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Neuro-oncologic Diseases of Women

by Tracy Batchelor, M.D., Director of Neuromedical Oncology
MGH Brain Tumor Center 

Neuro-oncologic 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


Approximately 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


Meningiomas 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 with age.5,6

The incidence 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

The association 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.

Despite 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

Since 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 evaluations.14

Pituitary Tumors

Pituitary tumors account for approximately 15% of all primary intracranial neoplasms and occur in higher frequency in women, mainly in the child-bearing years.

The female 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 1).21

Pituitary 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 Cushing’s disease (excess adrenocorticotrophic hormone). Other hormone secreting adenomas are rare.

Prolactinomas 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 with prolactinomas.24

Medical 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

Surgery 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

The incidence 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 or melanoma.35,36

Since 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

Treatment 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

Cranial 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

Chemotherapy 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

The method 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

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

Breast Cancer

Breast 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

Cranial Metastases

Metastases 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

Breast 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.

Other 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 metastasis.48

Leptomeningeal Metastases

Leptomeningeal 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 one year.62,64

Treatment 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

Approximately 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 and death.48

Epidural Metastases

Epidural 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 study.74

Intramedullary 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

Neuromuscular complications

Malignant 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. Horner’s 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

Evaluation 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

The brachial 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. Horner’s 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

The treatment 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.

Involvement 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

Approximately 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

 Paraneoplastic complications

The paraneoplastic complications most commonly occurring in breast cancer are cerebellar degeneration and the anti-Ri syndrome.

Paraneoplastic 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 further study.79

Breast 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.

Stiff-man 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

Intracranial 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

Metabolic 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

Gynecologic Cancers

Ovarian Cancer

Ovarian cancer uncommonly involves the nervous system. However, with improved treatment for this disease longer survival may increase the frequency of such complications.

Brain 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

Leptomeningeal 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.

Ovarian 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 course.72,78,87

Neurologic 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

Cis-platinum 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. Lhermitte’s 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

Cervical cancer

A recent 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

Choriocarcinoma/Gestational trophoblastic disease

Choriocarcinoma 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


Neuro-oncologic 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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