Original contributionDiffusion kurtosis imaging of a human nasopharyngeal carcinoma xenograft model: Initial experience with pathological correlation
Introduction
In recent decades, diffusion-weighted imaging (DWI) has become a well-established and widely used magnetic resonance (MR) functional imaging technique that enables the quantitative assessment of the water diffusion behavior in tissue. DWI is routinely used in daily MR exams as a conventional protocol, especially in oncology [1], [2]. The apparent diffusion coefficient (ADC), which is a quantitative biomarker of water diffusion in a microscopic environment, can be used to detect malignant lesions, assess tumor invasiveness, and even predict early treatment responses [1], [2], [3].
The theoretical premise of the DWI model was to assume that the water molecules in the body showed a normal distribution of diffusion, with the water motion in tissues following a Gaussian diffusion behavior. In fact, the diffusion of water molecules in biological tissues is more complex than the diffusion of free water due to the influence of diffusion barriers such as cell membranes and intracellular spaces. The displacement of water molecules in tissues deviates from the Gaussian distribution. Therefore, an advanced diffusion method based on a non-Gaussian diffusion model, which is known as diffusion kurtosis imaging (DKI), has been developed to account for the non-Gaussian diffusion behavior. This emerging technique was first described by Jensen et al. in 2005 [4]. Subsequent studies have suggested that DKI may better assess the complexity of microstructural environments and may provide more detailed information on tissue heterogeneity, vascularity and cellularity than conventional DWI [4], [5], [6], [7]. Although this Non-Gaussian diffusion model was primarily and largely applied for neural applications in the past [6], [7], increased studies have recently explored DKI to oncology [6], [7], [8], [9], [10], [11], [12], including Nasopharyngeal Carcinoma (NPC), which is one of the most common malignancies in Southeast Asia. Yuan et al. [13] attempted DKI using a maximal b value of 1500 s/mm2 in NPC, showing better fitting of DWI signal than the mono-exponential model. Lu et al. [14] and Wang et al. [15] have evaluated the use of DKI in early detection of radiation-induced temporal lobe necrosis in patients of NPC. Both studies supported that DKI might be a more sensitive imaging marker for detecting the microstructural abnormalities in temporal lobe before they were visible on conventional MRI. Another study showed a significant correlation between histogram parameters derived from DKI and the clinical stage of NPC [16]. In our previous study, we had successfully applied DKI in the pre-treatment evaluation of the NPC, and found that DKI might be superior to mono-exponential DWI in the early prediction of neoadjuvant chemotherapy (NAC) response in patients with locally advanced NPC [17].
Although these DKI-related researches on oncology all suggest that DKI can quantify changes in non-Gaussian water distribution to evaluate pathophysiological changes, few of them have investigated the relationships between DKI parameters and pathophysiological features. The aim of this study was to investigate the relationship between DKI-related parameters and pathological measures using human NPC xenografts in a nude mouse model.
Section snippets
Ethics statement
All mouse procedures were approved by the Institutional Animal Care and Use Committee (IACUC) of Fujian Cancer Hospital and performed according to institutional policies.
Human nasopharyngeal carcinoma xenograft models
Male BALB/c-nu nude mice that were four weeks old (Slack Laboratory Animal Co., Shanghai, China) were used for all the experiments. Twenty-six mice were divided into two groups that were injected with two different nasopharyngeal squamous cell carcinoma cell lines (CNE1 and CNE2). The human nasopharyngeal carcinoma cell lines
Results
All 26 mice had successful MR scans. For DK images, the tumor lesions were clearly shown as an increased signal intensity corresponding to the T2-weighted images(Fig. 1). It can be clearly seen that the non-Gaussian kurtosis analysis fits the data points better than does the monoexponential model. For pathological image analyses, all the HE-stained tissues sections were eligible and qualified for further analysis. Fig. 2 shows a typical HE tissue sample with the automated micro-anatomic
Discussion
Connecting DKI findings with tissue microstructures and pathophysiology can help us better understand the biological relevance of DKI parameters. Our research explored the potential utility of DKI for the characterization of tissue pathological features. The results of our study showed that the ADC and MD values were strongly and negatively correlated with CD and the N/ECS ratio, moderately and negatively correlated with the nuclei area portion, and positively correlated with ECS. The MK value
Limitations
Our study has several limitations. The ROIs we placed on DW/DK images were drawn manually on the maximum cross-sectional area of the tumor, but the HE images were selected randomly by the pathologists. Therefore, we could not associate the HE sections directly with the DW/DKI sections, which may affect the representativeness of tumor heterogeneity. Another limitation is the uneven color distribution of the HE images, and bias may occur on the boundaries between the nuclei, cytoplasm and ECS
Conclusions
In conclusion, the preliminary animal results demonstrated significant correlations between DKI parameters and tumor pathological features. These results provide insights into how the tissue microenvironment affects the MD and MK values, which also suggests that DKI findings can provide valuable bio-information for NPC tissue characterization. DKI can be utilized as a surrogate biomarker for the non-invasive assessment of tumor microstructures.
Acknowledgements
This work is a joint research project co-operated by Fujian Cancer Hospital and Fujian Normal University. The authors would like to thank every laboratory member involved in this cooperation. The project was supported by the Fujian Provincial Department of Science and Technology (NO. 2016Y0018 to Jing Zhong, NO. 2014Y0013 to Yunbin Chen), the National Science Foundation of China under Grant (NO. 61501121 to Peng Shi), and the National Clinical Key Specialty Construction Program of China.
The
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The first two authors contributed equally to this work.