Pheochromocytoma and Paraganglioma: Patient Guide

Both tumors grow from neural crest tissue. Those are the cells that build much of the nervous system before birth. The difference is where they end up.

A pheochromocytoma grows in the adrenal medulla. That is the inner core of the adrenal gland, which sits on top of each kidney. A paraganglioma grows outside the adrenal gland. It forms in sympathetic or parasympathetic nerve tissue elsewhere in the body.

They are uncommon. NCI puts the rate at 2 to 8 cases per million people each year. Among people with high blood pressure, 0.1% to 1% turn out to have one. Most cases appear between the ages of 20 and 50.

Many of these tumors make catecholamines. Those are the hormones behind the fight-or-flight response. MedlinePlus names three. They are dopamine, norepinephrine, and epinephrine, also called adrenaline.

NCI lists the classic signs. They are high blood pressure, headache, sweating, forceful palpitations, tremor, and a pale face. Symptoms often arrive in paroxysms, meaning sudden bursts. NCI names triggers too. Those include exertion, injury, surgery, and foods rich in tyramine, such as red wine, chocolate, and cheese.

Two numbers reframe the picture. Sustained high blood pressure between episodes, not only during them, occurs in 50% to 60% of patients. And about half of patients have no symptoms at all, their tumor turning up on abdominal imaging done for another reason or through genetic testing in an at-risk family.

Diagnosis starts with biochemistry, not a scan. NCI gives performance figures for both main tests.

Plasma free fractionated metanephrines are preferred for first-line screening. Sensitivity is 97% to 99%. That means very few true cases are missed. Specificity is 85%. That means false alarms happen.

24-hour urine fractionated metanephrines run the other way. Sensitivity is 77% to 90%. Specificity is 98%. That makes the urine test useful for confirming a positive blood result.

Preparation matters, because ordinary life can push these levels up. MedlinePlus says to skip caffeine for 2 to 3 days before testing. That covers coffee, tea, energy drinks, and chocolate. It also says to avoid alcohol, tobacco, bananas, citrus fruits, and foods with vanilla. Limit stress and hard exercise. Tell your provider every medicine you take.

A 24-hour urine collection means saving every void for a full day. It goes in a supplied container kept in the refrigerator. It ends exactly 24 hours after the start time. Missing one void ruins the test.

NCI gives figures for the scans as well.

• CT or MRI: sensitivity 90% to 100%, specificity 70% to 80%.
• 123I-MIBG scintigraphy: sensitivity 80% to 90%, specificity 95% to 100%.
• 68Ga-DOTATATE PET/CT: an emerging functional imaging option.

Notice the pattern. CT and MRI are good at finding a mass. They are weaker at proving what it is. The functional scans do better at confirming the tumor type.

This fact changes the most for a family. NCI reports that about 35% of all cases carry a germline mutation. That means an inherited change present from birth.

Inherited cases also show up earlier. NCI gives an average age of 24.9 years at diagnosis for hereditary cases. For sporadic cases it is 43.9 years.

NCI names the genes. They include SDHB, SDHD, SDHC, SDHA, and SDHAF2. The list also holds VHL, for von Hippel-Lindau disease, and RET, for MEN2A and MEN2B. NF1 causes neurofibromatosis type 1. TMEM127, MAX, and FH round out the panel.

NCI's testing guidance turns on age. Testing is often recommended for anyone diagnosed before age 40. The same holds for tumors on both sides, tumors in more than one site, and a positive family history. Testing should be considered for ages 40 to 50. It is not recommended above age 50.

SDHB deserves its own line. NCI reports SDHB variants in more than 40% of metastatic cases. And 25% to 50% of people with an SDHB variant go on to develop metastatic disease.

Surgery to remove the tumor is the definitive treatment for local and regional disease. But handling the tumor can flood the blood with catecholamines. Blood pressure can then spike during the operation.

NCI is explicit. Alpha-adrenergic blockade should begin at diagnosis. It should be pushed as high as tolerated before surgery. The goal is to prevent life-threatening heart and vessel events. Phenoxybenzamine is the agent of choice. Prazosin, terazosin, and doxazosin are alternatives. One to three weeks of blockade is usually enough.

The order is the part to remember. Beta-blockers start only after alpha blockade is in place. Giving a beta-blocker first can make blood pressure worse.

If a new doctor proposes a beta-blocker for palpitations before this diagnosis is settled, say the tumor is being investigated.

Only 3% to 8% of patients have metastases at diagnosis. After removal of local disease, NCI reports recurrence in 6.5% to 16.5%, usually 5 to 15 years after surgery. About 15% to 25% of those recurrences go on to spread to distant sites. Common sites are lymph nodes, bone, lungs, and liver. Five-year survival with metastatic disease is 50% to 70%.

Options for metastatic or unresectable disease are palliative, and NCI names them.

• Chemotherapy with cyclophosphamide, vincristine, and dacarbazine. Median survival was 3.3 years. The partial response rate was 44%.
• Tyrosine kinase inhibitors including sunitinib, cabozantinib, and axitinib.
• 131I-MIBG therapy. About 60% of metastases take up MIBG, and estimated 5-year survival was 64%.
• Other options including external-beam radiation, radiofrequency ablation, cryoablation, and somatostatin receptor-targeted therapy.

NCI says long-term follow-up is essential for every patient. That holds even when the first pathology showed nothing worrying. It means yearly lab testing and periodic imaging, continued for life.

If you were treated years ago and nobody has drawn metanephrines recently, that is worth raising.

• A paroxysm with chest pain, trouble breathing, weakness on one side, trouble speaking, or vision loss. Call 911. Do not drive yourself.
• A severe headache with pounding heartbeat, drenching sweat, and pale skin, especially if it started after exertion, an injury, or a tyramine-rich meal. This can be a hormone surge driving blood pressure to a dangerous level. Call 911 or go to an emergency department; it is not a wait-and-phone situation.
• Fainting, or a blood pressure reading far outside your usual range in either direction. Call 911 if the person has passed out, cannot be roused, or looks grey and clammy. Otherwise ring the team straight away and be seen the same day.
• Any planned procedure before your alpha blockade is in place. That includes dental surgery and endoscopy. Tell the team about the tumor first, before the appointment. NCI names surgery itself as a trigger.

• Was my diagnosis made on plasma metanephrines, urine metanephrines, or both?
• Which functional scan was used, and was the tumor avid on it?
• Has genetic testing been ordered, and which gene panel?
• If a gene is found, who in my family should be tested and starting at what age?
• Am I fully alpha-blocked, and for how many weeks before surgery?
• What is my lifelong follow-up schedule for labs and imaging?

For related reading, see Pathology Reports, Getting a Second Opinion, and Biomarker Testing and Precision Medicine.

• National Cancer Institute — Pheochromocytoma and Paraganglioma Treatment (PDQ), Health Professional Version
• MedlinePlus — Catecholamine Tests