Pheochromocytoma & Paraganglioma

Essentials of Diagnosis

• Attacks of headache, perspiration, palpitations, anxiety; multisystem crisis

• Hypertension: sustained but often paroxysmal, especially during surgery or delivery; may be orthostatic

• Elevated plasma free fractionated metanephrines with normal serum thyroxine (T₄) and thyroid-stimulating hormone (TSH)

• About 50% discovered as an incidental mass on imaging

• Frequent germline mutations

General Considerations

• Pheochromocytomas

  • Arise from the adrenal medulla

  • Usually secrete both epinephrine and norepinephrine

• Paragangliomas

  • Arise from sympathetic paraganglia and often metastasize

  • About 50% secrete norepinephrine; the rest are nonfunctional or secrete only dopamine, normetanephrine, or chromogranin A (CgA)

  • Tumoral secretion of norepinephrine or neuropeptide Y causes hypertension

  • Excessive epinephrine causes tachyarrhythmias

• Pheochromocytomas or paragangliomas may be located in either or both adrenals or anywhere along the sympathetic nervous chain, and sometimes in the mediastinum, heart, or bladder

• Attacks can be spontaneous; however, they can also be triggered by

  • Exercise

  • Bending

  • Lifting

  • Emotional stress

  • Surgery or minor procedures

  • Certain drugs (eg, fluoxetine, monoamine oxidase inhibitors, caffeine, nicotine, decongestants, amphetamines, cocaine, ionic intravenous contrast, and epinephrine)

• Germline mutations causing some hereditary forms of pheochromocytoma and paraganglioma identified in genes encoding mitochondrial succinate dehydrogenase subunit B (SDHB), D (SDHD), and rarely C (SDHC)

• Non-chromaffin paragangliomas arise in the head or neck, particularly in the carotid body, jugular-tympanic region, or vagal body; only about 4% secrete catecholamines

Demographics

• Pheochromocytomas are rare: < 0.4% of hypertension cases

• Incidence is higher with moderate to severe hypertension

• Yearly incidence is 6 new cases per million; however, many cases are undiagnosed during life, since the prevalence in autopsy series is 1 in 2000

Symptoms and Signs

• Some patients are normotensive and asymptomatic

• Manifestations are variable, but typically include

  • Hypertension (81%) that may be paroxysmal or sustained

  • Headache (60%)

  • Palpitations (60%)

  • Diaphoresis (52%)

• About 58% of patients have episodic nonspecific "spells"

• Other symptoms include

  • Anxiety (often with a sense of impending doom)

  • Weakness/fatigue

  • Dyspnea

  • Nausea/vomiting

  • Tremor

  • Dizziness

  • Chest pain

  • Abdominal pain

  • Paresthesias

  • Constipation

• Vasospasm changes during attack

  • Raynaud syndrome

  • Mottled cyanosis and facial pallor

  • Facial flushing and drenching sweats may occur as attack subsides

• Epinephrine secretion may cause

  • Episodic tachyarrhythmias

  • Orthostatic hypotension

  • Syncope

• Cardiac manifestations include acute coronary syndrome, cardiomyopathy, heart failure, and potentially fatal dysrhythmias

• Abdominal pain, nausea, vomiting, constipation, and even ischemic bowel can occur

• Large or hemorrhagic abdominal tumors can also cause abdominal pain

• Patients may experience nervousness and irritability, increased appetite, and loss of weight

• During pregnancy, pheochromocytomas can produce hypertension and proteinuria, mimicking eclampsia; vaginal delivery can produce hypertensive crisis followed by postpartum shock

• Catecholamine-induced cardiomyopathy can present with shock

• Confusion, psychosis, paresthesias, seizures, transient ischemic attacks, or stroke may occur with cerebrovascular vasoconstriction or hemorrhagic stroke

• Aortic aneurysms may dissect and rupture

• Multisystem crisis

  • Can occur spontaneously or it may be provoked by surgery, vaginal delivery, or treatment of metastatic disease

  • Manifestations include

    • Severe hypertension or hypotension

    • Acute respiratory distress syndrome

    • Cardiomyopathy with acute heart failure

    • Kidney failure

    • Liver failure

    • Death

Differential Diagnosis

• Other cause of secondary hypertension, eg, primary hyperaldosteronism, Cushing syndrome, renal artery stenosis

• Panic attacks

• Thyrotoxicosis

• Acute intermittent porphyria

• Carcinoid syndrome

• Paroxysmal tachycardia

• Preeclampsia-eclampsia

• Sleep apnea (catecholamines and metanephrines may be elevated)

Laboratory Tests

• Elevated WBC and glucose common

• Elevated erythrocyte sedimentation rate and plasma renin activity

• 24-h urine specimen for total and fractional catecholamines, metanephrines, and creatinine

  • > 2.2 mcg total metanephrine/mg creatinine and > 135 mcg total catecholamines/g creatinine usual

  • Urinary total metanephrines has 97% sensitivity

  • ~10% of hypertensive patients have misleadingly elevated level of tests

• Interference with assays (eTable 26–2)

  • Drugs: acetaminophen, labetalol, sotalol, buspirone, mesalamine, methyldopa, levodopa, and sulfasalazine

  • Foods: bananas, caffeine, coffee, peppers

  • Conditions: acute illness, vigorous exercise, severe emotion, carcinoid, brain lesions, kidney disease

• Because plasma levels of free metanephrines fluctuate and are lower when the patient is supine than when ambulatory,

  • Blood should ideally be drawn with the patient in a quiet room for at least 15 minutes

  • The test is 97% sensitive, so normal levels rule out pheochromocytoma and paraganglioma with some certainty

• Serum chromogranin A elevated in 85%; levels correlate with tumor size, being higher in patients with metastatic disease

• Clonidine suppression testing can be helpful to distinguish whether elevated plasma free normetanephrine levels are physiologic or indicative of pheochromocytoma

Imaging Studies

• Glucagon should not be used during scanning because it can provoke hypertensive crisis, especially uncontrolled hypertension

• Noncontrast CT scan of the abdomen is performed, with thin sections through the adrenals

• Only 0.5% of pheochromocytomas have a density below 10 HU

• For masses with a density greater than or equal to 10 HU, a contrast washout study is sometimes performed

  • A relative contrast washout of less than 40% is suspicious for pheochromocytoma or metastasis

  • However, a relative contrast washout of greater than or equal to 40% is not helpful

• If no adrenal tumor is found, CT scan is extended to abdomen, pelvis, and chest

• Whole-body ¹²³I metaiodobenzylguanidine (MIBG) single-photon emission computed tomography (SPECT) scan can localize tumors

• Drugs reducing MIBG update by pheochromocytoma

  • Tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors (for 2 weeks)

  • Amphetamines, phenothiazines, haloperidol

  • Cyclobenzaprine (for 6 weeks)

  • Labetalol

  • Decongestants

  • Cocaine

  • Diet pills

• Positron emission tomography (PET)/CT using [¹⁸F] fluorodeoxyglucose (¹⁸FDG) or ¹⁸F-dopamine may demonstrate tumors that are not visible on ¹²³I-MIBG scanning

• ⁶⁸Ga-DOTATOC-PET/CT is the most sensitive scan, detecting nearly 90% of paragangliomas and metastases

Medications

• Preoperative alpha-adrenergic blockade

  • Phenoxybenzamine, 10 mg orally every 12 hours, increasing by about 10 mg/day about every 3 days until hypertension is controlled

  • Usual maintenance dose ranges from 10–120 mg/day

  • Doxazosin (half-life 22 hours), a selective alpha-1-blocker, may also be used in doses of 2–32 mg/day

  • Optimal blockade achieved when supine blood pressure (BP) < 140/90 mm Hg and standing BP > 80/45 mm Hg

• Calcium channel blockers also effective and better tolerated than alpha-blockers

  • Nifedipine ER is initially given orally at a dose of 30 mg/day, increasing the dose gradually to a maximum of 60 mg twice daily

• Beta-blockers are often required by most patients after institution of alpha-blockade or calcium channel blockade to avoid paradoxical worsening of hypertension

• Maintain BP control at least 4–7 days or until optimal cardiac status established

• Preoperative autotransfusion and generous intraoperative intravenous fluid reduces risk of postresection hypotension

• Postoperative shock treated with intravenous saline or colloid and high doses of intravenous norepinephrine

• For inoperable or metastatic tumors, metyrosine, 250 mg four times daily orally

  • Increase daily by increments of 250–500 mg to maximum 4 g/day to reduce catecholamine synthesis

  • Side effects common

• For metastatic pheochromocytomas, combination chemotherapy (eg, intravenous cyclophosphamide, vincristine, and dacarbazine) over 2 days in cycles that are repeated every 3 weeks

• Another chemotherapy regimen, temozolomide 250 mg/day orally for 5 days, repeating the cycle every 28 days

• Sunitinib, a tyrosine kinase inhibitor, can also produce remissions, given in doses of 50 mg/day for 4 weeks on and then 2 weeks off; alternatively, a dose of 37.5 mg/day can be given continuously

• For patients with osteolytic bone metastases, intravenous zoledronic acid or subcutaneous denosumab may be administered

Surgery

• Laparoscopic removal of tumor or tumors is treatment of choice

• Open laparotomy for large tumors

• Nicardipine, 2–6 mcg/kg/min, or nitroprusside, 0.5–10 mcg/kg/min, continuous intravenous infusion, for severe intraoperative hypertension

• Atenolol (1 mg boluses), esmolol, or lidocaine intravenously for tachyarrhythmias

Therapeutic Procedures

• High-dose ¹³¹I-MIBG for metastatic pheochromocytomas

• External beam radiation for patients with osteolytic bone metastases

• Peptide receptor radionuclide treatment (PRRT)

  • Uses a radioisotope-tagged somatostatin analogue against neuroendocrine tumors that express somatostatin receptors

  • ¹⁷⁷Lu-DOTATATE (Lutathera) is FDA-approved for treating patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs)

  • It is being used off-label and on protocol to treat patients with metastatic pheochromocytoma and paraganglioma tumors

• Surgical decompression and kyphoplasty may be required for patients with vertebral metastases and spinal cord compression

Follow-Up

• Recheck urinary catecholamine levels 2 weeks after surgery to exclude multiple or metastatic tumors

• Check ¹³¹I-MIBG whole-body scan 2–3 months postoperatively

• Thereafter, recheck symptoms and BP regularly

• Lifetime clinical surveillance for recurrence or metastases

• Monitor chromogranin A if elevated before surgery

Complications

• Complications of severe hypertension

• Catecholamine-induced cardiomyopathy

• Severe heart failure and cardiovascular collapse

• Sudden death from cardiac arrhythmia

• Hypertensive crises with sudden blindness or stroke

• Multisystem crisis and ARDS can occur acutely and thus the initial manifestation of pheochromocytoma may be hypotension (or even shock) or respiratory failure

Prognosis

• Malignancy determined by whether metastases are present or develop

• Prognosis is good for patients with smaller, benign pheochromocytomas that are resected before causing cardiovascular damage

• In about 25%, hypertension persists or returns in spite of successful surgery

• Surgical mortality rate < 3%

• Prognosis is variable for patients with metastatic pheochromocytoma or paraganglioma

• Death may occur from hypertensive crisis induced by intravenous ionic contrast, glucagons, or needle biopsy