Classical and Non-Classical Phenotypes of Erdheim-Chester Disease: Correlating Clinical, Radiographic, and Genotypic Findings
Authors: Hazim Antonious Z. , Ruan Gordon , Acosta-Medina Aldo A. , Abeykoon Jithma P. , Ravindran Aishwarya , Vassallo Robert , Ryu Jay , Tobin W. Oliver , Koster Matthew , Bennani N Nora , Rech Karen , Shah Mithun V. , Young Jason R. , Goyal Gaurav , Go Ronald 
Published: November 2021

Abstract

Background: Erdheim-Chester disease (ECD) is characterized by multi-organ infiltration of clonal histiocytes bearing activating mutations predominantly in the MAPK pathway. The diagnosis of ECD is clinico-pathologic; histopathologic findings alone are often non-specific. Characteristic pathognomonic finding of ECD is the symmetric osteosclerosis of the distal femur and proximal tibia/fibula, seen in &gt;90% of cases, and referred to herein as classic ECD (C-ECD). There is a paucity of data on the phenotypic and mutational differences between C-ECD and non-classic ECD (NC-ECD). Determining phenotypic patterns may allow for earlier suspicion and diagnosis.
Methods: Patients who met the revised ECD criteria proposed by Haroche J et al (Blood 2020;135:1311-1318) and had full body imaging that included the lower legs (18-FDG-PET/CT or CT/bone scan) were included. ECD diagnosis was made when &gt;1 major criteria plus &gt;1 minor criteria were present. Major criteria: 1) symmetric meta-diaphyseal osteosclerosis in legs; 2) "hairy kidneys"; "coated aorta", right atrial pseudotumor, xanthelasma, exophthalmos; or osteosclerosis of paranasal sinuses. Minor criteria: 1) histologic finding of typical foamy histiocytes (CD68+/CD163+/CD1a-) associated with fibrosis; 2) mutation/gene fusion of BRAF, CSF1R, or MAPK/PI3K pathways. We compared the organ involvement and BRAF V600Emutational status between C-ECD and NC-ECD.
Results: A total of 105 patients were included. The median age at diagnosis was 57 years (range, 38-81) and most were males (62%). Majority had 18-FDG-PET/CT (83%) and BRAF V600E testing (65%). The main organ systems involved were skeletal (83%), renal (64%), adrenal (44%), and pulmonary (42%). Central diabetes insipidus (DI), "hairy kidneys", and "coated aorta" were present in 27 (26%), 54 (51%), and 44 (42%) patients, respectively. Among those tested, BRAF V600E mutation was found in 48/67 (72%) by immunohistochemistry. In our cohort, most patients (n=87. 83%) had C-ECD. NC-ECD had significantly lower number of organs/systems involved compared with C-ECD (median 3 vs 6, p=0.002). C-ECD had significantly higher rates of involvement of paranasal sinuses (51%/7%, p=0.002), DI (26%/0%, p=0.02), and similar rates of lung (44%/43%), cardiac (34%/14%), and skin (14%14%) involvement when compared to NC-ECD. BRAF V600E was significantly more common in C-ECD (88%/30%, p=0.004). Thirty-nine (37%) patients underwent next generation sequencing, of whom 33 (31%) had successful testing. In C-ECD, 3 patients had mutations other than BRAF V600E, these included: NRAS, MAP2K1, and MEF2C-FLT3 fusion. In NC-ECD, 5 patients had mutations other than BRAF V600E, these included: MAP2K1, KRAS, and NF1.
Conclusions: Our study suggests distinct differences in clinical presentation and molecular findings exist between C-ECD and NC-ECD. C-ECD has a higher degree of organ involvement and harbor BRAF V600E more frequently than NC-ECD. Further analysis of histopathologic findings and outcomes in this cohort may provide insights into these ECD subsets that can optimize future management of this disease.
Figure 1: Sites of involvement of classical Erdheim-Chester Disease (C-ECD) versus non-classical Erdheim-Chester Disease (NC-ECD)
Figure 1 Figure 1.

Disclosures
Vassallo: Bristol-Myers-Squibb: Research Funding; Sun Pharma.: Research Funding; Pfizer: Research Funding. Tobin: Mayo Clinic Center for MS and Autoimmune Neurology: Research Funding; Mallinckrodt Pharmaceuticals: Research Funding; National Institutes of Health: Research Funding. Bennani: Verastem: Other: Advisory Board; Purdue Pharma: Other: Advisory Board; Vividion: Consultancy, Other: Advisory Board; Daichii Sankyo Inc: Other: Advisory Board; Kyowa Kirin: Other: Advisory Board.