{"entity":{"id":"lch-multisystem","kind":"cancer","name":"Multisystem Langerhans cell histiocytosis (with or without risk-organ involvement)","aka":["Multisystem LCH","MS-LCH","Risk-organ-positive LCH","Letterer-Siwe disease (obsolete)","Hand-Schüller-Christian disease (obsolete)"],"tldr":"Multisystem Langerhans cell histiocytosis is the severe form of this rare histiocytosis, in which the abnormal cells involve several organs at once, most dangerously the liver, spleen and bone marrow of infants. It is treated with a year of vinblastine and prednisone, with stronger drugs or BRAF-targeted tablets for children who do not respond quickly; survival is now high but late effects remain.","summary":"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.\n\nThe 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.","asOf":"2026-09-18","wikipedia":"https://en.wikipedia.org/wiki/Langerhans_cell_histiocytosis","links":[{"label":"LCH-III (Blood 2013)","url":"https://doi.org/10.1182/blood-2012-09-455774"},{"label":"NCI PDQ Langerhans cell histiocytosis","url":"https://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq"},{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Langerhans_cell_histiocytosis"}],"tags":["subtype-page","paediatric"],"related":["lch-single-system","langerhans-cell-histiocytosis","erdheim-chester-disease"],"cancers":[],"sections":[],"technologies":["cytotoxic-chemotherapy","kinase-inhibitors","allogeneic-hsct","mri","ultrasound","liquid-biopsy","survivorship-care-plan"],"targets":["braf"],"drugs":["vinblastine","cladribine","vemurafenib","dabrafenib-trametinib","cobimetinib"],"companies":[],"institutions":[],"pathways":[],"terms":["late-effects","braf-v600-mutation","cytopenias"],"trials":["lch-iii"],"people":[],"bottlenecks":[],"keyPapers":["paper-lch-iii-therapy-prolongation-multisystem-lch-blood-2013","paper-donadieu-vemurafenib-refractory-multisystem-lch-jco-2019","paper-badalian-very-braf-mutations-lch-blood-2010"],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"About a third of childhood Langerhans cell histiocytosis, commonest in infants and toddlers; involvement of the liver, spleen or bone marrow (risk organs) once carried high mortality and still marks the group that needs intensive treatment.","subtypes":["Multisystem Langerhans cell histiocytosis without risk-organ involvement (vinblastine and prednisone)","Multisystem Langerhans cell histiocytosis with risk-organ involvement (liver, spleen, bone marrow)","Refractory or non-responding multisystem Langerhans cell histiocytosis (cytarabine, cladribine, BRAF inhibitors)","Central nervous system risk lesions and pituitary Langerhans cell histiocytosis (diabetes insipidus)","Neurodegenerative Langerhans cell histiocytosis (late complication)","Adult multisystem Langerhans cell histiocytosis (cytarabine or cladribine based)"],"biomarkers":["Risk-organ involvement at diagnosis (liver, spleen, cytopenias)","Response at week six (LCH-III)","BRAF V600E in tissue and cell-free DNA (burden, relapse)","MAP2K1 and other MAPK alterations","Pituitary MRI, water deprivation testing and anterior pituitary hormones","Brain MRI for neurodegenerative change; liver imaging for sclerosing cholangitis"],"standardOfCare":[{"setting":"Diagnosis and staging","approach":"Biopsy with BRAF testing; blood count, liver tests, coagulation, abdominal ultrasound, skeletal survey or whole-body MRI, pituitary assessment.","refs":["braf-v600-mutation","mri","ultrasound","histopathology-ihc"],"guideline":{"version":"Histiocyte Society evaluation and treatment guidelines; NCI PDQ","url":"https://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq"}},{"setting":"First line","approach":"Vinblastine and prednisone induction for six to twelve weeks, then continuation to twelve months in total (LCH-III); mercaptopurine added for risk-organ disease in some protocols.","refs":["vinblastine","lch-iii","cytotoxic-chemotherapy"],"guideline":{"version":"Histiocyte Society evaluation and treatment guidelines; NCI PDQ","url":"https://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq"}},{"setting":"Non-response at week six or risk-organ progression","approach":"Switch to cytarabine or cladribine; intensive cladribine-cytarabine for refractory risk-organ disease; BRAF inhibitor (vemurafenib, dabrafenib) for BRAF V600E-mutant disease; reduced-intensity allogeneic transplantation in selected cases.","refs":["cladribine","vemurafenib","dabrafenib-trametinib","allogeneic-hsct"],"guideline":{"version":"Histiocyte Society evaluation and treatment guidelines; NCI PDQ","url":"https://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq"}},{"setting":"Reactivation","approach":"Repeat vinblastine-prednisone or cytarabine; targeted therapy for repeated reactivation; enrolment in LCH-IV.","refs":["vinblastine","cladribine","vemurafenib"],"guideline":{"version":"Histiocyte Society evaluation and treatment guidelines; NCI PDQ","url":"https://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq"}},{"setting":"Long-term follow-up","approach":"Endocrine, neurological, hearing, hepatic and orthopaedic surveillance for late effects through a survivorship programme.","refs":["late-effects","survivorship-care-plan","mri"],"guideline":{"version":"Histiocyte Society evaluation and treatment guidelines; NCI PDQ","url":"https://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq"}}],"stateOfArt":["Standardised vinblastine-prednisone protocols and salvage therapy have made death rare even in risk-organ disease.","BRAF inhibitors rescue refractory infants but do not yet cure.","Circulating BRAF V600E DNA gives a marker of residual disease."],"history":[{"year":1924,"title":"Letterer describes the acute disseminated disease of infants","refs":[]},{"year":1991,"title":"LCH-I opens as the first international randomised trial in the disease","refs":["vinblastine"]},{"year":2010,"title":"BRAF V600E discovered in Langerhans cell histiocytosis","refs":["braf","ras-mapk"]},{"year":2013,"title":"LCH-III: twelve months of therapy halves reactivation; methotrexate adds nothing","refs":["lch-iii","vinblastine"]},{"year":2019,"title":"Vemurafenib reported to produce responses in refractory BRAF-mutant children","refs":["vemurafenib"]},{"year":2022,"title":"Cobimetinib approved for adults with histiocytic neoplasms including Langerhans cell histiocytosis","refs":["cobimetinib"]}],"pipeline":["dabrafenib-trametinib","vemurafenib","lch-iii","cobimetinib"],"openProblems":["Targeted therapy controls but does not cure; how to stop it safely is unknown.","Neurodegenerative disease appears years later and has no proven treatment.","Reactivation affects a third or more of children despite twelve months of therapy.","Adults are treated by extrapolation from paediatric protocols."],"parent":"langerhans-cell-histiocytosis"},"route":"/cancers/lch-multisystem/","neighbours":{"cancer":[{"id":"erdheim-chester-disease","kind":"cancer","name":"Erdheim-Chester disease","route":"/cancers/erdheim-chester-disease/"},{"id":"langerhans-cell-histiocytosis","kind":"cancer","name":"Langerhans cell histiocytosis (LCH)","route":"/cancers/langerhans-cell-histiocytosis/"},{"id":"lch-single-system","kind":"cancer","name":"Single-system Langerhans cell histiocytosis (bone, skin or one other organ)","route":"/cancers/lch-single-system/"}],"technology":[{"id":"allogeneic-hsct","kind":"technology","name":"Allogeneic stem cell transplantation","route":"/technologies/allogeneic-hsct/"},{"id":"cytotoxic-chemotherapy","kind":"technology","name":"Cytotoxic chemotherapy","route":"/technologies/cytotoxic-chemotherapy/"},{"id":"histopathology-ihc","kind":"technology","name":"Histopathology & immunohistochemistry","route":"/technologies/histopathology-ihc/"},{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"},{"id":"mri","kind":"technology","name":"MRI","route":"/technologies/mri/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"},{"id":"survivorship-care-plan","kind":"technology","name":"Survivorship care and late-effects surveillance","route":"/technologies/survivorship-care-plan/"},{"id":"ultrasound","kind":"technology","name":"Ultrasound","route":"/technologies/ultrasound/"}],"target":[{"id":"braf","kind":"target","name":"BRAF","route":"/targets/braf/"}],"drug":[{"id":"cladribine","kind":"drug","name":"Cladribine","route":"/drugs/cladribine/"},{"id":"cobimetinib","kind":"drug","name":"Cobimetinib","route":"/drugs/cobimetinib/"},{"id":"dabrafenib-trametinib","kind":"drug","name":"Dabrafenib + trametinib","route":"/drugs/dabrafenib-trametinib/"},{"id":"vemurafenib","kind":"drug","name":"Vemurafenib","route":"/drugs/vemurafenib/"},{"id":"vinblastine","kind":"drug","name":"Vinblastine","route":"/drugs/vinblastine/"}],"term":[{"id":"braf-v600-mutation","kind":"term","name":"BRAF V600E mutation","route":"/terms/braf-v600-mutation/"},{"id":"cytopenias","kind":"term","name":"Cytopenias and myelosuppression","route":"/terms/cytopenias/"},{"id":"late-effects","kind":"term","name":"Late effects and survivorship toxicity","route":"/terms/late-effects/"}],"trial":[{"id":"lch-iii","kind":"trial","name":"LCH-III","route":"/trials/lch-iii/"}],"paper":[{"id":"paper-lch-iii-therapy-prolongation-multisystem-lch-blood-2013","kind":"paper","name":"LCH-III: therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis","route":"/key-papers/paper-lch-iii-therapy-prolongation-multisystem-lch-blood-2013/"},{"id":"paper-badalian-very-braf-mutations-lch-blood-2010","kind":"paper","name":"Recurrent BRAF mutations in Langerhans cell histiocytosis","route":"/key-papers/paper-badalian-very-braf-mutations-lch-blood-2010/"},{"id":"paper-donadieu-vemurafenib-refractory-multisystem-lch-jco-2019","kind":"paper","name":"Vemurafenib for refractory multisystem Langerhans cell histiocytosis in children: an international observational study","route":"/key-papers/paper-donadieu-vemurafenib-refractory-multisystem-lch-jco-2019/"}],"pathway":[{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"}]}}