Frederic Castinetti1, Steven G Waguespack2, Andreas Machens3, Shinya Uchino4, Kornelia Hasse-Lazar5, Gabriella Sanso6, Tobias Else7, Sarka Dvorakova8, Xiao Ping Qi9, Rossella Elisei10, Ana Luisa Maia11, John Glod12, Delmar Muniz Lourenço13, Nuria Valdes14, Jes Mathiesen15, Nelson Wohllk16, Tushar R Bandgar17, Delphine Drui18, Marta Korbonits19, Maralyn R Druce19, Caroline Brain20, Tom Kurzawinski20, Atila Patocs21, Maria Joao Bugalho22, Andre Lacroix23, Philippe Caron24, Patricia Fainstein-Day25, Francoise Borson Chazot26, Marc Klein27, Thera P Links28, Claudio Letizia29, Laura Fugazzola30, Olivier Chabre31, Letizia Canu32, Regis Cohen33, Antoine Tabarin34, Anita Spehar Uroic35, Dominique Maiter36, Sandrine Laboureau37, Caterina Mian38, Mariola Peczkowska39, Frederic Sebag40, Thierry Brue41, Delphine Mirebeau-Prunier42, Laurence Leclerc43, Birke Bausch44, Amandine Berdelou45, Akihiro Sukurai46, Petr Vlcek47, Jolanta Krajewska5, Marta Barontini6, Carla Vaz Ferreira Vargas11, Laura Valerio10, Lucieli Ceolin11, Srivandana Akshintala48, Ana Hoff13, Christian Godballe15, Barbara Jarzab5, Camilo Jimenez2, Charis Eng49, Tsuneo Imai50, Martin Schlumberger45, Elizabeth Grubbs51, Henning Dralle52, Hartmut P Neumann44, Eric Baudin45. 1. Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale, Marseille Medical Genetics, Marseille, France; Assistance Publique-Hôpitaux de Marseille, Department of Endocrinology, Hôpital de la Conception, Centre de Référence des Maladies Rares de l'hypophyse, Marseille, France. Electronic address: frederic.castinetti@ap-hm.fr. 2. Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, Houston, TX, USA. 3. Department of General, Visceral and Vascular Surgery, Martin Luther University Halle-Wittenberg, Halle (Saale), Germany. 4. Noguchi Thyroid Clinic and Hospital Foundation, Beppu, Japan. 5. Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Institute, Oncology Center, Gliwice Branch, Gliwice, Poland. 6. Centro de Investigaciones Endocrinológicas, "Dr César Bergadá", Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina. 7. Division of Metabolism, Endocrinology, & Diabetes, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI, USA. 8. Department of Molecular Endocrinology, Institute of Endocrinology, Prague, Czech Republic. 9. Departments of Oncologic and Urologic Surgery, The 117th People's Liberation Army Hospital, People's Liberation Army Hangzhou Clinical College, Anhui Medical University, Hangzhou, China. 10. Department of Endocrinology, University Hospital, Pisa, Italy. 11. Thyroid Section, Endocrinology Division, Hospital de Cliínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. 12. Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. 13. Endocrine Genetics Unit, Endocrinology Division, Hospital das Clínicas, University of São Paulo School of Medicine, São Paulo, Brazil; Endocrine Oncology Division, Institute of Cancer of the State of São Paulo, Faculty of Medicine of the University of São Paulo, São Paulo, Brazil. 14. Department of Endocrinology and Nutrition, Hospital Universitario Central de Asturias, Oviedo, Spain; Unit of Endocrinology, Nutrition, Diabetes and Obesity, Institute of Sanitary Research of Asturias, Oviedo, Spain. 15. Department of Otorhinolaryngology, Head and Neck Surgery and Audiology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark. 16. Endocrine Section, Universidad de Chile, Hospital del Salvador, Santiago de Chile, Santiago, Chile. 17. Department of Endocrinology, Seth G S Medical College, King Edward Memorial Hospital, Parel, Mumbai, India. 18. L'Institut du thorax, Department of Endocrinology, Centre Hospitalier Universitaire Nantes, Nantes, France. 19. Department of Endocrinology, St Bartholomew's Hospital, London, UK; London School of Medicine and Dentistry, Queen Mary University of London, London, UK. 20. Division of Endocrine Surgery, University College Hospital and Great Ormond Street Hospital, London, United Kingdom. 21. Hungarian Academy of Sciences and Semmelweis University, HSA-SE "Lendület" Hereditary Endocrine Tumour Research Group, Budapest, Hungary. 22. Serviço de Endocrinologia, Diabetes e Metabolismo, Centro Hospitalar Universitário Lisboa Norte-Hospital Santa Maria, Lisboa, Portugal; Centro Académico de Medicina de Lisboa, Universidade Lisboa, Lisboa, Portugal. 23. Endocrine Division, Department of Medicine, Centre Hospitalier de l'Universite í de Montréal, Montreal, QC, Canada. 24. Centre Hospitalier Universitaire de Toulouse, Hôpital Larrey, Service d'Endocrinologie, Maladies métaboliques, Nutrition, Toulouse, France. 25. Endocrine and Nuclear Medicine Unit, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina. 26. Hospices Civils de Lyon, Fédération d'Endocrinologie, Université Claude Bernard Lyon 1, Lyon, France. 27. Department of Endocrinology, University Hospital, Nancy, France. 28. Department of Endocrinology, University Medical Center Groningen, University of Groningen, Groningen, Netherlands. 29. Department of Internal Medicine and Medical Specialties, Sapienza University of Rome, Rome, Italy. 30. Division of Endocrine and Metabolic Diseases, Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Auxologico Italiano, University of Milan, Milan, Italy; Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy. 31. Centre Hospitalier Universitaire de Grenoble, Hôpital Albert Michallon, Service d'Endocrinologie-Diabétologie-Nutrition, Grenoble, France. 32. Department of Experimental and Clinical Biomedical Sciences, Endocrinology Unit, University of Florence, Florence, Italy. 33. Endocrinologie et Métabolismes, Centre Hospitalier de Saint Denis, Saint-Denis, France. 34. Centre Hospitalier Universitaire de Bordeaux, Hôpital du Haut Lévêque, Service d'Endocrinologie-Diabétologie et Maladies Métaboliques, Pessac, France. 35. Department of Pediatrics, University Hospital Centre Zagreb, Zagreb, Croatia. 36. Service d'Endocrinologie et Nutrition, Cliniques Universitaires Saint-Luc, Universite Catholique de Louvain, Brussels, Belgium. 37. Department of Endocrinology, Diabetes and Nutrition, Reference Centre of Rare Thyroid Disease, Hospital of Angers, Angers, France. 38. Operative Unit of the Endocrinology, Department of Medicine, University of Padua, Padua, Italy. 39. Department of Hypertension, Institute of Cardiology, Warsaw, Poland. 40. Department of Endocrine Surgery, La Conception Hospital, Marseille, France. 41. Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale, Marseille Medical Genetics, Marseille, France; Assistance Publique-Hôpitaux de Marseille, Department of Endocrinology, Hôpital de la Conception, Centre de Référence des Maladies Rares de l'hypophyse, Marseille, France. 42. Département de Biochimie et Génétique, Centre Hospitalier Universitaire d'Angers, Angers, France. 43. Centre Hospitalier Régional Universitaire de Lille, Hopital Huriez, Service d'Endocrinologie, Lille, France. 44. Section for Preventive Medicine, Department of Nephrology and General Medicine, Freiburg, Germany. 45. Endocrine Oncology, Institut Gustave Roussy Ecole Doctorale de Cancerologie, Villejuif, France. 46. Department of Medical Genetics and Genomics, Sapporo Medical University School of Medicine, Chuo-ku, Sapporo, Hokkaido, Japan. 47. Department of Nuclear Medicine and Endocrinology, Second Faculty of Medicine, Charles University, Prague, Czech Republic; Motol University Hospital, Prague, Czech Republic. 48. Department of Pediatrics, New York University Langone Medical Center, New York, NY, USA. 49. Genomic Medicine Institute, Lerner Research Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA. 50. Department of Breast and Endocrine Surgery, National Hospital Organization Higashinagoya National Hospital, Nagoya, Japan. 51. Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. 52. Section of Endocrine Surgery, Department of General, Visceral, and Transplantation Surgery, University Hospital Essen, Essen, Germany.
Abstract
BACKGROUND: Multiple endocrine neoplasia type 2B is a rare syndrome caused mainly by Met918Thr germline RET mutation, and characterised by medullary thyroid carcinoma, phaeochromocytoma, and extra-endocrine features. Data are scarce on the natural history of multiple endocrine neoplasia type 2B. We aimed to advance understanding of the phenotype and natural history of multiple endocrine neoplasia type 2B, to increase awareness and improve detection. METHODS: This study was a retrospective, multicentre, international study in patients carrying the Met918Thr RET variant with no age restrictions. The study was done with registry data from 48 centres globally. Data from patients followed-up from 1970 to 2016 were retrieved from May 1, 2016, to May 31, 2018. Our primary objectives were to determine overall survival, and medullary thyroid carcinoma-specific survival based on whether the patient had undergone early thyroidectomy before the age of 1 year. We also assessed remission of medullary thyroid carcinoma, incidence and treatment of phaeochromocytoma, and the penetrance of extra-endocrine features. FINDINGS: 345 patients were included, of whom 338 (98%) had a thyroidectomy. 71 patients (21%) of the total cohort died at a median age of 25 years (range <1-59). Thyroidectomy was done before the age of 1 year in 20 patients, which led to long-term remission (ie, undetectable calcitonin level) in 15 (83%) of 18 individuals (2 patients died of causes unrelated to medullary thyroid carcinoma). Medullary thyroid carcinoma-specific survival curves did not show any significant difference between patients who had thyroidectomy before or after 1 year (comparison of survival curves by log-rank test: p=0·2; hazard ratio 0·35; 95% CI 0.07-1.74). However, there was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0·0001). There was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0·0001). In the other 318 patients who underwent thyroidectomy after 1 year of age, biochemical and structural remission was obtained in 47 (15%) of 318 individuals. Bilateral phaeochromocytoma was diagnosed in 156 (50%) of 313 patients by 28 years of age. Adrenal-sparing surgery was done in 31 patients: three (10%) of 31 patients had long-term recurrence, while normal adrenal function was obtained in 16 (62%) patients. All patients with available data (n=287) had at least one extra-endocrine feature, including 106 (56%) of 190 patients showing marfanoid body habitus, mucosal neuromas, and gastrointestinal signs. INTERPRETATION: Thyroidectomy done at no later than 1 year of age is associated with a high probability of cure. The reality is that the majority of children with the syndrome will be diagnosed after this recommended age. Adrenal-sparing surgery is feasible in multiple endocrine neoplasia type 2B and affords a good chance for normal adrenal function. To improve the prognosis of such patients, it is imperative that every health-care provider be aware of the extra-endocrine signs and the natural history of this rare syndrome. The implications of this research include increasing awareness of the extra-endocrine symptoms and also recommendations for thyroidectomy before the age of 1 year. FUNDING: None.
BACKGROUND:Multiple endocrine neoplasia type 2B is a rare syndrome caused mainly by Met918Thr germline RET mutation, and characterised by medullary thyroid carcinoma, phaeochromocytoma, and extra-endocrine features. Data are scarce on the natural history of multiple endocrine neoplasia type 2B. We aimed to advance understanding of the phenotype and natural history of multiple endocrine neoplasia type 2B, to increase awareness and improve detection. METHODS: This study was a retrospective, multicentre, international study in patients carrying the Met918ThrRET variant with no age restrictions. The study was done with registry data from 48 centres globally. Data from patients followed-up from 1970 to 2016 were retrieved from May 1, 2016, to May 31, 2018. Our primary objectives were to determine overall survival, and medullary thyroid carcinoma-specific survival based on whether the patient had undergone early thyroidectomy before the age of 1 year. We also assessed remission of medullary thyroid carcinoma, incidence and treatment of phaeochromocytoma, and the penetrance of extra-endocrine features. FINDINGS: 345 patients were included, of whom 338 (98%) had a thyroidectomy. 71 patients (21%) of the total cohort died at a median age of 25 years (range <1-59). Thyroidectomy was done before the age of 1 year in 20 patients, which led to long-term remission (ie, undetectable calcitonin level) in 15 (83%) of 18 individuals (2 patientsdied of causes unrelated to medullary thyroid carcinoma). Medullary thyroid carcinoma-specific survival curves did not show any significant difference between patients who had thyroidectomy before or after 1 year (comparison of survival curves by log-rank test: p=0·2; hazard ratio 0·35; 95% CI 0.07-1.74). However, there was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0·0001). There was a significant difference in remission status between patients who underwent thyroidectomy before and after the age of 1 year (p<0·0001). In the other 318 patients who underwent thyroidectomy after 1 year of age, biochemical and structural remission was obtained in 47 (15%) of 318 individuals. Bilateral phaeochromocytoma was diagnosed in 156 (50%) of 313 patients by 28 years of age. Adrenal-sparing surgery was done in 31 patients: three (10%) of 31 patients had long-term recurrence, while normal adrenal function was obtained in 16 (62%) patients. All patients with available data (n=287) had at least one extra-endocrine feature, including 106 (56%) of 190 patients showing marfanoid body habitus, mucosal neuromas, and gastrointestinal signs. INTERPRETATION: Thyroidectomy done at no later than 1 year of age is associated with a high probability of cure. The reality is that the majority of children with the syndrome will be diagnosed after this recommended age. Adrenal-sparing surgery is feasible in multiple endocrine neoplasia type 2B and affords a good chance for normal adrenal function. To improve the prognosis of such patients, it is imperative that every health-care provider be aware of the extra-endocrine signs and the natural history of this rare syndrome. The implications of this research include increasing awareness of the extra-endocrine symptoms and also recommendations for thyroidectomy before the age of 1 year. FUNDING: None.
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