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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 3 (August 1), 1998:
pp. 1011-1019
The Molecular and Phenotypic Profile of Primary Central Nervous
System Lymphoma Identifies Distinct Categories of the Disease and Is
Consistent With Histogenetic Derivation From Germinal
Center-Related B Cells
By
Luigi Maria Larocca,
Daniela Capello,
Alessandro Rinelli,
Simonetta Nori,
Andrea Antinori,
Annunziata Gloghini,
Antonella Cingolani,
Anna Migliazza,
Giuseppe Saglio,
Sophie Cammilleri-Broet,
Martine Raphael,
Antonino Carbone, and
Gianluca Gaidano
From the Institute of Pathology, Catholic University of the Sacred
Heart, Rome; Division of Internal Medicine, Department of Medical
Sciences, University of Torino at Novara, Novara; Institute of
Infectious Diseases, Catholic University of the Sacred Heart, Rome;
Division of Pathology, INRCCS-Centro di Riferimento Oncologico, Aviano;
Department of Clinical and Biological Sciences, University of Torino,
Orbassano-Torino, Italy; Division of Oncology, Department of Pathology,
College of Physicians & Surgeons, Columbia University, New York, NY;
Laboratoire de Neuropathologie, Pitié Salpètrière,
Paris; Service d'Hematologie Biologique, Hopital Avicenne, Bobigny,
Universitè de Paris XIII, Paris, France.
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ABSTRACT |
Primary central nervous system lymphoma (PCNSL) is a major cause of
morbidity and mortality among human immunodeficiency virus (HIV)-infected individuals. The precise histogenetic derivation and the
molecular pathogenesis of PCNSL is poorly understood. In an attempt to
clarify the histogenesis and pathogenesis of these lymphomas, 49 PCNSL
(26 acquired immunodeficiency syndrome [AIDS]-related and 23 AIDS-unrelated) were analyzed for multiple biologic markers, which are
known to bear histogenetic and pathogenetic significance for mature
B-cell neoplasms. PCNSL associated frequently (50.0%) with mutations
of BCL-6 5 noncoding regions, which are regarded as a
marker of B-cell transition through the germinal center (GC).
Expression of BCL-6 protein, which is restricted to GC B cells
throughout physiologic B-cell maturation, was detected in 100%
AIDS-unrelated PCNSL and in 56.2% AIDS-related cases. Notably, among
AIDS-related PCNSL, expression of BCL-6 was mutually exclusive with
expression of Epstein-Barr virus (EBV)-encoded latent
membrane protein (LMP)-1 and, with few exceptions, also of BCL-2. All
but one PCNSL expressed hMSH2, which among mature B cells selectively
stains GC B cells. These data suggest that PCNSL may be frequently
related to GC B cells and may be segregated into two major biologic
categories based on the expression pattern of BCL-6, LMP-1, and BCL-2.
BCL-6+/LMP-1 /BCL-2 PCNSL
occur both in the presence and in the absence of HIV infection and
consistently display a large noncleaved cell morphology. Conversely, BCL-6/LMP-1+/BCL-2+ PCNSL
are restricted to HIV-infected hosts and are represented by lymphomas
with immunoblastic features. These data are relevant for the
pathogenesis and histogenesis of PCNSL and may be helpful to segregate
distinct biologic and prognostic categories of these lymphomas.
© 1998 by The American Society of Hematology.
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INTRODUCTION |
PRIMARY CENTRAL NERVOUS system lymphoma
(PCNSL) is a major cause of morbidity and mortality among individuals
infected by the human immunodeficiency virus (HIV).1-4 The
relative risk of PCNSL among HIV-infected hosts approximates 1,000 when
compared with the HIV-negative population.3,5,6 Although
PCNSL has been formally considered rare in HIV
hosts, recent epidemiologic evidence suggests that the incidence of the
disease in apparently immunocompetent individuals has been increasing
dramatically during the last two decades.7 Virtually all
acquired immunodeficiency syndrome (AIDS)-related and the majority of
AIDS-unrelated PCNSL derive from B cells, and in all cases present as
clinically aggressive tumors.1-4,8 Histologically, the
overwhelming majority of PCNSL is represented by diffuse large B-cell
lymphomas (DLCL). Depending on the presence of immunoblastic plasmocytoid features, PCNSL may be further distinguished into large
noncleaved cell lymphoma (LNCCL) and immunoblastic plasmocytoid lymphoma (IBPL).8,9
The histogenetic derivation of PCNSL is poorly understood.
Because the central nervous system (CNS) lacks lymph nodes and lymphatics, it has been hypothesized that PCNSL may originate from B
cells derived from systemic lymphoid tissues and normally trafficking
in and out of the CNS.2,4 The molecular pathogenesis of
PCNSL is also uncertain, and existing evidence is mainly restricted to
the role of Epstein-Barr virus (EBV). Infection by EBV occurs in all
AIDS-related PCNSL, whereas it is negative in AIDS-unrelated cases.9-15 AIDS-related PCNSL frequently express the
EBV-encoded latent membrane protein-1 (LMP-1) antigen, which, in turn,
upregulates the expression of BCL-2.16 Because PCNSL are
consistently monoclonal, however, it is conceivable that EBV is not
sufficient for tumor development.
BCL-6 is a proto-oncogene coding for a zinc finger transcriptional
repressor which, in the B-cell lineage, is expressed selectively by
germinal center (GC) B cells.17-21 Notably, animal models
have demonstrated that expression of BCL-6 is an absolute requirement for physiologic GC formation and function.22,23 Genetic
alterations of BCL-6 occur frequently among systemic B-cell
non-Hodgkin's lymphomas (NHL) and are represented by gross
rearrangements and mutations of the 5 noncoding regions of the
gene.17-20,24 Among systemic B-NHL, rearrangements of
BCL-6 cluster with B-cell DLCL.25 Conversely,
mutations of the BCL-6 5 noncoding regions occur frequently and selectively in B-cell NHL arising from GC or post-GC B
cells.24,26-28 On this basis, BCL-6 mutations are regarded
as a marker of B-cell transition through the GC.
In an attempt to clarify the histogenesis and pathogenesis of PCNSL, we
have investigated the genetic status and expression pattern of BCL-6 in
AIDS-related and AIDS-unrelated PCNSL. Results were compared with
morphology, genetic profile of other cancer-related genes, and
expression status of several immunophenotypic markers. We report that
the molecular and phenotypic profile of PCNSL is consistent with an
origin from GC B cells in most cases. Furthermore, the expression
pattern of BCL-6, LMP-1, and BCL-2 segregates two major biologic
categories of PCNSL.
BCL-6+/LMP-1/BCL-2
PCNSL consistently display a large noncleaved cell morphology and occur
both in the presence and in the absence of HIV infection. Conversely,
BCL-6/LMP-1+/BCL-2+ PCNSL
are represented by lymphomas with immunoblastic features and are mainly
restricted to HIV-infected hosts.
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MATERIALS AND METHODS |
Tumor samples.
This study was based on tissue samples of a total of 49 cases of PCNSL,
including 26 AIDS-related and 23 AIDS-unrelated cases. Thirty cases (16 AIDS-related and 14 AIDS-unrelated) were derived from a retrospective
series observed at the Institute of Pathology, Catholic University of
the Sacred Heart, Rome, Italy. Nine cases (six AIDS-related and three
AIDS-unrelated) had been referred to the Neuropathological Laboratory
(Pitié Salpètrière, Prof J.J. Hauw). The remaining
cases had been referred to multiple different institutions in Europe.
In all instances, the specimen was collected at diagnosis before
starting radio and/or chemotherapy. For morphologic diagnosis,
hematoxylin-eosin and Giemsa staining was performed after 4% neutral
buffered formalin or Bouin solution fixation and paraffin embedding.
Pathologic specimens were classified according to the Working
formulation for NHL29 and to a revised European-American
classification of lymphoid neoplasms (REAL
classification).30 All PCNSL were classified as DLCL
according to the REAL classification.30 As previously reported,9,31,32 PCNSL cases were further subdivided into two histologic subtypes, ie, LNCCL and IBPL. In this report, the definition of LNCCL was based on the predominance (>80%) of cells resembling large noncleaved cells. The definition of IBPL was based on
the predominance (>80%) of cells resembling large cells, immunoblastic plasmocytoid. PCNSL cases containing a mixture of large
noncleaved cells and large cells, immunoblastic plasmocytoid were
classified separately as LNCCL/IBPL. In all cases, the cytologic definition of large noncleaved cell and large cell, immunoblastic plasmocytoid was based on previously reported criteria.29
Immunohistochemistry.
For immunophenotypic studies, the avidin-biotin-peroxidase complex
(ABC-px) method was performed on paraffin sections using a commercially
available kit (Dako LSAB 2; Dakopatts, Glostrup, Denmark) and the
following commercially available monoclonal antibodies (MoAbs): CD3,
CD20, CD30, CD45RA, CD45RO, CD57, CD68, CD74, anti- and -
immunoglobulin (Ig) light chains.
Immunostaining with BCL-2 MoAb (clone bcl2/100/D5; Ylem, Avezzano,
Italy) and BCL-6 MoAb (clone PG-B6 directed against the amino terminal
portion of the human BCL-6 product; obtained from Brunangelo Falini,
Institute of Hematology, University of Perugia, Perugia,
Italy)33 was performed using the alkaline antialkaline phosphatase (APAAP) methods, as previously described31
and/or the Dako Catalyzed Signal Amplification system (Dako K
1500; Dakopatts). In brief, sections were cut at a thickness of 4 µm,
mounted on glass slides coated with 3% aminopropyltrithoxysilane, and
allowed to air dry overnight (ON) at room temperature (RT). After
dewaxing in xylene and rehydration in a series of ethanols, the
sections were immersed in 1 mmol/L EDTA buffer pH 8.0 and pretreated
twice for 5 minutes at 750 W in a microwave oven (MWO) (MWO Philips M901; Philips, Eindhoven, The Netherlands; maximum power
900 W). After cooling down at RT, sections were rinsed in 0.05 mol/L
Tris-HCl buffer at pH 7.6 and incubated with primary antibodies ON at
4°C. Biotinylated antimouse Ig were then applied for 15 minutes,
followed by streptavidin-biotin-horseradish peroxidase complex.
Sections were washed, incubated with biotinylated tyramide for 15 minutes, washed again, and incubated with streptavidin-horseradish
peroxidase. After washing, diaminobenzidine (DAB) substrate was used as
chromogen. Finally, the slides were counterstained with hematoxylin and
mounted in permount. In negative controls, the primary antibody was
substituted with nonimmune mouse serum.
The LMP-1 antigen was detected on paraffin sections using the
APAAP method and a pool of four anti-LMP-1 MoAbs (CS 1-4; Dakopatts) after enzymatic digestion with pronase (Biomeda Co, Foster City, CA).
The hMSH2 protein was detected by using an anti-hMSH2 MoAb (clone FE11;
Oncogene Science, Cambridge, MA) after MWO pretreatment in
sodium-cytrate buffer (0.01 mol/L sodium cytrate monohydrate at pH
6.0). An ABC-px method was used with DAB as the chromogen. In negative
controls, the primary antibody was substituted with nonimmune mouse
serum. Nonneoplastic lymphoid samples from lymph node, spleen, tonsil,
and appendix were also investigated for the expression of hMSH2
protein.
The percentage of
BCL-6+/LMP-1+/BCL-2+, or
hMSH2+ neoplastic cells was assigned to one of the
following categories: 0, less than 10%; 10% to 25%; 25% to 50%;
50% to 75%; and greater than 75%.
Two-color staining.
Multiple immunohistochemical staining was performed to detect LMP-1
plus BCL-6 protein in selected AIDS-related PCNSL following a
previously reported strategy.31
In situ hybridization (ISH).
ISH analysis of EBV-encoded small RNAs (EBERs) is a highly sensitive
method for detecting latent EBV infection in paraffin-embedded tissue
sections, including autopsy material. For each case tested, paired
paraffin sections were mounted on silanized slides and EBER ISH studies
were performed by using a cocktail of
fluorescein-isothiocyanate-labeled oligonucleotides complementary to
the two nuclear EBER (1/2) RNAs, according to the instructions of the
supplier (Dakopatts). In selected cases, ISH mRNA studies of Ig light
chains were performed on paraffin-embedded tissue sections to assess
tumor clonality as previously reported.34
DNA extraction.
For cryopreserved PCNSL samples, genomic DNA was purified by cell lysis
followed by digestion with proteinase K, "salting out"
extraction, and precipitation by ethanol.35 For PCNSL
samples available only as paraffin-embedded blocks, DNA extraction was performed as previously reported.36
Oligonucleotides.
All of the oligonucleotides used in this study were synthesized
by the solid phase triester method. The sequence of oligonucleotides corresponding to BCL-6 exon 1-intron 1 boundary region
(fragments E1.10, E1.11, and E1.12) was as follows: E1.21B,
5-CTCTTGCCAAATGCTTTG-3, and E1.24,
5-TAATTCCCCTCCTTCCTC-3 (for fragment E1.10); E1.23, 5-AGGAAGGAGGGGAATTAG-3, and IP1.6,
5-AAGCAGTTTGCAAGCGAG-3 (for fragment E1.11); IP1.7,
5-TTCTCGCTTGCAAACTGC-3, and E1.26, 5-CACGATACTTCATCTCATC-3 (for fragment
E1.12).24 The oligonucleotides used as primers for the
mutational analysis of c-MYC first exon-first intron boundary
region have been reported previously.37 The oligonucleotides used as primers for the analysis of EBV and human herpesvirus type 8 (HHV-8) DNA sequences, as well as BCL-2
rearrangements, have also been described.36,37
Analysis of mutations of BCL-6 5 noncoding regions.
Analysis of mutations of BCL-6 5 noncoding regions was
performed by a combination of polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and DNA direct sequencing. PCR-SSCP was performed as previously reported.24,26
Briefly, 100 ng of genomic DNA, 10 pmol of each primer, 2.5 µmol/L
deoxynucleotides triphosphate (dNTPs), 1 µCi of
[ -32P]deoxycytidine triphosphate (dCTP)
(Amersham, Rainham, UK; specific activity, 3,000 Ci/mmol; 1 Ci = 37 giga becquerel), 10 mmol/L Tris-HCl (pH 8.8), 50 mmol/L KCL, 1 mmol/L MgCl2, 0.01% gelatin, 0.5 U AmpliTaq polymerase
(Perkin-Elmer, Norwalk, CT) were mixed in a final volume of 10 µL.
Thirty cycles of denaturation (94°C), annealing (annealing
temperatures were optimized for each pair of primers), and extension
(72°C) were performed in a temperature controller (DNA Thermal
Cycler, Perkin-Elmer). Samples were heated at 95°C for 5 minutes,
chilled on ice, and immediately loaded (3 µL) onto a 6%
acrylamide-tris-borate EDTA buffer gel containing 10% glycerol. Gels
were run at 8 W for 12 to 15 hours at RT, fixed in 10% acetic acid,
air dried, and analyzed by autoradiography using an intensifying screen
for 6 to 72 hours. For DNA sequencing of BCL-6 5
noncoding regions, a unique PCR product encompassing fragments E1.10,
E1.11, and E1.12 (nucleotides +404 to +1142) was amplified by primers
E1.21B and E1.26. Direct sequencing of the amplified PCR fragment was
performed with appropriate primers using a commercially available kit
(ThermoSequenase, Amersham Life Sciences, Amersham).
[-33P]-labeled terminator dideoxynucleotides were
included in the sequencing mixture. Both strands were sequenced for
each DNA fragment analyzed.
Molecular analysis of clonality and other genetic lesions.
The organization of the BCL-6 locus was analyzed by Southern
blot analysis hybridizing BamHI and Xba I digested DNA
to the human BCL-6 probes Sac 4.0 and Sac 0.8, which detect the
cluster of BCL-6 rearrangements of NHL.25 The
status of the c-MYC locus was analyzed by a combination of
Southern blot analysis and mutational studies of c-MYC
exon1-intron1 border, as previously reported.37 Analysis of
BCL-2 rearrangements was performed as described
previously.38 PCR analysis of EBV and HHV-8 infection were
also performed as reported previously.36
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RESULTS |
Characterization of the tumor panel.
All cases of AIDS-related and AIDS-unrelated PCNSL were histologically
classified as B-DLCL and had a B-cell phenotype in paraffin sections,
as demonstrated by tumor cell positivity for CD45RA, CD20, and CD74 and
negativity for CD45RO, CD3, and CD57. Molecular and/or ISH
studies demonstrated the monoclonality of all cases tested (n = 47; not
shown).
Characterization of BCL-6 molecular alterations in PCNSL.
All cases of AIDS-related and AIDS-unrelated PCNSL were investigated
for the presence of mutations of the 5 noncoding regions of
BCL-6. Mutations of BCL-6 5 noncoding regions
were investigated by PCR-SSCP analysis of three PCR fragments
encompassing a 740-bp region containing the mutational hot spot of
BCL-6 among NHL. This region has been previously shown to
harbor  95% of BCL-6 mutations occurring in both AIDS-related
and AIDS-unrelated systemic NHL.24,26 The PCNSL samples
investigated displayed a total of 29 PCR-SSCP variants, which were
unique to individual tumor samples (for representative results, see
Fig 1A and B). As described previously,
cases of PCNSL were considered positive for mutation when one ore more
PCR-SSCP displayed a variant pattern, which could not be ascribed to a
population polymorphism. On this basis, mutations of BCL-6 were
scored positive in 24 of 48 (50.0%) PCNSL, including 11 of 26 (42.3%)
AIDS-related and 13 of 22 (59.1%) AIDS-unrelated cases
(Table 1). In selected cases, mutations
were further characterized by DNA sequencing analysis (for
representative results, see Fig 1C and D). The characteristics of
BCL-6 mutations in PCNSL are summarized in
Table 2.
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| Fig 1.
Genetic analysis of BCL-6
5 mutations in PCNSL by PCR-SSCP (A and B) and DNA
direct sequencing (C and D). (A and B): Representative results obtained
for PCR products E1.10 (A) and E1.11 (B) are shown. Samples of PCNSL
are indicated at the top of each lane by a numbered code. A positive
control (POS), represented by a tumor sample known to harbor
BCL-6 5 mutations, as well as a normal (N) sample,
represented by a lymphoblastoid cell line, are also included for each
PCR-SSCP fragment shown. Samples were scored positive when their
migration pattern differed from the normal control and the migration
abnormalities could not be ascribed to population polymorphisms. Among
the PCNSL samples shown, cases scored as positive included cases 3, 14, and 11 (for PCR product E1.10); 8, 28, and 47 (for PCR product E1.11).
(C and D): Nucleotide sequencing analyses of BCL-6
5 mutations in PCNSL (cases 14, 43, and 47). The sequence
of each PCNSL case is matched either to the sequence of a normal
control (N) displaying germline BCL-6 alleles (D) or to the
sequence of a PCNSL sample harboring mutations at a different site (C).
The position of mutations is indicated by the nucleotide number of the
corresponding BCL-6 germline sequence (the first nucleotide of
the BCL-6 cDNA was arbitrarily chosen as position +1).
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Gross rearrangements of BCL-6 were investigated in selected
cases (n = 18; nine AIDS-related and nine AIDS-unrelated) for which
sufficient cryopreserved tissue was available. No rearrangement of
BCL-6 was observed among the cases tested (Table 1).
Characterization of other genetic lesions.
Infection by EBV was detected in 26 of 26 (100%) AIDS-related PCNSL
and was negative in all AIDS-unrelated PCNSL (Table 1). Among
AIDS-related PCNSL, ISH studies demonstrated that EBV infection was
harbored by the neoplastic cell population (not shown). All cases of
AIDS-related and AIDS-unrelated PCNSL were devoid of rearrangements of
BCL-2 and infection by HHV-8 (Table 1). Finally, all tested
cases (n = 18; 9 AIDS-related and 9 AIDS-unrelated) were devoid of
molecular alterations of c-MYC, including both gross
rearrangements and mutations of the regulatory regions of the
proto-oncogene (Table 1).
Expression of BCL-6, LMP-1, and BCL-2 in AIDS-related PCNSL.
Results are summarized in Table 3. All
AIDS-related PCNSL carried EBV infection of the tumor clone. Expression
of LMP-1 was detected in seven of 16 (43.7%) cases. In cases scored
positive, both the membrane surface and the cytoplasm of the neoplastic cells stained positive for LMP-1 (Fig 2).
All LMP-1+ PCNSL also expressed BCL-2
(Fig 3), while all LMP-1
cases failed to express BCL-2. Expression of BCL-6 was detected in 9 of
16 (56.2%) AIDS-related PCNSL. Positivity for BCL-6 was nuclear and
displayed a microgranular pattern (Fig 4).
The majority of BCL-6+ cases (7 of 9) failed to express
LMP-1 and BCL-2. On this basis, two major phenotypic profiles could be
identified among AIDS-related PCNSL, ie,
BCL-6+/LMP-1/BCL-2
and BCL-6/LMP-1+/BCL-2+.
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| Fig 2.
LMP-1 expression in a case of AIDS-related PCNSL (DLCL).
The microphotograph shows that the tumor is polymorphous and
predominantly consists of large tumor cells displaying an
immunoblastic-plasmacytoid morphology. LMP-1 positivity is evident as
cytoplasmic staining in some large tumor cells. Paraffin-embedded
tissue section, APAAP immunostaining, hematoxylin counterstain.
Original magnification × 630.
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| Fig 3.
BCL-2 protein expression in a case of AIDS-related PCNSL
(DLCL). The microphotograph shows that the tumor consists of large tumor cells with immunoblastic morphology. BCL-2 positivity is manifested as cytoplasmic staining in several tumor cells.
Paraffin-embedded tissue section, ABC-px immunostaining and tyramide
amplification, hematoxylin counterstain. Original magnification × 250.
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| Fig 4.
BCL-6 protein expression in a case of AIDS-related PCNSL
(DLCL). The microphotograph shows that the tumor is relatively
monomorphous and predominantly consists of large tumor cells displaying
a large noncleaved cell morphology. Several tumor cells display the
characteristic nuclear positivity for BCL-6. Paraffin-embedded tissue
section, APAAP immunostaining, hematoxylin counterstain. Original
magnification × 250.
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The phenotypic profile displayed by each individual AIDS-PCNSL was
compared with the morphologic features of the tumors, which had been
assessed independently without knowledge of the results of phenotypic
studies. Based on the absence or presence of a predominance (>80%)
of tumor cells with immunoblastic features (see Materials and Methods
for details), cases were classified as LNCCL or IBPL. Seven of seven
(100%) cases displaying the
BCL-6+/LMP-1/BCL-2
phenotype were classified as LNCCL (Table 3). Conversely, five of seven
(71.0%) cases displaying the
BCL-6/LMP-1+/BCL-2+
phenotype were classified as IBPL (Table 3).
Two cases of AIDS-related PCNSL (cases 15 and 16; Table 3) were found
to express BCL-6, LMP-1, and BCL-2. However, double-staining studies
ruled out the coexpression of BCL-6 and LMP-1 by the same neoplastic
cell (Fig 5). These two AIDS-related PCNSL
were composed of an admixture of immunoblasts and tumor cells
displaying an LNCCL morphology and were classified separately as
LNCCL/IBPL. When referring to the updated Kiel
classification,39 these two cases were consistent with the
diagnosis of centroblastic polymorphic lymphomas.
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| Fig 5.
AIDS-related PCNSL (DLCL). Two-color staining. (A) In
this microphotograph, several tumor cells exhibit nuclear staining
(blue) for BCL-6 and few cells show a strong cytoplasmic and membrane staining (reddish) for LMP-1. No coexpression of both markers by the
same tumor cell is detectable. (B) Microphotograph of a different field
in which there is a prevalence of LMP-1+ cells with few
BCL-6+ nuclei. No coexpression is detectable.
Paraffin-embedded tissue section, no counterstain. Original
magnification × 400.
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Expression of BCL-6, LMP-1, and BCL-2 in AIDS-unrelated PCNSL.
Results are summarized in Table 3. All AIDS-unrelated PCNSL were devoid
of EBV infection and, consequently, did not express LMP-1 (Tables 2 and
3). Expression of BCL-6 was detected in 14 of 14 (100%) AIDS-unrelated
PCNSL. Positivity for BCL-6 was nuclear and displayed a microgranular
pattern (not shown). Expression of BCL-2 was restricted to 2 of 14 cases (14.3%). All AIDS-unrelated PCNSL were histologically classified
as LNCCL.
Comparison between BCL-6 protein expression and mutation of BCL-6
5 noncoding regions in PCNSL.
Similiar to systemic lymphomas of HIV-infected
individuals,31,32 expression of BCL-6 protein was found to
occur both in the presence and in the absence of mutations of
BCL-6 5 noncoding regions. When considering cases
investigated for both mutations and protein expression of BCL-6,
mutations of BCL-6 5 noncoding regions occurred in 10 of
22 (45.4%) PCNSL expressing the BCL-6 protein, including 4 of 9 (44.4%) AIDS-related PCNSL and 6 of 13 (46.2%) AIDS-unrelated PCNSL.
However, because the immunohistochemistry technique used for BCL-6
protein detection does not allow quantitation of the cellular levels of
the protein, we were unable to assess variations, if any, of the BCL-6
expression levels in PCNSL harboring BCL-6 mutations as
compared with cases devoid of mutations.
Expression of hMSH2 in AIDS-related and AIDS-unrelated PCNSL.
hMSH2 is a DNA mismatch repair enzyme located in the nucleus and
involved in the control of fidelity of genomic
replication.40 Expression of hMSH2 has been studied
extensively in epithelial tissues and cancers, whereas its expression
pattern in normal and neoplastic lymphoid tissues is
unknown.41-44 Evidence obtained by one of us (L.M.L,
unpublished observation) had suggested that hMSH2 expression among
mature B-cell subsets clusters with GC cells, thus prompting our
analysis of this protein among PCNSL.
Immunoreactivity for the anti-hMSH2 MoAb was scored using the criteria
described above (see Materials and Methods).
Figure 6 shows that hMSH2 is a nuclear
located protein that in normal mature lymphoid tissues is selectively
expressed by follicular GC B cells; the mantle, paracortical, and
marginal zones score negative for hMSH2 expression with the exception
of isolated large cells (Fig 6A through D).
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| Fig 6.
hMSH2 expression in reactive secondary B-cell follicle in
lymphnode (A), spleen (B), appendix (C), and palatine tonsil (D). hMSH2
is a nuclear located protein selectively expressed by follicular germinal center B cell; the mantle, paracortical, and marginal zones
appear hMSH2 negative with the exception of large secondary blasts that
are crossing the mantle. (E) AIDS-related PCNSL; (F) AIDS-unrelated
PCNSL. Most neoplastic cells show a nuclear staining pattern with
anti-hMSH2 MoAb. Paraffin-embedded tissue section, ABC-px
immunostaining, hematoxylin counterstain. Original magnification × 100 (A), (B), × 250 (C through F).
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Among PCNSL, hMSH2 protein was expressed by 29 of 30 (96.7%) tested
cases, including 16 of 16 (100%) AIDS-related and 13 of 14 (92.8%)
AIDS-unrelated cases. The staining pattern was nuclear and of moderate
intensity (Fig 6E).
| |
DISCUSSION |
The aim of this study was to characterize the histogenesis and
pathogenesis of the clinicopathologic spectrum of PCNSL, including AIDS-related and AIDS-unrelated cases. The results indicate that PCNSL
frequently associate with molecular and phenotypic features consistent
with GC B-cell phenotype, suggesting that a large fraction of PCNSL may
be histogenetically related to GC B cell. Differential expression of
BCL-6, BCL-2, and LMP-1 segregates distinct phenotypic patterns, which
preferentially associate with specific morphologic variants of the
disease. These findings may bear implications for the classification
and diagnosis of PCNSL.
Our molecular analysis indicates that mutations of the 5
noncoding regions of BCL-6 represent the most frequent
proto-oncogene lesion presently detectable among PCNSL. The relevance
of this finding is threefold. First, mutations of BCL-6
5 noncoding regions are regarded as a genetic marker
specifically acquired by B cells at the time of transition through the
GC, whereas they are rare or absent in B-cell subsets that have not
transited through the GC.24,26-28,45 On this basis, the
frequent occurrence of BCL-6 mutations among PCNSL suggests
that a substantial fraction of these tumors may derive from B cells
related to the GC and localized subsequently to the CNS. Second, the
frequency of BCL-6 mutations and their location in the
proximity of the BCL-6 promoter suggest that these mutations
may have been selected during tumorigenesis based on their potential
ability to deregulate BCL-6 expression, as also indicated by data
obtained from in vitro models.45 Third, the frequency and
tumor specificity of BCL-6 mutations among PCNSL suggest that
these lesions may prove to be a valuable marker for the molecular
monitoring of the disease.
It is curious that, despite the frequent rate of BCL-6
mutations, PCNSL appear to be devoid of BCL-6 rearrangements,
which occur in approximately 30% to 40% of systemic DLCL of the
immunocompetent host and in 15% to 20% of AIDS-related
DLCL.25,32,46 The reason for the absence of BCL-6
rearrangements among AIDS-related and AIDS-unrelated PCNSL remains
unexplained. It is possible that the combination of BCL-6 mutations and
EBV infection may be sufficient for PCNSL development in the context of
AIDS, whereas an additional, presently unknown, genetic alteration may
substitute for EBV in AIDS-unrelated PCNSL.
The notion that PCNSL are histogenetically related to GC B cells is
further corroborated by our observation that PCNSL frequently express
the BCL-6 protein. In fact, BCL-6 expression clusters with GC B cells
throughout physiologic B-cell differentiation.21 Whereas
all AIDS-unrelated PCNSL score positive for BCL-6 expression, AIDS-related PCNSL display a certain degree of heterogeneity. Notably,
expression of BCL-6 is absent in AIDS-related PCNSL expressing the
EBV-encoded LMP-1 antigen. The mutually exclusive expression of BCL-6
and LMP-1 observed among AIDS-related PCNSL is reminiscent of that
detected among systemic AIDS-related NHL31,32 and is
consistent with data derived from in vitro models suggesting that LMP-1
is able to downregulate BCL-6.47 Consistent with the fact
that LMP-1 upregulates BCL-2,
BCL-6/LMP-1+ PCNSL generally express
BCL-2.16 Conversely, the majority of BCL-6+/LMP-1 PCNSL are
BCL-2.
The expression pattern of BCL-6, LMP-1, and BCL-2 might bear practical
implications for the differential diagnosis of PCNSL morphologic
subtypes, which are known to display a certain degree of overlap when
classified on pure histologic grounds. In fact, different expression
patterns of BCL-6, LMP-1, and BCL-2 preferentially associate with
distinct histologic variants of the disease. In particular,
BCL-6+/LMP-1/BCL-2
PCNSL tend to display a large noncleaved cell morphology, whereas BCL-6/LMP-1+/BCL-2+ PCNSL
are mainly represented by lymphomas with immunoblastic features. On
this basis, it is conceivable that expression of BCL-6, LMP-1, and
BCL-2 may contribute a valuable tool for the differential diagnosis of
PCNSL histologic variants. Ongoing studies are aimed at clarifying the
clinical relevance of the PCNSL phenotypic heterogeneity in terms of
the host's immune status, response to treatment, and outcome.
| |
FOOTNOTES |
Submitted December 29, 1997;
accepted March 26, 1998.
Supported by grants from Programma Nazionale di Ricerca
sull'AIDS-1997, Istituto Superiore di Sanità, Rome, Italy; the
Associazione Italiana per la Ricerca sul Cancro, Milan, Italy; and the
"Fondazione Piera, Pietro e Giovanni Ferrero," Alba, Italy. D.C.
is being supported by a fellowship from "Fondazione Piera, Pietro e
Giovanni Ferrero," Alba, Italy.
Address reprint requests to Luigi Maria Larocca, MD, Divison of
Pathology, Università Cattolica del Sacro Cuore, Largo F.Vito, 1, Rome I-00168, Italy; e-mail: ibiap{at}rm.unicatt.it.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
ACKNOWLEDGMENT |
The MoAb, PG-B6, was a kind gift of Prof Brunangelo Falini
(Institute of Hematology, University of Perugia, Perugia, Italy). The
human BCL-6 probes Sac 4.0 and Sac 0.8 were a kind gift of Dr
Riccardo Dalla-Favera (Division of Oncology, Department of Pathology,
College of Physicians & Surgeons, Columbia University, New York, NY).
| |
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Abstract
Introduction
Abstract