恶性淋巴瘤的多模态显像研究进展
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  国际放射医学核医学杂志  2018, Vol. 42 Issue (4): 363-368.  DOI: 10.3760/cma.j.issn.1673-4114.2018.04.014
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王剑杰, 王雪鹃, 蒲朝煜. 恶性淋巴瘤的多模态显像研究进展[J]. 国际放射医学核医学杂志 , 2018, 42(4): 363-368. DOI: 10.3760/cma.j.issn.1673-4114.2018.04.014
Wang Jianjie, Wang Xuejuan, Pu Chaoyu. The research progress of multimodal imaging in malignant lymphoma[J]. Int J Radiat Med Nucl Med, 2018, 42(4): 363-368. DOI: 10.3760/cma.j.issn.1673-4114.2018.04.014

基金项目

首都医学科研发展基金项目(2018-2-1024)

通信作者

蒲朝煜, Email:bashantree@163.com

文章历史

收稿日期:2017-12-29
恶性淋巴瘤的多模态显像研究进展
王剑杰1, 王雪鹃2, 蒲朝煜1     
1. 100039 北京, 武警总医院核医学科;
2. 100142, 北京大学肿瘤医院暨北京肿瘤防治研究所核医学科
摘要:医学影像学技术在肿瘤的临床分期、再分期、疗效评价甚至预后判断中发挥着重要作用,多模态影像技术(如PET/CT和PET/MR)近年来发展的非常迅速。18F-FDG PET/CT已广泛用于亲和18F-FDG的恶性淋巴瘤的初始分期以及疗效评估,治疗期间使用18F-FDG PET/CT评估治疗反应的价值尚不确定,初步的研究认为PET/MR应用于淋巴瘤的分期是可行的。笔者就多模态显像PET/CT、PET/MR在淋巴瘤中的研究现状及进展进行综述。
关键词: 淋巴瘤     正电子发射断层显像术     体层摄影术,X线计算机     多模态显像    
The research progress of multimodal imaging in malignant lymphoma
Wang Jianjie1, Wang Xuejuan2, Pu Chaoyu1     
1. Department of Nuclear Medicine, the General Hospital of Armed Police Force, Beijing 100039, China;
2. Department of Nuclear Medicine, Cancer Hospital of Peking University and Beijing Institute of Oncology and Prevention, Beijing 100142, China
Found programs: Capital Development Fund of Medical Scientific Research (2018-2-1024)
Corresponding author: Pu Chaoyu, Email:bashantree@163.com
Abstract: Medical imaging plays an important role in the clinical staging, restaging, and therapy assessment of tumors and may also serve as prognostic biomarker. Multimodal hybrid imaging technologies, such as PET/CT and recently PET/MR, have been rapidly developed in recent years. PET/CT is often recommended for the initial staging of FDG-avid lymphomas and therapy monitoring. The role of FDG PET/CT for interim therapy evaluation must be determined. Some feasibility studies indicated that using PET/MR for initial lymphoma staging is feasible. FDG PET/MR seemed to offer a comparable diagnostic performance compared with PET/CT. In this article, the research status and progress concerning multimodal hybrid imaging technologies, such as PET/CT and PET/MR, in malignant lymphoma are reviewed.
Key words: Lymphoma     Positron-emission tomography     Tomography, X-ray computed     Multimodal imaging    

医学影像为临床诊断提供了多种模态的医学图像,如B超、CT、MRI和PET等,为了综合解剖结构影像和功能影像的优势,多模态影像融合技术应运而生,它实现了不同模态的影像信息的有机融合和交叉验证,有利于医师全面获取复杂疾病的诊断信息并做出正确的判断。PET/CT作为一种可在细胞与分子水平上对肿瘤进行显像的融合分子影像技术,已经被广泛应用于恶性肿瘤的早期诊断、分期和疗效监测。研究显示,PET/CT检查使大约36.5%的患者的治疗方案发生改变[1]。随着一体化PET/MR成像系统成功应用于临床,多模态成像技术有了新的发展潜力,集代谢、结构和功能成像于一体的数据可由PET/MR一站式实时同步采集完成。初步研究显示,PET/MR在淋巴瘤中的临床应用是可行的,具有与PET/CT可比较的潜在优势。

笔者综述了PET/CT、PET/MR在恶性淋巴瘤中的研究现状及进展,并讨论了目前研究的热点和今后有可能转化于临床的新技术。

1 淋巴瘤及其疗效评估体系和标准 1.1 淋巴瘤概述

淋巴瘤是起源于淋巴结或淋巴组织的一组异质性疾病,包括霍奇金淋巴瘤(Hodgkin lymphoma,HL)和非霍奇金淋巴瘤(non-Hodgkin lymphoma,NHL),不同的组织学类型,其生物学行为和预后有很大差异;相比较而言,HL预后较好,5年生存率为85.3%,NHL预后较差,5年生存率仅69.3%[2];早期诊断和准确分期是提高疗效和远期生存率的关键。

1.2 淋巴瘤分期和疗效评估体系

临床上,淋巴瘤分期的意义在于针对不同病情选择个体化的治疗方案,即区分出可以通过放疗获益的患者和只能接受全身化疗的患者。1989年Colswolds会议推出的Colswolds-Ann Arbor改良分期至今仍被广泛应用于淋巴瘤的病情分期[3],它适用于HL,但对于NHL在判断预后和指导治疗方案上有很大局限性,尤其是惰性淋巴瘤和结外起病为主的NHL类型(如皮肤淋巴瘤、胃肠道淋巴瘤等),国际工作组不推荐使用[4]

CT成像主要用于病情的分期和疗效评估。基于病灶形态学测量的解剖影像在评估淋巴瘤疗效上存在一定的局限性;1999年,欧洲癌症研究与治疗组织第一次把功能影像PET引入到疗效评价中,发表了PET作为疗效评判标准的指南——Cheson标准[5]

目前,淋巴瘤疗效评估方法使用的是2013年提出的Lugano评效标准,它是PET淋巴瘤工作组在Deauville 5点评分系统基础上结合国际工作组(IWG)标准产生的新的评估标准[6],其中5点评分法以纵隔血池和肝脏作为参照,对病灶目测做出定性诊断,评分≥4分判为PET阳性,<4分判为PET阴性;该评估标准流程简单、可操作性强,大大促进了PET/CT在淋巴瘤疗效评估中的应用。Lugano标准对基于PET和CT的判读标准分别进行了定义:对于PET图像,原高代谢淋巴瘤灶,经过系统治疗后PET显像阴性且无新发灶为完全反应;PET阳性但其18F-FDG摄取减低、无新发病灶,可判为部分反应;病灶摄取程度较之前增高或出现新发灶,可判为疾病复发或进展;该评估系统推荐18F-FDG PET/CT作为HL和亲和18F-FDG的NHL治疗前分期的首选,对于非18F-FDG亲和的亚型,仍以增强CT为首选[7]

1.3 淋巴瘤免疫治疗评估标准

肿瘤免疫治疗近年来备受关注,免疫检定点抑制治疗是目前研究的热点之一。在临床试验中按照针对常规化疗方案的Lugano评效标准对免疫治疗效果进行评价,结果发现部分患者出现了假性进展[8]。如何重新界定疾病进展的标准,从而使不同的临床试验结果具有可比性,是研究者面临的挑战。为此,Cheson等[6]在Lugano评效标准基础上提出了淋巴瘤免疫治疗评估标准,该标准就如何正确判断假性进展与真进展进行了界定,即对依据Lugano标准判定为复发或进展的情形进行了重新定义;包括以下情况:(1)治疗12周后首次PET/CT评估疗效,病灶最大垂直直径之和增加≥50%,需要在12周后再次确认疗效;若最大垂直直径之和继续增加≥10%,或单一病灶(≤2.0 cm)最大径线增大0.5 cm,或单一病灶(>2.0 cm)最大径线增大1.0 cm,即可判断为真进展,否则需要4~8周随诊确认。(2)12周后再次评估疗效,测量包含新病灶在内的6个淋巴瘤病灶,若最大垂直直径之和增加≥50%可认为真进展。(3)病灶的18F-FDG摄取增高,但体积无变化,通常为治疗后炎性反应。该标准的意义在于使得假性进展的淋巴瘤患者获得了继续治疗的机会,使其生存获益,同时也为相关临床试验提供了统一的参照依据。

2 PET/CT、PET/MR用于淋巴瘤的治疗前初始分期

既往的研究表明,18F-FDG PET/CT在淋巴瘤的分期中显示出很高的诊断灵敏度和特异度,优于单纯的18F-FDG PET显像及增强CT[9]。修订后的淋巴瘤PET评估标准指出,18F-FDG PET/CT显像适合于HL以及多数侵袭性NHL治疗前的常规分期,尤其是针对HL和弥漫大B细胞淋巴瘤(diffuse large B cell lymphoma, DLBCL)(强力推荐)[10]。基线显像对于定量描述治疗前后18F-FDG摄取的变化非常重要,已有研究表明,PET/CT使15%~20%的患者分期结果发生改变(上调),从而使10%~15%的患者的治疗方案随之改变[11]。然而,一些研究认为增强CT联合应用18F-FDG PET/CT对淋巴瘤治疗评估的价值有限[12]

研究表明,18F-FDG PET/CT对亲和18F-FDG的淋巴瘤骨髓浸润灶有很高的灵敏度,其诊断效能优于骨髓穿刺[13]。对于HL,18F-FDG PET/CT可以取代HL的骨髓活检;对于DLBCL,由于18F-FDG PET/CT可能漏掉小的骨髓浸润灶[14],因此,如果骨髓活检涉及治疗方案的改变,对于PET显像阴性的病例,仍应进行骨髓活检。

关于PET/MR在淋巴瘤初始分期中的应用目前已经有许多报道。Platzek等[15]的研究结果表明使用PET/MR对淋巴瘤分期是可行的,但PET/MR是否可以取代PET/CT,以及功能MRI是否有增益价值,有待于进一步的研究来验证[16]。Afaq等[17]研究显示,PET/MR与PET/CT对病灶的检出具有较高一致性(k=0.979~1.000),二者的SUVmax具有明显相关性。但de Jong等[18]研究发现,磁共振弥散加权成像(diffusion weighted image,DWI)与18F-FDG PET对于DLBCL的分期无明显一致性,但二者对于病变特征的显示有互补作用。然而,就病变的检出而言,单纯的DWI-MRI的诊断效能稍逊于18F-FDG PET[19]。一些研究指出,DWI可导致临床分期过度[20]。Wu等[21]的一个关于18F-FDG PET联合PET/CT及MRI评估恶性淋巴瘤骨髓浸润的荟萃分析指出,与DWI-MRI相比,18F-FDG PET/CT具有更高的灵敏度和特异度,分别为91.6%和90.3%,DWI-MRI为90.3%和75.9%。

尽管MRI可提供高质量的软组织对比图像,其DWI序列可提供病变组织的水分子扩散功能信息,但DWI存在一些固有的缺陷:容易出现伪影,尤其在3T高场条件下,必须同时对扩散加权像和表观扩散系数进行评估。

3 PET/CT、PET/MR在恶性淋巴瘤治疗的早期和中期进行反应评估和判断预后的价值

与单独使用全剂量诊断CT或PET显像相比,18F-FDG PET/CT显像在疾病分期和再分期过程中有明显优势[22]

对于HL,Hutchings等[23]研究发现淋巴瘤的恶性程度与18F-FDG的摄取率呈正相关,治疗间期的18F-FDG PET/CT可把对治疗有响应的患者从无响应的群体中筛选出来。Ferrari等[24]使用Deauville标准的视觉判断法和半定量法(ΔSUVmax)对比研究了HL患者2周期化疗后行18F-FDG PET/CT对于判断预后的价值,结果显示,SUVmax的下降幅度(ΔSUVmax)与无进展生存期直接相关,半定量法有利于检出对治疗反应不佳的高危患者,且可以提高Deauville标准五点评分法的准确率(半定量法与五点评分法准确率分别为90%和70%);研究认为治疗后ΔSUVmax在评估疗效与判断预后方面优于视觉五分法[25],但二者实际应用需根据具体情况进行选择。PET/CT对于预后的价值也取决于疾病的分期、PET/CT显像的时间点以及化疗的方案;目前,使用PET/CT对淋巴瘤治疗中期(化疗3~4周期后)评价治疗反应的意义和时机尚有争议。

对于NHL,尤其DLBCL,研究显示,2~3周期化疗后的18F-FDG PET/CT代谢的变化可反映远期疗效[26];然而,一些新近的研究认为,治疗间期PET/CT检查结果对治疗方案的决策提供不了太大的帮助[27];一种解释是,与靶向治疗药物(如利妥昔单抗)的应用有关,这种药物有细胞毒性效应,从而导致假阳性[28]。对于DLBCL和外周T细胞淋巴瘤,同意推荐进行中期PET评估;对于其他类型的NHL,目前还没有确切的证据证实基于PET显像的中期评估导致的治疗方案修改能够明显地改善患者预后[29]

迄今为止,有关DWI-MRI在早期治疗反应评估中的研究数量很有限[30],但初步的研究显示,化疗后病变组织的表观扩散系数明显增加,可达89%,DWI是一种很有前途的评估早期治疗反应的方法[31]。Wu等[32]的研究显示DWI-MRI与18F-FDG PET/CT在评估早期治疗疗效中有较高的一致性。在早期治疗疗效评估中,目前没有证据表明DWI-MRI能够取代18F-FDG PET/CT的地位。

4 PET/CT、PET/MR在淋巴瘤化疗结束后的疗效评估

18F-FDG PET/CT显像是评估淋巴瘤治疗疗效的重要工具,可以鉴别残存肿块是纤维化还是仍有存活肿瘤组织[33]。Metser等[34]研究发现,基于Deauville标准的视觉判读提示18F-FDG PET/CT评估化疗后残余病灶的灵敏度、特异度和准确率分别为97.2%、92.1%和93.4%。

研究表明,HL患者化疗后的PET/CT结果阴性者极少复发,阴性预测值可达94%~100%;此外,PET/CT检查也有助于提高成本效益比[35]。Cerci等[36]对130例一线化疗后的HL患者进行了PET显像的成本-效益研究,对PET阳性的患者进行再次活检,对PET阴性患者仅随访观察,这一处理策略约降低了19%的再分期花费。Engert等[37]研究指出,对于进展期淋巴瘤,18F-FDG PET/CT的作用之一便是可以筛选出化疗后需要进行放疗的患者。然而,需要注意的是,对不同患者预后价值的评估必须要结合其所使用的化疗方案。对于侵袭性的NHL,18F-FDG PET/CT也有较高的阴性预测值[12]。由于18F-FDG PET/CT对侵袭性NHL的阳性预测值较低,如果计划进行进一步的治疗,活检是必要的[38]

已经有一些实验性研究初步印证了MRI-DWI在淋巴瘤疗效评价中的可行性[39]。Maggialetti等[40]研究显示,对于HL和侵袭性的NHL患者,全身MRI-DWI是一种适合于进行恶性淋巴瘤化疗后疗效评估的方法,且与传统的18F-FDG PET/CT评估结果比较,二者具有较好的一致性(K=0.824),其特异度和准确率可达91%和72%。Lin等[41]的研究结果显示,与基线MRI-DWI比较,残余淋巴结病灶的表观扩散系数值显著增加。

5 PET/CT、PET/MR用于淋巴瘤的复发监测

虽然既往有研究表明18F-FDG PET/CT有助于检出复发的病灶[42],但是没有足够证据表明PET/CT可作为淋巴瘤随访监测的常规手段,目前,CT仍是最为普遍的随访检查方式。但有以下情形时,推荐使用18F-FDG PET/CT评估病情:(1)通过常规检查及临床资料发现有明确或可疑的复发时;(2)治疗后再次复发,尤其高度可疑转化为侵袭性更强的类型时;(3)持续存在的病灶难以定性时。有关PET/MR在淋巴瘤复发监测中的初步研究显示,用PET/MR检测淋巴瘤的复发灶是可行的,有潜在的应用价值[43]

6 非18F-FDG显像剂的PET在恶性淋巴瘤中的应用

随着新示踪剂的出现,PET为淋巴瘤成像提供了新的有潜在价值的成像参数。使用18F-FDG作为显像剂有很多的局限性,Dhilly等[44]介绍了一种新的示踪剂18F标记的嘌呤类似物(18F-fludarabine),这种核素与其他药物联合使用可治疗惰性淋巴瘤,在临床前的研究中,18F-fludarabine可被荷淋巴瘤的小鼠迅速摄取,显像效果优于18F-FDG。此外,Mena等[45]研究显示,3-脱氧-3-18F-氟代胸腺嘧啶核苷(3-deoxy-3-fluorothymidine,18F-FLT)作为细胞增殖的标志物,在鉴别治疗后的炎症和肿瘤残余方面似乎要优于18F-FDG,18F-FLT的特异性更高。临床前研究和试验性研究显示,18F-FLT在预测无进展生存期和患者的总体生存期上有较好的表现[46]

7 展望与小结

显而易见,多模态分子影像技术已经在肿瘤的研究与临床治疗中显示出强大的生命力,拥有广阔的应用前景。但多模态分子影像技术尚有诸多问题需要解决,包括:如何开发出更多安全可靠的新型分子探针;如何加速分子探针从科研向临床的转化;如何科学合理地解读多模态影像[47]

现阶段临床上用来评估淋巴瘤疗效最好的工具仍是18F-FDG PET/CT,淋巴瘤国际工作组已经将18F-FDG PET/CT纳入到淋巴瘤的诊断和治疗评估工作流程中。对PET/MR来说,虽然初步的研究显示其在淋巴瘤疗效评估方面是可行的,但鉴于目前还缺乏大规模的前瞻性研究,其具体的临床价值尚未明确。MRI在显示淋巴瘤的软组织及中枢神经系统浸润方面具有不可替代的优势,这也可能成为未来PET/MR的一个重点应用领域。

利益冲突 本研究由署名作者按以下贡献声明独立开展,不涉及任何利益冲突。

作者贡献声明 王剑杰负责论文的选题,素材的搜集、整理、分析,论文的起草和撰写;王雪鹃负责文章的整体结构布局,并对论述的重点提出了重要建设性意见;蒲朝煜负责论文的校对、审核和润色。

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