Endocrine disorders account for about 5% to 10% of secondary hypertension. Pheochromocytoma and paraganglioma tumors are a well-established, albeit rare, cause of secondary hypertension. Pheochromocytomas and paragangliomas are tumors of the autonomic nervous system that arise from chromaffin tissue in the adrenal medulla and extraadrenal ganglia, respectively. Pheochromocytomas and most paragangliomas are derived from sympathetic nervous system tissue which secretes catecholamines and metanephrines. Some paragangliomas, however, are derived from parasympathetic ganglia, especially those in the head and neck, and most are nonsecretory.
Pheochromocytomas and paragangliomas occur in only 2 to 8 per million people and are rare cause of hypertension (0.2% to 0.6% of all patients with hypertension) ; however, pheochromocytomas make up 4% to 7% of adrenal incidentalomas. When left undiagnosed, these tumors are associated with high morbidity and mortality secondary to the uncontrolled catecholamine levels leading to hypertension, heart disease, stroke, and even death. Interestingly, pheochromocytomas and paragangliomas are the tumors most commonly associated with inherited genetic mutations. Although most tumors are benign, up to 25% can be malignant and are associated with a poor prognosis. Making the diagnosis in this disease is key; and once diagnosed, appropriate medical management is necessary to decrease morbidity of the tumor and of the associated surgical risks. Pheochromocytomas used to be thought of as the “tumor of tens,” with 10% of tumors being bilateral, 10% being extraadrenal, 10% being malignant, and 10% being asymptomatic. This is no longer true. In this chapter, we will discuss the unique features of pheochromocytomas and paragangliomas, diagnosis and management of these tumors, and the associated genetic disorders.
Screening and Diagnosis
Secondary causes for hypertension, including pheochromocytoma and paraganglioma, should be sought in young adults with hypertension and in patients of any age with new onset difficult to control hypertension. Screening for pheochromocytomas is also part of the adrenal incidentaloma evaluation for both hypertensive and normotensive patients. In addition, screening should be done when patients have symptoms suggestive of pheochromocytoma and paraganglioma, including the classic triad of headaches, palpitations, and diaphoresis, as well as anxiety, tremors, new onset or worsening of previously established diabetes mellitus, syncope, or presyncope. Patients may also be asymptomatic at a rate higher than previously appreciated. Often times, patients, especially those with episodic events, are dismissed for having anxiety or panic attacks. The differential diagnosis is long ( Table 15.1 ), and clinicians must suspect pheochromocytoma and paraganglioma to make the diagnosis.
| System | Differential |
|---|---|
| Cardiovascular Differential |
|
| Endocrine Differential |
|
| Neurologic Differential |
|
| Psychologic Differential |
|
| Pharmacologic Differential |
|
| Other |
|
Laboratory Testing
Once suspected, screening can be done in two ways, testing for plasma free metanephrines or 24-hour urine fractionated metanephrines. Both plasma and urine tests have over 90% sensitivity for pheochromocytoma and paraganglioma. Plasma metanephrines are favored because this test is easier to collect and has a higher specificity compared with the 24-hour urine tests (ranging from 79% to 98% versus 69% to 95%, respectively). Catecholamine and metanephrine measurements are susceptible to false-positive elevations for many reasons. An upright position or recent exercise can increase levels. Therefore, guidelines recommend the plasma tests be performed with the patient resting for 20 minutes in the supine position although this is not usually practical in the clinical setting. Plasma catecholamines are particularly sensitive to this, and therefore, are not recommended as a first line screening test because of increased likelihood of false-positive results. Most laboratories have different reference ranges for plasma tests drawn in the supine and upright positions which must be used when interpreting the results. The catecholamine and metanephrine levels for both plasma and urine tests can also be falsely elevated because of interfering medications ( Table 15.2 ).
| Acetaminophen |
| Levodopa |
| Monoamine oxidase inhibitors |
| Selective serotonin reuptake inhibitors |
| Sympathomimetics |
| Tricyclic antidepressants |
| Some beta-blockers (especially nonselective) |
| Some alpha-blockers (ie, phenoxybenzamine) |
Imaging
Once elevated levels of catecholamines and/or metanephrines are confirmed, imaging studies should be done to localize the tumor. Cross-sectional imaging with computed tomography (CT) or magnetic resonance imaging (MRI) of the abdomen/pelvis is the first recommended imaging test because the vast majority of tumors will be in the adrenal glands or in the abdomen or pelvis. For patients with known susceptibility gene mutations, imaging other locations may be necessary based on the associated phenotype (see Genetic Syndromes section). Paragangliomas derived from the parasympathetic chain, such as those in the head and neck for example, are often nonsecretory. Therefore, if a parasympathetic paraganglioma is suspected, imaging should be performed regardless of biochemical testing results. Furthermore, because parasympathetic paragangliomas are usually nonsecretory, if patients with a known parasympathetic tumor have elevated metanephrines, abdominal/pelvic imaging studies must be performed to evaluate for an additional sympathetic-derived primary pheochromocytoma or paraganglioma.
Imaging with 123 I-metaiodobenzylguanidine (MIBG) is not useful as first line study because normal adrenal glands can have increased symmetric or asymmetric physiologic uptake leading to false-positive results. Instead, 123 I-MIBG imaging is usually reserved for the patient in whom cross-sectional imaging did not reveal a tumor despite highly elevated biochemical testing or for the patient with metastatic disease to assess if the lesions are MIBG avid in preparation for possible treatment with 131 I-MIBG. Guidelines recommend fluorodeoxyglucose positron emission tomography ( 18 F-FDG PET)/CT scanning over 123 I-MIBG imaging to diagnosis metastatic disease, especially in patients with germline Succinate Dehydrogenase Subunit B (SDHB) gene mutations for whom the sensitivity of positron emission tomography (PET) imaging is 74% to 100%.
Treatment
Surgery
Surgical resection is the treatment of choice for pheochromocytoma and paraganglioma. Surgical resection was previously associated with a high perioperative morbidity and mortality because of the hypersecretion of catecholamines, but with the introduction of perioperative blockade, surgery is now relatively safe with morbidity and mortality rates as low as 0% to 2%. Improved outcomes have also been associated with laparoscopic surgery for pheochromocytoma and paraganglioma as opposed to open adrenalectomy procedures. In fact, laparoscopic adrenalectomy is the treatment of choice for adrenal pheochromocytoma and is often curative for small adrenal pheochromocytomas. Open adrenalectomy is usually reserved for very large tumors, greater than 8 cm, and extraadrenal paragangliomas. Usually the entire adrenal gland is removed; however, cortical sparing surgery should be attempted in patients with bilateral adrenal pheochromocytomas and in patients with a genetic predisposition to bilateral pheochromocytomas (such as Multiple Endocrine Neoplasia type 2 [MEN2] and von Hippel Lindau [vHL]). If a sufficient part of the cortex can be spared, these patients can avoid lifetime glucocorticoid and mineralocorticoid replacement. There is a higher risk of recurrence with cortical sparing surgery. During adrenalectomy, it is important not to violate the tumor capsule and not to rupture a cystic pheochromocytoma as cells that are spilled during surgery can seed the abdominal cavity resulting in recurrent growth in the adrenal bed or peritoneum. It is essential to have an experienced surgical team with an experienced anesthesiologist.
In preparation for surgery, patients should receive preoperative alpha-blockade for 10 to 14 days before surgery and should be instructed to take these medications on the morning of surgery. Certain induction agents and narcotics should be avoided during surgery (such as fentanyl, ketamine, and morphine) because they can potentially stimulate catecholamine release. Atropine, a parasympathetic nervous system blocking agent, should also be avoided as this causes tachycardia. Preferred induction agents include propofol, etomidate, barbiturates, and synthetic opioids. Most anesthetic gases can be used, but halothane and desflurane should be avoided. It is essential to provide close continuous hemodynamic and cardiovascular monitoring during surgery and in the perioperative period.
During surgery, patients will require either intraoperative intravenous phentolamine or nicardipine. During intubation, surgical excision, and tumor manipulation, it is common to see an increase in blood pressure; and once the tumor is removed, blood pressure can drop precipitously as a result of the large decrease in catecholamine levels. Risk factors for hemodynamic instability include tumors greater than 3 to 4 cm, higher catecholamine levels, uncontrolled blood pressure, or orthostatic hypotension preoperatively. After surgery, patients may require blood pressure support with fluids, colloids, and sometimes alpha-adrenergic agonists for 24 to 48 hours and may need monitoring in an intensive care unit setting. Postoperative hypotension is less common in patients who have received adequate preoperative alpha-blockade. Blood pressure usually returns to normal within a few days of surgery, but patients may remain hypertensive particularly if they have chronic underlying hypertension or widespread metastatic disease.
Perioperative Blockade
Perioperative blockade is important to lower morbidity and mortality associated with tumor resection. Blockade is also required before other surgical procedures and biopsies and should also be considered when undertaking treatment for metastatic disease such as chemotherapy, radiation, and high dose 131 I-MIBG therapy, particularly when catecholamine levels are very elevated. There are no standardized guidelines for the perioperative blockade regimen, and the data that exist are sparse with no randomized controlled trials. Preoperative alpha-blockade is usually started as soon as the diagnosis is made, and surgery is usually scheduled within 2 to 3 weeks of the diagnosis. There are many different medical regimens used to control the effects of catecholamine hypersecretion, and these include the use of alpha-blockers, calcium channel blockers and tyrosine hydroxylase inhibition. The typical drugs and dosing regimens are shown in Table 15.3 .
| Drug | Action | Characteristics | Common Dosing | Common Side Effects a |
|---|---|---|---|---|
| Phenoxybenzamine | Nonselective alpha-1 and alpha-2 blocker | Noncompetitive antagonist | 10 mg 2-3 daily (maximum 60 mg per day) | Orthostasis, nasal congestion |
| Doxazosin | Selective alpha-1 blocker | Competitive antagonist | 2-4 mg 2-3 × daily | Orthostasis, dizziness |
| Prazosin | Selective alpha-1 blocker | Competitive antagonist | 1-2 mg twice daily | Orthostasis, dizziness |
| Terazosin | Selective alpha-1 blocker | Competitive antagonist | 1-4 mg once daily | Orthostasis, dizziness |
| Nicardipine | Calcium channel blocker | Dihydropyridine long acting | 30 mg twice daily | Headache, edema, vasodilatation |
| Amlodipine | Calcium channel blocker | Dihydropyridine long acting | 5-10 mg daily | Headache, edema, palpitations |
| Metyrosine | Tyrosine hydroxylase inhibitor | Decreases catecholamine production | 250-500 mg 4 × daily (dose escalated every 2 days) | Severe lethargy, extrapyramidal neurologic side effects and gastrointestinal upset |
| Metoprolol | Selective beta-1 blocker | Used to treat reflex tachycardia only after full alpha blockade achieved | 25-50 mg 1-2 × daily | Fatigue, dizziness |
a Many common side effects are expected and are suggestive of complete perioperative blockade. If possible and when appropriate, these side effects should be managed without dose reduction.
Medications
Alpha-Blockers
Alpha-blockers are most commonly used in the perioperative management in patients with pheochromocytoma and paraganglioma. These tumors cause alpha-receptor activation in response to excess catecholamine secretion leading to severe vasoconstriction which can cause hypertension, arrhythmias, and myocardial ischemia. Both competitive and noncompetitive alpha-blockers can be used in perioperative management. The most commonly used alpha-blocker for perioperative management is phenoxybenzamine, which is a noncompetitive inhibitor that covalently binds to alpha-1 and alpha-2 receptors. This noncompetitive inhibition of both alpha receptors by phenoxybenzamine is difficult to displace during the excess release of catecholamines during surgery and tumor manipulation, and therefore, provides more complete blockade of alpha receptors. The irreversible binding significantly lowers the risk of an intraoperative hypertensive crisis; however, this can also result in hypotension after the tumor is resected. Vasopressor support and intravenous fluids may be required for 24 to 48 hours postoperatively to maintain blood pressure.
Selective alpha-1 receptor blockers include doxazosin, terazosin, and prazosin. These competitive inhibitors have a relatively short duration of action; and therefore, the receptor inhibition can be overcome by the excess catecholamine release intraoperatively and can potentially lead to a hypertensive crisis intraoperatively. The shorter half-life, however, results in less hypotension after the tumor is removed. We usually reserve use of selective alpha-blockers for chronic use of alpha-blockade in patients with symptomatic metastatic disease or for use when a lower dose alpha-blockade is required, for example in preparation for a dental extraction in patients with elevated catecholamine levels because of metastatic disease. These agents provide incomplete alpha-blockade but cost significantly less and are better tolerated than phenoxybenzamine.
Calcium Channel Blockers
Calcium channel blockers inhibit norepinephrine mediated transmembrane calcium influx into smooth muscle. Nicardipine is the most commonly used calcium channel blocker and can be given orally preoperatively and intravenously intraoperatively. There are no prospective studies directly comparing alpha blockade and calcium channel blockers for preoperative blockade, but some physicians prefer the use of calcium channel blockers given the cardiac and renal protective effects.
Beta-Blockers
Beta-blockers should never be used before alpha-blockade in patients with pheochromocytoma or paraganglioma because this can result in unopposed alpha-adrenergic stimulation, which can cause severe vasoconstriction and a hypertensive crisis. Selective beta-1 blockers like metoprolol are usually added after the patient has achieved full alpha-blockade and develops reflex tachycardia. This tachyarrhythmia is a desired side effect indicating complete alpha-blockade has been achieved. Metoprolol tartrate is usually added at a dose of 25 mg twice daily and can be titrated up to achieve a heart rate of 60 to 80 beats per minute. Labetalol, which has both alpha-blocking and beta-blocking properties, is not recommended because it has been reported to cause a paradoxical hypertensive response presumably as a result of incomplete alpha-adrenergic blockade. Labetalol may however be effective for management of blood pressure in patients with metastatic disease and chronic elevation of catecholamines.
Metyrosine
Alpha-methyl-tyrosine or metyrosine is a tyrosine hydroxylase inhibitor which blocks conversion of tyrosine to dopamine and thereby inhibits catecholamine biosynthesis. This medication can offer significant hemodynamic stability to patients because the lack of excessive catecholamine production will help prevent the potential intraoperative hypertension and hypotension experienced before and after tumor resection. Metyrosine can cause some significant side effects including severe lethargy, gastrointestinal upset, and extrapyramidal neurological symptoms. Nevertheless, metyrosine is used in some centers in combination with phenoxybenzamine, and it is usually started 8 to 10 days before surgery in titrating doses from 250 mg once a day increasing by 250 mg every 1 to 2 days to result in a dose of 250 mg or 500 mg four times daily by the day of surgery. Metyrosine in combination with phenoxybenzamine may offer a cardiovascular advantage and has been shown in a retrospective study to decrease cardiovascular morbidity perioperatively. This agent could be considered for use in patients at high cardiovascular risk or who have very high preoperative catecholamine levels. It also has a role in metastatic disease in patients with a very high catecholamine burden who are symptomatic.
There are several retrospective studies assessing the effects of different perioperative blockade protocols in pheochromocytoma and paraganglioma. The largest retrospective series compared the perioperative management protocol used at the Mayo Clinic versus the one used at the Cleveland Clinic. The Mayo Clinic protocol used phenoxybenzamine for 1 to 4 weeks before surgery, and patients were dosed until they had orthostatic hypotension to ensure full alpha-blockade. Beta-blockers were added if the patient’s heart rate was above 80 beats per minute, and a calcium channel blocker was added if the patient was still hypertensive. In addition, metyrosine was added if the tumor was very large. The Cleveland Clinic protocol involved treating with doxazosin as first line therapy often adding a calcium channel blocker to the regimen. Beta-blockade was added if needed to treat tachycardia. The retrospective analysis showed that there was a trend towards a shorter duration of severe intraoperative hypertension with phenoxybenzamine but more postoperative hypotension with 56% of phenoxybenzamine treated patients requiring phenylephrine pressor support versus 27% of doxazosin treated patients. Nevertheless, there were no differences between treatment regimens with regard to postoperative surgical outcomes or length of hospital stay. This study has significant limitations including that it was retrospective and compared nonstandardized protocols from two institutions with different patient populations, surgeons, and intraoperative care. Other small retrospective single center studies each with 39 patients or less also have found no difference in outcomes when comparing phenoxybenzamine with selective alpha-blockers perioperative blockades regimens.
In our experience, we recommend using noncompetitive alpha-blockade with phenoxybenzamine for surgical procedures. Phenoxybenzamine is usually dosed at 10 mg twice daily and this is titrated up usually to the maximum dose of 20 mg three times a day. Common side effects include orthostatic hypotension and nasal congestion. The goal is to maintain blood pressure in the high normal range with systolic blood pressure 120 to 140 mm Hg and diastolic blood pressure 70 to 90 mm Hg. We expect to see a reflex tachycardia when full alpha-blockade is achieved. We add a beta-blocker if the heart rate is consistently above 100 beats per minute. If patients have very large tumors or very high catecholamine levels, we will add metyrosine for 8 to 14 days before surgery to decrease catecholamine production. We often see some postoperative hypotension which rarely lasts more than 24 hours and can be an indication of complete and appropriate preoperative blockade. To treat postoperative hypotension, we recommend administering intravenous fluids and, if needed, vasopressor support with alpha-agonists such as levophed.
Historically, our treatment regimen consisted of metyrosine and phenoxybenzamine for all patients with pheochromocytoma and paraganglioma; however, there was a metyrosine shortage requiring that phenoxybenzamine be used alone. Therefore, we conducted a retrospective cohort study to determine the impact of preoperative phenoxybenzamine and metyrosine versus phenoxybenzamine alone. Of 174 patients, 142 (81.6%) were in the combined therapy group versus 32 in the phenoxybenzamine only group. Both groups of patients had comparable intraoperative use of antihypertensives (83.9 versus 78.1%; p = 0.443), vasopressors (74.6 versus 87.5%; p = 0.120), and fluid resuscitation (mean, 24.4 versus 24.8 mL per min; p = 0.761). Although the perioperative complication rate did not differ significantly between the two groups, the phenoxybenzamine only patients had a 15.8% higher rate of cardiovascular complications after controlling for confounders ( p = 0.034). Compared with the combined therapy group, the phenoxybenzamine only patients had significantly more hemodynamic instability intraoperatively, with a greater range in heart rate (7.4 beats per minute; p = 0.034) and systolic blood pressure (14.8 mm Hg; p = 0.020). This study demonstrated that preoperative metyrosine improved intraoperative hemodynamic stability and decreased cardiovascular complication rates in patients undergoing surgery for pheochromocytoma/paraganglioma resection.
Acute Hypertensive Crisis
Acute hypertensive crisis can be the presenting symptom in patients with an undiagnosed pheochromocytoma or paraganglioma and can occur in patients with a known tumor. In the setting of a hypertensive emergency, we recommend controlling blood pressure with an intravenous alpha-blockade with phentolamine. If needed, other intravenous vasodilators can be used such as sodium nitroprusside or nicardipine.
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