Brain tumors

• Tumors of the central nervous system are neoplasms of the central

nervous system. They are formed as a result of uncontrolled cell
division, in most cases - of glial cells, since the mature neurons
themselves lose their ability to divide.

• A feature of the central nervous system tumors in vertebrates,

including humans, is the pronounced mechanical effect of the
neoplasm on the surrounding tissues due to the presence of a skeletal
membrane around the brain and spinal cord. The localization of the
tumor, as a rule, significantly affects the clinical picture, which is
important for topical diagnosis.
• A brain tumor, known as an intracranial tumor, is an abnormal mass
of tissue in which cells grow and multiply uncontrollably, seemingly
unchecked by the mechanisms that control normal cells. More than
150 different brain tumors have been documented, but the two main
groups of brain tumors are termed primary and metastatic.
• Primary brain tumors include tumors that originate
from the tissues of the brain or the brain's
immediate surroundings. Primary tumors are
categorized as glial (composed of glial cells) or non-
glial (developed on or in the structures of the brain,
including nerves, blood vessels and glands) and
benign or malignant.

• Metastatic brain tumors include tumors that arise

elsewhere in the body (such as the breast or lungs)
and migrate to the brain, usually through the
bloodstream. Metastatic tumors are considered
cancer and are malignant.
• Metastatic tumors to the brain affect nearly one in four patients with
cancer, or an estimated 150,000 people a year. Up to 40 percent of
people with lung cancer will develop metastatic brain tumors. In the
past, the outcome for patients diagnosed with these tumors was very
poor, with typical survival rates of just several weeks. More
sophisticated diagnostic tools, in addition to innovative surgical and
radiation approaches, have helped survival rates expand up to years;
and also allowed for an improved quality of life for patients following
diagnosis.

Lung cancer
• Brain tumors are a relatively common neurologic disorder particularly when
one combines primary central nervous system (CNS) lesions and those
metastatic to the brain and its leptomeninges.
• Taken together, these tumors are some of the most common cerebral
disorders in adults, second only to Alzheimer disease, stroke, and multiple
sclerosis. In children with the exception of leukemia, primary brain tumors
are the most common malignancy.
• Glioblastoma multiforme (GBM) arising from within the glial cell matrix
occurs in all age groups but typically after age 65 years. A higher age at
onset is the most significant predictor of poor outcome.
• GBM is the most devastating of CNS malignancies; there are very few 2-year
survivors. Glial cell tumors comprise more than two thirds of all primary
brain tumors. Meningiomas are the next most common tumor and are the
prototype of the various primary benign brain tumors.
Brain tumors typically present with four clinical scenarios:

• (1) focal cerebral or cranial nerve deficits that are gradually progressive over a
few weeks to many months,
• (2) seizures,
• (3) headache and signs of increased intracranial pressure primarily demonstrating
papilledema and sixth-nerve palsies,
• or (4) stroke mimic, that is, with an apocalyptic onset.

• Personality changes, evolving language dysfunction, focal loss of sensory

discrimination or motor limitation such as a clumsy hand, and ataxic gait are focal
signs that usually accurately define the site of the tumor. However, there are
certain false localizing signs that may lend to initial confusion.
• When a slowly enlarging, previously asymptomatic cerebral tumor
decompensates, certain false localizing signs may cause diagnostic confusion.

• Transtentorial uncal-parahippocampal herniation occurs, with the offending

hemisphere herniating medially through the tentorium cerebri, compressing the
contralateral corticospinal tract carrying motor fibers. These fibers originating in
the opposite motor cortex control movement on the same side of the body as
the site of the tumor.

• For example, a very large right-sided tumor affects the left corticospinal tract
carrying right-sided motor fibers, leading to a paradoxical ipsilateral hemiparesis.
Similarly, another false localizing sign occurs when a large herniating tumor
compresses the opposite third nerve, thus leading to pupillary dilatation
contralateral to the side of the lesion.

• Today, these clinically confusing signs are less likely to occur with earlier MRI
diagnosis of these tumors before they reach a critical mass to cause these
herniation syndromes.
• The tumor types and their locations are essential determinants
significantly influencing seizure characteristics.

• Brain tumors with a high risk for epilepsy include slow-growing low-
grade gliomas, multiple metastases, and various developmental
tumors.
• The availability of magnetic resonance imaging (MRI) makes the differentiation
relatively simple for those occasional brain tumors that present so acutely that
they mimic a stroke.
• MRI primarily provides morphological and functional information, including
tumor localization, vascular permeability, cell density, and tumor perfusion.
Today the concurrent employment of positron emission tomography (PET)
enables the assessment of molecular processes, such as glucose consumption,
expression of nucleoside and amino acid transporters, as well as alterations of
DNA and protein synthesis. The value of combining these two modalities is
now being studied. Perhaps such will eventually allow one to differentiate a
focal “tumefactive” demyelinating lesion from the much more common
glioma.
• At present, it is necessary to perform a stereotactic brain biopsy to make this
tissue diagnosis before embarking on a specific therapeutic protocol.
Eventually the combined
• MRI/PET paradigm may also offer important therapeutic implications.
 Etiology

• Unclear

RISK FACTORS:
• Genetic
• Ionizing radiation
• Non-ionizing radiation
• Allergies, atopic diseases and systemic infections
In a number of studies, the inverse relationship between the incidence of allergies and glial tumors

• Viruses
In the tissues of glial tumors, viruses of the polyomavirus group
The relationship of carcinogenesis with the presence of herpes virus infection is assumed

• Neurocarcinogens and metals

Types of Benign Brain Tumors
• Chordomas are benign, slow-growing tumors that are most prevalent
in people ages 50 to 60. Their most common locations are the base of
the skull and the lower portion of the spine. Although these tumors
are benign, they may invade the adjacent bone and put pressure on
nearby neural tissue. These are rare tumors, contributing to only 0.2
percent of all primary brain tumors.
• Craniopharyngiomas typically are benign, but are difficult tumors to
remove because of their location near critical structures deep in the
brain. They usually arise from a portion of the pituitary gland (the
structure that regulates many hormones in the body), so nearly all
patients will require some hormone replacement therapy.
• Gangliocytomas, gangliomas and anaplastic
gangliogliomas are rare tumors that
include neoplastic nerve cells that are
relatively well-differentiated, occurring
primarily in young adults.

• Glomus jugulare tumors most frequently

are benign and typically are located just
under the skull base, at the top of the
jugular vein. They are the most common
form of glomus tumor. However, glomus
tumors, in general, contribute to only 0.6
percent of neoplasms of the head and
neck.
• Meningiomas are the most common benign
intracranial tumors, comprising 10 to 15 percent of
all brain neoplasms, although a very small
percentage are malignant. These tumors originate
from the meninges, the membrane-like structures
that surround the brain and spinal cord.

• Pineocytomas are generally benign lesions that

arise from the pineal cells, occurring
predominantly in adults. They are most often well-
defined, noninvasive, homogeneous and slow-
growing.
• Pituitary adenomas are the most common intracranial
tumors after gliomas, meningiomas and schwannomas.
The large majority of pituitary adenomas are benign
and fairly slow-growing. Even malignant pituitary
tumors rarely spread to other parts of the body.
Adenomas are by far the most common disease
affecting the pituitary. They commonly affect people in
their 30s or 40s, although they are diagnosed in
children, as well. Most of these tumors can be treated
successfully.
• Schwannomas are common benign brain tumors in
adults. They arise along nerves, comprised of cells
that normally provide the "electrical insulation" for
the nerve cells. Schwannomas often displace the
remainder of the normal nerve instead of invading
it.

Acoustic neuromas are the most common

schwannoma, arising from the eighth cranial nerve,
or vestibulocochlear nerve, which travels from the
brain to the ear.
Although these tumors are benign, they can cause
serious complications and even death if they grow
and exert pressure on nerves and eventually on the
brain. Other locations include the spine and, more
rarely, along nerves that go to the limbs. Bilateral massive
vestibular schwannomas
 Distinctive features of primary CNS tumors
• Malignant
• = rapid growth, invasion, spread in the central nervous system

• 40% of malignant brain tumors in children metastasize in the central nervous

system

• Rarely metastasize beyond the central nervous system - 3-5% extraneural mts:
- bone marrow, bones, liver, lymph nodes

• Benign tumors can be "malignant in localization"

- trunk glioma, bitalamic astrocytoma
Types of Malignant Brain Tumors
• Gliomas are the most prevalent type of adult brain tumor, accounting
for 78 percent of malignant brain tumors. They arise from the
supporting cells of the brain, called the glia. These cells are
subdivided into astrocytes, ependymal cells and oligodendroglial cells
(or oligos).

• Glial tumors include the following:

• Astrocytomas are the most common glioma,
accounting for about half of all primary brain and
spinal cord tumors. Astrocytomas develop from star-
shaped glial cells called astrocytes, part of the
Fibrillary astrocytoma
supportive tissue of the brain. They may occur in
many parts of the brain, but most commonly in the
cerebrum. People of all ages can develop
astrocytomas, but they are more prevalent in adults
— particularly middle-aged men. Astrocytomas in the
base of the brain are more prevalent in children or
younger people and account for the majority of
children's brain tumors. In children, most of these
tumors are considered low-grade, while in adults,
most are high-grade.
• Ependymomas are derived from a neoplastic transformation of the
ependymal cells lining the ventricular system and account for two to
three percent of all brain tumors. Most are well-defined, but some
are not.
• Glioblastoma multiforme (GBM) is the most invasive type of glial
tumor. These tumors tend to grow rapidly, spread to other tissue and
have a poor prognosis. They may be composed of several different
kinds of cells, such as astrocytes and oligodendrocytes. GBM is more
common in people ages 50 to 70 and are more prevalent in men than
women.
• Medulloblastomas usually
arise in the cerebellum, most
frequently in children. They
are high-grade tumors, but
they are usually responsive
to radiation and
chemotherapy.

• Oligodendrogliomas are
derived from the cells that
make myelin, which is the
insulation for the wiring of
the brain.
 Other Types of Brain Tumors
• Hemangioblastomas are slow-growing tumors, commonly located in
the cerebellum. They originate from blood vessels, can be large in size
and often are accompanied by a cyst. These tumors are most
common in people ages 40 to 60 and are more prevalent in men than
women.

• Rhabdoid tumors are rare, highly aggressive tumors that tend to

spread throughout the central nervous system. They often appear in
multiple sites in the body, especially in the kidneys. They are more
prevalent in young children, but also can occur in adults.
 Pediatric Brain Tumors

• Brain tumors in children typically come from different tissues than

those affecting adults. Treatments that are fairly well-tolerated by
the adult brain (such as radiation therapy) may prevent normal
development of a child's brain, especially in children younger than
age five.
• According to the Pediatric Brain Tumor Foundation, approximately
4,200 children are diagnosed with a brain tumor in the U.S. Seventy-
two percent of children diagnosed with a brain tumor are younger
than age 15. Most of these brain tumors grow in the posterior fossa
(or back) of the brain. Children often present with hydrocephalus
(fluid build up in the brain) or the face or body not working properly.

• Some types of brain tumors are more common in children than in

adults. The most common types of pediatric tumors are
medulloblastomas, low-grade astrocytomas (pilocytic),
ependymomas, craniopharyngiomas and brainstem gliomas.
The World Health Organization (WHO)
has developed a grading system to indicate a tumor's malignancy or
benignity based on its histological features under a microscope.
 • Most malignant
• Rapid growth, aggressive
• Widely infiltrative
• Rapid recurrence
• Necrosis prone
 World Health Organization (WHO) Brain Tumor Grades

Grade Characteristics Tumor Types

•Pilocytic astrocytoma
•Least malignant (benign) •Craniopharyngioma
WHO Grade I
•Possibly curable via surgery alone •Gangliocytoma
•Non-infiltrative •Ganglioglioma
Low Grade •Long-term survival
•Slow growing

•"Diffuse" Astrocytoma
WHO Grade II •Relatively slow growing •Pineocytoma
•Somewhat infiltrative •Pure oligodendroglioma
•May recur as higher grade

•Anaplastic astrocytoma
WHO Grade III •Malignant •Anaplastic ependymoma
•Infiltrative •Anaplastic oligodendroglioma
•Tend to recur as higher grade
High Grade
•Most malignant
•Gliobastoma multiforme (GBM)
•Raid growth, aggressive
•Pineoblastoma
WHO Grade IV •Widely infiltrative
•Medulloblastoma
•Rapid recurrence
•Ependymoblastoma
•Necrosis prone
 Brain Tumor Causes

Brain tumors are thought to arise when certain genes on the

chromosomes of a cell are damaged and no longer function properly.
These genes normally regulate the rate at which the cell divides (if it
divides at all) and repair genes that fix defects of other genes, as well as
genes that should cause the cell to self-destruct if the damage is
beyond repair. In some cases, an individual may be born with partial
defects in one or more of these genes. Environmental factors may then
lead to further damage. In other cases, the environmental injury to the
genes may be the only cause. It is not known why some people in an
"environment" develop brain tumors, while others do not.
Once a cell is dividing rapidly and internal mechanisms to check its
growth are damaged, the cell can eventually grow into a tumor.
Another line of defense may be the body's immune system, which
optimally would detect the abnormal cell and kill it. Tumors may
produce substances that block the immune system from recognizing
the abnormal tumor cells and eventually overpower all internal and
external deterrents to its growth.
A rapidly growing tumor may need more oxygen and nutrients than can
be provided by the local blood supply intended for normal tissue.
Tumors can produce substances called angiogenesis factors that
promote the growth of blood vessels. The new vessels that grow
increase the supply of nutrients to the tumor, and, eventually, the
tumor becomes dependent on these new vessels. Research is being
done in this area, but more extensive research is necessary to translate
this knowledge into potential therapies.
 Symptoms
Symptoms vary depending on the location of the brain tumor, but the following may
accompany different types of brain tumors:

• Headaches that may be more severe in the morning or awaken the patient at night
• Seizures or convulsions
• Difficulty thinking, speaking or articulating
• Personality changes
• Weakness or paralysis in one part or one side of the body
• Loss of balance or dizziness
• Vision changes
• Hearing changes
• Facial numbness or tingling
• Nausea or vomiting, swallowing difficulties
• Confusion and disorientation
 Diagnosis
Sophisticated imaging techniques can pinpoint brain tumors.

Diagnostic tools include computed tomography (CT or CAT scan) and

magnetic resonance imaging (MRI).
Other MRI sequences can help the surgeon plan the resection of the tumor
based on the location of the normal nerve pathways of the brain.
Intraoperative MRI also is used during surgery to guide tissue biopsies and
tumor removal. Magnetic resonance spectroscopy (MRS) is used to examine
the tumor's chemical profile and determine the nature of the lesions seen on
the MRI.
Positron emission tomography (PET scan) can help detect recurring brain
tumors.
Sometimes the only way to make a definitive diagnosis of a brain tumor
is through a biopsy.

The neurosurgeon performs the biopsy and the pathologist makes the
final diagnosis, determining whether the tumor appears benign or
malignant, and grading it accordingly.
Brain Tumor Treatment
Brain tumors (whether primary or metastatic, benign or malignant)
usually are treated with surgery, radiation, and/or chemotherapy —
alone or in various combinations.

While it is true that radiation and chemotherapy are used more often
for malignant, residual or recurrent tumors, decisions as to what
treatment to use are made on a case-by-case basis and depend on a
number of factors. There are risks and side effects associated with each
type of therapy.
 Surgery

• t is generally accepted that complete or nearly complete surgical removal of a

brain tumor is beneficial for a patient. The neurosurgeon's challenge is to
remove as much tumor as possible, without injuring brain tissue important to
the patient's neurological function (such as the ability to speak, walk, etc.).
• Traditionally, neurosurgeons open the skull through a craniotomy to insure
they can access the tumor and remove as much of it as possible. A drain
(EVD) may be left in the brain fluid cavities at the time of surgery to drain the
normal brain fluid as the brain recovers from the surgery.
Another procedure that is commonly performed, sometimes before a
craniotomy, is called a stereotactic biopsy. This smaller operation allows
doctors to obtain tissue in order to make an accurate diagnosis.

Usually, a frame is attached to the patient's head, a scan is obtained, and

then the patient is taken to the operating area, where a small hole is
drilled in the skull to allow access to the abnormal area. Based on the
location of the lesion, some hospitals may do this same procedure without
the use of a frame. A small sample is obtained for examination under the
microscope.
In the early 1990s, computerized devices called surgical navigation systems
were introduced. These systems assisted the neurosurgeon with guidance,
localization and orientation for tumors. This information reduced the risks and
improved the extent of tumor removal. In many cases, surgical navigation
systems allowed previously inoperable tumors to be excised with acceptable
risks.
Some of these systems also can be used for biopsies without having to attach a
frame to the skull. One limitation of these systems is that they utilize a scan (CT
or MRI) obtained prior to surgery to guide the neurosurgeon. Thus, they
cannot account for movements of the brain that may occur intraoperatively.
Investigators are developing techniques using ultrasound and performing
surgery in MRI scanners to help update the navigation system data during
surgery.
Intraoperative language mapping is considered by some as a critically
important technique for patients with tumors affecting language
function, such as large, dominant-hemisphere gliomas.

This procedure involves operating on a conscious patient and mapping

the anatomy of their language function during the operation. The
doctor then decides which portions of the tumor are safe to resect.
Recent studies have determined that cortical language mapping may
be used as a safe and efficient adjunct to optimize glioma resection
while preserving essential language sites.
Ventriculoperitoneal shunting may be required for some patients with brain
tumors.
Everyone has cerebrospinal fluid (CSF) within the brain and spine that is slowly
circulating all the time. If this flow becomes blocked, the sacs that contain the
fluid (the ventricles) can become enlarged, creating increased pressure within
the head, resulting in a condition called hydrocephalus. If left untreated,
hydrocephalus can cause brain damage and even death.
The neurosurgeon may decide to use a shunt to divert the spinal fluid away
from the brain and, therefore, reduce the pressure. The body cavity in which
the CSF is diverted usually is the peritoneal cavity (the area surrounding the
abdominal organs).
The shunt usually is permanent. If it becomes blocked, the symptoms are
similar to that of the original condition of hydrocephalus and may include
headaches, vomiting, visual problems and/or confusion or lethargy, among
others. Another method that may be used to control obstruction of the brain
fluid pathways is called an Endoscopic Third Ventriculostomy. This helps the
brain fluid be diverted around the obstruction without the need for a shunt.
 Radiation Therapy

Radiation therapy uses high-energy X-rays to kill cancer cells and abnormal
brain cells and to shrink tumors.

Radiation therapy may be an option if the tumor cannot be treated

effectively through surgery.
Standard External Beam Radiotherapy uses a variety of radiation beams
to create a conformal coverage of the tumor while limiting the dose to
surrounding normal structures.

The risk of long-term radiation injury with modern delivery methods is

very low. Newer techniques of delivery aside from 3-dimensional
conformal radiotherapy (3DCRT) include intensity-modulated
radiotherapy (IMRT).
Proton Beam Treatment employs a specific type of radiation in which
protons, a form of radioactivity, are directed specifically to the tumor.
The advantage is that less tissue surrounding the tumor incurs damage.
Stereotactic Radiosurgery (such as Gamma Knife, Novalis and
Cyberknife) is a technique that focuses the radiation with many
different beams on the target tissue. This treatment tends to incur less
damage to tissues adjacent to the tumor. Currently, there is no data to
suggest one delivery system is superior to another in terms of clinical
outcome, and each has its advantages and disadvantages.
 Gliomas
• Pathology

Gliomas typically exhibit features of

astrocytes, or oligodendrocytes, or both
(mixed glioma). Microscopically, gliomas
appear as diffusely infiltrating cancers of
Large, hemispheric glioblastoma multi-
three types: astrocytic, oligodendroglial, forme with central areas of necrosis;
and oligoastrocytic (combining the braindistorted to opposite side
morphologic features of both
oligodendroglioma and astrocytoma).
The World Health Organization uses a three-tiered classification system
based on histologic criteria that divides these tumors into low-grade
glioma, anaplastic glioma, and glioblastoma multiforme.
Grades of Gliomas
Low-grade tumors may contain a high density of almost normal-appearing cells. Here
the percentage of cells that are dividing (as determined by mib-1 or KI-67 staining) is
often 2% or less.
Anaplastic gliomas exhibit more atypical cells, with pleomorphic nuclei having growth
rates in the 5–10% range but no evidence of necrosis.
Gliomas with high growth rates (>10% mitotic figures) and necrosis are classified as
glioblastoma multiforme (GBM). The less common pilocytic astrocytomas are a
separate category of glioma that are histologically characterized by Rosenthal’s fibers,
usually occur in children, and often have a good prognosis if surgical resection can be
achieved. Tumor grade is the most reliable predictor of prognosis. Even if the lesion
cannot be safely excised, a needle biopsy is often indicated.
Gliomas are not staged as other cancers are because they rarely metastasize outside
the CNS. Analysis of tumor samples for genetic abnormalities can help predict response
to therapy and will likely lead to a better classification system for gliomas. This
classification is valuable prognostically; low-grade gliomas have median survivals of 5–
15 years, anaplastic gliomas 2–5 years, and GBM 12–18 months.
 GLIOBLASTOMA

• These extremely malignant tumors frequently present with seizures,

aphasia, or other focal symptomatology, pointing to the specific areas
of pathologic origin.
• This is the very common, most aggressive, and the least likely of the
gliomas to respond to therapy. “Multiforme” refers to the tumor’s
gross appearance. Often areas of necrosis, hemorrhage, and fleshy
tumor exist within the same tumor focus.
• Two types of GBM (Grade IV astrocytomas) are distinguished by molecular
features. The classic primary GBM arises relatively suddenly in an older person
with no preexisting history.

• Characteristically, primary GBM have an amplification and overexpression of

the epidermal growth factor receptor (EGFR) and ligand (EGF). A mutated form
of EGFR, EGFRvIII is another hallmark of primary GBM, present in about 15–
20% of cases. EGFRvIII may confer an unfavorable prognosis. p53 mutations
are uncommon. Classically secondary GBM arises gradually from a low-grade
astrocytoma in a younger adult and harbors a p53 mutation. As it undergoes
anaplastic transformation, the secondary GBM accumulates other genetic
derangements, most notably, mutation of the Rb gene, deletion of the tumor
suppressor gene p16/CDKN2A, and amplification of CDK4.
 Diagnosis, Treatment, and Prognosis
• MRI is the most specific diagnostic modality. On most occasions, one
sees focal heterogeneous irregular-margined cystic mass lesions with
perilesion edema, gadolinium rim enhancement, and often enough
mass effect to produce a transtentorial herniation. In contrast, the
occasional patients with gliomatosis cerebri have a characteristic
diffusely abnormal MRI picture characterized by multiple areas of
subtle white matter enhancement with extension into the cortical
mantle, extending far beyond what their clinical presentation usually
dictates.
• Even with early diagnosis, the prognosis remains grim and most
patients will fail therapy within 12 months of diagnosis.

• The first treatment step is to perform as wide a surgical resection as is

functionally tolerable. Younger patients with a normal examination
who have had a gross total resection have the best prognosis.

• Postoperative radiation therapy (RT) clearly benefits many patients as

those GBM patients who receive RT have a median survival twice that
of those who did not.
• Combining RT with concomitant and adjuvant chemotherapy is now the
standard of care for patients with GBM. RT plus temozolomide leads to a
modest benefit in overall survival (14.6 vs. 12.1 months).

• However, more importantly, there is a significant increase in the

percentage of those surviving 2 or more years (26.5% vs. 10.4%).
Bevacizumab, an antagonist of vascular endothelial growth factor, has
recently proven safe and effective in patients with recurrent GBM.

• Recent reports indicate a 6-month progression-free survival of 46%. It is

now an urgent priority to determine how best to use this new tool and
what agents might work synergistically with it.
 PRIMARY CNS LYMPHOMA

• Previously a relatively rare tumor, the incidence of primary CNS

lymphoma (PCNSL) has risen dramatically in the past 30 years. There
are two clinical subtypes of this disease. In immunocompetent
patients, PCNSL occurs in an older population. This is similar to other
non-Hodgkin lymphomas. Pathologic evaluation typically
demonstrates monoclonal B cells.
• Patients with AIDS or iatrogenically related immunosuppression much
more commonly develop a PCNSL. Histologically, this is a polyclonal B
cell tumor that is associated with activation of Epstein–Barr virus.
• MRI in PCNSL patients usually demonstrates a
homogeneously enhancing lesion(s) often adjacent to
a ventricle. A positive cerebrospinal fluid (CSF)
cytology is typically found in 25–50% of these
individuals.

• Systemic PCNSL involvement is rare; therefore

computed tomography (CT) or MRI scanning of the
chest, abdomen, and pelvis is not warranted.
• T1-weighted fast spin echo imagefollowing
• Biopsy is essential to make the diagnosis. A large gadolinium enhancementshows some
resection is usually not indicated as most of these slight heterogeneity withmedial
tumors respond well to chemotherapy and/or RT. hypointensity which mayrepresent small
cystic or degenerativeregions with
equivocal surroundingenhancement
• In some immunocompetent patients these enhancing (arrows).
brain lesions can disappear either spontaneously or
with corticosteroid therapy. For this reason, if PCNSL
is suspected, biopsy should be performed prior to
treatment with corticosteroids.
 Treatment of PCNSL

There are two approaches to treatment.

• The first involves high-dose intravenous (IV) methotrexate as a single
agent.

• The second combines a lower dose of IV methotrexate with ara-C,

intrathecal methotrexate, and whole brain RT. This approach is well
tolerated in younger patients; however, significant cognitive toxicity
occurs in patients older than age 60 years. Immunosuppressed
patients are less likely to benefit from chemotherapy and treatment
with RT alone. If possible, consideration should be given to reversing
the immunosuppression.
METASTATIC BRAIN TUMORS

CT with contrast enhancement shows similar large metastasis

in the right cerebellum with effacement of the fourth ventricle
(arrowhead).
 Clinical Vignette

• A 52-year-old right-handed woman physician had a 2-week history of clumsiness using her
right hand, particularly noticeable while performing electromyographies. Neurologic
evaluation revealed moderate weakness and clumsiness of her right hand and a hint of a
right central facial weakness. She had a 30 pack-year history of tobacco abuse but had
discontinued this habit 8 years earlier.

• Gadolinium-enhanced brain MRI demonstrated multiple, round ring-enhancing lesions

consistent with metastases. As she had no known primary lesion identified during this
evaluation, a stereotactic biopsy of a lesion close to the surface demonstrated small cell
carcinoma consistent with lung cancer. It took another 4 months before the presumed
primary lung lesion was identified with chest CT.

• She was treated with whole brain RT followed by systemic chemotherapy. Although she
had initial symptomatic improvement, her difficulties returned, focal motor seizures
developed followed by a dense hemiparesis.

• She died within 18 months despite three extensive and heroic attempts to achieve
remission with focused beam radiosurgery.
• For the medical oncologist and internist, metastatic brain tumors are the most
common neuro-oncologic challenge.
• Of all cancer patients, 25% develop CNS metastases, usually after the primary
tumor has been diagnosed, but occasionally as the initial sign as noted in this
vignette. Typically CNS metastases are either a single or multiple solid tumors
compressing the brain and spinal cord, or more diffusely with leptomeningeal
infiltration of cancer cells throughout the CSF and neuraxis, especially involving
spinal and cranial nerve roots.
• Lung cancer is the most common primary tumor that metastasizes to the CNS
(50%), followed by breast (33%), colon (9%), and melanoma (7%) (Fig. 52-11). The
interval between the primary diagnosis and presentation of a CNS metastasis
depends on the tumor type. For lung cancer, the median interval is 4 months; for
breast cancer, 3 years. CNS metastasis is an indicator of poor prognosis and
portends a survival of <6 months for most patients.
Common primary sources
Sagittal fat-saturated thoracic
postcontrast T1-weighted MR: Multiple
enhancing drop metastatic deposits on
Lung the surface of the thoracic spinal
cord(arrowheads) from esophageal
adenocarcinoma.

Metastatic metastases of small cell

anaplastic(oat cell) carcinoma of lung to
brain

Breast

CT with contrast enhancement shows

similar large metastasis in the right
Kidney cerebellum with effacement of the
fourth ventricle (arrowhead).

Melanoma (skin or
mucous membranes) Cerebellar metastasis of cutaneous melanoma
 Clinical Presentation and Diagnosis

As with primary CNS malignancies, clinical presentation depends on the tumor site.
The onset can be almost precipitous, mimicking a stroke, or can be indolent, with
gradual development of focal neurologic deficit:
• motor,
• sensory,
• language,
• visual,
• gait, or coordination.

• In other instances, patients may have focal or generalized seizures or present with
nonspecific symptoms, perhaps suggesting increased intracranial pressure, such as
positional headaches, cranial neuropathies, and rarely nausea, vomiting, or both.
• Gadolinium-enhanced MRI typically demonstrates the presence of
focal metastases.

• When there is a hemorrhagic component, an underlying melanoma is

most often responsible. Typically, a number of melanoma patients
have forgotten their seemingly innocuous and remote skin lesion or
thought it irrelevant as there is often a major delay in the eventual
presentation of the metastasis in comparison to the time of its initial
removal.
• The malignant enhancement usually has a very irregular character in
contrast to the very smooth enhancement seen with the very benign
low pressure syndrome.

• CSF cytologic analysis, in most instances of leptomeningeal cancer,

demonstrates an increased number of malignant cells, thus
confirming the diagnosis.

• Sometimes the initial CSF in this setting is negative. Here, if there is a

high clinical suspicion, one must make repeated spinal taps.
 Treatment

• Although treatment is clearly

palliative, most metastatic brain
cancer patients benefit some from
CNS-directed therapy.
• Whole brain RT is indicated for most
of these individuals.
• The patient with an isolated, single
brain lesion, who has no evidence of
systemic recurrence, is a candidate
for surgical resection.
BENIGN BRAIN TUMORS
 MENINGIOMAS

Clinical Vignette
A 48-year-old healthy woman had a history of chronic intermittent low-grade
generalized headaches with a family history of migraine. Recently she noted
that her headaches were occurring more frequently. These were not
responding to the modest simple analgesics that she had previously used.
She was unaware of any precipitating factors. Her family physician evaluated
her; she also reported that recently her marriage had fallen apart when it
became widely acknowledged in her small local community that her husband
was having multiple affairs. She was very embarrassed and had become
socially withdrawn.
Her practitioner requested a neurologic consultation. Subsequently this
neurologic consultant determined that her examination was normal. A
diagnosis of tension stress headache was made. Amitriptyline was prescribed
prophylactically. She was referred to a marriage counselor.
The headaches became increasingly bothersome, at times awakening her from
her sleep; she had periods of helplessness and spells of crying. She was
switched to a selective serotonin reuptake inhibitor for presumed increasing
depression.
However, she was not convinced of the diagnosis and sought another
neurologic opinion. Her history remained unchanged. The only possible
abnormal finding on neurologic examination was a subtle suggestion of a left
central facial weakness. When this was called to her attention as to whether
this finding was new or just a normal asymmetry, neither she nor her
accompanying sister had previously noted this, suggesting that this was a
significant observation.
Contrast-enhanced brain CT demonstrated a homogeneously enhancing mass
overlying the right frontal cortex. Brain MRI confirmed its superficial location.
There was concomitant dura mater enhancement within the area immediately
adjacent to the tumor. A meningioma was identified at surgery; a complete
surgical resection was successfully performed. Postoperatively, her headaches
ceased.
Meningiomas typically occur in
middle-aged and older individuals,
especially women, but do occur at any
age.
Approximately 15–20% of intracranial
tumors are meningiomas.

These tumors may present at any level

of the neuraxis; they are primarily
located intracranially, typically found
at the parasagittal falx cerebri
separating the two hemispheres, the
meninges covering the hemispheres,
along the sphenoid ridge medial skull
base, and the olfactory groove along
the anterior skull base. Meningioma is
typically a benign lesion arising from
arachnoid meningeal cells.
 Meningioma of falx. Axial T1-weighted FLAIR (A) and coronal
post–gadolinium-enhanced T1-weightedimages with fat
saturation demonstrate an extra axial, right falx-based mass (B),
which extends through the falx to the left (C). The lesion is
isointense to brain on T1- weighted sequences and enhances
homogeneously.

Classically, these are slow-growing tumors attaining large size before

becoming symptomatic; however, occasionally they seem to grow much
more rapidly, especially during pregnancy. Meningiomas arising adjacent to
the frontal lobe are particularly prone to being clinically silent because of
the disproportionately large size of this part of the brain where there is
much more tissue to be “forgiving.” Such a slowly enlarging lesion can
gradually compress brain tissue without producing definitive symptoms in
this “clinically silent” part of the brain. A good example occurs when a
meningioma affects the prefrontal cortex. Subtle personality changes
gradually develop that are only appreciated in retrospect. However, if the
tumor lies adjacent to overtly functional brain tissue, such as the motor
cortex, symptoms may present relatively early.
Meningiomas usually have an ingravescent course, presenting with a variety of
symptoms such as
• long-standing headache,
• personality change, particularly disinhibition when involving the prefrontal cortex,
• various types of focal seizures,
• gait difficulties,
• or varied cranial nerve palsies as simple as unilateral loss of smell with olfactory
groove lesions.
• On rare occasions, meningiomas may have a precipitous onset mimicking a stroke or
even a brief transient ischemic attack.
Today many relatively small and clinically silent meningiomas are first identified
incidentally on CT and MRI during evaluation of unrelated events, such as for
evaluation of posttraumatic injury.
Presumed meningiomas located at the base of the skull near blood vessels need to be
differentiated from cerebral aneurysms. These lesions are best evaluated with
magnetic resonance angiography (MRA) to distinguish these disorders prior to
consideration for possible neurosurgery.
 Treatment

A decision to treat meningiomas rests on several factors. Because many

are initially asymptomatic, it is important to determine that
subsequently appearing neurologic symptoms arise from the lesion.
Given the typical slow growth of these benign tumors when the patient
continues to be asymptomatic, radiographic follow-up is recommended
on an annual to biannual basis. No treatment is necessary for those
individuals who remain asymptomatic when follow-up CT and MRI
demonstrate no change in tumor size or configuration.

When the patient develops progressive symptoms or follow-up imaging

indicates increasing size of the tumor, surgical resection is in order.
• The surgical complexity is directly related to tumor site; those on the
brain convexity or along the falx cerebri are often easily resected.
Skull base tumors located near blood vessels and cranial nerves often
present a surgical challenge when the meningioma becomes
entwined with these structures. Radiation therapy, chemotherapy, or
both are rarely used to treat typical benign meningiomas.
Antiprogesterone agents to slow the growth of the meningiomas are
being investigated.
PITUITARY ADENOMA
 Clinical Vignette

Bilateral galactorrhea developed in a 32-year-old woman. Her menses had

stopped a few months earlier and she thought she was pregnant; however,
pregnancy testing was negative. Otherwise, she was in excellent health.
Three years earlier, she gave birth to a healthy child. Her neurologic
examination was normal.
Endocrinologic evaluation demonstrated a significantly elevated serum
prolactin with decreased follicle-stimulating hormone (FSH) and luteinizing
hormone (LH) levels in her blood. A mass was evident with MRI imaging of
her sella turcica. This was consistent with a primary pituitary adenoma.
Benign pituitary adenomas are the second most common of the various
benign brain tumors. Intrinsic pituitary lesions represent approximately
10% of all intracranial tumors; these are classified according to whether
they are endocrinologically active. The majority of pituitary adenomas
arise from the anterior portion of the pituitary gland
(adenohypophysis).
Endocrinologically active tumors secrete hormones, often resulting in
symptoms appropriate to the target glands to which the specific active cell type
is directed. The clinical picture characteristic of a pituitary tumor depends on its
primary cell type of origin.
For example, in the preceding vignette, abnormal galactorrhea was directly
related to the production of increased amounts of prolactin-secreting tumor
cells. These are one of the most common endocrinologically active pituitary
tumors.
Pituitary acidophil adenomas that primarily secrete growth hormone lead to
the clinical syndrome of acromegaly with gigantism and/or enlarged bony
features in the face, skull, and hands.
Cushing disease with truncal obesity, cervical buffalo hump, moon-like flushed
facies, proximal muscle weakness, hypokalemia, and glucose intolerance occurs
when pituitary adenomas primarily secrete adrenocorticotropic hormone,
leading to increased circulating serum cortisol.
Basophil adenoma of moderate size; characteristically no
enlargement of sella turcica.
• Typically, their diagnosis depends on the presentation of mass effect
symptoms. Bitemporal visual field cuts result when pituitary
macroadenomas extend above the sella and compress the overlying
optic chiasm.

• Pituitary apoplexy is a relatively rare clinical presentation for pituitary

adenomas. Classically, this is an acute-onset severe headache
associated with significant visual impairment and decreased mental
status. Sometimes this may well mimic a ruptured intracranial
aneurysm. The cause is often a hemorrhage into a preexisting
pituitary adenoma.
Patients with suspected pituitary adenomas are evaluated with a
combination of imaging and endocrinologic studies. Brain MRI is the
best radiographic modality to identify pituitary tumors.
In contrast, macroadenomas (measuring >25 mm) extend above the
sella or into the cavernous sinus on either side of the sella and are
easily identified with MRI. A thorough endocrine evaluation includes
serum levels of prolactin, follicle-stimulating hormone and luteinizing
hormone, cortisol, and growth hormone and thyroid function
parameters.
 Treatment
• Initially many pituitary adenoma patients
primarily require medical therapy. Prolactin
secreting tumors are often successfully controlled
with bromocriptine, a dopamine agonist that
suppresses prolactin production and
concomitantly decreases tumor volume. Growth
hormone–secreting tumors are often controlled
with octreotide, a somatostatin analog. Small,
nonsecreting pituitary tumors may often be Invasive(malignant) adenoma; extension
observed for endocrine dysfunction or signs of into right cavernous sinus
growth with combined clinical and MRI
modalities.
• Endocrinologically active tumors that cannot
be controlled with medication are a prime
indication for surgical treatment as are
patients harboring a macroadenoma
producing mass effect.

• The surgery is primarily performed using a

Large acidophil
transsphenoidal approach through the nasal adenoma; extensive destruction of pituitary
cavity and the sphenoid sinus, wherein the substance, compression of optic chiasm, Invasion
contents of the sella can be visualized and of third ventricle and floor of sella

the tumor can be removed, often sparing the

pituitary gland.
• Postoperatively, these patients require
follow-up for signs of hypopituitarism.
This is particularly important for those Bitemporal
individuals presenting with Cushing hemianopsia often
disease. Subsequent to surgery, their initial symptom
adrenocorticotropic hormone secretion is
diminished. These patients usually require
postoperative and sometimes lifelong
steroid replacement. Pituitary adenoma
surgery is associated with concomitant
sodium balance and fluid intake problems
leading to hyponatremia with polydipsia
and polyuria. This necessitates careful
follow-up and sometimes treatment with
desmopressin acetate (DDAVP) to replace
the naturally occurring antidiuretic
hormone (ADH). This is a synthetic May grow large due to lack of
analogue of the natural pituitary hormone early endocrine symptoms; optic
8-arginine vasopressin, an ADH affecting chiasm compressed
renal water conservation.