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Blood, Vol. 91 No. 3 (February 1), 1998:
pp. 747-755
By
From the Divisions of Pathology and Medical Oncology and AIDS
Program, Centro di Riferimento Oncologico, Istituto Nazionale di
Ricovero e Cura a Carattere Scientifico, Aviano, Italy; the Division of
Internal Medicine, the Department of Medical Sciences, University of
Torino at Novara, Novara, Italy; the Institutes of Pathology and of
Infectious Diseases, Università Cattolica del Sacro Cuore, Roma,
Italy; the Institute of Hematology, University of Perugia, Perugia,
Italy; and the Division of Oncology, the Department of Pathology,
College of Physicians and Surgeons, Columbia University, New York, NY.
This study was aimed at defining the histogenesis of the pathologic
spectrum of acquired immunodeficiency syndrome-related non-Hodgkin's
lymphomas (AIDS-NHL), including AIDS-related small noncleaved cell
lymphoma (AIDS-SNCCL), AIDS-related large noncleaved cell lymphoma
(AIDS-LNCCL), AIDS-related large cell immunoblastic lymphoma
plasmacytoid (AIDS-IBLP), and AIDS-related primary effusion lymphoma
(AIDS-PEL). Forty-six cases of AIDS-NHL were investigated for the
expression pattern of BCL-6, a protein specifically expressed by
germinal center (GC) B-cells, and CD138/syndecan-1 (syn-1), a marker of
post-GC B-cell differentiation. Expression of BCL-6 and syn-1
segregated two major phenotypic patterns among AIDS-NHL: (1) the
BCL-6+/syn-1
ACQUIRED IMMUNODEFICIENCY
syndrome-related non-Hodgkin's lymphomas (AIDS-NHL) represent a
markedly heterogeneous group of lymphomas derived from mature B
cells.1-3 The pathologic spectrum of AIDS-NHL includes
systemic NHL, primary central nervous system lymphomas (PCNSL), and
primary effusion lymphoma (PEL). Systemic AIDS-NHL are histologically
classified into AIDS-related small noncleaved cell lymphoma
(AIDS-SNCCL) and AIDS-related diffuse large cell lymphoma
(AIDS-DLCL).2 Depending on the presence of immunoblastic
features, AIDS-DLCL may be further distinguished into large noncleaved
cell lymphoma (LNCCL) and large cell immunoblastic lymphoma
plasmacytoid (IBLP).1,2,4 AIDS-related PCNSL (AIDS-PCNSL) are represented in all cases by IBLP or LNCCL,5 whereas
AIDS-related PEL (AIDS-PEL) morphologically bridges immunoblastic and
anaplastic features.6-8
The pathologic heterogeneity of AIDS-NHL correlates with the
heterogeneity of the molecular lesions associated with these lymphomas.2,3,9-11 AIDS-SNCCL selectively associates with activation of c-MYC, whereas rearrangements of BCL-6
are restricted to a fraction of AIDS-DLCL. Infection by Kaposi's
sarcoma-associated herpesvirus (KSHV) clusters selectively with
AIDS-PEL,6-8 whereas infection by Epstein-Barr virus (EBV)
occurs at different rates in different AIDS-NHL types.12-15
The histogenetic derivation of the various types of AIDS-NHL has not
been elucidated, although it has been suggested that a fraction of
AIDS-NHL may be related to germinal center (GC) B cells.16
More recently, the study of the histogenesis of mature B-cell neoplasms
has been facilitated by the availability of biologic markers of
distinct subsets of mature B cells. Two such markers are represented by
BCL-6 and CD138/syndecan-1 (syn-1). BCL-6 is a proto-oncogene product
coding for a zinc finger transcriptional repressor which, in the B-cell
lineage, is expressed selectively in GC B-cells.17-21
Notably, animal models have shown that expression of BCL-6 is an
absolute requirement for GC formation and function.22,23 Syn-1 is a proteoglycan belonging to the syndecan
family.24,25 Within the mature B-cell compartment, syn-1 is
not expressed in GC B cells whereas it is expressed in specific subsets
of post-GC B cells, including immunoblasts and plasma
cells.26-28
In an attempt to elucidate the histogenesis of AIDS-NHL, we have
investigated the expression pattern of BCL-6 and syn-1 throughout the
pathologic spectrum of these lymphomas as well as in nonneoplastic lymphoid tissues. The results indicate that AIDS-NHL may be subdivided into two main phenotypic categories corresponding to the GC
(BCL-6+/syn-1 Neoplastic samples.
This study included AIDS-NHL samples from 40 patients (27 systemic
AIDS-NHL, 8 AIDS-PCNSL, and 5 AIDS-PEL). Pathological specimens were
classified according to the Working Formulation for NHL and the revised
European-American classification of lymphoid neoplasms (REAL).4 AIDS-PEL were classified on the basis of their
clinico-pathological and virological (eg, KSHV positivity)
characteristics.6,7 Tissues from systemic AIDS-NHL and
AIDS-PCNSL were fixed in Bouin solution or neutral buffered formalin.
In most cases, a portion of unfixed tissue was snap frozen in liquid
nitrogen and stored at Cell lines.
In vitro established AIDS-NHL cell lines were also studied. The
detailed characterization of these cell lines has been reported previously. The cell lines HBL-6, BC-1 (purchased from American Type
Culture Collection [ATCC], Rockville, MD), BC-2 (purchased from
ATCC), BC-3, BCBL-1, and CROAP-2 were derived from
AIDS-PEL.29-33 Four AIDS-PEL cell lines (HBL-6, BC-1, BC-2,
and CROAP-2) carry EBV infection, whereas two AIDS-PEL cell lines (BC-3
and BCBL-1) are EBV Nonneoplastic samples.
Nonneoplastic lymph node samples from seven human immunodeficiency
virus (HIV)-seropositive patients with persistent generalized lymphadenopathy (PGL) were also included in the study. All PGL samples
carried EBV DNA sequences without evidence of monoclonal EBV episomes,
as assessed by Southern blot analysis. The histopathologic pattern of
PGL samples was predominantly represented by hyperplastic changes of
the lymphoid follicles.
Immunohistochemical studies and analysis of BCL-6 and syn-1
expression.
Deparaffinized and cryostat sections were used for immunophenotyping
and lineage assignment of AIDS-NHL and PGL samples. Sources and
specificities of the antibodies used in this study have been reported
in detail previously.29 Immunohistochemistry was performed by the avidin-biotin-peroxidase complex (ABC-px) or alkaline
phosphatase anti alkaline phosphatase (APAAP) methods as previously
described.34,35
Two-color staining.
Multiple immunohistochemical staining was performed to detect BCL-6
plus syn-1 in selected PGL samples. Formalin fixed paraffin-embedded tissue sections were first treated twice for 5 minutes in 1 mmol/L EDTA
buffer pH 8.0 and immunostained with anti-BCL-6 MoAb by the APAAP method35,37 using naphthol AS-MX phosphate along with Fast Blue BB salt (Sigma Chemical Co, St Louis, MO) for
the development of alkaline phosphatase; subsequently, sections were
treated twice for 5 minutes in citrate buffer (pH 6) in a microwave
oven to denature bound antibody molecules and to inactivate alkaline
phosphatase present in the APAAP complex. Finally, sections were
incubated overnight at 4°C with anti-syn-1 MoAb and immunostained by
the APAAP method using naphthol AS-MX phosphate along with Fast Red TR salt (Sigma) for the development of alkaline
phosphatase.
Analysis of viral infection.
All samples of AIDS-NHL and PGL included in this study were subjected
to determination of tumor infection by EBV and KSHV, according to
previously reported strategies.7,29 EBER in situ hybridization (ISH) studies were performed on AIDS-NHL and PGL samples
to identify the nature and distribution of EBV-infected cells. ISH
studies were performed on Bouin or formalin fixed paraffin-embedded tissues or cell block sections, as previously described.16
Analysis of c-MYC genetic lesions.
Genomic DNA of selected AIDS-NHL cases and of AIDS-PEL cell lines was
extracted by the "salting out" technique.38 Analysis of c-MYC genetic lesions was performed by a combination of
molecular approaches, including both Southern blot studies and
mutational analysis, as previously reported.9
Genetic studies of BCL-6.
The configuration of the BCL-6 locus was investigated by
Southern blot analysis using previously reported assays.10
The presence of mutations of BCL-6 5 Expression of BCL-6, syn-1, and LMP-1 among systemic AIDS-NHL.
The panel of 27 systemic AIDS-NHL biopsies included 11 cases of
AIDS-SNCCL and 16 cases of AIDS-DLCL (Table
1). Within the AIDS-DLCL group, 7 cases
were classified as AIDS-LNCCL and 9 cases were classified as AIDS-IBLP.
Immunologic/genotypic analyses showed a B-cell origin in all cases
(data not shown). Consistent with previous reports,9-16
infection of the tumor clone by EBV was detected in 6 of 11 AIDS-SNCCL,
2 of 7 AIDS-LNCCL, and 6 of 9 AIDS-IBLP cases (Table 1). As previously
observed,6,9-11 all samples were devoid of KSHV infection,
whereas structural alterations of c-MYC were detected in 100%
(8 of 8) of AIDS-SNCCL and in a minority (2 of 8) of AIDS-DLCL cases
(Table 1).
Expression of BCL-6, syn-1, and LMP-1 among AIDS-PCNSL.
The panel of AIDS-PCNSL biopsies (n = 8) displayed in all cases a
morphology consistent with AIDS-DLCL (Table 3). Four cases were
classified as AIDS-LNCCL and four cases were classified as AIDS-IBLP.
All AIDS-PCNSL were EBV+ and KSHV
Expression of BCL-6, syn-1, and LMP-1 in AIDS-PEL.
The panel of AIDS-PEL, all positive for KSHV, included 5 primary cases
and 6 AIDS-PEL-derived cell lines (Table 3). Three primary AIDS-PEL
and 4 AIDS-PEL cell lines carried the EBV genome (Table 3).
Immunologic/genotypic analyses showed a B-cell origin in all primary
samples and cell lines (not shown). Structural alterations of
c-MYC were absent in all cases (Table 3).
Expression of BCL-6 and syn-1 in PGL.
A panel of 7 PGL samples was used to define the expression pattern of
BCL-6 and syn-1 in nonneoplastic lymph nodes. In all PGL samples
tested, a strong and specific reactivity for BCL-6 was detectable
within the follicular GC (see Fig 4 for
representative results). The mantle and paracortical zones were mostly
negative with the exception of several small lymphoid cells and rare
isolated large cells, presumably represented by T cells.21
In the same lymph node samples, the anti-syn-1 MoAb showed a strong
cytoplasmic and membrane staining of plasma cells, but no reactivity in
other cell populations. Syn-1+ plasma cells were
consistently present in the interfollicular areas. In addition, a
variable number of plasma cells was also found in follicular GC and
their surrounding mantle zones. Thus, in the context of PGL, individual
lymphoid cells expressed selectively either BCL-6 or syn-1. In
particular, when considering PGL areas in which BCL-6+
cells and syn-1+ cells were simultaneously detectable,
double-labelling experiments ruled out the co-expression of BCL-6 and
syn-1 by the same cell (Fig 4).
The results presented in this study indicate that expression of BCL-6
and syn-1 segregates two major phenotypic subsets of AIDS-NHL, ie,
BCL-6+/syn-1
Submitted October 2, 1997;
accepted October 28, 1997.
The following reagent was obtained through the AIDS Research and
reference Reagent Program, Division of AIDS, NIAID, NIH, Bethesda, MD:
BCBL-1 SP from Drs Michael McGrath and Don Ganem. BC-3 was the kind
gift of Dr E. Cesarman (Cornell University, New York, NY). LAM
C3+ was the kind gift of Dr S. Roncella (IST, Genova,
Italy).
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|
Abstract
Introduction
pattern associated with
AIDS-SNCCL and AIDS-LNCCL; (2) the BCL-6
Abstract
80°C. Samples of AIDS-PEL were collected
under sterile conditions during standard diagnostic procedures and
treated according to a standard regimen used at the Division of
Pathology of the Centro di Riferimento Oncologico.
noncoding regions was
tested in a 740-bp fragment within BCL-6 intron 1 and in
BCL-6 exon 1 (fragments E1.10, E1.11, E1.12 according to
Migliazza et al
95% of mutations
detected in B-cell NHL of the immunocompetent host and
AIDS-NHL.
