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NEOPLASIA
Nodal marginal zone B-cell lymphomas may arise from different
subsets of marginal zone B lymphocytes
Annarita Conconi, Francesco Bertoni, Ennio Pedrinis, Teresio Motta, Enrico Roggero, Stefano Luminari,
Carlo Capella, Marzia Bonato, Franco Cavalli, and Emanuele Zucca
Nodal marginal zone B-cell lymphoma
(MZL) is a rare and not extensively studied entity that accounts for approximately
2% of all non-Hodgkin lymphomas.
Complementarity-determining regions 2
and 3 (CDR2, CDR3) of the immunoglobulin heavy-chain variable region (VH) genes
were amplified by polymerase chain reaction (PCR), cloned, and sequenced in 8
patients with nodal MZL. All showed a
potentially functional VH rearrangement.
The use of VH gene families was unbiased
and without overrepresentation of any
particular VH gene or gene family. The
presence of somatic VH mutations was
detected, with a deviation from the closest germ line sequence ranging from 4%
to 17% in 6 of 8 patients. In 3 mutations,
the replacement-to-silent mutation ratio
suggested the presence of an antigenselected process. Sequencing different
subclones of the same cloned PCR products allowed the detection of intraclonal
variability in 4 analyzed patients. The
observed pattern of VH mutations suggested that nodal MZL, formerly deemed
a malignancy of memory B cells, may
arise from different subsets of marginal
zone B cells—the naive B cells that express unmutated VH genes—from memory
B cells showing somatic mutations without intraclonal variation, and from germinal center B cells defined by their capacity to undergo the somatic hypermutation
process. (Blood. 2001;98:781-786)
© 2001 by The American Society of Hematology
Introduction
The entity traditionally designated as monocytoid B-cell lymphoma is classified in the Revised European American Classification of Lymphoid Neoplasms (REAL) and in World Health
Organization (WHO) Classification of Hematological Malignancies as nodal marginal zone B-cell lymphoma (MZL).1,2 By
definition, in the WHO classification the term nodal is used to
design cases primarily involving lymph nodes, and it excludes any
case with prior or concurrent localization in an extranodal site other
than bone marrow, liver, or spleen.3 Although nodal MZL shares
many histologic and immunologic features with extranodal MZL of
MALT type,1,2,4,5 clinical characteristics, natural history, and prognosis suggest that nodal MZL should be considered a distinct
disease entity.6,7 Based on molecular findings, the relation between
the 2 entities is still controversial.8,9
Generation of antigen receptors by somatic recombination of
variable, diversity, and joining segments is a unique feature of B
and T cells, occurring in an early phase of development. In B-cell
ontogenesis, after the successful construction of a functional,
nonautoreactive antigen receptor, naive B cells move to the
germinal centers of secondary lymphoid organs. In these structures,
upon antigen encounter, during T-cell–dependent B-cell development, the antibody expressed by a B cell may be modified by
class-switch recombination, somatic hypermutation,10 and, according to some suggestions, receptor editing.11 Somatic hypermuta-
tion, which introduces predominantly point mutations into the
immunoglobulin variable region genes, increases immunoglobulin
diversity and can modify the immunoglobulin affinity for antigen.12
Because somatic hypermutation appears to be restricted to B cells
proliferating within the microenvironment of the germinal center,13
somatically mutated V-region genes are a hallmark of germinal
center B cells and their descendants. Thus, sequence analysis of the
immunoglobulin variable region genes of normal B cells and B-cell
lymphomas can be applied to determine either the ancestral
derivation from follicle center cells or the continued influence of
the follicle center microenvironment.14
The pattern of somatic mutations in the VH genes of most B-cell
non-Hodgkin lymphomas, with clustering of replacement mutations in complementarity-determining regions (CDRs), indicates
that the tumor cells or their precursors were selected for antigenreceptor expression during the process of mutation.15 Furthermore,
intraclonal nucleic acid sequence variation, suggestive of ongoing
mutations, indicates that tumor B cells are still under the influence
of a mutation mechanism.15 Extranodal MZLs of MALT type are
thought to arise from post–germinal center B cells. In gastric MZL,
Helicobacter pylori–specific T cells drive the proliferation of the
neoplastic B cells.16 Immunoglobulin VH genes show a pattern of
somatic mutations consistent with a selection by antigen, suggesting that continued exposure to antigen may play a role in the
From the Oncology Institute of Southern Switzerland, Division of Medical
Oncology, Bellinzona, Switzerland; Department of Experimental Haematology,
St Bartholomew’s and The Royal London School of Medicine and Dentistry,
London, United Kingdom; Istituto Cantonale di Patologia, Locarno,
Switzerland; Anatomia Patologica e Citologia, Ospedali Riuniti Bergamo, Italy;
Servizio di Ematologia, Università Statale di Milano, Ospedale Maggiore
IRCCS, Milan, Italy; and Istituto di Anatomia e Istologia Patologica, Università
dell’Insubria, Varese, Italy.
the Fondazione “San Salvatore.” A.C. is supported by an ESMO Fellowship
grant.
Reprints: Emanuele Zucca, Division of Medical Oncology, Oncology Institute
of Southern Switzerland, Ospedale San Giovanni, 6500 Bellinzona,
Switzerland; e-mail: [email protected].
Submitted June 14, 2000; accepted March 15, 2001.
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.
Supported in part by the Fondazione Ticinese per la Ricerca sul Cancro and by
© 2001 by The American Society of Hematology
BLOOD, 1 AUGUST 2001 䡠 VOLUME 98, NUMBER 3
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BLOOD, 1 AUGUST 2001 䡠 VOLUME 98, NUMBER 3
CONCONI et al
persistence of lymphoma.17,18 The specificity of extranodal MZL B
cells for autoantigens and the characteristic growth of extranodal
MZLs in the background of autoimmune diseases represent important elements in the comprehension of the pathogenesis of this
lymphoma entity.19,20
Analyses of immunoglobulin heavy-chain variable region genes
in nodal MZLs have been limited to a few series of patients.21-23
Usually the sequences analyzed showed the presence of somatic
mutations, suggesting the derivation of the tumor population from
post-follicular, antigen-experienced B cells. Based on these results
and according to the immunophenotypical characteristics of the
tumor cells, nodal marginal zone B-cell lymphomas have been
suggested to represent malignancies of memory B cells.15 Nevertheless, in all these studies, the technical approach of amplifying
rearranged variable region genes, followed by direct sequencing of
the PCR products prevented the reliable detection of potential
ongoing mutations within the tumor cells.
Our study was aimed at acquiring insight into the nature of the
immunoglobulin heavy-chain variable region sequences in nodal
MZLs to confirm the presence of somatic mutations and identify
mutation patterns reminiscent of antigen selection processes. In
addition, the study was devised to explore the presence of ongoing
mutations by cloning and sequencing the VH genes of 8 patients
with histologically reviewed nodal MZLs.
Materials and methods
All molecular analyses were performed on tumor tissues collected at
diagnosis from patients with nodal MZL.
Pathology review
All specimens were histologically reviewed by expert hemopathologists
(E.P., T.M., C.C., M.B.) according to the criteria of the REAL/WHO
classifications.1,2 Tumor biopsies were examined by standard histologic
techniques, including immunohistochemistry.
DNA extraction
Genomic DNA was extracted from lymph nodes, bone marrow, and
peripheral blood specimens using phenol/chloroform extraction after 48hour proteinase K digestion at 56°C. In patients 1, 2, 3, and 8, DNA was
obtained from routinely processed formalin-fixed and paraffin-embedded
bioptic specimens; in patients 4 to 7, it was obtained from frozen tissue.
Prism Big Dye Terminator Kit (PerkinElmer, Foster City, CA) as recommended by the manufacturer. All clones were sequenced in both directions.
Sequence analysis
Tumor-related VH genes were identified based on the presence of analogous
CDR3 sequences. DNA sequences were analyzed for homologies in the
GenBank database using the Basic Local Alignment Search Tool (BLAST)
software, available at the National Center for Biotechnology Information
(NCBI). Homology with germ line VH, DH, and JH genes was identified
using the V-Base database44 and the IgBlast software of the NCBI.45 The
ability to code for functional heavy chains was determined by translation of
DNA sequences into amino acids.
Analysis of intraclonal heterogeneity
To evaluate the presence of ongoing mutations in nodal MZLs, at least 7
clones from each specimen were sequenced. For evaluation of intraclonal
heterogeneity, the following definitions were used: unconfirmed mutation—a substitution mutation observed in only one of the VH gene
molecular clones from the same tumor specimen; confirmed mutation—a
mutation observed in more than one of the VH gene molecular clones from
the same tumor specimen. Only the confirmed mutations were considered
as evidence of intraclonal heterogeneity; the unconfirmed mutations were
instead ascribed to Taq polymerase error.25
Antigen selection
To determine the pattern of somatic mutations compatible with antigen
selection, 2 different methods were applied.26 First, the ratio of replacementto-silent mutations (R/S) in the CDR2 and FW3 regions was studied. A
sequence was considered to be antigen selected when the R/S ratio in the
CDR2 was higher than 2.9 and the R/S ratio in the FW3 region was lower
than 1.5. Second, only the R/S ratio of the somatic mutations in the FW3
region was considered. A sequence was regarded as antigen selected when
the R/S ratio was less than 1.6.
Results
Assessment of clonality
CDR2 and CDR3 of the immunoglobulin heavy-chain variable
region (VH) genes were amplified in 10 patients with nodal MZL.
Eight patients, characterized by a single band on polyacrylamide
gel electrophoresis indicating a monoclonal rearrangement, underwent cloning and sequencing procedures and are the subjects of the
present study.
PCR amplification and cloning
Patients’ clinical characteristics
A seminested strategy was used for the PCR amplification of the VH genes
using the FR2A consensus primer, complementary to the conserved
framework-2 segment of the variable region, and the LJH and VLJH
consensus primers for the J region.24 Patient samples were analyzed
together with DNA from the Raji cell line as positive control and with a
negative reagent control containing all PCR reagents without any template
DNA. PCR products were visualized on 7% nondenaturing polyacrylamide
gels stained with ethidium bromide. Patients apparently lacking PCR
products were assessed for the presence of amplifiable DNA: a 268-bp
segment of the ␤-globin gene was amplified by PCR using specific primers
(PCO4: 5⬘ CAACTTCATCCACGTTCACC 3⬘; GH20: 5⬘ GAAGAGCCAAGGACAGGTAC 3⬘).
Cloning of monoclonal cases was performed with the pGEM T-easy
vector (Promega, Madison, WI) using DNA excised and purified with
Sephacryl MicroSpin S-400 HR columns (Amersham Pharmacia Biotech,
Uppsala, Sweden) from monoclonal bands in the polyacrylamide gels.
Randomly picked recombinant clones showing the expected insert size
were analyzed using fluorescence sequencing technology on a 377 automatic DNA sequencer (Applied Biosystems, Foster City, CA) using the ABI
Most patients showed advanced stage at presentation. In all of them
prominent and disseminated nodal involvement was present;
peripheral blood involvement was not detected in any of them.
Moderate spleen enlargement, not pathologically investigated, was
reported in 3 patients, none of whom had regional lymphadenopathy. No patient had a history of previous or concurrent autoimmune
disease. The main clinical characteristics at diagnosis are summarized in Table 1.
Immunohistochemistry
Table 2 shows immunohistochemical features of the patients analyzed.
Usage of VH, DH, and JH genes
Table 3 shows the number of tumor-derived clones identified
among the total number of clones sequenced for each sample.
Sequences not related differed individually and were likely derived
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BLOOD, 1 AUGUST 2001 䡠 VOLUME 98, NUMBER 3
IMMUNOGLOBULIN VH GENES IN MONOCYTOID LYMPHOMA
783
Table 1. Patients’ main clinical characteristics at diagnosis
Case
no.
Age
(y)
1
45
Sex
ECOG
PS
Ann Arbor
stage
F
0
IV A
Nodal sites of
involvement
Cervical, axillary,
Extramodal
sites of
involvement
Site of diagnostic
biopsy
LDH
␤-2
microglobulin
AbHCVs
Serum monoclonal
immunoglobulins
NA
NA
NA
Absent
Bone marrow
Inguinal node
Bone marrow
Axillary node
Normal
Elevated
⫺
Absent
Bone marrow
Supraclavicular
Normal
NA
NA
Absent
mediastinal,
para-aortic, iliac
2
50
M
0
IV A
Mediastinal,
coeliac, paraaortic, axillary
3
69
M
0
IV A
Cervical,
supraclavicular,
node
mediastinal
4
64
5
42
M
0
F
IV A
0
III A
Inguinal node
Elevated
Elevated
⫹
IgM␬ ⫽ 0.5 g/dL
None
Axillary node
Normal
Normal
⫺
Absent
Spleen
Axillary node
Normal
⫺
Absent
Spleen, bone
Supraclavicular
Normal
⫺
IgG␭ ⫽ 1.1 g/dL
⫺
IgM␭ ⫽ 0.4 g/dL
Inguinal, axillary,
Spleen, bone
mediastinal
marrow
Inguinal, iliac,
lombo-aortic
6
68
F
0
III A
Mediastinal,
NA
axillary, cervical
7
68
M
0
IV A
Supraclavicular,
cervical, axillary
8
50
M
0
II A
Retroperitoneal
marrow
Normal
node
None
Retroperitoneal
Normal
NA
node
ECOG PS indicates Eastern Cooperative Oncology Group performance status; LDH, lactate dehydrogenase; AbHCVs, anti–hepatitis C virus antibodies; NA, not
assessed; Ig, immunoglobulin.
from contaminating normal B cells. In Table 3, the VH gene used by
each tumor and its homology with the germ line counterpart are
also reported. In 4 patients, VH gene segments were derived from
the VH3 family, in 3 patients they were derived from the VH4
family, and in one patient they were derived from the VH2 family.
No bias with respect to the previously reported27 preferential use of
the segments VH 4-34 and VH 1-69 was observed. Assignment of D
gene segments was based on the homology between CDR3
sequences and the germ line D genes. Adopting the rules proposed
by Corbett et al,28 which require at least 10 consecutive nucleotides
of identity to assign a D segment, a D gene was identified in only 3
patients (patients 2, 3, 7). In 4 patients (patients 4-6, 8), the
assignment was based on less stringent rules29: minimal homology
of 6 matches in a row or 7 matches interrupted by one mismatch.
Priority was given to the homology with a D segment when both D
and JH homologous regions overlapped (only in patients 7 and 8).
In patient 1, no rule could support D-segment assignment. JH4 was
used in 2 patients, whereas in 2 patients sequence homology was
found with the JH6 segment. JH4 is the most commonly used JH
gene segment at all stages of ontogeny,30 but the small number of
patients with an assignable germ line JH segment did not allow us to
make any conclusion about the relative frequency of this usage. No
JH segment could be assigned to patients 2 and 4. CDR3s did not
show remarkable similarities in lengths or sequence.
Table 2. Immunohistochemical characteristics of the specimens analyzed
Case
no.
CD20
CD3
CD5
CD10
sigM
sigD
CD23
Light
chain
1
⫹
NA
⫺
⫺
⫹
⫺
⫺
␬
2
⫹
NA
⫺
⫺
(⫹)
⫺
⫺
NA
3
⫹
NA
⫺
⫺
⫺
⫺
⫺
␬
4
⫹
⫺
⫺
⫺
⫹
NA
NA
␬
5
⫹
⫺
⫺
⫺
⫹
NA
NA
␭
6
⫹
⫺
⫺/⫹
⫺
⫹
⫹
NA
␬
7
⫹
⫺
⫺
⫺
⫺
⫺
NA
␭
8
⫹
NA
⫺
⫺
⫹
⫺
⫺
NA
For abbreviations, see Table 1.
Somatic hypermutations in tumor-related VH genes
Table 3 summarizes mutation patterns of the VH region. In all but 2
patients, the sequences analyzed contained somatic mutations with
respect to the closest germ line sequences. The percentage of
sequence homology ranged from 83% to 96% (Figure 1). Most
hypermutation events consisted of single base changes, but double
and triple substitutions also frequently occurred, mostly in the same
codon. In addition to point mutations, patient 5 displayed a
multiple-base segment insertion (Figure 1) in the presence of a
maintained open-reading frame, an event believed to be linked to
the hypermutation process.31 The demonstration of this finding in
our small sample, according to the value found in normal germinal
center B cells,30 further suggests the relevance of the hypermutation process in this patient. Two patients (patients 3 and 6), as stated
before, showed no somatic mutations with respect to the germ line
VH segment.
Antigen selection and coding capacity
As already stated, 2 methods were applied for the estimation of
antigen selection in the mutated B cells. The 2 methods agreed in
identifying antigen selection criteria in one patient (patient 5). Two
other patients (patients 2 and 4) only satisfied the second method
criteria. On the contrary, the 3 remaining patients with mutations
lacked signs of antigen selection considering both methods. All
patients analyzed showed a functional VH rearrangement, devoid of
stop codons.
Intraclonal nucleotide sequence variation
Extensive molecular cloning was applied to search for intraclonal
heterogeneity. In 2 patients (patients 2 and 7), the extensively
mutated clonal VH gene isolates did not show intraclonal heterogeneity. In patient 7, the analyses were applied to DNA extracted
from both lymph node and peripheral blood of the patient, but no
confirmed mutation was assessed.
In all 4 remaining patients bearing somatic mutations (patients
1, 4, 5, 8), intraclonal variability was documented according to the
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BLOOD, 1 AUGUST 2001 䡠 VOLUME 98, NUMBER 3
CONCONI et al
Table 3. Analysis of tumor-derived VH genes
Case
no.
Patient
Clone
VH
family
Gem line
V gene
Homology
(%)
R/S
CDR2
Mutation
FW3
D
segment
JH
segment
Tumor-derived
clones/clones
sequenced
Frame
CDR2
R:S ratio
FW3
R:S ratio
1
PE
M4
V H3
3-30
90
4/1
6/3
—
JH6
10/14
In
4
2
2
GM
M5
V H2
2-26
91
4/0
5/3
3-10
—
11/13
In
4
1.6
3
BA
M7
V H4
4-59/4-61
100
—
—
3-3
JH6c
12/13
In
—
—
4
ML
M14-27
V H4
4-39
94
1/1
4/3
(1-26)
—
26/28
In
1
1.3
5
FMC
M15
V H4
4-34
83
7/1
10/7
(1-14)
JH4a/b
11/11
In
7
1.4
6
CG
M19
V H3
3-23
100
—
—
(6-25)
JH4d
7/7
In
—
—
7
JS
M20-28
V H3
3-15
93
2/3
4/2
6-19
—
25/26
In
0.7
2
8
ON
M22
V H3
3-48
96
4/0
2/0
(1-1/1-20)
—
15/15
In
4
2
NA indicates not assessed.
stringent criteria applied. In patient 4, the investigations were
extended to genomic DNA extracted from lymph node and bone
marrow samples. This approach allowed us to detect intraclonal
variations.
Discussion
Analyses of antigen-receptor genes in human lymphoma may
represent a useful tool in understanding their pathogenesis and
clonal history, and it may also produce clinically relevant information.32,33 The present study was undertaken to better define the
somatic mutation pattern of immunoglobulin VH genes in nodal
MZLs to identify the possible progenitor cells of this tumor.
The rare and controversial nature of this entity suggests the need
for stringent diagnostic criteria. In our patients, diagnoses were
made according to the REAL/WHO classification, taking into
account (Figure 2) the morphologic (a typical marginal zone
pattern assessed in all patients), immunophenotypical, and clinical features.
Seven of 8 patients had an immunophenotype clearly consistent
with the diagnosis of nodal MZL. The remaining patient (patient 6)
exhibited an atypical pattern with concomitant slight CD5 and
immunoglobulin D (IgD) expression. However, CD5⫹ MZLs have
already been described,7,34 and the concurrent IgD expression has
also been reported in the nodal MZL, although it is more frequent
in splenic MZL.35 The main clinical characteristics at diagnosis,
including the rate of bone marrow involvement, were consistent
with those reported in the literature.36-39
Based on the analysis of the VH gene rearrangements in our
series, nodal MZLs appear as a heterogeneous entity with respect to
the histogenetic derivation. Indeed, MZL seems to arise from
different subsets of marginal zone B cells—virgin B cells that
express unmutated VH genes, memory B cells showing somatic
mutations, and germinal center B cells defined by their capacity to
undergo the somatic hypermutation process. Analysis of the VH
genes in nonneoplastic marginal zone B cells has also produced
contradictory results. Indeed, the possible presence of both virgin B
cells and hypermutated B cells has been reported in nodal marginal
zone B cells40 and in monocytoid B cells,26 suggesting the presence
of different modalities for the recruitment of B cells in the marginal
zone. It is of interest that 3 distinct pathways have been shown in
animal models: (1) maturation of virgin recirculating B cells, a
process that occurs in the absence of T cells and does not require
B-cell proliferation; (2) colonization by memory B cells generated
in germinal centers; (3) recruitment of both virgin and memory
marginal zone B cells into antibody responses.41
Previous studies devoted to the genetic analysis of the antigen
receptor in nodal MZL have failed to show any intraclonal
variability, probably because the approach of amplifying the VH
genes from cell populations, followed by direct sequencing of the
Figure 1. Nucleotide and deduced amino acid sequences of VH genes derived from nodal MZLs. Comparisons were made with the most homologous germ line VH genes.
Dashes represent identity with the representative germ line sequence. Nucleotide differences are shown in lowercase letters whenever a replacement mutation is concerned.
Silent mutations are shown in capital letters. Replacement amino acids are also indicated at the bottom of each scheme. One insertion (case no. 5) is shown in FW2 as extra
nucleotides.
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BLOOD, 1 AUGUST 2001 䡠 VOLUME 98, NUMBER 3
IMMUNOGLOBULIN VH GENES IN MONOCYTOID LYMPHOMA
785
Figure 2. Morphologic and immunophenotypic features of nodal MZL. (A) Low-power view showing a
parafollicular/perisinusoidal distribution of the neoplastic
cells that surround some residual B-cell follicles (hematoxylin and eosin staining (H&E), ⫻ 100). (B) High-power
view showing marginal zone/monocytoid B cells with
medium-sized round (to irregular) nuclei and abundant
pale cytoplasm (H&E, ⫻ 100). (C) CD20 staining showing strong positivity of the neoplastic cells (⫻ 400).
(D) Immunostaining for IgM, showing strong surface
staining of the neoplastic lymphocytes (⫻ 400).
PCR products, likely prevented the detection of potential ongoing
mutations within the tumor cells.21-23
Whether the subsets of nodal MZLs showing intraclonal
heterogeneity or homogeneous somatic mutations originate from
germinal center cells and post–germinal center cells, respectively,
or whether the transforming events may render the cell independent
of the influence of germinal center microenvironment is unclear.
Because neither nodal MZLs nor extranodal MZLs of MALT type
display immunophenotypical characteristics of germinal center
cells, it could be speculated that the tumor cells located in the direct
vicinity of germinal centers might be affected by the mutation
machinery active in these neighboring germinal centers.
Analysis of mutations in VH genes can provide insight concerning the role of antigen before or during lymphoma clonal outgrowth.10 All our patients showed a potentially functional VH
rearrangement. Six patients had characteristics of the presence of
somatic mutations. In one patient, as previously described in
normal B cells and in follicular lymphoma,42 insertion events have
been observed at the coding region of the VH genes. In one patient
bearing somatic mutations, there was evidence of positive selection
as demonstrated by analysis of R/S ratios in CDR2 and FW3; the
low rate of R mutations in FRW3 also suggested the negative
selection of nonfunctional immunoglobulin in this tumor. In 2 other
cases the pattern of somatic mutation in FW3 is consistent with the
structural conservation of the antigen receptor. These findings
represent the prerequisites for the identification of an antigendriven process in that prolonged exposure to an antigen may play a
role in the pathogenesis of the lymphoma. A major question is,
what is the responsible antigen. Together with follicular center,
diffuse, large B-cell lymphoma and extranodal MZL, monocytoid
B-cell lymphoma was most frequently associated with hepatitis C
virus (HCV) infection.27,43 Our small series of patients, characterized by low prevalence of HCV infection, cannot give biologic
insights into this subject.
Several lines of evidence suggest the role of an autoimmune
process in the pathogenesis of extranodal MZL,19,20 but no significant
data support the role of autoantigens in the growth and persistence
of the nodal MZL. In our series, no homologies with known
autoantibody sequences were detected, nor was there a preferential
usage of the specific VH segments previously involved in autoimmune processes and described in HCV-negative nodal MZLs.27
The heterogeneous pattern of VH gene somatic mutations
observed in our series seems to reflect the heterogeneity described
in the immunophenotypic profile of primary nodal MZLs, with
some cases resembling splenic MZL.35 Interestingly, patient 6, one
of the few to lack evidence of somatic mutations, expressed surface
IgD. The identification of different subsets of nodal MZLs with
respect to the VH mutational status seems to indicate that heterogeneous entities may fall under the definition of nodal MZLs, as
already suggested on the basis of the immunophenotypic findings.35 The possible clinical implications of these different genophenotypic patterns are still not ascertained and warrant further
investigation.
Acknowledgments
We thank Miss Michela Gisi for her expert technical assistance, Dr
Claudio Realini for helpful discussion, Dr Andrea Rossi for help
with clinical data, and Dr Lewis Rowett for reviewing the
manuscript.
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From www.bloodjournal.org by guest on June 16, 2017. For personal use only.
2001 98: 781-786
doi:10.1182/blood.V98.3.781
Nodal marginal zone B-cell lymphomas may arise from different subsets of
marginal zone B lymphocytes
Annarita Conconi, Francesco Bertoni, Ennio Pedrinis, Teresio Motta, Enrico Roggero, Stefano Luminari, Carlo
Capella, Marzia Bonato, Franco Cavalli and Emanuele Zucca
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