Classical and <scp>non‐classical</scp> phenotypes of <scp>Erdheim–Chester</scp> disease: Correlating clinical, radiographic and genotypic findings

Abstract

Erdheim–Chester disease (ECD) is a rare neoplasm characterised by multiorgan infiltration of clonal histiocytes bearing activating mutations, predominantly in the MAPK–ERK pathway. BRAFV600E is the most common somatic mutation, reported in 50%–60% of patients.1 The diagnosis of ECD is based on a combination of radiographic and pathological findings, as microscopic features alone are often non-specific. Common organs of involvement (characteristic findings) include cardiovascular (right atrial pseudotumour), cutaneous (xanthelasma), endocrine (diabetes insipidus [DI]), neurological (brainstem and cerebellar tumour), orbital (exophthalmos), osseous (leg osteosclerosis) and retroperitoneal (‘hairy kidneys’).1-3 The characteristic finding of symmetric osteosclerosis of the distal femora and proximal tibiae/fibulae has been reported in >90% of cases with whole-body [18F] fluorodeoxyglucose positron emission tomography/computed tomography (18FDG-PET/CT) and, due to a high specificity, is considered pathognomonic of ECD (Figure S1).4, 5 In light of this unique feature, the revised classification of histiocytic disorders6 categorises cases with typical osseous involvement as classical-ECD (C-ECD). There are sparse data on the characteristics of patients who do not present with the classic osseous manifestations, hereafter referred to as non-classical ECD (NC-ECD). An understanding of the phenotypic and molecular features of NC-ECD may help with raising awareness and timely diagnosis of cases without osseous involvement. We conducted this study to address the gaps in knowledge about NC-ECD and to compare features of NC-ECD with C-ECD. This study was approved by our Institutional Review Board. Records of patients with ECD who were consecutively seen at the Mayo Clinic from January 2005 to November 2020 were retrospectively reviewed. The diagnosis of ECD was determined by clinico-radiological criteria in conjunction with histopathological findings as outlined by the international consensus recommendations.1 For NC-ECD, the diagnosis was determined based on histopathology, the presence of characteristic non-osseous lesions and supported by MAPK–ERK pathway mutations.1 All patients had full body imaging that included bilateral evaluation of distal lower extremities by 18FDG-PET/CT or CT/99mTc methylene diphosphonate bone scan. All radiographic imaging and pathology slides were independently reviewed by an expert radiologist (J.R.Y.) and two pathologists (A.R. and K.L.R.), respectively. BRAF mutational status was determined by (i) immunohistochemistry (IHC) for BRAFV600E by clone VE1; (ii) BRAF-directed polymerase chain reaction (PCR)-based assays; or, when available, by (iii) next-generation sequencing (NGS) mainly through the Tempus-xT® assay (Chicago, IL, USA) or FoundationOne® CDx assay (Cambridge, MA, USA) (Data S1). The limit of detection for assays were 5% for allele-specific PCR and a variant allele frequency of 2%–5% for NGS. Overall survival (OS) was calculated using the Kaplan–Meier method and compared using the log-rank test, with index date being the day of ECD diagnosis. Statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS®), version 27 (IBM Corp., Armonk, NY, USA). We included 101 patients with ECD in the study. The median (range) age at diagnosis was 57 (38–81) years and 63 (62%) were male. Of the entire cohort, 84 (83%) underwent 18FDG-PET/CT imaging, 81% brain magnetic resonance imaging (MRI), 52% 99mTc methylene diphosphonate bone scan, and 38% cardiac MRI. The most common organ systems involved were osseous (n = 89, 88%), nephric/perinephric (n = 63, 62%), adrenal (n = 44, 44%), and pulmonary (n = 42, 42%). Central DI, ‘hairy kidneys’, and ‘coated aorta’ were present in 27 (27%), 54 (54%), and 44 (45%) patients respectively. In all, 78 (77%) patients underwent BRAFV600E testing, including 69 patients (89%) with IHC, 25 (32%) with tumour-tissue PCR, and 33 (42%) with successful NGS. Of those evaluated, 49 (63%) tested positive for BRAFV600E. Five patients had an additional myeloid haematological neoplasm other than ECD. This included three cases of chronic myelomonocytic leukaemia and one case each of myelodysplastic syndrome and essential thrombocythemia. In all, 87 patients (86%) met the criteria for C-ECD and 14 (14%) had NC-ECD. NC-ECD had significantly lower number of organs involved compared with C-ECD (median [range] 3 [1–10] vs. 6 [2–18]; p = 0.002). C-ECD had significantly higher rates of involvement of paranasal sinuses (51% vs. 7%, p = 0.002) and DI (30% vs. 0%, p = 0.02), but similar rates of pulmonary (40% vs. 43%), cardiac (31% vs. 14%), and cutaneous (14% vs. 14%) involvement when compared with NC-ECD (Figures 1 and 2). Presence of BRAFV600E was significantly more common in C-ECD compared with NC-ECD (73.4% vs. 14.3%, p < 0.001). Among NC-ECD, eight of the 14 patients (57%) were found to have MAPK–ERK pathway alterations including BRAF alterations other than BRAFV600E and point mutations in KRAS and MAP2K1 (Table S1 and Data S1). After a median (95% confidence interval) follow-up of 45 (32.8–57.1) months, the 5-year OS was 84.4% in the entire cohort (Figure S2A). To date, 15 (15%) patients have died, of which, four were due to ECD-related complications (acute hypoxic respiratory failure in two, bone marrow failure and failure to thrive) and causes of death for eight patients were unknown. There was no significant difference in OS between C-ECD and NC-ECD (Figure S2B; p = 0.553). Our study is the first to comprehensively describe the clinical, radiographic, and molecular features of NC-ECD and compare them with C-ECD. The major highlight of our finding is the higher burden of organ involvement among patients with C-ECD compared with NC-ECD. Interestingly, we found cases with C-ECD to be predominantly associated with BRAFV600E, whereas other MAPK–ERK mutations were more prevalent in NC-ECD. Our findings raise important questions regarding the potential role of BRAFV600E in homing of the neoplastic histiocytes preferentially toward osseous sites around the knees and need further exploration. Additionally, we found that the OS for ECD remains excellent, but were unable to determine the cause of death in the majority of cases. Nevertheless, our study highlights that ECD should not be dismissed as a diagnostic possibility in the absence of pathognomonic osseous findings, especially in cases without BRAFV600E. Antonious Z. Hazim, Aldo A. Acosta-Medina, Gaurav Goyal and Ronald S. Go designed the research study, performed the research, analysed the data, and wrote the manuscript. Jason R. Young preformed research, interpreted the data and critically revised the manuscript. Gordon J. Ruan, Jithma P. Abeykoon, Aishwarya Ravindran, Robert Vassallo, Jay H. Ryu, W. Oliver Tobin, Matthew J. Koster, N. Nora Bennani, Karen L. Rech, Mithun V. Shah and Thomas E. Witzig interpreted the data and critically revised the manuscript. The study was supported in part by the University of Iowa/Mayo Clinic Lymphoma SPORE CA97274 (Thomas E. Witzig). Supported in part by the University of Iowa/Mayo Clinic Lymphoma SPORE CA97422 and the Walter B. Frommeyer, Jr., Fellowship Award in Investigative Medicine, University of Alabama at Birmingham (Gaurav Goyal). The authors declare no competing financial interests. Data will be provided upon direct request to the authors. For original data requests contact [email protected], [email protected], and [email protected]. Appendix S1 Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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