marginal zone lymphoma forms and therefore useful as a diagnostic marker for nmzl. mutations in genes such as: 1) notch2 (25% of cases) a membrane protein that regulates the development of marginal zone b-cells from their precursor cells and also is a tumor suppressor which acts to regulate cellar survival; 2) tnfaip3 (5-15% of cases) whose product is a deubiquitinating enzyme that functions to suppress the nf-κb transcription factor and thereby the nf-κb signaling pathway which controls cellular activation, proliferation, and survival; 3) birc3, which encodes the ciap2 protein that functions to regulate cell death caused by apoptosis; 3) myd88 (0-10% of cases) whose protein product indirectly regulates activation of the nf-κb cell signaling pathway; 4) klf2 whose product protein is a transcription factor which indirectly regulates the nf-κb cell signaling pathway; 5) ptprd whose product protein is a receptor tyrosine phosphatase that has tumor suppressor activity and indirectly regulates several signaling programs that regulate cell proliferation and responses to cytokines; and 5) in ~40% of cases one or more of various other genes such as mll2, sin3a, arid1a, ep300, crebbp, and tbl1xr1) that have chromatin remodeling activity to thereby regulate the expression of a wide range of other genes. diagnosis the diagnosis of nmzl depends upon identifying neoplastic b-cells in lymph nodes and in some cases the bone marrow but not, at least in early stage disease, in extra-nodal organs. these neoplastic cells should express the marker proteins common to marginal zone lymphomas (refer to previous section) and, in most cases, one or more of the genomic abnormalities indicated in the pathophysiology section. treatment recommended treatments for nmzl depend on the diseases state. asymptomatic nmzl may use watchful waiting with routine follow-up examinations every, e.g. 3–6 months, to check for disease progression. however, localized disease, even in asymptomatic patients, has been successively treated with surgery followed by local radiotherapy. disease that moves past a localized stage to become disseminated, rapidly progressive disease, and symptomatic disease have been treated with a single chemotherapy drug (e.g. cladribine, fludarabine, chlorambucil, or bendamustine); a single immunotherapy drug (e.g. rituximab); a multiple drug chemotherapy regimen (e.g. chop), or a combination multiple chemotherapy drug plus immunotherapy drug regimen (i.e. chop + rituximab). it is not clear that any one or more of these regimens achieves is superior to the others. prognosis nmzl is considered an incurable but relatively indolent disease that takes a slowly progressive, relapsing course. its prognosis appears to be slightly worse than that seen in extranodal and splenic marginal zone lymphomas with ~15% of people progressing to a more aggressive lymphoma, diffuse large b cell lymphoma, at median time of ~4.5 years after the diagnosis of nmzl. in different studies, people with the disease have 5 year survival rates of 62-90%. children in children nmzl has been classified by the world health organization (2016) as a separate variant of nmzl based on its presentation, histology of the involved lymph nodes, and clinical course. of the more than 60 published cases, 95% of pediatric nmzl cases occurred in adolescent boys with >90% of cases presenting as an asymptomatic, localized (stage i/ii) disease involving enlargement of the lymph nodes of the head and neck regions. these cases showed no associations with autoimmune or pathogen-induced inflammatory diseases. all of these findings contrast with those seen in extranodal marginal zone lymphomas occurring in children. histologically, the involved lymph nodes show infiltrations in the germinal centers of affected lymph nodes by lymphoid cells usually expressing cd20 and cd43, often (~50% of cases) expressing bcl2, and usually not expressing cd10 or bcl6. the marginal zone b-cells in these infiltrations have relatively few genomic abnormalities compared to nmzl in adults. trisomy of chromosome 18 has been reported in 21% of cases and, in rare cases, trisomy of chromosome 3. no recurrent gene mutations have been reported to occur in these cells. the course of pediatric nmzl is extremely indolent with the disease having a low relapse rate and typically an excellent outcome. observation periods of up to 12–18 years have found that patients have overall survival rates of 100% and relapse rates of ~4%. treatment of pediatric nmzl has used a watchful waiting strategy, rituximab, chemotherapy, and/or local radiation therapy. the watchful waiting strategy has done as well as the other therapies and is therefore the recommended initial treatment for the disease. recent research b-cell receptor. various new drugs such as b-cell receptor (see adjacent figure) signaling blockers and ibritumomab tiuxetan (zevlin) are being tested in clinical trials for mzl. these trials are important in determining dosages and safety of the drugs in study. as of january 19, 2017, the fda approved the first ever targeted drug for mzl, ibrutinib. this drug works by inhibiting bruton's tyrosine kinase (bkt), which is able to send signals to the nucleus for survival. in other words, it slows the growth of b-cells. vaccines have been developed that greatly reduce the number of helicobacter pylori in the stomach of animals previously colonized with these bacteria. one or more of these vaccines may be a promising candidates to control helicobacter pylori infection in humans as well as farm and domesticated animals.