Nodal T Follicular Helper Cell Lymphoma

Slide 1 · Nodal T-follicular helper cell lymphoma

Biology, morphology, immune dysregulation, and integrated diagnosis

From normal follicular help to a complex nodal malignancy

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Explain how T-follicular helper cells support germinal-centre B-cell maturation.

Relate clonal hematopoiesis, somatic mutations, and EBV-positive B-cell proliferations.

Recognize the architectural and immunophenotypic spectrum of nodal TFH lymphoma.

Integrate morphology, lineage, TFH phenotype, EBER, and molecular findings in differential diagnosis.

Scope

Robbins: Core disease biology and clinicopathology

WHO-HAEM5 and pathology reviews: Specified supplementary detail

Slide 3 · Disease identity in one diagnostic chain

Mature T-cell neoplasm

CD4⁺ TFH differentiation

Altered nodal microenvironment

Immune dysregulation

Cell lineage, architecture, and immune phenomena belong to the same disease process.

Avoid diagnosing the lymphoma from one isolated stain or viral result.

Slide 4 · Normal TFH cell versus malignant TFH cell

Physiological TFH cell

Germinal-centre localization

Support for B-cell selection and maturation

Coordinated antibody response

Nodal TFH lymphoma

Clonal expansion of TFH-phenotype T cells

Deranged B-cell support and stromal organization

Autoimmune and EBV-associated B-cell phenomena

The function of the cell of origin explains part of the clinical syndrome.

Slide 5 · Normal germinal-centre cooperation

Antigen-experienced B cell

TFH–B-cell interaction

B-cell selection and maturation

Plasma / memory B cells

TFH cells support the production of high-affinity antibodies.

Abnormal TFH activity can disturb output from this response.

Slide 6 · Where normal TFH cells operate

TFH cells home to the germinal centres of secondary lymphoid tissue.

Their main partner is the germinal-centre B cell.

TFH input influences B-cell expansion, selection, and differentiation.

Pathology link

A lymphoma derived from these cells can reshape nodal follicular architecture.

The immune phenotype preserves clues to this normal programme.

Slide 7 · TFH homing and marker logic

CD4 helper lineage

CXCR5 expression

Follicular localization

TFH–B-cell interaction

CXCR5 supports follicular positioning.

BCL6, PD-1, ICOS, CXCL13, and CD10 are used to identify TFH differentiation in tissue.

Slide 8 · Markers: Role versus interpretation

Marker

Biological / diagnostic role

Interpretive caution

CD4

Helper T-cell lineage

Not specific for TFH lymphoma

PD-1 / ICOS

TFH-associated phenotype

Reactive TFH cells also express them

CXCL13 / CXCR5

Follicular chemokine axis

Context and localization matter

CD10 / BCL6

Additional TFH differentiation clues

Not lineage-specific alone

Slide 9 · T-cell lineage is not the same as TFH lineage

Establish T-cell identity

Morphology and T-lineage markers

CD3 with contextual pan-T markers

Exclude a dominant B-cell neoplasm

Establish TFH differentiation

Assess several TFH markers

Localize staining to the atypical T cells

Interpret with architecture and clinical setting

A broad TFH panel is not a replacement for demonstrating neoplastic T-cell lineage.

Slide 10 · From TFH function to immune symptoms

Neoplastic TFH population

Disturbed B-cell maturation

Excess / altered immunoglobulins

Autoantibodies and cytopenias

Robbins explicitly links TFH dysfunction with hypergammaglobulinemia and autoimmune cytopenias.

Clinical findings help connect apparently disparate tissue and laboratory observations.

Slide 11 · Immune dysregulation is a defining association

Hypergammaglobulinemia can accompany abnormal germinal-centre activity.

Autoantibodies may develop in the setting of altered B-cell selection.

Autoimmune cytopenias can accompany the lymphoma.

Some clinical findings arise from immune dysfunction rather than direct tissue infiltration.

Diagnostic implication

A lymphadenopathy-plus-autoimmunity presentation is compatible with this disease spectrum.

Slide 12 · What hypergammaglobulinemia does not prove

Supportive clinical clue

Immunoglobulin excess fits TFH-driven immune disturbance.

May accompany multiple inflammatory or neoplastic states.

Not a diagnostic criterion alone

Does not establish the malignant cell lineage.

Does not replace node morphology and phenotyping.

Separate clinical association from tissue diagnosis.

Slide 13 · Inflammatory symptoms have several contributors

Neoplastic T cells

Immune dysregulation

Inflammatory milieu

Systemic symptoms / infections

Symptoms associated with immune abnormalities, infection, or inflammatory cytokines.

Do not attribute every symptom to a single unverified cytokine.

Slide 14 · Presentation: Look beyond lymph-node size

Lymphadenopathy is a common presenting feature.

Immune abnormalities may dominate the clinical assessment.

Infection can complicate the presentation.

Inflammatory symptoms may coexist with the tumor burden.

Clinical integration

History, examination, laboratory patterns, and biopsy are interpreted together.

Slide 15 · Typical age group and course

Most patients are older adults.

The natural history is variable; Not every case behaves identically.

Chemotherapy responses are often transient.

That most patients die within five years of diagnosis.

Qualification

This is the textbook’s broad prognostic statement, not an individualized prediction or current trial estimate.

Slide 16 · Three linked pathogenetic compartments

Hematopoietic stem cell

Neoplastic TFH cell

Nodal stromal compartment

B-cell / EBV expansion

Early mutations may appear across hematopoietic lineages.

Tumor-related immune disturbance and B-cell proliferations coexist within the same node.

Slide 17 · Clonal hematopoiesis: Concept

A hematopoietic stem / progenitor clone acquires somatic mutations.

Its descendants may populate more than one blood-cell lineage.

The presence of the same alteration in separate lineages can reveal a shared ancestral clone.

Core distinction

A shared ancestral mutation does not make mature T and B tumor cells the same cell type.

Slide 18 · Shared TET2 and DNMT3A mutations

Mutated hematopoietic stem cell

Myeloid descendants

Mature T-cell descendants

TFH lymphoma clone

Matching TET2 / DNMT3A mutations in tumor T cells and differentiated myeloid cells.

This supports—but does not directly prove in every patient—an early stem-cell origin.

Slide 19 · Early and later genetic events

Event class

Examples

Interpretation

Early shared clone

TET2; DNMT3A

Can be present in hematopoietic progenitors and myeloid cells

T-cell–restricted later events

RHOA G17V; IDH2 R172

Frequently associated with evolved neoplastic TFH clone

TCR signalling lesions

CD28 / related pathway abnormalities

Additional signalling dysregulation; Heterogeneous

Slide 20 · TET2: Mutation context matters

TET2 is frequently altered in nodal TFH lymphoma.

The same alteration can occur in clonal hematopoiesis.

TET2 positivity on tumor sequencing alone does not identify a unique disease subtype.

Paired lineage analysis can clarify whether a mutation predates transformation.

Pitfall

Do not interpret a TET2 mutation as lymphoma-specific without context.

Slide 21 · DNMT3A: A shared ancestral signal

DNMT3A is another commonly altered gene account.

Mutant DNMT3A can be detected in tumor and myeloid descendants.

A shared mutation supports clonal ancestry across differentiated lineages.

Mechanistic significance

Genetic kinship can coexist with distinct T-cell and B-cell malignant phenotypes.

Slide 22 · Multistep model of transformation

Clonal hematopoiesis

Acquisition of T-cell lesions

TFH lineage outgrowth

Clinically manifest lymphoma

WHO-HAEM5 reviews describe stepwise genetics, not one sufficient mutation.

The graphic is conceptual; It does not imply a fixed sequence for each patient.

Slide 23 · RHOA and IDH2 in the molecular landscape

RHOA G17V and IDH2 R172 are recurrent TFH-lymphoma–associated alterations in published classifications.

Unlike early shared TET2 / DNMT3A lesions, they may be concentrated in neoplastic T cells.

Mutation testing can support classification but cannot replace phenotype and morphology.

Interpretive discipline

Absence of a recurrent mutation does not exclude nodal TFH lymphoma.

Slide 24 · Molecular clonality versus tumor identity

Shared ancestral clone

Early mutations can occur in T, myeloid, and sometimes B cells.

Explains apparent cross-lineage relatedness.

Distinct mature neoplasms

T-cell lymphoma remains a T-lineage neoplasm.

A secondary B-cell lymphoma requires separate morphologic and phenotypic classification.

Common origin is not interchangeable lineage.

Slide 25 · Why EBV-positive B cells accumulate

TFH lymphoma / altered immunity

Impaired adaptive regulation

Expansion of EBV-positive B cells

Possible overt B-cell lymphoma

Increased EBV-positive B cells and occasional secondary EBV-positive B-cell lymphoma.

The exact cause of expansion is not fully established.

Slide 26 · EBV-associated B cells: Critical distinction

The neoplastic TFH compartment is of T-cell lineage.

EBER-positive cells in the involved node are often B-lineage immunoblasts.

The number and cytology of B cells may vary among cases.

An expanded B population should be evaluated for a separate B-cell lymphoma.

Major diagnostic trap

EBER positivity in a node does not establish an EBV-driven T-cell lymphoma.

Slide 27 · EBV-positive immunoblasts versus overt B-cell lymphoma

Associated EBV⁺ B-cell expansion

Often part of the nodal microenvironment.

Requires attention to B-cell distribution and atypia.

Possible secondary B-cell lymphoma

Distinct destructive B-cell population may emerge.

Apply full B-lineage workup and classification.

Do not label every EBER-positive immunoblast as a second lymphoma.

Slide 28 · Two hematologic tumors can share early mutations

TET2 / DNMT3A-mutant ancestor

TFH lymphoma

EBV-positive B-cell expansion

Occasional EBV⁺ B-cell lymphoma

Robbins documents some paired tumors with common TET2 / DNMT3A alterations.

Shared early mutations are evidence of an ancestral clone—not proof of identical final drivers.

Slide 29 · Nodal architecture: What to assess first

Is the normal follicular/paracortical arrangement preserved, distorted, or effaced?

Is growth follicular, vaguely nodular, interfollicular, or diffuse?

Are vessels conspicuous and is the dendritic meshwork expanded?

Where are atypical T cells positioned relative to follicles and vessels?

Sampling

Architectural analysis is better supported by excision than limited core tissue.

Slide 30 · Normal versus altered nodal organization

Organized node

Altered node

Change in nodal geography reflects the interplay of tumor cells, follicles, vessels, and stroma.

Original schematic — not a histologic section

Slide 31 · Angioimmunoblastic-type architecture

A diffuse or paracortical polymorphous infiltrate can efface the node.

Atypical T cells may be inconspicuous among reactive populations.

Branching high endothelial venules are a recognized clue.

Expanded follicular dendritic cell networks can envelop vascular structures.

Microscopy objective

Search for the vascular–stromal pattern, not only individual tumor-cell atypia.

Slide 32 · Vessels and dendritic-cell networks

High endothelial venule (HEV)

Expanded FDC meshwork

HEV

FDC markers (CD21 / CD23) visualize stromal networks; They are not the neoplastic T-cell markers.

Original schematic: HEV surrounded by expanded FDC network; Not a micrograph

Slide 33 · The infiltrate may look deceptively reactive

Small and medium-sized atypical T cells may be admixed with inflammatory cells.

Reactive B cells and immunoblasts can be prominent.

The tumor compartment may be less abundant than the accompanying reactive infiltrate.

Atypia and polyclonality must be evaluated in the relevant cell lineage.

Diagnostic risk

Reactive cellular diversity does not exclude an underlying neoplastic T-cell clone.

Slide 34 · Three WHO-HAEM5 morphologic categories

Angioimmunoblastic / follicular

Angioimmunoblastic: Vascular / FDC expansion, polymorphous infiltrate

Follicular: Tumor T cells populate nodules / follicles

Not otherwise specified

TFH phenotype with neither defining pattern

Often diffuse and variably tumor-cell-rich

These are morphologic categories inside a shared TFH-lymphoma family.

Slide 35 · Angioimmunoblastic type: Characteristic triad

Polymorphous lymphoid and inflammatory infiltrate.

Proliferation of arborizing high endothelial venules.

Expanded extrafollicular follicular dendritic cell meshworks.

TFH-phenotype neoplastic T cells support the integrated diagnosis.

Qualification

Features vary by pattern and tissue sample; The classic triad is not invariably conspicuous.

Slide 36 · Follicular-type tumor distribution

Red cells: Atypical TFH-phenotype T cells clustered within follicles / nodules.

A follicular pattern can belong to a T-cell lymphoma; Establish the lineage of the cells inside the follicles.

Original schematic: TFH-phenotype tumor cells centered in nodules; Not a micrograph

Slide 37 · Follicular type can mimic a B-cell lymphoma

Neoplastic T cells may accumulate within follicular structures.

An apparent follicular growth pattern does not establish B-cell lineage.

CD3 / CD4 and TFH-marker localization distinguish lesional T cells from resident B cells.

Native B-cell follicles can be distorted or displaced.

Practical approach

Determine which cell population actually constitutes the follicular lesion.

Slide 38 · Nodal TFH lymphoma, NOS

TFH-phenotype nodal T-cell lymphoma without defining angioimmunoblastic or follicular architecture.

May demonstrate a diffuse population of variably atypical T cells.

Should not be confused with generic PTCL-NOS.

Classification is challenging when architecture is limited.

Case selection

Use an integrated diagnosis; Avoid false precision in small biopsies.

Slide 39 · Excision versus core needle sample

Excision: Strongest architecture

Follicular, interfollicular, and diffuse relationships

HEV and FDC distribution

Spatial relationships among T and B cells

Core: Often adequate for phenotype

Lineage and multi-marker immunophenotype

Some molecular / EBER information

Subtype architecture may remain indeterminate

WHO reviews advise caution when assigning morphologic subtype on limited tissue.

Slide 40 · A practical immunohistochemistry panel

Question

Markers / methods

What is established

T or B lineage?

CD3, CD20 / PAX5

Separate abnormal T and B compartments

TFH differentiation?

PD-1, ICOS, CXCL13, CD10, BCL6

Composite TFH phenotype

Expanded FDC meshwork?

CD21 / CD23

Anatomic stromal pattern

EBV distribution?

EBER in situ hybridization

Which cells harbour EBV?

Slide 41 · TFH phenotype requires more than a single stain

WHO-HAEM5 defines the typical phenotype using CD4 and at least two TFH markers.

Many expert reviews recommend a broad TFH panel for improved specificity.

Interpret actual tumor-cell staining rather than nearby reactive follicles.

No universal positivity threshold solves every borderline case.

WHO-HAEM5

Markers support—not substitute for—clinical, morphologic, and lineage assessment.

Slide 42 · TFH markers have different limitations

Marker

Useful clue

Important caveat

PD-1

Often strong TFH-associated signal

Reactive TFH cells can stain

ICOS

TFH-associated co-stimulation

Not completely specific

CXCL13

Tissue TFH-associated chemokine

Distribution and technical factors matter

CD10 / BCL6

Additional TFH evidence

Also expressed in germinal-centre B cells

Slide 43 · CD21 and CD23 interrogate architecture

They highlight follicular dendritic cell meshworks rather than neoplastic T cells.

Extrafollicular expansion and association with vessels support angioimmunoblastic morphology.

The absence of a striking meshwork on a limited sample does not exclude TFH lymphoma.

Interpretation

Keep stromal markers conceptually distinct from tumor-lineage markers.

Slide 44 · EBER: Always assign positivity to a cell lineage

EBER demonstrates EBV-infected cells within the specimen.

Correlate stained cells with B-lineage markers and cell morphology.

Scattered EBV-positive B cells fit the documented disease microenvironment.

Widespread EBER positivity in neoplastic T / NK cells raises a different differential.

Critical distinction

EBV detection is not the same as proving EBV is the transforming driver of the T-cell clone.

Slide 45 · Integrated diagnostic workflow

Assess architecture + cytology

Establish neoplastic T-lineage

Document TFH phenotype

Evaluate FDC, EBV and B cells

Correlate clonality / genetics

Assign a morphologic subtype when sufficiently supported.

Maintain a broader family-level designation if sampling prevents reliable subtyping.

Slide 46 · Clonality is an adjunct, not a shortcut

What TCR testing can contribute

Support a clonal T-cell population in equivocal cases.

Complement morphology and immunophenotype.

What it cannot establish alone

Not every T-cell clone is lymphoma.

Does not distinguish TFH subtype.

Does not identify the reactive B-cell compartment.

TCR rearrangement testing for difficult PTCL–reactive differentials.

Slide 47 · Differential: What to discriminate

Competing diagnosis

Shared appearance

Discriminating investigation

PTCL, NOS

Nodal atypical T-cell infiltrate

Coherent TFH phenotype and architecture

Reactive hyperplasia

TFH-positive reactive follicles

Architectural preservation, cell atypia, integration

Follicular B-cell lymphoma

Follicular / nodular proliferation

Tumor-cell CD20 / PAX5 vs CD3 / TFH

Classic Hodgkin lymphoma

EBV⁺/CD30⁺ large B cells

Identify neoplastic compartment and background TFH cells

Slide 48 · Distinguish from peripheral T-cell lymphoma, NOS

PTCL-NOS is an exclusion category for other mature T-cell neoplasms.

Its morphology may overlap with tumor-cell-rich TFH lymphoma.

Assess multiple TFH markers and nodal architecture.

Classification should be conservative when evidence of TFH derivation is marginal.

Pitfall

PD-1 or ICOS positivity alone can be misleading.

Slide 49 · Distinguish from florid reactive lymphadenopathy

Reactive germinal centres contain normal TFH cells expressing several relevant markers.

Malignancy requires a convincing atypical T-cell population and pattern.

Examine cytology, architecture, immunophenotype, clinical course, and clonality together.

Key question

Are the stained TFH cells the atypical lesional population or a normal immune compartment?

Slide 50 · Distinguish from classic Hodgkin lymphoma

EBV-positive large B-cell immunoblasts may resemble Hodgkin-like cells.

TFH lymphoma can produce a prominent immunologic background.

Determine whether the defining tumor is T lineage, B lineage, or two neoplasms.

Use a proportionate B-cell / Hodgkin workup when large atypical cells are present.

Misclassification hazard

Do not let scattered CD30-positive B immunoblasts obscure the T-cell lymphoma.

Slide 51 · Distinguish from follicular B-cell lymphoma

A follicular pattern can be created by TFH-phenotype neoplastic T cells.

Use lineage markers to identify the cells within nodules.

BCL6 and CD10 cannot assign B lineage without CD20 / PAX5 and localization.

Take-home

Follicular architecture and germinal-centre markers are not lineage-specific.

Slide 52 · Distinguish EBV-positive nodal T/NK lymphoma

EBER-positive B immunoblasts are a recognized associated population in TFH lymphoma.

An EBV-driven T / NK neoplasm is a different diagnostic consideration.

The crucial first step is mapping EBER positivity to the malignant lineage.

Avoid an attribution error

Do not infer that tumor T cells contain EBV from an EBER-positive node.

Slide 53 · Clinical-laboratory correlation matrix

Finding

Pathobiologic interpretation

Diagnostic weight

Generalized adenopathy

Nodal lymphomatous involvement

Prompts tissue assessment

Hypergammaglobulinemia

Deranged TFH–B-cell help

Supportive; Nonspecific

Autoimmune cytopenias

Immune-system dysregulation

Supportive; Not subtype-specific

Infection / inflammatory symptoms

Altered adaptive immunity, inflammation

Explains clinical heterogeneity

Slide 54 · Specimen-level questions for the pathologist

What is the atypical cell?

Where is it located?

Which markers co-localize?

Is there a second B-cell clone?

These four questions prevent several common misinterpretations.

EBER, TFH stains, and FDC stains are interpreted in distinct cell compartments.

Slide 55 · Case 1: Lymphadenopathy with immune abnormalities

An older adult presents with generalized lymphadenopathy, hypergammaglobulinemia, and autoimmune hemolytic anemia. Biopsy shows atypical CD4⁺ T cells with multiple TFH markers.

What pathogenetic connection unifies the clinical and tissue findings?

Neoplastic TFH activity deranges germinal-centre B-cell function and favors abnormal antibody production.

Interpretive answer

Slide 56 · Case 2: EBER-positive cells in the node

A node contains atypical CD4⁺ T cells, expanded FDC meshworks, and scattered EBER-positive CD20⁺ immunoblasts.

Which compartment is most likely EBV-positive?

The associated B-cell immunoblasts. Their presence does not by itself establish EBV infection of tumor T cells.

Interpretive answer

Slide 57 · Case 3: Shared mutation across lineages

Sequencing identifies the same TET2 mutation in sorted tumor T cells and peripheral-blood monocytes.

What does this pattern support?

An early mutated hematopoietic progenitor contributing to both mature cell lineages; It does not make monocytes malignant T cells.

Interpretive answer

Slide 58 · Case 4: A deceptively follicular lymphoma

The lymph node contains nodules populated largely by CD3⁺ CD4⁺ PD-1⁺ CD10⁺ atypical lymphocytes; Scattered CD20⁺ B cells remain.

What is the decisive next interpretive step?

Recognize that the lesional follicular cells are T lineage; Evaluate nodal TFH lymphoma, follicular type.

Interpretive answer

Slide 59 · Case 5: Limited core biopsy

A core shows CD4⁺ atypical T cells coexpressing several TFH markers. There is insufficient tissue to assess full nodal pattern.

Should a precise morphologic TFH subtype be imposed?

No. A family-level nodal TFH lymphoma designation may be safer when architecture is inadequate.

Interpretive answer

Slide 60 · Case 6: A second abnormal B-cell population

Previously diagnosed TFH lymphoma is followed by an enlarged node with a destructive sheet of EBV-positive B cells.

What diagnostic possibility must be assessed separately?

A secondary EBV-positive B-cell lymphoma, rather than assuming simple reactive EBV-positive immunoblast expansion.

Interpretive answer

Slide 61 · Diagnostic synthesis across three compartments

Compartment

Core finding

Role in final report

Neoplastic T cells

CD4 and multiple TFH-associated markers

Establish lymphomatous lineage and differentiation

Nodal stroma

Vessel / FDC pattern

Supports architecture and subtype

B-cell background

EBV-positive B cells ± overt B-cell neoplasm

Identifies associated proliferation or a second tumor

Slide 62 · Why no single test is decisive

Morphology can be masked by a polymorphous reactive background.

TFH-associated markers also occur in benign follicular helper cells.

TET2 / DNMT3A mutations may predate the malignancy.

EBER may label associated B cells instead of the tumor clone.

Integrated diagnosis

The disease is recognized through concordance among several imperfect evidence streams.

Slide 63 · Risk, diagnosis, and prognosis are different claims

What supports diagnosis

Characteristic T-cell phenotype

Appropriate nodal architecture

Exclusion of competing lineages

What informs clinical discussion

Immune complications and concurrent neoplasms

Variable and often aggressive clinical course

Response assessed with clinical context

Do not reclassify diagnostic markers as validated prognostic or predictive biomarkers.

Slide 64 · Prognosis: Communicate uncertainty correctly

Variable outcomes with frequently transient chemotherapy responses.

The historical textbook summary reports poor overall long-term survival.

Prediction for an individual patient requires clinical staging, fitness, treatment, and broader context.

Do not extrapolate a single molecular mutation into an established individual prognosis.

Source discipline

No invented treatment effect sizes, survival curves, or patient-level forecasts.

Slide 65 · Whole-case diagnostic model

Clinical syndrome

Biopsy architecture

T-cell / TFH markers

EBV–B-cell analysis

Molecular integration

Each layer can corroborate or challenge the preceding interpretation.

A discrepant result should trigger review, not automatic override.

Slide 66 · Five concepts to retain

Nodal TFH lymphoma is a mature T-cell neoplasm related to germinal-centre helper function.

Immune dysregulation is integral to its biology and presentation.

TET2 / DNMT3A can connect lymphoma with clonal hematopoiesis.

EBV-positive B cells may coexist and sometimes progress to a second B-cell malignancy.

Diagnosis requires integrated T-cell phenotype, architecture, and compartment-aware interpretation.

Synthesis

Disease biology, not one stain, unifies the classification.

Slide 67 · Selected scientific sources

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. (2026), Chapter 13, p. 550.

WHO Classification of Haematolymphoid Tumours, 5th edition: lymphoid neoplasms framework (2022).

Marques-Piubelli ML, Amador C, Vega F. Frontiers in Oncology. 2023;13:1105651.

Alaggio R et al. Leukemia. 2022;36:1720–1748. DOI: 10.1038/s41375-022-01620-2.

Modern Pathology. 2024;37:100512. Mature T-cell, NK-cell and stroma-derived neoplasms.