NeuroAIDS Vol. 2, No. 2, February 1999
The pathology of primary central nervous system lymphoma (PCNSL) in AIDS
A. V. Moses1 and L. M. Dallasta2
1Oregon Health Sciences University, Department of Molecular Microbiology and Immunology, 3181 SW Sam Jackson Park Road, L220, Portland, Oregon 97201, United States
2University of Pittsburgh Medical Center, Department of Pathology, Division of Neuropathology, 200 Lothrup St., PUH Room A-515, Pittsburgh, Pennsylvania 15213, United States
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: What are the key features of PCNSL in the setting of AIDS?

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AIDS-related PCNSL (AIDS-PCNSL) is an aggressive non-Hodgkins's lymphoma (NHL) accounting for 20% of all AIDS-NHL that arises and is exclusively contained within the CNS (1) (2). Most AIDS-PCNSLs are histologically classified as either diffuse large cell or large cell immunoblastic lymphomas of B cell origin. Differences between PCNSL and systemic NHL in AIDS patients are well described (3) and include histological, genetic, immunophenotypic and clinical characteristics that suggest distinct pathogenic mechanisms. Estimates place the incidence of AIDS-PCNSL at 2-13% of all AIDS patients with profound immunosuppression being a common feature (4) (5). An intriguing question is whether current highly active anti-retroviral therapy (HAART) regimes will increase PCNSL frequency due to extended patient survival or protect against development due to improvement in immunocompetence. While insufficient time has elapsed to fully assess the effect of such therapy on cancer risk in AIDS patients, recent data has documented a declining incidence of PCNSL since the advent of HAART (6) (7) (8). AIDS-PCNSL are characterized by solitary or multiple intracerebral foci of perivascular cell infiltrates, raising important questions about the role of CNS-specific adhesion molecules and blood brain barrier disruption in lymphomagenesis. Whether PCNSL arise from intracranial transformation of infiltrating non-malignant lymphocytes, or whether peripheral neoplastic cells migrate to and bind exclusively within the CNS, remains controversial (9).

Q: What is known about the pathogenesis of PCNSL?

The pathogenesis of PCNSL is complex and multifactorial and remains ill-defined. HIV does not induce lymphoma via direct infection of B cells. Rather, HIV-induced immunosuppression, chronic B cell stimulation and cytokine dysregulation may facilitate genetically unstable oligoclonal B cell expansions and, in turn, predispose cells to malignant transformation (3). Genetic lesions identified in AIDS-NHL include rearrangement of the c-myc, bcl-1, bcl-2 and bcl-6 oncogenes, activation of ras genes and mutations/deletions in tumor suppressor p53 and retinoblastoma genes (10) (11). Different histological sub-types are characterized by distinct lesions, and lack of c-myc rearrangements, bcl-2 overexpression, and Epstein-Barr virus (EBV) infection have emerged as characteristic features of AIDS-PCNSL (12) (13). The almost universal presence of EBV suggests an etiologic role for this virus, but precise mechanisms remain controversial. EBV is a gamma herpes virus that is associated with several malignancies and immortalizes resting B cells in vitro. Genes implicated in the immortalization process include the nuclear antigens EBNA-1, -2, -3A, -3C and -LP and latent membrane protein 1 (LMP-1). LMP-1 may facilitate immortalization via constitutive association with TRAF (tumor necrosis factor receptor-associated factor) signalling molecules, thus allowing constitutive triggering of cellular growth and activation pathways that resemble those induced by ligand activation of members of the TNF-receptor molecule family such as CD40 (14). LMP-1 may also promote tumor development by protecting EBV+ lymphoma cells from apoptosis via induction of anti-apoptotic genes such as bcl-2 and A20. Potential interactions between specific endothelial cell or B lymphoma cell molecules that may regulate the site-specific development of lymphoma have also been identified (15) (16) but a precise relationship to PCNSL remains elusive. AIDS-NHL can be sub-divided into two phenotypes based on the expression of bcl-6 and CD138 (syndecan-1); a germinal center (GC) phenotype (BCL-6+/syndecan-1-) and a post-GC phenotype (BCL-6-/syndecan-1+) (17). PCNSL expressing both phenotypes have been detected in AIDS patients (18). Expression of LMP-1 shows a high correlation with the post-GC phenotype, while tumors with the GC phenotype are consistently LMP-1 negative (17). Identification of such distinct sub-types may lead to an increased understanding of PCNSL histogenesis and pathogenic mechanisms.

Q: Over half of PCNSL cases are only diagnosed at autopsy. What are the challenges associated with the diagnosis of PCNSL in AIDS patients?

Clinical features of PCNSL are non-specific and include confusion, lethargy, personality changes, memory loss and headache. Despite the discrete nature of the lesions, focal neurologic deficits and seizures are less common. Computerized tomography (CT) and magnetic resonance imaging (MRI) are important diagnostic techniques. However, unlike non-AIDS PCNSL which enhance uniformly, AIDS-associated lesions are often ring-enhancing and are thus radiographically indistinguishable from malignant glioma or cerebral toxoplasmosis. Positron emission tomography (PET) and thallium single photon emission computed tomography (SPECT) imaging, and toxoplasma serology may allow discrimination between AIDS-PCNSL and toxoplasmic encephalitis. Furthermore, analysis of cerebrospinal fluid (CSF) may assist in diagnosis since a consistent correlation between PCNSL and PCR-detectable EBV DNA in CSF has been reported (19) (20) (21). PCR for JC virus is also recommended given the high predictive value of a positive result for a diagnosis of progressive focal leukoencephalopathy (PML) (22). Due to the indistinct radiographic features of AIDS-PCNSL, and since opportunistic infections may arise concurrently in the setting of AIDS, steriotactic brain biopsy may ultimately be required for definitive diagnosis. Controversy as to the cost-benefit ratio of this procedure, as well as patient-surgeon concerns about its invasiveness, are issues worthy of debate. Since time to diagnosis and early therapeutic intervention are crucial for prolonged survival, patients with good prognostic factors should be considered for prompt brain biopsy. A recent study demonstrating the high diagnostic accuracy of combined thallium-201 SPECT and EBV-DNA PCR for AIDS-PCNSL suggests a viable non-invasive alternative (23).

Q: In the absence of treatment, progressive AIDS-PCNSL is rapidly fatal. What are current treatment regimens for AIDS-PCNSL and what novel regimens are being considered?

Due to location and multifocality, AIDS-PCNSL are generally not surgically resectable. Standard therapy is cranial radiation involving external beam RT at a dose of 4 000-5 000 cGy (24) (25). Clinical and radiographic improvement is rapid but, despite an initial effectiveness, median survival is only 2-5 months. Post-mortem studies reveal that the majority of treated patients die from systemic opportunistic infections or additional neurologic complications rather than from recurrence of AIDS-PCNSL (26). The short survival time, the likely consequence of the severe immunodeficiency that is an inherent feature of AIDS-PCNSL, obviates analysis of the long-term effectiveness of RT. Corticosteroids should only be used for the treatment of severe neurologic symptoms, since they exacerbate immunosuppression and can complicate radiographic diagnosis by temporarily shrinking an enhancing mass (4). Although chemotherapy is an effective adjunct in non-AIDS PCNSL, its use in AIDS patients is controversial due to their often severe pre-existing immunosuppression and poor tolerance for cytotoxic drugs (27). Adoptive immunotherapy using infusions of autologous EBV-specific CTL is a novel therapeutic approach (28). Antiviral agents such as foscarnet, hydroxyurea and 5-azacytidine are also under evaluation (29). The success of such regimens depends on the extent to which lymphoma growth is EBV driven.


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