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NEOPLASIA
From the Divisions of Pathology and Medical Oncology A,
Centro di Riferimento Oncologico, Istituto Nazionale Tumori, IRCCS,
Aviano, Italy; the Institute of Pathology, Università Cattolica
del Sacro Cuore, Rome, Italy; the Division of Internal Medicine,
Department of Medical Sciences, "Amedeo Avogadro" University of
Eastern Piedmont, Novara, Italy; and the Institute of Cancer Genetics,
Columbia University, New York, NY.
This study was aimed at defining the histogenesis of the pathologic
spectrum of lymphoma arising in the context of human immunodeficiency virus (HIV) infection. Toward this aim, 87 AIDS-related non-Hodgkin lymphomas (AIDS-NHL) and 16 Hodgkin lymphomas arising in
HIV+ patients (HIV-HL) were comparatively analyzed for the
expression pattern of several B-cell histogenetic markers, including
BCL-6 (expressed by centroblasts and centrocytes), MUM1/IRF4 (expressed by late centrocytes and post-germinal center [GC] B cells), and CD138/syn-1 (expressed by post-GC B cells). Expression of MUM1, BCL-6,
and syn-1 segregated 3 major phenotypic patterns among AIDS-NHL and
HIV-HL: (1) the
BCL-6+/MUM1 Acquired immunodeficiency syndrome-related
non-Hodgkin lymphoma (AIDS-NHL) represents a significant source of
morbidity and mortality among persons infected with human
immunodeficiency virus (HIV).1,2 The pathologic spectrum
of AIDS-NHL includes systemic AIDS-NHL, primary central nervous system
lymphoma (AIDS-PCNSL), primary effusion lymphoma (AIDS-PEL), and
plasmablastic lymphoma (AIDS-PBL) of the oral cavity.1-7
Systemic AIDS-NHL is histologically classified into AIDS-related
Burkitt lymphoma (AIDS-BL), AIDS-related diffuse large cell lymphoma
(AIDS-DLCL), and AIDS-related immunoblastic lymphoma
(AIDS-IBL).4,5 AIDS-PCNSL is classified into AIDS-DLCL and
AIDS-IBL.2,4,5,8 Hodgkin lymphoma (HL) has also been reported in HIV-infected patients, though this disease does not confer
a diagnosis of AIDS.6,7,9
In recent times, the field of B-cell lymphoma histogenesis has
progressed rapidly owing to the increasing availability of well-defined
histogenetic markers. Genotypic markers of B-cell lymphoma histogenesis
include mutations of immunoglobulin and BCL-6 genes
somatically acquired at the time of B-cell transit throughout the
germinal center (GC).10-13 Phenotypic markers are represented by expression of the BCL-6 protein, which is restricted to
GC B cells, and, at least in the context of immunodeficiency-related lymphomas, expression of CD138/syndecan-1 (syn-1), a proteoglycan clustering with late stages of B-cell maturation.1,12-16
Recently, MUM1/IRF4 (for multiple myeloma-1/interferon regulatory
factor-4) has been added to the panel of phenotypic markers available
for the characterization of B-cell lymphoma
histogenesis.12 MUM1 was discovered because of its
involvement in the t(6;14)(p25;q32) translocation of multiple myeloma,
which causes the juxtaposition of the MUM1 gene, mapping at 6p25, to
the IgH locus on 14q32.17 MUM1 is a
lymphocyte-specific member of the interferon regulatory factor (IRF)
family of transcription factors, also known as ICSAT (for interferon
consensus sequence binding protein for activated T cells) and Pip (for
PU.1 interaction partner).18 Recent studies have shown
that MUM1 expression may denote the final step of intra-GC B-cell
differentiation and subsequent steps of B-cell maturation toward plasma
cells.18-21 To refine the histogenesis of AIDS-NHL and
HIV-HL, we compared the expression pattern of MUM1, BCL-6, and syn-1
protein throughout the pathologic spectrum of these lymphomas.
Neoplastic samples
Systemic AIDS-NHL was classified according to the revised
European-American classification of lymphoid neoplasms.22
All AIDS-PCNSL cases were classified as DLCL or IBL. AIDS-PCNSL cases contained a mixture of large noncleaved cells and large cells; immunoblastic plasmacytoid were classified separately as
DLCL/IBL.23 AIDS-PEL, which morphologically bridges
immunoblastic and anaplastic features,24-26 was classified
on the basis of the peculiar clinicopathologic and virologic (eg,
Kaposi sarcoma-associated herpesvirus [KSHV] positivity)
characteristics of the lymphoma.24,25 AIDS-PBL was
classified in accordance to the morphologic (plasmablastic appearance),
immunophenotypic (expression of plasma cell-associated markers VS38c
and syn-1 in the absence of common B-cell-associated surface
antigens), and clinical features (presentation in the oral cavity and
jaw) of the disease.27 The CD30+,
CD45 Tissues 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 Nonneoplastic samples
Immunohistochemical studies Immunohistochemistry was performed by the avidin-biotin-peroxidase complex or alkaline phosphatase antialkaline phosphatase (APAAP) method.31,32The expression of MUM1 was investigated with an affinity-purified polyclonal goat antibody (ICSAT/M-17) specific for the MUM1 protein17 (Santa Cruz Biotechnology, Santa Cruz, CA). The M-17 antibody reacts with MUM1 of mouse, rat, and human origins, though it does not cross-react with other members of the IRF family proteins. Syn-1 expression was assessed using the B-B4 monoclonal antibody (mAb)33 (Serotec, Oxford, United Kingdom). The BCL-6 protein was detected by the PG-B6 mAb (Dakopatts A/S, Glostrup, Denmark).16 CD10 staining, detected by the 56C6 mAb (Novocastra Laboratories, Newcastle upon Tyne, United Kingdom), was also studied in cases of systemic AIDS-NHL and AIDS-PCNSL. All antigens were tested on paraffin-embedded tissue sections or cytospin preparations. For MUM1, BCL-6, and CD10 assessment, paraffin-embedded sections were treated in a microwave oven at 250 W for 30 minutes in EGTA solution (1 mM, pH 8) (for MUM1 and BCL-6) or citrate buffer (pH 6) (for CD10). Immunostaining for MUM1, BCL-6, and CD10 was performed on an automated immunostainer (Nexes; Ventana Medical Systems, Tucson, AZ) according to a modified version of the manufacturer's protocols. Immunostaining for syn-1 was performed by using the APAAP method.32 The percentage of antigen-positive neoplastic cells was assigned to one of the following categories: 0%, less than 10%, 10% to 25%, 25% to 50%, 50% to 75%, and more than 75%. Only definite and unambiguous staining on unequivocal malignant cells was accepted as positive. Negative control experiments were performed by pre-absorbing the anti-MUM1 antibody with a 5-fold weight excess of blocking peptide (Santa Cruz Biotechnology) overnight at 4°C and then carrying out immunostaining as described above. None of the negative control sections was immunostained. All the antibodies were also applied to frozen tissues from a representative subset of cases of AIDS-NHL for control purposes. In selected cases, the reactivity pattern of the ICSAT/M-17 polyclonal antibody was compared with that of MUM1p,20 a mAb raised against the human MUM1/IRF4 protein (kindly provided by Prof B. Falini, Institute of Hematology and Internal Medicine, University of Perugia, Italy). The reactivity pattern of each antibody recognizing MUM1/IRF4 was generally superimposable. 2-color staining Multiple color immunohistochemical stainings were performed to detect MUM1 plus BCL-6 in selected AIDS-NHL and PGL cases and to detect MUM1 plus syn-1 in PGL cases. Formalin-fixed, paraffin-embedded tissue sections were first immunostained with anti-BCL-6 or anti-syn-1 antibody by the APAAP method using naphthol AS-MX phosphate along with Fast Red (for BCL-6) and Fast Blue BB salt (for syn-1) 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 the alkaline phosphatase. Then, sections were immunostained with anti-MUM1 by using a DAB or a Fast Red detection kit (Ventana Medical Systems).Analysis of viral infection All cases included in this study were subjected to determination of tumor infection by Epstein-Barr virus (EBV) and KSHV.25,34,35 In the case of EBER+ cases, immunostaining for LMP1 was performed with an LMP1-specific antibody (Dakopatts A/S, Glostrup, Denmark), as described above. The percentage of LMP1+ neoplastic cells was assigned to one of the following categories: 0%, less than 10%, 10% to 25%, 25% to 50%, 50% to 75%, and more than 75%.Genetic studies of BCL-6 The presence of BCL-6 mutations was tested in a 740-bp fragment containing 95% or more mutations detected in B-cell NHL of the immunocompetent host and AIDS-NHL.36
Expression of MUM1, BCL-6, and syn-1 in nontransformed lymphoid tissue A panel of 10 PGL cases was used to define the expression pattern of MUM1, BCL-6, and syn-1 in nonneoplastic lymph nodes and tonsils of HIV-infected cases. Two-color staining and serial sections were also used to compare the immunoreactivity of these antibodies (Figure 1). Expression of BCL-6 selectively clustered with centroblasts and centrocytes within the follicular GC, whereas B cells of the mantle and paracortical zones scored negative (Figure 1A). Conversely, the expression of syn-1 clustered with plasma cells and was absent in all other cell populations (Figure 1 A-B). Syn-1-positive plasma cells were localized in the medullary cords, in the interfollicular areas, and, in variable proportion, also in follicular GC and their surrounding mantle zones.
In all cases tested, reactivity for MUM1 was detectable in a fraction
of GC cells and in all plasma cells (Figure 1A-C). Conversely, lymphoid
cells of the mantle zone were usually MUM1 Systemic AIDS-NHL The panel of 47 systemic AIDS-NHL cases included 19 AIDS-BL, 16 AIDS-DLCL, and 12 AIDS-IBL (Table 1). As expected,2,5 infection of the tumor clone by EBV was detected in 10 of 19 cases of AIDS-BL, 3 of 16 cases of AIDS-DLCL, and 10 of 12 cases of AIDS-IBL (Table 1). All cases were devoid of KSHV infection (not shown).Results of the expression pattern of MUM1, BCL-6, syn-1, LMP1, and CD10
are reported in Table 1. Representative examples are shown in Figure
2. Expression of MUM1 was detected in 17 of 47 (36%) cases of systemic AIDS-NHL and clustered with AIDS-IBL (12 of 12 cases, 100%) (Figure 2A), whereas it was restricted to 3 of 16 (19%) cases of AIDS-DLCL (Figure 2B). Occasional MUM1+
tumor cells could be detected in 2 of 19 (11%) cases of AIDS-BL (Table
1). Expression of BCL-6 staining was detected in 33 of 47 (70%) cases
of systemic AIDS-NHL (Table 1), clustered with AIDS-BL (19 of 19 cases,
100%) (Figure 2C) and AIDS-DLCL (14 of 16 cases, 87%), whereas it was
consistently negative in cases of AIDS-IBL (Table 1). As previously
observed,1 the expression of BCL-6 protein among cases of
systemic AIDS-NHL occurred both in the presence and the absence of
mutations of the BCL-6 gene (Table 1). Expression of syn-1
was detected in 7 of 47 (15%) cases of systemic AIDS-NHL (Table 1),
selectively associated with AIDS-IBL (7 of 12 cases, 58%), and
consistently negative in cases of AIDS-BL and AIDS-DLCL (Table 1).
Expression of CD10 occurred in 21 of 45 (47%) cases of systemic
AIDS-NHL. All but one case of CD10+ systemic AIDS-NHL (20 of 21 cases, 95%) expressed BCL-6 and stained negative for both MUM1
and syn-1. Expression of CD10 clustered with AIDS-BL (17 of 18 cases,
94%), whereas it was restricted to sporadic cases of AIDS-DLCL (3 of
15 cases, 20%) and was negative in all but one case of IBL.
Among cases of systemic AIDS-NHL carrying EBV infection (23 cases), the expression of LMP1 was detected in 7 cases (Table 1). Most cases of LMP1+ systemic AIDS-NHL were morphologically classified as having AIDS-IBL (6 of 7 cases, 86%), expressed both MUM1 and syn-1 (5 of 7 cases, 71%), and stained negative for BCL-6 (7 of 7 cases, 100%) (Table 1). Conversely, the expression of LMP1 was consistently absent in all cases of EBV+ systemic AIDS-NHL expressing BCL-6 (Table 1). AIDS-PCNSL All cases of AIDS-PCNSL were EBV+ and KSHV (not shown). The expression profile of MUM1, BCL-6,
syn-1, and LMP1 in cases of AIDS-PCNSL is summarized in Table 2.
Expression of MUM1 was detected in 15 of 22 (68%) cases of AIDS-PCNSL,
including 10 of 12 (83%) cases of AIDS-IBL, 2 of 3 (67%) cases of
AIDS-DLCL, and 3 of 7 (43%) cases of AIDS-DLCL/IBL (Table 2).
Expression of BCL-6 was detected in 8 of 22 (36%) cases of AIDS-PCNSL
(Table 2), including 3 of 3 cases of AIDS-DLCL and 5 of 7 cases of
AIDS-DLCL/IBL. Conversely, the expression of BCL-6 was scored negative
in all cases of AIDS-PCNSL classified as AIDS-IBL (Table 2). Expression
of BCL-6 protein among cases of AIDS-PCNSL occurred both in the
presence and in the absence of mutations of the BCL-6 gene
(Table 2). Expression of syn-1 was detected in 12 of 22 (54%) cases of
AIDS-PCNSL (Table 2), including 9 of 12 (75%) cases of AIDS-IBL and 3 of 7 (43%) cases of AIDS-DLCL/IBL (43%). Conversely, syn-1 scored
negative in cases of AIDS-PCNSL classified as AIDS-DLCL (Table 2). The expression of CD10 scored negative in all 9 tested cases (1 with DLCL
morphology, 5 with IBL morphology, and 3 with DLCL/IBL morphology).
Expression of LMP1 was detected in 17 of 22 cases of AIDS-PCNSL. All cases of LMP1+ AIDS-PCNSL were morphologically classified as having AIDS-IBL or LDLCL/IBL. Most of these cases expressed MUM1 (13 of 17, 76%) or syn-1 (10 of 17, 59%) and stained negative for BCL-6 (13 of 17, 76%) (Table 2). The expression of LMP1 was negative in all cases of AIDS-PCNSL with AIDS-DLCL morphology. AIDS-PEL The panel of AIDS-PEL cases, all positive for KSHV, included 11 cases (Table 3). Seven cases of AIDS-PEL carried the EBV genome.
The expression profile of MUM1, BCL-6, syn-1, and LMP1 in AIDS-PEL is summarized in Table 3. Cases of AIDS-PEL were found to express MUM1 (11 of 11, 100%) and syn-1 (10 of 11, 91%) but scored negative for BCL-6 protein expression (10 of 10, 100%) (Table 3). Mutations of the BCL-6 gene occurred in 5 of 11 (45%) tested cases. Of the 7 cases of AIDS-PEL carrying EBV infection, the expression of LMP1 was restricted to a small proportion of cells (Table 3). AIDS-PBL The panel of AIDS-PBL cases numbered 7 (Table 3). Six cases of AIDS-PBL carried the EBV genome. All cases were devoid of KSHV infection (not shown).The expression profile of MUM1, BCL-6, syn-1, and LMP1 in AIDS-PBL is summarized in Table 3. All cases of AIDS-PBL were found to express the MUM1 and syn-1 antigens (7 of 7, 100%). Conversely, all AIDS-PBL cases scored negative for BCL-6 protein and LMP1 expression (Table 3). HIV-HL The panel of HIV-HL numbered 16. Reed-Sternberg (RS) cell infection by EBV was scored positive in 13 of 16 (81%) cases. RS cells and their variants expressed MUM1 and syn-1 in all HIV-HL (16 of 16 cases, 100%), which were representative of the entire pathologic spectrum of classic HIV-HL (Table 4, Figure 3). Conversely, the expression of BCL-6 by RS cells was negative in the overwhelming majority of HIV-HL cases (15 of 16 cases, 94%), whereas one case of HIV-HL displayed a low proportion of BCL-6+ RS cells (less than 10%) (Table 4). All HIV-HL cases carrying EBV infection scored positive for LMP1 (Table 4).
Comparison between the major phenotyic patterns and pathologic subtypes The combination of MUM1, BCL-6, and syn-1 segregated 3 major phenotypic patterns among AIDS-NHL and HIV-HL (Table 5, Figure 4): (1) the BCL-6+/MUM1/syn-1 pattern,
which reflects GC centroblasts and MUM1 centrocytes and
associates with CD10 expression in a subset of cases; (2) the
BCL-6/MUM1+/syn-1 pattern,
which reflects late GC/early post-GC B cells; and (3) the
BCL-6/MUM1+/syn-1+ pattern, which
reflects post-GC B cells. These major phenotypic patterns display
preferential associations with specific clinicopathologic categories of
AIDS-NHL and HIV-HL. Thus, the
BCL-6+/MUM1/syn-1 pattern
associates with most cases of AIDS-BL (17 of 19) and systemic AIDS-DLCL
(12 of 16). Conversely, the
BCL-6/MUM1+/syn-1+ pattern
associates with most cases of AIDS-PEL (10 of 10), AIDS-PBL (7 of 7),
HIV-HL (15 of 16), and AIDS-IBL (14 of 24) arising systemically or
localized primarily to the central nervous system. Finally, the
BCL-6/MUM1+/syn-1 pattern
associates with the remaining fraction of AIDS-IBL (8 of 24). An
additional phenotypic pattern the
BCL-6+/MUM1+/syn-1 patternis
occasionally detected in systemic AIDS-NHL and AIDS-PCNSL.
The phenotypic patterns identified above also displayed preferential
associations with the virologic features of the tumors. In fact, among
systemic AIDS-NHL and AIDS-PCNSL, expression of LMP1 preferentially
associates with the
BCL-6
The aim of this study was to refine the histogenesis of the
pathologic spectrum of AIDS-NHL and HIV-HL and to identify novel criteria for the classification and diagnosis of these disorders. By
using a combination of several histogenetic markers, namely MUM1,
BCL-6, and syn-1, we report 3 major phenotypic subsets of AIDS-NHL and
HIV-HL In reactive lymphoid tissues, the phenotypic patterns identified by
MUM1, BCL-6, and syn-1 map to lymph node areas that are populated by B
cells at different stages of differentiation. Comparison of the
topography of MUM1 and BCL-6 within the GC reveals that the expression
of BCL-6 occurs immediately after a B cell enters the GC and is
maintained until GC exit (Figure 4), whereas MUM1 positivity begins
only at the centrocyte stage and is maintained during post-GC
maturation (Figure 4).12,19,20 In this respect, most B
cells within the GC, including all centroblasts and almost all
centrocytes, express the
BCL-6+/MUM1 The phenotypic profiles displayed by AIDS-NHL and HIV-HL, combined with
the distribution of MUM1, BCL-6, and syn-1 among normal B-cell subsets,
point to a histogenetic model of these neoplasms. According to this
model (Figure 4), AIDS-BL and systemic AIDS-DLCL express the
BCL-6+/MUM1 Besides correlating with morphology, the phenotypic patterns identified
by MUM1, BCL-6, and syn-1 correlate with the virologic features of
AIDS-NHL and HIV-HL. In fact, expression of the LMP1 antigen among
EBV-infected AIDS-NHL and HIV-HL associates preferentially with
BCL-6-/MUM1+/syn-1+ cases that
exhibit morphologic features consistent with an advanced stage of
B-cell maturation (eg, IBL) (Tables 1, 2). Conversely, LMP1 expression
is generally absent in
BCL-6+/MUM1 The expression pattern of MUM1, BCL-6, and syn-1 bears implications for
AIDS-NHL diagnosis. In fact, distinct pathologic and molecular
categories of AIDS-NHL selectively associate with different expression
patterns of the histogenetic markers used in this study. Remarkably,
the association between phenotype and histology appears to be
independent of the primary site of the disease, as exemplified by the
fact that both systemic AIDS-IBL and AIDS-PCNSL with IBL morphology
share the same BCL-6
We thank Barbara Canal, Paola Ceolin, and Ivana Zanette for excellent technical assistance in immunohistochemistry experiments and in situ hybridization studies. We also thank Prof B. Falini (Institute of Hematology and Internal Medicine, University of Perugia, Italy) for the gift of the mAb MUM1p.
Submitted July 26, 2000; accepted October 2, 2000.
Supported in part by Istituto Superiore di Sanità, II Programma nazionale di ricerca sull'AIDS-Progetto Patologia clinica e terapia dell'AIDS, Rome; by Ministero della Sanita', RF 1999, Rome; by the Associazione Italiana per la Ricerca sul Cancro, Milan, Italy; and by National Institutes of Health grant CA-37295.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Antonino Carbone, Division of Pathology, Centro di Riferimento Oncologico, Istituto Nazionale Tumori, IRCCS, via Pedemontana Occidentale, Aviano I-33081, Italy.
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Top
Abstract
Introduction
80°C. Cases 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.
