Blood, 1 August 2002, Vol. 100, No. 3, pp. 1095-1097
CORRESPONDENCE
To the editor:
Pathogenic complexity of gastric B-cell lymphoma
We read with great interest the recent work of Starostik
et al regarding gastric marginal zone B-cell lymphomas of
mucosa-associated lymphoid tissue (MALT) type and their findings,
suggesting 2 distinct pathogenic pathways of development for this
lymphoma type.1 The findings obtained by us with a
different technique and in an independent population2 are
in very good agreement with their data and thus support the conclusion
drawn by the authors, highlighted in the accompanying summary by
Dan Longo.3 They supplement various other studies in
this field,4-6 confirming our concept of at least 2, if not 3, distinct genetic subgroups.
We studied 52 extranodal B-cell lymphomas: 18 extranodal
marginal zone B-cell lymphomas of MALT type (MZBL-MTs), 7 MZBL-MTs of the gastrointestinal tract with a diffuse large B-cell
component (giMZBLplusLBCLs), and 27 diffuse large
B-cell lymphomas of the gastrointestinal tract without small cell
component (giLBCLs) using comparative genomic hybridization (CGH) and
fluorescence in situ hybridization (FISH). The translocation t(11;18)
was found as the sole aberration in 2 MZBL-MTs only, favoring the view
that this translocation blocks this lymphoma from further progression into a large-cell variant.7-9 In contrast,
t(11;18)-negative MZBL-MTs were characterized by frequent gains on
chromosome 3 and DNA amplifications on 2p13-p15, including the
REL proto-oncogene. Furthermore, we found a clonal lymphoma
progression from the small to the large cell component with
accumulation of gains and losses of chromosomal material in the
large-cell component in giMZBLplusLBCLs. Aberrations
overlapping with MZBL-MTs and giMZBLplusLBCLs
included losses on chromosome 13, amplifications of the REL
proto-oncogene or gains on chromosome 12. Additionally, the large-cell
component revealed gains on 8q24, including amplifications of the
MYC proto-oncogene, and losses on 2q. The giLBCLs had
frequent gains on chromosomes 12, 9, and 11q and losses on
6q.10 We concluded that, based on the distinctive and
partly overlapping patterns of genetic aberrations, MALT lymphomas can
be divided into different genetic subgroups (Figure
1). First, MZBL-MTs may be divided
according to presence or absence of t(11;18). t(11;18)-positive cases
have no further detectable aberrations and are therefore characterized by high biological stability. Second, t(11;18)-negative MZBL-MTs have a
characteristic pattern of gains and losses with frequent gains on
chromosome 3. But the presence of overlapping aberrations such as
amplifications of the REL proto-oncogene, losses on 13q, and
the identical IgH rearrangement of the small- and large-cell component
reflect clonal evolution of MZBL-MTs toward the LBCLs. Third, a subset
of giMZBLplusLBCLs shows a high frequency of
gains on 8q24, including amplifications of the MYC
proto-oncogene and losses on 2q. This suggests a different line of
lymphomagenesis and progression for at least some of these lymphomas,
since these aberrations are not present in giLBCLs and suggest the
presence of diffuse large B-cell lymphoma arising de novo. Furthermore, a recent report further fueled discussion by showing that biclonal gastric lymphomas exist as true composite stomach
lymphomas.11 Therefore, the pathogenic pathways leading to
gastric lymphomas are likely to be even more complex than suggested by
Starostik et al.
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| Figure 1.
Hypothetical grouping of mucosa-associated B-cell lymphomas on the
basis of molecular cytogenetics.
"+" refers to gains and " ," to losses of chromosomal material
on the given chromosomal region; "*" refers to aberrations
significantly more frequent in giMZBLplusLBCL.
(Figure slightly modified from Barth et al,2 ©2001
Wiley-Liss Inc, a subsidiary of John Wiley & Sons. Used by
permission.)
|
|
Thomas F. E. Barth, Martin Bentz, Frank Leithäuser, Stephan Stilgenbauer, Reiner Siebert, Magdalena Schlotter, Richard F. Schlenk, Hartmut Döhner, and Peter Möller
Correspondence: Thomas F. E. Barth, Institute of Pathology,
University of Ulm, Albert-Einstein-Allee 11, D-89 081 Ulm, Germany;
e-mail: thomas.barth{at} medizin.uni-ulm.de
References
1.
Starostik P, Patzner J, Greiner A, et al.
Gastric marginal zone B-cell lymphomas of the MALT type develop along 2 distinct pathogenetic pathways.
Blood.
2002;99:3-8[Abstract/Free Full Text].
2.
Barth TFE, Bentz M, Leithäuser F, et al.
Molecular-cytogenetic comparison of mucosa-associated marginal zone B-cell lymphoma and large B-cell lymphoma arising in the gastro-intestinal tract.
Genes Chromosomes Cancer.
2001;31:316-325[CrossRef][Medline]
[Order article via Infotrieve].
3.
Longo D.
Gastric lymphoma: a tale of 2 MALTs.
Blood.
2002;99:1[Free Full Text].
4.
Peng H, Du M, Diss TC, Isaacson PG, Pan L.
Genetic evidence for a clonal link between low and high-grade components in gastric MALT B-cell lymphoma.
Histopathol.
1997;30:425-429[CrossRef][Medline]
[Order article via Infotrieve].
5.
Hoeve MA, Gisbertz IAM, Schouten HC, et al.
Gastric low-grade MALT lymphoma, high-grade MALT lymphoma and diffuse large B cell lymphoma show different frequencies of trisomy.
Leukemia.
1999;13:799-807[CrossRef][Medline]
[Order article via Infotrieve].
6.
Zucca E, Bertoni F, Roggero E, et al.
Molecular analysis of the progression from Helicobacter Pylori-associated chronic gastritis to mucosa-associated lymphoid tissue lymphoma.
N Engl J Med.
1998;338:804-810[Free Full Text].
7.
Ott G, Katzenberger T, Greiner A, et al.
The t(11;18)(q21;q21) chromosome translocation is a frequent and specific finding in low-grade, but not high-grade malignant non-Hodgkin's lymphomas of mucosa-associated lymphoid tissue (MALT)-type.
Cancer Res.
1997;57:3944-3948[Abstract/Free Full Text].
8.
Dierlamm J, Baens M, Wlodarska I, et al.
The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with MALT lymphomas.
Blood.
1999;93:3601-3609[Medline]
[Order article via Infotrieve].
9.
Baens M, Maes B, Steyls A, et al.
The product of the t(11;18), an API2-MLT fusion, marks half of gastric MALT type lymphomas without large cell proliferation.
Am J Pathol.
2000;156:1433-1439[Abstract/Free Full Text].
10.
Barth TFE, Döhner H, Werner CA, Stilgenbauer S, et al.
Characteristic pattern of chromosomal gains and losses in primary large B-cell lymphomas of the gastro-intestinal tract.
Blood.
1998;91:4321-4330[Abstract/Free Full Text].
11.
Cabras AD, Candidus S, Fend F, et al.
Biclonality of gastric lymphomas.
Lab Invest.
2001;81:961-967[Medline]
[Order article via Infotrieve].
Response:
An emerging concept of diverse pathogenetic pathways in
gastric B-cell lymphoma
The pathogenesis of extranodal gastric marginal zone
B-cell lymphoma of MALT type (eMZBCL) and its aggressive counterpart, extranodal gastric diffuse large B-cell lymphoma (eDLBCL), is a jigsaw
puzzle composed of many pieces: genetic aberrations occurring during
lymphomagenesis. Taking the simplest approach, using classical cytogenetic analysis our group identified a translocation,
t(11;18)(q21;q21), whose presence or absence divides the eMZBCLs into 2 groups: t(11;18)-positive ones and t(11;18)-negative
ones.1,2 Already at that time, it was noticed that the
eDLBLs did not display this translocation. These findings were
confirmed by others later.3-5 In a recent paper,6 Barth and colleagues agree with these concepts of
fundamental difference in the pathogenesis of eMZBCLs and eDLBCLs and
offer a hypothesis on the further subgrouping of the t(11;18)-negative tumors. Although they have only 2 t(11;18)-positive lymphomas in their
series and the frequency of aberrations they are able to detect is
influenced by the lower sensitivity of the analytic method used
(comparative genomic hybridization), they arrive at similar conclusions
we presented in a recently published microsatellite study7: namely, that the API2-MALT1 rearrangement
introduced by the t(11;18) in 20%-50% of eMZBLs, but not in eDLBLs,
leads to an intriguing cytomorphologic and karyotypic stability of the tumors, which is reflected in the resistance of the t(11;18)-positive eMZBLs to lymphoma eradication by antibiotic treatment directed against
Helicobacter pylori.8 In contrast, the
t(11;18)-negative eMZBCLs are characterized by increased frequency of
genetic aberrations. The spectrum of alterations identified by both
groups (by different methods) in the t(11;18)-negative eMZBCLs is quite
similar (aberrations on chromosomes 3, 11, and 18). In the high-grade
eDLBCLs, with the exception of gains on 8q24 and 9q, the results for
chromosomes evaluated by Barth et al are analogous. Particularly, if
one compares studies performed using the same technique: the
comparative genomic hybridization (CGH) study of Barth et al with a
previously published CGH study by Peters et al,9 the
latter performed on exactly the same material we used for
microsatellite analysis.
But one must remain cautious regarding the grouping of the
t(11;18)-negative tumors, as depicted in Figure 1 of Barth et al's preceding letter. Aberrations displayed here are puzzle pieces that
have not found their proper places yet; they were just recognized to
belong to the game. Some of the alterations in the proposed groups,
such as gains on chromosomes 7 in the eMZBCL or 18 in the eDLBCL, have
been each identified in one case only, raising questions regarding the
significance of these findings. Other frequent aberrations from our
work (losses of the p53 and APC gene loci) not
detected by CGH due to the shortcomings of this method were not
considered in this scheme at all. Moreover, the analyzed material was
heterogeneous; only 50% of the eMZBLs were tumors of gastric origin.
This contrasts with our work, in which only gastric lymphomas were
analyzed. Differences in origin are known to be reflected in the
frequency of the t(11;18)10,11 in these lymphomas and
could lead also to different genetic aberrations suffered during
lymphomagenesis. Thus, conclusions based on the data obtained by Barth
et al should be called a hypothesis awaiting a confirmation.
Our data also support the role of aberrations on chromosomes 3, 11, and 18 in the development of (secondary?) eDLBCL. Deletions of 5q21
(APC), 9p21(INK4A/ARF), 13q14 (RB),
and 17p13 (p53) seem to make the difference between eMZBCLs
and eDLBCLs, as we detected them in the latter only. Most interesting,
however, is the striking difference in the frequency of 6q aberrations
in the eMZBCLs versus eDLBCLs and the fact that we were able to
identify 2 groups of DLBCLs characterized by the 3q and 6q aberrations,
respectively. These data invite the hypothesis that possibly the 3q
eDLBCL group could encompass secondary DLBCLs arising by
transformation from a pre-existing eMZBCL showing the same
aberration. The 6q aberration displaying cases might be primary
eDLBCLs. Currently, work is in progress to clarify the importance of 6q
deletions in primary high-grade eDLBL and in tumors containing both
eMZBCL and eDLBCL components. We will be happy to cooperate in the
further characterization of these tumors with other groups, especially
if they have suitable material available.
We agree completely that pathogenetic pathways in gastric B-cell
lymphoma are a puzzle that is still pretty far from being solved. The
scheme will not be simple, but we must start from a common denominator.
We must keep in mind that the aberrations described in both works
occurred at the genomic DNA level. It will be a major step to proceed
from the rather insensitive method of DNA screening to the
identification of the relevant candidate genes and the evaluation of
their role in the lymphomagenesis of gastric B-cell lymphoma.
Petr Starostik, Axel Greiner, Jörg Kalla, Andreas Zettl, and Hans Konrad Müller-Hermelink
Correspondence: Petr Starostik, Roswell Park Cancer Institute,
Department of Pathology and Laboratory Medicine, Elm & Carlton Streets,
Buffalo, NY 14263; e-mail: petr.starostik{at}roswellpark.org
References
1.
Ott G, Katzenberger T, Greiner A, et al.
The t(11;18)(q21;q21) chromosome translocation is a frequent and specific aberration in low-grade but not high-grade malignant non-Hodgkin's lymphomas of the mucosa-associated lymphoid tissue (MALT-) type.
Cancer Res.
1997;57:3944-3948[Abstract/Free Full Text].
2.
Rosenwald A, Ott G, Stilgenbauer S, et al.
Exclusive detection of the t(11;18) (q21;q21) in extranodal marginal zone B cell lymphomas (MZBL) of MALT type in contrast to other MZBL and extranodal large B cell lymphomas.
Am J Pathol.
1999;155:1817-1821[Abstract/Free Full Text].
3.
Baens M, Maes B, Steyls A, Geboes K, Marynen P, De Wolf-Peeters C.
The product of the t(11;18), an API2-MLT fusion, marks nearly half of gastric MALT type lymphomas without large cell proliferation.
Am J Pathol.
2000;156:1433-1439[Abstract/Free Full Text].
4.
Dierlamm J, Wlodarska I, Michaux L, et al.
Genetic abnormalities in marginal zone B-cell lymphoma.
Hematol Oncol.
2000;18:1-13[CrossRef][Medline]
[Order article via Infotrieve].
5.
Remstein ED, James CD, Kurtin PJ.
Incidence and subtype specificity of API2-MALT1 fusion translocations in extranodal, nodal, and splenic marginal zone lymphomas.
Am J Pathol.
2000;156:1183-1188[Abstract/Free Full Text].
6.
Barth TF, Bentz M, Leithauser F, et al.
Molecular-cytogenetic comparison of mucosa-associated marginal zone B-cell lymphoma and large B-cell lymphoma arising in the gastro-intestinal tract.
Genes Chromosomes Cancer.
2001;31:316-325[CrossRef][Medline]
[Order article via Infotrieve].
7.
Starostik P, Patzner J, Greiner A, et al.
Gastric marginal zone B-cell lymphomas of MALT type develop along 2 distinct pathogenetic pathways.
Blood.
2002;99:3-9[Abstract/Free Full Text].
8.
Liu H, Ruskon-Fourmestraux A, Lavergne-Slove A, et al.
Resistance of t(11;18) positive gastric mucosa-associated lymphoid tissue lymphoma to Helicobacter pylori eradication therapy.
Lancet.
2001;357:39-40[CrossRef][Medline]
[Order article via Infotrieve].
9.
Peters K, Zettl A, Starostik P, et al.
Genetic imbalances in primary gastric diffuse large B-cell lymphomas: comparison of comparative genomic hybridization, microsatellite, and cytogenetic analysis.
Diagn Mol Pathol.
2000;9:58-65[CrossRef][Medline]
[Order article via Infotrieve].
10.
Yonezumi M, Suzuki R, Suzuki H, et al.
Detection of AP12-MALT1 chimaeric gene in extranodal and nodal marginal zone B-cell lymphoma by reverse transcription polymerase chain reaction (PCR) and genomic long and accurate PCR analyses.
Br J Haematol.
2001;115:588-594[CrossRef][Medline]
[Order article via Infotrieve].
11.
Ye H, Dogan A, Liu H, et al.
Markedly variable frequencies of t(11;18)(q21;q21) in different MALT lymphomas [abstract].
Blood.
2001;98:767a.
