Diseases of Women
Tracy Batchelor, M.D., Director of Neuromedical Oncology
Brain Tumor Center
diseases include both primary and metastatic tumors of
the nervous system as well as non-metastatic disorders
such as paraneoplastic complications. Some neuro-oncologic
diseases occur more commonly or exclusively in women.
Primary Brain Tumors
17,500 persons in the United States will be diagnosed
with a primary brain tumor this year and 11,000 will die
from this disease.1,2 Incidence rates of nearly all primary
brain tumors are higher in males across all ages and geographic
regions.2,3 The age-adjusted sex ratios (male/female)
for specific histologic types of brain tumors are 1.69
for oligodendroglioma, 1.61 for glioblastoma multiforme,
1.45 for astrocytoma and 1.03 for malignant menigioma.2
However, surveillance data on meningiomas have consistently
shown higher incidence figures in females with a sex ratio
of 0.6 in one study. Pituitary adenomas are also more
common in females across all age groups.2,3
are tumors that are thought to arise from meningothelial
cells which make up the arachnoid villi of the meninges.4
These lesions account for approximately 20% of all intracranial
and 25% of all intraspinal tumors and the incidence increases
of meningiomas is approximately twice as high in women
as in men.7 Specifically, intracranial meningiomas are
twice as common and intraspinal meningiomas nine times
as common in females.5 Meningiomas also seem to have a
relationship to sex hormones with accelerated growth of
these tumors during the luteal phase of the menstrual
cycle and during pregnancy.7,8 There may also be an increased
incidence of meningiomas in women with breast cancer,
although one study contests this relationship.9-11 A large
number of studies have examined the role of androgen,
estrogen and progesterone receptors in meningiomas with
most finding progesterone and androgen receptors in a
high proportion and low levels of estrogen receptors in
a small proportion of meningioma specimens obtained at
the time of initial surgery and at recurrence. Other reports
suggest there may be aberrant estrogen receptors present
which escape detection by conventional methods.7,8,12,13
Progesterone receptors have been found on average in 72%
of meningiomas with a range of 28-98%. The wide range
may be partially accounted for by the different sensitivities
of the analytic methods used to measure progesterone receptors.14,15
The progesterone receptors are thought to be functionally
important and may have a role in the regulation of meningioma
growth.5,8 A small number of studies have suggested that
the presence of progesterone receptors in meningiomas
correlates with less aggressive clinical behavior as well
as histologic type with meningothelial and transitional
meningiomas more often progesterone receptor positive
than fibrous meningiomas.14,16,17 However, most studies
have found no clear relationship between progesterone
receptor activity and age, sex, histologic type, tumor
size, clinical behavior and menstrual status.8 Androgen
receptors have also been found in a high percentage of
meningiomas and there may be a correlation of these receptors
and progesterone receptors in these tumors.7
of meningiomas and sex steroids provides an opportunity
for hormonal therapy of these tumors. The progesterone
receptor antagonist mifepristone (RU 486) has been studied
as a potential anti-tumor agent in meningiomas. Mifepristone
has been shown to inhibit the growth of meningioma cell
lines in vitro and exerts a growth inhibitory effect on
transplanted human meningiomas in mice.18,19 Although
there have been a limited number of studies in humans
preliminary results are encouraging. One study of ten
patients with progressive meningiomas on neuroimaging
studies showed stabilization or slight regression of the
tumors in six cases during treatment for twelve months
with mifepristone at 200 milligrams (mg) per day. There
was no information on the receptor status of these tumors
and there were significant side effects including nausea,
vomiting and fatigue, attributable to the glucocorticoid
blocking effect of mifepristone.18 Another study of fourteen
patients showed objective tumor regression on computerized
tomography (CT) or magnetic resonance imaging (MRI) in
35% of individuals treated with this agent.20 Studies
of the anti-estrogen agent tamoxifen have demonstrated
less activity in meningiomas with partial responses observed
in 1 of 6 and 1 if 9 cases perhaps due to the low frequency
of estrogen receptors in meningiomas.12 Further trials
with anti-androgen agents and more specific anti-progesterone
agents with less glucocorticoid-blocking activity are
indicated based on these preliminary results.
the promise of hormonal therapy of meningiomas surgery
remains the mainstay of treatment. Despite the notion
that surgery for meningiomas is curative and safe, operative
mortality rates as high as 14% have been reported and
10 year survival rates vary from 43-77%. Despite gross
total removal 10 year recurrence rates of 9-20% have been
reported and with subtotal resection these figures increase
to 18-50%. Adjunctive radiation therapy has been shown
to increase local control rate, time to recurrence and
survival for subtotally resected lesions.8
most in vivo studies do not demonstrate a clear relationship
between the presence of progesterone receptors and tumor
size or behavior, interruption of hormonal therapy in
post-menopausal women with small or asymptomatic meningiomas
does not seem warranted as long as these individuals can
be followed closely with careful clinical and radiographic
tumors account for approximately 15% of all primary intracranial
neoplasms and occur in higher frequency in women, mainly
in the child-bearing years.
preponderance of these tumors is due to the increased
frequency of prolactinomas in women in the second and
third decades. Women are affected four times as commonly
as men and account for 78% of all prolactinomas (Figure
tumors arising from the glandular tissue are termed adenomas
and are arbitrarily divided into microadenomas (less than
10 mm) and macroadenomas (more than 10 mm) on the basis
of size. These may present clinically due to endocrine
dysfunction or displacement of surrounding structures
such as the optic chiasm or pain-sensitive dura. Pituitary
adenomas can result in excessive secretion of any anterior
pituitary hormone but the most common clinical syndromes
in order are amenorrhea-galactorrhea (excess prolactin);
acromegaly (excess growth hormone) and Cushings
disease (excess adrenocorticotrophic hormone). Other hormone
secreting adenomas are rare.
result in a clinical syndrome of infertility, amenorrhea
or irregular menses and a thin milky-white discharge from
the nipples either spontaneously or with stimulation (amenorrhea-galactorrhea
syndrome).22 Hyperprolactinemia results in a relative
or absolute estrogen deficiency which may cause accelerated
osteopenia and predispose to later osteoporosis.23 Because
of these clinically apparent symptoms prolactinomas in
women are usually discovered at a smaller size (less than
1 centimeter) than in men. These tumors produce an elevation
of the serum prolactin level usually in excess of 150
nanograms per milliliter (ng/ml). However, since the secretion
of prolactin from the anterior lobe of the pituitary is
under the inhibitory control of dopamine from the hypothalamus
any disruption in the transport of this substance through
the hypophyseal portal system results in elevation of
serum prolactin. This is termed the stalk section effect
and may be produced by any pituitary mass and result in
hyperprolactinemia although the elevation is usually in
the range of 30-100 ng/ml, below the level typically observed
therapy of prolactinomas is possible with the dopamine
agonist bromocriptine which is a potent inhibitor of the
synthesis and release of prolactin by the pituitary gland.
The drug has no tumoricidal activity and decreases the
size of the tumor by decreasing cytosolic volume.25 As
a result withdrawal of bromocriptine may result in re-expansion
of the tumor and return of hyperprolactinemia although
at least one study suggests this is uncommon.24,26 Whether
the pre-operative use of bromocriptine enhances the surgical
cure rate remains controversial.24,27 Long-term use (more
than 1 year) of the drug may increase fibrosis within
the tumor and thus reduce the possibility of surgical
cure.28 Bromocriptine is likely to be a good option in
patients with prolactin levels in excess of 500 ng/ml
where the chance of surgical cure is low.29
remains the mainstay of treatment for most pituitary tumors
with transphenoidal microsurgery providing the most direct
and rapid approach to the tumor. According to one authority
the indications for surgery of prolactin-secreting macroadenomas
include clinical evidence of mass effect (visual loss);
apoplexy; resistance to bromocriptine and desire for fertility.30
The surgical cure rate for macroadenomas is approximately
50% with the best surgical candidates having prolactin
levels less than 200 ng/ml.21 Although the best surgical
results are obtained with prolactin-secreting microadenomas
management remains controversial. In young women desirous
of pregnancy surgery is probably the best option as many
physicians do not recommend use of bromocriptine during
pregnancy and there is a risk of accelerated tumor growth
during pregnancy.31,32 Curative tumor resection and subsequent
pregnancy has been achieved in 84% of such patients.21,33
In women with moderate elevations of prolactin who do
not desire pregnancy conservative management with serial
clinical examinations, serum prolactin levels and MRI
studies or medical treatment with bromocriptine are options.
Given the usual success of medical and surgical treatment
of prolactinomas radiation therapy has a limited role
in the management of these tumors although one small series
has achieved durable reduction in prolactin levels and
tumor size with irradiation.27,34
Effects of Pregnancy
of all cancer during pregnancy is estimated to be between
.07 and 0.1%.35 Approximately 1 in 44,000 pregnancies
is complicated by the diagnosis of a maternal brain tumor
with approximately 89 cases identified in the United States
each year.36 There were 223 reported cases of a primary
brain or spinal cord tumor diagnosed during pregnancy
as of 1987.37 However, the incidence of primary brain
tumors which become symptomatic in pregnant women 15-44
years old is lower than expected for this age group.37,38
Similarly, the age at first pregnancy and the number of
pregnancies do not appear to affect brain tumor risk.39
The reason for the lower than expected incidence of brain
tumors in pregnancy is not known although women with subclinical
cancer may become pregnant less often or experience disruption
of their pregnancies at higher rates.38 The relative frequency
of different primary brain tumor types is not changed
by pregnancy with 85% of such tumors consisting of meningiomas,
gliomas, pituitary tumors and vestibular schwannomas.
However, basal meningiomas and vascular spinal tumors
are more common in pregnancy compared to the general population.37,40
Most of these tumors are diagnosed during the first pregnancy
and are most likely to become symptomatic in the third
trimester. However, gliomas tend to accumulate in the
first trimester with meningiomas increasing in onset during
the second and third trimesters. Although the relative
frequency of meningiomas and prolactinomas does not appear
to increase in relation to pregnancy tumor progression
and symptoms do increase over this period. Although the
reason for this tumor growth in pregnancy is not clearly
known some authorities have suggested it is due to engorgement
of blood vessels or expansion of the intracellular fluid
space while others contend hormonal influences may be
involved.36 A recent review found 44 cases of maternal
cancer metastatic to the products of conception with 12
such cases involving the fetus. In the latter cases the
maternal cancer was either a lymphoproliferative neoplasm
the symptoms of increased intracranial pressure including
headache upon awakening, nausea and vomiting are similar
to the symptoms of morning sickness evaluation can be
challenging.40 Should neuroimaging of the pregnant patient
with these symptoms become necessary MRI is the procedure
of choice as there is no exposure to ionizing radiation.36
Although there is no evidence that MRI affects the fetus
there is exposure to powerful electromagnetic fields and
this imaging modality should be avoided if possible in
the first trimester.41 Similarly, there is very little
evidence regarding the safety of the ferromagnetic contrast
agent gadolinium and this is not sanctioned for use in
pregnancy and should be avoided if possible.40 In the
patient with rapid neurologic deterioration computerized
tomography (CT) may be necessary. This does involve radiation
exposure of approximately 2.5 to 3 rads to the head of
the patient and a fetal exposure estimated to be approximately
1 mrad or less per slice which can be reduced by appropriate
shielding of the uterus with a lead apron.35 At fetal
exposures less than 10 rads no adverse effects in excess
of the background rate of spontaneous abnormalities in
3% of livebirths and the spontaneous abortion rate of
30% in all pregnancies.35,40 Medically indicated exposures
of up to 5 rads are considered acceptable in pregnancy
when unavoidable. There has been limited experience with
the use of iodinated contrast agents during pregnancy
and the risks are not precisely defined. Such agents should
be avoided in the first trimester.40
of brain tumors or their complications may be necessary
during pregnancy. Cerebral edema and increased intracranial
pressure may require the use of glucocorticoids and mannitol.
Glucocorticoids have been used during pregnancy for other
reasons including the prevention of neonatal respiratory
distress syndrome and there is no evidence of growth,
physical, motor or developmental deficiencies within the
first three years of life.42 However, fetal adrenal suppression
may occur with long-term, high dose therapy during any
part of pregnancy and necessitates the use of supplemental
steroids in the peri-partum period.43 Although mannitol
does cross the placenta and is excreted by the fetal kidney
into the amniotic fluid no adverse effects have been reported.44,45
irradiation exposes the fetus to higher doses of radiation
than diagnostic imaging. In general, radiation exposure
in utero carries a risk of adverse fetal outcomes including
spontaneous abortion, anatomic malformation, growth and
mental retardation and possibly childhood cancer with
the latter risk highest in the first trimester.35,40 The
exposure to the fetus from scatter is low when conventional
radiation therapy is delivered to parts distant from the
uterus and such exposure carries low risk. Strategies
to reduce fetal exposure include the use of focal rather
than whole brain irradiation, radiation dose reduction,
substitution of heavy charged particles for photons and
deferring radiation until after delivery.40
typically involves agents which are teratogenic in the
first trimester and associated with adverse fetal outcomes.35
Properties of chemotherapeutic agents which improve permeability
across the blood brain barrier also facilitate transport
across the placenta making these drugs especially hazardous.
Although there is data to suggest that certain chemotherapeutic
agents are associated with minimal risk in the second
and third trimesters, chemotherapy for malignant brain
tumors should be avoided during pregnancy.35,40
of delivery for a pregnant woman with a brain tumor remains
controversial. Perhaps the most important factor is the
presence and severity of increased intracranial pressure
(ICP). During labor uterine contractions do not typically
increase ICP in the mother although abdominal pressure
in the second stage of labor does significantly elevate
ICP.36 One authority has suggested that the decision whether
to perform a cesarean section should be based on obstetric
reasons alone and that if there is unusual concern about
intracranial hypertension a forceps delivery is indicated
to avoid the second stage of labor.36 However, cesarean
section is usually recommended in the presence of increased
ICP although other maternal and fetal factors such as
parity, neurologic condition of the mother, location and
grade of tumor, position and health of the fetus are important
in making this decision.40
Effects of Menopause
is associated with a decline and eventual cessation of
estrogen synthesis and a relative increase in the synthesis
of progesterone and androgens. Women who have undergone
natural menopause seem to have a reduced risk for development
of meningiomas which may be attributable to this decline
in estrogen levels. In women who have undergone bilateral
oophorectomy (artificial menopause) there is complete
and immediate cessation of ovarian hormone production
which confers not only a reduced risk for meningiomas
but for other brain tumors as well implicating these hormones
in tumor growth. Bilateral oophorectomy after natural
menopause does not further reduce the risk of brain tumors.39
Neurological Complications of Cancer
cancer is the most common malignancy among women in North
America accounting for 27% of all cancers. Approximately
181,000 new cases of breast cancer were diagnosed in 1992
and 46,000 women died from the disease the same year.46
Neurologic complications occur in approximately 25% of
patients with metastatic breast cancer although autopsy
studies have demonstrated central nervous system involvement
in 31-57% of examinations.46-48
from breast cancer may involve the skull, dura or brain.
Skull metastases are common and are usually associated
with disease in other bones. Calvarial metastases may
cause localized headache or swelling but are usually asymptomatic.
Metastases to the base of skull are less common but are
more likely to produce symptoms or signs from compression
of cranial nerves.49 Metastases to the mandible may involve
the mental nerve and produce the "numb chin syndrome"
which includes unilateral numbness of the lower lip, chin
and mucous membranes on the inside of the lip. Such lesions
are usually visible on CT or plain radiographs of the
mandible and treatment with regional radiation results
in symptomatic improvement in most patients.50 Breast
cancer is the most common cause of dural metastases which
affect 16-18% of patients with breast cancer at autopsy.47,51
These are often asymptomatic but may cause symptoms by
compression or invasion of brain, cranial nerves or venous
sinuses. These dural lesions may resemble meningiomas
on neuroimaging studies and since there may be an increased
frequency of meningiomas in breast cancer patients can
cause diagnostic confusion.48
cancer is the leading cause of brain metastases in women
affecting 10-20% of such cases during life.47,52 At the
time of diagnosis these lesions are single in 56-58% of
cases and multiple in 42-44% of cases.48,53 Brain metastases
develop more frequently and earlier in the course of the
disease in pre-menopausal women but menopausal status
does not affect survival.48,54 One study found that a
brain metastasis was the first site of relapse in 20%
of cases although most brain metastases occur in the context
of progressive extracranial disease.55 The most frequent
presenting symptoms include new seizure or subacute onset
of headache, altered mentation or gait disturbance.48
The most sensitive diagnostic study is a gadolinium-enhanced
cranial MRI (Figure 2). Treatment options include steroids,
radiation, surgery or chemotherapy. Dexamethasone at 16
milligrams per day will result in symptomatic improvement
in 70-80% of patients with brain metastases.56 Whole brain
irradiation and steroids result in improvement or stabilization
of symptoms in 95% of patients.48,52 Follow-up cranial
CT scans demonstrate disappearance or regression of lesions
in 35% and 40% of such patients, respectively. However,
median survival with this approach is only 3-4 months
with only 21% of patients surviving beyond one year.52
All patients who are to receive whole brain irradiation
should be maintained on steroids for 48-72 hours prior
to initiation of radiation to reduce intracranial pressure
and minimize acute radiation toxicity.56 In patients without
extensive extracranial disease single, surgically accessible
brain metastases can be excised with improvement of survival
and quality of life.57 Recent studies have suggested that
stereotactic radiosurgical approaches achieve results
similar to resection for single or multiple brain metastases.58
Chemotherapy has not been a conventional approach for
brain metastases although there is emerging interest in
the treatment of brain metastases from breast cancer with
this modality. Recent studies with a number of drug combinations
have demonstrated response rates and median survival times
comparable to whole brain radiation.52,55,59,60 Since
approximately 50% of breast cancer patients with brain
metastases will die of progressive extracranial disease
the ultimate prognosis for the majority of these patients
depends on the control of disease outside the brain. A
possible advantage of systemic chemotherapy is the ability
to treat both the intracranial and extracranial sites
of disease simultaneously.52 However, chemotherapy has
not been compared to radiation for this population in
a prospective randomized clinical trial.
intracranial sites of metastasis in breast cancer patients
include the optic nerve and pituitary gland. Although
optic nerve metastases are rare, breast cancer is the
most common cause of such lesions. Presentation is usually
painless, slowly progressive unilateral visual loss with
optic disc edema on examination. Metastasis to the choroid
occurs in approximately 10% of cases of advanced breast
cancer and presents with decreased visual acuity with
scotoma. Symptomatic visual impairment should be treated
with irradiation. Pituitary metastases from breast cancer
have been demonstrated in 9% of cases at autopsy. Most
of these lesions are asymptomatic but may cause headache,
ophthalmoplegia or diabetes insipidus. Visual loss and
hypopituitarism are uncommon symptoms and more suggestive
of a pituitary adenoma if there is no other evidence of
metastases (LM) from breast cancer occur in 2-5% of patients
with metastatic disease although some studies suggest
that only half of such cases are diagnosed during life.48,61
Breast cancer is the most common cause of LM and accounts
for 50% of cases associated with solid tumors.62 Leptomeningeal
metastases can occur at any time during the course of
breast cancer and clinical presentation is usually subacute
with multifocal symptoms and signs reflecting involvement
of multiple levels of the neuraxis (brain, cranial nerves
and spinal roots).63,64 In addition to cranial nerve palsies
which occur in 80% of cases of LM, altered mentation,
headache, meningismus, seizures and gait disturbance also
occur in varying frequencies. Diagnostic evaluation should
include cerebrospinal fluid (CSF) analysis which typically
shows a mononuclear pleocytosis with elevated protein
and low glucose levels. Identification of malignant cells
in the CSF is diagnostic.65 However, since this is a qualitative
test with significant interobserver variability, multiple
samples are usually necessary.61 Autopsy studies of patients
with LM demonstrate that approximately 50% have a positive
cytology after a single lumbar puncture (LP) with an additional
30% discovered after a second LP.64,65 Additionally, cisternal
puncture increased the yield of positive cytologies by
25% in one study of solid tumors with LM.61 Recent interest
in CSF tumor markers may result in better diagnostic capability
in the future.61 Neuroimaging of the brain with CT or
MRI may demonstrate effacement of the sulci and cisterns,
ependymal enhancement, enhancing cortical nodules, hydrocephalus
or may be normal. Spinal imaging with MRI or myelography
may show nodular or diffuse thickening of nerve roots
or CSF block which occurs in approximately 70% of LM cases
associated with solid tumors and is an important prognostic
factor.66,67 Despite poor prognosis and poor response
to treatment in LM associated with most solid tumors the
breast cancer subset of LM is more amenable to treatment
which usually includes delivery of intrathecal chemotherapy
via dural puncture or indwelling ventricular reservoir.62
Multiple drug therapy does not seem to confer an advantage
over single agent treatment with methotrexate.68 In patients
with focal symptoms or CSF block localized spinal radiation
is a treatment option. Median survival is 6-8 months with
treatment and 15-25% of such patients survive more than
with intrathecal methotrexate may result in acute meningoencephalitis
with confusion, headache, fever, nausea and vomiting approximately
2-4 hours after the injection. Pleocytosis and elevated
protein are usually seen on CSF evaluation. Symptoms usually
resolve over 12 to 72 hours but may recur with subsequent
treatments. Myelopathy and sudden death are rare complications
of intrathecal methotrexate.48
50% of breast cancer patients who survive more than one
year with leptomeningeal metastases treated with repeated
injections of intrathecal methotrexate develop a leukoencephalopathy
which includes confusion, dementia, somnolence or focal
neurologic signs.62 This usually occurs when intrathecal
methotrexate is combined with whole brain irradiation
and this combination should be avoided if possible. The
leukoencephalopathy may improve if intrathecal methotrexate
is discontinued although it may also progress to coma
spinal cord compression (ESCC) occurs in 3-4% of patients
with breast cancer during life with a 5-10% frequency
at autopsy.69 In cancer hospitals breast cancer is the
leading cause of ESCC accounting for 22% of all cases.48
Epidural spinal cord compression is most commonly the
result of direct spread of tumor from the bony elements
of the spine to the epidural space. Vertebral body metastases
occur in 60% of patients with breast cancer and may be
the consequence of mammary vein drainage into the vertebral
venous plexus. Compression of nerve roots or spinal cord
may result from spread of tumor into the epidural space
or intervertebral foramina or by collapse of the vertebral
body with encroachment of tumor and bone into the epidural
space.48 Epidural spinal cord compression from breast
cancer involves the thoracic spine 75-80% of the time,
cervical spine 15% of the time and lumbosacral spine 6-7%
of the time.70 Compression of the spine at more than one
level is not uncommon and mandates evaluation of the entire
spine. The most common presenting symptom is pain which
is usually confined to the back but may become radicular
with progression. Weakness and sensory loss may follow
with bladder and bowel symptoms usually occurring later.
In one retrospective study of symptoms in 70 breast cancer
patients with ESCC 96% had motor weakness, 94% pain, 79%
sensory disturbance and 61% sphincter disturbance.69 Progression
usually occurs over weeks to months but sudden deterioration
may occur in 20% of patients.71 Urgent investigation is
mandated if ESCC is suspected. Women in complete remission
from breast cancer are unlikely to present with ESCC as
first relapse (only 2 of 70 cases in one recent study).69
The majority of women presenting with ESCC have existing
bone metastases (93% in recent study) and this group of
women should be evaluated urgently. Although plain x-rays
are abnormal at the symptomatic level in 94% of patients
with breast cancer and ESCC spinal MRI is the preferred
diagnostic test to identify ESCC (Figure 3). When other
modalities are used initially most patients end up getting
a series of progressively advanced diagnostic tests to
identify ESCC.72 One advantage of MRI is the ability to
image the entire neuraxis thus identifying any areas of
asymptomatic disease. If back pain precludes the ability
of the patient to cooperate for the prolonged time necessary
for MRI then myelography should be performed. In patients
with neurologic signs of ESCC steroids should be started
prior to spinal imaging. Animal studies and anecdotal
experience suggest high dose dexamethasone is beneficial
in patients with spinal cord compression. In patients
with severe pain or myelopathy treatment with dexamethasone
as a 100 mg intravenous bolus followed by 24 mg every
six hours is recommended with tapering of the drug after
more definitive therapy has been started. In patients
without neurologic signs 16 mg per day in four divided
doses is recommended.72 Definitive treatment of ESCC consists
of radiation therapy or surgery. The goals of therapy
are pain alleviation and maintenance or return of neurologic
function. Most recent studies have failed to demonstrate
an outcome difference between radiation alone versus surgery
followed by radiation.69 Most authorities recommend initiation
of radiation therapy immediately after identification
of involved spinal levels on MRI or myelography.72 Surgery
may have a role in patients who have been previously irradiated,
in patients who progress despite radiation or in cases
with spinal instability. Ambulatory status at presentation
is the most important factor predictive of neurologic
outcome thus emphasizing the need for rapid evaluation
and diagnosis.73,74 In one study all ambulatory patients
at the start of radiation could walk post-treatment while
74% of paraparetic patients and 33% (1 of 3) of paraplegic
patients regained the ability to walk.74 The ability to
ambulate is also strongly associated with improved survival
in breast cancer patients with ESCC. In general cancer
patients with ESCC prognosis is poor with only 30% surviving
more than one year in one study. However, the breast cancer
subset of patients with ESCC have a better prognosis with
29% of patients surviving more than 3 years in this same
spinal metastases are rare but breast cancer accounts
for 15% of all cases and many of these patients will also
have brain metastases. Presentation is usually with back
pain and progressive asymmetric myelopathy. Diagnosis
is best made by MRI and treatment with steroids and radiation
may improve neurologic function.48
infiltration of the brachial plexus occurs in approximately
2.5% of all women with breast cancer.48 The tumor usually
compresses or invades the plexus from below with neurologic
symptoms progressing from lower to upper plexus. Severe
pain in the shoulder and arm usually precedes other symptoms
by weeks to months. The sensory symptoms are usually followed
by progressive weakness and wasting beginning in the small
muscles of the hand and progressively involving more proximal
parts of the arm. Horners syndrome may result if
the tumor extends into the paraspinal or epidural space.
Other signs include induration and tenderness in the supraclavicular
fossa, lymphedema of the arm and trophic changes in the
skin and nails.48,72
of the brachial plexus includes electromyography (EMG)
which may show neurogenic changes including fibrillations
and nerve conduction studies which may demonstrate prolonged
or absent F waves and lowered sensory and compound motor
action potentials. Imaging of this region includes CT
and MRI which may show a mass or loss of normal tissue
planes (Figure 4). Imaging should include evaluation of
the epidural space with MRI or myelography if such extension
is suspected. However, a normal imaging study does not
exclude malignant infiltration of the brachial plexus
and surgical exploration may be necessary.48
plexus may be involved by other processes in women with
breast cancer and these should be included in the differential
diagnosis. In women who have received radiation to the
axilla or upper thorax (after mastectomy for breast cancer)
several complications may arise. An acute brachial plexitis
with mild pain and shoulder weakness can begin approximately
four months after local radiation therapy for breast cancer.
Although the weakness may be severe it is usually reversible.
Radiation fibrosis usually occurs in 2-4% of patients
after radiation although frequencies as high as 15% have
been reported. This tends to develop more than 6 months
after completion of radiation and is usually painless
with involvement of the muscles of the shoulder before
the hand. Horners syndrome is uncommon but lymphedema
is more common than in cases of malignant infiltration
of the plexus. Myokymia on EMG is considered pathognomonic
of radiation fibrosis. The T2-weighted signal on MRI of
the brachial plexus tends to be low in radiation fibrosis
and high in cases of malignant infiltration. A late complication
of radiation is occlusion of the subclavian artery which
can result in sudden development of weakness without pain.
Angiography may be necessary to demonstrate the occlusion.48,72
of malignant infiltration of the brachial plexus by breast
cancer is radiation. This can reduce the size of the tumor
and may partially relieve the pain. However, relief is
usually incomplete and further treatment with narcotic
analgesics, nerve blocks and cortdotomy may be necessary.
of the lumbosacral plexus by metastatic breast cancer
is uncommon, usually occurring in the context of sacral
and pelvic bone metastases. Slowly progressive pain in
the back, buttock and thigh are early symptoms with later
development of unilateral, asymmetric lymphedema, weakness,
loss of sensation and reflexes in the involved leg. Evaluation
includes rectal examination since the mass may be palpable
as well as EMG and nerve conduction studies which usually
show neurogenic muscle changes and decreased amplitudes
of sensory and motor action potentials, respectively.
Imaging with CT or MRI usually reveals bone metastases,
adenopathy and a mass in the region of the plexus. The
treatment is the same as for malignant infiltration of
the brachial plexus.48
4-6% of post-mastectomy patients will develop pain due
to injury to the intercostobrachial nerve or cutaneous
branches of the intercostal nerves. A constricting or
burning sensation in the axilla, posteromedial upper arm
and anterior chest wall is the usual complaint. Onset
may be immediate or delayed for up to 6 months after surgery.
Treatment includes tricyclic antidepressants, nerve blocks
and topical anesthetics.75-77
complications most commonly occurring in breast cancer
are cerebellar degeneration and the anti-Ri syndrome.
cerebellar degeneration typically begins with slight incoordination
while walking with progression over weeks to months to
an incapacitated state. The symptoms and signs are usually
pancerebellar with both appendicular and truncal ataxia
but approximately 50% of patients will have other neurologic
signs on examination. The cerebellar symptoms precede
the identification of the cancer in approximately 2/3
of patients. Evaluation may include a lumbar puncture
which usually shows a lymphocytic pleocytosis, elevated
protein, immunoglobulin G and positive oligoconal bands
in the early phases of the illness. The cranial CT and
MRI studies are often normal early in the illness but
may show diffuse cerebellar atrophy later in the course.
Most patients with paraneoplastic cerebellar degeneration
in the context of breast cancer have serum antibodies
(anti-Yo) which react against the cytoplasm of Purkinje
cells.72 Although the disease is felt to be immune-mediated
therapies such as plasmapharesis and immunosuppressants
have been disappointing in these patients.78 Recent reports
of anecdotal success with immunoadsorption therapy require
cancer has been identified in 6 of 11 reported cases of
the anti-Ri syndrome. The symptoms of opsoclonus, myoclonus
and truncal ataxia typically wax and wane with some patients
experiencing spontaneous resolution. There is usually
a CSF pleocytosis and elevation of protein although cranial
CT and MRI are usually normal.72,80 By definition all
of these patients have an anti-neuronal antibody (anti-Ri)
which is similar to the anti-Hu antibody which reacts
with the nuclei of virtually all neurons of the central
and peripheral nervous system. Since there have been so
few cases and there is waxing and waning of symptoms efficacy
of specific treatments is not known.
syndrome is a rare neurologic disorder characterized by
fluctuating muscular rigidity and spasms and the presence
of antibodies against glutamic acid decarboxylase in the
majority of patients. Five cases of paraneoplastic stiff-man
syndrome have been reported including three with adenocarcinoma
of the breast. All of the breast cancer cases had an antibody
against a 128 kilodalton (kd) neuronal protein. Detection
of this antibody in any patient with stiff-man syndrome
should prompt a search for an occult breast cancer.81
Other neurologic complications
hemorrhages from brain metastases are unusual in breast
cancer patients although thrombocytopenia from chemotherapy,
radiation or bone marrow metastasis may result in intracerebral
or subdural hemorrhages. Dural metastases may result in
subdural bleeding and radiation should follow surgery
if such disease is identified at the time of surgery.
Breast cancer is one of the most common causes of disseminated
intravascular coagulation (DIC) in cancer patients and
this may result in small cerebral infarctions from multiple
fibrin thrombi producing confusion and focal neurologic
signs. Approximately 5-10% of cases of non-bacterial thrombotic
endocarditis occur in women with breast cancer. Platelet/fibrin
vegetations form on the heart valves resulting in cardiogenic
cerebral embolism and infarcts. Cranial CT or MRI will
demonstrate such infarcts and angiography may show multiple
embolic occlusions. Intravenous heparin may be beneficial.72
disorders may produce potentially reversible behavioral
changes in breast cancer patients with hypercalcemia one
of the more common causes. Complications of breast cancer
therapy include methotrexate leukoencephalopathy and radiation
injury of the brachial plexus as previously described.
Tamoxifen may produce a retinopathy which can impair vision
but may improve after discontinuation.48
cancer uncommonly involves the nervous system. However,
with improved treatment for this disease longer survival
may increase the frequency of such complications.
metastasis is a rare complication of ovarian cancer with
only 67 well documented cases in the literature according
to one recent review. A multi-institutional study of 4027
ovarian cancer patients over 30 years identified only
32 cases while an autopsy study of ovarian cancer reported
an incidence of 0.9%.82,83 However, there is some evidence
that this complication may be increasing with recent reports
reporting brain metastases in 1 to 4% of such patients.83
Serous cystadenocarcinoma is the most common histology
associated with brain metastases.84 The clinical presentation
is similar to other solid tumors with brain metastases
occurring on average 14.5 months after diagnosis of the
ovarian tumor.85 Approximately 50-90% of women with brain
metastases from ovarian cancer will have extra- or intraperitoneal
disease at the time of diagnosis. Conventional treatment
has consisted of dexamethasone and whole brain irradiation
and most patients treated in this manner achieve palliation
until death. Median survival in the multi-institutional
study of 32 patients was 4 months with whole brain irradiation
while other studies report survival times from 3 to 10
months.82 The addition of surgical resection, stereotactic
radiosurgery and chemotherapy may improve these results.83,84
metastasis is also a rare complication of ovarian cancer
with only 14 cases reported by 1994. The presentation
is similar to leptomeningeal metastasis from other solid
tumors. In the single case in which it was measured CSF
CA-125 was elevated.86 Treatment is usually with intrathecal
methotrexate and/or radiation but response rates vary
among the few cases reported.
cancer is the second leading cause of the approximately
300 reported cases of paraneoplastic cerebellar degeneration
according to one authority.72 In patients with ovarian
cancer a subset will have antibodies in the serum and
CSF directed against the cytoplasm of Purkinje cells (anti-Yo).88
The presence of the anti-Yo antibody should prompt evaluation
of the breast and reproductive organs. One authority has
suggested that failure to identify a cancer on routine
gynecologic examination, mammography and pelvic CT should
lead to examination under general anesthesia followed
by a dilatation and curettage. Finally, hysterectomy and
bilateral salpingo-oophorectomy should be considered in
those remaining women with no identifiable gynecologic
pathology. With few exceptions therapies such as plasmapharesis
and immunosuppression do not appreciably alter the disease
complications may result from chemotherapy directed against
ovarian cancer. Paclitaxel and docetaxel are novel chemotherapeutic
agents that promote polymerization and inhibit depolymerization
of microtubules and are commonly used in patients with
ovarian cancer.89 Approximately 60% of patients receiving
paclitaxel at a dose of 250 mg/m2 develop paresthesias
of the hands and feet. Although in most patients the symptoms
do not progress and may improve this toxicity may be dose-limiting.
Arthralgias and myalgias in the legs can develop 2 to
3 days after treatment with these drugs and may last for
2 to 4 days. A distal sensory and sensorimotor neuropathy
as well as a neuropathic proximal motor weakness may also
complicate treatment with these drugs.89 One report demonstrates
that the neuropathy is axonal in nature.90 Nerve growth
factor prevents paclitaxel neuropathy experimentally and
clinical trials are underway with this agent. Paclitaxel
has also been associated with a reversible encephalopathy
in a small number of reports.91
binds covalently to DNA bases and disrupts the cell cycle
in this manner. The drug is effective against ovarian
cancer and may be combined with paclitaxel in some protocols.
Peripheral neuropathy is the most common neurotoxicity
of cis-platinum and is common in doses greater than 400
mg/m2. The neuropathy involves large fiber sensory axons
and begins in the toes and feet with progression to more
proximal parts of the arms and legs. Proprioceptive loss
may produce sensory ataxia and impair gait. Treatment
is ineffective after the neuropathy has started although
it usually improves if the patient survives the cancer.
Lhermittes signs may appear during or shortly after
treatment with cis-platinum and presumably represents
a transient demyelinating lesion in the posterior columns
of the spinal cord. Ototoxicity may result from cis-platinum
damage of hair cells and is usually subclinical involving
the high frequency range. Acute deafness has been reported
with high dose cis-platinum. Vestibular toxicity is less
common than hearing loss and involves vertigo, oscillopsia
and nausea. Rarely seizures, cortical blindness and encephalopathy
may follow intravenous cis-platinum.72,92
review of 121 cases of invasive cervical cancer demonstrated
epidural spinal cord compression in 5 cases with 2 cases
occurring at initial diagnosis of cervical cancer. Back
pain is not an unusual complaint in many patients with
cervical cancer and has been attributed to the presence
of the pelvic tumor. However, as this report suggests
consideration of epidural metastasis is important as early
diagnosis and treatment may prevent neurologic deterioration.
The prognosis remains poor with a median survival of 4
months in this series.93
is a rare tumor of the placenta with an incidence of approximately
1 in 50,000 term pregnancies and 1 in 30 molar pregnancies.94,95
Brain metastases occur in 10 to 20% of patients with choriocarcinoma
and two-thirds of patients who die with this disease have
brain metastases.85,96 Intratumoral hemorrhage is not
uncommon with this type of brain metastasis. Human chorionic
gonadotropin (hCG) is a sensitive tumor marker produced
by gestational trophoblastic neoplasms and may be elevated
in both the serum and CSF. The level of hCG is commonly
followed serially as a measure of treatment effectiveness.94
Although mortality from choriocarcinoma is higher in those
patients with brain metastases the overall prognosis is
more favorable than in patients with brain metastases
from other primary tumors with an approximately 80-90%
chance of long-term survival after chemotherapy and whole
brain irradiation.96 One established approach includes
systemic methotrexate, actinomycin D and chlorambucil
with intrathecal methotrexate and whole brain irradiation
to 3000 cGy over 10 fractions.85 Serum and CSF hCG should
be in the normal range for at least 12 months prior to
discontinuing such therapy. Neoplastic intracranial aneurysms
may occur when embolic tumor lodges in an intracerebral
vessel and invades the vessel wall. Rupture of such an
aneurysm may produce subarachnoid or intracerebral hemorrhage.
This complication usually occurs in advanced cases of
choriocarcinoma and may be associated with cardiac metastases.85,96
diseases of women involve tumors which arise within the
central nervous system and the neurologic complications
of tumors which originate outside the nervous system.
Although all primary brain tumors may occur in both sexes
meningiomas and pituitary tumors occur with greater frequency
in women and may be influenced by hormonal factors. Sex
steroids affect tumor growth and may provide an opportunity
for the development of hormonal therapies. The unique
hormonal and vascular changes of pregnancy may also affect
tumor size and management. Fetal development and the physical
changes of pregnancy complicate the management of brain
tumors during this period. Breast cancer is the most common
type of cancer in women and results in more neuro-oncologic
complications than perhaps all other tumors combined.
Neurologic management of these complications requires
knowledge of the specific metastatic and non-metastatic
conditions associated with this disease.
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