What every physician needs to know:

Marginal zone lymphoma is an indolent B-cell non-Hodgkin lymphoma (NHL) that is sometimes associated with chronic infectious/autoimmune conditions.

Marginal zone lymphoma is comprised of the following principal subtypes:

  • Nodal marginal zone lymphoma

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  • Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) lymphoma

  • Splenic marginal zone lymphoma

Are you sure your patient has marginal zone lymphoma? What should you expect to find?

Nodal marginal zone lymphoma is typically characterized by slowly progressive lymphadenopathy. Most patients are otherwise asymptomatic at the time of diagnosis.

Patients with MALT lymphoma have a varied presentation depending on the primary site of disease. Common sites include the stomach, small intestines, lacrimal glands/orbit, thyroid, lungs, skin, and salivary glands. Involvement of lymph nodes (often localized at first) and bone marrow is also common. Despite proliferation of lymphoid tissues, patients are often asymptomatic and the disease may present as an incidental finding.

Patients with splenic marginal zone lymphoma (SMZL) commonly present with splenomegaly and bone marrow involvement, both of which may produce cytopenias. Villous lymphocytes may be present in the peripheral blood. Lymphadenopathy (other than splenic hilar lymph nodes) is rare.

The diagnosis is confirmed by examination of involved tissue. Because the diagnosis can be challenging, it is important to provide sufficient tissue to the pathologist. Excisional biopsies are preferred over core needle biopsies or fine needle aspirates.

Beware of other conditions that can mimic marginal zone lymphoma:

Other types of NHL can present with adenopathy or extranodal masses.

Diffuse large B-cell lymphoma (DLBCL)

Up to one third of cases may arise from extranodal sites, including the gastrointestinal tract (that is, many gastric lymphomas are not MALT lymphoma). Patients with DLBCL typically experience rapid progression of disease and are often symptomatic at the time of diagnosis. Pathologically, DLBCL and marginal zone lymphoma are quite different. Occasionally, marginal zone lymphoma can transform into a more aggressive lymphoma (for example, DLBCL). Physicians should consider searching for foci of transformation in patients with marginal zone lymphoma who experience rapid disease progression, or increase in clinical symptoms.

Follicular lymphoma (FL)

FL is the most common indolent NHL and can have a presentation that is similar to either nodal or extranodal marginal zone lymphoma. FL, however, is derived from a germinal center B lymphocyte, and, as such, is typically CD10+ and bcl-6+. FL is also is characterized by a follicular pattern with an underlying network of CD21+ follicular dendritic cells. A similar network may be present in the reactive follicles of marginal zone lymphomas. Bcl-2 overexpression is present in the majority of cases of FL but can also be seen in marginal zone lymphomas.

The t(14;18) seen in follicular lymphoma is distinct from the t(14;18) seen in MALT lymphoma; in follicular lymphoma, the bcl-2 gene is juxtaposed with the IgH (immunoglobulin heavy chain) genes, while in MALT lymphoma the MALT1 gene, not bcl-2, is involved.

Mantle cell lymphoma (MCL)

MCL typically presents with lymphadenopathy, but bone marrow and gastrointestinal tract involvement is very common. Morphologically, MCL and marginal zone lymphoma can appear similar. However, MCL is typically CD5+ and is characterized by the overexpression of cyclin D1 and/or the presence of t(11;14) by cytogenetics or fluorescent in situ hybridization (FISH). MCL is typically more aggressive than marginal zone lymphoma, although up to one third of cases may follow an indolent course for several months or years.

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)

CLL/SLL is characterized by small CD5+ CD23+ lymphocytes. Rare cases of CD5+ marginal zone lymphoma can be difficult to distinguish from CLL/SLL, in which case the pattern of involvement and clinical presentation can be helpful.

Lymphoplasmacytic lymphoma (LPL)

LPL is a low-grade lymphoma of small B lymphocytes with plasmacytic differentiation (that is, plasmacytoid lymphocytes and plasma cells are also present). Like marginal zone lymphoma, LPL is CD5-, CD10-, and CD23-. A paraprotein, usually immunoglobulin M (IgM), is common but is not diagnostic of LPL and can also occur in cases of marginal zone lymphoma with plasmacytoid differentiation, although usually to a lesser degree.

Hairy cell leukemia (HCL)

HCL is an uncommon indolent B-cell lymphoid malignancy that presents with splenomegaly, cytopenias, and circulating lymphoma cells, and can be confused with SMZL. Unlike SMZL, HCL is CD103+, CD25+, CD11c+, and annexin A1+ by immunohistochemistry, and tartrate-resistant acid phosphatase-positive (TRAP+) by cytochemistry. Hairy cells and the villous lymphocytes of SMZL can appear similar although classically, HCL cells have circumferential projections, while the projections of villous lymphocytes are restricted to the poles of the cell.

Which individuals are most at risk for developing marginal zone lymphoma:

Marginal zone lymphoma appears to be often associated with chronic antigenic stimulation of post-germinal center marginal zone B-lymphocytes. As a result, patients with chronic inflammatory conditions may be predisposed to developing the disease. MALT lymphomas, in particular, are associated with a variety of infectious/autoimmune disorders.

  • Gastric MALT lymphoma may be associated with Helicobacter pylori gastritis

  • Ocular adnexal MALT lymphoma may be associated with Chlamydia psittaci

  • Cutaneous MALT lymphoma may be associated with Borrelia burgdorferi

  • MALT lymphoma of the small intestine and immunoproliferative small intestine disease (IPSID) may be associated with Campylobacter jejuni

  • Thyroid MALT may be associated with Hashimoto’s thyroiditis

  • MALT lymphoma of the salivary glands may be associated with Sjogren’s syndrome

Like other non-Hodgkin lymphomas, nodal marginal zone lymphoma is more common at advanced ages. There are no clear factors that predispose to the disease.

SMZL may be more common in individuals with chronic hepatitis C infection. Autoimmune conditions such as hemolytic anemia and immune thrombocytopenia may be associated with SMZL.

Marginal zone lymphoma does not appear to be hereditary.

What laboratory studies should you order to help make the diagnosis and how should you interpret the results?

The diagnosis of marginal zone lymphoma can only be made by careful pathologic evaluation of involved tissue. It is of critical importance to provide the pathologist with sufficient tissue and clinical information.

Morphologically, marginal zone lymphoma is characterized by small to medium sized lymphocytes surrounding a reactive follicle. Plasmacytic differentiation is common. SMZL typically produces infiltrates of small lymphocytes in both the white and red pulp of the spleen.

The lymphoma cells are typically CD20+, CD79+ B cells but are CD5-, CD10-, CD23-. Rare cases may be CD5+ and may be more aggressive. Most marginal zone lymphomas are sIgM+ and IgD-, with sIgG+ or sIgA+ being less common. The SMZL cells often coexpress sIgM (surface immunoglobulin M) and sIgD (surface immunoglobulin M). The exception is primary cutaneous marginal zone lymphoma, which appear to undergo class switching and more commonly express IgG, IgA, and IgE (immunoglobulins G, A and E).

Extranodal marginal zone lymphomas are commonly associated with chromosomal abnormalities, including t(11;18)(q21;q21), t(14;18)(q32;q21), t(1;14)(p22;q32), t(3;14)(p12;q32), and trisomy 3 or 18. None of these translocations is common in nodal marginal zone lymphomas or SMZL.

The nuclear factor kappa B (NF-kB) pathway is frequently involved in the pathogenesis of marginal zone lymphomas. Mutations leading to constitutive activation of NF-kB have been detected in splenic and extranodal marginal zone lymphomas including BIRC3 and TRAF3. NOTCH1/2 and TP53 mutations have also been described and are associated with associated with inferior outcomes in SMZL. The tumor suppressor genes responsible for histone modification, KMT2D and MLL2, are often mutated in nodal marginal zone lymphoma. Panels which assess for many of these mutations are now available for further characterization of marginal zone lymphomas, and will likely become more useful from a prognostic standpoint as we continue to learn more about specific mutations.

In addition to identification of lymphoma, a causative etiology should be sought in selected cases of MALT lymphoma and may provide the basis for antibiotic therapy. Testing for H. pylori either through histologic examination of tumor tissue, urea breath testing, or serology is essential in early stage patients with gastric MALT lymphoma. Similarly, testing for Chlamydia psittaci in ocular adnexal lymphoma or B. burgdorferi in cutaneous marginal zone lymphoma is reasonable. The majority of these cases have been seen in Europe.

What imaging studies (if any) will be helpful in making or excluding the diagnosis of marginal zone lymphoma?

Investigations should be limited to those that are likely to influence choice of therapy and/or response assessment. Standard Ann Arbor lymphoma staging and response assessment is performed using computed tomography (CT) imaging of the neck, chest, abdomen, and pelvis. The orbits should also be imaged with CT or magnetic resonance imaging (MRI).

The utility of PET (positron emission tomography) imaging remains unclear, with a high false negative rate. Nonetheless, PET imaging can occasionally be useful to help identify sites of extranodal disease in patients that were previously felt to have nodal lymphoma. Similarly, dissemination of MALT lymphoma to regional nodes can occasionally be detected by PET scan in patients with normal CT imaging. PET is also useful if transformation is suspected. Nonetheless, PET imaging is not considered standard of care and generally has limited clinical utility.

MRI imaging is often helpful in assessing the extent of disease in patients with ocular adnexal MALT lymphoma.

Endoscopic evaluation should be performed in all patients with gastric or intestinal lymphoma. Endoscopic ultrasound is useful in determining the extent of gastric wall involvement and regional node involvement, both of which are predictive of response to antibiotic therapy in early stage patients.

Bone marrow biopsy, although not an imaging study, should be performed in all patients with limited stage disease and should be considered in patients with advanced stage disease prior to initiation of therapy.

If you decide the patient has marginal zone lymphoma, what therapies should you initiate immediately?

Marginal zone lymphoma is rarely an emergency. Due to the slow nature of progression, most patients present before developing significant complications. In the rare cases of life or organ-threatening marginal zone lymphoma, high dose corticosteroids (for example, dexamethasone 40mg daily) can be used to temporize matters before starting more definitive (immuno) chemotherapy or radiotherapy.

More definitive therapies?

Are there more definitive therapies?

Treatment of indolent lymphoma should be individualized according to the disease subtype, presentation, comorbid conditions, and patient preferences. When possible, the goal of therapy is to cure the disease and/or prolong survival. In all cases, the goal should be to improve quality of life; care must be taken to avoid over treatment.

Most patients with nodal marginal zone lymphoma present with advanced stage disease and are not likely to achieve cure, even with aggressive chemotherapy regimens. Moreover, there is little evidence that choice of initial therapy has any impact on survival. The relative degree of treatment intensity, therefore, is typically commensurate with the extent of disease, rate of progression, and urgency for treatment response. Asymptomatic patients with slowly progressive, non-bulky disease may be safely observed, often for many months, before developing indications for therapy. Patients with indications for therapy may be managed with rituximab +/- chemotherapy.

Patients with extranodal lymphoma are more likely to present with localized disease. Under some circumstances, these patients may benefit from treatment of the underlying infectious/inflammatory disorder when one is identified. For example, patients with H. pylori associated stage I gastric MALT lymphoma may achieve complete remission following antibiotic therapy directed at the H. pylori. Similarly, there are reports of resolution of ocular adnexal MALT lymphoma following antibiotic therapy of Chlamydia psittaci.

Patients with early stage MALT lymphoma with no underlying infectious etiology, or those for whom antibiotic therapy has failed, can be effectively managed with external beam radiotherapy. Surgery is rarely the primary mode of therapy for localized disease, but may be the only treatment necessary in cases where the entire tumor was removed during a diagnostic biopsy. Patients with symptomatic advanced stage disease, or those with symptomatic early stage disease not amenable to radiation therapy, may be managed with rituximab +/- chemotherapy, depending on comorbid conditions and urgency for treatment response. There is emerging data for radioimmunotherapy in patients with MALT lymphomas, but outside the context of a clinical trial this should probably be generally reserved for patients with relapsed disease.

Observation with deferred initial therapy should be considered in most patients with SMZL without cytopenias or symptoms. Traditionally, splenectomy has been considered the best first-line therapy for patients with SMZL and symptomatic splenomegaly or severe cytopenias. However, treatment with rituximab +/- chemotherapy may be equally likely to yield clinical benefit and will also result in a reduction in tumor bulk outside the spleen (that is, the bone marrow). In cases of SMZL associated with hepatitis C virus (HCV) treatment of HCV may result in regression of the lymphoma.

Rarely, marginal zone lymphoma can transform into a more aggressive lymphoma, typically DLBCL. These patients require aggressive therapy and may benefit from autologous stem cell transplantation. Although the aggressive subtype may resolve completely, patients are often left with a persistent low-grade lymphoma.

Is it possible to predict which patients with MALT lymphoma will respond to antibiotics?

Gastric MALT lymphoma is the sole subtype for which strong evidence of response to antibiotic therapy exists. However, among patients with early stage gastric MALT lymphoma, the response to H. pylori eradication can vary significantly.

First, only those patients with evidence of H. pylori infection can be expected to respond to antibiotic therapy. Second, tumors that demonstrate the t(11;18) abnormality are unlikely to respond to H. pylori eradication and should probably be managed with alternative therapies (for example, radiation). Finally, those patients with locally advanced disease (that is, involvement of the muscularis mucosae or local lymph nodes) appear to have a significantly lower complete response rate. Nonetheless, it may be reasonable to attempt antibiotic therapy in patients with locally advanced disease without other indications for more aggressive therapy, since the disease is likely to be indolent and H. pylori eradication would otherwise be recommended. Most of these patients will require radiotherapy or immunochemotherapy.

The evidence regarding treatment of ocular adnexal MALT lymphoma with antibiotic therapy directed at Chlamydia psittaci or treatment of cutaneous MALT lymphoma with antibiotics against B. burgdorferi is variable and controversial. In the absence of other indications for local or systemic therapy, it may be reasonable to attempt a course of antibiotics; antibiotic therapy should not supplant therapy with a higher chance of success in patients with symptoms or rapidly progressive disease.

How should patients be followed after initial therapy?

Following treatment with antibiotics, patients with gastric MALT lymphoma should undergo repeat endoscopy at 2 months to confirm eradication of H. pylori; a second course of antibiotics is occasionally required. Endoscopy should be repeated at least twice a year to confirm regression of the lymphoma. Complete remission may take up to 2 years. Patients that do not respond may be offered alternative therapy. Patients that respond but subsequently relapse may benefit from another course of H. pylori eradication in cases where reinfection occurs. Otherwise alternative therapy is appropriate.

Patients with other subtypes of nodal and extranodal marginal zone lymphoma are at high risk for relapse following initial therapy (advanced stage disease is rarely, if ever, curable). Nonetheless, there is typically a lag between relapse of disease and the point at which patients develop clinically relevant symptoms sufficient to warrant therapy. Therefore, it is reasonable to limit screening for relapse, particularly radiography, to those patients with new symptoms. Interestingly, MALT lymphoma often has a tropism for extranodal sites. Patients with cutaneous MALT lymphoma in particular may have multiple relapses at other cutaneous sites with limited dissemination to the lymph nodes.

What novel therapies are available?

The Bruton’s tyrosine inhibitor ibrutinib is indicated for treatment of relapsed/refractory marginal lymphoma based on the results of a phase 2 clinical trial in which it was dosed continuously at 560 mg daily. Half of the study population had extranodal disease and about one-quarter each had nodal and splenic subtypes. Patients were required to have had a prior anti-CD20 antibody; they received a median of 2 prior systemic therapies. Approximately half of patients responded to ibrutinib. Similar response rates were reported in the three subtypes of marginal zone lymphoma. As has been observed in other lymphomas, ibrutinib was associated with side effects including fatigue, anemia, and infections and should therefore be reserved for patients with symptomatic relapsed or refractory disease.

What should you tell the patient and the family about prognosis?

The prognosis of patients with MALT lymphoma is often quite good. Patients with limited stage extranodal MALT lymphoma should be treated with curative intent with antibiotics or locally directed therapy when possible. In circumstances where such therapy is not feasible, when patients present with advanced stage lymphoma, or when patients relapse at sites distal to their original presentation, cure is unlikely with anything short of allogeneic stem cell transplantation (something that is usually not indicated).

Nonetheless, patients typically live for many years, requiring intermittent therapy when the disease becomes symptomatic. The reported 5 year overall survival (OS) of patients with MALT lymphoma is around 80%. Because of the average patient population (that is, older individuals), many patients die from causes unrelated to lymphoma or complications of therapy.

Despite similar International Prognostic Index (IPI) scores at presentation and rates of aggressive transformation, patients with nodal marginal zone lymphoma fare somewhat worse than patients with MALT lymphomas, with a reported 5 year OS closer to 60%. The difference in OS is likely due to biological differences between the two tumor types, although the precise differences remain to be elucidated.

Patients with SMZL have a median OS that is similar to that of patients with MALT lymphoma. Various prognostic factors have been proposed. In a large retrospective series from Italy, hemoglobin less than 12g/L, lactate dehydrogenase (LDH) greater than the upper limit of normal, and albumin less than 3.5g/dL were associated with a 5 year OS of 88%, 73%, and 55% for one, two, or three factors.

What if scenarios.

Histologic transformation appears to occur at roughly the same frequency as other indolent lymphomas (approximately 2 to 4% per year) with the median time to transformation being about 5 years. Patients experiencing transformation will typically manifest new constitutional symptoms, rapid tumor growth, or resistance to less aggressive forms of therapy. Transformation is often associated with chemoresistance and poor prognosis; median survival is 1 to 2 years.

Transformed lymphomas should be managed similar to other aggressive lymphomas. Patients with previously untreated lymphomas, or those that have received only locally targeted therapy, are candidates to receive R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)-like regimens. Radioimmunotherapy may be appropriate for those patients that are not candidates for anthracycline based regimens, if hematologic and bone marrow parameters allow. Those with relapsed disease rarely achieve long-lasting remissions with existing regimens. Such patients should be considered for aggressive second-line regimens, followed by autologous stem cell transplantation. Alternatively, clinical trials with novel agents may be appropriate.

Pathophysiology

The pathogenesis of marginal zone lymphoma is one of the more fascinating topics in lymphoma. Although the tumor microenvironment clearly plays a role in the biology of many cancers, rarely is the relationship as strong as that which exists in marginal zone lymphoma. The association of MALT lymphomas with infectious/autoimmune conditions, the restricted variable gene repertoire, and ongoing somatic hypermutation, all strongly suggest a role for chronic antigenic stimulation. Moreover, expression of chemokine receptor CXCR3 on tumor cells (except maybe primary cutaneous marginal zone lymphoma) is consistent with the suggestion that they are dependent on inflammatory cytokines.

Exactly how chronic inflammation results in tumorigenesis is unclear and may be different among the different marginal zone lymphoma subtypes. It is likely that there is a stepwise progression from reactive B-cell, to localized antigen-dependent tumor, to antigen independence, and more aggressive phenotypes. Depending on the changes that occur along the way, these transitions may be more or less likely. For example, it has been hypothesized that the t(11;18) may be an early event that results in antigen independence, but is also associated with low incidence of transformation to DLBCL.

Recurrent gains of chromosome 18 are a hallmark of nodal marginal zone and MALT lymphomas. Genes affected include MALT1, a key downstream protein in the B cell signaling and NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) activation. Moreover, in MALT lymphomas, both the t(11;18) and the t(14;18) result in overexpression of MALT1. These data support the hypothesis that aberrant NF-kB activation plays an important role in the pathogenesis of marginal zone lymphomas. Additional studies will be required to determine whether the components of this signaling pathway could be targeted with novel therapeutic agents.

What other clinical manifestations may help me to diagnose marginal zone lymphoma?

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What other additional laboratory studies may be ordered?

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