周微，呂富榮

1 動態(tài)增強(qiáng)磁共振定量分析原理

動態(tài)增強(qiáng)磁共振(dynamic contrast-enhanced MRI，DCE-MRI)是基于小分子對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)過藥代動力學(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、血管滲透性等來間接反映腫瘤的微循環(huán)特點(diǎn)[1]。其后處理藥代動力學(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)，為對比劑在EES所占的體積比；血漿容積分?jǐn)?shù)(Vp，ml/100 m1)，為對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改變，尤其是惡性腫瘤，近年來定量DCE-MRI多用于對病變定位、常見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值來反映腫瘤微血管密度和生長速度。早期不同類型及級別的宮頸癌其治療方式不一樣，因此對其正確的分型、分級與分期十分重要。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值的大小也會受到組織微循環(huán)灌注的影響[25]。何永紅等[26]對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)血管通過時(shí)間值的腫瘤組織因相對缺氧而容易進(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。而對于定量分析在子宮肉瘤的研究，國內(nèi)尚無報(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

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Ktrans、相對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、部位無相關(guān)性。同時(shí)發(fā)現(xiàn)其中T2WI信號為均勻輕度高信號的肌瘤最特殊，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過程中，血管內(nèi)皮生長因子(vascular endothelial growth factor，VEGF)起著重要的作用，可以促進(jìn)其血管的生長。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)信號傳導(dǎo)通路有重要作用。所以對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。韋超等[38]搜集36例術(shù)前測量了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。對此他提出用更高的聲能來消融肌瘤內(nèi)高灌注區(qū)域，在設(shè)置聲能測試位置時(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

對于不同的研究對象即具有不同生理病理特點(diǎn)的組織選擇何種藥代動力學(xué)模型來分析是值得進(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。對于動脈輸入函數(shù)的穩(wěn)定性以及在后處理分析中感興趣區(qū)(region of interest，ROI)的選擇與畫法是否會影響最終的研究結(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之間有無相關(guān)性也可能成為未來的研究方向。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)圖像來全面評價(jià)腫瘤的生物學(xué)特性。所以未來需要動態(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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