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'''For more information about H.pylori infection click [[Helicobacter pylori infection|here]].'''
'''For more information about H.pylori infection click [[Helicobacter pylori infection|here]].'''
{{MALT lymphoma}}
{{MALT lymphoma}}
{{CMG}}; {{AE}}{{SR}}, {{AY}}
{{CMG}}; {{AE}} {{SR}}, {{AY}}, {{AEL}}  


==Overview==
==Overview==
MALT lymphoma is a form of [[lymphoma]] involving the [[mucosa-associated lymphoid tissue]] (MALT), frequently of the [[stomach]], but virtually any mucosal site can be afflicted. It is a [[cancer]] originating from [[B cell]]s in the [[marginal zone]] of the MALT. The evolution of gastric MALT lymphoma is a multistage process starting with the infection of ''[[helicobacter|H. pylori]]'' resulting in the recruitment of B- and T-cells and other inflammatory cells to the gastric mucosa. Genes involved in the pathogenesis of MALT lymphoma include ''[[FOXP1]]'' and BCL6. Chromosomal [[translocations]] are also involved in the pathogenesis of MALT lymphoma, which include t(1;14)(p22;q32), t(11;18)(q21;q21), t(14;18)(q32;q21), and t(3;14)(p14.1;q32). Gastric MALT lymphoma is frequently associated with chronic [[inflammation]] as a result of the presence of ''[[Helicobacter pylori]]'' (72-98%).<ref name="bjhjh">{{cite journal | author = Parsonnet J, Hansen S, Rodriguez L, Gelb A, Warnke R, Jellum E, Orentreich N, Vogelman J, Friedman G | title = Helicobacter pylori infection and gastric lymphoma. | journal = N Engl J Med | volume = 330 | issue = 18 | pages = 1267-71 | year = 1994 | id = PMID 8145781}}</ref> Chronic immune stimulation is also suspected in the pathogenesis of non-gastric MALT lymphoma, and hence often have a history of autoimmune disorders, such as [[Hashimoto's thyroiditis]], [[Sjögren's syndrome]], [[Celiac disease]], and [[relapsing polychondritis]].<ref name="KinkadeEsan2015">{{cite journal|last1=Kinkade|first1=Zoe|last2=Esan|first2=Olukemi A.|last3=Rosado|first3=Flavia G.|last4=Craig|first4=Michael|last5=Vos|first5=Jeffrey A.|title=Ileal mucosa-associated lymphoid tissue lymphoma presenting with small bowel obstruction: a case report|journal=Diagnostic Pathology|volume=10|issue=1|year=2015|issn=1746-1596|doi=10.1186/s13000-015-0353-6}}</ref> On microscopic histopathological analysis, MALT lymphoma is characterized by the presence of dense diffuse lymphoid infiltrate of marginal‐zone cells in the lamina propria with prominent lymphoepithelial lesions consisting of small atypical cells with monocytoid features.<ref>{{cite journal|last1=Taal|first1=B G|last2=Boot|first2=H|last3=van Heerde|first3=P|last4=de Jong|first4=D|last5=Hart|first5=A A|last6=Burgers|first6=J M|title=Primary non-Hodgkin lymphoma of the stomach: endoscopic pattern and prognosis in low versus high grade malignancy in relation to the MALT concept.|journal=Gut|date=1 October 1996|volume=39|issue=4|pages=556–561|doi=10.1136/gut.39.4.556}}</ref><ref name="pmid16950858">{{cite journal| author=Bacon CM, Du MQ, Dogan A| title=Mucosa-associated lymphoid tissue (MALT) lymphoma: a practical guide for pathologists. | journal=J Clin Pathol | year= 2007 | volume= 60 | issue= 4 | pages= 361-72 | pmid=16950858 | doi=10.1136/jcp.2005.031146 | pmc=PMC2001121 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16950858  }} </ref> A characteristic feature of MALT lymphoma is the presence of neoplastic cells within epithelial structures with associated destruction of the glandular architecture to form lymphoepithelial lesions.<ref>{{cite book|last1=Janusz|first1=edited by Jankowski,|title=Handbook of Gastrointestinal Cancer|date=2012|publisher=John Wiley and Sons Ltd|location=Chicester|isbn=978-0-470-65624-2|pages=243–244|edition=2}}</ref> The neoplastic cells of MALT lymphoma may be positive for B-cell associated antigens ([[CD19]], [[CD20]], [[CD22]], [[CD79a]]) that co-express [[BCL-2]], and are negative for [[CD5]], [[CD10]], [[CD43]], and [[cyclin D1]].<ref name="KinkadeEsan2015">{{cite journal|last1=Kinkade|first1=Zoe|last2=Esan|first2=Olukemi A.|last3=Rosado|first3=Flavia G.|last4=Craig|first4=Michael|last5=Vos|first5=Jeffrey A.|title=Ileal mucosa-associated lymphoid tissue lymphoma presenting with small bowel obstruction: a case report|journal=Diagnostic Pathology|volume=10|issue=1|year=2015|issn=1746-1596|doi=10.1186/s13000-015-0353-6}}</ref>
MALT lymphoma is a form of [[lymphoma]] involving the [[mucosa-associated lymphoid tissue]] (MALT), frequently of the [[stomach]], but virtually any mucosal site can be afflicted. It is a [[cancer]] originating from [[B cell]]s in the [[marginal zone]] of the MALT. The evolution of gastric MALT lymphoma is a multistage process starting with the infection of ''[[helicobacter|H. pylori]]'' resulting in the recruitment of B- and T-cells and other inflammatory cells to the gastric mucosa. Genes involved in the pathogenesis of MALT lymphoma include ''[[FOXP1]]'' and BCL6. Chromosomal [[translocations]] are also involved in the pathogenesis of MALT lymphoma, which include t(1;14)(p22;q32), t(11;18)(q21;q21), t(14;18)(q32;q21), and t(3;14)(p14.1;q32). Gastric MALT lymphoma is frequently associated with chronic [[inflammation]] as a result of the presence of ''[[Helicobacter pylori]]'' (72-98%). Chronic immune stimulation is also suspected in the pathogenesis of non-gastric MALT lymphoma, and hence often have a history of autoimmune disorders, such as [[Hashimoto's thyroiditis]], [[Sjögren's syndrome]], [[Celiac disease]], and [[relapsing polychondritis]]. On microscopic histopathological analysis, MALT lymphoma is characterized by the presence of dense diffuse lymphoid infiltrate of marginal‐zone cells in the lamina propria with prominent lymphoepithelial lesions consisting of small atypical cells with monocytoid features. A characteristic feature of MALT lymphoma is the presence of neoplastic cells within epithelial structures with associated destruction of the glandular architecture to form lymphoepithelial lesions. The neoplastic cells of MALT lymphoma may be positive for B-cell associated antigens ([[CD19]], [[CD20]], [[CD22]], [[CD79a]]) that co-express [[BCL-2]], and are negative for [[CD5]], [[CD10]], [[CD43]], and [[cyclin D1]].


== Pathophysiology ==
== Pathophysiology ==


===Pathogenesis===
===Pathogenesis===
* Mucosa Associated Lymphoid Tissue lymphoma (MALT lymphoma) resembles an extranodal subtype of Non-Hodgkin lymphoma. MALT lymphoma can occur in many sites extranodal but the most common site is the stomach.<ref name="TroppanWenzl2015">{{cite journal|last1=Troppan|first1=Katharina|last2=Wenzl|first2=Kerstin|last3=Neumeister|first3=Peter|last4=Deutsch|first4=Alexander|title=Molecular Pathogenesis of MALT Lymphoma|journal=Gastroenterology Research and Practice|volume=2015|year=2015|pages=1–10|issn=1687-6121|doi=10.1155/2015/102656}}</ref>
* Mucosa Associated Lymphoid Tissue lymphoma (MALT lymphoma) resembles an extranodal subtype of Non-Hodgkin lymphoma. MALT lymphoma can occur in many sites extranodal but the most common site is the stomach.<ref name="bjhjh">{{cite journal | author = Parsonnet J, Hansen S, Rodriguez L, Gelb A, Warnke R, Jellum E, Orentreich N, Vogelman J, Friedman G | title = Helicobacter pylori infection and gastric lymphoma. | journal = N Engl J Med | volume = 330 | issue = 18 | pages = 1267-71 | year = 1994 | id = PMID 8145781}}</ref><ref>{{cite journal|last1=Taal|first1=B G|last2=Boot|first2=H|last3=van Heerde|first3=P|last4=de Jong|first4=D|last5=Hart|first5=A A|last6=Burgers|first6=J M|title=Primary non-Hodgkin lymphoma of the stomach: endoscopic pattern and prognosis in low versus high grade malignancy in relation to the MALT concept.|journal=Gut|date=1 October 1996|volume=39|issue=4|pages=556–561|doi=10.1136/gut.39.4.556}}</ref><ref name="pmid16950858">{{cite journal| author=Bacon CM, Du MQ, Dogan A| title=Mucosa-associated lymphoid tissue (MALT) lymphoma: a practical guide for pathologists. | journal=J Clin Pathol | year= 2007 | volume= 60 | issue= 4 | pages= 361-72 | pmid=16950858 | doi=10.1136/jcp.2005.031146 | pmc=PMC2001121 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16950858  }} </ref><ref>{{cite book|last1=Janusz|first1=edited by Jankowski,|title=Handbook of Gastrointestinal Cancer|date=2012|publisher=John Wiley and Sons Ltd|location=Chicester|isbn=978-0-470-65624-2|pages=243–244|edition=2}}</ref><ref name="TroppanWenzl2015">{{cite journal|last1=Troppan|first1=Katharina|last2=Wenzl|first2=Kerstin|last3=Neumeister|first3=Peter|last4=Deutsch|first4=Alexander|title=Molecular Pathogenesis of MALT Lymphoma|journal=Gastroenterology Research and Practice|volume=2015|year=2015|pages=1–10|issn=1687-6121|doi=10.1155/2015/102656}}</ref><ref name="KinkadeEsan2015">{{cite journal|last1=Kinkade|first1=Zoe|last2=Esan|first2=Olukemi A.|last3=Rosado|first3=Flavia G.|last4=Craig|first4=Michael|last5=Vos|first5=Jeffrey A.|title=Ileal mucosa-associated lymphoid tissue lymphoma presenting with small bowel obstruction: a case report|journal=Diagnostic Pathology|volume=10|issue=1|year=2015|issn=1746-1596|doi=10.1186/s13000-015-0353-6}}</ref>


* MALT lymphoma can take place in other tissues as lung, thyroid, small intestine, and ocular adnexa.  
* MALT lymphoma can take place in other tissues as lung, thyroid, small intestine, and ocular adnexa.  
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==Genetics ==
==Genetics ==
*MALT lymphoma is strongly associated with chromosomal translocations as well as genetic mutations.  
*MALT lymphoma is strongly associated with chromosomal translocations as well as genetic mutations.  
*Chromosomal translocations:   
*'''Chromosomal translocations:'''  
**MALT lymphoma can arise as a result of many chromosomal translocation. The primary translocations associated with MALToma are the following:<ref name="pmid9989495">{{cite journal| author=Willis TG, Jadayel DM, Du MQ, Peng H, Perry AR, Abdul-Rauf M et al.| title=Bcl10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma and mutated in multiple tumor types. | journal=Cell | year= 1999 | volume= 96 | issue= 1 | pages= 35-45 | pmid=9989495 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9989495  }}</ref><ref name="pmid22229204">{{cite journal| author=Bertoni F, Coiffier B, Salles G, Stathis A, Traverse-Glehen A, Thieblemont C et al.| title=MALT lymphomas: pathogenesis can drive treatment. | journal=Oncology (Williston Park) | year= 2011 | volume= 25 | issue= 12 | pages= 1134-42, 1147 | pmid=22229204 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22229204  }}</ref>
**MALT lymphoma can arise as a result of many chromosomal translocation. The primary translocations associated with MALToma are the following:<ref name="pmid9989495">{{cite journal| author=Willis TG, Jadayel DM, Du MQ, Peng H, Perry AR, Abdul-Rauf M et al.| title=Bcl10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma and mutated in multiple tumor types. | journal=Cell | year= 1999 | volume= 96 | issue= 1 | pages= 35-45 | pmid=9989495 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9989495  }}</ref><ref name="pmid22229204">{{cite journal| author=Bertoni F, Coiffier B, Salles G, Stathis A, Traverse-Glehen A, Thieblemont C et al.| title=MALT lymphomas: pathogenesis can drive treatment. | journal=Oncology (Williston Park) | year= 2011 | volume= 25 | issue= 12 | pages= 1134-42, 1147 | pmid=22229204 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22229204  }}</ref>
***t(1;14) (p22;q32)
***t(1;14) (p22;q32)
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***This translocation has shown a closer position of FOXP1 to the heavy chain gene of immunoglobulins.   
***This translocation has shown a closer position of FOXP1 to the heavy chain gene of immunoglobulins.   
***FOXP1 is a transcription factor which plays a role in suppression of the apoptosis especially the genes suppressing the caspases.   
***FOXP1 is a transcription factor which plays a role in suppression of the apoptosis especially the genes suppressing the caspases.   
*General role of the translocation in pathogenesis of MALT lymphoma:   
*General role of the translocation in pathogenesis of MALT lymphoma:<ref name="TroppanWenzl2015">{{cite journal|last1=Troppan|first1=Katharina|last2=Wenzl|first2=Kerstin|last3=Neumeister|first3=Peter|last4=Deutsch|first4=Alexander|title=Molecular Pathogenesis of MALT Lymphoma|journal=Gastroenterology Research and Practice|volume=2015|year=2015|pages=1–10|issn=1687-6121|doi=10.1155/2015/102656}}</ref><ref name="pmid228082962">{{cite journal| author=Liu F, Karube K, Kato H, Arita K, Yoshida N, Yamamoto K et al.| title=Mutation analysis of NF-κB signal pathway-related genes in ocular MALT lymphoma. | journal=Int J Clin Exp Pathol | year= 2012 | volume= 5 | issue= 5 | pages= 436-41 | pmid=22808296 | doi= | pmc=3396059 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22808296 }}</ref>
**The previous translocations are responsible for activating Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathway as well as the uncontrolled expression of BCL10 and MALT1 which are antiapoptic mechanisms. 
**The BCL10 and MALT1 can bind together forming BCL2-MALT1 complex which has an important role in activating NF-kB via activation IkB kinase. 
**When the NF-kB be activate, it translocates into the nucleus to stimulate genes transcriptions especially those which encode growth factors important for cell growth and proliferation. 
*''TNFAIP3'' gene deletion is another gene mutation associated with adnexal MALToma. It is believed that ''TNFAIP3'' also has an important role in NF-kB pathway activation. ''TNFAIP3'' is normaly a tumor suppressor gene. 


**The occurrence of the recurrent translocations t(1;14)(p22;q32), t(14;18)(q32;q21), and t(11;18)(q21;q21) in MALT lymphoma, constitutively activating the NF-κB pathway by the association of ''BCL10'' and ''MALT1'' in malignant lymphocytes, defines this pathway as an oncogenic event. Physiologically, ''BCL10'' binds to the Ig-like domain of ''MALT1'', and this binding induces the ''MALT1'' oligomerization. The ''BCL10-MALT1'' complex promotes the ubiquitylation of IκB kinase-γ and NF-κB is released to translocate into the nucleus and to transactivate genes, such as those encoding factors for cytokines and growth factors for cellular activation, proliferation, and survival. In MALT lymphoma with t(1;14)(p22;q32), ''BCL10'' is believed to form oligomers through its CARD domain without the need for upstream signaling and thus triggers the ''MALT1'' oligomerization and aberrant NF-κB activation. In lymphoma cases with t(14;18)(q32;q21), ''MALT1'' is overexpressed. ''MALT1'' does not possess a structural domain mediating self-oligomerization and it does not activate NF-κB in vitro. It seems likely that ''MALT1'' interacts with and stabilizes ''BCL10'', causing its accumulation in the cytoplasm of t(14;18)(q32;q21) positive tumor cells resulting in oligomerization of ''MALT1'' and activation of NF-κB. In t(11;18)(q21;q21) positive MALT lymphomas, the ''BIR'' domain of the ''BIRC2-MALT1'' mediates self-oligomerization, which in turn leads to NF-κB activation.
*'''Other somatic mutations:'''  
**However, two different transgenic mice—overexpressing either of the two translocations, ''BCL10'' or ''BIRC2-MALT1'', seen frequently in MALT lymphomas—develop splenic marginal zone hyperplasia, but not lymphoma. However, Sagaert et al. reported lymphoma development when ''BIRC2-MALT1'' mice were exposed to antigen stimulation. Altogether, these data indicate that in MALT lymphoma chromosome translocations alone are not sufficient for full malignant transformation. Cooperation with a chronic infectious process seems to be necessary for lymphomagenesis. Recently, a novel molecular mechanism of the ''BIRC2-MALT1'' fusion protein has been identified. Nie et al. demonstrated that the tumor suppressor gene ''LIMA1'' binds ''BIRC2'' and is proteolytically cleaved by ''MALT1'' through its paracaspase activity. This cleavage generates a LIM domain—only (LMO)—containing fragment with oncogenic properties in vitro and in vivo.<ref name="TroppanWenzl2015">{{cite journal|last1=Troppan|first1=Katharina|last2=Wenzl|first2=Kerstin|last3=Neumeister|first3=Peter|last4=Deutsch|first4=Alexander|title=Molecular Pathogenesis of MALT Lymphoma|journal=Gastroenterology Research and Practice|volume=2015|year=2015|pages=1–10|issn=1687-6121|doi=10.1155/2015/102656}}</ref>
**Missense mutations of PIM1 and cMyc are reported with some of the MALT lymphomas.<ref name="pmid17197434">{{cite journal| author=Deutsch AJ, Aigelsreiter A, Staber PB, Beham A, Linkesch W, Guelly C et al.| title=MALT lymphoma and extranodal diffuse large B-cell lymphoma are targeted by aberrant somatic hypermutation. | journal=Blood | year= 2007 | volume= 109 | issue= 8 | pages= 3500-4 | pmid=17197434 | doi=10.1182/blood-2006-06-030494 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17197434  }}</ref>
 
**Framshift mutations of p53 has also been linked with pathogenesis of MALT lymphomas both gastric and extra-gastric.<ref name="pmid8541549">{{cite journal| author=Du M, Peng H, Singh N, Isaacson PG, Pan L| title=The accumulation of p53 abnormalities is associated with progression of mucosa-associated lymphoid tissue lymphoma. | journal=Blood | year= 1995 | volume= 86 | issue= 12 | pages= 4587-93 | pmid=8541549 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8541549  }}</ref>
===2) Numeric Chromosomal Aberration: Trisomies and Deletions===
**Card11, CD79B, and Myd88 somatic mutations are also important in NF-kB activation. However, they may be associated with other subtypes of Non-Hodgkin lymphomas as splenic marginal zone lymphoma and noda marginal zone lymphoma.<ref name="pmid22808296">{{cite journal| author=Liu F, Karube K, Kato H, Arita K, Yoshida N, Yamamoto K et al.| title=Mutation analysis of NF-κB signal pathway-related genes in ocular MALT lymphoma. | journal=Int J Clin Exp Pathol | year= 2012 | volume= 5 | issue= 5 | pages= 436-41 | pmid=22808296 | doi= | pmc=3396059 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22808296  }}</ref>
*Other cytogenetic alterations include trisomies 3, 12, and/or [[trisomy 18|18]], which are present as a sole abnormality in 22% of the cases, but they are often associated with one of the four main translocations described above.
*Taji et al. detected trisomy 3 as the most common aberration in gastrointestinal MALT lymphomas with a frequency of up to 35%. Partial trisomies of chromosomes 3 and 18 also have been observed, as published by Krugmann et al. In contrast, Ott et al. reported an incidence of only 20% trisomy 3 in low-grade MALT lymphoma and an even lower rate in high-grade ones. The genetic mechanism by which trisomy 3 may contribute to lymphomagenesis has not yet been experimentally addressed. However, an increased gene dosage effect resulting from higher copy numbers of genes relevant to lymphoma development is likely to explain the biological consequences underlying chromosomal trisomies. Several promising candidate genes are located on [[chromosome 3]] and have been implicated in lymphomagenesis, such as the protooncogene ''[[BCL6]]'' and the transcription factor ''[[FOXP1]]''. One of our previous studies describes CCR4—a chemokine receptor genomically located on chromosome 3 (3p24)—highly expressed in trisomy 3 + MALT lymphoma whereas transcripts for this chemokine receptor were missing in trisomy 3− MALT lymphomas.
*Apart from the typical chromosomal translocations, ''TNFAIP3'' (A20) has been identified as frequently deleted in ocular adnexal MALT lymphoma as detected by array comparative genomic hybridization. As an important player in the NF-κB pathway by various mechanisms, ''TNFAIP3'' acts as a tumor suppressor gene in various lymphoma subtypes. In ocular adnexal MALT lymphoma, complete ''TNFAIP3'' inactivation is associated with poor lymphoma-free survival. ''TNFAIP3'' deletion occurred in MALT lymphoma of the ocular adnexa (19%), salivary gland (8%), thyroid (11%), and liver (0.5%), but not, or at almost undetectable frequencies, in the lung, stomach, and skin. However, ''TNFAIP3'' inactivation alone is not sufficient for malignant transformation but nevertheless may represent a promising future therapeutic target.
 
===3) Somatic Mutations===
*The number of studies investigating somatic mutations in MALT lymphoma is low and a whole genome sequencing approach has not yet been done. Our group reported somatic missense mutations in ''PIM1'' and ''cMyc'' in 46% and 30% of MALT lymphomas (gastric and extragastric origin) and in 30% and 41% of transformed MALT lymphomas and 72% of primary cutaneous marginal zone B cell lymphomas (PCMZL), considered as integral part of MALT lymphomas. Du et al. [55] detected missense and frameshift mutations in ''[[p53]]'' in 20.8% of MALT lymphoma and 30% of transformed MALT lymphoma (both mainly of gastric origin). Mutation analysis of NF-κB signal pathway-related genes—''TNFAIP3'', ''Card11'', ''CD79B'', and ''Myd88'', known to be frequently mutated in aggressive lymphomas, demonstrated missense or frameshift mutations in 6% of MALT lymphoma cases in the ''Myd88'' locus and in 28.6% of ocular adnexal MALT lymphomas mutations in the ''TNFAIP3'' locus.
*Liu et al. [62] reported that ''Card11'' and ''CD79B'' were not affected in their cohort of ocular adnexal MALT lymphomas.
*These genetic lesions are not restricted to MALT lymphoma. Rinaldi et al. performed a comprehensive analysis of genomic DNA copy number changes in more than 200 samples of MZL and demonstrated a distinct distribution of lesions in different subtypes (MALT lymphoma, nodal MZL, and splenic MZL). Whereas 3q and 18q gains were common in all three subtypes, del (6q23)(''TNFAIP3'') could be used for differentiation between MALT lymphoma and splenic MZL.


==Associated Conditions==
==Associated Conditions==
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**Small intestinal MALT lymphoma and ''[[Campylobacter jejuni]]''
**Small intestinal MALT lymphoma and ''[[Campylobacter jejuni]]''
**Cutaneous MALT lymphoma and ''Borrelia afzelii'' infection
**Cutaneous MALT lymphoma and ''Borrelia afzelii'' infection
*MALT lymphoma can be associated with the following genetic conidtions:<ref name="pmid15609403">{{cite journal| author=Taji S, Nomura K, Matsumoto Y, Sakabe H, Yoshida N, Mitsufuji S et al.| title=Trisomy 3 may predict a poor response of gastric MALT lymphoma to Helicobacter pylori eradication therapy. | journal=World J Gastroenterol | year= 2005 | volume= 11 | issue= 1 | pages= 89-93 | pmid=15609403 | doi= | pmc=4205391 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15609403  }}</ref>
**Trisomies 3, 12, and 18: it is believed that increased the gene copies is related to lymphoma pathogenesis.
**
**
==Gross Pathology==
==Gross Pathology==
MALT lymphoma starts in the tissues or organs outside of the lymph nodes (''extranodal''). MALT lymphoma develops in mucosa-associated lymphoid tissue, in the mucosa, or tissue that lines body organs or body cavities including:<ref name="KinkadeEsan2015">{{cite journal|last1=Kinkade|first1=Zoe|last2=Esan|first2=Olukemi A.|last3=Rosado|first3=Flavia G.|last4=Craig|first4=Michael|last5=Vos|first5=Jeffrey A.|title=Ileal mucosa-associated lymphoid tissue lymphoma presenting with small bowel obstruction: a case report|journal=Diagnostic Pathology|volume=10|issue=1|year=2015|issn=1746-1596|doi=10.1186/s13000-015-0353-6}}</ref>
MALT lymphoma starts in the tissues or organs outside of the lymph nodes (''extranodal''). MALT lymphoma develops in mucosa-associated lymphoid tissue, in the mucosa, or tissue that lines body organs or body cavities including:<ref name="KinkadeEsan2015">{{cite journal|last1=Kinkade|first1=Zoe|last2=Esan|first2=Olukemi A.|last3=Rosado|first3=Flavia G.|last4=Craig|first4=Michael|last5=Vos|first5=Jeffrey A.|title=Ileal mucosa-associated lymphoid tissue lymphoma presenting with small bowel obstruction: a case report|journal=Diagnostic Pathology|volume=10|issue=1|year=2015|issn=1746-1596|doi=10.1186/s13000-015-0353-6}}</ref>

Latest revision as of 03:02, 29 January 2019


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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sujit Routray, M.D. [2], Ahmed Younes M.B.B.CH [3], Ahmed Elsaiey, MBBCH [4]

Overview

MALT lymphoma is a form of lymphoma involving the mucosa-associated lymphoid tissue (MALT), frequently of the stomach, but virtually any mucosal site can be afflicted. It is a cancer originating from B cells in the marginal zone of the MALT. The evolution of gastric MALT lymphoma is a multistage process starting with the infection of H. pylori resulting in the recruitment of B- and T-cells and other inflammatory cells to the gastric mucosa. Genes involved in the pathogenesis of MALT lymphoma include FOXP1 and BCL6. Chromosomal translocations are also involved in the pathogenesis of MALT lymphoma, which include t(1;14)(p22;q32), t(11;18)(q21;q21), t(14;18)(q32;q21), and t(3;14)(p14.1;q32). Gastric MALT lymphoma is frequently associated with chronic inflammation as a result of the presence of Helicobacter pylori (72-98%). Chronic immune stimulation is also suspected in the pathogenesis of non-gastric MALT lymphoma, and hence often have a history of autoimmune disorders, such as Hashimoto's thyroiditis, Sjögren's syndrome, Celiac disease, and relapsing polychondritis. On microscopic histopathological analysis, MALT lymphoma is characterized by the presence of dense diffuse lymphoid infiltrate of marginal‐zone cells in the lamina propria with prominent lymphoepithelial lesions consisting of small atypical cells with monocytoid features. A characteristic feature of MALT lymphoma is the presence of neoplastic cells within epithelial structures with associated destruction of the glandular architecture to form lymphoepithelial lesions. The neoplastic cells of MALT lymphoma may be positive for B-cell associated antigens (CD19, CD20, CD22, CD79a) that co-express BCL-2, and are negative for CD5, CD10, CD43, and cyclin D1.

Pathophysiology

Pathogenesis

  • Mucosa Associated Lymphoid Tissue lymphoma (MALT lymphoma) resembles an extranodal subtype of Non-Hodgkin lymphoma. MALT lymphoma can occur in many sites extranodal but the most common site is the stomach.[1][2][3][4][5][6]
  • MALT lymphoma can take place in other tissues as lung, thyroid, small intestine, and ocular adnexa.
  • The beginning of MALT lymphoma can be from H. pylori infection which results in recruiting a large amount of lymphocytes to the site of infection in the stomach.
  • T-cell lymphocytes recruited to the site of infection they stimulate B-cells and with underlying genetic abnormalities, B-cells undergo malignant transformation.
  • Lymphocytes activation take place as the following:[5]
    • Epithelial cells are activated with the chronic infection. They express class HLA-DR and CD80 costimulatory molecules. They present the antigens to T-cells.
    • CD80 can react with CD28 on CD4 T-cells activating T-cells.
    • CD40 ligand expressed on activated T-cells interact with CD40 on B-cells. Along side the cytokines and chemokines released from T-cells, this interaction leads to B-cell activation.
    • Activating B and T cells will result in lymphoepithelial proliferation.

Genetics

  • MALT lymphoma is strongly associated with chromosomal translocations as well as genetic mutations.
  • Chromosomal translocations:
    • MALT lymphoma can arise as a result of many chromosomal translocation. The primary translocations associated with MALToma are the following:[7][8]
      • t(1;14) (p22;q32)
      • t(11;18) (q21;q21)
      • t(14;18) (q32;q21)
      • t(3;14) (p14.1;q32)
    • Translocation t(1;14):[9]
      • It is associated more with MALToma of stomach, lung, and skin. Translocation between BCL10 gene on chromosome 1 and immunoglobulin heavy chain on chromosome 14.
      • BCL10 gene is responsible for preventing apoptosis. This translocation leads to unhindered BCL10 expression and no apoptosis takes place ending up with uncontrolled proliferation of B cells.
      • Patients with t(1;14) are refractory to Helicobacter pylori (H. pylori) eradication therapy.
    • Translocation t(11;18):[10][11]
      • This translocation was mainly reported in MALToma of lung and stomach. It is considered the most common translocation occurs in MALT lymphoma as overall.
      • It has been found associated with lymphoma at other sites as intestine, orbit and salivary glands.
      • This translocation shows fusion of BIRC2 gene on chromosome 11 and MALT1 gene on chromosome 18.
      • BIRC2 is antiapoptotic factor and overexpression can lead to unlimited cell proliferation.
      • Moreover, deletions of both genes have been reported. Deletions lead to DNA breaks which are repaired through a mechanism called non-homologous end joining (NHEJ) repair. The NHEJ repair mechanism has a high rate of error that may result in the genetic mutation responsible for the lymphoma.
    • Translocation t(14;18):
      • The translocation occurs between the heavy chain gene of immunoglobulin on chromosome 14 and MALT1 gene on chromosome 18.
      • This occurs mainly in MALT lymphomas outside the gastrointestinal tract.
    • Translocation t(3:14):
      • This translocation has shown a closer position of FOXP1 to the heavy chain gene of immunoglobulins.
      • FOXP1 is a transcription factor which plays a role in suppression of the apoptosis especially the genes suppressing the caspases.
  • General role of the translocation in pathogenesis of MALT lymphoma:[5][12]
    • The previous translocations are responsible for activating Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kB) pathway as well as the uncontrolled expression of BCL10 and MALT1 which are antiapoptic mechanisms.
    • The BCL10 and MALT1 can bind together forming BCL2-MALT1 complex which has an important role in activating NF-kB via activation IkB kinase.
    • When the NF-kB be activate, it translocates into the nucleus to stimulate genes transcriptions especially those which encode growth factors important for cell growth and proliferation.
  • TNFAIP3 gene deletion is another gene mutation associated with adnexal MALToma. It is believed that TNFAIP3 also has an important role in NF-kB pathway activation. TNFAIP3 is normaly a tumor suppressor gene.
  • Other somatic mutations:
    • Missense mutations of PIM1 and cMyc are reported with some of the MALT lymphomas.[13]
    • Framshift mutations of p53 has also been linked with pathogenesis of MALT lymphomas both gastric and extra-gastric.[14]
    • Card11, CD79B, and Myd88 somatic mutations are also important in NF-kB activation. However, they may be associated with other subtypes of Non-Hodgkin lymphomas as splenic marginal zone lymphoma and noda marginal zone lymphoma.[15]

Associated Conditions

  • Gastric MALT lymphoma is frequently associated with chronic inflammation as a result of the presence of Helicobacter pylori (72-98%).[1]
  • Chronic immune stimulation is also suspected in the pathogenesis of non-gastric MALT lymphoma, and hence often have a history of autoimmune disorders, such as:[6]
  • MALT lymphoma may be associated with infectious agents, which include:[3]
    • Ocular adnexal MALT lymphoma and Chlamydia psittaci
    • Salivary gland MALT lymphoma and hepatitis C virus
    • Small intestinal MALT lymphoma and Campylobacter jejuni
    • Cutaneous MALT lymphoma and Borrelia afzelii infection
  • MALT lymphoma can be associated with the following genetic conidtions:[16]
    • Trisomies 3, 12, and 18: it is believed that increased the gene copies is related to lymphoma pathogenesis.

Gross Pathology

MALT lymphoma starts in the tissues or organs outside of the lymph nodes (extranodal). MALT lymphoma develops in mucosa-associated lymphoid tissue, in the mucosa, or tissue that lines body organs or body cavities including:[6]

Microscopic pathology

  • On microscopic histopathological analysis, MALT lymphoma is characterized by the presence of dense diffuse lymphoid infiltrate of marginal‐zone cells in lamina propria with prominent lymphoepithelial lesions and consisting of small atypical cells with monocytoid features.[17][3]
  • A characteristic feature of MALT lymphoma is the presence of neoplastic cells within epithelial structures with associated destruction of the glandular architecture to form lymphoepithelial lesions.[18]
  • The morphology of the neoplastic cells is variable with small mature lymphocytes, cells resembling centrocytes (centrocyte-like cells), or marginal zone/monocytoid B cells.
  • Plasmacytoid or plasmacytic differentiation is frequent.
  • Lymphoid follicles are ubiquitous to MALT lymphoma but may be indistinct as they are often overrun or colonized by the neoplastic cells. Large transformed B cells are present scattered among the small cell population. If these large cells are present in clusters or sheets, a diagnosis of associated large B-cell lymphoma should be considered.

References

  1. ↑ 1.0 1.1 Parsonnet J, Hansen S, Rodriguez L, Gelb A, Warnke R, Jellum E, Orentreich N, Vogelman J, Friedman G (1994). "Helicobacter pylori infection and gastric lymphoma". N Engl J Med. 330 (18): 1267–71. PMID 8145781.
  2. ↑ Taal, B G; Boot, H; van Heerde, P; de Jong, D; Hart, A A; Burgers, J M (1 October 1996). "Primary non-Hodgkin lymphoma of the stomach: endoscopic pattern and prognosis in low versus high grade malignancy in relation to the MALT concept". Gut. 39 (4): 556–561. doi:10.1136/gut.39.4.556.
  3. ↑ 3.0 3.1 3.2 Bacon CM, Du MQ, Dogan A (2007). "Mucosa-associated lymphoid tissue (MALT) lymphoma: a practical guide for pathologists". J Clin Pathol. 60 (4): 361–72. doi:10.1136/jcp.2005.031146. PMC 2001121. PMID 16950858.
  4. ↑ Janusz, edited by Jankowski, (2012). Handbook of Gastrointestinal Cancer (2 ed.). Chicester: John Wiley and Sons Ltd. pp. 243–244. ISBN 978-0-470-65624-2.
  5. ↑ 5.0 5.1 5.2 Troppan, Katharina; Wenzl, Kerstin; Neumeister, Peter; Deutsch, Alexander (2015). "Molecular Pathogenesis of MALT Lymphoma". Gastroenterology Research and Practice. 2015: 1–10. doi:10.1155/2015/102656. ISSN 1687-6121.
  6. ↑ 6.0 6.1 6.2 Kinkade, Zoe; Esan, Olukemi A.; Rosado, Flavia G.; Craig, Michael; Vos, Jeffrey A. (2015). "Ileal mucosa-associated lymphoid tissue lymphoma presenting with small bowel obstruction: a case report". Diagnostic Pathology. 10 (1). doi:10.1186/s13000-015-0353-6. ISSN 1746-1596.
  7. ↑ Willis TG, Jadayel DM, Du MQ, Peng H, Perry AR, Abdul-Rauf M; et al. (1999). "Bcl10 is involved in t(1;14)(p22;q32) of MALT B cell lymphoma and mutated in multiple tumor types". Cell. 96 (1): 35–45. PMID 9989495.
  8. ↑ Bertoni F, Coiffier B, Salles G, Stathis A, Traverse-Glehen A, Thieblemont C; et al. (2011). "MALT lymphomas: pathogenesis can drive treatment". Oncology (Williston Park). 25 (12): 1134–42, 1147. PMID 22229204.
  9. ↑ Streubel B, Simonitsch-Klupp I, Müllauer L, Lamprecht A, Huber D, Siebert R; et al. (2004). "Variable frequencies of MALT lymphoma-associated genetic aberrations in MALT lymphomas of different sites". Leukemia. 18 (10): 1722–6. doi:10.1038/sj.leu.2403501. PMID 15356642.
  10. ↑ Dierlamm J, Baens M, Wlodarska I, Stefanova-Ouzounova M, Hernandez JM, Hossfeld DK; et al. (1999). "The apoptosis inhibitor gene API2 and a novel 18q gene, MLT, are recurrently rearranged in the t(11;18)(q21;q21) associated with mucosa-associated lymphoid tissue lymphomas". Blood. 93 (11): 3601–9. PMID 10339464.
  11. ↑ Takada S, Yoshino T, Taniwaki M, Nakamura N, Nakamine H, Oshima K; et al. (2003). "Involvement of the chromosomal translocation t(11;18) in some mucosa-associated lymphoid tissue lymphomas and diffuse large B-cell lymphomas of the ocular adnexa: evidence from multiplex reverse transcriptase-polymerase chain reaction and fluorescence in situ hybridization on using formalin-fixed, paraffin-embedded specimens". Mod Pathol. 16 (5): 445–52. doi:10.1097/01.MP.0000067421.92575.6E. PMID 12748251.
  12. ↑ Liu F, Karube K, Kato H, Arita K, Yoshida N, Yamamoto K; et al. (2012). "Mutation analysis of NF-κB signal pathway-related genes in ocular MALT lymphoma". Int J Clin Exp Pathol. 5 (5): 436–41. PMC 3396059. PMID 22808296.
  13. ↑ Deutsch AJ, Aigelsreiter A, Staber PB, Beham A, Linkesch W, Guelly C; et al. (2007). "MALT lymphoma and extranodal diffuse large B-cell lymphoma are targeted by aberrant somatic hypermutation". Blood. 109 (8): 3500–4. doi:10.1182/blood-2006-06-030494. PMID 17197434.
  14. ↑ Du M, Peng H, Singh N, Isaacson PG, Pan L (1995). "The accumulation of p53 abnormalities is associated with progression of mucosa-associated lymphoid tissue lymphoma". Blood. 86 (12): 4587–93. PMID 8541549.
  15. ↑ Liu F, Karube K, Kato H, Arita K, Yoshida N, Yamamoto K; et al. (2012). "Mutation analysis of NF-κB signal pathway-related genes in ocular MALT lymphoma". Int J Clin Exp Pathol. 5 (5): 436–41. PMC 3396059. PMID 22808296.
  16. ↑ Taji S, Nomura K, Matsumoto Y, Sakabe H, Yoshida N, Mitsufuji S; et al. (2005). "Trisomy 3 may predict a poor response of gastric MALT lymphoma to Helicobacter pylori eradication therapy". World J Gastroenterol. 11 (1): 89–93. PMC 4205391. PMID 15609403.
  17. ↑ Taal, B G; Boot, H; van Heerde, P; de Jong, D; Hart, A A; Burgers, J M (1 October 1996). "Primary non-Hodgkin lymphoma of the stomach: endoscopic pattern and prognosis in low versus high grade malignancy in relation to the MALT concept". Gut. 39 (4): 556–561. doi:10.1136/gut.39.4.556.
  18. ↑ Janusz, edited by Jankowski, (2012). Handbook of Gastrointestinal Cancer (2 ed.). Chicester: John Wiley and Sons Ltd. pp. 243–244. ISBN 978-0-470-65624-2.


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