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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 92 No. 9 (November 1), 1998:
pp. 3152-3162
Clinical Relevance of BCL2, BCL6, and MYC Rearrangements in
Diffuse Large B-Cell Lymphoma
By
M.H.H. Kramer,
J. Hermans,
E. Wijburg,
K. Philippo,
E. Geelen,
J.H.J.M. van Krieken,
D. de Jong,
E. Maartense,
E. Schuuring, and
P.M. Kluin
From the Departments of Pathology and Medical Statistics, Leiden
University Medical Center, Leiden; Department of Pathology, The
Netherlands Cancer Institute, Amsterdam; Department of Internal
Medicine, Reinier de Graaf Gasthuis, Delft; and the Comprehensive
Cancer Center West, Leiden, The Netherlands.
 |
ABSTRACT |
Diffuse large B-cell lymphoma (DLCL) is characterized by a marked
degree of morphologic and clinical heterogeneity. We studied 156 patients with de novo DLCL for rearrangements of the BCL2, BCL6, and
MYC oncogenes by Southern blot analysis and BCL2 protein expression. We
related these data to the primary site of presentation, disease stage,
and other clinical risk factors. Structural alterations of BCL2, BCL6,
and MYC were detected in 25 of 156, 36 of 116, and 10 of 151 patients,
respectively. Three cases showed a combination of BCL2 and BCL6
rearrangements, and two cases had a combination of BCL6 and MYC
rearrangements. BCL2 rearrangement was found more often in extensive
(39%) and primary nodal (17%) lymphomas than in extranodal cases
(4%) (P = .003). BCL2 rearrangement was present in none of
40 patients with stage I disease, but in 22% of patients with stage II
to IV (P = .006). The presence of BCL2 rearrangements did
not significantly affect overall survival (OS) or disease-free survival
(DFS). In contrast, high BCL2 protein expression adversely affected
both OS (P = .008) and DFS (P = .01). BCL2
protein expression was poorly correlated with BCL2 rearrangement: only
52% of BCL2-rearranged lymphomas and 37% of BCL2-unrearranged cases
had high BCL2 protein expression. Rearrangement of BCL6 was found more
often in patients with extranodal (36%) and extensive (39%)
presentation versus primary nodal disease (28%). No significant
correlation was found with disease stage, lymphadenopathy, or bone
marrow involvement. DFS and OS were not influenced by BCL6
rearrangements. MYC rearrangements were found in 16% of primary
extranodal lymphomas, versus 2% of primary nodal cases
(P = .02). In particular, gastrointestinal (GI) lymphomas
(5 of 18 cases, 28%) were affected by MYC rearrangements. The distinct
biologic behavior of these extranodal lymphomas was reflected by a high
complete remission (CR) rate: 7 of 10 patients with MYC rearrangement
attained complete remission and 6 responders remained alive for more
than 4 years, resulting in a trend for better DFS
(P = .07). These data show the complex nature of molecular events in DLCL, which is a reflection of the morphologic and clinical heterogeneity of these lymphomas. However, thus far, these genetic rearrangements fail as prognostic markers.
© 1998 by The American Society of Hematology.
| |
INTRODUCTION |
CLONAL CHROMOSOMAL abnormalities are
associated with but not always specific for distinct types of
non-Hodgkin's lymphoma (NHL). These include t(8;14) and its variants
t(2;8) and t(8;22) in Burkitt's lymphoma, t(14;18) in follicular
lymphoma, and t(11;14) in mantle cell lymphoma, involving MYC, BCL2,
and BCL1 loci, respectively.1
By karyotyping, t(14;18)(q21;q34) has been identified in up to 85% to
90% of all cases of follicular lymphoma1; most
translocations can be detected by Southern blot analysis. The reported
incidence of t(14;18) translocations in diffuse large B-cell lymphoma
(DLCL) is lower, with a range of 12% to 30%.2-7 The BCL2
gene was originally discovered by virtue of its involvement in this
translocation. This leads to constitutive activation and increased
expression of BCL2, which has been shown to inhibit apoptosis8 and, more generally, may block
chemotherapy-induced cell death. Multiple BCL2 homologs that inhibit or
promote cell death, as well as homologs that modulate BCL2 and
BCL-XL activity, have been described.9 However,
little is known about their possible involvement in cancer, especially
as to whether these genes can be mutated. Recently, BAX mutations have
been described in some B-cell lymphoma cell lines.10
The BCL6 gene was discovered due to its engagement in chromosomal
translocations involving band 3q27 in NHL.11 BCL6
rearrangements are found in DLCL in up to 35% of
cases.12-17 These rearrangements juxtapose heterologous
sequences derived from other chromosomes to the BCL6 coding domain,
causing its deregulated expression.18 The 5 noncoding
region of the BCL6 gene can also be altered by somatic point mutations
that are detectable, independent of rearrangement, in 70% of DLCL
cases.19 BCL6 encodes for a POZ/zinc-finger protein and
acts as a transcriptional repressor.20 BCL6 is normally expressed in both B cells and CD4+ T cells within germinal
centers, controlling germinal-center formation and Th2-type
inflammation,21 but its precise function is unknown.
Translocation t(8;14)(q24;q32) was the first recurring chromosomal
translocation shown to be associated with a lymphoproliferative disease.22 On the molecular level, the translocation
juxtaposes the MYC gene in chromosome region 8q24 next to the IgH locus
in chromosome region 14q32, leading to deregulation and overexpression of the transcription factor MYC. Translocation t(8;14) can be observed
in most, if not all, cases of Burkitt's lymphoma/leukemia, and in up
to 15% of large-cell lymphoma cases.23-26 In addition, in
Burkitt's lymphoma27 and less frequently in
DLCL,28 mutations affect both the coding and intron 1 sequences of MYC harboring MYC regulatory elements.
From both a clinical and histopathologic point of view, DLCL is highly
heterogeneous. Survival can be predicted on the basis of pretreatment
clinical characteristics as established by the International NHL
Prognostic Factors Project.29 The genetic and molecular
profile of DLCL in relation to biologic behavior and clinical outcome
has been elucidated to a certain extent.21 There is
controversy about the clinical significance of oncogene rearrangements
in nodal and extranodal DLCL. DLCL is relatively frequent at extranodal
sites. Studies of gastrointestinal (GI) and primary cutaneous
large-cell lymphomas30 demonstrated a very low frequency of
BCL2 rearrangements, whereas a higher frequency of MYC rearrangements
was found in DLCL of the GI tract.31-33 Furthermore, a
relatively high frequency of BCL6 rearrangements in extranodal DLCL was
found.14 In the latter study, BCL6 rearrangements
correlated with a favorable clinical outcome, but this could not be
confirmed by others.13 BCL2 rearrangements are often
confined to nodal DLCL, and here also, conflicting results are
reported about the clinical impact.2-7
The population-based NHL Registry of the Comprehensive Cancer Center
West (CCCW) in The Netherlands provided the opportunity to perform a
molecular study on frozen tumor tissue from 156 patients with de novo
DLCL to investigate the value of BCL2, BCL6, and MYC rearrangements in
relation to clinical presentation, response to therapy, and survival.
We correlated these results with BCL2 protein expression, which is a
strong independent clinical risk factor for DLCL as reported by our
group34 and others.6,7,35
| |
SUBJECTS AND METHODS |
Patients and materials.
In the population-based NHL Registry of the CCCW in The Netherlands,
1,168 patients with a histologically proven diagnosis of NHL were
included between 1981 and 1989.34 The region of the CCCW
contains 1.6 million inhabitants and 15 hospitals. Initial diagnoses
were made by the local pathologists. All patients had disease staging
according to the Ann Arbor classification.36 For adequate
staging, computed tomographic scans of the thorax and abdomen and bone
marrow histology were required. Patients were treated according to the
recommendation of the local internist, and this treatment was
considered "adequate" when doxorubicin-containing polychemotherapy with or without radiotherapy or radiotherapy alone was
administered for patients with fully documented stage I disease. All
tumors including immunohistochemistry were reviewed by a regional panel
of pathologists. Primary cutaneous T-cell lymphoma, plasmacytoma, acute
lymphoblastic leukemia, and chronic lymphocytic leukemia were excluded
from the registry. Clinical parameters and treatment modality and
outcome were recorded. The follow-up evaluation was updated annually
for patients who were still alive.
In the CCCW records, 508 B-cell lymphomas were recognized with a
histopathologic diagnosis of diffuse centroblastic-centrocytic (diff
CbCc), diffuse centroblastic (diff Cb), immunoblastic (Ib), and
mucosa-associated lymphoid tissue of high-grade malignancy (MALT high),
compatible with a diagnosis of DLCL as recently defined by the Revised
European-American Classification of Lymphoid Neoplasms (REAL)
classification.37 For 122 patients, no or only bad-quality tissue blocks were available. Representative paraffin-embedded tumor
tissue from the remaining 386 patients included material from all 15 hospitals of the CCCW. All cases were reviewed by three
hematopathologists and reclassified according to the updated Kiel and
REAL classification.37,38 In 14 of 386 patients, the initial diagnosis was revised: seven cases of diff CbCc were
reclassified as follicular CbCc (n = 2) and mantle cell lymphoma
(n = 5), and seven cases of diff Cb were reclassified as follicular
Cb (n = 6) and mantle cell lymphoma (n = 1). This resulted in a
final cohort of 372 patients with DLCL.
From 156 of these 372 cases, frozen tissue could be collected from the
frozen tissue bank of the Department of Pathology, Leiden University
Medical Center, for Southern blot analysis. The series includes 40 cases published previously; for these cases, only BCL2 and MYC
rearrangements were investigated.39 The remaining 116 patients were tested for BCL2, BCL6, and MYC rearrangements.
For 84 patients, treatment was adequate with doxorubicin-containing
polychemotherapy (with or without radiotherapy) or radiotherapy alone
for patients with fully documented stage I disease.
Three patterns of initial disease presentation were defined: (1)
primary nodal NHL with presentation in the lymph node, Waldeyer's ring, spleen, or bone marrow, (2) primary extranodal NHL with presentation in other sites with or without local lymph node
involvement, and (3) extensive NHL with presentation in both extranodal
and distant nodal sites (often the other side of the diaphragm).
Southern blot analysis.
High-molecular-weight DNA was isolated from frozen tissue blocks kept
at  80°C. Five to 10 tissue slides (20 µm) were treated by
standard proteinase K and phenol-chloroform extraction as described previously.39 One additional slide was used for estimation
of the presence of lymphoma cells in each particular DNA sample. Ten
micrograms of DNA were digested with each restriction enzyme using
buffers recommended by the supplier (Boehringer, Mannheim, Germany),
size-fractionated by gel electrophoresis on 0.8% agarose gels,
denatured, and transferred with 0.4 mol/L NaOH/1 mol/L NaCl onto nylon
membranes (Hybond N+; Amersham, Amersham, UK). After transfer, the
membranes were neutralized in 0.2 mol/L Trishydrochloride, pH 7.5/2×
SSC (1× SSC is 0.15 mol/L NaCl plus 0.015 mol/L sodium citrate),
dried, and baked at 80°C for 2 hours.
The membranes were prehybridized for 2 hours at 65°C in 6× SSC,
5× Denhardt solution (0.1% Ficoll, 0.1% polyvinylpyrrolidone, and
0.1% bovine serum albumin), 0.5% sodium dodecyl sulfate (SDS), 10%
PEG 6000, and 50 µg/mL salmon sperm DNA. Purified DNA probes were
radiolabeled with 20 µCi [ 32P]dCTP (> 3,000
Ci/mmol; Amersham) using the random-primed DNA labeling kit (Pharmacia,
Uppsala, Sweden) with a specific activity of approximately
10 8 to 109 cpm/µg DNA. After 16 hours
of hybridization, the membranes were washed for 30 minutes in 1×
SSC/0.1% SDS and 30 minutes in 0.1× SSC/0.1% SDS at 65°C and then
exposed to Kodak X-Omat AR films (Eastman Kodak, Rochester,
NY) with DuPont Cronex Lightning-Plus screens
(DuPont de Nemours, Wilmington, DE) at 70°C.
The following probes were used: pCµ51/Jh, a 2.5-kb
EcoRI-BgIII fragment of the Ig heavy chain-joining
genes (kindly provided by P. Leder, Boston, MA); pSP64/18-4RH, a 2.8-kb
EcoRI-HindIII fragment from the major breakpoint region
(MBR) of the BCL2 gene (kindly provided by Tsujimoto, Osaka, Japan);
pFL-2, a 4-kb Eco-HindIII fragment containing the minor cluster
region (mcr) of the BCL2 gene (kindly provided by M. Cleary, Stanford,
CA); pMYC/exIII/3138, a 1.4-kb ClaI-EcoRI fragment
representing exon 3 of MYC derived from the 10-kb
EcoRI-EcoRI genomic clone pHM-1 (kindly provided by I. Laird, Leiden, The Netherlands); pGSc4.0, a 4-kb Sac
I-Sac I fragment representing the 3 region of exon 1a of the
BCL6 gene (kindly provided by R. Dalla-Favera, New York, NY); p486a
(probe F372) and p486 (probe F370), a 2.6-kb BamHI-Xho
I and 3.4-kb Xba I-BamHI fragment, respectively,
covering the breakpoint region between exon 1a and 1b of the BCL6/LAZ3
gene (kindly provided by C. Bastard, Lille, France).
All DNAs digested with BgIII, EcoRI, and
HindIII were successively hybridized with all probes for Jh,
BCL2, BCL6, and MYC. Only DNA samples that carried one or more Jh
signals in addition to the germline signal (ratio
extra/germline > 10%) were included in the DNA analysis. The
presence of breakpoints within BCL2, BCL6, or MYC was defined when two
or more rearrangements were observed in three different digests. In the
BCL6 breakpoint region, breakpoints are scattered over a region of 10 kb and small mutations affecting the restriction enzyme recognition
sites, as well as restriction enzyme polymorphisms, are
observed.17 Similarly, point mutations affect the first
intron of MYC. For both genes, the clinical significance of the
mutations is unknown. Therefore, when a rearrangement was observed in
only one of the three digests, these DNA samples were additionally
digested with Xba I and BamHI and hybridized with BCL6
probes. A representative Southern blot with hybridized tumor DNA is
shown in Fig 1.
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| Fig 1.
Southern blot analysis of IgH, BCL2, and BCL6 gene
rearrangement. Tumor DNA samples from cases 35, 5, 152, 68, 27, 49, 44 (see Table 1) and 2 other lymphomas (lanes A and B) not included in the
study were digested with BgIII and hybridized with probes
for BCL2 (pSP64/18-4RH for MBR), JH (pCm51/JH), and BCL6
(pGSc4.0 for the 3 region of exon 1a of BCL6). All tumors except case
27 showed 1 or more rearranged JH bands, indicating sufficient tumor
DNA. Case 27 showed 2 strong rearranged JH bands in both the
HindIII and EcoRI digests (not shown), indicating that
the BgIII digest was false-negative. Case 35 showed
rearrangement for BCL2, and cases 68 and 44 showed rearrangements for
BCL6. Comigration of 1 rearranged BCL2 and 1 rearranged JH band in case
35 indicates t(14;18). Case 152 did not show BCL6 rearrangement but had
BCL6 rearrangement upon analysis with the pGSc4.0 probe in the
HindIII digest, as well as F370 and F372 BCL6 probes in the
BgIII digest and the F370 probe in the EcoRI digest.
This indicates that the BCL6 breakpoint is present in the MTC of BCL6
(not shown).
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Immunohistology for BCL2 protein expression.
Paraffin-embedded sections were cut and fixed on 3 aminopropyl
triethoxysilan (APES)-coated glass slides. The sections
were dried overnight at 37°C and deparaffinized in three changes of xylene for 5 minutes. Slides were incubated for 5 minutes
in methanol and 20 minutes in methanol plus peroxide 1%, followed by a
brief wash in deionized water. The slides were heated to
100°C in sodium citrate buffer (0.06 mol/L) for 20 minutes and slowly
cooled for at least 2 hours. They were washed in phosphate-buffered
saline (PBS) and preincubated with 10% normal goat serum for 15 minutes, followed by overnight immunostaining with the anti-BCL2
monoclonal antibody BCL2 124 (kindly provided by D. Mason, Oxford, UK)
and by incubation with biotinylated rabbit anti-mouse Igs (1:200) and
streptavidin-biotin peroxidase complex (1:100) (Dako, Glostrup, Denmark). The slides were stained with diaminobenzidine (Sigma, St
Louis, MO). In addition, immunostaining with the L26
monoclonal antibody specific for B cells (CD20) and UCHL1 specific for
T cells (CD45RO) (Dako) was performed to verify the B-cell nature of
the neoplastic cells.
The presence of BCL2 protein expression was investigated, and three
categories were defined: absent, none or less than 5% of tumor cells
with cytoplasmic staining; low, variable and weak cytoplasmic staining
of tumor cells; and high, strong cytoplasmic staining of almost all
tumor cells. In all cases, reactive T lymphocytes served as an internal
control.
Statistical analysis.
Survival curves were calculated according to the Kaplan-Meier method;
survival analysis was performed using the log-rank test. Overall
survival (OS) was calculated from the date of diagnosis until death or
last follow-up evaluation. For patients with a complete remission
(CR), disease-free survival (DFS) was estimated from the
date of CR until first relapse or last contact, if disease-free.
| |
RESULTS |
Pathologic and clinical characteristics.
Clinical characteristics of 156 patients are shown in Table
1, including
clinically and/or pathologically documented tumor sites and
staging data according to the Ann Arbor classification. Patients were
grouped according to site of presentation: primary nodal, extranodal,
or extensive.
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Table 1.
Primary Nodal, Extranodal, and Extensive LCL: Clinical
Presentation Versus Rearrangement of BCL2, BCL6, or MYC
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In 93 patients, lymphoma presented with lymphadenopathy, and these were
classified as primary nodal. Staging revealed additional extranodal
tumor sites in seven patients. In 18 (21%) of 85 patients with a bone
marrow biopsy, the marrow contained tumor. According to the Ann Arbor
system, 16 of 85 adequately staged patients had stage I disease (19%),
27 stage II (32%), 21 stage III (25%), and 21 stage IV (25%).
Sixteen additional patients presented with tonsillar localization, and
of these, 14 also had cervical lymphadenopathy.
Forty-five patients presented with extranodal disease: stomach
(n = 10), intestine (n = 8), breast (n = 4), soft tissue/muscle (n = 4), bone (n = 3), salivary gland (n = 2), lacrimal gland (n = 1), testis (n = 2), thyroid gland (n = 2), skin (n = 2), central nervous system ([CNS] n = 2), lung (n = 1), kidney
(n = 1), adrenal gland (n = 1), and paranasal cavity (n = 1).
Subsequent staging revealed that eight patients had multiple extranodal
tumor sites. It also disclosed additional lymph node involvement in 17 cases. In 6 (15%) of 39 assessable patients, the bone marrow contained
tumor. Nineteen (46%) of 41 adequately staged patients had stage I
disease, 10 stage II (24%), and 12 stage IV (29%).
Eighteen patients presented with both extensive nodal and extranodal
disease (GI tract, lung, pleura, breast, liver, bone, soft
tissue/muscle, parotic gland, kidney, testis, and CNS). All patients
had lymphadenopathy, 13 at both sides of the diaphragm (72%). In 7 of
16 adequately staged patients, the bone marrow showed infiltration of
tumor cells (44%).
Bone marrow involvement was found in 31 patients: in 18, it was mainly
concordant large cells; in five, it was discordant small cells; and in
five, it could not be determined. There was no relation between
discordant bone marrow involvement and any oncogene rearrangement
tested.
Oncogene rearrangements in relation to pathologic and clinical
characteristics.
The incidence of BCL2, BCL6, and MYC rearrangements in 156 patients is
displayed in Tables 1 and 2 in relation to
clinically and/or pathologically documented tumor sites and
staging data according to the Ann Arbor classification. The series
contained 40 cases published previously39: for these cases,
only MYC and BCL2 rearrangements (36 cases with the MBR and mcr probe
and four cases with the MBR probe only) were investigated. The
remaining 114 patients were tested for BCL2, BCL6, and MYC
rearrangements. Representative cases are shown in Fig 1. Survival
curves in association with oncogene rearrangements are shown in Figs 2-4. Survival
curves in association with BCL2 protein expression are shown in Fig
5.
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| Fig 2.
(A) Overall survival for BCL2-rearrangement positive
(n = 25) and BCL2-rearrangement negative (n = 131) lymphomas.
(B) DFS for BCL2-rearrangement positive (n = 11) and
BCL2-rearrangement negative (n = 77) lymphomas.
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| Fig 3.
(A) Overall survival for BCL6-rearrangement positive
(n = 36) and BCL6-rearrangement negative (n = 80) lymphomas.
(B) DFS for BCL6-rearrangement positive (n = 19) and
BCL6-rearrangement negative (n = 45) lymphomas.
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| Fig 4.
(A) Overall survival for MYC-rearrangement positive
(n = 10) and MYC-rearrangement negative (n = 141) lymphomas.
(B) DFS for MYC-rearrangement positive (n = 7) and
MYC-rearrangement negative (n = 79) lymphomas.
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| Fig 5.
(A) Overall survival for lymphomas with high BCL2 protein
expression (n = 63) and low/absent BCL2 protein expression
(n = 93). (B) DFS for lymphomas with high BCL2 protein expression
(n = 32) and low/absent BCL2 protein expression (n = 56).
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BCL2.
Sixteen of 93 nodal lymphomas (17%) versus 2 of 45 extranodal cases
(4%) showed rearrangement of BCL2. In extranodal cases, the tumor
presented in the thyroid gland and colon (with simultaneous rearrangement of BCL6). BCL2 rearrangement was found in none of 40 patients with stage I disease and in 25 (22%) of 116 patients with
stage II to IV disease (P = .006), including 7 (39%) of 18 patients with extensive disease (P = .003). BCL2
rearrangement was significantly correlated with the presence of
lymphadenopathy (24 of 123 patients with lymphadenopathy v 1 of
33 patients without, P = .03). Bone marrow involvement was
not correlated with the presence of BCL2 rearrangements. In all cases
with BCL2 rearrangement, comigration with a rearranged IgH gene
sequence was detected with the JH probe, indicating t(14;18). BCL2
rearrangements involved the MBR in 23 and the mcr in two cases. We also
analyzed BCL2 protein expression in these lymphomas. High expression
was not exclusively confined to tumors with BCL2 rearrangements: 49 of 131 cases without BCL2 rearrangements were strongly BCL2
protein-positive (37%). Of note, 12 (48%) of 25 cases with BCL2
rearrangements had low or absent expression of BCL2 protein (Table
3). BCL2 rearrangement was not associated
with induction of complete remission or with OS or DFS
(Fig 2A and B), in contrast to high BCL2 protein expression, which
correlated with OS and DFS (Fig 5A and B). These data were also found
for 84 patients who were adequately treated with doxorubicin-containing
polychemotherapy with or without radiotherapy, or radiotherapy alone
for patients with fully documented stage I disease (data not shown).
BCL6.
BCL6 rearrangements were studied in 116 patients, with 36 positive
cases (31%). Twenty-one of 74 nodal cases (28%), 10 of 29 extranodal
cases (34%), and 5 of 13 extensive cases (38%) showed rearrangement
for BCL6. No significant correlation was found with the disease stage
and the presence of lymphadenopathy. Bone marrow involvement was found
in 4 of 36 patients with BCL6 rearrangement, versus 21 of 95 patients
without rearrangement. Three of four patients with DLCL of the CNS
showed rearrangement of BCL6. In two patients with nodal DLCL and one
patient with extranodal DLCL, rearrangements of both BCL2 and BCL6 were
found. Combined rearrangement of BCL6 and MYC was found in one nodal
and one extensive case. Complete remission and OS and DFS was not
significantly different between BCL6 rearrangement-positive and
-negative cases (Fig 3A and B). These data were also observed for 65 patients who were adequately treated with doxorubicin-containing
polychemotherapy with or without radiotherapy, or radiotherapy alone
for patients with fully documented stage I disease (data not shown).
MYC.
MYC rearrangements were predominantly found in primary extranodal
large-cell lymphomas (7 of 45 cases, P = .02), particularly GI lymphomas (5 of 18 v 4 of 116 cases, P = .001);
the other sites were lung/pleura, soft tissue, and testis. Two nodal
lymphomas showed MYC rearrangement, one together with rearrangement of
BCL6. Additionally, one extensive case contained both MYC and BCL6
rearrangement. Comigration of rearranged MYC and JH gene sequences was
found in 4 of 10 cases. Seven of 10 patients with MYC rearrangement attained complete remission, and 6 responders remained alive for more
than 4 years (Fig 4A and B), resulting in a trend for better DFS
(P = .07).
| |
DISCUSSION |
According to all available studies, including the present one, BCL2
rearrangements are detectable in 12% to 30% of DLCL.2-7 In almost all cases, the rearrangement is caused by translocation t(14;18). We expanded our previous cohort of de novo DLCL39 with even stronger proof that BCL2 rearrangements are found more often
in primary nodal versus primary extranodal cases. Our data corroborate
the study by Offit et al3 in that their stage I to III
DLCLs with BCL2 rearrangement also presented with nodal involvement (no
data were presented for stage IV cases). Similarly, in a cytogenetic
analysis by Ott et al,33 no translocation t(14;18) was
reported in high-grade MALT lymphomas of the stomach and parotid gland.
Our results essentially differ from two other studies4,5 showing BCL2 rearrangements in some cases with primary extranodal involvement. However, the latter cohorts used different definitions for
nodal and extranodal disease. Interestingly, in the present study, BCL2
rearrangements were strongly associated with disseminated disease,
since none of 40 patients with stage I disease showed a rearrangement.
This is not reflected by a significantly higher percentage of bone
marrow involvement or by discordant morphology. It may be proposed that
a higher rate of bone marrow infiltration in BCL2
rearrangement-positive DLCL can be expected, since translocation t(14;18) is thought to arise from an error in the recombination process
of precursor B cells in bone marrow,40 and some believe that t(14;18)-positive DLCL may represent progressed follicle center
cell lymphoma, with bone marrow involvement in a high percentage of
cases.41 Nevertheless, the finding that DLCL with BCL2
rearrangement is restricted to disseminated disease and nodal
presentation fits with the hypothesis that these lymphomas have a
distinct origin.
Interestingly, and in accordance with the results of Gascoyne et
al,7 there is almost no correlation between BCL2
rearrangement and BCL2 expression in DLCL: almost half of DLCL cases
with BCL2 rearrangement have no or weak BCL2 protein expression, and in reverse, approximately 40% of DLCL cases with high BCL2 protein expression lack detectable rearrangement. The first observation is
difficult to justify, although this discrepancy can be explained by
mutations in the open reading frame of the translocated BCL2 gene.42 Alternatively, t(14;18) and deregulation of BCL2
may have played an essential role in the initial lymphomagenesis, but
may have lost their significance during further tumor progression. A
similar transient role has been attributed to Epstein-Barr virus in
African Burkitt's lymphoma.43 One explanation for the fact that so many DLCL cases without detectable BCL2 rearrangement show
overexpression of the protein is DNA amplification instead of
translocation. Indeed, amplification of the BCL2 gene has been recently
reported in a small series of DLCL cases with BCL2
overexpression.44,45 In our series, no significant
amplification of BCL2 could be detected with Southern blotting
analysis, with the possible exception of one case (data not shown).
In line with previous reports by our group34 and
others,3-7,35 we found a different prognostic impact for
BCL2 rearrangement and BCL2 protein expression in DLCL. No significant
difference in BCL2 rearrangements in relation to CR, DFS, and OS was
observed in the present study, in accordance with most
reports,4-7 whereas other studies found a difference for
DFS and one study also for OS.2,3,18 In contrast, in our
cohort of patients, BCL2 protein expression was associated with poor
DFS and OS. In a multivariate analysis, BCL2 protein expression was an
independent risk factor in relation to well-defined clinical risk
parameters.34 In a separate study on primary cutaneous
DLCL, a similar relation between BCL2 expression and prognosis was
found: primary DLCL of the head and trunk without BCL2 expression has a
favorable clinical course compared with primary DLCL of the leg with
concomitant high expression of BCL2 protein; both types of cutaneous
DLCL lacked a detectable t(14;18) as tested by PCR.46
Previous studies have indicated that MYC rearrangements are detectable
in 5% to 15%23-26 of patients with DLCL, especially in
the GI tract.31,32 In the present study, rearrangement of
MYC was found in 7% of cases with a majority of extranodal lymphomas
originating from the GI tract. These results corroborate recent data on
high-grade MALT lymphomas reported by Ott et al.33 They
found t(8;14) in tumor tissue of the stomach in three of 21 high-grade
MALT lymphomas. In our cohort, the distinct biologic behavior of these
lymphomas with MYC rearrangements was reflected by a high CR rate and
better DFS, with six of seven complete responders alive for more than 4 years. Offit et al14 reported nine cases with t(8;14); five of these presented at extranodal sites, but no correlation was found
with GI lymphoma. Of note, we did not find any case with a combined
t(14;18) and t(8;14) in the present series of de novo DLCL. Such cases
often represent progressed follicular lymphoma or de novo
leukemia/lymphoma with Burkitt-like morphology.47,48
The role of BCL6 rearrangements in DLCL is less distinct. BCL6
rearrangement is found in 23% to 37% of cases with Southern blotting,12-14 but only a minority are visible on the
cytogenetic level.49 Cytogenetic detection is impeded by
localization of the 3q27 breakpoint at the tip of chromosome 3q and by
the great diversity in chromosomal partners involved in the breakpoint. On the other hand, with Southern blot analysis, the frequent point mutations in BCL6 can be easily interpreted as chromosomal breakpoints, especially if too few restriction enzymes and/or probes are
used. The frequency of BCL6 rearrangements in the present series of DLCL (31%) is similar to that found by other groups.12-14
In the present study, no significant correlation was found between BCL6 rearrangement and the site of presentation, although there was a slight
preponderance of extranodal cases and cases with extensive disease. An
association with extranodal disease was also found by Offit et
al.14 We observed involvement of many different extranodal
sites (CNS, testis, and bone), including MALT of the stomach,
intestine, and breast. This relative unspecificity of BCL6
rearrangements is also encountered on the molecular level, since they
can coexist with BCL2 and MYC rearrangements as shown by our group and
others.14 Interestingly and in contrast to the present
results and those of Bastard et al,13 in the study by Offit
et al,14 patients with BCL6 rearrangements had a
significantly better clinical outcome. In a supplementary analysis,
Offit et al50 showed a correlation between prognosis and
occurrence of chromosomal aberrations additional to BCL6
rearrangements. Therefore, it cannot be excluded that these different
results for prognosis depend on a different occurrence of these
additional genetic events.
Our observations, in part, support the hypothesis that the natural
history of DLCL may vary depending on the pathogenesis of the
tumor.41 According to a model proposed by Dalla-Favera et
al,41 at least two distinct genetic pathways may lead to DLCL development: the first pathway consorts with DLCL transformed from
a clinically undetectable follicular phase with BCL2 rearrangement; the
second pathway involves BCL6. Our finding that BCL2 rearrangements are
mainly present in a subset of patients with nodal and disseminated disease supports a distinct BCL2 pathway. However, assuming that these
DLCLs arise from clinically occult follicular lymphoma, the events
secondary to t(14;18) seem to differ from the events involved in tumor
progression from overt follicular lymphoma, ie, P53
mutations51-53 and MYC activation by
translocation,54 especially since no such events were
encountered in a series of de novo DLCL with t(14;18)21 and
since we did not find any MYC rearrangements in the presently analyzed
t(14;18)-carrying DLCL. The occurrence of a distinct BCL6 pathway in de
novo DLCL is not strongly supported by the present data or by prior
data showing the coexistence of these rearrangements in (untransformed
or transformed) t(14;18)-carrying follicular
lymphomas.17,19
In conclusion, this report addresses the relevance of BCL2, BCL6, and
MYC rearrangements in the biologic and clinical behavior of DLCL.
Although these markers might, to some degree, delineate different
oncogenetic pathways in DLCL, they fail as prognostic markers,
especially when compared with the well-defined clinical variables of
the international prognostic index.29
| |
FOOTNOTES |
Submitted February 9, 1998;
accepted July 2, 1998.
Supported by the Institute of Radioprotection/J.A. Cohen Institute
(6.2.3), the Dutch Cancer Society (IKW 91-06), and the Ank van
Vlissingen Fund.
Address reprint requests to P.M. Kluin, MD, PhD, Department of
Pathology, Leiden University Medical Center, L1Q, PO Box 9600, 2300 RC
Leiden, The Netherlands.
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.
| |
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Abstract
Introduction
Abstract