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Holzheimer RG, Mannick JA, editors. Surgical Treatment: Evidence-Based and Problem-Oriented. Munich: Zuckschwerdt; 2001.

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Pheochromocytoma

, M.D. and , M.D.

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Pheochromocytomas are relatively uncommon tumors, with a prevalence of 0.3% to 0.95% in autopsy series. Patients with pheochromocytomas have a potentially curable cause of hypertension and, if undetected, pheochromocytomas present a high risk of morbidity and mortality especially during surgical procedures and pregnancy. Most pheochromocytomas are sporadic, but may be associated with other endocrine and familial disorders. Symptoms are due to excess catecholamine production.

Definition, origin, and epidemiology

Pheochromocytomas are functional catecholamine-secreting tumors of the paraganglionic chromaffin cells found in the adrenal medulla and the extra-adrenal paraganglia cells. Embryologically, the paraganglia system originates from the neural crest cells, which can differentiate and migrate to form the adrenal medullary chromaffin cells, autonomic ganglion cells, and the extra-adrenal paraganglionic cells. These cells belong to the amine precursor uptake decarboxylase (APUD) cells.

Pheochromocytomas represent about 4% of incidental adrenal masses, and are the cause of hypertension in 0.1% of hypertensive patients. Pheochromocytomas occur equally in men and women, with approximately equal frequency in both adrenal glands. Approximately 10% of pheochromocytomas are extra-adrenal, bilateral, multifocal, malignant, found in children, or associated with a hereditary or familial syndrome. Pediatric pheochromocytomas account for 10% of all pheochromocytomas; these are characterized by a slight male predominance and are less likely malignant than adult tumors. Approximately 30% of pediatric pheochromocytomas are bilateral, extra-adrenal, multiple, or familial.

Extra-adrenal pheochromocytomas

Extra-adrenal pheochromocytomas account for approximately 10% of pheochromocytomas in adults and 30% in children. These are often multicentric and are more likely to be malignant than adrenal pheochromocytomas (36% vs. 10%). They are rarely associated with familial and hereditary pheochromocytoma, except in Carney's syndrome, which is associated with functioning extra-adrenal paraganglioma, pulmonary chondroma, and gastric epithelioid leiomyosarcoma.

Extra-adrenal pheochromocytomas are most commonly found in the organ of Zuckerkandle at the distal aorta and aortic bifurcation, but can also be found between the base of the skull and the spermatic cords, with 85% of these extra-adrenal tumors located below the diaphragm. Bladder pheochromocytomas are usually located at the trigone or dome of the bladder; patients may present with hematuria or micturation induced symptoms.

Familial and hereditary pheochromocytomas

Approximately 10% of pheochromocytomas are familial, associated with neuroectodermal disorders (von Hippel-Lindau disease, von Recklinghausen's disease, tuberous sclerosis, Sturge-Weber syndrome or Carney's syndrome) or as a part of hereditary multiple endocrine neoplasia (MEN) 2A and 2B. In MEN-2, bilateral adrenal medullary hyperplesia (diffuse or nodular) is almost always present and precedes pheochromocytoma, which develops in 30–50% of patients. Pheochromocytomas are usually multicentric and bilateral in up to 50–80% of cases with long term follow-up. They are rarely extra-adrenal or malignant. The incidence of clinically significant adrenal medullary disease is greater in MEN-2B. In up to 25% of cases, the diagnosis of pheochromocytoma precedes that of C-cell disease. Therefore, mutation analyses of the RET proto-oncogene on exons 10 and 11 should be performed in all patients with pheochromocytoma to screen for MEN-2.

Pheochromocytomas associated with neuroectodermal disorders are most common in von Hippel-Lindau disease, occurring in approximately 25% of patients. They are often bilateral and rarely extra-adrenal except in Carney's syndrome, which is associated with functioning extra-adrenal paraganglioma. All patients with “sporadic” pheochromocytoma should be screened for MEN-2 and van Hippel-Lindau disaese.

Pathophysiology and symptomatology

Most pheochromocytomas are reddish brown and encapsulated, measuring between 3–5 cm, and weighing about 100 g. They are highly vascular with areas of focal hemorrhage and calcification. Tumor cells are usually arranged in whirls or sheets, have granular basophilic or esinophilic cytoplasm with nuclear pleomorphism.

Pheochromocytomas secrete predominantly norepinephrine. Phenylethanolamine N-methyltransferase enzyme, which converts norepinephrine to epinephrine, is present primarily in the adrenal medulla and organ of Zuckerkandle. Therefore high levels of epinephrine are suggestive of pheochromocytoma in these organs. Rarely, pheochromocytomas secrete other neurohormones such as dopamine, VIP, adrenocorticotrophic hormones, β-endorphines, and a variety of other substances that can complicate the clinical manifestations and the differential diagnosis.

Pheochromocytomas are the cause of hypertension in about 0.1% of hypertensive patients. The cardiovascular pathophysiology of pheochromocytoma is characterized by:

1.

Lack of correlation between plasma concentration of catecholamine and hemodynamic profile or heart disease.

2.

The hemodynamic features of hypertension in patients with pheochromocytoma are similar to those in patients with essential hypertension, and are characterized by vasoconstriction, increased peripheral vascular resistance, and left ventricular strain and hypertrophy.

3.

Orthostatic hypotension, with an average decrease of 14 mmHg in systolic pressure, and orthostatic tachycardia commonly occur in pheochromocytoma (71% and 58% respectively) due to failure of increased peripheral vascular resistance.

4.

50% of patients with pheochromocytoma exhibit sustained hypertension, 45% are normotensive between paroxysms of hypertension, and approximately 5% are normotensive. Hypertension is more often sustained rather than paroxysmal in 90% of children with pheochromocytoma.

5.

20% of patients with pheochromocytoma will have essential hypertension.

The mechanism of hypertension is complex and multifactorial involving both neural and hormonal (both vasopressors and vasolidators) mechanisms, as there is no correlation between catecholamines levels and hypertension. Neural mechanisms include increassed central sympathetic activity and downregulation of the adrenergic receptors. Increased plasma renin activity and renin dependdent mechanisms contribute to the pathogenesis of hypertension as evident by the effect of captropil in lowering the blood pressure in these patients. Plasma atrial natriuretic peptide and adrenomedullin levels are also increased in patients with pheochromocytoma but not in Patients with essential hypertension or normotensive patients. These potenz vasodilator hormones play a role in the physiological control of the vescular tone and pathogenesis of hypertension and/or orthostatic hypotension and tachycardia. The orthostatic hypotension and failure of increased peripheral vascular resistance is due to reduced responsiveness of the vasculare to norepinephrine, probably due to down regulation of α-adrenergic receptors resulting from persistent elevation of the physiological agonist norepinephrine. The tachycardia results from hypotension-stimulated, baroreceptor mediated, central neurogenic sympathetic stimulation of the heart.

Symptoms are rather non-specific and are attributed to excess catecholamines. There is no correlation between the size of pheochromocytoma and levels of circulating catecholamines. Small tumors tend to release larger amounts of catecholamines because of their rapid turnover. In larger tumors, catecholamines are metabolized within the tumor and small amounts are released into the circulation. The classical triade consists of three cardinal symptoms: headache, excessive and inappropriate sweating, and palpitations. Headache tend to be occipital rather than temporal, as is typical in patients with essential hypertension. Other symptoms include weakness, fatigue, tremulousness, abdominal and bone pain, nausea, anxiety, dizziness, flushing, weight loss, parathesia, and exercise induced headache. The most frequent physical findings include hypertension, tachycardia, orthostatic hypotension, myadriasis hyperglycemia, lactic acidosis, abdominal mass, and signs of associated familial or hereditary syndromes. ECG may show ST segment elevation or depression, inverted or flattened T-waves, prolonged QT intervals, high or peaked P waves, and tachyarrhythmias.

Hyper- or hypotensive crisis, myocardial ischemia, tachyarrhythmias, congestive heart failure and cerebral vascular accidents account for 75% of morbidity and mortality of untreated or undiagnosed pheochromocytomas. Other complications include tumor hemorrhage, renal infarction, rhabdomyolysis, renal failure, seizures, reversible cutaneous leukocytoclastic vasculitis, hypercalcemia, acute abdomen with marked hyperamylasemia, and disseminated intravascular coagulation.

Detailed history and physical examination can differentiate pheochromocytoma from other organic and psychiatric disorders frequently associated with hypertension, most commonly; anxiety/panic disorders, migraine and cluster headaches, post-traumatic stress disorder exacerbation, hyperthyroidism, menopausal syndrome, carcinoid syndrome, reactive hypoglycemia, and various drugs including amphetamines, ephedrine, pseudoephedrine, phenylephrine, and isoproterenol. Most of these conditions are not associated with markedly elevated catecholamine levels seen in pheochromocytoma.

Biochemical diagnosis

Assay of catecholamine production and excretion is required to confirm the diagnosis of suspected pheochromocytoma. Various tests for biochemical diagnosis of pheochromocytoma include measurement of plasma catecholamines (norepinephrine and epinephrine), and 24 h urine for catecholamines, normetanephrines, and metanephrines. Measurements of urinary vanillylmandelic acid, dopamine, dihydroxyphenylglycol, and dihydroxyphenylacetic acid are less sensitive and specific and are not recommended for screening. No single test is diagnostic for pheochromocytoma. The sensitivity and specificity increases when multiple tests are ordered. The measurement of 24 h urine metanephrines and normetanephrines appears to yield the highest sensitivity (97–100%) and specificity (84–98%), with the lowest false negative rate at 1% to 2%. The sensitivity and specificity of these chemical tests are much improved when high-pressure liquid chromatography, radioimmunoassay, or gas chromatography/mass spectrometry assays are employed rather than fluorometric and spectrophotometric techniques. These tests are diagnostic when plasma catecholamines or norepinephrine levels are > 2000 pg/ml, plasma epinephrine levels > 400 pg/ml, or urinary metanephrine levels > 3 mg/24 h. Recent reports suggest that plasma methoxycatecholamines (plasma metanephrines and normetanephrines) are elevated in 96.6% of pheochromocytoma patients with no false negative results. Plasma chromogranin A (a protein released with catecholamines) measurements in conjunction with plasma catecholamines can aid in the diagnosis with a sensitivity of 83% and specificity of 96%.

Diagnostic and screening biochemical tests for pheochromocytoma are indicated in the following situations:

1.

All patients with incidental adrenal tumors, regardless of size, especially before resection or needle biopsy.

2.

Family members of patients who have MEN syndrome or familial syndromes of pheochromocytoma, beginning at age 5–10 years.

3.

Accelerated or malignant hypertension, especially in children and during the first two trimesters of pregnancy.

4.

Hypertensive crisis during induction of anesthesia, intubation, manipulation of any abdominal tumor, labor or angiography.

5.

Hypertension resistant to standard multidrug therapeutic regimen.

6.

Paradoxical hypertensive response to antihypertensive drugs, especially beta-blockers.

7.

Unexplained wide fluctuation in blood pressure, especially when associated with orthostatic hypotension.

8.

Symptoms suggestive of pheochromocytoma, especially when paroxysmal and accompanied by hypertension.

9.

Children and young individuals with new onset of hypertension or seizures.

If the biochemical tests are non-diagnostically elevated, plasma catecholamines or timed urinary catecholamines should be repeated during paroxysmal episodes. It is not cost effective to screen every hypertensive patient for pheochromocytoma because pheochromocytoma is the cause of hypertension in less than 0.1% of all hypertensive patients, 45% of pheochromocytoma patients are normotensive between paroxysms of hypertension, and approximately 5% are normotensive.

Pharmacological tests

Pharmacological tests are indicated in selected hypertensive patients with high clinical suspicion for pheochromocytoma with repeatedly non-diagnostic urinary and plasma catecholamine levels (plasma catecholamines or norepinephrine level < 2000 pg/ml, plasma epinephrine level < 400 pg/ml, or urinary metanephrine levels < 3 mg/24 h), especially when performed during a paroxysmal episode. These pharmacological tests include:

1.

The clonidine suppression test: Clonidine is a centrally acting alpha2 agonist, which inhibits central neurogenic mediated catecholamine release but not catecholamine released autonomously by pheochromocytoma.

2.

Provocative stimulation tests: Glucagon, metoclopramide, histamine, tyramine and naloxone can be used to stimulate catecholamine secretion from pheochromocytomas.

These pharmacological tests require mandatory continuous monitoring of the blood pressure and the patient must fast overnight. An intravenous heparin lock should be placed while the patient is in the supine position. The patient should be in the supine position for at least 30 minutes before withdrawal of a baseline fractionated catecholamine level and throughout the testing period.

In the clonidine suppression test, fractionated catecholamines are withdrawn hourly for three hours after injection of 3 mg of clonidine. This results in decreased blood pressure and catecholamine levels in patients with essential hypertension. In patients with pheochromocytoma clonidine will often decrease the blood pressure, but will have no effect on plasma catecholamine levels. A normal clonidine test is defined as:

1.

Minimum plasma norepinephrine level of 500 pg/ml or less or a greater than 50% decrease in plasma norepinephrine level (most sensitive 97.3%).

2.

Total plasma catecholamine level of 500 pg/ml or less (most specific 96.1%).

The clonidine suppression test can cause severe hypotension or false positive results in patients who are on diuretics, antidepressants or beta blockers or in patients with baroreceptor dysfunction.

Provocative stimulation test is generally conducted using glucagon. After basal fractionated catecholamine levels are withdrawn, 1 mg of glucagon is given IV and serum catecholamines are withdrawn three minutes following the injection. Blood pressure and heart rate is monitored continuously for ten minutes to diagnose any hypertensive crisis, which can be treated with phentolamine. The hypertensive response can also be blocked without affecting catecholamine levels by premedication with oral prazosin or nifedipine 1–1½ h before glucagon is injected. A three-fold rise in plasma catecholamines or level > 2000 pg/ml is diagnostic for pheochromocytoma. The glucagon stimulation test is reported to have 81% sensitivity and 100% specificity.

Localization

Localization should be performed only after diagnosis has been confirmed biochemically. Helical or spiral high resolution CT scan is usually the initial imaging study of choice, as well as the least expensive. It has a sensitivity of 85–95% and specificity of 70–100% in localizing adrenal tumors as small as 1 cm. It is not accurate in the diagnosis of extra-adrenal tumors or tumors less than 1 cm, and does not provide functional or tissue characterization (i.e., it cannot differentiate between pheochromocytoma, adenoma [and its functional status], or metastatic tumor).

MRI has a sensitivity of 95% and a specificity of 100%. It requires no contrast dye injection and no radiation exposure. It is the imaging modality of choice in pregnancy and for extra-adrenal and cardiac pheochromocytoma. High-density T2-weighted images of the MRI can also distinguish pheochromocytoma from other adenomas and some malignant tumors.

MIBG (Meta-Iodo-Benzyl-Guanidine), an isotope similar to norepinephrine in molecular structure, specifically localizes in APUD tumors. It is usually tagged to I131 or I123, and therefore pretreatment with potassium iodide or Lugol's solution is indicated to prevent thyroid uptake and development of hypothyroidism. It is the least sensitive of all imaging modalities, but the most specific for pheochromocytoma. It has a sensitivity of 77% to 88% and a specificity of 88% to 100%. Because of its expense, limited accessibility and the high radiation dose it delivers to the adrenal gland, it is not routinely used. MIBG does not provide anatomical localization, and a CT scan or MRI is still required. MIBG is particularly useful to determine the functional status of adrenal tumors, to follow-up metastatic or recurrent pheochromocytoma, to identify multiple tumors when suspected (in children and familial pheochromocytoma), and to localize biochemically evident extra-adrenal tumors not seen by other imaging modalities. It is not recommend for screening patients with MEN-2. Certain drugs, such as reserpine, guanethidine, tricyclic antidepressants, labetalol and cocaine can interfere with MIBG scan.

Selective venous catheterization with sampling of the blood for catecholamine levels is rarely indicated. It is an expensive invasive study and is associated with substantial risks. Positron-electron tomography (PET) and octreotide scans have been reported to detect a variety of neuroendocrine tumors including pheochromocytoma. These tests are not widely available and are considered investigational.

Finally, fine needle aspiration cytology of adrenal lesions yields a diagnostic accuracy of 80% to 90%; This procedure carries the danger of precipitating a lethal hypertensive crises in patients with pheochromocytomas and is best reserved for patients who have normal biochemical studies, as patients with positive biochemical studies require excision regardles of the cytology findings.

Pre-operative management

Expansion of intravascular volume with salt containing solution; control of hypertension; correction of lactic acidosis, anemia and electrolyte imbalance; and treatment of arrhythmias, are the principles of medical management.

The traditional antihypertensive therapy is an alpha1-adrenergic receptor blockade with oral phenoxybenzamine (Dibenzyline), preferably for 10–14 days as opposed to 4–7 days. Other selective α-adrenergic blockers, Prazosin (Minipress), Terazosin (Hytrin), and Doxazosin (Cardura) are also effective. Common side effects for α-adrenergic blockers include nasal congestion, headache, palpitation, orthostatic hypotension and tachycardia. Alpha-adrenergic blockers facilitate volume expansion, control blood pressure, and decrease the frequency and severity of hypertensive responses during surgery. However, excessive alpha blockade should be avoided to avoid aggravating postoperative hypotension or masking occult tumors at time of resection. A study of 63 patients demonstrated that preoperative α-blockade did not reduce operative mortality, morbidity or length of hospitalization. Adequate α-blockade is defined as supine arterial pressure not greater than 160/90, presence of orthostatic hypotension not greater than 80/45, ECG without St segment or T wave changes for 2 weeks, and no more than one PVC every 5 minutes.

Metyrosine, a competitive tyrosine hydroxylase blocking agent which inhibits conversion of tyrosine to dihydroxyphenylalanine (dopa) and thereby inhibiting the synthesis of catecholamines, can be also used in patients who are difficult to control preoperatively, who cannot tolerate sufficient doses of phenoxybenzamine, or who have metastatic and inoperable pheochromocytoma. Perry and associates from the NCI have proposed from their experience that preoperative preparation with both metyrosine and phenoxybenzamine facilitated better intraoperative blood pressure management, reduced blood loss and the need for intraoperative fluid replacement. Unpleasant side effects include drowsiness, Parkinson-like symptoms, diarrhea and crystalluria.

Beta-adrenergic receptor blockade with proranolol is contraindicated until alpha-adrenergic receptor blockade is complete, to avoid unopposed α-vasoconstriction resulting in severe cardiovascular hypertensive crisis. Therapy with proranolol is usually indicated to control persistent tachycardia and/or arrhythmia after alpha blockade is established as evident by controlled blood pressure.

Calcium channel blockers (nifedipine and nicardipine) inhibit catecholamine release by blocking calcium entry. They are effective in controlling both hypertension and tachycardia, when used as a single agent or with α-blockers. They may also prevent catechol-amine induced coronary vasospasm, and are less likely to cause orthostatic hypotension.

Surgical management

Surgical resection is the definitive therapy for benign and malignant pheochromocytoma. Adrenalectomy morbidity is as high as 40% and is attributed to pulmonary embolism, sepsis, cardiac arrhythmia and myocardial dysfunction. Mortality for adrenalectomy has dropped significantly to 2%.

Surgical approaches

The principles of adrenalectomy for pheochromocytoma are:

1.

Complete tumor resection.

2.

Minimal tumor manipulation in avoidance of tumor seeding and hypertensive crisis.

3.

Control of vascular supply.

4.

Adequate exposure to avoid other organ injury.

5.

In MEN associated adrenal medullary disease, surgical options include bilateral adrenalectomy or cortical-sparing subtotal adrenalectomy for adrenal medullary hyperplesia. Our recommendation in MEN-2 patients is to perform unilateral adrenalectomy of the affected gland prior to onset of symptoms of catecholamine excess with lifelong follow up for contra lateral pheochromocytoma as only 30% oh these patients will patients will develop contralateral disease requiring surgery. This approach will avoid the issue of compliance and cost of glucocorticoid replacement therapy and the risk of Addisonian crises in bilateral adrenalectomy.

Operative approaches for adrenalectomy include:

1.

Open anterior transabdominal approach.

2.

Open thoracoabdominal approach.

3.

Open posterior or lateral retroperitoneal approach.

4.

Lateral transabdominal laparoscopic approach.

5.

Posterior retroperitoneal laparoscopic approach.

The open transabdominal anterior approach via bilateral subcostal incision is the standard approach because it allows complete exposure and inspection of the abdominal cavity for potential multiple tumors. However, with the accuracy of the new preoperative localizing imaging techniques, blind exploration (except for direct visualization and inspection of the contralateral gland) is unlikely to identify any preoperatively unlocalized tumor. The open transabdominal or thoracoabdominal approaches still give the best exposure for resecting very large tumors and in bilateral adrenalectomy or if intraperitoneal disease is considered for resection.

The open posterior approach has the advantage of virtually eliminating the need for blood transfusion, overall shorter hospitalization and decreased morbidity, and is technically easier, especially in patients with history of previous abdominal surgery. However, the posterior approach has the disadvantage of providing limited exposure for resecting tumors > 5 cm, the inability to explore for intraperitoneal or contralateral disease, and the need for bilateral incision in case of bilateral adrenalectomy.

Laparoscopic adrenalectomies in general have been found to decrease hospitalization, transfusion requirement, postoperative analgesia requirement, and convalescence. Laparoscopic adrenalectomy is technically difficult on the right side because of the difficult exposure, proximity of the gland to the IVC and the short right adrenal vein. Although laparoscopic resection for pheochromocytoma is being increasingly reported and is safe for small and benign pheochromocytomas, it should not be considered for malignant pheochromocytomas or tumors greater than 8 cm.

Anesthetic and intraoperative considerations

The main principle of intraoperative management in adrenalectomy for pheochromocytoma is to prevent sudden rise or fall in the blood pressure in order to prevent cardiac dysfunction and arrhythmia caused by the circulating catecholamines.

The most critical times during surgery are:

1.

Endotracheal intubation.

2.

Induction of general anesthesia, when the myocardium is specially sensitized to the effects of catecholamine.

3.

Pneumoperitoneum in laparoscopic adrenalectomy.

4.

Surgical manipulation of the tumor, due to increased release of catecholamines.

5.

Ligation of the tumor blood supply, resulting in rapid decrease in circulating catecholamines and severe hypotension.

The anesthetic team should be experienced and familiar with potential intraoperative complications. Continuous monitoring of the blood pressure is required with an arterial line. A large bore IV and a central line are required for rapid administration of IV fluids and assessment of intravenous volume status.

Anesthetic agents or medications that aggravate hypotension, cause unpredictable responses, or stimulate catecholamine or histamine release are generally avoided. These include atropine, chlorpromazine, curare, droperidol, opiates, succusinylcholine, and the inhalation agents, halothane and cyclopropane. The trachea can be anesthetized with 4% lidocaine prior to intubation. Intravenous pentothal is used for induction of deep anesthesia. Pancronium bromide is the muscle relaxant of choice. Anesthesia is then maintained with nitric oxide, oxygen and enflurane or isoflurane.

Intraoperative hypertensive crisis can be managed with sodium nitroprusside (preferred drug because of its rapid onset and short duration), nitroglycerin or intravenous phentolamine. Tachyarrhythmias are managed by intravenous esmolol (short acting β-blocker) and lidocaine.

Intraoperative hypotension can result from 1) alteration of vascular compliance after excision of the tumor and sudden drop in catecholamine levels, 2) residual effect of vigorous or prolonged preoperative α-blockade, 3) blood loss during surgery, 4) myocardial infarction, and 5) inadequate steroid replacement after bilateral adrenalectomy. Hypotension can be effectively managed with volume replacement and blood transfusion as indicated. Vasopressors are used only if hypotension fails to respond to adequate volume replacement.

Postoperative hypoglycemia can occur due to relative increase in sensitivity to insulin after sudden withdrawal of the catecholamines. Therefore, blood sugar should be monitored hourly for the first 3 or 4 hours after surgery.

Glucocorticoid preparations should be administered preoperatively when bilateral adrenalectomy is contemplated, especially in patients with bilateral tumors or in familial pheochromocytoma.

Surgical outcome and post-operative follow-up

Following surgical removal of pheochromocytoma 80% of patients are expected to become normotensive. Persistent postoperative hypertension may be due to residual tumor, metastatic disease, or intraoperative injury to the renal artery or the kidney. Around 20% of patients will remain hypertensive without biochemical evidence of residual tumor, however, due to associated essential hypertension or due to acquired renovascular changes.

Plasma fractionated catecholamine or urinary metanephrines should be measured two weeks after surgery. If the biochemical tests are still diagnostically high, residual or metastatic tumor should be suspected. Plasma catecholamines or urinary metanephrines should be measured every three months for the first year and then annually even in normotensive patients. The blood pressure should be monitored at monthly intervals for the first year and then twice a year thereafter. Any residual hypertension should be managed as essential hypertension if catecholamine levels are normal. Patients with pheochromocytomas should have life-long follow-up for possible recurrence or development of metastatic disease, which can occur as late as 40 years after resection of the tumor.

The five-year survival of patients with benign pheochromocytoma is 96%, compared with 44% in patients with malignant tumors as shown in the Mayo Clinic experience.

Malignant pheochromocytomas

Approximately 10% of adrenal pheochromocytomas are malignant, whereas 30% of extra-adrenal tumors are likely to be malignant. Malignant pheochromocytomas are less common in children than in adults and are predominantly extra-adrenal. Pheochromocytomas associated with familial syndromes are often diagnosed early and are less likely to be malignant than sporadic forms.

As in many endocrine tumors, there are no uniform definitive or accurate histological criteria to distinguish benign from malignant lesions. Malignancy is dependent on the clinical behavior of the tumor and is accurately diagnosed in the presence of adjacent organ invasion, recurrence or distant metastasis.

The most frequent sites of metastasis are bones, liver, regional L.N, lungs and peritoneum. Malignant tumors tend to be larger (with an average size of 8.8 cm versus 4.2 cm for benign lesions), with frequent presence of capsular and vascular invasion. They are often characterized by DNA aneuploidy or tetraploidy with increased mitotic figures, tumor necrosis, angiogenesis, c-myc oncogene expression and elevated serum levels of neuropeptide Y and neuron specific enolase. Most malignant pheochromocytomas demonstrate increased uptake of meta-iodo-benzyl-guanidine (MIBG).

Malignant pheochromocytomas should be resected if possible. Recurrence rate in large series ranges from 10% to 46%. Most recurrences will develop within 5 years, but can occur as late as 40 years. Imaging with 131I-MIBG can detect recurrence or metastatic disease. For any residual or recurrent tumor and in cases of inoperable tumors, patients can be treated with α-adrenergic blockade or metyrosine to control hypertension. Patients can also be treated with a high dose of MIPG or combination chemotherapy similar to the regimen used for neuroblastoma, which includes cyclophosphamide, vincristine and darcarpazine. This chemothe rapy regimen results in a 57% overall response with 79% hormonal response and 21% tumor response. No complete response was reported. Bone metastasis can be resected if possible, or external beam radiation can be used for palliation. Arterial embolization of metastatic liver lesions has been reported with transient response. Radioiodine labeled octeoratide has also been employed showing transient symptomatic relief.

The 5-year survival for malignant pheochromocytoma is 44%. Extra-adrenal pheochromocytomas have a worse prognosis than adrenal tumors. Patients with pulmonary metastasis also tend to have a poorer prognosis.

Pheochromocytoma in pregnancy

Undiagnosed pheochromocytoma during pregnancy is associated with a high maternal and fetal mortality rate of 58% and 56% respectively. Even when diagnosis is made during delivery, maternal mortality remains high (around 40%). If diagnosis is made during pregnancy, the mortality rate drops significantly to 11%.

A diagnosis of pheochromocytoma should be considered if severe hypertension is diagnosed in the first two trimesters of pregnancy, if hypertension is uncontrolled during the third trimester or associated with postural hypotension, or if there is sudden unexplained shock in the antepartum period. Diagnosis is confirmed by biochemical testing, and MRI is the localizing imaging technique of choice to avoid the risk of radiation. Provocative tests are contraindicated but the clonidine suppression test can be used in selected cases.

If diagnosis is made in early pregnancy, termination and tumor resection are recommended after adequate control of hypertension. In late pregnancy medical management is indicated to bridge pregnancy to term with elective cesarean section and immediate tumor resection during the same anesthetic. Spontaneous labor and vaginal delivery should be avoided because of increased risk of hypertensive crisis and fetal complications.

Conclusion

Pheochromocytomas carry significant morbidity and mortality if untreated. Biochemical diagnosis and precise tumor localization are mandatory. As in many endocrine tumors, there are no uniform definitive or accurate histological criteria to distinguish malignancy, which is dependent on the clinical behavior of the tumor. Complete surgical excision is the definitive treatment for benign and malignant pheochromocytoma with low morbidity and mortality. Laparoscopic adrenalectomy is not recommended for malignant pheochromocytoma and tumors larger than 8 cm. Life-long follow up is required to detect early biochemical signs of tumor recurrence or metastasis, which often precede the clinical evidence of catecholamine excess.

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