Hairy Cell Leukemia

Slide 1 · Hairy cell leukemia

Morphology • molecular pathogenesis • clinicopathologic diagnosis

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Identify the characteristic blood, marrow, spleen and liver findings.

Explain the BRAF mutation–MAPK pathway relationship.

Integrate clinical presentation, morphology and immunophenotype.

Distinguish this indolent mature B-cell tumor from neighboring entities.

Slide 3 · A distinctive mature B-cell neoplasm

Lineage

A mature B-cell tumor in the lymphoid-neoplasm group.

Principal organs

Bone marrow and spleen are major disease sites.

Behavior

Typically indolent, often with durable treatment responses.

Molecular association

Activating BRAF mutations are highly characteristic.

Slide 4 · A rare form of leukemia

Accounts for approximately 2% of all leukemias.

Uncommon relative to major mature B-cell lymphoid neoplasms.

Despite rarity, a coherent morphologic and molecular profile permits recognition.

Slide 5 · Typical demographic profile

Age

Median age at diagnosis: 55 years.

Sex

Male-to-female ratio approximately 5:1.

Population

Textbook reports a predominance among White patients.

Interpretation

Demographics support suspicion; They do not establish diagnosis.

Slide 6 · HCL within mature B-cell tumors

Entity

Cell-of-origin context

Characteristic driver in Robbins

Hairy cell leukemia

Memory B cell

Activating BRAF

Follicular lymphoma

Germinal-center B cell

BCL2::IGH

Mantle cell lymphoma

Naive B cell

Cyclin D1::IGH

CLL/SLL

Naive or memory B cell

Heterogeneous genetic lesions

Slide 7 · The characteristic clinical pattern

Physical examination

Splenomegaly, often marked; Nodes usually not prominent.

Peripheral blood

Cytopenias are common; Circulating tumor-cell numbers vary.

Marrow examination

Infiltration with reticulin may impair aspiration.

Natural history

Indolent course with generally excellent outcome.

Slide 8 · Anatomical distribution drives presentation

Bone marrow

Interstitial infiltration → cytopenias

Spleen

Red-pulp expansion → marked enlargement

Liver

Portal-triad infiltration → sometimes hepatomegaly

Slide 9 · Why the disease can be overlooked

Circulating tumor cells may be few, despite organ infiltration.

Lymphadenopathy is uncommon rather than a dominant presentation.

A marrow aspirate can fail even when marrow is involved.

The spleen and marrow provide complementary diagnostic clues.

Slide 10 · BRAF is the central molecular association

More than 90% of cases harbor an activating point mutation in BRAF.

BRAF encodes a serine/threonine protein kinase.

The kinase acts just downstream of RAS in the MAPK cascade.

This association is central to pathogenesis and therapeutic targeting.

Slide 11 · RAS–BRAF–MAPK signaling

RAS

BRAF

Downstream MAPK kinases

Growth-related transcription

BRAF is immediately downstream of RAS,.

Activating BRAF mutations increase signaling through downstream kinases.

Slide 12 · The molecular change is BRAF V600E

Position

Amino-acid residue 600 in BRAF.

Substitution

Valine (V) is replaced by glutamate (E).

Consequence

A kinase-activating point mutation.

Specificity caveat

The same alteration also occurs in other neoplasms.

Slide 13 · From kinase alteration to tumor behavior

BRAF V600E

Activated kinase signaling

Downstream signal propagation

Pro-growth output

The diagram represents the molecular logic Chapter 7.

It is not a quantitatively measured pathway activity assay.

Slide 14 · High prevalence is not absolute universality

The disease-specific section states BRAF mutation in more than 90% of cases.

A negative molecular result cannot, by itself, substitute for comprehensive clinicopathologic evaluation.

Mutation frequency and mutation identity answer different questions.

Slide 15 · BRAF is not unique to leukemia

Hairy cell leukemia

Very strongly associated with BRAF activation.

Melanoma

BRAF activating mutations occur in a substantial subset.

Langerhans cell histiocytosis

BRAF V600E is also identified in this neoplasm.

Diagnostic lesson

Context is required; A shared mutation does not imply a shared diagnosis.

Slide 16 · How genotype supports pathologic classification

Morphologic suspicion

Mature B-cell phenotype

Characteristic BRAF alteration

Integrated diagnosis

Molecular findings complement rather than replace morphology.

The source does not specify a mandatory test algorithm.

Slide 17 · Morphologic hallmark: Surface projections

Hair-like projections are most evident with phase-contrast microscopy.

Schematic: Original vector drawing, not a photomicrograph.

Slide 18 · Hairy projections are easiest by phase contrast

Clinical / pathologic observation

Fine surface extensions explain the name “hairy cell.”

Projections are most apparent by phase-contrast microscopy.

Interpretation

Conventional stained smears may emphasize cytoplasm and nuclear contours instead.

Avoid making diagnosis from apparent spicules alone.

Slide 19 · Stained blood-smear appearance

Fine surface projections

Rounded, oblong or folded nucleus

Moderate pale cytoplasm

Schematic: Original vector drawing, not a photomicrograph.

Slide 20 · Three described nuclear contours

Round

Oblong

Reniform

Schematic: Original vector drawing, not a photomicrograph.

Slide 21 · Cytoplasmic detail on routine smears

Moderate amounts of pale-blue cytoplasm are typical.

Peripheral threadlike projections or blebs may be visible.

The source figure legend describes cytoplasm as agranular.

Interpret cell morphology alongside lineage markers and marrow findings.

Slide 22 · The peripheral tumor-cell count varies

Possible finding

A recognizable leukemic population is evident on smear.

Alternative finding

Only a few suspicious cells circulate.

Implication

Absence of striking lymphocytosis does not exclude organ disease.

Practical correlate

Marrow and splenic involvement may dominate the presentation.

Slide 23 · Peripheral-blood observation is not sufficient

Suspicious blood morphology

Evaluate hematopoietic involvement

Characterize B-cell phenotype

Correlate genetic findings

This is a pedagogic reasoning sequence, not a prescribed clinical guideline.

Slide 24 · Bone marrow: Interstitial infiltration

Tumor cells infiltrate the marrow in a diffuse interstitial pattern.

Oblong or reniform nuclei and condensed chromatin are described.

Cytoplasm appears pale within the marrow infiltrate.

Marrow infiltration contributes to abnormal blood counts.

Slide 25 · Reticulin explains the dry-tap phenomenon

Marrow compartment

Sampling consequence

Reticulin-rich matrix entraps neoplastic cells.

Aspiration may yield a “dry tap.”

Core biopsy reveals interstitial infiltration.

Schematic — no tissue section shown

Slide 26 · What a dry tap means in this setting

Observation

Marrow aspiration yields little or no material.

Mechanism

Neoplastic cells lie within a reticulin-containing extracellular matrix.

Diagnostic consequence

A core biopsy may reveal infiltrates that aspiration misses.

Caution

A dry tap is not exclusive to this leukemia.

Slide 27 · Aspirate versus trephine biopsy

Specimen

What HCL source emphasizes

Interpretive limitation

Marrow aspirate

May be inaspirable because of reticulin

Negative/empty aspirate may be noninformative

Core marrow biopsy

Shows interstitial hairy-cell infiltrate

Requires morphologic / phenotype correlation

Peripheral smear

Can reveal cells with projections

Circulating cells are variable

Slide 28 · Marrow morphology and blood morphology agree

Blood smear

Hair-like border; Pale cytoplasm; Round to folded nucleus.

Marrow biopsy

Interstitial pale cells with oblong or reniform nuclei.

Why compare?

Two tissue environments change what is easiest to see.

Shared identity

Phenotype and genetics connect morphologically related populations.

Slide 29 · Splenic involvement centers on red pulp

Simplified normal spleen

Hairy cell leukemia

Red-pulp expansion; White-pulp effacement

Native schematic — not gross or histologic evidence

Slide 30 · Why splenic architecture changes

Extensive infiltration expands or replaces the red pulp.

The normal white-pulp compartments become obliterated.

The gross spleen may appear characteristically beefy red.

Anatomic alteration helps explain the marked splenomegaly.

Slide 31 · Splenomegaly may be the only examination clue

Major feature

Spleen enlargement is often substantial.

Sometimes isolated

The spleen can be the sole abnormal physical finding.

Contrast

Lymph node enlargement is uncommon.

Clinical link

The spleen may sequester circulating blood cells.

Slide 32 · Gross splenic appearance and mechanism

Clinical / pathologic observation

A heavy tumor burden involves splenic red pulp.

The white-pulp architecture is progressively obscured.

Interpretation

A beefy-red gross appearance.

The gross finding reflects the altered pulp distribution.

Slide 33 · Hepatic involvement: Portal triads

Hepatic portal triads may be infiltrated by tumor cells.

Hepatomegaly occurs less often than splenic enlargement.

When present, liver enlargement is generally less pronounced.

The liver is another component of the multisite disease pattern.

Slide 34 · Where clinical abnormalities arise

Bone marrow

Interstitial infiltration → cytopenias

Spleen

Red-pulp expansion → marked enlargement

Liver

Portal-triad infiltration → sometimes hepatomegaly

Slide 35 · Immunophenotype confirms mature B-cell identity

Hairy cells express the pan–B-cell antigens CD19 and CD20.

Surface immunoglobulin expression is typical.

IgG is the most commonly described surface immunoglobulin class.

B-lineage assignment precedes interpretation of the distinctive panel.

Slide 36 · Distinctive immunophenotypic marker combination

B-cell identity

CD19

CD20

Surface immunoglobulin (often IgG)

Relatively distinctive markers

CD11c

CD25

CD103

Annexin A1

Read the combined pattern with the morphologic and clinical picture.

Slide 37 · Four relatively distinctive antigens

Marker

How Robbins uses the marker

CD11c

Part of the characteristic HCL phenotypic group

CD25

Part of the characteristic HCL phenotypic group

CD103

Part of the characteristic HCL phenotypic group

Annexin A1

Part of the characteristic HCL phenotypic group

Slide 38 · Immunophenotyping is pattern recognition

CD19 / CD20

Surface immunoglobulin

CD11c / CD25 / CD103 / annexin A1

Morphologic fit

Neither a pan-B marker nor one isolated antigen captures the full textbook profile.

Slide 39 · Clinical manifestation: Pancytopenia

More than half of patients have pancytopenia account.

Marrow infiltration impairs the blood-cell compartment.

Splenic sequestration is an additional contributor.

Both mechanisms must be considered together.

Slide 40 · Two complementary routes to cytopenia

Marrow infiltration

Splenic sequestration

Pancytopenia

Both contributions are identified; This is not a quantitative weighting of mechanisms.

Slide 41 · Infections may be a presenting complaint

Frequency

Approximately one-third present with infections.

Hematologic setting

Cytopenias accompany marrow/splenic disease.

Notable association

Atypical mycobacterial infections are increased.

Clinical interpretation

Infection can be a clue to the underlying hematologic disorder.

Slide 42 · Monocytopenia and atypical mycobacteria

Monocytopenia is commonly encountered in HCL.

Its cause is described as uncertain.

An association with atypical mycobacterial infection is noted.

A possible relationship; Causality is not established.

Slide 43 · Lymphadenopathy is relatively unusual

Clinical / pathologic observation

Lymph node enlargement is a common lymphoma presentation.

Some other mature B-cell tumors have prominent nodal disease.

Interpretation

In hairy cell leukemia, lymphadenopathy is rare.

Marked splenomegaly with limited adenopathy is a stronger clue.

Slide 44 · A compact clinicopathologic profile

Domain

Characteristic HCL feature

Clinical

Marked splenomegaly; infections; cytopenias

Blood smear

Pale cytoplasm; variable circulating cells; surface projections

Bone marrow

Interstitial infiltrate; reticulin-associated dry tap

Spleen

Red-pulp involvement, white-pulp effacement

Immunophenotype

CD19/CD20 plus CD11c/CD25/CD103/annexin A1

Molecular

BRAF V600E strongly associated

Slide 45 · First-pass diagnostic reasoning

Cytopenias + spleen enlargement

Smear and marrow morphology

B-cell marker panel

BRAF correlation

This structured approach is an interpretation of the textbook features, not a formal guideline.

Slide 46 · When circulating cells are sparse

Do not equate a low circulating tumor burden with absent tissue involvement.

Marrow morphology may provide the diagnostic material.

A dry tap increases the importance of the biopsy core.

Phenotype and genetic context help secure the integrated impression.

Slide 47 · Differential: CLL/SLL versus HCL

Feature

Hairy cell leukemia

CLL/SLL

Dominant involvement

Marrow and spleen

Marrow and lymph nodes

Peripheral cells

Hair-like cytoplasmic edges

Small lymphocytes; smudge cells

Clinical clue

Marked spleen; nodes rare

Generalized adenopathy common

Typical phenotype

CD11c, CD25, CD103, annexin A1

CD5, CD23

Slide 48 · Differential: Mantle cell lymphoma

Feature

Hairy cell leukemia

Mantle cell lymphoma

Dominant pattern

Spleen / marrow

Often disseminated lymphadenopathy

Driver

BRAF activation

Cyclin D1::IGH translocation

Phenotype emphasized

CD11c/CD25/CD103/annexin A1

CD5+, often CD23−

Course

Very indolent

Moderately aggressive

Slide 49 · Differential: Follicular lymphoma

Feature

Hairy cell leukemia

Follicular lymphoma

Typical major site

Spleen and marrow

Generalized lymphadenopathy

Growth/morphology

Interstitial marrow; hairy cytoplasm

Follicles with centrocytes/centroblasts

Molecular

BRAF mutation

BCL2::IGH

Key phenotypic markers

CD11c/CD25/CD103/annexin A1

CD10 and BCL6

Slide 50 · Differential: Marginal zone lymphoma

Shared context

Both are mature, memory B-cell–associated neoplasms.

Hairy cell leukemia

Characteristic BRAF association and hairy morphology.

Marginal zone lymphoma

A heterogeneous group of nodal, splenic and extranodal B-cell tumors.

Key distinction

Antigen-linked pathogenesis for extranodal MALT lymphoma, not HCL.

Slide 51 · Molecular drivers distinguish related tumors

Neoplasm

Characteristic genetic association in Robbins

Hairy cell leukemia

BRAF activating point mutation

Follicular lymphoma

t(14;18) / BCL2::IGH

Mantle cell lymphoma

t(11;14) / cyclin D1::IGH

Extranodal marginal zone lymphoma

Selected translocations involving BCL10 or MALT1

Slide 52 · Three common diagnostic pitfalls

“No leukocytosis, so not leukemia”

Circulating hairy-cell numbers are highly variable.

“No aspirate, so no marrow disease”

Reticulin can cause an uninformative dry tap.

“BRAF V600E equals HCL”

The same mutation occurs in other tumor types.

“Splenomegaly is nonspecific”

Combine splenic pattern with smear and immunophenotype.

Slide 53 · Indolent course does not mean no morbidity

The neoplasm is typically slowly progressive.

Cytopenias and infections can nevertheless produce major clinical problems.

Marrow and splenic infiltration explain much of the disease burden.

Clinical behavior and treatment responsiveness are distinct questions.

Slide 54 · Unusually prolonged treatment responses

Exceptional sensitivity to relatively gentle chemotherapy.

Remissions are often long-lasting.

The explanation for this unusual chemosensitivity remains unclear.

The overall outlook is generally excellent.

Slide 55 · Late relapse does not necessarily imply resistance

Indolent onset

Slow course

Response

Gentle regimen

Long remission

Often prolonged

Late relapse

May respond again

Conceptual sequence; Timing is variable and the figure is not a survival curve.

Slide 56 · Retreatment can remain effective

Late relapse

Recurrence often occurs after five or more years.

Repeat treatment

Many relapsing tumors respond again to the same agents.

Unusual property

This pattern is uncommon among human cancers.

Interpretation

Recurrence and therapeutic failure are not synonymous in this disease.

Slide 57 · BRAF inhibition in difficult-to-treat disease

BRAF-driven tumor

Conventional therapy ineffective

BRAF inhibitor

Reported strong response

Excellent responses in tumors refractory to conventional chemotherapy.

No specific agent, dose or formal treatment algorithm is supplied by this section.

Slide 58 · Prognosis integrates biology and treatment

Biology

Generally indolent disease course.

Clinical morbidity

Complications from marrow and splenic infiltration.

Therapy

Long remissions, with frequent retreatment sensitivity.

Overall outcome

Excellent prognosis account.

Slide 59 · Case 1: Splenomegaly with cytopenias

Hypothetical teaching scenario

A middle-aged adult has substantial splenomegaly, multiple cytopenias and little palpable lymphadenopathy.

Which clinical pattern makes HCL worth considering?

What blood and marrow findings would strengthen that impression?

Slide 60 · Case 1: Pathologic interpretation

Clinical / pathologic observation

Marked splenomegaly and pancytopenia align with common findings.

Minimal lymphadenopathy is compatible with HCL.

Interpretation

Look for characteristic cells in peripheral blood.

Confirm marrow involvement and phenotypic features rather than diagnosing by examination alone.

Slide 61 · Case 2: A marrow aspirate yields no material

Hypothetical teaching scenario

Peripheral blood shows few suspicious B cells. The marrow aspirate is unsuccessful, although cytopenias persist.

What source-described matrix explains this event?

Which marrow specimen remains valuable?

Slide 62 · Case 2: Resolving the dry tap

Clinical / pathologic observation

Reticulin-rich extracellular matrix can entrap infiltrating cells.

Circulating neoplastic-cell numbers may be low.

Interpretation

Evaluate the marrow core biopsy for an interstitial infiltrate.

Use immunophenotype to correlate tissue and blood findings.

Slide 63 · Case 3: A BRAF V600E result

Hypothetical teaching scenario

A B-cell neoplasm harbors BRAF V600E, but the clinical setting and morphology have not yet been established.

Does this mutation alone prove hairy cell leukemia?

Which independent observations are needed?

Slide 64 · Case 3: Avoiding molecular overinterpretation

Clinical / pathologic observation

BRAF mutation occurs in more than 90% of hairy cell leukemias.

BRAF V600E also occurs in melanoma and Langerhans cell histiocytosis.

Interpretation

Use morphology, B-cell lineage and disease distribution.

A molecular alteration is evidence within an integrated diagnosis, not an identity label.

Slide 65 · Synthesis: One disease, five convergent domains

Distribution

Marrow, splenic red pulp and often hepatic portal triads.

Morphology

Projections; Folded nuclei; Reticulin-rich marrow infiltrate.

Phenotype

CD19/CD20; CD11c/CD25/CD103/annexin A1.

Genetic and clinical

Activating BRAF; Cytopenias, spleen enlargement, indolence.

Slide 66 · References and source limitations

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th ed. (2026), Chapter 13, page 549.

Chapter 13, Table 13.6 and adjacent mature B-cell neoplasm sections support comparisons.

Chapter 7 provides background on the RAS–BRAF–MAPK signaling cascade.

Original textbook Figure 13.17 was unavailable; morphology diagrams are labeled schematics, not clinical images.