Background: Erdheim-Chester disease (ECD) is a histiocyte neoplasm with multi-organ manifestations, including long bone, retroperitoneal, cardiovascular and/or central nervous system (CNS) involvements. The majority of ECD harbor a BRAF ^V600E mutation, and treatment with BRAF and/or MEK inhibitors is highly efficient in most patients. BRAF ^V600E is also frequent in Langerhans cell histiocytosis (LCH), which co-occurs in 14% of patients with ECD. Both ECD and LCH are associated with neurodegeneration (ND) predominating in cerebellum and pons. A micro-mosaicism was recently reported in microglia of brain samples of 8 patients with ECD or LCH, some of whom did not have ND [1]. In mice, both microglia and epidermal Langerhans cells are self-renewed cells derived from yolk-sac progenitors.

Objectives: Detecting BRAF ^V600E micromosaicism in healthy tissues of patients with ECD.

Methods: Patients with ECD with BRAF ^V600E mutation were included in this study. Normal skin samples were obtained either from biopsies in clinically healthy areas or from margin of basal cell carcinoma. All samples were stained with H&E, CD207 and SOX10, and rolls were analyzed using digital PCR for wild type and V600E variants of BRAF as described [2]. Samples were considered as negative for BRAF ^V600E , when sequencing depth of BRAF was >25,000.

Results: Eleven patients with ECD were included with median age 69 (IQR 56-75) years (7males/4females). Six patients were treated with BRAF or MEK inhibitors at time of skin biopsy. Seven patients had CNS involvement, and 4 had clonal hematopoiesis. Histology and immunohistochemistry confirmed that all skin biopsies contained normal intra-epidermal Langerhans cell and melanocytes, and excluded any tumor infiltration. BRAF ^V600E was detected in 10/11 patients. The variant allele frequency (VAF) was always <1% (range 0.01% to 0.46%, median 0.14%). Within ECD infiltrated biopsies, the VAF of BRAF ^V600E of ranged from 3.8% to 16.4%. One patient had 2 positive biopsies (margin of basal cell carcinoma resected 23 months ago, and recent normal skin biopsies). Bone marrow cells of 4 positive patients were negative for BRAF ^V600E .

Conclusion: The oncogenic BRAF ^V600E variant is frequently present, with very low VAF, in normal skin of patients with ECD. This suggest that these patients have a micro-mosaicism of BRAF ^V600E within self-renewing epidermal-resident Langerhans cells.

REFERENCES: NIL.

[1] Vicario et al. Mechanism of neurodegeneration mediated by clonal inflammatory microglia bioRxiv [Preprint]. 2024 Jul 31:2024.07.30.605867. doi: 10.1101/2024.07.30.605867.

[2] Hélias‐Rodzewicz et al. Molecular and clinicopathologic characterization of pediatric histiocytoses Am J Hematol . 2023 Jul;98(7):1058-1069. doi: 10.1002/ajh.26938. Epub 2023 Apr 28.

Acknowledgements: NIL.

Disclosure of Interests: None declared.

© The Authors 2025. This abstract is an open access article published in Annals of Rheumatic Diseases under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ). Neither EULAR nor the publisher make any representation as to the accuracy of the content. The authors are solely responsible for the content in their abstract including accuracy of the facts, statements, results, conclusion, citing resources etc.