BASICS
DESCRIPTION
- A pheochromocytoma is a rare neuroendocrine tumor arising from the adrenal or extra-adrenal chromaffin tissue and, less commonly, the sympathetic ganglia.
- These tumors are catecholamine-producing: norepinephrine (NE) > epinephrine (EPI) > dopamine
- System(s) affected: endocrine; nervous; cardiovascular
- Synonym(s): chromaffin tumors; paragangliomas
EPIDEMIOLOGY
Incidence
- 500 to 1,000 cases per year were diagnosed in the United States.
- <0.2% of people with severe hypertension (HTN)
Prevalence
Affects all genders and ages; usually diagnosed in 4th to 5th decades of life, familial cases diagnosed 1 decade earlier
ETIOLOGY AND PATHOPHYSIOLOGY
Pheochromocytoma is a tumor that releases catecholamines into the circulation. Catecholamines bind to adrenergic receptors to produce various effects that could induce severe or lethal cardiovascular and cerebrovascular complications.
- Stimulation ofα1 receptors (NE > EPI) causes smooth muscle constriction resulting in high BP (arteriolar vasoconstriction).
- Stimulation ofα2 receptors (EPI > NE) causes smooth muscle contraction, cardiac muscle relaxation, and inhibition of hormones, such as insulin, resulting in elevated blood glucose levels.
- Stimulation of ²1 receptors (EPI = NE) causes heart muscle contraction resulting in increased heart rate.
- Stimulation of ²2 receptors (EPI > NE) causes smooth muscle relaxation.
- In 80% of cases, it is a sporadic disease of unknown etiology.
- In 20% of cases, it has familial origin and is a component of one of the following four autosomal dominant diseases.
- Multiple endocrine neoplasia type 2 (MEN-2)
- von Hippel-Lindau syndrome (VHL)
- Hereditary paraganglioma syndrome (PGL)
- Neurofibromatosis type 1 (NF-1)
- Tumor location
- 80% are solitary and unilateral.
- 20% are divided between bilateral lesions and extra-adrenal masses (organ of Zuckerkandl, neck, mediastinum, abdomen, pelvis).
Genetics
Genetic testing is recommended; genes are identified in the pathogenesis.
- Rearranged during transfection (RET) proto-oncogene
- von Hippel-Lindau disease tumor suppressor gene (VHL)
- Neurofibromatosis type 1 tumor suppressor gene (NH-1)
- Genes encoding four succinate dehydrogenase complex (SDH) subunits
- Gene encoding the enzyme responsible for flavination of the SDHA subunit
- Tumor suppressor TMEM127 gene
RISK FACTORS
- Familial pheochromocytoma
- Familial paraganglioma
- MEN-2
- VHL disease
- von Recklinghausen NF-1
COMMONLY ASSOCIATED CONDITIONS
- MEN-2A (medullary thyroid carcinoma and primary hyperparathyroidism)
- MEN-2B (medullary thyroid carcinoma and mucosal neuromas)
- VHL disease (retinal angiomas, cerebellar hemangioblastomas, renal cysts, carcinomas, pancreatic cysts, epididymal cystadenomas)
- NF-1
- Sturge-Weber syndrome
- Tuberous sclerosis
- Carney syndrome (gastric epithelioid leiomyosarcoma, pulmonary chondroma, extra-adrenal paraganglioma)
- Familial paraganglioma
- Ataxia-telangiectasia
- Renal artery stenosis
DIAGNOSIS
HISTORY
- Classic "triad " of symptoms includes headache, palpitations, and diaphoresis.
- 5 Ps mnemonic
- Paroxysmal spells
- Pressure: sudden increase in BP
- Pain: headache, chest, abdominal pain
- Perspiration (profuse sweating common in children)
- Palpitations and pallor
- Additional symptoms: constipation, tremor, weight loss, anxiety, paresthesias, flushing, shortness of breath, nausea/vomiting
- Sudden death may occur in patients with an undiagnosed tumor who undergo surgery or biopsy due to lethal hypertensive crises and multiorgan failure.
- Dopamine-secreting pheochromocytomas lack the classic presentation of catecholamine excess.
PHYSICAL EXAM
- HTN: paroxysmal in 50% of affected patients; most common clinical sign
- Tachyarrhythmias
- Orthostatic hypotension
- Cafe au lait spots and Lisch nodules of the eye (in neurofibromatosis)
- Grades II to IV retinopathy
- Transient ischemic attacks/stroke
- Cardiomyopathy
- GI crisis
- Diabetes mellitus/insipidus
- Fever
- Hypercalcemia
- Erythrocytosis
DIFFERENTIAL DIAGNOSIS
- Labile essential HTN
- Anxiety and panic attacks
- Paroxysmal cardiac arrhythmia
- Thyrotoxicosis
- Menopausal syndrome
- Hypoglycemia
- Withdrawal of adrenergic-inhibiting medications
- Angina
- Hyperventilation
- Migraine headache
- Amphetamine or cocaine use
- Sympathomimetic ingestion/overdose
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
Diagnosis is typically confirmed by measurements of urine catecholamines and their metabolites (NE/EPI ’ [nor]metanephrine, NE/EPI ’ vanillylmandelic acid [VMA], dopamine ’ homovanillic acid). Their amount in the urine correlates with tumor size.
- Elevated metanephrine and catecholamines in 24-hour urine collection (sensitivity, 90%; specificity, 98%)
- A positive test is considered to be a 2-fold elevation above the upper limit of normal in urine.
- Elevated plasma fractionated metanephrine (sensitivity, 97%; specificity, 85%)
- Measured while patient is at rest
- Pheochromocytoma cannot be excluded if normal catecholamine values are obtained when the patient is normotensive and asymptomatic (record BP at time of blood draw).
- Elevated VMA in 24-hour urine collection (sensitivity, 64%; specificity, 95%)
- Dopamine-secreting pheochromocytomas are often missed if urine or plasma dopamine is not included as part of the catecholamine screening. Urine and plasma dopamine are the most widely used methods in the diagnosis of dopamine-secreting tumors.
- Proceed with imaging after positive laboratory evaluation.
- Abdominal imaging with MRI/CT has similar specificity and sensitivity.
- If CT/MRI is negative, but clinical suspicion is high, imaging can be done with 123-I-metaiodobenzylguanidine (MIBG) scan/pentetreotide scan.
Follow-Up Tests & Special Considerations
- Drugs that may increase measured levels of catecholamines and metabolites should be discontinued at least 2 weeks before assessment (1)[C].
- Tricyclic antidepressants
- Monoamine oxidase inhibitors (MAOIs)
- Levodopa, methyldopa
- Drugs containing adrenergic receptor agonists (e.g., decongestants)
- Amphetamines
- Cocaine
- Buspirone and most psychoactive agents (but not SSRIs)
- Prochlorperazine
- Reserpine
- Withdrawal from clonidine and other drugs
- Ethanol
- Acetaminophen (may increase measured levels of fractionated plasma metanephrine in some assays)
- Drugs that may decrease measured levels of catecholamines and metabolites.
- Reserpine
- Centrally actingα2-receptor agonists (dexmedetomidine, clonidine, tizanidine, guanfacine)
- Conditions that may alter lab results include major physical stress due to surgery, stroke, myocardial infarction, congestive heart failure, and so forth.
Diagnostic Procedures/Other
Clonidine-suppression test distinguishes between pheochromocytoma and essential HTN when urine and plasma tests are equivocal. In essential HTN, plasma and urine catecholamines decrease 3 hours after oral clonidine; in pheochromocytoma, they do not.
Test Interpretation
Pathology shows a tumor that demonstrates staining for chromogranin-A (catecholamine secretory granules).
TREATMENT
MEDICATION
First Line
Surgical resection of the tumor is the treatment of choice. Medical management of BP is essential prior to surgery.
- Preoperative control of BP (target <120/80 mm Hg) achieved first withα-adrenergic blockade followed by ²-adrenergic blockade starting 1 week before surgical removal of pheochromocytoma (longer for patients with recent history of cardiovascular complication) (2)[B]. Never initiate ²-adrenergic blockade beforeα-adrenergic blockade, as unopposedα stimulation will result in worsened HTN.
- α-Adrenergic blockade is achieved with the nonselectiveα-blocker phenoxybenzamine starting at a dose of 10 mg PO BID and increasing by 10 to 20 mg every 2 days as needed and tolerated for BP control (normal dose 100 mg/day, but up to 240 mg/day has been reported). Warn patient of postural hypotension.
- After adequateα-adrenergic blockade, ²-blockade is initiated at low doses using short-acting agent propranolol 10 mg PO q6h that can be titrated up until resting heart rate of 60 to 80 beats/min is achieved (max dose 120 mg/day). Avoid ²-blockers in acute decompensated heart failure, bradycardia, and patients with uncontrolled asthma.
- Alternatively, preoperative BP control has been achieved with calcium channel blocker nicardipine initiated 8 to 21 days before adrenalectomy in limited studies (3)[B].
Second Line
- Treat hypertensive crisis with nitroprusside, nicardipine, or phentolamine.
- For inoperable tumors requiring long-term medical management, specificα1-blocking agents can be used due to a more favorable side effect profile: prazosin, terazosin, doxazosin
- Selective ²1 blockers (no ²2 activity): atenolol, metoprolol, nadolol
- Combined ²- andα-blockers: labetalol and carvedilol
- Catecholamine synthesis inhibitor: metyrosine only if intolerant to first-line treatment (Mayo Clinic protocol). Avoid long-term use due to adverse reactions (sedation, depression, diarrhea, crystalluria or urolithiasis, and extrapyramidal signs).
SURGERY/OTHER PROCEDURES
- Removal of pheochromocytoma is the treatment of choice.
- It is a high-risk surgical procedure requiring experienced surgical and anesthesia teams.
- Laparoscopic approach for tumors in the adrenal gland may result in shorter hospitalization.
- Cortical-sparing subtotal adrenalectomy may preserve adrenocortical function in those with bilateral disease.
INPATIENT CONSIDERATIONS
Admission Criteria/Initial Stabilization
- Severe/refractory HTN
- Control of HTN and replacement of volume with IV normal saline.
- BG monitoring
Nursing
Monitor BP closely. Monitor blood glucose for the first 24 hours closely in those with prolonged surgical time, larger tumor, and greater preoperative 24-hour urinary metanephrine level (4)[B].
Discharge Criteria
When hemodynamically stable
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
- Monitor BP daily before surgery.
- Invasive hemodynamic monitoring intraoperatively
- Monitor urine metanephrine and catecholamine 2 weeks postoperatively and, if normal, recheck annually.
- Ensure resolution of HTN and normalization of blood glucose.
DIET
- Preoperatively, after initiation ofα-blocker, encourage high-sodium diet (>5,000 mg/day) to increase blood volume and prevent orthostasis. May be contraindicated in setting of renal or heart failure
- Postoperatively, resume general diet.
PATIENT EDUCATION
National Adrenal Disease Foundation (NADF), 505 Northern Blvd., Great Neck, NY 11021; 516-487-4992; e-mail: nadfmail@aol.com
PROGNOSIS
- Survival after surgical removal of a benign tumor is similar to age-matched controls.
- Recurrence rate is 8 " 15%.
- 5-year survival for malignant disease is <50% (5)[A].
COMPLICATIONS
- The most common lethal complications are myocardial infarction and cerebrovascular accident.
- Postural hypotension due toα-blockade can be ameliorated with saline volume expansion/high-sodium diet.
- Intraoperative hypertensive crisis can be managed with IV nitroprusside, nicardipine, and phentolamine.
REFERENCES
11 Karagiannis A, Mikhailidis DP, Athyros VG, et al. Pheochromocytoma: an update on genetics and management. Endocr Relat Cancer. 2007;14(4):935 " 956.22 Bruynzeel H, Feelders RA, Groenland TH, et al. Risk factors for hemodynamic instability during surgery for pheochromocytoma. J Clin Endocrinol Metab. 2010;95(2):678 " 685.33 Brunaud L, Boutami M, Nguyen-Thi PL, et al. Both preoperative alpha and calcium channel blockade impact intraoperative hemodynamic stability similarly in the management of pheochromocytoma. Surgery. 2014;156(6):1410 " 1417.44 Chen Y, Hodin RA, Pandolfi C, et al. Hypoglycemia after resection of pheochromocytoma. Surgery. 2014;156(6):1404 " 1408.55 Scholz T, Eisenhofer G, Pacak K, et al. Clinical review: current treatment of malignant pheochromocytoma. J Clin Endocrinol Metab. 2007;92(4):1217 " 1225.
SEE ALSO
Hypertension, Essential; Multiple Endocrine Neoplasia (MEN) Syndromes
CODES
ICD10
- D35.00 Benign neoplasm of unspecified adrenal gland
- D35.02 Benign neoplasm of left adrenal gland
- D35.01 Benign neoplasm of right adrenal gland
- C74.90 Malignant neoplasm of unsp part of unspecified adrenal gland
- C74.92 Malignant neoplasm of unspecified part of left adrenal gland
- C74.91 Malignant neoplasm of unsp part of right adrenal gland
ICD9
- 227.0 Benign neoplasm of adrenal gland
- 194.0 Malignant neoplasm of adrenal gland
SNOMED
- Pheochromocytoma (disorder)
- benign pheochromocytoma (disorder)
CLINICAL PEARLS
- Rare catecholamine-secreting tumor with serious and potentially lethal cardiovascular complications
- Clinical presentation is variable, but classic triad consists of episodic headaches, diaphoresis, and tachycardia/palpitations in association with HTN.
- Diagnosis by urine screen for catecholamines and their metabolites followed by imaging studies (CT, MRI)
- Surgical removal of tumor is a standard therapy that must be preceded by a period of BP stabilization with nonselectiveα-adrenergic blockade, followed by ²-adrenergic blockade several days later.
- High-salt diet is initiated afterα-blockade to minimize orthostasis and ensure volume expansion.
- Never initiate a ²-blocker before adequateα-blockade is achieved.