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9 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.
Erdheim-Chester disease is a rare histiocytosis, a cancer-like overgrowth of immune cells called histiocytes that scar the long bones, the tissue around the kidneys and heart, the brain and the skin. Most cases carry the BRAF V600E mutation or another fault in the same growth pathway, and the melanoma drugs vemurafenib and cobimetinib now control the disease in most patients.
Erdheim-Chester disease is a clonal neoplasm of foamy CD68-positive, CD1a-negative histiocytes that infiltrate and fibrose tissues in a characteristic distribution: symmetrical sclerosis of the long bones (seen on bone scan and PET in almost every patient), a rind of tissue around the kidneys and aorta ('hairy kidney' and 'coated aorta'), infiltration of the heart and pericardium, the pituitary (diabetes insipidus), the cerebellum and brainstem, the orbits and the skin (xanthelasma-like plaques). It was reclassified in 2016 with Langerhans cell histiocytosis in the L group of histiocytoses because the two share MAPK pathway mutations and often occur together, and the WHO now lists it among myeloid neoplasms; in some patients the histiocytes derive from a clone that also produces a myeloid neoplasm such as chronic myelomonocytic leukaemia. BRAF V600E is found in more than half of patients, and most of the rest have mutations in MAP2K1, ARAF, NRAS, KRAS or PIK3CA or kinase fusions, so the disease is almost always driven by one activating lesion in the RAS-MAPK pathway.
Interferon alfa, the standard from the 1990s to the 2010s, slowed the disease but rarely reversed it. The discovery of BRAF V600E in 2012 led to treatment with vemurafenib, which in the VE-BASKET trial produced responses in most patients and in 2017 became the first drug approved for Erdheim-Chester disease, and to the MEK inhibitor cobimetinib, which produced responses in most patients with or without a BRAF mutation in a phase 2 trial (Nature Medicine 2019) and was approved in the United States in 2022 for histiocytic neoplasms including Erdheim-Chester disease, Langerhans cell histiocytosis and Rosai-Dorfman disease. Dabrafenib with trametinib is used as an alternative BRAF-directed regimen. The 2020 consensus recommendations (Blood) advise targeted therapy for all patients with symptomatic or organ-threatening disease, with interferon alfa, anakinra, cladribine or methotrexate as second-choice options, and observation for the minority with asymptomatic disease confined to bone. Kinase inhibitors are usually continued indefinitely because relapse follows withdrawal, at doses lowered to limit skin, joint and cardiac toxicity, and plasma BRAF V600E cell-free DNA is used to follow response. Survival has improved from a median of a few years to a normal life expectancy for most patients treated early.
| Setting | Approach | Guideline |
|---|---|---|
| Diagnosis | Biopsy of an accessible lesion with BRAF V600E testing and broader sequencing; FDG-PET/CT, cardiac and brain MRI, endocrine assessment. | not mapped |
| BRAF V600E-mutant symptomatic disease | Vemurafenib (approved 2017) or dabrafenib with trametinib; cobimetinib as an alternative; dose reduction to limit toxicity, treatment continued long term. | not mapped |
| BRAF wild-type symptomatic disease | Cobimetinib (approved 2022 for histiocytic neoplasms); trametinib as an alternative MEK inhibitor. | not mapped |
| Second-choice or intolerant | Interferon alfa or pegylated interferon, anakinra, cladribine, methotrexate. | not mapped |
| Asymptomatic bone-limited disease | Observation with periodic PET and organ screening. | not mapped |