MRI and histopathologic study of a novel cholesterol-fed rabbit model of xanthogranuloma

Abstract

Purpose: To develop a rabbit model of xanthogranuloma based on supplementation of dietary cholesterol. The aim of this study was to analyze the xanthogranulomatous lesions using magnetic resonance imaging (MRI) and histological examination.

Materials and methods: Rabbits were fed a low-level cholesterol (CH) diet (n = 10) or normal chow (n = 5) for 24 months. In vivo brain imaging was performed on a 3T MR system using fast imaging employing steady state acquisition, susceptibility-weighted imaging, spoiled gradient recalled, T1 -weighted inversion recovery imaging and T1 relaxometry, PD-weighted and T2 -weighted spin-echo imaging and T2 relaxometry, iterative decomposition of water and fat with echo asymmetry and least-squares estimation, ultrashort TE MRI (UTE-MRI), and T2* relaxometry. MR images were evaluated using a Likert scale for lesion presence and quantitative analysis of lesion size, ventricular volume, and T1 , T2 , and T2* values of lesions was performed. After imaging, brain specimens were examined using histological methods.

Results: In vivo MRI revealed that 6 of 10 CH-fed rabbits developed lesions in the choroid plexus. Region-of-interest analysis showed that for CH-fed rabbits the mean lesion volume was 8.5 ± 2.6 mm(3) and the volume of the lateral ventricle was significantly increased compared to controls (P < 0.01). The lesions showed significantly shorter mean T2 values (35 ± 12 msec, P < 0.001), longer mean T1 values (1581 ± 146 msec, P < 0.05), and shorter T2* values (22 ± 13 msec, P < 0.001) compared to adjacent brain structures. The ultrashort T2* components were visible using UTE-MRI. Histopathologic evaluation of lesions demonstrated features of human xanthogranuloma.

Conclusion: Rabbits fed a low-level CH diet develop sizable intraventricular masses that have similar histopathological features as human xanthogranuloma. Multiparametric MRI techniques were able to provide information about the complex composition of these lesions. J. Magn. Reson. Imaging 2016;44:673-682.

Keywords: cholesterol; hypercholesterolemia; magnetic resonance imaging; rabbit model; xanthogranuloma.

FIGURE 1

In vivo FIESTA and SWAN. In vivo FIESTA images (A) and SWAN images (B) shows the mass xanthogranulomatous lesions in the choroid plexus. The tumorous masses (arrows) in the CH-fed rabbit show as areas of inhomogeneous hypointensity, interspersed with foci of signal voids. The lesions are accompanied with hydrocephalus and enlarged ventricle (A,B). Rabbit fed normal chow did not showed evidence of mass lesions in the brain. The Likert scale analysis indicated a total of 13 lesions (scores of 4 or 5) are present in the CH-fed rabbits (C, circle indicates the rabbits with no lesion found and square indicates the Likert scale of the lesions). Quantitative analysis shows the mean volume of lateral ventricle of CH-fed rabbits was significantly increased (D, **P < 0.01).

FIGURE 2

In vivo proton Density, T₁ and T₂-weighted images. The xanthogranulomatous lesions were heterogeneous in appearance on proton density, T₁, and T₂-weighted spin echo images (A), being slight hypointense in PD-weighted images (arrows), mixed isointense and foci of hypointensity on T₁-weighted images (arrows), and inhomogeneous low signal on the T₂-weighted images (arrows). The lesions showed intermediate-long T₁ relaxation times on T₁ maps (B, arrows) and short T₂ values interspersed with foci of marked reduced T₂ on T₂ maps (B, arrows). Quantitative analysis (C) shows the lesion exhibited short mean T₂ values comparing with adjacent cortex and subcortical structures and long mean T₁ values compared to adjacent cortex (**P < 0.001; *P < 0.05; The color bar is in units of milliseconds).

FIGURE 3

In vivo UTE-MRI and $T_2^{\ast }$ relaxometry. UTE-MRI and $T_2^{\ast }$ relaxometry of CH-fed rabbit show the mass xanthogranulomatous lesions. Short-T₂-selective UTE images (A) were obtained through the subtraction of a long TE images (TE = 5 msec) from the short TE images (TE = 8 μs). The xanthogranulomatous lesions exhibit as isointense in the images of TE = 8 μs (arrows) and inhomogeneous hypointensity in the images of TE = 5.0 msec (arrows). The lesions contain ultrashort T₂ species, which exhibit as the positive signal intensity in the subtracted images (arrows). $T_2^{\ast }$ maps indicate that the positive signal in the subtracted images has the marked reduced $T_2^{\ast }$ values (D, arrows). Quantitative analysis (C) shows that mean $T_2^{\ast }$ value of the lesion is significant shorter than the adjacent brain structures. (**P < 0.001; the color bar is in units of milliseconds).

FIGURE 4

Histopathologic examination of the lesion. Histopathologic examination of the lesion shows the foamy histiocytes, CH clefts, hemosiderin iron deposits, histiocytes capillary vasculature, consistent with the diagnosis of xanthogranuloma. A,B: H&E and Bielschowsky’s silver staining show foamy histiocytes are surrounded by needlelike CH clefts interspersed among foam cells. C: The foamy cells were positive for lipid in Oil-red-O-stain. D: Foamy cells stain positively with the Ram11, a marker for macrophages. E: CD31 immunostaining shows vasculature scattered among CH clefts and foamy cells. F: Prussian blue staining for iron in the hemosiderin shows the lesions are interspersed with iron deposits (scale bar represents 100 μm).