TOC  |  ENDO

Pheochromocytoma       SX |  DX  |  RX  | Diff-Dx  

Consider pheochromocytoma if the hypertensive patient has the triad of headache, sweating, & palpitations.   Although rare (0.1% of hypertensive patients), pheochromocytoma is a life-threatening but potentially curable condition. Over 90% of patients with pheochromocytoma have hypertension, and over half have sustained elevations of blood pressure.   Pheochromocytomas are chromaffin cell tumors that, although rare, must be considered in patients with hypertension, autonomic disturbances, panic attacks, adrenal incidentalomas, or familial diseases featuring a predisposition to develop pheochromocytoma.

Use history findings to determine the need for biochemical testing for pheochromocytoma.   * Consider evaluating patients with:

SX:

Determine the need for pheochromocytoma testing with physical exam or imaging studies.  Look for:

Lab. tests  for suspected pheochromocytoma

Consider measurement of metanephrines and catecholamines in a 24-hour urine collection and metanephrines in blood for patients with suspected pheochromocytoma.

  1. Measure 24-hour urinary metanephrine excretion if clinical suspicion for pheochromocytoma is low; for example, in the asymptomatic patient with:
    * New onset, stage 1 hypertension * An incidentally discovered adrenal mass with findings on CT that are consistent with a benign cortical adenoma
  2. Measure 24-hour urinary excretion of metanephrines and catecholamines and plasma metanephrines if clinical suspicion is high
    (start the 24-hour urine collection with the onset of a spell, if possible.)

24-hour urinary total metanephrines  - Sensitivity 76-95%, Specificity 94-99%.

24-hour urinary catecholamines  - Sensitivity 77-95%, Specificity 79-99%

Plasma metanephrines  - Sensitivity 99-100%,  Specificity  85-89%

Plasma catecholamines  - Sensitivity 85%, Specificity 80%  

CT abdominal scan  - Sensitivity 93-100%, Specificity 50%  

MRI abdominal scan  - Sensitivity 93-100%, Specificity 75%  

123I-MIBG scintigraphy  - Sensitivity 80%, Specificity 99%

Central venous blood sampling

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* Plasma free metanephrines provide the best test for exluding or confirming pheochromocytoma & should be the test of first choice for diagnosis of the tumor.  JAMA March 20, 2002;287:1427 Jacques W. Lenders, etc

Diagnosis of pheochromocytoma usually requires biochemical evidence of excessive catecholamine production by the tumor, usually achieved from measurements of catecholamines or catecholamine metabolites in urine or plasma. These biochemical approaches, however, have several limitations.

Since catecholamines are normally produced by sympathetic nerves and by the adrenal medulla, high catecholamine levels are not specific to pheochromocytoma and may accompany other conditions or disease states. In addition, sometimes pheochromocytomas do not secrete enough catecholamines to produce positive test results or typical signs and symptoms. In addition, pheochromocytomas often secrete catecholamines episodically. Between episodes, levels of catecholamines may be normal. Thus, commonly used tests of plasma or urinary catecholamines and metabolites and other biochemical tests, such as measurements of plasma chromogranin A levels, do not always reliably exclude or confirm a tumor. A recently developed biochemical test, involving measurements of plasma levels of free metanephrines (o-methylated metabolites of catecholamines), circumvents many of the above problems and offers a more effective means to diagnose pheochromocytoma than other tests .

A. Plasma catecholamine measurement, as plasma free metanephrines  

Plasma concentrations of normetanephrine greater than 2.5 pmol/mL or metanephrine levels greater than 1.4 pmol/mL (more than 4- and 2.5-fold above the upper reference limits) indicate a pheochromocytoma with 100% specificity.  

As with all biochemical tests, high plasma levels of normetanephrine or metanephrine do not necessarily prove a pheochromocytoma.  

Most patients with pheochromocytoma can be identified immediately by a single test of plasma metanephrines.   Many patients have marginally elevated plasma levels of normetanephrine or metanephrine. Among this group, differentiating true-positive from false-positive results remains a problem.  Additional follow-up biochemical tests should include measurements of plasma catecholamines and repeated measurements of metanephrines.  Since metanephrines are produced continuously by a pheochromocytoma, normal plasma levels of normetanephrine and metanephrine in a second test exclude pheochromocytoma, even if results of the first test or other tests are positive. If plasma metanephrines remain positive, then the pattern of alterations in other results can be helpful in planning a strategy for further testing, as the clonidine suppression test.]

Conclusion:   Plasma free metanephrines provide the best test for excluding or confirming pheochromocytoma and should be the test of first choice for diagnosis of the tumor.  JAMA  March 20, 2002;287:1427 - Jazques Lenders, etc.

B. Total metanephrine & normetanephrine in 24-hour urine specimen

C. Urinary free catecholamines

D. Urinary VMA

E. Provocative and suppression tests

These tests are useful if the laboratory studies are inconclusive.

1. The clonidine suppression test differentiates pheochromocytoma from essential hypertension in patients exhibiting elevated norepinephrine levels. Administration of 0.3 mg clonidine will suppress norepinephrine into the normal range within 3 hours after administration in essential hypertension patients but not in patients with pheochromocytoma. False-negatives and false-positives have been reported.
The clonidine suppression test is useful for distinguishing between high levels of plasma norepinephrine caused by release from sympathetic nerves and those caused by release from a pheochromocytoma. A decrease of more than 50% in plasma norepinephrine levels or a decrease after clonidine administration to less than 2.96 nmol/L indicate normal responses, whereas consistently elevated concentrations before and after clonidine administration indicate a pheochromocytoma. When the above criteria for a normal response are used, the test is highly specific. However, in patients with intermittently secreting tumors or those in whom plasma norepinephrine concentrations are normal or only marginally elevated, plasma norepinephrine levels may decrease regardless of a tumor, resulting in a false-negative test result. False-positive test results can occur in patients taking diuretics or tricyclic antidepressants. However, except in these cases, clonidine rarely fails to decrease plasma norepinephrine levels in patients without pheochromocytoma.
** Severe hypotensive episodes may occur during the test.  The test should be done by experienced clinician.

2. Pentolinium, a preganglionic-blocking agent, when administered in a dose of 2.5 mg, causes a drop in catecholamine levels in patients without pheochromocytoma. Since pheochromocytomas do not have a preganglionic nerve supply, no change is seen in catecholamine levels in these patients.

3. Glucagon and histamine can be used to provoke attacks but are associated with side effects as well as pressor crisis. Both glucagon and histamine are limited by false-positive and false-negative responses. If these agents are used, phentolamine should be available for administration in a dosage of 2.5 mg IV q5min should a pressor hypertensive crisis occur.
The glucagon stimulation test can be useful when high plasma levels of normetanephrine or metanephrine are noted and plasma catecholamine levels are normal or moderately elevated. A greater than threefold increase in norepinephrine levels 2 minutes after intravenous administration of glucagon indicates a pheochromocytoma with high specificity. However, the test is not sensitive, and a negative test result does not exclude pheochromocytoma.
** Severe hypertensive episodes may occur during the test, and it should be done by experienced clinicians.

Differential Diagnosis of Elevated plasma catecholamine & urin. metanephrine levels:


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Surgical excision of the tumor (adrenalectomy) is the definitive treatment for pheochromocytoma,  

Surgery for pheochromocytoma entails several considerations. Induction of anesthesia before surgery, manipulation of the tumor, or other stimulation can cause massive outpouring of catecholamines from the tumor, resulting in hypertensive crisis, stroke, arrhythmias, or myocardial infarction. To prevent these problems, patients with pheochromocytoma must undergo pharmacologic blockade of catecholamine synthesis or effects before surgery.

Preoperative therapy should precede surgery by at least 1-2 weeks to allow for volume repletion and the return of normal baroreflex function.
Many centers do not employ preoperative alpha blockade in patients who are clinically stable, and complete blockade is contraindicated because the surgeon will be unable to guide surgical removal by blood pressure response to palpation in the vicinity of the tumor.

The combination of metyrosine, phenoxybenzamine, a Beta-blocker, and liberal salt intake starting 10 to 14 days before surgery leads to better control of blood pressure and decreases surgical risks. Combined medical blockade also allows relaxation of the constricted vascular tree and expansion of the reduced plasma volume, thus avoiding shock after sudden diffuse vasodilation at the time of tumor removal. At midnight before surgery, the patient receives phenoxybenzamine and metyrosine and is assigned to bedrest to avoid orthostatic hypotension. Intravenous fluids are administered for hydration and to ensure adequate blood volume.

After adequate medical blockade and hydration, surgical excision of pheochromocytoma has been performed through a transabdominal incision, with palpation of the contralateral adrenal gland and sympathetic chain to identify possible additional tumors. Patient survival rates of 97.7% to 100% are usual after such procedure.

Steroid "replacement" therapy after bilateral adrenalectomy often does not suffice for normalizing quality of life. Between 25% and 33% of patients undergoing bilateral adrenalectomy develop Addisonian crisis at some point, and attendant mortality rates are high. Moreover, 30% of patients develop clinically significant fatigue, and 48% consider themselves handicapped.

In patients with pheochromocytoma, partial adrenalectomy can preserve adrenocortical function and avoid the morbidity of medical adrenal replacement.

Postoperative follow-up of patients with sporadic and familial forms of pheochromocytoma includes evaluation of plasma metanephrine levels at approximately 6 weeks and again at 6 months after surgery. Because of the high rate of tumor recurrence in familial pheochromocytoma, we recommend yearly follow-up in these patients. Imaging studies should be performed on the basis of follow-up test results.

[Dr. Y.I.C. - I usually give Dybenzyline (Phenoxibenzamine) 10 mg bid for 10 days prior to surgery and give about 60 to 70 mg at midnight before of the surgery. Perioperative management demands expert anesthesiologic care, sometimes pt. may require 8 to 12 liters of fluid in 24 hrs after the tumor is out. ]

Recognize the importance of drug preparation in maximizing chances of a successful surgical outcome.

  1. Administer both alpha-adrenergic and beta-adrenergic blockers preoperatively. C
  2. Consider long-acting, calcium channel blockade or tyrosine hydroxylase inhibition if alpha-adrenergic and beta-adrenergic blocking agents are ineffective or poorly tolerated. C
  3. Treat acute hypertensive crises with intravenously administered agents. C
  4. Consider treatment in patients with malignant or unresectable disease with tumor-directed therapy in addition to the previously outlined drug therapy with alpha-adrenergic blocker, beta-adrenergic blocker, and/or a calcium channel blocker.

A. Acute medical therapy

In the patient with severe hypertension or other dramatic symptoms in whom pheochromocytoma is known or suspected, acute therapy includes the following:

  1. Bed rest with the head of the bed elevated.
  2. Alpha-receptor blockade can be achieved with phentolamine, 2-5 mg IV q5min until blood pressure is stabilized.
  3. Sodium nitroprusside (100 mg in 500 ml dextrose as an infusion) can be titrated to control blood pressure.
  4. Beta blockade can be used to control arrhythmias only after alpha blockade has been achieved.  
    Propranolol (1-2 mg IV every 5-10 minutes)     or esmolol (0.5 mg/kg IV over 1 minute followed by an infusion of 0.1-0.3 mg/kg/min)
  5. Intravascular volume replacement may be necessary with adequate alpha blockade. The amount is best determined by monitoring pulmonary wedge pressure.

B. Prolonged medical therapy 
Patients who have had recent myocardial infarctions, evidence of catecholamine cardiomyopathy, or metastatic pheochromocytoma might require prolonged medical therapy. Patients who are in their last trimester of pregnancy are best managed by maintaining alpha blockade followed by cesarean delivery and tumor removal. Drug therapy includes the following:

  1. Alpha blockers.
    Dybenzyline (Phenoxybenzamine) 10 mg bid
    It is a long-acting alpha-adrenergic blocker, can be given 10 mg bid initially and gradually increased by 10-20 mg/day to a total daily dose of 40-200 mg.
    Prazosin    , a selective alpha-1 blocker, is also effective, with a usual required dosage of 1-2 mg bid or tid.
    Terazosin (Hytrin)     1-10 mg/d PO
    Doxazosin
  2. Beta blockers are used after adequate alpha blockade is achieved.
    Propranolol/ Inderal      (20-40 mg q6h) is effective for treatment of supraventricular arrhythmias.
    Metoprolol/Lopressor    , 50-100 mg, a relative cardioselective beta blocker, is more appropriate in most patients.
  3. Metyrosine, an inhibitor of tyrosine hydroxylase, is used in patients whose condition is inoperable or in those with metastatic malignant pheochromocytoma.
  4. Medications such as labetalol, captopril, verapamil, and nifedipine have been used successfully in selected situations. Combination therapy with cyclophosphamide, vincristine, and dacarbazine can be used in advanced malignant pheochromocytoma. Somatostatin has been used with success to control symptoms in patients with metastatic pheochromocytomas producing vasoactive intestinal polypeptide (VIP) and calcitonin.     

In patients with malignant or unresectable disease, consider treatment with tumor-directed non-drug therapy.

Drug Treatment for Pheochromocytoma:

Phenoxybenzamine (Dybenzyline)

alpha-methyl-?-L-tyrosine (metyrosine)

Nicardipine

Phentolamine

Nitroprusside

Differential Diagnosis of Pheochromocytoma                      

Thyrotoxicosis

Primary hypogonadism (e.g., menopausal syndrome)

Pancreatic tumors (e.g., insulinoma)

Medullary thyroid carcinoma

"Hyperadrenergic" spells

Essential hypertension - labile

Angina and cardiovascular deconditioning

Dilated cardiomyopathy

Syncope

Orthostatic hypotension and autonomic neuropathy

Paroxysmal cardiac arrhythmia

Renovascular hypertension

Anxiety, panic attacks, and hyperventilation

Withdrawal of adrenergic-inhibiting medications (e.g., clonidine)

Monoamine oxidase inhibitor treatment and concomitant ingestion of tyramine or a decongestant

Sympathomimetic ingestion

Illicit drug ingestion (e.g., cocaine, phencyclidine, lysergic acid)

Postural orthostatic tachycardia syndrome (POTS)

Mastocytosis (systemic or activation disorder)

Carcinoid syndrome

Recurrent idiopathic anaphylaxis

Unexplained flushing spells

REF:
ACP - PIER 2004
Ann Intern Med. 20 Feb. 2001;134:315-329 (NIH Conference)

         

122004