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Kimura N, Muroya K, Yonamine M, Takekoshi K, Sato T, Hirose R, Sasaki T, Tamai K, Mabe H, Kawashima J, Kijima H, Naruke Y, Katabami T. Clinicopathological and genomic analysis of pediatric pheochromocytoma and sympathetic paraganglioma. Endocr J 2025; 72:399-412. [PMID: 39894509 PMCID: PMC11997271 DOI: 10.1507/endocrj.ej24-0584] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Accepted: 12/17/2024] [Indexed: 02/04/2025] Open
Abstract
Pediatric patients with pheochromocytoma (PCC)/paraganglioma (PGL) (PPGL) are rare, and clinicopathological investigations, especially the relationship between gene analysis and histological features, are insufficient. We comprehensively examined the clinical data, germline/somatic variants (mutations), and pathological characteristics of operated tumors using immunohistochemical expression and histological grading by Grading of Adrenal PCC and PGL score. This study included 28 patients (15 males and 13 females) aged <19 years. The age at the diagnosis was 12.8 ± 4.5 years. The included patient often had multiple PPGLs, with 39 tumors, including 21 PCCs and 18 PGLs, with average tumor sizes of 45.0 ± 22.8 and 42.6 ± 23.6 mm, respectively. Genomic types examined by gene mutations and immunohistochemistry of CA9 for VHL, SDHB for SDHx, and MAX for MAX, classified them into 14 VHL (50%), ten SDHx (35.7%), one MAX (3.6%), and three unknown (10.7%) types. Tumor metastasis was limited to two SDHB-related PPGLs, but not to VHL-related PPGLs. In both patients, the metastatic sites were the bones. The average GAPP score of the PPGLs was 2.9 ± 1.5 in VHL and 5.3 ± 1.7 in SDHB, and histological grades were well-differentiated in VHL and moderately differentiated in SDHB. SSTR2 expression was positive in 90% of SDHB-related PPGLs, but negative in 75% and weakly or focally positive in 25% of VHL-related PPGLs. Most pediatric PPGLs (90%) demonstrated mutations in VHL, SDHB, and MAX, with histological features depending on the mutation type. Combined genetic and immunohistochemical examination is desirable for accurate genomic diagnosis, and clinicopathological study.
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Affiliation(s)
- Noriko Kimura
- Department of Clinical Research, and Department of Diagnostic Pathology, National Hospital Organization Hakodate Medical Center, Hakodate 041-8512, Japan
| | - Koji Muroya
- Department of Endocrinology and Metabolism, Kanagawa Children’s Medical Center, Yokohama 232-8555, Japan
| | - Masato Yonamine
- Laboratory of Laboratory/Sports Medicine, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
| | - Kazuhiro Takekoshi
- Laboratory of Laboratory/Sports Medicine, Division of Clinical Medicine, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
| | - Takeshi Sato
- Department of Pediatrics, Keio University School of Medicine, Tokyo 160-8582, Japan
| | - Rei Hirose
- Endocrinology and Diabetes Center, Yokohama Rosai Hospital, Yokohama 222-0036, Japan
| | - Takato Sasaki
- Department of Pediatric Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
| | - Kana Tamai
- Department of Pediatrics, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
| | - Hiroyo Mabe
- Department of Pediatrics, Kumamoto University, Kumamoto 860-8556 Japan
| | - Junji Kawashima
- Department of Metabolic Medicine, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
| | - Hiromichi Kijima
- Department of Diabetology and Endocrinology, Tonan Hospital, Sapporo 060-0004, Japan
| | - Yuki Naruke
- Department of Pathology, Chiba Children’s Hospital, Chiba 266-0007, Japan
| | - Takuyuki Katabami
- Department of Metabolism and Endocrinology, St. Marianna University Yokohama Seibu Hospital, Yokohama 241-0811, Japan
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Takenaka J, Watanabe S, Abe T, Takeuchi S, Hirata K, Kimura R, Ishii H, Wakabayashi N, Majigsuren M, Kudo K. Urinary Dopamine Levels Can Predict the Avidity of Post-Therapy [ 131I]MIBG Scintigraphy in Unresectable or Metastatic Pheochromocytomas and Paragangliomas: A Preliminary Clinical Study. Pharmaceuticals (Basel) 2025; 18:165. [PMID: 40005979 PMCID: PMC11858449 DOI: 10.3390/ph18020165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2024] [Revised: 01/21/2025] [Accepted: 01/24/2025] [Indexed: 02/27/2025] Open
Abstract
Background/Objectives: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that produce catecholamines. Unresectable or metastatic PPGLs are treated with [131I]metaiodobenzylguanidine (MIBG), but MIBG avidity is often heterogeneous. Identifying predictive factors for non-avid lesions on scintigraphy is clinically important. The primary objective of this study was to investigate the relationship between MIBG avidity and catecholamine secretion patterns in patients with unresectable or metastatic PPGLs. Methods: This retrospective study included 27 patients treated with [131I]MIBG for unresectable/metastatic PPGLs between 2001 and 2024. Patients received a single intravenous dose of [131I]MIBG (5.5-7.4 GBq), with post-therapy scintigraphy performed 3-7 days later. Non-avid lesions were assessed by imaging and confirmed using CT, MRI, and FDG-PET. Clinical factors, including age, sex, prior treatments, metastasis sites, and urine catecholamines, were evaluated using univariate logistic analysis. Predictive factors were assessed via receiver operating characteristic curves. Results: Non-avid lesions were found in nine patients (33.3%). These patients were younger (median age 38 vs. 62.5 years) and had higher urine dopamine levels (median 1510 vs. 779 μg/day) than those without non-avid lesions. Younger age (odds ratio: 0.892, p < 0.01) and higher urinary dopamine levels (odds ratio: 1.003, p < 0.01) were significantly associated with non-avid lesions. All patients > 45 years with urinary dopamine < 1190 μg/day had no non-avid lesions, whereas patients < 45 years with urinary dopamine > 1190 μg/day had non-avid lesions. Conclusions: Age and urinary dopamine levels may predict non-avid lesions in unresectable/metastatic PPGLs, aiding treatment decisions for [131I]MIBG therapy. This article is a revised and expanded version of a paper entitled "Urine dopamine level and age can predict non-avid lesion on scintigraphy after I-131 MIBG treatment for unresectable/metastatic PPGL", which was presented at SNMMI 2024, Toronto, from 8 June to 11 June 2024.
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Affiliation(s)
- Junki Takenaka
- Department of Diagnostic Imaging, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan (K.H.); (M.M.); (K.K.)
- Department of Nuclear Medicine, Hokkaido University Hospital, Sapporo 060-8648, Japan
| | - Shiro Watanabe
- Department of Diagnostic Imaging, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan (K.H.); (M.M.); (K.K.)
- Department of Nuclear Medicine, Hokkaido University Hospital, Sapporo 060-8648, Japan
- Global Center for Biomedical Science and Engineering, Faculty of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Takashige Abe
- Department of Renal and Genitourinary Surgery, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Satoshi Takeuchi
- Department of Medical Oncology, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
- Center of Neuroendocrine Neoplasms, Hokkaido University Hospital, Sapporo 060-8648, Japan
| | - Kenji Hirata
- Department of Diagnostic Imaging, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan (K.H.); (M.M.); (K.K.)
- Department of Nuclear Medicine, Hokkaido University Hospital, Sapporo 060-8648, Japan
- Global Center for Biomedical Science and Engineering, Faculty of Medicine, Hokkaido University, Sapporo 060-8638, Japan
- Center of Neuroendocrine Neoplasms, Hokkaido University Hospital, Sapporo 060-8648, Japan
- Medical AI Research and Development Center, Hokkaido University Hospital, Sapporo 060-8648, Japan
| | - Rina Kimura
- Department of Diagnostic Imaging, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan (K.H.); (M.M.); (K.K.)
- Department of Diagnostic and Interventional Radiology, Hokkaido University Hospital, Sapporo 060-8648, Japan
| | - Hiroshi Ishii
- Department of Diagnostic Imaging, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan (K.H.); (M.M.); (K.K.)
- Department of Nuclear Medicine, Hokkaido University Hospital, Sapporo 060-8648, Japan
| | - Naoto Wakabayashi
- Department of Diagnostic Imaging, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan (K.H.); (M.M.); (K.K.)
- Department of Diagnostic Radiology, National Hospital Organization, Hokkaido Cancer Center, Sapporo 003-0804, Japan
| | - Mungunkhuyag Majigsuren
- Department of Diagnostic Imaging, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan (K.H.); (M.M.); (K.K.)
- Department of Radiology, Diagnostic Imaging Center, Second State Central Hospital, Ulaanbaatar 210349, Mongolia
| | - Kohsuke Kudo
- Department of Diagnostic Imaging, Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan (K.H.); (M.M.); (K.K.)
- Global Center for Biomedical Science and Engineering, Faculty of Medicine, Hokkaido University, Sapporo 060-8638, Japan
- Medical AI Research and Development Center, Hokkaido University Hospital, Sapporo 060-8648, Japan
- Department of Diagnostic and Interventional Radiology, Hokkaido University Hospital, Sapporo 060-8648, Japan
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Rosenblum JS, Cole Y, Dang D, Lookian PP, Alkaissi H, Patel M, Cappadona AJ, Jha A, Edwards N, Donahue DR, Munasinghe J, Wang H, Knutsen RH, Pappo AS, Lechan RM, Kozel BA, Smirniotopoulos JG, Kim HJ, Vortmeyer A, Miettinen M, Heiss JD, Zhuang Z, Pacak K. Head and neck paraganglioma in Pacak-Zhuang syndrome. JNCI Cancer Spectr 2025; 9:pkaf001. [PMID: 39821441 PMCID: PMC11790058 DOI: 10.1093/jncics/pkaf001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2024] [Revised: 11/15/2024] [Accepted: 12/31/2024] [Indexed: 01/19/2025] Open
Abstract
BACKGROUND Head and neck paragangliomas (HNPGLs) are typically slow-growing, hormonally inactive tumors of parasympathetic paraganglia. Inactivation of prolyl-hydroxylase domain-containing 2 protein causing indirect gain-of-function of hypoxia-inducible factor-2α (HIF-2α), encoded by EPAS1, was recently shown to cause carotid body hyperplasia. We previously described a syndrome with multiple sympathetic paragangliomas caused by direct gain-of-function variants in EPAS1 (Pacak-Zhuang syndrome, PZS) and developed a corresponding mouse model. METHODS We evaluated a cohort of patients with PZS (n = 9) for HNPGL by positron emission tomography, magnetic resonance imaging, and computed tomography and measured carotid body size compared to literature reference values. Resected tumors were evaluated by histologic sectioning and staining. We evaluated the corresponding mouse model at multiple developmental stages (P8 and adult) for lesions of the head and neck by high resolution ex vivo imaging and performed immunohistochemical staining on histologic sections of the identified lesions. RESULTS hree patients had imaging consistent with HNPGL, one of which warranted resection and was confirmed on histology. Three additional patients had carotid body enlargement (Z-score > 2.0), and 3 had carotid artery malformations. We found that 9 of 10 adult variant mice had carotid body tumors and 6 of 8 had a paraganglioma on the cranio-caval vein, the murine homologue of the superior vena cava; these were also found in 4 of 5 variant mice at post-natal day 8. These tumors and the one resected from a patient were positive for tyrosine hydroxylase, synaptophysin, and chromogranin A. Brown fat in a resected patient tumor carried the EPAS1 pathogenic variant. CONCLUSIONS These findings (1) suggest HNPGL as a feature of PZS and (2) show that these pathogenic variants are sufficient to cause the development of these tumors, which we believe represents a continuous spectrum of disease starting from hyperplasia.
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Affiliation(s)
- Jared S Rosenblum
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Yasemin Cole
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Danielle Dang
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Pashayar P Lookian
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Hussam Alkaissi
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, United States
| | - Mayank Patel
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
- General Surgical Pathology Section, National Institutes of Health, Bethesda, MD, United States
| | - Anthony J Cappadona
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Abhishek Jha
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Nancy Edwards
- Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
| | - Danielle R Donahue
- Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
| | - Jeeva Munasinghe
- Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
| | - Herui Wang
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Russell H Knutsen
- Laboratory of Vascular and Matrix Genetics, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, United States
| | - Alberto S Pappo
- Division of Solid Tumor, St Jude Children’s Research Hospital, Memphis, TN, United States
| | - Ronald M Lechan
- Division of Endocrinology, Diabetes & Metabolism, Tufts Medical Center, Boston, MA, United States
| | - Beth A Kozel
- Laboratory of Vascular and Matrix Genetics, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD, United States
| | - James G Smirniotopoulos
- Department of Radiology, George Washington University, Washington, DC, United States
- MedPix® National Library of Medicine, Bethesda, MD, United States
| | - H Jeffrey Kim
- Department of Otolaryngology, Georgetown University School of Medicine, Washington, DC, United States
- Office of Clinical Director, National Institute on Deafness and Other Communication Disorders, Bethesda, MD, United States
| | - Alexander Vortmeyer
- Clinical Pathology & Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, United States
| | - Markku Miettinen
- General Surgical Pathology Section, National Institutes of Health, Bethesda, MD, United States
| | - John D Heiss
- Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States
| | - Zhengping Zhuang
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States
| | - Karel Pacak
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
- Center for Adrenal Endocrine Tumors, AKESO, Prague 5, Czech Republic
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Bechmann N, Rosenblum JS, Alzahrani AS. Current views on the role of HIF-2α in the pathogenesis and syndromic presentation of pheochromocytoma and paraganglioma. Best Pract Res Clin Endocrinol Metab 2024; 38:101955. [PMID: 39426935 DOI: 10.1016/j.beem.2024.101955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2024]
Abstract
Pathogenic variants (PVs) in EPAS1, which encodes hypoxia-inducible factor-2α (HIF-2α), could be the underlying genetic cause of about 3%-6% of pheochromocytoma and paragangliomas (PPGLs). EPAS1-related PPGLs may occur as isolated tumors or as part of Pacak-Zhuang Syndrome (PZS) with two or more of a triad of PPGL, polycythemia, and somatostatinoma. HIF-2α plays a critical role in the regulation of the cellular hypoxia pathway. When a gain-of-function PV is acquired, HIF-2α evades steady-state hydroxylation by the prolyl hydroxylase type 2 (PHD2), which accelerates von Hippel-Lindau (VHL)-mediated proteasomal degradation. In this situation, HIF-2α is stabilized and can translocate to the nucleus, inducing the expression of several genes involved in tumorigenesis. This leads to the development of PPGL and other manifestations of PZS. EPAS1-related PPGLs usually occur in the second or third decade of life, more frequently in females, and are usually multiple, adrenal and extra-adrenal, and norepinephrine-secreting. In addition, these tumors carry an increased metastatic potential and have been reported with metastatic disease in up to 30% of cases. While polycythemia is fairly common in PZS, somatostatinomas are rare. It has been suggested that the character of the acquired PV in EPAS1, which affects its binding to PHD2, correlates with certain phenotypes in PZS. PVs in EPAS1 that have been found in related sporadic PPGLs have also been associated with hypoxic conditions including cyanotic congenital heart disease, hemoglobinopathies and high altitude. Understanding the hypoxia pathway and its role in the pathogenesis of PPGL may open a new avenue for developing effective therapies for these tumors. Indeed, one of these therapies is Belzutifan, a HIF-2α inhibitor that is being tested in the treatment of metastatic PPGLs.
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Affiliation(s)
- Nicole Bechmann
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden 01307, Germany; Eunice Kennedy Shriver National Institute of Child Health and Development, Bethesda, MD 20892, United States; Department of Medicine and Department of Molecular Oncology, King Faisal Specialist Hospital & Research Center, Riyadh 11211, Saudi Arabia.
| | - Jared S Rosenblum
- Eunice Kennedy Shriver National Institute of Child Health and Development, Bethesda, MD 20892, United States.
| | - Ali S Alzahrani
- Department of Medicine and Department of Molecular Oncology, King Faisal Specialist Hospital & Research Center, Riyadh 11211, Saudi Arabia.
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Casey RT, Hendriks E, Deal C, Waguespack SG, Wiegering V, Redlich A, Akker S, Prasad R, Fassnacht M, Clifton-Bligh R, Amar L, Bornstein S, Canu L, Charmandari E, Chrisoulidou A, Freixes MC, de Krijger R, de Sanctis L, Fojo A, Ghia AJ, Huebner A, Kosmoliaptsis V, Kuhlen M, Raffaelli M, Lussey-Lepoutre C, Marks SD, Nilubol N, Parasiliti-Caprino M, Timmers HHJLM, Zietlow AL, Robledo M, Gimenez-Roqueplo AP, Grossman AB, Taïeb D, Maher ER, Lenders JWM, Eisenhofer G, Jimenez C, Pacak K, Pamporaki C. International consensus statement on the diagnosis and management of phaeochromocytoma and paraganglioma in children and adolescents. Nat Rev Endocrinol 2024; 20:729-748. [PMID: 39147856 DOI: 10.1038/s41574-024-01024-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/17/2024] [Indexed: 08/17/2024]
Abstract
Phaeochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumours that arise not only in adulthood but also in childhood and adolescence. Up to 70-80% of childhood PPGL are hereditary, accounting for a higher incidence of metastatic and/or multifocal PPGL in paediatric patients than in adult patients. Key differences in the tumour biology and management, together with rare disease incidence and therapeutic challenges in paediatric compared with adult patients, mandate close expert cross-disciplinary teamwork. Teams should ideally include adult and paediatric endocrinologists, oncologists, cardiologists, surgeons, geneticists, pathologists, radiologists, clinical psychologists and nuclear medicine physicians. Provision of an international Consensus Statement should improve care and outcomes for children and adolescents with these tumours.
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Affiliation(s)
- Ruth T Casey
- Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
- Department of Endocrinology, Cambridge Cancer Centre and Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
| | - Emile Hendriks
- Department of Paediatric Diabetes and Endocrinology, Cambridge Cancer Centre and Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Cheri Deal
- Endocrine and Diabetes Service, CHU Sainte-Justine and University of Montreal, Montreal, Québec, Canada
| | - Steven G Waguespack
- Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Verena Wiegering
- University Children's Hospital, Department of Paediatric Hematology, Oncology and Stem Cell Transplantation, University of Würzburg, Würzburg, Germany
| | - Antje Redlich
- Paediatric Oncology Department, Otto von Guericke University Children's Hospital, Magdeburg, Germany
| | - Scott Akker
- St Bartholomew's Hospital, Barts Health NHS Trust, London, UK
| | - Rathi Prasad
- Centre for Endocrinology, William Harvey Research Institute, Queen Mary University of London, London, UK
| | - Martin Fassnacht
- Department of Medicine, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg, Germany
| | - Roderick Clifton-Bligh
- Department of Diabetes and Endocrinology, Royal North Shore Hospital, Sydney, New South Wales, Australia
| | - Laurence Amar
- Université de Paris, Paris, France
- Hypertension Unit, Hôpital Européen Georges Pompidou, Assistance Publique - Hôpitaux de Paris, Paris, France
| | - Stefan Bornstein
- Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Letizia Canu
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
- Centro di Ricerca e Innovazione sulle Patologie Surrenaliche, Azienda Ospedaliera Universitaria (AOU) Careggi, Florence, Italy
| | - Evangelia Charmandari
- Division of Endocrinology, Metabolism and Diabetes, First Department of Paediatrics, National and Kapodistrian University of Athens Medical School, 'Aghia Sophia' Children's Hospital, Athens, Greece
| | | | - Maria Currás Freixes
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Institute of Health Carlos III (ISCIII), Madrid, Spain
| | - Ronald de Krijger
- Princess Maxima Center for Paediatric Oncology, Utrecht, Netherlands
- Department of Pathology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Luisa de Sanctis
- Department of Public Health and Paediatric Sciences, University of Turin, Turin, Italy
| | - Antonio Fojo
- Division of Hematology/Oncology, Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA
| | - Amol J Ghia
- Department of Radiation Oncology, University Hospital of Texas, MD Anderson Cancer Center, Houston, TX, USA
| | - Angela Huebner
- Department of Paediatrics, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Vasilis Kosmoliaptsis
- Department of Surgery, University of Cambridge and National Institute for Health Research Cambridge Biomedical Research Centre, Addenbrooke's Hospital, Cambridge, UK
- Blood and Transplant Research Unit in Organ Donation and Transplantation, National Institute for Health Research, University of Cambridge, Cambridge, UK
| | - Michaela Kuhlen
- Paediatrics and Adolescent Medicine, Faculty of Medicine, University of Augsburg, Augsburg, Germany
| | - Marco Raffaelli
- U.O.C. Chirurgia Endocrina e Metabolica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
- Istituto di Semeiotica Chirurgica, Università Cattolica del Sacro Cuore, Rome, Italy
| | - Charlotte Lussey-Lepoutre
- Service de médecine nucléaire, Inserm U970, Sorbonne université, Groupe hospitalier Pitié-Salpétrière, Paris, France
| | - Stephen D Marks
- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust and NIHR GOSH Biomedical Research Centre, University College London Great Ormond Street Institute of Child Health, London, UK
| | - Naris Nilubol
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Mirko Parasiliti-Caprino
- Endocrinology, Diabetes and Metabolism, Department of Medical Sciences, University of Turin, Corso Dogliotti, Turin, Italy
| | - Henri H J L M Timmers
- Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, Netherlands
| | - Anna Lena Zietlow
- Clinical Child and Adolescent Psychology, Institute of Clinical Psychology and Psychotherapy, Department of Psychology, TU Dresden, Dresden, Germany
| | - Mercedes Robledo
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO) and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Institute of Health Carlos III (ISCIII), Madrid, Spain
| | - Anne-Paule Gimenez-Roqueplo
- Université Paris Cité, PARCC, INSERM, Paris, France
- Service de Génétique, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France
| | - Ashley B Grossman
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK
- Centre for Endocrinology, Barts and the London School of Medicine, London, UK
- ENETS Centre of Excellence, Royal Free Hospital, London, UK
| | - David Taïeb
- Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille University, Marseille, France
| | - Eamonn R Maher
- Department of Medical Genetics, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK
| | - Jacques W M Lenders
- Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, Netherlands
| | - Graeme Eisenhofer
- Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Camilo Jimenez
- Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Karel Pacak
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, MD, USA
| | - Christina Pamporaki
- Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
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6
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Timmers HJLM, Taïeb D, Pacak K, Lenders JWM. Imaging of Pheochromocytomas and Paragangliomas. Endocr Rev 2024; 45:414-434. [PMID: 38206185 PMCID: PMC11074798 DOI: 10.1210/endrev/bnae001] [Citation(s) in RCA: 22] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 12/11/2023] [Accepted: 01/10/2024] [Indexed: 01/12/2024]
Abstract
Pheochromocytomas/paragangliomas are unique in their highly variable molecular landscape driven by genetic alterations, either germline or somatic. These mutations translate into different clusters with distinct tumor locations, biochemical/metabolomic features, tumor cell characteristics (eg, receptors, transporters), and disease course. Such tumor heterogeneity calls for different imaging strategies in order to provide proper diagnosis and follow-up. This also warrants selection of the most appropriate and locally available imaging modalities tailored to an individual patient based on consideration of many relevant factors including age, (anticipated) tumor location(s), size, and multifocality, underlying genotype, biochemical phenotype, chance of metastases, as well as the patient's personal preference and treatment goals. Anatomical imaging using computed tomography and magnetic resonance imaging and functional imaging using positron emission tomography and single photon emission computed tomography are currently a cornerstone in the evaluation of patients with pheochromocytomas/paragangliomas. In modern nuclear medicine practice, a multitude of radionuclides with relevance to diagnostic work-up and treatment planning (theranostics) is available, including radiolabeled metaiodobenzylguanidine, fluorodeoxyglucose, fluorodihydroxyphenylalanine, and somatostatin analogues. This review amalgamates up-to-date imaging guidelines, expert opinions, and recent discoveries. Based on the rich toolbox for anatomical and functional imaging that is currently available, we aim to define a customized approach in patients with (suspected) pheochromocytomas/paragangliomas from a practical clinical perspective. We provide imaging algorithms for different starting points for initial diagnostic work-up and course of the disease, including adrenal incidentaloma, established biochemical diagnosis, postsurgical follow-up, tumor screening in pathogenic variant carriers, staging and restaging of metastatic disease, theranostics, and response monitoring.
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Affiliation(s)
- Henri J L M Timmers
- Department of Internal Medicine, Radboud University Medical Centre, 6525 GA Nijmegen, The Netherlands
| | - David Taïeb
- Department of Nuclear Medicine, La Timone University Hospital, Aix-Marseille University, Marseille, France and European Center for Research in Medical Imaging, Aix-Marseille University, 13005 Marseille, France
| | - Karel Pacak
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892-1583, USA
| | - Jacques W M Lenders
- Department of Internal Medicine, Radboud University Medical Centre, 6525 GA Nijmegen, The Netherlands
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Jeeyavudeen MS, Mathiyalagan N, Fernandez James C, Pappachan JM. Tumor metabolism in pheochromocytomas: clinical and therapeutic implications. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2024; 5:349-373. [PMID: 38745767 PMCID: PMC11090696 DOI: 10.37349/etat.2024.00222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Accepted: 12/27/2023] [Indexed: 05/16/2024] Open
Abstract
Pheochromocytomas and paragangliomas (PPGLs) have emerged as one of the most common endocrine tumors. It epitomizes fascinating crossroads of genetic, metabolic, and endocrine oncology, providing a canvas to explore the molecular intricacies of tumor biology. Predominantly rooted in the aberration of metabolic pathways, particularly the Krebs cycle and related enzymatic functionalities, PPGLs manifest an intriguing metabolic profile, highlighting elevated levels of oncometabolites like succinate and fumarate, and furthering cellular malignancy and genomic instability. This comprehensive review aims to delineate the multifaceted aspects of tumor metabolism in PPGLs, encapsulating genetic factors, oncometabolites, and potential therapeutic avenues, thereby providing a cohesive understanding of metabolic disturbances and their ramifications in tumorigenesis and disease progression. Initial investigations into PPGLs metabolomics unveiled a stark correlation between specific genetic mutations, notably in the succinate dehydrogenase complex (SDHx) genes, and the accumulation of oncometabolites, establishing a pivotal role in epigenetic alterations and hypoxia-inducible pathways. By scrutinizing voluminous metabolic studies and exploiting technologies, novel insights into the metabolic and genetic aspects of PPGLs are perpetually being gathered elucidating complex interactions and molecular machinations. Additionally, the exploration of therapeutic strategies targeting metabolic abnormalities has burgeoned harboring potential for innovative and efficacious treatment modalities. This review encapsulates the profound metabolic complexities of PPGLs, aiming to foster an enriched understanding and pave the way for future investigations and therapeutic innovations in managing these metabolically unique tumors.
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Affiliation(s)
| | - Navin Mathiyalagan
- Department of Medical Oncology, Nottingham University Hospitals NHS Trust, NG5 1PB Nottingham, UK
| | - Cornelius Fernandez James
- Department of Endocrinology & Metabolism, Pilgrim Hospital, United Lincolnshire Hospitals NHS Trust, PE21 9QS Boston, UK
| | - Joseph M. Pappachan
- Department of Endocrinology and Metabolism, Lancashire Teaching Hospitals NHS Trust, PR2 9HT Preston, UK
- Faculty of Science, Manchester Metropolitan University, M15 6BH Manchester, UK
- Faculty of Biology, Medicine, and Health, The University of Manchester, M13 9PL Manchester, UK
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Ferens FG, Taber CC, Stuart S, Hubert M, Tarade D, Lee JE, Ohh M. Deficiency in PHD2-mediated hydroxylation of HIF2α underlies Pacak-Zhuang syndrome. Commun Biol 2024; 7:240. [PMID: 38418569 PMCID: PMC10902354 DOI: 10.1038/s42003-024-05904-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 02/09/2024] [Indexed: 03/01/2024] Open
Abstract
Pacak-Zhuang syndrome is caused by mutations in the EPAS1 gene, which encodes for one of the three hypoxia-inducible factor alpha (HIFα) paralogs HIF2α and is associated with defined but varied phenotypic presentations including neuroendocrine tumors and polycythemia. However, the mechanisms underlying the complex genotype-phenotype correlations remain incompletely understood. Here, we devised a quantitative method for determining the dissociation constant (Kd) of the HIF2α peptides containing disease-associated mutations and the catalytic domain of prolyl-hydroxylase (PHD2) using microscale thermophoresis (MST) and showed that neuroendocrine-associated Class 1 HIF2α mutants have distinctly higher Kd than the exclusively polycythemia-associated Class 2 HIF2α mutants. Based on the co-crystal structure of PHD2/HIF2α peptide complex at 1.8 Å resolution, we showed that the Class 1 mutated residues are localized to the critical interface between HIF2α and PHD2, adjacent to the PHD2 active catalytic site, while Class 2 mutated residues are localized to the more flexible region of HIF2α that makes less contact with PHD2. Concordantly, Class 1 mutations were found to significantly increase HIF2α-mediated transcriptional activation in cellulo compared to Class 2 counterparts. These results reveal a structural mechanism in which the strength of the interaction between HIF2α and PHD2 is at the root of the general genotype-phenotype correlations observed in Pacak-Zhuang syndrome.
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Affiliation(s)
- Fraser G Ferens
- Department of Laboratory Medicine & Pathobiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
- Department of Biochemistry, Faculty of Medicine, University of Toronto, 661 University Avenue, Toronto, ON, M5G 1M1, Canada
| | - Cassandra C Taber
- Department of Laboratory Medicine & Pathobiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
| | - Sarah Stuart
- Department of Laboratory Medicine & Pathobiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
- Department of Biochemistry, Faculty of Medicine, University of Toronto, 661 University Avenue, Toronto, ON, M5G 1M1, Canada
| | - Mia Hubert
- Department of Laboratory Medicine & Pathobiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
| | - Daniel Tarade
- Department of Laboratory Medicine & Pathobiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
| | - Jeffrey E Lee
- Department of Laboratory Medicine & Pathobiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
| | - Michael Ohh
- Department of Laboratory Medicine & Pathobiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.
- Department of Biochemistry, Faculty of Medicine, University of Toronto, 661 University Avenue, Toronto, ON, M5G 1M1, Canada.
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Richter S, Steenblock C, Fischer A, Lemm S, Ziegler CG, Bechmann N, Nölting S, Pietzsch J, Ullrich M. Improving susceptibility of neuroendocrine tumors to radionuclide therapies: personalized approaches towards complementary treatments. Theranostics 2024; 14:17-32. [PMID: 38164150 PMCID: PMC10750207 DOI: 10.7150/thno.87345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 09/30/2023] [Indexed: 01/03/2024] Open
Abstract
Radionuclide therapies are an important tool for the management of patients with neuroendocrine neoplasms (NENs). Especially [131I]MIBG and [177Lu]Lu-DOTA-TATE are routinely used for the treatment of a subset of NENs, including pheochromocytomas, paragangliomas and gastroenteropancreatic tumors. Some patients suffering from other forms of NENs, such as medullary thyroid carcinoma or neuroblastoma, were shown to respond to radionuclide therapy; however, no general recommendations exist. Although [131I]MIBG and [177Lu]Lu-DOTA-TATE can delay disease progression and improve quality of life, complete remissions are achieved rarely. Hence, better individually tailored combination regimes are required. This review summarizes currently applied radionuclide therapies in the context of NENs and informs about recent advances in the development of theranostic agents that might enable targeting subgroups of NENs that previously did not respond to [131I]MIBG or [177Lu]Lu-DOTA-TATE. Moreover, molecular pathways involved in NEN tumorigenesis and progression that mediate features of radioresistance and are particularly related to the stemness of cancer cells are discussed. Pharmacological inhibition of such pathways might result in radiosensitization or general complementary antitumor effects in patients with certain genetic, transcriptomic, or metabolic characteristics. Finally, we provide an overview of approved targeted agents that might be beneficial in combination with radionuclide therapies in the context of a personalized molecular profiling approach.
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Affiliation(s)
- Susan Richter
- Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Charlotte Steenblock
- Department of Internal Medicine III, University Clinic Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Alessa Fischer
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ), and University of Zurich (UZH), Zurich, Switzerland
| | - Sandy Lemm
- Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
- Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, Dresden, Germany
| | - Christian G. Ziegler
- Department of Internal Medicine III, University Clinic Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- University Hospital Würzburg, Division of Endocrinology and Diabetes, Würzburg, Germany
| | - Nicole Bechmann
- Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Svenja Nölting
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ), and University of Zurich (UZH), Zurich, Switzerland
- Department of Medicine IV, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - Jens Pietzsch
- Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
- Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, Dresden, Germany
| | - Martin Ullrich
- Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
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Rosenblum JS, Wang H, Nazari MA, Zhuang Z, Pacak K. Pacak-Zhuang syndrome: a model providing new insights into tumor syndromes. Endocr Relat Cancer 2023; 30:e230050. [PMID: 37450881 PMCID: PMC10512798 DOI: 10.1530/erc-23-0050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2023] [Accepted: 07/14/2023] [Indexed: 07/18/2023]
Abstract
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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Affiliation(s)
- Jared S Rosenblum
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, United States
| | - Herui Wang
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, United States
| | - Matthew A Nazari
- Eunice Kennedy Shriver National Institute of Child Health and Development, Bethesda, MD, 20892
| | - Zhengping Zhuang
- Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, United States
| | - Karel Pacak
- Eunice Kennedy Shriver National Institute of Child Health and Development, Bethesda, MD, 20892
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Fischer A, Kloos S, Maccio U, Friemel J, Remde H, Fassnacht M, Pamporaki C, Eisenhofer G, Timmers HJLM, Robledo M, Fliedner SMJ, Wang K, Maurer J, Reul A, Zitzmann K, Bechmann N, Žygienė G, Richter S, Hantel C, Vetter D, Lehmann K, Mohr H, Pellegata NS, Ullrich M, Pietzsch J, Ziegler CG, Bornstein SR, Kroiss M, Reincke M, Pacak K, Grossman AB, Beuschlein F, Nölting S. Metastatic Pheochromocytoma and Paraganglioma: Somatostatin Receptor 2 Expression, Genetics, and Therapeutic Responses. J Clin Endocrinol Metab 2023; 108:2676-2685. [PMID: 36946182 PMCID: PMC10505550 DOI: 10.1210/clinem/dgad166] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2022] [Revised: 03/01/2023] [Accepted: 03/17/2023] [Indexed: 03/23/2023]
Abstract
CONTEXT Pheochromocytomas and paragangliomas (PPGLs) with pathogenic mutations in the succinate dehydrogenase subunit B (SDHB) are associated with a high metastatic risk. Somatostatin receptor 2 (SSTR2)-dependent imaging is the most sensitive imaging modality for SDHB-related PPGLs, suggesting that SSTR2 expression is a significant cell surface therapeutic biomarker of such tumors. OBJECTIVE Exploration of the relationship between SSTR2 immunoreactivity and SDHB immunoreactivity, mutational status, and clinical behavior of PPGLs. Evaluation of SSTR-based therapies in metastatic PPGLs. METHODS Retrospective analysis of a multicenter cohort of PPGLs at 6 specialized Endocrine Tumor Centers in Germany, The Netherlands, and Switzerland. Patients with PPGLs participating in the ENSAT registry were included. Clinical data were extracted from medical records, and immunohistochemistry (IHC) for SDHB and SSTR2 was performed in patients with available tumor tissue. Immunoreactivity of SSTR2 was investigated using Volante scores. The main outcome measure was the association of SSTR2 IHC positivity with genetic and clinical-pathological features of PPGLs. RESULTS Of 202 patients with PPGLs, 50% were SSTR2 positive. SSTR2 positivity was significantly associated with SDHB- and SDHx-related PPGLs, with the strongest SSTR2 staining intensity in SDHB-related PPGLs (P = .01). Moreover, SSTR2 expression was significantly associated with metastatic disease independent of SDHB/SDHx mutation status (P < .001). In metastatic PPGLs, the disease control rate with first-line SSTR-based radionuclide therapy was 67% (n = 22, n = 11 SDHx), and with first-line "cold" somatostatin analogs 100% (n = 6, n = 3 SDHx). CONCLUSION SSTR2 expression was independently associated with SDHB/SDHx mutations and metastatic disease. We confirm a high disease control rate of somatostatin receptor-based therapies in metastatic PPGLs.
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Affiliation(s)
- Alessa Fischer
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ), and University of Zurich (UZH), CH-8091 Zurich, Switzerland
| | - Simon Kloos
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ), and University of Zurich (UZH), CH-8091 Zurich, Switzerland
| | - Umberto Maccio
- Department of Pathology and Molecular Pathology, University Hospital Zurich, CH-8091 Zurich, Switzerland
| | - Juliane Friemel
- Department of Pathology and Molecular Pathology, University Hospital Zurich, CH-8091 Zurich, Switzerland
| | - Hanna Remde
- Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, 97080 Würzburg, Germany
| | - Martin Fassnacht
- Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, 97080 Würzburg, Germany
| | - Christina Pamporaki
- Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
| | - Graeme Eisenhofer
- Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
| | - Henri J L M Timmers
- Division of Endocrinology, Department of Internal Medicine, Radboud University Medical Center, 6525 GA Nijmegen, Netherlands
| | - Mercedes Robledo
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain
| | - Stephanie M J Fliedner
- First Department of Medicine, University Medical Center Schleswig-Holstein, 23538 Lübeck, Germany
| | - Katharina Wang
- Department of Medicine IV, University Hospital, Ludwig-Maximilians-University Munich, 80336 Munich, Germany
| | - Julian Maurer
- Department of Medicine IV, University Hospital, Ludwig-Maximilians-University Munich, 80336 Munich, Germany
| | - Astrid Reul
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ), and University of Zurich (UZH), CH-8091 Zurich, Switzerland
| | - Kathrin Zitzmann
- Department of Medicine IV, University Hospital, Ludwig-Maximilians-University Munich, 80336 Munich, Germany
| | - Nicole Bechmann
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse, 01307 Dresden, Germany
| | - Gintarė Žygienė
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse, 01307 Dresden, Germany
| | - Susan Richter
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse, 01307 Dresden, Germany
| | - Constanze Hantel
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ), and University of Zurich (UZH), CH-8091 Zurich, Switzerland
- Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
| | - Diana Vetter
- Department of Visceral and Transplantation Surgery, University Hospital, 8091 Zürich, Switzerland
| | - Kuno Lehmann
- Department of Visceral and Transplantation Surgery, University Hospital, 8091 Zürich, Switzerland
| | - Hermine Mohr
- Institute for Diabetes and Cancer, Helmholtz Zentrum München, 85764 Neuherberg, Germany
| | - Natalia S Pellegata
- Institute for Diabetes and Cancer, Helmholtz Zentrum München, 85764 Neuherberg, Germany
- Department of Biology and Biotechnology, University of Pavia, 27100 Pavia, Italy
| | - Martin Ullrich
- Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
| | - Jens Pietzsch
- Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Dresden, Germany
- Faculty of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, Dresden, Germany
| | - Christian G Ziegler
- Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, 97080 Würzburg, Germany
- Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
| | - Stefan R Bornstein
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ), and University of Zurich (UZH), CH-8091 Zurich, Switzerland
- Department of Internal Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
| | - Matthias Kroiss
- Department of Medicine IV, University Hospital, Ludwig-Maximilians-University Munich, 80336 Munich, Germany
| | - Martin Reincke
- Department of Medicine IV, University Hospital, Ludwig-Maximilians-University Munich, 80336 Munich, Germany
| | - Karel Pacak
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, MD 20847, USA
| | - Ashley B Grossman
- Green Templeton College, University of Oxford, Oxford, UK
- NET Unit, ENETS Centre of Excellence, Royal Free Hospital, London, UK
| | - Felix Beuschlein
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ), and University of Zurich (UZH), CH-8091 Zurich, Switzerland
- Department of Medicine IV, University Hospital, Ludwig-Maximilians-University Munich, 80336 Munich, Germany
| | - Svenja Nölting
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ), and University of Zurich (UZH), CH-8091 Zurich, Switzerland
- Department of Medicine IV, University Hospital, Ludwig-Maximilians-University Munich, 80336 Munich, Germany
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Wahbi S, Cherkaoui SB, Aynaou H, Salhi H, El Ouahabi H. Pheochromocytoma in an Ectopic Adrenal Gland. Cureus 2023; 15:e40068. [PMID: 37425549 PMCID: PMC10326456 DOI: 10.7759/cureus.40068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/06/2023] [Indexed: 07/11/2023] Open
Abstract
A pheochromocytoma is an uncommon tumor that originates from the chromaffin cells of the adrenal medulla. Also, adrenal tissue not located in its typical position is referred to as ectopic adrenal tissue. It is relatively uncommon in adults and is usually asymptomatic. Therefore, a pheochromocytoma arising from ectopic adrenal tissue is even a rarer finding and presents as a unique diagnostic challenge. A 20-year-old man presented with vague abdominal pain, and upon imaging, a mass located behind the liver was initially discovered. Subsequently, it was identified as a mass growing in an ectopic adrenal gland. He underwent exploratory laparotomy and resection of the mass. A pheochromocytoma in an ectopic adrenal gland was confirmed by histopathology.
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Affiliation(s)
- Salma Wahbi
- Department of Endocrinology, Diabetology, Metabolic Diseases and Nutrition, Hassan II University Hospital, Fez, MAR
| | - Siham B Cherkaoui
- Department of Endocrinology, Diabetology, Metabolic Diseases and Nutrition, Hassan II University Hospital, Fez, MAR
| | - Hayat Aynaou
- Department of Endocrinology, Diabetology, Metabolic Diseases and Nutrition, Hassan II University Hospital, Fes, MAR
| | - Houda Salhi
- Department of Endocrinology, Diabetology, Metabolic Diseases and Nutrition, Hassan II University Hospital, Fez, MAR
| | - Hanan El Ouahabi
- Department of Endocrinology, Diabetology, Metabolic Diseases and Nutrition, Hassan II University Hospital, Fez, MAR
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Zhou Y, Cui Y, Zhang D, Tong A. Efficacy and Safety of Tyrosine Kinase Inhibitors in Patients with Metastatic Pheochromocytomas/Paragangliomas. J Clin Endocrinol Metab 2023; 108:755-766. [PMID: 36383456 DOI: 10.1210/clinem/dgac657] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2022] [Revised: 11/08/2022] [Accepted: 11/10/2022] [Indexed: 11/17/2022]
Abstract
CONTEXT Tyrosine kinase inhibitors (TKIs) can be used to treat locally unresectable or distantly metastatic pheochromocytomas/paragangliomas (PPGLs), such as sunitinib, according to the National Comprehensive Cancer Network guidelines in 2022. However, the precise effect of different TKIs in metastatic PPGLs is still unclear. OBJECTIVE The aim of this meta-analysis is to assess the efficacy and safety of TKIs in metastatic PPGLs. METHODS The PubMed, Cochrane Library, Scopus, Clinical Trial, and Embase databases were searched by synonyms of 48 TKIs and metastatic PPGLs from inception up to August 2022. Outcomes were tumor response or survival data and the incidence of adverse events (AEs) after treatment. The MIONRS scale and the JBI's tools for case series were used for interventional and observational studies to assess risk of bias, respectively. The combined effects with fixed- or random-effect models, the combined median with the weighted median of medians method and their 95% CIs were reported. RESULTS A total of 7 studies with 160 patients were included. Tumor responses in metastatic PPGLs in 5 studies with available data showed the pooled proportion of partial response (PR), stable disease, and disease control rate (DCR) of, respectively, 0.320 (95% CI 0.155-0.486), 0.520 (95% CI 0.409-0.630), and 0.856 (95% CI 0.734-0.979). The combined median progressive-free survival in 6 studies was 8.9 months (95% CI 4.1-13.5) and the proportion of those who discontinued due to AEs in 5 studies was 0.143 (95% CI 0.077-0.209). CONCLUSION This meta-analysis suggests that patients with metastatic PPGLs can benefit from TKI therapy with PR and DCR up to more than 30% and 80%. However, because of restricted studies, larger clinical trials should be performed in the future.
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Affiliation(s)
- Yue Zhou
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission of the People's Republic of China, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Yunying Cui
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission of the People's Republic of China, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Dingding Zhang
- Medical Research Center, State Key laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Anli Tong
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health Commission of the People's Republic of China, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
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14
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Bevere M, Gkountakos A, Martelli FM, Scarpa A, Luchini C, Simbolo M. An Insight on Functioning Pancreatic Neuroendocrine Neoplasms. Biomedicines 2023; 11:303. [PMID: 36830839 PMCID: PMC9953748 DOI: 10.3390/biomedicines11020303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Revised: 01/16/2023] [Accepted: 01/18/2023] [Indexed: 01/24/2023] Open
Abstract
Pancreatic neuroendocrine neoplasms (PanNENs) are rare neoplasms arising from islets of the Langerhans in the pancreas. They can be divided into two groups, based on peptide hormone secretion, functioning and nonfunctioning PanNENs. The first group is characterized by different secreted peptides causing specific syndromes and is further classified into subgroups: insulinoma, gastrinoma, glucagonoma, somatostatinoma, VIPoma and tumors producing serotonin and adrenocorticotrophic hormone. Conversely, the second group does not release peptides and is usually associated with a worse prognosis. Today, although the efforts to improve the therapeutic approaches, surgery remains the only curative treatment for patients with PanNENs. The development of high-throughput techniques has increased the molecular knowledge of PanNENs, thereby allowing us to understand better the molecular biology and potential therapeutic vulnerabilities of PanNENs. Although enormous advancements in therapeutic and molecular aspects of PanNENs have been achieved, there is poor knowledge about each subgroup of functioning PanNENs.Therefore, we believe that combining high-throughput platforms with new diagnostic tools will allow for the efficient characterization of the main differences among the subgroups of functioning PanNENs. In this narrative review, we summarize the current landscape regarding diagnosis, molecular profiling and treatment, and we discuss the future perspectives of functioning PanNENs.
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Affiliation(s)
- Michele Bevere
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy
- ARC-Net Applied Research on Cancer Centre, University and Hospital Trust of Verona, 37134 Verona, Italy
| | - Anastasios Gkountakos
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy
- ARC-Net Applied Research on Cancer Centre, University and Hospital Trust of Verona, 37134 Verona, Italy
| | - Filippo Maria Martelli
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy
- ARC-Net Applied Research on Cancer Centre, University and Hospital Trust of Verona, 37134 Verona, Italy
| | - Claudio Luchini
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy
| | - Michele Simbolo
- Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy
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15
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Pacak K. New Biology of Pheochromocytoma and Paraganglioma. Endocr Pract 2022; 28:1253-1269. [PMID: 36150627 PMCID: PMC9982632 DOI: 10.1016/j.eprac.2022.09.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 09/12/2022] [Accepted: 09/13/2022] [Indexed: 12/13/2022]
Abstract
Pheochromocytomas and paragangliomas continue to be defined by significant morbidity and mortality despite their several recent advances in diagnosis, localization, and management. These adverse outcomes are largely related to mass effect as well as catecholamine-induced hypertension, tachyarrhythmias and consequent target organ damage, acute coronary syndromes, and strokes (ischemic and hemorrhagic stroke). Thus, a proper understanding of the physiology and pathophysiology of these tumors and recent advances are essential to affording optimal care. These major developments largely include a redefinition of metastatic behavior, a novel clinical categorization of these tumors into 3 genetic clusters, and an enhanced understanding of catecholamine metabolism and consequent specific biochemical phenotypes. Current advances in imaging of these tumors are shifting the paradigm from poorly specific anatomical modalities to more precise characterization of these tumors using the advent and development of functional imaging modalities. Furthermore, recent advances have revealed new molecular events in these tumors that are linked to their genetic landscape and, therefore, provide new therapeutic platforms. A few of these prospective therapies translated into new clinical trials, especially for patients with metastatic or inoperable tumors. Finally, outcomes are ever-improving as patients are cared for at centers with cumulative experience and well-established multidisciplinary tumor boards. In parallel, these centers have supported national and international collaborative efforts and worldwide clinical trials. These concerted efforts have led to improved guidelines collaboratively developed by healthcare professionals with a growing expertise in these tumors and consequently improving detection, prevention, and identification of genetic susceptibility genes in these patients.
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Affiliation(s)
- Karel Pacak
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.
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16
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Yu R, Rao J, Zhai J, Hecht JR, Pisegna JR. Familial Duodenal Somatostatinomatosis Not Associated With a Known Genetic Syndrome. Pancreas 2022; 51:1056-1060. [PMID: 36607953 DOI: 10.1097/mpa.0000000000002126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
We report a father and his daughter who both had multiple somatostatinomas in the duodenal bulb without a known syndrome. The father, at age 68 years, was incidentally found to harbor 4 approximately 1.5-cm well-differentiated neuroendocrine tumors in the duodenal bulb. His preoperative somatostatin level was elevated. He underwent partial duodenectomy and regional lymph node dissection; one lymph node was positive for metastasis. One year postoperatively, a recurrence was found in the surgical bed; he was treated with octreotide for 2 years, which stabilized the recurrent tumor. Ten years postoperatively, the mucosa of his remaining duodenum was normal. His daughter, at age 53 years, was found to harbor multiple small neuroendocrine tumors in the duodenal bulb. Immunostaining of available specimens showed that the neuroendocrine tumors from the father and daughter both were strongly positive for somatostatin. Micronodules of somatostatin-expressing neuroendocrine cells were found in the parts of the specimens uninvolved with the tumors. Both patients exhibited no evidence of known syndromes associated with somatostatinoma. The daughter did not harbor mutations in 93 genes commonly found in genetic tumor syndromes. The 2 cases thus suggest a novel, autosomal dominant, genetic syndrome of familial duodenal somatostatinomatosis.
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Affiliation(s)
- Run Yu
- From the Departments of Medicine
| | - Jianyu Rao
- Pathology and Laboratory Medicine, UCLA David Geffen School of Medicine
| | - Jing Zhai
- Department of Pathology, Cedars-Sinai Medical Center
| | | | - Joseph R Pisegna
- Department of Veterans Affairs, UCLA David Geffen School of Medicine, Los Angeles, CA
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17
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Ohh M, Taber CC, Ferens FG, Tarade D. Hypoxia-inducible factor underlies von Hippel-Lindau disease stigmata. eLife 2022; 11:80774. [PMID: 36040300 PMCID: PMC9427099 DOI: 10.7554/elife.80774] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2022] [Accepted: 08/12/2022] [Indexed: 11/13/2022] Open
Abstract
von Hippel-Lindau (VHL) disease is a rare hereditary cancer syndrome that causes a predisposition to renal clear-cell carcinoma, hemangioblastoma, pheochromocytoma, and autosomal-recessive familial polycythemia. pVHL is the substrate conferring subunit of an E3 ubiquitin ligase complex that binds to the three hypoxia-inducible factor alpha subunits (HIF1-3α) for polyubiquitylation under conditions of normoxia, targeting them for immediate degradation by the proteasome. Certain mutations in pVHL have been determined to be causative of VHL disease through the disruption of HIFα degradation. However, it remains a focus of investigation and debate whether the disruption of HIFα degradation alone is sufficient to explain the complex genotype-phenotype relationship of VHL disease or whether the other lesser or yet characterized substrates and functions of pVHL impact the development of the VHL disease stigmata; the elucidation of which would have a significant ramification to the direction of research efforts and future management and care of VHL patients and for those manifesting sporadic counterparts of VHL disease. Here, we examine the current literature including the other emergent pseudohypoxic diseases and propose that the VHL disease-phenotypic spectrum could be explained solely by the varied disruption of HIFα signaling upon the loss or mutation in pVHL.
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Affiliation(s)
- Michael Ohh
- Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada.,Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, Canada
| | - Cassandra C Taber
- Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada
| | - Fraser G Ferens
- Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada.,Department of Biochemistry, Faculty of Medicine, University of Toronto, Toronto, Canada
| | - Daniel Tarade
- Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada
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18
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Nölting S, Bechmann N, Taieb D, Beuschlein F, Fassnacht M, Kroiss M, Eisenhofer G, Grossman A, Pacak K. Personalized Management of Pheochromocytoma and Paraganglioma. Endocr Rev 2022; 43:199-239. [PMID: 34147030 PMCID: PMC8905338 DOI: 10.1210/endrev/bnab019] [Citation(s) in RCA: 202] [Impact Index Per Article: 67.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Indexed: 02/07/2023]
Abstract
Pheochromocytomas/paragangliomas are characterized by a unique molecular landscape that allows their assignment to clusters based on underlying genetic alterations. With around 30% to 35% of Caucasian patients (a lower percentage in the Chinese population) showing germline mutations in susceptibility genes, pheochromocytomas/paragangliomas have the highest rate of heritability among all tumors. A further 35% to 40% of Caucasian patients (a higher percentage in the Chinese population) are affected by somatic driver mutations. Thus, around 70% of all patients with pheochromocytoma/paraganglioma can be assigned to 1 of 3 main molecular clusters with different phenotypes and clinical behavior. Krebs cycle/VHL/EPAS1-related cluster 1 tumors tend to a noradrenergic biochemical phenotype and require very close follow-up due to the risk of metastasis and recurrence. In contrast, kinase signaling-related cluster 2 tumors are characterized by an adrenergic phenotype and episodic symptoms, with generally a less aggressive course. The clinical correlates of patients with Wnt signaling-related cluster 3 tumors are currently poorly described, but aggressive behavior seems likely. In this review, we explore and explain why cluster-specific (personalized) management of pheochromocytoma/paraganglioma is essential to ascertain clinical behavior and prognosis, guide individual diagnostic procedures (biochemical interpretation, choice of the most sensitive imaging modalities), and provide personalized management and follow-up. Although cluster-specific therapy of inoperable/metastatic disease has not yet entered routine clinical practice, we suggest that informed personalized genetic-driven treatment should be implemented as a logical next step. This review amalgamates published guidelines and expert views within each cluster for a coherent individualized patient management plan.
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Affiliation(s)
- Svenja Nölting
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), CH-8091 Zurich, Switzerland.,Department of Medicine IV, University Hospital, LMU Munich, 80336 Munich, Germany
| | - Nicole Bechmann
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.,Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
| | - David Taieb
- Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille University, 13273 Marseille, France
| | - Felix Beuschlein
- Department of Endocrinology, Diabetology and Clinical Nutrition, University Hospital Zurich (USZ) and University of Zurich (UZH), CH-8091 Zurich, Switzerland.,Department of Medicine IV, University Hospital, LMU Munich, 80336 Munich, Germany
| | - Martin Fassnacht
- Department of Medicine, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, 97080 Würzburg, Germany
| | - Matthias Kroiss
- Department of Medicine IV, University Hospital, LMU Munich, 80336 Munich, Germany.,Department of Medicine, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, 97080 Würzburg, Germany
| | - Graeme Eisenhofer
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany.,Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
| | - Ashley Grossman
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX2 6HG, UK.,Centre for Endocrinology, Barts and the London School of Medicine, London EC1M 6BQ, UK.,ENETS Centre of Excellence, Royal Free Hospital, London NW3 2QG, UK
| | - Karel Pacak
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Rockville, MD 20847, USA
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19
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Genetics of Pheochromocytomas and Paragangliomas Determine the Therapeutical Approach. Int J Mol Sci 2022; 23:ijms23031450. [PMID: 35163370 PMCID: PMC8836037 DOI: 10.3390/ijms23031450] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 01/21/2022] [Accepted: 01/24/2022] [Indexed: 02/06/2023] Open
Abstract
Pheochromocytomas and paragangliomas are the most heritable endocrine tumors. In addition to the inherited mutation other driver mutations have also been identified in tumor tissues. All these genetic alterations are clustered in distinct groups which determine the pathomechanisms. Most of these tumors are benign and their surgical removal will resolve patient management. However, 5–15% of them are malignant and therapeutical possibilities for them are limited. This review provides a brief insight about the tumorigenesis associated with pheochromocytomas/paragangliomas in order to present them as potential therapeutical targets.
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20
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Jhawar S, Arakawa Y, Kumar S, Varghese D, Kim YS, Roper N, Elloumi F, Pommier Y, Pacak K, Del Rivero J. New Insights on the Genetics of Pheochromocytoma and Paraganglioma and Its Clinical Implications. Cancers (Basel) 2022; 14:cancers14030594. [PMID: 35158861 PMCID: PMC8833412 DOI: 10.3390/cancers14030594] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 01/19/2022] [Accepted: 01/20/2022] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Pheochromocytoma and paraganglioma (together PPGL) are rare neuroendocrine tumors that arise from chromaffin tissue and produce catecholamines. Approximately 40% of cases of PPGL carry a germline mutation, suggesting that they have a high degree of heritability. The underlying mutation influences the PPGL clinical presentation such as cell differentiation, specific catecholamine production, tumor location, malignant potential and genetic anticipation, which helps to better understand the clinical course and tailor treatment accordingly. Genetic testing for pheochromocytoma and paraganglioma allows an early detection of hereditary syndromes and facilitates a close follow-up of high-risk patients. In this review article, we present the most recent advances in the field of genetics and we discuss the latest guidelines on the surveillance of asymptomatic SDHx mutation carriers. Abstract Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare neuroendocrine tumors that arise from chromaffin cells. PHEOs arise from the adrenal medulla, whereas PGLs arise from the neural crest localized outside the adrenal gland. Approximately 40% of all cases of PPGLs (pheochromocytomas/paragangliomas) are associated with germline mutations and 30–40% display somatic driver mutations. The mutations associated with PPGLs can be classified into three groups. The pseudohypoxic group or cluster I includes the following genes: SDHA, SDHB, SDHC, SDHD, SDHAF2, FH, VHL, IDH1/2, MHD2, EGLN1/2 and HIF2/EPAS; the kinase group or cluster II includes RET, NF1, TMEM127, MAX and HRAS; and the Wnt signaling group or cluster III includes CSDE1 and MAML3. Underlying mutations can help understand the clinical presentation, overall prognosis and surveillance follow-up. Here we are discussing the new genetic insights of PPGLs.
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Affiliation(s)
- Sakshi Jhawar
- Life Bridge Health Center, Internal Medicine Program, Sinai Hospital of Baltimore, Baltimore, MD 21215, USA
| | - Yasuhiro Arakawa
- Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Suresh Kumar
- Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Diana Varghese
- Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Yoo Sun Kim
- Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Nitin Roper
- Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Fathi Elloumi
- Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Yves Pommier
- Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Karel Pacak
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Jaydira Del Rivero
- Developmental Therapeutics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA
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21
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Kuo MJM, Nazari MA, Jha A, Pacak K. Pediatric Metastatic Pheochromocytoma and Paraganglioma: Clinical Presentation and Diagnosis, Genetics, and Therapeutic Approaches. Front Endocrinol (Lausanne) 2022; 13:936178. [PMID: 35903274 PMCID: PMC9314859 DOI: 10.3389/fendo.2022.936178] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Accepted: 06/13/2022] [Indexed: 12/18/2022] Open
Abstract
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 (VHL) and succinate dehydrogenase subunit (SDHx) genes, with the highest risk for metastatic disease associated with variants in SDHB and SDHA. 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.
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Affiliation(s)
- Mickey J. M. Kuo
- Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Matthew A. Nazari
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Abhishek Jha
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Karel Pacak
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
- *Correspondence: Karel Pacak,
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22
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Kamihara J, Hamilton KV, Pollard JA, Clinton CM, Madden JA, Lin J, Imamovic A, Wall CB, Wassner AJ, Weil BR, Heeney MM, Vargas SO, Kaelin WG, Janeway KA, Perini RF, Zojwalla NJ, Voss SD, DuBois SG. Belzutifan, a Potent HIF2α Inhibitor, in the Pacak-Zhuang Syndrome. N Engl J Med 2021; 385:2059-2065. [PMID: 34818480 PMCID: PMC11245359 DOI: 10.1056/nejmoa2110051] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The integration of genomic testing into clinical care enables the use of individualized approaches to the management of rare diseases. We describe the use of belzutifan, a potent and selective small-molecule inhibitor of the protein hypoxia-inducible factor 2α (HIF2α), in a patient with polycythemia and multiple paragangliomas (the Pacak-Zhuang syndrome). The syndrome was caused in this patient by somatic mosaicism for an activating mutation in EPAS1. Treatment with belzutifan led to a rapid and sustained tumor response along with resolution of hypertension, headaches, and long-standing polycythemia. This case shows the application of a targeted therapy for the treatment of a patient with a rare tumor-predisposition syndrome. (Funded by the Morin Family Fund for Pediatric Cancer and Alex's Lemonade Stand Foundation.).
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Affiliation(s)
- Junne Kamihara
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA
- Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston MA
| | - Kayla V. Hamilton
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA
| | - Jessica A. Pollard
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA
- Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston MA
| | - Catherine M. Clinton
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA
| | - Jill A. Madden
- The Manton Center for Orphan Disease Research and The Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA
| | - Jasmine Lin
- The Manton Center for Orphan Disease Research and The Division of Genetics and Genomics, Boston Children’s Hospital, Boston, MA
| | - Alma Imamovic
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA
| | - Catherine B. Wall
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA
| | - Ari J. Wassner
- Division of Endocrinology, Boston Children’s Hospital, Harvard Medical School, Boston, MA
| | - Brent R. Weil
- Department of Surgery, Boston Children’s Hospital, Harvard Medical School, Boston, MA
| | - Matthew M. Heeney
- Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston MA
| | - Sara O. Vargas
- Department of Pathology, Boston Children’s Hospital, Harvard Medical School, Boston, MA
| | - William G. Kaelin
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA
- Howard Hughes Medical Institute, Chevy Chase, MD
| | - Katherine A. Janeway
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA
- Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston MA
| | | | | | - Stephan D. Voss
- Department of Radiology, Boston Children’s Hospital, Harvard Medical School, Boston, MA
| | - Steven G. DuBois
- Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston MA
- Division of Hematology/Oncology, Boston Children’s Hospital, Harvard Medical School, Boston MA
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23
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Steck A, Nebiker C, Capraro J, Yurtsever H, Toutonji AA, Struja T. [VIPoma of the Pancreas]. PRAXIS 2021; 110:637-642. [PMID: 34465193 DOI: 10.1024/1661-8157/a003714] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
VIPoma of the Pancreas Abstract. A 50-year old man was admitted for evaluation of progressive, chronic diarrhea with loss of weight and recurrent hypokalemia. Eventually, a neuroendocrine tumor of the pancreas secreting VIP (VIPoma) could be diagnosed. The patient was cured by a pancreaticoduodenectomy (Whipple procedure). With this case, we want to highlight the importance of a structured work-up in chronic diarrhea including thorough history and clinical assessment, laboratory tests and imaging studies.
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Affiliation(s)
- Andreas Steck
- Abteilung für Allgemeine Innere Medizin, Spital Zofingen, Zofingen
| | - Christian Nebiker
- Abteilung für Viszeralchirurgie, Klinik für Chirurgie, Kantonsspital Aarau, Aarau
| | - Joël Capraro
- Abteilung für Allgemeine Innere Medizin, Spital Zofingen, Zofingen
- bteilung für Endokrinologie, Diabetologie und Metabolismus, Medizinische Universitätsklinik, Kantonsspital Aarau, Aarau
| | | | - Ali Al Toutonji
- Abteilung für Allgemeine Innere Medizin, Spital Zofingen, Zofingen
| | - Tristan Struja
- Abteilung für Allgemeine Innere Medizin, Spital Zofingen, Zofingen
- bteilung für Endokrinologie, Diabetologie und Metabolismus, Medizinische Universitätsklinik, Kantonsspital Aarau, Aarau
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24
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Bechmann N, Eisenhofer G. Hypoxia-inducible Factor 2α: A Key Player in Tumorigenesis and Metastasis of Pheochromocytoma and Paraganglioma? Exp Clin Endocrinol Diabetes 2021; 130:282-289. [PMID: 34320663 DOI: 10.1055/a-1526-5263] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Germline or somatic driver mutations linked to specific phenotypic features are identified in approximately 70% of all catecholamine-producing pheochromocytomas and paragangliomas (PPGLs). Mutations leading to stabilization of hypoxia-inducible factor 2α (HIF2α) and downstream pseudohypoxic signaling are associated with a higher risk of metastatic disease. Patients with metastatic PPGLs have a variable prognosis and treatment options are limited. In most patients with PPGLs, germline mutations lead to the stabilization of HIF2α. Mutations in HIF2α itself are associated with adrenal pheochromocytomas and/or extra-adrenal paragangliomas and about 30% of these patients develop metastatic disease; nevertheless, the frequency of these specific mutations is low (1.6-6.2%). Generally, mutations that lead to stabilization of HIF2α result in distinct catecholamine phenotype through blockade of glucocorticoid-mediated induction of phenylethanolamine N-methyltransferase, leading to the formation of tumors that lack epinephrine. HIF2α, among other factors, also contributes importantly to the initiation of a motile and invasive phenotype. Specifically, the expression of HIF2α supports a neuroendocrine-to-mesenchymal transition and the associated invasion-metastasis cascade, which includes the formation of pseudopodia to facilitate penetration into adjacent vasculature. The HIF2α-mediated expression of adhesion and extracellular matrix genes also promotes the establishment of PPGL cells in distant tissues. The involvement of HIF2α in tumorigenesis and in multiple steps of invasion-metastasis cascade underscores the therapeutic relevance of targeting HIF2α signaling pathways in PPGLs. However, due to emerging resistance to current HIF2α inhibitors that target HIF2α binding to specific partners, alternative HIF2α signaling pathways and downstream actions should also be considered for therapeutic intervention.
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Affiliation(s)
- Nicole Bechmann
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,German Institute of Human Nutrition Potsdam-Rehbruecke, Department of Experimental Diabetology, Nuthetal, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Graeme Eisenhofer
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.,Department of Medicine III, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
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Ryder SJ, Love AJ, Duncan EL, Pattison DA. PET detectives: Molecular imaging for phaeochromocytomas and paragangliomas in the genomics era. Clin Endocrinol (Oxf) 2021; 95:13-28. [PMID: 33296100 DOI: 10.1111/cen.14375] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 11/15/2020] [Accepted: 11/20/2020] [Indexed: 01/26/2023]
Abstract
Phaeochromocytomas and paragangliomas (PPGLs) are rare tumours that arise from the adrenal medulla or extra-adrenal sympathetic or parasympathetic paraganglia. Recent advances in genetics have greatly enhanced understanding of the pathogenesis and molecular physiology of PPGL. Concomitantly, advances in molecular imaging mean four techniques are now available for use in PPGLs: [123 I]-MIBG coupled with SPECT/CT; [18 F]- FDG, [68 Ga]-DOTATATE and [18 F]-FDOPA coupled with PET/CT. Each modality relies on unique cellular uptake mechanisms that are contingent upon the tumour's molecular behaviour-which, in turn, is determined by the tumour's genetic profile. This genotype-phenotype correlation means the appropriate choice of radiotracer may depend on the known (or suspected) underlying genetic mutation, in addition to the clinical indication for the scan-whether confirming diagnosis, staging disease, surveillance or determining eligibility for radionuclide therapy. Given these rapid recent changes in genetic understanding and molecular imaging options, many clinicians find it challenging to choose the most appropriate scan for an individual with PPGL. To this end, recent guidelines published by the European Association of Nuclear Medicine and the Society of Nuclear Medicine and Molecular Imaging (EANM/SNMMI) have detailed the preferred radiotracer choices for individuals with PPGL based on their genotype and/or clinical presentation, providing timely clarity in this rapidly moving field. The current review summarizes the implications of the genotype-phenotype relationship of PPGL, specifically relating this to the performance of molecular imaging modalities, to inform and enable practising endocrinologists to provide tailored, personalized care for individuals with PPGL.
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Affiliation(s)
- Simon J Ryder
- Department of Endocrinology and Diabetes, Royal Brisbane and Women's Hospital, Herston, Australia
- Faculty of Medicine, University of Queensland, Brisbane, Australia
| | - Amanda J Love
- Department of Endocrinology and Diabetes, Royal Brisbane and Women's Hospital, Herston, Australia
| | - Emma L Duncan
- Faculty of Medicine, University of Queensland, Brisbane, Australia
- Professor of Clinical Endocrinology, Department of Twin Research & Genetic Epidemiology, School of Life Course Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK
- The Department of Endocrinology, St Thomas' Hospital, Guy's and St Thomas' NHS Trust, London, UK
| | - David A Pattison
- Faculty of Medicine, University of Queensland, Brisbane, Australia
- Department of Nuclear Medicine & Specialised PET Services, Royal Brisbane and Women's Hospital, Herston, Australia
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Abstract
PURPOSE OF REVIEW This review summarizes our current understanding of germline and somatic genetics and genomics of pheochromocytomas and paragangliomas (PCC/PGL), describes existing knowledge gaps, and discusses future research directions. RECENT FINDINGS Germline pathogenic variants (PVs) are found in up to 40% of those with PCC/PGL. Tumors with germline PVs are broadly categorized as Cluster 1 (pseudohypoxia), including those with SDH, VHL, FH, and EPAS1 PVs, or Cluster 2 (kinase signaling) including those with NF1, RET, TMEM127, and MAX PVs. Somatic driver mutations exist in some of the same genes (RET, VHL, NF1, EPAS1) as well as in additional genes including HRAS, CSDE1 and genes involved in cell immortalization (ATRX and TERT). Other somatic driver events include recurrent fusion genes involving MAML3. SUMMARY PCC/PGL have the highest association with germline PVs of all human solid tumors. Expanding our understanding of the molecular pathogenesis of PCC/PGL is essential to advancements in diagnosis and surveillance and the development of novel therapies for these unique tumors.
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Affiliation(s)
- Heather Wachtel
- Hospital of the University of Pennsylvania, Department of Surgery, Division of Endocrine and Oncologic Surgery and the Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Lauren Fishbein
- University of Colorado School of Medicine, Department of Medicine, Division of Endocrinology, Metabolism and Diabetes and the Division of Biomedical Informatics and Personalized Medicine, University of Colorado, Aurora, Colorado, USA
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Rosenblum JS, Wang H, Dmitriev PM, Cappadona AJ, Mastorakos P, Xu C, Jha A, Edwards N, Donahue DR, Munasinghe J, Nazari MA, Knutsen RH, Rosenblum BR, Smirniotopoulos JG, Pappo A, Spetzler RF, Vortmeyer A, Gilbert MR, McGavern DB, Chew E, Kozel BA, Heiss JD, Zhuang Z, Pacak K. Developmental vascular malformations in EPAS1 gain-of-function syndrome. JCI Insight 2021; 6:144368. [PMID: 33497361 PMCID: PMC8021124 DOI: 10.1172/jci.insight.144368] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 01/21/2021] [Indexed: 12/21/2022] Open
Abstract
Mutations in EPAS1, encoding hypoxia-inducible factor-2α (HIF-2α), were previously identified in a syndrome of multiple paragangliomas, somatostatinoma, and polycythemia. HIF-2α, when dimerized with HIF-1β, acts as an angiogenic transcription factor. Patients referred to the NIH for new, recurrent, and/or metastatic paraganglioma or pheochromocytoma were confirmed for EPAS1 gain-of-function mutation; imaging was evaluated for vascular malformations. We evaluated the Epas1A529V transgenic syndrome mouse model, corresponding to the mutation initially detected in the patients (EPAS1A530V), for vascular malformations via intravital 2-photon microscopy of meningeal vessels, terminal vascular perfusion with Microfil silicate polymer and subsequent intact ex vivo 14T MRI and micro-CT, and histologic sectioning and staining of the brain and identified pathologies. Further, we evaluated retinas from corresponding developmental time points (P7, P14, and P21) and the adult dura via immunofluorescent labeling of vessels and confocal imaging. We identified a spectrum of vascular malformations in all 9 syndromic patients and in all our tested mutant mice. Patient vessels had higher variant allele frequency than adjacent normal tissue. Veins of the murine retina and intracranial dura failed to regress normally at the expected developmental time points. These findings add vascular malformation as a new clinical feature of EPAS1 gain-of-function syndrome. We discovered vascular malformations due to failure of developmental vascular regression in patients with EPAS1 gain-of-function mutation syndrome and the corresponding transgenic mouse model.
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Affiliation(s)
- Jared S Rosenblum
- Neuro-Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Herui Wang
- Neuro-Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Pauline M Dmitriev
- Neuro-Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Anthony J Cappadona
- Neuro-Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Panagiotis Mastorakos
- Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA.,Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA
| | - Chen Xu
- Neuro-Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Abhishek Jha
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver, National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA
| | - Nancy Edwards
- Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA
| | - Danielle R Donahue
- Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA
| | - Jeeva Munasinghe
- Mouse Imaging Facility, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA
| | - Matthew A Nazari
- Internal Medicine and Pediatrics, MedStar Georgetown University Hospital, Washington, DC, USA
| | - Russell H Knutsen
- Laboratory of Vascular and Matrix Genetics, National Heart Lung and Blood Institute, NIH, Bethesda, Maryland, USA
| | - Bruce R Rosenblum
- Department of Neurosurgery, Riverview Medical Center, Red Bank, New Jersey, USA
| | - James G Smirniotopoulos
- Department of Radiology, School of Medicine and Health Sciences, George Washington University, Washington, DC, USA.,National Library of Medicine, Bethesda, Maryland, USA
| | - Alberto Pappo
- Oncology Department, Developmental Biology and Solid Tumor Program, St. Jude Comprehensive Cancer Center, St. Jude Children's Research Hospital, Memphis, Tennessee, USA
| | - Robert F Spetzler
- Department of Neurosurgery, Barrow Neurological Institute, St. Joseph's Hospital, and Medical Center, Phoenix, Arizona, USA
| | - Alexander Vortmeyer
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Mark R Gilbert
- Neuro-Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Dorian B McGavern
- Viral Immunology and Intravital Imaging Section, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA
| | - Emily Chew
- Division of Epidemiology and Clinical Applications, National Eye Institute, NIH, Bethesda, Maryland, USA
| | - Beth A Kozel
- Laboratory of Vascular and Matrix Genetics, National Heart Lung and Blood Institute, NIH, Bethesda, Maryland, USA
| | - John D Heiss
- Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA
| | - Zhengping Zhuang
- Neuro-Oncology Branch, National Cancer Institute, NIH, Bethesda, Maryland, USA
| | - Karel Pacak
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver, National Institute of Child Health and Human Development, NIH, Bethesda, Maryland, USA
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Shi F, Sun LX, Long S, Zhang Y. Pheochromocytoma as a cause of repeated acute myocardial infarctions, heart failure, and transient erythrocytosis: A case report and review of the literature. World J Clin Cases 2021; 9:951-959. [PMID: 33585644 PMCID: PMC7852630 DOI: 10.12998/wjcc.v9.i4.951] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 11/25/2020] [Accepted: 12/10/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Pheochromocytoma is a rare catecholamines-secreting tumor arising from chromaffin cells in the adrenal medulla. It classically presents with paroxysmal hypertension, headaches, palpitations, sweating, and metabolic disorders. Atypical presentations such as acute myocardial infarction, heart failure, cardiomyopathy, stroke, and transient erythrocytosis have been infrequently documented.
CASE SUMMARY We describe the case of a 72-year-old man diagnosed with pheochromocytoma presenting with non-ST segment elevation myocardial infarction, heart failure, and transient erythrocytosis with nonobstructed coronary arteries. This was his second heart attack. The patient was previously diagnosed with myocardial infarction, and an immense mass was found on the left adrenal gland 3 years prior. Based on clinical and laboratory findings, a diagnosis of pheochromocytoma was confirmed. His coronary angiogram showed nonobstructed coronary arteries except for a myocardial bridge in the left anterior descending branch. This was a form of type-2 myocardial infarction. The myocardial cell lesions were caused by sudden secretion of catecholamines by the pheochromocytoma. Even more atypically, his hemoglobin level was obviously elevated at admission, but after a few days of treatment with an alpha-adrenergic receptor blocker, it dropped to normal levels without additional treatment.
CONCLUSION Pheochromocytoma may be a cause of acute myocardial infarction, heart failure, and transient erythrocytosis.
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Affiliation(s)
- Fei Shi
- Department of Cardiology, Affiliated Hospital of Chengde Medical University, Chengde 067000, Hebei Province, China
| | - Li-Xian Sun
- Department of Cardiology, Affiliated Hospital of Chengde Medical University, Chengde 067000, Hebei Province, China
| | - Sen Long
- Department of Traditional Chinese Medicine, Affiliated Hospital of Chengde Medical University, Chengde 067000, Hebei Province, China
| | - Ying Zhang
- Department of Cardiology, Affiliated Hospital of Chengde Medical University, Chengde 067000, Hebei Province, China
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HIF2alpha-Associated Pseudohypoxia Promotes Radioresistance in Pheochromocytoma: Insights from 3D Models. Cancers (Basel) 2021; 13:cancers13030385. [PMID: 33494435 PMCID: PMC7865577 DOI: 10.3390/cancers13030385] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/15/2021] [Accepted: 01/18/2021] [Indexed: 12/30/2022] Open
Abstract
Pheochromocytomas and paragangliomas (PCCs/PGLs) are rare neuroendocrine tumors arising from chromaffin tissue located in the adrenal or ganglia of the sympathetic or parasympathetic nervous system. The treatment of non-resectable or metastatic PCCs/PGLs is still limited to palliative measures, including somatostatin type 2 receptor radionuclide therapy with [177Lu]Lu-DOTA-TATE as one of the most effective approaches to date. Nevertheless, the metabolic and molecular determinants of radiation response in PCCs/PGLs have not yet been characterized. This study investigates the effects of hypoxia-inducible factor 2 alpha (HIF2α) on the susceptibility of PCCs/PGLs to radiation treatments using spheroids grown from genetically engineered mouse pheochromocytoma (MPC) cells. The expression of Hif2α was associated with the significantly increased resistance of MPC spheroids to external X-ray irradiation and exposure to beta particle-emitting [177Lu]LuCl3 compared to Hif2α-deficient controls. Exposure to [177Lu]LuCl3 provided an increased long-term control of MPC spheroids compared to single-dose external X-ray irradiation. This study provides the first experimental evidence that HIF2α-associated pseudohypoxia contributes to a radioresistant phenotype of PCCs/PGLs. Furthermore, the external irradiation and [177Lu]LuCl3 exposure of MPC spheroids provide surrogate models for radiation treatments to further investigate the metabolic and molecular determinants of radiation responses in PCCs/PGLs and evaluate the effects of neo-adjuvant-in particular, radiosensitizing-treatments in combination with targeted radionuclide therapies.
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Snyder SE, Butch ER, Shulkin BL. Radiopharmaceuticals in Pediatric Nuclear Medicine. HANDBOOK OF RADIOPHARMACEUTICALS 2020:653-701. [DOI: 10.1002/9781119500575.ch21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Dmitriev PM, Wang H, Rosenblum JS, Prodanov T, Cui J, Pappo AS, Gilbert MR, Lutty GA, Chan CC, Chew EY, Pacak K, Zhuang Z. Vascular Changes in the Retina and Choroid of Patients With EPAS1 Gain-of-Function Mutation Syndrome. JAMA Ophthalmol 2020; 138:148-155. [PMID: 31876943 DOI: 10.1001/jamaophthalmol.2019.5244] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Importance Patients with the EPAS1 gain-of-function mutation syndrome (or Pacak-Zhuang syndrome) present with multiple paragangliomas or pheochromocytomas, duodenal somatostatinoma, polycythemia, headaches, and sometimes diminished visual acuity at an early age. The characteristic phenotype and known genetic cause of the syndrome provide an opportunity to study the role of hypoxia-inducible factor 2α (HIF-2α) in oxygen sensing, development in regions of physiologic hypoxia, and other pathological processes. Objectives To describe the ocular lesions in EPAS1 gain-of-function mutation syndrome and to establish whether early-onset diminished visual acuity is developmental or associated with long-term physiologic sequelae of the syndrome. Design, Setting, and Participants This clinical case series with a transgenic murine model study was conducted from July 2013 to June 2019. Participants were 3 patients referred by their primary care physicians to the National Institutes of Health for evaluation of recurrent and metastatic paragangliomas or pheochromocytomas accompanied by polycythemia. The syndrome and somatic mosaicism in patients were confirmed by the identification of gain-of-function mutations in the EPAS1 gene in resected tumors and other tissues. Main Outcomes and Measures Ocular findings in patients with EPAS1 gain-of-function mutation syndrome. Results A total of 3 patients (mean [SD] age, 29 [6.2] years) with confirmed ocular abnormalities were included in the study. Increased contrast accumulation at the posterior aspect of the globe was seen bilaterally on magnetic resonance imaging scans in all patients. Ophthalmoscopy images demonstrated fibrosis overlying the optic disc, tortuous and dilated retinal vessels, and retinal pigment epithelium changes. Optic disc edema and retinal exudates were also seen. Fluorescein angiography images showed leakage of dye from postcapillary venules surrounding the optic disc and highlighted aberrant retinal vascular patterns. Enhanced-depth imaging optical coherence tomography images showed substantial thickening of the choroid and dilation of choroidal vessels. The ocular features of the syndrome were confirmed with a transgenic model of mice with gain-of-function Epas1A529V mutation. Conclusions and Relevance In this case series, HIF-2α and hypoxia signaling was found to have a role in vessel development within the choroid and retina, indicating that the marked permanent choroidal thickening and tortuous and dilated veins seen in the choroid and retina in patients with EPAS1 gain-of-function mutation syndrome were suggestive of the persistence of venous elements within the developing mesenchyme. These findings may explain other eye and vascular abnormalities whose pathogenesis remains unclear.
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Affiliation(s)
- Pauline M Dmitriev
- Neuro-Oncology Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland
| | - Herui Wang
- Neuro-Oncology Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland
| | - Jared S Rosenblum
- Neuro-Oncology Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland
| | - Tamara Prodanov
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, Maryland
| | - Jing Cui
- Neuro-Oncology Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland
| | - Alberto S Pappo
- Division of Solid Tumor, St Jude Children's Research Hospital, Memphis, Tennessee
| | - Mark R Gilbert
- Neuro-Oncology Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland
| | - Gerard A Lutty
- Wilmer Ophthalmological Institute, Department of Ophthalmology, Johns Hopkins Hospital, Baltimore, Maryland
| | - Chi-Chao Chan
- Laboratory of Immunology, National Eye Institute (NEI), NIH, Bethesda, Maryland
| | - Emily Y Chew
- Division of Epidemiology and Clinical Applications, NEI, NIH, Bethesda, Maryland
| | - Karel Pacak
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH, Bethesda, Maryland
| | - Zhengping Zhuang
- Neuro-Oncology Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, Maryland.,Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke (NINDS), NIH, Bethesda, Maryland
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Därr R, Kater J, Sekula P, Bausch B, Krauss T, Bode C, Walz G, Neumann HP, Zschiedrich S. Clinical decision making in small non-functioning VHL-related incidentalomas. Endocr Connect 2020; 9:834-844. [PMID: 32869749 PMCID: PMC7487196 DOI: 10.1530/ec-20-0208] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 08/06/2020] [Indexed: 01/26/2023]
Abstract
The optimal treatment strategy for patients with small non-functioning VHL-related incidentalomas is unclear. We searched the Freiburg VHL registry for patients with radiologic evidence of pheochromocytoma/paraganglioma (PHEO/PGL). In total, 176 patients with single, multiple, and recurrent tumours were identified (1.84 tumours/patient, range 1-8). Mean age at diagnosis was 32 ± 16 years. Seventy-four percent of tumours were localised to the adrenals. Mean tumour diameter was 2.42 ± 2.27 cm, 46% were <1.5 cm. 24% of tumours were biochemically inactive. Inactive tumours were significantly smaller than active PHEO/PGL at diagnosis (4.16 ± 2.80 cm vs 1.43 ± 0.45 cm; P < 0.025) and before surgery (4.89 ± 3.47 cm vs 1.36 ± 0.43 cm; P < 0.02). Disease was stable in 67% of 21 patients with evaluable tumours ≤1.5 cm according to RECIST and progressed in 7. Time till surgery in these patients was 29.5 ± 20.0 months. A total of 155 patients underwent surgery. PHEO/PGL was histologically excluded in 4 and proven in 151. Of these, one had additional metastatic disease, one harboured another tumour of a different type, and in 2 a second surgery for suspected disease recurrence did not confirm PHEO/PGL. Logistic regression analysis revealed 50% probability for a positive/negative biochemical test result at 1.8 cm tumour diameter. Values of a novel symptom score were positively correlated with tumour size (Rs = 0.46, P < 0.0001) and together with a positive biochemistry a linear size predictor (P < 0.01). Results support standardised clinical assessment and measurement of tumour size and metanephrines in VHL patients with non-functioning incidentalomas <1.5 cm at one year following diagnosis and at individualised intervals thereafter depending on evolving growth dynamics, secretory activity and symptomatology.
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Affiliation(s)
- Roland Därr
- Department of Cardiology and Angiology I, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Department of Medicine IV, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Correspondence should be addressed to R Därr:
| | - Jonas Kater
- Department of Medicine IV, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Peggy Sekula
- Institute of Genetic Epidemiology, University Medical Center Freiburg, Freiburg, Germany
| | - Birke Bausch
- Department of Medicine II, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Tobias Krauss
- Department of Radiology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Christoph Bode
- Department of Cardiology and Angiology I, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Gerd Walz
- Department of Medicine IV, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Hartmut P Neumann
- Section for Preventive Medicine, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Stefan Zschiedrich
- Department of Medicine IV, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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Sandru F, Carsote M, Valea A, Albu SE, Petca RC, Dumitrascu MC. Somatostatinoma: Beyond neurofibromatosis type 1 (Review). Exp Ther Med 2020; 20:3383-3388. [PMID: 32905002 DOI: 10.3892/etm.2020.8965] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Accepted: 05/13/2020] [Indexed: 02/07/2023] Open
Abstract
Somatostatinoma is a tumour mainly originating from pancreas or duodenum; overall with an incidence of 1/40 million persons. We introduce a narrative review of literature of somatostatinoma including the relationship with neurofibromatosis type 1. Clinical presentation includes: Diabetes mellitus, cholelithiasis, steatorrhea, abdominal pain, and obstructive jaundice while papillary tumour may cause acute pancreatitis. The neoplasia may develop completely asymptomatic or it is detected as an incidental finding during an imaging or a surgical procedure. It may be sporadic or associated to genetic backgrounds especially for duodenal localisation as neurofibromatosis type 1 (NF1 gene with malfunction of RAS/MAPK pathway) or Pacak-Zhuang syndrome (EPAS1 gene encoding HIF). Surgery represents the central approach if feasible but the prognostic depends on location, and grading as indicated by WHO 2017 classification of neuroendocrine tumours. Previously known as Von Recklinghausen disease, neurofibromatosis type 1, the most frequent neurocutaneous syndrome, is an autosomal dominant disorder including: Café-au-lait spot, skin fold freckling on flexural zones, and neurofibromas as well as tumours such as gliomas of optic nerve, gastrointestinal stromal tumours (GISTs), iris hamartomas and brain tumours. Duodenal somatostatinoma is associated with the syndrome which actually involves more often a duodenal tumour of GIST type than a somatostatin secreting neoplasia. Other neuroendocrine tumours are reported: Gastrointestinal NENs at the level of rectum or jejunum and pheocromocytoma. Overall, one quarter of subjects have gastrointestinal tumours of different types. Somatostatinoma, when not located on pancreas but in duodenoum, may be registered in subjects with neurofibromatosis type 1 most probably in addition to other tumours. Overall, this type of neuroendocrine tumour with a challenging presentation has a poor prognosis unless adequate radical surgery is promptly offered to the patient.
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Affiliation(s)
- Florica Sandru
- Department of Dermatology, 'Elias' Emergency University Hospital, 125100 Bucharest, Romania.,Department of Dermatology, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Mara Carsote
- Department of Endocrinology, 'C.I. Parhon' National Institute of Endocrinology, 011863 Bucharest, Romania.,Department of Endocrinology, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Ana Valea
- Department of Endocrinology, Clinical County Hospital, 400000 Cluj-Napoca, Romania.,Department of Endocrinology, 'Iuliu Hatieganu' University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Simona Elena Albu
- Department of Gynecology, Emergency University Hospital, 050098 Bucharest, Romania.,Department of Gynecology, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Răzvan-Cosmin Petca
- Deparment of Urology, 'Prof. Dr. Theodor Burghele' Clinical Hospital, 925200 Bucharest, Romania
| | - Mihai Cristian Dumitrascu
- Department of Gynecology, Emergency University Hospital, 050098 Bucharest, Romania.,Department of Gynecology, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania
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Abdallah A, Pappo A, Reiss U, Shulkin BL, Zhuang Z, Pacak K, Bahrami A. Clinical manifestations of Pacak-Zhuang syndrome in a male pediatric patient. Pediatr Blood Cancer 2020; 67:e28096. [PMID: 31876082 PMCID: PMC7036331 DOI: 10.1002/pbc.28096] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 10/24/2019] [Accepted: 11/04/2019] [Indexed: 11/09/2022]
Abstract
We report an index case of a male patient who presented with all clinical manifestations of Pacak-Zhuang syndrome, including early-age polycythemia, multiple pheochromocytomas/paragangliomas, duodenal somatostatinoma, and ocular findings. Sequencing analysis detected an EPAS1 mutation in all tumors tested, but not in the germline.
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Affiliation(s)
- Adel Abdallah
- Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN
| | - Alberto Pappo
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN
| | - Ulrike Reiss
- Department of Hematology, St. Jude Children’s Research Hospital, Memphis, TN
| | - Barry L. Shulkin
- Department of Diagnostic Imaging, St. Jude Children’s Research Hospital, Memphis, TN
| | - Zhengping Zhuang
- Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD
| | - Karel Pacak
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD
| | - Armita Bahrami
- Department of Pathology and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN.,Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN.,Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN
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Hofland J, Kaltsas G, de Herder WW. Advances in the Diagnosis and Management of Well-Differentiated Neuroendocrine Neoplasms. Endocr Rev 2020; 41:bnz004. [PMID: 31555796 PMCID: PMC7080342 DOI: 10.1210/endrev/bnz004] [Citation(s) in RCA: 123] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Accepted: 02/28/2020] [Indexed: 02/07/2023]
Abstract
Neuroendocrine neoplasms constitute a diverse group of tumors that derive from the sensory and secretory neuroendocrine cells and predominantly arise within the pulmonary and gastrointestinal tracts. The majority of these neoplasms have a well-differentiated grade and are termed neuroendocrine tumors (NETs). This subgroup is characterized by limited proliferation and patients affected by these tumors carry a good to moderate prognosis. A substantial subset of patients presenting with a NET suffer from the consequences of endocrine syndromes as a result of the excessive secretion of amines or peptide hormones, which can impair their quality of life and prognosis. Over the past 15 years, critical developments in tumor grading, diagnostic biomarkers, radionuclide imaging, randomized controlled drug trials, evidence-based guidelines, and superior prognostic outcomes have substantially altered the field of NET care. Here, we review the relevant advances to clinical practice that have significantly upgraded our approach to NET patients, both in diagnostic and in therapeutic options.
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Affiliation(s)
- Johannes Hofland
- ENETS Center of Excellence, Section of Endocrinology, Department of Internal Medicine, Erasmus MC Cancer Center, Erasmus MC, Rotterdam, The Netherlands
| | - Gregory Kaltsas
- 1st Department of Propaupedic Internal Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Wouter W de Herder
- ENETS Center of Excellence, Section of Endocrinology, Department of Internal Medicine, Erasmus MC Cancer Center, Erasmus MC, Rotterdam, The Netherlands
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Rosenblum JS, Cappadona AJ, Argersinger DP, Pang Y, Wang H, Nazari MA, Munasinghe JP, Donahue DR, Jha A, Smirniotopoulos JG, Miettinen MM, Knutsen RH, Kozel BA, Zhuang Z, Pacak K, Heiss JD. Neuraxial dysraphism in EPAS1-associated syndrome due to improper mesenchymal transition. NEUROLOGY-GENETICS 2020; 6:e414. [PMID: 32337341 PMCID: PMC7164966 DOI: 10.1212/nxg.0000000000000414] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/04/2019] [Accepted: 02/06/2020] [Indexed: 01/25/2023]
Abstract
Objective To investigate the effect of somatic, postzygotic, gain-of-function mutation of Endothelial Per-Arnt-Sim (PAS) domain protein 1 (EPAS1) encoding hypoxia-inducible factor-2α (HIF-2α) on posterior fossa development and spinal dysraphism in EPAS1 gain-of-function syndrome, which consists of multiple paragangliomas, somatostatinoma, and polycythemia. Methods Patients referred to our institution for evaluation of new, recurrent, and/or metastatic paragangliomas/pheochromocytoma were confirmed for EPAS1 gain-of-function syndrome by identification of the EPAS1 gain-of-function mutation in resected tumors and/or circulating leukocytes. The posterior fossa, its contents, and the spine were evaluated retrospectively on available MRI and CT images of the head and neck performed for tumor staging and restaging. The transgenic mouse model underwent Microfil vascular perfusion and subsequent intact ex vivo 14T MRI and micro-CT as well as gross dissection, histology, and immunohistochemistry to assess the role of EPAS1 in identified malformations. Results All 8 patients with EPAS1 gain-of-function syndrome demonstrated incidental posterior fossa malformations—one Dandy-Walker variant and 7 Chiari malformations without syringomyelia. These findings were not associated with a small posterior fossa; rather, the posterior fossa volume exceeded that of its neural contents. Seven of 8 patients demonstrated spinal dysraphism; 4 of 8 demonstrated abnormal vertebral segmentation. The mouse model similarly demonstrated features of neuraxial dysraphism, including cervical myelomeningocele and spinal dysraphism, and cerebellar tonsil displacement through the foramen magnum. Histology and immunohistochemistry demonstrated incomplete mesenchymal transition in the mutant but not the control mouse. Conclusions This study characterized posterior fossa and spinal malformations seen in EPAS1 gain-of-function syndrome and suggests that gain-of-function mutation in HIF-2α results in improper mesenchymal transition.
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Affiliation(s)
- Jared S Rosenblum
- National Institutes of Health (J.S.R., A.J.C., H.W., Z.Z.), National Cancer Institute Neuro-Oncology Branch; National Institutes of Health (D.P.A., J.D.H.), National Institute of Neurological Disorders and Stroke, Surgical Neurology Branch; National Institutes of Health (Y.P., A.J., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Section on Medical Neuroendocrinology; Georgetown Hospital (M.A.N.), Internal Medicine and Pediatrics, Washington DC; National Institutes of Health (J.P.M., D.R.D.), National Institute of Neurological Disorders and Stroke, Mouse Imaging Facility, Bethesda, MD; George Washington University (J.G.S.), Radiology, Washington DC; National Library of Medicine (J.G.S.), MedPix®; National Institutes of Health (M.M.M.), Center for Cancer Research, National Cancer Institute, Laboratory of Pathology; and National Institutes of Health (R.H.K., B.A.K.), National Heart Lung and Blood Institute, Translational Vascular Medicine Branch, Bethesda, MD
| | - Anthony J Cappadona
- National Institutes of Health (J.S.R., A.J.C., H.W., Z.Z.), National Cancer Institute Neuro-Oncology Branch; National Institutes of Health (D.P.A., J.D.H.), National Institute of Neurological Disorders and Stroke, Surgical Neurology Branch; National Institutes of Health (Y.P., A.J., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Section on Medical Neuroendocrinology; Georgetown Hospital (M.A.N.), Internal Medicine and Pediatrics, Washington DC; National Institutes of Health (J.P.M., D.R.D.), National Institute of Neurological Disorders and Stroke, Mouse Imaging Facility, Bethesda, MD; George Washington University (J.G.S.), Radiology, Washington DC; National Library of Medicine (J.G.S.), MedPix®; National Institutes of Health (M.M.M.), Center for Cancer Research, National Cancer Institute, Laboratory of Pathology; and National Institutes of Health (R.H.K., B.A.K.), National Heart Lung and Blood Institute, Translational Vascular Medicine Branch, Bethesda, MD
| | - Davis P Argersinger
- National Institutes of Health (J.S.R., A.J.C., H.W., Z.Z.), National Cancer Institute Neuro-Oncology Branch; National Institutes of Health (D.P.A., J.D.H.), National Institute of Neurological Disorders and Stroke, Surgical Neurology Branch; National Institutes of Health (Y.P., A.J., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Section on Medical Neuroendocrinology; Georgetown Hospital (M.A.N.), Internal Medicine and Pediatrics, Washington DC; National Institutes of Health (J.P.M., D.R.D.), National Institute of Neurological Disorders and Stroke, Mouse Imaging Facility, Bethesda, MD; George Washington University (J.G.S.), Radiology, Washington DC; National Library of Medicine (J.G.S.), MedPix®; National Institutes of Health (M.M.M.), Center for Cancer Research, National Cancer Institute, Laboratory of Pathology; and National Institutes of Health (R.H.K., B.A.K.), National Heart Lung and Blood Institute, Translational Vascular Medicine Branch, Bethesda, MD
| | - Ying Pang
- National Institutes of Health (J.S.R., A.J.C., H.W., Z.Z.), National Cancer Institute Neuro-Oncology Branch; National Institutes of Health (D.P.A., J.D.H.), National Institute of Neurological Disorders and Stroke, Surgical Neurology Branch; National Institutes of Health (Y.P., A.J., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Section on Medical Neuroendocrinology; Georgetown Hospital (M.A.N.), Internal Medicine and Pediatrics, Washington DC; National Institutes of Health (J.P.M., D.R.D.), National Institute of Neurological Disorders and Stroke, Mouse Imaging Facility, Bethesda, MD; George Washington University (J.G.S.), Radiology, Washington DC; National Library of Medicine (J.G.S.), MedPix®; National Institutes of Health (M.M.M.), Center for Cancer Research, National Cancer Institute, Laboratory of Pathology; and National Institutes of Health (R.H.K., B.A.K.), National Heart Lung and Blood Institute, Translational Vascular Medicine Branch, Bethesda, MD
| | - Herui Wang
- National Institutes of Health (J.S.R., A.J.C., H.W., Z.Z.), National Cancer Institute Neuro-Oncology Branch; National Institutes of Health (D.P.A., J.D.H.), National Institute of Neurological Disorders and Stroke, Surgical Neurology Branch; National Institutes of Health (Y.P., A.J., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Section on Medical Neuroendocrinology; Georgetown Hospital (M.A.N.), Internal Medicine and Pediatrics, Washington DC; National Institutes of Health (J.P.M., D.R.D.), National Institute of Neurological Disorders and Stroke, Mouse Imaging Facility, Bethesda, MD; George Washington University (J.G.S.), Radiology, Washington DC; National Library of Medicine (J.G.S.), MedPix®; National Institutes of Health (M.M.M.), Center for Cancer Research, National Cancer Institute, Laboratory of Pathology; and National Institutes of Health (R.H.K., B.A.K.), National Heart Lung and Blood Institute, Translational Vascular Medicine Branch, Bethesda, MD
| | - Matthew A Nazari
- National Institutes of Health (J.S.R., A.J.C., H.W., Z.Z.), National Cancer Institute Neuro-Oncology Branch; National Institutes of Health (D.P.A., J.D.H.), National Institute of Neurological Disorders and Stroke, Surgical Neurology Branch; National Institutes of Health (Y.P., A.J., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Section on Medical Neuroendocrinology; Georgetown Hospital (M.A.N.), Internal Medicine and Pediatrics, Washington DC; National Institutes of Health (J.P.M., D.R.D.), National Institute of Neurological Disorders and Stroke, Mouse Imaging Facility, Bethesda, MD; George Washington University (J.G.S.), Radiology, Washington DC; National Library of Medicine (J.G.S.), MedPix®; National Institutes of Health (M.M.M.), Center for Cancer Research, National Cancer Institute, Laboratory of Pathology; and National Institutes of Health (R.H.K., B.A.K.), National Heart Lung and Blood Institute, Translational Vascular Medicine Branch, Bethesda, MD
| | - Jeeva P Munasinghe
- National Institutes of Health (J.S.R., A.J.C., H.W., Z.Z.), National Cancer Institute Neuro-Oncology Branch; National Institutes of Health (D.P.A., J.D.H.), National Institute of Neurological Disorders and Stroke, Surgical Neurology Branch; National Institutes of Health (Y.P., A.J., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Section on Medical Neuroendocrinology; Georgetown Hospital (M.A.N.), Internal Medicine and Pediatrics, Washington DC; National Institutes of Health (J.P.M., D.R.D.), National Institute of Neurological Disorders and Stroke, Mouse Imaging Facility, Bethesda, MD; George Washington University (J.G.S.), Radiology, Washington DC; National Library of Medicine (J.G.S.), MedPix®; National Institutes of Health (M.M.M.), Center for Cancer Research, National Cancer Institute, Laboratory of Pathology; and National Institutes of Health (R.H.K., B.A.K.), National Heart Lung and Blood Institute, Translational Vascular Medicine Branch, Bethesda, MD
| | - Danielle R Donahue
- National Institutes of Health (J.S.R., A.J.C., H.W., Z.Z.), National Cancer Institute Neuro-Oncology Branch; National Institutes of Health (D.P.A., J.D.H.), National Institute of Neurological Disorders and Stroke, Surgical Neurology Branch; National Institutes of Health (Y.P., A.J., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Section on Medical Neuroendocrinology; Georgetown Hospital (M.A.N.), Internal Medicine and Pediatrics, Washington DC; National Institutes of Health (J.P.M., D.R.D.), National Institute of Neurological Disorders and Stroke, Mouse Imaging Facility, Bethesda, MD; George Washington University (J.G.S.), Radiology, Washington DC; National Library of Medicine (J.G.S.), MedPix®; National Institutes of Health (M.M.M.), Center for Cancer Research, National Cancer Institute, Laboratory of Pathology; and National Institutes of Health (R.H.K., B.A.K.), National Heart Lung and Blood Institute, Translational Vascular Medicine Branch, Bethesda, MD
| | - Abhishek Jha
- National Institutes of Health (J.S.R., A.J.C., H.W., Z.Z.), National Cancer Institute Neuro-Oncology Branch; National Institutes of Health (D.P.A., J.D.H.), National Institute of Neurological Disorders and Stroke, Surgical Neurology Branch; National Institutes of Health (Y.P., A.J., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Section on Medical Neuroendocrinology; Georgetown Hospital (M.A.N.), Internal Medicine and Pediatrics, Washington DC; National Institutes of Health (J.P.M., D.R.D.), National Institute of Neurological Disorders and Stroke, Mouse Imaging Facility, Bethesda, MD; George Washington University (J.G.S.), Radiology, Washington DC; National Library of Medicine (J.G.S.), MedPix®; National Institutes of Health (M.M.M.), Center for Cancer Research, National Cancer Institute, Laboratory of Pathology; and National Institutes of Health (R.H.K., B.A.K.), National Heart Lung and Blood Institute, Translational Vascular Medicine Branch, Bethesda, MD
| | - James G Smirniotopoulos
- National Institutes of Health (J.S.R., A.J.C., H.W., Z.Z.), National Cancer Institute Neuro-Oncology Branch; National Institutes of Health (D.P.A., J.D.H.), National Institute of Neurological Disorders and Stroke, Surgical Neurology Branch; National Institutes of Health (Y.P., A.J., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Section on Medical Neuroendocrinology; Georgetown Hospital (M.A.N.), Internal Medicine and Pediatrics, Washington DC; National Institutes of Health (J.P.M., D.R.D.), National Institute of Neurological Disorders and Stroke, Mouse Imaging Facility, Bethesda, MD; George Washington University (J.G.S.), Radiology, Washington DC; National Library of Medicine (J.G.S.), MedPix®; National Institutes of Health (M.M.M.), Center for Cancer Research, National Cancer Institute, Laboratory of Pathology; and National Institutes of Health (R.H.K., B.A.K.), National Heart Lung and Blood Institute, Translational Vascular Medicine Branch, Bethesda, MD
| | - Markku M Miettinen
- National Institutes of Health (J.S.R., A.J.C., H.W., Z.Z.), National Cancer Institute Neuro-Oncology Branch; National Institutes of Health (D.P.A., J.D.H.), National Institute of Neurological Disorders and Stroke, Surgical Neurology Branch; National Institutes of Health (Y.P., A.J., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Section on Medical Neuroendocrinology; Georgetown Hospital (M.A.N.), Internal Medicine and Pediatrics, Washington DC; National Institutes of Health (J.P.M., D.R.D.), National Institute of Neurological Disorders and Stroke, Mouse Imaging Facility, Bethesda, MD; George Washington University (J.G.S.), Radiology, Washington DC; National Library of Medicine (J.G.S.), MedPix®; National Institutes of Health (M.M.M.), Center for Cancer Research, National Cancer Institute, Laboratory of Pathology; and National Institutes of Health (R.H.K., B.A.K.), National Heart Lung and Blood Institute, Translational Vascular Medicine Branch, Bethesda, MD
| | - Russell H Knutsen
- National Institutes of Health (J.S.R., A.J.C., H.W., Z.Z.), National Cancer Institute Neuro-Oncology Branch; National Institutes of Health (D.P.A., J.D.H.), National Institute of Neurological Disorders and Stroke, Surgical Neurology Branch; National Institutes of Health (Y.P., A.J., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Section on Medical Neuroendocrinology; Georgetown Hospital (M.A.N.), Internal Medicine and Pediatrics, Washington DC; National Institutes of Health (J.P.M., D.R.D.), National Institute of Neurological Disorders and Stroke, Mouse Imaging Facility, Bethesda, MD; George Washington University (J.G.S.), Radiology, Washington DC; National Library of Medicine (J.G.S.), MedPix®; National Institutes of Health (M.M.M.), Center for Cancer Research, National Cancer Institute, Laboratory of Pathology; and National Institutes of Health (R.H.K., B.A.K.), National Heart Lung and Blood Institute, Translational Vascular Medicine Branch, Bethesda, MD
| | - Beth A Kozel
- National Institutes of Health (J.S.R., A.J.C., H.W., Z.Z.), National Cancer Institute Neuro-Oncology Branch; National Institutes of Health (D.P.A., J.D.H.), National Institute of Neurological Disorders and Stroke, Surgical Neurology Branch; National Institutes of Health (Y.P., A.J., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Section on Medical Neuroendocrinology; Georgetown Hospital (M.A.N.), Internal Medicine and Pediatrics, Washington DC; National Institutes of Health (J.P.M., D.R.D.), National Institute of Neurological Disorders and Stroke, Mouse Imaging Facility, Bethesda, MD; George Washington University (J.G.S.), Radiology, Washington DC; National Library of Medicine (J.G.S.), MedPix®; National Institutes of Health (M.M.M.), Center for Cancer Research, National Cancer Institute, Laboratory of Pathology; and National Institutes of Health (R.H.K., B.A.K.), National Heart Lung and Blood Institute, Translational Vascular Medicine Branch, Bethesda, MD
| | - Zhengping Zhuang
- National Institutes of Health (J.S.R., A.J.C., H.W., Z.Z.), National Cancer Institute Neuro-Oncology Branch; National Institutes of Health (D.P.A., J.D.H.), National Institute of Neurological Disorders and Stroke, Surgical Neurology Branch; National Institutes of Health (Y.P., A.J., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Section on Medical Neuroendocrinology; Georgetown Hospital (M.A.N.), Internal Medicine and Pediatrics, Washington DC; National Institutes of Health (J.P.M., D.R.D.), National Institute of Neurological Disorders and Stroke, Mouse Imaging Facility, Bethesda, MD; George Washington University (J.G.S.), Radiology, Washington DC; National Library of Medicine (J.G.S.), MedPix®; National Institutes of Health (M.M.M.), Center for Cancer Research, National Cancer Institute, Laboratory of Pathology; and National Institutes of Health (R.H.K., B.A.K.), National Heart Lung and Blood Institute, Translational Vascular Medicine Branch, Bethesda, MD
| | - Karel Pacak
- National Institutes of Health (J.S.R., A.J.C., H.W., Z.Z.), National Cancer Institute Neuro-Oncology Branch; National Institutes of Health (D.P.A., J.D.H.), National Institute of Neurological Disorders and Stroke, Surgical Neurology Branch; National Institutes of Health (Y.P., A.J., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Section on Medical Neuroendocrinology; Georgetown Hospital (M.A.N.), Internal Medicine and Pediatrics, Washington DC; National Institutes of Health (J.P.M., D.R.D.), National Institute of Neurological Disorders and Stroke, Mouse Imaging Facility, Bethesda, MD; George Washington University (J.G.S.), Radiology, Washington DC; National Library of Medicine (J.G.S.), MedPix®; National Institutes of Health (M.M.M.), Center for Cancer Research, National Cancer Institute, Laboratory of Pathology; and National Institutes of Health (R.H.K., B.A.K.), National Heart Lung and Blood Institute, Translational Vascular Medicine Branch, Bethesda, MD
| | - John D Heiss
- National Institutes of Health (J.S.R., A.J.C., H.W., Z.Z.), National Cancer Institute Neuro-Oncology Branch; National Institutes of Health (D.P.A., J.D.H.), National Institute of Neurological Disorders and Stroke, Surgical Neurology Branch; National Institutes of Health (Y.P., A.J., K.P.), Eunice Kennedy Shriver National Institute of Child Health and Human Development, Section on Medical Neuroendocrinology; Georgetown Hospital (M.A.N.), Internal Medicine and Pediatrics, Washington DC; National Institutes of Health (J.P.M., D.R.D.), National Institute of Neurological Disorders and Stroke, Mouse Imaging Facility, Bethesda, MD; George Washington University (J.G.S.), Radiology, Washington DC; National Library of Medicine (J.G.S.), MedPix®; National Institutes of Health (M.M.M.), Center for Cancer Research, National Cancer Institute, Laboratory of Pathology; and National Institutes of Health (R.H.K., B.A.K.), National Heart Lung and Blood Institute, Translational Vascular Medicine Branch, Bethesda, MD
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Antonio K, Valdez MMN, Mercado-Asis L, Taïeb D, Pacak K. Pheochromocytoma/paraganglioma: recent updates in genetics, biochemistry, immunohistochemistry, metabolomics, imaging and therapeutic options. Gland Surg 2020; 9:105-123. [PMID: 32206603 DOI: 10.21037/gs.2019.10.25] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Pheochromocytomas and paragangliomas (PPGLs), rare chromaffin/neural crest cell tumors, are commonly benign in their clinical presentation. However, there are a number of cases presenting as metastatic and their diagnosis and management becomes a dilemma because of their rarity. PPGLs are constantly evolving entities in the field of endocrinology brought about by endless research and discoveries, especially in genetics. Throughout the years, our knowledge and perception of these tumors and their genetic background has greatly expanded and changed, and each new discovery leads to advancement in the diagnosis, treatment and follow-up of PPGLs. In this review, we discuss the recent updates in the genetics, biochemistry, immunohistochemistry, metabolomics, imaging and treatment options of PPGLs.
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Affiliation(s)
- Karren Antonio
- Section on Medical Neuroendocrinology, The Eunice Kennedy Shriver National Institutes of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.,Division of Endocrinology, University of Santo Tomas Hospital, Manila, Philippines
| | - Ma Margarita Noreen Valdez
- Section on Medical Neuroendocrinology, The Eunice Kennedy Shriver National Institutes of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.,Division of Endocrinology, University of Santo Tomas Hospital, Manila, Philippines
| | | | - David Taïeb
- Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille University, Marseille, France
| | - Karel Pacak
- Section on Medical Neuroendocrinology, The Eunice Kennedy Shriver National Institutes of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
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Taïeb D, Jha A, Treglia G, Pacak K. Molecular imaging and radionuclide therapy of pheochromocytoma and paraganglioma in the era of genomic characterization of disease subgroups. Endocr Relat Cancer 2019; 26:R627-R652. [PMID: 31561209 PMCID: PMC7002202 DOI: 10.1530/erc-19-0165] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2019] [Accepted: 09/12/2019] [Indexed: 12/13/2022]
Abstract
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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Affiliation(s)
- David Taïeb
- Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille University, Marseille, France
| | - Abhishek Jha
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
| | - Giorgio Treglia
- Clinic of Nuclear Medicine and PET/CT Center, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
- Department of Nuclear Medicine and Molecular Imaging, Lausanne University Hospital, Lausanne, Switzerland
- Health Technology Assessment Unit, General Directorate, Ente Ospedaliero Cantonale, Bellinzona, Switzerland
| | - Karel Pacak
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
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Nölting S, Ullrich M, Pietzsch J, Ziegler CG, Eisenhofer G, Grossman A, Pacak K. Current Management of Pheochromocytoma/Paraganglioma: A Guide for the Practicing Clinician in the Era of Precision Medicine. Cancers (Basel) 2019; 11:cancers11101505. [PMID: 31597347 PMCID: PMC6827093 DOI: 10.3390/cancers11101505] [Citation(s) in RCA: 102] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Revised: 09/18/2019] [Accepted: 09/24/2019] [Indexed: 12/13/2022] Open
Abstract
Pheochromocytomas and paragangliomas (PCC/PGLs) are rare, mostly catecholamine-producing neuroendocrine tumors of the adrenal gland (PCCs) or the extra-adrenal paraganglia (PGL). They can be separated into three different molecular clusters depending on their underlying gene mutations in any of the at least 20 known susceptibility genes: The pseudohypoxia-associated cluster 1, the kinase signaling-associated cluster 2, and the Wnt signaling-associated cluster 3. In addition to tumor size, location (adrenal vs. extra-adrenal), multiplicity, age of first diagnosis, and presence of metastatic disease (including tumor burden), other decisive factors for best clinical management of PCC/PGL include the underlying germline mutation. The above factors can impact the choice of different biomarkers and imaging modalities for PCC/PGL diagnosis, as well as screening for other neoplasms, staging, follow-up, and therapy options. This review provides a guide for practicing clinicians summarizing current management of PCC/PGL according to tumor size, location, age of first diagnosis, presence of metastases, and especially underlying mutations in the era of precision medicine.
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Affiliation(s)
- Svenja Nölting
- Department of Medicine IV, University Hospital, LMU Munich, Ziemssenstraße 1, 80336 München, Germany.
| | - Martin Ullrich
- Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstrasse 400, 01328 Dresden, Germany.
| | - Jens Pietzsch
- Department of Radiopharmaceutical and Chemical Biology, Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Bautzner Landstrasse 400, 01328 Dresden, Germany.
- Department of Chemistry and Food Chemistry, School of Science, Technische Universität Dresden, Mommsenstrasse 9, 01062 Dresden, Germany.
| | - Christian G Ziegler
- Department of Medicine III, University Hospital Carl Gustav Carus Dresden, Fetscherstraße 74, 01307 Dresden, Germany.
| | - Graeme Eisenhofer
- Department of Medicine III, University Hospital Carl Gustav Carus Dresden, Fetscherstraße 74, 01307 Dresden, Germany.
- Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus at Technische Universität Dresden, 01307 Dresden, Germany.
| | - Ashley Grossman
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford Ox3 7LJ, UK.
- Department of Gastroenterology, Royal Free Hospital ENETS Centre of Excellence, London NW3 2QG, UK.
| | - Karel Pacak
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20814, USA.
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40
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Taïeb D, Hicks RJ, Hindié E, Guillet BA, Avram A, Ghedini P, Timmers HJ, Scott AT, Elojeimy S, Rubello D, Virgolini IJ, Fanti S, Balogova S, Pandit-Taskar N, Pacak K. European Association of Nuclear Medicine Practice Guideline/Society of Nuclear Medicine and Molecular Imaging Procedure Standard 2019 for radionuclide imaging of phaeochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging 2019; 46:2112-2137. [PMID: 31254038 PMCID: PMC7446938 DOI: 10.1007/s00259-019-04398-1] [Citation(s) in RCA: 236] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2019] [Accepted: 06/10/2019] [Indexed: 01/11/2023]
Abstract
PURPOSE Diverse radionuclide imaging techniques are available for the diagnosis, staging, and follow-up of phaeochromocytoma and paraganglioma (PPGL). Beyond their ability to detect and localise the disease, these imaging approaches variably characterise these tumours at the cellular and molecular levels and can guide therapy. Here we present updated guidelines jointly approved by the EANM and SNMMI for assisting nuclear medicine practitioners in not only the selection and performance of currently available single-photon emission computed tomography and positron emission tomography procedures, but also the interpretation and reporting of the results. METHODS Guidelines from related fields and relevant literature have been considered in consultation with leading experts involved in the management of PPGL. The provided information should be applied according to local laws and regulations as well as the availability of various radiopharmaceuticals. CONCLUSION Since the European Association of Nuclear Medicine 2012 guidelines, the excellent results obtained with gallium-68 (68Ga)-labelled somatostatin analogues (SSAs) in recent years have simplified the imaging approach for PPGL patients that can also be used for selecting patients for peptide receptor radionuclide therapy as a potential alternative or complement to the traditional theranostic approach with iodine-123 (123I)/iodine-131 (131I)-labelled meta-iodobenzylguanidine. Genomic characterisation of subgroups with differing risk of lesion development and subsequent metastatic spread is refining the use of molecular imaging in the personalised approach to hereditary PPGL patients for detection, staging, and follow-up surveillance.
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Affiliation(s)
- David Taïeb
- Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille University, 264 rue Saint-Pierre, 13005, Marseille Cedex 05, France.
| | - Rodney J Hicks
- Centre for Cancer Imaging, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Elif Hindié
- Department of Nuclear Medicine, Hôpital Haut-Lévêque, Bordeaux University Hospitals, Pessac, France
| | - Benjamin A Guillet
- Department of Radiopharmacy, La Timone University Hospital, CERIMED, Aix-Marseille University, Marseille, France
| | - Anca Avram
- Nuclear Medicine/Radiology, University of Michigan, Ann Arbor, MI, USA
| | - Pietro Ghedini
- Nuclear Medicine Unit, Medicina Nucleare Metropolitana, University Hospital S.Orsola-Malpighi, Bologna, Italy
| | - Henri J Timmers
- Department of Endocrinology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
| | | | - Saeed Elojeimy
- Department of Radiology, University of New Mexico, Albuquerque, NM, USA
| | - Domenico Rubello
- Department of Nuclear Medicine, Radiology, Neuroradiology, Medical Physics, Clinical Laboratory, Microbiology, Pathology, Transfusional Medicine, Santa Maria della Misericordia Hospital, Rovigo, Italy
| | - Irène J Virgolini
- Department of Nuclear Medicine, Medical University Innsbruck, Anichstrasse 35, 6020, Innsbruck, Austria
| | - Stefano Fanti
- Nuclear Medicine Unit, Medicina Nucleare Metropolitana, University Hospital S.Orsola-Malpighi, Bologna, Italy
| | - Sona Balogova
- Department of Nuclear Medicine, Comenius University and St. Elisabeth Oncology Institute, Heydukova 10, 81250, Bratislava, Slovakia
- Department of Nuclear Medicine, Hôpital Tenon Assistance Publique-Hôpitaux de Paris and Sorbonne University, Paris, France
| | - Neeta Pandit-Taskar
- Department of Radiology, Molecular Imaging and Therapy Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Karel Pacak
- Eunice Kennedy Shriver National Institutes of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
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Lappin TR, Lee FS. Update on mutations in the HIF: EPO pathway and their role in erythrocytosis. Blood Rev 2019; 37:100590. [PMID: 31350093 DOI: 10.1016/j.blre.2019.100590] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2019] [Revised: 07/02/2019] [Accepted: 07/15/2019] [Indexed: 12/20/2022]
Abstract
Identification of the underlying defects in congenital erythrocytosis has provided mechanistic insights into the regulation of erythropoiesis and oxygen homeostasis. The Hypoxia Inducible Factor (HIF) pathway plays a key role in this regard. In this pathway, an enzyme, Prolyl Hydroxylase Domain protein 2 (PHD2), constitutively prolyl hydroxylates HIF-2α, thereby targeting HIF-2α for degradation by the von Hippel Lindau (VHL) tumor suppressor protein. Under hypoxia, this modification is attenuated, resulting in the stabilization of HIF-2α and transcriptional activation of the erythropoietin (EPO) gene. Circulating EPO then binds to the EPO receptor (EPOR) on red cell progenitors in the bone marrow, leading to expansion of red cell mass. Loss of function mutations in PHD2 and VHL, as well as gain of function mutations in HIF-2α and EPOR, are well established causes of erythrocytosis. Here, we highlight recent developments that show that the study of this condition is still evolving. Specifically, novel mutations have been identified that either change amino acids in the zinc finger domain of PHD2 or alter splicing of the VHL gene. In addition, continued study of HIF-2α mutations has revealed a distinctive genotype-phenotype correlation. Finally, novel mutations have recently been identified in the EPO gene itself. Thus, the cascade of genes that at a molecular level leads to EPO action, namely PHD2 - > HIF2A - > VHL - > EPO - > EPOR, are all mutational targets in congenital erythrocytosis.
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Affiliation(s)
- Terence R Lappin
- Centre for Cancer Research and Cell Biology, Queen's University, Belfast, UK.
| | - Frank S Lee
- Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
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Abstract
Since Felix Fränkel's account of pheochromocytoma in 1886, great discoveries and vast advancements in the diagnosis, genetics, anatomical and functional imaging techniques, and surgical management of pheochromcytoma and paraganglioma (P-PGL) have been made. The improved insight in the pathophysiology of P-PGL and more accurate detection methods enable physicians to tailor the treatment plan to an individual based on the genetic profile and tumor behavior. This review will cover briefly the clinical features, diagnosis, genetic mutations, and imaging modalities that are used to guide current surgical management of these rare and interesting endocrinopathies.
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Affiliation(s)
- Douglas Wiseman
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Mustapha El Lakis
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Naris Nilubol
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
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43
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Abstract
The mitochondrial enzyme succinate dehydrogenase (SDH) acts as a tumor suppressor. Biallelic inactivation of one of the genes encoding for SDH subunits (collectively named SDHx) leads to complete loss of the protein function and the development of diverse group of tumors. Pheochromocytomas-paragangliomas are the prime example of hereditary tumors caused by SDH deficiency. In this review, we discuss the roles of imaging examinations, and illustrate new insights into genotype-imaging phenotype relationships.
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Affiliation(s)
- David Taïeb
- Department of Nuclear Medicine, La Timone University Hospital, CERIMED, Aix-Marseille University, Marseille, France
| | - Henri Timmers
- Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Centre, Nijmegen, The Netherlands
| | - Karel Pacak
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA
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44
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Sanghani NS, Haase VH. Hypoxia-Inducible Factor Activators in Renal Anemia: Current Clinical Experience. Adv Chronic Kidney Dis 2019; 26:253-266. [PMID: 31477256 PMCID: PMC7318915 DOI: 10.1053/j.ackd.2019.04.004] [Citation(s) in RCA: 136] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Revised: 04/26/2019] [Accepted: 04/30/2019] [Indexed: 12/14/2022]
Abstract
Prolyl hydroxylase domain oxygen sensors are dioxygenases that regulate the activity of hypoxia-inducible factor (HIF), which controls renal and hepatic erythropoietin production and coordinates erythropoiesis with iron metabolism. Small molecule inhibitors of prolyl hydroxylase domain dioxygenases (HIF-PHI [prolyl hydroxylase inhibitor]) stimulate the production of endogenous erythropoietin and improve iron metabolism resulting in efficacious anemia management in patients with CKD. Three oral HIF-PHIs-daprodustat, roxadustat, and vadadustat-have now advanced to global phase III clinical development culminating in the recent licensing of roxadustat for oral anemia therapy in China. Here, we survey current clinical experience with HIF-PHIs, discuss potential therapeutic advantages, and deliberate over safety concerns regarding long-term administration in patients with renal anemia.
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Affiliation(s)
- Neil S Sanghani
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - Volker H Haase
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN; Department of Medical Cell Biology, Uppsala Universitet, Uppsala, Sweden; Department of Molecular Physiology & Biophysics and Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN.
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Oliveira JL. Algorithmic evaluation of hereditary erythrocytosis: Pathways and caveats. Int J Lab Hematol 2019; 41 Suppl 1:89-94. [PMID: 31069987 DOI: 10.1111/ijlh.13019] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 02/28/2019] [Accepted: 03/01/2019] [Indexed: 11/28/2022]
Abstract
Multiple algorithms have been published for the evaluation of hereditary erythrocytosis (HE). Typical entry points begin after excluding the more common acquired conditions through investigations of clinical history and assessment of cardiac, pulmonary, or vascular system disorders. Prior exclusion of JAK2 mutations, particularly the common JAK2 V617F mutation, is indicated in adults but less so in pediatric populations. Key decision trees are based on serum erythropoietin levels and p50 results. Recent data reveal some overlap in clinical presentation and laboratory findings in erythrocytosis. Caveats to consider when using algorithmic approaches are discussed.
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Affiliation(s)
- Jennifer L Oliveira
- Division of Hematopathology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
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46
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Vanoli A, Albarello L, Uncini S, Fassan M, Grillo F, Di Sabatino A, Martino M, Pasquali C, Milanetto AC, Falconi M, Partelli S, Doglioni C, Schiavo-Lena M, Brambilla T, Pietrabissa A, Sessa F, Capella C, Rindi G, La Rosa S, Solcia E, Paulli M. Neuroendocrine Tumors (NETs) of the Minor Papilla/Ampulla: Analysis of 16 Cases Underlines Homology With Major Ampulla NETs and Differences From Extra-Ampullary Duodenal NETs. Am J Surg Pathol 2019; 43:725-736. [PMID: 30913089 DOI: 10.1097/pas.0000000000001234] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Neuroendocrine tumors (NETs) of the minor papilla/ampulla (MIPA) are rare and poorly studied. Only individual case reports and no comprehensive analysis are available from the literature. We collected 16 MIPA NETs and investigated their clinicopathologic and immunohistochemical features, including markers such as somatostatin, pancreatic polypeptide, gastrin, serotonin, MUC1, cytokeratin 7, and somatostatin receptors type 2A and 5. The median age at diagnosis was 57.5 years, and the female-to-male ratio was 2.2:1. The median NET size was 1.45 cm, and most (94%) were low-grade (G1) tumors. Similarly to what was observed in the major ampulla, 3 histotypes were found: (i) ampullary-type somatostatin-producing tumors (ASTs, 10 cases), characterized by somatostatin expression in most tumor cells, focal-to-extensive tubulo-acinar structures, often with psammoma bodies, MUC1 reactivity, and no or rare membranous reactivity for somatostatin receptor type 2A; (ii) gangliocytic paragangliomas (3 cases), characterized by the coexistence of 3 tumor cell types: epithelioid, often reactive for pancreatic polypeptide, ganglion-like cells, and S100 reactive sustentacular/stromal cells; and (iii) ordinary nonfunctioning NETs (3 cases), resembling those more commonly observed in the extra-ampullary duodenum. Comparable histotypes could also be recognized among the 30 MIPA NETs from the literature. No NET-related patient death among MIPA cases was observed during a median follow-up of 38 months; however, MIPA ASTs showed lymph node metastases and invasion of the duodenal muscularis propria or beyond in 44% and 40% of cases, respectively. In conclusion, MIPA NETs closely resemble tumors arising in the major ampulla, with predominance of ASTs.
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Affiliation(s)
- Alessandro Vanoli
- Department of Molecular Medicine, Unit of Anatomic Pathology, University of Pavia
- Anatomic Pathology, IRCCS San Matteo Hospital Foundation, Pavia
| | | | - Stefania Uncini
- Department of Molecular Medicine, Unit of Anatomic Pathology, University of Pavia
| | - Matteo Fassan
- Department of Medicine (DIMED), Surgical Pathology & Cytopathology Unit
| | - Federica Grillo
- Department of Surgical Science and Integrated Diagnostics (DISC), Pathology Unit, University of Genoa
- San Martino Hospital, Genoa
| | - Antonio Di Sabatino
- First Department of Internal Medicine, IRCCS San Matteo Hospital Foundation, University of Pavia
| | - Michele Martino
- First Department of Internal Medicine, IRCCS San Matteo Hospital Foundation, University of Pavia
| | - Claudio Pasquali
- Department of Surgery 1 Pancreatic and Endocrine Digestive Surgical Unit, University of Padua, Padua
| | - Anna C Milanetto
- Department of Surgery 1 Pancreatic and Endocrine Digestive Surgical Unit, University of Padua, Padua
| | - Massimo Falconi
- Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, "Vita-Salute" University
| | - Stefano Partelli
- Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, San Raffaele Scientific Institute, "Vita-Salute" University
| | | | | | - Tatiana Brambilla
- Pathology Unit, Humanitas Research Hospital, Humanitas University, Rozzano, Milan
| | - Andrea Pietrabissa
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, Unit of General Surgery 2, University of Pavia and IRCCS San Matteo Hospital Foundation, Pavia
| | - Fausto Sessa
- Department of Medicine and Surgery, Anatomic Pathology Unit, University of Insubria, Varese
| | - Carlo Capella
- Department of Medicine and Surgery, Anatomic Pathology Unit, University of Insubria, Varese
| | - Guido Rindi
- Institute of Anatomic Pathology
- Rome ENETS Center of Excellence, University Hospital Foundation A. Gemelli IRCCS-Catholic University of Sacred Heart, Rome, Italy
| | - Stefano La Rosa
- Service of Clinical Pathology, Institute of Pathology, Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland
| | - Enrico Solcia
- Department of Molecular Medicine, Unit of Anatomic Pathology, University of Pavia
| | - Marco Paulli
- Department of Molecular Medicine, Unit of Anatomic Pathology, University of Pavia
- Anatomic Pathology, IRCCS San Matteo Hospital Foundation, Pavia
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Pang Y, Gupta G, Jha A, Yue X, Wang H, Huynh TT, Li A, Li L, Baker E, Chew E, Feelders RA, Korpershoek E, Zhuang Z, Yang C, Pacak K. Nonmosaic somatic HIF2A mutations associated with late onset polycythemia-paraganglioma syndrome: Newly recognized subclass of polycythemia-paraganglioma syndrome. Cancer 2019; 125:1258-1266. [PMID: 30644531 DOI: 10.1002/cncr.31839] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Revised: 08/30/2018] [Accepted: 09/11/2018] [Indexed: 12/16/2022]
Abstract
BACKGROUND Somatic mutations in hypoxia-inducible factor 2α (HIF2A) are associated with polycythemia-paraganglioma syndrome. Specifically, the classic presentation of female patients with recurrent paragangliomas (PGLs), polycythemia (at birth or in early childhood), and duodenal somatostatinomas has been described. Studies have demonstrated that somatic HIF2A mutations occur as postzygotic events and some to be associated with somatic mosaicism affecting hematopoietic and other tissue precursors. This phenomenon could explain the development of early onset of polycythemia in the absence of erythropoietin-secreting tumors. METHODS Correlation analysis was performed between mosaicism of HIF2A mutant patients and clinical presentations. RESULTS Somatic HIF2A mutations (p.A530V, p.P531S, and p.D539N) were identified in DNA extracted from PGLs of 3 patients. No somatic mosaicism was detected through deep sequencing of blood genomic DNA. Compared with classic syndrome, both polycythemia and PGL in all 3 patients developed at an advanced age with polycythemia at age 30, 30, and 17 years and PGLs at age 34, 30, and 55 years, respectively. Somatostatinomas were not detected, and 2 patients had ophthalmic findings. The biochemical phenotype in all 3 patients was noradrenergic with 18 F-fluorodopa PET/CT as the most sensitive imaging modality. All patients demonstrated multiplicity, and none developed metastatic disease. CONCLUSION These findings suggest that newer techniques need to be developed to detect somatic mosaicism in patients with this syndrome. Absence of HIF2A mosaicism in patients with somatic HIF2A mutations supports association with late onset of the disease, milder clinical phenotype, and an improved prognosis compared with patients who have HIF2A mosaicism.
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Affiliation(s)
- Ying Pang
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
| | - Garima Gupta
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.,Department of Medicine, The Jewish Hospital of Cincinnati, Cincinnati, Ohio
| | - Abhishek Jha
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
| | - Xupeng Yue
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland.,Department of Bioengineering, Zunyi Medical University-Zhuhai Campus, Zhuhai, Guangdong, 519041, P.R. China
| | - Herui Wang
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Thanh-Truc Huynh
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
| | - Aiguo Li
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Liping Li
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
| | - Eva Baker
- Radiology and Imaging Sciences, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland
| | - Emily Chew
- The Eye Clinic, National Eye Institute, National Institutes of Health, Bethesda, Maryland
| | - Richard A Feelders
- Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, The Netherlands
| | | | - Zhengping Zhuang
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.,Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
| | - Chunzhang Yang
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Karel Pacak
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland
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48
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Tarade D, Robinson CM, Lee JE, Ohh M. HIF-2α-pVHL complex reveals broad genotype-phenotype correlations in HIF-2α-driven disease. Nat Commun 2018; 9:3359. [PMID: 30135421 PMCID: PMC6105673 DOI: 10.1038/s41467-018-05554-1] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Accepted: 07/11/2018] [Indexed: 12/30/2022] Open
Abstract
It is definitively established that mutations in transcription factor HIF-2α are causative of both neuroendocrine tumors (class 1 disease) and polycythemia (class 2 disease). However, the molecular mechanism that underlies this emergent genotype–phenotype relationship has remained unclear. Here, we report the structure of HIF-2α peptide bound to pVHL-elongin B-elongin C (VBC) heterotrimeric complex, which shows topographical demarcation of class 1 and 2 mutations affecting residues predicted, and demonstrated via biophysical analyses, to differentially impact HIF-2α-pVHL interaction interface stability. Concordantly, biochemical experiments showed that class 1 mutations disrupt pVHL affinity to HIF-2α more adversely than class 2 mutations directly or indirectly via impeding PHD2-mediated hydroxylation. These findings suggest that neuroendocrine tumor pathogenesis requires a higher HIF-2α dose than polycythemia, which requires only a mild increase in HIF-2α activity. These biophysical data reveal a structural basis that underlies, and can be used to predict de novo, broad genotype-phenotype correlations in HIF-2α-driven disease. Hypoxia inducible factor (HIF)-2α transcription factor is mutated in polycythemia and various neuroendocrine tumors. Here the authors present the crystal structure of a HIF-2α peptide bound to the pVHL-elongin B-elongin C (VBC) heterotrimeric complex and propose a classification scheme for HIF-2α mutations that helps to predict disease phenotype outcome.
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Affiliation(s)
- Daniel Tarade
- Department of Laboratory Medicine & Pathobiology, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
| | - Claire M Robinson
- Department of Laboratory Medicine & Pathobiology, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada.,Department of Biochemistry, University of Toronto, 661 University Avenue, Toronto, ON, M5G 1M1, Canada
| | - Jeffrey E Lee
- Department of Laboratory Medicine & Pathobiology, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada
| | - Michael Ohh
- Department of Laboratory Medicine & Pathobiology, University of Toronto, 1 King's College Circle, Toronto, ON, M5S 1A8, Canada. .,Department of Biochemistry, University of Toronto, 661 University Avenue, Toronto, ON, M5G 1M1, Canada.
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Pang Y, Gupta G, Yang C, Wang H, Huynh TT, Abdullaev Z, Pack SD, Percy MJ, Lappin TRJ, Zhuang Z, Pacak K. A novel splicing site IRP1 somatic mutation in a patient with pheochromocytoma and JAK2 V617F positive polycythemia vera: a case report. BMC Cancer 2018. [PMID: 29534684 PMCID: PMC5850917 DOI: 10.1186/s12885-018-4127-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Background The role of the hypoxia signaling pathway in the pathogenesis of pheochromocytoma/paraganglioma (PPGL)-polycythemia syndrome has been elucidated. Novel somatic mutations in hypoxia-inducible factor type 2A (HIF2A) and germline mutations in prolyl hydroxylase type 1 and type 2 (PHD1 and PHD2) have been identified to cause upregulation of the hypoxia signaling pathway and its target genes including erythropoietin (EPO) and its receptor (EPOR). However, in a minority of patients presenting with this syndrome, the genetics and molecular pathogenesis remain unexplained. The aim of the present study was to uncover novel genetic causes of PPGL-polycythemia syndrome. Case presentation A female presented with a history of JAK2V617F positive PV, diagnosed in 2007, and right adrenal pheochromocytoma diagnosed and resected in 2011. Her polycythemia symptoms and hematocrit levels continued to worsen from 2007 to 2011, with an increased frequency of phlebotomies. Postoperatively, until early 2013, her hematocrit levels remained normalized. Following this, the hematocrit levels ranged between 46.4 and 48.9% [35–45%]. Tumor tissue from the patient was further tested for mutations in genes related to upregulation of the hypoxia signaling pathway including iron regulatory protein 1 (IRP1), which is a known regulator of HIF-2α mRNA translation. Functional studies were performed to investigate the consequences of these mutations, especially their effect on the HIF signaling pathway and EPO. Indel mutations (c.267-1_267delGGinsTA) were discovered at the exon 3 splicing site of IRP1. Minigene construct and splicing site analysis showed that the mutation led to a new splicing site and a frameshift mutation of IRP1, which caused a truncated protein. Fluorescence in situ hybridization analysis demonstrated heterozygous IRP1 deletions in tumor cells. Immunohistochemistry results confirmed the truncated IRP1 and overexpressed HIF-2α, EPO and EPOR in tumor cells. Conclusions This is the first report which provides direct molecular genetic evidence of association between a somatic IRP1 loss-of-function mutation and PHEO and secondary polycythemia. In patients diagnosed with PHEO/PGL and polycythemia with negative genetic testing for mutations in HIF2A, PHD1/2, and VHL, IRP1 should be considered as a candidate gene.
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Affiliation(s)
- Ying Pang
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Garima Gupta
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Chunzhang Yang
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Herui Wang
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Thanh-Truc Huynh
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Ziedulla Abdullaev
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Svetlana D Pack
- Laboratory of Pathology, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Melanie J Percy
- Department of Haematology, Belfast City Hospital, Belfast, Northern Ireland, BT9 7AB, UK
| | - Terence R J Lappin
- Centre for Cancer Research and Cell Biology, Queen's University, Belfast, Northern Ireland, BT9 7AB, UK
| | - Zhengping Zhuang
- Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, 20892, USA
| | - Karel Pacak
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 20892, USA.
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50
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Pheochromocytoma and paraganglioma: genotype versus anatomic location as determinants of tumor phenotype. Cell Tissue Res 2018; 372:347-365. [DOI: 10.1007/s00441-017-2760-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Accepted: 12/01/2017] [Indexed: 12/22/2022]
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