CEUS診斷乳腺癌研究進展

王云月，阮驪韜*，任 予，商 靜，黨 瑩

(1.西安交通大學第一附屬醫院超聲影像科，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，北美和歐盟等發達地區國家的乳腺癌死亡率已有所降低，而南美洲、非洲和亞洲欠發達國家乳腺癌的發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的診療方法有關[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，可安全、高效、實時動態地顯示臟器及腫瘤內部的微灌注情況[7]，在診斷乳腺癌、檢出前哨淋巴結(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、CEUS與生物標志物的關系、評價新輔助化療療效和輔助前哨淋巴結活檢術(sentinel lymph node biopsy, SLNB)等方面的研究進展進行綜述。

1 概述

CEUS是通過向周圍靜脈內注射直徑與紅細胞相似的氣體微泡造影劑，利用氣體較強的散射性及與人體組織不同的聲學特性，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)，可進入腫瘤微毛細血管，但不能透過血管內皮間隙彌散進入周圍組織[14]。

2 乳腺癌CEUS特點

2.1 定性診斷 乳腺癌CEUS多表現為不均勻增強，達峰時呈高增強，病灶范圍較增強前擴大，邊界不清，邊緣模糊呈“蟹足樣”或“放射狀”[10,15-16]。Liu等[15]認為增強是否均勻、病灶范圍有無擴大和增強程度是鑒別乳腺良、惡性病變的重要因素；惡性病變多表現為不均勻、向心性增強，而良性病變多表現為均勻性、離心性增強。Zhao等[17]觀察不同大小乳腺癌的增強模式，認為最大徑>20 mm的乳腺癌以非均勻性增強模式為主，而直徑≤20 mm者以均勻性增強模式為主。另有研究[18]表明，穿支血管常見于高級別腫瘤；根據腫瘤內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-強度曲線(time-intensity curve, TIC)定量分析法，可獲得CEUS定量參數，包括上升時間(rise time, RT)、達峰時間(time to peak, TTP)、峰值強度(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例浸潤性導管癌，發現浸潤性導管癌中，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]發現乳腺良惡性病灶間RT、TTP和MTT差異均有統計學意義，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]發現PI診斷乳腺癌的AUC為0.919，診斷效能較高。

3 CEUS與乳腺癌生物標志物的關系

隨著乳腺癌診療模式逐漸轉向精準醫學，根據乳腺癌分子分型進行精準對癥治療成為研究熱點。諸多學者致力于觀察CEUS與乳腺癌生物標志物雌激素受體(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等的相關性，以期建立對乳腺癌分子分型的預測模型。

研究[17]發現，CEUS增強后病灶范圍增大是ER(+)乳腺癌的獨立影響因素[回歸系數(B)=1.504，P=0.032]，而穿支血管缺失與ER(-)乳腺癌有關(B=1.396，P=0.022)；ER(-)或PR(-)乳腺癌的腫瘤最大灌注強度(maximum intensity of tumor perfusion， IMAX)高于ER(+)或PR(+)乳腺癌[18]。Ki-67(+)的浸潤性導管癌較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、不均勻性增強發生率差異均有統計學意義，這一特點可作為預測Her-2(+)分型的因素[18]。對不同Her-2表達水平的乳腺癌CEUS特點的研究[21]結果表明，HER-2過度表達與造影劑分布、穿支血流、增強后病灶范圍增大和灌注缺損有關；且與HER-2(-)組相比，HER-2過表達組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，而病灶增強程度和PI與HER-2的表達狀態無關。乳腺癌不同CEUS增強模式及量化參數與其生物學標志物的表達狀態存在一定關系，提示有望通過影像學手段在分子水平對乳腺癌進行觀察，從而達到精準診斷和治療的目的。

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或放療前全身應用化療，以縮小原發灶和(或)轉移淋巴結體積，從而達到增加手術機會、保乳或延長患者生存期的治療方法，現已廣泛應用于臨床。及時準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整治療策略、改善預后[22]，但目前臨床缺乏公認的有效評估手段。病理學是評估新輔助化療的金標準，但存在嚴重滯后性[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，現已用于評價新輔助化療療效。Saracco等[26]發現超聲造影劑藥物代謝動力學指標改變可反映新輔助化療后乳腺腫瘤新生血管網的早期改變，區分新輔助化療后腫瘤纖維化(無增強)與活性殘余腫瘤(增強)[27]。新輔助化療后腫瘤組織CEUS多表現為緩慢強化或無強化，可能是由于新輔助化療的抗血管作用使病灶內的血液灌注減少、腫瘤內血管內皮生長因子聚集減少、新生血管生成受阻所致[11]。Lee等[27]認為CEUS測量的化療后腫瘤大小與手術病理所示腫瘤大小的相關性(r=0.75，P<.001)優于MRI與手術病理的相關性(r=0.42，P=0.095)，而在預測乳腺癌病理學完全緩解(pathological complete response, pCR)方面，二者準確率相同，均為75.0%。Amioka等[11]發現CEUS評估乳腺癌新輔助化療后pCR的敏感度、特異度及準確率分別為95.7%、77.5%及84.1%，高于增強MRI和PET/CT；PI預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聯合其他超聲技術評估新輔助化療療效的效能更佳。Nam等[28]將CEUS與次諧波成像技術結合，利用次諧波輔助壓力評估技術(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域淋巴引流和發生腫瘤轉移的第一站淋巴結，可反映淋巴引流區域的腫瘤狀況，對判斷腫瘤分期至關重要。常用SLN檢測方法有藍染法、99mTc標記的放射性同位素法及二者聯合應用，但均存在侵襲性和放射性[29]。CEUS實時無創、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時顯示SLN和引流淋巴管，認為該方法優于核素淋巴顯像。Matsuzawa等[31]通過靜脈注射造影劑Sonazoid，發現CEUS診斷乳腺癌腋窩SLN轉移的準確率(90.6%)高于增強CT及彩色多普勒超聲；經乳暈注射Sonazoid造影劑后行CEUS，其診斷SLN轉移的效能與CT淋巴系統造影法及靛藍胭脂紅法相似。一項Meta分析[32]發現CEUS對乳腺癌SLN轉移的診斷效能較高，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與腋窩淋巴結清掃術(axillary lymph node dissection, ALND)的診斷準確率相似，且前者創傷小，已成為判斷乳腺癌腋窩淋巴結轉移情況的首選方法。Shimazu等[34]經乳暈注射Sonazoid，對臨床觸診及影像學檢查淋巴結陰性的乳腺癌患者行CEUS，結果表明該方法對SLN的檢出率為98%(98/100)，與Sever等[35-36]報道的檢出率相似；且CEUS與藍染法、放射性膠體法及二者聯合使用診斷SLN轉移的符合率為100%，提示CEUS有助于識別SLN并輔助SLNB，可提高術前乳腺癌臨床分期的準確率。

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