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Published online before print March 16, 2006, 10.1148/radiol.2392050277
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(Radiology 2006;239:554-562.)
© RSNA, 2006

Technical Developments

Liver Tumor Model with Implanted Rhabdomyosarcoma in Rats: MR Imaging, Microangiography, and Histopathologic Analysis1

Feng Chen, MD2, Xihe Sun, MD3, Frederik De Keyzer, MSc, Jie Yu, MD, Ronald Peeters, PhD, Walter Coudyzer, MSc, Vincent Vandecaveye, MD, Willy Landuyt, PhD, Hilde Bosmans, PhD, Paul Van Hecke, PhD, Guy Marchal, MD, PhD and Yicheng Ni, MD, PhD

1 From the Department of Radiology (F.C., X.S., F.D.K., J.Y., R.P., W.C., V.V., H.B., P.V.H., G.M., Y.N.) and Laboratory of Experimental Radiobiology and Oncology (W.L.), University Hospitals, Catholic University of Leuven, Herestraat 49, B-3000 Leuven, Belgium. Received February 17, 2005; revision requested April 14; revision received April 25; accepted June 3; final version accepted July 8. Address correspondence to Y.N. (e-mail: Yicheng.Ni{at}med.kuleuven.ac.be).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
In compliance with institutional regulations for care and use of laboratory animals, the aim of this study was to establish and characterize a rodent liver tumor model to provide a platform for preclinical assessment of new diagnostic and therapeutic strategies. A rhabdomyosarcoma tumor was implanted in the right and left liver lobes of 20 rats, for a total of 40 tumors. T1- and T2-weighted magnetic resonance (MR) images, diffusion-weighted images, and dynamic susceptibility contrast agent–enhanced perfusion-weighted images were obtained up to 16 days after tumor implantation and were compared with postmortem three-dimensional computed tomographic (CT) images, digital microangiograms, and histopathologic findings. Fifteen tumors were examined with proton (1H) MR spectroscopy. All tumors grew, with a mean volume doubling time of 2.2 days ± 0.9 (standard deviation) and a final size of 591 mm3± 124. The rhabdomyosarcoma tumor showed hypervascularity at MR imaging, three-dimensional CT, microangiography, and histologic analysis. On dynamic susceptibility contrast–enhanced perfusion-weighted images, the maximum signal intensity decrease differed in time and extent between the tumor and the liver, with a significantly (P < .001) higher relative blood volume, relative blood flow, and permeability value in the tumor than in the liver. With 1H MR spectroscopy, the rhabdomyosarcoma tumor and the liver featured significant (P < .001) choline and lipid peaks, respectively. Implantation of a rhabdomyosarcoma tumor in the livers of rats is feasible and reproducible, and this animal model seems promising for future testing of new diagnostic and therapeutic strategies.

© RSNA, 2006


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
An appropriate and readily available animal model is crucial in the evaluation of newly developed diagnostic and therapeutic strategies for use in the evaluation and treatment of hepatic malignancies. Despite a variety of malignant cell lines available for hepatic implantation in experimental magnetic resonance (MR) imaging studies (1–5), these liver tumor models have been used mainly in experiments (eg, detection of space-occupying lesions with improved imaging signal intensity or contrast enhancement with conventional spin-echo [SE] T1- and T2-weighted sequences) (1–5). Although the more comprehensive tumoral features—including morphologic, functional, and metabolic aspects—are vitally important, to our knowledge, they have not been well characterized thus far, mainly because of the outdated or insufficient imaging techniques available at the time. However, rapid advances in MR technology have been made in the past decade, and many powerful and versatile MR imaging sequences and methods have been developed and widely applied in clinical practice. Thus, it is appropriate to establish an updated and high-throughput experimental system that comprises both reproducible liver tumor models and reliable comprehensive MR imaging techniques to fully exploit the potential of these new developments, particularly for noninvasive monitoring of tumoricidal effects of drug candidates.

Because of its biologically stable nature and responsiveness to various therapeutic interventions, a rodent model of rhabdomyosarcoma has been successfully and widely used in cancer research (6–11). Subcutaneous implantation (tissue piece) and inoculation (cell suspension) have been the most favorable patterns and the most extensively studied rhabdomyosarcoma tumor models, mainly because of their experimental convenience (7,9,11–13). However, human malignant tumors are often deeply seated in visceral organs, and their vascular networks and microenvironment are quite different from those of subcutaneous tumors. We are unaware of any reports of solid rhabdomyosarcoma tumor implantation in the liver; therefore, we postulated that once the tumor was successfully implanted as a representative of various malignant cell lines, it may exhibit a different biologic behavior appreciable with advanced clinical MR imaging approaches and that such a liver tumor model would be useful in monitoring the responses of both the tumor and the surrounding normal liver to vasoactive agents (12,13).

We hypothesized that (a) the implantation of rhabdomyosarcoma tumor is feasible and can yield measurable solitary tumors in the liver and (b) this tumor model can be noninvasively characterized both morphologically and functionally by using a clinical 1.5-T MR imager and further validated with postmortem reference standard techniques. Thus, the purpose of our study was to establish and characterize a rodent liver tumor model to provide a platform for preclinical assessment of new diagnostic and therapeutic strategies.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Animal Model
This experiment was compliant with our current institutional regulations for use and care of laboratory animals. A rhabdomyosarcoma growing subcutaneously in the flank of an adult WAG/Rij rat was used as donor tissue (13); rats were maintained and provided by the laboratory in the department of clinical oncology in our institute. Liver rhabdomyosarcoma tumor implantation was performed (Y.N., F.C., X.S., and W.L.) in 20 male adult rats of the same strain, that had a mean weight of 300 g ± 20 (standard deviation). Rats were anesthetized with intraperitoneal injection of 40 mg of pentobarbital (Nembutal; Sanofi Sante Animale, Brussels, Belgium) per kilogram of body weight. The viable part of the donor tumor was minced into small cubes (approximately 2 mm3). Recipient rats underwent midline laparotomy. We modified a previously reported liver tumor implantation method (14). Briefly, the right and left liver lobes were exposed and a 3 x 3-mm incision (depth and length) was made through the capsule of both lobes, with a gelatin sponge stick inserted temporarily for hemostasis. One rhabdomyosarcoma tumor cube was inserted into the aperture made in each lobe, and the incision was sealed with a droplet of tissue glue (Histoacryl; Aesculap, Tuttlingen, Germany). The rats were allowed to recover for 1–2 hours after closure of the abdomen with layered sutures.

All rats survived open abdominal surgery for tumor implantation and subsequent imaging protocols performed with anesthesia, without intrahepatic or remote metastases found at autopsy. At day 16, all rats appeared healthy and without pallor, piloerection, aggression, restlessness, weakness, tremors, diarrhea, ascites, or loss of hair or appetite.

MR Imaging
Rats were initially anesthetized with inhalation of 4% isoflurane; anesthesia was maintained with 2% isoflurane in a mixture of 20% oxygen and 80% room air. Rats were placed in the supine position in a plastic holder and connected by means of a mask and a 10-m-long polyethylene tube to an information management system gas anesthesia system (Harvard Apparatus, Holliston, Mass) located outside the room containing the MR imager. The tail vein of the rat was cannulated for contrast agent injection.

MR imaging and MR spectroscopy were performed by using a 1.5-T whole-body MR imager (Sonata; Siemens, Erlangen, Germany) with a 40 mT/m maximum gradient capacity by using a four-channel phased-array wrist coil (MRI Devices, Waukesha, Wis). For each imaging sequence, 12 transverse images were acquired with a section thickness of 3.5 mm and a section gap of 0.7 mm.

Fast SE T1-weighted imaging was performed with the following parameters: repetition time msec/echo time msec, 457.0/8.6; turbo factor, seven; field of view, 140 x 70 mm; imaging acquisition matrix, 256 x 128; two concatenations; four signals acquired; in-plane resolution, 0.5 x 0.5 mm2; and total examination time, 1 minute 12 seconds.

Fast SE T2-weighted images were acquired with the following parameters: 2860/100; turbo factor, 19; field of view, 140 x 70 mm; acquisition matrix, 256 x 128; three signals acquired; and total examination time, 1 minute 4 seconds.

Diffusion-weighted (DW) imaging was performed with a two-dimensional SE echo-planar imaging sequence with a field of view of 140 x 82 mm and an acquisition matrix of 192 x 91, which led to an in-plane resolution of 0.7 x 0.9 mm. To reduce susceptibility artifacts and examination time, a parallel imaging technique—namely, generalized autocalibrating partially parallel acquisition—with an acceleration factor of two was applied with the following parameters: 1700/83 and six signals acquired, including repeated measurements for 10 different b values (0, 50, 100, 150, 200, 250, 300, 500, 750, and 1000 sec/mm2) and resulting in a total examination time of 4 minutes 51 seconds. For DW imaging, three directions (x, y, and z) were measured and averaged for the calculation of the isotropic apparent diffusion coefficient (ADC) value.

Dynamic susceptibility contrast-enhanced perfusion-weighted (PW) images were acquired by using a T2*-weighted (2000/46) echo-planar imaging sequence in combination with the generalized autocalibrating partially parallel acquisition technique to increase spatial homogeneity on the images. A dynamic PW imaging series of 100 measurements resulted in a total examination time of 3 minutes 24 seconds, with a field of view of 140 x 70 mm, and an acquisition matrix of 128 x 64, generating an in-plane resolution of 1.1 x 1.1 mm. During the dynamic series, administration of a triple-dose (0.3 mmol per kilogram of body weight) intravenous bolus of gadodiamide (Omniscan; Amersham, Norway) was started after the 30th measurement was obtained to ensure a sufficient number of precontrast baseline images were obtained. The bolus injection was performed manually in less than 1 second without a saline flush.

After the dynamic susceptibility contrast-enhanced PW images were obtained, postcontrast fast SE T1-weighted images were acquired. For proton (1H) MR spectroscopy, single-volume spectroscopy was performed by using an SE sequence (1500/135) with chemical-shift-selective water suppression, a voxel size of 1.0 x 1.0 x 1.0 cm, and 256 acquired signals, resulting in a data acquisition time of 6 minutes 30 seconds.

Study Protocol
All rats were examined with serial MR imaging 5, 7, 10, 12, 14, and 16 days after tumor implantation. For 5-, 7-, 10-, 12-, and 14-day follow-up, T1-weighted imaging, T2-weighted imaging, and DW imaging were used, without contrast agent administration, to monitor the evolution of rhabdomyosarcoma tumor growth in the liver. At 16-day follow-up, all MR imaging techniques—including MR spectroscopy (in 15 tumors with a diameter of more than 12 mm)—were performed for comprehensive tumor characterization, which typically took about 30 minutes for each animal.

Computed Tomography, Digital Microangiography, and Histologic Analysis
For postmortem verification of the tumor model, we performed the following macro- and microscopic procedures: Immediately after the last MR imaging session, the rat was sacrificed with an intravenous overdose of pentobarbital; laparotomy was performed, and a barium suspension (Micropaque; Guerbet, Roissy, Cedex, France) was injected for hepatic arteriography with a technique similar to that described by Ni et al (15). The entire specimen of the tumor-bearing liver was dissected and subjected to a three-dimensional computed tomographic (CT) examination to assess the overall tumor vasculature. CT was performed by using a multi–detector row scanner (Sensation 16; Siemens) with a section thickness of 0.75 mm and a reconstruction increment of 0.3 mm. CT scans were displayed with the volume-rendering and thick-slab maximum intensity projection techniques. Postmortem microangiography was performed with a digital mammographic unit (Embrace; Agfa-Gevaert, Mortsel, Belgium) at 26 kV and 9 mAs to facilitate correct matching of the lesion seen on MR images and histologic preparations and to facilitate better insight into the vascularization of the rhabdomyosarcoma tumor. These features were studied by several authors (F.C., X.S, Y.N., and J.Y.).

Thereafter, liver specimens were fixed in 10% formalin and processed with hematoxylin-eosin staining by an experienced pathologist (J.Y., with more than 20 years of experience) to enable the description of macro- and microscopic features, including tumor growth patterns, cellular differentiation, vascularity, and the presence or absence of intratumoral necrosis.

Image Analysis
All procedures were performed with consensus of three authors (F.C., X.S., and Y.N.). For quantification of tumor volume on MR images, the area of the tumor on each tumor-containing section on T2-weighted images was delineated by using an operator-defined region of interest (ROI), with the tumor volume being automatically generated by the software (Biomap; Novartis, Basel, Switzerland) off-line on a Linux workstation for each rat. The tumor doubling time (DT) was determined with the following equation: DT = (T – T0) x log 2/(log V – log V0), where T – T0 indicates the length of time between two measurements, and V0 and V denote the tumor volume at two points of measurement (16).

During postprocessing, a 75-mm2 ROI—which was further divided into 49 pixels (each 1.24 x 1.24 mm)—was placed at the region covering the aorta and the hepatic artery to measure the arterial input function. On the panel, we selected pixels that were representative of the aorta or hepatic artery branch. With use of the built-in software (Siemens), tumoral and normal hepatic tissue perfusion-weighted maps of relative blood flow and relative blood volume were derived automatically with arbitrary units. Local dynamic mean signal intensity curves were obtained by placing the ROI at tumoral and normal locations. The permeability weighted maps were generated by using dedicated Biomap software to process T2*-weighted data with the method described by Weisskoff et al (17) and further validated by Ostergaard et al (18) and Provenzale et al (19).

For delineation of the tumor on relative blood volume and relative blood flow maps derived with PW imaging, ROIs were copied and pasted from tumor-containing PW source images. The permeability weighted value was obtained by using the method described by Provenzale et al (19). An ROI of the normal liver was also used for corresponding values from all images and parameter maps to facilitate comparison between the tumor and normal liver.

Statistical Analysis
Numeric data were reported as means ± standard deviations. Statistical analysis was performed with commercially available software (SPSS for Windows, release 10.0; SPSS, Chicago, Ill). Paired and two-tailed Student t tests were used to compare the different MR imaging parameters between tumoral and normal liver tissues for different MR techniques. A difference was considered significant if the P value was less than .05. Given the sample size of 40 tumors in 20 rats, the calculated mean statistical power of 0.95 ± 0.06 was considered sufficient for the present study.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 
Intrahepatic Tumor Growth
After implantation, 20 rats yielded a total of 40 rhabdomyosarcoma tumors, with one mass in the right liver lobe and one mass in the left. Since there was no overall significant difference in the tumor volume between tumors in different liver lobes (P = .76), all tumors were combined into one group for analysis. The tumors grew slowly during the initial 5 days after implantation; thereafter, the rate of growth gradually accelerated and tumors reached the mean maximum size of 591 mm3± 124 at sacrifice on day 16 (Fig 1). The mean calculated tumor volume doubling time was 2.2 days ± 0.9.


Figure 1
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  		Figure 1: Tumor growth curve of rhabdomyosarcoma in rat liver.

 
MR Imaging Findings
All rhabdomyosarcoma tumors in the liver had a spherical shape, were clearly demarcated on MR images obtained with all sequences, and shared common MR imaging characteristics. Rhabdomyosarcoma tumors were homogeneously hyperintense on fast SE T2-weighted images, hypointense on fast SE T1-weighted images (Fig 2a, 2b), and positively enhanced on fast SE T1-weighted images after administration of the gadolinium-based contrast agent (Fig 2c). Various degrees of hyperintensity were seen on DW images obtained with different b values, and slightly high signal intensity was seen on the ADC map in comparison with the signal intensity of the surrounding liver parenchyma (Figs 2d, 2e). In the center of five tumors, minute necrosis could be discerned with higher signal intensity on T2-weighted images and ADC maps and lower signal intensity on DW images obtained with a high b value (Figs 3a–3d).


Figure 2
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  		Figure 2a: MR imaging findings of implanted rhabdomyosarcoma tumor in rodent liver. Tumors (arrows) showed homogeneous abnormal signal intensity on the (a) fast SE T2-weighted image (2860/100), (b) precontrast fast SE T1-weighted image (457/8.6), (c) postcontrast fast SE T1-weighted image, (d, e) DW images (1700/83), and (f) ADC map. (g, h) Postmortem multi–detector row three-dimensional CT scans show marked enhancement of tumors (arrows) with the maximum intensity projection (g) and volume-rendering (h) techniques. (i) Digital microangiogram shows rich irregular tumor vascularity (arrows). (j) Histopathologic and (k) macroscopic analyses confirmed the solitary, homogeneous, and malignant features of rhabdomyosarcoma tumors (arrows). Rectangular frames denote the areas where microscopy was focused. (l) Photomicrograph shows the tumor feeding artery (large arrow) and intratumoral vessels (small arrows) filled with barium suspension. L = liver parenchyma, T = rhabdomyosarcoma tumor. (Hematoxylin-eosin stain; original magnification, x50.)

 

Figure 2
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  		Figure 2b: MR imaging findings of implanted rhabdomyosarcoma tumor in rodent liver. Tumors (arrows) showed homogeneous abnormal signal intensity on the (a) fast SE T2-weighted image (2860/100), (b) precontrast fast SE T1-weighted image (457/8.6), (c) postcontrast fast SE T1-weighted image, (d, e) DW images (1700/83), and (f) ADC map. (g, h) Postmortem multi–detector row three-dimensional CT scans show marked enhancement of tumors (arrows) with the maximum intensity projection (g) and volume-rendering (h) techniques. (i) Digital microangiogram shows rich irregular tumor vascularity (arrows). (j) Histopathologic and (k) macroscopic analyses confirmed the solitary, homogeneous, and malignant features of rhabdomyosarcoma tumors (arrows). Rectangular frames denote the areas where microscopy was focused. (l) Photomicrograph shows the tumor feeding artery (large arrow) and intratumoral vessels (small arrows) filled with barium suspension. L = liver parenchyma, T = rhabdomyosarcoma tumor. (Hematoxylin-eosin stain; original magnification, x50.)

 

Figure 2
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  		Figure 2c: MR imaging findings of implanted rhabdomyosarcoma tumor in rodent liver. Tumors (arrows) showed homogeneous abnormal signal intensity on the (a) fast SE T2-weighted image (2860/100), (b) precontrast fast SE T1-weighted image (457/8.6), (c) postcontrast fast SE T1-weighted image, (d, e) DW images (1700/83), and (f) ADC map. (g, h) Postmortem multi–detector row three-dimensional CT scans show marked enhancement of tumors (arrows) with the maximum intensity projection (g) and volume-rendering (h) techniques. (i) Digital microangiogram shows rich irregular tumor vascularity (arrows). (j) Histopathologic and (k) macroscopic analyses confirmed the solitary, homogeneous, and malignant features of rhabdomyosarcoma tumors (arrows). Rectangular frames denote the areas where microscopy was focused. (l) Photomicrograph shows the tumor feeding artery (large arrow) and intratumoral vessels (small arrows) filled with barium suspension. L = liver parenchyma, T = rhabdomyosarcoma tumor. (Hematoxylin-eosin stain; original magnification, x50.)

 

Figure 2
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  		Figure 2d: MR imaging findings of implanted rhabdomyosarcoma tumor in rodent liver. Tumors (arrows) showed homogeneous abnormal signal intensity on the (a) fast SE T2-weighted image (2860/100), (b) precontrast fast SE T1-weighted image (457/8.6), (c) postcontrast fast SE T1-weighted image, (d, e) DW images (1700/83), and (f) ADC map. (g, h) Postmortem multi–detector row three-dimensional CT scans show marked enhancement of tumors (arrows) with the maximum intensity projection (g) and volume-rendering (h) techniques. (i) Digital microangiogram shows rich irregular tumor vascularity (arrows). (j) Histopathologic and (k) macroscopic analyses confirmed the solitary, homogeneous, and malignant features of rhabdomyosarcoma tumors (arrows). Rectangular frames denote the areas where microscopy was focused. (l) Photomicrograph shows the tumor feeding artery (large arrow) and intratumoral vessels (small arrows) filled with barium suspension. L = liver parenchyma, T = rhabdomyosarcoma tumor. (Hematoxylin-eosin stain; original magnification, x50.)

 

Figure 2
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  		Figure 2e: MR imaging findings of implanted rhabdomyosarcoma tumor in rodent liver. Tumors (arrows) showed homogeneous abnormal signal intensity on the (a) fast SE T2-weighted image (2860/100), (b) precontrast fast SE T1-weighted image (457/8.6), (c) postcontrast fast SE T1-weighted image, (d, e) DW images (1700/83), and (f) ADC map. (g, h) Postmortem multi–detector row three-dimensional CT scans show marked enhancement of tumors (arrows) with the maximum intensity projection (g) and volume-rendering (h) techniques. (i) Digital microangiogram shows rich irregular tumor vascularity (arrows). (j) Histopathologic and (k) macroscopic analyses confirmed the solitary, homogeneous, and malignant features of rhabdomyosarcoma tumors (arrows). Rectangular frames denote the areas where microscopy was focused. (l) Photomicrograph shows the tumor feeding artery (large arrow) and intratumoral vessels (small arrows) filled with barium suspension. L = liver parenchyma, T = rhabdomyosarcoma tumor. (Hematoxylin-eosin stain; original magnification, x50.)

 

Figure 2
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  		Figure 2f: MR imaging findings of implanted rhabdomyosarcoma tumor in rodent liver. Tumors (arrows) showed homogeneous abnormal signal intensity on the (a) fast SE T2-weighted image (2860/100), (b) precontrast fast SE T1-weighted image (457/8.6), (c) postcontrast fast SE T1-weighted image, (d, e) DW images (1700/83), and (f) ADC map. (g, h) Postmortem multi–detector row three-dimensional CT scans show marked enhancement of tumors (arrows) with the maximum intensity projection (g) and volume-rendering (h) techniques. (i) Digital microangiogram shows rich irregular tumor vascularity (arrows). (j) Histopathologic and (k) macroscopic analyses confirmed the solitary, homogeneous, and malignant features of rhabdomyosarcoma tumors (arrows). Rectangular frames denote the areas where microscopy was focused. (l) Photomicrograph shows the tumor feeding artery (large arrow) and intratumoral vessels (small arrows) filled with barium suspension. L = liver parenchyma, T = rhabdomyosarcoma tumor. (Hematoxylin-eosin stain; original magnification, x50.)

 

Figure 2
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  		Figure 2g: MR imaging findings of implanted rhabdomyosarcoma tumor in rodent liver. Tumors (arrows) showed homogeneous abnormal signal intensity on the (a) fast SE T2-weighted image (2860/100), (b) precontrast fast SE T1-weighted image (457/8.6), (c) postcontrast fast SE T1-weighted image, (d, e) DW images (1700/83), and (f) ADC map. (g, h) Postmortem multi–detector row three-dimensional CT scans show marked enhancement of tumors (arrows) with the maximum intensity projection (g) and volume-rendering (h) techniques. (i) Digital microangiogram shows rich irregular tumor vascularity (arrows). (j) Histopathologic and (k) macroscopic analyses confirmed the solitary, homogeneous, and malignant features of rhabdomyosarcoma tumors (arrows). Rectangular frames denote the areas where microscopy was focused. (l) Photomicrograph shows the tumor feeding artery (large arrow) and intratumoral vessels (small arrows) filled with barium suspension. L = liver parenchyma, T = rhabdomyosarcoma tumor. (Hematoxylin-eosin stain; original magnification, x50.)

 

Figure 2
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  		Figure 2h: MR imaging findings of implanted rhabdomyosarcoma tumor in rodent liver. Tumors (arrows) showed homogeneous abnormal signal intensity on the (a) fast SE T2-weighted image (2860/100), (b) precontrast fast SE T1-weighted image (457/8.6), (c) postcontrast fast SE T1-weighted image, (d, e) DW images (1700/83), and (f) ADC map. (g, h) Postmortem multi–detector row three-dimensional CT scans show marked enhancement of tumors (arrows) with the maximum intensity projection (g) and volume-rendering (h) techniques. (i) Digital microangiogram shows rich irregular tumor vascularity (arrows). (j) Histopathologic and (k) macroscopic analyses confirmed the solitary, homogeneous, and malignant features of rhabdomyosarcoma tumors (arrows). Rectangular frames denote the areas where microscopy was focused. (l) Photomicrograph shows the tumor feeding artery (large arrow) and intratumoral vessels (small arrows) filled with barium suspension. L = liver parenchyma, T = rhabdomyosarcoma tumor. (Hematoxylin-eosin stain; original magnification, x50.)

 

Figure 2
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  		Figure 2i: MR imaging findings of implanted rhabdomyosarcoma tumor in rodent liver. Tumors (arrows) showed homogeneous abnormal signal intensity on the (a) fast SE T2-weighted image (2860/100), (b) precontrast fast SE T1-weighted image (457/8.6), (c) postcontrast fast SE T1-weighted image, (d, e) DW images (1700/83), and (f) ADC map. (g, h) Postmortem multi–detector row three-dimensional CT scans show marked enhancement of tumors (arrows) with the maximum intensity projection (g) and volume-rendering (h) techniques. (i) Digital microangiogram shows rich irregular tumor vascularity (arrows). (j) Histopathologic and (k) macroscopic analyses confirmed the solitary, homogeneous, and malignant features of rhabdomyosarcoma tumors (arrows). Rectangular frames denote the areas where microscopy was focused. (l) Photomicrograph shows the tumor feeding artery (large arrow) and intratumoral vessels (small arrows) filled with barium suspension. L = liver parenchyma, T = rhabdomyosarcoma tumor. (Hematoxylin-eosin stain; original magnification, x50.)

 

Figure 2
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  		Figure 2j: MR imaging findings of implanted rhabdomyosarcoma tumor in rodent liver. Tumors (arrows) showed homogeneous abnormal signal intensity on the (a) fast SE T2-weighted image (2860/100), (b) precontrast fast SE T1-weighted image (457/8.6), (c) postcontrast fast SE T1-weighted image, (d, e) DW images (1700/83), and (f) ADC map. (g, h) Postmortem multi–detector row three-dimensional CT scans show marked enhancement of tumors (arrows) with the maximum intensity projection (g) and volume-rendering (h) techniques. (i) Digital microangiogram shows rich irregular tumor vascularity (arrows). (j) Histopathologic and (k) macroscopic analyses confirmed the solitary, homogeneous, and malignant features of rhabdomyosarcoma tumors (arrows). Rectangular frames denote the areas where microscopy was focused. (l) Photomicrograph shows the tumor feeding artery (large arrow) and intratumoral vessels (small arrows) filled with barium suspension. L = liver parenchyma, T = rhabdomyosarcoma tumor. (Hematoxylin-eosin stain; original magnification, x50.)

 

Figure 2
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  		Figure 2k: MR imaging findings of implanted rhabdomyosarcoma tumor in rodent liver. Tumors (arrows) showed homogeneous abnormal signal intensity on the (a) fast SE T2-weighted image (2860/100), (b) precontrast fast SE T1-weighted image (457/8.6), (c) postcontrast fast SE T1-weighted image, (d, e) DW images (1700/83), and (f) ADC map. (g, h) Postmortem multi–detector row three-dimensional CT scans show marked enhancement of tumors (arrows) with the maximum intensity projection (g) and volume-rendering (h) techniques. (i) Digital microangiogram shows rich irregular tumor vascularity (arrows). (j) Histopathologic and (k) macroscopic analyses confirmed the solitary, homogeneous, and malignant features of rhabdomyosarcoma tumors (arrows). Rectangular frames denote the areas where microscopy was focused. (l) Photomicrograph shows the tumor feeding artery (large arrow) and intratumoral vessels (small arrows) filled with barium suspension. L = liver parenchyma, T = rhabdomyosarcoma tumor. (Hematoxylin-eosin stain; original magnification, x50.)

 

Figure 2
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  		Figure 2l: MR imaging findings of implanted rhabdomyosarcoma tumor in rodent liver. Tumors (arrows) showed homogeneous abnormal signal intensity on the (a) fast SE T2-weighted image (2860/100), (b) precontrast fast SE T1-weighted image (457/8.6), (c) postcontrast fast SE T1-weighted image, (d, e) DW images (1700/83), and (f) ADC map. (g, h) Postmortem multi–detector row three-dimensional CT scans show marked enhancement of tumors (arrows) with the maximum intensity projection (g) and volume-rendering (h) techniques. (i) Digital microangiogram shows rich irregular tumor vascularity (arrows). (j) Histopathologic and (k) macroscopic analyses confirmed the solitary, homogeneous, and malignant features of rhabdomyosarcoma tumors (arrows). Rectangular frames denote the areas where microscopy was focused. (l) Photomicrograph shows the tumor feeding artery (large arrow) and intratumoral vessels (small arrows) filled with barium suspension. L = liver parenchyma, T = rhabdomyosarcoma tumor. (Hematoxylin-eosin stain; original magnification, x50.)

 

Figure 3
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  		Figure 3a: Rhabdomyosarcoma tumors on DW images obtained with different b values. (a) A minute necrotic lesion in the center of the tumor could not be detected by using DW imaging with a b value of 500 sec/mm2 or less. (b, c) A minute necrotic lesion (arrow) is seen as a hypointense dot on DW images obtained with a b value of 750 sec/mm2 (b) or 1000 sec/mm2 (c). (d) ADC map shows this lesion as a hyperintense dot (arrow). At histologic analysis, this lesion was proved with (e) macroscopy (rectangular frame indicates the area of focused microscopy) and (f) focused microscopy. N = necrosis. (Hematoxylin-eosin stain; original magnification, x50.)

 

Figure 3
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  		Figure 3b: Rhabdomyosarcoma tumors on DW images obtained with different b values. (a) A minute necrotic lesion in the center of the tumor could not be detected by using DW imaging with a b value of 500 sec/mm2 or less. (b, c) A minute necrotic lesion (arrow) is seen as a hypointense dot on DW images obtained with a b value of 750 sec/mm2 (b) or 1000 sec/mm2 (c). (d) ADC map shows this lesion as a hyperintense dot (arrow). At histologic analysis, this lesion was proved with (e) macroscopy (rectangular frame indicates the area of focused microscopy) and (f) focused microscopy. N = necrosis. (Hematoxylin-eosin stain; original magnification, x50.)

 

Figure 3
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  		Figure 3c: Rhabdomyosarcoma tumors on DW images obtained with different b values. (a) A minute necrotic lesion in the center of the tumor could not be detected by using DW imaging with a b value of 500 sec/mm2 or less. (b, c) A minute necrotic lesion (arrow) is seen as a hypointense dot on DW images obtained with a b value of 750 sec/mm2 (b) or 1000 sec/mm2 (c). (d) ADC map shows this lesion as a hyperintense dot (arrow). At histologic analysis, this lesion was proved with (e) macroscopy (rectangular frame indicates the area of focused microscopy) and (f) focused microscopy. N = necrosis. (Hematoxylin-eosin stain; original magnification, x50.)

 

Figure 3
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  		Figure 3d: Rhabdomyosarcoma tumors on DW images obtained with different b values. (a) A minute necrotic lesion in the center of the tumor could not be detected by using DW imaging with a b value of 500 sec/mm2 or less. (b, c) A minute necrotic lesion (arrow) is seen as a hypointense dot on DW images obtained with a b value of 750 sec/mm2 (b) or 1000 sec/mm2 (c). (d) ADC map shows this lesion as a hyperintense dot (arrow). At histologic analysis, this lesion was proved with (e) macroscopy (rectangular frame indicates the area of focused microscopy) and (f) focused microscopy. N = necrosis. (Hematoxylin-eosin stain; original magnification, x50.)

 

Figure 3
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  		Figure 3e: Rhabdomyosarcoma tumors on DW images obtained with different b values. (a) A minute necrotic lesion in the center of the tumor could not be detected by using DW imaging with a b value of 500 sec/mm2 or less. (b, c) A minute necrotic lesion (arrow) is seen as a hypointense dot on DW images obtained with a b value of 750 sec/mm2 (b) or 1000 sec/mm2 (c). (d) ADC map shows this lesion as a hyperintense dot (arrow). At histologic analysis, this lesion was proved with (e) macroscopy (rectangular frame indicates the area of focused microscopy) and (f) focused microscopy. N = necrosis. (Hematoxylin-eosin stain; original magnification, x50.)

 

Figure 3
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  		Figure 3f: Rhabdomyosarcoma tumors on DW images obtained with different b values. (a) A minute necrotic lesion in the center of the tumor could not be detected by using DW imaging with a b value of 500 sec/mm2 or less. (b, c) A minute necrotic lesion (arrow) is seen as a hypointense dot on DW images obtained with a b value of 750 sec/mm2 (b) or 1000 sec/mm2 (c). (d) ADC map shows this lesion as a hyperintense dot (arrow). At histologic analysis, this lesion was proved with (e) macroscopy (rectangular frame indicates the area of focused microscopy) and (f) focused microscopy. N = necrosis. (Hematoxylin-eosin stain; original magnification, x50.)

 
Functional Parameter Changes
Dynamic susceptibility contrast-enhanced PW images qualitatively and quantitatively demonstrated a signal intensity decrease in rhabdomyosarcoma tumors and normal liver tissue during first-pass PW imaging, with the decrease occurring 2–3 seconds earlier in rhabdomyosarcoma tumors. The mean maximum signal intensity decrease differed significantly (P < .001) in the rhabdomyosarcoma tumors (36.7%) and the normal liver tissue (67.4%) (Fig 4a).


Figure 4
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  		Figure 4a: Functional parameter changes of rhabdomyosarcoma tumors derived from dynamic susceptibility contrast-enhanced single-shot gradient-echo echo-planar PW imaging (2000/40) performed in the same rat as in Figure 2. (a) Time–signal intensity curves of the rhabdomyosarcoma tumor and liver parenchyma demonstrate that the mean signal intensity decrease appears 2–3 seconds earlier in the tumor than in the liver but that this decrease is significantly smaller (P < .001) than that in the normal liver. (b–d) Corresponding parameter maps show relative blood flow, relative blood volume, and permeability parameter were significantly higher (P < .001) in the tumor (arrows) than in the normal liver.

 

Figure 4
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  		Figure 4b: Functional parameter changes of rhabdomyosarcoma tumors derived from dynamic susceptibility contrast-enhanced single-shot gradient-echo echo-planar PW imaging (2000/40) performed in the same rat as in Figure 2. (a) Time–signal intensity curves of the rhabdomyosarcoma tumor and liver parenchyma demonstrate that the mean signal intensity decrease appears 2–3 seconds earlier in the tumor than in the liver but that this decrease is significantly smaller (P < .001) than that in the normal liver. (b–d) Corresponding parameter maps show relative blood flow, relative blood volume, and permeability parameter were significantly higher (P < .001) in the tumor (arrows) than in the normal liver.

 

Figure 4
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  		Figure 4c: Functional parameter changes of rhabdomyosarcoma tumors derived from dynamic susceptibility contrast-enhanced single-shot gradient-echo echo-planar PW imaging (2000/40) performed in the same rat as in Figure 2. (a) Time–signal intensity curves of the rhabdomyosarcoma tumor and liver parenchyma demonstrate that the mean signal intensity decrease appears 2–3 seconds earlier in the tumor than in the liver but that this decrease is significantly smaller (P < .001) than that in the normal liver. (b–d) Corresponding parameter maps show relative blood flow, relative blood volume, and permeability parameter were significantly higher (P < .001) in the tumor (arrows) than in the normal liver.

 

Figure 4
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  		Figure 4d: Functional parameter changes of rhabdomyosarcoma tumors derived from dynamic susceptibility contrast-enhanced single-shot gradient-echo echo-planar PW imaging (2000/40) performed in the same rat as in Figure 2. (a) Time–signal intensity curves of the rhabdomyosarcoma tumor and liver parenchyma demonstrate that the mean signal intensity decrease appears 2–3 seconds earlier in the tumor than in the liver but that this decrease is significantly smaller (P < .001) than that in the normal liver. (b–d) Corresponding parameter maps show relative blood flow, relative blood volume, and permeability parameter were significantly higher (P < .001) in the tumor (arrows) than in the normal liver.

 
The functional parameter maps derived with PW imaging (ie, relative blood volume, relative blood flow, and permeability value) were successfully reconstructed in all rats. Relative blood volume and relative blood flow were significantly different (P < .001) in rhabdomyosarcoma tumors (189 arbitrary units [au]± 137 and 708 au ± 665, respectively) and normal liver tissue (85 au ± 68 and 265 au ± 199, respectively) (Fig 4b, 4c). The permeability value was significantly (P < .001) higher in the tumor (0.003 au ± 0.004) than in the normal liver tissue (–0.013 au ± 0.003) (Fig 4d).

1H MR Spectroscopy
The tumor spectrum showed a higher integral value for choline at 3.2 ppm (5.6 au ± 1.5) than for normal liver tissue (1.0 au ± 0.7); this difference was statistically significant (P < .001). The lipid peak found at 1.2–1.4 ppm was much more prominent in the normal liver tissue than in the tumor (Fig 5).


Figure 5
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  		Figure 5a: 1H MR spectroscopy revealed a much higher choline (Cho) peak around 3.2 ppm in (a) the rhabdomyosarcoma tumor than in (b) the normal liver tissue. A large lipid peak was found at 1–2 ppm in the normal liver but not in the rhabdomyosarcoma tumor; this finding suggests totally different metabolic modes in the tumor and liver tissues.

 

Figure 5
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  		Figure 5b: 1H MR spectroscopy revealed a much higher choline (Cho) peak around 3.2 ppm in (a) the rhabdomyosarcoma tumor than in (b) the normal liver tissue. A large lipid peak was found at 1–2 ppm in the normal liver but not in the rhabdomyosarcoma tumor; this finding suggests totally different metabolic modes in the tumor and liver tissues.

 
Postmortem Three-dimensional CT, Microangiographic, and Histomorphologic Findings
Images acquired with maximum intensity projection and volume-rendering techniques displayed marked opacification of rhabdomyosarcoma tumors in the rat liver, thus indicating their hypervascular nature (Figs 2g, 2h). This was further confirmed with digital microangiography, which revealed tortuous feeding arteries and enriched irregular intratumoral vasculature (Fig 2i). The site and extent of hyperperfusion within the tumor on the relative blood volume and relative blood flow maps (Fig 4b, 4c) matched the areas of hypervascularity on the microangiograms (Fig 2i). Histologic analysis revealed that 16 days after implantation, rhabdomyosarcoma tumors were sharply demarcated from the surrounding liver parenchyma and had an expanding growth pattern (Figs 2j, 2k). The tumor predominantly consisted of viable sarcoma cells with numerous mitoses and evident hypervasculature (Fig 2l). Minute foci of necrosis in the center of five tumors, which could be seen on DW images and ADC maps obtained with a high b value, were histologically identified (Figs 3e, 3f).


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
ADVANCES IN KNOWLEDGE
 References
 
Our study results prove that rhabdomyosarcoma tumors can be successfully implanted in the rat liver, thus providing a well-defined and highly reproducible animal model of solitary tumor growth in a visceral organ. This model has some features that are different from the more widely used model of subcutaneous tumor implantation (6,7,9–11). First, the rodent rhabdomyosarcoma tumor implanted in the liver represents a well-vascularized tumor model, which more closely mimics a hypervascular human liver metastasis. Second, the tumor model was found to have a more homogeneous composition of viable malignant cells with rarely occurring minute necrotic foci, which were detected with MR imaging. This feature may be helpful in the evaluation of newly emerging therapeutic strategies, such as treatment with a tumor vascular targeting agent, by allowing more reliable quantitative analysis of the tissue consequences after therapy. Hence, possible confusion between the spontaneous and therapeutic necroses confronted in this type of investigation may become less problematic. Besides, the relatively short tumor doubling time of 2.2 days can meet the increasing demands for more efficient and higher throughput experimental research. This is especially true when use of this bifocal tumor model is combined with noninvasive longitudinal monitoring with MR imaging. This would jointly minimize the number of sacrificed animals, and it is an advocated practice in accordance with the current trend of animal and environmental protections. Our technique is unlike other techniques, such as cell suspension inoculation and fragment implantation, that do not use a gelatin sponge and tissue glue and tend to cause artificial remote metastasis and malignant ascites, which are features that may jeopardize therapeutic evaluations (14).

Our study results show that a 1.5-T clinical MR imager with advanced sequences—including DW imaging, dynamic susceptibility contrast-enhanced PW imaging, and MR spectroscopy—can be reliably used for in vivo noninvasive characterization of a rhabdomyosarcoma tumor implanted in the rodent liver. The imaging data were verified by using postmortem reference standard techniques (three-dimensional CT volume-rendering displays, digital microangiography, and histomorphologic analysis). To our knowledge, our study is the first to report DW imaging and PW imaging findings of liver tumors in rats, irrespective of whether an experimental or a clinical MR imager is used.

Although less powerful than dedicated small-animal MR imagers, low-field-strength clinical MR imagers proved to be useful, and they may be advantageous for easier extrapolation of the results to clinical human studies. Thus, lack of a dedicated small-animal MR imager should not be an obstacle to performing pertinent rat studies of anticancer drugs that are entering clinical trials or are still in the preclinical stage (9,10,13).

To extrapolate our findings to clinical human studies, a series of clinically relevant MR imaging sequences and techniques were introduced or adapted in our study. Instead of conventional SE T1- and T2-weighted imaging examinations, fast SE T1- and T2-weighted imaging examinations were used. A four-channel phased-array wrist coil was used to facilitate parallel imaging techniques, which allowed reduction of examination time and susceptibility artifacts with fast echo-planar imaging sequences in the entire liver for the DW imaging and dynamic susceptibility contrast-enhanced PW imaging examinations at relatively high temporal and spatial resolutions.

DW imaging has been demonstrated to be effective in the monitoring of tumor response after treatment, especially in the detection of tumor necrosis (13,20). We used 10 b values for the DW imaging sequences, since ADC measurements based on multiple b values may reduce the effects of respiratory movement and allow calculation of both diffusion and perfusion contributions to the ADC (13,21,22). Our results show that with b values greater than 500 sec/mm2, the background liver signal intensity on DW images will be largely diminished because of the short T2 of the liver (23). From the viewpoint of monitoring tumor treatment, however, DW imaging performed with a high b value (≥1000 sec/mm2) enables better contrast enhancement of tumor necrosis, which is potentially useful in the early detection of tumor response to therapy (13,20). The remaining high signal intensity in tumors on images obtained with a high b value can be attributed to the T2 shine-through phenomena on DW images (24) and the use of parallel imaging techniques (25).

Relative cerebral blood volume and relative cerebral blood flow measurements have been used in brain imaging (26,27). Our study indicates that the same approach may be used in rats for imaging of the abdominal solid organs. However, the dual blood supply of the liver (hepatic artery and portal vein) critically influences the application of dynamic susceptibility contrast-enhanced PW imaging (28). The transient signal intensity decrease due to the T2* effect caused by the bolus passage of the contrast agent through the vasculature appeared earlier, albeit lower, in the tumor than in the normal liver tissue in our study because of the prevailing portal venous (>70%) and arterial (<30%) supplies to the normal hepatic parenchyma, whereas liver tumors are predominantly supplied by a feeding artery. Thus, there is a larger amount of contrast agent in the intravascular and/or extracellular space of the normal liver tissue during the perfusion phase (hence, a more prominent T2* effect compared with that in the rhabdomyosarcoma tumor). For the relative blood volume and relative blood flow maps in our study, outcomes could be totally different depending on the chosen location to place the ROI for the vascular input function. The rhabdomyosarcoma tumor showed increased perfusion during the arterial first pass 2–3 seconds before the normal liver showed increased perfusion, while an ROI was covering the region of the hepatic artery and aorta. This hyperperfusion in the liver tumor is most likely caused by angiogenesis linked with the tumoral afferent arteries (28). However, if an ROI for vascular input function was placed elsewhere in the liver or portal vein region, hypoperfusion of rhabdomyosarcoma tumors appeared on relative blood volume and relative blood flow maps (data not shown). Thus, appropriate placement of vascular input function for PW imaging examinations of the liver seems crucial to enabling valid conclusions on tumor perfusion to be drawn. Since the vascular input function derived from the portal system is somewhat delayed without evidence of an abrupt first-pass bolus, estimates of relative blood volume and relative blood flow that are based on the portal system in normal hepatic tissue have been reported to be highly inaccurate (29).

Besides being used to obtain relative blood volume and relative blood flow maps, the T2*-weighted perfusion technique (ie, dynamic susceptibility contrast-enhanced PW imaging) is used to acquire permeability maps of tumors during a single acquisition (17,29). Our study showed an increased permeability in the rhabdomyosarcoma tumor compared with that of the normal liver, as reflected on the corresponding parameter map. Since vascular endothelial permeability can provide important information about the biologic behavior of the tumor, as well as its prognosis (29), a permeability index could be useful in the assessment of tumor response to therapy with antitumor agents.

1H MR spectroscopy can complement MR imaging by enabling sampling of useful biochemical information from both tumoral and normal tissues. In our study, the finding of increased choline signal measured in a rhabdomyosarcoma tumor larger than 12 mm in diameter agreed with the finding of previous reports that choline reflects tumor cellular proliferation and grade of malignancy (30,31). Thus, choline signal can be used as an indicator of tumor response after antitumor treatment when the present tumor model is applied.

Our study had limitations. Since it is difficult to use breath-holding or respiratory gating techniques in rats, respiratory movement during abdominal MR imaging might degrade image quality to some extent and cause variations in measurements. However, our results were satisfactory. We used only one tumor cell line; however, it seems feasible to use other cell lines for liver implantation in rats, as shown previously (14).

In conclusion, implantation of rhabdomyosarcoma tumors in the liver of rats was feasible and reproducible, with a 100% success rate in our study. This liver tumor model was investigated with comprehensive MR imaging techniques—including DW imaging, PW imaging, and MR spectroscopy with a clinical 1.5-T MR imager. Thus, the use of our model with other tumors may provide an upgraded research platform for preclinical evaluation of new diagnostic and therapeutic strategies.


   ADVANCES IN KNOWLEDGE
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
References
 


   FOOTNOTES
 

Abbreviations: ADC = apparent diffusion coefficient • DW = diffusion weighted • PW = perfusion weighted • ROI = region of interest • SE = spin echo

2 Current address: Department of Radiology, Zhong Da Hospital, Nanjing, Jiangsu Province, China Back

3 Current address: Department of Radiology, Affiliated Hospital, Weifang Medical University, Weifang, Shandong Province, China Back

Author contributions: Guarantors of integrity of entire study, F.C., Y.N.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; manuscript final version approval, all authors; literature research, F.C., X.S., F.D.K., J.Y., R.P., W.C., V.V., W.L., P.V.H., G.M., Y.N.; experimental studies, F.C., X.S., J.Y., W.C., W.L., P.V.H., G.M., Y.N.; statistical analysis, F.C., X.S., Y.N.; and manuscript editing, all authors

Authors stated no financial relationship to disclose.


   References
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 ADVANCES IN KNOWLEDGE
 References
 

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