What is Langerhans cell histiocytosis (LCH)?

What is Langerhans Cell Histiocytosis (LCH)?

Langerhans cell histiocytosis is a rare inflammatory myeloid neoplasm characterized by clonal proliferation and abnormal accumulation of pathologic Langerhans cells (CD1a+/Langerin+) that can infiltrate virtually any organ system, most commonly bone (60%), lung (50-60%), skin (15-30%), and the pituitary causing diabetes insipidus (40-70%). 1, 2

Disease Classification and Pathophysiology

LCH represents a clonal expansion of myeloid dendritic cells, not reactive skin Langerhans cells as historically believed. 2 The disease is now classified as an inflammatory myeloid neoplasm in the revised 2016 Histiocyte Society classification. 2

Key molecular features:

• BRAF V600E mutation is present in 50-60% of cases 1
• 100% of LCH cases demonstrate ERK phosphorylation, indicating activation of the MAPK/ERK pathway 2
• This molecular signature establishes LCH as a neoplastic rather than purely reactive process 2

Clinical Presentation Patterns

Bone involvement (60% of cases):

• Osteolytic lesions, particularly affecting the skull, femur, mandible, pelvis, and spine 1, 3, 4
• Aggressive cortically-based lytic bone lesions are characteristic 1
• Patients present with bone pain as an early clinical clue 1

Pulmonary involvement (50-60%):

• Predominantly affects smokers 1
• High-resolution CT shows upper and mid-lung predominant peribronchiolar nodular infiltrates progressing to irregular cysts with costophrenic angle sparing 5
• Early stage shows nodules; later stage shows cysts 5

Endocrine involvement (40-70%):

• Diabetes insipidus is the most common manifestation (20-30% of LCH patients) 1
• May present years before LCH diagnosis 1
• Up to 5-10% of apparently idiopathic central diabetes insipidus cases are due to LCH 1
• MRI shows T2 hyperintense, gadolinium-enhancing lesions of the pituitary stalk, pineal gland, and circumventricular regions 1

Dermatologic involvement (15-30%):

• Papular rash is most common 1
• Rarely presents as subcutaneous nodules or xanthelasma-like lesions 1, 6

Neurologic involvement (5%):

• Dural lesions, often extending from calvarium 1
• Symmetrical T2 hyperintense signals in cerebellar gray matter, pons, basal ganglia, and globus pallidus 1, 7
• Can be asymptomatic or associated with progressive neurologic decline (termed "neurodegenerative histiocytosis") 1

Lymph node involvement (5-10%):

• Rarely isolated; when present as part of multisystem disease, represents higher risk 1
• Distinct sinus pattern distinguishes it from reactive Langerhans cells 1

Diagnostic Approach

Histopathologic confirmation is mandatory: 8

• Lesions are typically more cellular than other histiocytic disorders with overt cytologic atypia 1
• Nuclei are slightly enlarged with delicate nuclear grooves and less condensed chromatin 1
• Intermixed eosinophils are commonly present and often numerous 1

Required immunohistochemical panel: 1

• CD1a: positive
• Langerin: positive
• S100: positive
• CD68: positive
• CD163: negative or weakly positive
• BRAF V600E: positive in 50-60% (requires molecular testing for definitive detection) 1

For pulmonary LCH:

• Bronchoalveolar lavage is diagnostic if CD1a-stained cells exceed 5% 5, 8
• Bronchoscopic or surgical lung biopsy provides definitive diagnosis 5

Critical diagnostic pitfall: Classic histopathologic features may not always be present, showing only nonspecific inflammation and fibrosis. In bone biopsies, process additional cores without decalcification or use EDTA-based decalcification to enable molecular analysis. 1

Disease Spectrum and Prognosis

Clinical forms:

• Single-system single-site (SS-s) 8
• Single-system multiple-site (SS-m) 8
• Multisystem disease (carries higher risk, especially with organ dysfunction) 9

Prognostic factors:

• Age <2 years at diagnosis predicts worse overall survival 9
• Organ dysfunction (particularly pulmonary, liver, or hematological involvement) significantly affects survival 9
• Multifocal and extranodal disease indicates less favorable prognosis 5
• Approximately 10% mortality rate in progressive pulmonary disease 5, 8

Course variability:

• Ranges from asymptomatic presentation to progressive respiratory failure 5
• Most patients with pulmonary involvement suffer persistent or progressive disease 5
• Overall survival rate is 84% at 8-year median follow-up 9

Treatment Principles

For pulmonary LCH:

• Smoking cessation is the cornerstone and may result in clinical improvement in approximately 33% of patients 5, 8
• Systemic corticosteroids for significant symptoms or progressive disease 5, 8

For systemic disease:

• Vinblastine with or without prednisolone is the most commonly used chemotherapy regimen 9
• BRAF inhibitors (e.g., vemurafenib) for BRAF V600E-mutant disease 8
• Cytarabine and cladribine for refractory disease 8

Monitoring schedule:

• First response assessment within 4 months of initiating treatment 5, 8
• If disease stabilizes or enters remission, extend surveillance intervals to 6-12 months 5, 8
• Monitor DLCO, which is frequently reduced in pulmonary LCH 5