Lymphoma

Slide 1 · Gastrointestinal lymphoma

Gastric MALT lymphoma: pathogenesis, morphology and diagnosis

A clinicopathologic lecture

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Explain why chronic Helicobacter gastritis can generate gastric MALT lymphoma

Trace antigen-dependent and antigen-independent NF-κB signaling

Recognize the defining morphology and immunophenotype

Integrate molecular findings with clinical response and diagnostic pitfalls

Slide 3 · Why the gastrointestinal tract matters

Extranodal setting

The GI tract is the commonest location for extranodal lymphomas.

Gastric emphasis

The stomach is a particularly important GI site for primary lymphomas.

Main entity

Indolent extranodal marginal zone B-cell lymphoma predominates among gastric lymphomas.

Slide 4 · Primary gastric lymphoma: The scale of the problem

Primary lymphomas account for nearly 5% of gastric malignancies.

Gastric MALT lymphoma is the characteristic indolent B-cell entity.

Its inflammatory pathogenesis separates it from most gastric epithelial cancers.

Conceptual distinction

Lymphoid malignancy ≠ epithelial malignancy

Slide 5 · Gastric lymphoma belongs to a broader family

Mature B-cell lymphoid neoplasms

Tumor lineage

Marginal zone lymphomas

Disease family

Extranodal marginal zone lymphoma (MALT lymphoma)

Site-defined category

Gastric MALT lymphoma

Common gastric presentation

Slide 6 · Marginal zone lymphoma: Three anatomic settings

Extranodal

Mucosal and other extranodal tissues; The stomach is a classical example.

Nodal

Marginal zone lymphoma occurring primarily in lymph nodes.

Splenic

Marginal zone lymphoma centered on the spleen.

Slide 7 · Why MALT is an unusual name in the stomach

Organized mucosa-associated lymphoid tissue is not normally present in the healthy stomach.

Chronic gastritis can induce acquired lymphoid aggregates in gastric mucosa.

These acquired immune structures provide the setting for lymphomatous evolution.

Surface epithelium

Lamina propria

Muscularis mucosae

Submucosa

Muscularis propria

Schematic gastric wall layers

Slide 8 · Normal intestinal MALT versus acquired gastric MALT

Small intestine

Peyer patches provide preexisting organized mucosal lymphoid tissue.

Stomach

Lacks normal organized MALT; Lymphoid aggregates emerge during chronic gastritis.

Slide 9 · Chronic immune stimulation is the recurring context

Stomach

Helicobacter-associated chronic gastritis

Salivary gland

Chronic autoimmune inflammation in Sjögren syndrome

Thyroid

Chronic autoimmune inflammation in Hashimoto thyroiditis

Slide 10 · The central sequence: Gastritis to lymphoma

Persistent H. Pylori infection

Microbial stimulus

Chronic gastric inflammation

Immune recruitment

Acquired gastric MALT

Local lymphoid organization

Expansion of B-cell clone

Potential tumor precursor

Slide 11 · How H. Pylori persists in gastric mucosa

Motility

Flagella allow movement through gastric mucus.

Chemical protection

Urease produces ammonia and supports local survival.

Adherence and injury

Adhesins and toxins facilitate epithelial interaction and inflammation.

Slide 12 · H. Pylori acts chiefly through the inflammatory niche

Chronic bacterial colonization sustains local immune-cell recruitment.

Antigen-dependent stimulation can maintain the emerging B-cell clone.

The pathological link to lymphoma is immune stimulation, not simple conversion of a gastric epithelial cell into a B-cell.

Causal logic

Bacterial antigen → lymphoid response → clonal selection

Slide 13 · An early phase may remain antigen dependent

Persistent antigen

Chronic infection

Activated T-helper cells

Immune help

Growth / survival signals to B cells

Still stimulus dependent

Expanding B-cell clone

Localized proliferation

Slide 14 · Reactive hyperplasia and lymphoma form a continuum

Polyclonal immune response

Inflammatory lesion

Emergent clonal population

Initiating genetic change

Antigen-dependent lymphoma

May regress after eradication

Antigen-independent lymphoma

Additional genetic events

Slide 15 · Polyclonality does not equal lymphoma

Reactive immune proliferation

Multiple B-cell clones respond to a continuing immune stimulus.

Emerging neoplastic clone

A favored clone acquires survival advantages; Clonal dominance may be demonstrable.

Slide 16 · What makes early gastric MALT lymphoma exceptional?

Often remains confined to its extranodal site for a prolonged period.

May respond to elimination of the underlying H. Pylori stimulus.

Can acquire lesions that remove the need for persistent antigen.

Clinical meaning

Biology can determine response to pathogen eradication.

Slide 17 · BCL10 and MALT1 form a signaling hub

Antigen receptor engagement

BCL10–MALT1 signaling complex

NF-κB activation

B-cell growth and survival

Editable pathway schematic: Physiological receptor input → NF-κB-dependent transcription

Slide 18 · NF-κB is a survival program, not a histologic pattern

NF-κB is a transcription factor involved in B-cell activation.

Physiological antigen receptor signaling can activate this pathway.

Abnormal constitutive activation allows neoplastic cells to survive with reduced antigen dependence.

Mechanistic pivot

Regulated signaling → persistent signaling

Slide 19 · Two routes to NF-κB activation

Antigen-driven route

H. Pylori–related inflammation supplies a continuing upstream signal.

Genetically autonomous route

MALT1/BCL10-related alterations maintain signaling despite withdrawal of antigen.

Slide 20 · Four recurrent gastric MALT lymphoma translocations

Rearrangement

Principal target

Consequent change

t(11;18)(q21;q21)

API2::MALT1

Fusion protein

t(1;14)(p22;q32)

BCL10 / IGH

Increased BCL10

t(14;18)(q32;q21)

IGH / MALT1

Increased MALT1

t(3;14)(p13;q32)

FOXP1 / IGH

Increased FOXP1

Slide 21 · T(11;18): The API2::MALT1 fusion

API2 locus (11q21)

Apoptosis inhibitor 2

T(11;18) rearrangement

With MALT1 (18q21)

API2::MALT1 fusion gene

Chimeric fusion product

Altered pro-survival signaling

Constitutive NF-κB

Slide 22 · Why the API2::MALT1 product matters

This rearrangement fuses material from the API2 and MALT1 genes.

The chimeric protein supports constitutive NF-κB activation.

Tumors harboring this alteration generally resist regression after H. Pylori clearance.

Mechanism to management

Oncogenic signaling becomes less reliant on bacterial antigen.

Slide 23 · T(1;14): Increased BCL10 expression

BCL10 locus (1p22)

Translocation

IGH regulatory context (14q32)

Immunoglobulin locus effect

Increased BCL10 protein

Signal-complex component

Constitutive NF-κB signaling

Pro-survival output

Slide 24 · T(14;18) in gastric MALT lymphoma

MALT1 locus (18q21)

Rearrangement

IGH regulatory context (14q32)

Promoter/enhancer influence

Increased intact MALT1

Signal-complex component

Constitutive NF-κB signaling

Pro-survival output

Slide 25 · T(3;14) involves FOXP1

FOXP1 (3p13)

Translocation partner

IGH (14q32)

Immunoglobulin locus

Increased FOXP1 expression

Transcription factor

Altered transcriptional program

Do not equate with BCL10–MALT1 fusion

Slide 26 · Genetic alterations converge on growth advantage

API2::MALT1

Fusion protein; Constitutive survival signaling

BCL10 or MALT1 upregulation

Increased signal-complex activity → NF-κB

FOXP1 upregulation

Transcription-factor overexpression; Biologically distinct alteration

Slide 27 · Not every gastric MALT lymphoma is fusion driven

Some tumors lack the listed chromosomal translocations.

In these tumors, antigen-dependent activation of NF-κB may remain essential.

The molecular state helps explain heterogeneous response to H. Pylori eradication.

Caution

Absence of a translocation does not itself prove eradication response.

Slide 28 · Why eradication can cause lymphoma regression

H. Pylori eradicated

Remove upstream trigger

Antigenic drive falls

Reduced immune stimulation

T-cell assistance diminishes

Less paracrine support

Dependent clone regresses

Possible tumor involution

Slide 29 · Why eradication can fail

Biologic independence

MALT1- or BCL10-related rearrangements allow self-sustaining survival signals.

Extent of disease

Deep muscular invasion and involved lymph nodes also correlate with resistance.

Slide 30 · Depth of infiltration changes response expectations

Mucosal-limited disease is conceptually distinct from deep wall infiltration.

Invasion into or through the muscularis propria correlates with reduced eradication responsiveness.

Lymph-node involvement is another adverse response correlate.

Surface epithelium

Lamina propria

Muscularis mucosae

Submucosa

Muscularis propria

Schematic gastric wall layers

Slide 31 · MALT lymphoma often remains localized

Extranodal marginal zone lymphomas may remain local for prolonged periods.

Systemic dissemination tends to occur later than in aggressive lymphomas.

Localized behavior should not be confused with absence of malignant potential.

Natural history

Indolent ≠ biologically inert

Slide 32 · Clonal evolution can change tumor behavior

Low-grade gastric MALT lymphoma

Indolent phase

Further genetic abnormalities

Additional selection

Emergence of large-cell disease

Transformation

DLBCL-type aggressive morphology

Histologically aggressive

Slide 33 · TP53 and CDKN2A can be affected in transformation

Progression with additional genetic changes.

Inactivation of genes encoding p53 and p16 is cited as an example.

These events illustrate loss of tumor-suppressive control during clonal evolution.

Interpretation

This is an association in the described progression model.

Slide 34 · MALT lymphoma: Low-power tissue pattern

Dense lymphoid expansion occupies the lamina propria.

Gastric glands persist within, and may be disrupted by, the infiltrate.

Architecture must be assessed together with cytology and immunophenotype.

Schematic — not a tissue specimen

Lamina propria expansion

Slide 35 · Lymphoepithelial lesions are the key clue

Neoplastic lymphocytes infiltrate glandular epithelium.

The affected gland becomes distorted or disrupted.

Recognize the lesion in context: It is not sufficient alone to establish the entire diagnosis.

Schematic — not a tissue specimen

Intraepithelial lymphocytes

Slide 36 · A lymphoepithelial lesion: Read it in steps

Identify a gastric gland

Epithelial structure

Find intraepithelial lymphocytes

Cellular infiltration

Assess epithelial distortion

True lymphoepithelial lesion

Correlate with expanded B-cell infiltrate

Integrated interpretation

Slide 37 · Reactive follicles may coexist with tumor

B-cell follicles with reactive-appearing centers may be present.

A reactive-looking follicle does not exclude adjacent lymphoma.

Assess the surrounding marginal-zone infiltrate and epithelial lesions.

Schematic — not a tissue specimen

Reactive-appearing follicle

Slide 38 · Plasmacytic differentiation is not rare

Frequency

Approximately 40% of gastric MALT lymphomas show plasmacytic differentiation.

Morphologic implication

The infiltrate may contain cells resembling plasma cells.

Diagnostic implication

Light-chain restriction can support clonality when appropriate.

Slide 39 · GI lymphoma can appear in different growth patterns

Mucosal involvement

Dense expansion of the gastric lamina propria

Small nodules

Some intestinal lymphomas form discrete nodular deposits

Diffuse wall involvement

Other GI lymphomas infiltrate the bowel wall broadly

Slide 40 · Immunophenotyping establishes B-cell lineage

Marker

Robbins pattern

What it supports

CD19

Positive

Mature B-cell lineage

CD20

Positive

Mature B-cell lineage

CD5

Usually negative

Helps exclude common CD5+ B-cell mimics

CD10

Usually negative

Helps exclude germinal-center B-cell mimics

CD43

Positive in ≈25%

Aberrant coexpression may be informative

Slide 41 · CD19 and CD20: Lineage, not unique identity

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

These markers confirm B-cell identity but are shared by several other B-cell lymphomas.

Morphology and an exclusionary immunophenotypic pattern remain essential.

Diagnostic reasoning

Lineage marker ≠ lymphoma subtype

Slide 42 · CD5− / CD10−: A useful exclusionary pattern

Typical gastric MALT lymphoma

CD5− and CD10− with preserved mature B-cell marker expression.

Why it matters

A different marker pattern should prompt reconsideration of alternate B-cell neoplasms.

Slide 43 · CD43 coexpression is a diagnostic clue

About one quarter of gastric MALT lymphomas express CD43.

Aberrant CD43 expression can help establish a neoplastic B-cell population.

Its absence cannot exclude MALT lymphoma because most cases lack this finding.

Common error

Do not treat a minority-feature marker as mandatory.

Slide 44 · Light-chain restriction supports a clonal population

Suspicious mucosal B-cell infiltrate

Biopsy morphology

Examine κ and λ expression

Immunoglobulin assessment

Predominance of one light chain

Restricted expression

Support for B-cell monoclonality

Must correlate with tissue context

Slide 45 · Clonal IGH rearrangement testing

Molecular analysis can detect clonal immunoglobulin heavy-chain gene rearrangement.

This is especially useful when lymphoepithelial lesions are absent.

A molecular clonal result contributes evidence; It does not replace morphologic interpretation.

Integration rule

Histology + phenotype + clonality > any isolated test

Slide 46 · Diagnosis is an evidence-integration problem

Tissue architecture / cytology

Infiltrate and epithelial lesions

CD19/CD20 and exclusion markers

B-cell phenotype

Light chains or IGH clonality

Support when needed

Clinicopathologic diagnosis

With gastritis/endoscopy context

Slide 47 · The major mimic is chronic H. Pylori gastritis

Chronic gastritis

Can induce mucosal lymphoid aggregates and similar symptoms.

MALT lymphoma

Clonal B-cell proliferation with characteristic infiltrative morphology and phenotype.

Slide 48 · Small biopsies are a particular challenge

Gastritis and lymphoma may coexist in the same gastric mucosa.

Both can share dyspeptic symptoms and similar endoscopic appearances.

Sampling may miss the most diagnostic lymphoepithelial lesions or deeper infiltration.

Practical implication

A limited negative feature may reflect sampling rather than absent disease.

Slide 49 · Morphology must be read with the stomach in mind

Background

Is there active or chronic Helicobacter-associated gastritis?

Architecture

Does the infiltrate expand the lamina propria and invade glands?

Clonality

Does the B-cell population show restricted light chains or clonal IGH?

Slide 50 · Dyspepsia and epigastric pain predominate

The most frequent clinical complaints are dyspepsia and epigastric discomfort.

These symptoms are nonspecific and overlap with H. Pylori gastritis.

The clinical presentation alone cannot establish lymphoma.

Clinicopathologic point

A common symptom can conceal a lymphoid neoplasm.

Slide 51 · Gastrointestinal bleeding may occur

Hematemesis

Upper GI bleeding can present with vomiting of blood.

Melena

Digested blood may produce black, tarry stools.

Underlying lesion

Lymphomatous mucosal involvement may contribute to bleeding symptoms.

Slide 52 · Constitutional features may accompany gastric disease

Weight loss is among the constitutional manifestations described.

The symptom pattern can include local gastric and systemic manifestations.

Clinical severity should not be inferred from symptoms alone without staging or pathology.

Symptom synthesis

Local discomfort ± bleeding ± weight loss

Slide 53 · Endoscopic appearances overlap with gastritis

Endoscopy

Surface appearances may not reliably distinguish H. Pylori gastritis from MALT lymphoma.

Histopathology

Biopsy reveals infiltrative pattern, B-cell phenotype and sometimes clonality.

Slide 54 · Anatomic involvement extends beyond the stomach

Stomach

Characteristic site of MALT lymphoma

Small bowel

Peyer patches are preexisting MALT; Other GI lymphomas also arise

Colon / bowel wall

May show nodular or diffuse infiltration depending on lymphoma subtype

Slide 55 · Post-transplant B-cell proliferations involve the bowel

The bowel is a frequent site for EBV-positive B-cell proliferations following transplantation.

Transplant-related T-cell dysfunction impairs immune control of EBV-infected B cells.

Intestinal predilection to local effects of orally absorbed immunosuppressants.

Separate mechanism

EBV-associated immune deficiency ≠ H. Pylori–driven gastric MALT lymphoma

Slide 56 · Immunosuppression changes the differential

Chronic Helicobacter inflammation

Typical context for indolent gastric MALT lymphoma.

Post-transplant T-cell dysfunction

Raises the possibility of EBV-positive B-cell lymphoproliferation.

Slide 57 · Not every GI B-cell lymphoma is MALT lymphoma

Entity

Characteristic GI connection

Gastric MALT lymphoma

Indolent, often H. pylori linked

Diffuse large B-cell lymphoma

Aggressive nodal or extranodal masses; may follow transformation

Mantle cell lymphoma

Can produce lymphomatoid polyposis

Sporadic Burkitt lymphoma

Often presents near ileocecum / peritoneum

Slide 58 · Large B-cell transformation changes morphology

Indolent MALT lymphoma

Small B-cell–rich infiltrates and lymphoepithelial lesions.

DLBCL-type transformation

A population of large, rapidly proliferating malignant B cells.

Slide 59 · Mantle cell lymphoma: Lymphomatoid polyposis

Mantle cell lymphoma may involve mucosal sites in the small bowel or colon.

Multiple polypoid deposits are termed lymphomatoid polyposis.

Its typical CD5 expression and cyclin D1 overexpression differ from the usual gastric MALT profile.

Differential focus

Polypoid distribution and phenotype redirect diagnosis.

Slide 60 · Burkitt lymphoma: Another GI-predominant pattern

Sporadic Burkitt lymphoma often appears as an ileocecal or peritoneal mass.

It has MYC rearrangement–associated rapid proliferation.

The morphologic and biological course differs substantially from indolent gastric MALT lymphoma.

Differential focus

Aggressive growth + ileocecal mass ≠ typical gastric MALT.

Slide 61 · Comparison: Indolent versus aggressive GI lymphoma

Feature

Gastric MALT

DLBCL / Burkitt

Characteristic tempo

Often indolent

Often aggressive

Microanatomy

Lamina propria; glands

Mass-forming / diffuse tumor

Molecular focus

MALT1 / BCL10 pathways

Other subtype-specific drivers

Antibiotic regression

Can occur in H. pylori–dependent cases

Not a defining biological feature

Slide 62 · Case 1: Dyspepsia with a dense B-cell infiltrate

A patient with persistent dyspepsia has gastric mucosal biopsies.

Histology shows lamina propria expansion and lymphocytes infiltrating gastric glands.

The infiltrate is CD20-positive, CD5-negative and CD10-negative.

What diagnosis is most strongly supported, and what evidence is still useful?

Slide 63 · Case 1: Integrate rather than overcall

The pattern strongly suggests gastric extranodal marginal zone (MALT) lymphoma.

Confirm the lymphoepithelial pattern and assess the Helicobacter background.

Light-chain restriction or IGH clonality may add support, particularly in equivocal samples.

Slide 64 · Case 2: Failure to regress after eradication

Gastric MALT lymphoma is identified in a Helicobacter-associated setting.

After H. Pylori eradication, lymphoma persists.

Molecular studies find t(11;18)(q21;q21).

Which pathway explains why withdrawal of antigen may be insufficient?

Slide 65 · Case 2: Antigen independence explains persistence

T(11;18) generates the API2::MALT1 fusion.

The rearrangement supports constitutive NF-κB survival signaling.

Such tumors are generally unresponsive to H. Pylori clearance alone.

Slide 66 · Case 3: New large-cell morphology

A previously indolent gastric MALT lymphoma develops an enlarging mass.

Histology shows a newly dominant population of large malignant lymphoid cells.

The clinical course appears more aggressive than before.

Which biological event should be considered?

Slide 67 · Case 3: Consider histologic transformation

Progression to diffuse large B-cell lymphoma–type morphology is a recognized event.

Additional genetic changes, including loss of p53 or p16 function, may accompany transformation.

The new large-cell component must be evaluated as aggressive lymphoma.

Slide 68 · Pathogenesis at a glance

H. Pylori → sustained mucosal immune response → acquired gastric MALT.

Clonal marginal-zone B-cell expansion can remain antigen dependent.

MALT1/BCL10 pathway alterations can provide constitutive NF-κB survival signaling.

Additional evolution may produce large B-cell transformation.

Slide 69 · Diagnosis at a glance

Recognize a dense lamina propria B-cell infiltrate with lymphoepithelial lesions.

Check CD19/CD20 positivity and typical CD5/CD10 negativity.

Use CD43 coexpression, light-chain restriction or IGH clonality as supporting evidence.

Interpret with H. Pylori status, depth and clinical context.

Slide 70 · Principal source and scope

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th ed. (2026).

Chapter 17: The Gastrointestinal Tract — Lymphoma, pp. 706–707.

Chapter 13: Marginal Zone Lymphomas, pp. 548–549.

Related context: Helicobacter pylori gastritis, DLBCL, mantle cell and Burkitt lymphomas.