Marginal zone lymphoma (MZL) is the third most common indolent non-Hodgkin’s lymphoma (iNHL). There are three types of marginal zone lymphomas: the extranodal MZL (EMZL) of mucosa-associated lymphoid tissue (MALT or gastric GALT), the splenic MZL, and the nodal MZL. EMZL can originate at virtually any extranodal site and arises in organs that normally lack lymphoid tissue (eg, stomach, intestine, thyroid, lung, and skin). The most frequently affected organ in EMZL is the stomach, and there is compelling evidence for a causal relationship between H. pylori and gastric EMZL. SMZL arises predominantly from the marginal zone memory B-cells located in the follicles of the spleen, splenic hilar lymph nodes, BM, and the peripheral blood. The pathogenesis of SMZL has yet to be fully understood; similar to other subtypes of MZL, it likely involves the persistent stimulation of BCR signaling pathway, with increasing proliferation and survival of malignant B cells. NMZL is the least common subtype of MZL. The molecular pathogenesis of NMZL is still incompletely described but likely involves constitutive BCR signaling, resulting in proliferation and survival of malignant B cells.
The three MZLs share common lesions and deregulated pathways but also present specific changes that can be used for their differential diagnosis. Since their differential diagnosis is not straightforward in the non-rare cases presenting with disseminated disease involving lymph nodes, spleen, peripheral blood, bone marrow, or other extranodal sites, a better understanding of the molecular events underlying each subtype may have practical relevance. MZL is considered a slow growing indolent disease with a favorable outcome. While the majority of MZL have a relatively indolent course, like other iNHLs, it too can transform to a more aggressive lymphoma. Histologic transformation to DLBCL occurs in 7.5% of cases, with the majority (73.5%) from EMZL, followed by NMZL (14.7%). Rarely, MZL can transform to Hodgkin lymphoma.
In the World Health Organization classification, the three different marginal zone lymphoma (MZL) entities with specific diagnostic criteria, behavior, and therapeutic implications occur at the following rates: the extranodal MZL of mucosa-associated lymphoid tissue (MALT) 70% of cases, the splenic MZL (SMZL) 10% of cases, and the nodal MZL (NMZL) 20% of cases. MZL accounts for 6% (literature ranges from 2 to 12%) of all B-cell lymphomas. Of the extranodal sites, the most common is stomach/gastric (GALT lymphoma) followed by ocular/adnexal, lung, skin, and salivary gland, the median age of a MZL diagnosis is 67 years and is slightly more common in men. It is estimated that there are 1000 to 2300 cases per year in the US. Five-year survival rates are reported as follows: 88.7 percent for MALT, 79.7 percent for splenic MZL, 76.5 percent for nodal MZL. Though the majority of SMZL run an indolent course similar to EMZL, overall, SMZL has poorer outcomes due to a relatively larger proportion of patients who present with aggressive disease. The overall prognosis for NMZL is worse than EMZL when presenting as disseminated disease and more comparable with SMZL and other indolent lymphomas.
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Current Treatment
Despite being the third most common indolent non-Hodgkin’s lymphoma (iNHL), marginal zone lymphoma (MZL) remains largely understudied, and given its underlying disease heterogeneity, it is challenging to define a single treatment approach for these patients. Molecular lesions may be of help to inform MZL diagnosis, prognosis, and therapeutic targeting. In general, the presence of trisomies of 3 and 18 as single lesions or associated only with TNFAIP3 loss or 7q deletions is highly indicative of MZL more than other small cell lymphomas. The presence of translocations affecting MALT1 and BIRC3 is basically exclusive to MALT lymphoma, in which they are associated with lower response rate to antibiotics treatment. From a diagnostic standpoint, NOTCH2 mutations are highly specific for SMZL and NMZL among mature B-cell tumors, including conditions that look alike, thus representing a biomarker with positive predictive value for non-MALT MZL specification. Within non-MALT MZL, PTPRD mutations are enriched in NMZL and thus may represent a genetic biomarker that, though not highly sensitive, is provided with a positive predictive value for NMZL specification. From a prognostic standpoint, KLF2 mutations and NOTCH2 mutations represent promising prognostic biomarkers associated with poor survival and transformation to aggressive lymphoma whose broad application in clinical practice requires the assessment of whether their incorporation into the currently available clinical prognostic models improves risk stratification of patients. Molecular aspects of MZL point to deregulated cellular programs worth exploring as therapeutic targets. Pharmacologic interference of NOTCH signaling, non-canonical NF-κB signaling, or upstream pathways that are connected to NF-κB, including BCR signaling, are attractive approaches in these lymphomas.
For localized disease, local therapy is recommended such as therapy for eradication of H. pylori in gastric extranodal MZL, splenectomy or weekly rituximab for splenic MZL, and radiotherapy for nodal MZL. For patients with hepatitis C virus, antiviral therapy should be the first-line approach as it can lead by itself to regression of the lymphoma. Asymptomatic patients with SMZL can undergo observation for multiple years with routine clinical examinations and blood counts; observation in these patients does not influence overall outcomes.
There are no treatment guidelines focusing specifically on NMZL. Treatment and management typically follow that of similarly staged FL. In localized disease, targeted radiotherapy is appropriate, while in both limited and advanced stage diseases with low tumor burden, watchful waiting is employed. No trials to date have looked at NMZL specifically; however, with more advanced-stage disseminated disease requiring treatment, immunochemotherapy regimens comprising rituximab plus chemotherapy with or without an anthracycline are typically used.
For disseminated disease with low tumor burden, a watch and wait or single-agent rituximab (anti-CD20) can be used. However, for symptomatic disease, a similar approach to follicular lymphoma (FL) can be used with chemoimmunotherapy approaches such as bendamustine/chlorambucil and rituximab. High FDG uptake is not common in MZL and is not diagnostic by itself of transformation to high-grade lymphoma but informs the choice of the site to be biopsied. Transformation into a large B cell lymphoma is treated with R-CHOP-like regimens. Patients with relapsing disease after at least one CD20-based therapy have several recently approved chemotherapy-free options including B cell receptor inhibitors such ibrutinib (approved specifically in MZL) and immunomodulatory agents such as lenalidomide and rituximab (FDA approved in MZL and FL). Phosphoinositide 3-kinase (PI3K) inhibitors have shown excellent activity in iNHL, specifically in MZL, with breakthrough designation status for copanlisib and umbralisib, allowing off label use of this class of agents in clinical practice. With the availability of prospective clinical trials using chemo-free approaches, specifically those targeting abnormal signaling pathways activated in MZL tumors and its microenvironment, treating physicians are encouraged to enroll patients on these clinical trials in order to better understand the underlying biology, mechanisms of response, and resistance to current therapies and help design future rationale combination strategies.
LLS Research
Perhaps indicative of the relatively small patient population, LLS does not have many grants that directly target MZL. However, research in other areas of blood cancers especially in other lymphoma sub-types will have impact on this disease. In 2019, LLS funded $22.5 million in lymphoma research with 12% of our total research spend going to indolent lymphomas like MZL. MZL shares many of the same deregulated pathways as other blood cancers and LLS research has been influential in advancing the understanding of these pathways and developing therapies. For example, Notch and PI3K pathways are noted in a host of malignancies as well as MZL and we have had two Specialized Center of Research (SCOR) grants totaling $12.5M assigned to Jon Aster M.D., Ph.D. of Brigham and Women’s Hospital in Boston studying Notch in lymphomas and Dr. Aster currently holds a Translational Research Program grant studying Notch. LLS has also invested in the BTK therapies both in our grants program and our Therapy Acceleration Program (TAP) where we invest in small pharma/biotech companies to accelerate drug development. Similarly, LLS has had a major impact in the development of Venetoclax with multiple SCOR grants awarded to Professor Jerry Adams, Ph.D. of the Walter and Eliza Hall Institute of Medical Research in Australia totaling approximately $20M.
Future Directions
Future needs for MZL research will focus primarily on further elucidating the roles that deregulated signaling pathways play in the disease. Because antigen stimulation is thought to play a role in the development and progression of the disease, a better understanding of the role of the tumor microenviroment may offer insights into new therapeutic strategies. In is known that a mutations affecting epigenetic genes are frequent in MZL yet this area is under explored. From a prognostic standpoint, KLF2 mutations and NOTCH2 mutations represent promising prognostic biomarkers associated with poor survival and transformation to aggressive lymphoma whose broad application in clinical practice requires the assessment of whether their incorporation into the currently available clinical prognostic models improves risk stratification of patients.
With the availability of prospective clinical trials using chemo-free approaches, specifically those targeting abnormal signaling pathways activated in MZL tumors and its microenvironment, treating physicians are encouraged to enroll patients on these clinical trials in order to better understand the underlying biology, mechanisms of response, and resistance to current therapies and help design future rationale combination strategies.
Finally, immunotherapy continues to revolutionize cancer therapy, and given the important role of the tumor microenvironment in MZL, there are several ongoing studies looking at immune checkpoint inhibitors such as pembrolizumab, the PD-1 inhibitor, in frontline iNHL (NCT03498612), or in the R/R setting as a single agent and in combination with B cell receptor inhibitors (NCT02332980), while other studies are evaluating CAR-T cell therapy in R/R iNHL, including MZL (NCT03105336). While immunochemotherapy has been the therapy backbone for disseminated MZL, we are witnessing a shift toward targeted therapies with approval of several agents that modulate the tumor microenvironment and its interaction with the underlying tumor. A precision medicine approach for this disease would require an integration of different molecular signatures, immune profiling, and clinic-pathological features in order to create accurate prognostic and therapeutic strategies that will be tailored for each individual patient. This can only be achieved through international collaborative efforts and the implementation of prospective clinical studies dedicated to patients with MZL.
The image was originally published in ASH Image Bank. Girish Venkataraman, MD, MBBS. Splenic marginal zone lymphoma-HE. ASH Image Bank. 2018;61754. © the American Society of Hematology.