The histiocytosis Erdheim–Chester disease is an inflammatory myeloid neoplasm

Abstract

Erdheim–Chester disease (ECD) is a rare, non-Langerhans histiocytosis, characterized by the infiltration of tissues by foamy CD68⁺CD1a⁻ histiocytes. ⁹⁹Technetium bone scintigraphy revealing almost constant tracer uptake by the long bones is highly suggestive of ECD, and a ‘hairy kidney’ appearance on abdominal computed tomography scan is observed in about half of all ECD cases. CNS involvement is a strong prognostic factor and independent predictor of death. IFN-α seems to be the best initial treatment for ECD. More than half of all ECD patients carry the BRAF^V600E mutation. More than 30 patients worldwide harboring this mutation and displaying multisystemic, refractory ECD have been treated with vemurafenib, a BRAF inhibitor, which has proven highly beneficial. Other recurrent mutations of the MAPK and PIK3 pathways (NRAS, PIK3CA) have recently been described. These mutations should lead to a new classification of histiocytic disorders such that Langerhans cell histiocytosis and ECD are classified as inflammatory myeloid neoplasms.

Keywords:

• BRAF
• Erdheim–Chester disease
• histiocytosis
• interferon alpha
• Langerhans-cell histiocytosis
• NRAS
• PIK3CA
• vemurafenib

Financial & competing interests disclosure

J Haroche received honoraria from GlaxoSmithKline for counseling of patients with histocytosis on treatments with targeted therapies. J Emile has consulted and/or had an advisory role for Roche and GlaxoSmithKline. J Emile has received honoraria from Roche and GlaxoSmithKline. J Emile receives research funding from Roche. Z Amoura has consulted and/or had an advisory role for GlaxoSmithKline, Amgen and Lilly. Z Amoura received research funding from GlaxoSmithKline (Inst), Roche (Inst), Actelion (Inst), Amgen (Inst), Lilly (Inst), UCB (Inst) and AstraZeneca (Inst) as well as funding for travel, accommodation and expenses from GlaxoSmithKline and LFB Biotechnologies. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• The diagnosis of Erdheim–Chester disease (ECD) involves the analysis of histiocytes in tissue biopsies: they are typically foamy and CD68+ CD1a−, whereas in Langerhans cell histiocytosis (LCH) they are CD68+ CD1a+. Overlap forms of histiocytoses are frequent.

• Technetium bone scintigraphy showing nearly constant tracer uptake by the long bones is highly suggestive of ECD and a ‘hairy kidney’ appearance on abdominal CT scan is observed in more than half ECD cases.

• CNS involvement is a strong prognostic factor and an independent predictor of death in cases of ECD.

• Optimal initial therapy for ECD appears to be administration of IFN-α (and/or pegylated IFN-α) and prolonged treatment significantly improves survival; however, tolerance may be poor.

• Best alternative therapies are anakinra, mainly effective for mild forms of the disease, and infliximab.

• Cases of ECD present with strong systemic immune activation, involving IFN-α, IL-1/IL1-RA, IL-6, IL-12, and MCP-1, consistent with the systemic immune Th-1-oriented disturbance associated with the disease.

• Between 57 and 75% of ECD patients carry the BRAF^V600E mutation, an activating mutation of the proto-oncogene BRAF.

• More than 30 cases harboring BRAF mutation and with severe multisystemic and refractory ECD (sometimes associated with LCH) have been treated worldwide with vemurafenib, a BRAF inhibitor that proved to be very beneficial.

• Other recurrent mutations of the MAPK and PIK3 pathways (NRAS, PIK3CA) have been found among ECD patients.

• As recurrent mutations in the MAPK pathway are found in ECD and LCH on a background of chronic inflammation, we believe that both conditions should be redefined as an inflammatory myeloid neoplasia.