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

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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.