Langerhans Cell Histiocytosis

High Yield Overview

Langerhans Cell Histiocytosis

Clonal proliferation of CD1a+ dendritic cells - spectrum from eosinophilic granuloma to multisystem disease

5-10 yearsPeak Age

M:F 2:1Gender Ratio

Skull 50%Most Common Site

50-60%BRAF V600E+

LCH Disease Classification

Critical Must-Knows

CD1a+ and Langerin+ on immunohistochemistry (pathognomonic)
Spectrum: Eosinophilic granuloma (unifocal) to Letterer-Siwe (disseminated)
Skull (50%), femur (20%), ribs (10%), vertebrae (7%)
Vertebra plana with PRESERVED disc spaces (vs infection)
BRAF V600E mutation in 50-60% - therapeutic target for refractory disease

Examiner's Pearls

"
Beveled edge skull lesion = pathognomonic for LCH in children
"
Unifocal: observation is valid (50% spontaneous resolution)
"
Risk organs (liver, spleen, marrow) determine prognosis
"
Diabetes insipidus develops in 18-25% with skull lesions

Clinical Imaging

Imaging Gallery

Langerhans cell histiocytosis of the bone. Immunohistochemical positive reaction with S100 in bone lesion ×10.Credit: Sarmadi S et al. via J Med Case Rep via Open-i (NIH) (Open Access (CC BY))

Fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging study. Demonstrating a 5×1.4 cm focal FDG uptake lesion with right frontal bone destruction in the right forehead area. — Fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging study. Demonstrating a 5×1.4 cm focal FDG uptake lesion with right frontal bone Credit: Kim S et al. via Arch Plast Surg via Open-i (NIH) (Open Access (CC BY))

Computed tomography imaging study. Demonstrating the irregularly beveled marginated lytic bone defect involving the right frontal skull vault including the inner table and the superolateral orbital wa — Computed tomography imaging study. Demonstrating the irregularly beveled marginated lytic bone defect involving the right frontal skull vault includinCredit: Kim S et al. via Arch Plast Surg via Open-i (NIH) (Open Access (CC BY))

The immunohistochemical stains for S-100 protein. Positive cells with elongated nuclei (×40).Credit: Kim S et al. via Arch Plast Surg via Open-i (NIH) (Open Access (CC BY))

High Yield Exam Topic

At a Glance

Langerhans cell histiocytosis (LCH) is a clonal proliferation of CD1a+ and Langerin+ dendritic cells with a spectrum ranging from solitary eosinophilic granuloma to disseminated multisystem disease (Letterer-Siwe). It predominantly affects children aged 5-10 years with male predominance (2:1), with the skull (50%) and femur (20%) being the most common skeletal sites. Characteristic findings include "punched-out" lytic skull lesions, vertebra plana in the spine, and histology showing Langerhans cells with coffee-bean nuclei and Birbeck granules. BRAF V600E mutation is present in 50-60% and is a therapeutic target. Treatment ranges from observation/curettage for unifocal bone disease to chemotherapy for multisystem involvement.

Mnemonic

SKULLFIRSTLCH Skeletal Sites

Skull (50% - most common)

Kids affected (peak 5-10 years)

Unifocal or multifocal bone

Long bones (femur 20%, humerus)

Lumbar/thoracic spine (vertebra plana)

Flat bones (ribs 10%, pelvis 10%)

Ilium and acetabulum

Ribs posterior

Solitary (60%) or multiple (40%)

Temporal bone (mastoid, petrous)

Memory Hook:SKULL FIRST for anatomical distribution

Exam Essentials:

Clonal proliferation of CD1a+ and Langerin+ dendritic cells
Spectrum: Eosinophilic granuloma (unifocal) to Letterer-Siwe disease (disseminated)
Peak incidence: Children 5-10 years, males more than females (2:1)
Skull and femur most common skeletal sites (50% and 20%)
Biopsy shows Langerhans cells with coffee-bean nuclei and Birbeck granules
BRAF V600E mutation in 50-60% of cases
Treatment: Observation (solitary lesion) to chemotherapy (multisystem)
Prognosis: Excellent for unifocal (90% cure), guarded for disseminated

Epidemiology & Pathogenesis

Demographics

Age Distribution:

Peak Incidence: 5-10 years (80% of cases under 15 years)
Adult Cases: 20% of all LCH, usually unifocal bone
Neonatal: Rare, often multisystem involvement
Median Age: 7 years for skeletal LCH

Gender:

Male to female ratio: 2:1 overall
Unifocal disease: Male to female 1.5:1
Multisystem disease: Male to female 3:1

Incidence:

Overall: 4-9 cases per million children per year
Skeletal involvement: 80% of all LCH cases
Multisystem disease: 20% of LCH cases
Geographic variation: Higher in Caucasian populations

Anatomical Distribution:

Skull: 50% (calvarium, temporal bone, orbit)
Femur: 20% (diaphysis more than metaphysis)
Ribs: 10% (posterior ribs common)
Pelvis: 10% (ilium, acetabulum)
Vertebrae: 7% (vertebra plana, thoracic greater than lumbar)
Mandible: 5% (loose teeth, gingival swelling)
Other: 8% (humerus, scapula, clavicle)

Pathogenesis

Molecular Biology:

BRAF V600E Mutation: Present in 50-60% of LCH cases
- Activating mutation in MAPK/ERK pathway
- Higher frequency in multisystem disease (60-70%)
- Associated with increased recurrence risk
- Therapeutic target for refractory disease
MAP2K1 Mutations: 20% of BRAF-negative cases
- Alternative MAPK pathway activation
- Similar clinical phenotype to BRAF-mutated LCH
Other Alterations: RAS pathway mutations, chromosomal abnormalities (rare)

Cellular Origin:

Clonal proliferation of myeloid dendritic cells
Cells express CD1a, CD207 (Langerin), S100 protein
Birbeck granules on electron microscopy (tennis racket appearance)
Eosinophils, lymphocytes, macrophages in infiltrate

Disease Classification:

Historical LCH Classification (Lichtenstein)

entity	sites	age	prognosis	current_term
Eosinophilic Granuloma	Unifocal or multifocal bone	5-30 years	Excellent (greater than 90% cure)	Unifocal or multifocal bone LCH
Hand-Schüller-Christian	Multifocal bone + soft tissue	2-6 years	Good with treatment	Multifocal LCH without risk organs
Letterer-Siwe Disease	Multisystem (bone, skin, organs)	Less than 2 years	Guarded (50-70% survival)	Multisystem LCH with risk organs

Modern Classification (Histiocyte Society):

Single-System LCH:
- Single-site (solitary eosinophilic granuloma)
- Multiple-site (polyostotic, pulmonary)
Multisystem LCH:
- Without risk organ involvement
- With risk organ involvement (liver, spleen, bone marrow, lung)

Clinical Presentation

Skeletal Manifestations

Symptoms:

Localized Pain: 60-70% (worse at night, not relieved by rest)
Swelling: 50% (soft tissue mass overlying bone lesion)
Functional Limitation: 30% (limp with lower limb lesions)
Incidental Finding: 20% (asymptomatic, found on imaging)
Pathological Fracture: 10-15% (long bone lesions)

Physical Examination:

Focal tenderness over lesion
Soft tissue fullness or mass
Limited range of motion (vertebral or juxta-articular)
Low-grade fever (30% of cases)
Regional lymphadenopathy (uncommon)

Site-Specific Presentations:

Skull:

Palpable defect or "hole" in calvarium
Scalp swelling (subperiosteal extension)
Mastoid involvement: Chronic otitis media, external auditory canal polyp
Orbital involvement: Proptosis, visual disturbance
"Button sequestrum" on X-ray (central bone fragment)

Vertebrae:

Back pain with activity
Thoracic kyphosis (vertebra plana)
Rarely neurological deficit (less than 5%)
Complete vertebral collapse possible
Adjacent disc spaces preserved (key feature)

Long Bones:

Diaphyseal more than metaphyseal
Periosteal reaction simulating infection
Pathological fracture with minor trauma
"Onion-skin" periosteal layering possible

Mandible:

Loose teeth, gingival swelling
"Floating tooth" appearance on X-ray
Jaw pain, trismus

Systemic Manifestations (Multisystem Disease)

Classic Triad (Hand-Schüller-Christian):

Diabetes insipidus (25% of multisystem cases)
Exophthalmos (orbital involvement)
Lytic skull lesions

Risk Organ Involvement:

Liver: Hepatomegaly, jaundice, dysfunction (poor prognosis)
Spleen: Splenomegaly, hypersplenism
Bone Marrow: Cytopenias, pancytopenia
Lung: Cough, dyspnea, pneumothorax (usually older children/adults)

Skin:

Seborrheic dermatitis-like rash (scalp, retroauricular)
Papular eruption (trunk, groin)
Present in 30-40% multisystem cases

Other:

Lymphadenopathy (cervical, axillary)
Hepatosplenomegaly
Failure to thrive (disseminated disease)

Key Findings:

LCH-I and LCH-II trials: 525 children with multisystem LCH
Risk organ involvement (liver, spleen, marrow): 5-year survival 74% vs 100% without risk organs
Skeletal-only LCH: 95% 5-year disease-free survival with observation or minimal intervention
Diabetes insipidus developed in 24% of multisystem cases, permanent in 18%
Chemotherapy (vinblastine + prednisolone) improved outcomes in multifocal disease

Clinical Implication: This evidence guides current practice.

Investigations

Imaging

Plain Radiography:

Skull:

"Punched-out" lytic lesions, well-defined margins
"Beveled edge" (inner table destruction greater than outer table)
"Button sequestrum" (central bone fragment)
"Geographic skull" (multiple coalescent lesions)

Spine:

Vertebra plana (complete vertebral collapse, pancake vertebra)
Preserved disc spaces (key to differentiate from infection)
Isolated vertebral body involvement
No paraspinal soft tissue mass (vs tumor, infection)

Long Bones:

Lytic lesion, diaphyseal or metaphyseal
"Moth-eaten" or permeative bone destruction
Periosteal reaction (laminated, solid, or "onion-skin")
Sequestrum formation possible
Pathological fracture

Advanced Imaging:

MRI:

T1: Low signal intensity in lesion
T2: High signal intensity, surrounding marrow edema
STIR: Bright signal, extensive edema pattern
Contrast: Marked enhancement (hypervascular)
Purpose: Define soft tissue extension, spinal canal involvement

CT:

Superior for cortical bone detail
Delineate skull base and orbital lesions
Assess vertebral body integrity
3D reconstruction for surgical planning

Nuclear Medicine:

Bone Scan (Tc-99m): Increased uptake at lesion sites
PET-CT: Valuable for staging, detecting occult lesions
- Higher sensitivity than skeletal survey for bone lesions
- Detects extraskeletal involvement
- Useful for monitoring treatment response

Skeletal Survey:

Mandatory for all LCH cases
AP and lateral skull, spine, pelvis
AP chest (include ribs)
AP long bones bilaterally
Detect multifocal disease (affects prognosis and treatment)

Imaging Key Points:

Vertebra plana with PRESERVED disc spaces distinguishes LCH from infection (discitis destroys disc) and metastasis
"Beveled edge" skull lesions are highly specific for LCH in children
PET-CT more sensitive than skeletal survey for detecting multifocal disease
MRI essential if spine lesion to rule out epidural extension or instability

Laboratory Investigations

Baseline Studies:

CBC: Assess for cytopenias (marrow involvement)
ESR/CRP: Often elevated but non-specific
LFTs: Screen for liver dysfunction
Coagulation: PT/PTT if hepatic involvement
Renal Function: Baseline before chemotherapy

Specialized Tests:

Water Deprivation Test: If diabetes insipidus suspected
Urinalysis: Polyuria, low specific gravity
Serum and Urine Osmolality: Confirm DI

Staging Investigations:

Skeletal survey (or PET-CT)
Chest X-ray/CT (pulmonary involvement)
Abdominal ultrasound or MRI (liver, spleen)
Consider bone marrow biopsy if cytopenias

Histopathology

Macroscopic:

Tan-gray soft tissue
Granular, friable consistency
No gross necrosis or hemorrhage

Microscopic Features:

Langerhans Cells: Large cells with abundant eosinophilic cytoplasm
- Reniform or "coffee-bean" nuclei (nuclear grooves)
- Eccentric nuclei with fine chromatin
Eosinophils: Prominent, may form microabscesses
Lymphocytes: T-cells, scattered macrophages
Giant Cells: Occasional multinucleated giant cells
Necrosis: May be present in active lesions

Immunohistochemistry:

CD1a: Positive (hallmark, membranous staining)
Langerin (CD207): Positive (cytoplasmic, more specific than CD1a)
S100 Protein: Positive (nuclear and cytoplasmic)
CD68: Variable positivity
Cytokeratin: Negative (helps exclude carcinoma)

Electron Microscopy (if available):

Birbeck Granules: "Tennis racket" or "zipper" appearance
Rod-shaped cytoplasmic inclusions
Diagnostic but not required (CD1a/Langerin sufficient)

Molecular Testing:

BRAF V600E: Mutation analysis (paraffin tissue or blood)
Positive in 50-60% of cases
Guides targeted therapy decisions
Higher positivity in multisystem disease

Mnemonic

LANGERHANSLCH Histological Diagnosis

Langerin (CD207) positive - most specific

Abundant eosinophils in infiltrate

Nuclear grooves (coffee-bean nuclei)

Granules (Birbeck) on electron microscopy

Eosinophilic cytoplasm of Langerhans cells

Reniform nuclei characteristic

Histiocytes mixed with lymphocytes

Absent cytokeratin (vs carcinoma)

No specific chromosomal abnormality

S100 protein positive

Memory Hook:LANGERHANS for diagnostic features

Management

Risk Stratification

Single-System Disease:

Unifocal Bone (60%): Solitary eosinophilic granuloma
- Prognosis: Excellent (greater than 90% spontaneous resolution or cure)
- Treatment: Observation or minimal intervention
Multifocal Bone (20%): Multiple bone lesions, no soft tissue
- Prognosis: Good with chemotherapy
- Treatment: Low-dose chemotherapy if 2 or more lesions

Multisystem Disease (20%):

Without Risk Organs: Bone + skin, lymph nodes
- Prognosis: Good (greater than 90% survival)
- Treatment: Combination chemotherapy
With Risk Organs: Liver, spleen, marrow involvement
- Prognosis: Guarded (70-80% survival)
- Treatment: Intensive chemotherapy protocols

Treatment by Disease Extent

Unifocal Bone Lesion:

Observation:

Indications: Asymptomatic, non-weight-bearing bone, no structural risk
Protocol: Clinical and radiographic monitoring every 3-6 months
Outcome: 50% spontaneous resolution within 1-2 years
Duration: Until lesion heals or stabilizes

Curettage ± Bone Grafting:

Indications: Symptomatic pain, weight-bearing bone, structural risk
Technique: Intralesional curettage, local adjuvant (phenol, H₂O₂), autograft/allograft
Outcomes: 90% local control, low recurrence (less than 10%)
Complications: Pathological fracture during healing (5-10%)

Steroid Injection:

Technique: Intralesional methylprednisolone (80-120 mg)
Indications: Vertebral lesions, inaccessible sites
Outcomes: Effective in 70-80%, may require repeat injection
Benefits: Minimally invasive, accelerates healing

En Bloc Resection:

Indications: Expendable bones (rib, fibula, clavicle)
Outcomes: Definitive local control (near 100%)
Advantage: Tissue diagnosis and cure in single procedure

Radiation Therapy:

Historical Use: Previously common, now avoided in children
Current Role: Very limited (refractory cases only)
Dose: 6-10 Gy if absolutely necessary
Concerns: Secondary malignancy risk, growth plate damage

High Yield

Unifocal Bone Treatment Principles:

Observation is VALID first-line (50% spontaneous resolution)
Curettage for symptomatic lesions or structural concern
Steroid injection excellent for vertebral lesions (avoid surgery)
En bloc resection if expendable bone (rib, fibula)
Avoid radiation in children (malignancy risk)
Pathological fractures heal with conservative management (cast/brace)

Multifocal Bone and Multisystem Disease:

Chemotherapy Protocols:

First-Line (Histiocyte Society LCH-III):

Vinblastine: 6 mg/m² IV weekly x 6 weeks, then every 3 weeks
Prednisolone: 40 mg/m² PO daily x 4 weeks, then taper
Duration: 12 months for multifocal bone, 12-24 months for multisystem

Intensification (Risk Organ Involvement):

Add Mercaptopurine or Methotrexate
More frequent dosing schedule
Extended duration (24 months)

Refractory Disease (Second-Line):

Cytarabine (Ara-C): High-dose protocols
Cladribine (2-CDA): 5 mg/m² IV daily x 5 days, monthly cycles
BRAF Inhibitors: Vemurafenib, dabrafenib (if BRAF V600E+)
MEK Inhibitors: Trametinib, cobimetinib

Targeted Therapy:

BRAF V600E Inhibitors: Vemurafenib 20 mg/kg PO BID
- Indications: Refractory multisystem disease with BRAF mutation
- Response Rate: 60-70% in salvage setting
- Toxicity: Rash, photosensitivity, arthralgia
MEK Inhibitors: For MAP2K1-mutated disease

Special Situations:

Vertebra Plana:

Observation: Usually spontaneous reconstitution (50-70%)
Bracing: If kyphotic deformity or instability
Steroid Injection: Accelerates healing, reduces pain
Surgery: Very rare (neurological compromise only)
Reconstitution: Gradual over 2-5 years, often incomplete

Spinal Lesions with Instability/Neurology:

MRI to assess epidural extension
Neurosurgical consultation
Decompression ± stabilization if cord compromise
Chemotherapy as definitive treatment (surgery adjunct only)

Pathological Fracture:

Conservative management (cast/splint)
Lesion usually heals concurrently with fracture
Surgery rarely needed (non-union, severe displacement)

Key Findings:

LCH-III trial: 279 patients with multisystem LCH randomized to vinblastine/prednisolone +/- mercaptopurine
Overall survival: 84% at 5 years (risk organ involvement main predictor)
Diabetes insipidus: 24% developed DI, 18% permanent, associated with craniofacial lesions
Reactivation rate: 46% (multisystem without risk organs) vs 58% (with risk organs)
Long-term sequelae: 40% had permanent consequences (DI, orthopedic deformities, neurodevelopmental)

Clinical Implication: This evidence guides current practice.

Surgical Considerations

Indications for Surgery:

Diagnostic biopsy (confirm diagnosis)
Symptomatic relief (pain, mass effect)
Structural instability (pathological fracture risk)
Neurological compromise (spinal cord compression)
Failed conservative management

Surgical Techniques:

Curettage:

Approach based on anatomical site
Thorough curettage of cavity
Local adjuvant (phenol, hydrogen peroxide)
Bone grafting (autograft or allograft)
Prophylactic fixation if structural concern

Vertebral Lesions:

Usually avoid surgery (steroid injection preferred)
Decompression only if neurological deficit
Posterior approach for epidural extension
Anterior corpectomy rarely needed

Pathological Fracture:

Closed reduction and casting usually sufficient
ORIF if unstable fracture pattern
Curettage at time of fixation (if accessible)

Complications & Prognosis

Complications

Diabetes Insipidus (18-25%):

Mechanism: Hypothalamic-pituitary axis involvement
Presentation: Polyuria, polydipsia, hypernatremia
Diagnosis: Water deprivation test, low urine osmolality
Management: Desmopressin (DDAVP) lifelong
Risk Factors: Craniofacial bone lesions, multisystem disease

Orthopedic Sequelae:

Vertebral collapse and kyphosis (10-15%)
Limb length discrepancy (femoral lesions)
Pathological fracture malunion/nonunion (rare)
Joint stiffness (juxta-articular lesions)
Premature physeal closure (metaphyseal lesions)

Neurocognitive Dysfunction (10-20%):

Associated with multisystem disease
Cerebellar involvement (ataxia, dysarthria)
Behavioral and learning difficulties
MRI: White matter changes, cerebellar atrophy

Pulmonary Complications:

Pneumothorax (spontaneous)
Respiratory failure (diffuse involvement)
Progressive fibrosis (chronic disease)

Other:

Hearing loss (temporal bone involvement)
Dental problems (mandibular lesions)
Sclerosing cholangitis (liver involvement)
Growth retardation (pituitary dysfunction)

Prognosis

Unifocal Bone Disease:

Survival: Near 100%
Recurrence: 10-20% (usually at same site)
Spontaneous Resolution: 50% without intervention
Long-term Sequelae: Minimal (cosmetic deformity rare)

Multifocal Bone Disease:

Survival: 95-100%
Disease-Free Survival: 70-80% at 5 years
Reactivation: 30-40% (new lesions or progression)
Permanent Disability: 20% (mainly DI, orthopedic)

Multisystem Disease Without Risk Organs:

Survival: 90-95%
Reactivation: 40-50%
Permanent Consequences: 40% (DI, neurocognitive)

Multisystem Disease With Risk Organs:

Survival: 70-80% (significantly worse if poor initial response)
Reactivation: 50-60%
Permanent Sequelae: 60-70%

Prognostic Factors:

Favorable:

Unifocal bone disease
Age greater than 2 years
Single-system involvement
Good response to initial therapy

Unfavorable:

Age less than 2 years
Risk organ involvement (liver, spleen, marrow)
Poor initial response to chemotherapy (6 weeks)
Multisystem disease with greater than 3 organs

Mnemonic

RISKORGANSLCH High-Risk Features

Refractory to initial chemotherapy (6-week non-responders)

Infant (age less than 2 years)

Spleen involvement (risk organ)

Kids with marrow dysfunction (cytopenias)

Organs greater than 3 involved (multisystem)

Recurrent/reactivation disease (46-58% rate)

Growth failure, hepatomegaly

Abnormal liver function tests

No BRAF mutation (less responsive to targeted therapy)

Systemic symptoms (fever, failure to thrive)

Memory Hook:RISK ORGANS for poor prognosis

Differential Diagnosis

Infection:

Osteomyelitis: Fever, elevated WBC/CRP, metaphyseal location
Discitis: Disc space narrowing (vs preserved in LCH vertebra plana)
Tuberculous Osteomyelitis: Chronic course, epidemiology
Differentiation: Blood cultures, bone biopsy, clinical course

Neoplastic:

Ewing Sarcoma: Diaphyseal, "onion-skin" periosteal reaction, soft tissue mass
Osteosarcoma: Metaphyseal, sunburst periosteal reaction, elevated ALP
Metastases: Neuroblastoma (children), carcinoma (adults)
Lymphoma: Older children/adults, systemic symptoms
Differentiation: Biopsy, immunohistochemistry

Other Histiocytic Disorders:

Erdheim-Chester Disease: Adults, bilateral femoral/tibial diaphyseal sclerosis
Rosai-Dorfman Disease: Massive lymphadenopathy, S100+ CD1a- cells
Juvenile Xanthogranuloma: Skin lesions, CD68+ CD1a- cells

Metabolic/Other:

Fibrous Dysplasia: Ground-glass matrix, no Langerhans cells
Hyperparathyroidism: Brown tumors, elevated PTH, multiple lesions
Multiple Myeloma: Adults, monoclonal protein, plasma cells on biopsy

LCH vs Key Differentials

feature	lch	ewing	osteomyelitis	fibrous_dysplasia
Age	5-10 years peak	10-20 years peak	Any age	Adolescents/adults
Location	Skull, femur, ribs	Diaphysis long bones	Metaphysis	Ribs, femur, skull
Radiograph	Lytic, punched-out	Permeative, onion-skin	Lytic, periosteal rxn	Ground-glass, sclerotic rim
Soft Tissue	Minimal to moderate	Large soft tissue mass	Abscess possible	None
Biopsy	CD1a+ Langerhans cells	Small blue cells, CD99+	Inflammatory, organisms	Fibrous stroma, woven bone
Systemic	May have multisystem	Metastases possible	Fever, sepsis	McCune-Albright (rare)

References

Key Findings:

Histiocyte Society international guidelines: Evidence-based management algorithms
BRAF V600E mutation discovery: Present in 57% of LCH cases, therapeutic target
LCH-II trial: Chemotherapy improves outcomes in multisystem disease
Long-term follow-up: 40% develop permanent sequelae (DI, orthopedic, neurocognitive)

Clinical Implication: This evidence guides current practice.

Exam Viva Scenarios

Practice these scenarios to excel in your viva examination

VIVA SCENARIOStandard

Child with Skull Lesion

EXAMINER

"A 7-year-old boy presents with a painless scalp swelling for 2 months. X-ray shows a 3 cm well-defined lytic lesion in the left parietal bone with 'beveled edge' appearance. Parents are very concerned about cancer."

EXCEPTIONAL ANSWER

This clinical and radiographic presentation is highly suggestive of Langerhans cell histiocytosis (eosinophilic granuloma). My approach: (1) History - confirm painless swelling, no systemic symptoms (fever, weight loss), recent trauma. (2) Examination - palpate skull defect, assess overlying skin (normal vs inflamed), check for other bony lesions, lymphadenopathy. (3) Imaging - complete skeletal survey to determine unifocal vs multifocal disease (affects treatment), consider PET-CT if available (more sensitive). (4) Laboratory - CBC (rule out cytopenias), ESR/CRP, LFTs, urinalysis (screen for multisystem). (5) Biopsy - obtain tissue for diagnosis (open biopsy or needle under fluoroscopy), send for H and E, CD1a, Langerin, BRAF mutation analysis. (6) Counseling - reassure family this is likely benign if unifocal LCH with excellent prognosis (greater than 90% cure). (7) Staging - once diagnosis confirmed, determine single-system vs multisystem (clinical exam, imaging, labs). (8) Treatment - if unifocal and asymptomatic: observation vs curettage. If multifocal: low-dose chemotherapy. (9) MDT discussion with pediatric oncology for chemotherapy planning if needed. (10) Long-term surveillance for diabetes insipidus and reactivation.

KEY POINTS TO SCORE

Beveled edge skull lesion in child strongly suggests LCH

Skeletal survey mandatory to determine unifocal vs multifocal (changes management)

Biopsy required for diagnosis: CD1a and Langerin positive cells

Unifocal bone LCH has excellent prognosis (greater than 90% cure)

Treatment options: Observation (50% spontaneous resolution) vs curettage

Screen for multisystem disease (CBC, LFTs, urinalysis, skeletal survey)

Long-term surveillance for diabetes insipidus (18-25% risk with skull lesions)

COMMON TRAPS

✗Assuming malignancy based on lytic lesion - LCH is benign histiocytic disorder

✗Not performing skeletal survey - multifocal disease requires chemotherapy

✗Rushing to surgery without staging - observation valid for unifocal asymptomatic

✗Missing diabetes insipidus on follow-up - screen for polyuria/polydipsia

✗Not involving pediatric oncology for multifocal/multisystem cases

✗Forgetting BRAF mutation testing - important for refractory disease treatment options

LIKELY FOLLOW-UPS

"What immunohistochemical stains confirm LCH diagnosis?"

"The skeletal survey shows 3 additional rib lesions. How does this change management?"

"What is the role of BRAF mutation testing in LCH?"

"Parents ask about radiation therapy. What do you tell them?"

"How do you screen for diabetes insipidus during follow-up?"

"What are risk organs and why are they important prognostically?"

VIVA SCENARIOStandard

Vertebra Plana in Adolescent

EXAMINER

"A 12-year-old girl presents with 3-month history of mid-thoracic back pain. MRI shows complete collapse of T7 vertebral body (vertebra plana) with preserved disc spaces and no epidural extension. Biopsy confirms Langerhans cell histiocytosis. Parents want aggressive treatment to restore vertebral height."

EXCEPTIONAL ANSWER

Vertebra plana from LCH has unique natural history with potential for spontaneous reconstitution. My management: (1) Confirm diagnosis - review biopsy (CD1a+, Langerin+), BRAF mutation status. (2) Staging - complete skeletal survey or PET-CT to determine single lesion vs multifocal disease, laboratory screen (CBC, LFTs, urinalysis, water deprivation test if DI suspected). (3) Neurological assessment - detailed neurological exam (currently normal), MRI confirms no cord compression or instability. (4) Pain management - NSAIDs, activity modification, consider TLSO brace for comfort and support during healing. (5) Treatment options: FIRST-LINE is intralesional steroid injection (methylprednisolone 80-120 mg under CT guidance) - accelerates healing, reduces pain, minimally invasive. ALTERNATIVE is observation only if pain controlled with conservative measures. CHEMOTHERAPY if multifocal bone disease (2 or more lesions) per Histiocyte Society protocols (vinblastine/prednisolone). (6) Counsel family: Vertebral reconstitution occurs in 50-70% cases over 2-5 years (gradual remodeling), complete height restoration uncommon but functional outcome excellent, surgery does NOT improve reconstitution and carries significant morbidity, residual kyphosis usually mild and well-tolerated. (7) Follow-up: Serial radiographs/MRI every 3-6 months to monitor reconstitution, screen for reactivation and diabetes insipidus, reassess neurological status. (8) Surgery indications: ONLY if neurological compromise (rare) or progressive kyphotic deformity with instability (very rare). (9) Long-term: Most patients return to full activities, residual kyphosis typically less than 20 degrees and asymptomatic.

KEY POINTS TO SCORE

Vertebra plana in LCH: Preserved disc spaces (key differential from infection/tumor)

Spontaneous reconstitution occurs in 50-70% over 2-5 years

First-line treatment: Intralesional steroid injection (minimally invasive, effective)

Surgery rarely indicated (only if neurological compromise or instability)

Complete height restoration uncommon but functional outcome excellent

Must stage disease (skeletal survey) - multifocal requires chemotherapy

Screen for diabetes insipidus (25% risk) and other endocrinopathies

COMMON TRAPS

✗Offering surgical vertebral reconstruction - high morbidity, doesn't improve natural reconstitution

✗Not recognizing spontaneous reconstitution potential - overly aggressive treatment

✗Missing multifocal disease - skeletal survey mandatory, changes to chemotherapy

✗Promising complete vertebral height restoration - set realistic expectations

✗Not screening for diabetes insipidus - higher risk with spinal involvement

✗Treating as infection based on vertebral collapse - preserved discs key distinguishing feature

LIKELY FOLLOW-UPS

"How do you perform intralesional steroid injection for vertebral LCH?"

"The patient develops polyuria and polydipsia. What is your concern and workup?"

"Skeletal survey shows additional lesions in femur and ribs. How does this change management?"

"What is the role of bracing in vertebra plana from LCH?"

"After 2 years, there is minimal vertebral reconstitution with 25-degree kyphosis. What now?"

"When would you involve pediatric oncology in this case?"

Key Findings:

Vertebra plana in LCH: 44 patients followed mean 8.2 years
Spontaneous reconstitution: 68% partial, 32% minimal, mean time 3.1 years
Final kyphotic deformity: Mean 18 degrees (range 5-35 degrees)
Functional outcome: 91% asymptomatic at final follow-up regardless of reconstitution
Surgical intervention: 2/44 patients (5%) required surgery for neurological compromise
Recommendation: Conservative management with observation or steroid injection

Clinical Implication: This evidence guides current practice.

Exam Day Cheat Sheet

MCQ Practice Points

Exam Pearl

Q: What are the diagnostic immunohistochemical markers for Langerhans cell histiocytosis?

A: CD1a positive and Langerin (CD207) positive - these are pathognomonic. Also S100 positive. Cytokeratin negative (differentiates from metastatic carcinoma). Histologically shows Langerhans cells with characteristic coffee-bean nuclei in a background of abundant eosinophils. Birbeck granules (tennis racket shape) on electron microscopy are diagnostic but no longer required.

Exam Pearl

Q: What is the classic radiographic finding of LCH in the spine?

A: Vertebra plana - complete collapse of a vertebral body with preserved disc spaces. This differentiates LCH from infection (disc destruction) and metastases (variable disc involvement). Most commonly affects thoracic and lumbar spine. Despite dramatic appearance, most cases reconstitute spontaneously and are treated conservatively with observation or bracing.

Exam Pearl

Q: What is the BRAF mutation significance in LCH?

A: BRAF V600E mutation is present in 50-60% of LCH cases. This establishes LCH as a clonal neoplastic proliferation rather than reactive disorder. Has therapeutic implications - BRAF inhibitors (vemurafenib, dabrafenib) can be used for refractory multisystem disease. Also useful for differentiating from other histiocytic disorders if tissue diagnosis unclear.

Exam Pearl

Q: How is LCH classified and what determines prognosis?

A: Unifocal (eosinophilic granuloma): Single bone lesion, excellent prognosis (90%+ cure). Multifocal unisystem: Multiple bone lesions, good prognosis. Multisystem without risk organ involvement: Involves bone plus other organs (skin, nodes). Multisystem with risk organ involvement (liver, spleen, bone marrow): Worst prognosis, 70-80% survival. Risk organs define need for systemic chemotherapy.

Exam Pearl

Q: What is the orthopaedic management approach for unifocal LCH (eosinophilic granuloma)?

A: Conservative management is first-line for most lesions. Options include: Observation alone (many lesions resolve spontaneously), intralesional corticosteroid injection (methylprednisolone), or curettage with bone grafting for large lesions or impending fracture. Surgery indicated only for: neurological compromise, pathological fracture, or diagnostic uncertainty. Radiation reserved for unresectable locations (skull base).

Australian Context

Australian Epidemiology and Management

Incidence and Referral Patterns:

Australian incidence: approximately 4-5 cases per million children per year
Centralised management through state-based children's hospitals with paediatric oncology services
Orthopaedic involvement typically for skeletal lesions requiring biopsy or curettage
Multi-disciplinary team (MDT) approach mandated for all cases in Australian paediatric oncology centres

RACS Orthopaedic Training Relevance:

LCH appears in FRACS Orthopaedic examination as a differential for lytic bone lesions in children
Key examination topics: differentiation from primary bone tumours, indication for biopsy, and surgical management of skeletal lesions
Understanding the spectrum from unifocal eosinophilic granuloma to multisystem disease is essential

Pharmaceutical Benefits Scheme (PBS) and TGA:

Vemurafenib (BRAF V600E inhibitor) is TGA registered for LCH refractory to first-line therapy
Cytarabine-based regimens available through PBS for multisystem LCH
Access to targeted therapies may require application through Special Access Scheme (SAS) for paediatric patients

Children's Cancer Institute Australia:

National research initiatives for rare paediatric cancers including LCH
Biobanking and genomic profiling programs for histiocytic disorders
Clinical trials coordination through Australian and New Zealand Children's Haematology/Oncology Group (ANZCHOG)

Management Algorithm