|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|
|Address correspondence to: firstname.lastname@example.org or email@example.com|
: What are the key features of PCNSL in the setting of AIDS?
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.
(1) So YT, Beckstead JH, Davis RL (1986). Primary central nervous system lymphoma in acquired immune deficiency syndrome: a clinical and pathological study. Ann Neurol 20(5): 566-72. Medline
(2) Rosenblum ML, Levy RM, Bredesen DE (1988). Neurosurgical implications of the acquired immunodeficiency syndrome (AIDS). Clin Neurosurg 34: 419-45. Medline
(3) Knowles DM (1996). Etiology and pathogenesis of AIDS-related non-Hodgkin's lymphoma. Hematol Oncol Clin North Am 10(5): 1081-109. Medline
(4) Forsyth PA, DeAngelis LM (1996). Biology and management of AIDS-associated primary CNS lymphomas. Hematol Oncol Clin North Am 10(5): 1125-34. Medline
(5) Said G, Saimot AG , Tardieu M, Lacroix C. Neurological Complications of HIV and AIDS (W. B. Saunders, London UK, 1997) pp. 33-45.
(6) Jones JL et al., Abstract S3. 2nd National AIDS MalignancyConference, Bethesda, MD (1998).
(7) Sparano J et al., Abstract S9. 2nd National AIDS MalignancyConference, Bethesda, MD (1998).
(8) Antinori A , Cingolani A, Ammassari A, Pezzotti P, Murri R, De Luca A, Larocca LM, and Ortona L (1999). AIDS-Related Focal Brain Lesions in the Era of HAART. 6th Conference on Retroviruses and Opportunistic Infections, Chicago, IL. Abstract 413
(9) Hochberg FH, Miller DC (1988). Primary central nervous system lymphoma. J Neurosurg 68(6): 835-53. Medline
(10) Ballerini P, Gaidano G, Gong JZ, Tassi V, Saglio G, Knowles DM, Dalla-Favera R (1993). Multiple genetic lesions in acquired immunodeficiency syndrome-related non-Hodgkin's lymphoma. Blood 81(1): 166-76. Medline
(11) Ong ST, Le Beau MM (1998). Chromosomal abnormalities and molecular genetics of non-Hodgkin's lymphoma. Semin Oncol 25(4): 447-60. Medline
(12) MacMahon EM, Glass JD, Hayward SD, Mann RB, Becker PS, Charache P, McArthur JC, Ambinder RF (1991). Epstein-Barr virus in AIDS-related primary central nervous system lymphoma. Lancet 338(8773): 969-73. Medline
(13) Hamilton-Dutoit SJ, Rea D, Raphael M, Sandvej K, Delecluse HJ, Gisselbrecht C, Marelle L, van Krieken HJ, Pallesen G (1993). Epstein-Barr virus-latent gene expression and tumor cell phenotype in acquired immunodeficiency syndrome-related non-Hodgkin's lymphoma. Correlation of lymphoma phenotype with three distinct patterns of viral latency. Am J Pathol 143(4): 1072-85. Medline
(14) Devergne O, Hatzivassiliou E, Izumi KM, Kaye KM, Kleijnen MF, Kieff E, Mosialos G (1996). Association of TRAF1, TRAF2, and TRAF3 with an Epstein-Barr virus LMP1 domain important for B-lymphocyte transformation: role in NF-kappaB activation. Mol Cell Biol (12):7098-108. Medline
(15) Aho R, Ekfors T, Haltia M, Kalimo H (1993). Pathogenesis of primary central nervous system lymphoma: invasion of malignant lymphoid cells into and within the brain parenchyme. Acta Neuropathol 86(1): 71-6. Medline
(16) Moses AV, Williams SE, Strussenberg JG, Heneveld ML, Ruhl RA, Bakke AC, Bagby GC, Nelson JA (1997). HIV-1 induction of CD40 on endothelial cells promotes the outgrowth of AIDS-associated B-cell lymphomas. Nat Med 3(11): 1242-9. Medline
(17) Carbone A, Gaidano G, Gloghini A, Larocca LM, Capello D, Canzonieri V, Antinori A, Tirelli U, Falini B, Dalla-Favera R (1998). Differential expression of BCL-6, CD138/syndecan-1, and Epstein-Barr virus-encoded latent membrane protein-1 identifies distinct histogenetic subsets of acquired immunodeficiency syndrome-related non-Hodgkin's lymphomas. Blood 91(3):747-55. Medline
(18) Larocca LM et al. (1998), Abstract 89. 2nd National AIDS Malignancy Conference, Bethesda, MD.
(19) Cinque P, Brytting M, Vago L, Castagna A, Parravicini C, Zanchetta N, D'Arminio Monforte A, Wahren B, Lazzarin A, Linde A (1993). Epstein-Barr virus DNA in cerebrospinal fluid from patients with AIDS-related primary lymphoma of the central nervous system. Lancet 342(8868): 398-401. Medline
(20) De Luca A, Antinori A, Cingolani A, Larocca LM, Linzalone A, Ammassari A, Scerrati M, Roselli R, Tamburrini E, Ortona L (1995). Evaluation of cerebrospinal fluid EBV-DNA and IL-10 as markers for in vivo diagnosis of AIDS-related primary central nervous system lymphoma. Br J Haematol 90(4): 844-9. Medline
(21) Cingolani A, De Luca A, Larocca LM, Ammassari A, Scerrati M, Antinori A, Ortona L (1998). Minimally invasive diagnosis of acquired immunodeficiency syndrome-related primary central nervous system lymphoma. J Natl Cancer Inst 90(5):364-9. Medline
(22) Antinori A, Ammassari A, De Luca A, Cingolani A, Murri R, Scoppettuolo G, Fortini M, Tartaglione T, Larocca LM, Zannoni G, Cattani P, Grillo R, Roselli R, Iacoangeli M, Scerrati M, Ortona L (1997). Diagnosis of AIDS-related focal brain lesions: a decision-making analysis based on clinical and neuroradiologic characteristics combined with polymerase chain reaction assays in CSF. Neurology 48(3):687-94. Medline
(23) Antinori A, De Rossi G, Ammassari A , Cingolani A , Murri R, Di Giuda D, De Luca A, Pierconti F, Tartaglione T, Scerrati M, Larocca LM, and Ortona L (1999). Value of Combined Approach With Thallium-201 Single-Photon Emission Computed Tomography and Epstein-Barr Virus DNA Polymerase Chain Reaction in CSF for the Diagnosis of AIDS-Related Primary CNS Lymphoma. J. Clin. Oncol. 17(2): 554-60. Medline
(24) Formenti SC, Gill PS, Lean E, Rarick M, Meyer PR, Boswell W, Petrovich Z, Chak L, Levine AM (1989). Primary central nervous system lymphoma in AIDS. Results of radiation therapy. Cancer 63(6):1101-7. Medline
(25) Ling SM, Roach M 3rd, Larson DA, Wara WM (1994). Radiotherapy of primary central nervous system lymphoma in patients with and without human immunodeficiency virus. Ten years of treatment experience at the University of California San Francisco. Cancer 73(10): 2570-82. Medline
(26) Lowenthal DA, Straus DJ, Campbell SW, Gold JW, Clarkson BD, Koziner B (1988). AIDS-related lymphoid neoplasia. The Memorial Hospital experience. Cancer 61(11): 2325-37. Medline
(27) Levine AM, Wernz JC, Kaplan L, Rodman N, Cohen P, Metroka C, Bennett JM, Rarick MU, Walsh C, Kahn J (1991). Low-dose chemotherapy with central nervous system prophylaxis and zidovudine maintenance in AIDS-related lymphoma. A prospective multi-institutional trial. JAMA 266(1): 84-8. Medline
(28) Vos JMH, Quattrocchi KB, Wendelburg BJ. Gene Therapy for Neurological Disorders and Brain Tumors, E. A. Chiocca and X. O. Breakefield, Eds. (Humana Press, Totowa, NJ), pp. 93-112.
(29) DeMario MD, Liebowitz DN (1998). Lymphomas in the immunocompromised patient. Semin Oncol 25(4): 492-502. Medline
|Copyright Information | Site map|