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- Author: Karel Pacak x
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Search for other papers by Ales Vicha in
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Department of Pediatric Hematology and Oncology, Service Central de Biophysique et de Médecine Nucléaire, Département d'Oncologie Moléculaire, Program in Reproductive and Adult Endocrinology, 2nd Medical School, Charles University and University Hospital Motol, Prague, Czech Republic
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Warburg's metabolic hypothesis is based on the assumption that a cancer cell's respiration must be under attack, leading to its damage, in order to obtain increased glycolysis. Although this may not apply to all cancers, there is some evidence proving that primarily abnormally functioning mitochondrial complexes are indeed related to cancer development. Thus, mutations in complex II (succinate dehydrogenase (SDH)) lead to the formation of pheochromocytoma (PHEO)/paraganglioma (PGL). Mutations in one of the SDH genes (SDHx mutations) lead to succinate accumulation associated with very low fumarate levels, increased glutaminolysis, the generation of reactive oxygen species, and pseudohypoxia. This results in significant changes in signaling pathways (many of them dependent on the stabilization of hypoxia-inducible factor), including oxidative phosphorylation, glycolysis, specific expression profiles, as well as genomic instability and increased mutability resulting in tumor development. Although there is currently no very effective therapy for SDHx-related metastatic PHEOs/PGLs, targeting their fundamental metabolic abnormalities may provide a unique opportunity for the development of novel and more effective forms of therapy for these tumors.
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Pheochromocytomas and paragangliomas (PPGLs) are defined as neuroendocrine tumors that produce catecholamines. Many recent advances in their management, localization, treatment, as well as surveillance have significantly improved outcomes for patients with PPGLs or carriers of pathogenic genetic variants linked to the development of these tumors. At present, those advances mainly include the molecular stratification of PPGLs into seven clusters, the 2017 WHO revised definition of these tumors, the presence of specific clinical features pointing toward PPGL, the use of plasma metanephrines and 3-methoxytyramine with specific reference limits to assess the likelihood of having a PPGL (e.g. patients at high and low risk) including age-specific reference limits, nuclear medicine guidelines outlining cluster- and metastatic disease-specific functional (here mainly positron emission tomography and metaiodobenzylguanidine scintigraphy) imaging in the precise diagnostic localization of PPGLs, the guidelines for using radio- vs chemotherapy for patients with metastatic disease, and the international consensus on initial screening and follow-up of asymptomatic germline SDHx pathogenic variant carriers. Furthermore, new collaborative efforts particularly based on multi-institutional and worldwide initiatives are now considered key forces in improving our understanding and knowledge about these tumors and future successful treatments or even preventative interventions.
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Search for other papers by Karel Pacak in
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Department of Endocrinology, Department of Biophysics and Nuclear Medicine, Diagnostic Nuclear Medicine Division, Program in Reproductive and Adult Endocrinology, Department of Nuclear Medicine, Institut Paoli‐Calmettes, La Timone University Hospital, Aix‐Marseille University, Marseille, France
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Although anatomic imaging to assess the precise localization of pheochromocytomas/paragangliomas (PHEOs/PGLs) is unavoidable before any surgical intervention on these tumors, functional imaging is becoming an inseparable portion of the imaging algorithm for these tumors. This review article presents applications of the most up-to-date functional imaging modalities and image-based treatment to PHEOs/PGLs patients. Functional imaging techniques provide whole-body localization (number of tumors present along with metastatic deposits) together with genetic-specific imaging approaches to PHEOs/PGLs, thus enabling highly specific and sensitive PHEO/PGL detection and delineation that now greatly impact the management of patients. Radionuclide imaging techniques also play a crucial role in the prediction of possible radioactive treatment options for PHEO/PGL. In contrast to previous imaging algorithms used for either assessement of these patients or their follow-up, endocrinologists, surgeons, oncologists, pediatricians, and other specialists require functional imaging before any therapeutic plan is outlined to the patient, and follow-up, especially in patients with metastatic disease, is based on the periodic use of functional imaging, often reducing or substituting for anatomical imaging. In similar specific indications, this will be further powered by using PET/MR in the assessment of these tumors. In the near future, it is expected that PHEO/PGL patients will benefit even more from an assessement of the functional characteristics of these tumors and new imaging-based treatment options. Finally, due to the use of new targeting moieties, gene-targeted radiotherapeutics and nanobodies-based theranostic approaches are expected to become a reality in the near future.
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Search for other papers by Abhishek Jha in
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Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital, Lausanne, Switzerland
Health Technology Assessment Unit, General Directorate, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
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In recent years, advancement in genetics has profoundly helped to gain a more comprehensive molecular, pathogenic, and prognostic picture of pheochromocytomas and paragangliomas (PPGLs). Newly discovered molecular targets, particularly those that target cell membranes or signaling pathways have helped move nuclear medicine in the forefront of PPGL precision medicine. This is mainly based on the introduction and increasing experience of various PET radiopharmaceuticals across PPGL genotypes quickly followed by implementation of novel radiotherapies and revised imaging algorithms. Particularly, 68Ga-labeled-SSAs have shown excellent results in the diagnosis and staging of PPGLs and in selecting patients for PRRT as a potential alternative to 123/131I-MIBG theranostics. PRRT using 90Y/177Lu-DOTA-SSAs has shown promise for treatment of PPGLs with improvement of clinical symptoms and/or disease control. However, more well-designed prospective studies are required to confirm these findings, in order to fully exploit PRRT’s antitumoral properties to obtain the final FDA approval. Such an approval has recently been obtained for high‐specific-activity 131I-MIBG for 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.
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Pheochromocytomas and paragangliomas (PHEOs/PGLs) represent diagnostically challenging and complex neuroendocrine tumors (NETs). Current biomarker tests for PHEOs/PGLs are technically complex or limited. We assessed the diagnostic utility of a NET-specific 51-marker gene blood assay (NETest) in patients with PHEOs/PGLs (n = 81), including ten pediatric patients, and age-/gender-matched controls (n = 142) using a prospective case:control (1:2) analysis. mRNA was measured (qPCR), and results were scaled from 0 to 100 (upper limit of normal < 20). Receiver operating curve (ROC) and non-parametric (Mann–Whitney) tests were used for analyses (two-tailed). All data are presented as mean ± s.e.m. NETest accuracy for PHEO/PGL diagnosis was 100%. PHEO/PGL scores were 70 ± 3 vs 8.5 ± 1 in controls (P < 0.0001), and ROC analysis was 0.99 ± 0.004 (P < 0.0001). Diagnostic metrics were 94% accurate, 100% sensitive, and 92% specific. Imaging correlation with 68Ga-PET-SSA was 100%. NETest levels in PHEOs (n = 26) were significantly (P < 0.0001) elevated (83 ± 4) vs 66 ± 4 in PGLs (n = 40) and mixed PHEOs/PGLs (n = 5: 37 ± 3). Adrenal-derived tumors (n = 30) exhibited higher scores (76 ± 5) than extra-adrenal-derived tumors (66 ± 4, P < 0.05). Cluster 2 tumors exhibited significantly (P = 0.034) elevated NETest levels (n = 4: 92 ± 2) vs cluster 1 tumors (n = 35: 69 ± 4). Regulatory pathway analysis identified elevated RAS-RAF, metastatic, pluripotential, neural and secretory gene cluster levels (P < 0.05) in PHEOs compared to PGLs. Cluster 2 PPGLs exhibited elevated (P = 0.046) levels of growth factor signaling genes compared to cluster 1. The PHEOs/PGLs in the pediatric cohort (n = 10) were all NETest-positive (81 ± 8) and exhibited a gene expression profile spectrum analogous to adults. Circulating NET transcript analysis identifies PHEOs/PGLs with 100% efficacy and is likely to have clinical utility in the diagnosis and management of PHEO/PGL patients.
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Precision medicine (PM) aims to maximize the risk–benefit balance of medical decisions by integrating individual patient and disease characteristics. This approach is gaining increasing recognition from clinicians, healthcare systems, pharmaceutical companies, patients, and governments. Nuclear medicine plays a critical role in PM by its virtue of providing critical information at every step of disease management, digital markers, and companion diagnostics/therapeutics. It is anticipated that technological breakthroughs and new tracers will continue to position nuclear medicine among the significant players in PM.
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This article is a summary of the plenary lecture presented by Jared Rosenblum that was awarded the Manger Prize at the Sixth International Symposium on Pheochromocytoma/Paraganglioma held on 19–22 October 2022 in Prague, Czech Republic. Herein, we review our initial identification of a new syndrome of multiple paragangliomas, somatostatinomas, and polycythemia caused by early postzygotic mosaic mutations in EPAS1, encoding hypoxia-inducible factor 2 alpha (HIF-2α), and our continued exploration of new disease phenotypes in this syndrome, including vascular malformations and neural tube defects. Continued recruitment and close monitoring of patients with this syndrome as well as the generation and study of a corresponding disease mouse model as afforded by the pheochromocytoma/paraganglioma translational program at the National Institutes of Health has provided new insights into the natural history of these developmental anomalies and the pathophysiologic role of HIF-2α. Further, these studies have highlighted the importance of the timing of genetic defects in the development of related disease phenotypes. The recent discovery and continued study of this syndrome has not only rapidly evolved our understanding of pheochromocytoma and paraganglioma but also deepened our understanding of other developmental tumor syndromes, heritable syndromes, and sporadic diseases.
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Computed tomography (CT; unenhanced, followed by contrast-enhanced examinations) is the cornerstone of imaging of adrenal tumours. Attenuation values of <10 Hounsfield units on an unenhanced CT are practically diagnostic for adenomas. When lesions cannot be characterised adequately with CT, magnetic resonance imaging (MRI) evaluation (with T1- and T2-weighted sequences and chemical shift and fat-suppression refinements) is sought. Functional nuclear medicine imaging is useful for adrenal lesions that are not adequately characterised with CT and MRI. Scintigraphy with [131I]-6-iodomethyl norcholesterol (a labelled cholesterol analogue) can differentiate adrenal cortical adenomas from carcinomas. Phaeochromocytomas appear as areas of abnormal and/or increased uptake of [123I]- and [131I]-meta-iodobenzylguanidine (a labelled noradrenaline analogue). The specific and useful roles of adrenal imaging include the characterisation of tumours, assessment of true tumour size, differentiation of adenomas from carcinomas and metastases, and differentiation of hyperfunctioning from non-functioning lesions. Adrenal imaging complements and assists the clinical and hormonal evaluation of adrenal tumours.
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Postoperative hypotension frequently occurs after resection of pheochromocytoma and/or paraganglioma (PPGLs). Epidural anesthesia (EA) is often used for pain control in open resection of these tumors; one of its side effects is hypotension. Our aim is to determine if EA is associated with an increased risk of postoperative hypotension after open resection of PPGLs. We conducted a retrospective review of patients who underwent open resection of PPGLs at the National Institutes of Health from 2004 to 2019. Clinical and perioperative parameters were analyzed by the use of EA. The primary endpoint was postoperative hypotension. Ninety-seven patients (46 female and 51 male; mean age, 38.5 years) underwent open resection of PPGLs and 69 (71.1%) received EA. Patients with EA had a higher rate beta-blocker use (79.7% vs 57.1%, P = 0.041), metastasis (69.6% vs 39.3%, P = 0.011), and were more frequently hypotensive after surgery (58.8% vs 25.0%, P = 0.003) compared to those without EA. Patients with postoperative hypotension had higher plasma normetanephrines than those without (7.3 fold vs 4.1 fold above the upper limit of normal, P = 0.018). Independent factors associated with postoperative hypotension include the use of beta-blockers (HR = 3.35 (95% CI: 1.16–9.67), P = 0.026) and EA (HR = 3.49 (95% CI: 1.25–9.76), P = 0.017). Data from this retrospective study suggest that, in patients with open resection of PPGLs, EA is an independent risk factor for early postoperative hypotension. Special caution is required in patients on beta-blockade. A prospective evaluation with standardized protocols for the use of EA and management of hemodynamic variability is necessary.
