Marginal zone lymphoma (MZL) refers to a heterogeneous group of mostly indolent lymphomas that may develop in lymph nodes, in the spleen, or mucosa-associated lymphoid tissue. The triggers of MZL development are poorly understood, but sustained antigenic stimulation due to chronic infection or autoimmune disorders seems to play a key role in the process. Accordingly, antimicrobial therapy is one of the pillars of MZL management. Affected individuals are also treated with cytostatics, immunomodulators, and/or radiotherapy. Most of them have a favorable prognosis.
The clinical presentation of MZL depends on the type of lymphoma and differs between extranodal MZL, splenic MZL, and nodal MZL :
MZL are indolent lymphomas and may be detected incidentally, e.g., by endoscopy or other techniques of diagnostic imaging . Nevertheless, neither type of image allows for a reliable diagnosis of MZL. The latter requires histopathological, immunophenotypic, and, ideally, genetic studies. Tissue samples have to be obtained from the affected tissue. MZL growth patterns are variable, and thus, diffuse, perifollicular, or nodal infiltration may be observed. Residual germinal centers may be recognized and are possibly surrounded by a mantle cuff. Tumor cells are clonal in origin and may show morphological features of monocytes, centrocytes, or plasma cells  . They may or may not contain Dutcher bodies . Immunophenotyping usually reveals the expression of CD19, CD20, CD22, CD79a, and PAX5, whereas most MZL test negative for CD5, CD10, and CD23  . With regards to genetic features, they may guide treatment decisions and be used as prognostic factors. Translocation t(11;18)(q21;q21), for instance, is predictive of a poor response to chemotherapy .
Once the diagnosis of MZL is confirmed, lymphoma staging needs to be carried out. It involves whole-body imaging as well as the examination of a bone marrow biopsy specimen . Peripheral blood samples should also be analyzed. In case of splenic MZL, there may be circulating lymphocytes displaying short villous projections with a polar orientation .
There is no standard treatment of MZL . Watchful waiting is a valid approach to the management of MZL in patients without cytopenias, constitutive symptoms, and autoimmune complications. Accordingly, this conservative strategy is often followed in those diagnosed with extranodal or splenic MZL . Beyond that, the following recommendations can be given:
What's more, Bruton's tyrosine kinase inhibitor ibrutinib has recently been tested in a clinical trial in distinct types of MZL . Ibrutinib has been developed as an antagonist of B-cell receptor signaling, which sustains tumor cell proliferation in MZL, but the drug has also been shown to interfere with Toll-like receptor signaling, B-cell adhesion and migration . All these effects may contribute to the drug's antitumor activity, and in fact, ibrutinib has been shown to induce durable responses with a favorable benefit-risk profile in patients suffering from relapsed or refractory MZL . It has been approved for that use in 2017.
MZL is considered an indolent type of lymphoma. The five-year overall survival rate is >60%, relative survival after that same period of time is >75%. Patients with extranodal MZL tend to have a better outcome than those diagnosed with nodal neoplasms . With regard to extranodal MZL, dissemination at the time of diagnosis doesn't seem to affect the outcome, and this fact further highlights the non-aggressive behavior of this type of lymphoma .
The patient's prognosis worsens if MZL transforms into diffuse large B-cell lymphoma . This is a rare event that may occur in any type of MZL .
The triggers of MZL remain unknown, but the disease has repeatedly been related to sustained immune stimulation due to autoimmune disorders or chronic infection. The incidence of MZL increases with age, which is usually attributed to an increased prevalence of immune disorders among the elderly and physiological immune senescence . In this context, patients suffering from Sjogren’s syndrome have a 40-fold increased risk of developing salivary gland MZL  . The persistent infection with Chlamydia psittaci, Helicobacter pylori, Campylobacter jejuni, Borrelia burgdorferi, or hepatitis C virus predisposes to MZL of the ocular adnexa, stomach, small intestine, skin, and spleen, respectively .
Furthermore, both genetic and environmental factors have been discussed as possible causes of MZL development. Patients with a family history of Non-Hodgkin lymphoma have been shown to be at higher risks of MZL, and this is possibly due to genetic variations in the major histocompatibility complex  . Similarly, occupation as a metalworker and the frequent use of hair dye may predispose to MZL . In sum, the individual roles of genetic, environmental, and immune factors in lymphomagenesis remain poorly defined, and further research is necessary to establish a sound risk assessment framework.
According to some studies, MZL account for only 3% of lymphoid neoplasms , but estimates as high as 10% of Non-Hodgkin lymphomas have been given elsewhere . In the United Kingdom, the annual incidence of MZL has been estimated to be 2.6 per 100,000 inhabitants . In the United States, incidence rates of 5.7 and 12.3 per million person-years have been reported for nodal and extranodal MZL, respectively. In the same study, an incidence of 1.6 per million person-years has been indicated for splenic MZL, rendering it the second most common form of extranodal MZL, preceded only by gastric MZL . The overall incidence of MZL has been rising during the last decades, but it is currently not known whether this trend reflects improvements in MZL diagnosis or a true increase of its incidence rate  .
MZL is usually diagnosed in the elderly; its incidence peaks in the seventh decade of life . Pediatric MZL rarely occurs but should be taken into account when diagnosing lymphoid neoplasms in children . In general, men are affected more often than women, and Caucasians are more frequently diagnosed with MZL than black people .
MZL are thought to arise from memory B cells to be found in the marginal zone of the secondary follicles in mucosa-associated lymphoid tissue, spleen, or lymph nodes . In the context of sustained antigenic stimulation, i.e., under conditions promoting the proliferation of lymphocytes or limiting their apoptosis, these cells' genetic instability may become a factor favoring lymphomagenesis . These conditions are met in patients suffering from inherited or acquired immune disorders, autoimmune disease, or infection. Presumably, (auto-)antigens mediate the permanent activation of B-cell receptors and stimulate the proliferation of lymphocytes. This is pathogenetically different from constitutive B-cell receptor signaling in other types of lymphoma, which is usually triggered by somatic mutations in downstream elements of the signaling cascade. In MZL patients, B-cell receptor signaling and tumor cell proliferation may thus be inhibited by antigen removal or pharmacological antagonism of the receptor  .
Considerable knowledge gaps remain with regards to additional factors involved in the development of MZL, which is assumed to be a multistep process implicating the consecutive loss of regulatory checkpoints. Both genetic and environmental factors are likely to contribute to the accumulation of genetic and molecular abnormalities culminates in the uncontrolled proliferation and neoplastic transformation of B cells .
Recommendations to prevent MZL can only be given insofar as the avoidance of risk factors as discussed above may possibly reduce the likelihood of developing this type of cancer. Sustained antigenic stimulation may be prevented by means of infection prophylaxis, antimicrobial therapies, or adequate treatment of autoimmune disorders, if available. Evidence on the role of genetic and environmental factors in MZL pathogenesis is scarce and doesn't yet allow for the definition of preventive measures.
According to the current classification of the World Health Organization, there are three main types of lymphoma, namely B-cell lymphoma, T-cell lymphoma, and Hodgkin lymphoma. MZL is a type of mature B-cell neoplasm. It may develop in distinct tissues, so nodal MZL is distinguished from splenic MZL and extranodal MZL of mucosa-associated lymphoid tissue . According to current knowledge, all types of MZL share common pathogenetic mechanisms, so they may respond to similar treatment regimens. The development of causal therapies is still in its early stages, though, and most patients are currently treated with cytostatics and immunomodulators, or radiotherapy. Due to the mostly indolent course of MZL, they generally have a favorable prognosis.
Lymphocytes are key players in the immune system. The uncontrolled proliferation of lymphocytes leads to lymphoma, which is a type of cancer. Marginal zone lymphoma (MZL), in turn, is a subtype of lymphoma. It originates from memory B cells in lymph nodes, in the spleen, or lymphoid tissue to be found in other organs. Memory B cells are required for the production of antibodies. Chronic infections, autoimmune disease, and other immune disorders favor the proliferation of these cells and have been shown to augment the risk of developing MZL. Otherwise, little is known about the causes of the disease.
Fortunately, MZL usually follows an indolent course. The majority of patients remains asymptomatic for prolonged periods of time, and the coincidental detection of MZL is not uncommon. Once the diagnosis of MZL is confirmed, a treatment schedule is established according to the general condition of the patient, the site of tumor growth and dissemination of the disease. Affected individuals may be treated with cytostatics and immunomodulators, or radiotherapy. Most patients have a favorable prognosis.