Expression of somatostatin receptors, dopamine D2 receptors, noradrenaline transporters, and vesicular monoamine transporters in 52 pheochromocytomas and paragangliomas

Abstract

While somatostatin receptors (sst), through somatostatin-radiolabeled analogs, are used, mainly in second line, in the diagnosis and treatment of pheochromocytomas (PCC) and paragangliomas (PGL), the clinical significance of dopamine receptor subtype 2 (D 2 ) in PCC/PGL is unknown. Indeed, radiolabeled dopamine (DA) analogs such as fluorine 18 ( 18 F)-DA, used for positron emission tomography in PCC localization, are mainly correlated to the presence of noradrenaline transporter (NAT) and vesicular monoamine transporters (VMAT) but not to D 2 . The aim of this study was to quantitate D 2 and sst expression in 52 PCC/PGL and to compare it with that of 35 gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Quantitative RT-PCR of sst 1-3 and sst 5 , D 2 , NAT, VMAT1/2 was performed in all tumors, while immunohistochemistry analysis of sst 2 and D 2 was performed in seven tumors. D 2 mRNA was expressed in all PCC/PGL. Mean expression was significantly higher in PCC/PGL than in GEP-NETs (4.8 vs 0.5 copy/copy b-glucuronidase (Gus)). sst 2 and sst 1 were expressed in most PCC/PGL, with sst 2 -dominant expression (mean mRNA: 1.6 vs 0.4 copy/copy b-Gus). sst 2 expression level was similar to that of GEP-NETs, whereas sst 5 expression level was significantly lower (0.12 vs 0.78 copy/copy b-Gus). Our study evidenced strong D 2 mRNA expression in PCC and for the first time in PGL. PCC/PGL express sst 2 mRNA at levels similar to those of GEP-NETs. New drugs can target ssts and D 2 more efficiently than current somatostatin analogs. Moreover, transporters like NAT and VMAT1/2, could be co-targeted with sst, as a basis of new radionuclide compounds in the imaging and treatment of these tumors.

Could 68Ga-somatostatin analogues replace other PET tracers in evaluating extra-adrenal paragangliomas?

“…Compared with morphological imaging, both 68 Ga-DOTATOC and 18 F-DOPA PET demonstrated a detection rate of 100 % on a per patient-and per lesion-based analysis in non-metastatic extraadrenal PGLs. On the other hand, in metastatic or multifocal extra-adrenal PGLs, the detection rate of 68 Ga-DOTATOC PET was 100 % compared to 56 % of 18 F-DOPA PET on a per lesion-based analysis.…”

“…Recent European Association of Nuclear Medicine (EANM) guidelines for nuclear medicine imaging of PGLs provided a practical algorithm for selecting the most appropriate imaging procedure based on a tailored approach, taking into account genetic mutation, location of the PGL and presence of metastases, starting from the assumption that there is no 'gold standard' imaging technique for all patients with extra-adrenal PGL [1][2][3]. 18 F-DOPA positron emission tomography (PET)/CT is suggested as first-line imaging method in H&N and abdominal non-metastatic extra-adrenal PGLs; this method may be useful in metastatic PGLs in the absence of succinate dehydrogenase B (SDHB) gene mutations or when genetic status is unknown [1,4]. 111 In-Pentetreotide single photon emission computed tomography (SPECT)(/CT) may be used as firstline evaluation of H&N PGLs in the absence of 18 F-DOPA PET/CT.…”

“…111 In-Pentetreotide single photon emission computed tomography (SPECT)(/CT) may be used as firstline evaluation of H&N PGLs in the absence of 18 F-DOPA PET/CT. 18 F-Fluorodeoxyglucose (FDG) PET/CT is especially sensitive in the setting of SDH-and von Hippel-Lindau disease (VHL)-related sympathetic extra-adrenal PGLs and it seems to be the imaging modality of choice for SDHB-related metastatic PGLs; this method may also provide useful prognostic information. 18 F-Fluorodopamine and 11 Chydroxyephedrine PET are both accurate methods in evaluating patients with extra-adrenal and metastatic PGL but, to date, these techniques have limited availability [1].…”

“…18 F-Fluorodeoxyglucose (FDG) PET/CT is especially sensitive in the setting of SDH-and von Hippel-Lindau disease (VHL)-related sympathetic extra-adrenal PGLs and it seems to be the imaging modality of choice for SDHB-related metastatic PGLs; this method may also provide useful prognostic information. 18 F-Fluorodopamine and 11 Chydroxyephedrine PET are both accurate methods in evaluating patients with extra-adrenal and metastatic PGL but, to date, these techniques have limited availability [1]. The diagnostic performance of PET or PET/CT with various radiopharmaceuticals is clearly superior to that of radioiodinated metaiodobenzylguanidine (MIBG) scintigraphy in patients with extra-adrenal and metastatic PGL; however, MIBG scintigraphy maintains a unique role in selecting patients suitable for 131 I-MIBG therapy [5].…”

“…Recent articles in the literature assessed the diagnostic accuracy of somatostatin receptor PET/CT using different somatostatin analogues labelled with 68 Ga ( 68 Ga-DOTATATE, 68 Ga-DOTANOC and 68 Ga-DOTATOC) in patients with extraadrenal PGL [8][9][10][11][12][13][14][15][16][17], based on the increased expression of somatostatin receptors in PGL neoplastic cells [18].…”