Frederic Castinetti1, Xiao-Ping Qi2, Martin K Walz3, Ana Luiza Maia4, Gabriela Sansó5, Mariola Peczkowska6, Kornelia Hasse-Lazar7, Thera P Links8, Sarka Dvorakova9, Rodrigo A Toledo10, Caterina Mian11, Maria Joao Bugalho12, Nelson Wohllk13, Oleg Kollyukh14, Letizia Canu15, Paola Loli16, Simona R Bergmann17, Josefina Biarnes Costa18, Ozer Makay19, Attila Patocs20, Marija Pfeifer21, Nalini S Shah22, Thomas Cuny23, Michael Brauckhoff24, Birke Bausch25, Ernst von Dobschuetz26, Claudio Letizia27, Marcin Barczynski28, Maria K Alevizaki29, Malgorzata Czetwertynska30, M Umit Ugurlu31, Gerlof Valk32, John T M Plukker33, Paola Sartorato34, Debora R Siqueira4, Marta Barontini5, Malgorzata Szperl6, Barbara Jarzab7, Hans H G Verbeek8, Tomas Zelinka35, Petr Vlcek36, Sergio P A Toledo10, Flavia L Coutinho10, Massimo Mannelli15, Monica Recasens18, Lea Demarquet23, Luigi Petramala27, Svetlana Yaremchuk37, Dmitry Zabolotnyi37, Francesca Schiavi38, Giuseppe Opocher39, Karoly Racz40, Andrzej Januszewicz6, Georges Weryha23, Jean-Francois Henry41, Thierry Brue42, Bernard Conte-Devolx42, Charis Eng43, Hartmut P H Neumann44. 1. Department of Endocrinology, La Timone Hospital, Hopitaux de Marseille and Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Aix-Marseille University, Marseille, France. Electronic address: frederic.castinetti@ap-hm.fr. 2. Departments of Oncologic and Urologic Surgery, The 117th PLA Hospital, PLA Hangzhou Clinical College, Anhui Medical University, Hangzhou, China. 3. Department of Surgery and Center of Minimally Invasive Surgery, Kliniken Essen-Mitte, Essen, Germany. 4. Thyroid Section, Endocrinology Division, Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Brazil. 5. Center for Endocrinological Investigations, Hospital de Ninos R Gutierrez, Buenos Aires, Argentina. 6. Department of Hypertension, Institute of Cardiology, Warsaw, Poland. 7. Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska Curie Memorial Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland. 8. Department of Endocrinology, University Medical Center Groningen, University of Groningen, Netherlands. 9. Department of Molecular Endocrinology, Institute of Endocrinology, Prague, Czech Republic. 10. Department of Endocrinology, University of Sao Paulo School of Medicine, Sao Paulo, Brazil. 11. Operative Unit of the Endocrinology Department of Medicine (DIMED), University of Padova, Padova, Italy. 12. Servico de Endocrinologia, Instituto Portugues de Oncologia de Lisboa Francisco Gentil E.P.E. and Faculdade de Ciencias Médicas, Universidade Nova de Lisboa, Lisbon, Portugal. 13. Endocrine Section, Universidad de Chile, Hospital del Salvador, Santiago de Chile, Chile. 14. Institute of Endocrinology, Kiev, Ukraine. 15. Department of Experimental and Clinical Biomedical Sciences, Endocrinology Unit, University of Florence, Florence, Italy. 16. Department of Endocrinology, Ospedale Niguarda Cà Granda, Milan, Italy. 17. Division of Endocrinology and Diabetology, Faculty of Medicine, Philipps University of Marburg, Marburg, Germany. 18. Hospital Universitari de Girona, Gerencia Territorial Girona, Institut Català de la Salut, Girona, Spain. 19. Department of General Surgery, Division of Endocrine Surgery, Ege University Hospital, Izmir, Turkey. 20. Molecular Medicine Research Group, HSA-SE "Lendület" Hereditary Endocrine Tumor Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary. 21. Department of Endocrinology, University Medical Center Ljubljana, Ljubljana, Slovenia. 22. Department of Endocrinology, Seth G S Medical College, King Edward Memorial Hospital, Parel, Mumbai, India. 23. Department of Endocrinology, University Hospital, Nancy, France. 24. Department of Endocrine Surgery, University of Bergen, Bergen, Norway. 25. 2nd Department of Medicine, University Medical Centre, Albert Ludwigs University of Freiburg, Freiburg, Germany. 26. Department of Visceral Surgery, University Medical Centre, Albert Ludwigs University of Freiburg, Freiburg, Germany. 27. Department of Internal Medicine and Medical Specialties, University La Sapienza, Rome, Italy. 28. Department of Endocrine Surgery, Third Chair of General Surgery, Jagiellonian University, Medical College, Krakow, Poland. 29. Endocrine Unit Evgenideion Hospital and Department of Medical Therapeutics, Alexandra Hospital, Athens University School of Medicine, Athens, Greece. 30. Department of Endocrinology, Maria Sklodowska Curie Memorial Center and Institute of Oncology, Warsaw, Poland. 31. Department of General Surgery, Breast and Endocrine Surgery Unit, Marmara University, Istanbul, Turkey. 32. Department of Internal Medicine, University Medical Centre Utrecht, Utrecht, Netherlands. 33. Department of Surgery, University Medical Centre, Groningen, Netherlands. 34. Department of Internal Medicine, General Hospital, Montebelluna, Treviso, Italy. 35. 3rd Department of Medicine-Department of Endocrinology and Metabolism, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic. 36. Department of Nuclear Medicine and Endocrinology, Second Faculty of Medicine, Charles University, Prague, Czech Republic. 37. Institute of Otolaryngology NAMS of Ukraine, Kiev, Ukraine. 38. Familial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology, IRCCS Padova, Padova, Italy. 39. Department of Medicine (DIMED), University of Padova, Padova, Italy. 40. 2nd Department of Internal Medicine, Semmelweis University, Budapest, Hungary. 41. Aix-Marseille University, Department of Endocrine Surgery, La Timone Hospital, Marseille, France. 42. Department of Endocrinology, La Timone Hospital, Hopitaux de Marseille and Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Aix-Marseille University, Marseille, France. 43. Genomic Medicine Institute, Lerner Research Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA. 44. Section for Preventive Medicine, Department of Nephrology and General Medicine, University Medical Centre, Albert Ludwigs University of Freiburg, Freiburg, Germany.
Abstract
BACKGROUND: The prevention of medullary thyroid cancer in patients with multiple endocrine neoplasia type 2 syndrome has demonstrated the ability of molecular diagnosis and prophylactic surgery to improve patient outcomes. However, the other major neoplasia associated with multiple endocrine neoplasia type 2, phaeochromocytoma, is not as well characterised in terms of occurrence and treatment outcomes. In this study, we aimed to systematically characterise the outcomes of management of phaeochromocytoma associated with multiple endocrine neoplasia type 2. METHODS: This multinational observational retrospective population-based study compiled data on patients with multiple endocrine neoplasia type 2 from 30 academic medical centres across Europe, the Americas, and Asia. Patients were included if they were carriers of germline pathogenic mutations of the RET gene, or were first-degree relatives with histologically proven medullary thyroid cancer and phaeochromocytoma. We gathered clinical information about patients'RET genotype, type of treatment for phaeochromocytoma (ie, unilateral or bilateral operations as adrenalectomy or adrenal-sparing surgery, and as open or endoscopic operations), and postoperative outcomes (adrenal function, malignancy, and death). The type of surgery was decided by each investigator and the timing of surgery was patient driven. The primary aim of our analysis was to compare disease-free survival after either adrenal-sparing surgery or adrenalectomy. FINDINGS: 1210 patients with multiple endocrine neoplasia type 2 were included in our database, 563 of whom had phaeochromocytoma. Treatment was adrenalectomy in 438 (79%) of 552 operated patients, and adrenal-sparing surgery in 114 (21%). Phaeochromocytoma recurrence occurred in four (3%) of 153 of the operated glands after adrenal-sparing surgery after 6-13 years, compared with 11 (2%) of 717 glands operated by adrenalectomy (p=0.57). Postoperative adrenal insufficiency or steroid dependency developed in 292 (86%) of 339 patients with bilateral phaeochromocytoma who underwent surgery. However, 47 (57%) of 82 patients with bilateral phaeochromocytoma who underwent adrenal-sparing surgery did not become steroid dependent. INTERPRETATION: The treatment of multiple endocrine neoplasia type 2-related phaeochromocytoma continues to rely on adrenalectomies with their associated Addisonian-like complications and consequent lifelong dependency on steroids. Adrenal-sparing surgery, a highly successful treatment option in experienced centres, should be the surgical approach of choice to reduce these complications.
BACKGROUND: The prevention of medullary thyroid cancer in patients with multiple endocrine neoplasia type 2 syndrome has demonstrated the ability of molecular diagnosis and prophylactic surgery to improve patient outcomes. However, the other major neoplasia associated with multiple endocrine neoplasia type 2, phaeochromocytoma, is not as well characterised in terms of occurrence and treatment outcomes. In this study, we aimed to systematically characterise the outcomes of management of phaeochromocytoma associated with multiple endocrine neoplasia type 2. METHODS: This multinational observational retrospective population-based study compiled data on patients with multiple endocrine neoplasia type 2 from 30 academic medical centres across Europe, the Americas, and Asia. Patients were included if they were carriers of germline pathogenic mutations of the RET gene, or were first-degree relatives with histologically proven medullary thyroid cancer and phaeochromocytoma. We gathered clinical information about patients'RET genotype, type of treatment for phaeochromocytoma (ie, unilateral or bilateral operations as adrenalectomy or adrenal-sparing surgery, and as open or endoscopic operations), and postoperative outcomes (adrenal function, malignancy, and death). The type of surgery was decided by each investigator and the timing of surgery was patient driven. The primary aim of our analysis was to compare disease-free survival after either adrenal-sparing surgery or adrenalectomy. FINDINGS: 1210 patients with multiple endocrine neoplasia type 2 were included in our database, 563 of whom had phaeochromocytoma. Treatment was adrenalectomy in 438 (79%) of 552 operated patients, and adrenal-sparing surgery in 114 (21%). Phaeochromocytoma recurrence occurred in four (3%) of 153 of the operated glands after adrenal-sparing surgery after 6-13 years, compared with 11 (2%) of 717 glands operated by adrenalectomy (p=0.57). Postoperative adrenal insufficiency or steroid dependency developed in 292 (86%) of 339 patients with bilateral phaeochromocytoma who underwent surgery. However, 47 (57%) of 82 patients with bilateral phaeochromocytoma who underwent adrenal-sparing surgery did not become steroid dependent. INTERPRETATION: The treatment of multiple endocrine neoplasia type 2-related phaeochromocytoma continues to rely on adrenalectomies with their associated Addisonian-like complications and consequent lifelong dependency on steroids. Adrenal-sparing surgery, a highly successful treatment option in experienced centres, should be the surgical approach of choice to reduce these complications.
Authors: Thomas G Papathomas; Diederik P D Suurd; Alfred K Lam; Ronald R de Krijger; Karel Pacak; Arthur S Tischler; Menno R Vriens Journal: Endocr Pathol Date: 2021-01-12 Impact factor: 3.943