marginal zone b-cell lymphoma marginal zone b-cell lymphoma marginal zone b-cell lymphomas, also known as marginal zone lymphomas (mzls), are a heterogeneous group of lymphomas that derive from the malignant transformation of marginal zone b-cells. marginal zone b cells are innate lymphoid cells that normally function by rapidly mounting igm antibody immune responses to antigens such as those presented by infectious agents and damaged tissues. they are lymphocytes of the b-cell line that originate and mature in secondary lymphoid follicles and then move to the marginal zones of mucosa-associated lymphoid tissue (i.e. malt), the spleen, or lymph nodes. mucosa-associated lymphoid tissue is a diffuse system of small concentrations of lymphoid tissue found in various submucosal membrane sites of the body such as the gastrointestinal tract, mouth, nasal cavity, pharynx, thyroid gland, breast, lung, salivary glands, eye, skin and the human spleen. marginal zone b-cell lymphomasother namesmarginal zone lymphomas (mzls)emzl infiltrating kidney tissue.typesextranodal marginal zone lymphoma, splenic marginal zone lymphoma, and nodal marginal zone lymphoma. in 2016, the world health organization classified mzls into three different types. extranodal marginal zone lymphomas (emzls) are mzls that develop in extranodal tissues. most emzls develop in malt and are often termed extranodal mzl of mucosa-associated lymphoid tissue or, more simply, malt lymphomas. splenic marginal zone lymphomas (smzls) are mzls that initially are confined to the spleen, bone marrow, and blood. nodal marginal zone lymphomas (nmzs) are mzls initially confined to lymph nodes, bone marrow, and blood. while all of these mzl involve malignant b-cells, they differ not only in the tissues they involve but also in their pathophysiology, clinical presentations, prognoses, and treatments. mzls represent 5–17% of all non-hodgkin lymphomas with the extranodal, splenic, and nodal forms accounting for 50–70%, ~20%, and ~10% of all mzls. the three mzl subtypes occur more often in older people (age 65–68 years) and are indolent diseases that may, in people without symptoms, be initially treated by a watchful waiting strategy. however, nmzl carries a somewhat worse long term outcome than the other subtypes and any of the mzl subtypes may progress in a low percentage of cases to a more aggressive lymphoma, particularly diffuse large b-cell lymphoma. one of the most distinctive feature of mzl is that many cases are associated with the persistent simulation of the immune system by the chronic inflammation that accompanies infections or autoimmune diseases. mzl cases associated with certain infectious pathogens can be cured by treatment directed at the pathogens causing or associated with these infections. extranodal marginal zone lymphoma emzls are a form of mzl in which malignant marginal zone b-cells initially infiltrate malt tissues of the stomach (50-70% of all emzl) or, less frequently, the esophagus, small intestine, large intestine, rectum, conjunctiva of the eye, nasal passages, pharynx, lung bronchi, vulva, vagina, skin, breast, thymus gland, meninges (i.e. membranes) that envelop the brain and spinal cord, or other organs. these emzls are classified into subtypes based on the organ(s) involved. for example, emzl of the stomach is termed primary gastric emzl. regardless of subtype, these emzls share similar pathophysiological (i.e. disordered physiological processes that cause the disease) and histopathological (i.e. microscopic features of diseased tissues). however, the subtypes differ in presentation, progression, severity, treatment, and instigating factors. the following two sections describe the common pathophysiologic and histopathologic features found in all emzl subtypes. features specific to each emzl subtype follow these two sections. pathophysiology histology of a normal lymphoid follicle, with marginal zone annotated at bottom. numerous factors appear involved in the development of emzl. in a small number of cases, the disease has an increased frequency in patients who have a family history of a hematological malignancy, particularly leukemia, or various autoimmune diseases such as sjögren syndrome and lupus erythematosus. inherited genetic, shared environmental, and other as yet unidentified factors may underlie these increased risks of developing an emzl. another key factor in the initiation of many emzl cases is chronic inflammation caused by a chronic infection or autoimmune reaction. the chronic inflammation stimulates b-cells to rearrange their immunoglobulin heavy chain locus so that they encode b-cell receptors that recognize unnatural antigens presented by the injured issues and/or infectious agents that underlie the inflammation. this rearrangement results in the b-cells responding to the ab\normal antigens by taking on features of marginal b-cells and proliferating excessively. in consequence, these b cells progressively acquire in a step-wise fashion chromosome abnormalities, gene mutations, and/or dis-regulated genes that contribute to their becoming malignant. the acquired genomic abnormalities found in emzl along with the frequency of occurrence in specific emzl subtypes include the following. chromosome translocations: 1) a translocation of the long (or "q") arm of chromosome 11 at position 21 with the q arm of chromosome 18 at position 21 (notated as a t(11;18)(q21;q21) translocation) occurs in 24% of gastric, 38% of lung, and rarely other emzl subtypes. this translocation places a part of the api2 gene with a part of the malt1 gene to create a fusion gene that encodes an api2-malt1 fusion protein. this chimeric protein promotes the continuous activation of a transcription factor, nf-κb. nf-κb controls the expression of various genes which increase the survival, cytokine production, and other potentially malignant behaviors of cells. 2) a t(14;18)(q32;q21) translocation occurs in 7% of ocular adnexa, 6% of lung, and rarely if at all in other cases of emzl. it causes the overexpression of malt1. this protein indirectly inhibits programmed cell death to prolong cell survival and also promotes activation of nf-κb. 3) a t(1;14)(p22;q32) ("p" stands for a chromosome's short arm) translocation occurs in ∼9% of lung, ∼4% of stomach, and rarely if at all in other cases of emzl. this translocation causes the overexpression of the bcl10 gene. bcl10 protein contributes to the activation of nf-κb. 4) a t(3;14)(p13;q32) translocation occurs in rare cases of emzl and is thought to cause overexpression of the foxp1 gene. foxp1 protein stimulates production of transcription factors such as prdm1, irf4, and xbp1 which promote the maturation of b-cells to plasma cells. 5) three translocations, t(1;14)(p21;q32), t(5;14)(q34;q32), t(9;14)(p24;q32), and t(x;14)(p11.4;q32), occur in rare cases of emzl but their effects on promoting malignancy are unknown. gene inactivations and mutations: 1) inactivation or the tnfaip3 gene due to its deletion on chromosome 6 about position 23 (i.e. a 6q23 deletion) or its mutation occur mainly in ocular adnexa, salivary gland, and thyroid gland emzl. tnfaip3 inactivation generally takes place in cases which do not have any of the above chromosome translocations. this gene's product, tumor necrosis factor, alpha-induced protein 3, functions to impair the activation of nf-κb. 2) gain-of-function mutations in the myd88 gene occur in ~5% of ocular adnexa emzl cases. the product of this gene, myeloid differentiation primary response 88, continuously activates nf-κb as well as the stat3 and ap1 transcription factors. 3) inactivating mutations in the notch1 (8% of all cases) and notch2 (8% of all cases) genes occur in emzl. the products of these genes are cell surface receptor proteins which when bound to their activating ligands move to the cell nucleus and contribute to the activation of genes that control the development, proliferation, survival, and migration of b cells. many emzl subtypes are associated with infectious agents or autoimmune diseases that may contribute to their malignant development. the following table reports on these emzl subtypes; the tissues they involve; the infectious agents/autoimmune diseases that may underlie the development of the emzl subtypes; the strength of evidence linking these infectious agents/autoimmune diseases to their malignancy; the incidence (i.e. percentage) of cases with the emzl subtype associated with the infectious agent/autoimmune disease; and some of the chimeric genes expressed by the neoplastic b-cells of the emzl subtype. subtypetissue(s) involvedinfectious agent or autoimmune diseasenstrength of evidenceincidencechimeric genes expressed (percentage of cases) primary gastric emzlstomachhelicobacter pyloriconfirmed~80%birc3-malt1 (23%), igh-foxp1 (3%), igh-bcl-10 (2%), and igh-malt1 (1%) primary gastric emzlstomachhelicobacter heilmannii sensu latolikely<1%similar to the antibiotics used for helicobacter pylori primary salivary gland emzlsalivary and lacrimal glandssjögren syndromeconfirmed~4.3%igh-malt1 (6%), birc3-malt1 (2%), and igh-bcl-10 (1%) primary thyroid emzlthyroid glandhashimoto's thyroiditisconfirmed~0.5%ich-foxp1 (50%) and birc3-mallt1 (9%) primary ocular adnexa emzlocular adenexa (i.e. orbit, conjunctiva, and eyelids)chlamydia psittacisuggestive10–50%igh-foxp1 (20%), igh-malt1 16%), and birc3-malt1 (7%) primary cutaneous emzlskinborrelia burgdorferisuggestivevariableigh-foxp1 (10%), igh-malt1 (7%), and birc3-malt1 (4%) primary small intestinal emzlsmall intestinecampylobacter jejunilowvariablebirc3-malt1 (19%) and igh-bcl10 (7%) primary pulmonary emzllungachromobacter xylosoxidanslow<50%birc3-malt1 (45%), igh-bcl10 (8%), and igh-malt1 (7%) histopathology the histopathologic (i.e. microscopic) examination of emzl lesions typically reveals a vaguely nodular or diffuse pattern of cells. the malignant cells in these lesions have, in varying proportions, the morphology of small-to-medium-sized lymphocytes, centrocyte-like b cells, centroblast-like b cells, monocyte-like b cells, plasma cell-like b cells, and/or large b cells. when the large b cells form prominent sheets that are clearly separated from cells with the other, low-grade malignant morphologies, the disease may be transforming to the far more aggressive malignancy, diffuse large b-cell lymphoma. this transformation occurs in ~18% of patients at a median of 4–5 years after the original diagnosis of emzl. immunophenotyping or the neoplastic large b cells in these lesions shows that they express cd20 but not cd3 surface membrane b cell marker proteins. the cells almost always express bcl2 and may express mnda (~70% of cases), cd23 (~33% of cases) and cd5 (~20% of cases) marker proteins but do not express the cyclin d1 marker protein., the t-cell marker, cd10, or bcl6. subtypes, diagnosis, treatment, and prognosis there are various emzl subtypes based on the organs they involve. almost all of these subtypes occur in the mucosa-associated lymphoid tissue of the affected organ and are often termed malt lymphomas of the affected organ (e.g. gastric malt lymphoma). however, these lymphomas are also termed primary emzl of the affected organ (e.g. primary gastric emzl). while both terms are used here for these subtypes, the primary (organ involved) emzl is preferred to indicate that the emzl subtype initially developed in and may remain limited to the indicated tissue. however, approximately 30% of cases disseminate to other sites, predominantly lymph nodes and in rare cases the bone marrow. the malignant b-cells in these subtypes may also circulate in the blood but this is very uncommon. regardless of the subtype of emzl or its dissemination to other tissues, the prognosis for these lymphomas is good with 5 year overall survivals generally ranging between 86% and 95%. primary gastric helicobacter pylori is the bacteria that often causes gastric ulcers and is a main cause of primary gastric emzl primary gastric emzl, also termed primary gastric malt lymphoma or, more often, just gastric malt lymphoma, is usually an indolent disease that in ~10% of cases also involves other gi tract and/or non-gi tract sites. patients commonly present at an early stage of the disease with various symptoms such as nausea, vomiting, indigestion, upper abdominal pain, and gastric bleeding as indicated by coughing up blood, bloody bowel movements, and/or iron deficiency anemia. rarely, patients present with perforation of the stomach or b symptoms such as fever and night sweats. individuals with chronic helicobacter pylori infection may also have halitosis. endoscopic inspection and biopsy of lesions and endoscopic-based ultrasound inspection of the upper gi tract show lesions, most often in the stomach's pyloric antrium, that are superficial mucosal erosions, shallow ulcers, nodules, enlarged rugae, and/or thickenings of the stomach wall. the histopathology of primary gastric malt lesions and the marker proteins and genomic abnormalities expressed by the malignant cells in these lesions are given in the histopathology section. primary gastric emzl is associated with infection of the stomach with helicobacter pylori in >80% of cases or with helicobacter heilmannii sensu lato in <1% of cases. indications that gastric helicobactor pylori is the causes for gastric emzl include: a positive urea breath test; a positive stool test that detects an antigen of the pathogen in the patient's feces; a positive urease test in a biopsied tissue specimen; a positive serum or whole blood test using specific antibodies directed against the pathogen; and growth of the pathogen in tissue cultures of a biopsied tissue. helicobacter heilmannii sensu lato designates at least 11 different helicobactor species of which 5 are known to infect the human stomach. it has been more difficult to determine that helicobacter heilmannii sensu lato is responsible for human gastric disease because the urea breath test is less often positive in infestations by these species, antibodies directed against