Diagnosis of pheochromocytoma and paraganglioma: Functional characterization of genotypic and phenotypic variants

嗜铬细胞瘤/副神经节瘤（P/PGL）是一种罕见的产生儿茶酚胺的嗜铬细胞瘤，通常起源于肾上腺，但也起源于交感肾上腺外副神经节，构成了慢性高血压的手术可纠正的原因。这些肿瘤的临床特征和有时危及生命的后果高度依赖于合成的儿茶酚胺的类型和数量，其可以在血液循环中持续释放，但也可以自发地或由于通常不会造成危险的刺激（例如剧烈运动、手术、全身麻醉和分娩）而突然发作。P/PGLs的诊断主要依赖于血浆和尿液中儿茶酚胺及其代谢产物的测量、标准动态测试（如可乐定抑制试验和胰高血糖素刺激试验）、各种核成像程序以及计算机断层扫描（CT）和磁共振（MR）成像。然而，尽管有这些成熟的程序，P/PGLs的诊断和定位可能是具有挑战性的。这尤其适用于腹腔内定位-生物化学沉默-或分化不良的恶性P/PGL，其中儿茶酚胺及其代谢物的测量和放射性碘化间碘苄胍（MIBG）造影术可在患有肿瘤的患者中产生假阴性结果。此外，动态测试的信息价值在很大程度上取决于合成的儿茶酚胺的类型。最后，CT和MR成像缺乏足够的特异性。本提案的重点是比较使用新型放射性示踪剂[18 F]-6 F-多巴胺的正电子发射断层扫描（PET）/CT和/或PET/MR扫描的诊断性能（[18F]-6F-DA），[18F]-L-3，4-二羟苯丙氨酸（[18F]-DOPA）和[68 Ga]-DOTA-[Tyr 3]-奥曲酸（[68 Ga]-DOTATATE）用于诊断和定位具有明确临床和生化表型的患者中的P/PGLs，肿瘤相关生殖系突变和病理组织学特征。此外，将在选定病例中评价罗米地辛预处理对[123 I]-MIBG摄取增强的益处。这些研究的结果应该允许开发合理的算法来诊断或排除P/PGL，并可能转化为恶性P/PGL患者的新治疗选择。

Pheochromocytomas/paragangliomas (P/PGLs) are rare catecholamine-producing chromaffin cell tumors that typically arise from the adrenal gland but also from sympathetic extra-adrenal paraganglia and constitute a surgically correctable cause of chronic hypertension. The clinical features, and at times, life-threatening consequences of these tumours are highly dependent on the type and quantity of synthesized catecholamines, which may be released continuously in the blood circulation but also in sudden bouts either spontaneously or as a result of stimuli that normally would not pose a hazard, such as strenuous exercise, surgery, general anesthesia, and childbirth. The diagnosis of P/PGLs relies primarily on measurements of catecholamines and their metabolites in plasma and urine, standard dynamic testing such as the clonidine suppression test and the glucagon stimulation test, various nuclear imaging procedures, as well as computed tomographic (CT) and magnetic resonance (MR) imaging. However, despite of these well established procedures, the diagnosis and localization of P/PGLs can be challenging. This holds especially true for intra-abdominally located -biochemically silent- or poorly differentiated malignant P/PGLs where measurements of catecholamines and their metabolites and radio-iodinated metaiodobenzylguanidine (MIBG) scintigraphy can yield false-negative results in patients harbouring the tumour. Also, the informational value of dynamic testing is largely determined by the type of synthesized catecholamines. Finally, CT and MR imaging lack sufficient specificity. The present proposal focuses on the comparison of the diagnostic performance of positron emission tomography (PET)/CT and/or PET/MR scanning using the novel radiotracers [18F]-6F-dopamine ([18F]-6F-DA), [18F]-L-3,4-dihydroxyphenylalanine ([18F]-DOPA) und [68Ga]-DOTA-[Tyr3]-octreotate ([68Ga]-DOTATATE) for the diagnosis and localization of P/PGLs in patients with defined clinical and biochemical phenotypes, tumour-associated germline mutations, and pathohistological features. Furthermore, the benefits of romidepsin pre-treatment for uptake enhancement of [123I]-MIBG will be evaluated in selected cases. The results of these investigations should allow for the development of rational algorithms for the diagnosis or exclusion of P/PGLs and will possibly translate into novel treatment options in patients with malignant P/PGLs.