Extranodal NK T Cell Lymphoma

Slide 1 · Extranodal NK-/T-cell lymphoma

An Epstein–Barr virus-associated, highly aggressive extranodal lymphoma

Clinicopathologic emphasis: nasal destruction, angiodestruction, and lineage assignment

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning outcomes

Recognize the principal extranodal sites and characteristic destructive presentation.

Explain EBV association, angiodestruction, and ischemic necrosis.

Interpret NK-/T-cell markers, EBER studies, and TCR findings.

Construct a tissue-based differential diagnosis and link pathology to clinical behavior.

Slide 3 · Defining the disease

Defining category

Characteristic expression

A mature NK- or cytotoxic T-cell malignancy arising characteristically at extranodal sites.

The usual lesion is a destructive mass centered on the upper aerodigestive tract.

Most cases have an NK-cell lineage, but a minority show a cytotoxic T-cell phenotype.

Slide 4 · Why “NK-/T-cell” rather than “NK-cell”?

NK-lineage tumors predominate and commonly lack T-cell receptor (TCR) rearrangements.

Mature cytotoxic NK/T category

NK-derived majority

T-derived minority

A subset genuinely belongs to the cytotoxic T-cell lineage and may have rearranged TCR genes.

Morphology, viral studies, and phenotyping must be interpreted together.

Slide 5 · The nasal presentation is a tissue-destructive process

The nasopharyngeal region is the most frequent presenting site.

Extranodal tumor

Vessel injury

Ischemia and tissue loss

The lesion may erode local tissue through vascular invasion and ischemic necrosis.

A destructive mass is a clinicopathologic clue—not itself a diagnostic criterion.

Slide 6 · Opening clinical problem

Illustrative scenario: An adult has a persistent destructive nasopharyngeal lesion.

A superficial biopsy shows prominent necrotic debris and scattered atypical lymphoid cells.

Diagnostic task: Decide what viable tissue, stains, and lineage studies are needed.

Which finding would most directly connect the clinical lesion to the tumor mechanism?

Slide 7 · Geographic pattern

Uncommon in the United States and Europe.

Accounts for as many as 3% of non-Hodgkin lymphomas in Asia,.

The distribution is a population-level observation, not a patient-level diagnostic test.

Slide 8 · Anatomic predilection

Typical primary site

Additional extranodal sites

Most often presents as a nasopharyngeal mass.

Skin and testis are less common primary presentations.

An extranodal distribution should direct sampling toward involved tissue rather than lymph nodes alone.

Slide 9 · Normal NK cells: Useful biologic context

NK cells participate in innate immune surveillance of infected or stressed cells.

NK-cell recognition

Cytotoxic apparatus

Target-cell killing

Their cytotoxic apparatus contains granules capable of killing target cells.

The tumor retains aspects of cytotoxic-cell differentiation, explaining the diagnostic value of granule-associated proteins.

Slide 10 · NK cells and cytotoxic T cells are not synonymous

NK lineage

Cytotoxic T lineage

Normal NK cells lack surface CD3 and generally lack rearranged TCR genes.

Cytotoxic T cells use a clonotypic TCR/CD3 complex.

Lymphoma typing therefore requires a lineage interpretation, not only a cytotoxic marker.

Slide 11 · What cytoplasmic azurophilic granules signal

Granules are an expected feature of normal cytotoxic lymphocytes.

Cytoplasmic granules

Cytotoxic differentiation

Ancillary-marker support

Large azurophilic granules in touch preparations of tumor cells.

Granule morphology supports cytotoxic differentiation but is not disease-specific.

Slide 12 · EBV is central to disease association

Tumor tissue

EBV detection

Lineage phenotype

Morphologic context

Extranodal NK-/T-cell lymphoma is highly associated with Epstein–Barr virus infection. • EBV positivity should be demonstrated in tumor cells rather than inferred from patient serology.

The association is central to current diagnostic frameworks.

Slide 13 · EBV episomes establish a clonal relationship

Identical EBV episomes in tumor cells within an individual patient.

EBV-infected precursor

Clonal expansion

Shared viral episomes

Identical episomes are evidence of expansion from one EBV-infected precursor.

This supports tumor clonality; It does not specify the complete sequence of oncogenic events.

Slide 14 · An unresolved biological question: EBV entry

Observed finding

Unresolved inference

The classic B-cell EBV receptor CD21 is not expressed by these tumor cells.

The route by which EBV enters the NK-/T-lineage precursor remains uncertain.

Do not replace this uncertainty with a speculative entry pathway.

Slide 15 · Association is not a complete mechanism

Strong EBV association and clonality support a critical relationship to tumor development.

EBV-associated precursor

Additional alterations

Malignant outgrowth

Host-cell mutations and disordered signaling are also reported.

A single universal sequence from infection to malignancy is not established section.

Slide 16 · No unique diagnostic chromosomal abnormality

Complex chromosomal aberrations are often present.

Robbins does not identify any one specific, defining aberration.

A molecular result must be interpreted with morphology, viral status, and phenotype.

Slide 17 · Recurring molecular categories

JAK/STAT

Epigenetic regulation

TP53

Genomic complexity

Reported alterations involve JAK/STAT signaling components. • Other affected genes encode epigenetic regulators.

TP53 is also recurrently mutated in reported cases.

Slide 18 · JAK/STAT: Signaling dysregulation

JAK/STAT proteins transduce cytokine-dependent growth and survival signals.

Cytokine-pathway components

Mutational alterations

Dysregulated signaling

Recurrent mutations affecting components of this pathway.

A detected mutation alone cannot substitute for diagnostic tissue findings.

Slide 19 · Epigenetic regulators: A separate alteration class

General role

Disease observation

Epigenetic control influences gene expression without changing the DNA sequence.

Mutations in regulatory components have been reported in this tumor.

The textbook does not specify a unique epigenetic mutation for routine diagnosis.

Slide 20 · TP53 is one reported genetic target

TP53 is involved in cellular responses to genomic injury and stress.

Genome-stress response

Altered TP53

Potential growth advantage

Recurrent TP53 mutations among reported tumors.

Presence or absence of a TP53 variant does not by itself establish the entity.

Slide 21 · Integrating virus and host-cell alterations

Disease biology

Diagnostic implication

EBV-associated clonal neoplasia coexists with heterogeneous host genomic lesions.

These observations explain why a single mutation is not a universal diagnostic hallmark.

The definitive diagnosis remains an integrated clinicopathologic classification.

Slide 22 · Angiocentric growth

Vascular lumen

Neoplastic lymphoid cells

Schematic — not a histologic specimen

Neoplastic cells typically accumulate around small vessels.

Perivascular localization is an architectural clue in tissue sections.

The degree of demonstrable vascular involvement can depend on available viable tissue.

Slide 23 · Angiodestruction: Invasion of vessel walls

Vascular lumen

Neoplastic lymphoid cells

Schematic — not a histologic specimen

Tumor cells may infiltrate and destroy small-vessel walls.

This is more specific mechanistically than simple perivascular inflammation.

Angiodestruction helps account for the striking destructive phenotype.

Slide 24 · Why the tumor produces ischemic necrosis

Small-vessel infiltration and damage impair local perfusion.

Vessel invasion

Perfusion impairment

Ischemic necrosis

Ischemic injury results in necrosis of adjacent tissue.

Necrosis may dominate the biopsy and obscure the neoplastic infiltrate.

Slide 25 · Linking the nasal mass to histologic damage

A destructive nasopharyngeal mass is the principal clinical pattern.

Nasal tumor infiltration

Angiocentric injury

Local tissue destruction

Vessel-centered tumor infiltration produces focal vascular injury.

Associated necrosis helps explain local mucosal destruction.

Slide 26 · Schematic field interpretation

Vascular lumen

Neoplastic lymphoid cells

Schematic — not a histologic specimen

At scanning magnification: Identify viable tissue, necrosis, and vessels.

At higher magnification: Assess the relationship of atypical cells to vessel walls.

Use immunophenotypic and EBV studies to determine whether the infiltrate is lymphoma.

Slide 27 · Touch preparation: Cytoplasmic granules

Observed cytology

Diagnostic limitation

Large azurophilic granules in tumor-cell cytoplasm.

This recapitulates a structural feature of cytotoxic NK cells.

The finding supports recognition, but cannot independently identify the lymphoma.

Slide 28 · Necrosis is a sampling problem

A specimen containing mostly necrotic tissue may contain few interpretable tumor cells.

Necrotic sample

Limited viable cells

Incomplete characterization

An adequate diagnosis requires representative viable tissue.

Sampling and repeat biopsy decisions belong to the treating pathology–clinical team.

Slide 29 · Cytologic heterogeneity

What varies

What remains essential

Neoplastic cells may range from small to large and show irregular nuclear contours.

Background inflammation and necrosis may complicate recognition.

Cell size alone does not classify the tumor.

Slide 30 · Inflammatory background can mislead

Potential mimic

Discriminating evidence

A mixed inflammatory infiltrate can coexist with neoplastic cells.

Prominent necrosis may prompt an infectious or inflammatory differential.

Convergent morphology and viral/lineage studies are more reliable than appearance alone.

Slide 31 · Three diagnostic anchors

Extranodal malignant cytotoxic lymphoid infiltrate.

Extranodal morphology

EBER in tumor cells

Cytotoxic NK/T phenotype

EBV detected in neoplastic cells by EBER in situ hybridization.

Compatible NK-cell or cytotoxic T-cell phenotype.

Slide 32 · What EBER in situ hybridization contributes

Useful evidence

Potential pitfall

EBER probes detect EBV-associated small RNAs in affected tissue.

The critical readout is nuclear signal within neoplastic lymphoid cells.

An EBV-positive background cell population must not be confused with EBV-positive tumor.

Slide 33 · Current classification: EBV in the tumor

Extranodal infiltrate

NK/cytotoxic T phenotype

EBER in most tumor cells

Integrated diagnosis

WHO-HAEM5 expects most neoplastic cells to be EBER-positive as an essential criterion. • EBER positivity should be interpreted together with cell morphology and phenotype.

A convincing EBER-negative candidate requires re-examination of the diagnosis.

Slide 34 · CD56: Supportive NK-associated marker

Value

Limitation

CD56 commonly marks the neoplastic population.

CD56 is not absolutely specific for NK-cell lineage.

A compatible lymphoma can show atypical marker expression; Use a panel, not one stain.

Slide 35 · Surface CD3 and cytoplasmic CD3ε differ

Surface CD3 / TCR

Cytoplasmic CD3ε

Typical NK cells are negative for surface CD3/TCR expression.

Paraffin-section staining for cytoplasmic CD3ε may be positive in this lymphoma.

Thus “CD3-negative” should not be equated with all CD3 immunohistochemistry being negative.

Slide 36 · Cytotoxic differentiation markers

TIA1

Granzyme B

Perforin

Interpret in context

TIA1, granzyme B, and perforin provide evidence of cytotoxic differentiation. • The expected panel is interpreted alongside CD2, CD56, CD3ε, and EBER.

Cytotoxic-marker positivity alone is shared by other lymphoid lesions.

Slide 37 · T-cell receptor gene rearrangement

Most cases lack detectable TCR gene rearrangements.

Extranodal NK-/T lymphoma

Most: No TCR rearrangement

Subset: Rearranged TCR

This supports the usual NK-cell derivation.

A subset has genuine T lineage; Absence of rearrangement is not an absolute diagnostic requirement.

Slide 38 · Lineage classification requires a panel

Test domain

Typical NK-lineage interpretation

Surface CD3/TCR

Usually absent

Cytoplasmic CD3ε

May be positive

CD56

Commonly positive

TCR gene rearrangement

Usually absent

Surface versus cytoplasmic antigen localization matters.

CD56 and cytotoxic markers support but do not uniquely determine NK lineage.

Slide 39 · Important immunophenotypic exceptions

Nonclassic result

Diagnostic response

Some tumors lack CD56 despite compatible cytotoxic and EBV findings.

CD30 or T-cell antigen expression can vary.

An unexpected single stain result should trigger a broader integrated review—not automatic exclusion.

Slide 40 · Integrating a core diagnostic panel

Question

Illustrative tests

Lymphoid/cytotoxic phenotype

CD3ε, CD2, TIA1, granzyme B

NK-associated differentiation

CD56, surface CD3/TCR if available

EBV within tumor

EBER in situ hybridization

Alternative lineage

CD20, ALK and others as indicated

Confirm hematolymphoid nature and exclude obvious lineage mimics.

Establish cytotoxic NK/T phenotype using CD3ε, CD2, CD56, and granule markers.

Slide 41 · Tissue-to-diagnosis workflow

Begin with an adequate biopsy of viable lesional tissue.

Viable tissue

Morphology

EBER + markers

Differential review

Identify the angiodestructive infiltrate and accompanying necrosis.

Establish EBV association and NK-/cytotoxic T-cell phenotype.

Exclude clinically and morphologically plausible mimics.

Slide 42 · Pitfall: A sample dominated by dead tissue

Failure mechanism

Practical remedy

Extensive necrosis can produce nondiagnostic or falsely reassuring biopsies.

Search for the viable neoplastic edge and vessel-associated infiltrate.

Lack of sufficient tissue is a specimen limitation—not proof against lymphoma.

Slide 43 · Mimic: Invasive infection

Shared feature

Distinguishing approach

Destructive nasal lesions and necrosis are not lymphoma-specific.

Microbiologic and fungal assessment depends on clinical findings and tissue morphology.

Do not attribute necrosis to lymphoma before excluding credible infection.

Slide 44 · Mimic: Granulomatosis with polyangiitis

Overlapping phenotype

Distinguishing observation

Inflammatory vasculitis can also damage vessels and destroy sinonasal tissue.

A neoplastic cytotoxic lymphoid population with EBER positivity redirects the diagnosis.

The pathology report should explain why a reactive vasculitic process is unlikely.

Slide 45 · Mimic: EBV-positive B-cell proliferation

EBV-positive B cells

NK-/T-cell lymphoma

EBV positivity by itself does not establish NK-/T-cell lymphoma.

Evaluate whether EBV signal localizes to the atypical cytotoxic cells.

B-cell marker expression and architectural context distinguish an EBV-associated B-cell process.

Slide 46 · Mimic: Anaplastic large-cell lymphoma

ALK-positive ALCL

Extranodal NK-/T lymphoma

Large atypical lymphoid cells and CD30 expression can create morphologic overlap.

ALK-positive ALCL is characterized by ALK rearrangement/protein expression.

EBER and the full phenotype are necessary to classify an ambiguous case.

Slide 47 · Mimic: Aggressive NK-cell leukemia

Predominant disease pattern

Key distinction

Both disorders involve NK-cell differentiation and may be clinically aggressive.

A leukemic systemic presentation differs from a dominant destructive extranodal mass.

Blood, marrow, and tissue distribution are integral to the differential.

Slide 48 · Mimic: Indolent NK-cell proliferation of the gut

Indolent NK-cell GI proliferation

Extranodal NK-/T lymphoma

WHO-HAEM5 separates an indolent gastrointestinal NK-cell proliferation from aggressive extranodal NK-/T-cell lymphoma.

The indolent gastrointestinal entity is EBV-negative.

Clinical behavior, anatomic pattern, tissue architecture, and EBER guide separation.

Slide 49 · EBV-positive nodal T-/NK-cell lymphoma is distinct

Primary nodal pattern

Primary extranodal pattern

WHO-HAEM5 recognizes a separate EBV-positive nodal T-/NK-cell lymphoma.

A chiefly nodal pattern should not automatically be called nasal-type extranodal disease.

Anatomic presentation and classification context remain important.

Slide 50 · Define disease extent before treatment decisions

Site of origin and extranodal extension affect clinical planning.

Pathologic diagnosis

Anatomic assessment

Clinical staging

Clinical staging integrates imaging and tissue findings.

A histologic diagnosis does not independently determine the distribution of disease.

Slide 51 · Biology helps explain treatment behavior

Local response

Systemic disease challenge

Extensive local infiltration and necrosis make disease control challenging.

Favorable response to radiation therapy.

The same text describes relative resistance to conventional chemotherapy.

Slide 52 · Radiation sensitivity of localized disease

The tumor commonly responds well to radiation.

Local mass

Radiation sensitivity

Potential local control

The observation is most relevant for treatment planning in localized presentation.

The exact regimen is outside the scope of this pathology lecture.

Slide 53 · Relative chemotherapy resistance

Robbins characterizes the disease as relatively resistant to chemotherapy.

Aggressive systemic potential

Relative drug resistance

Therapeutic challenge

This observation limits extrapolation from common B-cell lymphoma treatment approaches.

Advanced disease requires specialist multimodality assessment.

Slide 54 · Advanced disease has poor prognosis

Pathology signal

Prognostic implication

Prognosis is generally poor when disease is advanced.

Disease distribution and response to treatment are clinically relevant.

Do not quote survival estimates without a population, regimen, and study source.

Slide 55 · Allogeneic stem-cell transplantation

Potential role

Important qualification

Allogeneic hematopoietic stem-cell transplantation as a potential option in advanced disease.

This is a selected-patient strategy rather than a universal treatment.

A pathology lecture should not imply definitive benefit for every clinical setting.

Slide 56 · Immune-checkpoint blockade

Observed responses to checkpoint inhibitors in this virus-associated lymphoma.

Virus-associated tumor

Immune checkpoint therapy

Responses in some cases

The observation is biologically compatible with immune interactions in a virus-driven malignancy.

Responses are not an assurance of durable benefit for an individual patient.

Slide 57 · Immune-treatment toxicity matters

Therapeutic interest

Important risk

Potential harms include immune-mediated disease.

Severe inflammatory toxicity, including cytokine-related syndromes, may occur.

Therapeutic possibilities should not be presented separately from treatment risk.

Slide 58 · Case application: The necrotic nasal biopsy

Illustrative case: The first sample contains necrosis and a scant atypical lymphoid population.

The lesion remains clinically destructive despite an initially limited specimen.

Which two actions best improve the pathologic evaluation?

Propose a sampling strategy and the first decisive ancillary test.

Slide 59 · Case interpretation: Obtain interpretable cells

Prioritize representative viable tissue, especially at the edge of necrosis.

Viable lesional biopsy

Angiocentric morphology

EBER + lineage workup

Examine the relationship between neoplastic cells and vessels.

Avoid overcalling either lymphoma or inflammation from necrosis alone.

Slide 60 · Case interpretation: Assign EBV and lineage

EBER-positive atypical cells support an EBV-associated malignant population.

EBER in atypical cells

Cytotoxic NK/T phenotype

Integrated classification

A compatible cytotoxic NK/T marker profile supports extranodal NK-/T-cell lymphoma.

Clinical distribution and competing diagnoses complete the interpretation.

Slide 61 · Diagnostic synthesis

Morphology

Nasal tissue destruction + angiocentric/angiodestructive lymphoma is a strong morphologic pattern.

EBV

EBER within tumor cells is central, combined with NK/cytotoxic T immunophenotype.

Lineage

Most cases are NK-lineage; Molecular heterogeneity precludes a single defining host-gene test.

Clinical course

Clinical extent matters because advanced disease is aggressive and challenging to treat.

Slide 62 · Sources and scientific scope

Primary: Robbins, Cotran & Kumar, Pathologic Basis of Disease, 11th ed., ch. 13, p. 552.

Diagnostic supplement: WHO-HAEM5 T/NK classification review (J Clin Pathol, 2025).

Diagnostic supplement: 2022 ICC extranodal T/NK lymphoma review (Virchows Arch, 2023).

Morphologic supplement: ENKTCL review (Front Oncol, 2023).