Marginal Zone Lymphomas

Slide 1 · Marginal Zone Lymphomas

Mature B-cell neoplasms arising in nodal, splenic, and extranodal tissues

Pathogenesis · Gastric MALT lymphoma · Diagnostic morphology · Clinical correlation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Define the anatomic groups of marginal zone lymphomas (MZLs).

Explain chronic antigen stimulation and the transition to autonomy.

Connect BCL10–MALT1–NF-κB signaling to lymphoma survival.

Recognize gastric MALT lymphoma morphology and diagnostic evidence.

Apply the pathology to treatment response and transformation risk.

Slide 3 · Marginal zone lymphoma: Core definition

A heterogeneous family of mature B-cell tumors.

May arise in lymph nodes, the spleen, or extranodal tissues.

Many cases derive from antigen-experienced memory B cells.

Clinical behavior is often indolent, particularly at extranodal sites.

The anatomic site is a central organizing feature.

Slide 4 · Anatomic classification of MZLs

Nodal

Presentation centered in lymph nodes; A member of the MZL family.

Splenic

Presentation centered in the spleen; Shares the MZL umbrella designation.

Extranodal / MALT

Involves mucosal or nonmucosal sites; Often arises with persistent inflammation.

The inflammation-dependent mechanism is most clearly established for extranodal MZL.

Slide 5 · What does “MALT lymphoma” mean?

MALT is mucosa-associated lymphoid tissue.

Extranodal MZLs were first recognized at mucosal sites.

The term MALToma is often applied to these extranodal tumors.

Extranodal MZL also occurs in organs not normally rich in organized MALT.

Slide 6 · Memory B-cell origin: The biologic clue

Tumor immunoglobulin genes frequently show somatic hypermutation.

Somatic hypermutation is a record of prior antigen-driven B-cell maturation.

This favors an antigen-experienced, memory B-cell origin in many cases.

The site and molecular background remain heterogeneous across MZLs.

Slide 7 · From antigen exposure to a memory B cell

Antigen encounter

A B cell recognizes antigen.

B-cell activation

Immune activation with T-cell cooperation.

Somatic hypermutation

Antigen-experienced immunoglobulin genes.

Memory B cell

Long-lived antigen-experienced pool.

Slide 8 · Why extranodal MZL is a distinctive model

Inflammatory setting

Often associated with chronic immune stimulation from infection or autoimmunity.

Prolonged localization

May remain confined to one organ for substantial periods.

Potential reversibility

Some lesions regress after removal of the inciting antigen.

These features connect etiology, natural history, and therapeutic response.

Slide 9 · Organ-specific immune stimulation

Tissue

Associated inflammatory disorder

Extranodal MZL context

Stomach

Helicobacter-associated gastritis

Gastric MALT lymphoma

Salivary gland

Sjögren syndrome

Salivary extranodal MZL

Thyroid

Hashimoto thyroiditis

Thyroid extranodal MZL

Slide 10 · Sjögren syndrome: The salivary gland pathway

Chronic lymphocytic inflammation targets salivary and lacrimal glands.

Early infiltrates contain a mixture of polyclonal B and T cells.

A B-cell clone may acquire a growth advantage during sustained stimulation.

A dominant clonal B-cell population can signal emergence of MZL.

Slide 11 · Sjögren syndrome: Why lymphoma risk rises

An autoimmune microenvironment supplies persistent lymphocyte activation.

A strong increase in lymphoma risk in Sjögren syndrome.

Clonal selection is thought to follow acquisition of somatic mutations.

The lymphoma typically emerges in the chronically inflamed target gland.

Do not equate every clonal expansion with histologically established lymphoma.

Slide 12 · Hashimoto thyroiditis and thyroid MZL

Autoimmune thyroid inflammation provides ongoing local immune stimulation.

Extranodal marginal zone lymphoma may develop in the thyroid gland.

The organ-level link parallels salivary gland disease in Sjögren syndrome.

A thyroid lymphoid infiltrate must be interpreted with its inflammatory context.

Slide 13 · Helicobacter gastritis: The gastric association

Chronic Helicobacter pylori infection produces persistent gastric inflammation.

The associated immune response may generate organized lymphoid tissue.

Most gastric MALT lymphomas arise in this inflammatory setting.

Antigen removal is therapeutically relevant while growth remains dependent.

Slide 14 · Gastric MALT is generally acquired

Normal stomach

Typically lacks organized mucosa-associated lymphoid tissue.

Persistent gastritis

Chronic inflammation recruits lymphocytes and can induce gastric MALT.

Clonal evolution

A neoplastic B-cell population may emerge from persistent immune stimulation.

Slide 15 · Inflammation-to-lymphoma continuum

Chronic stimulus

Microbial or self antigen persists.

Polyclonal response

Many lymphocyte clones respond.

Clonal expansion

Growth-favored B-cell clone appears.

MALT lymphoma

Neoplastic proliferation establishes.

Slide 16 · Stage 1: An initially polyclonal reaction

Early chronic immune stimulation expands diverse reactive lymphocytes.

Multiple B-cell clones may respond to the same persistent antigen source.

Polyclonality belongs to the reactive end of the continuum.

Polyclonality alone is not evidence of an established lymphoma.

Slide 17 · Stage 2: A B-cell clone gains advantage

Unknown initiating mutations are proposed to confer a selective benefit.

A dominant B-cell population begins to emerge from a reactive background.

Clonality provides useful evidence but is not sufficient by itself.

Tissue architecture and clinical setting remain necessary for interpretation.

Slide 18 · The antigen-dependent stage

Persistent antigen

Chronic exposure continues.

T-helper-cell support

Antigen-activated helper T cells contribute.

Neoplastic B-cell signals

A clone still responds to external signals.

Growth and survival

Ongoing stimulation sustains the population.

Slide 19 · Why T-helper cells matter early

The early lymphoma clone may require signals from antigen-stimulated T cells.

The immune microenvironment therefore remains part of its growth program.

Removing antigen can suppress the upstream source of supportive signals.

This dependency distinguishes early disease from genetically autonomous clones.

Slide 20 · Antigen removal: A biologic intervention

Remove stimulus

Example: Eradicate H. Pylori.

Decline in immune drive

Less persistent inflammation.

Withdrawal of support

Antigen-dependent clone loses support.

Tumor regression

Regression is possible, not universal.

Slide 21 · Why H. Pylori eradication can work

Antibiotics target the initiating organism, not the tumor directly.

An antigen-dependent clone may regress when microbial stimulation ceases.

This is a compelling demonstration of microenvironmental dependence.

Response is not assured once the clone has acquired autonomous signaling.

Slide 22 · Stage 3: Acquired antigen independence

Additional mutations or translocations can confer growth autonomy.

Downstream survival pathways remain active without antigen exposure.

The clone no longer requires the original inflammatory stimulus.

This model explains resistance to microbial eradication.

Slide 23 · Antigen dependent versus antigen independent

Antigen-dependent phase

External stimulus remains important.

T-cell and receptor-linked signals support tumor survival.

Withdrawal of antigen can produce regression.

Antigen-independent phase

Lymphoma acquires constitutive growth/survival signaling.

BCL10 or MALT1 pathway changes can drive autonomy.

Eradication of the organism often fails to control tumor.

Slide 24 · Why extranodal MZL may remain localized

Prolonged restriction to an affected organ.

Local antigenic stimulation provides a plausible selective niche.

Late systemic spread can occur as tumor biology changes.

Site of origin and extent of dissemination are separate clinical questions.

Slide 25 · Late dissemination represents clonal evolution

Some extranodal tumors eventually spread beyond their original site.

Additional acquired alterations may promote more autonomous behavior.

A previously localized lesion does not guarantee permanent localization.

Clinical follow-up must account for possible change over time.

Slide 26 · Progression to diffuse large B-cell lymphoma

A subset of MALT lymphomas transforms to aggressive large B-cell lymphoma.

Histology then resembles diffuse large B-cell lymphoma (DLBCL).

This reflects further clonal evolution rather than ordinary reactive change.

Growth pattern and cytologic size should be reassessed in evolving lesions.

Slide 27 · NF-κB: A survival-related transcription factor

NF-κB promotes transcriptional programs supporting B-cell survival.

In lymphocytes, antigen receptor signaling can activate NF-κB.

Constitutive NF-κB activity can sustain lymphoma cells without antigen.

The pathway links external immune stimulation with genetic autonomy.

Slide 28 · Normal antigen receptor–NF-κB signaling

Antigen receptor

Stimulation by antigen.

BCL10–MALT1 complex

Relay downstream of receptor activation.

NF-κB activation

Signal reaches the nucleus.

B-cell response

Growth and survival programs.

Slide 29 · The BCL10–MALT1 signaling module

BCL10 and MALT1 are proteins acting in a receptor-linked complex.

The module participates in antigen-stimulated NF-κB activation.

Genetic lesions can increase signaling through this pathway.

The shared end point is enhanced B-cell growth and survival.

Slide 30 · Recurrent rearrangements in gastric MALT lymphoma

Rearrangement

Gene-level result

Core teaching implication

t(11;18)

API2–MALT1 fusion protein

Constitutive NF-κB activation

t(1;14)

Increased BCL10 expression

Constitutive NF-κB activation

t(14;18)

Increased MALT1 expression

Constitutive NF-κB activation

t(3;14)

Increased FOXP1 expression

Distinct transcription-factor route

FOXP1-related t(3;14) is distinct from the NF-κB-activating trio.

Slide 31 · T(11;18): The API2–MALT1 fusion

The chromosomal translocation juxtaposes genes on chromosomes 11 and 18.

The resulting fusion protein includes API2 and MALT1 components.

The fusion drives signaling that promotes constitutive NF-κB activity.

The molecular lesion supports antigen-independent survival.

Slide 32 · T(1;14): Increased BCL10 expression

Rearrangement involving the BCL10 locus can increase BCL10 abundance.

BCL10 is a component of the lymphocyte receptor–NF-κB pathway.

Excess signaling activity helps bypass antigen dependence.

This rearrangement is distinct from an API2–MALT1 fusion.

Slide 33 · T(14;18): Increased MALT1 expression

A subset of MALT lymphomas upregulates intact MALT1 through t(14;18).

MALT1 contributes to NF-κB-related antigen receptor signaling.

This MALT-associated rearrangement is not synonymous with the BCL2 rearrangement of follicular lymphoma.

The involved gene must be identified, not inferred from the numbers alone.

Slide 34 · T(3;14): The FOXP1-associated route

T(3;14) among gastric MALT lymphoma rearrangements.

This juxtaposes FOXP1 with an immunoglobulin locus.

FOXP1 transcription factor expression increases.

The textbook separates it from the three rearrangements that directly cause constitutive NF-κB activation.

Slide 35 · Convergence on NF-κB signaling

Genetic lesion

One of several MALT-related rearrangements.

BCL10 / MALT1 signaling

Pathway becomes unusually active.

NF-κB activity

Growth/survival signal persists.

Tumor autonomy

Microbial antigen less critical.

Slide 36 · Pathway contrast: Stimulus versus genetic bypass

Before signaling autonomy

Antigen receptor activation begins the cascade.

BCL10 and MALT1 function downstream.

Removing antigen may reduce pathway activity.

After genetic bypass

Rearrangement increases pathway signaling.

NF-κB-related survival support becomes persistent.

Removing antigen may no longer stop growth.

Slide 37 · Molecular predictors of eradication resistance

MALT1- or BCL10-associated translocations correlate with poor response to H. Pylori clearance.

The biologic explanation is sustained signaling despite stimulus removal.

Absence of a detected translocation does not guarantee response.

A complete assessment also requires tissue extent and nodal status.

Slide 38 · Other correlates of poor eradication response

Observation

Interpretive consequence

Extension into or through muscularis propria

Greater tissue penetration correlates with resistance

Lymph node involvement

More extensive disease correlates with resistance

MALT1/BCL10-related translocation

Antigen-independent signaling is more likely

Slide 39 · Gastric MALT lymphoma: Lamina propria expansion

Histology shows a dense lymphocytic infiltrate in the gastric lamina propria.

Neoplastic cells may extend toward and into adjacent gastric glands.

Reactive-appearing follicles may coexist with the infiltrate.

The pattern must be interpreted against chronic gastritis.

Slide 40 · Lymphoepithelial lesion: An architectural concept

Architectural schematic — not a histologic specimen

Glandular epithelium

Reactive or neoplastic lymphoid infiltrate

Lymphoepithelial lesion = lymphoid infiltration of gland epithelium

Slide 41 · What makes a lymphoepithelial lesion?

Lymphoma cells infiltrate glandular epithelium.

This can distort or damage gland structure in the mucosal biopsy.

The lesion is a strong morphologic clue in the appropriate tissue context.

Diagnosis integrates histology, immunophenotype, and clinical findings.

An architectural finding is evidence—not a stand-alone molecular diagnosis.

Slide 42 · Reactive follicles can persist in MALT lymphoma

Some gastric MALT lymphomas contain reactive-appearing B-cell follicles.

Follicles should not automatically be mistaken for follicular lymphoma.

Architecture may therefore look deceptively reactive.

The infiltrate around glands remains diagnostically important.

Slide 43 · Plasmacytic differentiation is a recognized pattern

A subset of gastric MALT lymphomas shows plasmacytic differentiation.

This in approximately 40% of tumors.

This feature can change the appearance of the infiltrate.

Light-chain restriction may help establish a clonal B-cell population.

Slide 44 · Morphologic context matters more than one feature

Dense mucosal lymphocytes support—but do not prove—lymphoma.

Lymphoepithelial lesions increase suspicion in the right context.

Reactive follicles and plasma cells can complicate interpretation.

Classification requires a coherent pattern of multiple findings.

Slide 45 · B-cell lineage markers: CD19 and CD20

Gastric MALT lymphomas express mature B-cell markers including CD19 and CD20.

These markers establish lineage, not the specific MZL subtype.

Marker expression is interpreted in the context of histology.

No single pan–B-cell marker establishes MALT lymphoma.

Slide 46 · CD5 and CD10: Useful negative evidence

Gastric MALT lymphoma is usually CD5 negative and CD10 negative.

This profile supports exclusion of several competing small B-cell lymphomas.

Negative findings are supporting evidence rather than absolute proof.

Interpretation must consider the entire staining panel.

Slide 47 · CD43: A supportive but incomplete clue

CD43 is expressed in a minority of gastric MALT lymphomas.

Positivity in about 25% of cases.

Because expression is variable, negativity cannot exclude lymphoma.

A positive result may be diagnostically useful in context.

Slide 48 · Immunoglobulin light-chain restriction

A normal reactive infiltrate typically comprises multiple B-cell clones.

Predominance of κ or λ expression supports clonality.

Restriction is especially valuable when clear lymphoepithelial lesions are absent.

A clonal pattern still requires clinicopathologic correlation.

Slide 49 · Immunoglobulin heavy-chain rearrangements

Molecular analysis may demonstrate a clonal IGH gene rearrangement.

This can support lymphoma in a histologically equivocal sample.

The assay addresses clonality rather than anatomic subtype by itself.

It is not a substitute for morphology and immunophenotype.

Slide 50 · Why a small gastric biopsy can be difficult

H. Pylori gastritis and gastric MALT lymphoma often coexist.

Symptoms and endoscopic appearances may overlap.

A limited biopsy can undersample lymphoepithelial lesions.

Ancillary studies are most useful when interpreted with adequate tissue.

Slide 51 · Integrated diagnostic workflow for gastric MALT lymphoma

1. Clinical context

Persistent gastritis, symptoms, and H. Pylori status.

2. Architecture

Lamina propria infiltrate, follicles, gland infiltration.

3. Immunophenotype

CD19/CD20; Usual CD5−/CD10− pattern; CD43 if present.

4. Clonality if needed

Light-chain restriction or clonal IGH rearrangement.

A composite diagnosis is stronger than any isolated test.

Slide 52 · Gastritis versus gastric MALT lymphoma

Finding

Reactive Helicobacter gastritis

Gastric MALT lymphoma

Inflammatory infiltrate

Expected in chronic infection

Dense lymphoid infiltrate also present

B-cell population

Generally polyclonal

Clonality may be demonstrable

Lymphoepithelial lesion

Not diagnostic on its own

An important morphologic clue

Ancillary tests

Not always required

Useful in equivocal biopsies

Slide 53 · Small B-cell lymphoma differential

Feature

MALT lymphoma

Mantle cell lymphoma

Typical CD5

Negative in gastric MALT

Usually positive

Cell of origin

Often memory B cell

Usually naive mantle-zone B cell

Cyclin D1

Not defining feature

Typically high expression

Classic genetics

MALT1/BCL10 pathway lesions

t(11;14), CCND1 upregulation

Slide 54 · T(14;18): A differential diagnostic trap

Follicular lymphoma is often driven by an IGH–BCL2 rearrangement.

Gastric MALT lymphoma may show t(14;18) involving IGH and MALT1.

Identical chromosome numbers can refer to distinct partner genes.

A precise gene-level assay resolves the biologic meaning.

Slide 55 · Gastric presentation: Symptoms are nonspecific

Dyspepsia and epigastric pain are common presenting symptoms.

Weight loss may occur but is not required.

Symptoms overlap with H. Pylori-associated gastritis.

A tissue diagnosis cannot be inferred from symptoms alone.

Slide 56 · Gastrointestinal bleeding as a presentation

Hematemesis or melena can be present in gastric MALT lymphoma.

Bleeding symptoms require appropriate clinical assessment.

Endoscopic changes are not unique to lymphoma.

Histology anchors the distinction from other gastric lesions.

Slide 57 · Disease extent affects clinical interpretation

Many extranodal MZLs remain localized for prolonged periods.

Lymph node involvement suggests more extensive disease.

Muscularis propria invasion is associated with poorer eradication response.

Local response and systemic spread must be followed separately.

Slide 58 · Transformation: Histology and genetics

Some low-grade MALT lymphomas progress to DLBCL.

Additional lesions such as inactivation of genes encoding p53 or p16 may accompany transformation.

This changes growth behavior beyond the usual indolent phenotype.

Emergent large-cell areas should not be dismissed as ordinary MALT morphology.

Slide 59 · Clinical application I: Antigen-dependent disease

Hypothetical case

A patient with chronic H. Pylori gastritis has a biopsy-supported gastric MALT lymphoma. Disease remains confined to the stomach, without an identified MALT1/BCL10 translocation.

Why might bacterial eradication lead to lymphoma regression?

Slide 60 · Clinical application I: Reasoning

Persistent microbial antigen may sustain the lymphoma through helper-cell signals.

Eradication can remove the initiating immune stimulus.

An antigen-dependent clone may then regress.

Molecular testing and localized stage do not make regression certain.

Slide 61 · Clinical application II: Biologic nonresponse

Hypothetical case

A gastric MALT lymphoma carries a rearrangement causing persistent BCL10–MALT1–NF-κB signaling. H. Pylori is cleared, but the lymphoma persists.

What biologic feature best explains this outcome?

Slide 62 · Clinical application II: Reasoning

The tumor can sustain survival signaling downstream of antigen recognition.

Removal of the organism no longer switches off the pathway.

Constitutive NF-κB activity is a central mechanistic explanation.

A persistent lesion requires reassessment rather than assuming eradication failure.

Slide 63 · Clinical application III: Autoimmune setting

Hypothetical case

A patient with Sjögren syndrome develops a persistent enlarging salivary gland lesion with a dense B-cell infiltrate and supportive evidence of clonality.

How does chronic autoimmunity connect to lymphoma emergence?

Slide 64 · Clinical application III: Reasoning

The gland contains a long-standing, activated lymphocyte population.

Repeated stimulation may favor a mutation-bearing B-cell clone.

Clonality supports a neoplastic possibility but needs tissue-context assessment.

The clinical setting is characteristic for extranodal MZL.

Slide 65 · Clinical application IV: The rearrangement pitfall

Hypothetical case

A mature B-cell lymphoma carries a reported t(14;18) rearrangement. A trainee assumes that every t(14;18) means follicular lymphoma.

What missing information changes this interpretation?

Slide 66 · Clinical application IV: Reasoning

Chromosomal breakpoints must be translated into the involved genes.

IGH–BCL2 supports the canonical follicular lymphoma pathway.

IGH–MALT1 is described in a subset of MALT lymphomas.

Morphology and a gene-specific result remain essential.

Slide 67 · Three anatomic groups: What this lecture established

MZL group

Established core information

Interpretive emphasis

Nodal

A mature B-cell MZL arising in lymph nodes

Interpret findings in nodal tissue context

Splenic

A mature B-cell MZL arising in spleen

Interpret findings in splenic tissue context

Extranodal

Often inflammation-associated; can remain localized

Gastric MALT is a well-characterized example

Slide 68 · Integrating the pathology

MZL is an anatomic family of mature, often antigen-experienced B-cell tumors.

Persistent immune stimulation can precede extranodal MALT lymphoma.

BCL10/MALT1-driven NF-κB signaling explains genetic autonomy.

Gastric morphology and clonality support diagnosis.

Antigen dependence, tissue extent, and clonal progression affect behavior.

Slide 69 · Selected textbook references

Robbins, Cotran & Kumar. Pathologic Basis of Disease, 11th ed. (2026): Chapter 13, Marginal Zone Lymphomas.

Same textbook: Chapter 17, Gastrointestinal Lymphoma (gastric MALT morphology, genetics, and diagnosis).

Same textbook: Sjögren syndrome section (autoimmunity and lymphomagenesis).

Same textbook: Chapter 13, mature B-cell neoplasms (context for differential diagnosis).