What is Langerhans cell histiocytosis (LCH) in pediatric patients?

What is Langerhans Cell Histiocytosis in Children?

Langerhans cell histiocytosis (LCH) is a rare clonal neoplastic disorder in children characterized by abnormal proliferation of pathological Langerhans cells driven by MAPK pathway mutations, most commonly BRAF V600E, affecting approximately 3-5 cases per million children aged 0-14 years. 1, 2

Disease Classification and Pathophysiology

LCH is fundamentally a myeloid neoplasm, not a reactive inflammatory process, with MAPK pathway mutations occurring in over 90% of cases. 1, 3 The disease presents with extreme clinical heterogeneity ranging from self-limited single bone lesions to life-threatening multisystem disease. 2

Key Molecular Features:

• BRAF V600E mutation is the primary oncogenic driver, present in >50% of pediatric cases 1, 4
• LCH cells express specific markers: S100+, CD1a+, and Langerin (CD207)+ by immunohistochemistry 1, 5
• Histologically shows pathological Langerhans cells admixed with eosinophils, lymphocytes, and other inflammatory cells 6

Clinical Presentation in Children

Age Distribution:

• Peak incidence occurs between ages 3-6 years (80.6% of cases), with male predominance 6
• Highest incidence in infants under 1 year: 9.0 cases per million child years 7
• Incidence decreases with age: 0.7 cases per million in ages 10-14 years 7

Common Organ Involvement:

• Bone (60-67%): Osteolytic lesions, most commonly involving the skull, presenting with local pain 8, 6
• Skin (15-37%): Papular rash, rarely subcutaneous nodules 8, 6
• Endocrine (40-70%): Diabetes insipidus is the most common presentation, often preceding diagnosis by years; hypothalamic and pituitary stalk lesions 8
• Respiratory (50-60%): Upper lobe-predominant nodules progressing to irregular cysts, particularly in smokers (though less relevant in young children) 8
• Nervous system (5%): Dural lesions, often extending from calvarium; neurodegenerative changes in cerebellar gray matter, pons, basal ganglia 8

Disease Stratification Critical for Prognosis

Single-System Disease (73.1% of pediatric cases):

• Single-system single-site (SS-s): One organ, one location 5, 6
• Single-system multiple-site (SS-m): One organ, multiple locations 5, 6
• Excellent prognosis with 98% overall survival at 5 years 6

Multisystem Disease (25-27% of pediatric cases):

Risk stratification is mandatory based on "risk organ" involvement: 2

• Low-risk group (no risk organ involvement): Not at risk for mortality but requires systemic therapy to control disease activity and prevent reactivations 2
• Risk group (involvement of hematopoietic system, liver, and/or spleen): 20% mortality risk overall 2, 7
• High-risk group (risk organ involvement + lack of therapy response after 6-12 weeks): Up to 40% mortality 2

Critical prognostic indicator: Patients with initial liver involvement have only 25% 5-year survival compared to 93% for those with bone lesions alone. 7

Diagnostic Approach

Required Confirmatory Testing:

• Histopathologic confirmation with immunohistochemistry is mandatory 5, 4
• Required stain panel: CD163/CD68, S100, CD1a, Langerin (CD207) 5, 4
• BRAF V600E testing through immunohistochemistry or molecular methods determines targeted therapy eligibility 5, 4

Imaging Studies:

• High-resolution CT for pulmonary involvement shows characteristic peribronchiolar nodular infiltrates with cystic spaces 5, 4
• 18F-FDG PET-CT for staging and response assessment in multifocal/multisystem disease 5
• Brain MRI for suspected CNS involvement: T2 hyperintense, gadolinium-enhancing lesions of pituitary stalk, pineal gland, circumventricular regions 8

Treatment Framework

Single-System Disease:

• Observation or local therapy (curettage, low-dose radiation) for isolated bone lesions 6
• Smoking cessation counseling (for adolescents with pulmonary LCH) 5, 4

Multisystem Disease - Standard First-Line:

The established standard regimen consists of vinblastine plus prednisolone: 2

• Initial phase: 1-2 six-week courses (continuous oral prednisolone 40 mg/m²/day for 4 weeks, tapered over 2 weeks + weekly vinblastine IV) 2
• Continuation phase: Three weekly pulses of oral prednisolone 40 mg/m²/day for 5 days + vinblastine injection 2
• Total treatment duration of at least 12 months reduces reactivation rate from 50% to lower levels 2

Response Assessment:

• First evaluation at 6-12 weeks determines risk stratification 2
• Lack of response defines high-risk group requiring salvage approaches 2
• Surveillance intervals extend to 6-12 months if disease stabilizes 5

Targeted Therapies for Refractory Disease:

• BRAF inhibitors (vemurafenib) for BRAF V600E-mutant disease, though most patients relapse upon discontinuation 4, 3
• MEK inhibitors for patients with MAP2K1 mutations or BRAF inhibitor resistance 3
• Cladribine and cytarabine for refractory cases 5, 4

CNS Complications Requiring Special Attention

CNS involvement occurs in 5-10% of pediatric LCH cases and carries devastating outcomes: 5, 3

• Diabetes insipidus is the most common endocrine manifestation, requiring baseline and ongoing endocrine evaluation 8, 5
• Neurodegenerative histiocytosis presents with MRI signal abnormalities (T1 hyperintensity in globus pallidus/dentate nucleus, T2 hyperintensity in brainstem/cerebellum) and progressive neurologic decline 8
• Early MAPK inhibition may benefit patients at high risk of neurodegeneration, though this remains an area of active investigation 3

Common Pitfalls to Avoid

• Do not dismiss diabetes insipidus as idiopathic: 5-10% of apparently idiopathic central DI in children is due to LCH 8
• Do not delay biopsy for definitive diagnosis: Clinical and radiographic features alone are insufficient; immunohistochemistry is mandatory 5, 4
• Do not undertreate multisystem disease: Even low-risk multisystem patients require systemic therapy for at least 12 months to prevent reactivations 2
• Do not assume single-agent therapy is adequate: Historical trials showed inferior outcomes with etoposide or vinblastine monotherapy compared to combination regimens 2