Serum vascular endothelial growth factor is associated with cardiovascular involvement and response to therapy in Erdheim-Chester disease

Abstract

Erdheim-Chester disease (ECD) is a rare histiocytosis, considered to be an inflammatory myeloid neoplasm. Tropism for specific involvements of the disease remains unexplained. Vascular endothelial growth factor-A (VEGF) is implicated in cancer pathophysiology and mutations of the RAS oncogene have been shown to induce upregulation of VEGF gene expression. We therefore hypothesized that VEGF might play a particular role in ECD pathophysiology. We conducted a retrospective, single-center study to assess serum VEGF (sVEGF) concentrations and determine whether they were associated with the characteristics of ECD patients, and to determine whether VEGF was expressed by histiocytes. We evaluated 247 ECD patients, 53.4% of whom had sVEGF levels above the normal range (>500 pg/mL). Patients with high sVEGF levels more frequently had cardiac and vascular involvement (58.3% vs. 41.4%, P=0.008 and 70.5% vs. 48.3%, P=0.0004, respectively). In treatment-naïve patients (n=135), the association of C-reactive protein >5 mg/L and sVEGF >500 pg/mL was strongly associated with vascular involvement (odds ratio=5.54 [95% confidence interval: 2.39-13.62], P<0.001), and independently associated with cardiac involvement (odds ratio=3.18 [95% confidence interval: 1.34-7.83], P=0.010) after adjustment for the presence of the BRAF V600E mutation. Changes in sVEGF concentration on treatment were associated with a response of cardiac involvement on consecutive cardiac magnetic resonance images. All histological samples analyzed (n=24) displayed histiocytes with intracytoplasmic expression of VEGF, which was moderate to high in more than 90% of cases. Our study suggests a role for VEGF in cardiac and vascular involvement in ECD.

Figure 1.

Distribution of serum vascular endothelial growth factor levels at initial determination. sVEGF: serum vascular en-dothelial growth factor.

Figure 2.

Change in serum vascular endothelial growth factor concentration in Erdheim-Chester disease patients over time. Change in serum vascular endothelial growth factor (sVEGF) concentration between the initial determination (M0) and determinations at (A) last visit, and (B) first follow-up visit at 6 months (M6).

Figure 3.

Change in serum vascular endothelial growth factor concentration in patients with Erdheim-Chester disease and cardiac involvement with a complete response, partial response, stability or progression on follow-up cardiac magnetic resonance imaging. ΔsVEGF: change in serum vascular endothelial growth factor. *P value <0.05; **P value <0.01

Figure 4.

Vascular endothelial growth factor staining on Erdheim-Chester disease lesions and reactional sinusal histiocytosis. Top. Erdheim-Chester disease (ECD) xanthelasma: (A) infiltration of the dermis with foamy histiocytes (HES x10); (B) Touton giant cell (HEX x40); (C) intense cytoplasmic VEGF staining of histiocytes (VEGF VG1 x40); (D) moderate cytoplasmic VEGF staining of histiocytes (VEGF F/PU483-UP x40). Middle. ECD perirenal infiltrate: (E) histiocyte aggregates embedded in fibrosis (HES x40); (F) cytoplasmic CD68 staining of histiocytes; (G) intense cytoplasmic VEGF staining of histiocytes (VEGF VG1 x40); (H) intense cytoplasmic VEGF staining of histiocytes (VEGF F/PU483-UP x40). Bottom. Reactional sinusal histiocytosis: (I, K) VEGF VG1 x 20; (J, L) VEGF F/PU483 x20.