超声造影在浅表淋巴结疾病鉴别诊断中的应用研究
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摘要
背景
肿瘤病人区域淋巴结的检测和切除十分重要，它不仅直接影响对患者预后的评估，而且影响选择合适的治疗手段。在颈部、腋窝和腹股沟等浅表解剖部位，传统超声成像技术通过形态学和血供特征可以为良恶性淋巴结的鉴别提供有用的信息，如淋巴结的纵横比、边界、内部回声、淋巴门有否缺失及淋巴结内血管分布模式等，但存在很多局限性。有很多淋巴结不显示任何血供，特别是淋巴结的短径小于3～4mm和部位较深时，而且邻近大血管的淋巴结存在彩色显像的伪像。淋巴瘤血供丰富，并常表现为类似于良性淋巴结的中央门型血流分布。此外，当转移性淋巴结内的肿瘤浸润灶太小而不足以造成淋巴结发生形态特征改变时，传统超声也不能探及淋巴结内的微小浸润灶。
为了克服这些局限性，第一代超声造影剂(如Levovist)首先被用来增强血管彩色和能量多普勒的信号。然而第一代超声造影剂稳定性相对较差，加之在高机械指数下成像，受到各种伪像的限制，不能反映淋巴结内的微循环。
使用第二代超声造影剂，如声诺维(SonoVue)，超声造影允许在低机械指数下成像，灰阶谐波成像技术可详细显示淋巴结内的微血管灌注情况。不同淋巴结疾病有不同的病理生理基础，特别是肿瘤组织有特异的肿瘤微循环，因此对淋巴结进行灰阶超声造影，研究造影剂在淋巴结内的生物学效应和分布，了解其微循环灌注情况，可大大提高超声对良恶性淋巴结的鉴别能力，并有助正确选择拟进行活检的淋巴结，也使得探测放、化疗后淋巴结内早期血供阻断成为可能，可早期、易行和准确地评估淋巴瘤、鳞癌等对放、化疗的治疗反应。本研究采用Cadence对比脉冲序列造影成像技术(CPS)和自动跟踪造影定量分析软件(ACQ)，使用第二代超声造影剂SonoVue，观察不同淋巴结疾病的灰阶超声造影灌注情况，并进行时间-强度曲线的定量分析，旨在寻求更为有效的鉴别良恶性淋巴结的方法。
材料与方法
2005年3～12月，对43例我院门诊与住院患者进行超声检查，其中男17例，女26例。年龄18～71岁，平均51岁。患鼻咽癌12例，乳腺癌19例，慢性非特异性淋巴结炎5例，慢性乳腺炎2例，非霍奇金淋巴瘤2例，乳腺导管内乳头状瘤1例，甲状腺乳头状癌1例，肺癌1例。共检出75个浅表肿大淋巴结。除1例淋巴瘤患者已接受化疗外，其他所有患者在超声检查时均未行任何治疗措施。
检查仪器为Acuson Sequoia 512，15L8w宽频线阵高分辨力探头，配有对比脉冲序列造影成像技术(CPS)和自动跟踪造影分析软件(ACQ)。先行二维超声检查，观察纵横比、边界、内部回声、淋巴门有否缺失。每个淋巴结在最大纵切面上测量其纵径和横径。再行彩色多普勒超声检查，评价淋巴结内血管分布模式。淋巴结纵横比小于2、边缘不规则、淋巴门缺失或移位、内部回声不均匀、周边型或混合型血流是恶性淋巴结诊断标准，彩色多普勒超声检查将具有周边型或混合型血流，同时具备上述1种二维恶性征象或无血流型同时具备上述2种二维恶性征象的淋巴结诊断为恶性淋巴结。
造影采用CPS技术，探头发射频率7.0MHZ，机械指数(MI)0.1～0.2，造影剂采用SonoVue，经肘浅静脉团注2.4ml造影剂／人次，随后注入5ml生理盐水冲管。注射造影剂后即刻用实时灰阶谐波超声成像扫查淋巴结，每个淋巴结造影观察约2分钟，记录动态图像。然后对储存图像回放分析，观察淋巴结造影后增强表现，并根据淋巴结内造影剂增强的程度不同，把感兴趣区(ROI)放置在淋巴结近包膜下皮质内高灌注或低灌注区，ROI面积相同。应用ACQ自动描记时间-强度曲线，观察指标有造影剂到达时间(AT，注射造影剂后感兴趣区的信号强度增强到超过其基础强度的10％时所需要的时间)、峰值时间(TTP，注射造影后感兴趣区内增强强度达最大时所需要的时间)、峰值强度(PI，注射造影剂后感兴趣区内所能达到的最大增强强度)、速度参数(β，指造影剂流入感兴趣区的速度)、曲线与指数的匹配程度指数(GOF)等。GOF值在0～1之间，GOF值越接近1表明该曲线及其参数越精确，越接近0表明这些参数的代表意义不大。本研究中所有曲线GOF均大于0.7。
最后通过淋巴结切除活检对所有淋巴结作病理检查，将病理诊断与造影前常规超声诊断结果、造影后评价淋巴结灌注不同表现类型的诊断结果进行比较。检查结果采用SPSS 11.0统计软件进行统计分析，评价常规超声和灰阶超声造影诊断良恶性淋巴结的敏感性、特异性和准确性，百分率的比较采用u检验。计量资料以((?)±s)表示，组间比较进行非配对t检验。以P＜0.05为差异有统计学意义。
结果
1、淋巴结造影后增强表现类型分为：Ⅰ型(均匀增强型)：整个淋巴结显著而均匀的增强；Ⅱ型(淋巴门不均匀增强型)：实质显著增强，灌注均匀，但在中央高回声淋巴门内见不规则形低或无灌注区；Ⅲ型(实质不均匀增强型)：显著增强的实质内有局灶性低或无灌注区；Ⅳ型(微弱增强型)：整个淋巴结微弱增强，灌注均匀或不均匀。良性淋巴结中57％(16／28)造影表现为Ⅰ型，36％(10／28)表现为Ⅱ型；转移性淋巴结中77％(30／39)表现为Ⅲ型，21％(8／39)表现为Ⅳ型。5个为未经治疗的淋巴瘤造影表现为Ⅰ型，3个治疗后的淋巴瘤造影表现为Ⅲ型。
2、将造影表现为Ⅰ、Ⅱ型的淋巴结判定为良性，造影表现为Ⅲ、Ⅳ型的淋巴结判定为恶性，则灰阶超声造影诊断良恶性淋巴结的敏感性为87％，特异性为93％，准确性89％。造影前常规二维和彩色多普勒超声诊断良恶性淋巴结的敏感性为70％，特异性为86％，准确性75％。与常规超声技术相比，造影对诊断准确率的提高有显著意义(P＜0.05)。
3、良性组和淋巴瘤组淋巴结造影时间-强度曲线形态上表现为上升支陡直，到达顶峰时先快速下降，随后缓慢下降。转移性组淋巴结曲线形态上表现为上升支陡直，到达顶峰时持续缓慢下降。
4、良性、转移性和淋巴瘤三组淋巴结造影时间-强度曲线定量参数比较：β值各组间无明显差异(P＞0.05)。良性组和转移性组淋巴结造影剂的到达时间(AT)及达峰时间(TTP)无显著差异(P均＞0.05)；但良性组峰值强度(PI)大于转移性组(P＜0.05)。淋巴瘤组造影剂到达时间(AT)短于良性组和转移组淋巴结(P均＜0.001)；达峰时间(TTP)短于良性组和转移组(P＜0.05和P＜0.001)；峰值强度(PI)大于良性组和转移组(P均＜0.001)。
结论
1、良性淋巴结超声造影增强主要表现为Ⅰ型和Ⅱ型；转移性淋巴结主要表现为Ⅲ型和Ⅳ型。
2、淋巴瘤治疗后造影增强主要表现为Ⅲ型，未经治疗时主要表现为Ⅰ型。
3、时间-强度曲线分析能反映淋巴结动态灌注情况。良性、转移性和淋巴瘤三组淋巴结造影时间-强度曲线都表现为上升支陡直，但转移性组下降支比良性组和淋巴瘤组缓慢。
4、定量参数分析表明淋巴结良性组和转移性组造影到达时间及达峰时间无显著差异；但良性组峰值强度大于转移性组。淋巴瘤组到达时间、达峰时间短于良性组和转移性组；峰值强度大于良性组和转移性组。
5、超声造影对良恶性淋巴结的鉴别诊断准确率要高于常规超声技术。
BACKGROUND
The detection or exclusion of lymph node metastasis in patients with tumors is of special importance because not only the patient's prognosis but also the therapeutic concept is directly influenced by the nodal status. Conventional ultrasonography including gray-scale imaging(B-mode), color-coded Doppler sonography(CCDS) and power Doppler(PD) have shown to serve as a promising and accurate tool in differentiating diagnosis of superficial lymphadenopathy by detecting the characteristics of morphology and angioarchitecture such as the longitudinal-transverse diameter ratio, margin, intranodal echogenicity, echogenic hilus and vascular pattern. However, malignant nodes may be the same shape as benign nodes when they are in the early stage of involvement. In metastatic as well as benign enlarged lymph nodes, a Doppler signal is not always detectable. Micrometastases are frequently discovered in the no-enlarged lymph nodes, and more than half of the nodes that had a maximum transverse diameter between 2 and 4 mm were found no vascularity. In some studies, a relatively lower sensitivity of vascular pattern was found in distinguishing reactive from lymphomatous nodes. This is probably due to the high incidence of hilar vascularity in lymphomatous nodes, which resulted in a high false-negative rate.
Some studies exploited the introduction of the first-generation air-based contrast agent (such as SH U 508A, Levovist) to improve the Doppler sonography signal. But the first-generation ultrasound contrast agent is not enough stable and always destroyed with high MI (mechanical index) imaging methods, and there are many color Doppler imaging artifacts, so the microcirculation can not be delineated.
Recently, new ultrasound techniques, such as pulse inversion harmonic imaging, have been developed that are extremely sensitive to non-linear effects of US interaction with microbubble contrast agents. With the second-generation ultrasound contrast agents, such as SonoVue, real-time evaluation of the lymph nodal perfusion can be carried out at a low MI. Different lymphadenopathy have different pathological characteristics, especially tumor tissue has peculiar tumor microcirculation. Real-time gray-scale contrast-enhanced ultrasound for superficial lymph nodes can differentiate benign from malignant nodes better by detecting the distribution and biologic effect of microbubble in the nodes, and may help to choose appropriate lymph node for biopsy. It may also be useful in early assessing the response of lymph nodes to radiochemotherapy. The objective of this study was to assess the enhancement of echogenicity and the characteristics of the time-intensity curves by using real-time gray-scale contrast-enhanced ultrasound for superficial lymph nodes.
Materials and methods
From March to December 2005 43 consecutive patients(26 women, 17 men; age range: 18 to 71 years, mean 51 years) with enlarged superficial cervical, axillary, or inguinal lymph nodes clinically suspected to be malignant were prospectively examined by ultrasound immediately. Of the 43 patients, 33 had metastatic nodes, 8 had reactive hyperplasia, and 2 had lymphoma. In the 33 patients with metastatic nodes, the primary tumors were in the nasopharynx(n=12),breast(n=19), lung(n=1), thyroid(n=1). A
total of 75 enlarged lymph nodes were found on sonography. At the time of the US examination, none but one patient with lymphoma had received treatment.
Scanning was performed by one experienced radiologist blinded to the final diagnosis with a commercially available scanner (Acuson Sequoia 512) using an electronically focused near-field linear array transducer with a 8-to 15-MHZ bandwidth and provided with contrast pulse sequences(CPS) contrast imaging and Axius? Auto-Tracking Contrast Quantification(ACQ) software.
In the first step, all patients were examined using conventional B-mode sonography. Echo texture, margin sharpness, longitudinal-transverse diameter ratio, and the location of the hilus were used as parameters. In the second step, patients were examined using color Doppler sonography. The vascular pattern was evaluated. Nodes having an inhomogeneous echo, blurred margins, absent or aberrant hilus, the longitudinal-transverse diameter ratio less than 2, and the preservation of peripheral or mixture vessels were classified as malignant. If the vascular pattern and at least one B-mode criterion were classified as malignant, the node was judged to be malignant and vice versa. In the nodes in which no vessels could be identified, the criteria of B-mode sonography were used as mentioned earlier.
Finally, the gray-scale contrast-enhanced sonography was performed after intravenous injection of the US contrast agent microbubble (SonoVue, Bracco, Milan, Italy)as a bolus at a 2.4mL dose, followed by 5mL of normal saline flush. A low frame rate (7MHZ)and a low mechanical index (MI=0.1～0.2) were used. Each exam lasted about 2 min following bolus injection. The cine clips were acquired for each nodes and digitally stored on the US unit, they were reviewed retrospectively on screen. Readers subjectively assessed in consensus node contrast enhancement. The regions-of interest (ROI) was placed in the parenchyma near the capsula,
and the time-intensity curve for each node was acquired and analyzed by ACQ. The arrival time (AT, the time that the contrast "arrives" in the image can be considered as when the image changes significantly), time-to peak (TTP, the interval from time zero to the image where the intensity in the ROI is a maximum.), peak intensity (PI, the value of the maximum intensity in the ROI), rate parameter (|3, the rate constant of the wash in and is expressed in units of I/seconds.), Goodness of Fit (GOF, the correlation coefficient between the measured data and the fitted values at the same points)were evaluated. GOF values range from 0 to 1. GOF values near 1 indicate that the fitted curve accurately represents the data. Low values of GOF indicate that the fit parameters should not be highly valued. GOF values must be lager than 0.7 in our study.
In all patients the final diagnosis was made by means of histological analysis of resected specimens. The sensitivity, specificity, and accuracy were calculated for conventional and contrast-enhanced sonography in differentiation between benign and malignant lymph nodes. The u-test was used. In the quantitative analysis, the results were expressed as means ± standard (s) and analyzed with Student's t-test. Significance was declared at the P<0.05 level.
Results
1、 The enhancement was classed as follows: type I , intense homogeneous enhancement; type II, intense but inhomogeneous enhancement, with perfusion defects in the echogenic hilus; type III, intense but inhomogeneous enhancement, with perfusion defects in the nodal parenchyma; type IV, scarce intranodal enhancement. The study showed enhancement of type I in 16 of 28(57%) benign lymph nodes, type II in 10 of 28 (36%)benign lymph nodes; type III in 30 of 39(77%) metastases, type IV in 8 of 39(21%) metastases; type I in 5 of 8 lymphomatous nodes, type III in 3 0f 8 lymphomatous nodes.
2、 The nodes with enhancement of type I and II were classified as benign, with enhancement of type III and IV were classified as malignant. The sensitivity, specificity, and accuracy of conventional techniques in differentiation between benign and malignant lymph nodes were 70%, 86%,and 75% versus 87%, 93%,and 89% for contrast-enhanced ultrasound. The increase in correct diagnosis was significant (P<0.05) when conventional ultrasound was tested against contrast-enhanced ultrasound.
3、 The time-intensity curves appeared quick-up and quick-down type in the benign and lymphoma groups, but quick-up and slow-down in the metastatic group.
4、 There were no significance in the AT and TTP between benign and metastatic groups (both P>0.05); but the PI in benign group was significantly higher than metastatic group(P<0.05).The AT and TTP in lymphoma were significantly lower than those in the benign (P<0.001 and P<0.05) and metastatic (both P<0.001) groups; and the PI in lymphoma were significantly higher than those of the benign and metastatic groups (both P<0.001).
Conclusions
1、 Type I and II mostly represent enhancement patterns of benign lymph nodes, type III and IV mostly represent enhancement patterns of malignant lymph nodes.
2、 The pretreatment lymphomatous nodes mostly show enhancement of type I, the post-treatment lymphomatous nodes mostly show enhancement of type II.
3、The time-intensity curve is well established criterion which represent the perfusion of nodes. The curves appeared quick-up and quick-down type in the benign and lymphoma groups, but quick-up and slow-down in the metastatic group.
4、 There were no significance in th AT and TTP between benign and
metastatic groups; but the PI in benign group was significantly higher than metastatic group.The AT and TTP in lymphoma were significantly lower than those in the benign and metastatic groups; and the PI in lymphoma were significantly higher than those of the benign and metastatic groups.
5、 With gray-scale contrast-enhanced ultrasound, we can do better in differentiations of superficial lymphadenopathy than conventional sonography.
肿瘤病人区域淋巴结的检测和切除十分重要，它不仅直接影响对患者预后的评估，而且影响选择合适的治疗手段。在颈部、腋窝和腹股沟等浅表解剖部位，传统超声成像技术通过形态学和血供特征可以为良恶性淋巴结的鉴别提供有用的信息，如淋巴结的纵横比、边界、内部回声、淋巴门有否缺失及淋巴结内血管分布模式等，但存在很多局限性。有很多淋巴结不显示任何血供，特别是淋巴结的短径小于3～4mm和部位较深时，而且邻近大血管的淋巴结存在彩色显像的伪像。淋巴瘤血供丰富，并常表现为类似于良性淋巴结的中央门型血流分布。此外，当转移性淋巴结内的肿瘤浸润灶太小而不足以造成淋巴结发生形态特征改变时，传统超声也不能探及淋巴结内的微小浸润灶。
为了克服这些局限性，第一代超声造影剂(如Levovist)首先被用来增强血管彩色和能量多普勒的信号。然而第一代超声造影剂稳定性相对较差，加之在高机械指数下成像，受到各种伪像的限制，不能反映淋巴结内的微循环。
使用第二代超声造影剂，如声诺维(SonoVue)，超声造影允许在低机械指数下成像，灰阶谐波成像技术可详细显示淋巴结内的微血管灌注情况。不同淋巴结疾病有不同的病理生理基础，特别是肿瘤组织有特异的肿瘤微循环，因此对淋巴结进行灰阶超声造影，研究造影剂在淋巴结内的生物学效应和分布，了解其微循环灌注情况，可大大提高超声对良恶性淋巴结的鉴别能力，并有助正确选择拟进行活检的淋巴结，也使得探测放、化疗后淋巴结内早期血供阻断成为可能，可早期、易行和准确地评估淋巴瘤、鳞癌等对放、化疗的治疗反应。本研究采用Cadence对比脉冲序列造影成像技术(CPS)和自动跟踪造影定量分析软件(ACQ)，使用第二代超声造影剂SonoVue，观察不同淋巴结疾病的灰阶超声造影灌注情况，并进行时间-强度曲线的定量分析，旨在寻求更为有效的鉴别良恶性淋巴结的方法。
材料与方法
2005年3～12月，对43例我院门诊与住院患者进行超声检查，其中男17例，女26例。年龄18～71岁，平均51岁。患鼻咽癌12例，乳腺癌19例，慢性非特异性淋巴结炎5例，慢性乳腺炎2例，非霍奇金淋巴瘤2例，乳腺导管内乳头状瘤1例，甲状腺乳头状癌1例，肺癌1例。共检出75个浅表肿大淋巴结。除1例淋巴瘤患者已接受化疗外，其他所有患者在超声检查时均未行任何治疗措施。
检查仪器为Acuson Sequoia 512，15L8w宽频线阵高分辨力探头，配有对比脉冲序列造影成像技术(CPS)和自动跟踪造影分析软件(ACQ)。先行二维超声检查，观察纵横比、边界、内部回声、淋巴门有否缺失。每个淋巴结在最大纵切面上测量其纵径和横径。再行彩色多普勒超声检查，评价淋巴结内血管分布模式。淋巴结纵横比小于2、边缘不规则、淋巴门缺失或移位、内部回声不均匀、周边型或混合型血流是恶性淋巴结诊断标准，彩色多普勒超声检查将具有周边型或混合型血流，同时具备上述1种二维恶性征象或无血流型同时具备上述2种二维恶性征象的淋巴结诊断为恶性淋巴结。
造影采用CPS技术，探头发射频率7.0MHZ，机械指数(MI)0.1～0.2，造影剂采用SonoVue，经肘浅静脉团注2.4ml造影剂／人次，随后注入5ml生理盐水冲管。注射造影剂后即刻用实时灰阶谐波超声成像扫查淋巴结，每个淋巴结造影观察约2分钟，记录动态图像。然后对储存图像回放分析，观察淋巴结造影后增强表现，并根据淋巴结内造影剂增强的程度不同，把感兴趣区(ROI)放置在淋巴结近包膜下皮质内高灌注或低灌注区，ROI面积相同。应用ACQ自动描记时间-强度曲线，观察指标有造影剂到达时间(AT，注射造影剂后感兴趣区的信号强度增强到超过其基础强度的10％时所需要的时间)、峰值时间(TTP，注射造影后感兴趣区内增强强度达最大时所需要的时间)、峰值强度(PI，注射造影剂后感兴趣区内所能达到的最大增强强度)、速度参数(β，指造影剂流入感兴趣区的速度)、曲线与指数的匹配程度指数(GOF)等。GOF值在0～1之间，GOF值越接近1表明该曲线及其参数越精确，越接近0表明这些参数的代表意义不大。本研究中所有曲线GOF均大于0.7。
最后通过淋巴结切除活检对所有淋巴结作病理检查，将病理诊断与造影前常规超声诊断结果、造影后评价淋巴结灌注不同表现类型的诊断结果进行比较。检查结果采用SPSS 11.0统计软件进行统计分析，评价常规超声和灰阶超声造影诊断良恶性淋巴结的敏感性、特异性和准确性，百分率的比较采用u检验。计量资料以((?)±s)表示，组间比较进行非配对t检验。以P＜0.05为差异有统计学意义。
结果
1、淋巴结造影后增强表现类型分为：Ⅰ型(均匀增强型)：整个淋巴结显著而均匀的增强；Ⅱ型(淋巴门不均匀增强型)：实质显著增强，灌注均匀，但在中央高回声淋巴门内见不规则形低或无灌注区；Ⅲ型(实质不均匀增强型)：显著增强的实质内有局灶性低或无灌注区；Ⅳ型(微弱增强型)：整个淋巴结微弱增强，灌注均匀或不均匀。良性淋巴结中57％(16／28)造影表现为Ⅰ型，36％(10／28)表现为Ⅱ型；转移性淋巴结中77％(30／39)表现为Ⅲ型，21％(8／39)表现为Ⅳ型。5个为未经治疗的淋巴瘤造影表现为Ⅰ型，3个治疗后的淋巴瘤造影表现为Ⅲ型。
2、将造影表现为Ⅰ、Ⅱ型的淋巴结判定为良性，造影表现为Ⅲ、Ⅳ型的淋巴结判定为恶性，则灰阶超声造影诊断良恶性淋巴结的敏感性为87％，特异性为93％，准确性89％。造影前常规二维和彩色多普勒超声诊断良恶性淋巴结的敏感性为70％，特异性为86％，准确性75％。与常规超声技术相比，造影对诊断准确率的提高有显著意义(P＜0.05)。
3、良性组和淋巴瘤组淋巴结造影时间-强度曲线形态上表现为上升支陡直，到达顶峰时先快速下降，随后缓慢下降。转移性组淋巴结曲线形态上表现为上升支陡直，到达顶峰时持续缓慢下降。
4、良性、转移性和淋巴瘤三组淋巴结造影时间-强度曲线定量参数比较：β值各组间无明显差异(P＞0.05)。良性组和转移性组淋巴结造影剂的到达时间(AT)及达峰时间(TTP)无显著差异(P均＞0.05)；但良性组峰值强度(PI)大于转移性组(P＜0.05)。淋巴瘤组造影剂到达时间(AT)短于良性组和转移组淋巴结(P均＜0.001)；达峰时间(TTP)短于良性组和转移组(P＜0.05和P＜0.001)；峰值强度(PI)大于良性组和转移组(P均＜0.001)。
结论
1、良性淋巴结超声造影增强主要表现为Ⅰ型和Ⅱ型；转移性淋巴结主要表现为Ⅲ型和Ⅳ型。
2、淋巴瘤治疗后造影增强主要表现为Ⅲ型，未经治疗时主要表现为Ⅰ型。
3、时间-强度曲线分析能反映淋巴结动态灌注情况。良性、转移性和淋巴瘤三组淋巴结造影时间-强度曲线都表现为上升支陡直，但转移性组下降支比良性组和淋巴瘤组缓慢。
4、定量参数分析表明淋巴结良性组和转移性组造影到达时间及达峰时间无显著差异；但良性组峰值强度大于转移性组。淋巴瘤组到达时间、达峰时间短于良性组和转移性组；峰值强度大于良性组和转移性组。
5、超声造影对良恶性淋巴结的鉴别诊断准确率要高于常规超声技术。
BACKGROUND
The detection or exclusion of lymph node metastasis in patients with tumors is of special importance because not only the patient's prognosis but also the therapeutic concept is directly influenced by the nodal status. Conventional ultrasonography including gray-scale imaging(B-mode), color-coded Doppler sonography(CCDS) and power Doppler(PD) have shown to serve as a promising and accurate tool in differentiating diagnosis of superficial lymphadenopathy by detecting the characteristics of morphology and angioarchitecture such as the longitudinal-transverse diameter ratio, margin, intranodal echogenicity, echogenic hilus and vascular pattern. However, malignant nodes may be the same shape as benign nodes when they are in the early stage of involvement. In metastatic as well as benign enlarged lymph nodes, a Doppler signal is not always detectable. Micrometastases are frequently discovered in the no-enlarged lymph nodes, and more than half of the nodes that had a maximum transverse diameter between 2 and 4 mm were found no vascularity. In some studies, a relatively lower sensitivity of vascular pattern was found in distinguishing reactive from lymphomatous nodes. This is probably due to the high incidence of hilar vascularity in lymphomatous nodes, which resulted in a high false-negative rate.
Some studies exploited the introduction of the first-generation air-based contrast agent (such as SH U 508A, Levovist) to improve the Doppler sonography signal. But the first-generation ultrasound contrast agent is not enough stable and always destroyed with high MI (mechanical index) imaging methods, and there are many color Doppler imaging artifacts, so the microcirculation can not be delineated.
Recently, new ultrasound techniques, such as pulse inversion harmonic imaging, have been developed that are extremely sensitive to non-linear effects of US interaction with microbubble contrast agents. With the second-generation ultrasound contrast agents, such as SonoVue, real-time evaluation of the lymph nodal perfusion can be carried out at a low MI. Different lymphadenopathy have different pathological characteristics, especially tumor tissue has peculiar tumor microcirculation. Real-time gray-scale contrast-enhanced ultrasound for superficial lymph nodes can differentiate benign from malignant nodes better by detecting the distribution and biologic effect of microbubble in the nodes, and may help to choose appropriate lymph node for biopsy. It may also be useful in early assessing the response of lymph nodes to radiochemotherapy. The objective of this study was to assess the enhancement of echogenicity and the characteristics of the time-intensity curves by using real-time gray-scale contrast-enhanced ultrasound for superficial lymph nodes.
Materials and methods
From March to December 2005 43 consecutive patients(26 women, 17 men; age range: 18 to 71 years, mean 51 years) with enlarged superficial cervical, axillary, or inguinal lymph nodes clinically suspected to be malignant were prospectively examined by ultrasound immediately. Of the 43 patients, 33 had metastatic nodes, 8 had reactive hyperplasia, and 2 had lymphoma. In the 33 patients with metastatic nodes, the primary tumors were in the nasopharynx(n=12),breast(n=19), lung(n=1), thyroid(n=1). A
total of 75 enlarged lymph nodes were found on sonography. At the time of the US examination, none but one patient with lymphoma had received treatment.
Scanning was performed by one experienced radiologist blinded to the final diagnosis with a commercially available scanner (Acuson Sequoia 512) using an electronically focused near-field linear array transducer with a 8-to 15-MHZ bandwidth and provided with contrast pulse sequences(CPS) contrast imaging and Axius? Auto-Tracking Contrast Quantification(ACQ) software.
In the first step, all patients were examined using conventional B-mode sonography. Echo texture, margin sharpness, longitudinal-transverse diameter ratio, and the location of the hilus were used as parameters. In the second step, patients were examined using color Doppler sonography. The vascular pattern was evaluated. Nodes having an inhomogeneous echo, blurred margins, absent or aberrant hilus, the longitudinal-transverse diameter ratio less than 2, and the preservation of peripheral or mixture vessels were classified as malignant. If the vascular pattern and at least one B-mode criterion were classified as malignant, the node was judged to be malignant and vice versa. In the nodes in which no vessels could be identified, the criteria of B-mode sonography were used as mentioned earlier.
Finally, the gray-scale contrast-enhanced sonography was performed after intravenous injection of the US contrast agent microbubble (SonoVue, Bracco, Milan, Italy)as a bolus at a 2.4mL dose, followed by 5mL of normal saline flush. A low frame rate (7MHZ)and a low mechanical index (MI=0.1～0.2) were used. Each exam lasted about 2 min following bolus injection. The cine clips were acquired for each nodes and digitally stored on the US unit, they were reviewed retrospectively on screen. Readers subjectively assessed in consensus node contrast enhancement. The regions-of interest (ROI) was placed in the parenchyma near the capsula,
and the time-intensity curve for each node was acquired and analyzed by ACQ. The arrival time (AT, the time that the contrast "arrives" in the image can be considered as when the image changes significantly), time-to peak (TTP, the interval from time zero to the image where the intensity in the ROI is a maximum.), peak intensity (PI, the value of the maximum intensity in the ROI), rate parameter (|3, the rate constant of the wash in and is expressed in units of I/seconds.), Goodness of Fit (GOF, the correlation coefficient between the measured data and the fitted values at the same points)were evaluated. GOF values range from 0 to 1. GOF values near 1 indicate that the fitted curve accurately represents the data. Low values of GOF indicate that the fit parameters should not be highly valued. GOF values must be lager than 0.7 in our study.
In all patients the final diagnosis was made by means of histological analysis of resected specimens. The sensitivity, specificity, and accuracy were calculated for conventional and contrast-enhanced sonography in differentiation between benign and malignant lymph nodes. The u-test was used. In the quantitative analysis, the results were expressed as means ± standard (s) and analyzed with Student's t-test. Significance was declared at the P<0.05 level.
Results
1、 The enhancement was classed as follows: type I , intense homogeneous enhancement; type II, intense but inhomogeneous enhancement, with perfusion defects in the echogenic hilus; type III, intense but inhomogeneous enhancement, with perfusion defects in the nodal parenchyma; type IV, scarce intranodal enhancement. The study showed enhancement of type I in 16 of 28(57%) benign lymph nodes, type II in 10 of 28 (36%)benign lymph nodes; type III in 30 of 39(77%) metastases, type IV in 8 of 39(21%) metastases; type I in 5 of 8 lymphomatous nodes, type III in 3 0f 8 lymphomatous nodes.
2、 The nodes with enhancement of type I and II were classified as benign, with enhancement of type III and IV were classified as malignant. The sensitivity, specificity, and accuracy of conventional techniques in differentiation between benign and malignant lymph nodes were 70%, 86%,and 75% versus 87%, 93%,and 89% for contrast-enhanced ultrasound. The increase in correct diagnosis was significant (P<0.05) when conventional ultrasound was tested against contrast-enhanced ultrasound.
3、 The time-intensity curves appeared quick-up and quick-down type in the benign and lymphoma groups, but quick-up and slow-down in the metastatic group.
4、 There were no significance in the AT and TTP between benign and metastatic groups (both P>0.05); but the PI in benign group was significantly higher than metastatic group(P<0.05).The AT and TTP in lymphoma were significantly lower than those in the benign (P<0.001 and P<0.05) and metastatic (both P<0.001) groups; and the PI in lymphoma were significantly higher than those of the benign and metastatic groups (both P<0.001).
Conclusions
1、 Type I and II mostly represent enhancement patterns of benign lymph nodes, type III and IV mostly represent enhancement patterns of malignant lymph nodes.
2、 The pretreatment lymphomatous nodes mostly show enhancement of type I, the post-treatment lymphomatous nodes mostly show enhancement of type II.
3、The time-intensity curve is well established criterion which represent the perfusion of nodes. The curves appeared quick-up and quick-down type in the benign and lymphoma groups, but quick-up and slow-down in the metastatic group.
4、 There were no significance in th AT and TTP between benign and
metastatic groups; but the PI in benign group was significantly higher than metastatic group.The AT and TTP in lymphoma were significantly lower than those in the benign and metastatic groups; and the PI in lymphoma were significantly higher than those of the benign and metastatic groups.
5、 With gray-scale contrast-enhanced ultrasound, we can do better in differentiations of superficial lymphadenopathy than conventional sonography.
引文
1 Ahuja A, Ying M. Sonography of Neck Lymph Nodes. Part Ⅱ: Abnormal Lymph Nodes. Clinical Radiology, 2003, 58: 359-366.
2 Podkrajsek M, Music MM, Kadivec M, et al. Role of ultrasound in the preoperative staging of patients with breast cancer. Eur Radiol, 2005, 15: 1044-1050.
3 Ying M, Ahuja A, Brook F. Accuracy of sonographic vascular features in differentiating causes of cervical lymphadenopathy. Ultrasound Med Biol, 2004, 30: 441-447.
4 Moritz JD, Ludwig A, Oestmann JW. Contrast-enhanced color Doppler Sonography for Evaluation of Enlarged Cervical Lymph Nodes in Head and Neck Tumors. Am J Roentgenol, 2000, 174: 1279-1284.
5 Schulte-Altedorneburg G, Demharter J, Linne R, et al. Does Ultrasound contrast agent improve the diagnosis value of colour and Power Doppler Sonography in superficial Lymph Node Enlargment?. European Radiology, 2003, 48: 252-257.
6 刘学明，潘敏强，莫国强，等．静脉超声造影彩色多普勒检查淋巴结的初步体会．中华超声影像学杂志，2004，13：148-149．
7 Rubaltelli K, Khadivi Y, Tregnaghi A, et al. Evaluation of lymph node perfusion using continuous mode harmonic ultrasonography with a second-geneation contrast agent. J Ultrasound Med, 2004, 23: 829-836.
8 Giovagnorio F, Drudi FM, Fanelli G, et al. Fatty Changes as a Misleading Factor in the Evaluation with Ultrasound of Superficial Lymph Nodes. Ultrasound Med Biol, 2005, 31: 1017-1022.
9 Shubik P. Vascularization of tumors: a review. Jcancer Res Clin Oncol, 1982, 103(3): 211-226.
10 李杰，董宝玮，于晓玲，等．肝不同部位灰阶超声造影定量分析的实验研究．中华超声影像学杂志，2004，13(6)：460-462．
11 张青萍，周翔，柳建华．新型超声造影剂对组织器官血流灌注的研究．放射学实践，2000，15(3)：170-172．
12 Ellegala DB, Leong-Poi H, Carpenter JE, et al. Imaging tumor angiogenesis with contrast ultrasound and microbubbles targeted to avβ3. Circulation 2003(3); 108: 336-41.
1 Albrecht T, Oldenburg A, Hohmann J, et al. Imaging of liver metastases with contrast-specific low-MI real-time ultrasound and SonoVue. Eur Radiol 2003, 13(S3): N79-N86
2 陈敏华，严昆．新型造影剂与灰阶超声造影技术对肝肿瘤的诊断价值．中华超声影像学杂志，2004，13：38-42
3 Steinkamp HJ, Wissgott C, Rademaker J, et al. Current atatus of power and color Doppler sonography in the differantial diagnosis of lymph node lesions. Eur. Radiol., 2002, 12: 1785-1793
4 Ying M, Ahuja A. Sonography of neck lymph nodes. Part Ⅰ: Mormal lymph nodes. Clinical Radiology, 2003, 58: 351-358
5 Ying M, Ahuja A. Sonography of neck lymph nodes. Part Ⅱ: Abnormal lymph nodes. Clinical Radiology, 2003, 58: 359-366
6 Ying M, Ahuja A, Brook F. Accuracy of sonographic vascular features in differentiating causes of cervical lymphadenopathy. Ultrasound in Med. & Biol., 2004, 30: 441-447
7 Tschammler A, Hahn D. Multivariate Analysis of the Ajustment of the Colour Duplex Unit for the Differential Diagnosis of Lymph Node Alterations. Eur Radiol, 1999, 9: 1445-1450
8 Schulte-Altedorneburg G, Demharter J, Linne R, et al. Does Ultrasound contrast agent improve the diagnosis value of colour and Power Doppler Sonography in superficial Lymph Node Enlargment?. European Journal of Radiology, 2003, 48: 252-257
9 Moritz JD, Ludwig A, Oestmann JW. Contrast-enhanced color Doppler Sonography for Evaluation of Enlarged Cervical Lymph Nodes in Head and Neck Tumors. AJR, 2000, 174: 1279-1284
10 刘学明，潘敏强，莫国强，等．静脉超声造影彩色多普勒检查淋巴结的初步体会．中华超声影像学杂志，2004，13：148-149
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20 Omoto K, Mizunuma H, Ogura S, et al. New method of sentinel node identification with ultrasonography using albumin as contrast agent: a study in pigs. Ultrasound in Med. & Biol.,2002,28:1115-1122
21 Mattrey RF, Kono Y, Baker K, et al. Sentinel lymph node imaging with microbubble ultrasound contrast material. Acad Radiol, 2002,9(suppl 1):231-235
22 Goldberg BB, Merton DA, Liu JB, et al. Sentinel lymph nodes in a Swine model with melanoma: contrast-emhanced lymphatic US. Radiology, 2004,230: 727-734
23 Hauff P, Reinhardt M, Breil A, et al. Molecular targeting of lymph nodes with L-selection Ligand-specific US contrast agent: a feasibility study in mice and dogsl. Radiology , 2004, 231: 667-673
2 Podkrajsek M, Music MM, Kadivec M, et al. Role of ultrasound in the preoperative staging of patients with breast cancer. Eur Radiol, 2005, 15: 1044-1050.
3 Ying M, Ahuja A, Brook F. Accuracy of sonographic vascular features in differentiating causes of cervical lymphadenopathy. Ultrasound Med Biol, 2004, 30: 441-447.
4 Moritz JD, Ludwig A, Oestmann JW. Contrast-enhanced color Doppler Sonography for Evaluation of Enlarged Cervical Lymph Nodes in Head and Neck Tumors. Am J Roentgenol, 2000, 174: 1279-1284.
5 Schulte-Altedorneburg G, Demharter J, Linne R, et al. Does Ultrasound contrast agent improve the diagnosis value of colour and Power Doppler Sonography in superficial Lymph Node Enlargment?. European Radiology, 2003, 48: 252-257.
6 刘学明，潘敏强，莫国强，等．静脉超声造影彩色多普勒检查淋巴结的初步体会．中华超声影像学杂志，2004，13：148-149．
7 Rubaltelli K, Khadivi Y, Tregnaghi A, et al. Evaluation of lymph node perfusion using continuous mode harmonic ultrasonography with a second-geneation contrast agent. J Ultrasound Med, 2004, 23: 829-836.
8 Giovagnorio F, Drudi FM, Fanelli G, et al. Fatty Changes as a Misleading Factor in the Evaluation with Ultrasound of Superficial Lymph Nodes. Ultrasound Med Biol, 2005, 31: 1017-1022.
9 Shubik P. Vascularization of tumors: a review. Jcancer Res Clin Oncol, 1982, 103(3): 211-226.
10 李杰，董宝玮，于晓玲，等．肝不同部位灰阶超声造影定量分析的实验研究．中华超声影像学杂志，2004，13(6)：460-462．
11 张青萍，周翔，柳建华．新型超声造影剂对组织器官血流灌注的研究．放射学实践，2000，15(3)：170-172．
12 Ellegala DB, Leong-Poi H, Carpenter JE, et al. Imaging tumor angiogenesis with contrast ultrasound and microbubbles targeted to avβ3. Circulation 2003(3); 108: 336-41.
1 Albrecht T, Oldenburg A, Hohmann J, et al. Imaging of liver metastases with contrast-specific low-MI real-time ultrasound and SonoVue. Eur Radiol 2003, 13(S3): N79-N86
2 陈敏华，严昆．新型造影剂与灰阶超声造影技术对肝肿瘤的诊断价值．中华超声影像学杂志，2004，13：38-42
3 Steinkamp HJ, Wissgott C, Rademaker J, et al. Current atatus of power and color Doppler sonography in the differantial diagnosis of lymph node lesions. Eur. Radiol., 2002, 12: 1785-1793
4 Ying M, Ahuja A. Sonography of neck lymph nodes. Part Ⅰ: Mormal lymph nodes. Clinical Radiology, 2003, 58: 351-358
5 Ying M, Ahuja A. Sonography of neck lymph nodes. Part Ⅱ: Abnormal lymph nodes. Clinical Radiology, 2003, 58: 359-366
6 Ying M, Ahuja A, Brook F. Accuracy of sonographic vascular features in differentiating causes of cervical lymphadenopathy. Ultrasound in Med. & Biol., 2004, 30: 441-447
7 Tschammler A, Hahn D. Multivariate Analysis of the Ajustment of the Colour Duplex Unit for the Differential Diagnosis of Lymph Node Alterations. Eur Radiol, 1999, 9: 1445-1450
8 Schulte-Altedorneburg G, Demharter J, Linne R, et al. Does Ultrasound contrast agent improve the diagnosis value of colour and Power Doppler Sonography in superficial Lymph Node Enlargment?. European Journal of Radiology, 2003, 48: 252-257
9 Moritz JD, Ludwig A, Oestmann JW. Contrast-enhanced color Doppler Sonography for Evaluation of Enlarged Cervical Lymph Nodes in Head and Neck Tumors. AJR, 2000, 174: 1279-1284
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