Histiocyte Society blueprint for Langerhans cell histiocytosis research: from cell-of-origin to a more comprehensive cure

Langerhans cell histiocytosis (LCH) is a rare myeloid neoplastic disorder driven by tissue-accumulating histiocytes expressing somatic mutations mostly in genes encoding components of the intracellular mitogen-activated protein kinase (MAPK) pathway. Its clinical presentation is highly variable, ranging from self-limiting unifocal lesions to severe, multisystem disease. As a result of new therapeutic strategies, the outcomes of patients with LCH have improved significantly during the past decade. Although mortality risk is minimal nowadays, a substantial proportion of patients experience significant morbidity due to (recurrent) disease reactivations or the development of (late) complications such as organ dysfunction – including neurodegeneration – or second hematologic cancers. To date, there are no prognostic tools that adequately predict who is at risk of developing such late sequelae. Given that all major clinical advances in the field of LCH have been driven by pivotal discoveries regarding its pathophysiology, we advocate that a deeper understanding of the cell-of-origin that gives rise to pathology-inducing cells found in the patients’ blood and tissues before treatment initiation and occasionally even after treatment completion is an important missing piece of evidence with respect to understanding the pathophysiology of LCH and its late effects. Emerging techniques, such as longitudinal monitoring of driver mutations in the blood, now offer the potential to unveil the biological dynamics of the disease over its natural history. It is hoped that the much needed information, obtainable only through international collaboration and sustained long-term research projects, will bridge current gaps in clinical decision-making with the ultimate goal of improving outcomes of LCH patients worldwide.