New Insights into the Molecular Pathogenesis of Pulmonary MALT Lymphomas
Since the first description of lymphomas of mucosa associated lymphoid tissue (MALT) in 1983 by
Isaacson and Wright  , there have been rapid advances in our understanding of the pathogenesis and
molecular pathology of these tumours.
Initial analysis concentrated on the histological
characterisation of the lymphoma and the confirmation that it represented a distinct lymphoma entity
separate from those lymphomas most commonly encountered within lymph nodes.  This is now fully
accepted with the adoption of the term "extranodal marginal-zone B cell lymphoma of MALT-type" in the
recent WHO Classification of Tumours of the Hematopoietic And Lymphoid Tissues. 
Most MALT lymphomas arise in mucosal sites devoid of organised lymphoid structure. Development of
MALT lymphoma is often preceded by a chronic inflammatory process which leads to the acquisition of
lymphoid tissue. This forms the background for the emergence of the lymphoma. The examples of chronic
inflammatory processes which are associated with MALT lymphoma development include Helicobacter pylori-associated gastritis in the stomach,
in the salivary glands and Hashimoto's thyroiditis in the thyroid.
MALT lymphomas are cytologically low-grade lymphoid neoplasms, and are thought to arise form marginal
zone B-cell compartment of the mucosal lymphoid follicles. The cytological features and the architecture
of the tumour often mimic the features of normal mucosal organised lymphoid tissues such the Peyer's
patches. For this reason many of the cases have been mistakenly diagnosed as pseudo-lymphomas before the
application of clonality and genetic studies.
MALT lymphomas tend to remain localised at the site of origin for many years and when they disseminate
they tend to disseminate to other sites mucosal sites; a phenomenon thought to be a result of homing
programming. Clinically most cases have an indolent course and respond to locally directed therapies
such as H.pylori eradication, surgery or radiotherapy.
Primary lymphomas of the lung are rare, accounting for 1% of all lymphomas.  Histologically half
of these cases are MALT lymphomas  and approximately 10% of all MALT lymphomas present in the lung.
Unlike MALT lymphomas of other sites, no preceding chronic inflammatory process or association
with an infectious agent have been reported for pulmonary MALT lymphomas. Morphological,
immunophenotypic and genetic features of pulmonary MALT lymphomas are similar to the MALT lymphomas of
other sites, in particular to those arising in the stomach.
Immunology of the neoplastic B-cell in MALT lymphomas
The neoplastic B-cells of the MALT lymphomas immunologically resemble postfollicular memory B-cells.
The rearranged immunoglobulin genes show evidence of somatic hypermutation indicating that the tumor
cells have gone through a germinal center reaction and the pattern of the mutations suggest that the
tumor cells have been selected by antigen recognition.
Phenotypically the tumor cells mimic
memory B-cells. They typically express IgM but not IgD, the expression of follicle centre markers such
as CD10 and Bcl-6 is downregulated. A third of the cases show plasma cell differentiation.  The
tumor cells may express homing receptors such as α4β7 integrin favoring recirculation and dissemination
through other mucosal sites.
Genetic alterations in Pulmonary MALT lymphomas
A number of recurrent chromosomal changes characteristic of MALT lymphomas have been identified.
These fall into two groups; the translocations and the numerical changes in chromosomes
The translocations and their frequencies in MALT lymphomas of different
sites are summarized in Tables 1 and 2.
Table 1: Recurrent translocations in MALT lymphomas.(16,17,18,19,20,21)
|Translocation ||Genes involved ||Consequence|
|t(11;18)(q21;q21) ||API2 and MALT1 ||A novel fusion gene and protein API2-MALT1|
Nuclear localization of BCL10
|t(14;18)(q32;q21) ||IgH and MALT 1 ||Overexpression of MALT1|
|t(1;14)(p22;q32) ||BCL10 and IgH ||Overexpression of BCL10|
Nuclear localization of BCL10
|t(1; 2)(p22; p12) ||BCL10 and IgK ||Overexpression of BCL10|
Nuclear localization of BCL10
|t(3;14)(p14.1;q32) ||FOXP1 and IgH ||Overexpression of FOXP1|
The translocations appear to be essentially specific for MALT lymphoma. They have not been reported
in other low grade B-cell lymphomas but they have been occasionally observed in cases of diffuse large
B-cell lymphomas, often arising at extranodal sites.
The characteristic translocations are seen
over half of the MALT lymphomas originating in the lungs, by far the highest proportion in MALT lymphomas
of various sites. The reasons for the increased frequency of translocations in lung lymphomas are not
Table 2: Frequency of recurrent translocations in MALT lymphomas
| Site ||t(11;18) ||t(1;14) ||t(14;18) ||t(3;14)* ||t(neg)|
|Stomach ||22% ||>1% ||3% ||- ||74%|
|Orbita ||7% ||0% ||12% ||20% ||61%|
|Salivary gland ||2% ||1% ||5% ||- ||92%|
|Lung ||42% ||8% ||6% ||- ||44%|
|Skin ||4% ||0% ||8% ||10% ||78%|
|Intestine ||15% ||10 ||0% ||- ||75%|
* Preliminary data, only a small number of cases have been tested so far
The precise mechanisms involved in the development of these translocations remain essentially unknown.
The ones involving the immunoglobulin heavy and light chain chains genes are likely to be caused by
errors during physiological Ig gene remodeling, including V(D)J recombination and somatic hypermutation.
 Whereas the genomic breakpoints of
t(11;18)(API2/MALT1), which involves
two non-Ig genes, are not associated with any known or putative sequence motif that may associate with
chromosomal recombination. Extensive sequence alterations including deletions, duplications and
non-template-based insertions occur commonly at the fusion junction.  It has been proposed that
t(11;18)(API2/MALT1) may result from illegitimate non-homologous end joining
following double strand breaks. Such double strand breaks may be a consequence of genotoxic insults
generated by the chronic inflammatory process preceding MALT lymphoma. 
The numerical chromosomal abnormalities seen in MALT lymphomas include
trisomy 3, 12 and 18.
Aneuploidy can be seen the in the presence or absence of the
translocations. However interestingly the MALT lymphomas carrying the t(11;18)(API2/MALT1) usually do not show aneuploidy.
Additionally mutations involving oncogenes such as c-myc and a number of tumour suppressor genes such
as p53, fas and p16 have been reported in MALT lymphomas, in particular those with a large cell
Biological consequences of genetic alterations in MALT lymphomas
Most of the translocations, t(11;18)(API2/MALT1), t(14;18)(IgH/MALT1), t(1;14)(BCL10/IgH) and t(BCL10/Igκ) in MALT lymphoma affect the same molecular
pathway critical in antigen mediated T and B-cell activation, through the nuclear factor κB
(NF-κB) family of transcription factors. Members of NF-κB family are key regulators of the
expression of genes that are essential for lymphocyte activation, proliferation and generation of immune
In normal B and T cells, antigen receptor mediated activation is thought to depend on the interaction
between cell membrane receptor associated kinases and a trimolecular complex involving
membrane-associated guanylate kinase (MAGUK) family member CARMA1, the adaptor protein BCL-10 and the
human paracaspase MALT1. (Figure 1) Following antigen-receptor stimulation, CARMA1 induces BCL10
oligomerization through caspase recruitment domain (CARD)–CARD interactions. BCL10 then binds the
Ig-like domain of MALT1 through its CARD and induces MALT1 oligomerization. Oligomerized MALT1 is
thought to induce activation of the inhibitor of NF-κB kinase (IKK) complex.
Figure 1: The structure of molecules thought to be involved in antigen receptor-mediated activation of
B-cells and MALT lymphomas. In API2-MALT1 fusion protein formed as the result of t11(11;18) the fusion
product always retains the baculovirus IAP repeats (BIR) domain of the AIP2 and caspase recruitment
domain (CARD) and at least one of the immunoglobulin-like (IG) domains of MALT1.The arrows indicate
domains involved in molecular interactions.
NF-κB proteins are normally sequestered in the cytoplasm in an inactive form, bound to inhibitory
κB (IκB) proteins.
 Activation of the IKK complex leads to phosphorylation and subsequent
ubiquitylation and degradation of IkB releasing NF-κB. NF-κB then translocates to the  nucleus
and transactivates genes important for cellular activation, proliferation and survival, and induction of
effector functions of lymphocytes. (Figure 2)
In MALT lymphomas the translocations involving BCL10 or MALT-1 is thought to induce constitutive NF-κB
activation without a need for antigen receptor mediated upstream signaling.
In cases with
t(1;14)(BCL10/IgH), BCL10 is placed under the regulation of the
Ig-heavy-chain gene enhancers and is overexpressed. It is thought that excess BCL10 can form oligomers
through its CARD domain without the need of upstream signals and engage MALT1 for the downstream events,
leading to NF-κB activation. In cases with t(14;18)(IgH/MALT1), MALT1 is
overexpressed and spontaneous oligomerization occurs possibly with the involvement of BCL10 . In MALT
lymphomas with t(11;18)(API2/MALT1), the resulting API2–MALT1 fusion protein
can bypass the requirement for BCL10 and oligomerizes through BIR domains of the API2 molecule, therefore
leading to NF-κB nuclear translocation.
Figure 2: The antigen-receptor-mediated NFkB activation through the CARMA-1, BCL10 and MALT1 in normal B-cells and the genetic alterations of the same pathway seen in MALT lymphomas and their consequences.
The most recent translocation that has been discovered in MALT lymphomas, t(3;14)(p14.1;q32) involves
IgH gene locus and forkhead box protein P1 (FOXP1).
 FOXP1 is a member of the FOXP
subfamily(FOXP1-4) of transcription factors, characterized by a commonDNA-binding,
winged-helix or forkhead domain, together withN-terminal zinc finger and
leucine zipper domains. FOXP1 is expressed in normal and activated B cells. However, the
physiologicrole of FOXP1 in lymphocytes remains unclear. In MALT lymphomas, the translocation juxtaposes
FOXP1 gene close to the IgH gene enhancers leading to overexpression of the protein. How this
contributes to neoplastic transformation is not yet known. Interestingly, in diffuse large B-cell
lymphomas strong expression of FOXP1 identifies a distinct subset of patients with poor clinical outcome.
FOXP1 translocation have not been observed in lung MALT lymphomas as yet.
Clinical consequences of molecular alterations in MALT lymphomas
The genetic alterations in MALT lymphomas, being largely
specific for MALT lymphoma, have become useful diagnostic tools. All of the translocation can be
detected by interphase FISH in paraffin embedded material, either using sections or isolated whole
A number of robust commercially available probes are already available. t(11;18)(API2/MALT1), by far the most frequent translocation in MALT lymphoma can be
identified by an RT-PCR strategy as the translocation leads to development of a unique fusion transcript.
Again the methods work well in paraffin embedded tissue blocks.
The alterations in protein expression patterns of BCL10 and MALT-1 can also be used as surrogate
markers for the translocation. In cases with the t(1;14)(BCL10/IgH)
involving the BCL10 gene, strong overexpression of BCL10 can be detected by immunohistochemistry. BCL10
is weakly expressed in the cytoplasm of normal B-cells.  The translocation leads not only to
overexpression of BCL10 but also to nuclear localization of the BCL10 protein. The biological
significance of nuclear localization is not known. Interestingly, (11;18)(API2/MALT1) cases also show nuclear BCL10 expression albeit weakly.  Similarly
cases with (14;18)(IgH/MALT1) show overexpression of MALT1.
Unfortunately the alterations in protein expression patterns are neither specific for individual
translocations nor to MALT lymphoma. The clinical utility of BCL10-MALT1 immunohistochemistry remains
Helicobacter pylori eradication has emerged as the first line
treatment for management of early stage gastric lymphoma.  Although most of the patients respond to
this treatment, approximately 25% of the cases are resistant. It has now been shown that these resistant
cases almost always carry the t(11;18)(API2/MALT1).
 It is likely that
the tumor cells are not reliant to the signals from the microenvironment since the molecular changes
override the normal signaling pathways. The prognostic significance of other rarer translocations is not
known. The prognostic significance of t(11;18)(API2/MALT1) in lung
lymphomas has not been studied due to relative rarity of this tumor and overall good prognosis of these
The molecular alterations in MALT lymphomas are attractive
targets for development of new treatment strategies interfering either BCL10-MALT1 pathway or downstream
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