Supplementary Material for: Combination of Cross-Sectional and Molecular Imaging Studies in the Localization of Gastroenteropancreatic Neuroendocrine Tumors

Molecular imaging modalities exploit aspects of neuroendocrine tumors (NET) pathophysiology for both diagnostic imaging and therapeutic purposes. The characteristic metabolic pathways of NET determine which tracers are useful for their visualization. In this review, we summarize the diagnostic value of all available molecular imaging studies, present data about their use in daily practice in NET centers globally, and finally make recommendations about the appropriate use of those modalities in specific clinical scenarios. Somatostatin receptor scintigraphy (SRS) continues to have a central role in the diagnostic workup of patients with NET, as it is also widely available. However, and despite the lack of prospective randomized studies, many NET experts predict that Gallium-68 (68Ga)-DOTA positron emission tomography (PET) techniques may replace SRS in the future, not only because of their technical advantages, but also because they are superior in patients with small-volume disease, in patients with skeletal metastases, and in those with occult primary tumors. Carbon-11 (11C)-5-hydroxy-L-tryptophan (5-HTP) PET and 18F-dihydroxyphenylalanine (18F-DOPA) PET are new molecular imaging techniques of limited availability, and based on retrospective data, their sensitivities seem to be inferior to that of 68Ga-DOTA PET. Glucagon-like-peptide-1 (GLP-1) receptor imaging seems promising for localization of the primary in benign insulinomas, but is currently available only in a few centers. Fluorine-18 (18F)-fluorodeoxyglucose (18F-FDG) PET was initially thought to be of limited value in NET, due to their usually slow-growing nature. However, according to subsequent data, 18F-FDG PET is particularly helpful for visualizing the more aggressive NET, such as poorly differentiated neuroendocrine carcinomas, and well-differentiated tumors with Ki67 values >10%. According to limited data, 18F-FDG-avid tumor lesions, even in slow-growing NET, may indicate a more aggressive disease course. When a secondary malignancy has already been established or is strongly suspected, combining molecular imaging techniques (e.g. 18F-FDG PET and 68Ga-DOTA PET) takes advantage of the diverse avidities of different tumor types to differentiate lesions of different origins. All the above-mentioned molecular imaging studies should always be reviewed and interpreted in a multidisciplinary (tumor board) meeting in combination with the conventional cross-sectional imaging, as the latter remains the imaging of choice for the evaluation of treatment response and disease follow-up.

分子成像技术可利用神经内分泌肿瘤（neuroendocrine tumors, NET）的病理生理学特征，同时服务于诊断成像与治疗目的。神经内分泌肿瘤的特征性代谢通路决定了可用于其可视化显像的显像剂类型。在本综述中，我们总结了所有现有分子成像研究的诊断价值，呈现了其在全球神经内分泌肿瘤诊疗中心日常临床实践中的应用数据，并最终针对不同临床场景下这类成像技术的合理应用提出推荐建议。

生长抑素受体显像（somatostatin receptor scintigraphy, SRS）因应用普及度高，目前仍是神经内分泌肿瘤患者诊断评估流程中的核心手段。尽管缺乏前瞻性随机对照研究，但诸多神经内分泌肿瘤领域专家预测，镓-68（Gallium-68, 68Ga）标记DOTA的正电子发射断层显像（positron emission tomography, PET）技术未来或可取代SRS：这不仅源于其技术优势，更因其在小体积病灶、骨转移患者以及隐匿性原发肿瘤患者中的显像效能更优。

碳-11（Carbon-11, 11C）标记5-羟色氨酸（5-hydroxy-L-tryptophan, 5-HTP）PET显像与18F-二羟基苯丙氨酸（18F-dihydroxyphenylalanine, 18F-DOPA）PET显像属于可及性有限的新型分子成像技术。基于回顾性研究数据，二者的灵敏度似乎低于68Ga-DOTA PET。

胰高血糖素样肽-1（Glucagon-like-peptide-1, GLP-1）受体成像在良性胰岛素瘤的原发灶定位中展现出良好应用前景，但目前仅少数中心可开展此项检查。

氟-18标记氟代脱氧葡萄糖（Fluorine-18, 18F-FDG）PET最初因神经内分泌肿瘤通常生长缓慢的特性，被认为临床价值有限。但后续研究数据显示，18F-FDG PET对显像侵袭性更强的神经内分泌肿瘤尤为有效，例如低分化神经内分泌癌以及Ki67指数＞10%的高分化肿瘤。现有有限数据表明，即便在生长缓慢的神经内分泌肿瘤中，18F-FDG摄取阳性的肿瘤病灶也可能提示疾病进程更具侵袭性。

当患者已确诊或高度疑似继发性恶性肿瘤时，联合使用多种分子成像技术（如18F-FDG PET与68Ga-DOTA PET）可利用不同肿瘤类型的摄取特性差异，区分不同来源的病灶。

上述所有分子成像检查均需结合常规横断面成像结果，在多学科（肿瘤MDT）会议中进行阅片解读——常规横断面成像仍是评估治疗反应与疾病随访的首选成像手段。