Chronic Inflammation (Lecture 2)

Slide 1 · Chronic inflammation and lymphoid neoplasia

How persistent immune stimulation can create a setting for lymphoma

Pathologic mechanisms • clinicopathologic correlations

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain why persistent local immune stimulation can predispose to lymphoid neoplasia.

Connect gastric MALT lymphoma, celiac-associated T-cell lymphoma, and implant-associated lymphoma to their inflammatory settings.

Distinguish antigen-dependent growth from genetically autonomous lymphoma.

Contrast localized inflammation with HIV-associated systemic immune dysregulation.

Slide 3 · This topic is about lymphomagenesis—not generic inflammation

Central question

Which chronic immune states predispose to lymphoma?

Why do some tumors arise at the inflamed site?

How can a reactive lymphoid expansion become neoplastic?

Scope boundary

Mechanisms and specific clinicopathologic examples

Contrasts with HIV-linked systemic lymphoma risk

General chronic inflammation is used only as background

Slide 4 · Chronic inflammation: Injury and repair coexist

Persistent stimulus

Mononuclear cell recruitment

Tissue injury

Ongoing repair

Unlike transient acute inflammation, the stimulus and response persist or recur over time.

Slide 5 · The histologic setting of a persistent immune response

Inflammatory infiltrate

Macrophages, lymphocytes and plasma cells.

Tissue injury

Persistent agent and immune mediators damage tissue.

Repair response

Angiogenesis and fibrosis may accompany the infiltrate.

Slide 6 · Persistent triggers are biologically diverse

Infection

Difficult-to-eradicate microbes sustain responses.

Immune dysregulation

Autoimmune and hypersensitivity reactions recur.

Persistent material

Nondigestible or other enduring stimuli may maintain injury.

Slide 7 · Localized inflammation and systemic dysregulation differ

Feature

Localized inflammatory setting

Systemic HIV-associated setting

Distribution

Prolonged stimulus within a tissue

T-cell dysregulation or immunodeficiency

Typical tumor relationship

Lymphoma often originates at inflamed site

B-cell lymphoma can arise in many organs

Illustrative contexts

Stomach, intestine, implant-associated site

HIV infection / AIDS

Slide 8 · Four settings to lymphoma risk

H. Pylori

Gastric B-cell lymphoma

Gluten-sensitive enteropathy

Intestinal T-cell lymphoma

Breast implants

Unusual T-cell lymphoma

HIV infection

B-cell lymphomas at varied sites

Slide 9 · From chronic stimulus to a permissive tissue niche

Antigen or stimulus persists

Immune-cell expansion

Survival and division signals

Opportunity for clonal selection

A predisposing environment is not equivalent to a malignant clone.

Slide 10 · Repeated proliferation increases opportunities for mutation

Biologic rationale

Immune activation repeatedly recruits cells into proliferation.

Replicating cells may acquire somatic genetic changes.

More rounds of division increase opportunities for selection.

Important distinction

Chronic inflammation raises risk; It does not automatically cause cancer.

Acquired transforming events are still needed.

Risk mechanisms vary with cell lineage and site.

Slide 11 · Inflammatory cells can create genomic stress

Activated inflammatory cells

Reactive oxygen species

Potential DNA damage

Selection if altered cells survive

This is a general inflammation–cancer mechanism, not a demonstrated unique cause of every listed lymphoma.

Slide 12 · Survival signaling changes the consequences of DNA damage

Inflammatory mediators

Promote continued immune-cell recruitment.

Support activated-cell survival.

May allow damaged cells to persist.

Cancer-enabling context

Clonal expansion requires growth or survival advantages.

Genomic lesions can cooperate with the inflammatory milieu.

These are convergent, not interchangeable, processes.

Slide 13 · Tertiary lymphoid structures form outside lymphoid organs

Chronic tissue inflammation

Organized B- and T-cell aggregates

Follicle-like immune architecture

Sustained local immune activity

H. Pylori gastritis can create mucosal collections resembling lymphoid tissue normally seen elsewhere.

Slide 14 · Normal germinal-center reactions involve DNA modification

Physiologic adaptation

Antigen activation drives germinal-center B-cell proliferation.

Activation-induced cytidine deaminase (AID) acts on immunoglobulin genes.

Class switching and somatic hypermutation diversify antibodies.

Pathologic opportunity

DNA breakage and off-target lesions may occur.

Proto-oncogene translocations and point mutations can arise.

The same diversification machinery may increase oncogenic risk.

Slide 15 · AID links normal immune diversification to oncogenic lesions

Germinal-center activation

AID-mediated Ig gene changes

Occasional off-target DNA lesions

Potential lymphoma driver alteration

MYC::IGH rearrangements and BCL6 alterations as illustrative consequences.

Slide 16 · Clonal evolution is distinct from reactive hyperplasia

Property

Reactive immune proliferation

Neoplastic lymphoid clone

Cell population

Typically polyclonal

Clonal expansion after genetic change

Growth input

Depends on normal immune signals

May be antigen-dependent initially

Evolution

Can regress with resolution

May become autonomous with further lesions

Slide 17 · An antigen-dependent lymphoma may still regress

Chronic antigenic drive

Emergence of a B-cell clone

Dependence on T-cell help

Remove antigen → involution may occur

This is a characteristic early model of extranodal marginal zone lymphoma, not a universal response pattern.

Slide 18 · Later mutations can remove dependence on the stimulus

Early antigen-dependent clone

Additional genetic lesions

Autonomous B-cell survival

Persistence despite stimulus removal

BCL10/MALT1 pathway dysregulation is one route described for extranodal marginal zone lymphoma.

Slide 19 · Inflammation is a risk setting, not a diagnosis

Association

Recognize the tissue-specific clinical link.

Causation

Identify plausible pathways without claiming inevitability.

Diagnosis

Demonstrate a genuine neoplasm; Inflammation alone is insufficient.

Slide 20 · Anatomic context predicts which lymphoma to suspect

Inflammatory site

Persistent stimulus

Associated lymphoid neoplasm

Stomach

Helicobacter gastritis

Extranodal marginal zone B-cell lymphoma

Small intestine

Gluten-sensitive enteropathy

Enteropathy-associated T-cell lymphoma

Breast implant setting

Implant-associated chronic inflammation (possible link)

Implant-associated anaplastic large cell lymphoma

Slide 21 · H. Pylori gastritis: The prototype of local lymphomagenesis

Underlying setting

Chronic gastric infection provides sustained antigenic stimulation.

The normal stomach lacks organized MALT.

Inflammation can induce mucosal lymphoid aggregates.

Lymphoma relationship

Gastric extranodal marginal zone B-cell lymphoma is strongly linked to this setting.

Most gastric MALT lymphomas occur with H. Pylori infection.

Localized disease can retain dependence on the stimulus.

Slide 22 · The inflamed stomach acquires organized lymphoid tissue

H. Pylori–driven gastritis

Mucosal lymphocyte recruitment

Acquired lymphoid follicles

Potential setting for B-cell clonal expansion

The appearance of acquired MALT does not by itself establish lymphoma.

Slide 23 · Gastric MALT lymphoma arises from a B-cell compartment

Cell lineage

Extranodal marginal zone lymphoma is a mature B-cell tumor.

Most show somatic hypermutation.

A memory B-cell origin is considered likely.

Anatomic behavior

Often arises in tissues involved by chronic inflammation.

May remain localized for extended periods.

Systemic dissemination may occur later.

Slide 24 · Polyclonal-to-monoclonal evolution: An instructive model

I. Reactive

Antigen-driven polyclonal response

II. Emerging clone

Early genetic alteration; Still antigen-dependent

III. Autonomous

Acquired survival pathway activation

IV. Progression

Possible spread or aggressive transformation

Slide 25 · The MALT microenvironment can sustain a lymphoma clone

Microbial antigen

T-helper cell activation

B-cell stimulation

Growth and survival of early MALT clone

The first neoplastic clone need not be immediately antigen-independent.

Slide 26 · Gastric MALT lymphoma: Characteristic tissue pattern

Microscopic observations

Dense lymphocytic infiltration of lamina propria.

Neoplastic cells infiltrate gastric glands.

The resulting gland involvement forms lymphoepithelial lesions.

Additional features

Reactive-appearing B-cell follicles may persist.

Plasmacytic differentiation can occur.

These features must be interpreted in the biopsy context.

Slide 27 · Lymphoepithelial lesions reflect gland infiltration

Gland epithelial cells

Blue circles = infiltrating lymphocytes

Simplified schematic—not a histologic image: Neoplastic lymphocytes infiltrate gastric gland epithelium.

Slide 28 · B-cell markers support the lineage of gastric MALT lymphoma

Characteristic pattern

Expression of B-cell markers CD19 and CD20.

Typically negative for CD5 and CD10.

CD43 expression can occur in a subset.

How the pattern is used

Interpret with the architectural features and clinical setting.

A marker pattern alone does not prove malignancy.

Reactive and neoplastic lymphocytes require integrated assessment.

Slide 29 · Clonality can clarify difficult gastric biopsies

Dense mucosal B-cell infiltrate

Morphology / lymphoepithelial lesions

Light-chain restriction or IGH analysis

Integrated lymphoma diagnosis

Clonality is an ancillary observation, not a substitute for clinicopathologic interpretation.

Slide 30 · NF-κB couples immune-receptor input to B-cell survival

Antigen receptor stimulation

BCL10–MALT1 signaling

NF-κB activation

B-cell growth and survival

In antigen-dependent MALT lymphoma, removal of the stimulus can interrupt this pathway.

Slide 31 · MALT lymphoma can acquire antigen-independent signaling

Genetic lesion

Principal affected product

Teaching implication

T(11;18)

API2::MALT1 fusion

Survival signaling can become autonomous

T(1;14)

BCL10 upregulation

Antigen-receptor pathway activated

T(14;18)

MALT1 upregulation

NF-κB pathway activation

T(3;14)

FOXP1 upregulation

Additional described MALT alteration

Slide 32 · Why H. Pylori eradication may cause lymphoma regression

Stimulus removed

Antigen-dependent T-cell help declines

Early B-cell clone loses survival support

Tumor regression may follow

This response is characteristic of some gastric MALT lymphomas; It is not guaranteed.

Slide 33 · Why eradication may fail despite successful clearance

Pathway autonomy

MALT1/BCL10-related translocations can confer reduced antigen dependence.

Tumor extent

Deeper wall invasion correlates with resistance.

Nodal involvement

Involved nodes correlate with resistance to eradication alone.

Slide 34 · Clonal progression may culminate in aggressive lymphoma

Indolent extranodal MZL

Additional genetic changes

Loss of growth constraints

Possible DLBCL transformation

Further lesions including tumor-suppressor inactivation in transformation.

Slide 35 · Reactive H. Pylori gastritis and MALT lymphoma overlap

Assessment

Reactive inflammation

Gastric MALT lymphoma

Lymphoid infiltrate

Common with chronic gastritis

Often dense and infiltrative

Glands

Inflammatory changes possible

Lymphoepithelial lesions support suspicion

Cell population

Usually reactive / polyclonal

Clonal B-cell population may be shown

Approach

Clinical and histologic context

Morphology + phenotype ± clonality

Slide 36 · Case: Persistent gastric symptoms and an infiltrative biopsy

Clinical vignette

A patient with chronic dyspepsia has H. Pylori gastritis and dense mucosal B-cell infiltrates. Some lymphocytes infiltrate gastric glands.

Question: Which findings favor extranodal marginal zone lymphoma over uncomplicated reactive gastritis?

Interpretation: Lymphoepithelial lesions, a compatible B-cell phenotype and—when needed—evidence of a clonal B-cell population.

Slide 37 · Autoimmune inflammation can similarly create acquired MALT

Salivary gland

Sjögren syndrome produces persistent autoimmune inflammation.

Extranodal marginal zone lymphoma may arise in involved salivary tissue.

Thyroid gland

Hashimoto thyroiditis creates sustained immune infiltration.

Extranodal marginal zone lymphoma can develop within the affected thyroid.

Slide 38 · The autoimmune example reinforces site specificity

Organ-directed autoimmunity

Chronic B- and T-cell aggregates

Persistent local survival signals

Possible extranodal B-cell lymphoma

This is a predisposition model, not evidence that every lymphoid aggregate is premalignant.

Slide 39 · Celiac disease creates a different lymphoma-prone compartment

Underlying immune enteropathy

Gluten-driven response occurs in genetically susceptible hosts.

Mucosal injury and lymphocyte recruitment persist during active disease.

Intraepithelial cytotoxic T cells are prominent.

Lymphoma link

Associated neoplasm is enteropathy-associated T-cell lymphoma.

The target lineage differs from H. Pylori–linked gastric MALT lymphoma.

The relevant tissue is small intestinal mucosa.

Slide 40 · Celiac immune activation is anatomically organized

Gluten peptide processing

HLA-DQ2/DQ8 presentation

CD4 T-cell response + IL-15

Intraepithelial cytotoxic T-cell activation

This is the immune injury context described in the supplied gastrointestinal chapter.

Slide 41 · Celiac disease produces recognizable mucosal injury

Intraepithelial lymphocytes

Expanded epithelial cytotoxic T-cell compartment.

Crypt hyperplasia

Proliferative epithelial response to injury.

Villous atrophy

Reduced absorptive surface in active disease.

Slide 42 · Villus, crypt and intraepithelial cell changes

Normal mucosal profile

Celiac-pattern injury

Long villi / short crypts

Short villi / longer crypts / IELs

Schematic comparison only: Normal villus/crypt organization versus celiac-pattern villous shortening and crypt hyperplasia.

Slide 43 · Enteropathy-associated T-cell lymphoma emerges from the IEL compartment

Cell of origin

An aggressive lymphoma of intraepithelial T lymphocytes.

Occurs with elevated frequency in celiac disease.

Links epithelial immune injury to malignant T-cell expansion.

Clinical significance

New symptoms can reflect refractory disease or neoplasia.

Persistent abdominal pain, diarrhea or weight loss warrant attention.

The diagnosis requires separate evaluation, not celiac history alone.

Slide 44 · Persistent symptoms on a gluten-free diet are a warning

Established celiac disease

Symptoms despite strict diet

Consider refractory sprue

Evaluate for associated malignancy

Refractory sprue as a possible precursor state to T-cell lymphoma.

Slide 45 · Reactive enteropathy and T-cell lymphoma are not synonymous

Issue

Active celiac disease

Associated T-cell lymphoma

Process

Gluten-triggered immune injury

Neoplastic T-cell population

Biopsy context

IEL increase, crypt hyperplasia, villous atrophy

Requires evaluation for malignant lymphoid infiltration

Symptoms

Malabsorption-related symptoms

Can arise with persistent / renewed symptoms

Clinical decision

Manage and assess enteropathy

Investigate possible lymphoma or refractory sprue

Slide 46 · Case: Clinical deterioration despite dietary exclusion

Clinical vignette

A person with established celiac disease reports progressive abdominal pain, diarrhea and weight loss despite a strict gluten-free diet.

Question: Which two processes must be considered in the differential?

Interpretation: Refractory sprue and enteropathy-associated T-cell lymphoma; Persistent symptoms alone do not establish either diagnosis.

Slide 47 · Implant-associated lymphoma is another localized association

Named entity

Breast implant–associated anaplastic large cell lymphoma.

An unusual T-cell lymphoma linked to the implant setting.

A localized chronic inflammatory milieu is considered a possible factor.

Evidence boundary

The supplied source states an association and a possible mechanism.

It does not establish a single definitive inflammatory pathway.

Do not infer incidence, implant-type risk, or diagnostic criteria from this passage.

Slide 48 · Distinguish plausible pathogenesis from confirmed findings

Claim

What the supplied Robbins text supports

Implant association

A rare T-cell lymphoma can arise in association with breast implants.

Inflammatory mechanism

Chronic inflammation is a plausible contributor.

Precise causal pathway

Not established in the cited text.

Clinical specifics

Require dedicated, independently verified sources.

Slide 49 · Three local examples involve different lymphoid populations

Clinical setting

Principal immune compartment

Linked neoplasm

H. Pylori gastritis

Acquired mucosal B-cell aggregates

Gastric marginal zone B-cell lymphoma

Celiac disease

Intestinal intraepithelial T cells

Enteropathy-associated T-cell lymphoma

Breast implant setting

Local T-cell–associated process

Implant-associated ALCL

Slide 50 · HIV is a contrast: Dysregulation is systemic

Localized inflammatory model

Tumors tend to develop at the chronically inflamed site.

Examples: Gastric mucosa and small intestine.

Ongoing tissue antigenic stimulation is prominent.

HIV-associated lymphoma risk

B-cell lymphomas may arise in almost any organ.

Early germinal-center dysregulation and later T-cell deficiency contribute.

Virus-associated lymphomas are particularly relevant in AIDS.

Slide 51 · Early HIV disease perturbs germinal-center B cells

HIV T-cell dysregulation

Systemic GC B-cell hyperplasia

Greater opportunities for B-cell neoplasia

Increased GC B-cell lymphoma incidence

This is the early-phase mechanism explicitly Chapter 13.

Slide 52 · Advanced HIV disease adds impaired immune control

Progressive CD4 T-cell loss

Severe T-cell immunodeficiency

Reduced control of oncogenic viruses

Higher risk of certain B-cell lymphomas

Robbins particularly links AIDS-associated lymphomas to EBV and KSHV/HHV8.

Slide 53 · EBV and KSHV/HHV8 have distinct lymphoid associations

Epstein–Barr virus

Present in many B-cell lymphomas in T-cell deficiency.

Also implicated in subsets of Burkitt and Hodgkin lymphoma.

Its frequency varies with the lymphoma setting.

KSHV / HHV8

Associated with an unusual effusion-forming B-cell lymphoma.

Its importance rises in severe immune dysfunction.

Not interchangeable with the H. Pylori antigen-driven model.

Slide 54 · Anatomic distribution helps separate two risk patterns

Question

Localized inflammation

HIV-associated immune deficiency

Where is the driver?

At a chronically injured tissue site

Throughout immune system

Where does lymphoma arise?

Typically in or near affected tissue

Potentially at many extranodal sites

What additional biology matters?

Antigen dependence and later mutations

T-cell dysregulation and oncogenic viruses

Slide 55 · One conceptual framework connects distinct mechanisms

Initiation

Persistent immune perturbation

Promotion

Repeated proliferation and survival

Selection

Acquisition of transforming genetic changes

Progression

Antigen independence / dissemination in some tumors

Slide 56 · B-cell and T-cell examples must not be conflated

B-cell pathway

H. Pylori-associated gastric MALT lymphoma.

Autoimmune-associated extranodal marginal zone lymphoma.

HIV-associated systemic B-cell lymphoma risk.

T-cell pathway

Celiac-associated enteropathy T-cell lymphoma.

Breast implant–associated anaplastic large cell lymphoma.

Different lineages imply different diagnostic workups.

Slide 57 · Diagnostic assessment begins with setting and tissue

Identify persistent stimulus

Locate affected tissue

Assess morphology and lineage

Use targeted ancillary tests

Source-based examples include gastric B-cell clonality testing and evaluation of abnormal small-intestinal T-cell disease.

Slide 58 · A multidisciplinary interpretation avoids shortcuts

Clinical history

Infection, immune enteropathy, autoimmunity or immune deficiency.

Pathologic pattern

Reactive architecture versus destructive or atypical infiltrate.

Ancillary evidence

Immunophenotype, clonality and relevant pathogen testing where indicated.

Slide 59 · Case synthesis: What predicts possible eradication response?

Clinical vignette

A gastric extranodal marginal zone lymphoma is discovered with H. Pylori infection. The clinical team considers pathogen eradication as the first intervention.

Question: What underlying biologic property explains a potential regression, and what could prevent it?

Interpretation: Antigen-dependent growth can regress when the stimulus is removed; Autonomy-associated genetic lesions and greater tumor extent correlate with resistance.

Slide 60 · Case synthesis: Widespread lymphoma risk in AIDS

Clinical vignette

A patient with advanced HIV infection develops a new extranodal mass; No localized chronic inflammatory lesion is identified at that site.

Question: Does the absence of a local H. Pylori-like stimulus exclude lymphomagenesis related to HIV?

Interpretation: No. Severe T-cell immunodeficiency allows B-cell lymphomas, including some EBV- and KSHV/HHV8-associated tumors, to arise in many organs.

Slide 61 · Clinical translation: Remove drivers; Investigate autonomy

Potentially modifiable drivers

H. Pylori clearance may remove growth input from an early gastric MALT clone.

Recognition and management of gluten-sensitive enteropathy addresses ongoing mucosal injury.

When a clone persists

Reassess tumor extent, tissue architecture and clonal biology.

Antigen-independent lesions explain why trigger removal is not uniformly curative.

Persistent or new symptoms require appropriate evaluation.

Slide 62 · Integrated concepts to retain

Localized, persistent immune reactions may predispose to lymphomas arising within the affected tissue.

Inflammatory proliferation and mutations cooperate; Neither chronic inflammation nor clonality alone defines every outcome.

Early gastric MALT lymphoma may remain antigen-dependent; BCL10/MALT1-linked lesions can confer autonomy.

Celiac disease predisposes to intestinal T-cell lymphoma, whereas HIV-associated risk reflects systemic immune dysregulation.

Slide 63 · Primary textbook sources

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. Chapter 13: White cell neoplasia and marginal zone lymphomas.

Chapter 3: Chronic inflammation and morphologic features.

Chapter 7: Acquired cancer predisposition and inflammation-associated carcinogenesis.

Chapter 17: Gastric MALT lymphoma and celiac disease.

Chapter 23: Breast implant–associated anaplastic large cell lymphoma.