Review
Erdheim-Chester Disease: Characteristics and Management

https://doi.org/10.1016/j.mayocp.2014.01.023Get rights and content

Abstract

Erdheim-Chester disease is a rare CD68+, CD1a non-Langerhans cell histiocytosis with multiorgan involvement. The etiology of Erdheim-Chester disease is unclear; there are no known associated infectious or hereditary genetic abnormalities. However, somatic BRAF mutations have recently been identified in these patients. Historically, the literature regarding the management of Erdheim-Chester disease consisted of case reports and small case series with anecdotal therapeutic responses to agents including, but not limited to, cytotoxic chemotherapy, bone marrow transplantation, cladribine, corticosteroids, IFN-α, the BCR-ABL/KIT inhibitor imatinib mesylate, the IL-1 receptor antagonist anakinra, the TNF-inhibitor infliximab, and recently the BRAF inhibitor vemurafenib. We performed a search of the literature using PubMed with the terms Erdheim Chester disease, without date limitations, including case reports, case series, original articles, and previous review articles. In the absence of large-scale studies, experience-based management prevails. The present review details our approach to the management of patients with Erdheim-Chester disease.

Section snippets

Differential diagnosis: Langerhans cell histiocytosis vs non-Langerhans cell histiocytosis

ECD is a non-Langerhans cell histiocytosis; however, it may coexist with Langerhans histiocytosis.2 As an example, Haroche et al12 reported overlapping histiocytosis in 12 of the 75 (16%) patients who have been followed at their institution. Mononuclear phagocytic cells are divided into macrophages and dendritic cells. The latter are thought to be the abnormal cells that trigger Langerhans cell histiocytosis.13 In contrast, non-Langerhans cell histiocytosis is believed to stem from an abnormal

Prognosis

Poorer prognosis is dictated by the degree of organ involvement, particularly the CNS.1 Sequelae range from asymptomatic bone sclerosis to life-threatening visceral infiltration. Although ECD is not curable, we have seen prolonged responses in our clinic after various agents. Survival in recent larger series1 is better than previously described in other older smaller series.24 Indeed, Arnaud et al1 reported 1- and 5-year survival rates of 96% and 68%, respectively, which is compatible with our

Pathophysiology

The underlying pathophysiology of ECD is largely unknown, although it seems to be associated with cytokine disturbances.3, 28, 29, 30, 31 Serum samples from 37 patients with ECD were assessed for 23 cytokines. It was found that IL-6 and IFN-α levels (TH-1–induced pro-inflammatory chemokines) were elevated in untreated patients; IL-1 and IFN-γ levels were high in patients treated with IFN-α.3 Earlier attempts to elucidate the etiology of ECD did not focus on the balance among cytokines, an

Therapy

Systemic treatment is deemed not to have curative potential, though, on the basis of retrospective analysis, it can improve symptoms as well as outcomes.1 There is no standard of care (approved therapies), and no randomized trials have been performed for ECD. Until recently, treatment included diverse approaches such as steroids, cladribine-based chemotherapy,6 and cytokine-based agents. The recent reports of BRAF mutations in patients with ECD support testing BRAF inhibitors in the clinic.5

The

Future Directions

Erdheim-Chester disease is an uncommon non-Langerhans histiocytosis that may coexist with Langerhans histiocytosis.80 It involves diverse organs, and it is often difficult to diagnose. Common features include bone sclerosis, orbital infiltration with proptosis, CNS involvement with diabetes insipidus, cardiac involvement, and pulmonary infiltration. Deregulation of cytokine pathways has been implicated in the pathogenesis of ECD. Responses have been seen with steroids, cytotoxic chemotherapy,

Conclusion

ECD is an uncommon multisystem non-Langerhans histiocytosis. Rare diseases are uniquely challenging from a therapeutic point of view, though increasingly many cancers may be stratified into small molecular subsets.83, 84, 85 The present review details our approach to the management of ECD.

Acknowledgments

Drs Munoz and Janku share first authorship because they contributed equally to this work.

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    Grant Support: R.K. has received research grant support from Genentech and Hoffmann-LaRoche.

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