Martin Reincke1, Adriana Albani1, Guillaume Assie2, Irina Bancos3, Thierry Brue4, Michael Buchfelder5, Olivier Chabre6, Filippo Ceccato7, Andrea Daniele7, Mario Detomas8, Guido Di Dalmazi9, Atanaska Elenkova10, James Findling11, Ashley B Grossman12, Celso E Gomez-Sanchez13, Anthony P Heaney14, Juergen Honegger15, Niki Karavitaki16,17,18, Andre Lacroix19, Edward R Laws20, Marco Losa21, Masanori Murakami1,22, John Newell-Price23, Francesca Pecori Giraldi24, Luis G Pérez-Rivas1, Rosario Pivonello25, William E Rainey26, Silviu Sbiera8, Jochen Schopohl1, Constantine A Stratakis27, Marily Theodoropoulou1, Elisabeth F C van Rossum28, Elena Valassi29, Sabina Zacharieva10, German Rubinstein1, Katrin Ritzel1. 1. Klinikum der Ludwig-Maximilians-Universität München, Medizinische Klinik und Poliklinik IV, Munich, Germany. 2. Department of Endocrinology, Université de Paris, Institut Cochin, INSERM, CNRS, Center for Rare Adrenal Diseases, Hôpital Cochin, Paris, France. 3. Division of Endocrinology, Mayo Clinic Minnesota, Diabetes, Metabolism, Nutrition, Rochester, Minnesota, USA. 4. Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Institut MarMaRa and Endocrinology Department, Conception Hospital, Assistance Publique-Hôpitaux de Marseille (APHM), Marseille, France. 5. Universitätsklinikum Erlangen, Neurochirurgische Klinik, Erlangen, Germany. 6. CHU Grenoble-Alpes, Unit of Endocrinology, Pavillon des Ecrins, Grenoble, France. 7. Department of Medicine, University of Padova, Padova, Veneto, Italy. 8. Division of Endocrinology and Diabetology, Department of Internal Medicine, University of Würzburg, Wurzburg, Bayern, Germany. 9. Department of Medical and Surgical Sciences, Endocrinology and Diabetes Prevention and Care Unit, University of Bologna, S. Orsola Policlinic, Bologna, Italy. 10. Department of Endocrinology, Medical University Sofia, Sofia, Bulgaria. 11. Division of Endocrinology and Molecular Medicine, Medical College of Wisconsin, Menomonee Falls, Wisconsin, USA. 12. Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Centre for Endocrinology, Barts and the London School of Medicine, Queen Mary University of London, UK. 13. Department of Pharmacology and Toxicology and Medicine, Endocrine Service, G.V. Montgomery VA Medical Center, University of Mississippi Medical Center, Jackson, Mississippi, USA. 14. Division of Endocrinology, Medical Director, Pituitary & Neuroendocrine Tumor Program, UCLA School of Medicine, Los Angeles, California, USA. 15. Department of Neurosurgery, University of Tübingen, Tübingen, Germany. 16. Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham. 17. Centre for Endocrinology, Diabetes and Metabolism, Birmingham Health Partners. 18. Department of Endocrinology, Queen Elizabeth Hospital, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK. 19. Division of Endocrinology, Department of Medicine, Centre hospitalier de l'Université de Montréal (CHUM), Montréal, Québec, Canada. 20. Pituitary/Neuroendocrine Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA. 21. Department of Neurosurgery, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milano, Italy. 22. Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan. 23. Dept of Oncology and Metabolism, The Medical School University of Sheffield, Sheffield, UK. 24. Department of Clinical Sciences & Community Health, University of Milan Neuroendocrinology Research Laboratory, Instituto Auxologico Italiano IRCCS, Milan, Italy. 25. Dipartimento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Università Federico II di Napoli, Naples, Italy. 26. Departments of Molecular & Integrative Physiology and Medicine, University of Michigan, Ann Arbor, Michigan, USA. 27. Section on Genetics & Endocrinology Eunice Kennedy Shriver National Insitute of Child Health & Human Development (NICHD) National Institute of Health (NIH), NIH Clinical Research Center, Bethesda, Maryland, USA. 28. Department of Internal Medicine, division of Endocrinology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 29. IIB-Sant Pau and Department of Endocrinology/Medicine, Hospital Sant Pau, UAB, and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBER-ER, Unidad 747), ISCIII, Barcelona, Spain.
Abstract
BACKGROUND: Corticotroph tumor progression (CTP) leading to Nelson's syndrome (NS) is a severe and difficult-to-treat complication subsequent to bilateral adrenalectomy (BADX) for Cushing's disease. Its characteristics are not well described, and consensus recommendations for diagnosis and treatment are missing. METHODS: A systematic literature search was performed focusing on clinical studies and case series (≥5 patients). Definition, cumulative incidence, treatment and long-term outcomes of CTP/NS after BADX were analyzed using descriptive statistics. The results were presented and discussed at an interdisciplinary consensus workshop attended by international pituitary experts in Munich on October 28, 2018. RESULTS: Data covered definition and cumulative incidence (34 studies, 1275 patients), surgical outcome (12 studies, 187 patients), outcome of radiation therapy (21 studies, 273 patients), and medical therapy (15 studies, 72 patients). CONCLUSIONS: We endorse the definition of CTP-BADX/NS as radiological progression or new detection of a pituitary tumor on thin-section MRI. We recommend surveillance by MRI after 3 months and every 12 months for the first 3 years after BADX. Subsequently, we suggest clinical evaluation every 12 months and MRI at increasing intervals every 2-4 years (depending on ACTH and clinical parameters). We recommend pituitary surgery as first-line therapy in patients with CTP-BADX/NS. Surgery should be performed before extrasellar expansion of the tumor to obtain complete and long-term remission. Conventional radiotherapy or stereotactic radiosurgery should be utilized as second-line treatment for remnant tumor tissue showing extrasellar extension.
BACKGROUND: Corticotroph tumor progression (CTP) leading to Nelson's syndrome (NS) is a severe and difficult-to-treat complication subsequent to bilateral adrenalectomy (BADX) for Cushing's disease. Its characteristics are not well described, and consensus recommendations for diagnosis and treatment are missing. METHODS: A systematic literature search was performed focusing on clinical studies and case series (≥5 patients). Definition, cumulative incidence, treatment and long-term outcomes of CTP/NS after BADX were analyzed using descriptive statistics. The results were presented and discussed at an interdisciplinary consensus workshop attended by international pituitary experts in Munich on October 28, 2018. RESULTS: Data covered definition and cumulative incidence (34 studies, 1275 patients), surgical outcome (12 studies, 187 patients), outcome of radiation therapy (21 studies, 273 patients), and medical therapy (15 studies, 72 patients). CONCLUSIONS: We endorse the definition of CTP-BADX/NS as radiological progression or new detection of a pituitary tumor on thin-section MRI. We recommend surveillance by MRI after 3 months and every 12 months for the first 3 years after BADX. Subsequently, we suggest clinical evaluation every 12 months and MRI at increasing intervals every 2-4 years (depending on ACTH and clinical parameters). We recommend pituitary surgery as first-line therapy in patients with CTP-BADX/NS. Surgery should be performed before extrasellar expansion of the tumor to obtain complete and long-term remission. Conventional radiotherapy or stereotactic radiosurgery should be utilized as second-line treatment for remnant tumor tissue showing extrasellar extension.
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