兔VX2种植性肝癌模型不同生长期的MR扩散加权成像及与病理对照研究
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摘要
目的建立实验性兔VX2种植性肝癌模型,行不同时间点不同b值下的肿瘤MR扩散加权成像(DWI)检查,从中筛选出合适的b值;比较不同时间点肿瘤DWI检查结果的差异及其病理基础,以初步探讨DWI检查对监测兔VX2种植性肝癌模型生长特点的价值;比较不同时间点肿瘤实性部分ADC值和eADC值的差异及其演变规律,分析不同时间点兔VX2种植性肝癌模型的肿瘤实性部分ADC值、eADC值与其细胞密度和增殖细胞核抗原(PCNA)指数的相关性,进一步探讨不同时间点肿瘤实性部分ADC、eADC值差异的病理基础。
材料与方法新西兰实验兔44只,采用开腹直视下肿瘤组织块穿刺接种法建立兔VX2种植性肝癌模型,每只实验兔只接种一个部位,均种植在肝左叶,成功建立模型38只。将实验兔随机分为两组,每组19只,分别于接种后第14天和22天行磁共振检查,使用美国GE公司生产的1.5T Twin Speed Infinity withExciteⅡ超导型磁共振成像系统,应用3英寸表面线圈,先行常规T_1WI和T_2WI检查,DWI检查采用单次激发SE-EPI序列,同时在X、Y、Z轴三个方向上施加敏感梯度脉冲,取0、200s/mm~2,0、400s/mm~2,0、600s/mm~2,0、800s/mm~2和0、1000s/mm~2五组b值,得到各b值下不同时间点兔VX2种植性肝癌模型肿瘤的DWI图像及工作站处理后的ADC图和eADC图,并分别测量各b值组的不同时间点肿瘤实性部分的ADC值及eADC值。MRI检查完毕后获取全部实验兔肝脏标本并按扫描方向切层,行常规HE染色和免疫组织化学PCNA染色。采用CMIAS多功能真彩色病理图像分析系统,细胞密度的计数方法是计算每个采集野内肿瘤细胞核总面积与细胞核外其余部分(包括肿瘤细胞胞浆、细胞外间隙)的面积比值,兼顾肿瘤组织细胞内及细胞外空间分布的总体致密程度,取5个视野的平均值作为肿瘤的细胞密度,以百分比表示;PCNA染色采用单克隆抗体二步法标记细胞核,选择PCNA染色阳性细胞分布最密集的区域,采集并计数PCNA染色阳性细胞数和肿瘤细胞总数,计算肿瘤PCNA指数(PCNA阳性细胞/肿瘤细胞总数),取5个视野的平均值作为肿瘤的PCNA指数,以百分比表示。分析指标包括:①观察不同时间点VX2种植性肝癌模型肿瘤的体积变化、倍增时间以及T_1WI、T_2WI和DWI图像的信号特点;②分析不同b值组DWI图像的肿瘤-肝实质信号强度比(SIR)、信噪比(SNR)和肿瘤-肝实质对比噪声比(CNR),评价DWI图像质量,选取最佳b值;③重点观察和分析不同时间点肿瘤DWI图、ADC图和eADC图的表现及其差异;并与大体病理进行对照;④进一步分析和比较不同时间点肿瘤实性部分ADC值和eADC值的差异及其演变规律;⑤重点分析不同时间点兔VX2种植性肝癌模型实性部分ADC值、eADC值与肿瘤细胞密度及PCNA指数之间的相关性。
结果①采用开腹直视下肿瘤组织块穿刺接种法建立兔VX2种植性肝癌模型的成功率为86%(38/44),均于肝左叶形成孤立性肿瘤,22天组与14天组比较,肿瘤体积增大明显,前者平均体积约为0.32cm~3,后者平均体积约为1.76cm~3,倍增时间为3.2天;②所有肿瘤在MR T_1WI呈稍低信号,在T_2WI上呈稍高信号,边界清楚,22天组中有4个肿瘤中心可见斑片状长T_2信号;③不同b值组所有肿瘤在DWI图像上均呈明显高信号,并与周围肝实质形成鲜明对比;④随b值的升高,DWI图像SIR逐渐增加,SNR和CNR逐渐下降,然而当b值为1000 s/mm~2时仍可清楚分辨肿瘤,并可进行实性部分ADC值和eADC值测量;⑤14天组所有肿瘤的ADC图、eADC图信号均匀,大体病理显示所有肿瘤质地均匀,无坏死囊变区,与ADC图和eADC图表现一致;22天组所有肿瘤中心部分在ADC图、eADC图上均可见斑片状坏死囊变区的信号,且与大体病理所显示的坏死囊变区范围基本一致,而在常规T_2WI上仅有4例肿瘤中心可见斑片状高信号;⑥同一时间点不同b值组肿瘤实性部分ADC值随b值增大而下降,eADC值随b增大而升高;⑦在各b值组22天组兔VX2种植性肝癌模型的肿瘤实性部分ADC值均较14天组下降,eADC值均较14天组升高,而细胞密度和PCNA指数较14天组上升。两个时间点肿瘤实性部分的ADC值与其细胞密度、PCNA指数呈负相关,(r=-0.695,p=0.000;r=-0.698,p=0.000);而eADC值则与其细胞密度、PCNA指数呈正相关,且以b值取0、1000 s/mm~2时相关性最强(r=0.673,p=0.000;r=0.682,p=0.000)。
结论①采用开腹直视下肿瘤组织块穿刺接种法建立兔VX2种植性肝癌模型成功率较高,该模型具有容易复制,生长迅速,较易出现坏死囊变等特点;②在兔VX2种植性肝癌模型的DWI成像参数中以选择b值为1000 s/mm~2比较合适;③MR DWI检查的ADC图和eADC图能早期检出兔VX2种植肝癌模型肿瘤的坏死囊变区,在动态追踪肿瘤发生、发展和生长特性方面具有重要的价值,是常规MR检查的有益补充;④随着肿瘤种植时间的延长,肿瘤实性部分ADC值减低,eADC值升高,具有一定的规律性;⑤在影响兔VX2种植性肝癌模型肿瘤实性部分ADC值及eADC值的因素中,细胞密度可能起关键作用,而肿瘤的恶性程度与其细胞密度、PCNA指数密切相关,通过测量肿瘤实性部分ADC值及eADC值,有可能为在体推测肿瘤恶性程度和病理分级提供新的方法。
Objective To establish rabbit models of liver VX2 tumor and perform MR diffusion weighted imaging (DWI) examination with different b value in different growth periods, choose the optimal b value of DWI for characterization of tumors; to compare the distinction of signal intensities on DWI and their pathologic changes, explore the value of DWI for monitoring the growth characteristic of rabbit models of liver VX2 tumor; to compare the distinction of apparent diffusion coefficient (ADC) value and exponent apparent diffusion coefficient (eADC) value in surrounding solid components of liver VX2 tumor in different periods and their variation pattern, to analyze the correlation between ADC, eADC value and the celiularity, proliferating cell nuclear antigen (PCNA) labeling index in surrounding solid components in rabbit models of liver VX2 tumor, explore the pathologic basement on which solid components of liver VX2 tumor in different periods showed different ADC and eADC values.
Materials and Methods Forty-four Zealand white rabbit were included in our study and VX2 tumor tissues were implanted into the left liver lobes after laparotomy. 38 successful implanted rabbits were assigned randomly into 2 equal groups and performed MR DWI in different periods (14d and 22d) after implantation respectively. MR scanning were performed on GE 1.5T Twin-Speed Infinity with Excite II scanner with 3 inch surface coil, single-shot spin-echo echo-planar diffusion-weighted imaging was performed with five different b values (200s/mm~2, 400s/mm~2, 600s/mm~2, 800s/mm~2, 1000s/mm~2), the diffusion sensitive gradient was applied to X, Y and Z directions at the same time. After DWI examination performed, ADC and eADC maps were obtained by postprocessing. Signal intensities of DWI, the values of ADC and eADC with different b value were measured in surrounding solid components in rabbit models of liver VX2 tumor in different periods respectively. Histological specimens of livers of all rabbits were sliced according to the direction of MR scanning rightly after MR examination and stained with hematoxylin, eosin and PCNA. Celiularity and PCNA labeling index of each specimen were measured in CMIAS (colored multifunction imaging analyzing system). The ratios of the total area of tumor cell nuclei to the area of sample field except for cell nuclei (including cytoplasm and extracellular space) were calculated in each specimen. The ratios of the PCNA stained positive tumor cell nuclei to the total tumor cell nuclei were measured in each specimen. The mean value of five visual fields was regarded as the cellularity and PCNA labeling index respectively, expressed by percentage. The following data were analyzed: 1. To observe the changes in tumor volume, tumor doubling time and signal intensities of T1WI、T2WI and DWI. 2. To analysis signal intensities ratio of tumor to liver (SIR), signal noise ratio (SNR) and contrast noise ratio of tumor to liver (CNR), evaluate imaging quality of DWI with different b value, choose the optimal b value. 3. To observe and analysis the signal intensities of DWI, ADC and eADC maps and their differences in different periods, and contrast with pathologic changes respectively. 4. To analysis and compare the distinction of ADC value and eADC value in surrounding solid components in rabbit models of liver VX2 tumor in different periods. 5. To analysis the correlation between ADC value, eADC value in surrounding solid components and cellularity, PCNA labeling index in different periods.
Results 1. The successful rate of implantation method of VX2 tumor tissues implanted into the left liver lobe of rabbits after laparotomy was 86%. Each tumor was solitary. Tumor volumes were enlarged greatly on 22d compared with 14d. The mean volume were 1.76cm~3 and 0.32cm~3 repectively, the doubling time of two groups was 3.2d. 2. On MR scanning, all tumors in different growth periods showed slightly long T1 and slightly long T2 signal intensities with clear margin. Four tumors on 22d demonstrated patchly long T2 signal intensity in their central part. 3. All tumors showed obviously high signal intensity on DWI in different b value. 4. On DWI, the SIR of tumors increased gradually with b value increasing, the SNR and CNR decreased gradually with b value increasing, however, we could still recognize the lesions and calculate the ADC and eADC values in surrounding solid components in rabbit models of liver VX2 tumor with b value of 1000s/mm~2. 5. On ADC and eADC maps, all tumors in the group of 14d showed homogeneously high/low signal intensity. According to pathology, all tumor of this group demonstrated well distributed texture without cystic necrosis. 6. The ADC values in surrounding solid components of liver VX2 tumor decreased gradually with b value increasing in each group. The eADC values increased gradually with b value increasing in each group. 7. The ADC values with different b value in surrounding solid components of liver VX2 tumor in the group of 22d decreased compared with the group of 14d. The eADC values with different b value, cellularity and PCNA labeling index in the group of 22d increased compared with the group of 14d. With different b values, there were negative correlation between ADC value of surrounding solid components of and cellularity, PCNA labeling index, especially with b value of 1000s/mm~2. There was positive correlation between eADC value and cellularity, PCNA labeling index, especially with b value of 1000s/mm~2.
Conclusions 1. The successful rate is much higher to establish the models of VX2 hepatic tumor by implanting tumor tissues into the liver after laparotomy. The characteristic of rabbit models of liver VX2 tumor is reproduction easily, growth rapidly, and appearing cystic necrosis easily. 2. The optimal b value in DWI examination is 1000s/mm~2 in present study. 3. ADC and eADC map could demonstrate the cystic and necrotic areas with typical imaging features in early time. They can early monitor the cystic necrosis areas in rabbit models of liver VX2 tumor, DWI plays an important value in dynamic detection of genesis and development of the tumor and the growth characteristic. DWI is helpful complement for conventional MR examination. 4. With the increasing of implantation time, the ADC values of the solid components of VX2 tumor decreased, and the eADC values increased. 5. Tumor cellularity is one of the important factors that affecting ADC and eADC values in solid components. Since the degree of malignancy is closely connected with cellularity and PCNA labeling index, measurement of ADC or eADC values may be a new method which could predict the degree of malignancy and pathology grading in vivo.
材料与方法新西兰实验兔44只,采用开腹直视下肿瘤组织块穿刺接种法建立兔VX2种植性肝癌模型,每只实验兔只接种一个部位,均种植在肝左叶,成功建立模型38只。将实验兔随机分为两组,每组19只,分别于接种后第14天和22天行磁共振检查,使用美国GE公司生产的1.5T Twin Speed Infinity withExciteⅡ超导型磁共振成像系统,应用3英寸表面线圈,先行常规T_1WI和T_2WI检查,DWI检查采用单次激发SE-EPI序列,同时在X、Y、Z轴三个方向上施加敏感梯度脉冲,取0、200s/mm~2,0、400s/mm~2,0、600s/mm~2,0、800s/mm~2和0、1000s/mm~2五组b值,得到各b值下不同时间点兔VX2种植性肝癌模型肿瘤的DWI图像及工作站处理后的ADC图和eADC图,并分别测量各b值组的不同时间点肿瘤实性部分的ADC值及eADC值。MRI检查完毕后获取全部实验兔肝脏标本并按扫描方向切层,行常规HE染色和免疫组织化学PCNA染色。采用CMIAS多功能真彩色病理图像分析系统,细胞密度的计数方法是计算每个采集野内肿瘤细胞核总面积与细胞核外其余部分(包括肿瘤细胞胞浆、细胞外间隙)的面积比值,兼顾肿瘤组织细胞内及细胞外空间分布的总体致密程度,取5个视野的平均值作为肿瘤的细胞密度,以百分比表示;PCNA染色采用单克隆抗体二步法标记细胞核,选择PCNA染色阳性细胞分布最密集的区域,采集并计数PCNA染色阳性细胞数和肿瘤细胞总数,计算肿瘤PCNA指数(PCNA阳性细胞/肿瘤细胞总数),取5个视野的平均值作为肿瘤的PCNA指数,以百分比表示。分析指标包括:①观察不同时间点VX2种植性肝癌模型肿瘤的体积变化、倍增时间以及T_1WI、T_2WI和DWI图像的信号特点;②分析不同b值组DWI图像的肿瘤-肝实质信号强度比(SIR)、信噪比(SNR)和肿瘤-肝实质对比噪声比(CNR),评价DWI图像质量,选取最佳b值;③重点观察和分析不同时间点肿瘤DWI图、ADC图和eADC图的表现及其差异;并与大体病理进行对照;④进一步分析和比较不同时间点肿瘤实性部分ADC值和eADC值的差异及其演变规律;⑤重点分析不同时间点兔VX2种植性肝癌模型实性部分ADC值、eADC值与肿瘤细胞密度及PCNA指数之间的相关性。
结果①采用开腹直视下肿瘤组织块穿刺接种法建立兔VX2种植性肝癌模型的成功率为86%(38/44),均于肝左叶形成孤立性肿瘤,22天组与14天组比较,肿瘤体积增大明显,前者平均体积约为0.32cm~3,后者平均体积约为1.76cm~3,倍增时间为3.2天;②所有肿瘤在MR T_1WI呈稍低信号,在T_2WI上呈稍高信号,边界清楚,22天组中有4个肿瘤中心可见斑片状长T_2信号;③不同b值组所有肿瘤在DWI图像上均呈明显高信号,并与周围肝实质形成鲜明对比;④随b值的升高,DWI图像SIR逐渐增加,SNR和CNR逐渐下降,然而当b值为1000 s/mm~2时仍可清楚分辨肿瘤,并可进行实性部分ADC值和eADC值测量;⑤14天组所有肿瘤的ADC图、eADC图信号均匀,大体病理显示所有肿瘤质地均匀,无坏死囊变区,与ADC图和eADC图表现一致;22天组所有肿瘤中心部分在ADC图、eADC图上均可见斑片状坏死囊变区的信号,且与大体病理所显示的坏死囊变区范围基本一致,而在常规T_2WI上仅有4例肿瘤中心可见斑片状高信号;⑥同一时间点不同b值组肿瘤实性部分ADC值随b值增大而下降,eADC值随b增大而升高;⑦在各b值组22天组兔VX2种植性肝癌模型的肿瘤实性部分ADC值均较14天组下降,eADC值均较14天组升高,而细胞密度和PCNA指数较14天组上升。两个时间点肿瘤实性部分的ADC值与其细胞密度、PCNA指数呈负相关,(r=-0.695,p=0.000;r=-0.698,p=0.000);而eADC值则与其细胞密度、PCNA指数呈正相关,且以b值取0、1000 s/mm~2时相关性最强(r=0.673,p=0.000;r=0.682,p=0.000)。
结论①采用开腹直视下肿瘤组织块穿刺接种法建立兔VX2种植性肝癌模型成功率较高,该模型具有容易复制,生长迅速,较易出现坏死囊变等特点;②在兔VX2种植性肝癌模型的DWI成像参数中以选择b值为1000 s/mm~2比较合适;③MR DWI检查的ADC图和eADC图能早期检出兔VX2种植肝癌模型肿瘤的坏死囊变区,在动态追踪肿瘤发生、发展和生长特性方面具有重要的价值,是常规MR检查的有益补充;④随着肿瘤种植时间的延长,肿瘤实性部分ADC值减低,eADC值升高,具有一定的规律性;⑤在影响兔VX2种植性肝癌模型肿瘤实性部分ADC值及eADC值的因素中,细胞密度可能起关键作用,而肿瘤的恶性程度与其细胞密度、PCNA指数密切相关,通过测量肿瘤实性部分ADC值及eADC值,有可能为在体推测肿瘤恶性程度和病理分级提供新的方法。
Objective To establish rabbit models of liver VX2 tumor and perform MR diffusion weighted imaging (DWI) examination with different b value in different growth periods, choose the optimal b value of DWI for characterization of tumors; to compare the distinction of signal intensities on DWI and their pathologic changes, explore the value of DWI for monitoring the growth characteristic of rabbit models of liver VX2 tumor; to compare the distinction of apparent diffusion coefficient (ADC) value and exponent apparent diffusion coefficient (eADC) value in surrounding solid components of liver VX2 tumor in different periods and their variation pattern, to analyze the correlation between ADC, eADC value and the celiularity, proliferating cell nuclear antigen (PCNA) labeling index in surrounding solid components in rabbit models of liver VX2 tumor, explore the pathologic basement on which solid components of liver VX2 tumor in different periods showed different ADC and eADC values.
Materials and Methods Forty-four Zealand white rabbit were included in our study and VX2 tumor tissues were implanted into the left liver lobes after laparotomy. 38 successful implanted rabbits were assigned randomly into 2 equal groups and performed MR DWI in different periods (14d and 22d) after implantation respectively. MR scanning were performed on GE 1.5T Twin-Speed Infinity with Excite II scanner with 3 inch surface coil, single-shot spin-echo echo-planar diffusion-weighted imaging was performed with five different b values (200s/mm~2, 400s/mm~2, 600s/mm~2, 800s/mm~2, 1000s/mm~2), the diffusion sensitive gradient was applied to X, Y and Z directions at the same time. After DWI examination performed, ADC and eADC maps were obtained by postprocessing. Signal intensities of DWI, the values of ADC and eADC with different b value were measured in surrounding solid components in rabbit models of liver VX2 tumor in different periods respectively. Histological specimens of livers of all rabbits were sliced according to the direction of MR scanning rightly after MR examination and stained with hematoxylin, eosin and PCNA. Celiularity and PCNA labeling index of each specimen were measured in CMIAS (colored multifunction imaging analyzing system). The ratios of the total area of tumor cell nuclei to the area of sample field except for cell nuclei (including cytoplasm and extracellular space) were calculated in each specimen. The ratios of the PCNA stained positive tumor cell nuclei to the total tumor cell nuclei were measured in each specimen. The mean value of five visual fields was regarded as the cellularity and PCNA labeling index respectively, expressed by percentage. The following data were analyzed: 1. To observe the changes in tumor volume, tumor doubling time and signal intensities of T1WI、T2WI and DWI. 2. To analysis signal intensities ratio of tumor to liver (SIR), signal noise ratio (SNR) and contrast noise ratio of tumor to liver (CNR), evaluate imaging quality of DWI with different b value, choose the optimal b value. 3. To observe and analysis the signal intensities of DWI, ADC and eADC maps and their differences in different periods, and contrast with pathologic changes respectively. 4. To analysis and compare the distinction of ADC value and eADC value in surrounding solid components in rabbit models of liver VX2 tumor in different periods. 5. To analysis the correlation between ADC value, eADC value in surrounding solid components and cellularity, PCNA labeling index in different periods.
Results 1. The successful rate of implantation method of VX2 tumor tissues implanted into the left liver lobe of rabbits after laparotomy was 86%. Each tumor was solitary. Tumor volumes were enlarged greatly on 22d compared with 14d. The mean volume were 1.76cm~3 and 0.32cm~3 repectively, the doubling time of two groups was 3.2d. 2. On MR scanning, all tumors in different growth periods showed slightly long T1 and slightly long T2 signal intensities with clear margin. Four tumors on 22d demonstrated patchly long T2 signal intensity in their central part. 3. All tumors showed obviously high signal intensity on DWI in different b value. 4. On DWI, the SIR of tumors increased gradually with b value increasing, the SNR and CNR decreased gradually with b value increasing, however, we could still recognize the lesions and calculate the ADC and eADC values in surrounding solid components in rabbit models of liver VX2 tumor with b value of 1000s/mm~2. 5. On ADC and eADC maps, all tumors in the group of 14d showed homogeneously high/low signal intensity. According to pathology, all tumor of this group demonstrated well distributed texture without cystic necrosis. 6. The ADC values in surrounding solid components of liver VX2 tumor decreased gradually with b value increasing in each group. The eADC values increased gradually with b value increasing in each group. 7. The ADC values with different b value in surrounding solid components of liver VX2 tumor in the group of 22d decreased compared with the group of 14d. The eADC values with different b value, cellularity and PCNA labeling index in the group of 22d increased compared with the group of 14d. With different b values, there were negative correlation between ADC value of surrounding solid components of and cellularity, PCNA labeling index, especially with b value of 1000s/mm~2. There was positive correlation between eADC value and cellularity, PCNA labeling index, especially with b value of 1000s/mm~2.
Conclusions 1. The successful rate is much higher to establish the models of VX2 hepatic tumor by implanting tumor tissues into the liver after laparotomy. The characteristic of rabbit models of liver VX2 tumor is reproduction easily, growth rapidly, and appearing cystic necrosis easily. 2. The optimal b value in DWI examination is 1000s/mm~2 in present study. 3. ADC and eADC map could demonstrate the cystic and necrotic areas with typical imaging features in early time. They can early monitor the cystic necrosis areas in rabbit models of liver VX2 tumor, DWI plays an important value in dynamic detection of genesis and development of the tumor and the growth characteristic. DWI is helpful complement for conventional MR examination. 4. With the increasing of implantation time, the ADC values of the solid components of VX2 tumor decreased, and the eADC values increased. 5. Tumor cellularity is one of the important factors that affecting ADC and eADC values in solid components. Since the degree of malignancy is closely connected with cellularity and PCNA labeling index, measurement of ADC or eADC values may be a new method which could predict the degree of malignancy and pathology grading in vivo.
引文
[1]Swistel AL,Bading JR,Raaf JH,et al.Intraarterial versus intravenous adriamycin in the rabbit VX2 tumor system[J].Cancer,1984,53(6):1397-1404.
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