Langerhans Cell Histiocytosis

Slide 1 · Langerhans Cell Histiocytosis

Pathogenesis • morphology • clinicopathologic patterns

A pathology teaching lecture

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Explain why LCH is considered a clonal myeloid neoplasm.

Link driver mutations and chemokine receptors to biological behavior.

Identify characteristic cellular features and immunophenotype.

Distinguish the major clinical patterns and their consequences.

Slide 3 · Histiocytosis is an umbrella designation

The term encompasses proliferations of dendritic cells or macrophages.

Its biological range extends from reactive to frankly malignant processes.

LCH occupies an unusual intermediate position on this spectrum.

Reactive

Benign macrophage proliferation

LCH

Clonal dendritic-cell disorder

Highly malignant

Histiocytic sarcoma / BPDCN

Slide 4 · LCH arises from an immature dendritic-cell lineage

The proliferating cell resembles the specialized Langerhans dendritic cell.

Langerhans cells belong to the innate immune system.

The defining process is clonal proliferation rather than ordinary inflammation.

Clonal Langerhans-type cell (schematic)

Schematic — not a histologic specimen

Slide 5 · Why LCH is grouped with myeloid neoplasms

Dendritic lineage links the lesional cell to the innate immune compartment.

Recurrent oncogenic driver mutations support neoplastic biology.

Clonal lineage and clinical behavior must be distinguished.

Lineage

Innate immune / dendritic

Genomics

Driver mutations are common

Clinical behavior

Ranges from regression to dissemination

Slide 6 · Clonality does not imply uniformly aggressive behavior

Most cases harbor cancer-associated driver mutations.

Spontaneous remission is nevertheless a recognized feature.

Biological classification and individual clinical prognosis are not equivalent.

NEOPLASM

Somatic clonal driver mutations

CLINICAL COURSE

May regress, remain localized, or disseminate

Slide 7 · RAS-pathway mutations predominate

RAS signaling-pathway driver mutations in over 85% of cases.

Mutation of pathway components provides a mechanistic basis for cell proliferation.

This frequency describes the overall LCH population, not every individual lesion.

>85%

Pathway-associated drivers

Reported across LCH cases in the cited Robbins edition

Slide 8 · BRAF V600E is the most frequent driver

A valine-to-glutamate substitution occurs at BRAF codon 600.

The substitution activates BRAF signaling.

BRAF V600E in approximately 55%–60% of cases.

55–60%

BRAF V600E

Share of LCH cases reported in the primary textbook

Slide 9 · MAPK1 is another recurrently mutated gene

MAPK1 encodes a kinase acting downstream of BRAF.

MAPK1 as the next most commonly mutated gene.

The shared theme is aberrant signaling within one growth-control network.

BRAF kinase

Downstream MAPK1 kinase

Disordered intracellular signaling

Slide 10 · Mutations converge on a signaling network

Different mutated genes can affect components of one RAS pathway.

Pathway convergence is more informative than treating every mutation separately.

The diagram is a simplified relationship—not a complete molecular cascade.

RAS signaling network

BRAF

MAPK1

LCH clone

Slide 11 · The molecular paradox of LCH

Oncogenic mutations establish a neoplastic framework.

A driver mutation alone does not dictate disseminated disease.

Some lesions undergo spontaneous regression despite clonality.

Mutation

Shared neoplastic mechanism

Distribution

One lesion or multiple systems

Outcome

Regression or progression

Slide 12 · Tissue homing depends on chemokine receptors

Lesional cells express receptors that recognize tissue chemokines.

Chemokine–receptor pairing provides a route to tissue-selective migration.

This explains localization beyond intrinsic proliferative signals.

Receptor expression

Tissue chemokine ligand

Migration / tissue homing

Slide 13 · Normal epidermal Langerhans cells express CCR6

CCR6 is expressed by normal epidermal Langerhans cells.

The chemokine CCL20 serves as a CCR6 ligand.

Receptor expression contributes to tissue-directed cell trafficking.

Normal epidermal Langerhans cell

CCR6

CCL20

Epidermal context

Ligand-directed tissue homing (schematic)

Slide 14 · Neoplastic cells coexpress CCR6 and CCR7

LCH cells aberrantly express both CCR6 and CCR7.

The additional receptor expands the repertoire of tissue destinations.

Receptor coexpression contributes to the disease’s distribution pattern.

NORMAL

CCR6 expression

NEOPLASTIC

CCR6 + CCR7 expression

Slide 15 · The CCR6–CCL20 axis directs skin and bone homing

CCL20 is present in skin and bone account.

CCL20 is a ligand for CCR6.

The pairing supports migration of neoplastic Langerhans cells to these sites.

LCH cell: CCR6

CCR6

CCL20

Skin

CCR6

CCL20

Bone

Ligand-directed tissue homing (schematic)

Slide 16 · The CCR7 axis supports lymphoid organ homing

CCL19 and CCL21 are ligands for CCR7.

These ligands guide lesional cells toward lymphoid sites.

Aberrant CCR7 expression helps explain lymphoid involvement.

LCH cell: CCR7

CCR7

CCL19

Lymphoid tissue

CCR7

CCL21

Lymphoid tissue

Ligand-directed tissue homing (schematic)

Slide 17 · Receptors connect genotype to organ distribution

Proliferative signals and tissue migration are different biological functions.

BRAF/MAPK1 alterations explain pathway dysregulation.

CCR6/CCR7 expression helps explain the organ sites of infiltration.

LCH cell with aberrant CCR6 + CCR7

CCR6

CCL20

Skin and bone

CCR7

CCL19 / CCL21

Lymphoid organs

Ligand-directed tissue homing (schematic)

Slide 18 · The defining cytology is recognizable across patterns

Lesional cells have abundant cytoplasm, sometimes vacuolated.

Nuclei are vesicular and typically contain grooves or folds.

These features apply regardless of the extent of clinical involvement.

Cellular morphology (schematic)

Schematic — not a histologic specimen

Slide 19 · Nuclear grooves are a primary recognition clue

Nuclei may show longitudinal linear grooves.

Folding creates irregular or reniform nuclear contours.

The finding must be interpreted with the cellular and immunophenotypic context.

Grooved / folded nucleus

Schematic — not a histologic specimen

Slide 20 · Cytoplasmic abundance is characteristic

LCH cells show moderately abundant or abundant pale cytoplasm.

Vacuoles may be present in the cytoplasm.

Morphology alone should not be mistaken for a complete diagnostic test.

Pale, sometimes vacuolated cytoplasm

Schematic — not a histologic specimen

Slide 21 · Birbeck granules are characteristic ultrastructures

Characteristic granules lie within the lesional cell cytoplasm.

They are pentalaminar tubular structures.

This ultrastructural feature links morphology to Langerhans differentiation.

Birbeck granule

Pentalaminar tubular structure

Dilated terminal end → “tennis racket” profile

Schematic — not electron microscopy

Slide 22 · The tennis-racket profile comes from terminal dilation

Birbeck granules commonly have a rod-like profile.

A dilated terminal end creates the classic “tennis racket” appearance.

This is an electron-microscopic feature; The drawing is explanatory only.

Birbeck granule

Pentalaminar tubular structure

Dilated terminal end → “tennis racket” profile

Schematic — not electron microscopy

Slide 23 · Langerin is present in Birbeck granules

The granules contain the protein langerin.

This connects an ultrastructural hallmark with a molecular cell marker.

Granule morphology and immunophenotype are complementary levels of evidence.

Birbeck granule

Pentalaminar tubular structure

Dilated terminal end → “tennis racket” profile

Schematic — not electron microscopy

Slide 24 · The textbook immunophenotypic profile

The lesional cells typically express CD1a.

S-100 and HLA-DR are also typically expressed.

Langerin is linked to the characteristic Birbeck granules.

CD1a

Typical lesional marker

S-100

Typical lesional marker

HLA-DR

Typical lesional marker

Langerin

Granule-associated protein

Slide 25 · Morphology and immunophenotype should be integrated

Grooved nuclei and pale cytoplasm suggest the lesional cell phenotype.

Typical markers provide corroborating cell-lineage evidence.

No single descriptive feature should be used in isolation.

Compatible cell morphology

CD1a / S-100 / HLA-DR profile

Integrated pathological interpretation

Slide 26 · The inflammatory background is variable

Lesional cells may be mixed with eosinophils, lymphocytes, and plasma cells.

Neutrophils can also be part of the admixture.

The reactive-cell population modifies the lesion’s appearance.

LCH cells

Neoplastic component

Eosinophils

Variable prominence

Lymphocytes

Background population

Others

Plasma cells / neutrophils

Slide 27 · Eosinophils are common—but not required

Eosinophils often stand out in unisystem lesions.

The number of eosinophils is variable.

An eosinophil-poor lesion is not excluded by this single feature.

EOSINOPHIL-RICH

Prominent associated eosinophils

EOSINOPHIL-POOR

Compatible LCH cells may still be present

Slide 28 · One cellular morphology, multiple clinical settings

The characteristic Langerhans cell morphology persists across presentations.

The clinical category reflects lesion number and distribution.

Organ infiltration determines the main symptoms and consequences.

LCH: Clinical patterns

Multifocal multisystem

Unifocal / multifocal unisystem

Pulmonary

Slide 29 · LCH is clinically heterogeneous

Multisystem, single-system, and pulmonary presentations.

Single-system disease can be unifocal or multifocal.

Extent of organ involvement—not a different cell phenotype—separates these groups.

LCH: Clinical patterns

Multifocal multisystem

Unifocal / multifocal unisystem

Pulmonary

Slide 30 · Age and disease distribution often correlate

Multifocal multisystem disease is most frequent before 2 years of age.

Multifocal single-system disease peaks in early childhood.

Unifocal bone disease more often presents in older children or adults.

Pattern

Typical age

Clinical distribution

Multisystem

Usually <2 years

Several organs

Multifocal unisystem

Peak 2–10 years

Multiple lesions, one system

Unifocal

Older children / adults

Usually bone

Slide 31 · Letterer–Siwe pattern: Multisystem LCH

The multisystem form often begins in infancy.

Disease can involve skin, lymph nodes, liver, spleen, lungs, bone, and marrow.

Its severity reflects widespread organ infiltration.

Skin

Seborrheic eruption

Reticuloendothelial

Liver / spleen / nodes

Lung / bone

Pulmonary and lytic lesions

Marrow

Cytopenias / infections

Slide 32 · The characteristic skin eruption mimics seborrhea

Cutaneous lesions resemble a seborrheic eruption.

Infiltrating LCH cells affect scalp and anterior/posterior trunk.

The skin finding may be an early clue to multisystem disease.

Scalp

Seborrheic-like eruption

Front of trunk

Infiltrative eruption

Back of trunk

Infiltrative eruption

Systemic clues

Check organ distribution

Slide 33 · Hepatosplenomegaly and lymphadenopathy reflect infiltration

Hepatomegaly and splenomegaly occur in multisystem disease.

Lymphadenopathy is also common in that clinical pattern.

These findings indicate disease beyond a single localized lesion.

Neoplastic tissue infiltration

Enlarged liver / spleen / nodes

Multisystem disease recognition

Slide 34 · Pulmonary and osteolytic lesions add tissue injury

Pulmonary lesions may accompany other systemic manifestations.

Destructive osteolytic bone lesions can develop over time.

Bone destruction explains pain and susceptibility to fracture.

LUNG

Pulmonary lesions in multisystem disease

BONE

Progressive destructive osteolytic lesions

Slide 35 · Marrow infiltration produces cytopenias

Extensive marrow infiltration impairs normal blood-cell production.

Anemia and thrombocytopenia may result.

This mechanism links pathological infiltration to systemic risk.

Marrow infiltration

Suppressed normal hematopoiesis

Anemia + thrombocytopenia

Slide 36 · Infections can complicate multisystem disease

Widespread disease predisposes to recurrent infections.

Otitis media and mastoiditis are specifically described.

Infection susceptibility is part of the clinical burden of marrow/systemic disease.

Extensive disease

Host / marrow compromise

Recurrent infection risk

Slide 37 · Anaplastic proliferations may be labeled sarcoma

Some proliferations show striking anaplasia.

The term “Langerhans cell sarcoma” for such cases.

This must be distinguished from the usual LCH cellular phenotype.

USUAL LCH

Recognizable grooved nuclei and clinical variability

ANAPLASTIC FORM

Markedly atypical cells; Sarcoma designation in source

Slide 38 · Multisystem disease has the greatest severity

The untreated multisystem pattern may be rapidly fatal.

Approximately 50% five-year survival with chemotherapy.

That textbook figure should not be treated as a current risk-stratified estimate.

~50%

5-year survival with chemotherapy

Historical textbook estimate for the disseminated Letterer–Siwe pattern; Not contemporary individualized prognosis

Slide 39 · Unisystem LCH has one-system distribution

Single-system LCH may consist of one or multiple lesions.

The bone marrow cavities are frequent sites of localized disease.

Identical histology is possible in skin, lung, or stomach.

LCH: Clinical patterns

Unifocal single-system

Multifocal single-system

Less commonly: Non-bone single-system

Slide 40 · The common skeletal sites are recognizable

The calvaria is a common site.

Ribs and femur are also frequent locations.

Bone lesions characteristically arise within medullary cavities.

Calvaria

Common skeletal site

Ribs

Common skeletal site

Femur

Common skeletal site

Medullary cavity

Typical anatomic setting

Slide 41 · Unifocal bone disease is often called eosinophilic granuloma

“Eosinophilic granuloma” is the older designation.

This form often affects older children and adults.

The name reflects a frequent inflammatory component, not a separate cell of origin.

HISTORICAL NAME

Eosinophilic granuloma

CURRENT PATHOLOGIC IDENTITY

Unifocal Langerhans cell histiocytosis

Slide 42 · Bone lesions can be silent or symptomatic

Some unifocal lesions are incidentally asymptomatic.

Others cause localized bone pain and tenderness.

The symptom profile depends on lesion location and tissue damage.

Silent lesion

No overt symptoms

Symptomatic lesion

Local pain and tenderness

Structural damage

Possible fracture

Slide 43 · Osteolysis can culminate in pathologic fracture

Destructive lesions erode normal bone substance.

Loss of structural integrity predisposes to fracture.

A fracture in this setting is a consequence of focal tissue destruction.

Medullary LCH lesion

Osteolytic destruction

Reduced mechanical strength

Pathologic fracture

Slide 44 · Unifocal disease is commonly indolent

The localized form may heal spontaneously.

When needed, local excision or irradiation may be curative.

This course contrasts with untreated disseminated disease.

Natural history

May spontaneously heal

Local therapy

Excision or irradiation

Clinical implication

Often favorable localized course

Slide 45 · Multifocal unisystem disease peaks at ages 2–10

Multiple lesions remain within a single involved organ system.

Young children are most often affected.

Peak onset between 2 and 10 years.

2–10

Years: Peak onset

Multifocal single-system LCH in the primary source

Slide 46 · Multifocal bone lesions can expand into soft tissue

The lesions appear as multiple erosive bony masses.

Some extend beyond bone into adjacent soft tissue.

Local extension should not be confused with involvement of another organ system.

Multiple bone foci

Erosion of bone cortex

Adjacent soft-tissue expansion

Slide 47 · Pituitary-stalk infiltration explains diabetes insipidus

The posterior pituitary stalk may be involved in childhood disease.

This involvement produces diabetes insipidus.

Diabetes insipidus in about 50% of multifocal cases.

Posterior pituitary stalk lesion

Posterior pituitary disruption

Diabetes insipidus

Slide 48 · The Hand–Schüller–Christian triad

Calvarial bone defects.

Diabetes insipidus.

Exophthalmos.

Calvaria

Destructive skull defects

Pituitary stalk

Diabetes insipidus

Orbit

Exophthalmos

Pattern

Classic historical triad

Slide 49 · Multifocal disease may regress or require therapy

Many patients experience spontaneous regression.

Other patients can be treated successfully with chemotherapy.

Clinical monitoring must reflect lesion location and disease extent.

Regression

Possible without therapy

Persistent disease

May need systemic therapy

Organ-specific risk

Depends on sites involved

Slide 50 · BRAF-mutated LCH has a targeted-treatment option

Activity of BRAF inhibitors in BRAF-mutated disease.

Mutation status connects a molecular lesion to a therapeutic mechanism.

Do not infer drug selection, dosing, or universal benefit from this statement.

BRAF-mutated LCH

BRAF-directed inhibitor

Activity in mutation-positive disease

Slide 51 · Pulmonary LCH is a special clinical category

Pulmonary LCH is most often described in adult smokers.

Its clinical context differs from infantile disseminated LCH.

Smoking is a distinctive contextual factor for this presentation.

PULMONARY LCH

Commonly in adult smokers

MULTISYSTEM LCH

Frequent infancy onset; Several organs

Slide 52 · Smoking cessation may lead to pulmonary regression

Pulmonary lesions can regress spontaneously after smoking cessation.

The smoking association does not exclude a neoplastic component.

Course and intervention can therefore differ from other LCH patterns.

Smoking

Associated exposure

Cessation

Exposure removed

Possible result

Lesion regression

Regression is possible, not guaranteed

Slide 53 · Pulmonary lesions may also harbor BRAF mutations

BRAF mutations in about 40% of pulmonary LCH cases.

This supports a neoplastic component in some lesions.

The source contrasts this with earlier descriptions of reactive proliferation.

~40%

BRAF-mutated pulmonary LCH

Textbook frequency; Separate from the overall 55%–60% BRAF V600E estimate

Slide 54 · How the major patterns compare

Pattern

Distinguishing context

Typical consequence

Multisystem

Infant; several organs

Organ infiltration, cytopenias

Unifocal unisystem

Usually solitary bone lesion

Pain or pathologic fracture

Multifocal unisystem

Child; multiple bony lesions

Erosion, possible DI

Pulmonary

Frequently adult smoker

Pulmonary disease, possible regression after cessation

Slide 55 · LCH and other histiocytic disorders are not synonymous

Reactive macrophage proliferation is not inherently clonal LCH.

Highly malignant histiocytic and dendritic tumors are distinct categories.

LCH should be interpreted using lineage, morphology, and biological context.

Reactive

Non-neoplastic macrophage increase

LCH

Clonal immature dendritic-cell tumor

Other neoplasms

Sarcoma / dendritic-cell malignancy

Slide 56 · Case 1: An infant with a persistent scalp eruption

An infant has seborrheic-like scalp and truncal lesions.

Hepatosplenomegaly and enlarged lymph nodes coexist.

Biopsy shows grooved-nucleus dendritic cells.

PATTERN RECOGNITION

Scalp + trunk eruption

Hepatosplenomegaly

Lymphadenopathy

INTERPRETATION

Multifocal multisystem LCH (Letterer–Siwe pattern)

Slide 57 · Case 2: A solitary femoral lytic lesion

An older child has focal femoral pain.

Imaging describes one osteolytic lesion.

Pathology shows characteristic LCH cells with an eosinophil-rich infiltrate.

PATTERN RECOGNITION

Localized femoral pain

Single destructive bone focus

LCH-like histology

INTERPRETATION

Unifocal single-system LCH (formerly eosinophilic granuloma)

Slide 58 · Case 3: Bone lesions and polydipsia

A child has several calvarial defects.

A posterior pituitary-stalk lesion causes diabetes insipidus.

Exophthalmos accompanies the skeletal lesions.

PATTERN RECOGNITION

Calvarial defects

Diabetes insipidus

Exophthalmos

INTERPRETATION

Classic Hand–Schüller–Christian triad

Slide 59 · Case 4: Adult smoking-associated pulmonary disease

An adult smoker has an LCH-type pulmonary lesion.

Other organ-system findings are not described.

Smoking cessation may be followed by disease regression.

PATTERN RECOGNITION

Adult smoker

Pulmonary involvement

Potential regression on cessation

INTERPRETATION

Pulmonary Langerhans cell histiocytosis

Slide 60 · Diagnostic reasoning: Integrate three evidence streams

Cellular findings: Nuclear grooves, pale cytoplasm, variable eosinophils.

Cell markers: CD1a, S-100, HLA-DR; Langerin/Birbeck connection.

Clinical pattern: Lesion distribution and organ-specific consequences.

Morphologic pattern

Supporting immunophenotype

Clinical distribution

Coherent LCH interpretation

Slide 61 · Core concepts to retain

LCH is a clonal dendritic-cell neoplasm with heterogeneous clinical outcomes.

RAS-pathway drivers and CCR6/CCR7-mediated homing explain different aspects of biology.

Grooved nuclei, Birbeck granules, and typical markers identify the cell phenotype.

The distinction between localized, multisystem, and pulmonary disease matters clinically.

Slide 62 · Primary reference

Robbins, Cotran & Kumar

Pathologic Basis of Disease

11th edition (2026)

Section: Langerhans Cell Histiocytosis

Photomicrographs are not reproduced in this deck; cell/granule drawings are editable schematics.