Decoding The Molecular Landscape of Erdheim–Chester Disease: From BRAF to Beyond

Abstract

Erdheim-Chester disease (ECD) is a rare, multisystemic non-Langerhans cell histiocytosis that causes clonal proliferation of lipid-laden CD68⁺/CD1a⁻ foamy histiocytes. ECD was formerly misdiagnosed as an inflammatory condition, but current improvements in molecular diagnostics have redefined it as a clonal hematopoietic neoplasm caused mostly by mutations in the mitogen-activated protein kinase (MAPK) pathway. The BRAF^V600E mutation is the most common, accounting for 50-60% of patients. It is linked to systemic involvement and a poor prognosis. Additional mutations in MAP2K1, NRAS, KRAS, and PIK3CA have been discovered, demonstrating the genetic variability and complexity of ECD etiology.This review delves deeply into the pathophysiological underpinnings of ECD, with an emphasis on MAPK and PI3K-AKT-mTOR pathway dysregulation, histiocyte immunohistochemistry profiles, and the significance of a Th1-skewed cytokine milieu. Molecular discoveries have not only increased diagnosis accuracy, but also influenced the development of targeted medicines. BRAF inhibitors (vemurafenib, dabrafenib) and MEK inhibitors (cobimetinib, trametinib) have shown significant effectiveness in mutation-specific cases. Furthermore, emerging resistance mechanisms, such as secondary KRAS mutations, have prompted research into combination therapies and alternative pathway blockade.  Diagnostic methods, including as liquid biopsy and next-generation sequencing (NGS), have improved mutation identification, particularly in low-yield or fibrotic tumors. Future directions include the integration of single-cell omics, spatial transcriptomics, and the identification of novel targets such as CSF1R, which would provide a precision oncology framework for ECD. This increasing molecular knowledge identifies ECD as a paradigm for mutation-driven, targeted treatment in uncommon histiocytic neoplasms, stressing the importance of routine genetic sequencing to enhance clinical outcomes and therapeutic methods.