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Once rare intracranial neoplasms, CNS lymphomas have substantially increased in prevalence in the past 2 decades. Although they previously accounted for only 0.3%-1.5% of all CNS neoplasms, primary CNS lymphomas now represent 6.6%-15.4% of all primary brain tumors (vs 3.3% before 1978) (1,2). As a result, the prevalence of primary CNS lymphoma is now equivalent to that of meningioma and low-grade astrocytoma (3). However, compared with other systemic lymphomas, primary CNS lymphoma is still relatively uncommon; only 0.7-0.9% of lymphomas are primary CNS lesions, and, of 24,000 cases of non-Hodgkin lymphoma diagnosed in the United States each year, only 1.5% occur in the CNS (4,5). The majority (93%) of CNS lymphomas are primary lesions (6), with the overwhelming majority of those lesions occurring in the brain. Supratentorial CNS lymphomas occur far more often than those in the posterior fossa (3-9:1) (7,8). Leptomeningeal involvement is not uncommon with primary CNS lymphoma and occurs in about 12% of cases (7). Dural involvement by primary CNS lymphoma is rare (9). Only about 1% of primary CNS lymphomas occur in the spinal cord.
The prevalence of primary CNS lymphoma is dramatically higher in immunocompromised patients. In 1963, at least a sixfold increase in CNS lymphoma cases in immunocompromised patients was reported compared with the number of cases occurring in the immunocompetent population (5). The immunocompromised states associated with CNS lymphoma include renal transplantation (10,11), Wiskott-Aldrich syndrome (12), immunoglobulin A deficiency (13), rheumatoid arthritis (14), antimyelin-associated glycoprotein IgM paraproteinemic neuropathy (15), and progressive multifocal leukoencephalopathy (7). In addition, primary CNS lymphoma is frequently associated with intraocular lymphoma, and symptoms of the latter condition commonly precede those of CNS lymphoma, sometimes by several years (16). Occasionally, chronic lymphocytic leukemia can spontaneously transform into a large-cell lymphoma (Richter syndrome) (16,17). However, patients with acquired immunodeficiency syndrome (AIDS) account for the largest group of immunocompromised patients with CNS lymphoma (18,19).
In the early 1980s, the prevalence of primary CNS lymphoma in immunocompromised patients was reported as being approximately 350 times that seen in the immunocompetent group (20), and this increase coincided with the first reported cases of AIDS. In 1990, because of the explosive growth of the AIDS population in the United States, it was estimated that the number of AIDS-related primary CNS lymphomas would surpass that of low-grade astrocytomas and almost equal the number of meningioma cases (3). Today, primary CNS lymphoma in a patient with a positive human immunodeficiency virus test is considered an AIDS-defining diagnosis (21). Furthermore, the effectiveness of treating AIDS patients with drugs such as azidothymidine increases the likelihood of their prolonged survival and, unfortunately, of their development of CNS lymphoma, particularly in those patients with profound immunosuppression with marked depletion of T4 cells (about 100 T4 lymphocytes per milliliter) (22).
In about 10% of AIDS patients, a neurologic disorder is the initial manifestation of disease, and 40% of AIDS patients develop significant neurologic symptoms some time during their illness (23,24,25). At autopsy, evidence of CNS disease is seen in 75% of patients with AIDS (23,24). In AIDS patients with neurologic symptoms and focal CNS lesions, the most common CNS disorder is toxoplasmosis (50%-70% of cases), with primary CNS lymphoma (20%-30%) and progressive multifocal leukoencephalopathy (10%-20%) accounting for most of the remaining cases (25). Viral, granulomatous, fungal, or bacterial infections produce focal CNS lesions less frequently (24). About 0.6% of patients with AIDS have primary CNS lymphoma as the initial manifestation of the disease, and about 2% of AIDS patients develop primary CNS lymphoma at some point during their illness. Primary CNS lymphoma is the second most common (following toxoplasmosis) CNS mass lesion in adult AIDS patients and is the most common mass lesion in pediatric AIDS patients (26).
Several features of primary CNS lymphoma have changed significantly in the past 2 decades for reasons apparently unrelated to the patient's immune status. First, in addition to the increasing prevalence of primary CNS lymphoma in the AIDS population, there has been a threefold increase in the number of primary CNS lymphoma cases in immunocompetent patients (1,7,8,27). This increase appears to be independent of improved imaging techniques (2), and whether it is related to increased physician awareness or some other factor is unclear. Second, at the same time that the increase in prevalence was observed, a "fundamental" change in the biologic behavior of primary CNS lymphoma was detected: The second most common cell type, intermediate-grade lymphoma, disappeared in 1983, and the cell types of primary CNS lymphoma occurring today appear to be more histologically aggressive (1). Third, multifocal involvement by CNS lymphoma is increasing in prevalence compared with the cases reported in the 1950s and 1960s. In 1984, 25%-50% of the cases were multicentric lesions. The reason for this finding is unclear, but it may be related to more aggressive primary CNS lymphomas or greater sensitivity of current imaging techniques, particularly contrast material enhanced magnetic resonance (MR) imaging (1,28).
Secondary CNS involvement by systemic lymphoma was reported to occur in approximately 25% of cases before the advent of effective chemotherapy (29). Secondary lymphoma now occurs at a much decreased rate; when present, it affects the dura mater and leptomeninges more commonly than the brain parenchyma (29). Hodgkin lymphoma rarely involves the CNS, and when it does, it is usually late in its course and arises from the dura mater (29).
CNS lymphoma is the most likely second cancer to develop after any first primary malignancy in men (30). Because patients with Hodgkin disease who underwent chemotherapy have prolonged survival, they are at increased risk for developing a second lymphoma. These cases of second lymphoma occur most frequently in the gastrointestinal tract or kidney, but several reports document the occurrence of CNS lymphoma after successful treatment of Hodgkin disease (31,32,33,34,35).
Prevalence