王云月，阮驪韜*，任 予，商 靜，黨 瑩

(1.西安交通大學(xué)第一附屬醫(yī)院超聲影像科，2.乳腺外科，陜西 西安 710061)

目前，乳腺癌是全球范圍內(nèi)女性最常見的惡性腫瘤[1]，居女性癌癥死因的第2位[2]。近年來，北美和歐盟等發(fā)達(dá)地區(qū)國家的乳腺癌死亡率已有所降低，而南美洲、非洲和亞洲欠發(fā)達(dá)國家乳腺癌的發(fā)病率及死亡率仍呈上升趨勢，這種差距與后者缺乏乳腺癌早期篩查手段和先進(jìn)的診療方法有關(guān)[1,3-4]。盡管乳腺鉬靶攝影是首選的乳腺癌篩查方法[5]，但我國女性乳腺致密型居多，影響鉬靶攝影的診斷效能。常規(guī)超聲檢查對檢出乳腺癌有重要價值，但其特異度較低[6]。CEUS是一種純血池顯像技術(shù)，可安全、高效、實(shí)時動態(tài)地顯示臟器及腫瘤內(nèi)部的微灌注情況[7]，在診斷乳腺癌、檢出前哨淋巴結(jié)(sentinel lymph node, SLN)[8-10]、評估新輔助化療療效[11-12]及輔助乳腺癌靶向治療[13]等方面的作用逐漸凸顯。本文就乳腺癌CEUS特點(diǎn)、CEUS與生物標(biāo)志物的關(guān)系、評價新輔助化療療效和輔助前哨淋巴結(jié)活檢術(shù)(sentinel lymph node biopsy, SLNB)等方面的研究進(jìn)展進(jìn)行綜述。

1 概述

CEUS是通過向周圍靜脈內(nèi)注射直徑與紅細(xì)胞相似的氣體微泡造影劑，利用氣體較強(qiáng)的散射性及與人體組織不同的聲學(xué)特性，增大血流或病變與相鄰組織間的聲阻抗差異，從而獲得反差較大的聲像圖。目前我國常用造影劑為SonoVue(聲諾維)。CEUS為純血池顯像，其微泡造影劑直徑較大(約2.5 μm)，可進(jìn)入腫瘤微毛細(xì)血管，但不能透過血管內(nèi)皮間隙彌散進(jìn)入周圍組織[14]。

2 乳腺癌CEUS特點(diǎn)

2.1 定性診斷 乳腺癌CEUS多表現(xiàn)為不均勻增強(qiáng)，達(dá)峰時呈高增強(qiáng)，病灶范圍較增強(qiáng)前擴(kuò)大，邊界不清，邊緣模糊呈“蟹足樣”或“放射狀”[10,15-16]。Liu等[15]認(rèn)為增強(qiáng)是否均勻、病灶范圍有無擴(kuò)大和增強(qiáng)程度是鑒別乳腺良、惡性病變的重要因素；惡性病變多表現(xiàn)為不均勻、向心性增強(qiáng)，而良性病變多表現(xiàn)為均勻性、離心性增強(qiáng)。Zhao等[17]觀察不同大小乳腺癌的增強(qiáng)模式，認(rèn)為最大徑>20 mm的乳腺癌以非均勻性增強(qiáng)模式為主，而直徑≤20 mm者以均勻性增強(qiáng)模式為主。另有研究[18]表明，穿支血管常見于高級別腫瘤；根據(jù)腫瘤內(nèi)部充盈缺損診斷乳腺癌的特異度較高[19]。

2.2 定量診斷 采用時間-強(qiáng)度曲線(time-intensity curve, TIC)定量分析法，可獲得CEUS定量參數(shù)，包括上升時間(rise time, RT)、達(dá)峰時間(time to peak, TTP)、峰值強(qiáng)度(peak intensity, PI)、平均渡越時間(mean transit time, MTT)和ROC曲線下面積(area under curve, AUC)等。Ji等[18]研究102例浸潤性導(dǎo)管癌，發(fā)現(xiàn)浸潤性導(dǎo)管癌中，高級別腫瘤(Ⅲ級)的RT和TTP均大于低級別腫瘤(Ⅰ級和Ⅱ級)。Yuan等[20]發(fā)現(xiàn)乳腺良惡性病灶間RT、TTP和MTT差異均有統(tǒng)計學(xué)意義，良性組和惡性組的RT分別為(16.52±4.15)s和(13.86±3.36)s(P=0.007)，TTP分別為(19.86±4.87)s和(16.52±4.85)s(P=0.009)，MTT分別為(80.55±18.65)s和(65.16±20.28)s (P=0.006)。Zhao等[10]發(fā)現(xiàn)PI診斷乳腺癌的AUC為0.919，診斷效能較高。

3 CEUS與乳腺癌生物標(biāo)志物的關(guān)系

隨著乳腺癌診療模式逐漸轉(zhuǎn)向精準(zhǔn)醫(yī)學(xué)，根據(jù)乳腺癌分子分型進(jìn)行精準(zhǔn)對癥治療成為研究熱點(diǎn)。諸多學(xué)者致力于觀察CEUS與乳腺癌生物標(biāo)志物雌激素受體(estrogen receptor， ER)、孕激素受體(progesterone receptor， PR)、人類表皮生長因子受體2(human epidermal growth factor receptor-2， HER-2)、Ki-67等的相關(guān)性，以期建立對乳腺癌分子分型的預(yù)測模型。

研究[17]發(fā)現(xiàn)，CEUS增強(qiáng)后病灶范圍增大是ER(+)乳腺癌的獨(dú)立影響因素[回歸系數(shù)(B)=1.504，P=0.032]，而穿支血管缺失與ER(-)乳腺癌有關(guān)(B=1.396，P=0.022)；ER(-)或PR(-)乳腺癌的腫瘤最大灌注強(qiáng)度(maximum intensity of tumor perfusion， IMAX)高于ER(+)或PR(+)乳腺癌[18]。Ki-67(+)的浸潤性導(dǎo)管癌較Ki-67(-)者RT更短、IMAX更高、造影劑廓清速度更慢[18]，灌注缺損也較常見[10]。Her-2(+)與Her-2(-)乳腺癌患者RT、不均勻性增強(qiáng)發(fā)生率差異均有統(tǒng)計學(xué)意義，這一特點(diǎn)可作為預(yù)測Her-2(+)分型的因素[18]。對不同Her-2表達(dá)水平的乳腺癌CEUS特點(diǎn)的研究[21]結(jié)果表明，HER-2過度表達(dá)與造影劑分布、穿支血流、增強(qiáng)后病灶范圍增大和灌注缺損有關(guān)；且與HER-2(-)組相比，HER-2過表達(dá)組TIC上升支斜率(K)更大、PT更短、下降支平坦、造影劑廓清時間延遲及AUC較大，而病灶增強(qiáng)程度和PI與HER-2的表達(dá)狀態(tài)無關(guān)。乳腺癌不同CEUS增強(qiáng)模式及量化參數(shù)與其生物學(xué)標(biāo)志物的表達(dá)狀態(tài)存在一定關(guān)系，提示有望通過影像學(xué)手段在分子水平對乳腺癌進(jìn)行觀察，從而達(dá)到精準(zhǔn)診斷和治療的目的。

4 CEUS評價乳腺癌新輔助化療療效

新輔助化療是指在乳腺腫瘤手術(shù)或放療前全身應(yīng)用化療，以縮小原發(fā)灶和(或)轉(zhuǎn)移淋巴結(jié)體積，從而達(dá)到增加手術(shù)機(jī)會、保乳或延長患者生存期的治療方法，現(xiàn)已廣泛應(yīng)用于臨床。及時準(zhǔn)確評估乳腺癌新輔助化療的療效、確定殘余腫瘤大小及邊界有助于及早調(diào)整治療策略、改善預(yù)后[22]，但目前臨床缺乏公認(rèn)的有效評估手段。病理學(xué)是評估新輔助化療的金標(biāo)準(zhǔn)，但存在嚴(yán)重滯后性[23]。MRI是評估腫瘤新輔助化療療效的首選方法，但檢查費(fèi)用昂貴、耗時長，且可能高估或低估殘余腫瘤范圍[24-25]，難以普遍應(yīng)用于臨床。

CEUS可獲得腫瘤的宏觀和微觀信息，評價腫瘤新生血管情況，現(xiàn)已用于評價新輔助化療療效。Saracco等[26]發(fā)現(xiàn)超聲造影劑藥物代謝動力學(xué)指標(biāo)改變可反映新輔助化療后乳腺腫瘤新生血管網(wǎng)的早期改變，區(qū)分新輔助化療后腫瘤纖維化(無增強(qiáng))與活性殘余腫瘤(增強(qiáng))[27]。新輔助化療后腫瘤組織CEUS多表現(xiàn)為緩慢強(qiáng)化或無強(qiáng)化，可能是由于新輔助化療的抗血管作用使病灶內(nèi)的血液灌注減少、腫瘤內(nèi)血管內(nèi)皮生長因子聚集減少、新生血管生成受阻所致[11]。Lee等[27]認(rèn)為CEUS測量的化療后腫瘤大小與手術(shù)病理所示腫瘤大小的相關(guān)性(r=0.75，P<.001)優(yōu)于MRI與手術(shù)病理的相關(guān)性(r=0.42，P=0.095)，而在預(yù)測乳腺癌病理學(xué)完全緩解(pathological complete response, pCR)方面，二者準(zhǔn)確率相同，均為75.0%。Amioka等[11]發(fā)現(xiàn)CEUS評估乳腺癌新輔助化療后pCR的敏感度、特異度及準(zhǔn)確率分別為95.7%、77.5%及84.1%，高于增強(qiáng)MRI和PET/CT；PI預(yù)測乳腺癌新輔助化療后pCR的最佳臨界值為25.65 dB，AUC為0.902(P<0.001)。CEUS聯(lián)合其他超聲技術(shù)評估新輔助化療療效的效能更佳。Nam等[28]將CEUS與次諧波成像技術(shù)結(jié)合，利用次諧波輔助壓力評估技術(shù)(subharmonic aided pressure estimation, SHAPE)評估新輔助化療對乳腺癌的療效，化療后緩解者腫瘤組織的次諧波信號增加幅度大于部分或無緩解者。

5 CEUS輔助SLNB

SLN是指最早接受腫瘤區(qū)域淋巴引流和發(fā)生腫瘤轉(zhuǎn)移的第一站淋巴結(jié)，可反映淋巴引流區(qū)域的腫瘤狀況，對判斷腫瘤分期至關(guān)重要。常用SLN檢測方法有藍(lán)染法、99mTc標(biāo)記的放射性同位素法及二者聯(lián)合應(yīng)用，但均存在侵襲性和放射性[29]。CEUS實(shí)時無創(chuàng)、無輻射、無污染，有望成為臨床定位和定性診斷SLN的新方法。

Rautiainen等[30]建立豬黑色素瘤模型，通過皮下注射超聲造影劑實(shí)時顯示SLN和引流淋巴管，認(rèn)為該方法優(yōu)于核素淋巴顯像。Matsuzawa等[31]通過靜脈注射造影劑Sonazoid，發(fā)現(xiàn)CEUS診斷乳腺癌腋窩SLN轉(zhuǎn)移的準(zhǔn)確率(90.6%)高于增強(qiáng)CT及彩色多普勒超聲；經(jīng)乳暈注射Sonazoid造影劑后行CEUS，其診斷SLN轉(zhuǎn)移的效能與CT淋巴系統(tǒng)造影法及靛藍(lán)胭脂紅法相似。一項(xiàng)Meta分析[32]發(fā)現(xiàn)CEUS對乳腺癌SLN轉(zhuǎn)移的診斷效能較高，其合并敏感度、特異度、陽性似然比及陰性似然比分別為0.80、0.94、6.28和0.218，診斷比值比為49.10，AUC為0.937，且其準(zhǔn)確率不受造影劑(SonoVue)注射方式的影響。研究[9,33]表明，SLNB與腋窩淋巴結(jié)清掃術(shù)(axillary lymph node dissection, ALND)的診斷準(zhǔn)確率相似，且前者創(chuàng)傷小，已成為判斷乳腺癌腋窩淋巴結(jié)轉(zhuǎn)移情況的首選方法。Shimazu等[34]經(jīng)乳暈注射Sonazoid，對臨床觸診及影像學(xué)檢查淋巴結(jié)陰性的乳腺癌患者行CEUS，結(jié)果表明該方法對SLN的檢出率為98%(98/100)，與Sever等[35-36]報道的檢出率相似；且CEUS與藍(lán)染法、放射性膠體法及二者聯(lián)合使用診斷SLN轉(zhuǎn)移的符合率為100%，提示CEUS有助于識別SLN并輔助SLNB，可提高術(shù)前乳腺癌臨床分期的準(zhǔn)確率。

[參考文獻(xiàn)]

[1] Harbeck N, Gnant M. Breast cancer. Lancet, 2017,389(10074):1134-1150.

[2] Ferlay J, Soerjomataram I, Dikshit R, et al. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer, 2015,136(5):E359-E386.

[3] Torre LA, Bray F, Siegel RL, et al. Global cancer statistics, 2012. CA Cancer J Clin, 2015,65(2):87-108.

[4] Malvezzi M, Carioli G, Bertuccio P, et al. European cancer mortality predictions for the year 2016 with focus on leukaemias. Ann Oncol, 2016,27(4):725-731.

[5] Fan L, Goss PE, Strasser-Weippl K. Current status and future projections of breast cancer in Asia. Breast Care (Basel), 2015,10(6):372-378.

[6] Meuwly JY. Ultrasound for breast cancer screening: An effective tool in a personalized screening. Praxis (Bern 1994), 2015,104(25):1399-1404.

[7] 何佳，冉海濤.超聲造影在乳腺腫瘤診斷中的應(yīng)用價值.臨床超聲醫(yī)學(xué)雜志,2017，19(7):471-473.

[8] 陜?nèi)?羅佳,梁瑾瑜,等.超聲造影鑒別診斷乳腺良惡性腫瘤.中國醫(yī)學(xué)影像技術(shù),2015,31(7):1045-1048.

[9] 畢世玥,冉海濤,張群霞,等.CEUS聯(lián)合染料法在乳腺癌前哨淋巴結(jié)活檢術(shù)中的應(yīng)用.中國介入影像與治療學(xué),2016,13(3):142-145.

[10] Zhao YX, Liu S, Hu YB, et al. Diagnostic and prognostic values of contrast-enhanced ultrasound in breast cancer: A retrospective study. Onco Targets Ther, 2017,10:1123-1129.

[11] Amioka A, Masumoto N, Gouda N, et al. Ability of contrast-enhanced ultrasonography to determine clinical responses of breast cancer to neoadjuvant chemotherapy. Jpn J Clin Oncol, 2016,46(4):303-309.

[12] 張萌璐,馬步云.乳腺癌新輔助化療前后超聲造影表現(xiàn).中國介入影像與治療學(xué),2015,12(1):52-55.

[13] Jiang Q, Hao S, Xiao X, et al. Production and characterization of a novel long-acting Herceptin-targeted nanobubble contrast agent specific for Her-2-positive breast cancers. Breast Cancer, 2016,23(3):445-455.

[14] Della-Longa S, Arcovito A. Structural and functional insights on folate receptor α (FRα) by homology modeling, ligand docking and molecular dynamics. J Mol Graph Model, 2013,44:197-207.

[15] Liu J, Gao YH, Li DD, et al. Comparative study of contrast-enhanced ultrasound qualitative and quantitative analysis for identifying benign and malignant breast tumor lumps. Asian Pac J Cancer Prev, 2014,15(19):8149-8153.

[16] Wang X, Xu P, Wang Y, et al. Contrast-enhanced ultrasonographic findings of different histopathologic types of breast cancer. Acta Radiol, 2011,52(3):248-255.

[17] Zhao LX, Liu H, Wei Q, et al. Contrast-enhanced ultrasonography features of breast malignancies with different sizes: Correlation with prognostic factors. Biomed Res Int, 2015,2015:613831.

[18] Ji CL, Li XL, He YP, et al. Quantitative parameters of contrast-enhanced ultrasound in breast invasive ductal carcinoma: The correlation with pathological prognostic factors. Clin Hemorheol Microcirc, 2017,66(4):333-345.

[19] Du J, Wang L, Wan CF, et al. Differentiating benign from malignant solid breast lesions: Combined utility of conventional ultrasound and contrast-enhanced ultrasound in comparison with magnetic resonance imaging. Eur J Radiol, 2012,81(12):3890-3899.

[20] Yuan Z, Quan J, Zhang Y, et al. Diagnostic value of contrast-enhanced ultrasound parametric imaging in breast tumors. J Breast Cancer, 2013,16(2):208-213.

[21] Wang XY, Hu Q, Fang MY, et al. The correlation between HER-2 expression and the CEUS and ARFI characteristics of breast cancer. PLoS One, 2017,12(6):e0178692.

[22] von Minckwitz G, Untch M, Blohmer JU, et al. Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol, 2012,30(15):1796-1804.

[23] Fisher ER, Wang J, Bryant J, et al. Pathobiology of preoperative chemotherapy: Findings from the National Surgical Adjuvant Breast and Bowel (NSABP) protocol B-18. Cancer, 2002,95(4):681-695.

[24] Kim HJ, Im YH, Han BK, et al. Accuracy of MRI for estimating residual tumor size after neoadjuvant chemotherapy in locally advanced breast cancer: Relation to response patterns on MRI. Acta Oncol, 2007,46(7):996-1003.

[25] Lobbes M, Prevos R, Smidt M. Response monitoring of breast cancer patients receiving neoadjuvant chemotherapy using breast MRI—a review of current knowledge. Journal of Cancer Therapeutics & Research, 2012,1(1):34.

[26] Saracco A, Szabó BK, Tánczos E, et al. Contrast-enhanced ultrasound (CEUS) in assessing early response among patients with invasive breast cancer undergoing neoadjuvant chemotherapy. Acta Radiol, 2016,58(4):394-402.

[27] Lee SC, Grant E, Sheth P, et al. Accuracy of Contrast-enhanced ultrasound compared with magnetic resonance imaging in assessing the tumor response after neoadjuvant chemotherapy for breast cancer. J Ultrasound Med, 2017,36(5):901-911.

[28] Nam K, Eisenbrey JR, Stanczak M, et al. Monitoring neoadjuvant chemotherapy for breast cancer by using three-dimensional subharmonic aided pressure estimation and imaging with US contrast agents: Preliminary experience. Radiology, 2017,285(1):53-62.

[29] Yamamoto S, Suga K, Maeda K, et al. Breast sentinel lymph node navigation with three-dimensional computed tomography-lymphography: A 12-year study. Breast Cancer, 2016,23(3):456-462.

[30] Rautiainen S, Sudah M, Joukainen S, et al. Contrast-enhanced ultrasound-guided axillary lymph node core biopsy: Diagnostic accuracy in preoperative staging of invasive breast cancer. Eur J Radiol, 2015,84(11):2130-2136.

[31] Matsuzawa F, Omoto K, Einama T, et al. Accurate evaluation of axillary sentinel lymph node metastasis using contrast-enhanced ultrasonography with Sonazoid in breast cancer: A preliminary clinical trial. Springerplus, 2015,4(1):509.

[32] Zhang YX, Wang XM, Kang S, et al. Contrast-enhanced ultrasonography in qualitative diagnosis of sentinel lymph node metastasis in breast cancer: A meta-analysis. J Cancer Res Ther, 2015,11(4):697-703.

[33] Ecanow JS, Abe H, Newstead GM, et al. Axillary staging of breast cancer: What the radiologist should know. Radiographics, 2013,33(6):1589-1612.

[34] Shimazu K, Ito T, Uji K, et al. Identification of sentinel lymph nodes by contrast-enhanced ultrasonography with Sonazoid in patients with breast cancer: A feasibility study in three hospitals. Cancer Med, 2017,6(8):1915-1922.

[35] Sever AR, Mills P, Weeks J, et al. Preoperative needle biopsy of sentinel lymph nodes using intradermal microbubbles and contrast-enhanced ultrasound in patients with breast cancer. AJR Am J Roentgenol, 2012,199(2):465-470.

[36] Cox K, Weeks J, Mills P, et al. Contrast-enhanced ultrasound biopsy of sentinel lymph nodes in patients with breast cancer: Implications for axillary metastases and conservation. Ann Surg Oncol, 2016,23(1):58-64.