超声造影在乳腺癌诊断及疗效评估中的应用研究
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摘要
第一部分乳腺癌超声造影表现与生物预后因子及微血管密度相关性的研究
研究目的：乳腺癌是一种血管依赖性病变,其生长、浸润和转移与新生血管密切相关。超声造影技术的发展使研究肿瘤的微循环灌注成为可能。本研究采用超声造影技术对乳腺浸润性导管癌进行动态观察,分析乳腺癌超声造影表现,并将乳腺癌的增强特征及血流灌注参数与其生物预后因子及微血管密度的相关性进行初步评估,旨在为乳腺癌的血管生成及预后研究提供依据。
研究方法：选取2010年10月至2012年2月在我院进行超声造影检查并经穿刺或手术病理证实为乳腺浸润性导管癌的45例患者,肿瘤最大直径9～86mmm,平均(30.5±18)mm。采用Philips公司IU22超声检查仪,L9-3宽频线阵探头与L5-1探头,超声造影剂为意大利Bracco公司的SonoVue,经肘正中静脉弹丸式注射4.8ml。分析乳腺癌超声造影增强特征,包括造影灌注模式、造影剂分布是否均匀、内部有无灌注缺损、造影剂进入的顺序、增强形态是否规则、边界是否清晰、周边有无扭曲或穿入血管等。并采用QLAB分析软件对肿瘤边缘和中心区域及周围正常乳腺组织取样获得时间-强度曲线,分析血流灌注参数指标,包括上升时间(RT)、峰值强度(PI)、达峰时间(TTP)、流入斜率(WIS)、平均渡越时间(MTT)等。将手术或穿刺病理标本进行HE染色利免疫组化染色,以细胞核、细胞膜或细胞浆内出现棕黄色颗粒为阳性标准,对乳腺癌生物预后因子,包括ER、PR、c-erb-B2、p53及Ki-67的表达结果进行判定,同时对肿瘤组织的微血管密度(MVD)进行计数。将超声造影增强特征及血流灌注参数与肿瘤预后因子、MVD结果进行相关性分析。
结果：1.乳腺癌超声造影增强特征：45例乳腺癌造影后除2例(4.4%)无增强外,其余43例(95.6%)均出现不同程度增强。其中25例(55.6%)不均匀增强,14例(31.1%)均匀增强,4例(8.9%)周边增强。27例(60%)有血流灌注缺损；37例(82.2%)增强形态不规则；25例(55.6%)向心性增强；32例(71.1%)有穿支血管；34例(75.6%)增强边界不清晰。
2.乳腺癌造影血流灌注参数分析：45例乳腺癌2例无增强外,43例(95.6%)造影时间-强度曲线表现为“快进快出”型或“快进慢出”型。肿瘤组织与周围正常乳腺组织相比,RT、TTP缩短,PI增高,WIS增大,差异有统计学意义(P<0.05)；肿瘤边缘与肿瘤中心区域相比,TTP缩短,PI增高, WIS增大,差异有统计学意义(P<0.05)；肿瘤直径≤2.Ocm和直径>2.Ocm两组血流灌注参数比较,差异无统计学意义(P>0.05)。
3.乳腺癌造影增强特征与肿瘤预后因子相关性：不均匀增强多存在于直径>2cm肿瘤内；向心性增强多发生在ER阴性肿瘤内；穿支血管在组织学分级高、直径>2cm肿瘤内多见；血流灌注缺损常见于ER阴性、c-erb-B2阳性、Ki-67阳性及直径>2cm肿瘤内。以血流灌注缺损判断ER表达的灵敏性为86.7%,特异性为53.3%,约登指数为40%；判断Ki-67表达的灵敏性为78.2%,特异性为59.1%,约登指数为37.3%。肿瘤增强形态及增强边界与预后因子的表达无明显相关(P>0.05)。
4.乳腺癌造影表现与肿瘤MVD相关性：肿瘤不均匀增强、血流灌注缺损均与高MVD有关(P<0.05)；肿瘤增强形态、增强边界及穿支血管与MVD无明显相关(P>0.05)。高MVD组PI大于低MVD组,两组差异有统计学意义(P<0.05)。而RT、TTP及WIS两组间差异无统计学意义(P>0.05)。
结论：1.超声造影不仅可以反映恶性肿瘤的形态学特征,还可以定量评价肿瘤的微循环灌注情况。
2.乳腺癌超声造影的某些增强特征与肿瘤生物预后因子有一定的相关性,可以对肿瘤的浸润、转移进行在体评价,在一定程度上反映了肿瘤的预后。
3.乳腺癌超声造影的某些增强特征及血流灌注参数与MVD有一定的相关性,可以作为评价肿瘤血管生成的依据。
第二部分超声造影在乳腺癌新辅助化疗疗效评估中的应用价值
研究目的：乳腺癌新辅助化疗已成为局部进展期乳腺癌系统治疗的常规方案,它的合理应用迫切需要切实有效的方法来动态监测并及时评价疗效。尽管常规超声已应用于乳腺癌新辅助化疗疗效的评估中,但其对于肿瘤大小测量的准确性一直受到质疑。本研究应用实时超声造影技术观察乳腺癌新辅助化疗前后原发灶的大小变化以及血流灌注参数变化,并与常规超声相比较,探讨超声造影在评估乳腺癌新辅助化疗疗效中的临床应用价值。
研究方法：选取2010年10月至2012年2月间收入我院进行新辅助化疗并最终手术的乳腺浸润性导管癌患者31例,肿瘤最大径22～108mm,平均(43±19)mm。所有患者均在新辅助化疗前经粗针穿刺活检并组织病理学检查证实为乳腺浸润性导管癌(Ⅱ～Ⅲ级)。采用Philips公司IU22超声检查仪,L9-3宽频线阵探头与L5-1探头。超声造影剂为SonoVue (Bracco, Italy)4.8ml,经肘正中静脉弹丸式注入。常规超声确定原发灶的部位,测量肿瘤最大切面相互垂直的两个径线；彩色多普勒观察肿瘤的血流等级；超声造影分析造影前后原发灶大小变化及造影增强强度、血流灌注参数指标,并同时比较化疗前后原发灶大小变化及血流灌注参数变化。31例患者分别于化疗开始前、化疗三个周期结束后进行超声及超声造影检查。
新辅助化疗用药方案：表柔比星(EPI)60mg/m2,第1天静脉滴注；多西他赛(DOC)75mg/m2,第1天静脉滴注。21天为一个周期,应用三个周期。新辅助化疗结束后,所有病人行乳腺全切手术。
结果：1.乳腺癌新辅助化疗前后原发灶大小改变：31例乳腺癌新辅助化疗后25例(80.6%)疗效缓解,4例(12.9%)疗效稳定,2例(6.5%)疾病进展。超声造影增强范围比常规超声测值增大,与手术标本大小显著相关,r值为0.976。常规超声测值小于手术标本,两者差异有显著性(P<0.05)。
2.超声造影评价乳腺癌新辅助化疗前后肿瘤血流灌注改变：常规超声显示化疗后肿瘤血流等级大部分从2-3级降至0-1级；超声造影显示化疗后除2例(6.5%)肿瘤增强强度较化疗前增加外,28例(90.3%)增强强度不同程度降低。有1例(3.2%)化疗前无血流灌注者化疗后内部可见不均匀血流灌注,而其大小化疗前后并无改变。超声造影较常规超声对肿瘤坏死液化区检测更敏感。超声造影显示化疗前可见肿瘤内血流灌注灌注缺损26例(83.9%),化疗后灌注缺损27例(87.1%)。而常规超声在化疗前后肿瘤内均未显示坏死液化区。
3.超声造影时间一强度曲线可以定量观察新辅助化疗前后血流灌注参数改变,常规超声不具备此功能。将化疗前后血流灌注参数进行比较,化疗后肿瘤达峰时间增加,峰值强度降低,流入斜率减小(P<0.05),而上升时间、平均渡越时间化疗前后差异无统计学意义(P>0.05)。
结论：1.超声造影不仅较常规超声更精确测量乳腺癌新辅助化疗前后肿瘤大小改变,而且可以显示肿瘤内部血流灌注缺损的存在,灌注缺损可作为预测化疗反应的重要指标。
2.超声造影可以定性定量评估化疗前后肿瘤内部血流灌注变化,肿瘤血流灌注变化早于肿瘤形态学改变,是判断肿瘤存活的主要指标之一,应用超声造影可以更早期评价和预测乳腺癌新辅助化疗疗效。
Part1
Association of contrast-enhanced ultrasound characteristics with biological prognostic factors and microvessel density in breast cancer
Objective:Breast cancer is a vascular-dependent lesion, and its growth, infiltration and metastasis are closely related to the neovascularization. The development of contrast-enhanced ultrasound (CEUS) technology make it possible to reveal the tumor microcirculation. The aim of the study was to analyse the CEUS enhancement characteristics of invasive ductal carcinoma, and to investigate the association of CEUS enhancement characteristics and blood perfusion parameters with prognostic factors and microvessel density (MVD), which can be helpful to evaluate the tumor angiogenesis and prognosis.
Methods:From October2010to February2012,45consecutive breast cancer patients were studied by CEUS. All patients were diagnosed with invasive ductal carcinoma on the basis of biopsy or surgery results. The tumor size was an average of (30.5±18) mm, ranging from9to86mm. Color Doppler Ultrasound Philips iU22with L9-3and L5-1probes were used in this study. The contrast agent used was SonoVue (Bracco, Italy). All patients accepted an elbow intravenous bolus injection of4.8ml. Breast cancer enhancement characteristics at CEUS imaging, including enhancement pattern, internal homogeneity, perfusion defect, enhancement order, margin, and penetrating vessels was analyzed. QLAB software was used with CEUS imaging to obtain the time-intensity curve of the periphery and inside region of tumor, and blood perfusion parameters (rising time, RT; time to peak, TTP; peak intensity, PI; wash-in slope, WIS; mean transit time, MTT) was evaluated. Pathologic prognostic factors, including estrogen receptor (ER) and progesterone receptor status (PR), c-erb-B2, p53, and Ki-67expression were determined by immunohistochemical staining, which considered positive when membranous or nuclear staining was observed. And the MVD were count. Association of CEUS enhancement characteristics with prognostic factors and MVD results was analyzed.
Results:1. CEUS enhancement characteristics of breast cancer. For2cases (4.4%) without contrast agent perfusion in CEUS imaging, blood perfusion was observed in43cases (95.6%). The45malignancies displayed heterogeneous enhancement in25cases (55.6%), homogeneous enhancement in14cases (31.1%), peripheral enhancement in4cases (8.9%). Local blood perfusion defect was observed in27cases (60%), irregular enhancement shape in37cases (82.2%), centripetal enhancement in25cases (55.6%), penetrating vessels in32cases (71.1%) and poorly-defined margin in34cases (75.6%),
2. CEUS blood perfusion parameters analysis. For2cases (4.4%) without contrast agent perfusion in CEUS imaging, the time-intensity curve of43cases was characterized as ascend rapidly and drop slowly or rapidly. Compared to that of the normal breast tissue, the RT and TTP seem faster (P<0.05), the PI and WIS seem higher in tumor tissues (P<0.05). Compared to that of the inside region of the tumor, TTP seem to be faster, PI and WIS seem higher in tumor periphery region (P<0.05). whereas blood perfusion parameters were no statistical differences in the2groups (≤2cm in diameter and>2cm in diameter)(P>0.05).
3. Association of CEUS enhancement characteristics with prognostic factors. Heterogeneous enhancement was common in larger tumors (>2cm in diameter), and centripetal enhancement was common in negative ER expression. Penetrating vessel was found more often in the higher histologic grade and larger tumors. Perfusion defect was seen in negative ER expression, positive c-erb-B2expression, positive Ki-67expression and larger tumor diameter. The sensitivity, specificity and accuracy of perfusion defect for detection ER expression were86.7%,53.3%, and40%m, respectively. The sensitivity, specificity and accuracy of perfusion defect for detection Ki-67expression were78.2%,59.1%, and37.3%, respectively. The enhancement margin and enhancement shape showed no significant correlation with prognostic factors (P>0.05).
4. Association of CEUS enhancement characteristics with MVD. Heterogeneous enhancement and perfusion defect were found more often in high-MVD group than in low-MVD group (P<0.05), whereas enhancement margin, enhancement shape and penetrating vessel showed no significant correlation with MVD (P>0.05). PI was higher in high-MVD group than that in low-MVD group (P<0.05), whereas the RT, TTP and WIS showed no significant correlation with MVD (P>0.05).
Conclusions:1. CEUS not only evaluate the morphologic features of breast cancer, but also evaluate quantitatively the degree of blood perfusion.
2. Some enhancement characteristics were associated with prognostic factors, which reflect in vivo the infiltration and metastasis of the tumor, and can be helpful to predict the breast caner prognosis.
3. Some enhancement patterns and blood perfusion parameters were associated with MVD, which can be used as a quantitative basis for evaluation of tumor angiogenesis.
Part2
Potential application value of contrast-enhanced ultrasound in neoadjuvant chemotherapy of breast cancer
Objective:Neoadjuvant chemotherapy (NAC) is the conventional treatment of choice for patients with locally advanced breast cancer. The reasonable application of NAC are pressing for a valuable tool to monitor and evaluate the response of breast cancer to neoadjuvant treatment. Although ultrasound (US) has applied to the efficacy evaluation of breast cancer, the accurate measurement of tumor sizes at US is still questioned all the time. The purpose of this study was to investigate the value of contrast-enhanced ultrasound (CEUS) in evaluating the response of breast cancer to NAC by assessing the tumor size changes and blood perfusion changes at CEUS before and after NAC.
Methods:Thirty-one breast cancer patients treated with NAC (from2010.10until2012.02) and ultimately underwent surgery included. All patients were diagnosed with infiltrating ductal carcinoma (stage Ⅱ and Ⅲ) on the basis of results from a percutaneous core needle biopsy. The pre-therapy tumor size (at its longest dimension) was an average of (43±19) mm, ranging from22to108mm. Color Doppler Ultrasound Philips iU22(Philips, Bothell WA, USA) with Philips L9-3and L5-1probes were used in this examination. US was used to determine the site and maximum size of the primary tumor. Color Doppler was used to assess the grade of vascularization. CEUS was used to observe the tumor size changes, enhancement intensity and blood perfusion parameter changes before and after NAC. US and CEUS were performed for the31patients before and after3cycles NAC. The chemotherapy regimen included60mg/m2EPI intravenously (i.v.) on day1and75mg/m2DOC via i.v. on day1; these doses were repeated every21days for a total of3cycles prior to surgery. After completion of chemotherapy, all patients underwent mastectomy.
Results:1. Tumor size changes before and after NAC. After NAC,25patients (80.6%) achieved a PR,4patients (12.9%) maintained a SD state, and2patients (6.5%) showed a PD state. The tumor sizes measured by CEUS were larger than those measured by US, and had high correlation with surgical specimens, with r values of 0.976. The sizes measured by US were smaller than the size of surgical specimens (P <0.05).
2. Tumor blood perfusion changes before and after NAC. After NAC, US revealed the grade of vascularization decreased from the grade of2-3to0-1in most of the case. By comparison, the CEUS images revealed the enhancement intensity decreased in28cases (90.3%), but increased in2cases (6.5%). For one case (3.2%) without contrast agent perfusion in CEUS imaging pre-therapy, heterogeneous perfusion was observed post-therapy, while the tumor size remained stable. CEUS provided a more sensitive detection of the tumor necrosis. CEUS showed local blood perfusion defect in26cases (83.9%) prior to NAC, and27cases (87.1%) after NAC. However, the US did not show any necrosis liquefied areas in all cases before and after NAC.
3. CEUS time-intensity curve analysis observed changes in blood perfusion quantitatively before and after chemotherapy, whereas US could not. After NAC, time to peak increased, peak intensity decreased, and wash-in slope decreased, with statistical differences between the two groups (P<0.05). However, the differences in the rise time and mean transit time were not statistically significant between the two groups (P>0.05).
Conclusions:1. As compared with US, CEUS not only offers a more accurate measurement of the tumor size, but also reveals local blood perfusion defect in the tumor, which is critical for evaluating of breast cancer response to NAC.
2. CEUS permits evaluation of the degree of blood perfusion in tumors qualitatively and quantitatively before and after NAC. Since a change in the tumor blood perfusion occurs earlier than a change in tumor size, which represents an indicator of the tumor survival, CEUS may represent a valuable tool for evaluating the early response of breast cancer to NAC.
研究目的：乳腺癌是一种血管依赖性病变,其生长、浸润和转移与新生血管密切相关。超声造影技术的发展使研究肿瘤的微循环灌注成为可能。本研究采用超声造影技术对乳腺浸润性导管癌进行动态观察,分析乳腺癌超声造影表现,并将乳腺癌的增强特征及血流灌注参数与其生物预后因子及微血管密度的相关性进行初步评估,旨在为乳腺癌的血管生成及预后研究提供依据。
研究方法：选取2010年10月至2012年2月在我院进行超声造影检查并经穿刺或手术病理证实为乳腺浸润性导管癌的45例患者,肿瘤最大直径9～86mmm,平均(30.5±18)mm。采用Philips公司IU22超声检查仪,L9-3宽频线阵探头与L5-1探头,超声造影剂为意大利Bracco公司的SonoVue,经肘正中静脉弹丸式注射4.8ml。分析乳腺癌超声造影增强特征,包括造影灌注模式、造影剂分布是否均匀、内部有无灌注缺损、造影剂进入的顺序、增强形态是否规则、边界是否清晰、周边有无扭曲或穿入血管等。并采用QLAB分析软件对肿瘤边缘和中心区域及周围正常乳腺组织取样获得时间-强度曲线,分析血流灌注参数指标,包括上升时间(RT)、峰值强度(PI)、达峰时间(TTP)、流入斜率(WIS)、平均渡越时间(MTT)等。将手术或穿刺病理标本进行HE染色利免疫组化染色,以细胞核、细胞膜或细胞浆内出现棕黄色颗粒为阳性标准,对乳腺癌生物预后因子,包括ER、PR、c-erb-B2、p53及Ki-67的表达结果进行判定,同时对肿瘤组织的微血管密度(MVD)进行计数。将超声造影增强特征及血流灌注参数与肿瘤预后因子、MVD结果进行相关性分析。
结果：1.乳腺癌超声造影增强特征：45例乳腺癌造影后除2例(4.4%)无增强外,其余43例(95.6%)均出现不同程度增强。其中25例(55.6%)不均匀增强,14例(31.1%)均匀增强,4例(8.9%)周边增强。27例(60%)有血流灌注缺损；37例(82.2%)增强形态不规则；25例(55.6%)向心性增强；32例(71.1%)有穿支血管；34例(75.6%)增强边界不清晰。
2.乳腺癌造影血流灌注参数分析：45例乳腺癌2例无增强外,43例(95.6%)造影时间-强度曲线表现为“快进快出”型或“快进慢出”型。肿瘤组织与周围正常乳腺组织相比,RT、TTP缩短,PI增高,WIS增大,差异有统计学意义(P<0.05)；肿瘤边缘与肿瘤中心区域相比,TTP缩短,PI增高, WIS增大,差异有统计学意义(P<0.05)；肿瘤直径≤2.Ocm和直径>2.Ocm两组血流灌注参数比较,差异无统计学意义(P>0.05)。
3.乳腺癌造影增强特征与肿瘤预后因子相关性：不均匀增强多存在于直径>2cm肿瘤内；向心性增强多发生在ER阴性肿瘤内；穿支血管在组织学分级高、直径>2cm肿瘤内多见；血流灌注缺损常见于ER阴性、c-erb-B2阳性、Ki-67阳性及直径>2cm肿瘤内。以血流灌注缺损判断ER表达的灵敏性为86.7%,特异性为53.3%,约登指数为40%；判断Ki-67表达的灵敏性为78.2%,特异性为59.1%,约登指数为37.3%。肿瘤增强形态及增强边界与预后因子的表达无明显相关(P>0.05)。
4.乳腺癌造影表现与肿瘤MVD相关性：肿瘤不均匀增强、血流灌注缺损均与高MVD有关(P<0.05)；肿瘤增强形态、增强边界及穿支血管与MVD无明显相关(P>0.05)。高MVD组PI大于低MVD组,两组差异有统计学意义(P<0.05)。而RT、TTP及WIS两组间差异无统计学意义(P>0.05)。
结论：1.超声造影不仅可以反映恶性肿瘤的形态学特征,还可以定量评价肿瘤的微循环灌注情况。
2.乳腺癌超声造影的某些增强特征与肿瘤生物预后因子有一定的相关性,可以对肿瘤的浸润、转移进行在体评价,在一定程度上反映了肿瘤的预后。
3.乳腺癌超声造影的某些增强特征及血流灌注参数与MVD有一定的相关性,可以作为评价肿瘤血管生成的依据。
第二部分超声造影在乳腺癌新辅助化疗疗效评估中的应用价值
研究目的：乳腺癌新辅助化疗已成为局部进展期乳腺癌系统治疗的常规方案,它的合理应用迫切需要切实有效的方法来动态监测并及时评价疗效。尽管常规超声已应用于乳腺癌新辅助化疗疗效的评估中,但其对于肿瘤大小测量的准确性一直受到质疑。本研究应用实时超声造影技术观察乳腺癌新辅助化疗前后原发灶的大小变化以及血流灌注参数变化,并与常规超声相比较,探讨超声造影在评估乳腺癌新辅助化疗疗效中的临床应用价值。
研究方法：选取2010年10月至2012年2月间收入我院进行新辅助化疗并最终手术的乳腺浸润性导管癌患者31例,肿瘤最大径22～108mm,平均(43±19)mm。所有患者均在新辅助化疗前经粗针穿刺活检并组织病理学检查证实为乳腺浸润性导管癌(Ⅱ～Ⅲ级)。采用Philips公司IU22超声检查仪,L9-3宽频线阵探头与L5-1探头。超声造影剂为SonoVue (Bracco, Italy)4.8ml,经肘正中静脉弹丸式注入。常规超声确定原发灶的部位,测量肿瘤最大切面相互垂直的两个径线；彩色多普勒观察肿瘤的血流等级；超声造影分析造影前后原发灶大小变化及造影增强强度、血流灌注参数指标,并同时比较化疗前后原发灶大小变化及血流灌注参数变化。31例患者分别于化疗开始前、化疗三个周期结束后进行超声及超声造影检查。
新辅助化疗用药方案：表柔比星(EPI)60mg/m2,第1天静脉滴注；多西他赛(DOC)75mg/m2,第1天静脉滴注。21天为一个周期,应用三个周期。新辅助化疗结束后,所有病人行乳腺全切手术。
结果：1.乳腺癌新辅助化疗前后原发灶大小改变：31例乳腺癌新辅助化疗后25例(80.6%)疗效缓解,4例(12.9%)疗效稳定,2例(6.5%)疾病进展。超声造影增强范围比常规超声测值增大,与手术标本大小显著相关,r值为0.976。常规超声测值小于手术标本,两者差异有显著性(P<0.05)。
2.超声造影评价乳腺癌新辅助化疗前后肿瘤血流灌注改变：常规超声显示化疗后肿瘤血流等级大部分从2-3级降至0-1级；超声造影显示化疗后除2例(6.5%)肿瘤增强强度较化疗前增加外,28例(90.3%)增强强度不同程度降低。有1例(3.2%)化疗前无血流灌注者化疗后内部可见不均匀血流灌注,而其大小化疗前后并无改变。超声造影较常规超声对肿瘤坏死液化区检测更敏感。超声造影显示化疗前可见肿瘤内血流灌注灌注缺损26例(83.9%),化疗后灌注缺损27例(87.1%)。而常规超声在化疗前后肿瘤内均未显示坏死液化区。
3.超声造影时间一强度曲线可以定量观察新辅助化疗前后血流灌注参数改变,常规超声不具备此功能。将化疗前后血流灌注参数进行比较,化疗后肿瘤达峰时间增加,峰值强度降低,流入斜率减小(P<0.05),而上升时间、平均渡越时间化疗前后差异无统计学意义(P>0.05)。
结论：1.超声造影不仅较常规超声更精确测量乳腺癌新辅助化疗前后肿瘤大小改变,而且可以显示肿瘤内部血流灌注缺损的存在,灌注缺损可作为预测化疗反应的重要指标。
2.超声造影可以定性定量评估化疗前后肿瘤内部血流灌注变化,肿瘤血流灌注变化早于肿瘤形态学改变,是判断肿瘤存活的主要指标之一,应用超声造影可以更早期评价和预测乳腺癌新辅助化疗疗效。
Part1
Association of contrast-enhanced ultrasound characteristics with biological prognostic factors and microvessel density in breast cancer
Objective:Breast cancer is a vascular-dependent lesion, and its growth, infiltration and metastasis are closely related to the neovascularization. The development of contrast-enhanced ultrasound (CEUS) technology make it possible to reveal the tumor microcirculation. The aim of the study was to analyse the CEUS enhancement characteristics of invasive ductal carcinoma, and to investigate the association of CEUS enhancement characteristics and blood perfusion parameters with prognostic factors and microvessel density (MVD), which can be helpful to evaluate the tumor angiogenesis and prognosis.
Methods:From October2010to February2012,45consecutive breast cancer patients were studied by CEUS. All patients were diagnosed with invasive ductal carcinoma on the basis of biopsy or surgery results. The tumor size was an average of (30.5±18) mm, ranging from9to86mm. Color Doppler Ultrasound Philips iU22with L9-3and L5-1probes were used in this study. The contrast agent used was SonoVue (Bracco, Italy). All patients accepted an elbow intravenous bolus injection of4.8ml. Breast cancer enhancement characteristics at CEUS imaging, including enhancement pattern, internal homogeneity, perfusion defect, enhancement order, margin, and penetrating vessels was analyzed. QLAB software was used with CEUS imaging to obtain the time-intensity curve of the periphery and inside region of tumor, and blood perfusion parameters (rising time, RT; time to peak, TTP; peak intensity, PI; wash-in slope, WIS; mean transit time, MTT) was evaluated. Pathologic prognostic factors, including estrogen receptor (ER) and progesterone receptor status (PR), c-erb-B2, p53, and Ki-67expression were determined by immunohistochemical staining, which considered positive when membranous or nuclear staining was observed. And the MVD were count. Association of CEUS enhancement characteristics with prognostic factors and MVD results was analyzed.
Results:1. CEUS enhancement characteristics of breast cancer. For2cases (4.4%) without contrast agent perfusion in CEUS imaging, blood perfusion was observed in43cases (95.6%). The45malignancies displayed heterogeneous enhancement in25cases (55.6%), homogeneous enhancement in14cases (31.1%), peripheral enhancement in4cases (8.9%). Local blood perfusion defect was observed in27cases (60%), irregular enhancement shape in37cases (82.2%), centripetal enhancement in25cases (55.6%), penetrating vessels in32cases (71.1%) and poorly-defined margin in34cases (75.6%),
2. CEUS blood perfusion parameters analysis. For2cases (4.4%) without contrast agent perfusion in CEUS imaging, the time-intensity curve of43cases was characterized as ascend rapidly and drop slowly or rapidly. Compared to that of the normal breast tissue, the RT and TTP seem faster (P<0.05), the PI and WIS seem higher in tumor tissues (P<0.05). Compared to that of the inside region of the tumor, TTP seem to be faster, PI and WIS seem higher in tumor periphery region (P<0.05). whereas blood perfusion parameters were no statistical differences in the2groups (≤2cm in diameter and>2cm in diameter)(P>0.05).
3. Association of CEUS enhancement characteristics with prognostic factors. Heterogeneous enhancement was common in larger tumors (>2cm in diameter), and centripetal enhancement was common in negative ER expression. Penetrating vessel was found more often in the higher histologic grade and larger tumors. Perfusion defect was seen in negative ER expression, positive c-erb-B2expression, positive Ki-67expression and larger tumor diameter. The sensitivity, specificity and accuracy of perfusion defect for detection ER expression were86.7%,53.3%, and40%m, respectively. The sensitivity, specificity and accuracy of perfusion defect for detection Ki-67expression were78.2%,59.1%, and37.3%, respectively. The enhancement margin and enhancement shape showed no significant correlation with prognostic factors (P>0.05).
4. Association of CEUS enhancement characteristics with MVD. Heterogeneous enhancement and perfusion defect were found more often in high-MVD group than in low-MVD group (P<0.05), whereas enhancement margin, enhancement shape and penetrating vessel showed no significant correlation with MVD (P>0.05). PI was higher in high-MVD group than that in low-MVD group (P<0.05), whereas the RT, TTP and WIS showed no significant correlation with MVD (P>0.05).
Conclusions:1. CEUS not only evaluate the morphologic features of breast cancer, but also evaluate quantitatively the degree of blood perfusion.
2. Some enhancement characteristics were associated with prognostic factors, which reflect in vivo the infiltration and metastasis of the tumor, and can be helpful to predict the breast caner prognosis.
3. Some enhancement patterns and blood perfusion parameters were associated with MVD, which can be used as a quantitative basis for evaluation of tumor angiogenesis.
Part2
Potential application value of contrast-enhanced ultrasound in neoadjuvant chemotherapy of breast cancer
Objective:Neoadjuvant chemotherapy (NAC) is the conventional treatment of choice for patients with locally advanced breast cancer. The reasonable application of NAC are pressing for a valuable tool to monitor and evaluate the response of breast cancer to neoadjuvant treatment. Although ultrasound (US) has applied to the efficacy evaluation of breast cancer, the accurate measurement of tumor sizes at US is still questioned all the time. The purpose of this study was to investigate the value of contrast-enhanced ultrasound (CEUS) in evaluating the response of breast cancer to NAC by assessing the tumor size changes and blood perfusion changes at CEUS before and after NAC.
Methods:Thirty-one breast cancer patients treated with NAC (from2010.10until2012.02) and ultimately underwent surgery included. All patients were diagnosed with infiltrating ductal carcinoma (stage Ⅱ and Ⅲ) on the basis of results from a percutaneous core needle biopsy. The pre-therapy tumor size (at its longest dimension) was an average of (43±19) mm, ranging from22to108mm. Color Doppler Ultrasound Philips iU22(Philips, Bothell WA, USA) with Philips L9-3and L5-1probes were used in this examination. US was used to determine the site and maximum size of the primary tumor. Color Doppler was used to assess the grade of vascularization. CEUS was used to observe the tumor size changes, enhancement intensity and blood perfusion parameter changes before and after NAC. US and CEUS were performed for the31patients before and after3cycles NAC. The chemotherapy regimen included60mg/m2EPI intravenously (i.v.) on day1and75mg/m2DOC via i.v. on day1; these doses were repeated every21days for a total of3cycles prior to surgery. After completion of chemotherapy, all patients underwent mastectomy.
Results:1. Tumor size changes before and after NAC. After NAC,25patients (80.6%) achieved a PR,4patients (12.9%) maintained a SD state, and2patients (6.5%) showed a PD state. The tumor sizes measured by CEUS were larger than those measured by US, and had high correlation with surgical specimens, with r values of 0.976. The sizes measured by US were smaller than the size of surgical specimens (P <0.05).
2. Tumor blood perfusion changes before and after NAC. After NAC, US revealed the grade of vascularization decreased from the grade of2-3to0-1in most of the case. By comparison, the CEUS images revealed the enhancement intensity decreased in28cases (90.3%), but increased in2cases (6.5%). For one case (3.2%) without contrast agent perfusion in CEUS imaging pre-therapy, heterogeneous perfusion was observed post-therapy, while the tumor size remained stable. CEUS provided a more sensitive detection of the tumor necrosis. CEUS showed local blood perfusion defect in26cases (83.9%) prior to NAC, and27cases (87.1%) after NAC. However, the US did not show any necrosis liquefied areas in all cases before and after NAC.
3. CEUS time-intensity curve analysis observed changes in blood perfusion quantitatively before and after chemotherapy, whereas US could not. After NAC, time to peak increased, peak intensity decreased, and wash-in slope decreased, with statistical differences between the two groups (P<0.05). However, the differences in the rise time and mean transit time were not statistically significant between the two groups (P>0.05).
Conclusions:1. As compared with US, CEUS not only offers a more accurate measurement of the tumor size, but also reveals local blood perfusion defect in the tumor, which is critical for evaluating of breast cancer response to NAC.
2. CEUS permits evaluation of the degree of blood perfusion in tumors qualitatively and quantitatively before and after NAC. Since a change in the tumor blood perfusion occurs earlier than a change in tumor size, which represents an indicator of the tumor survival, CEUS may represent a valuable tool for evaluating the early response of breast cancer to NAC.
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