What Is a Pheochromocytoma? Symptoms, Causes & Treatment

A pheochromocytoma is a rare tumor that grows in the adrenal glands and pumps out large amounts of adrenaline-like hormones called catecholamines, causing episodes of dangerously high blood pressure, pounding heartbeat, and drenching sweats.¹ Most of these tumors are not cancerous, but even benign ones can be life-threatening if the hormone surges go unrecognized. Because the symptoms overlap with so many common conditions, from panic attacks to ordinary high blood pressure, pheochromocytomas have long been nicknamed “the great masquerader.”²

Where the Tumor Grows and What It Does

Your adrenal glands sit on top of each kidney. The inner part of each gland, called the medulla, contains specialized cells known as chromaffin cells. These cells normally release catecholamines, the hormones adrenaline (epinephrine) and noradrenaline (norepinephrine), in small, controlled bursts when you encounter stress. A pheochromocytoma is an abnormal growth of those chromaffin cells, and it releases catecholamines unpredictably, often in massive amounts.¹

A closely related tumor can develop outside the adrenal glands, along the chain of nerve tissue that runs from the pelvis up to the base of the skull. When the tumor originates in these extra-adrenal locations, it is called a paraganglioma. The two tumors behave similarly, but paragangliomas in the head and neck tend to be smaller, while those in the trunk can be harder to detect early.³ In clinical shorthand, doctors often group them together as “PPGLs.”

The Classic Symptoms and the Ones People Miss

The textbook triad is headache, palpitations, and sweating. When all three appear together in someone with high blood pressure, the combination is a strong clinical indicator that catecholamine-producing tumor may be involved.⁴ The episodes can arrive without warning and last anywhere from a few minutes to an hour. Blood pressure may spike to alarming levels during an episode, then drop back to normal, which is why some people’s hypertension looks perfectly fine at a routine office visit.

The excess catecholamines can also produce chronic high blood pressure rather than dramatic spikes, making the tumor even easier to overlook.⁵ Beyond the classic triad, people often report tremor, a sense of impending doom, facial pallor (rather than flushing, because the catecholamines constrict blood vessels in the skin), nausea, and abdominal pain. Some people develop high blood sugar because adrenaline pushes the liver to dump glucose into the bloodstream.

One of the most underappreciated presentations is severe anxiety. Anxiety is actually the fourth most common symptom in people with pheochromocytoma, and there are documented cases of patients spending over a decade in psychiatric treatment before anyone tested for the tumor.⁶ In one reported case, a man’s major panic attacks completely disappeared after surgical removal of a malignant pheochromocytoma. The catecholamine surges had been mimicking psychiatric illness for years. Other cases describe patients diagnosed with depression and anxiety whose symptoms were actually driven by the tumor, sometimes because the classic cardiovascular signs were either mild or mistaken for the physical manifestations of a mood disorder.⁷

What Causes Pheochromocytoma

Most pheochromocytomas arise sporadically, meaning there is no identifiable inherited cause. But a surprisingly large fraction, perhaps a third or more, are linked to inherited genetic mutations. The list of known susceptibility genes includes VHL, RET, NF1, SDHB, SDHC, and SDHD.⁸ Each gene is associated with a recognizable hereditary syndrome:

VHL gene: linked to von Hippel-Lindau disease, which also raises the risk of kidney tumors, retinal growths, and central nervous system tumors.
RET gene: associated with multiple endocrine neoplasia type 2, a syndrome that includes thyroid cancer and parathyroid tumors.
NF1 gene: causes neurofibromatosis type 1, better known for the characteristic skin findings (café-au-lait spots and neurofibromas).
SDH genes (B, C, D): mutations in the succinate dehydrogenase complex are particularly associated with paragangliomas and carry a higher risk of malignant disease.

Because so many different genes can be involved, current guidelines generally recommend genetic testing for anyone diagnosed with a pheochromocytoma or paraganglioma.⁹ The results matter for the patient, since certain mutations carry higher risks of recurrence or metastatic disease, and they matter for the patient’s family, since first-degree relatives may need screening.

How It Is Diagnosed

The biochemical workup is the cornerstone. When your body breaks down catecholamines, it produces metabolites called metanephrines. Measuring these metabolites, rather than the catecholamines themselves, is far more reliable because catecholamines fluctuate from moment to moment while metanephrines remain elevated more consistently. Two main approaches exist: a blood draw for plasma free metanephrines, and a 24-hour urine collection for fractionated metanephrines.

A landmark comparison of several biochemical tests found that plasma free metanephrines had a sensitivity of about 99%, meaning they catch virtually every tumor, while urinary fractionated metanephrines had a sensitivity of about 97%.¹⁰ Earlier studies found the negative predictive value of normal plasma metanephrines was 100%, meaning that if the blood test comes back completely normal, you almost certainly do not have the tumor.¹¹

The trade-off is specificity. Plasma metanephrines are more likely to produce false positives than the urine test. One study that measured plasma metanephrines in a seated position (rather than the ideal supine position) found the specificity dropped to about 76%, compared to about 94% for the urine collection.¹² In the larger comparison study, the specificity gap was smaller but still present: about 89% for plasma free metanephrines versus roughly 88% for urinary catecholamines.¹⁰ In practice, many centers use the plasma test as a first-line screen because of its high sensitivity and add a urine collection when results are ambiguous. Stress, certain medications, caffeine, and even body position during the blood draw can nudge metanephrine levels upward, so a mildly elevated result sometimes just needs to be repeated under better conditions rather than triggering an imaging workup.

Incidentally, pheochromocytomas are sometimes found by accident. When a CT or MRI done for another reason reveals an adrenal mass, called an incidentaloma, biochemical testing for catecholamine excess is a standard part of the evaluation to make sure the mass is not a pheochromocytoma.¹³

Imaging and Finding the Tumor

Once the biochemistry confirms excess catecholamines, the next step is locating the tumor. CT and MRI are first-line imaging, and both are good at finding adrenal tumors. MRI has a slight edge for characterizing the tissue and is the only option during pregnancy, since it avoids radiation.

For more complex situations, particularly metastatic disease, hereditary syndromes, or tumors in unusual locations, functional imaging with PET/CT scans offers a significant advantage. A study comparing six different imaging methods head to head in people with sporadic pheochromocytoma found that a PET scan using a tracer called 18F-FDOPA detected every single tumor (100% positivity rate), as did MRI, while standard CT detected only about two-thirds.¹⁴

For patients with hereditary SDH-related tumors, a PET scan using 68Ga-DOTATATE has shown particular promise. In one study of SDH-associated cases, 68Ga-DOTATATE PET/CT had 100% sensitivity and specificity on a per-patient basis, compared to 85% sensitivity and 50% specificity for conventional MRI/CT. The PET results changed treatment decisions in about 40% of patients.¹⁵ Another study found that 68Ga-DOTATATE PET/CT was significantly more sensitive than the older MIBG scan for finding both primary tumors (94% vs. 75%) and metastatic lesions (85% vs. 59%).¹⁶

Preparing for Surgery

Surgery is the only cure, but you cannot simply go straight to the operating room. Manipulating the tumor during removal can trigger massive catecholamine release, causing dangerous blood pressure spikes, heart rhythm abnormalities, or cardiovascular collapse. To reduce that risk, patients undergo a carefully managed preoperative preparation lasting at least one to two weeks.

The centerpiece of preparation is alpha-adrenergic blockade, medications that block the hormone receptors responsible for constricting blood vessels. This is started first, followed later by beta-blockers if the heart rate remains too fast. Adding a beta-blocker before adequate alpha blockade is dangerous because it can worsen hypertension by leaving the blood vessel constriction unopposed. Fluid loading and, in some patients, insulin for elevated blood sugar round out the preparation.¹⁷

Two main alpha-blockers are used worldwide: phenoxybenzamine, a long-acting irreversible blocker, and doxazosin, a shorter-acting selective one. A randomized trial comparing the two found that both achieved similar control of blood pressure during surgery overall, with the median time outside the target blood pressure range being essentially identical (roughly 11-12%). However, phenoxybenzamine performed modestly better on a composite measure of hemodynamic instability, and patients in that group had lower peak blood pressure spikes and needed fewer additional blood-pressure-lowering drugs during the operation.¹⁸ Despite that edge, many centers still use doxazosin because phenoxybenzamine is expensive, hard to obtain in some countries, and causes more side effects like nasal congestion and prolonged low blood pressure after the tumor is removed.

The Surgery Itself

Laparoscopic (minimally invasive) adrenalectomy is the standard approach for most pheochromocytomas. The surgeon removes the entire adrenal gland containing the tumor. For very large tumors or those suspected of invading surrounding structures, an open surgical approach may be necessary. In patients with bilateral tumors or hereditary syndromes where tumors may recur in the remaining gland, surgeons sometimes try to preserve part of the adrenal gland (cortical-sparing surgery) to avoid lifelong steroid replacement.

Even with excellent preoperative preparation, surgery carries a real risk of wild blood pressure swings. Blood pressure can skyrocket when the surgeon handles the tumor, then plummet once the catecholamine source is clamped and removed.¹⁹ The anesthesiology team plays a critical role, using intravenous medications in real time to control surges and support blood pressure through drops. This is one surgery where the anesthesiologist’s skill is arguably as important as the surgeon’s.

Life After the Tumor Is Removed

Most patients feel dramatically better within days of surgery. The catecholamine-driven symptoms, the headaches, the sweats, the racing heart, typically vanish almost immediately. Blood pressure normalizes in about a third of patients, and most others see significant improvement even if they still need some blood pressure medication.²⁰ In a prospective study, about a third of patients who were hypertensive before surgery still had persistent hypertension three months later, and older age and coexisting diabetes were associated with that persistence. Diabetes itself improved in most patients who had it, and overall quality of life scores increased significantly after the operation.²¹

One important reality is that these tumors can come back, sometimes years later. This is especially true for people with hereditary mutations. Follow-up with periodic biochemical testing (the same metanephrine measurements used for diagnosis) is recommended indefinitely. There is no universally agreed-upon schedule, but annual or biannual testing is common practice.

When the Tumor Is Malignant

There is no reliable way to tell whether a pheochromocytoma is malignant just by looking at it under a microscope. The World Health Organization now classifies all pheochromocytomas and paragangliomas as having some metastatic potential, rather than calling them “benign” or “malignant” based on pathology alone. The only definitive proof of malignancy is the presence of tumor cells in locations where chromaffin tissue does not normally exist, such as bone, liver, or distant lymph nodes.

Pathologists have developed scoring systems to try to estimate the risk. The PASS score, introduced in 2002, looks at features like vascular invasion and cell division rate, but multiple studies have found significant disagreement between pathologists reviewing the same slides, and the score has not reliably predicted which tumors will metastasize.²² A newer system called the GAPP score combines pathology findings with clinical data, and it has shown a stronger link to metastatic disease. One study found that tumors with intermediate GAPP scores had roughly three times the risk of developing distant metastases compared to those with favorable scores.²³ A validation study confirmed that GAPP was better at separating metastatic from non-metastatic tumors and proposed a modified version that improved positive predictive value further.²⁴ Even so, no scoring system is reliable enough to replace long-term surveillance.

For people who do develop metastatic disease, treatment options have expanded considerably in recent years. Older approaches include combination chemotherapy (a regimen of cyclophosphamide, vincristine, and dacarbazine). Targeted radionuclide therapies deliver radiation directly to tumor cells, and two of these, high-specific-activity 131I-MIBG and 177Lu-DOTATATE, are now recommended in national guidelines for metastatic cases.²⁵ More recently, oral targeted therapies have arrived. Multi-target drugs like sunitinib and cabozantinib have shown substantial disease control in prospective trials. Most notably, belzutifan, which blocks a protein involved in oxygen-sensing pathways, became the first oral drug approved by the FDA specifically for metastatic pheochromocytoma and paraganglioma, demonstrating durable responses and improvement in hypertension.²⁶

Pheochromocytoma in Children

The tumor looks quite different in children compared to adults. In a large study comparing pediatric and adult cases, about 80% of childhood pheochromocytomas were hereditary, compared to roughly half in adults. Children were also far more likely to have tumors in extra-adrenal locations (about two-thirds of pediatric cases), to have more than one tumor, and to present with metastatic disease at diagnosis.²⁷ The genetic mutations driving pediatric tumors also tend to cluster differently, with a much higher proportion falling into a category associated with noradrenergic biochemistry. Practically, this means that some standard diagnostic tests are less sensitive in children because the tumors may not produce much metanephrine (the metabolite of adrenaline), relying instead on normetanephrine (from noradrenaline). The high rate of inherited disease in pediatric patients makes genetic testing especially critical, both for managing the child and for screening family members.

Pheochromocytoma During Pregnancy

Historically, an undiagnosed pheochromocytoma during pregnancy was catastrophic, with very high rates of maternal and fetal death. The danger comes from the fact that the hormonal surges can be mistaken for far more common pregnancy complications like preeclampsia or gestational hypertension. More recent evidence suggests outcomes have improved substantially when the tumor is recognized during pregnancy and managed with alpha-blockade.²⁸

Diagnosis in pregnant patients relies on the same biochemical tests (plasma or urine metanephrines), but imaging is limited to MRI and ultrasound to avoid radiation exposure. Treatment during pregnancy consists of alpha-blockade, with careful attention to dosing since over-treating blood pressure can compromise blood flow to the placenta.²⁹ If the tumor is found before the third trimester, many experts recommend surgical removal during the second trimester, when the risk to the pregnancy is relatively low. If the diagnosis comes in the third trimester, surgery is usually delayed until after delivery, as long as blood pressure can be controlled medically. Cesarean delivery is common in these patients, though vaginal delivery appears safe in selected, well-managed cases.²⁸ Decisions about timing of surgery and route of delivery are individualized, ideally by a multidisciplinary team experienced with this rare intersection of endocrine tumor and obstetric care.

What Triggers an Episode

People living with an unresected pheochromocytoma quickly learn that certain activities or substances can provoke a catecholamine surge. Physical exertion, straining during a bowel movement, abdominal pressure from bending or lifting, and even certain foods containing tyramine (like aged cheeses and red wine) are commonly reported triggers. Some medications are particularly dangerous: dopamine antagonists used for nausea, certain anesthetics, and beta-blockers given without prior alpha-blockade can all precipitate a crisis. Glucocorticoids and contrast dye used in imaging procedures have also been implicated. For surgeons and emergency physicians, simply palpating the abdomen in someone with an undiagnosed tumor can set off a life-threatening spike. The unpredictable nature of these attacks is part of what makes the tumor so disruptive to daily life and so urgent to diagnose and treat.

One underappreciated consequence of chronic catecholamine excess is what it does to the cardiovascular system over time. Animal models of pheochromocytoma have shown that sustained exposure to very high noradrenaline levels causes the heart and blood vessels to downregulate their receptors for that hormone, essentially trying to protect themselves from overstimulation. In rats with transplanted pheochromocytomas, heart receptor density dropped significantly, and the blood vessels became dramatically less responsive to noradrenaline, with one study reporting an eightfold decrease in the sensitivity of the aorta.³⁰ This desensitization helps explain why some patients with pheochromocytoma actually have normal blood pressure readings between episodes, and why blood pressure can crash abruptly after tumor removal, once the catecholamine flood stops but the body’s receptors have not yet recovered their normal sensitivity.

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