Highlights & Basics
- Pheochromocytoma can present with palpitations, diaphoresis, pallor, and paroxysmal hypertension.
- Risk factors include multiple endocrine neoplasia type 2, Von Hippel-Lindau syndrome, and neurofibromatosis type 1.
- Diagnosed by increased levels of urine and serum catecholamines, metanephrines, and normetanephrines.
- Treatment includes medical therapy for hypertension (phenoxybenzamine, phentolamine, alpha-blockers) and surgical excision of tumor (open or laparoscopic adrenalectomy). For unresectable tumors, alternative approaches include chemotherapy or radiopharmaceuticals.
- Complications include hypertensive crisis, myocardial infarction, and hypotension.
Quick Reference
History & Exam
Key Factors
headache
palpitations
diaphoresis
hypertension
hypertensive retinopathy
pallor
impaired glucose tolerance/diabetes mellitus
family history of endocrine disorders
history of prior pheochromocytoma
tachyarrhythmias and myocardial infarction
panic attacks or a "sense of doom"
Other Factors
orthostatic hypotension
hypercalcemia
Cushing syndrome
diarrhea
fever
papilledema
abdominal masses
tremors
Diagnostics Tests
1st Tests to Order
24-hour urine collection for catecholamines, metanephrines, normetanephrines, and creatinine
serum free metanephrines and normetanephrines
plasma catecholamines
genetic testing
Other Tests to consider
CBC
serum calcium
serum potassium
chromogranin A
clonidine suppression test
CT scan of the abdomen and pelvis
MRI of the abdomen and pelvis
I-123 metaiodobenzylguanidine (MIBG) scintigraphy
18F-fluoro-2 deoxy-D-glucose (18F-FDG) positron emission tomography (PET) or FDG, 18-F-dihydroxyphenylalanine (DOPA), Ga-68-DOTATATE
Treatment Options
presumptive
hypertensive crisis
antihypertensive agents
acute
without hypertensive crisis
without hypertensive crisis
surgical candidate with benign tumor: following initial medical treatment
surgical candidate with malignant tumor: following initial medical treatment
nonsurgical candidate with benign tumor: following initial medical treatment
nonsurgical candidate with malignant tumor: following initial medical treatment
Definition
Classifications
2017 World Health Organization classification of pheochromocytoma
- Adrenal origin
- Extra-adrenal origin.
- Benign
- Metastatic.
Vignette
Common Vignette
Other Presentations
Epidemiology
Etiology
- pseudohypoxic PPGLs: SDHA, SDHB, SDHC, SDHD, SDHAF2, FH, VHL, IDH1/2, MHD2, EGLN1/2, andHIF2/EPAS
- kinase signaling PPGLs: RET, NF1, TMEM127, MAX and HRAS
- Wnt signaling PPGLs: CSDE1 and MAML3.
Pathophysiology
Images
Abdominal CT scan with mass in the left adrenal gland, compatible with a pheochromocytoma
Metaiodobenzylguanidine (MIBG) scintigraphy identified hyperfixation in the left adrenal gland compatible with pheochromocytoma
Left laparoscopic adrenalectomy: (A) macroscopic examination, 6 cm tumor; (B) microscopic examination: neoplasm of the adrenal medulla with eosinophilic cytoplasm of large cells with positive fine granular chromogranin A; (C) round and oval nucleus and sustentacular cells S100+; (D) pheochromocytoma
Diagnostic Approach
History
- Palpitations
- Headaches
- Diaphoresis.
- Resistant intractable hypertension
- Young age at the onset of hypertension.
Physical exam findings
Laboratory evaluation
Genetic testing
Subsequent imaging
Risk Factors
History & Exam
Tests
Differential Diagnosis
Anxiety and panic attacks
Differentiating Signs/Symptoms
- Careful history-taking is required to differentiate these conditions from a pheochromocytoma.
- It is important to assess the patient's mental state, and enquire about phobias and other psychiatric conditions.
- Panic attacks and anxiety are often situational, whereas symptoms associated with a pheochromocytoma are episodic in nature.
Differentiating Tests
- Diagnosis is clinical.
- These patients will not have biochemical evidence of hypercatecholaminemia when they are not having a panic attack.
Essential or intractable hypertension
Differentiating Signs/Symptoms
- The presence of symptoms such as headache, palpitations, and diaphoresis are all suggestive for a pheochromocytoma, especially in the setting of hypertension.
Differentiating Tests
- Pheochromocytomas can usually be ruled out with measurement of urine metanephrines, normetanephrines, and catecholamines.
- Paroxysmal, drug-resistant hypertension is more suggestive for a pheochromocytoma. In contrast, essential hypertension is drug-responsive and easier to treat.
Hyperthyroidism
Differentiating Signs/Symptoms
- May mimic a pheochromocytoma as it is also associated with diaphoresis, palpitations, tremors, and weight loss.
Differentiating Tests
- Depressed TSH levels support a diagnosis of hyperthyroidism in the setting of an elevated free thyroxine level.
- Urinary work-up studies for a pheochromocytoma would be negative.
Consumption of illicit substances
Differentiating Signs/Symptoms
- Certain recreational drugs such as cocaine and amphetamines can cause symptoms similar to those of a pheochromocytoma. Additionally, cocaine can lead to false-positive serum and urine testing for a pheochromocytoma.[2]
Differentiating Tests
- Toxicology or a drug screen may be useful if drug abuse is suspected as catecholamine and metabolite levels may be acutely elevated after consumption of these substances, making it difficult to distinguish from a pheochromocytoma.
Carcinoid syndrome
Differentiating Signs/Symptoms
- This syndrome is characterized by periods of intense flushing usually associated with diarrhea, cramping, wheezing, and tricuspid valve and pulmonary valve abnormalities.
- Carcinoid tumors are characteristically associated with a dry skin flush; in contrast, pheochromocytomas are associated with pallor.
Differentiating Tests
- Carcinoid is diagnosed by increased urinary 5-hydroxyindole acetic acid levels, as well as a biopsy of the tumor.
Cardiac arrhythmias
Differentiating Signs/Symptoms
- Can also present with symptoms similar to those caused by a pheochromocytoma: namely, palpitations.
- Rarely, an underlying pheochromocytoma may actually be the precipitant of an arrhythmia (e.g., supraventricular tachycardia, ventricular fibrillation).
Differentiating Tests
- Negative ECG/telemetry/Holter monitoring while the patient is symptomatic can rule out this diagnosis.
- Catecholamines and metanephrines will be high in a pheochromocytoma and normal in patients with an isolated arrhythmia.
Menopause
Differentiating Signs/Symptoms
- Symptoms of menopause may mimic a pheochromocytoma.
- Patients commonly complain of profuse sweating and flushing.
- In contrast, patients with a pheochromocytoma have profuse sweating associated with pallor.
Differentiating Tests
- Catecholamines and their metabolites are not elevated during menopause.
Preeclampsia
Differentiating Signs/Symptoms
Differentiating Tests
- Preeclampsia patients have proteinuria and usually an elevated blood uric acid; these values are usually normal in patients with a pheochromocytoma.
- Catecholamines and metanephrines will be high in a pheochromocytoma and normal in preeclampsia.
Screening
Treatment Approach
Hypertensive crisis
Medical therapy
Alpha and beta blockade
Less-preferred antihypertensives
Benign pheochromocytoma
Metastatic pheochromocytoma
Unresectable tumor
Patient with hereditary pheochromocytoma
Treatment Options
hypertensive crisis
antihypertensive agents
Primary Options
- phentolamine
5-20 mg intravenously as a single dose
- phentolamine
Secondary Options
- nitroprusside
0.3 to 0.5 micrograms/kg/min intravenous infusion initially, increase according to response, maximum 8-10 micrograms/kg/min
- nitroprusside
Comments
- May be a presenting feature or an intraoperative complication if the patient has not received adequate preoperative medical therapy.
- A hypertensive crisis may be precipitated by drugs that inhibit catecholamine uptake, such as tricyclic antidepressants and cocaine; opiates; anesthesia induction; and radiographic contrast media.
- Hypertensive crisis should be managed with phentolamine. Calcium-channel blockers have been used as a single agent perioperatively. When administered intravenously, good blood pressure (BP) control can be achieved, with low morbidity and mortality.[88] [89] Alternatively, an intravenous (IV) infusion of nitroprusside can be used.[90]
- Possible consequences of a hypertensive crisis include cerebral hemorrhage, cardiac arrhythmias, myocardial infarction (MI), encephalopathy, and heart failure.[91]
without hypertensive crisis
alpha-blockers
Primary Options
- phenoxybenzamine
10 mg orally twice daily initially, increase by 10 mg/day increments every other day according to response, maximum 240 mg/day
- phenoxybenzamine
Secondary Options
- doxazosin
1 mg orally (immediate-release) once daily for 1-2 weeks initially, increase according to response, maximum 16 mg/day
- doxazosin
- prazosin
0.5 to 1 mg orally two to three times daily for 3-7 days initially, increase according to response, maximum 20 mg/day
- prazosin
Comments
- Used to control hypertension.
- A major disadvantage of phenoxybenzamine is that it blocks presynaptic alpha-2 receptors enhancing the release of norepinephrine, resulting in a reflex tachycardia.
- Prazosin and doxazosin are selective alpha-1 antagonists that are being used with increasing frequency since studies have shown that they are equally as effective as phenoxybenzamine, and they do not enhance the release of norepinephrine. However, treatment with these agents is not routinely used preoperatively as they do not provide complete alpha-adrenergic blockade.
- Doxazosin has the advantage of a once-daily dosing regimen in contrast to phenoxybenzamine, which has a twice-daily dosing regimen.
- It is recommended that a high-salt diet is started about 3 days after alpha-blocker is commenced.
beta-blockers after alpha blockade
Primary Options
- atenolol
25-100 mg orally once daily
- atenolol
- metoprolol tartrate
50 mg orally (immediate-release) twice daily initially, increase according to response, maximum 400 mg/day
- metoprolol tartrate
- propranolol hydrochloride
30-60 mg/day orally (immediate-release) given in 2-3 divided doses
- propranolol hydrochloride
Secondary Options
- labetalol
100 mg orally twice daily initially, increase by 200 mg/day increments every 2-3 days according to response, maximum 2400 mg/day
- labetalol
Comments
- The main role of beta-blockers is to prevent tachycardia and arrhythmias. The commonly employed agents are beta-1 selective agents such as atenolol and metoprolol.
- Beta-blockers must only be used after adequate alpha blockade is achieved preoperatively, as they can cause unopposed stimulation of alpha receptors leading to vasoconstriction and a possible hypertensive crisis.
- Adverse effects include bradycardia, bronchospasm, hypotension, and vasoconstriction; therefore, caution is needed when commencing patients with asthma, cardiomyopathies (this is particularly important as cardiomyopathy is a complication of prolonged catecholamine exposure), heart failure, or atrioventricular (AV) conduction abnormalities on beta-blockers.
- Labetalol is an alpha- and beta-blocker widely used in the treatment of hypertensive emergencies. However, paradoxical hypertensive responses have been reported in a few patients with pheochromocytoma. This is thought to be attributable to an incomplete alpha-adrenergic blockade. Not suitable for use in pheochromocytoma-related hypertensive crisis. May interfere with the urine assay for measurement of metanephrines and normetanephrines and can cause false elevations.[2]
hydration and high-salt diet (>5 g per day)
Comments
- All patients should be volume expanded with isotonic saline. In surgical patients, postoperative hypotension may be avoided by adequate intravenous fluid replacement preoperatively.
- On the second or third day after alpha-adrenergic blockade, a high salt diet (>5 g per day) should be instituted to counteract catecholamine-induced volume contraction and orthostasis, which can be associated with alpha-adrenergic blockade.
calcium-channel blocker or metyrosine
Primary Options
- nifedipine
10-20 mg orally (immediate-release) three times daily
- nifedipine
- amlodipine
5-10 mg orally once daily
- amlodipine
Secondary Options
- metyrosine
250 mg orally four times daily initially, increase by 250-500 mg/day increments according to response, maximum 4000 mg/day
- metyrosine
Comments
- Calcium-channel blockers play a role in supplementation of alpha blockade or combined alpha and beta blockade when BP control is inadequate or the patient has intolerable adverse effects secondary to alpha or beta blockade.
- Nifedipine and amlodipine are the most commonly recommended calcium-channel blockers in the setting of perioperative pheochromocytoma BP control.[2]
- Calcium-channel blockers lower BP by relaxing smooth muscle in peripheral arteries. This is achieved by inhibition of the norepinephrine-mediated release of intracellular calcium in vascular smooth muscle.
- They do not cause orthostatic hypertension and, therefore, have a role in patients with episodic hypertension.
- Metyrosine is used only as an adjunctive treatment in patients who do not respond to alpha or beta blockade, or when other agents have been ineffective. It is particularly useful in reducing catecholamines in patients with pheochromocytomas, particularly those with very high circulating levels of catecholamines that can be cytotoxic to myocardial cells.
- Metyrosine should be started 2 weeks prior to surgery. It can also be used when surgery is contraindicated.
- Adverse effects of metyrosine often limit the use of this drug and include crystalluria, fatigue, diarrhea, depression, nightmares, and extrapyramidal signs.[92] Patients should be instructed on maintaining an adequate fluid intake in order to avoid metyrosine crystalluria.
surgical candidate with benign tumor: following initial medical treatment
surgical excision of tumor
Comments
- Hypertension should be controlled first with antihypertensives.
- Postoperative hypotension may be avoided by adequate intravenous fluid replacement preoperatively.
- Surgical treatment options include open or laparoscopic total adrenalectomy, adrenal-sparing, or partial adrenalectomy. Robot-assisted adrenalectomy is another safe and effective surgical treatment option.[69]
- There is evidence in favor of cortical-sparing adrenalectomy in patients with hereditary pheochromocytomas.[2] [65] This method can avoid the need for lifelong corticosteroid therapy; however, patients do need to be monitored carefully postoperatively for local recurrence.[87] Furthermore, adrenal-sparing surgery for bilateral disease can now be done laparoscopically.
- One study showed that recurrence occurred over 10 years in 16% of patients who had biochemical evidence of eradication of tumor postoperatively.[93] Recurrence was higher in patients with familial pheochromocytomas or paragangliomas, right adrenal tumors, and extra-adrenal tumors. Excision of locally recurrent disease is indicated if feasible.
surgical candidate with malignant tumor: following initial medical treatment
surgical debulking
Comments
- As in benign disease, surgical removal/debulking to improve symptoms is the primary therapy; however, this may not be possible if the tumor has extensive local or metastatic spread.[73]
- One study showed that recurrence occurred over 10 years in 16% of patients who had biochemical evidence of eradication of tumor postoperatively.[93] Recurrence was higher in patients with familial pheochromocytomas or paragangliomas, right adrenal tumors, and extra-adrenal tumors. Excision of locally recurrent disease and metastasis is indicated if feasible.
postsurgical chemotherapy
Primary Options
Secondary Options
Comments
- Postsurgical chemotherapy is given to symptomatic patients and patients with metastatic disease.[35]
- There is no standard treatment approach for malignant pheochromocytoma.
- CVD (vincristine, dacarbazine, and cyclophosphamide) has been shown to have a complete and partial response rate of up to 57%; however, there was no significant difference in patient survival.[75] Responding patients had improvements in BP control and improved performance status.
- Chemotherapy is administered cyclically every 21 to 28 days. See local specialist protocol for dosing guidelines.
iobenguane I-131, radiation, or ablative therapy
Primary Options
iobenguane I 131
Comments
enrollment in clinical trial
Comments
- In cases of malignant pheochromocytomas refractory to both radiation therapy and chemotherapy, enrollment in a clinical trial is suggested and other treatment options, such as tyrosine kinase inhibitors (e.g., sunitinib), peptide receptor radionuclide therapy (lutetium Lu 177 dotatate also known as 177Lu-DOTATATE), immunotherapy (e.g., pembrolizumab), and hypoxia-inducible factor 2 alpha inhibitors (e.g., belzutifan), considered on a case-by-case basis.[25] [79] [85]
nonsurgical candidate with benign tumor: following initial medical treatment
continued medical treatment
Comments
- Patients with benign tumors, who are unable to undergo surgery - for example, due to a high surgical risk because of heart failure - should receive long-term BP control using alpha- and beta-blockers, as well as calcium-channel blockers if needed. Metyrosine is a less-preferred option for controlling hypertension.
- One study showed that recurrence occurred over 10 years in 16% of patients who had biochemical evidence of eradication of tumor postoperatively.[93] Recurrence was higher in patients with familial pheochromocytomas or paragangliomas, right adrenal tumors, and extra-adrenal tumors.
iobenguane I-131
Primary Options
iobenguane I 131
Comments
- Iobenguane I-131 (also known as I-131 metaiodobenzylguanidine [MIBG]) may be considered in symptomatic patients with an unresectable tumor if I-123 MIBG scintigraphy was positive.[75]
- See local specialist protocol for dosing guidelines.
nonsurgical candidate with malignant tumor: following initial medical treatment
continued medical treatment + chemotherapy
Primary Options
Secondary Options
Comments
- Symptomatic patients with extensive local or metastatic spread should receive long-term BP control using alpha- and beta-blockers, as well as calcium-channel blockers if needed. Metyrosine is a less-preferred option for controlling hypertension.
- In addition, chemotherapy regimens (usually consisting of cyclophosphamide, vincristine, and dacarbazine) should be administered cyclically every 21 to 28 days.[74] See local specialist protocol for dosing guidelines. Temozolomide is an alkylating drug and an alternative to dacarbazine, which can be used as monotherapy or in combination with other antitumoral drugs in patients with malignant pheochromocytomas and SDHB mutations.[80] [81]
- One study showed that recurrence occurred over 10 years in 16% of patients who had biochemical evidence of eradication of tumor postoperatively.[93] Recurrence was higher in patients with familial pheochromocytomas or paragangliomas, right adrenal tumors, and extra-adrenal tumors.
iobenguane I-131, radiation, or ablative therapy
Primary Options
iobenguane I 131
Comments
- Painful skeletal metastases can be treated with external beam radiation therapy.[77]
enrollment in clinical trial
Comments
- In cases of malignant pheochromocytomas refractory to both radiation therapy and chemotherapy, enrollment in a clinical trial is suggested and other treatment options, such as tyrosine kinase inhibitors (e.g., sunitinib), peptide receptor radionuclide therapy (lutetium Lu 177 dotatate also known as 177Lu-DOTATATE), immunotherapy (e.g., pembrolizumab), and hypoxia-inducible factor 2 alpha inhibitors (e.g., belzutifan), considered on a case-by-case basis.[25] [79] [85]
Emerging Tx
Targeted molecular therapies
HSP90 inhibitors
Prevention
Secondary Prevention
Follow-Up Overview
Prognosis
Benign disease
Metastatic disease
Monitoring
Complications
Citations
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Key Articles
Referenced Articles
Guidelines
Diagnostic
Summary
This guideline provides a comprehensive overview of the diagnostic approach for this cancer.Published by
National Comprehensive Cancer Network
Published
2023
Summary
Expert guidelines covering the evaluation of adrenal mass.Published by
American College of Radiology
Published
2021
Summary
Consensus guidelines on the medical management and surveillance of metastatic and unresectable pheochromocytoma and paraganglioma.Published by
North American Neuroendocrine Tumor Society
Published
2021
Summary
Provides evidence-based guidance on the diagnosis of pheochromocytoma and paraganglioma, including recommendations for biochemical testing, genetic testing, and imaging.Published by
Endocrine Society
Published
2014
Summary
Provides recommendations for evaluating neuroendocrine tumors, including pheochromocytomas.Published by
North American Neuroendocrine Tumor Society
Published
2013
Summary
Suspicion of pheochromocytoma requires early referral to a consultant. The initial test is 24-hour urine collection to measure metanephrines, which detect 70% to 91% of tumors.Published by
Towards Optimized to Practice Program
Published
2008; reviewed 2014
Treatment
Summary
This guideline provides a comprehensive overview of the management of this cancer.Published by
National Comprehensive Cancer Network
Published
2023
Summary
Evidence-based recommendations for adrenalectomy including surgical resection of paraganglioma/pheochromocytoma.Published by
American Association of Endocrine Surgeons
Published
2022
Summary
Provides evidence-based guidance on the management of pheochromocytoma and paraganglioma, including recommendations for surgery and perioperative care.Published by
Endocrine Society
Published
2014
Summary
Provides recommendations for treating neuroendocrine tumors, including pheochromocytomas.Published by
North American Neuroendocrine Tumor Society
Published
2013
Summary
Provides standardized clinical care for long-term follow-up in patients operated on for pheochromocytomas and paragangliomas.Published by
European Society of Endocrinology
Published
2016