Marginal zone lymphoma (MZL)

Overview

• 3rd most common B-cell lymphoma; median age ~6th decade; slight female predominance; usually a localized presentation. The prototype antigen-driven lymphoma (chronic inflammation / chronic antigenic stimulation).

Three WHO 2022 Subtypes

• Extranodal MZL of MALT (MALT lymphoma), ~70%: arises from chronic antigenic stimulation in mucosal tissues. Most common site is GI (gastric most common), then lung, ocular adnexa, salivary, thyroid, skin, dura. Gastric and non-gastric forms.
• Splenic MZL (SMZL), ~20%: spleen + BM ± peripheral blood (villous lymphocytes); rare nodal disease.
• Nodal MZL (NMZL), ~5 to 10%: rarest; primary nodal origin (no splenic/extranodal primary) but marrow involvement and advanced stage are common; MZL morphology within nodal architecture.

Pathology & Immunophenotype

• Morphology: clonal expansion of centrocyte-like and monocytoid-like B-cells from the marginal zone with interfollicular expansion; mature post-germinal-center subtype. Lymphoepithelial lesions in extranodal MALT (malignant lymphocytes infiltrating epithelium). Scattered immunoblasts can look larger but do not by themselves indicate transformation.
• Immunophenotype: CD20+, CD79a+, CD19+; CD5−, CD10−, CD23−, BCL6−, cyclin D1−; ± t(11;18), ± t(1;14).
• MYD88 usually negative: differentiates MZL from Waldenstrom macroglobulinemia / lymphoplasmacytic lymphoma (LPL).
• NF-kB pathway activation is central to MZL (via antigen-receptor signaling, translocations, copy-number changes, or mutations; detectable genetic lesions in subsets, varying by entity): MALT via balanced rearrangements; NMZL via trisomies or deletions; SMZL via trisomies or specific mutations.

MALT Lymphoma: Pathogenesis & Site Associations

• Gastric MALT: H. pylori in >90%; eradication achieves CR in ~60 to 80% of localized stage I/II disease (Wotherspoon 1993, classic).
• Ocular adnexa: Chlamydia psittaci association (variable by region); doxycycline trial in selected cases.
• Primary cutaneous marginal zone lymphoma (a separate WHO-HAEM5 entity, ICC 2022 "lymphoproliferative disorder," not MALT): variable Borrelia burgdorferi association in Europe.
• Small bowel (IPSID): Campylobacter jejuni (immunoproliferative small intestinal disease, Mediterranean).
• Salivary gland (parotid): Sjogren syndrome.
• Thyroid: Hashimoto thyroiditis.
• Pulmonary, dural, breast: chronic inflammation (variable).
• t(11;18)(q21;q21) API2-MALT1: most common translocation in gastric MALT; predicts H. pylori eradication failure and disseminated disease.
• Other translocations: t(14;18) IGH-MALT1 (lung, ocular), t(1;14) IGH-BCL10, t(3;14) IGH-FOXP1.

Splenic MZL

• HCV association, especially in Mediterranean / endemic regions (often with light-chain restriction); HCV eradication with direct-acting antivirals (DAA) achieves lymphoma response in ~75%, often without chemotherapy (DAA series: MZL response 73%, Arcaini Blood 2016; PMID: 27605512). Proof of concept was interferon-based: 7 of 9 CR (Hermine NEJM 2002; PMID: 12110736).
• Presentation: splenomegaly + cytopenias/pancytopenia (with lymphocytosis) + paraprotein (often low-level IgM) + circulating villous lymphocytes; rarely lymphadenopathy.
• Phenotype: CD20+, CD22+, CD5−, CD10−, CD23−, CD43±, FMC7+, cyclin D1−. Typically CD103-negative; CD25 is usually negative but expressed in a minority, so CD25 positivity alone does not exclude SMZL (HCL is CD25+, CD103+, CD11c+, CD123+, annexin A1+). NOTCH2 and KLF2 mutation status can help distinguish SMZL from other B-cell lymphomas.
• Cytogenetics: del 7q (~40%), KLF2 mut, NOTCH2 mut, MYD88 (small subset, overlaps with WM).

Workup

• Gastric MALT: EGD with multiple biopsies, H. pylori testing (histology, stool antigen, breath test, serology), EUS for depth/nodes, t(11;18) FISH.
• Splenic MZL: peripheral blood smear (villous lymphocytes), HCV serology + RNA, BM biopsy, CT, splenic imaging.
• Nodal MZL: PET-CT, BM biopsy, HCV, autoimmune workup.
• All: SPEP/UPEP (paraprotein common), HBV (rituximab planning), HIV.

Treatment

Gastric MALT: H. pylori Eradication

• H. pylori+ stage IE/IIE without t(11;18): antibiotic eradication is first-line. Optimized bismuth quadruple therapy (PPI + bismuth + tetracycline + metronidazole) x 14 d is preferred empirically; clarithromycin-based triple therapy (PPI + 2 antimicrobials) only if clarithromycin susceptibility is documented (rifabutin triple is an alternative).
• Eradication data (meta-analysis of 32 studies, >1400 patients; Ruskone-Fourmestraux EGILS Consensus, Gut 2011): lymphoma remission ~77.5% after H. pylori eradication; 78% (stage IE) vs 56% (stage II1E), and 82% (disease confined to mucosa/submucosa) vs 54% (deeper invasion) (Zullo, Clin Gastroenterol Hepatol 2010; PMID: 19631287).
• Follow-up: responses can be slow (lymphoma may regress over 12+ months); wait at least 3 months before assessing response. NCCN: repeat endoscopy/biopsy at 3 months if asymptomatic.
• t(11;18) predicts resistance to H. pylori eradication.

• H. pylori-negative, or t(11;18)+, or eradication failure: ISRT (24 to 30 Gy) highly effective, ~95% CR.
• Advanced/disseminated: rituximab monotherapy or BR, as for other indolent NHL.

Non-Gastric MALT

• Localized: ISRT 24 to 30 Gy, curative.
• Disseminated: rituximab ± bendamustine.
• Cutaneous (Borrelia+): doxycycline trial.

Splenic MZL

• HCV+: DAA therapy first (eradication often induces lymphoma response).
• Asymptomatic: watch & wait (appropriate for many patients).
• Indications for treatment: symptoms, threatened end-organ function, clinically significant or progressive cytopenias from lymphoma, bulky disease, or steady/rapid progression.
• Symptomatic first-line: rituximab monotherapy (ORR ~80%, durable); also BR, R-CHOP, or R-CVP. Rituximab is generally preferred first-line, but splenectomy remains a reasonable initial option in selected fit patients with symptomatic splenomegaly/hypersplenism and limited extrasplenic disease (not contingent on rituximab failure). If splenectomy is planned, give pneumococcal, meningococcal, H. influenzae, and hepatitis B vaccinations at least 2 weeks beforehand.
• Second-line: bendamustine + obinutuzumab, BR, BTK inhibitors (zanubrutinib preferred; ibrutinib US MZL indication withdrawn 2023), R-CHOP or R-CVP, lenalidomide + rituximab. Third-line: CAR T-cell therapy, lisocabtagene maraleucel (FDA Dec 2025 for MZL after ≥2 lines) or axicabtagene ciloleucel (not FDA-approved for MZL).

Nodal MZL

• Treat similar to follicular lymphoma: rituximab ± bendamustine for active disease.

Relapsed / Refractory MZL

• Zanubrutinib: FDA Sep 2021 for R/R MZL (MAGNOLIA trial, Opat Clin Cancer Res 2021; PMID: 34526366); ORR ~68%, durable; preferred BTKi.
• Ibrutinib: FDA Jan 2017 for R/R MZL; WITHDRAWN 2023 (confirmatory trial PFS not met).
• Lisocabtagene maraleucel (liso-cel): FDA Dec 2025 for R/R MZL after ≥2 prior lines of systemic therapy (TRANSCEND FL, MZL cohort: ORR 84%, CR 56%); the first FDA-approved CAR T for MZL.
• Lenalidomide ± rituximab: AUGMENT-style approach for indolent NHL.
• PI3K inhibitors: umbralisib was the only PI3K inhibitor FDA-approved for R/R MZL (accelerated, Feb 2021, after ≥1 anti-CD20 regimen; withdrawn May 2022 for an OS safety signal in UNITY-CLL). Idelalisib, copanlisib, and duvelisib were never FDA-approved for MZL (their FL indications were all withdrawn). No PI3K inhibitor is currently approved for MZL.
• BR, R-CHOP: standard chemo options. Allo-HSCT: rare, for transformation or refractory young fit patients.

High-Yield Pearls

• H. pylori eradication is first-line for gastric MALT; t(11;18) (API2-MALT1) predicts eradication failure.
• Wait at least 3 months (repeat endoscopy) before judging response to eradication; regression can take 12+ months.
• HCV+ splenic MZL: DAA first; lymphoma may regress without chemotherapy.
• Site-organism associations: gastric / H. pylori, ocular / Chlamydia psittaci, skin / Borrelia, small bowel / Campylobacter, salivary / Sjogren, thyroid / Hashimoto.
• MYD88 usually negative separates MZL from Waldenstrom/LPL; NF-kB pathway activation is central to MZL, with detectable NF-kB pathway lesions in a subset.
• SMZL is CD103-negative and usually CD25-negative (a minority express CD25), unlike hairy cell leukemia; rituximab monotherapy > splenectomy as first-line for symptomatic disease.
• Zanubrutinib (MAGNOLIA): preferred BTKi for R/R MZL.