Several models of pathogenesis have been proposed, but the reason for
the high incidence of NHL among patients with AIDS remains
incompletely understood. Initially, HIV was presumed to be a
transforming retrovirus, the presence of which was a requisite for
the development of NHL. Although HIV has been identified in a small
subset of tumors, with additional follow-up,we now appreciate that
this virus is rarely involved directly in B- and T-cell oncogenesis.
More apparent is the great molecular heterogeneity among lymphomas
seen in HIV-infected individuals. Specific characteristics that
distinguish the various subtypes include monoclonal or polyclonal
origin of the lymphoma, presence or absence of EBV or KSHV/HHV-8
viral integration or c-myc rearrangements in lymphoma cells, and type
of immunoglobulin gene rearrangements. The roles of cytokines and
tumor-suppressor genes in promoting and maintaining uncontrolled
B-cell growth and differentiation are additional areas of active research.
Role of c-myc Rearrangements and EBV
The foundation for molecular studies of AIDS-associated NHL is built
on information garnered during tumor analysis of samples from
non-HIV-infected patients with Burkitts lymphoma. Reciprocal
translocations contribute to the development of Burkitts
lymphoma by placing the activated c-myc gene under the control
of genes that actively transcribe immunoglobulin determinants,
resulting in clonal proliferation of a neoplastic B-cell population.
Subtle differences in site of translocation distinguish the endemic
African variant of lymphoma from the sporadic pleomorphic variant
typically seen in the United States. Proximal chromosomal
breakpoints near the first exon of c-myc are characteristic of
Burkitts lymphoma in the United States, whereas breakpoints in
African Burkitts lymphoma occur more distal from the first exon
of c-myc.[52,53] In addition, the endemic form consistently contains
episomal EBV genome in tumor tissue, whereas less than 10% to 20% of
sporadic cases have EBV in tumor tissue. Moreover, the epidemic form,
but not the sporadic form, characteristically presents in the jaw or
orbit. These differences suggest that the two forms may have
different pathogenic pathways.
In roughly 50% to 80% of cases of AIDS-associated Burkitts
lymphoma, similar chromosomal changes of the sporadic type are found;
that is, c-myc is most often mutated and rearranged with an
immunoglobulin heavy-chain switch region.[26,55] The presence of this
rearrangement in the switch region implies that the transforming
event is occurring in a more mature B-cell undergoing the transition
between heavy-chain isotopes.
The high frequency of rearranged c-myc genes appears to be
confined primarily to the small noncleaved cell histology. In one
study, c-myc rearrangements were seen in 100% of Burkitts
lymphoma cases but in only 33% or fewer of large cell or
immunoblastic cases. In another study, only 15% of large cell
lymphomas collected from patients with AIDS showed evidence of c-myc
rearrangements ,whereas roughly 50% of Burkitts-like lymphomas
had c- myc rearrangements.
Pelicci and associates have provided evidence for a multistep
progression to lymphoma involving c-myc rearrangements. They
described oligoclonal B-cell expansions in hyperplastic lymph nodes
from patients with HIV disease and c-myc rearrangements only
after lymphoma had developed. In this model, EBV mitogenically
stimulates oligoclonal B-cell proliferation, and a tumor develops
after c-myc activation. Translocation leading to c-myc
rearrangement, therefore, may play a critical role in the
pathogenesis of HIV-associated NHLs, predominantly those of the
Burkitts lymphoma subtype.
Immune suppression, EBV infection, polyclonal B-cell activation, and
aberrant B-cell regulation are all important factors contributing to
the development of epidemic Burkitts lymphoma and NHLs in
individuals with congenital or iatrogenic immune suppression.[11,59]
Persons infected with HIV are prone to EBV infections, have a
profound defect in T-cell immunity to EBV, and harbor abnormally high
numbers of EBV-infected B-cells. Moreover, the presence of EBV in
lymphadenopathy lesions correlates with a higher risk of developing
lymphoma over time, suggesting that EBV may constitute an early
promoter of HIV-lymphomagenesis.
The principal hypothesis advanced by various groups is that, in
HIV-induced immunodeficiency, EBV infection results in polyclonal
stimulation and immortalization of B-cell clones.[26,61] Such clones
are presumably predisposed to c-myc gene rearrangements. The
result is a collection of transformed, monoclonal EBV-containing
B-cells that are less likely to undergo apoptosis and that may
ultimately progress to NHL.
Findings bolstering this hypothesis include the presence of
monoclonal or oligoclonal B-cell populations infected with EBV in the
lymph nodes of patients with persistent generalized lymphadenopathy
and the concomitant occurrence or subsequent development of
EBV-containing NHL.[26,62] Further support comes from studies
demonstrating that the introduction of an activated c-myc gene into
EBV-infected lymphoblasts obtained from HIV-infected persons leads to
the malignant conversion of such cells.
Using polymerase chain reaction--based techniques, Ometto and
colleagues studied EBV types and variants in 28 lymphadenopathy
lesions and 20 lymphomas (15 large cell and 5 Burkitts-like
lymphomas). Epstein-Barr virus was detected in 89% of
lymphadenopathies and 80% of lymphomas; viral DNA content was
significantly higher in the latter. Epstein-Barr nuclear antigen 2
(EBNA 2) and latent membrane protein 1 (LMP 1) gene analysis
indicated that half of the
EBV-positive lymphadenopathies were coinfected with both EBV type 1
and 2 strains and/or multiple type 1 variants. Conversely, all but
one lymphoma carried a single viral variant, consistently type 1 in
large cell lymphomas and type 2 in Burkitts-like tumors. Most
lymphomas, but no lymphadenopathies, showed monoclonal immunoglobulin
An analysis of five large cell lymphomas and five lymphadenopathies
for EBV transcripts identified LMP 1 messenger RNA (mRNA) in most
samples and the EBNA 2 transcript in all tumors. These findings
provide evidence of a heterogeneous EBV population in lesions,
strengthen the notion that lymphomas arise from clonal expansion of
EBV-positive cells, and suggest different roles of EBV type 1 and 2
in HIV-related lymphoproliferations. Additional studies are required,
however, as not all groups have been able to show a relationship
between superinfection with EBV types and the development of NHL in
Just as c-myc activation is notably absent from some
HIV-associated lymphomas, EBV infection is not invariably linked to
all AIDS-associated lymphoproliferations. A substantial number of
cases of AIDS-associated NHL do not show evidence of EBV genome
detection. An EBV genome sequence is present in only 30% to 50% of
Burkitts lymphomas, and EBV-positive tumors are more likely to
be immunoblastic phenotype.[24,26,56]
Rearrangements of c-myc may precede EBV infection, further supporting
the notion that there is not necessarily a causal link between EBV
infection and c-myc activations. In cases in which no
etiologic evidence of EBV is present, bacterial, fungal, or other
viral agents may cause chronic antigenic stimulation and, like EBV,
increase the risk of chromosomal translocations, immunoglobulin gene
rearrangements, and ultimately, growth of NHL.
Roles of HIV and KSHV/HHV-8
As mentioned above, it is now appreciated that HIV is rarely involved
directly in B- and T-cell oncogenesis. More likely, the virus
acts in indirect ways to promote lymphomagenesis. How this occurs is uncertain.
Recently, Moses and colleagues used bone marrow stromal cultures
enriched with microvascular endothelial cells to demonstrate that HIV
infection of stromal microvascular endothelial cells from lymphoma
patients induces the outgrowth of malignant B-cells. They
suggested that HIV impacts on lymphomagenesis indirectly by
facilitating attachment of lymphoma cells to HIV-infected
microvascular endothelial cells.
The attachment of these cells may be mediated by enhanced expression
of CD40 and preferential induction of the vascular cell adhesion
molecule 1. The attachment of B-lymphoma cells to HIV-infected
microvascular endothelial cells would bring the lymphoma cells into
close proximity to membrane-bound or locally secreted growth factors,
thus promoting malignant B-cell growth. In AIDS patients, infection
of microvascular endothelial cells within such areas as the bone
marrow, brain, kidney, or liver might explain the unusual
predilection of these tumors to present at extranodal sites.
Another virus that may promote lymphomagenesis is the recently
described KSHV/HHV-8. This virus is a member of the gamma herpes
virinae subfamily, shares substantial sequence homology with EBV and
herpesvirus saimiri, and has the ability to replicate in
Although most commonly seen in KS lesions of homosexual men,
KSHV/HHV-8 sequences are also detected in the lymph nodes of patients
with Castlemans disease, possibly in the stromal cells of
patients with multiple myeloma and monoclonal gammopathy of uncertain
significance, and in patients with primary effusion lymphoma
(also known as body-cavity-based lymphoma). Body-cavity-based
lymphoma is a newly recognized entity whose epidemiology is similar
to that of epidemic KS. It accounts for roughly 1% to 3% of all
AIDS-associated lymphomas and appears most consistently among
homosexual or bisexual men but is distinctly uncommon in other
patients with AIDS.[72,73]
Lymphomas associated with KSHV/HHV-8 arise predominantly, but not
exclusively, in HIV-positive individuals and are characterized by
presentation as malignant effusions in the pleural, pericardial, and
abdominal cavities without solid tumor masses. The malignant
cells typically have abundant acidophilic to amphophilic cytoplasm,
as well as large, round, and regular to highly irregular nuclei
containing one or more nucleoli (Figure 1).
These cells also exhibit an indeterminate immunophenotype
characterized by lack of surface immunoglobulin and B-cell-associated
antigens, but they express leukocyte common antigen and various
antigens associated with activation of late stages of B-cell differentiation.[75-77]
In contrast, most lymphomas seen in the setting of HIV infection
express monotypic surface immunoglobulin or B-cell-associated
antigens, such as CD19, CD20, and CD22, and generally lack
T-cell-associated antigens.[25,78] Such immunophenotypes resemble
morphologically similar lymphomas seen in the non-HIV-infected
population. Like the body-cavity-based lymphomas, most
AIDS-associated NHLs demonstrate clonal immunoglobulin heavy- and
light-chain rearrangements and lack clonal T-cell receptor B-chain
rearrangements. Some of the unique clinical and biological features
of body-cavity-based lymphomas are outlined in Table
The vast majority of cases of body-cavity-based lymphomas contain
EBV. This dual viral infection is the first example of a consistent
dual herpes viral infection in a human neoplasm and provides a unique
model to study viral interactions. Recently, Horenstein and
colleagues analyzed the pattern of EBV-latent gene expression to
determine the pathogenic role of this agent in body-cavity-based
lymphomas. They found that body-cavity-based lymphomas exhibit a
restricted pattern of EBV latency. The sole expression of EBNA 1 in
the absence of significant expression of the major EBV
growth-transforming factors suggests that EBV, by itself, is not
responsible for transformation. The authors believe that KSHV plays a
dominant role in the pathogenesis of body-cavity-based lymphomas.
Furthermore, a secondary role for EBV in body-cavity-based lymphomas
has been suggested by the identification of a few cases containing
HHV-8 but not EBV. It remains to be determined, however, whether
KSHV/HHV-8 is sufficient in such cases, or whether additional genetic
mechanisms are involved in the transforming process.
Preliminary studies indicate that KSHV/HHV-8 encodes for a homolog of
cellular cyclin D2 (v-cyclin D). Cellular D-type cyclin proteins
regulate cell-cycle progression during the G1-phase by forming active
kinase complexes with a family of proteins termed
"cyclin-dependent kinases." Perhaps the expression of
v-cyclin in KSHV/HHV-8-infected cells may result in altered
cell-cycle progression during G1 and aberrant proliferation of
HHV-8-infected cells--a finding that may have relevance in
understanding the pathogenicity of KSHV/HHV-8.
1. Gottlieb MS, Schroff R, Shenker HM, et al: Pneumocystis carinii
pneumonia and mucosal candidiasis in previously healthy homosexual
men: Evidence of a new acquired cellular immunodeficiency. N Engl J
Med 305:1425-1431, 1981.
2. Centers for Disease Control: Kaposis sarcoma and
Pneumocystis carinii pneumonia among homosexual men: New York City
and California. Morbid Mortal Weekly Rep 30:305-308, 1981.
3. Centers for Disease Control: Diffuse, undifferentiated
non-Hodgkins lymphoma among homosexual males--United States.
Morbid Mortal Weekly Rep 31:277-279, 1982.
4. Doll DC, List AF: Burkitts lymphoma in a homosexual. Lancet
5. Ziegler JL, Drew WL, Miner RC, et al: Outbreak of
Burkitts-like lymphoma in homosexual men. Lancet 2:631-633, 1982.
6. Levine AM, Meyer PR, Begandy MK, et al: Development of B-cell
lymphoma in homosexual men: Clinical and immunologic features. Ann
Intern Med 100:7-13, 1984.
7. Ziegler JL, Beckstead JA, Volberding PA, et al: Non-Hodgkins
lymphoma in 90 homosexual men: Relation to generalized
lymphadenopathy and the acquired immunodeficiency syndrome. N Engl J
Med 311:565-570, 1984.
8. Centers for Disease Control: Revision of the case definition of
acquired immunodeficiency for national reporting--United States.
Morbid Mortal Weekly Rep 34:373-375, 1985.
9. Centers for Disease Control: Revision of the CDC surveillance case
definition for acquired immunodeficiency syndrome: Council of State
and Territorial Epidemiologists; AIDS Program, Center for Infectious
Diseases. Morbid Mortal Weekly Rep 36(suppl 1):1s-15s, 1987.
10. Longo DL, Mauch P, De Vita VT Jr., et al: Lymphocytic lymphomas
in: De Vita JT Jr, Hellman S, Rosenberg SA (eds). Cancer: Principles
and Practice of Oncology, 4th ed, pp 1859-1927. Philadelphia,
11. Penn I: Cancers complicating organ transplantation. N Engl J Med
12. Nalesnik MA, Makowa L, Starzl TE: The diagnosis and treatment of
posttransplant lymphoproliferative disorders. Curr Probl Surg
13. Deeg HJ, Storb R, Thomas ED: Bone marrow transplantation: A
review of delayed complications. Br J Haematol 57:185-208, 1984.
14. Zutter MM, Martin PJ, Sale GE, et al: Epstein-Barr virus B-cell
lymphoproliferation after bone marrow transplantation. Blood
15. Levine AM: Lymphoma complicating immunodeficiency disorders. Ann
Oncol 5:29-35, 1994.
16. Swinnen LJ, Costanzo-Nordin MR, Fisher SG, et al: Increased
incidence of lymphoproliferative disorders after immunosuppression
with the monoclonal antibody OKT3 in cardiac-transplant recipients. N
Engl J Med 323:1723-1728, 1990.
17. Opelz G, Henderson R: Incidence of non-Hodgkins lymphoma in
kidney and heart transplants. Lancet 342:1514-1516, 1993.
18. Starzl T, Porter K, Iwatsuki S, et al: Reversibility of lymphomas
and lymphoproliferative lesions developing under cyclosporin-steroid
therapy. Lancet 1:583-587, 1984.
19. Knowles DM, Cesarman E, Chadburn A, et al: Correlative
morphologic and molecular genetic analysis demonstrates three
distinct categories of posttransplantation lymphoproliferative
disorders. Blood 85:552-565, 1995.
20. Chadburn A, Chen JB, Hsu DT, et al: The morphologic and molecular
genetic classification of post-transplant lymphoproliferative
disorders (PT-LPDs) has clinical relevance. Cancer, 1998 (in press).
21. Prior P: Cancer and rheumatoid arthritis: Epidemiologic
considerations. Am J Med 78(suppl 1A):15-21, 1987.
22. Castor CW, Bull FE: Review of United States data on neoplasms in
rheumatoid arthritis. Am J Med 78(suppl 1A):33-38, 1985.
23. Purtilo DT: Immune deficiency predisposing to Epstein-Barr
virus-induced lymphoproliferative disease: The X-linked
lymphoproliferative syndrome as a model. Adv Cancer Res 34:279-312, 1981.
24. Hamilton-Dutoit SJ, Pallenson G, Franzmann MB, et al:
AIDS-related lymphoma: Histopathology, immunophenotype, and
association with Epstein-Barr virus as demonstrated by in situ
nucleic and hybridization. Am J Pathol 138:149-163, 1991.
25. Knowles DM, Dalla-Favera R: AIDS-associated lymphomas, in Broder
S, Merrigan TC, Bolognesi D (eds.): Textbook of AIDS Medicine, pp
431-463. Baltimore, Williams and Wilkins, 1994.
26. Subar M, Neri A, Inghirami G, et al: Frequent c-myc oncogene
activation and infrequent presence of Epstein-Barr virus genome in
AIDS-associated lymphoma. Blood 72:667-671, 1988.
27. Beral V, Peterman T, Berkelman R, et al: AIDS-associated
non-Hodgkins lymphoma.Lancet 337:805-809, 1991.
28. Nador RG, Horenstein MG, Chadburn A, et al: Correlative
morphologic and molecular genetic analysis of 75 AIDS-related
systemic non-Hodgkins lymphoma (abstract). J Acquir Immune
Defic Syndr Hum Retrovirol 14:450, 1997.
29. Devesa SS, Fears T: Non-Hodgkins lymphoma time trends:
United States and international data. Cancer Res 52(suppl
30. Parker SL, Tong T, Bolden S, et al: Cancer statistics, 1997. CA
Cancer J Clin 47:5-27, 1997.
31. Grufferman S: Epidemiology and hereditary aspects of malignant
lymphoma and Hodgkins disease, in Wiernick PH, Canellos GP,
Dutcher JP, et al (eds): Neoplastic Diseases of the Blood, pp
737-751. New York, Churchill Livingstone, 1996.
32. Aboulafia DM: Clinical implications of human T-cell leukemia
virus type I/II-associated disease. AIDS Reader 5:118-129, 1995.
33. Biggar RJ, Rabkin CS: The epidemiology of acquired
immunodeficiency syndrome-related lymphoma. Curr Opin Oncol
34. Biggar RJ, Rabkin CS: The epidemiology of AIDS-related neoplasms.
Hematol Oncol Clin North Am 10:997-1010, 1996.
35. Biggar RJ, Curtis RE, Cote TR, et al: Risk of other cancers
following Kaposis sarcoma: Relation to acquired immune
deficiency syndrome. Am J Epidemiol 139:362-368, 1994.
36. Kristal AR, Nasca PC, Burnett WS, et al: Changes in the
epidemiology of non-Hodgkins lymphoma associated with the
epidemic human immunodeficiency virus (HIV) infection. Am J Epidemiol
37. Cote TR, Howe HL, Anderson SP, et al: A systematic consideration
of the neoplastic spectrum of AIDS: Registry linkage in Illinois.
AIDS 5:49-53, 1991.
38. Pluda JM, Yarchoan R, Jaffe ES, et al: Development of
non-Hodgkins lymphoma in a cohort of patients with severe human
immunodeficiency virus (HIV) infection on long-term antiretroviral
therapy. Ann Intern Med 113:276-282, 1990.
39. Pluda JM, Venzon DJ, Tosato G, et al: Parameters affecting the
development of non-Hodgkins lymphoma in patients with severe
human immunodeficiency virus infection receiving antiretroviral
therapy. J Clin Oncol 11:1099-1107, 1993.
40. Levine AM, Bernstein L, Sullivan-Halley J, et al: Role of
zidovudine antiretroviral therapy in the pathogenesis of acquired
immunodeficiency syndrome-related lymphoma. Blood 86:4612-4616, 1995.
41. Ragni MV, Belle SH, Jaffe RA, et al: Acquired immunodeficiency
syndrome-associated non-Hodgkins lymphomas and other
malignancies in patients with hemophilia. Blood 81:1889-1897, 1993.
42. Rabkin CS, Hilgartner MW, Hedberg KW, et al: Incidence of
lymphomas and other cancer in HIV-infected and HIV-uninfected
patients with hemophilia. JAMA 267:1090-1094, 1992.
43. Gail MH, Pluda JM, Rabkin CS, et al: Projection of the incidence
of non-Hodgkins lymphoma related to the acquired
immunodeficiency syndrome. J Natl Cancer Inst 83:695-701, 1991.
44. Levine AM: AIDS-related malignancies: The emerging epidemic. J
Natl Cancer Inst 85:1382-1397, 1993.
45. Peters BS, Beck EJ, Coleman DG, et al: Changing disease patterns
in patients with AIDS in a referral center in the United Kingdom: The
changing face of AIDS. Br Med J 302:203-207, 1991.
46. Hammer SM, Katzenstein DA, Hughes MD, et al: A trial comparing
nucleoside monotherapy with combination therapy in HIV-infected
adults with CD4 cell counts from 200 to 500 per cubic millimeter:
AIDS Clinical Trial Group Study 175 Study Team. N Engl J Med
47. Connors M, Kovacs JA, Krevat S, et al: HIV infection induces
changes in CD4+ T-cell phenotype and depletions within the CD4+
T-cell repertoire that are not immediately restored by antivirals or
immune based therapies. Nature Med 3:533-540, 1997.
48. OBrien WA, Hartigan PM, Daar ES: Change in plasma HIV RNA
levels and CD4+ lymphocyte counts predict both response to
antiretroviral therapy and therapeutic failure: VA Cooperative Study
Group on AIDS. Ann Intern Med 126:939-945,1997.
49. Fatkenheuer G, Theisen A, Rockstroh J, et al: Virological
treatment of failure of protease inhibitor therapy in an unselected
cohort of HIV-infected patients. AIDS 11:F113-F116, 1997.
50. Mehta S, Moore RD, Graham NMH: Potential factors affecting
adherence with HIV therapy. AIDS 11:1665-1670, 1997.
51. Herndier BG, Shiramizu BT, Jewett NE, et al: Acquired
immunodeficiency syndrome-associated T-cell lymphoma: Evidence of
human immunodeficiency virus type I-associated T-cell transformation.
Blood 79:1768-1774, 1992.
52. Levine PH, Blattner WA: The epidemiology of
human-virus-associated hematologic malignancies. Leukemia 3(suppl
53. Rabkin CS, Ward MH, Manns A, et al: Epidemiology of
non-Hodgkins lymphomas, in McGrath I (ed): The Non-Hodgkins
Lymphomas, 2nd ed, pp 171-186. New York, Oxford University Press, 1997.
54. Barriga F, Kiwanuka J, Alvarez-Mon M, et al: Significance of
chromosome 8 breakpoint location in Burkitts lymphoma:
Correlation with geographical origin and association with
Epstein-Barr virus. Curr Top Microbiol Immunol 141:128-137, 1988.
55. Knowles DM. Etiology and pathogenesis of AIDS-related
non-Hodgkins lymphoma.Hematol Oncol Clin North Am 10:1081-1109, 1996.
56. Ballerini P, Giadono G, Gong JZ, et al: Multiple genetic lesions
in acquired immunodeficiency syndrome-related non-Hodgkins
lymphoma. Blood 81:166-176, 1993.
57. Shiramizu B, Herndier B, Meeker T, et al: Molecular and
immunophenotypic characterization of AIDS-associated, Epstein-Barr
virus-negative, polyclonal lymphoma. J Clin Oncol 10:383-389, 1992.
58. Pelicci PG, Knowles DM, Magrath I, et al: Chromosomal breakpoints
and structural alterations of the c-myc locus differ in endemic and
sporadic forms of Burkitts lymphoma. Proc Natl Acad Sci USA
59. De-The G, Gesar A, Day NE, et al: Epidemiological evidence for
causal relationship between Epstein-Barr virus and Burkitts
lymphoma from Ugandan prospective study. Nature 274:756-761, 1978.
60. Ometto L, Menin C, Masiero S, et al: Molecular profile of
Epstein-Barr virus in human immunodeficiency virus type 1-related
lymphadenopathies and lymphomas. Blood 90:313-322, 1997.
61. Goldschmidts WL, Bhatia K, Johnson JF, et al: Epstein-Barr virus
genotypes in AIDS-associated lymphomas are similar to those in
endemic Burkitts lymphoma. Leukemia 6:875-878, 1992.
62. Shibata D, Weiss LM, Nathwani BN, et al: Epstein-Barr virus in
benign lymph node biopsies from individuals infected with human
immunodeficiency virus is associated with concurrent or subsequent
development of non-Hodgkins lymphoma. Blood 77:1527-1533, 1991.
63. van Baarle D, Kersten MJ, Klein MR, et al: Superinfection with
EBV-types in HIV-1 infection is not related to the development of
non-Hodgkins lymphoma (abstract). Blood 10 (suppl 1):134a, 1997.
64. Roncella S, Di Celle PF, Cutrona G, et al: Cytogenetic
rearrangements of c-myc oncogene occurs prior to infection with
Epstein-Barr virus in the monoclonal malignant B cells from an AIDS
patient. Leuk Lymphoma 9:145-164, 1993.
65. Moses AV, Williams SE, Strussenberg JB, et al: HIV-1 induction of
CD40 on endothelial cells promotes the outgrowth of AIDS-associated
B-cell lymphomas. Nature Med 3:1242-1249, 1997.
66. Aboulafia DM, Mitsuyasu RT: Lymphomas and other cancers
associated with acquired immunodeficiency syndrome, in Curran J,
Essex M, Fauci AS (eds): AIDS: Etiology, Diagnosis, Treatment and
Prevention, 4th ed, pp 319-330. Philadelphia, Lippincott, 1996.
67. Roizman B: Herpesviridae: A brief introduction, in Fields BN
(ed): Virology, p 1787. New York, Raven, 1990.
68. Chang Y, Cesarman E, Pessin MS, et al: Identification of
herpesvirus-like DNA sequences in DS-associated Kaposis
sarcoma.Science 266:1865-1869, 1994.
69. Soulier J, Grollet L, Oksenhendler E, et al: Kaposis
sarcoma-associated herpesvirus-like DNA sequences in multicentric
Castlemans disease. Blood 86:1276-1280, 1995.
70. Rettig MB, Ma HJ, Vescio RA, et al: Kaposis
sarcoma-associated herpesvirus infection of bone marrow dendritic
cells from multiple myeloma patients. Science 276:1851-1854, 1997.
71. Brooks LA, Wilson A, Crook T: Kaposis sarcoma-associated
herpesvirus (KSHV)/human herpesvirus 8 (HHV8)--a new human tumour
virus. J Pathol 182:262-265, 1997.
72. Pastore C, Gloghini A, Volpe G, et al: Distribution of
Kaposis sarcoma herpesvirus sequences among lymphoid
malignancies in Italy and Spain. Br J Haematol 91:918-920, 1995.
73. Ansari MQ, Dawson DB, Nador R, et al: Primary body cavity-based
AIDS-related lymphomas. Am J Clin Pathol 105:221-229, 1996.
74. Nador RG, Cesarman E, Chadburn A, et al: Primary effusion
lymphoma: A distinct clinicopathologic entity associated with the
Kaposis sarcoma-associated herpesvirus. Blood 88:645-656, 1996.
75. Karcher DS, Dawkins F, Garett CT, et al: Body-cavity-based
non-Hodgkins lymphoma (NHL) in HIV-infected patients: B-cell
lymphoma with unusual clinical immunophenotypic and genotypic
features. Lab Invest 66:70a, 1992.
76. Cesarman E, Chang Y, Moore PS, et al: Kaposis
sarcoma-associated herpesvirus-like DNA sequences in AIDS-related
body-cavity-based lymphomas. N Engl J Med 332:1186-1191, 1995.
77. Gaidano G, Gloghini V, Gattei MF, et al: Association of
Kaposis-sarcoma-associated herpesvirus-positive primary
effusion lymphoma with expression of the CD138/ Synedacan-1 antigen.
Blood 90:4894-4900, 1997.
78. Aboulafia DM, Gown A, Kidd P: High-grade B-cell non-Hodgkins
lymphoma masquerading as T-cell lymphoma in a patient with acquired
immune deficiency syndrome. Am J Dermatopathol 19:66-72, 1997.
79. Horenstein MG, Nador RG, Chadburn A, et al: Epstein-Barr virus
latent gene expression in primary effusion lymphomas containing
Kaposis sarcoma-associated herpesvirus/human herpesvirus-8.
Blood 90:1186-1191, 1997.
80. Said JW, Tasaka T, Takeuchi S, et al: Primary effusion lymphoma
in women: Report of two cases of Kaposis sarcoma herpes
virus-associated effusion-based lymphoma in human immunodeficiency
virus-negative women. Blood 88:3124-3128, 1996.
81. Jenkins K, Opelenick SR, Struzel M, et al: Expression of human
herpesvirus-8-encoded cyclin in primary effusion lymphoma (abstract).
Blood 90(10;suppl 1):135a, 1997.
82. Ballerini P, Giardono G, Gong JZ, et al: Multiple genetic lesions
in acquired immunodeficiency syndrome-related non-Hodgkins
lymphoma. Blood 81:166-176, 1993.
83. De Re V, Carbone A, De Vita S, et al: p53 protein over-expression
and p53 gene abnormalities in HIV-1-related non-Hodgkins
lymphoma. Int J Cancer 56:662-667, 1994.
84. Gaidano G, Parsa NL, Tassi V, et al: In vitro establishment of
AIDS-related lymphoma cell lines: Phenotypic characterization,
oncogene and human suppressor gene lesions, and heterogeneity in
Epstein-Barr virus infection. Leukemia 7:1621-1629, 1993.
85. Ronen D, Rotter V, Reisman D: Expression from the murine p53
promoter is mediated by a factor binding to a downstream
helix-loop-helix recognition motif. Proc Natl Acad Sci USA
86. Gaidano G, Carbone A, Pastore C, et al: Frequent mutations in the
5_ noncoding region in the BCL-6 gene in acquired immunodeficiency
syndrome-related non-Hodgkins lymphoma. Blood 89:3755-3762, 1997.
87. Shiramizu B, Herndier B, Mecker T, et al: Molecular and
immunophenotypic characteristics of AIDS-associated Epstein-Barr
virus-negative, polyclonal lymphoma. J Clin Oncol 10:383-389, 1992.
88. Kaplan LD, Shiramizu D, Herndier B, et al: Influence of molecular
characteristics on clinical outcome in human immunodeficiency
virus-associated non-Hodgkins lymphoma: Identification of a
subgroup with favorable clinical outcome. Blood 85:1727-1739, 1995.
89. Levine AM, Shibata D, Weiss LM, et al: Molecular characteristics
of interdicted/high (I/H) grade lymphoma (NHL) arising in
HIV-positive vs HIV-negative PTS: Preliminary data from a population
(POP)-based study in the county of Los Angeles. Blood 80:259a, 1992.
90. Feigal E, Kipps TJ: Immunoglobulin heavy chain variable region
genes expressed in AIDS-associated monoclonal B-cell lymphoma. Blood
91. Reickmann P, Poli G, Fox CH, et al: Recombinant gp120
specifically enhances tumor necrosis factor-alpha production and Ig
secretion in B lymphocytes from HIV-infected individuals but not from
seronegative donors. J Immunol 147:2922-2927, 1991.
92. Konrad RJ, Kricka LJ, Goodman DB, et al: Brief report:
Myeloma-associated paraprotein directed against the HIV-1 p24 antigen
in an HIV-1 seropositive patient. N Engl J Med 328:1817-1819, 1993.
93. Freedman AR, Scadden DT: Viral activity in early HIV disease.
Curr Opin Hematol 16:19, 1994.
94. Breen EC, Rezai AR, Nakajima K, et al: Infection with HIV is
associated with elevated IL-6 levels and production. J Immunol
95. Emile D, Coumbaras J, Raphael M, et al: Interleukin-6 production
in high-grade B lymphomas: Correlation with the presence of malignant
immunoblasts in acquired immunodeficiency syndrome and in human
immunodeficiency virus-seronegative patients. Blood 80:498-504, 1992.
96. Delecluse HJ, Anagnostopoulous I, Dallenbach M, et al:
Plasmablastic lymphoma of the oral cavity: A new entity associated
with the human immunodeficiency virus infection. Blood 89:1413-1420, 1997.
97. Benjamin D, Knobloch TJ, Dayton MA: Human B-cell interleukin-10:
B-cell lines derived from patients with acquired immunodeficiency
syndrome and Burkitts lymphoma constitutionally secrete large
quantities of interleukin-10. Blood 80:1289-1298, 1992.
98. Rousset F, Garcia E, Defrance T, et al: Interleukin 10 is a
potent growth and differentiating factor for activated B human
lymphocytes. Proc Natl Acad Sci USA 89:1890-1893, 1992.
99. Emilie D, Touitou R, Raphael M, et al: In vivo production of
interleukin-10 by malignant cells in AIDS-lymphomas. Eur J Immunol
100. Masood R, Zhang Y, Bond MW, et al: Interleukin-10 is an
autocrine growth factor for acquired immunodeficiency
syndrome-related B-cell lymphoma. Blood 85:3423-3430, 1995.
101. Wachsman W, Burton D, Tu S, et al: PTHrP is overexpressed in
AIDS-related lymphoma (abstract). J Acquir Immune Defic Syndr Hum
Retrovirol 14:A46, 1997.