Guideline sources The following summarized guidelines for the evaluation and management of pheochromocytoma and paraganglioma are prepared by our editorial team based on guidelines from the Canadian Urological Association (CUA 2023; 2019), the American Association of Endocrine Surgeons (AAES 2022), the European Reference Network on Rare Adult Solid Cancers (EURACAN/ESMO 2020), the Canadian Hypertension Education Program (CHEP 2018; 2016), the European Society of Endocrinology (ESE 2016), the European Society of Endocrinology (ESE/ENSAT 2016), the Endocrine Society (ES 2014), and the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES 2013). 1 2 3 4 5 6 7 8 9 10 Pathway Calculator Calculat Pheochromocytoma and paraga Eastern Cooperative Oncology G Karnof Diagnosis and management https://web.pathway.md/diseases/recT8YGtwYb5w6FDx 1/10 6/29/23, 11:10 PM Pheochromocytoma and paraganglioma Pathway Guidelines 1. Screening and diagnosis Indications for testing: As per AAES 2022 guidelines, test for pheochromocytoma in patients with: adrenal incidentaloma with non-contrast adrenal CT findings of HU > 10 B extra-adrenal malignancy with an indeterminate adrenal mass, even if it is likely to be a metastasis. A As per ESMO 2020 guidelines, suspect and test for pheochromocytoma or paraganglioma based on: the presence of signs, symptoms, or other manifestations of presumed catecholamine excess incidental adrenal mass routine screening due to high risk associated with a hereditary predisposition or history of pheochromocytoma or paraganglioma. E As per CHEP 2016 guidelines, test for pheochromocytoma or paraganglioma in the following clinical settings: paroxysmal, unexplained, labile, and/or severe sustained hypertension refractory to usual antihypertensive therapy hypertension and multiple symptoms suggestive of catecholamine excess, such as headaches, palpitations, sweating, panic attacks, and pallor hypertension triggered by -blockers, monoamine oxidase inhibitors, micturition, or changes in abdominal pressure, surgery, or anesthesia incidentally discovered adrenal mass MEN2A or MEN2B, neurofibromatosis type 1, or Von Hippel-Lindau disease. B As per ES 2014 guidelines, test for pheochromocytoma or paraganglioma in the following clinical settings: signs and symbols of pheochromocytoma or paraganglioma, particularly if paroxysmal pheochromocytoma or paraganglioma symptoms provoked by the use of medications associated with adverse effects adrenal incidentaloma, with or without hypertension hereditary predisposition or syndromic features suggesting hereditary pheochromocytoma and paraganglioma previous history of pheochromocytoma and paraganglioma. 2. Classification and risk stratification Risk of malignancy: As per ESMO 2020 guidelines, define malignant pheochromocytoma or paraganglioma by the presence of metastasis, however, recognizing that all pheochromocytomas or paragangliomas have some malignant potential. E https://web.pathway.md/diseases/recT8YGtwYb5w6FDx 2/10 6/29/23, 11:10 PM Pheochromocytoma and paraganglioma Pathway As per ESE 2016 guidelines, define malignancy of pheochromocytoma or paraganglioma as the presence of metastasis in lymph nodes or other distant sites. A 3. Diagnostic investigations Clinical assessment: obtain careful clinical assessment for signs of adrenal hormone excess in all patients with suspected pheochromocytoma. E Metanephrine assays: As per CUA 2023 guidelines: Obtain plasma or 24-hour urinary metanephrines to evaluate for pheochromocytoma in patients with an adrenal incidentaloma displaying 10 HUs on non-contrast CT or having signs/symptoms of catecholamine excess. B Avoid obtaining evaluation for pheochromocytoma in patients with unequivocal adrenocortical adenomas confirmed on unenhanced CT (< 10 HUs) and no signs or symptoms of adrenergic excess. D As per ESMO 2020 guidelines, measure plasma or urinary metanephrines in all patients with suspected pheochromocytoma or paraganglioma. B As per CHEP 2018 guidelines, obtain 24-hour urinary total metanephrines and catecholamines or 24-hour urine fractionated metanephrines for the evaluation of pheochromocytoma. Obtain concomitant measurement of 24-hour urine creatinine to confirm accurate collection. Show 3 more As per ESE 2016 guidelines: Obtain plasma free metanephrines or urinary fractionated metanephrines to evaluate for pheochromocytoma in patients with adrenal incidentalomas. A Obtain plasma or urinary metanephrines to evaluate for pheochromocytoma in patients with extra-adrenal malignancy with an indeterminate adrenal mass, even if it is likely to be a metastasis. A As per ES 2014 guidelines, obtain plasma free metanephrines or urinary fractionated metanephrines as part of the initial biochemical testing for pheochromocytoma or paraganglioma. A Show 2 more Chromogranin A: consider obtaining chromogranin A preoperatively in patients with normal preoperative plasma or urinary levels of metanephrine and normetanephrine and 3- methoxytyramine. C Diagnostic imaging: As per CHEP 2016 guidelines, obtain diagnostic imaging, preferably with MRI or CT if MRI is unavailable, and/or iodine I-131 meta-iodobenzylguanidine scintigraphy, to localize the pheochromocytoma or paraganglioma in patients with positive biochemical screening tests. B As per ESE 2016 guidelines, consider screening for metastatic tumors by FDG positron emission tomography/CT, if possible preoperatively, in the following patients: https://web.pathway.md/diseases/recT8YGtwYb5w6FDx 3/10 6/29/23, 11:10 PM Pheochromocytoma and paraganglioma Pathway paragangliomas pheochromocytomas with elevated plasma or urine levels of 3-methoxytyramine carrying germline mutations of the SDHB gene. C As per ES 2014 guidelines, obtain imaging to locate pheochromocytoma or paraganglioma in patients displaying biochemical evidence of these diseases. B Show 6 more Genetic testing: As per ESMO 2020 guidelines, provide genetic counseling to all patients with pheochromocytoma or paraganglioma. E As per CUA 2019 guidelines, consider referring all patients with pheochromocytomas or paragangliomas for genetic testing. B As per ESE 2016 guidelines, consider obtaining genetic testing in all patients with pheochromocytoma or paraganglioma. B As per ES 2014 guidelines, engage all patients in shared decision-making for genetic testing. B Show 3 more 4. Diagnostic procedures Biopsy: do not perform biopsies of suspected pheochromocytoma or paraganglioma in most circumstances. D 5. Perioperative care Preoperartive alpha-blockers: As per AAES 2022 guidelines, administer either selective or nonselective alpha-blockers, depending on the drug availability/cost, experience, and preference of the care team, to safely prepare patients for surgical resection of pheochromocytoma or paraganglioma. Recognize that selective alpha-blockers (doxazosin, prazosin, terazosin) are associated with more intraoperative hemodynamic instability while nonselective alpha-blockers (phenoxybenzamine) result in more postoperative hypotension, although there is no significant difference in morbidity or mortality between groups. B As per ES 2014 guidelines: Administer preoperative adrenergic blockade to prevent cardiovascular complications in patients with hormonally functional disease. B Consider preferring alpha-blockers as the first-line choice for the adrenergic blockade. B Continue treatment for 7-14 days preoperatively to allow adequate time to normalize BP and HR. B Advise a high-sodium diet and liberal fluid intake preoperatively to reverse catecholamine- induced blood volume contraction and prevent severe hypotension after tumor removal. B As per SAGES 2013 guidelines: Consider administering alpha-blockers, preferably short-acting agents, C before laparoscopic adrenalectomy in all patients with pheochromocytoma. Continue alpha- https://web.pathway.md/diseases/recT8YGtwYb5w6FDx 4/10 6/29/23, 11:10 PM Pheochromocytoma and paraganglioma Pathway blockers when used preoperatively until signs of orthostatic hypotension are evident. Consider alpha-blockers. C Consider administering -blockers, only after adequate alpha-blockers are initiated, in appropriately selected patients. C Perioperative monitoring: As per ES 2014 guidelines, monitor BP, HR, and blood glucose levels, and adjust therapy accordingly in the immediate postoperative period. B As per SAGES 2013 guidelines, consider obtaining invasive hemodynamic monitoring during laparoscopic adrenalectomy for pheochromocytomas. B Show 3 more 6. Surgical interventions Indications for adrenalectomy: As per CUA 2023 guidelines, perform adrenalectomy, with a minimally invasive technique when feasible, in patients with pheochromocytomas. E As per AAES 2022 guidelines, consider performing cortical-sparing adrenalectomy, if technically feasible, in patients with bilateral pheochromocytomas because of the decreased rate of corticosteroid dependence, taking into account the patient's goals of care and a higher risk of recurrent pheochromocytoma. B Show 2 more As per ES 2014 guidelines, consider performing partial adrenalectomy in selected patients (hereditary pheochromocytoma, small tumors undergone contralateral complete adrenalectomy), in order to spare the adrenal cortex and prevent permanent hypocortisolism. C As per SAGES 2013 guidelines, consider performing laparoscopic cortical-sparing surgery as the procedure of choice in patients requiring bilateral adrenalectomy (such as for hereditary pheochromocytomas). C Choice of surgical approach: As per AAES 2022 guidelines: Perform minimally invasive adrenalectomy over open adrenalectomy for improved perioperative morbidity when patient and tumor characteristics are appropriate. B Use either a retroperitoneal or transperitoneal approach, determined by surgeon expertise and guided by tumor and patient characteristics, because of similar perioperative outcomes. B As per ES 2014 guidelines, perform minimally invasive adrenalectomy (such as laparoscopic) as the treatment of choice in most patients with adrenal pheochromocytoma. B Show 2 more As per SAGES 2013 guidelines, decide on the choice of laparoscopic adrenalectomy approach at the discretion of the surgeon, with the technique most familiar to them, which they have been trained to perform, and which has shown the best patient outcomes. B https://web.pathway.md/diseases/recT8YGtwYb5w6FDx 5/10 6/29/23, 11:10 PM Pheochromocytoma and paraganglioma Pathway Show 5 more Indications for debunking surgery: consider performing debulking surgery in all patients with metastatic pheochromocytoma or paraganglioma. E 7. Specific circumstances Patients with hereditary pheochromocytoma or paraganglioma: As per ES 2014 guidelines, individualize the management of hereditary pheochromocytoma or paraganglioma recognizing the distinct genotype-phenotype presentations. B As per SAGES 2013 guidelines, consider performing laparoscopic cortical-sparing surgery as the procedure of choice in patients requiring bilateral adrenalectomy, such as for hereditary pheochromocytomas. C 8. Follow-up and surveillance Indications for tertiary care referral: As per ESMO 2020 guidelines, refer all patients with suspected and proven pheochromocytoma or paraganglioma to be discussed in a multidisciplinary expert team meeting, at least at the time of initial diagnosis and in case of progressive disease. E As per CUA 2019 guidelines, discuss management of patients with malignant pheochromocytoma in a multidisciplinary setting including surgeons, interventional radiologists, endocrinologists, oncologists, and nuclear medicine physicians. E As per CHEP 2016 guidelines, refer patients with suspected pheochromocytoma or paraganglioma to a specialized hypertension center, particularly if biochemical screening tests have already been found to be positive. B As per ES 2014 guidelines, refer patients with pheochromocytoma or paraganglioma, especially in the following situations, to centers with appropriate expertise to provide multidisciplinary evaluation and treatment and ensure favorable outcomes: issues regarding diagnosis or localization genetic testing is required surgical treatment and preoperative preparation are required metastatic disease pregnant patients. Follow-up, laboratory: As per CUA 2019 guidelines, consider repeating plasma and/or 24-hour urinary metanephrines at the first postoperative follow-up to ensure complete resection. B Show 2 more As per ESE 2016 guidelines, measure plasma or urinary levels of metanephrines and 3- methoxytyramine 2-6 weeks after recovery from surgery in patients with elevated metanephrine levels preoperatively. A Show 3 more https://web.pathway.md/diseases/recT8YGtwYb5w6FDx 6/10 6/29/23, 11:10 PM Pheochromocytoma and paraganglioma Pathway As per ES 2014 guidelines, consider measuring plasma or urine levels of metanephrines on the follow-up to diagnose persistent disease. C As per SAGES 2013 guidelines, obtain long-term follow-up with annual BP measurements, plasma and/or urinary metanephrine levels, and if indicated, also abdominal imaging, to detect recurrence of disease in patients after pheochromocytoma removal. B Follow-up, imaging: As per CUA 2019 guidelines: Consider obtaining imaging every 1-2 years, in addition to yearly metanephrines, in patients with biochemically negative disease. C Consider obtaining CT/MRI as first-line imaging modalities, and 123 I- metaiodobenzylguanidine scintigraphy as a second-line modality in patients with biochemical recurrence. C As per ESE 2016 guidelines: Obtain imaging 3 months after presumably complete surgery in patients operated on for pheochromocytoma or paraganglioma with elevated metanephrines or 3-methoxytyramine postoperatively, in patients with normal metanephrines and 3-methoxytyramine preoperatively, and if metanephrines and 3-methoxytyramine were not measured preoperatively. A Consider obtaining imaging tests every 1-2 years in patients with biochemically inactive pheochromocytoma or paraganglioma, to screen for local or metastatic recurrences or new tumors. C Follow-up, duration: As per EURACAN/ESMO 2020 guidelines, obtain follow-up at regular intervals for at least 10 years in patients with resected pheochromocytoma or paraganglioma, and offer lifelong monitoring in patients with a germline mutation. E As per CUA 2019 guidelines: Consider obtaining annual follow-up for at least 10 years following complete resection to monitor for local or metastatic recurrences or new tumors. C Consider offering lifelong annual follow-up in high-risk patients (young age, genetic disease, larger tumor, and/or a paraganglioma). C As per ESE 2016 guidelines: Consider obtaining follow-up for at least 10 years in all patients operated on for pheochromocytoma or paraganglioma, to screen for local or metastatic recurrences or new tumors. C Offer lifelong annual follow-up in high-risk patients (young age, genetic disease, large tumor, and/or a paraganglioma). B As per ES 2014 guidelines, consider obtaining lifelong annual biochemical testing to assess for recurrent or metastatic disease. C Clinical findings Symptoms Past medical history https://web.pathway.md/diseases/recT8YGtwYb5w6FDx 7/10 6/29/23, 11:10 PM Pheochromocytoma and paraganglioma Pathway Abdominal pain Diabetes mellitus type 2 Anxiety Dilated cardiomyopathy Blurred vision Hypertension Change in voice Hypertrophic cardiomyopathy Cough MEN2A Diarrhea MEN2B Dysphagia Neurofibromatosis type 1 Fever Orthostatic hypotension Headache Von Hippel-Lindau syndrome Hearing loss Vital signs Hoarseness Nausea Hypertension Neck pain Paroxysmal hypertension Palpitations Tachycardia Panic attack-type symptoms Neurological exam Polydipsia Polyuria Cranial nerve deficits Shaking Dysphonia Shortness of breath Tremor Sweating Throat pain Diagnostic maneuvers Tinnitus Hildreth's sign Vomiting Weight loss Lab findings Family history Hyperglycemia plasma catecholamines Pheochromocytoma or paraganglioma plasma free metanephrines serum chromogranin A Vascular exam urine catecholamines urine fractionated metanephrines Carotid bruit Palpable thrill urine total metanephrines urine vanillylmandelic acid Head and neck exam Genetic testing Neck mass Max gene mutation Integument exam Nf1 gene mutation Pallor Ret gene mutation Sdha gene mutation Imaging findings Sdhaf2 gene mutation Adrenal mass Sdhb gene mutation Sdhc gene mutation Diagnostic procedures Sdhd gene mutation Tmem127 gene mutation clonidine suppression test https://web.pathway.md/diseases/recT8YGtwYb5w6FDx 8/10 6/29/23, 11:10 PM Pheochromocytoma and paraganglioma Pathway Likelihood Ratios Pertinent positives The following findings increase the probability of pheochromocytoma and paraganglioma in adults. 10 Finding LR+ Value Increased urine vanillylmandelic acid 12.8 Increased urine total metanephrines 11 Increased plasma free metanephrines 9 Increased urine catecholamines 7.2 Show 2 more Pertinent negatives The following findings decrease the probability of pheochromocytoma and paraganglioma in adults. 10 Finding LR- Value plasma free metanephrines not increased 0.01 urine fractionated metanephrines not increased 0.1 urine total metanephrines not increased 0.2 plasma catecholamines not increased 0.2 Show 2 more References 1. 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American Association of Endocrine Surgeons Guidelines for Adrenalectomy: Executive Summary. JAMA Surg. 2022 Aug 17. Open 6. Fassnacht M, Arlt W, Bancos I et al. Management of adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Endocrinol. 2016 Aug;175 2 G1 G34. Open 7. Leung AA, Nerenberg K, Daskalopoulou SS et al. Hypertension Canada's 2016 Canadian Hypertension Education Program Guidelines for Blood Pressure Measurement, Diagnosis, Assessment of Risk, Prevention, and Treatment of Hypertension. Can J Cardiol. 2016 May;32 5 569 88. Open https://web.pathway.md/diseases/recT8YGtwYb5w6FDx 9/10 6/29/23, 11:10 PM Pheochromocytoma and paraganglioma Pathway 8. Dimitrios Stefanidis, Melanie Goldfarb, Kent W Kercher et al. SAGES guidelines for minimally invasive treatment of adrenal pathology. Surg Endosc. 2013 Nov;27 11 3960 80. Open 9. Neal E Rowe, Ravi M Kumar, Nicola Schieda et al. Canadian Urological Association guideline: Diagnosis, management, and followup of the incidentally discovered adrenal mass. Can Urol Assoc J. 2023 Feb;17 2 12 24. Open 10. Butalia S, Audibert F, C t AM et al. Hypertension Canada's 2018 Guidelines for the Management of Hypertension in Pregnancy. Can J Cardiol. 2018 May;34 5 526 531. Open 11. Lenders JW, Pacak K, Walther MM et al. Biochemical diagnosis of pheochromocytoma: which test is best?. JAMA. 2002 Mar 20;287 11 1427 34. Open 12. Stein P, Black H. A simplified diagnostic approach to pheochromocytoma. A review of the literature and report of one institution's experience. Medicine Baltimore). 1991 Jan;70 1 46 66. Open 13. Taieb D, Hicks RJ, Hindie 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. 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