Brain Metastases

Introduction

Metastases to the brain are among the most clinically significant, because even a single one is likely to cause serious disability. Because most may be at least partially protected from otherwise effective systemic therapies by the blood–brain barrier, they present special management problems. But whether their pathogenesis differs from that of metastases at other sites is not known.

Origin of Primary Tumors

Since the first successful systemic treatment of a disseminated neoplasm – acute lymphoblastic leukemia (ALL) in children – the CNS has been recognized as a refuge for neoplastic cells. Permeation of the meninges at the base of the skull and spinal canal is mainly seen in certain types of lymphomas, though these occasionally produce nodular brain lesions. Such lesions are usually derived from epithelial neoplasms. Most are the result of hematogenous dissemination. The exceptions are those from prostatic carcinoma, and some breast cancers, where tumor reaches the brain from skull lesions, or the dura attached to involved bone. This occurs only rarely in myeloma and lymphomas.

Of all epithelial tumors, both small and non-small cell lung cancer are associated with the highest incidence of brain metastases (BM), which occur in 30–60% of cases, and become manifest early in the course of the disease, often even before the primary tumor is diagnosed ( ). Lung metastases may be especially likely to elicit edema, with ring enhancement and disruption of the blood–brain barrier, so that they produce focal deficits and other symptoms early ( ). Melanomas and renal cell carcinomas are also associated with a high incidence of BM ( ), but they are less common than breast or lung cancer.

Breast cancer is the second most common source of brain metastases, being a very common tumor in America; they ultimately develop in 35% of patients with metastatic disease ( ). They mainly occur in HER2+and triple negative breast cancer, arising less frequently from hormone receptor positive tumors ( ). Their natural history differs from those due to lung cancer. They are not usually symptomatic until late in the course of the disease, after metastases to bone and lung become detectable. The number of metastases per brain in breast cancer patients appears, in some, but not all studies ( ), significantly greater than those in the brains of lung cancer patients. But this may be, in part, due to gender; female lung cancer patients have been reported to have more metastases per brain than males ( ). The incidence of cerebellar metastases is highest in breast cancer patients ( ), but this does not necessarily indicate a predilection for cerebellar involvement. The incidence of breast metastases in the cerebellum correlates strongly with the total number of brain metastases present ( ). Thus, the occurrence of metastases in a given brain region may be a function of the total number of BM which have occurred.

Most lung cancer patients present with incurable disease, and systemic therapies are only effective in a minority. But the majority of breast cancer patients are potentially curable at presentation, especially with adjuvant therapies. Breast cancer metastases at any site are far more sensitive to systemic chemotherapy than those from lung cancer, and also respond to endocrine therapy in tumors expressing hormone receptors. Such treatments may delay overt progression of micrometastases for years, and 50% of patients with bone and lung metastases may be controlled by systemic therapy for many months. But the drugs used in systemic therapies may not reach the brain, so that metastases there may accumulate while other metastases are suppressed by therapy (Hengel et al., 2012). Thus, in breast cancer, the brain may be a refuge for metastatic disease.

Neoplastic Cell Meningitis

The leptomeninges are most often involved in ALL and certain lymphomas. This is assumed to be present in all ALL cases. It is rare in acute myeloblastic leukemia, though it occasionally occurs in the monoblastic subsets (M4 and M5). The lymphomas include Burkitt’s, T-cell, and a subset of especially aggressive and high stage diffuse large B-cell lymphomas. In the latter group, the presence of the typical 8;14 (myc) chromosome translocation should be ruled out, regardless of whether typical Burkitt’s histology is observed, because a posi- tive result implies an increased risk of meningeal involvement. Carcinomatous meningitis involvement is far less common. It is most frequently observed in small cell and breast carcinomas.

In fact, few such patients have a typical meningeal syndrome. They are usually alert, and without neck stiffness. The meninges at the bases of skull and cord are the most frequent sites of involvement. The usual clinical syndrome is that of mononeuritis multiplex, due to entrapment of nerve roots by meningeal growth. Ophthalmoplegias due to cranial nerve involvement are common, as are symptoms of lumbar root involvement.