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

Source: https://onco.cc/cancers/lch-multisystem/  
OnCo record `lch-multisystem` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

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.

## Fields

- Kind: Cancer
- Last checked: 2026-09-18
- Also known as: Multisystem LCH; MS-LCH; Risk-organ-positive LCH; Letterer-Siwe disease (obsolete); Hand-Schüller-Christian disease (obsolete)
- Tags: subtype-page; paediatric
- 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

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/lch-multisystem/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/lch-multisystem/#overview [3 state-of-the-art points]
- Types and stages (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/lch-multisystem/#what-it-is [6 subtypes]
- Symptoms and diagnosis (on the hub): How this cancer shows itself, how the diagnosis is confirmed, and the biomarkers clinicians test for. https://onco.cc/cancers/lch-multisystem/#finding-it [6 biomarkers]
- Treatment (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/lch-multisystem/#treating-it [5 settings, 5 decisions with options]
- Trials and papers (on the hub): Trials recruiting now, the landmark trials, the trials held by this cancer's subtypes, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/lch-multisystem/#evidence [1 trial, 3 key papers, 6 milestones]
- Biology and targets (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/lch-multisystem/#science [1 target, 1 pathway]
- Countries and centres (own page): Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes. https://onco.cc/cancers/lch-multisystem/where-you-are/
- Decisions and support (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/lch-multisystem/#living-with-it [18 questions, 6 red cards]
- Pipeline and open problems (own page): Everything in development, the medicines held by this cancer's subtypes, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/lch-multisystem/coming/ [5 medicines, 1 trial, 4 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/lch-multisystem/data/ [26 connected records]

## Standard of care

- Diagnosis and staging: Biopsy with BRAF testing; blood count, liver tests, coagulation, abdominal ultrasound, skeletal survey or whole-body MRI, pituitary assessment. ([BRAF V600E mutation](https://onco.cc/terms/braf-v600-mutation/), [MRI](https://onco.cc/technologies/mri/), [Ultrasound](https://onco.cc/technologies/ultrasound/), [Histopathology & immunohistochemistry](https://onco.cc/technologies/histopathology-ihc/))
- First line: 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. ([Vinblastine](https://onco.cc/drugs/vinblastine/), [LCH-III](https://onco.cc/trials/lch-iii/), [Cytotoxic chemotherapy](https://onco.cc/technologies/cytotoxic-chemotherapy/))
- Non-response at week six or risk-organ progression: 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. ([Cladribine](https://onco.cc/drugs/cladribine/), [Vemurafenib](https://onco.cc/drugs/vemurafenib/), [Dabrafenib + trametinib](https://onco.cc/drugs/dabrafenib-trametinib/), [Allogeneic stem cell transplantation](https://onco.cc/technologies/allogeneic-hsct/))
- Reactivation: Repeat vinblastine-prednisone or cytarabine; targeted therapy for repeated reactivation; enrolment in LCH-IV. ([Vinblastine](https://onco.cc/drugs/vinblastine/), [Cladribine](https://onco.cc/drugs/cladribine/), [Vemurafenib](https://onco.cc/drugs/vemurafenib/))
- Long-term follow-up: Endocrine, neurological, hearing, hepatic and orthopaedic surveillance for late effects through a survivorship programme. ([Late effects and survivorship toxicity](https://onco.cc/terms/late-effects/), [Survivorship care and late-effects surveillance](https://onco.cc/technologies/survivorship-care-plan/), [MRI](https://onco.cc/technologies/mri/))

## State of the art

- 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.

## Open problems

- 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.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Langerhans_cell_histiocytosis
- LCH-III (Blood 2013): https://doi.org/10.1182/blood-2012-09-455774
- NCI PDQ Langerhans cell histiocytosis: https://www.cancer.gov/types/langerhans/hp/langerhans-treatment-pdq
- Wikipedia: https://en.wikipedia.org/wiki/Langerhans_cell_histiocytosis

## Connected records

- cancers: [Erdheim-Chester disease](https://onco.cc/cancers/erdheim-chester-disease/), [Langerhans cell histiocytosis (LCH)](https://onco.cc/cancers/langerhans-cell-histiocytosis/), [Single-system Langerhans cell histiocytosis (bone, skin or one other organ)](https://onco.cc/cancers/lch-single-system/)
- technologies: [Allogeneic stem cell transplantation](https://onco.cc/technologies/allogeneic-hsct/), [Cytotoxic chemotherapy](https://onco.cc/technologies/cytotoxic-chemotherapy/), [Histopathology & immunohistochemistry](https://onco.cc/technologies/histopathology-ihc/), [Liquid biopsy (ctDNA)](https://onco.cc/technologies/liquid-biopsy/), [MRI](https://onco.cc/technologies/mri/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/), [Survivorship care and late-effects surveillance](https://onco.cc/technologies/survivorship-care-plan/), [Ultrasound](https://onco.cc/technologies/ultrasound/)
- targets: [BRAF](https://onco.cc/targets/braf/)
- drugs: [Cladribine](https://onco.cc/drugs/cladribine/), [Cobimetinib](https://onco.cc/drugs/cobimetinib/), [Dabrafenib + trametinib](https://onco.cc/drugs/dabrafenib-trametinib/), [Vemurafenib](https://onco.cc/drugs/vemurafenib/), [Vinblastine](https://onco.cc/drugs/vinblastine/)
- terms: [BRAF V600E mutation](https://onco.cc/terms/braf-v600-mutation/), [Cytopenias and myelosuppression](https://onco.cc/terms/cytopenias/), [Late effects and survivorship toxicity](https://onco.cc/terms/late-effects/)
- trials: [LCH-III](https://onco.cc/trials/lch-iii/)
- key papers: [LCH-III: therapy prolongation improves outcome in multisystem Langerhans cell histiocytosis](https://onco.cc/key-papers/paper-lch-iii-therapy-prolongation-multisystem-lch-blood-2013/), [Recurrent BRAF mutations in Langerhans cell histiocytosis](https://onco.cc/key-papers/paper-badalian-very-braf-mutations-lch-blood-2010/), [Vemurafenib for refractory multisystem Langerhans cell histiocytosis in children: an international observational study](https://onco.cc/key-papers/paper-donadieu-vemurafenib-refractory-multisystem-lch-jco-2019/)
- pathways: [RAS / RAF / MEK / ERK (MAPK)](https://onco.cc/pathways/ras-mapk/)

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JSON: https://onco.cc/api/v1/entities/lch-multisystem.json