1. Incidence. Autopsy series show that 25% of patients who die of cancer have intracranial metastases; 15% have brain and 10% have dural or leptomeningeal metastases.

2. Tumor of origin. The tumor that most commonly metastasizes to the brain is lung cancer, which is responsible for 30% of brain metastases. Brain metastases from pulmonary tumors can occur early in the course of malignancy, and their diagnosis is synchronous (i.e., before or at the same time as the primary tumor) in about one-third of cases. Other types of tumors that commonly metastasize to the brain include breast and renal cancers and melanoma (each comprising 10% of cases), along with metastases from tumors of unknown primary sites (15%). Carcinomas of the gastrointestinal tract, ovary, and uterus rarely produce intracerebral metastases.

3. Mechanism. Tumor dissemination to the central nervous system (CNS) is usually by the hematogenous route, and the distribution of lesions parallels the distribution of arterial blood flow. Of brain metastases, 80% are supratentorial, 15% are cerebellar, and 5% are in the brainstem. However, metastases from certain primaries have a predilection for particular regions in the brain. For example, colon cancer and pelvic primaries have a propensity to metastasize to the posterior fossa, whereas lung cancer tends to metastasize to the supratentorial compartment. About one-half of the metastases are single, especially those from lung, renal, and colon cancers; metastases from melanoma and breast cancer are more likely to be multiple. Metastases can be solid, cystic, or hemorrhagic (especially lung, choriocarcinoma, melanoma, and thyroid carcinoma).

B. Natural history. Left untreated, metastatic brain tumors cause progressive neurologic deterioration leading to coma and death; the median survival time is only 1 month. About one-half of patients with brain metastases die of their neurologic disease, and the remainder die of systemic causes. Among treated patients, the overall median survival is 3 to 8 months; however, patients with limited systemic disease and one to three brain metastases can have vigorous focal treatment and survive longer, sometimes years.

C. Clinical presentation. Metastases can cause focal or global cerebral dysfunction at presentation. Symptoms usually develop insidiously and progress over a few weeks. Occasionally, the onset is sudden when there is an acute hemorrhage into a metastatic lesion.

1. Global signs and symptoms. Headache and mental status changes are each seen in 50% of patients. Other nonlocalizing findings include symptoms of increased intracranial pressure, such as papilledema, nausea, and vomiting.

2. Focal signs and symptoms, including hemiparesis, visual field defect, and aphasia, depend on the site of metastasis.

3. Seizures are the presenting manifestation in about 20% of patients.

4. Differential diagnosis. Conditions that should be considered in the differential diagnosis of brain metastasis include the following:

a. Metabolic encephalopathy, including hyponatremia, hypercalcemia, hypoxemia, uremia, hepatic encephalopathy, and hypothyroidism

b. Drug-induced encephalopathy from analgesics, sedatives, glucocorticoids, chemotherapeutic agents, and other drugs

c. CNS infections, including bacterial and fungal meningitis, herpes encephalitis, progressive multifocal leukoencephalopathy, and cerebral abscess (see Chapter 35, Section III.B)

d. Nutritional deficiency, such as Wernicke encephalopathy

e. Cerebrovascular disease (CVD), including stroke, hemorrhage, and venous obstruction owing to thrombotic disorders and disseminated intravascular coagulation (DIC)

f. Paraneoplastic disorders, especially subacute paraneoplastic cerebellar degeneration (see Section V.A)

D. Evaluation. An MRI is the optimal test to detect brain metastases. A CT scan should only be used in those patients unable to undergo MRI (e.g., pacemaker). Most metastatic tumors enhance after administration of contrast material, and both a noncontrast and contrast study should be performed in every patient. Lesions detectable by CT or MRI that may resemble brain metastases include cerebral abscesses, parasitic disease, and occasionally stroke. Lumbar puncture is not useful in diagnosing brain metastases and is often contraindicated.

E. Management. The aims of therapy for patients with brain metastases are to relieve neurologic symptoms and prolong survival. Exact treatment recommendations depend on the histology of the tumor, the degree of systemic dissemination of the tumor, and the patient’s clinical condition.

1. Dexamethasone, usually 16 mg IV followed by 4 to 8 mg PO or IV twice a day, results in a dramatic reversal of neurologic deficits and alleviates headaches. The effect is short lived (weeks), however, but further improvement is possible with dose escalation and definitive treatment. Dexamethasone is unnecessary for asymptomatic patients whose brain metastases were identified on a screening MRI. In most patients, steroids can be tapered off once definitive therapy has been administered.

2. Anticonvulsant therapy should be administered only to patients who have had a seizure. Antiepileptics that do not induce the hepatic microsomal system, such as levetiracetam, valproic acid, lamotrigine, or others, are the best options. There is no role for prophylactic anticonvulsants in patients with brain metastases. They do not protect against future seizures, are associated with frequent side effects, and can enhance the metabolism and thus reduce the efficacy of many chemotherapeutic agents.

3. Radiation therapy (RT) is the standard treatment of brain metastases. The field usually encompasses the whole brain, and doses range from 2,000 to 4,000 cGy, administered by larger fractions in the lower-dose regimens.

4. Surgery provides a significant survival advantage for patients with a single brain metastasis. Median survival for surgically treated patients is 10 to 12 months, and 12% of patients live 5 years or longer. Candidates for surgical resection should have a single or possibly two brain metastases and limited or controlled systemic disease. Surgical resection is considered in other cases on an individual basis and may be influenced by the need for a tissue diagnosis. Whole-brain RT after surgical resection improves control of CNS disease but does not prolong survival.

5. Radiosurgery delivers a single large dose of radiation to a well-defined target; the steep dose curve of this technique ensures that little radiation is delivered to surrounding tissues. Radiosurgery can be delivered with equal efficacy by a
gamma knife or linear accelerator. It is an effective, minimally invasive outpatient procedure that is a treatment option for patients with one to three intracranial metastases. Radiosurgery may be used in place of surgical resection or whole-brain radiation therapy or as an adjunct to either treatment. Local control rates appear to be equal for surgery and radiosurgery. Radiosurgery offers an advantage for metastases that are not surgically accessible, for multiple metastases, or for tumor types that are resistant to standard radiation therapy (e.g., renal cell carcinoma, melanoma) where control by radiosurgery appears to be superior. Radiosurgery must be limited to lesions ≤3 cm in diameter and can occasionally produce symptomatic radionecrosis or a prolonged dependence on corticosteroids.

6. Chemotherapy. Cytotoxic agents are primarily used to treat brain metastases at relapse or occasionally asymptomatic lesions found on screening MRI. Responses have been documented in patients with metastatic breast cancer, small cell lung cancer, and lymphoma. Effective regimens are selected on the basis of the underlying primary and the patient’s prior therapies.

Temozolomide is effective for some patients with brain metastases from non-small cell lung cancer and melanoma. Targeted therapy has proven effective against tumors and even their CNS metastases that harbor sensitizing mutations such as erlotinib in EGFR mutant non-small cell lung cancer or BRAF inhibitors in BRAF mutant melanomas.

1. Incidence. Leptomeningeal metastases have been demonstrated at autopsy in 8% of patients with systemic malignancy.

2. Associated tumors. Although any systemic tumor can metastasize to the leptomeninges, those that do so most commonly are lymphoma, leukemia (especially acute), lung carcinoma (especially small cell), breast carcinoma, and melanoma.

3. Mechanism. Metastasis to the leptomeninges occurs by hematogenous spread through arachnoid vessels or the choroid plexus, by infiltration along nerve roots, and by extension from brain or dural metastases. The sites of heaviest infiltration are usually at the base of the brain, the major brain fissures, and the cauda equina.

B. Natural history. Leptomeningeal metastasis can involve any area of the CNS in direct contact with the cerebrospinal fluid (CSF). Tumor can grow as a sheet along the surface of the brain, spinal cord, cranial nerves, or nerve roots and can also invade these structures causing focal dysfunction. Tumor cells can obstruct the arachnoid villi and impair CSF reabsorption causing hydrocephalus.

C. Clinical presentation. The hallmarks of leptomeningeal metastasis are evidence of multilevel, noncontiguous neurologic signs and more neurologic findings identified on examination than the patient has symptoms. There are four basic clinical presentations that may be seen alone or in combination; meningismus is rarely present.

1. Spinal. At least 50% of patients with leptomeningeal metastasis have spinal symptoms. Symptoms and signs include back pain, radicular pain, weakness, numbness (leg more often than arm), and loss of bowel and bladder control.

2. Cerebral. About one-half of the patients present with cerebral symptoms and signs including headache, lethargy, change in mental status, ataxia, and seizures (partial and generalized).

3. Cranial nerve. Symptoms and signs include visual loss, diplopia, facial numbness, facial weakness, dysphagia, and hearing loss.

4. Hydrocephalus. Symptoms and signs of increased intracranial pressure include headache, decreased level of consciousness, gait apraxia, and urinary incontinence.

D. Evaluation. The diagnosis of leptomeningeal metastasis is often strongly suspected on clinical grounds, but it can sometimes be difficult to make a definitive diagnosis. The diagnosis may be confirmed by characteristic findings on MRI or by the demonstration of tumor cells in the CSF.

1. Imaging studies. Contrast-enhanced MRI of the brain and complete spine should be obtained in all patients to evaluate the full extent of disease. If the patient cannot have an MRI, CT scan of the head and CT myelography of the spine can be performed. Definitive neuroimaging findings include nodules on the cauda equina, enhancement of the cranial nerves, enhancement within sulci or the cisterns, or enhancement along the surface of the spinal cord. In a patient with known cancer, these findings suffice to establish the diagnosis and do not require CSF confirmation of tumor cells. Radiographic evidence of communicating hydrocephalus or brain metastases adjacent to a ventricular surface or deep within sulci are suggestive of leptomeningeal disease but require definitive spinal imaging or the demonstration of tumor cells in the CSF to confirm the diagnosis.

2. CSF examination. CSF is examined for protein and glucose concentrations, cell count, and cytology. Routine cultures should be performed because the differential diagnosis includes chronic infectious meningitis. CSF may be obtained by lumbar puncture or, in cases of suspected spinal block, by cervical puncture under radiographic guidance.

a. Opening pressure. The opening pressure should always be measured to assess the intracranial pressure (ICP). Patients can have marked elevation of ICP even in the absence of hydrocephalus.

b. Routine studies. Elevated protein and pleocytosis (usually lymphocytic) are nonspecific findings that occur in about 75% of patients with leptomeningeal metastases. A low glucose concentration occurs in <25% but is strongly suggestive when present.

c. Cytologic examination confirms the diagnosis in about one-half of patients on the first lumbar puncture. The diagnostic yield increases to about 90% by the third tap, but 10% of patients remain undiagnosed. The use of molecular diagnostic techniques, particularly for hematopoietic neoplasms, may be useful. Immunohistochemical staining and fluorescence in situ hybridization (FISH) to detect aneusomy of chromosome 1 may enhance the diagnostic yield. Flow cytometry studies, which evaluate DNA abnormalities and estimate the degree of aneuploidy, may also be useful in cases of suspected leptomeningeal metastasis (especially from leukemia or lymphoma) with a nondiagnostic CSF cytology.

d. Tumor markers may serve as additional diagnostic tests and are useful in following response to therapy. Tumor-specific biochemical markers include β₂-microglobulin (leukemia and lymphoma), carcinoembryonic antigen (solid tumors such as lung, colon, and breast cancer), cancer antigen 15-3 (breast cancer), human chorionic gonadotropin and a-fetoprotein (germ cell tumors), and lymphocyte markers (especially B-cell markers) to differentiate leukemic or lymphomatous cells from normal reactive T-lymphocytes. Nonspecific markers that may be elevated in a variety of tumor types include β-glucuronidase and lactate dehydrogenase isoenzyme 5; newer markers also include telomerase and vascular endothelial growth factor (VEGF). All tumor markers should be measured in the serum, and if the serum to CSF ratio is less than 60:1, the marker is being produced inside the CNS. Brain metastases do not increase CSF tumor marker concentration.

E. Management. The optimal therapy for neoplastic meningitis has not been established. The basic premise is to treat clinically active or bulky disease with RT and to treat the remainder of the neuraxis with intrathecal chemotherapy. Systemic chemotherapy appears, however, to have an important role and may be associated with improved outcome. A response can be achieved in about one-half of patients, but the median survival is <6 months. Patients with breast cancer, leukemia, and lymphoma have the best prognosis.

1. Dexamethasone is of limited benefit in patients with leptomeningeal disease, except in patients with lymphoma where it acts as a chemotherapeutic agent. It should be avoided unless the patient has elevated ICP.

2. RT is limited to areas of clinical involvement even if disease is not evident at that location radiographically. The typical dose is 3,000 cGy delivered in 10 fractions. This frequently relieves pain and may stabilize the patient neurologically. Fixed neurologic deficits do not usually improve. Complete neuraxis RT is avoided because it is associated with a high morbidity, causes myelosuppression, and does not improve outcome.

3. Intrathecal chemotherapy may be used to treat the entire subarachnoid space, although intrathecal drug does not penetrate into nodules of subarachnoid disease. The drug can be administered by lumbar puncture or preferably through an intraventricular reservoir (an Ommaya reservoir). The drug is usually given twice weekly until abnormal cells are no longer found in the CSF, and it is then given at progressively longer intervals. Preservativefree agents should be used. The dose is fixed and not calculated on a metersquared basis because the volume of CSF is identical in all adults regardless of size. There must be normal CSF flow dynamics for intrathecal chemotherapy to be effective. Patients with large bulky lesions or hydrocephalus always have impaired CSF flow, and intrathecal drug should not be administered to these patients until normal CSF flow is documented by an intrathecal indium radionuclide study. Intrathecal chemotherapy can be complicated by an acute chemical meningitis or arachnoiditis. This can cause headache, nausea, fever, and neck stiffness mimicking an infectious meningitis. Arachnoiditis may be seen with any agent but is pronounced with liposomal cytarabine (DepoCyt), and patients must be treated with corticosteroids for several days before and after each DepoCyt injection to minimize this toxicity.

a. Methotrexate, 12 mg twice weekly followed by leucovorin rescue

b. Cytarabine, 30 to 60 mg twice weekly

c. Thiotepa, 10 mg twice weekly

d. DepoCyt (liposomal cytarabine), 50 mg every other week

4. Systemic chemotherapy has the advantage of reaching all areas of disease, penetrating into bulky lesions that intrathecal drug cannot reach, and being independent of CSF flow to reach the whole subarachnoid space. The choice of drug is based on its ability to penetrate into the CSF and on the chemosensitivity spectrum of the underlying primary. The most widely used agents are high-dose methotrexate (≥3 g/m²), high-dose cytarabine (3 g/m²), and thiotepa. A wide variety of other drugs, however, have been used effectively, such as capecitabine (Xeloda) for breast cancer. There are isolated reports that bevacizumab has been beneficial.

Epidural spinal cord compression is a neuro-oncologic emergency. Any cancer patient with back pain should receive a prompt and thorough evaluation, and those with neurologic dysfunction localizing to the spinal cord or cauda equina require emergency evaluation and treatment.

1. Incidence. About 5% of patients with cancer develop clinical evidence of spinal cord compression.

2. Distribution. About 10% of epidural metastases occur in the cervical spine, 70% in the thoracic spine, and 20% in the lumbosacral spine. About 10% to 40% of patients have multifocal epidural tumor.

3. Responsible tumors. Any tumor can cause spinal cord compression, but lung cancer accounts for 15% of cases; breast, prostate, carcinoma of unknown primary site, lymphoma, and myeloma each account for about 10% of cases.

4. Mechanisms. A tumor reaches the epidural space by several mechanisms. The most common is direct extension from a metastasis to the vertebral body growing into the epidural space resulting in cord compression. Other tumors, particularly neuroblastoma and lymphoma, can grow into the spinal canal through the intervertebral foramina without destroying bone. Secondary vascular compromise can also occur resulting in venous infarction that can cause the sudden, irreversible deterioration seen in some patients. Direct metastasis to the spinal cord parenchyma is a rare cause of spinal cord dysfunction in cancer patients.

1. Natural history. The progression of disease from the spinal column to the epidural space with neural encroachment is manifested clinically as local back pain followed by radicular symptoms and eventually myelopathy.

a. The initial stage of localized pain can last for several weeks or, in tumors such as breast or prostate cancer and lymphoma, for several months.

b. Radicular symptoms, such as pain radiating in a root distribution, usually herald further progression of the metastatic tumor but are still a relatively early symptom.

c. Once paraparesis or ascending numbness of the legs occurs, the progression may be extremely rapid and a complete myelopathy may develop within hours. Rapid progression is especially common with lung cancer, renal cancer, and multiple myeloma.

2. Clinical presentation depends on the level of spinal involvement.

a. Back pain is the initial symptom in >95% of patients with spinal cord compression caused by malignancy. The pain is dull, aching, and often localized to the upper back; it typically worsens with recumbency, unlike back pain from spinal degenerative disease. Tenderness over the appropriate spinal level may be readily elicited.

b. Radiculopathy

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