Katherine I. Wolf

Are patients with hormonally functional phaeochromocytoma and paraganglioma initially receiving a proper adrenoceptor blockade? A retrospective cohort study

Pharmacological treatment is mandatory in patients with hormonally functional phaeochromocytoma and paraganglioma (PHAEO/PGL). We evaluated if patients initially diagnosed with hormonally functional PHAEO/PGL by various medical subspecialties received proper adrenoceptor blockade, and analysed factors predicting the prescription of adequate treatment.

Functional imaging signature of patients presenting with polycythemia/paraganglioma syndromes

Pheochromocytoma/paraganglioma (PPGL) syndromes associated with polycythemia have previously been described in association with mutations in the von Hippel–Lindau gene. Recently, mutations in the prolyl hydroxylase gene (PHD) 1 and 2 and in the hypoxia-inducible factor 2 α (HIF2A) were also found to be associated with multiple and recurrent PPGL. Such patients also presented with PPGL and polycythemia, and later on, some presented with duodenal somatostatinoma. In additional patients presenting with PPGL and polycythemia, no further mutations have been discovered. Because the functional imaging signature of patients with PPGL–polycythemia syndromes is still unknown, and because these tumors (in most patients) are multiple, recurrent, and metastatic, the goal of our study was to assess the optimal imaging approach using 4 different PET radiopharmaceuticals and CT/MRI in these patients. Methods: Fourteen patients (10 women, 4 men) with confirmed PPGL and polycythemia prospectively underwent 68Ga-DOTATATE (13 patients), 18F-FDG (13 patients), 18F-fluorodihydroxyphenylalanine (18F-FDOPA) (14 patients), 18F-fluorodopamine (18F-FDA) (11 patients), and CT/MRI (14 patients). Detection rates of PPGL lesions were compared between all imaging studies and stratified between the underlying mutations. Results: 18F-FDOPA and 18F-FDA PET/CT showed similar combined lesion-based detection rates of 98.7% (95% confidence interval [CI], 92.7%–99.8%) and 98.3% (95% CI, 90.9%–99.7%), respectively. The detection rates for 68Ga-DOTATATE (35.3%; 95% CI, 25.0%–47.2%), 18F-FDG (42.3; 95% CI, 29.9%–55.8%), and CT/MRI (60.3%; 95% CI, 48.8%–70.7%) were significantly lower (P < 0.01), irrespective of the mutation status. Conclusion: 18F-FDOPA and 18F-FDA are superior to 18F-FDG, 68Ga-DOTATATE, and CT/MRI and should be the radiopharmaceuticals of choice in this rare group of patients.

Anthracyclines suppress pheochromocytoma cell characteristics, including metastasis, through inhibition of the hypoxia signaling pathway

Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare, neuroendocrine tumors derived from adrenal or extra-adrenal chromaffin cells, respectively. Metastases are discovered in 3-36% of patients at the time of diagnosis. Currently, only suboptimal treatment options exist. Therefore, new therapeutic compounds targeting metastatic PHEOs/PGLs are urgently needed. Here, we investigated if anthracyclines were able to suppress the progression of metastatic PHEO. We explored their effects on experimental mouse PHEO tumor cells using in vitro and in vivo models, and demonstrated that anthracyclines, particularly idarubicin (IDA), suppressed hypoxia signaling by preventing the binding of hypoxia-inducible factor 1 and 2 (HIF-1 and HIF-2) to the hypoxia response element (HRE) sites on DNA. This resulted in reduced transcriptional activation of HIF target genes, including erythropoietin (EPO), phosphoglycerate kinase 1 (PGK1), endothelin 1 (EDN1), glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and vascular endothelial growth factor (VEGFA), which consequently inhibited the growth of metastatic PHEO. Additionally, IDA downregulated hypoxia signaling by interfering with the transcriptional activation of HIF1A and HIF2A. Furthermore, our animal model demonstrated the dose-dependent suppressive effect of IDA on metastatic PHEO growth in vivo. Our results indicate that anthracyclines are prospective candidates for inclusion in metastatic PHEO/PGL therapy, especially in patients with gene mutations involved in the hypoxia signaling pathway.

Endocrine tumors associated with the vagus nerve

The vagus nerve (cranial nerve X) is the main nerve of the parasympathetic division of the autonomic nervous system. Vagal paragangliomas (VPGLs) are a prime example of an endocrine tumor associated with the vagus nerve. This rare, neural crest tumor constitutes the second most common site of hereditary head and neck paragangliomas (HNPGLs), most often in relation to mutations in the succinate dehydrogenase complex subunit D (SDHD) gene. The treatment paradigm for VPGL has progressively shifted from surgery to abstention or therapeutic radiation with curative-like outcomes. Parathyroid tissue and parathyroid adenoma can also be found in close association with the vagus nerve in intra or paravagal situations. Vagal parathyroid adenoma can be identified with preoperative imaging or suspected intraoperatively by experienced surgeons. Vagal parathyroid adenomas located in the neck or superior mediastinum can be removed via initial cervicotomy, while those located in the aortopulmonary window require a thoracic approach. This review particularly emphasizes the embryology, molecular genetics, and modern imaging of these tumors.

Imaging Modalities for Pheochromocytoma and Paraganglioma

Pheochromocytomas and extra-adrenal paragangliomas, associated with the sympathetic nervous system, are rare neuroendocrine tumors of neural crest origin. These tumors behave differently from those associated with the parasympathetic system (i.e., head and neck paragangliomas). This chapter will particularly emphasize current and emerging knowledge of imaging options in these tumors.

Relevant Discordance Between 68Ga-DOTATATE and 68Ga-DOTANOC in SDHB-Related Metastatic Paraganglioma: Is Affinity to Somatostatin Receptor 2 the Key?

Pheochromocytomas/paragangliomas are somatostatin receptor 2-overexpressing tumors. Ga-DOTA-peptide imaging has recently shown excellent results in the detection of metastatic lesions in these tumors. However, currently used Ga-DOTA peptides show different somatostatin receptor affinities. Here, we report the remarkable differences in a patient who was imaged with Ga-DOTANOC and Ga-DOTATATE PET/CT within a 7-month period. The patient presented with a nearly negative Ga-DOTANOC PET/CT scan, whereas on Ga-DOTATATE PET/CT, multiple highly positive lesions were identified.