動(dòng)態(tài)增強(qiáng)磁共振定量分析在常見(jiàn)子宮腫瘤中的應(yīng)用

周微，呂富榮

1 動(dòng)態(tài)增強(qiáng)磁共振定量分析原理

動(dòng)態(tài)增強(qiáng)磁共振(dynamic contrast-enhanced MRI，DCE-MRI)是基于小分子對(duì)比劑在灌注程度和滲透性不同的組織中分布不同而引起信號(hào)變化的原理進(jìn)行成像。所得圖像可以進(jìn)行定性、半定量、定量分析，其中定量分析是經(jīng)過(guò)藥代動(dòng)力學(xué)模型處理后得到可重復(fù)的全定量參數(shù)，可以定量反映靶組織或器官的生理病理特性如血流量、血管滲透性等來(lái)間接反映腫瘤的微循環(huán)特點(diǎn)[1]。其后處理藥代動(dòng)力學(xué)模型多樣，如Tofts雙室模型、Reference region模型、Patlak模型、Exchange模型等。在選擇最適模型時(shí)，要考慮到在假設(shè)理想狀態(tài)下不同部位的組織具有不同的血流特點(diǎn)及對(duì)圖像質(zhì)量、采集時(shí)間及時(shí)間、空間分辨率等諸多因素的要求[2]，盡可能使參數(shù)值可以反映真實(shí)情況。如乳腺癌常選水交換模型，腦腫瘤中一般選擇雙室交換模型。大部分模型需要選取動(dòng)脈輸入函數(shù)，部分不需要。當(dāng)采用一個(gè)基于人群的輸入函數(shù)，可以提高重復(fù)性[3]。定量DCE-MRI常得到如下參數(shù)[2]：容量轉(zhuǎn)運(yùn)常數(shù)(Ktrans，min-1)，是反映單位時(shí)間內(nèi)從血管內(nèi)轉(zhuǎn)移到血管外細(xì)胞外間隙(extravascular extracellular space，EES)的對(duì)比劑的容積，其值于不同狀態(tài)下代表意義不同，當(dāng)血流量較大時(shí)主要反映血管的滲透性，反之則主要反映組織灌注的特點(diǎn)；速率常數(shù)(Kep，min-1)，為對(duì)比劑從EES反滲回到血管內(nèi)的速率常數(shù)；血管外細(xì)胞外間隙容積比(Ve，ml/100 m1)，為對(duì)比劑在EES所占的體積比；血漿容積分?jǐn)?shù)(Vp，ml/100 m1)，為對(duì)比劑在血漿所占的體積比。其中Ve= Ktrans/Kep；Ve+Vp≤1。

2 定量DCE-MRI在常見(jiàn)子宮腫瘤中的應(yīng)用

由于當(dāng)組織發(fā)生病變時(shí)其微血管生理特征也會(huì)改變，尤其是惡性腫瘤，近年來(lái)定量DCE-MRI多用于對(duì)病變定位、常見(jiàn)惡性腫瘤性病變的分期、治療方案的選擇、預(yù)后的判斷及良惡性腫瘤的鑒別[4]。

2.1 宮頸癌

宮頸癌是女性生殖系統(tǒng)中最常見(jiàn)的惡性腫瘤。張慶等[5]發(fā)現(xiàn)宮頸癌Ktrans、Kep及Ve值較正常宮頸顯著升高。Wang[6]證實(shí)宮頸癌組織內(nèi)血管密度(microvessel density，MVD)較正常宮頸組織明顯增高。也有研究顯示宮頸癌Ktrans值與表皮生長(zhǎng)因子(vascular endothelial growth factor，VEGF)、MVD有良好的相關(guān)性[7]。所以可以用定量參數(shù)Ktrans值來(lái)反映腫瘤微血管密度和生長(zhǎng)速度。早期不同類(lèi)型及級(jí)別的宮頸癌其治療方式不一樣，因此對(duì)其正確的分型、分級(jí)與分期十分重要。有人認(rèn)為宮頸腺癌的MVD水平、新生血管及微血管通透性高于鱗癌，張慶等[5]發(fā)現(xiàn)宮頸腺癌的Ktrans值較宮頸鱗癌高，而周星等[8]發(fā)現(xiàn)鱗癌Ktrans值高于腺癌，認(rèn)為鱗癌的MVD較腺癌高。多數(shù)研究均發(fā)現(xiàn)宮頸癌分化程度越低，分期越高，其Ktrans值越大。Qu等[9]提出宮頸癌MVD值隨著臨床分期、分級(jí)的增加而升高。張朝赫等[10]認(rèn)為宮頸鱗癌的Ktrans、Kep、Ve值與腫瘤分期不具有相關(guān)性。周延等[11]認(rèn)為隨著腫瘤級(jí)別增高，MVD和VEGF也增加。Haldorsen等[12]發(fā)現(xiàn)Ki-67和VIII因子可以反映微血管密度的變化，但它們和定量參數(shù)值之間有無(wú)關(guān)系有待研究。

劉偉峰等[13]認(rèn)為DCE-MRI定量參數(shù)可以預(yù)測(cè)宮頸癌放化療敏感度。Ellingsen等[14]認(rèn)為中晚期宮頸癌組織缺氧、放療效果差及生長(zhǎng)轉(zhuǎn)移等可能與低Ktrans值相關(guān)。Park等[15]和Mills等[16]提出在治療前具有較低的Ktrans值和較低的灌注的宮頸癌的放療效果差。Zahra等[17]提出宮頸癌放化療消退率與治療前半定量、定量參數(shù)間明顯相關(guān)。Himoto等[18]用定量DCE評(píng)價(jià)宮頸癌新輔助化療的早期療效發(fā)現(xiàn)治療前宮頸癌組織Ktrans值和Ve值與最初治療后4 w和結(jié)束治療后1個(gè)月腫瘤體積有明顯相關(guān)性。Kim等[19]發(fā)現(xiàn)Ktrans、Ve值在宮頸癌放化療后先升高后下降及治療前Ktrans、Ve值和治療后體積無(wú)明顯相關(guān)。Mills等[16]認(rèn)為Ve值因受到宮頸癌內(nèi)部的囊變壞死水腫等影響而不準(zhǔn)確。Andersen等[20]認(rèn)為定量參數(shù)可以預(yù)測(cè)宮頸癌放化療失敗的風(fēng)險(xiǎn)，并且其療效差可能與腫瘤內(nèi)缺氧有關(guān)。朱志軍等[21]發(fā)現(xiàn)Ⅱ期宮頸癌患者復(fù)發(fā)組較無(wú)復(fù)發(fā)組的Ktrans及Kep值顯著升高。在判斷轉(zhuǎn)移方面，Lollert等[22]發(fā)現(xiàn)，較大的Ktrans值意味著較高的淋巴結(jié)轉(zhuǎn)移風(fēng)險(xiǎn)，且Kep與腫瘤遠(yuǎn)處轉(zhuǎn)移和表皮生長(zhǎng)因子受體(epithelial growth factor receptor，EGFR)的表達(dá)呈正相關(guān)。楊曉棠等[23]認(rèn)為宮頸癌淋巴結(jié)轉(zhuǎn)移的定量參數(shù)值中Ve值敏感性及特異性較高。

周星等[8]認(rèn)為宮頸鱗癌病灶的表觀擴(kuò)散系數(shù)(apparent diffusion coefficient，ADC)值與Ktrans有相關(guān)性，但劉夢(mèng)秋[24]認(rèn)為兩者間不存在相關(guān)性。在人體中，一部分人認(rèn)為ADC值的大小也會(huì)受到組織微循環(huán)灌注的影響[25]。何永紅等[26]對(duì)100例宮頸癌患者和20名健康志愿者行常規(guī)MRI，擴(kuò)散加權(quán)成像(diffusion weighted imaging，DWI)和DCEMRI掃描，發(fā)現(xiàn)Ktrans、Kep和ADCmean聯(lián)合應(yīng)用可以提高宮頸癌的診斷效能。

2.2 子宮內(nèi)膜癌

子宮內(nèi)膜癌為一種來(lái)源于子宮內(nèi)膜的腺體且主要攻擊絕經(jīng)后女性的惡性腫瘤[27]。Haldorsen等[28]對(duì)55例子宮內(nèi)膜癌患者行DCE-MRI檢查及分析得到相關(guān)參數(shù)值如血流量(blood flow，F(xiàn)B)、攝取分?jǐn)?shù)(extraction fraction，EF)、Kep、血容量(blood volume，VB)、Ve、Ktrans等值。結(jié)果發(fā)現(xiàn)子宮內(nèi)膜癌組織的 FB、EF、VB、Ve、滲透率表面積乘積(permeability surface area product，PS)、Ktrans均較正常子宮肌層相應(yīng)值低，他認(rèn)為其中反映腫瘤毛細(xì)血管滲透性的EF、PS、Ktrans值低，可能是由于選擇了具有較內(nèi)膜血供豐富的子宮肌層作為參考組織。在分析子宮內(nèi)膜癌總體預(yù)后中，他認(rèn)為表現(xiàn)為低FB值、高EF值、高毛細(xì)血管通過(guò)時(shí)間值的腫瘤組織因相對(duì)缺氧而容易進(jìn)展、轉(zhuǎn)移及放化療療效差從而影響患者生存期。另外，他也發(fā)現(xiàn)非子宮內(nèi)膜樣腺癌組織FB值和EF值均較子宮內(nèi)膜樣腺癌低，兩者的區(qū)分對(duì)內(nèi)膜癌在選擇治療方案時(shí)尤為重要。郭永梅等[29]發(fā)現(xiàn)Ktrans值、Kep值及Ve值在子宮內(nèi)膜癌高分化、中分化及低分化組間均有差異。

2.3 子宮肉瘤

子宮肉瘤約占所有子宮惡性腫瘤的3%[30]，其惡性程度高、預(yù)后差。有研究者于動(dòng)態(tài)增強(qiáng)上觀察到子宮肉瘤多為形態(tài)不規(guī)則且血流豐富。薛康康等[31]用DWI及DCE-MRI半定量分析鑒別診斷子宮肉瘤與變性子宮肌瘤，發(fā)現(xiàn)兩者的半定量參數(shù)差異有統(tǒng)計(jì)學(xué)意義。而對(duì)于定量分析在子宮肉瘤的研究，國(guó)內(nèi)尚無(wú)報(bào)道。

2.4 子宮肌瘤的分型、診斷及高強(qiáng)度聚焦超聲消融的監(jiān)測(cè)

定量DCE-MRI也可以應(yīng)用于子宮良性腫瘤。子宮肌瘤是好發(fā)于育齡期女性的常見(jiàn)良性腫瘤，40歲以上的女性中其發(fā)病率高達(dá)40%[32]。在診斷及分型上，趙飛飛等[2]收集78個(gè)與患者自身子宮肌層相應(yīng)值進(jìn)行比較的子宮肌瘤的定量參數(shù)值相對(duì)Ktrans、相對(duì)Kep、感興趣組織Kep，發(fā)現(xiàn)子宮肌瘤的參數(shù)值低于肌層且與肌瘤體積、部位無(wú)相關(guān)性。同時(shí)發(fā)現(xiàn)其中T2WI信號(hào)為均勻輕度高信號(hào)的肌瘤最特殊，作者認(rèn)為可能和肌瘤亞型有關(guān)。鄭靜等[33]發(fā)現(xiàn)定量參數(shù)值可以提示肌瘤的病理亞型，其中細(xì)胞型肌瘤的Ktrans、Vp、血漿灌流量(plasma perfusion，PP)高于普通型、退變型肌瘤。Tal等[34]發(fā)現(xiàn)在子宮肌瘤的生成與生長(zhǎng)過(guò)程中，血管內(nèi)皮生長(zhǎng)因子(vascular endothelial growth factor，VEGF)起著重要的作用，可以促進(jìn)其血管的生長(zhǎng)。也有王玉玲等[35]提出，肌瘤的新生血管的形成及其滲透性會(huì)受到VEGF、雌孕激素等的影響。研究[36]表明子宮間質(zhì)腫瘤中雌激素受體介導(dǎo)的相關(guān)信號(hào)傳導(dǎo)通路有重要作用。所以對(duì)于子宮肌瘤定量參數(shù)值與各種生理因子、病理亞型等相關(guān)性可以進(jìn)一步深入研究。

王偉等[37]提出DCE-MRI定量分析可以用于肌瘤高強(qiáng)度聚焦超聲(high intensity focused ultrasound，HIFU)療效的監(jiān)測(cè)。韋超等[38]搜集36例術(shù)前測(cè)量了DCE-MRI定量參數(shù)值[Ktrans、Kep、Ve、Vp、血流量(blood flow，BF)、血容量(blood volume，BV) ]的子宮肌瘤患者信息，以術(shù)后70%的首次體積消融率為界分為H組和L組，發(fā)現(xiàn)術(shù)前Ktrans、BF、BV值越高，首次體積消融率越低，其中BF預(yù)測(cè)效能最好，Ktrans次之。但臨床應(yīng)用中發(fā)現(xiàn)有部分肌瘤的消融效果不好。劉柳恒等[39]收集65例子宮肌瘤患者HIFU術(shù)前的肌瘤本身和子宮肌層的動(dòng)態(tài)增強(qiáng)定量參數(shù)值，分析得出術(shù)前肌瘤Ktrans越高其消融率越低。Kim等[40]認(rèn)為肌瘤內(nèi)部的組織灌注狀態(tài)影響消融效果。Zhao等[41]發(fā)現(xiàn)DCEMRI圖像上子宮肌瘤呈輕度不均勻強(qiáng)化則容易消融，而呈均勻強(qiáng)化的子宮肌瘤消融率較低。同時(shí)部分肌瘤的消融效果欠佳是否和病理亞型相關(guān)還需要進(jìn)一步研究。Kim等[42]通過(guò)多因素回歸分析發(fā)現(xiàn)治療前高Ktrans值是子宮肌瘤HIFU消融治療療效不佳的顯著預(yù)測(cè)因素，其值越高就提示越多的能量被新生血管為主的滲透性部分帶走。對(duì)此他提出用更高的聲能來(lái)消融肌瘤內(nèi)高灌注區(qū)域，在設(shè)置聲能測(cè)試位置時(shí)要考慮到肌瘤內(nèi)部血管分布的非均質(zhì)性。因此Liu等[43]建議結(jié)合T2WI和可以展示血管分布的Ktrans圖對(duì)肌瘤高灌注區(qū)定位和定性。

3 鑒別子宮良、惡性腫瘤

趙飛飛等[2]和郭永梅等[44]用DCE-MRI定量分析子宮良、惡性腫瘤的各個(gè)參數(shù)，發(fā)現(xiàn)病變處Ktrans值均較正常子宮肌層低，子宮惡性病變的Ve值較正常子宮肌層和良性病變低，但他們各自選擇的參考組織不一樣，目前還沒(méi)有研究選擇不同的參考組織是否有差異。孫俊旗等[45]發(fā)現(xiàn)Ktrans、Kep值在宮頸癌、子宮肌瘤、正常宮頸間差異均有統(tǒng)計(jì)學(xué)意義。有人發(fā)現(xiàn)在鑒別子宮良惡性腫瘤中Ktrans值的診斷效能最高。目前還沒(méi)有研究顯示不同子宮惡性腫瘤間Ktrans值是否存在差異。

4 DCE-MRI定量分析的局限與前景

對(duì)于不同的研究對(duì)象即具有不同生理病理特點(diǎn)的組織選擇何種藥代動(dòng)力學(xué)模型來(lái)分析是值得進(jìn)一步研究的。以此建立一個(gè)分析的標(biāo)準(zhǔn)，促進(jìn)研究間的比較。對(duì)于動(dòng)脈輸入函數(shù)的穩(wěn)定性以及在后處理分析中感興趣區(qū)(region of interest，ROI)的選擇與畫(huà)法是否會(huì)影響最終的研究結(jié)果都具有不確定因素。這就需要大數(shù)據(jù)實(shí)驗(yàn)證明何種方法更加客觀準(zhǔn)確。對(duì)于子宮惡性腫瘤而言，其基因的表達(dá)和定量參數(shù)值反映的生物因子如MVD和VEGF之間有無(wú)相關(guān)性也可能成為未來(lái)的研究方向。臨床醫(yī)生制訂個(gè)體化的治療方案還需要結(jié)合其他反映組織結(jié)構(gòu)及功能方面的影像學(xué)圖像來(lái)全面評(píng)價(jià)腫瘤的生物學(xué)特性。所以未來(lái)需要?jiǎng)討B(tài)增強(qiáng)和其他能提供多種病理生理學(xué)及分子生物學(xué)信息的復(fù)合影像。

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