{"entity":{"id":"histiocytoses","kind":"cancer","name":"Erdheim-Chester disease, Rosai-Dorfman disease and other histiocytic neoplasms","aka":["ECD","Erdheim-Chester disease","Rosai-Dorfman disease","RDD","Rosai-Dorfman-Destombes disease","Histiocytic sarcoma","Juvenile xanthogranuloma","Mixed ECD-LCH","L-group and R-group histiocytoses"],"tldr":"Histiocytoses are diseases in which immune scavenger cells build up in bone, heart, brain, kidneys and skin. They used to be treated as inflammatory conditions with steroids and interferon. The discovery that most carry mutations in the same growth pathway as melanoma turned them into targetable cancers: BRAF and MEK inhibitor pills now produce responses in nearly every treated patient.","summary":"The histiocytic neoplasms are clonal disorders of macrophage or dendritic cell lineage. The 2016 revised Histiocyte Society classification groups them into L (Langerhans: LCH, ECD, mixed ECD-LCH), C (cutaneous non-LCH, including juvenile xanthogranuloma), R (Rosai-Dorfman disease), M (malignant histiocytoses such as histiocytic sarcoma) and H (haemophagocytic lymphohistiocytosis, a hyperinflammatory syndrome rather than a neoplasm). Erdheim-Chester disease (ECD) infiltrates long bones, the retroperitoneum ('hairy kidney'), the heart and aorta, the orbits and the brain; BRAF V600E is present in around half of patients, with most of the rest carrying other MAPK-pathway alterations (MAP2K1, ARAF, NRAS, KRAS, RAF1 fusions) or PIK3CA mutations. Rosai-Dorfman disease shows emperipolesis in S100-positive, CD1a-negative histiocytes and carries KRAS or MAP2K1 mutations in a large minority. The same mutations in the same lineage in adults and children unify these diseases with Langerhans cell histiocytosis, which has its own page.\n\nTreatment was transformed by targeted therapy. Interferon alfa was the previous first line for ECD. Vemurafenib produced responses in essentially every BRAF-mutant ECD patient in the VE-BASKET trial, leading to FDA approval in November 2017, the first approval for any histiocytosis. Cobimetinib, a MEK inhibitor, gave responses regardless of mutation status in a phase 2 trial (Diamond and colleagues, Nature Medicine 2019) and was FDA-approved in October 2022 for adult histiocytic neoplasms including ECD, RDD and LCH. Responses are deep and durable but relapse follows discontinuation in most patients, so therapy is often prolonged at reduced doses. Rosai-Dorfman disease is observed if asymptomatic, and treated with surgery, steroids, sirolimus, cladribine or MEK inhibitors when it causes harm. Histiocytic sarcoma is treated with lymphoma-type chemotherapy, radiotherapy and, increasingly, MAPK-pathway inhibitors. Mixed ECD-LCH and the neurodegenerative complications of both are the hardest problems.\n\nInternational consensus recommendations for ECD (Blood 2020) and the Histiocyte Society trials network coordinate care and research.","asOf":"2026-09-10","wikipedia":"https://en.wikipedia.org/wiki/Erdheim%E2%80%93Chester_disease","links":[{"label":"NCI PDQ: Langerhans cell histiocytosis (histiocytic disorders)","url":"https://www.cancer.gov/types/langerhans"},{"label":"Consensus recommendations for ECD (Blood 2020)","url":"https://doi.org/10.1182/blood.2019003507"},{"label":"Cobimetinib in histiocytic neoplasms (Nature Medicine 2019)","url":"https://doi.org/10.1038/s41591-019-0653-6"},{"label":"NCCN: Histiocytic Neoplasms","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1518"}],"tags":["nci-coverage","rare","haematologic","histiocytosis"],"related":["langerhans-cell-histiocytosis","melanoma","cmml"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","fdg-pet","liquid-biopsy","cgp","mri"],"targets":["braf","alk","pik3ca"],"drugs":["vemurafenib","cobimetinib","dabrafenib-trametinib","interferon-alfa","cladribine"],"companies":["roche-genentech"],"institutions":["histiocyte-society"],"pathways":["ras-mapk","pi3k-akt-mtor","clonal-haematopoiesis"],"terms":["braf-v600-mutation","driver-mutation","ctdna","retroperitoneum"],"trials":[],"people":[],"bottlenecks":["b-rare-cancers","b-generic-repurposing"],"keyPapers":["paper-durham-nat-med"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Erdheim-Chester disease has been described in only a few thousand patients worldwide, mostly adults in their fifties and sixties; Rosai-Dorfman disease and histiocytic sarcoma are similarly rare (Histiocyte Society registries).","subtypes":["Erdheim-Chester disease (BRAF V600E-mutant or wild-type)","Mixed ECD-LCH","Rosai-Dorfman-Destombes disease (nodal, extranodal, cutaneous, familial)","Juvenile xanthogranuloma and other C-group cutaneous histiocytoses","Histiocytic sarcoma and other malignant histiocytoses","ALK-positive histiocytosis (rare; responds to ALK inhibitors)"],"biomarkers":["BRAF V600E (tissue; plasma ctDNA for monitoring)","MAP2K1, ARAF, NRAS, KRAS, PIK3CA, RAF1 and ALK fusions on NGS","Immunophenotype: CD68, CD163, factor XIIIa positive; CD1a and langerin negative (ECD, RDD); S100 with emperipolesis (RDD)","FDG-PET/CT for extent and response","Cardiac MRI and brain MRI for organ involvement","Clonal haematopoiesis (mutations shared with myeloid clones in some patients)"],"standardOfCare":[{"setting":"ECD, BRAF V600E-mutant, needing treatment","approach":"Vemurafenib (FDA approval 2017) or dabrafenib, often with a MEK inhibitor to reduce toxicity; long-term treatment at the lowest effective dose.","refs":["vemurafenib","dabrafenib-trametinib","braf"],"guideline":{"version":"Consensus recommendations for ECD (Blood 2020)","url":"https://doi.org/10.1182/blood.2019003507"}},{"setting":"ECD or RDD, BRAF wild-type or intolerant of BRAF inhibitors","approach":"Cobimetinib (FDA approval October 2022 for histiocytic neoplasms) or another MEK inhibitor; interferon alfa or pegylated interferon as an alternative.","refs":["cobimetinib","interferon-alfa"],"guideline":{"nccn":"Category 2A","version":"NCCN Guidelines: Histiocytic Neoplasms","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1518"}},{"setting":"Rosai-Dorfman disease","approach":"Observation for asymptomatic nodal disease; surgery for isolated masses; steroids, sirolimus, cladribine or MEK inhibitors for symptomatic or multifocal disease.","refs":["cladribine","cobimetinib"],"guideline":{"version":"Consensus recommendations for RDD (Blood 2018)","url":"https://doi.org/10.1182/blood-2018-03-839753"}},{"setting":"Histiocytic sarcoma","approach":"Lymphoma-type chemotherapy (CHOP, ICE, or similar), radiotherapy for localised disease, MAPK-pathway inhibitors where mutations are found; clinical trials.","refs":["cyclophosphamide","doxorubicin","etoposide","cobimetinib"]}],"stateOfArt":["The MAPK pathway discovery (BRAF V600E in ECD, 2012) converted histiocytoses from mysterious inflammatory diseases into targetable neoplasms.","Vemurafenib (2017) and cobimetinib (2022) are the first drugs ever approved for a histiocytosis, with responses in nearly every treated patient.","Plasma BRAF V600E ctDNA and FDG-PET allow response monitoring and dose reduction without repeat biopsy.","The remaining challenges are stopping therapy without relapse, neurodegeneration, and histiocytic sarcoma."],"history":[{"year":1930,"title":"Erdheim and Chester describe 'lipoid granulomatosis'","refs":[]},{"year":1969,"title":"Rosai and Dorfman describe sinus histiocytosis with massive lymphadenopathy","note":"Destombes had reported cases in 1965.","refs":[]},{"year":2012,"title":"BRAF V600E found in ECD and LCH","note":"Haroche and colleagues (Blood 2012) after Badalian-Very's LCH discovery (2010).","refs":["braf"]},{"year":2016,"title":"Revised Histiocyte Society classification","note":"L, C, R, M and H groups (Emile et al., Blood 2016).","refs":[]},{"year":2017,"title":"Vemurafenib approved for ECD","note":"First approval for any histiocytosis (VE-BASKET); November 2017.","refs":["vemurafenib"]},{"year":2019,"title":"Cobimetinib effective regardless of genotype","note":"Diamond and colleagues, Nature Medicine 2019.","refs":["cobimetinib"]},{"year":2022,"title":"Cobimetinib approved for histiocytic neoplasms","note":"FDA approval October 2022 for adults with ECD, RDD and LCH.","refs":["cobimetinib"]}],"pipeline":["cobimetinib","vemurafenib","dabrafenib-trametinib"],"openProblems":["Most patients relapse when BRAF or MEK inhibitors stop; intermittent dosing and ctDNA-guided discontinuation are being tested.","Neurodegenerative ECD and LCH do not reverse with targeted therapy; earlier treatment and neuroprotective trials are the response.","Histiocytic sarcoma remains aggressive; MAPK inhibitors and immunotherapy are being tried.","Rarity: the Histiocyte Society, the ECD Global Alliance registry and NCCN's 2021 guideline coordinate what evidence exists."]},"route":"/cancers/histiocytoses/","neighbours":{"cancer":[{"id":"cmml","kind":"cancer","name":"Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms","route":"/cancers/cmml/"},{"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":"melanoma","kind":"cancer","name":"Melanoma","route":"/cancers/melanoma/"},{"id":"rosai-dorfman-disease","kind":"cancer","name":"Rosai-Dorfman-Destombes disease","route":"/cancers/rosai-dorfman-disease/"}],"technology":[{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"},{"id":"fdg-pet","kind":"technology","name":"FDG PET","route":"/technologies/fdg-pet/"},{"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/"}],"target":[{"id":"alk","kind":"target","name":"ALK","route":"/targets/alk/"},{"id":"braf","kind":"target","name":"BRAF","route":"/targets/braf/"},{"id":"pik3ca","kind":"target","name":"PIK3CA / PI3K-alpha","route":"/targets/pik3ca/"}],"drug":[{"id":"cladribine","kind":"drug","name":"Cladribine","route":"/drugs/cladribine/"},{"id":"cobimetinib","kind":"drug","name":"Cobimetinib","route":"/drugs/cobimetinib/"},{"id":"cyclophosphamide","kind":"drug","name":"Cyclophosphamide","route":"/drugs/cyclophosphamide/"},{"id":"dabrafenib-trametinib","kind":"drug","name":"Dabrafenib + trametinib","route":"/drugs/dabrafenib-trametinib/"},{"id":"doxorubicin","kind":"drug","name":"Doxorubicin","route":"/drugs/doxorubicin/"},{"id":"emapalumab","kind":"drug","name":"Emapalumab","route":"/drugs/emapalumab/"},{"id":"etoposide","kind":"drug","name":"Etoposide","route":"/drugs/etoposide/"},{"id":"interferon-alfa","kind":"drug","name":"Interferon alfa-2a/2b","route":"/drugs/interferon-alfa/"},{"id":"vemurafenib","kind":"drug","name":"Vemurafenib","route":"/drugs/vemurafenib/"}],"company":[{"id":"roche-genentech","kind":"company","name":"Roche / Genentech","route":"/companies/roche-genentech/"}],"institution":[{"id":"histiocyte-society","kind":"institution","name":"Histiocyte Society","route":"/institutions/histiocyte-society/"}],"pathway":[{"id":"clonal-haematopoiesis","kind":"pathway","name":"Clonal haematopoiesis (CHIP)","route":"/pathways/clonal-haematopoiesis/"},{"id":"pi3k-akt-mtor","kind":"pathway","name":"PI3K / AKT / mTOR","route":"/pathways/pi3k-akt-mtor/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"}],"term":[{"id":"braf-v600-mutation","kind":"term","name":"BRAF V600E mutation","route":"/terms/braf-v600-mutation/"},{"id":"ctdna","kind":"term","name":"Circulating tumour DNA (ctDNA)","route":"/terms/ctdna/"},{"id":"driver-mutation","kind":"term","name":"Driver mutation","route":"/terms/driver-mutation/"},{"id":"retroperitoneum","kind":"term","name":"Retroperitoneum","route":"/terms/retroperitoneum/"}],"bottleneck":[{"id":"b-generic-repurposing","kind":"bottleneck","name":"No incentive to repurpose cheap drugs","route":"/bottlenecks/b-generic-repurposing/"},{"id":"b-rare-cancers","kind":"bottleneck","name":"Rare and paediatric cancers without markets","route":"/bottlenecks/b-rare-cancers/"}],"paper":[{"id":"paper-durham-nat-med","kind":"paper","name":"Activating mutations in CSF1R and additional receptor tyrosine kinases in histiocytic neoplasms","route":"/key-papers/paper-durham-nat-med/"}],"trial":[{"id":"nct06153173","kind":"trial","name":"Mirdametinib in Histiocytic Disorders","route":"/trials/nct06153173/"}]}}