Pheochromocytomas (PCCs) are rare neuroendocrine tumors derived from the chromaffin cells of the adrenal medulla. When these tumors have an extra-adrenal location, they are called paragangliomas (PGLs) and arise from sympathetic and parasympathetic ganglia, particularly of the para-aortic location. Up to 25% of PCCs/PGLs are associated with inherited genetic disorders. The majority of PCCs/PGLs exhibit indolent behavior. However, according to their affiliation to molecular clusters based on underlying genetic aberrations, their tumorigenesis, location, clinical symptomatology, and potential to metastasize are heterogenous. Thus, PCCs/PGLs are often associated with diagnostic difficulties. In recent years, extensive research revealed a broad genetic background and multiple signaling pathways leading to tumor development. Along with this, the diagnostic and therapeutic options were also expanded. In this review, we focus on the current knowledge and recent advancements in the diagnosis and treatment of PCCs/PGLs with respect to the underlying gene alterations while also discussing future perspectives in this field.

2nd Department of Internal Medicine Gastroenterology and Geriatrics University Hospital Olomouc Faculty of Medicine and Dentistry Palacky University Olomouc Olomouc Czech Republic

Department of Comprehensive Cancer Care Masaryk Memorial Cancer Institute Faculty of Medicine Masaryk University Brno Czech Republic

Department of Gastroenterology and Digestive Endoscopy Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Gastroenterology and Internal Medicine University Hospital Brno Faculty of Medicine Masaryk University Brno Czech Republic

Department of Hematology Oncology and Internal Medicine University Hospital Brno Faculty of Medicine Masaryk University Brno Czech Republic

Department of Radiology and Nuclear Medicine University Hospital Brno Faculty of Medicine Masaryk University Brno Czech Republic

Department of Surgery University Hospital Brno Faculty of Medicine Masaryk University Brno Czech Republic

Zobrazit více v PubMed

Beard CM, Sheps SG, Kurland LT, Carney JA, Lie JT. Occurrence of pheochromocytoma in Rochester, Minnesota, 1950 through 1979. Mayo Clin Proc. 1983;58(12):802‐804. PubMed

Sutton MG, Sheps SG, Lie JT. Prevalence of clinically unsuspected pheochromocytoma. Review of a 50‐year autopsy series. Mayo Clin Proc. 1981;56(6):354‐360. PubMed

Mantero F, Terzolo M, Arnaldi G, et al. A survey on adrenal incidentaloma in Italy. Study Group on Adrenal Tumors of the Italian Society of Endocrinology. J Clin Endocrinol Metab. 2000;85(2):637‐644. doi:10.1210/jcem.85.2.6372 PubMed DOI

Yeomans H, Calissendorff J, Volpe C, Falhammar H, Mannheimer B. Limited value of long‐term biochemical follow‐up in patients with adrenal incidentalomas‐a retrospective cohort study. BMC Endocr Disord. 2015;15:6. doi:10.1186/s12902-015-0001-x PubMed DOI PMC

Patrova J, Jarocka I, Wahrenberg H, Falhammar H. Clinical outcomes in adrenal incidentaloma: experience from one center. Endocr Pract. 2015;21(8):870‐877. doi:10.4158/EP15618.OR PubMed DOI

Amodru V, Taieb D, Guerin C, et al. MEN2‐related pheochromocytoma: current state of knowledge, specific characteristics in MEN2B, and perspectives. Endocrine. 2020;69(3):496‐503. doi:10.1007/s12020-020-02332-2 PubMed DOI

Y‐Hassan S, Falhammar H. Clinical features, complications, and outcomes of exogenous and endogenous catecholamine‐triggered Takotsubo syndrome: a systematic review and meta‐analysis of 156 published cases. Clin Cardiol. 2020;43(5):459‐467. doi:10.1002/clc.23352 PubMed DOI PMC

Pamporaki C, Hamplova B, Peitzsch M, et al. Characteristics of pediatric vs adult pheochromocytomas and paragangliomas. J Clin Endocrinol Metab. 2017;102(4):1122‐1132. doi:10.1210/jc.2016-3829 PubMed DOI PMC

Patel D, Phay JE, Yen TWF, et al. Update on pheochromocytoma and paraganglioma from the SSO Endocrine/Head and Neck Disease‐Site Work Group. Part 1 of 2: advances in pathogenesis and diagnosis of pheochromocytoma and paraganglioma. Ann Surg Oncol. 2020;27(5):1329‐1337. doi:10.1245/s10434-020-08220-3 PubMed DOI PMC

Lenders JWM, Eisenhofer G. Update on modern management of pheochromocytoma and paraganglioma. Endocrinol Metab (Seoul). 2017;32(2):152‐161. doi:10.3803/EnM.2017.32.2.152 PubMed DOI PMC

Jochmanová I, Zelinka T, Widimský J, Pacak K. HIF signaling pathway in pheochromocytoma and other neuroendocrine tumors. Physiol Res. 2014;63(Suppl 2):S251‐S262. doi:10.33549/physiolres.932789 PubMed DOI

Thosani S, Ayala‐Ramirez M, Román‐González A, et al. Constipation: an overlooked, unmanaged symptom of patients with pheochromocytoma and sympathetic paraganglioma. Eur J Endocrinol. 2015;173(3):377‐387. doi:10.1530/EJE-15-0456 PubMed DOI

Gu YW, Poste J, Kunal M, Schwarcz M, Weiss I. Cardiovascular manifestations of pheochromocytoma. Cardiol Rev. 2017;25(5):215‐222. doi:10.1097/CRD.0000000000000141 PubMed DOI

Manger WM. The protean manifestations of pheochromocytoma. Horm Metab Res. 2009;41(9):658‐663. doi:10.1055/s-0028-1128139 PubMed DOI

Baguet JP, Hammer L, Mazzuco TL, et al. Circumstances of discovery of phaeochromocytoma: a retrospective study of 41 consecutive patients. Eur J Endocrinol. 2004;150(5):681‐686. doi:10.1530/eje.0.1500681 PubMed DOI

Kakoki K, Miyata Y, Shida Y, et al. Pheochromocytoma multisystem crisis treated with emergency surgery: a case report and literature review. BMC Res Notes. 2015;8:758. doi:10.1186/s13104-015-1738-z PubMed DOI PMC

Rezkalla MA, Rizk SN, Ryan JJ. Pheochromocytoma associated with polycythemia: case report. S D J Med. 1995;48(10):349‐351. PubMed

Gabi JN, Milhem MM, Tovar YE, Karem ES, Gabi AY, Khthir RA. Severe cushing syndrome due to an ACTH‐producing pheochromocytoma: a case presentation and review of the literature. J Endocr Soc. 2018;2(7):621‐630. doi:10.1210/js.2018-00086 PubMed DOI PMC

Lenders JWM, Duh QY, Eisenhofer G, et al. 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

Williams MD. Paragangliomas of the head and neck: an overview from diagnosis to genetics. Head Neck Pathol. 2017;11(3):278‐287. doi:10.1007/s12105-017-0803-4 PubMed DOI PMC

Eisenhofer G, Prejbisz A, Peitzsch M, et al. Biochemical diagnosis of chromaffin cell tumors in patients at high and low risk of disease: plasma versus urinary free or deconjugated o‐methylated catecholamine metabolites. Clin Chem. 2018;64(11):1646‐1656. doi:10.1373/clinchem.2018.291369 PubMed DOI

Timmers HJLM, Pacak K, Huynh TT, et al. Biochemically silent abdominal paragangliomas in patients with mutations in the succinate dehydrogenase subunit B gene. J Clin Endocrinol Metab. 2008;93(12):4826‐4832. doi:10.1210/jc.2008-1093 PubMed DOI PMC

Sue M, Martucci V, Frey F, et al. Lack of utility of SDHB mutation testing in adrenergic metastatic phaeochromocytoma. Eur J Endocrinol. 2015;172(2):89‐95. doi:10.1530/EJE-14-0756 PubMed DOI

Eisenhofer G, Huynh TT, Pacak K, et al. Distinct gene expression profiles in norepinephrine‐ and epinephrine‐producing hereditary and sporadic pheochromocytomas: activation of hypoxia‐driven angiogenic pathways in von Hippel‐Lindau syndrome. Endocr Relat Cancer. 2004;11(4):897‐911. doi:10.1677/erc.1.00838 PubMed DOI

Eisenhofer G, Lenders JWM, Timmers H, et al. Measurements of plasma methoxytyramine, normetanephrine, and metanephrine as discriminators of different hereditary forms of pheochromocytoma. Clin Chem. 2011;57(3):411‐420. doi:10.1373/clinchem.2010.153320 PubMed DOI PMC

Nölting S, Ullrich M, Pietzsch J, et al. Current management of pheochromocytoma/paraganglioma: a guide for the practicing clinician in the era of precision medicine. Cancers (Basel). 2019;11(10):1505. doi:10.3390/cancers11101505 PubMed DOI PMC

Pacak K. Phaeochromocytoma: a catecholamine and oxidative stress disorder. Endocr Regul. 2011;45(2):65‐90. doi:10.4149/endo_2011_02_65 PubMed DOI PMC

Bílek R, Vlček P, Šafařík L, et al. Chromogranin A in the laboratory diagnosis of pheochromocytoma and paraganglioma. Cancers (Basel). 2019;11(4):E586. doi:10.3390/cancers11040586 PubMed DOI PMC

Puliani G, Vito VD, Feola T, et al. NETest: a systematic review focusing on the prognostic and predictive role. Neuroendocrinology. 2022;112(6):523‐536. doi:10.1159/000518873 PubMed DOI

Pęczkowska M, Cwikla J, Kidd M, et al. The clinical utility of circulating neuroendocrine gene transcript analysis in well‐differentiated paragangliomas and pheochromocytomas. Eur J Endocrinol. 2017;176(2):143‐157. doi:10.1530/EJE-16-0727 PubMed DOI

Krempf M, Lumbroso J, Mornex R, et al. Use of m‐[131I]iodobenzylguanidine in the treatment of malignant pheochromocytoma. J Clin Endocrinol Metab. 1991;72(2):455‐461. doi:10.1210/jcem-72-2-455 PubMed DOI

Jimenez C, Erwin W, Chasen B. Targeted radionuclide therapy for patients with metastatic pheochromocytoma and paraganglioma: from low‐specific‐activity to high‐specific‐activity iodine‐131 metaiodobenzylguanidine. Cancers (Basel). 2019;11(7):1018. doi:10.3390/cancers11071018 PubMed DOI PMC

Sisson J, Shapiro B, Beierwaltes WH, et al. Treatment of malignant pheochromocytoma with a new radiopharmaceutical. Trans Assoc Am Physicians. 1983;96:209‐217. PubMed

Wieland DM, Swanson DP, Brown LE, Beierwaltes WH. Imaging the adrenal medulla with an I‐131‐labeled antiadrenergic agent. J Nucl Med. 1979;20(2):155‐158. PubMed

King KS, Chen CC, Alexopoulos DK, et al. Functional imaging of SDHx‐related head and neck paragangliomas: comparison of 18F‐fluorodihydroxyphenylalanine, 18F‐fluorodopamine, 18F‐fluoro‐2‐deoxy‐d‐glucose PET, 123I‐metaiodobenzylguanidine scintigraphy, and 111In‐pentetreotide scintigraphy. J Clin Endocrinol Metab. 2011;96(9):2779‐2785. doi:10.1210/jc.2011-0333 PubMed DOI PMC

Taïeb D, Hicks RJ, Hindié E, et al. European Association of Nuclear Medicine Practice Guideline/Society of Nuclear Medicine and Molecular Imaging Procedure Standard 2019 for radionuclide imaging of phaeochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging. 2019;46(10):2112‐2137. doi:10.1007/s00259-019-04398-1 PubMed DOI PMC

Michałowska I, Ćwikła JB, Pęczkowska M, et al. Usefulness of somatostatin receptor scintigraphy (Tc‐[HYNIC, Tyr3]‐octreotide) and 123I‐metaiodobenzylguanidine scintigraphy in patients with SDHx gene‐related pheochromocytomas and paragangliomas detected by computed tomography. Neuroendocrinology. 2015;101(4):321‐330. doi:10.1159/000381458 PubMed DOI

Vyakaranam AR, Crona J, Norlén O, Hellman P, Sundin A. 11C‐hydroxy‐ephedrine‐PET/CT in the diagnosis of pheochromocytoma and paraganglioma. Cancers (Basel). 2019;11(6):847. doi:10.3390/cancers11060847 PubMed DOI PMC

Han S, Suh CH, Woo S, Kim YJ, Lee JJ. Performance of 68Ga‐DOTA‐conjugated somatostatin receptor‐targeting peptide PET in detection of pheochromocytoma and paraganglioma: a systematic review and metaanalysis. J Nucl Med. 2019;60(3):369‐376. doi:10.2967/jnumed.118.211706 PubMed DOI

Taïeb D, Timmers HJ, Hindié E, et al. EANM 2012 guidelines for radionuclide imaging of phaeochromocytoma and paraganglioma. Eur J Nucl Med Mol Imaging. 2012;39(12):1977‐1995. doi:10.1007/s00259-012-2215-8 PubMed DOI PMC

Crona J, Taïeb D, Pacak K. New perspectives on pheochromocytoma and paraganglioma: toward a molecular classification. Endocr Rev. 2017;38(6):489‐515. doi:10.1210/er.2017-00062 PubMed DOI PMC

Schlisio S, Kenchappa RS, Vredeveld LCW, et al. The kinesin KIF1Bbeta acts downstream from EglN3 to induce apoptosis and is a potential 1p36 tumor suppressor. Genes Dev. 2008;22(7):884‐893. doi:10.1101/gad.1648608 PubMed DOI PMC

Welander J, Andreasson A, Juhlin CC, et al. Rare germline mutations identified by targeted next‐generation sequencing of susceptibility genes in pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2014;99(7):E1352‐E1360. doi:10.1210/jc.2013-4375 PubMed DOI PMC

Musil Z, Vícha A, Zelinka T, et al. [Hereditary pheochromocytoma and paraganglioma]. Klin Onkol. 2012;25(Suppl):S21‐S26. PubMed

Li SY, Ding YQ, Si YL, Ye MJ, Xu CM, Qi XP. 5P strategies for management of multiple endocrine neoplasia type 2: a paradigm of precision medicine. Front Endocrinol (Lausanne). 2020;11:543246. doi:10.3389/fendo.2020.543246 PubMed DOI PMC

Buffet A, Burnichon N, Favier J, Gimenez‐Roqueplo AP. An overview of 20 years of genetic studies in pheochromocytoma and paraganglioma. Best Pract Res Clin Endocrinol Metab. 2020;34(2):101416. doi:10.1016/j.beem.2020.101416 PubMed DOI

Currás‐Freixes M, Piñeiro‐Yañez E, Montero‐Conde C, et al. PheoSeq: a targeted next‐generation sequencing assay for pheochromocytoma and paraganglioma diagnostics. J Mol Diagn. 2017;19(4):575‐588. doi:10.1016/j.jmoldx.2017.04.009 PubMed DOI PMC

Ben Aim L, Pigny P, Castro‐Vega LJ, et al. Targeted next‐generation sequencing detects rare genetic events in pheochromocytoma and paraganglioma. J Med Genet. 2019;56(8):513‐520. doi:10.1136/jmedgenet-2018-105714 PubMed DOI

Burnichon N, Vescovo L, Amar L, et al. Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma. Hum Mol Genet. 2011;20(20):3974‐3985. doi:10.1093/hmg/ddr324 PubMed DOI

Winzeler B, Challis BG, Casey RT. Precision medicine in phaeochromocytoma and paraganglioma. J Pers Med. 2021;11(11):1239. doi:10.3390/jpm11111239 PubMed DOI PMC

Nölting S, Bechmann N, Taieb D, et al. Personalized management of pheochromocytoma and paraganglioma. Endocr Rev. 2022;43(2):199‐239. doi:10.1210/endrev/bnab019 PubMed DOI PMC

Fishbein L, Leshchiner I, Walter V, et al. Comprehensive molecular characterization of pheochromocytoma and paraganglioma. Cancer Cell. 2017;31(2):181‐193. doi:10.1016/j.ccell.2017.01.001 PubMed DOI PMC

Jiang J, Zhang J, Pang Y, et al. Sino‐European differences in the genetic landscape and clinical presentation of pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2020;105(10):dgaa502. doi:10.1210/clinem/dgaa502 PubMed DOI

Icard P, Lincet H. A global view of the biochemical pathways involved in the regulation of the metabolism of cancer cells. Biochim Biophys Acta. 2012;1826(2):423‐433. doi:10.1016/j.bbcan.2012.07.001 PubMed DOI

Alzofon N, Koc K, Panwell K, et al. Mastermind like transcriptional coactivator 3 (MAML3) drives neuroendocrine tumor progression. Mol Cancer Res. 2021;19(9):1476‐1485. doi:10.1158/1541-7786.MCR-20-0992 PubMed DOI PMC

Eisenhofer G, Lenders JWM, Siegert G, et al. Plasma methoxytyramine: a novel biomarker of metastatic pheochromocytoma and paraganglioma in relation to established risk factors of tumour size, location and SDHB mutation status. Eur J Cancer. 2012;48(11):1739‐1749. doi:10.1016/j.ejca.2011.07.016 PubMed DOI PMC

Ayala‐Ramirez M, Feng L, Johnson MM, et al. Clinical risk factors for malignancy and overall survival in patients with pheochromocytomas and sympathetic paragangliomas: primary tumor size and primary tumor location as prognostic indicators. J Clin Endocrinol Metab. 2011;96(3):717‐725. doi:10.1210/jc.2010-1946 PubMed DOI

Stenman A, Zedenius J, Juhlin CC. The value of histological algorithms to predict the malignancy potential of pheochromocytomas and abdominal paragangliomas‐a meta‐analysis and systematic review of the literature. Cancers (Basel). 2019;11(2):225. doi:10.3390/cancers11020225 PubMed DOI PMC

Thompson LDR. Pheochromocytoma of the Adrenal gland Scaled Score (PASS) to separate benign from malignant neoplasms: a clinicopathologic and immunophenotypic study of 100 cases. Am J Surg Pathol. 2002;26(5):551‐566. doi:10.1097/00000478-200205000-00002 PubMed DOI

Kimura N, Takayanagi R, Takizawa N, et al. Pathological grading for predicting metastasis in phaeochromocytoma and paraganglioma. Endocr Relat Cancer. 2014;21(3):405‐414. doi:10.1530/ERC-13-0494 PubMed DOI

Wachtel H, Hutchens T, Baraban E, et al. Predicting metastatic potential in pheochromocytoma and paraganglioma: a comparison of PASS and GAPP scoring systems. J Clin Endocrinol Metab. 2020;105(12):e4661‐e4670. doi:10.1210/clinem/dgaa608 PubMed DOI PMC

Granberg D, Juhlin CC, Falhammar H. Metastatic pheochromocytomas and abdominal paragangliomas. J Clin Endocrinol Metab. 2021;106(5):e1937‐e1952. doi:10.1210/clinem/dgaa982 PubMed DOI PMC

Lam AKY. Update on adrenal tumours in 2017 World Health Organization (WHO) of endocrine tumours. Endocr Pathol. 2017;28(3):213‐227. doi:10.1007/s12022-017-9484-5 PubMed DOI

Ayala‐Ramirez M, Palmer JL, Hofmann MC, et al. Bone metastases and skeletal‐related events in patients with malignant pheochromocytoma and sympathetic paraganglioma. J Clin Endocrinol Metab. 2013;98(4):1492‐1497. doi:10.1210/jc.2012-4231 PubMed DOI PMC

Patterson E, Webb R, Weisbrod A, et al. The microRNA expression changes associated with malignancy and SDHB mutation in pheochromocytoma. Endocr Relat Cancer. 2012;19(2):157‐166. doi:10.1530/ERC-11-0308 PubMed DOI PMC

Snezhkina A, Pavlov V, Dmitriev A, Melnikova N, Kudryavtseva A. Potential biomarkers of metastasizing paragangliomas and pheochromocytomas. Life (Basel). 2021;11(11):1179. doi:10.3390/life11111179 PubMed DOI PMC

Buitenwerf E, Osinga TE, Timmers HJLM, et al. Efficacy of α‐blockers on hemodynamic control during pheochromocytoma resection: a randomized controlled trial. J Clin Endocrinol Metab. 2020;105(7):dgz188. doi:10.1210/clinem/dgz188 PubMed DOI PMC

Livingstone M, Duttchen K, Thompson J, et al. Hemodynamic stability during pheochromocytoma resection: lessons learned over the last two decades. Ann Surg Oncol. 2015;22(13):4175‐4180. doi:10.1245/s10434-015-4519-y PubMed DOI

Kinney MAO, Narr BJ, Warner MA. Perioperative management of pheochromocytoma. J Cardiothorac Vasc Anesth. 2002;16(3):359‐369. doi:10.1053/jcan.2002.124150 PubMed DOI

van der Zee PA, de Boer A. Pheochromocytoma: a review on preoperative treatment with phenoxybenzamine or doxazosin. Neth J Med. 2014;72(4):190‐201. PubMed

Shah MH, Goldner WS, Benson AB, et al. Neuroendocrine and adrenal tumors, version 2.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2021;19(7):839‐868. doi:10.6004/jnccn.2021.0032 PubMed DOI

Pacak K. Preoperative management of the pheochromocytoma patient. J Clin Endocrinol Metab. 2007;92(11):4069‐4079. doi:10.1210/jc.2007-1720 PubMed DOI

Lenders JWM, Kerstens MN, Amar L, et al. Genetics, diagnosis, management and future directions of research of phaeochromocytoma and paraganglioma: a position statement and consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension. J Hypertens. 2020;38(8):1443‐1456. doi:10.1097/HJH.0000000000002438 PubMed DOI PMC

Bai S, Yao Z, Zhu X, et al. Comparison of transperitoneal laparoscopic versus open adrenalectomy for large pheochromocytoma: a retrospective propensity score‐matched cohort study. Int J Surg. 2019;61:26‐32. doi:10.1016/j.ijsu.2018.11.018 PubMed DOI

Fu SQ, Wang SY, Chen Q, Liu YT, Li ZL, Sun T. Laparoscopic versus open surgery for pheochromocytoma: a meta‐analysis. BMC Surg. 2020;20(1):167. doi:10.1186/s12893-020-00824-6 PubMed DOI PMC

Hue JJ, Alvarado C, Bachman K, et al. Outcomes of malignant pheochromocytoma based on operative approach: a National Cancer Database analysis. Surgery. 2021;170(4):1093‐1098. doi:10.1016/j.surg.2021.04.001 PubMed DOI

Stefanidis D, Goldfarb M, Kercher KW, et al. SAGES guidelines for minimally invasive treatment of adrenal pathology. Surg Endosc. 2013;27(11):3960‐3980. doi:10.1007/s00464-013-3169-z PubMed DOI

Vassiliou MC, Laycock WS. Laparoscopic adrenalectomy for pheochromocytoma: take the vein last? Surg Endosc. 2009;23(5):965‐968. doi:10.1007/s00464-008-0264-7 PubMed DOI

Wu G, Zhang B, Yu C, et al. Effect of early adrenal vein ligation on blood pressure and catecholeamine fluctuation during laparoscopic adrenalectomy for pheochromocytoma. Urology. 2013;82(3):606‐611. doi:10.1016/j.urology.2013.05.011 PubMed DOI

Bihain F, Klein M, Nomine‐Criqui C, Brunaud L. Robotic adrenalectomy in patients with pheochromocytoma: a systematic review. Gland Surg. 2020;9(3):844‐848. doi:10.21037/gs-2019-ra-05 PubMed DOI PMC

Zhu W, Wang S, Du G, Liu H, Lu J, Yang W. Comparison of retroperitoneal laparoscopic versus open adrenalectomy for large pheochromocytoma: a single‐center retrospective study. World J Surg Oncol. 2019;17(1):111. doi:10.1186/s12957-019-1649-x PubMed DOI PMC

Conzo G, Musella M, Corcione F, et al. Laparoscopic adrenalectomy, a safe procedure for pheochromocytoma. A retrospective review of clinical series. Int J Surg. 2013;11(2):152‐156. doi:10.1016/j.ijsu.2012.12.007 PubMed DOI

Arolfo S, Giraudo G, Franco C, Parasiliti Caprino M, Seno E, Morino M. Minimally invasive adrenalectomy for large pheochromocytoma: not recommendable yet? Results from a single institution case series. Langenbecks Arch Surg. 2022;407(1):277‐283. doi:10.1007/s00423-021-02312-8 PubMed DOI PMC

Fishbein L, Del Rivero J, Else T, et al. The North American Neuroendocrine Tumor Society consensus guidelines for surveillance and management of metastatic and/or unresectable pheochromocytoma and paraganglioma. Pancreas. 2021;50(4):469‐493. doi:10.1097/MPA.0000000000001792 PubMed DOI

Rossitti HM, Söderkvist P, Gimm O. Extent of surgery for phaeochromocytomas in the genomic era. Br J Surg. 2018;105(2):e84‐e98. doi:10.1002/bjs.10744 PubMed DOI

Jackson RS, Myhill JA, Padhya TA, McCaffrey JC, McCaffrey TV, Mhaskar RS. The effects of preoperative embolization on carotid body paraganglioma surgery: a systematic review and meta‐analysis. Otolaryngol Head Neck Surg. 2015;153(6):943‐950. doi:10.1177/0194599815605323 PubMed DOI

Lin EP, Chin BB, Fishbein L, et al. Head and neck paragangliomas: an update on the molecular classification, state‐of‐the‐art imaging, and management recommendations. Radiol Imaging Cancer. 2022;4(3):e210088. doi:10.1148/rycan.210088 PubMed DOI PMC

Kim KN, Lee KN, Roh MS, Choi PJ, Yang DK. Pulmonary paraganglioma manifesting as an endobronchial mass. Korean J Radiol. 2008;9(1):87‐90. doi:10.3348/kjr.2008.9.1.87 PubMed DOI PMC

Choi HR, Yap Z, Choi SM, et al. Long‐term outcomes of abdominal paraganglioma. Ann Surg Treat Res. 2020;99(6):315‐319. doi:10.4174/astr.2020.99.6.315 PubMed DOI PMC

Ji XK, Zheng XW, Wu XL, et al. Diagnosis and surgical treatment of retroperitoneal paraganglioma: a single‐institution experience of 34 cases. Oncol Lett. 2017;14(2):2268‐2280. doi:10.3892/ol.2017.6468 PubMed DOI PMC

Palmisciano P, Sagoo NS, Haider AS, et al. Primary paraganglioma of the spine: a systematic review of clinical features and surgical management in cauda equina versus non‐cauda equina lesions. World Neurosurg. 2022;161:190‐197.e20. doi:10.1016/j.wneu.2022.01.110 PubMed DOI

Ellis RJ, Patel D, Prodanov T, et al. Response after surgical resection of metastatic pheochromocytoma and paraganglioma: can postoperative biochemical remission be predicted? J Am Coll Surg. 2013;217(3):489‐496. doi:10.1016/j.jamcollsurg.2013.04.027 PubMed DOI PMC

Roman‐Gonzalez A, Zhou S, Ayala‐Ramirez M, et al. Impact of surgical resection of the primary tumor on overall survival in patients with metastatic pheochromocytoma or sympathetic paraganglioma. Ann Surg. 2018;268(1):172‐178. doi:10.1097/SLA.0000000000002195 PubMed DOI

Strajina V, Dy BM, Farley DR, et al. Surgical treatment of malignant pheochromocytoma and paraganglioma: retrospective case series. Ann Surg Oncol. 2017;24(6):1546‐1550. doi:10.1245/s10434-016-5739-5 PubMed DOI

Hamidi O, Young WF, Iñiguez‐Ariza NM, et al. Malignant pheochromocytoma and paraganglioma: 272 patients over 55 years. J Clin Endocrinol Metab. 2017;102(9):3296‐3305. doi:10.1210/jc.2017-00992 PubMed DOI PMC

Ayala‐Ramirez M, Feng L, Habra MA, et al. Clinical benefits of systemic chemotherapy for patients with metastatic pheochromocytomas or sympathetic extra‐adrenal paragangliomas: insights from the largest single‐institutional experience. Cancer. 2012;118(11):2804‐2812. doi:10.1002/cncr.26577 PubMed DOI PMC

Amar L, Servais A, Gimenez‐Roqueplo AP, Zinzindohoue F, Chatellier G, Plouin PF. Year of diagnosis, features at presentation, and risk of recurrence in patients with pheochromocytoma or secreting paraganglioma. J Clin Endocrinol Metab. 2005;90(4):2110‐2116. doi:10.1210/jc.2004-1398 PubMed DOI

King KS, Prodanov T, Kantorovich V, et al. Metastatic pheochromocytoma/paraganglioma related to primary tumor development in childhood or adolescence: significant link to SDHB mutations. J Clin Oncol. 2011;29(31):4137‐4142. doi:10.1200/JCO.2011.34.6353 PubMed DOI PMC

Grossman A, Pacak K, Sawka A, et al. Biochemical diagnosis and localization of pheochromocytoma: can we reach a consensus? Ann N Y Acad Sci. 2006;1073:332‐347. doi:10.1196/annals.1353.038 PubMed DOI

Korevaar TIM, Grossman AB. Pheochromocytomas and paragangliomas: assessment of malignant potential. Endocrine. 2011;40(3):354‐365. doi:10.1007/s12020-011-9545-3 PubMed DOI

Hescot S, Leboulleux S, Amar L, et al. One‐year progression‐free survival of therapy‐naive patients with malignant pheochromocytoma and paraganglioma. J Clin Endocrinol Metab. 2013;98(10):4006‐4012. doi:10.1210/jc.2013-1907 PubMed DOI

Vogel J, Atanacio AS, Prodanov T, et al. External beam radiation therapy in treatment of malignant pheochromocytoma and paraganglioma. Front Oncol. 2014;4:166. doi:10.3389/fonc.2014.00166 PubMed DOI PMC

Breen W, Bancos I, Young WF, et al. External beam radiation therapy for advanced/unresectable malignant paraganglioma and pheochromocytoma. Adv Radiat Oncol. 2018;3(1):25‐29. doi:10.1016/j.adro.2017.11.002 PubMed DOI PMC

Kohlenberg J, Welch B, Hamidi O, et al. Efficacy and safety of ablative therapy in the treatment of patients with metastatic pheochromocytoma and paraganglioma. Cancers (Basel). 2019;11(2):195. doi:10.3390/cancers11020195 PubMed DOI PMC

Pandit‐Taskar N, Modak S. Norepinephrine transporter as a target for imaging and therapy. J Nucl Med. 2017;58(Suppl 2):39S‐53S. doi:10.2967/jnumed.116.186833 PubMed DOI PMC

Noto RB, Pryma DA, Jensen J, et al. Phase 1 study of high‐specific‐activity I‐131 MIBG for metastatic and/or recurrent pheochromocytoma or paraganglioma. J Clin Endocrinol Metab. 2018;103(1):213‐220. doi:10.1210/jc.2017-02030 PubMed DOI

Pryma DA, Chin BB, Noto RB, et al. Efficacy and safety of high‐specific‐activity 131I‐MIBG therapy in patients with advanced pheochromocytoma or paraganglioma. J Nucl Med. 2019;60(5):623‐630. doi:10.2967/jnumed.118.217463 PubMed DOI PMC

Baudin E, Habra MA, Deschamps F, et al. Therapy of endocrine disease: treatment of malignant pheochromocytoma and paraganglioma. Eur J Endocrinol. 2014;171(3):R111‐R122. doi:10.1530/EJE-14-0113 PubMed DOI

Kolasinska‐Ćwikła A, Pęczkowska M, Ćwikła JB, et al. A clinical efficacy of PRRT in patients with advanced, nonresectable, paraganglioma‐pheochromocytoma, related to SDHx gene mutation. J Clin Med. 2019;8(7):952. doi:10.3390/jcm8070952 PubMed DOI PMC

Kong G, Grozinsky‐Glasberg S, Hofman MS, et al. Efficacy of peptide receptor radionuclide therapy for functional metastatic paraganglioma and pheochromocytoma. J Clin Endocrinol Metab. 2017;102(9):3278‐3287. doi:10.1210/jc.2017-00816 PubMed DOI

Nastos K, Cheung VTF, Toumpanakis C, et al. Peptide receptor radionuclide treatment and (131)I‐MIBG in the management of patients with metastatic/progressive phaeochromocytomas and paragangliomas. J Surg Oncol. 2017;115(4):425‐434. doi:10.1002/jso.24553 PubMed DOI

Niemeijer ND, Alblas G, van Hulsteijn LT, Dekkers OM, Corssmit EPM. Chemotherapy with cyclophosphamide, vincristine and dacarbazine for malignant paraganglioma and pheochromocytoma: systematic review and meta‐analysis. Clin Endocrinol (Oxf). 2014;81(5):642‐651. doi:10.1111/cen.12542 PubMed DOI

Huang H, Abraham J, Hung E, et al. Treatment of malignant pheochromocytoma/paraganglioma with cyclophosphamide, vincristine, and dacarbazine: recommendation from a 22‐year follow‐up of 18 patients. Cancer. 2008;113(8):2020‐2028. doi:10.1002/cncr.23812 PubMed DOI PMC

Patel SR, Winchester DJ, Benjamin RS. A 15‐year experience with chemotherapy of patients with paraganglioma. Cancer. 1995;76(8):1476‐1480. doi:10.1002/1097-0142(19951015)76:8<1476::aid-cncr2820760827>3.0.co;2-9 PubMed DOI

Tanabe A, Naruse M, Nomura K, Tsuiki M, Tsumagari A, Ichihara A. Combination chemotherapy with cyclophosphamide, vincristine, and dacarbazine in patients with malignant pheochromocytoma and paraganglioma. Horm Cancer. 2013;4(2):103‐110. doi:10.1007/s12672-013-0133-2 PubMed DOI PMC

Jawed I, Velarde M, Därr R, et al. Continued tumor reduction of metastatic pheochromocytoma/paraganglioma harboring succinate dehydrogenase subunit B mutations with cyclical chemotherapy. Cell Mol Neurobiol. 2018;38(5):1099‐1106. doi:10.1007/s10571-018-0579-4 PubMed DOI PMC

Hadoux J, Favier J, Scoazec JY, et al. SDHB mutations are associated with response to temozolomide in patients with metastatic pheochromocytoma or paraganglioma. Int J Cancer. 2014;135(11):2711‐2720. doi:10.1002/ijc.28913 PubMed DOI

Toledo R, Jimenez C. Recent advances in the management of malignant pheochromocytoma and paraganglioma: focus on tyrosine kinase and hypoxia‐inducible factor inhibitors. F1000Res. 2018;7:F1000 Faculty Rev‐1148. doi:10.12688/f1000research.13995.1 PubMed DOI PMC

Cassol CA, Winer D, Liu W, Guo M, Ezzat S, Asa SL. Tyrosine kinase receptors as molecular targets in pheochromocytomas and paragangliomas. Mod Pathol. 2014;27(8):1050‐1062. doi:10.1038/modpathol.2013.233 PubMed DOI PMC

O'Kane GM, Ezzat S, Joshua AM, et al. A phase 2 trial of sunitinib in patients with progressive paraganglioma or pheochromocytoma: the SNIPP trial. Br J Cancer. 2019;120(12):1113‐1119. doi:10.1038/s41416-019-0474-x PubMed DOI PMC

Jimenez P, Tatsui C, Jessop A, Thosani S, Jimenez C. Treatment for malignant pheochromocytomas and paragangliomas: 5 years of progress. Curr Oncol Rep. 2017;19(12):83. doi:10.1007/s11912-017-0643-0 PubMed DOI

Pichun MEB, Edgerly M, Velarde M, Bates SE, Daerr R, Adams K. Phase II clinical trial of axitinib in metastatic pheochromocytomas and paraganlgiomas (P/PG): preliminary results. J Clin Oncol. 2015;33(7):457. doi:10.1200/jco.2015.33.7_suppl.457 DOI

Hassan Nelson L, Fuentes‐Bayne H, Yin J, et al. Lenvatinib as a therapeutic option in unresectable metastatic pheochromocytoma and paragangliomas. J Endocr Soc. 2022;6(5):bvac044. doi:10.1210/jendso/bvac044 PubMed DOI PMC

Jasim S, Suman VJ, Jimenez C, et al. Phase II trial of pazopanib in advanced/progressive malignant pheochromocytoma and paraganglioma. Endocrine. 2017;57(2):220‐225. doi:10.1007/s12020-017-1359-5 PubMed DOI

Oh DY, Kim TW, Park YS, et al. Phase 2 study of everolimus monotherapy in patients with nonfunctioning neuroendocrine tumors or pheochromocytomas/paragangliomas. Cancer. 2012;118(24):6162‐6170. doi:10.1002/cncr.27675 PubMed DOI

Xu R, Wang K, Rizzi JP, et al. 3‐[(1S,2S,3R)‐2,3‐difluoro‐1‐hydroxy‐7‐methylsulfonylindan‐4‐yl]oxy‐5‐fluorobenzonitrile (PT2977), a hypoxia‐inducible factor 2α (HIF‐2α) inhibitor for the treatment of clear cell renal cell carcinoma. J Med Chem. 2019;62(15):6876‐6893. doi:10.1021/acs.jmedchem.9b00719 PubMed DOI

Jonasch E, Donskov F, Iliopoulos O, et al. Belzutifan for renal cell carcinoma in von Hippel‐Lindau disease. N Engl J Med. 2021;385(22):2036‐2046. doi:10.1056/NEJMoa2103425 PubMed DOI PMC

Pang Y, Liu Y, Pacak K, Yang C. Pheochromocytomas and paragangliomas: from genetic diversity to targeted therapies. Cancers (Basel). 2019;11(4):436. doi:10.3390/cancers11040436 PubMed DOI PMC

Jin XF, Spöttl G, Maurer J, Nölting S, Auernhammer CJ. Inhibition of Wnt/β‐catenin signaling in neuroendocrine tumors in vitro: antitumoral effects. Cancers (Basel). 2020;12(2):345. doi:10.3390/cancers12020345 PubMed DOI PMC

Jimenez C, Subbiah V, Stephen B, et al. Phase II clinical trial of pembrolizumab in patients with progressive metastatic pheochromocytomas and paragangliomas. Cancers (Basel). 2020;12(8):2307. doi:10.3390/cancers12082307 PubMed DOI PMC

Fanciulli G, Di Molfetta S, Dotto A, et al. Emerging therapies in pheochromocytoma and paraganglioma: immune checkpoint inhibitors in the starting blocks. J Clin Med. 2020;10(1):10088. doi:10.3390/jcm10010088 PubMed DOI PMC