What is the pathophysiology of Langerhans cell histiocytosis (LCH)?

Pathophysiology of Langerhans Cell Histiocytosis

Langerhans cell histiocytosis is fundamentally a clonal neoplastic disorder driven by activating mutations in the MAPK/ERK pathway, most notably BRAFV600E (present in 50-60% of cases), rather than a reactive inflammatory process. 1, 2

Molecular Basis

• MAPK pathway mutations (BRAF V600E, PI3K/AKT pathway alterations) occur in over 90% of LCH cases and represent the primary oncogenic driver 1, 3
• The BRAFV600E mutation can arise in multipotent hematopoietic progenitor cells (HPCs), particularly in multisystem disease, establishing LCH as a myeloid neoplasm rather than a localized reactive process 2
• These mutations activate the MAPK/ERK signaling cascade, leading to uncontrolled cellular proliferation and survival 4

Cellular Mechanisms

Senescence-Driven Pathology

• BRAFV600E expression in HPCs induces a senescence program that causes growth arrest, apoptosis resistance, and development of a senescence-associated secretory phenotype (SASP) 2
• SASP promotes HPC skewing toward the mononuclear phagocyte lineage, leading to accumulation of senescent cells in tissues and granuloma formation 2
• This senescence mechanism explains why proliferative indices of Langerhans cells are paradoxically low (~1.9%) despite disease progression 5

Immune Dysregulation

• Regulatory T cells (CD4+ CD25high FoxP3high T-regs) are markedly expanded in LCH lesions, comprising approximately 20% of T cells within granulomas compared to normal tissue 5
• T-regs are found in close contact with Langerhans cells and are also expanded in peripheral blood during active disease (7/7 patients showed impaired delayed-type hypersensitivity) 5
• This T-reg expansion creates an immunosuppressive microenvironment that prevents the host immune system from eliminating LCH cells, allowing disease persistence 5

Lesion Composition and Microenvironment

• The majority of proliferating cells in LCH granulomas are not Langerhans cells but rather endothelial cells, fibroblasts, and polyclonal T lymphocytes 5
• LCH lesions demonstrate active inflammation, tissue remodeling, and neo-angiogenesis 5
• Interleukin-10 is abundant within granulomas, contributing to the immunosuppressive environment 5
• Langerhans cells express RANK (TNF receptor family member), suggesting involvement of osteoclast-related pathways in bone lesions 5

Cellular Phenotype

• LCH cells show Langerhans cell differentiation markers: S100+, CD1a+, and Langerin+ by immunohistochemistry 1
• Cells display slightly enlarged nuclei with delicate nuclear grooves and less condensed chromatin compared to reactive Langerhans cells 1
• Intermixed eosinophils are commonly present and often numerous, with higher degrees of eosinophilia associated with single-system disease 1, 6
• BRAF V600E mutation can be demonstrated by immunohistochemistry in affected tissues 1

Key Pathophysiologic Distinction

The critical insight is that LCH results from cellular survival and accumulation rather than uncontrolled proliferation 5. The combination of:

• Oncogenic MAPK pathway activation
• Senescence-induced apoptosis resistance
• SASP-mediated tissue recruitment
• T-reg-mediated immune evasion

creates a self-perpetuating cycle where clonal Langerhans-type cells accumulate in tissues despite low proliferative activity, forming the characteristic granulomatous lesions of LCH 5, 2.