Consensus guidelines for the diagnosis and clinical management of Erdheim-Chester disease

Abstract

Erdheim-Chester disease (ECD) is a rare, non-Langerhans histiocytosis. Recent findings suggest that ECD is a clonal disorder, marked by recurrent BRAFV600E mutations in >50% of patients, in which chronic uncontrolled inflammation is an important mediator of disease pathogenesis. Although ∼500 to 550 cases have been described in the literature to date, increased physician awareness has driven a dramatic increase in ECD diagnoses over the last decade. ECD frequently involves multiple organ systems and has historically lacked effective therapies. Given the protean clinical manifestations and the lack of a consensus-derived approach for the management of ECD, we provide here the first multidisciplinary consensus guidelines for the clinical management of ECD. These recommendations were outlined at the First International Medical Symposium for ECD, comprised of a comprehensive group of international academicians with expertise in the pathophysiology and therapy of ECD. Detailed recommendations on the initial clinical, laboratory, and radiographic assessment of ECD patients are presented in addition to treatment recommendations based on critical appraisal of the literature and clinical experience. These formalized consensus descriptions will hopefully facilitate ongoing and future research efforts in this disorder.

Figure 1

Characteristic histopathologic and radiographic findings of ECD. (A) PET and (B) ^99mTc imaging demonstrating symmetric diametaphyseal radiotracer uptake in the long bones of the legs (arrows) commonly seen in ECD patients. R indicates the patient's right side. (C) CT and (D) MRI scans revealing sclerotic lesions of the metaphyses of femur and tibia (arrows). (E) Hematoxylin-eosin–stained biopsy section of ECD lesion revealing lipid-laden histiocytes characteristic of ECD. (F) IHC stain for CD68 revealing positivity of histiocytes.

Figure 2

Radiographic findings of internal organ systems commonly affected by ECD. (A) Axial CT scan of abdomen of an ECD patient demonstrating dense infiltration of perinephric fat commonly seen in ECD and referred to as a “hairy kidney” appearance (red arrow). Circumferential soft-tissue sheathing of the thoracic aorta seen in a subset of ECD patients and referred to as a “coated aorta” (blue arrow). Right atrial mass is demonstrated in B. (C) Lung parenchymal infiltration on chest CT in an ECD patient. Axial postgadolinium T1 MRI in (D) demonstrates expansile enhancement of the pachymeninges (thick arrow) as well as orbital masses (thin arrow) and (E) enhancing lesions in the dentate nuclei of the cerebellum. (F) Sagittal postgadolinium T1 MRI shows thickening and enhancement of the pituitary stalk.

Figure 3

Frequencies of recurrent clinicoradiographic findings in ECD patients. Frequency of recurrent clinical findings (A) and radiographic findings (B) in ECD based on a multicenter observational cohort study between 1981 and 2010. Frequency of patients with reported finding is listed on the x-axis.

Figure 4

Heterogeneous histopathologic findings in ECD lesional tissue. Brain biopsy in ECD yielded mostly lamellar fibrotic tissue (A) with only small regions (B) with lipid-laden histiocytes (yellow arrows) and Touton giant cells (blue arrow). (C) Another sample of a CNS lesion demonstrated a florid lymphohistiocytic infiltrate with regions of pale, nonfoamy histiocytes (inset). (D) Reactive astrocytes and Rosenthal fibers were seen in a separate CNS biopsy from the same case. (E) Biopsy of perinephric infiltrate on low power view demonstrates perirenal fat with septa widened by fibrous tissue and scant inflammatory infiltrate. The stranding apparent at low power correlates with the known radiographic appearance. (F) Higher power in this case shows a Touton giant cell but few histiocytes. (G) Pericardial biopsy shows pale and granular histiocytes without foamy appearance. Occasional lymphocytes, plasma cells, and eosinophils are present. (H) Lung biopsy from the same patient taken concurrently demonstrates septal fibrosis with scant cellular infiltrate including histiocytes. Higher power (inset) shows pale (nonfoamy) histiocytes.