PET/CT在多发性骨髓瘤中的临床应用及进展

李俊龙; 兰晓莉; 曹国祥

doi:10.3760/cma.j.cn121381-202109016-00150

Volume 46 Issue 3

Jun. 2022

Article Contents

Article Navigation > Int J Radiat Med Nucl Med > 2022, 46 > 3: (168-173)

Citation:

Clinical application and progress of PET/CT in multiple myeloma

Department of Nuclear Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China

Corresponding author: Guoxiang Cao, 623977983@qq.com
Received Date: 2021-09-18

Abstract

Multiple myeloma (MM) is a proliferous plasma cell malignancy. Abnormal proliferation of clonal plasma cells could not only involve skeletal system but also invade extramedullary and cause tissues or organs damage. ¹⁸F-fluorodeoxyglucose (FDG) PET/CT has become one of the most primary imaging methods for condition evaluation of MM by monitoring systemic glucose metabolism. The authors review the clinical application of ¹⁸F-FDG PET/CT in the diagnosis, staging, efficacy evaluation and prognosis prediction of MM, analyze its limitations, also introduce and prospect the application of new molecular probes in MM, in order to improve the clinicians' understanding of the clinical value of PET/CT in the diagnosis and treatment of MM, and further play the essential role of PET/CT in the clinical decision-making of MM.
- Multiple myeloma,
- Positron-emission tomography,
- Tomography, X-ray computed,
- Diagnosis,
- Prognosis,
- Efficacy evaluation

References

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多发性骨髓瘤（multiple myeloma，MM）是一种由浆细胞异常增殖引起的恶性血液疾病，是仅次于非霍奇金淋巴瘤的第2大常见的血液系统恶性肿瘤，约占血液系统恶性肿瘤的10%。MM在中老年人群中的发病率较高，确诊时患者的中位年龄为66岁，只有2%的患者确诊时年龄在40岁以下^[1]。MM以血清或尿液中出现过量的单克隆免疫球蛋白、轻链或重链片段为特征，临床上以高钙血症、肾功能损害、贫血、骨骼损害和感染等为主要表现，前4种表现在临床上被称为“螃蟹标准”（CRAB）。骨病是MM的典型特征，其影像学表现多样，可为弥漫性或局灶性骨浸润、髓外病变（extramedullary disease，EMD）等。

¹⁸F-FDG PET/CT因可显示细胞水平上的葡萄糖代谢情况而成为评估和监测MM病灶代谢变化的首选功能显像方法，且已被纳入国际骨髓瘤工作组（International Myeloma Working Group，IMWG）制定的最新的MM诊断标准中^[2]。相较于其他影像学检查方法，¹⁸F-FDG PET/CT反映的病灶糖摄取变化可帮助临床医师更早地评估治疗反应，并进一步预测预后。¹⁸F-FDG PET/CT还可与灵敏度高的骨髓监测技术联合使用以提高检测骨髓内外的微小残留病（minimal residual disease，MRD）的能力。此外，¹⁸F-FDG PET/CT能够通过对隐匿性溶骨病患者进行监测，从而推测冒烟型MM（smoldering myeloma，SMM）进展为活动性MM的时间；且作为一种全身显像技术，其对疑似髓外浆细胞瘤和孤立性骨浆细胞瘤的初步诊断也有一定价值。我们对PET/CT在MM中的临床应用及进展进行综述，以期提高临床医师对PET/CT在MM诊疗中临床价值的认识，从而进一步发挥PET/CT在MM临床决策中的重要作用。

1. ¹⁸F-FDG PET/CT在MM诊断和分期中的临床应用

¹⁸F-FDG PET/CT在MM的诊断和分期中有重要价值，研究结果表明，¹⁸F-FDG PET/CT对MM患者骨病灶的检出率较高^[3-4]。Mosci等^[5]比较了¹⁸F-FDG PET/CT与⁹⁹Tc^m-MIBISPECT/CT在MM诊断中的效能，发现两者对骨病灶的检出率相近，但前者更倾向于检出局灶性病灶（focal lesions，FLs），后者则在弥漫性骨病变的检出中更有优势。在一项纳入了46例MM患者的前瞻性研究中，患者同时进行了全身MRI和¹⁸F-FDG PET/CT，两者检出骨病灶的灵敏度分别为91.3%、69.6%^[6]。在一项纳入了134例MM患者的前瞻性研究中，91%确诊为MM的患者的¹⁸F-FDG PET/CT结果为阳性，而95%确诊为MM的患者的MRI结果为阳性^[7]。Waheed等^[8]在一项纳入了270例MM患者的回顾性研究中发现，¹⁸F-FDG PET/CT对骨病灶的诊断效能与MRI相当，且均优于全身X射线检查。

MM患者病情的严重程度与骨髓浆细胞的浸润比例高度相关^[9]。Sachpekidis等^[10]在一项纳入了40例MM患者的前瞻性研究中发现，与¹⁸F-FDG PET/CT结果为阳性的患者相比，¹⁸F-FDG PET/CT结果为阴性的患者的骨髓浆细胞浸润比例较低，这表明¹⁸F-FDG PET/CT能在一定程度上反映MM的病情进展。Lecouvet等^[11]在一项回顾性研究中分析了73例MM患者的共84对¹⁸F-FDG PET/CT和MRI图像，结果表明，MRI检测骨髓受累的灵敏度明显高于¹⁸F-FDG PET/CT（97% vs.76%），而MRI检测骨髓受累的特异度低于¹⁸F-FDG PET/CT（86% vs.93%），但差异无统计学意义。

相比于MRI和全身X射线检查，¹⁸F-FDG PET/CT能更早地检出骨质破坏，其联合实验室检查可提供可靠的分期信息，因此¹⁸F-FDG PET/CT或可改变患者的治疗方案，对患者的早期临床决策制定具有重要意义。

2. ¹⁸F-FDG PET/CT在MM预后预测中的临床应用

¹⁸F-FDG PET/CT显示的FLs、SUV_max、EMD、肿瘤代谢体积（metabolic tumor volume，MTV）和糖酵解总量（total lesion glycolysis，TLG）等可能是影响预后的主要因素^[12-16]。

Zamagni等^[12]的一项前瞻性研究分析了192例MM患者的临床资料，患者分别于诊断时、沙利度胺+地塞米松诱导治疗后、自体干细胞移植后进行了¹⁸F-FDG PET/CT显像，结果表明，初诊时¹⁸F-FDG PET/CT显示FLs>3个、SUV_max>4.2且有EMD的患者的无进展生存（progression-free survival，PFS）率和总生存（overall survival，OS）率明显较低，此类患者预后很差；沙利度胺+地塞米松诱导后SUV_max>4.2，且有EMD与较差的预后相关；自体干细胞移植后3个月，¹⁸F-FDG PET/CT结果为阴性的患者的4年PFS率和OS率均高于¹⁸F-FDG PET/CT结果为阳性的患者；对于不能接受自体干细胞移植的患者，FLs、SUV_max和EMD仍然是PFS率和OS率的不良预测因子。Patriarca等^[13]的一项回顾性研究共纳入67例MM患者，其中54例患者在行异基因造血干细胞移植前进行了¹⁸F-FDG PET/CT显像，生存分析结果显示，治疗前EMD的存在可以预测较短的PFS期；59例患者在行异基因造血干细胞移植后半年内进行了¹⁸F-FDGPET/CT显像，结果表明，治疗后EMD持续存在或未达完全缓解的患者的生存情况较差，这意味着在临床上需进一步加强对存在EMD的患者的重视。

近年来，反映肿瘤负荷的MTV和TLG在肿瘤预后研究中的应用日益广泛。吴增杰等^[14]在一项纳入了36例MM患者的回顾性研究中发现，预测PFS期和OS期的MTV最佳临界值分别为114.74、1 065.48 cm³，其能对MM患者的生存情况做出较好的预测。McDonald等^[15]回顾性分析了192例接受全面治疗的MM患者的临床资料，结果显示，TLG>205 g结合基因表达谱（GEP 70）评分能将后者定义的低风险组患者再细化分组，鉴别出原低风险组中生存情况更差的亚组。同时，TLG>205 g也能准确地将国际分期系统（ISS）确定为Ⅱ期的MM患者分为2个亚组，且患者的预后分别与国际分期系统（ISS）确定为Ⅰ期和Ⅲ期的患者相似，这对于治疗计划的调整有指导意义。对于复发和进展性的MM，一项对既往接受自体干细胞移植或异基因造血干细胞移植的患者于复发后行¹⁸F-FDG PET/CT的研究结果表明，FLs>10个、存在四肢骨骼病灶和EMD及SUV_max>18.6是PFS期和OS期的不良预测因子^[16]。

3. ¹⁸F-FDG PET/CT在MM疗效评估中的临床应用

¹⁸F-FDG PET/CT能检测到MM患者治疗后病灶早期的代谢活动变化，病灶内¹⁸F-FDG摄取的变化常与治疗效果有关。Spinnato等^[17]在一项回顾性研究中分析了210例MM患者的¹⁸F-FDG PET/CT和MRI图像，发现与增强MRI相比，¹⁸F-FDG PET/CT能更早地反映疗效良好的患者的病灶代谢变化情况，这表明¹⁸F-FDG PET/CT可能比MRI有更好的疗效评估能力。Caldarella等^[18]对6项前瞻性研究和4项回顾性研究进行了荟萃分析，共纳入690例MM患者或孤立性浆细胞瘤（solitary plasmacytoma，SP）患者，结果表明，在对MM患者进行疗效评估时，¹⁸F-FDG PET/CT结果持续为阳性往往预示着疾病缓解较差。以上结果均提示¹⁸F-FDG PET/CT可作为MM有效的疗效评估方法。

4. ¹⁸F-FDG PET/CT在MRD检测中的应用价值

临床研究已经初步探索了MRD与临床结局的相关性，相关研究者已建议将MRD作为新诊断MM（new diagnosed MM，NDMM）药物治疗理论上的调节终点^{[ 19]}。Munshi等^[20]在一项荟萃分析中纳入了14项研究以探索MRD对PFS的影响及12项研究以探索MRD对OS的影响，发现NDMM患者经治疗后无MRD与良好的PFS率和OS率相关。

目前，灵敏度较高的检测MRD的方法有多参数流式细胞术、第二代测序和等位基因特异性寡核苷酸定量PCR等，但这些方法操作复杂，不能在临床上广泛开展。其他诸如质谱^[21]、循环肿瘤细胞^[22]等方法尚在研究中。同时，MM中异常浆细胞复杂的浸润方式及EMD发病率的升高导致上述MRD检测方法的假阴性率增高，为了确定MM中异常浆细胞已经完全去除，共识建议将上述检测方法与¹⁸F-FDG PET/CT联合，这可能为患者接受综合治疗后MRD的存在状态提供更准确的诊断^[23]。Alonso等^[24]在一项纳入了103例NDMM患者的回顾性研究中通过联合多参数流式细胞术和¹⁸F-FDG PET/CT发现，2种检测结果均为阴性的患者的中位PFS期为92个月，且相较于其他患者，其预后明显更好。然而，随着针对肿瘤异常克隆不同作用机制的高效治疗方法的使用和推广，¹⁸F-FDG PET/CT在检测MRD中的增益价值仍需进行大样本量的研究予以验证。同时，尽管MRD相关新型功能成像技术的开发和应用已经取得重大进展，但MRD相关的影像采集准则、结果解释及报告的全球化标准尚未制定，未来需进一步统一^{[23, 25]}。

5. ¹⁸F-FDG PET/CT在SMM评估中的应用价值

SMM是指符合MM的诊断标准，但病情进展缓慢且没有临床症状的MM，其每年进展为活动性MM的概率为10%~40%^[26-27]。根据IMWG的建议，对于临床高度怀疑为SMM的患者，若全身X射线检查结果为阴性，且患者不能接受全身MRI检查，那么推荐¹⁸F-FDG PET/CT作为鉴别活动性MM与SMM的有效工具（证据级别1，A级）^[23]。

在一项应用¹⁸F-FDG PET/CT前瞻性评估存在隐匿性溶骨病变的SMM患者进展为MM的风险的相关研究中，患者的中位随访时间为2.2年，结果表明，¹⁸F-FDG PET/CT结果为阳性的患者中有19例（16%）在确诊SMM后2年内进展为活动性MM的风险较高，且¹⁸F-FDG PET/CT结果为阳性的患者的中位进展时间（1.1年）短于结果为阴性的患者（4.5年），这提示¹⁸F-FDG PET/CT结果为阳性的患者需要考虑进行早期治疗；同时该研究指出，80%满足以下肿瘤进展标志物（骨髓浆细胞浸润比例>60%、血清游离轻链比值≥100、MRI显示FLs>1个）中1项及以上的患者在确诊SMM后2年内发生进展^[28]。将¹⁸F-FDG PET/CT与上述肿瘤进展标志物联合是否能更准确地预测SMM进展为活动性MM的风险尚需进一步的临床试验来验证。也有研究者利用从SMM患者的¹⁸F-FDG PET/CT图像上提取的纹理特征量化肿瘤内的摄取异质性，进而预测SMM进展为活动性MM的时间^[29]，该研究已取得初步成效，或可成为一个有前景的研究方向。

6. ¹⁸F-FDG PET/CT在SP诊断中的应用价值

SP是一种罕见的浆细胞肿瘤，可同时发生于骨骼和软组织，常进展为活动性MM。SP的诊断是在无“螃蟹标准”（CRAB）临床表现的基础上同时经活体组织病理学检查证实存在单个溶骨性病变或软组织肿块中存在克隆浆细胞，SP病灶易发生¹⁸F-FDG高摄取。Albano等^[30]通过分析62例初治SP患者的基线资料发现，¹⁸F-FDG PET/CT结果为阳性的SP患者似乎更易进展为活动性MM，在半定量特征中，基于瘦体重（lean body mass，lbm）校正得到的SUV_lbm>5.2和基于体表面积（body surface area，bsa）得到的SUV_bsa>1.7与进展时间显著相关；且¹⁸F-FDG PET/CT能显示出30%~50%的患者经全身X射线检查不能发现的或超出MRI检测范围的隐匿性溶骨病变或软组织肿块。在这样的背景下，IMWG的共识声明建议可以将¹⁸F-FDG PET/CT作为疑似髓外浆细胞瘤或SP患者初步检查的一部分^[23]。

7. 其他分子探针PET/CT显像在MM中的应用

¹⁸F-FDG PET/CT在MM中的应用广泛，但是其在诊断中仍可能出现假阳性和假阴性结果^[31]。假阳性结果可能是由于伪影（如骨金属植入物的存在和生理性摄取）、炎症或感染、手术或活体组织病理学检查、骨折以及最近使用的放化疗药物或生长因子等导致的假性弥漫性骨髓浸润。假阴性结果主要与高血糖、近期类固醇药品的过量使用而导致的一过性代谢抑制或骨内存在亚厘米级别的小病变等有关。¹⁸F-FDG是非特异性显像剂，其可能很难鉴别与MM相似的低代谢病变和良性病变^[20]。故近年来研究者们也使用一些其他代谢显像剂或受体显像剂用于MM的诊断。

7.1. ¹¹C-蛋氨酸（methionine，MET）PET/CT

¹¹C-MET是一种氨基酸显像剂。Dankerl等^[32]首次提出将¹¹C-MET PET/CT用于MM患者的诊断和分期。Lapa等^[33]在一项前瞻性研究中对比了¹⁸F-FDG和¹¹C-MET对MM的诊断效能，该研究纳入了78例浆细胞瘤患者（其中69例患者为活动性MM），¹¹C-MET PET/CT检出的存在FLs的患者占患者总数的75%（59例），¹⁸F-FDG PET/CT为60%（47例）；44例患者通过¹¹C-MET PET/CT检出了¹⁸F-FDG PET/CT未检出的更多病灶，而仅有2例患者通过¹⁸F-FDG PET/CT检出了¹¹C-MET PET/CT未检出的更多病灶。在监测疗效方面，Lückerath等^[34]的研究结果显示，向MM模型小鼠注射硼替佐米后24 h，其病灶的¹¹C-MET摄取比治疗前下降30%~79%，但在治疗早期未能检测到明显的¹⁸F-FDG摄取差异；更重要的是，该研究发现早期¹¹C-MET摄取的减少也与小鼠OS期的延长相关，而¹⁸F-FDG在此方面的表现欠佳。以上研究结果表明，¹¹C-MET PET/CT在评估MM患者的早期疗效反应方面可能优于¹⁸F-FDG PET/CT。

7.2. ⁶⁸Ga-Pentixafor PET/CT

趋化因子受体4（CXCR4）是包括MM在内的多种人类肿瘤生长和转移的关键因子^[35]，CXCR4高表达的MM患者预后较差，近年来研发的⁶⁸Ga-Pentixafor是一种对CXCR4具有高亲和力的PET/CT分子探针。⁶⁸Ga-Pentixafor PET/CT对MM病灶的检出率显著高于¹⁸F-FDG PET/CT。Lapa等^[36]的研究结果显示，⁶⁸Ga-Pentixafor PET/CT结果为阳性的患者预后较差，这提示CXCR4可能是MM特异性治疗的潜在靶点。Pan等^[37]的研究初步比较了⁶⁸Ga-Pentixafor PET/CT和¹⁸F-FDG PET/CT对NDMM的诊断效能，结果显示，前者的病灶检出率显著高于后者。

7.3. ¹¹C/¹⁸F-胆碱 PET/CT

胆碱是磷脂合成的前体，¹¹C-胆碱是一种磷脂显像剂。Nanni等^[38]在一项小样本（n=10）临床试验中进行了初步探索，发现相比于¹⁸F-FDG PET/CT，¹¹C-胆碱PET/CT对MM的诊断灵敏度更高，4例（25%）患者的2种检查结果均为阴性，2例（20%）患者的2种检查结果均为阳性并检出了相同数量和部位的病灶；¹¹C-胆碱PET/CT的SUV_max平均值为5，共检出37个FLs，而¹⁸F-FDG PET/CT的SUV_max平均值为3.8；共检出22个FLs。Cassou-Mounat等^[39]的研究结果表明，相比于¹⁸F-FDG PET/CT，¹⁸F-胆碱PET/CT对疑似复发或进展性MM的诊断可能有更大优势。Mesguich等^[40]回顾了¹¹C-胆碱PET/CT在MM中的作用，强调了其能够克服¹⁸F-FDG在颅骨和肝脏病变检测中的局限性，且信噪比更高，¹¹C-胆碱PET/CT可与¹⁸F-FDG PET/CT提供的信息互补以提高诊断的准确率。

7.4. ¹¹C-乙酸盐 PET/CT

MM细胞可利用乙酸盐作为一种多功能的碳源来维持其活跃且密集的生物合成特性，故乙酸盐的代谢特点可被用于有效检测MM病灶并监测治疗反应^[41]。Ho等^[42]的研究结果表明，应用¹¹C-乙酸盐PET/CT进行脂质代谢评估比应用¹⁸F-FDG PET/CT进行糖代谢评估对MM的诊断、危险分层和治疗监测更准确，¹¹C-乙酸盐PET/CT对弥漫性和局灶性MM患者的鉴别价值明显高于¹⁸F-FDG PET/CT。

8. 小结与展望

¹⁸F-FDG PET/CT可将PET提供的分子水平代谢信息与CT提供的解剖学信息相结合，从而准确诊断骨髓内外代谢活跃的浆细胞瘤，并确定病灶的位置、大小和代谢特性，进而预测患者的临床转归，并可评估治疗后肿瘤细胞的代谢变化以指导临床。¹⁸F-FDG PET/CT对MM的诊断、治疗决策的制定及疗效的评估有着较好的临床应用价值。

然而，¹⁸F-FDG PET/CT存在以下局限性。（1）对于非¹⁸F-FDG亲和或不过量表达葡萄糖转运体的MM患者，其¹⁸F-FDG摄取较低，从而导致病灶的检出率较低；（2）对于弥漫性骨髓瘤浆细胞浸润的评估，¹⁸F-FDG也缺乏敏感性；（3）虽然¹⁸F-FDG PET/CT在MM的诊断和分期中十分重要，但其为非特异性显像剂，在诊断和分期中会出现假阳性或假阴性结果。以上情况导致¹⁸F-FDG PET/CT在部分MM患者中的诊断价值有限，因此研发新型特异性MM显像剂十分重要。尽管如此，目前还没有明确的循证医学证据表明任何一种新型显像剂对骨病灶的检出准确率高于¹⁸F-FDG^[20]。另外，¹⁸F-FDG PET和MRI在MM的诊断中各有优势，将两者联合（即应用一体化PET/MRI）以充分利用PET的代谢参数并结合MRI多序列、高对比度、高分辨率的优点或可成为MM诊疗过程中具有发展潜力的影像学工具之一。相信随着多分子探针、多模态影像联合诊断的发展，对MM的诊断、分期和预后评估将会更准确。未来我们需要进行大型临床前瞻性或回顾性研究来探索并证实新型分子探针和新型成像技术在MM中的临床价值，以进一步推进对MM的精准诊断。

利益冲突　所有作者声明无利益冲突

作者贡献声明　李俊龙负责文献的收集与整理、综述的撰写与修订；兰晓莉负责综述的审阅、建议的提出；曹国祥负责命题的提出、综述的审阅与修订

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Clinical application and progress of PET/CT in multiple myeloma