Secondary Hypertension: Pheochromocytoma and Paraganglioma

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 ).

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%.

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 .

Medications