Erdheim-Chester disease: consensus recommendations for evaluation, diagnosis, and treatment in the molecular era

Abstract

Erdheim-Chester disease (ECD) is a rare histiocytosis that was recently recognized as a neoplastic disorder owing to the discovery of recurrent activating MAPK (RAS-RAF-MEK-ERK) pathway mutations. Typical findings of ECD include central diabetes insipidus, restrictive pericarditis, perinephric fibrosis, and sclerotic bone lesions. The histopathologic diagnosis of ECD is often challenging due to nonspecific inflammatory and fibrotic findings on histopathologic review of tissue specimens. Additionally, the association of ECD with unusual tissue tropism and an insidious onset often results in diagnostic errors and delays. Most patients with ECD require treatment, except for a minority of patients with minimally symptomatic single-organ disease. The first ECD consensus guidelines were published in 2014 on behalf of the physicians and researchers within the Erdheim-Chester Disease Global Alliance. With the recent molecular discoveries and the approval of the first targeted therapy (vemurafenib) for BRAF-V600–mutant ECD, there is a need for updated clinical practice guidelines to optimize the diagnosis and treatment of this disease. This document presents consensus recommendations that resulted from the International Medical Symposia on ECD in 2017 and 2019. Herein, we include the guidelines for the clinical, laboratory, histologic, and radiographic evaluation of ECD patients along with treatment recommendations based on our clinical experience and review of literature in the molecular era.

Prevalence of Hypothyroidism in Patients With Erdheim-Chester Disease

“…This report followed Strengthening the Reporting of Observational Studies in Epidemiology ( STROBE ) reporting guideline. Patients were enrolled between January 2011 and December 2018, and the diagnosis was established based on ECD consensus criteria 2 , 19 and verified with history, physical examination, and laboratory, genetic, and imaging investigations, as previously reported. 14 ECD biopsy samples (common sites, perinephric or retroperitoneal tissue, bone and skin) were reviewed by a certified pathologist who confirmed the diagnosis of ECD.…”

“…While the incidence and prevalence of ECD is unknown, the medical literature contains a few hundred cases of ECD, which is characterized by male predominance and a mean age at presentation of 53 years. 1 , 2 Initially described by Erdheim and Chester in 1930 as lipoid granulomatosis, the disorder was reclassified in 2016 by the World Health Organization as a neoplasm of histiocytic origin, characterized by lipid-rich foamy macrophages infiltrating various organs. 3 , 4 , 5 Genetic perturbations in key molecular pathways, including BRAF V600E (OMIM 164757 ) and mitogen-activated protein kinase (MAPK), occur in a subset of hematopoietic cells and cause enhanced proliferation and increased survival of monocytic cells.…”

18F-FDG PET/CT versus anatomic imaging for evaluating disease extent and clinical trial eligibility in Erdheim-Chester disease: results from 50 patients in a registry study

“…In a recent trial of cobimetinib for histiocytic neoplasms, an overall response rate of 89% was observed by mPERCIST, compared with an overall response rate of 57% by RECIST, suggesting that [18]F-FDG PET/CT more readily detects response to treatment. The broad recommendation for implementation of [18]F-FDG PET/CT for response assessment in ECD [30] and other histiocytosis [31] reflects a belief among experts that metabolic assessment is useful to gauge response to treatment and that favorable metabolic response reflects a clinical benefit from treatment, but this has not been proven in ECD. There are limitations to this study.…”

Erdheim chester disease: A case report and review of the literature

“…20% of ECD patients may have mixed histiocytosis with simultaneous Langerhans cell histiocytosis lesions, which can be even identified in the same biopsy. [9,10] Moreover, the ECD histiocytes share the same morphological and immunohistochemical profile of the juvenile xanthogranuloma (JXG). Therefore, it has been postulated that ECD is a variant of a non-cutaneous JXG.…”

“…However, for ECD patients without BRAF V600 mutation, it is recommended to continue Next-generation Sequencing (NGS) to identify other MAPK-ERK pathway alterations. [9,15]…”