Treatment of pheochromocytoma in adults

INTRODUCTION — Pheochromocytoma is a rare neuroendocrine tumor, occurring in less than 0.2 percent of patients with hypertension [1,2]. In approximately 60 percent of patients, the tumor is discovered incidentally during computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen for unrelated symptoms [3].

The treatment of pheochromocytoma will be reviewed here (algorithm 1). The clinical manifestations, diagnosis, and genetics of pheochromocytoma and management of metastatic pheochromocytoma are discussed separately. (See "Clinical presentation and diagnosis of pheochromocytoma" and "Pheochromocytoma in genetic disorders" and "Paraganglioma and pheochromocytoma: Management of malignant (metastatic) disease".)

MEDICAL PREPARATION FOR SURGERY — Once a pheochromocytoma is diagnosed, all patients should undergo a resection of the pheochromocytoma following appropriate medical preparation. Agents known to provoke a pheochromocytoma paroxysm (eg, beta-adrenergic blocker in absence of alpha-adrenergic blockade, glucagon, histamine, metoclopramide, high-dose corticosteroids) should be avoided. Our approach is largely consistent with the Endocrine Society's 2014 Clinical Practice Guidelines [4].

Resecting a pheochromocytoma is a high-risk surgical procedure and an experienced surgeon/anesthesiologist team is required. Cardiovascular and hemodynamic variables must be monitored closely. Continuous measurement of intraarterial pressure and heart rhythm is required. In the setting of congestive heart failure or decreased cardiac reserve, monitoring of pulmonary capillary wedge pressure is indicated.

Preoperative medical therapy is aimed at:

●Controlling hypertension (including preventing a hypertensive crisis during surgery) and tachycardia

●Volume expansion

In patients with undiagnosed pheochromocytomas who undergo surgery for other reasons (and who therefore have not undergone preoperative medical therapy), surgical mortality rates are increased due to lethal hypertensive crises, malignant arrhythmias, and multiorgan failure [5]. Some form of preoperative pharmacologic preparation is indicated for all patients with catecholamine-secreting neoplasms. No randomized, controlled trials have compared the different approaches, and there is no universally accepted method of preparation for surgery in patients with pheochromocytoma [6]. Combined alpha and beta-adrenergic blockade, calcium channel blockers, and metyrosine have all been used successfully and are described below [7].

Combined alpha and beta-adrenergic blockade — Combined alpha and beta-adrenergic blockade is one approach to control blood pressure and prevent intraoperative hypertensive crises.

Alpha-adrenergic blockade — An alpha-adrenergic blocker is given for at least 7 days preoperatively to normalize blood pressure and expand the contracted intravascular space. A longer duration of preoperative alpha-adrenergic blockade is indicated in patients with recent myocardial infarction, catecholamine cardiomyopathy, refractory hypertension, and catecholamine-induced vasculitis.

Phenoxybenzamine is the preferred drug for preoperative preparation to control blood pressure and arrhythmia in most centers in the United States. It is an irreversible, long-acting, nonspecific alpha-adrenergic blocking agent.

●The initial dose is 10 mg once or twice daily, and the dose is increased by 10 to 20 mg in divided doses every two to three days as needed to control blood pressure and spells. In general, the patient is ready for surgery in 7 to 14 days after initiation of alpha-adrenergic blockade.

●The final dose of phenoxybenzamine is typically between 20 and 100 mg daily. The patient should be warned about the orthostasis, nasal stuffiness, and marked fatigue that occur in almost all patients. Men should be counseled about retrograde ejaculation, as well.

●With their more favorable side-effect profiles and lower financial cost, selective alpha-1-adrenergic blocking agents (eg, prazosin, terazosin, or doxazosin) are utilized in many centers or are preferred to phenoxybenzamine when long-term pharmacologic treatment is indicated (eg, for metastatic pheochromocytoma).

Blood pressure monitoring — Blood pressure should be monitored twice daily in the outpatient setting with the patient in the seated and standing positions. Target blood pressure is low-normal blood pressure for age (eg, less than 120/80 mmHg seated), with systolic blood pressure greater than 90 mmHg (standing); both targets should be modified on the basis of the patient's age and comorbid disease.

High sodium diet — On the second or third day of alpha-adrenergic blockade, patients are encouraged to start a diet high in sodium content (>5000 mg daily) because of the catecholamine-induced volume contraction and the orthostasis associated with alpha-adrenergic blockade. This degree of volume expansion may be contraindicated in patients with congestive heart failure or renal insufficiency.

Beta-adrenergic blockade — After adequate alpha-adrenergic blockade has been achieved, beta-adrenergic blockade is initiated, which typically occurs two to three days preoperatively. The beta-adrenergic blocker should never be started first, because blockade of vasodilatory peripheral beta-adrenergic receptors with unopposed alpha-adrenergic receptor stimulation can lead to a further elevation in blood pressure [4].

The clinician should exercise caution if the patient is asthmatic or has congestive heart failure. Chronic catecholamine excess can produce a cardiomyopathy that may become evident with the initiation of beta-adrenergic blockade, resulting in acute pulmonary edema. Therefore, when the beta-adrenergic blocker is administered, it should be used cautiously and at a low dose.

●As an example, a patient may be given 10 mg of propranolol orally every six hours on the first day of beta-adrenergic blockade. Another option is to start with low-dose metoprolol (eg, 12.5 mg twice daily).

●On the second day, the beta-adrenergic blockade (assuming the patient tolerates the drug) is converted to a single, long-acting dose.

●The dose is then increased as necessary to control the tachycardia (goal heart rate is 60 to 80 beats per minute). Typical maximum doses in this setting are 120 mg of propranolol or 200 mg of metoprolol.

Calcium channel blockers — Although perioperative alpha-adrenergic blockade is widely recommended, a second regimen that has been utilized involves the administration of a calcium channel blocker [8,9]. Nicardipine and amlodipine are the most commonly used calcium channel blockers in this setting; the starting dose of nicardipine is 30 mg twice daily of the sustained-release preparation and the starting dose of amlodipine is 2.5 or 5 mg administered once daily. The calcium channel blocker is given orally to control blood pressure preoperatively and nicardipine may be given as an intravenous infusion intraoperatively. Although there is less collective experience with calcium channel blockers than with alpha and beta-adrenergic blockade, when calcium channel blockers are used as the primary mode of antihypertensive therapy, they may be as effective [9,10].

Clearly, the exclusive use of calcium channel blockers for the perioperative management of patients with catecholamine-secreting tumors does not prevent all hemodynamic changes; however, its use has been associated with low morbidity and mortality [9].

The main role for this class of drugs may be either to supplement the combined alpha- and beta-adrenergic blockade protocol when blood pressure control is inadequate or to replace the adrenergic blockade protocol in patients with intolerable side effects.

Metyrosine — Another approach involves the administration of metyrosine (alpha-methyl-para-tyrosine), which inhibits catecholamine synthesis. In one report, the patients given metyrosine had a smoother perioperative course than those given phenoxybenzamine alone [11].

Metyrosine should be used with caution and only when other agents have been ineffective or in patients where tumor manipulation or destruction (eg, radiofrequency ablation of metastatic sites) will be marked [12,13]. Although some centers advocate that this agent should be used routinely preoperatively, most reserve it primarily for patients who cannot be treated with the typical combined alpha and beta-adrenergic blockade protocol because of intolerance or cardiopulmonary reasons [7].

The protocol used at the Mayo Clinic with short-term preprocedure preparation is to start with metyrosine 250 mg every six hours on day 1, 500 mg every six hours on day 2, 750 mg every six hours on day 3, and 1000 mg every six hours on the day before the procedure, with the last dose (1000 mg) the morning of the procedure [7,14]. With this short-course metyrosine therapy, the main side effect is hypersomnolence.

The side effects of metyrosine can be disabling and with long-term therapy they include sedation, depression, diarrhea, anxiety, nightmares, crystalluria and urolithiasis, galactorrhea, and extrapyramidal signs. Metyrosine may be added to alpha and beta-adrenergic blockade when the resection will be difficult (eg, malignant paraganglioma) or if destructive therapy is planned (eg, radiofrequency ablation of hepatic metastases or cryoablation of bone metastases) [7,12,13].

The extrapyramidal effects of phenothiazines or haloperidol may be potentiated, and their use concomitantly with metyrosine should be avoided. High fluid intake to avoid crystalluria is suggested for any patient taking more than 2 g daily. The metyrosine-phenoxybenzamine regimen has not been compared with the phenoxybenzamine-beta-adrenergic blocker regimen. The cost of metyrosine has increased dramatically recently and may make use of this medication prohibitive.

ADRENALECTOMY

Localized adrenal pheochromocytoma — A minimally invasive approach to the adrenal gland is the procedure of choice for patients with small, solitary intraadrenal pheochromocytomas that have no malignant radiologic features. Laparoscopic or robotic transabdominal and retroperitoneal approaches have been used successfully, although there is some evidence that the retroperitoneal approach is preferable [15-18]. Key to success is an endocrine surgeon with expertise in robotic or laparoscopic techniques and operating on pheochromocytomas. Inexperience can lead to critical errors in management; for example, intraoperative tumor capsule rupture with seeding of the retroperitoneum and creating an incurable situation [19].

Minimally invasive adrenalectomy can be safely performed for pheochromocytoma in more than 90 percent of cases. As an example, in an observational study of 102 patients with pheochromocytoma, 97 adrenalectomies were performed laparoscopically, seven were performed with open surgery, and four required conversion from laparoscopic to open surgery [20].

If the pheochromocytoma is in the adrenal gland, the entire gland should be removed in sporadic cases. (See 'Metastatic pheochromocytoma' below.)

Paragangliomas — Abdominal paragangliomas can also be approached laparoscopically in selected cases [21]. Conversion to an open operation from laparoscopic surgery for pheochromocytoma or abdominal paragangliomas is indicated if it is technically difficult to access the tumor or if malignant disease is suspected [22]. (See "Paraganglioma and pheochromocytoma: Management of malignant (metastatic) disease".)

Paragangliomas of the neck, chest, and urinary bladder require specialized approaches [23]. For example, neck paragangliomas may be in the carotid sheath or in the carotid body and thus require proximal and distal vascular control for resection. Preoperative embolization may reduce blood loss [24]. Most chest paragangliomas require a median sternotomy and may involve the heart and great vessels with cardiac bypass, although videoscopic removal may be possible in some cases [25]. (See "Paragangliomas: Treatment of locoregional disease".)

Familial pheochromocytoma — Up to 40 percent of pheochromocytomas and paragangliomas are associated with hereditary syndromes [23,26]. Patients with familial pheochromocytomas (eg, MEN2, VHL) have a high incidence of bilateral disease. Partial adrenalectomy can be considered for some patients with familial pheochromocytoma (ie, multiple endocrine neoplasia type 2 [MEN2] and von Hippel-Landau [VHL]) [27]. (See "Pheochromocytoma in genetic disorders", section on 'Familial pheochromocytoma'.)

Cortical-sparing bilateral adrenalectomy (partial adrenalectomy) may be considered for some patients with bilateral pheochromocytomas to prevent permanent glucocorticoid deficiency because some types of familial pheochromocytomas have less metastatic potential [27-34].

In a multicenter consortium-based registry, 849 adrenalectomies were performed between 1950 and 2018 in 625 patients with bilateral pheochromocytomas [27]. Approximately one-half of the adrenalectomies (324; 52 percent) were planned as cortical sparing and were successful in 248 patients (76.5 percent) [27]. Primary adrenal insufficiency occurred in all patients treated with total adrenalectomy but only in 23.5 percent of patients treated with attempted cortical-sparing adrenalectomy. Two patients developed recurrent pheochromocytoma in the adrenal bed despite total adrenalectomy, whereas 33 patients (13 percent) treated with successful cortical-sparing adrenalectomy developed another pheochromocytoma within the remnant adrenal after a median of eight years, all of which were successfully treated with another surgery.

The management of patients with MEN2 and VHL differs as follows:

●Patients with MEN2 have bilateral disease in 30 percent of cases and contralateral disease develops in 50 percent of the MEN2 patients with unilateral disease within 10 years [26,35,36]. For these reasons, when bilateral adrenal pheochromocytomas >2 cm in diameter are present, consideration of complete bilateral adrenalectomy is recommended for MEN2 patients. If partial adrenalectomies are performed for bilateral pheochromocytoma in the setting of MEN2, the patient should be informed about the risk of recurrent disease (3 percent in the remnant gland occurring 6 to 13 years after partial adrenalectomy) and need for annual long-term follow-up [34]. Patients with MEN2 have a high incidence of paroxysmal attacks and a higher prevalence of hypertension and other cardiovascular problems than do patients with VHL [26,34].

●Patients with some forms of VHL have less diffuse medullary disease, and cortical-sparing bilateral adrenalectomy is an option for these patients when bilateral disease is evident on imaging [30]. However, partial adrenalectomy potentially leaves residual adrenal medullary tissue behind, thus increasing the risk of recurrent pheochromocytoma [37]. In one study, as an example, 13 of 14 patients with VHL did not require glucocorticoid therapy during a mean of 11 years of follow-up; however, three patients had recurrent pheochromocytoma [30]. Similarly, in a study of 36 partial adrenalectomies in 26 patients with VHL, three patients became steroid dependent (11 percent), and there were five local recurrences (11 percent) with nine years of follow-up [38].

●Some variant forms of VHL (VHL type 2A) have high malignancy rates, and cortical-sparing adrenalectomy should be avoided in patients from these kindreds [39]. Patients with VHL should be referred for genetic counseling and screening for specific mutations associated with these variants. (See "Clinical features, diagnosis, and management of von Hippel-Lindau disease".)

If a bilateral adrenalectomy is planned preoperatively, the patient should receive glucocorticoid stress coverage while awaiting transfer to the operating room. (See "Treatment of adrenal insufficiency in adults" and "Persistent or recurrent Cushing disease: Surgical adrenalectomy", section on 'Hormone replacement'.)

Glucocorticoid coverage should be initiated in the operating room if unexpected bilateral adrenalectomy is necessary. Complete bilateral adrenalectomy with autotransplantation of adrenocortical tissue has also been attempted but has not been found to circumvent the need for lifelong glucocorticoid replacement therapy [40].

Surgical outcomes — Although no randomized trial data are available, observational studies and literature reviews report that intraoperative blood loss is less, perioperative pain, operative time is shorter, length of hospital stay is shorter, and costs are lower with laparoscopic when compared with open adrenalectomy [41-48].

Complications of surgery for pheochromocytoma are primarily due to severe preoperative hypertension, high secretion tumors, or repeat intervention for recurrence [49]. As an example, in a series of 143 patients who had open surgery, adverse perioperative events or complications occurred in 32 percent of cases [50]. The most common adverse event was sustained hypertension in 36 patients (25 percent). There were no perioperative deaths, myocardial infarctions, or cerebrovascular events. Perioperative factors associated with adverse perioperative events included larger tumor size, prolonged duration of anesthesia, and increased levels of preoperative urinary catecholamines and catecholamine metabolites. Despite premedication of most patients with phenoxybenzamine and a beta-adrenergic blocker, varying degrees of intraoperative hemodynamic lability occurred [50]. In a second study, additional factors associated with adverse perioperative events included systolic blood pressure ≥160 mmHg, mean arterial pressure <60 mmHg, and a history of coronary artery disease [51].

Complication rates are lower with laparoscopic surgery as compared with open surgery. In a report of 40,363 patients who underwent adrenalectomies between 1998 and 2006, the surgical outcomes were improved with laparoscopic adrenalectomy as compared with open surgery with regard to complication rates (4 versus 8 percent), pulmonary compromise (2 versus 4 percent), and length of hospital stay (three versus five days) [52].

Acute hypertensive crises — In spite of preoperative medical preparation, hemodynamic instability may still occur during surgical resection of a pheochromocytoma. Endotracheal intubation and manipulation of the adrenal gland can both induce release of catecholamines and, potentially, a hypertensive crisis.

Potential risk factors for intraoperative hemodynamic instability were identified in a retrospective study of 73 patients undergoing surgical resection of a pheochromocytoma at a single institution [53]. Higher preoperative plasma norepinephrine concentration, larger tumor size (>4 cm), and more pronounced postural blood pressure fall after alpha-adrenergic blockade (>10 mmHg) correlated with intraoperative hypertensive events.

Management — Treatment options for hypertensive crises include intravenous sodium nitroprusside, phentolamine, or nicardipine.

●Sodium nitroprusside is an ideal vasodilator for intraoperative management of hypertensive episodes because of its rapid onset of action and short duration of effect. It is administered as an intravenous infusion at 0.5 to 5.0 mcg/kg of body weight per minute and adjusted every few minutes for target blood pressure response; to keep the steady-state thiocyanate concentration below 1 mmol/L, the rate of a prolonged infusion should be no more than 3 mcg/kg per minute.

●Phentolamine is a short-acting, nonselective alpha-adrenergic blocker available in lyophilized form in 5 mg vials. An initial test dose of 1 mg is administered and, if necessary, followed by repeat 5 mg boluses or continuous infusion. The response to phentolamine is maximal in two to three minutes after a bolus injection and lasts 10 to 15 minutes.

●Nicardipine can be started at an infusion rate of 5 mg/hour and titrated for blood pressure control (the infusion rate may be increased by 2.5 mg/hour every 15 minutes up to a maximum of 15 mg/hour).

Other complications

●Cardiac arrhythmias should be managed with lidocaine (50 to 100 mg intravenously) or esmolol (50 to 200 mcg per kg per minute intravenously).

●Postoperative hypotension can be avoided by adequate fluid replacement and hypoglycemia (which can occur in 10 to 15 percent of patients due to removal of catecholamine suppression of insulin secretion [54]) by glucose infusion. After tumor removal, catecholamine secretion should fall to normal in approximately one week.

●Postoperative hypoglycemia has been reported in patients undergoing adrenalectomy for pheochromocytoma in 4 to 43 percent of patients based upon serum glucose cutoffs of <55 mg/dL (2.78 mmol/L) and <70 mg/dL (3.89 mmol/L), respectively [55,56]. Thus, serum glucose should be monitored for the first 24 to 48 hours postoperatively [4].

Prognosis — Surgical removal of a pheochromocytoma does not always lead to long-term cure of pheochromocytoma or hypertension, even in patients with a benign tumor. In one series of 176 patients, pheochromocytoma recurred in 29 (16 percent) and the recurrence was malignant in 15 of the 29 [57]. Recurrence was more likely in patients with familial pheochromocytoma or familial paraganglioma, right adrenal tumors, and extra-adrenal tumors.

Recurrence rates may be lower than previously estimated [58], particularly in patients with sporadic pheochromocytoma. In a meta-analysis of 13 studies including 430 patients with sporadic pheochromocytoma, the recurrence rate was 3 percent (95% CI 2 to 6 percent) [59]. Mean follow-up time was 77 months, and the mean time to recurrence was approximately 49 months. In spite of these reassuring data for those with sporadic pheochromocytoma, we still suggest long-term monitoring in all patients, even those apparently cured, as recurrences may occur years later.

Metastatic disease can be discovered as long as 53 years after the initial surgery [60]. Most patients should have annual biochemical screening [57].

METASTATIC PHEOCHROMOCYTOMA — There are no curative treatments for metastatic pheochromocytoma, unless the sites of disease are surgically resectable. We suggest resection with intent to cure, which may improve symptoms and possibly survival [61,62].

Approximately 10 percent of all catecholamine-secreting tumors are malignant. Malignant/metastatic pheochromocytoma are histologically and biochemically the same as benign ones. The diagnosis of malignant pheochromocytoma is based on documentation of metastatic disease. The risk of malignancy is higher for paragangliomas than for pheochromocytomas, especially if the patient has a mutation in succinate dehydrogenase subunit B (SHDB) [63]. Risk is also higher with larger tumors and some forms of variant VHL. (See "Paragangliomas: Epidemiology, clinical presentation, diagnosis, and histology".)

In a report on 272 patients with metastatic pheochromocytoma and paraganglioma, 29 had rapidly progressive disease and 188 had indolent disease [60]. Metastatic disease was diagnosed at a median age of 39 years (range 7 to 83 years), with synchronous metastases in 96 (35 percent) patients. In 176 (65 percent) of patients, metastases developed at a median of 5.5 years (range 0.3 to 53.4 years) from the initial diagnosis. Median overall and disease-specific survivals were 24.6 and 33.7 years, respectively. Shorter survival correlated with male sex, older age at the time of primary tumor, synchronous metastases, larger primary tumor size, elevated dopamine, and not undergoing primary tumor resection.

An individualized approach to patients with metastatic pheochromocytoma and paraganglioma is warranted. The only reliable clue to the presence of a malignant pheochromocytoma is local invasion or distant metastases, which may occur as long as 53 years after resection. The clinical features and management of malignant pheochromocytomas are reviewed separately. (See "Paraganglioma and pheochromocytoma: Management of malignant (metastatic) disease" and "Clinical presentation and diagnosis of pheochromocytoma", section on 'Tumor characteristics'.)

Systemic therapy — The use of systemic therapies, including iobenguane I-131 (therapeutic), to treat patients with malignant pheochromocytomas/paragangliomas is reviewed separately. (See "Paraganglioma and pheochromocytoma: Management of malignant (metastatic) disease".)

Radioactive iodine (I¹³¹) attached to the MIBG molecule produces iobenguane I-131, which functions as a semi-selective agent for malignant pheochromocytoma or paraganglioma. This treatment is only an option for the approximately 60 percent of tumors that take up MIBG as determined by iobenguane I-123 (diagnostic) scintigraphy. A lower fraction of dopamine-secreting paragangliomas take up iobenguane I-123.

Pheochromocytomas and extra-adrenal paragangliomas express somatostatin receptors at a level that is similar to that of other neuroendocrine tumors. Patients whose metastatic tumors express somatostatin receptors may benefit from therapy with radiolabeled somatostatin analogs, such as ¹⁷⁷Lu-DOTATATE. (See "Paraganglioma and pheochromocytoma: Management of malignant (metastatic) disease", section on 'Peptide receptor radioligand therapy'.)

Patients with unresectable malignant pheochromocytoma or paraganglioma may benefit from temozolomide treatment with or without olaparib as a second-line therapy to cyclophosphamide plus vincristine plus dacarbazine [64-66].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Adrenal incidentaloma" and "Society guideline links: Pheochromocytoma and paraganglioma".)

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Pheochromocytoma (The Basics)")

SUMMARY AND RECOMMENDATIONS — Pheochromocytoma is a rare neuroendocrine tumor with serious and potentially lethal cardiovascular complications due to the effects of secreted catecholamines. Although the clinical presentation may be quite variable, the classic triad is considered to be episodic headache, sweating, and tachycardia in association with hypertension.

Surgery

●For patients with biochemical documentation of pheochromocytoma, we recommend surgical resection of the pheochromocytoma following optimal medical preparation (Grade 1B). (See 'Medical preparation for surgery' above.)

●Because of the reduction in postoperative morbidity, hospital stay, and expense compared with open laparotomy, we suggest laparoscopic adrenalectomy by an experienced endocrine surgeon for adrenal pheochromocytomas (Grade 2C). (See 'Adrenalectomy' above.)

Preoperative preparation

●All patients with pheochromocytoma need to undergo preoperative alpha-adrenergic blockade; we suggest phenoxybenzamine as the first-line drug (Grade 2C). Alternative drug options and details for drug administration are outlined above. (See 'Alpha-adrenergic blockade' above.)

●After adequate alpha-adrenergic blockade has been achieved, beta-adrenergic blockade is begun. For beta-adrenergic blockade, we suggest cautious, low-dose administration. As an example, a patient is usually given either 10 mg of propranolol every six hours or metoprolol 12.5 mg twice daily to start. On the second day of treatment, the beta-adrenergic blockade (assuming the patient tolerates the drug) is converted to a single, long-acting dose. The dose is then increased as necessary to control the tachycardia (goal heart rate is 60 to 80 beats per minute). The typical maximum dose for propranolol is 120 mg/day. The beta-adrenergic blocker should never be started first. (See 'Beta-adrenergic blockade' above.)

Familial pheochromocytoma

●For patients with multiple endocrine neoplasia type 2 (MEN2) (which is a diffuse medullary disease) with evidence of bilateral disease >2 cm in diameter on imaging, we suggest consideration of complete bilateral adrenalectomy because of the risk of recurrent pheochromocytoma (Grade 2C). (See 'Familial pheochromocytoma' above.)

●For most patients with von Hippel-Lindau (VHL) (which is a less diffuse medullary disease) with evidence of bilateral disease on imaging, we suggest cortical-sparing bilateral adrenalectomy (Grade 2C). Because of the risk of recurrent disease in these patients, we recommend long-term biochemical monitoring.

●For patients with VHL and a high malignancy rate in the kindred, we suggest not performing cortical-sparing adrenalectomy (Grade 2C).

●In patients with MEN2 or VHL with unilateral pheochromocytoma, we suggest unilateral adrenalectomy or partial adrenalectomy if the tumor is small (Grade 2C). These patients then need annual biochemical testing indefinitely for evidence of contralateral pheochromocytoma.

Malignant disease

●We suggest resection of malignant pheochromocytoma with intent to cure, which may improve symptoms and possibly survival (Grade 2C). Other treatment options for malignant pheochromocytoma are reviewed separately. (See "Paraganglioma and pheochromocytoma: Management of malignant (metastatic) disease".)

DISCLOSURE — The views expressed in this topic are those of the author(s) and do not reflect the official views or policy of the United States Government or its components.

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Norman M Kaplan, MD, who contributed to earlier versions of this topic review.