The Role of Infectious Agents in B-cell Lymphomas
Moderators: Dr. Miguel A. Piris and Dr. Steven H. Swerdlow
Section 1 -
Kaposi's Sarcoma Herpesvirus and Lymphoid Malignancies
Daniel M. Knowles
In 1989, Knowles and colleagues and later other investigators described lymphomatous effusions,
usually occurring in the absence of a solid tissue mass, in homosexual men with AIDS. These unusual B
cell neoplasms were referred to as "body cavity-based lymphomas" because of their distinctive clinical
The Kaposi's sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus-8 (HHV-8), was
identified in 1994 by Chang, Moore, Cesarman, Knowles and co-workers. This virus has been shown to be
etiologically related to the development of Kaposi's sarcoma (KS) and also to be associated with
multicentric Castleman's disease (MCD). Cesarman, Knowles and colleagues demonstrated that KSHV is
preferentially associated with the "body cavity-based lymphomas" and showed that these KSHV-containing
"body cavity-based lymphomas" exhibit a unique constellation of clinical, morphologic, immunologic, and
molecular characteristics, thus constituting a distinct clinicopathologic entity. Knowles designated
these lesions primary effusion lymphomas (PEL) to distinguish them from all other lymphomas occurring in
the body cavities.
Primary effusion lymphomas comprise less than 3% of all AIDS-associated non-Hodgkin's
lymphomas; they occur even less commonly in the general population. Among HIV-positive individuals, they
occur almost entirely in severely immunocompromised homosexual men, median age 40 years. Approximately
60% of HIV-positive individuals who develop PEL have severe opportunistic infections and 40% have KS.
These patients also occasionally develop MCD. The tumor initially presents as a lymphomatous effusion in
the pleural, abdominal, and/or pericardial cavities and remains restricted to one or more body cavities
in more than 80% of cases. Patients in whom PEL presents as a solid lesion usually later develop an
effusion. These patients have a poor prognosis with a median survival of approximately five months.
Primary effusion lymphoma occurs very uncommonly in HIV-negative individuals, primarily
men, median age 74 years. Most of the HIV-negative individuals who develop PEL hail from a KSHV
seroprevalent region; they often have coexisting KS and/or MCD. These individuals are generally less
immunocompromised than HIV-positive individuals who develop PEL. The lesion nearly always presents
initially as an effusion in one or more body cavities, without extension to solid organs. Some
HIV-negative individuals who develop PEL survive several months to years.
In Wright-Giemsa-stained, air-dried cytospin preparations, PEL cells display
cytomorphologic features bridging immunoblastic and anaplastic large cell lymphoma. The malignant cells
are generally large, sometimes extremely so, and are round or ovoid to polygonal. They contain moderate
to abundant amphophilic to deeply basophilic cytoplasm and nuclei which may be large, round and regular
or highly irregular and pleomorphic. The nuclei possess coarsely reticular chromatin and one to four
large prominent nucleoli. Some of the cells may be bi- or multinucleated and resemble Reed-Sternberg
cells; others may possess wreath-like nuclei, reminiscent of anaplastic large cell lymphoma. Mitotic
figures are usually numerous. The PEL cells usually appear more uniform in size and shape in cell block
preparations. Here, they appear to possess moderate to abundant eosinophilic cytoplasm and round to
slightly irregular nuclei which contain one or more prominent nucleoli.
The immunophenotypic and molecular characteristics of PELs occurring in HIV-positive and
in HIV-negative patients are essentially the same. One notable distinction is that the EBV genome is
present in the majority of PELs occurring in HIV-positive individuals, but not in PELs occurring in
HIV-negative individuals. Approximately 90% of the tumors express CD45, 100% express various
activation-associated antigens, and 70% lack B cell-associated antigens and/or immunoglobulin. Nearly
all PELs exhibit clonal immunoglobulin gene rearrangements, indicative of a clonal B-cell derivation.
CD138 expression and evidence of immunoglobulin gene hypermutation suggests that PELs represent a
post-germinal center stage of B cell differentiation close to the plasma cell stage. Oncogenes and tumor
suppressor genes, i.e., C-MYC, BCL-1, BCL-2, BCL-6, RAS, and p53, which are commonly altered in various
categories of non-Hodgkin's lymphoma, remain in the wild type configuration in PELs, although nearly 60%
of PELs exhibit BCL-6 gene mutations.
Occasional, primarily HIV-positive, persons develop KSHV-positive solid tissue large cell
immunoblastic lymphomas unassociated with a lymphomatous effusion during the course of their disease.
Chadburn, Knowles and colleagues found that KSHV-positive solid lymphomas are virtually indistinguishable
from PELs based on morphology, immunophenotype, immunogenotype, and molecular characteristics, although
they may express B cell-associated antigens and immunoglobulin slightly more often than do PELs. Also,
patients with KSHV-positive solid lymphomas may have a better survival. Thus, KSHV-containing solid
lymphomas appear to represent a solid variant of PEL; Chadburn and Knowles have designated these lesions
The virtually invariable occurrence of KSHV in PELs suggests that this virus is necessary
for their development. PELs are latently infected with KSHV; latency allows the virus to remain in the
infected cell, ensuring that the cell survives and will not be recognized as infected by the host immune
system. KSHV contributes to lymphomagenesis by subverting the host-cell molecular signaling machinery to
deregulate cell growth and survival. KSHV expresses a selected repertoire of genes in PEL cells that
encode viral proteins which play important roles in lymphomagenesis. Deregulation of the NFK
B pathway is an important strategy used by KSHV to promote lymphoma cell survival; the viral protein
vFLIP is essential for this process.
Gene expression profiling has demonstrated that gene expression patterns can distinguish
KSHV-positive PELs from KSHV-negative malignant lymphomas and have shown that PELs exhibit a profile
lying between EBV-associated immunoblastic lymphoma and terminally differentiated multiple myeloma.
Cesarman, Chadburn, Knowles and colleagues demonstrated that about 500 genes, including apoptosis
regulators, cell cycle regulators, transcriptional factors, and signal transduction regulators are
differentially expressed between KSHV-positive PELs and KSHV-negative lymphomatous effusions and 40
genes, four of which are regulators of the mitogen-activated protein kinase pathway, are differentially
expressed between KSHV-positive, EBV positive and KSHV-positive, EBV negative PELs. Thus, alterations in
the mitogen-activated protein kinase pathway may act as a co-factor in PEL development.
KSHV also has been found in association with plasmablastic lymphoma associated with MCD
and germinotropic lymphoproliferative disorders occurring in HIV-negative individuals. The plasmablastic
lymphomas differ from PELs in being EBV negative and lacking immunoglobulin gene mutations; they are
thought to derive from na´ve IgM lambda expressing B cells rather than terminally differentiated B cells.
- Boulanger E, Gerard L, Gabarre J, Molina J-M, Rapp C, Abino J-F, Cadranel J,
Chevret S., Oksenhendler E: Prognostic factors and outcome of human herpesvirus 8-associated
primary effusion lymphoma in patients with AIDS. J Clin Oncol 23:4372-4380, 2005.
- Cesarman E, Chang Y, Moore PS, Said JW, Knowles DM: Kaposi's sarcoma-associated
herpesvirus-like DNA sequences in AIDS-related body-cavity-based lymphomas. N
Engl J Med 332:1186-1191, 1995.
- Cesarman E, Nador R, Aozasa K, Delsol G, Said JW, Knowles DM: Kaposi's sarcoma- associated
herpesvirus in non-AIDS related lymphomas occurring in body cavities. Am J Pathol 149:53-57, 1996.
- Chadburn A, Hyjek E, Mathew S, Cesarman E, Said J, Knowles DM: KSHV- positive solid
lymphomas represent an extracavitary variant of primary effusion lymphoma. Am J Surg Path 28:1401-1416, 2004.
- Chang Y, Cesarman E, Pessin MS, Lee F, Culpepper J, Knowles DM, Moore PS: Identification of
herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma. Science
- DePond W, Said JW, Tasaka T, de Vos S, Kahn D, Cesarman E, Knowles DM, Koeffler HP: Kaposi's
sarcoma-associated herpesvirus and human herpesvirus 8 (KSHV/HHV8)-associated lymphoma of the
bowel: report of two cases in HIV- positive men with secondary effusion lymphomas. Am J Surg Pathol 21:719-724, 1997.
- Du MQ, Diss TC, Liu H, Ye H, Hamoudi RA, Cabecadas J, Dong HY, Harris NL, Chan JK, Rees JW,
Dogan A, Isaacson PG: KSHV- and EBV-associated germinotropic lymphoproliferative disorder. Blood 100:3415-3418, 2002.
- Dupin N, Diss TL, Kellam P, Tulliez M, Du MQ, Sicard D, Weiss RA, Isaacson PG, Boshoff C: HHV-8 is
associated with a plasmablastic variant of Castleman disease that is linked to HHV-8-positive
plasmablastic lymphoma. Blood 95:1406-1412, 2000.
- Fan W, Bubman D, Chadburn A, Harrington WJ Jr, Cesarman E, Knowles
DM: Distinct subsets of primary effusion lymphoma can be identified based on their cellular gene
expression profile and viral association. J Virol 79:1244-1251, 2005.
- Klein U, Gloghini A, Gaidano G, Chadburn A, Cesarman E, Dalla-Favera R, Carbone A: Gene expression
profile analysis of AIDS-related primary effusion lymphoma (PEL) suggests a plasmablastic derivation and
identifies PEL-specific transcripts. Blood 101:4115-4121, 2003.
- Knowles DM, Inghirami G, Ubriaco A, Dalla-Favera R: Molecular genetic analysis of three
AIDS-associated neoplasms of uncertain lineage demonstrates their B-cell derivation and the possible
pathogenetic role of the Epstein-Barr virus. Blood 73:792-799, 1989.
- Mesri EA, Cesarman E, Arvanitakis L, Rafi S, Moore MAS, Posnett DN, Knowles DM, Asch AS:
Human herpesvirus-8/Kaposi's sarcoma-associated herpesvirus is a new transmissible virus that
infects B cells. J Exp Med 183:2385-2390,
- Moore PS, Boschoff C, Weiss RA, ChangY: Molecular mimicry of human cytokine and cytokine
response pathway genes by KSHV. Science 274:1739-1744, 1996.
- Nador RG, Cesarman E, Chadburn A, Dawson DB, Ansari MQ, Said J, Knowles DM: Primary
effusion lymphoma: a distinct clinicopathologic entity associated with the Kaposi's
sarcoma-associated herpes virus. Blood 88:645-656, 1996.
- Nador RG, Cesarman E, Knowles DM, Said JW: Herpes-like DNA sequences in a body- cavity based
lymphoma in an HIV-negative patient. N Engl J Med 33:943, 1995.
- Schulz TF: The pleiotropic effects of Kaposi's sarcoma herpesvirus. J
Path 208:187- 198, 2006.
- Wilson KS, McKenna RW, Kroft SH, Dawson DB, Ansari Q, Schneider NR: Primary effusion
lymphomas exhibit complex and recurrent cytogenetic abnormalities. Br J
Haematol 116:113-121, 2002.