Anaplastic Large Cell Lymphoma ALK Positive

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Lecture topics

What should a pathologist be able to explain?
Oncogenic signaling: RAS pathway
Clinical appearance can be nonspecific
Cytoplasmic volume and perinuclear zone
ALK: The decisive companion to CD30
Differential 1: Metastatic carcinoma
Problem-solving when the phenotype is sparse
Five findings worth retaining

Slide index & full transcript (68 slides)

Text from the original slides, in presentation order. Diagrams and images remain in the viewer above.

Slide 1 · Anaplastic Large-Cell

Lymphoma

ALK positive

Morphology · Molecular pathogenesis · Diagnosis

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · What should a pathologist be able to explain?

Place ALK-positive ALCL within mature T-cell lymphomas

Connect ALK fusion signaling with the neoplastic phenotype

Recognize hallmark cells and the sinusoidal growth pattern

Apply a lineage-conscious diagnostic approach

Slide 3 · Classification: A mature T-cell neoplasm

WHO-HAEM5 retains ALK-positive ALCL as a distinct entity

The broader ALCL family contains several clinically distinct disorders

Morphologic overlap does not establish identical biology

Classification schematic

Anaplastic large-cell lymphoma

ALK positive

ALK negative

Breast implant-associated

Slide 4 · The defining molecular event

A rearrangement disrupts ALK at chromosome 2p23

The fusion gene encodes an abnormal ALK tyrosine kinase

Constitutive kinase activity is the central oncogenic feature

Schematic

Chromosome 5 · NPM1

Chromosome 2 · ALK

NPM1::ALK fusion

Active ALK tyrosine kinase

Slide 5 · What ALK positivity does—and does not—mean

ALK positivity is a disease-defining result in the correct context

ALK expression alone does not establish T-cell lineage

Morphology and a complementary immunophenotypic panel remain essential

Slide 6 · Systemic ALCL is not a single molecular disease

ALK-positive ALCL: ALK rearranged, often younger patients

ALK-negative ALCL: Morphologic overlap, distinct genetic landscape

Breast implant-associated ALCL: Separate clinical entity, generally ALK negative

Classification schematic

Anaplastic large-cell lymphoma

ALK positive

ALK negative

Breast implant-associated

Slide 7 · The usual translocation: T(2;5)

The recurrent t(2;5)(p23;q35) joins NPM1 and ALK

NPM1::ALK is a constitutively activated fusion tyrosine kinase

Other ALK fusion partners also occur

Schematic

Chromosome 5 · NPM1

Chromosome 2 · ALK

NPM1::ALK fusion

Active ALK tyrosine kinase

Slide 8 · How fusion changes normal signaling

A fusion partner supplies aberrant kinase activation

The fusion is expressed in a cellular compartment where ALK is normally absent

Proliferation and survival signaling proceed without ordinary receptor control

Native PowerPoint workflow

ALK rearrangement

Active ALK fusion kinase

Oncogenic signaling

Potential therapeutic inhibition

Slide 9 · Oncogenic signaling: JAK/STAT3 axis

ALK signaling engages the JAK/STAT signaling network

STAT3-dependent transcription contributes to malignant-cell survival

The diagram depicts a simplified relationship, not a complete interactome

Simplified signaling scheme

ALK fusion kinase

JAK / STAT signaling

Transcriptional response

Slide 10 · Oncogenic signaling: RAS pathway

Constitutively active ALK can drive RAS-related signaling

Growth and proliferation become uncoupled from normal regulation

The textbook places RAS signaling among the principal downstream routes

Simplified signaling scheme

ALK fusion kinase

RAS-associated signaling

Proliferation / survival

Slide 11 · The kinase is a diagnostic and therapeutic target

Fusion-derived ALK is present in tumor cells rather than ordinary lymphocytes

Tumor-cell ALK can be demonstrated by immunohistochemistry

ALK blockade can exploit dependence on abnormal kinase activity

Native PowerPoint workflow

ALK rearrangement

Active ALK fusion kinase

Oncogenic signaling

Potential therapeutic inhibition

Slide 12 · ALK IHC provides a molecular surrogate

ALK is not normally expressed in lymphocytes

Positive tumor-cell staining strongly supports an ALK rearrangement

Interpret unusual patterns with tumor morphology and lineage markers

Native schematic · subcellular staining patterns

ALK: Cytoplasmic ± nuclear pattern

NPM1::ALK often nuclear + cytoplasmic

Slide 13 · Fusion partner influences ALK localization

NPM1::ALK usually yields nuclear and cytoplasmic staining

Several alternative fusions yield predominantly cytoplasmic staining

Staining distribution can suggest—but not definitively identify—the partner

Native schematic · subcellular staining patterns

ALK: Cytoplasmic ± nuclear pattern

NPM1::ALK often nuclear + cytoplasmic

Slide 14 · Testing molecular identity when necessary

ALK IHC is an efficient initial method

ALK break-apart FISH can document rearrangement in ambiguous cases

Targeted fusion assays may identify a partner when clinically useful

Diagnostic tests answer different questions

ALK immunohistochemistry

Rearrangement suspected

ALK break-apart FISH

Molecular confirmation, if required

Slide 15 · How molecular and tissue findings integrate

ALK rearrangement identifies the driver

Hallmark-cell morphology defines a recognizable appearance

CD30 and a broad lineage panel establish the diagnostic context

Native PowerPoint workflow

Molecular ALK driver

Characteristic morphology

CD30 + lineage context

Slide 16 · Typical age distribution

ALK-positive cases preferentially affect children and young adults

Age is a clue, not a stand-alone diagnostic criterion

Older patients can still have ALK-positive ALCL

Children / young adults

Characteristic tendency — not an exclusion rule

Slide 17 · Anatomical distribution

Lymph nodes are often involved in systemic disease

Extranodal soft-tissue involvement is frequent

Site alone cannot distinguish ALCL from another large-cell malignancy

Sites are clinical, not diagnostic, evidence

Lymph node

Extranodal soft tissue

Other systemic sites possible

Slide 18 · Clinical appearance can be nonspecific

Lymphadenopathy or an extranodal mass may prompt biopsy

Constitutional symptoms occur in systemic lymphomas

Diagnostic confirmation is tissue-based, not clinical alone

Native PowerPoint workflow

Initial morphology

Discriminating tests

Clinicopathologic integration

Slide 19 · Clinical question: Node or soft-tissue mass?

The initial differential spans lymphoma, carcinoma and other tumors

Perivascular or sinusoidal clusters can appear cohesive

Lineage-specific tests become critical when morphology is deceptive

Native PowerPoint workflow

Initial morphology

Discriminating tests

Clinicopathologic integration

Slide 20 · Nodal effacement is an architectural clue

Diffuse infiltration may replace normal lymph-node compartments

Residual follicles or sinuses may be partly retained

Architectural interpretation requires low-power examination

Schematic · not H&E microscopy

Neoplastic cells within sinuses

Slide 21 · Sinusoidal distribution can resemble metastasis

Tumor cells may fill lymph-node sinuses

Large cells can be arranged in cohesive-looking groups

Cytokeratin and lymphoid markers resolve a common diagnostic trap

Schematic · not H&E microscopy

Neoplastic cells within sinuses

Slide 22 · Perivascular growth is another recognizable pattern

Neoplastic cells may aggregate around venules

Perivascular foci can be found even when the dominant field is mixed

Search these zones for diagnostically useful hallmark cells

Schematic · not H&E microscopy

Tumor around venule

Slide 23 · Why carcinoma may be suspected

Large epithelioid cells may create a cohesive appearance

Sinus infiltration resembles some metastatic carcinomas

ALK-positive ALCL usually lacks convincing epithelial lineage markers

Schematic · not H&E microscopy

Neoplastic cells within sinuses

Slide 24 · Hallmark cell: The essential cytology

Large cell with ample cytoplasm

Eccentric, horseshoe-shaped or kidney-shaped nucleus

The distinctive shape is helpful, but not individually specific

Schematic · not a specimen

Abundant cytoplasm

Eccentric reniform / horseshoe nucleus

Slide 25 · Nuclear contour is more useful than cell size

Hallmark nuclei may be reniform, horseshoe-shaped or embryoid

Variable atypia and multinucleation can coexist

Look for recurring characteristic cells across fields

Schematic · not a specimen

Abundant cytoplasm

Eccentric reniform / horseshoe nucleus

Slide 26 · Cytoplasmic volume and perinuclear zone

The cytoplasm is often abundant and variably eosinophilic

A perinuclear pale or eosinophilic Golgi region may be conspicuous

This feature helps explain the distribution of CD30 staining

Schematic · not a specimen

Abundant cytoplasm

Eccentric reniform / horseshoe nucleus

Slide 27 · The common histologic pattern

Sheets of medium-to-large pleomorphic anaplastic cells

Hallmark cells are readily identifiable

High-grade cytology coexists with a molecularly defined entity

Slide 28 · The small-cell pattern is a diagnostic challenge

Smaller atypical lymphoid cells may dominate the infiltrate

Larger hallmark cells may be sparse or perivascular

ALK can highlight cells when CD30 is concentrated in large elements

Slide 29 · Lymphohistiocytic pattern: A masked tumor

Reactive histiocytes can obscure neoplastic cells

Scattered atypical cells may be difficult to recognize on H&E

ALK and CD30 stains assist localization of the tumor population

Slide 30 · Hodgkin-like morphology can mislead

Tumor cells may resemble Hodgkin/Reed–Sternberg variants

An inflammatory or sclerotic background may complicate classification

ALK testing and a complete phenotype prevent misassignment

Slide 31 · Variation occurs within the same tumor

Distinct histologic patterns may coexist in one case

A small biopsy can overrepresent one component

Immunophenotypic interpretation must consider the sampled architecture

Slide 32 · Morphologic patterns: Comparative view

Pattern

Dominant appearance

Diagnostic reminder

Common

Large pleomorphic cells

Hallmark nuclei conspicuous

Small cell

Mostly smaller tumor cells

ALK may show broad involvement

Lymphohistiocytic

Many reactive histiocytes

Tumor may be obscured

Hodgkin-like

HSR-like cells / background

Exclude classical Hodgkin

Slide 33 · CD30: A central phenotypic feature

ALCL is characterized by strong CD30 expression in large neoplastic cells

Membranous and perinuclear Golgi staining is characteristic

CD30 alone is insufficiently specific for the diagnosis

Native schematic · subcellular staining patterns

CD30: Membrane + perinuclear Golgi zone

Slide 34 · CD30 distribution matters

Golgi-associated accentuation provides a recognizable staining signature

In small-cell variants, smaller tumor cells may stain less intensely

An apparently focal stain must be interpreted against ALK and morphology

Native schematic · subcellular staining patterns

CD30: Membrane + perinuclear Golgi zone

Slide 35 · ALK: The decisive companion to CD30

ALK expression is expected in ALK-positive ALCL

Both staining intensity and cellular location are informative

Confirm that stained cells are the neoplastic population

Native schematic · subcellular staining patterns

ALK: Cytoplasmic ± nuclear pattern

NPM1::ALK often nuclear + cytoplasmic

Slide 36 · T-lineage markers may be absent

CD3, CD5 and CD7 may be lost in tumor cells

Some cases show a “null” immunophenotype despite T-cell origin

A negative CD3 stain does not exclude ALK-positive ALCL

Native PowerPoint workflow

Initial morphology

Discriminating tests

Clinicopathologic integration

Slide 37 · Cytotoxic and activation phenotype

Cytotoxic proteins such as TIA1 and granzyme B can be expressed

EMA is often present; CD4 may also be expressed

None replaces ALK/CD30 plus lineage and morphology assessment

Slide 38 · Practical initial immunohistochemical panel

Diagnostic question

Stain / assay

Caution

ALCL phenotype

CD30, ALK

Not independently specific

T-cell identity

CD2, CD3, CD5, CD7

Antigen loss possible

B-cell mimic

CD20, PAX5

Check plasmacytic markers

Carcinoma mimic

Broad cytokeratin

Interpret phenotype in context

Slide 39 · Interpret a discordant panel deliberately

ALK and CD30 positivity is compelling but not sufficient in isolation

Review stain distribution, controls and viable tumor areas

Expand testing for epithelial, B-cell or histiocytic mimics as indicated

Native PowerPoint workflow

Initial morphology

Discriminating tests

Clinicopathologic integration

Slide 40 · FISH confirms ALK locus disruption

A break-apart assay can show an ALK rearrangement

FISH supports genetics; It does not by itself prove T-cell lineage

A fusion-specific assay can add information beyond a break-apart result

Diagnostic tests answer different questions

ALK immunohistochemistry

Rearrangement suspected

ALK break-apart FISH

Molecular confirmation, if required

Slide 41 · The diagnostic sequence

Start with architecture and cytology on H&E

Establish strong CD30 expression and tumor-cell ALK positivity

Confirm a compatible mature T-cell phenotype and exclude mimics

Native PowerPoint workflow

H&E architecture / cytology

CD30 plus ALK staining

Lineage and exclusion panel

Clinical distribution / classification

Slide 42 · Biopsy quality determines diagnostic confidence

Preserve architecture when feasible

Avoid relying on a tiny reactive-looking area in heterogeneous disease

Interpret stains alongside adjacent H&E and clinical distribution

Native PowerPoint workflow

Initial morphology

Discriminating tests

Clinicopathologic integration

Slide 43 · Differential 1: Metastatic carcinoma

Shared clues: Large cells, sinusoidal distribution, cohesive clusters

Favor ALCL: Hallmark nuclei with CD30 and tumor-cell ALK

Epithelial lineage markers help adjudicate a carcinoma mimic

Feature

ALK+ ALCL

Carcinoma

Growth

May be sinusoidal

May colonize sinuses

Morphology

Hallmark cells possible

Epithelial differentiation

ALK / CD30

Usually coexpressed

Not a defining pair

Cytokeratin

Typically absent

Supports epithelial lineage

Slide 44 · Differential 2: Classical Hodgkin lymphoma

Both can contain bizarre large cells and CD30 positivity

Classical Hodgkin lymphoma typically lacks ALK expression

A broader B-cell/Hodgkin phenotype and architecture resolve overlap

Feature

ALK+ ALCL

Classical Hodgkin

CD30

Strong

Usually strong

ALK

Positive

Usually negative

Cells

Hallmark cells

Hodgkin / RS cells

Workup

T/cytotoxic phenotype

Hodgkin / B-cell panel

Slide 45 · Differential 3: ALK-positive large B-cell lymphoma

Both diseases may stain for ALK

ALK-positive large B-cell lymphoma usually has plasmablastic differentiation

CD30 is usually absent; B/plasma-cell markers and light chains assist

Feature

ALK+ ALCL

ALK+ large B-cell

ALK

Positive

CD30

Characteristically strong

Usually negative

Lineage

Mature T-cell

B / plasma-cell

Phenotype

Aberrant T markers

CD138, light chains

Slide 46 · Differential 4: PTCL, NOS

A CD30-positive peripheral T-cell lymphoma is not automatically ALCL

Characteristic morphology and ALK status are discriminating

PTCL, NOS remains an exclusionary category after classification workup

Feature

ALK+ ALCL

PTCL, NOS

ALK fusion

Defining

Absent by definition

CD30

Strong in large tumor cells

Variable

Cells

Hallmark morphology

Variable pleomorphism

Diagnosis

Distinct entity

Diagnosis of exclusion

Slide 47 · Differential 5: Systemic ALK-negative ALCL

Both systemic groups are typically CD30 positive

An ALK rearrangement defines the positive subtype

Age and prognosis differ at population level; Histology overlaps

Feature

ALK+ ALCL

ALK− ALCL

ALK protein

Expressed

Absent

CD30

Strong

Age

Often younger

Often older

Outcome

Generally more favorable

Generally less favorable

Slide 48 · Differential 6: Primary cutaneous ALCL

A skin-limited tumor requires clinical distribution and staging context

Primary cutaneous ALCL is usually ALK negative

A tumor in skin may represent secondary involvement by systemic disease

Feature

Systemic ALCL

Primary cutaneous ALCL

Distribution

Nodal / extranodal

Skin-limited at diagnosis

ALK

Positive in target topic

Usually negative

CD30

Strong

Needed

Systemic assessment

Skin / staging context

Slide 49 · Breast implant-associated ALCL is separate

Usually presents in relation to an implant capsule or effusion

This entity is generally ALK negative and CD30 positive

Do not classify a capsule-based lesion as ordinary systemic ALCL without history

Slide 50 · When TCR clonality is informative

Can support T-cell derivation in phenotypically ambiguous cases

Does not establish ALCL subtype by itself

Apparent clonality must be interpreted with assay limitations

Native PowerPoint workflow

Initial morphology

Discriminating tests

Clinicopathologic integration

Slide 51 · Problem-solving when the phenotype is sparse

Verify ALK staining in viable morphologically atypical cells

Look for a CD30-rich hallmark-cell component

Use molecular assays and broad lineage markers if needed

Native PowerPoint workflow

Initial morphology

Discriminating tests

Clinicopathologic integration

Slide 52 · Reporting: Communicate diagnostic certainty

Name the entity as ALK-positive anaplastic large-cell lymphoma

Record ALK/CD30 patterns and the relevant lineage results

Mention unresolved mimics or confirmatory molecular work, if applicable

Native PowerPoint workflow

Initial morphology

Discriminating tests

Clinicopathologic integration

Slide 53 · Prognosis contrasts with other aggressive T-cell tumors

ALK-positive ALCL as having a relatively favorable outlook

Its younger age distribution is part of the clinical context

Subtype and clinical stage still matter to individual prognosis

Slide 54 · Robbins treatment-outcome statement

Textbook reports a 75%–80% cure rate with chemotherapy

This is a summarized textbook estimate, not a patient-specific prediction

Clinical series and treatment eras vary; Avoid using it as a universal cutoff

75%–80%

Textbook-reported chemotherapy cure rate

Slide 55 · CD30 also creates a therapeutic opportunity

CD30 is an antigenic target of antibody–drug conjugates

The antigen can be expressed across different CD30-positive lymphomas

Clinical treatment selection depends on setting and current protocols

Native PowerPoint workflow

Tumor-cell CD30

CD30-directed conjugate

Antitumor effect

Slide 56 · ALK inhibitors exploit driver dependence

ALK-targeted agents can elicit responses in refractory disease

The rationale follows directly from constitutive fusion kinase signaling

Response does not make a diagnostic lineage assessment optional

Native PowerPoint workflow

ALK rearrangement

Active ALK fusion kinase

Oncogenic signaling

Potential therapeutic inhibition

Slide 57 · Treatment history can change immunostains

CD30 expression may change following CD30-targeted therapy

Rebiopsy and current staining should be interpreted in therapeutic context

Compare with the pretreatment specimen where available

Native PowerPoint workflow

Initial morphology

Discriminating tests

Clinicopathologic integration