Marginal Zone Lymphoma

Neoplastic MONDO:0017604 Pathograph 6 Show in embeddings browser B-cell non-Hodgkin lymphoma mature B-cell neoplasm

Marginal zone lymphoma (MZL) is a family of indolent mature B-cell non-Hodgkin lymphomas derived from B cells of the marginal zone, the outer compartment of the splenic white pulp and of secondary lymphoid follicles. Current classifications recognise three distinct entities separated by the anatomical compartment involved: extranodal MZL of mucosa-associated lymphoid tissue (MALT lymphoma), splenic MZL, and nodal MZL. The unifying pathogenic theme is chronic antigenic drive. Sustained stimulation by a persistent infection or an autoimmune process selects and expands marginal-zone B cells, and the expanded clone subsequently acquires genetic lesions that lock the NF-kB pathway into constitutive activity, rendering growth independent of the original antigen. Trisomies 3 and 18 and NF-kB deregulation are shared across all three entities; the entity-defining lesions are not. Extranodal disease is characterised by recurrent translocations that fuse or deregulate the BCL10-MALT1 axis, whereas splenic and nodal disease instead carry KLF2 and NOTCH2 mutations, with deletions of chromosome 7q largely confined to splenic disease. Because that antigenic drive is often removable, MZL is one of the few lymphomas in which eradicating an infection can itself be the treatment. This root entry deliberately carries only what holds for MZL as a family — the three-entity axis, the shared antigen-driven and NF-kB-dependent mechanism, the aetiological heterogeneity across anatomical sites, and the shared risk of histologic transformation to diffuse large B-cell lymphoma. The entity-specific genetics, presentation and management are not re-derived here: see `MALT_Lymphoma.yaml` and `Splenic_Marginal_Zone_Lymphoma.yaml`, which both already declare `marginal zone lymphoma` as a parent. Nodal MZL has no entry yet.

Ask OpenScientist

Ask a research question about Marginal Zone Lymphoma. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

4
Pathophys.
2
Phenotypes
1
Gaps
6
Pathograph
2
Medical Actions
3
Subtypes
◆

Subtypes

3
Extranodal Marginal Zone Lymphoma of MALT Type (MALT Lymphoma) MONDO:0007650
The most common of the three entities. Arises at extranodal mucosal and glandular sites that have acquired lymphoid tissue in response to chronic infection or autoimmune inflammation — stomach (Helicobacter pylori), ocular adnexa, lung, salivary gland, thyroid, skin and small intestine. Defined among the MZLs by recurrent translocations that activate NF-kB, most notably t(11;18)(q21;q21)/BIRC3::MALT1. Fully curated in `MALT_Lymphoma.yaml`.
Splenic Marginal Zone Lymphoma MONDO:0019462
Arises in the marginal zone of the splenic white pulp and presents with splenomegaly, circulating villous lymphocytes, cytopenias and bone marrow involvement rather than lymphadenopathy. Lacks the MALT translocations and instead carries NOTCH2 and KLF2 mutations and deletions of 7q. Associated with chronic hepatitis C virus infection in a subset. Fully curated in `Splenic_Marginal_Zone_Lymphoma.yaml`.
Nodal Marginal Zone B-Cell Lymphoma MONDO:0019465
Primary nodal disease without extranodal or splenic involvement, and the least well characterised of the three. Shares the KLF2/NOTCH2 mutational profile with splenic MZL but not the 7q deletions, and occurs at a slightly older median age than extranodal disease. No dismech entry yet; it is a candidate member of the `B-Cell_Non-Hodgkin_Lymphoma` grouping once curated.
?

Discussions and Knowledge Gaps

1
Is the three-entity division of marginal zone lymphoma a division of distinct diseases, or three anatomical presentations of one antigen-driven process that differ mainly in which secondary lesion the clone happens to acquire?
KNOWLEDGE GAP mzl_three_entity_lump_split
Attached to
pathophysiology#Deregulation of Marginal Zone B-Cell Differentiation Signalling
The entities share a cell of origin, a shared aetiological mechanism (chronic antigenic drive), a shared convergent effector (constitutive NF-kB activation), and a shared set of background lesions (trisomies 3 and 18, 6q23 deletion). They are separated by secondary lesions and by anatomical compartment. This is exactly the configuration in which the dismech lump/split question is undecided, and the classification literature itself frames it as an open challenge rather than a settled nosology. The practical consequence is not cosmetic: it determines whether a shared pathograph at this root, or three independent pathographs, is the honest representation.
Show evidence (1 reference)
PMID:41026919 SUPPORT Human Clinical
"They share some features, but differ significantly in clinical presentation, associated inflammatory conditions, anatomic sites of involvement, and molecular alterations."
The review's own framing — a heterogeneous group that shares features but differs significantly — is the statement of the open question, not its resolution.
⚙

Pathophysiology

4
Chronic Antigenic Stimulation of Marginal Zone B Cells
The initiating step across the MZL family is sustained, non-resolving antigenic drive rather than a germline lesion. A persistent infection (Helicobacter pylori in the stomach, hepatitis C virus in splenic disease, Chlamydia psittaci in the ocular adnexa) or a chronic autoimmune process (Sjogren syndrome, Hashimoto thyroiditis) maintains a reactive marginal-zone B-cell population at the affected site. This is the step that makes MZL aetiologically heterogeneous by anatomical location: which organism or autoimmune process supplies the drive differs by site, while the resulting selection pressure on marginal-zone B cells does not.
marginal zone B cell CL:0000845 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves marginal zone B cell, annotated with marginal zone B cell of spleen (CL:0000845). CL:0000845 is a cell type from the Cell Ontology.
B cell activation GO:0042113 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased B cell activation (GO:0042113), qualified as temporality chronic. GO:0042113 is a biological process from the Gene Ontology. ↑ INCREASED Temporal: CHRONIC
Downstream
Deregulation of Marginal Zone B-Cell Differentiation Signalling Sustained antigen and toll-like-receptor engagement acts on the same signalling pathways that physiologically specify marginal-zone B-cell identity, so the pathways under chronic load are precisely the ones later found mutated.
Show evidence (2 references)
PMID:41026919 SUPPORT Human Clinical
"Etiopathogenesis is strongly linked to chronic antigenic stimulation and specific infections or autoimmune disorders for extranodal disease."
States the antigen-driven aetiology directly, and scopes the infection/autoimmune link to extranodal disease rather than asserting it uniformly across all three entities.
PMID:24417667 SUPPORT Human Clinical
"The most common extranodal sites were stomach (IR = 3·8), spleen (IR = 1·6), eye/adnexa (IR = 1·4), and lung, skin, and salivary glands (IRs = 0·9-1·0)."
The site distribution is the epidemiological footprint of site-specific antigenic drive — the stomach leads, consistent with H. pylori being the best-characterised driver.
Deregulation of Marginal Zone B-Cell Differentiation Signalling
The expanded clone acquires lesions in the NOTCH, B-cell-receptor and Toll-like receptor pathways that normally specify marginal-zone B-cell identity. This is where the three entities diverge: extranodal disease acquires translocations engaging the BCL10-MALT1 axis, while splenic and nodal disease acquire KLF2 and NOTCH2 mutations, with 7q deletion largely restricted to splenic disease. The entity-specific detail is held in the member entries; what belongs at the root is that all three routes converge on the next node.
NOTCH2 hgnc:7882 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NOTCH2 (hgnc:7882). hgnc:7882 is a gene from the HUGO Gene Nomenclature Committee. KLF2 hgnc:6347 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves KLF2 (hgnc:6347). hgnc:6347 is a gene from the HUGO Gene Nomenclature Committee. MALT1 hgnc:6819 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves MALT1 (hgnc:6819). hgnc:6819 is a gene from the HUGO Gene Nomenclature Committee. BCL10 hgnc:989 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves BCL10 (hgnc:989). hgnc:989 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
Constitutive NF-kB Pathway Activation Each of the entity-specific lesion classes converges on constitutive NF-kB signalling, which is why NF-kB activation is a hallmark of the family rather than of any one entity.
Show evidence (2 references)
PMID:29657712 SUPPORT Human Clinical
"Although trisomies of chromosomes 3 and 18, deletions at 6q23, deregulation of nuclear factor kappa B, and chromatin remodeling genes are frequent events in all of them, the three MZLs differ in the presence of recurrent translocations, mutations affecting the NOTCH pathway, and the..."
The load-bearing shared-versus-distinct statement for this entry: trisomies 3/18, 6q23 deletion and NF-kB deregulation are common to all three, while translocations, NOTCH-pathway mutations, KLF2 and PTPRD separate them.
PMID:28288716 SUPPORT Human Clinical
"Consistent with the physiological involvement of NOTCH, NF-κB, B-cell receptor and toll-like receptor signaling in mature B-cells differentiation into the marginal zone B-cells, many oncogenic mutations of genes involved in these pathways have been identified in SMZL and NMZL."
Independent statement that the mutated pathways are the physiological marginal-zone differentiation pathways.
Constitutive NF-kB Pathway Activation
The convergent, rate-limiting node of the family. Once NF-kB signalling is constitutively active, survival and proliferation of the marginal-zone-derived clone no longer require the original antigenic stimulus. This is the mechanistic reason antimicrobial eradication works only in antigen-dependent disease and fails once a translocation such as t(11;18) has been acquired.
canonical NF-kappaB signal transduction GO:0007249 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves canonical NF-kappaB signal transduction (GO:0007249), qualified as gain of function. GO:0007249 is a biological process from the Gene Ontology. ⇑ GAIN OF FUNCTION
Downstream
Histologic Transformation to Diffuse Large B-Cell Lymphoma A minority of cases accumulate further lesions in cell-cycle, NF-kB and epigenetic regulators and transform to an aggressive large-cell lymphoma. The edge is indirect: constitutive NF-kB signalling sustains the clone in which those additional lesions accumulate, but is not by itself sufficient for transformation.
Show evidence (2 references)
PMID:41026919 SUPPORT Human Clinical
"Genetic hallmarks include constitutive NF-κB activation and common trisomies 3 and 18, alongside subtype-specific lesions such as translocations in extranodal MZL, recurrent KLF2/NOTCH2 mutations in both nodal and splenic MZL, and deletions involving chromosome 7q, predominantly observed in splenic MZL."
Establishes constitutive NF-kB activation as a shared genetic hallmark of MZL.
PMID:29657712 SUPPORT Human Clinical
"Although trisomies of chromosomes 3 and 18, deletions at 6q23, deregulation of nuclear factor kappa B, and chromatin remodeling genes are frequent events in all of them, the three MZLs differ in the presence of recurrent translocations, mutations affecting the NOTCH pathway, and the..."
Independently lists NF-kB deregulation among the events frequent in all three MZL entities.
Histologic Transformation to Diffuse Large B-Cell Lymphoma
Transformation of indolent MZL to diffuse large B-cell lymphoma occurs in a minority of patients and is the main route by which an otherwise indolent disease becomes rapidly life-threatening. Reported drivers include TNFAIP3, TP53 and CDKN2A/B alterations, which differ by entity.
TNFAIP3 hgnc:11896 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TNFAIP3 (hgnc:11896). hgnc:11896 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:41026919 SUPPORT Human Clinical
"Transformation to aggressive diffuse large B-cell lymphoma occurs in 3% to 15% of cases and is associated with the accumulation of genetic lesions, particularly in cell cycle, NF-κB, and epigenetic regulators, with subtype-specific drivers including TNFAIP3, TP53, and CDKN2A/B alterations."
Gives both the frequency range and the lesion classes associated with transformation.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Marginal Zone Lymphoma Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

2
Splenomegaly Clinical HP:0001744 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Splenomegaly (HP:0001744). HP:0001744 is a phenotype from the Human Phenotype Ontology.
Lymphadenopathy Clinical HP:0002716 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Lymphadenopathy (HP:0002716). HP:0002716 is a phenotype from the Human Phenotype Ontology.
💊

Medical Actions

2
Helicobacter pylori Eradication Therapy
Action: antibiotic therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is antibiotic therapy (NCIT:C15620). NCIT:C15620 is a clinical intervention from the NCI Thesaurus. Ontology label: Antibiotic Therapy NCIT:C15620
Antibiotic eradication of Helicobacter pylori in gastric MALT lymphoma. Removing the organism removes the antigenic drive, and early-stage disease commonly regresses without cytotoxic therapy. Effective only while the clone remains antigen-dependent: t(11;18)/BIRC3::MALT1-positive disease has already escaped antigen dependence and does not respond, which is why the translocation is tested for before relying on eradication alone.
Mechanism Target:
INHIBITS Chronic Antigenic Stimulation of Marginal Zone B Cells — Eradicating the organism removes the antigenic stimulus at the trigger node, so the intervention acts upstream of the tumour clone rather than on it.
Show evidence (1 reference)
PMID:39891871 SUPPORT Human Clinical
"Testing for infectious agents like Helicobacter pylori or Hepatitis C virus should be standard practice, as eradication therapy offers a targeted, less toxic, and effective option in select patients."
States that testing for H. pylori is standard practice precisely because eradication is itself a targeted and effective treatment in selected patients.
Show evidence (1 reference)
PMID:39891871 SUPPORT Human Clinical
"Testing for infectious agents like Helicobacter pylori or Hepatitis C virus should be standard practice, as eradication therapy offers a targeted, less toxic, and effective option in select patients."
Supports H. pylori eradication as a targeted, less toxic first-line option in infection-associated MZL.
Hepatitis C Virus Antiviral Therapy
Action: antiviral therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is antiviral therapy (NCIT:C16119). NCIT:C16119 is a clinical intervention from the NCI Thesaurus. Ontology label: Antiviral Therapy NCIT:C16119
Direct-acting antiviral treatment of chronic hepatitis C virus infection in HCV-associated splenic MZL. Clearing the virus can induce lymphoma regression by the same logic as H. pylori eradication in gastric MALT lymphoma: withdrawal of the chronic antigenic drive rather than cytotoxicity against the clone.
Mechanism Target:
INHIBITS Chronic Antigenic Stimulation of Marginal Zone B Cells — Viral clearance removes the sustained antigenic stimulus maintaining the marginal-zone B-cell population, acting at the trigger node.
Show evidence (1 reference)
PMID:39891871 SUPPORT Human Clinical
"Testing for infectious agents like Helicobacter pylori or Hepatitis C virus should be standard practice, as eradication therapy offers a targeted, less toxic, and effective option in select patients."
States that testing for hepatitis C virus is standard practice because eradication therapy is an effective targeted option in selected patients.
Show evidence (1 reference)
PMID:39891871 SUPPORT Human Clinical
"Testing for infectious agents like Helicobacter pylori or Hepatitis C virus should be standard practice, as eradication therapy offers a targeted, less toxic, and effective option in select patients."
Supports antiviral eradication as a targeted, less toxic first-line option in HCV-associated MZL.
📊

Prevalence

2
United States (SEER-18 registries, 2001-2009), extranodal MZL
Annual Incidence 1.23 per 100,000 1–9 per 100,000
Reported as 12.3 per 1,000,000 person-years for extranodal MZL, normalised here to 1.23 per 100,000. Extranodal disease is the largest of the three entities.
Show evidence (1 reference)
PMID:24417667 SUPPORT Human Clinical
"During 2001-2009, 4,081 (IR = 5·7/1,000,000 person-years) and 8,821 (IR = 12·3) individuals were diagnosed with nodal MZL and extranodal MZL, respectively."
Population-based incidence for the two largest MZL groupings, from 18 SEER registries covering roughly a quarter of the US population.
United States (SEER-18 registries, 2001-2009), nodal MZL
Annual Incidence 0.57 per 100,000 1–9 per 1,000,000
Reported as 5.7 per 1,000,000 person-years for nodal MZL, normalised here to 0.57 per 100,000 — roughly half the extranodal rate.
Show evidence (1 reference)
PMID:24417667 SUPPORT Human Clinical
"During 2001-2009, 4,081 (IR = 5·7/1,000,000 person-years) and 8,821 (IR = 12·3) individuals were diagnosed with nodal MZL and extranodal MZL, respectively."
Same population-based series; nodal MZL accounted for the smaller share of cases.
{ }

Source YAML

click to show 
name: Marginal Zone Lymphoma
creation_date: '2026-08-19T12:00:00Z'
category: Neoplastic
description: >
  Marginal zone lymphoma (MZL) is a family of indolent mature B-cell non-Hodgkin
  lymphomas derived from B cells of the marginal zone, the outer compartment of the
  splenic white pulp and of secondary lymphoid follicles. Current classifications
  recognise three distinct entities separated by the anatomical compartment involved:
  extranodal MZL of mucosa-associated lymphoid tissue (MALT lymphoma), splenic MZL,
  and nodal MZL.

  The unifying pathogenic theme is chronic antigenic drive. Sustained stimulation by
  a persistent infection or an autoimmune process selects and expands marginal-zone
  B cells, and the expanded clone subsequently acquires genetic lesions that lock the
  NF-kB pathway into constitutive activity, rendering growth independent of the
  original antigen. Trisomies 3 and 18 and NF-kB deregulation are shared across all
  three entities; the entity-defining lesions are not. Extranodal disease is
  characterised by recurrent translocations that fuse or deregulate the BCL10-MALT1
  axis, whereas splenic and nodal disease instead carry KLF2 and NOTCH2 mutations,
  with deletions of chromosome 7q largely confined to splenic disease. Because that
  antigenic drive is often removable, MZL is one of the few lymphomas in which
  eradicating an infection can itself be the treatment.

  This root entry deliberately carries only what holds for MZL as a family — the
  three-entity axis, the shared antigen-driven and NF-kB-dependent mechanism, the
  aetiological heterogeneity across anatomical sites, and the shared risk of
  histologic transformation to diffuse large B-cell lymphoma. The entity-specific
  genetics, presentation and management are not re-derived here: see
  `MALT_Lymphoma.yaml` and `Splenic_Marginal_Zone_Lymphoma.yaml`, which both already
  declare `marginal zone lymphoma` as a parent. Nodal MZL has no entry yet.
disease_term:
  preferred_term: marginal zone lymphoma
  term:
    id: MONDO:0017604
    label: marginal zone lymphoma
synonyms:
- MZL
- marginal zone B-cell lymphoma
categories:
- Hematologic Malignancy
- B-cell Neoplasm
- Non-Hodgkin Lymphoma
parents:
- B-cell non-Hodgkin lymphoma
- mature B-cell neoplasm

has_subtypes:
- name: Extranodal MZL
  display_name: Extranodal Marginal Zone Lymphoma of MALT Type (MALT Lymphoma)
  classification: anatomic
  description: >-
    The most common of the three entities. Arises at extranodal mucosal and glandular
    sites that have acquired lymphoid tissue in response to chronic infection or
    autoimmune inflammation — stomach (Helicobacter pylori), ocular adnexa, lung,
    salivary gland, thyroid, skin and small intestine. Defined among the MZLs by
    recurrent translocations that activate NF-kB, most notably
    t(11;18)(q21;q21)/BIRC3::MALT1. Fully curated in `MALT_Lymphoma.yaml`.
  subtype_term:
    preferred_term: MALT lymphoma
    term:
      id: MONDO:0007650
      label: MALT lymphoma
- name: Splenic MZL
  display_name: Splenic Marginal Zone Lymphoma
  classification: anatomic
  description: >-
    Arises in the marginal zone of the splenic white pulp and presents with
    splenomegaly, circulating villous lymphocytes, cytopenias and bone marrow
    involvement rather than lymphadenopathy. Lacks the MALT translocations and instead
    carries NOTCH2 and KLF2 mutations and deletions of 7q. Associated with chronic
    hepatitis C virus infection in a subset. Fully curated in
    `Splenic_Marginal_Zone_Lymphoma.yaml`.
  subtype_term:
    preferred_term: splenic marginal zone lymphoma
    term:
      id: MONDO:0019462
      label: splenic marginal zone lymphoma
- name: Nodal MZL
  display_name: Nodal Marginal Zone B-Cell Lymphoma
  classification: anatomic
  description: >-
    Primary nodal disease without extranodal or splenic involvement, and the least
    well characterised of the three. Shares the KLF2/NOTCH2 mutational profile with
    splenic MZL but not the 7q deletions, and occurs at a slightly older median age
    than extranodal disease. No dismech entry yet; it is a candidate member of the
    `B-Cell_Non-Hodgkin_Lymphoma` grouping once curated.
  subtype_term:
    preferred_term: nodal marginal zone B-cell lymphoma
    term:
      id: MONDO:0019465
      label: nodal marginal zone B-cell lymphoma

prevalence:
- population: United States (SEER-18 registries, 2001-2009), extranodal MZL
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 1.23
  notes: >-
    Reported as 12.3 per 1,000,000 person-years for extranodal MZL, normalised here to
    1.23 per 100,000. Extranodal disease is the largest of the three entities.
  evidence:
  - reference: PMID:24417667
    reference_title: >-
      Incidence of marginal zone lymphoma in the United States, 2001-2009 with a focus
      on primary anatomic site.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During 2001-2009, 4,081 (IR\u00a0=\u00a05\u00b77/1,000,000 person-years) and 8,821 (IR\u00a0=\u00a012\u00b73) individuals were diagnosed with nodal MZL and extranodal MZL, respectively."
    explanation: >-
      Population-based incidence for the two largest MZL groupings, from 18 SEER
      registries covering roughly a quarter of the US population.
- population: United States (SEER-18 registries, 2001-2009), nodal MZL
  measure_type: ANNUAL_INCIDENCE
  prevalence_class: BAND_1_9_PER_1000000
  rate_per_100000: 0.57
  notes: >-
    Reported as 5.7 per 1,000,000 person-years for nodal MZL, normalised here to 0.57
    per 100,000 — roughly half the extranodal rate.
  evidence:
  - reference: PMID:24417667
    reference_title: >-
      Incidence of marginal zone lymphoma in the United States, 2001-2009 with a focus
      on primary anatomic site.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During 2001-2009, 4,081 (IR\u00a0=\u00a05\u00b77/1,000,000 person-years) and 8,821 (IR\u00a0=\u00a012\u00b73) individuals were diagnosed with nodal MZL and extranodal MZL, respectively."
    explanation: >-
      Same population-based series; nodal MZL accounted for the smaller share of cases.

pathophysiology:
- name: Chronic Antigenic Stimulation of Marginal Zone B Cells
  conforms_to: "tumor_promoting_inflammation#Chronic Inflammatory Stimulus"
  biological_scale: TISSUE
  role: trigger
  description: >-
    The initiating step across the MZL family is sustained, non-resolving antigenic
    drive rather than a germline lesion. A persistent infection (Helicobacter pylori
    in the stomach, hepatitis C virus in splenic disease, Chlamydia psittaci in the
    ocular adnexa) or a chronic autoimmune process (Sjogren syndrome, Hashimoto
    thyroiditis) maintains a reactive marginal-zone B-cell population at the affected
    site. This is the step that makes MZL aetiologically heterogeneous by anatomical
    location: which organism or autoimmune process supplies the drive differs by site,
    while the resulting selection pressure on marginal-zone B cells does not.
  cell_types:
  - preferred_term: marginal zone B cell
    term:
      id: CL:0000845
      label: marginal zone B cell of spleen
  biological_processes:
  - preferred_term: B cell activation
    term:
      id: GO:0042113
      label: B cell activation
    modifier: INCREASED
    temporality: CHRONIC
  evidence:
  - reference: PMID:41026919
    reference_title: >-
      The biology of marginal zone lymphoma subtypes: challenge and relevance of
      classification.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Etiopathogenesis is strongly linked to chronic antigenic stimulation and specific infections or autoimmune disorders for extranodal disease."
    explanation: >-
      States the antigen-driven aetiology directly, and scopes the infection/autoimmune
      link to extranodal disease rather than asserting it uniformly across all three
      entities.
  - reference: PMID:24417667
    reference_title: >-
      Incidence of marginal zone lymphoma in the United States, 2001-2009 with a focus
      on primary anatomic site.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common extranodal sites were stomach (IR\u00a0=\u00a03\u00b78), spleen (IR\u00a0=\u00a01\u00b76), eye/adnexa (IR\u00a0=\u00a01\u00b74), and lung, skin, and salivary glands (IRs\u00a0=\u00a00\u00b79-1\u00b70)."
    explanation: >-
      The site distribution is the epidemiological footprint of site-specific antigenic
      drive — the stomach leads, consistent with H. pylori being the best-characterised
      driver.
  downstream:
  - target: Deregulation of Marginal Zone B-Cell Differentiation Signalling
    causal_link_type: DIRECT
    description: >-
      Sustained antigen and toll-like-receptor engagement acts on the same signalling
      pathways that physiologically specify marginal-zone B-cell identity, so the
      pathways under chronic load are precisely the ones later found mutated.
    evidence:
    - reference: PMID:28288716
      reference_title: Molecular pathogenesis of splenic and nodal marginal zone lymphoma.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Consistent with the physiological involvement of NOTCH, NF-\u03baB, B-cell receptor and toll-like receptor signaling in mature B-cells differentiation into the marginal zone B-cells, many oncogenic mutations of genes involved in these pathways have been identified in SMZL and NMZL."
      explanation: >-
        Makes the link explicit: the oncogenic mutations fall in the NOTCH, NF-kB, BCR
        and TLR pathways that normally drive marginal-zone B-cell differentiation.

- name: Deregulation of Marginal Zone B-Cell Differentiation Signalling
  biological_scale: MOLECULAR
  role: intermediate
  description: >-
    The expanded clone acquires lesions in the NOTCH, B-cell-receptor and Toll-like
    receptor pathways that normally specify marginal-zone B-cell identity. This is
    where the three entities diverge: extranodal disease acquires translocations
    engaging the BCL10-MALT1 axis, while splenic and nodal disease acquire KLF2 and
    NOTCH2 mutations, with 7q deletion largely restricted to splenic disease. The
    entity-specific detail is held in the member entries; what belongs at the root is
    that all three routes converge on the next node.
  genes:
  - preferred_term: NOTCH2
    term:
      id: hgnc:7882
      label: NOTCH2
  - preferred_term: KLF2
    term:
      id: hgnc:6347
      label: KLF2
  - preferred_term: MALT1
    term:
      id: hgnc:6819
      label: MALT1
  - preferred_term: BCL10
    term:
      id: hgnc:989
      label: BCL10
  evidence:
  - reference: PMID:29657712
    reference_title: Recent advances in understanding the biology of marginal zone lymphoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although trisomies of chromosomes 3 and 18, deletions at 6q23, deregulation of nuclear factor kappa B, and chromatin remodeling genes are frequent events in all of them, the three MZLs differ in the presence of recurrent translocations, mutations affecting the NOTCH pathway, and the transcription factor Kruppel like factor 2 ( KLF2) or the receptor-type protein tyrosine phosphatase delta ( PTPRD)."
    explanation: >-
      The load-bearing shared-versus-distinct statement for this entry: trisomies 3/18,
      6q23 deletion and NF-kB deregulation are common to all three, while
      translocations, NOTCH-pathway mutations, KLF2 and PTPRD separate them.
  - reference: PMID:28288716
    reference_title: Molecular pathogenesis of splenic and nodal marginal zone lymphoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Consistent with the physiological involvement of NOTCH, NF-\u03baB, B-cell receptor and toll-like receptor signaling in mature B-cells differentiation into the marginal zone B-cells, many oncogenic mutations of genes involved in these pathways have been identified in SMZL and NMZL."
    explanation: >-
      Independent statement that the mutated pathways are the physiological
      marginal-zone differentiation pathways.
  downstream:
  - target: Constitutive NF-kB Pathway Activation
    causal_link_type: DIRECT
    description: >-
      Each of the entity-specific lesion classes converges on constitutive NF-kB
      signalling, which is why NF-kB activation is a hallmark of the family rather than
      of any one entity.
    evidence:
    - reference: PMID:41026919
      reference_title: >-
        The biology of marginal zone lymphoma subtypes: challenge and relevance of
        classification.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Genetic hallmarks include constitutive NF-\u03baB activation and common trisomies 3 and 18, alongside subtype-specific lesions such as translocations in extranodal MZL, recurrent KLF2/NOTCH2 mutations in both nodal and splenic MZL, and deletions involving chromosome 7q, predominantly observed in splenic MZL."
      explanation: >-
        Names constitutive NF-kB activation as a genetic hallmark shared across MZL,
        alongside the subtype-specific lesions that produce it.

- name: Constitutive NF-kB Pathway Activation
  biological_scale: MOLECULAR
  role: central_effector
  description: >-
    The convergent, rate-limiting node of the family. Once NF-kB signalling is
    constitutively active, survival and proliferation of the marginal-zone-derived
    clone no longer require the original antigenic stimulus. This is the mechanistic
    reason antimicrobial eradication works only in antigen-dependent disease and fails
    once a translocation such as t(11;18) has been acquired.
  biological_processes:
  - preferred_term: canonical NF-kappaB signal transduction
    term:
      id: GO:0007249
      label: canonical NF-kappaB signal transduction
    modifier: GAIN_OF_FUNCTION
  evidence:
  - reference: PMID:41026919
    reference_title: >-
      The biology of marginal zone lymphoma subtypes: challenge and relevance of
      classification.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic hallmarks include constitutive NF-\u03baB activation and common trisomies 3 and 18, alongside subtype-specific lesions such as translocations in extranodal MZL, recurrent KLF2/NOTCH2 mutations in both nodal and splenic MZL, and deletions involving chromosome 7q, predominantly observed in splenic MZL."
    explanation: >-
      Establishes constitutive NF-kB activation as a shared genetic hallmark of MZL.
  - reference: PMID:29657712
    reference_title: Recent advances in understanding the biology of marginal zone lymphoma.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Although trisomies of chromosomes 3 and 18, deletions at 6q23, deregulation of nuclear factor kappa B, and chromatin remodeling genes are frequent events in all of them, the three MZLs differ in the presence of recurrent translocations, mutations affecting the NOTCH pathway, and the transcription factor Kruppel like factor 2 ( KLF2) or the receptor-type protein tyrosine phosphatase delta ( PTPRD)."
    explanation: >-
      Independently lists NF-kB deregulation among the events frequent in all three
      MZL entities.
  downstream:
  - target: Histologic Transformation to Diffuse Large B-Cell Lymphoma
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      A minority of cases accumulate further lesions in cell-cycle, NF-kB and
      epigenetic regulators and transform to an aggressive large-cell lymphoma. The
      edge is indirect: constitutive NF-kB signalling sustains the clone in which those
      additional lesions accumulate, but is not by itself sufficient for transformation.
    evidence:
    - reference: PMID:41026919
      reference_title: >-
        The biology of marginal zone lymphoma subtypes: challenge and relevance of
        classification.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Transformation to aggressive diffuse large B-cell lymphoma occurs in 3% to 15% of cases and is associated with the accumulation of genetic lesions, particularly in cell cycle, NF-\u03baB, and epigenetic regulators, with subtype-specific drivers including TNFAIP3, TP53, and CDKN2A/B alterations."
      explanation: >-
        Quantifies transformation risk across MZL and attributes it to accumulated
        lesions in cell-cycle, NF-kB and epigenetic regulators.

- name: Histologic Transformation to Diffuse Large B-Cell Lymphoma
  biological_scale: TISSUE
  role: consequence
  description: >-
    Transformation of indolent MZL to diffuse large B-cell lymphoma occurs in a
    minority of patients and is the main route by which an otherwise indolent disease
    becomes rapidly life-threatening. Reported drivers include TNFAIP3, TP53 and
    CDKN2A/B alterations, which differ by entity.
  genes:
  - preferred_term: TNFAIP3
    term:
      id: hgnc:11896
      label: TNFAIP3
  evidence:
  - reference: PMID:41026919
    reference_title: >-
      The biology of marginal zone lymphoma subtypes: challenge and relevance of
      classification.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transformation to aggressive diffuse large B-cell lymphoma occurs in 3% to 15% of cases and is associated with the accumulation of genetic lesions, particularly in cell cycle, NF-\u03baB, and epigenetic regulators, with subtype-specific drivers including TNFAIP3, TP53, and CDKN2A/B alterations."
    explanation: >-
      Gives both the frequency range and the lesion classes associated with
      transformation.

phenotypes:
- category: Clinical
  name: Splenomegaly
  description: >-
    Enlargement of the spleen, the dominant presenting finding in splenic MZL and a
    variable finding in the other entities.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
- category: Clinical
  name: Lymphadenopathy
  description: >-
    Lymph node enlargement, definitional for nodal MZL and characteristically absent or
    minimal in splenic MZL.
  phenotype_term:
    preferred_term: Lymphadenopathy
    term:
      id: HP:0002716
      label: Lymphadenopathy

treatments:
- name: Helicobacter pylori Eradication Therapy
  description: >-
    Antibiotic eradication of Helicobacter pylori in gastric MALT lymphoma. Removing
    the organism removes the antigenic drive, and early-stage disease commonly
    regresses without cytotoxic therapy. Effective only while the clone remains
    antigen-dependent: t(11;18)/BIRC3::MALT1-positive disease has already escaped
    antigen dependence and does not respond, which is why the translocation is
    tested for before relying on eradication alone.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: antibiotic therapy
    term:
      id: NCIT:C15620
      label: Antibiotic Therapy
  target_mechanisms:
  - target: Chronic Antigenic Stimulation of Marginal Zone B Cells
    treatment_effect: INHIBITS
    description: >-
      Eradicating the organism removes the antigenic stimulus at the trigger node,
      so the intervention acts upstream of the tumour clone rather than on it.
    evidence:
    - reference: PMID:39891871
      reference_title: "Advances in the Pathogenesis, Diagnosis, Treatment, and Prognosis of Marginal Zone Lymphoma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Testing for infectious agents like Helicobacter pylori or Hepatitis C virus should be standard practice, as eradication therapy offers a targeted, less toxic, and effective option in select patients."
      explanation: >-
        States that testing for H. pylori is standard practice precisely because
        eradication is itself a targeted and effective treatment in selected
        patients.
  evidence:
  - reference: PMID:39891871
    reference_title: "Advances in the Pathogenesis, Diagnosis, Treatment, and Prognosis of Marginal Zone Lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Testing for infectious agents like Helicobacter pylori or Hepatitis C virus should be standard practice, as eradication therapy offers a targeted, less toxic, and effective option in select patients."
    explanation: >-
      Supports H. pylori eradication as a targeted, less toxic first-line option
      in infection-associated MZL.
- name: Hepatitis C Virus Antiviral Therapy
  description: >-
    Direct-acting antiviral treatment of chronic hepatitis C virus infection in
    HCV-associated splenic MZL. Clearing the virus can induce lymphoma regression
    by the same logic as H. pylori eradication in gastric MALT lymphoma:
    withdrawal of the chronic antigenic drive rather than cytotoxicity against
    the clone.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: antiviral therapy
    term:
      id: NCIT:C16119
      label: Antiviral Therapy
  target_mechanisms:
  - target: Chronic Antigenic Stimulation of Marginal Zone B Cells
    treatment_effect: INHIBITS
    description: >-
      Viral clearance removes the sustained antigenic stimulus maintaining the
      marginal-zone B-cell population, acting at the trigger node.
    evidence:
    - reference: PMID:39891871
      reference_title: "Advances in the Pathogenesis, Diagnosis, Treatment, and Prognosis of Marginal Zone Lymphoma."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Testing for infectious agents like Helicobacter pylori or Hepatitis C virus should be standard practice, as eradication therapy offers a targeted, less toxic, and effective option in select patients."
      explanation: >-
        States that testing for hepatitis C virus is standard practice because
        eradication therapy is an effective targeted option in selected
        patients.
  evidence:
  - reference: PMID:39891871
    reference_title: "Advances in the Pathogenesis, Diagnosis, Treatment, and Prognosis of Marginal Zone Lymphoma."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Testing for infectious agents like Helicobacter pylori or Hepatitis C virus should be standard practice, as eradication therapy offers a targeted, less toxic, and effective option in select patients."
    explanation: >-
      Supports antiviral eradication as a targeted, less toxic first-line option
      in HCV-associated MZL.

discussions:
- discussion_id: mzl_three_entity_lump_split
  kind: KNOWLEDGE_GAP
  attaches_to:
  - "pathophysiology#Deregulation of Marginal Zone B-Cell Differentiation Signalling"
  prompt: >-
    Is the three-entity division of marginal zone lymphoma a division of distinct
    diseases, or three anatomical presentations of one antigen-driven process that
    differ mainly in which secondary lesion the clone happens to acquire?
  rationale: >-
    The entities share a cell of origin, a shared aetiological mechanism (chronic
    antigenic drive), a shared convergent effector (constitutive NF-kB activation), and
    a shared set of background lesions (trisomies 3 and 18, 6q23 deletion). They are
    separated by secondary lesions and by anatomical compartment. This is exactly the
    configuration in which the dismech lump/split question is undecided, and the
    classification literature itself frames it as an open challenge rather than a
    settled nosology. The practical consequence is not cosmetic: it determines whether
    a shared pathograph at this root, or three independent pathographs, is the honest
    representation.
  evidence:
  - reference: PMID:41026919
    reference_title: >-
      The biology of marginal zone lymphoma subtypes: challenge and relevance of
      classification.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They share some features, but differ significantly in clinical presentation, associated inflammatory conditions, anatomic sites of involvement, and molecular alterations."
    explanation: >-
      The review's own framing — a heterogeneous group that shares features but differs
      significantly — is the statement of the open question, not its resolution.

notes: >
  Scope. This is a thin root entry over an already-populated subtree. `MALT_Lymphoma.yaml`
  and `Splenic_Marginal_Zone_Lymphoma.yaml` both already declare `marginal zone lymphoma`
  as a parent but had nothing to point at; this entry binds MONDO:0017604 and carries the
  family-level mechanism once. Entity-specific genetics, staging and management stay in the
  member entries.

  Relationship to the B-Cell NHL grouping. `kb/groupings/B-Cell_Non-Hodgkin_Lymphoma.yaml`
  lists MALT lymphoma and splenic MZL as flat DISEASE members and names nodal MZL as a
  candidate member. That grouping and this root are complementary, not redundant: the
  grouping is an auditable union over curated entries, while this entry is the disease
  concept MONDO:0017604 itself, carrying the shared pathograph. No attempt has been made
  here to restructure the grouping.

  Nodal MZL has no dismech entry. It is modelled here only as a `has_subtypes` entry bound
  to MONDO:0019465; the KLF2/NOTCH2 statement about it rests on the cited reviews rather
  than on a curated entry of its own.

  Deliberately omitted. Splenic diffuse red pulp small B-cell lymphoma (MONDO:0017599) is a
  MONDO child of marginal zone lymphoma but is a separate provisional entity in the WHO
  classification and is not curated as a subtype here. Primary cutaneous MZL is likewise
  left to the extranodal entry.