Detection of an NRAS mutation in Erdheim-Chester disease

Eli L. Diamond, Omar Abdel-Wahab, Elena Pentsova, Laetitia Borsu, April Chiu, Julie Teruya-Feldstein, David M. Hyman and Marc Rosenblum

To the editor:

In a recent paper in Blood, Haroche et al reported dramatic efficacy of vemurafenib in 3 cases of multisystem and refractory Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis harboring the BRAF V600E mutation.1 The findings of an ∼50% prevalence of BRAF mutations in this disease and effective treatment with vemurafenib suggest that Ras/Raf/MEK/ERK pathway activation is central to the biology of these histiocytic diseases.2,3

We report a 66-year-old man who presented with several months of progressive cognitive impairment, deterioration of gait, fatigue, and urinary incontinence. A gadolinium-enhanced magnetic resonance imaging scan demonstrated multifocal contrast-enhancing lesions of the cerebral meninges (Figure 1A). Computed tomography and then positron emission tomography imaging of the chest, abdomen, and pelvis revealed paravertebral, pleural, presacral, and renal masses, as well as widespread lytic osseous lesions (Figure 1B). Biopsy results of both renal and presacral masses revealed an infiltrate with foamy CD68+/CD1a− histiocytes (Figure 1F-G). Nuclear bone scintigraphy results showed abnormal tracer uptake in the long bones of the lower extremities, consistent with ECD (Figure 1C). The tumor was interrogated for hotspot mutations in 8 commonly mutated oncogenes (EGFR, KRAS, BRAF, PIK3CA, NRAS, AKT1, ERBB2, and MAP2K1) using the Sequenom MassARRAY system (Figure 1D). This demonstrated absence of the BRAF V600E mutation but presence of the NRAS Q61R mutation. The presence of the somatic mutation, along with its absence in the germline, was confirmed by Sanger sequencing (Figure 1E). This report is, to our knowledge, the first to find an activating NRAS mutation in ECD.

Figure 1

Findings in a 66-year-old man with ECD. (A) Contrast-enhanced sagittal magnetic resonance imaging scan demonstrates lobulated enhancing masses arising from the cerebral meninges. (B) Fluorodeoxyglucose-avid lesions in the abdomen, pelvis, and long bones are shown, and (C) the classic scintigraphic uptake in the long bones is demonstrated. NRAS_182A>G (Q61R) mutation detection assay by MassARRAY (Sequenom) genotyping is demonstrated in (D). This method is designed to generate a small amplicon at a known mutation site from small amounts of tumor FFPE DNA. Mutation calls are based on the mass differences between the wild-type extension product and the mutant extension products as resolved by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The single nucleotide change in the extension product is detected by mass spectroscopy. The allele from the tumor (top panel) contains a mutated G allele at position 182. A control wild-type allele is shown (bottom panel). (E) Sanger sequencing of tumor tissue demonstrates the NRAS Q61R mutation in the tumor (left), NRAS wild type in the peripheral blood lymphocytes (middle), and NRAS Q61 mutant melanoma cell line (right) as a positive control. (F) Biopsy result of the presacral mass demonstrates a xanthomatous histiocytic infiltrate, consistent with ECD. (G) Immunohistochemistry result for phosphoextracellular signal-regulated kinase (pERK1/2) is positive in the nuclei of tumor histiocytes (blue arrow) and in the surrounding vasculature but is negative in the nontumor stromal cells (red arrow).

Activating mutations in the NRAS gene, predominantly in codon 61, have been implicated in the pathogenesis of malignant melanoma and other solid and liquid tumors,4,5 and treatment with MEK inhibitors is being actively explored in these diseases. The finding of an oncogenic NRAS mutation in ECD further supports the hypothesis that this disease is driven by activation of the Ras/Raf/MEK/ERK pathway. Further investigation into the role of this pathway in ECD and Langerhans cell histiocytosis is warranted and may open new opportunities for targeted therapies for these disorders.


Contribution: E.L.D., E.P., and M.R. collected the data; E.L.D., O.A.-W., L.B., A.C., J.T.-F., D.M.H., and M.R. analyzed and interpreted the data; E.L.D., O.A.-W., E.P., L.B., J.T.-F., D.M.H., and M.R. wrote the manuscript; and all authors approved the final manuscript.

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Correspondence: Eli L. Diamond, Department of Neurology, Memorial Sloan-Kettering Cancer Center, 1275 York Ave, New York, NY 10065; e-mail: diamone1{at}