Clinical features and treatment of Langerhans cell histiocytosis.

Abstract

Langerhans cell histiocytosis (LCH) is caused by the expansion of CD1a+/CD207+ cells and is characterised by a wide spectrum of organ involvement and dysfunction, affecting all ages. While almost all organs and systems can be affected, only the involvement and dysfunction of liver, spleen, and haematopoietic system influence survival. The LCH pathogenic cells are defined by universal activation of the mitogen-activated protein kinase (MAPK) signalling pathway. The most common alteration is a somatic BRAFV600E mutation, which is present in approximately two-thirds of the cases, followed by MAP2K1mutations. Treatment of LCH is risk-adapted; patients with single lesions may respond well to local treatment, whereas patients with multi-system disease require systemic chemotherapy. While survival for patients without organ dysfunction is excellent, mortality rates for patients with organ dysfunction may reach 20%. Despite progress made in the treatment of LCH, disease reactivation rates remain above 30%, and standard second-line treatment has yet to be established. Long-term effects, including neuroendocrine dysfunction and neurodegeneration, represent a major challenge for survivors. Treatment with BRAF or MEK inhibitors results in immediate responses, but reactivations are very common after discontinuation. Their role as single agents and in combination with chemotherapy is being explored.