lending a “chicken wire” pattern.
The WHO classification for oligodendrogliomas is a two-tiered
system of grade II (oligodendroglioma) and grade III (anaplastic
 Cancer of the Central Nervous System • CHAPTER 63 927

A B
Figure 63.11 • Histologic appearance of a low-grade astrocytoma versus an anaplastic astrocytoma. (A) A low-grade astrocytoma (World Health Organization
[WHO] grade II) shows low cellularity, slight nuclear pleomorphism, no endothelial proliferation, and no necrosis. (B) An anaplastic astrocytoma (WHO grade
III) shows increased cellularity, pleomorphism, and mitotic activity compared with the grade II tumor in (A). The anaplastic astrocytoma also lacks endothelial
proliferation and necrosis. (Courtesy Dr. Daniel Skovronsky, Department of Pathology, University of Pennsylvania School of Medicine, Philadelphia, PA.)

A B
Figure 63.12 • Glioblastoma (grade IV astrocytoma): histologic appearance. (A) Pseudopalisading cells surrounding regions of necrosis. (B) Endothelial
proliferation, which in this case has reached dramatic proportions, with the formation of tangled clusters of neovascular channels, often referred to as glomeruloid
blood vessels because of their resemblance to renal glomeruli. (From Maher EA, McKee AC. Neoplasms of the central nervous system. In: Skarin AT, ed.
Dana-Farber Cancer Institute Atlas of Diagnostic Oncology. 3rd ed. St Louis: Mosby; 2003.)

oligodendroglioma).216 Features suggestive of anaplasia include
cytologic atypia and increased mitotic activity (see Fig. 63.14B). In
the Mayo Clinic series, the 5- and 10-year survival rates and median
survival period for low-grade oligodendrogliomas were 75%, 46%,
and 9.8 years, respectively, versus 41%, 20%, and 3.9 years for high-
grade tumors.221
Overall, patients with oligodendrogliomas have a better prognosis
than patients with astrocytomas.148 For example, in the Mayo Clinic
experience, the 5- and 10-year survival rates and the median survival
period were 46%, 17%, and 4.7 years, respectively, for low-grade
diffuse astrocytomas, compared with 73%, 49%, and 9.8 years for
low-grade oligodendrogliomas.222
Molecular Classification of Supratentorial Gliomas
Isocitrate Dehydrogenase Mutations
The 2016 WHO classification of CNS tumors incorporates IDH
mutation status.216 Each grade of astrocytoma can be classified as
either IDH-mutant or IDH-wildtype. For instance, diffuse astrocytoma
can be IDH-mutant or IDH-wildtype; similarly, glioblastoma can
also be considered IDH-mutant or IDH-wildtype. IDH-mutant status
confers a survival advantage when compared with IDH wild-type
tumors of the same grade (Fig. 63.15).
Approximately 80% of all glioblastomas develop without any prior
history of a glioma and are termed primary glioblastomas. In 20%
of the cases, the patient has an antecedent history of a lower-grade
glioma (grade II or III), generally 5 to 10 years previously. These
secondary glioblastomas tend to arise in younger patients, with a
median age of 40 years. Furthermore, IDH mutation is seen more
commonly in secondary glioblastoma (73%) compared with primary
glioblastoma (4%).223
A genome-wide mutational analysis of glioblastomas identified
somatic mutations in the isocitrate dehydrogenase 1 gene (IDH1) in
12% of these tumors. These mutations occurred in a high percentage
of young patients and were seen in most secondary glioblastomas.224
In this analysis, IDH1 mutations were associated with longer
928 Part III: Specific Malignancies
overall survival (OS) with a median survival of 3.8 years in patients
with the mutated gene versus 1.1 years for patients with the wild-
type gene.
Both IDH1 and IDH2 mutation status were explored in a variety
of CNS and non-CNS tumors.225 These investigators identified muta-
tions in amino acid 132 of IDH1 in more than 70% of WHO grade
II and III astrocytomas and oligodendrogliomas, and in glioblastomas
that developed from these lower-grade gliomas. Often tumors without
mutated IDH1 had mutations in the analogous amino acid of the
IDH2 gene. Other investigators have found that IDH1 mutations
occurred in 88% of low-grade diffuse astrocytomas and in 82% of
secondary glioblastomas. In addition, no cases of IDH1 mutation
occurred after either acquisition of TP53 mutations or 1p/19q loss,
suggesting that IDH1 mutation is a very early event in gliomagenesis.
The majority of grade II astrocytomas (63%) contained both IDH1
and TP53 mutations, whereas 64% of grade II oligodendrogliomas
Figure 63.13 • Glioblastoma: gross specimen. The tumor appears as a
necrotic, hemorrhagic infiltrating mass. (From De Girolami U, Anthony DC,
Frosch MP. The central nervous system. In: Cotran RS, Kumar V, Collins T,
eds. Robbins’ Pathologic Basis of Disease. 6th ed. Philadelphia: WB Saunders;
2003.)
A B
Figure 63.14 • Histologic appearance of oligodendroglioma versus anaplastic oligodendroglioma. (A) In World Health Organization (WHO) grade II
oligodendroglioma, oligodendrocytes are uniform cells with small, round nuclei and a characteristic perinuclear halo (“fried egg” cells). (B) A grade III oligo-
dendroglioma shows cytologic atypia and increased mitotic activity compared with the tumor in (A). (Courtesy Dr. Daniel Skovronsky, Department of
Pathology, University of Pennsylvania School of Medicine, Philadelphia, PA.)
had both IDH1 mutation and 1p/19q loss. IDH1 mutations occurred
in 10% of pilocytic astrocytomas, 5% of primary glioblastomas, and
none of the ependymomas examined. These findings are important
because they provide evidence that different histologic types of low-grade
gliomas share a frequent genetic alteration.
IDH1 and IDH2 are nicotinamide adenine dinucleotide phosphate
(NADP+)–dependent enzymes that catalyze the oxidative decarbox-
ylation of isocitrate into α-ketoglutarate226 (see Fig. 63.15). The mutated
forms of IDH1 and IDH2 have been shown to result in the induction
of hypoxia-inducible factor-1α (HIF-1α), whereas levels of
α-ketoglutarate decreased (loss of function) and the conversion of
α-ketoglutarate to 2-hydroxyglutarate occurred (gain of function).227
The decreased enzymatic activity suggests that IDH1 and IDH2 are
tumor suppressor genes.205 However, the altered substrate specificity
seen in mutant IDH1 is more compatible with oncogenic function.205,228
Mutation in either a tumor suppressor or an oncogene would be
expected to be associated with poorer prognosis, but the opposite is
in fact seen in patients with this mutant gene.227
The reason that IDH mutations result in a better prognosis is
unknown. Some investigators have hypothesized that mutated IDH
decreases the reduced form of nicotinamide adenine dinucleotide
phosphate (NADPH) and α-ketoglutarate. Several pathways are affected
by changes in NADPH and α-ketoglutarate concentrations. A decrease
in these molecules, which normally rescue cells from oxidative stress,
results in increased radiosensitivity.229 IDH mutations might also be
important for cellular migration and the cellular hypoxic response.
Increased lactate production results from inhibition of cytosolic IDH1,
which results in increased glioma cell migration.230 In vitro and in
vivo studies have demonstrated that the IDH1 mutation reduces the
aggressiveness of an established glioma cell line.231
The discovery of the role of IDH1/IDH2 in gliomas has important
implications. First, this enzyme previously had no known role in
tumor formation, and it has prompted a resurgence of interest in the
field of altered metabolism in tumorigenesis. Second, it is now used
to more accurately classify patients because it is associated with
prolonged survival. IDH1 mutation is also associated with differentia-
tion between primary and secondary glioblastoma, with a sensitivity
of 70% to 73% and specificity of 96%.232 In addition, this mutation
can be used to differentiate between diffuse and pilocytic astrocytomas
with 73% to 83% sensitivity and 100% specificity. Finally, the pathways
affected as a consequence of this mutation may represent novel thera-
peutic targets (see Fig. 63.15).
 Cancer of the Central Nervous System • CHAPTER 63 929

Glucose

Acetyl CoA

OAA Cit Cit

Mal Isocitrate Isocitrate

NAD+ NADP– NADP–
IDH3 IDH2 IDH1
Fum
CO2 + NADPH NADPH + CO2 NADPH + CO2
αKG aKG
Suc

Glutamine

Glutamine
A

Glucose

Acetyl CoA

OAA Cit Cit

Mal Isocitrate Isocitrate

NAD+ NADP+ NADP–
IDH3 IDH2 IDH1
Fum CO2 + NADH NADPH + CO2 NADPH + CO2
αKG αKG
Suc NADPH αKG-dependent enzymes
NADPH and processes
IDH2*
D2

Glutamine IDH1*
HG

NADP+
NADP+
DH

2HG
Glutamine
Transcriptional regulation
2HG Proliferation
Angiogenesis
Apoptosis resistance
Migration and invasion

• Mitochondrial activity
• Ca2+ homeostasis
• 5-ALA and HO-Lys metabolism
B
Figure 63.15 • Metabolic reactions catalyzed by the isocitrate dehydrogenase (IDH) family. (A) IDH1 catalyzes the NADP+-dependent decarboxylation
of isocitrate to α-ketoglutarate (αKG) in the peroxisome and cytoplasm, whereas IDH2 mediates the same reaction in the mitochondria. Also, within the
mitochondrial compartment, heterotetrameric IDH3 catalyzes the conversion of isocitrate to αKG in an NADP+-dependent manner. (B) Mutations in IDH1
and IDH2 impart to these enzymes the ability to catalyze the reduction of αKG to 2-hydroxyglutarate (2HG). On the basis of the chemical similarity between
these two metabolites, it is possible that the activity of αKG-dependent enzymes is affected by the elevated level of 2HG in tumors harboring IDH1 and
IDH2 mutations. In this model, these events may trigger alterations in angiogenesis, epigenetic state, and extracellular matrix dynamics, which in turn may
affect proliferation, survival, and invasive properties of these tumors. Cit, Citrate; Fum, fumarate; Mal, malate; NAD, nicotinamide adenine dinucleotide;
NADPH, reduced form of nicotinamide adenine dinucleotide phosphate; OAA, oxaloacetate; Suc, succinate. (Modified from Yen KE, Bittinger MA, Su SM,
et al. Cancer-associated IDH mutations: biomarker and therapeutic opportunities. Oncogene. 2010;29:6409–6417.)

LOH of 1p and 19q is common in both grade II and grade III

1p19q Codeletion in Oligodendroglioma
Two chromosomal abnormalities have now become a defining
feature of oligodendrogliomas: deletion of 1p and deletion of 19q.
Oligodendrogliomas exhibit loss of heterozygosity (LOH) at 19q in
up to 88% of cases and LOH at 1p in up to 100% of cases.233
oligodendrogliomas, and thus these changes probably occur early during
tumorigenesis.234,235 The 2007 WHO CNS classification included
oligoastrocytoma, which shared both an astrocytic and oligodendroglial
component; this is discouraged in the 2016 WHO classification. The
two entities can now be molecularly distinguished through the use
930 Part III: Specific Malignancies
of 1p/19q codeletion, which is seen in oligodendroglioma but not in
astrocytoma.216
Genome Level Classification of Glioblastoma
Profiling and sequencing results are now being used to divide
glioblastomas into molecular subgroups. Phillips and colleagues236
used gene expression profiling to classify glioblastoma into three
groups: proneural, mesenchymal, and proliferative. More recent
work from The Cancer Genome Atlas has provided more detailed
information about the molecular genetic alteration of glioblastoma,
resulting in four distinct subtypes that resemble stages of neurogenesis:
classical, mesenchymal, neural, and proneural (Fig. 63.16).237 The
sequential genetic changes in the pathogenesis of glioma according
to subgroup have been well reviewed by Van Meir and colleagues238
(Fig. 63.17).
The classical subtype is characterized by chromosome 7 amplification
and chromosome 10 loss, which occur in 100% of classical subtypes.
This subtype is associated with EGFR amplification in about 97%
of the samples tested. TP53 mutations are also lacking in this subtype.
Other alterations include deletions of CDKN2A and high expression
of the neural precursor and stem cell marker NES, and signaling
pathways Notch and Sonic Hedgehog.239
The mesenchymal subtype is associated with deletions in regions
of the NF1 gene. These samples also expressed the mesenchymal
markers CHI3L1 and MET. In addition, genes in the tumor necrosis
factor superfamily and in the nuclear factor (NF)- κB pathway are
Figure 63.16 • Integrated view of gene expression and genomic alterations across four glioblastoma subtypes: (1) proneural, (2) neural, (3) classical, and
(4) mesenchymal. Key genetic for each subtype mutations are highlighted in the right column. (From Brennan C, et al. The somatic genomic landscape of
glioblastoma. Cell. 2013;155[2]:462–477.)
highly expressed, possibly as a result of higher levels of necrosis and
inflammatory infiltrates seen in this class.239
The proneural subtype samples were associated with alterations
in PDGFRA and IDH1. Samples in this group also contained most
of the TP53 mutations and TP53 LOH. Less common in proneural
samples were chromosome 7 amplification and chromosome 10 loss.
The proneural group showed high expression of oligodendrocytic
genes PDGFRA, NKX2-2, and OLIG2. Other proneural develop-
ment genes associated with this group include DCX, DLL3, ASCL1,
and TCF4.239
The neural subtype was associated with expression of the neuron
markers NEFL, GABRA1, SYT1, and SLC12A5.239
These four glioblastoma subtypes also have clinical implications.
Younger patients were overrepresented in the proneural subtype.
Furthermore, patients with the proneural subtype showed a trend
toward longer survival.239 Most secondary glioblastomas were classified
as proneural.239 Interesting to note, aggressive treatment reduced
mortality in patients with classical and mesenchymal subtype tumors,
and efficacy was suggested in the neural group, but it did not alter
survival in patients classified as having the proneural subtype.239
Other Genetic Changes in Glioblastomas
The Rb pathway, which regulates the G1/S transition, commonly is
disrupted in high-grade astrocytomas. This disruption can occur through
deletion or mutation of RB itself; deletion or mutation of CDKN2A,
which encodes the cyclin-dependent kinase inhibitor p16; deletion
or mutation of CDKN2B, which encodes the cyclin-dependent kinase
 Cancer of the Central Nervous System • CHAPTER 63 931

Putative GBM
cells of origin: Primary GBM subtypes:

EGFR mutation/amplification/overexpression
Neural stem Oligodendroglioma Classical PTEN loss/mutation
cell IDH1/2 mutations CDKN2A loss
NES overexpression
Notch & Shh pathways activation

Transit NF1 loss/mutation

amplifying cell PT53 loss/mutation
Mesenchymal
PTEN loss/mutation
MET, CHI3L1, CD44, MERTK overexpression
TIC BCPC TNF family & NFκB pathways activation
Neural/glial
progenitor
Sequential genetic EGFR mutation/amplification/overexpression
alterations and clonal Neural Gene signature of normal brain
evolution Neuron marker expression
(NEFL, GABRA1, SYT1, SLC12A5)
Remains to be better defined
Astrocyte
PDGFRA amplification
Juvenile pilocytic Proneural IDH1 mutation
Astrocytoma PIK3A/PIK3R1 mutation
Wild type IDH1/2 TP53, CDKN2A & PTEN loss/mutation
BRAF mutation Proneural marker expression
(SOX, DCX, DLL3, ASCL1, TCF-4)
Oligodendrocytic marker expression
BCPC
Grade II/III Secondary GBM (PDGFRA, OLIG2, TCF3 and NKX2-2)
Astrocytoma HIF, PI3 kinase & PDGFRA pathways
Oligodendrocyte IDH1/2 mutations activation

Figure 63.17 • Sequential genetic changes observed in the pathogenesis of different subtypes of glioblastoma. Some cells in the normal brain undergo
genetic alterations, which leads to a population of tumor-initiating cells (TICs), which can then further accumulate genetic and epigenetic changes and become
brain cancer–propagating cells (BCPC). The latter cells are responsible for the formation of glioblastoma. EGFR, Epidermal growth factor receptor; GBM,
glioblastoma multiforme; HIF, hypoxia-inducible factor; IDH, isocitrate dehydrogenase; PDGFRA, platelet-derived growth factor receptor–A; PI3 kinase,
phosphatidylinositol-3 kinase; PTEN, phosphatase and tensin homolog; TNF, tumor necrosis factor. (Modified from Van Meir EG, Hadjipanavis CG, Norden
AD et al. Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma. CA Cancer J Clin. 2010;60[3]:166–193.)

inhibitor p15; or amplification of the CDK4 gene. Ichimura and
coworkers240 noted that one of these changes had occurred in 67%
of glioblastomas and 21% of anaplastic astrocytomas but in none of
15 low-grade astrocytomas. These findings suggest that progression
to a higher-grade glioma is facilitated by deregulation of the G1/S
transition.
LOH of 13q and 9p has been identified in high-grade astrocytomas,
and these deletions may lead to alterations in the Rb pathway. LOH
of chromosome 13 occurs in 30% to 40% of higher-grade astrocy-
tomas.241 The Rb gene (RB), which maps to 13q14, is the likely target
of this deletion. CDKN2A is located on 9p21, and this chromosomal
region is homozygously deleted in at least 30% to 40% of glioblastomas
and in approximately 10% of anaplastic astrocytomas, but never in
diffuse astrocytomas.241 Because two different gene products, CdkN2A
and p14ARF, are both transcribed from a single locus on 9p21, deletion
of this region leads to simultaneous disruption of both the Rb and
p53 pathways.
Astrocytic tumors also frequently display high-level expression of
PDGF ligands and receptors.32 Most studies have found that the
PDFGα receptor is overexpressed in 60% to 90% of low- and high-
grade astrocytomas. By contrast, overexpression of the ligand PDGFA
or PDGFB is not very common in low-grade gliomas but is seen in
higher-grade tumors, suggesting that this growth factor participates
in an autocrine loop in these tumors.32
The p53 pathway frequently is disrupted in all grades of astrocy-
tomas. This disruption can occur by mutation of p53 itself, by
overexpression of MDM2, which degrades p53, or by mutation or
deletion of p14ARF, which positively regulates p53 by inhibiting MDM2
expression. In one study, the p53 pathway was disrupted by one of
these mechanisms in 67% of diffuse astrocytomas, 72% of anaplastic
astrocytomas, and 76% of glioblastomas.242 Therefore disruption of
the p53 pathway appears to be an early event in the genesis of
astrocytomas. It is possible that mutation of p53 in low-grade astro-
cytomas leads to genomic instability that sets the stage for additional
mutations that lead to the formation of higher-grade tumors. The
p53 gene (TP53) is located on the long arm of chromosome 17 (17p),
which frequently is lost in both low-grade and high-grade astrocytomas,
suggesting that p53 is the target for this genetic change (reviewed by
Ichimura and coworkers241).
EGFR amplification leading to overexpression is seen in
approximately 35% of primary glioblastomas, rarely in anaplastic
astrocytomas, and never in diffuse astrocytomas.31 Another 15%
of primary glioblastomas overexpress EGFR without amplification.
Approximately half of glioblastomas with EGFR amplification express
a mutant form of the receptor.31 The most common mutant is known
as ΔEGFR or EGFRvIII, which is missing exons 2 to 7, resulting in
an in-frame deletion of 801 base pairs of the coding sequence of the
extracellular domain.243,244 This particular mutant form of EGFR is
932 Part III: Specific Malignancies
constitutively activated and cannot be downregulated. Its expression
in glioblastoma cells has been associated with increased proliferation,
decreased apoptosis, and increased tumorigenicity and invasion in
vivo.244 Even in glioblastomas that overexpress wild-type EGFR, which
is not constitutively active, the ligands EGF and TGF-α often are
coexpressed, which may activate an autocrine loop that allows for
self-stimulation.31
Up to 90% of primary glioblastomas exhibit deletion of 10q, on
which is located the tumor suppressor gene PTEN.245 The retained
PTEN allele is mutated in approximately 50% of tumors with 10q
loss, leading to complete loss of functional PTEN protein. Therefore
the incidence of PTEN mutation in glioblastoma is at least 45%.241
One study suggested a potential association between lower PTEN
levels and shorter survival in patients with glioblastomas, although
this association did not reach statistical significance.246 PTEN mutations
have been found in anaplastic astrocytomas, although at a much lower
frequency than in glioblastomas.247 This study found the presence of
PTEN mutations in anaplastic astrocytoma to be a powerful prognostic
factor portending a poorer outcome.
In contrast to primary tumors, secondary glioblastomas rarely
display EGFR amplification.248–250 Secondary glioblastomas have loss
of 10q, but they do not have mutations of the retained PTEN gene.249
Both the p53 and Rb pathways generally are disrupted in secondary
glioblastomas, as is the case with primary glioblastomas; however, the
mechanisms tend to be different. Both wild-type p53 alleles are lost
in more than half of all secondary glioblastomas, generally one allele
by deletion and the second by mutation. By contrast, p53 mutations
are rarely seen in primary glioblastomas (occurring in fewer than 10%
of cases).248,250 The Rb pathway is disrupted in secondary glioblastomas,
often through loss of both wild-type alleles.241 Secondary glioblastomas
may also show disruption of the p53 and Rb pathways through promoter
methylation of CdkN2A and p14ARF.
Surgery for Supratentorial Gliomas: Extent of
Surgical Resection
The role of extent of surgical resection in the treatment of gliomas
has been controversial for many years.138,252,253 Virtually all of the
reviews in this subject area have been retrospective, and thus they are
subject to significant selection bias. It is likely that patients with the
most favorable, easily resectable lesions within noneloquent brain
regions have tended to undergo aggressive resections, whereas those
with deeper lesions in more eloquent brain regions have been selected
for stereotactic biopsy to minimize surgical morbidity. Some experts
have advocated maximal resection for gliomas, reasoning that this
approach is associated with improved survival in children, adults, and
even elderly persons.139,140,254 Others have advocated for supratotal
resection in low-grade glioma, with retrospective data demonstrating
prolonged survival.255 A possible explanation for this outcome may
be that fewer cells are left behind that need to be eradicated with
irradiation and chemotherapy.
Other investigators have advocated stereotactic biopsy alone as the
preferred mode of histologic diagnosis in the treatment of patients
with gliomas.253,256 Stereotactic biopsy affords a histologic diagnosis
with a low complication rate (2%–5%). However, stereotactic biopsy
may lead to an inaccurate pathologic diagnosis. In a review of data
for 81 consecutive patients initially diagnosed with stereotactic biopsy
who subsequently underwent a craniotomy, Jackson and colleagues252
showed that the histopathologic classification based on stereotactic
biopsy findings was incorrect in 38% of the patients. This finding
represented sampling error in these patients, 96% of whom underwent
biopsy at outside institutions. Despite the fact that these tumors
were located in eloquent brain areas and were previously treated by
neurosurgeons, gross total resection could be achieved in 57% of
these patients once they reached a major tertiary care hospital (The
MD Anderson Cancer Center, Houston, TX). Major complications
were seen in only 12.3% of the patients undergoing aggressive
craniotomy for resection of the malignant glioma located in eloquent
brain areas.
To specifically address the role of aggressive resection of gliomas
in prolonging survival, Lacroix and coworkers138 performed a retrospec-
tive multivariate analysis of outcomes in 416 patients through use of
prospectively collected data. Postoperative volumetric MRI scans were
obtained for all patients so that a blinded neuroradiologist was able
to determine the extent of resection given as a percentage of the
original tumor. Patients with a resection of 98% or more of the tumor
volume had a median survival period of 13 months, versus 8.8 months
for patients with a less than 98% resection. Also found to be significant
were age, KPS score, and extent of tumor necrosis. However, when
statistical analysis controlled for these other three factors, extent of
resection remained a significant variable. More recently, Sanai and
coworkers140 analyzed the effect of extent of resection in 500 consecu-
tively treated patients with newly diagnosed glioblastoma multiforme
(GBM). The authors found that extent of resection equal to or greater
than 78% conferred a survival benefit, and reasoned that 78% should
be the new threshold minimum. Using recursive partition analysis,
the group further demonstrated that a 95% extent of resection is the
single best predictor of survival in patients with glioblastoma.
Navigation During Surgery
Intraoperative MRI scanners have allowed for real-time evaluation of
the extent of tumor resection. Imaging of relevant anatomy can be
performed during surgery with MRI to provide real-time feedback
regarding the surgical resection. Schulder and colleagues257 reviewed
the cases of 93 patients who underwent neurosurgery aided by a
low-field intraoperative MRI scanner. These investigators found that
surgery was directly affected by imaging in 51% of the operations.
Second lesions not otherwise evident on the initial preoperative scan
were seen in 21 patients, and in another 14 patients, unnecessary
dissection was avoided as a result of real-time imaging. Intraoperative
MRI scanners are being used not only for anatomic imaging but also
for perfusion and MRA imaging. Frameless stereotactic units have
been available for many years, allowing preoperative MRI scans to be
downloaded to an intraoperative computer workstation to create a
three-dimensional reconstruction of the images. The patient’s head
can be directly referenced to the images for precise intraoperative
localization to less than 2 mm. Investigators have been able to import
PET, functional MRI, and DTI data into the frameless stereotactic
units to map out functional brain areas during surgery.119
Intraoperative cortical and subcortical mapping has been used to
define eloquent brain areas during resection of gliomas.258,259 Intra-
operative cortical mapping has enabled neurosurgeons to become more
aggressive with tumors located within eloquent brain regions. This
application is especially useful with low-grade gliomas that occur
immediately adjacent to motor and speech areas. Cortical mapping
may be performed with the patient lightly anesthetized but awake
enough to respond to questions so that speech areas can be mapped.
This technique has been shown to facilitate the extent of resection,
thereby improving long-term survival in patients with low-grade
gliomas.260
Complications of Surgery
Analysis by the Glioma Outcome Project, a prospectively compiled
database capturing information on 788 patients, reviewed perioperative
complications and neurologic outcomes for patients who underwent
craniotomy for the diagnosis and treatment of gliomas.261 Of these
patients, 499 underwent either a first or second craniotomy for treat-
ment of their malignant glioma, and the remaining 289 patients
underwent a stereotactic biopsy only. No difference was found in the
characteristics of the patients who underwent a first or second crani-
otomy. Analysis of the perioperative symptoms, however, revealed that
patients undergoing a second craniotomy had a higher incidence of
altered level of consciousness and papilledema, whereas those undergoing
a first craniotomy had a higher incidence of headache. The incidence

of depression was higher in patients undergoing a second craniotomy
(11% in the group undergoing the first craniotomy versus 20% in
the patients undergoing a second craniotomy). This difference may
reflect the presence of a chronic disease state. The rate of systemic
infections also was higher in patients undergoing a second craniotomy
at 4.4%, versus 0% in patients undergoing a first craniotomy. This
finding is not unexpected, because these patients frequently have been
heavily pretreated with radiation therapy and chemotherapy, in addition
to long-term steroid use, causing significant immunosuppression.
Postoperative neurologic status was the same or better in 92% of the
patients undergoing their first craniotomy, whereas this rate dropped
to 82% in patients undergoing their second craniotomy. Nevertheless,
the overwhelming majority of patients benefited from a debulking
procedure to reduce neurologic deficits.
The most important preoperative factor associated with good
neurologic outcome has been the KPS score. Patients with higher
KPS scores fared better with surgery than did patients with lower
scores. This finding is a reflection of degree of neurologic injury. The
Glioma Outcome Project revealed that the incidence of further
neurologic deficit with craniotomy is only 8% in patients undergoing
their first operation versus 18% in patients undergoing a second
craniotomy for resection of a malignant glioma. In view of the severity
of the disease, this risk is certainly acceptable. Of greater importance,
prospectively obtained data show improvement in neurologic outcome
with aggressive debulking surgery. An important point is that these
data were compiled from participating institutions, and the decision
about whether to perform surgery was left to the discretion of the
surgeon; therefore selection bias certainly played a role in terms of
who underwent radical surgery versus stereotactic biopsy. The investiga-
tors do not discuss the frequency of tumors in eloquent versus
noneloquent brain regions. Box 63.1 summarizes the recommended
approach to management of supratentorial gliomas.
Radiation Therapy for Supratentorial Gliomas
Radiation Therapy for Low-Grade Gliomas
Numerous retrospective reports have been published regarding the use
of radiation therapy for low-grade gliomas (summarized by Leighton
and associates262). The results of these retrospective studies have largely
Box 63.1. MANAGEMENT OF SUPRATENTORIAL
ASTROCYTOMAS
• Grade I (pilocytic) astrocytomas: Surgery is curative. If residual
tumor is seen on postoperative images, the patient should undergo a
second craniotomy to resect the entire tumor. Radiation therapy and
chemotherapy have limited usefulness for the treatment of these
tumors. Radiation can be considered for recurrent or unresectable
tumors.
• Grade II (low-grade) astrocytoma: Surgery is the mainstay of
therapy for tumors in noneloquent regions of brain. In patients
younger than 40 years who undergo gross total resection, no
additional therapy is given. Incomplete resection is typically treated
with radiation alone; however, increasing evidence suggests that
chemotherapy improves survival.
• Grade III astrocytoma (anaplastic astrocytoma) and grade IV
gliomas (glioblastoma): Surgery is required to establish tissue
diagnosis, preferably also with debulking. Chemotherapy is begun
with temozolomide during radiation therapy and continued for
six cycles after completion of the radiation regimen. The radiation
dose generally is 60 Gy. Tumor tissue is sent for analysis of O6-
methylguanine DNA-methyltransferase (MGMT) promoter activity.
Temozolomide is offered to all patients, however, regardless of
promoter methylation status.
Cancer of the Central Nervous System • CHAPTER 63 933
been superseded by the results of three randomized trials, two from
the European Organisation for Research and Treatment of Cancer
(EORTC) and one from the NCCTG (see Table 63.4). The EORTC
22844 trial randomly assigned adults with supratentorial low-grade
astrocytomas, oligodendrogliomas, or mixed oligoastrocytomas to receive
either 45 Gy or 59.4 Gy of radiation after surgery.263 The NCCTG
study was similar except that patients were randomly assigned to
receive either 50.4 or 68.4 Gy after surgery.148 Patients underwent a
range of surgical procedures, including biopsy and subtotal or gross
total resection. Neither study showed any benefit to the higher dose
in terms of OS or PFS. If anything, the NCCTG study showed a
worse survival rate in patients receiving the higher dose of radiation
(64.8 Gy). The 5-year survival rate in both studies ranged from
58% to 72%.
The EORTC also performed study 22845, in which patients who
underwent surgical treatment for astrocytomas, oligodendrogliomas,
or mixed oligoastrocytomas were randomized to receive either adjuvant
irradiation at a dose of 54 Gy or no up-front radiation therapy.264
Patients in the latter group had the option of receiving radiation if
progression of disease was observed. No difference was seen in OS
between the early radiotherapy and observation groups (Table 63.5);
the 5-year survival rate was 68% versus 66%, and the median survival
period was 7.4 versus 7.2 years. However, a statistically significant
advantage was observed in the patients who received radiation in
terms of PFS (55% versus 35% at 5 years; median time to progression,
5.3 versus 3.4 years; P < .0001). The absence of any difference in
survival has supported the position of experts who advocate delaying
radiation. Conversely, persons favoring up-front radiation in the
treatment of low-grade gliomas have cited the improved PFS in the
irradiated group and the fact that at 1 year, seizures were better
controlled in patients in the radiation treatment arm.
These randomized trials confirmed the importance of certain
prognostic factors in low-grade gliomas. In the NCCTG trial, three
prognostic factors—histologic subtype, patient age, and tumor
size—were consistently associated with OS in multivariate analysis.148
The 5-year survival rates for patients with oligodendroglioma-
predominant tumors and those with astrocytomas were 74% and
56%, respectively (P = .0001); for patients younger than 40 years and
those aged 40 years or older, 5-year survival rates were 77% and 60%,
respectively (P = .025); and for preoperative tumor size less than 5 cm
and 5 cm or greater, 5-year survival rates were 81% and 61%,
respectively (P = .008). In the EORTC 22844 study, the extent of
resection had a great impact on OS; patients who had more than
90% of their tumor removed did much better than did those who
underwent a biopsy. Multivariate analysis of data from the two EORTC
trials confirmed that astrocytoma histologic characteristics, age older
than 40 years, and preoperative size greater than 6 cm all were unfavor-
able prognostic factors but also uncovered a few other factors, such
as tumor crossing the midline and the presence of neurologic deficits
before surgery.265
On the basis of these randomized trials, a reasonable management
strategy would be observation in a patient with a completely resected
low-grade glioma in patients younger than 40 years. However, many
investigators still advocate radiation after complete resection in patients
older than 40 years or after incomplete resection. The standard dose
is 54 Gy given in 1.8-Gy daily fractions over 6 weeks. It is common
to treat the MRI-defined GTV with a 1-cm margin. Additional
prognostic factors include IDH mutation status and 1p/19q deletions,
which have been reviewed previously.
Radiation Therapy for High-Grade Gliomas
The earliest randomized trial to demonstrate that radiation therapy
was beneficial in the treatment of high-grade gliomas was conducted
by the Brain Tumor Study Group (BTSG 69-01)266 (Table 63.6).
Patients were randomly assigned to one of four groups: supportive
care, whole-brain radiation therapy (WBRT), BCNU, or WBRT plus
BCNU. This trial clearly showed a benefit for radiation alone versus
934 Part III: Specific Malignancies

Table 63.5 Results of Treatment for Low-Grade Gliomas: Select Randomized Trials
Treatment No. of
Study Years Histologic Type Protocol Patients 5-Yr Survival (%) 5-Yr PFS (%)
Karim et al 263
1985–1991 9% A, grade 1 45 Gy 171 58, P = .94 47, P = .73
EORTC 22844 60% A, grade 2 59.4 Gy 172 59 50
22% O
9% mixed
van den Bent et al264 1986–1997 2% A, grade 1 Observation 157 66, P = .87 35, P < .0001
EORTC 22845 60% A, grade 2 54 Gy 154 68 55
25% O
10% mixed
Shaw et al148 1986–1994 32% A or mixed (A > O) 50.4 Gy 101 72, P = .48 55, P = .65
NCCTG 68% O or mixed (O > A) 64.8 Gy 102 65 52
Shaw et al719 1998–2002 See footnotea 54 Gy 126 63, P = .33 46, P = .06
RTOG 98-02 (randomized arms) 54 Gy + PCV 126 72 63

a
Results of this study are currently available only in abstract form. Histologic type was not available in the abstract.
A, Astrocytoma; EORTC, European Organisation for Research and Treatment of Cancer; NCCTG, North Central Cancer Treatment Group; O, oligodendroglioma; PCV,
procarbazine, cisplatin, vincristine; PFS, progression-free survival; RTOG, Radiation Therapy Oncology Group.

supportive care, with a median survival of 9 months versus 3.5 months
and a 1-year survival rate of 24% versus 3% (P = .001). On the basis
of this trial, radiation therapy has remained an essential component
in the treatment of high-grade gliomas. A second randomized trial
from the Scandinavian Glioblastoma Study Group confirmed the
efficacy of radiation with a lower dose of WBRT (45 Gy) compared
with supportive care267 (see Table 63.6).
The results from BTSG 69-01 and two successive BTSG studies
were pooled to examine dose response.268 The original studies were
all randomized, but patients were not randomly assigned to different
radiation doses, and thus the analysis of dose was retrospective. With
this caveat, the study showed a benefit to use of 60 Gy versus 50 Gy
(median survival, 10.5 versus 7 months; P = .004).
The current standard of care in Radiation Therapy Oncology Group
(RTOG) studies is to define the initial volume as the preoperative
lesion with edema as seen on T2-weighted MRI images with a 2-cm
margin. This volume is treated with 46 Gy, followed by a boost to
60 Gy to the gadolinium-enhancing lesion seen on T1-weighted images
with a 2.5-cm margin.
By pooling the results of three RTOG studies and using a non-
parametric recursive partitioning analysis (RPA), Curran and associates269
identified several significant prognostic factors for survival in patients
with high-grade gliomas: histologic type, KPS score, age, neurologic
function, and duration of symptoms. Patients could be placed into
groups I through VI with different outcomes on the basis of these
factors. Classes I and II, which are only found in the RPA for anaplastic
astrocytomas and not in the RPA classification for glioblastoma, have
the best outcomes, whereas classes V and VI have the worst outcomes.
The prognostic significance of the RPA classes was confirmed even
in the era of temozolomide treatment for glioblastoma (discussed in
the next section).270 These RPA classes have been updated to reflect
the more than 16,000 patients in the RTOG glioma database.271 The
new RPA classification simplified the original model by combining
classes V and VI for patients with glioblastoma, resulting in three
distinct prognostic groups for glioblastoma defined by age, performance
status, extent of resection, and neurologic function.
Because of the poor survival of patients with high-grade astrocy-
tomas, numerous strategies have been tried to improve the results
with irradiation. These efforts fall into two main classes: first, increasing
radiation dose, and second, modulating the radiation response. Doses
higher than 60 Gy have been used, but to no avail. The RTOG
74-01–ECOG 1374 trial randomized patients between receiving 60-Gy
WBRT and a total dose of 70 Gy (60-Gy WBRT followed by a 10-Gy
boost) but showed no improved survival with the additional dose (see
Table 63.6).272 Hyperfractionation also has been used to try to increase
the total dose. In the Brain Tumor Cooperative Group (BTCG) study
77-02, patients who were randomly assigned to receive hyperfractionated
WBRT with BCNU showed no difference in survival compared with
those who received conventional WBRT (60 Gy).273 In RTOG trial
90-06, patients were randomized to receive either 60 Gy in conventional
fractionation or 72 Gy in a hyperfractionated regimen (1.2 Gy twice
daily). No differences in survival were found between the two groups.274
Radioactive implants also have been used to increase dose locally
to the tumor bed. Single-institution data suggested improved outcome
with this approach compared with conventional radiotherapy.275 In
the BTCG 87-01 trial, patients were randomized to receive either an
iodine-125 (125I) seed implant (60 Gy) or no implant at surgery (see
Table 63.6). Thereafter, patients received 60 Gy via external beam
radiation. Remarkably, no survival benefit was found for use of 120 Gy
delivered with brachytherapy and external beam irradiation.276 Similarly,
a trial conducted at the Princess Margaret Hospital that combined
125
I implants with external beam radiation showed no improvement
with the implant.
An implantable balloon has been developed for the delivery of
brachytherapy (GliaSite). This device has traditionally used a liquid
form of 125I (Iotrex) as the source for brachytherapy. This device
provides brachytherapy directly to the resection cavity, with minimal
exposure of unaffected brain to the radiation source, and is used for
treatment of primary gliomas and metastatic tumors.
Another means of increasing dose to the tumor region after
conventional radiation therapy has been stereotactic radiotherapy. This
approach was tested in RTOG study 93-05, in which patients in the
control group received standard fractionated radiotherapy (60 Gy in
30 fractions) with BCNU chemotherapy, whereas patients in the
experimental group received a radiosurgery boost (16 to 24 Gy based
on size) before external beam radiation therapy. Results showed no
significant difference in 2- and 3-year survival rates or in patterns of
failure between the two arms of the study.277
The one agent that has clearly been shown to be of benefit when
combined with radiation is the alkylating agent temozolomide. The
results with this drug for treatment of glioblastomas are discussed in
depth in the next section.
Tumor-Treating Fields for Glioblastoma
It has been demonstrated that the use of tumor-treating fields, with
alternating electric fields applied to the scalp, confers a survival advantage
when performed in addition to standard maintenance temozolomide
 Cancer of the Central Nervous System • CHAPTER 63 935

Table 63.6 Results of Treatment for High-Grade Astrocytomas: Select Randomized Trials Focusing on
Radiation and Radiation Modifiers
Median 18-Mo
Gliomas Treatment No. of Survival Survival
Study Years (%) Protocol Patients (mo) (%) Comment(s)
Walker et al282 1969–1972 90 Supportive care 31 3.5 0 RT superior to supportive
BTSG 69-01 BCNU 51 4.6 4 care (P = .001)
RT (60 Gy WBRT) 68 9 4
RT (60 Gy WBRT) + 72 8.6 18 RT + BCNU superior to
BCNU supportive care (P = .001)
Kristiansen et al267 1974–1978 — Supportive care 38 5.2 0 RT superior to supportive
care
SGSG RT (45 Gy WBRT) 35 10.8 13
RT (45 Gy WBRT) + 45 10.8 13
Bleo
Bleehen and 1983–1988 — RT (45 Gy) 144 — 11 60 Gy superior to 45 Gy
Stenning720 RT (60 Gy) 299 — 18 (P = .04)
Chang et al272 1974–1979 80 RT (60 Gy WBRT) 148 9.9 19
RTOG 74-01 RT (60 Gy WBRT) + 105 8.4 22 No difference between any
10 Gy boost groups
RT (60 Gy WBRT) + 165 10.0 29 No improvement with 70 Gy
BCNU
RT (60 Gy WBRT) + 136 9.8 26
DTIC + MeCCNU
Curran et al269 RT (60 Gy) + BCNU 13.2 No improvement with HFX
RTOG 90–06 RT (72 Gy HFX) + 11.2 For patients <50 yr, median
BCNU survival better with standard
fractionation
Selker et al276 1987–1994 85 125
I implant (60 Gy) 137 17 56 No improvement with
(10% AA) + BCNU + RTa implant
(60.2 Gy)
BTCG 87–01 RTa (60.2 Gy) + 133 14.8 44
BCNU
Laperriere et al721 1986–1996 92 RT (50 Gy) + BCNU 69 13.2
PMH RT (50 Gy) + BCNU 71 13.8 No improvement with
+ 125I implant implant
(60 Gy)
Nelson et al722 1979–1983 83 RT + BCNU 146 12.4 34
RTOG 79–18 RT + Miso + BCNU 147 10.7 27 No improvement with
misonidazole
Prados et al723 1994–1997 0b RT (60 Gy) + PCV 134 — 74
RTOG 94–04 RT (60 Gy) + BUdR 134 — 62 No improvement with BUdR;
+ PCV closed early at interim
analysis
Souhami et al277 1994–2000 100 RT (60 Gy) + BCNU 186 (total in 14.1 22 (2 yr)
both arms)
RTOG 93–05 Radiosurgery 13.7 18 (2 yr) No improvement with
boost + RT (60 Gy) radiosurgery boost
+ BCNU
Stupp et al286 2000–2002 100 RT (60 Gy) 286 12.1 10.9 (2 yr)
EORTC NCIC RT (60 Gy) + 287 14.6 27.2 (2 yr) Combined therapy was
26981-22981/CE.3 concurrent and beneficial in all prognostic
adjuvant TMZ groups; methylation of
MGMT promoter was
greatest predictor for
benefit from TMZ

a
During the early part of the study, external beam radiation was given to whole brain to a dose of 43 Gy, followed by a boost to the tumor volume for an additional 17.2 Gy.
From May 1989, WBRT was dropped, and the entire dose was restricted to tumor volume.
b
All patients in this trial had AAs.
AA, Astrocytoma; BCNU, carmustine; Bleo, bleomycin; BTCG, Brain Tumor Cooperative Group; BUdR, bromodeoxyuridine; DTIC, dacarbazine; EORTC, European Organisation for
Research and Treatment of Cancer; HFX, hyperfractionation; 125I, iodine 125; MeCCNU, semustine; MGMT, O6-methylguanine-DNA methyltransferase; Miso, misonidazole; NCIC,
National Cancer Institute of Canada; PCV, procarbazine, cisplatin, vincristine; RT, radiation therapy; RTOG, Radiation Therapy Oncology Group; SGSG, Scandinavian Glioblastoma
Study Group; TMZ, temozolomide; WBRT, whole-brain radiation therapy.
936 Part III: Specific Malignancies

therapy compared with maintenance temozolomide therapy alone.278 In
this study, all patients had completed standard chemoradiation therapy.
PFS was 7.1 months in the tumor-treating fields plus temozolomide
group compared with 4.0 months in the temozolomide alone group.
Furthermore, median OS in the per-protocol population was 20.5
months in the tumor-treating fields plus temozolomide group versus
15.6 months in the temozolomide-alone group. The tumor-treating
fields approach uses electric fields applied to the scalp at 200-kHz
frequency with four transducer arrays. These fields are applied, after
the head has been shaved, with a device contacting the scalp for up
to 22 hours per day with 2 to 3 days off treatment per 4 weeks of
treatment. The mechanism of action of these tumor-treating fields
is believed to be due to disruption of mitosis through perturbation
of chromosome segregation.279,280 The nature of this mechanism has
been questioned with potential confounding factors for this survival
benefit. One criticism was the lack of placebo control; there was no
sham study group, that may have led to an adherence bias. Another
criticism was the observation that the tumor-treating fields group
received six cycles of adjuvant chemotherapy compared with four cycles
in the temozolomide-alone group before randomization, which may
also have confounded the results.281 Further follow-up and investigation
into the use of tumor-treating fields may provide insight into the
mechanisms by which prolonged PFS and OS are conferred.
Chemotherapy for Gliomas
Chemotherapy for Newly Diagnosed High-Grade
Astrocytomas
Although prior studies demonstrated efficacy for chemotherapeutic
agents such as carmustine282,283 and procarbazine, lomustine, and
vincristine (PCV),284 the introduction of temozolomide has dramatically
altered the treatment of high-grade gliomas and currently remains the
standard of care. Temozolomide is an oral alkylating agent whose
levels are not affected by AEDs or other hepatic enzyme–inducing
drugs. Toxicity with this drug is relatively mild, and CNS penetration
is good. The pivotal study conducted jointly by the EORTC (trial
22981-26981) and the National Cancer Institute of Canada (NCIC)
(trial CE.3) confirmed the usefulness of temozolomide and radiation
in newly diagnosed glioblastomas.285 This study randomized 573
patients to receive 60 Gy of standard fractionated radiation or the
same radiation regimen with daily temozolomide at 75 mg/m2 followed
by six cycles of adjuvant temozolomide (150–200 mg/m2 for 5 days
during each 28-day cycle). The patients in the radiation plus temo-
zolomide arm had a statistically significant improvement in median
survival compared with patients in the radiation-only arm (P < .001).
At follow-up evaluation at a median of 28 months, the median survival
periods in the two arms were 14.6 and 12.1 months, respectively. The
2-year OS rates were 26.5% and 10.4%, respectively. The Stupp
protocol (named after lead author Roger Stupp) of maximal safe
resection followed by radiotherapy plus concomitant and adjuvant
temozolomide currently remains the standard of care for glioblastoma
(Fig. 63.18). Evaluation of these patients confirmed the 5-year durable
survival benefit of the regimen (Fig. 63.19A).286
Hegi and coworkers287 subsequently evaluated the status of the
epigenetic silencing of the MGMT DNA repair gene (MGMT) by
promoter methylation in patients enrolled in this trial. In a subgroup
analysis of 206 patients, MGMT promoter methylation occurred in
45% of these cases and was found to be an independent favorable
prognostic factor regardless of treatment. OS of the methylated promoter
group was 46% at 2 years and 14% at 5 years (P < .001). Patients
with a methylated MGMT promoter had better survival than those
without such a promoter (see Fig. 63.19B). The median, 2-year, and
5-year survival rates for patients receiving radiation versus radiation
and temozolomide based on MGMT promoter methylation status
are shown in Table 63.7. Even among patients with unmethylated
MGMT, a trend toward increased survival is recognized for those
receiving temozolomide. These data have made irradiation plus adjuvant
temozolomide the standard of care for all patients with glioblastoma
regardless of MGMT status. The relative contributions of oral daily
temozolomide during radiation versus after radiation are not clear,
and the optimal dose of temozolomide to inhibit MGMT activity
has not been established and is the subject of ongoing trials. In the
current RTOG trial, patients with newly diagnosed glioblastoma are
randomized to receive standard chemoradiation therapy followed by
12 rather than 6 monthly cycles of adjuvant temozolomide at a standard
dosage, or, alternatively, dose-intensive temozolomide (21 days on
and 7 days off ). Newly diagnosed glioblastoma treated with radiation

4 weeks
TMZ daily ¥ 42d 5d 5d 5d ¥ 6 cycles
4 weeks

1 6 10 14 18 22 week

RT 30 ¥ 2 Gy

RT; focal radiotherapy, 60 Gy in 6 weeks to tumor volume + 2-3 cm margin

TMZ; Temozolomide
During RT: 75 mg/m2 daily (including weekends) for up to 49 days.
Administration 1-2 hours before RT or in a.m. on days without RT.
Antiemetics: metoclopramide, usually needed only before initial doses.
Maintenance: 150-200 mg/m2 daily ¥ 5, for up to 6 cycles
Antiemetic prophylaxis with 5-HT3 antagonist or metoclopramide

Pneumocystis carinii prophylaxis during continuous TMZ administration only (lymphocytopenia)

Pentamidine inhalations or trimethoprim/sulfamethoxazole 3¥/week

Figure 63.18 • Outline of Stupp protocol, which consists of surgical resection followed by regimen of concomitant chemotherapy and radiotherapy (RT)
followed by maintenance chemotherapy. TMZ, Temozolomide. (From Amouheidari A, et al. The nexus between interdisciplinary approach and extended
survival in CNS tumors. Neuro-Oncology Scientific Club [NOSC] meeting report, 27 December 2012, Isfahan, Iran. Res Cancer Tumor. 2013;2[1]:1–9.)
 Cancer of the Central Nervous System • CHAPTER 63 937

100
90 Combined
Radiotherapy
80
70 p < 0.0001

Survival (%)
60
50
40
30
20
10 n = 287
n = 286
0
0 1 2 3 4 5 6 7
A Time (years)
Number at risk
Combined 254 175 76 39 23 14 6
Radiotherapy 278 144 31 11 6 3 0

100
Figure 63.19 • Survival of patients with glioblastoma based 90 Combined
on temozolomide administration or MGMT status. Patients Radiotherapy
enrolled in the European Organisation for Research and Treat- 80
ment of Cancer trial 22981–26981 and National Cancer Institute
of Canada trial CE.3 were randomized to receive radiotherapy 70 p = 0.004
alone or radiotherapy plus temozolomide. (A) Kaplan-Meier
Survival (%)

60
estimates of overall survival according to treatment group. The
hazard ratio for death among patients who received temozolomide 50
compared with those who received radiotherapy alone was 0.63
(95% confidence interval [CI], 0.53–0.75; P < .0001). (B) In 40
a subset of the patients enrolled in the trial in (A) the methylation
status of the O6-methylguanine DNA methyltransferase (MGMT) 30
gene promoter was assessed. The curves in (B) represent Kaplan- 20
Meier estimates of overall survival according to MGMT promoter
methylation status. The difference in survival between patients 10 n = 46 n = 46
with a methylated MGMT promoter and those with an
unmethylated MGMT promoter was highly significant (hazard 0
ratio, 0.49 [95% CI, 0.32–0.76]; P = .001), indicating that the 0 1 2 3 4 5 6 7
MGMT promoter methylation status has prognostic value.
(Modified from Stupp R, Hegi ME, Mason WP, et al. Effects B Time (years)
of radiotherapy with concomitant and adjuvant temozolomide Number at risk
versus radiotherapy alone ion survival in glioblastoma in a Combined 37 35 22 11 6 2
randomized phase III study: 5-year analysis of the EORTC-NCIC Radiotherapy 43 30 11 3 1 0
trial. Lancet Oncol. 2009;10[5]:459–466.)

therapy and temozolomide is now the standard comparison arm for
phase II studies seeking novel effective agents.
Even though the cited data on temozolomide were generated
in patients with glioblastomas, many oncologists have extrapolated
these findings to anaplastic astrocytomas and have used this agent
concurrently with radiation in this setting. However, some experts have
questioned whether concomitant temozolomide should be considered
standard therapy in patients with anaplastic gliomas in the absence of
randomized data.
Chemotherapy for Recurrent High-Grade Astrocytomas
Patients with high-grade astrocytomas in whom initial therapy with
radiation and temozolomide fails to provide benefit are candidates
for participation in phase I or II trials. In patients for whom some
interval has elapsed between initial temozolomide therapy and failure
to respond, retreatment with low-dose daily temozolomide may be
tried. Any benefit from chemotherapy for recurrent disease (Fig. 63.20)
must be measured against the roughly 4- to 5-month median survival
after repeat surgical removal of recurrent high-grade astrocytic tumors.
An important recent observation is that MGMT promoter methylation
status can change between the first surgery and second surgery for
recurrence.287
Some patients with recurrent high-grade astrocytomas are offered
reresection with use of either GliaSite (balloon catheter with liquid
radiation source) or Gliadel (intracavitary biodegradable BCNU wafers).
A placebo-controlled multicenter study in 22 patients reported a median
survival of 31 weeks in patients receiving BCNU polymers, compared
with 23 weeks in the patients receiving placebo polymers.289 The use
of Gliadel is limited to patients who can have meaningful reresection
of tumors that are relatively well circumscribed, unilateral, and in
noneloquent brain locations—a situation not typical for a majority
of anaplastic astrocytic tumors.
938 Part III: Specific Malignancies

Table 63.7 Results of Treatment for Glioblastomas Stratified by MGMT Promoter Status: EORTC Trial
22981-26981 and NCIC Trial CE.3
MGMT PROMOTER STATUS/TREATMENTa
UNMETHYLATED (n = 114) METHYLATED (n = 92)
Radiation Only Chemoradiation Radiation Only Chemoradiation
(n = 54) (n = 60) (n = 46) (n = 46)
Median overall survival (mo) 11.8 12.7 15.3 21.7
2-yr survival (%) 1.8 14.8 23.9 48.9
(P = .06) (P = .007)
5-yr survival (%) 0 8.3 5.2 13.8

a
Either radiation therapy only or chemotherapy plus radiation therapy.
EORTC, European Organisation for Research and Treatment of Cancer; MGMT, O6-methylguanine DNA methyltransferase; NCIC, National Cancer Institute of Canada.
Modified from Hegi ME, Diserens AC, Gorlia T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352:997; and Stupp R, Mason
WP, Vanden Bent MJ, et al. Effects of radiation therapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma: 5-year analysis of the
EORTC-NCIC trial. Lancet Oncol. 2009;10(5):459–466.

Figure 63.20 • Recurrence just outside the repeat resection margin of a patient with a 5-year survival period after right frontal glioblastoma. Investigational
options at recurrence include dose-intensified temozolomide, CCNU monotherapy, carmustine wafers, stereotactic radiosurgery with or without bevacizumab,
bevacizumab plus a cytotoxic agent, or Novo TTF-100A. Bevacizumab monotherapy is approved for recurrent glioblastoma. Concern with localized treatment
derives from abnormal fluid-attenuated inversion recovery (left) and T1 with gadolinium (right) signal abnormality crossing the corpus callosum.

Nitrosourea (lomustine, carmustine) and carboplatin-based
chemotherapy are second line chemotherapeutics agents. Lomustine
has shown clinical activity as the control arm in several randomized
trials.290,291
Bevacizumab, a humanized monoclonal antibody to VEGF, received
US Food and Drug Administration (FDA) approval for recurrent
high-grade gliomas in 2009. The approval in the United States was
based on two clinical trials that demonstrated improved response rates
either with bevacizumab monotherapy or in combination with irino-
tecan in patients who had received chemoradiation and adjuvant
temozolomide.292,293 The safety and efficacy of SRS and adjuvant
bevacizumab have been studied in 63 patients whose median PFS was
5.2 months with adjuvant bevacizumab versus 2.1 months without
adjuvant bevacizumab. In 2014, a randomized prospective trial of
bevacizumab as a primary agent demonstrated no significant difference
in OS (15.7 versus 16.1 months); however, a difference was seen in
PFS (10.7 versus 7.3 months).294 Current studies are investigating the
role of bevacizumab for recurrent glioblastoma.
This PFS benefit may be confounded by the fact that bevacizumab
produces rapid and marked reduction in edema and contrast enhance-
ment because of changes to tumor vasculature. Although initial MRI
and clinical changes are often dramatic, durable responses average
only about 4 to 6 months. Discontinuing bevacizumab, a very expensive
drug, may result in rapid rebound of vasogenic edema, and careful
discussion with patients about when to introduce and when to dis-
continue the agent is necessary.295,296
Chemotherapy in Addition to Radiotherapy for
Low-Grade Astrocytomas
Chemotherapy for low-grade astrocytomas usually is reserved for
patients whose unresectable tumors are progressively symptomatic.
Radiation therapy traditionally has been used as a first-line treatment
for progression. Potential toxicity of any proposed therapy for low-grade
gliomas must be balanced against the long natural history. Particularly
in younger patients and in those whose tumors have an oligodendroglial

component, median survival periods may approach 10 years, with
5-year survival rates of 75% or higher.128 Quality-of-life considerations,
with particular attention to cognitive status, justify a prolonged “wait
and see” policy in asymptomatic or clinically stable patients with
suspected low-grade glioma.296
However, more aggressive treatment for low-grade gliomas has
become a new paradigm, and recent studies have investigated the role
of the addition of chemotherapy and radiation in the treatment of
low-grade glioma. In 2016 Buckner and colleagues reported that the
addition of chemotherapy (procarbazine, CCNU, and vincristine)
after radiation resulted in both longer PFS (51% versus 21%) and
OS (13.3 versus 7.8 years; P = .003) in patients with grade 2 glioma.297
The positive survival difference for patients receiving chemotherapy
in addition to radiation therapy became apparent only after several
years of follow-up. In this study, patients younger than 40 years had
undergone subtotal tumor resection, whereas patients older than 40
had undergone either biopsy or resection of any of the tumor. Some
of the limitations of this study included the fact that molecular
diagnostic evaluation for mutations such as IDH1 was limited to a
small portion of the patients studied, thus limiting the assessment of
these molecular markers on outcome.
Currently, Baumert and colleagues are investigating the role of
temozolomide as adjuvant therapy for low-grade gliomas.298 At 48
months, no significant difference in survival has been detected. However,
given the known long natural history of low-grade gliomas, differences
may be detected with prolonged follow-up.
Chemotherapy for Low-Grade Oligodendrogliomas
and Oligoastrocytomas
Temozolomide has been used in patients with low-grade oligoden-
drogliomas or oligoastrocytomas that have recurred. The EORTC
conducted one study using temozolomide for patients who had received
PCV chemotherapy and irradiation for their initial disease,299 and
another study for patients who had received surgery and irradiation
without chemotherapy initially.300 These studies showed response rates
to temozolomide of 25% to 53%. Loss of 1p has been correlated with
response to temozolomide for first-line chemotherapy in patients with
recurrent oligodendrogliomas.301,302
Chemotherapy for Newly Diagnosed Anaplastic
Oligodendrogliomas
During the past decade, increasing evidence has accumulated to confirm
that anaplastic oligodendrogliomas are special types of malignant
gliomas that are sensitive to chemotherapy. Although the molecular
markers of chemosensitivity, allelic loss of 1p and 19q, have been
shown to have prognostic significance, the reason for oligodendroglial
chemosensitivity remains unknown.
In the first large study of chemotherapy for new or recurrent
anaplastic oligodendrogliomas, Cairncross and the NCIC conducted
a multicenter phase II trial of intensive PCV chemotherapy using
higher doses of the first two drugs than are found in the standard
PCV regimen.303 This study reported a 75% overall response rate,
with 38% complete responses. Time to tumor progression was at least
16.3 months for the entire eligible group and at least 25.2 months
for patients who had a complete response.
Two randomized trials have been conducted comparing radiation
only with radiation plus PCV chemotherapy in patients with newly
diagnosed anaplastic oligodendrogliomas or anaplastic oligoastrocy-
tomas.304,305 In RTOG 9402, patients were randomized to receive
radiation only or up to four cycles of intensive PCV chemotherapy
followed by radiation.305 In EORTC 26951, patients were randomized
to receive radiation only or radiation followed by six cycles of standard
PCV chemotherapy.304 Long-term follow-up has confirmed an OS
advantage with the addition of PCV. At a median follow-up of 140
months, EORTC 26951 showed that the addition of PCV increased
Cancer of the Central Nervous System • CHAPTER 63 939
OS from 30.6 months to 42.3 months.304 Subgroup analysis by 1p/19q
status showed that benefit of PCV may be greater in patients with
codeleted tumors, which is now a diagnostic criterion for oligoden-
droglioma. Similarly, patients with MGMT promoter methylation
and IDH-mutated tumors had better OS.306
The PCV regimen has significant toxicity including myelosup-
pression, cognitive or mood change, neuropathy, vomiting, hepatic
dysfunction, and allergic rash. Because temozolomide is also effective
for anaplastic oligodendrogliomas and it has a more favorable toxicity
profile, oncologists may elect to treat anaplastic oligodendrogliomas
with this drug. In spite of a lack of randomized data with temozolomide
in anaplastic oligodendrogliomas, many oncologists are currently using
this drug concomitantly with radiation, extrapolating from the experi-
ence with glioblastoma.285
Chemotherapy for Recurrent Anaplastic Oligodendroglioma
Most patients with recurrent anaplastic oligodendrogliomas who received
PCV at initial presentation are currently being treated with temo-
zolomide at relapse. Several small trials have shown the safety and
efficacy of temozolomide after prior PCV therapy. An open-label
phase II trial of temozolomide in 47 patients with anaplastic oligo-
dendroglioma or anaplastic oligoastrocytoma who experienced a relapse
after radiation and PCV chemotherapy demonstrated an objective
response rate of 43%, a median PFS of 7.5 months, and a 34% rate
of disease-free survival at 12 months.307 In another phase II multicenter
trial that included patients with anaplastic oligodendroglioma or
anaplastic oligoastrocytoma, a response was seen in 26% of patients
who had previously received PCV therapy and in two out of three
chemotherapy-naïve patients.308 A short time to tumor progression
appears to be a bad prognostic factor for response to both first-line
PCV chemotherapy and temozolomide.
In a study performed before the reclassification of oligodendro-
glioma, Brandes and associates309 reported on 67 patients with recurrent
anaplastic oligodendroglioma or anaplastic oligoastrocytoma who were
treated with first-time temozolomide at the time of disease progression
after prior surgery and radiotherapy. The overall response rate was
46% and was higher in patients with anaplastic oligodendroglioma
than in patients with anaplastic oligoastrocytoma (62% versus 25%;
P = .003). Combined 1p and 19q loss (present in 48% of patients)
significantly correlated with response rate (P = .04), time to progression
(P = .003), and OS (P = .0001).
Therapy for Elderly Patients With Malignant Gliomas
Almost half of patients with glioblastoma are older than 65 years, and
the incidence for all primary CNS tumors is highest among those
aged 75 to 84 years, whereas clinical trial participants have a median
age between 50 and 55 years.310 Elderly patients with malignant gliomas
have approximately 6-month median survival rates, which is consider-
ably shorter than those of younger patients. Brandes and coworkers311
evaluated the role of surgery, radiation therapy, and chemotherapy
for the treatment of newly diagnosed glioblastoma in patients older
than 65 years. These investigators found that the main predictive
factor in evaluating this treatment was perioperative KPS score. The
higher the KPS score, the better the patient fared, regardless of the
treatment. Patients were stratified into group A (surgery with radiation
therapy to a dose of 59.4 Gy), group B (surgery, radiation therapy,
and PCV chemotherapy), and group C (surgery, radiation therapy,
and temozolomide). The median time to disease progression was
significantly better in group C patients. OS was better in group C
but did not reach statistical significance. Hematologic toxicity was
higher in patients treated with a PCV regimen than in those treated
with temozolomide.
Another study evaluated the role of debulking craniotomy versus
stereotactic biopsy in the treatment of malignant gliomas in patients
older than 65 years; median survival was 171 days after craniotomy
versus 85 days after biopsy.312 The difference was not statistically
940 Part III: Specific Malignancies
significant but did suggest that patients undergoing a more aggressive
craniotomy survived longer. Both groups of patients tolerated the
radiation therapy well. A trial of 85 patients older than 70 years random-
ized participants to radiation therapy (25 fractions of 1.8 Gy) or best
supportive care alone and demonstrated improved survival with radiation
therapy (median survival of 6.8 versus 4.0 months).313 Two randomized
phase III trials compared temozolomide alone with radiation therapy
alone in older patients with glioblastoma. The Nordic Glioma Trial
found similar efficacy of temozolomide alone compared with radiation
alone, whereas the German Neuro-Oncology Working Party NOA-08
trial found that radiation therapy alone was superior to dose-intensified
temozolomide.314,315 Iwamoto and colleagues316 reviewed the Memorial
Sloan-Kettering experience in 394 patients older than 65 years, about
one-third of whom received adjuvant temozolomide after radiation
therapy, and they reported improved survival with adjuvant chemo-
therapy compared with radiation alone.
On the basis of these results, it appears that patients older than
65 years who have malignant gliomas may still benefit from aggressive
therapy if they have a reasonable performance status. Therefore older
age alone should not be a criterion for minimizing therapy. An
abbreviated radiotherapy regimen may be considered in older patients
with a poor performance status. Roa and associates317 randomized
patients with glioblastoma who were older than age 60 years to receive
a standard course of radiation (60 Gy in 30 fractions over 6 weeks)
or a shorter course (40 Gy in 15 fractions over 3 weeks). OS times
measured from randomization were similar at 5.1 months for standard
radiation therapy versus 5.6 months for the shorter course (P = .57).
The survival probabilities at 6 months were also similar, at 44.7% for
standard radiation therapy versus 41.7% for the shorter course. The
ongoing NCIC/EORTC 26062-22061 trial for patients with glio-
blastoma who are older than 65 years randomizes patients to either
short-course radiotherapy (40 Gy in 15 fractions) or temozolomide
concurrent with and adjuvant to the same radiotherapy regimen.318
Quality of Life After Therapy for Gliomas
Quality-of-life issues are paramount in the treatment of patients with
gliomas. The oncologist’s obligation to disclose prognosis and consider
palliative care choices occurs very early in the course of a patient’s
illness, and in patients with glioblastoma who have anticipated survival
that is usually less than 2 years, medical decision-making capacity
may be impaired very early on.319 A survey of patients and caregivers
on the experience of being diagnosed with high-grade glioma empha-
sized that in the setting of the initial diagnosis, detailed discussion of
diagnosis and prognosis must be carefully balanced with appreciation
for the emotional state of those concerned.320 As treatment progresses,
adverse effects of both disease and its therapy mount. An analysis of
quality of life was performed in patients participating in an EORTC
trial of randomization to either 59.4 or 45 Gy for low-grade gliomas.263
This analysis found that patients receiving the higher dose reported
more fatigue and insomnia immediately after radiotherapy and poorer
emotional functioning 7 to 15 months after institution of therapy.321
Some of the long-term consequences of radiation therapy as appreciated
at MRI may include diffuse white matter hyperintensities and brain
atrophy correlating with cognitive dysfunction, along with cavernous
angiomata.
The EORTC and NCIC performed a quality-of-life study as part
of a randomized trial of radiation versus radiation plus temozolomide
for patients with glioblastoma.322 The study investigators found that
health-related quality-of-life measures (e.g., fatigue, overall health,
social function, emotional function, future uncertainty, insomnia, and
communication deficit) did not deteriorate by a clinically meaningful
amount in either treatment group over time after treatment, and some
parameters even improved. Furthermore, the addition of the temo-
zolomide regimen to radiotherapy did not negatively affect health-related
quality of life. Notwithstanding these results, patients with malignant
gliomas face enormous stresses. They face the same physical, emotional,
and financial burdens of dealing with a terminal disease as patients
with breast cancer, lung cancer, and other malignancies, but they have
unique perspectives in that they are uniformly concerned about the
potential for damage to the brain and the effect of cognitive function.
Measurement of quality of life is important to elucidate the impact
of available treatments on the disease: The goal is to improve survival,
but not at the sacrifice of quality of life.323 The most frequent symptoms
in the last month of life are headache, lethargy, depression, dysphagia,
delirium, and seizures. Indications for artificial nutrition and parenteral
administration of drugs may require consideration. End-of-life prefer-
ences should be discussed early in the disease process with a goal
toward meeting patient preferences of palliative in-home care or
acceptable alternatives. In one Italian study, 82% of patients were
able to be at home with good symptom control through a multidis-
ciplinary home care unit.324
New Approaches to Therapy of Gliomas
The disappointing results with conventional cytotoxic chemotherapy
have led to efforts to find more effective and better-tolerated therapies.
The challenge of neurooncology is to develop new compounds or
procedures of gene transfer that specifically target the molecular altera-
tions of glioma tumor cells and restore normal gene expression, cell
cycle regulation, and apoptosis.325 Significant progress is likely to come
from technologic developments that allow large-scale genomic profiling
that distinguishes at the molecular level among histologically similar
tumors. Therapeutic strategies then could include some combination
of cytotoxic chemotherapy with biologic agents directed at genetic
alterations specific to brain tumors of the appropriate subtype. Current
pathways of interest include receptor tyrosine kinases (RTKs) EGFR,
PDGFR, and VEGFR, in addition to downstream effectors mammalian
target of rapamycin (mTOR), Akt, and MAPK. A number of agents
targeting the EGFR receptor and the EGFRvIII variant are being tested.
These EGFR-targeted agents have thus far shown limited usefulness
with brain tumors in the clinic and are effective only in patients with
tumors that have a susceptible target.326 In one study, patients who
had received treatment with gefitinib or erlotinib were analyzed for
expression of EGFR, the deletion mutant EGFRvIII, and the tumor
suppressor gene PTEN. Tumors that coexpressed EGFRvIII and PTEN
were most likely to respond to EGFR kinase inhibitors.327
RTKs such as PDGF and insulin-like growth factor receptors
regulate cell proliferation and differentiation. Deregulated RTK signaling
frequently is found in human astrocytic tumors. In addition, gefitinib
and erlotinib, mentioned earlier, and other inhibitors of RTKs, including
imatinib mesylate, have been evaluated in patients with malignant
glioma. Other agents target farnesyl transferase, histone deacetylase,
rapamycin (mTOR), protein kinase C, and the ubiquitin-proteosome
pathway. In general, the findings of small early trials have been disap-
pointing, although the agents were well tolerated. Most are metabolized
through the cytochrome P450-CYP3A4 system, and significant dose
modifications are necessary in patients with brain tumors who are
taking enzyme-inducing AEDs. Tumor resistance may in part be due
to cancer stem cells. Cancer stem cells are characterized by the ability
to self-renew and propagate tumor, and they use many of the same
signaling pathways found in normal stem cells such as Wnt, Notch,
and Hedgehog.328,329 Integrins, which are transmembrane surface
proteins that affect several pathways relevant to glioblastoma, promote
proliferation, motility, and angiogenesis and represent another potential
target for brain tumor therapy. Currently in development are several
antiintegrins, of which the best studied is cilengitide, an oral agent
that has been evaluated in several completed trials in patients with
recurrent glioblastoma; little toxicity and several durable responses
occurred, leading to a phase III trial of cilengitide for newly diagnosed
glioblastoma.330 Median survival was 19.7 months overall and 30
months in patients with MGMT promoter methylation. The 2-year
survival of 41% exceeded the 27% milestone of the EORTC temo-
zolomide trial.331

Because gliomas produce specific angiogenic peptides such as VEGF
(see the molecular genetics section earlier in this chapter) to stimulate
new blood vessel formation, angiogenesis inhibitors are a logical drug
development target. Hypoxic areas within gliomas may stimulate
angiogenesis and promote invasiveness of glial cells. Many of these
changes in gene expression are mediated by HIF-1. Antiangiogenic
agents directed against VEGF, VEGFR, and other targets are in clinical
trials. Bevacizumab, a humanized monoclonal antibody against VEGF,
showed a 63% radiologic response rate in patients with recurrent
high-grade gliomas.332
The transfer of genetic material to tumor cells to make them more
susceptible to chemotherapy, or to reverse the alterations that sustain
the neoplastic phenotype, has been studied in several centers. Gene
therapy strategies include transfecting antioncogenes or drug-activating
enzymes to glioma cells. The most extensively studied system is the
“suicide gene therapy” in which the herpes simplex virus thymidine
kinase (HSV-tk) gene is inserted into a replication defective murine
retrovirus. Clinical studies using this approach have been disappointing
because of poor tumor cell transfection efficiency, although some long
times to tumor progression have been reported.333–335 A prospective
controlled trial in patients with newly diagnosed glioblastoma showed
no improvement in survival or time to tumor progression when
intraoperative HSV-tk therapy and standard radiation therapy were
compared with surgery and irradiation alone.336 Adenoviral and
adeno-associated viral vector genes are also being studied.
Another strategy involves drugs that inhibit autophagy, such as
hydroxychloroquine, which in a single-institution phase II trial resulted
in more than doubling of overall median survival when added to
conventional therapy.337 Biologic response modifiers that stimulate or
restore the immune system include monoclonal antibodies, interferons,
and ILs. Inhibitors of TGF-β2, a cytokine that promotes invasion and
angiogenesis, have been shown to inhibit glioma growth in vitro.338
Finally, therapeutic targeting of other glioma cell surface receptors
such as IL-13Rα2 or death receptor DR5 have shown promise in
in vitro and preclinical studies.339–341 Because of the heterogeneity
of malignant glial tumors, treatment strategies probably will require
synergistic combinations of cytotoxic agents and noncytotoxic
specific molecular methods, with the hope that genetic profiling
eventually will help pinpoint appropriate choices for individual
patients.
More recently, treatments directed at immune modulation have
become a promising new line of therapy. These include new approaches
to immune modulation such as vaccines directed at different cell
surface receptors such as EGFRvIII based on chimeric antigens and
dendritic cell vaccines.342 Other work has targeted immune modulators
such as IL-13.343,344 Furthermore, current research is ongoing into
immune checkpoint inhibition in many cancers, including glioblastoma,
using antibodies directed at the PD-1/PD-L1 axis.345,346
Adult Brainstem Gliomas
As discussed previously, brainstem gliomas are much less common in
adults than in children; they account for less than 2% of all adult
brain tumors.347 In one study of 48 adults with brainstem gliomas,
the overall median survival period was 5.4 years, and the 3-year survival
rate was 66%.348 The study investigators categorized them into three
different groups. The most frequent type (in 48% of cases) occurred
in young adults and resembled the diffuse pontine glioma of childhood
in terms of clinical and radiologic presentation. The overall outcome
(median survival of 7.3 years) was much better than that for pediatric
diffuse pontine gliomas, however, perhaps because in adults many of
these tumors were low-grade gliomas (in 9 of 11 patients who underwent
biopsy, the tumor was found to have benign histologic features). The
other common tumor type (in 31%), which occurred in elderly patients,
showed ringlike contrast enhancement and was associated with a median
survival period of only 11 months. Tumors in this category that were
biopsied were found to be high-grade gliomas. The third group (8%)
Cancer of the Central Nervous System • CHAPTER 63 941
consisted of focal tectal gliomas, which affected young adults and had
a favorable outcome.
The conclusion that adults with this disease have a better prognosis
than do children also was reached in a study from the Memorial
Sloan-Kettering Cancer Center of 19 adult patients with brainstem
gliomas. The investigators found that the median survival period was
54 months and the 5-year survival rate was 45%.349
PRIMARY CENTRAL NERVOUS SYSTEM
LYMPHOMA
Histopathologic Features
PCNSL has been known previously by many other names, including
reticulum cell sarcoma, diffuse histiocytic lymphoma, and microglioma.
Ninety percent of non–HIV-associated PCNSLs are diffuse large B-cell
lymphomas, with 10% distributed among low-grade, Burkitt, or T-cell
lymphomas, the last of which represent 1% of all PCNSLs but are
more common in Japan. PCNSL arises from late-germinal center
or postgerminal center lymphocytes, and CNS tropism is not fully
understood.350 Tumor cells express pan–B-cell markers including CD19,
CD20, and CD79a, and many also express BCL6 and MUM1.351
A frequent finding is perivascular clusters of lymphocytes, and T-
lymphocyte infiltrates are common in immunocompetent patients.
Although the Epstein-Barr virus genome has been found in HIV-
infected patients with PCNSL, no consistent confirmation of viral
etiology of PCNSL has been possible among immunocompetent
patients. Unique molecular features distinguish PCNSL from systemic
lymphoma. ECM-related genes are upregulated in PCNSLs, as are X-box
binding protein 1 and STAT6, genes associated with the B-cell growth
factor IL-4.352
Tumor Biology
PCNSL arises in the brain leptomeninges, spinal cord, or eyes and
rarely spreads outside the CNS. Its predilection for the periventricular
white matter gives rise to the characteristic neuroimaging appearance
of a hyperdense mass on unenhanced CT or a hypointense appearance
on long TR-weighted MRI. More than 50% of immunocompetent
patients have a solitary enhancing mass lesion at presentation. After
administration of contrast material, most bulky masses of PCNSL
enhance, most often homogeneously but occasionally in a ringlike
pattern, particularly in immunocompromised patients (Fig. 63.21).
Because of the hypercellularity of PCNSL, diffusion-weighted restriction
with hypointensity on apparent diffusion coefficient maps may be
seen.353 PCNSLs, however, are likely to be diffusely infiltrative even
at the time of presentation. These areas of disease are not visible
on neuroimaging studies because they are behind a relatively intact
blood-brain barrier. When postmortem findings are compared with find-
ings on MRI performed shortly before death, widespread microscopic
infiltration is seen in areas that appear normal on the MRI scan.354
Therefore PCNSL can be classified as stage 1E disease and should
be considered for treatment purposes to be a whole-brain disease.
Until the 1980s, PCNSL was considered a rare tumor, accounting
for approximately 2% of CNS malignancies in immunocompetent
patients and 1% to 2% of all lymphomas.355 The demographics of
the disease have changed, however, both among immunocompetent
patients and among those with HIV infection and organ transplant
recipients. The incidence of PCNSL among immunocompetent persons
had increased 25-fold to 51 cases per 10 million by 2000. Among
immunocompetent patients with PCNSL, median age at diagnosis is
55 years, and males outnumber females by 2 to 1. Among patients
with acquired immunodeficiency syndrome (AIDS), the median age
is 35 years, and 95% of HIV-infected patients with PCNSL are male.356
Among organ transplant recipients, the peak incidence of PCNSL is
at 6 months after transplantation, a period much shorter than in the
precyclosporine transplantation era.
942 Part III: Specific Malignancies
A B
C D
E F
Recent data from the SEER program show an overall decline in
total PCNSL incidence rates, from a peak of 102 per million in 1995
to 51 in 1998, a decrease largely attributable to decline in the disease
in men younger than 59 years. The annual rate among patients older
than 60 years has remained unchanged since 1994.357 The decline in
the younger male population with PCNSL reflects the advent of
effective antiretroviral therapy and a declining incidence of PCNSL
in the HIV-infected population.358 PCNSL should be distinguished
from secondary spread of systemic lymphoma. In 2% to 5% of
immunocompetent patients with aggressive diffuse B-cell lymphoma,
CNS involvement is present at diagnosis or at disease progression or
relapse.359 This chapter discusses PCNSL and its treatment in the
immunocompetent population.
Figure 63.21 • Central nervous system lymphoma seen on
magnetic resonance images. (A) A T1-weighted postgadolinium
axial image shows a homogeneously enhancing frontal mass compress-
ing the ventricles. (B) A corresponding fluid-attenuated inversion
recovery (FLAIR) image shows extensive peritumoral edema. The
appearance of primary central nervous system lymphoma (PCNSL)
in immunocompromised patients may differ from that in immu-
nocompetent patients. (C and E) T1-weighted postgadolinium
imaging and (D and F) FLAIR imaging of PCNSL in human
immunodeficiency virus–positive patients. Ring enhancement is
shown in (C), and a more diffuse encephalitic pattern appears in
(E). The differential diagnosis in immunocompromised hosts should
include toxoplasmosis.
Clinical Diagnosis and Staging
Clinical presentation is variable, perhaps accounting for the 3-month
diagnostic delay in immunocompetent patients who are eventually
diagnosed with PCNSL.360 The most common presenting pattern is
progressive focal symptoms. Less commonly, progressive cognitive
decline without focal symptoms leads to the diagnosis. Several variant
clinical presentations are possible in the immunocompetent population:
primary ocular, meningeal (although isolated meningeal involvement
is more common in secondary CNS lymphoma), or relapsing-remitting
disease. Rare syndromes include intravascular malignant lymphomatosis
with strokelike onset and neurolymphomatosis with both peripheral
and CNS involvement. Considerations in the differential diagnosis

A B
Figure 63.22 • Central nervous system lymphoma: histologic features. (A) High-grade B-cell lymphoma with dense perivascular lymphocytic cuffing
(hematoxylin and eosin staining). (B) Dense staining with CD20 (a B-cell marker) in the same specimen as in (A).
for PCNSL include high-grade glial tumor, CNS metastases, neuro-
sarcoidosis, and tumefactive multiple sclerosis. Spinal cord PCNSL
is very rare. Ocular lymphoma may be the first manifestation of the
disease or its relapse. Patients with ocular lymphoma have a 50% to
80% chance of developing cerebral lymphoma.
Initial evaluation of patients with suspected PCNSL should include
a thorough physical examination to exclude possible extraneural sources
of lymphoma. Neurologic evaluation is directed at clarification of the
extent of CNS disease and confirmation that disease is solely in the
CNS. Although extra-CNS disease is uncommon, one study has
suggested that whole-body PET-CT localized systemic lymphoma in
11% of patients who were thought to have PCNSL.361 The International
PCNSL Collaborative Group has established guidelines for the
diagnostic evaluation of possible PCNSL. Clinical studies include
dilated eye examination with slit lamp evaluation, recording of
prognostic factors (age and performance status), and cognitive function
(MMSE). Laboratory studies include HIV serology, serum lactate
dehydrogenase level, CSF cytology, flow cytometry, and immuno-
globulin heavy-chain polymerase chain reaction (PCR) with 24-hour
urine collection for creatinine clearance in persons who will be treated
with high-dose methotrexate. Imaging studies include contrast-enhanced
cranial MRI; CT of the chest, abdomen, and pelvis; testicular ultra-
sonography; and possibly bone marrow biopsy.362
Some patients will be able to avoid brain biopsy for diagnosis by
either vitrectomy or CSF cytologic confirmation of PCNSL. Oph-
thalmologic consultation for slit lamp examination is a critical part
of the workup, because up to 10% to 15% of patients with PCNSL
will have vitreous involvement at the time of diagnosis, and half of
these will have no visual symptoms. Lumbar puncture should be
performed if it is not contraindicated because of the intracranial mass
location(s) with glucose and protein determinations, cell count,
cytomorphology, and flow cytometry. Flow cytometry has improved
detection rates from 6% to 22% in recent studies, although most
studies have involved patients with newly diagnosed aggressive B-cell
systemic lymphoma who are at risk for CNS disease.363 The advent
of molecular diagnosis of PCNSL through the demonstration of
monoclonality by amplification of the rearranged IgH genes by PCR
to the CDR-III region raises the possibility of definitive diagnosis,
even with few cells present in the CSF.364 In several cases, however,
the PCR analysis was negative even when conventional cytologic
findings were suggestive of malignancy. In another study, monoclonal
patterns in the CSF were found in 77% of biopsy-proved cases, with
no false-positive findings among control subjects.365 Examination of
Cancer of the Central Nervous System • CHAPTER 63 943
CSF for free kappa (κ) and lambda (λ) light chains is a potentially
useful technique. In one study, 52% of patients with PCNSL had
markedly increased free κ and λ light chain ratios.366 Investigational
use of microRNA detection in the CSF determined by real-time
PCR has helped to distinguish lymphoma from inflammatory CNS
disease.367,368
When the foregoing procedures fail to confirm the diagnosis, the
surgical procedure of choice is a stereotactic brain biopsy. Aggressive
surgical resection does not improve survival and may cause deterioration
because of the deep location of many PCNSLs. It is most important
to try to withhold corticosteroids from patients during initial evaluation
and surgical confirmation. Corticosteroids repair the blood-brain barrier
and also have a direct cytolytic effect on B-cell lymphomas. Although
the patient’s clinical symptoms may abate with early institution of
corticosteroids, with frequent nearly complete resolution of MRI-
enhancing abnormalities, diagnosis will be compromised, and
corticosteroids will have to be withdrawn in order to proceed with
definitive biopsy confirmation. However, a Mayo Clinic series found
that the majority of patients did not experience significant radiographic
change or require a second biopsy for diagnosis when corticosteroids
were used preoperatively, particularly if contrast enhancement persisted
after administration of corticosteroids.369 The findings of one study
suggest that initial marked diminution in MRI abnormalities in response
to glucocorticoids is a favorable prognostic parameter, with 117-month
survival in responders versus 5.5 months in those whose scans did
not change after administration of glucocorticoids.370
Recent interest has focused on immunohistochemical definition
of morphologic markers of prognostic significance on the biopsy
material (Fig. 63.22). Braaten and colleagues371 studied the expression
of BCL-6 antigen in persons with PCNSL and found that the presence
of this antigen predicted a median survival of 101 months, compared
with 14.7 months in patients without this marker. Other groups of
investigators, however, have found that the marker correlates with a
negative prognosis, and thus clinical decisions cannot be made on the
basis of early immunohistochemistry studies.372
Treatment
PCNSL is an aggressive disease for which median survival in immu-
nocompetent patients is only 3 months without treatment. Increasing
age and poor performance status are important negative prognostic
variables. A recently proposed scoring system divides patients into
three groups: (1) age younger than 50 years with KPS score above
944 Part III: Specific Malignancies
70; (2) age older than 50 years with KPS score above 70; and (3) age
older than 50 years with KPS score below 70.373 The goal of treatment
is to eradicate both contrast-enhancing mass lesions and microscopic
infiltration of brain, spine, leptomeninges, and vitreous. Treatment
must be designed to maximize efficacy but also to minimize toxicity
to the brain. Optimal treatment has not been established. The reason
for the lack of standardized treatment protocols is the relatively small
number of patients and the absence of a phase III randomized trial.374
In the past 15 years, however, steady increases in median survival have
been achieved in patients with PCNSL. Five-year survival rates on
the order of 40% are now being reported, with median survival periods
of 3 to 4 years.
Radiation treatment alone led to a median survival of 18 months in
early clinical trials, with 5-year survival rates of only 3% to 4%.375,376
Chemotherapy was first used as an adjunct to radiation therapy. Twelve
studies including more than 450 patients have established the efficacy
of multiple chemotherapeutic regimens. Initially, most were used
along with or after a course of WBRT. Extension of median survival
periods for up to 4 years with combined regimens was achieved in
the mid-1990s. DeAngelis and colleagues reported a 58% complete
response rate, with an additional 36% rate of partial responses and
progression-free median survival for 24 months.377 A worse prognosis
was associated with age older than 60 years (survival for 50.4 months
versus 21.8 months). With improved survival, however, severe delayed
neural toxicity developed in increasing numbers of patients. At 18
months, 15% to 50% of patients who had received combined radia-
tion therapy and chemotherapy were found to have extensive white
matter abnormalities, with consequent severe cognitive decline.378–381
This complication typically begins from 4 months to several years
after treatment.378 Recognition of the serious sequelae of combined
radiation therapy and chemotherapy led to attempts to provide
chemotherapy as the sole modality for treatment of newly diagnosed
PCNSL. Initial response rates to chemotherapy vary from 50% to
100%, with duration of response between 12 and 44 months. Typical
of the successes of many clinical trials are the results of Cher and
colleagues,382 who reported complete responses in 17 of 19 patients
receiving methotrexate alone, with an event-free median survival period
of 32 months and OS period of 53 months. Since that publication,
others have confirmed both the efficacy of methotrexate-based regimens
without radiation therapy and the long-term favorable cognitive
outcome.383 Therapeutic levels of methotrexate can be achieved in
the CSF after intravenous drug administration, making it possible to
achieve clearance of malignant cells from the CSF without intrathecal
administration.384
Attempts to improve on the results of methotrexate have included
a variety of other multidrug chemotherapy regimens. Standard regimens
effective in the treatment of comparable systemic non-Hodgkin
lymphomas (cyclophosphamide, hydroxydaunorubicin, Oncovin,
and prednisolone [CHOP]; Cytoxan, hydroxydaunorubicin, Oncovin,
and Decadron [CHOD]; or methotrexate, leucovorin, Adriamycin,
cyclophosphamide, Oncovin, prednisone, and bleomycin [MACOP-B])
are not effective for PCNSL. Attempts to disrupt the blood-brain
barrier with hyperosmolar intraarterial mannitol do not provide
additional survival benefit beyond that achieved with intravenous
methotrexate-based regimens.385
Many neuro-oncologists have therefore concluded that high-dose
methotrexate should be offered to all patients as the first-line agent
for treatment of PCNSL.386 However, dissenting opinions exist that
have been discussed in detail elsewhere.387 The role of radiation therapy
was investigated in the first large, randomized phase III trial completed
in persons with PCNSL. Omitting WBRT decreased PFS but not
OS in persons with PCNSL.388 The study provides the evidence base
for the current trend to reserve WBRT for disease recurrence. However,
a study reporting outcomes of a chemotherapy-only regimen in young
patients found reduced PFS in comparison with historical control
subjects treated with combined WBRT and chemotherapy, although
OS was similar. The authors questioned whether a more aggressive
up-front combined modality approach in younger patients could lead
to higher cure rates.389
Most centers currently base their therapy on methotrexate
regimens. Long-term follow-up of patients who achieved durable
remissions for more than 1 year suggests that chemotherapy alone
is associated with a low risk of neurotoxicity even in elderly persons,
although MRI may show significant areas of clinically asymptomatic
leukoencephalopathy.390–394 The neuropsychologic outcome after
chemotherapy alone for PCNSL is quite good, whereas increasing
numbers of studies document progressive dementia, sometimes with
gadolinium-enhancing lesions on MRI, as early as several months after
combined-modality treatment.381,395,396 Autopsy studies have confirmed
not only widespread “pan-brain” infiltrative lymphoma but also extensive
vascular changes and leukoencephalopathy in patients who received
radiation with or without chemotherapy.397
The following recommendations apply to immunocompetent
patients only. The goal of treatment is to achieve a complete response
while avoiding irradiation of normal brain. Patients with AIDS-related
PCNSL require individualized treatment based on their immune status
and presence of concurrent infections.398 Transplant recipients similarly
require an initial attempt at reducing immunosuppression, and their
treatment must also be tailored to the extent of organ dysfunction
due to the primary disease process and concurrent therapy.
No firmly established dose for methotrexate has been confirmed;
doses in excess of 3.5 g/m2 have been shown to achieve satisfactory
CSF drug levels. Fig. 63.23 presents an algorithm for the diagnosis
and management of PCNSL at the Hospital of the University of
Pennsylvania; the recommended approach to management of these
tumors is summarized in Box 63.2. Patients with PCNSL receive
methotrexate, 8 g/m2 every 14 days for up to eight cycles. The calculated
dose is diluted in 500 mL of 5% dextrose in water and given intra-
venously over a 4-hour period. Patients achieving a complete response
receive two additional doses of methotrexate at 14-day intervals,
followed by 11 monthly doses of methotrexate, 8 g/m2, as long as a
complete response is maintained. MRI scans are obtained monthly
Box 63.2. MANAGEMENT OF PRIMARY
CENTRAL NERVOUS SYSTEM
LYMPHOMA AT THE UNIVERSITY OF
PENNSYLVANIA
• Primary central nervous system lymphoma (PCNSL) is a non-Hodgkin
B-cell lymphoma that arises in the brain, leptomeninges, spinal cord,
or eyes. It should be regarded as a whole-brain disease. It rarely
spreads outside the nervous system.
• Optimal treatment of PCNSL is not yet fully established, but
experience acquired during the past decade with various
combinations of radiation therapy and chemotherapy suggests that
initial induction treatment should be attempted with a methotrexate-
based intravenous chemotherapy regimen and that concurrent
intrathecal chemotherapy is not necessary. The MATRix regimen of
methotrexate, cytarabine, thiotepa, and rituximab has been shown to
result in improved remission rates compared with other combination
therapies.
• Adequate delivery of chemotherapy to microscopically infiltrated
areas of brain protected by the blood-brain barrier remains a
significant challenge, and recurrence at multiple cerebral sites
remains a problem for which effective therapy remains to be
developed.
• Retreatment of a prior complete responder at relapse with the
foregoing intensive methotrexate regimen is feasible. Alternatives
include whole-brain radiation therapy, cytarabine, and investigational
regimens using temozolomide or rituximab.
 Cancer of the Central Nervous System • CHAPTER 63 945

CT/MRI findings
suspicious for PCNSL

Withhold corticosteroids
Chest x-ray, CT: chest, abdomen, pelvis, testicular ultrasound
CBC, HIV, LDH

SLE and lumbar puncture with

cytology and flow cytometry*

+ Cells in vitreous + CSF lymphoma – CSF and SLE

Vitrectomy Brain biopsy

– Lymphoma + Lymphoma + PCNSL – PCNSL

Brain biopsy

– PCNSL + PCNSL

Diagnosis— Liver function tests Diagnosis—

appropriate Creatinine clearance appropriate
therapy Spinal MRI therapy
Assess cognitive function (MMSE)
Figure 63.23 • Algorithm for diagnosis and manage-
ment of primary central nervous system lymphoma (PCNSL) Corticosteroids if necessary
at the University of Pennsylvania. CBC, Complete blood for symptom control
cell count; CSF, cerebrospinal fluid; CT, computed tomog-
raphy; HIV, human immunodeficiency virus; LDH, lactate
dehydrogenase; MMSE, Mini Mental State Examination;
MRI, magnetic resonance imaging; SLE, slit-lamp examina- Definitive treatment of PCNSL
tion. *See text for other CSF investigations.

during induction therapy and at 3-month intervals during maintenance
therapy. The methotrexate protocol involves close clinical monitoring,
adjustment of intravenous fluid, and calcium leucovorin rescue, in
addition to frequent monitoring of urine pH, renal function, and
methotrexate levels.
More recent trials have found survival benefits when including
other regimens in addition to methotrexate. In 2016 the MATRix
trial demonstrated that the use of methotrexate, cytarabine, thiotepa,
and rituximab (MATrix) had superior outcomes in patients with
HIV-negative PCNSL compared with treatment with methotrexate
plus cytarabine alone or with methotrexate plus cytarabine and
rituximab (complete remission rate of 49% with MATRix versus 23%
and 30%, respectively).399
Contraindications to methotrexate therapy include allergy to
methotrexate, inability to achieve adequate hydration because of cerebral
edema, or cardiac or pulmonary problems, and concurrent immunosup-
pressive treatment. Patients should not have received prior cranial
irradiation. Patients with renal dysfunction resulting in a creatinine
clearance of less than 50 mL/min or serum creatinine level greater
than 2 mg/dL should not receive methotrexate. Patients with significant
ascites or pleural effusions may experience delayed methotrexate
clearance because of third space accumulation.
Calcium leucovorin rescue therapy should begin 24 hours after
the start of methotrexate infusion. The dose is adjusted according to
methotrexate levels. Any dose of leucovorin greater than 50 mg should
be given intravenously. If the plasma concentration of methotrexate
at 24 hours is greater than 10−5 M, 100 mg/m2 of leucovorin is given
intravenously every 6 hours until rescue is achieved and continued at
25 mg intravenously or orally every 6 hours until the methotrexate
plasma concentration is less than 10−7 M. In most patients, the
methotrexate concentration clears to this level by 72 hours after the
infusion.
Patients with an established PCNSL diagnosis may receive concur-
rent corticosteroid therapy to alleviate symptoms. Concurrent use of
salicylates or other nonsteroidal antiinflammatory drugs or sulfonamide
medications is prohibited for at least 1 week before the initiation of
methotrexate therapy. Many patients with PCNSLs will continue to
take corticosteroids for extended periods. The combination of
corticosteroids and methotrexate may lead to a low CD4+ count, and
these patients will be at risk for P. jiroveci pneumonia. Like patients
with other brain tumors, patients with PCNSL should receive pro-
phylaxis with trimethoprim-sulfamethoxazole two or three times per
week, with discontinuation of this drug 1 week before institution of
methotrexate therapy.400 Concurrent AED therapy is acceptable, and
946 Part III: Specific Malignancies

management of nausea associated with chemotherapy does not differ

in this population from that for other patients receiving comparable Table 63.8 Meningiomas: Distribution by Anatomic
regimens. Location
The management of progressive or recurrent PCNSL is not yet FREQUENCY (%a)
well established. Age and performance status of the patient must be
taken into account. In general, greater than 25% enlargement of Tumor Location Series 1a Series 2b
previous areas of gadolinium contrast enhancement, the appearance Convexity 34 21
of new lesions, or the appearance of malignant cells in the CSF, vitreous, Parasagittal 22
or, rarely, elsewhere in the body constitutes treatment failure. Cher
and colleagues382 have reported that for patients who have completed Sphenoid ridge 17 16
their maintenance therapy, return to a more intensive methotrexate Lateral ventricle 5 —
dosage regimen may lead to a second complete response. For patients Tentorium 4 —
who have progressed through therapy, other chemotherapeutic agents Cerebellar convexity, posterior fossa 5 14
such as cytarabine given intravenously or intrathecally may be con- Parasellar 3 12
sidered. At relapse or in the case of failure to achieve a complete
response after eight cycles of methotrexate, many treating physicians Intraorbital 2 2
would consider palliative radiation therapy. The immediate palliation Cerebellopontine angle 2 —
of progressive signs and symptoms is a realistic goal but must be Olfactory groove 3 10
weighed against the possibility that survival will be extended enough Foramen magnum 1 —
to allow emergence of late cognitive neurotoxicity. At most centers, Clivus 1 —
whole-brain irradiation to 40 to 45 Gy in 20 fractions is given over
4 to 5 weeks. Spine — 8
After initial diagnosis, surgical intervention usually has little place Other 1 —
in treatment. The need for intrathecal chemotherapy, however, may a
mandate placement of an Ommaya reservoir. Development of com- Of 179 cases reported by Rohringer and associates404; this series included only
cases of intracranial meningiomas, with none of the spine.
municating hydrocephalus with or after treatment of meningeal b
Of 225 cases reported by Mirimanoff and co-workers.415
lymphoma may require shunting.
Parenchymal treatment failure is the most common pattern of
relapse. Ocular, meningeal, and late rare extra-CNS relapses (e.g.,
breast, abdominal wall, bone, or lymph nodes) have been described on epidemiology).10 Some relationship with breast cancer may exist,
and may be seen with increasing frequency as patients survive longer. because the likelihood of the development of a meningioma after
Temozolomide is under investigation as an agent for treatment of breast cancer, or the development of breast cancer after meningioma,
progressive PCNSL. Rituximab, a monoclonal antibody against the is higher than in the general population.408
B-cell–specific CD20 antigen, has been demonstrated to be effective Deletions of chromosome 22 are frequent in persons with menin-
against various non-Hodgkin lymphomas, but CSF drug levels attained giomas. The likely target of this chromosomal deletion is the NF2
with intravenous therapy are not high.401 Attempts to circumvent this gene, which is mutated in patients with NF2. One of the tumor types
problem have involved intraventricular administration through an commonly seen in these patients is meningioma.409 The NF2 gene
Ommaya reservoir, with some early reports indicating total clearing also appears to have an important role in the pathogenesis of sporadic
of tumor cells with leptomeningeal lymphoma.402 Whether rituximab meningiomas. One study found NF2 mutations in 60% of sporadic
will clear parenchymal masses is not known. Intensive chemotherapy meningiomas, all of which had lost one copy of chromosome 22.410
followed by hematopoietic stem cell rescue using a regimen of cytarabine However, 40% of meningiomas have neither allelic loss of chromosome
and etoposide has been reported to give a complete response rate of 22 nor NF2 gene mutation; therefore a second tumor suppressor gene
70%, with a median PFS period of 3 years.403 Several of the patients probably is linked to the development of meningiomas.
in the reported study, however, had intraocular lymphoma only. In case of non-NF2 meningiomas, through use of whole-genome
techniques, several other genes have been identified that cluster
meningiomas into distinct subtypes: TRAF7, KLF4, AKT1, and SMO.
MENINGIOMA TRAF7 is an E3 ubiquitin ligase, KLF is a transcription factor involved
Clinical and Pathologic Considerations in pluripotency, AKT1 is involved in the PI3 kinase pathway, and
SMO is an activator of the Hedgehog signaling pathway.411 POLR2A,
Meningiomas account for approximately 30% of all intracranial tumors an RNA polymerase, was also subsequently found to have a somatic
(see Table 63.1). The male-to-female ratio is 1 to 2, with the incidence mutation that clusters distinctly from the aforementioned genes.412
increasing with age and reaching a peak in the seventh decade.404
These tumors arise from arachnoidal cells in the meninges, not the Grading of Meningiomas
brain parenchyma; therefore they are extraaxial. They produce signs
and symptoms by compressing normal tissues. The locations of Grossly, meningiomas appear as rounded masses, well circumscribed
meningiomas in two large series are shown in Table 63.8.405,406 The in contour, with a well-defined dural base that can be easily separated
specific signs and symptoms depend on the anatomic location of the from the underlying brain tissue (Fig. 63.24). Often these tumors
meningioma. For example, meningiomas arising from the cerebral extend into the adjacent bone. Meningiomas are graded between grades
convexity can cause headache, altered mentation, and seizures, whereas I, II, and III based on histologic appearance. Histologically, several
those arising from the suprasellar region are likely to cause loss of different Grade I subtypes of benign meningiomas are recognized,
vision, bitemporal hemianopia, and optic atrophy. including syncytial, fibroblastic (fibrous), transitional (mixed), psam-
Numerous potential etiologic agents for meningiomas have been momatous, microcystic, and papillary; however, these distinctions carry
investigated, including radiation, trauma, viruses, occupational exposure, little prognostic significance.218 Of more importance prognostically
diet, and exposure to sex hormones (reviewed by Longstreth and is whether the meningioma is benign, which it is in 90% of the
colleagues)407 Only ionizing radiation, however, has been strongly cases.404 Grade II meningiomas are also known as atypical meningiomas.
implicated in the pathogenesis of these tumors—for example, after Features of atypical meningiomas are focal isolated necrosis, prominence
scalp irradiation for tinea capitis (as discussed previously in the section of nucleoli, and mitotic figures with high cell density. Grade III, or

Figure 63.24 • Meningioma: gross specimen. A large-convexity meningioma
severely displaces the underlying tissue downward and laterally, creating a
midline shift and resulting in marked ventricular compression. (From Maher
EA, McKee AC. Neoplasms of the central nervous system. In: Skarin AT, ed.
Dana-Farber Cancer Institute Atlas of Diagnostic Oncology. 3rd ed. St Louis:
Mosby; 2003.)
malignant, meningiomas are characterized by invasion into adjacent
normal brain tissue. In one large study based on data from the US
National Cancer Database, the overall 5-year survival rates in patients
with benign, atypical, and malignant meningiomas were 70%, 75%,
and 55%, respectively.413 More recently, analysis of the SEER database
consisting of more than 12,000 patients demonstrated 1- and 3-year
survival estimates of 95.4% and 92.4%, respectively, in patients with
histologically confirmed nonmalignant meningioma, suggesting progress
in the treatment of these tumors.414
Meningiomas have a distinctive appearance on radiologic studies.
On MRI, most meningiomas are isointense with gray matter on
T1-weighted scans and enhance intensely with gadolinium (Fig. 63.25).
Peritumoral edema is evident in 60% of meningiomas, and associated
bony changes, either destruction or hyperostosis, are seen in 20%.
The bony changes are better visualized on CT scans than with MRI.
Within the tumor may be seen calcifications, central necrosis, or
pseudocysts.
Surgery and Conventional Radiation Therapy
for Meningiomas
In a classic article describing the outcome in 225 patients with
meningiomas who were treated with surgery as the sole modality at
Massachusetts General Hospital (MGH), Mirimanoff and associates415
found PFS rates of 93%, 80%, and 68% at 5, 10, and 15 years,
respectively, for persons who underwent a total resection versus 63%,
45%, and 9% for persons who underwent a subtotal resection (P <
.0001). In general, lower rates of progression were seen with sites
associated with higher resectability rates. For example, meningiomas
in the convexity, 96% of which underwent total resection, had a
5-year recurrence or progression rate of 3%, versus 34% for lesions
in the sphenoid ridge, which had only a 28% rate of total resection.
These results suggested that surgery alone was inadequate therapy
for meningiomas if total resection could not be achieved. In a
subsequent study from MGH, Miralbell and coworkers416 reported
on 17 patients who underwent subtotal resection of a meningioma
followed by radiation therapy. Their 8-year PFS rate was 88%, which
was much better than the 48% rate calculated for the cohort of
patients with subtotal resections who did not receive postoperative
radiation.
Cancer of the Central Nervous System • CHAPTER 63 947
Figure 63.25 • Meningioma. Axial T1-weighted postgadolinium magnetic
resonance image shows an extraaxial enhancing mass that compresses the
underlying brain tissue.
Another retrospective study from the University of California at
San Francisco reached similar conclusions regarding the improvement
in local control with postoperative radiation therapy in patients who
have undergone a subtotal resection.417 This series included mostly
patients with benign meningiomas. A much poorer outcome was
observed for patients with malignant meningiomas than for those
with benign meningiomas (5-year PFS rate of 89% versus 48%;
P = .001).
The foregoing studies all used conventional fractionated radiation
therapy, usually with doses ranging from 50 to 60 Gy of radiation
via conventional fractionation and delivery techniques. Most investiga-
tors today would recommend approximately 54 Gy for benign
meningiomas after incomplete resection and up to 60 Gy for menin-
giomas that have atypical or malignant features.
Stereotactic Radiation Techniques for Meningiomas
Substantial experience with the use of stereotactic techniques in the
treatment of meningiomas has been accumulated. One of the centers
with extensive experience with this technique is the University of
Pittsburgh. In a long-term follow-up study of 99 patients with
meningiomas treated with Gamma Knife SRS from 1987 to 1992
with 9 to 25 Gy (median marginal dose of 16 Gy), the total rate of
failure was 11% at 63 to 120 months after SRS.418 A majority of
meningiomas showed a decrease in size with time by MRI. At years
4 to 6, 69% of cases showed a decrease in size on MRI scan; by years
8 to 10, this number had increased to 88%.
The Mayo Clinic and the Na Homolce Hospital in Prague have
also reported rates of local control ranging from 89% to 98%,
respectively, in benign meningiomas with the use of Gamma Knife
SRS.419,420 Even for meningiomas greater than 10 cm3, authors have
reported excellent tumor control—99% and 97% at 3 and 7 years,
948 Part III: Specific Malignancies
respectively—albeit with higher complication rates when these lesions
were located in the supratentorial space.421 Follow-up remains short,
however, with a median duration of 31 to 60 months. Patients with
atypical or malignant features performed less well. In the Mayo Clinic
series, the 5-year local control rates were 93%, 68%, and zero for
benign, atypical, and malignant meningiomas, respectively (P < .0001).
Despite the goal of delivering an extremely conformal dose, SRS can
cause significant complications. Rates of complications, often involving
cranial nerves, have been reported in the 5% to 13% range.418–420
With the reduction in radiation dose used to treat meningiomas,
however, this complication rate has decreased.
An extensive experience has been reported regarding the use of
SRS for treatment of cavernous sinus meningiomas. Because of their
location, surgical resection can cause significant complications, par-
ticularly cranial nerve morbidity and resulting extraocular muscle
paralysis.422 A number of institutions have reported high local control
rates, in the 91% to 98% range, with use of marginal doses that
typically range from 12 to 18 Gy, but with very short follow-up
(median, 2 to 3 years).423–425 The current standard dose delivered with
SRS or Gamma Knife for treatment of these tumors is a marginal
dose of 14 Gy. Furthermore, cranial nerve V appears to be sensitive
to single high-dose fractions, because the incidence of trigeminal nerve
dysfunction has ranged from 4% to 11% in these series when higher
doses are used.
In an effort to decrease late effects, fractionated stereotactic
radiotherapy (FSRT) also has been used to treat meningiomas. At the
University of Heidelberg, a mean dose of 56.8 Gy was given in 1.8-Gy
daily fractions and was delivered with a relocatable head frame for
treatment of large base-of-skull meningiomas.426 At a median follow-up
time of 35 months, the 5-year PFS rate was 94% for 180 patients
with benign meningiomas but 78% for patients with atypical features.
Another instance in which the fractionated technique has been used
instead of conventional SRS is for treatment of optic nerve sheath
meningiomas, because of the potential risk of optic nerve injury with
a single large dose of radiation. One group of investigators reported
using FSRT with 50 to 54 Gy in 1.8-Gy fractions to treat these
tumors.427 Of 22 optic nerves with vision before FSRT, 20 nerves
(92%) demonstrated preserved vision, and 42% manifested improve-
ment in visual acuity and/or visual field at follow-up.
A nonrandomized comparison of conventional (nonstereotactic)
fractionated radiotherapy versus Gamma Knife radiosurgery for
selected patients with cavernous sinus meningiomas was reported by
Metellus and coworkers.428 Thirty-eight patients received fractionated
radiotherapy, and 38 underwent Gamma Knife radiosurgery. Both
groups fared well, with PFS rates of 94.7% and 94.4%, respectively.
Permanent morbidity was seen in 2.6% of patients in the first group
and in none in the second group. These results suggest that in selected
patients, Gamma Knife radiosurgery can be performed with little
late morbidity.
In summary, numerous reports have described the use of stereotactic
techniques for delivering radiation to meningiomas as an alternative
to surgery or after subtotal resection. In view of the long natural
history of these tumors, however, much longer follow-up may be
needed to adequately evaluate these outcomes compared with surgical
resection.
Medical Therapy for Meningiomas
In the management of meningiomas, chemotherapy is reserved for
the time after all surgical and radiation therapy approaches have been
exhausted. A number of phase II studies have examined the potential
benefit of various chemotherapeutic agents (e.g., dacarbazine, Adria-
mycin, cyclophosphamide, vincristine, temozolomide, and irinotecan)
in persons with benign and malignant meningiomas. Unfortunately,
preliminary data have demonstrated either a modest response, stability
of disease, or no effect at all. Not only did most of the subjects in
these studies also receive radiation therapy, but these results are difficult
Box 63.3. MANAGEMENT OF MENINGIOMAS
• Meningiomas are extraaxial tumors that arise from dura; common
locations are cerebral convexity, parasagittal falx, and sphenoid ridge.
• A very long natural history is characteristic, mandating prolonged
follow-up.
• More than 90% of these tumors are benign; the remainder exhibit
atypical histologic features or frank invasion of brain parenchyma.
• Primary treatment is surgical, if feasible.
• Radiation therapy is reserved for tumors that are incompletely
resected, recur after surgery, are inaccessible to surgical resection, or
have atypical or invasive features.
• The standard radiation dose has been approximately 54 Gy for
benign meningiomas and up to 60 Gy for tumors with atypical or
invasive features.
• Stereotactic radiation therapy techniques have been used; however,
follow-up is still short in these studies.
• Anecdotal reports exist of responses to medical therapy (hydroxyurea
and antiestrogen and antiprogesterone agents).
to interpret because of our limited understanding of the natural history
of meningiomas. Similar modest, and inconclusive, results have been
obtained with interferon-α, tamoxifen, and mifepristone (RU-486).
Novel pharmacologic agents that target specific signaling molecules
and cellular pathways (e.g., PDGFR, EGFR, EGFR, and the MAPK
pathway) have been the focus of intense research and may represent
the future of medical therapy for meningiomas. The recommended
approach to management of meningiomas is summarized in Box 63.3.
More recently, targeted therapy against vascular endothelial growth
factor receptor (VEGFR) using the tyrosine kinase inhibitor sunitinib
has been studied, with evidence of differential effectiveness in VEGFR2
tumors compared with VEGFR2-negative tumors. As of 2017, a study
of an anti-PD-1 receptor antibody, pembrolizumab, is ongoing. This
targeted therapy is a form of immune modulation that relies on
overexpression of PD-L1 in tumor cells.429
PITUITARY ADENOMA
Clinical and Pathologic Considerations
Pituitary adenomas, which make up 10% to 15% of all intracranial
tumors, arise from the anterior lobe of the pituitary gland (Box 63.4).
They are extremely common and at autopsy can be found in up to
27% of cases, and in 10% of normal adult volunteers based on MRI
scanning. Symptomatic pituitary adenomas are much less common.
These tumors can give rise to signs and symptoms through secretion of
hormones or by compression of nearby structures, causing neurologic
disturbances such as headaches, bilateral bitemporal hemianopia from
compression of the optic chiasm, and cranial nerve palsies from invasion
into the cavernous sinus. Adenomas also can cause hypopituitarism
from compression of the pituitary stalk. Pituitary apoplexy, a rapid
and symptomatic expansion of a pituitary adenoma in the context
of hemorrhage or infarction, is a potentially devastating presentation
and typically warrants urgent surgical decompression.430–432 Apoplexy
is thought to be uncommon, although it occurred in 21% of patients
with pituitary adenomas who were being followed in one single-
center series.433
At one time, pituitary adenomas were classified according to their
staining characteristics (basophilic, eosinophilic, and chromophobe).
Today, however, they are classified according to the secretion of
hormones. In one series of 684 patients with pituitary adenomas who
underwent surgery, prolactinomas were the most common (43%),
followed by nonsecreting tumors (30%)434 (Table 63.9). TSH-secreting
tumors were rare in this series (2 of 684), as they are in others.

Population-based studies on adenoma prevalence have provided similar
results regarding the distribution of adenoma subtypes.435,436 Because
prolactin-secreting adenomas are primarily treated with dopamine
agonists, prolactinomas represent a smaller percentage of modern
surgical series as compared with older surgical literature. Adenomas
also are classified on the basis of size as either macroadenomas (>1 cm
in diameter) or microadenomas. Nonsecreting adenomas are generally
macroadenomas at the time of diagnosis because they usually come
to medical attention fairly late, when they are causing neurologic
symptoms owing to mass effect. The same is true for gonadotropin-
secreting adenomas, which are inefficient producers and secretors of
hormones. GH-secreting adenomas and prolactinomas in men often
are macroadenomas at the time of diagnosis, probably because their
Box 63.4. MANAGEMENT OF PITUITARY
ADENOMAS
• Pituitary adenomas are extremely common as an incidental finding
(in up to 10% of normal volunteers at magnetic resonance imaging
screening).
• These tumors may become symptomatic (i.e., the point at which the
patient comes to medical attention) because of hormone secretion,
compression of nearby structures causing neurologic symptoms, or
compression of the pituitary stalk, leading to hypopituitarism.
• These tumors are classified by size as microadenomas (≤1 cm in
diameter) or macroadenomas. They are also classified by secretion
of hormones (most commonly prolactin, growth hormone, or
adrenocorticotropic hormone).
• Initial therapy for most prolactin-secreting adenomas is with a
dopamine agonist (e.g., cabergoline or bromocriptine), which usually
decreases prolactin levels and shrinks the tumor.
• Initial therapy for most other pituitary adenomas is transsphenoidal
surgical resection, which is safe and leads to rapid reversal of
neurologic signs and symptoms. Surgery normalizes hormone levels
in most patients with microadenomas.
• Stereotactic radiosurgery or external beam radiation therapy
currently is reserved for treatment of residual disease or recurrence
after surgery, for surgically inaccessible tumors, and for patients who
are not eligible for surgery because of medical reasons or (in patients
with secreting pituitary adenomas) whose status is hormonally
uncontrolled after surgical and medical therapy options have been
exhausted. In patients with elevated hormones, normalization of
levels after radiation therapy may take years.
Table 63.9 Pituitary Adenomas: Clinical Presentation by Endocrine Secretion
Frequencya
Type (%) Signs and Symptoms
Prolactinoma 43 Women: amenorrhea, galactorrhea
Men: impotence, hypopituitarism
Nonsecreting gonadotropin 30 Hypopituitarism
GH secreting 17 Gigantism in children
Acromegaly in adults
ACTH secreting 7 Cushing syndrome
Nelson disease
TSH secreting <1 Hyperthyroidism
a
Among 684 cases reported by Oruckaptan et al. Pituitary adenomas: results of 684 surgically treated patients and review of the literature. Surg Neurol. 2000;53(3):211-9.
ACTH, Adrenocorticotropic hormone; GH, growth hormone; TSH, thyroid-stimulating hormone.
Cancer of the Central Nervous System • CHAPTER 63 949
clinical effects evolve over time and often are ignored early on. Because
the same pituitary stem cell can produce both GH and prolactin,
many patients have adenomas that secrete both hormones. Prolactinomas
in women and ACTH-secreting adenomas usually are microadenomas
at diagnosis. Prolactinomas in women commonly cause amenorrhea
and galactorrhea. ACTH-secreting adenomas often cause dramatic
clinical signs and symptoms associated with hypercortisolism that
rapidly bring patients to medical attention. ACTH-secreting pituitary
adenomas also can be seen in approximately 25% of patients who
have undergone bilateral adrenalectomies for Cushing syndrome as a
result of loss of negative feedback control by cortisol on the hypo-
thalamus. In a majority of these patients, hyperpigmentation develops
as a result of ACTH hypersecretion, which is termed Nelson syndrome;
in this setting the pituitary tumors usually are very large and often
are difficult to completely resect.437
MRI scans are the best diagnostic imaging test for pituitary adeno-
mas. However, interpretation can be challenging. The pituitary gland
and stalk normally are isointense with brain on T1-weighted MRI
scans. The gland and stalk, however, intensely enhance after contrast
administration because of the absence of a blood-brain barrier. Pituitary
adenomas generally are seen as hypointense foci on T1-weighted MRI
scans and do not enhance with gadolinium.405 Other abnormalities
that can appear as a hypointense, nonenhancing lesion in the pituitary
include pars intermedia cysts, metastases, infarctions, and epidermoid
cysts and abscesses.
Many investigators have studied the genetics of pituitary adeno-
mas. Patients with multiple endocrine neoplasia type 1 (MEN1) are
predisposed to the development of pituitary adenomas, in addition
to parathyroid and pancreatic islet tumors (reviewed by Thakker406).
Anterior pituitary tumors occur in 30% of patients with MEN1,
most commonly prolactinomas but also nonfunctional and GH-
secreting and ACTH-secreting tumors. MEN1 mutations are not
commonly found in sporadic pituitary adenomas; however, one gene
that is mutated in a substantial proportion of pituitary adenomas
is that encoding the α subunit of the GTP-binding protein Gs.438
Mutation of this gene leads to constitutive activation of the cyclic
adenosine monophosphate pathway. The mutated form of this
gene is called gsp and is present in 10% to 40% of GH-secreting
adenomas.438
Surgery for Pituitary Adenomas
The current therapy for most pituitary adenomas, excluding prolac-
tinomas, involves surgery. For nonsecreting tumors, which tend to be
large and manifest with neurologic signs and symptoms, surgery offers
rapid decompression of the visual pathways. For hormonally active
tumors, surgery leads to a rapid drop in hormone secretion. The
Typical Size at Diagnosis
Women: microadenoma
Men: macroadenoma
Macroadenoma
Macroadenoma
Microadenoma
Can be microadenoma; often macroadenoma owing
to delayed diagnosis
950 Part III: Specific Malignancies
current preferred technique is the transsphenoidal approach, which
was popularized by Harvey Cushing in the early 1900s. It then fell
out of favor but regained popularity in the 1960s.439 Transsphenoidal
resection is fairly safe, with a mortality rate less than 1%.440 The most
common complications arising from this surgery are nasal septum
perforation, anterior pituitary insufficiency, postoperative diabetes
insipidus (which usually is transient), and CSF leak, which may result
in meningitis.440 Rarer complications include carotid artery injury
and loss of vision. A recent variation of this approach has been to use
an endoscope through the nostril to gain access to the pituitary trans-
sphenoidally, thereby eliminating the need for conventional skin
incisions, improving intraoperative visualization, and allowing for more
dramatic resections of macroadenomas that are generally considered
unresectable through a standard transsphenoidal approach.441–444 The
transsphenoidal approach is used in more than 90% of pituitary
operations. Fibrous pituitary adenomas or those with extension into
the middle cranial fossa may require a transcortical approach, as a
transsphenoidal approach may limit adequate resection.
The success of surgery alone in curing adenomas depends on the
size and location of the tumor, especially invasion into the cavernous
sinus.445 In a large review of a single center series using modern
endoscopic endonasal techniques, Paluzzi and colleagues describe a
65% cure rate in 359 patients with nonfunctioning adenomas, 82.5%
cure rate in 57 Cushing disease patients, 65.3% cure rate in 49 patients
with acromegaly, and 54.7% cure rate in 53 patients with prolactinomas.
There was no visual worsening after surgery, and there was a 0.3%
carotid artery injury rate. The degree of cavernous sinus invasion was
considered to be an important predictor of the ability to resect tumor
completely. Similarly, in a review of transsphenoidal resection for
GH-secreting adenomas, hormonal normalization was seen in 67%
to 91% of microadenomas but in only 48% to 65% of macroadeno-
mas.446 ACTH-secreting adenomas, which generally are smaller than
1 cm at diagnosis, show a normalization of hormones after resection
in 75% to 96% of cases in most surgical series (reviewed by Lüdecke
and coworkers447). TSH-secreting adenomas are rare compared with
other pituitary adenomas, and when they are diagnosed, they are often
large. Normalization of TSH after resection of these tumors has varied
widely in different series, ranging from 33% to 86%.448
The results of surgery for hormone-inactive adenomas are harder
to document because the criteria for surgical success are less well
defined. Clinical improvement can be seen even without total removal
of the tumor. Series in which CT or MRI scans were performed a
few months after surgery show a wide range of gross complete resection
rates for these tumors, from 28% to 84%.449–451 A review of several
surgical series showed that the likelihood of normalization of visual
fields after surgery ranged from 16% to 53% and that visual field
improvement occurred in 26% to 70% of cases.452
Medical Therapy for Prolactinomas
The primary treatment for prolactinomas is medical because of the
availability of drugs that can suppress prolactin secretion and shrink
these tumors. Surgical resection and radiotherapy are still used for
the treatment of prolactinomas in the minority of patients who fail
to respond to drugs or who cannot tolerate them.453
Clinical manifestations of prolactinomas differ between the sexes.
In premenopausal women, oligomenorrhea or amenorrhea and galactor-
rhea are extremely common. Infertility also may be the presenting
sign, and women often have decreased libido. Because estrogens have
a marked stimulatory effect on prolactin synthesis and secretion,
pregnancy can stimulate the growth of these tumors. In men and
postmenopausal women, these tumors generally are asymptomatic
until they are large enough to compress nearby structures, causing
signs and symptoms such as visual deficits, headaches, and panhypo-
pituitarism. Chronic hyperprolactinemia leads to decreased libido and
impotence in 90% of men. Galactorrhea is uncommon in men but
can occur in 10% to 20% of cases.
Because secretion of prolactin by the lactotroph cells in the anterior
pituitary gland is negatively regulated by dopamine produced by the
hypothalamus, dopamine receptor agonists such as bromocriptine and
cabergoline are used to inhibit prolactin secretion by the lactotrophs.
Cabergoline has been increasingly preferred over bromocriptine after
large comparative trials found cabergoline to be equally if not more
efficacious, better tolerated, and with more convenient administration.454
Dopamine agonists decrease tumor size and normalize prolactin levels
in 70% to 90% of patients. Dopamine agonists also restore ovulation
and menses and improve visual fields in a similar percentage of cases.
Tumor shrinkage and decrease in prolactin levels can take anywhere
from days to weeks to months to occur. Unfortunately, the action of
dopamine agonists is reversible; therefore when the drug is discontinued,
regrowth of the tumor with an increase in the prolactin level is usually
seen. Therefore lifelong administration is the rule, and many patients
can tolerate prolonged treatment for years. Both cabergoline and
bromocriptine have been used prophylactically during pregnancy to
reduce symptomatic tumor enlargement, although bromocriptine is
the best studied. Of note, however, is that up to 20% of patients
experience adverse effects such as nausea, vomiting, dizziness, postural
hypotension, and headaches. Patients who have limiting toxicity or
fail to respond to one dopamine agonist may benefit from a trial of
a newer dopamine agonist such as lisuride, pergolide mesylate, or
terguride.455,456
A few drugs are now available for the treatment of endocrine
hypersecretion in pituitary tumors other than prolactinomas. For
GH-secreting adenomas, somatostatin analogues such as octreotide
and lanreotide have been shown to reduce GH levels in more than 90%
of patients, with almost complete suppression in half of patients.457
Dopamine agonists such as bromocriptine or cabergoline may also
be used alone or as an adjuvant to somatostatin analogue therapy.458
Pegvisomant is a GH receptor antagonist that can provide reduction
of GH levels and symptomatic relief in a majority of patients.459
In general, surgery remains the first-line treatment for patients
with symptomatic GH-secreting adenomas; however, these drugs
provide useful options in patients for whom surgical cure is not
possible.460,461
TSH-secreting adenomas often are very large at diagnosis, making
complete surgical resection difficult. Because these tumors express
somatostatin receptors, octreotide and lanreotide can decrease tumor
size and decrease TSH secretion.457
Radiation Options for Pituitary Adenomas
Radiation options can be highly effective in controlling pituitary
adenomas. Currently, however, radiation therapy is rarely used as sole
treatment for newly diagnosed tumors. In contrast with surgery,
radiation therapy will not result in a rapid reversal of neurologic signs
and symptoms or a rapid drop in hormonal secretion. Therapeutic
radiation for pituitary adenomas can be delivered either as single-session
SRS or as fractionated radiation therapy. SRS is generally the preferred
technique because this treatment is as efficacious as fractionated therapy
and is more convenient for patients. Fractionated radiation therapy
is indicated when treating a tumor that is near radiation-sensitive
normal tissue, such as the optic chiasm. Indications for radiation for
a nonfunctioning pituitary adenoma include medically inoperable
patients, tumor recurrence or progression after surgery, or a surgically
inaccessible tumor. Indications for radiation for a functioning pituitary
adenoma include a hormonally uncontrolled tumor after maximal
surgical resection and optimal medical management, tumor growth
in a poor surgical candidate, tumor recurrence, or a surgically inac-
cessible tumor.462
Stereotactic Radiosurgery for Pituitary Adenomas
The largest multicenter report regarding single-session, Gamma Knife
radiosurgery for nonfunctioning pituitary adenoma was published by

Sheehan and colleagues in 2013.463 In this study, nine centers pooled
outcome data on 512 patients, and an overall tumor control rate of
93.4% at last follow-up was achieved. Ten-year actuarial control was
85%, with predictors of control being smaller adenoma volume and
absence of suprasellar extension. Side effects of Gamma Knife radio-
surgery included new hypopituitarism in 21% of patients and new
optic nerve complications in 6%.
SRS for functioning adenomas has delayed benefit, usually years
after the procedure. In addition, its efficacy for Cushing disease,
acromegaly, and prolactinoma is variable. Nevertheless, success can
be seen in many series. In one of the larger series of almost 100
patients with refractory Cushing disease, Sheehan and colleagues
describe remission of Cushing disease in 70% of patients with a median
time to remission of 16.6 months.464
Publications and data on fractionated radiation therapy are more
difficult to assess because technology, dosing schemes, techniques,
accuracy have all changed over time. Often recommended doses for
fractionated radiation therapy are on the order of 45 to 50.4 Gy in
1.8-Gy daily fractions for nonfunctioning pituitary adenomas and
50.4 to 54 Gy in 1.8-Gy daily fractions for functioning pituitary
adenomas.462 Radiotherapy is rarely used to treat prolactinomas because
medical treatment with dopamine agonists is so effective.465 Of note,
it has been proposed that hormone-suppressing medications used to
treat pituitary adenomas, such as somatostatin analogues and dopamine
agonists, may exert radioprotective effects,466,467 and therefore these
medications are often discontinued before radiotherapy. However,
data to support this effect are limited. The overall 10-year control
rate using fractionated radiation therapy is on the order of 85% to
95%, based on a number of large retrospective series.468–472 In a study
from the University of Heidelberg, in 138 patients with pituitary
adenomas who received radiation as initial therapy or after recurrence,
the overall local control rate was 95% with a mean follow-up time
of 6 years.470 Likewise, in a study from the University of Florida
with a median follow-up time of 9.2 years, the overall local control
rate at 10 years was 93%.468 Ninety-eight patients in this series had
surgery and radiotherapy as initial therapy, and their 10-year local
control rate was 95%. This rate was comparable to the 10-year local
control rate of 90% for the 23 patients who received radiotherapy
alone for newly diagnosed adenomas, but better than the 80% control
rate seen in 20 patients who received radiation for a recurrence after
their initial surgery (P = .03). Similar findings regarding improved
local control in patients undergoing surgery and radiation “up-front”
compared with those receiving radiation at recurrence were obtained
from the Princess Margaret Hospital study, which examined 160
patients with hormonally inactive pituitary adenomas.469 Pituitary
adenomas can occur in the pediatric population, although they are
much less common than in adults. In one study in 11 patients aged
19 years or younger with pituitary adenomas, treatment consisted
of surgery plus radiation or radiation only.473 At a median follow-
up time of 15.6 years, only two patients had failed to respond
to treatment.
In the aforementioned studies, local control refers to lack of disease
progression, clinically and radiologically. In many patients who have
hormone elevations at the outset, however, complete normalization
may not be achieved after radiation therapy. In the University of
Heidelberg series, of 68 patients with hormonally active pituitary
adenomas, 52% of patients showed some reduction in their hormonal
overproduction, but only 38% demonstrated complete normalization.470
Furthermore, in patients who had a response, it often took years, and
in some cases up to 9 years. A study from the Princess Margaret
Hospital specifically analyzed data from 145 patients who received
radiation for hormonally active pituitary adenomas.471 The PFS rate
was 96% at 10 years; however, the actuarial long-term biochemical
remission rate was only 40%. Radiation is thus highly effective in
preventing pituitary adenomas from growing; however, it is far less
effective in normalizing hormone levels in patients with hormonally
active tumors.
Cancer of the Central Nervous System • CHAPTER 63 951
Late Effects After Pituitary Irradiation
In the series just discussed, the median doses ranged from 45 to
50 Gy.468–471 In the University of Heidelberg study, a statistically
significant dose-response relationship was found in favor of a dose of
45 Gy or less.470 One of the worrisome potential late effects of use
of higher total doses is the possibility of radiation-induced optic
neuropathy. In some series, visual problems develop in a few patients
after radiation, presumably as a result of optic nerve damage, but such
complications are uncommon, ranging in frequency from 0.7% to
2%.468,469 As discussed earlier (in the section on adverse effects after
irradiation of the brain or spine), the risk of optic nerve and chiasm
injury is dependent on both total dose and dose per fraction. At the
doses commonly used to treat pituitary adenomas (45–50 Gy), the
risk of radiation-induced optic neuropathy with standard fractionation
(1.8–2 Gy per day) is very low. When doses of 45 to 50 Gy were
given in fractions of less than 2.0 Gy, the risk of deterioration of
vision was less than 1%.474
Doses of 45 to 50 Gy to the pituitary gland carry a substantial risk
of causing hypopituitarism. In patients who did not have hormonal
deficiencies at the start, the risk of developing insufficiency of a given
hormone ranged from 10% to 30% in the series discussed earlier.468–472
It is likely that in half of all patients who received radiation doses of
45 to 50 Gy, deficiency of at least one pituitary hormone will develop
5 years after radiotherapy. Because this risk is ongoing after radiation
therapy and can occur many years later, patients must be monitored
indefinitely for this complication. GH is often the most sensitive to
radiation damage. Otherwise, the sensitivity of the different hormonal
axes (luteinizing hormone, follicle-stimulating hormone, ACTH, and
TSH) varies with many factors including dose, fractionation, age,
and sex. Panhypopituitarism occurs in 5% to 10% of patients at 5
years from treatment. Surgical manipulation before radiation therapy
is also associated with increased risk of hypothalamic-pituitary axis
dysfunction.462
Second malignant neoplasms are always a concern in patients who
receive radiation and who are expected to be long-term survivors. In
an analysis of 426 patients with pituitary adenomas treated at the
Royal Marsden Hospital with surgery and radiation therapy (median
dose of 45 Gy), a secondary brain tumor (two astrocytomas, two
meningiomas, and one meningeal sarcoma) developed in five patients,
for an actuarial risk of 2.0% at 10 years and 2.4% at 20 years. The
relative risk for developing a second tumor compared with the incidence
in the normal population was 28.6-fold in patents 20 years after
radiation.475
ACOUSTIC NEUROMA
Clinical and Pathologic Considerations
The term acoustic neuroma, although widely used, is actually a misnomer.
The tumor is not a neuroma, nor does it arise from the acoustic
(cochlear) nerve. It is a schwannoma derived from the myelin-generating
Schwann cells, and its origin is the superior or inferior vestibular
nerve. Schwannomas can affect other cranial nerves, such as the tri-
geminal nerve and the lower cranial nerves in the jugular foramen
region; however, these tumors are much less common than acoustic
neuromas.476,477
Acoustic neuromas account for 8% to 10% of all primary intracranial
tumors, and in general affect people in the fifth decade of life. These
tumors characteristically grow very slowly. Early on, they are
asymptomatic, but with enlargement they lead to progressive hearing
loss and tinnitus.478 The hearing loss typically is in the conversational
range. As the tumor expands and compresses cranial nerve VIII, it
may cause vertigo and unsteadiness of gait. With growth into the CP
angle, cranial nerves V and VII may be compressed, resulting in otalgia,
facial numbness, change in taste, and only very rarely facial palsy.
With continued growth, brainstem compression and obstruction of
952 Part III: Specific Malignancies
the fourth ventricle may develop, causing hydrocephalus. Because
signs and symptoms can arise insidiously, a progressive hearing loss
and gait unsteadiness may evolve over years in some patients before
the tumor is diagnosed.
Patients with NF2 often have bilateral acoustic neuromas; this
finding is diagnostic for NF2.409 Acoustic neuromas in patients with
NF2 contain mutations in the NF2 gene and chromosome 22 deletions.
Sporadic unilateral acoustic neuromas arising in patients without NF2
are also associated with chromosome 22 deletion and NF2 mutation.479
Interest in chemotherapeutic options for patients with NF2 whose
tumors cannot be controlled with surgery and/or radiotherapy is
increasing. Bevacizumab has shown promise in this population in
some patients, although its role at this point remains experimental or
palliative.480
Surgery for Acoustic Neuromas
Because acoustic neuromas are benign tumors without metastatic
potential, they have been traditionally treated with surgical resection.
A number of different approaches can be taken, including the trans-
labyrinthine approach, the suboccipital (retrosigmoid) approach, and
the middle fossa approach.481 Some centers strongly favor one approach
over the others, but many surgeons make a decision on a case-by-case
basis. The translabyrinthine approach is the only procedure that
inherently sacrifices hearing in the course of the procedure, and thus
it typically is not used in patients who have some residual useful
hearing.482 Hearing preservation is possible but not guaranteed with
either the suboccipital or middle fossa approach. In one series of
patients who underwent a resection with the suboccipital approach
with an attempt to preserve hearing, 18 of 46 patients (39%) who
had “functional” preoperative hearing maintained this hearing after
surgery.483 The middle fossa approach is indicated in patients who
have useful hearing and have tumors entirely contained within the
internal auditory canal. In one series using this approach, total tumor
removal was achieved in 98% of the cases, with hearing preservation
in 59% of patients.484 Approximately 89% of patients maintained
normal or near-normal facial nerve function.
Catastrophic complications such as brainstem stroke, postoperative
cerebellar hemorrhage, or death are rare after surgery for acoustic
neuromas.485 Two other serious complications that are more common
are CSF leak, which can lead to meningitis, and cranial nerve VII
palsy. Some surgical teams believe that CSF leak and damage to the
facial nerve are more likely with the suboccipital approach than the
translabyrinthine approach; however, both complications have been
described with both approaches.482,486 In an effort to decrease damage
to the facial nerve, many surgeons routinely perform intraoperative
electromyographic monitoring.485
Radiation Treatment Options for
Acoustic Neuromas
Radiation can be used to treat both recurrent and residual acoustic
neuromas in addition to primary acoustic neuromas.
The prototypical method of delivery of radiation to treat acoustic
neuromas has been through the widespread adoption of Gamma Knife
cobalt-60 units by neurosurgeons to treat acoustic neuromas. The
University of Pittsburgh has accumulated one of the most extensive
experiences with this approach. An analysis of the first 5 years of use
of Gamma Knife radiosurgery at the University with a 12- to 20-Gy
marginal dose showed a 98% local control.487 Of patients with normal
function of cranial nerves VII and V before radiosurgery, however,
15% and 16%, respectively, experienced some dysfunction afterward.
Furthermore, of patients with useful hearing before radiosurgery, only
47% maintained the same level of hearing. Other institutions have
also found high local control rates, along with high rates of cranial
nerve V and VII dysfunction, after single large stereotactic doses with
either the Gamma Knife488 or a linac.489 On the basis of their initial
results, the investigators at the University of Pittsburgh changed their
policy by decreasing the marginal dose and using MRI scans for
treatment planning purposes.490 From 1992 to 1997, 190 patients
underwent Gamma Knife radiosurgery with delivery of 11 to 18 Gy
to the margin of the tumor (median dose, 13 Gy). With a median
follow-up time of 30 months, the 5-year actuarial tumor control rate
was 97%, and 71% of patients retained useful hearing. The 5-year
rates for development of facial weakness and facial numbness were
1% and 2.7%, respectively.490 The tumor size and the prescription
dose correlate with cranial neuropathy.491
Linear accelerators can also be used to perform SRS in a single
session. Based on a series of 390 patients treated with linac-based
radiosurgery at the University of Florida, investigators determined
that each additional cubic centimeter of volume increased the odds
of facial weakness by 17%. The same series showed that each 250-cGy
dose increase resulted in 8.14 times the risk of facial weakness.492 The
range of hearing preservation in single-institution series is 32% to
71%. Long-term follow-up is required for these patients, because
hearing can continue to decline for many years after SRS.491
To potentially reduce late effects, a number of institutions have
fractionated their dose. Fractionation schemes have varied widely.
Both hypofractionation (25 Gy in 5-Gy fractions, 30 Gy in 3-Gy
fractions, or 21 Gy in 7-Gy fractions)493 and conventional fractionation
with 54 to 58 Gy in 1.8- to 2-Gy fractions,494,495 50 Gy in 2-Gy
fractions,496 or 36 to 44 Gy in 1.8-Gy fractions497 have been used.
Because of the variability in fractionation, dosage and administration,
and treatment volume, it is very difficult to assess outcomes measures
and even more difficult to draw meaningful conclusions across therapies.
Although the follow-up is very short in some of these series, the
control rates have ranged from 96% to 100%, with a useful hearing
rate ranging from 72% to 85% and low rates of cranial nerve V and
VII dysfunction. In a series from the University of Heidelberg, the
actuarial useful hearing preservation was 94% at 5 years. The diagnosis
of NF2 was a significant factor in hearing preservation; persons with
the diagnosis had a hearing preservation rate of 64% compared with
98% for those without NF2.498
The Heidelberg group compared their experiences in treating 200
patients who had acoustic neuroma with either SRS (a median of
13 Gy prescribed to the 80% isodose) or FSRT (a median of 57.6 Gy
in 1.8-Gy fractions).499 In general, tumors treated with SRS were
smaller. At a median follow-up of 75 months, no difference in local
control was found. No difference in hearing preservation occurred
between patients treated with SRS who received 13 Gy or less and
those treated with FSRT. However, when patients treated with SRS
who received more than 13 Gy are included, preservation of useful
hearing was more likely in patients treated with FSRT.499
This group reported rates of trigeminal nerve damage of 7% for
patients treated with SRS and 3% for patients treated with FSRT.
Facial nerve toxicity was observed in 17% of patients treated with
SRS and 2% of patients treated with FSRT. For patients treated with
SRS doses of 13 Gy or lower, the rate of facial nerve damage was 5%,
and no patients experienced trigeminal nerve damage.499 A group at
the University of California–Los Angeles reported on their experience
in treating 400 patients with SRS or FSRT.500 No significant difference
in hearing preservation was found between the two modalities for
patients with tumor volumes less than 3.0 cm3, but FSRT resulted
in better hearing preservation for patients with larger tumors.500
As indicated by the foregoing findings, radiation therapy can be
a useful alternative to surgery to control the growth of acoustic
neuromas. Undoubtedly, however, debate will continue regarding the
merits of one treatment over the other, and the optimal radiotherapy
technique. Although the previous discussion centered on the treatment
of acoustic neuromas, some evidence indicates that SRS is effective
in controlling the growth of trigeminal neuromas and alleviating
trigeminal neuralgia, as either an alternative or an adjunct to surgery.501
One recent development for patients with an inheritable form of
acoustic neuroma due to NF2 is the use of bevacizumab to control

tumor growth and to improve hearing. Plotkin and colleagues published
initial results with this technique in 2009, and ongoing studies have
shown favorable results.480 In 31 NF2 patients, tumor shrinkage and
hearing improvement were seen in more than 50% of vestibular
schwannomas, and stable or improved hearing was retained in the
majority of patients.502 The challenge, however, is that patients need
to stay on this drug for an extended period of time, and complications
include a 58% risk of hypertension and a 62% risk of proteinuria.503
Thus long-term outcomes remain to be defined.
CEREBELLAR HEMANGIOBLASTOMAS
Clinical and Pathologic Considerations
Hemangioblastomas are low-grade vascular tumors that constitute
1% to 2% of intracranial tumors. They usually occur in the cerebellar
hemispheres and vermis, although they can involve the pons, medulla,
and spinal cord. Most cases occur sporadically, but 20% occur as part
of the familial von Hippel-Lindau (VHL) syndrome.504 Patients with
this syndrome have a germline mutation in the VHL gene. Tumors
that develop in these patients have sustained a mutation in the second
VHL allele, leading to loss of VHL protein function and resulting in
stabilization of the HIF-1α protein under normoxic conditions.
Stabilization of HIF-1α leads to constitutive high levels of expression
of target genes, including VEGF (reviewed by Kaelin505). For this
reason, the tumors seen in patients with VHL syndrome are highly
vascular. Other abnormalities seen in these patients include retinal
angiomas, renal cell carcinomas, and cysts involving many organs
such as the pancreas, kidney, lungs, and liver. Pheochromocytomas
may also develop in these patients, who often display erythrocytosis
as a result of increased erythropoietin production. Sporadic heman-
gioblastomas, which occur in patients who do not have VHL syndrome,
also contain mutations in the VHL gene in at least 20% of cases.506
Cerebellar hemangioblastomas often manifest in the third decade
of life. Presenting manifestations stem from cerebellar dysfunction,
increased ICP, and involvement of nearby cranial nerves. These signs
and symptoms include headaches, nausea, vertigo, diplopia, tinnitus,
ataxia, and poor coordination.507 The lesion is well visualized at CT
scanning or MRI. Angiography, which typically is performed before
surgery, shows the highly vascular nature of these tumors.
Histologically, hemangioblastomas show numerous capillary and
sinusoidal channels lined with endothelial cells. A cystic component
is often present; the cyst is filled with xanthochromic, proteinaceous
fluid, with a vascular nodule in the cyst wall. In one series, 6 of 19
patients (32%) had a solid lesion without a cystic component.508
Lesions of this type are more likely to originate in the brainstem.
Therapy for Cerebellar Hemangioblastomas
The primary therapy for most patients with these tumors is surgical
resection, if surgery can be performed safely. If a cyst is present, it is
drained; then the solid component is dissected and removed. If the
tumor involves the brainstem, however, surgery may be extremely
risky, with the potential for massive hemorrhage or extensive postopera-
tive edema leading to death.508 Surgical resection historically has been
associated with high local control rates. In one series, recurrence was
noted in only 13 of 112 patients (12%) after surgery.507 In 6 patients,
disease recurred in the original tumor bed, after incomplete removal,
and in 10 patients, recurrence was in a different site or in the same
site after gross total resection.
For patients with unresectable or incompletely resected heman-
gioblastomas or for those whose tumors are medically inoperable,
radiation therapy usually is provided. In a series from the Mayo Clinic,
27 patients received radiation treatment, six because of microscopic
positive margins after surgery and 20 for gross residual disease.509 In
patients with gross residual disease, the rate of local control was 57%
for those who received 50 Gy or more but only 33% for those receiving
Cancer of the Central Nervous System • CHAPTER 63 953
less than this dose. In four of the six patients with microscopic residual
disease, this protocol achieved local control. For all 27 patients, the
overall 15-year survival rate was 58%, and the relapse-free survival
rate was 42%. Sung and associates510 also found that patients who
received a higher dose (40–55 Gy) had a superior survival compared
with those who received 20 to 36 Gy. On the basis of these results,
it would be reasonable to use approximately 50 Gy in patients requiring
radiation therapy. A series from two Canadian institutions reported
on the outcome of 18 patients treated with external beam radiotherapy,
50.0 to 55.8 Gy in 1.8- to 2.0-Gy daily fractions, for cerebellar or
spinal hemangioblastomas.511 Outcomes differed according to VHL
status. The 5-year OS was 100% for those with VHL-associated and
55% for those with non–VHL-associated hemangioblastomas. The
5-year disease-free survival was 80% for patients who had VHL
syndrome compared with 48% for patients who did not have VHL
syndrome.511
Radiosurgery has been used for cerebellar hemangioblastomas. In
a study from three institutions, 38 hemangioblastoma lesions in 22
patients were treated stereotactically, with single fractions ranging
from 12 to 20 Gy (median, 15.5 Gy).512 The vast majority of these
tumors had not undergone gross total resection. With a median
follow-up time of 24.5 months, the 2-year actuarial OS rate was 88%
and the 2-year PFS rate was 86%. A prospective evaluation of the
natural history of hemangioblastomas in 44 patients with VHL after
treatment with SRS (median dose 18.9 Gy at the tumor margin)
showed that the local control rates at 2, 5, 10, and 15 years after
treatment were 91%, 83%, 61%, and 51%, respectively.513
CHORDOMAS AND CHONDROSARCOMAS
INVOLVING THE BASE OF THE SKULL
Clinical and Pathologic Considerations
Chordomas are rare tumors with an incidence of less than 0.1 per
100,000 population per year.514,515 Originating from the remnant of
embryonal notochord, such lesions can occur along the spinal axis,
including the base of skull (dorsum sellae) to the coccyx.516 Fifty
percent of chordomas arise from the sacrococcygeal region (most
commonly in the fifth or sixth decade of life), with a third arising
from the base of the skull, most commonly the clivus but occasionally
the petrous bone; the remainder arise from the cervical region (with
a younger age distribution in the 30s to 40s). Chordomas rarely
metastasize, although there have been documented cases; rates of
metastasis range from 10% to 25%, with the most common sites
being lung, liver, and bone.517 Grossly, they are extradural, often
multilobulated, and pseudoencapsulated.518 They may have a consistency
that can range from extremely soft to woody or cartilaginous. Histologi-
cally, nests and cords of large vacuolated epithelioid cells can be seen
within a myxoid stroma with evidence of the physaliphorous cell.
Three subtypes exist: (1) conventional, (2) chondroid, and (3) dedif-
ferentiated, with the last subtype having a poor prognosis.519,520
Low-grade chondrosarcomas often are included in reports and
studies with chordomas given the low incidence of both tumors.
Chondrosarcomas arise from primary mesenchymal cells or embryonic
rests of cartilaginous matrix. Chondrosarcomas are composed of either
hyaline cartilage or myxoid cartilage or a mixture of the two. The
myxoid variant may be confused with chordoma. In one large series
of chondrosarcomas of the base of the skull, 66% arose from the
temporo-occipital region, 28% from the clivus, and 6% from the
sphenoethmoid complex.521
In a report from the Mayo Clinic, diplopia was the most common
symptom, followed by headaches, ptosis, retro-orbital pain, and neck
pain. Cranial deficits were very common, especially deficits of cranial
nerve VI, although deficits of cranial nerves III, IV, V, IX, X, and XII
were also seen.521 In the same study, MRI was shown to be the best
modality for demonstrating the entire extent of cranial chordomas
and the involvement of adjacent structures. These tumors typically
954 Part III: Specific Malignancies

appear hypointense (black) on T1-weighted images and hyperintense

(white) on T2-weighted images. Other possibilities to be considered
in the differential diagnosis for a clival lesion are metastasis, myeloma,
osteochondroma, meningioma, and chondrosarcoma.
Chordomas and low-grade chondrosarcomas have a similar radiologic
appearance. Together they account for almost all primary malignant
bone tumors arising from the base of the skull. They can result in
significant morbidity from local invasion and can be fatal. Even though
they are treated similarly, low-grade chondrosarcomas have a better
prognosis than do chordomas, as discussed next.

Therapy for Chordomas and Chondrosarcomas

Involving the Base of the Skull
Optimal treatment consists of maximal surgical resection (to establish
a diagnosis and to alleviate symptoms) followed by local radiation
therapy. Given the increased experience with endoscopic skull-based
techniques, improved instrumentation and, when necessary, the use
of arterially based mucosal flaps for CSF leak closure, the ability to
approach resections of these lesions has significantly improved. However,
obtaining a complete surgical resection, given the anatomic constraints
and infiltrative nature of the lesion, is very challenging. The surgery
often is performed jointly by a neurosurgeon and an otolaryngologist.
Complete resection can be curative, but this outcome is often not
possible because of the extent of disease. In the mobile spine, data have
shown that there is a 20% recurrence rate with negative margins, and
this rate rises to 70% in patients with positive margins.522 In a series
of 60 patients (46 with chordomas and 14 with chondrosarcomas)
from the University of Pittsburgh, the tumors were treated primarily
with surgery.523 Approximately 67% underwent total or near-total
resection, and 20% were treated with postoperative radiation because
of radiologic evidence of residual tumor. The 5-year recurrence-free
survival rates were 65% for patients with chordomas and 90% for
patients with chondrosarcomas (P = .09). Two common problems
after surgery were the development of CSF leakage and new cranial
nerve deficits, which occurred in 30% and 80% of cases, respectively.
Early treatment of chordomas with radiation (about 1950 to about
1980) consisted of photon radiation therapy delivered to a total dose
of 55 Gy with use of conventional two-dimensional techniques.517 In
a 1988 report by Fuller and Bloom, the 25 patients treated had a
median duration of freedom from local progression of 32 months,
with OS at 5 and 10 years of 44% and 17%, respectively. The
importance of a maximal safe resection was documented in a study
of 21 patients with chordoma from the Mallinckrodt Institute. Although
disease-free survival was not different among the groups reviewed,
those treated with surgery alone versus biopsy and radiation had an
improvement in 10-year survival.524 The Mayo Clinic reviewed the
role of postoperative radiation therapy after various surgical modalities
and found an increase in disease-free survival and an increase in OS
dependent on the extent of surgical resection (55% resection versus
36% for biopsy only).525
Given the poor outcomes with photon therapy alone in the 1960s
and 1970s, proton therapy was evaluated because of the potential
dosimetric advantages of higher dose deposition into tumor with the
ability to limit radiation dose to the surrounding tissue (Fig. 63.26).
MGH reported on the use of fractionated proton radiation therapy
in 1989 with 68 patients who received postoperative radiation therapy
to a median dose of 69 cobalt Gy equivalents (CGE) with a 5-year
actuarial local control rate of 82% and disease-free survival of 76%.526
A review of cases at MGH published in 1999 showed a 10-year local
control rate of combined proton-photon therapy that was highest for
chondrosarcomas, intermediate for male chordomas, and lowest for
female chordomas (94%, 65%, and 42%, respectively).527 A similar
review at Loma Linda University Medical Center with 58 patients
who had skull base chordomas and chondrosarcomas and were treated
with total doses between 64.8 and 79.2 CGE showed local control
rates of 92% for chondrosarcoma and 76% for chordomas.528 Actuarial
Figure 63.26 • Dosimetric proton therapy treatment plan for clival
chordoma. Dosimetric treatment planning for clival chordoma aims to maximize
dose to the target volume while minimizing dose to surrounding critical
structures as shown in color wash representing radiation dose distribution.
(From Walcott BP, Nahed BV, Mohyeldin A, et al. Chordoma: current concepts,
management, and future directions. Lancet Oncol. 2012;13:2.)
5-year survival rates were 100% for patients with chondrosarcoma
and 79% for patients with chordoma. Grade 3 and 4 late toxicities
(those requiring increased medical intervention or hospital admission)
were observed in four patients (7%) and were symptomatic in three
patients (5%). Other radiation techniques are also in use, including
SRS, but the data are limited. Finally, although some reports have
suggested anecdotal efficacy of chordoma to alkylating agents and
camptothecin analogues, systematic reviews of the literature have
unfortunately found chordomas to be generally refractory to conven-
tional chemotherapies.529
GLOMUS TUMORS OF THE BASE OF
THE SKULL
Clinical and Pathologic Considerations
Glomus tumors are low-grade tumors of neural crest origin arising
from the paraganglionic (glomus body) cells and therefore are also
referred to as nonchromaffin paragangliomas. Because they are thought
to be associated with chemoreceptor tissue, they are also known as
chemodectomas. Glomus tissue is found along the vagus nerve, the
glossopharyngeal nerve, and the jugular ganglion. Glomus tumors are
often divided into those arising in the soft tissue of the neck (glomus
vagale and carotid body) and those involving the temporal bone or
base of the skull (glomus jugulare and glomus tympanicum). The
focus of this section will be the skull base glomus tumors.
Glomus jugulare tumors originate from the jugular bulb in the
skull base, whereas glomus tympanicum tumors arise from the middle
ear cavity along the nerve of Jacobsen (cranial nerve X) or Arnold
(cranial nerve IX). In one series, 57 of 75 patients (76%) with glomus
tumors of the head and neck region had glomus jugulare tumors,
whereas 11 of 75 (15%) had glomus tympanicum tumors.530 In this
series, otologic signs and symptoms were common in patients with
both of these tumors. Conductive hearing loss and/or tinnitus occurred

in the majority of these patients. More than a third had bleeding from
the ear, ear pain, a polyp visible in the ear canal, and/or a mass behind
the tympanic membrane. Cranial nerve impairments were also very
common, specifically cranial nerve VII in patients with glomus
tympanicum tumors and cranial nerves V, VI, VII, VIII, IX, X, XI,
and XII in patients with glomus jugulare tumors.
CT and MRI often are diagnostic with these tumors. Cerebral
angiography will demonstrate the extremely vascular nature of these
tumors and in general is performed immediately before surgery.
Therapy for Glomus Tumors of the Base of the Skull
The treatment of glomus tumors is a very controversial topic, with
some experts strongly advocating surgery and others strongly advocating
irradiation. When surgery is performed, it generally is preceded by
embolization to reduce the subsequent operative time and blood loss.
Surgery for glomus tumors involving the base of the skull usually is
performed jointly by a neurosurgeon and a head and neck surgeon.
The results with surgery in the modern era have been excellent, with
local control rates ranging from 83% to 95%.531 The main complications
after surgery have been cranial nerve palsies, especially the facial nerve,
and CSF leak.
An extensive amount of literature regarding radiation treatment
for glomus tumors has been accumulated. In a series of 46 patients
with glomus tumors treated with radiation doses ranging from 35 to
66 Gy at the Royal Marsden Hospital, the 10-year local control rate
was 90%, with a median follow-up time of 9 years.532 Some late
relapses occurred, and thus the 25-year local control rate dropped to
73%. In two patients, both of whom had received 64 Gy or more, a
facial nerve palsy developed as a late complication. In a series from
the University of Florida, 53 patients with temporal bone glomus
tumors (46 with jugular tumors and 9 with tympanicum tumors),
most of whom had received no prior therapy, underwent radiation
therapy at doses ranging from 37.7 to 60 Gy (median dose, 45 Gy).531
The 10-year local control rate was 92%, with a median follow-up
time of 15 years. On the basis of their experience, the investigators
recommended a total dose of 45 Gy in 1.8-Gy fractions when radiation
was used. Their review of the literature showed local control rates
ranging from 83% to 100% in series using radiation therapy for
temporal bone glomus tumors.
A recent literature review sought to compare surgery with radiation
(either fractionated or SRS) in jugular and vagal glomus tumors.533
Tumor control failure, major complication rates, and the number of
cranial nerve palsies after treatment were significantly higher in surgical
than in radiotherapy series. No differences could be noted in tumor
control between fractionated or stereotactic treatment, and therefore
consideration for SRS may be an option in certain patient populations.
Although the evidence is based on a retrospective review, the authors
emphasize the importance of individualized and multidisciplinary care
in the management of these tumors. Considerations include size, age
of the patient, evidence of malignancy, genetic and family history,
risk of multiple tumors, and morbidities of treatment (usually neu-
rologic), which, most important, include cranial nerve palsies and
intracranial mass effect.
PINEAL REGION TUMORS
The pineal gland is located adjacent to the cerebral aqueduct and
brainstem, and therefore tumors in this location frequently obstruct
the posterior aspect of the third ventricle and aqueduct of Sylvius,
causing acute hydrocephalus with headaches, papilledema, nausea,
vomiting, diplopia, and lethargy. As tumors grow anteriorly, the
midbrain tegmentum and quadrigeminal plate are compressed, resulting
in Parinaud syndrome: paralysis of upward gaze, diminished pupillary
response to light, and refractory or convergence nystagmus.
In the United States and Europe, tumors of the pineal region
account for fewer than 0.5% to 1% of all intracranial tumors.534 In
Cancer of the Central Nervous System • CHAPTER 63 955
Japan, however, they account for 3% of all intracranial tumors. Tumors
in this location are much more common in childhood and account
for 3% to 11% of intracranial tumors in this age group.535
In series from the United States and Europe, roughly a third of
all pineal region tumors are germ cell tumors, a majority of which
are germinomas.534,536 In Japan, germ cell tumors constitute a larger
percentage of all pineal region tumors because germinomas are much
more common than in the West. Because germ cell tumors occur
most commonly in the second decade of life, they are discussed in
the section on childhood brain tumors. Approximately a third of
pineal region tumors are of glial origin, mostly astrocytomas, but
some are glioblastomas, oligodendrogliomas, and ependymomas.
These tumors are managed in a similar manner to management of
their counterparts in other parts of the brain, as discussed elsewhere in
this chapter.
Pineal parenchymal tumors (PPTs) account for slightly less than
a third of all pineal region tumors. A little less than half of PPTs are
pineocytomas; the other half are pineoblastomas. The papillary tumor
of the pineal region was introduced in the WHO 2007 classification.
Pineocytomas are histologically benign neoplasms composed of
well-differentiated pineal parenchymal cells. In general, these tumors
affect young adults and rarely disseminate. In one study the 5-year
actuarial survival rate for nine patients with pineocytomas was 86%.537
After resection, all of these patients were treated with local field
radiotherapy, receiving a dose greater than 50 Gy without craniospinal
irradiation.
Pineoblastomas, which consist of embryonal cells indistinguishable
from those that are characteristic of PNETs in other CNS sites, tend to
disseminate through the CSF and have a much poorer prognosis than
do pineocytomas. Pineoblastomas are rare in adults538 and typically
occur in the first two decades of life. A report reviewed the outcomes of
299 patients with pineoblastoma from 109 studies in the literature.539
At a mean follow-up of 31 months ± 1.9, the OS was 54%, with
patients diagnosed at 5 years of age or younger having poorer survival
than patients diagnosed at an older age. Furthermore, multivariate
analysis revealed that patients for whom gross total resection was
unable to be achieved had worse survival rates than did patients for
whom gross total resection was achieved.539 The addition of adjuvant
radiation therapy resulted in a survival benefit for patients who had a
subtotal resection, but not for patients for whom gross total resection
was obtained.539 Current standard treatment includes maximal safe
surgical resection followed by adjuvant cranial-spinal irradiation with
a boost to the postoperative bed, along with systemic chemotherapy.539
A small percentage of PPTs (less than 10%)—mixed pineocytoma-
pineoblastoma tumors or PPTs of intermediate differentiation—do
not fit either of the two categories.540 These tumors, like pineoblastomas,
have the capacity to seed the CSF, and thus some experts have recom-
mended craniospinal irradiation for management in such cases.540 In
one study the 5-year survival rate for patients with PPTs excluding
pineocytomas (15 pineoblastomas, 2 mixed PPTs, and 4 PPTs with
intermediate differentiation) was 49%.537 A multicenter retrospective
study examining adults with PPTs found that persons with tumors
of intermediate differentiation had a better outcome than did persons
with pineoblastomas, with 10-year survival rates of 72% versus 23%,
respectively (P = .001), and rates for control of spinal disease at 10
years of 81% and 50%, respectively (P = .04).538
TUMORS OF THE SPINAL AXIS
Clinical and Pathologic Considerations
Tumors of the spinal cord, which are far less common than intracranial
tumors, account for only 15% of all CNS tumors. The distribution
of histologic types of tumors involving the spinal axis is different from
that of tumors affecting the brain (Table 63.10).541 For example,
schwannomas (neuromas) account for almost one-fourth of all spinal
axis lesions but are very uncommon in the brain. Most primary spinal
956 Part III: Specific Malignancies
Table 63.10 Primary Spinal Axis Tumors:
Distribution by Histologic Type
Tumor Location Frequency (%)
Meningioma Intradural; extramedullary 42
Schwannoma Intradural; extramedullary 22
Ependymomaa Intradural; intramedullary 15
Astrocytoma Intradural; intramedullary 11
Other 6 tumor in 23 patients but only marginal or positive in 16 patients.
a
Ependymomas of the spinal cord are intramedullary, but myxopapillary
ependymomas of the cauda and filum terminale are intradural but extramedullary.
Data from Los Angeles County, 1972–1985 (reported by Preston-Martin541).
axis tumors are intradural, although chordomas are extradural (see
Table 63.10). Clinically these tumors manifest in one of three ways:
(1) radicular pain as a result of compression or infiltration of spinal
cord roots, causing a knifelike sensation along the nerve distribution;
(2) sensorimotor deficits dependent on the level of the tumor, character-
ized by muscle weakness and paresthesias (pain and temperature
abnormalities contralateral to the side of muscle weakness); and (3)
central syringomyelia with destruction of the central gray matter causing
motor neuron destruction, muscle wasting, and loss of pain and
temperature sensation with preservation of touch.
The imaging modality of choice for spinal tumors is MRI.542 Both
meningiomas and schwannomas are intradural but extramedullary.
The signal intensity of meningiomas on T1- and T2-weighted images
is similar to that of the normal cord, whereas for neuromas, the signal
is increased on T2-weighted images. Meningiomas typically enhance
with gadolinium. Spinal cord ependymomas and astrocytomas generally
are intramedullary tumors. The exception is ependymoma involving
the conus medullaris, which is not actually an intrinsic tumor of the
spinal cord. Ependymomas and astrocytomas of the spinal cord have
a similar appearance on MRI. T1-weighted images show an enlarged
spinal cord extending for several vertebral body segments. Both
astrocytomas and ependymomas may have cysts that are visible on
MRI. T2-weighted images show increased signal intensity in the region
of the tumor, with accompanying adjacent edema. Both tumor types
typically enhance with gadolinium, although there are rare exceptions.
The gadolinium enhancement in ependymomas tends to be very
homogenous with clear demarcation of the upper and lower extent,
unlike astrocytomas, in which the true extent often is underestimated
by MRI. Because they arise from cells in the central canal, ependymomas
are centrally located and expand circumferentially. In contrast,
astrocytomas can originate from anywhere in the spinal cord. The
differential diagnosis of these tumors includes various nonmalignant
conditions such as multiple sclerosis, transverse myelitis, and infarction
of the cord. Hemangioblastomas are much less common than astro-
cytomas or ependymomas. They show enlargement of the spinal cord
with multiple cysts. One or more intensely enhancing nodules may
be present in the cyst wall.
Chordomas Involving the Spinal Axis
Chordomas involving the base of the skull were discussed earlier;
however, these tumors also can involve the sacrum or the mobile
spine. Unlike the other histologic tumor types listed in Table 63.10,
chordomas are extradural tumors. Radiation therapy has been used,
but results have been poor. In a series from the Princess Margaret
Hospital, 48 patients with chordoma (23 of the sacrum, 5 of the
mobile spine, and 20 of the base of the skull) were treated with radiation
therapy, most immediately after the initial diagnosis but some after
local failure after surgery.543 Survival rates were 54% at 5 years and
20% at 10 years; patients with nonclival disease did just as poorly as
patients with clival disease.
Patients with chordomas of the sacrum or spine who are able to
undergo a radical resection have a reasonable chance for long-term
local control and cure. In a series from the Sahlgrenska University
Hospital in Sweden, 39 patients (30 with tumors involving the sacrum
and 9 with tumors involving the mobile spine) underwent surgery as
the primary treatment.544 Most patients had pain at presentation, but
many also had neurologic symptoms. En bloc surgical resection was
performed in 35 cases. The final surgical margins were negative for
With a mean follow-up time of 8.1 years, 23 patients (59%) were
found to be disease free at the time of last follow-up evaluation. Local
recurrence was seen in 17 patients (44%), and distant metastases
occurred in 11 patients (28%). The estimated 10- and 15-year survival
rates were 64% and 52%, respectively.
Spinal Meningiomas
Meningiomas are the most common spinal axis tumor (see Table
63.10). They are associated with NF2, as are their intracranial coun-
terparts.409 The prognosis with surgery is excellent. In a large series
of meningiomas from MGH treated with surgery alone, 18 (8%)
involved the spine (see Table 63.10).415 No failures were observed at
5 years, and a 13% recurrence rate was noted at 10 years. In a report
from the Milan Neurologic Institute, the crude recurrence rate was
6% in 150 patients with spinal meningiomas who had a complete
tumor resection versus 17% in the 6 patients who underwent subtotal
resection.545 Of 80 patients who had undergone a total resection at
the Cleveland Clinic, only one experienced a relapse, at 8 years.546
Even the seven patients who had a subtotal resection did well, with
only two relapsing, one at 13 years and one at 16 years. These findings
indicate that patients with these tumors do very well after total resection.
In the event of subtotal resection or if surgery is contraindicated
because of medical comorbidities or multifocality of lesions, radiation
therapy should be considered, as in the case of intracranial meningioma.
SRS has been used in one series of 51 patients with benign spinal
lesions, including meningiomas, who were not considered surgical
candidates, with a majority of patients demonstrating stability or
reduction in tumor size.547
Spinal Schwannomas
Schwannomas (neuromas) arise from the Schwann sheath, which covers
the extramedullary axons of the nerve roots. They are evenly distributed
throughout the cervical, thoracic, and lumbar regions but are uncom-
mon in the sacral region. The lesions are benign and well encapsulated;
therefore total surgical resection usually is possible and is curative.
Spinal Cord Ependymomas
Although spinal cord ependymomas are less common than meningiomas
and schwannomas involving the spinal axis, they account for 60% of
all intramedullary tumors. They occur more frequently in the middle
adult years and are rare in children. Because of their central location
within the spinal cord, ependymomas often manifest with dysesthesias
followed by progressive motor dysfunction but without objective
evidence of sensory dysfunction.548 A variety of histologic subtypes
have been described, including cellular (the most common), epithelial,
fibrillar, malignant, and myxopapillary. The last subtype is seen only
in the filum terminale or the conus medullaris and therefore is techni-
cally not an intramedullary tumor.
Spinal cord ependymomas have a more favorable outcome than
that noted for intracranial ependymomas. The primary treatment for
these tumors is surgery. Although not usually encapsulated, benign
spinal cord ependymomas generally do not infiltrate adjacent normal
tissue. Therefore the surgeon usually can find a plane between tumor

and normal tissue, allowing for gross total resection, which is associated
with a very low rate of recurrence. In one series of 38 patients with
spinal cord ependymomas who underwent a gross total resection,
none had recurred after a mean follow-up time of 24 months.548 In
multiple single-institution series, all with fewer than 100 patients,
gross total resection is consistently associated with longer PFS.549–553
However, two studies with 10-year follow-up data suggest that even
after gross total resection, recurrence can occur in up to 45% of
patients.552,553
It is difficult to assess the role of postoperative radiation for this
tumor because of the limited number of retrospective studies with
small numbers of patients. In general, postoperative radiation has
been given to patients who underwent a subtotal resection. In a review
of 11 series using surgery followed by postoperative radiation for
spinal ependymomas, both the 5- and 10-year survival rates ranged
from 60% to 100%, with most of the series showing 5-year survival
rates in the 80% to 90% range and local relapse rates of 13% to
33%.554 In two of the largest series from the Princess Margaret
Hospital555 and the Royal Marsden Hospital/Atkinson Morley’s
Hospital,556 patients with high-grade tumors had a much higher relapse
rate than those with low-grade tumors. In both of these series, when
failures occurred, they were usually local.
Because available data are limited, it is difficult to make strong
recommendations. However, patients who have benign ependymomas
that are totally resected do not appear to need postoperative radiation.
For incompletely resected benign ependymomas, it would be reasonable
to administer 45 to 50 Gy to the tumor bed. For high-grade epen-
dymomas, some persons would advocate giving all patients postoperative
radiation, regardless of the extent of surgical resection. The actual
volume that should be irradiated is unclear. High-grade spinal epen-
dymomas have been reported to recur intracranially, which has led
some persons to advocate craniospinal radiation,555 although little
evidence exists that the addition of cranial irradiation adds any benefit.556
If one considered craniospinal irradiation for a high-grade spinal
ependymoma, a reasonable dose would be 36 Gy followed by a boost
to the primary tumor bed to a cumulative dose of 50 to 54 Gy.
Spinal Cord Astrocytomas
Astrocytomas are slightly less common than ependymomas in the
spinal cord, accounting for approximately 40% of all intramedullary
spinal tumors. Most spinal astrocytomas are low grade; in adults, only
10% to 15% are high grade. In children, high-grade astrocytomas
are even less common, but pilocytic astrocytomas are seen. As with
ependymomas, the initial therapy for astrocytomas of the cord is
surgical resection. Astrocytomas tend to be more infiltrative than
ependymomas, however, making it difficult to find a plane of resection
between tumor and normal cord in order to perform a total resection.
Spinal astrocytomas have a poorer prognosis than do spinal
ependymomas. In a study from Hokkaido University of 13 patients
with astrocytomas and 22 patients with ependymomas, the 5-year
actuarial survival rates for the two groups were 50% and 96%,
respectively (P = .007). The histologic grade of the astrocytoma has
a significant influence on prognosis.557 In a series from the Mayo
Clinic, of 43 pilocytic astrocytomas and 25 diffuse fibrillary astrocy-
tomas, the 10-year survival rates were 81% and 15%, respectively.558
In a series from the University of California at San Francisco, 12
patients with low-grade spinal astrocytomas had a relapse-free survival
rate of 53%, whereas three patients with high-grade tumors all died
within 8 months.559 The 5-year survival rate for patients with low-grade
astrocytomas has been in the 55% to 79% range in other series.560,561
For high-grade astrocytomas, the prognosis is significantly worse, with
case series of grade III and IV astrocytomas having survival period of
1 year or less.561,562 Another series of 27 patients with anaplastic
astrocytoma and 8 patients with GBM found 1- and 5-year survival
rates to be 85% and 59% for anaplastic astrocytoma and 31% and
0% for GBM, respectively.563
Cancer of the Central Nervous System • CHAPTER 63 957
As with spinal ependymomas, it is difficult to conclusively dem-
onstrate that postsurgical radiation improves outcome; however, in
general it has been given to patients who have had a subtotal resection.
Most investigators have used 45 to 50 Gy to local fields for low-grade
astrocytomas. High-grade astrocytomas have been known to recur
with CNS dissemination, leading some persons to recommend cra-
niospinal irradiation. However, in spite of such aggressive therapy,
these tumors still recur.
No strong data exist to support the use of chemotherapy for spinal
cord astrocytomas. However, nitrosoureas and other agents used in
intracranial astrocytomas have been used with anecdotal reports of
efficacy (reviewed by Balmaceda564).
Miscellaneous Intramedullary Tumors
Of the 10% of intramedullary spinal cord tumors that are not
ependymomas or astrocytomas, a mixture of uncommon tumors is
found, including hemangioblastomas and gangliogliomas (reviewed
by Miller and McCutcheon565). Although exceedingly rare, primary
intramedullary germ cell tumors and PNETs have been reported.564,566
Hemangioblastomas are benign vascular lesions associated with
VHL disease in 10% to 30% of cases, as is the case for their cerebellar
counterpart (discussed in the section on cerebellar hemangioblastomas).
They typically occur in men in their fourth decade of life. Most of
these tumors appear as an enhancing tumor nodule within a cyst or
syrinx. Because they have well-defined margins, surgical resection
usually provides a cure, although care must be taken to avoid excessive
bleeding of these vascular tumors.567
Subependymomas are benign, well-circumscribed lesions that affect
men between 30 and 60 years of age. Subependymomas typically are
avascular and well demarcated from the normal cord, enhancing the
feasibility of complete surgical resection. In general, gangliogliomas
are benign tumors that have neuronal differentiation. They usually
are seen intracranially, but tumors in the spinal cord have been reported.
The primary treatment for these tumors is complete surgical resection;
however, this approach is associated with a significant risk of recurrence.
In one series of 30 spinal gangliogliomas, the 5-year actuarial survival
rate was 84%, but the 5-year event-free survival rate was only 36%.568
CHILDHOOD BRAIN TUMORS
Primary CNS tumors are the most common solid tumors and the
leading cause of cancer-related morbidity and mortality in children.569
CNS neoplasms constitute more than one-quarter of all malignancies
in children younger than 14 years in the United States.570 More than
3000 new cases are reported each year. Data collected by the Central
Brain Tumor Registry of the United States from 2007 to 2011 showed
that age-adjusted incidence rate of CNS tumors was highest in infants,
who had an overall incidence rate of 6.22 per 100,000. Children aged
1 to 4 years had the second highest rate at 5.52 per 100,000, followed
by children aged 5 to 14 years with a slightly lower age-adjusted
incidence of 5.00 per 100,000. During the period 1973 through
1994, the reported incidence of primary malignant brain tumors among
children in the United States increased by 35%.571 This apparent
increase may have been due to improved detection and reporting
facilitated by the availability of high-resolution neuroimaging.572 SEER
data limited to infant brain tumors confirmed an increase in reported
cases between 1975 and 1985 but no significant increase in tumor
incidence between 1985 and 2005.573
Reports of increased brain tumor incidence rates raise concern that
environmental factors may play a causative or contributory role in
childhood brain tumors. Despite these concerns, epidemiologic studies
investigating maternal nutritional intake, childhood diet, childhood
exposure to electromagnetic fields, air toxins, and parental occupational
exposure have not established direct links between these factors and
the development of childhood brain tumors.574–578 As noted earlier in
the section on epidemiology, however, strong data support a connection
958 Part III: Specific Malignancies
between cranial irradiation in childhood and the subsequent develop-
ment of brain tumors.
Hereditary factors are estimated to be primarily responsible for
approximately 2% of childhood brain tumors.29 Nearly 70% of all
optic pathway gliomas occur in patients with NF1,580 and almost
all childhood vestibular schwannomas occur in patients with NF2.
Hereditary immunosuppression disorders, as seen in Wiskott-Aldrich
syndrome and ataxia-telangiectasia; treatment-associated immunosup-
pression, as in organ transplant recipients; and exogenous immunosup-
pression, as in HIV infection, are known to be associated with an
increased risk of PCNSLs.581–583 The risk of a variety of childhood
primary brain tumors is elevated by germline p53 mutations (Li-
Fraumeni syndrome),584 whereas PTCH gene mutations (Gorlin
syndrome) predispose to medulloblastoma585,586 and mutations causing
defects in DNA mismatch repair (Turcot syndrome) predispose
to medulloblastoma and malignant glioma during childhood and
adolescence.587
Embryonal Brain Tumors in Childhood
Embryonal tumors in childhood are defined as tumors that arise
from pluripotent uncommitted neuroectodermal precursors cells of
the brain and are typically highly proliferative, with WHO grade IV
designation. The older 2007 WHO classification system of embryonal
tumors included medulloblastoma, atypical teratoid rhabdoid tumor
(ATRT), and PNET. PNET has been eliminated from the current
2016 classification system, and in its place are embryonal tumors
with multilayered rosettes with or without chromosome 19 (C19MC
region) amplification. Other embryonal tumors in this new classifi-
cation include medulloepithelioma, CNS neuroblastoma, and CNS
ganglioneuroblastoma.
Medulloblastoma
The most common CNS embryonal tumor is medulloblastoma, which
comprises approximately 10% of all pediatric brain tumors.570 Medul-
loblastomas arise in the cerebellum or dorsal brainstem and can be
seen growing into the fourth ventricle. The clinical presentation of a
medulloblastoma is dominated by signs and symptoms of obstructive
hydrocephalus and increased ICP that include headache, nausea and
vomiting, drowsiness, and ataxia. These clinical characteristics often
are indistinguishable from those of other posterior fossa tumors,
including ependymoma and cerebellar astrocytoma. CT scans typically
show evidence of hydrocephalus and relatively homogenous contrast
enhancement with little or no evidence of calcification. MRI scans
typically show a slightly increased T1 signal, homogenous contrast
enhancement, and diffusion restriction due to hypercellularity.589,590
A B
Figure 63.27 • Posterior fossa tumors. Sagittal T1-weighted postgadolinium magnetic resonance images of three different posterior fossa tumors. (A) A
medulloblastoma shows homogeneous contrast enhancement without evidence of cyst formation. (B) A cerebellar pilocytic astrocytoma shows prominent cyst
or multicyst formation, with one or more contrast-enhancing mural nodules. (C) An ependymoma arising from the floor of the fourth ventricle shows a
heterogeneous contrast enhancement pattern and extends inferiorly to the upper cervical spinal cord. Note that the pilocytic astrocytoma shows intense
enhancement despite being a low-grade glioma (World Health Organization grade I).
Research efforts to diagnose posterior fossa tumors preoperatively have
combined computer-based neural networks with data from advanced
neuroimaging studies (Fig. 63.27), and patient characteristics have
been studied. In a series of 33 children with posterior fossa tumors,
an experienced neuroradiologist was able to correctly predict the tumor
type in 73% of cases, whereas the neural networks using different
datasets had 95% accuracy.591
The 2016 WHO classification of medulloblastomas is based heavily
on molecular characterization. Histopathologic criteria are still used
in conjunction with the molecular subtyping, which allows for the
most precise prognostic information. Medulloblastomas are categorized
into four subgroups based on a several large-scale genetic profiling
studies: WNT (10%), Sonic Hedgehog (30%), and group 3 (20%)
and group 4 (40%).592–594 WNT and Sonic Hedgehog tumors have
one of many identified activating mutations along their respective
pathways. Groups 3 and 4 are less well defined, with MYC amplification
and chromosome 17 instability as identifiable molecular features. These
two latter groups have the highest potential for metastases to the
leptomeninges and spinal cord. The histopathology of medulloblastomas
can be one of the following: classic, desmoplastic/nodular, extensive
nodularity, and large cell/anaplastic. Patients with nodular tumors
have the best outcome among this group, whereas those with large
cell/anaplastic tumors have the worse outcome.595
Preoperative management of medulloblastoma includes the assess-
ment and treatment of increased ICP. Patients with papilledema and
significant visual impairment may require emergency placement of
an external ventricle drain, followed as soon as feasible by tumor
resection. Prolonged delay between ventricular drainage and tumor
resection significantly increases the risk of transtentorial upward hernia-
tion. For patients with less severe signs and symptoms of increased
ICP, corticosteroids and acetazolamide may be used to relieve symptoms,
reduce tumor swelling, and permit further surgical planning.
Surgical treatment of medulloblastoma has three objectives. First,
sufficient tissue must be obtained to permit accurate histopathologic
diagnosis. Second, tumor removal should be complete or nearly
complete, because complete tumor removal favorably influences
prognosis. However, efforts to remove residual tumor adherent to or
invading the brainstem may cause considerable postoperative neurologic
deficits, and a small residual tumor burden (e.g., <1.5 cm3) has no
apparent adverse effect on survival outcomes.596 Third, efforts should
be made to reestablish normal CSF flow. A majority of children with
medulloblastoma will not need a permanent ventriculoperitoneal shunt.
Furthermore, the increased use and success of endoscopic third
ventriculoscopy in which the floor of the third ventricle is fenestrated
and CSF is diverted from the third ventricle to the prepontine cistern
has significantly reduced the need for ventriculoperitoneal shunts and
their hardware-related higher infection risk.597 The incidence of tumor
C

dissemination to the abdomen by ventriculoperitoneal shunt is extremely
low, possibly because the peritoneal environment is not conducive to
neuroectodermal tumor growth, or possibly because concomitant
systemic chemotherapy may effectively prevent tumor implantation
or growth.598
Two postoperative syndromes may complicate the clinical course
of patients with medulloblastomas and other posterior fossa tumors.
Aseptic meningitis may occur in up to 5% of patients undergoing
posterior fossa surgery. Fever and meningismus, ranging in intensity
from mild to severe, develop 5 to 10 days after surgery. Although this
complication may occur more frequently in patients with large
postoperative pseudomeningoceles under tension, no clinical features
have been found to reliably distinguish this presumed chemical
meningitis from bacterial meningitis, and thus CSF analysis and culture
are essential. If no infectious cause is identified, this complication
may be effectively treated with corticosteroids. A second syndrome
of cerebellar mutism after resection of posterior fossa tumors was first
described by Hirsch and colleagues599 in 1979. More recently, these
deficits have been attributed to surgical disruption of the dentate-
thalamo-cortical pathway.600 This condition is far more common than
was originally reported and occurs in 15% to 25% of children with
large midline cerebellar tumors.601,602 Complete or near-complete loss
of speech often is accompanied by severe lower cranial nerve, cerebellar,
and motor abnormalities and visual disturbances.603 Cerebellar mutism
typically manifests 1 to 4 days after surgery and may be more frequent
in cases of aggressive surgical pursuit of medulloblastoma adherent
to or invading the brainstem.602 Most patients with this syndrome
recover functional speech during a period of several weeks to months
from onset, although it is common for them to have significant residual
dysfunction in speech, lower cranial nerve conduction, and motor
coordination. In a prospective study of cerebellar mutism by the
Children’s Oncology Group, the level of initial severity of signs and
symptoms directly correlated with coordination, speech and language
function, and intellectual function 1 year after onset, and these deficits
persisted in a significant fraction of patients.602
Postresection adjuvant therapy in persons with medulloblastoma
is determined by postoperative staging for prognostic risk factor
assessment. The most important clinical prognostic factor is metastatic
stage, followed by postoperative residual tumor volume, tumor location,
and the patient’s age at diagnosis.596,604,605 Approximately 20% to 30%
of medulloblastoma patients have dissemination at time of diagnosis.
Medulloblastoma is commonly associated with seeding of the spinal
cord (Fig. 63.28). Accordingly, three tumor staging studies prior to
treatment are important for medulloblastoma: (1) neuraxis staging
A B
Figure 63.28 • Disseminated medulloblastoma. (A) “Studding” of caudal nerve roots from spinal arachnoid spread of tumor. (B) Malignant cells identified
at cytologic examination of cerebrospinal fluid. (From Maher EA, McKee AC. Neoplasms of the central nervous system. In: Skarin AT, ed. Dana-Farber Cancer
Institute Atlas of Diagnostic Oncology. 3rd ed. St Louis: Mosby; 2003.)
Cancer of the Central Nervous System • CHAPTER 63 959
evaluation by spinal MRI (preoperative when feasible) to identify
metastatic tumor aggregates; (2) CSF cytologic examination (within
14 days after surgery) to identify leptomeningeal tumor spread; and
(3) postoperative neuroimaging to assess residual tumor.606 Based on
the results of these studies, patients with medulloblastomas are classified
into two risk-for-recurrence groups—standard risk and high risk.
Standard-risk patients must have no evidence of metastatic disease,
have 1.5 cm or less of residual tumor, be older than 3 years at diagnosis,
and have primary tumor located in the posterior fossa only.607 High-risk
patients have one or more of the following conditions: evidence of
leptomeningeal tumor spread; more than 1.5 cm of residual tumor;
age younger than 3 years at diagnosis; or primary tumor location
outside the posterior fossa. The prognostic significance of malignant
CSF cytologic findings in the absence of neuroimaging abnormalities
(i.e., M1 stage) has been the subject of debate for more than a decade.
However, multiple investigators have clearly demonstrated that M1
status has substantially poor prognostic implications and is sufficient
to warrant classification of the patient as high risk.608
Radiation treatment approaches for medulloblastomas are deter-
mined by assignment of the patient to either a standard- or a high-risk
category. High-risk patients receive 3600 cGy of radiation to the
craniospinal axis and chemotherapy, followed by a boost to the posterior
fossa tumor site to a total dose of approximately 5580 cGy. Standard-risk
patients typically receive a lower craniospinal dose (e.g., 2340 cGy),
followed by a posterior fossa boost to 5580 cGy. Radiation doses to
the primary tumor site of less than 5000 cGy increase the risk of
treatment failure.609 The lower craniospinal radiation therapy dose for
standard risk is intended to decrease the risk of neurocognitive and
other radiation-associated toxicities. Infants and children younger than
3 or 4 years of age may be given intensive chemotherapy alone to
postpone or avoid the neurotoxic effects of radiation on the developing
brain.610 Ten-year OS in these patients has been reported to be as
high as 60%.611
Treatment with craniospinal irradiation (to a dose of 36 Gy) and
local boost radiotherapy (for a total dose of 54 Gy) without adjuvant
chemotherapy typically yields long-term disease control in approximately
60% of children with medulloblastoma; however, 5-year survival rates
approaching 90% after radiation therapy alone have been reported.
After whole-brain radiotherapy, however, many children will have
significant long-term neurocognitive sequelae, including a demonstrable
drop in overall intelligence. This decline in intelligence is influenced
by age at irradiation and the dose used. Silber and colleagues reported
that patients who received a dose of 36 Gy to the whole brain scored
8.2 points lower on IQ testing than did those who received 24 Gy
960 Part III: Specific Malignancies
and 12.3 points lower than those who received 18 Gy.612 Older age
at the time of irradiation was associated with less decline in subsequent
IQ score.
Serious long-term adverse effects of radiotherapy on the developing
nervous system prompted efforts to reduce the dose of craniospinal
radiation therapy in nonmetastatic medulloblastoma. The lowest
craniospinal radiotherapy doses reported, 18 Gy in 10 fractions, with
50.4 to 55.8 Gy to the posterior fossa tumor bed, has been used in
combination with vincristine during irradiation and subsequent
vincristine, CCNU, and cisplatin.613 Ten patients aged 18 to 60 months
and without evidence of tumor dissemination received treatment
according to this approach. With a median follow-up time for living
patients of 6.3 years, the survival rate at 6 years was 70% ± 20%.
The three patients in whom relapse occurred all were found to have
spinal metastases, in association with brain or posterior fossa recurrence.
These data and others provided the foundation for a Children’s
Oncology Group prospective clinical trial for children with medul-
loblastomas who are older than 3 years at diagnosis in which the
craniospinal dose in two cohorts is randomized between 18 Gy (with
reduction in boost volume) and standard 23.4 Gy (with posterior
fossa radiotherapy). Preliminary results from this trial (ACNS0331)
showed that decreasing radiation boost volume to the primary site
was not inferior to standard posterior fossa radiotherapy, but nonin-
feriority could not be established for decreased 18-Gy craniospinal
dose.614 Prospective studies have demonstrated that chemotherapy has
an important role in the treatment of high-risk medulloblastoma.
Medulloblastomas are responsive to a variety of chemotherapeutic
agents, including cisplatin, cyclophosphamide, vincristine, CCNU,
and busulfan.615 Incorporation of cisplatin, CCNU, and vincristine
into a postirradiation chemotherapy regimen for high-risk patients
resulted in 5-year survival rates in excess of 80%.616 Of note, this
survival rate was significantly higher than survival rates for standard-risk
patients treated with radiation therapy alone (i.e., historical control
subjects). This study and other single-institution studies have provided
strong support for the use of effective adjuvant chemotherapy for all
patients with medulloblastoma. Efforts to increase the efficacy of
chemotherapy for clinically high-risk patients have focused on increasing
dose and dose intensity of the active agents previously noted through
the use of serial nonmyeloablative treatment cycles, each with stem
cell support. Gajjar and colleagues reported a 5-year event-free survival
of 83% for standard-risk patients and 70% for high-risk patients with
medulloblastoma who were treated with craniospinal radiation followed
by four cycles of cyclophosphamide-based, dose-intensive chemo-
therapy.617 For patients with supratentorial embryonal tumors, the
event-free survival rates were 75% for standard-risk and 60% for
high-risk patients with use of a similar treatment strategy.618
Effective treatment of recurrent medulloblastomas, in either cerebel-
lar or supratentorial sites, remains difficult. Whereas high-dose che-
motherapy with peripheral blood stem cell rescue is a therapeutic
strategy that has produced durable responses in selected patients,619
the effectiveness of this strategy as a curative therapy remains contro-
versial. For children with recurrent medulloblastoma, Kalifa and
associates620 used a high-dose busulfan-thiotepa regimen. Of 28 patients
evaluable for tumor response, complete tumor resolution was obtained
in 36%, a partial response was obtained in 39%, and no response
occurred in 25%. Dunkel and colleagues621 reported a series of 23
patients with recurrent medulloblastomas. The chemotherapy consisted
of carboplatin, thiotepa, and etoposide followed by peripheral blood
stem cell rescue. Three patients died of treatment-related toxicities.
Overall, 7 of the 23 patients (30%) remained free from tumor recurrence
at a median follow-up of 54 months after high-dose chemotherapy.
A review of high-dose chemotherapy for recurrent medulloblastoma
reported a 22% disease-free survival rate from eight different inter-
national studies.622 However, some of these included patients who
were never treated with radiation therapy, and the event-free survival
from larger international studies that reported results from the time
of relapse was only 4.2%. Temozolomide was shown to be effective
in a study that included 42 patients with recurrent medulloblastomas
or supratentorial embryonal tumors (PNET). Median OS rates at
6 and 12 months were 42.5% and 17.5%.623 At the current time,
it is clear that very few patients with relapsed medulloblastomas
have PFS in excess of 5 years. The majority of patients with recurrent
medulloblastomas are candidates for phase I and phase II trials.
Box 63.5 summarizes the recommended approach to management of
medulloblastomas.
Atypical Teratoid Rhabdoid Tumors
ATRTs are highly malignant embryonal tumors that mainly affect
children younger than 3 years. They make up about 10% of CNS
tumors in infancy and have a predilection for developing in the
brainstem in this age group. ATRT’s cell of origin is most likely a
pluripotent fetal cell because immunohistochemical analysis shows
that they express neural, epithelial, and mesenchymal markers. Because
they are highly cellular and densely packed, they appear on MRI with
increased diffusion restriction, similar to medulloblastomas.624 Unlike
medulloblastomas, they are less likely to have a heterogeneous appear-
ance from hemorrhage, cysts, and calcifications. Molecular analysis
of ATRT has identified a mutation in INI1 that now is a part of the
diagnosis of ATRT. The absence of INI1 staining is essential for the
identification of the ATRT. INI1 (also called SNF5 or SMARCB1)
encodes a protein that is a part of the SI/SNF complex, which mobilizes
nucleosomes and remodels chromatin to regulate transcription of
target genes.625 Two comprehensive epigenetic analyses found three
distinct patterns of methylation and gene expression patterns in tumors
classified as ATRT.626,627 The variable tumor response to treatment
was the impetus for these investigations; however, no studies have
yet been conducted to determine the treatment outcome of these
subgroups.
Prognosis for patients with ATRT is extremely poor, and treatment
is intensive and multimodal. In general, 5-year OS with radiation
and chemotherapy approaches only 30%, with the worst prognosis
Box 63.5. MANAGEMENT OF
MEDULLOBLASTOMAS AND
PRIMITIVE NEUROECTODERMAL
TUMORS
• Medulloblastoma (MB) and related primitive neuroectodermal tumor
(PNET) constitute the most common type of malignant childhood
brain tumor.
• Surgical objectives include gross total resection to establish
diagnosis, restore cerebrospinal fluid (CSF) flow, and improve survival.
• Postoperative staging should be undertaken in all patients and
should include magnetic resonance imaging (MRI) of the brain within
24 hours of surgery, an MRI study of the entire spine 10–14 days after
surgery, and CSF cytologic studies 10–14 days after surgery. These
studies determine subsequent risk-based treatments.
• Standard-risk patients must meet all of the following criteria: age
older than 3 years, cerebellar location, little or no residual tumor
(<1.5 mL), and no evidence of metastatic tumor spread. All other
patients are considered to be in the high-risk category.
• Treatment in standard-risk patients consists of lower-dose
craniospinal radiation therapy with doses of 23.8 Gy in 1.8-Gy daily
fractions, tumor irradiation with doses of approximately 55.8 Gy, and
less intensive chemotherapy.
• MB or PNET in high-risk patients is treated with craniospinal
irradiation with doses of approximately 36 Gy in 1.8-Gy daily
fractions, tumor irradiation with doses of approximately 55.8 Gy, and
intensive chemotherapy.

in children younger than 6 months.628,629 An example of a treatment
regimen for ATRT was used in a prospective study by Chi and colleagues
and consisted of surgery, radiation, and a five-phase chemotherapeutic
regimen of vincristine, dactinomycin, cyclophosphamide, cisplatin,
doxorubicin, and temozolomide with intrathecal chemotherapy of
methotrexate, cytarabine, and hydrocortisone. Outcome with this
treatment strategy was 53% 2-year PFS and 70% 2-year OS.630
Childhood Gliomas
Astrocytic tumors or gliomas are a diverse group of tumors with glial
cell origins, although the exact glial cell types that develop into these
tumors are still largely unknown. The new WHO classification system
separates these tumors into two main groups: diffuse, and other
astrocytic, which includes the low-grade gliomas. Diffuse glial tumors
include diffuse astrocytoma, anaplastic astrocytoma, glioblastoma,
oligodendroglioma, and diffuse midline gliomas. In the category of
other astrocytic tumors are pilocytic astrocytoma, subependymal giant
cell astrocytoma, and pleomorphic xanthoastrocytoma.
Diffuse Midline Gliomas
The majority of the diffuse gliomas are most commonly seen in adults,
except for the diffuse midline glioma. Tumors of this type occur in
the brainstem, thalamus, and spinal cord. Those that grow in the
pons were previously called diffuse intrinsic pontine glioma (DIPG).
DIPGs constitute more than 70% of all brainstem neoplasms. The
clinical presentation of diffuse pontomedullary brainstem gliomas
classically involves one or more of the following abnormalities: (1)
cranial nerve palsies, typically VI and VII; (2) ataxia; and (3) long
tract signs, including hyperreflexia and extensor plantar responses.
The prediagnostic symptomatic interval often is less than 3 months.
The MRI characteristics of DIPGs include diffuse infiltrative
enlargement of the pons and rostral medulla (Fig. 63.29).631 T1-weighted
MRI sequences usually show mass effect and reduced signal intensity
compared with normal brain. T2-weighted MRI sequences often reveal
Figure 63.29 • Diffuse pontine glioma. A sagittal fluid-attenuated inversion
recovery (FLAIR) magnetic resonance image shows diffuse infiltration of the
pons by tumor.
Cancer of the Central Nervous System • CHAPTER 63 961
regions of high signal intensity representing tumor infiltration with
rostral extension into the midbrain and brachium pontis and lateral
extension into the cerebellar peduncles. Brainstem enlargement may
be unilateral and often is asymmetric on diagnosis. The fourth ventricle
usually is distorted; however, obstructive hydrocephalus is distinctly
uncommon at initial presentation.
Because of the distinct characteristic of DIPGs on MRI and the
high risk of harm from biopsy of the brainstem, a multiinstitutional
collaboration in the early 1990s sponsored by the Children’s Cancer
Group determined that MRI was sufficiently accurate for DIPG.631
More recently, the impetus for biopsy and autopsy of these tumors
has stemmed from the need for tissue samples for research purposes.
Biopsy is still not widely adopted because of the ethical difficulty in
weighing the low benefit to the patient against the altruism of contribut-
ing to research that can benefit others.
From tissue that has been obtained during biopsies or postmortem,
several mutations have been discovered that are highly specific to this
tumor type. More than 70% of DIPG patients have a mutation in
the K27 position of the histone gene H3F3A that encodes H3.3,
which leads to a key lysine residue replacement with methionine that
results in biochemical inhibition of PRC2. The inhibition of this
protein causes a global loss of trimethylation of lysine 27 on all histone
H3 molecules.632 In about 20% of high-grade pontine gliomas, gain-
of-function mutations in ACVR1 occur in conjunction with H3.1
mutations. ACVR1 mutation leads to a hyperactivation of the bone
morphogenetic protein–ACVR1 developmental pathway.633
DIPGs are among the least responsive and most treatment-resistant
childhood solid tumors. Conventional radiation therapy consists of
54 to 60 Gy, delivered with use of an involved-field irradiation protocol
and administered in single daily fractions of approximately 1.8 to
2 Gy. This approach results in a median survival time of 9 to 13
months from diagnosis.634 Despite encouraging single-institution reports
suggesting prolonged PFS for children with gliomas who are treated
with hyperfractionated radiation therapy in which total radiation doses
reached 78 Gy, larger cooperative trials failed to demonstrate a thera-
peutic advantage for this approach, and substantially increased risk
of radiation-induced brain injury or radionecrosis was observed.635–637
Radiation implants (i.e., brachytherapy) are not appropriate for these
tumors, and the role of SRS has not been evaluated.
Standard chemotherapy has no current role in DIPGs because no
chemotherapy or biologic agent has demonstrated a significant ability
to reduce tumor volume as an objective response, let alone increase
PFS or OS. Single-agent phase I and phase II clinical trials continue
to have value in the search for active agents. A phase III trial using
CCNU, vincristine, and prednisone after radiation therapy failed to
show a survival advantage compared with use of radiation therapy
alone.638 The use of high-dose chemotherapy followed by autologous
stem cell reinfusion results in relatively brief responses, with few
instances of significant tumor reduction lasting 12 months or longer,
and no examples of curative activity.639 Accordingly, it is not possible
to support the routine use of chemotherapy in persons with brainstem
gliomas outside the setting of well-structured clinical trials.
Low-Grade Astrocytomas of Childhood
Low-grade gliomas-astrocytomas occur throughout the brain and spinal
cord. The predominant histologic subtype for cerebellar astrocytomas
is pilocytic, whereas optic pathway or hypothalamic low-grade gliomas
are either of pilocytic or fibrillary histology. Pilocytic astrocytomas
are the most common brain tumors in the pediatric population, making
up nearly a fifth of all pediatric brain tumors.570 Optic pathway or
hypothalamic gliomas may be classified by location as follows: (1)
those anterior to but not involving the chiasm; (2) chiasmal tumors
with extension posteriorly along the optic radiations; and (3) chiasmal-
hypothalamic tumors for which the initial site of tumor growth cannot
be determined. The majority of optic pathway gliomas occur in children
with NF1 who are younger than 6 years at diagnosis.
962 Part III: Specific Malignancies
Molecular factors influencing tumorigenesis of low-grade gliomas
are becoming more apparent. Many childhood low-grade astrocytomas
demonstrate a small nonrandom duplication of chromosome 7p
involving the oncogene BRAF that results in an upregulation of the
RAS-RAF-MEK pathway.
Optic nerve gliomas anterior to the chiasm manifest with progressive
visual loss, proptosis, or both. Their appearance on CT and MRI
studies usually is sufficiently diagnostic that routine biopsy is not
necessary. Meningiomas of the optic nerve sheath often can be dis-
tinguished from optic nerve gliomas on the basis of neuroimaging
characteristics.640 Optic nerve gliomas should be treated conservatively.
Documented evidence of progressive tumor growth together with
painful or disfiguring proptosis and complete or nearly complete loss
of vision may justify surgical resection of the nerve. Surgical resection
is curative when tumor-free margins are achieved, and no further
therapy is required. As a rule, optic nerve gliomas anterior to the
chiasm do not invade the chiasm itself. For patients with progressive
tumor growth and functional vision, radiation therapy is rarely
indicated, and current chemotherapy is similar to that for chiasmal
gliomas, as discussed later.
Chiasmal and chiasmal-hypothalamic gliomas constitute 60% to
85% of all optic pathway–hypothalamic tumors. Patients with these
tumors, especially very large chiasmal-hypothalamic gliomas, often
come to medical attention before the age of 5 years with signs and
symptoms of visual loss and hydrocephalus. Older children are more
likely to have symptoms including endocrinopathies and behavioral
changes. Children younger than 2 years may have a diencephalic
syndrome characterized by frequent vomiting, anorexia, and failure
to thrive.641 In children with NF1 and chiasmal tumors involving the
optic nerve, a diagnosis on the basis of radiographic criteria alone is
sufficient. For children who do not have NF1, especially those with
large globoid tumors extending through the hypothalamus, surgical
biopsy is standard.642 Although diagnostic confusion is not common,
these tumors may have a clinical and neuroimaging appearance similar
to that of solid craniopharyngiomas or germ cell tumors, for which
treatment is very different.
Most chiasmal and chiasmal-hypothalamic gliomas are not “cured”
with currently available surgical approaches, radiation therapy, or
chemotherapy. The slow and often erratic growth of these tumors has
led some experts to conclude that most of these “benign” tumors will
eventually be fatal.642 The development of more effective chemotherapy
has proved that this conclusion is incorrect, and a majority of patients
have long-term survival periods in excess of 10 years. In most cases,
rather than automatically initiating treatment at the time of tumor
diagnosis, the decision to initiate treatment is based on clinical or
radiographic evidence of tumor growth and evidence of progressive
visual or other neurologic dysfunction during serial observations.
Recent studies have suggested that serial assessment of the retinal
nerve fiber layer thickness by optic coherence tomography is likely to
add to the accuracy of visual function assessments, especially in younger
children.643 Patients with severe visual loss or clear historic evidence
of rapid clinical worsening represent exceptions to this approach.
Whereas some patients show significant changes in visual acuity or
neuroimaging scans within weeks or months of initial diagnosis, many
others remain clinically stable for months or years without interval
treatment.
For patients who retain a degree of useful vision, chiasmal and
chiasmal-hypothalamic gliomas cannot be completely resected without
complete visual loss. Surgical debulking of large chiasmal-hypothalamic
gliomas, however, is increasingly recognized to provide rapid relief of
symptoms caused by mass effect and hydrocephalus, delay the need
for radiation therapy in young children, result in years of clinical
stability without tumor growth, and improve the effectiveness of
subsequent radiation therapy.
Local involved-field radiation therapy has been shown to be effective
in arresting tumor growth and causing tumor shrinkage.644,645 Complete
tumor regression is rare after irradiation, however. Because more than
90% of patients with optic pathway–hypothalamic gliomas survive
longer than 10 years,644,646 the late effects of radiation therapy, including
neurocognitive problems, endocrinopathy, optic nerve injury, and
radiation-induced second neoplasms, are important considerations.
These issues have stimulated the investigation of alternative treatment
approaches, including chemotherapy.
Chemotherapy has a defined role in the treatment of optic
pathway–hypothalamic gliomas. For younger children, particularly
those younger than 5 years, the use of chemotherapy delays or obvi-
ates the need for radiation therapy, thereby reducing or eliminating
the severe neurologic morbidity associated with radiation therapy in
young children. Currently used chemotherapy regimens for optic
pathway tumors generally are well tolerated, are administered in the
outpatient setting, and are not associated with a high incidence of
serious late effects. In a large multiinstitutional trial of carboplatin
and vincristine, 60% of the patients with progressive low-grade glioma
had a significant reduction in tumor volume, and another 30% of
patients had tumor stabilization.647 A different regimen developed at
the University of California at San Francisco included procarbazine,
6-thioguanine, dibromodulcitol, CCNU, and vincristine. This treatment
protocol resulted in prolonged periods of disease stabilization with
a median time to tumor progression of 132 weeks in children with
low-grade gliomas.648 The Children’s Oncology Group completed a
large randomized clinical trial (A9952) comparing these two strategies.
Five-year PFS rates were 39% for carboplatin and vincristine and 52%
for thioguanine, procarbazine, CCNU, and vincristine; however, the
difference between these two treatment arms did not reach statistical
significance.649 Other chemotherapeutic agents have shown some efficacy
in the treatment of optic pathway tumors, including the use of weekly
vinblastine for recurrent or refractory low-grade astrocytomas and
bevacizumab with irinotecan.650,651 BRAF V600e mutation and fusion
variants have also paved the way for molecular targeted therapy.652
Inhibitors of key proteins in the MAPK pathway are being studied,
have yielded variable but some positive results, and have the potential
to soon be considered as first-line therapy for some gliomas with
BRAF mutations.653–655
The incidence of optic pathway tumors in patients with NF1 is
markedly higher than in the general population. Up to 15% of children
in whom the diagnosis of NF1 is confirmed will be found to have
optic pathway tumors when they undergo screening neuroimaging.656
Because optic pathway tumors nearly always arise in children younger
than 10 years, all young children with NF1 should undergo yearly
ophthalmologic evaluation and annual assessment of growth to monitor
for signs of precocious puberty. Most optic nerve gliomas in patients
with NF1 are anterior to the optic chiasm. In slightly more than half
of all children with radiographically identifiable optic pathway tumors,
however, signs or symptoms directly related to their tumors ultimately
developed. When studied systematically, these tumors appear to behave
in a more indolent fashion than their counterparts in children who
do not have NF1. However, low-grade gliomas in children with NF1
are notoriously erratic in their natural history. At times, these tumors
appear to undergo rapid growth and then spontaneously arrest or
even regress. Furthermore, progression of these tumors on MRI images
does not always correlate with vision loss. For these reasons, most
clinicians treat only patients who have a decline in visual acuity.
As with their non-NF1 counterparts, management of children
with NF1 and optic pathway glioma is dependent on the location
of the tumor. Anterior optic pathway gliomas do not invade the
chiasm in patients with NF1 and are managed according to the clinical
symptoms. Chiasmatic optic pathway gliomas should be watched closely
for neuroimaging or clinical evidence of tumor progression. Progressive
chiasmal tumors are treated with chemotherapy strategies associated
with a relatively low incidence of second malignancies (e.g., carboplatin
and vincristine). A fundamental question remains about whether the
use of chemotherapy results in a preservation or improvement of visual
function. In a recent multiinstitutional study of visual outcomes in
patients with NF1 optic pathway glioma, Fisher reported that the
 Cancer of the Central Nervous System • CHAPTER 63 963

visual acuity improved in 32% of subjects and remained stable in

40%.657 Only 28% of the 88 subjects studied had a decline in visual
acuity. Chemotherapy is preferred over other treatment modalities
because of potential functional injury to the pathway from surgery
and the unacceptably high risk of secondary tumors from radiation
in NF1 patients with a known cancer predisposition gene mutation.
Pilocytic or low-grade fibrillary tumors can also arise in other brain
regions including the cerebellum and cervicomedullary junction and
can appear as dorsally exophytic tumors and cystic nodular tumors
in the brainstem. Malignant gliomas of the cerebellum in childhood
are extremely rare. The survival rate is determined by the extent of
resection, not by histologic features. Use of radiation therapy is limited
to those cases of recurrent astrocytoma that cannot be resected because
of extensive invasion into the cerebellar peduncles or brainstem.
Cerebellar astrocytomas have, arguably, the best prognosis of any brain
tumor, with 10-year survival rates approaching 100%.658 If postoperative
MRI shows resectable tumor, reexploration may be indicated in order
to achieve complete resection. Despite excellent outcome statistics, it
is increasingly recognized that the long-term clinical consequences of
the tumor, its location, and surgical resection have been underestimated.
A significant number of children experience long-term neurologic
sequelae including cognitive deficits in up to 20% and emotional
disturbances in approximately 30%.659
When low-grade astrocytomas appear in the cervicomedullary region,
they can occupy the inferior two-thirds of the medulla and the upper
portion of the cervical spinal cord. These gliomas tend to extend
from their cervicomedullary center in conformance with anatomic
boundaries.660 In contrast with midbrain tumors, intratumoral cysts Figure 63.30 • Dorsally exophytic brainstem glioma. A sagittal T1-weighted
are uncommon. The prediagnostic symptomatic interval may extend postgadolinium magnetic resonance image shows an intensely enhancing lesion
for several years. Surgical resection of these tumors is indicated with filling the floor of the fourth ventricle, attached only at the floor at the level
of the pontomedullary junction. Enhancement is characteristic of juvenile
clinical or radiographic evidence of tumor growth. Although near-total pilocytic astrocytomas. (From Halperin EG, Constine LS, Tarbell NJ, Kun
resection is possible, the poorly defined interface between tumor and LE. Pediatric Radiation Oncology. 3rd ed. Philadelphia: Lippincott Williams
normal brainstem often precludes complete surgical removal of these & Wilkins; 1999.)
tumors. Long-term follow-up studies have indicated that many patients
will not have evidence of growth for more than 5 years. When tumor
growth is observed, its rate often is extremely slow, and malignant
transformation has not been documented. As with the dorsally exophytic Ependymoma
tumors, use of radiation therapy or chemotherapy is limited to those
few cases in which progressive symptomatic tumor growth is observed Childhood intracranial ependymomas represent approximately 5% to
and cannot be controlled by surgical approaches alone. 10% of all childhood brain tumors (see Table 63.2) and behave primarily
Pilocytic or low-grade fibrillary tumors can also appear as dorsally as localized, relatively noninvasive neoplasms that originate from the
exophytic tumors arising from the floor of the fourth ventricle. Although ventricular ependymal linings, possibly from radial glia.76 Nearly 70%
eventually the tumor often completely fills the ventricle, patients may of childhood ependymomas are located in the posterior fossa arising
have few if any neurologic signs for years before the development of from the floor of the fourth ventricle (see Fig. 63.27, C). The remaining
signs and symptoms of obstructive hydrocephalus. MRI demonstrates 30% are located in supratentorial periventricular regions. The classic
a well-demarcated lesion that is hyperintense on T2-weighted images histologic feature of ependymomas is the perivascular pseudorosette. Two
and hypointense on T1-weighted images but enhancing with gadolinium general histologic classifications have been described. Well-differentiated
(Fig. 63.30). Because these tumors are low-grade fibrillary or pilocytic ependymomas are moderately to highly vascular, with low mitotic
astrocytomas, they are amenable to surgical resection. If substantial indices and little cellular pleomorphism or evidence of necrosis. Ana-
surgical tumor removal is achieved, often no adjuvant treatment is plastic ependymomas exhibit higher mitotic rates, substantial cellular
necessary and the patient can be managed with close observation atypia, and prominent necrosis. The rare “ependymoblastoma” may
using serial MRI scans. Use of local radiation therapy or chemotherapy best be classified as an embryonal tumor with histologic evidence of
is limited to the uncommon cases of malignant dorsally exophytic ependymal differentiation and treated in a fashion identical to that
gliomas or the occurrence of significant tumor growth after surgery.661 for the medulloblastomas. The role of standard histologic classification
Pilocytic astrocytomas can also appear as cystic nodular brainstem in prognosis has been controversial, with difficulties in consensus
tumors that may be located in any region of the brainstem but most regarding the histologic features separating well-differentiated from
often are noted in the midbrain.662 These tumors have a radiographic anaplastic groups. However, agreement is emerging that histology has
appearance identical to that of their cerebellar counterparts, and their prognostic significance.664 Ependymomas originating from different
histologic features typically are those of a juvenile pilocytic astrocytoma. locations within the brain are indistinguishable histologically, but it
Surgery is appropriate treatment for those symptomatic patients with is well recognized that they are different clinically.665
unequivocal evidence of tumor growth on neuroimaging studies. When Recent molecular investigations have resulted in two classification
possible, resection of the mural nodule usually is curative. In cases in systems for ependymomas. The first is dependent of the presence of
which the major portion of the tumor is in the ventral midbrain, a RELA-fusion protein commonly seen in ependymoma. The 2016
surgical options are limited to a diagnostic biopsy, and treatment WHO classifications recognizes only this group as a distinct subtype
consists of radiation therapy or chemotherapy. Long-term survival for of ependymoma. This C11orf95-RELA fusion results from chro-
patients with these tumors often is in excess of 5 to 10 years, and a mothripsis, a shattering and reassembling of chromosomes that generates
conservative management approach often is advisable. this oncogenic product.666 The C11orf95-RELA fusion causes a
964 Part III: Specific Malignancies
constitutively active NF-κB pathway by an increase in a RELA-encoded
transcription factor p65.667 This fusion protein is seen almost exclusively
in supratentorial ependymomas. Although not a recognized subgroup
of its own in the WHO classification system, some ependymomas
also harbor a fusion of the YAP1 gene with other genes such as
MAMLD1 and FAM118B.666,667 Recent large-scale genomic and
epigenomic studies provided support for the dividing the posterior
fossa ependymomas into two subgoups: PF-EPN-A, occurring pre-
dominantly in infants and young children, and PF-EPN-B, typically
seen in adolescents and adults.668,669 Combining all of these classification
systems, a new system has been proposed that separates all ependymomas
into nine distinct subgroups. Among the three supratentorial subgroups
are the YAP1 and RELA-fusion anaplastic ependymomas; the third
is a supratentorial subependymoma with a balanced genome. The
three posterior fossa subgroups include PF-EPN-A and PF-EPN-B
and PF-SE (subependymoma). Three spine ependymomal subgroups
are based on the presence of 6q deletion, myopapillary feature with
chromosomal instability, and NF2 mutation.666
The primary challenge in ependymoma treatment is local control,
because metastatic disease at initial diagnosis or first relapse is uncom-
mon.670,671 Surgical resection of these tumors often is difficult, and
complete removal is achieved in fewer than 50% of the patients.
Ependymomas often are located close to brainstem structures, which
increases the risk of morbidity when complete resection is attempted.
Several studies confirmed the critical role of a radical surgical resection
in patients with newly diagnosed ependymomas.672,673 Five-year PFS
rates range from 50% to 70% after complete surgical resection and
from zero to 30% after incomplete resection.674,675 Better survival
is noted in children who have undergone complete resection. The
frequency of gross total resections has been increased by sophisticated
technologies including ultrasonic tissue dissociators, argon lasers, and
robotic localizing devices; by experience of the surgeon with childhood
tumors; and by the intent and preoperative plan to perform a radical
surgical resection.676 The availability of intraoperative neuroimaging
may provide immediate confirmation of the degree of resection
and allow the surgeon to reoperate, immediately, if necessary.677
For patients with residual tumor after initial surgery, reresection
immediately after the postoperative MRI study reveals residual tumor
remains an option. Alternatively, deferral of second surgery until the
child recovers and receives chemotherapy or radiotherapy may be
considered.
Involved-field radiotherapy represents standard therapy for children
older than 3 years who have intracranial ependymomas. Conventional
radiation therapy doses range from 54 to 56 Gy. Controversial aspects
of radiation therapy for ependymomas include treatment volume and
the necessity for craniospinal irradiation. On the basis of published
reports that indicated a significant risk of CSF seeding, craniospinal
irradiation initially was recommended.678 In subsequent studies, neuraxis
relapse in ependymoma occurred in less than 5% of cases.670 Routine
staging for relapse includes postoperative MRI of the brain to character-
ize the extent of resection. MRI of the spine and lumbar puncture to
evaluate CSF cytologic features are critically important to therapeutic
planning. In the absence of disseminated disease at diagnosis, the
pattern of relapse is local in the vast majority of cases and is not
influenced by the delivery of craniospinal irradiation. Therefore
prophylactic craniospinal irradiation is no longer recommended. Current
radiation therapy for ependymoma emphasizes strategies that reduce
or minimize the exposure of surrounding normal brain to radiation.
Merchant and colleagues679 reported clinical outcomes for 153 patients
with childhood ependymoma who were treated with conformal
radiotherapy after surgery. With careful staging methods, the 7-year
PFS and OS rates were 77% and 85%, respectively. Of note, the
incidence of radiation-induced second malignancy was 2.3% at 7
years. Similar survival results have been reported with proton radiation
in patients with childhood ependymoma.680 Dosimetric comparisons
between intensity-modulated radiation therapy and proton radiation
therapy show significant reduction of radiation exposure to surrounding
critical structures; however, radiation-induced second malignancy rates
5 to 7 years after proton radiation are not yet available.
The role of chemotherapy in the treatment of ependymoma is
controversial; in fact, no convincing role for conventional chemotherapy
has been established for the treatment of these tumors.681 In single-agent
studies, cisplatin has had an objective response rate approaching 30%.682
A Children’s Oncology Group study using lomustine (CCNU),
procarbazine, and vincristine failed to show a significant PFS or OS
advantage versus radiation therapy alone. By comparison, a single-agent
study of 19 children with newly diagnosed ependymoma reported a
74% 5-year PFS rate in children with postoperative residual tumor
treated with radiation therapy and carboplatin, vincristine, ifosfamide,
and etoposide.683 This rate was higher than published results for
radiotherapy alone for this group. On the basis of this finding, current
clinical trials use chemotherapy for patients whose postoperative imaging
studies are positive for significant residual tumor. For patients with
recurrent ependymoma, options for further therapy other than repeat
resection are limited and generally considered to be palliative in intent.
High-dose chemotherapy with autologous stem cell rescue may yield
longer PFS than conventional chemotherapy in a minority of
patients.684,685 Continued intensive study of ependymoma genomics
may identify new targets for therapeutic intervention with chemotherapy
and/or biologic agents.681 There is new interest in the role of reirradia-
tion for recurrent ependymoma. A study of 38 patients with childhood
ependymoma reported a 53% 4-year event-free survival with less than
anticipated toxicity, suggesting that further exploration of this strategy
is warranted.686
Intracranial Germ Cell Tumors
Germ cell tumors constitute 12.5% to 16% of all childhood tumors
in Japan but only 3% to 11% in the United States and Western
European countries.687 A majority are located in the pineal region and
approximately a third are located in the suprasellar region. The clinical
presentation of tumors involving the pineal region and the differential
diagnosis for these tumors were discussed earlier in the section on
tumors of the spinal axis. The clinical presentation of suprasellar germ
cell tumors includes panhypopituitarism, diabetes insipidus, and visual
disturbances with usually long prediagnostic symptomatic intervals,
often exceeding 1 year.
The neuroimaging characteristics of germ cell tumors, suprasellar
or pineal, do not provide sufficient differentiation between germ cell
tumor histologic types to render biopsy unnecessary.687,688 The diversity
of tumor types in the suprasellar or pineal region underscores the
general importance of adequate biopsy samples for accurate diagnosis.
Expression of tumor biomarkers in blood or CSF plays an important
role in diagnosis and therapeutic decisions and often indicates the
presence of a nongerminomatous germ cell tumor (NGGCT). Alpha-
fetoprotein (AFP) is produced by fetal yolk sac cells and later by
hepatocytes. Detection of elevated levels of AFP in a patient with a
CNS tumor indicates the presence of teratoid tumors687 (Table 63.11).
β-Human chorionic gonadotropin (β-hCG) indicates germ cell tumors
with syncytiotrophoblast activity such as choriocarcinomas. Although
pure germinomas may express relatively low levels of β-hCG (e.g.,
<50 mIU/dL), choriocarcinomas produce the highest levels of this
hormone (see Table 63.11). β-hCG expression is not a marker of
metastasis or tumor size. Placental alkaline phosphatase is another
marker that has been found to be elevated in patients with germ cell
tumors.689 Its diagnostic use lies more in immunohistochemistry.
Placental alkaline phosphatase immunostaining is positive and diagnosti-
cally definitive for germinomas.687
Current practice regarding diagnostic biopsy for these tumors is
evolving. Previously it was understood that small samples obtained
from stereotactic biopsy may not identify mixed tumor types, and
thus an open surgical approach with maximum feasible resection was
preferred. However, elevations of serum or CSF AFP greater than
twice the highest institutional normal value or elevation of serum or

Table 63.11 Cerebrospinal Fluid and Serum Tumor
Markers for Germ Cell Tumors
Tumor AFP β-hCG
Germinoma − ±
Nongerminomatous GCT
Embryonal carcinoma ± ±
Yolk sac tumor ++ −
Choriocarcinoma − ++
Teratoma, mature − −
Teratoma, immature-malignant ± ±
Mixed germ cell tumor ± ±
AFP, α-Fetoprotein; β-hCG, β-human chorionic gonadotropin; GCT, germ cell
tumor.
Modified from Kretschmar CS. Germ cell tumors of the brain in children: a review
of current literature and new advances in therapy. Cancer Invest. 1997;15:187.
CSF β-hCG greater than 50 mIU/dL clearly indicates the presence
of NGGCT and may obviate the need for either diagnostic biopsy
or extensive surgical resection pending response to chemotherapy and
radiation therapy. By contrast, complete resection is curative for
well-differentiated teratomas, whereas chemotherapy and radiation
therapies are ineffective with this tumor. The extent of surgical resection
is less important for germinomas, which are exquisitely sensitive to
chemotherapy and radiation therapy, or for the malignant NGGCTs,
which frequently spread throughout the CSF and are less responsive
to irradiation and chemotherapy.
Craniospinal irradiation is clearly indicated in cases of documented
leptomeningeal metastasis from germinoma; however, its use in patients
with normal findings on CSF examination and spinal MRI is con-
troversial. In a series from the University of Pennsylvania in which
39 patients with biopsy-proved germinomas all received craniospinal
irradiation, regardless of extent of disease, no relapses occurred during
a median follow-up time of 7.1 years, and the 10-year survival rate
was 97%.690 Of note, however, other institutions using more limited
radiation fields with or without chemotherapy for biopsy-proven
germinomas also have reported 5-year survival rates exceeding 90%.691,692
NGGCTs (choriocarcinomas, embryonal carcinomas, yolk sac tumors,
and malignant teratomas) have a high incidence of leptomeningeal
metastasis,693 and craniospinal radiation therapy is an important
component of the overall treatment plan with these tumors. Well-
differentiated teratomas generally are unresponsive to radiation, and
use of radiation therapy is limited to unresectable recurrent or progres-
sive teratomas in many centers. For these cases, SRS may prove to be
of greater therapeutic benefit.
Chemotherapy has an important role in the treatment of germinomas
and NGGCTs. Germinomas appear to be as sensitive to chemotherapy
as they are to radiation.694,695 Chemotherapy has been used effectively
for germinomas in three settings: (1) chemotherapy without radiation
therapy; (2) chemotherapy followed by reduced-dose radiation therapy
for tumors with incomplete tumor response; and (3) chemotherapy
after radiation therapy for tumors with incomplete tumor response.
Malignant NGGCTs carry a considerably worse prognosis than that
for pure germinomas.692 Accordingly, in patients with NGGCTs,
intensified chemotherapy and multimodality therapeutic strategies
have been used in an attempt to improve survival.696 Studies of preradia-
tion and postradiation chemotherapy for patients with NGGCT, but
no metastases, reported a 3-year PFS rate of 89%.697
Craniopharyngioma
Craniopharyngiomas constitute 6% to 10% of all childhood brain
tumors and represent one of the three major tumor groups frequently
Cancer of the Central Nervous System • CHAPTER 63 965
Figure 63.31 • Craniopharyngioma. A midline sagittal T1-weighted
postgadolinium magnetic resonance image shows an enhancing cystic
suprasellar mass.
found in the suprasellar region. These tumors may arise from embryonic
epithelial cell rests in the region of the Rathke cleft. However, an
embryonic origin is not certain for all such tumors, particularly those
that arise later in adulthood. Two histologic subtypes are described:
the adamantinomatous craniopharyngioma, which is more common
during childhood, and the papillary craniopharyngioma, which is
more common during adult years. No reported prognostic significance
is associated with the histologic subtypes. Radiographically, their
appearance typically includes a cystic or multicystic component and
a solid component (Fig. 63.31). Calcifications are present in a majority
of cases. Craniopharyngioma cyst fluid, similar to that of a Rathke
cleft cyst, is viscous, with a high cholesterol content. Rupture of the
cyst contents during surgical removal is well known to produce an
intense chemical meningitis.
The clinical presentation of craniopharyngiomas is similar to that
of other suprasellar tumors. The primary age at onset is in the first
decade of life; however, presentation before the age of 2 years is
uncommon. Approximately 25% of craniopharyngiomas are detected
in the third decade or later. The primary signs and symptoms include
visual dysfunction; headache; optic pallor; endocrinopathies, including
growth failure and diabetes insipidus; and behavioral or learning
dysfunction. On the basis of these findings, preoperative assessment
of patients with suspected craniopharyngioma should include a thorough
visual examination and endocrine evaluation. A study of 171 patients
with craniopharyngioma revealed that patients diagnosed before 10
years of age had higher rates of visual and endocrine dysfunction and
social dysfunction.698
The fundamentals of craniopharyngioma treatment emphasize local
control. Chemotherapy is ineffective for initial or recurrent tumor,
and metastatic disease is reported. Local treatment involves surgery,
radiation, or both. However, little progress has been made to determine
the best strategy—gross total resection with radiation therapy reserved
for residual or recurrent tumor versus surgical biopsy, cyst drainage, and
radiation. Complete surgical resection is often curative and obviates the
need for radiation therapy in a majority of cases.699 When postoperative
MRI and intraoperative visual assessment show no evidence of tumor,
966 Part III: Specific Malignancies

the rate of recurrence is less than 20%; a majority of recurrences occur
within the first 2 years after surgery.700 Gross total resection often results
in transection or sacrifice of the pituitary stalk, panhypopituitarism, and
a substantial risk of behavioral and neuropsychologic dysfunction or
stroke that often severely affects the patient’s quality of life.701–703 These
risks may be lower with smaller tumors. In addition, more surgeons
are using the transnasal transsphenoidal route for resection and cyst
decompression to lower surgical risk of damage to the pituitary, but
long-term outcome data are limited for this approach.704 Another
alternative surgical strategy involves planned incomplete resection
followed by radiation therapy. Radiation therapy represents standard
treatment for patients with residual craniopharyngioma.705–707 Fewer
than 50% of patients with known postoperative residual tumor who
do not receive radiation therapy will survive for 10 years. Patients
who receive local field radiation, typically at doses of 50 to 56 Gy,
have disease-free survival rates of approximately 80% at 10 years, and
some investigators have suggested that quality of life may be better
for these patients than for children managed with aggressive surgical
resection alone.706 Proton radiation may have distinct advantages for
craniopharyngioma patients, especially reduction of the dose to a
large portion of the brain and potential reduction of dose exposure
to the mesial temporal lobe and other brain regions responsible for
memory and cognition.708,709 Unfortunately, no prospective, randomized
clinical trial has been undertaken to compare surgical intent to achieve
gross total resection versus biopsy, drainage, and radiation outcomes
for recurrence and survival or adverse effects of treatment, including
endocrine and cognitive dysfunction, stroke, second malignancies,
and overall quality of life.
Chemotherapy has no established role in the treatment of newly
diagnosed craniopharyngioma. For patients whose tumor recurrence
after external beam irradiation consists primarily of a cystic component,
intracystic instillation of colloidal beta-emitting radionuclides, such
as phosphorus-32 or yttrium-90, may be therapeutically beneficial.710
Brain Tumors in Infants
in this age group have been significantly less favorable than in older
children, both overall and for specific tumor types.711 These children
also are at increased risk for substantial radiation-related neurotoxicity,
including mental retardation, growth failure, and leukoencephalopa-
thy.712,713 Therefore primary postoperative chemotherapy approaches
are used, especially in children 3 years of age or younger, to postpone
or replace radiation therapy. Between 1976 and 1988, 17 children
younger than 3 years of age with PNET/MB or ependymoma underwent
treatment with a multiagent chemotherapy regimen consisting of
mechlorethamine, vincristine, procarbazine, and prednisone.714
Radiotherapy was reserved for treatment of recurrent disease. Eight
of 12 children with PNET/MB and two of five children with epen-
dymoma survived, and the children who did not require radiation
therapy showed normal height and intellectual ability. Results from
the Children’s Cancer Group study of 299 infants with malignant
brain tumors randomly assigned to receive one of two regimens of
induction chemotherapy (vincristine, cisplatin, cyclophosphamide,
and etoposide or vincristine carboplatinum, ifosfamide, and etoposide)
showed no significant differences between the two induction regimens.715
The 5-year PFS rates for infant medulloblastoma, ATRTs, and
ependymoma were 32%, 17%, and 14%, respectively. These disap-
pointing results underscore the problems associated with treating
different tumor types with a single strategy.
A subset of infant PNET/MB can be cured by chemotherapy
alone,715,716 and multiinstitutional clinical trials are actively searching
for prognostic factors and improved survival outcomes for these infants.
In infant medulloblastoma, the histologic desmoplastic nodular feature
has a better survival outcome than do classic histologic features or
extensive nodularity.717 Patients with anaplastic large cell histology
have the worst survival outcomes.718 Ongoing cooperative group
studies are testing chemotherapy dose intensification, addition of
intrathecal chemotherapy, and earlier introduction of more limited
radiation therapy, with restriction of treatment volumes and use of
conformal techniques and proton radiation to minimize exposure of
normal tissue.

Approximately 20% of childhood brain tumors occur in infants and The complete reference list is available online at
children younger than 3 years. Unfortunately, the survival outcomes ExpertConsult.com.

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