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神经内分泌肿瘤（neuroendocrine neoplasm，NEN）是一种罕见的异质性肿瘤，其发病率近十年来逐年升高[1]。NEN主要起源于上呼吸道、小肠、十二指肠和胰腺等的神经内分泌细胞[2]。根据分化程度和增殖活性的不同，NEN可以分为神经内分泌瘤（neuroendocrine tumor，NET）和神经内分泌癌（neuroendocrine carcinoma，NEC），NET又可进一步分为G1、G2和G3级[3]。NEN具有高度的时空异质性，因此，行病灶局部穿刺活检难以反映其整体病理学特性[4]。功能显像能够无创且实时地反映肿瘤的受体表达和代谢活性等情况，对于NEN的诊疗起着重要作用。大多数NEN细胞表面表达生长抑素受体（somatostatin receptor，SSTR）。通常，NET中SSTR的表达水平高于NEC，因此，68Ga标记的生长抑素类似物（somatostatin analog，SSA）68Ga-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸（1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid，DOTA）-SSA主要用于NET的诊断和分级[5]；而NEC则表现出较高的增殖活性，因此更适合反映糖代谢状况的18F-FDG PET/CT[6]。
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目前，68Ga-DOTA-SSA PET/CT已被推荐为诊断NET的首选影像学检测手段[7]。68Ga-DOTA-SSA由以下3部分组成：SSA部分可以是酪氨酸3-奥曲肽（Tyr3-octreotide，TOC）、萘丙氨酸3-奥曲肽（NaI3-octreotide，NOC）或酪氨酸3-奥曲肽衍生物（Tyr3-octreotate，TATE），螯合剂部分为DOTA，二者相连后再与68Ga螯合形成示踪剂。根据SSA部分的不同，目前常用的68Ga-DOTA-SSA主要分为68Ga-DOTA-TOC，68Ga-DOTA-NOC和68Ga-DOTA-TATE。3种显像剂均与SSTR2有较强的亲和力，其中，68Ga-DOTA-TATE与SSTR2的亲和力最高，且能检测出更多病灶，因而在临床中得到广泛应用[8-9]。此外，68Ga-DOTA-TOC还可与SSTR5结合，68Ga-DOTA-NOC还可与SSTR3和SSTR5结合[10]。68Ga-DOTA-SSA PET/CT的诊断灵敏度比早期临床应用的111In-喷曲肽SPECT高[11-12]。同时，PET/CT也具有比SPECT/CT更高的空间分辨率、更少的扫描次数和更低的单次辐射暴露[13]。Treglia等[14]对16篇文献中共计567例患者的临床资料进行的荟萃分析结果显示，68Ga-DOTA-SSA PET或PET/CT对NET的诊断灵敏度和特异度分别为93%和91%，ROC的AUC为0.96，这说明68Ga-DOTA-SSA PET或PET/CT能够精确诊断NET。因为68Ga-DOTA-SSA PET/CT对NET的检出率明显高于常规CT和MRI[15]，故其对于转移患者原发肿瘤的寻找及较小的肿瘤转移灶的发现均具有重要价值。
目前，18F-FDG PET/CT在NEN中并不推荐常规应用，除非组织病理学检查结果提示为G3级NET或NEC[16-17]。这是因为中低分级的NET的增殖速率和代谢活性较低，18F-FDG PET/CT的诊断灵敏度较低。研究结果显示，18F-FDG PET/CT在G1和G2级胃肠胰NET中的诊断灵敏度为40%~60%，而在G3级肿瘤中的诊断灵敏度高达95%[18-19]。还有研究结果表明，NEN的糖代谢情况与肿瘤的侵袭性相关，因此，18F-FDG PET/CT更适用于侵袭性NEN的诊断[20]。
68Ga-DOTA-SSA PET/CT对NEN诊断和分期的准确率比18F-FDG高[18,21]，但其对NEC的诊断存在局限性，这是因为NEC细胞膜上SSTR的表达水平较低，故联合应用18F-FDG和68Ga-DOTA-SSA进行双示踪剂显像更有利于NEN的诊断。Kayani等[18]的研究结果表明，单独应用18F-FDG PET/CT诊断NEN的灵敏度为66%，单独应用68Ga-DOTA-TATE PET/CT的诊断灵敏度为82%，双示踪剂显像的诊断灵敏度为92%。
双示踪剂显像在NEN患者的术前分期中也有重要价值。研究结果显示，患者术前行68Ga-DOTA-SSA PET可以提供额外的信息，这使得20%~60%的患者改变了手术方案[15, 22-23]。Frilling等[15]的研究结果表明，与传统的CT或MRI相比，对52例NET患者行68Ga-DOTA-TOC PET/CT促使31例患者的手术方案发生改变，其中3例患者分别检出了空肠、回肠和胰腺的原发灶，22例患者检出了另外的肝内或肝外转移灶。Ilhan等[22]通过对术前行68Ga-DOTA-TATE PET的44例NET患者进行回顾性研究发现，18例胰腺NET患者和26例回肠NET患者中分别有6例和3例改变了手术方案，且从图像中获得了更多信息，如修正原发灶的长径、扩大或缩小淋巴结转移的范围等。Cingarlini等[24]通过对35例术前行68Ga-DOTA-TOC和18F-FDG PET/CT的低分级胰腺NET患者进行回顾性研究发现，21例18F-FDG PET/CT结果呈阳性的患者的病灶比结果呈阴性的患者的病灶体积更大，且更容易伴随区域淋巴结转移及远处转移，因此，他们认为应用双示踪剂显像进行术前评估可以指导患者手术方案的选择。
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依据核分裂象数和增殖细胞核抗原Ki-67（简称Ki-67）指数的不同，WHO将NEN分为G1、G2和G3 3个级别。G1级：核分裂象数<每10个高倍视野2个细胞，且Ki-67指数≤2%；G2级：核分裂象数为每10个高倍视野2~20个细胞，且Ki-67指数为3%~20%；G3级：核分裂象数>每10个高倍视野20个细胞，且Ki-67指数>20%[3]。Ki-67指数越高表明增殖活性越强，预后越差。
在胃肠胰NEN中，低分级的恶性肿瘤比高分级多[25]。通过对胰腺NEN患者的术后情况进行研究发现，肿瘤18F-FDG PET/CT的SUVmax与其分级显著相关，18F-FDG PET/CT鉴别G3级与G1或G2级肿瘤的灵敏度，特异度和准确率分别为100%、62.5%和66.7%[26]。Zhang等[27]对83例胃肠胰NEN患者行18F-FDG和68Ga-DOTA-TATE双示踪剂显像后发现，肿瘤68Ga-DOTA-TATE PET/CT的SUVmax与Ki-67指数呈显著负相关，18F-FDG PET/CT的SUVmax与Ki-67指数呈显著正相关。除了常规的SUVmax，双示踪剂显像的其他参数（如总病灶糖酵解和总病灶SSTR表达）也与肿瘤分级有相关性。此外，Abdulrezzak等[28]对41例NEN患者进行的研究结果表明，G1级NET患者68Ga-DOTA-TATE PET/CT的SUVmax和总病灶SSTR表达高于18F-FDGPET/CT的SUVmax和总病灶糖酵解；而G3级NET患者18F-FDG PET/CT的SUVmax和总病灶糖酵解高于68Ga-DOTA-TATE PET/CT的SUVmax和总病灶SSTR表达。
Fisseler-Eckhoff和Demes[29]发现，肺部的NEN多为高分级。高分级的NEC通常对18F-FDG高摄取而对68Ga-DOTA-SSA低摄取；相反，惰性的低分级肺部NET（即典型的支气管类癌）对18F-FDG低摄取，对68Ga-DOTA-SSA高摄取。68Ga-DOTA-SSAPET/CT在诊断的特异度方面优于18F-FDG PET/CT，尤其可以准确鉴别支气管内肿瘤与肺不张；肺部NEN对18F-FDG和68Ga-DOTA-TATE的摄取与肿瘤分级具有良好的相关性，典型的支气管类癌对68Ga-DOTA-TATE的摄取比18F-FDG高，而非典型类癌和高分级类癌则相反[30]。因此，临床上应用双示踪剂显像可以提示肿瘤的侵袭性程度，且对于肿瘤的分期、患者的随访以及疗效的评价等都有重要意义。
此前，研究者普遍认为18F-FDG PET在NET显像中的阳性率较低，因而较少用于NET的分级，但最新的研究结果表明，在NET的分级中，18F-FDG PET/CT可以比68Ga-DOTA-TATE PET/CT提供更多的信息，且68Ga-DOTA-TATE PET/CT和18F-FDG PET/CT的SUV均与肿瘤的分级相关，表现为低分级的肿瘤更多地摄取68Ga-DOTA-TATE，而高分级的肿瘤更多地摄取18F-FDG；然而，如果只考虑中低分级的肿瘤，只有18F-FDG PET/CT的SUV与肿瘤的分级有显著相关性，即G2级NET比G1级有更高的18F-FDG摄取；68Ga-DOTA-TATE在G1、G2级NET中的摄取相似[18]。
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分化程度低的NEC呈现出快速进展的生物学行为，而分化程度相对高的NET则进展缓慢，两者的治疗策略不同。由于现有的治疗方案长期使用有不良反应，因此，有效鉴别快速进展的NEC与相对惰性的NET十分重要。
68Ga-DOTA-SSA PET/CT可以显示NET细胞上SSTR的表达，是预测SSA和肽受体放射性核素治疗（peptide receptor radionuclide therapy，PRRT）疗效的有利工具[9]。有研究结果表明，68Ga-DOTA-SSA PET/CT的SUVmax与肿瘤细胞的SSTR表达水平相关[31]，SUVmax高的患者接受PRRT后的症状缓解率高[32]。因此，病灶的18F-FDG PET/CT结果呈阳性而68Ga-DOTA-SSA PET/CT结果呈阴性的患者不能进行PRRT，可能更需要传统的化疗[33]或其他靶向药物[如依维莫司（everolimus）或舒尼替尼（sunitinib）]治疗[34-35]。Thapa等[36]对50例转移性胃肠胰NEN患者接受PRRT前后的18F-FDG和68Ga-DOTA-TATE双示踪剂显像结果进行研究，结果表明，18F-FDG PET/CT结果呈阳性的患者的治疗效果较差，因此，他们认为双示踪显像更有助于筛选出PRRT获益的患者。
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NEN转移患者的生存期差异很大（从几周至数年），因此，准确的预后评估对优化疾病管理至关重要。由于NEN具有异质性，TNM分期和活检样本的Ki-67指数不能完全反映NEN的侵袭性和预后，因此，功能显像在预后的整体评估方面具有巨大潜力。
肿瘤对18F-FDG的摄取与Ki-67指数相关，高摄取预示高Ki-67指数和较差的患者预后。Binderup等[37]的研究结果表明，18F-FDG PET/CT结果呈阳性的NEN患者与结果呈阴性的患者的无进展生存期存在显著差异，18F-FDG PET/CT是预测NEN预后的独立因素，其中，18F-FDG PET/CT结果呈阳性的患者与结果呈阴性的患者的风险比率为10，其对死亡风险的预测准确率甚至超过了Ki-67指数。一项对38例胃肠胰NEN患者的长期随访研究结果显示，18F-FDG PET/CT结果呈阳性的患者的4年总生存率为0，而结果呈阴性的患者的4年总生存率为87%[38]。此外，一项针对转移性NEN患者的前瞻性研究结果显示，18F-FDG PET/CT结果呈阳性的患者的总生存期和无进展生存期更短，且预后更差[39]。对于非转移性NEN患者，18F-FDGPET/CT可以预测接受手术治疗的患者的预后。Tomimaru等[26]通过对36例非转移性胰腺NEN患者进行研究发现，18F-FDG PET/CT的SUVmax与肿瘤的分级相关，也与患者术后的无进展生存期显著相关。
将18F-FDG与68Ga-DOTA-SSA联合进行双示踪剂显像可以提供更多的预后信息。68Ga-DOTA-SSA多浓聚于低分级的NEN病灶，而18F-FDG多浓聚于更具侵袭性的高分级NEN病灶[40]。若转移灶摄取18F-FDG而不摄取68Ga-DOTA-SSA，其可能为高分级的NEC，疾病进展快速且预后较差；若转移灶摄取68Ga-DOTA-SSA而不摄取18F-FDG，则其疾病进展可能缓慢且预后较好。一项对83例接受双示踪剂显像的胃肠胰NEN患者进行的回顾性研究得到了相似结果，即18F-FDG的摄取与肿瘤的侵袭性相关，仅摄取18F-FDG的患者的预后最差，而仅摄取68Ga-DOTA-TATE的患者的预后最好[27]。因此，Chan等[41]提出用18F-FDG与68Ga-DOTA-TATE双示踪剂NETPET评分系统来描述病灶和评估预后，该系统将病灶的摄取分为P1级（18F-FDG摄取阴性而68Ga-DOTA-TATE摄取强阳性）至P5级（18F-FDG摄取强阳性而68Ga-DOTA-TATE摄取阴性）5个等级，P2级至P4级的病灶同时表现出2种示踪剂摄取阳性，从P2级至P4级，病灶对18F-FDG的摄取逐渐升高（相对于68Ga-DOTA-TATE的摄取），P0级病灶的双示踪剂显像结果正常。研究结果表明，患者的总生存期与NETPET分级显著相关，这为建立双示踪剂显像分级系统提供了临床依据。
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18F-FDG和68Ga-DOTA-SSA双示踪剂PET/CT对NEN的诊疗具有重要价值，其可以反映肿瘤的异质性，且可以用于肿瘤的诊断和分期、治疗方案的选择以及预后评估。68Ga-DOTA-SSA PET/CT常规应用于中低分级的NEN，而18F-FDG PET/CT多应用于增殖活性较高的NEN。在相对惰性的肿瘤中，18F-FDG的应用尚有争议，双示踪剂PET/CT或许是有价值的诊断工具。68Ga-DOTA-SSA PET/CT被认为是PRRT有效性的强预测因子，而18F-FDG PET/CT能否同样成为PRRT有效性的预测因子仍有待进一步的研究，同时，双示踪剂功能显像在早期治疗有效性评价中的作用还需要进一步证实。
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 赵润泽负责文献的检索、综述的撰写；张一帆负责综述的选题、审阅与修订。
18F-FDG和68Ga-DOTA-SSA双示踪剂PET/CT在神经内分泌肿瘤中的临床应用
Clinical application of 18F-FDG and 68Ga-DOTA-SSA dual-tracer PET/CT in neuroendocrine neoplasms
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摘要: 与常规CT和MRI影像学检查相比，68Ga-1,4,7,10-四氮杂环十二烷-1,4,7,10-四乙酸（DOTA）-生长抑素类似物（SSA）PET/CT在神经内分泌肿瘤（NEN）的诊断中具有较高的灵敏度和特异度，同时，在疗效评价和预后评估等方面也有重要的指导价值。18F-氟脱氧葡萄糖（FDG）PET/CT虽然在NEN的诊断中未被常规推荐，但其在良恶性肿瘤的鉴别诊断和预后评估中可提供额外的信息。笔者就近年来18F-FDG和68Ga-DOTA-SSA双示踪剂PET/CT在NEN中的临床应用进行综述。
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关键词:
- 神经内分泌瘤 /
- 正电子发射断层显像术 /
- 体层摄影术，X线计算机 /
- 氟脱氧葡萄糖F18 /
- 镓-68 /
- 生长抑素类似物
Abstract: Compared with conventional CT and MRI imaging examinations, 68Ga-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-somatostatin analog (SSA) PET/CT has higher sensitivity and specificity in the diagnosis of neuroendocrine neoplasm (NEN), and it also has important guiding value in the evaluation of curative effect and prognosis. Although not routinely recommended in the diagnosis of NEN, 18F-fluorodeoxyglucose (FDG) PET/CT can provide complementary information in the differential diagnosis of benign and malignant tumors and the evaluation of prognosis. An overview of the clinical application of 18F-FDG and 68Ga-DOTA-SSA dual-tracer PET/CT in NEN is presented. -
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