Pheochromocytoma is a rare tumor of the adrenal gland that floods the body with stress hormones, sometimes producing dramatic spikes in blood pressure, a pounding heart, and drenching sweats. It arises from the chromaffin cells of the adrenal medulla, the inner core of the small glands that sit on top of each kidney, and its hallmark is the uncontrolled production and release of catecholamines: dopamine, norepinephrine, and epinephrine.1PubMed Central. Intricacies of the Molecular Machinery of Catecholamine Biosynthesis and Secretion by Chromaffin Cells of the Normal Adrenal Medulla and in Pheochromocytoma and Paraganglioma Because these are the same chemicals your body releases in a “fight or flight” response, an overproducing tumor can wreak havoc on the cardiovascular system and mimic a wide range of other conditions, earning it a reputation as one of medicine’s great masqueraders.
What the Tumor Actually Does
Your adrenal medulla normally produces catecholamines in a tightly regulated way, releasing them in response to stress and then quickly shutting down. A pheochromocytoma short-circuits that regulation. The tumor cells keep synthesizing and dumping catecholamines into the bloodstream, either in unpredictable bursts or as a steady drip. The WHO classifies it as an intra-adrenal paraganglioma, meaning it belongs to a broader family of tumors that can arise anywhere along the chain of nerve-related tissue running from the base of the skull to the pelvis.2PubMed Central. Phaeochromocytoma: a catecholamine and oxidative stress disorder When a tumor in this family grows outside the adrenal gland, it is called a paraganglioma rather than a pheochromocytoma, though the two share most of the same biology and clinical concerns.
The catecholamine profile matters clinically. Some tumors predominantly secrete norepinephrine, which tends to cause sustained high blood pressure. Others produce mainly epinephrine, which is more likely to cause episodic surges and the classic triad of symptoms. A smaller subset produces dopamine, which can be tricky because dopamine-secreting tumors sometimes cause fewer of the textbook symptoms, delaying diagnosis. The specific mix of hormones a tumor releases seems to depend more on where in the body it sits and what type of cell it originated from than on the genetic mutation driving it.3PubMed Central. Pheochromocytoma and paraganglioma: genotype versus anatomic location as determinants of tumor phenotype
Recognizing the Symptoms
The textbook presentation is a triad of paroxysmal hypertension (sudden blood pressure spikes), sweating, and headaches, often accompanied by palpitations.4PubMed. Diagnosis and management of pheochromocytoma: a practical guide to clinicians These episodes can last a few minutes or several hours and are sometimes triggered by physical exertion, certain medications, abdominal pressure, or even specific foods. Between episodes, some people feel completely normal while others have persistently elevated blood pressure.
The trouble is that this triad is far from universal. Many patients present with just one or two of the classic features, and a meaningful number have sustained rather than episodic hypertension, which looks indistinguishable from ordinary high blood pressure. Others experience anxiety, tremor, nausea, or a feeling of impending doom during attacks. Still others have no symptoms at all and are found only because an imaging scan done for something else reveals an adrenal mass. This variability is why pheochromocytoma is often diagnosed late or initially misattributed to anxiety disorders, panic attacks, or essential hypertension.
Excess catecholamines can also damage the heart directly. In rare cases, the hormone surge triggers a condition called Takotsubo syndrome, a form of transient heart failure in which the left ventricle balloons out and stops contracting normally. Pheochromocytoma-induced Takotsubo is life-threatening and driven by direct toxic effects of catecholamines on heart muscle cells, coronary artery spasm, and microvascular dysfunction.5PubMed Central. Takotsubo syndrome with underlying pheochromocytoma This is one reason a pheochromocytoma crisis can be fatal if the tumor is not recognized and treated.
Biochemical Testing
If a doctor suspects pheochromocytoma, the first step is a blood or urine test measuring metanephrines, which are breakdown products of catecholamines. These metabolites are more reliable than measuring the catecholamines themselves because the tumor continuously produces metanephrines at a steady rate, whereas catecholamine levels can spike and fall quickly, potentially giving a normal reading between episodes.
Two main approaches exist: a plasma test (a blood draw) and a 24-hour urine collection. Both are highly sensitive, meaning they catch the overwhelming majority of true tumors. In head-to-head comparisons, both plasma and urine metanephrines show sensitivity around 95-97%.6PubMed. Diagnostic accuracy of free and total metanephrines in plasma and fractionated metanephrines in urine of patients with pheochromocytoma The difference is in specificity: urine metanephrines tend to produce fewer false positives. One study found that the plasma test drawn in a seated position had a specificity of about 76%, compared with roughly 94% for the urine test.7PubMed. Diagnostic accuracy of plasma free metanephrines in a seated position compared with 24-hour urinary metanephrines in the investigation of pheochromocytoma
In practice, the choice often depends on clinical context. For patients at low risk of having the tumor, such as someone being screened because of a mildly suspicious adrenal mass, the urine test is preferred because its lower false-positive rate means fewer unnecessary follow-up scans and biopsies. For patients at high risk, like those with a known genetic syndrome predisposing them to pheochromocytoma, the plasma test is often favored because its slightly higher sensitivity means it is less likely to miss a real tumor.8The Journal of Clinical Endocrinology & Metabolism. A Comparison of Biochemical Tests for Pheochromocytoma: Measurement of Fractionated Plasma Metanephrines Compared with the Combination of 24-Hour Urinary Metanephrines and Catecholamines
When a Mass Shows Up Unexpectedly
An increasingly common scenario is the incidental discovery of an adrenal mass on a CT or MRI done for an unrelated reason, such as investigating abdominal pain or staging a different cancer. These so-called adrenal incidentalomas are found in a significant fraction of abdominal scans, and while most turn out to be benign, non-functioning adenomas, current guidelines recommend that every adrenal incidentaloma be tested biochemically for pheochromocytoma before any procedure is performed on it.9Endocrinology and Metabolism. Clinical Guidelines for the Management of Adrenal Incidentaloma – Section: Pheochromocytoma Operating on or even biopsying an unsuspected pheochromocytoma without proper preparation can trigger a catastrophic catecholamine crisis.
Some pheochromocytomas are “silent,” meaning they do not produce enough catecholamines (or the right type) to cause obvious symptoms. These can still be detected biochemically or suspected on imaging. One characteristic pattern is an adrenal mass larger than four centimeters with high density on an unenhanced CT scan and slow contrast washout.10PubMed Central. Silent pheochromocytoma in adrenal incidentaloma: unveiling clinical and radiological characteristics That combination should raise suspicion even if the patient feels fine.
Finding the Tumor With Imaging
Once biochemistry confirms excess catecholamines, the next step is locating the tumor. A standard CT or MRI of the abdomen finds most adrenal pheochromocytomas easily. But when the tumor is extra-adrenal, multifocal, or potentially metastatic, functional nuclear medicine scans become essential because they can survey the whole body.
The traditional workhorse has been MIBG scintigraphy, a scan using a radioactive compound that is taken up by catecholamine-producing tissue. More recently, a newer PET/CT scan using a tracer called 68Ga-DOTATATE has shown superior sensitivity in many studies. In one comparison, 68Ga-DOTATATE PET/CT achieved 100% sensitivity in pheochromocytoma and paraganglioma patients on a per-patient basis, compared with about 78% for MIBG.11PubMed Central. 68Ga-DOTATATE PET/CT Compared with 131I-MIBG SPECT/CT in the Evaluation of Neural Crest Tumors The PET scan is especially good at finding head and neck paragangliomas and bony metastases that MIBG tends to miss.12PubMed. A comparison of the performance of ⁶⁸Ga-DOTATATE PET/CT and ¹²³I-MIBG SPECT in the diagnosis and follow-up of phaeochromocytoma and paraganglioma
That said, the two scans sometimes pick up different lesions. In a series of 15 patients, five had tumors visible only on 68Ga-DOTATATE and two had tumors visible only on MIBG.13PubMed. A comparison of the performance of ⁶⁸Ga-DOTATATE PET/CT and ¹²³I-MIBG SPECT in the diagnosis and follow-up of phaeochromocytoma and paraganglioma The choice of imaging modality, and whether to use both, depends on the clinical situation. In a case involving a young person with Von Hippel-Lindau syndrome, for instance, MIBG identified the adrenal pheochromocytomas that DOTATATE missed because DOTATATE was more avidly taken up by a pancreatic lesion instead.14PubMed. Comparison of 68 Ga-DOTATATE PET/CT and 123 I-MIBG SPECT/CT in the Imaging of Functional Pheochromocytoma in an Adolescent Patient With Von Hippel-Lindau Syndrome
The Genetics Behind It
Pheochromocytoma has one of the strongest genetic underpinnings of any tumor. Mutations in at least six well-known genes, including VHL, RET, NF1, SDHB, SDHC, and SDHD, can cause or predispose a person to developing it.15PubMed. A common pathway for genetic events leading to pheochromocytoma And the list keeps growing; researchers have identified additional susceptibility genes in recent years. Genetic events, either inherited or occurring spontaneously in the tumor itself, can now be found in at least 60% of cases.16PubMed Central. Pheochromocytoma and paraganglioma: genotype versus anatomic location as determinants of tumor phenotype
Many of these mutations tie into well-known hereditary syndromes. VHL mutations cause Von Hippel-Lindau disease, RET mutations cause multiple endocrine neoplasia type 2, NF1 mutations cause neurofibromatosis type 1, and SDH subunit mutations cause familial paraganglioma syndromes. Particularly important is the SDHB gene, because mutations in it carry a significantly higher risk of metastatic disease and can cause both pheochromocytoma and paraganglioma.17PubMed Central. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma
Because the genetic link is so strong, current practice increasingly favors genetic testing for every patient diagnosed with pheochromocytoma, not just those with a family history or young age at diagnosis. The genotype has direct clinical implications: it predicts the likelihood of bilateral tumors, extra-adrenal disease, metastatic potential, and the need for screening of family members.
Preparing for Surgery
Surgery is the definitive treatment, but operating on a catecholamine-secreting tumor without preparation is dangerous. Manipulating the tumor during surgery can trigger massive catecholamine release, causing severe blood pressure swings, cardiac arrhythmias, or stroke. To prevent this, patients receive preoperative alpha-adrenergic blockade, typically for at least two weeks before surgery.18PubMed. Pheochromocytoma: a review on preoperative treatment with phenoxybenzamine or doxazosin The alpha-blocker relaxes blood vessels, counteracting the constricting effect of excess catecholamines. A beta-blocker is usually added after the alpha-blocker is on board, but never before, because blocking beta receptors alone can worsen hypertension by leaving the alpha-mediated vasoconstriction unopposed.
Two alpha-blockers dominate practice: phenoxybenzamine, an older nonselective agent, and doxazosin, a newer selective one. Phenoxybenzamine provides more complete alpha-blockade, as shown by better blood pressure control during phenylephrine challenge testing. But in a randomized trial, the two drugs performed comparably on the main endpoint of cumulative time spent outside the blood pressure target during surgery, with phenoxybenzamine at about 11% and doxazosin at about 12%.19The Journal of Clinical Endocrinology & Metabolism. Efficacy of α-Blockers on Hemodynamic Control during Pheochromocytoma Resection: A Randomized Controlled Trial Phenoxybenzamine did show a lower overall hemodynamic instability score and fewer peak blood pressure spikes, but the clinical difference between the two was modest enough that many centers now use doxazosin routinely, particularly because phenoxybenzamine is harder to obtain and more expensive in many countries.20PubMed. Comparison of Preoperative Alpha-blockade for Resection of Paraganglioma and Pheochromocytoma
What Happens During and After the Operation
Most pheochromocytomas are now removed laparoscopically. Even with good alpha-blockade, blood pressure swings during surgery remain common. The main independent risk factors for intraoperative hemodynamic instability are tumor size and a history of hypertension before surgery.21PubMed Central. Risk factors for hemodynamic instability during laparoscopic resection of pheochromocytoma Larger tumors produce more catecholamines and are harder to handle without squeezing, so the surgical team keeps vasoactive drugs on standby.
Once the tumor is out, the catecholamine source vanishes almost instantly, and a paradoxical drop in blood pressure can follow. Patients may also develop low blood sugar (hypoglycemia) in the hours after surgery. The mechanism relates to insulin: high catecholamine levels suppress insulin secretion, and when those levels suddenly crash, insulin rebounds and can overshoot. In one large series, about 4% of patients experienced postoperative hypoglycemia, with most episodes occurring in the first 24 hours. Larger tumors, higher preoperative metanephrine levels, and longer operative times were all associated with higher risk.22Surgery. Hypoglycemia after resection of pheochromocytoma Encouragingly, the rate of postoperative hypoglycemia appears to be falling over time, likely because more aggressive preoperative alpha-blockade and better perioperative glucose monitoring have become standard. One recent study found zero episodes of hypoglycemia in their contemporary cohort, compared with 28% in an earlier era at the same institution.23PubMed Central. The frequency of postoperative hypoglycemia after pheochromocytoma surgery is decreasing
Postoperative hypotension is also common, with roughly 30% of patients experiencing it within six hours of surgery in one prospective series. The severity correlates with how much catecholamine the tumor was producing before the operation.24PubMed Central. Changes in blood pressure, blood sugar, and quality of life in patients undergoing pheochromocytoma surgery: a prospective cohort study
Metastatic Potential and Risk Scoring
One of the most important shifts in thinking about pheochromocytoma is that pathologists no longer divide these tumors neatly into “benign” and “malignant.” The WHO’s 2017 classification recognizes that all pheochromocytomas and paragangliomas carry some metastatic potential, and it reclassified them all as malignant tumors in the formal coding system.25PubMed Central. Risk Stratification on Pheochromocytoma and Paraganglioma from Laboratory and Clinical Medicine That does not mean they all spread; it means clinicians should think in terms of risk stratification rather than a binary label.
Several scoring systems have been developed to predict metastatic risk, including PASS, GAPP, COPPS, ASES, and SGAP. A recent validation study found that purely pathology-based scores like PASS and GAPP had limited predictive ability, with relatively low discriminative performance. The COPPS and ASES scores, which incorporate clinical and biochemical variables alongside pathology, performed better.26PubMed. Validation and Evaluation of 5 Scoring Systems for Predicting Metastatic Risk in Pheochromocytoma and Paraganglioma The take-home message is that predicting which tumors will behave aggressively remains difficult, and no single scoring tool is reliable enough on its own. This is precisely why lifelong follow-up is recommended.
Long-Term Follow-Up and Recurrence
Even after apparently successful surgery, pheochromocytoma can come back, sometimes decades later. One long-term study found an overall recurrence risk of about 13% at 10 years, rising to 33% at 30 years.27PubMed Central. Long-Term Outcomes after Surgery for Pheochromocytoma and Sympathetic Paraganglioma An earlier study reported pheochromocytoma-free survival rates of about 92% at five years and 80% at ten years, with recurrences appearing as late as 16 years after the initial operation.28PubMed. Tumor recurrence and hypertension persistence after successful pheochromocytoma operation
These numbers mean that follow-up cannot be treated as a short-term formality. Periodic biochemical testing and imaging should continue indefinitely, even for tumors that appeared completely benign and were removed with clean surgical margins. Patients with hereditary forms or tumors that showed a noradrenergic secretion pattern (meaning low epinephrine relative to norepinephrine) seem to face higher recurrence risk, but apparently sporadic tumors can recur too.
Pheochromocytoma in Children
Pheochromocytoma is uncommon in the general population, and in children it is genuinely rare. But when it does appear in a child, the odds of an underlying genetic cause are much higher than in adults. One large comparative study found that about 80% of pediatric cases were hereditary, compared with roughly half of adult cases.29The Journal of Clinical Endocrinology & Metabolism. Characteristics of Pediatric vs Adult Pheochromocytomas and Paragangliomas Children also had far more extra-adrenal tumors (about two-thirds versus one-third in adults), more multifocal disease, and higher rates of metastatic involvement.30PubMed Central. A Clinical Roadmap to Investigate the Genetic Basis of Pediatric Pheochromocytoma: Which Genes Should Physicians Think About? This makes genetic testing essentially mandatory in pediatric patients and also means that surveillance for recurrence or new primary tumors needs to start early and continue throughout their lives.
Pheochromocytoma During Pregnancy
Diagnosing a pheochromocytoma during pregnancy is a high-stakes scenario. Historically, an unrecognized tumor during pregnancy carried dangerously high rates of both maternal and fetal complications, including death. The good news is that outcomes have improved substantially as awareness has grown and as prenatal biochemical screening has become standard for pregnant women with unexplained hypertensive crises.31PubMed Central. The diagnosis and management of pheochromocytoma and paraganglioma during pregnancy
The diagnostic workup is the same as in non-pregnant patients with one imaging exception: MRI without gadolinium contrast replaces CT to avoid radiation exposure. Genetic testing is especially relevant in pregnant patients because of the younger population involved; some data suggest that up to two-thirds of pheochromocytomas presenting during pregnancy may be linked to hereditary syndromes.32JCEM Case Reports. Pheochromocytoma Diagnosed During First Trimester of Pregnancy Medical management with alpha-blockade followed by beta-blockade is the initial approach. If the tumor is found before about 24 weeks, surgical removal during pregnancy is generally preferred. Later in pregnancy the decision becomes more case-by-case, weighing the risks of surgery near the growing uterus against the risks of continued catecholamine exposure.
Treating Metastatic or Inoperable Disease
For the minority of patients whose tumors have spread or cannot be surgically removed, targeted radionuclide therapy has emerged as one of the more effective treatment options. Two main approaches exist. One uses high-specific-activity 131I-MIBG, which delivers radiation specifically to catecholamine-producing cells. The other uses peptide receptor radionuclide therapy (PRRT) with agents like 177Lu-DOTATATE, which targets somatostatin receptors on the tumor surface. Both have been recommended by the National Comprehensive Cancer Network for metastatic pheochromocytoma and paraganglioma, and high-specific-activity 131I-MIBG was approved by the FDA for this indication.33PubMed Central. High-Specific-Activity-131I-MIBG versus 177Lu-DOTATATE Targeted Radionuclide Therapy for Metastatic Pheochromocytoma and Paraganglioma Both approaches have shown efficacy with acceptable side-effect profiles, though head-to-head comparisons are still limited.34Journal of Nuclear Medicine. Systemic Radiopharmaceutical Therapy of Pheochromocytoma and Paraganglioma
Chemotherapy regimens exist as well, and newer targeted drugs are being tested in clinical trials, but the field is small and progress is slow because the disease is rare. Choices about how to treat metastatic disease depend heavily on which radiotracer the tumor takes up, how fast it is growing, and the patient’s overall health.
Living With the Diagnosis
The physical and emotional toll of pheochromocytoma goes beyond what lab tests capture. Patients with actively hormone-secreting tumors report significantly lower physical functioning compared with those whose tumors are hormonally inactive. In one quality-of-life study, physical health scores were meaningfully lower in the catecholamine-secreting group. Mental health takes a hit too, particularly in patients dealing with metastatic disease and ongoing hormone excess.35European Journal of Endocrinology. Quality of life in patients with pheochromocytoma and paraganglioma: influence of tumor type, genetics and surgical resection
Even after successful surgery, the experience of living through unpredictable catecholamine surges, the anxiety around possible recurrence, and the need for indefinite surveillance can affect well-being in ways that standard outcome studies do not always measure. Many patients describe the episodic symptoms, the pounding heart and sense of dread that come without warning, as deeply disruptive to everyday life.
Where the Name Comes From
The word pheochromocytoma is a mouthful with a surprisingly literal meaning. “Pheo” comes from the Greek for dusky, “chromo” for color, and “cytoma” for tumor. It refers to the fact that the tumor turns brown when treated with chromate-containing fixatives, a reaction caused by the oxidation of the catecholamines stored inside the cells. This color change, called the chromaffin reaction, was first described in the late 19th century and represented one of the earliest uses of histochemistry in tumor diagnosis.36PubMed Central. Max Schottelius: Pioneer in Pheochromocytoma Modern pathologists no longer rely on the chromaffin stain, using immunohistochemistry for chromogranin instead, but the name stuck.