Variable frequencies of MALT lymphoma-associated genetic aberrations in MALT
lymphomas of different sites
B Streubel1, I Simonitsch-Klupp1, L Mu ¨llauer1, A Lamprecht1, D Huber1, R Siebert2, M Stolte3, F Trautinger4, J Lukas5, A Pu ¨spo ¨k6,
M Formanek7, T Assanasen8, H-K Mu ¨ller-Hermelink8, L Cerroni9, M Raderer10and A Chott1
1Institute of Pathology, Vienna General Hospital, Medical University of Vienna, Vienna, Austria;2Institute of Human Genetics,
University Hospital Schleswig-Holstein, Campus Kiel, Germany;3Department of Pathology, Klinikum Bayreuth, Bayreuth,
Germany;4Institute of Dermatology, Vienna General Hospital, Medical University of Vienna, Vienna, Austria;5Institute of
Ophthalmology, Vienna General Hospital, Medical University of Vienna, Vienna, Austria;6Division of Gastroenterology, Internal
Medicine IV, Vienna General Hospital, Medical University of Vienna, Vienna, Austria;7Division of Oto-Rhino-Laryngology,
Vienna General Hospital, Medical University of Vienna, Vienna, Austria;8Institute of Pathology, Wu ¨rzburg University, Wu ¨rzburg,
Germany;9Institute of Dermatology, Medical University of Graz, Graz, Austria; and10Division of Oncology, Internal Medicine I,
Vienna General Hospital, Medical University of Vienna, Vienna, Austria
Although several recurrent genetic aberrations are known to
occur in MALT lymphoma, no comprehensive study on the
most prevalent MALT lymphoma-associated genetic aberra-
tions is available. We therefore screened 252 primary MALT
(q32;q21), and t(1;14)(p22;q32), and trisomies 3 and 18. The
above-listed translocations occurred mutually exclusively and
were detected overall in 13.5, 10.8, and 1.6% of the cases;
trisomy 3 and/or 18 occurred in 42.1%. The frequency at which
the translocations occurred varied markedly with the primary
site of disease. The t(11;18)(q21;q21) was mainly detected in
pulmonary and gastric tumors, whereas the t(14;18)(q32;q21)
was most commonly found in lesions of the ocular adnexa/
orbit, skin, and salivary glands. Trisomies 3 and 18 each
occurred most frequently in intestinal and salivary gland MALT
lymphomas. Our results demonstrate that the three transloca-
tions and trisomies 3 and 18 occur at markedly variable
frequencies in MALT lymphoma of different sites.
Leukemia (2004) 18, 1722–1726. doi:10.1038/sj.leu.2403501
Published online 9 September 2004
Keywords: MALT lymphoma; genetics; MALT1; API2; BCL10
Extranodal marginal zone B-cell lymphoma of mucosa-asso-
ciated lymphoid tissue (MALT lymphoma) is listed as a distinct
clinicopathologic entity in the WHO classification of malignant
lymphomas.1The majority of MALT lymphomas occur in the
stomach, but this type of lymphoma may affect virtually every
organ in the human body, including the ocular adnexa and
orbit, lung, salivary glands, thyroid, skin, and intestine.2
Histologically, MALT lymphomas are characterized by a
proliferation of neoplastic marginal zone-related cells that
invade epithelial structures to generate lymphoepithelial lesions
and colonize reactive lymphoid follicles.3The MALT lymphoma
concept suggests that these tumors correspond to cells of
postfollicular differentiation stages and usually arise from
lymphoid tissue acquired by chronic antigenic stimulation
triggered by persistent infections and/or autoimmune pro-
One of the most interesting aspects of MALT
lymphoma is the accumulating evidence of microbial agents
involved in its pathogenesis. The first to be reported has been
the association of Helicobacter pylori with gastric disease,6
followed by the linkeage of Borrelia burgdorferi with cutaneous
tumors,7then almost simultaneously the association of Chla-
mydia psittaci with ocular adnexal MALT lymphoma and of
Campylobacter jejuni with a extremely rare variant of MALT
lymphoma known as immunoproliferative small intestinal
disease (IPSID), respectively.8,9This acquired lymphoid tissue
becomes genetically unstable with the acquisition of structural
abnormalities such as t(1;14)(p22;q32),10t(11;18)(q21;q21),11,12
and the most recently described t(14;18)(q32;q21) involving the
immunoglobulin heavy chain locus (IGH) and MALT1,13as well
as numerical aberrations such as trisomy 3 and trisomy 18,14
leading to transformation into MALT lymphoma. The specific
events responsible for the genetic aberration(s) remain to be
discovered and, with the exception of the t(11;18)(q21;q21),
which fuses the amino terminal of the API2 gene to the carboxyl
terminal of the MALT1 gene generating a chimeric API2–MALT1
fusion transcript,15the true incidence of these genetic abnorm-
alities is unknown. In order to evaluate the overall frequency
and the frequency relative to lymphoma site, we analyzed a
large series of MALT lymphomas for the above-mentioned
translocations and the numerical aberrations þ3 and þ18.
Patients and methods
The study group comprised 252 MALT lymphoma cases derived
from the primary site of disease presentation. Formalin-fixed and
paraffin-embedded tissue samples of biopsies or surgical
resection specimens were retrieved from the authors’ institu-
tions. For inclusion in this study, the cases were required to
fulfill the histologic and immunohistologic criteria defined for
MALT lymphoma in the WHO classification of tumors of
hematopoietic and lymphoid tissues.1Furthermore, the cases
were selected for the amount of tumor tissue sufficient for
reverse transcriptase polymerase chain reaction (RT-PCR) and
fluorescence in situ hybridization (FISH) studies. The immuno-
phenotype of the tumor cells, as assessed on paraffin sections,
was CD20þ, cyclin D1?, CD23?, CD5?, bcl-6?, and
CD10?. Among the 252 MALT lymphoma cases, 71 cases
were from the stomach; 51 from the skin; 42 from the salivary
glands; 37 arose from the ocular adnexa/orbit; 16 from the
intestine (small intestine, n¼5; large intestine, n¼11); 15 from
the lung; six from the thyroid; five from the breast; four each
from the liver and urogenital tract; and one from the
Received 25 June 2004; accepted 3 August 2004; Published online 9
Correspondence: Dr A Chott, Institute of Pathology, Vienna General
Hospital, Wa ¨hringerGu ¨rtel18-20,
Fax: (þ431)404003707; E-mail: firstname.lastname@example.org
Leukemia (2004) 18, 1722–1726
& 2004 Nature Publishing Group All rights reserved 0887-6924/04 $30.00
The presence of tumor cells was evaluated in each tissue
block on hematoxylin and eosin-stained slides cut before and
after the sections used for FISH or RT-PCR analyses. Data on 75
patients have been part of previous publications.13,16–18
Detection of t(11;18) by RT-PCR
RNA was isolated from archival formalin-fixed, paraffin-
embedded lymphoma tissues. Total RNA was extracted from
10mm sections with a high pure RNA paraffin kit (Roche
Diagnostics, Mannheim, Germany). First-strand cDNA was
synthesized from 1mg total RNA with a superscript first-strand
synthesis system (Invitrogen, Carlsbad, CA, USA) using random
hexamers as primers. RT-PCR for the detection of the API2-
MALT1 fusion transcript was performed according to Inagaki
et al,19with one modification: first round RT-PCR products were
amplified in a second round separately and not as multiplex
nested PCRs in order to discriminate the various fusion signals.
Where indicated PCR products were sequenced using dRhoda-
mine dye terminators on an ABI Prism 310 (PE Applied
Biosystems, Foster City, CA, USA).
In all 252 cases, formalin-fixed paraffin-embedded tissue was
used for FISH. For a reliable interpretation of the hybridization
signals, we preferred the analysis of single-cell suspensions to
thin sections. FISH was performed on interphases with the
following probe sets: for the detection of the t(14;18)(q32;q21)
involving IGH and MALT1, P1 artificial chromosome (PAC)
152M5 (SpectrumOrange labeled) spanning the MALT1 gene
and flanking regions and bacterial artificial chromosome (BAC)
158A2 were used;13for rearrangements of BCL10, BACs RP11-
1077C10 and RP11-36L4 (SpectrumGreen) centromeric to
BCL10 and RP11-1080I1 and RP11-40K4 (SpectrumOrange)
telomeric to BCL10 were used.20In cases with rearrangement of
BCL10, FISH with a dual-color, break apart rearrangement
probe for IGH (Vysis, Downer’s Grove, IL) was performed; FISH
with BAC 158A2 for IGH and BACs RP11-1080I1 and RP11-
40K4 telomeric toBCL10
t(1;14)(p22;q32). For the detection of trisomies 3 and 18, we
applied centromere-specific probes for the chromosomes 3
(SpectrumOrange) and 18 (SpectrumGreen) (Vysis).
The cutoff value for the diagnosis of each probe set was the
mean percentage of cells with a false-positive signal constella-
tion plus 3 standard deviations, as assessed on tissue from 20
reactive lymph nodes.
The t(11;18)(q21;q21) and the t(14;18)(q32;q21)
occurred at markedly variable frequencies in MALT
lymphomas of different sites
The RT-PCR and FISH results are summarized in Table 1 and
schematically illustrated in Figure 1. Among the 252 MALT
lymphomas, 34 (13.5%) were positive for t(11;18)(q21;q21).
This finding was confirmed by FISH as all of these 34 cases
exhibited a split signal for MALT1, but no IGH/MALT1 fusion
signals. Conversely, FISH did not identify a t(11;18)(q21;q21)þ
case among those tested negative by RT-PCR, indicating 100%
concordance of the two techniques. Furthermore, in the
translocation-positive cases, two normal signals were generated
for BCL10, centromere 3 and centromere 18, indicating that the
t(11;18)(q21;q21) did not occur in combination with either
t(14;18)(q32;q21) or BCL10 rearrangement or any of the two
trisomies. The t(11;18)(q21;q21) was found at the highest
frequencies in MALT lymphomas derived from the lung
(53.3%) and stomach (23.9%), and at a moderate frequency in
those from the intestine (12.5%). The translocation was seen in
7.8% of cutaneous MALT lymphomas and in only one
lymphoma each of salivary gland (2.4%) and ocular adnexa/
orbit (2.7%), but was absent in tumors arising in the breast, liver,
and urogenital tract.
The distribution of breakpoints in both the API2 and MALT1
genes among MALT lymphomas of different sites was similar
(data not shown) and also similar to those reported.20
The t(14;18)(q32;q21) was identified in 27 (10.8%) of the 252
cases and, as already reported, was detected in all four hepatic
MALT lymphomas analyzed.13Among the more common sites
at which MALT lymphomas arise, the translocation was found in
lesions of the ocular adnexa/orbit (24.3%), skin (13.7%), salivary
gland (11.9%), and lung (6.7%), but was absent in the intestine,
breast, urogenital tract, and thyroid. In a series of MALT
lymphomas occurring in patients with Sjo ¨gren’s syndrome, we
t(14;18)(q32;q21)þ gastric MALT lymphoma,18who is included
in the present work. This patient was staged extensively
according to Raderer et al,16without evidence of extragastric
disease at presentation and at 2 years of follow-up. Separated
the first patientwitha
Table 1 Frequency of genetic aberrations in MALT lymphomas of different sites
Trisomy 3 cases,
cases, no. (%)
X1 Genetic aberration
cases, no. (%)
Total 25234 (13.5)27 (10.8)4 (1.6)78 (30.9) 28 (11.2)142 (56.4)
aIn an additional case, MALT1 amplification was detected.
Genetic aberrations in MALT lymphoma
B Streubel et al
MALT1 signals and hence MALT1 gene rearrangement were
confined to cases with either t(11;18)(q21;q21) or t(14;18)
(q32;q21), indicating that these two translocations represent the
main structural aberrations involving MALT1.
t(1;14)(p22;q32) is exceedingly rare in MALT lymphoma
BCL10 rearrangement was found in only four of the 252 cases
(1.6%) and IGH at band 14q32 represented the translocation
partner in all cases. Two of the MALT lymphomas harboring the
t(1;14)(p22;q32) arose from the rectum and sigmoid colon,
respectively, and were thus detected in 13% of the intestinal
tumors; the remaining two cases derived from the lung and
parotid gland. No amplification of BCL10 was observed.
Trisomy 3 and trisomy 18 occur at markedly variable
frequencies in MALT lymphomas of different sites
Trisomy 3 was observed in 30.9% of the cases and most
frequently occurred in MALT lymphomas of the intestine (75%),
salivary gland (54.8%), lung (20%), and skin (19.6%). The
overall incidence of trisomy 18 was lower (11.2%) and this
aberration occurred most frequently in MALT lymphomas of the
intestine (25%) and salivary gland (19%).
MALT lymphoma represents one of the most common B-cell
neoplasms and arises by definition at an extranodal site. As a
distinct disease entity listed in the WHO classification, the
definition of MALT lymphoma is supposed to be a combination
of morphology, immunophenotype, genetic, and clinical fea-
tures. Among the genetic aberrations reported to occur in MALT
lymphoma,the three translocations
t(11;18)(q21;q21),11,12and t(14;18)(q32;q21)13are of particular
importance because they appear to be specific for or at least
closely associated with the disease. The t(11;18)(q21;q21) has
been studied extensively in gastric MALT lymphoma and
recently a large series of MALT lymphomas has been screened
for the translocation, providing important information on its
frequency at the less common extragastric sites.20The major
goal of the present study for the first time was to analyze a large
series of MALT lymphomas of different sites for all the three
MALT lymphoma-associated structural aberrations, that is,
t(11;18)(q21;q21), t(14;18)(q32;q21), and t(1;14)(p22;q32), and
to additionally screen for the most common numerical aberra-
tions, that is, trisomy 3 and trisomy 18.
In the largerseries of
t(11;18)(q21;q21) was found in 14–48% of the cases.21–25In
the largest series of 138 cases reported to date, Ye et al20
detected the API2–MALT1 fusion transcript at exactly the same
23.9% as in our study. The detection of the t(11;18)(q21;q21) in
gastric MALT lymphoma is clinically important as most
translocation-positive tumors do not respond to H. pylori
eradication therapy, are associated with more advanced stage
of disease, and usually do not transform into aggressive
lymphoma.26–29The single t(14;18)(q32;q21)þ gastric MALT
lymphoma represents the first case reported to carry this
aberration within the gastrointestinal tract. Nevertheless, this
finding confirms previous studies and indicates that the
t(14;18)(q32;q21) is virtually absent among primary gastroin-
testinal MALT lymphomas.13,22
The MALT lymphoma-specific t(1;14)(p22;q32) causes dereg-
ulation of BCL10,30,31which specifically links the antigen
MALT lymphomas. Please note that the numbers given for trisomies 3/18 refer to cases that carry this aberration only, that is, are negative for any of
the three translocations. For clarity, the data on trisomies 3 and 18 were combined. The frequencies of the trisomies 3 and 18 are shown separately
in Table 1.
Graphical demonstration of frequencies of t(11;18)(q21;q21), t(14;18)(q32;q21), t(1;14)(p22;q32), and trisomies 3 and/or 18 in 252
Genetic aberrations in MALT lymphoma
B Streubel et al
receptor signaling to the NFkB pathway.32In contrast to normal
lymphoid cells and to MALT lymphomas negative for the
t(1;14)(p22;q32) typically show high nuclear BCL10 expres-
sion.33By screening 331 MALT lymphomas immunohistochemi-
cally for BCL10 expression, Ye et al identified 12 cases (3.6%)
comprising six gastric, five pulmonary, and one cutaneous
MALT lymphoma, and confirmed the rearrangement of BCL10
by FISH in five of seven cases tested.20Our molecular
cytogenetic study revealed BCL10 rearrangement in four of
252 cases (1.6%), two of which occurred in the colorectum and
one each in the lung and salivary gland, respectively. The reason
why none of our gastric MALT lymphomas harbored the
t(1;14)(p22;q32) is not clear.
Cutaneous MALT lymphoma, also referred to as cutaneous
marginal zone B-cell lymphoma, has been evaluated for the
t(11;18)(q21;q21), but so far no positive case has been reported,
including the larger series comprising 27, 24, and 12 cases,
respectively.20,34,35We found the translocation in four of 51
cases (7.8%), suggesting that it does occur in cutaneous MALT
lymphomas, albeit at low frequency. The t(14;18)(q32;q21) was
detected slightly more often (13.7%) and, because the two
translocations always occur mutually exclusively, one or the
other was found in 21.6% of the cases.
Among salivary gland MALT lymphomas, the t(11;18)
(q21;q21) is exceptionally rare. By combining the results of our
and the two other larger studies, only two of 144 cases tested
positive.20,22By contrast, the t(14;18)(q32;q21) was found in
roughly 12% in our series and in six of 28 cases (21.4%) in
another study,22reflecting our experience of an opposite
frequency of the two translocations at a given site. To the best
of our knowledge, the single t(1;14)(p22;q32)þ MALT lympho-
ma represents the first case arising at this site which, according
to the negative results of the BCL10 expression study,20appears
to be exceptional.
Similar to most other nongastric MALT lymphomas, those
arising at the ocular adnexa (conjunctiva, lacrimal gland, and
orbit) have not been studied genetically, except for the
t(11;18)(q21;q21), providing somewhat conflicting results. Ye
et al20detected the t(11;18)(q21;q21) in nine of 55 cases
(16.3%), whereas Adachi et al36reported on 51 cases, all of
which were negative and therefore closely resembled our
findings with only one of 37 tumors positive. We do provide
evidence, however, that among the prototypical MALT lympho-
ma sites tumors arising at the ocular adnexa/orbit are those that
most often harbor the t(14;18)(q32;q21), as detected in almost a
quarter (24.3%) of the cases studied herein.
All 16 intestinal MALT lymphomas harbored at least one of
the five aberrations examined, among which trisomy 3 and/or
18 were most prevalent, occurring in 13 of the 16 cases (81.5%),
and might be regarded as a genetic hallmark of the disease.
Conversely, we detected the t(11;18)(q21;q21) in only two of the
16 primary intestinal MALT lymphomas. Interestingly, Ye
et al1,20did not find the translocation in any of their 22 cases
of immunoproliferative small intestinal disease (IPSID), which
by definition arises in the intestine and represents a variant of
In agreement with previous studies showing that the
t(11;18)(q21;q21) is most commonly detected in pulmonary
MALT lymphomas with frequencies ranging from 25 to
41%,20,37,38we found the API2–MALT1 fusion transcript in
even53.5% of thesecases.
t(11;18)(q21;q21) in gastric MALT lymphoma has been linked
hypothetically to oxidative damage caused predominantly by
CagA-positive strains of Helicobacter pylori.20A similar etiology
The occurrence of the
involving a hitherto unidentified pathogen is conceiveable in
t(11;18)(q21;q21)-positive pulmonary MALT lymphoma.20This
hypothesisis supported by the recent
t(11;18)(q21;q21)-positive pulmonary MALT lymphoma is not
associated with autoimmune disease.37Our data confirm that
the t(14;18)(q32;q21) and the t(1;14)(p22;q32) occur at low
frequency in pulmonary MALT lymphoma.20,38Nevertheless,
MALT lymphoma arising at this site is somewhat exceptional, as
this tumor may carry any of the three translocations, and, by
combining their frequencies (66.7% in our study), is by far the
most ‘translocation-prone’ MALT lymphoma.
Among the few MALT lymphoma cases arising at the thyroid,
breast, liver, urogenital tract, and the sphenoorbital region, the
hepatic cases stand out because of the close association with the
Aneuploidy, most commonly trisomy 3 and/or trisomy 18,
frequently occurs in MALT lymphoma, but may also be detected
in other B-cell lymphomas, albeit at a much lower fre-
quency.14,39,40The high frequency of trisomy 3 in MALT
lymphoma, particularly in tumors arising from the intestine,
salivary glands, and ocular adnexa, suggests that one or more
genes at chromosome 3 are involved in the pathogenesis of
In summary, our results demonstrate that the three transloca-
tions t(11;18)(q21;q21), t(14;18)(q32;q21), and t(1;14)(p22;q32),
and the trisomies 3 and/or 18, occur at markedly variable
frequencies in MALT lymphoma of different sites. The genetic
data have to be correlated with clinical findings such as stage of
disease, response to treatment, and disease recurrence, in order
to evaluate their predictive value. The notion that a high
proportion of MALT lymphomas is negative for any of the above-
mentioned aberrations should encourage future research.
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