Pheochromocytoma

Pheochromocytoma is a tumor of chromaffin cells that are embryologically derived from neural crest tissue. Neural crest cells become part of the central nervous system and the sympathetic ganglia; they also migrate into the primitive gut. (1) These cells are part of the diffuse neuroendocrine system and possess amine precursor uptake and decarboxylation (APUD) properties. (2) Therefore, neural crest cells are capable of producing a variety of neurotransmitter biogenic amines and physiologically active peptides (Table 1).

Pheochromocytomas (and also ganglioneuromas and neuroblastomas) arise from neural crest tissue, and each of these tumors may contain a mixture of cell types. The common embryologic heritage of these tumors helps explain the heterogeneity of their composition as well as their differing locations and chemical production.

Epidemiology

Pheochromocytoma occurs in 0.1 percent or less of hypertensive patients, generally presenting in the fourth through sixth decades. Because of the variety of chemicals released by pheochromocytomas and the differing tumor sites, the initial symptoms can be quite variable, and the diagnosis is usually made many years after the first vasomotor symptoms occur. (3) Consequently, urine screening for pheochromocytoma should be performed in patients with hypertension and a history of any of the conditions listed in Table 2.

Conventionally, pheochromocytomas are said to follow the 10 percent rule": 10 percent are malignant, 10 percent are bilateral, 10 percent are extra-adrenal and 10 percent are multiple. Malignant pheochromocytomas probably occur more often than 10 percent of the time, but they are difficult to diagnose because of the potential for concurrent development of these tumors at different sites. They also lack any specific histologic or biochemical markers for malignancy.

The only way to be certain of malignancy is to document the spread of tumor to tissue in which embryologic remnants of paraganglionic tissue are not normally found, such as the liver, lungs, spleen, bone and lymph nodes. (4) In one report, (5) DNA ploidy studies were performed in patients who were then followed for ten years. Thirty to 40 percent of the pheochromocytomas with altered DNA patterns eventually showed evidence of malignancy. When pheochromocytomas are extra-adrenal, the malignancy rate increases to about 30 percent. Among children, malignancy rates as high as 25 percent have been reported. An increased prevalence of bilateral and multiple tumors has been noted in juvenile and familial cases of pheochromocytoma.

Newer methods of diagnosis, such as scintigraphy with I-metaiodobenzylguanidine ([.sup.131]I-MIBG), (3) have revealed that extra-adrenal lesions occur as frequently as 38 percent of the time; one-third of these tumors are extra-abdominal. (6) Tumor sites range from the base of the brain to the testicles: pheochromocytomas have been reported to occur in the bladder wall, the interatrial cardiac septum, the pericardium and the neck, as well as in more common sites in paraganglionic tissues.

Clinical Presentation

Symptoms depend on the chemicals being liberated by the pheochromocytoma. The amino acid tyrosine is taken up in the normal adrenal medulla and is sequentially converted into dopa, dopamine, norepinephrine and epinephrine. Fifty to 70 percent of the tumors produce elevated levels of epinephrine, and 75 to 85 percent produce elevated levels of norepinephrine; more than 95 percent of pheochromocytomas produce elevated levels of either norepinephrine or epinephrine or both.

Hypotension and tachycardia may be the presenting symptoms of tumors that primarily secrete epinephrine. Occasionally, dopamine is secreted in abundance, and tumors that primarily secrete dopamine may produce no cardiovascular symptoms. Nevertheless, hypertension, either sustained or intermittent, is the clinical hallmark of pheochromocytoma.

The symptomatic triad of episodic sweating, headaches and palpitations has been shown to be 89 to 91 percent sensitive and 67 to 92 percent specific in detecting pheochromocytomas in hypertensive persons. (3) Other findings include pallor, accelerated hypertension, catecholamine myocarditis, (7) hypertensive heart failure, flushing, constipation, diarrhea, vasoconstriction, orthostatic hypotension, polycythemial (8) and abnormal results on glucose tolerance tests.

The symptoms are episodic and variable in duration, lasting less than 15 minutes in half of patients. Symptoms increase in severity and frequency with time.

Diagnosis

The diagnosis of pheochromocytoma is based on elevated levels of catecholamines, which are usually measured in the urine.

To confirm the diagnosis, 24-hour urine determinations of metanephrines, catecholamines and vanillylmandelic acid (VMA) may need to be performed on more than one occasion (Table 3). A mildly elevated metanephrine level alone is found in 10 to 20 percent of normal patients, but the addition of VMA and fractionated catecholamine determinations eliminates most questions of diagnosis. Measurement of free norepinephrine in 24-hour urine specimens is reported as the best catecholamine index for pheochromocytoma, with 100 percent sensitivity and 98 percent specificity. (9)

Management

Management of pheochromocytoma consists of screening for other possible tumor sites and providing alpha-adrenergic blockade to prevent a hypertensive crisis during surgery and hypotension after surgery. (10)

[.sup.131]I-MIBG scintigraphy has been recommended as an initial procedure for tumor localization. This technique has shown that multiple tumors, extra-adrenal tumors and extra-abdominal tumors are more common than initially thought. (6) Computed tomographic (CT) scanning and magnetic resonance imaging (MRI) are complementary to [.sup.131]I-MIBG scintigraphy for further localization or delineation of tumors. If [.sup.131]I-MIBG, CT and MRI studies fail to reveal the location of a suspected tumor, venous sampling or angiography may be necessary.

Drug therapy for pheochromocytoma is summarized in Table 4 [omitted]. Phenoxybenzamine (Dibenzyline) is most commonly used for alpha-adrenergic blockade. Oral therapy is adjusted until hypertension and symptoms are controlled. The patient needs to be normotensive and symptom-free for one week before surgery is performed. A high-salt diet is often recommended to aid in volume expansion.

Some patients with pheochromocytomas require beta-adrenergic as well as alpha-adrenergic blockade (Table 5). Vasodilating beta blockade should not be initiated until some alpha blockade is present, since alpha-adrenergic vasoconstriction may then increase blood pressure further. Propranolol (Inderal) is started at a dosage of 5 to 10 mg three times a day, which is usually increased to no more than 30 to 60 mg per day. If the patient has a history of asthma, a beta-adrenergic specific blocker such as metoprolol (Lopressor) is started at a low dosage.

If phenoxybenzamine therapy alone is not effective or causes unacceptable side effects, metyrosine (Demser) may be added. This drug can decrease catecholamine synthesis by 35 to 80 percent. Urinary VMA concentrations are measured as an index of catecholamine production. Maximum effectiveness should be maintained for five to seven days before surgery. If the patient is normotensive and symptom-free, the goal is a 50 percent or more decrease in urinary VMA levels.

Prazosin (Minipress) is reported to be a more selective alpha-adrenergic blocking agent that is as effective as phenoxybenzamine, but without as many side effects. (11) However, this drug works by competitive inhibition, which may be overcome by a massive release of catecholamine. (12) Use of prazosin should be limited to situations in which phenoxybenzamine produces too many side effects.

Phentolamine mesylate (Regitine) is occasionally used for hypertensive emergencies caused by a suspected or newly discovered pheochromocytoma. For control of blood pressure during surgery, this agent has, in general, been replaced by nitroprusside (Nipride, Nitropress), which does not present the risk of continued severe hypotension after surgery.

Management During Pregnancy

The occurrence of pheochromocytoma during pregnancy is rare, but this situation carries an even greater risk than that of typical pheochromocytoma. Pheochromocytoma that is undiagnosed before labor is associated with a 58 percent maternal and 56 percent fetal mortality rate. When the diagnosis is made before labor, the maternal mortality rate is about 40 percent, and the fetal mortality rate may be as low as 10 percent. (13)

Symptoms of pheochromocytoma are the same in pregnant patients as in other patients, except that the incidence of headaches may be higher. Pheochromocytoma during pregnancy may present clinically in various ways (Table 6). To minimize fetal risk, confirmation of diagnosis after urinary studies is usually attempted with ultrasound or MRI.

One point is clear in the management of pregnant patients with pheochromocytoma: labor and vaginal delivery should not be attempted, since the outcome is poor for both mother and fetus, probably because of the elevation of catecholamines during labor.

Most authors recommend immediate surgical removal of a tumor found during the first or second trimester. If the tumor is discovered in the third trimester, the patient should receive alpha blockade therapy until the fetal lungs are mature, when a cesarean section should be performed. If the tumor cannot be resected or located early in pregnancy, alpha blockade should be instituted until a cesarean section is performed. When indicated, beta blockade should also be instituted, although this therapy has many potential effects on the fetus, including intrauterine growth retardation, hypoglycemia, bradycardia and respiratory depression. (13) Phenoxybenzamine has been used without fetal complications, but the possible adverse effects are unknown.

Postoperative Management

Postoperative management of pheochromocytoma involves control of continued hypertension and long-term followup for late recurrence. Approximately 40 percent of patients may continue to be hypertensive (blood pressure greater than 160/95 mm Hg) after surgery for pheochromocytoma. (14)

Because of this high rate of continued hypertension after surgery, recurrence of pheochromocytoma may be difficult to detect. Recurrence of initially benign-appearing pheochromocytomas may take six months to 21 years, with one report showing an average of eight years until recurrence. (5) The incidence of recurrence is reported to be 10 percent.

Recommendations for the detection of pheochromocytoma recurrence vary from annual screening for five years (1) to twice-yearly screening for 15 or more years. (4) Both [.sup.131]I-MIBG scanning and 24-hour urine collections to measure catecholamine levels have been recommended and should serve as complementary screening examinations. Early detection gives a much better long-term prognosis.

REFERENCES

1. Sheps, SG, Jiang NS, Klee GG. Diagnostic evaluation of pheochromocytoma. Endocrinol Metab Clin North Am 1988;17:397-414.

2. Pearse AG, Takor T. Embryology of the diffuse neuroendocrine system and its relationship to the common peptides. Fed Proc 1979;38: 2288-94.

3. Plouin PF, Chatellier G, Rougeot MA, et al. Recent developments in pheochromocytoma diagnosis and imaging. Adv Nephrol 1988; 17:275-86.

4. Scott HW Jr, Reynolds V, Green N, et al. Clinical experience with malignant pheochromocytomas. Surg Gynecol Obstet 1982;154: 801-18.

5 .Hosaka Y, Rainwater LM, Grant CS, Farrow GM, van Heerden JA, Lieber MM. Pheochromocytoma: nuclear deoxyribonucleic acid patterns studied by flow cytometry. Surgery 1986;100:1003-10.

6 .Cheung PS, Thompson NW, Dmuchowski CF, Sisson JC. Spectrum of pheochromocytoma in the [.sup.131]I-MIBG era. World J Surg 1988;12: 546-51.

7. Van Vliet PD, Burchell HB, Titus JL. Focal myocarditis associated with pheochromocytoma. N Engl J Med 1966;274:1102-8.

8. Shulkin BL, Shapiro B, Sisson JC. Pheochromocytoma, polycythemia, and venous thrombosis. Am J Med 1987;83:773-6.

9 .Duncan MK Compton P, Lazarus L, Smythe GA. Measurement of norepinephrine and 3,4-dihydroxyphenylglycol in urine and plasma for the diagnosis of pheochromocytoma. N Engl J Med 1988;319:136-42.

10. Ross EJ, Prichard BN, Kaufman L, Robertson Al, Harries BJ. Preoperative and operative management of patients with phaeochromocytoma. Br Med J 1967; 1(534):191-8.

11. Havlik RJ, Cahow CE, Kinder BK. Advances in the diagnosis and treatment of pheochromocytoma. Arch Surg 1988;123:626-30.

12. Reuse C, Vincent JL, Matos C, de Rood M, Unger J. Pheochromocytoma. Intensive Care Med 1987;13:371-8.

13. Ellison GT, Mansberger JA, Mansberger AR Jr. Malignant recurrent pheochromocytoma during pregnancy: case report and review of the literature. Surgery 1988; 103:484-9.

14. Stenstrom G, Ernest I, Tisell LE. Long-term results in 64 patients operated upon for pheochromocytoma. Acta Med Scand 1988;223: 345-52.

15. Sparagana M. Late recurrence of benign pheochromocytomas: the necessity for long-term follow-up. J Surg Oncol 1988;37:140-6.

JOHN J. HART, M.D. is assistant professor of family and community medicine at the University of Kansas School of Medicine-Wichita, HCA/Wesley Family Practice Residency Program, Wichita, where he also served a family practice residency. Dr. Hart is a graduate of the University of Missouri-Columbia School of Medicine.

COPYRIGHT 1990 American Academy of Family Physicians
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