Primary Central Nervous System Lymphoma

Non-Hodgkin lymphoma can involve the central nervous system either as a primary tumor or after spreading from an established systemic lymphoma. This occurs in 5% to 29% of patients with systemic lymphoma during the natural history of the disease and is usually associated with progressive widespread systemic disease [1]. Primary central nervous system lymphoma is a less commonly encountered clinical entity and is defined as lymphoma limited to the cranial-spinal axis without systemic disease. In the past, primary central nervous system lymphoma was considered a rare disorder, accounting for 1% to 2% of all cases of non-Hodgkin lymphoma and fewer than 5% of all cases of primary intracranial neoplasm [2-4]. These tumors were so rarely encountered that their lymphoid nature has only recently been recognized, thus accounting for their varied historical pseudonyms such as perithelial sarcoma, reticulum cell sarcoma, and microglioma [5-8]. In the 1970s, an increasing number of cases of primary central nervous system lymphoma were reported, primarily because of the increasing number of patients with congenital and iatrogenic immunosuppression (organ allograft recipients), a group known to be at increased risk for developing this tumor [9, 10]. Nevertheless, primary central nervous system lymphoma was still a relatively rare disease. This frequency changed, however, in the 1980s with the outbreak of the acquired immunodeficiency syndrome (AIDS) epidemic and the subsequent large increase in the number of immunocompromised patients developing primary central nervous system lymphoma [11]. Of equal concern are recent data showing a threefold increase in the incidence of primary central nervous system lymphoma in patients who are immunocompetent [12]. The causative factors accounting for this increase in the number of non-AIDS-associated cases are unknown. If the incidence of this disease continues to increase at the present rate, it will be the most common primary malignant neoplasm of the central nervous system in adults by the year 2000. The increasing number of cases of primary central nervous system lymphoma has resulted in a growing awareness of and interest in this disease and has prompted a large number of publications, isolated case reports, and small series with fewer than 10 patients. Although several reviews have been published, most have included only selected series published before 1980, when imaging of the central nervous system (CT and magnetic resonance image [MRI] scans) and relatively safe methods for biopsy (stereotactic techniques) were not available [13-15]. Few published summaries have directly contrasted AIDS-associated to non-AIDS- associated primary central nervous system lymphoma. We describe the key similarities and differences in the natural history and management of non-AIDS-associated and AIDS-associated primary central nervous system lymphoma. Because few prospective studies have been conducted, we have done a retrospective literature review of every case of primary central nervous system lymphoma reported in the English-language literature since 1980 (the beginning of the AIDS era and the time when modern imaging and neurosurgery became available). Our findings suggest that primary central nervous system lymphoma in patients with AIDS has a significantly different natural history than it does in immunocompetent persons. Data Sources and Extraction Using a MEDLINE search, we sought to identify all papers published in the English language between January 1980 and September 1992 that dealt with lymphoma and the brain, spinal cord, cerebral spinal fluid, or central nervous system. A search was also done of all literature dealing with AIDS, human immunodeficiency virus (HIV), lymphoma, and the central nervous system. Several series included overlapping patients. When these cases were identified, we extracted only the missing data for each case and attempted not to duplicate data. Patients were included in this analysis only if lymphoma was histologically documented. Data Synthesis Forty published series of predominantly non-AIDS-associated primary central nervous system lymphoma [16-53] and 32 series of AIDS-associated primary central nervous system lymphoma [54-85] were identified. Some data were present for 792 patients with non- AIDS-associated primary central nervous system lymphoma and 315 patients with AIDS-associated primary central nervous system lymphoma, although complete information regarding patient characteristics, type of treatment, and survival duration were seldom available for each person. The mean age of the patients without AIDS was 55.2 years; for the patients with AIDS it was 30.8 years (Table 1). The ratio of men to women was 1.35 for the patients without AIDS compared with 7.38 for the patients with AIDS. The average duration of symptoms before a definitive diagnosis was established was similar in the two groups (2.8 months for patients without AIDS compared with 1.8 months for patients with AIDS). A history of opportunistic infections or Kaposi sarcoma was present in 115 of 143 patients with AIDS (80%). Primary central nervous system lymphoma was the AIDS-defining illness in the remaining 28 patients (20%). Table 1. Patient Characteristics at Diagnosis The types of initial symptoms differed only slightly when the two groups were compared (Table 1): Specific neurologic deficits, mental status changes (including behavioral changes), seizures, and symptoms and signs suggestive of increased intracranial pressure (headache, nausea, vomiting, papilledema) occurred in 56%, 35%, 11%, and 32% of all patients without AIDS, respectively, and in 51%, 53%, 27%, and 14% of patients with AIDS. Radiographic imaging included 73 angiograms, all in patients with non-AIDS-associated primary central nervous system lymphoma. Sixty tumors were avascular, 10 showed a tumor blush, and 3 showed increased venous drainage (Table 2). Primary central nervous system lymphoma developed in supratentorial sites three times as often as in infratentorial locations. In addition, more than 60% of tumors were in a periventricular location, usually involving the corpus callosum, basal ganglia, or thalamus. Rarely, patients without obvious brain parenchymal tumors presented with only primary meningeal involvement. Findings from initial CT scans were similar in both groups of patients, with 80 of the 201 (90%) noncontrast scans demonstrating isodense or hyperdense lesions in the patients without AIDS compared with 61 of 167 (91%) scans in the patients with AIDS. Almost all lesions showed some degree of contrast enhancement (97% in patients without AIDS and 90% in patients with AIDS). Although the pattern of homogeneous enhancement (55% of patients without AIDS compared with 60.9% of patients with AIDS) was similar in the two groups, 52% of all AIDS-associated primary central nervous system lymphoma scans showed some degree of ring enhancement, a pattern not seen in the non-AIDS group. The other major radiographic difference between the two groups of patients was that multifocal disease was twice as common in patients with AIDS than in patients without AIDS (52% compared with 25%, respectively). Table 2. Radiographic Findings at Presentation Diagnosis was achieved by surgical resection, rather than biopsy, in 62% of all patients without AIDS, whereas only 30% of patients with AIDS had such resections (Table 3). Spinal fluid contained malignant cells in 31% of patients with non-AIDS-associated primary central nervous system lymphoma. Only 13 instances of spinal fluid examination were reported in patients with AIDS and primary central nervous system lymphoma, of which 3 showed cells that were consistent with malignant lymphoma (23%) (Table 3). Table 3. Method of Tissue Diagnosis and Histologic Findings When immunophenotyping was done, almost all lymphomas were of B-lymphocyte origin (Table 3). Differences in histologic pattern, using the Working Formulation terminology, showed only 22% of patients without AIDS having high-grade histologic findings (immunoblastic or small noncleaved cell) compared with 60% of patients with AIDS with the more aggressive, high-grade histologic findings. When reported, almost all AIDS-associated primary central nervous system lymphomas contained Epstein-Barr virus genomic DNA, whereas few tumors from immunocompetent patients contained Epstein-Barr viral DNA. Treatment strategies were defined for 86% of the patients without AIDS, but only 55% of patients with AIDS had treatment decisions reported, possibly reflecting the relatively high number of cases in patients with AIDS that were diagnosed after death (Table 4). Radiation therapy represented the sole form of treatment in a similar percentage of patients in both groups (65.8% for patients without AIDS and 66.1% for patients with AIDS). Chemotherapy was more likely to be added to the treatment regimen in patients without AIDS (25%) compared with patients with AIDS (8%). Table 4. Type of Treatment and Survival Without therapy both groups fared equally poorly (mean survival, 2.7 months for patients without AIDS; 0.9 months for patients with AIDS). However, the overall survival of all treated patients was substantially higher for patients without AIDS (18.9 months) compared with those with AIDS (2.6 months) (Table 4). Epidemiology Epidemiologic data strongly suggest that primary central nervous system lymphoma is increasing in incidence. Although the enhanced frequency in immunocompromised patients is related in part to the growing number of patients with iatrogenic immunosuppression (organ allograft recipients) and the longer survival of patients with congenital immunodeficiencies (owing to improved medical support), the principal reason for the large increase in case of primary central nervous system lymphoma in immunocompromised persons is the AIDS epidemic. A recent report from the National AIDS Cooperative Group described the develo