章澤宇, 程紅巖
(第二軍醫大學附屬東方肝膽外科醫院 核醫學科, 上海 201805)
PET/CT在肝細胞癌中的臨床應用及進展
章澤宇, 程紅巖
(第二軍醫大學附屬東方肝膽外科醫院 核醫學科, 上海 201805)
肝細胞癌病死率很高,常規診斷發現時患者多為中晚期。PET/CT作為分子影像的方法之一,已顯現出越來越重要的作用。然而,其也具有一定的局限性,如對高分化肝細胞癌及小肝癌的診斷多為假陰性。因此聯合應用多種示蹤劑可以提高PET/CT顯像對肝細胞癌診斷的靈敏度和特異度。對PET/CT在肝細胞癌的療效評估、復發監測及預后方面的研究進展進行了介紹。
癌, 肝細胞; 放射性示蹤劑; 體層攝影術; 綜述
在最新的2016年美國國立綜合癌癥網絡指南[1]中推薦的用于肝細胞癌(HCC)診斷的影像學技術主要有超聲、CT及MRI動態增強掃描3種方法。雖然CT與MRI對HCC的檢出率較高,但無法對全身腫瘤的侵襲情況與生物學性狀進行評估[2]。
PET/CT作為新型的影像檢查顯像技術,能有效提供解剖及功能學信息,并且一次檢查全身成像,同時兼具PET的高靈敏度和CT精確顯示解剖細節的優點,更有利于腫瘤的定性與分期。目前其在胃腸道腫瘤、肺癌及淋巴瘤等疾病中得到了廣泛應用,在HCC的檢查評估方面也有一定的應用,現就其研究現狀及進展進行文獻復習與綜述。
1.118F標記的脫氧葡萄糖(2-deoxy-2-18F-fluorodeoxglucose,18F-FDG)對HCC診斷的不足之處 目前臨床應用最廣泛的正電子顯像劑是18F-FDG,其作為一種葡萄糖類似物,可以反映腫瘤細胞的葡萄糖代謝過程。18F-FDG在細胞內的濃聚程度主要取決于磷酸化和去磷酸化水平的高低,18F-FDG進入細胞后磷酸化形成6-磷酸-18F-FDG,惡性腫瘤中磷酸酶含量低,去磷酸化水平低,使6-磷酸-18F-FDG不能轉運離開細胞,從而在細胞中沉積[3]。癌細胞惡性程度越高,去磷酸化程度越低,18F-FDG在癌細胞中沉積越多,所以中、低分化HCC通常可表現為18F-FDG濃集,而高分化HCC腫瘤細胞中葡萄糖-6-磷酸酶的活性較高,細胞內18F-FDG代謝含量低,在顯像時不能呈現高代謝,從而導致診斷出現假陰性[4]。此外,一些蛋白的表達上調也與HCC葡萄糖的攝取有著密切關系,HCC腫瘤細胞中存在P-糖蛋白高表達,其具有“藥物泵”的作用,18F-FDG作為這種“藥物泵”作用的底物之一可被泵出細胞外,即通過糖蛋白的泵式調節改變18F-FDG貯存量。以上原因造成部分HCC呈18F-FDG本底或低代謝灶,影響了18F-FDG PET/CT顯像對HCC的檢出靈敏度[5]。因此HCC作為最常見的原發性肝癌,PET/CT診斷的靈敏度僅約為50%~60%[6]。Wu等[7]研究發現18F-FDG診斷分化程度不同的HCC陽性率不同(低分化83.3% vs中等分化73.0% vs高分化35.0%)。有研究[8]顯示對HCC患者進行雙時相18F-FDG PET/CT掃描,有助于提高診斷HCC的靈敏度和準確度。劉東峰等[9]對小肝癌、結節型肝癌、巨塊型肝癌各40例進行雙時相顯像分析,結果顯示52.5%(21/40)的小肝癌、60.0%(24/40)的結節型肝癌及92.5%(37/40)的巨塊型肝癌病灶延遲相標準化攝取值(standard uptake value,SUVmax)較早期相升高,差異有統計學意義。18F-FDG PET/CT雙時相顯像方法簡單,有助于HCC的診斷,但該法在較小的HCC和分化高的HCC診斷方面仍存在不足。因此,近年來11C-乙酸鹽(11C-acetate)、11C-膽堿(11C-choline)等作為新的PET示蹤劑逐漸被應用于臨床,并與18F-FDG聯合應用于高分化HCC的診斷。
1.211C-acetate對HCC的診斷價值11C-acetate在細胞內的濃聚機制尚有爭論。有觀點認為高分化HCC有氧代謝占優勢,11C-acetate主要通過三羧酸循環被腫瘤細胞攝取,反映細胞內的有氧代謝情況[10]。也有觀點認為主要與腫瘤組織中脂肪合成增加有關,腫瘤細胞攝取11C-acetate的量與脂肪合成及磷脂膜形成呈正相關,當腫瘤細胞增殖時,細胞內的脂肪代謝活躍,從而使得11C-acetate在腫瘤組織內濃聚[11]。Ho等[12]通過對39例HCC患者(共55處病灶)聯合應用11C-acetate和18F-FDG進行PET 顯像,11C-acetate顯像對全部病灶檢測的靈敏度為87.3%,而18F-FDG則為47.3%,其中34%的病灶在兩種顯像均有顯示。二者聯合應用對病灶檢測的靈敏度可達100%。11C-acetate顯像可彌補18F-FDG 對高分化HCC顯像的不足,診斷上形成互補。雖然二者聯合應用使得HCC的診斷水平有了明顯的提高,但也有部分研究[13-15]顯示HCC的檢出率仍然受病灶大小的限制。Park等[13]對90例HCC患者(共110處病灶)研究發現,雙示蹤劑聯合顯像的檢出率約為 82.7%。但18F-FDG顯像根據腫瘤的大小(1~2 cm、2~5 cm、≥5 cm)檢測的靈敏度分別為27.2%、47.8%和92.8%,相應的11C-acetate分別為31.8%、78.2%和95.2%。Hwang等[15]對12例HCC患者的研究也得出相似的結果,由于對1~2 cm或更小的病灶檢出率仍較低,故有待于進一步的研究。
1.311C-choline對HCC的診斷價值11C-choline通過參與磷脂的合成,進而參與到腫瘤細胞內的代謝。研究[7,16]顯示11C-choline 與18F-FDG聯合應用大幅度提高了HCC 的診斷率。Wu等[7]入組了76例HCC患者,其中18F-FDG陽性者48例,在28例18F-FDG陰性患者中,11C-choline陽性率為71.4%(20/28);11C-choline檢測高分化HCC患者的陽性率高于18F-FDG(66.7% vs 35.7%),中分化HCC檢測的靈敏度相似(85.7% vs 72.0%,P=0.648)。雙示蹤劑聯合應用較18F-FDG單一顯像診斷的靈敏度由63.1%提高到89.5%(P<0.001)。Chotipanich等[17]研究同樣顯示11C-choline顯像對高分化HCC有更高的檢測率,而對中低分化HCC檢查則18F-FDG顯像更勝一籌。Yamamoto等[18]研究12例HCC患者(共16處病灶),11C-choline顯像的檢測靈敏度略高于18F-FDG(63% vs 50%)。但該研究無高分化HCC患者,且病例數較少,因此11C-choline的顯像價值尚需進一步驗證。吳湖炳等[19]對18例患者,21個18F-FDG PET/CT診斷不明確的HCC病灶,行肝局部11C-choline PET/CT顯像,11C-choline顯像的陽性檢出率為66.7%(14/21)。同時該研究結果顯示11C-choline顯像對直徑<2 cm的小肝癌陽性檢測率高于Park等[13]報道的18F-FDG和11C-acetate單獨顯像的陽性檢測率(27.2%、31.8%),提示11C-choline顯像可能適合小肝癌的檢測。但統計學顯示11C-choline顯像陽性與否和病灶的大小并無明顯的關系。由此認為11C-choline顯像與18F-FDG對診斷高分化HCC及小肝癌有較好的互補作用。綜上,11C-acetate和11C-choline顯像可明顯提高高分化HCC診斷的靈敏度,但由于11C的半衰期較短,故限制了其在臨床上的廣泛應用。
研究[20-21]表明,影響HCC預后的主要因素包括腫瘤的分期、分級及是否根治性切除等。PET/CT可通過測量SUV來反映HCC的代謝活性和分化程度。Cho等[22]對104例HCC患者進行回顧性分析,對HCC患者腫瘤病灶的SUVmax(tumor SUVmax, TSUVmax)與縱隔的SUVmean(mediastinum SUVmean, MSUVmean)比值和腫瘤指標(AFP、AST、腫瘤大小、TNM分期、BCLC分期)的相關性進行研究。結果顯示當TSUVmax/MSUVmean≥3.1時與腫瘤指標顯著相關;且比值≥3.1時,患者的病死率較<3.1時更高(48.1% vs 23.1%,P<0.001)。因此認為TSUVmax/MSUVmean可作為HCC獨立的預后指標,即≥3.1為診斷界值。
Lee等[23]研究發現腫瘤代謝體積與HCC患者的無進展生存期(progression-free survival,PFS)及總生存期(overall survival,OS)有密切的相關性,也可作為獨立的預后評價指標。因此對于經肝動脈化療栓塞術(TACE)后患者預后的評價,18F-FDG PET可提供有價值的信息。Song等[24]對73例TACE術后HCC患者(共91處病灶)進行回顧性分析,根據病灶內碘油的沉積情況(Ⅰ級: ≥60%;Ⅱ級:20%~60%;Ⅲ級:≤20%)分為3組,TSUVmax與肝臟SUVmean(liver SUVmean,LSUVmean)比值以1.65為界值,結果顯示TACE術后TSUVmax/LSUVmean≥1.65時,OS與腫瘤大小、碘油沉積分級及AFP水平明顯相關,但與病理學分級無明顯相關性;TSUVmax/LSUVmean<1.65組患者的OS明顯更長(P=0.024)。故18F-FDG PET/CT可有效評價TACE術后患者的預后,可能有助于決定治療策略。最近Lee等[25]對214例中晚期HCC患者(其中153例行TACE治療,61例聯合放化療)進行了一項回顧性研究,以腫瘤與正常肝臟攝取比(tumor-to-normal liver uptake ratio,TLR)評估兩種治療方式的生存期。多因素分析結果顯示,PFS及OS獨立的預后指標分別是年齡和TLR以及Child-Pugh分級和TLR。當TLR>2.0時,聯合放化療治療患者的PFS及OS優于單獨TACE治療;但≤2.0時兩種治療方式的生存期無明顯差異。由此可以推斷,18F-FDG PET可能有助于中晚期HCC患者治療方式的選擇。
有學者[26-28]認為血管侵犯、腫瘤大小及腫瘤的分化程度等是HCC治療后復發的主要危險因素,其中微血管侵犯(microvascular invasion,MVI)是影響復發及患者預后最關鍵的因素之一。Ahn等[28]通過對51例患者(共78處病灶)的術前MRI圖像和18F-FDG PET/CT表現進行回顧性分析,并評估其與MVI的相關性,當MRI增強上瘤周強化及18F-FDG顯像TSUVmax/LSUVmean≥1.2時,二者均與MVI明顯相關(P值分別為0.016、0.001)。高比值(TSUVmax/LSUVmean≥1.2)及瘤周強化對于MVI的靈敏度及特異度分別為64.3% vs 35.7%、86.7% vs 93.3%,若二者綜合評估則靈敏度及特異度有所提高(78.6% vs 80%)。Hsu等[29]對擬進行活體肝移植的147例HCC患者行18F-FDG PET掃描,結果顯示陽性者發生復發更早,提示FDG陽性是肝移植HCC術后復發的預測指標。單因素分析顯示,存在MVI、FDG高代謝、SUVmax≥4.8及腫瘤與非腫瘤比值≥2.0時預示著無復發生存期較差。高FDG攝取(腫瘤與非腫瘤比值≥2)強烈提示肝移植術后HCC復發率較高。Kim等[30]認為腫瘤代謝活性及代謝體積是肝移植術后HCC復發的有效預測指標,除臨床病理因素,這些指標也對是否行肝移植具有參考價值。
王曉燕等[31]對14例確診的HCC患者進行研究發現,18F-FDG PET/CT顯像聯增強CT可明顯提高診斷率(100% vs 78.6%)。但由于病例數較少,有待于大樣本的深入研究。陳志豐等[32]回顧性分析54例HCC治療后AFP增高患者的18F-FDG PET/CT及增強CT表現,結果顯示,在HCC治療后AFP增高患者中,18F-FDG PET/CT不但能早期診斷肝內腫瘤的殘余復發,并能有效地發現肝外轉移;而且對肝內病灶檢出的靈敏度及準確度明顯優于增強CT。梁英魁等[33]的研究也得出了類似的結果,即18F-FDG PET/CT代謝顯像能夠很好地揭示肝癌患者介入治療后AFP升高的原因,尤其對碘化油沉積較密實而增強CT陰性的患者18F-FDG PET/CT優于增強CT。
雖然PET/CT在HCC的診斷、預后及復發監測等方面得到了廣泛應用,但是18F-FDG對高分化HCC和小肝癌的陽性顯像率較低,而增強CT對小病灶較敏感,因此18F-FDG PET/CT聯合增強CT對小肝癌的臨床應用有待于進一步探討。新型PET示蹤劑11C-acetate及11C-choline逐漸應用于臨床,但由于其半衰期短,尚不能廣泛應用,而僅限于研究和對18F-FDG的補充,故仍需開發半衰期較長的新型示蹤劑用于HCC的檢測。
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引證本文:ZHANG ZY, CHENG HY. Clinical application of positron emission tomography/computed tomography in hepatocellular carcinoma and related research advances[J]. J Clin Hepatol, 2017, 33(7): 1365-1368. (in Chinese) 章澤宇, 程紅巖. PET/CT在肝細胞癌中的臨床應用及進展[J]. 臨床肝膽病雜志, 2017, 33(7): 1365-1368.
(本文編輯:葛 俊)
Clinical application of positron emission tomography/computed tomography in hepatocellular carcinoma and related research advances
ZHANGZeyu,CHENGHongyan.
(DepartmentofNuclearMedicine,EasternHepatobiliarySurgeryHospital,SecondMilitaryMedicalUniversity,Shanghai201805,China)
Hepatocellular carcinoma (HCC) has a high fatality rate and most patients are in advanced stage when diagnosed with routine methods. As a molecular imaging method, positron emission tomography/computed tomography (PET/CT) has become more and more important. However, it also has certain limitations, since it always has false-negative results for well-differentiated HCC and small HCC. Therefore, a combination of various tracers can improve the sensitivity and specificity of PET/CT in the diagnosis of HCC. This article reviews the role of PET/CT in the therapeutic effect evaluation, recurrence monitoring, and prognosis of HCC.
carcinoma, hepatocellular; radioactive tracers; tomography; review
10.3969/j.issn.1001-5256.2017.07.036
2017-02-08;
2017-03-06。
章澤宇(1990-),男,主要從事影像診斷方面的研究。
程紅巖,電子信箱:chengys9304@163.com。
R735.7
A
1001-5256(2017)07-1365-04