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.

2nd Department of Internal Medicine Semmelweis University Budapest Hungary

2nd Department of Medicine University Medical Centre Albert Ludwigs University of Freiburg Freiburg Germany

3rd Department of Medicine Department of Endocrinology and Metabolism 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Aix Marseille University Department of Endocrine Surgery La Timone Hospital Marseille France

Center for Endocrinological Investigations Hospital de Ninos R Gutierrez Buenos Aires Argentina

Department of Endocrine Surgery 3rd Chair of General Surgery Jagiellonian University Medical College Krakow Poland

Department of Endocrine Surgery University of Bergen Bergen Norway

Department of Endocrinology La Timone Hospital Hopitaux de Marseille and Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille Aix Marseille University Marseille France

Department of Endocrinology Maria Sklodowska Curie Memorial Center and Institute of Oncology Warsaw Poland

Department of Endocrinology Ospedale Niguarda Cà Granda Milan Italy

Department of Endocrinology Seth G S Medical College King Edward Memorial Hospital Parel Mumbai India

Department of Endocrinology University Hospital Nancy France

Department of Endocrinology University Medical Center Groningen University of Groningen Netherlands

Department of Endocrinology University Medical Center Ljubljana Ljubljana Slovenia

Department of Endocrinology University of Sao Paulo School of Medicine Sao Paulo Brazil

Department of Experimental and Clinical Biomedical Sciences Endocrinology Unit University of Florence Florence Italy

Department of General Surgery Breast and Endocrine Surgery Unit Marmara University Istanbul Turkey

Department of General Surgery Division of Endocrine Surgery Ege University Hospital Izmir Turkey

Department of Hypertension Institute of Cardiology Warsaw Poland

Department of Internal Medicine and Medical Specialties University La Sapienza Rome Italy

Department of Internal Medicine General Hospital Montebelluna Treviso Italy

Department of Internal Medicine University Medical Centre Utrecht Utrecht Netherlands

Department of Medicine University of Padova Padova Italy

Department of Molecular Endocrinology Institute of Endocrinology Prague Czech Republic

Department of Nuclear Medicine and Endocrine Oncology Maria Sklodowska Curie Memorial Center and Institute of Oncology Gliwice Branch Gliwice Poland

Department of Nuclear Medicine and Endocrinology 2nd Faculty of Medicine Charles University Prague Czech Republic

Department of Surgery and Center of Minimally Invasive Surgery Kliniken Essen Mitte Essen Germany

Department of Surgery University Medical Centre Groningen Netherlands

Department of Visceral Surgery University Medical Centre Albert Ludwigs University of Freiburg Freiburg Germany

Departments of Oncologic and Urologic Surgery The 117th PLA Hospital PLA Hangzhou Clinical College Anhui Medical University Hangzhou China

Division of Endocrinology and Diabetology Faculty of Medicine Philipps University of Marburg Marburg Germany

Endocrine Section Universidad de Chile Hospital del Salvador Santiago de Chile Chile

Endocrine Unit Evgenideion Hospital and Department of Medical Therapeutics Alexandra Hospital Athens University School of Medicine Athens Greece

Familial Cancer Clinic and Oncoendocrinology Veneto Institute of Oncology IRCCS Padova Padova Italy

Genomic Medicine Institute Lerner Research Institute and Taussig Cancer Institute Cleveland Clinic Cleveland OH USA

Hospital Universitari de Girona Gerencia Territorial Girona Institut Català de la Salut Girona Spain

Institute of Endocrinology Kiev Ukraine

Institute of Otolaryngology NAMS of Ukraine Kiev Ukraine

Molecular Medicine Research Group HSA SE Lendület Hereditary Endocrine Tumor Research Group Hungarian Academy of Sciences and Semmelweis University Budapest Hungary

Operative Unit of the Endocrinology Department of Medicine University of Padova Padova Italy

Section for Preventive Medicine Department of Nephrology and General Medicine University Medical Centre Albert Ludwigs University of Freiburg Freiburg Germany

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

Thyroid Section Endocrinology Division Hospital de Clínicas de Porto Alegre Universidade Federal do Rio Grande do Sul Brazil

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