Over the past decade, the understanding of Langerhans cell histiocytosis (LCH) has undergone a profound transformation, driven by advances in molecular genetics, advanced imaging techniques, and targeted therapies. These innovations have redefined the disease as a clonal disorder driven by alterations in the MAPK signaling pathway and have substantially changed both the diagnostic and therapeutic approach.
At the same time, it has become increasingly evident that many of the initial manifestations of LCH—including bone lesions, persistent skin rash, chronic otitis, polyuria/polydipsia, and lymphadenopathy—are first encountered by paediatricians, as they are often indistinguishable from common childhood conditions. Consequently, paediatricians play a pivotal role in early diagnosis, in recognizing atypical clinical features, and in promptly initiating the appropriate diagnostic work-up.
In this context, new personalized treatment options offer unprecedented therapeutic opportunities, but their effectiveness depends critically on the timely recognition of multisystem disease and the identification of patients at greatest risk of complications.
This review summarizes the major advances in the biology, classification, and treatment of LCH between 2015 and 2025, while highlighting their practical implications for paediatricians and the remaining challenges in diagnosis, follow-up, and the management of long-term sequelae.