PART ONE
General Cytology
Table 2.1
Four main recurrent chromosomal translocations observed in MALT lymphomas
t(11;18)(q21;q21)
t(1;14)(p22;q32)
t(14;18)(q32;q21)
t(3;14)(p14.1;q32)
Product
cIAP2-MALT1 fusion protein
Overexpression of BCL10
Overexpression of MALT1
Overexpression of FOXP1
% of cases
15-40
1-2
20
Unknown
Main lymphoma
localizations
Stomach, lung, intestine
Stomach, lung
Salivary glands, skin, ocular
adnexa, liver, lung
Thyroid, ocular adnexa, skin
Fig. 2.10 Karyotype
showing an interstitial
deletion of chromosome 7q as observed in
splenic
marginal zone lymphoma
. In the
present case, the deletion involves the 7q22q32
chromosomal segment.
15-40% of cases, and is observed in stomach, intestine, and
lung MALT lymphoma cases. It results in the reciprocal fusion
of the
API2
and
MALT1
genes.
API2
(cellular inhibitor of apop-
tosis protein 2) gene is believed to be an apoptosis inhibitor by
inhibiting the biological activity of caspases 3, 7, and 9.
The pathogenesis of those three translocations sharing the same
molecular pathway is beginning to be understood.28,29 NF-kB acti-
vation is driven by stimulation of cell-surface receptors, such as B-
or T-cell receptors. In unstimulated lymphocytes, NF-kB proteins
are bound with inhibitory kB (IkB) proteins and sequestered in
the cytoplasm. Phosphorylation of the IkB proteins by the IkB
kinase (IKK) heterodimer leads to ubiquitylation and degradation
of IkB, allowing NF-kB to migrate to the nucleus and transactivate
genes involved in cellular activation, proliferation and survival,
and induction of effector function of lymphocytes.
In MALT lymphoma with t(1;14) translocation and BCL10
overexpression, BCL10 is able to complex with MALT1 and trig-
ger aberrant NF-kB activation without the need for upstream
signaling. With the t(14;18) translocation causing MALT1 over-
expression, MALT1 interacts and stabilizes BCL10, leading to its
cytoplasmic accumulation. Both proteins in high cellular con-
centration will then synergistically favor a constitutive NF-kB
activity. In t(11;18) positive MALT lymphoma, the API2-MALT1
chimeric protein activates NF-kB through self-oligomerization,
and bears a gain of function when compared to wild type
MALT1. This higher activation is also due to the API2 protein
partner. Indeed, wild-type API2 downregulates BCL10 expres-
sion by ubiquitylation and degradation, a mechanism used
to regulate BCL10 activity after antigen receptor stimulation.
The API2-MALT1 protein is no longer able to ubiquitylate it
and high BCL10 expression will synergistically increase API2-
MALT1's intrinsic capacity for NF-kB activation, independently
of any antigen-receptor activation.
Because of their specificity, the identification of these chromo-
somal translocations can be of interest for diagnostic purposes.
They have also an immediate impact on treatment decisions, at
least for two of them. Indeed, a causal relationship between
H.
pylori
infection in the stomach and development of gastric MALT
lymphoma has been clearly demonstrated, and 75% of these lym-
phomas can be successfully treated with appropriate antibiotics
targeting
H. pylori.28
However, the presence of either the t(11;18)
or t(1;14) translocation defines patients who will not respond to
H. pylori
eradication. At the opposite, gastric MALT lymphoma
without these chromosomal translocations, sometimes carrying
trisomies of chromosomes 3, 12, and 18, can be effectively treated
by antibiotic treatment, at least at their early stages. However, they
can progress, become
H. pylori
-independent and transform into
high-grade tumors following the acquisition of additional genomic
alterations (such as TP53 and CKN2A inactivation). Intriguingly,
t(11;18) positive MALT lymphomas will rarely develop into high-
grade tumors, unlike their t(1,14) counterparts. These clinical
features indicate that chromosomal abnormalities in some MALT
lymphoma can also serve as prognostic parameters.
In splenic marginal zone lymphoma (SMZL), cytogenetic
alterations include mainly partial or complete trisomy 3, and
interstitial deletion of chromosome 7q involving segments of
variable size, usually centered around the 7q31q32 region (Fig.
2.10). Recent gene expression profiling revealed that genes
32
previous page 38 ComprehensiveCytopathology 1104p 2008 read online next page 40 ComprehensiveCytopathology 1104p 2008 read online Home Toggle text on/off