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Endocrine-related Cancer Oct 2023This article is a summary of the plenary lecture presented by Jared Rosenblum that was awarded the Manger Prize at the Sixth International Symposium on... (Review)
Review
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.
Topics: Animals; Mice; Pheochromocytoma; Syndrome; Paraganglioma; Basic Helix-Loop-Helix Transcription Factors; Adrenal Gland Neoplasms
PubMed: 37450881
DOI: 10.1530/ERC-23-0050 -
The Lancet. Digital Health Sep 2023Pheochromocytomas and paragangliomas have up to a 20% rate of metastatic disease that cannot be reliably predicted. This study prospectively assessed whether the...
BACKGROUND
Pheochromocytomas and paragangliomas have up to a 20% rate of metastatic disease that cannot be reliably predicted. This study prospectively assessed whether the dopamine metabolite, methoxytyramine, might predict metastatic disease, whether predictions might be improved using machine learning models that incorporate other features, and how machine learning-based predictions compare with predictions made by specialists in the field.
METHODS
In this machine learning modelling study, we used cross-sectional cohort data from the PMT trial, based in Germany, Poland, and the Netherlands, to prospectively examine the utility of methoxytyramine to predict metastatic disease in 267 patients with pheochromocytoma or paraganglioma and positive biochemical test results at initial screening. Another retrospective dataset of 493 patients with these tumors enrolled under clinical protocols at National Institutes of Health (00-CH-0093) and the Netherlands (PRESCRIPT trial) was used to train and validate machine learning models according to selections of additional features. The best performing machine learning models were then externally validated using data for all patients in the PMT trial. For comparison, 12 specialists provided predictions of metastatic disease using data from the training and external validation datasets.
FINDINGS
Prospective predictions indicated that plasma methoxytyramine could identify metastatic disease at sensitivities of 52% and specificities of 85%. The best performing machine learning model was based on an ensemble tree classifier algorithm that used nine features: plasma methoxytyramine, metanephrine, normetanephrine, age, sex, previous history of pheochromocytoma or paraganglioma, location and size of primary tumours, and presence of multifocal disease. This model had an area under the receiver operating characteristic curve of 0·942 (95% CI 0·894-0·969) that was larger (p<0·0001) than that of the best performing specialist before (0·815, 0·778-0·853) and after (0·812, 0·781-0·854) provision of SDHB variant data. Sensitivity for prediction of metastatic disease in the external validation cohort reached 83% at a specificity of 92%.
INTERPRETATION
Although methoxytyramine has some utility for prediction of metastatic pheochromocytomas and paragangliomas, sensitivity is limited. Predictive value is considerably enhanced with machine learning models that incorporate our nine recommended features. Our final model provides a preoperative approach to predict metastases in patients with pheochromocytomas and paragangliomas, and thereby guide individualised patient management and follow-up.
FUNDING
Deutsche Forschungsgemeinschaft.
Topics: United States; Humans; Pheochromocytoma; Retrospective Studies; Prospective Studies; Cross-Sectional Studies; Paraganglioma; Adrenal Gland Neoplasms; Machine Learning
PubMed: 37474439
DOI: 10.1016/S2589-7500(23)00094-8 -
Journal of Nuclear Medicine : Official... Sep 2021Whereas benign pheochromocytomas and paragangliomas are often successfully cured by surgical resection, treatment of metastatic disease can be challenging in terms of...
Whereas benign pheochromocytomas and paragangliomas are often successfully cured by surgical resection, treatment of metastatic disease can be challenging in terms of both disease control and symptom control. Fortunately, several options are available, including chemotherapy, radiation therapy, and surgical debulking. Radiolabeled metaiodobenzylguanidine (MIBG) and somatostatin receptor imaging have laid the groundwork for use of these radiopharmaceuticals as theranostic agents. I-MIBG therapy of neuroendocrine tumors has a long history, and the recent approval of high-specific-activity I-MIBG for metastatic or inoperable pheochromocytoma or paraganglioma by the U.S. Food and Drug Administration has resulted in general availability of, and renewed interest in, this treatment. Although reports of peptide receptor radionuclide therapy of pheochromocytoma and paraganglioma with Y- or Lu-DOTA conjugated somatostatin analogs have appeared in the literature, the approval of Lu-DOTATATE in the United States and Europe, together with National Comprehensive Cancer Network guidelines suggesting its use in patients with metastatic or inoperable pheochromocytoma and paraganglioma, has resulted in renewed interest. These agents have shown evidence of efficacy as palliative treatments in patients with metastatic or inoperable pheochromocytoma or paraganglioma. In this continuing medical education article, we discuss the therapy of pheochromocytoma and paraganglioma with I-MIBG and Y- or Lu-DOTA-somatostatin analogs.
Topics: Paraganglioma; Pheochromocytoma; Positron-Emission Tomography; Radionuclide Imaging
PubMed: 34475242
DOI: 10.2967/jnumed.120.259697 -
European Journal of Endocrinology Dec 2014Paragangliomas (PGLs) are rare vascular, neuroendocrine tumors of paraganglia, which are associated with either sympathetic tissue in adrenal (pheochromocytomas (PCCs))... (Review)
Review
Paragangliomas (PGLs) are rare vascular, neuroendocrine tumors of paraganglia, which are associated with either sympathetic tissue in adrenal (pheochromocytomas (PCCs)) and extraadrenal (sympathetic paraganglioma (sPGLs)) locations or parasympathetic tissue of the head and neck paragangliomas (HNPGLs). As HNPGLs are usually benign and most tumors grow slowly, a wait-and-scan policy is often advised. However, their location in the close proximity to cranial nerves and vasculature may result in considerable morbidity due to compression or infiltration of the adjacent structures, necessitating balanced decisions between a wait-and-see policy and active treatment. The main treatment options for HNPGL are surgery and radiotherapy. In contrast to HNPGLs, the majority of sPGL/PCCs produces catecholamines, in advanced cases resulting in typical symptoms and signs such as palpitations, headache, diaphoresis, and hypertension. The state-of-the-art diagnosis and localization of sPGL/PCCs are based on measurement of plasma and/or 24-h urinary excretion of (fractionated) metanephrines and methoxytyramine (MT). sPGL/PCCs can subsequently be localized by anatomical (computed tomography and/or magnetic resonance imaging) and functional imaging studies (123I-metaiodobenzylguanidine-scintigraphy, 111In-pentetreotide scintigraphy, or positron emission tomography with radiolabeled dopamine or dihydroxyphenylalanine). Although most PGL/PCCs are benign, factors such as genetic background, tumor size, tumor location, and high MT levels are associated with higher rates of metastatic disease. Surgery is the only curative treatment. Treatment options for patients with metastatic disease are limited. PGL/PCCs have a strong genetic background, with at least one-third of all cases linked with germline mutations in 11 susceptibility genes. As genetic testing becomes more widely available, the diagnosis of PGL/PCCs will be made earlier due to routine screening of at-risk patients. Early detection of a familial PGL allows early detection of potentially malignant PGLs and early surgical treatment, reducing the complication rates of this operation.
Topics: Adrenal Gland Neoplasms; Autonomic Nervous System Diseases; Carcinogenesis; Diagnostic Techniques, Endocrine; Genetic Testing; Head and Neck Neoplasms; Humans; Paraganglioma; Pheochromocytoma; Risk Factors
PubMed: 25063320
DOI: 10.1530/EJE-14-0396 -
Veterinary and Comparative Oncology Dec 2017Pheochromocytomas (PCCs) and paragangliomas (PGLs) are described in several species. In humans and dogs they have many similarities: the excessive catecholamine release... (Review)
Review
Pheochromocytomas (PCCs) and paragangliomas (PGLs) are described in several species. In humans and dogs they have many similarities: the excessive catecholamine release in hormonally active PCC causes similar clinical signs, the frequency of metastasis is similar, and they are histopathologically almost identical. Surgery is curative when PCC and PGL have not metastasized, while only palliative treatment is possible for patients with metastatic disease. Mutations in succinate dehydrogenase subunit B (SDHB) are associated with metastatic behaviour in human PCC/PGL and the same mutation has been described in dogs. The dog might therefore be a suitable model for study of the pathogenesis of metastatic PCC and PGL in humans. Further molecular studies of common tumourigenic pathways and comparative studies of histopathology of human and canine PCC and PGL are warranted.
Topics: Adrenal Gland Neoplasms; Animals; Dog Diseases; Dogs; Humans; Paraganglioma; Pheochromocytoma
PubMed: 28120550
DOI: 10.1111/vco.12291 -
Neuropathology and Applied Neurobiology Oct 2021HOXB13 is expressed in the tail bud of the developing embryo as well as in cauda equina paragangliomas and in myxopapillary ependymomas. In contrast, pheochromocytomas...
HOXB13 is expressed in the tail bud of the developing embryo as well as in cauda equina paragangliomas and in myxopapillary ependymomas. In contrast, pheochromocytomas and paraganglioma in other locations as well as many other tumors occuring in spinal cord regions are negative.
Topics: Animals; Cauda Equina; Central Nervous System Neoplasms; Diagnosis, Differential; Homeodomain Proteins; Mice; Paraganglioma
PubMed: 33768604
DOI: 10.1111/nan.12713 -
Current Opinion in Endocrinology,... Jun 2019Metastatic pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors with variable prognosis. This review highlights recent studies on outcomes and... (Review)
Review
PURPOSE OF REVIEW
Metastatic pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors with variable prognosis. This review highlights recent studies on outcomes and management of patients with metastatic PPGL.
RECENT FINDINGS
Latest advances were made in identifying predictors of favorable outcomes of patients with metastatic PPGL. Recent studies evaluated the efficacy of tyrosine kinase inhibitors, high-specific-activity radiopharmaceuticals, and peptide receptors radionuclide therapy in treatment of metastatic disease. Moreover, ongoing studies are assessing the effects of hypoxia-inducible factor 2αα and heat shock protein 90 inhibitors as potential therapies.
SUMMARY
Several active studies are evaluating the efficacy of systemic chemo, immuno, radiopharmaceutical, and peptide receptor radionuclide therapies to relieve local and adrenergic symptoms and provide survival benefit for patients with symptomatic and/or progressive advanced metastatic PPGL. Owing to rarity and wide-outcome variability, multidisciplinary team effort and personalized approach are central in caring for patients with metastatic PPGL.
Topics: Adrenal Gland Neoplasms; Endocrinology; Humans; Medical Oncology; Neoplasm Metastasis; Paraganglioma; Pheochromocytoma; Prognosis
PubMed: 30893083
DOI: 10.1097/MED.0000000000000476 -
Frontiers in Endocrinology 2022Although pediatric pheochromocytomas and paragangliomas (PPGLs) are rare, they have important differences compared to those in adults. Unfortunately, without timely... (Review)
Review
Although pediatric pheochromocytomas and paragangliomas (PPGLs) are rare, they have important differences compared to those in adults. Unfortunately, without timely diagnosis and management, these tumors have a potentially devastating impact on pediatric patients. Pediatric PPGLs are more often extra-adrenal, multifocal/metastatic, and recurrent, likely due to these tumors being more commonly due to a genetic predisposition than in adults. This genetic risk results in disease manifestations at an earlier age giving these tumors time to advance before detection. In spite of these problematic features, advances in the molecular and biochemical characterization of PPGLs have heralded an age of increasingly personalized medicine. An understanding of the genetic basis for an individual patient's tumor provides insight into its natural history and can guide clinicians in management of this challenging disease. In pediatric PPGLs, mutations in genes related to pseudohypoxia are most commonly seen, including the von Hippel-Lindau gene () and succinate dehydrogenase subunit () genes, with the highest risk for metastatic disease associated with variants in and . Such pathogenic variants are associated with a noradrenergic biochemical phenotype with resultant sustained catecholamine release and therefore persistent symptoms. This is in contrast to paroxysmal symptoms (e.g., episodic hypertension, palpitations, and diaphoresis/flushing) as seen in the adrenergic, or epinephrine-predominant, biochemical phenotype (due to episodic catecholamine release) that is commonly observed in adults. Additionally, PPGLs in children more often present with signs and symptoms of catecholamine excess. Therefore, children, adolescents, and young adults present differently from older adults (e.g., the prototypical presentation of palpitations, perspiration, and pounding headaches in the setting of an isolated adrenal mass). These presentations are a direct result of genetic determinants and highlight the need for pediatricians to recognize these differences in order to expedite appropriate evaluations, including genetic testing. Identification and familiarity with causative genes inform surveillance and treatment strategies to improve outcomes in pediatric patients with PPGL.
Topics: Adrenal Gland Neoplasms; Catecholamines; Genetic Testing; Humans; Paraganglioma; Pheochromocytoma
PubMed: 35903274
DOI: 10.3389/fendo.2022.936178 -
Annales D'endocrinologie Aug 2023Thoracic and cervical paragangliomas (PGLs) are rare neuroendocrine tumors arising from chromaffin cells of the neural crest progenitors located outside the adrenal... (Review)
Review
Thoracic and cervical paragangliomas (PGLs) are rare neuroendocrine tumors arising from chromaffin cells of the neural crest progenitors located outside the adrenal gland. We describe our current protocol as a multidisciplinary team for the management of cervical and thoracic PGLs. Surgery is generally considered the treatment of choice as it offers the best chance for cure. For resection of thoracic PGLs, video-assisted thoracoscopic surgery (VATS) is the main surgical approach, while open thoracotomy is preferred in case of tumors > 6cm, lacking confirmation of a plane of separation with adjacent structures, or with technical difficulties during VATS. In cervical PGLs, the surgical approach should be individualized according to location, mainly based on the Glasscock-Jackson and the Fisch-Mattox classifications. Surgery is the treatment of choice for most cervical and thoracic PGLs, but radiotherapy or observation could be more suitable options in unresectable cervical and thoracic PGLs or when resection has been incomplete.
Topics: Humans; Paraganglioma; Neuroendocrine Tumors; Adrenal Glands
PubMed: 36334803
DOI: 10.1016/j.ando.2022.10.013 -
Oncotarget Apr 2017Paragangliomas/pheochromocytomas comprise rare tumors that arise from the extra-adrenal paraganglia, with an incidence of about 2 to 8 per million people each year.... (Review)
Review
Paragangliomas/pheochromocytomas comprise rare tumors that arise from the extra-adrenal paraganglia, with an incidence of about 2 to 8 per million people each year. Approximately 40% of cases are due to genetic mutations in at least one out of more than 30 causative genes. About 25-30% of pheochromocytomas/paragangliomas develop under the conditions of a hereditary tumor syndrome a third of which are caused by mutations in the VHL gene. Together, the gene mutations in this disorder have implicated multiple processes including signaling pathways, translation initiation, hypoxia regulation, protein synthesis, differentiation, survival, proliferation, and cell growth. The present review contemplates the mutations associated with the development of pheochromocytomas/paragangliomas and their potential to serve as specific markers of these tumors and their progression. These data will improve our understanding of the pathogenesis of these tumors and likely reveal certain features that may be useful for early diagnostics, malignancy prognostics, and the determination of new targets for disease therapeutics.
Topics: Adrenal Gland Neoplasms; Animals; Biomarkers, Tumor; Cell Transformation, Neoplastic; Gene Expression Regulation, Neoplastic; Genetic Variation; Humans; Paraganglioma; Pheochromocytoma; Signal Transduction
PubMed: 28187001
DOI: 10.18632/oncotarget.15201