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Blood, Vol. 94 No. 7 (October 1), 1999:
pp. 2247-2251
Simultaneous Phenotypically Distinct but Clonally Identical
Mucosa-Associated Lymphoid Tissue and Follicular Lymphoma in a Patient
With Sjögren's Syndrome
By
Antonella Aiello,
Ming-Qing Du,
Tim C. Diss,
Huai-Zheng Peng,
Francesco Pezzella,
Daniela Papini,
Roberto Giardini,
Silvana Pilotti,
Lang-Xing Pan, and
Peter G. Isaacson
From the Department of Histopathology, University College London
Medical School, London, UK; and the Divisione Di Anatomia Patologica,
Istituto Nazionale Tumori, Milano, Italy.
 |
ABSTRACT |
A 44-year-old woman with a 12-year history of Sjögren's
syndrome (SS) developed a low-grade mucosa-associated lymphoid tissue (MALT) lymphoma in the parotid gland. Two years later, she presented with generalized lymphadenopathy and hepatosplenomegaly and a follicular lymphoma was diagnosed. To investigate the relationship of
the two histologically distinct lymphomas, we re-examined their histology and immunophenotype and studied the lymphomatous tissue from
the parotid, cervical lymph node, and spleen using molecular genetic
methods. Histologic and immunophenotypic studies confirmed the previous
diagnoses and also identified a previously unnoticed focus of
follicular lymphoma in the second parotid gland biopsy. Polymerase
chain reaction (PCR) amplification of the rearranged Ig heavy-chain
gene showed the same sized dominant product in the MALT lymphoma and
the follicular lymphoma. Similarly, PCR analysis of the t(14:18)
translocation yielded an identical sized band from both MALT and
follicular lymphoma. Cloning and sequencing of the Ig PCR products
showed an identical CDR3 sequence from each lesion,
indicating a common clonal lineage. The follicular lymphoma of the
parotid gland lymph node and the follicular lymphoma of the spleen
showed an identical mutation signature to that of the salivary gland
MALT lymphoma. We propose that follicular lymphoma in the parotid gland
lymph node may have resulted from colonization of lymphoid follicles by
MALT lymphoma cells, following which the tumor cells were induced to
express a follicular lymphoma phenotype, due to Bcl-2 overexpression
caused by t(14;18), leading to a change in clinical behavior resulting
in rapid widespread dissemination of disease. These observations
suggest that the distinct phenotypes of low-grade B-cell lymphomas may
be the consequence of interplay between genetic and local
microenvironmental factors.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
DIFFERENT LYMPHOID malignancies are
characterized by distinct cytomorphological, genetic, and clinical
features, which together form the basis of modern lymphoma
classifications. In this respect, genetic characteristics have adopted
increasing importance. An example is the t(14;18) translocation, which
results in overexpression of the bcl-2 gene and occurs in 90% of
follicular lymphomas, but is only rarely present in other low-grade
B-cell lymphomas.1 t(14;18) is believed to occur during
immunoglobulin (Ig) gene rearrangement in pre-B cells and to be the
first genetic abnormality leading to the development of follicular
lymphoma.2,3 Although t(14;18) alone is unable to cause
malignant transformation,4-7 the translocation appears to
be a crucial genetic element in predisposing the affected cell to
develop into follicular lymphoma in humans.1
B-cell lymphoma of mucosa-associated lymphoid tissue (MALT)-type is an
extranodal low-grade B-cell lymphoma that arises from lymphoid tissue
acquired after chronic inflammation, which usually has an autoimmune
basis. MALT lymphoma of the salivary glands typically occurs in
patients with chronic sialadenitis (MESA), which is often a consequence
of the autoimmune disorder Sjögren's syndrome (SS). Patients
with SS have a 44 times greater risk of developing non-Hodgkin's
lymphoma compared with normal individuals,8 and most of
these are MALT lymphomas.8-10 The lymphomas occurring in
individual SS patients frequently involve several sites, but always
belong to a single histological subtype.9,10 We report a SS
patient with both MALT and follicular lymphoma, both of which were
derived from the same precursor cell carrying t(14;18).
| |
MATERIALS AND METHODS |
Patient.
The patient was a 44-year-old woman who presented with a 12-year
history of dry mouth, symmetrical bilateral arthritis of both hands,
and swelling of the right parotid gland. Parotid biopsy showed the
histological features of SS (MALT lymphoma on review). One year later,
a repeat parotid gland biopsy showed the histological features of MALT
lymphoma. Eighteen months after the first biopsy, the patient presented
with enlargement of cervical lymph nodes and biopsy confirmed MALT
lymphoma involvement. Two years after the first biopsy, the patient
developed generalized lymphadenopathy with hepatosplenomegaly.
Laparotomy with mesenteric lymph node biopsy, liver biopsy, and
splenectomy was performed together with an inguinal lymph node biopsy.
Histologic examination of each of these tissues showed the classic
features of follicular lymphoma.
Histology and immunohistochemistry.
Routine hematoxylin and eosin (H&E)-stained sections were prepared from
each of the biopsies and their histology was reviewed. Paraffin
sections were immunostained with CD20, CD3, CD21, CD10, anti-IgM,
anti-IgD, anti- Ig light chain, anti- Ig light chain, and
anti-bcl-2 protein using the streptavidin-biotin method preceded by
heat retrieval of antigen using a domestic pressure
cooker.11 All antibodies were purchased from Dako (Bucks,
UK) with the exception of CD10, which was purchased from Novacastra
(Newcastle upon Tyne, UK).
DNA extraction and microdissection.
Genomic DNA was extracted from whole sections of both frozen and fixed
tissue samples of parotid gland, cervical and parotid lymph nodes, and
spleen as described previously.12 DNA samples were also
prepared from representative tumor cell populations of both MALT and
follicular lymphoma microdissected from CD10-stained sections of both
parotid gland (CD10 ) and spleen (CD10+)
using the method of Pan et al.13 Normal liver cells were
microdissected and the DNA extracted was used as germline control.
Polymerase chain reaction (PCR) of the rearranged Ig heavy-chain
gene and t(14;18) breakpoint.
The rearranged IgH gene was amplified from framework (Fr) 1, Fr2, and
Fr3 to the joining (J) region with consensus primers using previous
published PCR protocols.12 PCR products were analyzed on
6% (Fr1-JH, Fr2-JH) or 10% (Fr3-JH)
polyacrylamide gels.
The t(14;18) was amplified using primers directed to the major
breakpoint region (MBR) of the bcl2 gene and to the JH
region14 and products were analyzed on 7.5% polyacrylamide gels.
All PCR reactions were performed using a hot start
procedure15 and appropriate positive and negative controls
were included in each experiment. All samples were analyzed in
duplicate. To avoid any potential cross-contamination, analysis of
different tumor lesions was performed at different times.
Cloning and sequencing of PCR products.
The Fr2-JH PCR products were purified on Sephacryl S-400
MicroSpin columns (Pharmacia, St Albans, UK), then ligated to the pGEM-T vector and transformed into JM109 competent cells according to
the manufacturer's protocol (Promega, Southampton, UK). The transformed cells were selected on LB-ampicillin agar plates containing X-gal and isopropyl-1-thio- -D-galactoside (IPTG).
White colonies were screened using PCR with vector primers (Sp6 and
T7). The PCR products showing the expected insert size were sequenced
using an ABI sequencer with dye terminators (Perkin Elmer, Warrington, UK). At least 6 PCR clones from each sample were sequenced at both directions.
The Fr1-JH and t(14;18) breakpoint PCR products were directly
sequenced using an ABI sequencer with dye terminators (Perkin Elmer).
Sequence analysis.
The VH and JH germline segments used by the tumor IgH
gene were identified by sequence comparison to the V base, which is a
comprehensive database of human Ig germline gene sequences compiled from the published sequences, using online DNAPLOT (MRC
Centre for Protein Engineering,
http://www.mcr-cpe.cam.ac.uk/imt-doc/vbase-home-page.html). Mutations
in the VH region were identified by comparing the tumor sequence with
the closest published germlines, whereas mutations in the CDR3 region
were recorded according to the most closely related PCR clone.
The probability of the observed replacement or silent mutations in the
CDRs or Fr regions by chance was calculated using a binomial mutation
model as described elsewhere.16
Bcl2 and JH sequences in the t(14;18) breakpoint were
identified by comparison to the published t(14;18) breakpoint and
JH sequences using Wisconsin GCG software (provided by the
Human Genome Mapping Project, Cambridge, UK) and the GenBank Database.
| |
RESULTS |
Histology and immunohistochemistry.
Both parotid gland biopsies showed the histological features of
low-grade B-cell lymphoma of MALT-type (Fig
1A and B). The parotid gland was diffusely infiltrated by sheets of
centrocyte-like (CC-L) cells, which infiltrated parotid duct epithelium
to form characteristic lymphoepithelial lesions. There were occasional preserved reactive B-cell follicles. The CC-L cells were
CD20+, CD5, CD10,
IgM+, IgD and showed Ig light-chain
restriction. Residual CD21+ follicular dendritic cell (FDC)
meshworks were present sometimes associated with small aggregates of
CD10+ follicle center cells (Fig 1C). The cervical lymph
node biopsy showed effacement of its architecture by a diffuse
infiltrate of CC-L cells with the identical immunophenotype to those
comprising the parotid MALT-type lymphoma. As in the parotid, there was
immunohistochemical evidence of follicle center remnants (Fig 1D
through F).
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| Fig 1.
(A through C) Parotid gland MALT lymphoma. Low
magnification (A) shows diffuse infiltrate with numerous
lymphoepithelial lesions. High magnification (B) shows centrocyte-like
cells invading ductal epithelium. The lymphoma is CD10
(C) in contrast to residual reactive follicle centers. (D through F)
Cervical lymph node. Low magnification (D) shows effacement of lymph
node architecture by a diffuse infiltrate of centrocyte-like cells seen
at high magnification (E). The tumor cells are CD10 (F),
but small clusters of CD10+ residual follicle center
cells are present. (G through I) Inguinal lymph node showing the
features of follicular lymphoma at low magnification (G) and high
magnification (H). The tumor is CD10+ (I). (J through L)
Spleen showing involvement by follicular lymphoma at low magnification
(J), high magnification (K), and CD10 expression (L).
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The inguinal, mesenteric lymph nodes, and spleen showed the
histological features of follicular lymphoma. There was effacement of
normal lymphoid architecture by an infiltrate comprising closely packed
follicles characterized by a large follicle center surrounded by a
poorly formed mantle. Similar follicles were observed in the hepatic
portal triads. The follicle centers were comprised of
centrocytes and scattered centroblasts which were CD20+,
CD5, CD10+, bcl-2 protein+,
IgM+, IgD and showed light-chain
restriction (Fig 1G through L).
Review of the second parotid gland biopsy showed a small intraparotid
lymph node at one pole with retention of normal lymph node
architecture. However, on closer inspection, the B-cell follicles were
devoid of mantle zones and lacked tingible body macrophages. Moreover,
immunohistochemical staining showed that they shared the
immunophenotype of the follicular lymphoma as described above (CD10+, bcl-2 protein+, IgM+,
IgD, Ig light chain+,
[Fig 2A through
D]).
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| Fig 2.
Low magnification (A) shows parotid infiltrated by MALT
lymphoma (P) and intraparotid lymph node (LN) with preservation of
normal architecture. High magnification of intraparotid lymph node
follicle center (B) shows centrocytes with occasional centroblasts and
absence of tingible body macrophages. Immunostaining
with CD10 (C) shows absence of staining in MALT lymphoma. The lymph
node follicle centers are positive and emphasize the normal nodal
architecture. Expression of bcl-2 protein by the lymph node follicle
centers (D) is indicative of the neoplastic nature of the follicle
center cells.
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Analysis of the rearranged Ig gene.
PCR analysis of the rearranged Ig gene was first performed on DNA
samples prepared from whole sections of parotid gland, cervical lymph
nodes, and spleen biopsies. All samples yielded an identical sized band
on polyacrylamide gels with both Fr2-JH and Fr3-JH primers. The Fr2-JH PCR products were cloned and sequenced. A dominant clone was found in each of the above samples and was identical
in the CDR3 sequence in each lesion (Fig
3), indicating a common clonal origin. To verify that Fr2-JH
PCR truly reflected the MALT lymphoma examined rather than
a biased amplification of a minute disseminated
follicular lymphoma cell population due to somatic mutation of the MALT
lymphoma clone or vice versa, we performed Fr1-JH PCR, which
is less affected by somatic mutation, from high molecular DNA isolated
from frozen samples of parotid gland and spleen biopsies. Direct
sequencing Fr1-JH PCR yielded identical results to those
obtained from Fr2-JH PCR. Furthermore, Fr3-JH PCR
analysis of representative tumor cell populations microdissected from
both MALT (CD10 CCL cells of the parotid gland
biopsy) and follicular lymphoma (neoplastic follicle of the spleen)
showed the same sized monoclonal band.
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| Fig 3.
Comparison of IgH sequence among different lesions. PG1,
first parotid gland biopsy; PG2, second parotid gland biopsy; Neck-LN,
neck lymph node; Sp, spleen; Sp-FC, spleen CD10+ follicle
center cells; IPLN-FC, CD10+ follicle center cells of the
intraparotid lymph node in the second parotid biopsy. The number in
brackets shows the number of common clones of the number of total tumor
clones sequenced. Identity to the germline sequences is shown by
dashes, replacement mutations by uppercase, and silent mutations by
lowercase letters.
|
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The VH sequence of the tumor-derived Ig gene was aligned with
the closest germline VH segment obtained from a sequence
similarity search of the GenBank Database and mutations were
identified. Comparison of the Ig gene sequences of the different
lymphoma lesions showed the same sequence shared by MALT lymphoma of
the parotid gland, cervical lymph node, and surprisingly by the
follicular lymphoma of the spleen (Fig 3). The common lymphoma clone
showed a significantly low ratio of replacement/silent
(R/S) mutation in the Fr region (P < .02) and
intraclonal sequence variations were observed.
The microdissected neoplastic follicle centers in the intraparotid
lymph node of the second parotid gland biopsy and spleen were similarly
studied using the above strategy. The CD10+ cells of the
follicles were found to be clonally identical to the MALT lymphoma (Fig
3).
Analysis of the t(14;18) breakpoint.
PCR analysis of the t(14;18) breakpoint in DNA samples prepared from
the whole section of the lymphoma of the parotid gland, cervical lymph
node, and spleen yielded an identical sized band on polyacrylamide
gels. To ascertain that the finding of t(14;18) translocation in MALT
lymphoma was not the result of dissemination of the follicular lymphoma
cells, representative CD10 tumor cells from the MALT
lymphoma were microdissected, analyzed, and identical products were
seen. Sequencing of these PCR products showed identical breakpoint
sequences in each lesion (data not shown).
PCR analysis of DNA extracted from microdissected normal liver cells
showed no evidence of the translocation, which confirmed that t(14;18)
in the lymphoma was acquired rather than a germline characteristic.
| |
DISCUSSION |
The sequence of events in the case reported here appears to be as
follows. The initial parotid gland enlargement, 12 years after the
onset of SS, was due to the development of MALT lymphoma, which was
confirmed in the second parotid biopsy 1 year later and in the cervical
lymph node after a further 6 months. At this time, follicular lymphoma
was already present in germinal centers of an otherwise normal
appearing intraparotid lymph node and soon manifested as typical stage
IV disease with involvement of peripheral lymph nodes, spleen, and liver.
MALT lymphoma and follicular lymphoma are clinicopathologically
distinct tumors that are recognized in the revised European American
lymphoma classification as different "diseases."17 The former is an extranodal lymphoma that tends to remain localized (stage IE or IIE) for a prolonged period, which
is in keeping with its remarkable clinical indolence.18 The
normal cell counterpart of MALT lymphoma is thought to be the marginal
zone B cell, which accounts for its cytological features, CD10 negative
immunophenotype, and typical growth pattern as a diffuse infiltrate
initially around reactive B-cell follicles. MALT lymphoma is not yet
defined by a molecular genetic abnormality, although recently it has
been suggested that t(11;18) may be characteristic.19,20
Rare instances of t(14;18) in MALT lymphoma have been
reported.21,22 By contrast, follicular lymphoma is a nodal
tumor that only infrequently arises in extranodal sites and is usually
widely disseminated (stage IV) at the time of diagnosis. The normal
cell counterpart is the follicle center cell (centroblast and
centrocyte), and the tumor typically grows as a collection of
neoplastic follicles comprising CD10+ centroblasts and
centrocytes with a minor interfollicular diffuse component in some
cases.23 In over 90% of cases, t(14;18) is present.1
Analysis of the rearranged Ig gene and the t(14;18) breakpoint showed
that the MALT and follicular lymphomas in this patient had identical
CDR3 and breakpoint sequences, indicating a common clonal origin from
the same precursor cell, which harbored the t(14;18) translocation. How
can we explain the presence in this patient of these two
clinicopathologically and immunophenotypically different lymphomas
that, on molecular grounds, are clonally identical?
One explanation is that a "premalignant" cell bearing the
t(14;18) may have undergone separate transforming events at two distinct sites resulting in the two phenotypic lymphomas observed. Alternatively, the explanation may lie, in part, in the phenomenon known as follicular colonization.24,25 In this process MALT lymphoma cells selectively colonize reactive (ie, non-neoplastic) follicle centers where they may undergo a degree of transformation. This may occur either in the original extranodal site or in adjacent lymph nodes. Follicular colonization is typically a focal phenomenon and the cells in the colonized follicles retain their MALT lymphoma cytomorphology and immunophenotype, being CD10 and,
interestingly, often losing their bcl-2 expression.26 Because individual follicles in the intraparotid lymph node showed the
immunophenotypic and genotypic features of follicular lymphoma, the
possibility must be considered that the presence of t(14;18) in the
MALT lymphoma clone influenced the cells that colonized the follicle
centers in the intraparotid lymph node to acquire the cytomorphology,
immunophenotype, and biological characteristics of follicular
lymphoma.The t(14;18) translocation rarely occurs in MALT lymphoma, but is the
genetic hallmark of follicular lymphoma.1,22 The finding
that the same cell with the t(14;18) translocation evolved into both
MALT and follicular lymphoma is unprecedented. It has been shown that
the t(14;18) translocation is a crucial element in the genesis of
follicular lymphoma, but not in other lymphomas, despite occurrence of
the translocation at pre-B cells, several stages earlier in B-cell
development than the normal cell counterpart of this tumor. This is
best explained by the effect of deregulated bcl-2 expression on cell
growth or survival, which is maximized in the germinal center
microenvironment in which normal germinal center B cells undergo active
cell proliferation or apoptosis and do not express Bcl-2 before leaving
the germinal center.27 The same mechanisms may apply to
transformed clones, as shown in the present case. Thus, the genesis of
particular subtypes of B-cell lymphoma may depend on the interplay
between genetic [t(14;18)] and environmental (the follicle center) factors.
| |
ACKNOWLEDGMENT |
We thank Donata Penso for technical help on part of the sequencing work.
| |
FOOTNOTES |
Submitted February 25, 1999; accepted June 3, 1999.
Supported by the Leukaemia Research Fund and Associazione Italiana per
la Ricerca sul Cancro.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Peter G. Isaacson, MD,
Department of Histopathology, University College London Medical School,
Rockefeller Building, University St, London WC1E 6JJ, UK; e-mail:
p.isaacson{at}ucl.ac.uk.
| |
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ABSTRACT
INTRODUCTION