Erdheim-Chester disease, Rosai-Dorfman disease and other histiocytic neoplasms
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.
Overview
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.
Treatment 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.
International consensus recommendations for ECD (Blood 2020) and the Histiocyte Society trials network coordinate care and research.
State of the art today
- 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.
Where it starts and where it drains
Leukaemias, myeloma and MDS live in the marrow and blood; lymphomas grow in lymph nodes and spleen. The node stations are the disease map, not a route of spread, and staging counts them.
- Bone marrow (leukaemia, MDS, MPN, myeloma)Mixed ECD-LCH · Juvenile xanthogranuloma and other C-group cutaneous histiocytoses · Histiocytic sarcoma and other malignant histiocytoses · ALK-positive histiocytosis (rare; responds to ALK inhibitors)
- Lymph node germinal centre (lymphomas)
- Spleen
- Blood (leukaemic phase)
- Lytic bone lesions (myeloma)
- Skin and extranodal sitesRosai-Dorfman-Destombes disease (nodal, extranodal, cutaneous, familial) · Juvenile xanthogranuloma and other C-group cutaneous histiocytoses
- cervical
- axillary
- mediastinal
- para-aortic and mesenteric
- inguinal
In lymphoma the node stations are the disease itself; staging (Ann Arbor / Lugano) counts how many regions and sides of the diaphragm are involved.
Same organ: Acute myeloid leukaemia, Acute lymphoblastic leukaemia, Chronic lymphocytic leukaemia, Chronic myeloid leukaemia (CML), Diffuse large B-cell lymphoma, Follicular lymphoma, Hodgkin lymphoma, Mantle cell lymphoma, Multiple myeloma, Myelodysplastic syndromes / neoplasms (MDS), Myeloproliferative neoplasms (PV, ET, myelofibrosis), Waldenström macroglobulinaemia, Hairy cell leukaemia, Peripheral T-cell lymphomas (including cutaneous T-cell lymphoma), Blastic plasmacytoid dendritic cell neoplasm (BPDCN), Burkitt lymphoma, HIV-associated (AIDS-related) lymphomas, Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms, Systemic mastocytosis, Langerhans cell histiocytosis (LCH), Post-transplant lymphoproliferative disorder (PTLD)
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).
- Liquid biopsy (ctDNA)Standard of care
- AI in radiologyEstablished
- cfDNA fragmentomicsEstablished
- Colorectal cancer screening (colonoscopy, FIT, stool DNA, blood)Standard of care
- DNA methylation profilingEstablished
- HCC surveillance in cirrhosis (ultrasound + AFP)Standard of care
- A 28-day national pathway for people with a positive multi-cancer blood test
- A breath test to rule out cancer in people with vague symptoms
- A cancer blood test for older people arriving at A&E with unexplained symptoms
- A legislated, publicly reported 28-day standard from urgent referral to diagnosis
- A live national dashboard of stage at diagnosis as the scorecard for early detection
- A single 'cancer check at 60' appointment bundling all screening tests
Background: Alpha-fetoprotein (AFP), Barrett's oesophagus, CA 19-9, Early detection, Faecal immunochemical test (FIT). Also on OnCo: Symptoms and red flags · Early detection roadmap.
Where the cases are
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
Vemurafenib (FDA approval 2017) or dabrafenib, often with a MEK inhibitor to reduce toxicity; long-term treatment at the lowest effective dose.
Cobimetinib (FDA approval October 2022 for histiocytic neoplasms) or another MEK inhibitor; interferon alfa or pegylated interferon as an alternative.
Observation for asymptomatic nodal disease; surgery for isolated masses; steroids, sirolimus, cladribine or MEK inhibitors for symptomatic or multifocal disease.
Lymphoma-type chemotherapy (CHOP, ICE, or similar), radiotherapy for localised disease, MAPK-pathway inhibitors where mutations are found; clinical trials.
Subtypes & biomarkers
top- 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)
- 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)
Target prevalence in this cancer
- 1930Erdheim and Chester describe 'lipoid granulomatosis'
- 1969Rosai and Dorfman describe sinus histiocytosis with massive lymphadenopathy
Destombes had reported cases in 1965.
- 2012BRAF V600E found in ECD and LCH
Haroche and colleagues (Blood 2012) after Badalian-Very's LCH discovery (2010).
- 2016Revised Histiocyte Society classification
L, C, R, M and H groups (Emile et al., Blood 2016).
- 2017Vemurafenib approved for ECD
First approval for any histiocytosis (VE-BASKET); November 2017.
- 2019Cobimetinib effective regardless of genotype
Diamond and colleagues, Nature Medicine 2019.
- 2022Cobimetinib approved for histiocytic neoplasms
FDA approval October 2022 for adults with ECD, RDD and LCH.
Open problems, and what is being done about each
Most patients relapse when BRAF or MEK inhibitors stop; intermittent dosing and ctDNA-guided discontinuation are being tested.
and how the field plans to fix it →What is being done about thisRecurrence and residual diseaseAvailable now- Liquid biopsy (ctDNA)Standard of care
- MRD / molecular residual disease testingEstablished
- Multiparameter flow cytometry MRDStandard of care
- NGS-based MRD (clonoSEQ and molecular MRD)Standard of care
- SignateraEstablished
- Structured exercise programmes after curative treatmentEstablished
In trials- ADAURAPositive
- CAMBRIA-1 & CAMBRIA-2Recruiting
- CIRCULATE-Japan (GALAXY / VEGA / ALTAIR)Active
- ctDNA monitoring in lymphoma (PhasED-seq, clonoSEQ)Emerging
- DYNAMICPositive
- IMvigor011Positive
Ideas and roadmaps- A blood test for the pre-metastatic niche
- A bone marrow niche on a chip to study human dormancy
- A dedicated clinic for people whose blood test says the cancer is back
- A drug screen that only rewards killing sleeping cancer cells
- A national platform trial that every ctDNA-positive patient can join
- A national residual-disease weather service: serial blood tests for every curatively treated patient, pooled
Background: Circulating tumour DNA (ctDNA), Disseminated tumour cells (DTCs), Late recurrence, Minimal / molecular residual disease (MRD), MRD negativity (myeloma, 10⁻⁵ / 10⁻⁶). Also on OnCo: Treatment journeys · Survivorship planner.
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.
and how the field plans to fix it →What is being done about thisRare cancers and small trialsAvailable now- Comprehensive genomic profilingStandard of care
- AI trial matching & clinical decision supportEstablished
- Dinutuximab (ch14.18) / dinutuximab betaApproved
- Eflornithine (DFMO)Approved
- LarotrectinibApproved
- Limb-salvage surgery and endoprosthetic reconstructionStandard of care
In trials- ACTIONRecruiting
- COG AALL1731Positive
- COG ANBL0032Positive
- DeFiPositive
- Euro Ewing 2012Positive
- Functional (ex vivo) drug testingEmerging
Ideas and roadmaps- A digital second-opinion network answering community oncologists within 72 hours
- A DRUP-style protocol for off-label generic targeted drugs in rare tumours
- A funded expert second opinion for every new high-stakes or rare cancer diagnosis
- A global first-in-human network for academic cancer trials with single ethics review
- A global open trials operating system any hospital can plug into
- A live 'seats available' feed for trial slots, like airline inventory
Background: Basket, umbrella, and platform trials, Centralisation and high-volume centres, FNCLCC grade (soft-tissue sarcoma), Histotype-tailored therapy, INRG staging and risk groups. Also on OnCo: Find a trial · Expert centres.
Trials
topRecruiting now (live from ClinicalTrials.gov)
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Expert centres
topCentres linked to this cancer in OnCo
- Histiocyte SocietyPitman, USvia this cancer
- Wellcome Sanger InstituteHinxton, GBvia BRAF
Questions to ask
topQuestions to ask your oncologist about Erdheim-Chester disease, Rosai-Dorfman disease and other histiocytic neoplasms
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Why: Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example BRAF V600E, MAP2K1, ARAF, NRAS, KRAS, PIK3CA, RAF1 and ALK fusions on NGS, Immunophenotype: CD68, CD163, factor XIIIa positive; CD1a and langerin negative; S100 with emperipolesis, FDG-PET/CT for extent and response, Cardiac MRI and brain MRI for organ involvement), and what were the results?Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Why: Recognised subtypes for this cancer include Erdheim-Chester disease, Mixed ECD-LCH, Rosai-Dorfman-Destombes disease.
- Is germline (inherited) genetic testing recommended for me or my family?Why: Inherited variants can change treatment and matter for relatives.
ECD, BRAF V600E-mutant, needing treatment
- For my situation (ecd, braf v600e-mutant, needing treatment), which of the standard options do you recommend and why?Why: Guideline options include: Vemurafenib (FDA approval 2017) or dabrafenib, often with a MEK inhibitor to reduce toxicity; long-term treatment at the lowest effective dose.
- Am I a candidate for Vemurafenib, Dabrafenib + trametinib, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
ECD or RDD, BRAF wild-type or intolerant of BRAF inhibitors
- For my situation (ecd or rdd, braf wild-type or intolerant of braf inhibitors), which of the standard options do you recommend and why?Why: Guideline options include: Cobimetinib (FDA approval October 2022 for histiocytic neoplasms) or another MEK inhibitor; interferon alfa or pegylated interferon as an alternative.
- Am I a candidate for Cobimetinib, Interferon alfa-2a/2b, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Rosai-Dorfman disease
- For my situation (rosai-dorfman disease), which of the standard options do you recommend and why?Why: Guideline options include: Observation for asymptomatic nodal disease; surgery for isolated masses; steroids, sirolimus, cladribine or MEK inhibitors for symptomatic or multifocal disease.
- Am I a candidate for Cladribine, Cobimetinib, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Histiocytic sarcoma
- For my situation (histiocytic sarcoma), which of the standard options do you recommend and why?Why: Guideline options include: Lymphoma-type chemotherapy (CHOP, ICE, or similar), radiotherapy for localised disease, MAPK-pathway inhibitors where mutations are found; clinical trials.
- Am I a candidate for Cyclophosphamide, Doxorubicin, Etoposide or related drugs, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
Any stage
- Are there clinical trials I could join, for example of Cobimetinib, Vemurafenib, Dabrafenib + trametinib?Why: Trials are how the next standard of care is set; asking early keeps options open.
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Why: Supportive care improves quality of life and helps patients complete treatment.
- I read that “Most patients relapse when BRAF or MEK inhibitors stop; intermittent dosing and ctDNA-guided discontinuation are being tested”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “Neurodegenerative ECD and LCH do not reverse with targeted therapy; earlier treatment and neuroprotective trials are the response”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
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Direct links plus the targets, companies, and technologies of this cancer's products.
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topQuery for this cancer: (TITLE:"Erdheim-Chester disease, Rosai-Dorfman disease and other histiocytic neoplasms" OR ABSTRACT:"Erdheim-Chester disease, Rosai-Dorfman disease and other histiocytic neoplasms" OR TITLE:"ECD" OR ABSTRACT:"ECD" OR TITLE:"Erdheim-Chester disease" OR ABSTRACT:"Erdheim-Chester disease" OR TITLE:"Rosai-Dorfman disease" OR ABSTRACT:"Rosai-Dorfman disease" OR TITLE:"RDD" OR ABSTRACT:"RDD" OR TITLE:"Rosai-Dorfman-Destombes disease" OR ABSTRACT:"Rosai-Dorfman-Destombes disease") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Erdheim-Chester disease, Rosai-Dorfman disease and other histiocytic neoplasms, not a curated reading list.
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