Chapter 64: 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.

Other bacterial infections 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 and incompletely explained geographic variation in the strength of these associations.

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 most characterized, and, interestingly, they all appear to 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.

The most common site of MALT lymphoma is the stomach, encompassing 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.

Elevated serum lactic acid dehydrogenase (LDH) or serum β₂-microglobulin levels, as well as constitutional B symptoms, are extremely 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 is not uncommon, occurring in up to one-fourth of cases.

The presence H. pylori must be determined by histochemistry or, alternatively, 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 routine 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.

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

The initial staging procedures 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 (see Table 64–1).

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

Eradication of H. pylori with antibiotics plus proton-pump inhibitor regimens should be the sole initial treatment of localized (i.e., confined to the stomach) H. pylori-positive gastric MALT lymphoma. H. pylori eradication results in complete regression of gastric MALT lymphoma in approximately 50 to 75 percent of cases.

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.

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 (Table 64–2).

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

On the contrary, 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.

Patients with splenic marginal zone lymphoma usually have widespread disease. Nevertheless, a watch and wait approach is probably sufficient following splenectomy since most patients display an indolent course.