History & Epidemiology of Pheochromocytoma

Pheochromocytoma is a rare neuroendocrine disorder in which a tumor grows from chromaffin cells within the adrenal medulla of the adrenal glands.1 This tumor causes the continuous overproduction of epinephrine and norepinephrine, which, if left without pheochromocytoma treatment, can lead to severe or life-threatening damage to other body systems.2

Extra-adrenal pheochromocytomas, or paragangliomas, are pheochromocytomas that grow outside of the adrenal glands. Paragangliomas only make up approximately 15% to 20% of pheochromocytomas.1

Sometimes referred to as “the great masquerader” due to the large variety of clinical presentations, adrenal pheochromocytoma was first described by Felix Frankel in 1886, while paragangliomas were first described in 1908 by Alezais and Peyron.3 Ludwig Pick is accredited with naming the tumor in 1912 based on its brown or dusky (phaios) color (chroma) when stained with chromium salts.3 The first case of pheochromocytoma with a clinical diagnosis and therapeutic surgical resection was presented in 1937 by Dr. Charles Mayo.4

Pheochromocytomas and paragangliomas are rare, with an estimated incidence of 2 to 8 diagnoses per every 1 million people each year. However, the actual incidence is unknown, as many people with the tumors are never diagnosed.1 About 0.05 to 0.2% of hypertensive patients have a pheochromocytoma.

The incidence is equal for both genders, and diagnosis is typically made between the ages of 30 and 50 years; however, pheochromocytoma due to genetic predispositions, which account for approximately 35% of cases,5 may present at an earlier age.4 Most pheochromocytomas and paragangliomas are benign, with 10% of pheochromocytomas and 25% of paragangliomas being malignant.6

The causes of pheochromocytomas are largely unknown, with most cases occurring sporadically.5 However, approximately 35% of cases are caused by genetic mutations that are inherited in an autosomal dominant pattern.5 Pheochromocytomas are associated with familial syndromes, such as multiple endocrine neoplasia syndromes type IIA and type IIB, Von Hippel–Lindau syndrome, and type 1 neurofibromatosis.4

Pheochromocytoma Presentation

The presentation of pheochromocytoma varies widely.6 Pheochromocytoma can be asymptomatic—diagnosed incidentally during imaging procedures for unrelated conditions or found on routine periodic screenings for those patients that have been identified with genetic predispositions.6

It may also present with symptomatic attacks ranging in frequency from a couple of times a month to multiple times per day.1 These pheochromocytoma symptoms occur due to the excessive release of catecholamines (such as norepinephrine and epinephrine).5

Pheochromocytoma symptoms may include2:

  • hypertension
  • headache
  • diaphoresis
  • panic attack-type symptoms
  • anxiety or sense of doom
  • rapid heartbeat
  • weight loss
  • tremors
  • shortness of breath
  • pallor
  • nausea and vomiting5
  • blurry vision
  • constipation
  • pain in the chest or abdomen5

Hypertension is the most common pheochromocytoma symptom and may be sustained or paroxysmal.6 Headaches also occur in up to 90% of patients.6 If a patient with hypertension presents with the three Ps—pain (headache), palpitations, and perspiration—pheochromocytoma should be immediately suspected by the clinician.6

Pheochromocytoma Diagnosis

Pheochromocytoma diagnosis is confirmed by a combination of lab tests and imaging. Elevated levels of catecholamines or their metabolites on blood or urine analysis are highly indicative of pheochromocytomas or paragangliomas, while imaging tests such as computed tomography (CT) and magnetic resonance imaging (MRI) confirm the presence and determine the size and specific location of the tumor.5

The results from both lab and imaging tests are essential in making a proper diagnosis and developing a sound pheochromocytoma treatment plan.

Diagnostic Pheochromocytoma Workup

A diagnostic pheochromocytoma workup begins with a high degree of suspicion by the clinician based on a detailed patient history, a thorough clinical evaluation, and identification of characteristic findings, such as headaches, perspiration, and palpitations in patients with hypertension, hypertension that is unresponsive to standard treatment, and paroxysmal attacks.5,6

Once the clinician suspects a pheochromocytoma, the first step is biochemical laboratory testing.4 Plasma metanephrines are the recommended test in patients with high suspicion for pheochromocytoma, while 24-hour urine metanephrine testing is recommended in those with a low pretest probability.

Regardless of recommendations, many institutions prefer plasma metanephrines as an initial screening test, as 24-hour urine collection can be burdensome for patients and leaves more room for errors.4 It is important that abstinence from amphetamines, cocaine, ephedrine, and tricyclic antidepressants takes place before these biochemical tests, as these substances can affect plasma and urine metanephrine levels. The clinician should collect plasma samples on ice with the patient in a fasted state, lying in a supine position, in order to reduce the potential for false-positive results.

If metanephrine levels are four times higher than the normal reference value, the next step is to localize the hormone-secreting tumor. If metanephrine levels are only minimally elevated or ambiguous and the clinician still suspects pheochromocytoma, the clonidine suppression test can help confirm a diagnosis.4

Computed tomography (CT) scan or magnetic resonance imaging (MRI) should be used to localize the tumor and confirm a diagnosis of pheochromocytoma. MRI is indicated over a CT scan in certain conditions, such as for patients with contrast allergy, the pediatric population, and pregnant patients.4 It should be noted that these imaging modalities are sensitive but not specific; a very specific test for catecholamine-secreting tumors is the 123I-labeled metaiodobenzylguanidine (MIBG) scintigraphy.

MIBG can help to differentiate between adrenal and paraganglionic tumors and can also help reveal multiple lesions and metastases.4 Genetic testing should be determined on a case-by-case basis, with potential indications including a family history of catecholamine-producing tumor, multiple tumors at different sites, metastases, patient age of less than 50 years, or bilateral tumors.4

Pheochromocytoma Differential Diagnosis

The differential diagnosis for pheochromocytoma is extensive, as there is a wide variety of potential clinical presentations. A list of possible differential diagnoses is as follows:4

  • Endocrine
    • Hyperthyroidism, mastocytosis, hypoglycemia, carcinoid tumor, medullary thyroid carcinoma, and menopausal syndrome
  • Cardiovascular
    • Arrhythmias, ischemic heart disease, and heart failure
  • Neurological
    • Migraine, epilepsy, meningioma, stroke, and postural orthostatic tachycardia syndrome (POTS)
  • Miscellaneous
    • Panic disorder or anxiety, porphyria, drug treatment (monoamine oxidase inhibitors, sympathomimetic drugs, withdrawal of clonidine), use of illegal drugs (cocaine), and factitious disorders (from the use of sympathomimetic drugs such as ephedrine)

Pheochromocytoma Management

The primary pheochromocytoma treatment is surgical resection.7 The catecholamine effect must be blocked before surgery in all patients to prevent hypertensive crises and arrhythmias. Any alpha-adrenoceptor antagonist, calcium-channel blocker, or angiotensin-receptor blocker can be used, with no preference for one option over another.4

Beta-adrenergic blockers should never be started before adequate alpha-adrenergic blockade has been achieved, due to the risk for further elevations in blood pressure. The surgical technique will vary based on the specific circumstances of the case, although a laparoscopic procedure is preferred.6 Surgery is usually curative for non-metastatic tumors,4 and the risk of operative mortality is extremely low if performed by an experienced surgical team.6

Pheochromocytomas are usually benign, with only 10% being malignant.6 Typical pheochromocytoma metastases patterning involves the lungs, liver, bones, and lymph nodes.6 Surgical resection is the malignant pheochromocytoma treatment of choice ,4 with targeted therapies, radiation therapy, and chemotherapy being alternative options for metastasized tumors if surgery is contraindicated or unsuccessful.7

Monitoring

Lifelong monitoring after surgery will be required to ensure that the pheochromocytoma treatment was successful, identify complications, and monitor tumor recurrence.7 Repeating biochemical tests should be done no sooner than 14 days after surgery. If metanephrine levels are elevated for three months after surgical resection, further imaging is indicated to look for another tumor.4

Although the long-term prognosis after surgery is excellent, nearly 50% of patients will remain hypertensive, and roughly 17% of tumors will recur, with approximately half of these showing signs of malignancy.6 Close monitoring and coordination of an interprofessional team, both pre-and post-surgery, will provide the best outcomes for patients.

References

1. Pheochromocytoma: National Cancer Institute. National Cancer Institute.  Published February 12, 2020. Accessed September 28, 2022.

2. Pheochromocytoma: Symptoms and causes. Mayo Clinic. Published March 3, 2020. Accessed September 28, 2022.

3. Kantorovich V, Pacak K. Pheochromocytoma and paragangliomaProgress in brain research. 2010;182:343-373. doi:10.1016/S0079-6123(10)82015-1

4. Mubarik A, Aeddula NR. Cancer, Chromaffin Cell (Pheochromocytoma). In: StatPearls. NCBI Bookshelf version. Published 2020. Accessed September 28, 2022.

5. Pheochromocytoma: NORD (National Organization for Rare Disorders). NORD (National Organization for Rare Disorders). Published 2021.

6. Pacak K, Tella SH. Pheochromocytoma and Paraganglioma. In: Endotext. NCBI Bookshelf version. Updated January 4, 2018. Accessed September 28, 2022.

7. Pheochromocytoma: Diagnosis and treatment – Mayo Clinic. Mayo Clinic. Published 2018.

Author Bio

Jonathan Poole is a freelance writer and copyeditor with a BSc in Exercise Science living in West Lafayette, IN. When not writing, he owns and operates a fitness training company, Unstoppable Athletes. More information regarding his training business can be found here: unstoppableathletes.com