林志光,王靜
煙臺(tái)傳染病醫(yī)院 超聲醫(yī)學(xué)科,山東煙臺(tái) 264000
超聲造影在肝硬化基礎(chǔ)上不典型增生結(jié)節(jié)鑒別診斷中的研究進(jìn)展
林志光,王靜
煙臺(tái)傳染病醫(yī)院 超聲醫(yī)學(xué)科,山東煙臺(tái) 264000
超聲造影作為近年來不斷發(fā)展的新技術(shù),因其無輻射、無明顯毒副作用、易于操作等優(yōu)點(diǎn),而廣泛應(yīng)用于臨床診斷中,其在肝臟疾病的診斷與鑒別診斷中的作用已得到大家的一致認(rèn)可。本文首先介紹超聲造影的病理基礎(chǔ)及其造影方法,然后將肝硬化基礎(chǔ)上不典型增生結(jié)節(jié)與肝癌及再生結(jié)節(jié)的鑒別診斷中超聲造影的應(yīng)用進(jìn)展進(jìn)行了綜述,主要包括Kupffer期成像、超聲造影以及其他增強(qiáng)影像技術(shù)。文章的最后,說明了超聲造影對(duì)肝硬化基礎(chǔ)上不典型增生結(jié)節(jié)鑒別診斷的重要性。
超聲造影;增生性結(jié)節(jié);肝硬化;鑒別診斷;病理基礎(chǔ)
肝硬化是諸多慢性肝病進(jìn)程中的一個(gè)階段,它是因一種或多種疾病長(zhǎng)期或反復(fù)作用而形成的彌漫性肝損害,在病理組織學(xué)上以廣泛的肝細(xì)胞壞死和殘存肝細(xì)胞結(jié)節(jié)性再生為特征。在多種致癌因子的作用下,肝硬化可經(jīng)過再生結(jié)節(jié)(Regenerative Nodules,RN)、低度不典型增生結(jié)節(jié)(Low Grade Dysplastic Nodules,LGDN)、高度不典型增生結(jié)節(jié)(High Grade Dysplastic Nodules,HGDN)、早期肝癌(Hepatocellular Carcinoma,HCC)4個(gè)階段,最終發(fā)展為典型HCC,甚至是遠(yuǎn)處轉(zhuǎn)移[1-3]。LGDN和HGDN被認(rèn)為是HCC的癌前病變[4],約有63%的HGDN最終發(fā)展為HCC[5]。早期發(fā)現(xiàn)DN并給予適當(dāng)?shù)闹委?,有可能阻斷HCC的發(fā)生,從而降低HCC的發(fā)生率,因此,及時(shí)有效的對(duì)DN做出鑒別診斷具有重要的臨床意義。超聲造影(Contrast-Enhanced Ultrasound,CEUS)作為近年來不斷發(fā)展的新技術(shù)[6-7],能夠?qū)崟r(shí)顯示肝臟結(jié)節(jié)的血流灌注特征,并且它具有無輻射、無明顯毒副作用、易于操作等優(yōu)點(diǎn),所以在肝臟局灶性結(jié)節(jié)(Focal Liver Lesions,F(xiàn)LL)診斷中的作用已得到廣泛認(rèn)可[8-10],本文就近年來有關(guān)CEUS對(duì)肝硬化基礎(chǔ)上DN鑒別診斷的作用進(jìn)行綜述。
眾所周知,HCC的形成是一個(gè)多階段的過程[11-12]。從RN到HCC的進(jìn)展過程中伴隨著兩方面的重要改變[11]。
(1) 進(jìn)行性的細(xì)胞形態(tài)和功能變化。RN一般直徑較小,無明顯的結(jié)構(gòu)異型性,結(jié)節(jié)內(nèi)含正常的肝細(xì)胞及膽小管結(jié)構(gòu),周圍被纖維組織所包繞。DN直徑較RN大,無真正包膜形成,其結(jié)構(gòu)組成與周圍肝組織相比,具有核質(zhì)比有一定程度的增加、條索狀結(jié)構(gòu)更加明顯、細(xì)胞質(zhì)著色增加、假腺體形成等特點(diǎn)。HGDN細(xì)胞異型性程度較LGDN明顯。
(2)結(jié)節(jié)內(nèi)血供的動(dòng)態(tài)變化。一般來說,RN同周圍肝實(shí)質(zhì)血供類似,從LGDN開始,肝動(dòng)脈和門靜脈供血逐漸減少,到HGDN出現(xiàn)異常動(dòng)脈供血,并逐漸增多,最終進(jìn)展至中分化HCC時(shí),完全由異常肝動(dòng)脈供血。其中肝內(nèi)結(jié)節(jié)的血流變化特征,是影像學(xué)上早期發(fā)現(xiàn)和鑒別病變性質(zhì)以及評(píng)估預(yù)后的病理生理基礎(chǔ)。
由于腫瘤新生血管的生成對(duì)肝臟結(jié)節(jié)性質(zhì)的轉(zhuǎn)化和肝癌的持續(xù)生長(zhǎng)都起到了重要作用,而CEUS技術(shù)正是利用RN向HCC進(jìn)展過程中結(jié)節(jié)的血供不斷發(fā)生變化這一特點(diǎn),通過肘靜脈團(tuán)注第二代超聲造影劑(如Sonovue[12]),在低機(jī)械指數(shù)造影模式下,連續(xù)實(shí)時(shí)觀察病灶的動(dòng)態(tài)灌注過程,從而記錄肝臟結(jié)節(jié)在不同時(shí)相的實(shí)時(shí)血流動(dòng)力學(xué)信息及回聲情況,根據(jù)不同性質(zhì)病灶的超聲造影增強(qiáng)模式和特征的差異,對(duì)肝臟局灶性結(jié)節(jié)做出定性診斷,其準(zhǔn)確率高于常規(guī)超聲[13]。
CEUS定性診斷肝臟結(jié)節(jié)須通過3個(gè)時(shí)相的影像表現(xiàn)及變化,綜合分析,3個(gè)時(shí)相分別為:① 動(dòng)脈期:從注射造影劑10~20 s至30~45 s;② 門靜脈期:注射后30~45 s至120 s;③ 延遲期:注射后121 s至微泡消失。
2.1 D N與典型H C C的鑒別診斷
DN屬于HCC的癌前病變,增強(qiáng)表現(xiàn)復(fù)雜多樣,可呈現(xiàn)良性或惡性FLLs的增強(qiáng)模式,與組織的分化程度有關(guān)。通常來說,DN在CEUS中表現(xiàn)為動(dòng)脈期低增強(qiáng),門脈期和延遲期與周圍正常肝實(shí)質(zhì)同步等增強(qiáng)[14]。典型HCC主要由異常動(dòng)脈供血,基本無正常肝動(dòng)脈和門靜脈參與供血。美國(guó)肝病研究協(xié)會(huì)、歐洲肝臟研究協(xié)會(huì)、亞太肝臟研究協(xié)會(huì)和日本肝病協(xié)會(huì)的指南,均推薦動(dòng)脈期高增強(qiáng)伴隨門脈期和延遲期的消退作為典型HCC的增強(qiáng)模式[15],這種影像學(xué)特征對(duì)診斷肝癌具有高度特異性,有研究表明,利用典型HCC的增強(qiáng)模式可得到>95%的陽性預(yù)測(cè)值[16]。通過以上DN和典型HCC在CEUS中不同時(shí)相的增強(qiáng)模式,可將一部分DN和HCC區(qū)別開來。
2.2 D N與不典型H C C的鑒別診斷
不典型HCC多為早期高分化,此時(shí)異常動(dòng)脈供血尚未完全形成,仍存在正常肝動(dòng)脈和門靜脈供血,這種血供特點(diǎn)導(dǎo)致HCC在CEUS中不典型增強(qiáng)模式的出現(xiàn)。Martie等[17]研究表明,69.3%的HCC在CEUS中出現(xiàn)典型增強(qiáng)模式,且結(jié)節(jié)越小,典型增強(qiáng)模式出現(xiàn)的概率越低[17-18]。因此無動(dòng)脈期高增強(qiáng)的結(jié)節(jié)不能完全排除HCC可能,F(xiàn)orner等[19]的研究也證實(shí)了這點(diǎn)。另外,延遲期無消退是不典型增強(qiáng)模式的又一表現(xiàn),正是因?yàn)镠CC不典型增強(qiáng)模式的出現(xiàn)增加了DN與HCC鑒別的難度,DN與不典型HCC的鑒別也一直是我們?cè)谂R床工作中面臨的挑戰(zhàn)。
Giorgio等[20]研究發(fā)現(xiàn),早期HCC在CEUS中多表現(xiàn)為動(dòng)脈期不均勻、網(wǎng)狀的高增強(qiáng)(12/14),其鑒別早期HCC的敏感性和特異性分別為85.7%和96.1%,因此通過動(dòng)脈期血管增強(qiáng)方式的不同,CEUS可準(zhǔn)確的鑒別DN和早期不典型HCC。另外,Shin等[21]研究表明,90.9%(10/11)的EdmondsonⅠ期HCC表現(xiàn)為動(dòng)脈期網(wǎng)狀高增強(qiáng),其與DN的動(dòng)脈期增強(qiáng)方式具有顯著性統(tǒng)計(jì)學(xué)差異(P<0.001)。以上研究結(jié)果均提示我們CEUS能夠?yàn)镈N與不典型HCC的鑒別提供重要依據(jù)。
2.3 K u p f f e r期成像用于鑒別D N與H C C
近年來研究發(fā)現(xiàn),99%的第二代超聲造影劑Sonazoid可以被肝臟網(wǎng)狀內(nèi)皮系統(tǒng)的Kupffer細(xì)胞攝取[22],利用Sonazoid造影劑來進(jìn)行CEUS,不僅可獲得常規(guī)的動(dòng)脈期、門靜脈期和延遲期成像,在注射造影劑10 min后,還可獲得典型的稱之為Kupffer期成像或后血管期成像。由于不同性質(zhì)結(jié)節(jié)其Kupffer細(xì)胞含量是不同的,癌組織中Kupffer細(xì)胞數(shù)量明顯低于非癌組織,且組織分化程度越差,Kupffer細(xì)胞含量越低[23]。正常肝實(shí)質(zhì)和良性結(jié)節(jié)在Kupffer期表現(xiàn)為增強(qiáng),而惡性結(jié)節(jié)因?yàn)楹休^少或無Kupffer細(xì)胞,而表現(xiàn)為造影劑缺失。因此我們可以通過Kupffer期成像,或聯(lián)合血管期成像進(jìn)一步鑒別DN與HCC。
Sugimoto等[24]通過分析不同結(jié)節(jié)的Kupffer期分級(jí)評(píng)分發(fā)現(xiàn),低分化HCC明顯高于中高分化HCC,中低分化HCC明顯高于DN,而高分化HCC和DN的分級(jí)評(píng)分沒有統(tǒng)計(jì)學(xué)差異。Suzuki等[25]研究證實(shí),動(dòng)脈期低增強(qiáng)聯(lián)合Kupffer期等增強(qiáng)用于診斷早期高分化HCC,其敏感性、特異性、陽性預(yù)測(cè)值和陰性預(yù)測(cè)值可分別達(dá)到60.0%、90.9%、85.7%和71.4%,但文章并沒有對(duì)動(dòng)脈期聯(lián)合Kupffer期成像用于鑒別高分化HCC和DN做進(jìn)一步研究。通過以上研究我們不難發(fā)現(xiàn),Kupffer期成像對(duì)鑒別不同分化程度的HCC有一定意義,但其用于鑒別DN和高分化HCC的研究報(bào)道還較少,尚需要進(jìn)一步的研究去證實(shí)。
通過DN和HCC在CEUS中的不同表現(xiàn)可將二者部分區(qū)別開來,然而還有一部分HGDN具有更明顯的組織學(xué)異型性和惡性改變,異常動(dòng)脈供血增多,正常肝動(dòng)脈和門靜脈供血減少,這就導(dǎo)致DN和一部分早期高分化HCC在CEUS中的表現(xiàn)相似。單純通過影像學(xué)檢查不能對(duì)這類結(jié)節(jié)進(jìn)行鑒別,有時(shí)即便利用組織穿刺活檢也未必能明確診斷。在臨床實(shí)踐中,對(duì)于這種診斷不明的DN我們應(yīng)按照HCC進(jìn)行治療,因?yàn)锽orzio等[5]的研究表明約有63%的HGDN可最終發(fā)展為HCC。
一般來說,RN的血供組成同周圍正常肝實(shí)質(zhì)相似,無明顯的異常供血,因此多數(shù)RN在CEUS中與肝實(shí)質(zhì)同時(shí)增強(qiáng),3期均為等增強(qiáng),少數(shù)較大的病灶動(dòng)脈期增強(qiáng)稍晚于肝實(shí)質(zhì),增強(qiáng)水平稍低,門靜脈期及延遲期為等增強(qiáng)。Wu等[26]通過對(duì)102例病理證實(shí)為RN的病灶進(jìn)行CEUS發(fā)現(xiàn),95.1%(97/102)的RN在動(dòng)脈期表現(xiàn)為延遲或同步增強(qiáng),4.9%(5/102)表現(xiàn)為輕微增強(qiáng);26.5%的RN(27/102)在門靜脈期和延遲期表現(xiàn)為消退,73.5%(75/102)表現(xiàn)為無消退。RN和DN作為肝硬化基礎(chǔ)上肝細(xì)胞變性、壞死、再生形成的良性結(jié)節(jié),目前針對(duì)二者進(jìn)行系統(tǒng)鑒別診斷的研究報(bào)道還較少。
Numata等[27]通過分析6例HGDN和13例RN在CEUS中動(dòng)脈期增強(qiáng)模式及血管分布發(fā)現(xiàn),6例HGDN均表現(xiàn)為動(dòng)脈期低增強(qiáng)和周邊型的血管分布;92.3%(12/13)的RN表現(xiàn)為動(dòng)脈期低增強(qiáng)和中央型的血管分布,7.7%(1/13)的RN為高增強(qiáng)伴隨著中央型血管分布。由此得出結(jié)論:在CEUS中動(dòng)脈期表現(xiàn)為中央型血管分布的結(jié)節(jié)可診斷為RN,其診斷的敏感度、特異度和準(zhǔn)確度分別為100%、97.8%和98.0%。雖然本研究證實(shí)CEUS中動(dòng)脈期血管分布特點(diǎn)可用于鑒別DN和RN,但是上述研究中樣本例數(shù)較少,仍需要大規(guī)模研究去證實(shí)其在DN和RN鑒別診斷中的價(jià)值。
另外,劉怡彬等[28]通過對(duì)病理證實(shí)為肝硬化背景下增生結(jié)節(jié)(18例)、不典型增生結(jié)節(jié)(30例)進(jìn)行CEUS發(fā)現(xiàn),增生結(jié)節(jié)造影模式呈三期等增強(qiáng),不典型增生結(jié)節(jié)增強(qiáng)模式較為多樣;造影的定量參數(shù)隨病程進(jìn)展峰值強(qiáng)度逐漸增強(qiáng)、達(dá)峰時(shí)間及平均渡越時(shí)間逐漸縮短,而局部血容量、局部血流量在造影不同時(shí)相呈現(xiàn)不同特點(diǎn)。其中造影模式動(dòng)脈期、延遲期表現(xiàn)、延遲期局部血流量差異有統(tǒng)計(jì)學(xué)意義(P<0.05)。因此通過結(jié)合CEUS三期增強(qiáng)模式及CEUS定量參數(shù),可以為肝硬化基礎(chǔ)上增生結(jié)節(jié)、不典型增生結(jié)節(jié)的鑒別提供依據(jù)。
隨著肝硬化病程的進(jìn)展,DN(尤其是HGDN)的血供組成不斷發(fā)生變化,因此其在CEUS中的表現(xiàn)復(fù)雜多樣,單純依靠CEUS對(duì)所有DN做出鑒別是不可能的,需要結(jié)合其他影像學(xué)檢查來提高鑒別診斷率。近年來的研究表明,MRI對(duì)DN的鑒別診斷是有一定價(jià)值的。Hwang等[29]通過對(duì)53例患者(病理證實(shí)為高中分化HCC 25例、DN 31例)進(jìn)行增強(qiáng)MRI檢查發(fā)現(xiàn),T2加權(quán)、彌散加權(quán)成像高信號(hào)和門靜脈期低信號(hào)對(duì)于鑒別高中分化HCC與DN均具有統(tǒng)計(jì)學(xué)意義(P<0.05),且彌散加權(quán)成像的敏感度高于T2加權(quán)(72.0%對(duì)40.0%)。Li等[30]通過研究證實(shí)磁敏感加權(quán)成像結(jié)合HCC進(jìn)展過程中內(nèi)生鐵含量減少,能夠?yàn)镠CC與DN鑒別提供有價(jià)值的信息。除以上兩篇研究報(bào)道外,還有許多相關(guān)研究也證實(shí)了不同MRI成像技術(shù)在DN鑒別診斷中的重要作用。
CEUS是繼灰階及彩色多普勒超聲之后,超聲成像技術(shù)的又一革命性創(chuàng)新。目前,肝臟CEUS不僅應(yīng)用于肝臟局灶結(jié)節(jié)的定性診斷,在術(shù)中定位、術(shù)后療效評(píng)價(jià)和隨訪觀察等方面也發(fā)揮不可或缺的作用。CEUS檢查操作簡(jiǎn)便,相比CT和MRI具有以下優(yōu)點(diǎn)[30-31]:CEUS劑無輻射、無心臟和肝腎毒性、不良反應(yīng)少,可在一次造影過程中多次注射造影劑,重復(fù)觀察病灶的增強(qiáng)模式;可實(shí)時(shí)動(dòng)態(tài)觀察組織的強(qiáng)化過程,更直觀、有效地反映正常組織和病灶內(nèi)的血流動(dòng)力學(xué)變化;價(jià)格相對(duì)便宜,患者耐受性好。但是CEUS檢查有一定局限性[31-32],造影結(jié)果準(zhǔn)確性依賴于操作者經(jīng)驗(yàn)及熟練程度;另外對(duì)于特殊部位的病灶(比如靠近肝臟膈頂部或距離腹壁較遠(yuǎn)),尤其是肥胖患者,易受呼吸及腸道氣體干擾導(dǎo)致病灶顯示不清;此外一次造影過程很難對(duì)肝臟多發(fā)病灶做出全面評(píng)價(jià)。雖然CEUS在臨床應(yīng)用中有一定局限性,但這些不足之處均可以通過聯(lián)合其他影像學(xué)檢查得以解決。
總之,隨著超聲技術(shù)的逐步發(fā)展及新型超聲造影劑的臨床應(yīng)用,CEUS將為DN的診斷和鑒別診斷提供更多有意義的新途徑。
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本文編輯 王婷
Research Advances of Contrast-Enhanced Ultrasound in Differential Diagnosis of Dysplastic Nodules in Cirrhotic Liver
L I N Z h i-g u a n g, WA N G J i n g
Department of Ultrasound Medicine, Infectious Disease Hospital of Yantai, Yantai Shandong 264000, China
As a constantly developing technology, contrast-enhanced ultrasound (CEUS) is widely used in clinical diagnosis in recent years. There are a lot of advantages of CEUS, such as no radiation, no obvious side effects, easy to operate and so on. The role of CEUS in the diagnosis and differential diagnosis of liver disease have been
unanimous recognition at present. Firstly, the pathological basis and methods of CEUS were introduced in this paper. Then the application progress of CEUS when it was used in the differential diagnosis between dysplastic nodules and hepatocellular carcinoma, regenerative nodules in hepatic cirrhosis was summarized. Thay were Kupffer phase imaging, contrastenhanced ultrasound and other enhancements imaging techniques. These reviews shown that CEUS played an important role in the differential diagnosis of dysplastic nodules in hepatic cirrhosis.
contrast-enhanced ultrasound; dysplastic nodules; cirrhosis; differential diagnosis; pathological basis
R735.7
A
10.3969/j.issn.1674-1633.2017.07.027
1674-1633(2017)07-0097-04
2016-11-21
2016-12-08
林志光,副主任醫(yī)師,主要研究方向?yàn)楦闻K超聲診斷及介入治療。
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