Chapter 63: Marginal Zone B-Cell Lymphoma

• The marginal zone lymphomas (MZLs) are derived from memory-type or antigen-experienced B cells that reside in regions contiguous to the outer part of the mantle zones of B-cell follicles.

• The World Health Organization (WHO) defines three separate MZL entities, namely, the extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (currently known as MALT lymphoma), the nodal marginal zone B-cell lymphoma (previously termed monocytoid lymphoma), and the splenic marginal zone B-cell lymphoma (with or without circulating villous lymphocytes).

• Gastric MALT lymphoma is one of the best examples of a microbiologic (Helicobacter pylori) cause of a human malignancy.

• MALT lymphomas arise from mucosa-associated lymphoid tissues in the context of chronic inflammation.

• In addition to H pylori, other bacteria are possibly implicated in the pathogenesis of MZLs arising in the skin (Borrelia burgdorferi), in the ocular adnexa (Chlamydophila psittaci), and in the small intestine (Campylobacter jejuni).

• Hepatitis C virus (HCV) appears involved in the pathogenesis of splenic MZL through antigen-driven stimulation of the lymphoma clone.

• There is, however, a great geographic variation in the strength of these associations, which is not satisfactorily explained.

• An increased risk of developing MALT lymphoma has been also reported in individuals affected by autoimmune disorders, especially Sjögren syndrome and systemic lupus erythematosus.

• Several recurrent chromosomal translocations have been described in extranodal MZLs. Three of them—[t(11;18)(q21;q21), t(1;14)(p22;q32), and t(14;18)(q32;q21)]—are the best characterized; they each affect the same signaling pathway, activating nuclear factor-kappa B (NF-κB), a transcription factor that plays a major role in immunity, inflammation, and apoptosis (Table 63–1).

Clinical Features

• The most common site of MALT lymphoma is the stomach, representing at least one-third of all cases.

• Extranodal MZLs may also arise at many other sites, including the salivary gland, the thyroid, the upper airways, the lung, the ocular adnexa (lacrimal gland, conjunctiva, eyelid, orbital soft tissue), the breast, the liver, the urogenital system, the skin and other soft tissues, and even the dura.

• As a general rule, the presenting symptoms of extranodal MZLs are related to the primary location (eg, dyspepsia, pain, and nausea for gastric MALT lymphoma and nodules/papules for cutaneous MALT lymphomas).

• Elevated serum lactic acid dehydrogenase (LDH) or serum β₂-microglobulin levels, as well as constitutional B symptoms, are rare at presentation.

• MALT lymphoma can remain localized for a prolonged period within the tissue of origin, but regional lymph nodes can sometimes be infiltrated and dissemination at multiple sites occurs in up to one-fourth of cases. Transformation to a high grade lymphoma is unusual.

• Marrow or lymph node involvement is seen in 25% of cases or less.

• Immunoproliferative small intestinal disease (a special variant of intestinal MALT lymphoma) usually presents with severe, unremitting signs and symptoms of malabsorption.

Diagnosis

• The presence H pylori is determined by histochemistry or, alternatively, the urea breath test.

• The B cells of MZLs show the immunophenotype of the normal marginal zone B cells present in spleen, Peyer patches, and in lymph nodes. Therefore, the tumor B cells express surface immunoglobulins and pan-B antigens (CD19, CD20, and CD79a), express the marginal zone-associated antigens CD35 and CD21, and lack expression of CD5, CD10, CD23, or high-level expression of cyclin D1.

• The tumor cells of extranodal MZL typically express immunoglobulin (Ig) M, less often IgA, or IgG, whereas splenic zone lymphoma is typically IgD-positive.

• In addition to standard histology and immunohistochemistry, fluorescence in situ hybridization analysis or use of polymerase chain reaction for detection of t(11;18) may be useful for identifying patients who are unlikely to respond to antibiotic therapy for H pylori.

Staging

• The initial staging procedures for a gastric MALT lymphoma should include a gastroduodenal endoscopy with multiple biopsies taken from each region of the stomach, duodenum, gastroesophageal junction, and from any abnormal-appearing site.

• Endoscopic ultrasound is recommended to evaluate the regional lymph nodes and gastric wall infiltration.

• Other recommended laboratory and radiologic studies include measurement of serum LDH and β₂-microglobulin; computed tomography of the chest, abdomen, and pelvis; and marrow aspirate and biopsy.

• Multiorgan involvement is not uncommon and complete staging procedures are recommended for patients with nongastric mantle zone B-cell lymphoma.

Treatment

• Eradication of H pylori with antibiotics plus proton-pump inhibitor regimens should be the sole initial treatment of localized (ie, confined to the stomach) H pylori–positive gastric MALT lymphoma. H pylori eradication results in complete regression of gastric MALT lymphoma in approximately two-thirds of cases.

• Treatment of H pylori is based on triple or quadruple therapy, including a proton-pump inhibitor, clarithromycin and amoxicillin or metronidazole for 14 days, or a proton-pump inhibitor, metronidazole, tetracycline, and bismuth subcitrate for 14 days.

• Histologic evaluation of repeat biopsies remains an essential follow-up procedure, with multiple biopsies taken 2 to 3 months after treatment to document that the lymphoma is not progressing and that H pylori eradication has been achieved.

• Patients who do not respond or have only a partial response to antibiotic therapy should be considered for radiotherapy.

• Because gastric MALT lymphoma is multifocal, the surgical procedure is a total gastrectomy with its associated complications. Surgery has not been shown to achieve superior results in comparison with organ-preserving strategies.

• Alternatively, excellent disease control can be achieved with involved field radiotherapy alone for stages I and II MALT lymphoma of the stomach without evidence of H pylori infection or with persistent lymphoma after antibiotic eradication.

• The optimal management of nongastric disease is not clearly established and should be “patient-tailored,” taking into account the site, the stage, and the clinical characteristics of the individual patient.

• In general, the treatment used for H pylori–negative cases can be applied to nongastric MALT lymphoma. Radiation therapy is considered the treatment of choice for localized lesions. MALT lymphomas at different sites have been successfully eradicated with involved field radiation therapy encompassing the involved organ alone with doses of approximately 30 to 36 Gy.

• Patients with systemic disease should be considered for systemic chemotherapy and/or immunotherapy with anti-CD20 monoclonal antibodies (Table 63–2).

• This mature B-cell neoplasm involves white pulp follicles in the spleen, splenic hilar nodes, marrow, and blood.

• This very rare splenic MZL comprises less than 1% of all lymphomas. More than half of cases present with circulating villous lymphocytes with characteristic fine, short cytoplasm polar projections. When these are more than 20% of the lymphocyte count, the term splenic lymphoma with villous lymphocytes is commonly used.

• This condition is often associated with hepatitis C infection, and antiviral treatment can sometimes induce remission.

• Most common genetic abnormalities are 3q trisomy and gains of 12q.

• Patients usually present with isolated splenomegaly, cytopenias, and lymphocytosis without palpable lymphadenopathy.

• Autoimmune anemia or thrombocytopenia is seen in 10% to 15% of patients, and a monoclonal protein is frequent.

• It can be difficult to distinguish from lymphoplasmacytic lymphoma.

• Asymptomatic patients can be observed.

• Splenectomy is an excellent initial therapy and can result in prolonged remissions.

• Single-agent rituximab or rituximab combined with chemotherapy is also effective and the preferred initial therapy by some authorities.

• Transformation to diffuse large B-cell lymphoma is seen in 10% to 20% of cases.

• This condition is rare and less well defined than the other MZLs, representing less than 2% of all NHLs.

• The most common genetic abnormality is gain of several regions of chromosome 3.

• Patients usually present with peripheral and abdominal lymphadenopathy.

  — Marrow involvement is seen in less than half of patients, and blood involvement is unusual.

  — Ten percent of patients have a serum monoclonal immunoglobulin.

• Differentiation from follicular lymphoma and lymphoplasmacytic lymphoma can be difficult.

• No specific treatment guidelines exist. Patients are usually treated in a manner similar to follicular lymphoma.