Peripheral T and NK Cell Neoplasms

Slide 1 · Peripheral T- and NK-Cell Neoplasms

Mature T-cell and natural killer-cell lymphoid malignancies

Morphology • immunophenotype • mechanisms • clinicopathologic reasoning

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Distinguish mature T-cell from NK-cell neoplasms using lineage, site, and phenotype.

Recognize the morphologic and clinical profile of PTCL-NOS.

Explain Tfh-associated immune dysregulation, ALK signaling, and HTLV-1 oncogenesis.

Compare cutaneous, leukemic, and extranodal presentations.

Slide 3 · A heterogeneous mature lymphoid group

These neoplasms resemble mature peripheral T cells or natural killer (NK) cells.

Multiple entities are defined by distinct tissue tropism, phenotype, viral association, or molecular lesions.

A generic diagnosis must not displace a specific entity supported by clinicopathologic evidence.

Slide 4 · Geographic distribution

United States and Europe

Peripheral T-cell tumors represent approximately 5%–10% of non-Hodgkin lymphomas.

NK-cell tumors are distinctly uncommon.

East Asia

Both T- and NK-cell neoplasms occur more frequently.

The basis for this geographic difference is uncertain.

Slide 5 · Cellular lineage establishes the first branch

Mature lymphoid neoplasm

T-cell lineage: CD3 / TCR

NK lineage: NK markers; Usually no surface CD3

Entity-specific morphology and clinical context

Slide 6 · Mature T cells and NK cells

Peripheral T cells

Rearranged T-cell receptor genes.

Typical T-lineage antigens include CD2, CD3 and CD5.

Helper or cytotoxic subsets may express CD4 or CD8.

Natural killer cells

Cytotoxic innate lymphocytes; No conventional rearranged TCR.

NK-cell neoplasms may express markers including CD56.

Lineage interpretation uses a panel, not CD56 alone.

Slide 7 · Mature versus precursor T-cell tumors

“Peripheral” refers to a mature/post-thymic T-cell phenotype.

T-lymphoblastic leukemia/lymphoma belongs to precursor lymphoid neoplasms, not this group.

Morphology and differentiation antigens must be interpreted together.

Slide 8 · Tissue distribution guides the differential

Generalized nodes → nodal T-cell lymphoma

Skin → MF / Sézary; Also other subtypes

Blood + cytopenias → T/NK large granular lymphocytic leukemia

Nasal destructive mass → extranodal NK/T-cell lymphoma

Slide 9 · Nodal architecture carries diagnostic information

Diffuse architectural effacement favors an overt infiltrative lymphoma over preserved reactive architecture.

Pleomorphic tumor cells and a conspicuous inflammatory stroma may coexist.

Patterns involving follicles, vessels, sinuses, or skin help prioritize defined entities.

Slide 10 · Integrated diagnostic reasoning

Clinical syndrome / sites

Architecture and cytology

T/NK lineage and subtype markers

Viral or molecular support

Integrated disease assignment

Slide 11 · What each modality contributes

Evidence

Interpretive question

H&E morphology

Is there an abnormal infiltrate; What architecture is altered?

Immunophenotype

Which lineage and differentiation program is represented?

TCR clonality

Is an expanded T-cell clone detectable?

Clinical / virology

Does the distribution or virus association define an entity?

Slide 12 · T-cell clonality: Appropriate role

Clonal T-cell receptor rearrangements can support lymphoma in difficult reactive-versus-neoplastic cases.

TCR analysis does not identify all NK-derived tumors, which usually lack rearranged TCR genes.

A clonal result requires interpretation alongside morphology, immunophenotype, and clinical context.

Slide 13 · Recognizable signatures across the family

Entity

Characteristic association

PTCL-NOS

Pleomorphic nodal T-cell infiltrate; Diagnosis after exclusion

Nodal Tfh lymphoma

Tfh phenotype, immune dysregulation, clonal hematopoiesis

ALCL

CD30-rich anaplastic morphology; ALK rearrangement in subset

Adult T-cell leukemia/lymphoma

HTLV-1 associated CD4+ mature T-cell tumor

Extranodal NK/T lymphoma

EBV association, angiodestruction and necrosis

Slide 14 · PTCL-NOS is a diagnosis of exclusion

Many mature T-cell lymphomas cannot be assigned confidently to a defined subtype.

These cases are designated peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS).

The category is biologically and morphologically heterogeneous; No single feature is pathognomonic.

Slide 15 · Why “NOS” comes late, not early

Confirm malignant mature T-cell process

Assess Tfh, ALCL, cutaneous and leukemic patterns

Evaluate relevant viral and tissue associations

Retain PTCL-NOS when a specific entity is unsupported

Slide 16 · PTCL-NOS: Cytologic heterogeneity

Small cell

Intermediate cell

Large pleomorphic cell

Irregular nuclear contour

Schematic only — not a microscopic specimen

Size heterogeneity is characteristic but not diagnostic.

Illustrated cell shapes are schematic—not a histologic field.

Slide 17 · PTCL-NOS effaces nodal architecture

Lymph nodes are typically replaced by a diffuse malignant T-cell infiltrate.

A full low-power view helps assess loss of normal follicles and sinus structures.

The extent of architectural destruction must be reconciled with the clinical presentation.

Slide 18 · Why the infiltrate looks mixed

Malignant cells vary substantially in size and shape.

Reactive eosinophils, macrophages and other inflammatory cells may be conspicuous.

A polymorphous infiltrate should not be presumed reactive solely because many bystander cells are present.

Slide 19 · Tumor cytokines and the reactive background

Malignant T-cell population

Tumor-derived cytokines (proposed)

Recruitment of eosinophils and macrophages

Prominent reactive inflammatory stroma

Slide 20 · PTCL-NOS may exhibit neoangiogenesis

Brisk formation of new vessels may accompany the infiltrate.

Vascular proliferation can contribute to architectural distortion.

Neither vascularity nor inflammatory background alone is specific for PTCL-NOS.

Slide 21 · T-lineage immunophenotype in PTCL-NOS

Feature

Robbins description

Mature T-cell markers

Usually CD2, CD3 and CD5

T-cell receptor

αβ or γδ receptor expression

Helper / cytotoxic markers

Some tumors express CD4 or CD8

Phenotypic variation

Some tumors do not resemble a recognized normal T-cell subset

Slide 22 · A practical marker hierarchy

Establish T lineage: CD2 / CD3 / CD5

Assess CD4 and CD8 pattern

Characterize TCR phenotype when informative

Investigate competing defined entities

Slide 23 · CD4 and CD8 suggest functional origin

CD4 expression is compatible with a helper T-cell differentiation program.

CD8 expression is compatible with cytotoxic T-cell differentiation.

Some mature T-cell tumors show aberrant or unclassifiable phenotypes.

Slide 24 · T-cell receptors: αβ versus γδ

Normal mature T cells can express αβ or γδ T-cell receptors.

PTCL-NOS may retain either receptor phenotype.

A receptor category does not replace evaluation for other defined mature T-cell entities.

Slide 25 · PTCL-NOS and a reactive lymph node

Concern for lymphoma

Diffuse effacement with atypical pleomorphic T cells.

An abnormal T-cell population and supportive clonality.

Unexplained systemic lymphadenopathy.

Concern for reactivity

Clinical or infectious trigger with reactive architecture.

Heterogeneous activated T cells without a coherent neoplastic pattern.

Results of ancillary tests must be interpreted in context.

Slide 26 · Ancillary work-up when morphology is equivocal

Reassess architecture and distribution

Examine the complete lineage/subtype panel

Consider TCR gene rearrangement study

Integrate molecular and clinical evidence

Slide 27 · Typical clinical presentation of PTCL-NOS

Generalized lymphadenopathy is common.

Pruritus, eosinophilia, fever and weight loss may accompany disease.

Symptoms may reflect inflammatory cytokines as well as tumor burden.

Slide 28 · Symptoms linked to underlying processes

Lymphoma burden

Multiple enlarged nodal groups.

Systemic symptoms such as fever and weight loss.

Reactive and immune effects

Eosinophilia and pruritus.

Macrophage/eosinophil-rich histology supports an inflammatory milieu.

Slide 29 · PTCL-NOS: Prognosis in context

Durable cures can occur.

As a group, peripheral T-cell lymphomas have a worse outcome than comparably aggressive mature B-cell lymphomas.

Prognosis must not be inferred from a single morphologic feature.

Slide 30 · PTCL-NOS and diffuse large B-cell lymphoma

Axis

PTCL-NOS

DLBCL

Lineage

Mature T cell

Mature B cell

Microscopy

Variable pleomorphism; Often reactive admixture

Large B-cell lymphoma phenotype

Ancillary tests

T-cell markers / TCR studies

B-cell markers

Robbins prognosis

Overall less favorable

Comparator mature B-cell lymphoma

Slide 31 · Case: Pleomorphic nodal infiltrate

A patient has generalized lymphadenopathy; Biopsy shows diffuse effacement by irregular, variably sized lymphoid cells. Eosinophils are conspicuous.

Salient evidence

Mature T-cell antigen expression

No defining features for another specific T-cell entity

TCR rearrangement found on ancillary analysis

Peripheral T-cell lymphoma, NOS

A clonally expanded mature T-cell infiltrate with pleomorphism may support PTCL-NOS after exclusion of defined categories.

Slide 32 · PTCL-NOS: Report the evidence, not a shortcut

State architectural pattern and the degree of cytologic atypia.

Summarize mature T-cell phenotype and any aberrancies established by the actual panel.

Record why a more specific mature T-cell lymphoma is or is not supported.

Slide 33 · Tfh cells normally support germinal-center B cells

T-follicular helper (Tfh) cells home to germinal centers.

They promote B-cell expansion and affinity maturation.

Neoplastic distortion of this interaction underlies prominent immune abnormalities.

Slide 34 · Nodal Tfh lymphoma links two compartments

Neoplastic Tfh cell

Disturbed germinal-center B-cell maturation

Hypergammaglobulinemia / autoantibodies

Autoimmune cytopenias and immune dysfunction

Slide 35 · Clonal hematopoiesis is a key Tfh association

Nodal Tfh lymphoma often coexists with clonal hematopoiesis.

TET2 and DNMT3A mutations are found in both settings.

Shared mutations in lymphoma and myeloid cells support origin from an early mutated hematopoietic stem cell.

Slide 36 · Proposed shared precursor in Tfh lymphoma

Mutated hematopoietic stem cell

Myeloid descendants sharing mutations

Tfh-lineage malignant descendant

Occasionally EBV-positive B-cell neoplasm sharing mutations

Slide 37 · Tfh-associated immune dysregulation

Hypergammaglobulinemia may reflect distorted B-cell help.

Autoantibody formation can produce autoimmune cytopenias.

Immune dysfunction can also predispose to infections and EBV-positive B-cell expansions.

Slide 38 · EBV-positive B cells in Tfh lymphoma

Nodal Tfh lymphomas frequently contain increased EBV-positive immunoblasts.

Occasional patients develop overt EBV-positive B-cell lymphoma.

The associated B-cell proliferation should not be mistaken automatically for the malignant T-cell clone.

Slide 39 · Tfh markers: Interpret as a program

Markers

Interpretation

PD-1, CXCL13, CXCR5

Tfh-associated differentiation markers

CD10, BCL6

Additional Tfh-associated markers

CD4

Common neoplastic T-cell phenotype

Follicular dendritic expansion

Supportive architectural context

Slide 40 · Nodal Tfh lymphoma: Architecture

Vaguely nodular or follicular-appearing T-cell aggregates may develop.

Follicular dendritic-cell networks can expand.

Increased vascularity and EBV-positive immunoblasts commonly occupy intervening tissue.

Slide 41 · Nodal Tfh lymphoma: Clinical behavior

Most affected patients are older adults and present with lymphadenopathy.

Clinical manifestations may be driven by immune abnormalities or inflammatory cytokines.

Chemotherapy responses are often transient; Long-term outcome is generally unfavorable.

Slide 42 · ALK-positive ALCL has a defining kinase lesion

ALK rearrangements at chromosome 2p23 create chimeric genes.

The resulting fusion proteins are constitutively active tyrosine kinases.

This molecular lesion provides a strong diagnostic marker and a potential therapeutic target.

Slide 43 · ALK fusion drives proliferative signaling

ALK gene rearrangement

Constitutively active ALK fusion kinase

RAS and JAK/STAT signaling

Growth and survival of lymphoma cells

Slide 44 · ALCL: Hallmark cells and growth pattern

Large anaplastic cells have abundant cytoplasm and markedly atypical nuclei.

Some cells display horseshoe-shaped or embryoid nuclei (hallmark cells).

Tumor cells often cluster around venules or infiltrate lymphoid sinuses.

The epithelial-like arrangement can mimic metastatic carcinoma.

Slide 45 · Why ALCL can resemble carcinoma

Large anaplastic cells sometimes infiltrate lymphoid sinuses.

Perivenular clustering can amplify the epithelioid appearance.

The immunophenotypic work-up is essential when morphology is misleading.

Slide 46 · ALK immunostaining is mechanistically meaningful

Normal lymphocytes lack ALK protein expression.

Tumor-cell ALK staining strongly supports the presence of an ALK fusion.

ALK staining should be interpreted together with large-cell morphology and CD30.

Slide 47 · ALK-positive versus ALK-negative ALCL

Aspect

ALK-positive

ALK-negative

ALK alteration / stain

Rearranged / positive

Absent / negative

Typical age

Children / young adults

Usually older adults

General outcome

Relatively favorable

Substantially worse

CD30

Usually expressed

Usually expressed

Slide 48 · CD30: A shared target, not a lineage test

Both ALK-positive and ALK-negative ALCL usually express CD30.

CD30 is a member of the tumor necrosis factor receptor family.

CD30-targeted antibody–drug conjugates have antitumor activity in CD30-positive lymphomas.

Slide 49 · ALK-positive ALCL is an outcome exception

This subtype often occurs in younger patients and may involve soft tissues.

Chemotherapy cure rates around 75%–80%.

ALK inhibitors can be effective when conventional chemotherapy fails.

Slide 50 · Case: Large atypical cells in nodal sinuses

A young adult has a soft-tissue mass; Large anaplastic cells show horseshoe-shaped nuclei and grow around venules.

Salient evidence

Strong tumor-cell CD30 positivity

Tumor-cell ALK expression

Morphology raises metastatic carcinoma in the differential

ALK-positive anaplastic large-cell lymphoma

ALK expression connects the characteristic tumor morphology to an ALK rearrangement and explains targeted inhibitor activity.

Slide 51 · Adult T-cell leukemia/lymphoma is HTLV-1 linked

ATLL is a neoplasm of mature CD4-positive T cells.

The disease occurs in adults infected with human T-cell leukemia virus type 1 (HTLV-1).

All tumor cells contain clonally integrated HTLV-1 proviral material.

Slide 52 · HTLV-1 endemic settings

Regions emphasized

Southern Japan

West Africa

Caribbean basin

Clinicopathologic relevance

Exposure history supports diagnostic suspicion.

Infection is necessary description but transformation is uncommon.

Geography is a clue, not evidence of malignancy.

Slide 53 · HTLV-1 infection and prolonged latency

HTLV-1 infection

Long asymptomatic latent interval

Additional oncogenic alterations

Adult T-cell leukemia/lymphoma in a minority

Slide 54 · Clonal provirus supports a direct viral role

Identical proviral integration is present in the tumor-cell population.

This observation supports expansion of an infected progenitor clone.

The transformation process remains incompletely understood despite viral protein studies.

Slide 55 · ATLL accumulates additional genetic lesions

Aggressive ATLL commonly carries acquired tumor-suppressor alterations.

TP53 and CDKN2A, as well as chromosomal copy-number changes.

Viral infection alone does not explain why only a small fraction of carriers develop disease.

Slide 56 · ATLL: “flower” or “cloverleaf” nuclei

Blood and tissue tumor cells can have strikingly multilobated nuclei.

The “flower” or “cloverleaf” description reflects irregular nuclear contours.

Morphology is variable: Not every ATLL cell has this appearance.

Confirm the HTLV-1-associated clinicopathologic context rather than relying on a cell silhouette.

Slide 57 · ATLL involves blood, nodes, skin and organs

Peripheral blood lymphocytosis may occur.

Generalized lymphadenopathy and hepatosplenomegaly are frequent.

Skin lesions may be conspicuous at presentation.

Slide 58 · Hypercalcemia is a notable ATLL clue

Hypercalcemia is among the characteristic clinical findings.

It should raise suspicion when combined with lymphocytosis, cutaneous lesions and endemic exposure.

The supplied Robbins passage does not specify a complete mechanism for this finding.

Slide 59 · ATLL: Common manifestations and their correlates

Finding

Clinicopathologic interpretation

Lymphocytosis

Circulating malignant T cells

Nodal / splenic enlargement

Tumor infiltration

Skin lesions

Cutaneous involvement

Hypercalcemia

Important metabolic complication

“Flower” cells

Characteristic, variable cytology

Slide 60 · ATLL: Aggressive and less aggressive patterns

Most patients develop rapidly progressive disease.

Many aggressive cases as fatal within months to approximately one year despite intensive chemotherapy.

Less commonly, predominantly cutaneous disease can follow a more indolent course.

Slide 61 · Why ATLL and MF are not interchangeable

Adult T-cell leukemia/lymphoma

Associated with HTLV-1 infection.

Often involves blood and systemic organs.

Flower-cell morphology may be present.

Mycosis fungoides

Cutaneous-homing mature CD4 T-cell neoplasm.

Often remains clinically skin-limited for prolonged periods.

Characteristic epidermal infiltration and cerebriform nuclei.

Slide 62 · Case: Lymphocytosis with hypercalcemia

An adult from an HTLV-1 endemic region has lymphocytosis, skin lesions, generalized lymphadenopathy and hypercalcemia.

Salient evidence

Blood smear shows markedly lobulated nuclei

Mature CD4-positive T-cell phenotype

Evidence of HTLV-1 infection

Adult T-cell leukemia/lymphoma

The combination of viral setting, systemic syndrome and mature T-cell tumor phenotype is characteristic.

Slide 63 · Mycosis fungoides: Skin-homing T-cell neoplasm

A neoplasm of CD4-positive helper T cells that preferentially localizes to the skin.

Cutaneous lymphocyte antigen and CCR4 contribute to this tropism.

Clinical evolution may include patch/inflammatory, plaque and tumor stages.

Slide 64 · Mycosis fungoides: Morphology and course

Epidermis and upper dermis may be infiltrated by atypical T cells.

Tumor nuclei may be cerebriform because of nuclear membrane infolding.

Clinical disease often remains skin-limited for prolonged periods despite detectable systemic circulation.

Slide 65 · Mycosis fungoides versus Sézary syndrome

Dimension

Mycosis fungoides

Sézary syndrome

Typical skin pattern

Patches → plaques → possible tumors

Diffuse exfoliative erythroderma

Peripheral blood

Overt leukemia usually late

Characteristic leukemic involvement

Lymphadenopathy

Variable; Often later

Generalized

Course

Often prolonged / indolent

More aggressive

Slide 66 · Large granular lymphocytic leukemia

A tumor of cytotoxic T cells or NK cells, usually arising in adults.

Peripheral blood cells have pale cytoplasm and coarse azurophilic granules.

T-cell variants express surface CD3; NK-cell variants lack surface CD3 and can express CD56.

Slide 67 · STAT3 mutations in LGL leukemia

Acquired activating STAT3 mutation

Cytokine-independent STAT3 signaling

Persistent cytotoxic lymphocyte clone

Immune dysregulation and cytopenias

Slide 68 · LGL leukemia: Cytopenias dominate

Neutropenia and anemia often dominate even when marrow infiltration is sparse.

Autoimmune features and rheumatologic disorders may coexist.

Some patients with Felty syndrome have an underlying LGL proliferation.

Slide 69 · Extranodal NK/T lymphoma: Destructive anatomy

Often presents as a destructive nasopharyngeal mass.

Malignant cells surround and invade small vessels.

Vascular damage leads to ischemia and extensive necrosis.

Slide 70 · Angioinvasion explains tissue destruction

NK/T-cell malignant infiltrate

Invasion of small vessels

Ischemic injury

Extensive necrosis and destructive local mass

Slide 71 · Extranodal NK/T lymphoma: EBV and lineage

Strongly associated with Epstein–Barr virus infection.

Identical EBV episomes in tumor cells support clonal derivation from one infected cell.

Most cases lack surface CD3 and TCR rearrangements and express NK-cell markers.

Slide 72 · Extranodal NK/T lymphoma: Clinical implications

This neoplasm is more common in Asia than in the United States or Europe.

Many tumors respond to radiotherapy but are relatively chemotherapy resistant.

Advanced-stage disease generally has a poor outcome.

Slide 73 · Disease-defining biologic associations

Disease

Anchor association

PTCL-NOS

No pathognomonic marker; Exclusion of defined entities

Nodal Tfh lymphoma

Tfh program; TET2/DNMT3A and clonal hematopoiesis

ALK-positive ALCL

ALK rearrangement → active kinase

Adult T-cell leukemia/lymphoma

HTLV-1 proviral infection

Extranodal NK/T lymphoma

EBV and an angioinvasive destructive pattern

Slide 74 · Clinical syndrome as a diagnostic pointer

Presentation

Consider first

Generalized nodes + pleomorphism

PTCL-NOS; Nodal Tfh lymphoma

Nodes + immune abnormalities / autoantibodies

Nodal Tfh lymphoma

Younger patient + large CD30-positive cells

ALK-positive ALCL

HTLV-1 exposure + blood cells + hypercalcemia

Adult T-cell leukemia/lymphoma

Erythroderma with leukemic T cells

Sézary syndrome

Neutropenia + granulated lymphocytes

LGL leukemia

Destructive nasal lesion

Extranodal NK/T-cell lymphoma

Slide 75 · A mature T/NK work-up: Avoid common pitfalls

Begin with complete biopsy and syndrome

Resolve T-cell versus NK-cell lineage

Seek entity-defining phenotype / viral association

Use clonality selectively for equivocal processes

Integrate findings; Retain NOS only if required

Slide 76 · Integrated case: Immune dysregulation

An older adult has generalized lymphadenopathy, autoimmune cytopenia and hypergammaglobulinemia. The node has prominent vessels and follicular dendritic expansion.

Salient evidence

Abnormal CD4 T cells express PD-1 and CXCL13

EBV-positive reactive B immunoblasts are present

TET2 mutation also detected in a myeloid compartment

Nodal T-follicular helper cell lymphoma

The Tfh program, immune disturbance and shared clonal hematopoiesis are mutually reinforcing.

Slide 77 · Integrated case: Destructive nasal mass

A patient presents with an ulcerative destructive nasopharyngeal lesion. Biopsy shows an atypical lymphoid infiltrate centered on vessels with extensive necrosis.

Salient evidence

Tumor cells express NK-associated markers

No surface CD3 or rearranged TCR demonstrated

EBV is present in the tumor cells

Extranodal NK/T-cell lymphoma

Vascular injury explains necrosis; EBV association and NK phenotype help resolve lineage.

Slide 78 · Interpret common stains in the correct order

CD3/CD2/CD5 establish a mature T-cell context when appropriately expressed.

Tfh markers, ALK and CD30 can redirect classification toward defined entities.

NK markers and EBV studies become particularly important in destructive extranodal lesions.

No individual marker should overrule tissue distribution and architecture.

Slide 79 · Why the same lineage has different clinical courses

Indolent / prolonged patterns

Mycosis fungoides may remain skin-limited for years.

T-cell LGL leukemia is often dominated by chronic cytopenias.

Aggressive patterns

PTCL-NOS and nodal Tfh lymphoma frequently have adverse outcomes.

ATLL and advanced extranodal NK/T lymphoma often behave aggressively.

ALK-positive ALCL is an important relatively favorable exception.

Slide 80 · Four durable diagnostic principles

Classify the mature lymphoid lineage before assigning a subtype.

Explain the morphology: vascular injury, reactive recruitment, or tissue homing.

Use entity-defining viral and molecular associations only where actually present.

Reserve PTCL-NOS for cases not meeting a more specific disease definition.