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 :
- Extranodal MZL is the most common type of MZL. Its presentation varies depending on the site of tumor growth. Most frequently, it develops in the stomach. Gastric MZL, or other involvement of the digestive tract, usually provokes abdominal pain, nausea, vomiting, hematemesis, melena, or hematochezia. Tumors developing in the salivary glands, lung, or skin interfere with the function of the respective organs and may cause additional symptoms by compressing neighboring tissues. This also applies to any other site that may be affected. Constitutive symptoms are rare and don't usually develop until advanced stages of the disease, when the bone marrow and other organs have become involved.
- MZL of the spleen is characterized by involvement of the spleen, bone marrow, and peripheral blood without other sites of disease. Splenomegaly without lymphadenopathy is the clinical hallmark of splenic MZL. The infiltration of the bone marrow with numerous small lymphoid cells interferes with hematopoiesis and frequently results in anemia and thrombocytopenia. On the other hand, hemolytic anemia and immune thrombocytopenia may accompany splenic MZL, raising doubts as to the causes of cytopenias.
- About 10% of MZL cases correspond to nodal MZL. In adults, this variant of the disease is usually diagnosed in advanced stages, with multiple lymph nodes being affected. By contrast, localized nodal MZL following an indolent course is more commonly observed in pediatric patients . The vast majority of nodal MZL is reported in adults. Here, bone marrow involvement may be noted, but cytopenias are uncommon. Contrary to the aforedescribed types of the disease, nodal MZL is frequently associated with constitutive symptoms like fever, night sweats, and weight loss. Serum levels of lactate dehydrogenase are elevated; concentrations of β2 microglobulin may be increased, too.
Entire Body System
A 61-year-old (gravidity 2, parity 2) female was admitted complaining of postmenopausal vaginal bleeding for 2 months. An ultrasound revealed a slightly thickened endometrium. [ncbi.nlm.nih.gov]
discharge or itching unusual stiffness of the neck and discomfort around bright lights severe headaches. [lymphomas.org.uk]
We describe the unusual case of a patient with an adnexal mass secondary to MALT lymphoma with associated amyloid deposition. [ncbi.nlm.nih.gov]
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 .
Multiple Pulmonary Nodules
In all cases there were single or multiple pulmonary nodules, in one case associated with cysts. [ncbi.nlm.nih.gov]
Right Pleural Effusion
Computed tomography of the chest showed a posterior mediastinal mass in the right thoracic paravertebral region with right pleural effusion. [ncbi.nlm.nih.gov]
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:
- Treatment of extranodal MZL is usually tailored to the needs of the individual patient. If lymphomagenesis is related to chronic infection, eradication of the pathogen may induce tumor regression . Otherwise, cytostatics and immunomodulators such as chlorambucil, cyclophosphamide, and rituximab may be administered. Rituximab may be combined with either of the aforementioned drugs but may also be given with bendamustine, or with fludarabine and mitoxantrone . Patients diagnosed with localized tumor disease frequently benefit from radiotherapy .
- While surgery isn't usually considered in MZL of mucosa-associated lymphoid tissue, splenectomy has long since been the treatment of choice of splenic MZL. In case of hepatitis C-associated MZL, antiviral treatment should be provided before opting for the removal of the spleen. Poor candidates for surgery are more likely to improve under rituximab or combined chemotherapy .
- In the rare cases where nodal MZL is diagnosed during early stages of the disease, radiotherapy should be offered. Disseminated nodal MZL is generally treated with rituximab and chemotherapy. Distinct regimens have been proposed to this end, but no consensus has been reached as to the treatment schedule to achieve optimum results. Affected individuals have been treated with rituximab plus cyclophosphamide, vincristine, and prednisone; with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone; and with rituximab plus fludarabine .
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.
- Rosand CB, Valla K, Flowers CR, Koff JL. Effective management strategies for patients with marginal zone lymphoma. Future Oncol. 2017.
- Tadmor T, Polliack A. Nodal marginal zone lymphoma: Clinical features, diagnosis, management and treatment. Best Pract Res Clin Haematol. 2017; 30(1-2):92-98.
- van den Brand M, van Krieken JH. Recognizing nodal marginal zone lymphoma: recent advances and pitfalls. A systematic review. Haematologica. 2013; 98(7):1003-1013.
- Schreuder MI, van den Brand M, Hebeda KM, Groenen P, van Krieken JH, Scheijen B. Novel developments in the pathogenesis and diagnosis of extranodal marginal zone lymphoma. J Hematop. 2017; 10(3-4):91-107.
- Noy A, de Vos S, Thieblemont C, et al. Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma. Blood. 2017; 129(16):2224-2232.
- Nakamura S, Sugiyama T, Matsumoto T, et al. Long-term clinical outcome of gastric MALT lymphoma after eradication of Helicobacter pylori: a multicentre cohort follow-up study of 420 patients in Japan. Gut. 2012; 61(4):507-513.
- Cencini E, Fabbri A, Lauria F, Bocchia M. Long-term efficacy and toxicity of rituximab plus fludarabine and mitoxantrone (R-FM) for gastric marginal zone lymphoma: a single-center experience and literature review. Ann Hematol. 2018; 97(5):821-829.
- Hendriks RW, Yuvaraj S, Kil LP. Targeting Bruton's tyrosine kinase in B cell malignancies. Nat Rev Cancer. 2014; 14(4):219-232.
- Smith A, Crouch S, Lax S, et al. Lymphoma incidence, survival and prevalence 2004-2014: sub-type analyses from the UK's Haematological Malignancy Research Network. Br J Cancer. 2015; 112(9):1575-1584.
- Casulo C, Friedberg J. Transformation of marginal zone lymphoma (and association with other lymphomas). Best Pract Res Clin Haematol. 2017; 30(1-2):131-138.
- Khalil MO, Morton LM, Devesa SS, et al. Incidence of marginal zone lymphoma in the United States, 2001-2009 with a focus on primary anatomic site. Br J Haematol. 2014; 165(1):67-77.
- Teixeira Mendes LS, Wotherspoon A. Marginal zone lymphoma: Associated autoimmunity and auto-immune disorders. Best Pract Res Clin Haematol. 2017; 30(1-2):65-76.
- Suarez F, Lortholary O, Hermine O, Lecuit M. Infection-associated lymphomas derived from marginal zone B cells: a model of antigen-driven lymphoproliferation. Blood. 2006; 107(8):3034-3044.
- Bracci PM, Benavente Y, Turner JJ, et al. Medical history, lifestyle, family history, and occupational risk factors for marginal zone lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project. J Natl Cancer Inst Monogr. 2014; 2014(48):52-65.
- Vijai J, Wang Z, Berndt SI, et al. A genome-wide association study of marginal zone lymphoma shows association to the HLA region. Nat Commun. 2015; 6:5751.
- Ayyappan S, William BM. Marginal Zone Lymphoma: Clinicopathologic Variations and Approaches to Therapy. Curr Oncol Rep. 2018; 20(4):33.
- Swerdlow SH. Pediatric follicular lymphomas, marginal zone lymphomas, and marginal zone hyperplasia. Am J Clin Pathol. 2004; 122 Suppl:S98-109.
- Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016; 127(20):2375-2390.