Pediatric Langerhans Cell Histiocytosis of Bone: A systematic review of the unknown mechanism of self-healing

Langerhans cell histiocytosis (LCH) is a rare pediatric neoplasm frequently involving bone. While various therapeutic strategies exist, including surgery and systemic therapy, some lesions—particularly unifocal bone lesions—have demonstrated a capacity for spontaneous healing. This review explores the clinical characteristics, proposed mechanisms, and therapeutic implications of self-healing in pediatric LCH bone lesions. A systematic literature search was conducted in March 2025 using PubMed, Google Scholar, and SciSpace databases. Studies were selected following PRISMA guidelines, with inclusion criteria focusing on pediatric patients with LCH presenting bone involvement, particularly those demonstrating spontaneous regression post-biopsy, curettage, or conservative management. Data on clinical presentation, treatment approaches, and proposed pathophysiological mechanisms were extracted and analysed. Spontaneous resolution of bone lesions was most commonly observed in unifocal eosinophilic granuloma. Approximately 5–10 % of pediatric LCH cases demonstrated lesion regression post-biopsy or after minimal intervention. Proposed mechanisms include biopsy-induced inflammation, immune system modulation, apoptosis via the Fas/Fas-L pathway, and disruption of the MAPK signalling cascade—especially in the presence of BRAF V600E mutations. Nanoparticle-based delivery of targeted agents, such as anti-BCL2 or cytokine inhibitors, represents an emerging therapeutic strategy with potential to replicate this natural healing process. Spontaneous healing is a clinically significant but underreported aspect of pediatric LCH, with implications for reducing invasive treatment. Understanding the molecular and immunological drivers of lesion regression may guide future personalized therapies. Further research into targeted drug delivery and apoptosis modulation could shift the therapeutic paradigm, offering fewer toxic alternatives to systemic chemotherapy in select patients.