Histiocyte Society blueprint for non-Langerhans cell histiocytosis research: unraveling complex diseases through collaboration

Histiocytic neoplasms are rare hematologic disorders characterized by pathological infiltration of myeloid-derived cells in various organs, resulting in diverse manifestations. Traditionally, histiocytic neoplasms were classified into Langerhans cell histiocytosis (LCH) and non-LCH, the latter comprising a heterogeneous group of diseases including Erdheim-Chester disease, xanthogranuloma family of lesions, Rosai-Dorfman disease, indeterminate cell histiocytosis, and malignant histiocytic neoplasms. Over the past decade, the discovery of recurrent somatic alterations in the MAPK pathway has revolutionized the diagnosis and management of these disorders, enabling the use of targeted therapies and significantly improving patients' outcomes. Despite these advances, critical gaps remain in our understanding and treatment of non-LCH. Challenges include adverse effects from prolonged use of targeted therapies, insufficient data on the natural history of these diseases, outdated nomenclature and classification systems that fail to account for emerging insights, and limited availability of clinical trials due to the rarity of the conditions. In this article, we synthesize key advancements in the field and propose a blueprint for future research to address these unmet needs. We emphasize the importance of collaborative efforts, such as large, multi-institutional registries and novel clinical trials, to generate robust, high-quality data that can guide diagnostic, management, and prognostic strategies.