Helicobacter Pylori

Slide 1 · Helicobacter pylori

From persistent gastritis to gastric adenocarcinoma and MALT lymphoma

Persistent infection

Epithelial pathway

B-cell pathway

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain how H. Pylori persists in gastric mucus and initiates chronic inflammation.

Relate antral versus multifocal atrophic gastritis to divergent clinical outcomes.

Trace the proposed sequence from chronic injury to gastric adenocarcinoma.

Explain antigen-driven gastric MALT lymphoma and loss of dependence on infection.

Interpret key histologic findings and diagnostic tests in clinical context.

Slide 3 · One organism, two tumor lineages

Epithelial malignancy

Lymphoid malignancy

Chronic gastritis and injury of gastric epithelium

Atrophy → intestinal metaplasia → dysplasia

Gastric adenocarcinoma

Acquired mucosal lymphoid tissue

Persistent antigen-specific T-cell help

Extranodal marginal zone B-cell lymphoma (MALT lymphoma)

Slide 4 · Why H. Pylori is a carcinogenic infection

A bacterium can promote malignancy without invading the gastric epithelium.

Persistent infection generates chronic inflammation, epithelial turnover, and immune stimulation.

Bacterial virulence and host responses modify the carcinogenic trajectory.

Only a minority of infected persons develop gastric malignancy.

Slide 5 · Morphology and microbial niche

H. Pylori is a curved or spiral-shaped bacillus.

The organisms live predominantly in gastric mucus near surface and neck epithelial cells.

They adapt to strong luminal acidity by modifying and navigating their local microenvironment.

Direct mucosal invasion is not required for oncogenic effects.

Slide 6 · Colonization is commonly established in childhood

Transmission is thought to be predominantly fecal–oral, with humans as the principal reservoir.

Crowding and sanitation conditions during childhood influence acquisition.

Untreated colonization may persist for decades or lifelong.

Duration of chronic mucosal inflammation creates the setting for later complications.

Slide 7 · Three stages of persistent colonization

Reach gastric mucus

Buffer and navigate local acid

Attach near foveolar cells

Persist despite inflammation

Urease, flagella, and adhesins cooperate rather than act as isolated virulence factors.

Slide 8 · Where the organism resides

Gastric lumen

Mucus layer

Surface epithelial cells

Underlying lamina propria

Simplified schematic — not a photomicrograph

Tissue localization

Bacteria concentrate within the superficial mucus.

Organisms lie near surface and neck regions of gastric glands.

Sampling may miss patchy colonization.

Slide 9 · Flagella: Motility through viscous mucus

Flagella permit movement through viscous gastric mucus.

H. Pylori senses pH and avoids more acidic microenvironments.

Motility helps the bacterium remain close to the epithelium.

This spatial localization favors survival despite the acidic gastric lumen.

Slide 10 · Urease creates a local acid buffer

Bacterial urease

Urea hydrolysis

Ammonia formation

Higher local pH

Local neutralization facilitates survival; It does not abolish the stomach’s overall acidity.

Slide 11 · Adhesins stabilize mucosal colonization

Adhesion proteins bind bacteria to gastric foveolar epithelial cells.

Adherence anchors organisms at the epithelium–mucus interface.

Urease and adhesins are highly conserved colonization determinants.

Prolonged surface contact can sustain epithelial and immune activation.

Slide 12 · Bacterial factors versus host response

Bacterial inputs

Host inputs

Flagella and motility

Urease-dependent acid buffering

Adhesion to surface epithelial cells

CagA and other virulence mediators

Epithelial inflammatory responses

TNF, IL-1, and other cytokines

Immune-cell recruitment

Host susceptibility polymorphisms

Slide 13 · CagA defines a major virulence-associated pathway

The CagA pathogenicity island is associated with strains linked to gastric adenocarcinoma.

CagA is delivered into gastric epithelial-cell cytoplasm.

Once intracellular, it influences cellular signaling and structural remodeling.

Population associations do not prove that CagA alone determines individual cancer outcomes.

Slide 14 · CagA: Proposed direct epithelial effects

CagA-bearing H. Pylori

CagA enters epithelial cell

Growth factor–like signaling

Altered epithelial behavior

The Chapter 7 account describes this as one component of multifactorial oncogenesis.

Slide 15 · Direct bacterial effects are not the entire mechanism

Potential direct route

Inflammation-mediated route

CagA-associated signaling changes

Cellular structural remodeling

Altered epithelial proliferation

Persistent inflammatory infiltrates

Reactive oxygen species and genotoxic stress

Compensatory epithelial proliferation

Slide 16 · Interpreting virulence associations carefully

CagA-associated strains are enriched in populations with higher gastric cancer prevalence.

A pathogenicity factor is a risk modifier, not a deterministic cancer biomarker.

The textbook explicitly characterizes some experimental virulence-factor contributions as correlative.

The resulting phenotype depends on bacterial, mucosal, and host characteristics.

Slide 17 · Host cytokine polymorphisms influence outcome

Greater TNF or IL-1 expression may favor an exaggerated proinflammatory response.

Reduced IL-10 expression may weaken anti-inflammatory restraint.

Such inherited variants are associated with risk of pangastritis, atrophy, and metaplasia.

Associations do not establish that a single polymorphism diagnoses future cancer.

Slide 18 · Infection outcome emerges from three interacting systems

Bacterial virulence

Host genetic and immune response

Mucosal defense and acid physiology

Their interplay, rather than organism presence alone, determines the observed pattern of gastritis.

Slide 19 · Antrum-predominant gastritis is a common pattern

Organisms are often most abundant in the antrum.

Inflammation in this region enhances local gastrin production.

Normal or increased acid secretion commonly persists.

The clinical phenotype tends toward peptic-ulcer risk rather than atrophy-associated carcinogenesis.

Slide 20 · Antral inflammation links infection to acid hypersecretion

Antral colonization

Increased gastrin signaling

Parietal-cell expansion

Greater acid production

In this phenotype, increased acid promotes gastric or duodenal peptic-ulcer disease.

Slide 21 · Ulcer-prone and atrophy-prone phenotypes

Antrum-predominant

Corpus involvement / atrophy

Gastrin stimulation

Normal/increased acid secretion

Higher risk of duodenal peptic ulcer

Loss of functional parietal-cell mass

Decreased acid secretion

Intestinal metaplasia and higher cancer risk

Slide 22 · Progressive pangastritis changes the risk landscape

Long-standing infection can extend from the antrum to body and fundus.

Inflammatory injury may reduce oxyntic gland and parietal-cell mass.

Patchy mucosal atrophy and intestinal metaplasia can develop.

This atrophic phenotype is strongly linked to intestinal-type gastric carcinogenesis.

Slide 23 · Oxyntic gland loss reduces acid production

Chronic corpus gastritis

Parietal-cell loss

Less gastric acid

Feedback gastrin increase

Some acid secretion can persist; Gastrin elevation is generally less extreme than in autoimmune gastritis.

Slide 24 · Atrophy associated with H. Pylori is often patchy

Oxyntic atrophy can be distributed irregularly.

The pattern differs from the characteristic autoimmune oxyntic atrophy phenotype.

H. Pylori–associated atrophy lacks the autoantibodies characteristic of autoimmune gastritis.

Biopsy interpretation must account for anatomic site and sampling.

Slide 25 · Proposed epithelial carcinogenesis sequence

Chronic gastritis

Glandular atrophy

Intestinal metaplasia

Dysplasia

Adenocarcinoma

This is a conceptual progression, not an inevitable course for each infected person.

Slide 26 · Why chronic inflammation promotes mutation accumulation

Inflammatory cells release reactive oxygen species that may damage cellular DNA.

Continued epithelial injury generates compensatory epithelial proliferation.

Genotoxic stress during repeated cell division may favor selection of altered clones.

Inflammation is therefore a carcinogenic microenvironment, not merely a secondary reaction.

Slide 27 · Chronic injury connects inflammation with cell proliferation

Persistent infection

Inflammatory injury

Epithelial regeneration

Proliferative selection

Repeated turnover increases opportunities for acquired oncogenic alterations over time.

Slide 28 · Intestinal metaplasia marks a changed epithelial program

Gastric lining epithelial cells acquire intestinal-type differentiation.

The change accompanies prolonged atrophic H. Pylori gastritis.

It is a histologic marker within the proposed adenocarcinoma precursor sequence.

Metaplasia is not synonymous with invasive malignancy.

Slide 29 · Dysplasia is a neoplastic precursor, not invasive cancer

Dysplastic gastric epithelium shows nuclear enlargement, elongation, hyperchromasia, and pseudostratification.

Architectural complexity increases with higher-grade dysplasia.

Cribriform glands and glandular budding may accompany high-grade lesions.

Invasion distinguishes carcinoma from an intraepithelial dysplastic precursor.

Slide 30 · The epithelial route is prolonged and selective

Childhood acquisition

Chronic inflammation

Precancerous mucosal alteration

Cancer in a minority

A decades-long sequence culminating in cancer in fewer than 5% of infected individuals.

Slide 31 · Infection does not imply inevitable gastric cancer

Progression to adenocarcinoma in fewer than 5% of infected people.

The latency of progressive gastric carcinogenesis is often measured in decades.

Host genetics, bacterial virulence, topographic inflammation, and other influences modify risk.

Cancer risk cannot be assigned to an individual by infection status alone.

Slide 32 · Inflammation-associated cancer versus alternative etiology

H. Pylori–associated pathway

Not all gastric cancers follow this route

Chronic gastritis

Atrophy and metaplastic change

Predominantly implicated in intestinal-type pathway

A subset of gastric cancers is associated with EBV.

Diffuse cancers commonly involve cell-adhesion abnormalities.

H. Pylori is not a sufficient explanation for every gastric cancer.

Slide 33 · What distinguishes intestinal-type gastric adenocarcinoma?

Neoplastic glands are formed by cohesive epithelial cells.

Mass-forming or ulcerated infiltrative growth is typical.

Cells may contain apical mucin; Gland lumina may contain mucin.

Its association with chronic atrophy and metaplasia links morphology to the H. Pylori precursor pathway.

Slide 34 · Intestinal-type and diffuse-type gastric carcinoma

Feature

Intestinal type

Diffuse type

Growth

Gland-forming; often bulky/ulcerated

Discohesive infiltration; wall thickening

Typical cytology

Columnar cells; mucin-containing glands

Signet-ring cells; absent glands

Precursor context

Chronic atrophy / intestinal metaplasia

No established morphologic precursor

Mechanistic theme

Inflammation-associated epithelial sequence

Adhesion defects, including E-cadherin loss

Slide 35 · Endoscopic features may be subtle or misleading

Infected antral mucosa can appear erythematous, coarse, or nodular.

Severe inflammation can produce thickened rugal folds.

Rugal thickening may mimic the endoscopic appearance of early gastric cancer.

Endoscopic appearance alone cannot resolve inflammation from neoplasia.

Slide 36 · Organisms cluster in surface mucus

Gastric lumen

Mucus layer

Surface epithelial cells

Underlying lamina propria

Simplified schematic — not a photomicrograph

Biopsy implications

Look near surface mucus and epithelial necks.

Distribution can be irregular within a biopsy.

Heavy and sparse foci may be adjacent.

Slide 37 · Histologic detection of organisms

Curved or spiral organisms can be identified in H&E-stained tissue.

Histochemical methods such as Warthin–Starry silver stain may highlight organisms.

Immunostaining often improves recognition, particularly in difficult samples.

A negative limited biopsy must be interpreted with sampling and clinical context.

Slide 38 · Active chronic gastritis involves several cell populations

Gastric surface epithelium

Simplified schematic — not a photomicrograph

Core tissue findings

Superficial plasma-cell–rich chronic infiltrate.

Lymphocytes and macrophages in lamina propria.

Neutrophils enter epithelium and gastric pits.

Slide 39 · Plasma cells dominate the chronic component

Plasma cells accumulate within superficial lamina propria.

Clusters or sheets of plasma cells may be conspicuous.

Lymphocytes and macrophages are also recruited.

The pattern reflects sustained antigenic and inflammatory stimulation.

Slide 40 · Neutrophils indicate active epithelial injury

Gastric surface epithelium

Simplified schematic — not a photomicrograph

Activity means neutrophils

Neutrophils cross the epithelial basement membrane.

They infiltrate surface or glandular epithelium.

Accumulation in gastric pits produces pit abscesses.

Slide 41 · Ectopic lymphoid follicles arise during infection

Gastric surface epithelium

Simplified schematic — not a photomicrograph

Acquired gastric MALT

Lymphoid aggregates may form germinal centers.

Normal stomach lacks organized mucosal lymphoid tissue.

Chronic H. Pylori gastritis can induce organized mucosal lymphoid tissue.

Slide 42 · Reactive follicles are not themselves lymphoma

Reactive immune response

Features raising lymphoma concern

Aggregates and germinal centers

Mixed inflammatory population

Antigen-driven tissue organization

Dense neoplastic B-cell infiltrates

Invasion of glands: Lymphoepithelial lesions

Clonal immunoglobulin gene or light-chain evidence

Slide 43 · Atrophic H. Pylori and autoimmune gastritis

Feature

H. pylori–associated

Autoimmune

Distribution

Often patchy; can involve antrum + corpus

Predominantly oxyntic (body/fundus)

Causative association

Persistent bacterial infection

Autoimmune parietal-cell injury

Autoantibodies

Not a defining feature

Characteristic association

Gastrin response

Raised if acid reduced, often modest relative to autoimmune

Marked when acid loss is extensive

Slide 44 · Diagnosis requires organism and pattern interpretation

Identify H. Pylori with an appropriate validated tissue or noninvasive method.

Describe distribution, inflammatory activity, atrophy, and metaplasia where sampled.

Recognize that both neoplastic and reactive processes can coexist.

Morphology and clinical findings jointly determine further assessment.

Slide 45 · Available tests for H. Pylori infection

Approach

Examples

What the test contributes

Noninvasive

Urea breath test

Evidence of urease activity associated with infection

Noninvasive

Fecal bacterial detection

Evidence of infection without gastric biopsy

Noninvasive

Antibody serology

Exposure/immune response; not equivalent to ongoing infection

Biopsy-based

Histology; rapid urease; culture; PCR

Detection of bacteria, urease, or bacterial DNA

Slide 46 · Gastric MALT lymphoma begins with a chronic immune stimulus

Persistent H. Pylori

Acquired gastric MALT

H. Pylori–reactive T cells

B-cell stimulation

The earliest lymphoid expansion is antigen-dependent rather than autonomous cancer.

Slide 47 · Why the normal stomach develops lymphoid tissue

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

Chronic antigenic stimulation can induce lymphoid aggregates and follicles.

These provide an environment for T-cell–B-cell interactions.

Only some persistent lymphoid expansions undergo neoplastic transformation.

Slide 48 · T-cell help drives an initially polyclonal B-cell response

Bacterial antigens

Reactive T cells

B-cell stimulation

Polyclonal B-cell expansion

The bacterial signal acts indirectly through a reactive T-cell compartment.

Slide 49 · Clonal selection converts reactive proliferation into lymphoma

Persistent immune stimulation maintains opportunities for B-cell proliferation.

Acquired mutations can confer a proliferative or survival advantage.

A growth-advantaged B-cell clone may dominate, creating monoclonal lymphoma.

Early lymphoma may still require antigen-dependent T-cell signaling.

Slide 50 · NF-κB links T-cell help to B-cell survival

T-cell–dependent signals

B-cell signaling network

NF-κB activation

B-cell survival and growth

In early gastric MALT lymphoma, pathway activation remains responsive to infection-dependent immune stimulation.

Slide 51 · Early and late MALT lymphoma differ in dependence

Early / antigen-dependent

Later / more autonomous

Growth supported by H. Pylori–reactive T cells

Localized gastric disease may respond to eradication

NF-κB activity depends on upstream immune signals

Acquired molecular alterations can activate NF-κB constitutively

Growth can persist without bacterial antigen

Capacity for spread beyond stomach increases

Slide 52 · Lymphoepithelial lesions are a key clue

Gastric surface epithelium

Simplified schematic — not a photomicrograph

Microscopic pattern

Neoplastic small B cells permeate lamina propria.

B cells infiltrate and disrupt gastric glands.

Glandular infiltration creates lymphoepithelial lesions.

Slide 53 · Gastric MALT lymphoma: Histologic architecture

Lamina propria is expanded by a dense lymphocytic infiltrate.

Lymphoepithelial lesions arise when lymphoma cells infiltrate gastric glands.

Reactive-appearing B-cell follicles may coexist.

Plasmacytic differentiation may also occur.

Slide 54 · MALT lymphoma immunophenotype and clonality

Finding

Interpretation

CD19 and CD20 expression

Supports mature B-cell lineage

CD5 and CD10 negative

Characteristic immunophenotypic pattern described in Robbins

CD43 positive in some tumors

Potentially helpful adjunct, not a standalone criterion

Light-chain restriction or clonal IgH

Evidence supporting monoclonality when morphology is equivocal

Slide 55 · Clonality must be interpreted in morphologic context

Light-chain restriction can support a monoclonal B-cell process.

Molecular detection of clonal IgH rearrangement may help selected cases.

Immunophenotype alone does not substitute for tissue architecture.

Small biopsies with overlapping reactive gastritis can present a diagnostic challenge.

Slide 56 · The API2::MALT1 fusion alters dependence on infection

T(11;18)(q21;q21) creates an API2::MALT1 fusion.

The fusion protein activates signaling that promotes B-cell growth and survival.

Associated NF-κB activity may become independent of the original antigenic stimulus.

MALT lymphomas bearing this pathway alteration often resist H. Pylori eradication alone.

Slide 57 · Selected molecular rearrangements in gastric MALT lymphoma

Rearrangement

Main target / effect

t(11;18)(q21;q21)

API2::MALT1 fusion

t(1;14)(p22;q32)

BCL10 expression increased

t(14;18)(q32;q21)

MALT1 expression increased

t(3;14)(p13;q32)

FOXP1::IGH; FOXP1 expression increased

Slide 58 · The shift to autonomous NF-κB signaling

Early: Bacterial antigen

T-cell help → B-cell signal

Additional genetic events

Constitutive NF-κB activity

This conceptual switch explains loss of dependence on H. Pylori–stimulated T cells.

Slide 59 · Eradication therapy can remove the lymphoma stimulus

Some localized gastric MALT lymphomas regress when H. Pylori is eradicated.

Antibiotics remove the bacterial antigen driving reactive T-cell support.

Therapeutic response depends on the molecular state of the lymphoma.

Successful bacterial clearance does not guarantee regression of genetically autonomous lymphoma.

Slide 60 · Why some gastric MALT lymphomas resist eradication

MALT1/BCL10-related translocations may create constitutive survival signals.

Invasion of muscularis propria and lymph node involvement correlate with resistance.

Further evolution can permit spread beyond the gastric mucosa.

Histologic follow-up must assess the tumor, not merely disappearance of H. Pylori.

Slide 61 · MALT lymphoma and reactive gastritis can overlap

Shared findings

Evidence favoring MALT lymphoma

Dyspepsia or epigastric pain

Lymphoid aggregates in gastric biopsies

Coincident H. Pylori gastritis

Overlapping endoscopic appearance

Dense monotonous or infiltrative B-cell population

Lymphoepithelial lesions

B-cell immunophenotype

Light-chain restriction or clonal IgH when needed

Slide 62 · Clinical correlation: Antral infection and ulcer phenotype

Clinical vignette

A patient has antral-predominant H. Pylori gastritis, raised gastrin activity, and preserved oxyntic mucosa.

Pathologic interpretation

Mechanistic explanation

An ulcer-prone physiology rather than the fully developed atrophic cancer precursor phenotype.

Antral inflammation can increase gastrin stimulation and acid secretion; The pathways diverge with corpus atrophy.

Slide 63 · Clinical correlation: Multifocal atrophy and metaplasia

Clinical vignette

Gastric biopsies show chronic active gastritis, patchy gland loss, intestinal metaplasia, and H. Pylori.

Pathologic interpretation

Mechanistic explanation

A tissue background associated with the epithelial gastric carcinogenesis sequence.

Persistent injury plus epithelial turnover and inflammatory genotoxic mediators accompany atrophy and metaplasia.

Slide 64 · Clinical correlation: Gastric lymphoid infiltrate

Clinical vignette

A biopsy shows a dense B-cell infiltrate and lymphoepithelial lesions in a stomach colonized by H. Pylori.

Pathologic interpretation

Mechanistic explanation

Consider extranodal marginal zone B-cell lymphoma of MALT type.

Chronic infection can induce acquired MALT; Persistent B-cell stimulation and clonal selection may produce lymphoma.

Slide 65 · How the two neoplastic routes differ

Domain

Gastric adenocarcinoma

Gastric MALT lymphoma

Target cell

Gastric glandular epithelial cell

B lymphocyte in acquired MALT

Early drivers

Atrophy; metaplasia; inflammation-related genotoxicity

Persistent antigen-dependent T-cell help

Characteristic progression

Dysplasia → invasive carcinoma

Polyclonal → monoclonal B-cell expansion

Loss of stimulus

Precursor risk may persist after tissue alteration

Early tumors may regress with bacterial eradication

Slide 66 · Four interpretive traps in H. Pylori neoplasia

Not every H. Pylori–positive stomach develops a malignancy.

A CagA-associated strain does not independently establish cancer.

Reactive gastric lymphoid follicles are not equivalent to MALT lymphoma.

Eradicating H. Pylori is not proof that an established lymphoma has regressed.

Slide 67 · Integrating infection, topography, morphology, and clonality

Document infection using appropriate testing and tissue sampling.

Determine antral versus oxyntic involvement, activity, atrophy, and intestinal metaplasia.

For epithelial atypia, separate metaplasia, dysplasia, and invasive carcinoma.

For atypical lymphoid infiltrates, assess gland invasion, B-cell phenotype, and clonality where indicated.

Slide 68 · Final synthesis: infection can create two oncogenic microenvironments

Epithelial route: chronic inflammation → atrophy → metaplasia → dysplasia → carcinoma.

Lymphoid route: induced MALT → antigen-dependent B-cell proliferation → clonality → possible NF-κB autonomy.

Both outcomes are modified by virulence, host genetics, duration, and additional acquired events.

Pathologic interpretation requires both organism detection and the tissue response.