Langerhans Cell Histiocytosis (LCH)
Langerhans Cell Histiocytosis (LCH) is a rare inflammatory myeloid neoplasm characterized by the abnormal clonal proliferation of Langerhans-type dendritic cells that can affect multiple organ systems, with bone involvement being the most common (95%), followed by endocrine (50-70%), respiratory (50-60%), dermatologic (15-30%), and nervous system (5%) involvement. 1
Pathophysiology and Classification
LCH was historically considered an inflammatory disorder but is now classified as a neoplastic process due to:
- Discovery of recurrent activating mutations in the MAPK/ERK pathway in >90% of patients 2
- BRAF V600E mutations present in more than 50% of LCH cases 2
- Inclusion in the 2016 World Health Organization classification of hematopoietic and lymphoid tumors 2
Clinical Manifestations
Bone Involvement
- Osteolytic lesions, commonly in the skull
- Bone pain in approximately 50% of patients 1
Endocrine Manifestations
- Diabetes insipidus is the most common endocrine manifestation
- Often precedes diagnosis
- Associated with hypothalamic and pituitary stalk lesions
- Anterior pituitary deficiencies in >50% of patients with diabetes insipidus 1
Pulmonary Involvement
- More common in smokers
- Upper lobe predominant nodules progressing to irregular cysts
- "Hairy kidney" appearance due to perinephric infiltration
- "Coated aorta" appearance from circumferential soft-tissue sheathing of the aorta 1
- Symptoms include:
- Cough (50-66%)
- Dyspnea (38%)
- Spontaneous pneumothorax (25%)
- Constitutional symptoms (weight loss, fever)
- 15-16% of cases are asymptomatic 1
Dermatologic Manifestations
- Papular rash
- Rarely subcutaneous nodules or xanthelasma-like lesions 1
Neurological Involvement
- Dural lesions, often extending from calvarium
- Neurodegenerative histiocytosis with MRI signal abnormalities
- Cerebellar involvement causing ataxia and dysarthria 1
Diagnostic Evaluation
Imaging
- Full-body PET-CT (vertex-to-toes) to evaluate disease extent
- CT or MRI for detailed bone lesion characterization 1
Laboratory Studies
- Complete blood count with differential
- Comprehensive metabolic panel
- C-reactive protein, ESR, LDH
- Morning urine and serum osmolality
- Pituitary hormone panel (FSH, LH, testosterone/estradiol, ACTH, cortisol, TSH, free T4, prolactin, IGF-1) 1
Definitive Diagnosis
- Tissue biopsy is essential
- Immunohistochemistry panel must include:
- CD1a
- Langerin
- S100
- CD68
- Factor XIIIa 1
Treatment Approach
Risk-Stratified Treatment
- Local therapy for isolated lesions
- Observation for non-progressive disease
- Systemic chemotherapy for progressive multisystem disease 1
Pulmonary LCH Treatment
- Complete cessation of tobacco smoking (critical)
- First-line: Systemic corticosteroids (prednisolone 0.5 mg/kg tapered over 6 months)
- Most effective during nodular phase of disease
- Second-line: Cladribine for steroid non-responders 1
Targeted Therapies
- BRAF inhibitors (vemurafenib) for BRAF V600E-positive refractory disease
- MEK inhibitors for other MAPK pathway mutations 1
Complications and Prognosis
Permanent Consequences
- Orthopedic problems
- Diabetes insipidus
- Anterior pituitary dysfunction (up to 25% of patients) 1
Pulmonary Complications
- Pulmonary hypertension
- Pneumothorax
- Respiratory failure 1
Disease Course
- Disease reactivation in up to 18% of patients with bone disease
- Pulmonary LCH: variable and unpredictable course
85% survive 10 years
- ~10% develop respiratory failure 1
Poor Prognostic Factors
- Continued smoking
- Presence of pulmonary hypertension
- Extensive cystic disease
- Reduced DLCO at diagnosis
- Age <2 years
- Organ dysfunction 1, 3
Monitoring
- Spirometry and lung volumes
- DLCO
- Arterial blood gas (for respiratory symptoms)
- Echocardiogram to screen for pulmonary hypertension 1
Clinical Pitfalls and Challenges
- LCH is frequently misdiagnosed due to its diverse clinical manifestations mimicking other conditions 2
- Diagnosis is often delayed, sometimes requiring multiple biopsies of critical anatomical areas 2
- Patients may receive empiric treatments resulting in adverse effects before correct diagnosis 2
- High index of suspicion is required, especially in adults where the disease is less common 4