CEUS诊断乳腺癌研究进展

王云月，阮骊韬*，任 予，商 静，党 莹

(1.西安交通大学第一附属医院超声影像科，2.乳腺外科，陕西 西安 710061)

目前，乳腺癌是全球范围内女性最常见的恶性肿瘤[1]，居女性癌症死因的第2位[2]。近年来，北美和欧盟等发达地区国家的乳腺癌死亡率已有所降低，而南美洲、非洲和亚洲欠发达国家乳腺癌的发病率及死亡率仍呈上升趋势，这种差距与后者缺乏乳腺癌早期筛查手段和先进的诊疗方法有关[1,3-4]。尽管乳腺钼靶摄影是首选的乳腺癌筛查方法[5]，但我国女性乳腺致密型居多，影响钼靶摄影的诊断效能。常规超声检查对检出乳腺癌有重要价值，但其特异度较低[6]。CEUS是一种纯血池显像技术，可安全、高效、实时动态地显示脏器及肿瘤内部的微灌注情况[7]，在诊断乳腺癌、检出前哨淋巴结(sentinel lymph node, SLN)[8-10]、评估新辅助化疗疗效[11-12]及辅助乳腺癌靶向治疗[13]等方面的作用逐渐凸显。本文就乳腺癌CEUS特点、CEUS与生物标志物的关系、评价新辅助化疗疗效和辅助前哨淋巴结活检术(sentinel lymph node biopsy, SLNB)等方面的研究进展进行综述。

1 概述

CEUS是通过向周围静脉内注射直径与红细胞相似的气体微泡造影剂，利用气体较强的散射性及与人体组织不同的声学特性，增大血流或病变与相邻组织间的声阻抗差异，从而获得反差较大的声像图。目前我国常用造影剂为SonoVue(声诺维)。CEUS为纯血池显像，其微泡造影剂直径较大(约2.5 μm)，可进入肿瘤微毛细血管，但不能透过血管内皮间隙弥散进入周围组织[14]。

2 乳腺癌CEUS特点

2.1 定性诊断 乳腺癌CEUS多表现为不均匀增强，达峰时呈高增强，病灶范围较增强前扩大，边界不清，边缘模糊呈“蟹足样”或“放射状”[10,15-16]。Liu等[15]认为增强是否均匀、病灶范围有无扩大和增强程度是鉴别乳腺良、恶性病变的重要因素；恶性病变多表现为不均匀、向心性增强，而良性病变多表现为均匀性、离心性增强。Zhao等[17]观察不同大小乳腺癌的增强模式，认为最大径>20 mm的乳腺癌以非均匀性增强模式为主，而直径≤20 mm者以均匀性增强模式为主。另有研究[18]表明，穿支血管常见于高级别肿瘤；根据肿瘤内部充盈缺损诊断乳腺癌的特异度较高[19]。

2.2 定量诊断 采用时间-强度曲线(time-intensity curve, TIC)定量分析法，可获得CEUS定量参数，包括上升时间(rise time, RT)、达峰时间(time to peak, TTP)、峰值强度(peak intensity, PI)、平均渡越时间(mean transit time, MTT)和ROC曲线下面积(area under curve, AUC)等。Ji等[18]研究102例浸润性导管癌，发现浸润性导管癌中，高级别肿瘤(Ⅲ级)的RT和TTP均大于低级别肿瘤(Ⅰ级和Ⅱ级)。Yuan等[20]发现乳腺良恶性病灶间RT、TTP和MTT差异均有统计学意义，良性组和恶性组的RT分别为(16.52±4.15)s和(13.86±3.36)s(P=0.007)，TTP分别为(19.86±4.87)s和(16.52±4.85)s(P=0.009)，MTT分别为(80.55±18.65)s和(65.16±20.28)s (P=0.006)。Zhao等[10]发现PI诊断乳腺癌的AUC为0.919，诊断效能较高。

3 CEUS与乳腺癌生物标志物的关系

随着乳腺癌诊疗模式逐渐转向精准医学，根据乳腺癌分子分型进行精准对症治疗成为研究热点。诸多学者致力于观察CEUS与乳腺癌生物标志物雌激素受体(estrogen receptor， ER)、孕激素受体(progesterone receptor， PR)、人类表皮生长因子受体2(human epidermal growth factor receptor-2， HER-2)、Ki-67等的相关性，以期建立对乳腺癌分子分型的预测模型。

研究[17]发现，CEUS增强后病灶范围增大是ER(+)乳腺癌的独立影响因素[回归系数(B)=1.504，P=0.032]，而穿支血管缺失与ER(-)乳腺癌有关(B=1.396，P=0.022)；ER(-)或PR(-)乳腺癌的肿瘤最大灌注强度(maximum intensity of tumor perfusion， IMAX)高于ER(+)或PR(+)乳腺癌[18]。Ki-67(+)的浸润性导管癌较Ki-67(-)者RT更短、IMAX更高、造影剂廓清速度更慢[18]，灌注缺损也较常见[10]。Her-2(+)与Her-2(-)乳腺癌患者RT、不均匀性增强发生率差异均有统计学意义，这一特点可作为预测Her-2(+)分型的因素[18]。对不同Her-2表达水平的乳腺癌CEUS特点的研究[21]结果表明，HER-2过度表达与造影剂分布、穿支血流、增强后病灶范围增大和灌注缺损有关；且与HER-2(-)组相比，HER-2过表达组TIC上升支斜率(K)更大、PT更短、下降支平坦、造影剂廓清时间延迟及AUC较大，而病灶增强程度和PI与HER-2的表达状态无关。乳腺癌不同CEUS增强模式及量化参数与其生物学标志物的表达状态存在一定关系，提示有望通过影像学手段在分子水平对乳腺癌进行观察，从而达到精准诊断和治疗的目的。

4 CEUS评价乳腺癌新辅助化疗疗效

新辅助化疗是指在乳腺肿瘤手术或放疗前全身应用化疗，以缩小原发灶和(或)转移淋巴结体积，从而达到增加手术机会、保乳或延长患者生存期的治疗方法，现已广泛应用于临床。及时准确评估乳腺癌新辅助化疗的疗效、确定残余肿瘤大小及边界有助于及早调整治疗策略、改善预后[22]，但目前临床缺乏公认的有效评估手段。病理学是评估新辅助化疗的金标准，但存在严重滞后性[23]。MRI是评估肿瘤新辅助化疗疗效的首选方法，但检查费用昂贵、耗时长，且可能高估或低估残余肿瘤范围[24-25]，难以普遍应用于临床。

CEUS可获得肿瘤的宏观和微观信息，评价肿瘤新生血管情况，现已用于评价新辅助化疗疗效。Saracco等[26]发现超声造影剂药物代谢动力学指标改变可反映新辅助化疗后乳腺肿瘤新生血管网的早期改变，区分新辅助化疗后肿瘤纤维化(无增强)与活性残余肿瘤(增强)[27]。新辅助化疗后肿瘤组织CEUS多表现为缓慢强化或无强化，可能是由于新辅助化疗的抗血管作用使病灶内的血液灌注减少、肿瘤内血管内皮生长因子聚集减少、新生血管生成受阻所致[11]。Lee等[27]认为CEUS测量的化疗后肿瘤大小与手术病理所示肿瘤大小的相关性(r=0.75，P<.001)优于MRI与手术病理的相关性(r=0.42，P=0.095)，而在预测乳腺癌病理学完全缓解(pathological complete response, pCR)方面，二者准确率相同，均为75.0%。Amioka等[11]发现CEUS评估乳腺癌新辅助化疗后pCR的敏感度、特异度及准确率分别为95.7%、77.5%及84.1%，高于增强MRI和PET/CT；PI预测乳腺癌新辅助化疗后pCR的最佳临界值为25.65 dB，AUC为0.902(P<0.001)。CEUS联合其他超声技术评估新辅助化疗疗效的效能更佳。Nam等[28]将CEUS与次谐波成像技术结合，利用次谐波辅助压力评估技术(subharmonic aided pressure estimation, SHAPE)评估新辅助化疗对乳腺癌的疗效，化疗后缓解者肿瘤组织的次谐波信号增加幅度大于部分或无缓解者。

5 CEUS辅助SLNB

SLN是指最早接受肿瘤区域淋巴引流和发生肿瘤转移的第一站淋巴结，可反映淋巴引流区域的肿瘤状况，对判断肿瘤分期至关重要。常用SLN检测方法有蓝染法、99mTc标记的放射性同位素法及二者联合应用，但均存在侵袭性和放射性[29]。CEUS实时无创、无辐射、无污染，有望成为临床定位和定性诊断SLN的新方法。

Rautiainen等[30]建立猪黑色素瘤模型，通过皮下注射超声造影剂实时显示SLN和引流淋巴管，认为该方法优于核素淋巴显像。Matsuzawa等[31]通过静脉注射造影剂Sonazoid，发现CEUS诊断乳腺癌腋窝SLN转移的准确率(90.6%)高于增强CT及彩色多普勒超声；经乳晕注射Sonazoid造影剂后行CEUS，其诊断SLN转移的效能与CT淋巴系统造影法及靛蓝胭脂红法相似。一项Meta分析[32]发现CEUS对乳腺癌SLN转移的诊断效能较高，其合并敏感度、特异度、阳性似然比及阴性似然比分别为0.80、0.94、6.28和0.218，诊断比值比为49.10，AUC为0.937，且其准确率不受造影剂(SonoVue)注射方式的影响。研究[9,33]表明，SLNB与腋窝淋巴结清扫术(axillary lymph node dissection, ALND)的诊断准确率相似，且前者创伤小，已成为判断乳腺癌腋窝淋巴结转移情况的首选方法。Shimazu等[34]经乳晕注射Sonazoid，对临床触诊及影像学检查淋巴结阴性的乳腺癌患者行CEUS，结果表明该方法对SLN的检出率为98%(98/100)，与Sever等[35-36]报道的检出率相似；且CEUS与蓝染法、放射性胶体法及二者联合使用诊断SLN转移的符合率为100%，提示CEUS有助于识别SLN并辅助SLNB，可提高术前乳腺癌临床分期的准确率。

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