Multisystem Langerhans cell histiocytosis (with or without risk-organ involvement)

Multisystem Langerhans cell histiocytosis involves two or more organ systems, typically skin, bone, lymph nodes, pituitary, lungs and, in the highest-risk children, the liver, spleen and haematopoietic system. Risk-organ involvement, defined by hepatomegaly with liver dysfunction, splenomegaly or cytopenias, and a poor response to the first six weeks of therapy are the two strongest predictors of death; the mortality of risk-organ-positive disease has fallen from more than half in the 1980s to a small minority in the era of standardised protocols and salvage therapy. BRAF V600E is present in most multisystem cases, and the mutant clone can be traced to haematopoietic progenitors in the marrow, which explains why high-risk disease behaves like a systemic myeloid neoplasm; circulating BRAF V600E DNA tracks disease burden and predicts relapse.

The Histiocyte Society trials built the standard. LCH-I and LCH-II established vinblastine and prednisone as the backbone; LCH-III (Blood 2013), which randomised 376 patients, showed that adding methotrexate did not help but that extending treatment from six to twelve months roughly halved reactivation, and that children who respond by week six do well. For children with risk-organ disease who do not respond, cytarabine and cladribine (LCH-S-2005) or, in the most refractory, the intensive cladribine-cytarabine regimen followed by reduced-intensity allogeneic transplantation are salvage options, and the ongoing LCH-IV trial tests longer and intensified therapy. BRAF inhibitors changed refractory disease: vemurafenib and dabrafenib produce rapid responses in BRAF V600E-mutant children, including infants with risk-organ disease, though the disease returns when they stop, and cobimetinib is approved for adults with histiocytic neoplasms; combining targeted agents with chemotherapy to achieve durable remissions is the current trial question. Survivors face diabetes insipidus and anterior pituitary deficiency in a substantial minority, neurodegenerative disease years later, sclerosing cholangitis, hearing loss and orthopaedic problems, so structured long-term follow-up is standard.