Definition and epidemiology
Pheochromocytoma is a neuroendocrine tumor of chromaffin cells in the adrenal medulla that secretes catecholamines (epinephrine, norepinephrine, and sometimes dopamine). Extra-adrenal tumors arising from sympathetic paraganglia are termed paraganglioma; the two are grouped together clinically and genetically.
- Incidence is roughly 2-8 cases per million per year; it is a rare but important cause of secondary hypertension (under 1% of hypertensive patients)
- Peak incidence is in the 30s-50s, with no strong sex predominance
- Up to 10% are bilateral, up to 10% are extra-adrenal (paraganglioma), and up to 10-15% are malignant
- Roughly 30-40% are associated with a hereditary syndrome, so genetic counseling is recommended for most patients, especially those who are young, have bilateral or multifocal disease, or a family history
Associated hereditary syndromes include multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau (VHL) disease, neurofibromatosis type 1 (NF1), and hereditary paraganglioma syndromes from succinate dehydrogenase (SDHx) gene mutations.
- Rule of 10s: roughly 10% bilateral, 10% extra-adrenal, 10% malignant (approximate, not exact)
- Classic triad: episodic headache, sweating, and palpitations with paroxysmal hypertension
- Plasma or urine fractionated metanephrines are the preferred initial diagnostic test
- Never biopsy a suspected pheochromocytoma before biochemical workup
- Alpha-blockade must precede beta-blockade to avoid unopposed alpha-mediated vasoconstriction
- Associated syndromes: MEN2, VHL, NF1, and SDHx-related hereditary paraganglioma
- SDHB mutations carry the highest risk of malignant/metastatic disease
- Laparoscopic adrenalectomy is the preferred surgical approach for resectable tumors
Etiology and risk factors
Most cases are sporadic, but a substantial minority arise from germline mutations in susceptibility genes.
- MEN2A/2B - RET proto-oncogene mutations; associated with medullary thyroid carcinoma and primary hyperparathyroidism (2A) or mucosal neuromas/marfanoid habitus (2B)
- Von Hippel-Lindau disease - VHL gene mutation; associated with retinal and CNS hemangioblastomas, renal cell carcinoma, and pancreatic cysts
- Neurofibromatosis type 1 - NF1 gene mutation; café-au-lait spots, neurofibromas, Lisch nodules
- Hereditary paraganglioma syndromes - SDHB, SDHD, and related mutations; SDHB mutations carry the highest risk of malignancy and metastasis
SDHB-mutated tumors are more often extra-adrenal, multifocal, and malignant, making genetic testing clinically actionable for prognosis and surveillance.
Pathophysiology
Chromaffin cells synthesize and store catecholamines in secretory granules. Tumor cells retain this synthetic machinery but secrete catecholamines in an unregulated, often episodic fashion rather than in response to physiologic stimuli.
- Excess norepinephrine and epinephrine act on alpha-1 and beta receptors, causing vasoconstriction, increased cardiac contractility and rate, and increased hepatic glycogenolysis
- Episodic release (rather than continuous secretion) explains the classic paroxysmal pattern of symptoms, often triggered by exercise, stress, abdominal palpation, surgery, or certain drugs
- Chronic catecholamine excess can lead to a catecholamine-induced cardiomyopathy and increases perioperative cardiovascular risk if the tumor is not biochemically controlled before manipulation
- Some tumors predominantly secrete dopamine or its metabolites, which may present with hypotension rather than hypertension
Clinical features
The classic triad is episodic headache, sweating (diaphoresis), and palpitations/tachycardia, usually accompanying paroxysmal hypertension.
- Hypertension may be sustained, paroxysmal, or occasionally absent
- Pallor during attacks (not flushing) is typical
- Anxiety or a sense of impending doom, tremor, and nausea may occur
- Weight loss and glucose intolerance can result from chronic catecholamine excess
- Attacks may be triggered by abdominal pressure, exertion, anesthesia induction, or certain medications
- Orthostatic hypotension can coexist with supine hypertension due to volume depletion and receptor downregulation
Presentation can mimic panic attacks, hyperthyroidism, or other causes of paroxysmal hypertension, so a high index of suspicion is needed in resistant or episodic hypertension.
Diagnosis
Diagnosis proceeds in two steps: biochemical confirmation first, then anatomic localization.
Biochemical testing
- Plasma free metanephrines or 24-hour urine fractionated metanephrines and catecholamines are the preferred initial tests, with high sensitivity
- Testing should be done with the patient resting supine when possible, avoiding interfering substances (certain antidepressants, stimulants, acetaminophen in some assays) when feasible
- Mildly elevated results should be interpreted cautiously; markedly elevated levels are strongly suggestive
Localization
- CT or MRI of the abdomen and pelvis is used first to localize an adrenal or extra-adrenal mass once biochemistry is positive
- MIBG scintigraphy or functional PET imaging (such as FDG-PET or DOTATATE-based PET) helps confirm functional activity, detect metastatic or extra-adrenal disease, and plan surgery, especially in suspected paraganglioma or metastatic disease
Genetic testing
Germline genetic testing is recommended for most patients, guided by clinical features, tumor location, and family history, given the high rate of hereditary disease.
Biopsy of a suspected pheochromocytoma is generally avoided because it can precipitate a hypertensive crisis.
Differential diagnosis
| Condition | Distinguishing feature |
|---|---|
| Panic disorder/anxiety | No sustained hypertension; normal metanephrines |
| Hyperthyroidism | Elevated TSH/free T4 abnormalities, no episodic BP spikes |
| Primary hyperaldosteronism | Hypertension with hypokalemia, elevated aldosterone-renin ratio |
| Essential/resistant hypertension | No paroxysmal symptoms, normal catecholamine studies |
| Carcinoid syndrome | Flushing (not pallor) and diarrhea, elevated 5-HIAA |
| Clonidine withdrawal or stimulant use | History of medication/drug use, resolves with removal of trigger |
The combination of episodic symptoms with confirmed biochemical excess is what separates pheochromocytoma from these mimics.
Management
Surgical resection is curative therapy, but adequate preoperative medical preparation is essential to prevent intraoperative hypertensive crisis and cardiovascular instability.
Preoperative medical management
- Alpha-adrenergic blockade (commonly phenoxybenzamine or a selective alpha-1 blocker such as doxazosin) is started first, typically for one to two weeks before surgery, to control blood pressure and allow volume expansion
- Beta-blockade (such as propranolol or metoprolol) is added only after adequate alpha-blockade, to control reflex tachycardia; beta-blockade before alpha-blockade can cause unopposed alpha-mediated vasoconstriction and a hypertensive crisis
- Liberal salt intake and fluid intake are often encouraged preoperatively to counteract catecholamine-induced volume contraction
- Calcium channel blockers may be used as adjuncts or alternatives in some protocols
Surgery
- Laparoscopic (minimally invasive) adrenalectomy is preferred for most resectable tumors
- Open resection is reserved for large, invasive, or malignant-appearing tumors
- Close intraoperative hemodynamic monitoring is required, as catecholamine surges can occur during tumor manipulation
Malignant or metastatic disease
- Options include surgical debulking, MIBG-targeted radiotherapy (for MIBG-avid tumors), chemotherapy, and newer targeted or radionuclide therapies, chosen according to tumor biology and guideline-based multidisciplinary input
- Lifelong biochemical and imaging surveillance is recommended given recurrence risk, particularly in hereditary syndromes
Guideline societies (such as the Endocrine Society) broadly agree on this alpha-before-beta blockade sequence, though specific agent choice varies by institutional preference and availability.
Complications and prognosis
- Hypertensive crisis, especially during anesthesia induction, surgery, or tumor manipulation without adequate blockade
- Catecholamine-induced cardiomyopathy, arrhythmias, and myocardial infarction
- Stroke from severe uncontrolled hypertension
- Multisystem crisis (rare) with fever, hypertension or hypotension, encephalopathy, and multiorgan dysfunction
Most benign tumors have an excellent prognosis after complete resection, with cure of hypertension in the majority of patients. Malignant or metastatic disease (more common with SDHB mutations) carries a more variable prognosis. Long-term follow-up with periodic biochemical testing is recommended for all patients because of the risk of recurrence, even after apparently complete resection.
PHEO: Palpitations, Headache, Episodic, hypertension, with alpha-blockade before beta-blockade (remember: 'alpha before beta, or you'll see red').
Practice questions
1. A 38-year-old woman has recurrent episodes of pounding headache, sweating, and palpitations lasting about 20 minutes, several times per week. Blood pressure during an episode is 210/120 mmHg; between episodes it is 128/82 mmHg. Which test should be obtained next?
2. A 45-year-old man with a confirmed adrenal pheochromocytoma is scheduled for laparoscopic adrenalectomy in two weeks. Which medication should be started first as part of preoperative preparation?
3. A 29-year-old man with a history of medullary thyroid carcinoma and primary hyperparathyroidism is found to have an adrenal mass with elevated plasma metanephrines. Which genetic syndrome is most likely?
Frequently asked questions
What causes pheochromocytoma?
Most cases arise sporadically from chromaffin cells of the adrenal medulla, but about 30-40% are linked to hereditary syndromes such as MEN2, von Hippel-Lindau disease, neurofibromatosis type 1, or SDHx-related paraganglioma syndromes. These mutations drive uncontrolled catecholamine-secreting tumor growth. There is no known environmental or lifestyle cause.
What are the first symptoms of pheochromocytoma?
The earliest and most classic symptoms are episodic headache, sweating, and palpitations, often accompanied by sudden spikes in blood pressure. Episodes may be triggered by exertion, stress, or abdominal pressure and can mimic a panic attack. Pallor rather than flushing is typical during an episode.
How is pheochromocytoma diagnosed?
Diagnosis starts with biochemical testing, usually plasma free metanephrines or 24-hour urine fractionated metanephrines, which have high sensitivity for catecholamine-secreting tumors. If biochemistry is positive, CT or MRI localizes the tumor, and MIBG or PET imaging can confirm functional activity or detect metastases. Biopsy is avoided due to crisis risk.
Is pheochromocytoma curable?
Yes, most benign pheochromocytomas are curable with complete surgical resection after proper preoperative alpha- and beta-blockade. Hypertension resolves in the majority of patients after surgery. Malignant or metastatic disease is harder to cure and requires long-term multidisciplinary management, but can sometimes be controlled for years.
Pheochromocytoma vs paraganglioma — what is the difference?
Pheochromocytoma arises specifically from chromaffin cells within the adrenal medulla, while paraganglioma arises from extra-adrenal sympathetic or parasympathetic paraganglia, such as along the aorta or in the head and neck. Both can secrete catecholamines and share overlapping genetics, but paragangliomas are more often associated with SDHx mutations and have a higher malignant potential.
Key drugs
Related conditions and differentials
Sources and further reading
StatPearls (NCBI Bookshelf)MedlinePlusWHO ICD-10: C74.1
Educational content for medical students, prepared by the WhiteCoat Pro editorial team with AI assistance; every page is reviewed by a second AI model for factual errors. It is not medical advice and does not replace the product label, local guidelines or a clinician.