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10 slides generated from the cancer page, with a quiz from the open benchmark and speaker notes that cite the sources. Arrow keys move between slides; Print gives one slide per page.
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.
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.
| Setting | Approach | Guideline |
|---|---|---|
| ECD, BRAF V600E-mutant, needing treatment | Vemurafenib (FDA approval 2017) or dabrafenib, often with a MEK inhibitor to reduce toxicity; long-term treatment at the lowest effective dose. | not mapped |
| ECD or RDD, BRAF wild-type or intolerant of BRAF inhibitors | Cobimetinib (FDA approval October 2022 for histiocytic neoplasms) or another MEK inhibitor; interferon alfa or pegylated interferon as an alternative. | NCCN Category 2A |
| Rosai-Dorfman disease | Observation for asymptomatic nodal disease; surgery for isolated masses; steroids, sirolimus, cladribine or MEK inhibitors for symptomatic or multifocal disease. | not mapped |
| Histiocytic sarcoma | Lymphoma-type chemotherapy (CHOP, ICE, or similar), radiotherapy for localised disease, MAPK-pathway inhibitors where mutations are found; clinical trials. | not mapped |