Although the number of new cases of metastasis to the central nervous system diagnosed yearly is estimated at over 200,000, the exact incidence remains unknown. The reason for this is that although cancer as a disease is reportable, sites of metastatic disease are not routinely reported to any registry. Autopsy studies have reported the presence of intracranial metastases in 10% to 30% of all cancer patients (15% to the brain, 5% to the leptomeninges, 5% to the dura) as well as occult LM in an average of 20% of all cancer patients. The incidence of brain metastases has risen steadily over the last few decades, a phenomenon which is likely multifactorial: High-resolution imaging allows brain metastases to be detected more readily, and increasingly effective treatments lead to prolonged survival and thus a longer period during which neural metastases may develop. One conjectured reason for the very high incidence of metastatic disease to the brain is the highly selective permeability of the blood-brain barrier, which allows tumor cells sanctuary in the central nervous system (CNS) both from immune surveillance and the cytotoxic effects of chemotherapy, as most of these agents fail to cross the barrier adequately.

Although the brain parenchyma is the location most likely to be involved (80%) with metastatic disease to the nervous system, other common sites include the epidural space and leptomeninges. Less common sites include the dura, intramedullary spinal cord, optic apparatus, and cranial and peripheral nerves. Data regarding these less common sites are generally limited to case reports and small series, and therefore, this discussion will focus on CNS metastases, primarily of the parenchymal brain.

The molecular processes within cancer cells and their microenvironment that ultimately result in the development of metastatic disease are poorly understood and are the focus of much ongoing research. It is known that the shedding of tumor cells into systemic circulation is an early phenomenon in the natural history of malignancy, but these circulating tumor cells do not always lead to metastasis. It is estimated that less than 0.01% of these cells are able to establish a metastatic lesion at a distant anatomic site. This could well be a consequence of immune surveillance mechanisms. It is also known that certain malignancies have a predilection to metastasize to particular organs. This may be due in part to simple anatomy and physiology but may also be dependent on specific molecular characteristics, including the secretion of specific chemotactic factors by the organ or site involved; neurotropic growth factors in the CNS are thought to play such a role. Another possible factor is the expression of specific surface molecules on tumor cells that allow them to home to certain tissues. Melanoma cells are presumed to possess such molecular features, which allow them to have among the highest probabilities of metastasizing to the brain.

Possible pathways for spread of cancer include hematogenous, lymphatic, intrathecal, and perineural. (Fig. 97.1). Although not technically metastatic, tumors may directly extend into neighboring structures, including the CNS; for example, large tumors of the head and neck may invade the brain or spinal cord. The intravasation of the cancer cell requires multiple signals between that cell and its surrounding microenvironment. Some data suggest that transformation of the malignant cell into a mesenchymal, or connective tissue-like, state is crucial for this, a phenomenon referred to as epithelial-to-mesenchymal transformation, or EMT.

Once intravasated and in circulation, normal anatomic organs may act as a barrier. Regional lymph nodes may trap tumor cells. The hepatocytes of the liver filter the blood as the venous return from abdominal organs passes through it, and the liver is a frequent site of metastatic disease from gastrointestinal primaries. The blood-brain barrier presents another obstacle for circulating tumor cells. Logically, organs with a large volume of blood flow are more prone to metastatic disease, such as the pulmonary capillary bed with its high flow. The CNS and the bones receive approximately 20% of the cardiac output; it is therefore not surprising that the liver, lung, CNS, and bones are the most common sites of metastatic disease.

When cancer cells arrive at a distant site, they must extravasate from circulation and establish at this location, a complex process that requires multiple interactions with the new microenvironment. The nascent metastasis must also be capable of angiogenesis, the formation of new blood vessels, in order to sustain growth larger than approximately 1 mm. Despite all these required steps for the formation of distant metastases, metastatic disease from cancer is an all too real and common phenomenon, indicating that
this orchestrated process of dissociation, intravasation, circulation, avoidance of immune surveillance, extravasation, and metastatic growth is efficiently coordinated by a significant number of malignancies through sophisticated genetic interplay.

Metastatic disease to the nervous system may present with or without symptoms, and an appropriate clinical workup is indicated to make the diagnosis. In asymptomatic patients, metastatic disease is often found incidentally during their cancer workup and staging process or while concomitant nonmalignant comorbidities are being investigated. CNS metastases are often diagnosed in the context of a known history of malignancy, but symptomatic CNS metastasis may also be the initial clinical presentation of a previously unidentified malignancy. In this situation, biopsy or resection is required in order to pathologically confirm a diagnosis of cancer and to guide treatment. The most common primary malignancy that presents with metastatic disease in the brain is lung cancer. The most common primary malignancies that presents with metastatic disease to the spine are breast and prostate cancer. In some cases, the primary malignancy responsible for the metastatic disease is never identified despite a complete and thorough evaluation.

The most common type of cancer of the brain is metastatic disease; brain metastases outnumber primary brain tumors by a ratio of approximately 9:1. Up to 20% to 40% of all cancer patients will develop lesions in the brain. The brain may be a site of relapse at any time in the clinical course. The median time interval between the development of brain metastasis and the original cancer diagnosis is approximately 1 year, but the range can exceed 10 years. NSCLC is the most common source of brain metastases, likely because it is more common than other cancers. In comparison, a larger proportion of patients with diagnoses such as melanoma, small cell lung cancer, and specific subsets of breast cancer will develop brain metastases, but due to the lower number of patients diagnosed with these diseases, the total incidence from these primary tumors is lower than that from NSCLC.

Symptoms of CNS metastases result from both focal pressure on surrounding tissue, destruction of normal neurons, and global increases in ICP from the metastases or associated peritumoral edema. Presenting symptoms most often include headache (49%), altered mental status (32%), focal weakness (30%), ataxia (21%), and seizures (18%). Diffuse, small, miliary lesions scattered throughout the brain parenchyma are particularly associated with leukemia and small cell lung cancer and may manifest as a generalized encephalopathy (Fig. 97.2B).

Untreated brain metastases generally produce worsening symptoms over days to weeks. In some cases, symptoms are more acute and may mimic ischemic or hemorrhagic stroke. The more abrupt clinical course may particularly be seen with bleeding within the metastasis; hemorrhagic brain metastases are classically associated
with certain histologies, including melanoma, renal carcinoma, choriocarcinoma, NSCLC, and thyroid (Fig. 97.2C).

In the setting of a known diagnosis of cancer and new neurologic symptoms, multiple, spheroidal, enhancing brain lesions, mostly at the gray-white junction, with a disproportionate degree of edema on MRI, strongly suggest a diagnosis of brain metastases. Differential diagnosis include primary brain tumor, lymphoma, abscess, other infectious processes, stroke, multifocal demyelination, radiation necrosis, etc. A seminal series of 54 patients with a single brain lesion seen on imaging who underwent resection or biopsy reported pathologic discordance in 11%; in other words, 1 of 10 patients with MRI findings consistent with a single metastatic lesion in the brain might not have a brain metastasis.

Brain metastases may be single or multiple. The classic appearance of metastatic disease in the brain is a round, irregular, ringenhancing lesion at the gray-white matter interface with associated vasogenic edema (Fig. 97.2D). In comparison, high-grade gliomas may appear more infiltrative and irregularly shaped; gliomas are most commonly single and rarely present as multiple distinct lesions. CNS lymphoma tends to appear as periventricular, homogenously enhancing disease. Intracranial abscesses are high on the list of differentials in the setting of immunosuppression. These appear as well-circumscribed, thick-rimmed, ring-enhancing masses with central hypodensity. Stroke, both hemorrhagic and ischemic, may produce both similar symptoms and imaging findings as brain metastases. Multifocal demyelination has been reported after treatment with certain chemotherapy agents (5-fluorouracil and levamisole) and may also mimic metastases in appearance. Radiation necrosis is a known potential complication from RT, particularly SRS, and may also appear as a contrast-enhancing mass (Fig. 97.2E).

About 80% of brain metastases involve the cerebral hemispheres, 10% the cerebellum, and 5% the brain stem, a rate of incidence that appears consistent with the relative volume and percentage of blood flow. A high proportion of brain metastases are seen in the watershed regions. This is most likely due to smaller blood vessels and slower blood flow in these areas. For reasons that are not fully understood, different histologies may preferentially metastasize to different brain locations; lung cancer tends to metastasize to the cerebrum, whereas gastrointestinal malignancies tend to metastasize to the cerebellum.