Marginal Zone Lymphoma

Extranodal MALT, Nodal, and Splenic subtypes — antigen-driven indolent B-cell NHL with distinct clinical behavior, H. pylori eradication as curative therapy, and rituximab-based management

Key Points

• Marginal zone lymphoma (MZL) comprises three distinct subtypes — extranodal MZL of mucosa-associated lymphoid tissue (MALT lymphoma), nodal MZL (NMZL), and splenic MZL (SMZL) — collectively accounting for ~8–10% of all B-cell NHL.
• Gastric MALT lymphoma is uniquely associated with Helicobacter pylori infection in >90% of cases; antibiotic eradication of H. pylori achieves complete histologic remission in ~75–80% of localized, t(11;18)-negative gastric MALT — one of the only curative antimicrobial treatments for lymphoma.
• Extranodal MALT lymphomas arise at diverse sites (stomach, lung, ocular adnexa, thyroid, salivary gland, skin, GI tract) and are frequently associated with chronic antigenic stimulation from infections (H. pylori, C. psittaci, B. burgdorferi, HCV) or autoimmune conditions (Sjögren syndrome, Hashimoto thyroiditis).
• Nodal MZL is a primary lymph node disorder without extranodal or splenic predominance; it resembles follicular lymphoma clinically and is managed similarly with watch-and-wait for asymptomatic disease and rituximab-based chemoimmunotherapy when treatment is needed.
• Splenic MZL classically presents with massive splenomegaly, circulating villous lymphocytes in peripheral blood, and minimal lymphadenopathy; HCV infection is present in ~20–30% and antiviral therapy alone can induce lymphoma regression in HCV-associated SMZL.
• All MZL subtypes share an indolent biology with favorable long-term survival; treatment is withheld until symptoms or organ compromise develop, and rituximab monotherapy or chemoimmunotherapy (bendamustine-R, R-CHOP) are the mainstays of systemic therapy.

Classification, Epidemiology, and Pathogenesis

Marginal zone lymphomas arise from post-germinal center B cells of the marginal zone — the outer layer of the lymphoid follicle mantle that normally contains memory B cells poised to respond rapidly to T-independent antigens. The three WHO-recognized subtypes differ in anatomical origin, clinical behavior, and molecular pathogenesis, but share indolent biology and antigen-driven pathogenesis. **Extranodal MZL of MALT (MALT lymphoma, ~50–60% of MZL):** MALT lymphoma is the most common MZL subtype and the third most common B-cell NHL overall. It arises in sites that normally lack organized…

Clinical Presentation and Diagnosis

**Extranodal MALT Lymphoma:** Presentation depends heavily on the involved site: - *Gastric MALT:* Dyspepsia, epigastric pain, nausea, and occasionally GI bleeding — symptoms indistinguishable from peptic ulcer disease or gastritis. Endoscopic appearance ranges from subtle mucosal erythema to ulcerated masses; multiple biopsies (≥8 from different gastric regions) are required. Diagnosis: histopathology showing lymphoepithelial lesions, IHC (CD20+, CD79a+, BCL2+, CD5−, CD10−, CD23−, cyclin D1−), H. pylori testing (histology, urease breath test, stool antigen), and FISH for…

Staging and Risk Stratification

**Gastric MALT Staging (Lugano/Paris staging system):** The Paris staging system, derived from the TNM classification for GI lymphomas, is used for gastric MALT: - Stage T1m/T1sm: Mucosa/submucosa only - Stage T2: Muscularis propria - Stage T3: Serosa - Stage T4: Adjacent structures - N0–3: Regional lymph node involvement - M0/M1: No/distant metastasis Endoscopic ultrasound (EUS) is mandatory for assessing depth of invasion and regional lymph node involvement in gastric MALT — it guides both staging and prediction of antibiotic response. Confined mucosal/submucosal disease (T1) responds best…

Treatment

**Gastric MALT Lymphoma:** *H. pylori eradication (first-line for ALL H. pylori–positive gastric MALT, regardless of stage):* Triple or quadruple antibiotic therapy (per local resistance patterns — typically a PPI + clarithromycin + amoxicillin ± metronidazole, or bismuth quadruple therapy for clarithromycin-resistant regions) × 10–14 days achieves H. pylori eradication in >90% of cases. Histologic complete remission follows in ~75–80% of localized H. pylori–positive gastric MALT without t(11;18) translocation, typically within 3–18 months of eradication. Endoscopic surveillance every 3–6…

Prognosis and Long-term Considerations

All three MZL subtypes share an indolent clinical course with favorable long-term survival, though cure is uncommon outside localized MALT treated with radiation or H. pylori eradication. **Gastric MALT:** Patients achieving histologic CR after H. pylori eradication have an excellent prognosis — 10-year OS >85%; late relapses occur in ~10–15%, usually manageable with re-eradication or radiation. A small minority transform to DLBCL (~1–2%/year), requiring systemic therapy. **Non-gastric MALT:** 5-year OS >80% for most sites; pulmonary and ocular adnexal MALT carry particularly favorable…