IMPORTANCE: Large studies investigating long-term outcomes of patients with bilateral pheochromocytomas treated with either total or cortical-sparing adrenalectomies are needed to inform clinical management. OBJECTIVE: To determine the association of total vs cortical-sparing adrenalectomy with pheochromocytoma-specific mortality, the burden of primary adrenal insufficiency after bilateral adrenalectomy, and the risk of pheochromocytoma recurrence. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from a multicenter consortium-based registry for 625 patients treated for bilateral pheochromocytomas between 1950 and 2018. Data were analyzed from September 1, 2018, to June 1, 2019. EXPOSURES: Total or cortical-sparing adrenalectomy. MAIN OUTCOMES AND MEASURES: Primary adrenal insufficiency, recurrent pheochromocytoma, and mortality. RESULTS: Of 625 patients (300 [48%] female) with a median (interquartile range [IQR]) age of 30 (22-40) years at diagnosis, 401 (64%) were diagnosed with synchronous bilateral pheochromocytomas and 224 (36%) were diagnosed with metachronous pheochromocytomas (median [IQR] interval to second adrenalectomy, 6 [1-13] years). In 505 of 526 tested patients (96%), germline mutations were detected in the genes RET (282 patients [54%]), VHL (184 patients [35%]), and other genes (39 patients [7%]). Of 849 adrenalectomies performed in 625 patients, 324 (52%) were planned as cortical sparing and were successful in 248 of 324 patients (76.5%). Primary adrenal insufficiency occurred in all patients treated with total adrenalectomy but only in 23.5% of patients treated with attempted cortical-sparing adrenalectomy. A third of patients with adrenal insufficiency developed complications, such as adrenal crisis or iatrogenic Cushing syndrome. Of 377 patients who became steroid dependent, 67 (18%) developed at least 1 adrenal crisis and 50 (13%) developed iatrogenic Cushing syndrome during median (IQR) follow-up of 8 (3-25) years. Two patients developed recurrent pheochromocytoma in the adrenal bed despite total adrenalectomy. In contrast, 33 patients (13%) treated with successful cortical-sparing adrenalectomy developed another pheochromocytoma within the remnant adrenal after a median (IQR) of 8 (4-13) years, all of which were successfully treated with another surgery. Cortical-sparing surgery was not associated with survival. Overall survival was associated with comorbidities unrelated to pheochromocytoma: of 63 patients who died, only 3 (5%) died of metastatic pheochromocytoma. CONCLUSIONS AND RELEVANCE: Patients undergoing cortical-sparing adrenalectomy did not demonstrate decreased survival, despite development of recurrent pheochromocytoma in 13%. Cortical-sparing adrenalectomy should be considered in all patients with hereditary pheochromocytoma.

Aix Marseille University INSERM Marseille Medical Genetics Department of Endocrinology Assistance Publique Hopitaux de Marseille Marseille France

Department of Biochemistry and Molecular Biology School of Life Sciences Central South University Changsha China

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

Department of Endocrinology and Metabolic Diseases Leiden University Medical Center Leiden the Netherlands

Department of Endocrinology E E Eichwald Clinic 1 I Mechnikov Northwestern State Medical University St Petersburg Russia

Department of Endocrinology Ospedale Niguarda Cà Granda Milan Italy

Department of Endocrinology Seth GS Medical College and KEM Hospital Mumbai India

Department of Endocrinology University of Groningen University Medical Center Groningen Groningen the Netherlands

Department of Medicine 2 Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany

Department of Medicine Division of Endocrinology Tufts Medical Center Boston Massachusetts

Department of Molecular Endocrinology Institute of Endocrinology Prague Czech Republic

Department of Molecular Medicine and Surgery Karolinska Institutet Stockholm Sweden

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

Department of Oncologic and Urologic Surgery the 903rd PLA Hospital Wenzhou Medical University Hangzhou Zhejiang People's Republic of China

Department of Radiology Medical Center University of Freiburg Faculty of Medicine University of Freiburg Freiburg Germany

Department of Surgery Endocrinology Research Center Moscow Russia

Department of Surgery Huyssens Foundation Clinics Essen Germany

Department of Surgical Oncology Bakhrushin Brothers Moscow City Hospital Moscow Russia

Department of Urology Xiangya Hospital Central South University Changsha China

Division of Endocrinology and Metabolism Siriraj Hospital Mahidol University Bangkok Thailand

Division of Endocrinology Diabetes Metabolism and Nutrition Mayo Clinic Rochester Minnesota

Division of General Surgery Mayo Clinic Rochester Minnesota

Endocrine Section Hospital del Salvador Santiago de Chile Department of Medicine University of Chile Santiago Chile

Endocrinology Abdominal Center University of Helsinki and Helsinki University Hospital Helsinki Finland

Familial Cancer Clinic and Oncoendocrinology Veneto Institute of Oncology IOV IRCCS Padua Italy

Genomic Medicine Institute Lerner Research Institute and Taussig Cancer Institute Cleveland Clinic Cleveland Ohio

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

Institute of Cardiology Department of Hypertension Warsaw Poland

Institute of Endocrinology and Metabolism NAMS of Ukraine Kiev Ukraine

Instituto do Cancer do Estado de São Paulo Faculdade de Medicina da Universidade de São Paulo São Paulo Brazil

Neuroendocrine Tumor Unit Endocrinology and Metabolism Service Department of Medicine ENETS Centre of Excellence Hadassah Hebrew University Medical Center Jerusalem Israel

Neuroendocrine Tumors Service Sheba Medical Center and Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel

Neuroendocrinology Laboratory Endocrinology Institute Almazov National Medical Research Centre St Petersburg Russia

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

Section of Preventive Medicine Medical Center University of Freiburg Faculty of Medicine Albert Ludwig University Freiburg Freiburg Germany

See more in PubMed

Lenders JW, Eisenhofer G, Mannelli M, Pacak K. Phaeochromocytoma. Lancet. 2005;366(9486):-. doi:10.1016/S0140-6736(05)67139-5 PubMed DOI

Lloyd RV, Osamura R, Klöppel G, Rosai J, eds. WHO Classifiaction of Tumours of Endocrine Organs. 4th ed Lyon, France: IARC Publications; 2017.

Gupta G, Pacak K; AACE Adrenal Scientific Committee . Precision medicine: an update on genotype/biochemical phenotype relationships in pheochromocytoma/paraganglioma patients. Endocr Pract. 2017;23(6):690-704. doi:10.4158/EP161718.RA PubMed DOI PMC

Neumann HP, Bausch B, McWhinney SR, et al. ; Freiburg-Warsaw-Columbus Pheochromocytoma Study Group . Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002;346(19):1459-1466. doi:10.1056/NEJMoa020152 PubMed DOI

Pillai S, Gopalan V, Smith RA, Lam AK. Updates on the genetics and the clinical impacts on phaeochromocytoma and paraganglioma in the new era. Crit Rev Oncol Hematol. 2016;100:190-208. doi:10.1016/j.critrevonc.2016.01.022 PubMed DOI

Andrews KA, Ascher DB, Pires DEV, et al. . Tumour risks and genotype-phenotype correlations associated with germline variants in succinate dehydrogenase subunit genes SDHB, SDHC and SDHD. J Med Genet. 2018;55(6):384-394. PubMed PMC

Bausch B, Schiavi F, Ni Y, et al. ; European-American-Asian Pheochromocytoma-Paraganglioma Registry Study Group . Clinical characterization of the pheochromocytoma and paraganglioma susceptibility genes SDHA, TMEM127, MAX, and SDHAF2 for gene-informed prevention. JAMA Oncol. 2017;3(9):1204-1212. doi:10.1001/jamaoncol.2017.0223 PubMed DOI PMC

Casey R, Garrahy A, Tuthill A, et al. . Universal genetic screening uncovers a novel presentation of an SDHAF2 mutation. J Clin Endocrinol Metab. 2014;99(7):E1392-E1396. doi:10.1210/jc.2013-4536 PubMed DOI

Bausch B, Borozdin W, Neumann HP; European-American Pheochromocytoma Study Group . Clinical and genetic characteristics of patients with neurofibromatosis type 1 and pheochromocytoma. N Engl J Med. 2006;354(25):2729-2731. doi:10.1056/NEJMc066006 PubMed DOI

Buffet A, Morin A, Castro-Vega LJ, et al. . Germline mutations in the mitochondrial 2-oxoglutarate/malate carrier SLC25A11 gene confer a predisposition to metastatic paragangliomas. Cancer Res. 2018;78(8):1914-1922. doi:10.1158/0008-5472.CAN-17-2463 PubMed DOI

Calsina B, Currás-Freixes M, Buffet A, et al. . Role of MDH2 pathogenic variant in pheochromocytoma and paraganglioma patients. Genet Med. 2018;20(12):1652-1662. doi:10.1038/s41436-018-0068-7 PubMed DOI PMC

Castro-Vega LJ, Buffet A, De Cubas AA, et al. . Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas. Hum Mol Genet. 2014;23(9):2440-2446. doi:10.1093/hmg/ddt639 PubMed DOI

National Cancer Institute Pheochromocytoma and paraganglioma treatment: health professional version In: PDQ Cancer Information Summaries, 2002-2018. Bethesda, MD: National Cancer Institute; 2018.

Lenders JW, Duh QY, Eisenhofer G, et al. ; Endocrine Society . Pheochromocytoma and paraganglioma: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915-1942. doi:10.1210/jc.2014-1498 PubMed DOI

Gupta GN, Benson JS, Ross MJ, et al. . Perioperative, functional, and oncologic outcomes of partial adrenalectomy for multiple ipsilateral pheochromocytomas. J Endourol. 2014;28(1):112-116. doi:10.1089/end.2013.0298 PubMed DOI PMC

Nagaraja V, Eslick GD, Edirimanne S. Recurrence and functional outcomes of partial adrenalectomy: a systematic review and meta-analysis. Int J Surg. 2015;16(pt A):7-13. doi:10.1016/j.ijsu.2015.01.015 PubMed DOI

Castinetti F, Qi XP, Walz MK, et al. . Outcomes of adrenal-sparing surgery or total adrenalectomy in phaeochromocytoma associated with multiple endocrine neoplasia type 2: an international retrospective population-based study. Lancet Oncol. 2014;15(6):648-655. doi:10.1016/S1470-2045(14)70154-8 PubMed DOI

Gutmann DH, Aylsworth A, Carey JC, et al. . The diagnostic evaluation and multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. JAMA. 1997;278(1):51-57. doi:10.1001/jama.1997.03550010065042 PubMed DOI

Richards S, Aziz N, Bale S, et al. ; ACMG Laboratory Quality Assurance Committee . Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424. doi:10.1038/gim.2015.30 PubMed DOI PMC

Asari R, Scheuba C, Kaczirek K, Niederle B. Estimated risk of pheochromocytoma recurrence after adrenal-sparing surgery in patients with multiple endocrine neoplasia type 2A. Arch Surg. 2006;141(12):1199-1205. doi:10.1001/archsurg.141.12.1199 PubMed DOI

Diner EK, Franks ME, Behari A, Linehan WM, Walther MM. Partial adrenalectomy: the National Cancer Institute experience. Urology. 2005;66(1):19-23. doi:10.1016/j.urology.2005.01.009 PubMed DOI

Neumann HP, Bender BU, Reincke M, Eggstein S, Laubenberger J, Kirste G. Adrenal-sparing surgery for phaeochromocytoma. Br J Surg. 1999;86(1):94-97. doi:10.1046/j.1365-2168.1999.00974.x PubMed DOI

Walz MK, Peitgen K, Diesing D, et al. . Partial versus total adrenalectomy by the posterior retroperitoneoscopic approach: early and long-term results of 325 consecutive procedures in primary adrenal neoplasias. World J Surg. 2004;28(12):1323-1329. doi:10.1007/s00268-004-7667-y PubMed DOI

Castinetti F, Taieb D, Henry JF, et al. . Management of endocrine disease: outcome of adrenal sparing surgery in heritable pheochromocytoma. Eur J Endocrinol. 2016;174(1):R9-R18. doi:10.1530/EJE-15-0549 PubMed DOI

Wang W, Li P, Wang Y, et al. . Effectiveness and safety of laparoscopic adrenalectomy of large pheochromocytoma: a prospective, nonrandomized, controlled study. Am J Surg. 2015;210(2):230-235. doi:10.1016/j.amjsurg.2014.11.012 PubMed DOI

Neumann HP, Young WF Jr, Krauss T, et al. . 65 Years of the double helix: genetics informs precision practice in the diagnosis and management of pheochromocytoma. Endocr Relat Cancer. 2018;25(8):T201-T219. doi:10.1530/ERC-18-0085 PubMed DOI

Neumann HP. Pheochromocytoma In: Jameson JL, Kasper DL, Hauser SL, Loscalzo J, eds. Harrison’s Principles of Internal Medicine. 20th ed New York, NY: McGraw-Hill Professional; 2018.

Babic B, Patel D, Aufforth R, et al. . Pediatric patients with pheochromocytoma and paraganglioma should have routine preoperative genetic testing for common susceptibility genes in addition to imaging to detect extra-adrenal and metastatic tumors. Surgery. 2017;161(1):220-227. doi:10.1016/j.surg.2016.05.059 PubMed DOI PMC

Nockel P, El Lakis M, Gaitanidis A, et al. . Preoperative genetic testing in pheochromocytomas and paragangliomas influences the surgical approach and the extent of adrenal surgery. Surgery. 2018;163(1):191-196. doi:10.1016/j.surg.2017.05.025 PubMed DOI PMC

Park HS, Roman SA, Sosa JA. Outcomes from 3144 adrenalectomies in the United States: which matters more, surgeon volume or specialty? Arch Surg. 2009;144(11):1060-1067. doi:10.1001/archsurg.2009.191 PubMed DOI

Brauckhoff M, Gimm O, Thanh PN, et al. . Critical size of residual adrenal tissue and recovery from impaired early postoperative adrenocortical function after subtotal bilateral adrenalectomy. Surgery. 2003;134(6):1020-1027. doi:10.1016/j.surg.2003.08.005 PubMed DOI

Lee JE, Curley SA, Gagel RF, Evans DB, Hickey RC. Cortical-sparing adrenalectomy for patients with bilateral pheochromocytoma. Surgery. 1996;120(6):1064-1070. doi:10.1016/S0039-6060(96)80056-0 PubMed DOI