肝癌成像机制

1,肝癌成像机制,Yang Xuan December, 2014,HCC的发生,HCC发病率居恶性肿瘤第5位，约70-80%发生于肝硬化患者。HCC发生的危险因素包括：肝硬化的原因、肝硬化的程度、地域、性别、酗酒、肥胖、血色素沉着症、黄曲霉毒素等。HCC的发生是一个连续的、多步骤的、复杂的去分化过程，人为将其分为几个离散的阶段：硬化结节（也称再生结节）、低级别发育不良结节、高级别发育不良结节、早期肝癌、进展期肝癌,2,HCC的发生,硬化结节（Cirrhotic nodules）肝硬化中无数类圆形边界清楚的被瘢痕组织包绕的肝实质，直径1-15mm。硬化结节的细胞形态及组织结构是正常的。但是在分子水平观察，许多再生结节是由基因组异常的细胞克隆而来，因而它可以进展为发育不良结节。低级别发育不良结节（Low-grade dysplastic nodules）发育不良结节是宏观（大小、颜色、一致性）和微观水平均与正常肝实质不同的结节样病灶，但尚不能诊断为HCC。低级别发育不良结节与硬化结节的主要区别在于出现无伴动脉及克隆样细胞群（富含铜、铁或脂肪的细胞集合）。低级别发育不良结节仅具有较低的恶变率。,3,HCC的发生,高级别发育不良结节（High-grade dysplastic nodules）高级别发育不良结节类似于肝细胞癌同时具有细胞异型性及组织异型性，虽然尚不足以诊断为HCC。高级别发育不良结节具有较高的恶变风险一些高级别发育不良结节内可见高分化或中等分化的HCC，即所谓“结中结”结构。早期肝癌（Early HCCs）典型早期肝癌直径1-1.5cm，大体观为没有明确界限或包膜的模糊的结节。早期肝癌与高级别分化不良结节的关键区别在于基质侵犯早期肝癌的生长方式主要是逐步取代周围肝实质,4,HCC的发生,进展期肝癌（Progressed HCCs）进展期肝癌是具有侵犯血管及远处转移的能力的明显的恶性病灶，其宏观和微观特征多种多样。多灶性肝癌（Multifocal HCCs）在超过1/3的患者中，HCC是多灶性的，定义为肿瘤结节之间存在非肿瘤性肝实质。其成因有2种：1）多个、独立的肿瘤结节同步发生（multicentric hepatocarcinogenesis）2）原发肿瘤肝内多发转移（intrahepatic metastases）,5,肝癌发生过程中关键病理改变,肝癌发生过程中出现了许多病理改变，我们正是依靠这些改变诊断肝癌。血管生成（Angiogenesis）静脉回流（Venous Drainage）肿瘤包膜或纤维分隔（Tumor Capsule and Fibrous Septa） 脂肪成分（Fat Content）铁成分（Iron Conent）有机阴离子转运多肽（OATP）多耐药性相关蛋白（MRPs）,6,血管生成,血管生成主要包括三个方面：“无伴动脉”形成、肝血窦毛细血管化、肝门束消失“无伴动脉”形成“无伴动脉”是在HCC发生过程中形成的无胆管或门静脉伴随的肿瘤动脉。硬化结节内无“无伴动脉”，一些低级别发育不良结节内有少量“无伴动脉”，高级别发育不良结节、早期肝癌、进展期肝癌内“无伴动脉”数量和大小显著增加。肝血窦毛细血管化肝门束消失肝门束包括门静脉和非肿瘤性肝动脉硬化结节及低级别发育不良结节内肝门束正常，高级别发育不良结节、早期肝癌内肝门束减少，进展期肝癌内肝门束基本消失。,7,血管生成,无伴动脉形成与肝门束消失的总和效应低级别发育不良结节动脉及门脉血供与硬化结节相似，故各期增强程度与肝实质类似。高级别发育不良结节及早期HCC动脉、门静脉血供均减少，故动脉期、门脉期强化程度均减低。中分化进展期HCC动脉血流增加，门静脉血流减少，表现为动脉期明显强化，门脉期或延迟期廓清。,8,Figure 1: Hemodynamic and OATP expression changes during multistep hepatocarcinogenesis. Schematic drawing illustrates typical changes in intranodular hemodynamics and OATP expression during multistep hepatocarcinogenesis. As shown, multistep hepatocarcinogenesis is characterized by successive selection and expansion of less-differentiated subnodules within more well differentiatedparent nodules. The subnodules grow and eventually replace (blue arrows) the parent nodules. Progressed HCCs show expansile growth(red arrows) and characteristically are encapsulated with fibrous septa. Earlier nodules lack these structures and show replacing growth. During hepatocarcinogenesis, the density of portal triads diminishes while the density of unpaired arteries increases. The net effect is that intranodular arterial supply diminishes initially and then increases (bottom graph); progressed HCCs typically show arterial hypervascularity compared with background liver, while earlier nodules typically do not. OATP expression usually diminishes progressively (top graph); progressed HCCs, early HCCs, many high-grade dysplastic nodules, and some low-grade dysplastic nodules show OATP underexpression ompared with background liver. The shaded area in each graph represents the window of opportunity to detect nodules at different stages of tumor development based on net arterial flow or OATP expression; window of opportunity is larger and begins at earlier stages for OATP expression. Note that illustrations and graphs reflect typical changes in hemodynamics and OATP expression. Not all nodules exhibit the illustrated characteristics. Also note that during tumor development some stages may be skipped and not allHCCs arise from histologically definable precursor lesions. (Illustration by Matt Skalski, MD; copyright 2014, RSNA.),9,10,Christoph Johannes.Multislice-CT of the abdomen.Springer,静脉回流,HCC发生过程中静脉回流途径的转变经历了：肝静脉（硬化结节、发育不良结节、早期肝癌）肝血窦（无包膜的进展期肝癌）门静脉（有包膜的进展期肝癌）静脉回流的这种转变解释了HCC倾向于侵犯门静脉而非肝静脉由侵犯血管导致的肝内转移卫星灶分布于门静脉引流区域“晕征”富血供进展期肝癌，瘤体强化后数秒，临近肝实质的强化，由于流经瘤体的对比剂进入血窦及门脉引流区所致。,11,肿瘤包膜,肿瘤包膜作为进展期HCC的特征性结构，在约70%的进展期HCC中可以观察到，在硬化结节、发育不良结节、早期HCC中均无肿瘤包膜。肿瘤包膜包括两层结构内层以紧密的纤维组织为主外层以疏松的纤维血管组织为主，内含小的门静脉、胆管及占大多数的血窦。瘤体向周围组织的静脉引流需要跨越包膜的复杂结构。肿瘤包膜形成的结果有完整包膜的进展期HCC手术切除或射频治疗后复发率明显较无完整包膜的进展期HCC低。肿瘤包膜的延迟强化,12,脂肪成分,在肝癌发生的早期，肝细胞可能会集聚脂肪。低级别发育不良结节、高级别发育不良结节、早期HCC会出现局限性或弥漫性脂肪变。肝细胞脂肪变程度的变化早期同去分化程度呈正比，约在直径1.5cm的早期HCC中，弥漫性脂肪变达到峰值。随后随着肿瘤体积和级别的进展，脂肪变逐渐减轻。在3cm的进展期肝癌和低分化肝癌中脂肪变基本消失。肿瘤发生过程中脂肪集聚的机制肿瘤发生过程中一段时间血供减少，肝细胞处于缺血/缺氧环境，处理脂肪能力降低随着无伴动脉的形成，缺血/缺氧环境改善，细胞脂肪变减轻。,13,有机阴离子转运多肽（OATP）,OATP是一组表达于肝细胞血窦面的转运蛋白，其作用为转运胆盐（bile salts）。OATP8是转运人肝细胞特异性对比剂钆赛酸二钠（gadoxetate disodium）和钆贝葡胺的特异性转运蛋白。OATP8在HCC肿瘤发生过程中逐渐消失在硬化结节、低级别发育不良结节表达水平较高；在高级别发育不良结节、早期HCC、进展期HCC表达水平较低OATP8表达水平与HCC级别呈负相关矛盾的是，在5-12%的中等分化HCC和一些高分化HCC中OATP8表达水平升高。,14,OATP & MRPs,多耐药性相关蛋白（MRPs）是表达于肝细胞胆小管面的一组蛋白质，将钆赛酸二钠排泄到胆小管。肝硬化时MRPs表达水平升高。HCC肿瘤发生过程中MRPs表达水平的变化尚不清楚。,15,16,17,HCC的诊断,HCC的诊断主要通过影像学检查，而非活检在肝癌高危人群，通过影像学特征诊断HCC的正确率几乎100%，影像学属于无创检查活检有多种局限性，活检假阴性率较高，不适用于多灶性HCC，有肿瘤种植风险HCC的影像诊断方式包括1）细胞外对比剂增强检查，经过充分证实，现行大多数指南推荐的一线诊断方式2)肝细胞特异性对比剂增强检查，最敏感的发现HCC和癌前病变的检查方式，可靠性需要进一步证实,18,细胞外对比剂增强检查,细胞外对比剂增强检查实现了通过对病灶血供的评价来对HCC进行诊断和分期。由于CT和MR细胞外对比剂增强检查原理相似，故一并讨论。细胞外对比剂增强检查需要获得三个期相：动脉晚期期、门脉期、延迟期HCC的特征性影像学表现为动脉晚期明显强化，门脉期或延迟期廓清,19,动脉晚期明显强化,动脉晚期肝动脉及其分支强化达到顶峰，门静脉出现强化，肝静脉无强化。HCC动脉期明显强化或“富血供”定义为瘤体强化程度确切地高于周围肝实质。肝门束的逐步消失与无伴动脉形成的净效应构成了动脉期明显强化的病理基础。多数硬化结节、发育不良结节或早期HCC动脉期呈低或等强化；多数进展期HCC表现为明显强化。动脉期明显强化是HCC的特征性表现，但并非特异性表现小的ICCs、富血供转移瘤、小血管瘤等亦可出现动脉期明显强化,20,廓清效应,“廓清效应”定义为门脉期或延迟期视觉可见的瘤体强化程度较肝实质低。廓清效应可能在延迟期比门脉期更明显；在部分病灶，廓清效应只在延迟期显现。HCC廓清效应的机制尚不明确，可能由一些并存的因素共同导致1) 病灶内对比剂随静脉迅速回流2) 肝实质的逐渐强化3）病灶内门脉血供的减少4）结节固有的低密度/低信号廓清效应是HCC的特征性表现，但并非特异性表现硬化结节、发育不良结节等也可出现廓清,21,Figure 2: Images in a 51-year-old man with HCC and hepatitis Brelated cirrhosis: multiphasic CT technique. (a) There is no discernible lesion on precontrast CT image. (b) Late hepatic arterial phase image shows heterogeneously hyperenhancing mass with mosaic architecture in segment VIII. Notice enhancement of hepatic artery and portal vein branches in late hepatic arterial phase. Hepatic veins are not enhanced. (c, d) Relative to liver, mass de-enhances on (c) portal venous and (d) 3-minute delayed phase images to become isoattenuating with background parenchyma. Mass has capsule appearance in venous phases, shown to best advantage in delayed phase. Notice that hepatic veins are enhanced in portal venous and delayed phases. (e) Gross pathology photograph of resected specimen confirms progressed, encapsulated HCC with expansile growth pattern. Histologic examination showed moderately differentiated tumor (Edmondson grade II). As illustrated inthis case, delayed phase may show capsule appearance more clearly than portal venous phase.,22,动脉期明显强化 & 廓清效应,虽然“动脉期明显强化”和“廓清效应”都不具有HCC诊断特异性，但二者组合在HCC高危人群中却具有极高的特异性。20mm的HCC中，二者组合诊断正确率约为100%10-19mm的HCC中，二者组合诊断正确率约为90%鉴于二者结合的极高特异性，主流临床指南均将其作为一线检查方式。值得注意的是，在非肝癌高危人群中，二者组合并非HCC的特异性表现，鉴别诊断包括：转移瘤、肝细胞腺瘤等。极少数ICC也可出现动脉期明显强化+廓清效应。,23,包膜征（capsule appearance）,包膜征是指门脉期或延迟期瘤体周围光滑的明显强化的边，其强化程度往往随着时间延长而增加，在延迟期较门脉期更易识别。回顾性研究证实，多数包膜征与病理检查中的肿瘤包膜是对应关系。包膜的渐进性强化是由于包膜血管内血流缓慢，对比剂在血管外结缔组织内滞留。包膜征的出现强烈提示HCC的诊断，有的指南规定只要出现动脉期明显强化和包膜征，即使没有观察到廓清效应仍然可以诊断为HCC。值得注意的是，约1/4出现包膜征的结节并没有病理学的包膜，而是纤维组织和扩大的血窦组成的假包膜。,24,包膜征,Figure 1: Images in a 69-year-old man with encapsulated progressed HCC. (a) T1-weighted three-dimensional (3D) gradient-echo (GRE) MR image with fat suppression (repetition time msec/ echo time msec, 3.0/1.4; 10 flip angle) obtained in late hepatic arterial phase after administration of gadolinium-based contrast agent shows hyperenhancing mass (arrow) with mosaic architecture in segment VII. (b) Mass is isointense on portal venous phase image with a capsule appearance (arrow). Mosaic architecture and capsule appearance permit confident diagnosis of HCC, even though mass does not appear to wash out to hypointensity relative to liver in portal venous phase. (c) Photograph of gross pathologic specimen confirms progressed HCC with fibrous capsule.,25,细胞外对比剂检查总结,26,细胞外对比剂检查的缺点,最大的缺点是发现病灶的敏感性比较低。只有具有丰富新生血管，表现出动脉期明显强化、廓清效应或包膜征的病灶可以被确切地诊断为HCC。接近40%的HCC无动脉期明显强化，40%-60%较小的HCC不表现出廓清效应或包膜征。,27,肝细胞特异性对比剂检查,28,普美显,莫迪司,肝细胞特异性对比剂检查的应用实现了通过观察肝胆期信号强度评价肝细胞功能。,钆赛酸二钠 & 钆贝葡胺,投入临床的肝细胞特异性对比剂包括钆赛酸二钠和钆贝葡胺二者都是由OATP8摄取入肝细胞，由MRP2排泄入胆小管，由MRP3排泄入肝血窦，故肝细胞和胆道系统均可显影。二者的主要区别在于肝细胞摄取率的不同：钆赛酸二钠（50%）VS 钆贝葡胺（5%），造成：注射钆赛酸二钠后肝胆期肝实质强化达峰时间更早（钆赛酸二钠20min vs 钆贝葡胺13h），强度更高由于钆贝葡胺获得肝胆期图像所需时间过长，故除特殊原因外一般选用钆赛酸二钠检查。,29,肝细胞特异性对比剂MRI检查优势,肝细胞特异性对比剂最重要的优势即是更早发现、诊断早期HCC。早期HCC没有完成血管生成过程，通常表现为等或低强化，难以通过细胞外对比剂检查诊断。如前所述，HCC肿瘤发生过程中OATP8逐渐减少，且发生于血管生成之前，故HCC于肝胆期通常较早表现为低信号。有研究证实，许多动脉期等或低强化、肝胆期低信号结节12个月后进展为富血供HCC，1cm的结节进展的几率更高。动脉期等或低强化、肝胆期低信号结节需要与高级别发育不良结节、少数低级别发育不良结节等鉴别，DWI高信号是有效手段。,30,发现早期HCC,31,早期HCC的诊断,a,b,c,d,e,Images in a 59-year-old man with early HCC and hepatitis Brelated cirrhosis.(a)Gadoxetate disodiumenhanced T1-weighted 3D GRE MR image (2.5/0.9; 11 flip angle) obtained in late hepatic arterial phase shows no definite early enhancement.(b)Transitional phase image obtained at 3 minutes depicts hypointense nodule (arrow).(c)Nodule is not clearly delineated on T2-weighted fat-saturated turbo spin-echo image (3413/88).(d)Nodule (arrow) is hypointense on hepatobiliary phase image acquired 20 minutes after injection.(e)Gross pathologic evaluation of resected specimen reveals small, vaguely nodular HCC (arrow). Histologic examination confirmed well-differentiated early HCC. Early HCCs frequently are isoenhancing relative to liver in arterial phase (incomplete neoarterialization) but seen clearly as hypointense nodules in the hepatobiliary phase (underexpression of OATP transporters). Note motion artifact in the arterial phase.,肝胆期高信号HCC,如前所述，在5-12%的HCC中OATP8表达水平升高，这些HCC肝胆期表现为高信号。病理上，这些HCC多为中等分化，少数为高分化。肝胆期高信号HCC其他支持肝癌诊断的征象有局部区域无对比剂摄取，表现为低信号边缺乏FNH的结构特征（中心瘢痕和放射状纤维分隔）,32,肝胆期高信号HCC,33,a b c d,MR images in a 70-year-old man with HCC show hyperintensity in the hepatobiliary phase.(a)Gadoxetate disodiumenhanced T1-weighted 3D GRE image (2.5/0.9; 11 flip angle) in late hepatic arterial phase shows hyperenhancing mass (arrow) in right posterior liver.(b, c)Relative to liver, mass is slightly hyperintense in(b)portal venous phase and mildly hypointense in(c)transitional phase.(d)In the hepatobiliary phase, mass is hyperintense with hypointense rim, likely representing tumor capsule (arrow). Presence of hypointense rim permits confident diagnosis of HCC despite hyperintensity of lesion. N