Basics
Description
- Pheochromocytoma (pheo) is a catecholamine-producing tumor arising from the chromaffin tissues of the sympathetic nervous system.
- Origin from the adrenal medulla or sympathetic ganglia:
- 80% solitary adrenal (usually the right side)
- 10% bilateral (usually inherited form)
- 10% extra-adrenal in location:
- Abdominal, within mesenteric ganglia (86%)
- Thorax (10%), neck (3%), bladder (1%)
- 10% malignant (usually inherited form)
- Incidence:
- 0.2 " 0.4% of hypertensive patients, but higher proportion of patients with severe hypertension
- 2 " 8/million population per year
- Peaks in decades 3 " 5, 10% in children
- Male = female
- In about 1/2 of the cases, the diagnosis is made postmortem.
- 10% asymptomatic, incidental on CT
- Genetics:
- Inherited form 25%, autosomal dominant
- Usually associated with multiple endocrine neoplasia (MEN) 2A, less so with MEN 2B or von Hippel " Lindau (VHL) disease:
- MEN 2A (medullary thyroid carcinoma [CA], pheo, and hyperparathyroidism)
- MEN 2B (medullary thyroid CA, pheo, oral mucosal neuromas, skeletal and bony abnormalities)
- VHL (hemangioblastomas of retina and CNS, pancreas and renal cysts, and pheo
- Other associated diseases: Neurofibromatosis, tuberous sclerosis, Sturge " Weber syndrome, paragangliomas of the neck
Etiology
- The tumor synthesizes and stores catecholamines in the same manner as the normal adrenal medulla.
- Tumors predominantly secrete norepinephrine, and to a lesser extent epinephrine (some tumors are epinephrine predominant, in which hypotensive episodes are characteristic)
- Paroxysmal release of catecholamines:
- Spontaneously due to changes in blood flow or tumor necrosis
- Direct pressure on the gland from external forces (trauma, exercise)
- Precipitation of release (opiates, glucagon, metoclopramide, steroids, foods with tyramine, iodinated contrast media)
- Augmentation of catecholamine effect (tricyclic antidepressants [TCAs], ²-blockers, sympathomimetics)
Diagnosis
Signs and Symptoms
History
- Hypertension, moderate to severe, refractory to treatment:
- 40%: Paroxysms with normal BP between episodes
- 30%: Sustained hypertension with paroxysms
- 30%: Sustained hypertension without paroxysms
- Sometimes normotensive in familial forms and small tumors: <5%
- Paroxysmal symptoms
- Sudden onset, gradual resolution
- Duration: Minutes to hours (average 20 min)
- Intervals: Hours to months (average weekly)
- Increasing frequency, duration, and severity with time
- Clinical characteristics of paroxysms
- Hypertensive crisis or urgency
- Headache " abrupt, throbbing, bilateral
- Tachycardia/palpitations
- Profuse diaphoresis/pallor
- Apprehension/anxiety/tremulous
- Shock associated with trauma, surgery, parturition, anesthesia
- Acute crisis
- Prolonged (>24hr) severe paroxysm
- Severe HTN or shock, hyperpyrexia
- Multiorgan failure/lactic acidosis
- Pulmonary edema due to cardiomyopathy (dilated, hypertrophic or Takotsubo)
- Stroke (SAH, PRES, RCVS, embolic)
- Severe headache/encephalopathy
- Chest pain (MI/dissection)
- Acute abdomen
- Hemorrhagic tumor necrosis
- Mesenteric infarction
- Chronic symptoms
- Chest pains/palpitations
- Orthostasis (decreased plasma volume and blunted sympathetic reflexes)
- Constipation can be severe, leading to ileus or pseudo-obstruction (catecholamines inhibit peristalsis)
- Weight loss/fevers (increased metabolism)
- Lethargy, fatigue (catecholamine withdrawal))
- Polydipsia, polyuria (glucose intolerance)
- Anxiety, tremors, heat intolerance
Physical Exam
- Moderate to severe hypertension, often with orthostatic changes
- Tachycardic, diaphoretic, evidence of weight loss, low-grade fever
- Pallor, cold hands and feet (flushing not seen, except rarely after a paroxysm)
- Tremor, anxiety
- Mydriasis, hypertensive retinopathy
- Cafe au lait spots, neurofibromas, thyroid nodule
- No palpable masses (tumors tend to be small)
Essential Workup
- Accurate BP determination with orthostatic BPs
- ECG to exclude ischemia or dysrhythmias
Diagnosis Tests & Interpretation
- Overdiagnosis in >20% from misinterpretation of borderline biochemical tests and overzealous imaging
- Underdiagnosis is common from failure to consider the diagnosis or ignoring adrenal masses on CT.
Lab
- CBC:
- Elevated hemoglobin due to diminished plasma volume
- Elevated WBC from demargination
- Electrolytes, BUN, creatinine, glucose:
- Lactic acidosis
- Renal failure secondary to hypertensive nephropathy
- Hyperglycemia due to impaired response to insulin and effect of catecholamines
- Hypercalcemia due to excess parathyroid hormone
- Urinalysis: Proteinuria and hematuria
- Plasma-free metanephrine (fractionated):
- 96% sensitive, 85% specific " best screening test. Normal level excludes diagnosis, but many false positives
- Least likely to be interfered by medications or stress and no special prep for venipuncture
- 24 hr urine collection for free catecholamines and metanephrine (total and fractionated):
- 99.7% combined specificity and 87.5% sensitivity (best test for confirmation)
- Must include creatinine to verify adequate collection
- Medications that interfere: Levodopa, methyldopa, monoamine oxidase inhibitors (MAOIs), labetalol, propranolol, radiographic contrast media, sympathomimetics, benzodiazepines, TCAs, caffeine, nicotine
Imaging
- CT sensitive for adrenal masses >1 cm (IV contrast may pose a slight risk):
- 5% of incidental adrenal tumors seen on CT are pheos.
- MRI or positron emission tomography more sensitive in identifying adrenal pheos as well as identifying extra-adrenal tumors
- Metaiodobenzylguanidine (radionuclear scintiscan: High specificity for localization, but not sensitive enough to exclude pheo)
- Chest radiograph for pulmonary edema
- CT head for CVA/intracranial bleed
Diagnostic Procedures/Surgery
- Clonidine suppression test if diagnosis uncertain (levels not suppressed if pheo)
- Provocative testing with glucagon is not recommended.
- Fine-needle aspiration is contraindicated.
- Laparoscopic resection is feasible in many cases.
Differential Diagnosis
- Alcohol withdrawal syndrome
- Autonomic hyperreflexia
- Cerebral vascular accident
- Cocaine or amphetamine intoxication
- Hypertensive crisis
- Migraines/subarachnoid hemorrhage
- Panic attack
- Postural tachycardia syndrome
- Paroxysmal supraventricular tachycardia
- Posterior reversible encephalopathy syndrome
- Serotonin syndrome
- Thyrotoxicosis
- Toxemia
Treatment
Pre-Hospital
- IV access, oxygen
- Continuous cardiac/BP monitoring
- Nitroglycerin 0.4 mg SL for chest pain and HTN
Ed Treatment/Procedures
Management of Hypertensive Paroxysm
- Phentolamine:α-blockade:
- 1 mg IV test dose
- 2.5 " 5 mg IV bolus given at 1 mg/min repeat bolus every 5 " 15 min to BP control. Follow by infusion
- Infusion starting at 0.1 mg/min titrated up to 1 mg/min
- Vigorous fluid resuscitation required as vasoconstriction is relieved
- Traditional approach, but Nicardipine or Nitroprusside drip may be more practical
- ²-blockade:
- Add toα-blockade for further BP control
- If tachycardia develops during induction ofα-blockade
- NEVER USE ALONE: Institution of ²-blockade without priorα-adrenergic blockade may exacerbate hypertension by antagonizing ²-mediated vasodilation in smooth muscle.
- Esmolol: Load 500 Όg/kg over 1 min, followed by 50 Όg/kg/min for 4 min; if adequate therapeutic effect not achieved within 5 min, repeat loading dose and increase infusion to 100 Όg/kg/min; repeat loading dose and titrate infusion rate upward at 50 Όg/kg/min q4 " q5min as needed; omit further loading doses once nearing therapeutic target.
- Labetalol: Begin with 10 " 20 mg IV; BP falls within 5 min, maximum effect at 10 min; can double IV dose q15 " q30min until target reached (α-blockade inadequate to be relied on as a single agent).
- Metoprolol: 5 mg IV q15min until response
- Resistance toα- and ²-blockade or 1st-line option if unfamiliar with Phentolamine:
- Nitroprusside:
- Start at 0.5 Όg/kg/min
- Titrate by 0.5 Όg/kg/min increments
- Maximum dose 10, average needed 3 " 4
- Nicardipine:
- Start infusion at 5 mg/hr
- Titrate up by 2.5 mg/hr every 15 min
- 15 mg/hr maximum dose
- Add ²-blockade to vasodilator if needed
- Ventricular tachydysrhythmias:
- Lidocaine:
- 50 " 100 mg bolus
- Repeat bolus q5min (5 mg/kg max.)
- Esmolol 50 " 200 Όg/kg/min infusion
Medication
First Line
- Phenoxybenzamine: Start at 10 mg BID orally, titrate up 10 mg every other day until desired effect (start at least 7 days preop).
- Otherα-blockers (1st dose effect):
- Doxazosin: 1 " 8 mg/d (start at 1 mg)
- Terazosin: 1 " 10 mg/d (start at 1 mg)
- ²-blocker added to control reflex tachycardia:
- Metoprolol or atenolol: 25 " 100 mg/d
Second Line
- Calcium-channel blockers:
- Amlodipine, nicardipine, or nifedipine
- Inhibition of catecholamine synthesis:
- Metyrosine: 250 " 500 mg q6h
The following medications can precipitate hypertensive crisis in pheo:
- ²-blockers (if not pretreated withα-blocker)
- Glucagon
- Glucocorticoids
- Iodinated contrast media (ionic)
- Ketamine
- Metoclopramide
- Opiates
- Sympathomimetics, including over-the-counter decongestants
- May be confused with toxemia, but proteinuria is usually absent
- MRI is the preferred imaging modality.
- Nitroprusside should not be used for hypertensive crisis, but all other BP medications are acceptable.
- Spontaneous vaginal delivery will likely precipitate hypertensive crisis, such that C-section should be planned.
Follow-Up
Disposition
Admission Criteria
- Suspicion of pheo in an ill or toxic patient with labile swings in BP
- Hypertensive urgency or crisis
- Cardiac arrhythmias
- End organ compromise: Congestive heart failure, myocardial infarction, renal insufficiency, CVA, abdominal pain
Discharge Criteria
Stable patient with mild hypertension.
Follow-Up Recommendations
- Obtain plasma-free metanephrine during a hypertensive episode.
- Consider initiating doxazosin or terazosin or a calcium-channel blocker for BP control.
- Arrange close follow-up
Pearls and Pitfalls
- Paroxysms of severe hypertension, headache, intense diaphoresis, and palpitations comprise a tetrad very suggestive of pheo.
- Pallor and sweating, not flushing, is typical of pheo crisis.
- Orthostasis is common in pheo and it is further aggravated byα-blockade, unless volume repletion is not done concomitantly.
- Consider pheo in unexplained shock, multisystem organ failure, cardiomyopathy, new glucose intolerance with weight loss.
- Never administer ²-blockers (even labetalol) beforeα-blockade in patients with pheo
- Plasma-free metanephrine during an attack is very sensitive but not specific in the diagnosis
Additional Reading
- Anderson NE, Chung K, Willoughby E, et al. Neurologic manifestations of phaeochromocytomas and secretory paragangliomas: A reappraisal. J Neurol Neurosurg Psychiatry. 2013;84:452 " 457.
- Donckier JE, Michel L. Pheochromocytoma: State-of-the-art. Acta Chir Belg. 2010;110(2):140 " 148.
- Mannelli M, Lenders JW, Pacak K, et al. Subclinical pheochromocytoma. Best Pract Res Clin Endocrinol Metab. 2012;26:507 " 515.
- Prejbisz A, Lenders JW, Eisenhofer G, et al. Cardiovascular manifestations of pheochromocytoma. J Hypertens. 2011;29:2049 " 2060.
- Scholten A, Cisco RM, Vriens MR, et al. Pheochromocytoma is not a surgical emergency. J Clin Endocrinol Metab. 2013;98(2):581 " 591.
- Yu R, Nissen NN, Chopra P, et al. Diagnosis and treatment of pheochromocytoma in an academic hospital from 1997 to 2007. Am J Med. 2009;122:85 " 95.
Codes
ICD9
- 194.0 Malignant neoplasm of adrenal gland
- 227.0 Benign neoplasm of adrenal gland
ICD10
- C74.10 Malignant neoplasm of medulla of unspecified adrenal gland
- C74.12 Malignant neoplasm of medulla of left adrenal gland
- D35.00 Benign neoplasm of unspecified adrenal gland
- C74.11 Malignant neoplasm of medulla of right adrenal gland
- C74.1 Malignant neoplasm of medulla of adrenal gland
- D35.01 Benign neoplasm of right adrenal gland
- D35.02 Benign neoplasm of left adrenal gland
- D35.0 Benign neoplasm of adrenal gland
SNOMED
- 302835009 Pheochromocytoma (disorder)
- 91967007 Benign neoplasm of adrenal gland (disorder)
- 363355002 Malignant tumor of adrenal gland (disorder)