the name of mucosa - associated lymphoid tissue ( malt ) lymphoma was first established in 1983 by isaacson and du . from the beginning , it was adopted well and is still used in an unchanged form . marginal zone lymphoma of malt is , apart from diffuse large b - cell lymphoma , the most frequent type of lymphoma that occurs in the stomach . what is important is that it can develop in almost every organ and tissue , for instance lungs , breast , thyroid gland , bladder , skin , or orbital adnexa . it is an indolent type , but clinical outcomes and response to treatment vary among patients . malt lymphoma arises from the extranodal sites reach in b - lymphocytes , which appears in response to chronic antigenic stimulation caused by infection ( helicobacter pylori ) or autoimmune process ( hashimoto disease ) . this disorder is the best example of how infectious pathogens and genetic abnormalities lead to malignant transformation . gastric malt lymphoma pathogenesis is a complex process including many gene alternations that result in cancer appearance . better understanding of the background of the disease is crucial for discovering new prognostic factors , helpful in deciding when more aggressive treatment should be employed . the incidence of malignant lymphomas is at the rate of 3%-4% of all malignancy worldwide and has been increasing during the last 50 years . lately , some stabilization in the number of diagnosis was observed , but only in developed countries . malignant lymphomas are observed to be more frequent in north america , australia , and europe than in asia and africa . malt lymphomas determine almost 7% of all non - hodgkin 's lymphoma , and at least 40% is primarily located in stomach . it is confirmed that gastric malt lymphoma occurs in younger patients than the rest of malignant lymphomas . the malt lymphoma is mainly a disease of older adults , with a median age of 60 years . , there is much higher proportions of malt lymphomas , which can be caused by more frequent prevalence of helicobacter pylori in this region of the world . although 90% of population worldwide have confirmed bacteria colonization , only 2% will develop malignant lymphoma . it was confirmed by weber et al .   that almost 90% of patients with gastric malt lymphoma are infected with helicobacter pylori . this curved bacillus , previously called campylobacter pyloridis , is a gram negative pathogen found in the stomach . although over 80% of people are asymptomatic , chronic infection can lead to gastritis , gastric and duodenal ulcer , gastric adenocarcinoma , and malt lymphoma [ 5 , 6 ] . nowadays , it is widely accepted that helicobacter pylori gastritis is crucial in an evolution of malt lymphoma localized in stomach . it was confirmed by several studies that chronic gastric inflammation causes constant antigenic stimulation , which leads to clonal expansion of b - cell lymphocytes [ 7 , 8 ] . in the gastric mucosal cells , there are elevated levels of some cytokines , including proliferation - inducing ligand ( april ) , which belongs to the tumour necrosis factor ( tnf ) family . april is produced by macrophages present in the gastric malt infiltrate , located close to the neoplastic cells . april may also induce b - cells transformation and the progression to the diffuse large b - cell lymphoma ( figure 1 ) . they come either from t cells or directly by the antigenic autostimulation of lymphoma cells . gastric inflammation causes the appearance of a large number of macrophages , which , under a helicobacter pylori infection , release large amounts of april . importantly , a number of april - producing macrophages significantly decrease in complete remission after eradication therapy . other pathogens , are also suspected to play an important role in malt lymphoma pathogenesis . there are bacteria such as campylobacter jejuni , borrelia burgdorferi , and chlamydia psittaci and viruses like hepatitis c virus ( hcv ) that are potentially responsible for oncogenesis . these pathogens were found in histological material , but so far no strong evidences were established . patients with autoimmune disease have for sure higher risk of developing malt lymphoma . autoreactive b cells infiltrate the healthy organs and create lymphoid infiltrate similar to normal malt tissue with huge amount of reactive clonal b lymphocytes . this situation is observed in salivary gland in patients with diagnosis of sjgren syndrome and in the thyroid gland in hashimoto disease . sjgren syndrome is associated with 44 times increased risk of lymphoma , whereas hashimoto 's thyroiditis causes 70 times increased risk of thyroid lymphoma . some of them are proven to be strongly associated with the disease , but some are still not confirmed . it is believed , that on the background of chronic inflammation not only reactive b - cells are stimulated but also activated neutrophils which can lead to production of oxygen species . as a result , this genotoxins provoke dna damages , which are responsible for mutations and transformations of genetic material . it originates from a fusion of two proteins : apoptosis inhibitor 2 ( api2 ) and paracaspase malt lymphoma - translocation gene 1 ( malt1 ) . what is more important is that while t(11;18)(q21;q21 ) is detected , no other chromosome abnormality can be found . unfortunately , positive cases do not response to helicobacter pylori eradication , but , in contrast , they do not transform to more aggressive diffusive large b - cell lymphoma . it is known that complete remission can be seen in at least 20% of patients with t(11;18)(q21;q21 ) . the incidence of positivity for this translocation malt lymphoma is at approximately 20% in europe [ 16 , 17 ] but is not as common in the united states where only 5% are positive . moreover , it is usually connected with an advanced stage of disease and poor outcomes . bcl-10 gene is relocated from chromosome 1 to 14 , which in consequence triggers overexpression of bcl-10 protein also known as ciper , carmen , or me10 . in healthy organisms , higher expression is observed in lymph nodes , spleen , and testis . so far , it is believed that bcl-10 protein expression is responsible for proliferative effects [ 19 , 20 ] . the t(14;18)(q32;q21)(igh - bcl-2 ) is commonly present in follicular lymphoma , in about 20% of diffuse large b - cell lymphoma and sometimes in chronic lymphocytic leukemia . although this aberration is extremely rare in other types of lymphomas , it can be found in some cases of gastric malt lymphoma . bcl-2 is an antiapoptotic protein , which helps in survival and expansion of clonal b cells . so far , the role of t(14;18 ) in gastric malt lymphoma is not fully understood . overexpression of bcl-2 is found not only in translocation positive patients but also in the negative ones . it is believed that similar to other types of lymphomas , t(14;18)(igh - bcl-2 )  must coexist with other genetic abnormalities in order to develop neoplasm . t(3;14)(p14;q32)(igh - foxp1 ) is a newly described abnormality present in patients with malt lymphoma . the first study showed that positivity for this translocation is approximately 10% of all malt lymphoma patients . the most recent studies described the presence of t(3;14)(p14;q32 ) in diffuse large b - cell lymphoma , outside the lymph nodes especially [ 23 , 24 ] . only one study , so far , confirmed the existence of this translocation in gastric malt lymphoma   which involved bad clinical outcomes . in pathogenesis of malt lymphoma , the above described translocation promotes oncogenesis by similar well - known mechanism . the majority of them involve the same pathway , which leads to antigen receptor - mediated activation of nfb . this is a crucial transcript factor which plays a key role in malt lymphogenesis [ 26 , 27 ] . it regulates processes connected with b - cell development , growth , and survival by production of cytokines and growth factors , for example , tnf- family ( baff ) . latest studies have shown that b - cell activation in malt lymphoma can be strictly connected with tnf family . it can be also responsible for activation of cell apoptosis [ 28 , 29 ] . it is observed that in patients with higher baff levels in serum , the prognosis and survival are much worse . based on recent knowledge about genetic abnormalities in gastric malt lymphoma , there is a model of multistep pathogenesis . on the background of chronic inflammation and antigenic stimulation occurs genetic instability . as a result , many possible translocation and unbalanced aberrations are observed . gastric malt lymphoma can be long - time asymptomatic or associated with dyspepsia , abdominal pain , vomiting , diarrhea , obstruction , and nausea . sometimes bleeding from gastrointestinal tract or even perforation may occur while extensive lesions are present . as a result , symptoms of anemia like paleness , weakness , or easy fatigue can be observed . b symptoms ( weight loss , unexplained fever , and night sweats ) in gastric malt lymphoma are very rare , but the most common of the above is weight loss . a prompt diagnosis is crucial , but , unfortunately , it is usually made by incidence . patients with early stage of disease have usually low tumor growth and minimal possibility to spread . in contrast , patients with advanced stage of disease can undergo transformation to more aggressive lymphoma and may become resistant to treatment .   not only symptoms but also endoscopic picture can be inconclusive . difficulties often arise to differentiate between chronic gastritis or ulcer from an early - stage lymphoma . in order to confirm the diagnosis , there always must be made pcr or fish analysis for t(11;18 ) , which is important to separate groups that will not respond to standard treatment . characteristic for gastric malt lymphoma are lymphoepithelial lesions ( lel ) with the presence of mainly two types of cells : neoplastic centrocyte - like or small lymphoid . there is no specific immunohistochemical profile typical for gastric malt lymphoma diagnosis . in 50% of patients , there is coexpression of cd43/bcl2 . neoplastic cells are positive for cd-20 and negative for cd-10 , cd-23 , and cyclin d1 . if it is negative in histochemistry , rapid urea breath test or fecal antigen test have to be made . another analysis to prove absence of helicobacter pylori infection is serological test for caga antibodies and helicobacter pylori - igg antibodies . sometimes , there is possibility to detect other helicobacter species , for example , heilmannii or felis . before taking any decision on how aggressive the treatment should be , it is extremely important to perform a complete staging of the disease . what is more important is that risk factors and individual parameters , which can affect later therapy , are crucial . medical history must include information about the age , time of the first symptoms , the family history , and medical condition . the most important factor that we rely on during choosing method of treatment is clinical stage of the patient . during physical examination , it is important to remember about waldeyer 's ring , which is mandatory in every gastric lymphoma patient . staging in gastric malt lymphoma is similar to that in other types of lymphomas . according to recent european society for medical oncology ( esmo ) recommendations , it should include morphology with basic biochemical studies . if the blood cell count is lower , it can be caused by infiltration of bone marrow . biochemical tests can detect liver or kidney problems , which can be important before the beginning of a chemotherapy . lactate dehydrogenase ( ldh ) and 2-mikroglobulin are prognostic factors and will be abnormally high in patients with fast - growing tumor . every newly diagnosed patient should be examined in case of certain viral infections that can affect treatment , such as hepatitis b and c or human immunodeficiency virus ( hiv ) .   in every case , computed tomography ( ct ) scans of neck , chest , abdomen , and pelvis , which are crucial to evaluate enlarged lymph nodes , should be performed . core needle biopsy of bone marrow is made to diagnose possible infiltration of neoplastic cells . it was confirmed that 15% of gastric malt lymphoma patients have lymphoma cells in bone marrow . positron emission tomography ( pet ) has still not confirmed clinical necessity , but it can be extremely helpful in controversial cases . moreover , during staging procedures of gastric malt lymphoma , gastroduodenal endoscopy must be made . biopsies are taken from different sites of gastrointestinal tract ( e.g. , stomach , duodenum , and gastroesophageal junction ) and every location that looks suspicious . most often , ann arbour staging is employed , which describe the extend of all types of non - hodgkin lymphoma in adults . thus , staging of gastric lymphoma based upon the ann arbor system includes stage i e , which is disease limited to the stomach without nodal spread . stage ii e1 is tumor in the stomach with spread to adjacent contiguous lymph nodes . stage ii e2 is tumor in the stomach with spread to lymph nodes that are noncontiguous with the primary tumor . moreover , if the spleen is affected , we add s. if the person has any of the b symptoms , we add letter b , and if is asymptomatic , we assign a ( table 1 ) . prognostic factors in gastric malt lymphoma are similar to the value for non - hodgkin b - cells lymphoma . factors that determine poor outcome are age , high level of ldh in serum , higher ecog performance status , stages iii and iv in ann - arbour scale , white blood count , and more than one extranodal site . it was observed that patients with nodal invasion has difficulty with complete remission after eradication treatment . for instance patients , with t(11;18)(q21;q21 ) especially , are resistant to the first line therapy , and remission rate was lower than that in patients of api2-malt1 negative ( 78% versus 22.2% ; p = 0.0001 ) . only one study so far proved that the presence of t(3;14)(p14;q32 ) is connected with poor clinical outcomes of patients with gastric malt lymphoma . while helicobacter pylori plays a main role in the pathogenesis of malt lymphoma , it is also crucial in approach to the treatment . according to current international guidelines , first line treatment for localized helicobacter the treatment may be used with every highly effective antibiotics against helicobacter pylori , taking into consideration the locally expected antibiotic resistance . if there is no response to the therapy above , second line triple or quadruple therapy is used . it was reported that after two lines of treatment , 99.8% of patients were cured from gastritis . in a large study of 1408 patients , remission after eradication treatment in early stage unfortunately , in 5%10% of gastric malt lymphoma patients , we can not confirm helicobacter pylori infection . moreover , more than 30% patients are resistant to first line treatment , and 30% of them have t(11;18)(q21;q21 ) . treatment for this patients should be chosen individually depending on the clinical stage of disease . for those who have stable disease without any symptoms , radiotherapy , chemotherapy , and/or surgery can be considered after unsuccessful eradication treatment . further recommended surgery is considered to be a standard therapy in therapy of patients with gastric malt lymphomas , but , recently , the value of this therapy has been not confirmed . even if the lymphoma is localized at early stage , the gastrectomy should be rather extensive due to the nature of the disease . moreover , it is a major surgery and can be associated with serious complications and worsen a quality of life . german multicenter study group ( gmsg ) presented no difference between survival in patients treated with gastrectomy compared to eradication ( overall survival rate 82% to 84% ) . what is more important is that there were observed 50% long - term complications were observed after surgery . in few studies the use of a modest dose of involved fields was performed on resistant - to - eradication therapy patients with early - stage disease . the dose was 2535  gy to the stomach and perigastric nodes for the period of 4 weeks [ 42 , 43 ] . compared to surgery , no serious long - term complications and toxicity were observed . only nausea and anorexia were present during the time of radiotherapy . for a long time it was believed that gastric malt lymphoma is just a localized disease and that surgery and radiotherapy are the best treatment strategy . now , when it is well known that it is disseminated disorder chemotherapy , it became more important . still , there are no standard recommendations for relapse or progressive patients after therapy and for those with late stage of the disease from the beginning . it was observed that chemotherapy alone is more effective than surgery apart from some cases with gastric obstruction . complete remission ( cr ) after oral monochemotherapy with cyclophosphamide was 83% in a study by nakamura and coworkers . unfortunately , patients with positive translocation t(11 ; 18 ) are resistant to second line therapy with oral monochemotherapy with alkylating agents . nucleoside analogs are confirmed to be effective in treatment of different kinds of indolent lymphomas . a polychemotherapy with fludarabine and mitoxantrone ( fm ) has a very good effect on patients with gastric malt lymphoma in both first and second line treatment . the complete remission after 4 cycles achieved 84% of investigated and all of them reacted to the treatment . after 2-cda , there were observed complications such as toxicities of 3 and 4 grade of who , mainly leukopenia , infections , and secondary neoplastic disease . nowadays , immunotherapy became an extremely important part of treatment of non - hodgkin lymphomas . it is a chimeric mouse / human monoclonal antibody specified to cd20 antigen expressed on the surface of b lymphocytes . now it is widely used alone or in combination with chemotherapeutic drugs in many types of b - cell non - hodgkin lymphomas . rituximab binds to cd20 antigen and activates the lysis of b cells by mediating cytotoxicity of complement dependent ( cdc ) and cell - mediated cytotoxicity antibody dependent ( adcc ) . the role of this drug is still not clear in gastric malt lymphoma . in 2003 , there was a first - phase study by conconi et al . the cr was observed in 29% and overall response rate ( orr ) was 64% . the toxicity of this treatment was moderate or even mild , but the relapse rate was 36% . an important fact is that patients with translocation t(11;18 ) are responsive to rituximab treatment [ 58 , 59 ] . what is more important is that in a study by the international extranodal lymphoma study group ( ielsg ) , it was confirmed that chlorambucil in combination with rituximab was more effective than chlorambucil alone . the conclusion is that rituximab may a benefit in individual patients , but for the majority it is not sufficient when used alone . the efficacy of the combination of rituximab with chlorambucil was evaluated in a randomized study ( comparator was chlorambucil alone ) by the international extranodal lymphoma study group ( ielsg ) in gastric malt lymphomas that had failed antibiotics and in nongastric malt lymphomas . the preliminary report   showed that the 5-year event - free survival was significantly better for patients treated with chlorambucil plus rituximab . there were also studies by raderer et al . with cycles generally used in more aggressive lymphomas . twenty - six patients were administrated rituximab plus cyclophosphamide , doxorubicin or mitoxantrone , vincristine , and prednisone . lately , bortezomib , the first therapeutic proteasome inhibitor , was examined by kiesewetter et al . in 2012 with cr in 33% and pr in 27.8% . the results on phase ii studies with chemotherapy and immunotherapy are shown in table 2 . outcomes in gastric malt lymphoma patients with progressive , disseminated disease are very comparable with outcomes in follicular lymphoma . although gastric malt lymphoma has a very favorable outcome , it is still important to have a proper followup . it is possible that the disease will return even after 5 years of complete remission . the relapse can be due to reinfection of helicobcater pylori . in a study by zullo et al . the followup is obligatory in patients with gastric malt lymphoma to identify early phase of the recurrence of the disease . to confirm a complete remission , although , there are no specified recommendations for a followup , the biopsy of gastric sites should be made every 6 months in first two years , and later once a year for the next five years . systemic followup consist of blood tests and minimal adequate radiological and ultrasound and should be made at least once a year in the first 5 years . the transformation in more aggressive lymphoma is low at the level of 0.05% , but there is a higher risk of occurrence of secondary neoplasm   and gastric cancer . these studies confirm that patients with gastric malt lymphoma need a long - term followup not only to detect early recurrence but also to find secondary disease . recently , enormous progress has been made in better understanding of pathogenesis of gastric malt lymphoma . it has a great influence on the development of new and more effective treatment strategy . still , not enough clinical trials are performed due to rare expression and high effectiveness of first line treatment of gastric malt lymphoma . what is more important is that early diagnosis of gastric malt lymphoma is extremely important . while the symptoms are unspecific or not , always during the endoscopic exam the complete histological biopsies must be taken to make diagnosis correctly . the less advanced the stage of the disease , the bigger the chances to achieve complete remission
nowadays , it is believed that the main role in the development of gastric mucosa - associated lymphoid tissue ( malt ) lymphoma plays helicobacter pylori infection . 
 this world - wide distributed bacteria is in charge of most cases of not only upper gastrointestinal tract disorders but also some of extragastric problems . 
 constant stimulation of the immune system causes a b - lymphocytes proliferation , which is considered to be responsible for the neoplastic transformation . on the other hand , 
 there are 10%20% of patients who do not respond to helicobacter pylori eradication treatment . 
 this group has often a chromosome translocation , which suggests that there is another unknown , so far , pathogenetic mechanism of malt lymphoma . 
 majority of genetic abnormalities are connected with nuclear factor-b ( nf-b ) pathway , which activates the uncontrolled proliferation of neoplastic cells . 
 translocations already described in studies are t(11;18)(q21;q21 ) , which is the most common , t(14;18)(q32;q21 ) , t(14;18)(q32;q21 ) , and t(3;14)(p14.1;q32 ) . 
 this non - hodgkin 's lymphoma is an indolent type originated outside lymph nodes . in more than 50% of cases 
 , it occurs in the stomach . 
 occasionally , it can be found in salivary and thyroid gland , lung , breast , bladder , skin , or any other place in the human body . this paper is a review of the current knowledge on etiology , pathogenesis , treatment , and follow - up of gastric malt lymphoma .