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Phase-contrast CT

Posted Dec 31, 2016 Updated Apr 10, 2023
By Jianbo Jian MS , Wenxue Zhang PhD , Hao Yang MS , Xinyan Zhao PhD , Ruijiao Xuan MS , Dongyue Li MS , Chunhong Hu PhD
14 min read

Rationale and Objectives

Capillarization of sinusoids and change of trabecular thickness are the main histologic features in hepatocellular carcinoma (HCC). Of particular interest are the three-dimensional (3D) visualization and quantitative evaluation of such alterations in the HCC progression. X-ray phase-contrast computed tomography (PCCT) is an emerging imaging method that provides excellent image contrast for soft tissues. This study aimed to explore the potential of in-line PCCT in microstructure imaging of capillarized sinusoids and trabecular structure in human HCC tissues and to quantitatively evaluate the alterations of those fine structures during the development of HCC.

Materials and Methods

This project was designed as an ex vivo experimental study. The study was approved by the institutional review board, and informed consent was obtained from the patients. Eight human resected HCC tissue samples were imaged using in-line PCCT. After histologic processing, PCCT images and histopathologic data were matched. Fine structures in HCC tissues were revealed. Quantitative analyses of capillarized sinusoids (ie, percentage of sinusoidal area [PSA], sinusoidal volume) and trabecular structure (ie, trabecular thickness, surface-area-to-volume ratio [SA/V]) in low-grade (well or moderately differentiated) and high-grade (poorly differentiated) HCC groups were performed.

Results

Using PCCT, the alterations of capillarized sinusoids and trabecular structure were clearly observed in 3D geometry, which was confirmed by the corresponding histologic sections. The 3D qualitative analyses of sinusoids in the high-grade HCC group were significantly different ( P < 0.05) in PSA (7.8 ± 2.5%) and sinusoidal volume (2.9 ± 0.6 × 10 7 µm 3 ) from those in the low-grade HCC group (PSA, 12.9 ± 2.2%; sinusoidal volume, 2.4 ± 0.3 × 10 7 µm 3 ). Moreover, the 3D quantitative evaluation of the trabecular structure in the high-grade HCC group showed a significant change ( P < 0.05) in the trabecular thickness (87.8 ± 15.6 µm) and SA/V (2.2 ± 1.3 × 10 3 µm − 1 ) compared to the low-grade HCC group (trabecular thickness, 75.9 ± 7.1 µm; SA/V, 7.5 ± 1.3 × 10 3 µm − 1 ).

Conclusions

This study provides insights into the 3D alterations of microstructures such as capillarized sinusoids and the trabecular structure at a micrometer level, which might allow for an improved understanding of the development of HCC.

Introduction

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and has a very poor prognosis, making it the third leading cause of cancer-related mortality worldwide . According to the World Health Organization classification, HCCs are histologically classified as well-differentiated, moderately differentiated, poorly differentiated HCCs, and undifferentiated types. Well or moderately differentiated HCC is associated with better patient survival rate. Conversely, poorly differentiated HCC is characterized by poorer prognosis . The poor prognosis strongly correlates with the alterations of hepatic sinusoids and hepatictrabeculae, which are important structures in the liver. Exhibition and analysis of the alterations of these fine structures can improve the understanding of the development of HCC. In the normal liver, hepatic sinusoids are irregular, tubular, or saccular, with diameters ranging from 20 µm to 30 µm , and they are surrounded by hepatic trabeculae which are formed in hepatocyte rows . In HCC, capillarization of sinusoids is a well-recognized phenomenon and characterized by the deposition of a fibrillar extracellular matrix in Disse’s spaces, resulting in the impairment of the metabolic exchange between blood and liver cells . Moreover, the trabecular structure in the HCC tissues, which surrounds the capillarized sinusoids, is composed of malignant cells with trabecular growth of three or more cells in thickness . Conventionally, histologic analysis of pathologic sections has been used to provide the morphologic and quantitative assessment of the capillarized sinusoids and hepatic trabeculae in HCC. However, this invasive technique has some inherent limitations, such as its complexity, destructiveness, and sampling error . In addition, accurate visualization of the capillarized sinusoids and trabecular structure has been limited by the resolution and contrast available with current clinical imaging technologies, such as ultrasound, magnetic resonance imaging, conventional radiography, and computed tomography (CT). Thus, there is a need for sensitive, reliable, and noninvasive imaging techniques for assessing the anatomic and pathologic features of capillarized sinusoids and the trabecular structure in HCC tissues.

It has been demonstrated that x-ray phase-contrast imaging (PCI) has outstanding potential for medical applications . Compared to the traditional absorption-based x-ray imaging, PCI has approximately 1000 times greater sensitivity in the detection of soft tissues, and its spatial resolution can be in the order of microns or even submicrons . Combined with CT, x-ray phase-contrast computed tomography (PCCT) has been developed and is characteristic of high sensitivity and three-dimensional (3D) imaging of soft tissues . Several techniques are now available to exploit and visualize the phase contrast, such as the interferometric method , the analyzer-based method , the grating-based method , and the in-line method . In-line PCCT is a holography technique that generates intensity distribution including phase information . Among these PCCT techniques, in-line PCCT has the simplest experimental setup requiring no optical element . In-line PCCT has attracted increasing attention due to its promising application in various research fields . Moreover, its advantages over the current clinical imaging technologies, such as conventional CT and magnetic resonance imaging, have been demonstrated in previous studies . Based on the in-line PCCT technique, morphologic alterations of the sinusoids, such as the diameter, surface area, and volume, have been recently reported in human cavernous hemangioma of the liver . However, to our knowledge, the micro-architectures of human HCC, such as sinusoids and the trabecular structure, have rarely been investigated by PCCT.

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Materials and Methods

Sample Preparation

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Image Acquisition

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Figure 1, Schematic diagram of the experiment setup. X-rays are derived from a 3.5 GeV electron storage ring and are monochromatized by a double-crystal monochromator with 111 Si crystals. The beam is projected on a sample fixed on a rotation stage, and the transmitted beam is recorded by an image detector. Finally, the projection images of the sample are displayed via the image acquisition system.

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Image Reconstruction and 3D Visualization

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Image Analysis

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R=S1Vg−V1 R

=

S

1

V

g

−

V

1

where R R represents the SA/V, Vg V

g denotes the volume of interest, and S1 S

1 and V1 V

1 are the surface area and the sinusoidal volume of capillarized sinusoids, respectively. Trabecular thickness indicates the thickness of the trabecular plate, which consists of several rows of liver cells. The information about trabecular thickness could be indirectly obtained by analyzing the 3D structure of capillarized sinusoids, which run between the trabecular structure in HCC tissues. In HCC tissues, the structures such as sinusoids or trabeculae are sparsely distributed and always densely concentrated in a certain area (ie, sinusoidal area) . To quantitatively evaluate sinusoidal volume, SA/V, and trabecular thickness in HCC tissues, 20 3D-reconstructed cubes of 60 × 60 × 60 pixels were randomly acquired from sinusoidal areas in each group.

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Statistical Analysis

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Results

PCCT Imaging and Histopathologic Analysis

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Figure 2, Comparison between PCCT images and histologic sections in the same region of HCC tissues. (a) CT image of HCC. (b) The corresponding histologic section stained with H&E. (c) The same image seen in (a) is shown here with an overlaid (70% transparent) optical image in (b) on the left upper quadrant of the sample. Yellow arrows indicate the area of hemagglutination and red arrows indicate the structure of capillarized sinusoids. CT, computed tomography; HCC, hepatocellular carcinoma; H&E, hematoxylin and eosin; PCCT, phase-contrast computed tomography. (Color version of figure is available online.)

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The 3D Visualization of Capillarized Sinusoids

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Figure 3, 3D visualization of capillarized sinusoids. (a) The color-coded view of the sample described in Figure 2a showing HCC tissues with vessels ( red tubular ), hemagglutination ( orange pillars ), capillarized sinusoids ( yellow plates ), and liver parenchyma ( jacinth color ). (b) 3D visualization of HCC tissues without liver parenchyma. (c) Capillarized sinusoids in low-grade HCC. (d) Capillarized sinusoids in high-grade HCC. (e) and (f) illustrate the measurement of the trabecular thickness in low-grade HCC and high-grade HCC, respectively, and the thickness is obtained from the measurement of the minimum distance between two small branches of the sinusoids ( white ruler ). The corresponding histologic sections are shown in the lower right corners of (e) and (f) . A 3D visualization of HCC tissues is shown in Video S1 in Supplementary Data. 3D, three-dimensional; HCC, hepatocellular carcinoma. (Color version of figure is available online.)

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Quantitative Assessment of Capillarized Sinusoids and Trabecular Structure

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Figure 4, Statistical results of (a) percentage of sinusoidal area, (b) trabecular thickness, (c) SA/V of trabecular structure, and (d) sinusoidal volume in low-grade and high-grade HCC tissues. The results are expressed as the mean ± standard deviations. * P < 0.01, ** P < 0.05 compared to the low-grade group. HCC, hepatocellular carcinoma; SA/V, surface-area-to-volume ratio.

Figure 5, Pattern diagram of the correlations among histologic grades, the PSA and volume of the capillarized sinusoids, and the thickness and SA/V of trabecular structure. (a) Low-grade HCC has many small capillarized sinusoids and thin trabecular structure with a high SA/V. (b) High-grade HCC has a few large capillarized sinusoids and thick trabecular structure with a low SA/V. HCC, hepatocellular carcinoma; PSA, percentage of sinusoidal area; SA/V, surface-area-to-volume ratio.

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Discussion

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Acknowledgments

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Supplementary Data

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Figure S1

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Video S1

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Academic Radiology, Volume 24, Issue 1
Journals General Radiology
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