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Molecular Imaging and Radionuclide Therapy of Pheochromocytoma and Paraganglioma in the Era of Genomic Characterization of Disease Subgroups

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Molecular Imaging and Radionuclide Therapy of Pheochromocytoma and Paraganglioma in the Era of Genomic Characterization of Disease Subgroups 26 11 Theranostics of D Taïeb et al. 26:11 R627–R656 Endocrine-Related pheochromocytoma and Cancer paraganglioma REVIEW Molecular imaging and radionuclide therapy of pheochromocytoma and paraganglioma in the era of genomic characterization of disease subgroups David Taïeb1,*, Abhishek Jha2,*, Giorgio Treglia3,4,5 and Karel Pacak2 1Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille University, Marseille, France 2Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA 3Clinic of Nuclear Medicine and PET/CT Center, Ente Ospedaliero Cantonale, Bellinzona, Switzerland 4Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital, Lausanne, Switzerland 5Health Technology Assessment Unit, General Directorate, Ente Ospedaliero Cantonale, Bellinzona, Switzerland Correspondence should be addressed to K Pacak: [email protected] *(D Taïeb and A Jha contributed equally to this work) Abstract In recent years, advancement in genetics has profoundly helped to gain a more Key Words comprehensive molecular, pathogenic, and prognostic picture of pheochromocytomas f pheochromocytoma and paragangliomas (PPGLs). Newly discovered molecular targets, particularly those f paraganglioma that target cell membranes or signaling pathways have helped move nuclear medicine f PPGL in the forefront of PPGL precision medicine. This is mainly based on the introduction f succinate dehydrogenase and increasing experience of various PET radiopharmaceuticals across PPGL genotypes complex quickly followed by implementation of novel radiotherapies and revised imaging f SDHB algorithms. Particularly, 68Ga-labeled-SSAs have shown excellent results in the diagnosis f 18F-FDOPA and staging of PPGLs and in selecting patients for PRRT as a potential alternative to f 68Ga-DOTATATE 123/131I-MIBG theranostics. PRRT using 90Y/177Lu-DOTA-SSAs has shown promise for f 18F-FDG treatment of PPGLs with improvement of clinical symptoms and/or disease control. f 131I-MIBG However, more well-designed prospective studies are required to confirm these findings, f peptide receptor radionuclide therapy in order to fully exploit PRRT’s antitumoral properties to obtain the final FDA approval. f theranostics Such an approval has recently been obtained for high‐specific-activity 131I-MIBG for f somatostatin receptor inoperable/metastatic PPGL. The increasing experience and encouraging preliminary results of these radiotherapeutic approaches in PPGLs now raises an important question of how to further integrate them into PPGL management (e.g. monotherapy or in combination with other systemic therapies), carefully taking into account the PPGLs locations, genotypes, and growth rate. Thus, targeted radionuclide therapy (TRT) should preferably be performed at specialized centers with an experienced interdisciplinary team. Future perspectives include the introduction of dosimetry and biomarkers for therapeutic responses for more individualized treatment plans, α-emitting isotopes, and the combination of TRT with other systemic therapies. Endocrine-Related Cancer (2019) 26, R627–R652 https://erc.bioscientifica.com © 2019 Society for Endocrinology https://doi.org/10.1530/ERC-19-0165 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 01:10:59AM via free access -19-0165 Theranostics of D Taïeb et al. 26:11 R628 Endocrine-Related pheochromocytoma and Cancer paraganglioma Learning points These are now recognized to be caused by at least 20 susceptibility genes (Dahia 2014, Crona et al. 2017, Fishbein 1) Know the molecular taxonomy of pheochromocytoma et al. 2017, Jochmanova & Pacak 2018). A majority of PPGLs and/or paraganglioma (PPGL) and the relationship can be described as carrying either germline or somatic between various genotypes and imaging phenotypes; mutations. Depending on their transcription profile, recent data obtained from The Cancer Genome Atlas (TCGA) 2) Describe imaging features of SDHx-related PPGL; has divided PPGL into three clinically relevant clusters: 3) Understand pathophysiologic basis of theranostics using iodine-123/131 (123/131I)-metaiodobenzylguanidine 1. Pseudohypoxia group (cluster 1) is divided into (123/131I-MIBG) and peptide receptor radionuclide therapy at least two subgroups: the first, tricarboxylic acid (177Lutetium (177Lu) or 90Yttrium (90Y)-DOTA somatostatin (TCA) cycle-related germline mutations mainly analogs) and know the results of clinical studies; in succinate dehydrogenase subunits (SDHx) and 4) Understand the main areas of improvement of fumarate hydratase (FH). The second subgroup radiotherapeutics in the management of PPGL. includes von Hippel–Lindau tumor suppressor (VHL)- and endothelial PAS domain protein 1 (EPAS1)-related somatic and germline mutations. Key messages 2. Kinase signaling group (cluster 2) consists of germline or somatic mutations in ret proto-oncogene 1) Positron emission tomography imaging using (RET), neurofibromin 1 NF1)( , transmembrane protein gallium-68 (68Ga)-labeled somatostatin receptor 127 (TMEM127), MYC-associated factor X (MAX), and analogs (SSAs) is the most sensitive approach for PPGL HRas proto-oncogene (HRAS). localization and can select patients for peptide receptor 3. Wnt signaling group (cluster 3) includes newly radionuclide therapy (PRRT). recognized somatic mutations in cold shock domain 2) Approximately 234 (n = 166, 71% patients with containing E1 (CSDE1), as well as somatic gene fusions progressive disease) PPGL patients have been treated affecting mastermind-like transcriptional coactivator 3 on compassionate grounds with PRRT and promising (MAML3). results have been reported mostly in the setting of retrospective small case reports or case series. Most importantly from a clinical standpoint, some 3) Following a multicentric phase II study, high-specific- correlations exist between the gene(s) involved and activity iodine-131 (131I)-MIBG (Azedra®) has received tumor’s anatomic location: FDA approval for metastatic or locally aggressive PPGL. 4) Potential indications of radiotherapeutics in PPGL a) PHEO: RET, VHL, SDHx, NF1, MAX, TMEM127, HRAS. include inoperable PPGL with progressive and/or b) Extra-adrenal retroperitoneal PGLs: SDHx, FH, VHL symptomatic metastatic PPGL. (rare), prolyl hydroxylase 1 and 2 (PHD1/2) and 5) The future perspectives include the introduction of EPAS1/ hypoxia-inducible factor 2 alpha (HIF2A). dosimetry and biomarkers for therapeutic responses c) Head and neck PGL (HNPGL): SDHx. for more individualized treatment plans, α-emitting isotopes, and combination of targeted radionuclide Major predictors for hereditary PPGL include a family therapy with other forms of treatment, including and personal history of PPGL, inherited in an autosomal immunotherapy. dominant manner but with varying penetrance, characteristic syndromic presentation, young age at diagnosis, multifocality, unusual location/s (e.g. Current classification of PPGL heart, urinary bladder), and/or tumor recurrence, particularly in the adrenal gland (Neumann et al. 2009, Pheochromocytomas (PHEOs) and paragangliomas (PGLs, 2018, Welander et al. 2011, Jafri et al. 2013, Benn et al. together called PPGLs) are neuroendocrine tumors (NETs) 2015, Favier et al. 2015). Renal cell carcinoma (RCC), arising from neural crest-derived adrenal or extra-adrenal gastrointestinal stromal tumor (GIST), pituitary adenoma, paraganglia, respectively. Around 5–10% of solitary and rarely, pulmonary chondroma, neuroblastoma, and pheochromocytomas are hereditary, whereas tumor neuroendocrine neoplasms (usually carcinoid) can also be multiplicity or extra-adrenal tumors are related to currently related to SDHx and rarely to other PPGL susceptibility known germline mutations in 40–70% of patients. gene mutations (Pasini et al. 2008, Papathomas et al. 2014, https://erc.bioscientifica.com © 2019 Society for Endocrinology https://doi.org/10.1530/ERC-19-0165 Published by Bioscientifica Ltd. Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 01:10:59AM via free access Theranostics of D Taïeb et al. 26:11 R629 Endocrine-Related pheochromocytoma and Cancer paraganglioma Casey et al. 2017). Other clinical manifestations can also This meta-analysis demonstrated the intrinsic value of be suggestive of particular gene mutations. For example, 68Ga-DOTA-SSA PET/CT in the detection of PPGL even prior medullary thyroid cancer (MTC) for RET, café-au-lait when a physician is not aided by the knowledge of spots/neurofibromas for NF1, RCC/hemangioblastomas/ genetic status of the patient. On the contrary, in another pancreatic tumors for VHL, congenital polycythemia and meta-analysis (Kan et al. 2018), 68Ga-DOTA-SSA PET/CT duodenal somatostatinoma for EPAS1/HIF2A (Zhuang detected more PPGL lesions with germline mutations (did et al. 2012), and RCC/leiomyomas for FH (Castro-Vega not specify the exact mutation) than 18F-FDG PET/CT et al. 2014). (97 vs 79%); however, only four studies (pooled Furthermore, PPGL with an underlying SDHB patients = 79) included in this meta-analysis used both mutation are associated with a higher risk of aggressive radiopharmaceuticals (Janssen et al. 2015, 2016a, Tan behavior than other hereditary PPGLs leading ultimately et al. 2015, Chang et al. 2016). to death, particularly due to development of metastatic In a recent non-comparative study from the Royal disease. The risk of metastasis
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