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Blood, Vol. 93 No. 8 (April 15), 1999:
pp. 2749-2751
CORRESPONDENCE
Detection of Human Herpesvirus-8 and Epstein-Barr Virus DNA in
Primary Intraocular Lymphomas
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LETTER |
To the Editor:
Two herpesviruses, human herpesvirus-8 (HHV-8) and Epstein-Barr virus
(EBV), are able to contribute to lymphomagenesis in humans.1 HHV-8 is documented not only in a strong
association with Kaposi's sarcoma, but also in a high percentage of
primary effusion lymphoma, Castleman's disease, and multiple myeloma. Most recently, HHV-8 genome has been associated with primary central nervous system lymphoma (PCNSL) of patients with and without acquired immunodeficiency syndrome (AIDS).2 However, the role of
HHV-8 in the pathogenesis of PCNSL remains controversial.3
In vitro, EBV efficiently transforms human B lymphocytes, causing them
to proliferate continuously.1 EBV and the latent membrane
protein can be detected in tumor cells of almost all AIDS-related PCNSL.
Primary intraocular lymphoma, a component of PCNSL, is a large
B-cell, non-Hodgkin's lymphoma.4 The disease is
aggressive, with a 5-year survival rate of less than 33%. In the
past 15 years, the incidence of the tumor has increased dramatically,
coincident with the AIDS epidemic. We analyzed HHV-8 and EBV DNA
sequences in 13 primary intraocular lymphomas with and without
AIDS. Of the 13 specimens, 5 were whole eyes, 1 was a vitreoretinal
biopsy, and 7 were vitrectomy samples. Slides with cells from 2 noninfectious uveitis were also used as control.
The 13 patients (6 Americans and 7 Europeans) include 2 AIDS
patients (1 American and 1 French patient): the American
patient developed an early lymphoma and the French patient had an
advanced stage, aggressive lymphoma.5 At the time at which
the 13 specimens were obtained, only 3 (2 eyes and 1 vitrectomy
specimen) had a proven diagnosis of PCNSL involving the eyes. Of the 5 eyes, 2 had received radiation therapy. Nine patients were being
investigated for possible primary intraocular lymphoma and underwent
diagnostic procedures (7 vitrectomies, 1 vitreoretinal biopsy, and 1 enucleation). The eye of the American AIDS patient was diagnosed with
primary intraocular lymphoma at necropsy.
On examination of the histology and cytology slides of the 13 cases, only 6 specimens (3 of 5 eyes, 3 of 7 vitrectomies, and 0 of
1 vitreoretinal biopsy) showed typical large B-cell lymphoma (Fig
1). Of the 7 cases without obvious
typical lymphoma cells, 5 (4 vitreous and 1 vitreoretinal biopsy) were
also available for cytokine analysis and had high vitreous
interleukin-10 (IL-10) levels with high ratios of IL-10 to IL-6,
suggesting primary intraocular lymphoma.6
Finally, 2 cases (1 eye with AIDS and 1 eye that had received
radiation) showed only a few atypical lymphocytes in
the subretinal space. The microdissected morphologically
suspicious abnormal cells in all 13 cases had presented a rearrangement
in FR3A of the IgH gene that confirmed the diagnosis of primary
intraocular lymphoma (Fig 2).5
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| Fig 1.
Microphotograph showing typical intraocular lymphoma
(arrow) in the subretinal space (A; case no. 8; insert, higher
magnification of the lymphoma cells; R, retina; C, choroid) and a
vitrectomy specimen (B; case no. 7; arrowheads, normal lymphocytes).
(Original magnifications: A, hematoxylin & eosin, ×200, insert,
×400; B, Diff-Quick, ×400.)
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| Fig 2.
PCR amplification showing rearrangement of third
framework region in the VH region of heavy chain Ig gene in
the lymphoma cells of all 13 cases, HHV-8 genome in 4 cases (lanes 3 and 4, AIDS patients; lanes 7 and 9, non-AIDS patients), and EBV genome
in 1 case (lane 4, AIDS with lymphoma involving the orbit and eye).
Lanes 1 through 13, cases no. 1 through 13, respectively; lane 14, negative control; lane 15, positive control.
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Lymphoma cells of these 13 specimens, normal lymphocytes of 2 vitrectomy specimens, and the 2 uveitic cases were microdissected from
either deparaffinized sections or cytological slides.5 DNA
of these cells were extracted for polymerase chain reaction (PCR)
amplification and Southern hybridization for HHV-8 or EBV genome.
Multiple primers and positive and negative controls were also used to
confirm the results.
Four cases were positive for HHV-8 (Fig 2). Two were the
AIDS-related lymphoma eyes and 2 were non-AIDS vitreous samples. The 2 non-AIDS patients were diagnosed with suspicious primary intraocular
lymphoma both clinically and cytopathologically. These 4 positive
patients included 2 Americans and 2 French. Three samples (1 American AIDS eye and 2 vitreous specimens) were also
microdissected to obtain nonmalignant cells (retinal and optic
nerve cells from the eye and infiltrating lymphocytes from the other 2 vitreous specimens) for identification of the viral genome. HHV-8 DNA
was undetectable in the inflammatory or ocular cells without tumor infiltration in the 3 early cases with primary intraocular
lymphoma. EBV DNA was detected in only 1 of the 13 samples,
ie, the French AIDS eye with a diffuse lymphoma.
This investigation has shown HHV-8 DNA sequences in 2 of 2 AIDS-related
intraocular lymphoma and in 2 of 11 non-AIDS intraocular lymphoma. The
HHV-8 genome encodes homologs of cyclin D1, a cell-cycle control
element; certain cytokines, regulators, and receptors; and Bcl-2, an
antiapoptotic protein.7 The HHV-8 sequence also contains
homologs of vial IRFs that may be involved in modulating both HHV-8
replication and HHV-8-associated tumorigenicity.8 The
viral genome could therefore contribute to cellular growth and
transformation through activation of the cell cycle. Although the virus
could simply be an innocent passenger in this lymphoma, the so-far
ubiquitous association of HHV-8 with AIDS-related PCNSL and relatively
low incidence in non-AIDS patients, plus most other lymphoproliferative
disorders in both AIDS and non-AIDS patients, strongly favor a causal
role. In this series, HHV-8 was detected in 100% (2 cases: 1 American
and 1 French) of AIDS-related intraocular lymphoma and in 1 of the 6 European and 1 of the 5 American, non-AIDS cases. Furthermore, HHV-8
DNA was found only in the neoplastic cells. We speculate that the
nonneoplastic B lymphocytes in those AIDS patients who eventually
develop primary intraocular lymphoma may be infected with HHV-8, HIV,
or other viruses into the eye, in which ultimate transformation into
malignant cells occurs. Another possibility may be the promotion of a
second oncogenic virus.
Nine EBV genes are known to express as proteins in EBV-transformed
B-lymphoblastoid cell lines.9 One of the latent membrane proteins of the EBV engages members of the tumor necrosis factor receptor-associated molecules and then activates NF- B-driven expression of multiple viral and cellular genes. However,
only certain subsets of AIDS-non Hodgkin's lymphoma appear to be
EBV-related, although a high frequency of EBV is reported in
AIDS-PCNSL.10 Our data do not show a strong association
between EBV and primary intraocular lymphoma, suggesting that EBV may
not play a major role in the early development of primary
intraocular lymphoma with or without AIDS.
Chi-Chao Chan
De Fen Shen
Scott M. Whitcup
Robert B. Nussenblatt
National Eye Institute
National Institutes of
Health
Bethesda, MD
Phuc LeHoang
Francois G. Roberge
Nathalie Cassoux
Department of
Ophthalmology
Pitie-Salpetriere Hospital
Paris,
France
Carl Herbort
Department of Ophthalmology
Lausanne,
Switzerland
Zhengping Zhuang
National Cancer
Institute
National Institutes of Health
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