Symptoms of Pheochromocytoma and When to See Your Doctor

If you've been grappling with unexplained episodes of high blood pressure, rapid heart rate, or seemingly random surges of anxiety, there may be more to your story. These symptoms can be the hallmark of pheochromocytoma, a rare type of adrenal gland tumor.

While this condition affects only about 2 to 8 people per million each year, its symptoms often mimic more common disorders like anxiety, hypertension, or panic attacks, risking misdiagnosis and potentially life-threatening consequences. Recognizing pheochromocytoma symptoms is the first step toward receiving a timely diagnosis and improving patient outcomes.

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What Is Pheochromocytoma?

Pheochromocytoma is a rare tumor that develops in the adrenal glands, small organs located on top of each kidney. These glands are part of the body's endocrine system and produce hormones like adrenaline, cortisol, aldosterone, and dehydroepiandrosterone (DHEA). 

Pheochromocytomas are made of chromaffin cells, which are specialized cells within the inner part of the adrenal gland (adrenal medulla) responsible for producing catecholamines. These hormones, including epinephrine (adrenaline) and norepinephrine (noradrenaline), regulate various physiological processes, such as the stress ("fight-or-flight") response, blood pressure, and heart rate.

Paragangliomas are similar tumors made of chromaffin cells outside the adrenal glands, commonly along blood vessels and nerve pathways in the head and neck. 

Pheochromocytomas usually affect people between 30 and 50 years old. They are typically benign (non-cancerous) tumors; however, up to 10% of cases are malignant (cancerous) and can spread to other parts of the body. (31) 

The exact cause of pheochromocytoma is often unclear, but up to 35% of cases have a genetic link and may run in families (31). Scientists have found 20 different genes that can cause pheochromocytoma, and the incidence of pheochromocytoma is higher in people with other genetic conditions, including: 

• Multiple endocrine neoplasia type 2 (MEN2)
• von Hippel-Lindau (VHL) disease
• Neurofibromatosis type 1 (NF1)
• Hereditary paraganglioma-pheochromocytoma syndromes (HPPS)
• Carney-Stratakis dyad
• Carney triad (31)

Common Symptoms of Pheochromocytoma

Pheochromocytoma symptoms occur when the tumor secretes catecholamines and can vary widely in severity, frequency, and duration. Episodes may happen once a month to several times per day. As the tumor grows and produces increasing amounts of catecholamines, the symptoms often become more frequent and intense. (24) 

Emotional stress, physical exertion, dietary tyramines, and certain medications can trigger these episodes, but symptoms may also appear unexpectedly (34). 

The most common symptom of pheochromocytoma is high blood pressure (often resistant to treatment), affecting 60% of patients. A dangerous blood pressure spike over 180/120 mmHg is called a hypertensive crisis and can cause stroke, heart attack, loss of consciousness, and damage to the eyes and kidneys.  

The other cardinal symptoms of pheochromocytoma include episodic:

• Headache
• Sweating 
• Rapid heartbeat (tachycardia) 
• Tremors or shaking
• Anxiety

Less common symptoms can include:

• Chest pain
• Abdominal pain
• Nausea and vomiting
• Diarrhea or constipation
• Orthostatic hypotension (a drop in blood pressure with standing)
• Unexplained weight loss
• Pale skin
• Hyperglycemia (high blood sugar)

When to See a Doctor

Pheochromocytoma is rare. Most people with these symptoms don't have pheochromocytoma. However, you should talk to a doctor if you have any of the following:

• Episodic or constant high blood pressure, especially if it is resistant to treatment
• Episodes of unexplained headaches, rapid heart rate, sweating, tremors, and anxiety
• A family history of pheochromocytoma or paraganglioma
• A family or personal history of a related genetic condition, such as MEN2, VHL disease, NF1, or HPPS

If your at-home blood pressure reading is 180/120 mmHg or greater, retake your blood pressure after 1-2 minutes. If the second reading is just as high, call 911 if you have any of these symptoms:

• Chest pain
• Shortness of breath
• Back pain
• Numbness
• Muscle weakness
• Changes in vision
• Difficulty speaking 
• Confusion
• Dizziness
• Vomiting 

Diagnostic Process

If your doctor suspects pheochromocytoma, they will start the diagnostic process by ordering a blood or urine test:

• Plasma-Fractionated Metanephrines: This test measures the metabolites of epinephrine and norepinephrine in the blood. To reduce the risk of false-positive results, it is recommended to perform the blood draw after the patient has been lying down for at least 30 minutes. 
• 24-Hour Urinary-Fractionated Metanephrines: This test measures the metabolites of epinephrine and norepinephrine excreted in the urine over 24 hours. Urinary creatinine should also be measured to verify the adequacy of the urine sample.

A positive test (elevated fractionated metanephrines) requires follow-up imaging to locate the tumor. An abdominal and pelvic CT scan is the recommended first-line imaging modality; MRI is an acceptable alternative if CT is contraindicated (20).

Patients who have been diagnosed with pheochromocytoma should undergo genetic testing to detect mutations that increase their risk for an inherited syndrome and other related tumors (20).

Pheochromocytoma Differential Diagnosis

Conditions with similar clinical presentations to pheochromocytoma include: 

• Acute illness
• Hyperthyroidism
• Carcinoid tumors
• Hypoglycemia
• Medullary thyroid carcinoma
• Mastocytosis
• Menopause
• Arrhythmia 
• Postural orthostatic tachycardia syndrome (POTS)
• Migraine
• Porphyria
• Panic disorder
• Generalized anxiety disorder (GAD)
• Alcohol withdrawal
• Illicit drug use

Therefore, additional testing can be ordered to rule out these conditions and help pinpoint the exact cause of the patient's symptoms:

• Complete blood count (CBC)
• Comprehensive metabolic panel (CMP)
• Thyroid panel
• Female hormone panel

Other lab findings common in patients with pheochromocytoma include:

• High blood sugar (hyperglycemia)
• High red blood cell count (erythrocytosis)
• High calcium (hypercalcemia)

Treatment Options

Factors that help determine the best course of treatment for pheochromocytoma include the tumor's characteristics (e.g., size, location, benign vs. malignant), the presence of metastasis, genetic factors, and the patient's overall health and preferences. (45) 

When possible, surgery is the preferred treatment option for pheochromocytoma, with a success rate of 90%. In cases of inherited pheochromocytoma affecting one adrenal gland, your doctor will likely remove the entire adrenal gland. If both adrenal glands have pheochromocytomas, the surgeon will aim to remove the tumors while preserving as much normal adrenal tissue as possible to minimize the need for lifelong hormone replacement therapy. (30, 34) 

Medications will also be prescribed at diagnosis to manage pheochromocytoma symptoms before surgery. This includes:

• Drugs that normalize blood pressure (alpha-blockers)
• Drugs that keep heart rate regular (beta-blockers)
• Drugs that block the excess catecholamines made by the adrenal gland

For metastatic and recurrent pheochromocytoma, your doctor may recommend other treatment options, including:

• Radiation therapy
• Chemotherapy
• Ablation therapy (uses high or low temperatures to selectively kill tumor cells)
• Embolization therapy (blocks blood flow to the tumor)
• Targeted therapy (uses medications called tyrosine kinase inhibitors to prevent tumor growth)

Long-term Management and Follow-up

Follow-up is required postoperatively and then annually for at least ten years for patients with benign pheochromocytoma to confirm treatment success and monitor for tumor recurrence:

• Measure plasma or urine metanephrine levels
• Additional testing is also recommended annually for patients with RET gene mutations, including serum calcitonin and calcium.

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In addition to annual laboratory testing, patients at high risk for recurrence should have repeat imaging scheduled at regular intervals: 

• Every 3-4 months for the first year
• Every 4-6 months during the second year
• Every 6-12 months until ten years
• Every 24-48 months after ten years

Complications of Untreated Pheochromocytoma

While the prognosis of pheochromocytoma is good, untreated tumors can lead to potentially serious and life-threatening complications.

An adrenergic crisis is characterized by a sudden surge of catecholamines, causing intense symptoms such as severe hypertension and arrhythmias that can cause heart attack or stroke, in addition to damage to the eyes and kidneys. 

Other complications of untreated pheochromocytoma include:

• Cardiomyopathy (disease of the heart muscle)
• Myocarditis (inflammation of the heart muscle)
• Cerebral hemorrhage (bleeding in the brain)
• Pulmonary edema (fluid accumulation in the lungs)

Rarely, a pheochromocytoma is cancerous and can metastasize (travel) to other parts of the body, such as the lymphatic system, bones, liver, or lungs. 

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Key Takeaways

• Pheochromocytoma presents with hallmark symptoms such as severe headaches, excessive sweating, rapid heart rate, and hypertension, often manifesting as episodic adrenergic crises. 
• While the majority of these tumors are benign, they can lead to life-threatening complications if left untreated, including hypertensive crises and cardiovascular disease.
• Therefore, patients should consult their healthcare providers if they experience any of these symptoms. 
• Additionally, healthcare professionals should maintain pheochromocytoma on their differential diagnosis when patients present with these hallmark symptoms, particularly in cases of resistant hypertension, to ensure timely diagnosis and effective management.