Intraparenchymal Metastases

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Pathogenesis and Pathophysiology. To establish a metastatic colony, tumor cells must grow within the primary site of malignancy, escape from the primary tumor, penetrate the circulatory system either as single cells or small tumor emboli, survive while circulating, arrest in the microvasculature of other organs, extravasate into the organ parenchyma, and efficiently grow and compress or invade tissue at the secondary site.

Solid tumors or metastases larger than 1 or 2 mm in diameter must be able to induce blood vessel sprouting from vessels in surrounding normal brain tissue. For metastases to occur, tumor cells must be able to penetrate the basement membrane, enter the stroma, and cross the subendothelial membrane into capillaries. To perform this migration, tumor cells utilize proteolytic enzymes, particularly metalloproteinases and cathepsins, and tend not to retain fibronectin, collagen, or laminin, possibly the result of a change in their specific integrin receptors. Metastases tend to colonize specific organs. The preferential adhesion of tumor cells to endothelial cells in specific target organs reflects their metastatic distribution. These adhesive interactions are mediated by the expression on endothelial cells of a category of molecules named vascular addressins. Malignant cells also survive the local killing effects of macrophages, natural killer cells, and cells of the reticuloendothelial system. Very often tumor cells produce growth factors that stimulate their own growth. The presence in target organs of paracrine growth factors also influences the outcome of metastatic colonies.'!

Epidemiology and Risk Factors. Virtually all systemic cancers have the capacity for brain metastasis. The most common sources of metastases to the brain are tumors of the lung, breast, kidney, and gastrointestinal tract (colon and cecum) and malignant melanoma, reflecting the frequent occurrence of these primary malignancies (,X§bJe,47z2. ). The predilection of melanoma to spread to the brain is emphasized because its histological pattern is different from other metastases. Other sources that are relatively


I. Metastasis of Cancer to the Nervous System (Direct/Metastatic)

A. Intracranial (intraparenchymal and dural)

B. Leptomeningeal and ventricular

C. Bony (calvarium and skull base)

D. Spinal (vertebral, epidural. and intramedullary)

E. Nerves (cranial nerves, peripheral nerves, nerve plexus, or nerve roots)

II. Nonmetastatic Neurological Complications of Cancer

A. Vascular disorders

1. Cerebral hemorrhage in cancer patients

2. Intracerebral hematoma (intratumoral, coagulopathy, hypertension)

3. Subdural hematoma

4. Subarachnoid hemorrhage

5. Cerebral infarction

6. Atherosclerosis

7. Intravascular coagulation

8. Nonbacterial thrombotic endocarditis

9. Septic occlusion

10. Tumor embolus

11. Venous occlusion

B. Infections

1. Bacteria (Listeria, Nocardia)

2. Fungi (Cryptococcus, Coccidioides, Histoplasma)

3. Parasites (Toxoplasma, Strongyloides)

4. Viruses (varicella-zoster, papovavirus, cytomegalovirus, herpes simplex)

C. Metabolic and Nutritional Encephalopathy

1. Drugs

2. Sepsis

3. Oxygen deprivation (hypoxia, ischemia)

4. Hypercapnia

5. Fluid and electrolyte imbalance

6. Hepatic failure

7. Vitamin deficiencies

8. Endocrine disorders

D. Side effects of chemotherapy, radiation therapy, surgery, or other diagnostic procedures

E. Paraneoplastic syndromes

Data from Posner JB: Neurologic Complications of Cancer. Philadelphia, F. A. Davis, 1995.

infrequent include sarcoma and tumors of the gastrointestinal tract, thyroid, uterus, ovary, pancreas, and prostate.

As many as one in three patients with cancer develops a brain metastasis. Although causing subtle impairment, brain metastases are commonly identified at postmortem examination rather than during life. The rate of brain metastasis identified during life, a rate one third that at


Lung Breast

Gastrointestinal tract (colon and rectum)

Urinary tract



Leukemia Lymphoma Female genital tract

Data from references 2 and 5 through 8.

autopsy, demonstrates that these lesions often go undiagnosed. '4

Wide variability in the interval between the appearance of the primary cancer and that of the cerebral metastasis is observed. In many instances, the cerebral metastasis represents the first manifestation of a malignant neoplasm, usually of lung or melanoma origin. Slow-growing neoplasms of breast, ovarian, or uterine origin can result in cerebral metastasis up to 15 years after the diagnosis of the primary tumor. The average interval between the diagnosis of the primary carcinoma and the development of brain metastasis is 4 months for lung carcinoma and 3 years for breast cancer. The pulmonary circulation represents the major passage for lesions eventually entering the cranial vault.

Two thirds of brain metastases are intraparenchymal, with the remaining one third situated in the subdural or extradural space sometimes causing compression, though not necessarily invasion, of the brain. Metastatic cancers invade regions of brain in proportion to both tissue volume and blood flow. Thus, highly vascularized areas, including the leptomeninges, ventricles, and pituitary gland, receive a disproportionately large number of cancers. Hemispheric metastases prefer the anatomical "watershed areas"--the zones of marginal arteriolar supply from major intracranial arteries. This area representing 29 percent of the brain surface contains 37 percent of the metastases. '5

Twenty to 30 percent of patients with brain metastases have cerebellar involvement. Forty-four percent of cerebellar metastases are solitary, and the rest are associated with multiple metastases. In general, tumors of the pelvis or retroperitoneal space have a proclivity for the posterior fossa of the brain whereas those passing through the pulmonary circulation metastasize to supratentorial locations. '6 Metastases to the dura frequently result from contiguous masses in the cranial sinuses (carcinomas of the sinus epithelium or parotid, submandibular, or maxillary glands) or cranial lymphoid epithelium (lymphoma or plasma cell tumors) spreading directly through the bone and periosteum to the dura. Dural masses either produce masses in the subdural or epidural space or invade the cranial nerve exit zones within their foramina.1?] , 's1

Brain stem metastases are uncommon. Other uncommon metastatic sites include the pineal body, optic nerve, choroid plexus, hypothalamus, '9 and pituitary gland,'^1 although the latter site is favored by breast cancer. Cases of metastasis developing in another tumor, such as breast cancer metastasizing to intracranial meningiomas or to a vascular malformation, have been reported. y

The occurrence of two different primary tumors may have a number of explanations, including shared risk factors and treatment effects. Researchers have sought to identify potential risk factors for primary brain tumors that occur in the setting of systemic malignancy. Those brain tumors occurring after bladder cancer likely reflect the carcinogenic effects on the bladder and brain of occupational chemical exposure. Given the elevation of brain tumor risk after breast, endometrial, and colorectal cancer, an association between brain tumors and reproductive hormonal exposure is also possible. The occurrence of sporadic cases of brain tumor after acute leukemia is probably due to the treatment effects of cranial irradiation. Additionally,

shared genetic predispositions can explain associations between brain tumors and sarcoma observed in Li-Fraumeni syndrome and the association of brain tumors and colorectal cancer'111 in Turcot's syndrome.

Clinical Features and Associated Findings. The most common presenting symptoms of intracranial metastases are headache, weakness, and behavioral changes. These findings reflect brain edema, hydrocephalus, or compression of the dura (..X§.bJe.4Zz3 ). Headache, the presenting complaint in one half of patients, is mild and not particularly disabling. Patients with systemic cancer often exhibit impairment without being conscious of their symptoms. Seizures, the presenting complaint in up to one third of patients with intracranial metastasis, can also appear late in the disease. Careful examination discloses weakness in two thirds of patients, of whom only one half complain of focal weakness. Similarly, although only one third of patients note behavioral or mental status changes, when careful mental status testing is done, impaired cognitive function is apparent in three fourths. y Metastases in the frontal, temporal, and occipital lobes may be "silent" when not associated with focal weakness. Thus the apathy, inattention, and abulia that accompany frontal lobe lesions are commonly attributed to exogenous depression. Psychotic thought disorders, food intolerance, or olfactory or sensory hallucinations may accompany lesions of the temporal lobe. 'd , y Right parietal lobe lesions alter the ability to attend to one side of space, produce apraxia or difficulty with dressing, and may contribute to motor vehicle accidents. Miliary metastases can produce a progressive confusional state. Cerebellar metastases, likely the most symptom-inducing lesions of all intracranial tumors, are heralded by headache or gaze-evoked nystagmus, associated rarely with dizziness. Often gait is afflicted, appearing wide based and staggering. Dysarthria and tremor are uncommon. y

Intraparenchymal hemorrhage into a metastatic brain tumor, occurring in one tenth of patients, produces acute symptoms. Metastases of choriocarcinoma, melanoma, bronchogenic carcinoma, thyroid carcinoma, and renal cell carcinoma are most prone to bleeding. y , y These hemorrhages occur within the metastatic deposit, whereas the rarer subdural hematomas reflect the effects of head trauma or anticoagulation use.

Differential Diagnosis. Mass lesions in the brain are not necessarily metastatic. Abscess, granuloma, acute demyelinating disease, resolving cerebral hematoma, cerebral infarction, radiation necrosis, and postoperative changes represent other causes of mass lesions in patients with systemic cancer. Although the incidence of brain abscesses



Common Signs


Focal weakness or unexplained falls

Mental status change

Focal sensory deficits

Altered level of consciousness

Speech difficulty

Seizures occurring when older than 35 years of age

Aphasia, focal weakness

Papilledema or visual obscurations


Visual complaints or unexplained motor vehicle accidents

Visual field defect

is only one fiftieth as frequent as that of intracranial tumors, it is rising owing to the acquired immunodeficiency syndrome. [ial , y Granulomas in the brain are rare and result from infection with Mycobacterium, Candida, Aspergillus, Cryptococcus, and Histoplasma species. Sarcoidosis and central nervous system Whipple's disease can cause granulomas in the cerebral hemispheres. y Demyelinating lesions, commonly acute postinfectious or postimmunization, occasionally present as large ring-enhancing masses with the clinical presentation of acute-onset focal neurological dysfunction or seizures. y

Nonbacterial thrombotic endocarditis (NBTE) can cause cerebral infarction by embolization of cardiac vegetations to the brain or by intravascular thrombosis from an associated coagulation disorder. Tumors of the lung, gastrointestinal tract, breast, and genitourinary tract and tumors of hematopoietic origin most commonly result in NBTE. Although most patients with NBTE have disseminated cancer, rarely do vascular occlusions or vasospasms affect those with tumors in remission or before the diagnosis of malignancy. Stroke, metabolic encephalopathy, or complicated migraine is observed. Coagulopathy in the presence of anticardiolipin antibodies or of abnormalities of Russell viper venom coagulation studies may involve patients with breast cancer and leukemia. Intravascular coagulation produces a diffuse encephalopathy frequently characterized by focal signs. y

Evaluation. The evaluation of the number and extent of metastases depends solely on neuroimaging (,,,Fig, 4Z-.1 ). In the computed tomography (CT) era, 20 percent of seeming "solitary" lesions were found to be multiple after administration of nonionic contrast media. Multiple small metastases are often identified using magnetic resonance imaging (MRI) at gapless 3-mm intervals with single-dose and then triple-dose administrations of gadolinium, often with delayed imaging times ( ,,Fig:,4Z:.2 ).

The surgical evaluation of brain metastases provides definitive diagnostic information when systemic cancer has not previously been identified and is not apparent on clinical examination, chest radiograph, or mammogram. The histological evaluation of these surgical specimens makes use of antibodies that are tumor specific and/or organ specific (..Table.47-4.).

Management. Untreated, brain metastases are fatal within 1 month of diagnosis. Brain malfunction is the usual cause of death. Patients treated with whole-brain radiotherapy, the current mainstay of palliation, have a median survival of 3 to 6 months. y , y Radiotherapy typically consists of 30 Gy in 10 fractions over 2 weeks. Radiosurgery, utilizing single fractions provided by "gamma knife" or similar photon devices, protons, or interstitial x-ray generation, is a treatment option for lesions less than 3 cm in size in areas likely to tolerate the resulting foci of necrotic and edematous tumor.

Conventionally fractionated radiotherapy is successfully given to "radiation-sensitive" tumors of lung, breast, colon, or germ cell origin whereas "resistant" lesions are best treated with necrotizing single fractions and include those of melanoma, renal cell carcinoma, or sarcoma origin. y , '27] Future trends are likely to focus on the management of brain metastases and the role of improved chemotherapy, radiosensitizers, and radiotherapy techniques.

Figure 47-1 Evaluation of patients with suspected metastatic cancer to the central nervous system. AFP, alpha-fetoprotein; CEA, carcinoembryonic antigen; CT, computed tomography; EEG, electroencephalogram; EMG/NCV, electromyography/nerve conduction velocities; hCG, human chorionic gonadotropin; LEMS, Lambert-Eaton myasthenic syndrome; MRI, magnetic resonance imaging; PSA, prostate specific antigen; TAH/BSO, total abdominal hysterectomy/bilateral salpingo-oophorectomy.

Although brain metastases of lung origin may be identified before systemic deposits, 10 times as many brain metastases are discovered after the passage of 2 years from the diagnosis of the primary malignancy. Prophylactic cranial irradiation provided in the setting of small cell lung cancer reduces the likelihood of central nervous system relapse by 20 percent, although it does not provide long-term survival benefit.

Figure 47-2 Multiple metastases on MRI scan are associated with lung carcinom(Courtesy of Todd Brack, D.O.)

Prognosis and Future Perspectives. Therapy is often based on the prognosis of the systemic cancer. With surgical resection and whole-brain radiation therapy, patients with solitary brain metastases survive longer and remain functionally independent in comparison to recipients of radiation alone. y , y Multiple brain metastases of breast origin or absent systemic primary lesions may benefit from surgical removal of all lesions. y Similarly, reoperation for recurrent hemorrhagic, edematous, or posterior fossa brain metastases can prolong survival and improve quality of life. Poor prognoses are associated with extensive systemic disease, Karnofsky performance score below 70, recurrence within 4 months, age older than 40 years, and tumor of breast or melanoma origin. y , y

TABLE 47-4 --


Histologic Stain

Tumor Specificity



Mucicarmine (chromogranin)

Neuroendocrine tumors




Melanoma, sarcoma


Adenocarcinomas of colon, stomach, lung, breast, pancreas, uterus, ovary; medullary carcinoma of thyroid, squamous carcinoma

Estrogen and progesterone receptors

Breast and uterus

Muscle-specific actin


Alpha-fetoprotein, human chorionic gonadotropin

Genitourinary tumor

Placental alkaline phosphatase

Germ cell tumors

Prostatic acid phosphatase or prostate-specific antigen

Prostate carcinomas

Leukocytic common antigen, immunoglobulins, L26, UCHL 1, Leu-Ml, and CD30


The approach suggested in the evaluation of patients with suspected brain metastases is identified in Figure 47-1.





Lymphoma Melanoma

Adenocarcinoma of unknown origin

Data from Olsen ME, Chernik NL, Posner JB. Leptomeningeal metastases from systemic cancer: A report of 47 cases. Trans Am Neurol Assoc 1971;96:291-293; and Wasserstrom WR, Glass JP, Posner JB: Diagnosis and treatment of leptomeningeal metastases from solid tumors: Experience with 90 patients. Cancer 1982;49:759-772.

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