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Q: 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.
REFERENCES
(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
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