commonly, the circulation. while generally an indolent disease, about 5-10% of cases transform into a far more aggressive malignancy, diffuse large b-cell lymphoma. in a variable percentage of cases, smzl has been observed to occur with an increased incidence in individuals who are chronically infected with hepatitis c virus or have any one of various chronic autoimmune diseases or abnormalities. signs and symptoms at presentation, patients (median age 65 years; range 30–90 years) generally exhibit enlargement of their spleens (75% of cases). they typically do not have enlargements of their lymph nodes except for the lymph nodes around the hilum of their spleens. most patients have no systemic symptoms such as fever, night sweats, weight loss, or fatigue. blood tests reveal reductions in the levels of red blood cells, platelets, and/or white blood cells in 25% of cases; an abnormal circulating igm myeloma protein in <33% of cases; and in ~20% of cases evidence of autoimmunity abnormalities such as circulating autoantibodies (i.e. antibodies directed against the patients' own antigens), autoimmune hemolytic anemia, immune thrombocytopenic purpura, cold agglutinins, and/or anticoagulant antibodies. individuals with smzl also commonly exhibit increased levels of circulating blood lymphocytes which in some cases can be identified as malignant b-cells; these malignant cells may have hair-like projections similar to the malignant b-cells found in the circulation of patients with hairy cell leukemia. patients with smzl may also present with signs and symptoms of acquired von willebrand disease, angioedema due to c1-esterase inhibitor deficiency, or hepatitis c virus infection (e.g. clinical hepatitis, circulating hepatitis c virus). the association of hepatitis c virus infection with smzl varies with location and may be as high as 10% in some areas. finally, careful examination of patient bone marrows almost always finds pockets or more extensive accumulations of malignant b-cells. pathophysiology the malignant cells involved in smzl are tentatively identified as antigen-experienced b-cells. the disease appears to be initiated in at least some cases by chronic antigen stimulation of the precursor b-cells that thereby become antigen-experienced. evidence for this derivation comes from studies showing that the antigen-experienced b-cells inn smzl express structurally restricted immunoglobulins and b-cell receptors (see clonal selection) that likely bind specific but generally unidentified antigens. furthermore, patients with smzl are often found to have autoimmune abnormalities such as circulating autoantibodies (i.e. antibodies directed against patients' own antigens), autoimmune hemolytic anemia, immune thrombocytopenic purpura, cold agglutinin disease, circulating anticoagulant antibodies, acquired von willebrand disease, and angeoedema due to c1-esterase inhibitor deficiency. it is thought that the b-cell receptor binding of unidentified antigens including those involved in the cited autoimmune abnormalities stimulate the b-cells' proliferation, long-term survival, and thereby the step-wise acquisition of genomic abnormalities which ultimately cause the antigen-experienced b-cells to become malignant. the genomic abnormalities thought to contribute to this malignant transformation include: chromosome abnormalities such as: 1) deletions in the long (i.e. "q") arm of chromosome 7 (annotated as del7q) in 30-40% of cases (this deletion is rare in other lymphomas and therefore used as a marker for smzl); 2) deletion of a region on the short (i.e. "p") arm of chromosome 17 in 3-17% of cases to result in a loose of one of the two p53 genes that encode a tumor suppressor that acts to regulate cellular survival; and 3) gains in the q arm of chromosome 3 in 10-20% of cases. mutations in genes such as: 1 klf2 (21% of cases), a transcription factor that indirectly regulates the nf-κb signaling pathway of cellular survival, proliferation, and the production of cell-stimulating cytokines; 2) notch2 (20% of cases), a membrane protein that regulates the development of marginal zone b-cells from their precursor cells and has tumor suppressor activity to thereby promote cellular survival; 3) tp53 (14% of cases), a transcription factor that indirectly regulates cell proliferation and programmed cell death to thereby promote cellular survival; 4) igll5 (14% of cases) with unclear functions; 5) tnfaip3 (13% of cases), which acts indirectly to inhibit nf-κb activation and programmed cell death; and 6) in <10% of cases at least 16 other genes. overall, mutations in the notch, nf-κb, and klf2 signaling pathways appear particularly important in the pathogenesis of smzl. diagnosis the clearest evidence for the diagnosis of smzl is obtained by examination of patients' spleens obtained by splenectomy. these spleens characteristically show lymphoid infiltrates in the white pulp and, to a lesser and more variable extent, the red pulp. these infiltrates consist of small lymphocytes, marginal zone b-cells, centroblast-like b-cells, monocyte-like b-cells, and plasma cells. epithelioid-like histiocytes may be found in the red pulp. splenic hilar lymph nodes may show nodular infiltrates of small lymphocytes. careful and thorough examination of patients' bone marrow commonly shows aggregates of lymphoid cells between the organs trabeculae and within its sinuses. neoplastic b-cells may also circulate in patient's blood. the neoplastic cells in all of these tissues, similar the neoplastic cells in extranodal and nodal mzl, express cd20, cd27, and bcl2 but not cd10, cd23, cd5, cd43, cd38, bcl6, cyclin d1, or annexin a1 marker proteins. these cells may also express the del7q deletion (i.e. deletions in the q arm of chromosome 7) in 30-40% of cases and in lower percentages of cases the mutated genes listed in the pathophysiology section. while the diagnosis of smzl was initially based on the examination of splenic tissue, currently the diagnosis is made in most cases on clinical findings plus examinations of patients' bone marrow and/or blood that detect neoplastic b-cells that express some of the proteins and/or genomic abnormalities cited above; however, cases difficult to diagnose based on bone marrow and blood findings require examination of the spleen to obtain a definitive diagnosis of smzl. treatment given its rarity, there have been no systematic and controlled studies on the treatment of smzl. current recommendations for this include the following. watchful waiting, which is the withholding of specific treatments while performing follow-up examinations every 3 to 6 months to detect disease progression. this course is recommended for the ~33% of smzl patients who present with asymptomatic, non-progressive, or slowly progressive disease. these patients may not require therapeutic interventions for long periods. historically, the initial therapy for patients with rapidly progressing disease was splenectomy. some 90% of these patients show reductions in their symptoms and improvements in their low red blood cell, platelet, and white blood cell counts; they had median progression-free, 5 year overall, and 10 year overall survival rates of 8.2 years, 84%, and 67%, respectively. however, these patients show no alteration in the neoplastic b-cells levels in their blood, were subject to serious complications from their splenectomy (e.g. thrombosis, infections), and did not show alter overall survival rates better than those obtained with other treatment strategies. accordingly, splenectomy for smzl has been limited to cases of significantly symptomatic enlarged spleens in patients with mild-to-moderate bone marrow involvement and no bulky lymph node enlargements. current treatment recommendations for patients with symptomatic or rapidly progressive smzl rely on drugs. rituximab, a commercial preparation of a monoclonal antibody directed at the cd20 protein on b-cells, is significantly active in smzl, with short-term treatments (e.g. ~4 weeks) achieving overall response rates of 90-100%, complete remission rates of >50%, and a 7-year progression-free survival rate of 69%. long-term maintenance therapy with rituximab appears to improve these results and patients who relapse after rituximab therapy commonly respond to a second course of the drug. prior to rituximab availability, single drug chemotherapy (e.g. chlorambucil, cyclophosphamide, fludarabine, pentostatin, 2cda, or bendamustine) and multiple drug regimens (i.e. the cvp regimen of cyclophosphamide, vincristine, and prednisone, or the chop regimen of cvp plus doxorubicin) were used to treat the disease. however, current studies indicate that these chemotherapeutic agents are not superior to single agent rituximab therapy in terms of response rate as well as the quality and duration of these responses. a phase ii clinical trial has found that the treatment of smzl with a combination of rituximab plus bemdamustine achieves overall response and complete response rates of 91% and 73%, respectively, with percentage responses enduring for >3 years, progression-free survival rate, and overall survival rate of 93%, 90%, and 96%, respectively. the results of this trial, while requiring confirmation, strongly suggest that this two-drug regimen be used in place of rituximab alone, the cited chemotherapy regimens, or rituximab plus the cited chemotherapy regimens for patients with symptomatic/progressive smzl. experts recommend that smzl patients who also have hepatitis c virus infection should be treated with drugs that act to eliminate the virus as their first line approach. before the development of directly acting anti-viral agents, several studies reported that ifn-α treatment of these patients produced improvements not only in the viral infection but also remissions (~65% of cases) in their lymphomas. several newer, directly acting anti-viral agents, e.g. grazoprevir, daclatasvir, sofosbuvir, and dasabuvir, are more effective in treating hepatitis c viral infection and in s small number of patients have been or are expected to be more effective in producing lymphoma remissions in patients with smzl plus hepatitis c virus infection. prognosis smzl generally follows an indolent course with 10 year survival rates of 42-95%. about one-third of these deaths are unrelated to smzl and ~5-10 of these deaths are due to the transformation of their smzl disease to diffuse large c-cell lymphoma. nodal marginal zone lymphoma nodal marginal zone lymphoma (nmzl), previously termed monocytoid b-cell lymphoma, nodal monocytoid b-cell lymphoma, and nodal marginal zone lymphoma with or without monocytoid b-cells, is an infiltration of tissues with malignant lymphoid cells that have the morphological and phenotypical features of all marginal zone lymphomas. nmzl differs from the other subtypes of marginal zone lymphomas by its primary involvement of lymph nodes rather than other tissues and organs. nmzl is the least common subtype of the three marginal zone lymphomas. signs and symptoms almost all patients with nmzl present (median age 50–64 years; male to female ration 1.5 to 1) with non-bulky enlargement of their lymph nodes in the neck, groin, abdomen, and thoracic regions; some cases may also exhibit this involvement in their waldeyer's tonsillar ring. patients at presentation are generally fully functional but in 10-20% of cases complain of b symptoms such as fever, night sweats, weight loss, and/or fatigue. laboratory studies show malignant b biopsy of involved tissues various patterns (e.g. diffuse throughout lymph node, centered between the follicles of lymph nodes, and/or a nodules spread throughout the lymph node) lymphocyte infiltration. these patterns are similar to those seen in emzl malt lymphomas. the cells in these infiltrations ore, in varying proportions, small lymphocytes, marginal zone-like b-cells, centrocyte-like cells, monocyte-like cells, plasma cell-like cells, and in >20% of cases large blastic b-cells. the malignant b-cells in these infiltrations are, like those in other marginal zone lymphomas, marginal zone b-cells that typically express cd20, cd19, cd79, and bcl2 but not cd10, cd5, cd23, or cyclin d1. pathophysiology some 6-19% of nmzl cases have been reported to be associated with autoimmune diseases such as rheumatoid arthritis, sjögren syndrome, autoimmune hemolytic anemia, and chronic thyroiditis. however, there is little evidence that these diseases contribute to the development of nmzl. furthermore, the association of nmzl with hepatitis c virus infections found in earlier studies has not been confirmed in more recent studies. it therefore appears that the postulated role of chronic immune stimulation in promoting extranodal and splenic marginal zone lymphomas has not been clearly demonstrated in and may not apply to nmzl: the underlying initiating cause for developing this disease is currently unclear. nonetheless, instigating b-cells in nmzl acquire genomic abnormalities that are thought to contribute to their malignant transformation. these genomic abnormalities include the following. chromosomal abnormalities such as: 1) trisomy of chromosome 3 (24% of cases) which causes the overexpression of foxp1, nfkbiz, and bcl6 whose protein products promote cellular proliferation and survival; 2) trisomy of chromosome 18 (~50% of cases) causing the overexpression of nfatc1 whose protein product may act to promote cell proliferation and survival; 3) uncommonly, trisomy of chromosomes 7 and 12 and deletion of the long arm of chromosome 6 which have as yet unknown functional effects; and 4) chromosomal translocation between the short (i.e. "p") arm of chromosome 2 at position 24 and the long (i.e. "q") arm of chromosome 14 at position 32, a translocation of as yet unknown functional consequence but not found in the other