The clinical spectrum of Erdheim-Chester disease: an observational cohort study

Abstract

Erdheim-Chester Disease (ECD) is a rare, potentially fatal, multi-organ myeloid neoplasm occurring mainly in adults. The diagnosis is established by clinical, radiologic, and histologic findings; ECD tumors contain foamy macrophages that are CD68+, CD163+, CD1a-, and frequently S100-. The purpose of this report is to describe the clinical and molecular variability of ECD. Sixty consecutive ECD patients (45 males, 15 females) were prospectively evaluated at the NIH Clinical Center between 2011 and 2015. Comprehensive imaging and laboratory studies were performed, and tissues were examined for BRAF V600E and MAPK pathway mutations. Mean age at first manifestations of ECD was 46 years; a diagnosis was established, on average, 4.2 years after initial presentation. Bone was the most common tissue affected, with osteosclerosis in 95% of patients. Other manifestations observed in one-third to two-thirds of patients include cardiac mass and periaortic involvement, diabetes insipidus, retro-orbital infiltration, retroperitoneal, lung, CNS, skin and xanthelasma, usually in combination. Methods of detection included imaging studies of various modalities. Mutation in BRAF V600E was detected in 51% of 57 biopsies. One patient had an ARAF D228V mutation, and one had an activating ALK fusion. Treatments included interferon alpha, imatinib, anakinra, cladribine, vemurafenib and dabrafenib with trametinib; eleven patients received no therapy. The diagnosis of ECD is elusive because of the rarity and varied presentations of the disorder. Identification of BRAF and other MAPK pathway mutations in biopsies improves ECD diagnosis, allows for development of targeted treatments, and demonstrates that ECD is a neoplastic disorder.

Keywords: BRAF gene; Erdheim-Chester Disease (ECD); Non-Langerhans cell histiocytosis; foamy macrophages; histiocytic and dendritic cell neoplasm; myeloid neoplasm.

Graphical abstract

Figure 1.

Bone lesions in ECD. The red arrows show: (A) Whole-body bone scan with technetium-99 showing avid uptake in the knees and left hip of an ECD patient. Less intense uptake occurs bilaterally in the humeri and distal tibias. (B) FDG PET-CT scan showing increased FDG uptake in the knees and proximal and distal tibias. (C) Bone radiograph showing cortical osteosclerosis in the right humeri. (D) Bone radiograph showing cortical osteosclerosis in the distal right radius. (E) CT scan of the right knee of an ECD patient showing cortical osteosclerosis and mottled appearance of the bone. (F) MRI scan of the right knee of an ECD patient showing serpiginous areas of T1 signal hypointensity, indicative of osteosclerosis. (G) Panoramic radiograph showing bilateral osteosclerosis of the mandible and maxillary sinus disease.

Figure 2.

Cardiovascular, retroperitoneal, and lung images of ECD patients. (A) Sagittal reconstruction postcontrast CT demonstrates encasement of the thoracic aorta down to the bifurcation. (B) Coronal FDG PET-CT scan showing increased FDG uptake in the thoracic and abdominal aorta. Symmetrically encased kidneys “hairy kidney” showing increased FDG uptake. (C) Axial CT with contrast demonstrates mass-like enhancement encasing the kidneys symmetrically (“hairy kidney”). In addition, there is circumferential encasement and narrowing of the abdominal aorta (arrow). (D) Cardiac CT showing partial encasement of the right coronary artery. (E) Cardiac CT showing partial encasement of the right coronary artery. (F) Axial postcontrast CT image of the upper abdomen demonstrating mass-like perinephric stranding surrounding the kidneys with bilateral hydronephrosis. Hyperdense material within the right collecting system is a ureteral stent. (G) Postcontrast coronal MRI image of the kidneys demonstrating extension of the perinephric mass into the adrenal bed and encasement of the adrenals (arrows). (H) High-resolution CT of the chest showing interstitial fibrosis.

Figure 3.

Brain images in ECD. (A) Axial post contrast brain MRI showing suprasellar and cerebellar involvement in a patient with ECD. (B) Sagittal post contrast brain MRI (from panel A) showing suprasellar and cerebellar tumors in a patient with ECD. (C) Axial fluid attenuated inversion recovery brain MRI showing ECD tumors in cerebral hemispheres. (D) Axial fluid attenuated inversion recovery brain MRI showing ECD tumors in cerebral hemisphere. (E) Sagittal post contrast brain MRI showing an ECD tumor with cystic components in the midbrain-pons of a patient with ECD. (F) T2 fluid attenuated inversion recovery MRI image showing increased symmetrical signal intensity in the cerebellum. (G) Neurodegeneration and atrophy of the cerebellum in a patient with ECD seen on brain MRI. (H) Orbital involvement with tissue accumulation in the intraconal space secondary to histiocytes accumulation in ECD. (I) Orbital involvement showing increased thickening of the lateral rectus muscle. (J) Pituitary stalk is thickened secondary to macrophage accumulation in ECD and deviated to the right. (K) Hematoxylin and eosin stain for brain lesion showing foamy macrophages and inflammation in brain mass biopsy specimen (original magnification ×40). (L) CD68 KP-1 stain of panel K highlighting the foamy macrophages (original magnification ×40).

Figure 4.

Skin findings in ECD. (A) Periorbital xanthelasmas in a patient with ECD. Note mild exophthalmos secondary to retro-orbital mass. (B) Upper lid xanthelasmas are apparent when the patient’s eyes are closed. (C) Skin lesions containing foamy macrophages negative for S-100 protein but with activating ALK gene fusion. (D) Skin lesion positive for BRAF V600E mutation. (E) Foamy macrophages in skin lesion. Inset shows lipid-laden macrophages interspersed with inflammatory cells (original magnification ×20; hematoxylin and eosin stain).