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© 2010 by the American Institute of Ultrasound in Medicine
J Ultrasound Med 29:51-60 • 0278-4297

Technical Advance

Role of Sonography for Implantation and Sequential Evaluation of a VX2 Rabbit Liver Tumor Model

Wen Luo, MD, Xiaodong Zhou, MD, Xiaoying Zheng, MD, Guangbin He, MD, Ming Yu, MD, Qiuyang Li, MD and Qing Liu, MD

Department of Ultrasound, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China.

Address correspondence to Xiaodong Zhou, MD, Department of Ultrasound, Xijing Hospital, Fourth Military Medical University, 15th Changle Xi Rd, 710032 Xi’an, Shaanxi, China. E-mail: zhouxdong{at}gmail.com


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Objective. We investigated the role of sonography in the implantation process of a VX2 rabbit liver tumor model and sequential evaluation. Methods. Fifty rabbits were divided into 2 groups. Animals in group I underwent surgical implantation, whereas those in group II received percutaneous sonographically guided implantation. At 7, 14, 21, and 28 days after implantation, respectively, 5 rabbits in each group were examined with conventional, color Doppler (CD), contrast-enhanced (CE) pulse inversion harmonic (PIH), and CE CD sonography. Pathologic examination was performed with hematoxylin-eosin, nicotinamide adenine dinucleotide phosphate-diaphorase, and succinic dehydrogenase stains. Results. Twenty-one rabbits with tumors survived in group I, and 22 with tumors survived in group II. The mean duration of implantation ± SD in group II was 16.9 ± 3.4 minutes, whereas that in group I was 21.5 ± 4.1 minutes (P < .05). The tumor volume measured by conventional sonography increased from 0.28 ± 0.14 cm3 at 7 days to 16.49 ± 5.50 cm3 at 28 days in group I and from 0.31 ± 0.19 to 19.79 ± 4.70 cm3 in group II, whereas no significant difference existed between the groups. On CD, CE PIH, and CE CD sonography, most tumors were hypervascular before 14 days and after 14 days had peripheral vessels and central hypovascular areas, which were shown as necrotic areas by pathologic examination. Conclusions. Sonographically guided implantation achieved a good success rate with convenient inoculation performance. Conventional gray scale, CD, CE PIH, and CE CD sonography were useful in sequential evaluation of tumor growth and characteristic vascularity.

Key Words: animal • liver • sonography • VX2 carcinoma

Abbreviations: CD, color Doppler • CE, contrast-enhanced • H&E, hematoxylin-eosin • NADPH-d, nicotinamide adenine dinucleotide phosphate-diaphorase • PIH, pulse inversion harmonic • SDH, succinic dehydrogenase


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Sonography, with the advantages of having no radiation, being noninvasive, and having high repeatability, has spread widely and has been accepted as a vital modality for imaging diagnosis, and the advent of microbubble contrast agents has opened new possibilities in depicting the characteristic vascularity of tumors.1–4 Moreover, in recent years, great progress in techniques has prompted sonography to expand its potential role as an aid in some invasive procedures and therapies.5–8 In particular, sonographic guidance makes targeting of percutaneous punctures accurate and easy by exact localization and real-time imaging, considerably increasing its utility in histopathologic biopsy and minimally invasive ablation treatments.9,10

A VX2 rabbit liver tumor model, proposed in 1933,11 is regarded as useful in laboratory research on anticancer therapies.12–14 At present, direct implantation with VX2 tumor tissue fragments via surgical celiotomy is used frequently to establish VX2 rabbit liver tumor models.15–17 This method has been reported to have a high success rate but some disadvantages, such as being time-consuming, causing relatively serious wounds in animals with a risk of infection and hemorrhage, and requiring operators to have a good grasp of surgical skills. In a few studies,18–20 the percutaneous sonographically guided implantation method was used for hepatic VX2 tumor models, but to our knowledge, sequential evaluation of tumor growth has not been reported. To investigate the use of sonography in the implantation process and sequential observation of tumor growth, a comparison between the surgical celiotomy method and the percutaneous sonographically guided method is necessary, which can provide more exact information for the establishment of a VX2 tumor model. In addition, because of the progress in imaging methods, sequential evaluation of tumor growth via sonography, especially contrast-enhanced (CE) sonography, still needs further investigation.

In this study, by using conventional gray scale, color Doppler, CE pulse inversion harmonic (PIH), and CE CD sonography with a sulfur hexafluoride contrast agent (SonoVue; Bracco SpA, Milan, Italy), we compared the percutaneous sonographically guided implantation method with the surgical celiotomy implantation method in the implantation process and sequential tumor growth.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
The study was approved by the Animal Care Committee of the Fourth Military Medical University and was in compliance with institutional guidelines. The donor rabbit with a VX2 tumor in the thigh was obtained from the Department of Hepatobiliary Surgery of Xijing Hospital. As recipient animals, 50 healthy New Zealand White rabbits weighing 2000 to 2500 g were purchased from the Laboratory Animal Center of the Fourth Military Medical University.

VX2 Liver Tumor Implantation
Under aseptic conditions, fish meat–like tumor tissues were obtained from the thigh of the donor rabbit, put into 4°C Hanks balanced salt solution to remove necrotic tissues and fibers, and then gently cut into pieces of about 1 mm3. The tumor tissue fragments were kept in the 4°C Hanks balanced salt solution. The 50 recipient animals were divided into 2 groups randomly (25 animals in each group) and anesthetized by ear vein injection of a 3% pentobarbital solution (1 mL/kg). The abdomens of the rabbits were shaved and prepared with povidone iodine.

Rabbits in group I underwent laparotomy with a 2-cm midline incision in the epigastric region, and the livers were exposed. Eye forceps were used to pierce the hepatic parenchyma with a slope angle of 45° and to make a sinus of about 2 mm in width, 1.5 cm in length, and 1 cm in depth from the surface. Two VX2 tumor tissue fragments were transplanted into the bottom of the sinus, followed by a 1-mm3 piece of gelatin foam. After light pressure on the implantation point to prevent bleeding and leakage of tumor tissues, the liver lobe was returned to the abdominal cavity, and the abdomen was closed in double layers.

Rabbits in group II received implantation of VX2 liver tumor fragments via sonographically guided puncture. An HDI 5000 ultrasound system (Philips Healthcare, Bothell, WA) with a 7.5-MHz linear probe was used for imaging guidance. Before implantation, with the aid of conventional gray scale and CD sonography, the target position of implantation was selected in the liver lobe with a thickness of greater than 2 cm and not adjacent to main liver vessels. An 18-gauge needle consisting of a cannula and a core was used for puncture (Figure 1Go). Two VX2 tumor tissue fragments were placed into the lumen of the cannula, followed by 1 small piece of gelatin foam. Guided with conventional gray scale sonography, the puncture needle was inserted into the desired region. The tumor tissues and gelatin foam in the lumen of the needle were pushed out, and at the same time the hyper-echoic objects consisting of the tumor tissues and gelatin foam in the liver lobe were detected by 2-dimensional gray scale sonography with a Philips 7.5-MHz linear probe (Figure 2Go). The needle was then pulled out, and the abdomen was pressed for 2 minutes. The abdomen was examined by conventional sonography to detect bleeding and leakage of tumor tissues.


Figure 1
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  		Figure 1. Illustration of an 18-gauge needle used for VX2 tumor implantation in the rabbit liver.

 

Figure 2
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  		Figure 2. Conventional sonogram showing a hyperechoic object (arrow) consisting of VX2 tumor fragments and gelatin foam, which appeared in the liver parenchyma immediately after implantation.

 
During the recovery period, an intramuscular injection of buprenophrine (0.5 mg/kg) was administrated to all 50 animals for pain management. The implantation process in both groups was performed by the same physicians, who had training in the surgical and sonographically guided puncture techniques.

Sequential Sonographic Imaging
Five rabbits in each group selected randomly were examined by conventional gray scale, conventional CD, CE PIH, and CE CD sonography 7, 14, 21, and 28 days after implantation, respectively. Conventional gray scale and CD sonography were performed with an Acuson Sequoia 512 system (Siemens Medical Solutions, Mountain View, CA) and an 8- to 13-MHz linear 15L8 probe. Contrast-enhanced PIH sonography with a low mechanical index (<0.1) and CE CD sonography were performed with a Philips iU22 system and a 3- to 9-MHz linear L9-3 probe. On CE PIH and CE CD sonography, before scanning a 0.2-mL injection of SonoVue was administrated as a bolus via an ear vein in each animal, followed by a 2-mL 9% normal saline flush.

All image acquisitions were performed by the same experienced sonologist, who did not attend the tumor implantation procedure. The length (L, millimeters), width (W, millimeters), and depth (D, millimeters) of the VX2 tumors in each group were measured by conventional gray scale sonography. The volume (V ) was calculated according to the formula V = ({pi}/6) x L x W x D. On CD and CE CD sonography, the vascularity of the tumors was evaluated from low to high as follows: "dot," with dotlike blood flow signals detected within the tumors; "script," with script-like blood flow signals detected within the tumors; and "ring," with ringlike blood flow signals detected surrounding the tumors. The tumors were graded on basis of the highest vascularity assessed. On CE PIH sonography, the enhancement patterns of the tumors were assessed as homogeneous and heterogeneous.

Histopathologic Study
After being examined by sonography 7, 14, 21, and 28 days after implantation, the 5 animals in each group were killed. The livers were excised, and the lengths, widths, and depths of the tumors were measured. The tumor tissues were divided into 2 parts: the specimens in the first part were fixed in 10% formalin for 24 hours, embedded in paraffin, and then sectioned and stained with hematoxylin-eosin (H&E); the specimens in the other part were frozen, sectioned, and stained with nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) and succinic dehydrogenase (SDH) according to a previously described protocol.21,22

Statistical Analysis
SPSS version 11.0 software (SPSS Inc, Chicago, IL) was used to evaluate statistical differences. Differences between groups I and II were assessed with an independent Student t test and a {chi}2 test. Differences between the tumor size measurements by sonography and gross pathologic examination were assessed with a paired sample t test. For analysis of vascularity and enhancement in tumors, a Mann-Whitney U test or Fisher exact test was used for comparisons between the groups. Two-tailed P < .05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Comparison Between the Groups for the General Implantation Procedure
The mean duration of implantation ± SD in group II was 16.9 ± 3.4 minutes, whereas that in group I was 21.5 ± 4.1 minutes (P < .05). After the implantation process, all 50 animals were revived 1 hour after anesthesia. Three rabbits in group I died at 5, 10, and 20 days, respectively, and 2 in group II died at 16 and 23 days. The other rabbits survived until they were killed (P > .05). Among the surviving animals, 1 in each group did not have a VX2 tumor detected during the 28-day observation period (P > .05). Finally, 21 rabbits with VX2 tumors survived in group I, and 22 with tumors survived in group II. After 21 days, the weight and appetite of the animals in both groups decreased dramatically.

Pathologic Examination
The tumors were detected as having irregular shapes and were grayish white with an increased size during the 28-day period (Figures 3Go, 4AGo, and 5AGo and Table 1Go). At 21 and 28 days, gross pathologic observation showed large vessels with multiple branches on the surfaces of the tumors. Necrotic tissues were detected inside the tumors.


Figure 3
Figure 3
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  		Figure 3. Lengths, widths, and depths of VX2 rabbit liver tumors 7, 14, 21, and 28 days after implantation. A, Size measured by conventional gray scale sonography. No significant difference was detected between the groups (P > .05). B, Size measured by gross pathologic examination. No significant difference was detected between the groups (P > .05).

 

Figure 4
Figure 4
Figure 4
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  		Figure 4. Growth of a VX2 rabbit liver tumor from group II 14 days after implantation. A, Gross pathologic image showing the VX2 tumor with an irregular shape. B, The tumor appears slightly hypoechoic compared with the surrounding liver parenchyma on conventional gray scale sonography. C, Abundant blood flow signals are shown within the tumor on conventional CD sonography. Arrowheads indicate the tumor margin; S, areas surrounding the tumor; and T, tumor.

 

Figure 5
Figure 5
Figure 5
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  		Figure 5. Growth of a VX2 rabbit liver tumor from group II 28 days after implantation. A, Gross pathologic image showing expansive growth of the VX2 tumor and branches of feeding vessels on the surface. B, The tumor appeared to have uneven echogenicity with an anechoic necrotic area in the center on conventional gray scale sonography. C, Abundant blood flow signals are shown surrounding the tumor on conventional CD sonography. Arrowheads indicate the tumor margin; arrows, central necrotic area; S, areas surrounding the tumor; and T, tumor.

 

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  		Table 1. Volume of VX2 Rabbit Liver Tumors Measured by Conventional Gray Scale Sonography and Gross Pathologic Analysis
 
Hematoxylin-eosin staining showed tumor nests with a disorderly tissue structure and nuclear atypia under light microscopy (Figure 6Go). Islandlike necrosis areas were found within the tumors. In both groups, viable tumor tissues appearing blue with NADPH-d staining and purple with SDH staining were detected with the abnormal structures (Figures 7Go and 8Go).


Figure 6
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  		Figure 6. Light microscopic image showing cancer nests in a VX2 rabbit liver tumor and cancer cells with a high nuclear to cytoplasmic ratio (H&E). Scale bar indicates 250 µm.

 

Figure 7
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  		Figure 7. Light microscopic image showing viable VX2 rabbit liver tumor tissues with a disorderly structure and islandlike necrotic areas (arrow) within the tumor (NADPH-d). Scale bar indicates 250 µm.

 

Figure 8
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  		Figure 8. Light microscopic image showing viable VX2 rabbit liver tumor tissues with a disorderly structure (SDH). Scale bar indicates 100 µm.

 
Comparison Between the Groups for Tumor Growth on Sonography
Conventional Sonography for Sequential Observation
Sequential sonography was performed on 5 animals in each group 7, 14, 21, and 28 days after implantation, respectively. On conventional gray scale sonography, the VX2 tumors had uneven hypoechogenicity mixed with isoechogenicity and were well demarcated from the surrounding normal liver parenchyma (Figure 4BGo). A rim with low echogenicity surrounding the tumor tissues was detected in 12 lesions in group I and 15 in group II (P > .05). Anechoic areas of tissue necrosis in the center were found in 10 tumors in group I (2 at 14 days, 4 at 21 days, and 4 at 28 days) and 8 in group II (2 at 14 days, 2 at 21 days, and 4 at 28 days; P > .05; Figure 5BGo). On 2-dimensional gray scale sonography, ascites was detected in 11 rabbits in group I (3 at 14 days, 4 at 21 days, and 4 at 28 days) and 10 in group II (3 at 14 days, 3 at 21 days, and 4 at 28 days; P > .05). Distinct tumors in the abdominal walls were found in 6 rabbits in group I (2 at 14 days, 2 at 21 days, and 2 at 28 days) and 5 in group II (1 at 14 days, 2 at 21 days, and 2 at 28 days; P > .05). In each group, the tumor sizes from 7 to 28 days measured by conventional gray scale sonography and gross pathologic examination were summarized (Figure 3BGo and Table 1Go). No significant differences were detected between the measurements in the groups (P > .05), and no significant differences were detected between the measurements by sonography and pathologic examination (P > .05).

As shown in Table 2Go, on conventional CD sonography, most lesions (9 of 10 in group I and 8 of 10 in group II) had dot or script blood flow signals before 14 days (Figure 4CGo). After 14 days, ringlike blood flow signals surrounding the tumors were detected in most of the lesions in both groups (7 of 10 in group I and 9 of 10 in group II; Figure 5CGo). There was no significant difference between the vascularity of the groups (P > .05).


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  		Table 2. Assessment of the Vascularity of VX2 Rabbit Liver Tumors Measured by Conventional CD and CE CD Sonography
 
Contrast-Enhanced CD Sonography for Sequential Observation
On CE CD sonography 7 to 10 seconds after injection of SonoVue, obvious blood flow signals appeared inside all 40 tumors. Before 14 days, tumor vessels were detected mainly in the central area of the tumors in both groups (Figure 9AGo), and after 14 days, vessels were detected mainly in the peripheral area. Fifteen to 20 seconds after injection of SonoVue, enhancement of vessels in the normal liver parenchyma was detected. Twenty to 50 seconds after injection, enhancement of vessels in both the tumors and normal liver parenchyma was seen (Figure 9BGo). Fifty to 90 seconds after injection, the signals in the vessels within the tumors disappeared, whereas signals in the normal liver parenchyma remained (Figure 9CGo). The distribution of tumor vessels is shown in Table 2Go, and there was no significant difference between the groups (P > .05).


Figure 9
Figure 9
Figure 9
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  		Figure 9. Vascularity of a VX2 rabbit liver tumor from group II on CE CD sonography 14 days after implantation. A, Ten seconds after injection of the contrast agent, vessels within the tumor are enhanced. B, Twenty-five seconds after injection, vessels in the normal liver parenchyma (arrow) as well as those within the tumor are shown. C, Seventy seconds after injection, no enhancement of the vessels within the tumor is shown, whereas those in the normal liver parenchyma (arrow) show persistent enhancement. Arrowheads indicate the tumor margin.

 
Contrast-Enhanced PIH Sonography for Sequential Observation
On CE PIH sonography 7 to 10 seconds after injection of SonoVue, obvious tumor enhancement and tortuous vessels appeared, with perfusion from the periphery to the center (Figure 10AGo). Before 14 days, most tumors (7 of 10 in group I and 8 of 10 in group II) showed homogeneous enhancement during to 40 seconds after injection (Figure 10BGo), and after 14 days, most tumors (9 of 10 in group I and 10 of 10 in group II) showed heterogeneous enhancement with central unenhanced areas consisting of necrotic tissues (Table 3Go). Fifty to 90 seconds after injection, the microbubble density decreased quickly, and a perfusion defect in the location of the tumor was detected (Figure 10CGo). The lesions appeared hypoechoic compared with the surrounding liver parenchyma; this appearance was named a "wash-out change" and was obviously detected in all 40 tumors. On CE PIH sonography after 14 days, satellite metastasis lesions were detected as hypoechoic regions in the surrounding areas of 10 tumors in group I and 9 in group II.


Figure 10
Figure 10
Figure 10
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  		Figure 10. Assessment of a VX2 rabbit liver tumor from group II on CE PIH sonography 14 days after implantation. A, Ten seconds after injection of the contrast agent, the tumor is enhanced diffusely and shows intratumoral vessels. B, Twenty-five seconds after injection, the tumor shows isoechoic diffuse enhancement. C, Seventy seconds after injection, the tumor is hypoechoic, whereas the surrounding liver parenchyma shows persistent enhancement. Arrowheads indicate the tumor margin.

 

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  		Table 3. Enhancement Patterns of VX2 Rabbit Liver Tumors Measured by CE PIH Sonography
 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, we investigated the role of sonography in the establishment of a VX2 rabbit liver tumor model, including the implantation process and sequential follow-up. The results revealed that sonographically guided implantation had a success rate similar to that of surgical implantation with celiotomy. Conventional gray scale sonography used for imaging guidance during implantation with percutaneous puncture avoided surgery. No significant differences were found between the two methods for the total number of surviving animals and the number of animals with abdominal wall lesions and ascites, whereas the sonographically guided percutaneous puncture method provided a relatively short implantation time, convenient performance, a trend of reduced animal death before 14 days, and a low risk of abdominal wall metastasis compared with surgical implantation.

Whereas in a previous study we investigated sonographically guided tumor tissue transplantation using an automated biopsy instrument with a pullback cannula,20 a different device used for delivering tumor tissues and the puncture process in this study consisted of a core in the cannula to insert the tumor tissue forward into the liver parenchyma. In addition to making a comparison with the surgical implantation method, in this study we also focused on the further use of sonography for subsequent follow-up.

During subsequent follow-up, conventional gray scale sonography revealed the growth and echogenicity of the tumors. After 21 days, when the average length of the tumor was greater than 3 cm, in most tumors, the tissue in the central areas became necrotic and appeared anechoic. In some cases, the necrotic areas occupied more than 50% of the volumes of the tumors. Without a significant difference from the size measured by gross pathologic examination, conventional gray scale sonography proved to be as reliable and convenient a method for size measurement during follow-up.

VX2 carcinoma is an anaplastic squamous cell carcinoma derived from virus-induced papilloma in rabbits and has a hepatic artery blood supply similar to that in human liver tumors.23,24 The vascularity of VX2 tumors in this study was subsequently evaluated by sonography. Currently, the application of CE sonography benefits visualization of dynamic tumor vascularity from a new perspective, which exactly depicts blood perfusion in tumors by the reflected specific signals from microbubbles in the vessels. When CE PIH and CE CD sonography were used for follow-up evaluation in this study, vessels within tumors and tumor enhancement were obviously detected in the early period of the contrast process, which showed the viability of the tumors. Tortuous intratumoral vessels and diffuse enhancement were detected in most cases before 14 days, which showed a sufficient blood supply in the tumor tissues. After 14 days, whereas the tumor size was increased greatly, peritumoral vessels were detected in most cases, and necrotic tissue appeared as unenhanced areas within the tumors because of a relatively insufficient blood supply, which was confirmed by the results of H&E staining and enzyme activity examination. Fifty seconds after contrast agent injection, all of the lesions and satellite lesions appeared hypoechoic on CE PIH sonography, with sharp margins compared with the liver parenchyma and sustained enhancement. This wash-out change was also confirmed in other studies,25,26 which prompted a method to allow clear detection of tumors and surrounding satellite lesions during the late period of CE sonography.27,28 Lee et al29 compared the capability of detecting VX2 rabbit liver tumors during the late period of CE PIH sonography using SH U 508A (Levovist; Schering AG, Berlin, Germany) with that of conventional sonography, and the results showed that conventional sonography correctly showed 18 of 52 VX2 tumors, whereas CE PIH sonography showed 35 of 52. In particular, conventional sonography showed only 3 of 36 tumors smaller than 10 mm in diameter, but CE PIH sonography showed 19 such tumors.29 Dynamic CE sonography depicted the vascularity of the VX2 tumors, which is also considered effective in evaluation after thermal therapy, ie, radio frequency or high-intensity focused ultrasound ablation, for differentiation of necrotic and residual viable tissues.14,30

Some limitations were also found for the sonographically guided implantation method. In 1 rabbit, a tumor was not detected in the liver parenchyma after implantation because of leakage of inoculated tumor tissue fragments, which is a common disadvantage of implantation using tumor tissue fragments and other methods using injection of tumor cell suspensions.15,20 In some cases, lesions were found in the abdominal wall, which possibly resulted from seeding along the needle route or fallout of tumor tissue fragments.

In summary, a comparison between surgical and sonographically guided implantation revealed that with the aid of sonography, implantation using percutaneous puncture achieved a good success rate with convenient performance of the inoculation process. After implantation, conventional gray scale, CD, CE PIHI, and CE CD sonography showed useful roles in evaluation of tumor growth and characteristic vascularity.


   Footnotes
 
This work was supported by National Natural Science Foundation of China grant 30570489.

Received March 6, 2009, from the Department of Ultrasound, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China. Revision requested May 5, 2009. Revised manuscript accepted for publication August 19, 2009.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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